\r\n\tThe purpose of this book is to provide the readers with an understanding of the characteristics of the crisis itself, recognize the wide range and multi-layer of the crisis from a real situation, give ideas on how to minimize the damage, and find ways to increase resilience in the future. To adapt to the rapidly and diversely changing world, the necessary experience and appropriate management for all kinds of crisis issues will be discussed as well. At the same time, it is intended to suggest elements such as verified scientific and empirical knowledge and applicable technologies; more effective risk management operation; modeling of the risks, manuals, management plans, and strategies.
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Atherosclerosis is a generalized process which begins early in childhood (first decade of life) and develops silently and more or less rapidly during adolescence and young adulthood (Stary et al., 1994). Recent investigation using whole body multislice computed tomography in 52 ancient Egyptians mummies (mean age 45.1 ± 9.2 years) from the Middle Kingdom to the Greco-Roman period, a time span of more than 2,000 years, Allam et al. (Allam et al., 2011) showed that atherosclerosis (as in contemporary humans) was more evident and extensive with advancig age, and as common and devastating disease as at present time.
Atherosclerotic cardiovascular (CV) disease, which includes coronary artery disease, stroke and peripheral arterial disease, is the most common cause of premature death in the industrialized world thereby constituting an immense public health problem. This disease was formerly considered an inevitable consequence of aging. The Framingham Heart Study, the most important and influential investigation in CV diseases which laid the foundation for preventive medicine and for CV disorders in particular (Greenberg, 2010), enrolled its first patient in 1948. In the following 40 years a large body of scientific evidence from the Framingham cohort and other major epidemiological studies definitely established that multiple CV risks were responsible of the growing CV disease burden, mainly in high-income countries (Mendis 2010). The scientific Framingham Community gave foundation to the risk factor concept providing insights into their prevalence, incidence and prognostic value. Due to variation in prevalence of individual risk factors in different geographic regions specific approaches to CV disease prevention have been implemented in various countries. Accordingly, a WHO survey on CV risk factors in 2002 showed that more than three quarters of the global CV disease burden was attributable to the following 3: tobacco, blood pressure and cholesterol. And the INTERHART case-control study (Yusuf et al., 2004), involving 27,000 subjects from 52 countries representing all inhabited continents, provided evidence that approximately 80% of the population attributable risk of acute myocardial infarction was predicted by smoking, lipids, hypertension, diabetes and obesity.
As demonstrated in the Karelia Community(Puska, 2010), despite recent attempts to include new CV events predictors, it appears that targeting the already known major risk factors, identified 50 years ago in the Framingham community, remains a priority for the present time and the future. In addition to tobacco the most important modifiable risk factors are hypertension and hypercholesterolemia: due to distinct pathways of atherosclerosis in intracranial versus extracranial disease in patients with hypertension this risk factor has been thought to have major responsibility in the pathogenesis of cerebrovascular diseses whereas the second in coronary artery disese (Napoli et al., 2006). Increasing evidence suggests that atherosclerosis is a diffuse disease with first clinical manifestation in one territory often followed by symptoms coming from other vascular districts. Accordingly, a very high burden of preclinical (silent) coronary artery disease has been recently documented in patients with cerebral infarction(Amarenco, et al., 2010) In recent years, despite the wishful statement by the nobel prize winners Brown and Gldstein “heart attacks: gone with the century? (Brown & Godstein, 1996) CV diseases still remain the undisputed number one killer in most countries and will remain in the next future with an increasing contribution from eastern countries. The well known different gender susceptibility to advanced atherosclerotic lesions observed some 20 years before the occurence of clinical events, supports the pediatrician’s view that early preventive measures in young male people can significantly postpone the onset of clinical manifestations (Mc–Gill & McMahan, 2006). Some optimism comes from the percentage decrease (44% to 76%) in death due to coronary artery disease (CAD) during 1980 through 2000 attributed to risk-factor changes in 10 studies in different populations across the globe (Ford et al., 2007). According to Jeremia Stamler (Stamler et al., 2006) an important goal is to increase the population at low risk until it will be the overwhelming majority. He also mentioned the importance of improving life style from the time of preconception to birth and through school age to young adult: a statement in line with studies pioneered by DJP Barker (Barker 1992) on the association between measures of fetal growth and increased risk of CV diseses later in life. Somehow in line with these observations, it has been reported that maternal hypercholesterolemia is associated with enhanced lipid deposition in human fetal arteries (Napoli et al., 2006).
As far as the lipid story is concerned, after early pathological investigations demonstrating that younger hypercholesterolemic people manifest atheroscerotic plaques in their first or second decade of life, it became clear that serum cholesterol was responsible of the intimal atherosclerotic plaque formation laiding the foundation of the science of atherosclerosis as a major research target for the present time and years to come. It has been consistently shown in studies that on average each 1% raise in cholesterolemia is associated with an approximate 3% increase in risk for CV events, and that on the contrary, the HDL cholesterol level is inversely associated with CV diseases in both sexes at all ages ((Barker 1992). At present a great number of experimental, genetic, and epidemiologic papers support the notion that LDL cholesterol is the most important risk factor for atherosclerosis and responsible for clinical events both in men and women (Freeman et al., 2006; Napoli et al.,2006). Moreover, as a relevant finding from the ARIC study it has been shown that a lifelong history of reduced LDL cholesterol levels (by a nonsense mutations in PCSK9) over a 15-year period was associated with 47% reduction of coronary artery disease risk even in presence of multiple risk factors (Cohen et al., 2006), a larger result compared to that predicted from other LDL-lowering trials. These findings strongly support the view that benefits from cholesterol lowering treatments with statins are expected in relation with the effective duration of treatment along years. According to William Robert (Roberts, 2002) substantial evidence exists that keeping serum total cholesterol <150 mg/dl, LDL-cholesterol <100 mg/dl, and HDL cholesterol at least >20 mg/dl, the chances of forming atherosclerotic plaques are slim. Statins have been available since late-eighties and yet, more than 20 years later, most patients who have had atherosclerotic events or who are at high risk for atherosclerotic events unfortunately are not on statin therapy despite its proven benefit in decreasing first and repeated atherosclerotic events.
Atherosclerotic plaques develop over many years. Initiating event is focal subendothelial retention of apoB lipoproteins on extracellular matrix molecules particularly proteoglycans (Tabas et al., 2007). These retained molecules become aggregated and oxidized and induce a series of biological modifications producing a maladaptive inflammatory response by which monocytes enter the subendothelium and become cholesterol enriched foam cells after incorporating the modified lipoproteins. The fibrous cap of such a plaque may become thin and rupture as a result of the depletion of matrix components through the activation of proteolytic enzymes such as matrix-degrading proteinases. It has been shown that lipoprotein retention is amplified and retention continues to accelerate once lesions become established. This implies that lesions are more dangerous when formed early in life and suggests the great gain young subjects can have if don’t leave untreated their high blood cholesterol level and other risk factors. Endothelial dysfunction is the first step in atherosclerosis and the combined association of a decreased NO production with an increase of NO inactivation appears to be a marker of this condition. Major responsibility in the formation and progression of atherosclerotic is attributed to reduced adiponectin plasma levels. Adiponectin is thought to be also involved in the regulating of necrotic core development (see 3.4 section of this chapter).
Of note, arterial wall reverse (outward) remodelling is usually associated with vulnerable plaques with higher risk of rupture. Their vulnerability is defined as a relatively large necrotic lipid core, intraplaque haemorrhage, abundant vasa vasorum and/or calcification. They are also covered by a thin, inflamed, fibrous cap that may fissure (Naghavi et al., 2003; Virmani et al., 2005). Collagenous fibrous cap represents a form of scar-like response promoted by smooth muscle cells migration into the intima. Of note, plaque progression (Fig.1) is associated with dying macrophages giving rise to areas of necrosis with cholesterol crystals, extracellular debris, proteases and prothrombotic agents (Tabas et al., 2007). These advanced plaques (Fig. 2) are characterized by fibrous cap thinning, plaque erosion and rupture as a result of the depletion of matrix components through the activation of proteolytic enzymes such as matrix-degrading proteinases (MMPs) that are highly concentrated in atherosclerotic plaques by inflammatory cells (macrophages, foam cells), smooth muscle cells and endothelial cells, ultimately being responsible of clinical thrombotic events such as acute myocardial infarction or stroke. A number of research lines have been identified and a therapeutic window of opportunity appears to exist to selectively block proretentive subendothelial matrix-lipoprotein interaction with a potential for regression of advanced plaques
Great advancement of the knowledge in coronary plaque structure has been obtained in recent years by intravascular imaging modalities which can characterize the plaque according to the presence of thin fibrous cap and other findings such as active inflammation, lipid core disruption and severe stenosis, with high sensitivity specificity and predictive accuracy (Valgimigli et al., 2006; Hong et al., 2009). Much interest has been recently focused on the role of calcium which is incorporated into the plaque with an active process resembling bone formation preceded by apoptosis of smooth muscle cells and generation of apoptotic bodies acting as calcification sites with further steps ultimately leading to hydroxyapatite deposition (Mamm et al., 2011).
Plaque formation and progression in the carotid artery.B-mode ultrasound imaging of the left carotid artery in a long-axis during a 10 years period follow-up (1998-2008) in a healthy man from 45 to 55 years of age. Of note, this subject was normotensive and had surprisingly normal blood lipids level (total chol. 165 mg/dl, HDL chol. 71 mg/dl and tryglicerides 64 mg/dl). In 1998, at age 45 y.o., a small plaque was present (maximum short axis diameter: 1.3 mm). In the following ten years a progressive increase in plaque dimension occurred associated with a mild expansive arterial wall remodelling [Glagov phenomenon (
Vulnerable plaque of the carotid artery bifurcation referring to type VI lesion of the AHA plaque nomenclature. The asterisk indicates the area of the lipid necrotic core covered by a very thin fibrous cap (small arrow) with high risk of rupture. The plaque is associated with a marked outward vessel remodelling keeping intact the lumen of the artery.
Moreover, a recent non invasive ultrasound study of femoral arteries in animals opened a door for clinical application of quantification of adventitial vasa vasorum proliferation, a feature of plaque progression (Moguillansky et al., 2011).But evidence exists that despite core in vivo imaging strategies are promising, their invasive nature and limited spatial resolution, as well as ionizing radiation and poor penetration, limit their possible application in human beings. A future however most exists for hybrid technologies and advanced reconstruction and post-processing techniques.
Summarizing, atherosclerosis has top responsibility in total and CV mortality, either industrialized and in the developing countries, it is a cholesterol dependent disease, progressive in nature and characterized by a very long preclinical period. Total cholesterol plasma level > 130 mg/dl is the necessary causing factor. This process starts in the early decade of life and is accelerated by other major risk factors like hypertension, smoking, diabetes, obesity and male gender. It can be easily identified by B-Mode ultrasound of carotid and femoral arteries during the asymptomatic (preclinical) period long before clinical manifestations do occur, opening a window for early diagnosis and lipid-lowering interventions.
An ischemic event is usually associated with an advanced atherosclerotic lesion. Early studies in animals showed that removal of atherogenic factors reduced the prevalence of atherosclerotic lesions. As far as the regression studies of atherosclerosis in human beings is concerned, we must first acknowledge those studies pioneered at the University of California in 1978 by David Blankenhorn and his group (Blankenhorn et al., 1978; Blankenohorn 1978). These authors used advanced computer techniques for image processing derived from space-fly technology with a digital array depicting up to 256 shades of gray. This group first demonstrated the regression by treatment of atherosclerotic lesions with serial femoral artery angiograms (two exams at 13 months interval) performed in 25 hyperlipidemic subjects. During the following 15 years nine arteriographic human studies have been conducted by different groups with a total of 2.101 patients and a mean follow-up of 3,3 (1 to 10) years. These studies have been reviewed by Brown et al. (Brown et al., 1993). Despite several diversities among these studies the analysis showed a benefit from treatment: whether by diet, diet plus life style changes, by hypolipidemic drugs niacin and lovastatin, or plus ileal by-pass associated with resins (cholestipol or cholestiramine). The mean numbers of angiographic outcomes were the following: 53% progression and 8% regression in the control group, versus 26% progression and 26% regression in the treated groups. The authors concluded that this analysis has confirmed the hypothesis that lipid lowering therapy selectively depletes the atherosclerotic plaques lipid content and prevents plaque disruption and the associated clinical events. For what the plaque instability is concerned many factors concur to the phenomenon. The mechanical strength of the cap appears to be one of these and depends on the amount and structure of collagen and other tissue protein determinants of plaque rupture.
Mechanisms by which lipid lowering may stabilize vulnerable plaques in humans have been extensively investigated in recent years. Specific cellular and molecular alterations consequent to lipid lowering have been identified: matrix metalloproteinase (MMP) activity reduction with associated increase of collagen content in plaques appears to have major importance. Smooth muscle cells have a central role in the formation and stabilisation of the fibrous cap because they produce connective tissue matrix proteins. It has been suggested that the combination of lipid lowering and antioxidant agents has a rationale for preserving fibrous cap stabilization(Davies, 1998). On this line it has been shown (Aikawa et al., 1998; Crisby et al., 2001) that pravastatin not only decreases lipid content, oxydized LDL and inflammation, but also MMPs-2 and cell death, whereas it increases collagen content providing the first strong evidence of plaque stabilizing effect by statins in humans.
In 2001 Corti et al. (Corti et al., 2001)using serial black-blood MRI of the aorta and carotid arteries at baseline, 6 and 12 months after lipid-lowering therapy with simvastatin in hypercholesterolemic patients with aortic and/or carotid atherosclerotic plaques, demonstrated that persistent reduction in total and LDL cholesterol levels was associated with a significant inverse remodeling and lumen preservation of both aorta and carotid arteries at 12 months. In the REVERSAL study, published in 2004 by Nissen et al. (Nissen et al., 2005)intravascular ultrasound have been used in 502 patients divided into equal sized groups receiving either pravastatin 40 mg or atorvastatin 80 mg daily dose for 18 months: a complete halting of coronary disease progression was observed in the atorvastatin-treated patients but a continued disease progression occurred in the pravastatin-treated group, thereby suggesting that a very low levels of LDL cholesterol are needed to arrest and stabilize the ongoing atherosclerotic process and that 40 mg pravastatin is inadequate to this end. A step up progression of the results from lipid reducing drugs has been demonstrated by Corti et al. (Corti et al., 2005)in a further study in which a significant regression of atherosclerotic plaques has been obtained by effective and protracted lipid-lowering therapy: moreover and of major importance, the study suggested that the degree of LDL-cholesterol reduction rather than the statin dose was associated with plaque regression. Differently from previous intravascular studies in which statins administration was accompanied only by slowing or halting of the atherosclerotic process, Nissen et al. (Nissen et al., 2006)first demonstrated in 2006 a significant regression of coronary atherosclerosis with serial intravascular ultrasound examinations in the ASTEROID trial: the study was conducted during 24 months period in 349 patients submitted to high-intensity statin therapy with rosuvastatin 40 mg. Of interest, a 10-12 months period appears to be the appropriate time interval for initial appreciation of plaque regression in carotid and femoral arteries during statin treatment also in our experience in the last ten years period (Rusconi C, 2008; Rusconi et al., 2011).Thus, evidence exists allowing us to conclude that with appropriate statin use plaque regression and stabilization do occur. The phenomenon can be assessed non-invasively in patients using ultrasound imaging of carotid and femoral arteries and is further examined and described in details in the last part of this chapter.
As far as the story of secondary CV events prevention is concerned, it is worthy to mention the pioneering Scandinavian Simvastatin Survival Study (4S) trial (The Lancet, 1994) and its promoter Prof. Terjie Pedersen who opened the door to evidence based secondary CAD prevention by statin use. In this study it has been shown for the first time that simvastatin reduced mortality in patients with a high cardiovascular risk. Many large outcome trials of statins have been performed during the following years confirming the results of the 4S trial. Further recent confirmation that statin use continues to be useful comes from a double-blind randomised trial (SEARCH Study, 2007) comparing 80 versus 20 mg simvastatin administration in 12,064 men and women 18–80 years old with a history of myocardial infarction. In this study the higher simvastatin dosage has reduced from 25,7% to 24,5% (with 6% proportional reduction) the major vascular events. Consistent with previous trials, this result has been obtained by an average 0∙35 mmol/L greater reduction in LDL cholesterol. In this study the risk of statin-related myopathy was low with the 20–40 mg simvastatin dosage (about one per 10,000 patients per year) but increased about ten times (to about one per 1000 patients per year) with 80 mg simvastatin daily. Of importance, the excess risk mainly occurred during the first year and has been largely confined to those people carrying
There are now available multiple noninvasive imaging modalities that can identify subclinical atherosclerosis in different vascular beds. They include ultrasonography, coronary CCS assessment by CT, noninvasive CT angiography and MRI. All these methods have advantages and draw backs, but only CCS and ultrasonography have been mostly used. The CCS has provided powerful prognostic information in both sexes of multiple ethnic populations and a systematic review of both symptomatic and asymptomatic populations led investigators to conclude that who have a negative CCS are highly unlikely to have CAD (Sewer et al. 2009). But discordant results have been also reported. In our view, due to the associated radiation exposure and the need of repeated examination in the course of years also to establish the right moment for an interventional procedure, the coronary CCS should be used to this end only after careful evaluation of risk/benefit ratio. The issue will be later thoroughly treated in this chapter.
Patients with established CHD or other clinical manifestation of atherosclerosis, or diabetes, have by definition a substantial risk for future cardiovascular events and premature death. These people should have intensive lipid-lowering therapy because the benefit from these drugs is estimated to largely overweight the risk associated with such a treatment, even if low baseline LDL concentration is present (Cheung & Lam, 2010). On the other side, according to the results of several studies statin treatment appears appropriate in primary prevention setting only in presence of specific risk factors.
The first clinical trial to study the effect of statins in primary prevention setting in patients with a relatively low risk was the WOSCOPS trial (Shepherd et al., 1995) performed in 6.595 hypercholesterolemic patients using 40 mg pravastatin, obtaining a 32% risk reduction in major CV events during a 4.9 years period of follow-up. The following AFCAPS trial(Downs et al., 2001) studied the effects of lovastatin in healthy men and women and was associated with 39% reduction in major coronary events definitely confirming the benefits of statin treatment in healthy individuals. The results of the subsequent PROSPER trial (Shepherd et al., 2002) in 1,585 subjects taking pravastatin raised the question of the potential cancers risk and the problem of side effects with statins. The concern has been subsequently negated by the following studies: ASCOT (Sever et al., 2003) in 5,168 hypertensive patients, HPS (Heart Protection Study Collaborative Group, 2002) in 20,536 patients, CARDS (Colhoun et al. 2004.) in 1.428 diabetic patients, ASPEN(Knoop et al., 2006) in 959 diabetic patients. All the aforementioned studies have demonstrated mostly positive results on the incidence of coronary and cerebrovascular disease without increasing cancer risk.
Recently, in primary prevention setting the MEGA trial (Nakamura et al., 2006) in 3.966 hypercholesterolemic Japanese women during a mean follow-up of 5.3 years, randomly assigned to diet or diet plus 10-20 mg pravastatin, it has been shown that pravastatin reduced coronary events by 23% without any difference in the incidence of cancer or other adverse events between the two groups, suggesting that treatment with a low dose of pravastatin reduces the risk of coronary heart disease in Japan by much the same amount as higher doses have shown in Europe and the USA. In the year 2004 a meta-analysis (Grundy et al., 2004) from the National Cholesterol Education Program Adult Treatment Panel III Guidelines, including 26 randomized trial, 5 of them planned
In primary prevention setting (asymptomatic and apparently healthy subjects) statins are used in presence of risk factors and hypercholesterolemia in particular. Prototypic condition in which aggressive LDL-cholesterol reduction is mandatory is familial hypercholesterolemia. General agreement exists that in these patients should be used the highest tolerated statin dosage. In a study on this subset of patients it has been shown that atorvastatin 80 mg treatment was accompanied by regression of carotid intima media thickness whereas conventional LDL-cholesterol lowering was not (Smilde et al., 2001). Similarly, the great number of apparently healthy subjects with documented atherosclerosis, either by 2D-echo of carotid/femoral arteries or by CT scan of coronary calcium, in addition to life style modifications and other risk factors control, statin treatment appears appropriate according to the severity of the atherosclerotic process and the number and weight of risk factors.
Of note, for what the dietary alcohol is concerned, it has been shown that comparing alcohol consumers and abstainers for a 3 years period follow-up after femoral or carotid artery surgery, alcohol consumers had less cardiovascular event rate as well as more stable plaque cores and less macrophage infiltration (Gisbertz et al., 2011) confirming that mild-to moderate alcohol consumption may help to reduce atherosclerosis progression.
Clinical, experimental and epidemiological evidence consistently demonstrated the inverse association and causal relationship between low HDL levels and the risk of coronary artery disease (Gordon & Rifkind, 1989). Statin treatment of cardiovascular patients reduces clinicalevents by 25 to 45%. High-density lipoprotein (HDL) has beenproposed as a therapeutic target to further reduce this residualcardiovascular risk. The primary role of HDL and reverse cholesterol transport in the reduction of CHD risk is supported by a considerable amount of experimental data. The mechanism by which HDL can mediate protection from atherosclerosis is complex and multifactorial and evolving concepts of the role of HDL in protection from atherosclerosis have been recently pointed out (Farmer&Liao, 2011).
The HDL particles exert a strong antiatherosclerotic action through several mechanisms. These include a facilitatingcholesterol efflux from cholesterol-loaded foam cells, an antiinflammatory action, a positive effect on nitric oxide synthesis,serving as a plasma transport lipoprotein for biologically importantproteins and as an antithrombotic agent by improving thrombolytic balance. In addition to their beneficial effects on the coagulation system the HDL molecules have a favorable complex interaction with the protein C and protein S system and have a significant natural antioxidant effect which improves endothelial function and inhibits the oxidative step required for LDL uptake by the macrophage. These properties of HDL have been demonstrated to decreased apoptosis and promote endothelial repair. Clinical trials with new HDL-raising drugs are currently underway to provide definitive evidence that increasing HDL willreduce cardiovascular events (Brewer, 2011).
Low HDL levels are present in about 10% of the general population and represent the most frequent form of dyslipidemia in patients with CAD. Reduced HDL concentrations seem to be unable to eliminate efficiently the cholesterol excess at vascular wall level, contributing to the onset of the inflammatory response that typically occurs in the pathogenesis of atherosclerosis from its earliest stages. In keeping with this evidence the results of numerous studies quite convincingly suggest that HDL is capable of exerting anti-inflammatory activity either directly or by modulating the expression of a number of acute phase reactants. Endothelial repair and reduced apoptosis are other mechanism by which HDLs preserve vascular function (Kera et al., 2011).
In a recent careful examination of 20 randomized control trials (completed in the period from 1991 to 2009) in which statins have been used, for the first time clear evidence emerged that despite statin treatment a low HDL-cholesterol plasma level remains an independent predictor of higher cardiac events (Jafri et al., 2010) A post-hoc analysis of one of these studies, the TNT trial (Waters et al., 2004), showed that low levels of HDL-cholesterol was predictive of high rate of major CV events even at very low level of LDL-cholesterol thus suggesting that low levels of HDL and high levels of LDL cholesterol are indipendently important predictors of cardiovascular disease. Similarly, in another meta-analysis of 23 trials of various lipid-modifying drugs the sum of LDL-cholesterol percentage reduction and the HDL-cholesterol increase better predicted the benefit than the individual lipoprotein changes: it has been calculated that each 0.26 mmol/L (10 mg/dL) decrease in HDL-cholesterol level was associated with 7 additional myocardial infarction and 4 additional CV events/1000 person-years(Brown et al., 2004). It has been also underlined that despite the aforementioned undisputable evidence of the benefit associated with higher HDL-lipoprotein plasma levels, certain drugs (fibrates) do not appear to be associated with clear benefit (Joy et al., 2008).
In a recent and important study Kera et al. (Kera et al. 2011), measured the cholesterol efflux capacity from macrophages (a metric of HDL function) in 203 healthy volunteers who underwent carotid artery IMT assessment and in 442 angiographycally confirmed coronary patients, as well as in 351 patients without angiographic confirmed disease: in this study the authors demonstrated the followings: 1) HDL-cholesterol levels and apolipoprotein A-1 (the major protein component of HDL) were significant determinants of cholesterol efflux capacity accounting for less than 40% of the observed variation, 2) the efflux capacity was inversely related to IMT and was a strong inverse predictor of coronary artery disease status. The authors concluded that this capacity “is not explained simply by circulating levels of HDL-cholesterol or apoliprotein A-I and is independently related to both the presence and extent of atherosclerosis”.
Therapeutic options for raising HDL-cholesterol plasma levels still appear inconsistent either in experimental or in preclinical setting and, up to now, in clinical studies the cholesterol efflux capacity has not been enhanced in statins treated patients. Due to inability of statins to further reduce the risk associated with low HDL-cholesterol, a treatment has been suggested(Cziraky et al., 2008) to promote optimal lipid values in several at risk patients-populations based on the association of a statin with extended-release niacin, the most effective agent for raising HDL-cholesterol levels. This approach appears most justified in type 2 diabetes which is characterized by two to three times higher prevalence of hypertrigliceridemia usually associated with decreased HDL-cholesterol levels and increased small dense LDL-cholesterol particles, forming the powerful risk factor of the lipid triad (Temelkova- Kurktschiev & Hanefeld, 2004). As far as the antioxidant potential of HDL particles is concerned it has been shown that distribution of HDL subpopulations according to their particle mean size has important implication for their antioxidant potential and that HDL3 particles are more resistant to oxidation (Shuhei, 2010).
Inflammation and inflammatory pathways appear to have a fundamental role in the pathogenesis of atherosclerosis and coronary artery disease in particular(Hansson, 2005). Accelerated atherosclerosis has been described in patients with chronic inflammatory diseases such as rheumatoid arthritis, psoriasis and systemic lupus erythematosus. High sensitivity C-reactive protein (hsCRP), an acute phase reactant produced by the liver is the most studied, although nonspecific, marker of inflammation. In 1997 Ridker et al. (Ridker et al., 1997)gave first demonstration of hsCRP ability to predict future myocardial infarction and stroke in apparently healthy asymptomatic subjects, and several papers have been published in recent years on the subject supporting Ridker’s conclusions that hsCRP is a strong predictor of future major cardiovascular events. Moreover, evidence +has been published that the magnitude of this effect is similar to that of cholesterol and blood pressure and that also people with elevated hsCRP levels but without hyperlipidemia might benefit from statin treatment(Ridker et al., 2008).
However, in a recent report of the Heart Protection Study (HPS Collaborative Group, 2002) with 20.536 high risk patients randomly assigned to simvastatin 40 mg versus placebo for 5 years, it has been observed a 29% reduction of major vascular events without any significant difference between the four subgroup (defined by the combination of low or high baseline LDL-cholesterol and CRP) with clear evidence of benefits mainly in those with both low LDL-cholesterol and low CRP. These findings suggested that LDL-cholesterol reduction is the necessary condition to reduce the risk of cardiovascular events, independently of CRP changes. According to the authors, this conclusion appears to be mainly supported by the finding that LDL-cholesterol reduction by simvastatin reduced the event risk to a similar extent irrespective of baseline CRP levels. At present, it appears uncertain whether hsCRP should be considered only a clinically useful disease marker or whether it also may play a causal role in the atherothrombotic process. Of interest, in a recent study in the TNT study population (Arsenault et al., 2011) investigating the effects of atorvastatin 80 mg versus 10 mg in patients with stable coronary artery disease, it has been shown that in contrast to the blood lipid levels almost none among several non-lipid biomarkers predicted recurrent CV events after 1 year of treatment. According to the authors’ suggestion the cardiovascular benefits were primarily due to the effects of statins on lipids biomarkers rather than on non-lipid ones. According to 2009 Canadian Lipid Guidelines (Jenest et al., 2009) hsCRP should not performed on everyone but only in selected subjects and in patients with metabolic syndrome for better risk stratification.
More recent data from Molenkampf et al. (Molenkampf et al., 2011) suggest that in primary prevention setting hsCRP may help selecting in the general population those people with highest risk of coronary events but with low coronary calcium score (CCS). In particular they demonstrated that CCS was superior to hsCRP in the discrimination and reclassification of coronary risk and that further improvement in coronary risk assessment was obtained when CCS was added to Framingham risk variables and hsCRP, whereas adding hsCRP to Framingham risk variables and CCS did not increase risk prediction. In any case, and in complete agreement with the authors, in asymptomatic subjects and for all individuals, the first-line recommendation remains a healthy lifestyle including quit smoking, regular physical activity, healthy diet, blood pressure and weight control. The efforts that are necessary to implement effective lifestyle modification in larger cohorts must be weighed against the costs of extended risk assessment and, for what CCS is concerned, the risk attributable to radiation exposure (see later). Being hsCRP a nonspecific marker of inflammation, it has been suggested that among the other inflammatory markers interleukine-6 may provide valuable additional prognostic information. In conclusion, at present time it appears that hsCRP should not be considered neither a major player in the atherosclerotic process nor a major predictor for future events, but may be thought to better stratify the risk and to support clinical decision in the individual patient.
Finally, as far as the lipoprotein-(a) [Lp(a)] is concerned, the results from the recently published Young Finnish Study [a prospective population-based cohort study of 939 men and 1,141 women followed-up from the mean age of 17 and 38 years with repeated Lp(a) and both carotid IMT and flow-mediated dilation tests] do not provide any support for an early atherogenic effect of increased Lp (a) plasma levels (Kivimaki et al., 2010).
Adiponectin is the most abundant adipokine released by adipocytes in response to extracellular stimuli and metabolic changes (Berseghian, 2011).It is predominately, but not exclusively, produced by adipose tissue and recent studies suggest that it is also synthesized and secreted by human cardiomyocytes (Pineiro et al., 2005).It is reduced in obesity and type 2 diabetes and low plasma concentration has been associated with an increased risk of CAD and acute coronary syndrome in several though not all studies. Low plasma levels of adiponectin are also associated with increased NO inactivation combined with decreased NO production, both of which contribute to endothelial dysfunction, the first step in atherosclerosis. Adiponectin is thought to be also involved in the regulation of necrotic core development. In patients with stable CAD and in acute coronary syndrome, a decrease in plasma adiponectin values has been found to be associated with an increase in necrotic core in both culprit and non-culprit lesions assessed by intravascular ultrasounds, suggesting that in this clinical setting lower adiponectin levels reflect plaque vulnerability (Otake et al., 2008).Accordingly, the association of decreased plasma adiponectin level and increased necrotic core ratio has not been demonstrated in patients with stable CAD (Sawada et al., 2010).Although produced by adipocytes, adiponectin exhibits plasma levels inversely proportional to body mass index and visceral adiposity (Bajaj & Ben-Yehuda, 2006). Adiponectin is thought to decrease atherosclerosis progression through inhibition of both neointimal thickening and SMC proliferation and migration into the intima. As recently suggested by Barseghian et al.( Barseghian et al., 2011) direct adiponectin administration in humans is premature and warrants further investigation but indirect methods such as lifestyle modifications and pharmacological interventions may be used to increase adiponectin plasma levels at present time (Hermann et al., 2006).On this line, a meta-analysis of 19 studies confirmed an increase of endogenous adiponectin levels with thiazolidinediones use. Accordingly, pioglitazone exhibited the potential of coronary plaque stabilization in patients with type 2 diabetes by increasing adiponectin levels and reducing the necrotic-core component (Ogasawara et al., 2009; Riera-Guardia & Rothenbacher, 2008).
The stroke represents the second leading cause of death and is a major contributor to health-care cost. As recently reviewed by Endres et al (Endres et al., 2011) variations have been found between the main risk factors for haemorrhagic vs ischemic stroke and overwhelming evidence suggests that hypertension is a major cause of brain damage and that brain benefits more from high blood pressure treatment. Moreover, it has been indicated (Pischon et al., 2007) that the main modifiable risk factors such as diabetes, smoking, hypertension, and hypercholesterolemia, explain only 55% of variance for stroke events compared to 88% variance for myocardial infarction. In that review (Endres et al., 2011) it has been underlined that actually no randomized clinical trial exists providing a blood pressure target for effective prevention of first strokes. In several studies a close relationship between cholesterol plasma levels and stroke has not been found and hypercholesterolemia is thought to have major responsibility in atherothrombotic stroke only Endres et al., 2011). Although it is still unsettled whether statin use is useful in primary prevention of atherothrombotic stroke in subjects with mild hypercholesterolemia, evidence exists on the other side (Naghavi et al,. 2003)that even mild carotid atherosclerosis in apparently healthy subjects, and independently of lipid plasma values, identifies those subjects with more or less generalized subclinical disease which should be appropriately treated with statins.
Several cancer subtypes (gastrointestinal, hematological, female-specific, urologic and lung cancer) have been observed to be associated with low LDL-cholesterol levels and the mechanisms by which preclinical cancer might induce low LDL-cholesterol plasma levels are largely unknown. The issue of a potential increased risk of cancer in patients treated with hypolipidemic drugs has been already faced in previous pages (see section 3.1) where substantial evidence has been provided on the safety of statin use. The problem of an increased risk of cancer by hypolipidemic drugs has been raised since the late seventhies by the Clofibrate trial, a WHO Cooperative Trial on primary prevention of ischemic heart disease using clofibrate (Oliver et al., 1978). In this study a 47% excess mortality occurred in the treated group during the study period but it has not continued in the follow-up period with only 5% excess mortality after treatment has ended. Recent meta-analyses (Benn et al., 2011) from more than 90,000 patients have lessened the concern, raised in the previous three decades, on risk of cancer using LDL-cholesterol lowering drugs (Rose et al. 1974). However, the pendulum of the potential damage from cholesterol lowering thearpy has been again a little bit forced forward by the results from two studies in Denmark – the Copenhagen City Heart Study (CCHS) and the Copenhagen General Population Study (CGPS) on 59,566 and 6,816 subjects respectively– which have shown that, indipendently of statin use, participants with low plasma cholesterol level (<87 mg/dL) were associated with a 47% increased risk of cancer, a finding not observed in those patients with innate low plasma LDL-cholesterol level identified by genetic study of single-nucleotide polymorphisms in PCSK9, ABACG8 and APOE (Benn et al., 2011). This study has left unsettled the issue of the potential cause-effect relationship between LDL-cholesterol lowering by statin use and cancer. However, a recent metaanalysis of data on cancer from 166,000 paricipants in 25 randomized trials, it has been concluded that, at least in the five years treatment period no evidence emerged of any effect of statin therapy on cancer incidence or mortality at any particular site (Emerson et al., 2010). Has the story come to an end?
Atherosclerosis has been generally viewed as a chronic and inevitably progressive disease characterized by continuous accumulation of atheromatous plaque within the arterial wall. In the last 25 years an important step-up progression occurred with the introduction of a variety of anti-atherosclerotic therapies, the most important of which are the so called statins, which rank among the most extensively studied therapies in contemporary medicine, opening the door to an effective anti-atherosclerotic treatment in addition to standard non pharmacologic measures. Almost simultaneously, invasive and non-invasive imaging techniques of atherosclerosis have been attempted in the course of years and an extraordinary development in non-invasive assessment has been realized during the last two decades. X-ray angiography is still considered the gold standard imaging technique for vessel patency studies but it does not usually allow obtaining information on plaque structure as well as differentiating stable from unstable plaques and the risk of rupture. This technique typically suffers from these limitations and even to day many cardiologists unfortunately still behave as if the absence of angiographic abnormalities indicates the normality of coronary artery anatomy and absence of atherosclerosis(Davis et al., 2004) In a decreasing degree of complexity the new imaging modalities are represented by the following: 1) magnetic resonance imaging (MRI), 2) CT angiography, 3) CCS,4) B-mode ultrasonography of carotid and femoral arteries as well as abdominal aorta. All these methods are used in clinical setting and the type of investigation closely dependent on the clinical problem the individual patient has and on which techniques are locally available. As it has already been discussed in previous pages high-quality studies have demonstrated that a correlation exits between the severity of atherosclerosis in one arterial territory and involvement of other arteries and that these tests can predict the risk of future CAD events(Fowkes et al., 2008). Accordingly, noninvasive atherosclerosis imaging has evolved into a central method in clinical cardiology and both CCS and B-mode ultrasonography have recently become the most used techniques as first line approach for atherosclerosis detection in primary prevention setting (Greenland et al., 2003).Expert recommendations have endorsed the use of these imaging modalities in primary prevention (Stein et al., 2008) allowing a step-up progression towards an individualised CAD prevention through more effective use of drugs. According to 2009 Canadian Lipid Guidelines (Genest et al., 2009) the screening for high risk subjects should include the following as Class I Recommendation Grade, Level of Evidence C:
Moreover, the following test for atherosclerosis are suggested as Class IIa Recommendation Grade, Level of Evidence C :
These guidelines (Genest et al., 2009) indicate that the presence of atherosclerosis in one of these tests places the individual in the high risk category. In the following pages in addition to a brief review on the usefulness of noninvasive techniques the attention will be focused on noninvasive plaque imaging by ultrasound (which is available in every clinical setting) enabling first line study of plaque burden and structure with assessment of potential regression during statin treatment.
Due to inability of surface ultrasound to imaging coronary artery circulation, attention has focused on other techniques such as CT and MRI (Kim et al., 2001). As far as MRI is concerned, appropriate sequences are needed for plaque imaging and the contrast-enhanced MRI used for clinical purposes is inadequate to this end (Fig. 3).
Contrast-Enhanced MRI (left panel) and B-mode ultrasonography (right panel) of the left crotid artery in a patient with carotid atherosclerosis. In this case the MRI exam has been perfomed for the clinical purpose of a better assessment of vessel stenosis. Plaque imaging would have required a different exam with T1-T2 weighted sequences.
Due to its non-invasiveness carotid MRI has been recently proposed as tool for monitoring individual response to cardiovascular therapy (Yuan, 2008). High-resolution MRI has been recently used for the noninvasive evaluation of carotid plaques showing that is possible to analyze the structure and molecules inside the plaque and to distinguish symptomatic from asymptomatic plaques and patients with low versus high risk through identification of iron deposition (Raman et al., 2008). Moreover, discrimination between lipid core, fibrous cap, intraplaque haemorrhage and calcification as well as distinguishing macrophage-rich from macrophage–poor lesions is possible (Kooi et al., 2003).From these studies emerged the finding that patients with a lipid-rich necrotic core with or without intraplaque haemorrhage represent the desired phenotype for monitoring treatment effects. It has been recently also suggested (Underhill et al., 2011) that throughout advanced tissue specific sequences, acquisition resolution and scan time, in association with techniques allowing monitoring of inflammation and mechanical forces, this technique will enable early assessment of response to therapy. As far as CT is concerned, significant advances in the last ten years helped this technology to evolve as a real non-invasive alternative to conventional catheter based coronary angiography with the additional great advantage of the possibility of establishing the atherosclerotic burden and plaque characteristics with a radiation exposure less than 1mSv (when a heart rate is kept <60 bpm)which is less than the radiation dose of current CCS imaging. But new evidence that even low-dose ionizing radiation from cardiac imagingand therapeutic procedures is associated with an increased risk of cancer (Eisenberg et al., 2011), suggests that a new word of caution is worthy on the issue and that if the benefits to patients of a single cardiac imaging test probably outweigh any small excess risk of cancer, repeated examinations can induce more harm than good.
During the last 25 years, after the seminal papers by Pignoli and his coworkers (Pignoli, 1984; Poli et al., 1984)in mid eighties, on the feasibility of direct measurement of arterial wall thickness with B-mode imaging in vitro of specimens of human aortic and common carotid arteries, the use of this noninvasive approach through the measurement of the carotid intima-media thickness (CIMT) has become the standard reference method in assessing the presence and the amount of clinical atherosclerosis. Since early studies (Salonen & Salonen, 1991) it has been demonstrated that the presence of different degrees of carotid atherosclerosis (normal, thickening, plaque, stenosis) was associated with a progressive increase of coronary events incidence during a 4-years follow-up period. But at present, after dozens of published studies, the evidence to quantitatively support the use of a CIMT measurement to help in risk stratification on top of a risk function is limited (Platinga et al., 2009). As it will be reported later on, plaque detection by B-Mode ultrasound has become the method of choice for early detection and follow-up treatment in patients deemed to be at higher risk because of preclincal atherosclerosis by carotid and/or femoral plaques, a more reliable manifestation of atherosclerosis as well as stronger prognosticator for future events. Carotid artery plaque are defined as the presence of focal thickening 50% greater than that of the surrounding vessel wall, with a minimal thickness of 1.2 mm (Hurst et al., 2010)Cardiac CT began with electron-beam CT in the early 1980s and continues with multidetector CT. In early studies with electron-beam CT high risk subjects have been identified by a score greater than 80-160 (O’Rourke et al., 2000). The advent of modern CT and high resolution MRI, ranked these techniques at the first approach in the assessment of preclinical atherosclerosis by the American Heart Association guidelines (Greenland et al., 2007). Quantification of coronary artery calcium, the so called coronary calcium score (CCS), as an estimate of atherosclerotic plaque burden has become the current major application of non-contrast CT. Plaque burden is quantified by the Agatston score: according to different tertiles of CCS values (Tertile I = CCS 0-99, Tertile II = CCS 100-309, Tertile III = CCS ≥ 400) the estimated annual risk of CAD death or myocardial infarction rate appears to be 0,4%, 1,3% and 2.4% respectively (Greenland et al., 2007). It has been generally suggested that a zero CCS might exclude the need for coronary angiography among asymptomatic patients. However, it has been also shown in studies that increasing the cut-point for calcification markedly improved the specificity but decreased the sensitivity. For patients with CCS >100 the sensitivity to predict significant coronary artery stenosis on angiography was 87% and the specifity 79% (Haberl et al., 2001). Of note, in a meta-analysis a CCS grater than 400 was associated with an increased risk of CAD (Third Report of NCEP, 2002). But a number of recent studieschallenged this statement. The first study (Lester et al., 2009) in a young to middle-aged population with a low Framingham risk score where CCS was less sensitive than CIMT in the identification of preclinical atherosclerosis. The second from Mohlenkamp et al. (Mohlenkamp et al., 2011) in a group of 1934 healthy participants in whom, despite an improved discrimination was possible by adding CCS to traditional risk factors, the reclassification and the overall event rates appeared to low to justify CCS testing in all subjects. Moreover, and in contrast with the published recommendations on the subject, a third new study from Gottlieb et al. (Gottlieb et al., 2011) showed that even total coronary occlusion frequently occurs in the absence of any detectable calcification, definitely suggesting that a zero CCS value does not exclude obstructive stenosis or even the need for revascularization among patients with high enough clinical suspicion of coronary artery disease to be referred for coronary angiography.The finding of very low or even absent coronary calcium by CT in patients with documented carotid and femoral atherosclerosis has been found in a preliminary study from our group (Fig. 3) suggesting that B-Mode ultrasound imaging of carotid and femoral arteries probably overcomes the CCS approach for preclinical screening of atherosclerosis. As far as the effect on CCS by statin treatment is concerned, initial retrospective studies and observational data suggested that statin treatment resulted in reduction of coronary calcium but a recent exam of five randomized controlled trials proved that statin treatment does not reduce CCS values, with similar progression in either the treated and placebo group (Gill Jr, 2010).
Relationship between carotid and/or femoral atherosclerosis as assessed by B-Mode ultrasound (2D-ECHO) and CCS by compute tomography in 23 men, 35 to 65 y.o. The amount of carotid atherosclerosis has been arbitrarily graded into 6 grades from low to severe according to the amount of plaques in both arteries (IMT value has not been taken into account). CCS has been graded according to Agatstone score units. Close relationship exists on the presence and the amount of atherosclerosis between the two methods, with ultrasound findings being more sensitive than CCS in identifying subjects with atherosclerosis. These findings have been confirmed in studies and support the view that ultrasounds should be considered the first line approach in the screening for atherosclerosis in apparently healthy people with CV risk factors.
Of note, other clinical circumstances have been suggested to take advantage from use of CCS measurement, these include: 1) distinguishing ischemic from non-ischemic etiology of dilated cardiomyopathy, 2) identifying patients in emergency department with chest pain and nonspecific ECG, 3) predicting very low subsequent event rates in patients with acute MI and negative CCS test. However, and differently from asymptomatic patients setting, prognostic studies in symptomatic patients are lacking probably because a very large number of patients is needed in this setting to obtain the evidence. In any case, according to 2007 guidelines (Greenland et al., 2007) clinical monitoring of CCS progression is not recommended.
Finally, as far as the role of the race is concerned, despite a generally higher prevalence of cardiovascular risk factors also included a broad trait of endothelial dysfunction in this population group (Friedewald et al., 2008) a lower prevalence and extent of coronary calcification has been demonstrated in blacks. Accordingly, the Prospective Army Coronary Calcium (PACC) Project has found a higher prevalence of CCS in white (19.2%) than in black (10.3 %) military personnel with a mean age of 42 years (Mohlenkamp et al., 2011). Higher CCS scores have been also found in whites compared with blacks in the Cardiovascular Health Study (Raman et al., 2008) and lower prevalence of coronary calcium has been observed in Japanese (13%) than in the American men (47%). Overall, as reported in recent guidelines, despite a higher prevalence of cardiovascular risk factors in blacks, the majority of studies demonstrated a lower prevalence and amount of coronary calcification compared to whites. The recently published MESA study (Multi-Ethnic Study of Atherosclerosis) showed that traditional CV-risk-factor-based prediction models, such as the Framingham score, are improved by the addition of CCS especially in patients at intermediate risk for future coronary artery disease, ultimately suggesting the superiority of CCS and CIMT vs the Framingham risk score for risk prediction. In line with these conclusions are the results from the recent Heinz Nixdorf Recall study of 4,129 subjects (age 45 to 75 years, 53% female) without overt coronary artery disease at baseline in whom traditional risk factors and CCS scores were measured. The CCS resulted in a high reclassification rate in the intermediate-risk cohort, demonstrating the benefit of imaging of subclinical coronary atherosclerosis in carefully selected individuals with intermediate risk (Erbel R, et al. 2008)In any case, in the recently published ESNIER (Early Identification of Subclinical Atherosclerosis by Noninvasive Imaging Research) prospective randomized trial, it has been shown that compared with no scanning, the simple randomization to CAC scanning appears to improve patients’ lifestyle health behaviours (Rozanski et al. 2011).
As far as the CIMT is concerned, a recent reclassification analysis of the ten-year follow-up of the Carotid Atherosclerosis Progression Study (CAPS) has challenged its value as a marker of future CV events rate and did not support its clinical usefulness for risk stratification in primary prevention setting (Lorentz et al, 2010). But evidence has been provided that when associated with risk factor assessment the CIMT may still be a valid tool in risk prediction in dyslipidemic patients (Baldassarre et al, 2007). The bottom line was that we have clear evidence that these two noninvasive methods of risk assessment are superior to Framingham risk score alone, and we think that the time has come to incorporate into new guidelines the cheaper, and completely safe, B-Mode ultrasound technique in primary prevention setting mainly focused on plaque detection.The new high-resolution imaging technologies have enhanced our understanding of the atherosclerotic disease process and recently a new modified American Heart Association classification scheme system based on morphological plaque features and the propensity of plaque for thrombosis has been suggested for use (Donnelly et al., 2010). Based on lipid deposition, fibrous cap thickening, lipid pool transition into necrotic core, calcium deposition, plaque disruption, haemorrhage and thrombosis, a number of categories of coronary atherosclerotic lesions have been identified and reported in Table 1 (Stary et al. 1994; Virmani et al. 1999; Virmani et al 2000; Donnelly et al, 2010).Present status of CT technology clearly indicate that its diagnostic accuracy for the detection of the presence of atherosclerosis is superior over the detection of significant stenosis ultimately suggesting a progressive shift of this technique in the future towards the study of the atherosclerotic process per se rather than to simply assess the stenosis severity (Van Velzen et al., 2011).
Although primarily established for coronary lesions, in accordance with the recently emerged clinically relevant idea that carotid and femoral arteries can be considered the “sentinel vessels” of the coronary artery status (Heinecke, 2011., Joy & Hegel, 2008) we think that this classification can be usefully applied to the analysis of these vessels.As atherosclerosis begins early in life and then remains clinically silent for decades, a distinct opportunity for early intervention comes from the identification of subclinical stages of the disease. Accordingly, the concept that atherosclerosis must be viewed as a preventable disease, which should be approached not only in terms of risk-factor control but also in terms of early disease detection, plaque prevention and plaque stabilization, has rapidly gained acceptance (Naghavi et al., 2003). But even plaque regression (the holy grail for therapeutic interventions) appears possible and has become a new target in our clinical practice during the last ten years. Together with a proposal for a strategy for primary CV disease prevention this evidence will be accordingly presented in the following pages.
Coronary atherosclerosis starts early in the life and it is progressive in nature and when angiografically identified as minimal vessel stenosis its burden is already diffuse. By the time a patient has developed minor obstructive disease on angiography, an extensive systemic atheroma is already present. This finding underscores the importance of an aggressive risk factor modification (and statin use) since early stages of atherosclerosis in asymptomatic subjects (Lavoie et al., 2010). In recent years several studies addressed the prognostic implications of detecting asymptomatic atherosclerosis in the general apparently healthy population. Pathological, epidemiological and clinical studies indicate tha atherosclerosis is a systemic disease which develops with a variable extension and severity in all conduit arteries. In particular, an almost constant association exists between carotid, femoral, and coronary artery disease, with first clinical manifestation usually due to a CAD. Ten years ago in the CAFES-CAVE study (Belcaro et al., 2001), subclinical carotid and femoral artery plaques have been found strongly and independently associated with future adverse cardiovascular events rate in low risk subjects by Framingham criteria. Similarly, the presence of peripheral (occlusive or sub-occlusive) artery disease independently predicted myocardial infarction and death in 1,325 individuals with either carotid or femoral plaques by ultrasound (Lamina et al., 2006). And early atherosclerosis (increased IMT) in femoral arteries predicted single-vessel CAD whereas advanced atherosclerotic (plaques) was usually associated with more severe CAD (Sosnowski et al., 2007). Evidence of the systemic nature of the atherosclerotic process comes also fromseveral studies of prevalence of occult CAD in patients with peripheral artery disease or stroke. In a recent study in patients with cerebral infarction without history of CAD (Amarenco et al., 2011) it has been shown that a silent CAD was present in 62% of patients and that 31% and 26% had a 3 vessel disease and vessel stenosis > 50% respectively, and similar findings have been reported in another recent study in which the atherosclerotic process was quite advanced in coronary as well as in peripheral arteries of patients at their first presentation for acute coronary artery disease (Kranjec, 2011). Evidence of high prevalence of subclinical atherosclerosis in the general population comes also from another recent study on a randomly selectedsample of 292 subjects (mean age 59.5 years, 50% women) from the offspring cohort of the Framingham Heart Study free of clinically apparent cardiovascular disease, who exhibited high levels of subclinical atherosclerosis on more than 2 imaging testsincluding MRI of abdominal and thoracic aorta, coronary artery calcification by EBCT, and CIMT by ultrasonography (Kathiresan et al., 2007). Also on this line are the results from the mass screening recently introduced in United Kingdom where an ultrasound scan of the abdomen is offered to all men over 64 years for the screening of abdominal aorta aneurysm by ultrasonography. In a large randomized trial in 67,770 men, age 65 to 74 years, it has been shown that in the group invited for screening the mortality was halved (because of elective surgery): an approach that additionally proved to be highly cost-effective (Kim et al., 2007). As far as the role of carotid IMT as a predictor of future events is concerned, in a recent meta-anlaysis of 41 randomized trials it has been shown (Costanzo et al., 2010) that regression or slowed progression of carotid IMT by cardiovascular drugs is not accompanied by reduction in cardiovascular events, definitely suggesting that this parameter has a very limited role in cardiovascular risk prediction. Similarly, a recent review including 13.145 patients (Masson et al., 2011) has shown that presence of carotid plaques predicted future risk better than IMT value, supporting the view that when detecting plaque we are not just evaluating a surrogate objective but a process that in itself indicates the presence of the atherosclerotic disease.The American Society of Echocardiography consensus document (Stein et al., 2008) and the recently published Canadian guidelines (Genest et al., 2009) which formally classify patients with subclinical atherosclerosis as high risk and recommend preventive measures as intensive as those to be used in patients with clinically established atherosclerotic disease, are both in line with this suggestion. Neither those persons with a past history of intensive professional sport activity appear protected by the atherosclerotic assault of modern life as demonstrated by a recent paper in which former professional football players, despite their elite athletic histories, have a similar prevalence of advanced subclinical atherosclerosis as a clinically referred population of overweight and obese men (Hurst et al., 2010).In response to the wall lipid infiltration and plaque formation the arterial wall changes its structure according to two types of anatomical remodelling, positive and negative. Positive remodelling is characterized by outward expansion and negative remodelling by vessel shrinkage. Paradoxically the apparent beneficial and more frequent phenomenon of outward wall expansion is associated with the feature of unstable lesions (fig. 1) i.e. with histological characteristics of plaque vulnerability such as a large lipid core and high plaque macrophage content (Pasternak et al., 1998). These important morphological features have been studied in coronary vessels by intravascular ultrasound (IVUS) and angioscopy, but optical coherence tomography with its unique ability of identifying lipid content, fibrous cap thickness and its macrophage density, is the method of choice (Yabushita et al., 2002; Raffel et al., 2008). Recently, a first report on virtual histology-IVUS assessment of natural history (1 year follow-up with repeated examinations) of coronary artery lesions morphology has been published (Kubo et al., 2010). In this study it has been demonstrated that most thin capped fibroatheroma had plaque progression (most stabilized or healed but new developed) whereas fibrotic and fibrocalcific plaque did not demonstrate any geometric changes during the follow-up and no spontaneous plaque regression has been observed, as usual. AS highlighted in previous pages an ischemic event is usually associated with an advanced atherosclerotic lesion. And since early regression studies (Blankenhorn et al., 1978; Corti et al., 2001), the evidence clearly emerged that persistent and marked reduction of total and LDL cholesterol plasma levels (with LDL-cholesterol in the range of 50 mg /dl) is the key element for obtaining atherosclerosis regression and significant inverse remodelling with lumen preservation of both aorta and carotid arteries at 12 months, and that the degree of LDL-cholesterol reduction rather than the statin dose was associated with plaque regression. According to this line of conduct we have had evidence in the last 10 years on the possibility to induce plaque regression even up to complete disappearance: moreover we have realized how B-mode ultrasound imaging can help us and motivate patients in many ways in primary prevention setting. As it will be suggested in the next pages, our experience has confirmed the hypothesis that lipid lowering therapy selectively depletes the atherosclerotic plaques lipid content and prevents plaque disruption.
Notwithstanding large-scale clinical trials have proved that both primary and secondary prevention reduce myocardial infarction, stroke and overall mortality, the optimal level of plasma lipids to achieve these goals remains unresolved. Recent trend suggests “the lower the better” for all risk factors, but recent data suggest that lipid lowering appears to have larger impact than blood pressure lowering on plaque progression (Chhatriwalla et al., 2009) and hence also supporting the view that only intensive plasma lipid reduction can induced plaque regression. As already mentioned in previous pages, in vivo evidence of atherosclerosis regression in thoracic aorta by statin use has been first reported ten years ago (Corti et al., 2001) using MRI. More recently using dedicated carotid MRI protocol (Underhill et al., 2009) it has been demonstrated that intraplaque haemorrhage and statin therapy were key determinants of opposite changes in plaque burden: being intraplaque haemorrhage associated with accelerated plaque growth, whereas statin therapy was associated with plaque stabilization by slowing or halting lesion progression. According to these authors the phase of 16% to 49% of plaque induced vessel stenosis is probably a critical stage of the plaque natural history, whereas plaque regression has been associated with statin use.In the following pages we describe the process of atherosclerosis regression as it has been documented in a group of selected statin treated subjects in a primary prevention setting during the last ten years in our echo-lab. To be included in this retrospective analysis the subjects should have had at least two B-mode ultrasound plaque imaging examinations of at least 2 years apart during an uninterrupted statin treatment. Twelve subjects have been found to match such criteria. These subjects have been treated with simvastatin or rosuvastatin at a dosage aimed obtaining a total cholesterol plasma level kept round 140 mg/dl. None of them have had any CV events during the study period. The most representative structural findings associated with plaques regression are presented in the following pages and proposed as reference structural changes to be routinely examined in patients for an office-based practice as an alternative to the more demanding and expensive MRI based analyses. As largely reported in previous page, evidence exists on the possibility to identify subjects with preclinical atherosclerosis who can take advantage from its early detection by improving a safer life style and by statin use in particular. In fact, the possibility to monitor plaque dimension and structure changes along time with a completely noninvasive approach by using ultrasounds allows a safe and personalized treatment approach in the course of years, with an improved patient’ and doctor’ satisfaction. To recognize the great advancement in the field of primary prevention and of usefulness of early atherosclerotic disease detection by the way we are suggesting, a citation is worthy of David Blankenhorn’s intuition and early demonstration of this possibility more than 30 years ago in California and summarized in the following lines from a paper (George Lyman Duff Memorial Lecture) co-authored with Howard Hodis (Blankenhorn DH & Hodis HN, 1994): “Coronary atherosclerosis is ubiquitous, but we know that some individuals develop more severe coronary atherosclerosis at an earlier age than others. A case finding and treatment strategy based on noninvasive imaging would benefit those with premature atherosclerosis who are not recognized with current risk factor screening until they develop symptoms. Screening for peripheral vessel changes indicative of high risk is possible and cost effective with procedures now available“. The following cases we are going to describe closely match this position and add new evidence on the real possibility by the simple and totally noninvasive ultrasound exam to characterize carotid and femoral artery plaque structure and the profound changes induced by statin treatment (Fig 4 to 9).
Upper left panel - B-mode ultrasound of the right carotid artery bifurcation in a asymptomatic 50 y.o. man with hypercholesterolemia (280-300 mg/dl). A soft and lipid-rich atherosclerotic plaque (arrow) about 4 mm in thickness and 7 mm in length is present at the posterior wall of the carotid artery bifurcation associated with outward remodeling of the arterial wall. These charcteristics allow classification of the plaque as an advanced atherosclerotic plaque type IV lesion (see pag 12).
B-Mode ultrasound (with plaque outlining) of the right carotid artery in a 66 y.o. man with hypercholesterolemia (250 mg/dl) followed-up for 4 years during statin therapy (rosuvastatin 10 mg/day).
B-Mode ultrasonography imaging in a short axis (left side) and long axis view (right side) of the right carotid artery in asymptomatic man with hypercholesterolemia (240 mg/dl) followed-up for 6 years during statin therapy.
Upper line: At first examination (age 59 years) a small echolucent plaque was present in the far field of common carotid artery, better appreciated in its extension in the high lightened short axis view. Bottom line: Same imaging showing a complete plaque regression after five years of Simvastatin (20 mg/day) treatment. No further examinations were performed during this period. Arterial reverse remodelling, better appreciated in the short axis view, also occurred in association with plaque regression. Cholesterol plasma levels have been kept around 140 mg/dl during the whole treatment period.
Left panel: B-Mode ultrasonography imaging in a long- and short-axis view (with colour Doppler flow imaging) of femoral arteries in a 69 y.o. healthy man during a 20 months treatment period with rosuvastatin 20 mg/day and cholesterol plasma level kept around 140 mg/dl. Plaque volume reduction and inverse arterial remodelling haves occurred by statin treatment. Far field endothelial surface, total plaque area, and echo-lucent area within the plaques have been manually outlined for better understanding of the plaque structural changes. Plaque volume reduction and arterial reverse remodelling are better appreciated in the short axis view. Right panel: Further plaque reduction in the long axis view occurred after additional 10 months of statin treatment.
Left carotid plaque monitoring during a 2.5 years follow-up period in a 55 y.o. subject during statin treatment (rosuvastatin 20 mg/day) with a reduction of cholesterol level from 200 mg/dl to around 140 mg/dl. with HDL Cholesterol increase from 50 to 75 mg/dl. The plaque border and the echolucent areas within the plaque have been outlined for a better understanding of the structural findings associated with plaque regression. At first imaging (May 2008) the plaque exhibits the characteristics of a rupture-prone (vulnerable/instable) plaque represented by the triad of a very thin fibrous cap combined with large echolucent (lipid/necrotic) core and positive (outward) arterial wall remodelling. An impressive volume reduction (~75%) occurred during the treatment period. In this case, the close temporal images’ sequence allowed superior understanding of structural modifications associated with plaque regression and stabilization. According to these changes the following observations can be done: 1) The amount of baseline echolucent areas within the plaque predicts the regression potential by statin treatment, even to almost complete plaque regression when the echolucent area is predominant, 2) the reabsorbtion of these areas is progressive and is accompanied by plaque volume reduction and structural findings suggesting plaque stabilization (the arrows in the imaging of march 2009 indicate a partial plaque collapse due to early marked reduction of underlying echolucent area), 3) in association with plaque volume reduction a progressive reverse arterial wall remodelling also occurred, 4) the time interval needed for early regression appreciation appears to be 10 to 12 months. As occurred in this case, plaque regression appears to depend on “robust measures” such as marked reduction in plasma concentrations of LDL cholesterol and large increases in the reverse transport of lipids out of the plaque by an increased HDL-cholesterol.
Same case of the
After arteriographic studies on atherosclerosis regression by lipid lowering drugs pioneered by Blankenorn in late seventhies, conclusive demonstration of the plaque lipid depletion hypothesis in human beings during lipid lowering therapy has been possible only in recent years using ultrasound and MRI. During the last few years the sonographic characteristics of carotid plaques have been thoroughly studied by sophisticated methods enabling semiquantitative analysis of their structure (Reiter et al., 2007). However, as in depth discussed in this chapter we think that the simple, non-invasive, relatively cheap and totally innocuous B-Mode ultrasound examination of carotid and/or femoral arteries represents the first choice and still largely unmet opportunity for atherosclerosis screening of asymptomatic subjects deemed at intermediate risk by traditional risk factors (fig 10).
As already discussed, due to the associated radiation risk, the use of CCS as a screening tool in primary prevention setting (usually requiring subsequent examinations) should be considered in specific circumstances only as alternative to arterial ultrasound scanning when this imaging modality is not available. Definite superiority of the B-mode ultrasound approach is greatly supported by the possibility to monitor the natural course of plaque structural changes and, of outmost importance, to assess the drugs’ effect which we have observed to occur during statin use in a very short period of time, ten to twelve months apart.
Global energy consumption has increased gradually in recent years due to population growth, and economic development and industrialization. Also, global warming and environmental pollution worsened everyday too much of automobile vehicles and industrialization. Hence, the development of renewable energy sources became increasingly important. Hydrogen is one the most promising clean and sustainable energy sources because it emits only water as a byproduct and generates no carbon emissions [1]. Hydrogen has a quality of high energy carrier including high energy density that is more than ordinary petroleum and diesel fuel [2]. At the moment, global hydrogen production is estimated to over 500 billion cube meters per year [3]. It can be used in much industrial application including fertilizer, petroleum refining operation, fuel cell, chemical industries [4]. Hydrogen can be generated from variety of renewable and non-renewable sources like water and fossil fuels [5], oil reforming [6], coal gasification [7], biomass [8], water electrolysis [9].
Many approaches for manufacturing hydrogen are currently available however water electrolysis is one of the most capable methods for producing hydrogen as a product and oxygen as a by-product. At the moment, only 4% of hydrogen can be obtained by electrolysis of water [10]. Water electrolysis also provides a number of advantages, such as high cell efficiency and a greater hydrogen generation rate with excellent purity, making it a better method for converting water to electrical energy via low-temperature fuel cells. The water molecule is the reactant in the electrolysis process, and under the influence of electricity, it is split into hydrogen (H2) and oxygen (O2). Based on the electrolyte, operating conditions, and ionic agents (OH−, H+, O2−), water electrolysis is separated into four categories: alkaline water electrolysis (ii), solid oxide electrolysis (SOE), microbial electrolysis cells (MEC), and PEM electrolysis of water [11]. The phenomenon was first described by Troostwijk and Diemann in 1789 [12], and it is a well-established technique for commercial hydrogen production up to the megawatt range in the world.
The hydroxyl ions (OH−) flow through the porous diaphragm to the anode under the effect of the electrical circuit between anode and cathode, where they are discharged to 12 molecules of oxygen (O2) and one molecule of water (H2O). Alkaline electrolysis is performed at lower temperatures, such as 30–80°C, with an aqueous solution (KOH/NaOH) as the electrolyte and a 20–30% concentration. Alkaline water electrolysis uses an asbestos diaphragm and nickel materials as electrodes [13]. In the 1980s, Donitz and Erdle proposed solid oxide electrolysis (SOE). Solid oxide electrolysis has attracted a lot of interest since it converts electrical energy into chemical energy while also producing ultra-pure hydrogen with a higher efficiency. Solid oxide electrolysis runs at high pressures and temperatures of 500–850°C and consumes water in the form of steam. Nickel/zirconia is commonly utilized as an O2 conductor in solid oxide electrolysis [14].
Microbial electrolysis cell (MEC) technology may produce hydrogen from organic matter such as renewable biomass and wastewaters. MEC technology is similar to microbial fuel cells (MFCs), however the operational concept is reversed [15]. In 2005, two independent research institutions, Penn State University and Wageningen University in the Netherlands, established the first Microbial electrolysis cell (MEC) method. Electrical energy is turned into chemical energy in microbial electrolysis cells (MECs). Under the influence of an electric current, MECs created hydrogen from organic molecules. Microbes oxidize the substrate at the anode side of the microbial electrolysis process, producing CO2, protons, and electrons. The electrons move to the cathode side via the external circuit, while the protons travel to the cathode via a proton conducting membrane (electrolyte), where the protons and electrons combine to form hydrogen [15]. However, this MEC technology is still in the early stages of development, and various issues like as high internal resistance, electrode materials, and intricate design must be addressed before the technology can be commercialized [16].
In the early 1950s, Grubb achieved the first PEM water electrolysis, and General Electric Co. was created in 1966 to overcome the drawbacks of alkaline water electrolysis. PEM water electrolysis technique, which is similar to PEM fuel cell technology [17], used solid poly sulfated membranes (Nafion®, fumapem®) as an electrolyte (proton conductor). Lower gas permeability, strong proton conductivity (0.1 0.02 S cm−1), thinness (20–300 m), and high-pressure functionality are all advantages of these proton exchange membranes. In terms of sustainability and environmental impact, PEM water electrolysis is one of the most environmentally benign methods for converting renewable energy to high purity hydrogen. Another prospective PEM water electrolysis device has a small footprint, high current density (over 2 A cm−2), high efficiency, fast responsiveness, and operates at lower temperatures (20–80°C) while producing ultrapure hydrogen as a byproduct [17].
Fuel cell technology is gaining popularity in the automotive industry due to its ease of use, quiet operation, high efficiency, and modular structure. According to Mustafa et al., recent investigations have showed that the usage of fuel cells in vehicles has expanded rapidly, causing a revolution, and will be an alternative to conventional vehicles in the future (2021). Configuration, system components, control/management, technical obstacles, marketing, and future aspects are all categories for fuel cell cars. Based on chemical characteristics and operating temperature, fuel cells are classed as proton exchange membrane FCs, solid oxide FCs, direct methanol FCs, alkaline FCs, molten carbonate FCs, and phosphoric acid FCs. FCs are used in both commercial and research & development applications. Common stack size, theoretical cell voltage, operating temperature, electrical efficiency, benefits, and downsides are used to classify FC features [18]. In this environment, FCs are used in distributed generation, mobile power, backup power, military, space, and vehicle applications. Low temperature and pressure PEMFCs are the most used FCs in vehicle applications because of their high power density, lower working temperature (60–80°C), and reduced corrosion than other FCs [18].
In the construction of fuel cell hybrid electrical vehicles (FCEVs), fuel cell vehicles (FCs) are coupled to electric motors via controlled electronic interfacing components [19]. The basic components of traditional FCEVs are a voltage regulation converter, motor drive, electric motor, and auxiliary energy generation units [20]. For interfacing components and energy management algorithms, FCEVs vehicles have a variety of configuration topologies [21]. The powertrain structures, voltage regulation topologies, motor drive converters, and energy management technologies can all be used to classify FCEVs. In the operation of FCEVs, the FC stack feeds energy to the dc-bus and maintains the required DC bus voltage [22]. The FC is then connected directly to the Unidirectional DC-DC converter (UDC) as a system element to maintain the dc-bus voltage and send the energy generated for vehicle propulsion to the motor drive converter. A DC-AC converter checks the motor speed and torque for safe operation. Finally, the drive controller is in charge of monitoring the electric motors as they convert electrical energy into kinetic energy [23].
FCs have a higher energy density and efficiency than other power sources such as photovoltaics, batteries, ultra capacitors, and super conducting magnetic energy storage. Because of its modular design, FCs are also suitable for electric vehicle applications. Furthermore, FC has a 20–30 year lifespan [24]. As a portable/rechargeable energy storage system, the battery is also a preferred power source for FCEV hybridization. However, it has a short lifespan and is only useful for a short length of time [25]. Ultra capacitors (UC) are a type of storage element that can be used in FCEV applications to increase the dynamic response of the system. Photovoltaic (PV) is a gadget that generates energy, however it is too large to carry. The output of super conductive magnetic energy storage (SMES) generates a lot of power, however it has a low energy density. Short-duration energy storage is also included in SMES, albeit at a high expense [26]. Based on this, several hybridization topologies are recognized in the literature. Full FC, partial FC, and hybrid FC cars are classified as FC + battery hybridization, FC + UC hybridization, FC + battery + UC hybridization, FC + battery + PV, FC + flywheel hybridization, and FC + SMES [18]. FC + battery + PV, FC + battery + PV, FC + flywheel hybridization, and FC + SMES are all examples of FC-powered cars.
The FCEV scheme clearly shows that this topology’s energy generation is exclusively dependent on the FC stack. It simple construction includes a fuel tank, FC stack, DC-DC power converter, inverter, and electric motor [27]. These cars feature a long driving range, a fast charging time, high efficiency, cold start capabilities, silent operation due to the lack of mechanical components, energy supply continuity, and low emissions [27]. Full FCEVs are a suitable fit for low-speed vehicles including forklifts, busses, airline vehicles, trams, and marine vehicles. The combination of FC + battery units is the most common topology in FCEV hybridization [18]. A unidirectional DC-DC converter (UDC) connects FC to the DC bus, while a bidirectional DC-DC converter connects the battery to the DC bus. In the operating procedure of FC + battery hybridization, an initial start-up with the battery is provided to avoid the FC running in the low-efficiency zone. As a result, a huge amount of current is generated to start the electric motor [25]. When the car is turned on for the first time, the FC is activated to keep the electric motor going. After then, the battery is charged according to the charge status criteria. The UC only allows FC to be utilized in emergency situations to meet transient power demands. UC, on the other hand, has a low energy density and is not used to give energy on a long-term basis [28].
In contrast to earlier hybridization topologies, FC + battery + UC hybridization has a primary energy source (FC) and two secondary energy sources (battery and UC) (battery and ultra capacitor). In this design, the FC is connected to the DC bus through a one-way DC-DC converter. The energy storage units, battery and UC, are connected to the DC bus by bidirectional DC-DC converters (BDCs). This architecture combines the advantages of FC + battery and FC + UC systems to provide continuous energy while also boosting FC dynamic response during transient events [29]. In recent years, PV panels have been incorporated with FC-based electric vehicles for hybridization. In FC + battery + PV hybridization, PV panels generate DC voltage that is coupled to the DC bus via a unidirectional converter. The FC is the primary energy source in an FC + battery + PV system, with the PV panel acting as a backup. Both the FC and PV busses are connected to the DC bus by unidirectional converters. PV panels generate varying amounts of power based on the intensity of solar radiation, the temperature, and the sun’s direction. As a result, the PV electricity generated is fed directly into the electric motor or is used to charge the battery [30].
FC+ flywheel hybridization is similar to the preceding approach in that the FC serves as the major energy source and the flywheel, rather than batteries, serves as an energy storage method. Flywheels and generators are connected to store energy mechanically with a high rotating speed and transform that mechanical energy into electricity when EM requires a lot of it. Flywheels have a faster charging capability, higher efficiency, and higher power rating than batteries [30]. Flywheels are also environmentally friendly, as they operate over a wide temperature range, have a big energy storage capacity, and have a long lifespan [66]. There are three types of static FC models accessible in the literature. Chamberlin-Kim and Amphlett, Larminie, and Dicks models [31] are examples. The most common static model published in the literature is the Amphlett model, which is based on Nernst and Tafel equations. This model takes into account physical parameters like as pressure, temperature, and concentration. The other static model is the Larmine and Dicks model. This model calculates the FC voltage–current characteristic using empirical equations. This model yields the FC voltage versus current amplitude curve. Three zones can be found in this curve. The three zones are electrochemical activation, linear part, and gas diffusion kinetics [32]. The third static FC model is the Chamberlin-Kim model. In this approach, the FC voltage is described in terms of current density. In addition, the fuel-oxidant rate, local temperature, and humidity all affect five factors in this model [32].
Dynamic modeling of FC is described in the literature such as the impedance model, Becherif-Hissel model, and Dicks-Larminie model have been reported [33]. Layer capacitance, diffusion impedance, and ions transport, membrane, and contact resistances are all included in the impedance model [34]. The Nernst voltage, ohmic polarization, concentration, and activation are all modeled in the Dicks-Larminie model. A voltage supply, two resistances, and a capacitor make up this model. The Nernst voltage is demonstrated via the voltage source. The resistances represent electron-hydrogen flow and activation-concentration losses. The charge layers are represented by the capacitance. The pneumatic feature is taken into account in the Becherif-Hissel model to obtain the comparable model for electrical components. The conservation of mass, energy, and charge is taken into account in pneumatic properties [35].
Conventional diesel engine running on petroleum and diesel fuel emits more oxides of nitrogen (NOx), oxides of carbon (COx) and particulate matter (PM) around the world. Low-temperature combustion (LTC) technology in engine development has dropped the environmental effects by providing better combustion efficiency, and increased the engine efficiency and fuel economy. Several low-temperature combustion strategies are available such as homogeneous charged compression ignition (HCCI), premixed charged compression ignition (PCCI), and reactive controlled compression ignition (RCCI). Before combustion, the entire air and fuel is premixed in the LTC combustion mode. The combustion is controlled by a predetermined equivalency ratio and cylinder temperature which leads to reduce the soot formation, PM, and NOx emissions. In LTC mode, the combustion temperature could be maintained between 1800 and 2200 K, which means no NOx emissions are produced in the rich mixing region and no soot is formed below 1800 K in the lean mixing by Hoekman and Robbins.
The homogeneous charge compression ignition (HCCI) engine combines the combustion characteristics of both SI and CI engines in an IC engine. The fuel is premixed in the HCCI engine in the same in SI engines, and the fuel is auto-ignited to start the combustion in the same way in CI engines. Before combustion begins, the fuel is vaporized and homogeneously premixed with air. Due to lean-burn combustion, the HCCI has the ability to reduce NOx emissions and increased the brake thermal efficiency. The in-cylinder temperature is reduced via lean-burn combustion, resulting in decreased NOx emissions as observed by Komninos and Rakopoulos [36]. In addition, due to the increased displacement capacity, HCCI combustion improves brake thermal efficiency by 50%, while emitting less smoke than conventional diesel combustion. The HCCI engine’s compression ratio and premixed fuel combustion has improved the brake thermal efficiency of engine and lower the smoke emissions as noticed by Desantes et al. [37]. The multi-zone auto ignition and spontaneous combustion of the entire mixture is promoted by the homogenous mixture and uniform equivalence ratio in the cylinder. Furthermore, flame propagation has little effect on combustion in the HCCI mode [38].
The unanticipated pressure rise and cycle to cycle variation are exacerbated by multi-zone combustion and unexpected ignition location. Also, knocking is caused by high oscillation frequency and unanticipated pressure surge as noticed by Ganesh and Nagarajan [39]. Contino et al. [40] reported that some of the techniques such as early direct injection, early multiple injection, water injection, port fuel injection, external cold EGR, variable valve timing, variable compression ratio, air preheating, and alcohol injection are commonly employed in HCCI to control combustion and emission. The biofuel auto ignition temperature and viscosity are higher than diesel hence a higher compression ratio was used in HCCI engine. The compression ratio for the various loads can be adjusted to enhance the combustion efficiency as noticed by Zhang, et al. [41]. By modifying the spark timing and spark plug placement, the spark aided HCCI engine was able to achieve combustion phasing and emission reduction [42]. The key factors that have been employed to detect the combustion phenomena in the HCCI engine are the pressure increase rate, combustion noise, and ringing intensity. In a real-time combustion application, the ringing intensity is primarily employed to detect the combustion noise for the needed cylinder pressure [43].
Because of the increased stroke volume, the higher compression ratio HCCI engine improves brake thermal efficiency by achieving the auto-ignition temperature of the fuel. High to low octane fuels can be utilized as a port fuel to solve knocking and NOx formation. In HCCI engine, keeping the inlet charge temperature is critical. Similarly, the HCCI engine’s compression ratio could be maintained effectively between 10:1 and 28:1. Compression ratios of 10:1 were favored for higher cetane fuels like n-heptane, and 28:1 were preferred for high octane fuels like iso-octane. For biodiesel, the intermediate compression ratio was favored [44]. Alternative method for achieving lower emission in HCCI engine includes use of alcoholic fuels such as ethanol, n-butonal, and methanol. Due to oxygen enrichment, alcohol fuel accelerated premixed burning and complete oxidization of fuel. Also, because of the latent heat of vaporization is higher, it lowers the combustion temperature, enhancing the quenching effect [41]. The HCCI combustion’s power output is mostly determined by the equivalency ratio and fuel intake. For the higher power production, the equivalence ratio should remain at 1 as noticed by Vinod Babu et al. [45].
Too early injection of fuel with a higher injection pressure can result in premixed charge compression ignition. Due to early fuel injection, the time between commencement of injection and start of combustion has been extended, considerably improving the homogeneity of the air-fuel mixture prior to combustion [41]. With a slightly higher intake charge temperature maintained at 170°C, the PCCI engine may operate from a minimal air-fuel ratio of 34:1 to an excessively lean air-fuel ratio of 80:1 [46]. In comparison to a standard SI engine, the PCCI combustion strategy uses lean-burn technology and operates on a higher compression ratio engine. After all of the fuel had been injected, the PCCI began to burn. Also, unlike traditional combustion, the combustion events are primarily identified by chemical kinetics and do not follow the diffusion mixed combustion and speed of burning. As a result, the injection pattern and fuel combustion do not overlap, reducing the odds of direct combustion control [47]. To achieve the premixed charge in the PCCI combustion, a single stage fuel injection pattern with an earlier start of injection was adopted. However, starting the injection too early causes wall impingement and wall wetness, resulting in incomplete combustion and higher HC and CO emissions. The fuel injection pattern has been adjusted with a split and multiple injection method to alleviate these issues. Despite the fact that the period of the many injections is completed before combustion begins. Controlling auto ignition by early injection is also a critical job in PCCI combustion. To manage the auto ignition and lengthen the ignition delay interval, a higher amount of EGR is used. EGR also aids in lowering in-cylinder temperature and NOx generation due to the dilution of a fresh charge mixture [48].
PCCI combustion has performed better than HCCI combustion due to the stability of the combustion by partially premixed charge and controlled auto ignition rage and temperature. The phasing of combustion in the PCCI is mostly determined by chemical kinetics, but it can also be influenced by altering the inlet charge temperature, EGR rate, and fuel injection time and pressure. PCCI combustion has used a variety of fuel patterns, including early single pulse injection, port fuel injection, advanced multiple injections, and advanced injection with a tiny amount of late injection. In the previous section, the effects of early and late injection timings were explored. The modest amount of late injection is mostly used to reduce smoke emissions [49]. The spray angle of 70° was employed to atomize the fuel within the combustion chamber in order to eliminate wall wetness during advanced injection [49]. To avoid the generation of HC and CO emissions, the compression ratio of the PCCI engine was kept at the same level as that of a regular diesel engine. Due to the low volatility and strong flammability of the fuel, PCCI combustion has several limitations, according to a few studies [50].
For low volatile fuels like kerosene, diesel, and biofuels, spark assisted PCCI combustion has been applied. When compared to conventional CI combustion, the use of low-quality cetane fuel in the spark aided PCCI strategy engine enhanced engine performance [51]. The partially premixed combustion mixture is generated in PCCI-DI dual-mode combustion by injecting a large volume of fuel in the intake port or early pilot injection, followed by conventional direct injection of the same or another fuel. Due to the ignition delay interval, the combustion phasing of the PCCI-DI dual-mode combustion is primarily determined by the pilot fuel quantity, and the combustion rate is determined by the pilot fuel ratio [31]. For premixed compression ignition low-temperature combustion, port fuel injection is preferred (PCI-LTC). To create a premixed mixture with a proper air-fuel ratio, single fuel or dual fuel port injection is employed. Dual fuel premixed LTC has a better brake thermal efficiency than single fuel LTC and has achieved a significant reduction in NOx and soot emissions. The single fuel premixed LTC has a higher cycle to cycle variance due to the low temperature and lean air-fuel ratio [52, 53]. Reactivity controlled compression ignition (RCCI) is the name given to the dual-fuel premixed LTC, and a thorough description of the RCCI will be given in the following sections.
Partially premixed charge compression ignition is related to the PCCI method, which is a hybrid of traditional diesel and HCCI combustion. However, for low cetane fuels, PPCI combustion is favored. Similar to the PCCI combustion method, a longer ignition delay period and improved air-fuel mixing can be accomplished. Few studies have shown that improved and delayed injection strategies can result in extended ignition delay in PPCI combustion. To achieve a longer ignition delay, low and moderate compression ratio were used, as well as moderate to high EGR dilution. The key benefit of PPCI mode over HCCI mode is that it releases less particulate matter and NOx while providing better combustion phasing. PPCI is divided into two categories: early injection PPCI and late injection PPCI. The fuel is injected at the middle of the compression stroke in early injection PPCI, and at the end of the compression stroke in late injection PPCI. The fuel-injection gases of the early injected PPCI variant are denser and cooler due to partial compression. Similarly, in the late injected PPCI model, the fuel-injected gases are colder and denser due to injection occurring on the expansion cycle, which lowers the temperature in the later stage [54]. Due to incomplete oxidation and non-optimal combustion phasing, the PPCI combustion used slightly more fuel than standard diesel combustion [55].
At low load, a greater EGR rate and a delayed injection time reduce the power output of both low and higher power engines. In EGR assisted PPCI combustion, the advanced injection method was used to avoid a reduction in power output. Another disadvantage of PPCI combustion is that it produces more HC and CO because the amount of non-oxidized fuel in the piston bowl and high-pressure squish region increases [56]. The addition of gasoline to the PPCI is another way to achieve lower NOx and soot emissions without using EGR. The main benefits of adding gasoline to the PPCI are that it reduces HC and CO emissions by reducing residual products in the cylinder [57]. For longer ignition delay times, most of the premixed heat release phase was seen, resulting in higher peak cylinder pressure and noise levels. When the ignition delay periods shorten, the diffusion heat release phase occurs, resulting in a state similar to that of ordinary diesel combustion [58].
HCCI, PCCI, and RCCI are examples of sophisticated low-temperature combustion technology that have recently been created. RCCI, for example, increases research focus due to its versatility. By achieving low-temperature combustion, HCCI and PCCI improve engine efficiency and reduce pollutants, according to previous studies. These two technologies, however, have considerable limits, and they are not ideal for low and high load settings due to knocking, misfire, and a faster rate of pressure rise. Fuel alteration is required in the HCCI and PCCI combustion to overcome the difficulties [59, 60]. They also stated that combustion quality had improved across a broad range of engine operations (Bessonette et al. [61] investigated the effect of a partially mixed gasoline/diesel charge in a CI engine from low to high load. Raw diesel is favored for the lowest load situation, while a higher percentage of gasoline blend is suited for the highest load condition, according to them. In a subsequent stage, this dual fuel PCCI operation is referred to as RCCI combustion [62]. Adjusting the low to high reactive fuel ratio and the injection pattern of the high reactive fuels to achieve the NOx to smoke trade-off and higher efficiency. Reactivity stratification in RCCI combustion can also be influenced by fuel qualities such as viscosity, volatility, and ignite ability.
Biodiesel has been tested in a variety of engines and under a variety of operating circumstances all around the world. Due to the presence of oxygen in the biodiesel fuel, NOx emissions were higher for the engine [63, 64]. The RCCI engine driven by gasoline/biodiesel was mathematically analyzed by Li et al. [65]. When comparing raw biodiesel to gasoline/biodiesel, the study found decreased NOx emissions in the gasoline/biodiesel operation. As a result, using biodiesel under the RCCI method may be a better alternative for reducing NOx pollution than using biodiesel-powered diesel engines. Hanson et al. [58] study the RCCI combustion utilizing direct-injected diesel and biodiesel mixture (B20) as a direct-injected fuel and gasoline, E85 (85% ethanol and 15% diesel blend), and E20 as a port fuel. In the RCCI combustion, the findings of the E20/diesel mixture show that maximum pressure and HRR dropped, allowing the peak load to increase by 2 bar (from 8 bar to 10 bar BMEP). The usage of E20 improves combustion efficiency while lowering the heat release rate and exhaust leakage. The combustion efficiency of gasoline/B20 RCCI operation was also increased by lowering the UHC, albeit with a greater CO. Fuel efficiency also improved, resulting in a 1.68 percent increase in BTE. In comparison to the RCCI gasoline/diesel operation, E85/B20 allowed the RCCI operation to increase the BTE from 40 to 43%. The use of biodiesel as a pilot fuel has improved the stability of the cyclic operation of RCCI engine powered by natural gas/biodiesel, according to Gharehghani et al. [66]. This is due to the fact that biodiesel contains oxygen, which raises the cetane number. In comparison to natural gas/diesel, the mixture of natural gas/biodiesel produced 1.6% higher BTE as noticed by Gharehghani et al. [66].
The combustion temperature in the LTC mode was always lower than the combustion temperature in a regular diesel engine. There are primarily two strategies to achieve low-temperature combustion: one is to operate the engine with higher EGR, and the other is to operate with an excess air ratio 0 greater than 1 [67]. Fuel combusted and oxidized at higher temperatures under stoichiometric operating conditions, resulting in more NOx production. Also, due to a reduction in oxygen availability in the fuel spray periphery, maximum soot emission was observed under the stoichiometric condition compared to normal diesel combustion [68]. Higher fuel injection pressure is usually a viable approach for overcoming the aforementioned concerns. Higher fuel injection pressure promotes atomization, mixing, and vaporization. However, the key duty to be remedied in modern injection technology in low-temperature combustion is the wall impingement of fuel caused by spray tip penetration at increased fuel injection pressure [69]. Furthermore, improved injection strategies such as high-pressure injection and CRDI approaches reduce the ignition delay period and boost premixed phase combustion, resulting in increased NOx emissions. The ignition delay and combustion phasing will be lengthened by using a higher level of cold EGR, lowering the compression ratio, and using variable valve timing control to advance the exhaust valve opening. Increased ignition delay enhances air-fuel mixing, resulting in increased homogeneity in the air-fuel combination. Higher EGR rate and lower compression ratio reduce the cylinder peak pressure and temperature, which has a major impact on engine performance and higher fuel consumption.
Getting LTC mode to work in real-time settings with heavy engine load is difficult. It is impossible to manufacture engines with a larger amount of EGR. In addition, the engine’s higher BTE should compensate for the increased EGR. In the LTC condition, an external charge booster is necessary to produce higher BTE [70]. When the engine is running at a higher RPM, moderate EGR with an intake charge booster raises the cylinder peak pressure. The combustion process changes depending on the engine load, and it is influenced by the different equivalency ratio and fuel mixing zone, making the engine demanding and difficult to modify the operating state for each load [71]. The real-time modern diesel engine employs dual fuel technology, multiple injection method, and negative valve overlapping. However, these technologies are costly and difficult to implement across the board. By increasing the premixed charge quantity while lowering peak pressure and temperature, these innovations reduce the fuel-rich zone [72].
This study provides a comprehensive overview of hydrogen production techniques and fuel cell vehicle also described about the low-temperature combustion (LTC) techniques and how it is improve the reliability and fuel efficiency of the CI engine combustion cycle with low emissions and noise. The important findings are presented in this review can be summarized below:
Even though fuel cells have demonstrated and shown to be a very promising fuel, there are still a number of limitations that prohibit them from being used on a bigger scale than other fuels. The following are some of the most pressing issues that must be addressed right now: Compared to other kinds of energy, the FC has lower overall efficiency. The material and fabrication of the FC have high production costs.
One of the most pressing concerns is the cost of hydrogen, as well as its storage. Because hydrogen is a relatively light and dangerous gas, it must be stored in special containers. Thermal management in the case of high-temperature fuel cell like solid oxide fuel cell is a type of fuel cell in which the temperature is higher than the ambient temperature.
The size and weight of current fuel cell systems must be further reduced to meet the packaging requirements for automobiles. This applies not only to the fuel cell stack, but also to the ancillary components and major subsystems.
PCCI combustion efficiently decrease the CO and HC emission as compared to the HCCI engine, but NOx and soot emissions were significantly increased with increase in premixed charge percentage. However, the smoke and NOx emissions were identified as minimum level when compared with conventional diesel engine combustion.
Higher cycle-to-cycle variation, unpredictable pressure rise, combustion noise and knocking were occurred in the HCCI mode of combustion due to higher homogeneity and unpredictable auto-ignition zone.
RCCI combustion is preferable for higher load condition due to combustion phase control and higher brake thermal efficiency than PCCI and HCCI modes. The use of natural gas as a reactive fuel was extending the load limit and attained the efficient, clean combustion which significantly decreases the NOx and soot emission as compared to other techniques.
The double injection of high reactive fuel in the RCCI combustion decreases the peak pressure and ringing intensity which efficiently decrease the smoke and NOx emission. The advanced second injection in the RCCI increases the reactive controlled combustion and late second injection increase the mixed controlled combustion.
The combustion efficiency was increased while using the B20 as the high reactive fuel. Due to the oxygen availability in the biodiesel promotes the oxidization process, which decreases the HC and CO emission as compared to the diesel/gasoline RCCI combustion.
Many experiments have extensively demonstrated that there is a wide and unexploited scope for improving low-temperature combustion using different fuel injection parameter and different reactive fuel injection. The overall study infers that depending on the operating condition, engine configuration parameters, fuel injection mechanism and fuel mixing method influenced more on the engine performance and emission characteristics. Hence, further research work will be needed to the trade-off between the NOx and soot emission with improvement in the engine performance.
The authors would like to thank King Mongkut’s University of Technology North Bangkok (Grant Contract No. KMUTNB-KNOW63-28, KMUTNB-Post-65-09, KMUTNB-Post-65-05) for financial support during this work.
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\\n\\nMi koristimo kolačiće. Korištenjem IntechOpenove stranice slažete se s korištenjem kolačića u skladu s IntechOpenovom Politikom privatnosti. Većina modernih, interaktivnih stranica koristi kolačiće kako bi omogućila ponovno pronalaženje korisničkih detalja kod svakog posjeta. Na našoj stranici kolačići se uglavnom koriste kako bi omogućili funkcionalnost i olakšali posjetiteljima korištenje stranice.
\\n\\nIntechOpen ili njegovi suradnici niti u jednom slučaju neće biti odgovorni za štete (štete uključuju gubitak podataka ili profita, druge poslovne prekide, te sve ostale štete) koje nastanu zbog korištenja materijala na IntechOpenovoj stranici ili nemogućnosti da se iste koriste, čak i ako je IntechOpen ili njegov predstavnik o takvoj šteti obaviješten pismenim ili usmenim putem. Neke jurisdikcije ne dozvoljavaju ograničenja garancija ili ograničenja obveza za posljedične ili slučajne štete pa se u tom slučaju ova ograničenja možda ne odnose na vas.
\\n\\nMaterijali koji se pojavljuju na IntechOpenovoj stranici mogu sadržavati manje greške, tipfelere ili fotografske greške. IntechOpen može napraviti promjene na bilo kojem materijalu koji se nalazi na stranici u bilo koje vrijeme.
\\n\\nIntechOpen nije formalno povezan niti s jednom vanjskom stranicom čije poveznice vode na www.intechopen.com, osim ako to nije izravno navedeno. Iz tog razloga IntechOpen nije odgovoran za sadržaj koji se pojavljuje na takvim stranicama. Poveznica na IntechOpenovu stranicu ne implicira povezanost sa IntechOpenom. Korištenje takvih poveznica isključiva je odgovornost korisnika.
\\n\\nZadržavamo pravo vlasništva nad cjelokupnom stranicom www.intechopen.com i nad svim materijalom na toj stranici. Koristeći se našim uslugama, slažete se da maknete sve poveznice na našu stranicu odmah nakon što to od vas zatražimo. Također, zadržavamo pravo da ove Odredbe i uvjete, i politiku o poveznicama izmjenimo u bilo koje vrijeme. Koristeći se poveznicama na naše stranice slažete se s ovim Odredbama i uvjetima.
\\n\\nAko smatrate da je bilo koja poveznica na našoj stranici sumnjiva iz bilo kojeg razloga, molimo vas da nas kontaktirate. U tom slučaju razmotrit ćemo micanje poveznice s naše stranice, iako nismo obvezni to napraviti.
\\n\\nBez prethodne privole i izričite pisane dozvole, ne možete stvarati okvire oko naših stranica ili koristiti druge tehnike koje na bilo koji način mogu promijeniti prezentaciju ili izgled naše stranice.
\\n\\nIntechOpen može ove Odredbe izmijeniti u bilo koje vrijeme i bez prethodne obavijesti. Koristeći ovu stranicu vi se slažete s trenutnim Odredbama i uvjetima koje su na snazi.
\\n\\nOve Odredbe i uvjeti su sastavljeni u skladu s odredbama prava Ujedinjenog Kraljevstva, a za sve sporove nadležan je sud u Londonu, Ujedinjeno Kraljevstvo.
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\n\nSljedeća terminologija odnosi se na Odredbe i uvjete, te na sve naše ugovore:
\n\nKlijent, stranka, vi, vaš odnosi se na vas, osobu koja pristupa ovoj stranici i prihvaća IntechOpenove Odredbe i uvjete;
\n\nKompanija, tvrtka, mi, naše odnosi se na tvrtku IntechOpen;
\n\nStranke, strane odnosi se na klijenta i na nas, ili samo na klijenta ili nas.
\n\nSve odredbe koje se odnose na ponudu, prihvat ili razmatranje plaćanja, a za koja mi pružamo asistenciju klijentu, bilo na ugovoreni ili fiksni način, a s ciljem da se ostvare potrebe i želje klijenta u svezi s našim uslugama, su podložne zakonskim odredbama Ujedinjenog Kraljevstva.
\n\nOsim ako nije suprotno navedeno, IntechOpen i/ili svi davatelji licence vlasnici su intelektualnog vlasništva nad svim materijalima na www.intechopen.com. Sva prava intelektualnog vlasništva su pridržana. Stranice sa www.intechopen.com možete gledati, preuzimati, dijeliti, dijeliti poveznice i printati za osobnu uporabu, a temeljem pravila sadržanih u ovim Odredbama i uvjetima.
\n\nMi koristimo kolačiće. Korištenjem IntechOpenove stranice slažete se s korištenjem kolačića u skladu s IntechOpenovom Politikom privatnosti. Većina modernih, interaktivnih stranica koristi kolačiće kako bi omogućila ponovno pronalaženje korisničkih detalja kod svakog posjeta. Na našoj stranici kolačići se uglavnom koriste kako bi omogućili funkcionalnost i olakšali posjetiteljima korištenje stranice.
\n\nIntechOpen ili njegovi suradnici niti u jednom slučaju neće biti odgovorni za štete (štete uključuju gubitak podataka ili profita, druge poslovne prekide, te sve ostale štete) koje nastanu zbog korištenja materijala na IntechOpenovoj stranici ili nemogućnosti da se iste koriste, čak i ako je IntechOpen ili njegov predstavnik o takvoj šteti obaviješten pismenim ili usmenim putem. Neke jurisdikcije ne dozvoljavaju ograničenja garancija ili ograničenja obveza za posljedične ili slučajne štete pa se u tom slučaju ova ograničenja možda ne odnose na vas.
\n\nMaterijali koji se pojavljuju na IntechOpenovoj stranici mogu sadržavati manje greške, tipfelere ili fotografske greške. IntechOpen može napraviti promjene na bilo kojem materijalu koji se nalazi na stranici u bilo koje vrijeme.
\n\nIntechOpen nije formalno povezan niti s jednom vanjskom stranicom čije poveznice vode na www.intechopen.com, osim ako to nije izravno navedeno. Iz tog razloga IntechOpen nije odgovoran za sadržaj koji se pojavljuje na takvim stranicama. Poveznica na IntechOpenovu stranicu ne implicira povezanost sa IntechOpenom. Korištenje takvih poveznica isključiva je odgovornost korisnika.
\n\nZadržavamo pravo vlasništva nad cjelokupnom stranicom www.intechopen.com i nad svim materijalom na toj stranici. Koristeći se našim uslugama, slažete se da maknete sve poveznice na našu stranicu odmah nakon što to od vas zatražimo. Također, zadržavamo pravo da ove Odredbe i uvjete, i politiku o poveznicama izmjenimo u bilo koje vrijeme. Koristeći se poveznicama na naše stranice slažete se s ovim Odredbama i uvjetima.
\n\nAko smatrate da je bilo koja poveznica na našoj stranici sumnjiva iz bilo kojeg razloga, molimo vas da nas kontaktirate. U tom slučaju razmotrit ćemo micanje poveznice s naše stranice, iako nismo obvezni to napraviti.
\n\nBez prethodne privole i izričite pisane dozvole, ne možete stvarati okvire oko naših stranica ili koristiti druge tehnike koje na bilo koji način mogu promijeniti prezentaciju ili izgled naše stranice.
\n\nIntechOpen može ove Odredbe izmijeniti u bilo koje vrijeme i bez prethodne obavijesti. Koristeći ovu stranicu vi se slažete s trenutnim Odredbama i uvjetima koje su na snazi.
\n\nOve Odredbe i uvjeti su sastavljeni u skladu s odredbama prava Ujedinjenog Kraljevstva, a za sve sporove nadležan je sud u Londonu, Ujedinjeno Kraljevstvo.
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Abu-Eishah"}]},{id:"13747",doi:"10.5772/14702",title:"Application of Room Temperature Ionic Liquids in Electrochemical Sensors and Biosensors",slug:"application-of-room-temperature-ionic-liquids-in-electrochemical-sensors-and-biosensors",totalDownloads:9795,totalCrossrefCites:13,totalDimensionsCites:31,abstract:null,book:{id:"1373",slug:"ionic-liquids-applications-and-perspectives",title:"Ionic Liquids",fullTitle:"Ionic Liquids: Applications and Perspectives"},signatures:"Farnoush Faridbod, Mohammad Reza Ganjali, Parviz Norouzi, Siavash Riahi, and Hamid Rashedi",authors:[{id:"18565",title:"Prof.",name:"Mohammad Reza",middleName:null,surname:"Ganjali",slug:"mohammad-reza-ganjali",fullName:"Mohammad Reza Ganjali"},{id:"20605",title:"Dr.",name:"Parviz",middleName:null,surname:"Norouzi",slug:"parviz-norouzi",fullName:"Parviz Norouzi"},{id:"20606",title:"Dr.",name:"Farnoush",middleName:null,surname:"Faridbod",slug:"farnoush-faridbod",fullName:"Farnoush Faridbod"},{id:"20607",title:"Dr.",name:"Siavash",middleName:null,surname:"Riahi",slug:"siavash-riahi",fullName:"Siavash Riahi"}]}],mostDownloadedChaptersLast30Days:[{id:"20532",title:"1,2,3-Triazolium Salts as a Versatile New Class of Ionic Liquids",slug:"1-2-3-triazolium-salts-as-a-versatile-new-class-of-ionic-liquids",totalDownloads:6032,totalCrossrefCites:6,totalDimensionsCites:12,abstract:null,book:{id:"327",slug:"ionic-liquids-classes-and-properties",title:"Ionic Liquids",fullTitle:"Ionic Liquids - Classes and Properties"},signatures:"Zekarias Yacob and Jürgen Liebscher",authors:[{id:"52686",title:"Prof.",name:"Jürgen",middleName:null,surname:"Liebscher",slug:"jurgen-liebscher",fullName:"Jürgen Liebscher"},{id:"56807",title:"Prof.",name:"Zekarias Yacob",middleName:null,surname:"Fundusa",slug:"zekarias-yacob-fundusa",fullName:"Zekarias Yacob Fundusa"}]},{id:"72530",title:"Application of Vortex Control Principle at Pump Intake",slug:"application-of-vortex-control-principle-at-pump-intake",totalDownloads:1008,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"Vortex flow in a pump intake could affect a pump operation significantly if not treated appropriately. Many researches have been conducted to determine the best control method for vortex flow in pump sumps so that the pump lifespan can be maximized. In this study, a vortex control principle designed to minimize the impact of submerged vortex flow in pump sump on major pump components is presented. This principle employs a device called the plate type floor splitter which serves the function of eliminating vortices formed on the sump floor and reduces the intensity of swirling motion in the intake flow. A pump sump model was built to carry out the study by installing a floor splitter plate sample under the pump suction inlet and the corresponding parameters used to quantify the swirl intensity known as the swirl angle was measured. Procedures for the measurement were conducted based on ANSI/HI 9.8-2018 standard. A numerical simulation was performed to study the flow in a full-scale pump sump. The results showed that the installation of floor splitter plate can eliminate vortices efficiently and reduce swirl angle significantly. However, optimization of floor splitter design is needed to achieve a reduction effect that can reduce swirl angles to an acceptable value of lower than 5° according to ANSI/HI 9.8-2018 standard.",book:{id:"10080",slug:"vortex-dynamics-theories-and-applications",title:"Vortex Dynamics Theories and Applications",fullTitle:"Vortex Dynamics Theories and Applications"},signatures:"Zambri Harun, Tajul Ariffin Norizan and Wan Hanna Melini Wan Mohtar",authors:[{id:"243152",title:"Dr.",name:"Zambri",middleName:null,surname:"Harun",slug:"zambri-harun",fullName:"Zambri Harun"},{id:"313310",title:"Mr.",name:"Tajul Ariffin",middleName:null,surname:"Norizan",slug:"tajul-ariffin-norizan",fullName:"Tajul Ariffin Norizan"},{id:"317421",title:"Dr.",name:"Wan Hanna Melini",middleName:null,surname:"Wan Mohtar",slug:"wan-hanna-melini-wan-mohtar",fullName:"Wan Hanna Melini Wan Mohtar"}]},{id:"20216",title:"Ionic Liquids in Separation Techniques",slug:"ionic-liquids-in-separation-techniques",totalDownloads:8523,totalCrossrefCites:4,totalDimensionsCites:7,abstract:null,book:{id:"1300",slug:"applications-of-ionic-liquids-in-science-and-technology",title:"Applications of Ionic Liquids in Science and Technology",fullTitle:"Applications of Ionic Liquids in Science and Technology"},signatures:"Jolanta Flieger and Anna Czajkowska-Żelazko",authors:[{id:"20797",title:"Dr.",name:"Jolanta",middleName:null,surname:"Flieger",slug:"jolanta-flieger",fullName:"Jolanta Flieger"},{id:"136020",title:"Prof.",name:"Czajkowska",middleName:null,surname:"Żelazko",slug:"czajkowska-zelazko",fullName:"Czajkowska Żelazko"}]},{id:"71403",title:"Supercritical-Fluids Thermophysical Properties and Heat Transfer in Power-Engineering Applications",slug:"supercritical-fluids-thermophysical-properties-and-heat-transfer-in-power-engineering-applications",totalDownloads:1135,totalCrossrefCites:3,totalDimensionsCites:2,abstract:"Researches on specifics of thermophysical properties and heat transfer at supercritical pressures (SCPs) started as early as the 1930s with the study on free-convection heat transfer to fluids at a near-critical point. In the 1950s, the concept of using SC “steam” to increase thermal efficiency of coal-fired thermal power plants became an attractive option. Germany, USA, the former USSR, and some other countries extensively studied heat transfer to SC fluids (SCFs) during the 1950s till the 1980s. This research was primarily focused on bare circular tubes cooled with SC water (SCW). However, some studies were performed with modeling fluids such as SC carbon dioxide and refrigerants instead of SCW. Currently, the use of SC “steam” in coal-fired thermal power plants is the largest industrial application of fluids at SCPs. Near the end of the 1950s and at the beginning of the 1960s, several studies were conducted to investigate a possibility of using SCW as a coolant in nuclear reactors with the objective to increase thermal efficiency of nuclear power plants (NPPs) equipped with water-cooled reactors. However, these research activities were abandoned for some time and regained momentum in the 1990s. In support of the development of SCW-cooled nuclear-power reactor (SCWR) concepts, first experiments have been started in annular and various bundle flow geometries. At the same time, more numerical and CFD studies have been performed in support of our limited knowledge on specifics of heat transfer at SCPs in various flow geometries. As the first step in this process, heat transfer to SCW in vertical bare tubes can be investigated as a conservative approach (in general, heat transfer in fuel bundles will be enhanced with various types of appendages, that is, grids, end plates, spacers, bearing pads, fins, ribs, etc.). New experiments in the 1990–2000s were triggered by several reasons: (1) thermophysical properties of SCW and other SCFs have been updated from the 1950s–1970s, for example, a peak in thermal conductivity in the critical/pseudocritical points was “officially” introduced in 1990s; (2) experimental techniques have been improved; (3) in SCWRs, various bundle flow geometries will be used instead of bare-tube geometry; (4) in SC “steam” generators of thermal power plants, larger diameter tubes/pipes (20–40 mm) are used, however in SCWRs hydraulic-equivalent diameters of proposed bundles will be within 5–12 mm; (5) with Research and Development (R&D) of next-generation or Generation-IV nuclear-power-reactor concepts, new areas of application for SCFs have appeared—for example, SCP helium was proposed to be used as a reactor coolant, SCP Brayton and Rankine cycles with SC carbon dioxide as a working fluid are being developed, etc. A comparison of thermophysical properties of SCFs with those of subcritical-pressure fluids showed that SCFs as single-phase fluids have unique properties, which are close to “liquid-like” behavior below critical or pseudocritical points and are quite similar to the behavior of “gas-like” substances above these points. A comparison of selected SCW heat transfer correlations has shown that their results may differ from one to another by more than 200%. Based on these comparisons, it became evident that there is a need for reliable, accurate, and wide-range SCW heat transfer correlation(s) to be developed and verified. Therefore, the objective of this chapter is to summarize in concise form specifics of supercritical-fluids thermophysical properties and heat transfer in power-engineering applications.",book:{id:"9201",slug:"advanced-supercritical-fluids-technologies",title:"Advanced Supercritical Fluids Technologies",fullTitle:"Advanced Supercritical Fluids Technologies"},signatures:"Igor L. 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He completed a one-year Post-Doctoral Fellowship awarded by the DFAIT (Foreign Affairs and International Trade Canada) at the Institute of Biomedical Engineering of the University of New Brunswick (Canada) in 2010. Currently, he is Professor in the Faculty of Electrical Engineering (UFU). He has authored and co-authored more than 200 peer-reviewed publications in Biomedical Engineering. He has been a researcher of The National Council for Scientific and Technological Development (CNPq-Brazil) since 2009. He has served as an ad-hoc consultant for CNPq, CAPES (Coordination for the Improvement of Higher Education Personnel), FINEP (Brazilian Innovation Agency), and other funding bodies on several occasions. He was the Secretary of the Brazilian Society of Biomedical Engineering (SBEB) from 2015 to 2016, President of SBEB (2017-2018) and Vice-President of SBEB (2019-2020). He was the head of the undergraduate program in Biomedical Engineering of the Federal University of Uberlândia (2015 - June/2019) and the head of the Centre for Innovation and Technology Assessment in Health (NIATS/UFU) since 2010. He is the head of the Postgraduate Program in Biomedical Engineering (UFU, July/2019 - to date). He was the secretary of the Parkinson's Disease Association of Uberlândia (2018-2019). Dr. Andrade's primary area of research is focused towards getting information from the neuromuscular system to understand its strategies of organization, adaptation and controlling in the context of motor neuron diseases. His research interests include Biomedical Signal Processing and Modelling, Assistive Technology, Rehabilitation Engineering, Neuroengineering and Parkinson's Disease.",institutionString:null,institution:{name:"Federal University of Uberlândia",institutionURL:null,country:{name:"Brazil"}}},editorTwo:null,editorThree:null},{id:"9",title:"Biotechnology - Biosensors, Biomaterials and Tissue Engineering",coverUrl:"https://cdn.intechopen.com/series_topics/covers/9.jpg",isOpenForSubmission:!0,editor:{id:"126286",title:"Dr.",name:"Luis",middleName:"Jesús",surname:"Villarreal-Gómez",slug:"luis-villarreal-gomez",fullName:"Luis Villarreal-Gómez",profilePictureURL:"https://mts.intechopen.com/storage/users/126286/images/system/126286.jpg",biography:"Dr. Luis Villarreal is a research professor from the Facultad de Ciencias de la Ingeniería y Tecnología, Universidad Autónoma de Baja California, Tijuana, Baja California, México. 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For 20 years, he has studied the analysis and processing of biomedical images, emphasizing the full automation of measurement for a large inter-individual variability of patients. Dr. Koprowski has authored more than a hundred research papers with dozens in impact factor (IF) journals and has authored or co-authored six books. Additionally, he is the author of several national and international patents in the field of biomedical devices and imaging. 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His fields of interest are anterior segment disease, keratoconus, glaucoma, corneal dystrophies, and cataracts. His research topics include\nintraocular lens power calculation, eye modification induced by refractive surgery, glaucoma progression, and validation of new diagnostic devices in ophthalmology. \nHe has published more than 100 papers in international and Italian scientific journals, more than 60 in journals with impact factors, and chapters in international and Italian books. 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His research focuses on biochemistry, biophysics, genetics, molecular biology, and molecular medicine with specialization in the fields of drug design, protein structure-function, protein folding, prions, microRNA, pseudogenes, molecular cancer, epigenetics, metabolites, proteomics, genomics, protein expression, and characterization by spectroscopic and calorimetric methods.",institutionString:"University of Health Sciences",institution:null},{id:"180528",title:"Dr.",name:"Hiroyuki",middleName:null,surname:"Kagechika",slug:"hiroyuki-kagechika",fullName:"Hiroyuki Kagechika",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/180528/images/system/180528.jpg",biography:"Hiroyuki Kagechika received his bachelor’s degree and Ph.D. in Pharmaceutical Sciences from the University of Tokyo, Japan, where he served as an associate professor until 2004. 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He continues to lead research projects on developing new therapies for liver, skin disorders, and cancer. Dr. Badria was listed among the world’s top 2% of scientists in medicinal and biomolecular chemistry in 2019 and 2020. He is a member of the Arab Development Fund, Kuwait; International Cell Research Organization–United Nations Educational, Scientific and Cultural Organization (ICRO–UNESCO), Chile; and UNESCO Biotechnology France",institutionString:"Mansoura University",institution:{name:"Mansoura University",country:{name:"Egypt"}}},{id:"329385",title:"Dr.",name:"Rajesh K.",middleName:"Kumar",surname:"Singh",slug:"rajesh-k.-singh",fullName:"Rajesh K. Singh",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/329385/images/system/329385.png",biography:"Dr. Singh received a BPharm (2003) and MPharm (2005) from Panjab University, Chandigarh, India, and a Ph.D. (2013) from Punjab Technical University (PTU), Jalandhar, India. He has more than sixteen years of teaching experience and has supervised numerous postgraduate and Ph.D. students. He has to his credit more than seventy papers in SCI- and SCOPUS-indexed journals, fifty-five conference proceedings, four books, six Best Paper Awards, and five projects from different government agencies. He is currently an editorial board member of eight international journals and a reviewer for more than fifty scientific journals. He received Top Reviewer and Excellent Peer Reviewer Awards from Publons in 2016 and 2017, respectively. He is also on the panel of The International Reviewer for reviewing research proposals for grants from the Royal Society. He also serves as a Publons Academy mentor and Bentham brand ambassador.",institutionString:"Punjab Technical University",institution:{name:"Punjab Technical University",country:{name:"India"}}},{id:"142388",title:"Dr.",name:"Thiago",middleName:"Gomes",surname:"Gomes Heck",slug:"thiago-gomes-heck",fullName:"Thiago Gomes Heck",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/142388/images/7259_n.jpg",biography:null,institutionString:null,institution:{name:"Universidade Regional do Noroeste do Estado do Rio Grande do Sul",country:{name:"Brazil"}}},{id:"336273",title:"Assistant Prof.",name:"Janja",middleName:null,surname:"Zupan",slug:"janja-zupan",fullName:"Janja Zupan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/336273/images/14853_n.jpeg",biography:"Janja Zupan graduated in 2005 at the Department of Clinical Biochemistry (superviser prof. dr. Janja Marc) in the field of genetics of osteoporosis. Since November 2009 she is working as a Teaching Assistant at the Faculty of Pharmacy, Department of Clinical Biochemistry. In 2011 she completed part of her research and PhD work at Institute of Genetics and Molecular Medicine, University of Edinburgh. She finished her PhD entitled The influence of the proinflammatory cytokines on the RANK/RANKL/OPG in bone tissue of osteoporotic and osteoarthritic patients in 2012. From 2014-2016 she worked at the Institute of Biomedical Sciences, University of Aberdeen as a postdoctoral research fellow on UK Arthritis research project where she gained knowledge in mesenchymal stem cells and regenerative medicine. She returned back to University of Ljubljana, Faculty of Pharmacy in 2016. She is currently leading project entitled Mesenchymal stem cells-the keepers of tissue endogenous regenerative capacity facing up to aging of the musculoskeletal system funded by Slovenian Research Agency.",institutionString:null,institution:{name:"University of Ljubljana",country:{name:"Slovenia"}}},{id:"357453",title:"Dr.",name:"Radheshyam",middleName:null,surname:"Maurya",slug:"radheshyam-maurya",fullName:"Radheshyam Maurya",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/357453/images/16535_n.jpg",biography:null,institutionString:null,institution:{name:"University of Hyderabad",country:{name:"India"}}},{id:"418340",title:"Dr.",name:"Jyotirmoi",middleName:null,surname:"Aich",slug:"jyotirmoi-aich",fullName:"Jyotirmoi Aich",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000038Ugi5QAC/Profile_Picture_2022-04-15T07:48:28.png",biography:"Biotechnologist with 15 years of research including 6 years of teaching experience. Demonstrated record of scientific achievements through consistent publication record (H index = 13, with 874 citations) in high impact journals such as Nature Communications, Oncotarget, Annals of Oncology, PNAS, and AJRCCM, etc. Strong research professional with a post-doctorate from ACTREC where I gained experimental oncology experience in clinical settings and a doctorate from IGIB where I gained expertise in asthma pathophysiology. A well-trained biotechnologist with diverse experience on the bench across different research themes ranging from asthma to cancer and other infectious diseases. An individual with a strong commitment and innovative mindset. Have the ability to work on diverse projects such as regenerative and molecular medicine with an overall mindset of improving healthcare.",institutionString:"DY Patil Deemed to Be University",institution:null},{id:"349288",title:"Prof.",name:"Soumya",middleName:null,surname:"Basu",slug:"soumya-basu",fullName:"Soumya Basu",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000035QxIDQA0/Profile_Picture_2022-04-15T07:47:01.jpg",biography:"Soumya Basu, Ph.D., is currently working as an Associate Professor at Dr. D. Y. Patil Biotechnology and Bioinformatics Institute, Dr. D. Y. Patil Vidyapeeth, Pune, Maharashtra, India. With 16+ years of trans-disciplinary research experience in Drug Design, development, and pre-clinical validation; 20+ research article publications in journals of repute, 9+ years of teaching experience, trained with cross-disciplinary education, Dr. Basu is a life-long learner and always thrives for new challenges.\r\nHer research area is the design and synthesis of small molecule partial agonists of PPAR-γ in lung cancer. She is also using artificial intelligence and deep learning methods to understand the exosomal miRNA’s role in cancer metastasis. Dr. Basu is the recipient of many awards including the Early Career Research Award from the Department of Science and Technology, Govt. of India. She is a reviewer of many journals like Molecular Biology Reports, Frontiers in Oncology, RSC Advances, PLOS ONE, Journal of Biomolecular Structure & Dynamics, Journal of Molecular Graphics and Modelling, etc. She has edited and authored/co-authored 21 journal papers, 3 book chapters, and 15 abstracts. She is a Board of Studies member at her university. She is a life member of 'The Cytometry Society”-in India and 'All India Cell Biology Society”- in India.",institutionString:"Dr. D.Y. Patil Vidyapeeth, Pune",institution:{name:"Dr. D.Y. Patil Vidyapeeth, Pune",country:{name:"India"}}},{id:"354817",title:"Dr.",name:"Anubhab",middleName:null,surname:"Mukherjee",slug:"anubhab-mukherjee",fullName:"Anubhab Mukherjee",position:null,profilePictureURL:"https://intech-files.s3.amazonaws.com/0033Y0000365PbRQAU/ProfilePicture%202022-04-15%2005%3A11%3A18.480",biography:"A former member of Laboratory of Nanomedicine, Brigham and Women’s Hospital, Harvard University, Boston, USA, Dr. Anubhab Mukherjee is an ardent votary of science who strives to make an impact in the lives of those afflicted with cancer and other chronic/acute ailments. He completed his Ph.D. from CSIR-Indian Institute of Chemical Technology, Hyderabad, India, having been skilled with RNAi, liposomal drug delivery, preclinical cell and animal studies. He pursued post-doctoral research at College of Pharmacy, Health Science Center, Texas A & M University and was involved in another postdoctoral research at Department of Translational Neurosciences and Neurotherapeutics, John Wayne Cancer Institute, Santa Monica, California. In 2015, he worked in Harvard-MIT Health Sciences & Technology as a visiting scientist. He has substantial experience in nanotechnology-based formulation development and successfully served various Indian organizations to develop pharmaceuticals and nutraceutical products. He is an inventor in many US patents and an author in many peer-reviewed articles, book chapters and books published in various media of international repute. Dr. Mukherjee is currently serving as Principal Scientist, R&D at Esperer Onco Nutrition (EON) Pvt. Ltd. and heads the Hyderabad R&D center of the organization.",institutionString:"Esperer Onco Nutrition Pvt Ltd.",institution:null},{id:"319365",title:"Assistant Prof.",name:"Manash K.",middleName:null,surname:"Paul",slug:"manash-k.-paul",fullName:"Manash K. Paul",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/319365/images/system/319365.png",biography:"Manash K. Paul is a Principal Investigator and Scientist at the University of California Los Angeles. He has contributed significantly to the fields of stem cell biology, regenerative medicine, and lung cancer. His research focuses on various signaling processes involved in maintaining stem cell homeostasis during the injury-repair process, deciphering lung stem cell niche, pulmonary disease modeling, immuno-oncology, and drug discovery. He is currently investigating the role of extracellular vesicles in premalignant lung cell migration and detecting the metastatic phenotype of lung cancer via machine-learning-based analyses of exosomal signatures. Dr. Paul has published in more than fifty peer-reviewed international journals and is highly cited. He is the recipient of many awards, including the UCLA Vice Chancellor’s award, a senior member of the Institute of Electrical and Electronics Engineers (IEEE), and an editorial board member for several international journals.",institutionString:"University of California Los Angeles",institution:{name:"University of California Los Angeles",country:{name:"United States of America"}}},{id:"311457",title:"Dr.",name:"Júlia",middleName:null,surname:"Scherer Santos",slug:"julia-scherer-santos",fullName:"Júlia Scherer Santos",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/311457/images/system/311457.jpg",biography:"Dr. Júlia Scherer Santos works in the areas of cosmetology, nanotechnology, pharmaceutical technology, beauty, and aesthetics. Dr. Santos also has experience as a professor of graduate courses. Graduated in Pharmacy, specialization in Cosmetology and Cosmeceuticals applied to aesthetics, specialization in Aesthetic and Cosmetic Health, and a doctorate in Pharmaceutical Nanotechnology. Teaching experience in Pharmacy and Aesthetics and Cosmetics courses. She works mainly on the following subjects: nanotechnology, cosmetology, pharmaceutical technology, aesthetics.",institutionString:"Universidade Federal de Juiz de Fora",institution:{name:"Universidade Federal de Juiz de Fora",country:{name:"Brazil"}}},{id:"219081",title:"Dr.",name:"Abdulsamed",middleName:null,surname:"Kükürt",slug:"abdulsamed-kukurt",fullName:"Abdulsamed Kükürt",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/219081/images/system/219081.png",biography:"Dr. Kükürt graduated from Uludağ University in Turkey. He started his academic career as a Research Assistant in the Department of Biochemistry at Kafkas University. In 2019, he completed his Ph.D. program in the Department of Biochemistry at the Institute of Health Sciences. He is currently working at the Department of Biochemistry, Kafkas University. He has 27 published research articles in academic journals, 11 book chapters, and 37 papers. He took part in 10 academic projects. He served as a reviewer for many articles. He still serves as a member of the review board in many academic journals. He is currently working on the protective activity of phenolic compounds in disorders associated with oxidative stress and inflammation.",institutionString:null,institution:{name:"Kafkas University",country:{name:"Turkey"}}},{id:"178366",title:"Dr.",name:"Volkan",middleName:null,surname:"Gelen",slug:"volkan-gelen",fullName:"Volkan Gelen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/178366/images/system/178366.jpg",biography:"Volkan Gelen is a Physiology specialist who received his veterinary degree from Kafkas University in 2011. Between 2011-2015, he worked as an assistant at Atatürk University, Faculty of Veterinary Medicine, Department of Physiology. In 2016, he joined Kafkas University, Faculty of Veterinary Medicine, Department of Physiology as an assistant professor. Dr. Gelen has been engaged in various academic activities at Kafkas University since 2016. There he completed 5 projects and has 3 ongoing projects. He has 60 articles published in scientific journals and 20 poster presentations in scientific congresses. His research interests include physiology, endocrine system, cancer, diabetes, cardiovascular system diseases, and isolated organ bath system studies.",institutionString:"Kafkas University",institution:{name:"Kafkas University",country:{name:"Turkey"}}},{id:"418963",title:"Dr.",name:"Augustine Ododo",middleName:"Augustine",surname:"Osagie",slug:"augustine-ododo-osagie",fullName:"Augustine Ododo Osagie",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/418963/images/16900_n.jpg",biography:"Born into the family of Osagie, a prince of the Benin Kingdom. I am currently an academic in the Department of Medical Biochemistry, University of Benin. Part of the duties are to teach undergraduate students and conduct academic research.",institutionString:null,institution:{name:"University of Benin",country:{name:"Nigeria"}}},{id:"192992",title:"Prof.",name:"Shagufta",middleName:null,surname:"Perveen",slug:"shagufta-perveen",fullName:"Shagufta Perveen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/192992/images/system/192992.png",biography:"Prof. Shagufta Perveen is a Distinguish Professor in the Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia. Dr. Perveen has acted as the principal investigator of major research projects funded by the research unit of King Saud University. She has more than ninety original research papers in peer-reviewed journals of international repute to her credit. She is a fellow member of the Royal Society of Chemistry UK and the American Chemical Society of the United States.",institutionString:"King Saud University",institution:{name:"King Saud University",country:{name:"Saudi Arabia"}}},{id:"49848",title:"Dr.",name:"Wen-Long",middleName:null,surname:"Hu",slug:"wen-long-hu",fullName:"Wen-Long Hu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/49848/images/system/49848.jpg",biography:"Wen-Long Hu is Chief of the Division of Acupuncture, Department of Chinese Medicine at Kaohsiung Chang Gung Memorial Hospital, as well as an adjunct associate professor at Fooyin University and Kaohsiung Medical University. Wen-Long is President of Taiwan Traditional Chinese Medicine Medical Association. He has 28 years of experience in clinical practice in laser acupuncture therapy and 34 years in acupuncture. He is an invited speaker for lectures and workshops in laser acupuncture at many symposiums held by medical associations. He owns the patent for herbal preparation and producing, and for the supercritical fluid-treated needle. Dr. Hu has published three books, 12 book chapters, and more than 30 papers in reputed journals, besides serving as an editorial board member of repute.",institutionString:"Kaohsiung Chang Gung Memorial Hospital",institution:{name:"Kaohsiung Chang Gung Memorial Hospital",country:{name:"Taiwan"}}},{id:"298472",title:"Prof.",name:"Andrey V.",middleName:null,surname:"Grechko",slug:"andrey-v.-grechko",fullName:"Andrey V. Grechko",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/298472/images/system/298472.png",biography:"Andrey Vyacheslavovich Grechko, Ph.D., Professor, is a Corresponding Member of the Russian Academy of Sciences. He graduated from the Semashko Moscow Medical Institute (Semashko National Research Institute of Public Health) with a degree in Medicine (1998), the Clinical Department of Dermatovenerology (2000), and received a second higher education in Psychology (2009). Professor A.V. Grechko held the position of Сhief Physician of the Central Clinical Hospital in Moscow. He worked as a professor at the faculty and was engaged in scientific research at the Medical University. Starting in 2013, he has been the initiator of the creation of the Federal Scientific and Clinical Center for Intensive Care and Rehabilitology, Moscow, Russian Federation, where he also serves as Director since 2015. He has many years of experience in research and teaching in various fields of medicine, is an author/co-author of more than 200 scientific publications, 13 patents, 15 medical books/chapters, including Chapter in Book «Metabolomics», IntechOpen, 2020 «Metabolomic Discovery of Microbiota Dysfunction as the Cause of Pathology».",institutionString:"Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology",institution:null},{id:"199461",title:"Prof.",name:"Natalia V.",middleName:null,surname:"Beloborodova",slug:"natalia-v.-beloborodova",fullName:"Natalia V. Beloborodova",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/199461/images/system/199461.jpg",biography:'Natalia Vladimirovna Beloborodova was educated at the Pirogov Russian National Research Medical University, with a degree in pediatrics in 1980, a Ph.D. in 1987, and a specialization in Clinical Microbiology from First Moscow State Medical University in 2004. She has been a Professor since 1996. Currently, she is the Head of the Laboratory of Metabolism, a division of the Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology, Moscow, Russian Federation. N.V. Beloborodova has many years of clinical experience in the field of intensive care and surgery. She studies infectious complications and sepsis. She initiated a series of interdisciplinary clinical and experimental studies based on the concept of integrating human metabolism and its microbiota. Her scientific achievements are widely known: she is the recipient of the Marie E. Coates Award \\"Best lecturer-scientist\\" Gustafsson Fund, Karolinska Institutes, Stockholm, Sweden, and the International Sepsis Forum Award, Pasteur Institute, Paris, France (2014), etc. Professor N.V. Beloborodova wrote 210 papers, five books, 10 chapters and has edited four books.',institutionString:"Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology",institution:null},{id:"354260",title:"Ph.D.",name:"Tércio Elyan",middleName:"Azevedo",surname:"Azevedo Martins",slug:"tercio-elyan-azevedo-martins",fullName:"Tércio Elyan Azevedo Martins",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/354260/images/16241_n.jpg",biography:"Graduated in Pharmacy from the Federal University of Ceará with the modality in Industrial Pharmacy, Specialist in Production and Control of Medicines from the University of São Paulo (USP), Master in Pharmaceuticals and Medicines from the University of São Paulo (USP) and Doctor of Science in the program of Pharmaceuticals and Medicines by the University of São Paulo. Professor at Universidade Paulista (UNIP) in the areas of chemistry, cosmetology and trichology. Assistant Coordinator of the Higher Course in Aesthetic and Cosmetic Technology at Universidade Paulista Campus Chácara Santo Antônio. Experience in the Pharmacy area, with emphasis on Pharmacotechnics, Pharmaceutical Technology, Research and Development of Cosmetics, acting mainly on topics such as cosmetology, antioxidant activity, aesthetics, photoprotection, cyclodextrin and thermal analysis.",institutionString:null,institution:{name:"University of Sao Paulo",country:{name:"Brazil"}}},{id:"334285",title:"Ph.D. Student",name:"Sameer",middleName:"Kumar",surname:"Jagirdar",slug:"sameer-jagirdar",fullName:"Sameer Jagirdar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/334285/images/14691_n.jpg",biography:"I\\'m a graduate student at the center for biosystems science and engineering at the Indian Institute of Science, Bangalore, India. I am interested in studying host-pathogen interactions at the biomaterial interface.",institutionString:null,institution:{name:"Indian Institute of Science Bangalore",country:{name:"India"}}},{id:"329248",title:"Dr.",name:"Md. Faheem",middleName:null,surname:"Haider",slug:"md.-faheem-haider",fullName:"Md. Faheem Haider",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/329248/images/system/329248.jpg",biography:"Dr. Md. Faheem Haider completed his BPharm in 2012 at Integral University, Lucknow, India. In 2014, he completed his MPharm with specialization in Pharmaceutics at Babasaheb Bhimrao Ambedkar University, Lucknow, India. He received his Ph.D. degree from Jamia Hamdard University, New Delhi, India, in 2018. He was selected for the GPAT six times and his best All India Rank was 34. Currently, he is an assistant professor at Integral University. Previously he was an assistant professor at IIMT University, Meerut, India. He has experience teaching DPharm, Pharm.D, BPharm, and MPharm students. He has more than five publications in reputed journals to his credit. Dr. Faheem’s research area is the development and characterization of nanoformulation for the delivery of drugs to various organs.",institutionString:"Integral University",institution:{name:"Integral University",country:{name:"India"}}},{id:"329795",title:"Dr.",name:"Mohd Aftab",middleName:"Aftab",surname:"Siddiqui",slug:"mohd-aftab-siddiqui",fullName:"Mohd Aftab Siddiqui",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/329795/images/system/329795.png",biography:"Dr. Mohd Aftab Siddiqui is an assistant professor in the Faculty of Pharmacy, Integral University, Lucknow, India, where he obtained a Ph.D. in Pharmacology in 2020. He also obtained a BPharm and MPharm from the same university in 2013 and 2015, respectively. His area of research is the pharmacological screening of herbal drugs/natural products in liver cancer and cardiac diseases. He is a member of many professional bodies and has guided many MPharm and PharmD research projects. Dr. Siddiqui has many national and international publications and one German patent to his credit.",institutionString:"Integral University",institution:null},{id:"255360",title:"Dr.",name:"Usama",middleName:null,surname:"Ahmad",slug:"usama-ahmad",fullName:"Usama Ahmad",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/255360/images/system/255360.png",biography:"Dr. Usama Ahmad holds a specialization in Pharmaceutics from Amity University, Lucknow, India. He received his Ph.D. from Integral University, Lucknow, India, with his work titled ‘Development and evaluation of silymarin nanoformulation for hepatic carcinoma’. Currently, he is an Assistant Professor of Pharmaceutics, at the Faculty of Pharmacy, Integral University. He has been teaching PharmD, BPharm, and MPharm students and conducting research in the novel drug delivery domain. From 2013 to 2014 he worked on a research project funded by SERB-DST, Government of India. He has a rich publication record with more than twenty-four original journal articles, two edited books, four book chapters, and several scientific articles to his credit. He is a member of the American Association for Cancer Research, the International Association for the Study of Lung Cancer, and the British Society for Nanomedicine. Dr. Ahmad’s research focus is on the development of nanoformulations to facilitate the delivery of drugs.",institutionString:"Integral University",institution:{name:"Integral University",country:{name:"India"}}},{id:"333824",title:"Dr.",name:"Ahmad Farouk",middleName:null,surname:"Musa",slug:"ahmad-farouk-musa",fullName:"Ahmad Farouk Musa",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/333824/images/22684_n.jpg",biography:"Dato’ Dr Ahmad Farouk Musa\nMD, MMED (Surgery) (Mal), Fellowship in Cardiothoracic Surgery (Monash Health, Aust), Graduate Certificate in Higher Education (Aust), Academy of Medicine (Mal)\n\n\n\nDato’ Dr Ahmad Farouk Musa obtained his Doctor of Medicine from USM in 1992. He then obtained his Master of Medicine in Surgery from the same university in the year 2000 before subspecialising in Cardiothoracic Surgery at Institut Jantung Negara (IJN), Kuala Lumpur from 2002 until 2005. He then completed his Fellowship in Cardiothoracic Surgery at Monash Health, Melbourne, Australia in 2008. He has served in the Malaysian army as a Medical Officer with the rank of Captain upon completing his Internship before joining USM as a trainee lecturer. He is now serving as an academic and researcher at Monash University Malaysia. He is a life-member of the Malaysian Association of Thoracic & Cardiovascular Surgery (MATCVS) and a committee member of the MATCVS Database. He is also a life-member of the College of Surgeons, Academy of Medicine of Malaysia; a life-member of Malaysian Medical Association (MMA), and a life-member of Islamic Medical Association of Malaysia (IMAM). Recently he was appointed as an Interim Chairperson of Examination & Assessment Subcommittee of the UiTM-IJN Cardiothoracic Surgery Postgraduate Program. As an academic, he has published numerous research papers and book chapters. He has also been appointed to review many scientific manuscripts by established journals such as the British Medical Journal (BMJ). He has presented his research works at numerous local and international conferences such as the European Association for Cardiothoracic Surgery (EACTS) and the European Society of Cardiovascular Surgery (ESCVS), to name a few. He has also won many awards for his research presentations at meetings and conferences like the prestigious International Invention, Innovation & Technology Exhibition (ITEX); Design, Research and Innovation Exhibition, the National Conference on Medical Sciences and the Annual Scientific Meetings of the Malaysian Association for Thoracic and Cardiovascular Surgery. He was awarded the Darjah Setia Pangkuan Negeri (DSPN) by the Governor of Penang in July, 2015.",institutionString:null,institution:{name:"Monash University Malaysia",country:{name:"Malaysia"}}},{id:"30568",title:"Prof.",name:"Madhu",middleName:null,surname:"Khullar",slug:"madhu-khullar",fullName:"Madhu Khullar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/30568/images/system/30568.jpg",biography:"Dr. Madhu Khullar is a Professor of Experimental Medicine and Biotechnology at the Post Graduate Institute of Medical Education and Research, Chandigarh, India. She completed her Post Doctorate in hypertension research at the Henry Ford Hospital, Detroit, USA in 1985. She is an editor and reviewer of several international journals, and a fellow and member of several cardiovascular research societies. Dr. Khullar has a keen research interest in genetics of hypertension, and is currently studying pharmacogenetics of hypertension.",institutionString:"Post Graduate Institute of Medical Education and Research",institution:{name:"Post Graduate Institute of Medical Education and Research",country:{name:"India"}}},{id:"223233",title:"Prof.",name:"Xianquan",middleName:null,surname:"Zhan",slug:"xianquan-zhan",fullName:"Xianquan Zhan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/223233/images/system/223233.png",biography:"Xianquan Zhan received his MD and Ph.D. in Preventive Medicine at West China University of Medical Sciences. He received his post-doctoral training in oncology and cancer proteomics at the Central South University, China, and the University of Tennessee Health Science Center (UTHSC), USA. He worked at UTHSC and the Cleveland Clinic in 2001–2012 and achieved the rank of associate professor at UTHSC. Currently, he is a full professor at Central South University and Shandong First Medical University, and an advisor to MS/PhD students and postdoctoral fellows. He is also a fellow of the Royal Society of Medicine and European Association for Predictive Preventive Personalized Medicine (EPMA), a national representative of EPMA, and a member of the American Society of Clinical Oncology (ASCO) and the American Association for the Advancement of Sciences (AAAS). He is also the editor in chief of International Journal of Chronic Diseases & Therapy, an associate editor of EPMA Journal, Frontiers in Endocrinology, and BMC Medical Genomics, and a guest editor of Mass Spectrometry Reviews, Frontiers in Endocrinology, EPMA Journal, and Oxidative Medicine and Cellular Longevity. He has published more than 148 articles, 28 book chapters, 6 books, and 2 US patents in the field of clinical proteomics and biomarkers.",institutionString:"Shandong First Medical University",institution:{name:"Affiliated Hospital of Shandong Academy of Medical Sciences",country:{name:"China"}}}]}},subseries:{item:{id:"26",type:"subseries",title:"Machine Learning and Data Mining",keywords:"Intelligent Systems, Machine Learning, Data Science, Data Mining, Artificial Intelligence",scope:"The scope of machine learning and data mining is immense and is growing every day. It has become a massive part of our daily lives, making predictions based on experience, making this a fascinating area that solves problems that otherwise would not be possible or easy to solve. This topic aims to encompass algorithms that learn from experience (supervised and unsupervised), improve their performance over time and enable machines to make data-driven decisions. 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In recent years, the application of chemistry to biological molecules has gained significant interest in medicinal and pharmacological studies. This topic will be devoted to understanding the interplay between biomolecules and chemical compounds, their structure and function, and their potential applications in related fields. Being a part of the biochemistry discipline, the ideas and concepts that have emerged from Chemical Biology have affected other related areas. This topic will closely deal with all emerging trends in this discipline.",annualVolume:11411,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/15.jpg",editor:{id:"441442",title:"Dr.",name:"Şükrü",middleName:null,surname:"Beydemir",fullName:"Şükrü Beydemir",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00003GsUoIQAV/Profile_Picture_1634557147521",institutionString:null,institution:{name:"Anadolu University",institutionURL:null,country:{name:"Turkey"}}},editorTwo:{id:"13652",title:"Prof.",name:"Deniz",middleName:null,surname:"Ekinci",fullName:"Deniz Ekinci",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYLT1QAO/Profile_Picture_1634557223079",institutionString:null,institution:{name:"Ondokuz Mayıs University",institutionURL:null,country:{name:"Turkey"}}},editorThree:null,editorialBoard:[{id:"219081",title:"Dr.",name:"Abdulsamed",middleName:null,surname:"Kükürt",fullName:"Abdulsamed Kükürt",profilePictureURL:"https://mts.intechopen.com/storage/users/219081/images/system/219081.png",institutionString:null,institution:{name:"Kafkas University",institutionURL:null,country:{name:"Turkey"}}},{id:"241413",title:"Dr.",name:"Azhar",middleName:null,surname:"Rasul",fullName:"Azhar Rasul",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRT1oQAG/Profile_Picture_1635251978933",institutionString:null,institution:{name:"Government College University, Faisalabad",institutionURL:null,country:{name:"Pakistan"}}},{id:"178316",title:"Ph.D.",name:"Sergey",middleName:null,surname:"Sedykh",fullName:"Sergey Sedykh",profilePictureURL:"https://mts.intechopen.com/storage/users/178316/images/system/178316.jfif",institutionString:null,institution:{name:"Novosibirsk State University",institutionURL:null,country:{name:"Russia"}}}]},{id:"17",title:"Metabolism",keywords:"Biomolecules Metabolism, Energy Metabolism, Metabolic Pathways, Key Metabolic Enzymes, Metabolic Adaptation",scope:"Metabolism is frequently defined in biochemistry textbooks as the overall process that allows living systems to acquire and use the free energy they need for their vital functions or the chemical processes that occur within a living organism to maintain life. Behind these definitions are hidden all the aspects of normal and pathological functioning of all processes that the topic ‘Metabolism’ will cover within the Biochemistry Series. Thus all studies on metabolism will be considered for publication.",annualVolume:11413,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/17.jpg",editor:{id:"138626",title:"Dr.",name:"Yannis",middleName:null,surname:"Karamanos",fullName:"Yannis Karamanos",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002g6Jv2QAE/Profile_Picture_1629356660984",institutionString:null,institution:{name:"Artois University",institutionURL:null,country:{name:"France"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"243049",title:"Dr.",name:"Anca",middleName:null,surname:"Pantea Stoian",fullName:"Anca Pantea Stoian",profilePictureURL:"https://mts.intechopen.com/storage/users/243049/images/system/243049.jpg",institutionString:null,institution:{name:"Carol Davila University of Medicine and Pharmacy",institutionURL:null,country:{name:"Romania"}}},{id:"203824",title:"Dr.",name:"Attilio",middleName:null,surname:"Rigotti",fullName:"Attilio Rigotti",profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institutionString:null,institution:{name:"Pontifical Catholic University of Chile",institutionURL:null,country:{name:"Chile"}}},{id:"300470",title:"Dr.",name:"Yanfei (Jacob)",middleName:null,surname:"Qi",fullName:"Yanfei (Jacob) Qi",profilePictureURL:"https://mts.intechopen.com/storage/users/300470/images/system/300470.jpg",institutionString:null,institution:{name:"Centenary Institute of Cancer Medicine and Cell Biology",institutionURL:null,country:{name:"Australia"}}}]},{id:"18",title:"Proteomics",keywords:"Mono- and Two-Dimensional Gel Electrophoresis (1-and 2-DE), Liquid Chromatography (LC), Mass Spectrometry/Tandem Mass Spectrometry (MS; MS/MS), Proteins",scope:"With the recognition that the human genome cannot provide answers to the etiology of a disorder, changes in the proteins expressed by a genome became a focus in research. Thus proteomics, an area of research that detects all protein forms expressed in an organism, including splice isoforms and post-translational modifications, is more suitable than genomics for a comprehensive understanding of the biochemical processes that govern life. The most common proteomics applications are currently in the clinical field for the identification, in a variety of biological matrices, of biomarkers for diagnosis and therapeutic intervention of disorders. From the comparison of proteomic profiles of control and disease or different physiological states, which may emerge, changes in protein expression can provide new insights into the roles played by some proteins in human pathologies. Understanding how proteins function and interact with each other is another goal of proteomics that makes this approach even more intriguing. Specialized technology and expertise are required to assess the proteome of any biological sample. Currently, proteomics relies mainly on mass spectrometry (MS) combined with electrophoretic (1 or 2-DE-MS) and/or chromatographic techniques (LC-MS/MS). MS is an excellent tool that has gained popularity in proteomics because of its ability to gather a complex body of information such as cataloging protein expression, identifying protein modification sites, and defining protein interactions. The Proteomics topic aims to attract contributions on all aspects of MS-based proteomics that, by pushing the boundaries of MS capabilities, may address biological problems that have not been resolved yet.",annualVolume:11414,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/18.jpg",editor:{id:"200689",title:"Prof.",name:"Paolo",middleName:null,surname:"Iadarola",fullName:"Paolo Iadarola",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSCl8QAG/Profile_Picture_1623568118342",institutionString:null,institution:{name:"University of Pavia",institutionURL:null,country:{name:"Italy"}}},editorTwo:{id:"201414",title:"Dr.",name:"Simona",middleName:null,surname:"Viglio",fullName:"Simona Viglio",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRKDHQA4/Profile_Picture_1630402531487",institutionString:null,institution:{name:"University of Pavia",institutionURL:null,country:{name:"Italy"}}},editorThree:null,editorialBoard:[{id:"72288",title:"Dr.",name:"Arli Aditya",middleName:null,surname:"Parikesit",fullName:"Arli Aditya Parikesit",profilePictureURL:"https://mts.intechopen.com/storage/users/72288/images/system/72288.jpg",institutionString:null,institution:{name:"Indonesia International Institute for Life Sciences",institutionURL:null,country:{name:"Indonesia"}}},{id:"40928",title:"Dr.",name:"Cesar",middleName:null,surname:"Lopez-Camarillo",fullName:"Cesar Lopez-Camarillo",profilePictureURL:"https://mts.intechopen.com/storage/users/40928/images/3884_n.png",institutionString:null,institution:{name:"Universidad Autónoma de la Ciudad de México",institutionURL:null,country:{name:"Mexico"}}},{id:"81926",title:"Dr.",name:"Shymaa",middleName:null,surname:"Enany",fullName:"Shymaa Enany",profilePictureURL:"https://mts.intechopen.com/storage/users/81926/images/system/81926.png",institutionString:"Suez Canal University",institution:{name:"Suez Canal University",institutionURL:null,country:{name:"Egypt"}}}]}]}},libraryRecommendation:{success:null,errors:{},institutions:[]},route:{name:"profile.detail",path:"/profiles/15165",hash:"",query:{},params:{id:"15165"},fullPath:"/profiles/15165",meta:{},from:{name:null,path:"/",hash:"",query:{},params:{},fullPath:"/",meta:{}}}},function(){var e;(e=document.currentScript||document.scripts[document.scripts.length-1]).parentNode.removeChild(e)}()