The most common extrahepatic manifestations of chronic hepatitis C according to organ system involvement.
\r\n\tThis book intends to provide the reader with a comprehensive overview of the current state-of-the-art novel imaging techniques by focusing on the most important evidence-based developments in this area.
",isbn:null,printIsbn:null,pdfIsbn:null,doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,isSalesforceBook:!1,isNomenclature:!1,hash:"d9159ce31733bf78cc2a79b18c225994",bookSignature:"Dr. Gabriel Cismaru",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11867.jpg",keywords:"Hypertrophic Cardiomyopathy, Dilated Cardiomyopathy, Restrictive Cardiomyopathy, Transesophageal Echocardiography, Intracardiac Echocardiography, 3-Dimensional Echocardiography, Adult Congenital Heart Disease, Tetralogy of Fallot, Transposition of the Great Vessels, Coronary Artery Disease, Risk Stratification, Revascularization",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"April 21st 2022",dateEndSecondStepPublish:"May 19th 2022",dateEndThirdStepPublish:"July 18th 2022",dateEndFourthStepPublish:"October 6th 2022",dateEndFifthStepPublish:"December 5th 2022",dateConfirmationOfParticipation:null,remainingDaysToSecondStep:"3 months",secondStepPassed:!0,areRegistrationsClosed:!0,currentStepOfPublishingProcess:4,editedByType:null,kuFlag:!1,biosketch:"Dr. Cismaru Gabriel is an Assistant Professor at the University of Medicine and Pharmacy Cluj-Napoca, certified in Cardiology. After completing his certification in cardiology, Dr. Cismaru began his electrophysiology fellowship at the Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu. He has authored or co-authored peer-reviewed articles and book chapters in the field of cardiac pacing, defibrillation, electrophysiological study, and catheter ablation.",coeditorOneBiosketch:"Raluca Tomoaia is an MD, Ph.D. in novel techniques in Echocardiography at the University of Medicine and Pharmacy in Cluj-Napoca, Romania., assistant professor, and a researcher in echocardiography and cardiovascular imaging.",coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"191888",title:"Dr.",name:"Gabriel",middleName:null,surname:"Cismaru",slug:"gabriel-cismaru",fullName:"Gabriel Cismaru",profilePictureURL:"https://mts.intechopen.com/storage/users/191888/images/system/191888.png",biography:"Dr. Cismaru Gabriel is an assistant professor at the Cluj-Napoca University of Medicine and Pharmacy, Romania, where he has been qualified in cardiology since 2011. He obtained his Ph.D. in medicine with a research thesis on electrophysiology and pro-arrhythmic drugs in 2016. Dr. Cismaru began his electrophysiology fellowship at the Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu, France, after finishing his cardiology certification with stages in Clermont-Ferrand and Dinan, France. He began working at the Rehabilitation Hospital\\'s Electrophysiology Laboratory in Cluj-Napoca in 2011. He is an experienced operator who can implant pacemakers, CRTs, and ICDs, as well as perform catheter ablation of supraventricular and ventricular arrhythmias such as ventricular tachycardia and ventricular fibrillation. He has been qualified in pediatric cardiology since 2022, and he regularly performs device implantation and catheter ablation in children. 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Hematopoietic | Essential mixed cryoglobulinemiaMonoclonal gammopathyB-cell non-Hodgkin lymphoma |
Skin | Leukocytoclastic vasculitisPorphyria cutanea tardaLichen planus |
Kidneys | Membranoproliferative glomerulonephritisMembranous nephropathyRenal impairment |
Immunological | Autoimmune antibodies: rheumatoid factor, antinuclear, antithyroid, anticardiolipin, anti-smooth muscle antibodies |
Thyroid | ThyroiditisHypothyroidismHyperthyroidism |
Endocrine and exocrine glands | Type 2 diabetes mellitusSicca syndrome |
Musculoskeletal | Arthralgia/myalgia |
Neurological and neuropsychiatric disorders | FatigueDepressionImpaired cognitive functionSensory or sensorimotor polyneuropathyMononeuritis multiplex |
Cardiovascular | Accelerated atherosclerosisIncreased rate of cardiovascular and neurovascular incident and peripheral artery diseaseIncreased mortality from cardiovascular and neurovascular incidents |
The most common extrahepatic manifestations of chronic hepatitis C according to organ system involvement.
Autoimmune mechanism | Proliferative effect | Inflammatory/metabolic | Other mechanism |
---|---|---|---|
Autoantibodies | Essential mixed cryoglobulinemia | Insulin resistance and diabetes mellitus | Porphyria cutanea tarda |
Thyroiditis | Monoclonal gammopathy | Fatigue/malaise | |
Hepatitis | Non-Hodgkin lymphoma | Depression | |
Sicca syndrome | Cognitive function damage | ||
Arthralgia/myalgia | Cardiovascular disease (coronary disease, stroke) |
Proposed pathogenetic mechanism through which chronic HCV infection leads to extrahepatic manifestations.
Essential mixed cryoglobulinemia or type II cryoglobulinemia is classified into the group of lymphoproliferative disorders in which clonal B lymphocyte expansion leads to immunoglobulin production—polyclonal immunoglobulin (Ig) G class and monoclonal IgM as rheumatoid factor (RF)—leading to development of immune complexes that precipitate in the cold and are therefore called cryoglobulins. As a consequence of the precipitation of cryoglobulin complexes in small- and middle-sized blood vessels, the occurring complement activation leads to endothelial damage and cryoglobulinemic vasculitis [5]. The syndrome can affect blood vessels in different organs and manifest on the skin, large joints, peripheral nerves, or kidneys. Cryoglobulins are present in about 50% of patients with chronic hepatitis C infection, but do not always cause clinically manifest cryoglobulinemic vasculitis. On the other hand, over 90% of patients with essential mixed cryoglobulinemia have chronic hepatitis C infection. The skin is commonly affected in cryoglobulinemic syndrome manifesting as palpable purpura as a consequence of leukocytoclastic vasculitis [6]. Joint involvement manifests with arthralgias; perineural vasculitis is a cause of distal sensory or sensorimotor polyneuropathy, while kidney involvement most often leads to membranoproliferative glomerulonephritis with renal function impairment. Diagnosis is based on cryoglobulin presence, elevated RF, and immunofluorescence of complement fixing IgM in affected tissues. It is important to note that many studies have shown clinical manifestations of essential mixed cryoglobulinemia to withdraw after successful HCV infection treatment and that the presence of mixed cryoglobulinemia is associated with a reduced virological response rate [7]. Withdrawal of essential mixed cryoglobulinemia, with low recurrence levels, has been established earlier with interferon therapy, and recently some smaller scale studies showed a very good effect of combined direct-acting antiviral therapy (so-called “interferon-free” therapy) in cryoglobulin clearance, renal function improvement, and proteinuria reduction [8, 9]. The success rates seem to be lower than those observed in large registration studies, but the fact the treatment is new and that sample sizes were relatively small should be taken into account. It is important to highlight that, in some patients, interferon therapy can lead to the worsening of clinical manifestations and that in everyday practice optimal antiviral therapy with direct-acting antiviral drugs represents the standard of care for patients with clinically mild to moderate cryoglobulinemic vasculitis. In severe cases additional therapy modalities such as rituximab, corticosteroids, and plasmapheresis may be used before starting antiviral therapy. For refractory forms of cryoglobulinemia, cyclophosphamide and other immunosuppressants are sometimes used.
Hepatitis C virus is primarily hepatotropic, but it has also been shown to be lymphotropic, and a connection between chronic HCV infection and B-cell non-Hodgkin lymphoma (NHL) has been established [10, 11]. It is assumed that chronic B lymphocyte stimulation by the HCV antigen leads to monoclonal B-cell expansion present in mixed cryoglobulinemia. This seems to predispose to NHL occurrence, with studies showing increased risk relative to the general population [12]. In a retrospective study comparing untreated HCV-infected patients to those treated with interferon, it has been shown that the rates of malignant lymphoma occurrence (diffuse large cell lymphoma and follicular lymphoma) were significantly higher in untreated patients, as well as in those who did not achieve sustained virologic response (SVR), compared to those who were cured [13]. The importance of chronic HCV infection in lymphoma development was additionally confirmed with reports of successful NHL remission after HCV eradication. Results with new interferon-free therapies are so far only available as case reports but point to lymphoma withdrawal after hepatitis C eradication. It can be expected that the wide use of new therapies will show results in larger cohorts of patients.
There are studies suggesting HCV to be a risk factor for monoclonal gammopathies, but the results are inconsistent, and a routine screening of patients with chronic hepatitis C for monoclonal gammopathies is not recommended. In patients with HCV infection, polyclonal or oligoclonal hypergammaglobulinemia (mostly IgG) is present. The gamma globulin level often correlates with disease severity on liver biopsy, and its decrease after successful HCV treatment has been noted.
Chronic hepatitis C infection is connected with glomerular disease which is most probably a consequence of immune complex deposition in glomerular capillaries. The most common form of kidney disease is membranoproliferative glomerulonephritis, typically connected with essential mixed cryoglobulinemia, while membranous nephropathy is less common [14, 15]. Other non-cryoglobulin-based renal diseases described in HCV-infected patients include IgA nephropathy, postinfectious glomerulonephritis, as well as focal and segmental glomerulosclerosis. Patients most often present with proteinuria and microhematuria with different degrees of renal impairment and with renal biopsy showing glomerular immune complex deposition. Acute nephrotic or nephritic syndrome with new onset of arterial hypertension is also possible. The Kidney Disease Improving Global Outcomes (KDIGO) guidelines thus recommend screening for renal impairment at the time of HCV infection diagnosis and then once a year by determining serum creatinine and performing urinalysis. All patients with chronic kidney disease should also be tested for HCV infection [16]. The existence of renal impairment, especially membranoproliferative glomerulonephritis, is an indication for HCV infection treatment. Until now the standard of treatment was combined interferon and ribavirin (with necessary precaution and kidney function-adjusted dosage), while rituximab, corticosteroids, or immunosuppressants are added in patients with severe cryoglobulinemic vasculitis. Data about the efficacy of new interferon-free therapies in this indication is only available from studies involving a relatively small number of patients, but it can be expected that it could significantly change the clinical presentation and improve treatment of this group of patients [8].
Porphyria cutanea tarda (PCT) is a disease caused by the reduced activity of the hepatic uroporphyrinogen decarboxylase (UROD) which leads to accumulation of uroporphyrinogen in the blood and urine and is the most common porphyria. PCT can be inherited (autosomal dominant) or acquired (sporadic), and exactly this form was connected with HCV infection in many studies. Meta-analysis that included 50 studies and a total of 2167 patients with PCT showed that the prevalence of HCV infection was around 50%, while the frequency of PCT in patients with chronic HCV infection is about 1–5% [17]. The exact mechanism by which HCV can cause or induce PTC is not known, but it is presumed to be mediated through changes in iron metabolism. Namely, increased iron saturation, estrogens, and alcohol consumption can provoke or induce PCT. Skin changes develop as a consequence of photosensitivity and skin friability and, upon sun exposure and/or minor trauma, manifest as erythema and bullae which may turn hemorrhagic [18, 19]. In later stages hyperpigmentation, hypopigmentation, hirsutism, and sclerodermic changes can appear. In the liver, a spectrum of histological changes can be found, including steatosis, mild to severe inflammation, fibrosis, and cirrhosis. Diagnosis of PCT is made on the basis of clinical suspicion and is confirmed by measuring increased levels of porphyrin in urine and, if available, direct measurement of the UROD enzyme activity. Treatment consists of avoiding precipitating factors (sun, alcohol, estrogens) and, if necessary, lowering iron overload (venipuncture) as well as treating HCV infection in affected patients. In general, treatment of chronic HCV infection leads to the normalization of UROD enzymatic activity, levels of liver aminotransferase and urine porphyrin, as well as disappearance of skin changes.
Lichen planus is a chronic inflammatory disease of the skin and mucosa which can affect hair and nails and is characterized by pruritic papulae. These most often appear on the skin of extremities, face, scalp, nails, and mucosa of the gastrointestinal and genitourinary tract. Lichen planus occurs in various chronic liver diseases, and anti-HCV antibodies can be found in 10–40% of patients with lichen planus [20]. It is assumed that the occurrence of lichen planus is immunologically mediated, but the exact mechanism is unknown. It is also considered a premalignant condition and is known to progress to squamous cell carcinoma. The treatment of HCV infection with interferon therapy did not result in regression of lichen planus in most studies; on the contrary, there are reports of appearance or exacerbation of lichen planus during interferon therapy. A recent case series involving seven patients with oral lichen planus treated with interferon-free protocols showed an improvement of symptoms without adverse events [21].
Leukocytoclastic vasculitis is associated with essential mixed cryoglobulinemia and is a consequence of blood vessel involvement. It is clinically characterized by palpable pruritic changes and petechiae which usually affect lower extremities and is treated as other manifestations of essential cryoglobulinemia.
Necrolytic acral erythema, a condition characterized by painful, pruritic, and erythematous skin lesions of extremities is reported to be strongly associated with chronic HCV infection. Zinc supplementation has been associated with improvement of the condition.
Some data supports a possible connection of chronic HCV infection with chronic pruritus, while sporadic reports also suggest an association of HCV infection with psoriasis, chronic urticaria, pyoderma gangrenosum, erythema nodosum, and erythema multiforme.
Mooren’s corneal ulcer represents a rare painful peripheral corneal ulceration, usually without accompanying scleritis. Some studies have made a connection between this rare form of corneal ulcer and chronic HCV infection, but the pathogenetic mechanism is not known [22]. Chronic HCV infection has been linked to other diseases of the eye such as sicca syndrome, keratitis, increased intraocular pressure, and episcleritis, while some disorders such as retinal bleeding, vision impairment, as well as rare cases of retinal artery or vein obstruction have been described as possible complications of interferon therapy.
Thyroid disorders are relatively frequent in patients with chronic hepatitis C, especially in women. Antithyroid antibodies are, according to various reports, present in 5–17% (averaging at 10%) of patients with HCV infection, while thyroid diseases (mostly hypothyroidism) occur less often, in 2–13% of patients [23]. Thyroid function disorders appear even more often during interferon therapy, probably as a consequence of autoimmune activity precipitated by immunomodulatory therapy, but can persist even after treatment completion. There is some evidence of a possible HCV infection of thyroid tissue causing a local inflammatory response that might trigger the autoimmune process. In any case, determining thyroid hormones as well as anti-thyroglobulin and antithyroid peroxidase antibodies is necessary in all HCV-infected patients, especially before and periodically during interferon therapy. Substitution therapy with thyroid hormones is used in hypothyroidism treatment. In cases of mild hyperthyroidism, symptomatic therapy is used, while thyrostatic therapy is reserved for more severe cases. Interferon therapy should be stopped in cases of severe hyperthyroidism caused by the treatment. It will be interesting to see how the eradication of HCV infection with new drug combinations without interferon affects thyroid function disorders in patients with chronic hepatitis C.
The sicca syndrome develops in most patients with Sjögren’s syndrome. Lymphocytic sialadenitis resembling Sjögren’s syndrome has been described in patients with chronic HCV infection who complain of mouth or eye dryness in 20–30% of cases [15]. There are, however, histological (milder, mostly pericapillary lymphocytic infiltration without ductal destruction in HCV infection as opposed to periductal infiltration with destruction of excretory ducts in classic Sjögren’s syndrome) and clinical differences (less pronounced symptoms, later onset, increased levels of serum cryoglobulin and RF, lower complement levels, positive antinuclear, and negative Ro/La antibodies). Therefore, it seems that HCV does not cause Sjögren’s syndrome but rather symptoms that imitate it [14]. Treatment of chronic HCV infection leads to symptom resolution in patients with the sicca syndrome.
Various autoantibodies are frequently found in patients with chronic HCV infection. Rheumatoid factor (around 60%) is most often present followed by antinuclear antibodies (ANA, around 40%), antithyroid (35%), anticardiolipin (15%), and anti-smooth muscle antibodies (ASMA, around 7%), respectively. These antibodies appear in about one-half of patients with chronic HCV infection (40–65% according to different studies) but are commonly present in low titer and, for the most part, do not seem to affect the clinical course of the disease [1]. Antibodies to liver and kidney microsomes (anti-LKM-1) and actin are an exception and can be of clinical significance in some HCV-infected patients. These antibodies are usually characteristic for autoimmune hepatitis, and it has been noticed that, although patients with hepatitis C and anti-LKM-1 antibodies mostly benefit from interferon therapy, in some cases an increase in liver function tests can be observed. Some of these patients respond well to standard therapy for autoimmune hepatitis which consists of azathioprine and corticosteroids. Determining the primary cause of hepatitis in patients with overlapping HCV infection and autoantibodies can be very challenging, even though it has been shown that anti-LKM-1 antibodies in these patients are directed against different epitopes of cytochrome P450 2D6 compared to patients with autoimmune hepatitis [24]. Even though there are no recommendations for routinely determining the presence of these antibodies, if they are known to be present, greater caution during interferon therapy is recommended. The role of direct-acting antiviral drugs in these patients is yet to be determined.
Numerous studies have shown a connection between HCV infection and immune thrombocytopenic purpura (ITP) and/or hemolytic anemia, whether as a consequence of the infection itself or of interferon therapy. According to the results of one of the largest studies, it seems that chronic HCV infection is associated with a higher frequency of ITP in both treated and untreated patients, while increased risk of autoimmune hemolytic anemia was only present in patients treated with interferon therapy.
Arthralgia is common and reported by 40–80% of patients with chronic hepatitis C [1]. The joints are usually symmetrically affected, mostly knees and hands. The afflicted joints are painful, without deformities. True arthritis is rare, presenting as rheumatoid like arthritis in two-thirds and oligoarthritis in one-third of patients. Rheumatoid factor is present in 70–80% of patients with mixed essential cryoglobulinemia, but its presence does not correlate with joint affection [15]. Likewise, cyclic citrulline antibodies characteristic for rheumatoid arthritis are usually not present. Myalgia is also a common complaint. According to epidemiological studies, chronic HCV infection is associated with reduced bone mineral density and increased risk of fractures. The mechanism is probably linked to chronic inflammation and liver disease. Hepatitis C-associated osteosclerosis, mostly reported in patients with a history of intravenous drug abuse, is an uncommon disorder characterized by an increase in bone mass during adulthood. The increased bone turnover in periosteal, endosteal, and trabecular bone leads to the thickening of the skeleton and may respond to bisphosphonate or calcitonin therapy.
Neurological manifestations of HCV infection can vary from central nervous system (CNS) involvement to peripheral neuropathy including sensorimotor neuropathy and mononeuritis multiplex. Evidence of CNS involvement includes the demonstration of HCV RNA in brain tissue and cerebrospinal fluid suggesting active replication and as well as a possible association of HCV infection and small vessel cerebrovascular disease [25–27]. The most common form of nerve involvement is distal sensory or sensorimotor polyneuropathy, which clinically presents with painful, asymmetric paresthesia, while multiple mononeuropathy occurs rarely [15]. These changes are a consequence of vasculitis, sometimes associated with cryoglobulinemia, involving vasa nervorum.
In a recently published study, chronic HCV infection has been linked to Parkinson’s disease [28].
Neurocognitive damages can manifest with a wide array of neuropsychiatric conditions, such as tiredness, depression, and lack of concentration and working memory, of which patients with chronic HCV infection often complain. These disorders are often seen and intertwined with other associated additions, such as chronic liver disease, cirrhosis, the use of drugs, and others. Some studies have managed to show that these neurocognitive damages are a consequence of the HCV infection itself, regardless of comorbidities [29]. Functional imaging methods have shown metabolic changes in brains of chronic hepatitis C patients, with improvement of cognitive function and brain metabolism observed after treating the HCV infection [30]. Some of these disorders such as depression and fatigue are important because they can exacerbate under interferon therapy. This is why it is important to perform mental status evaluation at the beginning and during this therapy, so as to be able to timely act with suitable psychiatric support, antidepressants, and anxiolytics. Fatigue, depression, and cognitive damage significantly impair functional ability (at work and at home) and impact the quality of life of patients with chronic HCV infection, while the eradication of the virus positively correlates with an improvement in quality of life.
Disturbed glucose metabolism, onset of insulin resistance (IR), and type 2 diabetes mellitus (T2DM) are often associated with chronic HCV infection. A meta-analysis of 34 studies confirmed a positive correlation between HCV infection and risk of T2DM, which is 1.7 times greater than the general population and notably increased compared to chronic hepatitis B patients [31]. It appears that the risk of T2DM in patients with chronic HCV infection is increased in patients with risk factors such as older age, obesity, advanced liver fibrosis, and a family history of diabetes [32]. Likewise, results of multiple studies have shown that successful eradication of HCV infection decreases IR and that the risk of T2DM is decreased in patients who achieved SVR [33]. Multiple studies have confirmed an association between the HCV infection and IR development that can be present without manifest T2DM. Experimental studies have shown that HCV causes significant changes in the lipid and glucose metabolism and that it leads to IR in the liver and peripheral tissue through direct (immediate influence of HCV proteins on intracellular insulin signal pathways) and indirect (the influence of TNF-α and other cytokines on the development of peripheral IR) mechanisms. Insulin resistance causes a series of changes in lipid and lipoprotein metabolism and leads to the development of liver steatosis [34]. Clinical implications of HCV-induced IR, besides T2DM development, include a worse response to interferon therapy, accelerated fibrosis and development of cirrhosis, increased risk of hepatocellular carcinoma, as well as increased cardiovascular morbidity and mortality [35].
Chronic HCV infection has been associated with accelerated atherosclerosis [36]. Risk of early carotid artery atherosclerosis (determined by intima-media thickness measurement) was four times greater in HCV patients than noninfected patients [14, 37]. In several cohorts of HCV-positive patients, increased cardiovascular mortality (1.5–25 times) as well as a higher incidence of cerebrovascular and acute coronary syndromes was noted [38]. Besides coronary and cerebrovascular disease, an increased rate of peripheral arterial disease in patients with a chronic HCV infection has been described. Rates of acute coronary syndrome and ischemic stroke were significantly reduced in patients treated with peginterferon and ribavirin compared to untreated patients [39]. Although this association was found in studies originating from Far East countries, Western European and American studies, as well as a recent meta-analysis, have not established a clear correlation of HCV infection and increased cardiovascular and cerebrovascular risk [40, 41]. Likewise, the pathogenetic mechanism through which HCV leads to accelerated atherosclerosis has not been fully elucidated. There is evidence of HCV RNA presence in carotid plaques and endothelial cells in the brain, and it is possible that local infection leads to tissue damage, but atherosclerosis is more probably a consequence of the aforementioned IR, metabolism disturbance, and proinflammatory cytokine action. Many unsolved questions leave space for further research, and the arrival of new therapies opens new possibilities in treating patients with an expected decrease in cardiovascular morbidity and mortality.
Pulmonary fibrosis is a disease characterized by interstitial inflammation with focal fibroblast proliferation and collagen deposits leading to fibrosis, which clinically commonly manifests as dyspnea on exertion and nonproductive cough. The disease pathogenesis is unknown, and several studies have found a connection between pulmonary fibrosis and chronic HCV infection. A higher prevalence of pulmonary fibrosis was seen in HCV-infected patients than control groups, and vice versa, a group of patients with diagnosed idiopathic pulmonary fibrosis had an increased anti-HCV positivity rate (25%) [38].
Myasthenia gravis was associated with HCV infection in case reports only, and a clear link has not been established. Cases of this disease developing during interferon treatment have been described, but it is assumed that these cases were in fact exacerbations of subclinical disease precipitated by immunomodulatory therapy.
Chronic hepatitis C infection (HCV) is a systemic disease which, besides the liver as its primary target, affects a number of other organs and organ systems. So far more than 30 different conditions have been associated with chronic HCV infection. In general, the appearance of extrahepatic manifestations of HCV infection is unpredictable, that is, independent of the stage of the liver disease. A clear association with chronic hepatitis C has been established for many of these conditions, while, for some diseases, good-quality evidence linking them to HCV infection is still missing.
Considering the appearance of new direct-acting antiviral therapies that offer an excellent prospect for cure of infected patients, although at a relatively high expense, the practice in Croatia, as well as in many economically limited countries, is to set treatment priorities, so as to sooner treat the patients that need it most. Taking this into regard, patients with established extrahepatic manifestations of HCV infection have priority in receiving treatment, regardless of the stage of their liver disease, as stated in the latest guidelines.
For example, patients with essential mixed cryoglobulinemia and its skin (leukocytoclastic vasculitis), kidney (membranoproliferative glomerulonephritis or membranous nephropathy, renal failure), or nerve (neuropathy) manifestations, as well as patients with non-Hodgkin lymphoma, porphyria cutanea tarda, and some other more rare autoimmune disease manifestations, will benefit from treatment not only by eradicating HCV but also in treating the extrahepatic manifestation and its sometimes very debilitating symptoms.
It can be expected, and recent studies show promising results, that new therapies without interferon which greatly improve therapeutic success with fewer adverse effects will prove especially beneficial in patients with immunologically mediated extrahepatic manifestations.
The heart is composed of a special tissue and a unique electrical system. Though there are some hypotheses about the possibility of regeneration, the cardiac tissue is composed of non-regenerative muscle cells called myocytes which have the capacity to revert acute damages before necrosis and subsequent fibrosis are present. It is thought that this reversion could be related to multiple factors. A decrease in inflammatory markers, perfusion recovery, and possible RNA reactions reduce the fiber tension and inflammation that cause the shortening of the dilated fibers, and then the transient condition will improve. All reversible cardiomyopathies can be associated with cardiomegaly, systolic heart failure, structural changes, and an increase in mortality, but when the offensive agent is identified and stopped, these conditions tend to stop their progression and reverse. In a period of 6 weeks, we are usually able to evaluate positive results after the stunning myocardial cells recover. Most patients with reversible cardiomyopathy present with clinical picture similar to that of systolic heart failure (HF) as follows:
Dyspnea
Chest discomfort/pain
Lower extremity edema or peripheral edema
Weight gain
Orthopnea or paroxysmal nocturnal dyspnea (PND)
Decrease in exercise tolerance etc.
In this chapter, we have focused on important types of reversible cardiomyopathy (Figure 1).
Different types of reversible cardiomyopathy.
Cardiomyopathy includes a diverse and heterogeneous group of disorders affecting the myocardium and eventually leading to cardiac dysfunction [1]. The HF is a widely prevalent syndrome today and affects 5.1 million adult Americans over the age of 20 [1]. Cardiomyopathy is the leading cause of hospitalization in patients older than 65 years of age and it is an important cause for enormous healthcare expenditure. Interestingly, ischemic cardiomyopathy is responsible for about half of these patients. On the other hand, the prevalence of reversible nonischemic cardiomyopathy is also significant, as per several large clinical trials, and ranges from 20–50% [1]. The prognosis of reversible nonischemic cardiomyopathies is better than ischemic or other nonreversible cardiomyopathies which were suggested by the epidemiological evidence [1]. Additionally, it is important to diagnose etiology of HF early and precisely to determine prognosis and effective treatment.
Arrhythmia-induced cardiomyopathy (also known as tachycardia-induced cardiomyopathy, tachycardia-mediated cardiomyopathy, or tachymyopathy) is one of the reversible causes of dilated cardiomyopathy. Arrhythmia-induced cardiomyopathy is defined by the presence of a sustained tachycardia (or frequent episodes of tachycardia or very frequent ectopy) which results in left ventricular (LV) systolic dysfunction. It is a relatively rare, but well-recognized entity caused by long-standing tachycardia, which can be treated readily in most instances and have a good prognosis. A common clinical problem is differentiating whether tachycardia is the primary cause of the patient’s cardiomyopathy, or if the tachycardia is secondary to another cardiomyopathy of a different etiology. Arrhythmia-induced cardiomyopathy has been reported with nearly all types of tachyarrhythmia and frequent ectopy, both supraventricular and ventricular [2]. Different types of tachyarrhythmias associated with arrhythmia-induced cardiomyopathy include atrial fibrillation (AF), atrial flutter, atrial tachycardia, reentrant supraventricular tachycardias, and ventricular tachycardia. Regardless of the type of arrhythmia, therapy to restore normal sinus rhythm or to slow the ventricular rate (or eliminate ectopy) usually result in an improvement in left ventricular function.
The incidence of arrhythmia-induced cardiomyopathy is unclear, but an association between tachycardia and cardiomyopathy is well known. An insight into the prevalence of arrhythmia-induced cardiomyopathy can be derived from cohort studies. In one study of 1269 patients undergoing ablation for atrial flutter, 184 had reduced ejection fractions (<40 percent) at baseline [3]. In another study with a cohort of 625 patients undergoing catheter ablation for a variety of tachyarrhythmias, tachycardia-induced cardiomyopathy was present in 2.7 percent (17 of 625 patients) [4]. Similarly, in one cohort of 331 patients who had catheter ablation of incessant atrial tachycardia (AT), myocardial dysfunction was present in 9 percent of patients [5]. Additionally, the patients in the cohort with arrhythmia-induced cardiomyopathy were younger, predominantly male, and had continuous or very frequent paroxysmal tachycardia.
In general, chronic tachycardia eventually causes significant structural changes in the heart, including left ventricular dilatation and cellular morphologic changes. However, the exact mechanism by which tachycardia produces such changes is not well explained. Additionally, the morphologic and biochemical changes that result from arrhythmia-induced cardiomyopathy may produce electrophysiological abnormalities. Chronic tachycardia was associated with ventricular arrhythmias (including polymorphic ventricular tachycardia and sudden death) in a canine model which result from a prolongation in repolarization [6]. Many alterations in neurohumoral and cellular activation have been described in arrhythmia-induced cardiomyopathy patients, and several factors may contribute to the development of rate-related myocardial dysfunction. However, data supporting certain potential mechanisms are lacking, and it remains unclear whether such changes play an etiologic role or if they arise because of tachycardia.
The clinical presentation of arrhythmia-induced cardiomyopathy can vary and usually involves signs and/or symptoms related to HF (dyspnea, fatigue, orthopnea, PND, chest pain or discomfort, lower extremities edema), cardiac tachyarrhythmias (palpitations, lightheadedness, dizziness, anxiety, etc) or both. The approach to the patient with suspected arrhythmia-induced cardiomyopathy includes a thorough history and physical examination with appropriately selected tests to establish the diagnosis and assess acuity, severity, and etiology. All patients should have an electrocardiogram (ECG) to determine the cardiac rhythm and ventricular heart rate (Figure 2). There are no specific ECG findings that distinguish patients with and without arrhythmia-induced cardiomyopathy, and the ECG findings will vary depending upon the underlying tachyarrhythmia. It is important to determine which is the primary pathology, the arrhythmia, or the cardiomyopathy. Usually, the diagnosis of arrhythmia-induced cardiomyopathy can only be made after a successful trial of therapy to slow down the ventricular rate or to restore sinus rhythm after excluding the other potential causes of cardiomyopathy. Patients with suspected arrhythmia-induced cardiomyopathy should have continuous cardiac monitoring for 24 to 48 hours and have non-invasive imaging to assess cardiac structure and function. A transthoracic echocardiogram (TTE) is the preferred modality for assessing cardiac structure and function for most patients due to its widespread availability and ease of performance. However, cardiac magnetic resonance (CMR) imaging is also a reasonable alternative approach in centers with expertise in this modality.
ECG showing Atrial flutter that can lead to tachycardia-induced cardiomyopathy.
The initial treatments for a patient with HF and suspected arrhythmia-induced cardiomyopathy are similar to those of HF with reduced ejection fraction (HFrEF) and tachyarrhythmias. Treatment of HFrEF generally includes the use of angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), angiotensin receptor-neprilysin inhibitor (ARNI), beta-blockers, or diuretics. On the other hand, treatment of tachyarrhythmia includes rate-control medications, consideration of antiarrhythmic drugs, and/or cardioversion. Aggressive efforts should be made to achieve good ventricular heart rate control or to restore sinus rhythm due to the potentially reversible nature of arrhythmia-induced cardiomyopathy [2]. Additionally, an adequate trial of medical therapy is required before evaluating the patient for the need for cardiac resynchronization therapy (CRT) or an implantable cardioverter-defibrillator (ICD).
Following the restoration of sinus rhythm or appropriate ventricular rate control, most patients show significant improvement and/or normalization of left ventricular ejection fraction (LVEF) over a period of months. Generally, patients who have not experienced sudden cardiac arrest or sustained ventricular arrhythmia and whose LVEF has improved to 40% or greater, do not require implantation of an ICD. If arrhythmia-induced cardiomyopathy recurs, then these patients are at substantial risk for sudden death and ICD implantation should be considered. In some patients, the LV chamber may remain somewhat enlarged even after LVEF has normalized. Patients will also have ultrastructural abnormalities of the myocardium, despite improvement in cardiac function when a tachycardia has been terminated or rate controlled [7].
Long-term excess alcohol consumption is a leading cause of secondary dilated cardiomyopathy and is associated with up to 40% of dilated cardiomyopathy. Alcohol use can cause atrial enlargement, global chamber dilation, cardiomegaly, and heart failure. Once the structural changes are present, patients with alcoholic cardiomyopathy are at high risk for arrhythmias, especially atrial fibrillation (AF). The prevalence of alcoholic cardiomyopathy is similar in men and women; however, there is a higher disease burden in men. It is more common in the age group of 45–59 years old. Most patients who develop alcoholic cardiomyopathy have been drinking more than 80 to 90 g of ethanol per day for more than five years. This corresponds to approximately eight bottles of beer, one liter of wine, or one-half pint of hard liquor every day. The pathogenesis of alcoholic cardiomyopathy is not well understood, but experimental data have suggested that alcohol consumption may directly or indirectly cause oxidative stress, apoptosis, impaired mitochondrial bioenergetics, altered fatty acid metabolism, and increased myocardial protein catabolism via its metabolites. The pathophysiology of alcoholic cardiomyopathy can also be explained by myocardial toxicity due to adenosine accumulation caused by the impairment of ATP production secondary to thiamine deficiency (Thiamine serves as a co-factor for ATP production).
Common clinical features include classic symptoms of HF (dyspnea, fatigue, orthopnea, PND, chest pain or discomfort, lower extremities edema) and cardiac arrhythmias (palpitations, lightheadedness, dizziness, anxiety, etc). Patients may have a normal physical exam but can also have findings of heart failure such as the decreased intensity of the heart sounds, new S3 or S4 gallop, new murmurs due to valvular insufficiency, increased jugular venous pressure, hepatojugular reflux, and peripheral edema. An EKG usually does not show any specific findings, but may show atrial fibrillation, atrial enlargement, or left ventricular hypertrophy as the most common findings. The mainstay of treatment is abstinence from alcohol which can help in reversing the disease and management of HF. Thus, prognosis in such patients is usually good if they continue to avoid alcohol. If the patient does not stop drinking alcohol, the alcoholic cardiomyopathy may cause severe HF and could advance to severe valvular insufficiency, fatal arrhythmias, and sudden cardiac death.
Myocarditis is a global cardiomyopathy that leads to acute chamber dilation. It is a major cause of death in young adults, reaching up to 20% of deaths. The incidence of myocarditis, according to the International Classification of Diseases’ diagnosis codes, was 22 patients per 100,000 patients in the 2013 world population. Myocarditis is an inflammatory disease of the heart that may occur because of infections, immune system activation, or exposure to drugs. The common causes include coxsackievirus (most common), Lyme disease, Chagas disease [8], rheumatic fever, toxic (monoxide, diphtheria, doxorubicin, daunorubicin, cocaine) [9, 10], autoimmune or systemic diseases (SLE, sclerosis, sarcoidosis) [11]. Most patients diagnosed with acute myocarditis recover without clinically relevant residual damage. Patients usually present with viral illness (Fever, malaise, fatigue, etc.) [12]. Patients can also present with symptoms of acute heart failure and conduction abnormalities (Premature atrial complex, supraventricular tachycardia, ventricular ectopies, bradyarrhythmia) including fatal arrhythmia (Ventricular tachycardia, fibrillation) leading to sudden cardiac death [13].
Common physical examination findings may include chest pain, new gallop, friction rub, or new valvular insufficiency on auscultation; hepatomegaly, cardiogenic shock, tachypnea with or without respiratory distress [14]. The ECG in some patients with myocarditis is similar to the ECG pattern of acute isolated pericarditis (which is suggestive of myopericarditis) or acute MI, myocarditis may be associated with regional ST elevations and Q waves like acute MI [15]. Laboratory tests can reveal elevated levels of troponin, pro-BNP, and CK-MB [16]. Echocardiography can be useful by showing wall motion abnormalities and acute valvular insufficiency [17].
Coronary angiography should be considered in patients when acute coronary syndrome (ACS) cannot be distinguished from the myocarditis clinically [18]. CMR is indicated in patients with suspected myocarditis with elevated troponin level and/or ventricular dysfunction, without a clear cause such as ischemic heart disease [19]. The definitive diagnosis of myocarditis can be made by endomyocardial biopsy (EMB). The need for an EMB should be based upon the likelihood that the results will change management. Histologic examination of EMB in myocarditis reveals cellular infiltrates, which are usually histiocytic and mononuclear with or without associated myocyte damage; specific histological forms of myocarditis include eosinophilic, granulomatous, and giant cell myocarditis. Possible late complications include severe valvulopathies, biventricular failure, and conduction abnormalities [20]. The mainstay treatment is to treat the underlying cause. Most patients with acute myocarditis have partial or full clinical recovery. In some cases, the process may continue subclinically which eventually causes DCM [21]. The likelihood of these late complications is increased in patients who present with greatly diminished left ventricular function.
Sepsis-induced cardiomyopathy is a reversible condition causing left ventricular dilation that could lead to low filling pressures and low ejection fraction. It usually starts to normalize within 10 days of treatment of underlying sepsis [22]. Sepsis-induced myocardial dysfunction is one of the major predictors of morbidity and mortality in sepsis [23]. It is usually present in more than 40% of cases of sepsis and its presence can increase the mortality rate up to 70% [24, 25]. The exact physiopathology is not completely understood but the role of cytokines and endotoxins is thought to have an important role in the myocardial depression found in this condition. Other factors that are also related are metabolic disturbances, hypoxia, coagulopathies, and oxygen deprivation leading to myocardial injury [26]. Another theory is the high consumption of oxygen by the mitochondria creating an energy imbalance. Pro-inflammatory factors from infectious agents cause a release of cytokines and endotoxins that accelerate the oxygen consumption in a low oxygen environment eventually leading to the production of e metabolites such as free radicals and nitrogen species [27]. These metabolites then create a toxic environment and a transient myocardial injury [28, 29]. Sepsis can also cause Takotsubo cardiomyopathy which is described separately.
The clinical features include fever, elevated WBCs, weakness, and malaise along with clinical features of HF. Physical exam findings may include rash, conjunctivitis, wounds, or evident infection. Patients may also present with hypotension, chest pain, or altered mental status. EKG usually does not show any specific findings, but may show findings suggestive of ACS due to underlying myocardial inflammation [30]. Laboratory tests may show elevated inflammatory markers, such as elevated C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), ferritin due to systemic inflammation [31]. Additionally, cardiac markers may be also elevated due to underlying myocardial injury [32, 33]. Furthermore, cultures should be obtained to identify the causative agent before starting a patient on antibiotics. The treatment mainly includes treatment of underlying sepsis and stabilization of the patient when they are hemodynamically unstable to avoid myocardial injury secondary to profound hypotension or arrhythmia. The prognosis of the patient usually varies depending on the severity of sepsis, but generally, the prognosis is reserved.
Stress cardiomyopathy is also known as Takotsubo cardiomyopathy or broken heart syndrome, and the clinical presentation mimics acute myocardial infarction [34]. This condition is most common in post-menopausal women. The possible reason for involvement in such a patient group could be explained by hypotheses demonstrating a potential protective effect of estrogen in stress CM [35, 36, 37]. The patient with such type of cardiomyopathy should be treated as ACS until the obstructive coronary disease is ruled out by coronary angiography. The pathophysiology behind stress cardiomyopathy is not well understood [38], but the possible mechanism can be explained by the sudden release of catecholamine (Norepinephrine, epinephrine, and dopamine) [39, 40] that causes cardiac stunning by myocyte perfusion impairment and lead to myocardial tissue edema, necrosis, and fibrosis [41].
The clinical features include anxiety, tachycardia, and chest pain which can mimic chest pain of acute MI. EKG may vary from ST segment elevation (most common finding), ST segment depression (less common), QT interval prolongation, T wave inversion, abnormal Q waves, and non-specific abnormalities. Serum cardiac troponin levels are elevated in most patients with stress CM, while creatine kinase (CK) levels are generally normal or mildly elevated. Furthermore, brain natriuretic peptide (BNP) or N-terminal pro-BNP (NT-proBNP) levels are elevated in most patients with stress CM. Radionuclide myocardial perfusion imaging is generally not indicated in patients presenting with suspected stress cardiomyopathy since most have high-risk features for ACS and will require coronary angiography. Patients with suspected non-ST elevation ACS with low to intermediate-risk features may undergo radionuclide myocardial perfusion imaging. An echocardiogram can show a decrease in LVEF and LV wall motion abnormalities (Figure 3). Patterns of LV wall motion abnormality in patients with stress-induced cardiomyopathy include the apical type (most common), and atypical variants including mid-ventricular, basal, focal (limited to an isolated segment), and global types. CMR may be helpful in the diagnosis and evaluation of stress cardiomyopathy when the echocardiogram is technically suboptimal and/or there is coexistent coronary artery disease. Late gadolinium enhancement (LGE) on CMR is usually absent in stress cardiomyopathy in contrast to MI in which intense subendocardial or transmural LGE is seen.
Doppler image showing LVOT obstruction in a patient with Takotsubo Cardiomyopathy.
Stress-induced cardiomyopathy is generally a reversible disorder that is managed with supportive therapy [42]. Rapid resolution of symptoms can be usually seen with conservative treatment and resolution of the physical or emotional stress. However, some patients may develop acute complications such as shock and acute HF that require intensive therapy. Appropriate management of shock varies and depends on whether significant left ventricular outflow tract (LVOT) obstruction is present [43]. HF management during an acute presentation and following stabilization is generally performed according to standard guidelines. However, caution should be performed to avoid volume depletion and with use of vasodilator therapy in patients with LVOT obstruction. Recommendations for anticoagulation to prevent thromboembolism in patients with stress cardiomyopathy with LV thrombus or severe LV systolic dysfunction are similar to those for post-MI patients [44, 45].
Peripartum cardiomyopathy is an important cause of dilated cardiomyopathy and HF. It is also known as pregnancy-associated cardiomyopathy [46]. The diagnosis can be missed due to the lack of regular screening and overlap between clinical signs or symptoms of HF signs or symptoms of the pregnancy [47]. Peripartum cardiomyopathy usually occurs during the last trimester or within the 6 months of the postpartum period. Several risk factors have been identified which include greater age, multiple gestations, African descent, and a history of preeclampsia, eclampsia, or postpartum hypertension. The pathophysiology is not clearly understood but Honigberg and Givertz suggested the possible role of oxidative stress on myocardium caused by elevated prolactin levels [48].
The clinical features of peripartum cardiomyopathy are usually masked by signs and symptoms of pregnancy and are difficult to diagnose solely based on clinical findings. Patients usually present with similar clinical presentation as HF patients (shortness of breath, fatigue, orthopnea, lower extremities pitting edema). An echocardiogram is the modality of choice for definitive diagnosis of peripartum cardiomyopathy and usually shows dilated cardiomyopathy with an impairment of the ejection fraction [49]. Echocardiogram generally reveals a global reduction in LV systolic function with LVEF nearly always <45 percent. Management is similar to the treatment of HF with reduced EF, such as ACE inhibitors or ARBs or ARNI, beta-blockers, and diuretics. In addition to this treatment, use of bromocriptine should also be considered [50]. However, prophylactic anticoagulation should always be considered along with bromocriptine treatment as thromboembolic events have been noticed during the use of bromocriptine [50]. Patients should get a repeat echocardiogram six weeks after diagnosis has been made for prognostication [51].
Metabolic cardiomyopathy is a secondary cardiomyopathy that results from disturbed energy production leading to impaired cardiac function. It may be caused by a myriad of endocrine disorders, nutritional deficiencies, and familial storage diseases [52]. Thyroid hormones have been shown to affect myocytes by acting on various thyroid hormone receptors in the myocardium, including a-myosin heavy chain fusion, sarcoplasmic reticulum calcium-activated ATPase (SERCA), the cellular membrane Na+/K+ pump (Na+/K+ ATPase), β-adrenergic receptors, cardiac troponin I, and atrial natriuretic peptide (ANP) [53]. These interactions help upregulate α-chains but downregulate β-chains in myocytes, which ultimately leads to faster myocardial fibril shortening [54]. Thyroid hormones have also been shown to affect the ion channels, including Na+/K+ ATPase, Na+/Ca + 2 exchanger, and various K+ channels by inducing positive inotropic effects, thereby prolonging activation of Na + channels and shortening action potential durations [55]. Additionally, thyroid hormones have been known to have a vasodilatory effect on peripheral arteries [56]. The combined effort of these mechanisms can cause systemic changes in cardiac function by reducing peripheral vascular resistance, activating the renin-angiotensin mechanism, increasing LV end-diastolic volume (LVEDV), and increasing preload [57]. The increased preload and decreased peripheral vascular resistance lead to a high cardiac output, even at rest, resulting in cardiomyopathy. In contrast to hyperthyroidism, hypothyroidism causes a low cardiac output cardiomyopathy via the same pathways mentioned above, however, by downregulating the previously mentioned receptors/channels causing decreased myocardial excitation and contractility leading to a low-output cardiomyopathy [58]. The clinical features are similar to those seen in patients with HF.
Management of thyroid disease-induced cardiomyopathy follows a similar algorithm to the cardiomyopathies mentioned above, which includes the typical HF treatment regimen. Management also includes addressing the root etiology, whether it be excess or deficiency of thyroid hormones. However, there is promising data showing that the use of β-adrenergic blockade may be beneficial in these patients. Biondi et al. conducted a small study which demonstrated that hyperthyroid patients treated with the selective β1-adrenoceptor antagonist bisoprolol experienced normalization of the LV mass index and LV systolic function after 6 months of treatment [59]. Similar results were established in a case study published a year later in which the use of β-adrenoceptor blockers showed clinical improvement in a patient with dilated cardiomyopathy caused by hyperthyroidism [60]. It is also worth mentioning the association between hyperthyroidism and AF. The prevalence of AF in thyrotoxicosis is estimated to be 13% according to one study. This is especially important as uncontrolled AF is associated with tachycardia-induced cardiomyopathy as discussed above [61, 62].
Obstructive sleep apnea (OSA) is a potentially life-threatening condition that is characterized by repeated cessation of breathing while sleeping mostly due to complete or partial pharyngeal obstruction [63]. There has been evidence supporting the associations between obstructive sleep apnea and cardiovascular morbidity and mortality. The National Commission on sleep disorders research estimated that sleep apnea is probably responsible for 38,000 cardiovascular deaths per year [64]. Also, obstructive sleep apnea increases the risk of coronary artery disease by 30%, heart failure by 140%, and stroke by 60% [65]. OSA can be identified by a combination of symptoms and laboratory results, such as repetitive apneas and hypopneas accompanied by hypoxia, sleep arousals, and hemodynamic changes [66, 67, 68, 69]. Furthermore, activation of the sympathetic nervous system during respiratory events potentiates vasoconstriction and often triggers increases in blood pressure and heart rate [67, 70]. OSA is also associated with several cardiorespiratory problems such as loud snoring, loud gasps, and daytime breathlessness [71, 72].
The underlying mechanisms showing the associations between OSA and cardiovascular disease are not completely understood, but several intermediate mechanisms have been proposed. They include sustained sympathetic activation, changes in intrathoracic pressure and oxidative stress, and later vascular inflammation caused by nocturnal hypoxia and reoxygenation cycles [73, 74]. These mechanisms then results in increases in systolic blood pressure that might eventually lead to hypertension or worsening of this condition. A similar mechanism might explain the link between OSA and tachyarrhythmia [75]; whereas bradyarrhythmia, which is more common than tachyarrhythmia, might be the effect of an increase in vagal tone due to stimulation of receptor sites in the upper airway [76]. Other abnormalities observed among patients with OSA such as disorders in coagulation factors, endothelial damage, platelet activation, and an increase in inflammatory mediators might also be involved in the pathogenesis of cardiovascular disease [74, 76, 77, 78, 79]. Patients with OSA have characteristically higher levels of endothelin and lower levels of nitric oxide than healthy sleepers [74, 77]. This increased endothelin level is known to impair blood pressure regulation as well. Thus, patients with OSA often experience greater blood vessel constriction. Interestingly, with continuous positive airway pressure (CPAP) treatment, levels of endothelin and circulating nitric oxide invariably return to normal [77].
Recently, research interests have centered on the relative contribution of oxidative stress in explaining the associations between sleep apnea and cardiovascular morbidity [74, 79, 80]. Investigators have proposed that hypoxia, which is commonly observed in sleep apnea, promotes the formation of reactive oxygen species (ROS), which could activate the transcriptional activator hypoxia-inducible factor 1 (HIF-1), particularly during the reoxygenation period [81, 82]. ROS regulates the activation of critical transcription factors that are redox-sensitive, resulting in increased expression of genes, which encode proteins promoting adaptation to hypoxia [81]. It has been suggested that redox-sensitive transcription factors, which elicit inflammatory pathways are also activated, thereby affecting inflammatory and immune responses by promoting activation of endothelial cells, leukocytes, and platelets [74]. These cells once activated can express adhesion molecules and proinflammatory cytokines that may lead to endothelial injury and dysfunction, which inevitably lead to the development of cardiovascular morbidity [74]. Observing this chain of events, investigators surmise that atherogenesis apparently starts soon after the onset of sleep apnea [74]. Substantial atherosclerotic insults are likely incurred by the time a diagnosis is rendered since symptoms often become apparent around the age of 45 years [74, 80]. It is unclear whether such atherogenic damages can be reversed, but treatment can retard their progress [83].
Using CPAP therapy, investigators have shown significant reductions in levels of C-reactive protein and interleukin-6 [83], and atherogenic plaque regression has been observed among patients with dyslipidemia [84]. Therefore, sleep apnea diagnosis and treatment should be made as early as possible in order to prevent cardiovascular morbidity. The use of CPAP or bilevel PAP therapy have showed positive benefits in clinical trials. This therapeutic modality is highly effective in improving left ventricular ejection fraction and quality of life by decreasing blood pressure and sympathetic activity and reducing mortality among patients with congestive heart failure [85, 86]. Additionally, CPAP treatment significantly reduces risks of ACS, cardiovascular death, and hospitalization for heart failure among patients with coronary artery disease [87]. Furthermore, CPAP therapy has significant effects on lipid levels. CPAP studies show significant improvement in insulin sensitivity and left ventricular function with a corresponding decrease in blood pressure [88].
Dilated cardiomyopathy can result from direct exposure to toxins, such as cocaine, alcohol, medications, particularly chemotherapeutic drugs, and radiation in the absence of abnormal underlying cardiovascular conditions such as hypertension, valvular disease, or coronary artery disease. The true prevalence of toxic cardiomyopathy in the general population is not known. The mechanism of toxic cardiomyopathy caused by some common toxic substances has been mentioned here. Alcoholic cardiomyopathy has been discussed separately. Patients with toxic cardiomyopathy usually present with clinical features similar to patients with systolic HF and the treatment involves the avoidance of toxic substances along with treatment for systolic HF.
Cocaine use is associated with the development of cardiomyopathy. However, the relationship is not well understood as compared to the relationship between cocaine use and coronary ischemia. Multiple mechanisms have been explained including the excessive sympathetic stimulation with increased myocardial oxygen consumption, direct toxic effect, and infectious cardiomyopathy in a parenteral cocaine user. In young persons, cardiomegaly with otherwise unexplained HF should raise the suspicion of cocaine abuse. Abstinence from cocaine usually leads to complete reversal of the myocardial dysfunction.
A number of medications such as anticancer drugs, anti-diabetic drugs, or antiretroviral drugs are associated with cardiomyopathy, and discontinuation of such drugs may result in significant improvement in cardiac function.
Anticancer drugs, such as anthracycline, trastuzumab, and cyclophosphamide are known to cause CM. Anthracycline-induced cardiomyopathy has been the most extensively studied. The mechanisms of anthracycline-induced cardiotoxicity are primarily due to its mechanisms of action as anticancer drugs which is inhibition of topoisomerase II β and DNA cleavage. Additionally, metabolic or oxidative stress factors may play a part, together with interference with iron metabolism. On the other hand, trastuzumab is a monoclonal antibody directed against the c-erbB-2 (HER2/neu) receptor that is used in the treatment of breast cancer. Since the HER2 signaling pathway plays an important role in cardiac development and protection, there is biological plausibility for cardiac toxicity with the use of trastuzumab [89, 90]. cardiomyopathy is also known to develop when a loss of function mutation occurs in HER2 in ventricular myocytes [91].
Antidiabetic medications such as thiazolidinedione class drugs are known to cause cardiotoxicity. The possible mechanisms of cardiotoxicity caused by these drugs include oxidative stress and interference with mitochondrial respiration. On the other hand, antiretroviral medications like azidothymidine are also cardiotoxic as a result of mitochondrial toxicity. Azidothymidine also increases the production of mitochondrial reactive oxygen species (ROS) in addition to energy depletion.
Methamphetamine and related compounds are the second most widely used illicit drug in the United States after cannabis [92]. Methamphetamine-associated cardiomyopathy (MACM) may be seen in chronic methamphetamine users. The primary mechanism of action of methamphetamine is the increased release and decreased uptake of catecholamines at the neuronal synapse producing a marked effect on the cardiovascular system [92]. The increased levels of catecholamines can stimulate alpha and beta-adrenergic receptors leading to hypertension and tachycardia. Methamphetamine can lead to irreversible structural and functional changes in the heart which eventually lead to decompensated heart failure and ultimately requiring heart transplantation.
Carbon monoxide (CO) exposure is known to cause cardiomyopathy by causing hypoxic injury. CO causes direct toxic damage to the mitochondria leading to an impairment of the mitochondrial respiratory chain at the cytochrome c oxidase level and a decrease of glutathione concentrations and ATP production. In survivors of an acute exposure, there is no evidence for a delayed dilated cardiomyopathy. In one retrospective study of 626 patients with CO exposure, only 3.04% (n = 19) patients had CO induced CM [93].
Trace elements are known to play an important role in myocardial metabolism and their accumulation (cobalt, arsenic) or deficiency (selenium) can be responsible for a form of dilated cardiomyopathy that is indistinguishable from an idiopathic CM. The role of trace elements was assessed in one study in which myocardial and skeletal muscle biopsies were obtained from 13 patients with an idiopathic DCM, 35 patients with valvular or ischemic heart disease, and 4 normal subjects [94]. Patients with a dilated cardiomyopathy had a significant increase in the myocardial concentration of mercury (22,000 times normal), antimony (12,000-fold higher), gold (11-fold higher), chromium (13-fold higher), and cobalt (4 times higher). On the other hand, patients with valvular or ischemic heart disease had myocardial concentrations of trace elements that were ≤ 5 times greater than normal. Concentrations of trace elements in skeletal muscle were normal in all groups of patients.
Cobalt-associated cardiomyopathy probably results from interference with energy production and contractile mechanisms. Cobalt associated cardiomyopathy has been reported in drinkers of beer containing cobalt sulfate for foam stabilization (known as Quebec beer-drinkers’ cardiomyopathy) [95], individuals with work-related cobalt exposure, and in some individuals exposed to cobalt from metal hip prostheses [96]. There have been some reported cases where degeneration of metallic hip implants can lead to cobalt cardiomyopathy [97, 98]. Antimony may cause lethal oxidative stress and cell death mediated by elevation in intracellular calcium. Proposed mechanisms for mercury toxicity include depletion of glutathione, ROS production and interruption in selenium-dependent endogenous enzymatic reactions. The existence of lithium-induced cardiomyopathy is still debated.
Cardiovascular diseases are the leading cause of morbidity and mortality in chronic kidney disease (CKD) patients [99]. These adverse cardiovascular consequences are due to CKD related cardiomyopathy, which is termed uremic cardiomyopathy [100]. Uremic cardiomyopathy in patients with CKD or end-stage renal disease (ESRD) is the result of pressure overload, volume overload, and the uremic state itself. Epidemiological studies and studies using cardiac MRI have suggested that the primary manifestation of uremic cardiomyopathy is LV hypertrophy (LVH). It is present even in patients with very early stages of CKD. The prevalence of LVH in pre-dialysis patients is up to 65%. The pathogenesis of uremic cardiomyopathy is poorly understood and is generally multifactorial. Patients with CKD usually continue to have abnormal myocardial remodeling despite improvements made to dialysis and advancements in the treatment of CKD, hypertension, hypervolemia, anemia. Two factors play an important role in the pathophysiology of patients with CKD and mineral and bone disease (CKD-MBD) which include the hormone FGF23, and its cofactor, αKlotho. FGF23 is deleterious to the myocardium, while αKlotho is protective. Although αKlotho is an obligatory cofactor for FGF23 action as the primary phosphaturic hormone in phosphorus homeostasis, both factors are seen to have independent and antagonistic effects on the myocardium. Briefly, the main pathophysiology of uremic cardiomyopathy includes a triad of hyperphosphatemia, αKlotho deficiency, and elevated FGF23 levels [100].
The cause for very high cardiovascular risk in CKD patients can be explained by effects of traditional and non-traditional cardiovascular risk factors which are augmented by sequelae of CKD, such as uremia, anemia, hypervolemia, oxidative stress, inflammation, and insulin resistance eventually leading to faster progression of cardiovascular disease and increasing the number of cardiovascular events and mortality [101]. About 40% of deaths in dialysis patients are due to sudden cardiac death (SCD) which outweighs deaths due to HF, acute myocardial infarction (MI), and stroke in such population [102]. The major reason for sudden cardiac death in patients with uremic cardiomyopathy is fatal arrhythmia which is in contrast to the general population where the most common reason for SCD is acute MI. The risk factors for adverse cardiovascular events in dialysis patients include anemia, high parathyroid hormone levels, hypo or hypercalcemia, hyperphosphatemia, fast electrolyte shift, chronic volume overload, inflammation, coronary artery disease, autonomic dysfunction, atrial fibrillation, heart failure with systolic dysfunction, and left ventricular hypertrophy (LVH) [103].
The clinical features in uremic cardiomyopathy patients are similar to that of HF patients such as dyspnea, orthopnea, fatigue, weakness, elevated jugular venous pressure, an S3 gallop, rales, and peripheral edema. ECG can show findings suggestive of LVH and may show nonspecific ischemic changes. Echocardiography may reveal LV systolic dysfunction, LV diastolic dysfunction, or valve dysfunction. Laboratory tests may show elevated natriuretic peptides and cardiac enzymes like other cardiomyopathies, but the interpretation of those tests is difficult in a patient with CKD or ESRD as these patients usually have elevated levels of cardiac biomarkers at baseline due to poor renal clearance. Thus, an entire clinical picture with lab tests, ECG findings, and echocardiogram findings should be taken to make a diagnosis of uremic cardiomyopathy.
Conventional hemodialysis is the main treatment for uremic cardiomyopathy, and it may cause regression of LVH. Hemodialysis is also known to reverse the systolic dysfunction and thus improve LVEF in some patients with ESRD. However, patients tend to continue to have cardiac dysfunction or uremic cardiomyopathy even while on hemodialysis treatment, thus conventional hemodialysis may not be adequate treatment despite being the treatment of choice. Renal transplantation has been shown to reverse uremic cardiomyopathy and to confer a significant survival advantage over hemodialysis [104]. Future therapies targeting the underlying cellular mechanisms of uremic cardiomyopathy may help to reduce the burden of uremic cardiomyopathy in the CKD and ESRD population. In a study on uremic mice, Rapamycin has been shown to reduce cardiac hypertrophy and fibrosis [105]. Thus, rapamycin has the potential to be an effective therapy for uremic cardiomyopathy. LVH is the early and pertinent manifestation of uremic cardiomyopathy as well as a powerful independent predictor of survival in CKD. The regression of LVH can reduce cardiovascular risk and improve survival.
Cirrhotic cardiomyopathy (CCM) is defined as a cardiac dysfunction in patients with cirrhosis, which is characterized by impaired contractile responsiveness to stress and/or altered diastolic relaxation, with electrophysiological abnormalities, in the absence of other known cardiac disorder [106, 107, 108]. For years CCM was confused with alcoholic cardiomyopathy, but in 1953, Kowalski and Abelmann demonstrated the existence of a circulatory dysfunction specific to liver cirrhosis [109]. Since then many experimental and clinical studies have established the existence of CCM different than alcoholic cardiomyopathy. Cirrhosis of the liver leads to a hyperdynamic circulatory state, which induces cardiac dysfunctions that characterize the CCM syndrome which includes a combination of systolic and diastolic dysfunctions, prolonged ventricular repolarization, and the inability of the sinus node to increase heart rate during exercise [108].
CCM is a condition in which patients usually remain asymptomatic for months to years as they have a near-normal cardiac function at rest and develop symptoms only under conditions of physical or pharmacological stress [110]. Thus, the diagnosis of CCM is challenging and the actual prevalence of this condition remains unknown. Pathogenesis of CCM includes mechanisms such as the increased activity of the vasodilator pathway through the actions of NO, cytokines, cannabinoids, carbon monoxide, and cytokines, decreased beta-adrenergic function, and sodium and calcium transport kinetics downregulation in the cardiac muscle which can lead to an impaired contractile function of the cardiomyocyte. CCM is generally a silent condition as patients at rest do not develop any signs or symptoms of heart failure as peripheral vasodilatation protects the heart by reducing afterload [108]. However, CCM should be suspected in patients with cirrhosis presenting with a decrease in exercise tolerance and HF symptoms in the absence of any other underlying heart disease.
Echocardiogram and ECG are the most important tests to diagnose CCM. ECG can reveal prolongation of QT interval in such patients. The most common echocardiography finding in such patients is first-degree diastolic dysfunction which is characterized by reduced early diastolic ventricular filling and increased atrial filling (E/A < 1.0), deceleration time > 200 ms, and prolonged isovolumetric relaxation time (ITVR >80 ms) representing increased resistance to ventricular inflow [111]. Stress echocardiography is also a useful method that should be used in patients with advanced liver disease as it can detect subtle systolic and diastolic dysfunctions before the ventricular ejection fraction is decreased [112]. Laboratory tests usually show elevated levels of troponin, atrial natriuretic peptide (ANP), and NT-proBNP. Additionally, CMR can also serve as a useful tool in the diagnosis of CCM. In patients with CCM, late gadolinium enhancement has a diffuse myocardial distribution in MR images with the appearance of myocarditis [113].
The treatment of CCM is similar to the treatment of HF in non-cirrhotic patients. However, reduction in afterload is not recommended in patients with advanced cirrhosis as these patients are already significantly dilated. However, in patients with final-stage liver disease and associated with CCM, liver transplantation is the only effective established treatment. Liver transplantation has been shown to reverse the systolic and diastolic dysfunction and prolonged QT interval [114, 115]. However, the unavailability of organ donors and cost concerns should be considered. The candidates must be well evaluated, as patients are at risk of death by HF, coronary artery disease, tachyarrhythmias, and other cardiac deaths in the post-operative term of liver transplantation. There is no accurate data on the prognosis for liver transplantation in patients with CCM. Patients with CCM should avoid physical effort and other forms of stress and should be provided with oxygen in some situations.
Reversible cardiomyopathies have been considered as one of the under diagnosed etiologies of non-ischemic cardiomyopathy that require careful clinical insight. Although reversible in nature but if remain undiagnosed, it can lead to catastrophic effects. It is hypothesized to have better prognosis compared to ischemic cardiomyopathy. Early diagnosis is warranted to guide efficient treatment. Further research regarding diagnostic and therapeutic algorithm for this subset of cardiomyopathy is needed to improve long term outcomes (Table 1).
Etiology of cardiomyopathy | Pathophysiology | Management |
---|---|---|
Myocarditis | Inflammation due to infectious agent, most commonly viral. | Natural course with recovery, no definitive treatment. Steroid may be used in Giant cell myocarditis |
Sepsis-induced | Not well understood. Probably reaction due to cytokines release. | Treatment of underlying infection. |
Alcoholic | High incidence of cardiomegaly. Toxicity mediated due to adenosine accumulation. | Alcohol cessation |
Peripartum | Most commonly in the last trimester. Could be misdiagnosed. Not clear mechanism. | Standard CHF treatment. Bromocriptine may be helpful |
Stress Induced | Known as Takotsubo Cardiomyopathy. Caused by sudden release of catecholamine due to stress. | Spontaneous recovery |
Tachycardia induced | Arrythmia such as atrial tachycardia and PVC induced | Arrythmia ablation |
Thyroid disease-induced | It is a part of Metabolic Cardiomyopathy. Caused by hyper or hypothyroidism. Could lead to arrhythmias especially atrial fibrillation. | Treatment of underlying condition |
Hypoventilation Related | Most commonly due to OSA. Could cause structure and hemodynamic changes. | Better prognosis if early intervention of the OSA before severe changes in the intracardiac pressures. |
Toxic | Could be cause by licit or ilicit agents that results cardiotoxic | Most of the times reversible once the agent is stopped. |
Summary of Reversible Cardiomyopathies.
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The Gram-positive pathogen is armed with battery of virulence factors that facilitate to establish infections in the hosts. The organism is well known for its ability to acquire resistance to various antibiotic classes. The emergence and spread of methicillin-resistant S. aureus (MRSA) strains which are often multi-drug resistant in hospitals and subsequently in community resulted in significant mortality and morbidity. The epidemiology of MRSA has been evolving since its initial outbreak which necessitates a comprehensive medical approach to tackle this pathogen. Vancomycin has been the drug of choice for years but its utility was challenged by the emergence of resistance. In the last 10 years or so, newer anti-MRSA antibiotics were approved for clinical use. However, being notorious for developing antibiotic resistance, there is a continuous need for exploring novel anti-MRSA agents from various sources including plants and evaluation of non-antibiotic approaches.",book:{id:"5471",slug:"frontiers-in-i-staphylococcus-aureus-i-",title:"Frontiers in Staphylococcus aureus",fullTitle:"Frontiers in Staphylococcus aureus"},signatures:"Arumugam Gnanamani, Periasamy Hariharan and Maneesh Paul-\nSatyaseela",authors:[{id:"192829",title:"Dr.",name:"Arumugam",middleName:null,surname:"Gnanamani",slug:"arumugam-gnanamani",fullName:"Arumugam Gnanamani"},{id:"204388",title:"Dr.",name:"Periasamy",middleName:null,surname:"Hariharan",slug:"periasamy-hariharan",fullName:"Periasamy Hariharan"},{id:"204389",title:"Dr.",name:"Maneesh",middleName:null,surname:"Paul-Satyaseela",slug:"maneesh-paul-satyaseela",fullName:"Maneesh Paul-Satyaseela"}]},{id:"32282",doi:"10.5772/33983",title:"Bacteriophages of Ralstonia solanacearum: Their Diversity and Utilization as Biocontrol Agents in Agriculture",slug:"bacteriophages-of-ralstonia-solanacearum-their-diversity-and-utilization-as-biocontrol-agents-in-agr",totalDownloads:3755,totalCrossrefCites:7,totalDimensionsCites:23,abstract:null,book:{id:"555",slug:"bacteriophages",title:"Bacteriophages",fullTitle:"Bacteriophages"},signatures:"Takashi Yamada",authors:[{id:"98151",title:"Dr.",name:"Takashi",middleName:null,surname:"Yamada",slug:"takashi-yamada",fullName:"Takashi Yamada"}]},{id:"32276",doi:"10.5772/34642",title:"Bacteriophages and Their Structural Organisation",slug:"bacteriophages-and-their-structural-organisation-",totalDownloads:12433,totalCrossrefCites:9,totalDimensionsCites:17,abstract:null,book:{id:"555",slug:"bacteriophages",title:"Bacteriophages",fullTitle:"Bacteriophages"},signatures:"E.V. 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Rezek",authors:[{id:"107471",title:"Dr.",name:"Egor",middleName:null,surname:"Ukraintsev",slug:"egor-ukraintsev",fullName:"Egor Ukraintsev"}]}],mostDownloadedChaptersLast30Days:[{id:"69731",title:"Isolation and Purification of Sulfate-Reducing Bacteria",slug:"isolation-and-purification-of-sulfate-reducing-bacteria",totalDownloads:1551,totalCrossrefCites:1,totalDimensionsCites:6,abstract:"Sulfate-reducing bacteria (SRB) are a widespread group of microorganisms that are often isolated from the anoxygenic environments (lake depths, soil, or swamps), and they are also present in the human and animal intestines. This group is often detected in patients with inflammatory bowel disease, including ulcerative colitis. That is why new rapid methods for their isolation, purification, and identification are important and necessary. In this chapter, the methods of mesophilic SRB isolation from various environments are described. Particular attention is paid to the purification of mesophilic SRB since they can be in close interaction with other microorganisms (Clostridium, Bacteroides, Pseudomonas, etc.), which are their frequent satellites. Moreover, the main methods of mesophilic SRB identification based on their morphological, physiological, biochemical, and genetical characteristics are presented.",book:{id:"8997",slug:"microorganisms",title:"Microorganisms",fullTitle:"Microorganisms"},signatures:"Ivan Kushkevych",authors:[{id:"252191",title:"Associate Prof.",name:"Ivan",middleName:null,surname:"Kushkevych",slug:"ivan-kushkevych",fullName:"Ivan Kushkevych"}]},{id:"65773",title:"Life Cycle of Trypanosoma cruzi in the Invertebrate and the Vertebrate Hosts",slug:"life-cycle-of-em-trypanosoma-cruzi-em-in-the-invertebrate-and-the-vertebrate-hosts",totalDownloads:1497,totalCrossrefCites:4,totalDimensionsCites:7,abstract:"Trypanosoma cruzi (T. cruzi) is a protozoan parasite that causes Chagas disease, a zoonotic disease that can be transmitted to humans by blood-sucking triatomine bugs. T. cruzi is a single-celled eukaryote with a complex life cycle alternating between reduviid bug invertebrate vectors and vertebrate hosts. This article will look at the developmental stages of T. cruzi in the invertebrate vector and the vertebrate hosts, the different surface membrane proteins involved in different life cycle stages of T. cruzi, roles of different amino acids in the life cycle, carbon and energy sources and gene expression in the life cycle of T. cruzi. The author will also look at extracellular vesicles (EV) and its role in the dissemination and survival of T. cruzi in mammalian host.",book:{id:"8806",slug:"biology-of-em-trypanosoma-cruzi-em-",title:"Biology of Trypanosoma cruzi",fullTitle:"Biology of Trypanosoma cruzi"},signatures:"Kenechukwu C. Onyekwelu",authors:[{id:"245368",title:"Dr.",name:"Kenechukwu C.",middleName:null,surname:"Onyekwelu",slug:"kenechukwu-c.-onyekwelu",fullName:"Kenechukwu C. Onyekwelu"}]},{id:"54154",title:"Staphylococcus aureus: Overview of Bacteriology, Clinical Diseases, Epidemiology, Antibiotic Resistance and Therapeutic Approach",slug:"staphylococcus-aureus-overview-of-bacteriology-clinical-diseases-epidemiology-antibiotic-resistance-",totalDownloads:7218,totalCrossrefCites:14,totalDimensionsCites:27,abstract:"Staphylococcus aureus is an important human pathogen that causes wide range of infectious conditions both in nosocomial and community settings. The Gram-positive pathogen is armed with battery of virulence factors that facilitate to establish infections in the hosts. The organism is well known for its ability to acquire resistance to various antibiotic classes. The emergence and spread of methicillin-resistant S. aureus (MRSA) strains which are often multi-drug resistant in hospitals and subsequently in community resulted in significant mortality and morbidity. The epidemiology of MRSA has been evolving since its initial outbreak which necessitates a comprehensive medical approach to tackle this pathogen. Vancomycin has been the drug of choice for years but its utility was challenged by the emergence of resistance. In the last 10 years or so, newer anti-MRSA antibiotics were approved for clinical use. However, being notorious for developing antibiotic resistance, there is a continuous need for exploring novel anti-MRSA agents from various sources including plants and evaluation of non-antibiotic approaches.",book:{id:"5471",slug:"frontiers-in-i-staphylococcus-aureus-i-",title:"Frontiers in Staphylococcus aureus",fullTitle:"Frontiers in Staphylococcus aureus"},signatures:"Arumugam Gnanamani, Periasamy Hariharan and Maneesh Paul-\nSatyaseela",authors:[{id:"192829",title:"Dr.",name:"Arumugam",middleName:null,surname:"Gnanamani",slug:"arumugam-gnanamani",fullName:"Arumugam Gnanamani"},{id:"204388",title:"Dr.",name:"Periasamy",middleName:null,surname:"Hariharan",slug:"periasamy-hariharan",fullName:"Periasamy Hariharan"},{id:"204389",title:"Dr.",name:"Maneesh",middleName:null,surname:"Paul-Satyaseela",slug:"maneesh-paul-satyaseela",fullName:"Maneesh Paul-Satyaseela"}]},{id:"55437",title:"Biological Control of Parasites",slug:"biological-control-of-parasites-2017-07",totalDownloads:4334,totalCrossrefCites:7,totalDimensionsCites:7,abstract:"Parasites (ectoparasites or endoparasites) are a major cause of diseases in man, his livestock and crops, leading to poor yield and great economic loss. To overcome some of the major limitations of chemical control methods such as rising resistance, environmental and health risks, and the adverse effect on non‐target organisms, biological control (biocontrol) is now at the forefront of parasite (pests) control. Biocontrol is now a core component of the integrated pest management. Biocontrol is defined as “the study and uses of parasites, predators and pathogens for the regulation of host (pest) densities”. Considerable successes have been achieved in the implementation of biocontrol strategies in the past. This chapter presents a review of the history of biocontrol, its advantages and disadvantages; the different types of biological control agents (BCAs) including predators, parasites (parasitoids) and pathogens (fungi, bacteria, viruses and virus‐like particles, protozoa and nematodes); the effect of biocontrol on native biodiversity; a few case studies of the successful implementation of biocontrol methods and the challenges encountered with the implementation of biocontrol and future perspectives.",book:{id:"5527",slug:"natural-remedies-in-the-fight-against-parasites",title:"Natural Remedies in the Fight Against Parasites",fullTitle:"Natural Remedies in the Fight Against Parasites"},signatures:"Tebit Emmanuel Kwenti",authors:[{id:"191763",title:"Dr.",name:"Tebit Emmanuel",middleName:null,surname:"Kwenti",slug:"tebit-emmanuel-kwenti",fullName:"Tebit Emmanuel Kwenti"}]},{id:"70336",title:"Plastics Polymers Degradation by Fungi",slug:"plastics-polymers-degradation-by-fungi",totalDownloads:1459,totalCrossrefCites:3,totalDimensionsCites:8,abstract:"The studies on plastic degradation are very important for the development of biodegradable plastics, and for reduction of pollution, since plastic waste can remain in the environment for decades or centuries. We have showed the degradation of oxo-biodegradable plastic bags and green polyethylene by Pleurotus ostreatus. This fungus can also produce mushrooms using these plastics. The plastic degradation was possibly by three reasons: (a) presence of pro-oxidant ions or plant polymer, (b) low specificity of the lignocellulolytic enzymes, and (c) the presence of endomycotic nitrogen-fixing microorganisms. In this chapter, the plastic bags’ degradation by abiotic and microbial process using the exposure to sunlight and the use of a white-rot fungus will described. The physical, chemical, and biological alterations of plastic were analyzed after each process of degradation. 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Radiotherapy and Nuclear Medicine Technology has always been my aspiration and my life. As years passed I accumulated a tremendous amount of skills and knowledge in Radiotherapy and Nuclear Medicine, Conventional Radiology, Radiation Protection, Bioinformatics Technology, PACS, Image processing, clinically and lecturing that will enable me to provide a valuable service to the community as a Researcher and Consultant in this field. My method of translating this into day to day in clinical practice is non-exhaustible and my habit of exchanging knowledge and expertise with others in those fields is the code and secret of success.",institutionString:null,institution:{name:"Majmaah University",country:{name:"Saudi Arabia"}}},{id:"313277",title:"Dr.",name:"Bartłomiej",middleName:null,surname:"Płaczek",slug:"bartlomiej-placzek",fullName:"Bartłomiej Płaczek",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/313277/images/system/313277.jpg",biography:"Bartłomiej Płaczek, MSc (2002), Ph.D. (2005), Habilitation (2016), is a professor at the University of Silesia, Institute of Computer Science, Poland, and an expert from the National Centre for Research and Development. His research interests include sensor networks, smart sensors, intelligent systems, and image processing with applications in healthcare and medicine. He is the author or co-author of more than seventy papers in peer-reviewed journals and conferences as well as the co-author of several books. He serves as a reviewer for many scientific journals, international conferences, and research foundations. Since 2010, Dr. Placzek has been a reviewer of grants and projects (including EU projects) in the field of information technologies.",institutionString:"University of Silesia",institution:{name:"University of Silesia",country:{name:"Poland"}}},{id:"35000",title:"Prof.",name:"Ulrich H.P",middleName:"H.P.",surname:"Fischer",slug:"ulrich-h.p-fischer",fullName:"Ulrich H.P Fischer",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/35000/images/3052_n.jpg",biography:"Academic and Professional Background\nUlrich H. P. has Diploma and PhD degrees in Physics from the Free University Berlin, Germany. He has been working on research positions in the Heinrich-Hertz-Institute in Germany. Several international research projects has been performed with European partners from France, Netherlands, Norway and the UK. He is currently Professor of Communications Systems at the Harz University of Applied Sciences, Germany.\n\nPublications and Publishing\nHe has edited one book, a special interest book about ‘Optoelectronic Packaging’ (VDE, Berlin, Germany), and has published over 100 papers and is owner of several international patents for WDM over POF key elements.\n\nKey Research and Consulting Interests\nUlrich’s research activity has always been related to Spectroscopy and Optical Communications Technology. Specific current interests include the validation of complex instruments, and the application of VR technology to the development and testing of measurement systems. He has been reviewer for several publications of the Optical Society of America\\'s including Photonics Technology Letters and Applied Optics.\n\nPersonal Interests\nThese include motor cycling in a very relaxed manner and performing martial arts.",institutionString:null,institution:{name:"Charité",country:{name:"Germany"}}},{id:"341622",title:"Ph.D.",name:"Eduardo",middleName:null,surname:"Rojas Alvarez",slug:"eduardo-rojas-alvarez",fullName:"Eduardo Rojas Alvarez",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/341622/images/15892_n.jpg",biography:null,institutionString:null,institution:{name:"University of Cuenca",country:{name:"Ecuador"}}},{id:"215610",title:"Prof.",name:"Muhammad",middleName:null,surname:"Sarfraz",slug:"muhammad-sarfraz",fullName:"Muhammad Sarfraz",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/215610/images/system/215610.jpeg",biography:"Muhammad Sarfraz is a professor in the Department of Information Science, Kuwait University. His research interests include computer graphics, computer vision, image processing, machine learning, pattern recognition, soft computing, data science, intelligent systems, information technology, and information systems. Prof. Sarfraz has been a keynote/invited speaker on various platforms around the globe. He has advised various students for their MSc and Ph.D. theses. He has published more than 400 publications as books, journal articles, and conference papers. He is a member of various professional societies and a chair and member of the International Advisory Committees and Organizing Committees of various international conferences. Prof. Sarfraz is also an editor-in-chief and editor of various international journals.",institutionString:"Kuwait University",institution:{name:"Kuwait University",country:{name:"Kuwait"}}},{id:"32650",title:"Prof.",name:"Lukas",middleName:"Willem",surname:"Snyman",slug:"lukas-snyman",fullName:"Lukas Snyman",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/32650/images/4136_n.jpg",biography:"Lukas Willem Snyman received his basic education at primary and high schools in South Africa, Eastern Cape. He enrolled at today's Nelson Metropolitan University and graduated from this university with a BSc in Physics and Mathematics, B.Sc Honors in Physics, MSc in Semiconductor Physics, and a Ph.D. in Semiconductor Physics in 1987. After his studies, he chose an academic career and devoted his energy to the teaching of physics to first, second, and third-year students. After positions as a lecturer at the University of Port Elizabeth, he accepted a position as Associate Professor at the University of Pretoria, South Africa.\r\n\r\nIn 1992, he motivates the concept of 'television and computer-based education” as means to reach large student numbers with only the best of teaching expertise and publishes an article on the concept in the SA Journal of Higher Education of 1993 (and later in 2003). The University of Pretoria subsequently approved a series of test projects on the concept with outreach to Mamelodi and Eerste Rust in 1993. In 1994, the University established a 'Unit for Telematic Education ' as a support section for multiple faculties at the University of Pretoria. In subsequent years, the concept of 'telematic education” subsequently becomes well established in academic circles in South Africa, grew in popularity, and is adopted by many universities and colleges throughout South Africa as a medium of enhancing education and training, as a method to reaching out to far out communities, and as a means to enhance study from the home environment.\r\n\r\nProfessor Snyman in subsequent years pursued research in semiconductor physics, semiconductor devices, microelectronics, and optoelectronics.\r\n\r\nIn 2000 he joined the TUT as a full professor. Here served for a period as head of the Department of Electronic Engineering. Here he makes contributions to solar energy development, microwave and optoelectronic device development, silicon photonics, as well as contributions to new mobile telecommunication systems and network planning in SA.\r\n\r\nCurrently, he teaches electronics and telecommunications at the TUT to audiences ranging from first-year students to Ph.D. level.\r\n\r\nFor his research in the field of 'Silicon Photonics” since 1990, he has published (as author and co-author) about thirty internationally reviewed articles in scientific journals, contributed to more than forty international conferences, about 25 South African provisional patents (as inventor and co-inventor), 8 PCT international patent applications until now. Of these, two USA patents applications, two European Patents, two Korean patents, and ten SA patents have been granted. A further 4 USA patents, 5 European patents, 3 Korean patents, 3 Chinese patents, and 3 Japanese patents are currently under consideration.\r\n\r\nRecently he has also published an extensive scholarly chapter in an internet open access book on 'Integrating Microphotonic Systems and MOEMS into standard Silicon CMOS Integrated circuitry”.\r\n\r\nFurthermore, Professor Snyman recently steered a new initiative at the TUT by introducing a 'Laboratory for Innovative Electronic Systems ' at the Department of Electrical Engineering. The model of this laboratory or center is to primarily combine outputs as achieved by high-level research with lower-level system development and entrepreneurship in a technical university environment. Students are allocated to projects at different levels with PhDs and Master students allocated to the generation of new knowledge and new technologies, while students at the diploma and Baccalaureus level are allocated to electronic systems development with a direct and a near application for application in industry or the commercial and public sectors in South Africa.\r\n\r\nProfessor Snyman received the WIRSAM Award of 1983 and the WIRSAM Award in 1985 in South Africa for best research papers by a young scientist at two international conferences on electron microscopy in South Africa. He subsequently received the SA Microelectronics Award for the best dissertation emanating from studies executed at a South African university in the field of Physics and Microelectronics in South Africa in 1987. In October of 2011, Professor Snyman received the prestigious Institutional Award for 'Innovator of the Year” for 2010 at the Tshwane University of Technology, South Africa. This award was based on the number of patents recognized and granted by local and international institutions as well as for his contributions concerning innovation at the TUT.",institutionString:null,institution:{name:"University of South Africa",country:{name:"South Africa"}}},{id:"317279",title:"Mr.",name:"Ali",middleName:"Usama",surname:"Syed",slug:"ali-syed",fullName:"Ali Syed",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/317279/images/16024_n.png",biography:"A creative, talented, and innovative young professional who is dedicated, well organized, and capable research fellow with two years of experience in graduate-level research, published in engineering journals and book, with related expertise in Bio-robotics, equally passionate about the aesthetics of the mechanical and electronic system, obtained expertise in the use of MS Office, MATLAB, SolidWorks, LabVIEW, Proteus, Fusion 360, having a grasp on python, C++ and assembly language, possess proven ability in acquiring research grants, previous appointments with social and educational societies with experience in administration, current affiliations with IEEE and Web of Science, a confident presenter at conferences and teacher in classrooms, able to explain complex information to audiences of all levels.",institutionString:null,institution:{name:"Air University",country:{name:"Pakistan"}}},{id:"75526",title:"Ph.D.",name:"Zihni Onur",middleName:null,surname:"Uygun",slug:"zihni-onur-uygun",fullName:"Zihni Onur Uygun",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/75526/images/12_n.jpg",biography:"My undergraduate education and my Master of Science educations at Ege University and at Çanakkale Onsekiz Mart University have given me a firm foundation in Biochemistry, Analytical Chemistry, Biosensors, Bioelectronics, Physical Chemistry and Medicine. After obtaining my degree as a MSc in analytical chemistry, I started working as a research assistant in Ege University Medical Faculty in 2014. In parallel, I enrolled to the MSc program at the Department of Medical Biochemistry at Ege University to gain deeper knowledge on medical and biochemical sciences as well as clinical chemistry in 2014. In my PhD I deeply researched on biosensors and bioelectronics and finished in 2020. Now I have eleven SCI-Expanded Index published papers, 6 international book chapters, referee assignments for different SCIE journals, one international patent pending, several international awards, projects and bursaries. In parallel to my research assistant position at Ege University Medical Faculty, Department of Medical Biochemistry, in April 2016, I also founded a Start-Up Company (Denosens Biotechnology LTD) by the support of The Scientific and Technological Research Council of Turkey. Currently, I am also working as a CEO in Denosens Biotechnology. The main purposes of the company, which carries out R&D as a research center, are to develop new generation biosensors and sensors for both point-of-care diagnostics; such as glucose, lactate, cholesterol and cancer biomarker detections. My specific experimental and instrumental skills are Biochemistry, Biosensor, Analytical Chemistry, Electrochemistry, Mobile phone based point-of-care diagnostic device, POCTs and Patient interface designs, HPLC, Tandem Mass Spectrometry, Spectrophotometry, ELISA.",institutionString:null,institution:{name:"Ege University",country:{name:"Turkey"}}},{id:"267434",title:"Dr.",name:"Rohit",middleName:null,surname:"Raja",slug:"rohit-raja",fullName:"Rohit Raja",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/267434/images/system/267434.jpg",biography:"Dr. Rohit Raja received Ph.D. in Computer Science and Engineering from Dr. CVRAMAN University in 2016. His main research interest includes Face recognition and Identification, Digital Image Processing, Signal Processing, and Networking. Presently he is working as Associate Professor in IT Department, Guru Ghasidas Vishwavidyalaya (A Central University), Bilaspur (CG), India. He has authored several Journal and Conference Papers. He has good Academics & Research experience in various areas of CSE and IT. He has filed and successfully published 27 Patents. He has received many time invitations to be a Guest at IEEE Conferences. He has published 100 research papers in various International/National Journals (including IEEE, Springer, etc.) and Proceedings of the reputed International/ National Conferences (including Springer and IEEE). He has been nominated to the board of editors/reviewers of many peer-reviewed and refereed Journals (including IEEE, Springer).",institutionString:"Guru Ghasidas Vishwavidyalaya",institution:{name:"Guru Ghasidas Vishwavidyalaya",country:{name:"India"}}},{id:"246502",title:"Dr.",name:"Jaya T.",middleName:"T",surname:"Varkey",slug:"jaya-t.-varkey",fullName:"Jaya T. Varkey",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/246502/images/11160_n.jpg",biography:"Jaya T. Varkey, PhD, graduated with a degree in Chemistry from Cochin University of Science and Technology, Kerala, India. She obtained a PhD in Chemistry from the School of Chemical Sciences, Mahatma Gandhi University, Kerala, India, and completed a post-doctoral fellowship at the University of Minnesota, USA. She is a research guide at Mahatma Gandhi University and Associate Professor in Chemistry, St. Teresa’s College, Kochi, Kerala, India.\nDr. Varkey received a National Young Scientist award from the Indian Science Congress (1995), a UGC Research award (2016–2018), an Indian National Science Academy (INSA) Visiting Scientist award (2018–2019), and a Best Innovative Faculty award from the All India Association for Christian Higher Education (AIACHE) (2019). She Hashas received the Sr. Mary Cecil prize for best research paper three times. She was also awarded a start-up to develop a tea bag water filter. \nDr. Varkey has published two international books and twenty-seven international journal publications. She is an editorial board member for five international journals.",institutionString:"St. Teresa’s College",institution:null},{id:"250668",title:"Dr.",name:"Ali",middleName:null,surname:"Nabipour Chakoli",slug:"ali-nabipour-chakoli",fullName:"Ali Nabipour Chakoli",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/250668/images/system/250668.jpg",biography:"Academic Qualification:\r\n•\tPhD in Materials Physics and Chemistry, From: Sep. 2006, to: Sep. 2010, School of Materials Science and Engineering, Harbin Institute of Technology, Thesis: Structure and Shape Memory Effect of Functionalized MWCNTs/poly (L-lactide-co-ε-caprolactone) Nanocomposites. Supervisor: Prof. Wei Cai,\r\n•\tM.Sc in Applied Physics, From: 1996, to: 1998, Faculty of Physics & Nuclear Science, Amirkabir Uni. of Technology, Tehran, Iran, Thesis: Determination of Boron in Micro alloy Steels with solid state nuclear track detectors by neutron induced auto radiography, Supervisors: Dr. M. Hosseini Ashrafi and Dr. A. Hosseini.\r\n•\tB.Sc. in Applied Physics, From: 1991, to: 1996, Faculty of Physics & Nuclear Science, Amirkabir Uni. of Technology, Tehran, Iran, Thesis: Design of shielding for Am-Be neutron sources for In Vivo neutron activation analysis, Supervisor: Dr. M. Hosseini Ashrafi.\r\n\r\nResearch Experiences:\r\n1.\tNanomaterials, Carbon Nanotubes, Graphene: Synthesis, Functionalization and Characterization,\r\n2.\tMWCNTs/Polymer Composites: Fabrication and Characterization, \r\n3.\tShape Memory Polymers, Biodegradable Polymers, ORC, Collagen,\r\n4.\tMaterials Analysis and Characterizations: TEM, SEM, XPS, FT-IR, Raman, DSC, DMA, TGA, XRD, GPC, Fluoroscopy, \r\n5.\tInteraction of Radiation with Mater, Nuclear Safety and Security, NDT(RT),\r\n6.\tRadiation Detectors, Calibration (SSDL),\r\n7.\tCompleted IAEA e-learning Courses:\r\nNuclear Security (15 Modules),\r\nNuclear Safety:\r\nTSA 2: Regulatory Protection in Occupational Exposure,\r\nTips & Tricks: Radiation Protection in Radiography,\r\nSafety and Quality in Radiotherapy,\r\nCourse on Sealed Radioactive Sources,\r\nCourse on Fundamentals of Environmental Remediation,\r\nCourse on Planning for Environmental Remediation,\r\nKnowledge Management Orientation Course,\r\nFood Irradiation - Technology, Applications and Good Practices,\r\nEmployment:\r\nFrom 2010 to now: Academic staff, Nuclear Science and Technology Research Institute, Kargar Shomali, Tehran, Iran, P.O. Box: 14395-836.\r\nFrom 1997 to 2006: Expert of Materials Analysis and Characterization. Research Center of Agriculture and Medicine. Rajaeeshahr, Karaj, Iran, P. O. Box: 31585-498.",institutionString:"Atomic Energy Organization of Iran",institution:{name:"Atomic Energy Organization of Iran",country:{name:"Iran"}}},{id:"248279",title:"Dr.",name:"Monika",middleName:"Elzbieta",surname:"Machoy",slug:"monika-machoy",fullName:"Monika Machoy",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/248279/images/system/248279.jpeg",biography:"Monika Elżbieta Machoy, MD, graduated with distinction from the Faculty of Medicine and Dentistry at the Pomeranian Medical University in 2009, defended her PhD thesis with summa cum laude in 2016 and is currently employed as a researcher at the Department of Orthodontics of the Pomeranian Medical University. She expanded her professional knowledge during a one-year scholarship program at the Ernst Moritz Arndt University in Greifswald, Germany and during a three-year internship at the Technical University in Dresden, Germany. She has been a speaker at numerous orthodontic conferences, among others, American Association of Orthodontics, European Orthodontic Symposium and numerous conferences of the Polish Orthodontic Society. She conducts research focusing on the effect of orthodontic treatment on dental and periodontal tissues and the causes of pain in orthodontic patients.",institutionString:"Pomeranian Medical University",institution:{name:"Pomeranian Medical University",country:{name:"Poland"}}},{id:"252743",title:"Prof.",name:"Aswini",middleName:"Kumar",surname:"Kar",slug:"aswini-kar",fullName:"Aswini Kar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/252743/images/10381_n.jpg",biography:"uploaded in cv",institutionString:null,institution:{name:"KIIT University",country:{name:"India"}}},{id:"204256",title:"Dr.",name:"Anil",middleName:"Kumar",surname:"Kumar Sahu",slug:"anil-kumar-sahu",fullName:"Anil Kumar Sahu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/204256/images/14201_n.jpg",biography:"I have nearly 11 years of research and teaching experience. I have done my master degree from University Institute of Pharmacy, Pt. Ravi Shankar Shukla University, Raipur, Chhattisgarh India. I have published 16 review and research articles in international and national journals and published 4 chapters in IntechOpen, the world’s leading publisher of Open access books. I have presented many papers at national and international conferences. I have received research award from Indian Drug Manufacturers Association in year 2015. My research interest extends from novel lymphatic drug delivery systems, oral delivery system for herbal bioactive to formulation optimization.",institutionString:null,institution:{name:"Chhattisgarh Swami Vivekanand Technical University",country:{name:"India"}}},{id:"253468",title:"Dr.",name:"Mariusz",middleName:null,surname:"Marzec",slug:"mariusz-marzec",fullName:"Mariusz Marzec",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/253468/images/system/253468.png",biography:"An assistant professor at Department of Biomedical Computer Systems, at Institute of Computer Science, Silesian University in Katowice. Scientific interests: computer analysis and processing of images, biomedical images, databases and programming languages. He is an author and co-author of scientific publications covering analysis and processing of biomedical images and development of database systems.",institutionString:"University of Silesia",institution:{name:"University of Silesia",country:{name:"Poland"}}},{id:"212432",title:"Prof.",name:"Hadi",middleName:null,surname:"Mohammadi",slug:"hadi-mohammadi",fullName:"Hadi Mohammadi",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/212432/images/system/212432.jpeg",biography:"Dr. Hadi Mohammadi is a biomedical engineer with hands-on experience in the design and development of many engineering structures and medical devices through various projects that he has been involved in over the past twenty years. Dr. Mohammadi received his BSc. and MSc. degrees in Mechanical Engineering from Sharif University of Technology, Tehran, Iran, and his PhD. degree in Biomedical Engineering (biomaterials) from the University of Western Ontario. He was a postdoctoral trainee for almost four years at University of Calgary and Harvard Medical School. He is an industry innovator having created the technology to produce lifelike synthetic platforms that can be used for the simulation of almost all cardiovascular reconstructive surgeries. He’s been heavily involved in the design and development of cardiovascular devices and technology for the past 10 years. He is currently an Assistant Professor with the University of British Colombia, Canada.",institutionString:"University of British Columbia",institution:{name:"University of British Columbia",country:{name:"Canada"}}},{id:"254463",title:"Prof.",name:"Haisheng",middleName:null,surname:"Yang",slug:"haisheng-yang",fullName:"Haisheng Yang",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/254463/images/system/254463.jpeg",biography:"Haisheng Yang, Ph.D., Professor and Director of the Department of Biomedical Engineering, College of Life Science and Bioengineering, Beijing University of Technology. He received his Ph.D. degree in Mechanics/Biomechanics from Harbin Institute of Technology (jointly with University of California, Berkeley). Afterwards, he worked as a Postdoctoral Research Associate in the Purdue Musculoskeletal Biology and Mechanics Lab at the Department of Basic Medical Sciences, Purdue University, USA. He also conducted research in the Research Centre of Shriners Hospitals for Children-Canada at McGill University, Canada. Dr. Yang has over 10 years research experience in orthopaedic biomechanics and mechanobiology of bone adaptation and regeneration. He earned an award from Beijing Overseas Talents Aggregation program in 2017 and serves as Beijing Distinguished Professor.",institutionString:null,institution:{name:"Beijing University of Technology",country:{name:"China"}}},{id:"89721",title:"Dr.",name:"Mehmet",middleName:"Cuneyt",surname:"Ozmen",slug:"mehmet-ozmen",fullName:"Mehmet Ozmen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/89721/images/7289_n.jpg",biography:null,institutionString:null,institution:{name:"Gazi University",country:{name:"Turkey"}}},{id:"265335",title:"Mr.",name:"Stefan",middleName:"Radnev",surname:"Stefanov",slug:"stefan-stefanov",fullName:"Stefan Stefanov",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/265335/images/7562_n.jpg",biography:null,institutionString:null,institution:{name:"Medical University Plovdiv",country:{name:"Bulgaria"}}},{id:"242893",title:"Ph.D. Student",name:"Joaquim",middleName:null,surname:"De Moura",slug:"joaquim-de-moura",fullName:"Joaquim De Moura",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/242893/images/7133_n.jpg",biography:"Joaquim de Moura received his degree in Computer Engineering in 2014 from the University of A Coruña (Spain). In 2016, he received his M.Sc degree in Computer Engineering from the same university. He is currently pursuing his Ph.D degree in Computer Science in a collaborative project between ophthalmology centers in Galicia and the University of A Coruña. His research interests include computer vision, machine learning algorithms and analysis and medical imaging processing of various kinds.",institutionString:null,institution:{name:"University of A Coruña",country:{name:"Spain"}}},{id:"294334",title:"B.Sc.",name:"Marc",middleName:null,surname:"Bruggeman",slug:"marc-bruggeman",fullName:"Marc Bruggeman",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/294334/images/8242_n.jpg",biography:"Chemical engineer graduate, with a passion for material science and specific interest in polymers - their near infinite applications intrigue me. \n\nI plan to continue my scientific career in the field of polymeric biomaterials as I am fascinated by intelligent, bioactive and biomimetic materials for use in both consumer and medical applications.",institutionString:null,institution:null},{id:"255757",title:"Dr.",name:"Igor",middleName:"Victorovich",surname:"Lakhno",slug:"igor-lakhno",fullName:"Igor Lakhno",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/255757/images/system/255757.jpg",biography:"Igor Victorovich Lakhno was born in 1971 in Kharkiv (Ukraine). \nMD – 1994, Kharkiv National Medical Univesity.\nOb&Gyn; – 1997, master courses in Kharkiv Medical Academy of Postgraduate Education.\nPh.D. – 1999, Kharkiv National Medical Univesity.\nDSC – 2019, PL Shupik National Academy of Postgraduate Education \nProfessor – 2021, Department of Obstetrics and Gynecology of VN Karazin Kharkiv National University\nHead of Department – 2021, Department of Perinatology, Obstetrics and gynecology of Kharkiv Medical Academy of Postgraduate Education\nIgor Lakhno has been graduated from international training courses on reproductive medicine and family planning held at Debrecen University (Hungary) in 1997. Since 1998 Lakhno Igor has worked as an associate professor in the department of obstetrics and gynecology of VN Karazin National University and an associate professor of the perinatology, obstetrics, and gynecology department of Kharkiv Medical Academy of Postgraduate Education. Since June 2019 he’s been a professor in the department of obstetrics and gynecology of VN Karazin National University and a professor of the perinatology, obstetrics, and gynecology department. He’s affiliated with Kharkiv Medical Academy of Postgraduate Education as a Head of Department from November 2021. Igor Lakhno has participated in several international projects on fetal non-invasive electrocardiography (with Dr. J. A. Behar (Technion), Prof. D. Hoyer (Jena University), and José Alejandro Díaz Méndez (National Institute of Astrophysics, Optics, and Electronics, Mexico). He’s an author of about 200 printed works and there are 31 of them in Scopus or Web of Science databases. Igor Lakhno is a member of the Editorial Board of Reproductive Health of Woman, Emergency Medicine, and Technology Transfer Innovative Solutions in Medicine (Estonia). He is a medical Editor of “Z turbotoyu pro zhinku”. Igor Lakhno is a reviewer of the Journal of Obstetrics and Gynaecology (Taylor and Francis), British Journal of Obstetrics and Gynecology (Wiley), Informatics in Medicine Unlocked (Elsevier), The Journal of Obstetrics and Gynecology Research (Wiley), Endocrine, Metabolic & Immune Disorders-Drug Targets (Bentham Open), The Open Biomedical Engineering Journal (Bentham Open), etc. He’s defended a dissertation for a DSc degree “Pre-eclampsia: prediction, prevention, and treatment”. Three years ago Igor Lakhno has participated in a training course on innovative technologies in medical education at Lublin Medical University (Poland). Lakhno Igor has participated as a speaker in several international conferences and congresses (International Conference on Biological Oscillations April 10th-14th 2016, Lancaster, UK, The 9th conference of the European Study Group on Cardiovascular Oscillations). His main scientific interests: are obstetrics, women’s health, fetal medicine, and cardiovascular medicine. \nIgor Lakhno is a consultant at Kharkiv municipal perinatal center. He’s graduated from training courses on endoscopy in gynecology. He has 28 years of practical experience in the field.",institutionString:null,institution:null},{id:"244950",title:"Dr.",name:"Salvatore",middleName:null,surname:"Di Lauro",slug:"salvatore-di-lauro",fullName:"Salvatore Di Lauro",position:null,profilePictureURL:"https://intech-files.s3.amazonaws.com/0030O00002bSF1HQAW/ProfilePicture%202021-12-20%2014%3A54%3A14.482",biography:"Name:\n\tSALVATORE DI LAURO\nAddress:\n\tHospital Clínico Universitario Valladolid\nAvda Ramón y Cajal 3\n47005, Valladolid\nSpain\nPhone number: \nFax\nE-mail:\n\t+34 983420000 ext 292\n+34 983420084\nsadilauro@live.it\nDate and place of Birth:\nID Number\nMedical Licence \nLanguages\t09-05-1985. Villaricca (Italy)\n\nY1281863H\n474707061\nItalian (native language)\nSpanish (read, written, spoken)\nEnglish (read, written, spoken)\nPortuguese (read, spoken)\nFrench (read)\n\t\t\nCurrent position (title and company)\tDate (Year)\nVitreo-Retinal consultant in ophthalmology. Hospital Clinico Universitario Valladolid. Sacyl. National Health System.\nVitreo-Retinal consultant in ophthalmology. Instituto Oftalmologico Recoletas. Red Hospitalaria Recoletas. Private practise.\t2017-today\n\n2019-today\n\t\n\t\nEducation (High school, university and postgraduate training > 3 months)\tDate (Year)\nDegree in Medicine and Surgery. University of Neaples 'Federico II”\nResident in Opthalmology. Hospital Clinico Universitario Valladolid\nMaster in Vitreo-Retina. IOBA. University of Valladolid\nFellow of the European Board of Ophthalmology. Paris\nMaster in Research in Ophthalmology. University of Valladolid\t2003-2009\n2012-2016\n2016-2017\n2016\n2012-2013\n\t\nEmployments (company and positions)\tDate (Year)\nResident in Ophthalmology. Hospital Clinico Universitario Valladolid. Sacyl.\nFellow in Vitreo-Retina. IOBA. University of Valladolid\nVitreo-Retinal consultant in ophthalmology. Hospital Clinico Universitario Valladolid. Sacyl. National Health System.\nVitreo-Retinal consultant in ophthalmology. Instituto Oftalmologico Recoletas. Red Hospitalaria Recoletas. \n\t2012-2016\n2016-2017\n2017-today\n\n2019-Today\n\n\n\t\nClinical Research Experience (tasks and role)\tDate (Year)\nAssociated investigator\n\n' FIS PI20/00740: DESARROLLO DE UNA CALCULADORA DE RIESGO DE\nAPARICION DE RETINOPATIA DIABETICA BASADA EN TECNICAS DE IMAGEN MULTIMODAL EN PACIENTES DIABETICOS TIPO 1. Grant by: Ministerio de Ciencia e Innovacion \n\n' (BIO/VA23/14) Estudio clínico multicéntrico y prospectivo para validar dos\nbiomarcadores ubicados en los genes p53 y MDM2 en la predicción de los resultados funcionales de la cirugía del desprendimiento de retina regmatógeno. Grant by: Gerencia Regional de Salud de la Junta de Castilla y León.\n' Estudio multicéntrico, aleatorizado, con enmascaramiento doble, en 2 grupos\nparalelos y de 52 semanas de duración para comparar la eficacia, seguridad e inmunogenicidad de SOK583A1 respecto a Eylea® en pacientes con degeneración macular neovascular asociada a la edad' (CSOK583A12301; N.EUDRA: 2019-004838-41; FASE III). Grant by Hexal AG\n\n' Estudio de fase III, aleatorizado, doble ciego, con grupos paralelos, multicéntrico para comparar la eficacia y la seguridad de QL1205 frente a Lucentis® en pacientes con degeneración macular neovascular asociada a la edad. (EUDRACT: 2018-004486-13). Grant by Qilu Pharmaceutical Co\n\n' Estudio NEUTON: Ensayo clinico en fase IV para evaluar la eficacia de aflibercept en pacientes Naive con Edema MacUlar secundario a Oclusion de Vena CenTral de la Retina (OVCR) en regimen de tratamientO iNdividualizado Treat and Extend (TAE)”, (2014-000975-21). Grant by Fundacion Retinaplus\n\n' Evaluación de la seguridad y bioactividad de anillos de tensión capsular en conejo. Proyecto Procusens. Grant by AJL, S.A.\n\n'Estudio epidemiológico, prospectivo, multicéntrico y abierto\\npara valorar la frecuencia de la conjuntivitis adenovírica diagnosticada mediante el test AdenoPlus®\\nTest en pacientes enfermos de conjuntivitis aguda”\\n. National, multicenter study. Grant by: NICOX.\n\nEuropean multicentric trial: 'Evaluation of clinical outcomes following the use of Systane Hydration in patients with dry eye”. Study Phase 4. Grant by: Alcon Labs'\n\nVLPs Injection and Activation in a Rabbit Model of Uveal Melanoma. Grant by Aura Bioscience\n\nUpdating and characterization of a rabbit model of uveal melanoma. Grant by Aura Bioscience\n\nEnsayo clínico en fase IV para evaluar las variantes genéticas de la vía del VEGF como biomarcadores de eficacia del tratamiento con aflibercept en pacientes con degeneración macular asociada a la edad (DMAE) neovascular. Estudio BIOIMAGE. IMO-AFLI-2013-01\n\nEstudio In-Eye:Ensayo clínico en fase IV, abierto, aleatorizado, de 2 brazos,\nmulticçentrico y de 12 meses de duración, para evaluar la eficacia y seguridad de un régimen de PRN flexible individualizado de 'esperar y extender' versus un régimen PRN según criterios de estabilización mediante evaluaciones mensuales de inyecciones intravítreas de ranibizumab 0,5 mg en pacientes naive con neovascularización coriodea secunaria a la degeneración macular relacionada con la edad. CP: CRFB002AES03T\n\nTREND: Estudio Fase IIIb multicéntrico, randomizado, de 12 meses de\nseguimiento con evaluador de la agudeza visual enmascarado, para evaluar la eficacia y la seguridad de ranibizumab 0.5mg en un régimen de tratar y extender comparado con un régimen mensual, en pacientes con degeneración macular neovascular asociada a la edad. CP: CRFB002A2411 Código Eudra CT:\n2013-002626-23\n\n\n\nPublications\t\n\n2021\n\n\n\n\n2015\n\n\n\n\n2021\n\n\n\n\n\n2021\n\n\n\n\n2015\n\n\n\n\n2015\n\n\n2014\n\n\n\n\n2015-16\n\n\n\n2015\n\n\n2014\n\n\n2014\n\n\n\n\n2014\n\n\n\n\n\n\n\n2014\n\nJose Carlos Pastor; Jimena Rojas; Salvador Pastor-Idoate; Salvatore Di Lauro; Lucia Gonzalez-Buendia; Santiago Delgado-Tirado. Proliferative vitreoretinopathy: A new concept of disease pathogenesis and practical\nconsequences. Progress in Retinal and Eye Research. 51, pp. 125 - 155. 03/2016. DOI: 10.1016/j.preteyeres.2015.07.005\n\n\nLabrador-Velandia S; Alonso-Alonso ML; Di Lauro S; García-Gutierrez MT; Srivastava GK; Pastor JC; Fernandez-Bueno I. Mesenchymal stem cells provide paracrine neuroprotective resources that delay degeneration of co-cultured organotypic neuroretinal cultures.Experimental Eye Research. 185, 17/05/2019. DOI: 10.1016/j.exer.2019.05.011\n\nSalvatore Di Lauro; Maria Teresa Garcia Gutierrez; Ivan Fernandez Bueno. Quantification of pigment epithelium-derived factor (PEDF) in an ex vivo coculture of retinal pigment epithelium cells and neuroretina.\nJournal of Allbiosolution. 2019. ISSN 2605-3535\n\nSonia Labrador Velandia; Salvatore Di Lauro; Alonso-Alonso ML; Tabera Bartolomé S; Srivastava GK; Pastor JC; Fernandez-Bueno I. Biocompatibility of intravitreal injection of human mesenchymal stem cells in immunocompetent rabbits. Graefe's archive for clinical and experimental ophthalmology. 256 - 1, pp. 125 - 134. 01/2018. DOI: 10.1007/s00417-017-3842-3\n\n\nSalvatore Di Lauro, David Rodriguez-Crespo, Manuel J Gayoso, Maria T Garcia-Gutierrez, J Carlos Pastor, Girish K Srivastava, Ivan Fernandez-Bueno. A novel coculture model of porcine central neuroretina explants and retinal pigment epithelium cells. Molecular Vision. 2016 - 22, pp. 243 - 253. 01/2016.\n\nSalvatore Di Lauro. Classifications for Proliferative Vitreoretinopathy ({PVR}): An Analysis of Their Use in Publications over the Last 15 Years. Journal of Ophthalmology. 2016, pp. 1 - 6. 01/2016. DOI: 10.1155/2016/7807596\n\nSalvatore Di Lauro; Rosa Maria Coco; Rosa Maria Sanabria; Enrique Rodriguez de la Rua; Jose Carlos Pastor. Loss of Visual Acuity after Successful Surgery for Macula-On Rhegmatogenous Retinal Detachment in a Prospective Multicentre Study. Journal of Ophthalmology. 2015:821864, 2015. DOI: 10.1155/2015/821864\n\nIvan Fernandez-Bueno; Salvatore Di Lauro; Ivan Alvarez; Jose Carlos Lopez; Maria Teresa Garcia-Gutierrez; Itziar Fernandez; Eva Larra; Jose Carlos Pastor. Safety and Biocompatibility of a New High-Density Polyethylene-Based\nSpherical Integrated Porous Orbital Implant: An Experimental Study in Rabbits. Journal of Ophthalmology. 2015:904096, 2015. DOI: 10.1155/2015/904096\n\nPastor JC; Pastor-Idoate S; Rodríguez-Hernandez I; Rojas J; Fernandez I; Gonzalez-Buendia L; Di Lauro S; Gonzalez-Sarmiento R. Genetics of PVR and RD. Ophthalmologica. 232 - Suppl 1, pp. 28 - 29. 2014\n\nRodriguez-Crespo D; Di Lauro S; Singh AK; Garcia-Gutierrez MT; Garrosa M; Pastor JC; Fernandez-Bueno I; Srivastava GK. Triple-layered mixed co-culture model of RPE cells with neuroretina for evaluating the neuroprotective effects of adipose-MSCs. Cell Tissue Res. 358 - 3, pp. 705 - 716. 2014.\nDOI: 10.1007/s00441-014-1987-5\n\nCarlo De Werra; Salvatore Condurro; Salvatore Tramontano; Mario Perone; Ivana Donzelli; Salvatore Di Lauro; Massimo Di Giuseppe; Rosa Di Micco; Annalisa Pascariello; Antonio Pastore; Giorgio Diamantis; Giuseppe Galloro. Hydatid disease of the liver: thirty years of surgical experience.Chirurgia italiana. 59 - 5, pp. 611 - 636.\n(Italia): 2007. ISSN 0009-4773\n\nChapters in books\n\t\n' Salvador Pastor Idoate; Salvatore Di Lauro; Jose Carlos Pastor Jimeno. PVR: Pathogenesis, Histopathology and Classification. Proliferative Vitreoretinopathy with Small Gauge Vitrectomy. Springer, 2018. ISBN 978-3-319-78445-8\nDOI: 10.1007/978-3-319-78446-5_2. \n\n' Salvatore Di Lauro; Maria Isabel Lopez Galvez. Quistes vítreos en una mujer joven. Problemas diagnósticos en patología retinocoroidea. Sociedad Española de Retina-Vitreo. 2018.\n\n' Salvatore Di Lauro; Salvador Pastor Idoate; Jose Carlos Pastor Jimeno. iOCT in PVR management. OCT Applications in Opthalmology. pp. 1 - 8. INTECH, 2018. DOI: 10.5772/intechopen.78774.\n\n' Rosa Coco Martin; Salvatore Di Lauro; Salvador Pastor Idoate; Jose Carlos Pastor. amponadores, manipuladores y tinciones en la cirugía del traumatismo ocular.Trauma Ocular. Ponencia de la SEO 2018..\n\n' LOPEZ GALVEZ; DI LAURO; CRESPO. OCT angiografia y complicaciones retinianas de la diabetes. PONENCIA SEO 2021, CAPITULO 20. (España): 2021.\n\n' Múltiples desprendimientos neurosensoriales bilaterales en paciente joven. Enfermedades Degenerativas De Retina Y Coroides. SERV 04/2016. \n' González-Buendía L; Di Lauro S; Pastor-Idoate S; Pastor Jimeno JC. Vitreorretinopatía proliferante (VRP) e inflamación: LA INFLAMACIÓN in «INMUNOMODULADORES Y ANTIINFLAMATORIOS: MÁS ALLÁ DE LOS CORTICOIDES. 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Dr. Wang was awarded two research project grants focused on multimodal optical coherence tomography imaging and deep learning in cataract and retinal disease, from the National Natural Science Foundation of China. He has published around 30 peer-reviewed journal papers and four book chapters and co-edited one book.",institutionString:null,institution:null},{id:"7227",title:"Dr.",name:"Hiroaki",middleName:null,surname:"Matsui",slug:"hiroaki-matsui",fullName:"Hiroaki Matsui",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Tokyo",country:{name:"Japan"}}},{id:"312999",title:"Dr.",name:"Bernard O.",middleName:null,surname:"Asimeng",slug:"bernard-o.-asimeng",fullName:"Bernard O. 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We encourage the submission of manuscripts that provide novel and mechanistic insights that report significant advances in the fields. Topics can include but are not limited to: Biotechnology such as biotechnological products and process engineering; Biotechnologically relevant enzymes and proteins; Bioenergy and biofuels; Applied genetics and molecular biotechnology; Genomics, transcriptomics, proteomics; Applied microbial and cell physiology; Environmental biotechnology; Methods and protocols. Moreover, topics in biosensor technology, like sensors that incorporate enzymes, antibodies, nucleic acids, whole cells, tissues and organelles, and other biological or biologically inspired components will be considered, and topics exploring transducers, including those based on electrochemical and optical piezoelectric, thermal, magnetic, and micromechanical elements. Chapters exploring biomaterial approaches such as polymer synthesis and characterization, drug and gene vector design, biocompatibility, immunology and toxicology, and self-assembly at the nanoscale, are welcome. Finally, the tissue engineering subcategory will support topics such as the fundamentals of stem cells and progenitor cells and their proliferation, differentiation, bioreactors for three-dimensional culture and studies of phenotypic changes, stem and progenitor cells, both short and long term, ex vivo and in vivo implantation both in preclinical models and also in clinical trials.",annualVolume:11405,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/9.jpg",editor:{id:"126286",title:"Dr.",name:"Luis",middleName:"Jesús",surname:"Villarreal-Gómez",fullName:"Luis Villarreal-Gómez",profilePictureURL:"https://mts.intechopen.com/storage/users/126286/images/system/126286.jpg",institutionString:null,institution:{name:"Autonomous University of Baja California",institutionURL:null,country:{name:"Mexico"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"35539",title:"Dr.",name:"Cecilia",middleName:null,surname:"Cristea",fullName:"Cecilia Cristea",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYQ65QAG/Profile_Picture_1621007741527",institutionString:null,institution:{name:"Iuliu Hațieganu University of Medicine and Pharmacy",institutionURL:null,country:{name:"Romania"}}},{id:"40735",title:"Dr.",name:"Gil",middleName:"Alberto Batista",surname:"Gonçalves",fullName:"Gil Gonçalves",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYRLGQA4/Profile_Picture_1628492612759",institutionString:null,institution:{name:"University of Aveiro",institutionURL:null,country:{name:"Portugal"}}},{id:"211725",title:"Associate Prof.",name:"Johann F.",middleName:null,surname:"Osma",fullName:"Johann F. 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