Protein concentration in homogenate and mitochondria during aging in heart (yet unpublished data).
\r\n\t
",isbn:"978-1-83969-506-3",printIsbn:"978-1-83969-505-6",pdfIsbn:"978-1-83969-507-0",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,hash:"0e5d67464d929fda6d8c83ec20c4138a",bookSignature:"Dr. Endre Zima",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/10704.jpg",keywords:"Anatomy, Physiology, Perioperative, Non-Cardiac Causes, Antiarrhythmic Drugs, Development, SARS-CoV2, Infection, Cardiac Arrest, Resuscitation, PPE, Arrhythmias",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"February 11th 2021",dateEndSecondStepPublish:"March 11th 2021",dateEndThirdStepPublish:"May 10th 2021",dateEndFourthStepPublish:"July 29th 2021",dateEndFifthStepPublish:"September 27th 2021",remainingDaysToSecondStep:"2 days",secondStepPassed:!1,currentStepOfPublishingProcess:2,editedByType:null,kuFlag:!1,biosketch:"Prof. Dr. Endre Zima works as the chief of Cardiac ICU at Semmelweis University Heart and Vascular Center. His fields of interest are intensive cardiac care, CPR, post-cardiac arrest care, device therapy of arrhythmias, defibrillator waveform, and AED development.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"201263",title:"Dr.",name:"Endre",middleName:null,surname:"Zima",slug:"endre-zima",fullName:"Endre Zima",profilePictureURL:"https://mts.intechopen.com/storage/users/201263/images/system/201263.jpg",biography:"Prof. Dr. Endre Zima works as the chief of Cardiac ICU at Semmelweis University Heart and Vascular Center. Dr. Zima is specialized in anesthesiology-intensive care and cardiology. He has authored 13 book chapters and more than 130 journal papers, achieved a Hirsch-index of 14, g-index of 22, and more than 650 independent citations. \nHe has been holding graduate and postraduate lectures and practices in anesthesiology since 2006, and in cardiology since 2008. He is a PhD Lecturer in Semmelweis University since 2010. He obtains an accreditation of EHRA on Cardiac Pacing and Implantable Cardioverter Defibrillators, he is accredited AALS Instructor of European Resuscitation Council. \nHe is a Fellow of the European Society of Cardiology, member of the European Heart Rhythm Association and Acute Cardiovascular Care Association, board member of the Hungarian Society of Cardiology (HSC), president of Working Group (WG) on Cardiac Pacing of HSC , board member of WG of Heart Failure. Dr. Zima is also a member the Hungarian Society of Resuscitation, Hungarian Society of Anesthesiology. 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Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"878",title:"Phytochemicals",subtitle:"A Global Perspective of Their Role in Nutrition and Health",isOpenForSubmission:!1,hash:"ec77671f63975ef2d16192897deb6835",slug:"phytochemicals-a-global-perspective-of-their-role-in-nutrition-and-health",bookSignature:"Venketeshwer Rao",coverURL:"https://cdn.intechopen.com/books/images_new/878.jpg",editedByType:"Edited by",editors:[{id:"82663",title:"Dr.",name:"Venketeshwer",surname:"Rao",slug:"venketeshwer-rao",fullName:"Venketeshwer Rao"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"4816",title:"Face Recognition",subtitle:null,isOpenForSubmission:!1,hash:"146063b5359146b7718ea86bad47c8eb",slug:"face_recognition",bookSignature:"Kresimir Delac and Mislav Grgic",coverURL:"https://cdn.intechopen.com/books/images_new/4816.jpg",editedByType:"Edited by",editors:[{id:"528",title:"Dr.",name:"Kresimir",surname:"Delac",slug:"kresimir-delac",fullName:"Kresimir Delac"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"57765",title:"Interplay Between Mitochondrial Proteins and Age-Associated Risk of Cardiovascular Diseases",doi:"10.5772/intechopen.71789",slug:"interplay-between-mitochondrial-proteins-and-age-associated-risk-of-cardiovascular-diseases",body:'\nThe world population ages rapidly, mostly because of increasing longevity and declining fertility [1]. The average lifespan of the human populations is increasing worldwide and it is predicted that in 2035, nearly every fourth individual will be 65 years or older [2]. Aging is a complex phenomenon with a large impact on society. Aging is recently an emerging topic since the life expectancy is rising and because aging itself is the basis for the development of age-related diseases such as cardiovascular disease (CVD), cancer, neurodegenerative diseases and degenerative metabolic diseases (e.g. diabetes mellitus type 2) [3]. Since age is the largest risk factor for CVD, the prevalence of these ailments increases dramatically with increasing age. Over 80% of all cases of coronary artery disease and more than 75% of those of congestive heart failure are observed in elderly patients [4]. In order to improve prevention and care for patients, it is important to analyze processes linked with cardiac aging. Prevalence of high blood pressure, obesity and metabolic syndrome correlate with age, and all these conditions facilitate the development of cardiomyopathies that are the major cause of chronic disability, morbidity and mortality in the elderly. Although the long-term exposure to cardiovascular risk factors plays a major role in the etiopathogenesis of CVD and neurodegeneration, intrinsic alterations in the heart and the vascular system occur during lifespan and render the cardiovascular system more vulnerable during senescence. The possible link between aging and senescence was first described in 1961 [5] and it based on the inability of telomeres to sustain their lengths. In addition to this, other events and signals were identified including non-telomeric/genotoxic stress generated by various signals, such as mitochondrial deterioration, oxidative stress, DNA-replication “stress” or activated oncogenes [6]. Several lines of evidence indicate mitochondrial dysfunction to be a major contributor to cardiovascular senescence. Damaged mitochondria are bioenergetically less efficient and they are producing excessive amounts of reactive oxygen species (ROS) with detrimental structural and functional consequences [7]. The ROS impair excitation-contraction coupling, cause arrhythmias, and contribute to cardiac remodeling by inducing cardiac hypertrophy, apoptosis, necrosis, and fibrosis [8]. However, antioxidant interventions in patients with CVD yielded only disappointing results so far [9].
\nThe accumulation of abnormal/dysfunctional mitochondria is usually a consequence of impaired clearance of damaged organelles by autophagy and inadequate replenishment of the cellular mitochondrial pool by mitochondriogenesis [7]. Autophagic flux is generally decreased in aging hearts. Murine loss-of-function models for autophagy develop exacerbated cardiac dysfunction that is accompanied by accumulation of misfolded proteins and dysfunctional organelles. On the other hand, stimulation of autophagy in mouse models improves cardiac function and enables to study a protein aggregation by removing accumulated misfolded proteins, dysfunctional mitochondria, and damaged DNA, thereby alleviating aging-associated pathology in the heart. Multiple lines of evidence suggest that autophagy is required for many mechanisms that mediate lifespan extension, such as caloric restriction. These results are pointing out the possibility that autophagy may play an important role in combating the adverse effects of aging in the heart [10]. At the molecular level, the aging process is associated with accumulation of damaged proteins and organelles, partially due to defects in protein quality control systems. Since most cellular functions are performed by proteins, aging may be, in part, the consequence of a deregulation or malfunction of the cellular proteome [11]. Modern techniques enabled the investigation of the internal structure and morphology of mitochondria and revealed a highly complex compartmentalization [12] with the challenge to dissect the communication and maintenance of the individual compartments. Part of this is to ensure proteostasis (folding, unfolding and degradation) to generate a homeostasis of the functional proteome and to clear mistargeted/damaged proteins. It is not easy, because every submitochondrial compartment needs to control its redox milieu, which is interestingly highly different, e.g. the inner membrane separates the reducing matrix from the more oxidizing intermembrane space [13]. The complexity of the proteome supersedes that of the genome due to alternative splicing events and post-translational modifications (PTMs). Specific position has the mitochondrial intermembrane space (MIMS) with its role in protein and lipid transport, regulation and assembly of the respiratory transport system, regulation of redox processes, coordination of apoptosis and metal ion homeostasis [14]. One of the big challenges of future research will be to investigate how the mitochondrion communicates with the cytosol and the nucleus. The MIMS exhibits specific redox environment and controlled porine-facilitated leakiness through the outer membrane allowing the free diffusion of small molecules (less than 5 kDa) that might harbor candidates mediating the communication from signaling pathways occurring inside the mitochondria toward other organelles [15].
\nMitochondrial homeostasis is associated with overall cellular fitness and cellular longevity. Therefore, it determines also normal physiology of organ systems and performance of the body. Recent studies suggest that restoration of mitochondrial dynamics and mitophagy could delay organ senescence and prevent age-associated cardiac diseases. Here, we discuss the current understanding of mitochondria with particular focus on the heart, specifically the close relationship between mitochondrial dynamics or mitophagy suggesting a possible link to the regulation of redox metabolism, and intercellular protein communication.
\nCells undergo widespread changes and develop specific characteristics during senescence that are considered as senescence markers. However, no individual marker has been so far identified as entirely selective parameter for cellular senescence. Nevertheless, a combination of several markers might be evaluated and can help to define the current stage of senescence. Phenotypically, the increase in size and protein content was reported in senescent cells [16, 17] which is in agreement with our results. The data in Table 1 show that the total protein concentration was elevated in senescent (27 months old) rat mitochondria by 40% (p < 0.01). However, the protein content in homogenates as well as in isolated mitochondrial fraction was maintained during overall aging process comparing the samples from old (14 months old) and adult (6 months old) rat hearts.
\nProtein concentration (mg/ml) | \nAge (months) | \n||
---|---|---|---|
6 | \n14 | \n27 | \n|
Homogenate | \n20.87 ± 2.50 | \n23.96 ± 1.46 | \n19.19 ± 2.96 | \n
Mitochondria | \n5.69 ± 0.61 | \n5.38 ± 0.49 | \n9.56 ± 0.05** | \n
Protein concentration in homogenate and mitochondria during aging in heart (yet unpublished data).
Values are expressed as Mean ± SEM of 5 individual experiments, **p<0.01; significantly different in comparison to 6 months old rats.
Further, senescent cells exhibit enlarged nuclei and lysosomes, which possess elevated senescence-associated β-galactosidase activity (SA-β-Gal), the most widely used marker [17]. They also enter a proliferative arrest state, detected by cell cycle inhibitor levels such as p53/p21, tumor suppressor p16INK4a [18, 19] and markers of proliferation like Ki-67 and 5-bromodeoxyuridine [20]. Other factors secreted during senescence are cytokines, chemokines, growth factors, proteases, fibronectin as well as ROS and reactive nitrogen species (RNS). Additionally, proteostatic changes during senescence accompanied by an increase in modified proteins, accumulation of protein aggregates and reduced functionality of the proteasomal and autophagy systems [3] will be discussed in following chapters. Only two parameters currently correlate with species longevity in the right sense: the mitochondrial rate of ROS production and the degree of fatty acid unsaturation of tissue membranes. Their basal level is in both cases low in long-lived animals. In addition, the best-known manipulation that extends longevity, dietary restriction, also decreases the rate of mitochondrial ROS production and oxidative damage to mtDNA [21]. The available information supports a mitochondrial free radical theory of aging focused on low generation of endogenous damage and low sensitivity of membranes to oxidation in long-lived animals.
\nAccording to mitochondrial theory of aging, mitochondria are both the main source and targets of detrimental reactions initiated in association with age-dependent deterioration of the cellular functions. Reactions leading to increased ROS generation, mtDNA mutations, oxidation of mitochondrial proteins and lipids result in subsequent induction of apoptotic events, impaired oxidative phosphorylation capacity, mitochondrial dynamics, and autophagy [22]. In addition, mitochondrial function may be affected by subject parameters like physical activity history [23], caloric restriction [21], drugs [24] and various comorbidities including obesity [25], insulin resistance and hypertension [26]. The primary function of mitochondria is to produce adenosine triphosphate (ATP) by the process of oxidative phosphorylation. In fact, about 90–95% of cellular oxygen is used up in oxidative phosphorylation and 3% from that pool can be converted to superoxide anion radical (O2•−). This is a very strong argument to mitochondria as a main source of this oxygen radical [27]. Among the most relevant ROS sources in heart belong NADPH oxidases (NOX) and mitochondria [28]. Recent studies demonstrate that mitochondrial ROS play a critical role in mediating the cellular effects of angiotensin II in the cardiovascular system [29]. Angiotensin II binds to angiotensin receptor 1, thereby activating NOX isoform 2 and 4 leading to increased mitochondrial ROS production in vascular endothelial cells as well as in cardiac myocytes [30].
\nTwo principal scenarios can be envisioned that favor increased mitochondrial ROS-formation: increased formation of O2•− at the electron transport chain (ETC) and decreased elimination of O2•− or hydrogen peroxide (H2O2) in the mitochondrial matrix. In heart failure, the first scenario occurs when modifications of ETC complexes like disturbed stoichiometry and PTMs hamper electron flux along the ETC to provoke excessive O2•− formation [31] mostly by NADH dehydrogenase (complex I) and Cytochrome c reductase (complex III) causing functional uncoupling of the respiratory chain. The extent and way of individual ETC complexes inhibition is different. According to Figure 1, the decline in activity of complex I and cytochrome c oxidase (complex IV) was more obvious during aging when compared to the succinate dehydrogenase (complex II) and complex III activities. Literature data are inconsistent among the studies, mainly due to differences in the experimental age groups and animal models, isolation/purity of mitochondria or enzyme substrate/inhibitor used for study. Complex I is considered to be the most important player in the game of ROS production and/or proton-motive cascade. Loss of its activity has been attributed to the mutations in mitochondrial DNA (mtDNA) in aging animals and recently was linked to the apoptotic cell death pathway [32].
\nActivities of ETC complexes in heart mitochondria during aging (yet unpublished data). Values are expressed as Mean ± SEM of 5 individual experiments, **p < 0.01, ***p < 0.001; significantly different in comparison to 6 months old rats.
Reduced complex I activity was seen in the rat heart [33], brain synaptic mitochondria [34] as well as continual decrease in the frontal cortex of Parkinson disease patients [35]. It is important to note that the activity and stability of this respiratory complex are determined by its abundance, PTMs and/or specific protein–protein interactions. In contrary, other studies have reported no age-related decrease in complex I activity [36]. Most of the inconsistencies are related to the complexes II, III and IV, where activities of respiratory complexes have been also shown to decline [37], remain unchanged or increased during aging [38]. Our data show age-dependent decrease in all ETC enzyme activities, although the extent of inhibition is different (Figure 1). Among them, complex IV was most affected throughout aging and reached 63.4% of adult respiring mitochondria. While complexes I, II and III maintained activities in 14 months old rat mitochondria, cytochrome c oxidase showed deprivation by 21.6% (p < 0.01) when compared to the adults. Unique role in both, Krebs cycle and ETC, has in inner mitochondrial membrane (IMM) embedded complex II. Its function is cardiolipin-independent and is not taking part in respiratory supercomplexes but has been identified as an isolated entity in mildly solubilized mitochondrial membranes [39]. This confirms the least damage by 13.6% in senescent mitochondria when compared to the other respiratory complexes. Interestingly, recent works described the direct connection of the O2•− formation and respiratory chain complex II [40] when lack of succinate was present. At saturated succinate concentration and high membrane potential complex II is tightly bound with reverse transfer of electrons to O2•− -producing complex I [41].
\nSeveral factors have impact on ETC with specific role of mtDNA. ETC complexes are composed of both nuclear DNA-encoded (more than 80 proteins subunits) and 13 mtDNA-encoded subunits proteins. Respiratory chain and F1F0-ATPase deficits are adverse effects on a variety of cellular and tissue functions, causing a wide range of complex clinical phenotypes. The incidence of inherited mitochondrial diseases is estimated to be about 1 in 5000 but a much larger population may be affected when somatic genetic defects, such as mtDNA mutation and deletions accompanying normal aging, are considered. The frequency of the common 4977-bp mtDNA deletion, a typical consequence of oxidative stress [42], increases with age in the human heart and is estimated to be 5- to 15-fold higher in people over 40 years of age relative to younger individuals [43]. This deletion affects genes encoding 7 polypeptide components of the mitochondrial ETC. Bioenergetic consequences of 4977-bp deletions will be reflected when the proportion of deleted mtDNA exceeds 50–55% of total mtDNA. The involvement of mtDNA mutations in cardiac aging is supported by findings in mice that express a proof reading deficient version of mtDNA polymerase (PolG) [44]. A high load of mtDNA mutations and deletions accumulate in the heart of these mice, in conjunction with the early onset of several age-associated changes including cardiac enlargement, fibrosis, impairment of systolic and diastolic function [30], and reduced activity of ETC complexes [44].
\nTo maintain proton-motive force and electron transfer through ETC, reduced equivalents are required. In mitochondria, the Krebs cycle generates NADH, which delivers electrons to the ETC inducing translocation of protons across the inner mitochondrial membrane. This establishes a membrane potential that fuels the F1F0-ATPase to generate ATP. At the ETC, electrons can leak to produce O2• which is dismutated to H2O2 by Mn-dependent superoxide dismutase (Mn-SOD) and, in turn, is detoxified by enzymes that require NADPH. Accordingly, equilibrium exists between reduced and oxidized forms of equivalents NADH/NAD+ and NADPH/NADP+ [45].
\nIn experiments, citrate synthase is frequently used as basal mitochondrial activity marker to avoid possible effects of different yield of mitochondria. Increase in its activity shown in Figure 2 led to more pronounced activity changes in ETC complexes with age. Starting from citrate synthase, some of the Krebs cycle enzymes play inevitable role in reduced equivalents machinery, such as NAD(P)+-isocitrate dehydrogenase (ICDH) and α-ketoglutarate dehydrogenase (KGDH). Both of the enzymes share some common features as NADH production and they are regulated by calcium (Ca2+). Calcium uptake dynamically controls the redox state of NAD(P)H in working cardiac myocytes [28] and availability of NADPH together with reduced glutathione is required for H2O2 removal by glutathione peroxidase/glutathione reductase cycling. Therefore regeneration of NADPH is very important and depends on Krebs cycle enzymes, especially ICDH [46]. Interestingly, the activity of ICDH was affected only in senescent mitochondria but by a significant 42.5% decrease (from 246.52 ± 1.90 to 144.04 ± 5.58) μmol/min/mg protein. Almost equivalent to ICDH activity in senescent hearts was drop in KGDH activity but this enzyme has shown gradual decline during whole aging process (Figure 2). In heart failure, elevated intracellular Na+ promotes ROS-formation by reducing mitochondrial Ca2+ uptake. Therefore, mitochondrial Ca2+ uptake critically regulates mitochondrial ROS production/removal [28] in cooperation with Krebs cycle enzymes and other ions to maintain mitochondrial homeostasis. Activation of ion channels in the IMM such as mitochondrial permeability transition pore (MPTP), the inner membrane anion channel (IMAC) and ATP-dependent K+-channel causes depolarization of IMM. This is accompanied by an increase in electron flux required to maintain ATP production. Opening of these channels might promote ROS production, but interestingly they can be activated by ROS themselves. Moreover, O2•− can be released from mitochondria via MPTP and IMAC. ROS in such a situation trigger oscillations of membrane potential leading to higher incidence of arrhythmias during reperfusion in the heart [47]. It seems that oxidative stress is one of the key events in myocardial senescence progression and development; however, during evolution cells were equipped with antioxidant defense mechanisms that can prevent/recover cells from an oxidative to a reductive state.
\nActivities of Krebs cycle enzymes in heart mitochondria during aging (yet unpublished data). Values are expressed as Mean ± SEM of 5 individual experiments, **p < 0.01, ***p < 0.001; significantly different in comparison to 6 months old rats.
Mitochondria play important role in generation of ROS and RNS but they are themselves players in different signaling pathways, in which the mitochondrial oxidative defense system contributes to maintain redox homeostasis. Cellular redox state is determined by the reduction potentials and reducing capacities of the redox couples, such as GSH/GSSG, NAD(P)H/NAD(P)+, thioredoxin (reduced/oxidized), glutaredoxin (reduced/oxidized) and cysteine/cystine, From these the GSH/GSSG system is considered to be the most abundant among endogenous antioxidants with 2 to 4-fold higher abundance than other redox systems.
\nReduced form of GSH (γ-L-glutamyl-L-cysteinyl glycine) is two electron donating molecule and in humans is almost uniquely present in a quite high concentration (1–10 mmol/L). This allows GSH to scavenge ROS either directly or indirectly. As an antioxidant, it reacts with reactive forms and radicals produced in association with electron transport, xenobiotic metabolism and inflammatory responses [48]. GSH homeostasis is not only regulated by its de novo synthesis, but also by other factors such as utilization, recycling and cellular export. Cooperation with other antioxidant, redox-related enzymes is important for recycling and maintenance of the optimal redox environment. It was reported that GSH level decreases over time in heart mitochondria [49] and several brain regions [50]. This phenomenon was confirmed by GSH measurement in three age groups (Table 2). Rapid decline of GSH level was accompanied by increase in oxidized GSSG form in senescent rat hearts. Interestingly, 14 months old hearts were able to maintain basal concentrations of that present in adult ones. The relative GSH/GSSG ratio indicates a decrease in GSH levels leading to more oxidized environment in senescent cardiomyocytes and experimentally dilated cardiomyopathy in mice [51]. The total content of thiol-containing compounds (R-SH), in contrary to GSH, decreases very slowly (by 19.2% in senescent) during aging process.
\n(μmol/g of tissue) | \nAge (months) | \n||
---|---|---|---|
6 | \n14 | \n27 | \n|
R-SH content | \n8.66 ± 0.46 | \n7.12 ± 0.26 | \n7.00 ± 0.09* | \n
GSH content | \n3.00 ± 0.25 | \n3.74 ± 0.39 | \n1.68 ± 0.19** | \n
GSSG content | \n1.77 ± 0.21 | \n1.61 ± 0.25 | \n3.81 ± 0.31** | \n
GSH/GSSG ratio | \n1.64 | \n2.10 | \n0.51 | \n
Enzyme activity (μmol/min/mg protein) | \n|||
GPx activity | \n9.033 ± 0.860 | \n8.239 ± 0.081*** | \n6.489 ± 0.112*** | \n
GR activity | \n4.790 ± 0.093 | \n4.194 ± 0.306** | \n3.960 ± 0.124*** | \n
TrxR activity | \n0.085 ± 0.018 | \n0.050 ± 0.008** | \n0.052 ± 0.013** | \n
The content and activities of GSH cycle-related molecules in heart during aging (yet unpublished data).
Values are expressed as means ± SEM of 5 individual experiments. *p < 0.05, **p < 0.01, ***p < 0.001; significantly different in comparison to 6 months old rats.
Aerobic respiration may result in an increase of H2O2, which is metabolized by glutathione peroxidase (GPx), while GSH is recycled by the action of glutathione reductase (GR). Since both of the enzymes were affected in old as well as senescent rat hearts, overproduction of H2O2 or lack of reduced NADPH was present. Moreover, peroxidase-mediated elimination of H2O2 will also augment the level of GSSG. This in turn, may not only lower the glutathione redox potential, but also increase in amount of protein mixed disulfides. Addition of GSH to protein cysteine residues results to post-translational modification known as S-glutathionylation. It is a reversible process with potential to activate or inactivate protein function by modulating different cellular pathways. It is able to influence gene expression by affecting different transcription factors such as Nrf2 (nuclear factor erythroid 2-related factor 2) or NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) [52]. The Nrf2-Keap1 (Kelch-like ECH-associated protein 1) pathway is the major regulator of cytoprotective responses to oxidative and electrophilic stress. In the presence of ROS, critical cysteine residues in Keap1 become oxidized leading to a conformational change, which prevents its binding to Nrf2. As a consequence, Nrf2 degradation is stopped and its nuclear translocation promoted [53]. Recently was shown that S-glutathionylation of endothelial NO synthase (eNOS) at Cys689 and Cys908 leads to eNOS uncoupling, diminished NO production and enhanced oxidative stress linked with superoxide overproduction [54]. S-glutathionylation as well as GSH alone interacts with earlier mentioned nuclear factor Nrf2. This factor is key transcription factor of 4-hydroxy-2-nonenal (HNE). HNE is highly reactive aldehyde product of lipid peroxidation with potential to modulate function of proteins and lipids. The Nrf2 under stress conditions activates HNE-mediated antioxidant protection, when at a sub-lethal concentration 5 μmol/l HNE stimulates biosynthesis of GSH in cardiomyocytes. In contrary, glutathione after oxidation to the glutathione radical (GS•) has deleterious effects. It is able to take H+ from lipid side chains and polyunsaturated fatty acids or to induce lipid peroxidation [55]. Altogether, S-glutathionylation may be a double-edged sword in the sense that it promotes antioxidant or pro-oxidant responses.
\nPeroxidase activity is found in GPx and in the thiol-specific proteins called peroxiredoxins (Prx). They react with H2O2 at a very high rate and their activity depends on cysteine residue in the active site. Peroxiredoxins can also reduce and detoxify peroxynitrite anion and a wide range of organic hydroperoxides. The highest reaction rate and abundance has Prx2 which traps almost all H2O2in vivo [56]. The level of this powerful thiol-specific protein was maintained until the age of 14 months, but senescent mitochondria lost 35.1% of Prx2 amount (Figure 3). Oxidized cysteine residues of Prx are specifically reduced by Trx. Oxidized Trx as well as other oxidized cellular proteins can be reversibly reduced by TrxR in a NADPH-dependent manner. The Trx/TrxR system appears to have a protective function against oxidative stress, e.g. supports the activity of ribonucleotide reductase and inhibits apoptosis signal-regulated kinase-1 [57]. Thioredoxin reductase has been severely affected during aging process by 41.9% in group of 14 months old hearts with an extension until the age of 27 months (Table 2). The same scenario was observed in Trx protein level where the amount of protein has decreased to 62.4% in 14 months old as well as 27 months old rat hearts (Figure 3). Low Trx level is probably result of TrxR malfunctioning due to lack of NADPH, overproduction of ROS and/or RNS. Thioredoxin also plays a role in the reversible S-nitrosylation of cysteine residues in target proteins, and thereby contributes to the response of intracellular nitric oxide (NO). In addition, Trx is able to block caspase-3 activity through nitrosylation of the active cysteine site in response to NO. Therefore, Trx protein deficiency may contribute to the stimulation of caspase-dependent apoptosis. The most studied enzyme in the process of protein S-glutathionylation is glutaredoxin (Grx). The high specificity of Grx to S-glutathionylated proteins is used as a tool for studying and identifying them. In general, it is stated that the main task of Grx is to remove GSH from S-glutathionylated proteins. Thus, reduced thiol-containing protein is restored, which was confirmed in experiments with siRNA (small interfering RNA). The suppression of Grx genes with siRNA is an approach to study not only the “antioxidant” properties of Grx but also the role of protein S-glutathionylation [58]. Grx2 catalyzes S-glutathionylation of IMM proteins in a relatively reduced GSH/GSSG ratio equal to 6. The fact that thiol-disulfide oxidoreductases can catalyze both oxidizing and reducing reactions is not exclusive to Grx. Thioredoxin can act as an oxidant in oxidizing environment. Currently, the biggest challenge of researchers is to identify which enzymes are responsible for (de)glutathionylation, and if it is spontaneous process or catalyzed by enzymes. Existing information suggests that the mechanisms involved in resistance to various types of stress together with maintenance of bioenergetic capacity and redox homeostasis may be critical in the evolution of longevity.
\nScheme of (A) Thiol-disulfide network and (B) protein level for Prx2, Trx (yet unpublished data). GSH-reduced glutathione, GSSG-oxidized glutathione, GPx-Glutathione peroxidase, GR-Glutathione reductase, Grx-Glutaredoxin, Prx-Peroxiredoxin, Trx-Thioredoxin, TrxR-Thioredoxin reductase, SH-reduced and SS-oxidized form of Protein, ICDH-isocitrate dehydrogenase.
One of the major goals of gerontology is to understand the comprehensive mechanisms involved in aging at different levels and hopefully to help understand age-related diseases. The complexity of the proteome supersedes that of the genome, due to alternative splicing events and PTMs of proteins. Proteomes are expected to be two to three orders of magnitude more complex than would be predicted from numbers of protein-encoding genes present in the respective genomes [59]. It is widely recognized that cellular aging causes changes in the proteome. However, the nature and targets of these changes and their consequences have not yet been completely identified. In recent years, mass spectrometry (MS) has been recognized as a golden standard tool for the identification and analysis of individual proteins. For further understanding of the molecular changes during heart aging, we have identified several proteins and compared the differences in the mitochondrial protein expression profiles among two age groups.
\nPrecipitated proteins from mitochondria of 6 and 27 months old rat hearts were separated with two-dimensional electrophoresis (2-DE) to provide a protein profile (Figure 4). Interestingly, the change in protein level was statistically significant (1.5-fold change, 95% confidence interval) in only 12 proteins (marked with red circles) from the total protein pool of mitochondria. All the proteins were down-regulated in senescent mitochondria in comparison to the adult ones. Despite the small number of quantitatively modified proteins, these create an interesting protein-protein network. The strength of data support represents line thickness of protein-protein interaction network generated by String software and using gene IDs (Figure 5). Two proteins, methylmalonate-semialdehyde dehydrogenase [acylating] (Gene ID: Aldh6a1) and carnitine O-palmitoyltransferase 2 (Cpt2) did not fit to the protein-protein interaction map. However, their role in fatty acid metabolism is very important in connection to the heart muscle work and energy production. The rest of the proteins participate in various metabolic pathways of mitochondria. Three take part in Krebs cycle – malate dehydrogenase (Mdh1), dihydrolipoyl dehydrogenase (Dld) and aconitate hydratase (Aco2). Post-translational cysteine-related modification of aconitase was reported to be a key in linkage between Krebs cycle, redox signaling and metabolism of ROS [60]. Next five down-regulated proteins were directly connected with cardiac muscle contraction and the risk of developing age-related neuronal disorders - Huntington, Parkinson and Alzheimer disease. All of them are subunits of ETC, thus regulate production of energy in mitochondria: NADH dehydrogenase 1 alpha subcomplex subunit 5 (Ndufa5), cytochrome bc1 complex subunit 1 (Uqcrc1) and cytochrome bc1 complex subunit Rieske (Uqcrsf2), cytochrome c oxidase subunit 5B (Cox5b), electron transfer flavoprotein subunit beta (Etfb). Combined defects in oxidative phosphorylation and fatty acid beta oxidation were detected in mitochondrial diseases [61]. Creatine kinase M-type (Ckm) was only one cytoplasmic enzyme interacting with mitochondria through transfer of phosphate and the last one is voltage-dependent anion-selective channel protein 1 (Vdac1), which plays a role in outer mitochondrial membrane permeabilization and cellular death. This outer mitochondrial membrane protein is tightly bound with Alzheimer disease, where mediates amyloid β toxicity and represents a potential target for Alzheimer disease therapy [62].
\nRepresentative 2-DE analysis of mitochondrial proteins in aging rat heart (yet unpublished data).
Functional protein-protein interactions during aging in rat mitochondria (yet unpublished data).
Currently available evidence indicates that the steady-state amounts of structural damage to proteins accumulated during life are relatively small, and are often present only in trace amounts. On the other hand, the pro-oxidizing changes in the redox state reflected by the decline in redox potential, increases in production of H2O2 and level of protein modifications are significant and ubiquitous. However, the oxidative PTMs are relevant only if these are connected to functional consequences. It is important to consider that a slight modification in low abundance proteins may be of physiological importance. Distinguishing between inconsequential modifications and functionally significant ones requires careful biochemical/biophysical analysis of target proteins [63]. Thus, proteomic approaches represent powerful tools to address these questions by identifying the targeted proteins and the extent of their modifications.
\nThe detailed examination of enzyme molecules by mass spectrometry and other techniques continues to identify hundreds of distinct PTMs. Global analyses of enzymes using proteomics revealed widespread distribution of PTMs on many key enzymes located in all cellular compartments. Multiple PTMs within a single enzyme molecule and their mutual interplays are critical for the regulation of catalytic activity. Enzymatic PTMs can be detected in ever increasing amounts and they appear to be critical for folding and assembly (e.g. glycosylation), function as key regulators of catalytic activity of enzymes (e.g. binding of prosthetic groups, phosphorylation), or mark enzyme molecules for targeted destruction (e.g. ubiquitylation). In parallel with these processes there are non-enzymatic PTMs caused by ROS and RNS continuously interacting with individual enzyme molecules. These PTMs contribute to molecular aging and may also be involved in regulation of enzymes’ catalytic activity [64]. There are two groups of PTMs observed during oxidative stress mediated aging, reversible and irreversible. The major types of irreversible PTMs are carbonylation and 3-nitrotyrosilation.
\nCarbonylation is covalent adduction of lipid aldehyde to the side chains of lysine, histidine or cysteine residues. Extensive amount of information about this modification can be found in the recently published book [65].
3-nitrotyrosilation, frequently called tyrosine nitration is formed between RNS (peroxynitrite anion) and a tyrosine residue of target protein. Extensive research was done during last years in failing human [66] and rat hearts [67].
Second group of reversible PTMs which are related to the aging process are sulfur-mediated S-Sulfenylation, S-nitrosylation, S-glutathionylation and lipid peroxidation pathway-related HNE modification.
\nProtein S-Sulfenylation leads to the production of sulfur-hydroxylation product (P-SOH), disulfide bond and sulfenyl-amide bond formation. It may be a precursor to the process of S-sulfinylation and S-sulfonylation. This type of modification is believed to be a fleeting molecular switch that regulates non-enzymatic oxidative folding [68].
S-nitrosylation occurs when NO is covalently incorporated into the Cysteine thiol group forming S-nitrosothiol (SNO). It plays important role in redox metabolism through GSH interaction in failing heart in rats [67] and human heart disease [69]. This PTM has been progressively implicated in virtually every NO-regulated process within the cardiovascular system. The current, widely-held paradigm is that S-nitrosylation plays an equivalent role as phosphorylation, providing a stable and controllable PTM [70].
S-glutathionylation is covalent attachment of GSH to protein thiol groups. The function of protein S-glutathionylation reactions in metabolism is a rapid and reversible redox signaling mechanism that involves the conjugation and removal of glutathione from cysteine switches. Several observations have shown that unlike other redox modifications S-glutathionylation reactions fulfill the requisite criteria to serve as an effective PTM that controls protein function, links energy metabolism to redox signaling in mitochondria. Because of its role in modulation of ROS production in myocardial mitochondria, currently the usage of mitochondria penetrating antioxidants is discussed in context of the heart disease treatment [71].
During last decade HNE modification was under extensive research because of its dual role as pro- and anti-oxidant. This most abundant reactive aldehyde attacks predominantly nitrogen of histidine, lysine (less commonly arginine) or cysteine, and it is related to wide range of metabolic diseases [72].
Above mentioned PTMs occur the most frequently during oxidative stress-related aging process. However, there are virtually hundreds of additional PTMs that may occur in enzymes. To support results from protein profiling of mitochondria is important to focus on deep protein analyzes of individual selected proteins, their interactions within the individual compartments, between different organelles or the intercellular communication. For this purpose, proteomics is now integrated with molecular genetics, transcriptomics, and other areas leading to systems biology strategies.
\nProper functioning of mitochondria is crucial for cardiac function. Damaged mitochondria produce less ATP, release greater amounts of ROS, and have a lower threshold for cytochrome c release resulting in apoptosis, undergo mitochondrial permeability transition pore opening resulting in necrosis or may release mitochondrial components into cytosol where are recognized by receptors for removal. Mitochondrial turnover is therefore an integral aspect of quality control in which dysfunctional mitochondria are selectively eliminated through autophagy or mitochondrial autophagy (mitophagy) and replaced through expansion of preexisting mitochondria (biogenesis). In the heart mitochondria turnover is with a half life of 14 days. Rat cardiomyocytes have roughly 1000 mitochondria per cell, suggesting that under basal resting conditions, one mitochondrion per cell is replaced every 40 minutes [73]. In order to facilitate and initiate mitophagy, mitochondrial fusion and fission play a critical role in mitochondrial turnover. Fission of mitochondria into smaller fragments is a crucial requirement for mitophagy to occur. The key regulator of this process is dynamin-related protein 1 (Drp1), which in concert with proteins fission 1 (Fis1), mitochondrial fission factor (Mff), mitochondrial dynamics proteins of 49 kDa (MiD49) and 51 kDa (MiD51) is responsible for mitochondrial fragmentation. The role of last three proteins appears essential. Mff assists in the assembly of Drp1. MiD49 and MiD51 may play a regulatory role by recruiting Drp1 and maintaining it in inactive state until fission is required [74]. Proteins that promote outer mitochondrial membrane (OMM) fusion such as Mitofusin 1 and 2 (Mfn1 and 2) are ubiquitinated and eliminated by the ubiquitin proteasome system. E3 ubiquitin ligase Parkin (also known as Park2) and PTEN-induced putative kinase 1 (PINK1) have been shown to play an important role in mitophagy. PINK1 targets to the mitochondria but is normally degraded by presenilin associated rhomboid-like protease (PARL). In response to loss of mitochondrial membrane potential, PARL is inactivated; PINK1 is stabilized and recruits Parkin. Parkin ubiquitinates several mitochondrial associated proteins and they are then recognized by p62 and bring mitochondria to the autophagosomes. Thus mitochondria with membrane potential loss can be selectively degraded. Parkin substrates include e.g. voltage-dependent anion-selective channel protein (VDAC), translocase of the outer membrane (TOM), mitochondrial fission 1 (FIS1), hexokinase, mitochondrial Rho-GTPase (MIRO) 1 and 2, although whether ubiquitination of these proteins is required or sufficient for mitophagy is unclear and highly dependent on the specific cellular context [75].
\nThe importance of mitophagy for the preservation of cardiovascular homeostasis, the cardiomyocyte-specific deletion of Parkin and the expression of a mutant Mfn2 (mitofusin 2) at birth prevented the switch from fetal to adult mitochondria in the mice heart [76]. Another example, mice bearing a heart-specific deletion of Mfn2 prematurely succumbed to a progressive cardiomyopathy characterized by impaired contractile function [77]. Such a detrimental phenotype could be reversed, at least partially by Mfn2 to prevent the targeted mitochondria from rejoining the mitochondrial network through fusion. Under basal conditions Mfn2 functions in mitochondrial fusion events and links endoplasmic reticulum to mitochondria. Also acts as Parkin receptor during mitophagy following phosphorylation by PINK1 and recruiting Parkin to the mitochondria. So even in case of Parkin-dependent mitophagy, some outer mitochondrial membrane proteins are recycled through transfer to the endoplasmic reticulum. Most studies have relied on the systemic modulation of autophagy with nutritional or pharmacological interventions or the homozygous/heterozygous deletion of a relevant gene. Nutritional and pharmacological interventions commonly used to modulate autophagy in the cardiovascular system in vivo, including caloric restriction or caloric restriction mimetics, rapamycin, 3-methyladenine, and lysosomal inhibitors, are rather nonspecific. Genetic interventions offer increased specificity, but are not devoid of potential problems that should be kept under attentive consideration. Linking mitophagy with cardiomyocytes is the field of interest in many publications [78]. While mitophagy is responsible for bulk degradation of mitochondria, turnover of individual components may proceed at asynchronous rates through redistribution of components via fusion events, selective degradation of proteins by mitochondrial proteases, and proteasomal elimination of some outer mitochondrial membrane proteins. Some studies suggest that inner mitochondrial membrane proteins, especially oxidative phosphorylation constituents, may be primarily cleared via mitophagy. There is more to discuss, especially communication between intracellular organelles (mitochondria and endoplasmic reticulum) and oxidative phosphorylation events in mitochondria in relation to redox network, apoptosis/necrosis or mitophagy. These appear to be key players in cardiomyocytes survival during aging.
\nMaintenance of mitochondrial function and energy/redox homeostasis requires both generation of newly synthesized and elimination of dysfunctional mitochondria. Taken together, age-dependent decline of mitophagy inhibits removal of dysfunctional or redundant mitochondria as well as impairs mitochondrial biogenesis. It results to progressive mitochondrial accretion and consequently, deterioration of cardiomyocytes function. At present it is pointed out that the steady-state amounts of structural damage accumulated during life are relatively small. However, changes in the redox state reflected by the decline in redox potential, increases in production of H2O2 and level of protein modifications are significant and ubiquitous. Activities of ETC complexes revealed that the most affected throughout aging was complex IV, in contrast to relatively small age-related changes in complex II. These non-uniform changes in ETC enzyme complexes may lead to altered electron transfer through the chain, leading to impairment of ATP synthesis and overall functionality of cardiomyocytes during aging. The ability of the main regulatory Krebs cycle enzymes to supplement NADH to ETC was altered in senescent mitochondria. ICDH and KGDH had only half activity in senescent mitochondria; however ICDH was not affected in group of 14 months old. This might support promotion of H2O2 in senescent cardiac myocytes where peroxiredoxin 2 ability to trap H2O2 was also significantly affected. Decrease in GSH levels indicates low GSH/GSSG ratio leading to more oxidized environment in senescent cardiomyocytes but 14-month old hearts were able to maintain basal levels of adult mitochondria. Despite the variations in enzyme activities, the overall proteomic analyses revealed only 12 significantly affected proteins during aging. All these were more or less deprived but question is what is responsible for such a changes. Are these proteins really relevant? Is change in protein amount important? These and other questions are waiting for us and other researchers to be answered.
\nSpecific marker of senescence was yet not identified, but evaluating a series of markers can help to define the senescent state. Senescent cells have greater proportion of protein content, which might be modulated by several PTMs. If these protein modifications are connected to functional consequences and protein-protein interactions are revealed, link may lead to the solution. Unfortunately, the proteome is much more complicated than the genome. To fit all the proteins together with their different characteristics in various pathways and cellular compartments is almost infeasible. At present, various nutritional, pharmacological and genetic interventions have higher or lower specificity, but are not devoid of potential problems that should be kept under attentive consideration. Collectively, these studies suggest that dysfunctional proteostasis has a causative role in aging and that restoration of protein homeostasis is protective against age-related diseases. New window is opened and hopefully with help of bioinformatics collecting huge amounts of data from proteomics, genomics and other scientific approaches will lead to personalized therapeutic procedures for individual patient and age-related disorder(s).
\nThis work was supported by the project APVV-15-0107 and the project “Competence Center for Research and Development in the field of Diagnostics and Therapy of Oncological diseases”, ITMS: 26220220153, co-financed from EU sources. We thank Mrs. Zdena Cetlova for technical assistance.
\nDiabetes is the fastest growing chronic condition worldwide. The prevalence of people with type 2 diabetes (T2D) is growing in each country [1]. Diabetes is also the seventh leading cause of deaths in the world. Around 1.6 million people died due to diabetes in 2016 [1]. Higher blood glucose levels also caused an additional 2.2 million deaths, by increasing the risks of cardiovascular and other complications such as kidney disease, blindness, neuropathy, and limb amputation [2, 3, 4]. Successful glycemic control can prevent and reduce these complications. However, to maintain optimal glycemic control requires ongoing monitoring and treatment, which can be costly and challenging [5]. Advances in health information technologies (HITs) have introduced approaches that support effective and affordable health-care delivery and education. Technologies in mobile, computer, e-mail, and Internet approaches have shown evidence in enhancing chronic disease management including diabetes management, via supporting provider decision-making (through electronic risk assessment, alerts, guidelines, formularies, and prescribing) and facilitating patient self-management (through risk communication, Web portals, telemedicine, e-mailing, and secure messaging) [6, 7, 8]. In this chapter, we summarized the current findings on HITs in managing T2D, especially on glycemic control and CVD risks management. In addition, we discussed limitations in the current research in this area and implications for future research. Further, we presented challenges of applying HITs in T2D management in the real-world context and suggested steps to move forward.
\nHITs include a broad range of technologies, electronic tools, applications, or systems that provide patient care, information, recommendations, or services for promotion of health and health care [9]. The advantages of using HITs in health care have been well documented [10, 11, 12, 13]. They have the potential to empower patients and support a transition from a role in which the patient is the passive recipient of care services to an active role in which the patient is informed, has choices, and is involved in the decision-making process [10]. They are also designed to promote communication and relationships between clinicians and patients and overcome geographical barriers and logistical inconvenience when seeking health-care services [11]. In the realm of chronic disease management, a variety of technologies have shown their positive effects. For examples, electronic health record system provides reminders at the point of care for providers to identify high-priority clinical areas for patients with complex chronic illness [14]; telemonitoring system provides asthma patients with continuous individualized help in the daily routine of asthma self-care [12]; Web-based applications increase knowledge, problem-solving skills, and social support via an interactive system for patients with cancers [13]; mobile technology devices such as personal digital assistants (PDAs) and cellular phones enable additional resources to care and change the location of care; and mobile phone short message service (SMS) were able to remind patients of scheduled visits, deliver test results, and monitor side effects of treatment [15, 16, 17]. The HIT-enabled self-care keeps evolving and attempts to address more challenging health-care issues, such as diabetes management where patients need comprehensive information and ongoing guidance as they work to develop a diverse knowledge and skills.
\nA growing research attention has been given to evaluate HITs’ impact on diabetes management, including the primary management goal, glycemic status, and major complications such as cardiovascular conditions. Previous reviews on this subject suggested that HITs have the potential to improve these disease outcomes [18, 19, 20, 21, 22, 23]. However, effect size is specific to the main outcome; glycated hemoglobin (HbA1c) varied between studies with reported mean difference ranging from −0.20 to −0.57% [19, 20, 21, 22, 23]. Table 1 presented the synthesized findings from the latest systematic reviews. Heitkemper et al. searched randomized control trials (RCTs) that studied the effect of HITs on HbA1c among medically underserved patients [21]. In this meta-analysis of 10 eligible trials, HITs were associated with significant HbA1c reduction at 6 months (pooled standardized difference in mean: −0.36, 95% CI −0.53, −0.19) with diminishing but still significant effect at 12 months (pooled standardized difference in mean: −0.27, 95% CI −0.49, −0.04). The authors also performed analyses by HIT type including computer software without Internet (n = 2), cellular/automated telephone (n = 4), Internet-based (n = 4), and telemedicine/telehealth (n = 3). The Internet-based interventions demonstrated the greatest reduction in HbA1c at both 6 months (pooled standardized difference in mean: −0.50, 95% CI −0.69, −0.32) and 12 months (pooled standardized difference in mean: −0.87, 95% CI −1.58, −0.21). Cellular and automated telephone interventions showed the smallest reduction. In Tao and colleagues’ systematic review on consumer-centered HITs, they identified a significant pooled reduction of −0.31 (95% CI −0.38, −0.23) in HbA1c from 18 RCTs [18]. Similarly, Alharbi et al. also found HITs were associated with a statistically significant reduction in HbA1c levels (mean difference: −0.33%, 95% CI −0.40, −0.26%) [19]. In addition, Alharbi and colleagues found studies focusing on electronic self-management systems demonstrated the greatest reduction in HbA1c (−0.50%), followed by those with electronic medical records (−0.17%), an electronic decision support system (−0.15%), and a diabetes registry (−0.05%) [19]. Faruque et al. identified 11 RCTs with specific focus on effect of telemedicine [20]. Telemedicine refers to the use of telecommunications to deliver health services, expertise, and information on glycemic control [20]. In this study, the authors demonstrated a significant reductions in HbA1c all three follow-up periods (mean difference at ≤3 months: −0.57%, 95% CI −0.74, −0.40%, at 4–12 months: −0.28%, 95% CI −0.37, −0.20%, and at >12 months: −0.26%, 95% CI −0.46, −0.06%). In another meta-analysis that specially focused on telemedicine, Marcolino and colleagues found telemedicine was associated with a statistically significant and clinically relevant decline in HbA1c level compared to control (mean difference = −0.44%, 95% CI −0.61, −0.26%) [22]. Pal et al. examined the effect of computer-based intervention in self-management in adults with T2D. The authors found modest effect associated with the interventions (mean difference: −0.2%, 95% CI −0.4, −0.1%) [24]. Liang et al. assessed the effect of mobile phone intervention on glycemic control in diabetes self-management and found a significant common reduction of HbA1c (mean difference: −0.5%, 95% CI −0.3, −0.7%) among 22 trials over a median follow-up of 6 months [23].
\nAuthor, year | \nObjective and intervention(s) under review | \nInclusion criteria | \nSample | \nHbA1c reduction (absolute difference in means) | \nHbA1c reduction (standardized difference in means and Hedges’ g) | \nCVD risk factor assessment | \nIntervention period | \nHIT subgroup analysis | \nMajor limitations | \n
---|---|---|---|---|---|---|---|---|---|
Yoshida et al., 2018 [33] | \nEvaluating of effect of HITs on T2D glycemic control in general T2D patients, including mobile phone-based HITs, Web-based HITs, short message/text, and other HITs | \nRCTs conducted from 1946 to December 2017 | \n34 RCTs (40 estimation points); 3983 participants with T2D | \n−0.65% (95% CI −0.99, −0.64%) | \nStandard mean difference: −0.57 (95% CI −0.71, −0.43); Hedges’ g: −0.56 (95% CI −0.70, −0.43) | \nA separate analysis focusing on CVD risk factors is upcoming | \n2–12 months | \nMobile phone-based approaches [Hedges’ g = −0.66 (95% CI −0.88, −0.45)]; SMS/text [Hedges’ g = −0.63 (95% CI −1.07, −0.19)]; Web-based [Hedges’ g = −0.48 (95% CI −0.65, −0.30)] | \nDid not provide analysis at different time points | \n
Heitkemper et al., 2017 [21] | \nEvaluating of effect of HIT self-management interventions on glycemic control in medically underserved adults with diabetes, including computer software without Internet, cellular/automated telephone, Internet-based HITs, and telemedicine/telehealth | \nRCTs conducted from 2000 to 2015 | \n10 RCTs; 3257 medically underserved adults with diabetes | \nNot reported | \nStandard mean difference: −0.36, 95% CI −0.53, −0.19 at 6 months and −0.27, 95% CI −0.49, −0.04 at 12 months | \nNo | \nUp to 12 months | \nInternet-based HITs (standard mean difference = −0.50, 95% CI −0.69, −0.32 at 6 months and −0.87, 95% CI −1.58, −0.21 at 12 months); cellular/automated telephone HITs (standard mean difference = −0.26, 95% CI −0.49, −0.03 at 6 months and not significant at 12 months); telehealth (standard mean difference = −0.37, 95% CI −0.68, −0.06 at 6 months and not significant at 12 months) | \nExternal validity issue (only focused on a specific patient group); mixed participants with type 1 and 2 diabetes | \n
Tao et al., 2017 [18] | \nEvacuating of effect of consumer-oriented HITs in diabetes management | \nRCTs conducted up until July 2016 | \n18 RCTs; participants in trials ranged from 14 to 1382 | \nNot reported | \nStandard mean difference: −0.31, 95% CI −0.38, −0.23; glycemic control was significant at intervention duration of 3, 6, 8, 9, 12, 15, 30, and 60 months | \nNo | \nUp to 60 months | \nNot reported | \nLumped all types of HITs into analysis; mixed participants with type 1 and 2 diabetes | \n
Faruque et al., 2017 [20] | \nEvaluating of effect of telemedicine on glycemic control, including broad forms of electronic forms communication. | \nRCTs conducted from 1946 to November 2015 | \n111 RCTs; 23,648 participants with diabetes | \n−0.57% (95% CI −0.74, −0.40%) at ≥3 months; −0.28% (95% −0.37, −0.20%) at 4–12 months; −0.26% (95% −0.46, −0.06%) at >12 months | \nNot reported | \nNo | \n3–68 months | \nThe effect was the greatest in trials where providers used Web portals or text messaging to communicate with patients [mean difference: −0.35% (95% −0.56, −0.14) and −0.28% (95% CI −0.52, −0.14)] at 4–12 months | \nMixed participants with type 1 and 2 diabetes | \n
Alharbi et al., 2016 [19] | \nEvaluating of effect of HITs in glycemic control in T2D patients. HITs included Web-based approaches, telephone-based system, mobile phone-based system, and telemedicine | \nRCTs conducted up until July 2016 | \n32 RCTs; 40,454 participants with T2D | \n−0.33%, (95% CI −0.40, −0.26) | \nNot reported | \nNo | \n3–36 months | \nElectronic self-management systems [mean difference: −0.50% (95% CI −0.67, −0.43%)]; EHR [mean difference: −0.33% (95% CI −0.40, −0.26%)]; electronic decision support system [mean difference: −0.15% (95% CI −0.34, −0.16%)]; diabetes registry [mean difference: −0.05% (95% CI −0.15, −0.19%)] | \nDid not provide analysis at different time points | \n
Pal et al., 2014 [24] | \nEvaluating computer-based interventions in self-management in T2D patients. Intervention delivered via clinics, the Internet, and mobile phone | \nRCTs conducted up until November 2011 | \n16 RCTs; 3578 participants with T2D | \n−0.2% (95% CI −0.4, −0.1%) | \nNot reported | \nYes. Did not find improvement of blood pressure, lipids, or weight due to interventions | \n8 weeks to 12 months | \nMobile phone intervention (mean difference: −0.5%, 95% CI −0.3, −0.7) | \nDid not provide analysis at different time points | \n
Marcolino et al., 2013 [22] | \nEvaluating of effect of telemedicine on diabetes care | \nRCTs conducted up until April 2012 | \n13 RCTs; 4207 participants with diabetes | \n−0.44% (95% CI −0.61, −0.26%) | \nNot reported | \nYes. Only found telemedicine was associated with reduction in LDL (−6.6 mg/dL, 95% CI −8.3, −4.9 mg/dL) | \n6–18 months | \nNot reported | \nMixed participants with type 1 and 2 diabetes; did not provide analysis at different time points | \n
Liang et al., 2010 [23] | \nEvaluating of effect of mobile phone intervention for diabetes on glycemic control | \nRCTs conducted from January 2010 to February 2010 | \n22 trials including 11 RCTs and 11 non-RCTs; 1657 participants with diabetes | \n−0.5% (95% CI −0.3, −0.7%) | \nNot reported | \nNo | \n3–12 months | \nNot reported | \nLumped nonrandomized and randomized trials together into evaluation | \n
Synthesized findings of effect of HITs on HbA1c and cardiovascular risk factors among diabetes patients.
Many of review studies including those mentioned above have shed light on the effect of HITs in glycemic control. However, these studies often included limited number of trials [21], lack of adherence to standard quantitative methods [25], inadequate attention to heterogeneity across studies [26], lumped nonrandomized and randomized trials together into evaluation [19, 23, 25, 27, 28, 29], mixed participants with type 1 or type 2 diabetes into analysis [18, 22, 25, 27, 28, 29], or restricted searching criteria to a particular patient population or a specific type of HIT [27, 30, 31, 32]. To address these limitations and to verify if and how much HITs impact glycemic control, Yoshida and colleagues recently conducted a meta-analysis to examine the most current state of evidence from RCTs concerning the effect of HITs on HbA1c reduction among patients with T2D [33]. From an analysis of 34 eligible studies (40 estimates) identified from multiple databases from January 1946 to December 2017, the study reported that introduction of HITs to standard diabetes treatment resulted in a statistically reduced HbA1c. The absolute mean difference in HbA1c pre- and postintervention between intervention and control group was −0.65% (95% CI −0.99, −0.64%). The pooled reduction (standardized difference in means) of HbA1c was −0.57 (95% CI −0.71, −0.43) (Figure 1). In addition, Yoshida et al. also found the reduction was significant across each of the four types of HIT interventions (i.e., mobile phone-based, Web-based technologies, SMS/text, or others) under review, with mobile phone-based approaches generating the largest effects [pooled reduction was −0.67 (95% CI −0.90, −0.45)] followed by SMS/text [−0.64 (95% CI −1.09, −0.19)], and Web-based [−0.48 (95% CI −0.65, −0.30)] [33].
\nPooled reduction of HbA1c due to HITs. Adopted from the study of Yoshida et al [33].
HITs also have significant clinical impact in reducing HbA1c among patients with T2D. It is reported that every 1% decrease in HbA1c over a 10-year period is associated with a risk reduction of 21% for diabetes-related death and 37% of microvascular complications [34]. This reduction results from HIT interventions may be bigger than effects of many targeted pharmacological therapies. Oral antidiabetic agents reduced HbA1c levels of 0.5–1.25%, with thiazolidinedione and sulfonylureas showing the best reduction (1–1.25%) [35]. Biguanide reduced HbA1c by 1.0–2.0%; dipeptidyl peptidase 4 (DPP-IV) inhibitor, 0.5–0.8%; GLP-1 agonists, 0.5–1.5%; and TZD, 0.5–1.4% [36]. It is questionable that the effects on HbA1c yielded from the HIT trials were a mixed product of both HITs and standard diabetes care including medication adherence and lifestyle modifications. This concern was addressed in the systematic review of Yoshida et al. [33]. The authors conducted a subset analysis of 18 studies that exclusively compared the outcome between a combined HITs and standard care intervention group vs. standard care control group. The effect size estimated from this analysis was −0.63 (Hedges’ g: −0.63 95% CI −0.84, −0.42), which is attributable to HIT tools in addition to the usual care [33]. This result suggests that HITs are the key to the effectiveness rather than tools or components of these trials. Additionally, pharmacotherapies often use motivated patients’ sample and they cannot generate their full effects without patients’ adherence to treatment and persistence in usage [33]. In this sense, HITs may add additional value in the effectiveness by addressing challenges in adherence of a pharmacological therapy or of behavioral interventions.
\nT2D is commonly accompanied by cardiovascular complications. Adults with diabetes have a 77–87% prevalence of hypertension, a 74–81% prevalence of elevated low-density lipoprotein cholesterol (LDL), and a 62–67% prevalence of obesity [37]. Cardiovascular disease (CVD) is recognized as the most frequent cause of morbidity and mortality in patients with diabetes, causing up to 70% of all deaths in this patient group [2]. Type 2 diabetes (T2D) confers an approximate twofold elevation of CVD risk, equivalent to that of a previous myocardial infarction [3, 38]. In light of CVD burden in those with diabetes, the management of modifiable CVD risk factors, including hypertension, dyslipidemia, and obesity, is critical to minimizing the risk of macrovascular complications as well as death of diabetes. Yet, the implementation of preventive strategies to CVD among individuals with T2D is often not adequate [39, 40, 41] and less than half of patients who visit their care provider meet recommended levels for blood pressure (BP) and lipids [42]. Innovative approaches such as HITs are needed to facilitate CVD risk factor management among patients with T2D.
\nIn the context of cardiovascular care among general populations, HITs were documented to offer numerous benefits and have been associated with improvements in the measurement and monitoring of heart health, including risk factors such as BP, arrhythmia, cholesterol, and weight, as well as the implementation of guideline-based decision support for providers [43]. However, CVD outcomes are usually secondary and less described compared to glycemic status in T2D management trials [26, 44]. Furthermore, many review studies examining HITs’ effect in diabetes management often overlooked CVD outcomes [26, 44] or include insufficient sample size or limited CVD parameters for analysis [22, 24]. In the study by Marcolino et al., only 13 studies were included in the final analysis, within which 8 studies assessed the effect on SBP, 7 on DBP, and 5 on LDL [22]. No effects of telecommunication and information technologies were seen on SBP and DBP. They did, however, find a statistically significant reduction on LDL (−6.6 mg/dL, 95% CI −8.3, −4.9 mg/dL) associated with the technologies evaluated. They were not able to perform analysis on weight outcome, because only two studies assessed the effect of HITs on weight and both studies demonstrated a nonsignificant reduction on weight. In the systematic review by Pal et al., among 11 RCTs included in their final analysis, 5 studies looked into changes in BP (only 1 showed improvement in BP), 7 reported changes in BMI or weight (5 were combined in a meta-analysis), and 10 measured serum lipids (7 were combined in a meta-analysis) [24]. The overall pooled effect did not reach statistical significance for all of these outcomes [24].
\nThe current research on the effect of HITs in diabetes management has several limitations. First of all, the published trials often do not provide protocols for studies [45]. There is also lack of information on the theoretical bases of the interventions, and whether the HIT interventions are accompanied by other pharmaceutical or lifestyle therapies in their publications. As these HIT interventions are main therapeutic agents, it would be beneficial to explicitly prescribe interventions for trials and state the active components (behavior-change techniques), dose (frequency and intensity of interactions), route (mode of delivery), and duration of treatment [45]. There is also a need to clarify other ingredients in the intervention such as medication, standard care from health professionals, so that the major role of the HITs to the effectiveness of the interventions can be estimated, separating the effects from usual care and treatment [33].
\nAdditionally, intervention periods in published trials are short (most trials under 1 year) [33] and few systematic reviews provided effect estimation by length of follow-up. Studies by Tao et al. and Heitkemper et al. showed that HITs’ effect on glycemic control was diminishing as the interventions proceeded [18, 21]. It is not clear whether intervention effect and compliance with the HIT interventions would sustain in the long term. Misuse or nonuse of technological support is a common problem in disease management, which greatly affects patient’s outcomes. There is also lack of focus on cardiovascular health assessments in HIT interventions for diabetes management. We only found two systematic reviews that discussed CVD outcomes in addition to glycemic control. Because very few trials included cardiovascular risk factor evaluations, the synthesized findings were modest (Table 1). As we discussed earlier, because CVD causes major morbidity and mortality among T2D patients, designing and evaluating HITs for diabetes management should include cardiovascular health indicators. Further, many review studies only reported standardized difference in means [18, 21], which may be less intuitive to patients who care the absolute changes (i.e., mean difference) in outcomes (e.g., HbA1c) due to an intervention. Moreover, it remains unclear whether there are harms associated with the intervention. It has been reported that people may suffer from negative consequences of excessive self-monitoring by finding it uncomfortable, intrusive, and unpleasant [46, 47]. Studies found patients with diabetes who self-monitor their own blood glucose concentration did not benefit from increased glycemic control but rather found their disease more intrusive [48]. The interaction between a HIT device and a patient can be complex, and further studies need to consider these in more detail. Further, whether the interventions would be cost-effective if it required significant health professional support in a long-run has not been documented well in the literature [33, 49]. Additional research with more time points of follow-up is warranted to maximize data to inform the compliance with the HITs, long-term impact on health outcomes, to look for evidence of harms and to determine the cost-effectiveness in the intervention [49]. Studies with CVD risk factor assessments and absolute outcome measurement are also needed.
\nMoreover, it is unknown which populations will benefit the most from the HIT intervention as the current research in HITs has not always directly engaged diverse end users. There are also many questions surrounding the “digital divide” in HITs use, where the access, usability, and effectiveness of diabetes technologies are divided by users’ age, education, computer literacy, culture, and affluence [49]. These issues highlight the importance of engaging more research to design, test, and implement HITs for diverse patients with diabetes.
\nWhile features of HITs can expand patients’ ability in diabetes management and the results from the existing research showed their positive effects on outcomes of HbA1c and CVD risk factors, many of these applications described above have so far been explored predominantly within clinical trials rather than a real-world context. For those that have been widely used in real health-care setting, such as electronic patient record system; both health-care providers and patients have reported difficulties for engagement [50]. Multiple sources of tension contribute to these barriers (Table 2).
\nBarriers | \nPossible solutions | \n
---|---|
Validity and reliability | \n\n
| \n
Privacy and security | \n\n
| \n
Adaptability | \n\n
| \n
Barriers of using HITs in the real-world context and possible solutions.
First of all, the reliability and validity of some HITs is concerning. For example, many manufacturers market their products under the premise that they will help in improving health, but they often do not provide empirical evidence to support the effectiveness of their products [51]. Recent comparisons between different wearable devices for tracking physical activities yielded large heterogeneity in accuracy [52, 53]. The medical apps market also showed the similar discrepancy [54]. Lack of reliability is a serious obstacle that needs to be addressed before a HIT could be considered for medical use. Moreover, whether technological designs incorporated evidence-based guidelines is questionable [55]. It is reported that features of diabetes management apps on the online market did not cover evidence-based recommendations. A recent study evaluated 137 diabetes management apps from two major app stores (iTunes and Google Play) and compared the features with the American Association of Diabetes Educators (AADE) Self-Care Behavior guidelines. The author found an unbalanced feature development of current diabetes management apps. Few apps provided features supporting problem solving, reducing risks, and healthy coping, which are critical for user engagement and successful diabetes self-management [56].
\nSecondly, the privacy and security of personal data generated by HITs remains problematic. Users of these devices or technologies usually do not own the data; rather, data may be collected and stored by the manufacturers [51]. While some companies are willing to share user’s “anonymizing” data via a simple distortion or removal of identifying features, these techniques do not provide adequate levels of anonymity and are not sufficient to prevent identity fraud [57]. Moreover, some devices are easily to be hacked as a result of various communication technologies that aid the transfer of data between the devices and smartphones. It has been reported that wireless digital pacemakers and glucose pumps are vulnerable to cyberattacks [58].
\nFurther, even in relatively widely adopted HIT systems, such as the electronic patient records system, there are still many unfilled promises due to lack of interoperability between systems, difficult-to-use interface, and lack of consideration on patients’ backgrounds [50]. In the United States, for example, the patient records systems are not designed to talk to each other [59]. Until now, health-care providers have had little incentive to acquire or develop interoperable systems [50]. As a result, the current electronic health records do not allow a patient or provider to access needed health information anywhere at any time. Additionally, many clinicians are reluctant to invest the considerable time and effort to master difficult-to-use technology, which hindered the anticipated productivity gains of HITs [59]. Moreover, there are limited data collection on patient backgrounds, such as race/ethnicity, language preference, and health literacy in the patient records systems [49]. Lack of this set of data could cause fragmented care delivery and lead to patients’ misunderstanding of provider instruction and lose trust in the medical system [49].
\nTo transform HITs a real asset for diabetes care, further steps need to be considered (Table 2). First is to create a simple regulatory framework that does not suppress innovation but helps HITs, especially some wearable devices and apps become valid in the context of their health-oriented value [51]. A risk-based classification that promotes innovation, protects patient safety, and avoids regulatory duplications has recently been proposed [60]. As part of this model, the U.S. Food and Drug Administration jurisdiction covers higher-risk medical apps [61]. The National Health Service in the United Kingdom adopts similar pathway with their regulatory framework for mobile apps, which can be classified as “medical devices” by Medicines and Health Products Regulatory Agency [61].
\nA simple and powerful guide is also needed to transform the HIT system, especially the electronic patient records system. Health data stored in one system should be readily retrievable by others, subject to patient consent [50, 62]. For true interoperability, standardization must be achieved across three dimensions: how messages are sent and received; the structure and format of the information; and terms used within these dimensions [50]. HITs should also facilitate the work of clinicians by providing a system that is intuitive to use and without extensive retraining. Easy-to-use HIT systems not only will increase the productivity of providers but also will be safer [50].
\nAdditionally, HIT systems need to include automated and standardized categories for a patient background (e.g., race/ethnicity, language), facilitate communication among multiple providers and patients, and tailor to the needs of diverse populations [9]. Moreover, a genuine partnership should be fostered between patients and health-care providers through the use of HITs. Engagement can range from patients being simply better informed to individuals themselves being dynamically engaged in the HIT management, giving feedbacks about the HIT interventions, and even controlling who has access to their data [62, 63]. Furthermore, future technologies developed for diabetes management should incorporate balanced features from creditable guidelines to better support changing self-management behaviors of people with diabetes.
\nOverall, the current evidence shows that HITs have favorable impact on glycemic control and CVD risk management among patients with T2D. Future studies should examine the long-term effects of HITs and their cost-effectiveness, potential harms, and test and verify their effectiveness in glycemic control and other important health indicators such as CVD risk factors, among diverse populations. HITs may be valuable tools in enhancing human health and well-being overall. However, their advances also pose challenges in aspects of validity and reliability, patients’ privacy, security, and engagement. These issues need to be addressed before a broader implementation of HITs in the real-world setting.
\nWe pride ourselves on our belief that scientific progress is generated by collaboration, that the playing field for scientific research should be leveled globally, and that research conducted in a democratic environment, with the use of innovative technologies, should be made available to anyone.
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