|Year : 2016 | Volume
| Issue : 4 | Page : 7-18
|Date of Web Publication||8-Apr-2016|
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
. Invited talks. J Pract Cardiovasc Sci 2016;2, Suppl S1:7-18
Heart Failure Management in India: Continuing Challenges
K. K. Talwar
Department of Cardiology, Max Healthcare Institute, New Delhi, India
Heart failure (HF) is a major public health problem and its epidemiology in India is quite different from that seen in the west. Clinical examination and investigations viz echocardiography, biomarkers, coronary angiography are helpful to identify the severity and underlying aetiology to plan therapy. Endomyocardial biopsy (EMB) may help to diagnose myocarditis, infiltrative disorders and cardiac follow cases with transplant for any rejection. Optimum use of diuretics, digoxin, beta-blockers, ACE inhibitors, angiotensin receptor blockers and aldosterone antagonists were documented to improve left ventricular function. Patients with systolic heart failure (< 35%) and wide QRS (LBBB) benefit from cardiac resynchronization therapy (CRT). Sudden cardiac death is an important problem in patients with systolic heart failure. All patients with left ventricular ejection fraction less than 30% should be considered for implantable cardioverter defibrillator (ICD) therapy for primary prevention. Those patients who continue to be refracting to available therapy should be considered for LV assist devices which are useful both as destination or bridge therapy for cardiac transplant. These treatment facilities are again limited to only a few centers in the country because of the limited expertise and high cost of these devices.New drugs like Angiotension Neprilysin Inhibitor (Enteresto) have been recently approved by FDA are shown to be superior to ACEI. Newer devices to enhance vagal stimulation are being evaluated as increased vagal tone may help patient with HF. Anti viral therapy and immunosuppressive therapies are being studied in patients with viral positive and viral negative myocarditis patients with promising results. Regenerative therapy using stem cell and cytoskeletol protein regeneration approaches appear promising as future therapies. Thus HF management continues to be challenge in medicine and needs research in the newer fields of therapy.
Prevention of Diabetes and Coronary Artery Disease
Madras Diabetes Research Foundation, Chennai, Tamil Nadu, India
The epidemic of diabetes in India is still spiraling upwards and the recent national Indian Council of Medical Research, India Diabetes (ICMR-INDIAB) study, the largest epidemiological study on the prevalence of diabetes, estimated the current numbers as 62.4 million individuals with diabetes and 77.2 million with prediabetes in India. The Chennai Urban Population Study (CUPS) and Chennai Urban Rural Epidemiology Study (CURES) reported the overall prevalence of coronary artery disease (CAD) in the population as 11.0% and that among those with diabetes, as 21.4%. These figures are much higher than that reported in white Caucasians. The high rates of diabetes and CVD among Indians has been attributed to the "Asian Indian or South Asian Phenotype" which is characterized by dyslipidemia, decreased adiponectin and increased high sensitivity C-reactive protein despite low rates of obesity. Additionally Indians have been shown to have increased small dense LDL. The ICMR-INDIAB study showed that about 80% had dyslipidemia which is fairly consistent across different regions of India and also across urban and rural areas. Most of this is attributed to low HDL cholesterol which is ubiquitous in Indians. Though genetic factors undoubtedly play a major role in the predisposition of diabetes in Indians, environmental factors contributes to over 50% of the risk and indeed the epidemic is driven by environmental factors as our genes did not change in 40 years. Rapid economic growth in India has resulted in rapid nutritional transition contributing to excess calories (high glycemic loads) along with decreased physical activity. A recent study from our centre has shown that replacing white rice with brown rice could improve 24 hour blood glucose and insulin levels. Adopting a diet that is rich in whole grains along with increasing physical activity and reduction of weight in those who are overweight or obese could be a cost-effective, feasible and sustainable approach to prevention of both diabetes and coronary artery disease in India.
Cardiomyopathy: Insights from Phenotype and Genotype
Department of Cardiology, Royal Brompton and Harefield NHS Foundation Trust, London, UK
In recent years there has been tremendous understanding of the interface between phenotype and genotype in patients presenting with cardiomyopathy. Dilated cardiomyopathy is a classic example where ten years ago much of the condition was felt to have a viral or idiopathic aetiology. Increasingly it is now recognised that somewhere between 20%-50% of cases have a familial predisposition or aetiology. In particular, identification of the TITIN gene has identified major advances in our understanding of the process and therefore facilitated the opportunity for both early identification and hopefully going forward novel therapeutic targets. It has also provided an understanding of why patients remodel and will hopefully going forward indicate where patients may remodel. Hypertrophic cardiomyopathy is the current paradigm for how this information may best be gleaned. What is still missing in our current loop however is using the genetic information in guiding risk stratification. Going forward there will be much work required in understanding the interface between genotype and phenotype to guide this aspect and importantly to enable and initiate early risk stratification therapies before patients declare themselves to be at risk.
Heart Failure in India
Deaprtment of Cardiology, All India Institute of Medical Sciences, New Delhi, India
Projected Burden: The prevalence of heart failure is increasing worldwide. The overall prevalence of HF in US is 1.76% (4.8 million individuals). Assuming the causation of HF due to the complex of age, coronary heart disease, hypertension and diabetes is similar worldwide and projecting the prevalence in US to Indian population, the approximate prevalence of HF in India would be about 10 million (~ 0.9% of total population). Prevalence: We examined the burden of heart failure in 10163 adults aged ≥ 20 years, comprising the entire adult population of 6 villages, in rural Delhi. The prevalence of heart failure was 0.98/1000 with a mean age of 59.5 11.9 years. In a southern India rural population based project in 45 villages, HF was responsible for 2.4% of all-cause mortality of 1170 deaths in adults ≥ 30 years of age. Coronary heart disease, cerebrovascular disease, other heart diseases accounted for 3.9% of all-cause mortality. A substantial proportion of this would be due to heart failure as well; thereby contributing to almost 4-6% of all-cause mortality in adults. This could be even higher considering the fact that half of all ill-defined deaths (18% of total) occurred in elderly and were mostly likely to be cardiovascular in origin. These data are for rural India, which has majority of Indian population but had lower burden of cardiovascular disease. The burden is likely to be higher in urban areas which have higher prevalence of CVD. Causes: In a study from central India looking at aetiology of decompensated heart failure in a large secondary hospital, Rheumatic Heart Disease (RHD) was responsible for more than half (52%) of all admissions for heart failure (n = 125). Ischemic and/or hypertensive heart disease was found in 27% of all patients. Similarly a study of 500 consecutive outpatients from a tertiary hospital in North India found Framingham criteria based heart failure in 20% patients. Majorities (52%) were due to RHD and the mean age was much younger at 39 years. Though RHD is often overrepresented among referral government hospitals the data still suggests that it is still an important contributor apart from major causes like CAD and hypertension.
Progression of Dilated Cardiomyopathy
Department of Cardiology, Post Graduate Institute of Medical Education and Research, Chandigarh, India
Despite improvements in medical management and device therapy, patients with dilated cardiomyopathy (DCM) have variable clinical course. Some patients recover while others have only mild symptoms despite persistent ventricular dysfunction. Many however progress to end stage heart disease. Several etiopathological factors could be responsible for this variable course. These include severity of initial insult, persistent or recurrent myocardial injury, residual valvular regurgitant lesions and electrical conduction delays. Each one of these factors is important. In this review the importance of left and right ventricular function will be discussed. Conduction delays are especially important. With currently recommended medical therapy, one-fourth patients with non-ischemic DC have sustained improvement, and over one-third of those who improve, relapse. Shorter QRS duration is associated with recovery of LVEF and longer QRS duration is associated with relapse. Thus once the conduction system is involved, the capacity to recover LVEF decreases in these patients. The important question is whether the QRS widening occurs at the onset or whether the QRS continues to widen as the disease progresses. The QRS duration either remains unchanged or shows only a minor increase in vast majority of patients. This indicates that though the conduction delay is an important prognostic marker, progression of conduction delay does not contribute to disease progression.
Dilated Cardiomyopathy: Pathological Variants
Uma Nahar Saikia
Department of Histopathology, Post Graduate Institute of Medical Education and Research, Chandigarh, India
Cardiomyopathy or "heart muscle disease" is defined as inability of the myocardium to contract, usually leading to heart failure. Dilated cardiomyopathy (DCM) is the most common type occurring in adults of age range 20 to 60 years with male predominance. The term DCM was applied to all those sub-acute or chronic disorders of the myocardium associated with congestive cardiac failure with cardiomegaly in absence of valvular heart disease, hypertension, coronary artery disease or any observable cause at autopsy. Nearly a quarter to one-third cases of DCM is genetic in origin. Myocarditis is described as an inflammatory infiltrate of the myocardium with necrosis and/or degeneration of adjacent myocytes resulting in progressive heart failure and arrhythmia. Ischemic cardiomyopathy is a common cause of heart failure and is the most common type of cardiomyopathy in the US affecting middle-aged and elderly people. Peripartum or postpartum cardiomyopathy (PPCM) is characterized by rapid onset heart failure during the final weeks of pregnancy or up to 6 months postpartum. Alcoholic Cardiomyopathy is a type of acquired DCM associated with long-term heavy alcohol consumption. Endocardial fibroelastosis (EFE) was first introduced by Weinberg and Himmelfarb in 1943. Drug Induced Cardiomyopathy (Anthracyclins, Adriamycin) may be due to drug toxicity, acute myocardial damage (myocarditis), chronic damage (idiopathic DCMP). While most cases of cocaine-related cardiomyopathy have proved to be reversible, others have resulted in permanent cardiac dysfunction or death. Muscular dystrophy (MD) is a heterogeneous group of inherited disorders characterized by progressive wasting and weakness of the skeletal muscles resulting in cardiac dysfunction. DCM is a feature of Duchenne and Becker MD caused due to mutations in the DMD gene. Characteristic features include sub-epicardial fibrosis in the myocardium on histology. Familial dilated cardiomyopathy (FDC) exhibits familial transmission consistent with autosomal dominant (AD) inheritance (~90%), but X-linked (5-10%) and autosomal recessive (AR) or mitochondrial inheritance have been reported. The important mutations involve Cardiac troponin T, Lamin A/C, Muscle LIM Protein, PSEN1 and PSEN2.
A Multilevel Approach to Inherited Sarcomeric Cardiomyopathies
John A. Mercer
Center for Cardiovascular Biology and Disease, Institute for Stem Cell Biology and Regenerative Medicine, Bengaluru, Karnataka, India
Our multinational consortium is studying disease-causing mutations in genes encoding sarcomeric proteins with the goal of identifying small-molecule activators and inhibitors as therapeutics. At the whole-organism level, given that mutations in the MYH7 gene are the most prevalent in inherited cardiomyopathies, we have constructed an improved mouse model in which the gene encoding the predominant mouse alpha-cardiac myosin heavy chain isoform (Myh6) has been replaced by human MYH7. We have shown that in heterozygotes, approximately equal amounts of alpha and beta isoforms are expressed and phenotypes are normal. No significant differences relative to wild-type controls were observed when the heterozygous mice are stressed by either voluntary exercise or by isoproterenol administration. At the biochemical/biophysical level, among known mutants are thirty single-residue substitutions in TPM1, the gene encoding alpha-tropomyosin. We examined six mutants chosen based on their clinical severity and locations along the molecule. Measurements of Ca2+ sensitivity of myosin ATPase activity were consistent with the hypothesis that hypertrophic cardiomyopathies are hypersensitive to Ca2+ activation and dilated cardiomyopathies are hyposensitive. Moreover, we observed changes in protein stability and protein-protein interactions in these mutants. Our results suggest multiple mechanistic pathways to hypertrophic and dilated cardiomyopathies. Finally we examined a computationally designed mutant, E181K, which is hypersensitive, confirming predictions derived from in silico structural analysis. We noted interesting correlations between ATPase activity at maximum Ca2+ concentrations and conformational changes in TnC measured using a fluorescent probe, suggesting a simple method for high-throughput screening for small-molecule activators and inhibitors.
microRNAs as Potential Therapeutics in Cardiac Remodelling
Department of Experimental Medicine and Biotechnology, PGIMER, Chandigarh, India
Cardiovascular diseases account for significant morbidity and mortality in both developing world and developed populations. Cardiac remodelling is an established pathological feature of the heart failure due to variety of causes. Cardiomyocyte hypertrophy and myocardial fibrosis are the major pathological changes responsible for cardiac remodelling and are associated with dysregulation of gene expression of key pathway genes. The search for the basic mechanisms that are responsible for the development and progression of cardiac remodelling has been exhaustive, but strategies to prevent and reverse cardiac remodelling remain elusive. Recent studies have uncovered a potentially important role for a family of tiny noncoding regulatory RNAs, known as microRNAs (miRNAs or miRs), in the transcriptional and post transcriptional regulation of gene expression. Further, microRNAs have been reported to regulate diverse aspects of cardiac function and also play an important role in the pathogenesis of heart failure through their ability to regulate the expression levels of genes that govern the process of adaptive and maladaptive cardiac remodeling. However, our understanding of the role that microRNAs play in cardiac remodelling is limited. An overview of putative role of micro RNAs targeting various pathways involved in the pathogenesis of cardiac hypertrophy and cardiac fibrosis in diabetes milieu will be presented.
Catestatin Modulates Adrenergic Signaling and Reverses the Hypertrophic Effects of Norepinephrine in H9c2 Cardiac Myoblasts
Md. Jahangir Alam, Nitish R. Mahapatra 1 , Shyamal K. Goswami
School of Life Sciences, Jawaharlal Nehru University, New Delhi, 1 Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai, Tamil Nadu, India
Catestatin (CST), a catecholamine release inhibitory peptide, is derived from chromogranin A. It is released along with the catecholamines from the adrenal glands and the adrenergic neurons. It is involved in the regulation of cardiovascular functions and associated diseases including hypertension, cardiomyopathy, myocardial infarction and heart failure; but the mechanisms of its actions are not known. We demonstrate that CST reverses the induction of fetal genes in H9c2 cardiac myoblasts by norepinephrine (NE). CST attenuates the ROS generated by NE treatment. It modulates the redox responsive transcription factors AP-1 and Nrf2, either alone or in presence of NE. Expression of fosB and AP-1 promoter-reporter constructs is also modulated by CST alone or in association with NE, though it has preference for the β- rather than α-AR signaling. However, it does not prevent apoptosis induced by a higher dose of NE. Effects of CST on reporter gene expression suggest that it acts through multiple signaling pathways. Taken together, this study for the first time establishes an insight into the modulation of adrenergic signaling by CST.
Hsp90 Mediates Biphasic Activation of STAT-3 Mediated Fibrosis During Cardiac Hypertrophy Involving Fibroblast-Myocyte Crosstalk
Department of Zoology, University of Calcutta, Kolkata, West Bengal, India
Cardiomyocyte hypertrophy due to chronic pressure overload is accompanied by excessive collagen deposition in heart. It is reported earlier that such increase in collagen biosynthesis by cardiac fibroblasts is being mediated via prohypertrophic signalling from cardiomyocytes during disease progression. However, the precise mechanism of cardiac fibroblast-cardiomyocyte crosstalk still lacks a comprehensive understanding. The present study is a continuation of our earlier observation that effect of Hsp90 inhibition on STAT-3 mediated signalling differs significantly between isolated fibroblast cells (in vitro) and rat hearts (in vivo). In this study, cardiomyocyte targeted knockdown of Hsp90 in renal artery ligated rats (Rattus norvegicus) along with conditioning of fibroblasts with Hsp90 inhibited myocyte supernatant in vitro facilitated the exploration of cardiomyocyte driven regulation of cardiac fibrosis during hypertrophy. Our data suggests that Hsp90 from myocytes is not only essential for p65 mediated IL-6 synthesis but also a critical player in exosome mediated transfer of IL-6 from myocyte to fibroblast during hypertrophy. Both secreted and exosomal IL-6 are responsible for the activation and maintenance of STAT-3 signalling in cardiac fibroblasts which culminates in excess collagen synthesis from fibroblasts. Our study thus unravels for the first time Hsp90 driven regulation of IL-6 mediated biphasic activation of STAT-3 in collagen upregulation process via myocyte-fibroblast crosstalk.
Mitochondrial Dysfunction, Oxidative Damage and Apoptotic Cell Death Stress Mechanisms in Diabetic Cardiomyopathy
Sandeep Kumar, Santosh Kumar, Vasundhara Kain, Prachi Umbarkar, Sandhya Sitasawad
National Centre for Cell Science, Pune, Maharashtra, India
Diabetic cardiomyopathy, a disorder of the heart muscle in diabetic patients, is a major cause of heart failure. Diabetic heart is characterized by compromised ventricular contraction and prolonged relaxation attributable to multiple causative factors including calcium accumulation, oxidative stress and apoptosis. Therapeutic interventions to prevent calcium accumulation and oxidative stress could hence be helpful in improving the cardiac function under diabetic condition. We investigated the protective role of multiple antioxidants (MA) and long-acting calcium channel blocker (CCB), Azelnidipine (AZL) on cardiac dysfunction and cardiac cell apoptosis in streptozotocin (STZ)-induced diabetic rat. Diabetic cardiomyopathy in STZ-treated animals was characterized by declined systolic, diastolic myocardial performance, oxidative stress and apoptosis in cardiac cells. Contractile functions were traced from live diabetic rats to isolated individual cardiomyocytes including peak shortening (PS), time-to-PS (TPS), time-to-relengthening (TR90), maximal velocity of shortening/relengthening ( dL/dt) and intracellular Ca2+ fluorescence. Diabetic rats on supplementation with MA or AZL treatment showed decreased oxidative stress and Nitrosative stress, decreased activity of catalase with down-regulation of heme-oxygenase-1 mRNA, normalized lipid profile and decreased levels of pro-inflammatory transcription factor NF-κB as well as cytokines such as TNF-α, IFN-γ, TGF-β, and IL-10. MA decreased the expression of ROS-generating enzymes like xanthine oxidase, monoamine oxidase-A along with 5-Lipoxygenase mRNA and/or protein expression. Further, left ventricular function was re-established as evidenced by increase in dp/dtmax, heart rate, decrease in blood pressure and TUNEL positive cardiac cells. In addition, MA supplementation decreased cell death and activation of NF-κB in cardiac H9c2 cells. Based on our results, we conclude that MA supplementation or AZL treatment significantly attenuated cardiac dysfunction in diabetic rats; and may have important clinical implications in terms of prevention and management of diabetic cardiomyopathy.
SIRT6 Deacetylase Regulates the Development of Lipotoxicity in Heart
Nagalingam Ravi Sundaresan
Department of Microbiology and Cell Biology, Indian Institute of Science, Bengaluru, Karnataka, India
Diabetic patients' heart exhibit contractile dysfunction, due to the lipotoxicity i.e. accumulation of neutral lipids inside cardiomyocytes. Lipotoxicity develops in cardiomyocytes due to increased uptake, but inefficient utilization of fatty acids in cardiomyocytes. Recent studies indicate that calorie restriction could prevent or delay the onset of metabolic diseases. Although calorie restriction is mediated through multiple cellular signaling pathways, signaling through Sirtuins, a family of lysine deacetylates, is considered more significant. Sirtuins are family of NAD dependent histone and non-histone protein deacetylases, which are homolog of yeast silencing regulator 2 (Sir2), evolutionarily conserved across prokaryotes to eukaryotes. There are seven Sirtuin isoforms are identified in mammals. Among them, SIRT6 is the nuclear localized chromatin-associated deacetylase. SIRT6 predominantly has histone H3K9, H3K56 deacetylase activity, modulates telomeric chromatin structure and also known to repress several transcription factors such as HIF-1α, NF-κB, c-Myc and FoxO. SIRT6 deficient mice die within a month and show hyper aging phenotype. On the other hand, SIRT6 overexpressing mice exhibit extended lifespan. Recent studies also show that SIRT6 play a key role in inflammation, where SIRT6 promotes the secretion of TNF alpha. SIRT6 favors DNA repair process by deacetylation of PARP-1, a major enzyme involved in the DNA repair process. Our previous findings indicate that SIRT6 blocks development of cardiac hypertrophy by targeting c-Jun. However the role of SIRT6 in the development of lipotoxicity is not well understood. In this talk, I will discuss our recent findings that suggest SIRT6 as a major regulator of the expression of fatty acid transporters, uptake of fatty acids into cardiac myocytes and the development of lipotoxicity in heart.
Atrial Natriuretic Peptide/Natriuretic Peptide Receptor-A Mediated Signaling: An Endogenous Anti-hypertrophic Protective Mechanism of the Heart
Department of Biochemistry, University of Madras, Chennai, Tamil Nadu, India
The natriuretic peptides (NPs) family is consists of three important peptides namely atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP). ANP and BNP elicits its physiological action by specific binding to natriureitc peptide receptor-A (NPR-A), while CNP binds to natriureitc peptide receptor-B (NPR-B). Recent studies suggest that ANP/BNP/NPR-A system is present in the heart as a negative regulatory mechanism to antagonize the cardiac growth response to hypertrophic stimuli. Notably, the mice carrying targeted disruption of Npr1 (conding for NPR-A) exhibit blood pressure independent progressive cardiac hypertrophy, which eventually leads to congestive heart failure. On the other hand, over expression of Npr1 gene/ or ANP specifically in myocardial cells reduces hypertrophic agonist-induced myocyte growth suggesting that ANP/NPRA system locally present in the heart as a negative regulatory mechanism to antagonize the cardiac growth response to hypertrophic stimuli. Since ANP and BNP peptides has the potential to inhibit cardiac hypertrophic growth via NPR-A, understanding the regulation and expression of NPR-A and other subtypes in the heart during the diseased conditions will help to target specific NPRs subtype to increase the physiological actions of NPs, and thus may be useful as therapy for cardiac hypertrophy and heart failure. My laboratory is actively involved in understanding the expression pattern and regulation of NPs/NPRs in diseased heart. Cardiomyoblast H9C2 (2-1) cells and experimental cardiac hypertrophy in rats (hypertrophic agonist-induced) are the two model systems used in our laboratory to delineate the expression profile and regulation of NPRs in diseased heart. Recently, we have demonstrated that in vivo infusion (subcutaneous) of angiotensin-II (ANG II) suppressed the ventricular Npr1 gene expression, which was associated with down regulation of NPR-A dependent GC activity. These studies will be discussed during the presentation.
Molecular Insights into the Mitochondrial Calcium Mediated Modulation of Cardiac Function
Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA
Calcium is thought to play an important role in regulating mitochondrial function and reciprocally, mitochondria are multivariate signal processors of cytoplasmic Ca 2+ flux. The transport of Ca 2+ across the inner mitochondrial membrane is an essential signaling pathway for cellular metabolic functions such as energy production and cell death. Due to the selective permeability of the inner mitochondrial membrane, Ca 2+ uptake is tightly regulated by channels, transporters, and exchangers. Dysregulation of mitochondrial Ca 2+ -dependent bioenergetics has been implicated in various pathophysiological settings including myocardial infarction and heart failure. The Mitochondria Ca 2+ Uniporter (MCU) is a multimeric complex that mediates the rapid uptake of cytosolic Ca 2+ from intracellular store release. Our studies, using in vitro and in vivo genetic approaches have identified several key components of the MCU complex and their physiological roles in modulating the cardiac function. However, mitochondrial Ca 2+ overload promotes the opening of the mitochondrial permeability transition pore (PTP), a protein complex in the mitochondrial membrane, which leads to bioenergetic crisis and cell death. PTP opening has been implicated in ischemia/reperfusion injury and myocardial infarction. Our studies revealed the molecular identity of the PTP with SPG7 (spastic paraplegia 7) being a core component of PTP. In summary, our studies identified essential molecules that are involved in both mitochondrial Ca 2+ uptake and retention. Therapeutic targeting of these molecules would be a key to the treatment of cardiovascular diseases such as heart attack and stroke, where extensive mitochondrial dysfunction and cell death hinder tissue recovery.
Nutrient-mediated Teratogenesis: Molecular Mechanism of Fetal Programming of Cardio-metabolic Risk
Giriraj Ratan Chandak
Centre for DNA Fingerprinting and Diagnostics, Hyderabad, Telangana, India
India is known as the Diabetic Capital of the World and also suffers from the rare distinction of being capital of Low Birth Weight (LBW) in the World. This double burden is likely to provide an interesting link that can be exploited to restrain the ever-exploding burden of type 2 diabetes, metabolic syndrome and its related complications. Recent spurt of genome-wide association studies, mainly in Europeans has led to identification of many variants that predict risk of type 2 diabetes, cardiovascular disorders; several of them are also associated with birth weight and other anthropometric parameters. Our studies in Indian population has interesting mix of results; some loci replicating, several others replicating with higher effect size and few not showing similar effect as identified in Europeans. The latter category comprises those which influence intermediate traits for type 2 diabetes, such as obesity and insulin resistance. These observations provide an interesting link to the established phenotypic differences in Indians and Europeans, better known as "Thin-Fat Phenotype", characterized by less muscle mass and high fat percentage is present at birth and predicts future risk of cardiometabolic disorders. Strong evidence also exists that maternal hyperhomocysteinemia is risk factor for LBW, higher adiposity and insulin resistance, suggesting a paradigm for "Nutrient-Mediated teratogenesis". Since, Vitamin B 12 is central to S-adenosyl methionine production, the universal methyl-donor to almost all kinds of methylation reactions in the cell, we have initiated attempts to understand the molecular mechanism of B 12 action and genes/pathways influenced by B 12 intervention, as a model of understanding molecular basis of Nutrient-mediated teratogenesis and Fetal programming of cardio-metabolic traits. I will present preliminary data to advance suggestions that epigenetic regulation of key genes may underlie the fetal programming of intermediate traits related to cardio-metabolic disorders and thus may be an interesting strategy to rein the epidemic of type 2 diabetes in Indians and other developing countries.
A Common Genetic Variant of Catestatin (Ser-364) is Associated with Atherogenesis and Hypertension in a Japanese Population
Kazuhiro Takekoshi, Yoshio Nakata, Seiji Maeda 1 , Nitish R. Mahapatra 2
Faculty of Medicine, Division of Sports Medicine, University of Tsukuba, 1 Division of Sports Medicine, Faculty of Health and Sport Sciences, University of Tsukuba, Tsukuba, Japan, 2 Department of Biotechnology, Indian Institute of Technology Madras, Chennai, Tamil Nadu, India
Chromogranin A (CHGA) is a major protein in the secretory granules of chromaffin cells. CHGA also gives rise to cardiovascular/metabolism regulatory peptides, such as catestatin (CST) and pancreastatin (PST). While CST is a potent inhibitor of catecholamine secretion, PST is a potent physiological inhibitor of glucose-induced insulin secretion. Recently, several SNPs were identified in the CST and PST domains of CHGA locus in different populations. Among the discovered SNPs, CST variant allele Ser-364 was associated with blood pressure alteration and PST variant allele Ser-297 was associated with significantly higher plasma glucose level. In this study, we examined whether these CST and PST variant alleles exist and influence cardiovascular and metabolic phenotypes in Japanese population. Our study comprised of 343 Japanese subjects aged 45-85 years (143 men and 200 women, mean age 66 8 years). We determined the genotypes of CST and PST by PCR-direct sequencing method and carried out genotype-phenotype association analysis. In 343 participants, the minor allele frequency of CST variant Ser-364 was 6.10%. On the other hand, we did not detect the PST variant Ser-297 in this entire study population. The presence of Ser-364 allele was associated with increased in baPWV (an index of systemic arterial stiffness) that suggests an initiation and/or progression atherogenesis and hypertension. The Ser-364 allele was also associated with elevated systolic blood pressure and pulse pressure, consistent with increased baPWV. In conclusion, the CST Ser-364 allele may increase the risk for cardiovascular diseases in Japanese population.
Genetic Heterogeneity of Cardiomyopathy: Indian Perspectives
Centre for Cellular and Molecular Biology, Hyderabad, Telangana, India
Cardiomyopathy due to sarcomeric gene mutations is a major cause for heart failure. However, its genetic etiology remains largely unknown, particularly in the Indian subcontinent. Therefore, we have analysed sarcomeric genes, including; MYBPC3, TNNT2, TNNI3, TPM1 and MYH7 in dilated (DCM) and hypertropic cardiomypathy (HCM). We found a 25 bp deletion in the MYBPC3 that is associated with heritable cardiomyopathies and an increased risk of heart failure in Indian populations (OR = 6.99 (3.68- 13.57), P = 4 X 10 -11 ) and that disrupts cardiomyocyte structure in vitro. We have also screened for this mutation in different ethnic populations inhabiting all the continent and found its prevalence was high (~4%) in populations of the Indian subcontinent. We further estimated that more than 55 million people are at risk worldwide, almost 1% of the world's population, whereas, other mutations are either in low frequency or private, affecting only single family. Detailed genetic study and why the frequencies of disease causing variations are different in India would be discussed at the time of presentation.
Cardiomyopathies: From Genes to Therapies
Department of Pediatrics, Icahn School of Medicine, New York, USA
Cardiomyopathies are a group of life-threatening heart muscle diseases that represent a large proportion of heart failure and are one of the leading causes of heart transplantation. Every year about 1,000-5,000 new cases per 100,000 persons are diagnosed with cardiomyopathies, with the majority of the patients being less than 12 months old. The cause of a significant percentage of cardiomyopathies (~50%) remains unknown with poorly defined mechanisms. While decades of research have identified therapies (such as beta-blockers) to treat symptoms of cardiomyopathies, none are curative. All clinical approaches are symptomatic or reactive such as early intervention for developmental delays or beta-blockers for heart failure secondary to cardiomyopathies. My talk will be focused on identification of novel genes, relative mechanisms and possible therapies for cardiomyopathies using various model organisms.
CLADS: An Indigenous Automated Anesthesia Delivery System for Cardiothoracic Surgery (Anesthesia Robot)
G. D. Puri
Department of Anaesthesia, Post Graduate Institute of Medical Education and Research, Chandigarh, India
All anesthetic agents have varying degree of cardio respiratory depressant effect resulting in increased vulnerability of patients with myocardial dysfunction. This assumes more importance in view of the fact that altered hemodynamic in the form of decreased cardiac output and misdistribution of this blood flow to various vital organs can affect the pharmacokinetics or drug disposition including anesthetic agents. This may be further complicated by altered pharmacodynamic of anesthetic agents in such patients. In view of the above there is need to titrate the anesthetic drug dosages based on the desired clinical effects of such drugs which is further complicated by the muscle relaxants used as part of balanced anesthesia technique. A number of objective anesthetic depth indicator monitors are in clinical use which can be utilized for automated feedback control of anesthetic drugs. Automation in clinical environment has been shown to be an asset as it helps in doing routine repetitive task more efficiently as well as more accurately without any burnt out effect 24x7. CLADS is an EEG derived Bispectral index feedback controlled closed loop anesthesia delivery system which has been indigenously developed to control both intravenous as well as inhalational anesthetic drugs and has been used extensively in both cardiac as well as non cardiac surgery for anesthetic management of patients with cardiac dysfunction. The system can be used both for induction as well as maintenance of anesthesia as well as for postoperative sedation. It has been tested in both children as well as adults with cardiac diseases undergoing cardiac surgery. Efficacy and reliability of CLADS has been established over manual control of anesthetic drug administration and it has been shown to perform more consistently despite variations in patient and surgical variables as well as differences in anesthetic practices among different anesthesiologists. The closed loop systems bear the promise of becoming a useful tool to anesthesiologists in delivering a consistent depth of anesthesia, without causing major hemodynamic deterioration in various surgical settings in various patient population and at the same time, take a significant burden off the anesthesiologists' shoulder and thus allowing them to devote attention to other demanding tasks in the operating room.
Cyclophilin A as a Predictor of Vascular Risk in Patients with Type II Diabetes Mellitus
Ajit S. Mullasari
Department of Cardiology, The Madras Medical Mission, Chennai, Tamil Nadu, India
T2DM is one of the strong risk factors for development cardiovascular disease. Chronic low grade inflammation has been implicated both in the development of T2DM and its vascular complications. Chronic hyperglycaemia in T2DM leads to formation of advanced glycation end products in combination with important proteins and lipids. This in turn activates innate immune system resulting in inflammation. T2DM has been shown to be associated with increased circulating levels of IL-6, IL-1β, TNF-α and C-reactive protein. Further, therapy with statin, angiotensin converting enzyme inhibitors and antiplatelets were associated with decrease in the incidence of vascular complications partially through their anti-inflammatory effect. However, the exact link between T2DM and vascular complications is not known. Cyclophilin A is an immunophilin widely distributed in various cell types. It is secreted from vascular smooth muscle cells (VSMC) and endothelial cells in response to reactive oxygen species (ROS). It may play an important role in various stages of atherosclerosis promoting immigration and proliferation of smooth muscle cells. In addition, it is chemotactic for inflammatory cells. Further, it increases expression of adhesion molecules for inflammatory cells on endothelial cells and facilitate their migration by promoting secretion of matrix metalloprotinases. The recruited inflammatory cells secrete cytokines and further promote inflammation. Moreover, cyclophilin A exacerbates further generation of ROS. Thus cyclophilin A may be an important marker of atherosclerosis. Plasma Cyclophilin A levels indicate the extent of both oxidative stress and inflammation. A number of studies have shown a positive correlation between the plasma cyclophilin A levels and presence and severity of vascular disease. Recent studies by our group showed that hyperglycaemia as a strong stimulus for secretion of cyclophilin A from inflammatory cells, and both CAD and T2DM were associated with significantly higher plasma levels of cyclophilin A. A prospective study is ongoing to test the hypothesis of cyclophilin A as a marker of vascular disease in 1000 diabetic patients with and without vascular disease.
MicroRNAs: A Promising Therapeutic Option Against Cardiovascular Diseases
M. Zahid Ashraf
Defense Institute of Physiology and Allied Sciences, DRDO, New Delhi, India
MicroRNAs are a class of short endogenous non-coding RNAs that post-transcriptionally regulate gene expression either through transcript degradation or translational repression by binding to the 3′ UTR of the target mRNA. Each miRNA may have several target mRNAs suggesting that an mRNA could be regulated by multiple miRNAs. Distinct miRNA signatures have been observed in cardiovascular diseases, including arrhythmias (miR-1, miR-133 and miR-208a), fibrosis (miR-21and miR-29), cardiac remodelling (miR-208 and miR-133) etc. Similarly miR-21, miR-155, and miR-126 have been implicated in vascular diseases. The miRNAs have also been reported to be involved in different stages of atherosclerosis, including endothelium dysfunction, cellular adhesion and plaque formation. miRNAs in therapeutics in CVD is a promising field, and new findings are continuously emerging. We carried out a comprehensive miRNA profiling to generate a miRNA signature for third most common cardiovascular disease -Thrombosis. We started with systems biology approach to identify potential miRNAs involved in pathogenesis of this disease. Among potential candidate miRNAs, an inverse correlation with thrombus formation was observed. The in silico analysis and in vitro studies culminated in novel miRNA target identification and validation. These miRNA target genes showed an important role in regulation of extrinsic coagulation pathway. Restoration of miRNAs in thrombotic animals via in vivo delivery of the miRmimic resulted in a significant reduction in thrombus size, without disturbing hemostasis. Interestingly, we also found reduced miRNA levels clinically confirmed venous thrombosis patients when compared to control. Our translational study identifies a novel mechanism involving miRNA in regulating thrombus formation and widens the scope for miRNAs to be used as a therapeutic option against cardiovascular diseases.
Targeting Cardiovascular Disease with a Novel Dietary Molecule, Malabaricone C
Jitesh Singh Rathee, Subrata Chattopadhyay
Bio-Organic Division, Bhabha Atomic Research Centre, Mumbai, Maharashtra, India
Cardiovascular disease (CVD) mediated pathogenesis affects heart, kidney and blood vessels. India has the dubious distinction of being known as the coronary and diabetes capital of the world. By 2020, CVD is likely to become the single leading cause of death and disability in India. Major contributing factors to CVD are hypertension (HT), hypertrophy, endothelial dysfunction and electrical remodeling. The clinically used drugs against HT and CVD have several side effects, warranting search for newer alternatives possibly from natural and dietary sources. To this end, we have analyzed the cardiovascular remodeling property of malabaricone C (mal C), a natural phenolic constituent of Myristica malabarica in the DOCA-salt hypertensive (DSH) rat model which shows severe pathological cardiovascular remodeling. Administration of mal C to DSH rats significantly attenuated the rise in following parameters: systolic and diastolic blood pressures, inflammatory cell infiltrations, interstitial collagen depositions, plasma Na + and Ca 2+ levels, vasoconstrictors (big ET, ET-1 and AVP), oxidative stress and passive diastolic stiffness in perfused hearts. Besides, mal C also restricted the prolongation of action potential durations of repolarization in papillary muscle, decrease in the plasma K + concentrations, development of left ventricular hypertrophy, reduction in eNOS expression and vascular dysfunction in DSH rats. It also corrects the changes in QRS, QTc, P, PR durations, and heart rate of DSH rats as revealed by ECG profiles. The cardiac structural and functional parameters along with the cardiac output of DSH rats were also improved by the mal C administration as evident by the ECHO analysis. Overall, it increased the antioxidant status and survivability of the DSH rats. The results suggested that mal C can be a potential non-toxic cardiovascular protecting agent.
Cardiac Arrhythmia: Looking Beyond Drug
Biotronik Medical Devices Private Limited, New Delhi, India
The management of cardiac arrhythmia has undergone a tremendous change in the last decade. Besides drugs, two important tools have gained immense prominence viz Catheter Ablation and Device Therapy. The talk will give an insight into these technologies, some of the newer exciting advancements and what lies ahead.
Genetics and Congenital Heart Diseases
Department of Paediatric Cardiology, Institute of Cardiovascular Diseases, The Madras Medical Mission, Chennai, Tamil Nadu, India
Congenital heart disease (CHD) is the most common of birth defects, and is an important cause of morbidity and mortality during infancy and childhood. CHD is a multifactorial disorder associated with both genetic and environmental influences. Chromosomal abnormalities (CAs) are an important cause of congenital heart disease. We aimed to determine the frequency, type and clinical characteristics of chromosomal abnormalities identified by high-resolution karyotype/FISH/DNA analysis in patients with congenital heart disease. After precise diagnosis and clinical assessment, genetic testing was performed on 150 cases (50.6% males) according to the specific clinical phenotype. CAs were observed in 50 patients, 24 (46%) were numeric (19 patients with Down syndrome, 2 with Edward syndrome, 1 with variant Klinefelter syndrome and 2 with Turner syndrome). 27 (54%) had no numerica but structural abnormalities and included 17 patients with Digeorge syndrome, 5 with William syndrome, 2 with Noonan syndrome. Out of 87 FISH tested 17 were positive. Tetralogy of fallot (TOF) was seen in 10 patients. In the Trisomy 21 group 20 samples sent for karyotyping and 2 samples sent for FISH study based on downs phenotype, 17 KT samples and both FISH study were positive. Among the 17 patients with Down syndrome who underwent surgery 10 had stormy post operative course which includes 6 patients in ASD/VSD group, needed prolonged duration of ventilation, inotropic support, antibiotic course and PICU stay. Among the 5 patients with William syndrome 3 had LVOTO lesions 1 has B/L branch PA stenosis. The CHD associated with Edward syndrome (1 DORV and 1 PDA), Noonan (HOCM, CoA, Valvar PS), Turner syndrome (Aortic stenosis). The findings indicated that genetic associations complicated the anatomy by making the manifestations more severe. Thus, professionals, especially those working in Paediatric Cardiology Department, must be aware of the implications that performing the genetic testing can bring to the diagnosis, treatment and prognosis and for genetic counselling of patients and families.
Clinical Correlation of the Markers of Collagen Metabolism in Human Plasma in Rheumatic Heart Disease
Arun Bandyopadhyay, Somaditya Mukherjee, Tanima Banerjee, Sudip Ghosh, Monodeep Biswas, Santanu Datta, Sanjib Pattari
Cell Biology and Physiology Division, CSIR-Indian Institute of Chemical Biology, Kolkata, West Bengal, India
Rheumatic Heart Disease, a common health problem in developing countries affects around 12 million people worldwide. In India, rheumatic heart disease (RHD) is, responsible for 30-40% of cardiovascular disease related hospital admissions. The disease is characterized by damaged and deformed mitral valves predisposing them to scarring and narrowing (stenosis) that results in left atrial hypertrophy followed by heart failure. It is mainly diagnosed by imaging techniques. Despite the high prevalence and increased morbidity, no biochemical indicators are available for prediction, diagnosis and management of the disease. The present study was performed for understanding pathophysiology of Rheumatic Mitral Stenosis by proteome analysis. Six plasma samples, three each from the control and patient groups were pooled and subjected to low abundance protein enrichment. Pooled plasma samples (crude and equalized) were then subjected to in-solution trypsin digestion separately. Digests were analyzed using nano LC-MS E . Label-free protein quantification was performed in crude plasma only. A total of 130 proteins spanning 9-192 kDa were identified. Of these 83 proteins were common to both groups and 34 were differentially regulated. Functional annotation of overlapping and differential proteins revealed that more than 50% proteins are involved in inflammation and immune response. Verification of selected protein candidates by immunotechniques in crude plasma corroborated our findings from label-free protein quantification. Circulating levels of markers of collagen turnover were also monitored by immunoassay. Plasma level of C terminal propeptide of type I collagen (PICP) in rheumatic heart disease subjects (n = 75) was 400% higher than in controls (P < 0.0001). Levels significantly decreased one month after valve replacement surgery (240%, P < 0.0001). This protein profile of blood plasma, or any of the individual proteins, could serve as a focal point for future mechanistic studies on Mitral Stenosis.
Translational Pre-clinical Studies Identified Novel Dietary Cardioprotective Nutraceuticals
B. Raja 1 , J. Manivannan 1,2 , T. Silambarasan 1
1 Department of Biochemistry and Biotechnology, Annamalai University, Chidambaram, 2 KBC Research Centre, Anna University, Chennai, Tamil Nadu, India
Lifestyle factors, including nutrition, play an important role in the etiology of cardiovascular diseases (CVD). Nutraceuticals such as bioactive phytochemicals are non-nutrient plant compounds present in fruit, vegetables, grains and other plant foods have been linked to reductions in the risk of major chronic diseases. Scientific discoveries and the basic research of nutraceutical interventions could be translated into effective strategies to combat CVD. Over the past, five years in our laboratory we screened the cardioprotective effect of various phytochemicals such as morin, diosmin, borneol, piperine, veratric acid, diosgenin, syringic acid, vanillic acid, troxerutin and sinapic acid against nitric oxide deficient or DOCA salt induced hypertensive rat models. In these studies, we evaluated the cardioprotective potential of above phytochemicals starting from in vitro evolution in endothelial and cardiomyoblast cell lines to preclinical studies in rat model using Tail cuff Plethysmograph, Isolated Langendorff heart and Organ bath protocols. The comparative and the meta-analysis of our preliminary screening distinguishes five novel cardioprotective compounds out of ten based on their antioxidant, antihypertensive, prevention of cardiovascular structural and functional remodeling, signaling pathways interruption and its non toxic nature. Overall current evidences about the nutraceutical intervention of CVD will drive future development of translational nutraceutical therapies.
In vivo Preclinical Micro-ultrasound Imaging: A New Perspective in Cardiovascular Imaging for Small Animal Research
Fujifilm Visualsonics, Gurgaon, Haryana, India
Anatomical, Functional (Flow), Physiological and Molecular Data for Cardiovascular Research available from the same in vivo imaging platform in real-time for Pre Clinical Research.
In pre-clinical imaging, most scientists utilize small animals, such as mice and rats, to further their studies. High-frequency ultrasound allows for high image resolution of the smaller organs and structures present in these animals, without compromising on depth of field required. This enhanced image quality provides more accuracy in measurements and calculated data obtained from these images. Ultrasound imaging is a gold standard in cardiology for cardiac function assessment. The Vevo systems offer a full measurement package for the determination of cardiac function, cardiac wall abnormalities including dyssynchrony and myocardial infarction, and blood flow and valvular defects. Advance analysis tools are also available, such LV trace for quick cardiac function assessment, and VevoStrain for detection of early regional myocardial dysfunction".
Mechanisms and Significance of Protease Activation in Ischemic-reperfusion Injury to the Heart
Naranjan S. Dhalla
St. Boniface Hospital Research Centre, Institute of Cardiovascular Sciences, Winnipeg, MB, Canada
It is now well known that both calpains and matrix metalloproteases (MMPs) are activated in the heart during the development of ischemic-reperfusion injury. By employing isolated rat hearts, subjected to 30 min ischemia followed by 30 min reperfusion, we have shown that the depressed recovery of contractile function was associated with marked increases in calpain and MMP-2 activities as well as reduced sarcoplasmic reticular Ca 2+ -pump and sarcolemmal Na + -pump activities. Furthermore, the ischemia-reperfusion induced abnormalities in cardiac function, activation of proteolytic enzymes and defects in subcellular activities were attenuated upon treatment with antioxidants (N-acetylcysteine and mercaptopropionylglycine) as well as with inhibitors of both calpain (MDL 28170) and MMP-2 (doxycycline) activities. The alterations in cardiac contractile behaviour, proteolytic activities and subcellular function due to ischemia-reperfusion were not only dependent upon the concentration of extracellular Ca 2+ but were also simulated upon perfusing the hearts with an oxyradical generating mixture as well as an oxidant, H 2 0 2 . These observations support the view that oxidative stress and intracellular Ca 2+ -overload as well as the activation of proteolytic enzymes and subcellular defects plays a critical role in cardiac dysfunction due to ischemia-reperfusion injury. (Infrastructure support for this project was provided by the St. Boniface Hospital Research Foundation).
Remodeling of Cardiac Endothelium in Pressure Overload Left Ventricular Hypertrophy
0G. S. Ajithkumar, A. Vinitha, S. S. Binilraj, G. Sanjay 1 , C. C. Kartha
Division of Cardiovascular Diseases and Diabetes Biology, Rajiv Gandhi Center for Biotechnology, 1 Department of Cardiology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum, Kerala, India
Cross talk between cardiac endothelial cells and cardiomyocytes could significantly modulate remodeling in a diseased heart. We analyzed the molecular changes that occur in cardiac endothelial cells during evolution of pressure overload cardiac hypertrophy and progression to heart failure in Wistar rats. Constriction of ascending aorta was done in 40 Wistar rats and 40 rats had sham operation. Rats were sacrificed at the end of 1, 2, 3, 6 and 12 months after aortic constriction. In echocardiographic studies, a significant increase in inter ventricular septal thickness (IVST), left ventricular posterior wall thickness (LVPWT) and decrease in the left ventricular lumen size were observed at the end of 1 to 3 months in rats with aortic constriction. A significant change in ejection fraction (EF) was observed at 6 months after aortic constriction. After 12 months IVST and LVPWT were decreased and the LV lumen size was increased in rats with aortic constriction. EF was considerably reduced and BNP level were above 300 pg/ml of blood. Heart weight/body weight ratio and ventricular weight/ body weight ratio were significantly higher in aorta constricted rats. A significant increase in the expression of nitric oxide synthases (eNOS, iNOS), ABCG2, ACE 1&2, endothelin (ET), VEGFa and VEGFr was observed in isolated microvascular endothelial cells in rats with cardiac hypertrophy. A gradual decrease in expression of all these molecules was seen in rats with evidence of heart failure. Endothelial remodelling during evolution of left ventricular hypertrophy is secondary to aortic constriction and later progression to cardiac failure. Increased expression of the ABCG2 (transporter protein) during compensatory cardiac hypertrophy and its decreased expression during cardiac failure could be a significant flux given that ABCG2 is important in maintaining endothelial cell homeostasis. ABCG2 over expression may be an adaptive mechanism of the endothelial cell for transport of glutathione out of the cells to counter the deleterious effects of pressure overload induced 'uncoupling' of eNOS enzyme and production of excess superoxide anions that can be converted to hydrogen peroxide, a strong inducer of cardiomyocyte hypertrophy.
Targeting Scleraxis: Cardiac Fibrosis in the Crosshairs
Michael P. Czubryt, Rushita A. Bagchi, Patricia Roche, Ryan Wang
St. Boniface Hospital Research Centre, Institute of Cardiovascular Sciences, Winnipeg, MB, Canada
Fibrosis of the heart occurs when extracellular matrix synthesis outpaces degradation. Cardiac fibrosis significantly and adversely affects systolic and diastolic function, increases arrhythmogenesis and contributes to heart failure, increasing patient morbidity and mortality. Unfortunately, therapies directed specifically at fibrosis represent a notable gap in the current treatments available to patients, due in part to poor target options for drug interventions. We previously showed that the transcription factor scleraxis directly regulated expression of type I collagen, the major form found in the heart, by cardiac fibroblasts and myofibroblasts. Our data now demonstrates that scleraxis is a powerful inducer of cardiac extracellular matrix synthesis and fibroblast to myofibroblast phenotype conversion. Conversely, attenuation of scleraxis expression or activity blocks conversion to the myofibroblast phenotype, reduces matrix synthesis and interferes with the function of other fibrotic signaling pathways including TGFβ/Smads, angiotensin II and Connective Tissue Growth Factor. We have further identified phosphorylation as a post-translational modification of scleraxis required for full transcriptional activity. Together, these data identify scleraxis as a tantalizing novel target for the development of anti-fibrosis therapies aimed at reducing scleraxis expression, interfering with its ability to interact with transcription complexes, or promoting its dephosphorylation. Preliminary data further suggest that scleraxis may play a role in fibrosis in other tissues besides the heart, and thus scleraxis-targeted therapies may prove beneficial in a wide variety of fibrotic diseases.
My Life, My Heart and My (Osin) Binding Protein-C
Department of Cell and Molecular Physiology, Loyola University Chicago, Chicago, IL, USA
Contractile proteins first caught my interest during my graduate studies when I discovered genetic alterations in sarcomeric protein coding genes in Indian patients with cardiomyopathies. The size of the Indian population, coupled with its genetic/ethnic diversity, significantly broadens the scope of both genetic and epidemiological studies. This population also engages in consanguineous marriages, a cultural practice which substantially raises the frequency of recessive mutations contributing to hypertrophic cardiomyopathy (HCM), which is a global genetic heart disease affecting 1 in 500 individuals. Earlier, we identified four novel mutations, two in the cardiac b-myosin heavy chain gene and two in the cardiac myosin binding protein-C gene (MYBPC3) in Indian families with HCM. One of these mutations in MYBPC3 was a 25bp deletion (MYBPC3 r25bp ). In 2002, we first identified and described the MYBPC3 r25bp variant as a cause for HCM, subsequently characterizing it as a polymorphic variant inherited in 4% of South Asian descendants, causing various cardiomyopathies and heart failure. MYBPC3 r25bp is characterized by incomplete penetrance and expressivity. While those carrying this variant are at high risk for the development of HCM and heart failure, its functional and molecular effects remain unknown. Using cultured adult rat cardiomyocytes, we recently showed that expression of MYBPC3 r25bp is pathogenic in vitro. In the current study, a genetically engineered mouse model expressing a moderate amount of MYBPC3 r25bp was established with HCM phenotype, including diastolic dysfunction. Overall, we determined that MYBPC3 r25bp alone is sufficient to develop HCM, implicating the direct relevance of these studies to the development of heart disease among South Asian populations.
Key Players in Cardiac Disease: Potential and Challenges
Vaithinathan Selvaraju, Sumanth C. Suresh, Mahesh Thirunavukkarasu, Jocelyn L. C. Foye 1 , Nilanjana Maulik
University of Connecticut Health Center, Molecular Cardiology and Angiogenesis Laboratory, Department of Surgery, Farmington Avenue, Farmington, Connecticut, 1 ESSEN BioScience, Ann Arbor, MI, USA
Coronary heart disease (CAD) is common in human with diabetes. Almost 60% patients with diabetes die from CAD. The heat shock proteins have shown to facilitate cardioprotection through the activation and phosphorylation of Akt and eNOS in ischemic tissue. In specific, the role of HSPA12B, a member of HSP70 subfamily to rescue cardiac function during diabetes was examined both in vitro and in vivo. The adenoviral mediated overexpression of HSPA12B in HUVECs showed increased migration potential acquired during scratch assay. The in vivo analysis was made through adenoviral HSPA12B gene therapy in streptozotocin induced type I diabetes in rats followed by LAD ligation. The animals were grouped as 1) Non-diabetic sham 2) Non-diabetic lacZ MI 3) Non-diabetic HSPA12B-MI 4) Diabetic sham 5) Diabetic lacZ-MI 6) Diabetic-HSPA12B-MI. We observed increased capillary density and improvement in the ejection fraction and fractional shortening in Diabetic-HSPA12B-MI compared to the Diabetic lacZ-MI group. Western blot analysis documented increased HSPA12B and VEGF protein expression in Diabetic-HSPA12B-MI treated group compared to Diabetic lacZ-MI group. We also showed that HSPA12B can rescue cardiac collagen ECM from undergoing fibrosis through picrosirius red staining. These findings support an important role for HSPA12B in CAD patients with diabetes.
Role of PKC-z in NADPH Oxidase-PKCa-Gia Axis Dependent Inhibition of b-Adrenergic Response by U46619 in Pulmonary Artery Smooth Muscle Cells
Sajal Chakraborti, Tapati Chakraborti
Department of Biochemistry and Biophysics, University of Kalyani, Nadia District, West Bengal, India
Treatment of bovine pulmonary artery smooth muscle cells (BPASMCs) with the thrombaxane A 2 mimetic U46619 attenuated isoproterenol induced increase in adenyl cyclase activity and cAMP production. Pretreatment with SQ29548 (Tp receptor antagonist), apocynin (NADPH oxidase inhibitor) and Go6976 (PKC-α inhibitor) eliminated U46619 caused attenuation of isoproterenol stimulated adenyl cyclase activity. Pretreatment with SQ29548 and apocynin prevented U46619 induced increase in NADPH oxidase activity, PKC-α activity and Giα phosphorylation. However, pretreatment with CZI, a PKC-ζ inhibitor, markedly, but not completely, inhibited U46619 induced increase in NADPH oxidase activity, PKC-α activity, Giα phosphorylation and also significantly eliminated U46619 caused attenuation of isoproterenol stimulated adenyl cyclase activity and cAMP production. Pretreatment with Go6976 (PKC-α inhibitor) inhibited U46619 induced increase in Giα phosphorylation, but not PKC-ζ activity and NADPH oxidase activity. Pretreatment with pertussis toxin eliminated U46619 caused attenuation of isoproterenol stimulated adenyl cyclase activity without any discernible change in PKC-ζ, NADPH oxidase and PKC-α activities. Transfection of the cells with Tp, PKC-ζ and PKC-α siRNA duplexes corroborate the findings observed with their respective pharmacological inhibitors on the responses produced by U46619. Taken together, we suggest involvement of PKC-ζ in U46619 caused attenuation of isoproterenol stimulated β-adrenergic response, which is regulated by cross-talk between NADPH oxidase-PKCα and Giα in pulmonary artery smooth muscle cells.
Enhancing Skeletal Muscle Metabolism to Control Obesity and Type 2 Diabetes: Major Risk Factors of Cardiovascular Disease
Muthu Periasamy, Santosh Maurya
Center for Metabolic Origins of Disease, Sanford Burnham Prebys Medical Discovery Institute at Lake Nona, Orlando, FL, USA
Obesity is increasing at an alarming rate both in adults and adolescents across the globe due to increased consumption of caloric rich diet and physical inactivity. Obesity and its associated complications appear to be the major contributing factors not only to diabetes/heart disease but also to cancer, and neurological diseases causing a huge burden on the health care system. To date, there are no effective treatments to reduce weight gain other than caloric restriction and exercise, which are often difficult to enforce. There are very few drugs available for treating obesity and those that are available only reduce obesity by ~10%. Thus, identifying mechanisms to increase energy expenditure, in addition to voluntary exercise, would be more beneficial to control weight gain. Our laboratory recently identified that sarcolipin (SLN), a regulator of SERCA -Ca 2+ transport pump, is a key regulator of muscle thermogenesis and metabolism. SLN binding to SERCA pump promotes futile cycling, increased ATP hydrolysis, and energy expenditure. Using genetically manipulated mouse models of SLN, we showed that enhancing SLN activity provides resistance against high caloric diet induced obesity by increasing oxidative metabolism and fat utilization. Our studies suggest that SLN in muscle could serve as a novel therapeutic target for enhancing whole-body energy expenditure and controlling obesity and its associated complications including CV disease.
Experimental Study to Find the Role of SIRT1 on Cardiac Complication in Diabetes
Sanjay K. Banerjee
Drug Discovery Research Center, Translational Health Science and Technology Institute, Faridabad, Haryana, India
Cardiac oxidative stress, mitochondrial dysfunction, inflammation and cardiac fibrosis are commonly observed phenomenon in diabetic heart. The mechanism by which diabetic condition is vulnerable to myocardium is a key for developing new therapeutic targets. Acetylation and deacetylation play vital role in metabolic regulation in heart by altering gene expression. The beneficial effect of deacetylation in heart is linked to sirtuin-1 (SIRT-1) activation. However, little is known about the effect of SIRT-1 activation on cardiac complications associated with diabetes. Recently, we have demonstrated that SIRT-1 activation by resveratrol ameliorates cardiac hypertrophy, electrocardiographic abnormalities and oxidative stress in the fructose-fed diabetic rat heart. Our data revealed that fructose feeding to male rats over a period of eight weeks leads to cardiac hypertrophy and increased oxidative stress through increased activity of NADPH oxidase (NOX) and reactive oxygen species production. We found decreased SIRT-1 activity along with increased activity of nuclear factor kappa B (NFκB) in the fructose-fed diabetic heart. Activation of SIRT-1 by resveratrol deacetylates NFκB-p65 at lysine 310 and histone 3 (H3) at lysine 9 positions. SIRT1 activation leads to decreased binding of NFκB-p65 to DNA and attenuated cardiac hypertrophy and oxidative stress through reduced transcription of NADPH oxidase subunits. In vitro analysis with H9C2 cells also revealed that SIRT-1 activation by resveratrol is associated with decreased NFκB-p65 activity and NOX transcription. Similarly, knockdown or inhibition of SIRT1 in H9C2 cells increased acetylation of NFκB-p65 K310 and H3K9. In conclusion, our data demonstrated that SIRT-1 activation by resveratrol leads to deacetylation of both NFκB-p65 and H3, thereby attenuating cardiac oxidative stress and complications in diabetes.
Chronic Hyperinsulinemia Imparts a Pro-inflammatory Phenotype to Endothelial Cells by Modulating Bioavailability of Nitric Oxide
Department of Biotechnology, Indian Institute of Technology Madras, Chennai, Tamil Nadu, India
Vascular aberrations are triggered prior to the onset of hyperglycemia in diabetic patients. These changes in the vasculature are characterized by endothelial inflammation and decreased bio-availability of nitric oxide during insulin resistance. Compensatory hyperinsulinemia observed during insulin resistance is a potential risk factor for cardiovascular complications. Numerous clinical studies have demonstrated that despite sugar control, diabetic patients suffer from episodes of macro-vascular complications. Additionally, studies have reported positive correlation between circulating levels of insulin and incidences of cardiovascular events. Unlike its well characterized role in metabolic tissues, such as liver, skeletal muscle and adipocytes; the role of insulin in blood vessels is ill defined and heavily debated. We observed that sustained exposure (up to 48 hours) of human umbilical vein derived endothelial cells (HUVECs) to insulin (1-100 nM) enhances the surface expression of cell adhesion molecules and consequent adherence of leukocytes onto the endothelial monolayer. This is due to decrease in intracellular levels of nitric oxide and enhanced expression and activity of protein tyrosine phosphatase SHP2. Decrease in nitric oxide levels is due to inactivation of endothelial nitric oxide synthase (eNOS) and up-regulation of its competitive inhibitor, arginase. Inactivation of endogenous SHP2 via NSC87877 and its down-regulation by siRNA successfully blocks endothelial inflammation and restores NO levels. The talk will summarize our understanding on the underlying molecular mechanism.
Aldose Reductase/SIRT-1 Axis: A Potential Target for Vascular Complications of Diabetes
Lifestyle Disease Biology Group, School of Chemical and Biotechnology, SASTRA University, Thanjavur, Tamil Nadu, India
Diabetes Mellitus (DM) is rapidly gaining pandemic proportions in India. There are approximately 30 to 40 million diabetics in India presently, and this number is expected to reach a staggering 79 million in 2030. The complications of diabetes and more importantly the vascular complications are devastating; they represent leading causes of heart attacks and strokes, kidney failure, blindness and amputations of digits and limbs, as examples. Polyol flux through Aldose Reductase (AR) has been proven to be one of the major pathways through which hyperglycemia contribute to complications. Therapeutic strategies targeting AR has failed due to poor efficacy. We describe here a new pathway wherein AR regulates the Histone deacetylase SIRT-1 by modulating the NAD/NADH ratio and impact acetylation of transcription factor Egr-1 thereby promoting atherosclerosis in a diabetic mice model. The described pathway could impact many such transcription factors and targeting the AR/SIRT-1 axis could be a novel approach to treat diabetic vascular complications.
Anthropometric Measures During Infancy and Childhood and Risk of Developing Cardiovascular Disease in Later Life
M. Singh 1,2 , K. K. Thumburu 2 , J. Kaur 2 , S. Singh 2 , A. Chauhan 2 , N. Jaiswal 2 , A. Agarwal 2 , S. Dhatwalia 2 , N. Paul 2 , S. Sagwal 2 , P. Pant 2
1 Department of Pediatrics, Postgraduate Institute of Medical Education and Research, 2 ICMR Advanced Center for Evidence Based Child Health, Postgraduate Institute of Medical Education and Research, Chandigarh, India
Background: We present here a summary from published articles from 10 different cohort studies to demonstrate the association between anthropometric measures earlier in life and the development of obesity, cardiovascular and metabolic diseases in adulthood. Search Strategy: Two independent literature searches with predetermined search strategy were conducted at ICMR Advanced Centre for Evidence based child health, PGIMER, Chandigarh, India; comprising PubMed, Embase, Ovid SP and manual searching of references from the relevant articles thus obtained. Selection Criteria: We selected published cohort or longitudinal studies evaluating the associations between infancy & childhood anthropometric measures and the risk of developing cardiovascular disease/stroke in later life. The studies where the outcomes were restricted to associations between anthropometric measurements at birth and adulthood were not included in the systematic review. Data Extraction and Analysis: Five reviewers extracted the data independently and the discrepancies were resolved by consensus rating. Two reviewers independently evaluated the study quality using Newcastle-Ottawa scale and disagreements were resolved by discussion with the arbiter. Meta-analysis where-ever possible was done using Random effects inverse variance model using Stata MP 12 developed by Stata Corp Ltd. Results: A total of 10 birth cohorts (includes one study with three British cohorts) were identified and examined the relationship between childhood and adolescent BMI and cardiac diseases like coronary heart disease and ischemic heart disease. Two of the articles were from the Helsinki Birth Cohort based in Finland, Four from cohorts based in the United Kingdom, two from cohorts based in the United States, and one each from Norway and Denmark.
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