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| ABSTRACT |
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| Year : 2017 | Volume
: 3
| Issue : 4 | Page : 7-17 |
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Abstract
| Date of Web Publication | 6-Apr-2017 |
Correspondence Address:
 Source of Support: None, Conflict of Interest: None  | Check |
How to cite this article:
. Abstract. J Pract Cardiovasc Sci 2017;3, Suppl S1:7-17 |
| P. L. Wahi Oration Talk | |  |
Management of Advanced Heart Failure
Balram Airan
Department of Cardio-vascular Thoracic Surgery, Chief Cardiothoracic Centre, All India Institute of Medical Sciences, New Delhi, India
Heart failure is a major health problem globally and become a highly lethal pandemic. Average prevalence of heart failure in most countries is 1.5–2% and many of these patients progress to the stage advanced heart failure. It places major drain on healthcare systems in terms of resources consumed and also causes severe family disturbance to the persons afflicted with this entity. Guidelines from American Heart Association help to identify the patients with advanced heart failure. Left untreated, almost 50% of the patients die within 1 year of diagnosis; this mortality rate is higher than many forms of cancer and HIV infection also. Various treatment options are available for such patients and all of them target to achieve control of patients' symptoms and possibly reverse the anatomical and physiological alterations caused due to chronic advanced heart failure. These options include medicines like ACE inhibitors and Beta blockers which have significantly reduced mortality and newer drugs like ARNI (Angiotensin Receptor Neprilysin inhibitor). Surgical options aim to either treat the causative factor for heart failure (viz. CABG for coronary artery disease and myocardial infarction; Valve repair or replacement for mitral valve disease etc.); or mechanical procedures on the dilated left ventricle to improve contractile efficiency of the failing left ventricle. Aggressive surgical options for patients in end stage heart failure include LVAD implantations and heart transplantation. LVADs, in spite of their high costs; are finding an increasing place in the destination therapy management of advanced heart failure patients. Donor availability is the only major hindrance that limits the use of the gold standard surgery for advanced heart failure – heart transplantation. Newer research into stem cell biology, matrix protein structure and 3D printing enables taking the treatment field of AHF from clinics to laboratories. Many laboratories in the world are engaged in developing greater understanding to find the genetic/molecular triggers that set off the cascade of events leading to heart failure; or to synthesize healthy functioning human myocardium in a petri dish which can eventually be used to replace damaged muscles in human heart. The field of heart failure research is immensely active in generating newer and reproducible breakthroughs in order to tackle the ever-growing burden of heart failure.
| Manjit Singh Oration Talk | | |
Cardiomyopathy: Genetic and Evolutionary Perspectives
K. Thangaraj
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 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, who are inhabiting all the continent and found its prevalence was high (~4%) in populations of 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, affection only single family. Apart from sarcomeric genes, we discovered rare, functional RAF1 mutations in 3 cohorts (South Indian, North Indian and Japanese). Remarkably, we found these mutations only in childhood-onset DCM. Detailed genetic study and why the frequencies of disease causing variations are different in India would be discussed at the time of presentation.
Store Operated Ca2+-Channel Blocker SKF-36365 as a Potential Therapy for Hypertension
Naranjan S. Dhalla, Yan Jun Xu
Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre, Max Rady College of Medicine, University of Manitoba, Winnipeg, Canada
Hypertension is invariably associated with elevated levels of intracellular Ca 2+, which is determined by the functional status of both L-type Ca 2+-channels and store-operated Ca 2+ channels as well as Na +-Ca 2+ exchange system in the vascular smooth muscle. Although L-type Ca 2+-antagonists such as verapamil are known to exert anti-hypertensive actions, the effects of store-operated blockers such as SKF-36365 (SK) on blood pressure and cell proliferation have not been examined. In this study, SK was observed to reduce systolic and diastolic blood pressures in rats in a dose and time dependent manner. While SK showed no effect on basal [Ca 2+]i in rat aortic smooth muscle cells, the increase in [Ca 2+]i due to lysophosphatidic acid (LPA) or angiotensin II was depressed by this agent. On the other hand, norepinephrine- or the endothelin-induced increase in [Ca 2+]i was not affected by SK. The cell proliferation, as determined by cell number as well as thymidine incorporation in the absence or presence of LPA, was reduced by SK. This agent was also observed to augment the verapamil-induced reduction in diastolic blood pressure without any effect on the verapamil-induced reduction in systolic blood pressure. In addition, verapamil was found to depress LPA-induced or ATP-induced increase in [Ca 2+]i; these actions of verapamil were promoted by SK. The results suggest that store-operated Ca 2+-channel blockers, which affect sites different from those for L-type Ca 2+-channel antagonists, either alone or in combination, may be useful for the treatment of hypertension.
Epidemiology of Acute Heart Failure in India
Sandeep Seth
Department of Cardiology, All India Institute of Medical Sciences, New Delhi, India
In a study done from AIIMS (The AFAR study), the patients were relatively young (mean age 53 years), the causes were usually ischemic cardiomyopathy or idiopathic cardiomyopathy though RHD was also a contributor. Mortality was high though patients were receiving medications as per the HF guidelines though at lower doses. The mean age (53 years) was lower than Western cohorts (ranging from 65 to 73 years) such as EuroHeart Failure (EURO-HF) Study, the Acute Decompensated Heart Failure National Registry (ADHERE), the Organized Program to Initiate Life-Saving Treatment in Hospitalized Patients with Heart Failure (OPTIMIZE-HF), and the Effects of Oral Tolvaptan in Patients Hospitalized for Worsening Heart Failure (EVEREST). This supports the concept that cardiovascular disease affects patients in India at a younger age than their Western counterparts. Overall, the mean ejection fraction was lower (29.2%) than ADHERE (34.4%) and OPTIMIZE-HF (39%). The patients had high rates of in-hospital mortality (30.8%), 6-month mortality (26.3%) and 6-month re-hospitalization (39.5%). Data from ADHERE, OPTIMIZE-HF, EURO-HF demonstrate an overall in-hospital mortality rate of 4-7%, 90-day (limit of follow-up) mortality rate of 5-15%. Inpatient medication rates were different from rates in Western literature. Intravenous inotropes were used more commonly in our inpatient cohort (75%) compared to OPTIMIZE-HF data (5.4%). In-hospital mortality of the subset of patients who received inotrope therapy and had admission systolic BP <120 mmHg was 17.9% in OPTIMIZE-HF and 44.4% in our patient cohort, reflecting the severity of disease in this subgroup. Baseline mean renal function, which typically affects the clinical decision to begin inotrope therapy, appeared lower compared to OPTIMIZE-HF. Mean serum sodium, which is another prognostic marker for HF, was also lower compared to OPTIMIZE-HF (134.8 mmol/dl compared to 136.7 mmol/dl). Discharge medication rates of ACE-I/ARB (71.1%) were at or above levels seen in ADHERE and OPTIMIZE-HF. Despite similar diagnostic rates and adherence to performance measures as compared to Western literature, 6-months mortality and 6-months re-hospitalization rates in the patients were 26.3% and 39.5%, respectively, which may reflect the severity of illness presentation in this cohort. This data and similar data from some small studies from other parts of India suggest that acute heart failure is a major problem in India which needs to be tackled on an urgent basis.
A Step Closer to Unravel the Mystery of Myocyte Self-regeneration during Cardiac Hypertrophy
Sagartirtha Sarkar
Department of Zoology, Genetics and Molecular Cardiology Laboratory, University of Calcutta, Kolkata, West Bengal, India
Cardiac hypertrophy leading to heart failure is one of the major causes of mortality worldwide that is triggered by nitrosative stress mediated apoptosis of terminally differentiated cardiomyocytes. S- nitrosylation of NEMO was studied in regulation of myocyte fate during cardiac hypertrophy. Myocyte targeted overexpression of S-nitrosyl mutants of NEMO in renal artery ligated rats showed significant downregulation of hypertrophy marker genes and betterment of cardiac function. S-nitrosyl mutants of NEMO showed downregulation of apoptotic potential of myocytes along with excess nuclear translocation of p65 protein within these cells during hypertrophy. Our lab earlier showed downregulation of p65 during regression of hypertrophy as a concomitant effect of reduced apoptotic load in cardiomyocytes. However, S-nitrosyl mutants of NEMO showed constitutive activation of p65 even when apoptotic load was lowered during regression of hypertrophy, thus inducing a subset of genes involved in cellular proliferation that shifted the balance towards regeneration of terminally differentiated cardiomyocytes and subsequent improvement in cardiac function. Thus, introducing S-nitrosyl mutants of NEMO in pathological cardiac microenvironment promises to be a potential tool for damaged tissue engineering via regeneration of quiescent myocyte population.
Use of Stem Cells for Cardiovascular Diseases: Current Status
Sujata Mohanty
Stem Cell Facility (DBT - Centre of Excellence for Stem Cell Research), All India Institute of Medical Sciences, New Delhi, India
Cardiovascular diseases (CVDs) has become one of the leading causes of death worldwide. Despite several recent advancements in surgery and medicine, no treatment has come up as the fundamental care for cardiac disease modulation, yet. In this regard, regenerative medicine has endowed with new light to restore structural and electrophysiological function of the damaged heart in treatment of MI. Currently, the two different sources of stem cells are used in various applications in regenerative medicine; these are embryonic stem cells (ESCs) and adult stem cells (ASCs). ASCs are preferred over ESCs due to ethical acceptance, less/no risk of teratoma formation, easy isolation from different adult tissues and easier expansion in culture. ASCs have being tested in several clinical trials and have shown promising results. However, there is inconsistency in the results due to non-uniform isolation techniques, donor specificity and culture conditions adopted for expansion of ASCs. Currently, the focus of research is to find out most optimum source of ASCs along with its mode of transplantation so as to enhance its efficacy. Use of ASCs is being combined with tissue engineering, so as to avoid the issues of loss of stem cells during direct injection. Various scaffolds have been tested in animal models of myocardial infarct and have shown better results. Along with this, other strategies currently under investigation which may contribute in the future to regenerative medicine include use of induced pluripotent stem cells (iPSCs)-derived cardiac progenitor cells, directly reprogrammed cardiomyocytes from and acellular therapies using cytokines and growth factors. In the talk, I shall be discussing about the achievements and current status of Stem Cell Research within and outside India in the cardiovascular diseases. Also, I shall be talking about the stumbling blocks at present in this research areas and the future prospects.
Growing 3D Hearts: A Perspective on Organoids for Translational Research
Debojyoti Chakraborty
CSIR-Institute of Genomics and Integrative Biology, New Delhi, India
The field of regenerative medicine has experienced a rapid boost since the development of mini organs in the lab, also known as organoids. These miniature organs have paved the way for studying models of development and establishment of platforms for personalized medicine. Growing cardiac organoids is a relatively new area of research and offers exciting avenues for modelling heart disorders. Current technologies allow organoid development from cells originating from the organ or from reprogrammed induced pluripotent stem cells (iPSCs), the latter being a powerful tool for personalized therapies. Combining bioengineering techniques for providing optimal scaffolds to efficient methods of organoid development, scientists are currently striving to utilise organoids for solving complex disease pathways and modelling developmental programmes.
Current Management of Chronic Stable Angina
Balram Bhargava, Anunay Gupta
Department of Cardiology, All India Institute of Medical Sciences, New Delhi, India
Chronic stable angina (CSA) is defined as chest discomfort which occurs predictably and reproducibly at a certain level of exertion and is relieved with either rest or nitroglycerin. The management of CSA has three major aspects which are preventive therapy, pharmacological therapy for angina and revascularization. Preventive therapy includes low dose aspirin, risk factor reduction such as treatment of hypertension, diabetes and cessation of smoking. All patient should be on at least moderate intensity statins. ACE inhibitors have a major role in patients who are having hypertension, diabetes and chronic kidney disease. Beta blockers, nitrates and calcium channel blockers are three first line class of anti-anginal drugs. Ranolazine and Nikorandil are newer drugs which may be used as combination therapy with the above. All patients who continue to be having angina despite maximal tolerable doses of anti-anginals should be considered for coronary angiography followed by revascularization as deemed appropriate either by percutaneous coronary intervention or coronary artery bypass surgery. Other indications of angiography are intermediate or high risk criteria on non invasive stress testing irrespective of severity of angina. The choice of initial stress test such as treadmill test, nuclear imaging, or pharmacologic stress testing with imaging depends on patients baseline ECG and ability to perform exercise. The management of CSA has improved tremendously over the past few years and is more evidence based now. Consequently, the outcome seems to have been improving.
Promoting Inflammation Resolution Response as a Therapeutic Strategy in Atherosclerosis
Manikandan Subramanian
CSIR-Institute of Genomics and Integrative Biology, New Delhi, India
Atherosclerosis is a non-resolving chronic inflammatory disease triggered by the sub-endothelial retention of lipoproteins in large and medium-sized arteries. A small proportion of these atherosclerotic plaques display a “vulnerable phenotype” characterized by large necrotic cores and thin fibrous cap, which are harbingers of plaque rupture and acute luminal thrombosis leading to clinical conditions such myocardial infarction and stroke. Our studies have established that the dominant cellular processes that lead to vulnerable plaque development are (1) increased atherosclerotic lesional cell apoptosis, (2) defective phagocytic clearance of apoptotic cells (efferocytosis), and (3) failed inflammation resolution. Over the past few years, our research has focused on unraveling the mechanistic basis of these molecular events with a particular emphasis on the role of innate-adaptive immune cell interactions and inflammatory cytokine cross-talk in shaping these processes. Most recently, using a nanomedicine approach, we have demonstrated the possibility of enhancing efferocytosis efficiency within the atherosclerotic plaque to promote inflammation resolution and stabilization of advanced plaques.
Creating ST-Elevation Myocardial Infarction Program in India
Ajit Mullasari
Cardiology, The Madras Medical Mission, Chennai, Tamil Nadu, India
The burden of cardiovascular disease is increasing at an unprecedented rate in the low and middle income countries (LMICs) because of ageing population, widespread exposure to increasing levels of risk factors such as unhealthy diet, physical inactivity, obesity, tobacco use, diabetes, raised blood pressure and abnormal blood lipids. The consequences of globalization and urbanization are also contributory factors. There are no accurate estimates of STEMI in the LMIC, but it is possible that there could be upwards of 3 million cases per year. The almost universal use of Primary PCI as the reperfusion therapy of choice in ST-Elevation Myocardial Infarction (STEMI) and utilization of other evidence based medications, has dramatically improved the results of STEMI management in the United States and Western Europe. The challenges for LMIC in Asia and Africa are entirely different. Regional Systems of care for STEMI care are virtually non-existent. Cardiac catheterisation laboratories are inadequate in number to serve the large numbers of patients with STEMI and are almost always clustered in urban locations. Poor transportation infrastructure, lack of adequately trained and equipped paramedics and ambulances, make access to these invasive centres difficult. Added to this is the financial constraints and lack of insurance coverage for the large majority of the population that limit these expensive procedures and costly medications to a small proportion of the patients. In an environment of resource constraints with a burgeoning population of patients in LMIC with STEMI who require emergency care, the challenge is to address these issues in an effective and equitable manner. For this, innovation, particularly the use of technology can help deliver reperfusion for all. This TNSTEMI project tries to address the management of STEMI and to utilize algorithms of STEMI management that may be more appropriate and easier to implement in LMIC.
Acute Coronary Syndrome in India: Observations and Opportunities
Nitish Naik
Department of Cardiology, Cardiothoracic and Neurosciences Centre, All India Institute of Medical Sciences, New Delhi, India
Coronary artery disease (CAD) is the leading cause of death amongst the non-communicable diseases in India. Acute coronary syndromes often herald the clinical presentation of CAD. While immediate assessment and percutaneous intervention is the standard of care for ST elevation myocardial infarction, most patients are unable to access such care even in urban areas due to a variety of reasons including late recognition, absence of adequate infrastructure and socio-economic factors. Significant health care delivery reforms and public education and awareness are required to improve patient.
Sleep Apnea and Coronary Artery Disease: Current Concepts
Rishi Sethi
Department of Cardiology, King George's Medical University, Lucknow, Uttar Pradesh, India
Obstructive sleep apnoea (OSA) is a prevalent but under recognised form of sleep-disorder of breathing and is an emerging risk factor for acute coronary syndrome (ACS). 46–66% of the OSA patients end up with ACS. We sought to determine the effects of ethnicity on the prevalence of OSA which may differ not only between Western and Asian countries, but also within Asia itself. A pooled analysis using patient-level data from the ISAACC Trial and Sleep and Stent Study was performed. Using the same portable diagnostic device, OSA was defined as an apnoea-hypopnoea index of ≥15 events per hour. A total of 1961 patients were analysed, including Spanish (n = 1050), Chinese (n = 500), Indian (n = 235), Malay (n = 119), Brazilian (n = 34) and Burmese (n = 23) populations. BMI was significantly different among the various ethnic groups. The prevalence of OSA was highest in the Spanish (63.1%), followed by the Chinese (50.2%), Malay (47.9%), Burmese (43.5%), Brazilian (41.2%), and Indian (36.1%) patients. The estimated odds ratio of BMI on OSA was highest in the Chinese population (1.17; 95% confidence interval: 1.10–1.24). The area under the curve (AUC) for the Asian patients (ranging from 0.6365 to 0.6692) was higher than that for the Spanish patients (0.5161). There was significant variation in the prevalence of OSA in patients with ACS in different ethnic group. However the effect of BMI on OSA was greater in the Chinese population as compared to other groups.
Approaches to Arrhythmias with Heart Failure
C. Narasimhan
Arrhythmia and Electrophysiology Service, Care Hospitals, Hyderabad, Telangana, India
Patients with Heart Failure develop arrhythmias frequently. There are certain situations wherein Arrhythmias leads to development of Heart failure viz. tachycardiomyopathy. This review will address two common arrhythmias. (a) atrial fibrillation and (b) ventricular tachycardia and fibrillation. Atrial fibrillation is a common in HF population and results in significant morbidity and mortality. It increases the risk of thromboembolic events and worsens heart failure. Effective rate control and use of anticoagulants in appropriately selected patients results in improved outcome. In patients persistent AF, a more definitive therapy involves catheter ablation of AF, or AV junction ablation and implantation of CRT. Ventricular arrhythmias in heart failure are a prognostic marker for sudden death. There are certain situations where Ventricular arrhythmias are frequent like myocarditis, Lamin mutation etc. Optimal beta blocker therapy is useful to prevent sudden cardiac arrest in this population. Implantable cardioverter therapy and CRT-D are extremely useful to further minimize the risk of sudden cardiac death.
Genotyping of Cardiac Channelopathies: Indian Data
Bijal Vyas, R. D. Puri, N. Namboodiri, R. Saxena, M. Nair, S. Sivasubbu, I. C. Verma
University School of Medical and Paramedical Sciences, Guru Gobind Singh Indraprastha University, New Delhi, India
Introduction: Cardiac channelopathies have a prevalence of about 1:2000-2500 in different populations worldwide. The common life threatening cardiac channelopathies, Long QT (LQTS type 1-13) and Brugada (BrS type 1-12) present with syncope/palpitations/seizures/aborted cardiac arrest. They have incomplete penetrance and variable expressivity. The three common genes (KCNQ1, KCNH2 and SCN5A) account for 75% of all LQTS cases, and SCN5A in BrSaccounts for 25% of all cases. Aim: To identify the causative variation in the associated genes responsible for causing cardiac channelopathies in Indian patients. Materials and Methods: Fifty patients who fulfilled the inclusion criteria of the study were enrolled. Mutation analysis was performed in most probable candidate gene by direct sequencing. If a mutation was not identified, NGS was performed to identify mutations in other cardiac genes. Parents and siblings were screened if a mutation was identified in the proband. Novel mutations were evaluated for pathogenicity using bioinformatics and molecular modeling softwares. Results: Mutations was identified in twenty-five patients by Sanger sequencing, twenty-two had LQTS and three were affected with BrS. Among the LQT syndromes, mutations were identified in nineteen in KCNQ1 (LQTS1), one in KCNH2 (LQTS2)and two in SCN5A (LQTS3). Among the LQTS1 patients, ten were identified with biallelic mutations. The three BrS patients had mutations in SCN5A, agene responsible for BrS1. Eleven of twenty-five mutations were novel. NGS identified mutation in twelve of the remaining twenty-five patients. Of which, ten had LQTS and two had BrS. Of these mutations, seven were novel. Conclusion: Genotyping is important for confirming type of LQTS/BrS, which has implications for management, and identification of asymptomatic at risk individuals.
Zebra Fish in Cardiovascular Research
Sridhar Sivasubbu
CSIR-Institute of Genomics and Integrative Biology, New Delhi, India
NMDA receptors (NMDAR) are a subtype of ionotropic glutamate receptors mediating calcium uptake upon their activation by co-agonists glutamate and glycine. NMDAR exhibit distinct patterns of developmental expression in the central nervous system. However their role in heart development and function remains elusive. We employed a gene trapping based insertional mutagenesis approach to isolate zebrafish mutant animals that displayed pronounced cardiac arrhythmia followed by chamber enlargement and cardiac hypertrophy. Owing to the phenotype of an enlarged heart, we have named this mutant as bigheart (bh). The mutation in bh, maps to an intron of the NMDAR gene family member that forms calcium permeable ion channels. Our investigation revealed the presence of a novel transcript within the intron of the NMDAR gene. We name this transcript as NMDAR Associated RNA Transcript (NMDAR-ART). We characterized the novel transcript and shown that the NMDAR-ART is a putative long non-coding RNA (lncRNA). bh mutant zebrafish embryos and adults exhibited calcium handling defects and differential expression of calcium handling genes as well as cardiac remodelling markers were also documented. In summary, we report the identification of a novel lncRNA transcript called NMDAR-ART that expresses in specific zebrafish heart chambers. We show that NMDAR-ART has a potential role in cardiac rhythm function by regulating calcium flux. We hypothesize that NMDAR-ART regulates key calcium handling genes for maintaining intracellular calcium homeostasis in the zebrafish heart.
Understanding Antiarrhythmics: From Cell to Bed Side
Praloy Chakraborty
Department of Cardiology, Vardhman Mahavir Medical College, Safdarjang Hospital, New Delhi, India
Although antiarrhythmics have versatile mechanisms of action, they suppress arrhythmias either by preventing enhanced automaticity or by altering the electrophysiological properties of reentrant pathways. Inhibition of reentry occurs due to reduction of conduction velocity or due to increase in the refractory period. Sodium channel blockers (Class I agents) reduce the conduction velocity of fast conducting tissue (i.e. Ventricular Myocardium, accessory pathways) where as calcium channel antagonists exerts action by slowing conduction through slow conducting tissue (i.e AV node). So, Sodium channel antagonists terminate accessory pathway dependent reentry (AVRT) as well as atrial and ventricular tachycardias whereas calcium channel antagonists terminate AV node dependant tachycardias. Calcium channel antagonists also inhibit after depolarization induced triggered activities. Repolarization blocking agents (Class III agents), by prolonging the action potential duration, increase the refractory period of reentry circuit and terminate large numbers of atrial and ventricular tachyarrhythmias. Beta blockers block multiples steps in arrhythmogenesis. Other AV nodal blocking agents block AV node directly or via vagomimetic action and terminate AV node dependent tachyarrhythmias.
Genetics of Type 2 Diabetes in India: Association to Causality
Dwaipayan Bharadwaj1,2
1Systems Genomics Laboratory, School of Biotechnology, Jawaharlal Nehru University,2 CSIR-Institute of Genomics and Integrative Biology, New Delhi, India
The rapid increase in the prevalence of type 2 diabetes in the 21st century has earned it's name as a global epidemic, affecting over 347 million people worldwide. Several risk factors for T2D including age, sex, obesity, low physical activity, smoking and diet have already been identified. Exploring the hereditary components of T2D has been highlighted by several research groups till date, majorly involving genome wide association studies to find the causal route to this disease. Our lab at CSIR-IGIB has carried out a type 2 diabetes GWAS in Indian population, taking about 12,535 human samples under consideration. We found five novel signals at the 2q21 position of human genome within TMEM163 gene that encodes for a synaptic vesicular membrane protein. Further experimentations are being done in order to find out the biological role of TMEM163 with respect to T2D etiology.
Tackling the Diabetes Epidemic in India
Nihal Thomas
Department of Endocrinology, Diabetes and Metabolism, Christian Medical College, Vellore, Tamil Nadu, India
The questions which concern the pathogenesis of diabetes mellitus in the Indian Subcontinent are many, owing to the high prevalence of the disease, the comparatively lower age of onset and a relatively low body mass index amongst Asian Indians. The foetal origins of diseases- propounded by Barker and colleagues may in part be responsible. This maybe a critical factor, considering that the prevalence of low birth weight (LBW) in India is amongst the highest in the world and approaches a figure of 15 to 20% of all live births in some parts of the country. The fetal insulin hypothesis (FIH) proposed by Hattersley states that genetic variants associated with insulin resistance may lead to impaired insulin – mediated growth prenatally, leading to low birth weight and adverse metabolic outcomes in adulthood. Thus, low birth weight is part of a syndrome that may be associated with in utero insulin resistance which in turn may manifest with diabetes and hypertension at the time of adulthood. We successfully enrolled 60 LBW and 60 NBW males, born in and still living in rural environments around the city of Vellore. We confirmed that low birth weight adult males who had fully completed puberty were shorter in height and lighter in body weight when compared to their NBW counterparts. Moreover, the LBW individuals had a significantly lower lean body mass when compared to their NBW counterparts. This difference was present in the total body lean mass and extended to include the upper and lower limbs of these subjects and was associated with a lower bone mineral content in the LBW group. Interestingly, 8% of the LBW individuals had impaired glucose tolerance, which was not present in the NBW individuals. However, this was not reflected in the 'm' values (measure of insulin sensitivity) - that were obtained from the hyperinsulinemic euglycaemic clamp studies done on these individuals, who were all incidentally associated with a low median BMI (19.5 kg/m 2) in both the LBW and NBW groups. The LBW subjects had a marginally significant higher supine resting diastolic blood pressure level when compared to NBW subjects, when adjusted for height and weight. Measurement of High Density Lipoprotein Levels (HDL levels) showed values which were low, which bore similarity to what is seen in the Southern Indian population, moreover there was no difference in the measurements in HDL between the LBW and NBW subjects. There was no difference in resting energy expenditure when measured by indirect calorimetry between the LBW and the NBW group of subjects, nor was there any difference in Glucose or Fat oxidation between the groups. When the data of all 120 subjects were taken as a whole, and the m-value correlated with the insulin resistance indices including HOMA-IR, QUICKI, Fasting Insulin levels, Glucose insulin ratio, McCauley's index and Matsuda Index: The strongest correlation was obtained in the association between the m-value and the McCauley's index and the Matsuda index. In fact more recent studies by our group have shown that complex calculations apart, that the fasting glucose-insulin ratio correlates well with the hyperinsulinemic euglycaemic clamp studies and is superior to HOMA-IR, QUICKI and McCauley's index. The Dietary intake of protein was significantly lower in quantum in the LBW subjects when compared to the normal birth weight subjects at the time of recruitment into the study. This was associated with a lower proportion of energy being extracted from the protein intact per se. The mothers and the fathers of the LBW subjects were shorter than the NBW subjects, suggesting the possibility of an intergenerational influence on birth weight (though the difference did not achieve statistical significance. The LBW group had a greater Fat mass/fat free mass reduction when compared to their pre-exercise baseline status and a significant decline in FM/body weight following a 45 minute exercise intervention for a 6 week period on a bicycle. The NBW subjects had a small but significant increase in fat percentage. Moreover, there was a statistically significant reduction in fasting plasma insulin levels in the LBW group, while the reduction was not statistically significant in the NBW group. Regarding reductions in insulin secretion, HOMA-IS a change were significant in the LBW and NBW groups, while reductions in HOMA-IR was only significant in the NBW group. The subjects had spectroscopic assessment of micro-quantitities of fat in the liver and the muscle, through NMR spectroscopy. It was found that there was a negligible quantum of ectopic fat storage in the liver in particular, and to some extent in the muscle, which is unlike what is seen in Caucasian subjects at a similar age. There was no difference in ectopic fat storage between the NBW and LBW subjects. Measurements of insulin resistance (HOMA-IR), did not have any relationship with hepatic, intramyocellular or extramyocellular fat content In fact the only independent predictor of intra-myocellular and extramyocellular fat content was with the total body fat percentage. Our study has shown a significant elevation in diastolic blood pressure, alterations in systolic pressure have been shown in LBW subjects in a number of cohorts, and occur in both gender groups. MODY genetic testing to identify mutations in a comprehensive panel of ten MODY genes was carried out in 80 subjects of Asian-Indian origin with young onset diabetes A novel multiplex polymerase chain reaction (PCR) based target enrichment was established, followed by Next Generation Sequencing (NGS) on the Ion Torrent Personal Genome Machine (PGM). All the mutations and rare variants were confirmed by Sanger sequencing. We identified mutations in 11 (19%) of the 56 clinically diagnosed MODY subjects and seven of these mutations were novel. The identified mutations include p.H241Q, p.E59Q, c-162G'A 5' UTR in NEUROD1, p.V169I co-segregating with c.493-4G'A and c.493-20C'T, p.E271K in HNF4A, p.A501S in HNF1A, p.E440X in GCK, p.V177M in PDX1, p.L92F in HNF1B and p.R31L in PAX4 genes. Interestingly two patients with NEUROD1 mutation were also positive for the p.E224K mutation in PDX1 gene. These patients with co-existing NEUROD1-PDX1 mutations showed a marked reduction in glucose induced insulin secretion. None of the 24 subjects who had not met the clinical criteria of MODY were positive for mutations. To the best of our knowledge, this is the first report of PDX1, HNF1B, NEUROD1 and PAX4 mutations from India. Multiplex PCR coupled with NGS provides a rapid, cost-effective and accurate method for comprehensive parallelized genetic testing of MODY. When compared to earlier reports, we have identified a higher frequency and a novel digenic mutation pattern involving NEUROD1 and PDX1 genes. The work performed above clearly established next generation sequencing as he modality of choice for looking to the genetic profile of young onset diabetes, MODY, syndromic disorders and neonatal diabetes and at present CMC, Vellore as a single library preparation capable of handling 30 genes simultaneously in a cost effective manner. In summary, there are a number of factors which are responsible for that shift in the phenotype of towards the left in India with regards to the leanness of body habitus as well as the age of these patients. More work is required to be done to identify these pathogenic factors at a cellular level to establish the reasons for this propensity.
Roles of Altered Hepatic miRNA Signatures during Diabetes
Malabika Datta
Functional Genomics Unit, CSIR-Institute of Genomics and Integrative Biology, New Delhi, India
microRNAs (miRNAs) are a class of small (~22 nucleotides) non-coding RNA species that act by regulating the expression of their target genes by either mRNA degradation or translational repression. miRNAs are now widely believed to participate in several physiological cellular pathways and aberrant signatures are associated with the onset and progression of diverse diseases. We have been studying altered miRNA patterns in the livers of diabetic mice and the mechanisms by which these alterations precipitate into the observed metabolic deregulations during diabetes. Specifically, levels of miR-107 and miR-22-3p are abnormally increased in the livers of diabetic db/db mice. We show that miR-22-3p binds to the 3' UTR of TCF7 and downregulates it and this miR-mediated regulation of TCF7 increases the expression of enzymes of the gluconeogenic pathway in HepG2 cells. siRNA-mediated knockdown of TCF7 in HepG2 cells also cause similar upregulation of gluconeogenic genes. In vivo silencing of miR-22-3p by antagomiR administration lowered random as well as fasting glucose levels in diabetic mice. miR-22-3p antagonism improved glucose tolerance and insulin sensitivity. Importantly, the hepatic Tcf7 levels were restored along with reduced hepatic glucose output which was also reflected by decreased expression of gluconeogenic genes. Our results support a critical role for miR-22-3p and its target, Tcf7 in the pathogenesis of diabetes by up-regulating gluconeogenesis. miR-107, on the other hand, regulates fatty acid synthase (FASN) and reduces its protein levels. Overexpression of miR-107 led to significant accumulation of malonyl CoA, accompanied by ER stress induction. This was followed by increased triglyceride formation and lipid accumulation in the presence of miR-107. These indicate that miR-107 inhibits FASN levels and this interaction promotes ER stress induction and malonyl CoA and lipid accumulation in HepG2 cells and primary hepatocytes. miR-107 also significantly inhibited the mitochondrial β-oxidation enzyme, HADHA, in HepG2 cells and this was rescued by ER stress inhibition. Over-expression of miR-107 in mice increased random blood glucose levels, impaired oral glucose tolerance and promoted hepatic lipid accumulation. These suggest that altered miRNA levels regulate metabolic processes that are reflected in terms of hyperglycemia and increase hepatic lipid accumulation during diabetes.
Metabolic Syndrome, Systemic Autoimmunity and Type I Interferons: A Ménage à Trois
Dipyaman Ganguly
IICB-Translational, Research Unit of Excellence, CSIR-Indian Institute of Chemical Biology, Kolkata, West Bengal, India
Plasmacytoid dendritic cells (pDC) are major producers of type I interferons (IFN-I) in response to recognition of pathogen-derived nucleic acid molecules by endosomal toll-like receptors (TLRs). Involvement of pDC-derived IFN-I in a number of autoimmune diseases as well is established. Recognition of self-nucleic acids leads to induction of IFN-I from pDCs and drives innate initiation of inflammation in Systemic Lupus Erythematosus (SLE), Psoriasis and a number of other autoimmune contexts. Thus induction of pDC-derived IFN-I is a shared initiator event in discreet clinical contexts, leading to a model where these clinical contexts are grouped together as a syndrome of inadvertent pDC activation. We propose the name 'Plasmacytoidopathy'. Interestingly, we also identified role of pDC-derived IFN-I in obesity associated metaflammation and insulin resistance. We found chemerin, an adipose-derived chemokine, recruits pDCs in obese adipose tissue and initiates the metaflammation cascade. TLR9 activation in recruited PDC induces IFN-I, which drive in situ macrophage polarization and adipose tissue insulin resistance. Of note, systemic autoimmune contexts are often associated with insulin resistance. We actually could link systemic IFN-I response with susceptibility to insulin resistance in an autoimmune context. In rodent models of the disease TLR9 deficiency has also recently been shown to ameliorate insulin resistance, thus validating our model. Moreover, a distinct autoantibody response can be detected in obese individuals, like IFN-I-driven autoimmunities.
We think that a syndromic description ('Plasmacytoidopathy') of these different clinical contexts, from systemic autoimmune diseases to metabolic derangements, will enable identification of important biomarkers as well as novel therapeutic targets.
The Impact of Lower Vitamin D Metabolites Levels on Coronary Artery Disease in Type 2 Diabetes Patients in India
Sanjay K. Banerjee
Drug Discovery Research Center, Translational Health Science and Technology Institute, Faridabad, Haryana, India
The association of vitamin D insufficiency and increased risk of metabolic diseases has been reported in several scientific journals. However, it is not clear which vitamin D metabolite should be measured and the association of each metabolite with increased risk of metabolic diseases. Among all vitamin D metabolites, only 25(OH)D and 1,25(OH)2D have received great attention. Hence in the present study six vitamin D (D2/D3) metabolites have been quantified by LC-MS method. The purpose of the present study is to measure six vitamin D metabolites, total 25(OH)D and total 1,25(OH)2D levels and to find the association between vitamin D deficiency and coronary artery diseases in diabetes. Four groups [control, type 2 diabetes (T2DM), coronary artery diseases (CAD), T2DM with CAD (T2DM_CAD)] were included for the study. Glycated hemoglobin (HbA1c) and fasting blood sugar (FBS) levels were increased significantly (p<0.05) in patients having 20–30ng/ml and <20ng/ml at 25(OH)D levels as compared with subjects having >30ng/ml of 25(OH)D. Our data revealed that all the vitamin D metabolites were significantly (p<0.05) decreased in T2DM_CAD as compared to both control and T2DM subjects. However, only two metabolites i.e., 25(OH)D3 and total 25(OH)D were significantly (p<0.05) decreased in the T2DM subjects as compared with the control subjects. Multiple logistic regression analysis revealed that total 25(OH)D and total 1,25(OH)2D can be used to predict T2DM and T2DM with CAD respectively. This study concludes that lower vitamin D metabolites levels is associated with type 2 diabetes coexisting with coronary artery diseases in Indian subjects.
Understanding Endothelial Dysfunction in Diabetic Cardiovascular Complications Using Mass Spectrometry-based Proteomics
Mahesh Kulkarni
CSIR-National Chemical Laboratory, Pune, Maharashtra, India
One of the initial steps in the development of cardiovascular diseases involves endothelial dysfunction (ED), wherein the regulatory functions of the vascular endothelium are disrupted. ED can be caused by chemically-modified plasma proteins that are present in vivo whose levels are elevated by metabolites and drugs found in the bloodstream. Under conditions such as prolonged hyperglycemia in diabetes, there are elevated plasma levels of glucose-modified proteins, also known as advanced glycation end-products (AGEs). The interaction of these AGEs with their receptor RAGE has been implicated in different complications and could also be major contributory factors towards the development of ED in diabetes leading to cardiovascular disease and clinical complications. Since cardiovascular disease is a major pathological outcome in patients that exhibit diabetes, there is importance in understanding the mechanism underlying of how AGEs cause ED. In our study, we have synthesized AGE-HSA, characterized mass spectrometrically, developed ion library for targeted quantification in the clinical plasma. Furthermore, AGE-HSA was used to study AGE-RAGE signaling in human umbilical vein endothelial cells (HUVECs) cells. Differential total cell proteomics of control and stimulated endothelial cells was performed using mass spectrometry. Total cell proteomic analysis shows differential expression of numerous proteins regulating endothelial function including those affecting barrier function, inflammation and angiogenesis. This shows that AGEs can elicit ED, thus predisposing diabetic patients to increased risk of cardiovascular complications.
Hypertension Burden: Trends from India
Ambuj Roy
Department of Cardiology, All India Institute of Medical Science, New Delhi, India
High blood pressure is one of the leading risk factors for mortality in India. The prevalence of HBP has progressively increased in both rural and urban India over the last decades. On basis of two large cross-sectional study in rural and urban Delhi done 20 years apart, we found that the age and sex standardised prevalence of hypertension increased from 11.2% to 28.9% (P<0.001) and 23.0% to 42.2% (P<0.001) in rural and urban NCR respectively. In both surveys, those with high education, alcohol use, obesity and high fasting blood glucose were at a higher risk for hypertension. However, the change in hypertension prevalence between the surveys was independent of these risks. Overall there was with no improvement in awareness, treatment and control rates of hypertension in the population.
Gi Proteins and Regulation of Blood Pressure
Madhu Anand-Srivastava
Department of Pharmacology and Physiology, University of Montreal, Montreal, Quebec, Canada
Guanine nucleotide regulatory proteins (G proteins) play an important role in the regulation of a variety of physiological functions including blood pressure through the activation of different effectors. Alterations in the levels of inhibitory G proteins (Gi) that negatively regulate adenylyl cyclase result in the impaired cellular functions that lead to various pathological states such as hypertension. We have previously shown an overexpression of inhibitory G proteins (Gialpha proteins) in spontaneously hypertensive rats (SHR) and other models of hypertensive rats. The enhanced expression of Gialpha proteins precedes the development of hypertension in SHR and DOCA-salt hypertensive rats. Treatment of prehypertensive SHR with pertussis toxin that inactivates both Gialpha-2 and Gialpha-3 proteins prevented the development of hypertension in SHR suggesting the implication of enhanced expression of Gialpha proteins in the pathogenesis of hypertension. In the present study, we investigated if both the Gialpha-2 and Gialpha-3 proteins are implicated in the development of hypertension and used the antisense (AS) approach. The knockdown of Gialpha-2 protein by Gialpha-2 AS prevented the development of hypertension up to 6 weeks of age, thereafter it started increasing and reached the same level at 9 weeks as that of untreated SHR. On the other hand, the treatment of SHR with Gialpha-3 AS did not significantly attenuate the increased BP. Furthermore, the levels of Gialpha-2 and Gialpha-3 proteins in heart, kidney and aorta from 6 week-old SHR treated with Gialpha-2-AS and Gialpha-3-AS were significantly decreased compared to control SHR. However, these treatments did not attenuate the increased BP and overexpression of Gialpha-2 and Gialpha-3 proteins in 9 week-old SHR. Furthermore, treatment of prehypertensive SHR with C-ANP4-23; an agonist of natriuretic peptide receptor-C (NPR-C) and resveratrol, attenuated the development of hypertension and overexpression of Giα proteins in heart and aorta. These results suggest that Gialpha-2 protein plays an important role in the development of hypertension in SHR and that the new therapies targeting Gialpha proteins may be developed for the treatment of hypertension (Supported by grant from CIHR).
Role of Store-operated Calcium Entry in Angiotensin-II-induced Expression of Egr-1 in Vascular Smooth Muscle Cells
Ashok K. Srivastava
Research Centre, Centre Hospitalier de l'Université de Montréal, Montreal, Canada
An upregulation of Egr-1 expression has been reported in models of atherosclerosis and intimal hyperplasia and, various vasoactive peptides and growth promoting stimuli have been shown to induce the expression of Egr-1 in vascular smooth muscle cells (VSMC). Angiotensin-II (Ang-II) is a key vasoactive peptide that has been implicated in the pathogenesis of vascular diseases. Ang-II elevates intracellular Ca 2+ through activation of the store-operated calcium entry (SOCE) involving an inositol-3-phosphate receptor (IP3R)-coupled depletion of endoplasmic reticular Ca 2+ and a subsequent activation of the stromal interaction molecule 1 (STIM-1)/Orai-1 complex. However, the involvement of IP3R/STIM-1/Orai-1-Ca 2+- dependent signaling in Egr-1 expression in VSMC remains unexplored. Therefore, in the present studies, we have examined the role of Ca 2+ signaling in Ang-II-induced Egr-1 expression in VSMC and investigated the contribution of STIM-1 or Orai-1 in mediating this response. 2-aminoethoxydiphenyl borate (2-APB), a dual non-competitive antagonist of IP3R and inhibitor of SOCE, decreased Ang-II-induced Ca 2+ release and attenuated Ang-II-induced enhanced expression of Egr-1 protein and mRNA levels. Egr-1 upregulation was also suppressed following blockade of calmodulin and CaMKII. Furthermore, RNA interference-mediated depletion of STIM-1 or Orai-1 attenuated Ang-II-induced Egr-1 expression as well as Ang-II-induced phosphorylation of ERK1/2 and CREB. In addition, siRNA-induced silencing of CREB resulted in a reduction in the expression of Egr-1 stimulated by Ang-II. In summary, our data demonstrate that Ang-II-induced Egr-1 expression is mediated by STIM-1/Orai-1/Ca 2+- dependent ERK1/2 and CREB signaling pathways in A-10 VSMC. (Supported by CIHR).
Long-term Outcomes of Dilated Cardiomyopathy Patients
Ajay Bahl
Department of Cardiology, PGIMER, Chandigarh, India
Long term outcomes of patients with dilated cardiomyopathy (DCM) have improved with medical therapy. In our cohort, with currently recommended medical therapy, one-fourth patients with non-ischemic DCM had sustained improvement, and over one-third of those who improved, relapsed. QRS duration predicted both recovery and relapse. Survival of patients in the improved group was significantly better than the non-improved groups. Forty DCM patients in our cohort who were very long term survivors were studied. These patients had survived for more than 10 years from initial diagnosis. A significant number of patients (45%) among this cohort had sustained recovery in ejection fraction and a large majority of our patients (90%) were either in NYHA class I or II at the end of study period. Narrow QRS at baseline, younger age at onset, smaller left atrial diameter, smaller left ventricular end diastolic diameter and lower grade of mitral regurgitation and pulmonary arterial hypertension were significant parameters in predicting good long-term outcomes.
Genetic Basis of Idiopathic Cardiomyopathies
Madhu Khullar
Department of Experimental Medicine and Biotechnology, PGIMER, Chandigarh, India
Idiopathic cardiomyopathies are a heterogeneous group of diseases of the myocardium and are responsible for significant morbidity and mortality and leading indication for heart failure and transplant. Idiopathic cardiomyopathies are due to a variety of causes that frequently are genetic. Hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM) and estrictive cardiomyopathy (RCM) are the major types of cardiomyopathies caused by mutant sarcomeric and non sarcomeric genes. Myosin Heavy Chain (MYH7), Myosin Binding Protein C (MYBPC3), Troponin T (TNNT2) and Troponin I (TNNI3) are frequently mutated genes in cardiomyopathy. Several of the mutant genes linked to DCM encode the same contractile sarcomeric proteins that are responsible for HCM; however, mutations in other genes encoding cytoskeletal/sarcolemmal, nuclear envelope, sarcomere, and transcriptional coactivator proteins like lamin A/C, dystrophin, desmin, caveolin, sarcoglycan, as well as the mitochondrial respiratory chain gene have been also observed. Despite advances in technology for detection of gene variants such as next generation sequencing, causal genes of cardiomyopathies remain to be identified in approximately 1/3rd of patients. Genotype-phenotype studies have shown large clinical variability and genetic heterogeneity among cardiomyopathy patients which is not solely associated with the causal mutations. Clinical phenotypes are also likely to be modified by age, sex hormones, diet and polymorphisms in many genes. Characterization and mechanistic study of cardiomyopathies are therefore challenging due to the complex protein structures, the multitude of disease-causing mutations, and modulations of pathology by genetic background.
Evaluating the Combined Effect of Insulin Like Growth Factor-1, Transforming Growth Factor-ß and Fibroblast Growth Factor on Cardiac Progenitor Stem Cells: Implications in Regenerative Therapeutics of Acute Myocardial Infarction
Gururao Hariprasad1, Domada Ratna Kumar1, Surabhi Swarnkar1, Ashish Kumar Gupta1, Mohd Imran Khan1, Anupama Kakkar1, Sujata Mohanty2, Milind Hote3, Pankaj Sharma4, Subir Kumar Maulik4, Senthil Kumaran5, Sudhir Kumar Arava6
Departments of 1 Biophysics,2 Stem Cell Facility,3 Cardiothoracic Vascular Surgery,4 Pharmacology,5 Pathology and 6 Nuclear Magnetic Resonance, All India Institute of Medical Science, New Delhi, India
Background of the Study: Cardiac stem cells trigger paracrine mechanisms mediated by cytokines that repair infracted tissue and certain cytokines in turn bestow stem cells with effective regenerative functions. We have sought to study the effect of growth factor cocktail on cardiac progenitor stem cells, and the translational value of administering growth factors along side cardiac stem cells in animal myocardial infarction models. Methods and Results: Cardiac stem cells were isolated from the hearts of twelve laboratory-bred female Wistar albino rats. Stem cell progeny was confirmed by flow cytometry studies and cardiac progeny was established by Immuno-electro fluorescence studies using troponin antibody. Cultured stem cells grown in the presence and absence of growth factor cocktail was compared by inverted phase contrast microscopy for cellular morphology, MTT assay for proliferative functions and, DIGE coupled with mass spectrometric experiments to delineate possible cellular pathways. Animal experiments included injecting saline, growth factors, stem cells, and combination of stem cell and growth factor cocktail in four groups of myocardial infarction rat models. Myocardial infarction was established by magnetic resonance imaging, and post-intervention follow up studies was done for four weeks by two-dimensional M-mode echocardiography. Cells grown with growth factors were seen to have distinct cardiac morphology showing elongated cells with branching fibers and centrally placed nucleus; functionally these showed 30% increase viability, and had over expression of proteins which are known to confer cardiac protection and counter oxidative stress. Rats that received combination therapy showed significant improvement in fractional shortening, stroke volume, ejection fraction and left ventricular internal dimension as compared to rats that received individual therapy of either saline, stem cells or growth factors alone. Conclusions: Insulin like growth factor-1, transforming growth factor-ß and fibroblast growth factors confer distinct advantages are in terms of growth, differentiation, proliferation and cell cycle signaling. These benefits have a clear translational value in regenerative therapeutics of myocardial infarction.
Differential Expression and Regulation of Anti-hypertrophic Genes Npr1 and Npr2 during β-adrenergic Receptor Activation-induced Hypertrophic Growth in Rats
Elangovan Vellaichamy
Department of Biochemistry, Peptide Research and Molecular Cardiology Unit, 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/Guanylyl cyclase-A (NPR-A/GC-A), while CNP binds to Natriureitc Peptide Receptor-B/Guanylyl cyclase-B (NPR-B/GC-B). Recent studies have suggested that ANP/NPR-A/GC-A and CNP/NPR-B/GC-B system are present in the heart as a negative regulatory mechanisms to antagonize the cardiac growth response to hypertrophic stimuli. Since NPs has the potential to inhibit cardiac hypertrophic growth via NPR-A/NPR-B receptors, understanding the regulation and expression of NPR-A and –B 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. In this context, we have studied left ventricular (LV) expression of NPR-A (coded by Npr1) and NPR-B (coded by Npr2), and the functional activity of these receptors during β-adrenergic receptor (β-AR) activation induced hypertrophic growth in experimental rats. The NPR-A expression was markedly reduced (3.5-fold), while the NPR-B expression was up regulated (4-fold) in Isoproterenol (ISO)-treated heart as compared with controls. Further, in-vitro membranes assay shows that NPR-A dependent guanylyl cyclase (GC) activity was down-regulated (2-fold), whereas NPR-B dependent GC activity was increased (5-fold) in ISO treated hearts. β –blocker (atenolol) treatment normalized the altered expression of NPR-A and –B proteins. Our results suggests that the chronic β-AR activation differentially regulates NPR-A/GC-A and NPR-B/GC-B in the heart. The signifcance of this finding will be discussed during the presentation.
Rheumatic Heart Disease: Current Understanding of Disease Burden, Pathogenesis and Prevention
G. Karthikeyan
Department of Cardiology, All India Institute of Medical Science, New Delhi, India
This talk will present new data on disease burden from the Global Burden of Disease Study and provide an update on recent data from clinical and echocardiographic studies. The talk will also summarize recent insights and ongoing work on the genetics and pathogenesis of RHD. Finally, an update on the current status of preventive strategies will also be presented.
Plasma Proteomics in Rheumatic Heart Disease and Coronary Artery Disease
Arun Bandyopadhyay1, Somaditya Mukherjee1, Tanima Banerjee1, Apabritaayan Das1, Devasmita Chakravarty1, Sudip Ghosh2, Santanu Dutta2, Prakash Chandra Mandal3
1Cell Biology and Physiology Division, CSIR-Indian Institute of Chemical Biology,2 Institute of Post Graduate Medical Education and Research, SSKM Hospital,3 Apollo Gleneagles Hospital, Kolkata, West Bengal, India
The traditional approach to study cardiovascular disease (CVD) and develop new biomarkers was to look at one or a few candidate molecules. But, the advent of new proteomic techniques in CVD research allows analysing the expression of a plethora of proteins at one go. Proteomics and bioinformatics are powerful tools to identify protein based biomarkers involved in a disease state. The current advancement in proteomic technologies helps studying global protein expression changes associated with human disease processes. One of the advantages of these proteomic studies is that new biomarkers (diagnostic and/or prognostic) can be discovered which will help provide a better framework for treatment of cardiovascular diseases. Thus, the detection, identification and characterization of variations in the proteome occurring during the course of heart disease will provide both (i) insight into the underlying molecular mechanisms and (ii) potential cardiac specific biomarkers for regular, systematic observation and assessment of cardiac status. The aim of this study was to provide a list of potential blood based protein markers for RHD and CAD. We utilized on-line label-free MS/MS using blood plasma as the source material. On-line LC-ESI-MS is the method of choice because the initial LC separation step decreases the amount of analytes that can be simultaneously ionized. Thus, the possibility of ion suppression is reduced rendering the method quantitative in nature. Such label-free quantitative LC-MS approaches can compare innumerable samples. Therefore, they are ideal for biomarker discovery because experimental workflows normally compare a large number of specimens to validate the results from a statistical point of view. Consequently, the label-free quantitative LC-MS methods employed in this thesis helped analyse the full potential of clinical plasma samples as a source of disease biomarkers in RHD and CAD respectively. Some of which might play important roles in the pathophysiology of RHD and CAD and improve the existing diagnostic strategies. Taken together, it may be said that the results of the proteome analysis may be useful to understand the pathophysiological changes associated with RHD and CAD. Some of the altered protein(s) unique to these diseases might qualify as potential CVD biomarker(s). Those biomarkers may be utilized for the development of diagnostics which in turn, would help therapeutic intervention timely and might save human lives [This work is supported by CSIR grant no. MLP123 to AB.
Balloon Aortic Valvuloplasty in Rheumatic Aortic Valve Disease
Santhosh Satheesh
Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India
Rheumatic Heart Disease causes significant morbidity and mortality. Though the Mitral Valve is most commonly involved, Aortic Valve is affected in over 50% of patients. Balloon Valvuloplasty is the treatment of choice in Mitral Stenosis of Rheumatic Etiology but scant data was available in the literature about the efficacy of Balloon Aortic Valvuloplasty in rheumatic heart disease. In JIPMER we evaluated 92 patients who underwent Balloon Valvuloplasty. The procedure was successful in 85% of patients and majority of them did not nned an open heart surgery over the 5 year follow up period, with significant improvement in cardiac haemodynamics with relief of symptoms. BAV is a effective treatment strategy in Rheumatic Valvular Aortic Stenosis.
Emerging Therapies in Pulmonary Hypertension
S. Ramakrishnan
Department of Cardiology, All India Institute of Medical Sciences, New Delhi, India
Idiopathic pulmonary hypertension (IPAH) is a rare disease associated with high morbidity and mortality. The pathogenesis is not fully understood. Diagnostic evaluation focuses on ruling out other aetiologies of pulmonary hypertension and prognosticating the disease. Congenital heart disease and left sided heart disease associated pulmonary hypertension are more common in India. Therapies for idiopathic pulmonary hypertension have evolved over the past decade. Phosphodiesterase 5 inhibitors (sildenafil, tadalafil), endothelin antagonists (Bosentan and ambrisentan) and prostanoids are the class of drugs shown to be useful in pulmonary hypertension. An initial combination of ambrisentan and tadalafil may be beneficial in selected patients with IPAH. Riociguat and macitentan are the newer agents approved for use in PAH following landmark clinical trials confirming their efficacy. After prostanoids, initial combination therapy, riociguat and macitentan have shown improvement in hard clinical end points. Balloon atrial septostomy, Pott's shunt, stem cell therapy, and radiofrequency ablation are the other therapies that could benefit an IPAH patient with refractory symptoms. Despite these advances, the outcomes of various forms of pulmonary hypertension remains poor especially in India, where some forms of therapy are not available and patients often are diagnosed at an advanced stage of disease.
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