Towards a Healthier Heart
Double Helical takes a look at the current status of research into cardiovascular diseases (CVD) with emphasis on emerging information on risk factors and Indian efforts for arresting the disease’s growing incidence, providing affordable care, and discovering new remedies.
Practice of modern cardiology and treatment of heart disease with allopathic drugs became a reality in India soon after the World War II, and research on the pathogenic and therapeutic aspects of cardiovascular diseases (CVD) was also initiated during the same period.
Ayurvedic physicians of ancient India (2500 and 500 BC) recognized the heart as a controlling centre connected to the entire body through channels (shiras and dhamanis), which supplied nutrients to various tissues and provided passage for waste products. They claimed that any obstruction in these channels led to sickness in the body and performed treatment on the basis of personal knowledge of various herbal formulations, which continue to be used by current practitioners of the traditional Indian systems of medicine.
Epidemiological Transition in CVDs
Epidemiological studies on CVD in India have been reviewed recently. During the last decade, CVDs have emerged as the leading cause of morbidity and mortality in India and are responsible for healthcare burden to the tune of $237 billion during 2005 to 2015. Hospital-based studies from 1946 to 1962 reported an incidence rate of coronary heart disease ranging from 6% to 23% in cardiac patients of low-income groups and as high as 35% in high- and middle-income groups.
A dramatic epidemiological transition has been witnessed during the last two decades. This transition is coupled with increased life expectancy from 58.3 to 65.2 years, lifestyle changes, rapid unplanned expansion of cities, and rural migration. CVDs presently account for two thirds of the mortalities because of non communicable diseases with 52% of deaths occurring more than 70 years of age and the mortality rates being higher in urban areas (>35%) and lower in rural areas (<10%).
Cross-sectional studies from different parts of the country indicate that the prevalence of CVD has gone up from 1.7% in rural and 2% in urban areas, respectively, in 1960 to 1970 to 7.4% in rural and 14% in urban areas by 2013. Hypertension is also a leading cause of morbidity (30% in the adult population). Prevalence of diabetes mellitus is 17% in urban and 9% in rural India. Mortality from heart failure is 18.6%. A recent population-based urban stroke registry at Ludhiana found age-standardized stroke incidence rate of 130 per 100 000 population. It has to be noted that large-scale longitudinal studies to estimate the burden of heart diseases have not been conducted in India.
Risk Factors for CVDs in Indian Population
Major non-modifiable risk factors for CVDs in the Indian population are advancing age, family history, sex, and ethnicity. Major modifiable risk factors include hypertension, dyslipidemia, diabetes mellitus, obesity, and lifestyle risk factors, such as smoking, inadequate physical activity, and less use of fresh vegetables and fruits (zero to 1 serving of fruit in a week). There are 275 million tobacco consumers in India in the age group ≥15 years; 164 million use smokeless forms of tobacco. Although conventional risk factors are important, novel risk factors are considered to increase the risk of CVD in Indians. These factors include high lipoprotein (a), plasminogen activator inhibitor-1, fibrinogen, and low tissue plasminogen activator.
The added cardiovascular risk in people of South Asian origin cannot be explained by conventional risk factors alone. Several candidate gene studies have reported that Indians have a genetic predisposition to atherothrombotic risk. A genetic basis for an increased coronary heart disease risk among South Asians is supported by the finding that South Asians tend to have higher lipoprotein (a) levels than other ethnic groups.
Asian Indian phenotype refers to certain unique clinical and biochemical abnormalities in Indians, which include increased insulin resistance, greater abdominal adiposity, that is, higher waist circumference, despite lower body mass index, lower adiponectin, and higher high-sensitivity C-reactive protein levels. It seems likely that South Asians’ enhanced susceptibility to CVD results from both genetic and environmental influences. There is evidence that a traditional vegetarian diet consumed by populations as found in Pune in India could lead to a genetic mutation in the gene FADS, which codes for a fatty acid denaturize catalyzing the rate limiting steps in the biosynthesis of long-chain poly unsaturated fatty acids that may increase inflammatory potential and individual’s risk for heart disease.
Current Indian pursuits that have translational potential are (1) discoidin domain receptors and cardiac fibrosis, (2) cyclophilin A and vascular disease in diabetes mellitus, (3) in-terleukin-1 receptor–associated kinase in atherosclerosis, (4) catestatin in hypertension, (5) genetic and evolutionary perspectives of dilated cardiomyopathy, (6) targeting cytochrome b5 reductase 3 to modulate hypertension, (7) identifying strategies to control acute coronary syndrome, (8) unravelling the role of sleep apnea in coronary artery disease, (9) exome-sequencing guided diagnostics for cardiomyopathy, and (10) community-level interventional studies.
Development of Valve and Vaccine for Rheumatic Heart Disease
Rheumatic heart disease (RHD) continues to be a major cardiovascular problem in India. More than 2 million patients are estimated to experience RHD. The RE-LY (randomized evaluation of long term anticoagulant therapy) investigators observed that RHD contributes to 33% of the atrial fibrillation burden in India. RHD is also the leading cause of structural heart-valve damage in the country. Because a large majority of patients with RHD in India are unable to afford expensive imported artificial valves, an indigenous TTK Chitra valve was developed at Sree Chitra Tirunal Institute for Medical Sciences and Technology at Trivandrum.
This valve has >90 000 implantations to date. Efforts are also being made to develop a vaccine against group A Streptococcus — the causative agent for rheumatic fever. The wide heterogeneity of group A Streptococcus isolates from throat swabs of children with rheumatic fever poses challenges for development of an ideal vaccine.
Development of Fibrinolytics and Coronary Stents
Given the limited access, thanks to high cost of imported streptokinase, investigators at the Institute of Microbial Technology at Chandigarh developed an indigenous natural streptokinase in 2001 and a recombinant streptokinase in 2009, and recently, a third generation of clot-specific strepto-kinase by fusing the core of streptokinase with fibrin-binding domain 4 and 5 of human fibronectin. This clot buster has been given permission for phase II clinical trial. The requirement for coronary stents has increased considerably in India. Sahajanand Medical Technology at Surat has developed minimally invasive coronary stent systems. Their sirolimus and everolimus drug-loaded stents have a blend of biodegradable polymers and a hydrophilic top layer. Institute of Chemical Technology at Mumbai developed infinnium—a drug-eluting stent, which received CE (Conformité Européenne) mark for biodegradable polymeric drug-coating technology.
Stem Cell Research in India
Indian efforts in research on cardiac regeneration include investigations using induced pluripotent stem cells, attempts to enhance the yield of cardiac stem cells for implantation, genetically modify progenitor cells for improving their function, and assessing efficacy of stem cell transplantation through clinical trials.
Translational Research on Herbal Medicines
India has a rich heritage of ancient knowledge on herbal drugs. An early major contribution to cardiovascular sciences in modern India is the discovery by Rustom J. Vakil on the use of reserpin—an alkaloid from the extract of roots of Rauwolfia serpentina—in treating patients with hypertension. Recently, several herbal medicines have been shown to possess antiplatelet, hypolipidemic, anti-inflammatory, hypo-glycemic, and hypotensive actions. Gugulipid—a cholesterol-lowering agent developed from the plant Commiphoramukul by scientists at Central Drug Research Institute at Lucknow has an activity comparable with clofibrate. Allyl methyl sul-fide and allyl methyl sulfoxide, two ingredients of garlic, have been shown to increase the expression of Na+/K+-ATPase protein, decrease intracellular calcium levels, and attenuate cardiac hypertrophy. Herbs namely Withania somnifera, Curcuma longa, and Ocimum sanctum and their combinations have been found beneficial in reducing myocardial injury.
The government of India has established a separate ministry Ayurveda, Yoga and Naturopathy, Unani, Siddha, and Homeopathy to encourage research and promotion of Indian traditional systems of medicine. Ayurvedic Biology Programme of Department of Science and Technology is an independent new programme which supports basic and translational research on Ayurvedic concepts and Ayurvedic medicines for use in clinical practice. Ayurnutrigenomics is an emerging field of research for understanding pathogenesis and evolving strategies for management of CVD.
Funding for Cardiovascular Research
In 2007, the government created the Department of Health Research under the Ministry of Health and Family Welfare with a mandate to promote basic, applied, and clinical research through development of infrastructure, manpower, and skills in cutting-edge areas. The problem of non-communicable diseases was addressed in the National Health Policy in 2017, and the Government announced an increase in public health expenditure to 2.5% of the gross domestic product. The major objective of this policy was to shift focus from sick care to wellness and target reduction of morbidity and mortality because of CVDs by 25 percent.
Indian Council of Medical Research (ICMR) under the Department of Health Research coordinates Department of Science and Technology, Science and Engineering Research Board, Department of Biotechnology, and Council of Scientific and Industrial Research for funding various research projects. Funds disbursed by these agencies for cardiovascular research are not available in the public domain. Currently, there is no separate and specific budgetary provision for funding cardiovascular research.
The budget of ICMR for funding research in all domains in the year 2017– 2018 was an equivalent of $232 million, which is significantly less in comparison with 32 billion dollars a year the budget of National Institute of Health in the United States. Funding for projects is based on recommendations of programme advisory committees of the funding agencies, which call for proposals from investigators, review them, and make recommendations for funding. Universities and institutions also support investigator centric projects.
A few Indian scientists have been successful in obtaining funding from international agencies, such as The Wellcome Trust, Melinda Gates Foundation, National Institutes of Health, United States, and through bilateral pro-grams between India and countries, such as Australia, Canada, France, Germany, United Kingdom, and the United States.
(With inputs from Prof. Dr. Ramesh K. Goyal, Vice Chancellor, Delhi Institute of Pharmaceutical Sciences and Research University, New Delhi)