|Year : 2018 | Volume
| Issue : 1 | Page : 22-28
Prevention or reversal of cardiometabolic diseases
Gundu HR Rao
Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota, USA
|Date of Web Publication||11-Jan-2018|
Prof. Gundu HR Rao
12500 Park Potomac Ave, Unit 306N, Potomac, MD 20854
Source of Support: None, Conflict of Interest: None
Cardiometabolic risk is a condition in which the possibilities of developing vascular diseases including hypertension, metabolic syndrome, obesity, type 2 diabetes, ischemic heart disease, and stroke are significantly enhanced as a consequence of the presence of various risk factors, which are known to promote these conditions. Cardiovascular diseases (CVDs) cause one-third of all deaths worldwide. Noncommunicable Disease Risk Factor Collaboration, in their seminal article in the Lancet (April 2016), concluded that “if the post-2000 trends continue in the incidence and rise of diabetes, the probability of meeting the global target of halting the rise in the prevalence of diabetes by 2025–2020 level worldwide is lower than one percent.“ According to the Institute for Health Metrics and Evaluation, today, 2.1 billion people, nearly 30% of the global population, are either obese or overweight – a new, first-of-a-kind analysis of trend data from 180 countries. As part of the 2020 impact goals, the American Heart Association (AHA) has set out seven ideal health goals; not smoking, maintaining a normal weight, increased physical activity, a healthy diet, normal blood lipid levels, normal blood pressure, and a normal fasting glucose. An analysis of the National Health and Nutritional Examination Survey showed that individuals who met five of the seven ideal metrics of AHA had a 78% reduction in the hazard ratio for all-cause mortality. The INTERHEART study estimated that modifiable risk factors accounted for 90% of the population attributable risk for heart disease in men and 94% of the risk in women. Consistent with this, Khera et al. (NEJM: 375:2349–582,016) showed that in four studies with over 55,000 participants, a favorable lifestyle intervention was associated with nearly 50% lower risk for coronary artery disease, in spite of the genetic risk. In this overview, we discuss some prevention strategies for the major cardiometabolic conditions such as hypertension, obesity, type 2 diabetes, and ischemic heart disease. We also discuss results of studies in which reversal of these disease conditions has been claimed.
Keywords: Coronary artery disease, hypertension, metabolic diseases, obesity, type 2 diabetes
|How to cite this article:|
Rao GH. Prevention or reversal of cardiometabolic diseases. J Clin Prev Cardiol 2018;7:22-8
| Introduction|| |
According to the recent World Health Organization (WHO) report (2106), type 2 diabetes is on the rise worldwide, markedly in the world's middle-income countries. As part of the 2030 agenda for sustainable development, member states have set an ambitious target to reduce premature mortality from noncommunicable diseases (NCDs) including diabetes by one third, achieve universal health coverage, and provide access to affordable essential medicines to all by 2030. Global estimate of type 2 diabetics stood at 422 million in 2014, compared to 108 million in 1980. Diabetes caused 1.5 million deaths in 2012. Effective approaches are available to prevent or manage better, type 2 diabetes and to prevent its clinical complications. The approaches include all policies across whole populations that contribute to good health for everyone, regardless of whether they have diabetes, such as exercising regularly, eating healthy food, avoiding smoking, and controlling blood pressure, blood glucose, and excess blood lipids.
As we have mentioned in our early writings, the starting point for the prevention of type 2 diabetes is early diagnosis and better management of the observed risks.,,, Because the longer an individual lives with an undiagnosed diabetic condition, the worse their health outcomes will be. Having said that, what is the earliest time that we can diagnose the biomarkers for the development of cardiometabolic diseases? We have discussed this topic many a times before. In brief, 30% of the children born in India and China are of low birth weight and according to many studies done in India and abroad; low birth weight children are highly predisposed to the development of cardiometabolic disorder (CMD).,,,,,, These low birth weight children develop excess CMDs, according to the studies done at Mission Hospital, Mysore, India and KEM Hospital, Pune. In view of this observations, we have initiated a bilateral study on molecular mechanisms involved in the fetal origin of adult diseases, between the research group of Children's National Memorial Hospital (CNMH), Washington DC, USA, and the research staff at the Diabetes Clinic, KEM Hospital, Pune, India.,,,,,
How did global epidemiology and prevention studies get started? In 1948, Framingham Heart Study (FHS) (A project of the National Heart and Blood Institute and Boston University) scientists and participants embarked on an ambitious project to identify risk factors for heart disease. Today, after seven decades, the study remains a world-class epicenter for cutting-edge heart, brain, bone, and sleep research according to their claims on their web page (https://www.framinghamheartstudy.org). We are delighted to inform the readers that the principal investigator and co-director of this project are none other than Professor Vasan S. Ramachandran, Chief, Preventive Medicine and Epidemiology, Boston University School of Medicine. The FHS for the first time, based on epidemiological research, demonstrated the risk factors such as smoking, elevated cholesterol levels, increased blood pressure, lack of physical activity, and electrocardiogram abnormalities as the primary promoters of heart disease. Based on their findings, FHS researchers also developed simple coronary artery disease risk prediction algorithm (https://www.mdcalc.com/framingham-coronary-heart-disease-risk-score).
During the same period, a Professor at the University of Minnesota (Dr. Ancel Keys) developed a unique epidemiological study, which later became the well known, much publicized, world's first multicountry epidemiological study: The Seven Countries Studies. Although it was conceptualized as early as 1947, the real US-funded study began in 1956,, and continues to have a significant impact after over 50 years. The study was first started in Yugoslavia in 1958 then extended to 16 cohorts in seven countries (Italy, Greece, Yugoslavia, the Netherlands, Finland, Japan, and the USA) in four regions of the world (the USA, Northern Europe, Southern Europe, and Japan). It demonstrated that the risk and rates of heart attack and stroke at the population level as well as at the individual level were directly and independently related to the level of total blood cholesterol. Based on the results of these studies and other major investigations, the AHA and the Public Health Service (PHS), USA, developed dietary guidelines for the prevention of heart disease. Since the time Uffe Ravnskov published his book, The Cholesterol Myths www.ravnskov.nu/cholesterol, there is increased debate about the “Good Fats, Bad Fats,“ and the need to replace saturated fats in our diet with polyunsaturated or monounsaturated fats. We will review these controversies in a separate review in the near future. As of now, various professional organizations including SASAT, WebMd, Mayo Clinic, and the US PHS, recommend that health-conscious individuals avoid or minimize saturated fats and replace them with polyunsaturated or monounsaturated fats. In spite of the controversies related to this topic, the 2017 guidelines by the AHA still conclude that “prospective observational studies in many populations have shown that lower intake of saturated fat coupled with higher intake of polyunsaturated and monounsaturated fat is associated with lower rates of CVD and of other causes of death and all-cause mortality.”,
In response to a petition from the representative population of North Karelia in Finland, North Karelia project was launched in 1972,, for comprehensive population-based intervention. The intervention was based on “at that time“ the new scientific information available on the risk factors, serum cholesterol, blood pressure, tobacco use, and dietary changes. Thus, was launched the world's first major community-based preventive study in the field of CMDs. Main objectives of the project were to initially (1972–1982) reduce mortality by CVD in local populations, subsequently to reduce major chronic (NCDs) mortality and promote good health in the local population. Main target risk factors included smoking, elevated serum cholesterol, and elevated blood pressure. As to the prevention strategies, major emphasis was on improvement of general lifestyles. According to Professor Pekka Puska, the principal investigator of this project, “findings of these studies in North Karelia have indisputably revealed that these NCDs or events leading to them have their roots in unhealthy lifestyles or adverse physical and social environments”. The major lifestyle factors implicated were unhealthy nutrition, smoking, physical inactivity, excess use of alcohol, and psychosocial stress.
The North Karelia project and the Finnish experience in the community-based prevention of chronic diseases provide strong evidence and serve as a model for low- and middle-income countries, which bear the maximum NCD burden. These diseases to a great extent are preventable. Population-based prevention, influencing lifestyles, broad collaboration, and sound policies are the most cost-effective ways to combat this growing epidemic in low- and middle-income countries. In a recent article in Harvard Gazette, Harvard Professor Paul Ridker contemplates about the major milestones in preventive cardiology the following way: “In my lifetime, I've gotten to see three broad eras of preventative cardiology. In the first, we recognized the importance of diet, exercise, and smoking cessation. In the second, we saw the tremendous value of lipid-lowering drugs such as statins. Now, we're cracking the door open on the third era,“ said Paul M. Ridker Professor, leader of CANTOS Clinical Trial on the anti-inflammatory drug (Ilaris), Canakinumab (Harvard Gazette, 2017/08) at Brigham and Women's Hospital, Boston., The early studies he refers to are the studies we have discussed above following the FHS findings. The second studies he refers to are the clinical studies evaluating the beneficial effects of statins; Justification for the Use of Statins in Prevention: Trial Evaluating Rosuvastatin. Results of the third studies he refers to are published recently in the New England Journal of Medicine. We have come a long way from the time; FHS demonstrated a correlation between the risk factors and development of acute coronary syndromes. Looking back at the three prominent eras that Dr. Ridker refers to in his article, we can find one thing that is common. Once the risk factors were recognized as the causative agents for the development of acute vascular events, Pharma companies developed appropriate drugs to reduce or prevent these recognized risks. However, the results of North Karelia project has demonstrated that the intervention with drugs is a very small part of the prevention program compared to other approaches such as education, creating awareness, early diagnosis of the risks, changes in lifestyle, and diet. In this overview, we will discuss more the novel approaches such as these than the drug-induced risk reduction or disease management.
Hypertension or high blood pressure occurs one in three Americans, and there are over a billion hypertensives worldwide. This condition places a severe stress on the arteries as well as the heart. Hypertension is known as the silent killer as it may progress for several years without any symptoms. High blood pressure is the major underlying cause of heart attacks, stroke, and kidney failure. In my opinion, hypertension should be described as a vascular disease developed in response to alterations in the vascular tissues, functions, and altered blood flow dynamics. According to the current AHA guidelines, hypertension is clinically defined as a systolic pressure >140 or a diastolic pressure >90. The Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure task force publishes guidelines periodically. The latest update was published March of 2017. Results of the Hypertension Optimal Treatment Trial; a 5-year study involving 19,000 participants from 26 countries was published in the Journal of Hypertension. Authors of this study concluded that participants who could lower their diastolic pressure to 138 and systolic to 82 had a major reduction in heart attack and stroke incidence. Authors concluded that the quality of life was linked to the level of blood pressure achieved: the lower the blood pressure, the better the quality of life., According to a study published in JAMA in 1999, a decrease in diastolic pressure of only 5 or 6 points lowers the risk of stroke by 42%.
In the majority of situations, the blood pressure is monitored in the clinic as one-time measurement. According to many sources, by monitoring blood pressure this way (one-time measurement), millions of individuals may be misclassified as hypertensive. If in doubt, one should get a 24-h ambulatory blood pressure (ABP) monitored. Since this method of monitoring the blood pressure is not covered by the health insurance in the USA, even at this time of writing individuals get checked for blood pressure only when they visit a clinic for their checkup. ABP device monitors the blood pressure every 15 min and the software charts the average for the entire 24 h. Professional societies have published guidelines and they keep updating guidelines regularly.,,,,, A summary of the WHO guidelines is published in the Journal of Hypertension. Full text of these guidelines is available as PDF version from the WHO. In view of the importance of effective hypertension management in reducing acute cardiac events, a special issue of Indian Guidelines on Hypertension was published in 2013. There are guidelines for hypertension management, which are disease specific.,, Readers are urged to consider geographic-specific or disease-specific guidelines that will suit for their use in clinical practice.
Obesity like hypertension is a serious global public health problem. As we have reported in our earlier writings, according to the Institute for Health Metrics and Evaluation currently, 2.1 billion people, nearly 30% of the global population, are obese or overweight – a new trend data from 180 countries., Since 1980, obesity has increased worldwide by two-fold. The Lancet's executive summary, in its series on obesity (2015), states that “Today's food environments exploit people's biological, physical social and economic vulnerabilities, making it easier to eat unhealthy foods. This reinforces preferences and demands for foods poor in nutritional quality, furthering the unhealthy food environments.“ Regulatory actions from governments and increased efforts from industry and civil society will be necessary to break these vicious cycles. In 2011, the Lancet published the first series with science-based recommendation for actions.
The Lancet's five messages on obesity included; the obesity will not be reversed without government leadership; business “as usual“ would be costly in terms of population health, health-care expenses, and loss of productivity; assumptions about sustainability of weight are wrong; we need to accurately monitor and evaluate basic population weight and data and intervention outcomes; a systems approach is needed with multiple sectors involved., According to most estimates, nothing has changed since the Lancet published the first series. Indeed, according to the NCD Risk Factor Collaboration, if the post-2000 trends continue, the global target of halting the rise in prevalence of metabolic diseases by 2025–2020 level is lower than 1% (Lancet, April 2016). Contrary to these expectations, increases in overweight and obesity in adults are widely projected to increase in the coming decades. Roberto et al. in their article in the Lancet say “No country has reversed obesity epidemic.” The WHO Global Action Plan for the Prevention and Control of NCDs has clear agreements on what strategies should be implemented and tested to address obesity. The real challenge is how to implement the specific actions in various countries where obesity is a growing concern and then how to prioritize the importance of this condition compared to many other problems facing them.
When considering childhood obesity, one should look at a bigger picture as the causes may differ depending on the countries. For instance, in countries like India, China, and many other developing or resource-poor countries, maternal, neonatal, and children's nutrition or the lack of it may play a big role. In India and China, a significant number of children are born with low birth weight. These low birth weight children are predisposed to develop excess metabolic diseases. We have initiated a bilateral study between the researchers of CNMH, Washington DC, and Diabetes Research Group at the KEM Hospital, Pune, to explore if the exosomes shed by the obese pregnant women “tweet signals“ that alter the metabolism of the growing child. Considering a large number of children born with low birth weight (30% of the births) in India, it will be a great preventive strategy to develop appropriate interventions at this stage. When considering interventions, by and large, majority of strategies include diet and exercise as one of the major approaches. Lifestyle changes are hard to implement at the population level, and we will discuss this aspect in general terms at a later stage.
Professor Henry Buchwald and associates at the University of Minnesota have been doing bariatric surgery for obese individuals for several decades. In a recent conference on obesity that I participated in Dubai (2017), I was surprised to see that most of the papers presented were by bariatric surgeons, claiming success over type 2 diabetes, obesity, and clinical complications associated with these diseases. Buchwald and associates in a meta-analysis done on data from 136 studies, which included over 22,000 patients, conclude that “Effective weight loss was achieved in morbidly obese patients after undergoing bariatric surgery. A substantial majority of patients with diabetes, hyperlipidemia, hypertension, and obstructive sleep apnea experienced complete resolution or improvement.”, The procedures are relatively safe, having said that sustained weight loss depends on patient re-education in terms of diet, need for regular exercise, and follow-up evaluations.
Susan Henning and associates at the David Geffen School of Medicine, University of California, Los Angeles, report that black tea through a specific mechanism through gut microbiome may contribute to weight loss in humans. Both green tea (GTP) and black tea polyphenols (BTP) stimulate the growth of the gut bacterium, which facilitates the formation of short-chain fatty acids (SCFA). Authors conclude that GTP and BTP induced a significant increase in hepatic 5'adenosylmonophosphate-activated protein kinase (AMPK) phosphorylation. They hypothesize that BTP increased pAMPK through increased intestinal SCFA production while GTP increases hepatic AMPK through GTP present in the liver.,, Yet, another novel approach to the management of metabolic diseases is gene therapy, a method to replace mutated or disease gene with a normal gene. Gene therapy-based treatment provides long-term and sustained expression of the gene. In brief, the gene of interest is packaged inside a carrier molecule. This carrier can be an engineered virus, liposome arginine-graft cystamine-bisacrylamide-diaminohexane polymer, or a nano-complex. Obesity and related clinical complications or compounded by multiple genetic and epigenetic factors. Several genes have been reported to be directly or indirectly responsible for regulating fat deposition as well as fat metabolism. The genes of interest to us for gene therapy applications are PER3, CLOCK, and Rev-Erb-alpha gene along with regulatory sites AANT and CSNK1E. We at the School of Biosciences and Technology, Cellular and Molecular Theranostics at the Vellore Institute of Technology, Vellore, India, are interested in using some of these cutting-edge technologies for developing novel approaches for the management of obesity and associated metabolic dysfunctions.
We have not made any attempts to comprehensive review the topic of obesity; readers are urged to refer to the latest reviews and guidelines for better understanding of the obesity-related clinical complications and better management of these metabolic disorders.,, In this connection, it is worthwhile considering the position of the Academy of Nutrition and Dietetics, “It is the position of the Academy of Nutrition and Dietetics that successful treatment of overweight and obesity in adults requires adoption and maintenance of lifestyle behaviors contributing to both dietary intake and physical activity.”
Type 2 diabetes has become a global epidemic, poses a great public health crisis, and contributes significantly to the health-care burden. NCD Risk Factor Collaboration in their article in the Lancet (April 2016) concluded that “if the post-2000 trends continue in the incidence and rise of diabetes, the probability of meeting the global target of halting the rise in the prevalence of diabetes by 2025–2020 level worldwide is lower than one percent.” Since 1980, the incidence of type 2 diabetes has increased by four folds. Diabetes caused 1.5 million deaths in 2012. Elevated blood glucose caused an additional 2.2 million deaths, by increasing the risks for cardiovascular and other diseases. Forty-three percent of these 3.7 million deaths occur before the age of 70 years. The percentage of deaths attributable to high blood glucose or diabetes in under the age of 70 is higher in low- and middle-income countries. Effective approaches are available to prevent complications and premature death related to diabetes-related complications. These include policies and practices across the populations that contribute to good health for everyone, regardless of whether they have diabetes or not such as exercise, eating healthy, avoiding smoking, and controlling blood pressure.
Compared to the incidence of type 2 diabetes in Western populations, Asians and Chinese population develop diabetes at a younger age. Asians account for 60% of the global diabetic population; unlike in the Western countries, obesity per se does not directly correlate with the incidence or rate of diabetes. In India for instance, in spite of the relatively low prevalence of obesity, there exists a high rate of diabetes. Studies at the Madras Diabetes Research Foundation, Chennai, India, in collaboration with the University of Minnesota researchers demonstrated that compared to the American adults, based on hip/waist ratios, Asian population exhibits “normal-weight metabolically obese“ phenotype., This altered fat distribution (elevated visceral fat) seems to predispose this population to increased prevalence of insulin resistance. In addition, low-grade inflammation seems to promote the pathogenesis of type 2 diabetes. Major contributors to the development of this chronic metabolic disorder are hyperglycemia, insulin resistance, dyslipidemia, hypertension, endothelial dysfunction, oxidative stress, and inflammation. Studies at the Newcastle University (UK) by Professor Roy Taylor and associates have demonstrated that type 2 diabetes can be reversed even in well-characterized cases by putting the participants on very low-calorie diets. They have shown that type 2 diabetes can be kept in remission for over 6 months after the low-calorie diet regimen was completed. The question that comes to mind when considering such serious interventions is, can such interventions sustainable?
According to the International Diabetes Federation Guidelines, there is increasing evidence that supports the importance of controlling all the three components of the glucose triad; hemoglobin A1c, fasting glucose, and postprandial glucose Postmeal glucose is defined as 140 mg of glucose/dl 2 h after the ingestion of a meal. Americans on an average consume 250–300 g of carbohydrates per day, accounting for 55% of their daily intake. On the other hand, South Asians consume lot more carbohydrates per day. Professor Stephen Phinney and associates at the University of California, Davis, in their 12-week study put 40 participants on a 1500-calorie diet. Half of the participants were on low-fat high-carbohydrate diet and the other half on low-carbohydrate and high-fat diet. Despite the high fat that the low-carbohydrate diet group had at the end of the study, the levels of triglycerides had dropped by 50% in this group. Levels of good cholesterol had increased by 15%. They concluded that the dietary fat intake was not directly related to blood fat., They demonstrated that a very low-carbohydrate diet resulted in profound alterations in fatty acid composition and reduced inflammation compared to low-fat diet. “Fat is not the problem,“ says Dr. Walter Willet, Chairman of the Department of Nutrition at the Harvard School of Public Health (LA Times 21/20/2016). “If Americans could eliminate sugary beverages, potatoes, white bread, pasta, white rice and sugary snacks, we would wipe out almost all the problems we have with excess weight and diabetes and other metabolic diseases.”
Progress in coronary artery disease and cerebrovascular diseases causes heart attacks and stroke. There is currently no cure for this kind of vascular disease. Neither medication alone nor bypass surgery can cure the disease. The best choice one has at present is to manage the observed risks for vascular disease efficiently. Having said that I want to assure the readers that it is possible to slow down the build-up of blockages inside coronary and cerebral arteries. It is even possible to cause existing block to be partially removed. This process is called the reversal of coronary artery disease by risk factor modification. Website of Professor Dean Ornish, a pioneer in this approach (https://www.ornish.com.undo-it/), claims that their program of lifestyle medicine is the first program scientifically proven to “undo“ (reverse) heart disease by optimizing four important areas of your life; what you eat, how you manage stress, how much you move, and how much love and support you have? They also claim that 37 seven years of scientific evidence conducted by Professor Dean Ornish and his colleagues in collaboration with the University of California, San Francisco, and other leading institutions show that changes in diet and lifestyle can make a powerful difference in your heart function and overall well-being.,,,,
As part of the 2020 impact goals, the AHA has set out seven ideal health goals; not smoking, maintaining a normal weight, increased physical activity, a healthy diet, normal blood lipids, and a normal fasting glucose. An analysis of the National Health and Nutritional Examination Survey of the USA showed that individuals who met five of the seven ideal metrics of AHA had a 78% reduction in the hazard ratio for the all-cause mortality. From the INTERHEART study under the leadership of Professor Salim Yusuf, which included 52 countries, it is estimated that modifiable risk factors account 90% of the population attributable risk for heart disease in men and 94% of the risk in women. However, a recent study by Khera et al. described in New England Journal of Medicine (2016) showed that in four studies with over 55,685 participants, a favorable lifestyle intervention was associated with nearly 50% lower relative risk for coronary artery disease than was with unfavorable lifestyle.
CMDs are a combination of metabolic dysfunctions mainly characterized by insulin resistance, impaired glucose tolerance, dyslipidemia, hypertension, and central abdominal adiposity (visceral adiposity). These disorders are now recognized by the WHO and American Society of Endocrinology as a disease entity. Individuals with CMDs are two times more likely to die from coronary artery disease and three times more likely to have a heart attack or stroke than those who do not have this syndrome. CVD is the leading cause of death worldwide, accounting for 31% of all deaths in 2012 according to the WHO. In this brief overview, we have tried to highlight some of the strategies to reverse or prevent these diseases. Readers urged to consult comprehensive reviews on these participants when planning their treatment protocols or when developing disease reversal and prevention strategies.
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