The Cardiovascular Continuum in Asia-A New Paradigm for the Metabolic Syndrome

Abstract

Atherosclerosis, myocardial infarction, and heart failure are cardiovascular complications in a continuum that begins with risk factors such as hypertension, diabetes, and dyslipidemia. These particular cardiovascular risk factors commonly occur together in obese individuals as components of the metabolic syndrome. In Asia, there is a trend toward an increase in the prevalence of the metabolic syndrome and cardiovascular disease. Abdominal adiposity is arguably the key factor underlying the development of insulin resistance and the metabolic syndrome. It is now known that adipose tissues secrete adipokines, and in obese subjects, there is a chronic low-grade inflammation. The inflammation and the associated endothelial dysfunction are reversible in the early stages. The Asian diet is low in animal fat but high in carbohydrates. Recent studies suggest that low-carbohydrate diets are more effective than low fat diets in inducing weight loss, suggesting that excessive carbohydrate rather than fat is the cause of obesity. Strategies to combat cardiovascular disease should now focus on tackling the epidemic of obesity and developing innovative and effective lifestyle and pharmacological interventions.

THE CARDIOVASCULAR CONTINUUM IN ASIA

Cardiovascular Disease in Asia

The incidence of cardiovascular disease is on an increase in Asia.¹ By 2025, a large share of the incidence of cardiovascular disease worldwide will occur in Asia. Thus, it is important to consider factors that lead to the rise in cardiovascular disease in Asia and discuss the measures that may prevent it.

The INTERHEART study is very important in demonstrating that the same set of factors explains the risk of cardiovascular diseases worldwide.² This implies that increases in these risk factors will predict an increase in coronary heart disease in the future. It also implies that there is a window of opportunity for preventive measures. The increase in cardiovascular disease in Asia has been attributed to changes in lifestyle and Westernization.³ For instance, Asians living in England have more coronary heart disease than those who have not emigrated.⁴ However, the absolute incidence of cardiovascular disease is still lower in Asian populations as compared with white populations, which may be explained by the length of exposure to risk factors. In Asia, the prevalence of obesity, diabetes mellitus, and hyperlipidemia has been increasing only in the last few decades. There may also be ethnic differences in the susceptibility to coronary heart disease; in Singapore, Indians appear to be more susceptible than Chinese or Malays.⁵ Thus, genetic differences in the susceptibility to atherosclerosis may modulate the development of cardiovascular disease and account for some of the differences in the prevalence of coronary heart disease in different parts of the world.

The Cardiovascular Continuum

The concept of a chain of events that lead to cardiovascular complications was encapsulated in the concept of the cardiovascular continuum, proposed by Dzau and Braunwald in 1991 as a new paradigm for cardiovascular diseases (Fig. 1).⁶ It arose from the realization that cardiovascular events such as heart failure and myocardial infarction are really late complications in a chain of events that begins with cardiovascular risk factors and continues as a progressive pathogenic process lasting for decades. Atherosclerosis and myocardial necrosis cannot be easily reversed, and heart failure is still associated with poor prognosis and a high rate of morbidity and mortality, so addressing the early components of the continuum, such as hypertension, diabetes, hyperlipidemia, and smoking, offers a chance of arresting the progression of cardiovascular disease at an early stage. These cardiovascular risk factors may not give rise to symptoms and are rarely immediately life-threatening, but because they are asymptomatic, the person may not want treatment. Much effort has been devoted to increasing public awareness of these risk factors, to detecting these in the community, and to modifying them by lifestyle changes and drug treatment.^7,8 There are now multiple classes of drugs to treat hypertension, and large clinical trials have established their effectiveness in preventing myocardial infarction, stroke, heart failure, and death.⁹ The development of HMG-CoA reductase inhibitors, or statins, that lower cholesterol effectively has transformed the management of lipid disorders. Large-outcome trials have conclusively proven that statins prevent myocardial infarction and mortality not only in patients who have already developed cardiovascular complications but also in individuals who have not had any cardiovascular events and who do not even have elevated cholesterol levels.¹⁰ Antihypertensive drugs and statins demonstrate the clinical utility of the cardiovascular continuum concept, namely, that the correction of cardiovascular risk factors prevents the escalation of cardiovascular disease and the downstream complications, including the ultimate event, death. Angiotensin-converting enzyme inhibitors, in particular, address different parts of the continuum, including hypertension, diabetes, left ventricular hypertrophy, remodeling, and heart failure.¹¹

FIGURE 1: The cardiovascular continuum, adapted from Dzau and Braunwald.⁶

The progress in cardiovascular risk factor research in the last 15 years allows us to know enough about cardiovascular risk factors to prevent 80% of cardiovascular events, which we can do using evidence-based and cost-effective treatment. One such treatment is the “polypill,” consisting of a statin, diuretic, β-blocker, angiotensin-converting enzyme inhibitor, folic acid, and aspirin.¹² Can we do better? Can we trace the origins of cardiovascular disease and be proactive rather than reactive?

Obesity and the Metabolic Syndrome

Hypertension, diabetes, and hyperlipidemia are all related to obesity. Reaven first drew attention to the their coexistence in overweight people.¹³ Type 2 diabetes develops in overweight individuals.¹⁴ Hyperlipidemia responds to diet and weight control. Clinical studies showed that weight control, if successful, is the most effective nonpharmacological means of lowering blood pressure.^15-19 Although there are numerous causes of hypertension, overweight is the leading cause of hypertension in the majority of Chinese people in Hong Kong; an overweight person is 2.9 times more likely to have hypertension and 3.3 times more likely to have diabetes.^20-22

Conventionally, the body mass index (BMI), defined as the weight in kilograms divided by the square of the height in meters, is used as an index of obesity. In whites, a BMI of over 30 is obese, and one over 25 is overweight. In Asia, a lower cutoff for overweight is used because people with a BMI of under 25 already have increased cardiovascular risk, and many have the metabolic syndrome.^23-27 BMI is imperfect because it does not reflect adiposity. Moreover, the distribution of fat is as important as its amount. Men tend to have abdominal or central obesity, whereas women tend to have adiposity around the hips and legs. The former is more associated with risk of cardiovascular disease. Therefore, the waist circumference might be a better measure of obesity because it is more closely associated with cardiovascular risk (Table 1).²¹ A waist circumference of ≥90 cm in men and ≥80 cm in women is thought to be undesirable.

TABLE 1: Correlation between waist circumference and cardiovascular risk factors

The clustering of abdominal obesity, high triglycerides, low levels of high-density lipoprotein cholesterol (HDLC), high blood pressure, and elevated fasting glucose levels is now known as the metabolic syndrome.⁸ The underlying abnormality is believed to be insulin resistance. The cause of the metabolic syndrome is almost certainly a combination of genetic predisposition and environmental factors, the most important of which is abdominal obesity.^28-30

In recent years, there has been an alarming increase in the metabolic syndrome in Asia.^31,32 The prevalence of the metabolic syndrome stands at 11% in Koreans, 21%-24% in Chinese, and 29% in Indians.^32-34 These are high compared with the United States.³⁵ In Japan, type 2 diabetes has overtaken type 1 diabetes as the cause of diabetes in children and adolescents, accounting for 80% of cases.³¹ The increase in type 2 diabetes and the metabolic syndrome is believed to be caused by increasing obesity, by Asian standard, in the population.

The mechanisms whereby obesity leads to insulin resistance are multiple and complex.³⁶ One theory is that free fatty acids released from visceral fat into the portal circulation stimulate the liver to produce more glucose, leading to a state of hyperinsulinemia and insulin resistance. In recent years, new data have emerged to suggest that adipose tissues are not simply inert tissues that store fat. The fat cells, or adipocytes, are highly active and play a central role in energy homeostasis³⁷ and do so by secreting a number of hormones, including leptin, adiponectin, resistin, and acylation-stimulating protein (ASP).³⁸ These regulate appetite and insulin sensitivity. For example, leptin suppresses appetite. Resistin decreases insulin sensitivity, whereas adiponectin increases it. ASP, a cleavage product of complement C3, stimulates triacylglycerol synthesis and its storage in adipocytes.

Obesity and Inflammation

There is another unexpected and fascinating aspect of adipose tissues that may hold the key to the development of cardiovascular disease. In adipose tissues, inflammation occurs.³⁹ When adipocytes are laden with fat, macrophages become recruited and start a vicious circle of inflammation and recruitment of more macrophages. The process is analogous to what goes on in the atherosclerotic plaque, except in magnitude; an obese person may have half the body weight in fat, so even a low-grade inflammation may have profound systemic effects. Levels of C-reactive protein (CRP) are raised in obese people and correlate with the degree of obesity.⁴⁰ Losing weight reduces the CRP level.⁴¹ Elevated CRP levels are predictive of future development of diabetes and cardiovascular events.⁴² Besides CRP, adipocytes also secrete tumor necrosis factor-α and plasminogen activator inhibitor-1.³⁷ Inflammation in adipose tissues is therefore an early event in the cardiovascular continuum, preceding the development of diabetes, endothelial dysfunction, and atherosclerotic disease. Increase in proinflammatory cytokines and decrease in adiponectin may lead to endothelial dysfunction and facilitate the development of hypertension and atherosclerosis. Alarmingly, children with endothelial dysfunction, hypertension, and type 2 diabetes are increasingly found.⁴³ In obese children, the CRP level is elevated, indicating a low-grade systemic inflammatory response.^44,45

Diet and Obesity

The cause of the “epidemic of obesity” is highly controversial. Some blame the sedentary lifestyle in a modern society in which so much is automated. Exercise and a reduced-calorie diet are the cornerstones of any weight control program. Obese children have endothelial dysfunction, which can be reversed by regular exercise.⁴⁶ However, the amount of exercise recommended in the latest WHO directive,⁴⁷ at least 30 minutes on most days of the week, is not feasible in the community without profound changes in lifestyle, such as fewer social engagements and less television viewing and internet surfing.

Others blame the obesity epidemic on the ready availability and the commercial promotion of foods with high energy content. There have been lawsuits in the United States against a fast food chain. In the last couple of years, a new angle has emerged. A string of publications in the most prestigious journals suggest that the current recommendation of a low-fat, high-carbohydrate diet⁴⁸ may be wrong; a low-carbohydrate diet is more effective than a low-fat diet in inducing weight loss.^49-53 Dr Atkins was right: one can eat steaks, but as long as the carbohydrate intake is low, one can lose weight effectively. Surprisingly, a low-carbohydrate diet will significantly raise HDL-cholesterol but not LDL-cholesterol and will reduce plasma triglycerides and CRP.⁵³

Not all carbohydrates are equally unhealthy.⁵⁴ The concept of the glycemic index is useful and has direct relevance to diabetes and the metabolic syndrome.^55,56 It is a comparison of how much the food raises the blood glucose compared with glucose itself. Glucose has a glycemic index of 100 by definition. Baked potatoes have a glycemic index of 85. Foods with high glycemic indices are undesirable because a high blood glucose peak stimulates insulin secretion, causing hunger a few hours later.⁵⁷ Obviously, patients with diabetes should avoid foods with high glycemia index. When eating foods with low glycemic indices, such as green vegetables, the glucose is made available more gradually. If the food is rich in fiber as well, then there are extra benefits such as improved lipid profile, regulation of bowel motions, and lower risk of colorectal cancer. In a study in laboratory animals comparing low- and high-glycemic-index diets with the same total calories, rats and mice weighed the same in both groups, but the animals fed the high-glycemic-index diet had twice as much body fat and a lower lean body mass.⁵⁸

Polished rice, the staple food in much of Asia, is low in fiber and high in glycemic index, ranging from 50 to 94 depending on the variety and how it is cooked.⁵⁹ Congee, popularly believed to be a healthy food item, can cause a particularly high peak in plasma glucose.⁶⁰ Rice-based meals have a place in rural societies where people walk more and do manual labor. Their appropriateness for an urbanized society is now questionable. Sumo wrestlers have a lot of subcutaneous fat but have little visceral fat because of heavy exercise.⁶¹ The Chinese diet with its emphasis on green vegetables and rice (which has a lower glycemic index than potatoes) is comparable to the Mediterranean diet and has a low fat content.⁶² Paradoxically, Chinese populations have a very high incidence of impaired glucose tolerance.³² In the Hong Kong Cardiovascular Risk Factor Prevalence Survey-2 (CRISPS2) cohort, one-third of those who were over the age of 65 had diabetes.²² A nutritional survey of the same cohort showed that the intake of rice and pasta was high in patients with diabetes of normal body weight.⁶³ Thus, obesity and insulin resistance in much of Asia are not caused by excess fat in the diet but by carbohydrates in excess of the energy expenditure requirement (Fig. 2).

FIGURE 2: A new paradigm.

A New Paradigm

It is now generally agreed that the different cardiovascular risk factors must be assessed and addressed in patients at risk rather than by having hypertension, diabetes, dyslipidemia, and obesity treated as separate entities by different specialists in different clinics using different sets of drugs. Obesity is at the center of the metabolic syndrome and needs to be treated as seriously as hypertension and diabetes. Treatment of obesity not only reduces body weight but also waist circumference, body fat percentage, blood pressure, plasma glucose, and lipid levels.⁶⁴

In theory, diet should work. Lifestyle changes have been shown to prevent diabetes.⁶⁵ A “polymeal” that includes wine, fish, dark chocolate, fruits, vegetables, garlic, and almonds has been proposed as a natural, safe, and evidence-based alternative to the “polypill” to reduce cardiovascular disease by more than 75%.⁶⁶ In practice, therapeutic lifestyle changes are plagued by poor compliance and high dropout rates.

The United States Food and Drug Administration has currently approved only 5 drugs for the treatment of obesity, orlistat and sibultramine being the most widely used. Because people cannot change their dietary habits easily, drugs are needed to combat excess carbohydrates in the same way as statins are effective treatments for high cholesterol. It would be some time before such treatments are available and proven in clinical trials. The epidemic of obesity is happening here and now. Drastic rethinking is needed. We can start by discarding the food pyramid, which is now of historical interest, rather like those pyramids in Egypt. Basing a diet on foods of high glycemic load, prepared in ways that increase the glycemic index, is disastrous. However, asking people to count glycemic load and glycemic index in addition to counting calories, cholesterol, and sodium is just impractical. The more practical way is to encourage the consumption of foods that are low in glycemic load and index and high in fiber. Daily exercise should be encouraged and should be seen as an essential human activity, like eating and sleeping.

ACKNOWLEDGMENTS

The Hong Kong Cardiovascular Risk Factor Prevalence Survey-2 (CRISPS2) is supported by the Research Grants Council and the Sun Chieh Yeh Heart Foundation. BMY Cheung is a member of the Institute of Cardiovascular Science and Medicine and the Research Centre of Heart, Brain, Hormones and Healthy Ageing, the University of Hong Kong.