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NEJM Editorial 1 August 2002

Obesity and Heart Failure � Risk Factor or Mechanism?

As has been noted repeatedly by expert panels and the lay press, nearly 60 percent of the adult population of the United States is overweight or obese, with substantial resulting morbidity and mortality.1 Since obesity increases the risk of the most frequent causes of heart failure, an association between these conditions is to be expected. Indeed, an increased risk of heart failure has previously been noted in the Framingham Heart Study and in other cohort studies.2,3,4 However, controversy has persisted with regard to whether obesity is an independent risk factor for heart failure or even coronary heart disease. For instance, the Framingham risk score for the prediction of coronary heart disease excluded obesity because it was thought to affect risk indirectly, through its effects on other major risk factors.5

In this issue of the Journal, Kenchaiah and colleagues6 report a progressive increase in the risk of heart failure as the body-mass index (the weight in kilograms divided by the square of the height in meters) increases from the normal range (18.5 to 24.9) to values indicating overweight (25.0 to 29.9) and obesity (>=30.0), with the hazard in obese persons approximately double that in persons with a normal body-mass index. Overweight women, but not overweight men, also had a significantly increased risk. On the basis of multivariate and time-dependent analyses, the authors conclude that the increase in the risk of heart failure is at least partially independent of the other risk factors associated with excessive body weight. Obesity alone was estimated to account for 11 percent of cases of heart failure in men and 14 percent of those in women. Several aspects of these important observations warrant further discussion.

The definition of heart failure in the Framingham Heart Study requires that at least two major criteria or one major criterion and two minor criteria be met. Unfortunately, obesity itself is frequently associated with many of these findings, including orthopnea, cardiomegaly, edema, dyspnea on exertion, and weight loss in response to treatment, which makes it difficult to diagnose heart failure in obese patients.7 Nonetheless, it is unlikely that the number of false positive diagnoses was large enough to invalidate the findings of this study.

The most intriguing question raised by the report by Kenchaiah et al. is how an increased body-mass index leads to heart failure. Overweight and obesity are associated with increased rates of hypertension, coronary heart disease, left ventricular hypertrophy, and diabetes, all of which are important causes of heart failure. Nonetheless, in multivariate models, the body-mass index emerged as a significant independent predictor of heart failure and remained so when these other factors were analyzed together with body-mass index as time-dependent covariates. These analyses suggest that obesity itself or some intermediary mechanisms are responsible for heart failure.

Severe obesity (a body weight exceeding the ideal weight by 75 percent) has long been recognized as causing a form of cardiomyopathy characterized by chronic volume overload, left ventricular hypertrophy, and left ventricular dilatation.8 Obesity-related hypoventilation and sleep apnea may also contribute. However, given the continuous relation between the body-mass index and the risk of heart failure, as well as the clear increase in risk with mild-to-moderate obesity, it is unlikely that either of these syndromes is a primary cause of heart failure in the Framingham cohort.

It is more likely that the increased risk of heart failure is mediated by physiological and metabolic consequences of excess body weight that were not measured or were undetected. The Framingham investigators have previously reported that an increasing body-mass index, after adjustment for age and blood pressure, was an independent predictor of left ventricular hypertrophy; its prevalence as evaluated by echocardiography exceeded 30 percent among obese persons and 10 percent among overweight persons.9 In contrast, in the current study left ventricular hypertrophy (as diagnosed by electrocardiography) was not more common in the overweight or obese groups. Thus, the contribution of left ventricular hypertrophy, which was among the most powerful predictors of heart failure in previous Framingham studies, was markedly underestimated in the current analyses.

The effect of the metabolic consequences of obesity was similarly underestimated, since diabetes and total cholesterol were the only relevant measures used. It is now recognized that overweight and obese persons without diabetes, particularly those with abdominal obesity, often have a cluster of clinical and metabolic findings that is termed the metabolic syndrome.10 This syndrome is characterized by insulin resistance and a particularly atherogenic dyslipidemia (high levels of low-density lipoprotein cholesterol, very-low-density lipoprotein cholesterol, and triglycerides and low levels of high-density lipoprotein cholesterol), but it is also associated with elevated C-reactive protein levels, an increased propensity to thrombosis, and activation of the sympathetic nervous system. Not surprisingly, the metabolic syndrome has emerged as a major risk factor for cardiovascular events11 and is probably an undetected precursor of heart failure in the Framingham cohort.

Does it matter whether obesity is an independent predictor of heart failure or whether the risk is mediated through other physiological and metabolic abnormalities? The answer is both no and yes. No, because it is clear that excess body weight is responsible to a great degree for these processes and that prevention or successful treatment of overweight and obesity should reduce the risk of heart failure. The success of lifestyle modification in preventing diabetes in a generally obese, prediabetic population provides some hope of success.12 However, even in the absence of such success, identification of the mediators of the excess risk of heart failure may facilitate the development of additional strategies for preventing this outcome. For instance, inhibitors of the renin�angiotensin system should be preferred agents for treating hypertension because they have proved effective in causing regression of left ventricular hypertrophy, preventing diabetes, preventing heart failure, and reducing mortality and vascular morbidity among high-risk patients with hypertension, diabetes, and vascular disease.13,14 Similarly, metformin should be the preferred hypoglycemic agent in overweight persons with type 2 diabetes, given the results of the United Kingdom Prospective Diabetes Study and should be considered for patients who are at high risk for diabetes.12,15

Intuitively, one would anticipate that obesity should adversely affect the outcome for patients with heart failure. Surprisingly, it has not done so, and some even suggest that overweight and obese patients may have a better prognosis.16,17 This paradox cannot be fully explained by the adverse effect of unplanned weight loss on the prognosis for patients with heart failure, but it is premature to translate these findings into a recommendation to avoid weight loss in overweight patients, although overly aggressive weight loss should probably be discouraged.

On the basis of the findings of Kenchaiah and others,2,3,4,6 overweight and, particularly, obesity should now be added to the list of risk factors for the development of heart failure. This excess risk cannot be fully explained by accompanying conditions such as hypertension, coronary heart disease, and diabetes, but it seems likely that other physiological and metabolic abnormalities that accompany a high body-mass index play a part. An increased risk of heart failure is yet another reason to encourage lifestyle modification for the prevention or treatment of obesity. Certain therapies for hypertension and diabetes, such as inhibitors of the renin�angiotensin system and metformin, appear to be particularly effective for treating or preventing some of the consequences of overweight and obesity and may thereby reduce the risk of heart failure. Other therapies, such as antiplatelet agents and drugs for dyslipidemia, may accomplish the same goal by preventing coronary heart disease. Recognition of the excessive risk of heart failure and other vascular events associated with overweight and obesity should lead to more frequent inclusion of overweight and obese patients in clinical trials, which would, in turn, help to identify additional therapies that may be particularly effective in preventing adverse cardiovascular outcomes in this population.

 


Barry M. Massie, M.D.
Veterans Affairs Medical Center
San Francisco, CA 94121

Editor's note: Dr. Massie receives research support from Sanofi, Bristol-Myers Squibb, Merck, and Novartis; he has served as a consultant to Bristol-Myers Squibb and Merck.

References

 

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