The Paradox in Defining Obesity in Patients With Heart Failure

Dubbed by the World Health Organization (WHO) as a disease that requires long-term treatment in 1995, obesity has emerged as a “new infectious disease of the 21st century”.¹⁾ According to the WHO, the global prevalence of obesity tripled in 2016 from 1975. In 2017, the Centers for Disease Control and Prevention named obesity as the most common chronic disease afflicting 42% of the U.S. population.²⁾,³⁾ In Korea, the proportion of adults with a body mass index (BMI) ≥25 kg/m² has been increasing rapidly, the prevalence of obesity was 38.3% in 2020.⁴⁾

Obesity causes several health problems, either independently or in association with other diseases.⁵⁾ As obesity is associated with several metabolic disorders, such as insulin resistance, dyslipidemia, inflammation, and endothelial dysfunction, it is a well-known risk factor in the development of atherosclerotic cardiovascular disease.⁶⁾,⁷⁾ It increases the risk of heart failure (HF), arrhythmia, and even sudden cardiac death by altering central hemodynamics, cardiac structure, and ventricular function.⁸⁾,⁹⁾

However, there have been many reports that BMI-defined obesity was significantly associated with a low mortality risk in chronic diseases as coronary artery disease, diabetes, and renal failure.¹⁰⁾,¹¹⁾,¹²⁾,¹³⁾ This observation defies the previously accepted notion that obesity is a risk factor for various diseases, including cardiovascular disease, leading to the conceptualization of the “Obesity Paradox”.

A meta-analysis of 9 observational studies (n=28,209) showed that patients with HF who are overweight and obese had a 16% and 33% lower risk of death, respectively, compared with patients with HF and a normal BMI.¹⁴⁾ A post-hoc analysis of candesartan use in the reduction of mortality and morbidity and a randomized study of 7,599 patients with HF also confirmed the obesity paradox.¹⁵⁾ However, the obesity paradox has not been universally observed when taking into account etiology, gender, and comorbidity, and ethnicity. In particular, people living in East Asian countries have relatively lower BMI than those living in Westerncountries.¹⁶⁾ Using a registry of 4,146 patients with acute HF in Korea, Hwang et al. observed an ascending mortality risk in patients with overweight (BMI, 23–25 kg/m²), ideal body weight (BMI, 18.5–23 kg/m²), and underweight (BMI <18.5 kg/m²) compared to those with severe obesity (BMI ≥30 kg/m²).¹⁷⁾ The inverse relationship between mortality risk and BMI was consistent when parameters, such as age, sex, hypertension, diabetes, atrial fibrillation, ischemic heart disease, and type of HF, were considered, reaffirming the obesity paradox in the East Asian population.

Several hypotheses attempt to explain the obesity paradox in patients with HF. In general, patients with high BMI have greater energy reserve, muscle mass, and high blood pressure, so it is easier to increase guideline-directed medications to their target dose, which may affect the prognosis in this population Some studies suggest that the impact of increased fat or lean mass on neuro-hormonal, inflammatory, and adipokine physiology was protective.⁹⁾,¹⁸⁾,¹⁹⁾,²⁰⁾,²¹⁾ Consequently, obese patients are less responsive to renin-angiotensin-aldosterone system, which is implicated in worsening HF.⁹⁾,¹⁸⁾,²²⁾

Adipose tissue plays two roles: it serves as an efficient energy reservoir; but it also leads to a chronic inflammatory condition in metabolic syndrome.²³⁾,²⁴⁾ BMI does not accurately measure the impact of adipose tissue on the pathophysiology of HF. Epicardial fat, a marker of visceral adiposity, is associated with atrial fibrillation, left ventricular hypertrophy, and onset of HF.²⁵⁾ A recent study for patients with HF mildly reduced ejection fraction and HF with preserved ejection fraction reported that obese patients with an increased epicardial adipose tissue (EAT) had a worse prognosis compared with obese patients with low EAT.²⁶⁾ Therefore, in HF prognostication, it seems to be reasonable to consider the distribution and function of adipose tissue rather than obesity determined by BMI.

Furthermore, obese patients may be more physically fit than non-obese patients in general. This may be attributed to a greater contribution of muscle mass in BMI. Inflammatory cytokines play a role in metabolic disorders, decreased muscle mass, and deteriorated muscle strength. HF is known to induce and sustain a chronic inflammatory state. This may explain the reduced muscle mass in patients with HF, thereby affirming the obesity paradox.¹⁹⁾ In the study by Hwang et al.,¹⁷⁾ 92% of underweight patients had low muscle mass. In non-underweight patients, low muscle mass was associated with increased mortality. Muscle serves as a metabolic and functional reservoir in the body. Cachexia and sarcopenia are known to negatively affect the prognosis of patients with HF, a catabolic disease. Lower extremity muscle strength increases the risk of hospitalization for HF.¹⁹⁾,²⁷⁾,²⁸⁾,²⁹⁾ Therefore, a generally better prognosis in patients with HF and BMI-defined obesity may be attributed to a greater muscle mass in these patients.

The conflicting views of the role of obesity in HF and other conditions continue to be controversial. On one hand, obesity increases the risk of HF; on the other hand, it has a protective role in HF. The current approach to diagnosis and risk stratification (i.e., BMI measurement) may not have captured the protective and risk factors that explain the obesity paradox. BMI does not accurately reflect or estimate body composition; therefore, it does not predict the risk attributed to excess fat. Muscle mass may play a role in HF and in the mechanism of the obesity paradox.

In conclusion, we have to consider that underweight and/or sarcopenic patients with HF may have poor clinical outcomes. Therefore, it is necessary to revisit the present definition and classification of obesity and to find new diagnostic or classification criteria that can be used to better predict risk. Further studies on the clinical usefulness of interventions, such as increasing muscle mass in patients with HF and low muscle mass, are warranted.