Obesity and heart failure with preserved ejection fraction

Heart failure (HF) can occur in the presence of normal pump function or preserved left ventricular ejection fraction (HFpEF). The prevalence of HFpEF continues to increase in the developed world because of the increasing prevalence of common risk factors, including older age, female sex, hypertension, metabolic syndrome, renal dysfunction and obesity.1,2 Obesity-related HFpEF is an important phenotype present in the community, especially in people with metabolic disorders such as dyslipidemia and diabetes. They exhibit a marked expansion of plasma volume, but ventricular distensibility is limited, most likely as a result of cardiac microvascular dysfunction with myocardial and pericardial fibrosis. The increase in plasma volume causes a disproportionate increase in cardiac filling pressures, leading to HF, even though systolic ejection is not impaired.3 This syndrome appears to be related to the overproduction of adipocyte-derived cell-signalling molecules, including aldosterone and neprilysin, together with the increased effects of other adipocytokines.4 The diagnosis of HFpEF is made by confirming the clinical diagnosis of HF and finding a preserved ejection fraction (>50%) on echocardiography in the absence of significant valve or pericardial disease. Even the risk of HF increases with body mass index (BMI), patients with heart failure with reduced ejection fraction (HFrEF) who are overweight or obese usually have better outcomes than those who are normal weight or underweight. A meta-analysis from the Global Group in Chronic Heart Failure (MAGGIC) included 31 studies, both randomised controlled trials and observational studies revealed a relationship between BMI and mortality in both HFrEF and HFpEF.5 Another meta-analysis including 22,000 patients who had chronic HF (HFrEF and HFpEF) and follow-up for almost 3 years demonstrated the same outcome. The overweight patients presented with the lowest total and cardiovascular mortality rate compared with those who were normal weight, while underweight patients had the highest mortality rate.6 From these data, many investigators have tried to explore the mechanisms of the obesity paradox. The reason is related to the inaccuracy of the BMI in characterising the severity of obesity. The World Health Organization (WHO) definitions of obesity imply that individuals with a BMI of 25 kg/m2 or higher have increased fat mass.7 However, this implication is not necessarily true. BMI has several limitations because it considers a measurement of heaviness not of body composition. Patients with increased BMI may not necessarily have increased fat mass while normal BMI does not preclude an individual from having increased fat mass. Thus an accurate measurement of body composition, rather than BMI, may play a crucial role in the development and progression of HF (Table 1). Relationship between obesity phenotypes, cardiac function and cardiopulmonary fitness. BMI: body mass index. Relationship between obesity phenotypes, cardiac function and cardiopulmonary fitness. BMI: body mass index. When sarcopenia and increasing fat mass are combined this could induce body composition abnormalities, sarcopenia and obesity. Sarcopenic obesity is extremely prevalent and is related to poor outcomes in HF patients.8 A prospective cohort of studies with a large number of patients demonstrated that sarcopenic obesity had a 24% increased risk for all-cause mortality compared with those patients who had non-sarcopenic obesity.9 So, identifying patients with sarcopenic obesity as early as possible is a very important thing to do to improve the outcomes of these patients. In this issue of the journal, Campbell et al.10 report the results of an important study that focused on the threshold BMI and sex-specific waist circumference for the increased risk of HFpEF. The investigators addressed identifying BMI and waist circumference thresholds for the increased incidence of HFpEF that may guide HFpEF prevention strategies. They demonstrated that after a follow-up of 5.6 years in 3842 participants aged 60 years and older with one or more of the following: self-reported treatment for hypertension or diabetes for 2 years or longer; myocardial infarction or other ischaemic or valvular heart disease; irregular or rapid heart rhythm; cerebrovascular disease; or renal impairment, 271 non-HF-related deaths were recorded. HF was diagnosed in 162 participants (73 with HFpEF, 53 with HFrEF and 36 with valvular heart failure). The median time to HFpEF diagnosis was 4.5 years. The BMI threshold of 27.5 kg/m2 or less and waist circumference thresholds of 100 cm or less in men and 90 cm or less in women were demonstrated from this study as a cut point. They reported that 32 of 73 HFpEF cases (44%) could be attributed to a BMI of 27.5 kg/m2 or greater, and 36 of 73 HFpEF cases (49%) could be attributed to a waist circumference above these thresholds. These data suggested that the maintenance of BMI and waist circumference below a BMI and waist circumference threshold in a community may reduce the incidence rate of HFpEF by as much as 50%. The strength of this study is a large number of participants and long follow-up period (median 5.6 years). The limitations of this research are the considerable number of lost to follow-up participants. The numbers of HFpEF participants at each visit were not clearly shown and the authors did not provide arguments for promoting these BMI and waist circumference thresholds beyond significant differences between groups in the comparison with BMI of 25 kg/m2 or less and waist circumference quintile 1. However, I agree with the authors that the prospective investigation about the effect of weight reduction in a well selected HFpEF population with overweight will give the correct answer about the effect of obesity with HFpEF. Despite BMI and waist circumference thresholds that influence the prognosis of HFpEF and HFrEF, Van Iterson et al.11 also reported that the low haemoglobin content can provoke the strongest impairment in peak exercise oxygen uptake. The low haemoglobin content is a potent contributor to the stimulation of known factors affecting a negative impact on oxidative metabolic capacity universal to HF patients. The authors also observed the implication of haemoglobin content as accounting for a significant proportion of the variability in cardiopulmonary exercise testing responses for patients above or below the generalised obesity threshold.11 BMI and waist circumference could be reduced effectively by dietary approaches to stop hypertension and supervised aerobic exercise 2 days per week. The exercise should be high volume and high intensity interval training, which offers an optimal non-pharmacological tool in the maintenance of BMI and waist circumference below a threshold of obesity patients with HFpEF.12 To maintain BMI and waist circumference below a threshold is a preventive strategic approach, but medical treatment for HFpEF is also a significant issue to be elucidated. This is because of patients with HFpEF having expanded plasma volume, restricted left ventricular distension with increased end-diastolic volume and depressed natriuretic peptide levels. They are resistant to treatment with drugs usually used for the treatment of HFrEF. The latest meta-analysis on HF treatment, which included data from 25 randomised controlled trials comprising data for 18,101 patients, demonstrated that all-cause mortality was reduced with beta-blocker therapy compared with placebo and no effect was seen with angiotensin-converting enzyme inhibitors, aldosterone receptor blockers, mineralocorticoid receptor antagonists and other drug classes, compared with placebo.13 Another meta-analysis which included three large randomised controlled trials and two large retrospective cohorts (368,636 participants) demonstrated that sodium glucose transport protein 2 inhibitor (SGLT2i) significantly reduced the risk of cardiovascular death or hospitalisation for HF by 23% and hospitalisation for HF by 31%. SGLT2i has a novel and unique mechanism of action by inhibiting sodium and glucose reabsorption in the proximal tubule, resulting in glucosuria, weight loss, osmotic diuresis and natriuresis, which should be beneficial in HFpEF.14 We hope that in the near future, the new medications for HFpEF will improve the treatment outcomes in parallel with the control of obesity below the BMI and waist circumference thresholds. The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. The author(s) received no financial support for the research, authorship, and/or publication of this article.