Obesity and cardiovascular disease: revisiting an old relationship
Introduction
According to World Health Organization (WHO) estimates, over half of the global adult population is overweight or obese [1]. In many regions of the world, obesity prevalence is still increasing rapidly, and if the current trends continue, it will reach globally 18% in men and surpass 21% in women by 2025, imposing a heavy burden upon individuals, societies and health care systems [2]. Based on these data, obesity has been justifiably characterized as a modern global epidemic disease [3].
A wealth of clinical and epidemiological evidence has linked obesity to a broad spectrum of cardiovascular diseases (CVD) including coronary heart disease (CHD), heart failure (HF), hypertension, cerebrovascular disease, atrial fibrillation (AF), ventricular arrhythmias and sudden cardiac death (SCD). Obesity has been also linked to obstructive sleep apnea and other hypoventilation syndromes, which adversely affect cardiovascular function [4].
Obesity can increase CVD morbidity and mortality directly and indirectly. Direct effects are mediated by obesity-induced structural and functional adaptations of the cardiovascular system to accommodate excess body weight, as well as by adipokine effects on inflammation and vascular homeostasis, leading to a pro-inflammatory and pro-thrombotic milieu. Indirect effects are mediated by concomitant CVD risk factors such as insulin resistance, type 2 diabetes mellitus (T2DM), visceral adiposity, hypertension and dyslipidemia [5].
Body mass index (BMI), defined as body weight in kg divided by height in meters squared, is the most widely used anthropometric index to define obesity [6]. Although simple and reproducible, it has been heavily criticized for its intrinsic weakness to discriminate between fat and lean body mass and its inability to account for different patterns of body composition and regional fat distribution [7]. These limitations partly explain why concepts like the obesity paradox and the metabolically healthy obese (MHO) phenotype have raised scepticism and fuelled controversies in obesity research [8,9]. In support of the problematic use of BMI as an obesity index, various large-scale epidemiological studies including the case-control INTERHEART study, have shown that central adiposity is more strongly related to CVD risk than total adiposity expressed by BMI [[10], [11], [12]]. It has been therefore argued that anthropometric indices of central fat distribution such as waist circumference (WC), waist-to-hip ratio (WHR), waist-to-height ratio (WHtR) and imaging measurements of visceral fat by computed tomography (CT) or magnetic resonance imaging (MRI), should be assessed on top of BMI due to their better predictive power for CVD risk [13].
It has been further suggested that adipose tissue (AT) integrity and functionality are more relevant aspects for cardiometabolic risk determination than its total amount [14]. AT can regulate the fate of excess dietary lipids and determine whether metabolic homeostasis will be maintained or a state of low-grade systemic inflammation and insulin resistance will develop with deleterious cardiometabolic consequences. AT may also orchestrate interactions with other vital organs such as the brain, liver, skeletal muscle, heart and blood vessels within the framework of an inter-tissue metabolic cross-talk [15]. The consequences of AT expansion are both local and systemic: the local include inflammation [16], hypoxia [17], fibrosis [18], dysregulated adipokine secretion [19], and impaired mitochondrial function [20]; the systemic comprise insulin resistance, abnormal glucose and lipid metabolism, hypertension, a pro-inflammatory and pro-thrombotic state and endothelial dysfunction, all of which provide linking mechanisms between obesity and CVD [21].
The present narrative review summarizes the major pathophysiological links between obesity and CVD, analyses the heterogeneity of obesity-related cardiometabolic consequences, and provides an overview of the cardiovascular impact of weight loss interventions.
Section snippets
Epidemiological Evidence
The American Heart Association (AHA) has officially classified obesity as a major modifiable risk factor for CVD [22]. The relationship between obesity and CVD may be partly influenced by obesity-related comorbidities. There has been considerable debate as to whether it is necessary to adjust for these conditions in statistical models estimating the absolute CVD risk attributable to obesity, or whether such adjustments may actually inflate instead of control for the overall risk of bias [21].
Cardiovascular Adaptations to Obesity
Obesity induces adverse hemodynamic effects and a plethora of maladaptive modifications in cardiovascular structure and function. Major cardiac adaptations include [37]: increase in total circulating blood volume as a result of expanded intravascular volume due to sodium retention, increased cardiac output (CO) through an increase in stroke volume (SV) and a mild increase in heart rate (HR) due to sympathetic activation, in order to meet the metabolic demands of the enlarged adipose and lean
Cardiovascular and Metabolic Heterogeneity of Obesity
BMI-defined obesity is a remarkably heterogeneous condition with varying cardiometabolic risk across individuals with similar BMI [69]. Part of this variability is attributed to different patterns of fat distribution and the intrinsic properties of regional fat depots, including their developmental origin, adipogenic and proliferative capacity, insulin sensitivity, hormonal control, thermogenic ability and vascularization [21]. This cardiometabolic heterogeneity becomes particularly evident
Cardiovascular Impact of Weight Loss Interventions
The controversy surrounding the obesity paradox has raised the intriguing question whether purposeful weight loss in patients with established CVD may be beneficial or harmful [95]. In terms of body composition, preferential loss of body fat without losing lean body mass seems to be beneficial, and associated with lower mortality in obese patients with CVD [132,133].
According to a recent meta-analysis, low-fat weight loss diets are associated with reduced all-cause mortality, but have no
Cardiovascular Effects of Anti-Obesity Pharmacotherapy
Anti-obesity medications have been plagued in the past by high rates of CVD adverse effects. Agents withdrawn from the market due to unexpected CVD side effects include fenfluramine/dexfenfluramine (valvular abnormalities), sibutramine (HR, BP and CVD event increases), ephedrine (sympathetic activation and thermodysregulation), and phenylpropanolamine (hemorrhagic stroke) [150]. Rimonabant was withdrawn due to neuropsychiatric side effects. Orlistat, for years the only approved weight loss
Summary and Conclusions
Obesity is linked to a broad spectrum of CVD including CHD, HF, hypertension, stroke, AF, ventricular arrhythmias and SCD, independently of concomitant risk factors. AT has long been recognized as an active endocrine organ, able to synthesize and release a variety of bioactive molecules, collectively termed adipokines. Adipokines are at the crossroads between obesity and CVD, and their dysregulation is a prominent hallmark of dysfunctional AT in obesity. Regional fat distribution, the size of
Acknowledgements
We thank the architect engineer Vassiliki Koliaki for her important artistic contribution in the preparation of Fig. 1.
Funding
None.
Conflict of Interest Statement
The authors declare no conflict of interest.
Authors' Contributions
C.K. reviewed the literature and drafted the manuscript; S.L. edited and critically reviewed the manuscript; A.K. conceived the outline, coordinated writing and provided critical review. All authors approved the final version of the manuscript.
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