Focusing the problem
Obesity a modern pandemic
The epidemic of obesity is recognized as one of the most important public health problems facing the world today. According to 2014 World Health Organization (WHO) data,1 39% of adults worldwide are overweight (body mass index, BMI ≥ 25 kg/m2) and 13% of adults are obese (BMI ≥ 30 kg/m2). Thus, more than half a billion adults worldwide are classified as obese.
The prevalence of obesity varies by geographical region, gender and income level. The highest prevalence is found in the USA (61% overweight, 27% obese), closely followed by Europe (59% overweight, 23% obese), with the lowest prevalence in South–East Asia (22% overweight, and 5% obese). In Europe, the vast majority of countries have an overweight prevalence of more than 60%.1 Asians generally have a higher percentage of body fat than Caucasians of the same age, sex and BMI. Even below the usual cut-off of BMI = 25 kg/m2 Asian people seem to be at increased risk for type 2 diabetes.2 This may have implications for obesity diagnostic criteria. Indeed, the proposed optimal BMI cut-off values by WHO in Asian populations seems to vary from 22 to 25 kg/m2 based on the ethnic background. A Consensus Statement for Diagnosis of Obesity, Abdominal Obesity and the Metabolic Syndrome for Asian Indians has suggested the following BMI cut-off values: normal BMI = 18.0–22.9 kg/m2; overweight = 23.0–24.9 kg/m2; and obesity > 25 kg/m2.3 Thus it is indeed debatable whether uniform BMI cut-off values to diagnose obesity and/or for cardiovascular risk stratification purposes can be use worldwide. The use of additional anthropometric measurements e.g. waist-circumference or CT based quantification of abdominal/subcutaneous fat volume could help to better delineate obesity and risk parameters and to implement preventive strategies against obesity in each specific ethnic scenario.
See Supplementary material online, Appendix.
White adipose tissue as a cardiovascular risk factor
Obesity and overweight are risk factors for the development atherosclerosis. The adipose tissue (AT) was traditionally considered an energy storage organ. However, a large body of evidence highlights the AT as an active endocrine organ that secretes numerous hormones and bioactive molecules.4 These adipokines (or adipocytokines) can act in an endocrine, autocrine and paracrine manner regulating not only AT metabolism, but also other organs, such as liver, muscle, the central nervous system and pancreas. Thus, adipokines represent key regulators of glucose level, lipid metabolism, blood pressure, inflammation, and oxidative stress.5 Several lines of evidence point to adipokine deregulation as the link between obesity and development of cardiovascular disease (CVD).6 Various adipokines, including adiponectin, leptin, omentin, and resistin, have been implicated in modulating the atherogenic environment of the vessel wall by affecting endothelial and arterial smooth muscle cell function, as well as macrophages.
Interestingly, certain AT depots show a stronger correlation with obesity-associated co-morbidities than total AT mass, reinforcing the concept of depot-specific metabolic functions.7 The principal depots of white AT (WAT) include the visceral AT (VAT), surrounding the visceral organs, the subcutaneous AT (SAT) located below the skin, and the ectopic AT which consists of non-storage depots. Although overall fat mass is important for the development of obesity-associated co-morbidities, VAT accumulation is an independent risk factor for obesity-related metabolic and CVD.8 This differential impact on cardiovascular risk seems to be related to the adipokines secreted from the different fat depots. Specifically, leptin, mainly secreted by SAT, is positively correlated with body fat whereas adiponectin which is more influenced by VAT is reduced in obesity.
One particular ectopic AT depot that has attracted major attention is fat surrounding the vasculature, also known as perivascular AT (PVAT), which appears to play an essential role in the control of vascular function and remodelling.9 In lean individuals PVAT exerts vasodilatory and anti-inflammatory functions. These beneficial actions of PVAT are blunted in obesity where the pro-inflammatory state leads to insulin resistance and increased oxidative stress, thereby contributing to vascular dysfunction and remodelling.9
See Supplementary material online, Appendix.
Brown adipose tissue
Brown AT (BAT) has a different cellular structure, metabolic profile, and function than WAT. Brown AT dissipates energy by uncoupled UCP-1-mediated respiration resulting in heat production (thermogenesis), increased fatty acid oxidation and decreased lipid storage. Brown AT in humans has been traditionally found in neonates; however, the presence of some BAT depots in human adults has also been reported.10 Initially identified in rodents, beige AT (‘brite’, ‘brown-like’, or ‘inducible brown’ AT) is an inducible form of thermogenic AT with a low UCP-1 content in basal conditions that can be induced to increase energy consumption.11 Although its origin has not been clearly identified yet, clusters of these brite adipocytes can be found within WAT in response to certain activators.12 Interventions increasing the number and/or activity of BAT or inducing the formation of beige adipocytes arise as promising therapeutic options to treat obesity and its related metabolic disturbances.
Pathophysiology
Obesity, inflammation and thrombosis
In healthy conditions, AT is composed of a variety of cells including mature adipocytes, adipocyte progenitors, endothelial cells, fibroblasts, and immune cells (primarily resident anti-inflammatory M2-like macrophages together with T regulatory cells (Tregs) and eosinophils). Yet, as AT expands, adipocytes enlarge and there is a rapid and active recruitment of monocytes from the blood into the obese AT, where they differentiate into M1 polarized macrophages with pro-inflammatory activity.13 Obesity-induced adipocytes release free fatty acids (FFA), stimulate macrophages via toll-like receptor-4 resulting in NF-κB activation and TNF-α production. In turn, macrophage-derived TNF-α activates the adipocytes to secrete MCP-1, intercellular adhesion molecule-1 (ICAM-1) and IL-6. Both, adipocyte-derived MCP-1 expression and macrophage-related c-Jun kinases promote further monocyte infiltration.14
See Supplementary material online, Appendix.
This chronic pro-inflammatory state affects the vascular endothelium, platelets, and other circulating cells leading to an upregulation of procoagulant factors and adhesion molecules, downregulation of anti-coagulant regulatory proteins, increased thrombin generation, and enhanced platelet activation.15 , 16 Indeed, obese patients have increased plasma concentration of FVII, thrombin, thrombin–antithrombin complexes, circulating monocyte tissue factor procoagulant activity, decreased fibrinolytic activity, and platelet hyperactivity. Noteworthy, platelet activation has implications for both thrombosis and inflammation. Thus, several platelet activation markers are elevated in obese patients including the mean platelet volume, circulating levels of platelet microparticles, thromboxane B2 metabolites, soluble P-selectin, and platelet-derived CD40L.17 Causes of enhanced platelet activation include the altered exposure and/or increased expression of surface receptors for agonists and adhesion molecules, decreased membrane fluidity, altered platelet metabolism, disruptions in intraplatelet signalling, and increased oxidative stress.18 Chronic inflammation is also associated with the deregulation of endogenous anticoagulant mechanisms, including tissue factor pathway inhibitor, antithrombin, and the protein C anticoagulation system leading to imbalanced haemostasis and an increased risk of thrombosis.19 Upon FFA and TNF-α exposure AT also releases PAI-1, the most important physiologic inhibitor of plasminogen. Thus, obesity is consistently associated with impaired fibrinolysis further promoting the pro-thrombotic state (Figure 1).17
Simplified diagram of obesity-related changes in inflammation and thrombosis. Under lean circumstances, adipose tissue is composed of a variety of immune cells including resident anti-inflammatory M2-like macrophages together with T regulatory cells and eosinophils. As adipose tissue expands adipocytes release free fatty acids (FFA) which stimulate macrophages to induce TNF-α production. In turn, macrophage-derived TNF-α activates adipocytes to secrete monocyte chemoattractant protein-1 (MCP-1), intercellular adhesion molecule-1 (ICAM-1) and interleukin (IL)-6 enhancing the recruitment of blood monocytes into the obese adipose tissue where they are transformed into M1 polarized macrophages with pro-inflammatory potential. In addition, expansion of adipose tissue is accompanied by a reduction in eosinophils and Tregs and an increase in neutrophils, B cells, mast cells, and interferon γ-producing Th1 and CD8+T cells that overall forms a pro-inflammatory milieu. Concomitantly, adipose tissue expansion is accompanied by an increase oxidative stress and a decrease in the release of an adiponectin, an adipokine with protective features. The perpetuation of this vicious cycle leads to the development of a low-grade systemic inflammation that induces endothelial dysfunction, a hypercoagulable sate and increases platelet reactivity leading to an overall increase risk of thrombosis.
See Supplementary material online, Appendix.
Obesity and cardiometabolic dysfunction
The normal heart uses both FFA and glucose as substrates to maintain its energy balance (Figure 2). In obesity, plasma levels of FFA and triacylglycerol increase, modifying not only uptake of FFA, but also that of glucose.20 – 22 This results in intracellular accumulation of lipids and thus alterations of cardiac metabolism, primarily due to excessive fatty acids utilization as substrate. Interestingly, this pathway is accentuated in obese women.23 In fact, gender independently predicts lower glucose utilization and myocardial oxygen consumption, both of which are correlated with BMI in females but not males.23
Simplified schema of obesity-induced cardiac cell dysfunction leading to impaired metabolic regulation of coronary microcirculation. In obesity, fatty acid availability and uptake increases leading to lipotoxicity, reduced glucose consumption and mitochondrial energy dysbalance and uncoupling. This results in reduced adenosine triphosphate (ATP) production and mechanical performance of the heart, and increased H2O2 production. These events favour the development of a mismatch between coronary blood flow supply and cardiac demands.
Regardless of gender the increased oxidation of FFA still cannot keep up with the accumulation of FFA resulting in the formation and accumulation of lipotoxins such as ceramides. A more detailed picture emerged from studies showing that increased levels of FFA inhibit glucose uptake driven by insulin.21 , 22 In addition, the mitochondrial oxidative capacity is reduced, while mitochondrial uncoupling is increased, which, together with decreased glucose utilization, impairs myocardial energetics and consequently mechanical performance.20 Finally, increased levels of FFA inhibit oxidation of pyruvate and pyruvate dehydrogenase activity. These mechanisms may contribute to the systolic dysfunction, increased end-diastolic volume and cardiac hypertrophy.20 , 21 , 23–25
See Supplementary material online, Appendix.
Obesity and vascular tone
Obesity is associated with altered endothelial function that shifts the balance towards constriction by impairing release and activity of relaxing factors and concomitantly enhancing production of vasoconstrictors. The resulting enhanced vascular tone compromises regional blood flow to different tissues and organs (including the coronary circulation) and consequently impairs organ function. A standard approach to examine endothelial function in humans is the assessment of flow-induced dilation and multiple studies have demonstrated its impairment in obese subjects.26 Moreover, BMI was inversely related to flow-dependent dilation and even modest voluntary weight gain (∼4 kg) attenuated endothelial function reversibly in young healthy adults.27 Impaired dilator responses to endothelial agonists have also been demonstrated in isolated small arteries from obese subjects.28 In experimental animal studies the impaired endothelial function has been related to attenuation of NO bioavailability due to exaggerated oxidative stress and production of reactive oxygen species (ROS) degrading NO, with xanthine oxidase as well as NADPH oxidase as suggested sources of ROS production.28
On the other hand, vasoconstrictor influence is enhanced (Figure 3). This is in part due to an enhanced sympathetic tone in obese subjects29 but the endothelium also contributes by releasing the potent vasoconstrictor endothelin-1 (ET-1) as well as by cyclooxygenase (COX) dependent constrictor pathways (specifically COX-1).30 , 31
Effects of obesity on vascular function. A shift from vasodilator to vasoconstrictor mediators that is related to enhanced oxidative stress was observed in many animal models of obesity. This common theme in diverse pathophysiologic settings includes decreased bioavailability of NO and enhanced release of vasoconstrictor mediators (COX products, endothelin-1). In addition, the beneficial effects of perivascular fat (PVAT) turn bad in obesity with decreased release of vasodilatative adiponectin and of a possible adipocyte-derived relaxing factor (ADRF) as well as enhanced secretion of leptin and pro-inflammatory mediators that exert detrimental effects on endothelial function.
See Supplementary material online, Appendix.
Obesity and coronary microvascular dysfunction
There is ample evidence stemming from both clinical and experimental studies that obesity is an independent risk factor for coronary microvascular dysfunction.28 , 32 , 33 In addition, studies indicate that obesity is associated with perturbations in the adjustments in coronary blood flow to increased metabolic demands (Figure 4).28
Mechanisms of coronary microvascular dysfunction in obesity. Obesity-related microvascular tone control and microvascular structure regulation through changes in mechanical forces, endothelial function and neurohumoral, adipokine, and cytokine secretion.
See Supplementary material online, Appendix.
Obesity and sympathetic nervous system
Increased sympathetic nervous system (SNS) activity is known to be causally involved in heart failure (HF) and hypertension development and flags subjects at increased risk for future cardiovascular events.34 Obesity and SNS overactivity are closely inter-related and this may partly mediate the increased risk of obesity-related cardiovascular disease. Obese individuals have increased catecholamine urinary levels and whole-body noradrenaline plasma spillover compared with lean subjects.35
See Supplementary material online, Appendix.
Obesity and adipose-derived stem cells
See Supplementary material online, Appendix.
Clinical impact
Obesity and acute coronary syndromes
Obesity represents an independent risk factor for the development of ischaemic heart disease (IHD), cerebrovascular disease and HF. The INTERHEART study found that obesity, measured by the waist-to-hip ratio, exhibits a graded and highly significant association with acute myocardial infarction (AMI) risk worldwide.36 Similarly, the Prospective Studies Collaboration analysing 57 prospective studies through North America and Europe revealed that BMI is a strong predictor of overall mortality36 especially abdominal obesity.37–39 A prospective, multicentre international registry found that in individuals without known CAD, an increase in BMI was positively associated with greater prevalence, extent and severity of CAD.40 Higher BMI categories were associated with an increase in all-cause mortality and increased risk of AMI.40
In patients with suspected angina pectoris undergoing elective coronary angiography a significant interaction between BMI and gender in regards to risk of AMI and cardiovascular death was observed; indeed, obese men had an increased risk of AMI and cardiovascular death but, surprisingly, overweight women had a decreased risk of AMI compared with normal weight women.41 Similarly, in a meta-analysis with 218.523 ACS patients, overweight, obese, and severely obese patients had lower mortality compared with patients with normal BMI.42 It should be noted, however, that obese patients were younger (1–10 years), as first NSTEMI occurred 12 years earlier in severely obese patients than in non-obese people, and that obese patients had less bleeding complications, which could have influenced their survival rate. Also they had less often a history of stroke and in-hospital stroke, which could be explained by the differences in age.69 An additional confounding factor could be that in ACS patients, medication was used more frequently in overweight and obese patients: angiotensin-converting-enzyme (ACE) inhibitor, statin and beta-blockers and coronary angiography were reported more often in overweight and obese patients.
Obesity and atrial fibrillation
Obesity has consistently emerged as a risk factor for atrial fibrillation (AF). The risk of AF increases progressively with rising BMI. In the Framingham Heart Study (FHS), an approximate 5% increase in AF risk per unit increase in BMI was observed, in both women and men.43 Obesity is also a risk factor for the progression of paroxysmal to permanent AF.44 In the FHS 10-year45 and the Atherosclerosis Risk In Communities (ARIC)46 AF risk calculators, BMI is included as a major risk factor. The epidemiological evidence consistently indicate a strict relationship between development of obesity and subsequent risk for AF, however the reasons for such an association are still obscure. Indeed, obesity may interact with multiple additional factors to contribute to AF risk. As such, hypertension is strongly associated with obesity and it is as well a known risk factor for AF,47 and diabetes has also been significantly associated with an increased risk for AF ranging from 1.4-fold risk increase in men to 1.6-fold in women.47 Obesity, diabetes, hypertension as well as dyslipidaemia, have common risk profiles, as they are components of the metabolic syndrome which, in turn, is a risk factor for AF.48 The metabolic syndrome and obesity seem to increase left atrial size and promote diastolic dysfunction.49 More recently, pericardial and epicardial AT have been suggested to be factors associated with paroxysmal and persistent AF,50 and with AF recurrence after ablation.51 Prior work demonstrated that pericardial fat, but not intrathoracic or visceral abdominal fat, was significantly associated with AF.50 To support these findings a recent study showed that epicardial AT adipo-fibrokines, such as activin A (a member of the TGF family), but not SAT adipo-fibrokines, induce atrial fibrosis.52 This, in turn, suggests that AT location may actually be more important than its overall abundance as it has also been reported for other fat depots.53
See Supplementary material online, Appendix.
Obesity and heart failure
Obesity is an independent risk factor for HF. Myocardial remodelling and diastolic dysfunction due to increased heamodynamic load, endothelial dysfunction, neurohormonal activation and increased oxidative stress may result in congestive HF. All of the aforementioned factors are a direct result of high metabolic activity of excessive fat tissue and lipotoxicity.
Having all the adverse health effects of obesity in mind, it was assumed that obese patients with HF had a significantly worse outcome than those of normal weight. However, initial research showed no difference in long-term survival, with many studies even showing a better outcome in patients with increased BMI. Horwich et al. 54 studied 1203 individuals with class IV HF and found that higher BMI was associated with better survival. In multivariate analysis, higher percentage of body fat and higher BMI were second only to lower BNP as independent predictors of improved time-dependent survival. This phenomenon denominated ‘obesity paradox’ is also described in coronary heart disease (CHD) patients. The underlying mechanisms for this paradox remain elusive. The paradox was attributed to changes in neurohormonal system, enhanced protection against endotoxin/inflammatory cytokines and increased nutritional and metabolic reserve (‘surplus calorie theory’) in obese patients.55 Nevertheless, several caveats in the interpretation of the paradox may be advocated in relation to HF. Most of these studies have focused on BMI and a few on percentage of body fat, and there is little information regarding other parameters. Obese individuals were characterized by a younger age, higher blood pressure, fewer arrhythmias, less anaemia, less valvular regurgitation, better left ventricular systolic function, and better respiratory and renal function. The diagnosis of HF in obese patients was questionable, especially when made only using the physical examination. Finally, many of the studies did not adjust for smoking and chronic obstructive pulmonary disease among underweight and leaner subjects which may have contributed to a worse prognosis.
The obesity paradox revisited
See Supplementary material online, Appendix.
Prevention and treatment
Life style changes
Obese individuals should be included in cardiovascular rehabilitation programs directed to reduce body weight and increase physical activity thereby improving other cardiovascular risk factors, such as hypertension, diabetes, and dyslipidaemia. The standard recommendation for the prevention and treatment of obesity is restricting dietary energy intake and increasing physical activity. Because of the high energy of fat, the belief still persists that increased dietary fat intake will lead to weight gain, whereas reduced fat intake will promote weight loss. However, long-term adherence to low-fat diets is limited56 and for those who lost weight, gain relapses usually occur after 6–12 months.57 In addition, a meta-analysis comparing low- vs. high-fat dietary intervention trials favoured high-fat diets for weight loss, albeit only in the context of energy-restricted diets.58 In the last decades, the perception of dietary fat as unhealthy has resulted in decreased fat consumption as percentage of energy in the US population, but increasing rates of obesity and diabetes have not slowed down, most likely because fat content was substituted with extra sugar. On the other hand, high-fat diets can be beneficial for cardiovascular health if salutary vegetable fats are consumed, such as polyunsaturared fatty acids (PUFA) or olive oil-monounsaturated fatty acids (MUFA).59
See Supplementary material online, Appendix.
In addition exercise training also is a useful tool to fight against obesity. The World Health Organization (WHO, 2010) recommends practicing moderate exercise 30 min or more a day and trying to increase this exercise to 60 min a day, 5 days a week depending on age, physical fitness and previous diseases. In a recent meta-analysis including 117 studies (n = 4815), both exercise and diet caused a reduction of body weight and also of visceral adiposity, which is a stronger predictor of morbidity and mortality. Interestingly, the hypocaloric diet tended to decrease body weight, whereas exercise tended to have superior effects in reducing visceral adiposity.60 Recommendations are to maintain a waist circumference lower or equal 94 cm in men and lower or equal 80 cm in women.61
Therapy: pharmacotherapy and surgical interventions
Treatment of an overweight or obese person incorporates a two-step process: assessment and management. Assessment includes determination of the degree of obesity and overall health status. Management involves not only weight loss and maintenance of body weight but also measures to control other risk factors. Assessment of an individual's overall risk status includes determining the degree of BMI, the presence of excess abdominal fat (waist circumference), and the concurrent presence of cardiovascular risk factors and/or comorbidities related to obesity. Those conditions that denote high risk include established CHD, other atherosclerotic diseases, type 2 diabetes, and sleep apnoea, but also non-alcoholic fatty liver disease. Three or more risk factors also confer high absolute risk.
Management
Weight loss therapy is recommended for patients with a BMI > 30 as well as patients with a BMI between 25 and 29.9 or a high-risk waist circumference (men > 102 cm, women > 88 cm) and two or more risk factors.62 , 63 The goal of therapy is to prevent, reverse, or ameliorate the complications of obesity. Weight loss, through energy restriction and/or exercise, improves metabolic health and reduces obesity-associated morbidity and mortality. It has been estimated that losing 5–15% of initial body weight is associated with increased insulin sensitivity, improved plasma lipid profile and decreased blood pressure.64 An initial weight loss of 10% of body weight achieved over 6 months is a recommended target. The rate of weight loss should be 0.5–1.0 kg each week. A diet that is individually planned to help create a deficit of 500–1000 kcal/day should be advisable. Physical activity should be an integral part of weight-loss therapy. Early observational studies, however, have indicated that overall and cardiovascular mortality is increased after weight loss.65 This paradox has been related to the inability of such studies to distinguish intentional from unintentional weight loss. Thus, the observed weight loss might be the consequence of co-morbidities that unintentionally lead people to die from non-CVD causes. Indeed more recent data have shown that intentional weight loss carried out for personal reasons is associated with a significant reduction in all-cause mortality in markedly overweight men, and the data suggest that the earlier the intervention, the greater the chance of benefit.66 Intentional weight loss during cardiac rehabilitation in patients with CAD was a marker of favourable long-term (6.4 years) outcome.67
Pharmacotherapy
Pharmacotherapy to promote weight loss may be helpful for eligible high-risk patients, but is currently limited to subjects with a BMI > 30, or those who have a BMI > 27 if concomitant obesity-related risk factors or diseases exist. The role of drug therapy has been questioned because of concerns about efficacy, the potential for abuse, and side effects. Currently, many drugs are approved by the European Medicines Agency (EMA)62 and the Food and Drug Administration (FDA)63 for long and short-term use in weight loss (Supplementary material online, Table S1), the most used being Orlistat, which inhibits approximately 30% of dietary fat absorption from the intestine. Data on Orlistat are consistent. A meta-analysis of 11 randomized controlled trials68 found that a larger number of participants in the Orlistat group gained clinically significant weight loss, with 21 and 12% of them achieving ≥5 and ≥10% weight loss, respectively. A more recent randomized trial on weight loss on adolescents69 showed a reduction of BMI by 0.55 kg/m2 in subjects treated with Orlistat and an increase by 0.31 kg/m2 in subjects in the placebo group at 54 week follow-up. Of note, waist circumference decreased in the Orlistat group but increased in the placebo group. Orlistat has been approved for sale without prescription in the US since 2007. There is, however, some concern about its side effects. The most commonly reported adverse effects include steatorrhoea, oily evacuation, faecal urgency, and faecal incontinence. The percentage of patients experiencing the most disturbing side effect, faecal incontinence, is around 7–8%. In summary, treatment with Orlistat, in conjunction with reduced-calorie diet, exercise, and behavioural modification, improves weight management in obese people, without raising major safety issues.
Long-term use of medications
See Supplementary material online, Appendix.
Weight loss surgery
Surgery is an option for well-informed and motivated patients with extreme obesity. Patients with a BMI of 35–40 kg/m2 are at high risk, and those with a BMI above 40 kg/m2 are at very high risk. Several surgical approaches collectively referred to as ‘bariatric surgery’, have been used to treat severe obesity.
See Supplementary material online, Appendix.
Promising therapies
See Supplementary material online, Appendix.
Summary
See Supplementary material online, Appendix.
Future research and concluding remarks
In conclusion, obesity is a serious health problem and a social burden, as it represents a major risk factor for CHD, including stable CAD, AMI, AF, and HF. Significant advances in our understanding of the pathogenesis of obesity, the various fat tissues and derived factors and their pathophysiological consequences for the cardiovascular system have been made over the past two decades (Summarizing Figure). It is likely that a multi-disciplinary approach is needed to reduce or prevent the obesity-associated global epidemic. Nevertheless, future research is required to elucidate the exact molecular pathways underlying the effects of AT and obesity on cardiovascular pathophysiology in order to improve management and treatment of obese patients.
Future research should aim:
To improve our basic understanding of metabolism in relation to body weight regulation and the improvement of weight maintenance strategies.
To enhance our understanding of the specific effects of AT and obesity on the functional and structural macro- and micro-vascular alterations, as well as in systemic inflammation.
To gain understanding on the effect of obesity and AF and fat infiltration on cardiomyocyte regulation and function.
To study the effects of ‘uncomplicated’ obesity, i.e. without the overt presence of co-morbid conditions such as dyslipidaemia, hyperglycaemia and hypertension, to address the question to what extent obesity per se produces coronary macro- and micro-vascular dysfunction.
To better understand the optimal weight in the HF population. How do we reconcile the apparently ambiguous observations of the obesity paradox? Could it be that the current view of ‘ideal’ weight is biologically inappropriate?
To better understand energy balance and imbalance in terms of weight trajectory and eating practices, using appropriate methods to assess bias and causality.
Supplementary material
Supplementary material is available at European Heart Journal online.
Funding
Spanish Ministry of Economy and Competitiveness of Science (SAF2016-76819-R to L.B.); Institute of Health Carlos III, ISCIII (TERCEL RD16/00110018 and CB16/11/0041 to L.B.); FEDER ‘Una Manera de Hacer Europa’; the Secretary of University and Research, Department of Economy and Knowledge of the Government of Catalonia (2014SGR1303 to L.B.); and ‘CERCA Programme/Generalitat de Catalunya’ Spain. European Commission (FP7-Health-2010; MEDIA-261409 to D.J.D.) and Cardiovascular Research Initiative Netherlands with financial support of the Dutch Heart Foundation (CVON2014-11 RECONNECT). Spanish Ministry of Economy and Competitiveness (SAF2015-71653-R to G.V.). Hungarian Scientific Research Fund (OTKA K108444 to A.K.).
Conflict of interest: none declared.
References
Author notes
The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.
