Obesity Phenotypes, Diabetes, and Cardiovascular Diseases
This article has been corrected.
VIEW CORRECTIONAbstract
This review addresses the interplay between obesity, type 2 diabetes mellitus, and cardiovascular diseases. It is proposed that obesity, generally defined by an excess of body fat causing prejudice to health, can no longer be evaluated solely by the body mass index (expressed in kg/m2) because it represents a heterogeneous entity. For instance, several cardiometabolic imaging studies have shown that some individuals who have a normal weight or who are overweight are at high risk if they have an excess of visceral adipose tissue—a condition often accompanied by accumulation of fat in normally lean tissues (ectopic fat deposition in liver, heart, skeletal muscle, etc). On the other hand, individuals who are overweight or obese can nevertheless be at much lower risk than expected when faced with excess energy intake if they have the ability to expand their subcutaneous adipose tissue mass, particularly in the gluteal-femoral area. Hence, excessive amounts of visceral adipose tissue and of ectopic fat largely define the cardiovascular disease risk of overweight and moderate obesity. There is also a rapidly expanding subgroup of patients characterized by a high accumulation of body fat (severe obesity). Severe obesity is characterized by specific additional cardiovascular health issues that should receive attention. Because of the difficulties of normalizing body fat content in patients with severe obesity, more aggressive treatments have been studied in this subgroup of individuals such as obesity surgery, also referred to as metabolic surgery. On the basis of the above, we propose that we should refer to obesities rather than obesity.
Obesity, traditionally defined as an excess of body fat causing prejudice to health, is usually assessed in clinical practice by the body mass index (BMI), which is expressed as the ratio of body weight in kilograms divided by height in square meter (kg/m2).1 Since its introduction, many large population studies have reported a J-shaped relationship between the BMI and mortality/morbidity risk—a BMI above 30 kg/m2 (defining obesity in many guidelines) being clearly associated with increased morbidity/mortality risk.2–5 Despite its limitations, BMI has been adopted as a quick and simple clinical tool to first classify patients into risk categories and to monitor changes in adiposity over time both at the individual and population levels.
Despite considerable research efforts devoted to understanding the biology of obesity and energy balance, it has become obvious that available knowledge has to date been of little help to curb the obesity epidemic and that no part of the world has been spared from this phenomenon.6 It has been estimated by the Global Burden of Disease Obesity Collaborators that >603.7 million adult individuals are obese.7 The Global Burden of Disease group has also estimated that elevated BMI values were responsible for 4 million deaths in 2015, with two-thirds of this number attributed to cardiovascular disease (CVD).7 In the United States, the prevalence of obesity has reached almost 40% in 2015 to 2016 in a nationally representative survey (National Health and Nutrition Examination Survey).8 Furthermore, severe obesity (class III and above), defined by a BMI ≥40 kg/m2, has been reported to reach 7.7% with considerable disparities among ethnic groups.9
On the basis of such widespread growth, it is obvious that our evolving scientific knowledge about the etiology of obesity and its management at the individual level has not been translated into successful, large-scale clinical programs.10–12 The prescription of moving more and eating less has now been proven as a crude oversimplification of a complex interaction between physiology and the presence of obesity-promoting environments. Thus, beyond a better understanding of the biology of energy balance and obesity, the major social, environmental, and economic drivers of this epidemic must be understood, and holistic solutions targeting them should be evaluated.6,13 Potential intergenerational transmission of obesity, diabetes mellitus, or CVD susceptibility must also be taken into account when approaching interventions designed to reduce the burden of these diseases at the population level.14
Despite outstanding progress made in our ability to combat CVD, obesity remains the modifiable CVD risk factor that has not been adequately tackled either by lifestyle or pharmacotherapy, as opposed to hypertension, dyslipidemias, diabetes mellitus, and smoking. Furthermore, a previous study has revealed that the bulk of the CVD risk resulting from a high BMI or an elevated waist circumference was largely mediated by altered intermediate risk factors (atherogenic dyslipidemia, hypertension, and diabetes mellitus).15 Because physicians have powerful tools to target lipids, blood pressure, and glycemic control with drugs that have shown their clinical benefits through large randomized outcome trials, they may be more tempted to treat these established CVD risk factors with drugs that have shown their clinical efficacy rather than to target the upstream causes of these altered risk factors, that is, high-risk adiposity (Figure 1). In the present article, we propose that there are benefits to be gained from identifying the subgroups of the highest risk overweight/obese patients and targeting visceral adiposity and ectopic fat while also paying attention to the expanding population of patients with severe obesity.
Relationship of Body Weight/Fat to Diabetes Mellitus and CVD: From Population Studies to Individual Risk
Heterogeneity of Risk at Any Given BMI Value
The relationship of obesity with type 2 diabetes mellitus has been long recognized and clearly explains the high prevalence of type 2 diabetes mellitus achieved in many countries. Type 2 diabetes mellitus is a major risk factor for CVD. Because obesity is often associated with hypertension and dyslipidemia, many high-risk patients with obesity are characterized by a clustering of metabolic and cardiovascular risk factors.1,16,17 Thus, obesity (at least the high-risk forms described in this article) is a prevalent driver of altered metabolic and cardiovascular risk factors that can be targeted by pharmacotherapies but also modified by lifestyle. On this basis, it is not surprising that many studies have shown a progressive increase in CVD risk associated with higher BMI values.
There is, however, a controversy in cardiovascular medicine. Obesity may be associated with improved survival in patients with established CVD—a finding that is termed the obesity paradox.18–20 This concept is much debated because results from studies are inconsistent. There is a growing body of literature on potential methodological explanations for the obesity paradox, such as (1) misclassification bias caused by using BMI as a measure of obesity instead of body fat distribution, (2) unmeasured confounding factors (eg, cardiorespiratory fitness, sarcopenia, smoking), and (3) potential for bias due to illness-related weight loss. In addition, individuals with obesity often develop CVD at a younger age when they are generally healthier with fewer comorbid conditions than individuals with CVD who are not obese. Addressing this controversy is beyond the scope of this article, and the reader is referred to comprehensive reviews that have covered this topic.21–25
Although increased body mass has been associated with higher likelihood of finding altered cardiovascular risk factors, not every patient who is overweight or obese shows the alterations in cardiovascular risk factors that are expected from excess body fat. In the early 80’s, 2 pioneers, Ahmed Kissebah in the United States and Per Björntorp in Sweden, reported almost simultaneously that a high proportion of upper body (or abdominal) fat evaluated by the ratio of waist-to-hip circumferences (waist-to-hip ratio) was predictive of an increased risk of finding glucose intolerance, evidence of insulin resistance, hypertension, and hypertriglyceridemia.26–28 At any BMI level, increased proportion of abdominal fat as determined by an elevated waist-to-hip ratio was found to be associated with increased health risk, providing the first evidence of the limitations of the BMI in individual patient health risk assessment.
The development of imaging technologies has brought a revolution in the study of body adiposity and its relationship with health outcomes. Because of distinct properties of fat, muscle, and bone tissues, it has become possible to precisely assess body composition and body fat partitioning phenotypes.29–31 Early imaging studies first using computed tomography (CT)31,32 and later magnetic resonance imaging (MRI)33,34 revealed that the amount of adipose tissue located in the abdominal cavity, also called visceral adipose tissue (VAT), was a key correlate of the health risk resulting from a large waistline for a given BMI. When the cardiometabolic risk profile of individuals who were matched for their BMI (or matched for their level of total body fat) but with either a low versus a high accumulation of VAT was compared, it was found that subjects with excess VAT, irrespective of their BMI or total adiposity, had an altered cardiometabolic risk profile predictive of an increased risk of type 2 diabetes mellitus and cardiovascular outcomes.35–42 Since these early studies conducted in the late 80’s/early 90’s, many large cardiometabolic imaging studies have confirmed the notion that excess VAT is predictive of an increased health risk.40
Tale of the Tape
Because imaging is costly and requires expertise and expensive equipment, it was of interest to identify simple tools that could be used in primary care to identify patients at high risk of being viscerally obese. In 1994, we proposed the tape measurement of waist circumference as a simple index of abdominal adiposity.43 Despite the fact that there is a rather strong correlation between the BMI and waist circumference at the population level (r values ≥0.80 depending upon the cohort examined), there is nevertheless considerable variation in waist circumference at any given BMI value (Figure 2).44 Within each specific BMI unit, it has been shown that an elevated waist circumference was predictive of an increased accumulation of VAT.45 Unfortunately, current guidelines recommend single sex-specific waist circumference values (102 cm in men and 88 cm in women) to define abdominal obesity.4 Although these cutoff values have been shown to be helpful in identifying a subgroup of patients who are overweight or obese and at greater risk of being characterized by the features of the metabolic syndrome, they are not BMI specific. For instance, it is obvious that a waist circumference of 102 cm for a man with a BMI of 24.5 kg/m2 does not describe the same adiposity phenotype as another male individual with the same waistline but a BMI of 33 kg/m2. In this example, the man who presumably has normal weight actually has central obesity with a probable VAT excess, whereas the man who is obese with the same waistline is rather characterized by general obesity. These 2 simple clinical cases show why waist circumference should not be used in isolation to replace the BMI as an adiposity metric. Rather, waist should be added to the information provided by the BMI to further refine risk classification.46 Large prospective observational studies have confirmed that within every single BMI category, an elevated waistline is associated with increased mortality risk (Figure 3).15,47 As emphasized in a recent International Atherosclerosis Society–International Chair on Cardiometabolic Risk consensus statement on waist circumference,46 there is a need to identify BMI-specific waist circumference values associated with increased cardiometabolic and mortality risk.
Despite its added value over the BMI, a large waistline may result from an excess of either subcutaneous or visceral abdominal adipose tissue. Several groups have suggested that blood triglyceride levels may represent a simple and useful marker of excess visceral adiposity when observed in the presence of a large waistline.48–52 For instance, using CT imaging, we have proposed that in the presence of increased triglyceride levels, some individuals may be viscerally obese if they have waist circumference values above 90 cm in men and 85 cm in women—a condition that we have described as hypertriglyceridemic waist.48,50 Prospective studies have shown that the presence of hypertriglyceridemic waist was, indeed, not only predictive of excess VAT but that this simple clinical phenotype was also associated with an altered cardiometabolic risk profile predictive of an increased CVD risk.51 Other approaches incorporating the information provided by waist circumference and blood triglyceride levels such as the lipid accumulation product53,54 and the Visceral Adiposity Index55 have also been reported to be useful in discriminating visceral obesity and related cardiometabolic risk.
Severe Obesity: a Rapidly Expanding Subgroup of High-Risk Patients
Severe obesity, defined by a BMI ≥40 kg/m2, has not only emerged as an important clinical problem but has rapidly become a preoccupying public health issue. Recent data show that the relative increase in the prevalence of severe obesity has been much greater than the relative increase in the prevalence of moderate obesity. For instance, between 1986 and 2010, the prevalence of the US population with a BMI above 40 kg/m2 has increased by 4-fold, whereas the prevalence of individuals with a BMI above 50 has increased by >10-fold. In comparison, the prevalence of a BMI above 30 kg/m2 has been reported to double during the same period. Severe obesity has a 50% greater prevalence in women than in men and is the highest among non-Hispanic black compared with other ethnic groups.56 Management of severe obesity is a challenge in clinical practice because this condition is associated with additional health issues compared with less-severe forms of obesity.57 Because of the health burden and risk associated with severe obesity, more invasive treatments may be considered including weight-loss surgery—a topic to be addressed in later sections.
From Obesity to Obesities
Because of the remarkable heterogeneity observed among individuals meeting the current definition of obesity (BMI ≥30 kg/m2), it is proposed that this condition is too complex to be considered as a homogeneous entity. First, among obese individuals with class I and II obesities (BMI between 30 and 40 kg/m2), the level of risk markedly differs depending upon factors such as regional body fat distribution, overall nutritional quality, level of physical activity, and cardiorespiratory fitness.39 Although the concept of metabolically healthy obesity has been debated, the term has been coined to refer to a lower risk subgroup of individuals who have low levels of VAT despite being obese, who eat well and who are fit because they are physically active.58 At the other end of the moderate obesity spectrum, some individuals are characterized by visceral obesity and show the features of the metabolic syndrome, putting them at high risk for cardiovascular events, particularly if they are sedentary and have poor dietary patterns.38 These observations reemphasize the notion that the BMI is not the appropriate index to assess health risk in class I and II obesities. Second, the rapidly expanding subgroup of patients with severe obesity represents another entity with additional health outcomes having special needs in terms of assessment and medical management. Thus, the singular term obesity does not properly describe the reality of having to deal with these different forms of obesities in terms of adipose tissue mass, body fat distribution, adipose tissue function, and patient lifestyle habits. On that basis, it is proposed that we should move away from the term obesity and rather refer to obesities that would better reflect the clinical reality and distinct treatment challenges associated with dealing with severe obesity versus more moderate forms of obesity.
Obesities and Cardiovascular Risk: Pathophysiological Aspects
As mentioned previously, many large cardiometabolic imaging studies (CT and MRI) have confirmed that excess visceral adiposity is strongly associated with metabolic abnormalities initially thought to be associated with excess fatness per se.40 Because excess visceral adiposity can be found not only in patients who are obese but also in those who are overweight or even have normal weight, and because excess visceral adiposity and ectopic fat accumulation are the main drivers of the insulin resistance syndrome, we can estimate the prevalence of visceral adiposity to be >20% in the overall population,38 although such prevalence is again dependent upon several factors such as age, sex, ethnicity, and lifestyle habits. Thus, even after control for BMI or the amount of total body fat, individuals with high levels of VAT show insulin resistance, hyperinsulinemia, glucose intolerance, a typical atherogenic dyslipidemia (high triglyceride and apolipoprotein B levels, increased proportion of small, dense LDL [low-density lipoprotein] particles, low HDL [high-density lipoprotein] cholesterol levels, and small HDL particles), inflammation, and increased blood pressure levels.37–39,42
Several factors contribute to explain the relationship of excess visceral adiposity to metabolic complications, and they have been discussed in many review articles.36–39,42 The concept of adipose tissue dysfunction has emerged in the past decade as a major determinant of these metabolic complications. Adipose tissue dysfunction can be defined as adipocyte hypertrophy, impaired adipogenesis, low free fatty acid uptake, reduced triglyceride synthesis, resistance to the inhibitory effect of insulin on lipolysis, fat tissue fibrosis, adipocyte autophagy stimulation,59,60 immune cell infiltration, and inflammatory cytokine secretion.42,61–64
Adipose tissue accretion takes place through the expansion of the lipid droplet in existing adipocytes (hypertrophy), the adipogenic differentiation of precursor cells to new lipid-storing adipocytes (hyperplasia), or a combination of both phenomena.65 Interestingly, there is a reciprocal relationship between adipocyte hypertrophy and hyperplasia, where low adipogenic capacity relates to adipocyte hypertrophy and high adipogenic capacity relates to smaller adipocytes.66 Accordingly, in both humans and animals, most studies report a reduction of the adipogenic potential in the obese state (reviewed in the study by Lessard and Tchernof67). In terms of regional differences, preadipocytes from the visceral fat depots such as the greater omentum are known to have lower adipogenic capacity compared with those from the subcutaneous fat compartments.67,68 In this regard, expansion of the visceral fat compartments in humans appears to take place mostly through adipocyte hypertrophy, which could partly explain the stronger association between visceral fat accumulation and obesity-related metabolic abnormalities. This is illustrated in Figure 4, showing that the number of metabolic syndrome features increases with adipocyte hypertrophy and fat mass accumulation, but that individuals with small adipocytes show a low number of metabolic syndrome features, even with an elevated body fat mass. This association is particularly pronounced in omental adipocytes (Figure 4), again most likely due to the predominantly hypertrophic expansion of this compartment.
Low adipogenic capacity has been related to dramatically altered metabolic phenotypes in many mouse models of lipodystrophy (reviewed in the studies by Pap et al69 and Rochford70), as well as in genetic forms of partial lipodystrophy in humans (reviewed in the studies by Hussain and Garg71 and Garg72). We have performed studies on the expression of genes involved in lipodystrophy showing consistent results in patients who do not have genetic lipodystrophy.73 In vitro adipogenic potential of preadipocytes from the visceral and subcutaneous fat depots has also been examined in a small number of studies.68,74 These publications have shown that reduced adipogenic potential in preadipocytes obtained from the subcutaneous fat compartment is associated with increased prevalence of metabolic abnormalities,68,74 as well as visceral adipocyte hypertrophy and increased visceral fat accumulation measured by CT.68 Elegant studies have now identified cellular senescence as a key mechanism in the determination of interindividual variation in the adipogenic capacity of subcutaneous adipocytes.75,76
Altered adipose tissue extracellular matrix remodeling has also emerged as a key factor mediating adipose tissue dysfunction and limited expansion capability (reviewed in the studies by Ruiz-Ojeda et al77 and Lin et al78). Seminal studies using picrosirius red staining of collagens in adipose tissue had shown that collagen distribution patterns differed as a function of the fat compartment examined, as well as the presence of obesity.79 In particular, adipose tissue fibrosis could be quantified either through the presence of bundles of collagen fibers in bands of varying in thickness or as specific depots surrounding the adipocytes, termed pericellular fibrosis.79,80 In our study of visceral and subcutaneous adipose tissues in women, we found that pericellular fibrosis in both fat compartments was strongly related to macrophage infiltration in the corresponding depot, whereas pericellular fibrosis of visceral fat was a predictor of altered cardiometabolic risk variables.61 Interestingly, adipose tissue fibrosis in subcutaneous adipose tissue was related to reduced mobilization of adipose tissue up to 12 months after gastric bypass surgery.79 These results obviously need to be considered in the broader context of an emerging role for many other components of the extracellular matrix as markers of adipose tissue dysfunction.
Immune cell infiltration and alterations in adipose-derived inflammatory cytokines also represent critical aspects of adipose tissue dysfunction. Reviewing the plethora of studies on this topic is obviously beyond the scope of the present article. Briefly, we now know that adipose tissue homeostasis involves complex interactions of many immune cell types including not only macrophages but B cells, natural killer and regulatory T cells, eosinophils, and innate lymphoid cells.81 In a recent study of the stromal-vascular fraction of subcutaneous and VAT using single-cell RNA sequencing,82 we were able to detect up to 17 different immune cell type clusters, including 5 distinct clusters of macrophages. Some of these clusters showed depot-related differences and, most interestingly, a unique expression pattern of metallothionein genes, which are known to be involved in cellular matrix remodeling.82 There is strong evidence that infiltrating immune cells contribute to the low-grade inflammation pattern frequently associated with abdominal-visceral obesity and in turn alter the metabolic ability of adipose tissues to efficiently store lipids and expand.81
In the context of the increasing interest for the gut microbiota in obesity, we now know that gut bacteria and their fragments can translocate past the intestinal barrier, colonize, or accumulate in the blood and extraintestinal tissues.83,84 There, they can exert immunogenic roles that affect glucose homeostasis and other physiological parameters.85,86 Bacterial cell wall components such as peptidoglycans and lipopolysaccharides have been shown to alter glucose homeostasis in a detrimental87,88 or beneficial89,90 manner, suggesting that translocating bacteria or bacterial components can exert a complex modulatory role in metabolic tissues of the host. In a recent study, we have performed a comparative analysis of the microbial profile found in human plasma, liver, and 3 different adipose tissue depots (omental, mesenteric, and subcutaneous).91 Through the use of an optimized 16S metagenomic sequencing pipeline84 and extensive contamination controls, we identified reliable bacterial signatures in the liver, mesenteric, omental, and subcutaneous adipose tissues. Our analysis showed higher copy numbers of the 16S rRNA gene in omental adipose tissue and liver compared with mesenteric and subcutaneous adipose tissues. Microbial abundance of firmicutes, bacteroides, and proteobacteria in mesenteric adipose tissue was lower in participants with type 2 diabetes mellitus compared with BMI-matched individuals who did not have diabetes mellitus. Whether these results reflect actual bacterial translocation or sampling of bacterial nucleic acid sampling by infiltrating immune cells remains to be demonstrated. Yet, tissue microbial signatures may represent a new component of adipose tissue dysfunction.92
The above-cited alterations defining adipose tissue dysfunction collectively alter adipogenic differentiation, adipose tissue expansion capacity, and ultimately lipid storage and retention in adipose tissue. From the metabolic standpoint, nonesterified fatty acid spillover in the postprandial state resulting from poorly inhibited lipolysis and reduced triglyceride synthesis in hypertrophic lipid-storing adipocytes creates increased fatty acid flux to lean tissues, which in turn induces lipotoxicity and increased triglyceride storage in these ectopic sites (reviewed in the study by Noll and Carpentier93). Accordingly, excess VAT deposition has been shown to be frequently accompanied by accumulation of lipids in normally lean tissues such as the liver, the heart, the kidney, the pancreas, and skeletal muscles—a phenomenon described as ectopic fat deposition. For instance, many imaging studies have shown that excess liver fat accumulation is essentially associated with the same dysmetabolic state as visceral adiposity, leading some investigators to even suggest that liver fat was the key culprit for the abnormalities found in visceral adiposity.94,95 Because the liver plays a central role in glucose homeostasis and in lipid metabolism, fatty liver may obviously be a key driver of the full-blown dysmetabolic state found among insulin-resistant individuals. The question is rather whether excess liver fat found in isolation is associated with increased CVD risk. Mendelian randomization studies considering genetic variants associated with increased liver fat have not produced evidence of such an association with CVD.96 From a clinical standpoint, it is important to keep in mind that although liver steatosis can be found in the absence of visceral adiposity, it is rather infrequent as its most prevalent form also features an excess of VAT.95 In this regard, imaging studies have revealed that the shared variance between liver fat and visceral adiposity is about 25% to 30%97,98—a finding suggesting that there are substantial individual differences in the amount of liver fat for any given level of visceral adiposity. We know that susceptibility to visceral adiposity has a strong genetic basis.99,100 The factors explaining the considerable individual variation in liver fat content for any given adiposity level is a subject of considerable interest and of great clinical relevance. For instance, why would a subgroup of viscerally obese individuals be relatively protected against excess liver fat deposition? Are there additional genetic and environmental (eg, sugar content of the diet, lack of vigorous regular physical activity) factors involved? Some candidate genes for liver steatosis have been proposed, and this issue is the topic of great interest.95 One notion appears to emerge at this stage: although visceral adiposity and liver fat content are both independently associated with metabolic abnormalities, the most exacerbated dysmetabolic state is found among individuals with high levels of both VAT and liver fat.40,95
Regarding the genetic contribution to visceral obesity, Karlsson et al100 performed a genome-wide association study for predicted VAT mass. They identified 209 (including 102 novel) loci associated with VAT. In a sample of 325 153 white British participants of the UK Biobank, they confirmed that VAT mass was indeed associated with increased risk of hypertension, myocardial infarction/angina, type 2 diabetes mellitus, and dyslipidemia. Mendelian randomization analyses suggested that VAT was causally related to the development of these clinical outcomes. Accordingly, Ji et al101 found alleles associated with opposite effects on total adiposity and risk of type 2 diabetes mellitus, heart disease, and hypertension. For instance, alleles predictive of a lower risk of cardiometabolic diseases were found to be associated with more subcutaneous adipose tissue and lower levels of ectopic fat such as less liver fat. These results are concordant with the concept that the inherited capacity of some low-risk adipose depots (such as gluteal and femoral adipose tissue) to store excess triglycerides is an important driver (Figure 5) of the risk of CVD and type 2 diabetes mellitus associated with an excess of VAT and liver fat.102
Thus, according to the above model, the dysmetabolic environment of visceral adiposity can also be explained by considering the expanded VAT both as a driver and as a marker of cardiometabolic risk resulting from a dysfunctional subcutaneous adipose tissue. As for obesity, which is not a single condition, the large number of alterations defining adipose tissue dysfunction can no longer be considered to represent a homogeneous entity.
High-Risk Obesities and the Heart
Visceral Adiposity, Ectopic Fat, and Coronary Artery Disease
Obesity and related metabolic conditions/comorbidities negatively impact the cardiovascular system in several ways.103 Individuals with obesity are more likely to develop CVD and manifestations of CVD, particularly coronary artery disease, angina, myocardial infarction, heart failure, atrial fibrillation, and sudden cardiac death (Figure 5).104 Evidence also indicates that the distribution of excess adiposity is an important determinant of cardiovascular risk; visceral and ectopic adiposity confer a much higher risk than subcutaneous adiposity.105,106 Among obese individuals with coronary artery disease, it appears that the distribution of fat, rather than BMI itself, is more directly associated with mortality.107 Large cohort studies such as the Framingham Heart Study and the Jackson Heart Study have documented excess VAT as a predictor for the development of cardiovascular risk factors over time, independently of total body fat mass or subcutaneous adipose tissue levels.108,109 In a 10-year longitudinal study of Japanese American men, greater VAT levels were found in cases developing coronary artery disease compared with controls.110 Over the 10-year follow-up of study participants, excess visceral adiposity, regardless of BMI, has been documented as an independent precursor of coronary artery disease.110 In the Health, Aging and Body Composition Study, excess VAT in women aged 70 to 79 years was identified as an independent predictor of myocardial infarction over a 4.6-year follow-up.111
Excess adiposity, and especially VAT adiposity, accelerates the progression of atherosclerosis decades before the clinical manifestations of coronary artery disease, as shown in postmortem studies among young individuals.112 Importantly, greater vulnerability of atherosclerotic lesions within the coronary arteries and aorta was described for those with abdominal adiposity independently of other cardiovascular risk factors, indicating the major role of central adiposity in the pathogenesis of atherosclerotic diseases.113 Using coronary artery calcification as a subclinical predictor of coronary artery disease, data from the CARDIA study (Coronary Artery Risk Development in Young Adults) concluded that longer duration of abdominal adiposity was associated with subclinical coronary artery disease and its progression through midlife independent of the degree of adiposity.114
Similarly to VAT, ectopic cardiac adipose tissue accumulation was found to be associated with the development of metabolic and cardiac complications, including coronary artery disease.24,115 Although the long-term relationship between ectopic cardiac adipose tissue accumulation (in any depot) and coronary artery disease is largely unknown, a few cross-sectional studies have reported a potential association between excess ectopic cardiac adipose tissue and coronary artery disease. Cardiac fat depots, including pericardial and epicardial fat, have been associated with coronary events in the general population independent of traditional cardiovascular risk factors.116 However, the precise role of these localized cardiac fat depots in the development of the atherosclerotic process remains controversial.
In the MESA (Multi-Ethnic Study of Atherosclerosis), pericardial adipose tissue was associated with increased risk of all-cause CVD and atherosclerosis burden.116 Excess epicardial adipose tissue deposition measured by ultrasound, CT, and MRI has been related to abnormal myocardial flow reserve, coronary plaque vulnerability, coronary artery calcification, and coronary artery disease severity.117 Epicardial adipose tissue-derived adipocytokines, inflammation, and systemic mediators such as reactive oxygen species may favor the development of a local proatherogenic environment by paracrine and vasocrine mechanisms, thus promoting the pathogenesis of coronary artery disease.118
Besides effects on atherosclerosis in larger arteries, excess adiposity is linked to abnormalities in the coronary microvasculature—a key regulator of coronary flow reserve.119,120 Coronary microvascular disease is related to endothelial dysfunction and small vessel remodeling in responses to neural, mechanical, and metabolic factors. Microvascular disease is independently associated with BMI and provides prognostic information regarding cardiovascular risk among individuals with obesity.121 Importantly, the severity of coronary microvascular dysfunction has been correlated with the amount of VAT.122–124 In prospective studies, surgical weight-loss procedures have been associated with improvements in coronary microvascular function.125
Visceral Adiposity, Ectopic Fat, and Heart Failure
Obesity is a major risk factor for heart failure—an association not fully explained by obesity-related cardiovascular risk factors.126 Individuals with obesity are 2× more at risk of developing heart failure than those who have normal body weight.127,128 According to the Framingham Heart Study, each BMI increment by 1 unit is associated with a 5% increased heart failure risk in men and 7% in women after adjusting for other cardiovascular risk factors, and the risk of heart failure was found to be increased across the entire spectrum of BMI.128 In a meta-analysis looking at the association between obesity and heart failure incidence, each 10-cm increase in waist circumference was associated with an increased incidence of heart failure, with higher incidence for heart failure starting in the overweight BMI range.129
Approximately 50% of individuals with obesity have heart failure with preserved ejection fraction (HFpEF), which means that the usual clinical parameter (left ventricular ejection fraction) is normal, posing a substantial challenge in clinical practice. Although left ventricular ejection fraction has generally been found to be preserved in patients with obesity, many investigators have found evidence of subclinical myocardial dysfunction when sensitive cardiac imaging measurements such as myocardial strain are used.130,131 The prevalence of abnormal subclinical myocardial function (ie, abnormal myocardial strain) in obesity has been reported to range from 37% to 54%.131 Abnormal subclinical myocardial function in asymptomatic obese patients with diabetes mellitus has been associated with the progression of adverse CVD.131 Longer duration of obesity and its severity (BMI ≥40 kg/m2) have been identified as major factors predisposing to cardiac dysfunction and heart failure.132 Surgical treatment of obesity prevents development of heart failure and improves established heart failure, including HFpEF.133 Although the relationship between obesity and incident heart failure may involve hemodynamic and anatomic cardiac changes related to excess adiposity, evidence suggests that the relationship is also mediated by obesity-related metabolic, inflammatory, and hormonal changes (Figure 5).132
Only limited data are available regarding adiposity phenotypes or specific fat depots and the risk of heart failure or subsequent prognosis in individuals with heart failure. Recent evidence suggests that VAT plays a major role in the development, pathophysiology, and adverse outcomes of obese individuals with HFpEF.134 In the MESA cohort free of CVD, VAT levels (measured by CT scan) were independently associated with incident HFpEF but not heart failure with reduced ejection fraction.135 Among the 3310 participants from the TOPCAT trial (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) who had HFpEF, abdominal adiposity was associated with increases in all-cause mortality and CVD mortality during the 3.5-year follow-up.136 Heart failure is a major cause of morbidity and mortality in obesity; the cardiovascular prognosis of HFpEF is comparable to heart failure with reduced ejection fraction but remains without any known effective treatment.137 Compared with nonobese subjects with HFpEF, obese subjects with HFpEF display greater volume overload, more adverse biventricular remodeling, greater right ventricular dysfunction, and worse exercise capacity.138 Surgical weight loss prevents the onset of heart failure and improves heart failure symptoms and exercise tolerance.133,139 In a retrospective study, surgical weight reduction was found to reduce risk of developing heart failure and hospitalizations for heart failure in patients with a history of heart failure in both reduced ejection fraction and HFpEF.140 Interestingly, brain natriuretic peptide levels are much lower in obese patients with documented heart failure compared with normal-weight patients.141–144 Brain natriuretic peptide levels paradoxically increase following successful weight-loss therapy.145 A potential explanation includes the increase in the clearance of active natriuretic peptides by higher expression of clearance receptors on adipocytes.146,147
Visceral Adiposity, Ectopic Fat, and Arrhythmias
There is now compelling evidence to support the role of excess adiposity in determining arrhythmic risk, particularly focused on atrial fibrillation and sudden cardiac death.148–152 In a meta-analysis involving 125 000 individuals, those who were obese had an ≈50% increase in the prevalence of atrial fibrillation.153 Importantly, cohort studies have identified a significant dose relationship where increased risk of developing atrial fibrillation is observed with higher severity of obesity.148 Each 1-unit increase in BMI was associated with a 4% increased risk of new-onset atrial fibrillation during the follow-up in the Framingham Heart Study.152 Left atrial enlargement seen in patients with obesity appears to be mechanistically important as the association between BMI and atrial fibrillation was significantly weakened when adjustments were made for left atrial size.149 Every 5-unit increment in BMI confers an ≈29% greater risk of incident atrial fibrillation.154 Moreover, excess adiposity seems to be an important risk factor for the progression of paroxysmal atrial fibrillation to more permanent atrial fibrillation, which is related to higher morbidity and mortality.155 Progression of the disease has been documented in the context of obesity with a BMI in the range of 30 to 34.9 kg/m2 associated with a 54% increase in the likelihood of progression from paroxysmal to permanent atrial fibrillation and severe obesity (BMI ≥40 kg/m2) associated with an 87% increase in risk.155 Overweight and obesity increased the risk of atrial fibrillation through multiple mechanisms including atrial structural and electrical remodeling, which contribute to development of the arrhythmogenic substrate.
Besides overall adiposity, ectopic cardiac fat deposition (in any depot) has been associated with the prevalence and severity of atrial fibrillation (trends toward persistent atrial fibrillation and more symptoms).148 Epicardial adipose tissue has emerged as an important proarrhythmic substrate that may explain the excess risk of atrial fibrillation in obesity.156,157 The strength of this relationship is greater than for measures of abdominal and overall adiposity.158 In the Framingham Heart cohort including 3217 participants, CT-measured pericardial fat (but not VAT) was an independent predictor of prevalent atrial fibrillation even after adjusting for established atrial fibrillation risk factors (age, sex, systolic blood pressure, PR interval, and clinically significant valvular disease) and other measures of adiposity such as BMI.159 The amount of epicardial adipose tissue is a predictor for persistence of atrial fibrillation.160 Higher recurrence rate of atrial fibrillation after catheter ablation or electrical cardioversion was reported in relation with excess epicardial adipose tissue.161 The mechanisms by which increased epicardial adipose tissue contributes to the development and burden of atrial fibrillation are unclear. Epicardial adipose tissue may lead to atrial fibrillation via structural and electrical remodeling of the atrial. Pathophysiological mechanisms involve adipose tissue infiltration, profibrotic and proinflammatory epicardial adipose tissue paracrine effects, and oxidative stress.148,149,162 Increase in sympathetic or parasympathetic tone related to dense innervation of cardiac adipose tissue depots in contiguity with the atrial and pulmonary veins may also play a role.148,163,164
Visceral Adiposity, Ectopic Fat, and Sudden Death
Longitudinal studies have demonstrated the association between obesity and cardiac dysrhythmias with increased risk of sudden cardiac death.150–152,165 In the Framingham Heart Study, the annual rate of sudden cardiac death was ≈40-fold higher in individuals who were obese.166 Both mild and severe obesity are reported to associate with greater risk of ventricular tachycardia/fibrillation.167,168 The potential mechanisms for this association are multiple and may include increased cardiac electrical irritability, abnormal late potentials, and disrupted sympathovagal balance, leading to more frequent and complex ventricular dysrhythmias, even in the absence of clinically overt heart failure.169 Left ventricular hypertrophy as a result of obesity has been shown to give rise to increased ventricular ectopy.170 Obesity is also associated with delayed ventricular repolarization as evidenced by prolongation of the QT/QTc interval, which has been shown to independently predict cardiovascular mortality.171 Pathological changes in the cardiac conduction system have been shown from autopsy of young individuals with obesity and sudden cardiac death.172 Obesity was an independent risk factor for ventricular tachyarrhythmias in patients with ischemic cardiomyopathy treated with an implantable cardioverter-defibrillator in the MADIT II (Multicenter Automatic Defibrillator Implantation Trial II).167
Data suggest that there may be an important role for body fat partitioning, implicating abdominal adiposity as a marker of sudden cardiac death.173,174 In a multicenter, prospective study involving 14 941 patients, central adiposity was independently associated with sudden cardiac death independent of traditional risk factors.174 Epicardial adipose tissue was reported to be associated with increased incidence of premature ventricular contractions, ventricular tachycardia/fibrillation, and mortality due to sudden cardiac death.175,176
Severe Obesity and Cardiovascular Outcomes
Individuals with severe obesity (BMI ≥40 kg/m2) who are 100 or 200 pounds (45–90 kg) or more overweight have more complex CVD issues and encounter different challenges in the healthcare system.103 Among individuals with severe obesity, nearly one-third had clinical evidence of heart failure, and the probability of heart failure increased dramatically with increasing duration of severe obesity, with prevalence rates exceeding 70% at 20 years and 90% at 30 years.177 Severe obesity affects cardiac structure and function as it has been demonstrated to be associated with left ventricular remodeling and decreased left ventricular systolic function, as well as left ventricular diastolic dysfunction, which may eventually lead to heart failure.178,179 Additionally, several metabolic, inflammatory, and neurohormonal changes associated with severe obesity may contribute with impairment of the cardiovascular system.132 Histologically, cardiomyocyte hypertrophy, myocardial fat infiltration, and fibrosis have been described in severe obese hearts from postmortem studies.180 Increased pulmonary vascular resistance and pulmonary artery pressure with increase in right ventricular afterload may also occur in severe obesity, leading to the development of right ventricular dysfunction.126,181 Data suggest that weight loss achieved by any intervention may improve cardiac structure and function (through reverse remodeling) and decreased cardiovascular risk in this population. In addition, weight-loss surgery (ie, bariatric surgery) may reduce cardiac morbidity and mortality in patients with established cardiac disease.182 Although recent heart failure guidelines have not emphasized weight reduction, these guidelines recognize the high risk associated with severe obesity. Risk of developing atrial fibrillation has been reported to significantly increase with higher BMI, a BMI ≥30 kg/m2, increasing the lifetime risk of developing atrial fibrillation by 49%.127,153 Among individuals with severe obesity, those treated with weight-loss surgery had a lower rate of new-onset atrial fibrillation than did those receiving usual care.183 Severe obesity is also associated with increased mortality after in-hospital cardiac arrest due to either nonventricular fibrillation or ventricular fibrillation arrhythmias.184
Myocardial Metabolic Changes
Altered myocardial metabolism has been considered among the potential mechanisms leading to obesity-related cardiac disease.185 Obesity causes changes in myocardial metabolism, which include an increase in fatty acid oxidation and a decrease in glucose oxidation.186,187 These metabolic changes modify metabolism in the heart, culminating in abnormal cardiac substrate utilization, impaired cardiac efficiency, and decreased energy generation, producing functional consequences that are linked to the increased rate of heart failure in this population.188–190
Evidence for the role of the expansion of cardiac fat depots in the pathogenesis of myocardial metabolic diseases is accumulating.191–193 Advanced metabolic cardiac imaging (ie, magnetic resonance spectroscopy) provides a unique way of noninvasively investigating cardiometabolic consequences of excess adiposity on myocardial metabolism leading to cardiac disease.185 Using phosphorus magnetic resonance spectroscopy (31P-magnetic resonance spectroscopy), cardiac energy metabolism can be assessed noninvasively by quantifying the relative concentrations of phosphocreatine (PCr) and ATP in the myocardium to derive the PCr/ATP ratio—a sensitive index of the cardiac energetic state.188 Decreased PCr/ATP ratio is linked to cardiac dysfunction194 and is a predictor of mortality.188 In heart failure, the PCr/ATP ratio correlates with left ventricular systolic function and has been shown to be a better prognostic indicator than left ventricular ejection fraction.188,195 Using this index, a significant decline in the PCr/ATP ratio in association with increasing BMI was found.196,197 Visceral adiposity was also found to be associated with impaired myocardial energetics (ie, reduced cardiac PCr/ATP ratio) in obese diabetic men with no cardiovascular risk factors.192 Excess intramyocardial fat content (ie, cardiomyocyte accumulation of lipids) and impaired myocardial energetics have been identified as important contributors to the development of cardiac dysfunction in obese adults.198 Taken together, these results proposed interesting new areas of investigation to better understand obesity-related metabolic and cardiac diseases.
Myocardial Structure and Function Changes
Accumulating evidence shows the adverse effects of excess adiposity and weight gain on central and peripheral hemodynamics, as well as on cardiac structure and function.103,199,200 Facilitated by obesity-related comorbidities, as well as neurohormonal and metabolic alterations, these abnormalities may predispose to cardiac dysfunction and heart failure (Figure 5).57 Such maladaptation is most pronounced in individuals with visceral adiposity and severe obesity.132,201 These alterations have also been described in children and adolescents with obesity.126 Substantial weight loss from lifestyle intervention or weight-loss surgery is capable of reversing many of the alterations in cardiac performance and morphology associated with excess adiposity.132
Abnormalities of left ventricular diastolic performance are frequent in obesity; the prevalence of left ventricular diastolic dysfunction ranges from 23% to 75%, depending on the diagnostic criteria.131 As mentioned previously, left ventricular ejection fraction (ie, clinical parameter of left ventricular systolic function) has been reported to be usually preserved in obesity. However, novel sensitive measures of myocardial function with strain imaging by echocardiography and cardiac MRI have revealed subclinical alterations of cardiac function in individuals with obesity, even in the presence of a preserved left ventricular ejection fraction.202,203 The prevalence of abnormal subclinical cardiac function (abnormal myocardial strain) in obesity has been reported to range from 37% to 54%.131 Subclinical abnormalities of right ventricular function may also occur, leading to the development of right ventricular failure.204
Not only overall adiposity but also abnormal body fat distribution may lead to adverse cardiac adaptations. In the Dallas Heart Study, a cohort of 2710 participants without CVD, abdominal VAT levels measured by MRI were associated with concentric left ventricular remodeling and adverse hemodynamics.205 In a relatively healthy cohort of 1941 participants, the combination of excess VAT and lower skeletal muscle mass was associated with subclinical deterioration in left ventricular structure and left ventricular diastolic function.206 Excessive fat accumulation in visceral and ectopic sites results in local and systemic proinflammatory factors, which lead to left ventricular remodeling, concentric left ventricular hypertrophy, and ultimately diastolic and systolic cardiac failure.117,132,205 Recognition of high-risk obesities and the presence of subclinical cardiac structural/functional heart failure precursors are critical, because starting treatment at the preclinical stage may prevent heart failure progression and improve outcomes.
Double Hit: High-Risk Obesities, Type 2 Diabetes Mellitus, and Cardiovascular Outcomes
Obesity is an important driving factor for the development of type 2 diabetes mellitus.207 However, countless studies that have used either anthropometric indices of upper body/abdominal adiposity or direct imaging measurements (CT or MRI) have shown that while overall obesity increases the risk of type 2 diabetes mellitus, there is a substantial increase in risk associated with an augmented waistline, waist-to-hip ratio, or with higher levels of VAT, at any BMI level.36–40,42 Patients with type 2 diabetes mellitus have larger waistlines and more VAT than BMI-matched individuals without type 2 diabetes mellitus.208,209 Both visceral or severe obesities and type 2 diabetes mellitus predispose to cardiovascular abnormalities and CVD; their simultaneous presence should further increase the risk of cardiovascular outcomes.210 The increasing coexistence of type 2 diabetes mellitus and high-risk forms of obesity presents complex treatment challenges owing to the elevated risk of developing cardiovascular complications and heart failure. Ectopic and visceral adiposity are linked to insulin resistance, which may partly mediate the link between obesity, type 2 diabetes mellitus, and cardiovascular risk. The metabolic syndrome and insulin resistance have been recognized as a risk factor for cardiovascular morbidity and mortality.211,212 Studies have also shown that the presence of the metabolic syndrome increased to risk of developing cardiac dysfunction and heart failure.213 In the Uppsala Longitudinal Study of Adult Men, the presence of the metabolic syndrome (BMI >29.4 kg/m2 was used instead of waist circumference) increased the risk of developing heart failure >3-fold during the 20-year follow-up and remained significant after adjustment for established risk factors for heart failure.214 The MESA study also demonstrated that the metabolic syndrome predicts heart failure in a cohort free of CVD.215 Thus, the presence of features of the metabolic syndrome in type 2 diabetes mellitus further increases the risk of CVD found among people with chronically elevated glycemia and impaired plasma glucose homeostasis. As the main drivers for the presence of the metabolic syndrome are excessive amounts of VAT and of ectopic fat, it is proposed that particular attention should be given to the prevalent subgroup of patients with type 2 diabetes mellitus who are also viscerally obese and who show features of the metabolic syndrome. Type 2 diabetes mellitus accompanied by visceral adiposity and an excess of ectopic fat clearly represents a high-risk phenotype for cardiovascular outcomes.
Obesities: Implications for Assessment of Cardiometabolic Risk
Cardiometabolic imaging studies reviewed in this article suggest that in this world of precision medicine,216 we need to refine the current concept that obesity is a disease that can be assessed with the BMI. Measuring the patient’s BMI should be considered as the initial step to classify the patient into relative weight categories. Then, a waist circumference measurement has been shown to considerably refine cardiovascular risk assessment associated with a given BMI category by allowing the discrimination of patients with central, upper body, abdominal fat accumulation compared with individuals having a more uniformly distributed adipose tissue mass. As discussed above, an increased waistline for a given BMI along with the presence of metabolic syndrome features is predictive of visceral obesity and excess ectopic fat. As resources to manage obesity are not unlimited, it is proposed that attention should be given to the clinical management of this high-risk and prevalent group of overweight and moderately obese subjects. Furthermore, another rapidly expanding group of patients, individuals with severe obesity, should be highly prioritized considering the additional health burden associated with a large excess of body fat. Thus, applying the notions of precision or personalized medicine would imply that we refer to obesities rather than to obesity.
Obesities: Implications for Management by Lifestyle
Overweight/Moderate Obesity: Giving Lifestyle a Chance
Although environmental factors affecting human behaviors relevant to energy intake (overall caloric intake and diet quality, energy density, added sugar content, highly processed foods, food production, transformation and distribution systems, etc) and energy expenditure (walkability and safety of urban environments, parks, public facilities for physical activity, public transportation, etc) are not addressed by clinical weight-loss programs, many studies have shown that moderate weight loss (>5%) is associated with clinical benefits although long-term maintenance of a reduced body weight is a challenge because of the permissive obesogenic environments that we have designed for ourselves.6 In addition, because of substantial individual differences in regional adiposity, a moderate weight loss is likely to have markedly different consequences depending upon the patient’s form of obesity.217 As a general rule, lifestyle (diet and physical activity or exercise) intervention studies have shown that among individuals initially characterized by an excess of VAT and ectopic fat, there is a preferential and rapid loss of VAT and of, for instance, liver fat, associated with moderate weight loss.39,40 Furthermore, among individuals with type 2 diabetes mellitus who are viscerally obese, there is a selective loss of VAT with exercise training even in the absence of weight loss.218 This phenomenon is frequent as sedentary individuals with visceral obesity often show sarcopenia related to their sedentary behaviors. Under such circumstances, the absence of or moderate weight loss may mask or not properly capture substantial changes in body composition (increased in muscle mass and loss of VAT, liver fat, and mobilization of other ectopic fat depots).217,219 This phenomenon has been extensively studied, and for these reasons, the change in waist circumference has been recommended as a better therapeutic target than magnitude of weight loss as the former may be reduced even in the absence of weight loss.39,46 This notion is particularly relevant to patients with type 2 diabetes mellitus who are viscerally obese and who also often show liver steatosis. Change in body weight may not be sensitive enough to track changes in visceral/ectopic fat induced by a lifestyle modification program in these patients.
In addition to monitoring changes in waist, these high-risk, viscerally obese patients with features of the metabolic syndrome considerably benefit from increasing their level of cardiorespiratory fitness, which has been shown to be a powerful protective factor against CVD in individuals who are either obese or nonobese,220–223 leading to the introduction of the fat-and-fit concept.224,225 Thus, in the absence of weight loss, an increase in cardiorespiratory fitness and a reduction in waist circumference should be considered as highly desirable outcomes. Finally, both overall nutritional quality226 and level of physical activity227 have been shown to be negatively related to cardiovascular outcomes in a manner that is independent from weight loss.
In summary, among overweight and moderately obese individuals with excess visceral adiposity and ectopic fat, improving nutritional quality, increasing level of physical activity, improving cardiorespiratory fitness, and reducing waist circumference are highly desirable outcomes predictive of marked improvements in cardiometabolic risk (even in the absence of weight loss). It is, therefore, proposed to make these 4 indices lifestyle vital signs.228,229
Lifestyle Management of Severe Obesity: Does It Work?
Despite advances in medical management and lifestyle interventions, the clinical outcomes associated with cardiac disease and heart failure are worse for patients with severe obesity. There are 3 treatment options for individuals with severe obesity: (1) lifestyle modification therapy, (2) pharmacotherapy, and (3) bariatric surgery. Lifestyle modification therapy can be useful for improving cardiovascular risk factors and comorbid conditions but often fails to achieve sustainable weight loss and durable metabolic recovery. For example, individuals with severe obesity who underwent intensive lifestyle intervention in the Look AHEAD trial (Action for Health in Diabetes) and who achieved a 4-year weight loss ≥10% of initial body weight experienced significant improvements in several cardiovascular risk factors even within the context of persistent severe obesity.230 However, those who reached such an outcome represented only 25% of the sample characterized by severe obesity. The majority (75%) of individuals with severe obesity in that study did not maintain a weight loss ≥10% of initial body weight at 4 years.230 Pharmacological treatment is also of limited efficacy. Even when lifestyle modification231 or pharmacotherapy treatments are successful, the body weight loss is usually completely regained within 12 months. Lifestyle management may have a role in helping patients maintain long-term weight loss or expanding weight loss after bariatric surgery. Prospective studies have shown the effectiveness of lifestyle interventions carried out within 12 months of bariatric surgery, either pre- or postoperatively on weight loss and weight-loss maintenance.232,233 In a randomized controlled study, a structured lifestyle intervention program increased weight loss when initiated following bariatric surgery.234 Lifestyle modification thus represents a crucial aspect of obesity management, even in the context of bariatric surgery.
Pharmacological Management of Cardiometabolic Risk in Obesities
Additionally, on a background of lifestyle changes, newer pharmacological agents may facilitate both long-term weight loss and reduction in cardiovascular risk.235 Recently, new classes of glucose-lowering therapies originally developed for patients with type 2 diabetes mellitus have shown promising results for the treatment of obesity-related cardiac disease. GLP-1 (glucagon-like peptide-1) receptor agonists and SGLT2 (sodium-glucose co-transporter 2) inhibitors have demonstrated efficacy for weight loss and reduction of cardiovascular events.236,237 A meta-analysis showed that SGLT2 inhibitors, as a class, reduced the risk of cardiovascular death or hospitalization for heart failure by 23%, with a similar benefit in patients with and without atherosclerotic CVD and in patients with and without a history of heart failure.238 A 10% relative risk reduction in the 3-point major adverse CVD event (CVD death, nonfatal myocardial infarction, and nonfatal stroke) and a 13% risk reduction in cardiovascular mortality was reported in a meta-analysis of patients with type 2 diabetes mellitus using GLP-1 receptor agonists.239 The mechanisms by which SGLT2 inhibitors and GLP-1 receptor agonists modulate the cardiovascular system are unclear. The underlying mechanisms that have the greatest plausibility for both of these agents including the impact of ventricular loading conditions, direct effects on cardiac structure and function, myocardial energetics metabolism for SGLT2 inhibitors, and the antiatherosclerotic, anti-inflammatory, and modulation of endothelial function for GLP-1 receptor agonists.240 Recent studies evaluating the coadministration of SGLT2 inhibitors with other classes of drugs have also shown promising results.241
Little data are available describing the effects of these medications on visceral and ectopic fat depots. Data from small substudies within larger randomized trials of medications such as liraglutide (GLP-1 receptor agonist) have shown interesting results with greater reduction in VAT compared with subcutaneous adipose tissue. In the SUSTAIN 8 (Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes) substudy (n=178), reductions in visceral fat mass were observed in each treatment arm (GLP-1 receptor agonist semaglutide and SGLT2 inhibitor canagliflozin).242 In a prospective study of obese Japanese individuals treated with liraglutide over 24 weeks, decreases in visceral fat mass (mean reduction, 11.9%) and intrahepatic lipid content (mean reduction, 49.2%) were observed with no change in subcutaneous fat levels.243 Whether these reductions in visceral and ectopic adiposity translate to improvements in cardiovascular risk outcomes in high-risk individuals remains unknown.
Surgical Treatment of Obesities: Metabolic Surgeries
Cardiovascular Benefits
Cardiovascular benefits of weight-loss surgery, determined largely from nonrandomized studies, are being increasingly recognized. Surgical treatment of obesity is more effective than standard medical approaches to induce sustained weight loss and durable metabolic conditions/comorbidities remission.178,179,244,245 In the STAMPEDE randomized trial (Surgical Treatment and Medications Potentially Eradicate Diabetes Efficiently), weight-loss surgery was found to be superior to intensive medical therapy in terms of glycemic control, weight reduction, decreasing medication use (antidiabetic, antihypertensive, and lipid-lowering agents), and improvement in quality of life during the 5-year follow-up period. These beneficial effects were also observed among patients with mild obesity (BMI, 27–34 kg/m2).245 For severe obesity, surgery is now the preferred and currently only effective treatment modality. Surgical techniques differ in terms of morbidity and mortality rate, magnitude of weight loss, weight-loss maintenance, and rate of resolution of comorbidities over time.178 The various weight-loss surgery procedures promote weight loss through 2 general mechanisms according to the type of surgery: (1) restrictive surgeries limit the amount of food consumed by reducing the size of the stomach, (2) malabsorptive surgeries limit the absorption of nutrients by reorganizing or bypassing portions of the small intestine. Sleeve gastrectomy is the most popular restrictive procedure worldwide.246 It promotes weight loss through reduced meal volume and reduced appetite.178 Mechanistic studies have described a large number of metabolic improvements following malabsorptive surgeries, which have led to referring to these weight-loss surgery procedures as metabolic surgeries. Benefits of surgical treatment of obesity have been also demonstrated for the clinical manifestations of obesity-related cardiac disease.247–249 Both gastric bypass (ie, slightly malabsorptive surgery) and gastric sleeve (ie, restrictive surgery) significantly reduce visceral fat, with more modest reductions in subcutaneous fat levels.250
In the long term, surgical treatment of obesity is associated with reduced incidence of type 2 diabetes mellitus and with reduced overall mortality.251 In the Swedish Obese Subjects study, weight-loss surgery led to a 30% reduction in the incidence of cardiovascular events and a 50% reduction in cardiovascular deaths in individuals with severe obesity compared with those who received usual care after 15 years of follow-up.251 In a retrospective study including 6795 patients who underwent bariatric surgery, patients with severe obesity and coronary artery disease (n=249) were at greater risk of adverse cardiovascular outcomes compared with matched severely obese patients without coronary artery disease throughout the follow-up (mean, 7.4 years).252 A retrospective study of 20 235 surgical and nonsurgical patients shows that weight-loss surgery is associated to a lower incidence of coronary artery disease (acute myocardial infarction, unstable angina, percutaneous coronary intervention, or coronary artery bypass grafting).253 Observational analyses also suggest benefits after weight-loss surgery for individuals with heart failure (both preserved and reduced ejection fraction).132 In a retrospective study of 14 patients with heart failure with reduced ejection fraction who underwent weight-loss surgery, a significant reduction in BMI was found (50.8±2.04 to 36.8±1.72 kg/m2) with a significant improvement in left ventricular ejection fraction at 6 months (from 23±2% to 32±4%).254 Similarly, in another retrospective study, 12 patients with severe obesity and heart failure with reduced ejection fraction who underwent weight-loss surgery had improvement in left ventricular ejection fraction following surgery.255 In both of these reports, patients also had improvements in New York Heart Association functional class. Current guidelines proposed surgical treatment of obesity for adults with BMI ≥40 or ≥35 kg/m2 with obesity-related comorbidities such as systemic hypertension, type 2 diabetes mellitus, and obstructive sleep apnea that are difficult to control with lifestyle and pharmacotherapy. No guideline suggests a given procedure to be more appropriate than others for individuals with cardiac conditions.
Mechanistic Insight on the Impact of Weight-Loss Surgery
Our studies and collaborations on bariatric surgery over the past few years have allowed us to examine the dynamic nature of the relationship between severe obesity and cardiometabolic abnormalities. An interesting feature of bariatric surgery is the rapid remission of type 2 diabetes mellitus and improvement in insulin sensitivity, which typically occurs within days of the surgery, often in the absence of pronounced weight loss.256–258 A significant decrease in post-glucose or postprandial glycemia is observed a few days after surgery.259 This is accompanied by reduced insulin levels, as well as increased GLP-1, GIP (glucose-sensitive insulinotropic peptide), and pancreatic polypeptide secretion.259 Decreases in homeostasis model assessment–insulin resistance index and increases in glucose disposition index are also observed.259,260 However, peripheral insulin sensitivity measured with a euglycemic-hyperinsulinemic clamp is not significantly improved in the days following bariatric surgery.260 Interestingly, the blunted glucose excursion is particularly dramatic with malabsorptive surgeries such as the biliopancreatic diversion with duodenal switch, in which biliopancreatic secretions are channeled to the last 100 cm of ileum, allowing a much shorter time for digestion in a section of the gut that is initially nutrient naive.259,260 Hence, bypass of a significant portion of the gut represents one of the mechanisms driving the short-term improvements in glucose-insulin homeostasis. However, the most significant mechanism explaining such an early effect after surgery is fasting. For example, when unoperated individuals with severe obesity underwent a fasting protocol similar to that of patients who are operated, we found that the improvements in insulin sensitivity and β-cell function were recapitulated in large part.256 The significant increase in postprandial GLP-1 secretion, which is observed with both malabsorptive and restrictive surgeries,256,259,261 may mediate part of this effect. At such an early stage after surgery, weight loss is often minimal. Accordingly, early metabolic improvements are observed in the absence of changes in markers of adipose tissue function including subcutaneous adipocyte size and secretion of adipose-derived cytokines such as adiponectin and tumor necrosis factor-α.259,260 Despite this apparent dissociation between insulin resistance and adipose tissue dysfunction, important changes in substrate flux are observed in the early postsurgical period, in particular with nonesterified fatty acids. In a recent study performed 10 to 12 days after sleeve gastrectomy or biliopancreatic diversion with duodenal switch, Carreau et al262 used positron emission tomography coupled with CT imaging and showed a substantial reduction in cardiac fatty acid uptake over 6 hours in the postprandial state. Cardiac uptake values actually reached the range observed in healthy normal-weight individuals in all but 1 participant. At the same time, systemic fatty acid spillover was significantly decreased and uptake in the visceral fat compartment was increased. Interestingly, fatty acid uptake in the liver and subcutaneous adipose tissue, either in the thigh or abdomen, was unchanged.262
In the longer term after bariatric surgery, our studies and those of others have shown that surgery-induced weight loss is accompanied by extensive adipose tissue remodeling and improved adipose tissue-derived cytokine secretion, which can be measured starting around 3 months and up to 1 year after surgery and beyond.260,263 For example, our survey of the literature on adipose tissue and bariatric surgery indicated increases in anti-inflammatory factors such as adiponectin and omentin, as well as decreases in interleukin-6, C-reactive protein, visfatin, chemerin, and others.263 Our serial analysis of subcutaneous adipose tissue over the course of 1 year post-surgery indicates a reduction in the proportion of large subcutaneous adipocytes and median cell size, which can be measured 3 months and 1 year after biliopancreatic diversion with duodenal switch. Interestingly, smaller subcutaneous adipocyte size predicted better glycemic control 1 year after surgery.260
These results suggest that in the short term, even in the absence of extensive adipose tissue remodeling, bariatric surgery rapidly improves hepatic insulin sensitivity and glycemic control—a phenomenon that is due to changes in nutrient channeling and absorption, increased incretin effects, as well as acute caloric restriction (Figure 6). This is associated with improvements in fatty acid metabolism including a reduction in cardiac uptake and systemic spillover, as well as increased uptake in VAT.264 Longer term effects involve weight loss and extensive adipose tissue remodeling including reduced subcutaneous adipocyte size and improved adipose tissue-derived cytokines, which is associated with improved peripheral insulin sensitivity.260,263
High-Risk Obesities: From Precision Medicine to Precision Population Health?
Considerable knowledge relevant to the biology of obesities has been gained over the last 40 years. Unfortunately, such information has had little impact on obesity prevalence rates worldwide. It is, therefore, clear that although we better understand the biology of energy balance, we have not been in a position to properly decipher the complex interactions among environmental factors affecting behaviors (eg, choice and consumption of highly processed foods determined, among other factors, by food systems and their availability/marketing, level of physical activity affected by permissive environments and socioeconomic factors, psychosocial issues, quality of sleep, etc) modulating energy intake and expenditure. Thus, it is not surprising that classical clinical intervention studies focusing on the individual and not on his/her living environment have had limited long-term success. Large studies incorporating individual and environmental data are underway to hopefully design and evaluate community interventions that will not only target individuals but also features of their living environments and communities. By having access to massive data and with the help of artificial intelligence, it is hoped that the study of complex phenomena such as obesities will be facilitated, leading to the development of clinical solutions better aligned to population-based approaches—a concept described as precision lifestyle medicine,228 a notion embracing precision population health.265
Acknowledgments
We would like to acknowledge the support of many colleagues/students/ residents who have contributed to the work from their institution relevant to this article. We also want to acknowledge the generous help and trust of our study subjects and patients.
Footnote
Nonstandard Abbreviations and Acronyms
- BMI
- body mass index
- CARDIA
- Coronary Artery Risk Development in Young Adults
- CT
- computed tomography
- CVD
- cardiovascular disease
- GIP
- glucose-sensitive insulinotropic peptide
- GLP-1
- glucagon-like peptide-1HDLhigh-density lipoprotein
- HFpEF
- heart failure with preserved ejection fraction
- LDL
- low-density lipoprotein
- Look AHEAD
- Action for Health in Diabetes
- MADIT II
- Multicenter Automatic Defibrillator Implantation Trial II
- MESA
- Multi-Ethnic Study of Atherosclerosis
- MRI
- magnetic resonance imaging
- PCr
- phosphocreatine
- SGLT2
- sodium-glucose co-transporter 2
- STAMPEDE
- Surgical Treatment and Medications Potentially Eradicate Diabetes Efficiently
- SUSTAIN
- Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes
- TOPCAT
- Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist
- VAT
- visceral adipose tissue
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Published online: 21 May 2020
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A. Tchernof receives research funding from Johnson & Johnson Medical Companies and Medtronic for studies related to bariatric surgery. The other authors report no conflicts.
Sources of Funding
M.-E. Piché is a recipient of Early Career Research Grants from the Fonds de recherche du Québec-Santé and the Fondation of the Québec Heart and Lung Institute. J.-P. Després is the Scientific Director of the International Chair of Cardiometabolic Risk supported by the Fondation de l’Université Laval. Research from J.-P. Després discussed in this article has been and is currently supported by the Canadian Institutes of Health Research (Foundation grant, FDN-167278), as well as by the Fondation of the Québec Heart and Lung Institute. A. Tchernof is a codirector of the Research Chair in bariatric and metabolic surgery.
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