A primer on obesity-related cardiomyopathy
2021; American Physiological Society; Volume: 102; Issue: 1 Linguagem: Inglês
10.1152/physrev.00023.2021
ISSN1522-1210
AutoresWillis K. Samson, Gina L. C. Yosten, Carol Ann Remme,
Tópico(s)Metabolism, Diabetes, and Cancer
ResumoEditorialA primer on obesity-related cardiomyopathyWillis K. Samson, Gina L. C. Yosten, and Carol Ann RemmeWillis K. SamsonDepartment of Pharmacology and Physiology, Saint Louis University, St. Louis, Missouri, Gina L. C. YostenDepartment of Pharmacology and Physiology, Saint Louis University, St. Louis, Missouri, and Carol Ann RemmeDepartment of Experimental Cardiology, Amsterdam UMC, location Academic Medical Center, Amsterdam, The NetherlandsPublished Online:04 Oct 2021https://doi.org/10.1152/physrev.00023.2021This is the final version - click for previous versionMoreSectionsPDF (518 KB)Download PDFDownload PDFPlus ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInEmail AbstractDownload figureDownload PowerPoint1. INTRODUCTIONAlthough much has been written about the syndrome of diabetic cardiomyopathy, clinicians and research scientists are now beginning to realize that an entirely unique syndrome exists, albeit with several commonalities to the diabetic syndrome, that being obesity cardiomyopathy. This syndrome develops independent of such comorbidities as hypertension, myocardial infarction, and coronary artery disease, and it is characterized by specific alterations in adipose tissue function, inflammation, and metabolism. Recent insights into the etiology of the syndrome and its consequences have focused on the roles played by altered intracellular calcium homeostasis, reactive oxygen species (ROS), and mitochondrial dysfunction. A timely and comprehensive review by Ren, Wu, Wang, Sowers, and Zhang (1) identifies unique mechanisms underlying this syndrome, its relationship to heart failure, and the recently identified incidence of COVID-19-related cardiovascular mortality. Importantly, the review concludes by advancing recommendations for novel approaches to the clinical management of this dangerous form of cardiomyopathy.2. THE CASE FOR A UNIQUE SYNDROME: OBESITY CARDIOMYOPATHYThe worldwide incidence, as well as the underlying causes, of obesity and the attempts by research scientists to develop appropriate animal models have been and continue to be a main focus of the medical and scientific literature. However, an increasing number of studies have revealed the existence of a unique consequence of obesity itself, a syndrome characterized by changes in myocardial structure and pump function. This form of cardiovascular disease (CVD) presents in obese individuals independent of the risk factors common to other forms of CVD, including age, sex, hypertension, and dysregulated glucose homeostasis. Excessive accumulation of adipose tissue results in increased plasma levels of proinflammatory cytokines and an imbalance of leptin to adiponectin concentrations. As summarized in Figure 3 of the review (1), this leads to left ventricular dilation, hypertrophy, and heart failure. In addition, adipocyte-derived cytokines and excess circulating lipid levels independently cause vascular and cardiac remodeling. Obesity cardiomyopathy is characterized as well by elevated aldosterone levels leading to mineralocorticoid receptor activation, greater amiloride-sensitive endothelial sodium channel (EnNaC) activation, and coronary artery and cardiomyocyte stiffness (2). Contributing to this dangerous symphony of cardiac insults is the occurrence of sleep apnea in obese individuals, which by itself leads as a result of hypoventilation to hypoxia, acidosis, pulmonary hypertension, and right ventricular failure. Not to be overlooked in the syndrome of cardiomyopathy are the consequences of obesity on vascular function, including increased risk of thrombotic events and atherosclerosis (3). As such, obesity appears to be an important risk factor for COVID-19 patients because of their compromised renal, respiratory, and endothelial functions (3–7). A retrospective meta-analysis in hospitalized patients reported association of obesity with increased risk of intensive care admission, invasive mechanical ventilation, and in-hospital mortality (8). Early results from the French hospital consortium CORONADO study identified a positive correlation between body mass index (BMI) and intubation or death in hospitalized diabetic patients (9). However, other than the incidence of heart failure, the incidence of cardiomyopathy in these subjects was not reported. In a follow-up study the CORONADO investigators identified, using multivariate analysis, a direct correlation between obesity and intubation or death, but only in patients under the age of 75 years. This association was not observed in older patients (10). Other biological variables determined to carry increased risk were macro- and microvascular complications and treated sleep apnea, which were independently associated with the risk of death within 7 days of hospitalization. In most studies reported to date, obesity emerges as a consistent and significant risk factor for the complications of SARS-CoV-2 infection (3). Recent reviews (3–6) pay particular attention to pulmonary, metabolic, and adipocyte function as markers of COVID-19 susceptibility and outcomes.There are several hallmarks of obesity cardiomyopathy (FIGURE 1). Most well established is cardiac remodeling that precipitates hypertrophy, fibrosis, and diastolic dysfunction. Such structural alterations, together with electrophysiological changes including alterations in action potential duration and intracellular calcium homeostasis, predispose to cardiac arrhythmias, predominantly atrial fibrillation but also ventricular arrhythmias and potentially sudden cardiac death (11, 12). Contributing to the insult to cardiac function are obesity-related changes in hemodynamic function, including increased blood volume, hypoxemia, and increased filling pressures and cardiac output. Activation of both the sympathetic nervous system and the renin-angiotensin-aldosterone system contributes to the increased blood pressure that prevails in obesity, and endothelial dysfunction compromises arterial compliance. The review by Ren and colleagues (1) highlights hemodynamic and structural sequelae that contribute to the increased risk for CVD in obese individuals and summarizes the apparent paradox of improved survival in the face of existing CVD, in particular during heart failure, of some obese individuals. This in itself is a topic for more extensive discussion; however, it is clear that the obesity paradox may be partly secondary to other underlying factors, such as dyspnea (13) and the perhaps inappropriate current use of BMI to define the obese condition (14), and therefore not in reality a paradox. One must remember that the definition of the obesity paradox is based on observational epidemiology and not comprehensive mechanistic studies (15).FIGURE 1.Obesity can be the result of a genetic predisposition or sedentary lifestyle and poor diet. The increased adipocyte mass can trigger changes in a variety of tissues, leading to the syndrome of obesity cardiomyopathy. LV, left ventricle; RAAS,Download figureDownload PowerPoint3. THE BASIC MECHANISMS OF OBESITY CARDIOMYOPATHYAlthough the review by Ren and colleagues (1) provides an excellent description of the syndrome itself, its strength lies in the text introducing the basic mechanisms of obesity cardiomyopathy. Clearly this is initiated at the levels of the adipocyte because of chronic inflammation, which by itself can lead to insulin resistance, diabetes (16), and shift in the ratio of pro- versus anti-inflammatory cytokines. As displayed in Figure 4 of the Physiological Reviews review article by Ren et al. (1), this results in a myriad of effects on cellular function, in particular cardiac metabolism. Key alterations include an increase in fatty acid oxidation and a decrease in glucose oxidation, which ultimately leads to mitochondrial uncoupling, reduced oxygen efficiency, and increased ROS production (1). Consequent to the reduced glucose oxidation, cardiomyocytes generate less ATP, resulting in decreased cardiac efficiency and contractile function. Increased ROS has well-established detrimental effects, inducing intracellular calcium dysregulation and affecting numerous signaling pathways, ultimately resulting in abnormal contraction and relaxation. Crucially, abnormal calcium homeostasis is also a key driver of pro-arrhythmia, mediated by inappropriate release of calcium from the sarcoplasmic reticulum; this is furthermore modulated by alterations in SERCA, RyR2, L-type calcium channel, and CamKII activity. Reduced mitophagy, removal of dysfunctional mitochondria, further compromises mitochondrial function, whereas disrupted endoplasmic reticulum (ER) homeostasis promotes the buildup of unfolded and misfolded proteins and consequently leads to ER stress. Lipotoxicity is another important feature; excess accumulation of fatty acids is associated with ultrastructural changes in cardiomyocytes, and intramyocardial lipid overload predisposes to contractile dysfunction. In an attempt to compensate for the reduced glucose oxidation, alternative sources for energy production are promoted, including glycolysis, lactate, ketone bodies, and branched chain amino acids (BCAAs). In obese individuals, however, insulin resistance (17) blunts BCAA oxidation and catabolism, and BCAA plasma levels are consequently increased. High levels of BCAAs disrupt mitochondrial pyruvate utilization, suppress glucose metabolism, and induce oxidative stress and furthermore lead to chronic activation of mammalian target of rapamycin (mTOR) activity, which in turn suppresses cardioprotective autophagy (17–19). This dysregulation in BCAA metabolism is known to have a detrimental impact on cardiac contractility and has also recently been shown to potentially increase the risk for cardiac arrhythmias (20). Hence, a myriad of metabolic derangements and alterations in signaling pathways mediate detrimental changes in cardiac contractile and electrical function in the obese individual.4. STRATEGIES FOR THE PREVENTION AND TREATMENT OF OBESITY CARDIOMYOPATHYIt is one thing to describe the epidemiology of an emerging disease or to detail efforts to understand its etiology; however, just as important is the discussion of what can be done at present to relieve the disease burden and what developments might be anticipated in terms of treatment options. Clearly the management of obesity-related conditions begins with the prevention of excessive weight gain and then weight loss once established. In obese patients, success has been attained with caloric restriction and increased physical activity regimens (21). Given the observed detrimental effects of increased BCAAs in metabolically compromised individuals, a diet with reduced BCAA intake may be of potential value. The "brass ring" sought by academic researchers and industrial laboratories, however, is an effective, safe, and economical pharmacological approach. As detailed in the review by Ren et al. (1), the FDA has set weight loss targets for drug approval, and to date several monotherapies and two combined therapies have been approved (22). Most recently, advances in chemical biology have led to the development of analogs of the endogenous incretin hormone glucagon-like peptide-1 (GLP-1), which are approved for the treatment of Type 2 diabetes (T2D) (23, 24), control of plasma cholesterol levels (25), and, just this year, weight loss (26). The development of the GLP-1 receptor agonists was the culmination of more than four decades of work (27, 28), which identified the multiple biological effects of GLP-1, in both preclinical and clinical trials (28–41). Just as impressive is the body of work identifying a second member of the incretin family of peptide hormones, glucose-dependent insulinotropic peptide (GIP) (28). Although GLP-1 has a more profound effect on appetite, both are potent postprandial insulin secretagogues, and in fact some investigators hypothesize a more significant role of GIP than GLP-1 in healthy individuals (28, 42). Both GLP-1 and GIP suffer in vivo from relatively short half-lives, and this has led to structural modifications in the case of GLP-1 analogs with greater resistance to clearance by endogenous peptidases. Taking a unique approach to the development of potent agonists, several groups have collaborated to create dual GIP-GLP-1 receptor agonists, conjoined molecules possessing the biological activity of both hormones (43, 44). In an extensive dose-response trial, LY3298176, the dual GLP-1 and GIP agonist, outperformed the GLP-I agonist dulaglutide, with minimal side effects, mostly gastrointestinal like those seen with the GLP-1 agonists (43). These novel molecules demonstrate increased potency in terms of not only glycemic control but also weight loss and suggest that they or similar modifications may show efficacy even greater that that observed with semaglutide, liraglutide, or dulaglutide (23–26, 45).As pointed out in the review by Ren and colleagues (1), there are other FDA-approved therapeutics for weight loss including orlistat, which inhibits pancreatic lipase and lowers fat absorption (22). Orlistat will certainly remain an important option for the treatment of obesity-related cardiomyopathy, particularly when addressing the issue of adipocyte expansion (46). Lorcaserin activates the serotonin 5-HT2C receptor in hypothalamus, resulting in suppression of appetite, and when added to a physical activity regimen is indicated for obese individuals with attendant comorbidities such as diabetes and dyslipidemia (47). Other agents approved for weight loss include the phentermine-topiramate and naltrexone-bupropion combinations. However, the leading candidates for weight loss and treatment of obesity cardiomyopathy are the GLP-1 analogs and the GLP-1-GIP congeners (28, 29).In addition to therapeutic approaches for weight loss, it is important to consider not only treatment strategies aimed at preventing the detrimental consequences of obesity in terms of cardiac structural and electrical remodeling, including diuretics and aldosterone agonists, but also approaches aiming to reduce fibrosis and improve calcium homeostasis. Other promising targets include autophagy, adiponectin, and inflammatory cytokines and insulin secretion/sensitivity. Lifestyle modifications, including dietary reduction in BCAA intake by decreasing the consumption of, e.g., animal protein, are certainly going to be important adjunctive therapies. The efficacy of caloric restriction when partnered with a regular exercise regimen has been demonstrated (20). Surgical approaches to weight loss and glycemic control also have been successful (48, 49). Indeed, sleeve gastrectomy was shown to not only improve glucose homeostasis but also improve systolic and diastolic function in T2D patients (49). Similarly, in an animal model of diabetes, the high-fat feed, low-dose streptozotocin-treated rat, sleeve gastrectomy, or duodenal-jejunal bypass relieved diabetic cardiomyopathy, improved cardiomyocyte calcium homeostasis, and attenuated autophagy (50).5. CONCLUSIONSAs elegantly reviewed by Ren et al. (1), our knowledge on obesity cardiomyopathy and its underlying mechanisms has grown exponentially in recent years. Nevertheless, there are many areas of research that remain underexplored, including the role of circadian rhythm, autonomic regulation, gut microbiome, and epigenetics. Moreover, as with all cardiomyopathies, patients with obesity cardiomyopathy are at increased risk not just for abnormalities in cardiac contraction and relaxation but also for electrical disturbances and potentially life-threatening arrhythmias. Hence, further research into this complex disorder is paramount in order to facilitate the development of novel preventive and therapeutic strategies.DISCLOSURESNo conflicts of interest, financial or otherwise, are declared by the authors.AUTHOR CONTRIBUTIONSW.K.S. and C.A.R. prepared figures; W.K.S., G.L.C.Y., and C.A.R. drafted manuscript; W.K.S., G.L.C.Y., and C.A.R. edited and revised manuscript; W.K.S., G.L.C.Y., and C.A.R. approved final version of manuscript.REFERENCES1. Ren J, Wu NN, Wang S, Sowers JR, Zhang Y. Obesity cardiomyopathy: evidence, mechanisms, and therapeutic implications. Physiol Rev, 2021. doi:10.1152/physrev.00030.2020. Link | Google Scholar2. Hill MA, Yang Y, Zhang L, Sun Z, Jia G, Parrish AR, Sowers JR. 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