Left ventricular hypertrophy and enlargement are common in obese patients. In early post-mortem and biopsy studies, it demonstrated that severe and long-standing obesity, particularly when accompanied by hypertension and congestive heart failure, was associated with left ventricular dilation and hypertrophy and, to a lesser extent, right ventricular dilation and hypertrophy (Harmancey et al., 2008; Alpert et al., 2014). Obesity could predispose to heart failure of both ventricles. Post-mortem studies on obese subjects consisted largely of morbidly obese patients, it might overlook cardiac morphology of asymptomatic and symptomatic persons with various degrees of obesity. Then, several echocardiographic studies found a significant positive correlation between the severity of obesity and left ventricular mass, and left ventricular chamber size even after adjustment for height. In a large cohort study enrolling 11,792 obese patients with preserved ejection fraction, there was a prevalence of 49% for abnormal left ventricular geometry including concentric remodeling, eccentric and concentric hypertrophy (Lavie et al., 2007). And abnormal left ventricular geometry occurred much more commonly in obese than in nonobese patients (Patel et al., 2014). These structural abnormalities in left ventricle per se give rise to increased ventricular arrhythmias.

Obesity cardiomyopathy occurs when these cardiac structural and hemodynamic changes result in congestive heart failure (Harmancey et al., 2008; Ren et al., 2021). Obesity cardiomyopathy usually happens to individuals with severe and long-standing obesity. Left ventricular hypertrophy and diastolic dysfunction are early manifestations in the disease course, left ventricular systolic function becomes decompensated and finally symptomatic heart failure occurs (Alpert et al., 2014; Plourde et al., 2014). There are always two causes of death for obesity cardiomyopathy patients, one is progressive congestive heart failure, and the other is SCD(Plourde et al., 2014).

Volume and pressure overload might take part in the process of left ventricular remodeling for obese subjects. Obesity is associated with increased total blood volume and cardiac output induced by the high metabolic activity of excessive adiposity, which will lead to volume overload (Alpert, 2001). Besides, hypertension is so common in obese populations, chronic cardiac pressure overload caused by elevated systemic blood pressure may partly contribute to left ventricular hypertrophy (Cavalera, 2014). Volume and pressure overload have different effects on the cardiomyocytes, volume overload leads to chamber dilation and matrix degradation, whereas pressure load induces concentric hypertrophy, increased collagen deposition, and diastolic dysfunction (Ulasova et al., 2011; Cavalera, 2014). It is difficult to evaluate the relative contribution of these pathophysiologic changes during the remodeling process in obese patients. Pulmonary hypertension and coexisting obstructive sleep apnea/obesity hypoventilation syndrome will increase right ventricular wall stress, finally do damage to right ventricular structure and function (Jordan et al., 2014). Abnormal neuroendocrine activation ensues further bringing in progression of both diastolic and systolic dysfunction.

Myocardial fibrosis has been documented in most animal models of obesity. db/db mice with a mutation which caused a truncated long-form of the leptin receptor, had a hyperphagic appetite, rapidly significant obesity and diabetes during the first months of life. At the age of 4–6 months, cardiac interstitial fibrosis and diastolic dysfunction could be easily observed in db/db mice (Sloan et al., 2011; Gonzalez-Quesada et al., 2013). Obese hyperinsulinemic Zucker rats also showed perivascular cardiac fibrosis, associated with increased left ventricular mass and cardiac hypertrophy (Fredersdorf et al., 2004). Not only genetically edited obese mice but also diet-induced obese mice, could develop the phenotype of cardiac fibrosis. In male C57BL6J mice fed a high-fat high-carbohydrate diet for 6 months, histological and echocardiographic findings demonstrated progressive left ventricular hypertrophy, interstitial fibrosis, and diastolic dysfunction (Qin et al., 2012). Obesity might also enhance the effects of other fibrotic changes. In models of hypertensive fibrosis, obesity increased cardiac hypertrophy, collagen deposition and extracellular matrix remodeling (van Bilsen et al., 2014). In mice with reperfused myocardial infarction, both genetic and diet-induced obesity accentuated post-infarction ventricular dilation (Thakker et al., 2006).

Fatty infiltration is prevalent in the obese heart. Excessive fat might be widely visible on the epicardium, the pericardium and the perivascular tissues. It could also infiltrate into the myocardium (Plourde et al., 2014). Increased volume of fat might secrete inflammatory cytokines and promote inflammatory responses within the myocardium via an autocrine or paracrine manner. Myocardial steatosis is another potential mechanism in obesity cardiomyopathy at the pathological level.

Prolonged and heterogeneous ventricular repolarization is the characteristic of obesity-associated electrical abnormalities (Mukerji et al., 2012a). QT interval and QT interval corrected to the heart rate (QTc) represent ventricular repolarization duration, and prolonged QT interval is always considered as the increased risk of fatal ventricular arrhythmias including ventricular tachycardia and ventricular fibrillation (Omran et al., 2018). The Bazett formula is most commonly used that correlate QTc to SCD. A QTc of 440 ms has been widely identified as a cut-off value indicative of increased SCD risk. QT dispersion is the difference between the longest and shortest QT interval, and is thought to reflect heterogeneity of repolarization (Omran et al., 2018).

Cohort studies showed that obese patients were more likely to have prolonged QT intervals than those with normal weight (Mukerji et al., 2012a). In the EURODIAB Type 1 Complications Study, the overall prevalence of QT prolongation was 16%, that was 11% in men, and 21% in women (Veglio et al., 1999). Obvious QTc prolongation and enhanced QT dispersion could be even evidenced at an early age in obese children. A meta-analysis also found that QT/QTc and QT dispersion in obese and overweight populations was much longer than in those with normal weight (Omran et al., 2016). QRS fragmentation, a surrogate for heterogeneous conduction, was also manifested in obesity and obesity-mediated SCD(Narayanan et al., 2015). And QRS fragmentation was confirmed as an independent predictor of SCD.

Among obese patients, those who had left ventricular hypertrophy showed much longer QTc interval. Left ventricular hypertrophy was an indicator of the onset of cardiac decompensation, and the development of electrical abnormalities was involved as a consequence (Russo et al., 2011). Obesity cardiomyopathy was taken as the key culprit to the delayed ventricular repolarization and increased repolarization dispersion, which facilitated the occurrence of reentrant ventricular arrhythmias (Ren et al., 2021).

In the obese population, left ventricular dilation was associated with premature ventricular contractions, since the structural abnormalities always brought in the changes in electrical properties. Premature ventricular beats, despite generally unharmful, conferred a higher risk of ventricular tachyarrhythmias and mortality in the general population, even if the overall burden was low. Continuous ECG monitoring demonstrated obese subjects had increased frequency of ventricular beats (Messerli et al., 1987). When the prolonged QTc and increased dispersion concurred with premature ventricular beats, it might result in the development of ventricular arrhythmias triggered by early or delayed after-depolarization (Bikkina et al., 1993).

Epicardial adipose tissue was found to have close relationships with high probability of premature ventricular beats, ventricular tachyarrhythmias, and all-cause mortality from SCD(Wu et al., 2015). The intramyocardial adiposity and heterogeneous conduction led to abnormal electrophysiological properties, and higher propensity for ventricular tachycardia. In addition, epicardial fatty infiltrations, myocardial steatosis, and subsequent cardiac fibrosis might form reentrant circuits for lethal arrhythmias (Pouliopoulos et al., 2013).

Late potentials are considered to represent abnormal conduction in the myocardium, providing a possible site for re-entry and then ventricular tachyarrhythmias initiation (Plourde et al., 2014). A filtered QRS duration >114 ms in signal averaged electrocardiography is thought to be the optimal value associated with arrhythmic risk (Goldberger et al., 2008). Late potentials were documented in obese patients, there was a positive relationship between BMI and the number of late potentials, indicating an increased susceptibility to ventricular tachyarrhythmias and SCD(Lalani et al., 2000).

It is well-known that QTc prolongation, QT dispersion and premature ventricular beats are common manifestations of electrocardiogram, the fundamental cellular electrophysiological mechanisms are attribute to the expression and function changes of various cardiac ion channels, including voltage-dependent potassium channels, sodium channels and calcium channels, and perturbation of intracellular Ca²⁺ homeostasis mediated by calcium receptors and channels (Remme, 2022). Cardiac ion channels are the key mediators between obesity, abnormal repolarization and SCD.

There was a decreased expression of the inward potassium current in animal models of obesity. In mice with diet-induced obesity, the reduction of voltage-gated potassium channel resulted in action potential prolongation, subsequent clinically observed QTc prolongation, and more frequent premature ventricular contractions (Huang et al., 2013). It seemed K_ATP channels played an important role in prolonged QT. In drug-induced long QT syndromes in dogs and rabbits, the administration of K_ATP opener nicorandil led to a reduction of the action potential duration, early after depolarization, and premature ventricular beats (Biermann et al., 2011). It indicated K_ATP channels were inhibited in obese cardiomyocytes, and its openers could rescue the repolarization abnormalities, demonstrating a significant anti-arrhythmic effect.

Voltage-dependent L-type calcium current was reported to be decreased in obesity models, resulting in the extension of phase 2 plateau period and prolonged repolarization. The magnitude of late sodium current was increased, which caused more sodium entry into the cardiomyocyte, and increased calcium influx via the reverse mode of the sodium/calcium exchanger, facilitating calcium-dependent pro-arrhythmic outcome (Yang et al., 2015).

Defective calcium handling could do harm to ventricular cardiomyocytes and bring in pro-arrhythmic effects. In high-fat diet animal models, it caused abnormal oxidation of ryanodine receptor type 2 (RyR₂, calcium release channel in sarcoplasmic reticulum), greater calcium release via RyR₂, and subsequent calcium overload inducing delayed after-depolarizations. Ca²⁺/calmodulin protein kinase II (CaMKII) was thought to be vital to intracellular calcium handling. Increased activity of CaMKII took an important role in calcium-dependent pro-arrhythmic effects for inducing mitochondrial calcium overload and mitochondrial dysfunction (Hegyi et al., 2021; Remme, 2022).

These changes in ion channels were proposed as drivers of ventricular arrhythmias in obese patients. Coupled with the structural changes above, which provided the arrhythmogenic substrate, a milieu for ventricular arrhythmogenesis existed in the obese heart (Ha et al., 2022).

Activation of the renin-angiotensin-aldosterone system (RAAS), which always occurred in response to hemodynamic disturbances, was described in animal models of obesity. In obese salt-sensitive rats and db/db mice, it demonstrated increased expression and enhanced functional activity of angiotensin converting enzyme (ACE) and AT1 receptor (Singh et al., 2008; Takatsu et al., 2013). Activation of the RAAS would finally prompt cardiac fibrosis and remodeling through multiple signal pathways.

Pharmacological intervention with RAAS inhibitor showed positive effects on obesity related fibrosis and metabolic dysfunction. Both ACE inhibitors and AT1 blockers attenuated collagen synthesis and cardiac fibrosis, downregulated TGF-β levels, and reduced superoxide production (Zaman et al., 2001; Sloan et al., 2011; Vázquez-Medina et al., 2013). Stimulation of the mineralocorticoid receptor resulted in left ventricular hypertrophy, pro-fibrotic, and pro-inflammatory actions. The use of aldosterone antagonist could prevent these pathophysiological abnormities, and improve the survival for heart failure patients (Kosmala et al., 2013). When treated with mineralocorticoid receptors blocker, obese mice demonstrated decreased expression of proinflammatory and prothrombotic adipokines playing roles in obesity cardiomyopathy (Guo et al., 2008).

Adiponectin is an insulin-sensitizing adipokine which is exclusively produced by adipocytes. The physiological function of adiponectin includes improved insulin resistance, anti-arteriosclerosis, and anti-inflammation (Ouchi et al., 2006). The plasma level of adiponectin has good predictive value for type 2 diabetes mellitus and coronary heart disease (Ouchi et al., 2003), both of these diseases have close relationships with obesity and SCD.

The risk of SCD for obese subjects may be associated with decreased serum concentrations of adiponectin. In obese patients, there was a reduction of adiponectin which might possibly concur with other risk factors for the development of cardiomyopathy (Plourde et al., 2014). In animal models, decreased levels of adiponectin could lead to left ventricular hypertrophy through AMP kinase signaling and adrenergic receptor stimulation. Modulation of serum levels of adiponectin in knock-out mice might attenuate these adverse effects (Shibata et al., 2004).

Leptin, produced by white adipose tissue, is a key mediator in metabolic regulation by acting on leptin receptor. In a state of low energy or reduced body fat (such as starvation), serum leptin levels decrease significantly, conversely, when body fat increases, serum levels of leptin rise to inhibit eating and speed up metabolism. Leptin regulates energy balance and body weight through such a negative feedback mechanism (Gautron and Elmquist, 2011).

Leptin also acts as an important factor in the pathogenesis of obesity-related cardiac remodeling. In satiety-induced obesity state, increased leptin cannot result in more energy consumption, which is considered as “leptin resistance”. Serum levels of leptin was elevated, and was positively associated with left ventricular hypertrophy in obese patients (Perego et al., 2005). It seemed leptin could directly increase myocardial fat volume, induce cardiomyocyte hypertrophy (Rajapurohitam et al., 2003), which might be partly explained by leptin resistance. In addition, leptin regulates the phenotype of fibroblast, initiating a fibrogenic process (Fukui et al., 2013).