Abstract
Aims: Although previous studies have shown that epicardial adipose tissue (EAT) volume is increased in patients with acute coronary syndrome (ACS), its correlation with left ventricular (LV) remodeling and LV ejection fraction (LVEF) after ACS remains unknown. This study evaluated the association between the EAT volume and temporal LVEF changes in patients with ACS.
Methods: This prospective cohort study included 197 patients hospitalized for ACS. Among them, 143 (86 males, 67±12 years) underwent follow-up. Echocardiography was performed for three years. The patients were divided into three groups according to their LVEF: heart failure with reduced EF (HFrEF), heart failure with mildly reduced EF (HFmrEF), and heart failure with preserved EF (HFpEF).
Results: There was no association between the EAT volume at the onset of ACS and the difference in LVEF during follow-up (β = −0.08,p = 0.42). Peak creatine phosphokinase levels during ACS were most strongly correlated with the chronic-phase LVEF (r = −0.51,p＜0.01). Patients with HFrEF had the highest EAT volume (HFrEF: 134±38 mL; HFmrEF: 102±35 mL; HFpEF: 120±51mL;p = 0.04). Among patients with chronic HFmrEF and HFpEF, but not HFrEF, EAT volume was positively correlated with body mass index (r = 0.37,p = 0.03, and r = 0.45,p＜0.01, respectively).
Conclusions: EAT volume was not associated with LVEF changes at 3 years after ACS. However, patients with chronic HFrEF had a significantly higher EAT volume despite not being obese.
Keywords: Epicardial adipose tissue, ACS, LVEF, HFrEF, Non-obese
See editorial vol. 33: 117-119
1. Introduction and Aim
Epicardial adipose tissue (EAT), which is visceral fat between the pericardium and external myocardium, has recently attracted widespread interest because of its diverse effects on the cardiac structure and function in heart failure (HF). The EAT plays important physiological and pathological roles in the regulation of the myocardial function. By sharing the same microcirculation as the myocardium, the EAT may maintain cardiac health via mechanical, metabolic, thermogenic, and paracrine functions. Meanwhile, EAT inflammation in obesity may mediate myocardial dysfunction and HF 1 , 2) .
EAT can directly affect coronary arteries, leading to endothelial dysfunction, impaired vasodilation, and reduced blood flow to the myocardium, further contributing to adverse cardiac remodeling 3 , 4) . In particular, EAT accumulation has a harmful effect on HF with preserved ejection fraction (HFpEF). In the general population, increased EAT is linked with incident HF, specifically HFpEF 5) . The role of EAT in HF is mostly limited to HFpEF and is related to the obese HFpEF phenotype. In HFpEF, the EAT assumes a pro-inflammatory profile, with higher EAT values related to worse outcomes 6) .
EAT accumulation is associated with the severity of coronary artery disease severity 7 - 9) . Adipocytokines secreted from epicardial fat are thought to contribute to the development of myocardial infarction by inducing inflammation of the coronary arteries and making plaques more vulnerable. The EAT volume is also independently associated with the risk of myocardial infarction, which is independent of traditional cardiovascular risk factors in the general population 10 , 11) . However, the volume of the EAT does not necessarily correlate with the extent of myocardial infarction. This may be because adipocytokines exert myocardial protective effects. While our previous study demonstrated that EAT volume increased in patients with acute coronary syndrome (ACS) 12) , its effects on left ventricular (LV) remodeling in these patients remain unclear. Thus, this study evaluated the association between EAT volume and temporal changes in left ventricular ejection fraction (LVEF) in patients with ACS.
2. Methods
2.1. Study Population
This single-center study included 223 Japanese patients hospitalized for ACS between June 2011 and November 2014. Among the included patients, 182 had ST-elevation myocardial infarction (STEMI) and 41 had non-STEMI. Patients with STEMI were defined as those who presented with ischemic chest discomfort, an elevated ST-segment on electrocardiography, and increased circulating troponin-I level, whereas individuals presenting with ischemic chest discomfort and increased troponin-I level, but without ST-segment elevation, were classified as non-STEMI patients. All patients underwent coronary angiography and percutaneous coronary intervention, and culprit lesions were identified based on the presence of pronounced stenosis. All patients also underwent cardiac computed tomography (CT) during hospitalization, and venous blood samples were collected for analysis after overnight fasting. In addition to those who underwent coronary artery bypass graft surgery (n = 8), we excluded patients who died after hospitalization (n = 2), those who underwent cardioverter defibrillator implantation (n = 1), those who required postoperative dialysis (n = 2), those who did not regain consciousness after resuscitation for ventricular fibrillation (n = 2), those who were diagnosed with cancer after hospitalization (n = 1), and those who did not undergo cardiac CT (n = 10). Among 197 patients, 143 who underwent follow-up echocardiography and blood tests were enrolled.
The study protocol was approved by the ethics committee of Chubu Rosai Hospital and conducted in accordance with the Declaration of Helsinki. All patients provided their written informed consent to participate in the study.
2.2. EAT Volume Quantification
The EAT content was determined based on cardiac CT scans. Images were obtained using a 64 detector-row CT scanner (LightSpeed; GE Healthcare, Wisconsin, USA). The EAT volume was defined as the total amount of adipose tissue between the surface of the heart and the visceral layer of the pericardium, and was measured as described previously 12) . The EAT volume was semi-automatically quantified by a single experienced investigator (K. H.) using a dedicated image analysis software program. The segmented pericardial contours were interpolated to the remaining slices and carefully adjusted if necessary. They were visually checked by other investigators (M. K. and T. K.) who were blinded to the patients’ characteristics.
2.3. Echocardiography
Echocardiography was performed by experienced cardiac sonographers who were blinded to the patient data during hospitalization and follow-up examinations. Echocardiographic parameters were evaluated according to the current recommendations for cardiac chamber quantification and included LV dimensions, systolic function, LV diastolic function, and valvular stenosis and/or regurgitation 13) . The Simpson method was used to calculate the LVEF from apical four- and two-chamber views; values measured by the technician were double-checked by a cardiologist (M. K.). Based on LVEF, patients ≤ 40%, 41%–49%, and ≥ 50%, respectively, were categorized as having HF with a reduced ejection fraction (HFrEF), HF with a mildly reduced ejection fraction (HFmrEF), and HFpEF, as per the current guidelines 14) . Additionally, the absence of epicardial effusion was verified using echocardiography to ensure the reliability of the EAT measurements.
2.4. Data Collection and Follow-Up
Study patients were seen every 6 months for the next 3 years (mean, 3.2±0.8 years). The LVEF and brain natriuretic peptide (BNP) levels were measured when the patients’ symptoms and conditions were stable. All patients received optimal medication and their data, including blood test results, body measurements, and echocardiography, were obtained when they were in a stable condition.
2.5. Statistical Analysis
For baseline characteristics, categorical variables were described as numbers and percentages, and continuous variables as means with standard deviations or medians with interquartile ranges if their distribution was skewed. Differences between the mean values of the two groups were evaluated using Student’s unpaired t-test or the Mann–Whitney U test. Differences in characteristics were compared using the chi-squared test for categorical variables and an analysis of variance for continuous variables. Potential correlations between LVEF during follow-up and other clinical parameters, as well as between body mass index (BMI) and EAT volume for each heart failure group, were determined using Spearman’s rank correlation coefficient. A multivariate regression analysis was performed to determine the relationship between the difference in LVEF and other clinical parameters, including the EAT volume. The difference in LVEF was treated as a continuous variable. All statistical analyses were performed using the R software program (ver. 4.0.2, Vienna, Austria). Statistical significance was set at P＜0.05.
3. Results
3.1. Clinical Characteristics of the Study Population
The clinical characteristics of the patients are summarized in Table 1 . The mean age of all patients was 67±12 years and did not differ to a statistically significant extent between the LVEF categories. Overall, 60% of the patients were male. The proportion of males was lowest in the HFrEF group, highest in the HFpEF group, and intermediate in the HFmrEF group (HFpEF: 69±11 years, 52% men; HFmrEF: 63±12 years, 23% male; HFrEF: 64±13 years, 11% male). The mean BMI was 24.2 kg/m2. In Japan, obesity is defined as BMI ≥ 25 kg/m2; therefore, most patients were classified as non-obese.
Table 1. Characteristics of the study participants.
| All (n = 143) | HFpEF (n = 90) | HFmrEF (n = 35) | HFrEF (n = 18) | |
|---|---|---|---|---|
| Age, years | 67±12 | 64±13 | 65±11 | 62±12 |
| Gender, men n (%) | 86 (60) | 72 (80) | 31 (88) | 17 (94) |
| Height, cm | 164±8.0 | 163±8.0 | 164±8.4 | 167±6.2 |
| Weight, kg | 66.3±13 | 65.8±14 | 65.3±12 | 70.8±12 |
| Body mass index, kg/m2 | 24.2±3.7 | 24.6±3.8 | 24.0±3.1 | 24.1±4.4 |
| Systolic BP, mmHg | 130±21 | 132±22 | 125±18 | 126±22 |
| Diastolic BP, mmHg | 76±15 | 77±16 | 73±12 | 77±13 |
| Current smoking, n (%) | 81 (57) | 48 (53) | 20 (57) | 13 (72) |
| Comorbidity | ||||
| Hypertension, n (%) | 68 (48) | 48 (53) | 15 (43) | 5 (28) |
| Diabetes mellitus, n (%) | 30 (21) | 19 (21) | 8 (23) | 3 (17) |
| Dyslipidaemia, n (%) | 44 (31) | 29 (32) | 11 (31) | 4 (22) |
| Aetiology, | ||||
| STEMI, n (%) | 112 (78) | 67 (74) | 30 (86) | 17 (94) |
| non-STEMI, n (%) | 31(22) | 23 (26) | 5 (14) | 1 (6) |
| Culprit vessel | ||||
| LAD, n (%) | 74 (52) | 51 (57) | 13 (37) | 10 (56) |
| LCX, n (%) | 24 (17) | 13 (14) | 7 (20) | 4 (22) |
| RCA, n (%) | 45 (31) | 26 (29) | 15 (43) | 4 (22) |
| Laboratory results | ||||
| HDL cholesterol, mg/dL | 44±11 | 46±12 | 40±10 | 45±9 |
| LDL cholesterol, mg/dL | 115±37 | 121±37 | 114±37 | 126±37 |
| TG, mg/dL | 134±90 | 127±72 | 123±69 | 130±80 |
| TG/HDL ratio | 3.3±2.5 | 3.0±1.8 | 3.3±2.0 | 3.3±2.7 |
| Haemoglobin A1c, % | 6.3±1.3 | 6.0±1.0 | 6.2±1.5 | 6.3±2.0 |
| eGFR, mL/min/1.73m2 | 75±21 | 73±21 | 76±20 | 69±22 |
| BNP, pg/mL | 100 (38, 227) | 93 (35, 201) | 116 (63, 221) | 164 (113, 481) |
| hs-CRP, mg/L | 0.29 (0.10, 0.84) | 0.29 (0.10, 0.72) | 0.40 (0.11, 0.86) | 0.72 (0.25, 1.01) |
| Echocardiography | ||||
| LVEF, % | 52±11 | 58±5.8 | 45±2.7 | 31±6.8 |
| LVDd, mm | 50±4.4 | 50±3.4 | 52±4.6 | 53±5.2 |
| LVDs, mm | 39±2.1 | 30±2.1 | 35±2.8 | 39±2.0 |
| E/e’ | 11.9±2.8 | 13.4±2.8 | 11.9±2.0 | 8.0±2.4 |
| Medication | ||||
| ACEI or ARB, n (%) | 107 (75) | 66 (73) | 27 (76) | 14 (78) |
| Antiplatelet, n (%) | 139 (97) | 88 (98) | 34 (97) | 17 (94) |
| β-blocker, n (%) | 93 (65) | 55 (61) | 23 (65) | 15 (83) |
| Diuretic, n (%) | 42 (29) | 26 (29) | 8 (22) | 8 (45) |
| Statin, n (%) | 130 (91) | 83 (92) | 30 (86) | 17 (94) |
| EAT volume, mL | 118±47 | 120±51 | 102±35 | 130±43 |
Data are presented as means±standard deviation, number (%) or median (25th quartile-75th quartile).
ACEI, angiotensin-converting enzyme inhibitor; ACS, acute coronary syndrome; ARB, angiotensin receptor blocker; BNP, brain natriuretic peptide; BP, blood pressure; hs-CRP, high-sensitivity C-reactive protein; EAT, epicardial adipose tissue; eGFR, estimated glomerular filtration rate; HDL, high-density lipoprotein; LAD, left anterior descending artery; LCX, left circumflex artery; LDL, low-density lipoprotein; LVDd, left ventricular diastolic diameter; LVDs, left ventricular systolic diameter; LVEF, left ventricular ejection fraction; RCA, right coronary artery; STEMI, ST-elevated myocardial infarction; TG, triglyceride.
3.2. Association between EAT Volume and the Chronic-Phase LVEF
The association between the EAT volume in the acute phase and LVEF in the chronic phase is shown in Table 1 . Overall, the mean EAT volumes of the HFrEF (n = 18), HFmrEF (n = 35), and HFpEF (n = 90) groups were 134±38 mL, 102±35 mL, and 120±51 mL, respectively. The EAT volume was significantly higher in the HFrEF group (p = 0.042) ( Supplementary Fig.1 ) .
Supplementary Fig.1.
The EAT volume was significantly increased in the HFrEF group.
ANOVA, analysis of variance; EAT, epicardial adipose tissue; LVEF, left ventricular ejection fraction; HFpEF, heart failure with preserved ejection fraction; HFmrEF, heart failure with mildly reduced ejection fraction; HFrEF, heart failure with reduced ejection fraction.
Fig.1 shows the relationship between changes in LVEF and EAT volume. The change in LVEF was 0.1%±9.3% in the HFpEF group, −1.2%±10% in the HFmrEF group, and −4.8% ±11% in the HFrEF group; however, the differences were not statistically significant (p = 0.156).
Fig.1. Scatterplot for chronic-phase LVEF demonstrating the relationship between LVEF change over time and EAT volume.
LVEF changes were did not differ to a statistically significant extent among the LVEF categories.
ANOVA, analysis of variance; EAT, epicardial adipose tissue; LVEF, left ventricular ejection fraction; HFpEF, heart failure with preserved ejection fraction; HFmrEF, heart failure with mildly reduced ejection fraction; HFrEF, heart failure with reduced ejection fraction.
A regression analysis was conducted to evaluate the relationship between the chronic-phase LVEF and clinical variables. The chronic-phase LVEF was negatively correlated with the peak creatine phosphokinase (r = −0.51, p＜0.001) and BNP (r = −0.25, p = 0.003) levels, and was positively correlated with hypertension (r = 0.24, p = 0.005). Notably, the chronic-phase LVEF was not correlated with EAT volume or BMI ( Table 2 ) . The differences in LVEF were not associated with EAT volume, peak CPK, β-blocker use, ACE inhibitor/ARB use, or LAD lesion involvement ( Table 3 ) .
Table 2. Correlations between follow-up LVEF and clinical variables among patients with ACS.
| R | p-value | |
|---|---|---|
| Age, years | 0.09 | 0.284 |
| Gender, men | 0.11 | 0.267 |
| Body mass index, kg/m2 | 0.06 | 0.547 |
| EAT volume, mL | 0.03 | 0.694 |
| Peak CPK, mg/dL | −0.51 | ＜0.01 |
| BNP, pg/mL | −0.25 | ＜0.01 |
| Haemoglobin A1c, % | −0.02 | 0.384 |
| Hypertension treatment | 0.24 | ＜0.01 |
ACS, acute coronary syndrome; BNP, brain natriuretic peptide; CPK, creatine phosphokinase; EAT, epicardial adipose tissue; LVEF, left ventricular ejection fraction; R, correlation coefficient.
p-value ＜0.05 indicates a significant correlation.
Table 3. Association between ΔLVEF and clinical parameters.
| Multivariate | ||
|---|---|---|
| β | p-value | |
| Age, years | 0.02 | 0.852 |
| Gender, men | 0.02 | 0.837 |
| Body mass index, kg/m2 | 0.03 | 0.851 |
| EAT volume, mL | −0.08 | 0.416 |
| Peak CPK, mg/dL | −0.14 | 0.195 |
| β-blocker use | −0.05 | 0.670 |
| ACEI or ARB use | −0.01 | 0.940 |
| LAD lesion | −0.09 | 0.384 |
Multivariate regression analysis adjusted for all variables. β, regression coefficient. Other abbreviations as in Table 2.
p value ＜0.05 indicates a significant correlation.
3.3. Relationship between EAT Volume and BMI
In the chronic phase, there was a positive correlation between EAT volume and BMI among patients with HFpEF and HFmrEF (r = 0.45, p＜0.01, r = 0.37, p = 0.029, respectively), but not among patients with HFrEF (r = 0.31, p = 0.251) ( Fig.2A ) . Fig.2B shows the relationship between EAT volume and BMI during the acute phase (during hospitalization). The cutoff EAT volume of 100 ml was based on our previous study 12) . A positive correlation was observed between EAT volume and BMI among patients with HFpEF and HFrEF (r = 0.46, p＜0.01, and r = 0.33, p = 0.047, respectively) but not among patients with HFmrEF (r = 0.29, p = 0.103).
Fig.2.Scatterplots for chronic phase (A) and acute phase (B) LVEF showing the relationship between EAT volume and BMI.
The correlation coefficients for each heart failure group are shown. Values for individual patients are divided into four groups based on an EAT volume of 100 mL and a cutoff BMI of 25 kg/m2.
Six patients with HFrEF were classified as non-obese with an EAT volume ＞100 mL and six patients with HFrEF were classified as non-obese with an EAT volume ＜100 mL in the acute phase (B). In contrast, nine patients with HFrEF were classified as non-obese with an EAT volume of ＞100 mL, and one patient with HFrEF was classified as non-obese with an EAT volume of ＜100 mL in the chronic phase (A)
BMI, body mass index; r, correlation coefficient. Other abbreviations are shown in Figure 1.
The relationship between EAT volume and BMI in patients with HFrEF and HFmrEF during the acute phase differed from that during the chronic phase.
4. Discussion
This study examined the impact of EAT volume on subsequent LV remodeling in patients with ACS. Although there was no direct relationship between EAT volume and LVEF change, patients who developed HFrEF had a higher EAT volume, which was more obvious in non-obese patients.
4.1 EAT Plays Divergent Roles in Patients with ACS and HF
Previous studies have analyzed the mechanisms through which the EAT affects post-infarct cardiac remodeling 15 , 16) . However, few studies have investigated the association between the EAT volume and LVEF in patients with ACS.
Patients with an increased EAT are at higher risk of developing HFpEF. This is thought to involve inflammatory cytokines secreted from the EAT, which cause inflammation in the myocardium. The EAT volume is increased in patients with HFpEF in comparison to controls, and is related to inflammatory markers, even in patients with similar BMI values 17) . This inflammation induces myocardial fibrosis and remodeling and contributes to the progression of heart failure 18) . However, in patients with severe HF, EAT may decrease because of systemic malnutrition or cachexia 19) . According to Tromp et al., patients with HFrEF have reduced EAT thickness and volume, which may reflect EAT depletion owing to increased myocardial energy demand 20) .
In patients with HFpEF, a positive correlation between increased EAT volume and right-sided ventricular constrictive pattern on echocardiography was observed, supporting the hypothesis that EAT has mechanical constrictive effects on myocardial distensibility 21) . In our study, patients with a higher EAT volume during the acute phase of ACS were more likely to develop HFrEF in the chronic phase. Some studies have shown an association between decreased EAT volume and improved LVEF in patients with HF 22) . These findings suggest that the role of the EAT may differ between patients with ACS and those with HF. The types of adipocytokines secreted by the EAT may also vary.
However, the potential role of EAT in HFrEF remains unclear. Wu et al. reported that the EAT volume was higher in patients with HFpEF than in those with HFrEF or controls 23) . Pugliese et al. reported that the EAT mass and thickness were significantly decreased in patients with HFrEF relative to both healthy controls and those with HFpEF 24) . In their study, a reduced EAT volume in patients with HFrEF was associated with a worse cardiac function and adverse myocardial remodeling, in contrast to our findings. Another study reported that although the EAT mass is increased in patients with HFrEF, the EAT mass/LV mass ratio was reduced, and the right ventricular EAT thickness was lower than that in healthy controls and patients with HFpEF 25) . EAT may exert a different pathophysiological effect on HF in relation to the EF status.
The inflammatory response following myocardial infarction (MI) is common and associated with ischemia-reperfusion injury, adverse cardiac remodeling, infarct size, and a poor prognosis. The EAT functions as an endocrine organ by secreting adipocytokines that influence the myocardium and cardiovascular system. These effects occur primarily through paracrine signaling rather than through systemic action 26) . Major cytokines, such as IL-6, IL-1, and TNF-α, facilitate the MI-induced inflammatory response that could lead to adverse LV remodeling after MI 27 - 30) . Parisi et al. observed EAT remodeling three months after STEMI. In some patients, the EAT thickness increased, whereas it decreased in others. An increase in EAT volume was related to intensified myocardial remodeling and a lower LVEF. Simultaneously, circulating levels of IL-13, an anti-inflammatory cytokine involved in cardiac regeneration, decreased 3 months after STEMI and were negatively associated with the increase in EAT thickness. Furthermore, increased IL-13 levels are associated with preservation of the LVEF after STEMI 31) .
Adiponectin and omentin-1 are cardioprotective anti-inflammatory adipokines. Adiponectin levels are associated with a decrease in the severity of cardiac damage and improvement in the cardiac function after reperfusion therapy in patients with MI 32) . Increased omentin-1 levels are associated with an improved cardiac function and prevention of myocardial ischemic injury after MI 33) . The secretion of these adipocytokines is influenced by the degree of ischemia, BMI, and insulin resistance 34 - 36) .
As the levels of released adipocytokines differ among patients depending on the presence of obesity or the degree of cardiac ischemia, the association between the EAT volume and LV remodeling may not be consistent. Further research is needed to determine whether the increase in EAT in patients with HFrEF after ACS is a direct cause or consequence of the condition.
4.2. Effect of EAT Volume on LV Remodeling after ACS in Non-Obese Patients
In this study, some non-obese patients with an increased EAT volume showed a decreased LVEF during the chronic phase. Conversely, non-obese patients with HFrEF and low EAT volumes were expected to have an improved LVEF in the chronic phase ( Fig.2 ) . These findings suggest that non-obese patients with increased EAT volume may develop HFrEF during the chronic phase. Thus, EAT may promote the release of proinflammatory cytokines and adipokines, which can lead to myocardial dysfunction and impaired cardiac contractility. Hence, reduced EAT volume may contribute to favorable myocardial remodeling in patients with ACS. The secretion of adipocytokines is significantly influenced by obesity. Whether adipocytokines are detrimental or protective to the myocardium is not determined solely by the amount of EAT.
Asians have greater abdominal and visceral fat volumes and worse insulin resistance than Westerners, with similar BMI values 37 , 38) . Generally, the EAT volume tends to increase with BMI, but some non-obese individuals with ACS have been reported to have an increased EAT volume; these were mostly older patients with insulin resistance 39) . Chang et al. reported that the removal of the EAT improves the cardiac function after MI 40) , which is consistent with our findings.
4.3. Study Limitations
This study had some limitations. The study design was cross-sectional and the results did not imply causality. Additionally, the influence of medication effects on the EAT and LVEF remains unclear. Some reports suggest that sodium-glucose cotransporter 2 (SGLT-2) inhibitors reduce the EAT volume 41) . During the study period, SGLT-2 inhibitors were not commonly used in HF patients. Given its widespread use, our results may not be generalizable. Furthermore, the small number of cases, especially in the HFrEF group, limits the statistical power of the study.
The EAT volume was measured by a single investigator, so there is a possibility of measurement bias that could affect the results. Follow-up EAT volume measurements were not performed due to concerns about the issue of radiation exposure. However, Park et al. reported that the EAT volume increases by 1.9%±3.8% per year in parallel with BMI, and the ratio of triglycerides (TG) to high-density lipoprotein (HDL) cholesterol was proposed as a surrogate marker of insulin resistance 42) and glucose levels in Korean patients 43) . In our patients, the BMI and TG/HDL ratio remained unchanged over 3 years, which may suggest minimal changes in EAT volume. Another limitation was that the study population was limited to Japanese patients. In contrast to Western HF populations, most Asian patients with HF have normal body weight but higher rates of type 2 diabetes despite the lower prevalence of obesity 44) .
Additional robust evidence is necessary to evaluate whether the EAT volume affects the LVEF in patients with ACS. Further investigations should be conducted to explore its implications for clinical practice.
5. Conclusion
Although the EAT volume was not measured during follow-up, the EAT volume at the onset of ACS was not associated with changes in the LVEF over three years. However, patients with HFrEF in the chronic phase had an increased EAT volume despite not being obese. In Asian patients after ACS, EAT may contribute to the development of HFrEF, independent of its association with obesity.
Conflicts of Interest
The authors declare no conflicts of interest, and there are no relationships with industry or financial associations with respect to this manuscript.
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