Plasma Free Fatty Acid Is Associated with Ischemic Cardiomyopathy and Cardiac Dysfunction Severity in Systolic Heart Failure Patients with Diabetes

Plasma Free Fatty Acid Is Associated with Ischemic Cardiomyopathy and Cardiac Dysfunction Severity in Systolic Heart Failure Patients with Diabetes

Heart failure (HF) is a significant global health issue, contributing to substantial morbidity and mortality among patients with cardiovascular diseases. The PARADIGM-HF trial highlighted that ischemic heart disease is the most common cause of HF, particularly in cases of HF with reduced ejection fraction (HFrEF), accounting for 60% of such cases. Despite this, there is an urgent need for effective predictors to identify ischemic cardiomyopathy (ICM) in HF patients.

Diabetes mellitus (DM) is prevalent in over 40% of HF patients, and cardiac events are more frequent in these individuals. Recent studies have shown that plasma free fatty acid (FFA) levels are elevated in DM patients and are associated with HF and cardiovascular mortality. However, the relationship between FFA and ICM, as well as cardiac dysfunction severity in systolic HF patients with DM, remains unclear. This study aimed to investigate the role of plasma FFA in these patients and its effects on ICM and cardiac dysfunction severity.

The study retrospectively analyzed data from 229 HF patients with type 2 DM treated at the Department of Cardiology of Ruijin Hospital from January 2016 to June 2019. After data screening, 155 HF patients with DM were included in the final analysis. Additionally, a subgroup of 100 HFrEF patients (EF <40%) was selected to confirm the association of FFA with ICM and cardiac dysfunction severity. The study was approved by the Institutional Review Board of Ruijin Hospital, and all procedures followed the Helsinki Declaration of 1975. Informed consent was obtained from all participants.

HF patients enrolled in the study had symptoms and signs of HF for at least three months or had been hospitalized for HF at least once. Patients were confirmed to have elevated levels of N-terminal pro-brain natriuretic peptide (NT-proBNP), echocardiographic anomalies, reduced left ventricular ejection fraction (LVEF <50%), and left atrial enlargement or left ventricular hypertrophy. Type 2 DM was diagnosed based on fasting plasma glucose levels (≥7.0 mmol/L), 2-hour postprandial blood glucose (≥11.1 mmol/L), and the use of antidiabetic drugs. ICM was identified in patients with previously documented myocardial infarction, confirmed by imaging studies showing coronary artery disease with corresponding areas of akinesis, dyskinesis, or severe hypokinesis on maximal appropriate medical therapy and a confirmed decreased ejection fraction (<50%). Patients with primary valvular heart disease, known malignant tumors, acute infections, acute coronary syndrome, or LVEF ≥50% were excluded.

Statistical analyses were performed using Stata 15.0. Multivariate logistic regression and linear regression analysis were used to evaluate the predictive value of FFA for ICM, LVEF <35%, and NT-proBNP among HF patients with DM. Results were adjusted for confounding factors, and statistical significance was defined as P < 0.05.

The study divided patients into three tertiles based on FFA levels: low FFA (≤0.46 mmol/L, First tertile, T1), median FFA (0.46–0.69 mmol/L, Second tertile, T2), and high FFA (≥0.69 mmol/L, Third tertile, T3). The level of NT-proBNP was significantly higher in the higher FFA group compared to the lower group (T1: 1700 pg/mL vs. T2: 1506 pg/mL vs. T3: 2144 pg/mL, Z = 3.151, P = 0.036). However, the percentages of coronary artery disease (T1: 76.5% vs. T2: 60.8% vs. T3: 43.4%, x² = 11.866, P = 0.003) and ICM (T1: 64.7% vs. T2: 51.0% vs. T3: 34.0%, x² = 9.878, P = 0.007) were significantly higher in the lower FFA group compared to the higher FFA group.

Univariate logistic regression analysis showed that FFA was negatively associated with ICM in systolic HF patients with DM (OR = 0.133; 95% CI: 0.032–0.559; P = 0.006) and HFrEF patients with DM (OR = 0.162; 95% CI: 0.031–0.852; P = 0.032). This negative association remained significant in multivariate logistic regression analysis after adjusting for relevant confounders (OR = 0.145; 95% CI: 0.026–0.817; P = 0.029). The results were confirmed by dividing FFA into three tertiles, showing that patients in the second FFA tertile had a greater risk of ICM than those in the third FFA tertile, both in systolic HF patients with DM (OR = 2.939; 95% CI: 1.036–8.336; P = 0.043) and HFrEF patients with DM (OR = 4.466; 95% CI: 1.038–19.224; P = 0.044). The difference was more pronounced in the first FFA tertile in systolic HF patients with DM (OR = 3.093; 95% CI: 1.109–8.630; P = 0.031).

The FFA level was significantly higher in the LVEF <35% group compared to the LVEF ≥35% group (0.654 ± 0.302 vs. 0.532 ± 0.183 mmol/L, P = 0.002). Multivariate logistic regression analysis showed that FFA is an independent risk factor for LVEF <35% in systolic HF patients with DM (OR = 5.248, 95% CI: 1.088–31.932; P = 0.046) and HFrEF patients with DM (OR = 9.687; 95% CI: 1.109–84.615; P = 0.040). The results by dividing FFA into three tertiles showed that patients in the second FFA tertile had less risk of LVEF <35% than those in the third FFA tertile in systolic HF patients with DM (OR = 0.201; 95% CI: 0.074–0.548; P = 0.002) and HFrEF patients with DM (OR = 0.085; 95% CI: 0.018–0.404; P = 0.002). The difference was also observed in the first FFA tertile in systolic HF patients with DM (OR = 0.408; 95% CI: 0.154–1.081; P = 0.071) and HFrEF patients with DM (OR = 0.179; 95% CI: 0.039–0.833; P = 0.028).

Multivariate linear regression analyses showed that FFA is an independent risk factor for NT-proBNP in systolic HF patients with DM (b = 3781.27, P = 0.078) and HFrEF patients with DM (b = 7837.637, P = 0.008). Additionally, patients in the second FFA tertile had less risk of high NT-proBNP than those in the third FFA tertile in systolic HF patients with DM (b = -3022.741, P = 0.022). The difference was also observed in the first FFA tertile in systolic HF patients with DM (b = -3598.513, P = 0.007) and HFrEF patients with DM (b = -6108.677, P = 0.003).

FFA provides a significant portion of the adenosine triphosphate (ATP) consumed during cardiac contraction. Recent studies have identified FFA as a risk factor for major adverse cardiovascular events in acute coronary syndrome patients with DM. However, this study found that FFA is negatively associated with ICM in HF patients with DM. This discrepancy may be due to differences in the study population, as all subjects were HF patients with DM, who already had higher FFA levels than those without HF. Thus, FFA levels in DM patients with ICM were higher than in those without HF but lower than in DM patients without ICM.

The study demonstrated that FFA is an independent risk factor for cardiac dysfunction severity in systolic HF patients with DM. This aligns with previous studies, suggesting that accumulated FFA enhances lipid accumulation and lipotoxicity in cardiomyocytes, leading to cardiomyocyte apoptosis and contractile dysfunction. Additionally, switching myocardial fuel utilization to fatty acid oxidation is one mechanism by which empagliflozin protects left ventricular systolic function, indicating that enhancing FFA use may be a promising approach to reduce adverse left ventricular remodeling in HF patients with DM.

In conclusion, this study provides evidence that plasma FFA is negatively associated with ICM in HF patients with DM. Furthermore, plasma FFA is an independent risk factor for cardiac dysfunction severity in systolic HF patients with DM and HFrEF patients with DM.

doi.org/10.1097/CM9.0000000000001167

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