Abstract
Metabolic remodeling contributes to the pathological process of heart failure (HF). We explored the effects of cardiac contractility modulation (CCM) on myocardial metabolic remodeling in the rabbit model with HF. The HF in rabbit model was established by pressure uploading and then CCM was applied. We evaluated the cardiac structure and function by echocardiography, serum BNP level, and hematoxylin and eosin and Masson’s trichrome staining. We detected the accumulation of glycogen and lipid droplets in myocardial tissues by periodic acid-Schiff and Oil Red O staining. Then, we measured the contents of glucose, free fatty acid (FFA), lactic acid, pyruvate, and adenosine triphosphate (ATP) levels in myocardial tissues by corresponding kits and the expression levels of key factors related to myocardial substrate uptake and utilization by western blotting were analyzed. CCM significantly restored the cardiac structure and function in the rabbit model with HF. CCM therapy further decreased the accumulation of glycogen and lipid droplets. Furthermore, CCM reduced the contents of FFA, glucose, and lactic acid, and increased pyruvate and ATP levels in HF tissues. The protein expression levels related to myocardial substrate uptake and utilization were markedly improved with CCM treatment by further activating adenosine monophosphate-activated protein kinase and peroxisome proliferator-activated receptor-α signaling pathways.
Highlights
Heart failure (HF) is one of the leading causes of death worldwide and continues to increase in prevalence throughout the world
The morphological assessments by H and E and Masson’s staining revealed that contractility modulation (CCM) alleviated myocardial necrosis, infiltration of inflammatory cells and myocardial interstitial fibrosis, and restored the physiological arrangement of myocardial cells (Figure 2a–c). These findings suggest that CCM may potentially improve cardiac function and structure in patients with HF
CCM intervention further increased AMPK, peroxisome proliferator-activated receptor-α (PPAR-α), and PGC-1α expressions (Figure 6a and b). These results indicate that CCM could activate the AMPK and PPAR-α pathways and promote the expression of key factors related to myocardial substrate uptake and utilization
Summary
Heart failure (HF) is one of the leading causes of death worldwide and continues to increase in prevalence throughout the world. The drug therapies including, beta-blockers, reninangiotensin system inhibitor, mineralocorticoid receptor antagonists, ivabradine, sodium-glucose cotransporter 2 inhibitors, vericiguat, and device therapies, including cardiac resynchronization therapy, left bundle branch area pacing, and ventricular assist devices for HF, have made impressive progress in the last decade [1] Despite these therapeutic and technological advancements in managing the morbidity and mortality in HF patients, a considerable subset of patients are not eligible for either of these preestablished therapies, which often make the prognostic outcomes challenging for these patients [2]. Because of the loss of metabolic flexibility, the failing heart switches its energy metabolism and substrate utilization preferences from high-energy fatty acids to other alternative substrates, resulting in a significant lack of ATP production, prompting the
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