Cardiac contractility modulation ameliorates myocardial metabolic remodeling in a rabbit model of chronic heart failure through activation of AMPK and PPAR-α pathway

Q: What are the key findings of this study?

Cardiac contractility modulation for 4 weeks significantly improved LVEF, increased myocardial ATP, and reduced glucose, free fatty acid, and lactate accumulation in rabbits with heart failure (p<0.05).

Q: What is the clinical evidence from this study?

Population: Chronic heart failure (pressure overload-induced via transverse aortic constriction in rabbits) (n=30). Intervention: Cardiac contractility modulation (CCM) vs. Untreated heart failure group (TAC without CCM) and sham thoracotomy control group. Primary outcome: Myocardial metabolic remodeling (myocardial ATP, glucose, FFA, lactic acid, and pyruvate levels; AMPK and PPAR-α pathway protein expression) and cardiac structure/function (LVEF, LVFS, LVESD, LVEDD, serum NT-proBNP) (p=<0.05).

Q: What does this research mean for the field?

Cardiac contractility modulation significantly improves cardiac function, enhances ATP production, and ameliorates myocardial metabolic remodeling in heart failure through activation of the AMPK and PPAR-α signaling pathways. Novelty: ClaimNovelty.INCREMENTAL. Consensus alignment: ConsensusAlignment.NEUTRAL.

Q: What question did this study set out to answer?

To determine whether cardiac contractility modulation therapy ameliorates myocardial metabolic remodeling in a rabbit model of chronic heart failure and to elucidate the underlying signaling pathways.

Feifei Zhang; Litian Liu; Yuetao Xie; Jiaqi Wang; Xuefeng Chen; Shihang Zheng; Yingxiao Li; Yi Dang

doi:10.1515/med-2022-0415

January 1, 2022Open MedicineOpen Access

Cardiac contractility modulation ameliorates myocardial metabolic remodeling in a rabbit model of chronic heart failure through activation of AMPK and PPAR-α pathway

View Full Paper

Ask AI

Bookmark

Share

Key result

Cardiac contractility modulation improves LVEF and myocardial energetics in preclinical heart failure.

P<0.05
n=30

Figures

Why the study?

Metabolic remodeling contributes to the pathological process of HF, prompting exploration of the effects of cardiac contractility modulation on myocardial metabolic remodeling.

Does cardiac contractility modulation ameliorate myocardial metabolic remodeling and improve cardiac structure and function via the AMPK and PPAR-α pathways in a rabbit model of chronic heart failure?

Key Points

To determine whether cardiac contractility modulation therapy ameliorates myocardial metabolic remodeling in a rabbit model of chronic heart failure and to elucidate the underlying signaling pathways.
Chronic heart failure was established in rabbits by pressure overload via transverse aortic constriction at 12 weeks, followed by cardiac contractility modulation therapy.
Cardiac structure and function were evaluated using echocardiography, serum BNP and NT-proBNP measurements, and histological analysis with hematoxylin and eosin and Masson's trichrome staining.
Myocardial glycogen and lipid accumulation were visualized with periodic acid-Schiff and Oil Red O staining, and levels of ATP, glucose, free fatty acids, lactic acid, pyruvate, and metabolic pathway proteins were quantified.
Cardiac contractility modulation significantly restored left ventricular end-systolic and end-diastolic dimensions, increased ejection fraction and fractional shortening, and improved serum NT-proBNP levels (P < 0.05 vs. untreated heart failure group).
Therapy reduced myocardial fibrosis, glycogen accumulation, and lipid droplets, while decreasing contents of free fatty acids, glucose, and lactic acid and raising pyruvate and ATP levels (P < 0.05 vs. heart failure group).
Treatment upregulated protein expression of PDH, CD36, CPT-1, ACADM, AMPK, PPAR-α, and PGC-1α, and downregulated PDK4, LDH, and ACC (P < 0.05 vs. heart failure group), correcting the uncoupling of glycolysis from glucose oxidation.

Structured PICO

Does cardiac contractility modulation ameliorate myocardial metabolic remodeling and improve cardiac structure and function via the AMPK and PPAR-α pathways in a rabbit model of chronic heart failure?

P

Population

30 six-month-old New Zealand white rabbits (28 surviving for final analysis: 10 sham, 9 untreated HF, 9 CCM-treated HF) with transverse aortic constriction-induced chronic heart failure (LVEF ≤40%), followed over a 16-week experiment.

I

Intervention

Cardiac contractility modulation (CCM) delivered via a pediatric temporary pacing lead stitched to the left ventricular anterior wall during the absolute refractory period (biphasic square wave pulses, phase duration 2 ms, stimulus amplitude 7 V, 30 ms delay after R-wave sensing) for 6 hours per day for 4 weeks.

C

Comparator

Untreated heart failure control group (received thoracotomy, TAC to 60% of original aortic circumference, and pacing lead placement without CCM stimulation, n=9) and sham group (received thoracotomy only, n=10).

O

Outcome

Myocardial metabolic remodeling (myocardial contents of ATP, glucose, free fatty acids, lactic acid, and pyruvate; glycogen and lipid droplet accumulation; protein expression of GLUT4, HK2, PFK6, PDH, PDK4, LDH, CD36, CPT-1, ACADM, ACC, AMPK, PPAR-α, and PGC-1α) and cardiac function/structure (LVESD, LVEDD, LVEF, LVFS, serum NT-proBNP, and collagen volume fraction) at 16 weeks (after 4 weeks of CCM therapy).surrogate

Main Result

p-value: p=<0.05

This preclinical study demonstrates that cardiac contractility modulation reverses myocardial metabolic remodeling and restores ATP production in chronic heart failure by activating the AMPK and PPAR-α signaling pathways, providing mechanistic insight into how CCM improves cardiac function without increasing oxygen consumption.

Implication

Hypothesis-generating for CCM in HF models; leaves open clinical translation pending human trials.

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.

Discussion

No takes yet. Share an insight, caveat, or question.

Cite This Study

Zhang et al. (2022) studied Chronic heart failure (pressure overload-induced via transverse aortic constriction in rabbits) (n=30). Cardiac contractility modulation (CCM) vs. Untreated heart failure group (TAC without CCM) and sham thoracotomy control group was evaluated on Myocardial metabolic remodeling (myocardial ATP, glucose, FFA, lactic acid, and pyruvate levels; AMPK and PPAR-α pathway protein expression) and cardiac structure/function (LVEF, LVFS, LVESD, LVEDD, serum NT-proBNP) (p=<0.05). Cardiac contractility modulation for 4 weeks significantly improved LVEF, increased myocardial ATP, and reduced glucose, free fatty acid, and lactate accumulation in rabbits with heart failure (p<0.05).

synapsesocial.com/papers/6a730ba6176483c18ef5c636 https://doi.org/10.1515/med-2022-0415

View Full Paper

Ask AI

Bookmark

Share

Cardiac contractility modulation ameliorates myocardial metabolic remodeling in a rabbit model of chronic heart failure through activation of AMPK and PPAR-α pathway

Figures

Key Points

Structured PICO

Main Result

Implication

Abstract

Discussion

Cite This Study

Cardiac contractility modulation ameliorates myocardial metabolic remodeling in a rabbit model of chronic heart failure through activation of AMPK and PPAR-α pathway

Figures

Key Points

Structured PICO

Main Result

Implication

Abstract

Discussion

Cite This Study

Keep reading

Keep reading