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Benefits of Cardiac Resynchronization Therapy in an Asynchronous Heart Failure Model Induced by Left Bundle Branch Ablation and Rapid Pacing
Published on: December 11, 2017
HDAC-dependent ventricular remodeling
1Department of Internal Medicine (Cardiology), University of Texas Southwestern Medical Center, Dallas, TX 75390-8573, USA.
Insights
Histone deacetylase (HDAC) inhibitors show promise in treating heart failure by reducing cardiac remodeling and cell death. These therapies may offer new hope for patients with heart failure.
Area of Science:
- Cardiovascular Biology
- Molecular Medicine
- Epigenetics
Background:
- Heart failure is a prevalent condition with high morbidity and mortality, despite current therapies.
- Pathological cardiac remodeling, driven by stress, leads to myocardial injury and heart failure.
- Reversible protein acetylation, regulated by histone acetyltransferases (HATs) and histone deacetylases (HDACs), plays a key role in biological processes, including cardiac remodeling.
Purpose of the Study:
- To investigate the therapeutic potential of HDAC inhibitors in mitigating pathological cardiac remodeling and preventing heart failure.
- To elucidate the mechanisms by which HDAC inhibitors affect cardiac stress responses.
Main Methods:
- Utilized models of pressure overload and ischemia/reperfusion to induce pathological cardiac remodeling.
- Administered HDAC inhibitors to assess their impact on cardiac structure and function.
- Examined molecular mechanisms including cardiomyocyte death, hypertrophy, and ventricular fibrosis.
Main Results:
- HDAC inhibitors effectively blunted pathological cardiac remodeling in response to pressure overload and ischemia/reperfusion.
- HDAC inhibition reduced stress-induced cardiomyocyte death, hypertrophy, and ventricular fibrosis.
- These effects collectively diminish the emergence and progression of heart failure.
Conclusions:
- HDAC inhibitors represent a promising novel therapeutic strategy for heart failure.
- Targeting HDACs may arrest the adverse consequences of pathological cardiac stress.
- This approach holds potential clinical benefit for millions of heart failure patients.
Abstract:
Heart failure, a syndrome culminating the pathogenesis of many forms of heart disease, is highly prevalent and projected to be increasingly so for years to come. Major efforts are directed at identifying the means of preventing, slowing, or possibly reversing the unremitting progression of pathological stress leading to myocardial injury and ultimately heart failure. Indeed, despite widespread use of evidence-based therapies, heart failure morbidity and mortality remain high. Recent work has uncovered a fundamental role of reversible protein acetylation in the regulation of many biological processes, including pathological remodeling of the heart. This reversible acetylation is governed by enzymes that attach (histone acetyltransferases, HATs) or remove (histone deacetylases, HDACs) acetyl groups. In the latter case, small molecule inhibitors of HDACs are currently being tested for a variety of oncological indications. Now, evidence has revealed that HDAC inhibitors blunt pathological cardiac remodeling in the settings of pressure overload and ischemia/reperfusion, thereby diminishing the emergence of heart failure. Mechanistically, HDAC inhibitors reduce stress-induced cardiomyocyte death, hypertrophy, and ventricular fibrosis. Looking to the future, HDAC inhibitor therapy may emerge as a novel means of arresting the untoward consequences of pathological cardiac stress, conferring clinical benefit to millions of patients with heart failure.
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