Heart failure (HF) is a complex condition categorized by left ventricular ejection fraction (EF) into two main types: heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF). While HFrEF and HFpEF share clinical similarities, their underlying mechanisms often differ significantly. Understanding both the shared and distinct pathophysiological features is crucial for enhancing our knowledge of HF and developing targeted therapies for each subtype. This study provides a detailed comparison of Comparative Model Features in two novel murine models of non-ischemic HFrEF and cardiometabolic HFpEF, examining myocardial structure, left ventricular function, gene expression, cardiomyocyte calcium handling, mitochondrial polarization, and protein acetylation.
Myocardial Structural Remodeling
Our research revealed that under similar hemodynamic stress, the HFrEF myocardium exhibited more pronounced hypertrophic and fibrotic remodeling compared to HFpEF. This suggests that the structural changes in the heart muscle are more severe in HFrEF models, potentially contributing to the reduced ejection fraction characteristic of this condition. The comparative model features highlight a key difference in how these two types of heart failure affect the physical structure of the heart.
Inflammatory Response
In contrast to the structural remodeling, inflammation appeared to be more significant in the HFpEF myocardium. This finding underscores the role of inflammation in the pathophysiology of HFpEF, which is increasingly recognized as a key driver in this phenotype. The comparative model features indicate that while both conditions involve myocardial stress, the nature of the biological response differs, with inflammation playing a more dominant role in HFpEF in this comparative setting.
Cardiomyocyte Calcium Handling
Distinct differences were also observed in cardiomyocyte calcium handling between the two models. Calcium release was diminished in HFrEF cardiomyocytes, whereas it was enhanced in HFpEF cardiomyocytes. This divergence in calcium handling, a critical aspect of cardiac muscle contraction, points to fundamentally different cellular mechanisms at play in HFrEF and HFpEF. These comparative model features related to calcium dynamics are vital for understanding contractile dysfunction in each condition.
Mitochondrial Polarization
Mitochondrial function, assessed by polarization, was found to be similarly impaired in both HFrEF and HFpEF cardiomyocytes. This shared feature suggests that metabolic dysfunction, reflected in reduced mitochondrial polarization, is a common characteristic in both types of heart failure, potentially contributing to the overall energy deficit in failing hearts. Despite other differences, these comparative model features indicate a convergence on mitochondrial impairment.
Protein Acetylation
Hyperacetylation of cardiac proteins was observed in both models, indicating a common post-translational modification in heart failure. However, this hyperacetylation was more pronounced in the HFpEF heart. Protein acetylation, a process that can alter protein function, appears to be a significant factor in both HF subtypes, but its degree of impact may vary, as revealed by these comparative model features.
Distinct Phenotypes and Triggering Mechanisms
Despite the shared features like mitochondrial impairment and protein hyperacetylation, the study highlights unique triggering mechanisms for each HF subtype. Neurohormonal overactivation seems to be a primary driver in HFrEF, while inflammation appears to be more central to HFpEF. These distinct triggers likely determine the divergent phenotypes observed. Understanding these comparative model features related to initiating factors is crucial for developing targeted interventions.
Conclusion
This comparative study of murine models of HFrEF and HFpEF reveals both shared and divergent pathophysiological features. While both models exhibit mitochondrial dysfunction and protein hyperacetylation, they differ significantly in myocardial remodeling, inflammatory response, and cardiomyocyte calcium handling. The distinct triggering mechanisms – neurohormonal overactivation in HFrEF versus inflammation in HFpEF – underscore the need for further investigation into the specific pathways underlying each condition. Ultimately, these comparative model features emphasize the importance of developing phenotype-specific therapies for heart failure patients, rather than a one-size-fits-all approach. Further research into these differential mechanisms is essential to improve treatment strategies for both HFrEF and HFpEF.
