A Potential Biochemical Mechanism for Heart Failure with A Preserved Ejection Fraction
Introduction. Heart Failure with preserved ejection (HFpEF) is a type of heart failure that does not currently have a definitive mechanism due to multiple factors. It is fundamentally an issue with diastole, where the heart cannot fully relax. An average left ventricular ejection fraction (LVEF) ranges from 55% to 70%, but as long as LVEF is above 50%, the heart failure is considered HFpEF1, 2 .These patients often have other comorbidities and have vague symptoms. The vague symptoms of HFpEF are easily confused with other non-cardiac diseases. Only recently, confirmation of HFpEF with Doppler with E/e’ and biomarkers like p-BNP was discovered.2 Mechanism. Through inflammation, we get endothelial damage, which leads to cytokine infiltration3. An excessive inflammatory response may weaken of the infarcted myocardium. Elevated levels of endothelial adhesion molecules with increased inflammatory chemo/cytokines lead to endothelial dysfunction. These cytokines interfere with the healing process and encourage replacement with collagen fibers3, 4. Cardiac scar formation and altered paracrine communication between endothelial cells and surrounding cardiomyocytes deprive cardiomyocytes of nitric oxide (NO) and of cyclic guanosine monophosphate (cGMP), which renders them hypertrophied and stiff4, 5. This altered signaling interferes with cGMP activating PDE2. PDE2 hydrolyzes both cAMP and cGMP at a high Vmax and low Km. PDE2 mediates negative cross-talk between the cGMP and cAMP signaling pathways5, 6. Through PDE2 activation, cGMP is able to reduce the cAMP signal and affect cardiac function. In fact, PDE2 has been shown to regulate the L-type calcium channel in cardiac myocytes. L-type calcium channels are activated by β-adrenergic receptor-stimulated cAMP and cAMP-dependent protein kinase (PKA), exerting chronotropic and inotropic effects on the heart6, 7. Now with increased β-adrenergic receptor activation, we have decreased relaxation time and further the loss of diastolic function6. Results. This potential mechanism could be supported by cardiac contractility modulation (CCM). CCM allows the re-uptake of calcium that was not being performed by the body due to the lack of NO and cGMP in this tissue by augmenting extracellular calcium influx and calcium-induced calcium release from the SR8. Studies prove CCM efficacy and mechanism and support the proposed mechanism. Conclusion. HFpEF is a unique cardiac definition with an ill-defined mechanism in the scientific community; however, through current research, a mechanism can be constructed through the definitive mechanism of treatments, inflammation, and cardiac relaxation.
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