Summary: |
Heart failure with preserved ejection fraction (HFpEF) accounts for a rising proportion of over 50% of cases of heart failure, a leading cause of mortality, morbidity and health care resource consumption (2). ts prognosis remains ominous and t:herapy is mainly empirical,focusing on symptom relief (5). Furthermore, diagnostic guidelines and procedures are far from consensual and proper case detection is still hampered by heterogeneity in patient characteristics and diagnostic methodologies (6-7, 9). Complex cardiomyocyte remodelling mechanisms that disturb myofilament function, Ca2+ handling and bioenergetics in HFpEF lead to impaired relaxation and increased diastolic stiffness which may explain Jung congestion and dyspnoea during effort.
Exercise testing is, thus, frequently advocated to enhance diagnostic sensitivity (12), but it becomes impractical or impossible in a large number of suspected HFpEF patients, who are usually elderly and have extensive comorbidities (15). Though various mechanlsms have been evoked to justlfy exerclse lntolerance, one of the most llkely Is lmpalred response to myocardlal stretch (13). Research on contractile response to acute myocardial stretch is extensive and the molecular mechanisms underlying both Frank-Starling and Anrep responses have been well characterized (20). Surprisingly, and despite t:he potential molecular pathways shown to acutely modulate myocardial stiffness the issue remains unexplored. We have gathered preliminary data
that robustly support a strong effect of decreased myocardial stiffness (increased distensibility) induced by stretch within the physiological sarcomere lengths, which is accompanied by post-translational modifications of myofilaments and is amenable to pharmacological manipulation ex vivo by targeting cGMP-dependent pathways. This can be a vital adaptive mechanism to
increased venous return under physiological conditions, but,most importantly,since it may fail in the diseased myocardium,it |
Summary
Heart failure with preserved ejection fraction (HFpEF) accounts for a rising proportion of over 50% of cases of heart failure, a leading cause of mortality, morbidity and health care resource consumption (2). ts prognosis remains ominous and t:herapy is mainly empirical,focusing on symptom relief (5). Furthermore, diagnostic guidelines and procedures are far from consensual and proper case detection is still hampered by heterogeneity in patient characteristics and diagnostic methodologies (6-7, 9). Complex cardiomyocyte remodelling mechanisms that disturb myofilament function, Ca2+ handling and bioenergetics in HFpEF lead to impaired relaxation and increased diastolic stiffness which may explain Jung congestion and dyspnoea during effort.
Exercise testing is, thus, frequently advocated to enhance diagnostic sensitivity (12), but it becomes impractical or impossible in a large number of suspected HFpEF patients, who are usually elderly and have extensive comorbidities (15). Though various mechanlsms have been evoked to justlfy exerclse lntolerance, one of the most llkely Is lmpalred response to myocardlal stretch (13). Research on contractile response to acute myocardial stretch is extensive and the molecular mechanisms underlying both Frank-Starling and Anrep responses have been well characterized (20). Surprisingly, and despite t:he potential molecular pathways shown to acutely modulate myocardial stiffness the issue remains unexplored. We have gathered preliminary data
that robustly support a strong effect of decreased myocardial stiffness (increased distensibility) induced by stretch within the physiological sarcomere lengths, which is accompanied by post-translational modifications of myofilaments and is amenable to pharmacological manipulation ex vivo by targeting cGMP-dependent pathways. This can be a vital adaptive mechanism to
increased venous return under physiological conditions, but,most importantly,since it may fail in the diseased myocardium,it can also be a decisive pathophysiological contributor to effort intolerance in HFpEF and therefore potentially used as a low-cost and effective diagnostic toai. With the current project we aim to characterize the effect thoroughly in distinct animal species,
lncludlng a large animal model,and experimental setups, from the myofllament and cardlomyocyte level to the lntact organlsm, as well as its disturbances under pathologic conditions in models of hypertrophy and diastolic dysfunction and also in patients undergoing cardiac surgery. We will confirm the physiological effect in humans by gold standard invasive and non-invasive evaluation, and study myocardial samples after stretch in comparison to their non-stretched counterparts. Subgroups of patients with distinct degrees of diastolic function impairment, as well as contrai samples from healt:hy human myocardium will be compared. Changes in titin, the large myofilamentary protein that accounts for most of cardiomyocyte stiffness in the physiological sarcomere length, will be assessed as well the activity and role of kinases that acutely modulate it by
phosphorylation of specific residues, namely protein kinase G and Ca2+/calmodulin dependent kinase II. Findings will be translated to the clinics by assaying acute load-manipulations as manoeuvres to enhance HFpEF diagnosis and by conducting a pre-clinical triai with PKG pathway enhancer the soluble guanylate cyclase activator Riociguat in animal models of HFpEF and/or diastolic dysfunction. |