Challenges and opportunities in improving left ventricular remodelling and clinical outcome following surgical and trans-catheter aortic valve replacement

Over the last half century,surgical aortic valve replacement(SAVR)has evolved to offer a durable and efficient valve haemodynamically,with low procedural complications that allows favourable remodelling of left ventricular(LV)structure and function.The latter has become more challenging among elderly patients,particularly following trans-catheter aortic valve implantation(TAVI).Precise understanding of myocardial adaptation to pressure and volume overloading and its responses to valve surgery requires comprehensive assessments from aortic valve energy loss,valvular-vascular impedance to myocardial activation,force-velocity relationship,and myocardial strain.LV hypertrophy and myocardial fibrosis remains as the structural and morphological focus in this endeavour.Early intervention in asymptomatic aortic stenosis or regurgitation along with individualised management of hypertension and atrial fibrillation is likely to improve patient outcome.Physiological pacing via the His-Purkinje system for conduction abnormalities,further reduction in para-valvular aortic regurgitation along with therapy of angiotensin receptor blockade will improve patient outcome by facilitating hypertrophy regression,LV coordinate contraction,and global vascular function.TAVI leaflet thromboses require anticoagulation while impaired access to coronary ostia risks future TAVI-in-TAVI or coronary interventions.Until comparable long-term durability and the resolution of TAVI related complications become available,SAVR remains the first choice for lower risk younger patients.

SIRT3-mediated inhibition of FOS through histone H3 deacetylation prevents cardiac fibrosis and inflammation

Sirtuin 3(SIRT3)is a deacetylase that modulates proteins that control metabolism and protects against oxidative stress.Modulation of SIRT3 activity has been proposed as a promising therapeutic target for ameliorating metabolic diseases and associated cardiac disturbances.In this study,we investigated the role of SIRT3 in inflammation and fibrosis in the heart using male mice with constitutive and systemic deletion of SIRT3 and human cardiac AC16 cells.SIRT3 knockout mice showed cardiac fibrosis and inflammation that was characterized by augmented transcriptional activity of AP-1.Consistent with this,SIRT3 overexpression in human and neonatal rat cardiomyocytes partially prevented the inflammatory and profibrotic response induced by TNF-α.Notably,these effects were associated with a decrease in the mRNA and protein levels of FOS and the DNA-binding activity of AP-1.Finally,we demonstrated that SIRT3 inhibits FOS transcription through specific histone H3 lysine K27 deacetylation at its promoter.These findings highlight an important function of SIRT3 in mediating the often intricate profibrotic and proinflammatory responses of cardiac cells through the modulation of the FOS/AP-1 pathway.Since fibrosis and inflammation are crucial in the progression of cardiac hypertrophy,heart failure,and diabetic cardiomyopathy,our results point to SIRT3 as a potential target for treating these diseases.