Transcatheter aortic valve replacement is now indicated across all risk categories of patients with symptomatic severe aortic stenosis and has been proposed as first line option for the majority of patients >74 years old. However, median age of patients enrolled in the transcatheter aortic valve replacement low-risk trials is 74 years and transcatheter aortic valve replacement has never been systematically investigated in young low risk patients. Although the long-term data in surgical aortic valve replacement in young patients (age <75) are well known, such data remain lacking in transcatheter aortic valve replacement. In the absence of clear guideline recommendations in patients with challenging anatomies (eg, hostile calcium, bicuspid), it is important to know the potential advantages and disadvantages of each treatment and to consider how they might integrate with each other in the lifetime management of such patients. In this review, we discuss current outstanding issues on the management of severe aortic stenosis from a lifetime management perspective, particularly in terms of initial intervention and future reinterventions.

Aims: The impact of sexuality in patients with significant tricuspid regurgitation (TR) undergoing transcatheter tricuspid valve intervention (TTVI) is unknown. The aim of this study was to investigate sex-specific outcomes in patients with significant TR treated with TTVI vs. medical therapy alone.Methods and results: The Transcatheter Tricuspid Valve Therapies (TriValve) registry collected data on patients with significant TR from 24 centres who underwent TTVI from 2016 to 2021. A control cohort was formed by medically managed patients with ≥severe isolated TR diagnosed in 2015–18. The primary endpoint was freedom from all-cause mortality. Secondary endpoints were heart failure (HF) hospitalization, New York Heart Association (NYHA) functional status, and TR severity. One-year outcomes were assessed for the TriValve cohort and compared with the control cohort with the inverse probability of treatment weighting (IPTW). A total of 556 and 2072 patients were included from the TriValve and control groups, respectively. After TTVI, there was no difference between women and men in 1-year freedom from all-cause mortality 80.9% vs. 77.9%, P = 0.56, nor in HF hospitalization (P = 0.36), NYHA Functional Classes III and IV (P = 0.17), and TR severity >2+ at last follow-up (P = 0.42). Multivariable Cox-regression weighted by IPTW showed improved 1-year survival after TTVI compared with medical therapy alone in both women (adjusted hazard ratio 0.45, 95% confidence interval 0.23–0.83, P = 0.01) and men (adjusted hazard ratio 0.42, 95% confidence interval 0.18–0.89, P = 0.03).Conclusion: After TTVI in high-risk patients, there were no sex-related differences in terms of survival, HF hospitalization, functional status, and TR reduction up to 1 year. The IPTW analysis shows a survival benefit of TTVI over medical therapy alone in both women and men.

Mitral transcatheter therapies represent the treatment of choice for all patients deemed unsuitable for cardiac surgery. So far, the largest clinical experience has been limited to percutaneous repair techniques. However, given the complexity and heterogeneity of mitral valve anatomy and pathology, transcatheter mitral valve implantation will widen the mitral valve therapies horizon, toward a patient-tailored approach. Current data about transcatheter mitral valve implantation is still limited and, although some data are promising, there are still some issues to be addressed. This review provides a comprehensive insight into the available devices and describes potential advantages and limitations of transcatheter mitral valve implantation.

Methylation of non-histone proteins is emerging as a central regulatory mechanism in health and disease. The methyltransferase SETD7 has shown to methylate and alter the function of a variety of proteins in vitro; however, its function in the heart is poorly understood. The present study investigates the role of SETD7 in myocardial ischaemic injury. Experiments were performed in neonatal rat ventricular myocytes (NRVMs), SETD7 knockout mice (SETD7^−/−) undergoing myocardial ischaemia/reperfusion (I/R) injury, left ventricular (LV) myocardial samples from patients with ischaemic cardiomyopathy (ICM), and peripheral blood mononuclear cells (PBMCs) from patients with ST-elevation MI (STEMI). We show that SETD7 is activated upon energy deprivation in cultured NRVMs and methylates the Hippo pathway effector YAP, leading to its cytosolic retention and impaired transcription of antioxidant genes manganese superoxide dismutase (MnSOD) and catalase (CAT). Such impairment of antioxidant defence was associated with mitochondrial reactive oxygen species (mtROS), organelle swelling, and apoptosis. Selective pharmacological inhibition of SETD7 by (R)-PFI-2 restored YAP nuclear localization, thus preventing mtROS, mitochondrial damage, and apoptosis in NRVMs. In mice, genetic deletion of SETD7 attenuated myocardial I/R injury, mtROS, and LV dysfunction by restoring YAP-dependent transcription of MnSOD and CAT. Moreover, in cardiomyocytes isolated from I/R mice and ICM patients, (R)-PFI-2 prevented mtROS accumulation, while improving Ca²⁺-activated tension. Finally, SETD7 was up-regulated in PBMCs from STEMI patients and negatively correlated with MnSOD and CAT. We show a methylation-dependent checkpoint regulating oxidative stress during myocardial ischaemia. SETD7 inhibition may represent a valid therapeutic strategy in this setting. Schematic summarizing the main study findings. Myocardial ischaemia favours SETD7-dependent methylation of YAP, leading to its cytosolic retention and reduced transcription of antioxidant genes MnSOD and CAT. The reduction of antioxidant defence precipitates myocardial injury and cardiomyocyte dysfunction. In contrast, SETD7 inhibition prevents YAP methylation, thus promoting its nuclear localization and binding to the promoter of antioxidant genes. These events lead to the restoration of antioxidant defence with subsequent cardiac protection. MnSOD, manganese superoxide dismutase; CAT, catalase.