Valvular heart disease: the quest for new pharmacological targets

With thanks to Amelia Meier-Batschelet, Johanna Huggler, and Martin Meyer for help with compilation of this article. For the podcast associated with this article, please visit https://academic.oup.com/eurheartj/pages/Podcasts. This Focus Issue on valvular heart disease contains the State of the Art Review article entitled ‘Current recommendations and uncertainties for surgical treatment of infective endocarditis: a comparison of American and European cardiovascular guidelines’ by Andrew Wang from Duke University Hospital in Durham, NC, USA and Emil L. Fosbøl from the University Hospital of Copenhagen in Denmark.1 The authors note that surgery is an effective therapy in the treatment of left-sided infective endocarditis (IE) in patients for whom antibiotic treatment alone is unlikely to be curative or may be associated with ongoing risk of complications. However, the interplay between indication for surgery, its risk, and timing is complex and there continue to be challenges in defining the effects of surgery on disease-related outcome. Guidelines published by the American College of Cardiology/American Heart Association and the European Society of Cardiology provide recommendations for the use of surgery in IE, but these are limited by a low level of evidence, related to predominantly observational studies with inherent selection and survival biases. Evidence to guide the timing of surgery in IE is less robust, and predominantly based on expert consensus. Delays between IE diagnosis and recognition of an IE complication as a surgical indication and transfers to surgical centres also impact surgical timing. This comparison of the two guidelines exposes areas of uncertainty and gaps in current evidence for the use of surgery in IE across different indications, particularly related to its timing and consideration of operative risk. Randomized clinical trials demonstrated transcatheter edge-to-edge repair (TEER) efficacy in improving outcome vs. medical management for functional mitral regurgitation (MR), but limited randomized data are available for the treatment of degenerative MR (DMR).2,3 In a Clinical Research article entitled ‘Association of transcatheter edge-to-edge repair with improved survival in older patients with severe, symptomatic degenerative mitral regurgitation’, Giovanni Benfari from the Mayo Clinic in Rochester, MN, USA, and colleagues aimed to compare the outcome of older patients treated with TEER vs. unoperated DMR.4 Registries including consecutive patients ≥65 years old with symptomatic severe DMR treated with TEER (MitraSwiss and Minneapolis Heart Institute registries) or unoperated (MIDA registry) were analysed. Survival was compared overall and after matching for age, sex, EuroSCORE II, and ejection fraction. The study included 1187 patients. During 24 months of follow-up, 430 patients died. Patients undergoing TEER were of similar age and sex to unoperated patients, but had higher surgical risk/comorbidity, more symptoms, and atrial fibrillation (P < 0.0001). TEER was associated with lower mortality accounting for age, sex, EuroSCORE II, New York Heart Association class, atrial fibrillation, and ejection fraction [hazard ratio (HR) 0.47]. After propensity matching (247 pairs of patients), TEER consistently showed better survival compared with unoperated patients (P < 0.0001) even in comprehensive multivariable analysis (HR 0.60; P = 0.03). Procedural failure was infrequent, but post-procedural MR, remaining moderate to severe in 66 (7.6%) patients, was associated with excess mortality vs. trivial residual regurgitation (30 ± 6% vs. 11 ± 1% at 1 year, P < 0.0001) (Figure 1). Comparison of patients with degenerative mitral regurgitation treated with transcatheter edge-to-edge mitral valve repair vs. unoperated.4 The authors conclude that amongst older patients with severe symptomatic DMR at high surgical risk, mitral TEER is associated with higher survival vs. unoperated patients. Successful control of MR is key to survival improvement with mitral TEER, which should be actively considered in patients deemed inoperable. The contribution is accompanied by an Editorial by Bernard Iung and Marina Urena from the Bichat Hospital in Paris, France.5 The authors highlight that dedicated registries are useful to fill gaps in knowledge which will probably never be assessed by randomized trials but are relevant for clinical practice. Baseline renal dysfunction (RD) adversely impacts outcomes among patients with heart failure (HF) and severe secondary MR.6–9 HF and MR, in turn, accelerate progression to end-stage renal disease (ESRD), worsening prognosis. In a Clinical Research article entitled ‘Impact of baseline renal dysfunction on cardiac outcomes and end-stage renal disease in heart failure patients with mitral regurgitation: the COAPT trial’, Nirat Beohar from the Columbia University Division of Cardiology at Mount Sinai Medical Center in Miami Beach, FL, USA, and colleagues sought to determine the impact of RD in HF patients with severe MR and the impact of TEER on new-onset ESRD and the need for renal replacement therapy (RRT).10 The COAPT trial randomized 614 patients with HF and severe MR to MitraClip plus guideline-directed medical therapy (GDMT) vs. GDMT alone. Patients were stratified into three RD subgroups based on baseline estimated glomerular filtration rate (eGFR). ESRD was defined as eGFR <15 mL/min/1.73 m2 or RRT. The authors assessed 2-year rates of all-cause death, HF hospitalization (HFH), new-onset ESRD, or RRT according to baseline RD and treatment. Baseline RD was present in 77% of patients. Worse RD was associated with greater 2-year risk of death or HFH (P < 0.0001). MitraClip vs. GDMT alone improved outcomes regardless of baseline RD (Pinteraction = 0.62) and reduced new-onset ESRD (HR 0.34, P = 0.008) and the need for new RRT (HR 0.33, 95%, P = 0.011). The authors conclude that baseline RD is common in HF patients with severe MR enrolled in COAPT and strongly predicts 2-year death and HFH. MitraClip treatment reduces new-onset ESRD and the need for RRT, contributing to the improved prognosis after TEER. The contribution is accompanied by an Editorial by Volker Rudolph from the Ruhr-Universität Bochum in Bad Oeynhausen, Germany.11 Rudolph concludes that several consequences for daily clinical practice should be derived from the study of Beohar et al.: in light of the high prevalence of overall and severe RD, clinicians and interventionalists treating patients suffering from secondary MR need to realize that they are dealing with complex and very sick patients, in which ‘isolated’ treatment of MR will fail to be beneficial, if HF is not appropriately addressed and comorbidities are disregarded. This starts with being mindful about the indication for TEER, where RD and its expected course is an important consideration in the evaluation of advanced HF therapies such as continuous mechanical support or transplantation. It also pertains to the need for a continuous follow-up of these patients in the HF clinic with regular monitoring of renal function, not only to prevent deterioration of renal function but potentially also to seize the chance of using TEER as a strategy to maintain or even extend GDMT. Proposed mechanisms of valvular endothelial cell (VEC)-derived tetrahydrobiopterin (BH4) in aortic valve calcification. Decreased BH4 levels lead to peroxynitrite production by VECs. Peroxynitrite promotes dynamin-related protein 1 tyrosine nitration at Y628 in valvular interstitial cells (VICs), which subsequently results in VIC osteogenic differentiation and valvular calcification.12 Tetrahydrobiopterin (BH4) is a critical determinant of the biological function of endothelial nitric oxide synthase. In a Translational Research article entitled ‘Endothelial cell-derived tetrahydrobiopterin prevents aortic valve calcification’, Zongtao Liu from the Huazhong University of Science and Technology in Hubei, China, and colleagues investigate the role of valvular endothelial cell (VEC)-derived BH4 in aortic valve calcification.12 Plasma and aortic valve BH4 concentrations and the BH4:BH2 ratio were significantly lower in calcific aortic valve disease patients than in controls. There was a significant decrease of the two key enzymes of BH4 biosynthesis, guanosine 5′-triphosphate cyclohydrolase I (GCH1) and dihydrofolate reductase, in calcified aortic valves compared with normal valves. Endothelial cell-specific deficiency of Gch1 in Apoe−/− (Apoe−/−Gch1fl/flTie2Cre) mice showed a marked increase in transvalvular peak jet velocity and calcium deposition in aortic valve leaflets compared with Apoe−/−Gch1fl/fl mice after a 24-week western diet challenge. Oxidized LDL (ox-LDL) induced osteoblastic differentiation of valvular interstitial cells (VICs) co-cultured with si-Gch1-transfected VECs, while the effects could be abolished by BH4 supplementation. Deficiency of BH4 in VECs caused an increase in peroxynitrite formation. Folic acid significantly attenuated aortic valve calcification in western diet-fed Apoe−/− mice through salvaging of BH4 biosynthesis. Liu and colleagues conclude that the reduction in endothelial-dependent BH4 levels promotes peroxynitrite formation, which subsequently results in osteoblastic differentiation of VICs, thereby leading to aortic valve calcification. Supplementation of folic acid in the diet attenuates hypercholesterolaemia-induced aortic valve calcification by salvaging BH4 bioavailability. This manuscript is accompanied by an Editorial by Alexander Akhmedov and Simon Kraler from the University of Zurich in Switzerland, and Vidu Garg from the Nationwide Children’s Hospital in Columbus, OH, USA.13 The authors conclude that advances in our mechanistic understanding of calcific aortic valve disease (CAVD) pathogenesis such as those on BH4 reported by Liu and colleagues may set the stage for innovative clinical trials targeting mediators beyond those tested in previous studies and thus may provide novel therapeutic opportunities to eventually treat CAVD by non-interventional means. Results of currently ongoing randomized controlled trials are eagerly awaited, as such studies broaden our understanding of the valvular NO· signalling pathway at large while providing translational evidence on whether interfering with this pathway may prove effective to slow CAVD progression. Mitral valve prolapse (MVP) is a common valvular heart disease with a prevalence of >2% in the general adult population. Despite this high incidence, there is a limited understanding of the molecular mechanism of this disease, and no medical therapy is available. In another Translational Research article entitled ‘Genome-wide association study reveals novel genetic loci: a new polygenic risk score for mitral valve prolapse’, Carolina Roselli from the Broad Institute of the MIT and Harvard University in Cambridge, MA, USA, and colleagues aimed to elucidate the genetic basis of MVP.14 They performed a meta-analysis of six genome-wide association studies that included 4884 cases and 434 649 controls. They identified 14 loci associated with MVP in their primary analysis and two additional loci associated with a subset of the samples that additionally underwent mitral valve surgery. Integration of epigenetic, transcriptional, and proteomic data identified candidate MVP genes. The authors created a polygenic risk score for MVP and showed an improved MVP risk prediction beyond age, sex, and clinical risk factors. Roselli and colleagues conclude that they identified 14 genetic loci that are associated with MVP. Multiple analyses identified candidate genes including two transforming growth factor-β signalling molecules and spectrin β. They present the first polygenic risk score for MVP that could eventually aid risk stratification of patients for MVP screening in a clinical setting. The contribution is accompanied by an Editorial by Teresa Trenkwalder from the Technical University Munich in Germany and Markus Krane from the Yale University School of Medicine in New Haven, CT, USA.15 The authors conclude that the current study by Roselli and colleagues adds an important piece of evidence to the multifactorial heritability of MVP and provides a deeper understanding of the signalling pathways involved. Hopefully, this will also increase the awareness of a positive family history for patients with MVP and their relatives in clinical practice, and eventually encourages us to carefully dissect this common phenotype into clinically distinct subgroups in the future. The editors hope that this issue of the European Heart Journal will be of interest to its readers.