Understanding aortic stenosis: advances in the identification of actionable pharmacological targets

For the podcast associated with this article, please visit https://academic.oup.com/eurheartj/pages/Podcasts. This Focus Issue on valvular heart disease (VHD) contains the State of the Art Review article ‘Unmet needs in valvular heart disease’ by David Messika-Zeitoun from the University of Ottawa Heart Institute in Canada, and colleagues.1 The authors point out that VHD is the next epidemic in the cardiovascular field, affecting millions of people worldwide and having a major impact on healthcare systems.2 With ageing of the population, the incidence and prevalence of VHD will continue to increase. However, VHD has not received the attention it deserves from both the public and policymakers. Despite important advances in the pathophysiology, natural history, management, and treatment of VHD, including the development of transcatheter therapies, the condition remains underdiagnosed, identified late, and often undertreated with inequality in access to care and treatment options, and there is no medication that can prevent disease progression.3,4 The present review article discusses these gaps in the management of VHD and potential actions to undertake to improve the outcome of patients with VHD. There is a pandemic of physical inactivity that appears to parallel the widespread prevalence of cardiovascular disease (CVD). More than one in four adults fail to meet World Health Organization recommendations regarding aerobic physical activity (PA), i.e. 150–300 or 75–150 min/week of moderate or vigorous PA, respectively, or a combination thereof.5–8 Yet, regular PA and exercise can play an important role not only in primary cardiovascular prevention but also in secondary prevention. In a State of the Art Review article entitled ‘Exercise benefits in cardiovascular diseases: from mechanisms to clinical implementation’, Pedro Valenzuela from the University of Alcala in Madrid, Spain, and colleagues discuss some of the main cardiovascular effects of PA/exercise and the mechanisms involved.9 Regular PA and exercise can induce major beneficial effects in the context of both primary and secondary CVD prevention. Furthermore, the benefits of an active lifestyle are fundamentally dose dependent (with some evidence for PA benefits even above current WHO recommendations). Notably, there are numerous biological mechanisms supporting PA/exercise-induced cardiovascular benefits involving not only the heart tissue but also the metabolic and inflammatory milieu. Indeed, the recognition of the multisystem benefits of exercise can help to create a more holistic perspective in cardiovascular research as well as in patient care. The current evidence for safe implementation of PA and exercise in patients with CVD is also summarized. Conventional randomized controlled trials (RCTs) can be expensive, time intensive, and complex to conduct. In a State of the Art Review article entitled ‘Leveraging electronic health records to streamline the conduct of cardiovascular clinical trials’, Muhammad Shahzeb Khan from Duke University School of Medicine in Durham, NC, USA, and colleagues indicate that trial recruitment, participation, and data collection can burden participants and research personnel.10 In the past two decades, there have been rapid technological advances and an exponential growth in digitized healthcare data. Embedding RCTs, including cardiovascular outcome trials, into electronic health record systems or registries may streamline screening, consent, randomization, follow-up visits, and outcome adjudication.11–13 Moreover, wearable sensors (i.e. health and fitness trackers) provide an opportunity to collect data on cardiovascular health and risk factors in unprecedented detail and scale, while growing internet connectivity supports the collection of patient-reported outcomes. There is a pressing need to develop robust mechanisms that facilitate data capture from diverse databases and guidance to standardize data definitions. This review highlights recent progress towards the use of routinely generated data to conduct RCTs and discusses potential solutions for ongoing barriers. Adjustment variables included age, sex, race/ethnicity, diabetes, coronary artery disease, heart failure, chronic lung disease/chronic obstructive pulmonary disease, sodium, and estimated glomerular filtration rate. CKD, chronic kidney disease; HFH, heart failure hospitalization; HTN, hypertension; LFT, liver function test; LV, left ventricular; Mod, moderate; MR, mitral regurgitation; RDW, red cell distribution width; RV, right ventricular; TR, tricuspid regurgitation. *Primary TR as reference group.16 Severe tricuspid regurgitation (TR) exhibits high 1-year morbidity and mortality, yet long-term cardiovascular risk overall and by subgroups remains unknown.14,15 In a Clinical Research article entitled ‘Long-term outcomes of phenoclusters in severe tricuspid regurgitation’, Vishal Rao from Duke University Medical Center in Durham, NC, USA, and colleagues characterize 5-year outcomes and identify distinct clinical risk profiles of severe TR.16 Patients were included from a large US tertiary referral centre with new severe TR by echocardiography based on the four-category American Society of Echocardiography grading scale between 2007 and 2018. Patients were categorized by TR aetiology (with lead present, primary, and secondary) and by supervised recursive partitioning (survival trees) for outcomes of death and the composite of death or heart failure hospitalization. The Kaplan–Meier estimates and Cox regression models were used to evaluate any association by (i) TR aetiology and (ii) groups identified by survival trees and outcomes over 5 years. Among 2379 consecutive patients with new severe TR, median age was 70 years, 61% were female, and 40% were black. Event rates were 30.9 events/100 patient-years for death and 49.0 events/100 patient-years for the composite endpoint, with no significant difference by TR aetiology. After applying supervised survival tree modelling, four phenoclusters with distinct clinical prognoses were identified for death and the composite endpoint. Variables discriminating both outcomes were age, albumin, blood urea nitrogen, right ventricular function, and systolic blood pressure (all P < 0.05) (Figure 1). The authors conclude that patients with newly identified severe TR have high 5-year risk for death and death or heart failure hospitalization. Partitioning patients using supervised survival tree models, but not TR aetiology, discriminates clinical risk. These data aid in identifying relevant subgroups in clinical trials of TR and clinical risk/benefit analysis for TR therapies. This manuscript is accompanied by an Editorial by Ehud Chorin and Yan Topilsky from the Tel Aviv Medical Center and Sackler School of Medicine in Israel.17 The authors highlight that aetiology-based classification of TR provides limited clinical information regarding risk for clinical deterioration. Application of supervised recursive partitioning algorithms can successfully separate clinical risk profiles (clusters) in patients with severe TR. This machine learning-based ‘clustering’ of patients may be used in future TR trials both for event enrichment and to assess the ‘clean’ treatment effect. Survival tree analysis may be used at the individual patient level to determine patient risk under conservative therapy. A future trial will be needed to determine their role in optimizing individual decisions about the timing of interventions in TR. Nevertheless, the results of this study should be interpreted in the context of several limitations. Because patients underwent limited echocardiographic exams, the role of aetiology-based classification of TR in predicting outcome will need to await future prospective studies. In addition, the single-centre retrospective design limits broader generalizability, and future work will be needed to validate the supervised recursive partitioning algorithm risk model and decision trees in a diverse and heterogeneous cohort of patients with severe TR. Although highly heritable, the genetic aetiology of calcific aortic stenosis (AS) remains incompletely understood.18–20 In a Translational Research article entitled ‘Dyslipidaemia, inflammation, calcification, and adiposity in aortic stenosis: a genome-wide study’, Hao Yu Chen from McGill University in Montreal, Quebec, Canada, and colleagues sought to discover novel genetic contributors to AS and to integrate functional, expression and cross-phenotype data to identify mechanisms of AS.21 A genome-wide meta-analysis of 11.6 million variants in 10 cohorts involving 653 867 European ancestry participants (13 765 cases) was performed. Seventeen loci were associated with AS at P ≤ 5 × 10−8, of which 15 replicated in an independent cohort of 90 828 participants (7111 cases), including CELSR2-SORT1, NLRP6, and SMC2. A genetic risk score comprising the index variants was associated with AS [odds ratio (OR) per standard deviation, 1.31] and aortic valve calcium (OR per standard deviation, 1.223), after adjustment for known risk factors. A phenome-wide association study indicated multiple associations with coronary artery disease, apolipoprotein B, and triglycerides. Mendelian randomization supported a causal role for apolipoprotein B-containing lipoprotein particles in AS (OR per g/L of apolipoprotein B, 3.85) and replicated previous findings of causality for lipoprotein(a) (OR per natural logarithm, 1.20) and body mass index (OR per kg/m2, 1.07). Co-localization analyses using the GTEx database identified a role for differential expression of the genes LPA, SORT1, ACTR2, NOTCH4, IL6R, and FADS. Chen and colleagues conclude that dyslipidaemia, inflammation, calcification, and adiposity play important roles in the aetiology of AS, implicating novel treatments and prevention strategies. The contribution is accompanied by an Editorial by Sébastien Thériault, Yohan Bossé, and Patrick Mathieu from the Université Laval in Quebec City, Canada.22 The authors point out that this study may have reached the effective sample size in AS where the rate of locus discovery is ramping up. While the results point to potentially actionable pathways such as blood lipids, obesity, and inflammation, further molecular and functional studies in relevant cells, tissues, and living organisms are needed to fully characterize the molecular mechanisms at play. The development of genetic risk scores in addition to evidence from Mendelian randomization nevertheless provide valuable information to guide the design of future RCTs. This study is an important step in the journey towards the identification of molecular targets for medical management of AS and may represent, with international collaborations, the tipping point of a new era in genetics of AS. Mosaic loss of Y chromosome and mortality post-TAVR.23 Mosaic loss of Y chromosome (LOY) in blood cells is the most common acquired mutation, increases with age, and is related to CVD. In a Translational Research article entitled ‘Mosaic loss of Y chromosome in monocytes is associated with lower survival after transcatheter aortic valve replacement’, Silvia Mas-Peiro from the Goethe University Hospital in Frankfurt, Germany, and colleagues point out that LOY induces cardiac fibrosis in murine experiments, mimicking the consequences of AS, the prototypical age-related disease.23 Cardiac fibrosis is the major determinant of mortality even after transcatheter aortic valve replacement (TAVR). It was hypothesized that LOY affects long-term outcomes in men undergoing TAVR. Using digital PCR in DNA of peripheral blood cells, LOY (Y/X ratio) was assessed by targeting a 6 bp sequence difference between AMELX and AMELY genes using TaqMan. The genetic signature of monocytes lacking the Y chromosome was deciphered by scRNAseq (single-cell RNA sequencing). In 362 men with advanced AS undergoing successful TAVR, LOY ranged from −4% to 83.4%, and was >10% in 48% of patients. Three-year mortality increased with LOY. Receiver operating characteristic (ROC) curve analysis revealed an optimal cut-off of LOY >17% to predict mortality. In multivariate analysis, LOY remained a significant (P < 0.001) independent predictor of death during follow-up. scRNAseq disclosed a profibrotic gene signature with LOY monocytes displaying increased expression of transforming growth factor (TGF) β-associated signalling, while expression of TGFβ-inhibiting pathways was down-regulated (Figure 2). Mas-Peiro and colleagues conclude that this is the first study to demonstrate that LOY in blood cells is associated with profoundly impaired long-term survival even after successful TAVR. Mechanistically, the profibrotic gene signature sensitizing the patient-derived circulating LOY monocytes for the TGFβ signalling pathways supports a prominent role for cardiac fibrosis in contributing to the effects of LOY observed in men undergoing TAVR. The manuscript is accompanied by an Editorial by Aeron Small and Peter Libby from Harvard Medical School Boston, USA.24 Small and Libby indicate that the puny Y chromosome has engendered considerable concern of late. In men, the partner to the X chromosome measures up poorly. If size matters, the Y chromosome comes up short. Only one-third the expanse of its X counterpart, it encodes a mere 55 genes, while its sister X boasts some 900 genes. The Y chromosome may even be shrinking, raising concerns about its eventual erasure. In another blow to the status of this runty chromosome, much of its length, such as it is, contains repetitive sequences of DNA of dubious genetic utility. To add insult to injury, with age, many men accumulate blood cells which have cast away this challenged chromosome, making mosaic males with the acquired condition LOY. These novel findings of the Frankfurt group raise several interesting questions ripe for future investigation. Do individuals with AS have a higher prevalence of LOY than age- and risk factor-matched men? Could LOY lead to more rapid progression of calcific AS than in those without LOY? Or even, in the presence of AS, could LOY lead to more rapid progression of ventricular remodelling before valve intervention than in those without LOY? In conclusion, many have questioned the utility of the Y chromosome. Perhaps the recent plethora of findings regarding heightened cardiovascular risk may cast a new light on this prodigal son of our genetic material. The Y chromosome cannot save us from cardiovascular disease, but its absence may aggravate certain cardiovascular conditions. At long last, we can point to a post-natal use for the shrinking violet of our chromosomal complement. The issue is also complemented by two Discussion Forum contributions. In a commentary entitled ‘Degenerative mitral regurgitation: improving clinical decision-making and risk stratification before valve surgery or trans-catheter repair’, Michael Dandel from the German Centre for Heart and Circulatory Research (DZHK) in Berlin, Germany and colleagues comment on the recent publication ‘Factors influencing post-surgical survival in degenerative mitral regurgitation’ by Steele Butcher from Leiden University Medical Center in the Netherlands, and colleagues.25,26 Butcher et al. respond in a separate comment.27 The editors hope that this issue of the European Heart Journal will be of interest to its readers. Dr. Crea reports speaker fees from Abbott, Amgen, Astra Zeneca, BMS, Chiesi, Daiichi Sankyo, Menarini outside the submitted work. With thanks to Amelia Meier-Batschelet, Johanna Huggler, and Martin Meyer for help with compilation of this article.