Frontiers of valvular heart disease: from aortic stenosis to the tricuspid valve and congenital anomalies

Valvular heart disease has moved from being the Cinderella of cardiology to centre stage in recent years. The development of transcatheter aortic valve implantation or TAVI1 and its remarkable clinical sucess2 have stimulated epidemiological3 and outcomes research, imaging as a modality for the planning of such interventions,4,5 technological research for new and better tools for such procedures,6,7 and more recently also the field of antiplatelet agents and antithrombotics. The most recent progress is summarized in a Current Opinion ‘The year in cardiology 2016: valvular heart disease’, by Ottavio Alfieri and colleagues from the San Raffaele University Hospital in Milan, Italy.8 The authors note that as expected in this era of rapidly evolving therapeutic modalities and technologies, many scientific contributions are related to the expanded role of percutaneous interventions. New data are now available, consolidating the validity of the transcatheter approach in a variety of subsets of patients and therefore offering new strategies and perspectives in management as outlined in detail in their comprehensive review. A novel frontier in valvular heart disease is the tricuspid valve, as reviewed by Paul A. Grayburn and colleagues from the Baylor Heart and Vascular Institute in Dallas, Texas in their article ‘Tricuspid regurgitation: diagnosis and treatment’.9 The authors note that tricuspid regurgitation is the most common lesion of the tricuspid valve, with mild regurgitation being common and usually benign. However, moderate or severe tricuspid regurgitation can lead to irreversible myocardial damage and adverse outcomes. Despite these findings, few patients with significant tricuspid regurgitation undergo surgery. Indeed, the treatment of functional or secondary tricuspid regurgitation remains controversial because of high rates of residual or recurrent tricuspid regurgitation and poor outcomes following surgery. Traditional teaching that functional tricuspid regurgitation resolves on its own if the underlying disease is successfully treated has proven to be incorrect. This review therefore aims to clarify the current management of tricuspid regurgitation by describing the anatomy, pathophysiology, diagnosis, and treatment of tricuspid regurgitation, including the eventual possibility of percutaneous tricuspid valve therapy. The latter, most innovative aspect is discussed in detail in a second clinical review manuscript entitled ‘Percutaneous tricuspid valve therapies: the new frontier’ by Maurizio Taramasso and colleagues from the University Hospital, Zurich, Switzerland.10 The authors remind us that moderate to severe tricuspid regurgitation affects ∼1.6 million patients in the USA, of whom only 8000 undergo tricuspid surgery annually, leaving an extremely large number of patients untreated. Percutaneous procedures are an attractive alternative to surgery for patients deemed to be high-risk surgical candidates. Whereas over the past few years, the development and clinical use of percutaneous approaches such as TAVI, Mitraclip, and mitral valve replacement has increased dramatically, only little progress has been made as regards to the percutaneous treatment of tricuspid regurgitation. In this review, the currently available technologies, among them Mitraclip11,12 and novel devices,13,14 which are currently under evaluation, mostly echo-guided,15 are described in detail and their preliminary clinical results discussed. Assessment of the distance between the right coronary artery (RCA) and the tricuspid valve annulus.The long-axis 2- and 4-chamber views (A and B) were aligned to reconstruct a short-axis view of the tricuspid valve annulus (C). At the level of the anterior and posterior tricuspid valve leaflet insertions, the distance to the RCA was assessed. Panel D shows the volume rendered reconstruction demonstrating the course of the RCA completely along the tricuspid valve annulus. (from van Rosendael PJ, Kamperidis V, Kong WKF, van Rosendael AR, van der Kley F, Ajmone Marsan N, Delgado V, Bax JJ. Computed tomography for planning transcatheter tricuspid valve therapy. See pages 665–674.) Notch1 in valvular endothelial cells promotes apoptosis of valvar interstitial cells during development of arterial valves. TUNEL assay shows apoptotic cells (green) in arterial valves of E14.5 control (A and D), N1KO (B and E), and N1ICD+ embryos (C and F). Pecam1 staining marks valvar endothelial cells (red). Bar = 50 μm. (G) and (H) show quantitative results. The data are presented as the ratio of TUNEL+ cells/total valvar endothelial cells or valvar interstitial cells. Statistical comparison was performed using one-way analysis of variance followed by Tukey’s test. A P-value of, 0.05 was considered significant. Asterisk indicates comparison with the control in each individual valve leaflet, hash indicates comparison with the non-adjacent leaflet (G) or anterior leaflet (H) in each genotype, and open triangle indicates comparison with the left coronary leaflet (G) in each genotype. (from Wang Y, Wu B, Farrar E, Lui W, Lu P, Zhang D, Alfieri CM, Mao K, Chu M, Yang D, Xu D, Rauchman M, Taylor V, Conway SJ, Yutzey KE, Butcher JT, Zhou B. Notch-Tnf signalling is required for development and homeostasis of arterial valves. See pages 675–686.) Heart failure is an important complication of valvular, coronary, or hypertensive heart disease. Although huge progress has been made in this condition, as again outlined by the most recent ESC Guidelines,20 treatment remains essentially palliative in nature. Thus, novel regenerative approaches have been tested with some positive,21 but mainly neutral results.22,23 However, cardiopoietic cells, produced through cardiogenic conditioning of patients’ mesenchymal stem cells, have shown preliminary efficacy. In a FAST TRACK entitled ‘Cardiopoietic cell therapy for advanced ischaemic heart failure: results at 39 weeks of the prospective, randomized,double-blind, sham-controlled CHART-1 clinical trial’, Andre Terzic and colleagues for the CHART Program present results of the Congestive Heart Failure Cardiopoietic Regenerative Therapy trial that aimed to validate cardiopoiesis-based biotherapy in a larger heart failure cohort.24 This multinational, randomized, double-blind, sham-controlled study was conducted in 39 hospitals. A total of 484 patients with symptomatic ischaemic heart failure on guideline-directed therapy were screened and 348 underwent bone marrow harvest and mesenchymal stem cell expansion. Of those, 315 who achieved >24 million mesenchymal stem cells were randomized to cardiopoietic cells delivered endomyocardially with a retention-enhanced catheter or sham procedure. Of the 271 patients, procedures were performed as randomized in 271. The primary efficacy endpoint was a Finkelstein–Schoenfeld hierarchical composite of all-cause mortality, worsening heart failure, Minnesota Living with Heart Failure Questionnaire score, 6-min walk distance, left ventricular end-systolic volume, and ejection fraction at 39 weeks. The primary outcome was neutral. Exploratory analyses suggested a benefit of cell treatment on the primary composite in the two-thirds of the patients with baseline left ventricular end-diastolic volume 200–370 mL. No difference was observed in serious adverse events. One cardiopoietic cell patient and nine sham patients experienced aborted or sudden cardiac death. Thus, the authors conclude that the primary endpoint was neutral, with safety demonstrated across the cohort. Further evaluation of cardiopoietic cell therapy in patients with elevated end-diastolic volume is warranted. These findings are put into perspective in an Editorial authored by Joshua M. Hare from the University of Miami in Florida, USA.25 The editors hope that this issue of the European Heart Journal will be of interest to its readers.