Valvular heart disease: new risk factors and new challenges

In less than two decades, valvular heart disease has seen a true revival in cardiovascular medicine since the first percutaneous replacement of a pulmonary valve by Philipp Bonhoeffer in 2000,1 and the first catheter-based implantation of an aortic bioprosthesis by Alain Cribier in 2002.2 This enormous progress in the percutaneous treatment of valvular heart disease3–5 has stimulated research into the causes and mechanisms of these disorders. In the first article of this Focus Issue, Eileen Gentleman and colleagues from King’s College London in the UK discuss ‘Aortic valve calcification: a bone of contention’,6 a major mechanism of degenerative aortic stenosis which affects as many as 26% of individuals over the age of 65 even before valve disease occurs. Until recently, calcification was believed to be a passive process associated with agring. However, the identification of osteogenic morphogens in calcific lesions in the 1990s caused a paradigm shift. Since then, calcification has been linked to bone formation. While calcific lesions share similarities with bone, modern techniques have shown that, in most cases, their compositions vary tremendously, and ubiquitous features of calcific lesions are absent in bone. Nevertheless, understanding of the process of normal bone formation provides important insights into potential mechanisms through which pathological minerals form in other organs. To open doors for future measures to prevent the formation of aortic stenosis, further research into the initiation and progression of calcification rather than seeking to reverse it appear most promising. A future focus on interdisciplinary efforts that complement current biological approaches may allow us to better understand and perhaps eventually prevent calcific disease. Calcified aortic stenosis and mitral annular calcification have certain similar pathophysiological mechanisms and aetiology. Mitral annular calcification is frequently encountered in pre-procedural computed tomgraphy (CT) imaging of patients undergoing transcatheter aortic valve replacement, but its prognostic implications for these patients have not been thoroughly investigated. In a clinical research article entitled ‘Concomitant mitral annular calcification and severe aortic stenosis: prevalence, characteristics, and outcome following transcatheter aortic valve replacement’, Raj Makkar and colleagues from the Cedars-Sinai Heart Institute in Los Angeles, California sought to evaluate the prevalence of mitral annular calcification among patients with severe aortic stenosis and to assess the clinical implications of mitral annular calcification for these patients during and following transcatheter aortic valve replacement.7 Consecutive patients that underwent transcatheter aortic valve replacement were compared according to the presence of mitral annular calcifications and their severity in pre-transcatheter aortic valve replacement CT scans. From the entire cohort of 761 patients, 49% had mitral annular calcification and 51% did not. Mild mitral annular calcification was present in 30%, moderate mitral annular calcification in 10%, and severe mitral annular calcification in another 10%. Thirty-day mortality and major complications were similar in those with and without mitral annular calcification. In a multivariable survival analysis, severe mitral annular calcification was an independent predictor of overall mortality following transcatheter aortic valve replacement. Severe mitral annular calcification was also found to be an independent strong predictor of new permanent pacemaker implantation after transcatheter aortic valve replacement, with an odds ratio of 2.8. The authors conclude that half of the patients with severe aortic stenosis evaluated for transcatheter aortic valve replacement have mitral annular calcification. Severe mitral annular calcification is associated with increased all-cause and cardiovascular mortality and with conduction abnormalities following transcatheter aortic valve replacement, and should be included in future risk stratification models for transcatheter aortic valve replacement. These relevant observations are discussed further in an Editorial by Lars Sondergaard from the Rigshospitalet in Copenhagen, Denmark.8 Today’s catheter-based treatment of cardiac valves would not have been possible without Andreas Grüntzig’s seminal first balloon angioplasty9 and the later development of implantable metallic scaffolds, so-called coronary stents. Ulrich Sigwart from the Université de Geneve in Switzerland reports, in a Special Article entitled ‘Living history of medicine: vascular scaffolding, from dream to reality’, his own seminal first implantation of a coronary stent.10 He reminds us that following the first balloon angioplasty in 1977, its deficiencies, in particular abrupt coronary closure requiring emergency bypass surgery in 1 in 20 attempts and recurrent angina due to restenosis in one of 3 cases,11 soon became apparent. The attempts to eliminate the element of chance from this otherwise highly attractive technique resulted in the concept of intravascular scaffolding. Following the inception of self-expanding mesh stents made from stainless steel and extensive bench testing and animal experiments, the first clinical data were obtained in Switzerland almost 30 years ago in 1986 with promising, albeit not undisputed, results. Technical improvements including potent platelet inhibitors have made the technique a cornerstone of catheter treatment of vascular disease. Ulrich Sigwart gives a personal account of the sometimes difficult beginnings of coronary and non-coronary stenting, with a high incidence of stent thrombosis, a problem that today has become a rare event,11 and other issues at the University of Lausanne in Switzerland in the pioneering 1980s. Today, percutaneous coronary intervention is the treatment of choice in most patients with stable12 and in those with acute coronary artery disease.13 However, percutaneous valve implantation, although already matured compared with the early days, faces unforeseen problems. The presence of hypo-attenuated leaflet thickening and/or reduced leaflet motion on multidetector row CT has been proposed as a possible marker for early transcatheter aortic valve thrombosis.14 However, its association with abnormal valve haemodynamics on echocardiography, another potential marker of thrombosis, and clinical outcomes such as stroke remains unclear. In their clinical research article entitled ‘Transcatheter aortic valve thrombosis: the relation between hypo-attenuated leaflet thickening, abnormal valve haemodynamics, and stroke’, Jeroen J. Bax and colleagues from the Leiden University Medical Center in The Netherlands evaluated the prevalence of hypo-attenuated leaflet thickening on multidetector row CT and abnormal valve haemodynamics on echocardiography. In addition, the occurrence of ischaemic stroke and/or transient ischaemic attack in 434 patients who underwent transcatheter aortic valve replacement was documented.15 Transcatheter valve haemodynamics were assessed on echocardiography at discharge, 6 months, and thereafter yearly up to 3 years. The presence of hypo-attenuated leaflet thickening and/or reduced leaflet motion was assessed by multidetector row CT 35 days after transcatheter aortic valve replacement in 128 of these 434 patients. Possible transcatheter aortic valve replacement valve thrombosis was defined by mean transvalvular gradient ≥20 mmHg and aortic valve area ≤1.1cm2 on echocardiography or by the presence of hypo-attenuated leaflet thickening or reduced leaflet motion on multidetector row CT. The occurrence of ischaemic stroke/transient ischaemic attack at follow-up was recorded. The authors found that hypo-attenuated leaflet thickening and/or reduced leaflet motion was present in 12.5% of patients undergoing multidetector row CT, and was associated with a slightly higher mean transvalvular gradient of 12 mmHg as compared with those who did not develop this in which the gradient averaged 9 mmHg. Also, hypo-attenuated leaflet thickening was associated with a smaller aortic valve area of 1.5 cm2 compared with controls with 1.8 cm2. Notably, only one patient with hypo-attenuated leaflet thickening on multidetector row CT revealed abnormal valve haemodynamics on echocardiography. At 3-year follow-up, abnormal valve haemodynamics on echocardiography were observed in 3% of patients. Importantly, hypo-attenuated leaflet thickening on multidetector row CT and abnormal valve haemodynamics on echocardiography were not associated with increased risk of ischaemic stroke or transient ischaemic attack. Bax et al. conclude that on multidetector row CT, one in seven patients showed hypo-attenuated leaflet thickening or reduced leaflet motion, whereas only one of the patients overall developed abnormal valve haemodynamics. Neither hypo-attenuated leaflet thickening nor increased transvalvular gradient were associated with stroke or transient ischaemic attack. These clinically important findings are discussed further in an Editorial authored by Franz-Josef Neumann from the the Universitäts-Herzzentrum Freiburg in Bad Krozingen, Germany.16 ROC curves for MPR and symptom-limited exercise testing (A. conventional definition, B. strict definition) for predicting the primary outcome (from Singh A, Greenwood JP, Berry C, Dawson DK, Hogrefe K, Kelly DJ, Dhakshinamurthy V, Lang CC, Khoo JP, Sprigings D, Steeds RP, Jerosch-Herold M, Neubauer S, Prendergast B, Williams B, Zhang R, Hudson I, Squire IB, Ford I, Samani NJ, McCann GP. Comparison of exercise testing and CMR measured myocardial perfusion reserve for predicting outcome in asymptomatic aortic stenosis: the PRognostic Importance of MIcrovascular Dysfunction in Aortic Stenosis (PRIMID AS) Study. See Pages 1222–1229). Right-censored Kaplan–Meier survival curves accounting for left-truncation with age as time scale of 3,311 adult survivors with congenital heart disease. A, Comparison of median age at death (MAD) by sex. B, Comparison of MAD between patients with simple, moderate or severe complexity lesions. Other abbreviations: CI, confidence interval (from Oliver JM, Gallego P, Gonzalez AE, Garcia-Hamilton D, Avila P, Yotti R, Ferreira I, Fernandez-Aviles F. Risk factors for excessmortality in adults with congenital heart diseases. See Pages 1233–1241). This issue concludes with an analysis of cardiovascular research. The growing burden of cardiovascular disease also requires an appropriate growth in research and innovation. In a Special Article entitled ‘Mapping cross-border collaboration and communication in cardiovascular research from 1992 to 2012’, Karin R. Sipido and colleagues from the University of Leuven in Belgium examined worldwide participation and citation impact across the cardiovascular research landscape from 1992 to 2012.21 The authors investigated cross-fertilization between countries and examined whether cross-border collaboration affects impact. The publication output in cardiovascular research has grown steadily from 1992 to 2012 with increased participation worldwide. China has the highest growth as relative share. The USA’s share initially predominated, yet reduced steadily. Over time, the EU-27 supranational region increased its participation above that of the USA, though on average it has not had a greater citation impact than the USA. However, several European countries, as well as Australia and Canada, have improved their absolute and relative citation impact above that of the USA. Europe is a hub of cross-fertilization, with strengthening collaborations and strong citation links; the UK, Germany, and France remain central in this network. The USA has the highest number of strong citation links with other countries. All countries, but especially smaller, highly collaborative countries, have higher citation impact for their internationally collaborative research when compared with their domestic publications. Sipido et al. conclude that participation in cardiovascular research is growing, but growth and impact show wide variability between countries. Cross-border collaboration is increasing within the EU and is associated with greater citation impact. The editors hope that the papers published in this issue of the European Heart Journal will be of interest to its readers.