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Adverse cardiovascular disease outcomes in patients with aortic sclerosis and mitral annular calcification even when valve function is normal
  1. Bernard Iung1,
  2. Claire Bouleti2
  1. 1 Cardiology, Bichat Hospital, Paris, France
  2. 2 Cardiology, University of Poitiers, Clinical Investigation Center (CIC) INSERM 1402, Poitiers University Hospital, Poitiers, France
  1. Correspondence to Professor Bernard Iung, Cardiology, Bichat Hospital, Paris 75018, France; bernard.iung{at}bch.aphp.fr

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The severity of stenosis or regurgitation, the presence of symptoms and the consequences on the left ventricle are the main drivers of decision-making for the management of valvular diseases in current guidelines.1 2 Interventions are generally considered in severe valvular diseases and most publications focus therefore on severe lesions, although more attention is now paid on moderate valvular disease, in particular regarding aortic stenosis. The originality of the paper by Taylor et al 3 is to also analyse the prognostic impact of the least severe valvular heart disease, that is, mild valvular disease, as well as calcific valve lesions without functional effect on the same valve, that is, aortic sclerosis and mitral annular calcification (MAC). Separating functional and anatomical valvular lesions is challenging since there is a close interaction between valve function and anatomy. As an illustration, the quantification of calcium burden using the calcium score is now recommended to assess aortic stenosis severity, which is complementary to echocardiography.1 2 Nevertheless, the definitions used in the paper by Taylor et al allow for separate assessment of the prognostic impact of the severity of valvular disease and of the extent of calcific valve lesion.

Mild valvular disease and anatomical lesions without functional consequences can be studied only by using systematic echocardiographic screening, which is an important feature of the OxValve cohort. Although this is not current recommended practice, a reliable detection of valvular disease requires systematic echocardiography, with only 10% of valvular disease detected by cardiac auscultation. This is particularly true for mild valvular disease and calcific valve lesions, which are usually silent and likely to be overlooked by a clinical approach. Given the prognostic impact of calcific lesion reported in the OxValve Study, their diagnosis is of major importance. These findings thus raise the question of the usefulness of echocardiographic screening beyond population-based cohorts, such as presented in the OxValve Study.

Thanks to this approach, the OxValve Study reported as many as 44.9% of patients with mild valvular disease, while only 5.2% had moderate or severe valvular disease. Any degree of calcific valve disease without functional effect on the same valve was present in 53.5% of patients. Since OxValve is a population-based cohort, the findings can be generalised to subjects aged 65 years or older in industrialised countries. These results are particularly striking and deserve attention by their frequency and the potential prognostic impact of calcific lesion.

Despite the originality and relevance of the paper of Taylor et al, there may be some concerns with regard to the conclusion that mild valvular disease is not associated with increased mortality. Adjusted HR for all-cause mortality was 1.20 with a 95% CI of 0.96 to 1.51; the lower boundary was close to 1 and it is likely that the lack of association with mortality is due to a lack of statistical power rather than the absence of prognostic impact. Indeed, larger series reported increased mortality in case of mild valvular disease, at least regarding mild aortic stenosis, although series based on echocardiographic databases are subject to greater likelihood of selection bias than the population-based OxValve cohort.4 The follow-up of the OxValve cohort provides reassuring findings on the prognosis of mild valvular disease; however, this condition should not be considered as fully benign. Patients with mild valvular disease should be informed on the potential of evolution toward more severe valve dysfunction, the need for follow-up and should be aware of the importance of referring new symptoms. Even more striking, the lack of association between moderate or severe valvular disease and mortality is not in accordance with the knowledge on their prognosis and also illustrates lack of statistical power. Only 182 patients did have moderate or severe valvular disease, which also explains the very low number of valvular interventions reported in this cohort (only 12 interventions). Without the exact number of patients with severe valvular disease, no comment can be made on this low interventional rate. An analysis of the relationship between different severities of valvular disease and cardiovascular mortality would be of interest since we may imagine that patients with moderate or severe valvular disease would have suffered preferentially from cardiovascular death.

The relationship between aortic sclerosis or MAC and an increased risk of mortality has been previously reported5 6 ; however, the analysis of the OxValve cohort strengthens these associations by showing a relationship between the extent of calcific valvular lesion and the risk of all-cause death, independently of an impaired function of the corresponding aortic or mitral valve. The presence of aortic sclerosis and MAC has been related to cardiovascular risk factors and shares a number of common pathophysiological pathways with vascular remodelling encountered in atherosclerosis.7 It is generally acknowledged that fibrocalcific remodelling is the main determinant of the clinical consequences of calcific valvular disease through valvular obstruction, while the clinical consequences of atherosclerosis are more related to the inflammatory component of vascular remodelling and plaque rupture. These differences may contribute to explain why statins failed to slow the progression of aortic stenosis although they play a key role in the prevention of atherosclerosis vascular-related complications. According to the findings of Taylor et al, calcific valvular lesion has a prognostic impact per se, regardless of the severity of valvular disease, thereby suggesting that calcium deposit would be a marker of atherosclerosis without valvular direct causal relationship with mortality. However, the prevalence of comorbidities and calcific valve lesion increase together with age, but the multivariate analysis of factors associated with mortality did not include comorbidities. It is therefore not possible to exclude residual confounding in the association between calcific valve lesion and all-cause mortality since the majority of deaths were not from cardiovascular cause.

The paper by Taylor et al also draws attention on multivalve disease since the association of aortic sclerosis or MAC with a significant valvular disease on another valve, in particular the tricuspid valve, resulted in an increased mortality as compared with aortic sclerosis or MAC without any valve dysfunction. Multiple valve disease encompasses a wide range of heterogeneous combinations of valvular diseases which make its analysis particularly difficult. There is therefore a paucity of studies on multiple valve disease as compared with single-valve diseases. The OxValve cohort stresses the need to increase the awareness on the combination on anatomical and functional impairment of multiple valves.

Beyond original findings, the present analysis also highlights the considerable potential offered by merging dedicated studies with administrative databases. Dedicated studies or registries on valvular disease include variables of major prognostic interest, such as the severity of valvular disease and the presence of symptoms, which cannot be analysed from hospital discharge codes using the International Classification of Diseases. On the other hand, the linkage with administrative databases allows for obtaining follow-up data which are difficult to be reliably collected during patient follow-up.8

This analysis of the OxValve cohort suggests that more attention should be paid to the extent of the calcific valve lesion as assessed by echocardiography even at the early stages of valvular disease. Although this cannot translate in effective prevention measures at the present time, these findings further highlight the need for continuous research on the pathophysiology of calcific valve diseases, and the identification of metabolic pathways which may reduce the consequences of calcium deposits. This is of particular importance due to the predicted increase in the burden of calcific aortic stenosis or MAC in the following decades.

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  • Contributors BI and CB both drafted and approved this editorial.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests BI—speaker’s fee from Edwards Lifesciences.

  • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

  • Provenance and peer review Commissioned; externally peer reviewed.

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