Atrial form of secondary mitral regurgitation dominates in the general population

Moderate or severe mitral regurgitation affects roughly one in forty middle-aged and older adults, and about two-thirds of those cases are of the secondary rather than the primary form, according to the first population-based study to break secondary mitral regurgitation down into its atrial and ventricular subtypes. Among the secondary cases, the atrial subtype overwhelmingly predominated, accounting for 84.5 percent, while the ventricular subtype made up just 15.5 percent. The findings come from the Hamburg City Health Study and are published in Clinical Research in Cardiology.

The study analyzed the first 10,000 participants of the Hamburg City Health Study, a prospective, population-based cohort enrolled between 2016 and 2019. All residents of Hamburg aged 45 to 74 years were eligible, and individuals were randomly selected and invited to a baseline examination at the Study Center Hamburg-Eppendorf. Of the 10,000 participants, 8,543 transthoracic echocardiographic examinations were available for analysis. Mitral valve morphology and function were assessed independently by two trained cardiologists using standardized imaging views and predefined operating procedures aligned with American Society of Echocardiography and European Association of Cardiovascular Imaging guidelines.

The investigators distinguished three mechanistic forms of mitral regurgitation. Primary mitral regurgitation results from intrinsic structural abnormalities of the mitral valve leaflets, chordae tendineae, or papillary muscles, such as prolapse, flail leaflet, or severe calcification or thickening that restricts leaflet motion. Secondary mitral regurgitation arises despite structurally normal leaflets, driven either by dilatation of the mitral annulus in the context of left atrial enlargement, termed atrial secondary mitral regurgitation, or by left ventricular remodelling and geometric distortion, termed ventricular secondary mitral regurgitation. In this study, secondary regurgitation was classified as ventricular when the left ventricular ejection fraction was below 50 percent, or below 55 percent together with geometric distortion defined as a tenting area of at least 150 square millimeters or a coaptation depth of at least 10 millimeters; cases with an ejection fraction of 50 percent or above were classified as atrial secondary regurgitation.

Within the cohort, 280 individuals were initially identified as having moderate or severe mitral regurgitation. After exclusion of cases with insufficient image quality, missing data, or reclassification to grade 1 by the second investigator, 216 cases remained, corresponding to a prevalence of 2.53 percent (95 percent confidence interval 2.20 to 2.89 percent). Of these, 148 cases, or 68.5 percent, were classified as secondary mitral regurgitation, while the remaining 68 cases, or 31.5 percent, were mainly of primary etiology. Among the secondary cases, 125 were categorized as atrial secondary and 23 as ventricular secondary. The cohort as a whole had a median age of 69 years, was nearly half female, and was relatively healthy: 87 percent were in NYHA functional class I, median NT-proBNP levels were only mildly elevated at 163 nanograms per liter, and comorbidities such as heart failure (21.3 percent), atrial fibrillation (19.2 percent), and coronary artery disease (9.5 percent) were comparatively infrequent, although hypertension was highly prevalent at 73.5 percent.

Comparing the two secondary subtypes revealed a distinct clinical picture for the small ventricular group. Participants with ventricular secondary regurgitation tended to be older (p = 0.059) and were less frequently female (p = 0.078), although these differences did not reach statistical significance. They more frequently had coronary artery disease (p = 0.003) and self-reported heart failure (p < 0.001), and they more often reported advanced dyspnea and atrial fibrillation, accompanied by higher circulating NT-proBNP levels (p = 0.046). Echocardiographically, they showed the expected more severely impaired left ventricular ejection fraction, a higher E/e′ ratio as a surrogate marker of diastolic dysfunction, and a lower left atrial ejection fraction, indicating more advanced cardiac remodelling and dysfunction. Notably, only 16.1 percent of individuals in the atrial secondary group had atrial fibrillation.

Multivariable logistic regression sharpened this contrast. In the adjusted model, atrial fibrillation was the only statistically significant predictor of the ventricular subtype, associated with an approximately threefold higher likelihood of ventricular secondary regurgitation compared with the atrial subtype. Female sex was associated with a more than 50 percent lower odds of the ventricular form, although this effect did not reach statistical significance, and body mass index, arterial hypertension, and echocardiographic parameters including interventricular septal thickness, left ventricular end-diastolic diameter, and left atrial volume measures were not significant predictors after adjustment. The authors note that this prominence of atrial fibrillation in the ventricular group challenges the prevailing pathophysiological concept that the atrial subtype is primarily driven by atrial fibrillation in the setting of heart failure with preserved ejection fraction and elevated left atrial pressure.

When primary and secondary regurgitation were compared directly, participants with the primary form had greater regurgitation severity: severe mitral regurgitation was present in 60.3 percent of primary cases versus 38.5 percent of secondary cases (p = 0.003). Participants with primary regurgitation also had a significantly higher NYHA functional class (p = 0.008), a higher left ventricular ejection fraction, a smaller left ventricular end-diastolic diameter, and markedly higher left atrial strain. Median age (70.0 versus lower values in the secondary groups) and the proportion of women (55.9 percent) were numerically higher in the primary group without reaching statistical significance, and female sex showed a numerical tendency toward the primary form (odds ratio 0.71, 95 percent confidence interval 0.40 to 1.26). Diabetes prevalence was numerically higher in the primary group (8.1 percent versus 4.3 percent), while heart failure and hypertension were comparable between the etiology groups.

Follow-up data were available for 185 participants, comprising 58 with primary, 111 with atrial secondary, and 16 with ventricular secondary regurgitation. Over a median follow-up of 4.56 years, corresponding to a total of 906.4 patient-years, 10 participants died: 7 with primary regurgitation over 288.0 patient-years, 2 with atrial secondary regurgitation over 545.0 patient-years, and 1 with ventricular secondary regurgitation over 73.4 patient-years. All-cause mortality was significantly higher among participants with primary regurgitation than among those with the atrial secondary subtype (p = 0.0077), a difference the authors suggest may partly reflect the greater regurgitation severity in the primary group. During the time-to-first-event analysis, incident heart failure was diagnosed in 4 participants with primary and 4 with atrial secondary regurgitation, while incident atrial fibrillation occurred in 1 participant with primary, 4 with atrial secondary, and 2 with ventricular secondary regurgitation, although the small number of events limits interpretation.

The prevalence of moderate or severe mitral regurgitation in this cohort was higher than the 0.46 percent reported by Dziadzko and colleagues in a retrospective community-based study of 29,390 individuals, but the authors caution that direct comparison is complicated by substantial differences in study design and echocardiographic assessment. The Hamburg protocol was not specifically designed for valvular heart disease and graded regurgitation severity primarily qualitatively, whereas the earlier study applied a comprehensive integrative approach with quantitative grading and counted only clinically indicated examinations and isolated mitral regurgitation. In a subcohort of 727 patients with stored images allowing etiological assessment, however, the proportion of secondary regurgitation was comparable to the present cohort, at 65.3 percent versus 68.5 percent, although the majority of cases in that clinically referred population were of the ventricular subtype, consistent with symptomatic patients carrying higher comorbidity burdens.

The authors emphasize that this is, to their knowledge, the first population-based study specifically investigating primary, atrial secondary, and ventricular secondary mitral regurgitation, and they frame their findings as hypothesis-generating. The study has important limitations: the relatively small size of the regurgitation subgroups, particularly the 23 cases of ventricular secondary regurgitation, and the limited number of outcome events restricted statistical power and may have precluded detection of smaller differences between groups. Exclusion of examinations with insufficient image quality or missing data may have introduced selection bias, some degree of misclassification cannot be excluded despite independent assessment by two investigators, residual confounding remains possible despite prespecified multivariable models, and the qualitative assessment of regurgitation severity is an additional constraint. The authors conclude that the distinct echocardiographic and clinical profiles observed across the three forms, together with the unexpected distribution of atrial fibrillation, underscore the need for refined subclassification of secondary mitral regurgitation and for longitudinal, prospective studies with serial echocardiographic assessments, including deformation imaging, to define the prognostic implications and establish clinically meaningful, pathophysiologically sound definitions of the atrial and ventricular subtypes.

Subject of Research: Prevalence and clinical profiles of primary, atrial secondary, and ventricular secondary mitral regurgitation in a general population cohort

Article Title: Primary, atrial secondary, and ventricular secondary mitral regurgitation in the general population

Article References: Keil, L., Hapfelmeier, A., Wenzel, J.-P., Nikorowitsch, J., Kalbacher, D., Reichenspurner, H., Blankenberg, S., & Girdauskas, E. (2026). Primary, atrial secondary, and ventricular secondary mitral regurgitation in the general population. Clinical Research in Cardiology. https://doi.org/10.1007/s00392-026-03046-7

Image Credits: AI Generated

DOI: 10.1007/s00392-026-03046-7

Keywords: mitral regurgitation, secondary mitral regurgitation, primary mitral regurgitation, echocardiography, Hamburg City Health Study, population-based cohort, atrial fibrillation, heart failure, left ventricular remodelling, valvular heart disease, all-cause mortality, cardiology