About the Study: What is the global disease burden attributable to elevated low-density lipoprotein cholesterol (LDL-C)? In 2023, high LDL-C caused 3.6 million deaths (6.0% of all deaths) and 90.7 million disability-adjusted life years (DALYs) (3.2% of total DALYs). Despite declines of 45.6% in age-standardized mortality rates and 39.5% in DALY rates, the absolute LDL-C–related burden increased by 38.5% from 1990 to 2023, driven by population growth and aging, with notable regional disparities shifting toward middle-sociodemographic settings. Strategic approaches to prevent, diagnose, and treat elevated LDL-C across populations globally are needed.

Corresponding Author: Christian Razo, PhD, Department of Health Metrics Sciences, School of Medicine, Institute for Health Metrics and Evaluation, University of Washington, 3980 15th Ave NE, Seattle, WA 98195. For interviews, contact the communications team at Institute of Health Metrics and Evaluation at University of Washington School of Medicine (ihmemedia@uw.edu).

10.1001/jama.2026.8628

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Mitral annular disjunction is a structural abnormality characterized by a separation or “sliding” of the mitral valve’s annulus from the underlying ventricular myocardium. Under normal physiology, the mitral valve annulus serves as a firm attachment point tethering the leaflets to the left ventricle, thus ensuring efficient valve closure during systole. However, in MAD, this anchoring relationship is disrupted, compromising the mechanical stability of the mitral apparatus. This anatomical derangement has been increasingly associated with electrical instability of the ventricular myocardium, leading to potentially fatal arrhythmogenic events, most notably ventricular tachycardia and sudden cardiac arrest.

Mitral valve prolapse, an often coexisting condition with MAD, affects approximately 2.5% of the global population and involves the abnormal displacement of one or both mitral valve leaflets into the left atrium during ventricular contraction. This aberrant leaflet movement causes mitral regurgitation, whereby blood flows retrograde into the left atrium, imposing volume overload and precipitating progressive cardiac remodeling. The clinical manifestations frequently include fatigue, palpitations, and exertional dyspnea. Historically, surgical correction via mitral valve repair or replacement has been the cornerstone for alleviating symptoms and preventing progression to heart failure in severe cases.

The critical question addressed by the current large-scale observational study was whether the presence of MAD continues to portend a significant arrhythmogenic risk after valve surgery aimed at correcting related anatomical abnormalities. Investigators meticulously followed 599 patients diagnosed with mitral valve prolapse who underwent surgical intervention at Karolinska University Hospital from 2010 to 2022. Notably, 16% of these patients exhibited preoperative evidence of MAD. This longitudinal cohort study thus offers a unique window into long-term postoperative outcomes regarding cardiac rhythm disturbances.

Intriguingly, patients harboring MAD were disproportionately younger—by an average of eight years—and predominantly female compared to their MAD-negative counterparts. This demographic skew raises compelling questions about sex-specific cardiac structural vulnerability and age-related myocardial plasticity in the context of valvular pathology. Furthermore, these individuals presented with more advanced mitral disease, which potentially signals an intrinsic link between structural severity and electrical instability.

Despite surgical correction deemed successful in anatomical terms, the group with preoperative MAD demonstrated over threefold increased incidence of ventricular arrhythmias over a five-year follow-up period. Ventricular arrhythmias, characterized by rapid and irregular beating of the lower heart chambers, are known to compromise hemodynamic stability and can culminate in cardiac arrest if left unmanaged. These findings reveal that MAD confers a persistent pro-arrhythmic substrate independent of mechanical correction, emphasizing that valvular repair alone may not suffice as a comprehensive therapeutic endpoint.

The study’s senior author, cardiologist and associate professor Bahira Shahim, underscores the clinical imperative to implement vigilant long-term monitoring protocols for patients exhibiting MAD, regardless of ostensibly successful surgical outcomes. This paradigm shift advocates for integrating advanced cardiac imaging and electrophysiological assessments into postoperative care strategies for affected individuals, aiming to preempt catastrophic arrhythmogenic events.

To unravel the pathophysiological underpinnings behind these persistent arrhythmic risks, the research team is currently probing several hypotheses. One proposed mechanism is that MAD induces chronic mechanical stress on the adjacent myocardium, incrementally driving fibrotic remodeling and scar formation that serve as foci for arrhythmic circuits. Alternatively, MAD itself may be a phenotypic marker of a broader, intrinsic cardiomyopathic process that predisposes patients to electrical instability. Advanced cardiac magnetic resonance imaging (MRI) modalities are being deployed to detect myocardial fibrosis and tissue characterization in this regard.

In parallel, the team is analyzing myocardial tissue biopsies obtained during surgery to discern cellular and molecular alterations characteristic of fibrotic and inflammatory pathways within the ventricular myocardium. Decoding these mechanisms holds the potential to identify novel biomarkers predictive of arrhythmic risk and targets for therapeutic intervention aimed at myocardial stabilisation.

This study represents a paradigm-shifting advance in the understanding of valvular heart disease and its intersection with cardiac electrophysiology. It teaches that structural valve repair, while essential, does not invariably translate into resolution of electrical dysregulation caused by underlying myocardial abnormalities. At a time when sudden cardiac arrest remains a leading cause of mortality worldwide, identifying higher-risk subsets and tailoring follow-up care accordingly can fundamentally improve patient survival and quality of life.

The collaborative research efforts led by Bahira Shahim alongside Magnus Dalén and Klara Lodin at Karolinska Institutet underscore the power of integrating surgical, cardiologic, and research expertise to confront complex cardiovascular challenges. Funded by multiple Swedish research foundations and institutional grants, this study exemplifies the crucial role of well-supported clinical research in transforming patient care paradigms.

For clinicians, the critical takeaway is clear: patients with mitral valve prolapse complicated by mitral annular disjunction require not only surgery but also comprehensive longitudinal arrhythmia surveillance and possibly adjunctive therapies. For patients and families, awareness of this persistent risk is vital to ensure early symptom recognition and timely medical intervention. For the broader research community, these findings open new avenues for investigating the molecular substrates of arrhythmogenesis associated with mitral apparatus abnormalities.

As research progresses, the hope is that advanced imaging, genetic profiling, and novel pharmacological agents can synergistically mitigate arrhythmia risk in this vulnerable population, heralding a new era of precision cardiovascular medicine tailored to individual structural and electrophysiologic phenotypes. Until then, this pivotal study serves as a clarion call to both clinicians and patients to remain vigilant long after the operating room lights dim.

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Subject of Research: People

Article Title: Mitral annular disjunction and mitral valve prolapse: long-term risk of ventricular arrhythmias after surgery

News Publication Date: 15-Apr-2025

Web References:
https://academic.oup.com/eurheartj/article-lookup/doi/10.1093/eurheartj/ehaf195
http://dx.doi.org/10.1093/eurheartj/ehaf195

References:
Lodin K, Da Silva C, Wang Gottlieb A, Bulatovic I, Rück A, George I, Cohen DJ, Braunschweig F, Svenarud P, Eriksson MJ, Haugaa KH, Dalén M, Shahim B. “Mitral annular disjunction and mitral valve prolapse: long-term risk of ventricular arrhythmias after surgery.” European Heart Journal. 2025 Apr 15. doi: 10.1093/eurheartj/ehaf195.

Keywords:
Health and medicine, Surgery, Heart disease, Cardiac arrest, Heart muscle, Cardiac arrhythmias, Cardiology, Heart failure