Orphanet Journal of Rare Diseases | Left Ventricular Hypertrabeculation as a Novel Predictor of Life-Threatening Arrhythmic Events in Long QT Syndrome Patients

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This study is the first to systematically evaluate the clinical features and genetic mutations in long QT syndrome (LQTS) patients with left ventricular hypertrabeculation (LVHT), identifying LVHT as an independent risk factor for life-threatening arrhythmic events in LQTS patients, offering a new biomarker for clinical risk stratification.

 

Literature Overview

The article titled 'Left ventricular hypertrabeculation is a novel predictor of life-threatening arrhythmic events in long QT syndrome patients' was published in Orphanet Journal of Rare Diseases, Volume 20, 2025. It reviews and summarizes the prevalence of LVHT among LQTS patients and analyzes its correlation with life-threatening arrhythmic events (LAEs), proposing that LVHT serves as a novel predictor of malignant cardiac events in LQTS.

Background Knowledge

Long QT syndrome (LQTS) is a hereditary arrhythmia disorder usually characterized by a structurally normal heart but with a predisposition to torsades de pointes (Tdp), syncope, or even sudden cardiac death. Left ventricular hypertrabeculation (LVHT), also known as left ventricular noncompaction, is characterized by excessive trabeculations in the ventricular myocardium. It was once considered a benign anatomical variant, but recent studies have linked it to arrhythmias, heart failure, and thromboembolism. Although both LQTS and LVHT are rare diseases, clinical case reports have shown coexistence of LVHT and LQTS, suggesting potential genetic or pathophysiological overlap. Currently, genetic screening and ECG assessment for LQTS are well-established, while diagnostic criteria for LVHT remain controversial, with differing imaging standards (e.g., Jenni and Petersen criteria) yet to be unified. This study aims to clarify the clinical characteristics, genetic background, and prognosis of LQTS patients with LVHT, providing new evidence for clinical diagnosis and intervention.

 

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Study Methods and Experiment

The study enrolled 170 genetically confirmed LQTS patients, categorized into LQTS-LVHT group (n=8) and LQTS without LVHT group (LQTS-N-LVHT, n=162) based on established LVHT diagnostic criteria. A retrospective analysis of clinical history, ECG, 24-hour Holter monitoring, echocardiography, and cardiac MRI (CMR) data was conducted to compare differences in symptomatology, QTc interval, and arrhythmic events between the two groups. All patients were followed up for 52.8±32.3 months, during which major arrhythmic events (LAEs) were recorded. Kaplan-Meier survival analysis and Cox proportional hazards models were used to assess the predictive value of LVHT for LAEs.

Key Findings and Insights

• 8 out of 170 (4.7%) LQTS patients met the diagnostic criteria for LVHT, suggesting that LVHT coexistence in LQTS is not uncommon.
• The LQTS-LVHT group showed a higher incidence of ventricular fibrillation (VF) documented on Holter monitoring (25.0% vs 2.7%, p=0.036), indicating that LVHT may exacerbate arrhythmic risk.
• Although no significant differences were observed in QTc, Schwartz score, PVC burden, or Tdp incidence between the groups, Kaplan-Meier analysis revealed significantly lower arrhythmic event-free survival in the LQTS-LVHT group (p<0.001).
• Multivariate Cox regression analysis confirmed LVHT as an independent predictor of LAEs (HR: 3.02, 95% CI: 1.24–7.36, p=0.015).
• Genetic analysis revealed coexistence of mutations in LQTS-associated genes (KCNH2, KCNQ1, SCN5A) and LVHT phenotypes, suggesting potential cross-regulation between gene function and myocardial development.
• Some LVHT patients experienced malignant events during follow-up despite β-blocker therapy, indicating the need for intensified management including ICD implantation and sympathetic denervation.

Significance and Future Directions

This study is the first to systematically demonstrate the clinical value of LVHT as a novel predictive biomarker for life-threatening arrhythmic events in LQTS patients, highlighting the need for routine cardiac imaging evaluation in LQTS diagnosis. Future studies should explore the genetic interaction mechanisms between LVHT and LQTS, the role of ion channels in trabecular myocardium development, and hormonal influences on phenotypic expression across genders. Additionally, broader multicenter studies are necessary to validate the prognostic significance of LVHT in LQTS patients.

 

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Conclusion

In summary, this study identifies a notable prevalence of LVHT among LQTS patients, significantly increasing the risk of malignant arrhythmic events. LVHT acts as an independent risk factor for syncope, ventricular tachycardia, and fibrillation in LQTS patients, and suggests that structural cardiac anomalies may further influence disease progression in the context of underlying genetic mutations. Kaplan-Meier and multivariate regression analyses demonstrate LVHT’s significant predictive value for LAEs. Therefore, enhanced cardiac imaging, particularly echocardiography or CMR, should be incorporated into the clinical evaluation of LQTS patients to screen for LVHT and improve risk stratification and intervention strategies. This study provides novel insights into the clinical management of LQTS patients with LVHT and underscores the importance of combined genotype-phenotype analysis in rare disease research.

 

Jing Yang, Kun Li, Fang Liu, Fulan Liu, and Ping Zhang. Left ventricular hypertrabeculation is a novel predictor of life-threatening arrhythmic events in long QT syndrome patients. Orphanet Journal of Rare Diseases.