Threshold values by electrocardiogram and echocardiography indicating transition to an arrhythmic phenotype in cardiac laminopathies: a primary prevention cohort study
Authors: Rootwelt-Norberg C , Skjolsvik ET , Chivulescu M , Bogsrud MP , Ribe MP , Beitnes JO , Brekke PH , Haland TSF , Hasselberg NE , Lie OH , Haugaa KH 
Published: May 2022

Abstract

Funding Acknowledgements
Type of funding sources: Public grant(s) – EU funding. Main funding source(s): 1) Precision Health Care Center for optimized cardiac care (ProCardio) supported by the Norwegian Research Council
2) European Research Area Network on Cardiovascular Diseases (ERA-CVD)

Background/Introduction
Cardiac laminopathies are malignant and pro-arrhythmic variants of familial dilated cardiomyopathy caused by mutations in the LMNA gene. Correct timing of implantable cardioverter defibrillator (ICD) implantation is crucial in these patients, but optimal timing of primary preventive ICD remains a great challenge in clinical practice.

Purpose
We aimed to explore threshold values by electrocardiogram and echocardiography to identify transition to a more arrhythmic phenotype in LMNA disease.

Methods
We prospectively included consecutively recruited LMNA genotype positive patients in a primary prevention cohort study. Patients underwent repeated clinical-, electrocardiogram- and echocardiographic examinations during long-term follow-up. Ventricular arrhythmia was defined as sustained ventricular tachycardia, appropriate therapy by a primary preventive ICD or aborted cardiac arrest. We explored electrocardiographic and echocardiographic cut-off values for increased odds of experiencing first-time ventricular arrhythmia during follow-up by threshold regression analyses. The cardiac phenotype at time of ventricular arrhythmia was assessed from electrocardiogram recording and echocardiographic examinations acquired ±12 months of the arrhythmic event.

Results
We included 94 LMNA genotype positive patients with no history of ventricular arrhythmia at baseline (age 38±15 years, 32% probands, 53% female). Incidence of VA was 20% (19 patients) during 4.6 (inter quartile range [IQR] 2.1-7.3) years follow-up, at mean age 50±11 years. We analysed 261 electrocardiogram recordings and 536 echocardiographic examinations. At time of first ventricular arrhythmia, most patients had pronounced conduction delay (PR interval 312 [IQR 204-430] ms) and evident left ventricular pathology (left ventricular ejection fraction [LVEF] 40±12 %, left ventricular end diastolic volume indexed [LVEDVi] 83±22 ml/m2). Electrocardiographic threshold values for increased arrhythmic risk were PR interval 280 ms (OR 1.9, 95% CI 1.5-2.5, per 5 ms increase after threshold, p&lt;0.001), and QRS width 108 ms (OR 2.6, 95% CI 1.9-3.7, per 5 ms increase after threshold, p&lt;0.001). Echocardiographic threshold values were LVEF 44 % (OR 1.6, 95% CI 1.4-2.0, per 5 % decrease after threshold, p&lt;0.001), and LVEDVi threshold 77 ml/m2 (OR 1.5, 95% CI 1.3-1.8, per 5 ml/m2 increase after threshold, p&lt;0.001) (Figure).

Conclusions
Incidence of first time ventricular arrhythmic event was 20% in LMNA genotype positive patients during 4.6 years of follow up. PR interval &gt;280ms, LVEF &lt;44% or LVEDVi &gt;77 ml/m2 should alert the clinician of transition to a more arrhythmic phenotype in cardiac laminopathies and implantation of a primary preventive ICD should be considered.