Postema, Pieter G.

Abstract Background Increased QRS voltages in athletes’ ECGs are attributed to electrophysiological cellular adaptations, complicating the detection of left ventricular hypertrophy (LVH). Conversely, higher extracellular volume (ECV), indicative of diffuse fibrosis, reduces QRS voltages – so-called ‘relative voltage deficiency’– and can mask true LVH on ECG. Purpose To investigate sex-specific associations between QRS voltages and myocardial ECV and assess the impact of ECV on false-positive and negative ECG-LVH detection in elite athletes. Methods We conducted a cross-sectional, sex-specific, contrast-enhanced CMR study in healthy, elite athletes with normal ECGs and no complete right bundle branch blocks. Myocardial ECV (%) was measured from pre- and post-contrast T1 mapping. LVH on CMR was defined as an indexed LVM >75 g/m² (men) or >59 g/m² (women). Primary analyses evaluated correlations between ECV, LVM, and summed 12-lead ECG voltages (including voltage/LVM to assess independence), as well as Sokolow-Lyon and Cornell voltages. Secondary multivariable logistic regression examined the association of ECV on false-positive and false-negative ECG-LVH rates using Sokolow-Lyon (≥3.5 mV) and sex-specific Cornell (≥2.8 mV in men; ≥2.3 mV in women) criteria for CMR-LVH. Results In 162 elite athletes (median age 25 years, 44% female, 45% endurance, 96% Caucasian), 23% met Sokolow-Lyon criteria, 6% met Cornell criteria, and 17% had LVH on CMR. The median myocardial ECV was 23% (range 19–31%), which was lower in male compared to female athletes (22% [Q1-Q3: 21–23%] vs 25% [23–26%]; p<0.001). In both sexes, summed 12-lead voltages were inversely correlated with ECV (ρ=–0.36 to –0.37; p=0.001), independent of LVM (voltage/LVM: ρ=–0.33; p=0.004). Only in female athletes did 12-lead voltages correlate with LVM (ρ=0.37; p=0.001). Logistic regression confirmed that lower ECV was associated with an increased likelihood of false-positive Sokolow-Lyon (OR: 0.64 per 1% ECV increment; p=0.011), independent of body mass index (OR: 0.77 per kg/m²; p=0.039) male sex (OR: 2.7; p=0.123) and age (OR: 0.93 per year; p=0.075; AUROC 0.82). Higher ECV conferred greater odds of a false-negative (OR 3.98 per %; p=0.041), though this was limited by small LVH-positive sample size. In Cornell-based models, lower ECV was not statistically significantly associated with increased false-positive rate (OR 0.59; p=0.059). Conclusion In elite athletes, lower ECV ("denser" myocardium) is associated with increased QRS voltages and higher false-positive ECG-LVH rate, particularly for Sokolow-Lyon, while higher ECV may dampen voltages and can mask true LVH on the ECG. Although sex-specific criteria partly mitigate ECV-related effects, these findings demonstrate inherent limitations of voltage-based LVH criteria in athletes. Unexpectedly low QRS voltages in athletes with otherwise high LVM may imply increased ECV, though further research is warranted.Figure:Likelihood of False Pos SL rate Table:Population characteristics

Abstract The pharmacological provocation test is a pivotal tool in cardiac electrophysiology for the diagnosis of potential causes of sudden cardiac death, sudden cardiac arrest (SCA), arrhythmias, symptoms, or ECG abnormalities. The 2022 European Society of Cardiology Guidelines for the Treatment of Ventricular Arrhythmias and Prevention of Sudden Cardiac Death offered guidance on provocation testing but did not describe the indications and requirements in depth. This clinical consensus statement, led by the European Heart Rhythm Association and approved by major international stakeholders, aims to advise the general cardiologist and the arrhythmia expert who to test and when, where, and how to do it. The statement focuses on current practice for the diagnosis of subclinical arrhythmia syndromes and the causes of SCA, building upon the recommendations of the Guidelines. We address the sodium channel blocker provocation test for patients suspected of Brugada syndrome as well as the use of epinephrine, isoproterenol, adenosine, ergonovine, and acetylcholine.

Importance Sudden death and cardiac arrest frequently occur without explanation, even after a thorough clinical evaluation. Calcium release deficiency syndrome (CRDS), a life-threatening genetic arrhythmia syndrome, is undetectable with standard testing and leads to unexplained cardiac arrest. Objective To explore the cardiac repolarization response on an electrocardiogram after brief tachycardia and a pause as a clinical diagnostic test for CRDS. Design, Setting, and Participants An international, multicenter, case-control study including individual cases of CRDS, 3 patient control groups (individuals with suspected supraventricular tachycardia; survivors of unexplained cardiac arrest [UCA]; and individuals with genotype-positive catecholaminergic polymorphic ventricular tachycardia [CPVT]), and genetic mouse models (CRDS, wild type, and CPVT were used to define the cellular mechanism) conducted at 10 centers in 7 countries. Patient tracings were recorded between June 2005 and December 2023, and the analyses were performed from April 2023 to December 2023. Intervention Brief tachycardia and a subsequent pause (either spontaneous or mediated through cardiac pacing). Main Outcomes and Measures Change in QT interval and change in T-wave amplitude (defined as the difference between their absolute values on the postpause sinus beat and the last beat prior to tachycardia). Results Among 10 case patients with CRDS, 45 control patients with suspected supraventricular tachycardia, 10 control patients who experienced UCA, and 3 control patients with genotype-positive CPVT, the median change in T-wave amplitude on the postpause sinus beat (after brief ventricular tachycardia at ≥150 beats/min) was higher in patients with CRDS ( P < .001). The smallest change in T-wave amplitude was 0.250 mV for a CRDS case patient compared with the largest change in T-wave amplitude of 0.160 mV for a control patient, indicating 100% discrimination. Although the median change in QT interval was longer in CRDS cases ( P = .002), an overlap between the cases and controls was present. The genetic mouse models recapitulated the findings observed in humans and suggested the repolarization response was secondary to a pathologically large systolic release of calcium from the sarcoplasmic reticulum. Conclusions and Relevance There is a unique repolarization response on an electrocardiogram after provocation with brief tachycardia and a subsequent pause in CRDS cases and mouse models, which is absent from the controls. If these findings are confirmed in larger studies, this easy to perform maneuver may serve as an effective clinical diagnostic test for CRDS and become an important part of the evaluation of cardiac arrest.

Abstract In the early nineties, few years before the birth of Europace, the clinical and scientific world of familial arrhythmogenic conditions was revolutionized by the identification of the first disease-causing genes. The explosion of genetic studies over a 15-year period led to the discovery of major disease-causing genes in practically all channelopathies and cardiomyopathies, bringing insight into the pathophysiological mechanisms of these conditions. The birth of next generation sequencing allowed a further step forward and other significant genes, as CALM1–3 in channelopathies and FLN C and TTN in cardiomyopathies were identified. Genotype–phenotype studies allowed the implementation of the genetic results in diagnosis, risk stratification, and therapeutic management with a different level of evidence in different arrhythmogenic conditions. The influence of common genetic variants, i.e. SNPs, on disease manifestation was proved in mid-twenties, and in the last 10 years with the advent of genome-wide association studies performed in familial arrhythmogenic diseases, the concept of polygenic risk score has been consolidated. Now, we are at the start of another amazing phase, i.e. the initiation of first gene therapy clinical trials.

Background: Long QT syndrome (LQTS) is a rare genetic disorder and a major preventable cause of sudden cardiac death in the young. A causal rare genetic variant with large effect size is identified in up to 80% of probands (genotype positive) and cascade family screening shows incomplete penetrance of genetic variants. Furthermore, a proportion of cases meeting diagnostic criteria for LQTS remain genetically elusive despite genetic testing of established genes (genotype negative). These observations raise the possibility that common genetic variants with small effect size contribute to the clinical picture of LQTS. This study aimed to characterize and quantify the contribution of common genetic variation to LQTS disease susceptibility. Methods: We conducted genome-wide association studies followed by transethnic meta-analysis in 1656 unrelated patients with LQTS of European or Japanese ancestry and 9890 controls to identify susceptibility single nucleotide polymorphisms. We estimated the common variant heritability of LQTS and tested the genetic correlation between LQTS susceptibility and other cardiac traits. Furthermore, we tested the aggregate effect of the 68 single nucleotide polymorphisms previously associated with the QT-interval in the general population using a polygenic risk score. Results: Genome-wide association analysis identified 3 loci associated with LQTS at genome-wide statistical significance ( P <5×10 −8 ) near NOS1AP , KCNQ1 , and KLF12 , and 1 missense variant in KCNE1 (p.Asp85Asn) at the suggestive threshold ( P <10 −6 ). Heritability analyses showed that ≈15% of variance in overall LQTS susceptibility was attributable to common genetic variation ( h2SNP 0.148; standard error 0.019). LQTS susceptibility showed a strong genome-wide genetic correlation with the QT-interval in the general population (r g =0.40; P =3.2×10 −3 ). The polygenic risk score comprising common variants previously associated with the QT-interval in the general population was greater in LQTS cases compared with controls ( P <10−13), and it is notable that, among patients with LQTS, this polygenic risk score was greater in patients who were genotype negative compared with those who were genotype positive ( P <0.005). Conclusions: This work establishes an important role for common genetic variation in susceptibility to LQTS. We demonstrate overlap between genetic control of the QT-interval in the general population and genetic factors contributing to LQTS susceptibility. Using polygenic risk score analyses aggregating common genetic variants that modulate the QT-interval in the general population, we provide evidence for a polygenic architecture in genotype negative LQTS.