Physical Activity and Functional Capacity in Patients With Congenital Long QT Syndrome

Background

Congenital long QT syndrome (LQTS) is a genetically determined channelopathy characterized by delayed ventricular repolarization, which may cause syncope, ventricular arrhythmias and sudden cardiac death. The three most frequent subtypes, associated with variants in KCNQ1 (LQT1), KCNH2 (LQT2) and SCN5A (LQT3), account for about 90% of genotype-positive cases and have specific arrhythmic triggers: exercise in LQT1, auditory stimuli in LQT2 and rest in LQT3.

Patients with LQTS have historically been advised against most sports. Recent American and European recommendations are less restrictive and favor shared decision-making, especially in asymptomatic genotype-positive, phenotype-negative individuals. Registry data suggest a low rate of sport-related events in athletes with LQTS who remain active under appropriate management, including beta-blocker therapy. On the other hand, children with LQTS have shown lower peak oxygen consumption and ventilatory anaerobic threshold than healthy controls, possibly due to beta-blocker-induced chronotropic limitation and deconditioning. There are no data on the physical activity profile and functional capacity of patients with LQTS followed in Brazilian clinical practice.

The Channelopathies Movement and Exercise Study (CANMOVE) is a broader initiative to analyze physical activity in patients with cardiac channelopathies. This project is its first step, focused on congenital LQTS.

Study design

Single-center observational study at the Heart Institute (Instituto do Coração, InCor), Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, Brazil. The study combines a historical cohort, with physical activity data partially obtained from a previously approved study on physical activity in patients with cardiac arrhythmias (SDC 5310/21/085), and prospective inclusion of new patients with LQTS during the study period. The control group will consist of patients with cardiac arrhythmias and a structurally normal heart already included in the previous study, selected by propensity score matching.

Procedures

1. Questionnaires: the International Physical Activity Questionnaire short form (IPAQ), validated for the Brazilian population; the 12-Item Short Form Health Survey (SF-12) for quality of life; and a structured questionnaire on daily life after diagnosis of arrhythmia or device implantation, including reasons for not exercising and the desire to engage in physical exercise. Questionnaires will be applied before the outpatient visit.
2. Resting 12-lead electrocardiogram (ECG): heart rate, baseline corrected QT interval (QTc) by Bazett's formula and presence of T-wave notching in at least three contiguous leads. Diagnosis of LQTS will follow the criteria of the 2022 European Society of Cardiology (ESC) guidelines for ventricular arrhythmias and prevention of sudden cardiac death.
3. Cardiopulmonary exercise testing (CPET): treadmill ramp protocol with continuous metabolic, ventilatory and 12-lead ECG monitoring until exhaustion. Variables include peak oxygen consumption (VO2 peak), ventilatory anaerobic threshold, respiratory compensation point, heart rate and blood pressure responses, and QTc at rest (supine and standing, with orthostatic provocation), at peak exercise and during recovery.
4. 24-hour Holter monitoring: continuous 3-channel ECG recording for arrhythmia detection and heart rate variability (HRV) analysis.
5. Genetic testing: next-generation sequencing (NGS) panel including genes associated with LQTS, with variant classification according to the American College of Medical Genetics and Genomics (ACMG) criteria and discussion by a multidisciplinary group. Genetic data will be obtained from the clinical database of the Arrhythmia Unit.

All prospective participants will undergo CPET and 24-hour Holter monitoring using a standardized protocol for patients with LQTS. Beta-blocker therapy and other treatments (antiarrhythmic drugs, implantable cardioverter-defibrillator [ICD], sympathectomy) will be recorded. Data will be collected from electronic medical records and stored in the Research Electronic Data Capture (REDCap) platform.

Statistical analysis

Approximately 60 patients with congenital LQTS are expected. Categorical variables will be presented as absolute and relative frequencies, and continuous variables as mean and standard deviation or median and interquartile range. Patients with LQTS will be compared with controls matched by propensity score, calculated by logistic regression. Associations between categorical variables will be assessed by chi-square or Fisher's exact test, and continuous variables will be compared by Student's t test or Mann-Whitney test, according to distribution. P values below 0.05 will be considered statistically significant.