Role of genetic testing in young patients with idiopathic atrioventricular conduction disease.

AIMS: To investigate the role of genetic testing in patients with idiopathic atrioventricular conduction disease requiring pacemaker (PM) implantation before the age of 50 years. METHODS AND RESULTS: All consecutive PM implantations in Southern Switzerland between 2010 and 2019 were evaluated. Inclusion criteria were: (i) age at the time of PM implantation: < 50 years; (ii) atrioventricular block (AVB) of unknown aetiology. Study population was investigated by ajmaline challenge and echocardiographic assessment over time. Genetic testing was performed using next-generation sequencing panel, containing 174 genes associated to inherited cardiac diseases, and Sanger sequencing confirmation of suspected variants with clinical implication. Of 2510 patients who underwent PM implantation, 15 (0.6%) were young adults (median age: 44 years, male predominance) presenting with advanced AVB of unknown origin. The average incidence of idiopathic AVB computed over the 2010-2019 time window was 0.7 per 100 000 persons per year (95% CI 0.4-1.2). Most of patients (67%) presented with specific genetic findings (pathogenic variant) or variants of uncertain significance (VUS). A pathogenic variant of PKP2 gene was found in one patient (6.7%) with no overt structural cardiac abnormalities. A VUS of TRPM4, MYBPC3, SCN5A, KCNE1, LMNA, GJA5 genes was found in other nine cases (60%). Of these, three unrelated patients (20%) presented the same heterozygous missense variant c.2531G > A p.(Gly844Asp) in TRPM4 gene. Diagnostic re-assessment over time led to a diagnosis of Brugada syndrome and long-QT syndrome in two patients (13%). No cardiac events occurred during a median follow-up of 72 months. CONCLUSION: Idiopathic AVB in adults younger than 50 years is a very rare condition with an incidence of 0.7 per 100 000 persons/year. Systematic investigations, including genetic testing and ajmaline challenge, can lead to the achievement of a specific diagnosis in up to 20% of patients. Heterozygous missense variant c.2531G > A p.(Gly844Asp) in TRPM4 gene was found in an additional 20% of unrelated patients, suggesting possible association of the variant with the disease.

Cardiovascular evaluation of middle-aged individuals engaged in high-intensity sport activities: implications for workload, yield and economic costs.

BACKGROUND: The European Association of Cardiovascular Prevention and Rehabilitation (EACPR) recommends cardiovascular evaluation of middle-aged individuals engaged in sport activities. However, very few data exist concerning the impact of such position stand. We assessed the implications on workload, yield and economic costs of this preventive strategy. METHODS: Individuals aged 35-65 years engaged in high-intensity sports were examined following the EACPR protocol. Athletes with abnormal findings or considered at high-cardiovascular risk underwent additional examinations. The costs of the overall evaluation until diagnosis were calculated according to Swiss medical rates. RESULTS: 785 athletes (73% males, 46.8±7.3 years) were enrolled over a 13-month period. Among them, 14.3% required additional examinations: 5.1% because of abnormal ECG, 4.7% due to physical examination, 4.1% because of high-cardiovascular risk and 1.6% due to medical history. A new cardiovascular abnormality was established in 2.8% of athletes, severe hypercholesterolaemia in 1% and type 2 diabetes in 0.1%. Three (0.4%) athletes were considered ineligible for high-intensity sports, all of them discovered through an abnormal ECG. No athlete was diagnosed with significant coronary artery disease on the basis of a high-risk profile or an exercise ECG. The cost was US$199 per athlete and US$5052 per new finding. CONCLUSIONS: Cardiovascular evaluation of middle-aged athletes detected a new cardiovascular abnormality in about 3% of participants and a high-cardiovascular risk profile in about 4%. Some of these warranted exclusion of the athlete from high-intensity sport. The overall evaluation seems to be feasible at reasonable costs.

Adherence to the medical regime in patients with heart failure.

AIMS: To assess adherence to medical treatment in patients with heart failure (HF) using a specific questionnaire and measurement of the serum concentration of digoxin. METHODS AND RESULTS: Forty patients with symptomatic HF and a clinical indication for digoxin were included in this pilot study. The assessment of adherence to the medical regime was based on two different methods: (i) the CARDIA-Questionnaire and (ii) the measurement of serum digoxin concentration (SDC) at 1 and 6 months. All patients were placed on digoxin treatment (target SDC 0.6-0.8 ng/mL) at baseline. Poor adherence was defined if the patient self-reported taking < or =75% of the prescribed HF medication or had an SDC < 0.4 ng/mL (subtherapeutic range) at the follow-up visits. During the entire follow-up, the proportion of patients with poor adherence was 15% as assessed by the questionnaire, 20% as assessed by the SDC, and 25% if both methods were combined. CONCLUSION: Although HF is a symptomatic disease, the proportion of patients with poor adherence to the medical regime in our study was high (up to 25%). The objective methodology based on the measurement of the SDC identified a higher number of patients with poor adherence when compared with the CARDIA-Questionnaire.

Cardiac work up in primary renal hypokalaemia-hypomagnesaemia (Gitelman syndrome).

BACKGROUND: Potassium and magnesium depletion prolongs the duration of the action potential of the cardiomyocyte, which predisposes to ventricular arrhythmias. In addition, potassium or magnesium depletion might impair cardiac performance and facilitate coronary artery thrombosis. METHODS: Continuous 24-h ambulatory electrocardiographic monitoring, treadmill exercise testing and echocardiography were assessed in 21 patients (11 female and 10 male subjects, aged 5.9-39, median 19 years) with primary renal hypokalaemia-hypomagnesaemia. RESULTS: The QT interval corrected for heart rate was normal (between 379 and 430 ms) in 10 and slightly to moderately prolonged in the remaining 11 patients (between 446 and 509 ms). Plasma potassium, magnesium and bicarbonate were similar in patients with normal and in those with prolonged QT interval. Continuous ambulatory electrocardiography over 24 h and exercise testing did not detect significant abnormalities of cardiac rhythm or features suggestive of myocardial ischaemia. Finally, echocardiographic and Doppler assessment failed to reveal any abnormalities in myocardial morphology and function. CONCLUSION: The QT interval is often prolonged in primary renal hypokalaemia-hypomagnesaemia, confirming that potassium and magnesium depletion tends to prolong the duration of the action potential of the cardiomyocyte. The results of continuous ambulatory electrocardiography, exercise testing and echocardiography are reassuring. Nonetheless, we assume that dangerous cardiac arrhythmias may occur in patients with very severe hypokalaemia, during medication with drugs that prolong the QT interval or in the context of short-term non-adherence to the recommended regimen of care.

Prevention of cardiac arrhythmias in pediatric patients with normotensive-hypokalemic tubulopathy. Current attitude among European pediatricians.

Potassium deficiency predisposes to cardiac arrhythmias culminating in syncope or sudden death. Because of the uncertainty related to the possible occurrence of such cardiac arrhythmias in the context of normotensive-hypokalemic tubulopathies, 19 European pediatric nephrologists with a large experience of normotensive-hypokalemic tubulopathies were asked to answer a questionnaire. The responses suggest that inherited normotensive-hypokalemic tubulopathies per se do not strongly predispose to dangerous cardiac arrhythmias. However, cardiac arrhythmias may be acutely precipitated by drugs that prolong the QT interval, by diarrhea, or vomiting, and perhaps even by physical activity. Finally, the likelihood of dangerous arrhythmias in normotensive-hypokalemic tubulopathy is currently unknown.