Clinical and genetic yield of familial screening after a sudden unexplained death at a young age.

BACKGROUND: In a population under 45 years of age, the predominant causes of sudden cardiac death (SCD) are inherited cardiac diseases. Determining the underlying cause may help identify relatives at risk and prevent further events but is more difficult if an autopsy has not been performed. AIMS: We aimed to assess the diagnostic value of clinical and genetic screening in relatives of young non-autopsied sudden unexplained death (SUD) victims. MATERIAL AND METHODS: Eighty-seven relatives of 65 young non-autopsied SUD victims from 39 families were evaluated from 2016 to 2019. The relatives underwent extensive noninvasive cardiac workup. Genetic examinations were performed in 39 families. RESULTS: The definite diagnoses were made in 17 of 39 (44%) families. Cardiomyopathies were identified in 10 families (5 hypertrophic, 4 dilated, and 1 arrhythmogenic), followed by long QT syndrome (5 families). In 3 families, probable diagnoses were made, whereas in 20 families no diagnosis was achieved. In total, definite and probable diagnoses were made in 18 and 5 patients, respectively. All affected relatives were offered medical management, one of them died of heart failure and one underwent transplantation during the median follow-up of 3 years. Disease-causing variants were found in 7 of 39 (18%) probands; all in families with a definite diagnosis. Variants of unknown significance were found in 2 probands. CONCLUSION: Screening of relatives of SUD victims is warranted and may save lives, even if it is not guided by autopsy results. Genetic testing in families without the disease phenotype has little effectiveness.

Outcomes of transcatheter pulmonary SAPIEN 3 valve implantation: an international registry.

BACKGROUND AND AIMS: Transcatheter pulmonary valve implantation (TPVI) is indicated to treat right-ventricular outflow tract (RVOT) dysfunction related to congenital heart disease (CHD). Outcomes of TPVI with the SAPIEN 3 valve that are insufficiently documented were investigated in the EUROPULMS3 registry of SAPIEN 3-TPVI. METHODS: Patient-related, procedural, and follow-up outcome data were retrospectively assessed in this observational cohort from 35 centres in 15 countries. RESULTS: Data for 840 consecutive patients treated in 2014-2021 at a median age of 29.2 (19.0-41.6) years were obtained. The most common diagnosis was conotruncal defect (70.5%), with a native or patched RVOT in 50.7% of all patients. Valve sizes were 20, 23, 26, and 29 mm in 0.4%, 25.5%, 32.1%, and 42.0% of patients, respectively. Valve implantation was successful in 98.5% [95% confidence interval (CI), 97.4%-99.2%] of patients. Median follow-up was 20.3 (7.1-38.4) months. Eight patients experienced infective endocarditis; 11 required pulmonary valve replacement, with a lower incidence for larger valves (P = .009), and four experienced pulmonary valve thrombosis, including one who died and three who recovered with anticoagulation. Cumulative incidences (95%CI) 1, 3, and 6 years after TPVI were as follows: infective endocarditis, 0.5% (0.0%-1.0%), 0.9% (0.2%-1.6%), and 3.8% (0.0%-8.4%); pulmonary valve replacement, 0.4% (0.0%-0.8%), 1.3% (0.2%-2.4%), and 8.0% (1.2%-14.8%); and pulmonary valve thrombosis, 0.4% (0.0%-0.9%), 0.7% (0.0%-1.3%), and 0.7% (0.0%-1.3%), respectively. CONCLUSIONS: Outcomes of SAPIEN 3 TPVI were favourable in patients with CHD, half of whom had native or patched RVOTs.

Exercise-Induced Arrhythmia or Munchausen Syndrome in a Marathon Runner?

A 36-year-old professional marathon runner reported sudden irregular palpitations occurring during competitions, with heart rates (HR) up to 230 bpm recorded on a sports HR monitor (HRM) over 4 years. These episodes subsided upon the cessation of exercise. Electrocardiograms, echocardiography, and cardiac magnetic resonance imaging results were borderline for athlete's heart. Because an electrophysiology study and standard exercise tests provoked no arrhythmia, doctors suspected Munchausen syndrome. Ultimately, an exercise test that simulated the physical effort of a competition provoked tachyarrhythmia consistent with the HRM readings. This case demonstrates the diagnostic difficulties related to exercise-induced arrhythmia and the diagnostic usefulness of sports HRMs.

Reintervention and Survival After Transcatheter Pulmonary Valve Replacement.

BACKGROUND: Transcatheter pulmonary valve (TPV) replacement (TPVR) has become the standard therapy for postoperative pulmonary outflow tract dysfunction in patients with a prosthetic conduit/valve, but there is limited information about risk factors for death or reintervention after this procedure. OBJECTIVES: This study sought to evaluate mid- and long-term outcomes after TPVR in a large multicenter cohort. METHODS: International registry focused on time-related outcomes after TPVR. RESULTS: Investigators submitted data for 2,476 patients who underwent TPVR and were followed up for 8,475 patient-years. A total of 95 patients died after TPVR, most commonly from heart failure (n = 24). The cumulative incidence of death was 8.9% (95% CI: 6.9%-11.5%) 8 years after TPVR. On multivariable analysis, age at TPVR (HR: 1.04 per year; 95% CI: 1.03-1.06 per year; P < 0.001), a prosthetic valve in other positions (HR: 2.1; 95% CI: 1.2-3.7; P = 0.014), and an existing transvenous pacemaker/implantable cardioverter-defibrillator (HR: 2.1; 95% CI: 1.3-3.4; P = 0.004) were associated with death. A total of 258 patients underwent TPV reintervention. At 8 years, the cumulative incidence of any TPV reintervention was 25.1% (95% CI: 21.8%-28.5%) and of surgical TPV reintervention was 14.4% (95% CI: 11.9%-17.2%). Risk factors for surgical reintervention included age (0.95 per year [95% CI: 0.93-0.97 per year]; P < 0.001), prior endocarditis (2.5 [95% CI: 1.4-4.3]; P = 0.001), TPVR into a stented bioprosthetic valve (1.7 [95% CI: 1.2-2.5]; P = 0.007), and postimplant gradient (1.4 per 10 mm Hg [95% CI: 1.2-1.7 per 10 mm Hg]: P < 0.001). CONCLUSIONS: These findings support the conclusion that survival and freedom from reintervention or surgery after TPVR are generally comparable to outcomes of surgical conduit/valve replacement across a wide age range.

Implantable cardiac defibrillator events in patients with arrhythmogenic right ventricular cardiomyopathy.

OBJECTIVE: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is associated with a risk of sudden cardiac death. Optimal risk stratification is still under debate. The main purpose of this long-term, single-centre observation was to analyse predictors of appropriate and inappropriate implantable cardioverter-defibrillator (ICD) interventions in the population of patients with ARVC with a high risk of life-threatening arrhythmias. METHODS: The study comprised 65 adult patients (median age 40 years, 48 men) with a definite diagnosis of ARVC who received ICD over a time span of 20 years in primary (40%) or secondary (60%) prevention of sudden cardiac death. The study endpoints were first appropriate and inappropriate ICD interventions (shock or antitachycardia pacing) after device implantation. RESULTS: During a median follow-up of 7.75 years after ICD implantation, nine patients died and six individuals underwent heart transplantation. Appropriate ICD interventions occurred in 43 patients (66.2%) and inappropriate ICD interventions in 18 patients (27.7%). Multivariable analysis using cause-specific hazard model identified three predictors of appropriate ICD interventions: right ventricle dysfunction (cause-specific HR 2.85, 95% CI 1.56 to 5.21, p<0.001), age <40 years at ICD implantation (cause-specific HR 2.37, 95% CI 1.13 to 4.94, p=0.022) and a history of sustained ventricular tachycardia (cause-specific HR 2.55, 95% CI 1.16 to 5.63, p=0.020). Predictors of inappropriate ICD therapy were not found. Complications related to ICD implantation occurred in 12 patients. CONCLUSIONS: Right ventricle dysfunction, age <40 years and a history of sustained ventricular tachycardia were predictors of appropriate ICD interventions in patients with ARVC. The results may be used to improve risk stratification before ICD implantation.

Multicenter Study of Endocarditis After Transcatheter Pulmonary Valve Replacement.

BACKGROUND: Endocarditis has emerged as one of the most impactful adverse events after transcatheter pulmonary valve replacement (TPVR), but there is limited information about risk factors for and outcomes of this complication. OBJECTIVES: The purpose of this study was to evaluate risk factors for and outcomes of endocarditis in a large multicenter cohort. METHODS: The authors established an international registry focused on characterizing endocarditis after TPVR, including the incidence, risk factors, characteristics, and outcomes. RESULTS: Investigators submitted data for 2,476 patients who underwent TPVR between July 2005 and March 2020 and were followed for 8,475 patient-years. In total, 182 patients were diagnosed with endocarditis a median of 2.7 years after TPVR, for a cumulative incidence of 9.5% (95% CI: 7.9%-11.1%) at 5 years and 16.9% (95% CI: 14.2%-19.8%) at 8 years (accounting for competing risks: death, heart transplant, and explant) and an annualized incidence of 2.2 per 100 patient-years. Staphylococcus aureus and Viridans group Streptococcus species together accounted for 56% of cases. Multivariable analysis confirmed that younger age, a previous history of endocarditis, and a higher residual gradient were risk factors for endocarditis, but transcatheter pulmonary valve type was not. Overall, right ventricular outflow tract (RVOT) reintervention was less often to treat endocarditis than for other reasons, but valve explant was more often caused by endocarditis. Endocarditis was severe in 44% of patients, and 12 patients (6.6%) died, nearly all of whom were infected with Staphylococcus aureus. CONCLUSIONS: The incidence of endocarditis in this multicenter registry was constant over time and consistent with prior smaller studies. The findings of this study, along with ongoing efforts to understand and mitigate risk, will be critical to improve the lifetime management of patients with heart disease involving the RVOT. Although endocarditis can be a serious adverse outcome, TPVR remains an important tool in the management of RVOT dysfunction.

Quality and utility of [123I]I-metaiodobenzylguanidine cardiac SPECT imaging in nondiabetic postinfarction heart failure patients qualified for implantable cardioverter defibrillator.

OBJECTIVE: Impaired cardiac adrenergic activity has been demonstrated in heart failure (HF) and in diabetes mellitus (DM). [123I]I-metaiodobenzylguanidine (MIBG) enables assessment of the cardiac adrenergic nervous system. Tomographic imaging of the heart is expected to be superior to planar imaging. This study aimed to determine the quality and utility of MIBG SPECT in the assessment of cardiac innervation in postinfarction HF patients without DM, qualified for implantable cardioverter defibrillator (ICD) in primary prevention of sudden cardiac death. METHODS: Consecutive patients receiving an ICD on the basis of contemporary guidelines were prospectively included. Planar MIBG studies were followed by SPECT. The essential analysis was based on visual assessment of the quality of SPECT images ("high", "low" or "unacceptable"). The variables used in the further analysis were late summed defect score for SPECT images and heart-to-mediastinum rate for planar images. MIBG images were assessed independently by two experienced readers. RESULTS: Fifty postinfarction nondiabetic HF subjects were enrolled. In 13 patients (26%), the assessment of SPECT studies was impossible. In addition, in 13 of 37 patients who underwent semiquantitative SPECT evaluation, the assessment was equivocal. Altogether, in 26/50 patients (52%, 95% confidence interval 38-65%), the quality of SPECT images was unacceptable or low and was limited by low MIBG cardiac uptake and by comparatively high, interfering MIBG uptake in the neighboring structures (primarily, in the lungs). CONCLUSIONS: The utility of MIBG SPECT imaging, at least with conventional imaging protocols, in the qualification of postinfarction HF patients for ICD, is limited. In approximately half of the postinfarction HF patients, SPECT assessment of cardiac innervation can be impossible or equivocal, even without additional damage from diabetic cardiac neuropathy. The criteria predisposing the patient to good-quality MIBG SPECT are: high values of LVEF from the range characterizing the patients qualified to ICD (i.e., close to 35%) and left lung uptake intensity in planar images comparable to or lower than heart uptake.

Systemic right ventricle in elderly patients with congenitally corrected transposition of the great arteries: Clinical profile, cardiac biomarkers, and echocardiographic parameters.

OBJECTIVE: The number of patients with congenitally corrected transposition of the great arteries (ccTGA) surviving to old age is increasing. This study therefore sought to characterize 'geriatric' systemic right ventricle (sRV) in terms of clinical profile, cardiac biomarkers, and echocardiography-derived function when compared with findings in younger patients. METHODS: A single-center cross-sectional study of adults with ccTGA was performed. Patients underwent clinical assessment; transthoracic echocardiography; and venous blood sampling including N-terminal pro-B-type natriuretic peptide (NTproBNP), galectin-3, and soluble suppression of tumorgenicity 2 (sST2) measurements. In the echocardiographic study, the sRV function was assessed using fractional area change (FAC), tricuspid annular plane systolic excursion (TAPSE), systolic pulsed-wave Doppler velocity (s'), and longitudinal strain (LS). RESULTS: Ten patients with ccTGA aged 60 years or older and 53 patients younger than 60 years of age were included. There were significantly more individuals with hypertension (40% vs. 5.7%), dyslipidaemia (50% vs. 5.7%), and atrial fibrillation (70% vs. 20.7%) in the older group; similarly, we found higher NTproBNP (2706 pg/mL vs. 784.7 pg/mL; p<0.001), and galectin-3 (10.15 ng/mL vs. 7.24 ng/mL; p=0.007) concentrations in elderly ccTGA individuals, while sST2 content did not vary significantly according to age. Upon echocardiographic assessment, lower sRV FAC (28.6% vs. 36.1%; p=0.028) and LS (-12% vs. -15.5%; p=0.017) values were observed in patients aged 60 years or older. TAPSE and s' did not differ between the age groups. CONCLUSION: Careful screening for acquired comorbidities, particularly atrial fibrillation, in elderly ccTGA patients is warranted. Examining selected cardiac biomarkers and echocardiography-derived parameters are useful in the assessment of the aging sRV.

Prolonged left ventricular contraction duration in apical segments as a marker of arrhythmic risk in patients with long QT syndrome.

AIMS: Long QT syndrome (LQTS) is an inherited cardiac ion channelopathy predisposing to life-threatening ventricular arrhythmias and sudden cardiac death. The aim of this study was to investigate left ventricular mechanical abnormalities in LQTS patients and establish a potential role of strain as a marker of arrhythmic risk. METHODS AND RESULTS: We included 47 patients with genetically confirmed LQTS (22 LQT1, 20 LQT2, 3 LQT3, and 2 SCN3B) and 25 healthy controls. A history of cardiac events was present in 30 LQTS subjects. Tissue Doppler and speckle tracking echocardiography were performed and contraction duration was measured by radial and longitudinal strain. The radial strain characteristic was subdivided into two planes - the basal and the apical. Left ventricular ejection fraction and global longitudinal strain were normal in LQTS patients. Mean contraction duration was longer in LQTS patients compared with controls in regard to basal radial strain (491 ± 57 vs. 437 ± 55 ms, P < 0.001), apical radial strain (450 ± 53 vs. 407 ± 53 ms, P = 0.002), and longitudinal strain (445 ± 34 vs. 423 ± 43 ms, P = 0.02). Moreover, contraction duration obtained from apical radial strain analysis was longer in symptomatic compared with asymptomatic LQTS mutation carriers (462 ± 49 vs. 429 ± 55 ms, P = 0.024), as well as in subject with mutations other than LQT1 considered to be at higher risk (468 ± 50 vs. 429 ± 49 ms, P = 0.01). CONCLUSION: Myocardial contraction duration is prolonged for both radial and longitudinal directions in LQTS patients. Regional left ventricular function analysis may contribute to risk stratification. Apical radial deformation seems to select subjects at higher risk of arrhythmic events.

Can Circulating Cardiac Biomarkers Be Helpful in the Assessment of LMNA Mutation Carriers?

Mutations in the lamin A/C gene are variably phenotypically expressed; however, it is unclear whether circulating cardiac biomarkers are helpful in the detection and risk assessment of cardiolaminopathies. We sought to assess (1) clinical characteristics including serum biomarkers: high sensitivity troponin T (hsTnT) and N-terminal prohormone brain natriuretic peptide (NT-proBNP) in clinically stable cardiolaminopathy patients, and (2) outcome among pathogenic/likely pathogenic lamin A/C gene (LMNA) mutation carriers. Our single-centre cohort included 53 patients from 21 families. Clinical, laboratory, follow-up data were analysed. Median follow-up was 1522 days. The earliest abnormality, emerging in the second and third decades of life, was elevated hsTnT (in 12% and in 27% of patients, respectively), followed by the presence of atrioventricular block, heart failure, and malignant ventricular arrhythmia (MVA). In patients with missense vs. other mutations, we found no difference in MVA occurrence and, surprisingly, worse transplant-free survival. Increased levels of both hsTnT and NT-proBNP were strongly associated with MVA occurrence (HR > 13, p ≤ 0.02 in both) in univariable analysis. In multivariable analysis, NT-proBNP level > 150 pg/mL was the only independent indicator of MVA. We conclude that assessment of circulating cardiac biomarkers may help in the detection and risk assessment of cardiolaminopathies.

Natural History and Risk Stratification in Andersen-Tawil Syndrome Type 1.

BACKGROUND: Andersen-Tawil Syndrome type 1 (ATS1) is a rare arrhythmogenic disorder, caused by loss-of-function mutations in the KCNJ2 gene. We present here the largest cohort of patients with ATS1 with outcome data reported. OBJECTIVES: This study sought to define the risk of life-threatening arrhythmic events (LAE), identify predictors of such events, and define the efficacy of antiarrhythmic therapy in patients with ATS1. METHODS: Clinical and genetic data from consecutive patients with ATS1 from 23 centers were entered in a database implemented at ICS Maugeri in Pavia, Italy, and pooled for analysis. RESULTS: We enrolled 118 patients with ATS1 from 57 families (age 23 ± 17 years at enrollment). Over a median follow-up of 6.2 years (interquartile range: 2.7 to 16.5 years), 17 patients experienced a first LAE, with a cumulative probability of 7.9% at 5 years. An increased risk of LAE was associated with a history of syncope (hazard ratio [HR]: 4.54; p = 0.02), with the documentation of sustained ventricular tachycardia (HR 9.34; p = 0.001) and with the administration of amiodarone (HR: 268; p < 0.001). The rate of LAE without therapy (1.24 per 100 person-years [py]) was not reduced by beta-blockers alone (1.37 per 100 py; p = 1.00), or in combination with Class Ic antiarrhythmic drugs (1.46 per 100 py, p = 1.00). CONCLUSIONS: Our data demonstrate that the clinical course of patients with ATS1 is characterized by a high rate of LAE. A history of unexplained syncope or of documented sustained ventricular tachycardia is associated with a higher risk of LAE. Amiodarone is proarrhythmic and should be avoided in patients with ATS1.

Heart of the World's Top Ultramarathon Runner-Not Necessarily Much Different from Normal.

The impact of ultramarathon (UM) runs on the organs of competitors, especially elite individuals, is poorly understood. We tested a 36-year-old UM runner before, 1-2 days after, and 10-11 days after winning a 24-h UM as a part of the Polish Championships (258.228 km). During each testing session, we performed an electrocardiogram (ECG), transthoracic echocardiography (TTE), cardiac magnetic resonance imaging (MRI), cardiac 31P magnetic resonance spectroscopy (31P MRS), and blood tests. Initially, increased cholesterol and low-density lipoprotein cholesterol (LDL-C) levels were identified. The day after the UM, increased levels of white blood cells, neutrophils, fibrinogen, alanine aminotransferase, aspartate aminotransferase, creatine kinase, C-reactive protein, and N-terminal type B natriuretic propeptide were observed. Additionally, decreases in hemoglobin, hematocrit, cholesterol, LDL-C, and hyponatremia were observed. On day 10, all measurements returned to normal levels, and cholesterol and LDL-C returned to their baseline abnormal values. ECG, TTE, MRI, and 31P MRS remained within the normal ranges, demonstrating physiological adaptation to exercise. The transient changes in laboratory test results were typical for the extreme efforts of the athlete and most likely reflected transient but massive striated muscle damage, liver cell damage, activation of inflammatory processes, effects on the coagulation system, exercise-associated hyponatremia, and cytoprotective or growth-regulatory effects. These results indicated that many years of intensive endurance training and numerous UMs (including the last 24-h UM) did not have a permanent adverse effect on this world-class UM runner's body and heart. Transient post-competition anomalies in laboratory test results were typical of those commonly observed after UM efforts.

Early outcomes of percutaneous pulmonary valve implantation using the Edwards SAPIEN 3 transcatheter heart valve system.

AIMS: Multiple surgical revisions are often necessary in individuals with congenital heart defects affecting the RVOT or pulmonary valve. There are no multicentre data on the feasibility and safety of percutaneous pulmonary valve implantation (PPVI) using the SAPIEN 3 (S3) transcatheter heart valve. The aim of this study was to explore the short-term safety, feasibility, and haemodynamic outcomes of PPVI using the S3 transcatheter heart valve. METHODS AND RESULTS: Pulmonic S3 is an observational registry of patients undergoing PPVI with the S3 valve across centres in Europe and Canada. Data for 82 patients (mean age 27.3 years) were obtained. The most common underlying diagnosis was tetralogy of Fallot (ToF) (58.5%), with 16.0% of patients having native RVOT anatomy; 90.2% received pre-stenting. Prosthesis dislodgement occurred in one patient and conduit perforation in another. Both were successfully resolved without the need for open surgery. Peak systolic gradient over the RVOT fell from 46.3 mmHg to 17.2 mmHg, moderate/severe pulmonary regurgitation from 86.3% to 0.0%, and NYHA ≥II from 86.0% to 15.2%. During follow-up, valve thrombosis was observed in two patients which resolved with adequate anticoagulation. No other procedural complications, endocarditis, stent fracture or death were reported within two years. CONCLUSIONS: PPVI with the S3 valve appears feasible and safe in a wide range of patients with congenital heart defects, with good short-term haemodynamic and functional outcomes.

Identification novel LQT syndrome-associated variants in Polish population and genotype-phenotype correlations in eight families.

Congenital long QT syndrome (LQTS) is a primary cardiac channelopathy. Genetic testing has not only diagnostic but also prognostic and therapeutic implications. At present, 15 genes have been associated with the disease, with most mutations located in 3 major LQTS-susceptibility genes. During a routine genetic screening for KCNQ1, KCNH2 and SCN5A genes in index cases with LQTS, seven novel variants in KCNH2 and SCN5A genes were found. Genotype-phenotype correlations were analysed in these patients and their families. An open reading frame and splice site analysis of the exons was conducted using next-generation sequencing. In novel variants, phenotypes of carriers and their affected relatives were analysed. In 39 unrelated patients, 40 pathogenic/putative pathogenic mutations were found. Thirty-three of them, predominantly missense, were reported previously: 11 were in the KCNQ, 17 in the KCNH2 and 5 in the SCN5A gene. Seven novel missense variants were found in eight families. Among them, four variants were in typical for LQTS location. Two variants in the KCNH2 gene (p.D803Y and p.D46F) and one in the SCN5A gene (G1391R) were in amino acid (AA) position which up to present has not been reported in LQTS. Phenotype analysis showed the life-threatening course of the disease in index cases with a history of sudden cardiac death in six families. Mutation carriers presented with ECG abnormalities and some of them received beta-blocker therapy. We report three novel variants (KCNQ1 p.46, KCNH2 p.D803Y, SCN5A p.G1391R) which have never been reported for this AA location in LQTS; the phenotype-genotype correlation suggests their pathogenicity.