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.

Association of left atrial enlargement and increased left ventricular wall thickness with arrhythmia recurrence after cryoballoon ablation for atrial fibrillation.

BACKGROUND: Left atrial enlargement (LAE) predicts atrial fibrillation (AF) recurrence after cryoballoon-based pulmonary vein isolation (CB). Increased left ventricular wall thickness (LVWT) is pathophysiologically associated with LAE and atrial arrhythmias. AIMS: To assess effect of increased LVWT on long-term outcomes of CB depending on coexistence of LAE. METHODS: LAE was defined using either echocardiography ( > 48 cm³/m²) or multislice computer tomography (MSCT, ≥63 cm³/m²). Increased LVWT was echocardiographic septal/posterior wall thickness > 10 mm in males and > 9 mm in females. All patients achieved 2-year follow-up. RESULTS: Of 250 patients (median [interquartile range, IQR] age of 61 [49.0-67.3] years; 30% female) with AF (40% non-paroxysmal), 66.5% had hypertension, and 27.2% underwent redo procedure. MSCT was done in 76%. During follow-up of 24.5 (IQR, 6.0-31.00) months the clinical success rate was 72%, despite 46% of patients having arrhythmia recurrence. Arrhythmia recurrence risk was increased by LAE and increased LVWT (hazard ratio [HR], 1.801; P = 0.002 and HR, 1.495; P = 0.036; respectively). The highest arrhythmia recurrence (61.9% at 2 years) was among patients with LAE and increased LVWT (33.6% of patients); intermediate (41.8%) among patients with isolated LAE; and lowest among patients with isolated increased LVWT or patients without LAE or increased LVWT (36.8% and 35.2% respectively, P = 0.004). After adjustment for body mass index (BMI), paroxysmal AF, CHA2DS2-VASc score, clinically-significant valvular heart disease, and cardiomyopathy, patients with LAE and concomitant increased LVWT diagnosis had a 1.8-times increased risk of arrhythmia recurrence (HR, 1.784; 95% confidence interval [CI], 1.017-3.130; P = 0.043). CONCLUSION: Joint occurrence of LAE and increased LVWT is associated with the highest rate of arrhythmia recurrence after CB for AF.

Association between the acquisition of antibodies against Lyme disease and the risk of atrial arrhythmias.

INTRODUCTION: The impact of antibodies against Borrelia burgdorferi (BB) on the occurrence of cardiac arrhythmias in patients without typical symptoms of Lyme disease (LD) is largely unknown. OBJECTIVES: We aimed to assess the risk of atrial fibrillation (AF) and other atrial arrhythmias (AAs) in patients who tested positive for anti-LD antibodies. PATIENTS AND METHODS: We included consecutive patients referred for the diagnosis and treatment of AAs who had no history of erythema migrans or other symptoms of LD. The presence of anti-BB antibodies (immunoglobulin [Ig] M and IgG) was assessed in each patient, and the diagnostic workup of cardiac arrhythmias was performed. RESULTS: Of the 527 patients enrolled in the study, 292 (55%) were diagnosed with AAs, and we detected BB antibodies in 131 individuals (24.8%). The patients with a serological history of Borrelia infection were older (mean [SD], 55.6 [15.7] vs 50.3 [18.6] years; P = 0.01), had a higher probability of developing AF or other supraventricular arrhythmias (SAs) (66.4% vs 51.8%; P = 0.03), and had elevated levels of N­terminal pro-B ­type natriuretic peptide (NT­proBNP) (58% vs 47.5%; P = 0.04). We also found an as-sociation between the occurrence of AF and other SAs in patients with anti-BB antibodies and elevated NT­proBNP values, and the risk of AAs in these patients increased almost 3­fold (P = 0.01). CONCLUSION: Our data indicated an association between the exposure to Borrelia infection and the risk for AF and other AAs in the patients with elevated levels of NT­proBNP, suggesting the need for a more efficacious diagnostic approach to patients with SAs, especially in LD­endemic regions.

Titin-Related Dilated Cardiomyopathy: The Clinical Trajectory and the Role of Circulating Biomarkers in the Clinical Assessment.

Titin truncating variants (TTNtv) are known as the leading cause of inherited dilated cardiomyopathy (DCM). Nevertheless, it is unclear whether circulating cardiac biomarkers are helpful in detection and risk assessment. We sought to assess 1) early indicators of cardiotitinopathy including the serum biomarkers high-sensitivity cardiac troponin T (hs-cTnT) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) in clinically stable patients, and 2) predictors of outcome among TTNtv carriers. Our single-center cohort consisted of 108 TTNtv carriers (including 70 DCM patients) from 43 families. Clinical, laboratory and follow-up data were analyzed. The earliest abnormality was left ventricular dysfunction, present in 8, 26 and 47% of patients in the second, third and fourth decade of life, respectively. It was followed by symptoms of heart failure, linked to NT-proBNP elevation and severe left ventricular systolic dysfunction, and later by arrhythmias. Hs-cTnT serum levels were increased in the late stage of the disease only. During the median follow-up of 5.2 years, both malignant ventricular arrhythmia (MVA) and end-stage heart failure (esHF) occurred in 12% of TTNtv carriers. In multivariable analysis, NT-proBNP level ≥650 pg/mL was the best predictor of both composite endpoints (MVA and esHF) and of MVA alone. In conclusion, echocardiographic abnormalities are the first detectable anomalies in the course of cardiotitinopathies. The assessment of circulating cardiac biomarkers is not useful in the detection of the disease onset but may be helpful in risk assessment.

A Novel DSP Truncating Variant in a Family with Episodic Myocardial Injury in the Course of Arrhythmogenic Cardiomyopathy-A Possible Role of a Low Penetrance NLRP3 Variant.

Mono-allelic dominant mutations in the desmoplakin gene (DSP) have been linked to known cardiac disorders, such as arrhythmogenic right ventricular cardiomyopathy and dilated cardiomyopathy. During the course of DSP cardiomyopathy, episodes of acute myocardial injury may occur. While their mechanisms remain unclear, myocarditis has been postulated as an underlying cause. We report on an adolescent girl with arrhythmogenic biventricular cardiomyopathy and three acute myocarditis-like episodes in whom we found a novel truncating DSP variant accompanied by a known low penetrance R490K variant in the NLRP3. Upon family screening, other carriers of the DSP variant have been identified in whom only mild cardiac abnormalities were found. We hypothesized that the uncommon course of cardiomyopathy in the proband as well as striking discrepancies in the phenotype observed in her family may be explained by the co-existence of her low penetrance genetic autoinflammatory predisposition.

A combination of quinidine/mexiletine reduces arrhythmia in dilated cardiomyopathy in two patients with R814W SCN5A mutation.

SCN5A gene mutations are described in 2% of patients with dilated cardiomyopathy (DCM) and different rhythm disturbances, including multifocal ectopic Purkinje-related premature contractions. Recent data indicate that sodium channel blockers are particularly effective monotherapy in carriers of the R222Q SCN5A variant. Our purpose is to describe the effectiveness of antiarrhythmic treatment in a family with genetically determined arrhythmogenic DCM associated with the R814W variant in the SCN5A gene. We examined a family with arrhythmogenic DCM (multifocal ectopic Purkinje-related premature contractions phenotype, atrial tachyarrhythmias, automatism, and conduction disorders) and described antiarrhythmic treatment efficacy in heart failure symptoms reduction and myocardial function improvement. We found a heterozygotic mutation R814W in SCN5A by whole exome sequencing in the proband and confirmed its presence in all affected subjects. There were two sudden cardiac deaths and one heart transplantation among first-degree relatives. The 58-year-old father and his 37-year-old daughter had full spectrum of symptoms associated with R814W SCN5A mutation. Both had implanted cardioverter defibrillator. In the father, adding mexiletine to quinidine therapy reduced ventricular arrhythmia (50-60% â†’ 6-8% of whole rhythm) and reverted long-standing atrial fibrillation to sinus rhythm. In the daughter, mexiletine and overdrive pacing were effective in ventricular arrhythmia reduction (25% â†’ 0.01%). Because of a growing number of atrial fibrillation recurrences, a reduced dose of quinidine (subsequently flecainide) was added, resulting in arrhythmia significant reduction. In both cases, antiarrhythmic effectiveness correlated with clinical improvement. In SCN5A R814W-associated DCM, a combination of Class I antiarrhythmics and overdrive pacing is an effective treatment of severe ventricular and atrial arrhythmias.

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.

Analysis of De Novo Mutations in Sporadic Cardiomyopathies Emphasizes Their Clinical Relevance and Points to Novel Candidate Genes.

The vast majority of cardiomyopathies have an autosomal dominant inheritance; hence, genetic testing is typically offered to patients with a positive family history. A de novo mutation is a new germline mutation not inherited from either parent. The purpose of our study was to search for de novo mutations in patients with cardiomyopathy and no evidence of the disease in the family. Using next-generation sequencing, we analyzed cardiomyopathy genes in 12 probands. In 8 (66.7%), we found de novo variants in known cardiomyopathy genes (TTN, DSP, SCN5A, TNNC1, TPM1, CRYAB, MYH7). In the remaining probands, the analysis was extended to whole exome sequencing in a trio (proband and parents). We found de novo variants in genes that, so far, were not associated with any disease (TRIB3, SLC2A6), a possible disease-causing biallelic genotype (APOBEC gene family), and a de novo mosaic variant without strong evidence of pathogenicity (UNC45A). The high prevalence of de novo mutations emphasizes that genetic screening is also indicated in cases of sporadic cardiomyopathy. Moreover, we have identified novel cardiomyopathy candidate genes that are likely to affect immunological function and/or reaction to stress that could be especially relevant in patients with disease onset associated with infection/infestation.

Positional sleep disordered breathing in patients with arrhythmia. Should we advise our patients to avoid supine position during sleep?

BACKGROUND: Sleep disordered breathing [SDB] is a well-known problem in patients with cardiovascular diseases. Around 50% of pts. with SDB present positional sleep disordered breathing [PSDB]. AIMS: The aim of this study was the investigation of the frequency of PSDB in patients with different forms of arrhythmias. METHODS: We analyzed the presence of SDB in 53 pts. with diagnosed atrial fibrillation (paroxysmal or persistent), 88 pts. before ablation of ventricular ectopy and 110 pts. that had Holter monitoring due to the symptoms suggesting arrhythmia. RESULTS: Finally, we could collect all the data in 243 pts. - 150 men 93 women. AHI < 15 was recorded in 136 (56%) pts., AHI > 15 in 107 (44%) pts. Moderate sleep disordered breathing was diagnosed in 59 (24%) pts. (AHI 15-30), severe sleep disordered breathing (AHI > 30) was recognized in 48 (20%) pts. In all of the analyzed groups, AHI in supine position was significantly higher than in nonsupine position. PSDB was recorded in 55% of pts. with AHI > 15 and in 29% of pts. (n = 14) with AHI > 30. Percentage of time in supine position was an independent factor related with the presence of at least moderate or severe sleep disordered breathing. CONCLUSION: 1. Moderate or severe SDB is recorded in 44% of pts. with arrhythmias, almost 50% of them have positional SDB. 2. Percent of time of sleeping in supine position has an important independent impact on the presence of SDB. 3. Big studies should be conducted to verify if avoidance of sleeping in supine position may improve clinical outcome. CONDENSED ABSTRACT: Sleep disordered breathing SDB is a frequent problem of pts. with cardiovascular diseases. It may influence the prognosis. Moderate or severe SDB is recorded in 44% of pts. with arrhythmias, almost 50% of them have positional SDB. Percent of time of sleeping in supine position has an important independent impact on the presence of SDB. 3. Big studies should be conducted to verify if avoidance of sleeping in supine position may improve clinical outcome. What is new?

Impact of exercise-based cardiac rehabilitation on attitude to the therapy, aims in life and professional work in patients after myocardial infarction.

BACKGROUND: Comprehensive cardiac rehabilitation aims to restore pathophysiological and psychosocial consequences of myocardial infarction (MI). The aim of the study was to assess how exercise-only-based cardiac rehabilitation (ECR) influences the attitude to the therapy (ATT), to the aims in life and professional work (AAL) amongst men and women after MI. MATERIAL AND METHODS: The study comprised 44 post-MI patients: 28 men and 16 women, mean age 58±10 years old, referred to ECR. Patients underwent 24 interval cycle ergometer trainings 3 times a week. At the beginning and after the training program (TP) each patient underwent exercise stress test (EST) and was scored to ATT and ALL based on the Psychological Effects of Rehabilitation Score Scale (PERSS) according to Tylka and Makowska. The analysis covered: 1) EST findings: maximal workload and test duration (min), 2) ATT and AAL based on PERSS, 3) resuming professional work. RESULTS: Exercise capacity improved significantly after TP. Attitude to the aims in life and professional work significantly increased in the whole group (4.4±2.8 vs. 5.1±2.4, p < 0.01) and separately in men (4.5±2.9 vs. 5.1±2.5, p < 0.05) and women (4.3±2.6 vs. 5.0±2.0, p < 0.05). Attitude to the therapy did not change significantly in the whole group (5.6±2.8 vs. 6.0±2.8) and in men (5.9±2.9 vs. 6.0±2.9), but increased significantly in women (5.0±2.5 vs. 6.1±2.7, p < 0.05). Professional work was resumed, averagely by 86.4% of all patients (85.7% men and 87.5% women). CONCLUSIONS: Physical training beneficially influenced post-MI men's and women's attitude to the aims in life, professional work and attitude to the therapy in women. Med Pr. 2019;70(1):1-7.

Sudden cardiac arrest in patients without overt heart disease: a limited value of next generation sequencing.

INTRODUCTION Unexplained sudden cardiac arrest (SCA), occurs in up to 10% of patients and is often attributed to an inherited arrhythmia syndrome. Family screening and genetic testing may help clarify the cause of unexplained SCA. OBJECTIVES We aimed to assess the usefulness of clinical evaluation and genetic testing in patients after unexplained SCA and in their families. PATIENTS AND METHODS In the years 2014-2017, we studied 44 unrelated patients after unexplained SCA and 96 of their relatives. All patients and relatives underwent comprehensive cardiac evaluation. In 31 patients with SCA, next generation sequencing (NGS) was performed. The Kaplan-Meier survival curve was constructed to compare the event-free survival depending on clinical diagnosis or genotype. An adverse event was defined as an adequate implantable cardioverter-defibrillator discharge. RESULTS Based on the clinical evaluation, diagnosis was established in 39% of probands (long QT syndrome 21%; short QT syndrome 7%; Brugada syndrome 7%; catecholaminergic polymorphic ventricular tachycardia, 2%; and early repolarization syndrome, 2%). Ventricular arrhythmia was identified in the relatives of 19% of probands. In 18 of the 31 probands (54.8%), 23 rare gene variants were identified, of which only 2 were classified as pathogenic. The event-free survival over a median of 4.5 years was similar in patients with or without clinical diagnosis and in carriers and noncarriers of a rare genetic variant. CONCLUSIONS This study shows the significance of an extensive clinical assessment in unexplained SCA victims and their relatives. Routine genetic testing by NGS has low diagnostic and prognostic value.

Rapid and effective response of the R222Q SCN5A to quinidine treatment in a patient with Purkinje-related ventricular arrhythmia and familial dilated cardiomyopathy: a case report.

BACKGROUND: Mutations of the SCN5A gene are reported in 2-4% of patients with dilated cardiomyopathy (DCM). In such cases, DCM is associated with different rhythm disturbances such as the multifocal ectopic Purkinje-related premature contractions and atrial fibrillation. Arrhythmia often occurs at a young age and is the first symptom of heart disease. CASE PRESENTATION: We present the case of 55-year old male with a 30-year history of heart failure (HF) in the course of familial DCM and complex ventricular tachyarrhythmias, which constituted 50-80% of the whole rhythm. The patient was qualified for heart transplantation because of the increasing symptoms of HF. We revealed the heterozygotic R222Q mutation in SCN5A by means of whole exome sequencing. After the quinidine treatment, a rapid and significant reduction of ventricular tachyarrhythmias and an improvement in the myocardial function were observed and this effect remained constant in the 2.5-year follow-up. This effect was observed even in the presence of concomitant coronary artery disease. CONCLUSIONS: Patients with familial DCM and Purkinje-related ventricular arrhythmias should be offered genetic screening. The quinidine treatment for the SCN5A R222Q mutation can be life saving for patients.

Ventricular fibrillation induced by radiofrequency energy delivery for premature ventricular contractions arising from the right ventricular outflow tract: is implantablecardioverterdefibrillator indicated?

INTRODUCTION    Inadvertently induced ventricular fibrillation (VF) by radiofrequency (RF) energy delivery for premature ventricular complexes (PVCs) is a rare phenomenon; nevertheless, it is crucial to assess long­term risk of sudden cardiac death in these patients. OBJECTIVES    The aim of our study was to define the long­term prognosis in patients with normal ejection fraction (EF), in whom VF was inadvertently induced by RF energy application during ablation of symptomatic idiopathic PVCs originating from the right ventricular outflow tract (RVOT). PATIENTS AND METHODS    Among over 20 000 RF catheter ablations performed at 5 tertiary centers (2008-2016), 6 patients (5 men) had VF induced by RF application to the RVOT. The mean (SD) age of patients was 35.2 (16.8) years. All patients had normal EF (≥60%). We analyzed the risk of malignant ventricular arrhythmias and assessed heart function during follow­up. RESULTS    After ablation, baseline contrast­enhanced magnetic resonance imaging was performed in 4 of the 6 patients; no area of late gadolinium enhancement was observed. One patient received an implantable cardioverter­defibrillator (ICD). Exercise tests revealed only rare PVCs. All patients completedthe follow­up (mean [SD] duration of follow­up, 64.0 [34.9] months). All patients were alive, with no cases of syncope, documented ventricular tachycardia, or VF. The patient with an ICD received 2 inappropriate high­voltage therapies. CONCLUSIONS    Patients with inadvertently induced VF via RF energy application during ablation of PVCs from the RVOT, who have normal left ventricular function and no electrocardiography abnormalities have good prognosis and low VF risk during long­term follow­up. Therefore, ICD placement seems to be not indicated for these patients.