ERRATUM: Genetic testing for inherited cardiovascular diseases. A position statement of the Polish Cardiac Society endorsed by Polish Society of Human Genetics and Cardiovascular Patient Communities.

According to the latest guidelines of European and American medical societies, genetic testing (GT) is essential in cardiovascular diseases for establishing diagnosis, predicting prognosis, enabling initiation of disease-modifying therapy, and preventing sudden cardiac death. The GT result may be relevant for cascade GT in the patient's relatives, for planning his/her profession and physical activity, and for procreative counseling. This position statement has been prepared due to the scarcity of GT in cardiovascular diseases in Poland and the need to expand its availability. We give a concise description of the genetic background of cardiomyopathies, channelopathies, aortopathies, familial hypercholesterolemia, pheochromocytomas, and paragangliomas. The article discusses various aspects of GT in specific populations, such as children or athletes, and also presents prenatal genetic diagnostics. We propose recommendations for GT and counselling, which take into account Polish needs and capabilities. We give an outline of legal regulations, good clinical practice in GT with respect for patient rights, the role of cardiologists and clinical geneticists in GT planning and post-test counseling, and the requirements for laboratories performing genetic tests. The Polish Cardiac Society and Polish Society of Human Genetics experts speak with one voice with cardiovascular patient communities to underline the need for a law on GT and increasing the availability of GT for cardiovascular patients.

Genetic testing for inherited cardiovascular diseases. A position statement of the Polish Cardiac Society endorsed by Polish Society of Human Genetics and Cardiovascular Patient Communities.

According to the latest guidelines of European and American medical societies, genetic testing (GT) is essential in cardiovascular diseases for establishing diagnosis, predicting prognosis, enabling initiation of disease-modifying therapy, and preventing sudden cardiac death. The GT result may be relevant for cascade GT in the patient's relatives, for planning his/her profession and physical activity, and for procreative counseling. This position statement has been prepared due to the scarcity of GT in cardiovascular diseases in Poland and the need to expand its availability. We give a concise description of the genetic background of cardiomyopathies, channelopathies, aortopathies, familial hypercholesterolemia, pheochromocytomas, and paragangliomas. The article discusses various aspects of GT in specific populations, such as children or athletes, and also presents prenatal genetic diagnostics. We propose recommendations for GT and counselling, which take into account Polish needs and capabilities. We give an outline of legal regulations, good clinical practice in GT with respect for patient rights, the role of cardiologists and clinical geneticists in GT planning and post-test counseling, and the requirements for laboratories performing genetic tests. The Polish Cardiac Society and Polish Society of Human Genetics experts speak with one voice with cardiovascular patient communities to underline the need for a law on GT and increasing the availability of GT for cardiovascular patients.

Implantable cardioverter defibrillator use in arrhythmogenic right ventricular cardiomyopathy in North America and Europe.

BACKGROUND AND AIMS: Implantable cardioverter-defibrillators (ICDs) are critical for preventing sudden cardiac death (SCD) in arrhythmogenic right ventricular cardiomyopathy (ARVC). This study aims to identify cross-continental differences in utilization of primary prevention ICDs and survival free from sustained ventricular arrhythmia (VA) in ARVC. METHODS: This was a retrospective analysis of ARVC patients without prior VA enrolled in clinical registries from 11 countries throughout Europe and North America. Patients were classified according to whether they received treatment in North America or Europe and were further stratified by baseline predicted VA risk into low- (<10%/5 years), intermediate- (10%-25%/5 years), and high-risk (>25%/5 years) groups. Differences in ICD implantation and survival free from sustained VA events (including appropriate ICD therapy) were assessed. RESULTS: One thousand ninety-eight patients were followed for a median of 5.1 years; 554 (50.5%) received a primary prevention ICD, and 286 (26.0%) experienced a first VA event. After adjusting for baseline risk factors, North Americans were more than three times as likely to receive ICDs {hazard ratio (HR) 3.1 [95% confidence interval (CI) 2.5, 3.8]} but had only mildly increased risk for incident sustained VA [HR 1.4 (95% CI 1.1, 1.8)]. North Americans without ICDs were at higher risk for incident sustained VA [HR 2.1 (95% CI 1.3, 3.4)] than Europeans. CONCLUSIONS: North American ARVC patients were substantially more likely than Europeans to receive primary prevention ICDs across all arrhythmic risk strata. A lower rate of ICD implantation in Europe was not associated with a higher rate of VA events in those without ICDs.

Coronary artery disease in older adults with congenital heart defects: risk factors and pharmacotherapy.

INTRODUCTION: With advancing age, adults with congenital heart disease (ACHD) are at a higher risk of developing atherosclerotic coronary artery disease (CAD). OBJECTIVES: We aimed to determine the prevalence of CAD, its risk factors, and use of guideline­directed pharmacotherapy among older patients with ACHD.  Patients and methods: We studied all ACHD patients aged 60 years or older hospitalized in our department between the years 2013 and 2020. CAD was defined as a history of acute coronary syndrome or coronary revascularization, or more than 50% diameter stenosis on coronary angiography. Data regarding the underlying heart defect, prevalence of cardiovascular risk factors, and drug prescriptions were collected. RESULTS: A total of 198 patients with known coronary artery status (mean [SD] age, 66.2 [5.3] years; 43.3% men) were included in the analysis. Of them, 54 (27.3%) had CAD. The individuals with CAD were more often men, and they were more likely to have a mild heart defect, dyslipidemia, and a history of hypertension and tobacco use. Multivariable analysis showed that male sex (P = 0.001), dyslipidemia (P = 0.003), and hypertension (P = 0.04) were positive independent predictors of CAD, whereas overweight / obesity was identified as a negative independent predictor (P = 0.04). The proportion of CAD patients on antiplatelet and / or anticoagulant drugs was 92.6%. ß­Blockers were prescribed to 87% of the patients, and a lipid­lowering agent to 96% of the study population. CONCLUSIONS: CAD is common in older patients with ACHD. Our results underline the importance of identification and treatment of modifiable CAD risk factors in individuals with ACHD. The obesity paradox might also play a role in this population. The rate of guideline­recommended pharmacotherapy implementation seems to be satisfactory.

A new model for predicting adverse outcomes in arrhythmogenic right ventricular cardiomyopathy.

INTRODUCTION: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a progressive disease leading to ventricular arrhythmias and heart failure. Determining optimal time for heart transplantation (HTx) is challenging; therefore, it is necessary to identify risk factors for disease progression. OBJECTIVES: The study aimed to identify predictors of end­stage heart failure and to evaluate the role of biomarkers in predicting adverse outcomes in ARVC. PATIENTS AND METHODS: A total of 91 individuals with ARVC (59 men; mean [SD] age, 47 [16] years) were included. In all patients, information on medical history was collected, electrocardiography and echocardiography were performed, and serum levels of selected biomarkers (soluble form of the ST2 protein [sST2], galectin­3 [Gal­3], extracellular matrix metalloproteinases [MMP­2 and MMP­9], N­terminal pro-B­type natriuretic peptide [NT­proBNP], and high­sensitivity troponin T [hs­TnT]) were measured. Thereafter, the participants were followed for the primary end point of death or HTx, as well as the secondary end point of major arrhythmic events (MAEs), defined as sudden cardiac death, ventricular fibrillation, sustained ventricular tachycardia, or appropriate implantable cardioverter­defibrillator intervention. RESULTS: During the median (interquartile range) follow­up of 36.4 (29.8-41.2) months, 13 patients (14%) reached the primary end point of death or HTx, and 27 (30%) experienced MAEs. The patients who achieved the primary end point had higher levels of sST2, MMP­2, NT­proBNP, and hs­TnT, but not of Gal-3 and MMP-9. Three factors turned out to be independent predictors of death or HTx: higher NT­proBNP concentration (≥890.3 pg/ml), greater right ventricular end­diastolic area (≥39 cm2), and a history of atrial tachycardia. None of the biomarkers predicted MAEs. CONCLUSIONS: An NT­proBNP concentration greater than or equal to 890.3 pg/ml, right ventricular end-diastolic area of 39 cm2 or greater, and a history of atrial tachycardia were identified as risk factors for death or HTx in ARVC. Higher levels of sST2, MMP­2, NT­proBNP, and hs­TnT were associated with reaching the primary end point of death or HTx. The biomarkers had no value in predicting ventricular arrhythmias.

Predictors of COVID-19 outcomes in adult congenital heart disease patients - anatomy versus function.

BACKGROUND: It is unclear whether patients with adult congenital heart disease (ACHD) should be considered as an increased risk population with poor outcomes when suffering from COVID-19. AIMS: This study aimed to collect clinical outcome data and to identify risk factors of a complicated course of COVID-19 among ACHD patients. METHODS: Among all outpatients who came to medical attention via telemedicine or direct physician contact at our institution between September 1, 2020 and March 31, 2021, we included all with a COVID-19 diagnosis. The incidence of COVID-19, a clinical course of the disease, and outcome were determined. RESULTS: One hundred and four (8.7%) out of 1 197 patients who were seen at our outpatient clinic for ACHD patients met the definition of COVID-19. Most of them reported a mild course of COVID-19 (99 [95.5%]). Five patients (4.5%) experienced severe symptoms and needed hospitalization. Two patients (1.9% of all with a confirmed diagnosis, 40% with severe infection) died. In the multivariable analysis, decreased systemic ventricular systolic function and any significant valve stenosis were predictors of a complicated disease course. CONCLUSIONS: Our study confirmed previous results showing that a physiology-based model, rather than an anatomy-based model, better predicted COVID-19 outcomes among ACHD patients, which is of importance for patients and healthcare providers during the COVID-19 pandemic.

Pathogenic variants in plakophilin-2 gene (PKP2) are associated with better survival in arrhythmogenic right ventricular cardiomyopathy.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is mainly caused by mutations in genes encoding desmosomal proteins. Variants in plakophilin-2 gene (PKP2) are the most common cause of the disease, associated with conventional ARVC phenotype. The study aims to evaluate the prevalence of PKP2 variants and examine genotype-phenotype correlation in Polish ARVC cohort. All 56 ARVC patients fulfilling the current criteria were screened for genetic variants in PKP2 using denaturing high-performance liquid chromatography or next-generation sequencing. The clinical evaluation involved medical history, electrocardiogram, echocardiography, and follow-up. Ten variants (5 frameshift, 2 nonsense, 2 splicing, and 1 missense) in PKP2 were found in 28 (50%) cases. All truncating variants are classified as pathogenic/likely pathogenic, while the missense variant is classified as variant of uncertain significance. Patients carrying a PKP2 mutation were younger at diagnosis (p = 0.003), more often had negative T waves in V1-V3 (p = 0.01), had higher left ventricular ejection fraction (p = 0.04), and were less likely to present symptoms of heart failure (p = 0.01) and left ventricular damage progression (p = 0.04). Combined endpoint of death or heart transplant was more frequent in subgroup without PKP2 mutation (p = 0.03). Pathogenic variants in PKP2 are responsible for 50% of ARVC cases in the Polish population and are associated with a better prognosis. ARVC patients with PKP2 mutation are less likely to present left ventricular involvement and heart failure symptoms. Combined endpoint of death or heart transplant was less frequent in this group.

Pregnancy-related cardiac non-elective hospitalizations and pregnancy outcomes. A tertiary referral cardiac center experience.

BACKGROUND: Pregnant women with cardiovascular diseases (CVD) and their offspring are at higher risk of morbidity and mortality. AIMS: To provide data on pregnancy outcomes among women with different types of CVD requiring non-elective cardiac hospitalization in a tertiary referral cardiac center. METHODS: We identified all records of non-elective hospitalizations of pregnant women hospitalized between January 2009 through March 2018, at our institution - a tertiary referral cardiac center. The incidence and types of cardiac complications during pregnancy, as well as the pregnancy and offspring outcomes, were determined. RESULTS: One hundred and sixty-one out of 328 pregnancy-related hospitalizations in 140 pregnancies were non-elective. Cardiac complications occurred in 62 (44%) pregnancies, with the most frequent being episodes of arrhythmia (22.1% pregnancies), followed by heart failure exacerbations (6.4% pregnancies). Maternal mortality reached 2.1% and affected only women with primary cardiomyopathies (CMP). Offspring mortality was 2.8%. Newborns of mothers with cardiac complications had significantly lower Apgar scores and gestational age at delivery, compared to mothers without cardiac complications. CONCLUSIONS: In our series mortality and morbidity among pregnant women with CVD hospitalizations were high. An unfavorable maternal outcome mainly affected women with CMP. Offspring of mothers with cardiovascular complications are prone to have a lower gestational age and Apgar score.

The impact of pulmonary regurgitation on right ventricular size and function in patients with repaired tetralogy of Fallot and additional haemodynamic abnormalities.

PURPOSE: Right ventricular (RV) outflow tract obstruction (RVOTO) was demonstrated to be protective against RV dilatation in patients with repaired tetralogy of Fallot and chronic pulmonary regurgitation (PR). We hypothesised that the presence of additional haemodynamic abnormalities (more than mild tricuspid regurgitation, residual ventricular septal defect) reduces this protective association. Accordingly, we aimed to assess the impact of PR on RV size and function in this population. MATERIAL AND METHODS: Consecutive patients with additional haemodynamic abnormalities after tetralogy of Fallot (TOF) repair, who had undergone cardiovascular magnetic resonance, were included. RESULTS: Out of 90 patients studied, 18 individuals (mean age 32.5 ± 10.7 years, 72.2% males) met the inclusion criteria. There were no differences in RV volumes and ejection fraction between patients with and without RVOTO. Neither PR fraction (PRF) nor PR volume (PRV) correlated with RV end-diastolic volume (r = 0.36; p = 0.15 and r = 0.37; p = 0.14, respectively, for PRF and PRV) or RV end-systolic volume (r = 0.2; p = 0.42 and r = 0.19; p = 0.45, respectively, for PRF and PRV). Similarly, no significant correlations were observed between PRF or PRV and RV ejection fraction (r = -0.04; p = 0.87 and r = -0.03; p = 0.9, respectively). CONCLUSIONS: Additional haemodynamic abnormalities are associated with the abolition of the protective effect of RVOTO on RV size. There was no significant relationship between measures of PR and RV volumes in patients after TOF repair with concomitant haemodynamic abnormalities. These abnormalities acted as confounding factors in the assessment of the impact of pulmonary regurgitation on RV size and function.

Galectin-3 plasma levels in adult congenital heart disease and the pressure overloaded right ventricle: reason matters.

Aim: To assess galectin-3 (Gal-3) levels and their relationship with clinical status and right ventricular (RV) performance in adults with RV pressure overload of various mechanisms due to congenital heart disease. Materials & methods: A cross-sectional study was conducted. Patients underwent clinical examination, blood testing and transthoracic echocardiography. Results: The study included 63 patients with congenitally corrected transposition of the great arteries, 41 patients with Eisenmenger syndrome and 20 healthy controls. Gal-3 concentrations were higher in patients compared with controls (7.83 vs 6.11 ng/ml; p = 0.002). Biomarker levels correlated with age, New York Health Association class, N-terminal probrain natriuretic peptide and RV function only in congenitally corrected transposition of the great arteries patients. Conclusion: Gal-3 profile in congenital heart disease patients and pressure-overloaded RV differs according to the cause of pressure overload.

A Recurrent Exertional Syncope and Sudden Cardiac Arrest in a Young Athlete with Known Pathogenic p.Arg420Gln Variant in the RYR2 Gene.

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is one of causes of sudden cardiac death in the young, especially in athletes. Diagnosis of CPVT may be difficult since all cardiological examinations performed at rest are usually normal, and exercise stress test-induced ventricular tachycardia is not commonly present. The identification of a pathogenic mutation in RYR2 or CASQ2 is diagnostic in CPVT. We report on a 20-year-old athlete who survived two sudden cardiac arrests during swimming. Moreover, he suffered repeated syncopal spells on exercise. The diagnosis was made only following genetic testing using a multi-gene panel, and the p.Arg420Gln RYR2 variant was identified. We present diagnostic and therapeutic issues in this young athlete with CPVT.

Factors associated with the need for pulmonary valve replacement in asymptomatic patients with isolated pulmonary regurgitation after repair of tetralogy of Fallot: a cardiac magnetic resonance study.

BACKGROUND: Pulmonary regurgitation (PR) is the most common late complication in patients after repair of tetralogy of Fallot (TOF). Most patients remain asymptomatic over years, but eventually, the compensatory mechanisms fail, leading to right ventricular (RV) dilation and dysfunction, limited exercise capacity, ventricular arrhythmia, and sudden death. AIMS: We aimed to evaluate associations between cardiac magnetic resonance (CMR) parameters and the need for either surgical or percutaneous pulmonary valve replacement (PVR) in asymptomatic patients with significant PR after repair of TOF. METHODS: Of 209 patients with repaired TOF who had undergone a CMR study, we selected 61 asymptomatic patients with moderate­to­severe PR and followed them for up to 4 years (mean [SD], 21.4 [13.7] months). We excluded patients with residual ventricular septal defect, a peak RV outflow tract gradient of 30 mm Hg or higher, or at least moderate tricuspid regurgitation. RESULTS: Receiver operating characteristic curve analyses revealed that the ratio of RV to left ventricular (LV) volume (RV/ LV ratio; threshold >2.4) and PR fraction (PRF; threshold >33%) had acceptable discriminatory capacity to differentiate between patients requiring PVR and those treated conservatively. The Cox proportional hazards regression and the Kaplan­Meier curves revealed that the RV / LV ratio and PRF was significantly associated with the need for PVR. The combination of the RV / LV ratio and PRF provided significant discrimination in terms of survival without PVR (P <0.001; log­rank test for trend). CONCLUSIONS: The RV/ LV ratio and PRF were significantly associated with the need for PVR in asymptomatic patients with isolated moderate­to­severe PR after repair of TOF.

Transcatheter pulmonary valve implantation in 100 patients: a 10-year single-center experience.

Introduction: Transcatheter pulmonary valve implantation (TPVI) is a non-surgical method of treatment for patients with right ventricular outflow tract (RVOT) dysfunction after surgical repair of congenital heart defects (CHD). Aim: To evaluate the long-term results of TPVI performed in a single center.Material and methods: Over 10 years, TPVI was performed in 100 patients (mean age: 26.4 ±8.1 years), using Melody Medtronic or Sapien Edwards valves. Results: The initial success rate of TPVI was 93%. In 7 cases (5 urgent), a switch to surgical intervention was necessary due to periprocedural complications (all patients survived). Following TPVI, none of the 93 patients had severe pulmonary regurgitation. The pulmonary gradient decreased from 49.0 ±37.8 before to 27.6 ±14.9 mm Hg directly after TPVI (p < 0.0001). Right ventricular end-diastolic volume decreased, while NYHA class and pVO2 uptake significantly improved in 1 year after TPVI. Freedom from reintervention was 100% in 1 year. Freedom from serious adverse events was 86% in mean 5.5 years of observation. The main reason for reintervention was infective endocarditis (IE) (1.6% patients/year). Increased risk of IE was associated with severe PS before valve implantation and the suboptimal result of TPVI. The incidence of IE seems to be lower in patients treated permanently with antiplatelet therapy (1.8% vs. 0.9% patients/year, NS). Conclusions: TPVI is a safe and effective method of treatment in patients with RVOT dysfunction after surgical correction of CHD. To achieve a good outcome, precise patient selection and rigorous IE prevention are necessary.

Coincidence of Andersen-Tawil syndrome and Marfan syndrome: A case report.

We report on a 44-year-old woman with coincidence of two genetic disorders: Andersen-Tawil syndrome and Marfan syndrome. In both, life-threatening arrhythmias could occur. A 44-year-old woman presented acute ascending aortic dissection with aortic arch involvement and chronic thoracic descending and abdominal aortic dissection. Clinical and genetic examination confirmed Marfan syndrome (MFS) diagnosis. Due to repolarization disorder in ECG and premature ventricular contractions in Holter ECG, the sequencing data were analyzed again and mutation in KCNJ2 gene was identified. The case showed that coincidence of Andersen-Tawil syndrome (ATS) and MFS did not provoke life-threatening arrhythmias. Complication was rather caused by expression of FBN1 mutation.

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.

Pregnancy After Transcatheter Pulmonary Valve Implantation.

Transcatheter pulmonary valve implantation (TPVI) is a relatively new method of treating patients with significant pulmonary regurgitation or pulmonary stenosis, or both, after reconstruction of the right ventricular outflow tract. It is an attractive alternative to conduit replacement in this group of patients, who are typically young and active. This report includes 4 young women who after successful TPVI became pregnant and gave birth. Transthoracic echocardiography, cardiopulmonary exercise testing, and cardiac magnetic resonance imaging were performed in all patients. The results suggest that pregnancy and delivery after successful TPVI is safe when the appropriate precautions have been taken.