Relationship Between Genotype Status and Clinical Outcome in Hypertrophic Cardiomyopathy.

BACKGROUND: The genetic basis of hypertrophic cardiomyopathy (HCM) is complex, and the relationship between genotype status and clinical outcome is incompletely resolved. METHODS AND RESULTS: We assessed a large international HCM cohort to define in contemporary terms natural history and clinical consequences of genotype. Consecutive patients (n=1468) with established HCM diagnosis underwent genetic testing. Patients with pathogenic (or likely pathogenic) variants were considered genotype positive (G+; n=312; 21%); those without definite disease-causing mutations (n=651; 44%) or variants of uncertain significance (n=505; 35%) were considered genotype negative (G-). Patients were followed up for a median of 7.8 years (interquartile range, 3.5-13.4 years); HCM end points were examined by cumulative event incidence. Over follow-up, 135 (9%) patients died, 33 from a variety of HCM-related causes. After adjusting for age, all-cause and HCM-related mortality did not differ between G- versus G+ patients (hazard ratio [HR], 0.78 [95% CI, 0.46-1.31]; P=0.37; HR, 0.93 [95% CI, 0.38-2.30]; P=0.87, respectively). Adverse event rates, including heart failure progression to class III/IV, heart transplant, or heart failure death, did not differ (G- versus G+) when adjusted for age (HR, 1.20 [95% CI, 0.63-2.26]; P=0.58), nor was genotype independently associated with sudden death event risk (HR, 1.39 [95% CI, 0.88-2.21]; P=0.16). In multivariable analysis, age was the only independent predictor of all-cause and HCM-related mortality, heart failure progression, and sudden death events. CONCLUSIONS: In this large consecutive cohort of patients with HCM, genotype (G+ or G-) was not a predictor of clinical course, including all-cause and HCM-related mortality and risk for heart failure progression or sudden death. G+ status should not be used to dictate clinical management or predict outcome in HCM.

Effect of metoprolol in hypertrophic obstructive cardiomyopathy patients after alcohol septal ablation.

Background: The use of beta-blockers in hypertrophic obstructive cardiomyopathy (HOCM) patients after alcohol septal ablation (ASA) lacks data support. We aimed to evaluate the effect of metoprolol on exercise capacity, hemodynamic and laboratory parameters, and quality of life in HOCM patients after ASA. Methods: This was a prospective randomized single-center open-label crossover trial in 21 HOCM patients after ASA. Patients received metoprolol and no beta-blocker for two periods of three months. The endpoints were: peak oxygen uptake (pVO2), maximal left ventricular outflow tract (LVOT) pressure gradient at peak exercise, a ratio of mitral peak velocity of the early filling (E) to early diastolic mitral annular velocity (e') (E/e') at rest, Kansas City Cardiomyopathy Questionnaire (KCCQ) overall summary score, and N-terminal prohormone of brain natriuretic peptide (NT-proBNP) plasmatic concentration. Results: No significant association was found between the treatment and any of the endpoints in the assessed patients: 1) pVO2 (19.5 ± 5.3 ml/kg/min vs. 19.4 ± 4.1 ml/kg/min, p = 0.90), 2) exercise-induced pressure gradient in LVOT 32 ± 37 mmHg vs. 32 ± 30 mmHg, p = 0.84, 3) E/e' ratio at rest (11 ± 4 vs. 10 ± 4, p = 0.23), 4) KCCQ overall summary score (78 ± 11 vs. 77 te ± 15, p = 0.56), 5) NT-proBNP (215 pg/ml [121-333] vs. 153 pg/ml [102-228], p = 0.19). Conclusions: In HOCM patients after successful ASA, metoprolol treatment did not improve exercise capacity, hemodynamic and laboratory parameters, or quality of life.

Alcohol septal ablation for hypertrophic obstructive cardiomyopathy and bilateral lung transplantation for idiopathic pulmonary fibrosis: a case report.

Background: We present an uncommon case of a patient with hypertrophic obstructive cardiomyopathy and idiopathic pulmonary fibrosis. The case demonstrates the importance of pre-transplant cardiology workup and the need of interdisciplinary approach in diagnosing the cause of dyspnoea. Case summary: The 52-year-old male patient was diagnosed with idiopathic pulmonary fibrosis in 2019 and gradually became oxygen dependent due to progression of dyspnoea. Bilateral lung transplantation was recommended in 2021. During pre-transplant cardiology workup, the patient was diagnosed with hypertrophic cardiomyopathy with left ventricular outflow tract (LVOT) obstruction. Considering the high surgical risk of the patient, alcohol septal ablation was performed with subsequent decrease of LVOT gradient. Bilateral lung transplantation was successfully performed afterwards. The patient's symptoms improved to NYHA class II at one year follow-up. Discussion: We present a rare case of combined cause of dyspnoea-coexistence of hypertrophic obstructive cardiomyopathy and idiopathic pulmonary fibrosis in one patient. Due to high surgical risk, the patient underwent alcohol septal ablation with successful elimination of LVOT gradient and subsequently bilateral lung transplantation.

Analysis of risk stratification and prevention of sudden death in pediatric patients with hypertrophic cardiomyopathy: Dilemmas and clarity.

Hypertrophic cardiomyopathy (HCM) has been considered the most common cause of sudden death (SD) in the young. However, introduction of implantable cardioverter-defibrillators (ICDs) in HCM has proved highly effective and the mainstay of preventing SD in children, adolescents, and adults by terminating malignant ventricular tachyarrhythmias. Nevertheless, ICD decision making is generally regarded as more difficult in pediatrics, and the strategy for selecting ICD patients from this population remains without consensus. Prospective studies in HCM children and adolescents have shown the American Heart Association/American College of Cardiology traditional major risk marker strategy to be reliable with >90% sensitivity in selecting patients for SD prevention. International data in >2000 young HCM patients assembled over 20 years who were stratified by major risk markers showed ICDs effectively prevented SD in 20%. Alternatively, novel quantitative risk scoring initiatives provide 5-year risk estimates that are potentially useful as adjunctive tools to facilitate discussion of prophylactic ICD risks vs benefit but are as yet unsupported by prospective outcome studies. Risk scoring strategies are characterized by reasonable discriminatory statistical power (C-statistic 0.69-0.76) for identifying patients with SD events but with relatively low sensitivity, albeit with specificity comparable with the risk marker strategy. While some reticence for obligating healthy-appearing young patients to lifelong device implants is understandable, underutilization of the ICD in high-risk children and adolescents can represent a lost opportunity for fulfilling the long-standing aspiration of SD prevention. This review provides a critical assessment of the current strengths and weaknesses of SD risk stratification strategies in young HCM patients in an effort to clarify clinical decision making in this challenging subpopulation.

Do Implantable Cardioverter-Defibrillators Really Belong on the Athlete Field?

High-risk athletes with implanted cardioverter-defibrillators who are competing in intense sports represent a controversial issue in cardiovascular medicine. Such devices have the capability to protect patients with a variety of cardiovascular diseases from sudden death and have aborted potentially lethal events during competitive sports but they can also lead to adverse clinical consequences for athletes with implants and other participants. In conclusion, clinicians and athletes should consider the data presented here in making prudent and informed recommendations regarding the eligibility of this patient group with implanted cardioverter-defibrillators for intense competitive sports.

Outcomes of Alcohol Septal Ablation in Patients With Severe Left Ventricular Outflow Tract Obstruction: A Propensity Score Matching Analysis.

BACKGROUND: The current ACC/AHA guidelines on hypertrophic cardiomyopathy (HCM) caution that alcohol septal ablation (ASA) might be less effective in patients with left ventricular outflow tract obstruction (LVOTO) ≥ 100 mm Hg. METHODS: We used a multinational registry to evaluate the outcome of ASA patients according to baseline LVOTO. RESULTS: A total of 1346 ASA patients were enrolled and followed for 5.8 ± 4.7 years (7764 patient-years). The patients with baseline LVOTO ≥ 100 mm Hg were significantly older (61 ± 14 years vs 57 ± 13 years; P < 0.01), more often women (60% vs 45%; P < 0.01), and had a more pronounced HCM phenotype than those with baseline LVOTO < 100 mm Hg. There were no significant differences in the occurrences of 30-day major cardiovascular adverse events in the 2 groups. After propensity score matching (2 groups, 257 pairs of patients), the long-term survival was similar in both groups (P = 0.10), the relative reduction of LVOTO was higher in the group with baseline LVOTO ≥ 100 mm Hg (82 ± 21% vs 73 ± 26%; P < 0.01), but the residual resting LVOTO remained higher in this group (23 ± 29 mm Hg vs 13 ± 13 mm Hg; P < 0.01). Dyspnoea (NYHA functional class) at the most recent clinical check-up was similar in the 2 groups (1.7 ± 0.7 vs 1.7 ± 0.7; P = 0.85), and patients with baseline LVOTO ≥ 100 mm Hg underwent more reinterventions (P = 0.02). CONCLUSIONS: After propensity matching, ASA patients with baseline LVOTO ≥ 100 mm Hg had similar survival and dyspnoea as patients with baseline LVOTO < 100 mm Hg, but their residual LVOTO and risk of repeated procedures were higher.

Risks of the Athletic Field Revisited: Report of Unusual Occurrences of Cardiac Arrest and Sudden Death in Professional Soccer Players.

BACKGROUND: Sudden deaths in competitive athletes are highly visible but potentially preventable events that generate great interest amongst the cardiovascular community and general public. METHODS: Internet searches were performed using a combination of keywords and operators to produce search results for sudden death or cardiac arrest on the field in professional soccer players. RESULTS: We identified 35 male professional soccer players (mean age 26 ± 5 years) who experienced collapse and cardiac arrest on the field (most during matches) in Europe from December 2002 to February 2022 with 63% in the last 6 years. Twenty-five have died on the field or later in a hospital despite cardiopulmonary resuscitation. Of the 10 survivors, eight were implanted with cardioverter-defibrillators for secondary (n = 6) or primary (n = 2) prevention and returned to full competition; five of the 8 required successful device therapy during matches or training. CONCLUSIONS: Cardiac arrest and sudden death can occur not uncommonly in professional athletes highly trained over decades and participating at an elite sports level. Our observations also underscore the importance of targeted preparticipation cardiovascular screening, and availability of external defibrillators on the playing field.

Outcomes of Patients With Hypertrophic Obstructive Cardiomyopathy and Pacemaker Implanted After Alcohol Septal Ablation.

BACKGROUND: Atrioventricular block is a frequent major complication after alcohol septal ablation (ASA). OBJECTIVES: The aim of this study was to evaluate the outcomes of patients with implanted permanent pacemaker (PPM) related to a high-grade atrioventricular block after ASA for hypertrophic obstructive cardiomyopathy. METHODS: We used a multinational registry (the Euro-ASA registry) to evaluate the outcome of patients with PPM after ASA. RESULTS: A total of 1,814 patients were enrolled and followed up for 5.0 ± 4.3 years (median = 4.0 years). A total of 170 (9.4%) patients underwent PPM implantation during the first 30 days after ASA. Using propensity score matching, 139 pairs (n = 278) constituted the matched PPM and non-PPM groups. Between the matched groups, there were no long-term differences in New York Heart Association functional class (1.5 ± 0.7 vs 1.5 ± 0.9, P = 0.99) and survival (log-rank P = 0.47). Patients in the matched PPM group had lower long-term left ventricular (LV) outflow gradient (12 ± 12 mm Hg vs 17 ± 19 mm Hg, P < 0.01), more pronounced LV outflow gradient decrease (81% ± 17% vs 72% ± 35%, P < 0.01), and lower LV ejection fraction (64% ± 8% vs 66% ± 8%, P = 0.02) and were less likely to undergo reintervention (re-ASA or myectomy) (log-rank P = 0.02). CONCLUSIONS: Patients with hypertrophic obstructive cardiomyopathy treated with ASA have a 9% probability of PPM implantation within 30 days after ASA. In long-term follow-up, patients with PPM had similar long-term survival and New York Heart Association functional class but lower LV outflow gradient, a more pronounced LV outflow gradient decrease, a lower LV ejection fraction, and a lower likelihood of reintervention compared with patients without PPM.

Prediction of Sudden Cardiac Arrest After Alcohol Septal Ablation for Hypertrophic Obstructive Cardiomyopathy: ASA-SCARRE Risk Score.

This study aimed to derive a new score, the Alcohol Septal Ablation-Sudden Cardiac ARREst (ASA-SCARRE) risk score, that can be easily used to evaluate the risk of sudden cardiac arrest events (sudden cardiac death, resuscitation, or appropriate implantable cardioverter-defibrillator discharge) after alcohol septal ablation (ASA) in patients with hypertrophic obstructive cardiomyopathy. We analyzed 1,834 patients from the Euro-ASA registry (49% men, mean age 57 ± 14 years) who were followed up for 5.0 ± 4.3 years (9,202 patient-years) after ASA. A total of 65 patients (3.5%) experienced sudden cardiac arrest events, translating to 0.72 events per 100 patient-years. The independent predictors of sudden cardiac arrest events were septum thickness before ASA (hazard ratio 1.09 per 1 mm, 95% confidence interval 1.04 to 1.14, p <0.001) and left ventricular outflow tract (LVOT) gradient at the last clinical checkup (hazard ratio 1.01 per 1 mm Hg, 95% confidence interval 1.01 to 1.02, p = 0.002). The following ASA-SCARRE risk scores were derived and independently predicted long-term risk of sudden cardiac arrest events: "0" for both LVOT gradient <30 mmHg and baseline septum thickness <20 mm; "1" for LVOT gradient ≥30 mm Hg or baseline septum thickness ≥20 mm; and "2" for both LVOT gradient ≥30 mm Hg and baseline septum thickness ≥20 mm. The C statistic of the ASA-SCARRE risk score was 0.684 (SE 0.030). In conclusion, the ASA-SCARRE risk score may be a useful and easily available clinical tool to predict risk of sudden cardiac arrest events after ASA in patients with hypertrophic obstructive cardiomyopathy.

Genetic Testing in Patients with Hypertrophic Cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is a common inherited heart disease with an estimated prevalence of up to 1 in 200 individuals. In the majority of cases, HCM is considered a Mendelian disease, with mainly autosomal dominant inheritance. Most pathogenic variants are usually detected in genes for sarcomeric proteins. Nowadays, the genetic basis of HCM is believed to be rather complex. Thousands of mutations in more than 60 genes have been described in association with HCM. Nevertheless, screening large numbers of genes results in the identification of many genetic variants of uncertain significance and makes the interpretation of the results difficult. Patients lacking a pathogenic variant are now believed to have non-Mendelian HCM and probably have a better prognosis than patients with sarcomeric pathogenic mutations. Identifying the genetic basis of HCM creates remarkable opportunities to understand how the disease develops, and by extension, how to disrupt the disease progression in the future. The aim of this review is to discuss the brief history and recent advances in the genetics of HCM and the application of molecular genetic testing into common clinical practice.

Alcohol dose in septal ablation for hypertrophic obstructive cardiomyopathy.

BACKGROUND: The aim of this study was to evaluate short- and long-term outcomes related to dose of alcohol administered during alcohol septal ablation (ASA) in patients with hypertrophic obstructive cardiomyopathy (HOCM). Current guidelines recommend using 1-3 mL of alcohol administered in the target septal perforator artery, but this recommendation is based more on practical experience of interventionalists rather than on systematic evidence. METHODS: We included 1448 patients and used propensity score to match patients who received a low-dose (1.0-1.9 mL) versus a high-dose (2.0-3.8 mL) of alcohol during ASA. RESULTS: The matched cohort analysis comprised 770 patients (n = 385 in both groups). There was a similar occurrence of 30-day post-procedural adverse events (13% vs. 12%; p = 0.59), and similar all-cause mortality rates (0.8% vs. 0.5%; p = 1) in the low-dose group and the high-dose group, respectively. In the long-term follow-up (5.4 ± 4.5 years), a total of 110 (14%) patients died representing 2.58 deaths and 2.64 deaths per 100 patient-years in the low dose and the high dose group (logrank, p = 0.92), respectively. There were no significant differences in the long-term dyspnea and left ventricular outflow gradient between the two groups. Patients treated with a low-dose of alcohol underwent more subsequent septal reduction procedures (logrank, p = 0.04). CONCLUSIONS: Matched HOCM patients undergoing ASA with a low-dose (1.0-1.9 mL) or a high-dose (2.0-3.8 mL) of alcohol had similar short- and long-term outcomes. A higher rate of repeated septal reduction procedures was observed in the group treated with a low-dose of alcohol.

Effectiveness of alcohol septal ablation for hypertrophic obstructive cardiomyopathy in patients with late gadolinium enhancement on cardiac magnetic resonance.

BACKGROUND: According to European guidelines, alcohol septal ablation (ASA) for hypertrophic obstructive cardiomyopathy (HOCM) may be less effective in patients with extensive septal scarring on cardiac magnetic resonance (CMR). This study aimed to analyze the impact of late gadolinium enhancement (LGE) on CMR on the effectiveness of ASA. METHOD: We conducted an observational retrospective study involving adult patients with symptomatic drug-refractory HOCM who underwent CMR before ASA at two European centres from May 2010 through June 2019. Patients were compared in binary format based on LGE presence. Moreover, a subanalysis focused on patients with septal fibrosis was performed. The effectiveness of ASA was evaluated by echocardiographic, ECG and clinical findings. RESULTS: Of the 113 study patients, 54 (48%) had LGE on CMR. The LGE quantification performed in 29 patients revealed septal fibrosis in 17. The mean follow-up was 4.4 ±â€¯2.6 years. Baseline parameters were similar between groups except for basal septal thickness that was greater in LGE+ group (21.1 ±â€¯3.9 mm for LGE+ vs. 19.2 ±â€¯3.2 mm for LGE-: p = .005). ASA improved symptoms in all groups and reduced left ventricular outflow tract obstruction (LVOTO) (delta gradient reduction: LGE+: 62 ±â€¯37.3%; septal LGE+: 75.6 ±â€¯20.8%; LGE-: 72.5 ±â€¯21.0%). However, 13% of the LGE+ and 2% of the LGE- group had residual LVOTO above 30 mmHg (p = .027). CONCLUSION: ASA was effective in all patients with HOCM, whether they had LGE on CMR or not and whether they had septal fibrosis or not.

Patients with hypertrophic obstructive cardiomyopathy after alcohol septal ablation have favorable long-term outcome irrespective of their genetic background.

BACKGROUND: The genetic background of patients with hypertrophic cardiomyopathy (HCM) treated with alcohol septal ablation (ASA) and its relationship to the outcomes are not known. We aimed to investigate whether the outcome of genotype positive (G+) patients differs from genotype negative (G-) patients treated with ASA. METHODS: We included 129 HCM patients (mean age 54±13 years) treated with ASA in a tertiary cardiovascular center and performed next generation sequencing (NGS) based genomic testing. All patients were followed-up three months after the procedure and yearly thereafter. RESULTS: A total of 30 (23%) HCM patients were G+ patients. At the 3-months follow-up, both groups of patients had similar left ventricular outflow tract PG (16.9±15.7 mmHg in G+ vs. 16.3±18.8 mmHg in G-, P=0.73) and symptoms (follow-up NYHA class 1.40±0.62 vs. 1.37±0.53, P=0.99, follow-up CCS class 0.23±0.52 vs. 0.36±0.65, P=0.36). The independent predictors of all-cause mortality were baseline interventricular septum (IVS) thickness (HR 1.12, 95% CI: 1.00-1.26, P=0.049) and age at the time of ASA (HR 1.11, 95% CI: 1.06-1.17, P<0.01). The adjusted all-cause mortality rate did not differ significantly between G+ and G- patients (P=0.52). The adjusted combined mortality event rate did not differ between both groups (P=0.78). CONCLUSIONS: Despite more severe phenotype in G+ HCM patients, ASA is an equally effective treatment for LVOTO in G+ patients as it is for treating LVOTO in G- patients. The long-term outcome after ASA is similar in G+ and G- patients.

Clinical perspective on the myocarditis and cardiomyopathies.

Myocardial diseases are often encountered in cardiology and pose a significant diagnostic challenge. Myocarditis is an acute inflammatory disease of the heart muscle. Pathophysiology of myocarditis is a complex interplay of genetic background, innate immunity, viral or bacterial agents and formation of autoreactive antibodies and lymphocytes that maintain the inflammation after the infection was eliminated. Differentiation of myocardial infarction or heart failure of different etiology is crucial in the acute stage. Cardiac magnetic resonance imaging (MRI) enables with sufficient sensitivity and specificity diagnosis of myocardial inflammation and scar. Endomyocardial biopsy (EMB) with histology and immunohistochemistry is a gold standard for detection of myocarditis. EMB is indicated in selected patients with life-threatening symptoms where EMB may have therapeutic consequences. Giant cell myocarditis and eosinophilic myocarditis are specific examples of such a condition. Polymerase chain reaction (PCR) of the myocardial sample is used to detect viral genome. Serum antibodies or PCR from blood are not helpful in determining the etiology of myocarditis. Viral presence in myocardium is found in patients who do not have histological evidence of myocarditis which makes the association of positive PCR and etiology of myocarditis obscure. Cardiomyopathies (CMP) are characterized by structural and functional cardiac abnormalities that cannot be explained by coronary artery disease or abnormal loading conditions (valvular disease, arterial hypertension, congenital heart disease). CMP are classified based on the prevailing morphology regardless of primary (genetic, idiopathic) or secondary (systemic disease) etiology. European Society of Cardiology defines five types of CMP: hypertrophic, dilated, restrictive, arrhythmogenic and unclassified. CMP diagnosis is based on the imaging with echocardiography, coronary angiography, invasive hemodynamics and cardiac MRI. EMB is rarely indicated in dilated or restrictive CMP. Genetic testing is used to determine pathogenic mutations in phenotype positive patients and in familiar screening. Genetically determined CMP are mostly monogenic and autosomal dominant. Incomplete penetrance and variable expressivity cause variable or even negative phenotypes in genotype positive individuals. Genetic screening of a large number of genes and non-coding DNA results in findings of many variants of uncertain significance which make the interpretation of the genetic testing difficult.

The utility of the Mayo Score for predicting the yield of genetic testing in patients with hypertrophic cardiomyopathy.

INTRODUCTION: The yield of genetic testing in hypertrophic cardiomyopathy (HCM) is variable. The Mayo HCM Genotype Predictor score (Mayo Score) provides the pre-test probability of a positive HCM genetic test. In the original cohort of Mayo Score patients, only 9 HCM-associated myofilament genes were evaluated. The aim of this study was to validate the Mayo Score in the national HCM cohort and assess the yield of genetic testing using next generation sequencing (NGS) evaluating up to 229 genes. MATERIAL AND METHODS: We included 336 consecutive unrelated HCM patients (41% women, mean age: 53 ±15 years). We performed NGS-based genomic testing with classification of identified variants according to American College of Medical Genetics and Genomics guidelines. NGS findings were compared with the Mayo Score (ranging from -1 to 5) based on clinical and echocardiographic variables. RESULTS: We identified 72 variants classified as pathogenic or likely pathogenic in 70 (21%) HCM patients. One patient with the highest Mayo Score of 5 had a pathogenic mutation (100% yield). Patients with a Mayo Score of 4 had a pathogenic mutation in 71% of cases. Patients with a Mayo Score of 3 or 2 had a pathogenic mutation in 50 and 35% of cases, respectively. The yield of genetic testing in patients with a Mayo Score of -1 to 1 was low (6-21%). CONCLUSIONS: The overall yield of genetic testing using NGS evaluating up to 229 genes was low. The yield of genetic testing was consistently predicted with Mayo Score values.