The Influence of Genotype on the Phenotype, Clinical Course, and Risk of Adverse Events in Children with Hypertrophic Cardiomyopathy.

Genetic testing in children with hypertrophic cardiomyopathy (HCM) can modify clinical management and lifestyle counseling. However, predicting long-term outcome and response to management in individual patients remains challenging, because of the peculiar genetic heterogeneity of the disease in the pediatric age range. Children with HCM secondary to an inborn error of metabolism or malformation syndromes tend to have a worse outcome compared with those with the classic sarcomeric form. Among the latter, adverse genetic features are represented by the identification of a pathogenic variant in MYH7, often associated with severe hypertrophy, a complex genotype, or a de novo variant.

Cancer Treatment-Related Complications in Patients With Hypertrophic Cardiomyopathy.

OBJECTIVE: To describe the potential clinical cardiotoxicity of oncological treatments in a cohort of consecutive patients with hypertrophic cardiomyopathy (HCM), systematically followed-up at two national referral centers for HCM. Cardiotoxicity relates to the direct effects of cancer-related treatment on heart function, commonly presenting as left ventricular contractile dysfunction. However, limited data are available regarding cardiotoxic effects on HCM as most studies have not specifically analyzed the effects of oncological treatment in HCM populations. This gap in knowledge may lead to unjustified restriction of HCM patients from receiving curative cancer treatments. METHODS: We retrospectively analyzed clinical and instrumental data of all consecutive HCM patients who underwent oncological treatment between January 2000 and December 2020 collected in a centralized database. RESULTS: Of 3256 HCM patients, 121 (3.7%) had cancer; 110 (90.9%) underwent oncological surgery, 45 (37.2%) received chemotherapy, and 22 (18.2%) received chest radiation therapy (cRT). After a median follow-up of 5.2 years (Q1-Q3: 2-13 years) from oncological diagnosis, 32 patients died. The cumulative survival at 5 years was 79.9%. The cause of death was mainly attributed to the oncological condition, whereas four patients died of sudden cardiac death without receiving previous chemotherapy or cRT. No patient interrupted or reduced the dose of oncological treatment due to cardiac dysfunction. No sustained ventricular tachyarrhythmia was induced by chemotherapy or radiation therapy. CONCLUSION: Cancer treatment was well tolerated in HCM patients. In our consecutive series, none died of cardiovascular complications induced by chemotherapy or cRT and they did not require interruption or substantial treatment tapering due to cardiovascular toxic effects. Although a multidisciplinary evaluation is necessary and regimens must be tailored individually, the diagnosis of HCM per se should not be considered a contraindication to receive optimal curative cancer treatment.

The Importance of Left Ventricular Outflow Tract and Mid-Ventricular Gradients in Stress Echocardiography: A Narrative Review.

This review aims to serve as a guide for clinical practice and to appraise the current knowledge on exercise stress echocardiography in the evaluation of intraventricular obstruction in HCM, in patients with cardiac syndrome X, in athletes with symptoms related to exercise, and in patients with normal left ventricular systolic function and exercise-related unexplained tiredness. The appearance of intraventricular obstruction while exercising is considered rare, and it usually occurs in patients with hypertrophy of the left ventricle. The occurrence of intraventricular obstruction when exercising has been evidenced in patients with hypertrophic cardiomyopathy, athletes, patients with cardiac syndrome X, patients with syncope or dizziness related to exercise, and patients with dyspnea and preserved ejection fraction. The clinical significance of this observation and the exercise modality that is most likely to trigger intraventricular obstruction remains unknown. Supine exercise and lying supine after exercise are less technically demanding, but they are also less physiologically demanding than upright exercise. Importantly, in everyday life, human beings generally do not become supine after exercise, as takes place in post-exercise treadmill stress echocardiograms in most echocardiography labs. The presence of induced intraventricular obstruction might be considered when patients have exercise-related symptoms that are not understood, and to assess prognosis in hypertrophic cardiomyopathy.

Clinical scenarios of hypertrophic cardiomyopathy-related mortality: Relevance of age and stage of disease at presentation.

The evolving epidemiology of hypertrophic cardiomyopathy (HCM) has progressively changed our perception of HCM-related mortality. However, recent studies detailing individual causes of death based on age and clinical setting are lacking. Thus, the present study aimed to describe the modes of death in a consecutive cohort of HCM patients based on presenting clinical features and stage of disease. METHODS: By retrospective analysis of a large HCM cohort, we identified 161 patients with >1 year follow-up who died between 2000 and 2020 and thoroughly investigated their modes of death. HCM stage at presentation was defined as "classic", "adverse remodeling" or "overt dysfunction". RESULTS: Of the 161 patients, 103 (64%) died of HCM-related causes, whereas 58 (36%) died of non-HCM-related causes. Patients who died of HCM-related causes were younger than those who died of non-HCM related causes. The most common cause of death was heart failure (HF). Sudden cardiac death (SCD) ranked third, after non cardiovascular death, and mostly occurred in young individuals. The proportion of HF related death and SCD per stage of disease was 14% and 27% in "classic", 38% and 21% in "adverse remodeling" and 74% and 10% in "overt dysfunction". CONCLUSIONS: Most HCM patients die due to complications of their own disease, mainly in the context of HF. While SCD tends to be juvenile, HF related deaths often occur in age groups no longer amenable to cardiac transplant. Modes of death vary with the stage of disease, with SCD becoming less prevalent in more advanced phases, when competitive risk of HF becomes overwhelming.

[Therapeutic approaches in hypertrophic cardiomyopathy: from symptom relief to precision therapy]. / Approcci terapeutici nella cardiomiopatia ipertrofica: dal controllo dei sintomi alla terapia di precisione.

Hypertrophic cardiomyopathy is the most common genetic cardiomyopathy. Main complications include the development of arrhythmias and heart failure, and the latter may be triggered by left ventricular outflow tract obstruction. The treatment of left ventricular outflow tract obstruction includes pharmacological therapies (beta-blockers, calcium channel blockers, disopyramide) and septal reduction therapies (alcohol septal ablation, surgical myectomy). Myosin inhibitors represent a new therapeutic opportunity and in recent clinical trials proved effective in symptom relief, improvement of functional capacity and quality of life in patients with obstructive hypertrophic cardiomyopathy. In this narrative review we will summarize the available and under development therapeutic approaches for hypertrophic cardiomyopathy.

Genetic Testing and Counselling in Hypertrophic Cardiomyopathy: Frequently Asked Questions.

Genetic counselling and genetic testing in hypertrophic cardiomyopathy (HCM) represent an integral part of the diagnostic algorithm to confirm the diagnosis, distinguish it from phenocopies, and suggest tailored therapeutic intervention strategies. Additionally, they enable cascade genetic testing in the family. With the implementation of Next Generation Sequencing technologies (NGS), the interpretation of genetic data has become more complex. In this regard, cardiologists play a central role, aiding geneticists to correctly evaluate the pathogenicity of the identified genetic alterations. In the ideal setting, geneticists and cardiologists must work side by side to diagnose HCM as well as convey the correct information to patients in response to their many questions and concerns. After a brief overview of the role of genetics in the diagnosis of HCM, we present and discuss the frequently asked questions by HCM patients throughout our 20-year genetic counselling experience. Appropriate communication between the team and the families is key to the goal of delivering the full potential of genetic testing to our patients.

The Genetic Architecture of Hypertrophic Cardiomyopathy in Hungary: Analysis of 242 Patients with a Panel of 98 Genes.

Hypertrophic cardiomyopathy (HCM) is a primary disease of the myocardium most commonly caused by mutations in sarcomeric genes. We aimed to perform a nationwide large-scale genetic analysis of a previously unreported, representative HCM cohort in Hungary. A total of 242 consecutive HCM index patients (127 men, 44 ± 11 years) were studied with next generation sequencing using a custom-designed gene-panel comprising 98 cardiomyopathy-related genes. A total of 90 patients (37%) carried pathogenic/likely pathogenic (P/LP) variants. The percentage of patients with P/LP variants in genes with definitive evidence for HCM association was 93%. Most of the patients with P/LP variants had mutations in MYBPC3 (55 pts, 61%) and in MYH7 (21 pts, 23%). Double P/LP variants were present in four patients (1.7%). P/LP variants in other genes could be detected in ≤3% of patients. Of the patients without P/LP variants, 46 patients (19%) carried a variant of unknown significance. Non-HCM P/LP variants were identified in six patients (2.5%), with two in RAF1 (p.Leu633Val, p.Ser257Leu) and one in DES (p.Arg406Trp), FHL1 (p.Glu96Ter), TTN (p.Lys23480fs), and in the mitochondrial genome (m.3243A>G). Frameshift, nonsense, and splice-variants made up 82% of all P/LP MYBPC3 variants. In all the other genes, missense mutations were the dominant form of variants. The MYBPC3 p.Gln1233Ter, the MYBPC3 p.Pro955ArgfsTer95, and the MYBPC3 p.Ser593ProfsTer11 variants were identified in 12, 7, and 13 patients, respectively. These three variants made up 36% of all patients with identified P/LP variants, raising the possibility of a possible founder effect for these mutations. Similar to other HCM populations, the MYBPC3 and the MYH7 genes seemed to be the most frequently affected genes in Hungarian HCM patients. The high prevalence of three MYBPC3 mutations raises the possibility of a founder effect in our HCM cohort.

Pulmonary congestion during Exercise stress Echocardiography in Hypertrophic Cardiomyopathy.

BACKGROUND: B-lines detected by lung ultrasound (LUS) during exercise stress echocardiography (ESE), indicating pulmonary congestion, have not been systematically evaluated in patients with hypertrophic cardiomyopathy (HCM). AIM: To assess the clinical, anatomical and functional correlates of pulmonary congestion elicited by exercise in HCM. METHODS: We enrolled 128 HCM patients (age 52 ± 15 years, 72 males) consecutively referred for ESE (treadmill in 46, bicycle in 82 patients) in 10 quality-controlled centers from 7 countries (Belgium, Brazil, Bulgaria, Hungary, Italy, Serbia, Spain). ESE assessment at rest and peak stress included: mitral regurgitation (MR, score from 0 to 3); E/e'; systolic pulmonary arterial pressure (SPAP) and end-diastolic volume (EDV). Change from rest to stress was calculated for each variable. Reduced preload reserve was defined by a decrease in EDV during exercise. B-lines at rest and at peak exercise were assessed by lung ultrasound with the 4-site simplified scan. B-lines positivity was considered if the sum of detected B-lines was ≥ 2. RESULTS: LUS was feasible in all subjects. B-lines were present in 13 patients at rest and in 38 during stress (10 vs 30%, p < 0.0001). When compared to patients without stress B-lines (n = 90), patients with B-lines (n = 38) had higher resting E/e' (14 ± 6 vs. 11 ± 4, p = 0.016) and SPAP (33 ± 10 vs. 27 ± 7 mm Hg p = 0.002). At peak exercise, patients with B-lines had higher peak E/e' (17 ± 6 vs. 13 ± 5 p = 0.003) and stress SPAP (55 ± 18 vs. 40 ± 12 mm Hg p < 0.0001), reduced preload reserve (68 vs. 30%, p = 0.001) and an increase in MR (42 vs. 17%, p = 0.013) compared to patients without congestion. Among baseline parameters, the number of B-lines and SPAP were the only independent predictors of exercise pulmonary congestion. CONCLUSIONS: Two-thirds of HCM patients who develop pulmonary congestion on exercise had no evidence of B-lines at rest. Diastolic impairment and mitral regurgitation were key determinants of pulmonary congestion during ESE. These findings underscore the importance of evaluating hemodynamic stability by physiological stress in HCM, particularly in the presence of unexplained symptoms and functional limitation.

Imaging Quality Control, Methodology Harmonization and Clinical Data Management in Stress Echo 2030.

Stress echo (SE) 2030 study is an international, prospective, multicenter cohort study that will include >10,000 patients from ≥20 centers from ≥10 countries. It represents the logical and chronological continuation of the SE 2020 study, which developed, validated, and disseminated the "ABCDE protocol" of SE, more suitable than conventional SE to describe the complex vulnerabilities of the contemporary patient within and beyond coronary artery disease. SE2030 was started with a recruitment plan from 2021 to 2025 (and follow-up to 2030) with 12 subprojects (ranging from coronary artery disease to valvular and post-COVID-19 patients). With these features, the study poses particular challenges on quality control assurance, methodological harmonization, and data management. One of the significant upgrades of SE2030 compared to SE2020 was developing and implementing a Research Electronic Data Capture (REDCap)-based infrastructure for interactive and entirely web-based data management to integrate and optimize reproducible clinical research data. The purposes of our paper were: first, to describe the methodology used for quality control of imaging data, and second, to present the informatic infrastructure developed on RedCap platform for data entry, storage, and management in a large-scale multicenter study.

Prognostic Value of Reduced Heart Rate Reserve during Exercise in Hypertrophic Cardiomyopathy.

BACKGROUND: Sympathetic dysfunction can be evaluated by heart rate reserve (HRR) with exercise test. OBJECTIVES: To determine the value of HRR in predicting outcome of patients with hypertrophic cardiomyopathy (HCM). METHODS: We enrolled 917 HCM patients (age = 49 ± 15 years, 516 men) assessed with exercise stress echocardiography (ESE) in 11 centres. ESE modality was semi-supine bicycle in 51 patients (6%), upright bicycle in 476 (52%), and treadmill in 390 (42%). During ESE, we assessed left ventricular outflow tract obstruction (LVOTO), stress-induced new regional wall motion abnormalities (RWMA), and HRR (peak/rest heart rate, HR). By selection, all patients completed the follow-up. Mortality was the predetermined outcome measure Results: During ESE, RWMA occurred in 22 patients (2.4%) and LVOTO (≥50 mmHg) in 281 (30.4%). HRR was 1.90 ± 0.40 (lowest quartile ≤ 1.61, highest quartile > 2.13). Higher resting heart rate (odds ratio 1.027, 95% CI: 1.018-1.036, p < 0.001), older age (odds ratio 1.021, 95% CI: 1.009-1.033, p < 0.001), lower exercise tolerance (mets, odds ratio 0.761, 95% CI: 0.708-0.817, p < 0.001) and resting LVOTO (odds ratio 1.504, 95% CI: 1.043-2.170, p = 0.029) predicted a reduced HRR. During a median follow-up of 89 months (interquartile range: 36-145 months), 90 all-cause deaths occurred. At multivariable analysis, lowest quartile HRR (Hazard ratio 2.354, 95% CI 1.116-4.968 p = 0.025) and RWMA (Hazard ratio 3.279, 95% CI 1.441-7.461 p = 0.004) independently predicted death, in addition to age (Hazard ratio 1.064, 95% CI 1.043-1.085 p < 0.001) and maximal wall thickness (Hazard ratio 1.081, 95% CI 1.037-1.128, p < 0.001). CONCLUSIONS: A blunted HRR during ESE predicts survival independently of RWMA in HCM patients.