Associations between genotype and arrhythmia manifestations in patients with hypertrophic cardiomyopathy

Background: Hypertrophic cardiomyopathy (HCM) is a common inherited cardiovascular disease associated with increased risks of heart failure, sudden cardiac death (SCD), and stroke. Over 1,400 pathogenic variants, primarily in MYH7 and MYBPC3, have been identified, yet the prognostic significance of genetics remains unclear. Recent studies suggest genotype-positive (G+) HCM is linked to earlier diagnosis, greater disease severity, and poorer outcomes, necessitating further research to clarify the relationship between genotype, disease progression, and clinical management. Objectives: 1. Examine the association between genetic mutations (MYBPC3, MYH7, TNNT2, TNNI3) and both clinical outcomes (AF, syncope, ventricular arrhythmias, SCD, stroke) and structural cardiac characteristics (left atrial/ventricular thickness, LVEF) in HCM patients. 2. Conduct a systematic review and meta-analysis to evaluate the prognostic significance of genotype-positive HCM, aiming to inform clinical risk stratification and management strategies. Methods: A systematic literature search in PubMed for English-language articles from 2000 onward using relevant Medical Subject Headings (MeSH) terms identified six studies meeting inclusion criteria. G+ HCM was defined as mutations in MYBPC3, MYH7, TNNT2, or TNNI3. Data analysis employed the Cochrane Database of Systematic Reviews, assessing outcomes via risk ratios and mean differences with random-effects models. Heterogeneity was evaluated using appropriate statistical methods. Results: G+ HCM showed significantly increased risk of AF (RR 1.20, p = 0.02) and ventricular arrhythmias (RR 1.56, p = 0.04), with greater left atrial thickness (p = 0.004). No significant differences were found in syncope (p = 0.33), stroke (p = 0.98), or SCD (p = 0.22), left ventricular thickness (p = 0.13), or LVEF (p = 0.10) between G+ and G- patients. These findings underscore the impact of genetic mutations on arrhythmic risk and structural remodeling in HCM. Conclusions: Genetic mutations in MYBPC3, MYH7, TNNT2, and TNNI3 increase AF, ventricular arrhythmias, and left atrial remodeling risks in HCM patients, but do not significantly affect stroke, SCD, syncope, or left ventricular structure. Genetic status is crucial in risk assessment, necessitating close arrhythmia monitoring in G+ patients and further research to refine risk stratification and management strategies in HCM.

Background: Hypertrophic cardiomyopathy (HCM) risk is incompletely explained by pathogenic variants and polygenic background. Mendelian randomization studies have implicated body mass index (BMI) as a modifiable risk factor for HCM in individuals with a pathogenic HCM variant (‘genotype-positive’; G+) and in those without (‘genotype-negative’; G-), and diastolic blood pressure (DBP) as a modifiable risk factor for genotype-negative HCM only. Research Questions: How do BMI, DBP, and HCM polygenic risk influence HCM diagnoses and echocardiographic endophenotypes by genotype status? Methods: Penn Medicine BioBank participants with and without HCM were identified using electronic health records. G+ participants carried pathogenic variants in definitive HCM genes. To avoid confounding, BMI and DBP were represented by polygenic scores (PGSs). PGSs for BMI, DBP, and common variant HCM risk were identified from the PGS Catalog (IDs PGS004150, PGS004604, PGS004910). Stratifying by pathogenic variant status (G+/G-), we tested PGS associations with HCM status with logistic regression. We evaluated their associations with interventricular septal thickness and left ventricular ejection fraction (EF) on echocardiogram using linear regression. Models included age and sex as covariates. Formal interaction testing between each PGS and monogenic variant status was performed. Results: Among 32,615 unrelated participants, 363 (1.1%) were diagnosed with HCM. G+ status conferred a 58-fold increased HCM risk (p=2.6x10 -135 ). Estimated associations between BMI and HCM PGSs and HCM were positive regardless of pathogenic variant status (p<0.05 for HCM PGS only); DBP was associated with HCM only among G- individuals (OR 1.63; 95% CI 1.09 to 1.39; p=7.0x10 -4 ; Figure 1A). All PGSs were positively associated with septal thickness, a defining feature of HCM (Figure 1B). A significant (p<0.05) interaction term was observed between monogenic and polygenic HCM risk. DBP and BMI PGSs were negatively associated with EF among G- individuals, discordant with the typical HCM phenotype (Figure 1B). Conclusions: Increased polygenic BMI, DBP, and HCM risk may promote septal thickening. The interaction between HCM PGS and variant carrier status suggests a synergistic role of common- and rare-variation directly related to HCM. In contrast, DBP appears to modify the risk of genotype-negative disease only. These findings suggest distinct roles of modifiable risk factors in G- and G+ HCM.

To determine if myocardial perfusion (MP) during hyperaemia is decreased in young patients with hypertrophic cardiomyopathy (HCM). Also, to determine if an MP decrease is associated with diastolic dysfunction, and to investigate if young subjects at risk of HCM show differences in MP compared with controls. This study included 10 HCM patients (age 22.3 ± 6.4 years), 14 subjects at risk for HCM 'HCM risk' (age 18.9 ± 3.8 years), and 12 controls (age 22.8 ± 4.5 years). HCM patients were examined at rest and during hyperaemia (adenosine 140 µg/kg/min) with cardiovascular magnetic resonance (CMR) and echocardiography. MP was calculated as the ratio of coronary sinus flow and left ventricular mass (LVM) from CMR. Myocardial fibrosis was assessed using late gadolinium enhancement. Diastolic function was quantified with both echocardiography and CMR. At rest, MP (mL/min/g) was similar in the control, HCM risk, and HCM patients (0.8 ± 0.1, 1.0 ± 0.1, and 0.9 ± 0.1, respectively, P = ns). During adenosine, MP was lower in HCM patients (2.5 ± 0.4, P < 0.05) compared with both HCM risk (5.0 ± 0.5) and controls (3.9 ± 0.3). Subjects at HCM risk showed no significant difference in MP during adenosine compared with controls. One HCM patient showed mild diastolic dysfunction. Neither controls nor HCM risk individuals showed any sign of myocardial fibrosis, whereas 7/10 HCM patients had fibrosis (5 ± 1% of the total LVM). Young individuals with HCM, but not those at risk, show decreased MP during hyperaemia compared with controls even in the absence of diastolic dysfunction or LV outflow obstruction. These results may suggest that microvascular disease contributes to the decreased MP in the investigated population.

A 48-year-old man, with only a history of mild systemic hypertension, was initially evaluated after presenting with symptoms of exertional dyspnea occurring predominantly with inclines. At that time, an abnormal 12-lead ECG was obtained demonstrating left ventricular hypertrophy by conventional voltage criteria, prompting additional testing with a 2-dimensional echocardiogram that showed normal systolic function (ejection fraction=65%), with 14-mm ventricular septal thickness and 12 mm in the posterolateral wall, and mild systolic anterior motion (SAM) of the mitral valve (bend of anterior leaflet into outflow tract without septal contact). A stress nuclear stress test showed no myocardial ischemia at rest or at peak exercise with a normal blood pressure response and no arrhythmias or ST-T changes during exercise or in recovery. The patient was prescribed a β-blocker for treatment of systemic hypertension. During the next 2 years, the patient developed more limiting exertional symptoms with routine activities. β-Blocker dosage was increased, and a repeat echocardiogram demonstrated similar findings to the initial study, borderline left ventricular (LV) wall thickness despite well-controlled blood pressure. The abnormal ECG, and mild SAM at rest, raised consideration for a diagnosis of hypertrophic cardiomyopathy (HCM) and management for limiting heart failure symptoms. HCM is often suspected in a patient based on the presence of cardiovascular symptoms, detection of abnormal ECG, systolic ejection murmur on routine examination, or as part of pedigree screening.1,2 Abnormalities on ECG are present in >90% of patients with HCM, although no specific ECG pattern is pathognomonic.1 Clinical diagnosis of HCM can reliably be made in the majority of patients with 2-dimensional transthoracic echocardiography by imaging increased LV wall thickness (≥15 mm) with a nondilated cavity in the absence of any disease known to cause LV hypertrophy of that magnitude (ie, systemic hypertension or aortic stenosis).1–5 In …

Impaired myocardial energetics in both sarcomere positive and negative HCM are linked to arrhythmic risk

2378Blunted stress myocardial oxygenation and not myocardial perfusion reserve is associated with arrhythmic risk in hypertrophic cardiomyopathy

A 20-year-old asymptomatic man was diagnosed with hypertrophic cardiomyopathy (HCM) after routine physical examination during which a systolic heart murmur was detected.Echocardiography showed massive left ventricular (LV) hypertrophy with ventricular septal thickness of 36 mm extending into the anterolateral wall (30 mm); outflow obstruction was absent.Ambulatory (Holter) ECG showed 3 isolated premature ventricular contractions, and blood pressure response to exercise was normal.Echocardiographic examinations in parents and siblings were negative for HCM.Although 2 centers advised against an implantable cardioverter-defibrillator (ICD) based on the presence of only 1 risk factor for sudden death (ie, extreme hypertrophy), a prophylactic device was recommended by a third cardiac consultant.After an uneventful 16-month period during which the ICD neither detected nor treated arrhythmias, an unprovoked episode of ventricular fibrillation triggered a defibrillation shock that immediately restored sinus rhythm (Figure 1).

P5270Impaired myocardial deformation assessed by cardiac magnetic resonance is associated with increased arrhythmic risk in hypertrophic cardiomyopathy

Background: Hypertrophic Cardiomyopathy (HCM) and Dilated cardiomyopathy (DCM) are diseases of mutant sarcomeric proteins. However, there is marked variation in disease severity and progression, even among patients with identical causal mutation. The renin- angiotensin system plays a major role in the pathophysiology of heart failure and genetic variations in these genes may modulate the risk of disease and be partly responsible for the disease heterogeneity and severity. OBJECTIVE: To evaluate the association of angiotensinogen (AGT) gene polymorphisms (T174M and M235T) with risk of developing severe disease phenotype in HCM and DCM patients. MATERIAL AND METHODS: 275 prospectively enrolled patients (122 HCM and 153 DCM) and 200 normal controls were genotyped for T174M and M235T polymorphisms of AGT gene. Effect of AGT genotypes on interventricular septum thickness and left ventricular ejection fraction (LVEF) were analyzed using linear regression model. RESULTS: We observed significantly higher prevalence of 235T allele in DCM patients which was associated with increased risk of DCM (OR 2.37, CI 1.07-5.25, p=0.04), however T174M polymorphism did not show a significant association with risk of DCM (OR 1.1, CI 0.65-1.84, p=0.79). The frequency of 174M allele was significantly higher in HCM patients as compared to controls and associated with increased risk of HCM (OR 1.95, CI 1.16-3.25, p=0.01), but no significant association of M235T polymorphism was observed with HCM (OR=1.10, CI 0.54-2.22,p=0.8). We did not observe any significant difference in mean LVEF in DCM patients carrying either M235 allele or 235T allele (M235: 27.22±7.13; 235T: 28.60±10.40; p=0.6) or carrying T174 allele or 174M allele (28.83±10.34 vs 28.09±9.93; p=0.7). No significant difference in left ventricular hypertrophy (LVH, mean septal thickness) was observed between 235T and M235 allele carriers [(24.07±5.16mm vs 23.26±6.04mm, p=0.6] or between 174M and T174 allele carriers (T174: 23.41±5.12mm, 174M: 22.83±7.17mm; p=0.6) in HCM patients. CONCLUSION: The variant AGT M235T and AGT T174M alleles confer increased risk of DCM and HCM respectively, but do not appear to be associated with disease severity or progression in these patients.

Aims: Ventricular arrhythmia triggers sudden cardiac death (SCD) in hypertrophic cardiomyopathy (HCM), yet electrophysiological biomarkers are not used for risk stratification. Our aim was to identify distinct HCM phenotypes based on ECG computational analysis, and characterize differences in clinical risk factors and anatomical differences using cardiac magnetic resonance (CMR) imaging.Methods: High-fidelity 12-lead Holter ECGs from 85 HCM patients and 38 healthy volunteers were analyzed using mathematical modeling and computational clustering to identify phenotypic subgroups. Clinical features and the extent and distribution of hypertrophy assessed by CMR were evaluated in the subgroups.Results: QRS morphology alone was crucial to identify three HCM phenotypes with very distinct QRS patterns. Group 1 (n = 44) showed normal QRS morphology, Group 2 (n = 19) showed short R and deep S waves in V4, and Group 3 (n = 22) exhibited short R and long S waves in V4-6, and left QRS axis deviation. However, no differences in arrhythmic risk or distribution of hypertrophy were observed between these groups. Including T wave biomarkers in the clustering, four HCM phenotypes were identified: Group 1A (n = 20), with primary repolarization abnormalities showing normal QRS yet inverted T waves, Group 1B (n = 24), with normal QRS morphology and upright T waves, and Group 2 and Group 3 remaining as before, with upright T waves. Group 1A patients, with normal QRS and inverted T wave, showed increased HCM Risk-SCD scores (1A: 4.0%, 1B: 1.8%, 2: 2.1%, 3: 2.5%, p = 0.0001), and a predominance of coexisting septal and apical hypertrophy (p < 0.0001). HCM patients in Groups 2 and 3 exhibited predominantly septal hypertrophy (85 and 90%, respectively).Conclusion: HCM patients were classified in four subgroups with distinct ECG features. Patients with primary T wave inversion not secondary to QRS abnormalities had increased HCM Risk-SCD scores and coexisting septal and apical hypertrophy, suggesting that primary T wave inversion may increase SCD risk in HCM, rather than T wave inversion secondary to depolarization abnormalities. Computational ECG phenotyping provides insight into the underlying processes captured by the ECG and has the potential to be a novel and independent factor for risk stratification.

Background: Mutations in Four and Half Lim domain 1 ( FHL1 ), an X-chromosome gene, have been described in rare cases of Hypertrophic Cardiomyopathy (HCM), mainly associated with myopathy. The current knowledge of the outcome of HCM caused by FHL1 mutations relies only on isolated case series. Objective: We aim to establish the prevalence of FHL1 mutations in a large population with overt HCM and clinically characterize HCM patients carrying FHL1 pathogenic and likely pathogenic genetic variants. Methods: From a total population of 794 HCM patients from 3 Referral Centers for hereditary cardiomyopathies, 349 HCM probands, who tested negative for sarcomeric mutations, were genetically screened by using Next Generation Panels including FHL1 . Moreover, all patients underwent personal and family history collection, physical examination, 12-lead electrocardiogram and echocardiography; while Cardiac Magnetic Resonance (CMR) was performed in a subgroup. Clinical and genetic data of FHL1 mutation carriers from our cohort were pooled with those of 52 FHL1 positive HCM cases from literature. Results: We identified 2 FHL1 pathogenic and 2 likely pathogenic variants (1 missense: c.764G&gt;C; 2 duplications: c.762dup and c.599dupT; and 1 deletion: c.210delG) in 6 HCM probands (0.8% of all HCM and 1.7 % of non sarcomeric HCM). As shown in Fig.1 A, pooled analysis suggested that clinical phenotype of FHL1-HCM was characterized by early-onset, severe diastolic dysfunction independently from the degree of hypertrophy and fibrosis at CMR (Fig 1 B), high sudden death risk, increased incidence of atrial fibrillation and evolution toward heart failure requiring heart transplantation, and variable skeletal muscle involvement. Conclusions: HCM patients carrying FHL1 mutations present with a worse prognosis as compared with the classic sarcomeric-HCM. A better characterization of these patients is needed for a personalized preventive and therapeutic approach.

Hypertrophic Cardiomyopathy

Case Presentation: A 38-year-old man with hypertrophic cardiomyopathy (HCM) was referred for management of intermittent palpitations and exertional dyspnea with routine activities despite escalated β-blocker therapy. His initial examination was notable for a regular pulse at 72 bpm and harsh systolic murmur that increased with the Valsalva maneuver. A 12-lead electrocardiography revealed sinus rhythm with increased QRS voltage, repolarization abnormalities, and a QTc of 430 milliseconds. Echocardiography was notable for severe asymmetrical hypertrophy (septal thickness, 22 mm), normal systolic function, severe outflow tract obstruction (70 mm Hg), and left atrial (LA) enlargement. A 24-hour Holter monitor detected 6 minutes of rapid atrial fibrillation (AF) that coincided with his palpitations. Therapy was recommended with warfarin to prevent stroke and with disopyramide to minimize outflow tract obstruction and frequency of AF. HCM, which affects 0.2% of the population, is an important cause of heart failure and is the leading cause of nonviolent sudden death in the young. Traditionally defined as left ventricular hypertrophy that develops in the absence of abnormal hemodynamics, it is caused by dominant mutations in sarcomere genes.1 Prevention of sudden death and management of left ventricular outflow tract obstruction (LVOTO) have been the primary focus of HCM clinical research and management since its original descriptions. However, AF is more prevalent than either sudden death or medically refractory obstruction and is the most common sustained arrhythmia in HCM.2 The combination of HCM and AF is associated with a markedly increased risk of stroke, overall mortality, and heart failure. This Clinician Update focuses on the epidemiology, pathophysiology, and clinical management of AF in patients with HCM. AF represents the most common sustained arrhythmia in both the general and HCM populations. In the general population, AF prevalence increases progressively with age and occurs predominantly in patients >60 years of age.3 …

An asymptomatic athletic 42-year-old man has an abnormal 12-lead ECG obtained during his initial employment examination at a new job (Figure 1). He had no family history of hypertrophic cardiomyopathy (HCM) or unexplained sudden deaths. Echocardiogram demonstrated a 13-mm ventricular septal thickness without systolic anterior motion of the mitral valve. The patient exercised on a standard Bruce protocol stress (exercise) echocardiogram for 12 minutes, without symptoms or arrhythmias, and with appropriate blood pressure augmentation. In the immediate recovery period, systolic anterior motion was absent and outflow tract velocities were normal. A 24-hour ambulatory (Holter) ECG demonstrated normal sinus rhythm without ventricular ectopy. This clinical evaluation left a number of unanswered questions for the patient regarding the diagnosis of HCM, prognosis, and whether a genetic heart disease was present in his family. Figure 1. Abnormal 12-lead ECG in a 42-year-old man demonstrating normal sinus rhythm with left anterior fascicular block, RSR′ in leads V1 and V2, and left ventricular hypertrophy. Since the early 1970s, cardiovascular imaging has played a critical role in describing the structure and function of the heart in HCM.1–5 Indeed, HCM is a disorder uniquely suited to noninvasive imaging, given HCM’s characteristic heterogeneous morphology and hemodynamics, including dynamic left ventricular (LV) outflow obstruction.2,3 For much of 40 years, echocardiography has been the dominant imaging technique, first with rudimentary M-mode and then ultimately 2-dimentional imaging and Doppler,2 now widely available and accessible. The past decade has witnessed the introduction of cardiac magnetic resonance (CMR) into clinical HCM practice.1,3–10 This contemporary technique provides images with high spatial and temporal resolution and sharp contrast between the myocardial border and blood pool, allowing precise measurements of LV wall thickness and complete tomographic reconstruction of the entire cardiac chamber (without …

Hypertrophic cardiomyopathy (HCM) is a primary genetic myocardial disorder associated with sudden cardiac death (SCD) due to ventricular arrhythmias, however risk stratification remains challenging. Electrocardiographic (ECG) markers may offer non-invasive tools for improved risk assessment, but their prognostic value remains unclear. The purpose of this study is to systematically evaluate the association between ECG markers and the risk of major arrhythmic events (MAEs) in HCM patients. We conducted a systematic search of PubMed, Cochrane Central Register of Controlled Trials (CENTRAL) and Clinical Trials from inception to December 2024, including studies providing data on ECG variables and MAEs in patients with HCM. Pooled effect estimates were calculated using Der Simonian-Laird random-effects model. 12 studies with 3,419 HCM patients were included. Pooled results demonstrated that the presence of fragmented QRS (fQRS) was significantly associated with MAEs (OR: 7.03, 95% CI: 3.19; 15.48) with moderate diagnostic performance [AUC = 0.76, sensitivity 59% (95% CI: 37%; 78%), specificity 80% (95% CI: 64%; 90%)]. Prolonged QTc interval (MD: 10.57ms, 95% CI: 1-20.15), T-wave peak-to-end (Tp-e) interval (MD: 15.35ms, 95% CI: 9.45; 21.26) and QT dispersion (QTd) (SMD: 0.48; 95% CI: 0.19; 0.77) were also associated with MAEs. In contrast, PR interval, P-wave, QRS duration and the presence of right bundle branch block (RBBB) demonstrated no significant associations. This meta-analysis highlights the potential prognostic utility of specific ECG markers, particularly fQRS and repolarization abnormalities in stratifying arrhythmic risk in HCM. CRD42025635276.