Geske, Jeffrey B.

Abstract Background Hypertrophic cardiomyopathy (HCM) is a heritable cardiac disorder characterized by increased left ventricular (LV) wall thickness, often leading to heart failure (HF). The role of cardiovascular magnetic resonance (CMR) imaging in predicting new onset of HF symptoms in patients with HCM remains unknown. This study aimed to identify CMR predictors of new-onset HF symptoms in individuals with HCM. Methods This study was a single-centre retrospective cohort study of HCM patients treated at a tertiary referral centre in the USA who underwent CMR examination between 1998 and 2018, had no HF symptoms at baseline CMR, and at least 1 year of follow-up. Clinical data were collected by review of electronic medical records, and CMR images were analyzed by a blinded expert cardiac radiologis. The primary outcome was new onset of HF symptoms, defined as New York Heart Association (NYHA) class ≥ II at follow-up. Kaplan–Meier analyses and Cox proportional hazard analyses were performed. Results Of 1462 patients diagnosed with HCM who had at least 1 CMR, 276 HCM patients without HF symptoms (average age 52.7 years, 33.3% female),median maximum left ventricular (LV) wall thickness was 19 mm ([IQR] 17–22) with a and median LV ejection fraction of 71% (IQR 66–77). Late gadolinium enhancement was detected in 56.2%) patients (60.7% had mild; 30.7% moderate; 8.6% severe). During a median follow-up period of 6.3 years, 93 patients developed HF symptoms (NYHA class II in 56 (60.2%); class III in 31 (33.3%); and class IV in 6 (6.5%). Multivariable analysis adjusted for age showed that LA enlargement (HR 1.626; 95% CI 1.01–2.62; P = .045) and LV mass index (HR 1.014; 95% CI 1.007–1.022; P≤ .001) and sex (HR 1.7; 95% CI 1.074–2.691; P = .023) were independent predictors of new onset of HF symptoms in patients with HCM. Conclusions Nearly half of the patients with HCM developed HF symptoms within 6.3 years. Left atrial enlargement, LV mass index, and sex were independent predictors of new onset of HF symptoms in HCM patients. These findings emphasize the value of CMR in HF risk stratification.

Importance Current risk prediction guidelines for hypertrophic cardiomyopathy predict only sudden cardiac death and are imperfect, leading to avoidable deaths and unnecessary implantable cardioverter defibrillators. Objective To combine prospectively collected clinical history, imaging, genetic, and biomarker data to improve risk prediction of adverse events in hypertrophic cardiomyopathy. Design, Setting, and Participants A total of 2750 patients with hypertrophic cardiomyopathy were prospectively enrolled in the registry-based study from 44 sites in North America and Europe with expertise in hypertrophic cardiomyopathy and cardiac magnetic resonance (CMR) imaging. Participants were enrolled from April 1, 2014, to April 7, 2017. Exposures Patients underwent a health history questionnaire, blood sampling for biomarkers and genotyping, and contrast-enhanced CMR. Patients were followed up yearly by telephone and through records review regarding event documentation. Main Outcomes and Measures The predefined composite adjudicated primary end point was time to first event for hypertrophic cardiomyopathy–related deaths; nonfatal sustained ventricular arrhythmias (VAs) requiring cardioversion or defibrillation; and left ventricular (LV) assist device implant or heart transplant. A secondary end point was a composite of sudden cardiac death and nonfatal VA events. The elastic-net method identified the most important predictors. Cox proportional hazards regression assessed associations with time to the first end point. Results Of the 2750 prospectively enrolled patients, 2698 (98%) had analyzable data after 9 were excluded because they had hypertrophic cardiomyopathy phenocopies and 43 withdrew. Of these remaining patients, 1919 (71%) were male, mean age was 50 years (SD, 11 years), and 423 (16%) were from underrepresented racial and minority groups. The mean follow-up was 6.9 years (SD, 2.1 years). The primary event model in 104 patients included LV scar as a percentage of LV mass by late gadolinium enhancement (LGE%; hazard ratio [HR], 1.86; 95% CI, 1.58-2.20; P < .001), LV mass index (HR, 1.09; 95% CI, 1.01-1.17; P = .03), LV end-systolic volume index (HR, 1.28; 95% CI, 1.12-1.46; P < .001 ), all per 10-unit increase, history of heart failure at study entry (HR, 2.89; 95% CI, 1.75-4.77; P < .001), and log N-terminal pro–B-type natriuretic peptide (NT-proBNP; HR, 1.41; 95% CI, 1.17-1.70; P < .001) level per log unit, (C index for all, 0.77). An LGE percentage of the LV mass of 9% or higher substantially increased the primary composite event rate ( P = .001). The secondary sudden cardiac death and VA risk factor model (in 69 patients) included LGE%, LV mass index, LV ejection fraction, and log(NT-proBNP) (C index, 0.76). Conclusions and Relevance These results provide prospective evidence for incorporating cardiac magnetic resonance and NT-proBNP in the evaluation of patients with hypertrophic cardiomyopathy. Trial Registration ClinicalTrials.gov Identifier: NCT01915615

Abstract Background Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment and are increasingly associated with cardiovascular toxicities, including myocarditis and accelerated atherosclerosis. While ICI myocarditis has received substantial attention, thrombotic complications remain underrecognized and may be difficult to distinguish from immune-mediated cardiac inflammation and cancer-related hypercoagulable state. We present a case of non-bacterial thrombotic endocarditis (NBTE) and myocardial microthrombi mimicking ICI myocarditis. Case summary A 76-year-old woman with metastatic adenosquamous lung carcinoma presented with progressive dyspnoea 3 weeks after initiating pembrolizumab. Pulmonary arterial and coronary imaging were unremarkable, but cardiac magnetic resonance imaging (MRI) showed late gadolinium enhancement (LGE) and myocardial oedema suggestive of ICI myocarditis. Chest computed tomography revealed inflammatory lung changes, and empirical corticosteroids were initiated with initial clinical improvement. One week later, brain MRI showed multifocal infarcts, and Doppler ultrasound identified bilateral lower extremity deep vein thromboses. Transoesophageal echocardiography showed thickened mitral and aortic valves with moderate regurgitation. Non-bacterial thrombotic endocarditis with embolic phenomena was suspected. Anticoagulation was escalated from apixaban to therapeutic enoxaparin, followed by warfarin. Despite initial stabilization, the patient died 2 months later. Post-mortem examination revealed fibrin-rich valvular vegetations consistent with NBTE, widespread intramyocardial thrombi, and no histopathologic evidence of myocarditis. Discussion This case underscores how microthrombotic complications of ICI therapy may closely mimic myocarditis on imaging. Nonspecific cardiac MRI findings, such as LGE and T2 signal elevation, can result from thrombotic or ischaemic injury alike. Histopathologic confirmation may be required for accurate diagnosis, as misclassification can lead to suboptimal treatment.

Abstract Aims Obesity is linked with worse outcomes in hypertrophic cardiomyopathy (HCM). While both bariatric surgery (BS) and GLP-1 receptor agonists (GLP-1RA) promote weight loss and may improve cardiometabolic risk, their comparative outcomes in HCM remain unclear. Methods and results Adults with HCM and body mass index (BMI) ≥ 30 kg/m were divided into two cohorts: (i) GLP-1 RA users who never had BS, and (ii) BS patients who never received GLP-1 RA. Propensity score matching (1:1) was performed to balance demographics, comorbidities, and medications. Outcomes over 24 months include all-cause mortality, acute heart failure (HF) hospitalization, arrhythmias, change in BMI, and cardiovascular symptoms. Hazard ratios with 95% confidence intervals were estimated using Cox models. Of 5002 patients, 955 were included in each matched cohort after matching (mean age 54 ± 13 years, 70% female, BMI 40.0 kg/m). GLP-1 RA was associated with a significantly lower observed rate of all-cause mortality compared with BS (2.0% vs. 4.4%; HR 0.46; 95% CI 0.27–0.80; P = 0.004) and HF hospitalization (8.7% vs. 14.0%; HR 0.60; 95% CI 0.46–0.79; P < 0.001). Similarly, GLP-1 RA use was associated with a lower incidence of composite cardiovascular outcomes (10.7% vs. 17.2%; HR 0.60; 95% CI 0.47–0.77; P < 0.001). Rates of arrhythmia and cardiovascular symptoms were comparable between the two groups. BMI reduction was greater after bariatric surgery (−4.0 vs. −2.6 kg/m; P < 0.001). Conclusion In obese patients with HCM, GLP-1 RA therapy was associated with lower all-cause mortality and fewer HF events compared with BS. Future studies are warranted to confirm our findings.

ABSTRACT Introduction Cardiac myosin inhibitors (CMIs) improve hemodynamics and symptoms in hypertrophic cardiomyopathy (HCM), but recent real‐world data have raised concerns regarding an increased risk of atrial fibrillation (AF). We sought to reassess AF risk using randomized controlled trial (RCT) evidence and to contextualize discrepancies with observational reports. Methods and Results We performed a systematic review and random‐effects meta‐analysis of RCTs evaluating the effect of CMIs on incident AF in HCM. MEDLINE, Scopus, and CENTRAL were searched through November 25, 2025. Eight RCTs ( n = 1581) comparing mavacamten or aficamten with placebo or active control were included. Event counts were pooled as risk ratios (RRs) with 95% confidence intervals (CIs). CMIs were not associated with increased AF risk (RR 1.11, 95% CI 0.62–1.98; heterogeneity I 2 = 0%). No differences were observed between mavacamten and aficamten, with consistent findings across HCM subtypes (obstructive and non‐obstructive). Importantly, most trials (7/8) excluded patients with uncontrolled, persistent, or permanent AF, five excluded paroxysmal AF at screening, and one excluded any AF history. Baseline left atrial enlargement was generally in the mild to moderate range across trials, suggesting limited representation of high‐risk AF phenotypes. Conclusion Randomized evidence to date does not demonstrate an increased AF risk with CMIs. Differences between RCT populations and real‐world cohorts, including restrictive AF eligibility criteria, lower baseline atrial remodeling, and limited rhythm surveillance may explain discordant observational findings and highlight the need for longitudinal monitoring in clinical practice.

Abstract Background The mechanisms of left ventricular outflow tract obstruction (LVOTO) in hypertrophic cardiomyopathy (HCM) with moderate septal hypertrophy (≤ 18 mm) remain uncertain with therapeutic implications. This study investigated the role of three-dimensional echocardiography (3DE)-derived myocardial mechanics in LVOTO. Methods We retrospectively analyzed 216 HCM patients with moderate septal hypertrophy, stratified into nonobstructive (n = 38), provokable LVOTO (n = 63), and resting LVOTO (n = 115). Transthoracic echocardiography assessed LV geometry, LVOT diameter, anterior mitral leaflet length, and papillary muscle abnormalities (via a composite SubMV score). 3DE-derived strain parameters, including global longitudinal (GLS), circumferential, radial, area (GAS) strain, twist, and torsion, were quantified. Determinants of LVOTO were evaluated using multivariate regression, restricted cubic splines (RCS), and receiver operating characteristic (ROC) analysis. Results Both LVOTO subgroups showed significantly augmented strain mechanics versus nonobstructive patients, greatest in resting LVOTO (p < 0.05); twist and torsion were the strongest discriminators (p < 0.001). Multivariate regression showed that, beyond LVOT diameter and SubMV score, torsion (B = 9.47), twist (B = 1.92), and GAS (B = 1.29) independently predicted provoked LVOT gradients (all p < 0.05); RCS demonstrated nonlinear twist/torsion–LVOTO relationships, with obstruction risk rising sharply above twist = 15° and torsion = 3°/cm, especially under provocation. Torsion discriminated provokable LVOTO achieving 81% specificity (cutoff 2.4°/cm, AUC = 0.72), outperforming all structural parameters. Integrating 3DE-derived mechanics with structural metrics improved diagnostic accuracy, especially in provokable LVOTO (AUC 0.84 vs. 0.76, DeLong p = 0.003). Conclusions In moderate-hypertrophy HCM, 3DE-derived strain mechanics, especially twist and torsion, independently determine LVOTO beyond structural narrowing, particularly under provocation, strengthening mechanistic insight and clinical applicability.

Case Description: Immune checkpoint inhibitors (ICIs) have transformed cancer therapy but are associated with immune-related adverse events, including cardiovascular toxicity. While ICI-myocarditis is rare but potentially fatal, thrombotic complications—such as venous thromboembolism, arterial occlusion, and non-bacterial thrombotic endocarditis (NBTE)—are underrecognized. These raise questions about the roles of malignancy-associated hypercoagulability versus ICI-induced effects. We present a case of NBTE and myocardial microthrombi mimicking ICI-myocarditis. A 76-year-old woman with metastatic adenosquamous lung cancer and recent DVT (on apixaban and aspirin) presented with worsening dyspnea three weeks after starting pembrolizumab (Image 1). One week earlier, CT pulmonary angiography and coronary angiography were unrevealing. On presentation, she was stable but had peripheral edema, a late diastolic murmur, and elevated hs troponin (706→657→656 ng/L). NT-proBNP was 11,500 pg/mL. Cardiac MRI showed mid-wall late gadolinium enhancement (LGE), myocardial edema, and elevated T2 values—findings concerning for ICI-myocarditis. She initially improved on intravenous methylprednisolone. A week later, brain MRI showed multifocal embolic infarcts. Doppler ultrasound revealed a new left-sided DVT. TEE showed no intracardiac thrombus but identified a thickened aortic valve with moderate-to-severe regurgitation, a thickened mitral A2 segment with moderate regurgitation, and a patent foramen ovale (PFO) with left-to-right shunting. Findings raised concern for NBTE with systemic embolism or paradoxical embolism. Anticoagulation was transitioned to heparin, then warfarin. She was discharged on oral prednisone without further cancer therapy. Two months later, she died suddenly. Autopsy revealed fibrin-rich vegetations on the mitral valve consistent with NBTE and thromboembolic infarcts in small myocardial arteries, without inflammatory infiltrates or myocardial scarring (Image 2 and 3). Conclusion: This case highlights NBTE and microthrombi as important mimics of ICI-myocarditis. Despite MRI features suggestive of inflammation, pathology confirmed ischemic injury. ICIs have been suggested to promote thrombosis through elevated factor VIII, von Willebrand factor, reduced protein S, and systemic inflammation. Clinicians should consider thrombotic mimics in ICI-treated patients with cardiac symptoms and abnormal imaging. Tissue diagnosis may be necessary to guide management.

Background: Several studies have described anteroapical displacement of the anterolateral papillary muscle (PM) in patients with hypertrophic cardiomyopathy (HCM), implying a role in left ventricular outflow tract obstruction. Some surgeons address PM position during myectomy, but no quantitative imaging measures of abnormal versus normal PM anatomy exist. Objective: To quantify PM anatomy in HCM using cardiac magnetic resonance imaging (CMR) and determine if differences in PM anatomy alter myectomy outcomes. Methods: 143 patients with HCM (median age 58 (IQR 48-65) years, 64% male) who had undergone CMR were compared to 50 healthy controls (median age 32 (IQR 28-50) years, 40% male). The HCM cohort included 50 patients with non-obstructive HCM, 50 with obstructive HCM requiring transaortic myectomy, and 43 with obstructive HCM requiring transapical myectomy. Six independent measurements of PM anatomy were performed (Figure), comprising both established and novel measurements. Intergroup comparisons were made, and correlative analysis of PM measurements was performed using echocardiographic data and surgical outcomes. Results: There was significant variability in PM anatomy in all patients. The SXAd measurement was smaller (26.76 +/- 6.10 mm vs 32.10 +/- 4.85 mm, p < 0.001) in HCM patients versus controls. The 4Cd measurement was smaller in patients with apical HCM than in all other groups (p < 0.001). D_PM, d_apex, and the ratio between these measurements were consistent among all groups. No PM quantification in HCM patients correlated to pre-, intra-, or postoperative LVOT obstruction, NYHA class, or postoperative length of stay. Conclusions: Although there were some statistically significant differences between healthy patients and those with HCM, analysis of six different PM measurements yielded no associations with LVOT obstruction or outcomes of septal myectomy.

A previously healthy 55-year-old man presented to his local family medicine clinic after waking up with a buzzing sensation in his chest. What would you do next?