Maron, Martin S.

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

Once considered rare and essentially untreatable with a grim prognosis and reduced life expectancy, hypertrophic cardiomyopathy (HCM) has evolved substantially over 6 decades. Ultimately, HCM has become a contemporary global disease with pharmacologic and interventional options offering effective personalized treatment for all adverse disease pathways. Striking reduction in HCM‐related mortality to ≤0.5%/year in optimally treated cohorts is now comparable to that expected in the US general population, lower than most other disease risks to living, and 10‐fold less than the earliest estimates. The few deaths directly related to HCM are now largely attributable to advanced (end‐stage) heart failure in patients with nonobstructive HCM. Determinants of this transformation to a lower risk disease are evident in hallmark clinical inflection points and breakthroughs, including dedicated HCM programs assembling large clinical databases in which focused (and unfunded) physician‐investigators have derived data directly from patients in clinical practice. Evidence‐based observational studies report emergence of contemporary treatment strategies enhancing survival: implantable defibrillators prevent arrhythmic sudden death globally with 95% sensitive patient selection using an American Heart Association/American College Cardiology risk stratification algorithm; low‐risk, high‐benefit surgical myectomy reverses outflow obstruction and heart failure in >90% with a long‐term survival benefit; and aggressive anticoagulation has reduced embolic strokes. Recent novel pharmacologic alternatives (cardiac myosin inhibitors) are proving effective in relieving obstruction/symptom burden and changing disease management. These principles and time‐tested patient‐centered research strategies uniquely tailored to the heterogeneous HCM clinical spectrum are pivotal in providing practice insights, offering a vulnerable population more optimistic prognosis including opportunity to achieve normal longevity not available to prior generations of patients.

Background: Treatment of progressive heart failure, due to left ventricular (LV) outflow tract obstruction has been a major component of hypertrophic cardiomyopathy (HCM) disease management for 50 years. Septal myectomy has been the primary treatment option to abolish gradients and relieve heart failure symptoms. The role of myectomy in HCM management has depended on effectiveness in relieving heart failure symptoms, but also an acceptable operative risk. Methods: Over the most recent 15-year period, we reviewed 3,700 consecutive isolated myectomy operations performed at major North American HCM institutions. Composite operative mortality (first 30 days) was only 0.4%. Seventeen operative deaths were at ages 24 to 82 (≥70 years), and only 6 occurred after 2010. Notably, 2 of the 4 Mayo Clinic deaths were in patients with prior alcohol septal ablation. Septal myectomy, when performed in experienced HCM centers, was much safer when compared to operative mortality with coronary artery bypass grafting (2.3%); valve replacement (3.5%); mitral valve replacement specifically (5.7%) (STS Database), similar to atrial or ventricular septal defect closure and 15-fold less than myectomy in community hospital or low volume surgical settings. Conclusions: Surgical myectomy performed in dedicated HCM centers with experienced surgeons and staff is one of the safest open-heart procedures currently practiced, with a mortality rate as low as 0.4%. The large mortality discrepancy for myectomy between community hospitals and dedicated HCM centers underscores that this operation should be considered a specialized procedure best performed in high volume HCM institutions.

Background: Sodium-glucose cotransporter-2 inhibitors (SGLT2i) have been demonstrated to improve outcomes in congestive heart failure (HF). However, their effect in hypertrophic cardiomyopathy (HCM) is unknown. Research Question: Can SGLT2i improve clinical outcomes in HCM patients? Methods: Using TriNetX Global Research Network from March 2013 to February 2021, patients diagnosed with HCM (ICD-10 codes I42.1, I42.2) were identified and categorized into 2 groups: those on SGLT2i vs. those who are not. To avoid inclusion of other causes of left ventricular hypertrophy, patients with aortic stenosis or systemic hypertension were excluded. Propensity score matching (PSM) was used to limit confounders. Primary outcome was all-cause mortality and secondary outcomes were HF exacerbation, all-cause hospitalization, and documented cardiovascular symptoms (chest pain, dyspnea, palpitations, or leg edema) over a 2-year follow-up period. Results: A total of 27,561 HCM patients were identified; 408 (1.5%) on SGLT2i and 27,153 (98.5%) were not. Patients on SGLT2i were older (55 ± 15 vs. 48 ± 19, p<0.01) and had more comorbidities, including a nearly 6-fold higher prevalence of diabetes mellitus (44% vs. 7%, p<0.01) and congestive HF (65% vs. 10%, p<0.01). After PSM, each group consisted of 355 patients. HCM patients on SGLT2i had lower rates of all-cause mortality (OR 0.22 [95% CI: 0.12, 0.39]; p<0.01), hospitalizations (OR 0.72 [95% CI: 0.53, 0.98]; p=0.04), and cardiovascular symptoms (OR 0.71 [95% CI: 0.52, 0.97]; p=0.029) when compared to patients not on SGLT2i. There was no statistical difference in the rate of HF exacerbation (OR 0.82 [95% CI: 0.54, 1.24]; p=0.3). Conclusion: In this large dataset, SGLT2i use in a select subset of HCM patients was associated with improved survival, less hospitalizations, and fewer cardiovascular symptoms. These data support future randomized trials to evaluate the efficacy and safety of SGLT2i in more diverse HCM patient populations.

Introduction: Safety of vigorous exercise for individuals with appropriately-treated HCM remains debated. Physical activity practices in this population have not been described. The objective of this report is to describe physical activity pattern in HCM patients. Long term follow up which is ongoing will determine safety of vigorous exercise. Methods: The NIH-funded LIVE-HCM study prospectively enrolled individuals age 8-60 years with clinically overt HCM or patients with a positive genetic test for sarcomeric HCM. Participants (or parents, for children) answered surveys describing activity patterns. Vigorous exercise was defined as > 6 METS for > 60 hours per year. Clinical and demographic data were derived from medical record review. Results: Among 1798 participants, 745 (41%) reported exercising vigorously, including 296 competitive athletes, with 59 at high-school or college varsity level, 770 (43%) were exercising at moderate, and 283 (16%) at low levels. Of those working, 6% described jobs more active than walking, including 16 in protective services, and 11 in sports/coaching. Clinical/demographic data including imaging characteristics and treatments, are shown in Table, and were mostly similar amongst the exercise-groups. Conclusions: Many patients with HCM are engaged in vigorous exercise including competitive athletics. Prospective follow-up of this cohort is ongoing. Comparison of arrhythmic outcomes outcomes in vigorous exercisers vs moderate/low level exercisers will help determine the safety of exercise in HCM patients.

Background: Marked septal hypertrophy is considered a requirement for effective myectomy in obstructive hypertrophic cardiomyopathy (HCM), with mitral valve replacement recommended as the alternative strategy in patients with minimal hypertrophy. However, it remains uncertain whether relief of obstruction can be effectively abolished without mitral valve replacement in patients with minimal septal wall thickening. Methods: Of 500 patients who underwent surgical myectomy from 2004 to January 2014, 21 (4.2%) were identified with a maximum LV wall thickness ≤ 15mm and constitute the study cohort. Results: All 21 patients (56 ± 10 years old; 62% male) were followed for advanced heart failure symptoms refractory to drug therapy with a maximal septal wall thickness of 13.6 ± 1.7 mm (range: 10-15 mm; ≤ 12 mm in 5 patients). Outflow obstruction ≥ 30 mmHg due to mitral valve-septal contact was present after exercise in 17 of 21 patients (range: 50-150 mmHg), and under resting conditions in 4 patients (range: 30-65 mmHg). In all patients, surgical relief of obstruction consisted of muscular resection of the basal septum with revision of abnormal and apically displaced papillary muscles, which were judged intraoperatively to be contributing to obstruction. In addition, in 10 patients (47%) myectomy alone was not sufficient to relieve obstruction due to the limited opportunity for septal reduction and adjunctive mitral valve repair was performed to shorten an elongated anterior leaflet. No patient required mitral valve replacement or incurred a ventricular septal defect. Post-operatively, 4 patients developed complete heart block requiring permanent pacemaker (1 patient with pre-operative right bundle branch block) and 1 had a cerebrovascular event. At most recent follow up 18 ± 19 months post-myectomy, septal thickness was reduced to 10 ± 2 mm, no patient had an outflow gradient at rest or with provocation, and all patients were alive with the majority asymptomatic (class I: n=13; 62% and class II n=8; 38%). Conclusion: In patients with minimal septal hypertrophy, outflow obstruction can be effectively abolished with surgical myectomy and adjunctive mitral valve repair with a small increased risk of heart block, but without the need for mitral valve replacement.

Background— Hypertrophic cardiomyopathy (HCM) is the most common genetic heart disease characterized by a diverse clinical and phenotypic spectrum. This study reports the prevalence, morphology, clinical course, and management of an underrecognized subgroup of HCM patients with left ventricular apical aneurysms. Methods and Results— Of 1299 HCM patients, 28 (2%) were identified with left ventricular apical aneurysms, including a pair of identical twins. Aneurysms were recognized at a wide age range (26 to 83 years), including 12 patients (43%) who were ≤50 years of age. Apical aneurysms varied considerably in size (maximum dimension, 10 to 66 mm), were dyskinetic/akinetic with thin rims, and were associated with transmural (and often more extensive) myocardial scarring identified by late gadolinium enhancement cardiovascular magnetic resonance. Apical aneurysms were recognized by echocardiography in only 16 of 28 patients (57%) but by cardiovascular magnetic resonance in the 12 patients undetected by echocardiography. Left ventricular chamber morphology varied; however, 19 patients (68%) showed an “hourglass” contour, with midventricular hypertrophy producing muscular narrowing and intracavitary gradients in 9 patients (74±42 mm Hg). Sarcomeric protein missense mutations known to cause other phenotypic expressions of HCM were present in 3 patients. Over 4.1±3.7 years of follow-up, 12 patients (43%) with left ventricular apical aneurysms experienced adverse disease complications (event rate, 10.5%/y), including sudden death, appropriate implantable cardioverter-defibrillator discharges, nonfatal thromboembolic stroke, and progressive heart failure and death. Conclusions— Patients with left ventricular apical aneurysms represent an underappreciated subset in the heterogeneous HCM disease spectrum with important clinical implications, often requiring a high index of suspicion and cardiovascular magnetic resonance for identification. Apical aneurysms in HCM are associated with substantial cardiovascular morbidity and mortality and raise novel treatment considerations.