Maron, Barry J.

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— The risks of sports participation for implantable cardioverter-defibrillator (ICD) patients are unknown. Methods and Results— Athletes with ICDs (age, 10–60 years) participating in organized (n=328) or high-risk (n=44) sports were recruited. Sports-related and clinical data were obtained by phone interview and medical records. Follow-up occurred every 6 months. ICD shock data and clinical outcomes were adjudicated by 2 electrophysiologists. Median age was 33 years (89 subjects <20 years of age); 33% were female. Sixty were competitive athletes (varsity/junior varsity/traveling team). A pre-ICD history of ventricular arrhythmia was present in 42%. Running, basketball, and soccer were the most common sports. Over a median 31-month (interquartile range, 21–46 months) follow-up, there were no occurrences of either primary end point—death or resuscitated arrest or arrhythmia- or shock-related injury—during sports. There were 49 shocks in 37 participants (10% of study population) during competition/practice, 39 shocks in 29 participants (8%) during other physical activity, and 33 shocks in 24 participants (6%) at rest. In 8 ventricular arrhythmia episodes (device defined), multiple shocks were received: 1 at rest, 4 during competition/practice, and 3 during other physical activity. Ultimately, the ICD terminated all episodes. Freedom from lead malfunction was 97% at 5 years (from implantation) and 90% at 10 years. Conclusions— Many athletes with ICDs can engage in vigorous and competitive sports without physical injury or failure to terminate the arrhythmia despite the occurrence of both inappropriate and appropriate shocks. These data provide a basis for more informed physician and patient decision making in terms of sports participation for athletes with ICDs.

Background —Dual-chamber pacing (DDD) has been proposed as a treatment alternative to surgery for severely symptomatic patients with obstructive hypertrophic cardiomyopathy (HCM), based largely on uncontrolled studies. Methods and Results —This prospective, multicenter trial assessed pacing in 48 symptomatic HCM patients with ≥50 mm Hg basal gradient, refractory to drug therapy. Patients were randomized to 3 months each of DDD pacing and pacing backup (AAI-30) in a double-blind, crossover study design, followed by an uncontrolled and unblinded 6-month pacing trial. With randomization, no significant differences were evident between pacing and no pacing for subjective or objective measures of symptoms or exercise capacity, including NYHA functional class, quality of life score, treadmill exercise time or peak oxygen consumption. After 6 additional months of unblinded pacing, functional class and quality of life score were improved compared with baseline ( P <0.01), but peak oxygen consumption was unchanged. Outflow gradient decreased 40%, 82±32 mm Hg to 48±32 mm Hg ( P <0.001), and was reduced in 57% of patients but showed no change or an increase in 43%. At 12 months, 6 individual patients (12%) showed improved functional capacity; each was 65 to 75 years of age. Left ventricular wall thicknesses in the overall study group showed no remodeling between baseline (22±5 mm) and 12 months (21±5 mm; P= NS). Conclusions —(1) Pacing cannot be regarded as a primary treatment for obstructive HCM; (2) with randomization, perceived symptomatic improvement was most consistent with a substantial placebo effect; (3) longer, uncontrolled pacing periods were associated with some subjective benefit but unaccompanied by objective improvement in cardiovascular performance and should be interpreted cautiously; (4) modest reduction in outflow gradient was achieved in most patients; and (5) a small subset (12%) ≥ 65 years of age showed a clinical response, suggesting that DDD pacing could be a therapeutic option for some elderly patients.