Unmasking obstruction in hypertrophic cardiomyopathy with postprandial resting and treadmill stress echocardiography.

BACKGROUND: Latent left ventricular outflow tract obstruction (LVOTO) is an important cause of symptoms in patients with hypertrophic cardiomyopathy (HCM) but can be challenging to provoke. OBJECTIVES AND METHODS: To examine the value of postprandial resting and stress echocardiography and utilization of invasive or enhanced drug therapies (surgical myectomy, alcohol septal ablation, disopyramide and mavacamten) in patients with postprandial LVOTO. Consecutive HCM patients without LVOTO underwent routine and postprandial echocardiography at rest, with provocation (Valsalva and standing) and after symptom-limited treadmill stress. RESULTS: Among 252 patients (mean age 58 years, 39% women), postprandial LVOT gradients were higher compared with routine echocardiography at rest (median 9.0 [0-38.0] vs 0 [0-14.0] mmHg, p<0.0001) and with provocation (18.5 [0-70.3] vs 1.5 [0-41.0] mmHg, p<0.0001). Postprandial exercise (PPXSE) gradients were higher in a subset of 44 patients who underwent both postprandial and fasting stress echocardiography, (47.0 [5.3-81.0] vs 17.5 [0-46.0] mmHg, p<0.0001). In total, 49 (19.5%) patients achieved the ≥50 mmHg threshold under routine conditions (rest/provocation); 90 (35.7%) additional patients achieved postprandial gradients ≥50 mmHg (rest/provocation/exercise), 38 (15.1%) with PPXSE alone. A total of 71 patients were treated with 91 invasive or enhanced drug therapies, 32 (45.1%) of whom had gradients ≥50 mmHg only after eating (rest/provocation) and 8 (11.3%) only with PPXSE, with symptom relief in the majority. CONCLUSIONS: Postprandial echocardiography was useful at unmasking LVOTO in more than one third of patients who did not have high gradients otherwise. Eating before echocardiography is a powerful provocative tool in the evaluation of patients with HCM.

Efficacy and Safety of Aficamten in Symptomatic Nonobstructive Hypertrophic Cardiomyopathy: Results From the REDWOOD-HCM Trial, Cohort 4.

BACKGROUND: This open-label phase 2 trial evaluated the safety and efficacy of aficamten in patients with nonobstructive hypertrophic cardiomyopathy (nHCM). METHODS: Patients with symptomatic nHCM (left ventricular outflow tract obstruction gradient ≤ 30 mmHg, left ventricular ejection fraction [LVEF] ≥ 60%, N-terminal pro-B-type natriuretic peptide [NT-proBNP] > 300 pg/mL) received aficamten 5-15 mg once daily (doses adjusted according to echocardiographic LVEF) for 10 weeks. RESULTS: We enrolled 41 patients (mean ± SD age 56 ± 16 years; 59% female). At Week 10, 22 (55%) patients experienced an improvement of ≥ 1 New York Heart Association class; 11 (29%) became asymptomatic. Clinically relevant improvements in Kansas City Cardiomyopathy Questionnaire Clinical Summary Scores occurred in 22 (55%) patients. Symptom relief was paralleled by reductions in NT-proBNP levels (56%; P < 0.001) and high-sensitivity cardiac troponin I (22%; P < 0.005). Modest reductions in LVEF (mean ± SD) of -5.4% ± 10 to 64.6% ± 9.1 were observed. Three (8%) patients had asymptomatic reduction in LVEF < 50% (range: 41%-48%), all returning to normal after 2 weeks of washout. One patient with prior history of aborted sudden cardiac death experienced a fatal arrhythmia during the study. CONCLUSIONS: Aficamten administration for symptomatic nHCM was generally safe and was associated with improvements in heart failure symptoms and cardiac biomarkers. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04219826.

Mitral Leaflet Shortening as an Ancillary Procedure in Obstructive Hypertrophic Cardiomyopathy.

BACKGROUND: Mitral leaflet elongation is common in hypertrophic cardiomyopathy (HCM), contributes to obstructive physiology, and presents a challenge to the dual surgical goals of abolition of outflow gradients and abolition of mitral regurgitation. Anterior leaflet shortening, performed as an ancillary surgical procedure during myectomy, is controversial. METHODS: This was a retrospective study of all patients undergoing myectomy from January 2010 to March 2020, with analysis of survival and echocardiographic results. The study compared outcomes of patients treated with myectomy and concomitant mitral leaflet shortening with patients treated with myectomy alone. Over this time, the technique for mitral shortening evolved from anterior leaflet plication to residual leaflet excision (ReLex). RESULTS: Myectomy was performed in 416 patients aged 57.5 ± 13.6 years, and 204 (49%) patients were female. Average follow-up was 5.4 ± 2.8 years. Survival follow-up was complete in 415 patients. Myectomy without valve replacement was performed in 332 patients, of whom 192 had mitral valve shortening (58%). Mitral leaflet plication was performed in 73 patients, ReLex in 151, and both procedures in 32. Hospital mortality for patients undergoing myectomy was 0.7%. At 8 years, cumulative survival was 95% for both the myectomy combined with leaflet shortening group and the myectomy alone group, with no difference in survival between the 2 groups. There was no difference in survival between the anterior leaflet plication and ReLex groups. Echocardiography 2.5 years after surgery showed a decrease in resting and provoked gradients, mitral regurgitation, and left atrial volume and no difference in key variables between patients who underwent ancillary leaflet shortening and patients who underwent myectomy alone. CONCLUSIONS: These results affirm that mitral shortening may be an appropriate surgical judgment for selected patients.

Clinical course of adults with co-occurring hypertrophic cardiomyopathy and hypertension: A scoping review.

Introduction: Hypertension affects approximately 50 % of patients with hypertrophic cardiomyopathy (HCM) but clinical course in adults with co-occurring HCM and hypertension is underexplored. Management may be challenging as routine anti-hypertensive medications may worsen obstructive HCM, the most common HCM phenotype. In this scoping review, we sought to synthesize the available literature related to clinical course and outcomes in adults with both conditions and to highlight knowledge gaps to inform future research directions. Methods: We searched 5 electronic databases (PubMed, CINAHL, Scopus, Embase, Web of Science) to identify peer-reviewed articles, 2011-2023. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses-Scoping Review (PRISMA-ScR) guideline. Results: Eleven articles met eligibility. Adults with both conditions were older and had higher rates of obesity and diabetes than adults with HCM alone. Results related to functional class and arrhythmia were equivocal in cross-sectional studies. Only 1 article investigated changes in medical therapy among adults with both conditions. Hypertension was a predictor of worse functional class, but was not associated with all-cause mortality, heart failure-related mortality, or sudden-death. No data was found that related to common hypertension-related outcomes, including renal disease progression, nor patient-reported outcomes, including quality of life. Conclusions: Our results highlight areas for future research to improve understanding of co-occurring HCM and hypertension. These include a need for tailored approaches to medical management to optimize outcomes, evaluation of symptom burden and quality of life, and investigation of hypertension-related outcomes, like renal disease and ischemic stroke, to inform cardiovascular risk mitigation strategies.

Obstructive Hypertrophic Cardiomyopathy and Takotsubo Syndrome: How to Deal With Left Ventricular Ballooning?

Currently, there are 2 proposed causes of acute left ventricular ballooning. The first is the most cited hypothesis that ballooning is caused by direct catecholamine toxicity on cardiomyocytes or by microvascular ischemia. We refer to this pathogenesis as Takotsubo syndrome. More recently, a second cause has emerged: that in some patients with underlying hypertrophic cardiomyopathy, left ventricular ballooning is caused by the sudden onset of latent left ventricular outflow tract obstruction. When it becomes severe and unrelenting, severe afterload mismatch and acute supply-demand ischemia appear and result in ballooning. In the context of 2 causes, presentations might overlap and cause confusion. Knowing the pathophysiology of each mechanism and how to determine a correct diagnosis might guide treatment.

Histopathology of the Mitral Valve Residual Leaflet in Obstructive Hypertrophic Cardiomyopathy.

BACKGROUND: Mitral valve (MV) elongation is a primary hypertrophic cardiomyopathy (HCM) phenotype and contributes to obstruction. The residual MV leaflet that protrudes past the coaptation point is especially susceptible to flow-drag and systolic anterior motion. Histopathological features of MVs in obstructive hypertrophic cardiomyopathy (OHCM), and of residual leaflets specifically, are unknown. OBJECTIVES: The purpose of this study was to characterize gross, structural, and cellular histopathologic features of MV residual leaflets in OHCM. On a cellular-level, we assessed for developmental dysregulation of epicardium-derived cell (EPDC) differentiation, adaptive endocardial-to-mesenchymal transition and valvular interstitial cell proliferation, and genetically-driven persistence of cardiomyocytes in the valve. METHODS: Structural and immunohistochemical staining were performed on 22 residual leaflets excised as ancillary procedures during myectomy, and compared with 11 control leaflets from deceased patients with normal hearts. Structural components were assessed with hematoxylin and eosin, trichrome, and elastic stains. We stained for EPDCs, EPDC paracrine signaling, valvular interstitial cells, endocardial-to-mesenchymal transition, and cardiomyocytes. RESULTS: The residual leaflet was always at A2 segment and attached by slack, elongated and curlicued, myxoid chords. MV residual leaflets in OHCM were structurally disorganized, with expanded spongiosa and increased, fragmented elastic fibers compared with control leading edges. The internal collagenous fibrosa was attenuated and there was collagenous tissue overlying valve surfaces in HCM, with an overall trend toward decreased leaflet thickness (1.09 vs 1.47 mm, P = 0.08). No markers of primary cellular processes were identified. CONCLUSIONS: MV residual leaflets in HCM were characterized by histologic findings that were likely secondary to chronic hemodynamic stress and may further increase susceptibility to systolic anterior motion.

How common is hypertrophic cardiomyopathy really?: Disease prevalence revisited 27 years after CARDIA.

Hypertrophic cardiomyopathy (HCM) is a heterogeneous albeit treatable cardiac disease of variable severity, with the potential for heart failure, atrial fibrillation and arrhythmic sudden death, characterized by otherwise unexplained left ventricular (LV) hypertrophy and affecting all ages and races. Over the last 30 years, several studies have estimated the prevalence of HCM in the general population, employing echocardiography and cardiac magnetic resonance imaging (CMR), as well electronic health records and billing databases for clinical diagnosis. The estimated prevalence in the general population based on the disease phenotype of LV hypertrophy by imaging is 1:500 (0.2%). This prevalence was initially proposed in 1995 in the population-based CARDIA study employing echocardiography, and more recently confirmed by automated CMR analysis in the large UK Biobank cohort. The 1:500 prevalence appears most relevant to clinical assessment and management of HCM. These available data suggest that HCM is not a rare condition but likely underdiagnosed clinically and by extrapolation potentially affects about 700,000 Americans and possibly 15 million people worldwide.

Weight loss in hypertrophic cardiomyopathy: A clinical case series.

Background: Obesity is prevalent among patients with hypertrophic cardiomyopathy (HCM). Obese HCM patients have greater wall thickness, LV mass, worse hemodynamic function and NYHA class. Weight loss may favorably influence the HCM phenotype. Case summary: We describe six patients with hypertrophic cardiomyopathy who lost weight through diet and lifestyle changes (n = 4) or bariatric surgery (n = 2). Radiographic imaging, with cardiac MRI or CT scan, was performed before and after their weight loss. There was a mean decrease in LV mass and indexed LV mass, and a mean numerical decrease in mean wall thickness in up to 14 out of 18 LV segments. There was also NYHA class reduction in symptoms. Discussion: In this case series, we have shown that substantial weight loss in HCM patients can be associated with a decrease in LV mass, wall thickness and improvement in symptoms. These observations indicate the potential for positive remodeling of the heart by weight loss. Prospective studies of the benefits of weight loss in HCM are needed.

Apical Aneurysms and Mid-Left Ventricular Obstruction in Hypertrophic Cardiomyopathy.

BACKGROUND: Apical left ventricular (LV) aneurysms in hypertrophic cardiomyopathy (HCM) are associated with adverse outcomes. The reported frequency of mid-LV obstruction has varied from 36% to 90%. OBJECTIVES: The authors sought to ascertain the frequency of mid-LV obstruction in HCM apical aneurysms. METHODS: The authors analyzed echocardiographic and cardiac magnetic resonance examinations of patients with aneurysms from 3 dedicated programs and compared them with 63 normal controls and 47 controls with apical-mid HCM who did not have aneurysms (22 with increased LV systolic velocities). RESULTS: There were 108 patients with a mean age of 57.4 ± 13.5 years; 40 (37%) were women. A total of 103 aneurysm patients (95%) had mid-LV obstruction with mid-LV complete systolic emptying. Of the patients with obstruction, 84% had a midsystolic Doppler signal void, a marker of complete flow cessation, but only 19% had Doppler systolic gradients ≥30 mm Hg. Five patients (5%) had relative hypokinesia in mid-LV without obstruction. Aneurysm size is not bimodal but appears distributed by power law, with large aneurysms decidedly less common. Comparing mid-LV obstruction aneurysm patients with all control groups, the short-axis (SAX) systolic areas were smaller (P < 0.007), the percent SAX area change was greater (P < 0.005), the papillary muscle (PM) areas were larger (P < 0.003), and the diastolic PM areas/SAX diastolic areas were greater (P < 0.005). Patients with aneurysms had 22% greater SAX PM areas compared with those with elevated LV velocities but no aneurysms (median: 3.00 cm2 [IQR: 2.38-3.70 cm2] vs 2.45 [IQR: 1.81-2.95 cm2]; P = 0.004). Complete emptying occurs circumferentially around central PMs that contribute to obstruction. Late gadolinium enhancement was always brightest and the most transmural apical of, or at the level of, complete emptying. CONCLUSIONS: The great majority (95%) of patients in the continuum of apical aneurysms have associated mid-LV obstruction. Further research to investigate obstruction as a contributing cause to apical aneurysms is warranted.

Ventricular Septal Myectomy for Obstructive Hypertrophic Cardiomyopathy (Analysis Spanning 60 Years Of Practice): AJC Expert Panel.

Surgical myectomy remains the time-honored primary treatment for hypertrophic cardiomyopathy patients with drug refractory limiting symptoms due to LV outflow obstruction. Based on >50 years experience, surgery reliably reverses disabling heart failure by permanently abolishing mechanical outflow impedance and mitral regurgitation, with normalization of LV pressures and preserved systolic function. A consortium of 10 international currently active myectomy centers report about 11,000 operations, increasing significantly in number over the most recent 15 years. Performed in experienced multidisciplinary institutions, perioperative mortality for myectomy has declined to 0.6%, becoming one of the safest currently performed open-heart procedures. Extended myectomy relieves symptoms in >90% of patients by ≥ 1 NYHA functional class, returning most to normal daily activity, and also with a long-term survival benefit; concomitant Cox-Maze procedure can reduce the number of atrial fibrillation episodes. Surgery, preferably performed in high volume clinical environments, continues to flourish as a guideline-based and preferred high benefit: low treatment risk option for adults and children with drug refractory disabling symptoms from obstruction, despite prior challenges: higher operative mortality/skepticism in 1960s/1970s; dual-chamber pacing in 1990s, alcohol ablation in 2000s, and now introduction of novel negative inotropic drugs potentially useful for symptom management.

Quality of life and physical functioning in black and white adults with hypertrophic cardiomyopathy.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is a common and clinically heterogeneous inherited cardiac disease. Quality of life (QOL) and physical functioning are important clinically but are underexplored in diverse populations with HCM. OBJECTIVES: To examine predictors for and compare QOL and physical functioning in Black and White adults with HCM. METHODS: We analyzed a sub-sample from a longitudinal prospective study on HCM. Eligibility criteria included self-identified Black and White adults (≥18 years) with clinical HCM. QOL was measured with the Minnesota Living with Heart Failure Questionnaire (MLWHF);physical functioning included age-adjusted exercise capacity and NYHA class. Covariates included HCM structural characteristics and common comorbidities. We analyzed data from 434 individuals, 57 (13.1%) of whom self-identified as Black/African American. RESULTS: In this sample, the Black cohort had higher MLWHF scores, 31.2 (27.2) v. 23.9 (22.1), p=0.042, signifying worse QOL, but there were no intergroup differences when QOL was dichotomized. Mean metabolic equivalents (METs) on symptom-limited stress testing were similar, though the Black cohort was younger, 54.6 (13.4) v.62.5 (14.8) years, p=0.001. No one from the Black cohort achieved an "excellent-for-age" exercise capacity, and 64.1% had a "below-average-for-age" exercise capacity vs 47% in the White cohort, though this was not statistically significant, p=0.058. There was no difference between groups in advanced NYHA class. Female gender was associated with worse QOL and physical functioning irrespective of covariates. CONCLUSIONS: This study is a starting point that underscores the need for a more comprehensive examination of well-being and physical functioning in Black populations with HCM.

Diagnosis and Evaluation of Hypertrophic Cardiomyopathy: JACC State-of-the-Art Review.

Hypertrophic cardiomyopathy (HCM) is a relatively common often inherited global heart disease, with complex phenotypic and genetic expression and natural history, affecting both genders and many races and cultures. Prevalence is 1:200-1:500, largely based on the disease phenotype with imaging, inferring that 750,000 Americans may be affected by HCM. However, cross-sectional data show that only a fraction are clinically diagnosed, suggesting under-recognition, with most clinicians exposed to small segments of the broad disease spectrum. Highly effective HCM management strategies have emerged, altering clinical course and substantially lowering mortality and morbidity rates. These advances underscore the importance of reliable HCM diagnosis with echocardiography and cardiac magnetic resonance. Family screening with noninvasive imaging will identify relatives with the HCM phenotype, while genetic analysis recognizes preclinical sarcomere gene carriers without left ventricular hypertrophy, but with the potential to transmit disease. Comprehensive initial patient evaluations are important for reliable diagnosis, accurate portrayal of HCM and family history, risk stratification, and distinguishing obstructive versus nonobstructive forms.

Management of Hypertrophic Cardiomyopathy: JACC State-of-the-Art Review.

Hypertrophic cardiomyopathy (HCM), a relatively common, globally distributed, and often inherited primary cardiac disease, has now transformed into a contemporary highly treatable condition with effective options that alter natural history along specific personalized adverse pathways at all ages. HCM patients with disease-related complications benefit from: matured risk stratification in which major markers reliably select patients for prophylactic defibrillators and prevention of arrhythmic sudden death; low risk to high benefit surgical myectomy (with percutaneous alcohol ablation a selective alternative) that reverses progressive heart failure caused by outflow obstruction; anticoagulation prophylaxis that prevents atrial fibrillation-related embolic stroke and ablation techniques that decrease the frequency of paroxysmal episodes; and occasionally, heart transplant for end-stage nonobstructive patients. Those innovations have substantially improved outcomes by significantly reducing morbidity and HCM-related mortality to 0.5%/y. Palliative pharmacological strategies with currently available negative inotropic drugs can control symptoms over the short-term in some patients, but generally do not alter long-term clinical course. Notably, a substantial proportion of HCM patients (largely those identified without outflow obstruction) experience a stable/benign course without major interventions. The expert panel has critically appraised all available data and presented management insights and recommendations with concise principles for clinical decision-making.