Faculty Bibliography

OBJECTIVES/OBJECTIVE:To investigate the potential value of adding a tagged three-chamber (3Ch) cine to clinical hypertrophic cardiomyopathy (HCM) magnetic resonance imaging (MRI) protocols, including to help distinguish HCM patients with regionally impaired cardiac function. METHODS:Forty-eight HCM patients, five patients with "septal knuckle" (SK), and 20 healthy volunteers underwent MRI at 1.5T; a tagged 3Ch cine was added to the protocol. Regional strain, myocardial wall thickness, and mitral valve leaflet lengths were measured in the 3Ch view. RESULTS:In HCM, we found a reduced tangential strain with decreased diastolic relaxation in both hypertrophied (p = 0.003) and remote segments (p = 0.035). Strain in the basal septum correlated with the length of the coaptation zone + residual leaflet (r = 0.48, p < 0.001). In the basal free wall, patients with SK had faster relaxation compared to HCM patients with septal hypertrophy. DISCUSSION/CONCLUSIONS:The 3Ch tagged MRI sequence provides useful information for the examination of suspected HCM patients, with minimal additional time cost. Local wall function is closely associated with morphological changes of the mitral apparatus measured in the same plane and may provide insights into mechanisms of obstruction. The additional strain information may be helpful when analyzing local myocardial wall motion patterns in the presence of SK.

BACKGROUND:Patients with nonobstructive hypertrophic cardiomyopathy (nHCM) often experience a high burden of symptoms; however, there are no proven pharmacological therapies. By altering the contractile mechanics of the cardiomyocyte, myosin inhibitors have the potential to modify pathophysiology and improve symptoms associated with HCM. OBJECTIVES/OBJECTIVE:MAVERICK-HCM (Mavacamten in Adults With Symptomatic Non-Obstructive Hypertrophic Cardiomyopathy) explored the safety and efficacy of mavacamten, a first-in-class reversible inhibitor of cardiac-specific myosin, in nHCM. METHODS:The MAVERICK-HCM trial was a multicenter, double-blind, placebo-controlled, dose-ranging phase II study in adults with symptomatic nHCM (New York Heart Association functional class II/III), left ventricular ejection fraction (LVEF) ≥55%, and N-terminal pro-B-type natriuretic peptide (NT-proBNP) ≥300 pg/ml. Participants were randomized 1:1:1 to mavacamten at a pharmacokinetic-adjusted dose (targeting plasma levels of 200 or 500 ng/ml), or placebo for 16 weeks, followed by an 8-week washout. Initial dose was 5 mg daily with 1 dose titration at week 6. RESULTS:Fifty-nine participants were randomized (19, 21, 19 patients to 200 ng/ml, 500 ng/ml, placebo, respectively). Their mean age was 54 years, and 58% were women. Serious adverse events occurred in 10% of participants on mavacamten and in 21% participants on placebo. Five participants on mavacamten had reversible reduction in LVEF ≤45%. NT-proBNP geometric mean decreased by 53% in the pooled mavacamten group versus 1% in the placebo group, with geometric mean differences of -435 and -6 pg/ml, respectively (p = 0.0005). Cardiac troponin I (cTnI) geometric mean decreased by 34% in the pooled mavacamten group versus a 4% increase in the placebo group, with geometric mean differences of -0.008 and 0.001 ng/ml, respectively (p = 0.009). CONCLUSIONS:Mavacamten, a novel myosin inhibitor, was well tolerated in most subjects with symptomatic nHCM. Furthermore, treatment was associated with a significant reduction in NT-proBNP and cTnI, suggesting improvement in myocardial wall stress. These results set the stage for future studies of mavacamten in this patient population using clinical parameters, including LVEF, to guide dosing. (A Phase 2 Study of Mavacamten in Adults With Symptomatic Non-Obstructive Hypertrophic Cardiomyopathy [MAVERICK-HCM]; NCT03442764).

Clinical spectrum of hypertrophic cardiomyopathy (HC) has been expanded to include patients with mild or no thickening of the left ventricle (LV), who nevertheless have outflow tract obstruction at rest or after exercise, due to systolic anterior motion (SAM) and ventricular septal contact, with mitral valve elongation and papillary muscles anomalies. Apical ballooning mimicking a takotsubo syndrome (TS) wall motion pattern can occur in HC with mild septal thickening when latent obstruction becomes unrelenting. To define the prevalence of anatomic abnormalities characteristic of HC in patients diagnosed with TS, we analyzed echocardiograms of 44 unselected TS patients, age 67±12 years, 95% women including studies performed before the event (n = 11, median 515 days) and after recovery of left ventricular function (n = 33, median 92 days, interquartile range = 29 to 327) and compared the findings to 60 age and sexed matched controls. Analysis of echocardiograms was blinded to event timing, and patient vs. control status. During the ballooning event, 13 patients (30%) had SAM including 9 with LV outflow obstruction, peak gradients 71±40 mmHg, as well as: ventricular septal thickening (16 ± 4 mm), elongated anterior leaflets (30 ± 3mm), and increased mitral coaptation to posterior wall distance (17 ± 5 mm), consistent with diagnosis of the HC phenotype. Compared to 31 TS patients without SAM, study patients with SAM had longer anterior leaflets (30 ± 3 vs 26 ± 4 mm, p = 0.006), thicker septum (16 ± 4 vs 12 ± 3 mm), increased coaptation to posterior wall distance (17 ± 5 vs 14 ± 4 mm, p < 0.04) and reduced distance from coaptation to septum (19 ± 5 vs 27 ± 5, p < 0.001). In the 13 patients with SAM, morphologic characteristics of HC persisted after normalization of LV function. In conclusion, a subset of patients experiencing TS events demonstrates a constellation of morphologic abnormalities characteristic of HC that persist after recovery of LV wall motion. These findings suggest that dynamic outflow obstruction may cause apical ballooning in susceptible patients.

Background Recently the clinical spectrum of hypertrophic cardiomyopathy (HCM) has been expanded to include patients with mild or no thickening of the left ventricle (LV) yet who have outflow tract obstruction at rest or after exercise, principally due to characteristic HCM anterior mitral leaflet (AML) elongation and papillary muscle anomalies. Apical ballooning mimicking a takotsubo syndrome (TTS) wall motion pattern can occur in mild-septal-thickening HCM when latent obstruction becomes unrelenting. The objective of this study is to define the prevalence of anatomic abnormalities characteristic of HCM in an unselected population of patients diagnosed clinically with TTS. Methods We analyzed echocardiograms of 44 admitted TTS patients including studies performed during admission, before the event (n=11, median 515 days before) and after recovery of left ventricular function (n=33, median 92 days, IQR=29-327) and compared them to 60 controls, age-matched normal women. Analysis of 148 echocardiograms was blinded to timing, and patient vs. control status. Results Age was 67+/-12 years, 42 female (95%). During the ballooning event, 13 (30%) had SAM and 9 patients (20%) had LV outflow tract obstruction (LVOTO), gradients 71+/-40 mmHg. Compared to TTS patients without SAM, those with SAM had longer AML (30 vs. 26mm), and thicker septum (16 vs. 12 mm) and less distance from septum to coaptation (19 vs. 27mm), all p <=0.006. Eleven of the SAM patients had >=2 anatomic abnormalities predisposing to obstruction (defined as > 2 SD above normal), and/or an anomalous papillary muscle/chordae. In the 44 TTS patients each parameter differed from controls before, during and after the TTS event. Eight (18%) had abnormal right ventricular wall motion, none of whom were obstructed. Conclusion Thirty percent of unselected TTS patients have SAM and 20% have significant LVOT gradients. This subset had AML abnormalities and septal thickening typical of obstructive HCM and known to predispose to LVOT obstruction. They are phenotypically identical to patients with documented HCM with mild septal thickening and LVOT obstruction, who have experienced episodes of ballooning.

Cardiac amyloid A (AA) amyloidosis is rare. We present the case of a 72-year-old woman with obstructive hypertrophic cardiomyopathy (HCM) and biopsy-proven renal AA amyloidosis whose dyspnea and exercise intolerance had worsened over the previous year. Her AA amyloidosis was suspected to be secondary to chronic diverticulitis for which she had undergone hemicolectomy and sigmoidectomy 3 years prior. Echocardiographic findings were consistent with worsening left ventricular outflow tract obstruction at rest. Cardiac magnetic resonance imaging revealed patchy areas of midwall late gadolinium enhancement. Right ventricular endomyocardial biopsy did not reveal amyloid deposition, and cardiac technetium-99m pyrophosphate scintigraphy did not suggest transthyretin amyloidosis. The patient underwent septal myectomy with resection of an accessory papillary muscle. Pathological examination of the myectomy specimen was consistent with HCM. In addition, there was a thick layer of diffuse endocardial and vascular amyloid deposition that was identified as AA type by laser-microdissection with liquid chromatography-coupled tandem-mass spectrometry. This case report highlights the presence of 2 distinct disease processes occurring simultaneously and the importance of tissue diagnosis of AA amyloidosis, a condition that is not commonly associated with HCM.