Vigorous Exercise in Patients With Hypertrophic Cardiomyopathy.

Importance: Whether vigorous intensity exercise is associated with an increase in risk of ventricular arrhythmias in individuals with hypertrophic cardiomyopathy (HCM) is unknown. Objective: To determine whether engagement in vigorous exercise is associated with increased risk for ventricular arrhythmias and/or mortality in individuals with HCM. The a priori hypothesis was that participants engaging in vigorous activity were not more likely to have an arrhythmic event or die than those who reported nonvigorous activity. Design, Setting, and Participants: This was an investigator-initiated, prospective cohort study. Participants were enrolled from May 18, 2015, to April 25, 2019, with completion in February 28, 2022. Participants were categorized according to self-reported levels of physical activity: sedentary, moderate, or vigorous-intensity exercise. This was a multicenter, observational registry with recruitment at 42 high-volume HCM centers in the US and internationally; patients could also self-enroll through the central site. Individuals aged 8 to 60 years diagnosed with HCM or genotype positive without left ventricular hypertrophy (phenotype negative) without conditions precluding exercise were enrolled. Exposures: Amount and intensity of physical activity. Main Outcomes and Measures: The primary prespecified composite end point included death, resuscitated sudden cardiac arrest, arrhythmic syncope, and appropriate shock from an implantable cardioverter defibrillator. All outcome events were adjudicated by an events committee blinded to the patient's exercise category. Results: Among the 1660 total participants (mean [SD] age, 39 [15] years; 996 male [60%]), 252 (15%) were classified as sedentary, and 709 (43%) participated in moderate exercise. Among the 699 individuals (42%) who participated in vigorous-intensity exercise, 259 (37%) participated competitively. A total of 77 individuals (4.6%) reached the composite end point. These individuals included 44 (4.6%) of those classified as nonvigorous and 33 (4.7%) of those classified as vigorous, with corresponding rates of 15.3 and 15.9 per 1000 person-years, respectively. In multivariate Cox regression analysis of the primary composite end point, individuals engaging in vigorous exercise did not experience a higher rate of events compared with the nonvigorous group with an adjusted hazard ratio of 1.01. The upper 95% 1-sided confidence level was 1.48, which was below the prespecified boundary of 1.5 for noninferiority. Conclusions and Relevance: Results of this cohort study suggest that among individuals with HCM or those who are genotype positive/phenotype negative and are treated in experienced centers, those exercising vigorously did not experience a higher rate of death or life-threatening arrhythmias than those exercising moderately or those who were sedentary. These data may inform discussion between the patient and their expert clinician around exercise participation.

Hemodynamic stress and microscopic remodeling.

BACKGROUD: Heart responds to physiologic and pathologic conditions and sympathetic drive plays an important role. It has been documented that LV base is more dominantly affected by sympathetic drive compared to the other regions. LV base is more dominantly exposed to wall stress in the initial period of remodeling due to pressure-overload, since LV cavity is the largest at base. Basal septal hypertrophy (BSH) in cross-sectional data is associated with the early phase of hypertensive heart disease. BSH was confirmed by 3rd generation microscopic ultrasound in small animals. BSH as the closest location to increased afterload could be detected in variety of stress stimuli and result in a huge septal hypertrophy in advance cases possibly related to earlier exposure of hemodynamic stress to septal wall. CONCLUSION: Effective geometric and functional evaluation of initial remodeling due to hemodynamic stress is important according to both human and animal data. These findings possibly contribute to early recognition of adaptive phase of hypertensive remodeling and more effective management in a timely fashion.

Fropofol prevents disease progression in mice with hypertrophic cardiomyopathy.

AIMS: Increased myofilament contractility is recognized as a crucial factor in the pathogenesis of hypertrophic cardiomyopathy (HCM). Direct myofilament desensitization might be beneficial in preventing HCM disease progression. Here, we tested whether the small molecule fropofol prevents HCM phenotype expression and disease progression by directly depressing myofilament force development. METHODS AND RESULTS: Force, intracellular Ca2+, and steady-state activation were determined in isolated trabecular muscles from wild-type (WT) and transgenic HCM mice with heterozygous human α-myosin heavy chain R403Q mutation (αMHC 403/+). αMHC 403/+ HCM mice were treated continuously with fropofol by intraperitoneal infusion for 12 weeks. Heart tissue was analysed with histology and real-time PCR of prohypertrophic and profibrotic genes. Fropofol decreased force in a concentration-dependent manner without significantly altering [Ca2+]i in isolated muscles from both WT and αMHC 403/+ HCM mouse hearts. Fropofol also depressed maximal Ca2+-activated force and increased the [Ca2+]i required for 50% activation during steady-state activation. In whole-animal studies, chronic intra-abdominal administration of fropofol prevented hypertrophy development and diastolic dysfunction. Chronic fropofol treatment also led to attenuation of prohypertrophic and profibrotic gene expression, reductions in cell size, and decreases in tissue fibrosis. CONCLUSIONS: Direct inhibition of myofilament contraction by fropofol prevents HCM disease phenotypic expression and progression, suggesting that increased myofilament contractile force is the primary trigger for hypertrophy development and HCM disease progression.

Structural and Functional Correlates of Myocardial T1 Mapping in 321 Patients With Hypertrophic Cardiomyopathy.

OBJECTIVE: The aim of this study was to evaluate the structural and functional correlates of T1 mapping in 321 patients with hypertrophic cardiomyopathy (HCM). METHODS: Three hundred twenty-one patients with HCM who underwent cardiac magnetic resonance from 2003 to 2013 were retrospectively identified from our institution's HCM registry. Left ventricular volume, function, late gadolinium enhancement (LGE), and Look-Locker T1 time were quantified. T1 time was normalized to blood pool to calculate T1 ratio. Correlations between LGE%, T1 ratio, and structural and functional features were performed using Pearson correlation coefficient. RESULTS: Late gadolinium enhancement showed stronger correlation with left ventricular mass index (r = 0.41, P < 0.001) compared with T1 ratio (r = -0.17, P = 0.004). Both LGE% and T1 ratio correlated with ejection fraction (r = -0.18 and P = 0.002 vs r = 0.21 and P < 0.001, respectively). E/e' showed correlation with LGE% but not with T1 ratio. CONCLUSIONS: Late gadolinium enhancement was more strongly correlated with the phenotypic expression of HCM compared with T1 ratio.

Safety profile and utility of treadmill exercise in patients with high-gradient hypertrophic cardiomyopathy.

BACKGROUND: Exercise echocardiography in the evaluation of hypertrophic cardiomyopathy (HCM) provides valuable information for risk stratification, selection of optimal treatment, and prognostication. However, HCM patients with left ventricular outflow tract gradients ≥30mm Hg are often excluded from exercise testing because of safety considerations. We examined the safety and utility of exercise testing in patients with high-gradient HCM. METHODS: We evaluated clinical characteristics, hemodynamics, and imaging variables in 499 consecutive patients with HCM who performed 959 exercise tests. Patients were divided based on peak left ventricular outflow tract gradients using a 30-mm Hg threshold into the following: obstructive (n=152), labile-obstructive (n=178), and nonobstructive (n=169) groups. RESULTS: There were no deaths during exercise testing. We noted 20 complications (2.1% of tests) including 3 serious ventricular arrhythmias (0.3% of tests). There was no difference in complication rate between groups. Patients with obstructive HCM had a higher frequency of abnormal blood pressure response (obstructive: 53% vs labile: obstructive: 41% and nonobstructive: 37%; P=.008). Obstructive patients also displayed a lower work capacity (obstructive: 8.4±3.4 vs labile obstructive: 10.9±4.2 and nonobstructive: 10.2±4.0, metabolic equivalent; P<.001). Exercise testing provided incremental information regarding sudden cardiac death risk in 19% of patients with high-gradient HCM, and we found a poor correlation between patient-reported functional class and work capacity. CONCLUSION: Our results suggest that exercise testing in HCM is safe, and serious adverse events are rare. Although numbers are limited, exercise testing in high-gradient HCM appears to confer no significant additional safety hazard in our selected cohort and could potentially provide valuable information.

Echocardiographic Characterization of a Murine Model of Hypertrophic Obstructive Cardiomyopathy Induced by Cardiac-specific Overexpression of Epidermal Growth Factor Receptor 2.

Although rare, hypertrophic cardiomyopathy (HCM) with midventricular obstruction is often associated with severe symptoms and complications. None of the existing HCM animal models display this particular phenotype. Our group developed a mouse line that overexpresses the ErbB2 receptor (ErbB2(tg)) in cardiomyocytes; we previously showed that the ErbB2 receptor induces cardiomyocyte hypertrophy, myocyte disarray, and fibrosis compatible with HCM. In the current study, we sought to further echocardiographically characterize the ErbB2(tg) mouse line as a model of HCM. Compared with their wild-type littermates, ErbB2(tg) mice show increased left ventricular (LV) mass, concentric LV hypertrophy, and papillary muscle hypertrophy. This hypertrophy was accompanied by diastolic dysfunction, expressed as reduced E:A ratio, prolonged deceleration time, and elevated E:e' ratio. In addition, ErbB2(tg) mice consistently showed midcavity obstruction with elevated LV gradients, and the flow profile revealed a prolonged pressure increase and a delayed peak, indicating dynamic obstruction. The ejection fraction was increased in ErbB2(tg) mice, due to reduced end-diastolic and end-systolic LV volumes. Furthermore, systolic radial strain and systolic radial strain rate but not systolic circumferential strain and longitudinal strain were decreased in ErbB2(tg) compared with wild-type mice. In conclusion, the phenotype of the ErbB2(tg) mouse model is consistent with midventricular HCM in many important aspects, including massive LV hypertrophy, diastolic dysfunction, and midcavity obstruction. This pattern is unique for a small animal model, suggesting that ErbB2(tg) mice may be well suited for research into the hemodynamics and treatment of this rare form of HCM.

Age-related changes in familial hypertrophic cardiomyopathy phenotype in transgenic mice and humans.

ß-myosin heavy chain mutations are the most frequently identified basis for hypertrophic cardiomyopathy (HCM). A transgenic mouse model (αMHC(403)) has been extensively used to study various mechanistic aspects of HCM. There is general skepticism whether mouse and human disease features are similar. Herein we compare morphologic and functional characteristics, and disease evolution, in a transgenic mouse and a single family with a MHC mutation. Ten male αMHC(403) transgenic mice (at t-5 weeks, -12 weeks, and -24 weeks) and 10 HCM patients from the same family with a ß-myosin heavy chain mutation were enrolled. Morphometric, conventional echocardiographic, tissue Doppler and strain analytic characteristics of transgenic mice and HCM patients were assessed. Ten male transgenic mice (αMHC(403)) were examined at ages -5 weeks, -12 weeks, and -24 weeks. In the transgenic mice, aging was associated with a significant increase in septal (0.59±0.06 vs. 0.64±0.05 vs. 0.69±0.11 mm, P<0.01) and anterior wall thickness (0.58±0.1 vs. 0.62±0.07 vs. 0.80±0.16 mm, P<0.001), which was coincident with a significant decrease in circumferential strain (-22%±4% vs. -20%±3% vs. -19%±3%, P=0.03), global longitudinal strain (-19%±3% vs. -17%±2% vs. -16%±3%, P=0.001) and E/A ratio (1.9±0.3 vs. 1.7±0.3 vs. 1.4±0.3, P=0.01). The HCM patients were classified into 1st generation (n=6; mean age 53±6 years), and 2nd generation (n=4; mean age 32±8 years). Septal thickness (2.2±0.9 vs. 1.4±0.1 cm, P<0.05), left atrial (LA) volume (62±16 vs. 41±5 mL, P=0.03), E/A ratio (0.77±0.21 vs. 1.1±0.1, P=0.01), E/e' ratio (25±10 vs. 12±2, P=0.03), global left ventricular (LV) strain (-14%±3% vs. -20%±3%, P=0.01) and global LV early diastolic strain rate (0.76±0.17 s(-1) vs. 1.3±0.2 s-1, P=0.01) were significantly worse in the older generation. In ß-myosin heavy chain mutations, transgenic mice and humans have similar progression in morphologic and functional abnormalities. The αMHC(403) transgenic mouse model closely recapitulates human disease.

Discrepant uptake of the radiolabeled norepinephrine analogues hydroxyephedrine (HED) and metaiodobenzylguanidine (MIBG) in rat hearts.

PURPOSE: (11)C-Hydroxyephedrine (HED) and radioiodinated metaiodobenzylguanidine ((123)I/(131)I-MIBG) are catecholamine analogue tracers for sympathetic nerve positron emission tomography/single photon emission computed tomography (PET/SPECT) imaging. In contrast to humans, rat hearts demonstrate high nonneural catecholamine uptake-2 in addition to neural uptake-1, the contributions of which to tracer accumulation are not fully elucidated. METHODS: Wistar rats were studied using the following pretreatments: uptake-1 blockade with desipramine 2 mg/kg IV, both uptake-1 and -2 blockade with phenoxybenzamine 50 mg/kg IV, or control with saline IV. HED or (123)I-MIBG was injected 10 min after pretreatment, and rats were sacrificed 10 min later. Heart to blood tissue count ratio (H/B ratio) was obtained using a gamma counter. To determine regional tracer uptake, dual-tracer autoradiography was performed with HED and (131)I-MIBG in Wistar rats with chronic infarction by transient coronary occlusion and reperfusion and in healthy control rats. Local tracer distributions were analyzed, and the infarcted rats' local tracer distributions were compared with histology. RESULTS: The H/B ratios in control hearts were 34.4 ± 1.7 and 25.5 ± 2.1 for HED and (123)I-MIBG, respectively. Desipramine led to a significant decrease in HED (3.2 ± 0.5, p < 0.0001), while there was no change in (123)I-MIBG (25.5 ± 6.4, p = n.s.). Phenoxybenzamine led to a significant decrease in both HED and (123)I-MIBG (3.5 ± 0.02, 4.3 ± 0.7, p < 0.0001). Only HED showed a subepicardium-subendocardium gradient in healthy control hearts which is consistent with physiological innervation, while (131)I-MIBG was evenly distributed throughout the myocardium. (131)I-MIBG uptake defect closely matched the scar area determined by histology [3.8 ± 2.3% ((131)I-MIBG defect) vs 4.0 ± 2.4% (scar)]. However, the scar area was clearly exceeded by the HED uptake defect (9.1 ± 2.2%, p < 0.001). CONCLUSION: HED uptake showed high specificity to neural uptake-1 in rat hearts. On the other hand, (123)I/(131)I-MIBG demonstrated distinct characters of regional tracer distribution and uptake mechanism that are compatible with significant contribution of nonneural uptake-2.

In hypertrophic cardiomyopathy reduction of relative resting myocardial blood flow is related to late enhancement, T2-signal and LV wall thickness.

OBJECTIVES: To quantify resting myocardial blood flow (MBF) in the left ventricular (LV) wall of HCM patients and to determine the relationship to important parameters of disease: LV wall thickness, late gadolinium enhancement (LGE), T2-signal abnormalities (dark and bright signal), LV outflow tract obstruction and age. MATERIALS AND METHODS: Seventy patients with proven HCM underwent cardiac MRI. Absolute and relative resting MBF were calculated from cardiac perfusion MRI by using the Fermi function model. The relationship between relative MBF and LV wall thickness, T2-signal abnormalities (T2 dark and T2 bright signal), LGE, age and LV outflow gradient as determined by echocardiography was determined using simple and multiple linear regression analysis. Categories of reduced and elevated perfusion in relation to non- or mildly affected reference segments were defined, and T2-signal characteristics and extent as well as pattern of LGE were examined. Statistical testing included linear and logistic regression analysis, unpaired t-test, odds ratios, and Fisher's exact test. RESULTS: 804 segments in 70 patients were included in the analysis. In a simple linear regression model LV wall thickness (p<0.001), extent of LGE (p<0.001), presence of edema, defined as focal T2 bright signal (p<0.001), T2 dark signal (p<0.001) and age (p = 0.032) correlated inversely with relative resting MBF. The LV outflow gradient did not show any effect on resting perfusion (p = 0.901). Multiple linear regression analysis revealed that LGE (p<0.001), edema (p = 0.026) and T2 dark signal (p = 0.019) were independent predictors of relative resting MBF. Segments with reduced resting perfusion demonstrated different LGE patterns compared to segments with elevated resting perfusion. CONCLUSION: In HCM resting MBF is significantly reduced depending on LV wall thickness, extent of LGE, focal T2 signal abnormalities and age. Furthermore, different patterns of perfusion in HCM patients have been defined, which may represent different stages of disease.

Matrix rigidity controls endothelial differentiation and morphogenesis of cardiac precursors.

Tissue development and regeneration involve tightly coordinated and integrated processes: selective proliferation of resident stem and precursor cells, differentiation into target somatic cell type, and spatial morphological organization. The role of the mechanical environment in the coordination of these processes is poorly understood. We show that multipotent cells derived from native cardiac tissue continually monitored cell substratum rigidity and showed enhanced proliferation, endothelial differentiation, and morphogenesis when the cell substratum rigidity closely matched that of myocardium. Mechanoregulation of these diverse processes required p190RhoGAP, a guanosine triphosphatase-activating protein for RhoA, acting through RhoA-dependent and -independent mechanisms. Natural or induced decreases in the abundance of p190RhoGAP triggered a series of developmental events by coupling cell-cell and cell-substratum interactions to genetic circuits controlling differentiation.

Cardiac MRI evaluation of hypertrophic cardiomyopathy: left ventricular outflow tract/aortic valve diameter ratio predicts severity of LVOT obstruction.

PURPOSE: To evaluate if left ventricular outflow tract/aortic valve (LVOT/AO) diameter ratio measured by cardiac magnetic resonance (CMR) imaging is an accurate marker for LVOT obstruction in patients with hypertrophic cardiomyopathy (HCM) compared to Doppler echocardiography. MATERIALS AND METHODS: In all, 92 patients with HCM were divided into three groups based on their resting echocardiographic LVOT pressure gradient (PG): <30 mmHg at rest (nonobstructive, n = 31), <30 mmHg at rest, >30 mmHg after provocation (latent, n = 29), and >30 mmHg at rest (obstructive, n = 32). The end-systolic dimension of the LVOT on 3-chamber steady-state free precession (SSFP) CMR was divided by the end diastolic aortic valve diameter to calculate the LVOT/AO diameter ratio. RESULTS: There were significant differences in the LVOT/AO diameter ratio among the three subgroups (nonobstructive 0.60 ± 0.13, latent 0.41 ± 0.16, obstructive 0.24 ± 0.09, P < 0.001). There was a strong linear inverse correlation between the LVOT/AO diameter ratio and the log of the LVOT pressure gradient (r = -0.84, P < 0.001). For detection of a resting gradient >30 mmHg, the LVOT/AO diameter ratio the area under the receiver operating characteristic (ROC) curve was 0.91 (95% confidence interval [CI] 0.85-0.97). For detection of a resting and/or provoked gradient >30 mmHg, the LVOT/AO diameter ratio area under the ROC curve was 0.90 (95% CI 0.84-0.96). CONCLUSION: The LVOT/AO diameter ratio is an accurate, reproducible, noninvasive, and easy to use CMR marker to assess LVOT pressure gradients in patients with HCM.