Subset Of Hypertrophic Cardiomyopathy Patients Research Articles

Myocardial Inflammation in Sarcomere Mutation Hypertrophic Cardiomyopathy

Introduction: Hypertrophic cardiomyopathy (HCM) caused by sarcomere gene mutations leads to myocyte disarray and myocardial fibrosis. Previous studies have demonstrated that a component of this fibrosis may be attributable to an upregulation of a proinflammatory signaling cascade. HCM clinical heterogeneity exists due to varying phenotypic expression. The identification of patients with inflammation at the site of myocardial hypertrophy may provide better insight into the underlying physiology of myocardial remodeling of sarcomere gene mutation HCM. Hypothesis: A subset of hypertrophic cardiomyopathy patients with known sarcomere genetic mutations may demonstrate focal inflammation at the site of myocardial hypertrophy that can be demonstrated by fluorodeoxyglucose-positron emission tomography (FDG/PET-CT) analysis. Methods: Multimodality imaging utilizing cardiac magnetic resonance imaging (CMR) and FDG/PET-CT after a 72-hour pretest diet was utilized to assess for myocardial inflammation in a patient with suspected apical hypertrophic cardiomyopathy versus cardiac sarcoidosis. The FDG/PET-CT study was performed twice at 2 different institutions to confirm the findings. Genetic testing was also performed given a family history of sudden cardiac death. Results: The CMR images revealed focal, mild thickening of the anteroapical wall of the left ventricle of 13 mm. The FDG/PET-CT studies both revealed focal isolated FDG uptake in the anteroapical wall correlating to the area of focal hypertrophy on CMR. Genetic testing resulted positive for a c.927-9 (G > A) mutation in the MYBPC3 gene, which is a known pathologic variant. Conclusions: Our findings suggest that in certain patients with sarcomere mutation hypertrophic cardiomyopathy, focal active myocardial inflammation may exist at the site of myocardial hypertrophy and can be detected by FDG/PET-CT. Identification of the timing and role of myocardial inflammation in sarcomere gene mutation HCM myocardial remodeling may lead to better understanding of their varied phenotypic expression.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Exercise-QTc is associated with diffuse interstitial fibrosis reflected by lower approximated T1 relaxation time in hypertrophic cardiomyopathy patients

Hypertrophic cardiomyopathy (HCM) is frequently associated with exercise-related sudden death. One possible contributor to arrhythmias is pathologic hypertrophy, which can lead to QTc prolongation. Since β-adrenergic stimulation increases inward ionic currents and can increase spatial repolarization heterogeneity, we hypothesized that exercise would prolong QTc and predispose to arrhythmias in HCM patients. We tested this hypothesis by measuring QTc at rest and peak exercise, and examining ECGs for arrhythmias during exercise/recovery in 163 patients with a clinical diagnosis of HCM. Since hypertrophy and fibrosis are risk factors for arrhythmias in HCM, left ventricular (LV) mass and cardiac fibrosis were quantified using cardiac magnetic resonance imaging. Exercise led to an increase in QTc interval (436±37 to 482±45, p<0.001), QRS duration (100±9 to 109±12, p<0.001) and ST-T abnormalities. The proportion of patients with QTc prolongation (>470ms) increased from 28% at rest, to 58% at peak exercise. An inverse correlation was detected between the approximated T1 relaxation time (using the Look–Locker sequence) and rest-QTc (r=−0.68, p<0.001); this association was increased during exercise (r=−0.81, p<0.001). Late gadolinium enhancement (LGE) and LV mass were weakly associated with exercise-QTc. A weak inverse correlation was also observed between approximated T1 relaxation time and rest/exercise-QRS duration. A trend for association with arrhythmia (non-sustained ventricular tachycardia on Holter) was observed for rest-QTc>470ms (OR=3.0; p=0.06). We conclude that exercise leads to QTc prolongation in a subset of HCM patients. The association between the approximated T1 relaxation time and QTc interval may reflect concomitant electrical and structural remodeling in HCM.

T1 mapping in children and young adults with hypertrophic cardiomyopathy.

To assess the global and segmental left ventricular (LV) native T1 and extracellular volume fraction (ECV) in children and young adults with hypertrophic cardiomyopathy (HCM) compared to a control cohort. The study population included 21 HCM patients (mean 14.1 ± 4.6 years) and 21 controls (mean 15.7 ± 1.5 years). Native modified Look-Locker inversion recovery sequence was performed before and after contrast injection in 3 short axis planes. Global and segmental LV native T1 and ECV were quantified and compared between HCM patients and controls. Mean native T1 in HCM patients and controls was 1020.4 ± 41.2 and 965.6 ± 30.2ms respectively (p < 0.0001). Hypertrophied myocardium had significantly higher native global T1 and global ECV compared to non-hypertrophied myocardium in HCM (p < 0.0001, = 0.14 and 0.048, = 0.01 respectively). In a subset of patients, ECV was higher in LV segments with LGE compared to no LGE (p < 0.0001). No significant correlation was identified between global native T1 and ECV and parameters of LV structure and function. Native T1 cut-off of 987ms provided the highest sensitivity (95 %) and specificity (91 %) to separate HCM patients from controls. Global and segmental native T1 are elevated in HCM patients. LV segments with hypertrophy and/or LGE had higher ECV in a subset of HCM patients. LV native T1 and ECV do not correlate with parameters of LV structure and function. T1 in children and young adults may be used as a non-invasive tool to assess for HCM and related fibrosis.

Native T1 mapping in children and young adults with hypertrophic cardiomyopathy

To assess the global and segmental left ventricular (LV) native T1 and extracellular volume fraction (ECV) in children and young adults with hypertrophic cardiomyopathy (HCM) compared to a control cohort. The study population included 21 HCM patients (mean 14.1 ± 4.6 years) and 21 controls (mean 15.7 ± 1.5 years). Native modified Look-Locker inversion recovery sequence was performed before and after contrast injection in 3 short axis planes. Global and segmental LV native T1 and ECV were quantified and compared between HCM patients and controls. Mean native T1 in HCM patients and controls was 1020.4 ± 41.2 and 965.6 ± 30.2 ms respectively (p < 0.0001). Hypertrophied myocardium had significantly higher native global T1 and global ECV compared to non-hypertrophied myocardium in HCM (p < 0.0001, = 0.14 and 0.048, = 0.01 respectively). In a subset of patients, ECV was higher in LV segments with LGE compared to no LGE (p < 0.0001). No significant correlation was identified between global native T1 and ECV and parameters of LV structure and function. Native T1 cut-off of 987 ms provided the highest sensitivity (95 %) and specificity (91 %) to separate HCM patients from controls. Global and segmental native T1 are elevated in HCM patients. LV segments with hypertrophy and/or LGE had higher ECV in a subset of HCM patients. LV native T1 and ECV do not correlate with parameters of LV structure and function. T1 in children and young adults may be used as a non-invasive tool to assess for HCM and related fibrosis.

TRANSAPICAL MYECTOMY IN CHILDREN WITH HYPERTROPHIC CARDIOMYOPATHY: EARLY AND MID-TERM

The transapical approach to myectomy in hypertrophic cardiomyopathy (HCM) has been utilized in the subset of HCM patients with heart failure, midventricular obstruction and apical cavity obliteration with low stroke volume. However, minimal outcome data are reported addressing the role of

A subset of hypertrophic cardiomyopathy patients is predisposed to angulated septum

Background Hypertrophic cardiomyopathy (HCM) is a complex genetic disease with marked morphofunctional heterogeneity. Some HCM patients develop obstructive symptoms later in life, long after cessation of hypertrophic progression. The mechanism underlying this phenomenon is poorly understood. It is known that aorto-septal angulation progresses with age. However, the relationship between age, septal angulation, and HCM subtype has not been explored. In this present study, we examined the relationship between age, aorto-septal angulation and subtypes of HCM. Methods Control normal subjects (n=19) and consecutive HCM patients with apical, concentric, and septal subtypes (n=53) were identified from the MRI database at YaleNew Haven Hospital. Angulated septal angle, the angle between the right septal surface and anterior aortic wall during end systole and diastole, was measured blindly by two readers. Disagreements between two reads >10˚ were excluded. In addition, we further age stratified our cohort of septal subtype (above or below 40 years) to explore differences in the pattern of aorto-septal angle over age. Results Patients with septal, but not apical or concentric subtypes, exhibit more acute angulated septum versus controls in end-systole (p=0.008, 0.326, and 0.167, respectively). The acuity of this angle increased with age in controls (p=0.0009). Interestingly, HCM patients with septal hypertrophy deviated from this pattern, demonstrating early angulation without progression over age (p=0.918). The associations above remained significant in end-diastole.

Comparison of Electrocardiographic Criteria in Hypertrophic Cardiomyopathy Patients with and without Apical Aneurysm

OP-157 Apical aneurysms in patients with hypertrophic cardiomyopathy(HCM) represent an underrecognized but clinically important subset of HCM patients,often requiring a high index of suspicion.It is commonly associated with adverse clinical course,including sudden cardiac death and embolic stroke;

Response to Letter Regarding Article, “Prevalence, Clinical Significance, and Natural History of Left Ventricular Apical Aneurysms in Hypertrophic Cardiomyopathy”

We thank Dr Giuseppe Ando et al for their interest in our description of left ventricular (LV) apical aneurysms occurring in patients with hypertrophic cardiomyopathy (HCM), a newly recognized and important subgroup within this heterogeneous disease spectrum.1 Ando et al have raised a number of important issues relative to nomenclature, mechanism, and the treatment of LV apical aneurysms in HCM patients. With respect to nomenclature, we agree that the term diverticula should be …

Missense mutations in the beta-myosin heavy-chain gene cause central core disease in hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is an important cause of sudden death in apparently healthy young individuals. In less than half of kindreds with HCM, the disease is linked to the beta-myosin heavy-chain gene locus (MYH7). We have recently described two missense MYH7 gene mutations [Arg-403 to Gln (R403Q) and Leu-908 to Val (L908V)] and found that the mutant message is present in skeletal muscle soleus) and that the mutant beta-myosin obtained from soleus muscle has abnormal in vitro motility activity. Having identified a second kindred with the R403Q mutation, and 3 other kindreds with two additional mutations (G741R and G256E), we performed histochemical analysis of soleus muscle biopsies from 25 HCM patients with one of these four mutations. Light microscopic examination of the NADH-stained biopsies revealed the presence of central core disease (CCD) of skeletal muscle, a rare autosomal dominant nonprogressive myopathy characterized by a predominance of type I "slow" fibers and an absence of mitochondria in the center of many type I fibers. CCD was present in 10 of 13 patients with the L908V mutation, 5 of 8 patients with the R403Q mutation, 1 of 3 patients with the G741R mutation, and 1 patient with the G256E mutation. Mild-to-moderate myopathic changes with muscle fiber hypertrophy were present in 16 patients. Notably, CCD was present in 2 adults and 3 children with the L908V mutation who did not have cardiac hypertrophy. In contrast, soleus muscle samples from 5 patients from 4 kindreds in which HCM was not linked to the MYH7 locus showed no myopathy or CCD. Soleus muscle biopsies from 5 control subjects also showed normal histology. This work demonstrates that (i) MYH7-associated HCM is often a disease of striated muscle but with predominant cardiac involvement and (ii) a subset of HCM patients with MYH7 gene missense mutations have CCD.