Hypertrophic cardiomyopathy (HCM) exhibits genetic heterogeneity that is dominated by variation in eight sarcomeric genes. Genetic variation in a large number of non-sarcomeric genes has also been ...implicated in HCM but not formally assessed. Here we used very large case and control cohorts to determine the extent to which variation in non-sarcomeric genes contributes to HCM.
We sequenced known and putative HCM genes in a new large prospective HCM cohort (n = 804) and analysed data alongside the largest published series of clinically genotyped HCM patients (n = 6179), previously published HCM cohorts and reference population samples from the exome aggregation consortium (ExAC, n = 60 706) to assess variation in 31 genes implicated in HCM. We found no significant excess of rare (minor allele frequency < 1:10 000 in ExAC) protein-altering variants over controls for most genes tested and conclude that novel variants in these genes are rarely interpretable, even for genes with previous evidence of co-segregation (e.g. ACTN2). To provide an aid for variant interpretation, we integrated HCM gene sequence data with aggregated pedigree and functional data and suggest a means of assessing gene pathogenicity in HCM using this evidence.
We show that genetic variation in the majority of non-sarcomeric genes implicated in HCM is not associated with the condition, reinforce the fact that the sarcomeric gene variation is the primary cause of HCM known to date and underscore that the aetiology of HCM is unknown in the majority of patients.
Hypertrophic cardiomyopathy (HCM) patients present altered myocardial mechanics due to the hypertrophied ventricular wall and are typically diagnosed by the increase in myocardium wall thickness. ...This study aimed to quantify regional left ventricular (LV) shape, wall stress and deformation from cardiac magnetic resonance (MR) images in HCM patients and controls, in order to establish superior measures to differentiate HCM from controls. A total of 19 HCM patients and 19 controls underwent cardiac MR scans. The acquired MR images were used to reconstruct 3D LV geometrical models and compute the regional parameters (i.e., wall thickness, curvedness, wall stress, area strain and ejection fraction) based on the standard 16 segment model using our in-house software. HCM patients were further classified into four quartiles based on wall thickness at end diastole (ED) to assess the impact of wall thickness on these regional parameters. There was a significant difference between the HCM patients and controls for all regional parameters (
< 0.001). Wall thickness was greater in HCM patients at the end-diastolic and end-systolic phases, and thickness was most pronounced in segments at the septal regions. A multivariate stepwise selection algorithm identified wall stress index at ED (σ
) as the single best independent predictor of HCM (AUC = 0.947). At the cutoff value σ
< 1.64, both sensitivity and specificity were 94.7%. This suggests that the end-diastolic wall stress index incorporating regional wall curvature-an index based on mechanical principle-is a sensitive biomarker for HCM diagnosis with potential utility in diagnostic and therapeutic assessment.
Patients were followed up for clinical events (atrial fibrillation AF, stroke, congestive cardiac failure CCF and death) up to September 2016. Table 1 Univariate Cox Regression Hazard Ratios for AF / ...Death / All Composite Events AF Death All Hazard Ratio (95% CI) p value Hazard Ratio (95% CI) p value Hazard Ratio (95% CI) p value Age 1.01 (0.98, 1.05) 0.496 1.06 (1.01, 1.11) 0.017 1.02 (0.99, 1.05) 0.140 Female 4.74 (1.53, 14.7) 0.007 1.05 (0.36, 3.05) 0.927 1.83 (0.95, 3.52) 0.071 Race Malay 1.48 (0.33, 6.61) 0.609 4.83 (1.23, 19.0) 0.024 2.85 (1.16, 7.01) 0.022 Indian 0.61 (0.08, 4.72) 0.638 5.30 (1.55, 18.2) 0.008 1.78 (0.68, 4.67) 0.241 AF at diagnosis 0.04 (0.00, 33.3) 0.350 3.62 (1.13, 11.6) 0.030 1.33 (0.52, 3.43) 0.554 LA Size 1.26 (0.66, 2.40) 0.481 3.13 (1.50, 6.54) 0.002 2.01 (1.30, 3.10) 0.002
Hypertrophic cardiomyopathy (HCM) is defined as left ventricular end-diastolic maximal wall thickness (WTMax) ≥15.0 mm, without accounting for ethnicity, sex, and body size. It is well-established ...that Asians have smaller hearts than do Caucasians.
This study aims to examine the implications of this single absolute WTMax threshold on the diagnosis of HCM in Asians.
The study consisted of 360 healthy volunteers (male: n = 174; age: 50 ± 12 years) and 114 genetically characterized patients with HCM (male: n = 83; age: 52 ± 13 years; genotype-positive, n = 39). All participants underwent cardiovascular magnetic resonance. WTMax was measured semiautomatically at end-diastole according to the standard 16 myocardial segments.
Healthy male volunteers had increased WTMax compared with that of female volunteers (8.4 ± 1.2 mm vs 6.6 ± 1.1 mm, respectively; P < 0.001). Conversely, WTMax was similar between male and female patients with HCM (15.2 ± 3.4 mm vs 14.7 ± 3.0 mm, respectively; P = 0.484) and between those with and without a pathogenic gene variant (P = 0.828). Using the recommended diagnostic threshold of 15.0 mm, 56 patients with HCM had WTMax <15.0 mm and no healthy volunteers had WTMax >15.0 mm (specificity of 100% and sensitivity of 51%). Lowering WTMax thresholds to 10.0 mm in female patients and 12.0 mm in male patients did not affect specificity (100%) but significantly improved sensitivity (84%). Despite lower left ventricular mass, female patients with HCM demonstrated more features of adverse cardiac remodeling than did male patients: increased myocardial fibrosis, higher asymmetric ratio, and disproportionately worse myocardial strain.
The study highlights cautious application of guideline-recommended WTMax to diagnose HCM in Asians. Lowering WTMax to account for ethnicity and sex improves diagnostic sensitivity without compromising specificity.
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Hypertrophic cardiomyopathy (HCM) is a genetic disease that leads to left ventricle (LV) hypertrophy with or without the presence of LV outflow tract obstruction. The aim of this study was to find an ...easy and useful indicator based on cardiac magnetic resonance (CMR) images for control subjects and patients with and without obstruction. CMR scans were performed for 19 control subjects and 19 HCM patients. Endocardial strain was defined as
S
endo
=
ln
L
ES
,
endo
L
ED
,
endo
×
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, with
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ED
,
endo
L
ES
,
endo
being the length of endocardium at end-diastole (end-systole); similarly for epicardial strain (
S
epi
). The strains were evaluated in cine CMR two-, three- and four-chamber views. Six atrioventricular junction (AVJ) points from three CMR views were semi-automatically tracked. The peak systolic velocity (Sm1), peak early diastolic velocity and late diastolic velocity (Em, Am) were extracted and analysed. Compared with control subjects, HCM patients had significantly smaller three-dimensional strains and AVJ motion incorporating measurements from three long-axis views (all
P
< 0.05). Moreover, ROC analysis found that three-dimensional global epicardial strain <17.2% had the best sensitivity 94.4% and specificity 94.7% to differentiate HCM from control (AUC = 0.97). Therefore, three-dimensional endocardial and epicardial strains provide an easy and effective approach to manage and triage hypertrophic cardiomyopathy patients.
The MitraClip system has been used extensively in high-risk patients with severe degenerative mitral regurgitation (MR). Recent reports have demonstrated the feasibility of using the MitraClip device ...to treat systolic anterior motion (SAM) of the mitral valve in obstructive hypertrophic cardiomyopathy (HOCM).
We report the case of a 76-year-old lady who had both symptomatic severe degenerative MR and HOCM that were refractory to medical therapy. Both pathologies were treated successfully using the MitraClip system.
In patients who are deemed to be at high risk for open surgery, our case demonstrated the feasibility of a percutaneous avenue, the MitraClip system, to treat not just degenerative MR, but also SAM from HOCM in a single procedure.
The imaging features of dilated cardiomyopathy (DCM) overlap with physiological exercise-induced cardiac remodeling in active and otherwise healthy individuals. Distinguishing the two conditions is ...challenging. This study examined the diagnostic and prognostic roles of exercise stress imaging in asymptomatic patients with suspected DCM.
Exercise stress cardiovascular magnetic resonance (CMR) was performed in 60 asymptomatic patients with suspected DCM (dilated left ventricle and/or impaired systolic function on CMR), who also underwent DNA sequencing for DCM-causing genetic variants. Confirmed DCM was defined as genotype- and phenotype-positive (G+P+). Another 100 healthy subjects were recruited to establish normal exercise capacities (peak exercise cardiac index; Peak
). The primary outcome was a composite of all-cause mortality, cardiac decompensation and ventricular arrhythmic events.
No patients with confirmed G+P+ DCM had Peak
exceeding the 35th percentile specific for age and sex. Applying this threshold in G-P+ patients, those with Peak
below 35th percentile had characteristics similar to confirmed DCM while patients with higher Peak
were younger, more active and higher longitudinal strain. Adverse cardiovascular events occurred only in patients with low exercise capacity (P = 0.004).
In individuals with suspected DCM, exercise stress CMR demonstrates diagnostic and prognostic potential in distinguishing between pathological DCM and physiological exercise-induced cardiac remodeling.
A predictable relation between genotype and disease expression is needed in order to use genetic testing for clinical decision-making in hypertrophic cardiomyopathy (HCM). The primary aims of this ...study were to examine the phenotypes associated with sarcomere protein (SP) gene mutations and test the hypothesis that variation in non-sarcomere genes modifies the phenotype.
Unrelated and consecutive patients were clinically evaluated and prospectively followed in a specialist clinic. High-throughput sequencing was used to analyse 41 genes implicated in inherited cardiac conditions. Variants in SP and non-SP genes were tested for associations with phenotype and survival.
874 patients (49.6±15.4 years, 67.8% men) were studied; likely disease-causing SP gene variants were detected in 383 (43.8%). Patients with SP variants were characterised by younger age and higher prevalence of family history of HCM, family history of sudden cardiac death, asymmetric septal hypertrophy, greater maximum LV wall thickness (all p values<0.0005) and an increased incidence of cardiovascular death (p=0.012). Similar associations were observed for individual SP genes. Patients with ANK2 variants had greater maximum wall thickness (p=0.0005). Associations at a lower level of significance were demonstrated with variation in other non-SP genes.
Patients with HCM caused by rare SP variants differ with respect to age at presentation, family history of the disease, morphology and survival from patients without SP variants. Novel associations for SP genes are reported and, for the first time, we demonstrate possible influence of variation in non-SP genes associated with other forms of cardiomyopathy and arrhythmia syndromes on the clinical phenotype of HCM.
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