Sarcomeric Hypertrophic Cardiomyopathy Research Articles

Assessing the Phenotypic Burden of Preclinical Sarcomeric Hypertrophic Cardiomyopathy—New Assessments to Guide Diagnosis and Management

Assessing the Phenotypic Burden of Preclinical Sarcomeric Hypertrophic Cardiomyopathy—New Assessments to Guide Diagnosis and Management

Left Atrial structure and function in hypertrophic cardiomyopathy sarcomere mutation carriers with and without left ventricular hypertrophy

BackgroundImpaired left atrial (LA) function is an early marker of cardiac dysfunction and predictor of adverse cardiac events. Herein, we assess LA structure and function in hypertrophy in hypertrophic cardiomyopathy (HCM) sarcomere mutation carriers with and without left ventricular hypertrophy (LVH).MethodSeventy-three participants of the HCMNet study who underwent cardiovascular magnetic resonance (CMR) imaging were studied, including mutation carriers with overt HCM (n = 34), preclinical mutation carriers without HCM (n = 24) and healthy, familial controls (n = 15).ResultsLA volumes were similar between preclinical, control and overt HCM cohorts after covariate adjustment. However, there was evidence of impaired LA function with decreased LA total emptying function in both preclinical (64 ± 8%) and overt HCM (59 ± 10%), compared with controls (70 ± 7%; p = 0.002 and p = 0.005, respectively). LA passive emptying function was also decreased in overt HCM (35 ± 11%) compared with controls (47 ± 10%; p = 0.006). Both LAtotal emptying function and LA passive emptying function were inversely correlated with the extent of late gadolinium enhancement (LGE; p = 0.005 and p < 0.05, respectively), LV mass (p = 0.02 and p < 0.001) and interventricular septal thickness (p < 0.001 for both) and serum NT-proBNP levels (p < 0.001 for both).ConclusionLA dysfunction is detectable by CMR in preclinical HCM mutation carriers despite non-distinguishable LV wall thickness and LA volume. LA function appears most impaired in subjects with overt HCM and a greater extent of LV fibrosis.

Relationship between aetiology and left ventricular systolic dysfunction in hypertrophic cardiomyopathy

BackgroundSevere left ventricular (LV) systolic dysfunction is an uncommon complication of hypertrophic cardiomyopathy (HCM) that is associated with poor prognosis. Small observational series suggest that patients with rare causes of...

Aortic Stiffness in Youth with Hypertrophic Cardiomyopathy Genotype.

Clinical events in hypertrophic cardiomyopathy (HCM) patients are related to the degree of hypertrophy. Aortic stiffness in adult HCM patients has been reported to be higher than control patients. Increased stiffness may cause more LV hypertrophy and thus lead to more clinical events. We sought to (a) noninvasively compare aortic structure and function between youth with sarcomeric HCM genotype versus control youth and (b) explore the relation between aortic function and degree of left ventricular (LV) hypertrophy. In a prospective study from a single referral center, clinical, anthropometric, and hemodynamic data were acquired on 28 consecutive pathogenic HCM gene mutation carriers and 26 unrelated controls (mean age 16.3, 50% girls). Hemodynamic data included applanation tonometry measured central pulse pressure, carotid-femoral pulse wave velocity (CFPWV), reflected wave augmentation index (AIx). In the HCM gene carriers, LV mass-to-volume ratio was extracted from clinically indicated echocardiograms as an index of hypertrophy. Associations were assessed using multivariable adjusted linear regression. The HCM group was comprised of 14 myosin binding protein C3 carriers, 13 myosin heavy chain 7 carriers, and 1 child with both. HCM and control groups did not differ by age, sex, height, body mass index, heart rate, or blood pressure. HCM carriers had significantly lower CFPWV than controls (4.46±0.88 vs. 4.97±0.44m/s, p=0.01) and higher AIx magnitude (27±19 vs. 18±7%, p=0.04). These associations persisted after adjustment for age, sex, height, heart rate, mean pressure, and medication use. Within the HCM group, LV hypertrophy was related to AIx but not CFPWV. CFPWV nor AIx differed by genotype. Aortic stiffness appears lower, but wave reflection appears higher in youth carrying HCM gene mutations. The degree of wave reflection appears correlated with LV hypertrophy in this high-risk cohort, suggesting that mitigation of wave reflection may possibly attenuate LV hypertrophy.

BESIDE TOOLS FOR STRATIFICATION OF THE ETIOLOGY OF CARDIAC HYPERTROPHY

Left ventricular hypertrophy (LVH) is a common finding in multiple different cardiovascular conditions including hypertension, infiltrative amyloid, myocardial storage disorders and sarcomeric hypertrophic cardiomyopathy (HCM). We aimed to identify novel techniques for bedside stratification of LVH

0178 : Global and regional echocardiographic strain to assess early phase of hypertrophic cardiomyopathy due to sarcomeric mutations

Hypertrophic cardiomyopathy (HCM) is a genetic disease with delayed cardiac expression. Our objective was to characterize global and regional LV myocardial strain by two-dimensional imaging in sarcomeric HCM families and hypothesized that early systolic dysfunction, before hypertrophic stage, may be diagnosed by this technique. We analyzed 79 adults: HCM patients with LV hypertrophy (LVH+, n=38), mutation carriers without LV hypertrophy (LVH-/G+, n=20), and normal control subjects (n=21). We calculated global longitudinal strain (GLS) and regional peak longitudinal strain. Age, sex ratio and body surface area were not significantly different between groups. Maximal 2D wall thickness of left ventricle was 10.1±1.6 mm in LVH-/G+ and not different from controls (9.9 ±1.2 mm). We observed that LV GLS was not different in LVH-/G+ as compared to controls (–20.6% IQ:–24.2/– 8.3 vs –22.9% IQ:-26.8/-20.9) but was reduced in HCM patients (–14.1% IQ:–18.5/–11.8) although a normal ejection fraction. Interestingly, regional peak longitudinal strain was similar in LVH-/G+ and controls except in four segments: basal anteroseptal (BAS) wall (–16% vs –19%, p=0.018), basal inferoseptal wall (–16.0% vs –19.0%, p=0.047), basal inferior wall (–21.0% vs –24.0%, p=0.006) and mid anteroseptal wall (–21.0% vs –22.5%, p=0.022). Regional BAS strain <-16.5% yielded a sensitivity of 57% and a specificity of 90% to differentiate LVH-/G+ patients from controls. We also evaluated accuracy of ratio between normal and abnormal segments. Septo-basal/Latero-basal strain ratio <0.76 yielded a sensitivity of 73% and a specificity of 92% to differentiate LVH-/G+ patients from controls. Regional longitudinal strain but not global strain, was significantly reduced at early stage of HCM before development of LVH. This suggests the integration of myocardial deformation in the evaluation of HCM relatives to identify better mutation carriers and early LV abnormalities. The author hereby declares no conflict of interest

Abnormal Mitral Valve Dimensions in Pediatric Patients with Hypertrophic Cardiomyopathy.

The hearts of patients with hypertrophic cardiomyopathy (HCM) show structural abnormalities other than isolated wall thickening. Recently, adult HCM patients have been found to have longer mitral valve leaflets than control subjects. The aim of the current study was to assess whether children and adolescents with HCM have similar measureable differences in mitral valve leaflet dimensions when compared to a healthy control group. Clinical and echocardiographic data from 46 children with myocardial hypertrophy and a phenotype and/or genotype consistent with sarcomeric HCM were reviewed. Cardiac magnetic resonance imaging studies were evaluated. The anterior and posterior mitral valve leaflet lengths and myocardial structure were compared to 20 healthy controls. The anterior mitral valve was longer in the HCM group than in the control group (28.4 ± 4.9 vs. 25.2 ± 3.6 mm in control patients, p = 0.013) as was the posterior mitral valve leaflet (16.3 ± 3.0 vs. 13.1 ± 2.3 mm for controls <0.0001). There was no correlation between the resting left ventricular outflow tract gradient and anterior mitral valve leaflet length, nor was the anterior mitral valve leaflet longer in those with systolic anterior motion of the mitral valve compared to those without (28.9 ± 6.1 vs. 28.1 ± 4.5 mm, p = 0.61). Children and adolescents with HCM have abnormally long mitral valve leaflets when compared with healthy control subjects. These abnormalities do not appear to result in, or be due to, obstruction to left ventricular outflow. The mechanism of this mitral valve elongation is not clear but appears to be independent of hemodynamic disturbances.

0198: Global and regional echocardiographic strain to assess early phase of hypertrophic cardiomyopathy due to sarcomeric mutations

Hypertrophic cardiomyopathy (HCM) is a genetic disease with delayed cardiac expression. Our objective was to characterize global and regional LV myocardial strain by two-dimensional imaging in sarcomeric HCM families and hypothesized that early systolic dysfunction, before hyper-trophic stage, may be diagnosed by this technique. We analyzed 81 adults: HCM patients with LV hypertrophy (LVH+, n=38), mutation carriers without LV hypertrophy (LVH/G+, n=20), and normal control subjects (n=23). We calculated global longitudinal strain (GLS), regional peak longitudinal strain and the Echo/TDI score (combination of 3 parameters about remodeling and pulse TDI). Age, sex ratio and body surface area were not significantly different between groups. Maximal 2D wall thickness of left ventricle was 10.1±1.6mm in LVH-/G+ and not different from controls (9.9±1.2mm). We observed that LV GLS was not different in LVH-/G+ as compared to controls (–21.6%±3.2 vs –23.5%±3.3) but was reduced in HCM patients (–15.3%±4.5) although a normal ejection fraction. Interestingly, regional peak longitudinal strain was similar in LVH-/G+ and controls except antero-septo-basal segment strain that was decreased in LVH-/G+ as compared to controls (–15.6%±7.2 vs –20.0%±3.9, p=0.025). A cut-off of –16% for abnormal strain of antero-septo-basal segment identified LVH-/G+ subjects with a sensitivity of 47% and a specificity of 90%. The Echo/TDI score was different in LVH-/G+ as compared to controls (p=0.0008) and sensitivity of previous defined cut-off was 83% for identification of LVH-/G+. All LVH-/G+ subjects with abnormal regional strain, except one, had abnormal Echo/TDI score. We observed that regional longitudinal strain, but not global strain, was significantly reduced at early stage of HCM. This tool may be useful for clinical evaluation of relatives in daily practice, but does not provide significant additional information as compared to the Echo/TDI score.

The clinical course of hypertrophic cardiomyopathy and the role of polymorphisms in the intronic and promoter regions of the gene alpha-galactosidase A

The article reflects the importance of timely diagnosis sarcomeric and non sarcomeric hypertrophic cardiomyopathy (HCM). The results of the phenotypic and genotypic screenings aimed at identifying HCM phenocopies and, in particular Fabry disease, in the structure of left ventricular hypertrophy of unknown origin in patients of the North-West region of Russia. We analyzed the influence of polymorphisms in the intronic and promoter regions of the GLA gene on clinical course and the presence of extracardiac manifestations.

Cardiac Findings in Infants of Diabetic Mothers

Hypertrophic cardiomyopathy (HCM) associated with diabetes during pregnancy has been relatively recently described. The echocardiographic findings are similar to those found in the classic sarcomeric familial HCM. In addition, the hemodynamics and clinical presentation may be significant and can include impaired cardiac output and pulmonary hypertension as a result of diastolic dysfunction, left ventricular outflow tract obstruction, and systolic dysfunction. Unlike sarcomeric HCM, neonatal HCM associated with diabetes during pregnancy is self-limited and in fact tends to resolve in weeks to months. On the other hand, in the impaired neonate, a rational management plan needs to be instituted. This article describes the history, potential causes, and pathophysiology of HCM and details a rational management plan for the treatment of these patients.

Exacerbation of cardiac energetic impairment during exercise in hypertrophic cardiomyopathy: a potential mechanism for diastolic dysfunction.

Hypertrophic cardiomyopathy (HCM) is the commonest cause of sudden cardiac death in the young, with an excess of exercise-related deaths. The HCM sarcomere mutations increase the energy cost of contraction and impaired resting cardiac energetics has been documented by measurement of phosphocreatine/ATP (PCr/ATP) using (31)Phosphorus MR Spectroscopy ((31)P MRS). We hypothesized that cardiac energetics are further impaired acutely during exercise in HCM and that this would have important functional consequences. (31)P MRS was performed in 35 HCM patients and 20 age- and gender-matched normal volunteers at rest and during leg exercise with 2.5 kg ankle weights. Peak left-ventricular filling rates (PFRs) and myocardial perfusion reserve (MPRI) were calculated during adenosine stress. Resting PCr/ATP was significantly reduced in HCM (HCM: 1.71 ± 0.35, normal 2.14 ± 0.35 P < 0.0001). During exercise, there was a further reduction in PCr/ATP in HCM (1.56 ± 0.29, P = 0.02 compared with rest) but not in normals (2.16 ± 0.26, P = 0.98 compared with rest). There was no correlation between PCr/ATP reduction and cardiac mass, wall thickness, MPRI, or late-gadolinium enhancement. PFR and PCr/ATP were significantly correlated at rest (r = 0.48, P = 0.02) and stress (r = 0.53, P = 0.01). During exercise, the pre-existing energetic deficit in HCM is further exacerbated independent of hypertrophy, perfusion reserve, or degree of fibrosis. This is in keeping with the change at the myofilament level. We offer a potential explanation for exercise-related diastolic dysfunction in HCM.

Cardiovascular magnetic resonance findings in patients with PRKAG2 gene mutations.

BackgroundAutosomal dominantly inherited PRKAG2 cardiac syndrome is due to a unique defect of the cardiac cell metabolism and has a distinctive histopathology with excess intracellular glycogen, and prognosis different from sarcomeric hypertrophic cardiomyopathy. We aimed to define the distinct characteristics of PRKAG2 using cardiovascular magnetic resonance (CMR).MethodsCMR (1.5 T) and genetic testing were performed in two families harboring PRKAG2 mutations. On CMR, segmental analysis of left ventricular (LV) hypertrophy (LVH), function, native T1 mapping, and late gadolinium enhancement (LGE) were performed.ResultsSix individuals (median age 23 years, range 16–48; two females) had a PRKAG2 mutation: five with an R302Q mutation (family 1), and one with a novel H344P mutation (family 2). Three of six mutation carriers had LV mass above age and gender limits (203 g/m2, 157 g/m2 and 68 g/m2) and others (with R302Q mutation) normal LV masses. All mutation carriers had LVH in at least one segment, with the median maximal wall thickness of 13 mm (range 11–37 mm). Two R302Q mutation carriers with markedly increased LV mass (203 g/m2 and 157 g/m2) showed a diffuse pattern of hypertrophy but predominantly in the interventricular septum, while other mutation carriers exhibited a non-symmetric mid-infero-lateral pattern of hypertrophy. In family 1, the mutation negative male had a mean T1 value of 963 ms, three males with the R302Q mutation, LVH and no LGE a mean value of 918 ± 11 ms, and the oldest male with the R302Q mutation, extensive hypertrophy and LGE a mean value of 973 ms. Of six mutations carriers, two with advanced disease had LGE with 11 and 22 % enhancement of total LV volume.ConclusionsPRKAG2 cardiac syndrome may present with eccentric distribution of LVH, involving focal mid-infero-lateral pattern in the early disease stage, and more diffuse pattern but focusing on interventricular septum in advanced cases. In patients at earlier stages of disease, without LGE, T1 values may be reduced, while in the advanced disease stage T1 mapping may result in higher values caused by fibrosis. CMR is a valuable tool in detecting diffuse and focal myocardial abnormalities in PRKAG2 cardiomyopathy.

Abstract 19583: Autonomous and Non-Autonomous Defects Underlie Hypertrophic Cardiomyopathy in BRAF-Mutant hiPSC-Derived Cardiomyocytes

Hypertrophic cardiomyopathy (HCM) is a pathological disorder predominantly due to mutations in sarcomeric components. Germline mutations in BRAF cause a developmental syndrome called cardio-facio-cutaneous syndrome (CFCS), in which 40% of patients also develop HCM. Since the role of the RAS/MAPK pathway in HCM is still unclear, we generated a human induced pluripotent stem cell model for CFCS from three patients with activating BRAF T599R or Q257R mutations. In order to examine hiPSC-derived cell-type specific phenotypes and cellular interactions underpinning HCM, we generated a method to purify cardiomyocytes and non-cardiomyocytes simultaneously by cell sorting based on SIRPα and CD90 expression. Purified BRAF-mutant SIRPα+/CD90- cells were &gt;95% cardiomyocytes, displayed cellular hypertrophy with pro-hypertrophic gene expression, and dysregulation of the RAS/MAPK pathway. BRAF-mutant cardiomyocytes also displayed intrinsic calcium handling defects, including increased calcium transient irregularity and increased stored calcium within the sarcoplasmic reticulum. In addition, purified BRAF-mutant SIRPα-/CD90+ cells, which were fibroblast-like, displayed activation of the RAS/MAPK pathway and exhibited a pro-fibrotic phenotype. Cross-culture studies revealed that BRAF-mutant fibroblast-like cells critically modulate cardiomyocyte hypertrophy through TGFβ paracrine signaling, as TGFβ inhibition prevented cardiomyocyte hypertrophy induced by BRAF-mutant fibroblast-like cells. Additionally, inhibition of RAS/MAPK signaling was capable of rescuing BRAF-mutant cardiomyocyte hypertrophy and cardiomyocyte-intrinsic calcium handling abnormalities. Thus, we show for the first time that cell autonomous and non-autonomous defects underlie RASopathy-associated HCM. As fibroblast activation has been documented previously in sarcomeric HCM, our findings suggest that cardiac fibroblasts may contribute to pathologic hypertrophy in addition to causing fibrosis in primary forms of HCM. TGFβ inhibition may be a useful therapeutic option for patients with HCM due to RASopathies or other etiologies.

Abnormal Cardiac Formation in Hypertrophic Cardiomyopathy

Background— Mutations in genes coding for sarcomeric proteins cause hypertrophic cardiomyopathy. Subtle abnormalities of the myocardium may be present in mutation carriers without left ventricular hypertrophy (G+LVH−) but are difficult to quantify. Fractal analysis has been used to define trabeculae in left ventricular noncompaction and to identify normal racial variations. We hypothesized that trabeculae measured by fractal analysis of cardiovascular magnetic resonance images are abnormal in G+LVH− patients, providing a preclinical marker of disease in hypertrophic cardiomyopathy. Methods and Results— Cardiovascular magnetic resonance was performed on 40 G+LVH− patients (33±15 years, 38% men), 67 patients with a clinical diagnosis of hypertrophic cardiomyopathy (53±15 years, 76% men; 31 with a pathogenic mutation [G+LVH+]), and 69 matched healthy volunteers (44±15 years, 57% men). Trabeculae were quantified by fractal analysis of cine slices to calculate the fractal dimension, a unitless index of endocardial complexity calculated from endocardial contours after segmentation. In G+LVH− patients, apical left ventricular trabeculation was increased compared with controls (maximal apical fractal dimension, 1.249±0.07 versus 1.199±0.05; P =0.001). In G+LVH+ and G−LVH+ cohorts, maximal apical fractal dimension was greater than in controls ( P &lt;0.0001) irrespective of gene status (G+LVH+: 1.370±0.08; G−LVH+: 1.380±0.09). Compared with controls, G+LVH− patients also had a higher frequency of clefts (28% versus 8%; P =0.02), longer anterior mitral valve leaflets (23.5±3.0 versus 19.7±3.1 mm; P &lt;0.0001), greater septal systolic wall thickness (12.6±3.2 versus 11.2±2.1 mm; P =0.03), higher ejection fraction (71±4% versus 69±4%; P =0.03), and smaller end-systolic volumes (38±9 versus 43±12 mL; P =0.03). Conclusions— Increased myocardial trabecular complexity is one of several preclinical abnormalities in hypertrophic cardiomyopathy sarcomere gene mutation carriers without LVH.

Faster Cross-Bridge Relaxation Rates Correlate with Increased Tension Cost in Hcm with the R403Q Myh7 Mutation

The first mutation found to be associated with hypertrophic cardiomyopathy (HCM) is the R403Q mutation in the gene encoding β-myosin heavy chain. R403Q is located in the globular head of myosin (S1), responsible for actin interaction, and hence motor function of myosin. According to the 2-state model of actin-myosin interaction total cross-bridge turnover rate can be described by the sum of the cross-bridge association (fapp) and detachment (gapp) rates. Gapp is equivalent to the slow rate of cross-bridge relaxation (slow krel), which equals the energetic cost of tension generation, i.e. tension cost (expressed by ATP utilization/tension). In the present study we investigated to what extent cross-bridge kinetics in HCM with the R403Q mutation correlated with cross-bridge energetics.Left ventricular multicellular muscle strips and myofibrillar preparations were isolated from 3 HCM patients with the R403Q mutation. 8 HCM sarcomere mutation negative (HCMsmn) patients served as control. In the muscle strips force generating capacity and ATP utilization were measured to assess tension cost and in the myofibrillar preparations cross-bridge kinetics was analyzed. The fraction of mutated R403Q mRNA was analyzed using specific restriction digests and realtime-PCR. Compared to HCMsmn tension cost was higher in the muscle strips of the 3 R403Q patients which showed a positive linear correlation with relaxation kinetics in the corresponding myofibrillar preparations. Variation in cross-bridge function among the 3 R403Q patients could not be explained by differences in R403Q mRNA levels.Cross-bridge cycling efficiency was decreased in HCM due to the R403Q mutation, while cross-bridge kinetics was increased. This suggests that the apparent gain in function evident from increased kinetics leads to a loss of function with respect to cross-bridge cycling efficiency in HCM caused by the R403Q mutation.

Deformation patterns in genotyped patients with hypertrophic cardiomyopathy

Echocardiographic strain imaging with two-dimensional speckle tracking is an emerging tool for defining cardiac function and identifying preclinical hypertrophic cardiomyopathy (HCM). In HCM, a reverse septal contour is a strong predictor of mutation positive sarcomeric HCM. The objective of this study was to determine whether left ventricular (LV) deformation patterns can differentiate between genotype positive and negative patients within a large HCM cohort. One hundred and thirty one patients (89 males, age 55 ± 15 years) with clinically diagnosed HCM underwent comprehensive transthoracic echocardiography inclusive of LV strain imaging, LV dimensions and ejection fraction, septal contour and thickness, and identification of obstructive physiology. Longitudinal peak systolic strain was assessed from 17 LV myocardial segments blinded to the patient's genetic test results derived from comprehensive genotyping of nine myofilament HCM-associated genes. Genotyping revealed that 51 of 131 patients (39%) were mutation positive for sarcomeric/myofilament-HCM (genotype positive). Regional strain was lower in genotype-positive patients in mid inferoseptal (P = 0.004), basal anteroseptal (P = 0.04), and basal inferoseptal segments (P = 0.002) compared with HCM patients lacking a mutation (genotype negative). Strain patterns in reverse-curve, genotype-positive HCM differed significantly from genotype negative, sigmoidal HCM in multiple segments. However, when comparing genotype-negative and genotype-positive patients with the same septal morphology, there were no significant regional strain differences. Septal thickness positively correlated with global and basal anteroseptal longitudinal strain (r = 0.34 and r = 0.54, respectively, P < 0.0001). Significant regional strain differences in genotyped HCM patients are dependent upon septal morphology or thickness, not genotype. Phenotypic expression of deformation patterns appears heterogeneous.

Late onset cardiomyopathy due to transthyretin Ile68Leu mutation: a cardiogenic variant of familial amyloidosis potentially mimicking sarcomeric hypertrophic cardiomyopathy

Late onset cardiomyopathy due to transthyretin Ile68Leu mutation: a cardiogenic variant of familial amyloidosis potentially mimicking sarcomeric hypertrophic cardiomyopathy

Comparison of Echocardiographic and Cardiac Magnetic Resonance Imaging in Hypertrophic Cardiomyopathy Sarcomere Mutation Carriers Without Left Ventricular Hypertrophy

Left ventricular hypertrophy (LVH) typically manifests during or after adolescence in sarcomere mutation carriers at risk for developing hypertrophic cardiomyopathy. Guidelines recommend serial imaging of mutation carriers without LVH (G+/LVH-) to monitor for phenotypic evolution, but the optimal strategy is undefined. Compared with echocardiography (echo), cardiac MRI (CMR) offers improved endocardial visualization and potential to assess scar. However, the incremental advantage offered by CMR for early diagnosis of hypertrophic cardiomyopathy is unclear. Therefore, we systematically compared echo and CMR in G+/LVH- subjects. A total of 40 sarcomere mutation carriers with normal echo wall thickness (<12 mm or z score <2.5 in children) underwent concurrent CMR. Mean age was 21.7±11.1 years, 55% were female. If left ventricular wall thickness seemed nonuniform, the size and location of relatively thickened segments were noted. Late gadolinium enhancement was assessed with CMR. Diagnostic agreement between echo and CMR was good (90%), although CMR measurements of left ventricular wall thickness were ≈19% lower than echo. Four subjects had mild hypertrophy (12.6-14 mm; ≤2 segments) appreciated by CMR but not echo. No subjects had late gadolinium enhancement. During median 35-month follow-up, 2 subjects developed overt hypertrophic cardiomyopathy, including 1 with mild LVH by CMR at baseline. Echo is unlikely to miss substantial LVH; however, CMR identified mild hypertrophy in ≈10% of mutation carriers with normal echo wall thickness. CMR may be a useful adjunct in hypertrophic cardiomyopathy family screening, particularly in higher risk situations, or if echocardiographic images are suboptimal or suggest borderline LVH.

T1 Measurements Identify Extracellular Volume Expansion in Hypertrophic Cardiomyopathy Sarcomere Mutation Carriers With and Without Left Ventricular Hypertrophy

Myocardial fibrosis is a hallmark of hypertrophic cardiomyopathy (HCM) and a potential substrate for arrhythmias and heart failure. Sarcomere mutations seem to induce profibrotic changes before left ventricular hypertrophy (LVH) develops. To further evaluate these processes, we used cardiac magnetic resonance with T1 measurements on a genotyped HCM population to quantify myocardial extracellular volume (ECV). Sarcomere mutation carriers with LVH (G+/LVH+, n=37) and without LVH (G+/LVH-, n=29), patients with HCM without mutations (sarcomere-negative HCM, n=11), and healthy controls (n=11) underwent contrast cardiac magnetic resonance, measuring T1 times pre- and postgadolinium infusion. Concurrent echocardiography and serum biomarkers of collagen synthesis, hemodynamic stress, and myocardial injury were also available in a subset. Compared with controls, ECV was increased in patients with overt HCM, as well as G+/LVH- mutation carriers (ECV=0.36±0.01, 0.33±0.01, 0.27±0.01 in G+/LVH+, G+/LVH-, controls, respectively; P≤0.001 for all comparisons). ECV correlated with N-terminal probrain natriuretic peptide levels (r=0.58; P<0.001) and global E' velocity (r=-0.48; P<0.001). Late gadolinium enhancement was present in >60% of overt patients with HCM but absent from G+/LVH- subjects. Both ECV and late gadolinium enhancement were more extensive in sarcomeric HCM than sarcomere-negative HCM. Myocardial ECV is increased in HCM sarcomere mutation carriers even in the absence of LVH. These data provide additional support that fibrotic remodeling is triggered early in disease pathogenesis. Quantifying ECV may help characterize the development of myocardial fibrosis in HCM and ultimately assist in developing novel disease-modifying therapy, targeting interstitial fibrosis.

Increased Tension Cost in Human Familial Hypertrophic Cardiomyopathy Caused by the MYH7 Mutation R403Q

Familial hypertrophic cardiomyopathy (HCM) is frequently caused by mutations in genes encoding sarcomeric proteins. Energy depletion of the heart is thought to initiate and promote HCM disease development. It has been hypothesized that HCM sarcomere gene mutations increase ATP utilization for myofilament contraction and thereby increase energy demand of the heart. Previous studies in single left ventricular myofibrils from myocardium harbouring the first identified causal HCM mutation R403Q in the gene encoding β-myosin heavy chain revealed increased rates of tension generation and relaxation in R403Q compared to myofibrils from healthy control myocardium. The altered kinetics observed in the mutant sample predicted a 3-fold increase in the energy cost of tension generation in R403Q sarcomeres. In the present study we investigated if tension cost was indeed increased in human myocardium harbouring the R403Q mutation.Maximal force generating capacity (Fmax) and ATP consumption (ATPmax) were simultaneously measured in Triton-permeabilized left ventricular muscle strips (n=8) from a patient carrying the R403Q mutation. Left ventricular muscle strips (n=17) from 5 HCM sarcomere mutation negative patients (HCMsmn) and strips (n=6) from 2 patients with secondary hypertrophy due to aortic stenosis (LVHao) served as a control groups. Economy of myofilament contraction is expressed as tension cost (TC), i.e. amount of ATP used during force development (ATPmax/Fmax). Both Fmax and ATPmax were significantly lower in R403Q compared to HCMsmn and LVHao. TC was significantly increased in R403Q (3.8±0.5 μmolL−1s−1/kNm−2) compared to HCMsmn and LVHao (1.6±0.1 and 1.7±0.1 μmolL−1s-1/kNm−2, respectively).Our data provide direct evidence that TC is increased in myocardium harbouring the MYH7 mutation R403Q, indicating that expression of R403Q in the heart impairs economy of myocardial contraction.Funding: Seventh Framework Program of the European Union “BIG-HEART,” grant agreement 241577