Hypertrophic cardiomyopathy (HCM) is the most common monogenic heart disease with a frequency as high as 1 in 200. In many cases, HCM is caused by mutations in genes encoding the different components ...of the sarcomere apparatus. Hypertrophic cardiomyopathy is characterized by unexplained left ventricular hypertrophy, myofibrillar disarray, and myocardial fibrosis. The phenotypic expression is quite variable. Although most patients with HCM are asymptomatic, serious consequences are experienced in a subset of affected individuals who present initially with sudden cardiac death or progress to refractory heart failure. The Hypertrophic Cardiomyopathy Registry study is a National Heart, Lung, and Blood Institute–sponsored 2,750-patient, 44-site, international registry and natural history study designed to address limitations in extant evidence to improve prognostication in HCM (NCT01915615). In addition to the collection of standard demographic, clinical, and echocardiographic variables, patients will undergo state-of-the-art cardiac magnetic resonance for assessment of left ventricular mass and volumes as well as replacement scarring and interstitial fibrosis. In addition, genetic and biomarker analyses will be performed. The Hypertrophic Cardiomyopathy Registry has the potential to change the paradigm of risk stratification in HCM, using novel markers to identify those at higher risk.
In hypertrophic cardiomyopathy (HC), electrocardiographic (ECG) changes have been postulated to be an early marker of disease, detectable in sarcomere mutation carriers when left ventricular (LV) ...wall thickness is still normal. However, the ECG features of mutation carriers have not been fully characterized. Therefore, we systematically analyzed ECGs in a genotyped HC population to characterize ECG findings in mutation carriers (G+) with and without echocardiographic LV hypertrophy (LVH), and to evaluate the accuracy of ECG findings to differentiate at-risk mutation carriers from genetically unaffected relatives during family screening. The ECG and echocardiographic findings were analyzed from 213 genotyped subjects (76 G+/LVH−, 57 G+/LVH+ overt HC, 80 genetically unaffected controls). Cardiac magnetic resonance imaging was available on a subset. Q waves and repolarization abnormalities (QST) were highly specific (98% specificity) markers for LVH− mutation carriers, present in 25% of G+/LVH− subjects, and 3% of controls (p <0.001). QST ECG abnormalities remained independently predictive of carrying a sarcomere mutation after adjusting for age and impaired relaxation, another distinguishing feature of G+/LVH− subjects (odds ratio 8.4, p = 0.007). Myocardial scar or perfusion abnormalities were not detected on cardiac magnetic resonance imaging in G+/LVH− subjects, irrespective of the ECG features. In overt HC, 75% had Q waves and/or repolarization changes, but <25% demonstrated common isolated voltage criteria for LVH. In conclusion, Q waves and repolarization abnormalities are the most discriminating ECG features of sarcomere mutation carriers with and without LVH. However, owing to the limited sensitivity of ECG and echocardiographic screening, genetic testing is required to definitively identify at-risk family members.
Abstract Background Mild hypertrophy but increased arrhythmic risk characterizes the stereotypic phenotype proposed for hypertrophic cardiomyopathy (HCM) caused by thin-filament mutations. However, ...whether such clinical profile is different from more prevalent thick-filament–associated disease is unresolved. Objectives This study aimed to assess clinical features and outcomes in a large cohort of patients with HCM associated with thin-filament mutations compared with thick-filament HCM. Methods Adult HCM patients (age >18 years), 80 with thin-filament and 150 with thick-filament mutations, were followed for an average of 4.5 years. Results Compared with thick-filament HCM, patients with thin-filament mutations showed: 1) milder and atypically distributed left ventricular (LV) hypertrophy (maximal wall thickness 18 ± 5 mm vs. 24 ± 6 mm; p < 0.001) and less prevalent outflow tract obstruction (19% vs. 34%; p = 0.015); 2) higher rate of progression to New York Heart Association functional class III or IV (15% vs. 5%; p = 0.013); 3) higher prevalence of systolic dysfunction or restrictive LV filling at last evaluation (20% vs. 9%; p = 0.038); 4) 2.4-fold increase in prevalence of triphasic LV filling pattern (26% vs. 11%; p = 0.002); and 5) similar rates of malignant ventricular arrhythmias and sudden cardiac death (p = 0.593). Conclusions In adult HCM patients, thin-filament mutations are associated with increased likelihood of advanced LV dysfunction and heart failure compared with thick-filament disease, whereas arrhythmic risk in both subsets is comparable. Triphasic LV filling is particularly common in thin-filament HCM, reflecting profound diastolic dysfunction.
Objectives The aim of this study was to describe the clinical profile associated with triple sarcomere gene mutations in a large hypertrophic cardiomyopathy (HCM) cohort. Background In patients with ...HCM, double or compound sarcomere gene mutation heterozygosity might be associated with earlier disease onset and more severe outcome. The occurrence of triple mutations has not been reported. Methods A total of 488 unrelated index HCM patients underwent screening for myofilament gene mutations by direct deoxyribonucleic acid sequencing of 8 genes, including myosin binding protein C ( MYBPC3 ), beta-myosin heavy chain ( MYH7) , regulatory and essential light chains (MYL2, MYL3), troponin-T (TNNT2), troponin-I ( TNNI3 ), alpha-tropomyosin (TPM1), and actin (ACTC). Results Of the 488 index patients, 4 (0.8%) harbored triple mutations, as follows: MYH7 -R869H, MYBPC3 -E258K, and TNNI3 -A86fs in a 32-year-old woman; MYH7 -R723C, MYH7 -E1455X, and MYBPC3 -E165D in a 46-year old man; MYH7 -R869H, MYBPC3 -K1065fs, and MYBPC3 -P371R in a 45-year old woman; and MYH7 -R1079Q, MYBPC3 -Q969X, and MYBPC3 -R668H in a 50-year old woman. One had a history of resuscitated cardiac arrest, and 3 had significant risk factors for sudden cardiac death, prompting the insertion of an implantable cardioverter-defibrillator in all, with appropriate shocks in 2 patients. Moreover, 3 of 4 patients had a severe phenotype with progression to end-stage HCM by the fourth decade, requiring cardiac transplantation (n = 1) or biventricular pacing (n = 2). The fourth patient, however, had clinically mild disease. Conclusions Hypertrophic cardiomyopathy caused by triple sarcomere gene mutations was rare but conferred a remarkably increased risk of end-stage progression and ventricular arrhythmias, supporting an association between multiple sarcomere defects and adverse outcome. Comprehensive genetic testing might provide important insights to risk stratification and potentially indicate the need for differential surveillance strategies based on genotype.
Objectives The aim of this study was to evaluate the effects of losartan on left ventricular (LV) hypertrophy and fibrosis in patients with nonobstructive hypertrophic cardiomyopathy (HCM). ...Background Despite evidence that myocardial hypertrophy and fibrosis are mediated by angiotensin II and are important determinants of morbidity and mortality in patients with HCM, no prior studies have evaluated the effects of angiotensin receptor blockers on LV hypertrophy and fibrosis with cardiac magnetic resonance imaging. Methods In double-blind fashion, 20 patients (3 women, 17 men; age: 51 ± 13 years) with HCM were randomly assigned to receive placebo (n = 9) or losartan 50 mg twice a day (n = 11) for 1 year. Cardiac magnetic resonance imaging was performed at baseline and 1 year to measure LV mass and extent of fibrosis as assessed by late gadolinium enhancement. Results There was a trend toward a significant difference in the percent change in LV mass (median interquartile range: +5% −4% to +21% with placebo vs. −5% −11% to −0.9% with losartan; p = 0.06). There was a significant difference in the percent change in extent of late gadolinium enhancement, with the placebo group experiencing a larger increase (+31% ± 26% with placebo vs. −23% ± 45% with losartan; p = 0.03). Conclusions This pilot study suggests attenuation of progression of myocardial hypertrophy and fibrosis with losartan in patients with nonobstructive HCM. Confirmation of these results in a larger trial is required to confirm a place for angiotensin receptor blockers in the management of patients with HCM. (Effect of Losartan in Patients With Nonobstructive Hypertrophic Cardiomyopathy; NCT01150461 )
Genetic testing has become more accessible and is increasingly being incorporated into the care of patients with hypertrophic cardiomyopathy. Genetic test results can help to refine diagnosis and ...distinguish at-risk relatives from those who are not at risk.
Abstract Objectives The study sought to assess the safety, feasibility, and effect of diltiazem as disease-modifying therapy for at-risk hypertrophic cardiomyopathy (HCM) mutation carriers. ...Background HCM is caused by sarcomere mutations and characterized by left ventricular hypertrophy (LVH) with increased risk of heart failure and sudden death. HCM typically cannot be diagnosed early in life, although subtle phenotypes are present. Animal studies indicate that intracellular calcium handling is altered before LVH develops. Furthermore, early treatment with diltiazem appeared to attenuate disease emergence. Methods In a pilot, double-blind trial, we randomly assigned 38 sarcomere mutation carriers without LVH (mean 15.8 years of age) to therapy with diltiazem 360 mg/day (or 5 mg/kg/day) or placebo. Treatment duration ranged from 12 to 42 months (median 25 months). Study procedures included electrocardiography, echocardiography, cardiac magnetic resonance imaging, and serum biomarker measurement. Results Diltiazem was not associated with serious adverse events. Heart rate and blood pressure did not differ significantly between groups. However, mean left ventricular (LV) end-diastolic diameter improved toward normal in the diltiazem group but decreased further in controls (change in z -scores, +0.6 vs. –0.5; p < 0.001). Mean LV thickness-to-dimension ratio was stable in the diltiazem group but increased in controls (–0.02 vs. +0.15; p = 0.04). Among MYBPC3 mutation carriers, LV wall thickness and mass, diastolic filling, and cardiac troponin I levels improved in those taking diltiazem compared with controls. Four participants developed overt HCM, 2 in each treatment group. Conclusions Pre-clinical administration of diltiazem is safe and may improve early LV remodeling in HCM. This novel strategy merits further exploration. (Treatment of Preclinical Hypertrophic Cardiomyopathy With Diltiazem; NCT00319982 ).
Background Assessment of volume status is vital for successful management of patients in heart failure (HF) programs. Bedside determination of elevated left-sided filling pressure (LFP) can be ...challenging and frequently inaccurate; therefore, incorporating technology such as handheld echocardiography, to aid in estimation of LFP, may improve patient care. In this study, we evaluated the feasibility and accuracy of handheld echocardiography by a nonexpert for potential use in the point of care evaluation of compensation. Methods Subjects were recruited from the HF clinic or inpatient service at a single center. Each subject underwent a focused handheld transthoracic echocardiogram by a medical resident trained for 10 hours. Subjects were assigned to 1 of 4 filling patterns (1 = normal, 2 = abnormal relaxation, 3 = pseudonormal, 4 = restrictive) based on measurements by pulsed wave and tissue Doppler. A 3-step echocardiography test for congestion in HF (TEC-HF) was devised for estimation of LFP. The gold standard for determining elevated LFP was clinical evaluation by a HF specialist, who classified subjects as being euvolemic or hypervolemic. Results A total of 100 consecutive subjects (72% male) were recruited, with average age of 60 years and left ventricular ejection fraction of 27%. All subjects had evaluable echocardiographic data. Based on TEC-HF, filling patterns 3 and 4 predicted hypervolemia and patterns 1 and 2 predicted euvolemia, with sensitivity and specificity of 86% and 92%, respectively, and positive and negative predictive values of 86% and 92%, respectively. Conclusions Applying TEC-HF with handheld echocardiography accurately reflects clinical LFP as assessed by HF specialists. This procedure was easily taught to nonexpert medical staff who obtained adequate images in all patients. Handheld echocardiography could be a useful tool for assessing volume status in nonspecialized community settings.
Lysosome-associated membrane protein (LAMP2) cardiomyopathy is an X-linked and highly progressive myocardial storage disorder associated with diminished survival, which clinically resembles ...sarcomeric hypertrophic cardiomyopathy. As shown here in a young woman, the natural history of LAMP2 may demonstrate an extreme profile of left ventricular remodeling with regression of hypertrophy (i.e. marked wall thinning), chamber dilatation, and severe systolic dysfunction, all of which are associated with widespread transmural scarring.
Objectives We sought to further define the role of sarcomere mutations in dilated cardiomyopathy (DCM) and associated clinical phenotypes. Background Mutations in several contractile proteins ...contribute to DCM, but definitive evidence for the roles of most sarcomere genes remains limited by the lack of robust genetic support. Methods Direct sequencing of 6 sarcomere genes was performed on 334 probands with DCM. A novel D230N missense mutation in the gene encoding alpha-tropomyosin ( TPM1 ) was identified. Functional assessment was performed by the use of an in vitro reconstituted sarcomere complex to evaluate ATPase regulation and Ca2+ affinity as correlates of contractility. Results TPM1 D230N segregated with DCM in 2 large unrelated families. This mutation altered an evolutionarily conserved residue and was absent in >1,000 control chromosomes. In vitro studies demonstrated major inhibitory effects on sarcomere function with reduced Ca2+ sensitivity, maximum activation, and Ca2+ affinity compared with wild-type TPM1 . Clinical manifestations ranged from decompensated heart failure or sudden death in those presenting early in life to asymptomatic left ventricular dysfunction in those diagnosed during adulthood. Notably, several affected infants had remarkable improvement. Conclusions Genetic segregation in 2 unrelated families and functional analyses conclusively establish a pathogenic role for TPM1 mutations in DCM. In vitro results demonstrate contrasting effects of DCM and hypertrophic cardiomyopathy mutations in TPM1 , suggesting that specific functional consequences shape cardiac remodeling. Along with previous reports, our data support a distinctive, age-dependent phenotype with sarcomere-associated DCM where presentation early in life is associated with severe, sometimes lethal, disease. These observations have implications for the management of familial DCM.
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