Hypertrophic cardiomyopathy (HCM) is a common, serious, genetic heart disorder. Rare pathogenic variants in sarcomere genes cause HCM, but with unexplained phenotypic heterogeneity. Moreover, most ...patients do not carry such variants. We report a genome-wide association study of 2,780 cases and 47,486 controls that identified 12 genome-wide-significant susceptibility loci for HCM. Single-nucleotide polymorphism heritability indicated a strong polygenic influence, especially for sarcomere-negative HCM (64% of cases; h
= 0.34 ± 0.02). A genetic risk score showed substantial influence on the odds of HCM in a validation study, halving the odds in the lowest quintile and doubling them in the highest quintile, and also influenced phenotypic severity in sarcomere variant carriers. Mendelian randomization identified diastolic blood pressure (DBP) as a key modifiable risk factor for sarcomere-negative HCM, with a one standard deviation increase in DBP increasing the HCM risk fourfold. Common variants and modifiable risk factors have important roles in HCM that we suggest will be clinically actionable.
The HCMR (Hypertrophic Cardiomyopathy Registry) is a National Heart, Lung, and Blood Institute–funded, prospective registry of 2,755 patients with hypertrophic cardiomyopathy (HCM) recruited from 44 ...sites in 6 countries.
The authors sought to improve risk prediction in HCM by incorporating cardiac magnetic resonance (CMR), genetic, and biomarker data.
Demographic and echocardiographic data were collected. Patients underwent CMR including cine imaging, late gadolinium enhancement imaging (LGE) (replacement fibrosis), and T1 mapping for measurement of extracellular volume as a measure of interstitial fibrosis. Blood was drawn for the biomarkers N-terminal pro–B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin T (cTnT), and genetic analysis.
A total of 2,755 patients were studied. Mean age was 49 ± 11 years, 71% were male, and 17% non-white. Mean ESC (European Society of Cardiology) risk score was 2.48 ± 0.56. Eighteen percent had a resting left ventricular outflow tract (LVOT) gradient ≥30 mm Hg. Thirty-six percent had a sarcomere mutation identified, and 50% had any LGE. Sarcomere mutation–positive patients were more likely to have reverse septal curvature morphology, LGE, and no significant resting LVOT obstruction. Those that were sarcomere mutation negative were more likely to have isolated basal septal hypertrophy, less LGE, and more LVOT obstruction. Interstitial fibrosis was present in segments both with and without LGE. Serum NT-proBNP and cTnT levels correlated with increasing LGE and extracellular volume in a graded fashion.
The HCMR population has characteristics of low-risk HCM. Ninety-three percent had no or only mild functional limitation. Baseline data separated patients broadly into 2 categories. One group was sarcomere mutation positive and more likely had reverse septal curvature morphology, more fibrosis, but less resting obstruction, whereas the other was sarcomere mutation negative and more likely had isolated basal septal hypertrophy with obstruction, but less fibrosis. Further follow-up will allow better understanding of these subgroups and development of an improved risk prediction model incorporating all these markers.
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Hypertrophic cardiomyopathy (HCM) is often caused by pathogenic variants in sarcomeric genes and characterized by left ventricular (LV) hypertrophy, myocardial fibrosis and increased risk of heart ...failure and arrhythmias. There are no existing therapies to modify disease progression. In this study, we conducted a multi-center, double-blind, placebo-controlled phase 2 clinical trial to assess the safety and efficacy of the angiotensin II receptor blocker valsartan in attenuating disease evolution in early HCM. In total, 178 participants with early-stage sarcomeric HCM were randomized (1:1) to receive valsartan (320 mg daily in adults; 80-160 mg daily in children) or placebo for 2 years ( NCT01912534 ). Standardized changes from baseline to year 2 in LV wall thickness, mass and volumes; left atrial volume; tissue Doppler diastolic and systolic velocities; and serum levels of high-sensitivity troponin T and N-terminal pro-B-type natriuretic protein were integrated into a single composite z-score as the primary outcome. Valsartan (n = 88) improved cardiac structure and function compared to placebo (n = 90), as reflected by an increase in the composite z-score (between-group difference +0.231, 95% confidence interval (+0.098, +0.364); P = 0.001), which met the primary endpoint of the study. Treatment was well-tolerated. These results indicate a key opportunity to attenuate disease progression in early-stage sarcomeric HCM with an accessible and safe medication.
Hypertrophic cardiomyopathy (HCM) is a genetic cardiomyopathy with a wide spectrum of clinical manifestations. Patients can be asymptomatic or suffer major adverse events including sudden cardiac ...death, ventricular arrhythmias, and heart failure. Identification of individuals with HCM who are at risk for these complications remains challenging. While echocardiography remains the mainstay of diagnostic evaluation, cardiac magnetic resonance imaging (CMR) is an important adjunctive diagnostic modality with emerging applications for risk-stratification of adverse events in the HCM population. Although not included in current guidelines for HCM management, there is increasing evidence to support the use of CMR for routine prognostic assessment of HCM patients. In this review we discuss the use of CMR techniques, including late gadolinium enhancement, T1 mapping, and quantification of extracellular volume fraction, for the risk stratification of three major adverse events in HCM: sudden cardiac death, ventricular arrhythmias, and congestive heart failure.
Integrated Imaging in Hypertrophic Cardiomyopathy Choudhury, Lubna, MD; Rigolin, Vera H., MD; Bonow, Robert O., MD, MS
The American journal of cardiology,
01/2017, Letnik:
119, Številka:
2
Journal Article
Recenzirano
Abstract Hypertrophic cardiomyopathy (HC) has a very heterogeneous clinical spectrum and lends itself to multimodality imaging for evaluation and management. This review addresses clinical ...applications of cardiac imaging in patients with HC. Integrating various modalities of echocardiography and cardiac magnetic resonance (CMR) are discussed in the clinical context such as diagnosis, evaluation, management, risk stratification and family screening of HC patients. The utility of peri-procedure imaging techniques are highlighted for guiding surgical and transcatheter septal reduction procedures. More limited roles of invasive or computed tomography (CT) coronary angiography are discussed for HC patients with chest pain and risk factors for coronary artery disease. Nuclear techniques though available for decades, play a more limited role in contemporary routine management, but may assist in risk assessment. Newer CMR and echo imaging techniques are discussed in their emerging roles for further characterization of HC patients and family members with prospects of preclinical diagnosis. The strengths of the different imaging modalities are presented as well as a flow diagram summarizing integrated imaging in this disease. In conclusion, integrated imaging using the various imaging modalities predominantly echocardiography and CMR based on the clinical picture, plays an essential role in the management of HC patients.
This study aims to understand and describe the clinical impact of SARS-CoV-2 (COVID-19) infection in patients with Hypertrophic Cardiomyopathy (HCM).
A data repository of over 6.6 million patients in ...a large metropolitan (Chicago IL) healthcare system was queried to identify adults with a history of HCM and COVID-19 infection between 2019 and 2021. Propensity score-matched analysis was performed based on age, sex, BMI, and elements of the cardiovascular history, including tobacco use, hypertension, hyperlipidemia, myocardial injury, and heart failure.
Individuals with HCM and COVID-19 infection had more total hospitalizations (41.6 v 23 per 100 persons,
< 0.01), more heart-failure-related hospitalizations (24.2 v 8.7 per 100-persons,
< 0.01), more non-ST elevation myocardial injury (NSTEMI) hospitalizations (8.6 v 4.6 per 100-persons,
< 0.01), and increased mortality (10.8 v 5 per 100-persons,
< 0.01) compared to HCM patients without a history of COVID-19 infection. Patients with HCM and COVID-19 were also noted to have a higher peak CRP when compared to those without prior COVID-19 (Inter-quartile range of 9.0-106.9 v 1.8-21.3,
< 0.01).
In patients with HCM, COVID-19 infection is associated with increased incidence of myocardial injury, increased number of total and heart-failure specific hospitalizations, and increased mortality.
Many cardiomyopathy-associated
pathogenic variants are heterozygous truncations, and
pathogenic variants are associated with arrhythmias. Arrhythmia triggers in filaminopathy are incompletely ...understood.
We describe an individual with biallelic
pathogenic variants, p.Arg650X and c.970-4A>G, with peripartum cardiomyopathy and ventricular arrhythmias. We also describe clinical findings in probands with
variants including Val2715fs87X, Glu2458Serfs71X, Phe106Leu, and c.970-4A>G with hypertrophic and dilated cardiomyopathy, atrial fibrillation, and ventricular tachycardia. Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) were generated. The
truncation, Arg650X/c.970-4A>G, showed a marked reduction in filamin C protein consistent with biallelic loss of function mutations. To assess loss of filamin C, gene editing of a healthy control iPSC line was used to generate a homozygous
disruption in the actin binding domain. Because filamin C has been linked to protein quality control, we assessed the necessity of filamin C in iPSC-CMs for response to the proteasome inhibitor bortezomib. After exposure to low-dose bortezomib,
null iPSC-CMs showed an increase in the chaperone proteins BAG3, HSP70 (heat shock protein 70), and HSPB8 (small heat shock protein B8) and in the autophagy marker LC3I/II.
null iPSC-CMs had prolonged electric field potential, which was further prolonged in the presence of low-dose bortezomib.
null engineered heart tissues had impaired function after low-dose bortezomib.
pathogenic variants associate with a predisposition to arrhythmias, which can be modeled in iPSC-CMs. Reduction of filamin C prolonged field potential, a surrogate for action potential, and with bortezomib-induced proteasome inhibition, reduced filamin C led to greater arrhythmia potential and impaired function.
To noninvasively assess left atrial (LA) kinetic energy (KE) in hypertrophic cardiomyopathy (HCM) patients using 4D flow MRI and evaluate coupling associations with mitral regurgitation (MR) and left ...ventricular outflow tract (LVOT) obstruction. Twenty-nine retrospectively identified patients with HCM underwent 4D flow MRI. MRI-estimated peak LVOT pressure gradient (∆P
MRI
) was used to classify patients into non-obstructive and obstructive HCM. Time-resolved volumetric LA kinetic energy (KE
LA
) was computed throughout systole. Average systolic (KE
LA-avg
) and peak systolic (KE
LA-peak
) KE
LA
were compared between non-obstructive and obstructive HCM groups, and associations to MR severity and LVOT ∆P
MRI
were tested.The study included 15 patients with non-obstructive HCM (58.6 45.9, 65.2 years, 7 females) and 14 patients with obstructive HCM (51.9 47.6, 62.6 years, 6 females). Obstructive HCM patients demonstrated significantly elevated instantaneous KE
LA
over all systolic time-points compared to non-obstructive HCM (P < 0.05). Obstructive HCM patients also demonstrated higher KE
LA-avg
(14.8 10.6, 20.4 J/m
3
vs. 33.4 23.9, 61.3 J/m
3
, P < 0.001) and KE
LA-peak
(22.1 15.9, 28.7 J/m
3
vs. 57.2 44.5, 121.4 J/m
3
, P < 0.001) than non-obstructive HCM. MR severity was significantly correlated with KE
LA-avg
(rho = 0.81, P < 0.001) and KE
LA-peak
(rho = 0.79, P < 0.001). LVOT ∆P
MRI
was strongly correlated with KE
LA
metrics in obstructive HCM (KE
LA-avg
: rho = 0.86, P < 0.001; KE
LA-peak
: rho = 0.85, P < 0.001).In HCM patients, left atrial kinetic energy, by 4D flow MRI, is associated with MR severity and the degree of LVOT obstruction.
The VANISH trial (Valsartan for Attenuating Disease Evolution in Early Sarcomeric Hypertrophic Cardiomyopathy) targeted young sarcomeric gene mutation carriers with early-stage hypertrophic ...cardiomyopathy (HCM) to test whether valsartan can modify disease progression. We describe the baseline characteristics of the VANISH cohort and compare to previous trials evaluating angiotensin receptor blockers.
Applying a randomized, double-blinded, placebo-controlled design, 178 participants with nonobstructive HCM (age, 23.3±10.1 years; 61% men) were randomized in the primary cohort and 34 (age, 16.5±4.9 years; 50% men) in the exploratory cohort of sarcomeric mutation carriers without left ventricular hypertrophy.
In the primary cohort, maximal left ventricular wall thickness was 17±4 mm for adults and
score 7.0±4.5 for children. Nineteen percent had late gadolinium enhancement on cardiac magnetic resonance. Mean peak oxygen consumption was 33 mL/kg per minute, and 92% of participants were New York Heart Association functional class I. New York Heart Association class II was associated with older age,
variants, and more prominent imaging abnormalities. Six previous trials of angiotensin receptor blockers in HCM enrolled a median of 24 patients (range, 19-133) with mean age of 51.2 years; 42% of patients were in New York Heart Association class ≥II, and sarcomeric mutations were not required.
The VANISH cohort is much larger, younger, less heterogeneous, and has less advanced disease than prior angiotensin receptor blocker trials in HCM. Participants had relatively normal functional capacity and mild HCM features. New York Heart Association functional class II symptoms were associated with older age, more prominent imaging abnormalities, and
variants, suggesting both phenotype and genotype contribute to disease manifestations.
URL: https://www.clinicaltrials.gov. Unique identifier: NCT01912534.
Ventricular septal myectomy in patients with obstructive hypertrophic cardiomyopathy (HC) has been shown to reduce left ventricular (LV) outflow tract (LVOT) gradient and improve symptoms, although ...little data exist regarding changes in left atrial (LA) volume and LV diastolic function after myectomy. We investigated changes in LA size and LV diastolic function in patients with HC after septal myectomy from 2004 to 2011. We studied 25 patients (age 49.2 ± 13.1 years, 48% women) followed for a mean of 527 days after surgery who had serial echocardiography at baseline and at most recent follow-up, at least 6 months after myectomy. In addition to myectomy, 3 patients (12%) underwent Maze surgery and 13 (52%) underwent mitral valve surgery, of whom 5 had a mitral valve replacement or mitral annuloplasty. Patients with mitral valve replacement or mitral annuloplasty were excluded from LV diastolic function analysis. LA volume index decreased (from 47.2 ± 17.6 to 35.9 ± 17.0 ml/m2 , p = 0.001) and LV diastolic function improved with an increase in lateral e′ velocity (from 7.3 ± 2.9 to 9.8 ± 3.1 cm/sec, p = 0.01) and a decrease in E/e′ (from 14.8 ± 6.3 to 11.7 ± 5.5, p = 0.051). Ventricular septal thickness and LVOT gradient decreased, and symptoms of dyspnea and heart failure improved, with reduction in the New York Heart Association functional class III/IV symptoms from 21 (84%) to 1 (4%). In conclusion, relief of LVOT obstruction in HC by septal myectomy results in improved LV diastolic function and reduction in LA volume with improved symptoms.
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