First name
Sharlene
Middle name
M
Last name
Day

Title

Left Ventricular Systolic Dysfunction in Patients Diagnosed With Hypertrophic Cardiomyopathy During Childhood: Insights From the SHaRe Registry (Sarcomeric Human Cardiomyopathy).

Year of Publication

2023

Date Published

05/2023

ISSN Number

1524-4539

Abstract

BACKGROUND: The development of left ventricular systolic dysfunction (LVSD) in hypertrophic cardiomyopathy (HCM) is rare but serious and associated with poor outcomes in adults. Little is known about the prevalence, predictors, and prognosis of LVSD in patients diagnosed with HCM as children.

METHODS: Data from patients with HCM in the international, multicenter SHaRe Registry (Sarcomeric Human Cardiomyopathy) were analyzed. LVSD was defined as left ventricular ejection fraction <50% on echocardiographic reports. Prognosis was assessed by a composite of death, cardiac transplantation, and left ventricular assist device implantation. Predictors of developing incident LVSD and subsequent prognosis with LVSD were assessed using Cox proportional hazards models.

RESULTS: We studied 1010 patients diagnosed with HCM during childhood (<18 years of age) and compared them with 6741 patients with HCM diagnosed as adults. In the pediatric HCM cohort, median age at HCM diagnosis was 12.7 years (interquartile range, 8.0-15.3), and 393 (36%) patients were female. At initial SHaRe Registry site evaluation, 56 (5.5%) patients with childhood-diagnosed HCM had prevalent LVSD, and 92 (9.1%) developed incident LVSD during a median follow-up of 5.5 years. Overall LVSD prevalence was 14.7% compared with 8.7% in patients with adult-diagnosed HCM. Median age at incident LVSD was 32.6 years (interquartile range, 21.3-41.6) for the pediatric cohort and 57.2 years (interquartile range, 47.3-66.5) for the adult cohort. Predictors of developing incident LVSD in childhood-diagnosed HCM included age <12 years at HCM diagnosis (hazard ratio [HR], 1.72 [CI, 1.13-2.62), male sex (HR, 3.1 [CI, 1.88-5.2), carrying a pathogenic sarcomere variant (HR, 2.19 [CI, 1.08-4.4]), previous septal reduction therapy (HR, 2.34 [CI, 1.42-3.9]), and lower initial left ventricular ejection fraction (HR, 1.53 [CI, 1.38-1.69] per 5% decrease). Forty percent of patients with LVSD and HCM diagnosed during childhood met the composite outcome, with higher rates in female participants (HR, 2.60 [CI, 1.41-4.78]) and patients with a left ventricular ejection fraction <35% (HR, 3.76 [2.16-6.52]).

CONCLUSIONS: Patients with childhood-diagnosed HCM have a significantly higher lifetime risk of developing LVSD, and LVSD emerges earlier than for patients with adult-diagnosed HCM. Regardless of age at diagnosis with HCM or LVSD, the prognosis with LVSD is poor, warranting careful surveillance for LVSD, especially as children with HCM transition to adult care.

DOI

10.1161/CIRCULATIONAHA.122.062517

Alternate Title

Circulation

PMID

37226762
Featured Publication
No

Title

Transforming Growth Factor-β Analysis of the VANISH Trial Cohort.

Year of Publication

2023

Number of Pages

e010314

Date Published

04/2023

ISSN Number

1941-3297

DOI

10.1161/CIRCHEARTFAILURE.122.010314

Alternate Title

Circ Heart Fail

PMID

36999957
Featured Publication
No

Title

Transforming Growth Factor-β Analysis of the VANISH Trial Cohort.

Year of Publication

2023

Number of Pages

e010314

Date Published

04/2023

ISSN Number

1941-3297

DOI

10.1161/CIRCHEARTFAILURE.122.010314

Alternate Title

Circ Heart Fail

PMID

36999957
Featured Publication
No

Title

Transforming Growth Factor-β Analysis of the VANISH Trial Cohort.

Year of Publication

2023

Number of Pages

e010314

Date Published

03/2023

ISSN Number

1941-3297

DOI

10.1161/CIRCHEARTFAILURE.122.010314

Alternate Title

Circ Heart Fail

PMID

36999957
Featured Publication
No

Title

Valsartan in early-stage hypertrophic cardiomyopathy: a randomized phase 2 trial.

Year of Publication

2021

Date Published

2021 Sep 23

ISSN Number

1546-170X

Abstract

<p>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.</p>

DOI

10.1038/s41591-021-01505-4

Alternate Title

Nat Med

PMID

34556856

Title

Clinical characteristics and outcomes in childhood-onset hypertrophic cardiomyopathy.

Year of Publication

2021

Date Published

2021 Mar 26

ISSN Number

1522-9645

Abstract

<p><strong>AIMS: </strong>Childhood-onset hypertrophic cardiomyopathy (HCM) is far less common than adult-onset disease, thus natural history is not well characterized. We aim to describe the characteristics and outcomes of childhood-onset HCM.</p>

<p><strong>METHODS AND RESULTS: </strong>We performed an observational cohort study of 7677 HCM patients from the Sarcomeric Human Cardiomyopathy Registry (SHaRe). Hypertrophic cardiomyopathy patients were stratified by age at diagnosis [&lt;1 year (infancy), 1-18 years (childhood), &gt;18 years (adulthood)] and assessed for composite endpoints reflecting heart failure (HF), life-threatening ventricular arrhythmias, atrial fibrillation (AF), and an overall composite that also included stroke and death. Stratifying by age of diagnosis, 184 (2.4%) patients were diagnosed in infancy; 1128 (14.7%) in childhood; and 6365 (82.9%) in adulthood. Childhood-onset HCM patients had an ∼2%/year event rate for the overall composite endpoint, with ventricular arrhythmias representing the most common event in the 1st decade following baseline visit, but HF and AF becoming more common by the end of the 2nd decade. Sarcomeric variants were more common in childhood-onset HCM (63%) and carried a worse prognosis than non-sarcomeric disease, including a greater than two-fold increased risk of HF [HRadj 2.39 (1.36-4.20), P = 0.003] and 67% increased risk of the overall composite outcome [HRadj 1.67 (1.16-2.41), P = 0.006]. When compared with adult-onset HCM, childhood-onset was 36% more likely to develop life-threatening ventricular arrhythmias [HRadj 1.36 (1.03-1.80)] and twice as likely to require transplant or ventricular assist device [HRadj 1.99 (1.23-3.23)].</p>

<p><strong>CONCLUSION: </strong>Patients with childhood-onset HCM are more likely to have sarcomeric disease, carry a higher risk of life-threatening ventricular arrythmias, and have greater need for advanced HF therapies. These findings provide insight into the natural history of disease and can help inform clinical risk stratification.</p>

DOI

10.1093/eurheartj/ehab148

Alternate Title

Eur Heart J

PMID

33769460

Title

Associations Between Female Sex, Sarcomere Variants and Clinical Outcomes in Hypertrophic Cardiomyopathy.

Year of Publication

2020

Date Published

2020 Dec 07

ISSN Number

2574-8300

Abstract

<p><strong>Background&nbsp;</strong>- The impact of sex on phenotypic expression in hypertrophic cardiomyopathy (HCM) has not been well characterized in genotyped cohorts. <strong>Methods&nbsp;</strong>- Retrospective cohort study from an international registry of patients receiving care at experienced HCM centers. Sex-based differences in baseline characteristics and clinical outcomes were assessed. <strong>Results&nbsp;</strong>- Of 5,873 patients (3,788 genotyped), 2,226 (37.9%) were women. At baseline, women were older (49.0±19.9 vs. 42.9±18.4 years, p&lt;0.001) and more likely to have pathogenic/likely-pathogenic sarcomeric variants (SARC+; 51% vs 43%, p&lt;0.001) despite equivalent utilization of genetic testing. Age at diagnosis varied by sex and genotype despite similar distribution of causal genes. Women were 3.6 to 7.1 years older at diagnosis (p&lt;0.02) except for patients with variants where age at diagnosis was comparable for women and men (n=492; 34.8±19.2 vs 33.3±16.8 years, p=0.39). Over 7.7 median years of follow up, NYHA III-IV heart failure (HF) was more common in women (HR 1.87, CI 1.48-2.36, p&lt;0.001), after controlling for their higher burden of symptoms and outflow tract obstruction at baseline, reduced ejection fraction, SARC+, age and hypertension. All-cause mortality was increased in women (HR 1.50, CI 1.13-1.99, p&lt;0.01), but neither ICD utilization nor ventricular arrhythmia varied by sex. <strong>Conclusions&nbsp;</strong>- In HCM, women are older at diagnosis, partly modified by genetic substrate. Regardless of genotype, women were at higher risk of mortality and developing severe HF symptoms. This points to a sex-effect on long-term myocardial performance in HCM, which should be investigated further.</p>

DOI

10.1161/CIRCGEN.120.003062

Alternate Title

Circ Genom Precis Med

PMID

33284039

Title

Baseline Characteristics of the VANISH Cohort.

Year of Publication

2019

Number of Pages

e006231

Date Published

2019 Dec

ISSN Number

1941-3297

Abstract

<p><strong>BACKGROUND: </strong>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.</p>

<p><strong>METHODS: </strong>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.</p>

<p><strong>RESULTS: </strong>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.</p>

<p><strong>CONCLUSIONS: </strong>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.</p>

<p><strong>CLINICAL TRIAL REGISTRATION: </strong>URL: https://www.clinicaltrials.gov. Unique identifier: NCT01912534.</p>

DOI

10.1161/CIRCHEARTFAILURE.119.006231

Alternate Title

Circ Heart Fail

PMID

31813281

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