First name
James
Middle name
S
Last name
Ware

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

Genetic Variants Associated with Cancer Therapy-Induced Cardiomyopathy.

Year of Publication

2019

Date Published

2019 Apr 16

ISSN Number

1524-4539

Abstract

<p><strong>BACKGROUND: </strong>Cancer therapy-induced cardiomyopathy (CCM) is associated with cumulative drug exposures and pre-existing cardiovascular disorders. These parameters incompletely account for substantial inter-individual susceptibility to CCM. We hypothesized that rare variants in cardiomyopathy genes contribute to CCM.</p>

<p><strong>METHODS: </strong>We studied 213 CCM patients from three cohorts: retrospectively recruited adults with diverse cancers (n=99), prospectively phenotyped breast cancer adults (n=73) and prospectively phenotyped children with acute myeloid leukemia (n=41). Cardiomyopathy genes, including nine pre-specified genes were sequenced. The prevalence of rare variants was compared between CCM cohorts and The Cancer Genome Atlas (TCGA) participants (n=2053), healthy volunteers (n=445), and ancestry-matched reference population. Clinical characteristics and outcomes were assessed, stratified by genotypes. A prevalent CCM genotype was modeled in anthracycline-treated mice.</p>

<p><strong>RESULTS: </strong>CCM was diagnosed 0.4-9 years after chemotherapy; 90% of these patients received anthracyclines. Adult CCM patients had cardiovascular risk factors similar to the U.S.</p>

<p><strong>POPULATION: </strong>Among nine prioritized genes CCM patients had more rare protein-altering variants than comparative cohorts (p≤1.98e-04). Titin-truncating variants (TTNtv) predominated, occurring in 7.5% CCM patients versus 1.1% TCGA participants (p=7.36e-08), 0.7% healthy volunteers (p=3.42e-06), and 0.6% reference population (p=5.87e-14). Adult CCM patients with TTNtv experienced more heart failure and atrial fibrillation (p=0.003) and impaired myocardial recovery (p=0.03) than those without. Consistent with human data, anthracycline-treated TTNtv mice and isolated TTNtv cardiomyocytes showed sustained contractile dysfunction unlike wildtype (p=0.0004 and p&lt;0.002, respectively).</p>

<p><strong>CONCLUSIONS: </strong>Unrecognized rare variants in cardiomyopathy-associated genes, particularly TTNtv, increased the risk for CCM in children and adults, and adverse cardiac events in adults. Genotype, along with cumulative chemotherapy dosage and traditional cardiovascular risk factors improves identification of cancer patients at highest risk for CCM.</p>

<p><strong>CLINICAL TRIAL REGISTRATION: </strong>URL: https://www.clinicaltrials.gov. Unique identifiers: NCT01173341; AAML1031; NCT01371981.</p>

DOI

10.1161/CIRCULATIONAHA.118.037934

Alternate Title

Circulation

PMID

30987448

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