Sharon Cresci, MD

Appointments

Professor of Medicine and Genetics
Associate Director, WUMS/BJH Hypertrophic Cardiomyopathy Center
Director, Adult HCM Clinical Database and Biorepository
Director, IMPACT (Initiative for Mentoring, Promoting networking and Advocacy for Cardiology Trainees)

Research interests

A focus of our laboratory is to identify clinical, molecular, genetic and environmental factors that will allow us to better identify, treat, and improved outcomes in patients with HCM.

HYPERTROPHIC CARDIOMYOPATHY

HCM is inherited in an autosomal dominant pattern but has variable penetrance and variable expression. Even within a single family, individuals with the same causative variant have different onset, progression and severity of disease. This makes studying this disease challenging, and prompts the need for model systems that recapitulate non-genetic disease triggers. Furthermore, there are sex and race differences in diagnosis, treatment, response to medications and outcomes in individuals with HCM.

Sex-related Differences in Response to Treatment in HCM:

Women with HCM have been observed to be older at the time of diagnosis, to have higher rates of left ventricular outflow track obstruction, to be more likely to have heart failure, and to have worse outcomes, including mortality. Women with HCM have also been observed to have different hemodynamics, including higher left sided filling pressures, worse diastolic dysfunction, and higher rates of pulmonary hypertension, compared with men with HCM.

We recently investigated baseline clinical and echocardiographic characteristics and response to mavacamten among women, compared with men, in the EXPLORER-HCM study (a blinded, randomized trial of mavacamten versus placebo in symptomatic patients with obstructive HCM). Although at baseline women with symptomatic oHCM enrolled in EXPLORER-HCM were older and had worse heart failure and health status than men, treatment with mavacamten resulted in similar improvements in the primary and most secondary EXPLORER-HCM endpoints, and greater improvements in health status and NT-proBNP. These results showed that there are sex-related differences in the symptomatic expression of, and in the response to treatment of, HCM.

Disparities in HCM Treatments:

We recently assessed disparities in HCM diagnosis and treatments across social risk factors using the largest publicly available all-payer inpatient care database in the US, the National Inpatient Sample. We aimed to determine, among individuals hospitalized between 2012 and 2018 with a diagnosis of HCM: a) clinical and demographic characteristics, b) rates of HCM treatments and in-hospital mortality, and c) the association between sociodemographic risk factors and HCM treatments and in-hospital mortality. In this data from the largest publicly available inpatient healthcare database in the US – a national random sample of 53,117 admissions for patients with HCM – we observed that race, gender, insurance status and geography were associated with significant disparities in the receipt of septal reduction therapy and in implantable cardioverter-defibrillator treatment and in-hospital mortality among patients with HCM. This study provides important insights for clinicians and policymakers regarding the next steps in identifying and addressing the sources of these inequities.

MOLECULAR MECHANISMS OF DISEASE

Our laboratory serves as the Applied Genomics Core Laboratory for TRIUMPH (Translational Research Investigating Underlying disparities in acute Myocardial infarction Patients’ Health status). The TRIUMPH study is a large, prospective, observational cohort study of 4,340 consecutive patients with acute myocardial infarction presenting to 24 US hospitals from April, 2005 to December, 2008. This cohort has extensive phenotypic data and is an ideal cohort to investigate pharmacogenetic and genetic contributors to post-myocardial infarction (MI) outcomes.

Genetic contributors to post-myocardial infarction outcomes in TRIUMPH:

We examined the association of CHRNA5 haplotypes with gene expression and mortality among patients with acute myocardial infarction (AMI) and explored potential mechanisms of this association. We found that one haplotype, HAP3, was associated with decreased mortality one year after AMI (adjusted HR = 0.42, 95% CI 0.26, 0.68; p = 0.0004). This association was validated in an independent cohort (N= 637) of post-MI patients. Differences in CHRNA5 expression by haplotype were investigated in human heart samples.

Compared with non-carriers, HAP3 carriers had threefold lower cardiac CHRNA5 mRNA expression. Circulating levels of the inflammatory marker hsCRP were significantly lower in HAP3 carriers versus non-carriers. Activation of the inflammasome, an important inflammatory complex involved in cardiovascular disease that is necessary for release of the pro-inflammatory cytokine IL-1 β, was assessed in bone marrow derived macrophages (BMDM) from CHRNA5 knockout mice and wild-type controls.

In BMDM from CHRNA5 knockout mice, IL-1β secretion was reduced by 50% compared to wild-type controls. These results implicate CHRNA5 and the cholinergic anti-inflammatory pathway in survival following AMI.