Clinical Research
Cardiomyopathy
Microvascular Function Is Selectively Impaired in Patients With Hypertrophic Cardiomyopathy and Sarcomere Myofilament Gene Mutations

https://doi.org/10.1016/j.jacc.2011.05.018Get rights and content
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Objectives

The purpose of this study was to assess myocardial blood flow (MBF) using positron emission tomography in patients with hypertrophic cardiomyopathy (HCM) according to genetic status.

Background

Coronary microvascular dysfunction is an important feature of HCM, associated with ventricular remodeling and heart failure. We recently demonstrated the increased prevalence of systolic dysfunction in patients with HCM with sarcomere myofilament gene mutations and postulated an association between genetic status and coronary microvascular dysfunction.

Methods

Maximum MBF (intravenous dipyridamole, 0.56 mg/kg; Dip-MBF) was measured using 13N-labeled ammonia in 61 patients with HCM (age 38 ± 14 years), genotyped by automatic DNA sequencing of 8 myofilament-encoding genes (myosin-binding protein C, beta-myosin heavy chain, regulatory and essential light chains, troponin T, troponin I, troponin C, alpha-tropomyosin, and alpha-actin). In 35 patients, cardiac magnetic resonance imaging was performed.

Results

Fifty-three mutations were identified in 42 of the 61 patients (genotype positive; 69%). Despite similar clinical profiles, genotype-positive patients with HCM showed substantially lower Dip-MBF compared with that of genotype-negative patients (1.7 ± 0.6 ml/min/g vs. 2.4 ± 1.2 ml/min/g; p < 0.02). A Dip-MBF <1.5 ml/min/g had 81% positive predictive value for genotype-positive status and implied a 3.5-fold independent increase in likelihood of carrying myofilament gene mutations (hazard ratio: 3.52; 95% confidence interval: 1.05 to 11.7; p = 0.04). At cardiac magnetic resonance imaging, the prevalence of late gadolinium enhancement was greater in genotype-positive patients (22 of 23 [96%] compared with 8 of 12 [67%] genotype-negative patients; p = 0.038).

Conclusions

Patients with HCM with sarcomere myofilament mutations are characterized by more severe impairment of microvascular function and increased prevalence of myocardial fibrosis, compared with genotype-negative individuals. These findings suggest a direct link between sarcomere gene mutations and adverse remodeling of the microcirculation in HCM, accounting for the increased long-term prevalence of ventricular dysfunction and heart failure in genotype-positive patients.

Key Words

genetic testing
hypertrophic cardiomyopathy
microvascular dysfunction
positron emission tomography

Abbreviations and Acronyms

CMD
coronary microvascular dysfunction
Dip-MBF
myocardial blood flow following dipyridamole infusion
GLA
galactosidase
HCM
hypertrophic cardiomyopathy
LGE
late gadolinium enhancement
LV
left ventricle/ventricular
MYBPC3
myosin-binding protein C
MYH7
beta-myosin heavy chain
PET
positron emission tomography
VOI
volume of interest

Cited by (0)

This work was supported by Ministero Istruzione Università e Ricerca and the European Union (STREP project 241577 “BIG HEART,” 7th European Framework Program). Dr. Ackerman is supported by the Mayo Clinic Windland Smith Rice Comprehensive Sudden Cardiac Death Program. Dr. Cecchi has received honoraria from Genzyme (research grant) and Shire (fees). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.