Microvascular function is selectively impaired in patients with hypertrophic cardiomyopathy and sarcomere myofilament gene mutations

Iacopo Olivotto, Francesca Girolami, Roberto Sciagr, Michael John Ackerman, Barbara Sotgia, J. Martijn Bos, Stefano Nistri, Aurelio Sgalambro, Camilla Grifoni, Francesca Torricelli, Paolo G. Camici, Franco Cecchi

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)839-848
Number of pages10
JournalJournal of the American College of Cardiology
Volume58
Issue number8
DOIs
StatePublished - Aug 16 2011

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Sarcomeres
Myofibrils
Hypertrophic Cardiomyopathy
Mutation
Genotype
Genes
Heart Failure
Magnetic Resonance Imaging
Troponin C
Ventricular Myosins
Ventricular Dysfunction
Tropomyosin
Troponin T
Ventricular Remodeling
Troponin I
Dipyridamole
Myosin Heavy Chains
Gadolinium
Microcirculation
DNA Sequence Analysis

Keywords

  • genetic testing
  • hypertrophic cardiomyopathy
  • microvascular dysfunction
  • positron emission tomography

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Microvascular function is selectively impaired in patients with hypertrophic cardiomyopathy and sarcomere myofilament gene mutations. / Olivotto, Iacopo; Girolami, Francesca; Sciagr, Roberto; Ackerman, Michael John; Sotgia, Barbara; Bos, J. Martijn; Nistri, Stefano; Sgalambro, Aurelio; Grifoni, Camilla; Torricelli, Francesca; Camici, Paolo G.; Cecchi, Franco.

In: Journal of the American College of Cardiology, Vol. 58, No. 8, 16.08.2011, p. 839-848.

Research output: Contribution to journalArticle

Olivotto, I, Girolami, F, Sciagr, R, Ackerman, MJ, Sotgia, B, Bos, JM, Nistri, S, Sgalambro, A, Grifoni, C, Torricelli, F, Camici, PG & Cecchi, F 2011, 'Microvascular function is selectively impaired in patients with hypertrophic cardiomyopathy and sarcomere myofilament gene mutations', Journal of the American College of Cardiology, vol. 58, no. 8, pp. 839-848. https://doi.org/10.1016/j.jacc.2011.05.018
Olivotto, Iacopo ; Girolami, Francesca ; Sciagr, Roberto ; Ackerman, Michael John ; Sotgia, Barbara ; Bos, J. Martijn ; Nistri, Stefano ; Sgalambro, Aurelio ; Grifoni, Camilla ; Torricelli, Francesca ; Camici, Paolo G. ; Cecchi, Franco. / Microvascular function is selectively impaired in patients with hypertrophic cardiomyopathy and sarcomere myofilament gene mutations. In: Journal of the American College of Cardiology. 2011 ; Vol. 58, No. 8. pp. 839-848.
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abstract = "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.",
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T1 - Microvascular function is selectively impaired in patients with hypertrophic cardiomyopathy and sarcomere myofilament gene mutations

AU - Olivotto, Iacopo

AU - Girolami, Francesca

AU - Sciagr, Roberto

AU - Ackerman, Michael John

AU - Sotgia, Barbara

AU - Bos, J. Martijn

AU - Nistri, Stefano

AU - Sgalambro, Aurelio

AU - Grifoni, Camilla

AU - Torricelli, Francesca

AU - Camici, Paolo G.

AU - Cecchi, Franco

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N2 - 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.

AB - 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.

KW - genetic testing

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KW - positron emission tomography

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