title: Microvascular function is selectively impaired in patients with hypertrophic cardiomyopathy and sarcomere myofilament gene mutations.
abstract: OBJECTIVE
  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 (13)N-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.
authors.affiliation: Referral Center for Myocardial Diseases, Cytogenetics Unit and Department of Clinical Physiopathology, and Nuclear Medicine Unit, Careggi University Hospital, Florence, Italy. olivottoi@aou-careggi.toscana.it
authors.forename: Iacopo
authors.initials: I
authors.lastname: Olivotto
authors.forename: Francesca
authors.initials: F
authors.lastname: Girolami
authors.forename: Roberto
authors.initials: R
authors.lastname: Sciagrà
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Ackerman
authors.forename: Barbara
authors.initials: B
authors.lastname: Sotgia
authors.forename: J Martijn
authors.initials: JM
authors.lastname: Bos
authors.forename: Stefano
authors.initials: S
authors.lastname: Nistri
authors.forename: Aurelio
authors.initials: A
authors.lastname: Sgalambro
authors.forename: Camilla
authors.initials: C
authors.lastname: Grifoni
authors.forename: Francesca
authors.initials: F
authors.lastname: Torricelli
authors.forename: Paolo G
authors.initials: PG
authors.lastname: Camici
authors.forename: Franco
authors.initials: F
authors.lastname: Cecchi
mesh_terms: D008841:Actin Cytoskeleton / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000641:Ammonia; D024722:Cardiac Myosins / Q000235:genetics; D024741:Cardiomyopathy, Hypertrophic, Familial / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics; D003326:Coronary Circulation; D004176:Dipyridamole; D005260:Female; D005838:Genotype; D006801:Humans; D019028:Magnetic Resonance Imaging, Cine; D008297:Male; D008833:Microcirculation; D009154:Mutation; D009206:Myocardium / Q000473:pathology; D018995:Myosin Heavy Chains / Q000235:genetics; D009590:Nitrogen Radioisotopes; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals; D012044:Regression Analysis; D012518:Sarcomeres / Q000235:genetics*; D012720:Severity of Illness Index; D014335:Tropomyosin / Q000235:genetics; D020107:Troponin T / Q000235:genetics; D014665:Vasodilator Agents; D020257:Ventricular Remodeling; D055815:Young Adult; D000099163:Myosin Binding Protein C
chemical_list: D000641:Ammonia; D024722:Cardiac Myosins; D002352:Carrier Proteins; D004176:Dipyridamole; D018995:Myosin Heavy Chains; D009590:Nitrogen Radioisotopes; D019275:Radiopharmaceuticals; D014335:Tropomyosin; D020107:Troponin T; D014665:Vasodilator Agents; D000099163:Myosin Binding Protein C; C501641:MYH7 protein, human; C545568:TNNT2 protein, human; C490775:TPM1 protein, human