ORIGINAL ARTICLEMyofilament Protein Gene Mutation Screening and Outcome of Patients With Hypertrophic Cardiomyopathy
Section snippets
PATIENTS AND METHODS
The study included 203 unrelated index patients with a confirmed clinical diagnosis of HCM, consecutively enrolled at the Azienda Ospedaliera-Universitaria Careggi, in Florence, Italy, and Ospedale San Camillo, in Rome, Italy, since the beginning of a systematic screeningprogram for myofilament gene mutations.13 Patients were enrolled from January 1, 2002, through December 31, 2003. The study patients had already been diagnosed as having HCM and were followed up for a median of 4.1 years before
Comprehensive Mutational Analysis
In 126 (62%) of the 203 study patients, we identified 87 distinct mutations, of which 51 were classified as novel (Figure 1, Table 2). These 126 patients were considered to have myofilament-positive HCM. The remaining 77 patients (38%) had no discernible myofilament mutations and were considered to have myofilament-negative HCM. The most frequent disease-associated gene was MYBPC3 (n=68; 34%; including 9 patients with double mutations in this gene). The MYBPC3 E258K mutation, which was found in
DISCUSSION
Our study shows that the identification of 1 or more cardiac myofilament gene mutations is associated with increased risk of LV dysfunction and adverse outcome due to heart failure in patients with HCM. In our cohort, myofilament-positive HCM was characterized by an almost 30% prevalence of severe systolic and/or diastolic LV dysfunction, which was increasingly common after the fourth decade of life and occurred at a similar rate for each of the 3 major myofilament subtypes involved. By
CONCLUSION
Hypertrophic cardiomyopathy due to myofilament gene mutations is characterized by adverse outcome and more frequent derangement of LV function compared with myofilament-negative disease, irrespective of the myofilament type involved. These findings support a clinical and prognostic role for genetic testing in patients with clinically diagnosed HCM.
REFERENCES (39)
- et al.
American College of Cardiology/European Society of Cardiology clinical expert consensus document on hypertrophic cardiomyopathy: a report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents and the European Society of Cardiology Committee for Practice Guidelines
J Am Coll Cardiol
(2003) - et al.
Hypertrophic cardiomyopathy
Lancet
(2004) - et al.
Comprehensive analysis of the beta-myosin heavy chain gene in 389 unrelated patients with hypertrophic cardiomyopathy
J Am Coll Cardiol
(2004) - et al.
Alpha-tropomyosin and cardiac troponin T mutations cause familial hypertrophic cardiomyopathy: a disease of the sarcomere
Cell
(1994) - et al.
Sudden death due to troponin T mutations
J Am Coll Cardiol
(1997) - et al.
Prevalence and clinical profile of troponin T mutations among patients with hypertrophic cardiomyopathy in Tuscany
Am J Cardiol
(2003) - et al.
Prevalence and age-dependence of malignant mutations in the beta-myosin heavy chain and troponin T genes in hypertrophic cardiomyopathy: a comprehensive outpatient perspective
J Am Coll Cardiol
(2002) - et al.
Echocardiography-guided genetic testing in hypertrophic cardiomyopathy: septal morphological features predict the presence of myofilament mutations
Mayo Clin Proc
(2006) - et al.
Hypertrophic cardiomyopathy in Tuscany: clinical course and outcome in an unselected regional population
J Am Coll Cardiol
(1995) - et al.
Determination of left ventricular filling pressure by Doppler echocardiography in patients with coronary artery disease: critical role of left ventricular systolic function
J Am Coll Cardiol
(1997)
Restrictive left ventricular filling pattern in dilated cardiomyopathy assessed by Doppler echocardiography: clinical, echocardiographic and hemodynamic correlations and prognostic implications
J Am Coll Cardiol
Lifelong left ventricular remodeling of hypertrophic cardiomyopathy caused by a founder frameshift deletion mutation in the cardiac myosin-binding protein C gene among Japanese
J Am Coll Cardiol
Reviews of translational medicine and genomics in cardiovascular disease: new disease taxonomy and therapeutic implications
J Am Coll Cardiol
The molecular genetic basis for hypertrophic cardiomyopathy
J Mol Cell Cardiol
Human homozygous R403W mutant cardiac myosin presents disproportionate enhancement of mechanical and enzymatic properties
J Mol Cell Cardiol
Hypertrophic cardiomyopathy due to sarcomeric gene mutations is characterized by impaired energy metabolism irrespective of the degree of hypertrophy
J Am Coll Cardiol
Molecular and functional characterization of a human frataxin mutation found in hypertrophic cardiomyopathy
Mol Genet Metab
Myosin binding protein C mutations and compound heterozygosity in hypertrophic cardiomyopathy
J Am Coll Cardiol
A missense mutation in a ubiquitously expressed protein, vinculin, confers susceptibility to hypertrophic cardiomyopathy
Biochem Biophys Res Commun
Cited by (316)
Current RNA strategies in treating cardiovascular diseases
2024, Molecular TherapySeptal Myectomy Outcomes in Children and Adolescents With Obstructive Hypertrophic Cardiomyopathy
2023, Annals of Thoracic SurgeryWhat Causes Hypertrophic Cardiomyopathy?
2022, American Journal of CardiologyMolecular characterization of linker and loop-mediated structural modulation and hinge motion in the C4-C5 domains of cMyBPC
2022, Journal of Structural BiologyCardiomyopathies
2022, Cardiovascular Pathology
This study was supported by grants from the Italian Ministry for Scientific and Technologic Research (MURST - COFIN 2004), the Fondazione Ente Cassa di Risparmio di Firenze, and the Mayo Clinic Windland Smith Rice Comprehensive Sudden Cardiac Death Program.