Myocardial Fibrosis as an Early Manifestation of Hypertrophic Cardiomyopathy

Cardiovascular Division, Brigham and Women's Hospital, Boston, MA 02115, USA.
New England Journal of Medicine (Impact Factor: 55.87). 08/2010; 363(6):552-63. DOI: 10.1056/NEJMoa1002659
Source: PubMed


Myocardial fibrosis is a hallmark of hypertrophic cardiomyopathy and a proposed substrate for arrhythmias and heart failure. In animal models, profibrotic genetic pathways are activated early, before hypertrophic remodeling. Data showing early profibrotic responses to sarcomere-gene mutations in patients with hypertrophic cardiomyopathy are lacking.
We used echocardiography, cardiac magnetic resonance imaging (MRI), and serum biomarkers of collagen metabolism, hemodynamic stress, and myocardial injury to evaluate subjects with hypertrophic cardiomyopathy and a confirmed genotype.
The study involved 38 subjects with pathogenic sarcomere mutations and overt hypertrophic cardiomyopathy, 39 subjects with mutations but no left ventricular hypertrophy, and 30 controls who did not have mutations. Levels of serum C-terminal propeptide of type I procollagen (PICP) were significantly higher in mutation carriers without left ventricular hypertrophy and in subjects with overt hypertrophic cardiomyopathy than in controls (31% and 69% higher, respectively; P<0.001). The ratio of PICP to C-terminal telopeptide of type I collagen was increased only in subjects with overt hypertrophic cardiomyopathy, suggesting that collagen synthesis exceeds degradation. Cardiac MRI studies showed late gadolinium enhancement, indicating myocardial fibrosis, in 71% of subjects with overt hypertrophic cardiomyopathy but in none of the mutation carriers without left ventricular hypertrophy.
Elevated levels of serum PICP indicated increased myocardial collagen synthesis in sarcomere-mutation carriers without overt disease. This profibrotic state preceded the development of left ventricular hypertrophy or fibrosis visible on MRI. (Funded by the National Institutes of Health and others.)


Available from: Arantxa González
  • Source
    • "Given that only eight cats had LVH in the screened cohort, comparison between cats with and without LVH was not carried out, but this may represent an area for future study. The inverse correlation between PIIINP and LA size over all 48 cats in the study should be interpreted with caution, due to the correlation being weak and possibly affected by the influence of a small number of outlier cats. of PICP:CITP were significantly higher in G+ than G− patients, but there was no significant difference in CITP concentration (Ho et al. 2010). Unlike in human patients, where recent controversy has been highlighted (Ellims et al. 2014), there is no evidence that the results presented here directly relate to changes in the collagen content of the feline myocardium. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Human carriers of hypertrophic cardiomyopathy associated sarcomeric mutations have abnormal collagen metabolism before overt left ventricular hypertrophy is detectable. This study investigated whether differences in collagen biomarkers were present in blood samples of ragdoll cats positive for the MYBPC3:R820W mutation compared with negative controls. Cats were recruited for hypertrophic cardiomyopathy screening using echocardiography and genotyping. Circulating markers of collagen turnover (C-terminal telopeptide of type I collagen [CITP; type I collagen degradation] and N-terminal propeptide of type III procollagen [type III collagen synthesis]) and cardiac biomarkers (N-terminal B-type natriuretic peptide and cardiac troponin I) were measured. Correlation between concentrations of collagen biomarkers and echocardiographic variables was analysed, and collagen biomarker concentrations were compared between MYBPC3 mutation positive and negative cats, without left ventricular hypertrophy. Linear regression analyses showed that genotype was independently associated with CITP concentration. CITP was higher in mutation carriers (25 · 4 µg/L, interquartile range 16 · 0-29 · 2 µg/L) than non-carriers (14 · 6 µg/L, interquartile range 9 · 38-19 · 2 µg/L; P = 0 · 024). Circulating CITP was higher in MYBPC3-positive ragdoll cats than negative controls and may indicate altered collagen metabolism. Further studies are necessary to determine whether alterations in circulating collagen biomarker concentration relate to an early stage of hypertrophic cardiomyopathy. © 2015 British Small Animal Veterinary Association.
    Journal of Small Animal Practice 01/2015; 56(6). DOI:10.1111/jsap.12332 · 1.09 Impact Factor
  • Source
    • "Hypertrophy can also be developed as a response to physiological stimuli such as chronic exercise. On the other hand, pathological hypertrophy is associated with an altered pattern of gene expression, presence of myofibrillar disarray, fibrosis, and contractile dysfunction and thus can lead to heart failure and sudden cardiac death (SCD) (Ho, 2010; Ho et al., 2010; Abel and Doenst, 2011). Most commonly hypertrophic cardiomyopathy (HCM) occurs in response to genetic mutations in all major sarcomeric proteins, including the myosin essential light chain (ELC) encoded by the MYL3 gene (Alcalai et al., 2008). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Cardiac hypertrophy represents one of the most important cardiovascular problems yet the mechanisms responsible for hypertrophic remodeling of the heart are poorly understood. In this report we aimed to explore the molecular pathways leading to two different phenotypes of cardiac hypertrophy in transgenic mice carrying mutations in the human ventricular myosin essential light chain (ELC). Mutation-induced alterations in the heart structure and function were studied in two transgenic (Tg) mouse models carrying the A57G (alanine to glycine) substitution or lacking the N-terminal 43 amino acid residues (Δ43) from the ELC sequence. The first model represents an HCM disease as the A57G mutation was shown to cause malignant HCM outcomes in humans. The second mouse model is lacking the region of the ELC that was shown to be important for a direct interaction between the ELC and actin during muscle contraction. Our earlier studies demonstrated that >7 month old Tg-Δ43 mice developed substantial cardiac hypertrophy with no signs of histopathology or fibrosis. Tg mice did not show abnormal cardiac function compared to Tg-WT expressing the full length human ventricular ELC. Previously reported pathological morphology in Tg-A57G mice included extensive disorganization of myocytes and interstitial fibrosis with no abnormal increase in heart mass observed in >6 month-old animals. In this report we show that strenuous exercise can trigger hypertrophy and pathologic cardiac remodeling in Tg-A57G mice as early as 3 months of age. In contrast, no exercise-induced changes were noted for Tg-Δ43 hearts and the mice maintained a non-pathological cardiac phenotype. Based on our results, we suggest that exercise-elicited heart remodeling in Tg-A57G mice follows the pathological pathway leading to HCM, while it induces no abnormal response in Tg-Δ43 mice.
    Frontiers in Physiology 09/2014; 5:353. DOI:10.3389/fphys.2014.00353 · 3.53 Impact Factor
  • Source
    • "Cardiac enlargement and myocardial fibrosis are hallmarks of hypertrophic cardiomyopathy [24]. ANP, BNP and c-Myc are cardiac hypertrophy markers usually used in clinical diagnosis [25]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Growing evidence indicates that polycyclic aromatic hydrocarbons (PAHs) can lead to cardiac hypertrophy and recent research indicates that exposure to low dose crude oil during early embryonic development may lead to impacts on heart health at later life stages. The aim of this study was to evaluate whether exposure during early life stages to low dose benzo[a]pyrene (BaP), as a high-ring PAH, would lead to cardiac hypertrophy at later life stages. Zebrafish were exposed to low dose BaP until 96 hpf, then transferred to clean water and maintained for a year before histological and molecular biological analysis. Our results showed that exposure to low level BaP during early life stages increased heart weight to body weight ratios and deposited collagen in the heart of adult zebrafish. ANP, BNP and c-Myc were also induced in the heart of adult zebrafish by BaP. These results proved that low level BaP exposure during early life stages caused symptoms similar to cardiac hypertrophy in adult zebrafish. Our results displayed an elevated expression of CdC42, RhoA, p-ERK1, 2 and Rac1. Therefore, the mechanism of the cardiac hypertrophy caused by BaP exposure during early life stages may be through inducing the expression of CdC42, RhoA and Rac1, together with activating ERK1, 2.
    Journal of Hazardous Materials 07/2014; 276:377–382. DOI:10.1016/j.jhazmat.2014.05.057 · 4.53 Impact Factor
Show more