Clinical Investigation
Congestive Heart Failure
Matrix metalloproteinases and tissue remodeling in hypertrophic cardiomyopathy

https://doi.org/10.1016/j.ahj.2008.01.035Get rights and content

Background

Hypertrophic cardiomyopathy (HCM) is defined by the presence of unexplained left ventricular hypertrophy, myocyte disarray, and interstitial fibrosis. An increase in extracellular matrix produces interstitial fibrosis, by raised amounts of collagen type I/III. Regions of myocardial late gadolinium enhancement by cardiac magnetic resonance (CMR) represented increased myocardial collagen. Regarding the role of matrix metalloproteinases (MMPs) in myocardial remodeling and subsequent fibrosis, the aim of our study was to explore the relation between MMP system and myocardial late gadolinium enhancement by CMR (as expression of image-documented fibrosis) and N-terminal pro-brain natriuretic peptide (NT-proBNP) (as a marker of cardiac overload) in HCM.

Methods

We included 67 HCM patients (44 men aged 49 ± 14 years) and were compared to 58 controls with similar age and sex. Risk factors for sudden death were recorded. A blinded CMR was performed with gadolinium. Matrix metalloproteinase 1, MMP-2, and MMP-9 plasma levels were assayed by enzyme-linked immunosorbent assay. Serum samples were used for measurement of NT-proBNP.

Results

In patients, >50% of MMP-1 values were below the lowest limit of detection of the technique. Raised levels of MMP-2, MMP-9, and NT-proBNP were observed in HCM patients (all P < .01). Matrix metalloproteinase 2 was associated with dyspnea (P = .049) and correlated with MMP-9 (r = 0.28, P = .025) and NT-proBNP (r = 0.39, P = .001). Matrix metalloproteinase 9 was associated with the presence of gadolinium enhancement in CMR (P = .001) and correlated with NT-proBNP (r = 0.52, P < .001). NT-proBNP was also associated with gadolinium enhancement (P = .006). Both MMP-2 and MMP-9 correlated negatively with exercise capacity (metabolic equivalent units), (r = −0.36 and r = −0.42 respectively, both P < .01). On multivariate analysis (adjusted by sudden death risk factors and echocardiographic markers), only MMP-9 was associated with fibrosis (P = .011).

Conclusions

Matrix metalloproteinase 9 is independently associated with gadolinium enhancement on CMR in patients with hypertrophic cardiomyopathy, suggesting that the MMP system has an important role in cardiac remodeling and fibrosis in this condition.

Section snippets

Patients and methods

We included 67 HCM patients from two referral hospitals in Spain (Hospital Universitario Virgen de la Arrixaca from Murcia and Hospital General Universitario from Alicante) [44 men (67.5%)] 49±14 years of age. The criteria for diagnosis of HCM was the presence of a left ventricular wall thickness of at least 15 mm without any other cause that could lead to ventricular hypertrophy, and in the case of first-degree relatives of affected individuals, proposed familial criteria were used.21 A

Results

Clinical data of patients are resumed in Table I. Forty-five patients (67%) showed impaired functional class (New York Heart Association ≥II), and only 2 patients presented systolic dysfunction. About half of the patients (48%) had gadolinium enhancement assessed by CMR. Fifty patients (75%) showed any risk factors for sudden death (median, 2 [interquartile range 0-3]).

Discussion

It has been described that collagen turnover is enhanced in HCM, maintaining collagen I synthesis over degradation.12 So, the carboxyl-terminal propeptide of procollagen type I, a serum marker of collagen synthesis, is increased in patients with HCM, with decreased concentration of MMP-1 and raised concentration of its inhibitor, TIMP-1.14 Interestingly, an important increase in collagen content has been shown in young patients with HCM who died suddenly.22 These features are associated with

References (33)

  • J.E. Jalil et al.

    Fibrillar collagen and myocardial stiffness in the intact hypertrophied rat left ventricle

    Circ Res

    (1989)
  • E.D. Frohlich

    Risk mechanisms in hypertensive heart disease

    Hypertension

    (1999)
  • C. Laviades et al.

    Abnormalities of the extracellular degradation of collagen type I in essential hypertension

    Circulation

    (1998)
  • C.V. Thomas et al.

    Increased matrix metalloproteinase activity and selective upregulation in LV myocardium from patients with end-stage dilated cardiomyopathy

    Circulation

    (1998)
  • F.G. Spinale et al.

    A matrix metalloproteinase induction/activation system exists in the human left ventricular myocardium and is upregulated in heart failure

    Circulation

    (2000)
  • A. Jordán et al.

    Matrix metalloproteinase-1 and its inhibitor, TIMP-1, in congestive heart failure: relation to functional data and prognosis

    J Intern Med

    (2007)
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