Abnormal matrix metalloproteinase (MMP) activity and diastolic dysfunction may affect left ventricular (LV) remodeling and prognosis, but it is not known whether the combined evaluation of MMP-3 and MMP-9 and variables of diastolic dysfunction are useful for the risk stratification of patients with systolic heart failure (HF). Therefore, this study was designed to assess the value of combining circulating levels of MMPs and tissue Doppler measures of LV diastolic dysfunction to risk-stratify patients with systolic HF. Consecutive patients with systolic HF due to either ischemic or nonischemic cardiomyopathy (n = 134) and LV ejection fractions <45% were submitted to complete echocardiographic and Doppler examinations. The ratio of mitral E peak velocity and averaged e′ velocity (E/e′) was calculated. Plasma levels of MMP-3 and MMP-9 were measured at the time of index echocardiography. All-cause mortality was defined as the end point. The mean LV ejection fraction was 28 ± 9%. There was a total of 32 deaths during follow-up (24 ± 14 months). Several clinical, biochemical, Doppler, and echocardiographic parameters were associated with the outcome on univariate Cox regression analysis. After statistical adjustment for the potentially confounding factors by multivariate analysis, E/e′ (hazard ratio 1.11, p = 0.0028), ejection fraction (hazard ratio 0.92, p = 0.017), and MMP-9 (hazard ratio 1.01, p = 0.027) remained significant independent predictors of the end point. Kaplan-Meier curves showed that survival was worse in patients with E/e′ ratios ≥13 and MMP-9 levels >89.9 ng/mL (p <0.0001). In conclusion, the assessment of circulating MMP levels and tissue Doppler measures of LV diastolic dysfunction may improve the prognostic stratification of patients with systolic HF.
In patients with systolic heart failure (HF), altered matrix metalloproteinase (MMP) activity has been implicated in the structural changes associated with left ventricular (LV) dilatation and remodeling. However, there are controversial reports on the prognostic significance of MMP species in patients with HF. The presence of LV diastolic dysfunction, evaluated by the ratio of mitral to myocardial early velocities (E/e′), is a frequent finding in patients with ventricular dilatation and systolic HF and has been found to be useful for risk assessment in patients with LV remodeling and HF. Because LV diastolic dysfunction has an impact on the prognosis of patients with systolic HF, we sought to investigate whether the combined evaluation of circulating levels of MMPs and the E/e′ ratio may contribute to the risk stratification of these patients. Hence, the aim of this study was to assess the value of MMP-3 and MMP-9 activities and the E/e′ ratio in the prognostication of patients with HF due to either ischemic or nonischemic dilated cardiomyopathy (DCM).
Methods
One hundred and thirty-four consecutive patients diagnosed with HF secondary to DCM were enrolled. All patients were previously hospitalized for congestive HF. Inclusion criteria were systolic LV dysfunction, as defined by an LV ejection fraction <45%, LV end-diastolic volume index >75 mL/m 2 , and sinus rhythm. Exclusion criteria were primary valvular disease, mechanical valve prosthesis, and permanent atrial fibrillation. All patients were under medical treatment with loop diuretics, angiotensin-converting enzyme inhibitors, β blockers, and antialdosterone drugs.
Transthoracic 2-dimensional and Doppler echocardiographic examinations were carried out with an Acuson Sequoia C256 ultrasound instrument (Siemens Medical Solutions USA, Inc, Mountain View, California) with second-harmonic imaging and a 3.5-MHz transducer. Echocardiographic measurements included LV volumes, LV mass, and the LV ejection fraction and were obtained according to current American Society of Echocardiography guidelines. Pulsed Doppler flow tracings and tissue Doppler analysis of mitral annular motion were obtained according to recent recommendations. The E/e′ ratio was calculated. Tricuspid annular plane systolic excursion (TAPSE) was measured as previously described.
Plasma levels of MMP-3 and MMP-9 were assessed at the time of index echocardiography. MMP-3 and MMP-9 plasma levels were measured using a commercially available enzyme-linked immunosorbent assay (R&D Systems, Minneapolis, Minnesota). Receiver-operating characteristic curves were generated to define cut-off values for prognostic indicators.
Study patients were followed up after index Doppler echocardiography. The end point was all-cause mortality. Survival data were obtained through follow-up of patients and verified through local authority registry and hospital records.
Continuous variables are expressed as mean ± SD or as medians and interquartile ranges (IQRs). Cumulative survival probability was explored using the Kaplan-Meier method, followed by the log-rank test. The independent effects of variables on the risk of cardiovascular events were explored by stepwise Cox proportional-hazards regression and are expressed as hazard ratios and 95% confidence intervals (CIs). The following variables were tested in the models: age, gender, New York Heart Association class, indexed LV mass, indexed LV end-diastolic volume, indexed LV end-systolic volume, the LV ejection fraction, E-wave deceleration time, E/e′ ratio, TAPSE, MMP-3, and MMP-9. A probability of F to enter ≤0.05 and a probability of F to remove ≥0.10 were used as selection criteria for the stepwise regression procedure, and only variables meeting these criteria were included in the final models. A p value <0.05 was considered statistically significant. All tests were 2 tailed. SPSS version 15.0 for Windows (SPSS, Inc., Chicago, Illinois) was used to perform all analyses.
Results
The mean age of the study patients was 68 ± 12 years, and most patients were men (77%). Sixty-two percent of them were in New York Heart Association classes III and IV. The mean LV ejection fraction was 28 ± 9%. The median values of MMP-3 and MMP-9 were 15.9 ng/ml (IQR 5.1 to 22.2) and 405.3 ng/ml (IQR 80.0 to 903.0), respectively. In patients with ischemic DCM, MMP-3 was 8.5 ng/ml (IQR 17.8 to 24.8), and MMP-9 was 411.0 ng/ml (IQR 79.0 to 1,130.2). In patients with nonischemic DCM, MMP-3 and MMP-9 were 14.1 ng/ml (IQR 5.2 to 20.2) and 396.0 ng/ml (IQR 80.0 to 894.3), respectively. Patients with elevated markers of collagen degradation exhibited more advanced New York Heart Association classes, lower LV ejection fractions, higher E/e′ ratios, and lower TAPSE. The characteristics of the study patients are listed in Table 1 .
