Plasma biomarkers that reflect determinants of matrix composition identify the presence of left ventricular hypertrophy and diastolic heart failure

Abstract

Background: Chronic pressure overload (such as arterial hypertension) may cause left ventricular (LV) remodeling, alterations in cardiac function, and the development of diastolic heart failure. Changes in the composition of the myocardial extracellular matrix may contribute to the development of pressure-overload-induced LV remodeling. We hypothesized that a specific pattern of plasma biomarker expression that reflected changes in these pathophysiological mechanisms would have diagnostic application to identify (1) patients who have development of LV hypertrophy (LVH) and (2) patients with LVH who have development of diastolic heart failure.

Methods and results: Plasma concentration of 17 biomarkers (matrix metalloproteinase [MMP]-1, -2, -3, -7, -8, and -9; tissue inhibitors -1, -2, -3, and -4; N-terminal propeptide of brain natriuretic peptide (NT-proBNP); cardiotrophin; osteopontin; soluble receptor for advanced glycation end products; collagen I teleopeptide; collagen I NT-proBNP; and collagen III N-terminal propetide [PIIINP]), an echocardiogram, and 6-minute hall walk were performed on 241 referent control subjects, 144 patients with LVH but no evidence of heart failure, and 61 patients with LVH and diastolic heart failure (DHF). A plasma multibiomarker panel consisting of increased MMP-7, MMP-9, TIMP-1, PIIINP, and NT-proBNP predicted the presence of LVH with an area under the curve of 0.80. A plasma multibiomarker panel consisting of increased MMP-2, TIMP-4, PIIINP, and decreased MMP-8 predicted the presence of DHF with an area under the curve of 0.79. These multibiomarker panels performed better than any single biomarker including NT-proBNP and better than using clinical covariates alone (area under the curve, 0.73 for LVH and 0.68 for DHF).

Conclusions: Plasma biomarkers reflecting changes in extracellular matrix fibrillar collagen homeostasis, combined into a multibiomarker panel, have discriminative value in identifying the presence of structural remodeling (LVH) and clinical disease (DHF).

Figure 1

A: Receiver operator curve analysis for plasma biomarker detection of left ventricular hypertrophy (LVH). Observed area under the curve (AUC) for LVH using clinical covariates plus the 5 biomarker panel = 0.80 [0.76, 0.84]. B: Cross-validated analysis for plasma biomarker detection of LVH. The ROC curves generated from a 30 random simulated simulations of a 5-fold split of the data are presented. The cross validated ROC curves are similar in shape to those obtained in Figure 1A.

Figure 2

A: Receiver operator curve analysis for plasma biomarker detection of diastolic heart failure (DHF). Observed area under the curve (AUC) for DHF using clinical covariates plus the 4 biomarker panel = 0.79 [0.73,0.86]. B: The ROC curves generated from 30 random simulated simulations of a 5-fold split of the data are presented. The cross-validated ROC curves are similar in shape to those obtained in Figure 2A.

Figure 3

The calibration of risk predictors for LVH and DHF. Predicted risk based on the clinical covariates plus 5 biomarker panel and clinical covariates plus 4 biomarker panel, for LVH and DHF, respectively, were grouped into deciles. Observed versus predicted risk of LVH (or DHF) was plotted for each decile. Both calibration curves show a linearly increasing relationship between predictive and observed risk.