Myocardial collagen turnover in normotensive obese patients: relation to insulin resistance

Abstract

OBJECTIVES:The present study was undertaken to assess the differential impact of insulin resistance, leptin and body composition on myocardial mass and serum markers of cardiac fibrosis in obese subjects, within a small range of elevated BMI (30-40 kg/m 2 ), without pulmonary disease, cardiovascular disease, hypertension, cardiac hypertrophy or other cardiovascular disease. BACKGROUND: Obesity is an independent predictor of left ventricular mass (LVM) and is associated with disturbances in cardiac structure. The extent of the interstitial fibrosis in obese patients is not known, especially in the absence of cardiac hypertrophy. METHODS AND RESULTS:We included 160 obese subjects. The LVM was obtained using the Devereux formula. Body composition was estimated from a total body scan. Insulin sensitivity was assessed by homeostasis model assessment (HOMA), and cardiac collagen turnover by measurement of procollagen type III aminopeptide (PIIINP). PIIINP was correlated to the E/A ratio (r ¼ 0.24; P ¼ 0.012), a marker of ventricular function. PIIINP was independently correlated with glucose concentration (r ¼ 0.27; P ¼ 0.004), indexes of insulin resistance (HOMA (r ¼ 0.27; P ¼ 0.003), insulin (r ¼ 0.24; P ¼ 0.008)), and parameters associated with the insulin-resistance syndrome (HDL-cholesterol r ¼ À0.27; P ¼ 0.004) and fat trunk/fat leg ratio (r ¼ 0.24; P ¼ 0.053)). The variable most correlated with PIIINP was HDL-cholesterol, followed by HOMA (r 2 ¼ 0.13). When HOMA was substituted for blood glucose concentration and insulinemia (Model 2), HDL-cholesterol was strongly related to lower PIIINP levels, followed by higher glucose concentration (r 2 ¼ 0.21). Regression analyses showed that LVM had the strongest independent positive correlation with fat-free mass (FFM) (r ¼ 0.39; P ¼ 0.0002), followed by systolic blood pressure (r ¼ 0.19; P ¼ 0.034). Neither adipose mass nor height independently added information to multivariate models. The ratio leptin/fat mass was correlated with LVM (r ¼ À0.27; P ¼ 0.004), but not independently of the FFM. Markers for fibrosis were not significantly correlated with LVM. As a result, FFM was the most predictive factor of LVM in obese subjects. CONCLUSION: We found that serum levels of markers of cardiac collagen synthesis were significantly associated with insulin resistance in normotensive, nondiabetic obese subjects, and not related to the LVM. As a result, PIIINP could be a very early marker of ventricular dysfunction in these patients. Furthermore, we suggest that, for better detection of left ventricle hypertrophy in obese subjects, LVM should be indexed to FFM rather than to body surface area, or height.

Clinical and echocardiographic correlates of plasma procollagen type III amino-terminal peptide levels in the community

“…35 Interestingly, a recent study of obese individuals found that PIIINP levels were independently correlated with indices of insulin resistance, which has also been postulated to play a role in the development of LV hypertrophy. 36 We found a positive association between PIIINP levels and hypertension, but this association was not significant after accounting for the effects of age and BMI. Diez and colleagues reported higher levels of PIIINP in 50 individuals with essential hypertension compared with 30 controls, but that study did not adjust for baseline differences in age or BMI.…”

Dynamic Relation of Changes in Weight and Indices of Fat Distribution With Cardiac Structure and Function: The Dallas Heart Study

“…Excess adiposity may influence LV remodeling by a variety of mechanisms including endothelial dysfunction,37 inflammatory cytokines,38 neurohormonal alterations,39 and myocardial fibrosis 40. These mechanisms lead to pathologic LV remodeling,4, 11 and eventually heart failure 2.…”

Features of Cardiac Remodeling, Associated With Blood Pressure and Fibrosis Biomarkers, Are Frequent in Subjects With Abdominal Obesity

“…Our results further suggest that enhanced collagen type III turnover is associated with early diastolic dysfunction independently from the adipokine pathways (the latter associated with LVM but not with diastolic dysfunction). In our previous report, in obese healthy subjects, 7 PIIINP and E/A ratio were significantly positively correlated. The transformation of the extracellular matrix into a more substantial collagen component potentiated by the increase in LV mass may alter ventricular filling, possibly contributing to the development of LV diastolic dysfunction in subjects with AO.…”

“…7 In such subjects, we had previously reported that PIIINP was independently associated with insulin resistance, 7 which is a common state in AO, and could contribute specifically to increase myocardial fibrosis. Our results further suggest that enhanced collagen type III turnover is associated with early diastolic dysfunction independently from the adipokine pathways (the latter associated with LVM but not with diastolic dysfunction).…”

“…5 Our group has also reported that early changes in extracellular matrix biomarkers could be detected not only in patients with diabetes mellitus and hypertension 6 but also in obese and otherwise healthy subjects. 7 Whether subjects with AO develop adverse cardiac and vascular remodeling has not been investigated to date. The aim of the present study is to assess whether changes in cardiac and arterial remodeling can be detected at an early stage in subjects with AO and otherwise healthy and normotensive and to investigate the contribution of blood pressure (BP) and myocardial fibrosis turnover to such potential changes.…”