Cardiothoracic
Cardiotropin-1 and Myocardial Strain Change Heterogeneously in Cardiomyopathy

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Background

The pacing model of heart failure produces heterogeneous changes in wall stress and myocyte diameter. The purpose of this study was to measure regional changes in cardiotrophin-1 (CT-1), a cytokine thought to play a role in LV remodeling, and regional changes in LV strain as measured with magnetic resonance imaging.

Materials and methods

Dilated cardiomyopathy was induced in nine mongrel dogs over 4 wk by rapid pacing using a right ventricular epicardial lead. Baseline CT-1 was measured from an apical myocardial biopsy, and regional CT-1 was measured from anterior, lateral, inferior, and septal walls after the induction of heart failure and in six control dogs. Tissue tagged images were divided into similar regions and minimal principal strain (MPS), ejection fraction, and ventricular volumes were compared after induction of heart failure.

Results

After induction of heart failure, LV ejection fraction and end-diastolic volume differed significantly from baseline (P < 0.01 and P = 0.02, respectively). Additionally, regional CT-1 and MPS were significantly different (P < 0.01 for both). Cardiotrophin-1 increased significantly in the inferior and septal walls (both P < 0.01) but not in the anterior or lateral walls (both P = NS). Minimum principal strain decreased significantly in the inferior and septal walls (both P < 0.01) but not in the anterior or lateral walls (both P = NS).

Conclusion

The pacing model of heart failure produces heterogeneous changes in regional CT-1 and wall motion as measured by MPS. The greatest regional changes are closest to the pacemaker site: the inferior and septal walls. These differences in regional CT-1 may account for previously noted myocyte hypertrophy and preserved ventricular function in these regions.

Introduction

Cardiotrophin-1 (CT-1) is a member of the interleukin-6 family of cytokines that has been associated with cardiomyocyte hypertrophy in vitro [1]. Increased gene expression of CT-1 has been demonstrated in atrial and ventricular tissue from dogs paced into dilated cardiomyopathy [2], and in humans with end-stage dilated cardiomyopathy [3]. Ventricular CT-1 gene activation positively correlates with increased left ventricular mass [2] and precedes ventricular B-type natriuretic peptide (BNP) expression in tachycardia-induced dilated cardiomyopathy in dogs [4], suggesting that CT-1 may be an important paracrine/autocrine factor of myocyte hypertrophy associated with dilated cardiomyopathy. To date, little is known concerning regional expression of CT-1 and BNP and their association with regional ventricular function.

The rapid ventricular pacing model of dilated cardiomyopathy in dogs closely resembles human dilated cardiomyopathy with respect to hemodynamic adaptations, neurohumoral changes, and ventricular hypertrophy [5]. Early left ventricular dysfunction progresses to overt congestive failure with increased filling pressures, depressed left ventricular systolic function, left ventricular dilation, and increased plasma BNP levels. Pacing from a single site on the right ventricle causes mechanical discoordination resulting in decreased systolic function and increased wall stress [6]. This increased wall stress is heterogeneous and is highest in the late-activated regions (regions remote from pacemaker lead) because of additional preload in early systole and increased afterload in late systole. These changes have been associated with myocardial remodeling [7] and altered regional protein expression. Regional heterogeneity of function in dilated cardiomyopathy has been identified [8, 9, 10, 11] and quantified [12] in humans, however, these changes in function have not been demonstrated in the pacing model of dilated cardiomyopathy nor correlated to changes in CT-1 or BNP expression.

We have previously used magnetic resonance imaging (MRI) with myocardial strain analysis to quantitate regional changes in regional left ventricular function after coronary artery bypass grafting [13], and in patients with dilated cardiomyopathy [14]. The goals of this study were to quantitate regional changes in left ventricular function in dogs with dilated cardiomyopathy using myocardial strains and to identify changes in tissue expression of CT-1 and BNP associated with these changes in function.

Section snippets

Overview

After approval by our institution’s animal care and use committee, nine mongrel dogs of either gender underwent baseline cardiac MRI for regional strain, regional wall thickness, and global cardiac volume measurements. The dogs then had a pulmonary artery catheter placed for thermodilution hemodynamic measurements, a blood draw for baseline plasma BNP levels, and an epicardial right ventricular pacemaker lead was implanted. After 1 wk of recovery, the dogs were rapidly paced into a dilated

Regional Myocardial Strains

Although myocardial strain decreased in all four walls in the heart failure group, the change in strain was statistically significant in the posterior and septal walls (both P < 0.01), but not the anterior or lateral walls (both P = NS, Fig. 2) when compared with baseline. When comparing regional strain values in the dilated cardiomyopathy group, the changes were significantly different between regions (Friedman test, P < 0.01). The percent change in the posterior wall was the greatest and was

Comments

The major findings of this study were that levels of regional CT-1 expression are homogenous in normal ventricular tissue, however, regional CT-1 expression changed heterogeneously with induction of dilated cardiomyopathy in dogs. Similarly, regional myocardial strain changed heterogeneously with induction of dilated cardiomyopathy, however, these changes in regional CT-1 and strain did not correlate. Interestingly, ventricular BNP expression was more homogenous in both the control and dilated

Acknowledgments

This study was supported by grants T32-HL-07776 and R01-HL62291-04 from the National Heart, Lung, and Blood Institute and an internal grant from the Department of Radiology, Mayo Clinic and College of Medicine, Rochester, MN.

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