Published Online
on January 27, 2003

A more recent version of this article appeared on February 18, 2003

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Submitted on July 19, 2002
Revised on October 25, 2002
Accepted on November 1, 2002

Myocardial Proinflammatory Cytokine Expression and Left Ventricular Remodeling in Patients With Chronic Mitral Regurgitation

Hakan Oral MD^*, Natarajan Sivasubramanian PhD, David B. Dyke MD, Rajendra H. Mehta MD, P. Michael Grossman MD, Kerri Briesmiester BS, William P. Fay MD, Francis D. Pagani MD, Steven F. Bolling MD, Douglas L. Mann MD, and Mark R. Starling MD

From the Divisions of Cardiology (H.O., D.B.D., R.H.M., P.M.G., K.B., W.P.F., M.R.S.) and Adult Cardiac Surgery (F.D.P., S.F.B.), University of Michigan and Veterans Affairs Medical Centers, Ann Arbor, Mich, and Winters Center for Heart Failure Research (N.S., D.L.M.), Baylor College of Medicine, Houston, Tex.

^* To whom correspondence should be addressed. E-mail: oralh{at}umich.edu.

Background--In an animal model, stretch was shown to induce myocardial tumor necrosis factor- (TNF-) expression. The purposes of this study were to determine whether the left ventricular (LV) volume overload that occurs in patients with chronic mitral regurgitation (MR) can induce myocardial and systemic TNF- expression and whether there is a relationship between TNF- expression and LV remodeling.

Methods and Results--Plasma TNF- and its receptors were measured before mitral valve (MV) repair surgery in 26 MR patients and 23±12 months after MV repair surgery in 9 MR patients. Myocardial mRNA copies of TNF- were determined in 11 MR and 10 donor hearts using quantitative RT-PCR. Compared with 15 control subjects, pre-MV repair plasma TNF- (3.59±1.81 versus 2.03±1.02 pg/mL, P<0.005) and its receptor levels were elevated in MR patients. Myocardial TNF- mRNA copies (corrected for -actin mRNA expression) in MR patients and donor hearts were 38.96±42.74x10⁶ and 0.88±0.75x10⁶, respectively (P=0.01). After MV surgery, there was a decrease in the plasma levels of TNF- (2.79±1.14 versus 3.51±1.34 pg/mL, P=0.02) and its receptors. There was a correlation between myocardial TNF- expression and preoperative LV end-diastolic and end-systolic volumes. Moreover, there was an inverse correlation between myocardial TNF- expression and regression in LV end-diastolic (r=-0.76, P=0.007) and end-systolic (r=-0.73, P=0.01) volumes after MV surgery.

Conclusions--TNF- is expressed in the myocardium and plasma of MR patients. Correction of the LV volume overload with MV surgery results in reversal of TNF- expression. There is a relationship between TNF- expression and parameters of LV remodeling, suggesting that TNF- may play a role in the pathogenesis of the LV remodeling that occurs in MR.

Key words: mitral valve • cytokines • remodeling • hemodynamics • surgery

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