Diastolic tissue Doppler indexes correlate with the degree of collagen expression and cross-linking in heart failure and normal ejection fraction

Abstract

Objectives: We attempted to correlate echocardiographic analysis of diastolic function with changes of myocardial collagen in middle-aged patients with heart failure (HF) despite normal ejection fraction (EF).

Background: Increased collagen deposition may contribute to the deterioration of the left ventricular compliance and diastolic dysfunction in HF.

Methods: We investigated 41 patients (median age 50 years [interquartile range: 41 to 57 years]) with normal EF (median 62% [interquartile range: 56% to 70%]) whose endomyocardial biopsies were taken previously. Assessment of diastolic function was performed by mitral-flow and tissue Doppler measurements. Sirius red and immunohistologic staining was performed to determine collagen volume fraction (CVF) and cross-linking, collagen types I and III expression, and lysyl-oxidase (LOX) expression. Expression of collagen messenger ribonucleic acid was determined by real-time polymerase chain reaction.

Results: Twenty-six patients with HFNEF with diastolic dysfunction showed a significant increase in total collagen and collagen I expression compared with that of 15 controls. This was accompanied with enhanced collagen cross-linking and LOX overexpression in HFNEF. Among all flow Doppler, only deceleration time of E was associated with CVF (R = 0.43), whereas tissue Doppler parameters correlated with CVF, collagen I at the protein and mRNA levels (E' [R = -0.58, -0.60, -0.45]; E'/A' [R = -0.32, -0.36, -0.31]), and left ventricular filling index (E/E' [R = 0.72, 0.68, 0.63]), respectively. No correlation with collagen III was found. The degree of collagen cross-linking and LOX expression was related to E' (R = -0.55 and -0.60) and E/E' (R = 0.72 and 0.71), respectively, but not to flow Doppler. Collagen overexpression correlated with reduced exercise capacity.

Conclusions: Patients with HFNEF showed increased content of myocardial collagen type I, enhanced collagen cross-linking, and LOX expression, which were associated with impaired diastolic tissue Doppler parameters.