Diastolic Tissue Doppler Indexes Correlate With the Degree of Collagen Expression and Cross-Linking in Heart Failure and Normal Ejection Fraction

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.