Presently, diastolic heart failure (DHF) accounts for ~50% of HF cases. Its pathophysiology is ascribed to impaired relaxation or increased myocardial stiffness. Chronic pressure-overload (PO) such as hypertension (HT) or aortic valve stenosis (AS) often lead to DHF. However, diastolic dysfunction mechanisms in AS and HT seem to differ, and remain to clarify.
Patients with severe isolated AS (n=26), arterial hypertension (n=20) and healthy subjects (CTRL, n=8) with preserved left ventricular (LV) ejection fraction and no clinical or angiographic signs of coronary artery disease were studied. Doppler echocardiographic data was used to compare in vivo LV function. Biopsies were used to assess fibrosis, cardiomyocyte hypertrophy (CMH), advanced glycation endproducts (AGEs) and phosphorylation of myofilamentary proteins. Cardiomyocytes were also isolated and permeabilized to measure active force (Factive), resting force (Fpassive) and calcium sensitivity (pCa50). Data are means ± SEM, p < 0.05: a vs CTRL, b vs EA.
EA and HTA groups presented higher ventricular pressures than the CTRL group: systolic (CTRL: 136 ± 5; EA: 234 ± 10a; HT: 179 ± 6ab mmHg) and end-diastolic (CTRL: 13 ± 1; EA: 24 ± 2a; HT: 26 ± 2a mmHg). AS and HT groups displayed concentric hypertrophy represented by a significant increase in wall thickness (CTRL: 9.2 ± 0.4, EA: 10.9 ± 0.3a and HT: 10.9 ± 0.3a mm) and LV mass normalized to their end-diastolic volume (CTRL: 1.27 ± 0.04; EA: 2.44 ± 0.21a; HT: 1.74 ± 0.08b, g/mL). Fibrosis and CMH were significantly higher for EA and HT. Besides displaying increased systolic pressures, EA promoted a further increase of these parameters compared to HT (fibrosis: 3.8 ± 0.8; EA: 13.6 ± 1.4 and the HT: 11.0 ± 1.3ab and CMH: CTRL: 13.1 ± 0.3, EA: 23.7 ± 0.7 and the HT: 20.5 ± 0.9ab µM) and induced changes in relaxation, in particular, decreased E/A ratio ( < 1) and significantly increased E-wave-deceleration time compared to other groups (>280ms). Functional analysis of isolated cardiomyocytes showed an increase in myocardial stiffness in HT group represented by augmented Fpassive (AS: 2.6 ± 0.4; HT: 7.4 ± 0.7ab; CTRL: 3.6 ± 0.7mN/mm2). The increased stiffness in the HT was partially normalized by PKA-phosphorylation of the stiff isoform of titin, although the relative expression of each isoform of titin was not changed.
In conclusion, diastolic dysfunction presented in EA may be attributed to the high deposition of collagen and AGEs and myocardial hypertrophy, while in HT dysfunction is ascribed to increased cardiomyocyte stiffness. These results indicate the need for different therapeutic approaches in the prevention of diastolic HF.