Early-stage heart failure with preserved ejection fraction in the pig: a cardiovascular magnetic resonance study

Left ventricular and myocardial function

During ?-adrenergic stress, an adequate increase in LV ejection fraction and a decrease in ESV accounted for normal contractility reserves in both groups. However, EDV significantly decreased during stress in DOCA pigs, inhibiting stroke volume and cardiac index from properly increasing with the heart rate. A similar response was reported in patients with HFpEF during dynamic exercise [38, 39].

Echocardiographic studies in HFpEF patients document reduced longitudinal and circumferential strain [40] as well as failure to increase LV ejection fraction and global longitudinal strain rate during stress [41]. In our study, DOCA pigs with early-stage HFpEF did not show failure to increase LV ejection fraction during stress, but they demonstrated a significantly lower LL rate_min compared to control animals; thus systolic function – though normal at rest – showed signs of impairment during stress. These results are in accordance with findings in hypertensive patients with LV hypertrophy, where authors showed that systolic dysfunction may develop in parallel to diastolic dysfunction [40, 42, 43]. Moreover and in line with findings in patients with hypertensive LV hypertrophy [44], MAPSE was reduced in the DOCA group at rest but significantly increased during stress enabling adequate increase in LV ejection fraction with heart rate.

E’ was significantly decreased in the DOCA group at rest and during dobutamine stress, and accordingly E/E’ and (E/E’)/EDV ratios were higher in DOCA than in control animals. It was previously shown in HFPEF patients that E/E’ correlates well with the LV end-diastolic pressure [39]. The significant higher E/E’ in DOCA compared to control pigs at rest and during stress indicates slightly higher LV filling pressures in DOCA animals, which is up to statistical significance in accordance with the invasive results reported by Schwarzl et al. [17]. Decreased E’ and increased (E/E’)/EDV might be interpreted as marker for increased diastolic myocardial stiffening in DOCA pigs [32], caused by both, increased levels of collagen shown in the present study and reduced total-titin phosphorylation reported by Schwarzl et al. [17]. Similar changes in E’ and (E/E’)/EDV were observed also in HFpEF patients [32, 39, 45]. In DOCA pigs, increased (E/E’)/EDV may further be related to the prolonged IVRT at rest [46, 47] and/or subtle stress-induced myocardial ischemia [48], as indicated by the lower global myocardial perfusion reserve during dobutamine in the hypertrophied LV myocardium in DOCA pigs.

Due to increased D-wave peak velocities in the DOCA group, the pulmonary venous S/D ratio was significantly lower at rest in DOCA pigs than in control pigs. As LV relaxation is the main determinant of pulmonary venous flow [49, 50], observed pulmonary venous flow patterns in DOCA pigs again indicate altered LV relaxation. The observed failing of systolic and diastolic pulmonary venous peak velocities to increase during stress in the DOCA group could be due to a mild LA pressure increase [17, 50], which could in turn be related to the increased E/E’ in DOCA animals.

LV torsion is known to be dependent on LV shape, and in LV concentric hypertrophy increased torsion is due to an increased lever arm for epicardial fibers [51]. Accordingly, torsion and systolic torsion rate_max were higher in DOCA than control pigs. Diastolic torsion rate_min significantly increased during ?-adrenergic stimulation in the control group, indicating that intraventricular pressure gradients appropriately increased [52]. In DOCA animals, the difference in torsion rate_min between stress and rest failed to properly increase; this failure relates to reduced intraventricular pressure gradients and impairment of LV relaxation [53].