Functional adaptations of the coronary microcirculation to anaemia in fetal sheep

Abstract

Key points: In fetuses, chronic anaemia stimulates cardiac growth; simultaneously, blood flow to the heart muscle itself is increased, and reserve blood flow capacity of the coronary vascular bed is preserved. Here we examined functional adaptations of the capillaries and small blood vessels responsible for delivering oxygen to the anaemic fetal heart muscle using contrast-enhanced echocardiography. We demonstrate that coronary microvascular flux rate doubled in anaemic fetuses compared to control fetuses, both at rest and during maximal flow, suggesting reduced microvascular resistance consistent with capillary widening. Cardiac fractional microvascular blood volume was not greater in anaemic fetuses, suggesting that growth of new microvascular vessels does not contribute to the increased flow per volume of myocardium. These unusual changes in microvascular function during anaemia may indicate novel adaptive strategies in the fetal heart.

Abstract: Fetal anaemia causes cardiac adaptations that have immediate and life-long repercussions on heart function and health. It is known that resting and maximal coronary conductance both increase during chronic fetal anaemia, but the coronary microvascular changes responsible for the adaptive response are unknown. Until recently, technical limitations have prevented quantifying functional capillary-level adaptations in the in vivo fetal heart. Our objective was to characterise functional microvascular adaptations in chronically anaemic fetal sheep. Chronically instrumented fetuses were randomized to a control group (n = 11) or were made anaemic by isovolumetric haemorrhage (n = 12) for 1 week prior to myocardial contrast echocardiography at 85% of gestation. Anaemia augmented cardiac mass by 23% without changing body weight. In anaemic fetuses, microvascular blood flow per volume of myocardium was twice that of control fetuses at rest, during vasodilatory hyperaemia, and during hyperaemia plus increased aortic pressure. The elevated blood flow was attributable almost entirely to an increase in microvascular blood flux rate whereas microvascular blood volumes were not different between groups at baseline, during hyperaemia, or with hyperaemia plus increased aortic pressure. Increased coronary microvascular flux rate in response to chronic fetal anaemia is consistent with expected reductions in capillary resistance from capillary diameter widening detected in earlier histological studies.

Keywords: coronary circulation; fetal anemia; fetal heart; microvascular imaging.

Figure 1. Baseline LV microvascular perfusion

Baseline microvascular volume (A) was not different between groups. Microvascular blood flux rate (B) in anaemic fetuses was twice that of control fetuses, thus LV microvascular flow (C) was also increased. As the rate–pressure product was not different between groups, microvascular flow per work (D) was almost doubled in anaemic fetuses. At low arterial oxygen contents, flow per work was elevated (E; open circles, control; filled circles, anaemic), thus oxygen delivery per work (F) was not different between groups. ^*Different from control (P < 0.05). Values shown as mean ± SEM (control, n = 10–11; anaemic, n = 12).

Figure 2. LV microvascular perfusion during hyperaemia

During adenosine‐mediated coronary vasodilatation, microvascular volume (A) was not different between groups. Microvascular blood flux rate (B) in anaemic fetuses was twice that of control fetuses. Hence, microvascular flow (C) and conductance (D) were elevated. ^*Different from control (P < 0.05). Values shown as mean ± SEM (control, n = 5; anaemic, n = 6).

Figure 3. LV microvascular perfusion during hyperaemia and elevated perfusion pressure

During occluder‐mediated elevation of perfusion pressure with simultaneous adenosine‐mediated coronary vasodilatation, LV microvascular volume (A) remained similar between control and anaemic fetuses. Both microvascular blood flux rate (B) and flow (C) in anaemic fetuses were more than twice that in control fetuses. Perfusion pressure was not different between groups, thus LV microvascular conductance (D) doubled in anaemic fetuses. E, demonstration of the relationship between pressure (aortic (Ao) minus right atrial (RA)) and microvascular hyperaemic flow in anaemic and control fetuses. Perfusion pressures were similar between groups at the two different points. ^*Different from control (P < 0.05). Mean and raw data shown (control, n = 2; anaemic, n = 2).