Birth is associated with substantial shifts in cardiovascular physiology. Little is known about coronary vascular adaptations during this period. We used fetal and neonatal lambs to measure coronary function at late gestation (92% of term) and shortly after birth (5–6 days postnatal age). In each animal we measured unanesthetized myocardial perfusion and oxygen delivery using a circumflex artery flow probe. We used inflatable occluders and adenosine to determine coronary conductance and flow reserve. In a subset of animals, we used myocardial contrast echocardiography (MCE, anesthetized) to assess its utility as a tool for studying changes in regional myocardial perfusion in normal development. Separate age‐matched animals were instrumented with aortic and coronary sinus sampling catheters to determine myocardial oxygen extraction (unanesthetized). With an average of 17 days of developmental time separating our neonatal and fetal cohorts we found that heart‐to‐body weight ratio was significantly greater in neonates than fetuses. In resting animals, we found significant decreases in weight‐normalized perfusion of, and oxygen delivery to, neonatal relative to fetal myocardium. Similar results were seen when measuring baseline MCE‐derived perfusion. Pressure‐flow relationship studies revealed lower baseline and maximal coronary conductance in neonates than fetuses, with similar coronary flow reserve between groups. There was greater oxygen extraction in neonates than fetuses. Combined analysis of oxygen extraction with coronary flow suggested greater oxygen consumption by the fetal than neonatal myocardium. We conclude that, during the immediate perinatal period, cardiac growth outpaces coronary microvascular growth resulting in lower capacity for microvascular perfusion in the early neonate.

New Findings What is the central question of this study?How does the microvascular perfusion of striated muscle change during the dynamic developmental period between the late gestation fetus and early neonate? What is the main finding and its importance?In both myocardium and skeletal muscle, perfusion of striated muscle is significantly reduced in the neonate compared to the late term fetus, but flow reserve is unchanged. The results suggest striated muscle capillary networks grow more slowly relative to the myofibres they nourish during the perinatal period. Abstract Microvascular perfusion of striated muscle is an important determinant of health throughout life. Birth is a transition with profound effects on the growth and function of striated muscle, but the regulation of microvascular perfusion around this transition is poorly understood. We used contrast‐enhanced ultrasound perfusion imaging (CEUS) to study the perfusion of left ventricular myocardium and hindlimb biceps femoris, which are populations of muscle with different degrees of change in pre‐ to postnatal workloads and different capacities for postnatal proliferative growth. We studied separate groups of lambs in late gestation (135 days’ gestational age; 92% of term) and shortly after birth (5 days’ postnatal age). We used CEUS to quantify baseline perfusion, perfusion during hyperaemia induced by adenosine infusion (myocardium) or electrically stimulated unloaded exercise (skeletal muscle), flow reserve and oxygen delivery. We found heart‐to‐body weight ratio was greater in neonates than fetuses. Microvascular volume and overall perfusion were lower in neonates than fetuses in both muscle groups at baseline and with hyperaemia. Flux rate differed with muscle group, with myocardial flux being faster in neonates than fetuses, but skeletal muscle flux being slower. Oxygen delivery to skeletal muscle at baseline was lower in neonates than fetuses, but was not significantly different in myocardium. Flow reserve was not different between ages. Given the significant somatic growth, and the transition from hyperplastic to hypertrophic myocyte growth occurring in the perinatal period, we postulate that the primary driver of lower neonatal striated muscle perfusion is faster growth of myofibres than their associated capillary networks.

The transition from fetal to neonatal life is among the most universal and rapid changes in physiology encountered in mammalian life. In this study, we sought to directly characterize the effects of birth on the function and capacity of the coronary vasculature in a large animal model of cardiac development. We hypothesized that significant increases in coronary reserve and oxygen delivery would accompany the increased demands placed on the myocardium by the challenges of postnatal life, including dramatic increases in pulmonary blood flow, left ventricular preload, and cardiac output. Near term fetuses (N = 7), and term‐born lambs (N = 5) of mixed western breed ewes were instrumented with catheters (aortic arch, right atrium, left atrium), inflatable occluders (inferior vena cava, postductal thoracic aorta), and a Transonic flow probe (left circumflex coronary artery). Studies (unanesthetized) were carried out at least 3 days later (135‐136 days gestation (term = 147 days)) or 5‐6 d postnatal. Pressure‐flow relationships were determined at rest or at maximal adenosine‐induced hyperemia. The mass of myocardium served by the artery from which flow was measured was determined by postmortem Evan's Blue perfusion; all reported flow values are normalized to this mass. Cardiac work is the double product of driving (aortic minus right atrial) pressure. We define coronary conductance as the slope of the pressure‐flow relationships, and coronary flow reserve as the fold change in coronary flow between resting and hyperemic conductance. Differences between fetuses and neonates were assessed by the Mann‐Whitney U‐test and considered significant when p < 0.05. Basal cardiac work was significantly greater after birth, as heart rate and driving pressure were 1.3 and 1.6‐fold greater in neonate than fetus (p = 0.009, p = 0.003, respectively). Resting coronary flow was 1.8‐fold lower in the neonate than the fetus (p = 0.048). Despite a 1.6‐fold increase in arterial blood oxygen content (p = 0.006), baseline oxygen delivery per work in the neonate was less than half that in the fetus (p = 0.005; Figure 1A). Pressure‐flow relationships (Figure 1B) likewise showed a reduction in coronary conductance from fetus to neonate both at rest (2.3‐fold, p = 0.073) and with adenosine hyperemia (2‐fold, p = 0.048). Estimated hyperemic coronary flow at resting daily pressures were decreased by 1.6‐fold in the neonate (p = 0.03). Coronary flow reserve was similar between fetuses and lambs (p = 1; Figure 1C). Despite the increased cardiac demands of postnatal life, these results suggest that there is not an increase in coronary reserve or capacity following birth. Rather, we find evidence of lower resting and maximal coronary flow in the postnatal period such that flow reserve is maintained. This evidence of an actively regulated decrease in coronary capacity shows the functional consequence of a known reduction in capillary to fiber ratio occurring in the myocardium between birth and maturity. Future studies of myocardial perfusion focusing on ...

Considerable changes are expected in the regulation of myocardial and limb skeletal muscle perfusion from the pre‐ to post‐natal condition based on changes in gravitational force, work load, and arterial O2 content. Yet the impact of birth on the growth and function of microvasculature in striated muscle is poorly understood. Our objective was to assess resting and maximal microvascular flow in the cardiac left ventricle (LV; with high workload before and after birth), and biceps femoris (BF; hindlimb muscle with little workload before birth). We hypothesized that resting flow in the fetus exceeds that in the neonate because of low fetal arterial O2 content, but that flow reserve is greater in the neonate in order to support ambulation. We expected this increase in reserve to be greater in skeletal than myocardial muscle. Fetuses (N=8) were instrumented at 130 d gestational age (dGA, birth is at 146 d) and studied exteriorized from the uterus at 135 dGA. Lambs (N=8) were instrumented 2 d after birth and studied at 5 d. Instrumentation included arterial, venous, and left atrial catheters for systemic pressure monitoring, arterial blood sampling, and drug delivery; and an inflatable occluder around the descending thoracic aorta. Myocardial perfusion (Q) in mL/min/g of tissue was assessed by transthoracic contrast echocardiography at rest, during adenosine‐induced hyperemia, and during combined hyperemia and increased perfusion pressure produced by transient constriction of the postductal aorta. Work was determined by the product of heart rate and perfusion pressure. Hindlimb BF muscle Q was assessed at rest, and during contractile work produced by electrostimulation (2 Hz, 10 mA). Differences were assessed by the Mann‐Whitney U‐test. One fetus and one lamb were excluded from analysis because of abnormal blood gasses at the time of study. At rest, LV myocardial Q was 2‐fold higher in fetuses than neonates (Fig 1A), as was Q normalized to work; whereas, O2 delivery was similar between groups (Fig 1B). Maximal flow during hyperemia followed a similar pattern, with fetal Q, as well as Q per work, exceeding that in the neonate by a factor of 7, whereas maximal O2 delivery per work was similar between age groups. Skeletal muscle (BF) flow in the fetus was highly variable both at rest and during exercise. Median resting Q, resting O2 delivery, and exercised flow were all at least 5‐fold higher in the fetus than neonate, however the difference only reached statistical significance for resting flow (Fig 1A,B). Exercise O2 delivery was similar between ages. Flow reserve was similar between the fetus and neonate in both myocardium and skeletal muscle (Fig 1C). At rest, elevated flow in the fetal LV supported similar levels of O2 delivery per work as found in the newborn. Surprisingly, there was a tendency for increased O2 delivery in the fetal skeletal muscle compared to the newborn; we speculate that this reflects differences in regulation of non‐nutritive flow between the ages studied. Overall, the results of this study sug...