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Journal of Physiology (2002), 547.1, pp. 53-59
© Copyright 2003 The Physiological Society
DOI: 10.1113/jphysiol.2002.023283
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ABSTRACT |
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Maximal coronary conductance with adenosine in anaemic fetal sheep is twice that of non-anaemic fetuses. To investigate whether this increase in conductance persists into adulthood we studied twin sheep as fetuses and again as adults. Nine anaemic fetuses (118 days gestation) underwent isovolaemic haemorrhage for 18.0 ± 4.6 days (means ± S.D.) during which time the haematocrit was reduced from 39.9 ± 5.2 % to 16.3 ± 3.4 % and oxygen content from 8.6 ± 1.3 to 2.3 ± 0.2 ml dl-1. At 138 days the anaemic fetuses were transfused; at delivery the haematocrit was 29.3 ± 6.8 % compared to nine control fetuses in which the haematocrit was 38.5 ± 4.3 %. The weight at delivery was 3.5 ± 0.36 kg in the anaemic fetuses vs. 4.2 ± 0.83 kg in controls. Twenty-eight weeks later, we placed an occluder on the descending thoracic aorta and inferior vena cava, a flow probe around the proximal left circumflex coronary artery, and catheters in the left atrial appendage, jugular and carotid vessels. Maximal coronary conductance was determined in the adults by recording coronary blood flow as driving pressure was altered by inflating the occluders while adenosine was infused into the left atrium. Right atrial, left atrial, systolic and mean arterial pressures, systemic vascular resistance and haematocrit were not different between 'in utero anaemic' and control adults. The adults that were anaemic in utero weighed less than the controls 39.4 ± 4.6 kg vs. 45.0 ± 5.6 kg. Maximal conductance was greater in the adults that were anaemic in utero: 11.2 ± 4.0 ml min-1 (100 g)-1 mmHg-1 as compared to 6.1 ± 1.8 ml min-1 (100 g)-1 mmHg-1 in the controls. Vascular reactivity of the mesenteric arteries was not different. These data suggest that coronary conductance can be modified in utero by anaemia (high flow and hypoxaemia) and that the remodelled coronary tree persists to adulthood.
(Received 24 April 2002; accepted after revision 9 July 2002; first published online 18 October 2002)
Corresponding author L. Davis: Department of Obstetrics and Gynecology, Oregon Health Sciences University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239-3098, USA. Email: davislo{at}ohsu.edu
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INTRODUCTION |
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It is now well established that the risk for coronary disease in adulthood is much higher in individuals that were born small at term compared to their large-at-term counterparts (Barker, 2000). One of the cardinal features of babies born at the small end of the weight spectrum is their propensity for having abnormal placental flow and accompanying hypoxaemia. In an attempt to understand the role of a low oxygen state in remodelling the coronary tree we have studied maximal coronary conductance in adult sheep that were made anaemic only during intrauterine life.
Maximal coronary conductance is the slope of the relationship between myocardial blood flow during maximal vasodilatation with adenosine infusion and coronary perfusion pressure (Hoffman, 1984; Thornburg & Reller, 1999). It is a physiological measure of the total resistance vessel area of the coronary circulation and therefore can be used to index vascular growth of resistance vessels. In the adult, it has been suggested that maximal coronary conductance once established does not increase (Hoffman, 1984). For example, in response to an increase in afterload accompanied by left ventricular hypertrophy in adult studies, several reports have shown that coronary conductance decreases (Bache et al. 1986; Flanagan et al. 1994; Dunker et al. 1995; Kalkman et al. 1996). This fall in conductance is not well understood and is ascribed to either vascular rarefication as myocyte growth outstrips resistance vessel growth, medial hypertrophy of resistance vessels leading to decreased conductance or functional vascular changes secondary to increased transmission of pressure. Others have found that although coronary reserve is decreased, arteriolar density is not changed despite an increase in left ventricular mass, suggesting a relative increase in arteriolar length density (Bishop et al. 1996). None, however, have found an increase in maximal coronary conductance in the adult.
In contrast, in the perinatal period the coronary vasculature appears to exhibit significant plasticity. Maximal coronary flow in response to adenosine when expressed per unit weight of heart normally decreases with increasing age, being higher in the fetus than in the newborn, and lower in the adult (Toma et al. 1985; Flanagan et al.1994; Davis et al. 1999). This has direct functional implications because after aortic banding in 4-week-old lambs, coronary conductance is maintained, whereas banding in adult sheep results in a 67 % decrease in left ventricular coronary conductance (Flanagan et al. 1994). However, in fetal sheep, under conditions of anaemia (hypoxaemia and increased flow) as well as during direct infusion of adenosine (normoxaemia and increased flow), remodelling of the coronary vasculature occurs and coronary conductance significantly increases (Davis et al. 1999; Wothe et al. 2002). Taken together, these data suggest that if challenged during a period of rapid growth, the coronary vasculature may be capable of increasing conductance. It is unknown, however, whether a relative increase in conductance in the immature heart will persist in the adult once the challenge causing the initial change is no longer present. To answer this question we studied twin fetal sheep, one of which was made temporarily anaemic prior to delivery. At 7 months of age coronary conductance was measured in both 'in utero anaemic' and non-anaemic twins. In order to determine if durable changes occur in a vascular bed other that the coronary system, vascular reactivity studies were also performed in mesenteric arteries.
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METHODS |
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General anaesthesia was induced in 12 ewes at 117-119 days gestation with intravenous diazepam and maintained with 1.5 % halothane and nitrous oxide-oxygen (1:1) as previously described (Davis et al. 1991, 1999). All animal procedures were reviewed and approved by the Oregon Health Sciences University Institutional Animal Care and Use Committee. Following a midline peritoneal incision, the right side of the fetal neck was exposed through a uterine incision. A polyvinyl catheter, V8 (1.19 mm i.d.) was placed in the carotid artery in each twin and advanced into the ascending aorta. The ear of the first twin selected was notched and the catheter marked for identification. The uterine incision was closed and the catheters tunnelled to a pouch on the ewe's flank. One million units of penicillin were given in the amniotic space.
Fetal protocol
Blood gases, oxygen content and haematocrit were measured by an Instrumentation Laboratories (IL; Lexington, MA, USA) 482 CO-Oximeter and IL 1610 pH Blood Gas analyser calibrated at 39 °C and one twin was selected for isovolaemic haemorrhage, starting on the day following surgery. On a daily basis initially, 25-100 ml of blood was rapidly withdrawn from the 'anaemic' twin and replaced with an equal volume of normal saline as previously described (Davis et al. 1999). The withdrawn blood was stored in sterile citrate phosphate dextrose adenine solution to which penicillin was added. A goal to maintain the haematocrit at less than 50 % of the initial value for approximately 10 days was chosen. Arterial blood gases, arterial pH, arterial oxygen content and haematocrit were measured prior to each haemorrhage and volume replacement in the anaemic twin. Arterial blood gases, arterial pH, arterial oxygen content and haematocrit were measured approximately every 4 days in the control twin. At 138 days, the anaemic twin was transfused with approximately 120 ml of stored packed red blood cells through a Pall rcxl 1 high-efficiency leukocyte filter (Pall Biomed, East Hills, NY, USA) to remove aggregate material. The day following spontaneous delivery, the lambs were weighed, haematocrit and venous blood gas were measured and 1 ml of iron dextran containing 100 mg of elemental iron (Bulter Company, Columbus OH, USA) was given intramuscularly. A week later the lambs and ewes were returned to the farm to be raised in the usual fashion.
Adult protocol
At approximately 7 months of age, the fully grown sheep were returned from the farm. General anaesthesia was induced in 10 control and 9 'in utero anaemic' adults with intravenous diazepam and maintained with 1.2 % halothane and nitrous oxide-oxygen (1:1). Two V8 catheters were placed in the jugular vein and advanced to the right atrium. A V8 catheter was placed in the carotid artery and advanced to the aorta. An abdominal incision was made and a section of omentum containing several arterial segments was removed for myograph studies. The abdominal incision was then closed. The descending thoracic aorta was mobilized by blunt dissection through a left fourth intercostal thoracotomy and a 10 mm inflatable vascular occluder (In Vivo Metric Systems, Heraldsburg, CA, USA) was placed around the descending thoracic aorta distal to the ligamentum arteriosus. A second inflatable vascular occluder (8 mm) was placed around the inferior vena cava above the diaphragm. The pericardial sac was opened and two V5 catheters with 4 mm-long V8 tips were placed in the left atrial appendage. A Transonic flow probe 3S (Transonic Systems, Ithaca, NY, USA) was placed on the proximal left circumflex coronary artery. The thoracotomy incision was covered but remained open during the remainder of the study. The halothane inhalation was discontinued to limit myocardial depression, and for the remainder of the study anaesthesia was maintained with a fentanyl intravenous infusion at 416 µg min-1 with intermittent boluses of ketamine and nitrous oxide 1:1 with oxygen via the ventilator. Baseline hydrostatic pressures including aortic arterial, right atrial and left atrial pressures, were measured with Transpac transducers (Abbott Critical Care Systems, Chicago, IL, USA) that were calibrated prior to use with a manometer and zeroed to atmosphere at the level of the right atrium. The pressures, flow signal and heart rate were recorded with a TA-6000 chart recorder (Gould, Valley View, OH, USA) and stored on-line using a MacADIOS equipped Apple Macintosh 8100-100AV computer and Superscope II software (GW instruments, Somerville, MA, USA). Mean blood pressures and the signal from the Transonic flowprobe were sampled every 10 ms, averaged every 250 ms and recorded over ~60 s. Aortic arterial blood gases and oxygen content were measured. Propranolol (2 mg) and atropine (2 mg) were given intravenously and the aortic arterial blood gases, oxygen content measurements and haemodynamic measurements were repeated. Propranolol and atropine blockade were used to minimize baroreceptor-induced heart rate changes during the subsequent pressure flow studies.
Left circumflex coronary artery arterial blood flow was first measured in response to coronary arterial pressure changes without adenosine (saline conductance) by slowly inflating either the inferior vena cava or thoracic aortic occluder over 15 s in a randomized order, releasing the occluder and waiting until flow and pressure returned to baseline, and then inflating the second occluder. The entire procedure could generally be accomplished in 1 min. Following a recovery period, a dose-response curve to adenosine was generated by increasing the adenosine infusion (5 mg ml-1) infused in the left atrium in steps until maximal circumflex coronary artery flow was reached. The lowest infusion rate that produced maximal steady state vasodilatation was then selected for use in determining coronary conductance relationships.
The pressure-flow relationship during maximal steady state vasodilatation with adenosine was then recorded by inflating in random order either the aortic or inferior vena caval occluder followed by the other occluder.
A 16R Transonic flow probe was then placed around the pulmonary artery and haemodynamic pressures and pulmonary artery flow were recorded. Heparin was injected into the sheep, following which the sheep was killed with an intravenous injection of sodium pentobarbital. The heart was dissected from the chest cavity. A needle with a blunt end was secured in the proximal circumflex coronary artery at the site where the flow probe had been placed earlier, and the artery was then injected slowly with Evan's blue dye to demarcate the proximal circumflex coronary artery distribution. The myocardium supplied by the circumflex coronary artery was dissected from the other myocardium and weighed. One investigator performed all of the dye perfusions and dissections and did not know to which group the tissue belonged. One control was excluded from analysis due to an unsatisfactory perfusion. Thus, haemodynamic data were obtained in nine adults that were anaemic in utero and in nine controls.
Pressure-flow relationships were described by linear regression in order to interpolate resting blood flow at 90 mmHg. Flow was expressed per 100 g of perfused tissue. Coronary reserve at 90 mmHg was determined as the difference between left ventricular blood flow interpolated at 90 mmHg under resting conditions and during adenosine infusion. Data such as haemodynamic data taken at baseline and after blockade, coronary reserve, the slope of the adenosine conductance, and maximum flow at a pressure of 90 mmHg between control and 'in utero anaemic' sheep were compared using t tests. All data are presented as means ± S.D. and considered significant at P < 0.05.
Isolated vessel protocol
To evaluate the mesenteric arteries, a large section of the mesenteric artery bed was cut out from the omental segment, immersed in physiological saline solution and used to prepare two arterial segments per animal, 1-3 mm in length; 250-350 µm in diameter. These segments were carefully cleaned from fat, mounted in a dual channel wire myograph capable of measuring isometric tension and bathed in a physiological salt solution maintained at pH 7.4 with a 5 %-95 % CO2-O2 gas mixture. The arterial wall thickness was measured with a micrometer eyepiece and a microscope after stretching the arteries to achieve 80 % of the lumen diameter that the arteries had at a transmural pressure of 100 mmHg (Mulvany et al. 1977; Roullet et al. 1995). All preparations were subjected to a conditioning procedure which involved five consecutive stimulations with potassium chloride buffer (100 mM) and noradrenaline (norepinephrine; NA, 10 µM).
The reactivity to potassium chloride (5-100 mM), NA (10 nM- 0.1 mM) and 10-8 M angiotensin II was first examined. Then the arteries were precontracted with NA (70 % of maximal contraction established from the NA dose-response curve) and challenged with vasodilatory agonists: acetylcholine (0.1 nM- 30 µM), adenosine (0.1 nM-10 µM), calcium (1.5-5.0 mM) and sodium nitroprusside (10 nM-30 µM). Each agonist was assayed individually by cumulative addition and after extensive washout of the previous agonist to allow return to baseline. The response to vasoconstrictors was expressed as active stress in mN mm-2, whereas relaxation was expressed as a percentage of the precontraction level (Roullet et al. 1995). The data from the two arterial segments were averaged. Results are presented as mean ± S.D., with n = 9 and 10 animals in the 'in utero anaemic' and control groups, respectively.
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RESULTS |
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The gestational age, and aortic arterial blood gases, oxygen content and haematocrit on the first post-operative day were similar in both control and 'in utero anaemic' groups at the start of the study (Table 1). The anaemic fetuses were haemorrhaged for 18.0 ± 4.6 days before transfusion at 138 days with a volume transfused of 139 ± 46.1 ml. As expected, the anaemic fetuses reached a nadir in oxygen content of 2.3 ml dl-1 and haematocrit of 16.3 % that was less than that of the control non-haemorrhaged fetuses in which the oxygen content was 8.6 ml dl-1 and haematocrit 38.2 %, both P < 0.01. The anaemic fetuses were transfused with 139 ± 46.1 ml of stored blood prior to delivery. The haematocrit level the day after delivery was 29.3 ± 6.8 % in the transfused animals versus 38.5 ± 4.3 % in the controls (P < 0.01). The birth weight of the 'in utero anaemic' group was less than that of the controls (3.5 ± 0.36 kg vs. 4.2 ± 0.83 kg, P < 0.05).
Both 'in utero anaemic' and control groups were studied at 7 months of age (Table 2). The haematocrit of the 'in utero anaemic' (26.4 ± 2.6 %) and control (27.1 ± 2.8 %) groups at the time of the final surgery as well as arterial blood gases and oxygen content were not different. The weight of the adults that were anaemic as fetuses remained less than the control (39.4 ± 4.6 kg vs. 45.0 ± 5.6 kg, P < 0.05). Mean arterial, systolic, diastolic, left atrial, right atrial pressure and heart rate under anaesthesia were not different between the two groups. Resting left ventricular blood flow was not different between the two groups before blockade: 103.4 ± 58.2 in the controls vs. 148.3 ± 41.8 ml min-1 (100 g left ventricle)-1, nor after blockade with atropine and propranolol: 89.3 ± 40.2 in the controls vs. 118.2 ± 47.4 (100 g left ventricle)-1. Furthermore, after blockade all other haemodynamic values were not different between the two groups.
The dose of adenosine infused to study the maximal coronary conductance was not different in either group and averaged 66.3 µg min-1 (kg body weight)-1. A representative example of coronary pressure flow relationships during saline infusion and during maximal adenosine infusion is shown in Fig. 1. Following dissection, the heart weights and heart/body weight ratios were not different between the in utero, 'in utero anaemic' and control groups. Resting blood flow interpolated at 90 mmHg during saline infusion was 96 ± 36.8 in the controls vs. 121 ± 50.7 ml min-1 (100 g left ventricle)-1in the 'in utero anaemic' group and was not significantly different. At 90 mmHg, the interpolated blood flow during adenosine infusion was 483 ± 168.6 in the controls vs. 815 ± 323.2 ml min-1 (100 g left ventricle)-1 (P < 0.02) in the 'in utero anaemic' group. Thus, the coronary reserve (the difference between saline and adenosine infusion interpolated at 90 mmHg) between the two groups was different, 407 ± 150.1 vs. 695 ± 282.2 ml min-1 (100 g)-1 (P < 0.03, Fig. 2). Finally, maximal coronary conductance measured during adenosine infusion was 6.1 ± 1.8 ml min-1 (100 g)-1 mmHg-1 in the control adults and 11.2 ± 4.0 ml min-1 (100 g)-1 mmHg-1 (P < 0.01) in the adults that were anaemic in utero.
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Figure 1. Coronary pressure-flow relationships Representative example of coronary pressure-flow relationships without adenosine (saline conductance) and with maximal adenosine infusion (adenosine conductance). | ||
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Figure 2. Interpolated flow at 90 mmHg Left ventricular coronary blood flow interpolated from pressure-flow relationships at 90 mmHg. Resting blood flow, blood flow in response to adenosine and the difference, which represents coronary reserve in adult sheep. Control, n = 9; anaemic, n = 8. | ||
Arterial wall thickness and lumen diameter of the mesenteric arteries were similar in both groups: 27.3 ± 1.6 and 295.1 ± 12.2 µm in the controls vs. 26.1 ± 1.6 and 283.4 ± 9.6 µm in the 'in utero anaemic' group. The results of the vascular reactivity experiments are summarized in Table 3. The reactivity of the mesenteric arteries to angiotensin II, potassium chloride, noradrenaline, acetylcholine, adenosine, extracellular calcium or sodium nitroprusside was not different.
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DISCUSSION |
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The major finding of this study was the observation that maximal coronary conductance and coronary reserve in sheep that were anaemic in utero was greater than in adult sheep that were not anaemic in utero. In this study we have defined maximal coronary conductance as the slope of the pressure-flow relationship during maximal chemical vasodilatation with adenosine (Hoffman, 1984). This is useful as it allows the determination of coronary reserve if resting blood flow is known. Thus, maximal coronary conductance differs from the ordinary use of the term 'coronary conductance', which is simply the inverse of resistance. These data follow a previous study in which coronary conductance was nearly doubled in fetuses made anaemic over a 1 week time period (Davis et al. 1999). Data reported here indicate that the relationship was thus maintained into adulthood. Similarly, in fetuses in which coronary flow was increased without hypoxaemia by chronic intracoronary adenosine infusion, coronary conductance was also increased (Wothe et al. 2002). These data are summarized in Fig. 3. In interpreting measurements of coronary conductance across development it is important to note that maximal coronary blood flow when expressed per unit weight of heart has been shown to decrease with age, being higher in the fetus than the newborn, and lower in the adult (Toma et al. 1985; Flanagan et al. 1994; Davis et al. 1999; Dalshaug et al. 2002). This is thought to reflect postnatal decreased capillary density (Smolich et al. 1989) and increased vascular resistance accompanied by increases in arterial blood oxygen content and arterial blood pressure. Finally, the coronary conductance values we observed in the adult sheep which were not anaemic in utero, were similar to previously reported values (Flanagan et al. 1994).
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Figure 3. Maximal coronary conductance during adenosine infusion Results are shown from the fetus (anaemic and control; Davis et al. 1999), the fetus infused with chronic adenosine to increase coronary blood flow without hypoxaemia (chronic adenosine and control; Wothe et al. 2002) and in adults that were anaemic as fetuses (anaemic adult and control, present study). Data presented as means ± S.D. | ||
We did not remeasure the haematocrit past the first day of life until 7 months had passed. We therefore do not know at what point the haematocrit normalized in the 'in utero anaemic' group, as the haematocrit was lower than for the control group on the first day of life despite transfusion prior to birth. As the anaemic fetuses were transfused with packed red blood cells prior to delivery, and all newborn lambs received iron supplementation, it is likely that iron stores were replenished. Others have shown that fetal sheep that were haemorrhaged of 40 % of their blood volume and were not supplemented with iron nearly restored their haematocrit within 10 days (Gruslin-Giroux et al. 1997). It is therefore likely that the anaemia did not extend beyond the first weeks of life postnatally.
We were not surprised that the vascular reactivity in the mesenteric arteries did not differ between the two groups, nor did the response to adenosine differ in the mesenteric arteries. We hypothesized that the responsiveness of systemic (omental) arteries would not be different, as the flow rate in response to fetal anaemia of systemic vessels is significantly less than in the myocardial circulation (Davis et al. 1991). Due to the differences in oxygen extraction between these tissues, when the haematocrit was reduced to 13 %, resting blood flow to the large intestine only increased 2.5-fold while coronary blood flow increased 5-fold (Davis et al. 1991). Thus vascular remodelling in response to intrauterine events may be different in various tissues. The vascular reactivity of the coronary arteries was not studied because the injection of Evan's blue that was necessary to demarcate the perfused region of the myocardium altered the vascular responsiveness of the coronary vessels and made the study of coronary arteries impractical.
Several reports suggest that coronary conductance can be modified in the perinatal period. First, exercise training in young swine resulted in an initial increase in capillary density that subsequently normalized as the number of small (20-30 µm) arterioles increased (White et al. 1998). These investigators suggested that the 'extra' capillaries developed into arterioles. Second, after aortic banding in four-week-old lambs, coronary conductance as well as capillary density is maintained, whereas banding in adult sheep results in a 67 % decrease in left ventricular coronary conductance and 17 % decrease in capillary density (Flanagan et al. 1994). Third, there is the recent observation that in arterioles of female hearts transplanted into male recipients, 45 % of the smooth muscle cells show the presence of a Y chromosome. This suggests that under conditions of immunosupression and increased workload, (the female hearts were significantly smaller than the male recipient hearts) resistance vessels may be reprogrammed (Quaini et al. 2001). Taken together, these data suggest that under certain circumstances, the concept that maximal coronary conductance is fixed during adult life may need to be reconsidered.
Speculation
We have shown that the oxygen and haemodynamic environment during fetal life may alter the architecture of the coronary circulation for life. The physiological consequence is unknown. A coronary 'supertree' might be more able to compensate for hypoxic stresses. This may well be advantageous and represent the opposite side of the Barker hypothesis, not all events in utero leading to long term programming will be deleterious. Alternatively, because the resting blood flow is not different and the coronary reserve is greater, it implies that the adult coronary artery in an individual that was anaemic as a fetus is relatively vasoconstricted in comparison to its non anaemic twin. It is thus possible that the increased coronary blood flow that is present in the fetal anaemic heart may have a long term negative effect on endothelial function or vascular reactivity in the non-anaemic adult coronary vasculature. These issues are vital to our understanding of the role of the oxygen environment in programming for lifelong disease (Barker, 2000), and remain to be determined.
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Acknowledgements
This study was supported by the NHLBI grant HL45043 and NICHD grand P01HD34430.
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