David D. Laxson

Effects of adenosine on human coronary arterial circulation.

Adenosine is a potent vasodilator used extensively to study the coronary circulation of animals. Its use in humans, however, has been hampered by lack of knowledge about its effects on the human coronary circulation and by concern about its safety. We investigated in humans the effects of adenosine, administered by intracoronary bolus (2-16 micrograms), intracoronary infusion (10-240 micrograms/min), or intravenous infusion (35-140 micrograms/kg/min) on coronary and systemic hemodynamics and the electrocardiogram. Coronary blood flow velocity (CBFV) was measured with a 3F coronary Doppler catheter. The maximal CBFV was determined with intracoronary papaverine (4.5 +/- 0.2.resting CBFV). In normal left coronary arteries (n = 20), 16-micrograms boluses of adenosine caused coronary hyperemia similar to that caused by papaverine (4.6 +/- 0.7.resting CBFV). In the right coronary artery (n = 5), 12-micrograms boluses caused maximal hyperemia (4.4 +/- 1.0.resting CBFV). Intracoronary boluses caused a small, brief decrease in arterial pressure (similar to that caused by papaverine) and no changes in heart rate or in the electrocardiogram. The duration of hyperemia was much shorter after adenosine than after papaverine administration. Intracoronary infusions of 80 micrograms/min or more into the left coronary artery (n = 6) also caused maximal hyperemia (4.4 +/- 0.1.resting CBFV), and doses up to 240 micrograms/min caused a minimal decrease in arterial pressure (-6 +/- 2 mm Hg) and no significant change in heart rate or in electrocardiographic variables. Intravenous infusions in normal patients (n = 25) at 140 micrograms/kg/min caused coronary vasodilation similar to that caused by papaverine in 84% of patients (4.4 +/- 0.9.resting CBFV). At submaximal infusion rates, however, CBFV often fluctuated widely. During the 140-micrograms/kg/min infusion, arterial pressure decreased 6 +/- 7 mm Hg, and heart rate increased 24 +/- 14 beats/min. One patient developed 1 cycle of 2:1 atrioventricular block, but otherwise, the electrocardiogram did not change. In eight patients with microvascular vasodilator dysfunction (delta CBFV, less than 3.5 peak/resting velocity after a maximally vasodilating dose of intracoronary papaverine), the dose-response characteristics to intracoronary boluses and intravenous infusions of adenosine were similar to those found in normal patients.(ABSTRACT TRUNCATED AT 400 WORDS)

Evidence for structural sympathetic reinnervation after orthotopic cardiac transplantation in humans

BackgroundCardiac transplantation (CT) causes total cardiac denervation. Methods and ResultsTo test directly for sympathetic reinnervation in humans, we measured the cardiac release of norepinephrine (NE) in response to tyramine (an agent that causes NE release from intact sympatheticnerve terminals) and sustained handgrip exercise (a reflex sympathetic stimulus) in 12 patients less than 5 months after CT, in 50 patients 1 year or more after CT, and in eight patients without CT. Plasma [NE] was measured in the aorta ([NE]A0) and coronary sinus ([NE]cs) at rest, after tyramine administration (55 μg/kg, i.v.), and during sustained handgrip exercise. Cardiac NE release was determined by subtracting [NE]AO from [NE]cs ([NE]cs-AO). NE release was defined as [NE]cs-AO during the intervention — [NE]cs-AO at rest (Δ[NE]cS-AO). In patients studied within 5 months of CT, no significant NE release occurred after tyramine administration (Δ[NE]cS-AO, 33±18 pg/ml; range, -98 to 117 pg/ml) or handgrip exercise (Δ[NE]cs-Ao, -34±10 pg/ml; range, -46 to 8 pg/ml; n = 10). Conversely, in 39 of 50 patients studied 1 year or more after CT, tyramine administration caused a significant cardiac NE release (Δ[NE]cs-AO, 500±59 pg/ml; range, -11 to 1,918 pg/ml), and handgrip exercise caused a significant NE release in 17 of 41 patients (Δ[NE]cs-Ao, 189±34 pg/ml; range, -211 to 949 pg/ml). In normally innervated patients, tyramine caused an even larger NE release (Δ[NE]AO-cs, 1,943±210 pg/ml; range, 1,152 to 2,977 pg/ml), and handgrip exercise caused a significantNE release in two of seven patients (Δ[NE]cs-AO, 143±51 pg/ml; range, -15 to 338 pg/ml). ConclusionsEarly after CT, neither tyramine nor handgrip exercise caused a significant cardiac release of NE, suggesting sympathetic denervation. Late after CT, most patients had a significant, but subnormal, NE release in response to pharmacological or reflex stimuli, suggesting that limited sympathetic reinnervation occurs in most patients after orthotopic CT.

INTENSE MICROVASCULAR CONSTRICTION AFTER ANGIOPLASTY OF ACUTE THROMBOTIC CORONARY ARTERIAL LESIONS

Immediately after balloon dilation of a fresh thrombotic coronary lesion, 5 patients had angina, ST segment elevation, and a striking reduction of blood flow in the dilated artery. A mean (SEM) pressure gradient across the dilated lesion of only 3(1) mm Hg and an average minimum lesion diameter of 1.7 mm indicated that the decline in resting blood flow was not due to obstruction at the site of the original lesion. Neither distal vascular emboli nor side branch occlusions were visible on the angiogram. An increase in distal coronary artery pressure during a subsequent balloon inflation suggested that the site of vasoconstriction was distal to the origin of collateral vessels. The syndrome lasted 48-80 min and was not reversed with nitroglycerin or thrombolytic drugs. Papaverine lessened the syndrome transiently on one occasion. Such microvascular constriction, caused by release of potent vasoconstrictors from the clot, may partly explain the failure of emergency angioplasty to reduce infarct size in acute myocardial infarction.

Regional differences in sympathetic reinnervation after human orthotopic cardiac transplantation.

BackgroundIn the majority of humans 21 year after cardiac transplantation, cardiac norepinephrine (NE) stores reappear, suggesting late sympathetic reinnervation. Methods and ResultsTo determine whether there are regional differences in reinnervation, we measured markers of sympathetic reinnervation of the sinus node (SN) and left ventricle (LV) in five early transplant recipients (c4 months after cardiac transplantation), 45 late transplant recipients (21 year after cardiac transplantation), and seven normally innervated control patients. SN reinnervation was defined as an increase in heart rate by more than five beats per minute after injection of tyramine into the artery supplying the SN. LV reinnervation was defined as a measurable LV NE release after left main coronary injection of 8

Oxygen consumption and coronary reactivity in postischemic myocardium.

μg/kg tyramine. In 13 patients with previously known LV reinnervation, regional LV reinnervation was assessed by NE release after subselective injection of tyramine (4

The role of alpha 1- and alpha 2-adrenergic receptors in mediation of coronary vasoconstriction in hypoperfused ischemic myocardium during exercise.

μg/kg) into the proximal left anterior descending and circumflex arteries. Five of five patients <4 months after cardiac transplantation had no change in heart rate and no LV NE release, confirming early, total denervation. In contrast, .1 year after cardiac transplantation, tyramine caused a heart rate increase (eight to 49 beats per minute) in 32 of 45 patients and LV NE release in 33 of 45. Although LV NE release was correlated with the change in heart rate in late cardiac transplantation recipients (r=.61), eight of 45 had only heart rate response, nine had onl LV NE release, and four had neither. In late cardiac transplantation recipients with LV reinnervation, tyramine caused NE release from both the anterior descending and circumflex perfusion fields in 10 of 14, but one of 14 patients released NE only after circumflex tyramine and three of 14 only after left anterior descending tyramine stimulation. Tyramine caused a marked heart rate increase and LV NE release in all control patients. ConclusionsSympathetic reinnervation after cardiac transplantation is regionally heterogeneous. SN reinnervation is not associated necessarily with LV reinnervation, and LV reinnervation can involve the anterior and posterior walls together or separately.

Effect of exercise intensity and duration on regional function during and after exercise-induced ischemia.

Coronary vascular responses in regions of reversible postischemic myocardial contractile dysfunction (stunned myocardium) were examined in chronically instrumented, awake dogs. Left anterior descending coronary artery blood flow and oxygen extraction, aortic and left ventricular pressures, and regional myocardial segment shortening were determined. Regional myocardial blood flow was measured with microspheres. Coronary reactive hyperemia and vasodilator reserve, and regional myocardial oxygen consumption were determined. Three sequential 10-minute left anterior descending coronary artery occlusions separated by 30-minute reperfusion periods resulted in progressive postischemic dysfunction so that 1 hour after the final coronary artery occlusion, myocardial segment shortening was reduced to 37% of baseline. Despite this decrease in contractile function, left anterior descending artery flow (19.6±2.6 vs. 18.4±3.0 ml/min), myocardial blood flow and the transmural distribution of flow measured with microspheres, and regional myocardial oxygen consumption were unchanged. Although the coronary vasodilator reserve hi response to adenosine was unaltered (63±9 vs. 70±15 ml/min), the reactive hyperemia response to a 10-second coronary occlusion was decreased in intensity (debt repayment ratio=474±78% vs. 322±74%; p<0.05) and duration (57±9.1 vs. 35±4.5 seconds; p<0.05), while the peak flow response was unchanged (57±6.8 vs. 60±7.1 ml/min). Thus, in the intact awake animal postischemic myocardial contractile dysfunction was not associated with decreased myocardial oxygen consumption and did not impair the normal relation between coronary blood flow and myocardial oxygen utilization. Although coronary vessels showed a normal ability to vasodilate in response to adenosine, coronary reactive hyperemia was reduced.

Effect of serotonin and thromboxane A2on blood flow through moderately well developed coronary collateral vessels

This study was carried out to test the hypothesis that adrenergic coronary vasoconstriction limits blood flow to hypoperfused regions of myocardium during exercise. The vasoconstrictor influence of alpha-adrenergic receptor subtypes was assessed by use of selective adrenergic blocking agents. Dogs chronically instrumented with a circumflex coronary artery hydraulic occluder and an intra-arterial catheter underwent treadmill exercise in the presence of a coronary stenosis that decreased distal perfusion pressure to 40 mm Hg. Myocardial blood flow was measured with radioactive microspheres (15 microns) before and during selective alpha 1- or alpha 2-adrenergic receptor blockade produced by intracoronary infusion of prazosin (1 microgram/kg/min x 10 min) or idazoxan (1 microgram/kg/min x 10 min), respectively. Coronary perfusion pressure was held equal before and during receptor blockade with the hydraulic occluder. Compared with control exercise, subendocardial blood flow increased during alpha 1-receptor blockade with prazosin from 0.60 +/- 0.14 to 1.12 +/- 0.17 ml/min/g (p less than 0.05), and mean transmural flow increased from 1.07 +/- 0.19 to 1.60 +/- 0.22 ml/min/g (p less than 0.05). In contrast, subendocardial and mean transmural blood flow were not different from control during selective alpha 2-adrenergic receptor blockade with idazoxan (0.48 +/- 0.10 vs. 0.67 +/- 0.14 ml/min/g, p = 0.33, and 0.82 +/- 0.15 vs. 1.02 +/- 0.20 ml/min/g, p = 0.45, respectively). These data indicate that even in the presence of a coronary stenosis that causes substantial myocardial underperfusion during exercise, residual coronary vasoconstrictor tone is present in ischemic myocardium, and this vasoconstriction is mediated predominantly by the alpha 1-adrenergic receptor.

Coronary vasodilator reserve in ischemic myocardium of the exercising dog.

BackgroundTransient reversible myocardial dysfunction has been documented after episodes of exercise-induced ischemia. This study was undertaken to determine whether the duration or intensity of exercise affects the severity of postischemic dysfunction in this setting. Methods and ResultsTen dogs were instrumented with ultrasonic microcrystals for measurement of wall thickening, with circumflex coronary artery flow probes, and with hydraulic occluders. Dogs performed low-intensity exercise, which was sufficient to increase coronary perfusion 50% above control, and high-intensity exercise, which was sufflicient to double coronary blood flow. To investigate the effects of exercise intensity on postischemic dysfunction, we had dogs perform high-intensity exercise for 5 minutes in the presence of a stenosis. On the alternate day, dogs performed low-intensity exercise for 10 minutes in the presence of a stenosis. These two protocols provide equivalent coronary flow debts. Mean transmural blood flow during high-intensity exercise without stenosis (2.61 ± t0.54 ml/min/g) was significantly higher than that during low-intensity exercise (1.74 ± 0.61 ml/min/g, p < c0.002). During highintensity exercise with coronary artery stenosis, subendocardial blood flow was significantly lower than that during low-intensity exercise with stenosis (0.64 ± 0.40 versus 1.08+0.28 ml/min/g, p < 0.02). This difference in subendocardial perfusion was associated with greater degrees of regional dysfunction during exercise (circumflex wall thickening was 44± 23% of control for high-intensity exercise versus 60 ± 18% of control for low-intensity exercise, p < 0.01). In addition, from 10 to 30 minutes after exercise, wall thickening in myocardium perfused by the circumflex coronary artery remained significantly lower after high-intensity exercise than that after low-intensity exercise. To assess the effects of exercise duration on the severity of postischemic dysfunction, we had dogs perform low-intensity exercise in the presence of a coronary stenosis for 10 minutes and low-intensity exercise for only 5 minutes on alternate days. Systolic wall thickening was significantly lower after low-intensity exercise for 10 minutes than after low-intensity exercise for 5 minutes. ConclusionsHigh-intensity exercise results in greater degrees of subendocardial hypoperfusion and greater degrees of regional dysfunction both during and after exercise-induced ischemia than does low-intensity exercise. Second, exercise duration also exerts an effect on the severity of postischemic dysfunction, although the magnitude of this effect is less important than the effect of exercise intensity. (Circulation 1991;83:2029—2037)

Recovery of transmural and subepicardial wall thickening after subendocardial infarction

This study was performed to determine whether thromboxane A2 (as the analogue U46619) and serotonin can cause vasoconstriction of moderately well developed coronary collateral vessels. Studies were carried out in seven adult mongrel dogs 2 to 4 months after embolic occlusion of the left anterior descending coronary artery had been performed to stimulate collateral vessel growth. At the time of study this artery was cannulated to determine interarterial collateral flow from measurements of retrograde blood flow. Radioactive microspheres were administered during retrograde flow collection to determine continuing tissue flow for evaluation of microvascular collateral communications. Serotonin (50 micrograms/min) resulted in a 48 +/- 11% decrease in retrograde flow (p less than 0.01), with a 36 +/- 10% decrease in total collateral blood flow (p less than 0.02). Infusion of U46619 (0.01 microgram/kg per min) caused a 38 +/- 13% decrease in retrograde blood flow (p less than 0.01), with a 34 +/- 13% decrease in total collateral flow (p less than 0.05). Serotonin caused a significant increase in tissue flow to the subepicardium of the collateral-dependent region, whereas U46619 caused no change in tissue blood flow. These data demonstrate that both serotonin and thromboxane A2 can cause vasoconstriction of interarterial coronary collateral vessels. The findings suggest that platelet activation in coronary arteries from which collateral vessels originate has potential for causing collateral vasoconstriction, thereby compromising blood flow to the dependent myocardium.