Betsy V. Christensen

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.

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

Evidence for Functional Sympathetic Reinnervation of Left Ventricle and Coronary Arteries After Orthotopic Cardiac Transplantation in Humans

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

Myocardial perfusion reserve: assessment with multisection, quantitative, first-pass MR imaging.

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.

Accuracy of exercise electrocardiography in detecting physiologically significant coronary arterial lesions.

BACKGROUND Structural sympathetic reinnervation of the transplanted human heart is believed to occur > 1 year after cardiac transplantation. The functional effects of reinnervating neurons, however, are undefined. METHODS AND RESULTS To test directly for functional sympathetic reinnervation, we measured left ventricular or coronary hemodynamics in 11 patients < or = 4 months after transplantation, in 45 patients > or = 1 year after transplantation, and in 13 untransplanted, normally innervated patients. Sympathetic neurons were stimulated with left coronary injection of tyramine (10 micrograms/kg), which causes norepinephrine release from intact sympathetic nerve terminals. Reinnervation was defined as a measure of cardiac norepinephrine release after intracoronary tyramine injection. Left ventricular pressure was measured before and at 1-minute intervals after tyramine with a micromanometer-tipped catheter (Millar Instruments). Coronary blood flow velocity (CBFV) was measured with a 3F Doppler catheter (Numed), and coronary artery cross-sectional area was calculated using quantitative coronary angiography. In both early patients and patients studied > or = 4 months after transplantation without reinnervation (late denervated), there was no change in left ventricular function in response to tyramine (delta dP/dt = 31 +/- 61 and 49 +/- 54 mm Hg/s, respectively; P = NS). In transplant recipients with reinnervation (late reinnervated), left ventricular dP/dt rose significantly (delta dP/dt = 210 +/- 97 mm Hg/s; P < .05) but less than in healthy patients (delta dP/dt = 577 +/- 66 mm Hg/s; P < .05). In both early and late denervated patients, there was no change in CBFV in response to tyramine (CBFV = 1.02 +/- 0.1 and 1.0 +/- 0.1 x basal, respectively; P = NS). In late reinnervated patients, CBFV fell significantly (CBFV = 0.94 +/- 0.1 x basal; P < .05). In healthy patients, CBFV fell even more (CBFV = 0.88 +/- 0.1 x basal; P < .05). CONCLUSIONS Stimulation of reinnervating sympathetic neurons with tyramine in transplant recipients causes a significant but subnormal increase in dP/dt and a transient decrease in CBFV, suggesting that reinnervating sympathetic neurons can produce physiologically meaningful changes in left ventricular function and coronary artery tone.