Physiologic assessment of the coronary collateral circulation in transplanted human hearts.

Coronary arteries of transplanted hearts frequently develop a vasculopathy characterized by severe lumenal narrowing in the distal coronary arteries. It has been thought, on the basis of angiographic studies, that the coronary circulation of transplanted hearts with vasculopathy fails to develop collateral vessels normally. To determine the extent of the collateral circulation in transplanted hearts with a significant coronary stenosis, we measured an index of the collateral circulation, the coronary artery occlusion pressure, during single-vessel coronary angioplasty in seven patients with allograft vasculopathy and 18 patients with atherosclerotic disease who did not undergo transplantation. Aortic and coronary artery pressure distal to the stenosis in the epicardial artery were measured during balloon occlusion (> or = 45 seconds). Measurement variability for determination of coronary occlusion pressure was assessed by measuring occlusion pressure on two separate balloon inflations (n = 17). The severity of the dilated stenotic lesion was assessed with quantitative angiography (Reiber-PIE Data method). The indexes of stenosis severity were similar in coronary arteries of transplanted and native hearts. Coronary occlusion pressure measurements were highly reproducible (mean absolute difference between measurements, 1 +/- 1 mm Hg, r = 0.98). Coronary occlusion pressure in transplanted hearts (32 +/- 4 mm Hg) was nearly identical to that measured in coronary arteries of native hearts (29 +/- 2 mm Hg). When vessels with total occlusion were excluded and corrections were made for minor differences in hemodynamics (heart rate and blood pressure) were made, the coronary occlusion pressure in transplanted hearts remained nearly identical to native hearts.(ABSTRACT TRUNCATED AT 250 WORDS)

Interstudy variability of coronary flow reserve. Influence of heart rate, arterial pressure, and ventricular preload.

To define the long-term variability of serial coronary flow reserve (CFR) measurements in humans and to evaluate the influence of changes in heart rate, mean arterial pressure, and left ventricular preload on CFR, 45 patients with normal left ventricular function (38 cardiac allograft recipients, five patients with normal coronary arteries, and two patients with minimal coronary artery disease [less than 50% diameter stenosis]) were studied. CFR (ratio of peak hyperemic [h] to resting [r] coronary blood flow velocity [CBFV]) was measured with a 3F coronary Doppler catheter and intracoronary papaverine. Initial CFR measurements were highly correlated with repeat measurements obtained 11 +/- 0.6 months later (r = 0.95; mean absolute difference, 0.3 +/- 0.1; n = 17). Differences in CFR between studies were related to changes in heart rate (r = 0.61, p = 0.01) but not to changes in mean arterial pressure (r = 0.25, p = 0.33). To define the effects of rapid changes in heart rate, mean arterial pressure, and preload on CFR, these variables were altered by atrial pacing, handgrip exercise, and volume expansion, respectively. Atrial pacing produced a rate-related increase in rCBFV but did not change hCBFV. Consequently, CFR was significantly reduced as heart rate was increased progressively from 76 +/- 2 in sinus rhythm (4.5 +/- 0.2) to 100 (3.8 +/- 0.2, p less than 0.05, n = 32) to 120 beats/min (3.2 +/- 0.1, p less than 0.05, n = 7). Despite a 19 +/- 2 mm Hg rise in mean arterial pressure during handgrip exercise, CFR was unchanged from baseline (3.7 +/- 0.3 vs. 3.7 +/- 0.4, p = NS, n = 7) because rCBFV rose proportionally with hCBFV. When pulmonary capillary wedge pressure was increased from 9 +/- 1 to 16 +/- 1 mm Hg after volume expansion, CFR was significantly decreased (from 3.8 +/- 0.2 to 2.9 +/- 0.2, p less than 0.05, n = 9) because rCBFV was increased while hCBFV remained unchanged. Hence, serial CFR measurements in humans are highly reproducible in the absence of conditions known to affect resting or hyperemic coronary blood flow. Increases in heart rate or preload reduced CFR because rCBFV was increased while hCBFV was unchanged. In contrast, changes in mean arterial pressure did not alter CFR. Proper interpretation of CFR measurements should take into account the hemodynamic conditions at which they are obtained.

Coronary vasodilator reserve after human orthotopic cardiac transplantation.

Cardiac transplantation is frequently associated with accelerated coronary atherosclerosis and immune-mediated microvascular injury. To determine if orthotopic cardiac transplantation impairs the capacity of the coronary vasculature to vasodilate and conduct hyperemic blood flow, maximal coronary vasodilator reserve was measured in 25 cardiac allograft recipients with no evidence of rejection 6-57 months after transplantation and in 20 normal subjects. Left ventricular wall thickness was assessed echocardiographically, and epicardial coronary anatomy was evaluated by quantitative coronary angiography. Coronary vasodilator reserve (CVDR) was measured in all patients with a coronary Doppler catheter and a maximally vasodilating dose of intracoronary papaverine. CVDR measured in the transplant recipients with normal coronary arteries, left ventricular function, and wall thickness (5.0 +/- 0.3 [mean +/- SEM] peak/resting velocity; range, 3.8-7.3; n = 16) was not different from that of normal subjects (4.8 +/- 0.2; range, 3.7-8.3). CVDR in the five cardiac allograft recipients with diffuse coronary atherosclerosis producing 30 +/- 5% narrowing (range, 25-38%) of epicardial vessel diameter also was normal (5.1 +/- 0.3; range, 4.3-6.2; n = 5). The CVDR was reduced, however, in two of the four cardiac allograft recipients with left ventricular hypertrophy. In the only transplant recipient in whom a regional wall motion abnormality was present, CVDR was abnormal in the vascular distribution of the hypokinetic wall segment (1.8) but was normal in the artery that supplied normally functioning myocardium (4.0). These findings demonstrate that in the absence of allograft rejection, acquired left ventricular hypertrophy, and regional wall motion abnormalities, coronary vasodilator reserve is normal after orthotopic human cardiac transplantation.(ABSTRACT TRUNCATED AT 250 WORDS)

Evidence for functional sympathetic reinnervation of left ventricle and coronary arteries after orthotopic cardiac transplantation in humans.

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.

Regional differences in sympathetic reinnervation after human orthotopic cardiac transplantation.

BACKGROUND: In the majority of humans > or = 1 year after cardiac transplantation, cardiac norepinephrine (NE) stores reappear, suggesting late sympathetic reinnervation. METHODS AND RESULTS: To 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 (< or = 4 months after cardiac transplantation), 45 late transplant recipients (> or = 1 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 micrograms/kg tyramine. In 13 patients with previously known LV reinnervation, regional LV reinnervation was assessed by NE release after subselective injection of tyramine (4 micrograms/kg) into the proximal left anterior descending and circumflex arteries. Five of five patients < or = 4 months after cardiac transplantation had no change in heart rate and no LV NE release, confirming early, total denervation. In contrast, > or = 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 only 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. CONCLUSIONS: Sympathetic 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.

Allograft vasculopathy and death in a cardiac transplant patient with angiographically normal coronary arteries.

A cardiac transplant patient died of severe left ventricular dysfunction 2 weeks after coronary angiography demonstrated normal coronary arteries. Post mortem examination showed significant and diffuse allograft vasculopathy. Coronary angiography may have limited sensitivity in detecting allograft vasculopathy.