Demonstration of an imbalance between coronary perfusion and excessive load as a mechanism of ischemia during stress in patients with aortic stenosis

Patients with aortic stenosis are susceptible to myocardial ischemia during hemodynamic stress, which may be caused by two mechanisms. First, vascular abnormalities inherent in myocardial hypertrophy may impair coronary vasodilation, limiting the ability to increase coronary blood flow to meet increased metabolic demands. Second, aortic stenosis itself may cause an imbalance between oxygen supply and demand during hemodynamic stress by decreasing aortic pressure (decreasing coronary perfusion or oxygen supply) and increasing left ventricular pressure (increasing oxygen demand). By decreasing aortic valve gradient without immediately altering ventricular hypertrophy, aortic balloon valvuloplasty offers the opportunity to distinguish these mechanisms. We hypothesized that aortic valvuloplasty would improve the balance between myocardial oxygen supply and demand, especially during isoproterenol infusion. Nine patients undergoing aortic balloon valvuloplasty were assessed at baseline and during isoproterenol infusion (5 +/- 2 micrograms/min, mean +/- SD) before and after valvuloplasty. Valvuloplasty increased myocardial oxygen supply. After valvuloplasty, isoproterenol decreased diastolic pressure time index (DPTI) less and increased coronary sinus blood flow more than before valvuloplasty (-630 +/- 367 vs. -292 +/- 224 mm Hg.sec/min, p = 0.02 and 53 +/- 137 vs. 179 +/- 145 ml/min, p = 0.001, respectively). Valvuloplasty also decreased oxygen demand, decreasing systolic pressure time index (SPTI) from 4,135 +/- 511 to 3,021 +/- 492 mm Hg.sec/min (p = 0.0002). Valvuloplasty improved the balance between myocardial oxygen supply and demand, increasing baseline DPTI:SPTI, decreasing aortocoronary sinus oxygen content difference (0.51 +/- 0.15 to 0.68 +/- 0.14, p = 0.005 and 96 +/- 14 to 78 +/- 15 ml O2/l, p = 0.002, respectively), and decreasing myocardial lactate production during isoproterenol infusion (mean lactate extraction fraction, -0.26 +/- 0.40 to 0.14 +/- 0.17; p = 0.01). We conclude that aortic valvuloplasty improves the balance between myocardial oxygen supply and demand during hemodynamic stress induced by isoproterenol infusion. We speculate that the clinical improvement, which often occurs in these patients after valvuloplasty despite persistence of hemodynamically "critical" aortic stenosis, is in part attributable to immediate improvement in the myocardial oxygen supply:demand ratio.     

Changes in coronary blood flow and myocardial metabolism during aortic balloon valvuloplasty

The effects of balloon inflation on myocardial perfusion and metabolism were studied during aortic valvuloplasty in 17 patients with aortic stenosis, including 6 with associated coronary artery disease. Coronary sinus flow and blood samples were obtained before and during the first inflation, and 5 to 10 minutes after the last inflation. During inflation, coronary blood flow decreased (272 +/- 111 standard deviation to 166 +/- 92 ml/min; p less than 0.05), myocardial oxygen uptake fell and transcardiac lactate handling shifted from extraction to production (35 +/- 54 to -41 +/- 48 mumol/min; p less than 0.01). At the end of the procedure, aortic valve area had increased from 0.51 +/- 0.22 to 0.81 +/- 0.48 cm2 (p less than 0.002). Coronary sinus flow increased slightly above control values (+6%; difference not significant) and myocardial oxygen and lactate uptakes were back to control values. However, myocardial alanine production had increased from -3.6 to -6.6 mumol/min (p less than 0.05) and glutamine production was reduced or replaced by extraction (-3.3 +/- 2.1 to 3.5 +/- 3.8 mumol/min; p less than 0.05). Recovery of coronary flow, oxygen and lactate uptakes was not significantly different in patients with or without coronary artery disease, although the former patients tended to have less glutamine extraction and less improvement in their ejection fraction at the end of the procedure. Thus, aortic balloon valvuloplasty produces brief episodes of low-flow ischemia. Recovery of oxidative metabolism is almost immediate after deflation and no detrimental effect seems to persist at the end of the procedure.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of atrial natriuretic factor on coronary hemodynamics and myocardial energetics in patients with heart failure

Synthetic analogues of atrial natriuretic factor (ANF) have been developed for potential use as therapeutic agents in the treatment of congestive heart failure and hypertension. We studied the effects of 14 intravenous infusions of synthetic ANF (anaritide, human ANF 102-126) on coronary hemodynamics and myocardial energetics in six patients with heart failure. ANF infusion caused no change in coronary blood flow and a fall in coronary vascular resistance from 1.22 +/- 0.22 to 1.08 +/- 0.18 mm Hg-min/ml (p less than 0.05). Myocardial oxygen and lactate consumption were unchanged from baseline values. Mean arterial pressure fell from 91 +/- 4 to 78 +/- 3 mm Hg (p less than 0.01), right atrial pressure fell from 10 +/- 1 to 8 +/- 1 mm Hg (p less than 0.01), pulmonary capillary wedge pressure fell from 21 +/- 3 to 16 +/- 2 mm Hg (p less than 0.01), heart rate and cardiac index were unchanged, and systemic vascular resistance fell from 1346 +/- 130 to 1087 +/- 98 dyne-sec/cm5 (p less than 0.05). We conclude that infusion of ANF in hemodynamically effective doses in patients with heart failure decreases coronary vascular resistance with no change in coronary blood flow or myocardial oxygen or lactate metabolism.     

Myocardial energetics and efficiency in patients with idiopathic cardiomyopathy: response to dobutamine and amrinone

Nine consecutive patients having severe idiopathic dilated cardiomyopathy were studied for their response in ventricular function, coronary sinus blood flow and myocardial oxygen consumption, lactate extraction and efficiency following incremental doses of dobutamine, followed by the combination of dobutamine and the phosphodiesterase inhibitor amrinone. Results, presented as baseline and the response to the peak dose (15 micrograms/kg/min) of dobutamine and to the combination of dobutamine and amrinone (each at 15 micrograms/kg/min) (differences compared with baseline) were: wedge pressure decreased from 28 +/- 7 to 26 +/- 8 mm Hg (p = NS) and to 20 +/- 6 mm Hg (p less than 0.01); cardiac index rose from 1.47 +/- 0.44 L/min/m2 to 2.89 +/- 1.1 L/min/m2 (p less than 0.01) and to 3.64 +/- 1.05 L/min/m2 (p less than 0.001); myocardial oxygen consumption remained invariant (18 +/- 8, 17 +/- 5, and 19 +/- 5 ml/min) despite progressive increments in minute work from 2.96 +/- 1.1 to 6.98 +/- 3.9 kg - m/min (p less than 0.01) and to 9.38 +/- 4.3 kg - m/min (p less than 0.001); myocardial lactate extraction rose from 21 +/- 10% to 30 +/- 15% (p = NS) and to 35 +/- 10% with the addition of amrinone (p less than 0.01). No patient had net lactate efflux into the coronary sinus, and myocardial efficiency improved from 9.5 +/- 5% to 21.7 +/- 13.0% (p less than 0.01) and to 28.0 +/- 18.0% (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)     

Quantitative relation between increased intrapericardial pressure and Doppler flow velocities during experimental cardiac tamponade

To establish whether a quantitative relation exists between pericardial pressure and respiratory variation in intracardiac blood flow velocities, a spontaneously breathing closed chest canine model of pericardial tamponade was created. In seven dogs, pericardial pressure was sequentially increased in stages from a mean of -4 +/- 1 to 10 +/- 2 mm Hg while aortic and pulmonary Doppler flow velocities, pleural pressure changes (respiratory effort), blood pressure and cardiac output were measured. The variation in the Doppler-detected peak transaortic velocity (AV) during inspiration (IV) increased linearly from -5 +/- 3% at baseline (pericardial pressure -4 mm Hg) to -32 +/- 9% at a pericardial pressure of 10 mm Hg [IVAV = -2 (pericardial pressure)--13.1; r = 0.78, p less than 10(-6)]. The inspiratory variation in the peak transpulmonary velocity increased from 13 +/- 3% at baseline to 71 +/- 19% at a pericardial pressure of 10 mm Hg. The inspiratory variation in the pulmonary Doppler peak velocity (IVPV) was dependent on both pericardial pressure and degree of respiratory effort [IVPV = 3.8 (pericardial pressure) + 2.6 (respiratory effort) + 10.9; r = 0.88, p less than 10(-8)]. Thus, quantitative relations exist between increases in intrapericardial pressure and increases in inspiratory variation of peak aortic and pulmonary flow velocities. Additionally, pulmonary artery flow velocity is influenced more than aortic velocity by intrathoracic pressure.     

Energy cost of postextrasystolic potentiation in man

The energetic costs of post-extrasystolic potentiation (PEP) were assessed by evaluating left ventricular function and coronary blood flow in 16 patients with different forms of cardiac disease during cardiac catheterisation under basal conditions and sustained coupled right ventricular pacing. The coronary blood flow was measured by thermodilution techniques with sampling in the aorta and coronary sinus to measure O2 concentration, glucose, and plasma lactate and catecholamine levels. Parameters of LV function were calculated from data obtained from biplane left cineventriculography. During PEP, the ejection fraction increased from 0.48 +/- 0.8 to 0.62 +/- 0.22, the mean velocity of circumferential fibre shortening from 0.79 +/- 0.37 to 1.12 +/- 0.45 circ/s (p less than 0.001) and systolic work from 97 +/- 46 to 139 +/- 67 g/m2 (p less than 0.05). Coronary blood flow increased from 176 +/- 60 to 305 +/- 155 ml/min; myocardial oxygen consumption per potentialized beat rose from 0.15 +/- 0.07 to 0.50 +/- 0.33 ml/beat (p less than 0.001) whilst cardiac efficiency fell from 19.1 +/- 8 to 9.2 +/- 4% (p less than 0.001). PEP was associated with increased myocardial noradrenaline secretion (-3.1 +/- 31.5 ng/min under basal conditions to 30.2 +/- 42.8 ng/min, p less than 0.05). Therefore, the inotropic effect of PEP imposes a high metabolic demand and is associated with increased myocardial noradrenaline secretion.     

Systemic and coronary hemodynamic effects of intravenous nicardipine at rest and in ischemia induced by rapid atrial stimulation

The systemic and coronary haemodynamic effects of intravenous nicardipine were investigated in 10 patients with a more than 70 p. 100 stenosis of the left coronary artery. Two brief atrial pacing tests (ST1 and ST2) were performed. ST2 was performed 30 minutes after an intravenous injection of nicardipine 2.5 mg over 5 minutes. Nicardipine produced a 25 p. 100 decrease in ventricular systolic pressure and a substantial increase in cardiac index (from 2.74 +/- 0.48 to 3.46 +/- 0.35 l/min/m2, p less than 0.001). Measurement of the coronary flow rate by the thermodilution method showed a 40 p. 100 increase in sinus blood flow while coronary resistance decreased not only in territories with normal supply but also in myocardial territories distal to the coronary stenosis (from 2.76 +/- 2.3 to 1.83 +/- 1.5 mmHg/ml, p less than 0.02). With the same paced heart rate the ventricular function parameters were significantly improved during ST2 (cardiac index ST2 3.56 +/- 0.65 vs ST1 2.8 +/- 0.48, p less than 0.001; dp/dt max ST2 2143 +/- 369 vs ST1 1874 +/- 301 mmHg/sec, p less than 0.05), reflecting a lower degree of myocardial ischaemia. This was confirmed by the lower amplitude of electrocardiographic depression and by a higher lactate extraction coefficient (LE ST1 6 +/- 7 p. 100 vs LE ST2 12 +/- 12 p. 100, p less than 0.05). Mean arterial blood pressure and coronary sinus blood flow rate values were identical during the two atrial pacing tests.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cardiac tamponade in dogs with normal coronary arteries. II. Myocardial flow and metabolism with moderate and severe hemodynamic impairment

Summary To determine the effects of cardiac tamponade on myocardial blood flow and its distribution, dogs were prepared with indwelling pericardial catheters. Hemodynamic, myocardial blood flow, and myocardial metabolic data were collected in 5 closed-chest, spontaneously breathing animals with normal blood volumes and hemoglobin concentrations and 6 with acute anemia. Instillation of an average of 89.0±14.9 ml of modified Normosol® into the pericardial space in dogs with normal hemoglobin levels produced mild tamponade with a modest decline in aortic pressure (119.5±14.3 to 96.8±12.1 mm Hg) and significant rises in left and right atrial and pericardial pressures to 7–8 mm Hg. Increasing the pericardial volume to 124.0±13.6 ml produced hypotension (mean aortic pressure 86.2±10.5 mm Hg) and rises in the left and right ventricular filling pressures and pericardial pressure to 10–11 mm Hg. Total myocardial blood flow fell from 1.19±0.18 to 0.73±0.17 ml/min/g (p<0.02) during mild tamponade, and fell further to 0.56±0.17 ml/min/g (p<0.05) with more severe tamponade. Despite these declines, the left ventricular wall inner/outer flow ratio and left ventricular flow as a proportion of total cardiac output were unchanged. In dogs with anemia more severe tamponade was created, with consequently more marked hemodynamic abnormalities. However, the relative changes in myocardial blood flow and inner/outer flow ratio were similar. Myocardial metabolic parameters could be evaluated only in the dogs with less severe tamponade. The coronary arteriovenous oxygen difference changed little during induced tamponade, and, therefore, quantitated myocardial oxygen consumption declined in proportion to the fall in myocardial flow. Furthermore, myocardial lactate extraction and the lactate/pyruvate ratio were not affected by cardiac tamponade. Thus, these experiments cannot support the hypothesis that myocardial ischemia is a pathophysiologic factor in the production of abnormal hemodynamics in cardiac tamponade.Dr. Cohen is the recipient of a Research Career Development Award from the National Heart, Lung and Blood Institute Grant HL-00281.This study was supported in part by National Heart, Lung and Blood Institute Grant HL-17809.     

Systemic and coronary effects of intravenous milrinone and dobutamine in congestive heart failure

The effects of dobutamine and intravenous milrinone on systemic hemodynamics, coronary blood flow and myocardial metabolism were studied in 11 patients with severe congestive heart failure. Although milrinone and dobutamine similarly increased cardiac index from 1.9 +/- 0.4 to 2.5 +/- 0.4 liters/min per m2 (p less than 0.001) and from 1.9 +/- 0.4 to 2.8 +/- 0.8 liters/min per m2 (p less than 0.001), respectively, milrinone decreased left ventricular end-diastolic pressure to a greater extent than dobutamine, that is, from 26 +/- 6 to 12 +/- 8 mm Hg (p less than 0.001) versus 26 +/- 8 to 20 +/- 8 mm Hg (p less than 0.001). In contrast to dobutamine, milrinone significantly reduced mean systemic arterial and right atrial pressures. Dobutamine increased the first derivative of left ventricular pressure (dP/dt) from 1,013 +/- 309 to 1,360 +/- 538 mm Hg/s (p less than 0.01) but milrinone did not. Similarly, blood flow and myocardial oxygen consumption were increased by dobutamine from 152 +/- 87 to 187 +/- 118 ml/min (p less than 0.05) and from 17.7 +/- 10.9 to 21.5 +/- 14.9 ml O2/min (p less than 0.05), respectively, but were unchanged by milrinone. Both drugs significantly decreased coronary vascular resistance and myocardial oxygen extraction but did not change myocardial lactate extraction. Thus, dobutamine and milrinone produce similar improvement in cardiac index. However, dobutamine increases myocardial oxygen consumption, whereas milrinone does not. This difference can probably be explained by the substantial vasodilating properties of milrinone.     

Oxygen consumption and coronary reactivity in postischemic myocardium

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 in 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 less than 0.05) and duration (57 +/- 9.1 vs. 35 +/- 4.5 seconds; p less than 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.     

Acute effect of lidocaine on coronary blood flow and myocardial function

The acute effects of lidocaine on coronary blood flow, hemodynamic parameters, and wall function were studied in 14 anesthetized pigs. Lidocaine was infused intravenously as a bolus (dosage range from 1.5 to 4.0 mg/kg). At ten to thirty seconds after infusion, coronary blood flow reached 154 +/- 38% (mean +/- SD) of the baseline resting flow (p less than 0.001). The double product, an estimate of myocardial oxygen demand, decreased from a baseline value of 9221 +/- 2174 to 8008 +/- 1923 mmHg beats/min (p less than 0.01). Sixty seconds postinfusion myocardial function decreased from baseline wall thickening of 46 +/- 25% to 41 +/- 17% (p = 0.04). An acute bolus of lidocaine appears to transiently increase coronary blood flow, by decreasing coronary vascular resistance, and also decrease myocardial function. Thus, an acute lidocaine bolus may favorably alter the myocardial oxygen supply/demand ratio.     

Myocardial metabolic and hemodynamic effects of dichloroacetate in coronary artery disease

Dichloroacetate (DCA), which activates pyruvate dehydrogenase, has the potential to enhance carbohydrate and lactate utilization in animals, but data from patients with coronary artery disease are lacking. Accordingly, 9 patients (ages 49 to 72 years) with angina and coronary artery disease undergoing catheterization were studied. Systemic and coronary hemodynamic and metabolic measurements were made before and during DCA administration (mean dose 35 mg/kg, intravenously). DCA increased left ventricular (LV) stroke volume from 77 +/- 7 to 87 +/- 7 ml and decreased systemic vascular resistance from 1,573 +/- 199 to 1,319 +/- 180 dynes.s.cm-5 (both, p less than 0.01). There were no significant changes in heart rate, mean aortic pressure, LV end-diastolic pressure, LV dP/dt max, coronary sinus flow, coronary resistance or myocardial oxygen consumption, but myocardial efficiency index (LV work/myocardial oxygen consumption) improved from 24 to 32% (p less than 0.05). Myocardial lactate consumption was maintained (21 +/- 8 vs 19 +/- 11 X 10(-3) mEq/min, p is not significant at p less than or equal to 0.05 level) at a lower arterial lactate concentration (0.72 +/- 0.09 to 0.47 +/- 0.08 mEq/liter, p less than 0.05). DCA appears to stimulate myocardial lactate utilization at a lower arterial concentration, cause peripheral vasodilation, augment stroke volume and enhance myocardial efficiency in patients with coronary artery disease.     

Effect of diltiazem on coronary reactive hyperemia in patients with flow-limiting coronary artery stenosis

The acute effects of diltiazem on coronary reactive hyperemia were studied in 12 patients with flow-limiting coronary stenosis. Reactive hyperemia was elicited by injection of 8 ml contrast medium into the left coronary artery, while coronary sinus blood flow and left ventricular and aortic pressures were continuously recorded. Relative magnitude of hyperemia was estimated by the ratio of coronary flow at peak hyperemia to baseline flow (hyperemic ratio). Coronary resistance was calculated as the ratio between mean aortic pressure minus left ventricular mean diastolic pressure and coronary sinus blood flow. The 12 patients studied had flow-limiting coronary stenosis since their hyperemic ratio was significantly restrained when compared to that of seven control subjects (1.45 +/- 0.17 vs 2.02 +/- 0.24, respectively; p less than 0.001). The intravenous infusion of diltiazem (0.30 mg X kg-1) reduced heart rate, mean aortic pressure, and myocardial oxygen consumption (all p less than 0.001). After diltiazem the hyperemic ratio was blunted when compared to the basal state (1.36 +/- 0.15 vs 1.45 +/- 0.17, respectively; p less than 0.05), and hyperemia volume was reduced (-33%; p less than 0.001). The decrease in coronary resistance at peak hyperemia was also reduced from -30 +/- 8% to -25 +/- 8% (p less than 0.05). We conclude that diltiazem blunts coronary reactive hyperemia in patients with demonstrated flow-limiting coronary stenosis. This reduction of coronary flow response to a hyperemic stimulus could favorably influence blood flow distribution in patients with significant coronary stenosis.     

Influences on the distribution of blood flow during cardiac tamponade in the conscious dog

Cardiac tamponade is a spectrum ranging from pericardial effusions with minimal hemodynamic impairment to effusions causing circulatory collapse. In this study, we examined the roles played by the sympathetic nervous system and the renin-angiotensin system in controlling the distribution of blood flow in chronically instrumented conscious dogs during progressive cardiac tamponade. Fifty-one episodes of acute cardiac tamponade were induced to decompensation (decline in mean aortic blood pressure to 70% of the level present when the pericardium was free of fluid) in 6 dogs by intrapericardial infusion of warmed saline solution. Cardiac output (electromagnetic flow probe), intrapericardial pressure, aortic and right atrial blood pressures, and renal, coronary, and mesenteric artery blood flows (Doppler flow probes) were recorded during tamponade in the absence of blockade (control), during alpha-adrenergic blockade (phenoxybenzamine), beta-adrenergic blockade (propranolol), or angiotensin-converting enzyme blockade (captopril). Aortic and mesenteric artery blood flow decreased progressively during cardiac tamponade regardless of the presence or absence of blockade. Coronary artery blood flow did not significantly change during alpha-adrenergic blockade, suggesting that the continuous decline observed during cardiac tamponade in the absence of blockade was at least in part mediated by alpha-adrenergic mechanisms. Renal artery blood flow, in contrast, was well maintained in all situations, confirming the importance of autoregulation in this vascular bed during cardiac tamponade.     

Coronary hemodynamics and myocardial metabolism of lactate, free fatty acids, glucose, and ketones in patients with septic shock

To investigate disturbances in the coronary circulation and myocardial metabolism during septic shock, we examined coronary sinus blood flow and myocardial substrate extraction in 40 patients with septic shock and 13 control patients. Patients with coronary artery disease were excluded from this study. The global hemodynamic pattern of the septic patients was characterized by a lower stroke volume, despite an elevated cardiac index. Coronary sinus blood flow was high (187 +/- 47 vs 130 +/- 21 ml/min in the control group, p less than .001) due to marked coronary vasodilation, especially in the subgroup of nonsurvivors. In contrast to the control group, myocardial lactate uptake was elevated, while that of free fatty acids, glucose, and ketone bodies was diminished in patients with septic shock. These findings were especially prominent in the nonsurvivors. Expressed as oxygen equivalents, the contribution of free fatty acids as an energy source of the myocardium was markedly diminished in septic patients (12% vs 54% in the control group, p less than .005), while that of lactate was increased (36% vs 12%, p less than .01). The observed shift in myocardial substrate extraction was associated with a discrepancy between measured myocardial oxygen consumption and that calculated chemically from commonly available exogenous substrates: 41% of myocardial oxygen consumption was not explained by the utilization of commonly available substrates extracted from coronary circulation in all patients with septic shock.(ABSTRACT TRUNCATED AT 250 WORDS)     

Sympathetic nervous system activation in postextrasystolic potentiation: role of catecholamine release in enhancement of ventricular function

The role of catecholamines in postextrasystolic potentiation was assessed in 30 patients during continuous coupled right ventricular pacing. Hemodynamic data were recorded in 15 patients (group 1); in the other 15 patients (group 2), coronary blood flow and metabolic variables, including catecholamines, were measured. Data were recorded in the control state and after 10 minutes of coupled pacing. Both groups had similar control pulse rates and mean aortic pressures: these variables decreased abruptly by 32 beats/min and 12 mm Hg, respectively, (p less than 0.001 for each) after the initiation of coupled pacing. In group 1, all indexes of left ventricular function and contractility increased during coupled pacing (p less than 0.001 for each), thus confirming postextrasystolic potentiation. In group 2, coupled pacing increased coronary blood flow, myocardial oxygen consumption and free fatty acid uptake (p less than 0.001 for each) but not lactate extraction. Plasma epinephrine was unchanged, but norepinephrine levels increased in arterial (421 +/- 27 to 576 +/- 41 ng/liter) and coronary sinus plasma (611 +/- 46 to 836 +/- 46 ng/liter) (p less than 0.001 for both). Indirectly calculated norepinephrine release within the myocardium increased from 25.6 +/- 2.8 to 39.7 +/- 5.2 ng/min (SEM) (p less than 0.05), suggesting a sympathetic nervous system activation. It is argued that coupled pacing acutely lowered mean aortic pressure, leading to baroreflex sympathetic activation which may contribute to augmented cardiac contractility in postextrasystolic potentiation.     

Tumor necrosis factor-alpha and troponin I release in porcine cardiac lymph and coronary sinus blood before and after cardiopulmonary bypass

To assess the concentrations of cardiac troponin I (cTnI) and tumor necrosis factor-alpha (TNFalpha) in cardiac lymph compared with coronary sinus (CS) blood and to measure cardiac lymph flow before and after cardiopulmonary bypass (CPB). In 21 pigs, the main cardiac lymph trunk was cannulated before institution of standardized CPB. Lymph flow, cTnI and TNFa in cardiac lymph and CS blood were measured before and after CPB for 6 hours. Before CPB, cTnI concentration was 215 +/- 36 nglml in cardiac lymph and 0.5 +/- 0.1 nglml in CS blood, respectively. After aortic declamping a significant elevation of cTnI values was measured in cardiac lymph and CS blood. cTnl concentration in cardiac lymph and CS blood peaked 6 hrs after CPB (10,556 +/- 4,735 vs. 22.2 +/- 3.7 nglml, p < 0.01). TNFalpha concentration at baseline was 23.2 +/- 5.6 pg/ml in lymph and 18.7 +/- 9.5 pg/ml in CS blood, and there was no significant release of TNFalpha up to the end of the experiment. Baseline cardiac lymph flow was 3.07 +/- 0.35 ml/h and declined after aortic clamping (0.72 +/- 0.16 ml/h; p < 0.01) and peaked one hour after CPB (5.66 +/- 0.97 ml/h; p < 0.01). In conclusion, very high cTnI concentrations in cardiac lymph suggest serious perioperative myocardial damage after CPB with cardioplegia, which is underestimated by cTnI release into the bloodstream. In our study, the myocardium was not a major source of TNFalpha release.     

Myocardial lactate release during ischemia in swine. Relation to regional blood flow

To determine the relation between regional myocardial blood flow, contractile function, and myocardial lactate release during mild-to-moderate regional myocardial ischemia, nine open-chest swine were instrumented for measurement of regional myocardial blood flow (microsphere method), contractile function (sonomicrometry), and hemodynamics. L-[1-14C]Lactate or L-[U-13C]lactate was infused intravenously using a primed continuous infusion technique to quantify regional myocardial lactate release. D-[U-13C]glucose or D-[6-14C]glucose was simultaneously infused to determine the contribution of exogenous glucose to lactate release. Graded coronary ischemia (two to three levels) was created in the left anterior descending coronary arterial distribution by mechanically constricting the artery in five animals or by decreasing flow through a cannulated left anterior descending artery in four animals. In all nine animals, subendocardial blood flow was 0.99 +/- 0.21 (ml/min)/g during control and 0.34 +/- 0.14 (ml/min)/g during the most severe grade of underperfusion (p less than 0.001) in the left anterior descending coronary arterial distribution. Regional myocardial lactate release was 0.15 +/- 0.09 and 1.19 +/- 0.75 mumols/ml, respectively (p less than 0.003). A highly significant inverse correlation was observed between subendocardial blood flow and myocardial lactate release during the graded reductions in blood flow (r = -0.71, p less than 0.001). Results from sonomicrometry showed a significant reduction in contractile ventricular function in the anterior wall during the graded reductions in blood flow. The regional arterial-venous glucose difference increased significantly with underperfusion in the left anterior descending coronary arterial distribution, from 0.14 +/- 0.15 to 0.56 +/- 0.37 mumols/ml (p less than 0.003). The contribution of exogenous glucose to lactate release also increased significantly; 0.04 +/- 0.03 mumols/ml of the lactate came from exogenous glucose during control compared with 0.64 +/- 0.59 mumols/ml during the most severe underperfusion (p less than 0.02). A significant positive correlation exists between lactate release and lactate from exogenous glucose during graded underperfusion (r = 0.96, p less than 0.001). In summary, these data demonstrate a close inverse relation between regional myocardial lactate release and regional subendocardial blood flow during graded ischemia.     

Effects of intravenous and intracoronary nicardipine

The systemic and coronary hemodynamic effects of nicardipine, a calcium antagonist, were studied in 30 patients. Increased coronary blood flow (from 102 +/- 9 to 147 +/- 13 ml/min; p less than 0.001), heart rate (from 69 +/- 3 to 81 +/- 3 beats/min; p less than 0.001), stroke volume (108 +/- 6 to 123 +/- 6 ml; p less than 0.001) and cardiac output (from 7.3 +/- 0.5 to 9.9 +/- 0.5 liters/min; p less than 0.001) were demonstrated in 15 patients administered intravenous nicardipine (2 mg bolus given over 1 minute, followed by infusion of 50 micrograms/min to maintain 10 to 20 mm Hg decrease in systolic blood pressure). Systemic vascular resistance decreased (from 1,183 +/- 70 to 733 +/- 33 dynes s cm-5) as did coronary resistance (from 1.47 +/- 0.1 to 0.7 +/- 0.1 mm Hg/ml/min; p less than 0.001). Other hemodynamic parameters such as left ventricular end-diastolic pressure, stroke volume and work, aortic blood flow and acceleration, ejection and external power, myocardial oxygen consumption and time constant for left ventricular isovolumic relaxation also were evaluated. To distinguish between direct myocardial effects of nicardipine and peripheral effects, 15 patients were given intracoronary nicardipine (0.1 or 0.2 mg) during cardiac catheterization. Nicardipine produced slight depression of left ventricular contractile function and impairment of left ventricular relaxation; but these changes were mild and transient compared with the marked and sustained increase in coronary blood flow that persisted 7 minutes after administration. Thus, nicardipine is a relatively selective vasodilator with minimal direct myocardial depressant activity n humans.     

Antiischemic and metabolic effects of glutamate during pacing in patients with stable angina pectoris secondary to either coronary artery disease or syndrome X.

The effects of glutamate on anginal threshold, cardiac metabolism and hemodynamics were studied in 11 patients with stable angina pectoris, positive stress test results, and pacing-induced myocardial lactate release due to coronary artery disease (CAD) (n = 9) or syndrome X (n = 2). Data were obtained before, during and after 2 identical periods of coronary sinus pacing, the second being preceded by an intravenous injection of monosodium glutamate 1.2 (n = 7) or 2.5 (n = 4) mg/kg body weight. After glutamate administration, pacing time to onset of angina increased from mean +/- standard deviation 103 +/- 53 to 166 +/- 71 seconds (p less than 0.01) and ST-segment depression after pacing decreased from 2.3 +/- 1.0 to 1.6 +/- 1.1 mm (p less than 0.01). Arterial glutamate concentration increased 60% (p less than 0.01) after the low dose and 150% (p less than 0.01) after the high dose of glutamate. Regardless of dose, myocardial glutamate uptake increased by 25% (p less than 0.01). Pacing-induced cardiac release of lactate diminished 50% (p less than 0.05), whereas the releases of xanthine and hypoxanthine were unchanged by glutamate. Arterial free fatty acids decreased 20% (p less than 0.01). Circulating levels and cardiac exchanges of alanine, glucose and citrate were unchanged. Glutamate did not influence heart rate, arterial blood pressure, coronary blood flow, coronary vascular resistance or myocardial oxygen consumption. One patient complained of short-lasting burning sensations after receiving the high glutamate dose. In conclusion, augmented provision of glutamate enhances pacing tolerance in stable angina, presumably by a metabolic improvement of cardiac energy production during ischemia.