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In 70 patients (94% were a consecutive series) with angina pectoris and normal coronary angiograms, we measured cardiac exchange of lactate, glucose, free fatty acids (FFAs), glutamate, alanine, citrate, and oxygen together with coronary sinus blood flow and blood pressure in response to pacing (150 beats/min). Twelve patients had an abnormal exercise stress test; 26 developed ST depression and 46 had chest pain in response to pacing. Sixteen patients had no ST changes (exercise/ pacing) and no pain during pacing. Pacing induced an increase in cardiac carbohydrate extraction and a decrease in FFA extraction in the entire group of patients. Less than 3% of patients had significant cardiac lactate release in response to pacing, and there were no consistent differences in the cardiac metabolic or hemodynamic responses between patient groups. The pacing-induced shift from FFA to carbohydrate extraction probably reflects the cardiac response to an acute workload. A definite sign of cardiac ischemia (lactate production) was a rare finding in these patients and not confined to the demonstration of electrocardiographic signs of ischemia.

The effect of nitroglycerin, beta-blockers, and calcium antagonists on the main parameters of central hemodynamics and myocardial metabolism is described. The original algorithm of the choice of the most effective drug or a combination of drugs depending on the initial state of central hemodynamics and coronary venous blood flow is presented.

The effects of oral atenolol on coronary hemodynamics and prostaglandin metabolism have been investigated in 8 chronic stable angina pectoris patients who underwent the supine bicycle ergometer. At rest, atenolol taken orally reduced the pressure-rate product significantly (P < 0.05) but did not significantly affect the coronary sinus blood flow or the coronary sinus pressure. During exercise, atenolol also reduced the pressure-rate product significantly (P < 0.05) but did not significantly affect the coronary sinus blood flow, the coronary sinus pressure, or the coronary vascular resistance. Atenolol also did not significantly affect the thromboxane B2/6-keto prostaglandin F1 alpha ratio in the arterial blood before and after exercise but did reduce this ratio in the coronary sinus blood by 15% from 1.9 +/- 1.1 to 1.5 +/- 0.46 (P < 0.10) after exercise. These results indicate that atenolol taken orally does not significantly depress the coronary hemodynamics. However, the effects of atenolol on the prostaglandin metabolism could not be clearly determined.

As the myocardial carnitine content, a key control factor in myocardial oxidative metabolism and energy transfer, is reduced in heart failure, administration of L-propionylcarnitine (LPC), a potent analogue of L-carnitine, potentially may improve cardiac function, possibly through a positive inotropic effect. As its hemodynamic profile is unknown in humans, 32 fasting normotensive patients with coronary artery disease received either 15 mg/kg of LPC (n = 16) or vehicle (mannitol/acetate, n = 16) infused over 5 min. Hemodynamic, radionuclide [peak ejection and filling rates (PER and PFR, respectively)], and metabolic variables (myocardial O2, lactate, and carnitine uptake) were studied at baseline and 1, 3, 5, 10, 15, and 45 min postdrug. The baseline ejection fraction was depressed in LPC patients (40 +/- 3% vs. 48 +/- 4% in the vehicle group, p less than 0.05) as a result of a significant high incidence of previous infarctions. Immediately following LPC, the cardiac total carnitine uptake changed from 102 +/- 181 to 5,335 +/- 1,761 mumol/L (p less than 0.05). In both groups, left ventricular systolic and end-diastolic pressures increased significantly by 5 and 20%, respectively, during the first 5 min. In the vehicle group, contractility decreased by 5%, accompanied by a significant 11% fall in the stroke volume. In contrast, following LPC, isovolumetric contractility indices remained unaltered. Instead, both the PER and PFR improved by 16% at 45 min. Moreover, the cardiac output increased by 8%. LPC did not affect systemic or coronary hemodynamics. Lactate uptake increased by 42%, but myocardial O2 consumption did not change.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

Beta-blocking agents with partial agonist activity seem to reduce heart rate at rest slightly less than those without this property. Cardio-selective drugs have no effect on stroke volume at rest contrary to the non-selective ones which will reduce it somewhat. This difference is abolished during exercise. The only difference seen during work between different beta-blockers is the effect on the peripheral vascular resistance. The selective drugs lower the arterial pressure with unchanged resistance.

During repeat exercise testing in 10 patients with stable angina, individual optimal doses of nicardipine were determined. Hemodynamic values and cardiac metabolism were studied during 2 pacing periods carried out before and after this dose (mean 5.3 mg). Postpacing ST-segment depression diminished (1 mm) after nicardipine administration (p less than 0.05), whereas pacing time to onset of angina did not change. Nicardipine administration increased heart rate 16% (p less than 0.005) and reduced systolic (10%) and diastolic (8%) blood pressures (both p less than 0.005). Coronary blood flow increased 16% (p less than 0.05) and coronary vascular resistance decreased 24% (p less than 0.01). Myocardial oxygen consumption was unchanged despite an 11% decrease in rate-pressure product during pacing (p less than 0.02). In the control state before nicardipine administration, metabolic signs of ischemia included release of lactate across the heart in 7 patients, decreased mean free fatty acid and glutamate uptake and alanine release during pacing, together with increased glucose uptake and citrate release during recovery. After nicardipine lactate release decreased in 5 of the 7 patients, pacing no longer changed free fatty acid, glutamate and alanine uptake/release from the level at rest. During recovery glucose uptake was reduced and citrate release was unaffected. The hemodynamic data indicate that nicardipine is a systemic and coronary vasodilator, increasing oxygen supply to the ischemic myocardium. The metabolic results indicate a change in substrate utilization toward that of normal heart, suggesting improved aerobic energy supply.

Seventy-six patients with anginalike chest pain (ALCP) and angiographically normal coronary arteries (NCA) had a study of the myocardial metabolism at rest and during maximal atrial pacing. The results were compared with pain characteristics, electrocardiogram, left ventricular, and coronary hemodynamic data. Coronary blood flow (CBF) was measured by continuous thermodilution. At maximal paced heart rate, the study of the myocardial metabolism distinguished two groups: (1) a first group of 50 patients whose lactate extraction coefficient was equal to or exceeded 9% and was considered as normal (Gr. I, K greater than or equal to 9%); (2) a second group of 26 patients whose lactate extraction coefficient was below 9% (Gr. II, K less than 9%), significant of myocardial ischemia. In group I (K greater than or equal to 9%), chest pain was usually atypical (typical in only 25% of cases) and rapid atrial pacing most often caused neither pain nor ECG changes. The hemodynamic and angiographic study showed minor alterations of the left ventricular cavity in 50% of cases. In group II (K less than 9%), chest pain was typical in 50% of the patients and maximal atrial pacing most often caused chest pain (85%) and ST-segment depression (80%). In almost every case, the left ventricular and the coronary angiograms were normal. Only in this group, which had clinical, electrical, and metabolic signs of myocardial ischemia, could the diagnosis of angina pectoris with angiographically normal coronary arteries be upheld.(ABSTRACT TRUNCATED AT 250 WORDS)

Coronary haemodynamic and metabolic effects of propranolol and glyceryl trinitrate were studied in 12 patients with coronary artery disease and 5 without coronary heart disease, at rest and during tachycardia stress. Propranolol-associated reductions in indices of myocardial oxygen demand, left ventricle work, tension time, and left ventricle oxygen utilisation (LVVO2) were reversed when heart rate was controlled by atrial pacing. Adding glyceryl trinitrate at rest also restored heart rate but decreased the left ventricular work index and tension time index as coronary resistance declined paradoxically. Tachycardia-related increases in tension time index and LVVO2 were unchanged after propranolol, and ischaemia (angina, ST depression, and reduced lactate extraction) was not altered in most of the patients. During tachycardia, the addition of glyceryl trinitrate decreased the tension time index and LVVO2; angina recurred in only 4 patients, and ST depression and lactate extraction improved. Similar haemodynamic changes occurred in the patients with normal coronary arteries. In contrast with propranolol administered alone, propranolol plus glyceryl trinitrate enhances tachycardia tolerance and prevents tachycardia-induced manifestations of ischaemia. This action is attributed to glyceryl trinitrate-associated improvement in the adequacy of myocardial perfusion.

Angina pectoris results from an imbalance between oxygen supply and demand in the subendocardium. The haemodynamic effects contributing to this imbalance have been studied in 10 patients with coronary artery disease. Myocardial oxygen demand was estimated from the tension time index (TTI), potential subendocardial flow from a diastolic pressure time index (DPTI), and the oxygen supply/demand ratio from (DPTI/TTI. With progressively increasing pacing rates up until induction of angina, no significant change in TTI was found whereas a significant fall in DPTI and DPTI/TTI occurred (P less than 0.001). During pacing runs with induction of angina DPTI/TTI reached a minimum value 5 s before,and at the onset of angina. No such relationship was seen for TTI or DPTI alone. A significant rise in LVEDP (P less than 0.05) and fall in dP/dt min (P less than 0.01) occurred at angina both contributing to a further reduction in DPTI and DPTI/TTI. Changes in DPTI/TTI may then reflect changes in the myocardial blood flow supply/oxygen demand ratio in the presence of coronary artery disease and haemodynamic changes before and at the induction of angina lead to a further reduction of this ratio.

Hemodynamic and metabolic responses to pacing from either the coronary sinus or right atrium were evaluated in 41 patients with chest pain and normal coronary arteriograms. A group of patients (group II) with angina, lactate production, or significant ST segment depression had a significantly higher mean pulmonary capillary pressure on peak pacing or angina than did a group of patients considered to have a normal pacing response (group I). In 6 of 9 group II patients, the left ventricular end-diastolic pressure either rose abnormally with pacing or was greater than 14 mm Hg immediately after pacing and resembled that of a group of patients with coronary artery disease; Patients with a prolapsing mitral valve (group III) also had a significantly higher pulmonary capillary pressure on peak pacing as compared to those of group I, although abnormal left ventricular pressure responses occurred in only 2 of 9 of these patients. The stroke index was significantly lower in group III on peak pacing while group II was no different from group I. Lactate production occurred in 6 of 9 group II patients. However, only 1 of 6 patients with a prolapsing mitral valve who were studied for lactate production was found to produce lactate, suggesting a different mechanism for their pain.

Myocardial substrate extraction, coronary sinus flow, left ventricular pressure, and cardiac output were measured in 11 patients with angina pectoris at three pacing rates before and after atenolol (0.2 mg/kg). Left ventricular pressures, and the product of systolic pressure time index and heart rate did not change, but max dP/dt and KV max fell after atenolol. Only at the lowest pacing rate did the drug reduce cardiac output. Coronary sinus blood flow and myocardial oxygen uptake did not change after atenolol. At the highest pacing rate before atenolol four patients developed angina, accompanied by a rise in end-diastolic pressure. After atenolol angina was abolished in three, but the end-diastolic pressure still rose at the highest pacing rate. Myocardial lactate extraction ratio fell as heart rate increased, and was lower in the patients who developed angina. After atenolol, lactate extraction ratio increased significantly at the highest and lowest pacing rates. Myocardial pyruvate extraction rose after the drug. Arterial concentrations of hydroxybutyrate and acetoacetate fell after atenolol, but the decrease in their extraction was not significant. Myocardial extraction of free fatty acids was related to arterial concentration, which fell after atenolol. The changes in lactate and pyruvate extraction after atenolol were related inversely to changes in arterial free fatty acid concentration suggesting that the improvement in myocardial metabolism could have been secondary to reduced peripheral lipolysis. The increase in lactate extraction was associated with relief of angina, but did not abolish the rise in end-diastolic pressure induced by pacing.

We evaluated the effects of selective activation of H1 receptors on coronary hemodynamics in 16 patients divided into two groups: group A, 11 patients with atypical angina or valvular heart disease and normal coronary arteries, and group B, five patients with spontaneous angina, four of whom had significant (greater than 70% stenosis) coronary artery disease and one with normal coronaries. Selective H1 receptor stimulation was achieved by infusing 0.5 microgram/kg/min of histamine intravenously for 5 min after pretreatment with cimetidine (25 mg/kg). Heart rate was maintained constant (100 beats/min) by coronary sinus pacing and coronary blood flow (CBF) was measured by thermodilution. In group A, during histamine infusion mean aortic pressure fell from 99 +/- 5 to 77 +/- 4 mm Hg (mean +/- SEM, p less than .001), coronary vascular resistance (CVR) decreased from 1.07 +/- 0.17 to 0.82 +/- 0.14 mm Hg/ml/min (p less than .02), and CBF and myocardial oxygen consumption remained unchanged. None of the patients in this subgroup developed angina during histamine infusion. In group B, while no significant average changes in mean arterial pressure, CVR, or CBF were observed, two of the five patients (40%) developed angina during histamine infusion, accompanied by ST-T elevation, a decrease in CBF, and an increase in CVR. In one of these two patients circumflex coronary arterial spasm was angiographically demonstrated during histamine-induced angina. Our results suggest that stimulation of the H1 receptor induces a reduction of CVR, probably resulting from vasodilation of small coronary resistance vessels.(ABSTRACT TRUNCATED AT 250 WORDS)

To determine whether the association of nicardipine with propranolol had additive effects on myocardial metabolism, 16 patients with angina pectoris were studied invasively before and after 1 month of therapy with a combination of nicardipine and propranolol and compared to a group of 42 patients treated with nicardipine (n = 17) or propranolol (n = 25) alone. When data were compared at a fixed heart rate (atrial pacing), mean blood pressure was reduced with combined treatment from 96 +/- 19 to 76 +/- 13 mm Hg (p less than 0.003). Myocardial oxygen uptake and coronary sinus flow decreased significantly from 20 +/- 9 to 14 +/- 6 ml/min (p less than 0.015) and from 152 to 111 ml/min (p less than 0.05), respectively. The arterio-coronary sinus difference in oxygen content also decreased (13.3 to 12.5 ml/dl; p less than 0.0025), suggesting an improved balance between oxygen supply and demand. Such changes in coronary blood flow and myocardial oxygen uptake were not observed in the group of patients assigned to monotherapy. Lactate uptake rose and the abnormal glutamine production, which worsened with propranolol monotherapy, improved with nicardipine and propranolol (-2.0 to -1.4 mumol/min; p less than 0.05 vs propranolol). The superiority of nicardipine and propranolol over propranolol monotherapy was maintained during a pacing stress test. Thus the combination of nicardipine with a beta blocker had greater oxygen-sparing effects and restored aerobic metabolism better than either drug alone, allowing optimal use of the coronary reserve.

The effects of oral dipyridamole administration (150 mg) on coronary hemodynamics, myocardial metabolism, and pacing threshold were studied in 10 patients with significant coronary artery disease (CAD). Following dipyridamole through 120 minutes, there was no significant change in resting heart rate, arterial pressure, coronary venous flow, coronary resistance, myocardial lactate extraction, or myocardial oxygen consumption. Rapid atrial pacing performed before and at 60, 90, and 120 minutes after dipyridamole failed to demonstrate any significant reduction in pacing threshold or evidence of increased ischemia after dipyridamole. Blood dipyridamole levels showed variable and slow absorption which probably explains the difference between intravenous and oral dipyridamole on coronary dynamics and myocardial response to pacing.

Hemodynamic and metabolic effects of nitroglycerin ointment (40 mg nitroglycerin) were tested on 15 patients with clinical evidence of stable angina. Basal value (B) and atrial pacing (AP)-dependent changes were evaluated before and 30 min after ointment administration. After treatment tension time index (TTI) basal value showed a 19% reduction (p less than 0.05). Compared to the control a lesser AP-dependent increase was also noted (27%, compared to 45%; p less than 0.005). According to TTI reduction, MVO2 showed an evident decrease both in basal conditions and during AP (21% and 29.6%, respectively). On the contrary, diastolic pressure time index (DPTI) does not result significantly influenced by the treatment. Consequently, DPTI/TTI ratio increase is largely the result of TTI reduction, which is well correlated to myocardial oxygen demand. Coronary sinus blood flow decrease (16% and 27% under basal conditions and during AP, respectively) confirms that the therapeutic efficacy of the ointment does not result from an increase in myocardial oxygen supply. Finally, during AP nitroglycerin ointment resulted in a significant decrease in myocardial lactate release (L% mean value ranges from-17.5% to 3.4%; p less than 0.001). Such an improvement probably reflects a primary influence of the drug on the extracoronary vascular bed.

In 14 patients during exercise, intravenous nitroglycerin improved anginal threshold and increased workload compared with control subjects. At similar workloads, the decreased left ventricular volumes suggested decreased myocardial oxygen consumption due to peripheral unloading. At maximal exercise with nitroglycerin (50 +/- 17 to 79 +/- 15 watts), rate-pressure product and end-diastolic volumes were higher with less ischemia, suggesting myocardial supply was improved by nitroglycerin.

Seventeen subjects ranging from 36 to 58 years of age presented with chest pain suggestive of myocardial ischemia. Each patient had a positive double Master's two-step test with ST segment depression of 0.5 mm. or more in the postexercise ECG. In each case coronary angiography and left ventriculography were normal. Hemodynamic and metabolic investigations were carried out during sinus rhythm and atrial pacing. Thirteen patients experienced pain during pacing but only one showed an abnormal hemodynamic response. Two patients showed abnormal myocardial lactate metabolism during the control period and four during pacing-induced tachycardia. The increase in ejection fractions in this group suggests hyperdynamic ventricular contraction which could result in increased oxygen requirements and thus induce ischemic pain in the absence of arteriographically demonstrable coronary artery disease.

External pressure counterpulsation (ECP) has been reported to improve the clinical status of patients with angina pectoris. To document the mechanisms for such an improvement left ventricular oxygen consumption and lactate metabolism, coronary sinus blood flow, and cardiac index were studied in 10 patients with angina pectoris 1) prior to and during ECP; and 2) during right atrial pacing before and after 4 consecutive 2-hour sessions of ECP treatment. During ECP peak early and mean arterial diastolic pressures were significantly raised above control values by 32 and 13% respectively. However, coronary sinus blood flow, left ventricular oxygen consumption and left ventricular lactate extraction, mean systolic arterial pressure and cardiac index were not significantly altered by ECP. Right atrial pacing at 140 beats/min increased coronary sinus blood flow 70% over control values and induced angina and ischemic ST segment changes in 8 patients before and after 4 consecutive treatments of ECP. ECP treatment did not significantly modify the above metabolic and hemodynamic responses at rest or during atrial pacing. Although 5 patients reported improvement in angina symptoms the effect was transitory. No significant improvement over pre ECP-treatment exercise angina threshold was observed immediately following or at 1 and 3 months post treatment. This method of noninvasive circulatory assistance appears to be of doubtful value in the management of patients with stable angina pectoris.