J. P. Bagger

Effect of Verapamil in Intermittent Claudication A Randomized, Double-Blind, Placebo-Controlled, Cross-over Study After Individual Dose-Response Assessment

BACKGROUNDnThe calcium antagonist verapamil is a vasodilator drug that has been shown to increase oxygen extraction of ischemic tissues in coronary and peripheral vascular disease.nnnMETHODS AND RESULTSnSince the balance between the positive and the negative effects of vasodilation may be delicate in ischemic diseases a dose-response study (dose range, 120 to 480 mg) was established to determine optimal, individual dosages of slow-release verapamil in 44 patients with stable intermittent claudication (Fontaine classification stage II) with respect to walking capacity. A randomized, double-blind, placebo-controlled, cross-over study (4 weeks) was performed to assess clinical and hemodynamic effects of verapamil. The optimal daily dose of verapamil on maximal walking ability was 120 (8 patients), 240 (8 patients), 360 (14 patients), and 480 mg (14 patients). Walking distances were measured at a metronome-controlled speed of 60 steps per minute on level surface. Optimal individual doses of verapamil increased mean pain-free walking distance by 29% from 44.9 to 57.8 meters (P < .01) and maximal walking distance by 49% from 100.7 to 149.8 meters (P < .001) compared with placebo. The increase in maximal walking distance correlated positively only with initial systolic ankle pressure (r = .49, P < .001) and ankle/brachial pressure index (r = .37, P < .013). Verapamil had no effect on systolic ankle pressure, ankle/brachial pressure index, peripheral leg temperature, or blood pressure, which suggests that the drug may have extrahemodynamic effects, possibly brought about through improved oxygen metabolism.nnnCONCLUSIONSnVerapamil showed significant clinical benefits in patients with moderate intermittent claudication in this short-term study. Individual optimization of drug dosage should be considered an option both in trials and in the clinical setting in these patients.

Functional significance of recruitable collaterals during temporary coronary occlusion evaluated by 99mTc-sestamibi single-photon emission computerized tomography.

OBJECTIVESnThe present study evaluated the impact of recruitable collaterals on regional myocardial perfusion measured by 99mtechnetium (Tc)-sestamibi single-photon emission computerized tomography (SPECT) during temporary coronary occlusion and related these estimates to the coronary wedge pressure and electrocardiographic (ECG) ST-segment changes.nnnBACKGROUNDnClinical variables (angina and ECG changes) and intracoronary flow and pressure recordings have indicated a protective role of recruitable collaterals on myocardial perfusion during percutaneous transluminal coronary angioplasty (PTCA).nnnMETHODSnThirty patients (mean age 55 years, SD 9; 20 men) with stable angina pectoris and proximal nonocluding single-vessel left anterior descending coronary artery (LAD)-stenosis scheduled for PTCA were included. Visualization of recruitable collaterals by ipsilateral and contralateral contrast injection, registration of coronary wedge pressure and injection of 99mTc-sestamibi during 90-s LAD occlusions were undertaken. A rest perfusion study was performed within four days before PTCA. As an estimate of the severity of regional hypoperfusion during occlusion, an occlusion/rest count ratio was calculated (mean defect pixel count during occlusion divided by mean pixel count in identical regions at rest).nnnRESULTSnThe scintigraphic occlusion/rest count ratio was higher in patients with recruitable collaterals (n = 16), 67 +/- 11%, compared to patients without collaterals (n = 14), 60 +/- 6% (p < 0.05). The occlusion/rest count ratio correlated with the coronary wedge pressure (R2 = 0.34; p < 0.001). The occlusion/rest count ratio was lower, 61 +/- 6%, in patients with ST-segment elevation (n = 23) versus 74 +/- 9% in patients without ST-segment elevation (n = 7) (p < 0.0001).nnnCONCLUSIONSnUsing 99mTc-sestamibi SPECT imaging during brief episodes of coronary occlusion, the severity of regional myocardial hypoperfusion was reduced by the presence of recruitable collaterals in a selected patient population with proximal LAD stenoses. Our results demonstrate a protective effect of recruitable collaterals on myocardial perfusion during temporary coronary occlusion.

Effects of Ranolazine on Ischemic Threshold, Coronary Sinus Blood Flow, and Myocardial Metabolism in Coronary Artery Disease

Cytoprotection or metabolic modulation is a new principle in the treatment of angina pectoris. The effect of ranolazine (a cytoprotective drug) on ischemic threshold, coronary sinus blood flow, and myocardial metabolism was evaluated by means of two pacing sequences in nine male patients with coronary artery disease (CAD) and in eight male controls. Ranolazine was given as an intravenous bolus followed by continuous infusion; the mean total dose was 32.7 mg and 31.7 mg in patients and controls, respectively. Angina pectoris was relieved in two patients after ranolazine but pacing time to pain was unchanged in the remaining patients. Maximal ST depression was lower (p = 0.02), but pacing time to maximal and to 1-mm ST depression remained unchanged after the drug. Ranolazine had no overall influence on coronary sinus blood flow, cardiac oxygen consumption, blood pressure, and heart rate. Cardiac uptake of free fatty acids (FFA) was reduced (p = 0.01), and net uptakes of glucose (p = 0.07) and lactate (p = 0.06) tended to be lower after ranolazine in CAD patients and controls. Ranolazine had no direct influence on cardiac exchange of glutamate, alanine, and citrate or on the arterial concentration of any metabolite. In the present study ranolazine had minimal clinical effects. A decrease in myocardial FFA utilization, however, allows greater myocardial glucose oxidation, which may increase the energy production in relation to oxygen availability.

Mechanics of porcine coronary arteriesex vivo employing impedance planimetry: A new intravascular technique

Our objective was to evaluate methodological aspects of impedance planimetry, a new balloon catheter-based technique, for the investigation of coronary artery mechanical wall properties. We used a four ring-electrode electrical impedance measuring system that was located inside a balloon. Two of the electrodes were used for excitation and connected to a generator producing a constant alternating current of 250 mA at 5 kHz. The other two electrodes for detection were placed midway between the excitation electrodes. The balloon was distended with electrically conducting fluid through an infusion channel. The vessel cross-sectional area (CSA) was measured according to the field gradient principle by measuring the impedance of the fluid inside the balloon. Impedance planimetry was applied in the three major branches of the coronary arteries of seven extracted porcine hearts to assess luminal CSAs in response to internal pressurization. The biomechanical wall properties were evaluated by computing the strain [(r−r0)·r0−1, wherer is the vessels inner radius computed as (CSA · π−1)½ andr0 is the radius of the vessel at a minimal distension pressure], the tension [(r·dP), wheredP is the transmural pressure difference], and the pressure elastic modulus (ΔP·r·Δr−1). We found thatin vitro testing demonstrated that impedance planimetry was accurate and reproducible. The technique has controllable sources of crror. Measurements were performed with consecutively increasing pressures in the range 1–25 kPa (8–188 mmHg, 0.01–0.25 atm). The CSAs increased nonlinearly and were significantly larger in the left anterior descendent coronary artery (LAD) (1 kPa, mean 5.0 mm2; 25 kPa, mean 21.8 mm2) than in both the left circumflex (Cx) (4.5–16.0 mm2) and the right coronary artery (RCA) (2.8–15.6 mm2) (analysis of variance,P<0.001 for both). The circumferential wall tension-strain relation showed exponential behavior. For a given strain, tension values for LAD were significantly lower than those of Cx (P<0.01). The pressure elastic modulus-strain relation also was exponential, and values for Cx were significantly lower than values for LAD (P<0.001) and RCA (P<0.05). Impedance planimetry was applied to the study of coronary artery biomechanicsex vivo. The LAD had the largest CSA, and the Cx was the least compliant. Methodological aspects of anin vivo introduction of the method require additional evaluation.

Placebo-controlled, double-blind study of the effect of verapamil in intermittent claudication

The clinical effect of verapamil was tested in 24 patients with intermittent claudication in a randomized, placebo-controlled, double-blind, crossover study. Slow-release verapamil or placebo was given for two periods of three weeks. The walking distance, systemic blood pressure, and ankle-brachial blood pressure index were measured. Furthermore, a possible change in peripheral vascular tone was provoked by hyperventilation. The walking distance rose after both verapamil (40%) and placebo (31%) (p<0.01 for both) but tended to increase only after verapamil (7%) as compared with placebo. Blood pressure fell equally after both verapamil and placebo (p<0.05 for both). Verapamil did not influence the ankle-brachial blood pressure index. No signs of vasoactivity in the lower extremities were seen after hyperventilation. Although the greatest individual improvements in walking distance were seen after verapamil administration, it was not possible to predict positive responders among the patients.

A NEW METHOD FOR COMBINED ISOMETRIC AND ISOBARIC PHARMACODYNAMIC STUDIES ON PORCINE CORONARY ARTERIES

1. The principal aim of the present study was to explore the isometric and isobaric capacity of a new intravascular technique, impedance planimetry, in basic pharmacodynamic investigations on porcine isolated epicardial coronary arteries.

In Vivo Assessment of Luminal Cross-Sectional Areas and Circumferential Tension-Strain Relations of the Porcine Aorta

UNLABELLEDnThe objectives were to measure the pressure--cross-sectional area relations and intrinsic stiffness of the porcine aorta in vivo.nnnMETHODSnMeasurements were made in 12 pigs, weight 30, 50 or 75 kg, proximal and distal to the bifurcation of the renal arteries, using an electrical impedance system which was located inside a balloon mounted on a catheter. Vessel cross-sectional area (CSA) was assessed by measuring impedance of the fluid inside the balloon during distension.nnnRESULTSnIn vitro testing demonstrated the accuracy and reproducibility of impedance planimetry. In vivo steady-state CSA values showed non-linear relationship with rising distension pressures. Mean CSA values rose with increasing weight of the pigs. the suprarenal aorta was larger than the infrarenal only in 75 kg pigs (p < 0.05). At three measurements the within-subject variation was 0.89% and the between-subject variation 99.11%. Nitroglycerine infusion produced only minor, insignificant CSA increase, indicating negligible tone in the abdominal aorta. All segments showed circumferential wall strain-tension relations with exponential behaviour uninfluenced by weight class or site in the aorta.nnnCONCLUSIONnInformation of vascular mechanics in vivo is obtainable by catheterization of the abdominal aorta.

Increased coronary sinus lactate concentration during pacing induced angina pectoris after clinical improvement by glyceryl trinitrate.

Ten patients with stable angina pectoris and obstructed coronary arteries (greater than 75% reduction in diameter) were studied before and during two periods of pacing, the second of which was preceded by sublingual administration of glyceryl trinitrate (mean dose 0.78 mg). Coronary sinus blood flow measurements and aortocoronary sinus blood sampling for metabolite determinations were carried out. Although the rate of pacing was increased by 10 beats/minute after glyceryl trinitrate administration, the onset of angina was delayed in eight patients during pacing. Drug administration decreased coronary sinus blood flow by 42% and myocardial oxygen uptake by 41% during pacing and induced a shift in mean lactate extraction towards a net release (from 3.1% to -12.6%). It increased the number of patients producing lactate from three to five. Glyceryl trinitrate administration decreased myocardial glucose uptake throughout the study, decreased lactate extraction during recovery, and increased the aortocoronary sinus citrate gradient at rest and during recovery, while the exchange of free fatty acids remained unchanged. A decrease in aortocoronary sinus lactate difference during pacing after glyceryl trinitrate administration correlated positively with the fall in coronary sinus blood flow. The metabolic data do not indicate an augmented myocardial lactate production after glyceryl trinitrate administration. A decrease in coronary sinus blood flow seems, therefore, to be of primary importance in explaining the elevated coronary sinus lactate concentration. Our finding that coronary sinus lactate concentration increased during pacing after glyceryl trinitrate administration despite clinical improvement questions the validity of its use as a quantitative index of ischaemia.

Myocardial release of citrate and lactate during atrial pacing-induced angina pectoris

Arterio-coronary sinus (A-Cs) differences of plasma citrate, glucose, free fatty acids and blood lactate were measured in 19 patients with coronary artery disease (CAD) and in eight control subjects exposed to atrial pacing. Among patients with CAD 11 showed a myocardial release of lactate during pacing (lactate producers, LP) while myocardial lactate extraction was unchanged in the remaining eight patients (lactate non-producers, LNP). In patients with CAD, (A-Cs) plasma citrate differences became increasingly negative during recovery from pacing, values at rest and at 3-5 min of recovery were: -5 +/- 2 mumol/l (mean +/- SD) vs. -12 +/- 5 mumol/l in LP (P less than 0.001) and -6 +/- 3 mumol/l vs. -8 +/- 4 mumol/l in LNP (P less than 0.01). In controls, (A-Cs) citrate difference varied inversely, from -8 +/- 4 mumol/l at rest to -2 +/- 4 mumol/l at 3-5 min of recovery (P less than 0.001). An increasingly negative (A-Cs) plasma citrate difference during recovery from pacing-induced angina pectoris is suggested to reflect a wash-out of accumulated citrate from ischaemic heart cells; and is proposed as a more sensitive marker of ischaemia in man than a myocardial release of lactate.

Whole blood versus plasma measurements of glutamate and alanine across the human myocardium

Comparison of whole blood and plasma aorto-coronary sinus concentration differences of glutamate and alanine were made before, during and after coronary sinus pacing in seven patients with normal and six patients with stenotic coronary arteries. Mean differences between duplicate analyses were greater in whole blood than plasma both of glutamate (7.5 +/- 5.8 vs. 3.3 +/- 3.0 mumol/l, p less than 0.001) and of alanine (7.9 +/- 7.0 vs. 3.8 +/- 3.4 mumol/l, p less than 0.001). Concentrations of glutamate were 3.4 and of alanine 1.4 times higher in whole blood than in plasma. Blood cells were calculated to be responsible for about 20% of glutamate and alanine blood exchanges across the heart. Plasma and whole blood fluxes were closely positively correlated (glutamate:r = 0.81, alanine:r = 0.88) and had always the same direction. Differences in myocardial exchanges of amino acids between the patients with and without coronary artery disease, as well as rapid changes during pacing, could be demonstrated in plasma analyses but were not significantly reflected in whole blood glutamate determinations. This seemed to be due to the greater variations in whole blood analysis. In conclusion, differences in aorto-coronary sinus plasma concentrations reflected, although underestimated, whole blood fluxes. Because of considerable gains in precision of analysis, plasma should be preferred to whole blood for evaluations of glutamate and alanine exchanges across the human heart.