The effect of a neuropeptide Y Y1 receptor antagonist in patients with angina pectoris.

AIMS: Neuropeptide Y (NPY) is a potent vasoconstrictor released during sympathetic activation that may be involved in myocardial ischaemia. We examined the effect of a Y1 receptor antagonist on haemodynamic and ischaemic responses to exercise in patients with coronary artery disease. METHODS AND RESULTS: Eighty-two evaluable male patients were included in a randomized, double blind, two-way crossover study with a low dose (6.7 microg/kg/min; n=59)and a high dose (13.3 microg/kg/min; n=23) of the Y1 receptor antagonist AR-H040922 given as infusions for 2h or placebo. Myocardial ischaemia during a symptom-limited exercise test was monitored by conventional ST-segment analysis and heart rate (HR)-adjusted ST changes including the ST/HR slope and ST/HR recovery. Administration of the high dose AR-H040922 attenuated systolic blood pressure by 6-11 mmHg (p<0.05) during and after exercise without affecting HR. None of the two doses of AR-H040922 influenced any of the ischaemic parameters or duration of exercise, however. The maximal increase in NPY was higher during AR-H040922 (p<0.05) compared with placebo. CONCLUSIONS: Selective NPY Y1 receptor blockade attenuates the increase in blood pressure during exercise indicating a role for endogenous NPY in blood pressure regulation. Despite this effect, the Y1 receptor antagonist did not influence exercise-induced ischaemic parameters in patients with coronary artery disease.

A new method to quantify postexercise ST-deviation--the ST-deficit. A study in men at high and low-risk for coronary heart disease.

BACKGROUND: Quantitative heart rate adjusted exercise ST criteria like microV/beats per minute (bpm) improve the diagnostic accuracy of the exercise ECG. However, there are few quantitative HR adjusted postexercise variables available. The aim of the present exercise study was to evaluate a new such variable from computerized averaging of the postexercise ECG. METHODS: The presence of possible myocardial ischaemia in a population based sample of 74 elderly male hypertensives at high-risk of coronary heart disease, and in 42 age-matched clinically healthy males (reference group) at low-risk was assessed by exercise ECG. All men had a normal resting ECG without signs of ischaemia. VARIABLES STUDIED: standard ST-criteria, ST/HR slope < or =-2.4 microV. bpm-1, shape of the rate-recovery loop, the latter also with a new quantitative variable, the ST-deficit. RESULTS: In spite of a normal resting ECG many subjects showed an abnormal ST/HR slope during exercise, 43% in the hypertension group and 26% in the reference group. An abnormal rate-recovery loop (ST-deficit) also contributed substantially to identify patients with possible myocardial ischaemia, 30 vs. 10%, respectively (P<0.02); cumulatively for the two HR adjusted criteria 53% vs. 29%, respectively (P<0.02). Mean ST-deficit was significantly lower in the high-risk group. CONCLUSIONS: Effort-related myocardial ischaemia is frequently silent in elderly high-risk hypertensives and necessitates testing, preferably with computerized exercise ECG and heart rate adjusted ST criteria. A new quantitative variable to assess the postexercise rate-recovery loop in the time domain, the ST-deficit is described. This variable seems to effectively discriminate between subjects with low and high-risk for coronary heart disease and thus provides new information. Further studies are warranted to validate this variable against myocardial perfusion scintigraphy and coronary angiography.

Postexercise ischemia is associated with increased neuropeptide Y in patients with coronary artery disease.

BACKGROUND: Neurohormones may influence vascular tone both during and after exercise. Neuropeptide Y (NPY), which is costored and released with norepinephrine (NE) during sympathetic activity, is a potent vasoconstrictor with a relatively long half-life. We therefore examined its possible association with the ischemic response to exercise in patients with coronary artery disease. METHODS AND RESULTS: Twenty-nine male patients with effort-induced angina pectoris underwent a symptom-limited exercise test. In addition to conventional ST-segment analysis, we examined ischemia on the basis of heart rate (HR)-adjusted ST-segment changes through calculation of the ST/HR slope during the final 4 minutes of exercise and of the ST/HR recovery loop after exercise. Blood samples were taken before, during, and after exercise for an analysis of several neurohormones. Mean ST-segment depression was -223+/-20.2 microV (P:<0.0001) just before the termination of exercise, followed by a gradual normalization, but it remained significant after 10 minutes (-49+/-8.9 microV, P:<0.0001). At the end of exercise, the ST/HR slope, which reflects myocardial ischemia, was -6.0+/-0.77 microV/HR. In most patients, ST-segment levels at a given HR were lower during recovery than during exercise, here referred to as ST "deficit." Exercise increased the plasma levels of NPY, NE, epinephrine, and N-terminal proatrial natriuretic peptide, but big endothelin remained unchanged. Although NE and epinephrine peaked at maximal exercise, the highest levels of NPY and N-terminal proatrial natriuretic peptide were observed 4 minutes after exercise. The maximal increase in the NPY correlated significantly with ST-segment depression at 3 minutes after exercise (r=-0.61, P:= 0.0005), the ST deficit at the corresponding time point (r=-0.66, P:= 0.0001), and the duration of ST-segment depression after exercise (r= 0.42, P:=0.02). In contrast, no such correlations were found for NE. CONCLUSIONS: The present study has for the first time demonstrated a correlation between plasma NPY levels and the degree and duration of ST-segment depression after exercise in patients with coronary artery disease, which suggests that NPY may contribute to myocardial ischemia in these patients.

Excretion of thromboxane A2 and prostacyclin metabolites before and after exercise testing in patients with and without signs of ischemic heart disease.

We addressed the hypothesis that platelets are not activated in association with effort-induced myocardial ischemia in stable coronary disease. Seventy-two patients undergoing a diagnostic bicycle exercise test were stratified according to the development of chest pain (yes/no, 33/39) and of exercise-induced ST-segment depression of at least 200 microV in the electrocardiogram (yes/no, 12/60). Noninvasive indexes of platelet activation and of platelet/vessel wall interaction (urinary excretion of the 2,3-dinor-metabolites of thromboxane A2 [Tx-M] and prostacyclin [PGI-M], respectively) were analyzed in samples collected in the basal state and after the test. Basal Tx-M and PGI-M did not differ in patients with (236 +/- 35 and 131 +/- 22 pg/mg creatinine, respectively) and without (185 +/- 16 and 101 +/- 13 pg/mg creatinine, respectively) chest pain, or in those with (178 +/- 45 and 162 +/- 41 pg/mg, respectively) and without (216 +/- 22 and 104 +/- 11 pg/mg, respectively) ST-segment depression during the test. Patients without chest pain or without ST-segment depression moderately increased (p less than 0.05) their urinary Tx-M (by 21% and 13%, respectively) and PGI-M (by 28% and 23%, respectively) after exercise. No significant increases were observed in those developing chest pain or ST depression during exercise. These data indicate that effort-induced myocardial ischemia is not associated with an increase in platelet activation or platelet/vessel wall interaction in patients with stable coronary disease.

The importance of nose-breathing for the systolic blood pressure rise during exercise.

The effect of nose breathing on the systolic blood pressure was examined in ten healthy men. Nose breathing was increased above normal by exercise and tested by maximum bicycle ergometry. When the anterior part of the nose was dilated with Nozovent the nasal airflow increased by on average 29%. In this condition, all ten men could cycle at maximum load without mouth breathing and there was a significantly lower increase (13 mmHg) in the systolic blood pressure than when the nasal dilator was not used. The reason for this lower blood pressure increase is unknown. The hypothesis is put forward, however, that facilitated nose breathing decreases the respiratory work, which in turn lowers the systolic blood pressure during exercise.

A cross-sectional analysis of glucose tolerance and cardiovascular disease in 67-year-old men.

The relationship between degree of glucose tolerance and cardiovascular disease has been studied in a cross-sectional population survey of 644 men born in 1913, randomly sampled and examined at the age of 67. The cohort was divided into different groups according to current diagnostic criteria for diabetes and impaired glucose tolerance. An almost 2-fold higher prevalence of hypertension, myocardial infarction, angina pectoris, and congestive heart failure was found in the group with impaired glucose tolerance compared to the group with a normal glucose tolerance. Fifty per cent of the men with impaired glucose tolerance were being treated with some drug for cardiovascular disease, usually diuretics for hypertension. Intermittent claudication showed a 2.5-fold higher prevalence among the diabetic patients. A computerized 12-lead exercise-ECG test, with a unique accuracy in measuring ST-segment changes, was performed in a subset of 135 men. This showed no association between ST-segment depression and different degrees of glucose tolerance, even when accounting for confounding factors such as treatment with beta-blocker agents or digoxin, pathological Q-waves, and differences in maximal heart rate.

Effects of cold on ST amplitudes and blood pressure during exercise in angina pectoris.

To investigate the mechanisms of cold susceptibility in angina pectoris nine male angina patients were studied. All were cold susceptible by history and had developed ischaemic ST changes during a previous exercise test. The patients underwent two additional bicycle exercise tests, one in a cold chamber with an average temperature of -8 degrees C, and the other at room temperature. The ECG was computer analysed and the intra-arterial blood pressure was measured. No significant decrease in work capacity was found during exercise in the cold chamber. In the cold, systolic blood pressure was consistently higher throughout the test and in seven of nine subjects ST depression was more pronounced at corresponding workloads. ST depression was also analysed versus heart work which was assessed as rate pressure product. In the cold, 1 mm ST depression appeared at a somewhat higher rate pressure product when compared to room temperature. It was concluded, therefore, that an augmented heart work, secondary to substantial increases in blood pressure, appears to account for the cold-induced increase in ST depression found in the angina patients in this study.

Correlation of coronary arteriography after acute myocardial infarction with predischarge limited exercise test response.

This study of post-acute myocardial infarction (AMI) patients compared the extent and distribution of coronary narrowings and left ventricular dysfunction in 45 patients who had greater than or equal to 1 mm ST-segment depression on a predischarge low-level exercise test (positive-result group) with those found in 78 patients who had less than 1 mm ST depression (negative-result group). Cardiac catheterization was done 50 +/- 20 days (mean + standard deviation) after AMI. Patients with positive responses more often had multivessel coronary artery disease (80 vs 47%, p = 0.001) and a greater than or equal to 75% narrowing in the left anterior descending (LAD) (87 vs 62%, p = 0.003) and left circumflex (71 vs 37%, p = 0.001) arteries, as well as in the proximal LAD segment before the first septal branch (58 vs 29%, p = 0.002). Among patients with positive responses 93% had normal or hypokinetic wall motion in the vascular territory of a severely diseased coronary artery (viable but potentially ischemic myocardium) while 63% of the negative-result group had these findings (p = 0.001). No difference in ejection fraction could be identified between the 2 groups (54 +/- 15% vs 54 +/- 16%). Prior studies of AMI patients have shown that ST-segment depression on a predischarge low-level exercise test will identify patients at higher risk of subsequent cardiac death. Our observations have identified differences in cardiac angiographic findings between patients with positive and negative responses to this test that may explain this difference in outcome.

Early heart failure in the population. The study of men born in 1913.

A cross-sectional analysis of characteristics possibly associated with congestive heart failure (CHF) was performed among 644 men, all 67 years of age and randomly selected from the general population. A total of 13% had symptoms and signs of overt CHF. Another 10% had early or "latent" CHF. Among overt CHF cases, 46% had hypertension, 55% coronary heart disease and 79% any one of these conditions. Among "latent" CHF cases, the corresponding proportions were 52%, 25% and 65%. Simple indices of left ventricular diastolic function and filling pressure as well as of pulmonary artery pressure were closer related to the CHF stage, than were measures of systolic left ventricular function. Smoking habits, hypertension, blood lipids, weight and other measures of body fat, blood glucose, and serum insulin were all correlated to CHF stage. In a multivariate analysis, smoking habits, hypertension, body weight, and serum insulin were independently and significantly correlated to CHF stage.

Cardiac anti-ischemic effect of metoprolol: role of beta-blockade within the ischemic region.

The distribution of metoprolol and atenolol into ischemic and nonischemic myocardium was studied in anesthetized dogs, pigs, and cats. The beta-blockers were administered intravenously after coronary artery occlusion. Metoprolol was found to be significantly more efficiently distributed to the ischemic myocardium than atenolol in all three species. To investigate the functional implications of this difference in tissue distribution, the anti-ischemic effects of the two beta-blockers were studied in the 2-h period following coronary artery occlusion in anesthetized cats, in which heart rate was kept at a constant level. In this model, metoprolol (0.3 mg.kg-1 + 0.15 mg.kg-1.h-1) was found to attenuate or delay the developing ischemic process. This is shown by its significant reduction of (a) the decline of CK activity in ischemic myocardium, (b) the ST elevation in a precordial ECG lead, and (c) the decrease of arterial pressure and cardiac output. In contrast to metoprolol, atenolol (0.3 mg.kg-1 + 0.15 mg.kg-1.h-1) caused no significant anti-ischemic effect in this cat model. The difference in the effectiveness of the two drugs can most probably be explained by their differential distribution in the ischemic heart. Furthermore, the anti-ischemic effect of metoprolol shows that the presence of a beta-blocker in ischemic left ventricular myocardium can favorably affect the early phase of developing infarction.

Computer aided exercise electrocardiographic testing and coronary arteriography in patients with angina pectoris and with myocardial infarction.

A set of electrocardiographic criteria for the diagnosis of coronary artery disease was evaluated in two different groups of patients examined by computer aided 12 lead exercise electrocardiographic stress testing and coronary arteriography. One group consisted of patients with severe angina pectoris and the other of patients who had suffered a myocardial infarction three years before the study. Angiographically determined categories of patients could be identified with satisfactory precision by the electrocardiographic criteria under test in the patients with angina pectoris but not in those with infarction. A new method of classifying patients on the basis of data from coronary arteriography improved the correlation with ST segment analysis compared with conventional classification.

Pafenolol, a new beta 1-selective blocking agent, in mild hypertension. Result of an inpatient study and a subsequent outpatient follow-up.

Pafenolol, a new selective adrenergic beta 1-blocking agent, has been tested for the first time in 6 hypertensive patients. After single oral doses of pafenolol 25 to 100 mg, there was a marked reduction in heart rate and systolic blood pressure during exercise tests. These effects were dose dependent. A significant positive correlation was found between the reduction in heart rate during exercise and the plasma level of pafenolol 5 hours after drug intake (correlation coefficient r = 0.94). Side effects were mild and seemed to be dose dependent. It is concluded that this new beta 1-blocking agent was effective in reducing blood pressure and was well tolerated.

A program for processing of multiple-lead exercise ECGs in real time.

A computer program for continuous recording and real-time processing of 8-channel exercise ECGs is presented. Current average ECG complexes and trends of various morphological and rhythmic parameters can be displayed on a TV monitor during the stress test. Average complexes computed every 10 s, the time of occurrence and 6 morphological coefficients of all detected tentative QRS complexes, and data manually entered by the operator are stored in a file on disk. The operational procedures and the principal signal processing are briefly presented. The main attention is given to a description of the software structure, explaining the subdivision of the program into dedicated autonomous sections and the system for the coordination of simultaneous activities of different priority.

Real-time processing of multiple-lead exercise electrocardiograms.

A system for continuous recording and real-time processing of eight-channel exercise ECGs is presented with emphasis on the algorithms performing the principal signal processing. The hardware and the operational procedures are briefly described. New methods have been developed for the detection, alignment, and selection of complexes to be used in the creation of eight-dimensional average ECG complexes every 10 s. These algorithms are based on digital filter functions approximating low-order Legendre polynomials in order to be robust in the presence of noise.

Computerized exercise ECG in the diagnosis of critical coronary lesions.

Different ECG criteria are evaluated with respect to their ability to identify individuals with critical lesions of the coronary arteries in a population of patients with severe angina. Six chest leads and the the limb leads were recorded in 85 patients by computer during maximal, symptom-limited exercise ECG testing. Averaging of ECG complexes enhances the signal quality and makes it possible to use measurements of the limb leads recorded during exercise. 14 patients with abnormal Q waves in lead V2 were excluded from ST analysis. In the remaining 71 patients, more than 1/3 mm ST depression in lead I and/or more than 2.0 mm ST depression in any of the chest leads had a sensitivity of 85% and a specificity of 67% for lesions in the main stem and/or proximal LAD and/or three-vessel disease. The predictive value of a positive test was 83%. This and other criteria were evaluated for different disease groups and a different stages during the exercise test.

Beta-receptor blocker withdrawal. A preoperative problem in general surgery?

A prospective randomized study was performed in 91 patients scheduled for general surgery on 99 occasions. The patients were chronically (greater than 3 months) treated with beta-receptor blockers because of ischaemic heart disease and/or hypertension and the beta-receptor blockade was either gradually withdrawn (n = 51) during 4 days preoperatively or continued until surgery (n = 48). The effects on arterial blood pressure (BP), heart rate (HR) and rate-pressure product (RPP) at rest and the incidence of chest pain during daily activities were registered. A withdrawal of the beta-receptor blockade was associated with increases of HR (in eight patients greater than 30 beats min-1) and RPP and in patients treated for hypertension there were also increases of systolic and diastolic BP (in five patients greater than or equal to 30/15 mmHg). Patients who continued the beta-receptor blockade until surgery showed no changes. Nine out of 23 patients with a previous history of ischaemic heart disease had an increase of chest pain after withdrawal of the beta-receptor blockers, whereas none of the corresponding 25 patients who continued the therapy suffered from an increased chest pain. Due to the severity of symptoms after beta-receptor blocker withdrawal, surgery had to be postponed in 4 patients. The observations suggest that a 4-day preoperative withdrawal of long-term beta-receptor blockade is potentially hazardous in ischaemic and/or hypertensive patients.

Beta-receptor blockade and spinal anaesthesia. Withdrawal versus continuation of long-term therapy.

A prospective study was performed in 43 men scheduled for transurethral resections under spinal anaesthesia. All patients were on chronic beta-receptor blockade because of hypertension and/or ischaemic heart disease. The patients were randomly subjected to either a gradual preoperative withdrawal or a continuation of the beta-receptor blockade. Haemodynamics were measured non-invasively. Spinal anaesthesia was performed and an i.v. injection of atropine given. The patients were then placed in a lithotomy position. Mean anaesthetic level included T6. After beta-receptor blocker withdrawal consistently elevated heart rates, a high incidence of arhythmias, angina pectoris and postoperative ST-T changes indicating myocardial ischaemia were seen. These changes were not seen in patients with continued beta-receptor blockade. Withdrawal of beta-receptor blockers was also associated with an increased total peripheral vascular resistance in connection with spinal anaesthesia. These results suggest that patients on long-term beta-receptor blockade should continue the therapy during and after spinal anaesthesia.