Hemodynamic and antiischemic effects of intravenous elgodipine,a new dihydropyridine calcium channel blocker,in patients with chronic stable angina

Summary Elgodipine is a new second-generation dihydropyridine calcium antagonist. Its hemodynamic and antiischemic properties were evaluated in a single-blind, placebocontrolled trial in 22 males with chronic stable angina. Coronary artery disease was angiographically confirmed. Measurements were performed with a Swan-Ganz thermodilution catheter during a 30-minute period of rest and before the end of a 4-minute bicycle exercise test at maximum individual workload, both with placebo (IV infusion of 5 ml saline over 30 minutes) and elgodipine (10 µg/kg/2 min bolus IV, then IV infusion of 1 µ/kg/min for 28 minutes. Elgodipine caused very similar hemodynamic changes at rest and during exercise. Its major hemodynamic modification was the marked decrease in systemic vascular resistance, which was accompanied by an increase in cardiac index and stroke volume. Mean arterial blood pressure was slightly reduced, whereas the opposite small increase in heart rate meant that the double product remained unchanged. Contrary to resting conditions, pulmonary capillary wedge pressure, pulmonary artery pressures, pulmonary vascular resistance, and mean right atrial pressure remained normal or increased to a lesser extent during exercise after elgodipine. After elgodipine ischemic ST depression during exercise was diminished, and 11 of 16 assessable patients remained free from angina pectoris. We conclude that elgodipine is an efficacious antianginal drug. Its major mechanism of action is lowering of systemic vascular resistance. Thus elgodipine improves systolic cardiac function in patients with chronic stable angina and may delay the onset of ischemic diastolic dysfunction during exercise, as indicated by a normal left ventricular end-diastolic pressure (LVEDP). The data also suggest an improvement in coronary blood flow during exercise.     

Hemodynamic effects of intravenous elgodipine in coronary artery disease during rest and exercise, and basic pharmacokinetic parameters

Summary Using an echo-Doppler method (Quantascope), the hemodynamic profile of the calcium channel antagonist elgodipine (64 g/kg, iv) was investigated in 22 patients with angina pectoris at rest and during exercise. A placebo control was used. At rest, elgodipine significantly decreased systemic vascular resistance as well as systolic and diastolic blood pressure, while increasing cardiac output and stroke volume. During supine bicycle exercise at constant workload, elgodipine significantly increased cardiac output and stroke volume, and decreased the rate-pressure-product (double product); the exercise systolic blood pressure was decreased without change in the diastolic component. Elgodipine significantly reduced the incidence and severity (self-rated pain score) of exercise-induced anginal symptoms. Heart rate was not affected by elgodipine, either at rest or during exercise. In particular, no negative inotropy could be inferred from the echo-Doppler data. In the elgodipine plasma concentration profile (HPLC), three phases of elimination with half-life times of less than 1 hour, between 3 and 7 hours, and between 10 and 24 hours may be distinguished, indicating a shallow and a deep compartment. The hemodynamic data indicate an intermediate pharmacodynamic profile of elgodipine, lying between that of other dihydropyridines and that of compounds such as verapamil or diltiazem.     

Hemodynamic effects of disopyramide at rest and during exercise in normal subjects

The hemodynamlc effects of disopyramide phosphate, 2.0 mg/kg body weight, given intravenously over a period of five minutes were studied at rest and during exercise in ten patients without clinical or anglographlc evidence of heart disease. Following disopyramide, the resting cardiac index was lower (4.0 ± 0.6 vs 4.3 ± 0.6 iners/min/m², mean ± 1 SO, P <0.05), while left ventricular end-dlastollc pressure (16 ± 4 vs 11 ± 4 mm Hg, P <0.001), pulmonary arterial (PA) mean pressure (20 ± 5 vs 17 ± 5 mm Hg, P <0.05), and brachlal arterial (BA) mean pressure (105 ± 8 vs 96 ± 7 mm Hg, P <0.05) were higher than the pre-infuslon resting values. During exercise, there was no change in left ventricular end-diastollc pressure while cardiac index rose from 4.0 ± 0.6 to 6.5 ± 0.6 itters/mln/m² (P <0.001) and left ventricular stroke work index increased from 62 ± 19 to 84 ± 22 gm/beat/m² (P <0.001). The normal hemodynamlc response during exercise after disopyramide despite the apparent depression of left ventricular function at rest probably reflects the positive inotroplc effect of enhanced sympathoad-renergic activity.     

Hemodynamic and antiischemic effects of tedisamil in humans

Twenty-four patients with angiographically documented coronary artery disease, chronic stable angina, and reproducible ST-segment depression took part in this openlabel, baseline-controlled study on the hemodynamic, antiischemic, metabolic, and neurohumoral effects of tedisamil following IV doses of 0.1, 0.2, and 0.3 mg/kg (eight patients in each dose group). Tedisamil produced a dose-dependent decrease in both heart rate [rest: 2.4, 7.5 (p<.01), and=" 9.2=" beats/min="><.001); exercise:=" 6,=" 4.6,=" and=" 8.9=" beats/min="><.01), respectively]=" and=" the=" index=" of=" myocardial=" oxygen=" consumption=" (exercise:=" 6–9%=" in=" each=" group)=" associated=" with=" an=" improvement=" of=" st-segment=" depression=" [–12.1%,=" –10.7%,=" –41.9%=" (p=">.01), resp.]. While cardiac output was found decreased due to the heart-rate reduction both at rest [–8.5%, –5.7%, and –10.2% (p<.05), respectively]=" and=" during=" exercise=" (2–8%),=" being=" significant=" only=" at=" rest=" in=" the=" highest=" dose=" group,=" stroke=" volume=" remained=" unaltered.=" pulmonary=" artery=" pressure,=" pulmonary=" capillary=" wedge=" pressure,=" right-ventricular=" ejection=" fraction,=" and=" pulmonary=" vascular=" resistance=" were=" without=" significant=" changes.=" blood=" pressure=" and=" systemic=" vascular=" resistance=" tended=" to=" increase,=" associated=" with=" a=" decrease=" in=" plasma=" catecholamines=" (20–40%).=" tedisamil=" produced=" a=" dose-dependent=" prolongation=" of=" qtc=" duration=" [+2%,=" +6%,=" +12%="><.05), respectively]=" with=" pq=" and=" qrs=" unaltered.=" the=" elimination=" half-life=" of=" tedisamil=" iv=" ranges=" between=" 6.8=" and=" 7.8=" hours.=" in=" conclusion,=" tedisamil,=" at=" a=" dose=" of=" 0.3=" mg/kg=" iv,=" was=" well=" tolerated=" and=" was=" found=" to=" have=" favorable=" hemodynamic=" and=" antiischemic=" effects=" in=" patients=" with=" ischemic=" heart=">     

Influence of nifedipine on left ventricular dysfunction at rest and during exercise

In order to determine the acute hemodynamic effect of nifedipineat rest and during a standardized supine bicycle exercise test(3 min, 50 W), 14 patients with left ventricular dysfunctionwere studied before and 60 min after taking 30 mg nifedipinesublingually. At rest (R) and during exercise (E), nifedipine produced a significantincrease in left ventricular systolic performance in terms ofstroke volume index (R: 33±6 to 38±4 ml/m², P<0.005;E: 32±5 to 37±6 ml/m², P<0.005) and cardiacindex (R: 2.9±0.4 to 3.6±0.5 l/min/m², P<0.001;E: 4.1±0.7 to 4.9±0.9 l/min/m², P<0.001) dueto a marked reduction in systemic vascular resistance (R: 1517±246to 1129±247 dynes s cm^–5, P<0.001; E: 1170±176to 908±129 dynes s cm^–5, P< 0.01). Pulmonary artery pressures did not change at rest, but droppedsignificantly during exercise, probably due to a shift in theleft ventricular pressure-volume relationship. The findingsof this study indicate that acute hemodynamic improvement canbe achieved by the sublingual use of nifedipine both at restand during exercise in patients with left ventricular dysfunction.Because the hemodynamic response in individual subjects mayvary, careful clinical observation or hemodynamic control isrecommended.     

Haemodynamic effects of intravenous diltiazem at rest and exercise in patients with coronary artery disease

The acute effects of intravenous diltiazem on exercise performancewere studied in 10 patients with coronary artery disease. Haemodynamicmeasurements were made at rest and during exercise before andafter 0-5 mgkg^–1 of diltiazem. Diltiazem prolonged theduration of exercise (+2.85 min, P>0.001) and delayed theonset of ischaemic ST depression or angina in all patients.The highest tolerated heart rate and pressure rate product wereincreased in all but one patient after diltiazem. At rest diltiazem decreased mean arterial pressure (–10.8%,P>0.005), systemic vascular resistance (SVR) (-11.8%, P>005)and left ventricular stroke work index (SWI) (–14.1%,P>0.005). During exercise under diltiazem therapy, at the level achievedbefore the drug, the pulmonary capillary wedge pressure (-30%,P>0005) and the SVR (–13.6%, P>0.02) were lowered,the SWI (+13%, P>0.01) was increased: at the end of exerciseonly the SVR (14%, P>0.05) was reduced. Two patients experiencedangina on lying down and one had orthostatic hypotension afterexercise with diltiazem. This study indicates that intravenousdiltiazem is a potentially useful agent for the treatment ofangina by reducing myocardial oxygen demand at rest and by improvingleft ventricular performances on exercise.     

Effects of the calcium antagonist, isradipine, and nifedipine on resting and exercise haemodynamics and the neurohumoral system in patients with stable chronic angina

In a randomized double-blind study, the haemodynamic and anti-ischaemic effects of the new dihydropyridine calcium channel blocker isradipine (5 mg and 10 mg thrice daily (t.i.d.) were investigated over 1 week in nine patients with coronary artery disease and chronic effort angina and compared with nifedipine (20 mg t.i.d.) and placebo. In standardized exercise stress tests and exercise radionuclide ventriculography, haemodynamics improved under medication compared with placebo: resting end-diastolic and end-systolic volume index decreased on isradipine 5 mg, 10 mg and on nifedipine, and ejection fraction at rest increased with all medications. Resting mean arterial pressure was reduced compared with placebo accompanied by a decrease in systemic vascular resistance (P less than 0.05) and systolic wall tension (P less than 0.05). Cumulative ST-segment depression was significantly reduced by all three medications (-48%, -23%, -36%), while the increase in work capacity was insignificant. No significant change was found for either heart rate, double product, cardiac index, or stroke work index. Resting plasma levels of noradrenaline, adrenaline and renin activity increased with all three medications (except adrenaline at isradipine 5 mg). Isradipine has favourable effects comparable with those of nifedipine in patients with chronic stable angina and can be safely administered in these patients.     

Anti-ischaemic and haemodynamic effects of elgodipine, a potent new generation calcium antagonist, in chronic stable angina

The effects of oral elgodipine, a new dihydropyridine calciumantagonist on ischaemia and left ventricular function were assessedby a single blind placebo controlled study in 12 patients withchronic stable angina. Graded treadmill exercise and echocardiographylDoppler were performed before and 90 min after single oral dosesof elgodipine of 20 mg, 40 mg and 60 mg, or placebo, given atweekly intervals. Elgodipine significantly increased exercisetime by 1.1, 2.0 and 2.4 min, (P<0.001 in each case) andtime to onset of angina by 1.1 (P<0.01), 19 (P<0.001)and 2.6 min (P<0.001) with increasing doses of the drug.Angina was abolished in 50% of patients with significant improvementin ST depression at peak exercise (P<0.001) with the 60mgdose. Blood pressure fell significantly at rest and peak exercisewith a corresponding significant increase in heart rate. Ejectionfraction was increased by 78% (P<0.001) and 8.4% (P<0.001)as was the stroke volume by 9.3 ml (P<0.001) and 12.5 ml(P<0.001) at 40 mg and 60 mg respectively. Peak mitral Ato E velocity ratio and total peripheral resistance decreasedsignificantly in a dose related linear trend. Only minor sideeffects were noted and no patient required withdrawal from thestudy. The results demonstrate that oral elgodipine is a potentanti-ischaemic agent. An improvement in the echocardiographicparameters of left ventricular systolic and diastolic functionwas also seen     

The slope of ST segment/heart rate relationship during exercise in the prediction of severity of coronary artery disease

The results of a new excercise electrocardiography test werecompared with those of coronary arteriography in 120 patients.Thirty patients were under beta-blocker therapy and 90 patientswere not. In each patient the rate of progression of ST segmentdepression with respect to increases in heart rate was measuredin 13 electrocardiographic leads; the steepest slope of regressionlines relating ST segment depression to heart rate (maximalST/HR slope) was used as an index of myocardial ischaemia. Theresults of coronary angiography revealed 105 patients with significantcoronary artery disease (> 75% luminal narrowing); 32 patientshad single-vessel disease, 43 patients had double-vessel diseaseand 30 patients had triple-vessel disease. Significant coronaryartery disease could not be demonstrated in 15 patients. Theranges of the maximal ST/HR slope were different in the fourgroups of patients and the differences between the means werestatistically significant (P<0.0005); these differences weremaintained irrespective of beta-blocker therapy and there wereno false results or indeterminate test results. In contrastusing usual exercise criteria a definitive test result couldnot be obtained in 20 patients and there was an overlap betweenthe four groups. It is concluded that the maximal ST/HR slope can be used reliablyto predict the presence or absence and the severity of coronaryartery disease in individual patients with anginal pain, whetherthey are on beta-blocker therapy or not.     

Acute hemodynamic effects of propranolol, glycerylnitrate, and exercise in coronary patients with left ventricular dysfunction

Some adverse effects of beta-blockers in heart failure are counteracted by glycerylnitrate. However, the hemodynamics in this condition after giving both drugs are not well known. We examined the drug combination in exercising coronary patients with left ventricular dysfunction. Elevated left ventricular end-diastolic pressure was a measure of dysfunction. A right-heart catheterization with three successive exercise stress tests was done in 40 patients. At repeated exercise without drugs a "warming up" phenomenon was observed, consisting of small but statistically significant reductions in pulmonary capillary wedge pressure, and heart rate. At exercise propranolol reduced heart rate, cardiac output, systemic blood pressure, left ventricular work, and increased arteriovenous oxygen difference. Glycerylnitrate reduced pulmonary capillary wedge pressure at exercise, but, contrary to the findings at rest, it did not increase heart rate or reduce cardiac output. The drug combination resulted in hemodynamics that were similar to those after propranolol alone, except for a lower pulmonary capillary wedge pressure. The drug combination allowed the patients to exercise with the benefits of the beta-blocker, but at a lower ventricular filling pressure. Thus, the potential hazard of giving beta-blockers to patients with left ventricular dysfunction may be reduced by adding glycerylnitrate.     

运动负荷试验中心电图QT离散度和缺血性ST段下移对冠心病的诊断价值

目的 分析心电图平板运动负荷试验中QT离散度(QTd)及ST段变化对冠心病的诊断价值。方法 观察158例经冠状动脉造影诊断为冠心病的患者及96例平板运动试验阴性的健康者QTd与ST段的变化。结果 冠心病组较对照组QTd明显延长(P<0.05),其延长程度与心电图ST段压低程度相关,QTd≥60ms对冠心病诊断的准确性优于传统的ST段诊断标准。结论 心电图平板运动试验QT离散度的变化可成为临床诊断及治疗冠心病的新指标。     

冠脉病变程度对运动试验中QTc,QTd的影响

目的 探讨冠脉病变程度对运动试验中ＱＴｃ、ＱＴｄ的影响。方法 ８４例经冠脉造影和平板运动试验检查的患者,根据冠脉病变程度分为正常组、单支冠脉病变组及多支冠脉病变组,观察运动试验前后ＱＴｃ、ＱＴｄ的变化。结果 １．运动前三组ＱＴｃ、ＱＴｄ无明显差异（Ｐ〉０．０５）。２．运动后正常组ＱＴｃ、ＱＴｄ无明显变化,单支组ＱＴｄ无变化（Ｐ〉０．０５）,但ＱＴｃ延长（Ｐ〈０．０１）;多支病变组ＱＴｃ且ＱＴｄ均增     

The magnitude of exercise-induced ST segment depression and the predictive value of exercise testing.

The assess whether the magnitude of exercise induced ST segment depression improves the predictive values of symptom limited exercise tests, and helps in the recognition of patients with more severe coronary heart disease, 90 consecutive patients with positive treadmill tests who also underwent selective coronary arteriography were reviewed. The predictive value improved progressively with the increasing ST depression and was most reliable in a select group of patients with normal electrocardiographic baseline who were not receiving digitalis (73% with ST depression greater than or equal to 1 mm to 100% with ST depression greater than or equal to 4 mm). The incidence of 2 and 3 vessel disease increased from 61% with ST depression greater than or equal to 1 mm in the overall population to 100% with ST depression greater than or equal to 4 mm in the select group, and the incidence of left main trunk lesions increased, respectively from 6 to 30%. The prediction of 2 and 3 vessels disease was found to be significantly greater when patients were dichotomized into those with ST depression greater than or equal to 4 mm compared to less than 4 mm. It is concluded that the magnitude of ST segment depression definitely improves the predictive values of exercise tests as well as the ability to recognize the patients with more severe disease. However, the markedly positive exercise tests cannot be utilized to accurately predict the presence of 2 or 3 vessel disease in individual cases unless ST depression attains 4 mm or more in patients with normal electrocardiographic baseline who are not taking digitalis. In this group, the ability to predict left main trunk lesion is approximately 30%.     

Predictors of the variation of the ejection fraction during exercise in patients with and without coronary heart disease

The aim of this study was to determine the factors influencing the different response of the ejection fraction (EF) of the left ventricle at exercise observed in patients with and without significant coronary heart disease. We have studied 98 patients referred for coronary angiography (82 men, 16 women), of whom 49 patients had a previous myocardial infarction and 71 patients had significant coronary heart disease. Exercise testing was performed and combined with a cardiac blood pool imaging at equilibrium. The variation of the EF between rest and peak exercise (delta EF) was measured. Twelve clinical, exercise-related, isotopic, and coronary arteriographic variables were examined in a linear univariate and statistical analysis. In the univariate regression, seven variables were significant regressors on the delta EF. In the multivariate regression, only four variables were significant regressors on the delta EF. Three independent predictors were found: the rate-pressure product, the ST depression, and the occurrence of a previous myocardial infarction. These three independent predictors reflect the myocardial functional reserve.     

A Computerized approach to evaluating rest and exercise-induced ecg/vcg changes after cardiac rehabilitation

Summary: A computerized method of acquiring and analyzing rest and exercise test 12-lead electrocardiographic and three-dimensional lead vectorcardiographic data before and after cardiac rehabilitations is described. Fourteen coronary heart disease patients were exercise tested before and after a mean of five months of aerobic exercise training. The only significant ST-segment improvements were found in three-dimensional space. Spatial measurements should be considered in the assessment of electrocardiographic changes secondary to exercise training.     

Correlation between R-wave amplitude and left ventricular volume at rest and with exercise

In 52 patients with exercise angiography (12 normals, 31 with coronary heart disease, 9 with congestive cardiomyopathy) exercise ECGs were examined for R-wave changes. An increasing R-wave amplitude was found an insensitive sign of ischemia in patients with coronary heart disease (sensitivity 29%, specificity 81%). Sensitivity and specificity of the observed ST depression in this study were 83% and 71%, respectively, as reported by others. There was no positive correlation between the changes in the R-wave amplitude and left ventricular end-diastolic volume during exercise, thus there was no proof of the existence of the so-called Brody effect in humans.     

心率校正的ST段改变诊断冠心病的准确性探讨

目的评价运动心电图ＳＴ段压低的几个变量对诊断冠心病价值。方法９７例冠心病病人和５０例健康人作对照组进行Ｂｒｕｃｅ方案的活动平板试验，受试对象计算运动末ＳＴ段（ＳＴｅｎｄ）压低，恢复期ＳＴ段（ＳＴｒｅｃ）压低，ＳＴ／ＨＲＩｎｄｅｘ和ＳＴ／ＨＲｈｙｓｔｅｒｅｓｉｓ，其中ａＶＲ导联不计其内。结果冠心病组和健康对照组的ＳＴ／ＨＲｈｙｓｔｅｒｅｓｉｓ指标的敏感性和特异性均高于其它三个指标的任何一个（Ｐ均＜００５）。结论ＳＴ／ＨＲｈｙｓｔｅｒｅｓｉｓ反映了心率校正后的运动期与恢复期的ＳＴ段差值的平均值，因而比ＳＴｅｎｄ、ＳＴｒｅｃ和ＳＴ／ＨＲＩｎｄｅｘ三个指标均准确，值得临床推广。     

The prognostic value of a QRS score during exercise testing

BACKGROUND: Values of a QRS score have been positively related to the number of narrowed coronary arteries and to the extent of myocardial ischemia in radionuclide imaging techniques. HYPOTHESIS: This study was conducted to evaluate the potential prognostic information of abnormal values of this QRS score during treadmill exercise testing in patients with established coronary artery disease (CAD). METHODS: In all, 309 patients (258 men, 51 women, mean age 56.1 +/- 10.0 years) with documented CAD, underwent a treadmill exercise test and coronary arteriography at baseline. Subsequently, they were prospectively followed to a maximum of 36 months (mean follow-up 23 +/- 13 months, median 25 months). RESULTS: During the follow-up period, 20 patients (6.5%) died from acute myocardial infarction. Abnormal QRS score values were found to be significantly and independently associated with cardiac mortality (QRS < or = -4: relative risk 11.7; 95% confidence interval = 2.5-55.4; p = 0.002). CONCLUSIONS: Taking into consideration the importance of exercise testing in the management of ischemic heart disease, the use of this QRS score could be of clinical value in predicting the outcome of patients with documented CAD.     

Ambulatory monitoring and exercise testing in the evaluation of a new long-acting calcium ion antagonist KB-944 (Fostedil) for the treatment of exertional angina pectoris

The anti-anginal effects of KB-944 (Fostedil), a new calcium ion antagonist with a half life of approximately 23-28 hr, were evaluated in 20 patients with exertional angina pectoris in a placebo-controlled single-blind dose titration trial. Ambulatory monitoring and multistage treadmill exercise with computer-assisted electrocardiographic analysis was performed after 2 weeks of placebo therapy and after two 2-weekly periods of KB-944 therapy. The mean (+/- SEM) exercise time to the development of angina on treadmill walking increased from 6.9 +/- 0.4 min on placebo to 9.4 +/- 0.5 min on KB-944 100 mg/day (P less than 0.001) and 9.7 +/- 0.8 min on KB-944 200 mg/day (P less than 0.001 vs placebo and not significant vs KB-944 100 mg/day). The time to the development of 1 mm ST-segment depression of 5.3 +/- 0.4 min on placebo increased to 6.5 +/- 0.5 and 6.6 +/- 0.5 min on KB-944 100 and 200 mg/day, respectively (P less than 0.01 vs placebo). The heart rate at rest of 77 +/- 3 beats/min on placebo was reduced to 68 +/- 3 beats/min on KB-944 100 mg/day (P less than 0.001) and 71 +/- 2 beats/min on KB-944 200 mg/day (P less than 0.01). The maximal heart rate and the rate-pressure product were not altered by KB-944 therapy. One patient developed unstable angina during the treatment phase of KB-944 200 mg/day and was withdrawn. Five patients complained of dyspepsia and one of headache and lethargy during KB-944 200 mg/day. One patient developed ventricular tachycardia during treadmill testing while on KB-944 200 mg/day. The 24-hr ambulatory monitoring data confirmed the findings of exercise testing. KB-944 (Fostedil) in a dose of 100 mg once daily was well tolerated as compared to KB-944 200 mg once daily and both the doses were equally effective. The drug merits further evaluation for the treatment of exertional angina pectoris.     

Persistence of improved exercise tolerance and degree of revascularization after coronary bypass surgery. A prospective randomized study.

Exercise tolerance was repeatedly determined over a 2-year period in a series of 100 patients with coronary heart disease randomly allocated for medical therapy and coronary bypass surgery. The surgical group had a consistently better exercise tolerance than the medical group during the whole follow-up. Completeness of the revascularization, assessed by repeated graft and native vessel angiography, resulted in a marked improvement whereas incompletely revascularized patients exhibited only a marginal improvement which, nevertheless, to some degree exceeded the result of medical management alone. It is concluded that coronary bypass surgery and medical therapy, when indicated, result in markedly better exercise tolerance than medical management alone. This improvement persists up two years after the operation and is largely dependent on the completeness of the revascularization.