The association between cardiac events and myocardial ischaemia following thrombolysis in acute myocardial infarction and the impact of carvedilol.

The majority of post-myocardial infarction studies with beta-blocking drugs involved earlier generations. Newer drugs of this family with additional vasodilating and free-radical suppression properties, such as carvediol, are now available which may improve the prognosis still further. This double-blind, randomized, placebo-controlled, parallel group study was designed to assess the extent of myocardial ischaemia in clinically stable patients 6 weeks after acute myocardial infarction and thrombolysis, and to determine the influence of carvedilol on ischaemic events during the subsequent 6 months. One hundred and one patients who remained event free at 6 weeks post myocardial infarction underwent rest and exercise thallium-201 (TI-201) imaging. Reversible ischaemia was detected in 70 of the patients and there were 13 events in this group compared to one event in the 31 patients without ischaemia (P = 0.07). Four of the 56 patients on carvedilol and 10 of the 45 on placebo had adverse cardiac events (P = 0.04). In patients with reversible ischaemia carvedilol was more effective in reducing these events than was placebo (P = 0.03). These studies demonstrate that reversible myocardial ischaemia detected by TI-201 imaging is present in a large proportion of clinically stable patients following thrombolysis. In these patients, there is an increased cardiac event rate which is significantly reduced by carvedilol.

Ambulatory intraarterial blood pressure in essential hypertension. Effects of age, sex, race, and body mass--the Northwick Park Hospital Database Study.

Twenty-four-hour recordings of intraarterial blood pressure (IABP) from 723 untreated hypertensive patients were analyzed for the effects of age, sex, race, and body mass index on the level of IABP and its circadian variation. Age had a highly significant positive relationship (P < .001) with the cuff systolic and diastolic blood pressures, with regression coefficients (SE) of +0.83 (0.07) and -0.24 (0.04) mm Hg/year, respectively. There was a similar (P < .001) positive relationship between age and 24-h mean systolic IABP, measuring +0.71 (0.07) mm Hg/year, but 24-h mean diastolic IABP did not increase significantly with age. There was a significant (P < .001) inverse relationship between age and 24-h mean heart rate (HR), at -0.17 (0.03) beats/min/year. Nocturnal fall in systolic and diastolic IABP, calculated as the difference between daytime and nighttime mean IABP, had a significant (P < .001) negative relationship with age. Nocturnal fall in HR, calculated similarly, also significantly (P < .001) decreased with age. Age did not affect long-term systolic and diastolic IABP variability but did decrease long-term HR variability significantly (P < .001). Hypertensive men and women of similar age, had comparable daytime mean systolic and diastolic IABP (P = .15 and P = .03 respectively), but women had significantly (P < .001) lower nighttime mean systolic and diastolic IABP than men. The nocturnal fall in systolic and diastolic IABP was significantly (P < .002) greater in women as compared to men. Women also had significantly (P < .01) greater long-term systolic and diastolic IABP variability than men. Women had significantly (P < .001) greater 24-h, daytime mean and nighttime mean HR than men. Twenty-four-hour, daytime and nighttime mean IABP were all significantly higher (P < .01) in Afro-Caribbeans as compared to whites and Asians. No significant differences were observed in the magnitude of nocturnal IABP fall or long-term IABP variability between the three races. Asians and Afro-Caribbeans had significantly (P < .001) lower nocturnal HR falls and long-term HR variability (P < .01) than whites. Body mass index (BMI) did not relate directly to the level of daytime blood pressure, clinic cuff, or daytime mean IABP, in either men or women. BMI did have a highly significant (P < .001) positive relationship with nighttime mean IABP in men, but not in women. The degree of nocturnal fall of IABP had a significant (P < .001) inverse relationship with BMI in hypertensive men.

The preventative effects of vasodilating beta-blockers in cardiovascular disease.

The beta-blocking drugs are known to modify the course of hypertensive and atherosclerotic heart disease and significantly reduce the mortality and morbidity associated with these diseases. The place of vasodilating beta-blocking drugs, of which carvedilol is an example, has not been so clear, although they have obvious theoretical advantages. We performed a study on 12 hypertensive subjects using the technique of continuous ambulatory intra-arterial blood pressure recording which demonstrated that carvedilol (50 mg bid) achieved satisfactory blood pressure control throughout the full 24 h cycle. The addition, there was a marked reduction in left ventricular end-systolic and end-diastolic volumes with prolonged administration, suggesting a decrease in heart size, confirmed in other studies. A second study in patients with chronic stable angina and impaired left ventricular wall motion showed that carvedilol 25 mg bid not only improved exercise tolerance, but also reduced heart size, improved left ventricular ejection fraction, and abolished wall motion abnormalities. These results prompted a further study in 17 patients with chronic ischaemic heart failure. The haemodynamic and clinical responses to intravenous carvedilol followed by the oral drug 50 mgm b.i.d. for 8 weeks were studied. There was an improvement in all haemodynamic indices, although postural hypotension necessitated withdrawing two patients and clinical deterioration was evident in two others. The beneficial effects of carvedilol were considered to be related to the combined reduction in afterload and inhibition of neurohumeral activation. These results have been confirmed in placebo-controlled, double-blind studies from other workers.

Diagnostic accuracy of dobutamine stress echocardiography for detection of coronary heart disease in hypertensive patients.

To compare the diagnostic accuracy between dobutamine echocardiography and treadmill exercise electrocardiography in detecting coronary artery disease in hypertensive patients, 43 patients without electrocardiographic evidence of left ventricular hypertrophy and basal ST-T changes, who had also undergone coronary angiography, were further evaluated by dobutamine echocardiography. The patients also underwent treadmill exercise echocardiography. Left ventricular mass index was calculated by echocardiography. Twenty-nine patients had coronary artery disease, of whom 22 had multi-vessel disease and 14 a normal coronary anatomy. Twenty-eight patients had an increased left ventricular mass index. The sensitivities of dobutamine echocardiography and exercise electrocardiography for detecting coronary artery disease were 93% and 72% (P = 0.08), respectively, and the specificities were 100% and 29% (P < 0.005), respectively. Logistic regression analysis showed exercise electrocardiography to be a poor predictor of coronary artery disease (P < 0.09) but dobutamine echocardiography was significantly better (P < 0.001). When patients with increased left ventricular mass index were excluded, prediction of coronary anatomy by exercise electrocardiography improved only marginally (p = 0.4) while dobutamine echocardiography was significantly better (P < 0.001). Thus dobutamine echocardiography is superior to exercise electrocardiography for diagnosis of coronary artery disease in hypertensive patients.

Dobutamine echocardiography and thallium-201 imaging predict functional improvement after revascularisation in severe ischaemic left ventricular dysfunction.

OBJECTIVES: To evaluate the concordance between thallium-201 uptake and echocardiographic wall thickening, which are both indicators of potentially reversible myocardial dysfunction, in patients with chronic ischaemic left ventricular failure and to assess their relative contribution to predicting improvement in regional function after revascularisation in a subgroup. PATIENTS AND METHODS: 45 patients with chronic ischaemic left ventricular dysfunction (mean (SD) ejection fraction 25 (8)%) underwent echocardiography before and after dobutamine infusion (10 micrograms/kg/min). Of these, 22 patients underwent rest echocardiography at a mean (SD) of 9 (1) weeks after revascularisation. 201Tl imaging was performed during dobutamine echocardiography and at rest, 1, and 4 h after treatment with sublingual glyceryl trinitrate on two separate days. Potentially reversible dysfunction was thought to be present when a myocardial segment contained a Tl score of > or = 3 (ascending score 1-4), or showed improved wall thickening of a dysynergic segment during dobutamine stimulation. RESULTS: Of the 201Tl protocols, the redistribution scan 1 h after treatment with glyceryl trinitrate best demonstrated myocardial viability. Concordance between 201Tl and dobutamine induced wall thickening was 82% (kappa = 0.59) for detecting potentially reversible myocardial dysfunction before revascularisation (n = 45). Regional function improved in 18 of 22 patients after revascularisation. There were 168 dysynergic segments before intervention. The sensitivity of echocardiography and 201Tl imaging for detecting "recoverable" or viable segments after revascularisation was 87% and 92% respectively and specificity was 82% and 78% respectively (P = NS). CONCLUSIONS: Dobutamine echocardiography and 201Tl imaging may be used to predict mechanical improvement in dysynergic segments after revascularisation in patients with chronic ischaemic left ventricular dysfunction.

Vasodilating beta-blockers in heart failure.

Carvedilol is a non-selective beta-adrenoceptor antagonist with vasodilating properties which has been shown to be effective in the management both of hypertension and of stable angina pectoris. In order to explore its wider efficacy in patients with manifest heart failure, a preliminary study was performed in patients with chronic stable angina pectoris accompanied by abnormal left ventricular wall motion, but without overt heart failure (mean ejection fraction < 40%). Six patients were given carvedilol 25 mg b.i.d. for 2 weeks followed by 50 mg b.i.d. for a further 2 weeks according to a single-blind placebo-controlled protocol. At the end of the 4 week period of treatment, in four patients left ventricular wall motion was improved, in two it was unchanged, and in none was there any deterioration; mean ejection fraction increased from 40 to 48%. These results prompted a further study in 17 patients with chronic ischaemic heart failure. The haemodynamic and clinical responses to intravenous carvedilol followed by the oral drug (50 mg b.i.d.) for 8 weeks were studied. There was an improvement in all haemodynamic variables, although postural hypotension necessitated withdrawing two patients, and clinical deterioration was evident in two others. The beneficial effects of carvedilol were considered to be related to the combined reduction in afterload and inhibition of neurohumeral activation. These results have been confirmed in placebo-controlled, double-blind studies.

Synergistic value of simultaneous stress dobutamine sestamibi single-photon-emission computerized tomography and echocardiography in the detection of coronary artery disease.

The relative value of exercise electrocardiography, simultaneous dobutamine technetium 99m-sestamibi (MIBI) single-photon-emission computerized tomography (SPECT), and echocardiography were evaluated for the diagnosis of coronary artery disease in patients with chest pain. Sixty-one consecutive patients underwent exercise electrocardiography and simultaneous graded dobutamine echocardiography and MIBI imaging. All patients underwent coronary arteriography. The exercise electrocardiogram was found to be a poor predictor of coronary artery disease (p not significant). Individually, MIBI SPECT and echocardiography were significantly predictive of coronary artery disease (p < 0.001). According to logistic regression analysis, the combined imaging modalities significantly increased the prediction of coronary artery disease for any vessel (p < 0.001), for multiple vessels (p < 0.001), and for the left anterior descending (p < 0.001), for right coronary artery (p < 0.001), and for left circumflex arteries (p < 0.01), compared with either MIBI SPECT or echocardiography alone. The results suggest a synergism in the detection of coronary artery disease when MIBI SPECT and echocardiography are combined during dobutamine stress.

Comparison of radionuclide ventriculography and 2D echocardiography for the measurement of left ventricular ejection fraction following acute myocardial infarction.

To compare the measurement of left ventricular ejection fraction obtained by two-dimensional echocardiography and by radionuclide ventriculography in patients following acute myocardial infarction, 49 consecutive patients with acute myocardial infarction underwent echocardiography and radionuclide ventriculography on the same day, pre-discharge. Left ventricular ejection fraction was assessed by two blinded observers for each method and reproducibility was also assessed for each technique. The limits of agreement for the differences in ejection fraction (%) between the two methods was--11.4, 12.2; the mean difference 0.4 was not significantly different from zero. The limits of agreement for the intra- and inter-observer differences in ejection fraction by radionuclide ventriculography were--9.4, 7.6 and -8.6, 11.0, respectively; the mean differences--0.9 and 1.2 were not significantly different from zero. The limits of agreement for the intra- and inter-observer differences by echocardiography were--5.8, 6.6 and--8.9, 9.5 respectively; the mean differences 0.4 and 0.3 were not significantly different from zero. Thus, two-dimensional echocardiography compares well with radionuclide ventriculography for the assessment of ejection fraction without the disadvantage of radiation.

Antihypertensive efficacy of twice daily controlled release diltiazem using 24 hour intra-arterial blood pressure monitoring.

The aim of the study was to examine the efficacy of a new controlled release formulation of diltiazem administered in a twice-daily dose in patients with essential hypertension using 24 hour intra-arterial ambulatory blood pressure monitoring. Sixteen patients (2 female) of mean age 53 years with mild to moderate essential hypertension, defined as a supine resting diastolic cuff blood pressure > or = 95 mm Hg, were recruited to a sequential dose ranging study of controlled release (CR) diltiazem. After a six week run-in period without any anti-hypertensive medication, intraarterial blood pressure monitoring with 60 degrees tilt, isometric handgrip and bicycle exercise testing were performed. Patients were then treated for one week with CR diltiazem 120 mg b.i.d. If supine resting diastolic cuff blood pressure fell by < 10 mm Hg compared to the last run-in value and remained > 90 mm Hg, the dose was increased to 240 mg b.i.d. for a week, and if necessary to 360 mg b.i.d. for a week. Patients continued for further one month on the dose of CR diltiazem at which they achieved target blood pressure reduction. At the end of this maintenance treatment, 24 hour intra-arterial blood pressure monitoring was repeated. Twelve patients were satisfactorily controlled on 120 mg b.i.d. CR diltiazem, three on 240 mg twice daily and one on 360 mg twice daily. During rest and exercise, blood pressure and heart rate were significantly lower after treatment with CR diltiazem than before treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Early diagnosis of acute myocardial infarction with use of a rapid immunochemical assay of creatine kinase MB isoenzyme.

In 195 patients presenting with chest pain and referred acutely for cardiological assessment, blood was taken immediately for assay of creatine kinase (CK; EC 2.7.3.2) MB isoenzyme by an immunochemical method and results [mass units of enzyme per liter of plasma (microgram/L)] were obtained within 30 min of sampling. Diagnosis of acute myocardial infarction in the patients was made independently, based on electrocardiograms and conventional cardiac enzyme profiles. The administration of any thrombolytic therapy in response to the CK-MB concentration result was also noted, allowing assessment of the assay's potential influence on patient management in addition to the diagnostic efficiency evaluation. The study demonstrated that, when blood samples were collected on admission to hospital and the decision level suggested by the manufacturers was utilized, the assay had an immediate sensitivity of 52% and a specificity of 97%. Of the 81 patients who were shown by conventional means to have had acute myocardial infarction, 8 (10%) had equivocal electrocardiograms but positive CK-MB concentration results. In four of these patients (5%), thrombolytic therapy was given on the basis of the clinical features and a positive CK-MB concentration result alone.

Infection of left ventricular thrombus in a patient with silent myocardial infarction--a unique complication.

A 72-year-old male was admitted to hospital with exertional dyspnoea of recent onset. Echocardiography showed a left ventricle which was severely hypokinetic on the anteroseptal and anterior wall with an akinetic inferior wall and apex. A string of globular masses was seen to be floating in the left ventricle, attached to the septum near the apex. Coronary arteriography showed severe two-vessel disease. Urgent surgery revealed degenerated thrombus in the left ventricle containing green pus. The infected thrombus was attached to an area of septal infarction. The pus-filled thrombus was removed and by-pass grafting was effected. No infective organism was identified.

A double-blind comparison of a beta-blocker and a potassium channel opener in exercise induced angina.

This randomized, double-blind, parallel study compared the anti-anginal effects of nicorandil and atenolol in 37 patients with exercise-induced angina pectoris. At the end of a single-blind placebo period, patients were randomized and received either atenolol 50 mg o.d. or nicorandil 10 mg b.d. for 3 weeks. On the third week, the dosage was increased (nicorandil 20 mg b.d. or atenolol 100 mg o.d.) for the final 3-week period. Treadmill exercise tolerance tests were performed immediately before and 2 h after dosing at the end of the placebo period, and at the end of the third and sixth week of active treatment. Demographic characteristics and exercise performance with placebo were comparable between both treatment groups, and at the end of the treatment periods a significant improvement in exercise time was observed: an increase in the time to peak exercise of 1.33 +/- 0.29 min (mean +/- standard error of the mean) in atenolol-treated patients (P < 0.001), and of 1.47 +/- 0.40 min (P < 0.005) in nicorandil-treated patients. While the anti-anginal activity of the two drugs was comparable, their effects on the rate-pressure product heart rate x systolic blood pressure were clearly different; atenolol induced a decrease at peak exercise, but this parameter was not changed or was slightly increased with nicorandil. One patient with severe three-vessel disease died suddenly after 3 days of treatment with nicorandil 10 mg twice daily. The most frequent adverse effect in both groups was headache, which led to discontinuation of one patient in the atenolol group and of five patients in the nicorandil group.(ABSTRACT TRUNCATED AT 250 WORDS)

Prognostic value of noninvasive cardiac tests in the assessment of patients with peripheral vascular disease.

Two hundred thirty-six patients with peripheral vascular disease were prospectively studied to assess whether noninvasive cardiac investigations could predict prognosis better than simple clinical assessment. Clinical history, examination and resting electrocardiography were considered in all patients; exercise electrocardiography, Holter monitoring, radionuclide ventriculography and dipyridamole thallium imaging were performed in a subgroup of 168 patients. Follow-up for 6 to 30 months revealed major cardiac events in 21 patients. Cox survival analysis showed that clinical evidence of prior coronary artery disease was the best variable from clinical assessment that predicted cardiac events, with no other clinical variable adding to the statistical model. When variables from noninvasive cardiac assessment were added to the model, which included clinical evidence of coronary artery disease, dipyridamole thallium heart:lung ratio and left ventricular ejection fraction added significantly and incrementally to the prediction of cardiac events. Results of exercise electrocardiography or Holter monitoring did not add significantly. It is concluded that high lung uptake of thallium during dipyridamole stress, and impaired left ventricular ejection fraction help to identify patients with peripheral vascular disease who are at high cardiac risk, and should therefore be used for selecting subsequent cardiovascular medical, surgical and anesthetic management.

Carvedilol in hypertension.

Ambulatory intra-arterial blood pressure recording provides a precise and objective method for the study of antihypertensive drugs and their effects on blood pressure. Application of this technique has shown that beta-adrenoceptor-blocking drugs are only effective during the day when the subject is active. They have little effect on the early-morning rise in blood pressure, which is the time of greatest sympathetic nervous activity. Addition of a diuretic to the beta blocker produces a uniform reduction in blood pressure, which is sustained throughout the 24-hour cycle. Carvedilol is a beta blocker with alpha-blocking activity and its profile of action is similar to that of a combination of a beta blocker and a diuretic. The possession of both properties in a single molecule is advantageous.

Indapamide reduces hypertensive left ventricular hypertrophy: an international multicenter study.

The effect of 6 months of treatment with indapamide (IND, 2.5 mg/day) on regression of left ventricular hypertrophy (LVH), an independent predictor of poor prognosis in hypertension, was compared by echocardiography to that of nifedipine (NFD, 40 mg/day), enalapril (ENL, 20 mg/day), atenolol (ATL, 100 mg/day), and hydrochlorothiazide (HCTZ, 25 mg/day) in four parallel double-blind studies in 151 hypertensive patients with a diastolic blood pressure between 95 and 120 mm Hg and a raised left ventricular mass index (LVMI) (mg/m2) (Devereux). Patients were randomized to IND or comparator following a 2-week washout (1 month in the IND vs. ATL study). Respective baseline and 6-month LVMI values (mg/m2) were: IND (n = 20) vs. HCTZ (n = 20): 151.4 +/- 6.3 and 125.70 +/- 4.6 (p < 0.001) vs. 141.3 +/- 6.6 and 135.6 +/- 8.3 (p = N.S.); IND (n = 22) vs NFD (n = 19): 144.1 +/- 5.3 and 125.1 +/- 4.3 (p < 0.001) vs. 170.4 +/- 6.6 and 148.2 +/- 6.2 (p < 0.001); IND (n = 9) vs. ENL (n = 9): 155.1 +/- 6.3 and 143.4 +/- 5.2 (p < 0.001) vs. 142.0 +/- 6.7 and 130.0 +/- 5.9 (p < 0.001); IND (n = 17) vs. ATL (n = 12): 146.2 +/- 5.1 and 130.8 +/- 6.5 (p < 0.001) vs. 156.7 +/- 8.4 and 142.9 +/- 10.3 (p < 0.01). All drugs significantly reduced diastolic blood pressure, and all except HCTZ induced a significant and similar reduction in left ventricular mass.

Right atrial thrombus migration during echocardiography: a case for urgent intervention.

A 65-year-old woman presented with increasing shortness of breath, chest pain and ST-T wave abnormalities on the electrocardiogram suggestive of unstable angina. Cross-sectional echocardiography performed to assess wall-motion abnormality and left ventricular function revealed a pedunculated right atrial thrombus prolapsing into the right ventricle which suddenly dislodged and migrated into the pulmonary circulation during the examination. A diagnosis of recurrent pulmonary thromboembolism was made, necessitating urgent pulmonary angiography with infusion of streptokinase. The patient made an uneventful recovery.

Intra-arterial monitoring of the antihypertensive effects of once-daily amlodipine.

Amlodipine is a dihydropyridine calcium antagonist with a long elimination half life making it suitable for once-daily dosing. This study used sphygmomanometric and intra-arterial ambulatory blood pressure (BP) monitoring to confirm the antihypertensive effect of a once-daily dose of amlodipine over the dosing interval. After a 2-week single-blind placebo run in, amlodipine was administered to 11 patients at a starting dose of 5 mg daily for 2 weeks increasing to 10 mg daily for a further 4 weeks if diastolic blood pressure (DBP) measured sphygmomanometrically was not < 90 mmHg or decreased by > 10 mmHg from baseline values. Intra-arterial blood pressure recordings for 24-hour periods were made at the end of the placebo run in and on completion of the active treatment phase. The effects of isometric and dynamic exercise and head-up tilting (60 degrees) on BP and heart rate were measured during ambulatory monitoring. Mean supine cuff BP was 169/104 mmHg (n = 11) at the end of the placebo treatment period and was reduced to 153/95 mmHg (n = 11) after 2 weeks of amlodipine treatment and 146/92 mmHg (n = 11) after 6 weeks of amlodipine treatment. There was no significant change in heart rate. Intra-arterial ambulatory monitoring showed that BP was controlled for the whole dosing interval with once-daily doses of amlodipine. The normal circadian pattern of BP changes was not altered. BP was reduced by amlodipine during exercise and physiological tests, but there was no postural hypotension and the BP and heart rate responses to exercise were not blunted.(ABSTRACT TRUNCATED AT 250 WORDS)

Improvement in left ventricular function after rapid weight loss in obesity.

The effect of rapid weight reduction on left ventricular function and blood pressure was studied in 34 obese subjects, who all weighed more than 30% above their ideal body weight. Subjects with co-existing hypertension (N = 15) and proven coronary artery disease (N = 9) were included to assess contributions from these factors. Blood pressure (BP) was measured both indirectly and by direct ambulatory intra-arterial methods. Radionuclide ventriculography was performed at rest and at exercise, before and after dieting, which was supervised in hospital (daily intake 330 kCal day-1 for 4 weeks). Dieting induced a weight loss of (mean +/- SD) 9.6 +/- 3.5 kg (P less than 0.0001) in the whole group. The mean daytime intra-arterial blood pressure fell from 157 +/- 23/90 +/- 15 to 144 +/- 21/85 +/- 13 mmHg (P less than 0.0001). The fall in ambulatory intra-arterial diastolic blood pressure did not reach significance in the normotensive and ischaemic groups. The mean resting left ventricular ejection fraction (LVEF) in the whole group showed a significant reduction after weight loss from 61 +/- 10% to 56 +/- 6% (P less than 0.005). Although the individual groups showed a fall in LVEF, the effect was most marked in the hypertensive group, from 65 +/- 9% to 57 +/- 5% (P less than 0.002). Before dieting none of the groups achieved a 'normal' 5% rise in LVEF above basal in response to exercise, the hypertensive and the ischaemic groups both showing non-significant falls. This phenomenon was, however, reversed after weight loss.(ABSTRACT TRUNCATED AT 250 WORDS)