Beta-blockade Therapy Research Articles

Beta-blocker therapy in heart failure: Myths or realities

The cumulative evidence acquired over 20 years suggests that beta-blockers improvefunctional capacity, ventricular function, and decrease mortality in patients with heart failure either due to dilated cardiomyopathy or ischaemic heart disease. This effect is independent of the beneficial effects of digoxin, diuretics and particularly ACE inhibitors and has resulted in re-evaluation of requirements for transplantation in patients with advanced cardiac failure. Ninety percent of patients appear to respond to beta-blockers but no clinical or biochemical parameters can identify a favourable response. The beneficial effects occur slowly but last for years. Further ongoing trials will provide more information but beta-blockade therapy should be considered in addition to other therapy in the management of heart failure.

Exercise Testing and Prescription

A sedentary lifestyle is prevalent in most industrialised societies. Persuasive evidence allows us to demonstrate that a physically active lifestyle protects against the development and progression of many chronic diseases. The assessment of sedentary individuals for the purpose of exercise testing and or exercise prescription should always culminate in the determination of the relative risk of the individual for traumatic events which may be precipitated by participation in moderate physical activity. Sedentary individuals may be categorised in a low to high risk stratification as apparently healthy (Class I), higher risk (Class II), or known coronary heart disease and/or symptomatic of chronic disease (Class III). An expanded role for allied health professionals, such as a clinical exercise physiologist, may enhance and extend the services of physicians and nurses as they relate to exercise testing, exercise prescription and preventative healthcare in general. Risk stratification will determine the type of exercise test, the exercise prescription and the exercise environment (low to high levels of supervision). The exercise prescription may include a determination of mode, duration, frequency, intensity, and progression of activity. Although target heart rate remains one of the most effective instruments for monitoring exercise intensity, the rate of perceived exertion should be incorporated especially in the titration of exercise prescriptions for those on beta-blockade therapy. Finally the benefits of an exercise programme, derived from a foundation of proper assessment, are numerous and include improvements in cardiovascular fitness, body composition, blood lipid profile and retention of essential muscle mass during the course of the life-cycle. A considerable public health benefit will result if sedentary individuals become regularly more physically active.

The use of ratings of perceived exertion for exercise prescription in patients receiving beta-blocker therapy.

The ratings of perceived exertion (RPE) scale has received widespread acceptance for gaining a subjective estimate of work intensity and as a means of monitoring and regulating exercise intensity across a variety of populations. The original premise for the use of the scale was its high correlation with heart rate (HR). Although individual correlations between HR and RPE in individuals on beta-blocker therapy are probably as high as in untreated individuals, there is evidence to suggest that the RPE response is mediated at a given work rate, particularly at higher absolute work rates. The variation in the RPE response appears to be mediated by the type of beta-blocker therapy administered. In the interests of safety it is necessary for the exercise specialist to develop at least a basic understanding of the mechanism and effects of beta-blocker therapy as they relate to exercise prescription. beta-Blocking drugs cause a decrease in HR and cardiac output at rest and during exercise, a decrease in myocardial contractility and a decrease in coronary and muscle blood flow. These effects can initiate premature fatigue and apprehension in the exercising patient. In the light of these responses, the RPE scale provides important information and may be used to increase the accuracy of monitoring and the prescription of exercise intensity in the cardiac population. While results regarding the use and accuracy of the scale during beta-blocker treatment are equivocal, this appears to be due mainly to variations in dosage of the drug, the mode, intensity and duration of exercise and the health status of the individuals used. Overall, the RPE scale appears to be an appropriate monitoring tool, particularly when it is used after a learning period. It is concluded that nonselective beta-blockade therapy increases RPE, particularly localised RPE. This could be attributed to a decreased blood flow and oxygen delivery to the muscle and altered glycolytic metabolism, which increases local muscle fatigue. There is no evidence to suggest a decrease in the total level of oxygen consumption at given work rates. However, as beta-blocker therapy reduces the maximal oxygen consumption (VO2max) attainable, this serves to increase the exercise intensity at all work rates. Thus, for a given absolute work rate, the RPE response is higher. However, when the work rate is expressed as a proportion of the VO2max attainable during beta-blockade, the differences in RPE are minimised or disappear. Although the evidence is not conclusive, it appears that cardioselective beta-blocker therapy does not have such profound effects on the RPE response, compared with nonselective beta-blocker therapy, when this is expressed as a proportion of VO2max. However, localised RPE tends to be higher for nonselective beta-blocker therapy. Thus, the evidence indicates that RPE can be used to estimate exercise intensity, provided the specific effects of the type of beta-blocker therapy on local and central fatigue (and local and central RPE) are taken into account. Studies which have examined the effects of an endurance training programme during beta-blocker therapy have shown that RPE are decreased at given work rates after training. This has been observed for cardioselective and nonselective beta-blocker therapy, and local and central RPE. There is also some evidence to suggest that the RPE can be used as the controlling variable to regulate the exercise response. Patients on cardioselective beta-blocker therapy produce similar exercise intensities to other cardiac patients who are not receiving beta-blocker treatment.

The effect of beta‐blockade therapy on the response to exercise training in postmyocardial infarction patients

Cardiac rehabilitation after a myocardial infarction has been shown to improve exercise capacity. Beta blockade has been shown to be effective in treating angina and reducing mortality, but studies are controversial as to whether beta-blockade therapy attenuates the effects of training. We attempted to study the effects of beta blockade (metoprolol) on the response to training in patients enrolled in a cardiac rehabilitation program after an uncomplicated myocardial infarction. We studied 27 patients with a recent uncomplicated myocardial infarction who were subdivided in two groups: Group 1 (13 patients) not taking a beta blocker, and Group 2 (14 patients) taking metoprolol (mean 142 +/- 57 mg daily). All patients underwent a maximal cardiopulmonary exercise test before and after a 3-month training program. The training intensity was designed to approximate the ventilatory threshold. Results showed an increase in peak VO2 in both Group 1 (27%, p < 0.01) and Group 2 (33%, p < 0.001), and an increase in VO2 at the ventilatory threshold (39% in Group 1 and 28% in Group 2, p < 0.01). The mean changes in exercise capacity were not different between groups. It was concluded that metoprolol did not influence the beneficial effects of a cardiac rehabilitation program in postmyocardial infarction patients.

Unresolved issues in early trials of cholesterol lowering

A reexamination of early intervention trials in patients with coronary artery disease (CAD) shows that a pessimistic view of cholesterol reduction in such patients is inappropriate. In observational studies, individuals with documented coronary artery disease and elevated cholesterol levels fare worse than individuals with normal or low cholesterol levels. Early trials of cholesterol reduction in individuals with coronary artery disease succeeded in lowering total cholesterol levels by only 5-15%. Nevertheless, when reviewed in meta-analysis, these trials demonstrated borderline effects on total mortality, statistically significant benefits in terms of morbidity and mortality due to cardiovascular disease and CAD, and no increase in mortality from noncardiovascular causes. Substantially greater lowering of low density lipoprotein (LDL) levels was achieved in early regression studies. In these studies, examples of improvement were noted in individual coronary artery segments. What was not appreciated initially was the dramatic reduction in coronary events. Older secondary prevention trials did not definitively address the benefits of cholesterol reduction in individuals whose cholesterol levels were only modestly elevated (total cholesterol, 160-240 mg/dl [4.14-6.21 mmol/liter], and LDL cholesterol levels 100-160 mg/dl [2.59-4.14 mmol/liter]). Several other issues were not addressed in these early studies, including the effect of declines in triglyceride levels, increases in high density lipoprotein (HDL) levels, and the effects in women and individuals aged > 60 years. Even with these limitations, a comparison of meta-analyses of other medical interventions--i.e. beta blockade and aspirin therapy--indicates that declines in coronary mortality are in the same range as obtained in older studies with modest cholesterol reduction--i.e., 20-25%.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of beta-blockade on regional left ventricular function in patients with dilated cardiomyopathy.

It has been reported that beta-blockade has beneficial effects on the cardiac function and prognosis of patients with congestive heart failure. However, the mechanism for these effects remained unclear. This study compared the use of an angiotensin-converting enzyme (ACE) inhibitor (enalapril, 2.5 to 5.0 mg/day, or delapril, 15 to 30 mg/day) alone with the effects of beta-blockade therapy (metoprolol, 40 to 60 mg/day) coupled with an ACE inhibitor on global and regional left ventricular (LV) function in patients with dilated cardiomyopathy. In 12 patients with dilated cardiomyopathy, the global LV ejection fraction (EF), regional EF (rEF), and regional ejection time (rET) were determined by sector analysis of the radionuclide ventriculogram before and after therapy (duration 14 +/- 9 months). The coefficients of variation of rEF and rET were calculated as indexes of the heterogeneity of regional LV systolic wall motion. EF increased significantly from 20% +/- 8% to 30% +/- 8% (p < 0.05) in patients who received beta-blockade and an ACE inhibitor (n = 5). Furthermore, the coefficients of variation of rET decreased from 27% +/- 13% to 16% +/- 7% (p < 0.05). In contrast, patients treated with an ACE inhibitor only (n = 7) showed no significant improvements in any of these parameters. These results suggest that, compared with an ACE inhibitor alone, beta-blockade improves global and regional LV function in dilated cardiomyopathy by synchronizing myocardial contraction.

A randomized trial of beta-blockade in heart failure. The Cardiac Insufficiency Bisoprolol Study (CIBIS). CIBIS Investigators and Committees.

Functional benefit in heart failure due to idiopathic dilated cardiomyopathy has been observed after beta-blockade, but improvement in survival has not been established in a large-scale randomized trial. This was the main objective of the Cardiac Insufficiency Bisoprolol Study (CIBIS). Six hundred forty-one patients with chronic heart failure of various etiologies and a left ventricular ejection fraction of < 40% entered this placebo-controlled, randomized, double-blind study. Patients were in New York Heart Association functional class III (95%) or IV (5%) at inclusion. All received background diuretic and vasodilator therapy (an angiotensin-converting enzyme inhibitor in 90% of cases). A total of 320 patients was randomized to bisoprolol and 321 to placebo. Mean follow-up was 1.9 years. Bisoprolol was well tolerated without between group difference in premature treatment withdrawals (82 on placebo, 75 on bisoprolol; NS). The observed difference in mortality between groups did not reach statistical significance: 67 patients died on placebo, 53 on bisoprolol (P = .22; relative risk, 0.80; 95% confidence interval, 0.56 to 1.15). No significant difference was observed in sudden death rate (17 on placebo, 15 on bisoprolol) or death related to documented ventricular tachycardia or fibrillation (7 on placebo, 4 on bisoprolol). Bisoprolol significantly improved the functional status of the patients; fewer patients in the bisoprolol group required hospitalization for cardiac decompensation (90 on placebo versus 61 on bisoprolol, P < .01), and more patients improved by at least one New York Heart Association functional class (48 on placebo versus 68 on bisoprolol, P = .04) by the end of follow-up period. These results confirm previous trials evidence that a progressively increasing dose of beta-blocker in severe heart failure confers functional benefit. Subgroup analysis suggested that benefit from beta-blockade therapy was greater for those with nonischemic cardiomyopathy. However, improvement in survival while on beta-blockade remains to be demonstrated.

Association of lipoprotein subclass distribution with use of selective and non-selective beta-blocker medications in patients with coronary heart disease

The relationship of beta-blocker drug use to plasma low density lipoprotein-cholesterol (LDL-C), lipoprotein mass distribution, (LDL, S f0–12), intermediate density lipoproteins (IDL, S f12–20), very low density lipoproteins (VLDL, S f20–400), and high density lipoproteins (HDL, F 1.20–9) were examined in 206 men with coronary heart disease. Thirty-three used non-selective (NSEL), 49 used selective (SEL), and were compared to 124 who used no beta-blockade (NoBB). No significant between group differences were seen for potentially confounding variables. LDL and IDL mass, total cholesterol and LDL-cholesterol were not significantly different between groups. HDL-C was significantly lower in both NSEL ( P < 0.005) and SEL ( P < 0.01). NSEL and SEL had significantly lower HDL mass ( P < 0.005 and P < 0.02), HDL 2 mass ( P < 0.01 and P = 0.06), and HDL 3 mass ( P < 0.01 and P < 0.05). VLDL mass was significantly higher ( P < 0.02) only in NSEL. Small LDL (S f0–7) was not significantly different between groups and large LDL (S f7–12) was significantly lower in NSEL ( P < 0.05) and SEL ( P < 0.05). LDL peak S f was significantly lower in both NSEL ( P < 0.005) and SEL ( P < 0.02) compared to NoBB. Despite the lack of differences in levels of LDL-cholesterol, beta-blocker use is associated with a significant difference in the distribution of larger, more buoyant to smaller, more dense LDL particles. Reduced HDL levels in subjects on beta-blockade therapy are associated with reductions in both HDL 2 and HDL 3 subclasses. These results suggest that beta-blocker use may predispose to expression of a relatively atherogenic lipoprotein subclass profile

Beneficial antiarrhythmic effect of beta-blockade in patients with dilated cardiomyopathy.

Antiarrhythmic effects of beta-blockade (BB) in patients with dilated cardiomyopathy were compared with those of various antiarrhythmic agents using ambulatory Holter monitoring. The BB therapy effectively suppressed ventricular extrasystoles (VEs) in 85% of patients, as evidenced by improvement in Lown's grade or a reduction in the number of the highest grade VEs greater than 50%. In contrast, conventional antiarrhythmic agents, except flecainaid and amiodarone, were poorly effective in suppressing VEs. BB therapy gradually increased left ventricular fractional shortening (16 +/- 6% to 22 +/- 12%) and improved 12-month survival rates as compared with those receiving conventional therapy (93 vs 69%). This antiarrhythmic potency seemed to be an additional therapeutic efficacy of BB in the management of patients with dilated cardiomyopathy, which frequently associated with serious VEs.

Effects of long-term beta-blockade therapy in patients with dilated cardiomyopathy--serial clinical and echocardiographic observations.

Twenty-three patients with dilated cardiomyopathy (DCM) were treated with metoprolol and their clinical courses compared with those of 26 patients untreated with beta-blocking agents (non beta group). Of the 23 patients treated with metoprolol, 20 (beta group) were treated for 6 months or longer, while the remaining 3 patients were intolerant of the drug and suffered aggravation of heart failure. In the beta group, 2 deaths occurred, while of the remaining 18 patients 4 were considered clinically improved in NYHA class 6 or 12 months later, and none suffered clinical deterioration during the follow-up period. In the non-beta group, clinical improvement was found in 2 patients and deterioration of functional class in 10. Heart rate and pressure rate product were significantly decreased by 1 month after the treatment with metoprolol. At that time, blood pressures, systolic and diastolic left ventricular dimensions, indices of systolic function (% FS, mVcf) and exercise capacity had not changed, while cardiac output was decreased and systemic peripheral vascular resistance was significantly increased. In the beta group, significant improvements in left ventricular dimensions, systolic function and exercise tolerance were delayed and observed within 3 to 6 months during the follow-up period, while no such improvements occurred in patients of the non-beta group. During the follow-up period, 2 patients of the beta group and 10 patients of the non-beta group died. The survival curve for patients of the beta group, prepared using the Kaplan Meier's Method, was better than that for patients of the non-beta group. Metoprolol was therefore found to be useful for treatment of DCM.

91. Effects on insulin sensitivity in glucose-intolerant hypertensive subjects when beta-blockade therapy was replaced by captopril during a 12-month observation period

91. Effects on insulin sensitivity in glucose-intolerant hypertensive subjects when beta-blockade therapy was replaced by captopril during a 12-month observation period

91. Effects on insulin sensitivity in glucose-intolerant hypertensive subjects when beta-blockade therapy was replaced by captopril during a 12-month observation period

91. Effects on insulin sensitivity in glucose-intolerant hypertensive subjects when beta-blockade therapy was replaced by captopril during a 12-month observation period

Central Nervous System Side Effects of β-Adrenergic Blocking Agents with High and Low Lipid Solubility

beta-adrenergic blocking agents have undesirable effects believed to be mediated through the central nervous system (CNS). If these effects are due to direct CNS action, less lipid soluble agents ought to have fewer effects. Accordingly, several formal psychological tests of items such as mood, motivation, and anxiety were used in a double-blinded crossover study in 17 hypertensive subjects taking equipotent beta blocking agents with high (propranolol) and low (atenolol) lipid solubility. Patients had less negative effects (p less than 0.05) on 12 of 21 items evaluated with atenolol compared to propranolol while peripheral beta blockade [beta 1, exercise heart rate (HR), and blood pressure (BP)] was equivalent. These results suggest that the mental changes which accompany beta blockade therapy are mediated directly in the CNS and that less soluble drugs can be expected to have fewer CNS effects.

Increase in PaO2 following Intravenous Administration of Propranolol in Acutely Hypoxemic Patients

To define the effects of beta-blockade therapy on PaO2, arterial blood gas levels were determined before and after therapeutic administration of propranolol in 44 acutely ill patients. With a FIo2 of 0.33 +/- 0.08, the PaO2 increased from 89.6 +/- 3.6 to 95.3 +/- 3.8 mmHg (p less than 0.01), 10 minutes after intravenous administration of 1 to 3 mg of propranolol. Simultaneous hemodynamic measurements obtained in six patients demonstrated a dramatic decrease in venous admixture, associated with decreases in cardiac output and mixed venous Po2. Propranolol administration generally results in a moderate increase in PaO2, which is related to a significant decrease in pulmonary shunt. The clinical implications of these findings are limited by the expected decrease in tissue oxygen delivery after beta-blockade therapy.

A randomized trial of low-dose beta-blockade therapy for idiopathic dilated cardiomyopathy

Beta-blockade therapy to improve survival in idiopathic dilated cardiomyopathy (IDC) has been both advocated and criticized. However, randomized studies have not been performed. Thus, 50 patients with IDC were randomized in pairs to standard therapy (C) alone or with β blockade (BB). Betablockade therapy with metoprolol was titrated from 12.5 to 50 mg twice daily as tolerated (final average dose, 61 mg/day). Groups were comparable in age (C, 50 ± 15 years; BB, 51 ± 13 years), gender (C, 76% male; BB, 56% male), entry functional class (C, 2.8 ± 0.8; BB, 2.7 ± 0.7), and left ventricular ejection fraction (C, 27 ± 12%; BB, 29 ± 10%). Follow-up averaged 19 months (range 1 to 38). One subject in each group was lost to follow-up. There were 3 early BB dropouts (within 2 days) due to low-output syndrome (2 patients) or fatigue (1 patient). Eleven patients died. By intention to treat, 5 BB and 6 C patients died (difference not significant). By actual treatment, 3 BB patients died, including 2 late dropouts (at 0.2, 10 and 17 months), and 8 C patients died (at 2, 9, 9, 15, 18, 24, 29 and 32 months, p = 0.12). In addition, functional evaluation on follow-up (functional class, San Diego questionnaire and exercise time) all tended to favor those receiving BB. Low-dose BB is tolerated in 80% of IDC patients on a long-term basis. Those continuing to take BB have a good prognosis. Mortality in C patients, however, is less than in some retrospective studies. The improved survival trend in the BB group may be due to selection of less ill patients and to possible protective effects of BB. A randomized multicenter study appears appropriate for definitive evaluation of survival effects of BB in IDC.

Chronic beta blockade therapy in patients after myocardial infarction

This report is a review of >18 years of experience with clinical trials that have examined the effect of beta blockers on mortality after acute myocardial infarction (MI). Despite inadequate sample size, a substantial number of the early randomized trials demonstrated a trend toward reduction in mortality after MI using a number of beta blockers. This review highlights the larger prospective randomized trials, especially the Multicenter International Trial of practolol, the Norwegian Multicenter Study of timolol and the Beta-Blocker Heart Attack Trial (BHAT) of propranolol. The combined strength of these longterm trials, comprising > 8,000 patients, demonstrates a consistent and statistically significant reduction in mortality after MI. Both the Norwegian timolol study and BHAT further document a substantial reduction in mortality in patients stratified according to risk groups, with a reduction in mortality after complicated or uncomplicated first MI or in patients with prior MI. These 2 studies also document a reduction in sudden death mortality in the first year after MI. Data regarding subendocardial MI is more variable, but the Norwegian timolol study documents a substantial reduction in mortality after subendocardial MI. Based on this review, we recommend treatment of all patients who can tolerate beta blockade after acute MI, beginning in the late hospitalization phase and continuing for at least 2 years.

Beta blockers in ischemic heart disease

Many trials have reported that beta blockers increase survival after myocardial infarction; these trials are reviewed. The timolol trial was randomized and showed that mortality was reduced for all patients randomized to beta blockers. Similar findings have been found in both the metoprolol trial in Göteburg and the Beta-Blocker Heart Attack Trial in the U.S. Chronic beta-blockade therapy appears to reduce mortality in patients who survive acute myocardial infarction. The mechanism is as yet unknown.

Acute Traumatic Disruption of the Thoracic Aorta: A Ten-Year Experience

During a ten-year period, 44 patients were treated for acute traumatic disruption of the thoracic aorta. Of the 44 patients, 21 had operative repair within 48 hours of injury (Group 1); 14 patients had operative therapy electively delayed for 2 to 79 days (Group 2); 5 had operative therapy electively delayed indefinitely (Group 3); 2 had immediate operative repair when a delayed diagnosis was made at 21 and 56 days, respectively (Group 4); 1 patient died during angiography and 1 refused operation (Group 5). Mortality was as follows: Group 1, 24%; Group 2, 14%; Group 3, 0; Group 4, 100%; and Group 5, 100%. All operative deaths occurred in the subgroup of 23 patients in whom left heart bypass was utilized. Immediate operative intervention with a heparinized shunt is preferable as soon as the diagnosis of thoracic aortic disruption has been established, but elective delay of operation in patients with severe concomitant injuries can be achieved safely with beta blockade and antihypertensive therapy.

Long-term benefit of cardioselective beta blockade with once-daily atenolol therapy in angina pectoris

The long-term efficacy of once-daily atenolol cardioselective beta-blockade therapy for chronic stable angina pectoris was studied in nine coronary disease patients. After a placebo-controlled single-blind dose-ranging trial with 2-week drug periods of 25, 50, 100, and 200 mg, they continued on 100 or 200 mg daily for 1 year. Treadmill exercise tests (ET) were performed at times of peak and trough serum stenolol concentrations and 24-hour ECG ambulatory recordings were obtained after placebo, after 2 weeks of 100 and 200 mg atenolol, and after 3, 6, 9, and 12 months of 100 or 200 mg atenolol. During early and chronic atenolol therapy, angina frequency and nitroglycerin consumption were decreased ( p < 0.01to< 0.001). Twenty-four hour ECG and ET showed sustained heart rate suppression. Exercise duration until angina onset was prolonged during all periods of atenolol administration. Maximal improvement in exercise tolerance and angina relief was not reached until 3 months of atenolol therapy despite stable serum drug concentrations. During the 14 months fatigue occurred in three patients which was dose-limiting in only one. Thus atenolol 100 or 200 mg given once daily, provided well-tolerated and potent anti-ischemic myocardial actions which were effectively maintained during chronic therapy of angina pectoris.

Effect of beta blockade therapy on hypertensive cardiac hypertrophy

Effect of beta blockade therapy on hypertensive cardiac hypertrophy