Long-term Β-blocker Therapy Research Articles

Nadolol inhibits reactive oxygen species generation by leukocytes and linoleic acid oxidation

We studied the effect of short-term nadolol administration on the reactive oxygen species (ROS) generation by polymorphonuclear leukocytes and mononuclear cells in 8 normal subjects. At a oral dose of 40 mg/day for 5 days, nadolol produced a decrease in the ROS generation by leukocytes. ROS generation by polymorphonuclear leukocytes decreased by 38% from 134 ± 44 mV at baseline to 83 ± 34 mV after 5 days (p = 0.005), and ROS generation by mononuclear cells decreased by 33% from 174 ± 69 mV at baseline to 117 ± 55 mV after 5 days (p = 0.015). There was also a significant reduction in linoleic acid oxidation as reflected by the lower levels of 9- and 13- hydroxy-octadecadienoic acid after 5 days. There was no change in the plasma thiobarbituric acid-reacting substances, a less sensitive index of oxidative damage to lipids. There was also no significant change in the levels of metatyrosine and orthotyrosine, which are known indexes of oxidative damage to amino acids and proteins. The absence of a significant change in metatyrosine, orthotyrosine, and thiobarbituric acid-reacting substances may reflect the short duration of nadolol administration and the decreased ROS load. Because ROS may induce lipid peroxidation, this inhibitory effect of nadolol on ROS generation by leukocytes and linoleic acid oxidation may inhibit low-density lipoprotein oxidation and thus atherogenesis. This effect may partly explain the favorable outcomes observed in patients with coronary artery disease on long-term β-blocker therapy.

Long-term β-blocker therapy improves autonomic nervous regulation in advanced congestive heart failure: A longitudinal heart rate variability study

Background β-Blocker therapy is believed to modulate the detrimental effect of overcompensating neurohormonal activation in chronic heart failure. However, clinical doubts remain, particularly the physiologic sympathovagal balance. Methods To respond to clinical concern about worsening autonomic nervous perturbation in β-blocker therapy of advanced congestive heart failure, 15 consecutive patients were longitudinally studied to elucidate the evolution of cardiac function versus 24-hour heart rate variability (HRV) before and after 1, 3, and 6 to 9 months of atenolol-combined therapy. Results Two patients died prematurely within 1 month. All 13 surviving patients showed improvement in New York Heart Association functional class, with decrease in left ventricular end-systolic and end-diastolic dimensions and increase in fraction shortening and ejection fraction by echocardiography after at least 3 months of atenolol use. The retarded therapeutic effect was accompanied by a general rise of total, very low, low-, and high-frequency components (9.0 ± 0.5, 8.8 ± 0.5, 6.2 ± 0.6, and 6.1 ± 0.5 vs 10.9 ± 0.3, 10.7 ± 0.4, 8.6 ± 0.3, and 7.8 ± 0.3; all P < .02) of daily HRV. This implied recovery of parasympathetic and baroreceptor function. Return of sympathovagal interaction was further supported by the suppression of Cheyne-Stokes type HRV as detected by Wigner-Ville distribution. Conclusions Long-term β-blocker therapy for advanced congestive heart failure upwardly regulates the autonomic nervous interaction in synchrony with the evolution of cardiac function performance. (Am Heart J 1999;137:658-65.)

Changes of the inducibility of mechanical alternans in patients with chronic heart failure after long-term β-blocker therapy

Changes of the inducibility of mechanical alternans in patients with chronic heart failure after long-term β-blocker therapy

Adding the new calcium antagonist mibefradil to patients receiving long-term β-blocker therapy results in improved antianginal and antiischemic efficacy

Objective The objective of this study was to evaluate the efficacy, tolerability, and safety of mibefradil, a new selective T-type calcium channel blocker, in patients with chronic stable angina pectoris receiving concomitant β-blocker therapy. Design This was a multicenter, double-blind, placebo-controlled study. Methods Ninety-five patients receiving a stable dose of β-blockers, which was not changed for the purpose of the study, were administered either 50 mg mibefradil once daily for 2 weeks, then 100 mg once daily for 2 weeks, or matching placebo. Efficacy was evaluated by treadmill exercise tolerance testing 24 hours after dose and by diary registration of anginal episodes and nitroglycerin consumption. Results Two weeks of treatment with 50 mg mibefradil resulted in a significant increase in symptom-limited exercise duration and a significant delay in the onset of persistent 1 mm ST-segment depression (placebo-corrected treatment effect: 23.2 and 51.7 seconds, respectively). Treatment with the 100 mg dose for 2 additional weeks resulted in a larger improvement in treadmill exercise tolerance testing duration and onset of ischemia (placebo-corrected treatment effect: 52.7 and 75.8 seconds, respectively). In addition, a significant decrease in weekly anginal episodes was observed with the 100 mg dose of mibefradil compared with the effect in the placebo group (-53% vs -12%, p = 0.037). Conclusions The combined treatment of mibefradil and β-blockers was well tolerated, and the overall incidence of adverse events was no different from that with β-blockers alone. The results indicate that adding mibefradil to chronic β-blocker treatment is associated with significant improvement in efficacy, which is not achieved at the expense of tolerability. (Am Heart J 1998;135:272-80.)

Prediction of the effectiveness of long-term β-blocker therapy for dilated cardiomyopathy by signal-averaged electrocardiography: a prospective study

Prediction of the effectiveness of long-term β-blocker therapy for dilated cardiomyopathy by signal-averaged electrocardiography: a prospective study

941-18 Antiarrhythmic Effect of Long-term β-Blocker Therapy for Dilated Cardiomyopathy on Survival Rate

To clarify how the long-term β-blocker (β) therapy for the patients (pts) with dilated cardiomyopathy (DCM) improves the rate of freedom from cardiac death (RFCD), 57 DCM pts with β (metoprolol; 40–60 mg/day)(G-l, followup; 6–120 M) and 72 DCM pts without β (G-2, follow-up; 6–102 M) were followed up. The survival was confirmed by annual interview. The cause of death and the preterminal condition of the pts were obtained from family members, medical personnel or medical recordings. The RFCO was analyzed with Kaplan-Meier life table method. At entry, there were no significant differences in age, sex, blood pressure, heart rate, left ventricular end-diastolic dimension (64.0 ± 6.0 vs 63.5 ± 6.8 mm) and ejection fraction (40.7 ± 9.1 vs 42.3 ± 8.3%) measured by echocardiography, and the severity of ventricular arrhythmia by 24 hours Holter monitoring (according to the Lawn's grade) between G-l and G-2. During the follow-up period, non-cardiac death occurred in 2 pts in G-1 and in 3 pts in G-2. The annual RFCD were calculated as shown below; 1Y 2Y 3Y 4Y 5Y 6Y 7Y G-1 1.0 * 1.0 # 0.98 * 0.98 # 0.98 # 0.98 # 0.87 * G-1 0.91 0.86 0.84 0.84 0.72 0.62 0.62 * p &lt; 0.05 # P &lt; 0.01 vs G-2 The number of death from heart failure did not show significant difference between G-1 (3 of 57 pts) and G-2 (4 of 72 pts). On the other hand, sudden death has occurred more often in G-2 (10 of 72 pts) than in G-1 (1 of 57 pts) (p &lt; 0.05), resulting in that the RFCD was significantly better in G-l than in G-2. These results indicate that the long-term β-blocker therapy for DCM might improve the rate of freedom from cardiac death due to prevention of sudden death rather than of death from heart failure.

Management of patients after myocardial infarction and thrombolytic therapy

On the basis of the available data concerning the indications for and the timing of arteriography after thrombolysis, the inevitable conclusion is that conservative instead of aggressive management is indicated for the 40% to 50% of patients at low risk who do not have spontaneous myocardial ischemia or myocardial ischemia that was provoked. Factors to be considered in treatment decisions for individual patients after thrombolytic therapy include risk factors before and after thrombolytic therapy, the results of studies assessing conservative versus aggressive postthrombolytic management, the accuracy of risk stratification by noninvasive testing, and the relevance of the “open artery” hypothesis. The low-risk patient with a left ventricular ejection fraction above 40% and no ischemia during adequate stress testing has a low 3-year mortality rate. Although benefits of routine coronary arteriography exist relative to determining the severity of coronary artery disease and whether the infarct-related artery is patent, selective coronary arteriography is a more feasible and less expensive approach for appropriate patients. The low annual mortality rate with this approach is equal to that obtained when patients undergo routine coronary arteriography with myocardial revascularization based upon the result of the routine procedure. The modification of various coronary risk factors appears as valuable able for patients who have undergone thrombolytic therapy as for those who did not. Specifically, the cessation of smoking, the control of hypertension, and the treatment of hypercholesterolemia are indicated for patients after thrombolysis when any of these modifiable risk factors are present. Secondary prevention with pharmacologic agents appears to be similar for those who have undergone standard or thrombolytic therapy. Long-term aspirin therapy is routine for secondary prevention; long-term β-blocker therapy is useful for high-risk patients; and long-term treatment with angiotensin-converting enzyme inhibitors is indicated for patients after thrombolysis who have a low left ventricles ejection fraction.

Beta-adrenergic blocker withdrawal

Abrupt withdrawal of long-term β-blocker therapy in patients with angina may be associated with unstable angina and myocardial infarction. It appears that an “overshoot” in heart rate from pretreatment values occurs, which increases myocardial oxygen demand. This increase in heart rate may be secondary to increased β receptor numbers or increased receptor sensitivity. Another possible mechanism for the increased risk of myocardial infarction after β-blocker withdrawal is increased platelet aggregability. Withdrawal reactions may be less severe with β blockers that have partial agonist activity. In patients undergoing coronary artery bypass surgery, β-blocker withdrawal reactions have also been observed. Maintenance of β-blocker therapy on the morning of surgery appears to reduce this risk. Gradual withdrawal regimens in outpatients with angina may be associated with lower risk for a β-blocker withdrawal reaction. The gradual withdrawal of β blockers in hypertensive patients requires further study.

Exercise training during long-term beta-blockade treatment in healthy subjects

Although it is well accepted that treatment with β-blocking drugs impairs endurance exercise capacity acutely, whether a trained state can be achieved while receiving long-term β-blocker therapy is controversial. The apparent attenuation of training reported in some studies has given rise to the theory that adrenergic stimulation represents a unifying mechanism by which endurance training effects are produced. This theory is supported by studies of long-term β-agonist infusions that show apparent training responses. To assess the role of β-adrenergic stimulation produced by exercise in the development of cardiovascular training effects, 39 healthy men were assigned in a random, double-blind fashion to receive oral propranolol, atenolol or matched placebo. Drug doses were titrated individually to minimize the heart rate response to submaximal exercise (dose ranges: atenolol, 50 to 200 mg/day; propranolol, 160 to 320 mg/day). After beginning chronic drug administration, all subjects participated in an intense, supervised 6-week exercise training program (5 days/week, 45 min/day, at least 75% peak heart rate). Adherence to training was monitored by daily supervision; compliance to the medication regimen was assessed by weekly pill counts, medication diaries and plasma drug assay. Maximal exercise testing was performed before and after training. Peak oxygen consumption increased significantly with training in all 3 groups, whether comparisons were made in the presence or absence of medication. The magnitude of change in oxygen consumption did not differ between groups (F = 0.12, p >0.88). Similarly, peak work rate and duration of work increased in all 3 groups. In the absence of drug treatment, submaximal exercise heart rate decreased with training in all groups. Thus, cardiovascular training effects can be produced in healthy men despite the presence of substantial β 1-selective or nonselective β blockade.

Effects of 10 different beta-adrenoceptor antagonists on hemodynamics, plasma renin activity, and plasma norepinephrine in hypertension: the key role of vascular resistance changes in relation to partial agonist activity.

Summary The literature was surveyed for the acute and long-term hemodynamic effects of 10 different β-adrenoceptor antagonists and their long-term effects on plasma renin activity and plasma norepinephrine concentrations. The β-blockers are pindolol, practolol, alprenolol, oxprenolol, acebutolol, penbutolol, metoprolol, atenolol, propranolol, and timolol. Forty-four acute and 41 long-term hemodynamic studies in 430 and 482 patients, respectively, 54 renin studies in 784 patients, and 17 norepinephrine studies in 217 patients were analyzed. In the acute studies, blood pressure was hardly lowered. In spite of many pharmacological and physicochemical differences, the drugs appeared to possess a hypotensive potency of approximately equal magnitude in long-term studies. The degree of cardiodepression and the suppression of renin as exerted by the different β-blockers were inversely correlated with their pharmacologically defined quantity of partial agonist activity (PAA) or intrinsic sympathomimetic activity. In the acute studies, the increments in vascular resistance were proportional to the degree of cardiodepression, suggesting that increased vasoconstrictor nerve activity mediated through the baro-reflex had prevented an acute fall in arterial pressure in response to a given fall in cardiac output. The resistance response to cardiodepression was similar for β1- and non-selective blockers, indicating that vascular β2- adrenoceptors are relatively unimportant for maintaining basal vascular tone. After long-term therapy the inverse correlation between changes in cardiac output and changes in vascular resistance was shifted to a lower level of vascular resistance. Thus, the onset of blood pressure reduction during long-term therapy with β-blockers is always associated with a fall in vascular resistance at any given value of cardiac output. Therefore, the level of vascular resistance appears to be determined mainly by the degree of PAA, irrespective of the quality of cardioselectivity. Plasma renin activity and vascular resistance are inversely correlated during long-term β-blocker therapy. Consequently, the fall in vascular resistance that appears to underlie the fall in blood pressure reduction cannot be explained by the suppression of plasma renin activity. The accessibility of the central nervous system to the different β-blockers neither determines the time of onset of blood pressure reduction nor the magnitude of this effect. The nonessentiality of cardiodepression, renin suppression, and blockade of central β-receptors suggests that blockade of presynaptic β-receptors underlies the vasodilatory and antihypertensive effects of these drugs. Changes in the concentrations of norepinephrine in plasma are compatible with this supposition, provided that changes in clearance of norepinephrine from plasma are taken into account.