Protective Effect Of Beta-blockers Research Articles

Repurposing Antihypertensive and Statin Medications for Spinal Pain: A Mendelian Randomization Study.

Mendelian randomization (MR) study. To examine whether antihypertensive medications (beta-blockers, calcium channel blockers, and angiotensin-converting enzyme inhibitors) and statins can be repurposed to prevent or treat spinal pain (back or neck pain). Observational studies and a recent MR study have found associations between elevated blood pressure and a greater risk of back pain. Observational studies have found associations between hyperlipidemia and statin use and greater risk of back pain. No prior MR studies have examined the effects of antihypertensives or statins on spinal pain. This was a two-sample MR study using publicly available summary statistics from large-scale genome-wide association studies (GWAS). Sample sizes in exposure GWASs were n=757,601 (systolic blood pressure) and n=173,082 (low-density lipoprotein cholesterol), and n=1,028,947 for the outcome GWAS of spinal pain defined as health care seeking for any spinal pain-related diagnosis. Genes and cis-acting variants were identified as proxies for the drug targets of interest. MR analyses used inverse-variance weighted meta-analysis. The threshold for statistical significance after correction for multiple testing was P <0.0125. No statistically significant associations of these medications with spinal pain were found. However, findings were suggestive of a protective effect of beta-blockers on spinal pain risk (odds ratio [OR] 0.84, 95% confidence interval [CI] 0.72-0.98; P =0.03), and calcium channel blockers on greater spinal pain risk (OR 1.12, 95% CI 1.02-1.24; P =0.02). A protective effect of beta-blockers on spinal pain was suggested in the current study, consistent with findings from observational studies of various other pain phenotypes. The detrimental effect of calcium channel blockers on spinal pain suggested in the current study must be interpreted in the context of conflicting directions of effect on nonspinal pain phenotypes in other observational studies.This Mendelian randomization study examined whether antihypertensive medications (beta-blockers, calcium channel blockers, and angiotensin-converting enzyme inhibitors) and statins can be repurposed to prevent or treat spinal.This was a two-sample MR study using publicly available summary statistics from large-scale genome-wide association studies ranging size from 173,082 to 1,028,947 adults.While no statistically significant associations were found, a protective effect of beta-blockers on spinal pain was suggested (odds ratio [OR] 0.84, 95% confidence interval [CI] 0.72 to 0.98; p= 0.03), as was a detrimental effect of calcium channel blockers on spinal pain (OR 1.12, 95% CI 1.02 to 1.24; p= 0.02).

Are beta blockers effective in preventing stroke-associated infections? - a systematic review and meta-analysis.

Background: Excessive sympathoexcitation could lead to stroke associated infection. Inhibiting sympathetic excitation may reduce the infection risk after stroke. Thus, the present study aimed to determine the protective effect of beta blockers on stroke associated infection through systematic review and meta-analysis.Methods: A systematic search of multiple databases were performed up to February 2022. The included studies required beta blockers therapy in stroke patients and assessed the incidence of stroke-associated infections. Outcomes of interest included infections, pneumonia, urinary tract infection and sepsis. Random-effects model was used for analysis. Heterogeneity was evaluated using I2 statistics and publication bias was evaluated by the funnel plot.Result: A total of 83 potentially relevant publications was identified in the initial search. Six studies met the inclusion criteria for meta-analysis. The risk of bias in the included articles satisfies the quality requirement of meta-analysis. No significant associations between beta blockers therapy and the prevention of stroke associated infection, stroke associated pneumonia and septicemia were found, However, subgroup analyses revealed an association between beta blockers treatment and the increased risk of post-stroke urinary tract infection or stroke associated pneumonia in some stroke patients (OR = 1.69 [1.33, 2.14], P < 0.0001; OR = 1.85 [1.51, 2.26], P < 0.0001).Conclusion: Due to the lack of robust evidence, this meta-analysis may not support the preventive effect of beta blockers on stroke associated infection. But beta blockers treatment may be associated with development of post-stroke urinary tract infection and stroke associated pneumonia in some stroke patients.

Beta-blocker exposure and long-term survival in patients with transthyretin amyloid cardiomyopathy

Abstract Aims To investigate a potential association between beta-blocker exposure and long-term survival in patients with transthyretin amyloid cardiomyopathy (ATTR-CM). Methods Real world prospective registry of 128 consecutive patients with ATTR-CM recruited in 7 hospitals. The long-term survival of patients who were receiving beta-blockers (n=65) at baseline was compared with the one of untreated controls (n=63), by means of both unweighted and inverse probability of treatment weighting (IPTW) Cox's regression analyses. Tolerance and side effects of beta-blockers were recorded. Median study follow-up was 520 days. Results Patients with ATTR-CM who were receiving beta-blockers at baseline showed statistically significant lower all-cause mortality than untreated controls (figure 1), as compared either by means of unweighted Cox's regression (hazard ratio = 0.31; 95% CI 0.12–0.19; p=0.015), or by means of Cox's regression with IPTW (hazard-ratio = 0.18; 95% CI 0.08–0.41; p&amp;lt;0.001). The protective effect of beta-blockers was stronger in the subgroups of ATTR-CM patients with previous atrial fibrillation/flutter, previous heart failure hospitalization, left ventricular ejection fraction &amp;lt;50%, NTproBNP&amp;gt;1000 pg/ml, and NYHA class III or IV (figure 2). The overall rate of beta-blocker suspension due to side effects in the study population was 25% (95% CI 15.5%–34.5%). Bradycardia and hypotension were the most frequent side effects leading to drug withdrawal. Conclusions In this real world, prospective, multi-institutional registry, patients with ATTR-CM who received beta-blockers presented lower all-cause mortality than untreated controls. Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): PFIZERSOCIEDAD GALLEGA DE CARDIOLOGIA Figure 1. SurvivalFigure 2. Subgroup analysis

Long-Term Effect of Non-Selective Beta-Blockers in Patients With Rheumatoid Arthritis After Myocardial Infarction-A Nationwide Cohort Study.

Objectives: Rheumatoid arthritis (RA) is an independent nontraditional risk factor for incidence of myocardial infarction (MI) and post-MI outcome is impaired in the RA population. Use of beta-blockers improves the long-term survival after MI in the general population while the protective effect of beta-blockers in RA patients is not clear. We investigate the impact of beta-blockers on the long-term outcome of MI among RA patients.Methods: We identified RA subjects from the registries for catastrophic illness and myocardial infarction from 2003 to 2013. The enrolled subjects were divided into three groups according to the prescription of beta-blockers (non-user, non-selective, and β1-selective beta-blockers). The primary endpoint was all-cause mortality. We adjusted clinical variables and utilized propensity scores to balance confounding bias. Cox proportional hazards regression models were used to estimate the incidence of mortality in different groups.Results: A total of 1,292 RA patients with myocardial infarction were enrolled, where 424 (32.8%), 281 (21.7%), and 587 (45.5%) subjects used non-user, non-selective, and β1-selective beta-blockers, respectively. Use of beta-blockers was associated with lower risk of all-cause mortality after adjustment with comorbidities, medications (adjusted hazard ratio [HR] 0.871; 95% confidence interval [CI] 0.727–0.978), and propensity score (HR 0.882; 95% CI 0.724–0.982). Compared with β1-selective beta-blockers, treatment with non-selective beta-blockers (HR 0.856; 95% CI 0.702–0.984) was significantly related to lower risk of mortality. The protective effect of non-selective beta-blockers remained in different subgroups including sex and different anti-inflammatory drugs.Conclusion: Use of beta-blockers improved prognosis in post-MI patients with RA. Treatment with non-selective beta-blockers was significantly associated with reduced risk of mortality in RA patients after MI rather than β1-selective beta-blockers.

Effects of Beta-Blockers on Melanoma Microenvironment and Disease Survival in Human.

Background: The regulation of melanoma by noradrenergic signaling has gain attention since pre-clinical and clinical studies suggested a benefit of using beta-blockers to control disease progression. We need to confirm that human melanoma recapitulates the mechanisms described from pre-clinical models. Methods: The sources and targets of norepinephrine in the microenvironment of 20 human melanoma samples was investigated using immunostaining. The effect of an exposure to beta-blockers on immune cell type distribution and expression of immune response markers was assessed with immunostaining on 212 human primary melanoma. A statistical analysis explored the effect of an exposure to beta-blockers on progression free survival, melanoma related survival, and overall survival on the 286 eligible patients. Results: Tumor cells and macrophages may be a source of norepinephrine in melanoma microenvironment. Tumors from patients exposed to wide spectrum beta-blockers recapitulate the increased infiltration of T-lymphocytes and the increased production of granzyme B observed in pre-clinical models. An exposure to beta-blockers is associated with a better outcome in our cohort of melanoma patients. Conclusion: This study shows the association between an exposure to wide spectrum beta-blockers and markers of an effective anti-tumor immune response as well as the protective effect of beta-blockers in human melanoma patients.

Diagnosis and clinical management of long-QT syndrome.

To give an overview over the substantial advances in the diagnosis and management of Long-QT syndrome since its first description 60 years ago. LQT syndrome remains the most common inherited arrhythmia and is a leading cause for sudden unexplained death accounting for up to 20-25% of cases. Rapid progress of genetic technology over the past 2 decades has significantly improved our understanding of molecular and genetic mechanisms of LQT. Despite all those novel insights, phenotype assessment and appropriate risk stratification in LQT remains challenging - even for the expert. This review outlines our current understanding and approach to the clinical diagnosis and management of LQT as well as recent insights into genotype-phenotype correlations. Genetic testing has evolved beyond a pure diagnostic tool and is in addition increasingly integrated as complementary prognostic marker. With regard to the management of LQT, there is now evidence that the protective effect of beta-blockers is rather substance-specific than a class effect. Novel approaches - in conjunction with standard beta-blockers - are emerging including gene-specific treatment for certain subtypes of LQT. A specialized inherited arrhythmia clinic is the preferred resource for the complex risk stratification and individualized management of individuals with LQT.

Experience with bisoprolol in long-QT1 and long-QT2 syndrome.

The protective effect of beta-blockers in patients with inherited Long-QT syndrome is well established. Recent reports have suggested that beta-blockers are not equally effective in Long-QT (LQT). Bisoprolol is an attractive candidate for use in LQT because of its cardioselective properties and favorable side-effect profile. We performed a retrospective cohort study of 114 consecutive patients with gene-positive Long-QT syndrome type 1 (LQT1) or Long-QT syndrome type 2 (LQT2) treated with bisoprolol, nadolol or atenolol with a total of 580 person-years of follow-up. Electrocardiogram (ECG) parameters and cardiac events during follow-up were compared. In addition, exercise treadmill testing was performed in bisoprolol-treated patients. Fifty-nine patients were treated with bisoprolol, 39 with atenolol and 16 with nadolol. Overall, 59% were females and 62% had LQT1. Baseline heart rate and corrected QT (QTc) interval were similar between the groups. QTc shortening was observed in individuals on bisoprolol (ΔQTc -5 ± 31ms; p = 0.049) and nadolol (ΔQTc -13 ± 16ms; p = 0.02) but not on atenolol (ΔQTc +9 ± 24ms; p = 0.16). Median follow-up was similar for bisoprolol and nadolol (3years), but longer for atenolol (6years; p = 0.03); one cardiac event occurred in the bisoprolol group (1.7%) and two events occurred in the atenolol group (5.1%; p = 0.45), whereas none occurred in nadolol-treated patients. Beta-blocker efficacy was not affected by the underlying genotype. The antiadrenergic effect of bisoprolol correlated with the reduction of peak heart rates at exercise testing. Bisoprolol treatment results in QTc shortening in gene-positive LQT1 and LQT2 patients and is well tolerated during long-term administration. The equivalence of bisoprolol for protection from ventricular arrhythmia in LQT patients compared to established beta-blockers remains unknown. Further large-scale studies are required.

The relationship of temperature and air pollution with heart failure and possible protective effects of beta-blockers

The relationship of temperature and air pollution with heart failure and possible protective effects of beta-blockers

Protective effects of spironolactone against anthracycline-induced cardiomyopathy.

The protective effect of beta-blockers, ACE inhibitors, and ARBs on anthracycline cardiotoxicity has already been demonstrated, but the effect of aldosterone antagonism, which inhibits the last step of the renin-angiotensin-aldosterone system (RAAS), was questioned. This study sought to investigate whether spironolactone protects the heart against anthracycline-induced cardiotoxicity. Eighty-three female patients who were diagnosed with breast cancer were included in the study. The study population was randomized into spironolactone and control groups. A dose of 25 mg/day spironolactone was administered to the patients in the spironolactone group. There were 43 patients (mean age 50 ± 11 years) in the spironolactone group and 40 patients (mean age 51 ± 10 years) in the control group. LVEF decreased from 67.0 ± 6.1 to 65.7 ± 7.4 (P = 0.094) in the spironolactone group, and from 67.7 ± 6.3 to 53.6 ± 6.8 in the control group (P < 0.001). When the general linear model was applied, the interaction of LVEF decrease between groups was significantly lower in the spironolactone group than in the control group (P < 0.001). The diastolic functional grade of subjects in the spironolactone group was protected (P = 0.096), whereas it deteriorated in the control group (P < 0.001). We showed that spironolactone administration used simultaneously with anthracycline group chemotherapeutics protects both myocardial systolic and diastolic functions. Spironolactone can be used to protect against anthracycline-induced cardiotoxicity. NCT02053974.

Beta-blocker use and COPD mortality: a systematic review and meta-analysis

BackgroundDespite the benefits of beta-blockers in patients with established or sub-clinical coronary artery disease, their use in patients with chronic obstructive pulmonary disease (COPD) has been controversial. Currently, no systematic review has examined the impact of beta-blockers on mortality in COPD.MethodsWe systematically searched electronic bibliographic databases including MEDLINE, EMBASE and Cochrane Library for clinical studies that examine the association between beta-blocker use and all cause mortality in patients with COPD. Risk ratios across studies were pooled using random effects models to estimate a pooled relative risk across studies. Publication bias was assessed using a funnel plot.ResultsOur search identified nine retrospective cohort studies that met the study inclusion criteria. The pooled relative risk of COPD related mortality secondary to beta-blocker use was 0.69 (95% CI: 0.62-0.78; I2=82%).ConclusionThe results of this review are consistent with a protective effect of beta-blockers with respect to all cause mortality. Due to the observational nature of the included studies, the possibility of confounding that may have affected these results cannot be excluded. The hypothesis that beta blocker therapy might be of benefit in COPD needs to be evaluated in randomised controlled trials.

Use of blockers and the risk of death in hospitalised patients with acute exacerbations of COPD

Cardiovascular disease is a major cause of death in patients with chronic obstructive pulmonary disease (COPD) and predicts hospitalisation for acute exacerbation, in-hospital death and post-discharge mortality. Although beta blockers improve cardiovascular outcomes, patients with COPD often do not receive them owing to concerns about possible adverse pulmonary effects. There are no published data about beta blocker use among inpatients with COPD exacerbations. A study was undertaken to identify factors associated with beta blocker use in this setting and to determine whether their use is associated with decreased in-hospital mortality. Administrative data from the University of Alabama Hospital were reviewed and patients admitted between October 1999 and September 2006 with an acute exacerbation of COPD as a primary diagnosis or as a secondary diagnosis with a primary diagnosis of acute respiratory failure were identified. Demographic data, co-morbidities and medication use were recorded and subjects receiving beta blockers were compared with those who did not. Multivariate regression analysis was performed to determine predictors of in-hospital death after controlling for known covariates and the propensity to receive beta blockers. 825 patients met the inclusion criteria. In-hospital mortality was 5.2%. Those receiving beta blockers (n = 142) were older and more frequently had cardiovascular disease than those who did not. In multivariate analysis adjusting for potential confounders including the propensity score, beta blocker use was associated with reduced mortality (OR = 0.39; 95% CI 0.14 to 0.99). Age, length of stay, number of prior exacerbations, the presence of respiratory failure, congestive heart failure, cerebrovascular disease or liver disease also predicted in-hospital mortality (p<0.05). The use of beta blockers by inpatients with exacerbations of COPD is well tolerated and may be associated with reduced mortality. The potential protective effect of beta blockers in this population warrants further study.

Protective effects of beta-blockers in cerebrovascular disease

Because activated sympathetic tone is associated with poorer outcome after stroke, we investigated whether beta-blocker treatment was associated with lesser stroke severity and improved outcome. We prospectively studied 111 patients with stroke. Stroke severity on presentation gauged by Canadian Neurologic Scale (CanNS) and medication use verified from medical records. Power spectral analysis of heart rate variability estimated cardiac sympathovagal tone. Coagulation and inflammatory activity were assessed. On multiple linear regression, beta-blocker use was the sole independent predictor of less severe stroke on presentation (95% CI: 0.12 to 1.86: p = 0.03). When CanNS was dichotomized, multiple logistic regression revealed that beta-blocker use (odds ratio [OR] 3.70, 95% CI: 1.24 to 11.01, p = 0.02) and female gender (OR 2.96, 95% CI: 1.14 to 7.69, p = 0.03) were independent predictors of CanNS score >8.5. There was no difference in blood pressure and blood glucose between these two groups. Beta-blocker treatment was associated with lower sympathovagal tone (p = 0.001), thrombin (p = 0.009), hemoglobin A(1)C levels (p = 0.02), and erythrocyte sedimentation rate (p = 0.003). Beta-blocker use is associated with less severe stroke on presentation and may be cerebroprotective due to a sympatholytic effect associated with decreased thrombin, inflammation, and hemoglobin A(1)C.

Short to long term mortality of patients hospitalised with heart failure in the Czech Republic—a report from the EuroHeart Failure Survey

The European Society of Cardiology initiated the EuroHeart Failure Survey to obtain more data about the quality of care in patients hospitalised with suspected heart failure (HF). The Czech Republic was 1 of the 24 European Society countries included in the survey. The aim of this report is to extend the original follow-up period of 12 weeks out to 4 years to assess mortality. All admitted patients were screened according to the EuroHeart Survey Protocol, over a 6-week period in six hospitals in Pilsen, Prague and Brno in the year 2000. Annual mortality and cause of death were obtained from the Prague Institute for Health Statistical Information (UZIS Praha). A total of 2365 patients were screened and about 25% of all admitted patients fulfilled the criteria for HF. About 14% of patients died between admission and the 12-week follow-up, 36% of male and 42% of female patients died during the 4-year follow-up (2000-2003). Cardiovascular diseases were the main causes of death (92%). Deceased patients were significantly older, had lower haemoglobin and total plasma cholesterol level, and had renal insufficiency and higher levels of big endothelin and BNP than the survivors. Mortality risk was increased independently by positive history of previous myocardial infarction OR=2.39 (1.59-3.59), by age OR=1.03 (1.01-1.05) and by plasma creatinine level OR=1.04 (1.01-1.07). Treatment with diuretics and digoxin was associated with a higher risk of death; by contrast, a protective effect of beta-blockers and statins was found in these HF patients. Patients with HF were older and had a poor prognosis; approximately one third of the patients will die within 3 years.

Triggering of Ventricular Tachycardia by Meteorologic and Emotional Stress: Protective Effect of -Blockers and Anxiolytics in Men and Elderly

A circadian pattern with a morning peak and the triggering role of emotional stress have been suggested for ventricular arrhythmias. After controlling for participant baseline characteristics and medication used, the authors studied the association of emotional upset, physical activity, and meteorologic parameters with occurrence of ventricular tachycardia (VT) in 457 Croatian participants aged 11-88 years consecutively assigned to undergo continuous 24-hour Holter monitoring. In 2001, multivariate analysis of possible VT precipitators was performed separately for men, women, those aged <65 years, and those aged >64 years. A U-shaped pattern of wind speed (either very weak or very strong), rising relative air moisture, falling atmospheric pressure, and emotional upset were independent predictors of VT episodes in all participant subgroups. Positive association of VT with higher atmospheric temperature or pressure was observed in women and elderly. After adjustment for external triggers, a circadian variation in VT episodes persisted in women (p = 0.01) and those aged <65 years (p < 0.0001) only. A protective effect of beta-blockers and anxiolytics was especially apparent for men and elderly, as well as an adverse effect of digitalis in women. Results suggest that meteorologic and emotional stress could be considered external triggers of VT, with age- and sex-dependent susceptibility.

Betablocker in der Therapie der chronischen Herzinsuffizienz

Once contraindicated, beta-blockers have become an established, evidence-based, recommended treatment concept in chronic heart failure during the last years. The increased activation of the adrenergic system in heart failure syndrome, which leads to transmission of several adverse biological signals to myocytes through adrenergic receptors, provides the rationale for the use of beta-blockers in patients with chronic heart failure. Long-term treatment with different types of beta-blockers addictive to an ACE-inhibitor and diuretics results in normalization of left ventricular shape, an improvement of left ventricular function, and a reduction of hospitalization rate for heart failure. Hemodynamic and clinical improvement is independent of etiology and severity of left ventricular dysfunction. THERAPEUTICAL RECOMMENDATIONS ACCORDINGS TO STUDIES: Adequately powered clinical trials (CIBIS II, MERIT-HF, COPERNICUS) testing different types of beta-blockers (bisoprolol, metoprolol, carvedilol) clearly demonstrated that total mortality and the incidence of sudden cardiac death were significantly reduced in heart failure patients by each of these agents. On the basis of all available evidence, all patients with chronic, stable heart failure (NYHA class II-IV) and with impaired left ventricular function (LVEF < 45%) should receive one of the three above mentioned beta-blockers. Protective effects of beta-blockers in heart failure comprise decrease in heart rate, a decrease of energy consumption, antifibrillatory effects, protection against adrenergic overactivation, and hence, inhibition of myocardial cell necrosis. Moreover, several beta-blockers induce an up-regulation of beta-receptors leading to an improvement of contractility during long-term treatment. It should be mentioned that even a low dosage of beta-blockers exert negative inotropic effects and may lead to a deterioration of hemodynamics and heart failure symptoms in patients with heart failure. The patients treated should be informed that the success of the "paradoxical intervention" will be obvious until 2-3 months after initiation of additional beta-blocker therapy. Beta-blocker treatment for heart failure should be started in stable patients with a very low initial dosage and then up-titrated to the maximal tolerated dosage and should be continued indefinitely. Mortality reduction by beta-blockade in heart failure is no class effect. So far, beneficial effects could only be demonstrated for lipophilic agents. Whether the non-selective beta-blocker carvedilol with additional properties has advantages over the beta-1-selective metoprolol is currently investigated in the COMET (Carvedilol or Metoprolol European Trial) study. Despite the impressive effects in terms of morbidity and mortality reduction, the transfer of these benefits to the clinical practice setting is difficult, with international data showing only 10% of patients with heart failure being treated.

Exercise-induced upward shift of diastolic left ventricular pressure-volume relation in patients with dilated cardiomyopathy. Effects of beta-adrenoceptor blockade.

The effectiveness of beta-blocker therapy for dilated cardiomyopathy (DCM) may be attributed to the inhibition of detrimental effects on the failing heart of sympathetic stimulation during exertion. However, the harmful effects of activity as well as the protective effects of beta-blockers have not been demonstrated. Diastolic ventricular function is known to be sensitive to transient myocardial metabolic insult. In this study, we investigated the effect of modest exercise with or without beta-blockade on the diastolic left ventricular pressure-volume (P-V) relation in patients with DCM. The diastolic left ventricular P-V relation was obtained by high-fidelity pressure measurements and digital subtraction left ventriculography at rest and immediately after modest supine bicycle exercise in 12 patients with DCM. The effects of intravenous administration of 0.1 mg/kg propranolol on resting and exercise P-V relations were studied. The end-diastolic and lowest left ventricular pressures were significantly elevated by exercise (20 +/- 9 to 32 +/- 13 mm Hg, P < .01, and 12 +/- 6 to 21 +/- 11 mm Hg, P < .01, respectively) despite insignificant changes in left ventricular volumes. The administration of propranolol did not alter the resting diastolic P-V relation. However, propranolol significantly attenuated the exercise-induced upward shift of the diastolic P-V relation despite a significant increase in end-diastolic volume. The significant upward shift and attenuation by propranolol were also observed even when the left ventricular pressure was corrected by the subtraction of right atrial pressure. These results indicate that even modest exercise exerts detrimental effects on diastolic left ventricular function of the failing heart through beta-adrenergic stimulation. The clinical effectiveness of beta-blocker therapy in patients with DCM can be attributed in part to the inhibition of detrimental myocardial effects of sympathetic stimulation during daily activity.

Ventricular arrhythmias, sudden death, and silent myocardial ischemia

T HE ASSOCIATION between acute ischemia and ventricular arrhythmia in experimental animals is well established. Kaplinsky et al’ found two periods of early ventricular arrhythmia within 30 minutes of coronary occlusion in dogs. Janse et al* described two mechanisms of ventricular arrhythmia during acute experimental ischemia. At the normal side of the ischemic border they found a focal mechanism, induced possibly by injury currents in the normal Purkinje fibers, whereas in the ischemic myocardium they found macroand microreentry ventricular arrhythmia. Coronary occlusion in cats3 caused increased conduction time through the myocardium and epicardial regions, asynchronous depolarization and shortening of the refractory period, accompanied by ventricular arrhythmias. Kabell et al4 demonstrated that ischemia induced by reduction of collateral flow to an infarcted area in experimental animals, induced fractionation and delay of the electrogram in the infarcted zone and a higher frequency of pacing-induced ventricular tachycardia (VT). The effect of repeated 5-minute periods of ischemia followed by reperfusion on ventricular arrhythmia was assessed by Shiki and Hearse5 in rats; during reperfusion all animals exhibited VT and 83% of them exhibited ventricular fibrillation (VF). After conversion to sinus rhythm and following recovery, they were again subjected to 5-minute periods of ischemia and reperfusion. Following a short recovery period from the initial bout of ischemia only 8% to 17% of the experimental animals developed VT and none had VF, whereas longer recovery periods were associated with a progressive return of vulnerability. Thus, a very short period of ischemia and reperfusion “preconditioned” and protected the myocardium from reperfusion arrhythmias, but for only a short period of time. Recent evidence suggests that platelet activation may contribute to arrhythmogenesis during myocardial ischemia. Flores et al6 found that in ischemic myocardium platelets increased conduction time and reduced action potential duration. Further support for the role of platelets in inducing life-threatening arrhythmias was provided by Davies et al7 who described platelet aggregation as a frequent finding in patients with unstable angina suffering sudden ischemic cardiac death. The association between catecholamines, ischemia, and arrhythmia is a complex one. Within 10 minutes of ischemia the noradrenaline concentration in the myocardium is increased.8l” The accumulation of catecholamines in the extracellular space during ischemia in viable myocardium can cause malignant arrhythmia and acceleration of cell damage.‘O High doses of epinephrine decrease the resting membrane potential and action potential amplitude, slow conduction, and produce undirectional block; all these alterations predispose to reentrant arrhythmias. Epinephrine can also induce triggered activity, the underlying cause of automatic arrhythmias. i1,12 The importance of the sympathetic system during ischemia-induced arrhythmias is further substantiated by the protective effects of beta blockers both against myocardial ischemia and necrosisi3s14 and cardiac arrhythmias. 15.1h In human hearts no enhanced cardiac release of noradrenaline during coronary angioplastyinduced ischemia could be detected by sampling of coronary sinus blood.17 An association between ischemia and arrhythmias in humans was demonstrated by Garan et al’s in 17 patients with multivessel disease who survived out-ofhospital cardiac arrest. Before bypass surgery all developed VT during pacing-induced ischemia; after surgery VT or VF could not be induced in 10 patients, suggesting that ischemia was a major contributing factor for arrhythmia in these patients. Morady et al’” performed electrophysiological stimulation in 15 survivors