Relevance of heart rate as a prognostic factor in patients with acute myocardial infarction: insights from the GISSI-2 study.

AIMS: It is as yet undefined whether simple indexes of autonomic balance such as heart rate (HR) may play a role in risk stratification in patients with acute myocardial infarction (MI). The aim of this study was to quantify the prognostic significance of HR from the surface ECG obtained both at entry and at discharge, in a large population of patients all treated with fibrinolysis during the acute phase and having confirmed acute MI. METHODS AND RESULTS: Surface ECGs obtained at entry and at discharge in patients with confirmed MI enrolled in the GISSI-2 study, a large multicentre trial of different thrombolytic agents, were retrieved. Heart rhythm was evaluated and HR was measured; these data were then added to the main database of GISSI-2 allowing a complete evaluation of the prognostic significance of HR. Patients not in sinus rhythm or with grade 2-3 atrioventricular block were excluded. The prognostic significance of HR (cut-offs predefined at 60, 80, 100 beats.min-1) at entry for in-hospital mortality and at discharge for 6-month mortality was evaluated in the general population and in predefined subgroups. Multivariate analyses were used to assess the independent prognostic value of HR. A total of 8915 patients (more than 70% of the original population) were suitable for the analysis. There was a progressive increase in mortality with increasing HR in the general population (from 7.1% for HR < 60 beats.min-1) to 23.4% for HR > 100 beats.min-1) and in the predefined subgroups. Multivariate analysis showed that HR exerted an independent prognostic significance. Data for analysis of HR at discharge were available for 7831 patients. Consistent with the data observed at entry, a progressive increase of 6-month mortality with increasing HR was present in the general population (from 0.8% for HR < 60 beats.min-1) to 14.3% for HR > 100 beats.min-1) and for the different predefined subgroups. Multivariate analysis confirmed the independent prognostic significance of HR. There was no relation between HR and the incidence of fatal and non-fatal reinfarction. CONCLUSION: The present study indicates that HR values from a standard 12-lead ECG independently predict mortality in patients with acute MI during the in-hospital phase and after discharge. This simple index appears very useful for risk stratification in clinical practice.

Impact of pharmacological treatment on mortality after myocardial infarction in diabetic patients.

Several studies performed before and after the introduction of fibrinolysis as a routine treatment of patients with myocardial infarction (MI) consistently showed that diabetic patients have a higher mortality in-hospital and after discharge. Women with insulin-dependent diabetes (IDD) appear to have a particularly ominous prognosis. So far, very few randomized prospective studies evaluated the effect of pharmacological treatments on prognosis of diabetic patients during acute MI: most of the information on the effect of commonly used cardiovascular drugs in diabetic patients with acute MI (AMI) has been obtained only from retrospective subgroup analyses of some of the large trials or as nonrandomized comparisons. The overview of fibrinolytic trials in acute MI found that fibrinolytic treatment was associated with a 35 days mortality of 13.6% versus 17.3% in diabetics (-21.7%) and 8.7% versus 10.2% in nondiabetics (-14.3%). Data from trials with aspirin suggest that the beneficial effect of this drug is maintained in diabetic patients with acute MI, but the optimal dosage remains undefined. Based on available evidence, beta blockers appear to be able to reduce mortality post-MI in diabetic patients, with an absolute and relative beneficial effect that is, in most cases, larger than that observed in nondiabetic patients. The pooled data from studies non beta blockers indicate a 37% mortality reduction in diabetic patients, compared to 13% in nondiabetics during the acute phase, and a 48% reduction of mortality compared to 33% in nondiabetics post-discharge. Data on outcome of diabetic patients in trials evaluating calcium antagonists are lacking, and there is a strong need for a reevaluation of data from completed trials to obtain some hints on the possible effect of these agents in this population. The "long-term" studies on angiotensin-converting enzyme (ACE) inhibitors in patients with left ventricular dysfunction some time after AMI have shown that the beneficial effect documented in the overall population is present also when limiting the analysis to patients with a history of diabetes, whereas the "acute" studies enrolling patients within 24-36 h after the onset of symptoms have shown a marked beneficial effect of ACE inhibitors in diabetic patients. For example, in the GISSI 3 study, treatment with lisinopril was associated with a decreased 6-week mortality in both IDD (11.8% versus 21.1, p < 0.05) and non-IDD (8.0% versus 10.6%, p < 0.05) patients corresponding to a 44.1% and 24.5% reduction, respectively. All these results must be taken with great caution because in no studies the effect of treatment in diabetic patients was a predefined analysis. They strongly suggest, however, that ACE inhibitors and beta blockers may be particularly beneficial during the acute phase of MI and also post-discharge, offering a strong rationale for their widespread use in diabetic patients with acute MI.

Use of beta-blocking agents in secondary prevention after myocardial infarction: a case for evidence-based medicine? GISSI experience, 1984-1993. The Gruppo Italiano di Studio sulla Sopravvivenza nell'Infarto Miocardico (GISSI) Investigators.

AIMS: Many clinical trials conducted in the 1970s and early 1980s have shown that the long-term use of beta-blockers after an acute myocardial infarction significantly reduces mortality and reinfarction rates. This study assessed the impact of these findings in clinical practice. METHODS: We retrospectively analysed the beta-blocker prescriptions for 36,817 patients with acute myocardial infarction included in three large randomized clinical trials (Gruppo Italiano di Studio sulla Sopravvivenza nell'Infarto Miocardico--GISSI, 1, 2, and 3), conducted by a highly representative sample (about 75%) of Italian coronary care units in 1984-85, 1988-89 and 1991-93. RESULTS: The prescription of beta-blockers at discharge increased gradually from 8.5% in 1984-85 to 25.0% in 1988-89 and to 31.4% in 1991-93. A similar trend was apparent for beta-blocker prescriptions 6 months after acute myocardial infarction. The strongest predictors of beta-blocker prescription are the presence of post-infarctual angina and a history of arterial hypertension. Besides the classical contraindications, advanced age, transitory cardiac failure or arrhythmias in the acute phase of acute myocardial infarction are important predictors of nonprescription. CONCLUSION: The use of beta-blockers after acute myocardial infarction in Italy has increased more than three-fold in the last decade, but they are still prescribed to too few patients, especially those at higher risk, for whom the expected benefit is greater.

Effect of the ACE inhibitor lisinopril on mortality in diabetic patients with acute myocardial infarction: data from the GISSI-3 study.

BACKGROUND: Mortality of diabetic patients with acute myocardial infarction (MI) remains high despite recent improvement in their management. There is a need to evaluate efficacy and safety of novel treatments of MI in this high-risk population. We evaluated whether treatment with an ACE inhibitor begun within 24 hours from the onset of symptoms is able to decrease mortality and morbidity of diabetic patients with acute MI. METHODS AND RESULTS: A retrospective analysis of the data of the GISSI-3 study in patients with and without a history of diabetes was performed. Patients with suspected acute MI were randomized to treatment with lisinopril (2.5 to 5 up to 10 mg/d) with or without nitroglycerin (5 to 20 microg I.V. then 10 mg/d) begun within 24 hours and continued for 6 weeks. The main end point was mortality at 6 weeks, and the secondary end point was a combined evaluation of mortality and severe left ventricular dysfunction. Information on diabetic status was available for 18,131 patients (approximately 94% of the total population enrolled), of whom 2790 patients had a history of diabetes. Treatment with lisinopril was associated with a decreased 6-week mortality in diabetic patients (8.7% versus 12.4%; OR, 0.68; 95% CI, 0.53 to 0.86; 37+/-12 lives saved per 1000 treated patients), an effect that was significantly (P<.025) higher than that observed in nondiabetic patients. The survival benefit in diabetics was mostly maintained at 6 months despite withdrawal from treatment at 6 weeks (12.9% versus 16.1%; OR, 0.77; 95% CI, 0.62 to 0.95). CONCLUSIONS: Early treatment with the ACE inhibitor lisinopril in diabetic patients with acute MI is associated with a decreased 6-week mortality. This beneficial effect supports a widespread and early use of ACE inhibitors in diabetic patients with acute MI. The burden of mortality plus morbidity for ventricular dysfunction in diabetics remains clinically important and warrants further testing of novel therapeutic approaches.

Lisinopril. A review of its pharmacology and clinical efficacy in the early management of acute myocardial infarction.

Following establishment of its efficacy in hypertension and congestive heart failure, the ACE inhibitor lisinopril has now been shown to reduce mortality and cardiovascular morbidity in patients with myocardial infarction when administered as early treatment. The ability of lisinopril to attenuate the detrimental effects of left ventricular remodelling is a key mechanism; however, additional cardioprotective and vasculoprotective actions are postulated to play a role in mediating the early benefit. The GISSI-3 trial in > 19 000 patients has demonstrated that, when given orally within 24 hours of symptom onset and continued for 6 weeks, lisinopril (with or without nitrates) produces measurable survival benefits within 1 to 2 days of starting treatment. Compared with no lisinopril treatment, reductions of 11% in risk of mortality and 7.7% in a combined end-point (death plus severe left ventricular dysfunction) were evident at 6 weeks. Advantages were apparent in all types of patients. Thus, those at high risk-women, the elderly, patients with diabetes mellitus and those with anterior infarct and/or Killip class > 1 -also benefited. These gains in combined end-point events persisted in the longer term, despite treatment withdrawal after 6 weeks in most patients. At 6 months, the incidence rate for the combined end-point remained lower than with control (a 6.2% reduction). The GISSI-3 results concur with those from recent large investigations (ISIS-4, CCS-1, SMILE) of other ACE inhibitors as early management in myocardial infarction. However, the results of the CONSENSUS II trial (using intravenous enalaprilat then oral enalapril) were unfavourable in some patients. These findings, together with the development of persistent hypotension and, to a lesser extent, renal dysfunction among patients in the GISSI-3 trial, have prompted considerable debate over optimum treatment strategies. Present opinion generally holds that therapy with lisinopril or other ACE inhibitors shown to be beneficial may be started within 24 hours in haemodynamically stable patients with no other contraindications; current labelling in the US and other countries reflects this position. There is virtually unanimous agreement that such therapy is indicated in high-risk patients, particularly those with left ventricular dysfunction. The choice of ACE inhibitor appears less important than the decision to treat; it seems likely that these benefits are a class effect. Lisinopril has a tolerability profile resembling that of other ACE inhibitors, can be given once daily and may be less costly than other members of its class. However, present cost analyses are flawed and this latter points remains to be proven in formal cost-effectiveness analyses. In conclusion, early treatment with lisinopril (within 24 hours of symptom onset) for 6 weeks improves survival and reduces cardiovascular morbidity in patients with myocardial infarction, and confers ongoing benefit after drug withdrawal. While patients with symptoms of left ventricular dysfunction are prime candidates for treatment, all those who are haemodynamically stable with no other contraindications are also eligible to receive therapy. Lisinopril and other ACE inhibitors shown to be beneficial should therefore be considered an integral part of the early management of myocardial infarction in suitable patients.

Prognostic significance of heart rate variability in post-myocardial infarction patients in the fibrinolytic era. The GISSI-2 results. Gruppo Italiano per lo Studio della Sopravvivenza nell' Infarto Miocardico.

BACKGROUND: Studies performed before the introduction of fibrinolysis showed that a low heart rate variability (HRV) is associated with higher mortality in post-myocardial infarction (MI) patients. We evaluated whether HRV adds information relevant to risk stratification in patients treated with fibrinolysis as well. METHODS AND RESULTS: From 24-hour ECG recordings obtained at discharge in patients treated with recombinant tissue-type plasminogen activator or streptokinase, we measured several time-domain indexes of HRV: standard deviation (SDNN), root-mean-square of successive differences (RMSSD), and number of RR interval increases > 50 ms ("NN50+"). The prognostic value of HRV for total and cardiovascular mortality was assessed. Of 567 patients with valid recordings, 52 (9.1%) died during the 1000 days of follow-up, 44 (7.8%) of cardiovascular causes. All indexes of low HRV were able to identify patients (16% to 18% of total population) with a higher total mortality (20.8% to 24.2% versus 6.0% to 6.8%, depending on index used). The independent predictive value of low HRV was confirmed by the adjusted analysis with the following relative risks: NN50+, 3.5 (95% CI, 1.9 to 6.7); SDNN, 3.0 (95% CI, 1.55 to 5.9); and RMSSD, 2.8 (95% CI, 1.5 to 5.3). Advanced age, previous MI, Killip class at entry, and use of digitalis were also independent predictors. Similar data were obtained for cardiovascular mortality. CONCLUSIONS: Time-domain indexes of HRV retain their independent prognostic significance even in post-MI patients of all ages treated with fibrinolysis.

Trends and determinants of calcium antagonist usage after acute myocardial infarction (the GISSI experience).

In the last decade, several clinical trials in patients with, or recovering from, acute myocardial infarction (AMI) have evaluated the role of calcium antagonists in affecting patients' prognosis. Results have been disparate, with evidence of possible harm, no effect, or some benefit, depending on the agent used. We evaluated how the evidence from these trials has influenced the pattern of prescription of calcium antagonists and assessed the important determinants of use of these agents in patients after AMI. We analyzed retrospectively the prescription of calcium antagonists at discharge in all patients recovering from AMI enrolled in 3 large randomized clinical trials (Gruppo Italiano per lo Studio della Sopravvivenza nell' Infarto-1 [GISSI-1], GISSI-2, and GISSI-3) during the last 10 years. A progressive decrease in prescriptions for calcium antagonists was evident, from 47.2% in GISSI-1 to 35.1% in GISSI-2 to 19.0% in GISSI-3 (p<0.001). The presence of post AMI angina, history of hypertension, and occurrence of reinfarction were associated with a higher usage of calcium antagonists, whereas the use of beta blockers at discharge was a major independent negative determinant. Use of calcium antagonists for secondary prevention after AMI (i.e., without specific clinical indications for their use) decreased by approximately 60% (from 26.1% to 10.3%). The data indicate that the usage of calcium antagonists in GISSI studies has been strongly affected by the results of other large multicenter trials evaluating calcium antagonists. These agents are now prescribed in patients after AMI almost exclusively in the presence of specific indications such as systemic hypertension or angina.

Myocardial infarction: when and how should we initiate treatment with ACE inhibitors? GISSI-3 Investigators.

Recent trials have shown that angiotensin-converting enzyme (ACE) inhibitors can reduce mortality and the occurrence of severe left ventricular dysfunction (LVD) when started within the first day after acute myocardial infarction and continued for 4-6 weeks thereafter. When started within this time window, ACE inhibitors are safe in relatively unselected myocardial infarction (MI) patients provided they are clinically and hemodynamically stable. GISSI-3, ISIS-4 and CCS-1 studies show that more than half of the lives are saved by ACE inhibitor treatment within the first week of therapy. Although the benefit from ACE inhibitors is larger in patients presenting with congestive heart failure (Killip class > 1), the number of lives saved in patients at low risk, who represent the majority of the population, is relevant. This supports the approach of treating all hemodynamically stable MI patients. Treatment could be stopped after about 1 month in patients without evidence of LVD while those with LVD should follow a long-term therapy with ACE inhibitors.

Arrhythmias and the autonomic nervous system.

This review discusses the current evidence relating to the prevalence and significance of markers of electrical instability and of autonomic dysfunction in patients who have suffered acute myocardial infarction in light of recent studies performed in patients given thrombolytic therapy during the acute phase. Among markers of electrical instability, emphasis is placed upon the frequency of ventricular arrhythmias during Holter monitoring, the presence of late potentials at signal averaging and the inducibility of ventricular tachycardia during programmed electrical stimulation. Among indices of autonomic nervous system dysfunction, data relating to heart rate variability and baroreflex sensitivity are summarized and discussed.

Influence of diabetes on mortality in acute myocardial infarction: data from the GISSI-2 study.

OBJECTIVES: This study was conducted to determine the role of insulin-dependent and noninsulin-dependent diabetes in the prognosis of patients after myocardial infarction and treatment with fibrinolytic agents. BACKGROUND: Several studies have shown that diabetic patients have a high mortality rate after acute myocardial infarction. However, the impact of diabetes on survival in patients treated with fibrinolytic agents is still undefined. It is also not known whether the type of diabetes or gender affects prognosis. METHODS: We analyzed prevalence and prognostic significance of a history of diabetes in patients enrolled in the GISSI-2 study, all of whom received fibrinolytic agents. The incidence of deaths in the hospital and at 6 months after study entry was computed for patients without diabetes and for insulin-dependent and noninsulin-dependent diabetic patients; relative risks were evaluated by univariate and multivariate analysis. RESULTS: Information on diabetic status was available for 11,667 patients, 94.2% of those randomized in the GISSI-2 study. The prevalence of diabetes was higher in women than in men (8.75% vs. 1.85%, p < 0.01 for insulin-dependent and 23.7% vs. 13.8%, p < 0.01 for noninsulin-dependent diabetic patients). The type of fibrinolytic agent did not affect mortality rates; the increase in in-hospital mortality of diabetic patients was moderate and similar for men with insulin- and noninsulin-dependent diabetes (8.7% and 10.1%, respectively, vs. 5.8% in nondiabetic patients); in women, mortality was markedly higher for insulin-dependent and only slightly higher for noninsulin-dependent diabetic patients (24.0% and 15.8%, respectively, vs. 13.9% for nondiabetic patients). The adjusted relative risks were 1.9 (95% confidence interval 1.2 to 2.9) for insulin-dependent diabetic women and 1.4 (95% confidence interval 1.1 to 1.8) for noninsulin-dependent diabetic men. The mortality rate after discharge showed a similar gender difference, and in insulin-dependent diabetic women, prognosis was ominous even in the absence of left ventricular damage before discharge. CONCLUSIONS: A history of diabetes is associated with a worse prognosis after myocardial infarction, even in patients treated with fibrinolytic agents. Gender and type of diabetes appear to be critical in affecting survival. In men, both insulin-dependent and noninsulin-dependent diabetes are associated with a moderately higher mortality rate; in women, insulin-dependent diabetes is, in itself, a strong risk factor for death after myocardial infarction.

Prevalence and prognostic significance of ventricular arrhythmias after acute myocardial infarction in the fibrinolytic era. GISSI-2 results.

BACKGROUND: Several studies performed before the advent of thrombolysis have shown that the presence of ventricular arrhythmias is an independent risk factor for subsequent mortality in patients recovering from acute myocardial infarction. Since fibrinolysis affects the natural history of infarction and may alter the clinical relevance of different risk factors, the aim of the present study was to establish the prevalence and prognostic value of ventricular arrhythmias in post-myocardial infarction patients treated with fibrinolytic agents during the acute phase. METHODS AND RESULTS: Twenty-four-hour Holter recordings obtained before discharge from the hospital in 8,676 post-myocardial infarction patients of the GISSI-2 study were analyzed for the presence of ventricular arrhythmias. Patients were followed for 6 months from the acute event; total and sudden cardiovascular mortality rates were computed, and relative risks in univariate and multivariate analyses were calculated. Ventricular arrhythmias were present in 64.1% of the patients, more than 10 premature ventricular beats per hour were recorded in 19.7% of the patients, and nonsustained ventricular tachycardia was present in 6.8% of the patients. Ventricular arrhythmias were more frequent when signs or symptoms of left ventricular damage were present. During follow-up, there was a total of 256 deaths 2.0% in patients without ventricular arrhythmias, 2.7% in patients with one to 10 premature ventricular beats per hour, 5.5% in those with more than 10 premature ventricular beats per hour, and 4.8% in those with complex premature ventricular beats. Even after adjusting for several risk factors, the presence of frequent (more than 10 premature ventricular beats per hour) ventricular arrhythmias remained a significant predictor of total (RRCox, 1.62; 95% confidence interval, 1.16-2.26) and sudden mortality (RRCox, 2.24; 95% confidence interval, 1.22-4.08). On the other hand, the presence of nonsustained ventricular tachycardia was not associated with a worsening of the prognosis in the adjusted analysis (RRCox, 1.20; 95% confidence interval, 0.80-1.79). CONCLUSIONS: This study shows that approximately 36% of patients recovering from acute myocardial infarction presented with less than one premature ventricular beat per hour in Holter recordings obtained before discharge from the hospital, whereas almost 20% of patients showed frequent (more than 10 premature ventricular beats per hour) ventricular arrhythmias. Due to the large size of the population of this study, these figures may be used as a reliable estimate of the prevalence of arrhythmias in postinfarction patients treated with fibrinolytic agents during the acute phase. Frequent premature ventricular beats are confirmed as independent risk factors of total and sudden death in the first 6 months following the acute event; the significance of nonsustained ventricular tachycardia in this population appears more controversial.

Heart rate variability in patients with ventricular arrhythmias: effect of antiarrhythmic drugs. Antiarrhythmic Drug Evaluation Group (ADEG).

The purpose of this study was to investigate whether heart rate variability could be reliably assessed in patients with ventricular arrhythmias and to evaluate whether it is affected by antiarrhythmic drugs. The study was based on an analysis of 239 ambulatory electrocardiographic (ECG) recordings obtained from 67 patients with frequent and complex ventricular arrhythmias enrolled in the Antiarrhythmic Drug Evaluation Group (ADEG) study. In each recording, after exclusion of premature ventricular complexes, the number of times during a 24 h period in which two consecutive sinus RR intervals differed by more than 50 ms was calculated. The total 24 h count from each recording was then used as an index of heart rate variability. This method is a reliable marker of cardiac parasympathetic activity. Recordings were analyzed at baseline (n = 56), during long-term treatment with amiodarone (n = 17), flecainide (n = 22) or propafenone (n = 17) and after washout in selected patients (n = 5). Despite the presence of a different number of arrhythmias, total 24 h counts in the same patient appeared reproducible over time (r = 0.83 between two different recordings, n = 49, p less than 0.0001). Baseline counts (median 1,698, range 26 to 13,648) were not correlated (r = 0.15) with the number of arrhythmias. The three antiarrhythmic drugs had a disparate effect on total 24 h counts: no change was observed in patients treated with amiodarone (median percent change [delta %]-8, p = NS), whereas a significant (p less than 0.025) decrease occurred in patients treated with flecainide (median delta % -56%) or propafenone (median delta % -64%).(ABSTRACT TRUNCATED AT 250 WORDS)

Antiarrhythmic efficacy of a new class III agent, UK-68,798, during chronic myocardial infarction: evaluation using three-dimensional mapping.

UK-68,798 is a potent class III antiarrhythmic agent that selectively lengthens the effective refractory period (ERP) in isolated tissue without affecting conduction velocity. The present study was performed to evaluate the antiarrhythmic efficacy of UK-68,798 (30 micrograms/kg i.v.) in dogs with a previous myocardial infarction. UK-68,798 did not alter the PQ interval or QRS duration of the surface electrocardiogram but did increase the Q-Tc interval significantly. The ventricular ERP was increased significantly (P less than .01) at a basic cycle length of stimulation of either 300 ms (ERP increased 24 +/- 10 ms) or 250 ms (ERP increased 20 +/- 12 msec), indicating that the response was preserved at more rapid rates. UK-68,798 prevented the induction of sustained ventricular tachycardia in six of seven animals (86%, P = .03). However, UK-68,798 failed to prevent the induction of ventricular fibrillation (VF) in dogs where VF was the only arrhythmia induced. To evaluate the mechanisms responsible for the prevention of ventricular tachycardia and lack of efficacy against inducible VF, detailed three-dimensional activation mapping of the heart in vivo was used. Induction of ventricular tachycardia was prevented by UK-68,798 due to a lengthening of the ERP in the epicardial region surrounding the infarct with no effect on conduction velocity even in periinfarct regions bordering the infarct. In contrast, the induction of VF was dependent on a rapid nonreentrant or focal mechanism that was not altered by the lengthening of ERP with UK-68,798. Thus, UK-68,798 is a selective class III antiarrhythmic agent that is likely to be efficacious in preventing arrhythmias due to a reentrant mechanism in patients with a previous myocardial infarction.

Beta-adrenergic-mediated influences on microscopic conduction in epicardial regions overlying infarcted myocardium.

Slowing in conduction and functional block in the epicardial tissue overlying a region of transmural necrosis are pivotal in the genesis of many lethal arrhythmias during the healing phase of myocardial infarction. The mechanisms responsible for these alterations in conduction in the epicardial region have not been completely elucidated. In the present study, the microscopic abnormalities in conduction were investigated in vitro using high-density mapping with 224 bipolar electrodes (interelectrode distance, 350 microns) in isolated epicardial tissue excised from the hearts of dogs 2 weeks after anterior myocardial infarction. Seven epicardial tissue slices (group 1) exhibited uninterrupted sequential activation after stimulation at the basic cycle length as well as after premature stimuli. Four tissues (group 2) demonstrated microscopic alterations in conduction both during basic drive and premature stimuli, with the extent of conduction delay dependent on the stimulation site. In three tissues (group 3), the activation sequence was normal during the basic drive but became abnormal after premature stimulation, with the appearance of functional block in the direction transverse to fiber orientation. Superfusion with isoproterenol (10(-6) M) did not significantly modify resting membrane potential, amplitude, or maximum rate change of voltage (Vmax) of phase 0 depolarization but decreased action potential duration. Isoproterenol did not alter the activation sequence during basic drive, but it reduced the slowing in conduction elicited by premature stimulation in group 1 (p less than 0.01 in the transverse direction), alleviated microcircuitous conduction in group 2, and prevented the occurrence of functional block in tissues in group 3. Despite this salutary effect on conduction velocity, arrhythmias occurred after isoproterenol because of focal activity (three of 14, 21%) or reentry (one of 14, 7%) at very short coupling intervals of premature stimulation. These findings indicate that microscopic abnormalities in conduction occur in response to premature stimulation in epicardial regions overlying an infarct, eliciting conduction block that is more prone to occur in the direction transverse to fiber orientation and is dependent on the direction of activation. beta-Adrenergic stimulation prevents or attenuates the alterations in the pattern of activation elicited by premature stimulation. However, this potential beneficial effect of beta-adrenergic stimulation is offset by the occurrence of focal activity and reentry at short coupling intervals of premature stimulation.

[Digitalis intoxication in the presence of amiodarone-induced acute hepatitis]. / Intossicazione digitalica in presenza di epatite acuta da amiodarone.

In this report, we describe a case of acute atypical hepatitis during chronic treatment with amiodarone in a patient in which symptoms of digitalis toxicity also developed. The sudden onset of these side effects, whose mechanisms are herein discussed, stresses the importance of a careful monitoring of patients treated with amiodarone.

Demonstration of a different sensitivity to epinephrine in isolated and in vivo hearts.

Studies in isolated preparations dealing with myocardial effects of catecholamines usually employ epinephrine concentrations 10-1,000 times higher (10(-7)-10(-5) M) than those observed during maximal cardiac adrenoceptor activation in vivo (10(-9)-5 x 10(-8) M) to obtain measurable cardiac responses. The reason for this discrepancy is still unclear, but it may reflect a diminished sensitivity to catecholamines in vitro. The main purpose of this study was to evaluate if a different myocardial sensitivity to epinephrine in vivo and in vitro does exist and to investigate which epinephrine concentrations in vitro mimic the effect of cardiac adrenoceptor activation in vivo. We compared concentration-response curves to cumulative increasing concentrations of of epinephrine, measured by high pressure liquid chromatography, in chloralose anesthetized or pithed rats (in vivo) and in isolated Langendorff perfused rat hearts (in vitro). We found that the amplitude of response to epinephrine was significantly higher in vivo at all concentrations. For example, an increase of 50 beats/min was observed at an epinephrine concentration of 29 +/- 6 nM in chloralose anesthetized, 25 +/- 4 nM in pithed rats and 149 +/- 52 nM in isolated hearts (P less than 0.05 vs. in vivo). Data on contractility closely parallel those on heart rate. These data indicate that, when methodological differences are minimized, there is a marked reduction in the amplitude of the response to epinephrine in vitro.(ABSTRACT TRUNCATED AT 250 WORDS)