Giulio Zuanetti

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

Backgound. 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 ResultsTwenty-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 (3.0%o of patients), 84 of which (32.8% of total deaths) were cardiac sudden deaths. Mortality rates were 2.01% 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 (RRc1, 1.62; 95% confidence interval, 1.16-2.26) and sudden mortality (RRc., 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 (RRc., 1.20; 95% confidence interval, 0.80-1.79). ConclusionThis 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%o 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.

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.

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.

Heart rate variability in patients with ventricular arrhythmias: Effect of antiarrhythmic drugs

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 longterm 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 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 [Δ%]-8, p = NS), whereas a significant (p These results indicate that heart rate variability can reliably be assessed by this total 24 h counts method in patients with frequent ventricular arrhythmias. The presence or suppression of arrhythmias itself did not modify heart rate variability. Class IC antiarrhythmic drugs may significantly affect heart rate variability, and this influence may contribute to the overall effect of these agents on mortality.

The effect of antiarrhythmic drugs on life-threatening arrhythmias induced by the interaction between acute myocardial ischemia and sympathetic hyperactivity

Transient myocardial ischemia, with attendant sympathetic hyperactivity, seems to play a major role in sudden cardiac death among patients with ischemic heart disease. Ventricular tachycardia (VT) and fibrillation (VF) are consistently and repeatedly elicited in cats by the interaction between a 2-minute occlusion of the left descending coronary artery and a 30-second stimulation of the left stellate ganglion. When three consecutive trials yield almost identical results, time alone will not modify the response and a given drug can be injected to test its efficacy with an internal control analysis. In 90 cats the efficacy of the following drugs was assessed: lidocaine (n = 11), mexiletine (n = 12), propafenone (n = 12), propranolol (n = 19), prazosin (n = 10), amiodarone (n = 14), and verapamil (n = 12). Class I antiarrhythmic drugs completely failed to afford protection and worsening of arrhythmia was observed in several instances. Propranolol and prazosin showed efficacy in approximately 80% and 60% of the animals, respectively. Amiodarone and verapamil completely prevented the onset of VT and VF. Protection from arrhythmias seems to be related to the combined presence of a noncompetitive adrenergic blockade associated with salutary effects on coronary circulation. These findings correlate with and help to explain the results of clinical trials in postmyocardial infarction patients. This model may help to provide a rational choice of antiarrhythmic drugs to be tested in clinical trials.

Ventricular fibrillation induced by the interaction between acute myocardial ischemia and sympathetic hyperactivity: Effect of nifedipine

Sympathetic hyperactivity plays a major role in the genesis of malignant arrhythmias during acute myocardial ischemia. An experimental model in which life-threatening arrhythmias are specifically and consistently induced by the interaction between acute myocardial ischemia and left stellate ganglion stimulation has been developed in alpha-chloralose anesthetized cats. In this preparation, drugs that share antiischemic, antiadrenergic, and specific electrophysiologic effects, such as verapamil, diltiazem, and amiodarone, were most effective. To evaluate the relative role of these different properties in mediating the effect of antiarrhythmic drugs, we used this same model to test nifedipine, a calcium channel blocker that is able to counteract the consequences of sympathetic stimulation on coronary circulation but has no electrophysiologic properties at concentrations relevant in the clinical setting. Nifedipine (15 micrograms/kg) prevented the occurrence of ventricular fibrillation in 10 of 13 animals (77%). Its efficacy was independent of changes in the peripheral hemodynamics. Plasma concentrations of nifedipine were within the therapeutic range in humans. To evaluate if this rather striking protective effect was specifically related to the prevention of the deleterious consequences of sympathetic stimulation, the effect of nifedipine on ventricular fibrillation threshold was studied in an additional group of 13 cats in the nonischemic state, during acute myocardial ischemia and during ischemia plus sympathetic stimulation. Nifedipine did not modify ventricular fibrillation threshold in nonischemic or in ischemic conditions. However, nifedipine specifically prevented the further reduction in ventricular fibrillation threshold occurring when sympathetic stimulation was superimposed on acute ischemia. These data suggest that the extension of ischemic damage by sympathetic stimulation is an important progenitor of arrhythmogenic action during acute ischemia.(ABSTRACT TRUNCATED AT 250 WORDS)

Efficacy of diltiazem in two experimental feline models of sudden cardiac death

The potential role of calcium entry blockers in the prevention of life-threatening arrhythmias associated with acute myocardial ischemia and reperfusion is still controversial. In 98 anesthetized cats, the effect of diltiazem was examined in two experimental models. In protocol I, ventricular tachycardia or fibrillation was consistently induced by the interaction between a 2 minute coronary artery occlusion and a 30 second left stellate ganglion stimulation. After three trials under control conditions, if the same pattern of arrhythmia was induced, the drug under study was administered and three additional trials were performed. In 16 animals the administration of saline solution did not modify the pattern of arrhythmias. In contrast, diltiazem (0.1 mg/kg body weight plus 0.2 mg/kg per h) abolished both ventricular tachycardia and fibrillation that had occurred in 64 and 36%, respectively, of the cats in the control state. In protocol II, a 20 minute coronary artery occlusion was released in three groups; one served as the control group, one received diltiazem 15 minutes before occlusion and one received diltiazem 3 minutes before reperfusion. The incidence of reperfusion ventricular fibrillation was 62% (16 of 26) in the control group. It was significantly (p less than 0.05) reduced by diltiazem administered before the occlusion to 25% (4 of 16), whereas it was not affected when diltiazem was administered just before reperfusion (7 [47%] of 15). These results indicate that diltiazem exerts a striking protective effect against the malignant arrhythmias induced by the combination of acute myocardial ischemia and sympathetic hyperactivity. Diltiazem was also effective in reducing the incidence of life-threatening reperfusion arrhythmias.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of three new anthracyclines and doxorubicin on the rat isolated heart

The acute cardiac toxicity of three second‐generation anthracycline analogues and doxorubicin was compared in a model of the rat isolated Langendorff perfused heart. The drugs, doxorubicin (DX), 4‐epi‐doxorubicin (4′EDX), 4‐demethoxy‐daunorubicin (4DMDR) and 4′‐deoxy‐doxorubicin (4′dxDX) were infused for 40 min at a concentration of 26 μM into the isolated hearts. All four compounds significantly reduced cardiac work and its first derivative. The time to 50% decrease in work (TW50) was respectively 36, 23, 9 and 7 min for DX, 4′EDX, 4′dxDx and 4DMDR. The three anthracycline derivatives, but not DX, significantly increased coronary resistance. Heart rate was reduced by all compounds compared with baseline, but not compared with controls. Rhythm disturbances were seen with all five hearts perfused with 4DMDR, which stopped beating before 40 min; 2/5 hearts in the 4′EDX group and 1/5 hearts in the 4′dxDX group also stopped before the end of perfusion. All the compounds reached concentrations in the myocardium 8 to 50 times higher than in the perfusing medium. The more cardiotoxic the compound, the higher was its myocardial concentration; a significant correlation was found for all four agents. Noradrenaline was never measurable in the perfusate of control and DX hearts; perfusion with the three anthracycline derivatives caused some release, but the pattern was not clearcut and the maximum concentrations attained in the perfusate were relatively low (< 1ṁ6 times 10−9 M). In conclusion, in the rat isolated perfused heart, the early cardiotoxicity induced by equimolar concentrations of the three anthracycline compounds was greater than that induced by DX and was directly related to drug accumulation in the myocardium. Catecholamines do not seem to have a major role in the development of toxicity in this model.

Lack of correlation between occlusion and reperfusion arrhythmias in the cat

Recently it has been stated that in dogs absence of arrhythmias during coronary artery occlusion identifies a subgroup at almost no risk for developing ventricular fibrillation (VF) during reperfusion. A potential implication would be that prevention of ischemic arrhythmias may also prevent the most severe reperfusion arrhythmias. This concept is at variance with available clinical evidence. In order to reexamine this problem the left anterior descending coronary artery was occluded for 20 minutes in 41 anesthetized cats; the incidence and type of arrhythmias during occlusion and during the first minute of reperfusion were analyzed. Five animals had VF during occlusion and were not resuscitated. Twenty animals had ischemic arrhythmias, and among them the incidence of reperfusion VF was 50%. Sixteen animals did not have ischemic arrhythmias, but they did have a very similar incidence of reperfusion VF (44%). Thus, in this feline preparation, absence of ischemic arrhythmias did not help to predict a favorable outcome at the moment of reperfusion. This disparity with previous studies does not depend on the protocol used, but it may be partly due to species difference. These results demonstrate a lack of correlation between reperfusion VF and ischemic arrhythmias and provide further support for the concept of different mechanisms involved in occlusion and reperfusion arrhythmias.

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.