Diabetes mellitus and risk of idiopathic dilated cardiomyopathy. The Washington, DC Dilated Cardiomyopathy Study.

An epidemiologic study was carried out to examine the possible role of diabetes mellitus and other factors in the development of idiopathic dilated cardiomyopathy. Possible associations with diabetes and other factors were examined by comparing newly diagnosed case patients (n = 129) ascertained from five Washington, DC area hospitals with neighborhood control subjects (n = 258) identified using a random-digit dialing technique. The case patients and control subjects were matched by sex and 5-year age intervals and were compared in the analysis using conditional logistic regression methods. A statistically significant association was observed between idiopathic dilated cardiomyopathy and history of diabetes (relative odds = 2.2; 95% confidence interval: 1.5 to 3.3). The association with diabetes was not explained by race, income, cigarette usage, or hypertension. A total of 28.7% (37/129) of the case patients had a reported history of diabetes, as compared with 13.6% (35/258) of the control subjects (P < 0.05). A possible interactive effect was also observed between diabetes and history of hypertension (P > 0.05). These findings support the view that diabetics, particularly those with a history of hypertension, may be at increased risk of idiopathic dilated cardiomyopathy.

Double-blind, placebo-controlled study of the efficacy of flosequinan in patients with chronic heart failure. Principal Investigators of the REFLECT Study.

OBJECTIVES: The aim of this study was to assess the efficacy of flosequinan in chronic heart failure. BACKGROUND: Flosequinan is a new vasodilator drug that acts by interfering with the inositol-triphosphate/protein kinase C pathway, an important mechanism of vasoconstriction. The drug dilates both peripheral arteries and veins, is orally active and has a long duration of action that permits once-daily dosing. Previous studies have shown that flosequinan produces sustained hemodynamic benefits in heart failure, but large scale studies evaluating its clinical efficacy have not been reported. METHODS: One hundred ninety-three patients with chronic heart failure (New York Heart Association functional class II or III and left ventricular ejection fraction < 40%) receiving digoxin and diuretic drugs were randomly assigned (double-blind) to the addition of flosequinan (100 mg once daily, n = 93) or placebo (n = 100) for 3 months. The clinical status and exercise tolerance of each patient was evaluated at the start of the study and every 2 to 4 weeks during the trial while background therapy remained constant. RESULTS: After 12 weeks, maximal treadmill exercise time increased by 96 s in the flosequinan group but by only 47 s in the placebo group (p = 0.022 for the difference between groups). Maximal oxygen consumption increased by 1.7 ml/kg per min in the flosequinan group (n = 17) but by only 0.6 ml/kg per min in the placebo group (n = 23), p = 0.05 between the groups. Symptomatically, 55% of patients receiving flosequinan but only 36% of patients receiving placebo benefited from treatment (p = 0.018). In addition, fewer patients treated with flosequinan had sufficiently severe worsening of heart failure to require a change in medication or withdrawal from the study (p = 0.07). By intention to treat, seven patients in the flosequinan group and two patients in the placebo group died. CONCLUSIONS: These findings indicate that flosequinan is an effective drug for patients with chronic heart failure who remain symptomatic despite treatment with digoxin and diuretic drugs. The effect of the drug on survival remains to be determined.

Pharmacologic management of ischemic heart disease with beta-blockers and calcium channel blockers.

In myocardial ischemia beta-blockers reduce myocardial oxygen demand, improve flow toward ischemic regions, and have mild antiplatelet and antiarrhythmic effects. These agents are effective in chronic stable angina and unstable angina. In chronic myocardial ischemia, the beta-blockers timolol, metoprolol, atenolol, and propranolol have cardioprotective effects, reducing overall mortality and the incidence of recurrent myocardial infarction. Calcium channel blockers, which reduce myocardial oxygen demand and improve oxygen supply, are effective in the treatment of chronic stable angina, vasospastic angina, and unstable angina. Although calcium channel blockers generally have no effect or adverse effects when used as primary therapy for acute myocardial infarction, diltiazem (when used concomitantly with nitrates or beta-blockers) has been shown to reduce the incidence of reinfarction in patients after non-Q wave myocardial infarction.

Liposomal amphotericin B for treatment of pulmonary aspergillosis in a heart transplant patient.

Pulmonary aspergillosis developed in a 52-year-old man 2 months after heart transplantation for ischemic cardiomyopathy. Conventional amphotericin B therapy caused marked deterioration of his already compromised kidney function after only 10% of the projected total dose. Conversion to liposomal encapsulated amphotericin B was associated with reversal of the kidney dysfunction and clearing of the pulmonary infiltrate. It is now 16 months since completion of therapy, and there is no evidence of recurrent infection.

Reduction in coronary heart disease: clinical and anatomical considerations.

Coronary artery bypass surgery, percutaneous transluminal coronary angioplasty and thrombolytic therapy in acute myocardial infarction have relieved symptoms, preserved myocardium, and prolonged life but have not modified the progression of atherosclerosis in the coronary arteries. In the last 10 years, however, progress has been made in establishing the cholesterol-atherogenesis hypothesis. Epidemiologic studies have demonstrated that the higher the total plasma cholesterol and low density lipoprotein cholesterol (LDL-C), the greater the risk that coronary artery disease will develop. Recently, clinical trials including the Coronary Drug Project, the Lipid Research Clinics Coronary Primary Prevention Trial (LRC-CPPT), and the Helsinki Heart Study provided evidence that lowering cholesterol reduces the frequency of fatal and nonfatal coronary events. In addition, the National Heart, Lung, and Blood Institute (NHLBI) Type II Coronary Intervention Study and the Cholesterol Lowering Atherosclerosis Study demonstrated that lowering of cholesterol was associated with a decreased incidence of progression of coronary disease, as well as with the potential for reduction in the atherosclerotic plaque. Beneficial effects of diet and lifestyle changes also have an important effect on atherosclerosis. The impact of lowering cholesterol has been limited primarily by pharmacologic programs which lower cholesterol only 10-20% and are associated with a high incidence of intolerable side effects. With the recent introduction of the HmG co-A reductase inhibitors and their more profound effect on serum lipids, it may be possible to further promote plaque regression. The future of all these interventions, however, must still be assessed by overall mortality; studies to date have demonstrated beneficial effects on cardiovascular mortality but age-adjusted total mortality has remained unchanged. Future management of patients with acute and chronic coronary artery disease will involve a collaboration of cardiologists, endocrinologists, and epidemiologists to coordinate screening, recognition, and treatment of this disease.

Calcium antagonists in acute myocardial infarction.

Calcium antagonists have proved effective in stable angina, unstable angina and vasospastic angina. However, despite a strong theoretical rationale for their use and promising experimental data, these agents have not reduced infarct size in acute myocardial infarction (AMI) in the large clinical trials performed to date. Their role as adjunctive therapy in combination with reperfusion needs to be examined. Diltiazem has been demonstrated to reduce angina and reinfarction in the 2-week period after AMI in patients receiving multidrug therapy. Results of the single large trial of a calcium antagonist (verapamil) for secondary prevention after AMI were negative; however, several well-designed studies are currently ongoing.

Changes in drug prescribing patterns related to commercial company funding of continuing medical education.

In order to determine the impact of commercial company funding of continuing medical education (CME) courses, a survey was undertaken. Drug prescribing rates for drugs related to course content were determined by self-report survey of physician attendees (374 in number) for three different CME courses. The survey was performed immediately before and six months after the courses. A single, though different, drug company provided the majority of the funding for each course. Courses I and III were related to calcium channel blockers and Course II to beta blockers. The return rate before Course I was 73.0 percent; after, 54.0 percent (unmatched). The return rate for Course II was 49.4 percent before and 42.9 percent after (unmatched). There were 121 (61.4%) matched returns for Course III. While the rates for prescribing some of the related drugs increased after the courses, overall the sponsoring drug company's products were favored. Although physicians attending CME and accredited sponsors of CME need to be aware of this potential influence, the final burden of adequate evaluation of drugs remains with the physician prescriber. Further studies should be done to substantiate the findings and elucidate the mechanism(s) of the increase in sponsoring company's drug prescriptions.

Late angiographic follow-up after successful coronary arterial thrombolysis and angioplasty during acute myocardial infarction.

Emergency percutaneous transluminal coronary angioplasty (PTCA) is accepted as an important reperfusion intervention for acute myocardial infarction (AMI). Although its primary success rate is well documented, the frequency of restenosis after this procedure is unclear. The frequency of restenosis was determined in patients undergoing emergency PTCA at least 6 months after PTCA was performed during AMI. Of 66 consecutive patients undergoing emergency PTCA, 25 had a second, elective catheterization at an average of 22 months after AMI and 6 underwent repeat catheterization because of recurrent chest pain. Restenosis of the PTCA site was found in 10 of the 31 patients (32%) restudied. Also, 14 (45%) of these 31 patients showed progression of narrowing in the non-infarct-related coronary arteries. In summary, patients in whom AMI is treated by PTCA are at risk for restenosis and for progressive narrowing of the non-infarct artery.

Metabolic support during coronary reperfusion.

The limitation of infarct size by thrombolysis could potentially be improved by an early metabolic intervention. We therefore evaluated the effects of a 48-hour infusion of glucose-insulin-potassium (GIK) in patients with anterior infarctions. Seventeen patients were randomized to receive intravenous GIK (n = 10) or placebo (n = 7). All patients additionally received streptokinase. Changes in left ventricular function were assessed by comparing the global ejection fractions and the regional infarct area ejection fractions of the first ventriculogram with the 10-day second ventriculogram. There was a significantly greater improvement in the global ejection fraction of patients receiving GIK (increases 0.07 +/- 0.04) than in those randomized to placebo (decreases 0.08 +/- 0.04) (p less than 0.02). There was also a much greater improvement in the area ejection fractions of the group receiving GIK vs the group receiving placebo in the anterolateral (increases 0.24 +/- 0.07 vs decreases 0.02 +/- 0.04 [p less than 0.02]) and diaphragmatic (increases 0.08 +/- 0.08 vs decreases 0.17 +/- 0.05 [p less than 0.005]) segments. Thus in patients with anterior infarctions receiving streptokinase, GIK improves ventricular function and reduces the size of the segmental wall motion abnormality.

Assessment of residual coronary arterial stenosis after thrombolytic therapy during acute myocardial infarction.

Maximal myocardial salvage appears to be related to the severity of residual coronary arterial stenosis after thrombolysis. The degree of residual infarct vessel stenosis was assessed in 119 consecutive patients with patent arteries who received streptokinase during acute myocardial infarction. After administration of streptokinase, 99 of 119 patients (83%) had a residual stenosis 70% or more in diameter. Assuming that a residual diameter stenosis of at least 70% is flow limiting, the feasibility for percutaneous transluminal coronary angioplasty (PTCA) was determined by the following criteria: length less than 10 mm, no significant distal narrowing or left main stenosis, and an adequate-sized distal artery. In 81 of 99 patients (82%), arterial anatomy was suitable for PTCA. Thus, after therapy with streptokinase for acute myocardial infarction, most patients have a significant infarct arterial residual stenosis and are candidates for PTCA.

Determinants of cardiac failure after coronary bypass surgery within 30 days of acute myocardial infarction.

Timing of coronary artery bypass grafting after acute myocardial infarction (MI) is controversial, especially if myocardial function is depressed. Early coronary artery bypass grafting may result in reperfusion injury causing cardiac failure. Delay, however, may risk a second ischemic event. This study was performed to determine if four preoperative factors--time after MI, ejection fraction, ischemia (need for intravenous administration of nitroglycerin), and failure (need for inotropic support)--independently predict postoperative cardiac failure. Postoperative failure was defined as the need for inotropic support or intraaortic balloon pumping. The study group consisted of 145 patients who underwent isolated coronary artery bypass grafting between January, 1980, and July, 1985, within 4 weeks of an acute MI. Postoperatively 38 patients (26%) had cardiac failure. Five patients, all of whom had postoperative cardiac failure, died. Univariate and stepwise logistic regression analyses showed preoperative failure (p = .0001), ejection fraction less than 45% (p = .002), and preoperative ischemia (p = .02) were predictors of postoperative cardiac failure. Time after MI was not found to be an independent predictor (p = .96). We conclude that if ischemia or threatening coronary anatomy is present early after MI and clinical improvement is not occurring, operative intervention should be strongly considered at that time, as it does not appear that delay itself reduces the risk of cardiac failure and may risk a second ischemic event.

Ventricular arrhythmias during reperfusion.

Accelerated idioventricular rhythm has been used as a marker for coronary reperfusion. The incidence of accelerated idioventricular rhythm and ventricular tachycardia was evaluated in 52 consecutive patients undergoing thrombolysis with intracoronary streptokinase during acute myocardial infarction. Complete 12-hour Holter recordings during and after intracoronary streptokinase were obtained in 39 patients. Reperfusion was documented in 17 patients (44%), no reperfusion in 14 (36%), and subtotal occlusion in eight (20%). Accelerated idioventricular rhythm occurred in 83%, 57%, and 63% of patients by group, respectively (p greater than 0.05). Ventricular tachycardia occurred in 100%, 71%, and 100% of patients by group, respectively (p less than 0.05). These data demonstrate that accelerated idioventricular rhythm is not specific for reperfusion and cannot be used as a marker for this event, and that ventricular tachycardia is more common with reperfusion and subtotal occlusion.

The assessment of contractile reserve after thrombolytic therapy for acute myocardial infarction.

"Stunned" myocardium prevents the assessment of myocardial salvage after streptokinase. In order to unmask "stunning," we sought to evaluate left ventricular inotropic contractile reserve of patients after streptokinase. Radionuclide ventriculograms were obtained in 75 consecutive patients 2 weeks after myocardial infarction, at rest and during intravenous isoproterenol infusion. Resting and isoproterenol-stressed ejection fractions were compared in the patent and closed-infarct vessel groups. Although there was no difference in the resting ejection fractions between the patent group (0.48 +/- 0.02) and the closed group (0.48 +/- 0.02), isoproterenol increased the ejection fractions in the patent group (increase 0.14 +/- 0.01) significantly more than in the closed group (increase 0.06 +/- 0.01) (p less than 0.0001). Thus, despite identical resting ventricular function, the greater inotropic contractile reserve in the patent infarct vessel group suggests that restoration of blood flow in acute myocardial infarction salvages myocardium.

Noninvasive detection of coronary artery patency using continuous ST-segment monitoring.

Continuous ST-segment Holter recordings were analyzed from 46 patients with acute myocardial infarction (AMI) receiving intracoronary streptokinase (SK) during the first 48 hours of hospitalization. Changes in ST deviation and the time periods of these changes were quantitated and correlated with angiographic evidence of reperfusion. Thirty-six patients had total occlusion of the infarct vessel and 10 had subtotal occlusion. Of the 36 vessels that were totally occluded, 19 were reperfused and 17 were not. In patients in whom reperfusion was successful, an ST steady state was achieved 55 +/- 32 minutes after SK administration. In patients in whom it was not successful, a steady state was achieved in 219 +/- 141 minutes (p less than 0.001). Achievement of steady state within 100 minutes after SK reperfusion indicated successful reperfusion with 89% sensitivity and 82% specificity. All patients with subtotal occlusion achieved an ST steady state before SK infusion. No patient with total occlusion achieved a steady state before SK. Achievement of ST steady state before SK infusion was 100% sensitive and 100% specific for subtotal occlusion at initial angiography. Continuous, quantitative ST-segment analysis is a sensitive and specific noninvasive technique for following coronary artery patency during AMI.

Thrombolysis in acute myocardial infarction.

Emergency cardiac catheterization and angiography in patients have resulted in an appreciation of the pathogenesis of AMI and the efficacy of thrombolytic therapy. Simple reperfusion of the infarcted myocardium, however, does not necessarily guarantee myocardial salvage, and preliminary studies have been somewhat confusing as to its beneficial effects. Metabolic support of the ventricle during early reperfusion may enhance left ventricular performance. Although the potential effects of thrombolytic therapy are still unclear, the routine administration of these agents has resulted in more frequent performance of early coronary angiography, with the result that appropriate therapeutic decisions can be made immediately regarding medical treatment, coronary angioplasty, or complete myocardial revascularization. In fact, in prolonged chest pain syndromes, emergency angiography may play a very important role in establishing appropriate initial therapy early in the course of hospitalization, potentially lowering mortality, morbidity, and cost. These issues will be answered ultimately only by carefully designed long-term randomized trials.

Use of hemodynamic measurements for management of acute myocardial infarction.

The modern coronary care unit now can provide hemodynamic measurements that characterize the determinants of myocardial oxygen consumption and mechanical performance. These determinants of preload, afterload, contractile state, and heart rate can be obtained from measurements with the Swan-Ganz catheter, systemic blood pressure, assessment of ventricular function, and heart rate. With the hemodynamic characterization of the determinants of left ventricular function, drugs can be selected that either decrease or increase the specific determinants in order to optimize left ventricular performance. Thus, a physiologic approach can be taken to the pharmacologic management of patients with acute myocardial infarction based on hemodynamic measurements and appropriate therapeutic strategies.

Ischemia during angioplasty after streptokinase: a marker of myocardial salvage.

Although thrombolytic therapy can result in lysis of a coronary artery thrombus, salvage of myocardium as measured by enzymatic, electrocardiographic and regional wall motion evaluation has not been clearly documented. Many patients after successful reperfusion continue to experience recurrent chest pain. The presence of recurrent chest pain suggests salvaged myocardium. Controlled reocclusion of the infarct vessel with the use of coronary angioplasty may support evidence for myocardial salvage. Experience in 50 patients who underwent angioplasty was reviewed retrospectively. Sixteen of the 50 patients had electrocardiographic or clinical evidence of ischemia at the time of balloon inflation. Prospectively, all patients who underwent angioplasty after they had received streptokinase were evaluated, and 5 of 5 patients had chest pain and ST-segment elevation during balloon inflation. The development of ischemic changes during balloon catheter inflation suggests the presence of persistently viable, salvaged myocardium after successful thrombolysis.

Inhibition of a physiologic pacing system due to its anti-pacemaker-mediated tachycardia mode.

Newer programmable DDD pacemakers prevent pacemaker-mediated tachycardia by automatic extension of the atrial refractory period after a detected premature ventricular contraction. We present an example in which the automatic extension of the atrial refractory period resulted in pacemaker inhibition, which should not automatically be assumed to represent pacemaker malfunction. A careful understanding of pacemaker timing intervals may allow for identification and correction of this problem.

Nifedipine in acute myocardial infarction.

Preliminary experimental and clinical data suggest that nifedipine can abort early acute myocardial infarction (AMI) or decrease infarct size by reversal of coronary artery spasm, improved coronary flow to the ischemic zone, reduction in myocardial oxygen demand or protection of ischemic cells. The first large clinical trial testing the ability of nifedipine to reduce infarct size, the Nifedipine Angina Myocardial Infarction Study, was recently reported. Nifedipine treatment failed to prevent progression of threatened infarction to AMI or to reduce infarct size in patients with AMI. The study suggested an increased early mortality rate in patients with AMI treated with nifedipine, but this finding should be interpreted with caution pending the results of similar trials now in progress.