Gender differences in survival in advanced heart failure. Insights from the FIRST study.

BACKGROUND: Previous natural history studies in broad populations of heart failure patients have associated female gender with improved survival, particularly in patients with a nonischemic etiology of ventricular dysfunction. This study investigates whether a similar survival advantage for women would be evident among patients with advanced heart failure. METHODS AND RESULTS: The study analysis is based on the Flolan International Randomized Survival Trial (FIRST) study which enrolled 471 patients (359 men and 112 women) who had evidence of end-stage heart failure with marked symptoms (60% NYHA class IV) and severe left ventricular dysfunction (left ventricular ejection fraction 18+/-4.9%). A Cox proportional-hazards model, adjusted for age, gender, 6-minute walk, dobutamine use at randomization, mean pulmonary artery blood pressure, and treatment assignment, showed a significant association between female gender and better survival (relative risk of death for men versus women was 2.18, 95% CI 1.39 to 3.41; P<0.001). Although formal interaction testing was negative (P=0.275), among patients with a nonischemic etiology of heart failure, the relative risk of death for men versus women was 3.08 (95% CI 1.56 to 6.09, P=0.001), whereas among those with ischemic heart disease, the relative risk of death for men versus women was 1.64 (95% CI 0.87 to 3.09, P=0.127). CONCLUSIONS: Women with advanced heart failure appear to have better survival than men. Subgroup analysis suggests this finding is strongest among patients with a nonischemic etiology of heart failure.

Prognostic significance of ST segment depression in lateral leads I, aVL, V5 and V6 on the admission electrocardiogram in patients with a first acute myocardial infarction without ST segment elevation.

OBJECTIVES: We sought to investigate the short-term prognostic value of the admission electrocardiogram (ECG) in patients with a first acute myocardial infarction (MI) without ST segment elevation. BACKGROUND: ST segment depression on hospital admission predicts a worse outcome in patients with a first acute MI, but the prognostic information provided by the location of ST segment depression remains unclear. METHODS: In 432 patients with a first acute MI without Q waves or > or = 0.1 mV of ST segment elevation, we evaluated the ability of the initial ECG to predict in-hospital death. RESULTS: The presence, magnitude and extent of ST segment depression were associated with an increased mortality, but the only electrocardiographic variable that was significant in predicting death after adjusting for baseline predictors was ST segment depression in two or more lateral (I, aVL, V5, or V6) leads (odds ratio 3.5, 95% confidence interval 1.2 to 10.6). Patients with lateral ST segment depression (n = 91, 21%) had higher rates of death (14.3% vs. 2.6%, p < 0.001), severe heart failure (14.3% vs. 4.1%, p < 0.001) and angina with electrocardiographic changes (20.0% vs. 11.6%, p = 0.04) than did the remaining patients, even though they had similar peak creatine kinase, MB fraction levels (129 +/- 96 vs. 122 +/- 92 IU/liter, p = NS). In contrast, ST segment depression not involving the lateral leads did not predict a poor outcome. Among patients who were catheterized, those with lateral ST segment depression had a lower left ventricular ejection fraction (57 +/- 12% vs. 66 +/- 13%, p = 0.001) and more frequent left main coronary artery or three-vessel disease than did the remaining patients (60% vs. 22%, p < 0.001). CONCLUSIONS: In patients with a first non-ST segment elevation acute MI, ST segment depression in the lateral leads on hospital admission predicts a poor in-hospital outcome.

Thrombin formation and fibrinolytic activity in patients with acute myocardial infarction or unstable angina: in-hospital course and relationship with recurrent angina at rest.

OBJECTIVES: The goal of this study was to investigate possible differences in thrombin generation or fibrinolytic capacity in patients with unstable angina (UA) or acute myocardial infarction (AMI) with or without recurrent angina at rest. BACKGROUND: Angina at rest in patients with AMI or UA is generally produced by a reduction in coronary flow, but it is unclear whether patients with or without this event differ in their thrombin generation or in their fibrinolytic capacities, which might influence the course of the culprit lesion. METHODS: Thrombin-antithrombin complex (TAT), D-dimer, fibrinogen and plasminogen activator inhibitor (PAI-1) antigen plasma levels were determined in 40 patients with AMI and in 23 with UA on admission, at 10 days and at three months. RESULTS: First day values for TAT, fibrinogen and D-dimer were comparable in patients with AMI and in those with UA. At 10 days they increased significantly in each group, and at 3 months they decreased to a similar extent. First day PAI-1 levels, however, were highest in both groups and declined in AMI patients at 10 days and at three months, whereas they also decreased at 10 days in UA patients but not any further at three months. Ten patients with AMI (25%) and 12 with UA (52%) developed in-hospital angina at rest. First day values for TAT, fibrinogen and D-dimer were similar in patients with or without angina, but PAI-1 levels were higher in the former subset (p < 0.008). At 10 days, however, TAT (p < 0.013) and D-dimer (p < 0.013) were higher in patients who developed angina than in those who did not. CONCLUSIONS: The higher inhibition of fibrinolytic activity in the first day in patients with AMI or UA who will develop recurrent angina suggests that maintenance of a prothrombotic status may contribute to its mechanisms, perhaps by preventing passivation of the culprit thrombus/plaque. This is consistent with greater thrombin generation and greater levels of fibrynolitic products at 10 days observed in these patients compared with those who attain early stability.

Medical management of selected patients with left ventricular free wall rupture during acute myocardial infarction.

OBJECTIVES: This study sought to evaluate the effects of prolonged rest and blood pressure control on survival of patients in whom left ventricular free wall rupture (LVFWR) was strongly suspected. BACKGROUND: Left ventricular free wall rupture in myocardial infarction is often fatal, and only a few patients may undergo operation. However, survival without surgical repair has not yet been evaluated. METHODS: Eighty-one consecutive patients with a first transmural acute myocardial infarction in Killip class I or II who presented with acute hypotension due to cardiac tamponade, with electromechanical dissociation (EMD) in 72, were prospectively evaluated. Patients with early recovery were managed with prolonged bed rest and blood pressure control with beta-blockade as tolerated. RESULTS: Forty-seven patients died within 2 h of acute tamponade, and autopsy in 21 showed LVFWR in all. In 15 others, an emergency surgical repair resulted in 2 survivors. The remaining 19 patients, 10 with EMD, had early recovery with dobutamine and colloid solution, and 15 required pericardiocentesis. Shortly thereafter, these 19 patients still showed a paradoxic pulse > or = 20 mm Hg, relevant pericardial effusion (24 +/- 7 mm [mean +/- SD]) and comparable elevation of right and left ventricular filling pressures (15.8 +/- 3.9 and 15.9 +/- 3.8 mm Hg, respectively). Subsequent management included bed rest (8.2 +/- 4.8 days) and control of systolic blood pressure (< or = 120 mm Hg) with beta-adrenergic blocking agents as tolerated (n = 12). Four patients died, and autopsy in three revealed a rupture that was sealed in two. A sealed rupture was also seen at thoracotomy in 2 other patients who, like the remaining 13, survived for 52.5 +/- 35.2 months. CONCLUSIONS: Long-term survival of selected patients with prompt hemodynamic recovery after LVFWR is possible without surgical repair. Prolonged bed rest and blood pressure control are likely to contribute favorably to their initial outcome.

Purulent pericarditis: review of a 20-year experience in a general hospital.

OBJECTIVES: The purpose of this study was to review the features of purulent pericarditis in patients from a general hospital during a recent 20-year period. BACKGROUND: Although studies published from 1974 to 1977 suggested a changing spectrum for purulent pericarditis, this view has not been proved. METHODS: We retrospectively evaluated the records of 33 patients from one general hospital who had a diagnosis of purulent pericarditis during the period 1972 to 1991. All autopsy protocols from the same period were also reviewed. In 19 patients (group I), the condition was diagnosed during life; in 14 (group II), it was identified at autopsy. RESULTS: In group I, the possible sources of pericardial infection were identified in 17 patients; pneumonia (6 patients) was the most common source. Empyema was present in 10 patients; 15 had cardiac tamponade. The most common microorganisms were streptococci, pneumococci and staphylococci. Six patients developed constrictive pericarditis and required pericardiectomy. Three patients died, 1 patient was lost to follow up and 15 patients had a favorable outcome at a mean follow-up interval of 35 months. In group II, the clinical diagnoses included pneumonia (five patients) among other infections, with empyema in six patients. Purulent pericarditis was probably the direct cause of death in two patients. CONCLUSIONS: In our experience, the spectrum of purulent pericarditis has not changed in recent years. Many patients do not have the classical findings of pericarditis, and diagnosis is made only at autopsy or after tamponade has developed. Empyema remains a common predisposing condition. Purulent pericarditis is still a severe disease, but its prognosis is excellent in patients who can be discharged from the hospital.

Relevance of delayed hospital admission on development of cardiac rupture during acute myocardial infarction: study in 225 patients with free wall, septal or papillary muscle rupture.

OBJECTIVES: We analyzed the possible relation between the presence of a hospital admission delay (> or =24 h), undue physical effort or recurrence of anginal pain, alone or in combination, with the development of free wall rupture (FWR), septal rupture (SR) or papillary muscle rupture (PMR) in patients with an acute myocardial infarction (AMI). BACKGROUND: Physical activity as a trigger of FWR in AMI remains controversial, and its contribution to SR or PMR remains unknown. Moreover, the role of ischemia or reinfarction as an additional cause of rupture has not been explored. METHODS: The incidence of hospital admission delay > or =24 h with maintenance of some ambulatory activity and the incidence of postinfarction angina were analyzed in consecutive patients with a first AMI with (n = 225) or without rupture (n = 1,012 [control group]) over different time periods. RESULTS: An admission delay > or =24 h occurred in 27 (27.6%) of 98 patients with FWR, 47 (47.0%) of 100 with SR and 14 (51.9%) of 27 with PMR but in only 81 (8%) of 1,012 control patients (p < 0.0001). Information on undue in-hospital effort preceding rupture was available for 111 patients and was present in 17 (32.7%) of 52 with FWR, 9 (18.4%) of 49 with SR and 3 (30%) of 10 with PMR versus only 76 (7.5%) of 1,012 control patients (p < 0.001). Information on postinfarction anginal pain was available for 114 patients with rupture and occurred in 30 (56.6%) of 53 with FWR, 30 (60%) of 50 with SR and 4 (36.4%) of 11 with PMR versus 120 (11.9%) of 1,012 control patients (p < 0.0001). Mean age and incidence of male gender, hypertension, absence of heart failure, single-vessel disease or occlusion of the infarct-related artery were comparable among the groups with FWR, SR or PMR. CONCLUSIONS: Delayed hospital admission or undue in-hospital physical activity appears to increase the risk of rupture in patients prone to this complication (i.e., a first transmural AMI, absence of overt heart failure and advanced age); recurrence of ischemia/infarction emerges as a potential additional trigger in a proportion of these patients.

Tuberculous pericarditis: ten year experience with a prospective protocol for diagnosis and treatment.

Thirteen patients with tuberculous pericarditis (12 men and 1 woman aged 13 to 70 years [mean 41]) were identified in a group of 294 patients consecutively admitted for primary acute pericardial disease. The diagnosis was made by the following studies: sputum culture (n = 4), culture of pericardial fluid obtained by pericardiocentesis (n = 3), histologic study and culture of pericardial biopsy (n = 3), lymph node biopsy (n = 2) and pleural biopsy (n = 1). Clinical presentation was remarkably variable: four patients had an acute, apparently self-limited course, one had relapsing tamponade, four had tamponade effectively treated with pericardiocentesis and four had toxic symptoms with persistent fever. The interval from hospital admission to diagnosis ranged from 1 to 14 weeks (mean 5.2). Constrictive pericarditis developed in six patients and effusive-constrictive pericarditis in one; all seven required pericardiectomy 2 to 3.5 months after admission. No patient died. It is concluded that 1) tuberculous pericarditis has a variable clinical presentation and therefore it should be considered in the evaluation of all instances of pericarditis without a rapidly self-limited course; 2) the diagnosis should be based only on objective data obtained with a systematic study protocol; 3) early definitive diagnosis is still difficult to achieve; and 4) development of subacute constrictive pericarditis requiring pericardiectomy is common.

Limitations of head-up tilt test for evaluating the efficacy of therapeutic interventions in patients with vasovagal syncope: results of a controlled study of etilefrine versus placebo.

OBJECTIVES: This study assessed the efficacy of oral etilefrine (10 mg three times a day) in preventing a positive response to head-up tilt testing. BACKGROUND: Previous reports have suggested that oral etilefrine can be effective either in preventing a positive response to head-up tilt testing or in reducing syncopal recurrences in patients with vasovagal syncope. Up to now most studies assessing drug therapy in these patients have been uncontrolled. METHODS: This was a randomized double-blind crossover study of etilefrine versus placebo in 30 consecutive patients with syncope and a baseline positive head-up tilt test. After the first test, patients had no treatment for 3 days and were randomized to receive etilefrine or placebo for 4 additional days. They underwent tilt testing under treatment and again after 3 days of washout; they then received the alternative treatment for 4 days, and a third test was performed. RESULTS: Head-up tilt test results were negative in 13 (43%) patients with etilefrine and 15 (50%) with placebo (p = NS). Therefore, the statistical power of the study was only 10%. The rate of positive responses decreased with repeated testing irrespective of the assigned treatment: A positive response was obtained during the second head-up tilt test in 20 patients (10 with placebo, 10 with etilefrine) but in only 12 during the third (7 with etilefrine, 5 with placebo) (p < 0.05). CONCLUSIONS: Oral etilefrine (10 mg three times a day) was not superior to placebo in preventing a positive response to head-up tilt testing. Despite a low statistical power, the high rate of negative response with placebo (50%) suggests that controlled trials are needed to assess the real efficacy of any treatment in patients with vasovagal syncope.

Cardiac index quantification by Doppler ultrasound in patients without left ventricular outflow tract abnormalities.

OBJECTIVES: We attempted to ascertain whether cardiac index can be directly estimated from Doppler mean velocity. BACKGROUND: Although diverse Doppler echocardiographic methods have been described for cardiac output quantification, they are not widely used in clinical practice. Cross-sectional area measurement has been identified as the main source of error in flow volume quantification. METHODS: A three-phase study by Doppler echocardiography was conducted in 306 patients. In phase I, the normal mean velocity ratio of the left and right ventricular outflow tracts was established in 170 normal subjects. In phase II, cardiac index, calculated as the product of aortic annular area index by mean velocity (conventional method), and mean velocity determined in the left ventricular outflow tract and ascending aorta by pulsed and continuous wave Doppler, respectively, were correlated with thermodilution cardiac index in 66 patients. In phase III, the accuracy of the regression equations obtained was prospectively assessed in an additional 70 patients. RESULTS: The normal left/right ventricular outflow tract mean velocity ratio by pulsed wave Doppler was 1.1 +/- 0.1. Cardiac index (CI) calculated by the conventional method and thermodilution (TD) showed acceptable correlation (r = 0.90, CITD = 1.20 CIPWD + 357; r = 0.86, CITD = 0.90 CICWD + 262) for pulsed (PWD) and continuous wave (CWD) Doppler, respectively, but with systematic underestimation (-28 +/- 13%, p < 0.01) by pulsed wave Doppler. Mean velocity (MV) showed excellent correlation with the thermodilution cardiac index (r = 0.97, CITD = 172 MVPWD - 172; r = 0.93, CITD = 129 MVCWD - 255). When these regression equations were prospectively applied, better agreement with the thermodilution cardiac index was obtained by pulsed wave Doppler directly from mean velocity (SD 240 ml/min per m2) than when aortic annular area was considered in the calculation (SD 428 ml/min per m2). Similar results were obtained by continuous wave Doppler (SD 433 vs. 599 ml/min per m2) but with less accuracy. CONCLUSIONS: Left ventricular outflow tract mean velocity determined by pulsed wave Doppler permits easy, accurate cardiac index quantification in the absence of left ventricular outflow abnormalities. The simplicity of this method enhances its clinical applicability in noninvasive monitoring of cardiac index.

Predisposing factors and prognostic value of sustained monomorphic ventricular tachycardia in the early phase of acute myocardial infarction.

OBJECTIVES: The purpose of the study was to analyze the factors that favor the occurrence of sustained monomorphic ventricular tachycardia in the early phase (< 48 h) of acute myocardial infarction and to establish its prognostic implications. BACKGROUND: Sustained monomorphic ventricular tachycardia early in the course of an acute myocardial infarction is an uncommon arrhythmia, and its significance has not been specifically studied. METHODS: The clinical characteristics and prognosis of sustained monomorphic ventricular tachycardia were studied in 21 (1.9%) of 1,120 consecutive patients admitted to the coronary care unit with a diagnosis of myocardial infarction. RESULTS: Patients with sustained monomorphic ventricular tachycardia had a larger infarct on the basis of peak creatine kinase, MB fraction (CK-MB) isoenzyme activity (435 +/- 253 IU/liter vs. 168 +/- 145 IU/liter, p < 0.001) and higher mortality rate (43% vs. 11%, p < 0.001). By logistic regression analysis, independent predictors of sustained monomorphic ventricular tachycardia were CK-MB (odds ratio [OR] 11.8), Killip class (OR 4.0) and bifascicular bundle branch block (OR 3.1). Moreover, sustained monomorphic ventricular tachycardia was itself an independent predictor of mortality (OR 5.0). Compared with patients with ventricular fibrillation, those with sustained monomorphic ventricular tachycardia had a worse Killip class (Killip class > I: 63% vs. 30%, p < 0.05), higher CK-MB activity (430 +/- 260 IU/liter vs. 242 +/- 176 IU/liter, p < 0.01) and higher arrhythmia recurrence rate (31% vs. 4%, p < 0.01). During the follow-up period, 5 (42%) of 12 survivors in the sustained monomorphic ventricular tachycardia group died of cardiac-related causes. Recurrence of ventricular tachycardia was seen in two patients (17%). CONCLUSIONS: Sustained monomorphic ventricular tachycardia during the first 48 h of myocardial infarction is a sign of extensive myocardial damage and an independent predictor of in-hospital mortality.

Intravenous amiodarone in treatment of recent-onset atrial fibrillation: results of a randomized, controlled study.

OBJECTIVES: This study was designed to determine the efficacy of intravenous amiodarone in the management of recent-onset atrial fibrillation. BACKGROUND: The optimal approach for acute atrial fibrillation has not been established. Amiodarone is a unique antiarrhythmic agent with activity in both supraventricular and ventricular tachyarrhythmias, but its value for the restoration of sinus rhythm in patients with recent-onset atrial fibrillation has not been demonstrated. METHODS: Sample size was calculated to detect a 25% increase in reversion rate with amiodarone with a statistical power of 80%. One hundred consecutive patients with recent-onset (<1 week) atrial fibrillation and not taking antiarrhythmic agents were randomized to receive either intravenous amiodarone, 5 mg/kg body weight in 30 min followed by 1,200 mg over 24 h, or an identical amount of saline. Both groups received intravenous digoxin, 0.5 mg initially, followed by 0.25 mg at 2 h and 0.25 mg every 6 h thereafter, to complete 24 h while the ventricular rate was >100 beats/min. Amiodarone and digoxin blood levels were determined. Both groups were homogeneous regarding underlying heart disease, time from onset to treatment, initial ventricular rate and left atrial size. RESULTS: By the end of the 24-h treatment period, 34 patients (68%, 95% confidence interval [CI] 53% to 80%) in the amiodarone group and 30 (60%, 95% CI 45% to 74%) in the control group had returned to sinus rhythm (p = 0.532). Mean times (+/-SD) of conversion were 328 +/- 335 and 332 +/- 359 min, respectively (p =0.957). Among patients who did not convert to sinus rhythm, treatment with amiodarone was associated with a slower ventricular rate (82 +/- 15 beats/min in the amiodarone group vs. 91 +/- 23 beats/min in the control group, p = 0.022). After restoration of sinus rhythm, atrial fibrillation recurred during a 15-day follow-up period in 4 (12%) of 34 patients (95% CI 3% to 27%) in the amiodarone group and in 3 (10%) of 30 (95% CI 2% to 26%) in the control group (p = 0.861). CONCLUSIONS: Intravenous amiodarone, at the doses used in this study, produces a modest but not significant benefit in converting acute atrial fibrillation to sinus rhythm.

Strategies for prognostic assessment of uncomplicated first myocardial infarction: 5-year follow-up study.

OBJECTIVES: Our aim was to use noninvasive studies early after infarction to assess medium-term prognosis in patients with a first uncomplicated myocardial infarction. BACKGROUND: Although the use of early postinfarction assessment to gauge short-term prognosis in myocardial infarction is well established, there have been few comprehensive evaluations of noninvasive methods for assessing medium- and long-term prognosis. METHODS: We prospectively studied 115 consecutive patients < 65 years old with a first acute uncomplicated myocardial infarction to evaluate the prognostic role of predischarge cardiac studies. These included submaximal exercise testing, thallium-201 scintigraphy, radionuclide exercise ventriculography, two-dimensional echocardiography, ambulatory electrocardiographic (Holter) monitoring and cardiac catheterization. All patients without complications were followed up > or = 5 years. RESULTS: During the follow-up period, 78 patients (68%) developed complications, which were severe in 37 (32%). Exercise thallium-201 scintigraphy yielded the highest percentage (77%) for correctly classified patients. It also had the highest predictive value for complications (97%) and severe complications (92%) when it was used in association with exercise testing and radionuclide ventriculography. The addition of cardiac catheterization did not improve on the predictive power of noninvasive studies. Four decision trees (exercise testing + echocardiography, exercise testing + radionuclide ventriculography, thallium-201 + echocardiography, thallium-201 + radionuclide ventriculography) allowed stratification of all patients in a high, intermediate or low risk category. The combination of thallium-201 scintigraphy and radionuclide ventriculography yielded the best results (90% predictive value for complications if the outcome of both tests was positive), but there were no significant differences with the other models. CONCLUSIONS: Any combination of a test detecting residual ischemia or functional capacity, or both (exercise testing or thallium-201 scintigraphy), and a test assessing ventricular function (echocardiography or radionuclide ventriculography) results in useful prognostic information in patients with an uncomplicated first acute myocardial infarction.

Diagnosis of ascending aortic dissection by transesophageal echocardiography: utility of M-mode in recognizing artifacts.

OBJECTIVES: This study sought to assess the reliability of biplanar transesophageal echocardiography in the diagnosis of ascending aortic dissection and to test the utility of M-mode information in the differential diagnosis of ascending aortic ultrasound artifacts and intimal flap images. BACKGROUND: Transesophageal echocardiography is a useful technique in the diagnosis of aortic dissection. However, ultrasound artifacts in the ascending aorta are an important limitation. METHODS: Transesophageal echocardiography was performed in 132 consecutive patients with clinically suspected aortic dissection. Two-dimensional and M-mode echocardiography and color Doppler were used to diagnose intimal flap and artifact images. Diagnoses were validated either anatomically or with reference techniques. RESULTS: The sensitivity and specificity of transesophageal echocardiography in the diagnosis of ascending aortic dissection were 96.8% and 100%, respectively. Ninety-three artifacts were observed in 56 (55%) of 101 patients without ascending aortic dissection. Two-dimensional echocardiography easily identified 74 artifacts (80%). Color Doppler showed no ascending flow abnormalities in 71% of artifact images. M-mode echocardiography showed three location and mobility artifact patterns related to the posterior wall of the aorta or the right pulmonary artery. In contrast, intimal flap movement showed no relation to the aortic wall movement in 25 cases (83%). Blind analysis of transesophageal echocardiographic study tapes underlined the utility of M-mode in the differential diagnosis. Ranges of sensitivity, specificity and positive predictive value (established by including doubtful results as either positive or negative) improved from 87.1-93.5% to 93.5-96.8%, from 85.1-94.1% to 99-100% and from 65.9-81.8% to 96.8-100%, respectively, with the inclusion of M-mode data. CONCLUSIONS: Biplanar transesophageal echocardiography permits reliable diagnosis of ascending aortic dissection. Ultrasound artifacts are common, but assessment of the location and mobility of intraluminal images by M-mode echocardiography definitely improves diagnostic accuracy.

Simultaneous dipyridamole/maximal subjective exercise with 99mTc-MIBI SPECT: improved diagnostic yield in coronary artery disease.

OBJECTIVES: We attempted to demonstrate that simultaneous dipyridamole administration and maximal subjective exercise in patients who are unable to achieve a good exercise level can improve the diagnostic efficacy of technetium-99m methoxy isobutyl isonitrile (99mTc-MIBI) myocardial single-photon emission computed tomography (SPECT). BACKGROUND: The results of myocardial perfusion scintigraphy are unsatisfactory if the level of exercise achieved by the patient is insufficient. The use of dipyridamole with maximal subjective stress testing has been shown to improve the quality of the thallium-201 myocardial perfusion images, but there are no studies demonstrating that this combination improves the diagnostic accuracy of myocardial perfusion SPECT. METHODS: Two hundred thirty-one consecutive patients, without a previous myocardial infarction, were classified into three groups: group 1, 91 patients with an adequate exercise test; group 2, 68 patients with an inadequate exercise test; group 3, 72 patients with an inadequate exercise test who then received intravenous dipyridamole (0.56 mg/kg body weight over 4 min) simultaneously with exercise. RESULTS: Results for sensitivity (89%) and negative predictive value (83%) in group 3 were significantly better than those in group 2 (71% [p = 0.03] and 56% [p = 0.002], respectively) and not significantly different from those in group 1. The polar maps of 20 patients studied with an without dipyridamole at the same exercise level revealed a significantly greater extent of ischemia in each territory and in a global assessment (19 + 20% vs. 8 + 11%, p < 0.0001) when dipyridamole was administered during physical exercise. CONCLUSIONS: Intravenous dipyridamole administration during exercise testing is advisable in all patients who are unable to achieve an adequate exercise level. This approach permits physicians to avoid missing ergometric information while optimizing myocardial SPECT results.

Infective endocarditis due to Staphylococcus aureus: deleterious effect of anticoagulant therapy.

BACKGROUND: The use of anticoagulant therapy in patients with infective endocarditis (IE) is a controversial issue. OBJECTIVE: To study the impact of anticoagulant therapy on the clinical outcome, mortality, and cause of death in a series of patients with native and prosthetic left-sided Staphylococcus aureus IE. METHODS: This report is based on all consecutive cases of IE diagnosed at our hospital between 1975 to 1997. Clinical data, including the use of anticoagulant therapy at the time of diagnosis, were prospectively obtained, and antibiotic treatment and surgical indications were uniform throughout the study period. Computed tomographic scans of all clinical records were reviewed. RESULTS: Of 637 consecutive patients with IE, 56 had left-sided S aureus IE affecting native valves in 35 patients and prosthetic valves in 21 patients. Of the patients with prosthetic valve IE, 19 (90%) were taking oral anticoagulant therapy at the time of diagnosis while no patient with native valve IE was receiving such treatment. There were no differences between native valve IE and prosthetic valve IE in age, sex, embolic episodes, and number of central nervous system complications. Mortality was higher in prosthetic valve IE than in native valve IE (71% vs 37%; P=.02). No patient with native valve IE died due to central nervous system complications, while 73% (11 of 15 patients) with prosthetic valve IE died due to central nervous system complications. The difference in the distribution of the type of death (stroke vs other) was significant (P<.007). CONCLUSIONS: Our results suggest that in left-sided S aureus IE anticoagulant therapy is closely associated with death due to neurologic damage. According to our data, as soon as the clinical diagnosis of S aureus IE is indicated the use of anticoagulant therapy should be immediately stopped until the septic phase of the disease is overcome.

Neurally mediated depressor hemodynamic response induced by intracoronary catheter balloon inflation in pigs.

OBJECTIVES: To assess whether intracoronary catheter balloon inflation triggers a neurally mediated hemodynamic response that interacts with the ischemia-induced myocardial dysfunction. METHODS: Forty-eight chloralose anesthetized pigs underwent a 60 s intraluminal catheter balloon inflation of the proximal left anterior descending (LAD) coronary artery before and after one of these treatments: disruption of LAD pericoronary nerves with phenol (n=6), bilateral stellectomy (n=8), bilateral cervical vagotomy (n=6), atropine (n=5), and ganglionic blockade with hexamethonium (n=10). In 13 other pigs, we assessed the reproducibility of two balloon inflations spaced 15 min (n=6) or 60 min (n=7). The ECG, left ventricular (LV) pressure, and LV dP/dt were recorded during each intervention. Right ventricular (RV) pressure, RV dP/dt, and aortic blood flow were also measured in a subset of pigs. RESULTS: Balloon inflation induced an early (10 s) and reproducible (ANOVA, P<0.001) drop in systolic pressure and peak dP/dt; a decrease in aortic blood flow; a rise in end-diastolic pressure; and elevation of the ST segment. Pericoronary denervation, stellectomy and ganglionic blockade attenuated (P<0.001) the drop in LV parameters during coronary inflation, but atropine and vagotomy did not. CONCLUSIONS: A depressor hemodynamic response subserved by pericoronary nerves worsens the LV dysfunction induced by brief coronary catheter balloon inflation in anesthetized pigs. Cholinergic fibers do not appear to play a major role.

Urodilatin limits acute reperfusion injury in the isolated rat heart.

OBJECTIVES: Hypercontracture is an important mechanism of myocyte death during reperfusion. cGMP modulates the sensitivity of contractile myofilaments to Ca2+, and increasing cGMP concentration during the last minutes of anoxia prevents reoxygenation-induced hypercontracture in isolated cardiomyocytes. The purpose of this study was to determine whether stimulation of particulate guanylyl cyclase with the natriuretic peptide urodilatin, given at the time of reperfusion, reduces myocardial necrosis in the rat heart submitted to transient ischemia. METHODS: Isolated rat hearts (n = 38) were submitted to either 40 or 60 min of no-flow ischemia and 2 h of reperfusion, and were allocated to receive or not receive 0.05 microM urodilatin during the first 15 min of reperfusion or non-reperfusion treatment. RESULTS: A marked reduction in myocardial cGMP concentration was observed in control hearts during reperfusion after 40 or 60 min of ischemia. Urodilatin significantly attenuated cGMP depletion during initial reperfusion, markedly improved contractile recovery after 40 min of ischemia (P < 0.0309), and reduced reperfusion-induced increase in left ventricular end-diastolic pressure (P = 0.0139), LDH release (P = 0.0263), and contraction band necrosis (P = 0.0179) after 60 min of ischemia. The beneficial effect of urodilatin was reproduced by the membrane permeable cGMP analog 8-Bromo-cGMP. CONCLUSIONS: These results indicate that reduced cGMP concentration may impair myocyte survival during reperfusion. Stimulation of particulate guanylyl cyclase may appear as a new strategy to prevent immediate lethal reperfusion injury.

Reperfusion arrhythmias after chronic regional denervation of the ischaemic myocardium in pigs.

OBJECTIVE: The aim was to assess the effects of chronic regional denervation of the ischaemic myocardium on reperfusion arrhythmias in a model with sparse coronary collateral circulation. METHODS: Baseline ventricular refractoriness and epicardial activation times were measured together with reperfusion arrhythmias after 15 min (I-15') or 30 min (I-30') of left anterior descending coronary artery occlusion in 38 barbiturate anaesthetised open chest pigs. Twenty pigs (11 in I-15' and nine in I-30') had a chronic (two week) denervation of the left anteroseptal region, whereas 18 pigs (10 in I-15' and eight in I-30') were sham operated (non-denervated) controls. Denervation was induced by pericoronary application of phenol and verified by absence of adrenergic histofluorescence. RESULTS: As compared with controls, denervated pigs showed: (1) longer activation times: 20.3 (SD 5.2) ms v 16.5 (4.6) ms, p < 0.001; (2) slightly longer refractory periods: 348(28) ms v 334(27) ms; (3) a tendency to lower postreperfusion ectopic activity: ectopic beats divided by time free of ventricular tachycardia: 0.13(0.19) v 0.34(0.40) in I-15', and 0.21(0.24) v 0.39(0.44) in I-30'; (4) slower ventricular tachycardia in I-30': 140(29) beats.min-1 v 185(29) beats.min-1, p < 0.009; and (5) comparable incidence of postreperfusion ventricular fibrillation: 4/11 pigs v 2/10 in I-15', and 5/9 v 4/8 in I-30'. CONCLUSIONS: Selective chronic denervation of the ischaemic myocardium was unable to protect against malignant reperfusion arrhythmias in hearts with human-like coronary collaterals. This was confirmed at two ischaemic periods known to produce progressive catecholamine accumulation and increased adrenoceptor density in the ischaemic myocardium.

Pre-treatment with trimetazidine increases sarcolemmal mechanical resistance in reoxygenated myocytes.

OBJECTIVE: Cytoskeletal and sarcolemmal fragility secondary to anoxia may contribute to sarcolemmal rupture and cell death during reoxygenation of cardiomyocytes. This study investigated the influence of trimetazidine (TMZ), a drug with effects on lipid metabolism and cell membranes, on reoxygenation-induced sarcolemmal rupture. METHODS: Isolated adult rat myocytes were submitted to 60 min of metabolic inhibition and 5 min of hypo-osmotic reoxygenation to simulate reperfusion edema in situ. Cells were allocated to 3 groups of treatment: in one group, TMZ 100 mumol/l was added to both the metabolic inhibition and reoxygenation buffers (group TMZ); another group was submitted to the same treatment but cells had previously been incubated with TMZ 100 mumol/l for 3 h (group TMZ-Pre); a control group underwent metabolic inhibition and hypo-osmotic reoxygenation without any treatment. Cell morphology was monitored throughout the experiment and sarcolemmal integrity was assessed by quantification of LDH activity and trypan blue exclusion test. RESULTS: After 60 min of metabolic inhibition most cells (83.1 +/- 2%) presented rigor contracture without between-group differences. Reoxygenation resulted in hypercontracture of 84.2 +/- 2.3, 91.2 +/- 1.4 and 84.1 +/- 2.1% of cells in TMZ, TMZ-Pre and control groups, P = NS. The trypan blue exclusion test revealed a higher proportion of cells with sarcolemmal integrity in TMZ and TMZ-Pre groups than in controls (12.7 +/- 2.0, 10.0 +/- 1.5 and 6.3 +/- 0.8%, respectively, P = 0.002). No between-group differences in LDH activity in the extracellular medium were observed at the onset or at the end of metabolic inhibition. However, LDH release was significantly lower (P = 0.002) in the TMZ-Pre group (1.6 +/- 0.1 IU/1000 cells) than in the TMZ and control groups (1.9 +/- 0.2 and 2.2 +/- 0.1 IU/1000 cells). CONCLUSION: Preincubation of cardiomyocytes with TMZ does not prevent rigor contracture induced by metabolic inhibition or hypercontracture during subsequent reoxygenation, but does improve sarcolemmal resistance to reoxygenation-induced mechanical stress. This could help to explain the beneficial effect of TMZ on infarct size.

Effect of osmotic stress on sarcolemmal integrity of isolated cardiomyocytes following transient metabolic inhibition.

OBJECTIVE: Exposure to hypotonic medium induces sarcolemmal rupture in metabolically inhibited cardiomyocytes. This study investigated the effect of osmotic stress applied during reoxygenation and the possible cooperation between cell swelling and hypercontracture to produce sarcolemmal disruption. METHODS: Freshly isolated adult rat myocytes were submitted to 60 min of metabolic inhibition (NaCN 2 mM). Reoxygenation was simulated by changing to one of 3 inhibitor free buffers: (1) normo-osmotic (312 mOsm); (2) hypo-osmotic (80 mOsm); (3) low Na+ normo-osmotic (312 mOsm). The contribution of hypercontracture-induced reoxygenation on sarcolemmal rupture was investigated in myocytes submitted to hypo-osmotic reoxygenation in presence of 2,3-butanedione monoxime 30 mM, a blocker of contractility. Recovery from mechanical fragility was studied by exposing cells to hypotonic buffer 20 or 40 min after restoration of metabolic activity, in either presence or absence of 2,3-butanedione monoxime. Two control groups without metabolic inhibition were used. One was exposed to osmotic stress after 60 min incubation in control conditions, the other was induced to hypercontract by exposure to hypo-osmotic, high-calcium buffer. Cell viability was assessed by the Trypan blue test. RESULTS: Before any intervention 81.9(1.2)% of cells were rod-shaped. After 60 min of metabolic inhibition most cells developed rigor contracture and only 16.4(1.8)% remained rod-shaped. Restoration of metabolic activity induced hypercontracture of most cells with rigor independently of buffer osmolality. Cell viability, however, significantly differed among groups: only 25.9(4.4)% of cells reoxygenated with hypo-osmotic buffer were viable vs. 74.1(7.6)% in the normo-osmotic reoxygenation group, and 82.9(2.9)% in the control group. Addition of 2,3-butanedione monoxime 30 mM during hypo-osmotic reoxygenation prevented hypercontracture and preserved cell viability. Delaying osmotic stress 20 or 40 min after the onset of reoxygenation did not improve viability [19.3(3.9) and 34.9(1.3)%, respectively]. Contractile blockade with 2,3-butanedione monoxime during the first 20 or 40 min of reoxygenation was associated with a reduction in the number of hypercontracted cells after the removal of the inhibitor but did not increase the proportion of hypercontracted viable cells (25% and 27%, respectively). CONCLUSIONS: (1) Osmotic stress following transient metabolic inhibition produces sarcolemmal disruption, and this effect is not related to the low Na+ concentration present in the hypo-osmotic buffer; (2) reoxygenation-induced hypercontracture cooperates with cell swelling to produce sarcolemmal disruption; and (3) osmotic fragility persists for at least 40 min after restoration of metabolic activity.