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Background— Cardiomyopathy associated with pregnancy was first described more than half a century ago. However, because of its rare occurrence and geographical differences, the clinical profile of this condition has remained incompletely defined. Methods and Results— Data obtained from 123 women with a history of cardiomyopathy diagnosed during pregnancy or the postpartum period were reviewed. One hundred women met traditional criteria of peripartum cardiomyopathy; 23 were diagnosed with pregnancy-associated cardiomyopathy earlier than the last gestational month. Peripartum cardiomyopathy patients had a mean age of 31±6 years and were mostly white (67%). Common associated conditions were gestational hypertension (43%), tocolytic therapy (19%), and twin pregnancy (13%). Left ventricular ejection fraction at the time of diagnosis was 29±11% and improved to 46±14% ( P ≤0.0001) at follow-up. Normalization of left ventricular ejection fraction occurred in 54% and was more likely in patients with left ventricular ejection fraction >30% at diagnosis. Maternal mortality was 9%. A comparison between the peripartum cardiomyopathy and early pregnancy-associated cardiomyopathy groups revealed no differences in age, race, associated conditions, left ventricular ejection fraction at diagnosis, its rate and time of recovery, and maternal outcome. Conclusions— This study helps to define the clinical profile of patients with pregnancy-associated cardiomyopathy diagnosed in the United States. Clinical presentation and outcome of patients with pregnancy-associated cardiomyopathy diagnosed early in pregnancy are similar to those of patients with traditional peripartum cardiomyopathy. These 2 conditions may represent a continuum of a spectrum of the same disease.

Background —Previous studies have suggested that women with acute myocardial infarction (AMI) are less aggressively managed than are men. The aim of this study was to assess sex differences in medical and invasive coronary procedures (angiography, PTCA, and CABG) in AMI patients admitted to cardiac care units (CCUs) in Israel in the mid 1990s and their association with early and 1-year prognosis. Methods and Results —We studied 2867 consecutive AMI patients (2125 men, 74%) hospitalized in all 25 CCUs in Israel from 3 prospective nationwide surveys conducted in 1992, 1994, and 1996. Women were, on average, older than men (69 versus 61 years, P Conclusions —This prospective nationwide observational community-based study of consecutive AMI patients hospitalized in the CCUs in the mid 1990s indicates that women fare significantly worse than do men at 30 days but not thereafter at 1-year. The difference in 30-day outcome was not influenced by the use of different therapeutic modalities, including thrombolysis and invasive coronary procedures, but was rather due to the older age and greater comorbidity of women; these findings seem also to explain the less frequent use of invasive procedures in women.

Background —Organic nitrates are widely used in the treatment of chronic heart failure (CHF). No information, however, is available regarding their effect in patients already treated with ACE inhibitors. Methods and Results —In a randomized, double-blind, crossover design, we studied the effects of high-dose (50 to 100 mg) transdermal nitroglycerin (NTG) and placebo given daily for 12 hours in 29 patients with CHF (NYHA functional classes II to III). Exercise time (4 hours after patch application) showed a progressive improvement during NTG administration, with an increase of 38±35 seconds (9±7%) at the end of the first month ( P =NS), 76±28 seconds (16±6%) at the end of the second month ( P =0.01), and 117±34 seconds (27±6%) at the end of the third month ( P =0.003). No significant change was seen during placebo administration (12±20, 5±26, and 19±28 seconds, all P =NS). Exercise time 8 hours after NTG application measured at 3 months was also significantly longer, with a difference of 87±28 seconds ( P =0.006), but not with placebo (23±36 seconds, P =0.53). Assessment of quality of life and need for additional diuretics or hospitalizations for CHF failed to demonstrate a significant difference between the 2 treatment periods. In contrast, NTG decreased left ventricular end-diastolic (−2.1±0.1%, P P P Conclusion —High-dose nitrate therapy significantly improves exercise tolerance and left ventricular size and systolic function in patients with chronic, mild to moderate CHF already treated with ACE inhibitors. These findings support the role of organic nitrates as an adjunctive therapy to ACE inhibitors in patients with chronic CHF.

Abstract —The natural history of non–insulin-dependent diabetes mellitus (NIDDM) differs markedly between patients with diet treated and pharmacologically treated disease. However, the interrelationship between hypertension and these common diabetes types has not been specifically addressed in previous studies. This study was designed to evaluate the prognostic significance and prevalence of hypertension in coronary patients with diet versus pharmacologically treated NIDDM over a 5-year follow-up period. The study sample comprised 11 515 patients aged 45 to 74 years with a previous myocardial infarction and/or anginal syndrome who had been screened but were not included in the Bezafibrate Infarction Prevention study. Among them, 9033 were nondiabetics and 2482, diabetics (987 diet treated and 1495 pharmacologically treated). The prevalence of hypertension among nondiabetics, diet-treated diabetics, and pharmacologically treated diabetics was 31%, 42%, and 43%, respectively. Crude all-cause mortality (CM) was lower in the nondiabetic patients (11.2% versus 22.0%; P

BACKGROUND Supply of sulfhydryl groups with the administration of N-acetylcysteine (NAC) has been reported to reverse tolerance to nitroglycerin but not to isosorbide dinitrate (ISDN). Lack of interaction between NAC and ISDN was suggested as an explanation for these findings. The present study was therefore designed to further evaluate this hypothesis. For this purpose, we compared the hemodynamic and hormonal effects of ISDN when given alone and in combination with NAC. METHODS AND RESULTS We performed a randomized, cross-over design evaluation of the hemodynamic and hormonal effects of ISDN and ISDN + NAC in 14 patients with chronic congestive heart failure due to left ventricular systolic dysfunction. The findings of this study demonstrated a substantial NAC-mediated potentiation of ISDN effect on mean right atrial pressure (-11 +/- 21% versus -38 +/- 27%, -17 +/- 20% versus -34 +/- 27%, and -7 +/- 20% versus -25 +/- 26% at 2, 3, and 4 hours, respectively; all P < .05), mean pulmonary artery wedge pressure (-18 +/- 16% versus -33 +/- 14%, -15 +/- 25% versus -33 +/- 19%, -14 +/- 22% versus -25 +/- 22%, and -16 +/- 16% versus -26 +/- 16% at 2, 3, 4, and 5 hours, respectively; all P < .05), mean pulmonary artery pressure (-8 +/- 11% versus -20 +/- 15% at 3 hours, P < .05), and cardiac output (an increase of 2 +/- 16% versus 25 +/- 20% at 4 hours, P < .05). Although there were no significant changes in serum catecholamine levels and plasma renin concentration with both regimens, ISDN + NAC resulted in a greater fall in plasma levels of atrial natriuretic peptide (296 +/- 251 pg/mL after ISDN versus 202 +/- 118 pg/mL after ISDN + NAC, P < .05). CONCLUSIONS The results of this study provide strong evidence for the existence of an interaction between thiols and ISDN and further support the role of sulfhydryl groups in the activation and therapeutic action of organic nitrates. The discrepancy between the results of this study demonstrating NAC-induced potentiation of ISDN effects and a previous study showing failure to reverse ISDN tolerance with NAC may suggest that ISDN-NAC interaction requires normal intracellular levels of sulfhydryl groups and does not occur after intracellular sulfhydryl group depletion.

In the isolated working rat heart model, we studied metabolic and hemodynamic effects of 5- and 30-min global ischemia followed by reperfusion and assessed the potentially beneficial effect of captopril 80 micrograms/ml added throughout the experiment. Creatine kinase (CK) and catecholamines were measured in coronary effluent. De novo eicosanoids (prostaglandin E2) synthesis was assessed in endocardial explants. Hemodynamic alterations occurred after 30-min ischemia and were reflected most dramatically by a reduction in cardiac output (CO 72 +/- 10% of baseline values in captopril vs. 68 +/- 16% in controls) without significant differences as a result of treatment. Captopril shortened reperfusion ventricular fibrillation (VF) duration (6.9 +/- 1.2 vs. 13.6 +/- 8.7 min, p less than 0.05) but had no effect on VF incidence. No differences occurred in norepinephrine (NE) outflow, whereas total CK release was greater in controls. Five controls versus none of the treated hearts (p less than 0.05) released trace amounts of epinephrine during reperfusion. Increased de novo PGE2 synthesis was demonstrated after 5-min I (465 +/- 168 vs. 238 +/- 75 pg/100 mg tissue per hour, p less than 0.01). Captopril stimulated production of PGE2 in normoxic hearts (p less than 0.02), but the difference was no more apparent in ischemic hearts. We conclude that captopril produces some biochemical and electrophysiologic evidence of myocardial salvage, but these effects are not sufficient to induce hemodynamic improvement after global ischemia and reperfusion.

BACKGROUND Early development of nitrate tolerance has been shown in patients with chronic congestive heart failure (CHF) receiving continuous nitroglycerin therapy. The influence of dosing interval of oral isosorbide dinitrate (ISDN), the nitrate preparation most widely used for the treatment of CHF, has not been investigated. METHODS AND RESULTS We performed a prospective, randomized study to evaluate the effect of various regimens of oral ISDN on the development of early tolerance to its effect on left ventricular filling pressure in patients with moderate to severe CHF. Forty-four responders (20% or greater reduction in mean pulmonary artery wedge pressure lasting 1 hour or longer) were divided into four groups of 11 patients each, and randomized to receive their effective ISDN dose (40-120 mg) Q 4 hours, Q 6 hours, Q 8 hours, or t.i.d. (drug given at 0, 6, 12, and 24 hours allowing 12 hours of ISDN washout interval between the third and fourth doses). All groups demonstrated a significant and comparable reduction in LV filling pressure following administration of the first ISDN dose. Early attenuation of hemodynamic response was demonstrated with frequent dosing (Q 4 hours and Q 6 hours) ISDN. Tolerance was with a Q 8-hour regimen as demonstrated by preserved hemodynamic response to each dose. The effect of each dose, however, was short-term, with return of pulmonary artery wedge pressure to baseline level at 2 to 4 hours, resulting in an intermittent effect totaling no longer than 12 hours of the 30-hour study period. The use of a t.i.d. regimen resulted in marked attenuation of response after the third dose with complete restoration of nitrate effect following a 12-hour washout period between the third and fourth doses. ISDN plasma concentration was measured in five patients in each of the Q 4- and Q 8-hour groups. In the Q 4-hour group, plasma levels were significantly higher after administration of the last dose than after the first dose (area under the curve, 242 +/- 216 versus 123 +/- 130 ng/ml, p less than 0.05), and trough levels before administration of the second and the fifth dose (15 +/- 17 and 27 +/- 27 ng/ml, respectively) were both markedly higher than the baseline value of 2 +/- 4 ng/ml. CONCLUSIONS Our data demonstrate the development of tolerance and early attenuation of effect on left ventricular filling pressure with frequent oral dosing (Q 4 and Q 6 hours) with ISDN in patients with chronic CHF, which may be related to persistently elevated trough blood levels of ISDN. The development of tolerance can be reversed after a washout period of 12 hours and can be prevented with a Q 8-hour administration. These regimens, however, are limited by an inconsistent effect. Although long-term implications of these findings need further evaluation, the present study demonstrates the difficulty of maintaining a persistent ISDN-mediated reduction in left ventricular filling pressure in patients with chronic, moderate to severe CHF. These results suggest the need to use intermittent ISDN therapy allowing a daily nitrate washout interval and the rationale for combined vasodilator therapy in patients with CHF.

P126 Objective: To assess characteristics and severity of coronary heart disease (CHD) predisposing to ischemic stroke, beyond conventional vascular risk factors. Methods: We prospectively followed up 3,122 patients with documented CHD included in a secondary prevention trial of lipid modification, the Bezafibrate Infarction Prevention trial. Patients had CHD documented by a history of myocardial infarction ≥6 months and Results: During a mean follow-up period of 8.2 years, 186 patients developed an ischemic stroke. The rate of ischemic stroke was 8.8% among patients with an active anginal syndrome[class ≥2 according to the Canadian Cardiovascular Society angina Classification, (CCSC)]vs. 5.1% in patients with a CCSC class of 1 (pConclusion: Active angina (CCSC class ≥2)and hospitalization for unstable angina during follow-up among CHD patients,confer an independent increased risk of ischemic stroke, beyond conventional vascular risk factors.