Pregnancy in women with hypertrophic cardiomyopathy: data from the European Society of Cardiology initiated Registry of Pregnancy and Cardiac disease (ROPAC).

AIMS: We report the maternal and foetal outcomes at birth and after 6 months in a cohort of pregnant women with hypertrophic cardiomyopathy (HCM). Although most women with HCM tolerate pregnancy well, there is an increased risk of obstetric and cardiovascular complications. METHODS AND RESULTS: All pregnant women with HCM entered into the prospective worldwide Registry of Pregnancy and Cardiac disease (ROPAC) were included in this analysis. The primary endpoint was a major adverse cardiovascular event (MACE), which included death, heart failure (HF), thrombo-embolic event, and arrhythmia. Baseline and outcome data were analysed and compared for patients with MACE vs. without MACE and for patients with obstructive HCM vs. non-obstructive HCM. Sixty pregnant women (mean age 30.4 ± 6.0 years) with HCM (41.7% obstructive) were included. No maternal mortality occurred in this cohort. In 14 (23%) patients at least one MACE occurred: 9 (15.0%) HF and 7 (12%) an arrhythmia (6 ventricular and 1 atrial fibrillation). MACE occurred most commonly during the 3rd trimester and postpartum period. In total, 3 (5.0%) women experienced foetal loss. Women with MACE had a higher rate of emergency Caesarean delivery for cardiac reasons (21.4% vs. 0%, P = 0.01). No significant differences in pregnancy outcome were found between women with obstructive and non-obstructive HCM. NYHA functional class of ≥II and signs of HF before pregnancy, were associated with MACE. CONCLUSION: Although most women with HCM tolerated pregnancy well, cardiovascular complications were not uncommon and predicted by pre-pregnancy status facilitating pre-pregnancy counselling and targeted antenatal care.

The effect of valvular heart disease on maternal and fetal outcome of pregnancy.

OBJECTIVES: The aim of this study was to evaluate the association between valvular heart disease (VHD) and maternal and fetal outcome in a relatively large group of patients by a comparison to a well-matched control group. BACKGROUND: Available information regarding outcome of pregnancy in women with VHD is limited to either anecdotal reports or small series of patients without an appropriate control. A better understanding of the effects of valvular abnormalities on pregnancy outcome is of value for risk assessment and the design of a therapeutic plan. METHODS: A retrospective evaluation was made of 66 pregnancies in 64 women with VHD cared for at a tertian-care center with a high-risk obstetrics/cardiology clinic and 66 individually selected normal pregnant women matched in age, ethnicity, obstetrical and medical history, time of initial prenatal care, and year of pregnancy. RESULTS: Women with VHD had a significantly higher incidence of congestive heart failure (38% vs. 0%; p < 0.00001), arrhvthmias (15% vs. 0%, p = 0.002), initiation or increase of cardiac medications (41% vs. 2%, p < 0.0001), and hospitalizations (35% vs. 2%, p < 0.0001). Mortality, however, occurred in only one patient (2% vs. 0%, p = NS) with aortic stenosis (AS) and coarctation. Moreover, VHD also had an effect on fetal outcome, resulting in an increased preterm delivery (23% vs. 6%, p = 0.03), intrauterine growth retardation (21% vs. 0%, p < 0.0001), and a reduced birth weight (2,897 +/- 838 g vs. 3,366 +/- 515 g, p = 0.0003). Increased maternal morbidity and unfavorable fetal outcome were seen mostly in patients with moderate and severe mitral stenosis (MS) and AS. CONCLUSIONS: Pregnancy in women with MS and AS is associated with marked increase in maternal morbidity and unfavorable effect on fetal outcome, which are related to severity of disease. Despite high maternal morbidity, mortality is rare.

Comparison of the occurrence of ventricular arrhythmias in patients with acutely decompensated congestive heart failure receiving dobutamine versus nesiritide therapy.

Ventricular arrhythmias are common in patients with congestive heart failure (CHF) and may be exacerbated by positive inotropic therapy. Because human B-type natriuretic peptide (nesiritide), an arterial and venodilator, inhibits sympathetic activity, it may decrease the incidence of arrhythmias. Our investigation compares the arrhythmogenicity of dobutamine with nesiritide. A total of 305 patients with decompensated CHF requiring intravenous vasoactive therapy were randomized to receive standard therapy (n = 102) or nesiritide (0.015 microg/kg/min [n = 103] or 0.030 microg/kg/min [n = 100]) to gain additional data on the relative safety and efficacy of nesiritide compared with standard parenteral care. Dobutamine was chosen as the standard care agent in 58 subjects. During study drug infusion, all patients had continuous clinical hemodynamic and electrocardiographic monitoring. The dobutamine and nesiritide groups were similar with respect to baseline use of antiarrhythmic agents, including beta blockers. Serious arrhythmias and the incidence of cardiac arrest were more common in patients who received dobutamine than in those taking nesiritide: sustained ventricular tachycardia, 4 (7%) versus 2 (1%), respectively (p = 0.014); nonsustained ventricular tachycardia, 10 (17%) versus 23 (11%), respectively (p = 0.029); cardiac arrest, 3 (5%) versus 0, respectively (p = 0.011). We conclude that among patients with decompensated CHF for whom dobutamine is selected as standard therapy, the incidence of serious ventricular arrhythmias and cardiac arrest is significantly greater than the incidence of these events in patients randomized to nesiritide.

A randomized multicenter study comparing the efficacy and safety of intravenous milrinone and intravenous nitroglycerin in patients with advanced heart failure.

A randomized, open-label, parallel-group design was used to determine the percentage of patients achieving improvements in predetermined baseline hemodynamic end points (>20% to 30% increase in cardiac index depending on baseline values and >25% decrease in pulmonary capillary wedge pressure), assessed at hour 0 (end of initial dose titration) and 1, 2, 4, 8, and 24 hours after the infusion of milrinone or nitroglycerin. In total, 125 patients (60 milrinone, 65 nitroglycerin) enrolled in this study, and 119 (58 milrinone, 61 nitroglycerin) were evaluable for the efficacy analysis. A significantly greater proportion of milrinone-treated patients reached (45% v 14%, P =.005) and maintained (24% v 6%, P =.026) hemodynamic goals than did nitroglycerin-treated patients; the time to achieve hemodynamic goals was significantly less in milrinone-treated patients (33 +/- 2 v 54 +/- 10 minutes, P <.001). Milrinone was also significantly more effective in decreasing systemic vascular resistance (P =.004), increasing stroke volume (P =.008), and improving global clinical status. Inodilator therapy with milrinone seems more efficacious in attaining sustained hemodynamic improvement than does pure intravenous vasodilator therapy with nitroglycerin in treating patients with decompensated heart failure.

Maternal and fetal outcomes of subsequent pregnancies in women with peripartum cardiomyopathy.

BACKGROUND: Peripartum cardiomyopathy is a rare and sometimes fatal form of heart failure. Little is known about the outcomes of subsequent pregnancies in women who have had the disorder. METHODS: Through a survey of members of the American College of Cardiology, we identified 44 women who had had peripartum cardiomyopathy and had a total of 60 subsequent pregnancies. We then reviewed the medical records of these women and interviewed the women or their physicians. RESULTS: Among the first subsequent pregnancies in the 44 women, 28 occurred in women in whom left ventricular function had returned to normal (group 1) and 16 occurred in women with persistent left ventricular dysfunction (group 2). The pregnancies were associated with a reduction in the mean (+/-SD) left ventricular ejection fraction both in the total cohort (from 49+/-12 percent to 42+/-13 percent, P<0.001) and in each group separately (from 56+/-7 percent to 49+/-10 percent in group 1, P=0.002; and from 36+/-9 percent to 32+/-11 percent in group 2, P=0.08). During these pregnancies, a decrease of more than 20 percent in the left ventricular ejection fraction occurred in 21 percent of the women in group 1 and 25 percent of those in group 2, and symptoms of heart failure occurred in 21 percent of the women in group 1 and 44 percent of those in group 2. The mortality rate was 0 percent in group 1 and 19 percent in group 2 (P=0.06). In addition, the frequency of premature delivery was higher in group 2 (37 percent vs. 11 percent), as was that of therapeutic abortions (25 percent vs. 4 percent). CONCLUSIONS: Subsequent pregnancy in women with a history of peripartum cardiomyopathy is associated with a significant decrease in left ventricular function and can result in clinical deterioration and even death.

Endothelial function in patients with chronic heart failure.

Congestive heart failure is characteristically associated with systemic vasoconstriction and impaired vasodilatory capacity, leading to decreased peripheral perfusion. Factors identified as possible causes of reduced vasodilatory capacity include activation of the sympathetic nervous system and the renin-angiotensin system, vascular stiffness due to increased sodium and fluid retention, and structural vascular changes. More recently, the role of the endothelium as a mediator of vasoregulation and tissue perfusion has been recognized.

Intravenous nesiritide, a natriuretic peptide, in the treatment of decompensated congestive heart failure. Nesiritide Study Group.

BACKGROUND: Intravenous infusion of nesiritide, a brain (B-type) natriuretic peptide, has beneficial hemodynamic effects in patients with decompensated congestive heart failure. We investigated the clinical use of nesiritide in such patients. METHODS: Patients hospitalized because of symptomatic congestive heart failure were enrolled in either an efficacy trial or a comparative trial. In the efficacy trial, which required the placement of a Swan-Ganz catheter, 127 patients with a pulmonary-capillary wedge pressure of 18 mm Hg or higher and a cardiac index of 2.7 liters per minute per square meter of body-surface area or less were randomly assigned to double-blind treatment with placebo or nesiritide (infused at a rate of 0.015 or 0.030 microg per kilogram of body weight per minute) for six hours. In the comparative trial, which did not require hemodynamic monitoring, 305 patients were randomly assigned to open-label therapy with standard agents or nesiritide for up to seven days. RESULTS: In the efficacy trial, at six hours, nesiritide infusion at rates of 0.015 and 0.030 microg per kilogram per minute decreased pulmonary-capillary wedge pressure by 6.0 and 9.6 mm Hg, respectively (as compared with an increase of 2.0 mm Hg with placebo, P<0.001), resulted in improvements in global clinical status in 60 percent and 67 percent of the patients (as compared with 14 percent of those receiving placebo, P<0.001), reduced dyspnea in 57 percent and 53 percent of the patients (as compared with 12 percent of those receiving placebo, P<0.001), and reduced fatigue in 32 percent and 38 percent of the patients (as compared with 5 percent of those receiving placebo, P<0.001). In the comparative trial, the improvements in global clinical status, dyspnea, and fatigue were sustained with nesiritide therapy for up to seven days and were similar to those observed with standard intravenous therapy for heart failure. The most common side effect was dose-related hypotension, which was usually asymptomatic. CONCLUSIONS: In patients hospitalized with decompensated congestive heart failure, nesiritide improves hemodynamic function and clinical status. Nesiritide is useful for the treatment of decompensated congestive heart failure.

Unstable angina during pregnancy in two patients with premature coronary atherosclerosis and aortic stenosis in association with familial hypercholesterolemia.

Obstructive atherosclerotic coronary artery disease is uncommon in women during childbearing age, and the occurrence of myocardial ischemia during pregnancy has therefore been anecdotal. Two young patients with premature coronary artery disease in association with familial hypercholestrolemia had unstable angina in the second trimester of pregnancy. Workup revealed coronary artery disease and aortic stenosis. One patient opted for abortion at the twentieth week of gestation, and the other decided to continue pregnancy and was delivered by cesarean at 28 weeks' gestation. Coronary artery bypass grafting was performed after pregnancy in both patients. In addition, one of the patients underwent aortic valve replacement, and other had replacement of the narrowed ascending aorta with uneventful recovery. Our report describes an uncommon presentation of unstable angina during pregnancy in 2 young women with premature coronary artery disease and aortic valvular and supravalvular stenosis as a result of familial hypercholesterolemia. The management of these conditions during pregnancy is influenced by the effects of available therapeutic modalities on both maternal and fetal outcome.

Effect of mibefradil, a T-type calcium channel blocker, on morbidity and mortality in moderate to severe congestive heart failure: the MACH-1 study. Mortality Assessment in Congestive Heart Failure Trial.

BACKGROUND: Calcium antagonists have proved disappointing in long-term congestive heart failure (CHF) studies. Mibefradil, a new calcium antagonist that selectively blocks T-type calcium channels, has been shown to be an effective antihypertensive, antianginal, and anti-ischemic agent, and because of its different mechanism of action, it may be beneficial as adjunct therapy in CHF patients. METHODS AND RESULTS: This multicenter, randomized, double-blind study compared mibefradil with placebo as adjunct to usual therapy in 2590 CHF patients (NYHA class II to IV; left ventricular fraction <35%). The initial 50-mg daily dose of mibefradil was uptitrated to 100 mg after 1 month and continued up to 3 years. Patients were monitored at 1 week; 1, 2, and 3 months; and every 3 months thereafter. All-cause mortality, cardiovascular mortality, and cardiovascular morbidity/mortality were analyzed by use of the log-rank test (alpha=0.05). Substudies included exercise tolerance, plasma hormone and cytokines, echocardiography, and quality of life. Total mortality was similar between mibefradil- and placebo-treated patients (P=0.151). The 14% increased risk of mortality with mibefradil in the first 3 months was not statistically significant (P=0.093). Treatment groups had similar cardiovascular mortality (P=0.246), cardiovascular morbidity/mortality (P=0.783), and reasons for death or hospitalization. Patients comedicated with mibefradil and antiarrhythmics (class I or III), including amiodarone, had a significantly increased risk of death. Substudies demonstrated no significant differences between treatments. CONCLUSIONS: When used as adjunct therapy, mibefradil did not affect the usual outcome of CHF. The potential interaction with antiarrhythmic drugs, especially amiodarone, and drugs associated with torsade de pointes may have contributed to poor outcomes early in the study.

A randomized trial of ecadotril versus placebo in patients with mild to moderate heart failure: the U.S. ecadotril pilot safety study.

OBJECTIVE: To determine the short-term safety and tolerability of the addition of ecadotril to conventional therapy in patients with mild to moderate heart failure. METHODS: Fifty ambulatory patients, 18 to 75 years of age, with mild to moderate heart failure, left ventricular ejection fraction

The role of organic nitrates in the treatment of heart failure.

Nitrates have been widely used in the treatment of patients with chronic congestive heart failure. Although the use of these drugs has not been approved by the Food and Drug Administration, multiple studies have shown their favorable effects. Organic nitrates have been shown to have a beneficial effect on ischemia, hemodynamic profile, magnitude of a mitral regurgitation, endothelial function, and cardiac remodeling. These drugs, when used in combination with hydralazine, have improved exercise capacity and survival. Recent studies have shown that the use of nitrates in patients already treated with standard heart failure therapy, including angiotensin converting enzyme (ACE) inhibitors, resulted in hemodynamic improvement, marked enhancement of exercise tolerance, reduction of left ventricular size, and augmentation of systolic function. These data suggest a role for organic nitrates as an adjunctive therapy to ACE inhibitors in patients with chronic heart failure and for nitrates in combination with hydralazine as an alternative treatment in patients who are intolerant to ACE inhibitors.

Double-blind, placebo-controlled study to evaluate the effect of organic nitrates in patients with chronic heart failure treated with angiotensin-converting enzyme inhibition.

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<0.05) and end-systolic (-3.2+/-1.3%, P<0.05) dimensions and augmented LV fractional shortening (24.7+/-10.5%, P<0.03). The effect of placebo on these parameters was not statistically significant. 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.

Favorable response of Eisenmenger syndrome to inhaled nitric oxide during pregnancy.

OBJECTIVE: Our goal was to evaluate the effectiveness of therapy with a specific pulmonary vasodilator, nitric oxide, in a woman with Eisenmenger syndrome during pregnancy. STUDY DESIGN: Eisenmenger syndrome consists of a congenital communication between the systemic and pulmonary circulation with secondary pulmonary hypertension causing reversal of flow through the shunt. Maternal morbidity is approximately 50% with the greatest risk of death being in the peripartum period. Pharmacologic therapy to relieve worsening pulmonary hypertension is confounded by the undesired effects of vasodilators on the systemic circulation. Therapy with a specific pulmonary vasodilator, nitric oxide, was attempted. RESULTS: A 27-year-old woman with Eisenmenger syndrome at 36 weeks' gestation was treated with inhaled nitric oxide during the second stage of labor and the postpartum period when she experienced progressive refractory hypoxemia. Administration of nitric oxide was followed by improved oxygenation and lowering of pulmonary artery pressures. A brief episode of methemoglobinemia responded to lowering of the nitric oxide concentration and administration of intravenous methylene blue. Nitric oxide was discontinued after 48 hours. The patient died 2 days later despite continued vasodilator therapy including intra-pulmonary artery prostacyclin. CONCLUSION: Inhaled nitric oxide can be used to correct the hypoxemia of Eisenmenger syndrome. Nitric oxide inhalation is easily performed, and pulmonary vasodilatory effects commence within minutes after administration.

Pharmacokinetic and pharmacodynamic evaluation of atenolol during and after pregnancy.

STUDY OBJECTIVE: To evaluate changes due to pregnancy on atenolol's pharmacokinetics, response of maternal heart rate to atenolol, and the drug's effect on fetal heart rate. DESIGN: Prospective study. SETTING: Large university teaching hospital. PATIENTS: Fourteen pregnant women who were receiving oral atenolol for cardiac disease were enrolled and 10 completed the study. INTERVENTIONS: Patients were studied for 12 hours during the third trimester (TT) and again 6 weeks postpartum (PP). MEASUREMENTS AND MAIN RESULTS: Fetal heart rates, and maternal heart rates at rest and during exercise were recorded. Maternal plasma and urine atenolol concentrations were measured. Average resting heart rates (TT 68+/-10, PP 62+/-9 beats/min) and maximum heart rate during exercise (TT 100+/-6, PP 87+/-7 beats/min) were significantly higher in the third trimester than postpartum (p<0.05). The 12-hour atenolol area under the curve (TT 0.208+/-0.061, PP 0.215+/-0.089 ng/ml/day) and maximum plasma concentrations during the time of exercise tests (TT 1.07+/-0.39, PP 1.14+/-0.53 mmol/L) were not significantly different. Individual and population pharmacokinetics did not differ significantly between study periods. The fetal heart rate did not correlate with maternal atenolol concentration. CONCLUSION: Constant dosages of atenolol result in higher heart rates during pregnancy compared with the postpartum period. This lack of heart rate control is not due to significant changes in atenolol's pharmacokinetics or plasma concentrations.

Renal circulatory effects of adenosine in patients with chronic heart failure.

OBJECTIVES: We sought to study the renal circulatory effects of adenosine in patients with chronic congestive heart failure (CHF). BACKGROUND: Renal blood flow (RBF) is often reduced in patients with chronic CHF and may lead to decreased renal function. The cause of reduced RBF is multifactorial and involves systemic as well as local vasoregulatory mechanisms. Stimulation of renal adenosine A1 receptors in animal models has resulted in a significant vasoconstriction of afferent and efferent glomerular arterioles and deterioration of renal function. Although adenosine serum levels have been shown to be elevated in patients with CHF, their effect on the renal circulation in this patient population has not been studied. METHODS: Nine patients with CHF from left ventricular systolic dysfunction were studied. The effects of adenosine at a dose of 10(-5) mol/liter infused directly into the main renal artery on heart rate, renal artery blood pressure, renal artery cross-sectional area (measured by intravascular ultrasound), renal Doppler blood flow velocity (measured by a Doppler flow wire in the renal artery), RBF and renal vascular resistance (RVR) were evaluated. RESULTS: Infusion of adenosine resulted in no significant effect on heart rate or renal artery blood pressure but caused a substantial increase in RVR (11,204 +/- 1,469 to 31,494 +/- 3,911 dynes x s x cm(-5), p = 0.0005), which led to a marked fall in RBF in every patient (mean values 376 +/- 36 to 146 +/- 22 ml/m2, p = 0.0002). These changes in RVR and RBF were associated with no significant change in renal artery cross-sectional area (0.389 +/- 0.040 to 0.375 +/- 0.033 cm2, p = 0.3). CONCLUSIONS: Stimulation of renal adenosine receptors in patients with CHF results in marked renal vasoconstriction that leads to an important reduction in RBF. Lack of change in renal artery cross-sectional area suggests that adenosine affects intrarenal resistance blood vessels rather than large conductance vessels. These results may indicate a rationale for investigation of renal adenosine receptor blockade for enhancement of RBF and improvement of renal function in patients with chronic CHF.

Calcium channel blockers in heart failure.

A considerable effort has been made in the last 15 years to evaluate the safety and efficacy of calcium channel blockers (CCBs) in the treatment of patients with chronic congestive heart failure (CHF). Available studies have provided strong evidence for a potential detrimental effect of the first-generation calcium antagonists in patients with CHF, indicating the need for great caution when these drugs are used in patients with significant depression of left ventricular systolic function. A number of second-generation CCB have demonstrated a strong vasodilatory effect and favorable hemodynamic action but failed to show a similar improvement in exercise capacity, morbidity and mortality. Moreover, drugs such as nicardipine and nisoldipine have resulted in a detrimental effect in some patients and, therefore, cannot be considered safe when used in patients with moderate-to-severe heart failure. Available information from the V-HeFT III study demonstrate a lack of an unfavorable effect of felodipine on exercise tolerance in patients with chronic heart failure. Although mortality rate was similar in both the felodipine and the placebo group, because of the relatively small number of patients in this study, no clear conclusion can be drawn regarding the effect of felodipine on mortality in patients with CHF. An encouraging signal regarding a potential role of CCB in the treatment of chronic heart failure has been provided by the recently completed PRAISE study. This prospective large-scale study demonstrated the safety of amlodipine, a long-acting dihydropyridine derivative, when used in patients with heart failure due to coronary artery disease. Furthermore, this study demonstrated a substantial reduction in mortality in patients with CHF due to nonischemic cardiomyopathy and provided a strong indication for a potential therapeutic benefit of amlodipine when added to standard CHF therapy in this patient population. No clear explanation is available at the present time regarding the reason for the deleterious effect demonstrated with some of the dihydropyridines and the contrasting benefit seen with amlodipine. Finally, more information regarding the safety and efficacy of dihydropyridines should become available in the next year. The PRAISE II study is ongoing and will provide further information regarding the therapeutic role of amlodipine in patients with nonischemic dilated cardiomyopathy. The MACH-1 study is evaluating the effect of mibefradil, a predominant T-type channel blocker with an ideal activity profile, on morbidity and mortality in patients with chronic CHF.

Comparative effects of losartan and enalapril on exercise capacity and clinical status in patients with heart failure. The Losartan Pilot Exercise Study Investigators.

OBJECTIVES: This study was designed to determine 1) whether 12-week oral administration of losartan, an angiotensin II receptor antagonist, in patients with heart failure is well tolerated; and 2) whether functional capacity and clinical status of patients with heart failure in whom treatment with an angiotensin-converting enzyme (ACE) inhibitor is replaced with losartan for 12 weeks will remain similar to that noted in patients in whom treatment with an ACE inhibitor is continued. BACKGROUND: Losartan is a specific, nonpeptide angiotensin II receptor antagonist. Although specific receptor blockade with losartan has certain theoretic advantages over nonspecific ACE inhibition, definitive demonstration of comparable effects in patients with congestive heart failure is lacking. METHODS: A double-blind, multicenter, randomized, parallel, enalapril-controlled study was conducted in 116 patients with congestive heart failure (New York Heart Association functional classes II to IV) and left ventricular ejection fraction < or = 45% previously treated with stable doses of ACE inhibitors and diuretic agents, with or without concurrent digitalis and other vasodilators. After a baseline exercise period, open-label ACE inhibitors were discontinued, and patients were randomly assigned to 12 weeks of therapy with losartan, 25 mg/day (n = 38); losartan, 50 mg/day (n = 40); or enalapril, 20 mg/day (n = 38). Drug efficacy was evaluated by changes in maximal treadmill exercise time (using a modified Naughton protocol), 6-min walk test, left ventricular ejection fraction and dyspnea-fatigue index. Safety was measured by the incidence of clinical and laboratory adverse experiences. RESULTS: The treadmill exercise time and the 6-min walk test did not change significantly after replacement of ACE inhibitor therapy with losartan. Similarly, a significant change was not observed in either the dyspnea-fatigue index or left ventricular ejection fraction at the end of double-blind period relative to baseline. CONCLUSIONS: Losartan was generally well tolerated and comparable to enalapril in terms of exercise tolerance in this short-term (12-week) study of patients with heart failure. The clinical effects of long-term angiotensin II receptor blockade compared with ACE inhibition remain to be studied.

Incidence of arrhythmias in normal pregnancy and relation to palpitations, dizziness, and syncope.

We assessed the relation between symptoms and cardiac arrhythmias in 110 consecutive pregnant patients without evidence of heart disease referred for evaluation of palpitations, dizziness, and syncope (study group) and in 52 consecutive patients referred for evaluation of an asymptomatic functional precordial murmur (control group). Both groups had a high incidence of arrhythmias on Holter monitoring with atrial premature complexes (APCs) of 56% in the study group and 58% in the control group, > 100 APCs in 7% and 4% of the patients, respectively, and isolated ventricular premature complexes (VPCs) in 59% and 50%, respectively. The number of isolated VPCs was higher and > 50 VPCs/hour were seen in more patients in the study group (3,235 +/- 6,397 vs 678 +/- 3,358 beats/24 hours p < 0.05 and 22% vs 2% p = 0.03). Similarly, the incidence of multifocal VPCs was higher in the study patients (12% vs 2%, p < 0.05). There was no correlation between the incidence of both VPCs or APCs and symptoms, and only 10% of symptomatic episodes were accompanied by the presence of arrhythmias. Repeated Holter monitoring 6 weeks postpartum in 9 women with multiple premature contractions during pregnancy (9,073 +/- 9,210/24 hours) showed a substantial reduction to 1,345 +/- 1,997/24 hours (p < 0.05). Thus, this study confirms an increased incidence of arrhythmias during normal pregnancy. These arrhythmias consist mostly of APCs and VPCs. The number of simple and multifocal VPCs is higher in patients presenting with symptoms of palpitations, dizziness, or syncope; however, there is no correlation between the incidence of arrhythmias and symptoms, and only 10% of symptomatic episodes were accompanied by the presence of arrhythmias.