Rationale and design of ACTIVE: the atrial fibrillation clopidogrel trial with irbesartan for prevention of vascular events.

BACKGROUND: Atrial fibrillation (AF) is the most frequently occurring cardiac arrhythmia with often serious clinical consequences. Many patients have contraindications to anticoagulation, and it is often underused in clinical practice. The addition of clopidogrel to aspirin (ASA) has been shown to reduce vascular events in a number of high-risk populations. Irbesartan is an angiotensin receptor-blocking agent that reduces blood pressure and has other vascular protective effects. METHODS AND RESULTS: ACTIVE W is a noninferiority trial of clopidogrel plus ASA versus oral anticoagulation in patients with AF and at least 1 risk factor for stroke. ACTIVE A is a double-blind, placebo-controlled trial of clopidogrel in patients with AF and with at least 1 risk factor for stroke who receive ASA because they have a contraindication for oral anticoagulation or because they are unwilling to take an oral anticoagulant. ACTIVE I is a partial factorial, double-blind, placebo-controlled trial of irbesartan in patients participating in ACTIVE A or ACTIVE W. The primary outcomes of these studies are composites of vascular events. A total of 14000 patients will be enrolled in these trials. CONCLUSIONS: ACTIVE is the largest trial yet conducted in AF. Its results will lead to a new understanding of the role of combined antiplatelet therapy and the role of blood pressure lowering with an angiotensin II receptor blocker in patients with AF.

Effects of omapatrilat on hemodynamics and safety in patients with heart failure.

Omapatrilat, a novel vasopeptidase inhibitor, is a highly potent and selective inhibitor of neutral endopeptidase and angiotensin-converting enzyme; its therapeutic potential is being investigated for treatment of hypertension and heart failure. In the present study, the safety, tolerability, and hemodynamic effects of single oral doses of omapatrilat (1 to 50 mg) are compared with placebo in patients with heart failure. Patients with heart failure (New York Heart Association functional class II to IV) and a resting left ventricular ejection fraction < or = 40% were enrolled in a double-blind, placebo-controlled, sequential-panel study of single doses of omapatrilat of 1, 2.5, 5, 10, 25, or 50 mg, followed by hemodynamic assessment for 24 hours. At 4 to 6 hours after dosing, the 25- and 50-mg doses of omapatrilat, compared with placebo, reduced mean pulmonary capillary wedge pressure by approximately 6 mm Hg from 20 and 23 mm Hg at baseline to 14 and 16 mm Hg. The 50-mg omapatrilat dose maintained this effect compared with placebo with an approximately 2.5-mm Hg reduction in mean pulmonary capillary wedge pressure at 24 hours. Omapatrilat improved additional hemodynamic parameters, including cardiac index, systemic vascular resistance, stroke volume index, and mean arterial pressure. Additionally, by 2 hours after dosing with omapatrilat 25 and 50 mg, a trend in peak increases from baseline in plasma atrial natriuretic peptide (twofold) and cyclic guanosine monophosphate (nearly twofold) was observed. Moreover, omapatrilat was well tolerated. Thus, omapatrilat administered orally to patients with heart failure was safe and well tolerated and resulted in improved hemodynamic performance.

Renin-angiotensin II response to the hemodynamic pathology of ovines with ventricular septal defect.

We studied the response of the renin-angiotensin system (RAS) to a surgically created ventricular septal defect (VSD) in immature ovines and also the role of angiotensin II in the pathophysiology of VSD in the chronically instrumented ovine. Plasma renin activity (PRA) was increased from 2.39 +/- 1.1 to 3.78 +/- 1.4 ng/ml/hr (p less than 0.05, n = 17) after VSD but not after sham procedure. The change in PRA was positively correlated with the amount of left-to-right shunt through the VSD (r = 0.74, p less than 0.05). Inhibition of angiotensin II effect with saralasin (10 micrograms/kg/min) or angiotensin II production with captopril (2 mg/kg) lowered systemic resistance (Rs) by 14% and 34%, respectively (p less than 0.05), and raised pulmonary resistance (Rp) by 35% and 77%, respectively (p less than 0.05). Thirty minutes following captopril, the ratio of pulmonary to systemic flow (Qp/Qs) decreased from 3.31 +/- 0.18 to 2.15 +/- 0.18 (p less than 0.05) while total pulmonary flow fell from 7.15 +/- 0.38 to 5.92 +/- 0.34 l/min/M2 (p less than 0.05, n = 11). Systemic flow increased from 2.17 +/- 0.14 to 2.86 +/- 0.33 l/min/M2 (p less than 0.05) despite a reduction in left atrial pressure (17.3 +/- 1.0 vs. 13.0 +/- 1.7, p less than 0.01). Reinfusion of angiotensin II (0.02 micrograms/kg/min) into the central aorta after captopril returned the hemodynamics to baseline including a rise in Rs and fall in Rp. Exogenous angiotensin II alone (0.08 micrograms/kg/min) or a threefold stimulation in PRA with furosemide (2 mg/kg) caused little hemodynamic effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Graded experimental myocardial contusion: impact on cardiac rhythm, coronary artery flow, ventricular function, and myocardial oxygen consumption.

Current management of myocardial contusion is based on experience with ischemic heart disease, but the mechanism responsible for cardiac dysfunction may be quite different. The purpose of this study was to characterize the pathophysiology of myocardial contusion in a controlled animal model. Sprague-Dawley rat hearts were prepared on a standard Langendorff apparatus, and myocardial function (DP, + dP/dT, - dP/dT) measured via a left ventricular balloon. Bipolar atrial and ventricular leads were placed to define conduction changes. Coronary sinus effluent was sampled for pO2, pH, creatine phosphokinase (CPK), and lactic dehydrogenase (LDH). The hearts were freeze-clamped to measure phosphocreatine (PC) and adenosine triphosphate (ATP). Myocardial contusion was produced by a single blow with a weighted pendulum. Hearts were divided into control (n = 5), moderate impact--Group I (n = 5), and major impact--Group II (n = 5). Group I sustained a 25% decrease in function after an impact of 78 +/- 5 mJoules/gm, and Group II a 50% deficit after 87 +/- 7 mJoules/gm. Impact resulted in complete electrical arrest, followed by sequential ventricular, atrial, and AV nodal recovery; recovery time correlated directly with degree of injury. Coronary flow at 2 min postinjury was decreased (p less than 0.05) in Group I (12.8 +/- 0.8 ml/min) and Group II (11.5 +/- 1.3) compared to control (17.2 +/- 0.5), and returned to baseline levels at 20 min. LDH and CPK levels were twice as high in Group II as in Group I. The PC/ATP ratio in Group II increased from 1.63 at baseline to 2.54 (p less than 0.05) at 25 min, confirming ischemic reperfusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Atrial distension of isolated rabbit hearts and release of atrial natriuretic factor.

Interventions that increase atrial pressures in humans or laboratory animals release atrial natriuretic factor (ANF) into the circulation. We studied the relation between distension of the right or left atrium and release of ANF in retrograde-perfused isolated rabbit hearts. A fluid-filled balloon within the right or left atrium was inflated to a mean pressure of 5, 10, 15, or 20 mmHg, and ANF in the cardiac effluent was measured by radioimmunoassay. The slope of the regression line relating ANF release to atrial distending pressure was steeper for the left than right atrium (P less than 0.001), indicating that, at comparable increases in mean pressures, the left atrium releases more ANF than does the right atrium. Left atrial tissue concentration of ANF was greater than right atrial (1.58 +/- 0.15 vs. 1.05 +/- 0.09 micrograms ANF/mg protein, P less than 0.01). In contrast to previous studies showing right atrial dominance in rats, the left atria of isolated, perfused rabbit hearts contain more ANF and release more in response to atrial distension.

Electrophysiological effects of acute ventricular dilatation in the isolated rabbit heart.

We examined the effects of left ventricular dilatation on epicardial pacing threshold, conduction velocity, and effective refractory period (ERP) in the isolated, retrograde perfused rabbit heart. Left ventricular size was modified by acutely changing the volume of a fluid-filled balloon anchored within the vented left ventricle. Increases in left ventricular volume, associated with increases in left ventricular end-diastolic pressure from 0 +/- 1 to 35 +/- 2 mm Hg, were not associated with significant changes in pacing threshold or conduction velocity. The left ventricular ERP decreased significantly with an added volume of 1.5 ml (91.4 +/- 5.5 msec) compared with starting volume (117.7 +/- 3.8 msec, p less than 0.01). Right ventricular ERP did not change significantly with increases in left ventricular volume. The left and right ventricular ERPs were comparable at starting volume (117.7 +/- 3.8 and 117.6 +/- 3.5 msec, respectively; p = NS) but were significantly different with an added volume of 1.5 ml (91.4 +/- 5.5 and 112 +/- 5.6 msec, p less than 0.05). These changes were independent of coronary perfusion pressure and paced cycle length, suggesting that ischemia is an unlikely explanation for the observed effects. Changes in left ventricular volume decreased left ventricular ERP in a regionally heterogeneous manner, increasing the temporal dispersion of recovery over the left ventricle nearly twofold. Induced ventricular arrhythmias (ventricular tachycardia or fibrillation) were significantly more frequent at high (35%) than at low (3%) volumes during left ventricular pacing. We conclude that ventricular dilatation is associated with increased dispersion of refractoriness in this model, a finding that correlates with propensity for reentrant arrhythmias.

Aortic root dilatation and mitral valve prolapse in the fragile X syndrome.

Forty patients with fragile X [fra(X)] or Martin-Bell syndrome, confirmed by chromosome analysis, underwent full cardiac evaluation including physical examination, chest film, electrocardiography (ECG), and M-mode and 2-dimensional echocardiography. Thirty-four males and six females were studied. Although all patients were asymptomatic, seven males were found to have mild aortic root dilatation. All seven also had evidence of mitral valve prolapse. Twenty-two (55%) of the study patients had mitral valve prolapse with either a click or murmur heard on physical examination and confirmation by M-mode echocardiography. The frequency of mitral valve prolapse was the same in males and females, but 80% of males older than 18 years had mitral valve prolapse. These findings support the hypothesis of a connective tissue dysplasia in the fra(X) syndrome.

Hemodynamic consequences of inotropic support with digoxin or amrinone in lambs with ventricular septal defect.

Inotropic support with digoxin is commonly used in patients with left ventricular volume overload due to ventricular septal defect (VSD). However, the hemodynamic consequences of inotropic agents with VSD have not been experimentally explored. We studied two inotropic agents, digoxin and amrinone, in chronically instrumented lambs with left ventricular volume overload due to a surgically created VSD. Intravenous digoxin (40 micrograms/kg) produced serum levels of 3.5 +/- 0.9 ng/ml (mean +/- SD) in seven lambs 60 min after administration, reduced the heart rate by 16% (172 to 149 beats/min, p less than 0.05), increased the stroke volume 16% (29.8 to 34.5 ml/beat, p less than 0.05) but did not significantly alter the systemic flow index (Qs), the pulmonary flow index (Qp), or the volume of left to right shunt (QL-R, 6.74 to 6.77 liter/min/m2). The mean left atrial pressure (LA) was unchanged (17.6 versus 17.1 mm Hg) following digoxin. Chronic digoxin use in four lambs for 4 days (25 +/- 8 micrograms/kg/8 h) produced trough serum levels of 1.2 +/- 0.2 ng/ml. There was no additional hemodynamic effect compared to acute digoxin, the Qp/Qs ratio was unchanged (3.10 versus 3.08) and evidence of left ventricular volume overload (LA - 14.0 versus 13.4) was unchanged. Amrinone lowered the systemic resistance index in a dose dependent fashion. The peak reduction of 20% (25.3 to 20.3 U/m2, p less than 0.01) occurred at 20 min after an intravenous (3 mg/kg) bolus in seven lambs. The Qs increased from 2.58 to 3.10 liter/min/m2 (p less than 0.01). The Qp was unchanged, thus the Qp/Qs ratio was lowered by 16% (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Taussig-Bing anomaly and coarctation of the aorta in infancy: surgical options.

The coexistence of the Taussig-Bing anomaly and coarctation of the aorta is a highly complex situation carrying a dismal prognosis. Through our experience and a review, we have observed that neonates requiring coarctation repair, pulmonary artery banding, and patent ductus ligation are at high risk of expiring before reaching an age at which a difficult total repair is feasible. It appears that patients presenting beyond the neonatal period have a better chance of surviving an initial surgical procedure and the definitive repair. A surgical management protocol has been suggested. Although associated with an uncertain late prognosis, arterial level repairs are the most physiologic, and their results to date are encouraging.

Vasodilators and ventricular septal defect: comparison of prazosin, minoxidil, and hydralazine in a chronic lamb model.

The volume overloading of the left ventricle which results from left to right (L-R) shunting through a ventricular septal defect (VSD) may be reduced by pharmacologic agents which lower systemic vascular resistance (Rs) in excess of pulmonary arteriolar vascular resistance (Rpa). To study agents capable of decreasing the L-R shunt through systemic vasodilatation, we created a chronic lamb model with VSD and administered three vasodilators, prazosin (0.05 mg/kg), hydralazine (0.75 mg/kg), and minoxidil (0.25 mg/kg). Prazosin increased the Rpa while lowering Rs, resulting in an increase in Rpa/Rs by 43% (p less than or equal to 0.005). Prazosin decreased the pulmonary flow (Qp) slightly, decreased L-R shunt by 16%, reduced the pulmonary to systemic flow ratio (Qp/Qs) by 22% (p less than or equal to 0.005), and lowered the left atrial mean pressure (LA) by 16% (p less than or equal to 0.005) with no effect on heart rate. Hydralazine lowered the Rpa and Rs equally and thus did not change the Rpa/Rs or the volume of L-R shunt (7.6 versus 8.1 liters/min/m2). No change in LA was seen with hydralazine but heart rate increased from 162 to 200/min (p less than or equal to 0.01). Minoxidil did not change the L-R shunt (6.9 versus 6.8 liters/min/m2) and, in general, produced effects intermediate between prazosin and hydralazine. The data support a selective systemic vasodilation with prazosin, a property not shared by either minoxidil or hydralazine, which results in a reduction of shunting and left ventricular volume overloading in lambs with VSD.(ABSTRACT TRUNCATED AT 250 WORDS)

Mitral valve prolapse and aortic dilatation in the fragile X syndrome.

Four patients with the fragile X syndrome including 3 males and one woman, were evaluated for cardiological abnormalities. One patient had an obvious murmur. All 4 were shown to have mitral valve prolapse by echocardiography. Two male patients also demonstrated mild dilatation of the ascending aorta. We recommend thorough cardiological evaluations of all fragile X patients.

Surgical and medical experience with 734 premature infants with patient ductus arteriosus.

During the past 5 years, patent ductus arteriosus (PDA) presented in 734 preterm infants (less than 2.5 kg and 37 weeks gestation) of 2,532 admissions (29%). The ductus presented with murmur, bounding pulses, and often congestive heart failure. Medical treatment consisted of the following: fluid restriction, furosemide, respiratory support, and rarely digoxin. The patients who were unresponsive to medical treatment had surgical ligation (306 of 734 or 42%). The patients who had ductal ligation were smaller, i .e., 82% of the surgical patients weighed less than 1.5 kg as compared to 38% of the medical patients. Of those patients weighing less than 1.5 kg, the surgical and medical groups were compared and the following observations made: The incidence of respiratory distress syndrome was greater in the surgical group (86% or 216 of 252 patients versus 69% or 111 of 161 medical patients, p less than 0.001) and the long-term survival was better (89% or 224 of 252 surgical patients versus 77% or 124 of 161 medical patients, p less than 0.005). In addition, the average duration of intubation was shorter in this surgical subgroup (8.9 versus 13.6 days). Significant left atrial enlargement and echocardiographic left atrial/aortic (LA/Ao) ratios of greater than 1.5:1 occurred in 58% or 171 of 290 surgical patients versus 32% or 59 of 190 medical patients (p less than 0.001). During the first 3 years of this study (medical treatment averaged 5 days), the duration of intubation in the surgical patients averaged 15.2 days; by comparison, in the last 2 years of this study (medical treatment averaged 1 to 2 days), the duration of intubation was 6.5 days (p less than 0.001). Necrotizing enterocolitis (NEC) occurred in 11% or 46 of 428 medical patients versus 0.3% (one of 305 patients) in the ligated group postoperatively (p less than 0.001). Late deaths were related to lung disease, central nervous system problems, NEC, and so on. From this study, it was determined that ligation of a significant PDA is associated with (1) zero surgical risk, (2) a reduced incidence of NEC, (3) reduced duration of intubation, especially with early ligation, and (4) improvement in late survival. Thus the surgical approach is our treatment of choice for a refractory PDA.

Secondary sternal closure: a method of preventing cardiac compression.

A patient with severe congenital pulmonary stenosis who underwent pulmonary valvulectomy is reported. Acute cardiac compression and left ventricular failure developed in the immediate postoperative period. Because of extreme cardiac dilatation, the chest wall could not be closed. A technique of secondary sternal closure is described.

Separation of conjoined thoracopagous twins joined at the right atrial.

A case of conjoined thoracopagous twins with a shared atrial myocardium who were successfully surgically separated is described. Twin B had hypoplastic right heart syndrome and was dependent on Twin A for oxygenation of her blood. The twins were surgically separated by dilating Twin B's ductus arteriosus with an infusion of prostaglandin E1 and creating an aortopulmonary shunt to increase her pulmonary blood flow; both twins survived the operation. However, 1 week after surgery Twin B had hepatic and renal failure and died.

Hemodynamic effects of vasodilator agents in dogs with experimental ventricular septal defects.

The ratio of pulmonary to systemic vascular resistance (Rp/Rs) largely determines the amount of left-to-right shunting and pulmonary to systemic flow rat (Qp/Qs) in the presence of a large isolated ventricular septal defect. The possibility that pharmacologic reduction of systemic vascular resistance with alpha-adrenergic receptor blockade or beta-adrenergic receptor stimulation would increase the ratio Rp/Rs, and therefore reduce the ratio Qp/Qs, was studied in dogs in which ventricular septal defects had been surgically created. Administration of phentolamine and phenoxybenzamine caused a 42% reduction in Rs and no reduction in Rp. Qs was unchanged and Qp declined by 24% and the ratio Qp/Qs fell by 32%. Infusion of the beta-adrenergic receptor stimulant isoproterenol also reduced Qp/Qs. However, this was accomplished as a result of an increase in Qs and at the expense of an increase in heart rate. As a decline in the ratio Qp/Qs has been shown to be beneficial to patients with large left-to-right shunts, pharmacologic reduction of systemic vascular resistance may prove to be helpful in treating congestive heart failure in those patients with large left-to-right shunts at the ventricular level who are refractory to the usual decongestive measures.