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Studies of left ventricular dysfunction (SOLVD)--rationale, design and methods: two trials that evaluate the effect of enalapril in patients with reduced ejection fraction.

The Studies of Left Ventricular Dysfunction (SOLVD) is an extensive program of research that has 3 components. (1) Two large double-blind randomized trials evaluate the effects of enalapril on mortality, morbidity and quality of life of patients with left ventricular (LV) dysfunction with overt congestive heart failure (CHF) (Treatment Trial in 2,500 patients) and without overt CHF (Prevention Trial in 4,600 patients). (2) Seven detailed sub-studies evaluate the effect of enalapril on a number of intermediate outcomes such as right and LV function and hemodynamics, LV mass and wall stress, hormones, arrhythmias, exercise capacity and quality of life in subsets of patients in the 2 large trials. (3) Finally, a registry of 6,336 patients with congestive heart failure or LV dysfunction is designed to describe the clinical course of an unselected group of patients. The rationale and design of a tiered approach to clinical trials that are large enough to provide reliable information on mortality and morbidity, yet provide relevant information on other endpoints, are described.

Adult

Is the morphology of ventricular premature beats a marker for left ventricular dysfunction?

The morphology of ventricular premature beats has been described as a marker for the presence or absence of myocardial disease. Furthermore, the premature beat has been reported to be a potential marker for a dilated and hypokinetic left ventricle. To verify this previously tested hypothesis, 37 healthy patients with ventricular premature beats on an electrocardiogram (ECG), Holter monitor ECG, or a stress test ECG were classified according to the ventricular premature beat morphology. Group 1 had ventricular premature beat QRS complexes with a smooth contour or with narrow (less than 40 msec) notching. Group 2 had ventricular premature beats with broad (greater than 40 msec) notching or shelves. All of these patients had normal or borderline normal ECGs and normal multiple-gated acquisition (MUGA) scans. Nine patients had type 1 ventricular premature beats, 20 patients had type II ventricular premature beats, and eight patients had both type I and type II ventricular premature beats. We conclude that the presence of group 2 ventricular premature beats is so frequent in patients with normal left ventricular ejection fractions that the use of this marker in identifying abnormal left ventricular function is suspect.

Adult

[Pulmo cardialis: effect of inhaled bronchodilators on airway resistance of acute left ventricular dysfunction].

Disturbance of left ventricular function leads to an impairment of ventilation: airway resistance increases, while pulmonary compliance is reduced. We therefore studied the effect of inhalable bronchodilators (Fenoterol, Ipratropium bromide) on oscillatory airway resistance in 16 patients with an acute left heart failure. The results show that the resistance can be significantly reduced to normal values by the bronchodilators. Fenoterol has the greatest spasmolytic potency, but Ipratropium bromide is also effective. Recompensation of left heart function alone does not lead to comparable acute effects on airway resistance. The possibility of immediate improvement of ventilation through the use of inhalable bronchodilators should therefore be considered in the treatment of acute left heart failure.

Airway Resistance

[Effect of denopamine on residual left ventricular dysfunction after complete revascularization].

Denopamine (15 mg/day) was administered to 20 patients with residual left ventricular dysfunction after successful percutaneous transluminal coronary angioplasty (75% or more diameter stenosis). Echocardiography was performed before and 6 months after denopamine administration to analyze the left ventricular function. There were significant decreases in both end-diastolic and end-systolic dimensions from 58 +/- 8.3 to 54 +/- 8.4 mm (p = 0.001), and from 44 +/- 10.1 to 40 +/- 10.3 mm (p = 0.005)), respectively, while % fractional shortening remained nearly constant (from 25 +/- 8.3 to 27 +/- 9.6%). Thus, denopamine improved the left ventricular function by decreasing left ventricular size while maintaining wall contractility.

Adrenergic beta-Agonists

[The relationship between anomalies in the autonomous nervous system and left ventricular dysfunction in patients with hypertrophic cardiomyopathy].

This study was undertaken to assess autonomic nervous system (ANS) activity and its relation to left ventricular function in 40 patients (mean age: 41 +/- 17 years) with hypertrophic cardiomyopathy (HC), in sinus rhythm, off-drugs. Patients were grouped according to the results of radionuclide angiography: 26 had an ejection fraction > 50% (Group A), whereas 14 had an ejection fraction < or = 50% (Group B). Evaluation of parasympathetic activity showed abnormalities in: heart rate (HR) response during Valsalva (< or = 1.1) in 2 Group A (8%) and 12 Group B (86%) patients (p < 0.001); HR variability during deep breathing (< or = 10 b/min) in 2 Group A (8%) and 14 Group B (100%) patients (p < 0.001); immediate HR response to standing (30:15 < or = 1.0) in 2 Group A (8%) and 6 Group B (43%) patients (p < 0.025). Assessment of sympathetic activity showed abnormalities in: systolic blood pressure fall to standing (> 20 mmHg) in 2 Group B (14%) patients only (NS); diastolic blood pressure response to handgrip (< 10 mmHg) in 4 Group B (29%) patients only (p < 0.025). Thus, in HC: impaired parasympathetic control is common in those patients showing left ventricular dysfunction; concurrent sympathetic abnormality may also occur in this subgroup of patients; ANS dysfunction seems to be merely an epiphenomenon which marks the severity of left ventricular derangement.

Adult

[The accuracy of echocardiography during the infusion of low-dose dobutamine in identifying vital myocardium in patients with obstructive coronary disease and chronic left ventricular dysfunction].

The identification of viable myocardium has important therapeutic implications in patients with coronary artery disease (CAD) and chronic left ventricular dysfunction. To assess the accuracy of transthoracic echocardiography (TTE) during dobutamine infusion for identification of viable myocardium, we have analyzed 14 patients affected by CAD and chronic abnormalities of left ventricular wall motion (RWM), present at rest, referred for coronary artery bypass grafting (CABG): 8 of 14 patients had a history of myocardial infarction with evidence of Q waves at the surface ECG. All patients had a clinical stable CAD. RWM response to dobutamine (5 mcg/kg/min and 10 mcg/kg/min) was evaluated using TTE and compared to RWM changes after CABG analyzed by intraoperative epicardial echocardiography (EE). RWM was analyzed qualitatively by dividing the left ventricle into 16 segments and a score index was assigned to each region (0: normal; 1: hypokinetic; 2: akinetic; 3: dyskinetic). Of 125 akinetic segments present at rest before CABG, 93 showed functional improvement after CABG at intraoperative EE. The RWM response to dobutamine infusion predicted intraoperative improvement after CABG in 85 of 93 segments (sensitivity: 91.3%) and identified 25 of the 32 segments which did not exhibit intraoperative improvement (specificity: 78.1%). The TTE performed 15 days after CABG showed no worsening or further improvement in RWM when compared with intraoperative EE study. Summed segment scores in 14 patients showed significantly improvement from 17.9 +/- 7, medium values at rest, to 5.1 +/- 4 after dobutamine infusion (p less than 0.001) and 5 +/- 7 after CABG (p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult

Left ventricular filling pattern and pulmonary wedge pressure are closely related in patients with recent anterior myocardial infarction and left ventricular dysfunction.

To determine whether mitral flow velocity can be used to estimate mean pulmonary wedge pressure (PWP) in patients with left ventricular dysfunction, 50 patients with recent Q-wave anterior infarction and a reduced ejection fraction (less than 40%) underwent simultaneous pulsed-wave Doppler measurements of mitral flow and right heart catheterization. Doppler tracings and PWP were recorded at rest, after passive leg lifting (45 degrees) and (in 15 patients with increased PWP) after 5 mg sublingual ISDN. Significant correlations were found between the ratio of peak early to peak late diastolic velocity (E/A) and PWP (r = 0.83). Early diastolic deceleration and the ratio of the time velocity integral of atrial contribution to the total time velocity integral were also correlated to PWP (r = 0.80 and r = 0.79 (respectively). The E/A ratio was less than 1 in 25 patients and more than 1 in the remaining 25. An E/A ratio of at least 1 predicted a PWP of more than 20 mmHg with a sensitivity of 100% and a specificity of 86%. In all five patients, in whom the PWP was less than 20 mmHg at baseline and became greater with leg lifting, the E/A ratio changed from less than 1 to more than 1. After ISDN, changes in E/A ratio from more than 1 to less than 1 identified all 12 patients with a PWP falling below 20 mmHg. In conclusion, patients with recent Q-wave anterior infarction and a reduced ejection fraction mitral flow velocity-derived variables correlate with PWP representing a reliable index for the diagnosis of markedly increased PWP.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult

[Identification of viable myocardium in patients with chronic ischemic disease and left ventricular dysfunction: correlations between blood flow, metabolic activity and regional function].

To identify the presence of viable myocardium in areas of severe systolic dysfunction, we studied 22 patients (age 45 to 78 years) with chronic coronary artery disease and left ventricular dysfunction (mean ejection fraction 29 +/- 9%). All subjects underwent thallium-201 single photon emission computed tomography (SPECT), using the reinjection technique, positron emission tomography (PET) with H2(15)O and 18-fluorodeoxyglucose (FDG) to measure regional blood flow and exogenous glucose uptake, respectively, and nuclear magnetic resonance imaging (MRI). From matched transaxial PET, SPECT and MRI tomograms, a total of 290 left ventricular myocardial regions were analyzed. According to the regional wall thickening, measured from MRI, 3 groups of myocardial regions were identified: akinetic-dyskinetic (n = 60), showing either absence of systolic thickening or systolic thinning; hypokinetic (n = 97), showing an absolute wall thickening less than or equal to 2 mm; normal (n = 133), showing an absolute wall thickening greater than 2 mm. Of the 60 akinetic or dyskinetic regions, 3 were normal by SPECT and 37 corresponded to either a total or partially reversible thallium defect: 34 of these 40 regions also showed presence of FDG uptake by PET. The remaining 20 akinetic or dyskinetic regions showed a thallium defect that remained irreversible after reinjection: in 7 of these 20 regions, however, there was evidence of metabolic activity, as expressed by FDG uptake. Thus, 47 (78%) of the myocardial akinetic or dyskinetic regions showed presence of viable tissue.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged

Serial evaluation of right ventricular dysfunction associated with acute inferior myocardial infarction.

Right ventricular (RV) function was evaluated serially by multigated blood pool imaging in 18 patients with RV dysfunction associated with acute inferior myocardial infarction. Radionuclide ventriculograms were performed on all patients within 18 hours of chest pain and again at 10 days. In addition, 15 of 18 patients had rest and exercise radionuclide ventriculograms at 3 months. The mean resting right ventricular ejection fractions (RVEF) at admission, 10 days, and 3 months in these patients was 31.8 +/- 12.6% (SD), 46.9 +/- 11.2% (p less than 0.05), and 44.5 +/- 10.2% (p less than 0.05), while the left ventricular ejection fractions were 55.9 +/- 10.6%, 57.9 +/- 13.3%, and 53.1 +/- 11.2% (p = ns). The 3-month exercise radionuclide ventriculogram demonstrated an increase in RVEF greater than 5% in 6 of 15 patients. In eight catheterized patients, neither the location nor the severity of coronary artery narrowing nor the presence of collaterals correlated with the RV exercise response. Improvement in RV function over a 10-day interval following acute inferior myocardial infarction suggests the presence of significant reversible right ventricular dysfunction during the acute phase.

Cardiac Catheterization

Cardiovascular and neurohormonal effects of atrial natriuretic peptide in conscious dogs with and without chronic left ventricular dysfunction.

Atrial natriuretic peptide (hANP 4-28) was infused for 1 h (0.3 microgram/kg/min) in 11 normal awake dogs and seven awake dogs with chronic left ventricular dysfunction, induced 16 weeks earlier by repetitive DC shock. The responses were similar in the two groups and included decreases in arterial pressure (107-99 mm Hg), heart rate (83-72 beats/min), and cardiac output (3.6-2.8 L/min), without changes in right or left ventricular filling pressures. Systemic vascular resistance (SVR) tended to rise during the infusion and was significantly increased (2,847-3,442 dyn s cm-5, p less than .05) during the postinfusion recovery period. Regional blood flows (microspheres) during infusion revealed a decrease in skin and splanchnic flow. Despite the apparent vasoconstrictor effect, plasma norepinephrine (PNE), renin activity (PRA), and arginine vasopressin (AVP) levels all fell during ANP infusion. These data suggest that ANP exerts a cardioinhibitory effect, possibly similar to that of arginine vasopressin (AVP), and that the net systemic vasoconstrictor effect of ANP in these dogs is mediated by a complex interrelationship between direct vascular effects, neurohormonal inhibition, and central reflex activation.

Animals

Effect of indecainide in patients with left ventricular dysfunction.

Indecainide, a new antiarrhythmic agent classified as type Ic was evaluated in 11 patients with heart disease who had greater than or equal to 30 ventricular premature complexes/hour, moderate-to-marked left ventricular dysfunction, and mean ejection fraction 34% +/- 8%. Patients received indecainide, 50 mg by mouth, every 6 hours and the dose was increased until greater than or equal to 80% suppression was noted, adverse effects occurred, or a maximum dose of 100 mg indecainide was given every 6 hours. Ventricular premature complexes were suppressed greater than or equal to 80% in nine patients (p less than 0.05) and ventricular tachycardia episodes were completely suppressed in five of eight patients. The effective or maximal mean daily indecainide dose was 191 +/- 32 mg; half of the responders achieved achieved efficacy at serum drug concentration greater than or equal to 600 ng/ml. Serum drug concentration was directly related to gender (r = 0.78, p less than 0.04) and inversely related to creatinine clearance (r = 0.74, p less than 0.05) and ejection fraction (r = 0.71, p less than 0.02). Indecainide prolonged mean PR and QRS intervals (p less than 0.05) but not QT or QTc. There was a linear relation between percent change in PR (r = 0.80, p less than 0.001) and QRS (r = 0.66, p less than 0.001) intervals and serum drug concentration. After starting or increasing the dose, careful observation of patients with decreased renal function or reduced ejection fraction should be exercised because they attain higher drug concentration than normal subjects.

Adult

Acute haemodynamic effects of the beta 1-adrenoceptor partial agonist xamoterol at rest and during supine exercise in patients with left ventricular dysfunction due to ischaemic heart disease: a double-blind randomized trial.

The effects of xamoterol 0.2 mg kg-1 i.v. and placebo on left ventricular function at rest and on exercise were compared in patients with left ventricular dysfunction due to ischaemic heart disease. Improvements were seen in systolic and diastolic function at rest, and at up to 50% of maximal exercise, without evidence of worsening myocardial ischaemia.

Adrenergic beta-Agonists

Comparative hemodynamic effects of mexiletine and quinidine in patients with severe left ventricular dysfunction.

Mexiletine and quinidine are often administered to patients with severe congestive heart failure, but their hemodynamic effects have not been adequately studied in these individuals. In a randomized, crossover study, the hemodynamic responses to single oral doses of quinidine (600 mg) and mexiletine (400 mg) were compared in 20 patients with marked left ventricular dysfunction. Quinidine predominantly caused vasodilation, with mean arterial, left ventricular filling, and right atrial pressures all decreasing (-7 +/- 2, -2.3 +/- 1.0, and -1.1 +/- 0.5 mm Hg, respectively) and the systemic vascular resistance also declining (-308 +/- 84 dynes.sec.cm5). In contrast, the systemic vascular resistance increased (314 +/- 84 dynes.sec.cm-5) and the mean arterial, left ventricular filling, and right atrial pressures also increased (+2 +/- 2, +6.1 +/- 1.8, and +1.8 +/- 0.6 mm Hg, respectively) after mexiletine. Cardiac performance declined with mexiletine (cardiac and stroke work indexes decreasing -0.3 +/- 0.1 L/min/m2 and -5 +/- 1 gm.m/m2, respectively), but there was no significant change in cardiac or stroke work indexes with quinidine (+0.1 L/min/m2 and -0.3 +/- 0.9 gm.m/m2, respectively). The response to the two agents significantly differed for all parameters measured (p less than 0.005). These hemodynamic changes were accompanied by clinical effects. Mexiletine induced increased dyspnea in five patients and quinidine led to symptomatic hypotension in two patients. Plasma concentrations of mexiletine and serum concentrations of quinidine were within or below the therapeutic range in all patients. In conclusion, mexiletine and quinidine exert different hemodynamic effects when given to patients with severe congestive heart failure.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral

Acute hemodynamic and arrhythmogenic effects of high-dose intravenous salbutamol in patients with chronic left ventricular dysfunction.

The short-term hemodynamic and possible arrhythmogenic effects of intravenous salbutamol at a dose of 30 or 60 micrograms/min were evaluated in 14 patients with severe chronic left ventricular dysfunction using equilibrium radionuclide angiocardiography and electrocardiographic monitoring. Salbutamol infusions at a dose of 30 micrograms/min did not cause significant hemodynamic changes; however, at a dose of 60 micrograms/min there was a significant increase in stroke volume, cardiac output, and left ventricular ejection fraction. Heart rate increased significantly while systemic peripheral resistance decreased significantly. Two patients developed ventricular premature beats and another two supraventricular tachycardia, but none were associated with adverse consequences. Thus, high-dose intravenous salbutamol is effective and safe, and may be used in the acute management of patients with poor left ventricular function.

Adult

Short-term haemodynamic evolution and late follow-up of post-infarct patients with left ventricular dysfunction undergoing a physical training programme.

The aims of this study were to investigate the short-term haemodynamic changes occurring in post-infarct patients with left ventricular dysfunction undergoing a physical training programme and the prognostic implications of such changes. Ninety-five male patients with no evidence of congestive heart failure, consecutively admitted for exercise testing with haemodynamic monitoring in the supine position, in whom exercise pulmonary artery diastolic pressure (PAdP) exceeded 20 mmHg were enrolled in an in-hospital one-month physical training programme. After training all patients' exercise capacity increased by 24% (P less than 0.001) with no change of PAdP. At matched work load, heart rate decreased (126 +/- 21 vs 120 +/- 19 bt min-1, P less than 0.05) as did PAdP (27 +/- 5 vs 25 +/- 6 mmHg, P less than 0.05) and A-VO2 difference increased (9.5 +/- 1.7 vs 10 +/- 1.6 ml%, P less than 0.01). Similar results were observed in a subset of patients with exercise PAdP greater than 30 mmHg (30 patients). In 11 patients with inadequate cardiac output neither heart rate nor PAdP decreased after training and a disproportionate increase in blood pressure was noted. Clinical follow-up ranged from 1 to 8 years (62 +/- 32 months). Seven deaths, 12 reinfarctions and 14 coronary artery bypass graftings occurred. The modifications, after training in work capacity, heart rate and PAdP, were not predictive of events.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult

Long-term treatment of ventricular tachycardia with amiodarone in presence of severe left ventricular dysfunction.

A group of 34 consecutive patients with coronary artery disease (n = 29) or dilated cardiomyopathy (n = 5) (3 women, 31 men, age 38-80 yr) who had severely impaired left ventricular function (left ventricular ejection fraction less than or equal to 40%) and high-grade ventricular ectopic activity (sustained or nonsustained ventricular tachycardia or ventricular fibrillation) were treated with amiodarone (mean dose: 206 mg/d) and followed for 1-117 (mean: 49) months. In the total group, there were seven sudden deaths, five deaths due to pump failure, one non-cardiac death, and two successful heart transplantations during follow-up. Thus the annual cardiac mortality in these carefully selected and followed patients was 8, 6%, the annual cardiac event rate was 10, 1%. The cumulative cardiac survival-rate was 62% after 5 years and 41% after 10 years. In five patients, treatment was interrupted after 10 to 43 months, three of the patients were alive at follow-up and two suffered cardiac death, resulting in an annual cardiac death rate of 12% in this subgroup of treatment. Based on the results of this retrospective analysis we conclude that in patients with low left ventricular ejection fraction and nonsustained or sustained ventricular tachycardia treated with low dose amiodarone, mortality was unexpectedly low. Thus, it may be the antiarrhythmic treatment to be considered in patients with ventricular tachycardia and severe left ventricular dysfunction.

Adult

Hemodynamic effects of intravenous pimobendan in patients with left ventricular dysfunction.

Sequential hemodynamic effects of intravenous pimobendan (UD-CG 115 BS), a novel compound with positive inotropic and vasodilating properties, were investigated during left heart catheterization in nine patients with left ventricular dysfunction (ejection fraction less than or equal to 40%) and moderate congestive heart failure (NYHA classes II and III). Studies were carried out before (C) and for 60 min after intravenous administration of 5 mg of pimobendan over 1 min. Pimobendan immediately and progressively reduced systemic resistance [16 and 28% at 10 and 60 min postdrug, respectively (p less than 0.05 vs. C)] and left ventricular end diastolic pressure [from 24 +/- 3 (C) to 12 +/- 3 mm Hg at 60 min, p less than 0.001)]. Cardiac output gradually increased by 24%, but stroke volume did not, due to an equally progressive 14% rise in heart rate, whereas stroke work increased by 21% (all p less than 0.05 vs. C). Both contractility and relaxation, measured at fixed heart rates, significantly improved by 30 and 20%, respectively, at 50 min postdrug. Thus, pimobendan has immediate and prolonged arterial vasodilating effects, together with positive inotropic and lusitropic properties, resulting in an early but sustained improvement of left ventricular pump function and filling pressures.

Aged

Hemodynamic comparison of dopexamine hydrochloride and dopamine in ischemic left ventricular dysfunction.

The hemodynamic dose-response effects of intravenous dopexamine hydrochloride (0.5 to 2.0 micrograms/kg/min) have been compared with dopamine (2.5 to 10 micrograms/kg/min) in 12 patients with ischemic left ventricular dysfunction in an open randomized crossover study. Both drugs increased cardiac output and decreased systemic vascular resistance. Dopexamine hydrochloride appeared to increase heart rate more than dopamine although this did not reach statistical significance. Dopexamine hydrochloride produced small increases in systolic and decreases in diastolic blood pressure, whereas dopamine had a biphasic effect resulting in a decrease in mean blood pressure at low doses and an increase at the highest dose studied. With increasing dosage, there was a trend toward more vasodilator activity with dopexamine hydrochloride than with dopamine. Dopexamine hydrochloride produced fewer adverse effects than dopamine.

Adult