A simplified method for determining regurgitant fraction by Doppler echocardiography in patients with aortic regurgitation.

OBJECTIVES: This study attempted to develop and validate a simple method for calculating aortic regurgitant fraction by use of pulsed wave Doppler echocardiography. BACKGROUND: Although several investigators have been able to determine aortic regurgitant fraction by Doppler echocardiography, the methods used require accurate determination of the cross-sectional areas of intracardiac sites at which the volumetric flow is calculated. METHODS: Our concept was based on a constant relation that exists between the cross-sectional area of the left ventricular outflow tract and the mitral valve annulus in normal subjects. To verify this, we used Doppler echocardiography to measure the flow velocity integral of the left ventricular outflow tract and the mitral annulus in the apical view in 50 normal subjects (32 men, 18 women, mean age 34 years). RESULTS: Close correlation (r = 0.95) was observed between the flow velocity integral (FVI) of the outflow tract (OT) and that of the mitral annulus (MA): FVIMA/FVIOT = 0.77. Because mitral flow equals aortic flow in normal subjects, the ratio of the cross-sectional area of the mitral annulus to that of the outflow tract was 1/0.77. In patients with aortic regurgitation, the regurgitant fraction (RF) = (Aortic flow-Mitral flow)/Aortic flow = 1-Mitral flow/Aortic flow. Substituting 0.77 for the area component of flow, RF = 1-(1/0.77).(FVIMA/FVIOT). To evaluate the accuracy of this method, we compared the regurgitant fraction derived by Doppler echocardiography with that from catheterization findings in 20 patients with aortic regurgitation (an isolated lesion was found in 14). The regurgitant fraction by catheterization was the difference between total (angiographic) and forward (thermodilution) stroke volumes as a percent of total flow. Good correlation was observed between catheterization and Doppler regurgitant fraction (r = 0.88, SEE 9%, p < 0.01). CONCLUSIONS: Thus, regurgitant fraction can be estimated from Doppler echocardiography in patients with aortic regurgitation by a method that requires only measurements of the flow velocity integral from the mitral annulus and left ventricular outflow tract.

Prognostic value of Doppler transmitral flow patterns in patients with congestive heart failure.

OBJECTIVES: This study was designed to determine whether Doppler echocardiographic transmitral flow patterns can predict cardiac mortality in patients with congestive heart failure. BACKGROUND: Previous studies have indicated that Doppler transmitral flow patterns are related to New York Heart Association functional class and exercise capacity in patients with congestive heart failure. However, the prognostic significance of these flow patterns is not known. METHODS: We analyzed the relation of transmitral flow patterns and cardiac mortality in 100 consecutive patients (76 men, 24 women; mean [+/- SD] age 60 +/- 11 years) with congestive heart failure symptoms and left ventricular ejection fraction < 40%. At the time of entry into the study, functional class and ejection fraction by radionuclide angiography were determined, and Doppler echocardiography was performed in all patients. Transmitral flow was obtained from the apical four-chamber view at the mitral annulus level. Measurements included early (E) and atrial (A) filling velocities, E/A ratio and deceleration time of the E wave. The patients were assigned to two groups according to E/A ratio or deceleration time of transmitral flow patterns, or both: a non-restrictive group (42 patients) with E/A < or = 1 or E/A = 1 to 2 and deceleration time > 140 ms, and a restrictive group (58 patients) with E/A > or = 2 or E/A = 1 to 2 and deceleration time < or = 140 ms. RESULTS: Of 100 patients, 26 died during a mean follow-up period of 16 +/- 8 months. The cumulative cardiac mortality rate determined by the Kaplan-Meier method was 14% at 1 year and 35% at 2 years. Cox proportional hazards model analysis revealed that transmitral flow (restrictive vs. nonrestrictive, chi-square 6.99, p = 0.008), patient gender (female vs. male, chi-square 4.59, p = 0.03) and New York Heart Association functional class (IV vs. II, chi-square 3.95, p = 0.05) were significantly related to cardiac mortality in patients with congestive heart failure. Mortality rate in the restrictive group was markedly higher than that in the nonrestrictive group at 1 year (19% vs. 5%, respectively, p < 0.05) and at 2 years (51% vs. 5%, respectively, p < 0.01) by log-rank test. Relative risk for cardiac death was estimated as 4.1 at 1 year and 8.6 at 2 years in the restrictive group compared with the nonrestrictive group. CONCLUSIONS: In patients with congestive heart failure, a restrictive transmitral flow pattern, female gender and advanced functional class are predictive of higher cardiac mortality. The restrictive transmitral flow pattern by Doppler echocardiography is the single best clinical predictor for cardiac death in patients with congestive heart failure.

Influence of alterations in loading produced by lower body negative pressure on aortic blood flow acceleration.

The objectives of this study were to evaluate the effects of alterations in loading induced by lower body negative pressure on aortic blood flow velocity and acceleration. Twenty-seven normal men were studied during various levels of lower body negative pressure (0 to -60 mm Hg) during which echocardiographic, Doppler and hormonal measurements were obtained. Lower body negative pressure induced a decrease in left ventricular diastolic diameter from 5.18 +/- 0.08 to 4.41 +/- 0.1 cm (p less than 0.0001) and in left ventricular systolic diameter from 3.33 +/- 0.09 to 2.84 +/- 0.1 cm (p less than 0.0001). Shortening fraction remained unchanged. The decrease in diastolic diameter resulted in a reduction in flow velocity integral from 13.8 +/- 0.8 to 7.5 +/- 0.4 cm (p less than 0.0001) and, therefore, in stroke volume from 89.6 +/- 4.7 to 49.5 +/- 2.8 ml (p less than 0.0001). Heart rate reflexly increased from 62.5 +/- 1.9 to 82.2 +/- 2.3 beats/min (p less than 0.0001) as did systemic vascular resistance from 1,280.8 +/- 69.5 to 1,863.4 +/- 121.4 dyne.s.cm-5 (p less than 0.0001). The increase in heart rate was insufficient to maintain cardiac output, which decreased from 5.53 +/- 0.29 to 3.99 +/- 0.21 liters/min (p less than 0.0001). Systolic, diastolic and mean arterial blood pressure was maintained. The negative pressure resulted in a concomitant significant increase in norepinephrine levels from 1.46 +/- 0.09 to 2.056 +/- 0.2 nmol/liter (p = 0.0019) but no change in plasma epinephrine: 0.845 +/- 0.22 to 0.78 +/- 0.11 nmol/liter (p = NS).(ABSTRACT TRUNCATED AT 250 WORDS)

Reduction of left ventricular preload by lower body negative pressure alters Doppler transmitral filling patterns.

The objective of this study was to evaluate the effect of alterations in preload induced by lower body negative pressure on Doppler transmitral filling patterns. Echocardiograms and Doppler recordings were performed in 18 normal young men (aged 23 to 32 years) during various levels of lower body negative pressure (0, -20 and -50 mm Hg). Lower body negative pressure induced a reduction in diastolic velocity integral (from 12.17 +/- 0.79 to 8.42 +/- 0.71 cm, p = 0.0067) and consequently left ventricular diastolic diameter (from 5.11 +/- 0.09 to 4.45 +/- 0.1 cm, p less than 0.0001). There was a significant reflex increase in heart rate from 59.9 +/- 1.9 to 77.1 +/- 2.4 beats/min (p less than 0.0001), but blood pressure was unchanged. This reduction in preload altered Doppler transmittral filling patterns as follows: 1) peak early velocity (E) decreased from 59.2 +/- 3.8 to 39.1 +/- 1.7 cm/s (p less than 0.0001); 2) atrial filing velocity (A) was unchanged (35.58 +/- 1.5 to 33.52 +/- 1.4 cm/s, p = 0.517); 3) E/A ratio decreased from 1.7 +/- 0.13 to 1.19 +/- 0.08 (p = 0.0087); 4) mean acceleration (from 482 +/- 37 to 390 +/- 27 cm/s2, p = 0.03) and mean deceleration (from 327 +/- 31 to 169 +/- 21 cm/s2, p less than 0.001) of the early filling wave were significantly reduced; and 5) peak acceleration (from 907 +/- 42 to 829 +/- 29 cm/s2) and peak deceleration (from 771 +/- 94 to 547 +/- 76 cm/s2) also decreased, but not significantly.(ABSTRACT TRUNCATED AT 250 WORDS)

Baroreceptor sensitivity in prehypertensive young adults.

Decreased baroreceptor reflex sensitivity has been implicated in the pathogenesis of hypertension. The purpose of this study is to determine if alterations of baroreceptor function precede the development of hypertension in humans. Baroreceptor function was evaluated in 13 young adult white men with relatively high blood pressures sustained for 12 to 15 years and 12 age-matched men with sustained relatively low blood pressures. High pressure baroreceptor activity was evaluated by measuring change in pulse interval in response to decreases and increases of arterial pressure, induced by graded infusions of nitroprusside and angiotensin II, respectively. In response to both agents, baroreceptor slopes did not differ in the high and low blood pressure groups. Plasma norepinephrine also increased similarly in both blood pressure groups in response to nitroprusside. To study low-pressure baroreceptor function, responses to graded levels of lower-body negative pressure (LBNP) were measured. Comparing both blood pressure groups, there were similar increases of heart rate, total peripheral resistance, and plasma norepinephrine in response to LBNP. Both blood pressure groups also had similar increases of heart rate and blood pressure in response to isometric (handgrip) exercise. Thus, high-pressure and low-pressure baroreceptor function is not altered in prehypertensive young adults. However, continued follow-up will be required to determine if these individuals with sustained relatively high blood pressures are truly prehypertensive.

Reversible thallium-201 perfusion defects of the septal and inferoapical segments in a patient with incomplete right bundle branch block and normal coronary angiogram.

Possible causes of reversible perfusion defect in exercise-rest 201Tl myocardial images in a patient with a normal coronary artery angiogram include left bundle branch block, coronary spasm, myocardial bridges, hypertrophic cardiomyopathy, mitral valve prolapse, aortic valve disease and anomalous origin of the left coronary artery arising from the pulmonary artery. This case is a report of a 34-yr-old man with incomplete right bundle branch block and angiographically normal coronary arteries who was found to have reversible defects involving septal and inferoapical walls on stress-rest 201Tl-chloride myocardial imaging.

Beneficial effect of atrial pacing in severe acute aortic regurgitation and role of M-mode echocardiography in determining the optimal pacing interval.

The effect of atrial pacing on cardiac performance was assessed in 11 men (aged 20 to 64 years) with recent-onset severe aortic regurgitation (AR), all of whom had diastolic closure of the mitral valve on the echocardiogram. Thermodilution cardiac outputs were determined, and aortic, left ventricular and pulmonary arterial wedge pressures recorded. Once baseline recordings were completed, the pacing rate was increased by increments of 10 beats/min (70, 80, 90...) to a maximal rate of 140 beats/min. The optimal pacing interval, obtained from hemodynamic data, was defined as that at which the lowest filling pressure was associated with the highest cardiac index. This was then compared with a pacing interval derived from the R wave of the electrocardiogram to the diastolic mitral closing point on the M-mode echocardiogram. Such an interval would shorten diastole without affecting forward mitral flow. Atrial pacing improved the overall hemodynamic state in all patients; the most favorable hemodynamics were achieved at heart rates between 110 and 130 beats/min (mean: 120 +/- 8). At the optimal rate, left ventricular end-diastolic pressure decreased from 46 +/- 7 to 23 +/- 12 mm Hg (p less than 0.001), and the pulmonary arterial wedge pressure from 28 +/- 8 to 16 +/- 7 mm Hg (p less than 0.001), while the cardiac index increased from 2.34 +/- 0.46 to 2.63 +/- 0.49 liters/min/m2 (p less than 0.01). The mean difference between the optimal pacing interval determined from the hemodynamic data and the interval derived from the echocardiogram was 18 +/- 21 ms.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of blood pressure and afterload on Doppler echocardiographic measurements of left ventricular systolic function in normal subjects.

Doppler echocardiographic measurements of blood flow velocity and acceleration in the ascending aorta have been shown to be useful descriptors of left ventricular (LV) systolic function. Few data exist, however, regarding the influence of loading conditions, particularly afterload, on these Doppler measurements in human subjects. Therefore, 14 normal volunteers (mean age 28 years) were studied using continuous wave Doppler echocardiography performed from the suprasternal notch both at baseline and during a controlled infusion of methoxamine. LV peak systolic (delta pk) and end-systolic (delta ES) wall stresses were calculated noninvasively using blood pressure and echocardiographic dimensions. Heart rate was kept constant by transesophageal atrial pacing. Methoxamine resulted in significant increases in mean systolic (163 +/- 8 vs 129 +/- 10 mm Hg) and diastolic (93 +/- 7 vs 71 +/- 12 mm Hg) blood pressure, as well as delta pk (277 +/- 25 vs 222 +/- 40 g/cm2 x 10(3] and delta ES (97 +/- 26 vs 77 +/- 19 g/cm2 x 10(3] (p less than or equal to 0.0004 for all). Conversely, peak velocity decreased from 0.91 +/- 0.18 m/s at baseline to 0.8 +/- 0.18 m/s (p less than or equal to 0.002) and peak acceleration decreased from 22 +/- 5 m/s2 at baseline to 19 +/- 5 m/s2 (p less than or equal to 0.006) during methoxamine infusion. Flow velocity integral and LV end-diastolic dimension remained unchanged. Thus, aortic flow velocity and peak acceleration are inversely related to afterload. This relation should be considered when using serial determinations of these Doppler parameters for patients in whom changing levels of afterload might occur.

Maternal and fetal sequelae of anticoagulation during pregnancy in patients with mechanical heart valve prostheses.

Previous reports indicate an increased risk of thrombotic and embolic events in patients with mechanical heart valve prostheses during pregnancy. We prospectively followed 50 pregnancies in 49 patients with 62 cardiac prostheses from presentation at the antenatal clinic through the remainder of the pregnancy. Of the 60 mechanical prostheses, 39 were Medtronic-Hall, 7 St. Jude Medical, 7 Starr-Edwards and 7 Björk-Shiley. Forty-three patients were in New York Heart Association functional class I or II and 6 were in functional class III or IV. Forty-five patients were in sinus rhythm and 4 had chronic atrial fibrillation. All patients received warfarin during the first and second trimesters. Forty-one pregnancies proceeded beyond 28 weeks. In 23 of these (group I) warfarin was replaced with heparin at 36 weeks gestation. In the remaining 18 (group II) warfarin was not substituted owing to premature onset of labor. The target prothrombin ratio (international normalized ratio) in patients receiving warfarin was 2.0 to 2.5. The partial thromboplastin time was maintained at 1.5 to 2.5 times the control value in patients receiving heparin. Eleven patients received dipyridamole plus warfarin for the duration of pregnancy. There were no maternal thromboembolic complications or deaths associated with pregnancy. Antepartum hemorrhage occurred in 1 patient at 35 weeks gestation. One patient (group I) experienced peripartum hemorrhage. All patients were hemodynamically stable before delivery, but 2 developed pulmonary edema during labor. The mean fetal birth weight was low (2.54 +/- 0.98 kg). There were 9 abortions (18%), 7 stillbirths (14%), 2 neonatal deaths (4%) and 2 instances of warfarin embryopathy (4%).(ABSTRACT TRUNCATED AT 250 WORDS)

Quantification of mitral regurgitant volume by the color Doppler proximal isovelocity surface area method: a clinical study.

In vitro studies have demonstrated that regurgitant flow rate can be estimated by the color Doppler "proximal isovelocity surface area" (PISA) method. By applying the PISA method and continuity principle, we developed a formula to calculate mitral regurgitant volume: 2 pi r2.VN.FVI/Vo, where r = distance from the first jet alias to mitral leaflets, VN = aliasing velocity, FVI = flow velocity integral or regurgitant jet, and Vo = peak velocity through the regurgitant orifice. Doppler echocardiography was performed in 20 patients with mitral regurgitation. The mitral regurgitant volume was estimated by PISA and compared to cine ventriculographic grading. The results showed an increase in regurgitant volume by PISA compared with increasing angiographic grades of mitral regurgitation: 19 +/- 0.6, 18 +/- 5, 25 +/- 12, and 44 +/- 4 ml for grades 1+ to 4+, respectively (r = 0.77). Thus a formula developed from PISA is able to identify patients with a severe grade of mitral regurgitation and to provide an alternate approach to the noninvasive quantitation of mitral regurgitation.

Comparative efficacy of short-term intravenous infusions of milrinone and dobutamine in acute congestive heart failure following acute myocardial infarction. Milrinone-Dobutamine Study Group.

The purpose of this study was to compare the hemodynamic and clinical effects of milrinone, a vasodilating and positive inotropic agent, with those of dobutamine in patients with congestive heart failure (CHF) following acute myocardial infarction (AMI). Thirty-three patients in Killip classification II or III within 12 h to 5 days after AMI were randomized in a multicenter, open-label clinical trial to receive a 24-h infusion of milrinone or dobutamine. Drugs were titrated to achieve at least a 30% increase in cardiac index (CI) from mean baseline or at least a 25% decrease in mean pulmonary capillary wedge pressure (MPCWP) from baseline. Both drugs improved CI, MPCWP, and other hemodynamic parameters. Criteria for decrease in MPCWP were met by 94% (15/16) of the milrinone-treated patients and 57% (8/14) of dobutamine-treated patients (p = 0.03). Both groups met the minimum efficacy criterion for CI. Maximal reduction in MPCWP over 0-3 h was greater in the milrinone group (-53.2%) than in the dobutamine group (-31.0%; p < or = 0.01); reductions were sustained over 24 h. Both drugs improved echocardiographic global ejection fraction and were generally well tolerated. The short-term infusion of milrinone may have a role in the management of CHF following AMI, especially when the aim is the rapid reduction of pulmonary congestion.

Non-typhoid salmonella infections after renal transplantation. A serious clinical problem.

A retrospective study of 410 renal transplant recipients showed that 1.96% (8/410) of patients had developed severe non-typhoid salmonella infections. The clinical features seen were fever, leucopenia, pneumonia, diarrhoea, abscesses, pyelonephritis, venous thrombosis and pleural effusion. Neither uraemia nor repeated high doses of steroids seemed to be major precipitating events. All isolates were strains of Salmonella enteritidis. All 8 patients were cured and none became permanent carriers. Salmonella infections cause severe, life-threatening infections in renal transplant patients and require vigorous treatment often with a long-term low-dose regimen. Patients seemed to respond best to chloramphenicol, but ampicillin and co-trimoxazole were useful in some. Bilateral nephrectomy should be performed before the transplantation if the organism is grown from the urine.

Relation of Doppler transmitral flow patterns to functional status in congestive heart failure.

We analyzed the relation of Doppler transmitral flow patterns and New York Heart Association (NYHA) classification in 60 consecutive patients with heart failure (44 men and 16 women; mean age 58 +/- 13 years) with left ventricular ejection fraction of < 40 percent. Of the study population, 40 patients with mild to moderate heart failure underwent symptom-limited exercise testing. The relation of transmitral flow pattern and exercise tolerance was also analyzed. Doppler echocardiography was performed in all patients. The patients were subdivided into nonrestrictive and restrictive groups according to the pattern. The univariate analysis showed a relation for left ventricular ejection fraction (p = 0.01 by analysis of variance testing) and transmitral flow pattern (p = 0.0003 by chi-squared test) with NYHA classification. When the multivariate regression analysis was performed, only the restrictive pattern by Doppler emerged as an independent determinant of the advanced NYHA class (p = 0.005). In mild to moderate congestive heart failure, patients with nonrestrictive pattern exercised significantly longer than those with the restrictive pattern by an average of 133 seconds (p = 0.003) despite comparable reductions in ejection fraction. Thus the restrictive transmitral flow pattern by Doppler is a noninvasive marker for severe symptoms and diminished exercise tolerance in heart failure patients.

Doppler echocardiographic evaluation of diastolic dysfunction.

Recently, considerable effort has been directed toward the application of Doppler methods for detecting diastolic dysfunction. Recordings of transmitral filling velocity as obtained from pulsed-wave Doppler have been extensively investigated as a noninvasive method for determining left ventricular diastolic filling properties. Although Doppler parameters appear to reflect volumetric transmitral flow, close correlations with invasive descriptors of diastolic performance have not been found. Furthermore, Doppler transmitral velocities are sensitive to changes in ventricular preload, afterload, and heart rate. However, at least two distinct Doppler spectral patterns have been identified that are associated with impaired ventricular relaxation and restrictive physiology. Thus, Doppler recordings have proven to be of value in identifying the presence and type of diastolic dysfunction, and in the future they may be helpful in following the response to therapeutic interventions. The purpose of this paper is to review the available information relating Doppler transmitral recordings with catheterization and clinical descriptors of diastolic function. Additionally, the aim is to provide an understanding of the value and limitations of these noninvasive measurements in identifying and treating patients with diastolic abnormalities.

Left atrial function in congestive heart failure: assessment by transmitral and pulmonary vein Doppler.

The relation of transmitral flow patterns and pulmonary venous velocities was analyzed from 50 heart failure patients (28 men, 22 women; mean [+/- SD] age 61 +/- 9 years) with a left ventricular ejection fraction < 40%. Doppler echocardiography was performed in all patients. Transmitral flow measurements included early (E) and atrial (A) velocities and deceleration time of E wave (DT). Patients were assigned to two groups according to E/A ratio, DT, or both: 20 patients in the restrictive group, and 30 patients in the nonrestrictive group. Pulmonary venous flow was obtained by the transthoracic approach. Systolic (S), diastolic (D) and atrial reversal (Ar) velocities were measured. Of the study population, 13 patients had simultaneously determined pulmonary capillary wedge pressure (PCWP). The results showed a lower S (28 +/- 11 vs. 51 +/- 10 cm/sec, p < 0.01), a higher D (66 +/- 13 vs. 44 +/- 10 cm/sec, p < 0.01) and a smaller Ar (12 +/- 10 vs. 24 +/- 9 cm/sec, p < 0.01) in the restrictive group compared with those in nonrestrictive group. In the subgroup of patients undergoing invasive hemodynamic studies, there was no relationship between PCWP and atrial reversal velocity. However, a significant correlation was observed for pulmonary systolic (r = -0.70, p < 0.01) and diastolic (r = 0.76, p < 0.01) velocities to PCWP. These findings suggest a reduction in left atrial compliance and atrial systolic function and both play important roles in heart failure patients with the restrictive transmitral flow pattern.

Relation of echocardiographic morphology of the mitral apparatus to mitral regurgitation in mitral valve prolapse: assessment by Doppler color flow imaging.

Few data exist regarding the relationship of valvular anatomy and coaptation to the presence of mitral regurgitation (MR) in patients with mitral valve prolapse (MVP). Therefore this study was undertaken to assess the ability of two-dimensional echocardiographic features of mitral valve morphology to predict the presence, direction, and magnitude of MR as assessed by color Doppler flow imaging. MR was present in 21 of 46 patients with MVP on two-dimensional echocardiography. Echocardiograms were specifically evaluated for leaflet apposition, leaflet morphology, and mitral anulus diameter. Color flow images were analyzed for presence of MR, direction of the regurgitant jet, and area encompassing the largest jet visible in any view. Abnormal mitral leaflet coaptation on two-dimensional echocardiography was strongly associated with the presence of MR (p = 0.003), being present in 15 of 21 patients with as compared with 5 of 25 patients without MR. Similarly, mitral leaflet thickness and MR were closely associated (p = 0.0035), with the latter being present in 9 of 30 patients with normal and 12 of 16 patients with excessive leaflet thickness. MR jet direction tended to be anterior to central with posterior leaflet prolapse and posterior or central with anterior leaflet prolapse (p = 0.02). Maximal jet area of MR tended to be larger in patients with compared with those without mitral annular dilatation (5.4 +/- 2.3 versus 2.1 +/- 1.9 cm2, p = 0.001), and in those with abnormal rather than normal leaflet thickness (4.5 +/- 2.7 versus 2.0 +/- 1.6 cm2, p = 0.009). Thus the presence, direction, and size of MR jets in MVP are related to structural abnormality of the mitral apparatus on echocardiography.

Pulsed Doppler and two-dimensional echocardiographic findings in coronary arteriovenous fistula complicated by bacterial endocarditis. A case report.

Coronary arteriovenous fistula (CAVF) may occasionally be complicated by bacterial endocarditis. The actual anatomical site of infection has not been clearly defined. A 13-year-old boy with a CAVF and Streptococcus viridans bacteraemia is described. The origin of the fistulous tract and a vegetation in close proximity to the distal drainage site into the right ventricle was demonstrated by Doppler two-dimensional echocardiography.

Can further benefit be achieved by adding flosequinan to patients with congestive heart failure who remain symptomatic on diuretic, digoxin, and an angiotensin converting enzyme inhibitor? Results of the flosequinan-ACE inhibitor trial (FACET).

BACKGROUND: Angiotensin converting enzyme inhibitors, diuretics, and digoxin are each effective in treating congestive heart failure, but many patients remain symptom-limited on all three medications. This trial was designed to determine whether the addition of oral flosequinan, a new direct-acting arterial and venous vasodilator with possible dose-dependent positive inotropic effects, improves exercise tolerance and quality of life in such patients. METHODS AND RESULTS: In a randomized, double-blind multicenter trial, 322 patients with predominantly New York Heart Association class II or III congestive heart failure and left ventricular ejection fractions of 35% or less, who were stabilized on a diuretic, angiotensin converting enzyme inhibitor, and digoxin, were treated with 100 mg flosequinan once daily, 75 mg flosequinan twice daily, or matching placebo. Efficacy was evaluated with serial measurements of treadmill exercise time, responses to the Minnesota Living With Heart Failure Questionnaire (LWHF), and clinical assessments during a baseline phase and a 16-week treatment period. After 16 weeks, 100 mg flosequinan once daily produced a significant increment in median exercise time (64 seconds at 16 weeks) compared with placebo (5 seconds), whereas the higher-dose flosequinan group did not show a statistically significant increase. Flosequinan (100 mg once daily) also improved the overall LWHF score significantly compared with placebo; both active therapies decreased the physical component, but 75 mg flosequinan twice daily was associated with a trend toward worsening of the emotional component. Most clinical assessments tended to improve on active therapy. CONCLUSIONS: These results indicate that additional symptomatic benefit can be attained by adding flosequinan to a therapeutic regimen already including a converting enzyme inhibitor. Because in the future most patients will fall into this category, flosequinan is a potential adjunctive agent in the management of severe congestive heart failure. However, because recent evidence indicates that the flosequinan dose studied in the present trial has an adverse effect on survival, the benefit-to-risk ratio must be assessed in individual patients.