A multicenter, randomized, double-blind, placebo-controlled trial of pimobendan, a new cardiotonic and vasodilator agent, in patients with severe congestive heart failure.

Pimobendan, a new oral cardiotonic and vasodilator agent, increases myocardial contractile force through specific inhibition of phosphodiesterase type III and increased calcium sensitivity of the myocardial contractile elements. The effects of pimobendan on left ventricular performance and maximal exercise capacity were studied in a multicenter, randomized, double-blind, placebo-controlled trial involving 52 patients with severe congestive heart failure despite diuretics, digoxin, and angiotensin-converting enzyme inhibitors. The acute hemodynamic evaluation included three single doses of 2.5, 5.0, and 10.0 mg of oral pimobendan, which was subsequently administered at a daily dose of 5 or 10 mg for 4 weeks. Acute administration of pimobendan significantly increased the resting cardiac index and lowered pulmonary capillary wedge pressure in a dose-dependent manner, whereas heart rate and systemic arterial pressure were not substantially altered. Patients receiving pimobendan, 5 and 10 mg daily, had a significantly greater increase in maximal exercise duration than those receiving placebo, that is, 144 +/- 30 and 124 +/- 33 seconds versus 58 +/- 25 seconds (p = 0.05). Peak oxygen uptake increased by 1.7 +/- 0.8 and 2.2 +/- 1.3 ml/kg/min in patients receiving pimobendan at a daily dose of 5 and 10 mg, respectively, whereas it decreased by 0.1 +/- 0.6 ml/kg/min in patients receiving placebo (p = 0.06). Thus pimobendan acutely improves resting left ventricular performance and chronically increases exercise duration and peak oxygen uptake in patients with severe congestive heart failure concomitantly treated with digoxin, diuretics, and angiotensin-converting enzyme inhibitors.     

Assessment of patient outcome with the Minnesota Living with Heart Failure questionnaire: reliability and validity during a randomized, double-blind, placebo-controlled trial of pimobendan. Pimobendan Multicenter Research Group.

To determine the reliability and validity of a patient outcome questionnaire for chronic heart failure, a randomized, double-blind, placebo-controlled, 3-month trial of pimobendan, an investigational medication with inotropic and vasodilator activities, was performed. Evaluated were 198 ambulatory patients with primarily New York Heart Association (NYHA) class III heart failure from 20 referral centers. Baseline therapy included digoxin, diuretics and, in 80%, a converting enzyme inhibitor. Oral pimobendan at 2.5 (n = 49), 5.0 (n = 51), or 10 (n = 49) mg daily or matching placebo (n = 49) was administered. The Minnesota Living with Heart Failure (LIhFE) questionnaire was a primary outcome measure, along with an exercise test. Interitem correlations identified subgroups of questions representing physical and emotional dimensions. Repeated baseline scores were highly correlated (r = 0.93), as were the physical (r = 0.89) and emotional (r = 0.88) dimension scores. Placebo did not have a significant effect with median (25th, 75th percentile) changes from baseline scores of 1 (-3, 5), 1 (-2, 3), and 0 (-1, 2), respectively (all p values greater than 0.10). The 5 mg dose significantly improved the total score, 7.5 (0, 18; p = 0.01) and the physical dimension, 4 (0, 8; p = 0.01), compared with placebo. Changes in the total (r = 0.33; p less than 0.01) and physical (r = 0.35; p less than 0.01) scores were weakly related to changes in exercise times, but corresponded well with changes in patients' ratings of dyspnea and fatigue.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pimobendan (UDCG 115 BS) in long-term therapy of chronic heart failure]

Pimobendan is a positive inotropic agent with additional calcium-sensitizing effects of the phosphodiesterase III-inhibitor group. In short-term studies, beneficial hemodynamic effects have been demonstrated in patients with congestive heart failure. The aim of this prospective study was to examine the long-term effect of pimobendan (during at least 6 months) on subjective state, hemodynamic parameters, and arrhythmias in patients with congestive heart failure NYHA classes II and III. After double-blind randomization, 24 patients received pimobendan 5 mg bid or placebo orally in addition to a basic therapy (diuretics, digitalis). After 3 months, pimobendan-treated patients showed a significant clinical improvement (p < 0.03). In the placebo group, one patient underwent acute cardiac transplantation due to rapid clinical deterioration; another patient died suddenly after 5 months. No cardiac events occurred in the pimobendan group. In comparison to placebo, no proarrhythmogenic effect of pimobendan was detected. Clinical stabilization of patients in the pimobendan group was not paralleled by improvement of the hemodynamic parameters of left-ventricular performance.     

Hemodynamic effects of pimobendan given orally in congestive heart failure secondary to ischemic or idiopathic dilated cardiomyopathy

Pimobendan (UD-CG 115 BS) was administered orally to 23 patients with congestive heart failure (functional class IV) caused by coronary artery disease (11 patients) or idiopathic dilated cardiomyopathy (12). All patients received maintenance doses of digoxin, furosemide and warfarin. Baseline data, collected during 15 hours, stayed within a 10% range. A 10-mg oral dose of pimobendan increased the heart rate from 95 +/- 20 to 109 +/- 24 beats/min (p less than 0.003). The pulmonary artery wedge pressure decreased from 23.0 +/- 5.9 to 10.1 +/- 5.2 mm Hg (p less than 0.0001), the cardiac index increased from 1.9 +/- 0.4 to 3.3 +/- 0.7 liters/min/m2 (p less than 0.0001) and the left ventricular stroke work index increased from 2,005 +/- 927 to 3,065 +/- 1,161 ml/mm Hg/m2 (p less than 0.0001). Statistically significant improvements in hemodynamic variables were still present 10 hours after the administration of pimobendan. Most patients felt better and reported no angina or other side effect, the incidence of ventricular arrhythmias was unchanged and no electrocardiographic changes suggesting ischemia were observed. Patients with severe congestive heart failure experienced a prolonged improvement of their cardiovascular condition after a single dose of pimobendan.     

The prognostic value of functional capacity in patients with mild to moderate heart failure

Thirty patients with ischemic (n = 14) or idiopathic dilated (n = 16) cardiomyopathy were followed long-term to determine the prognostic value of measuring entry exercise capacity. At the time of referral for management of symptomatic heart failure, studies included radionuclide angiography, M-mode echocardiography, 24-hour Holter and graded exercise testing with measured oxygen peak consumption (peak VO2). Inclusion criteria were NYHA class II (n = 16) or III (n = 14) despite at least 3 months of treatment with digitalis and diuretics, left ventricular ejection fraction less than 50%, left ventricular end-diastolic diameter (LVEDD) greater than 50 mm, and exercise capacity limited by dyspnea or fatigue. Patients were treated with diuretics (100%), digitalis (83%), and vasodilators (60%) and were followed for at least 6 months (mean 15). The 1-, 2- and 3-year cumulative survival rates were 75.4%, 70.2%, and 70.2%, respectively. Univariate predictors of survival included measured peak VO2 (p = 0.0026), as well as age, estimated peak VO2 (based on exercise time), presence of left bundle branch block, LVEDD, and frequency of ventricular arrhythmias. Multivariate analysis revealed that measured peak VO2 was the single best independent predictor of survival (p less than 0.001). We conclude that assessment of functional capacity provides useful independent prognostic information in patients with mild to moderate heart failure.     

Comparison of enalapril versus digoxin for congestive heart failure

A multicenter, randomized, double-blind, parallel-group trial was conducted to compare the effects of enalapril and digoxin on clinical signs and symptoms, as well as exercise capacity, in 142 patients with congestive heart failure classified as mild to severe (New York Heart Association functional classes II to IV). The patients received optimal treatment with digitalis and diuretics for 2 to 4 weeks. Thereafter, they were randomly assigned to receive either enalapril plus diuretics (n = 72) or digoxin plus diuretics (n = 70). After 8 weeks of treatment, a significant improvement in classification was observed in 22 of 63 patients (35%) in the enalapril group and in 17 of 61 (28%) in the digoxin group (difference not significant [NS]). Similarly, duration of exercise increased in both groups (p less than 0.005; p = NS between groups). Blood pressures decreased in the enalapril group (from 129 +/- 19/80 +/- 10 to 121 +/- 20/78 +/- 11 mm Hg; p less than 0.001), but not in the digoxin group (from 134 +/- 19/82 +/- 12 to 138 +/- 19/85 +/- 10 mm Hg; NS). Serum creatinine and electrolytes did not exhibit any significant change from baseline values, except for serum potassium, which increased slightly in the enalapril group (from 4.24 +/- 0.48 to 4.43 +/- 0.49 mmol/liter; p less than 0.05) and decreased slightly in the digoxin group (from 4.28 +/- 0.47 to 4.18 +/- 0.40 mmol/liter; p less than 0.05). Adverse events were reported in 13 patients (5 withdrawals) in the enalapril group and in 7 patients (2 withdrawals) in the digoxin group (p = NS).(ABSTRACT TRUNCATED AT 250 WORDS)     

Hemodynamic effects of vasodilators and long-term response in heart failure

Hemodynamic responses to vasodilators are commonly assessed when starting long-term vasodilator treatment in patients with chronic left ventricular failure, although the relation between short- and long-term responses is not established. Thus, short- and long-term hemodynamic responses to placebo and vasodilators (isosorbide dinitrate, minoxidil and enalapril or captopril) were measured and long-term clinical efficacy was assessed by changes in exercise capacity after 1 to 5 months of vasodilator administration (plus digitalis and diuretic agents) in 46 patients with New York Heart Association functional class II to IV heart failure caused by cardiomyopathy. There were no significant changes in hemodynamics or exercise capacity during placebo treatment. After initial doses and during long-term administration of vasodilator drugs, hemodynamics were significantly improved. After long-term vasodilator treatment, maximal oxygen uptake during exercise increased by 2.9 +/- 5.7 ml/min per kg from a control value of 14.1 +/- 5.6 ml/min per kg (p less than 0.01), and exercise duration also increased by 1.8 +/- 3.5 minutes (p less than 0.01). Changes in maximal oxygen uptake, however, did not correlate with short-term changes in pulmonary wedge pressure (correlation coefficient [r] = -0.14), cardiac index (r = -0.01) or systemic vascular resistance (r = -0.20). Long-term hemodynamic changes also failed to correlate with changes in exercise capacity. Baseline hemodynamics, cardiac dimensions and left ventricular ejection fraction before vasodilator administration all failed to correlate with baseline exercise capacity or with long-term changes in exercise capacity. Thus, hemodynamic measurements at initiation or during follow-up of vasodilator therapy do not relate to long-term clinical efficacy assessed by exercise capacity in patients with chronic left ventricular failure. Therefore, the rationale for making invasive hemodynamic measurements before initiating long-term vasodilator therapy for heart failure is questioned.     

Beta-adrenoceptor blockade in the treatment of postoperative adynamic ileus

Abdominal trauma, such as surgery and peritonitis, leads to inhibition of intestinal motility, partly mediated by alpha- and beta-adrenoceptors. To investigate the effect of nonselective beta-blockade on adynamic ileus, propranolol was compared with placebo in the postoperative course after elective colonic surgery in a double-blind randomized study. Ten patients received 4 mg propranolol intravenously twice daily, and ten received 10 mg intravenously twice daily. Nineteen patients received placebo. The time to first passage of stool was 110 +/- 9 h in the placebo group and 82 +/- 11 h in the 4-mg propranolol group. In the 10-mg propranolol group, the time was 79 +/- 8 h. The difference between the placebo-treated group and the propranolol-treated groups was significant (p less than 0.01). The effect of propranolol was most marked in older patients and after surgery on the distal colon. In patients older than 60 years the time to first stool in the placebo group was 127 +/- 13 h (n = 8), compared with 73 +/- 8 h (n = 11) in the propranolol group (p less than 0.01). In patients who had undergone surgery on the distal colon the time to first stool was 125 +/- 13 h (n = 8) in the placebo group and 76 +/- 8 h (n = 11) for propranolol (p less than 0.01). Adverse effects on the respiratory or cardiovascular system were not seen during medication. It is concluded that propranolol shortens the period of adynamic ileus after colonic surgery.     

Preload-dependent hemodynamic effects of milrinone in moderate heart failure.

Milrinone, a bipyridine derivative with positive inotropic and balanced type vasodilating properties, acutely improves cardiac pump function in patients with severe and moderate to severe heart failure. Whether it has similar effects in patients with mild to moderate heart failure is unknown. A hemodynamic evaluation of oral milrinone in dosage of 2.5, 5 and 10 mg was carried out on 3 consecutive days in 18 patients with NYHA class 2.7 heart failure. Patients continued with diuretics and digitalis, administered 15 h before each hemodynamic study. Peak milrinone plasma levels ranged from 77 to 252 micrograms/ml and were attained at 60-90 min following administration. Concomitantly, milrinone significantly reduced pulmonary wedge and right atrial pressures with 24, 47 and 44, and 25, 42 and 38% with the 2.5-, 5- and 10-mg doses, respectively. Milrinone had no effect on cardiac or stroke indices with either dose. Moreover, systemic vascular resistance only decreased by 12% with the highest dose, together with a 7% fall in mean arterial pressure and a 13% rise in heart rate (all p less than 0.05 vs. baseline). Patients were subsequently grouped depending on baseline pulmonary wedge pressure greater than or equal to 18 mm Hg (Gr I, n = 9) or less than 18 mm Hg (Gr II, n = 9). Changes in pulmonary wedge, pulmonary artery and right atrial pressure were similar in both groups following each dose. In contrast, the effect on cardiac pump function clearly differed in patients with high versus normal baseline wedge pressure. In Gr I, cardiac index increased significantly by 16% (5 and 10 mg). In Gr II, cardiac index decreased with 13% following the 10-mg dose (p less than 0.05 vs. baseline). When maximal individual changes in cardiac index were compared, 10 mg milrinone resulted in an improvement of cardiac index in all patients with baseline wedge pressures greater than 15 mm Hg, but in a decrease in cardiac index in patients with lower wedge pressures. It is concluded that milrinone induces contrasting effects on cardiac pump function in patients with mild to moderate heart failure, which may negatively affect its early and, possibly, also late efficacy in this patient group.     

Reduction in left ventricular volume and improvement in hemodynamics following intravenous administration of pimobendan (UDGG 115 BS) in dilated cardiomyopathy

Acute cardiovascular effects of 5 mg (group I, n = 6) and 10 mg (group II, n = 6) i.v. pimobendan (UDCG 115 BS) were studied by right and left heart catheterizations in patients suffering from idiopathic dilated cardiomyopathy (NYHA II and III). Before and 2.5 h after application of pimobendan left ventricular volumes and left ventricular dP/dtmax were evaluated by left heart catheterization. Right atrial pressure (RAP), pulmonary capillary wedge pressure (PCP), cardiac output (CO), heart rate, and systemic blood pressure were assessed before and 2.5, 4, and 6 h after administration of pimobendan. PCP was reduced from 12.2 +/- 7.5 to 8.3 +/- 7.1 mm Hg (p less than 0.05) by 5 mg of pimobendan, and from 18.3 +/- 6.2 to 6.2 +/- 3.4 mm Hg (p less than 0.005) by 10 mg of pimobendan. Reduction of RAP was significant only in group II (from 6.2 +/- 3.2 to 1.2 +/- 0.9 mm Hg; p less than 0.05). In contrast to other hemodynamic parameters, the significant increase of CO exhibited no dose-dependency. Only 10 mg of pimobendan induced a temporary reduction of mean arterial blood pressure. An increase in heart rate occurred only in group I and was merely transient. Left ventricular end diastolic and end systolic volume indices were clearly reduced by 5 mg as well as by 10 mg of pimobendan. A significant rise of left ventricular ejection fraction occurred only in group II. However, left ventricular dP/dtmax was increased significantly in both groups. No adverse effects were noted during acute administration of pimobendan. Therefore, intravenous pimobendan may be a useful drug in the treatment of acute cardiac failure.     

Acute and long-term effects of pimobendan (UD-CG 115) in NYHA II and III heart failure. Results of a randomized multicenter double-blind study]

The effects of pimobendan (UD-CG 115) on hemodynamics and exercise capacity after acute (single dose) and chronic (6 month) oral treatment, as well as acute treatment after 6 months were investigated in 67 patients with chronic heart failure of NYHA classes II or III, which had persisted in spite of treatment with diuretics and digitalis. They were treated with pimobendan (2.5 mg bid or 5 mg) or placebo in a randomized, double-blind multicenter trial. With a single administration before and after 6 months' treatment there was-compared to placebo-a significant fall in pulmonary capillary pressure (PCP) at rest (R) and during exercise (E) of 7% to 24%. Right atrial pressure (R) and pulmonary arterial pressure (PAP) (R, E) decreased after pimobendan on day 1; cardiac index (E) increased significantly. All other parameters were not influenced. After chronic therapy, PCP (E), PAP (E), LV stroke work index (E), and pulmonary resistance (R and E) values were significantly lowered by pimobendan when compared to day 1. Exercise duration was prolonged after 6 months by 83 s and 47 s after 5 and 10 mg/day, resp., compared to the placebo group (group difference not significant). Subjective wellbeing was improved in all three groups (no group difference). Clinical symptoms were not altered; six patients (two in each group) died suddenly. Another nine patients discontinued the trial prematurely because of poor efficacy or adverse events (no group difference). Overall, pimobendan was well-tolerated and had favorable effects on both acute and chronic hemodynamics and on exercise capacity. There was no evidence of any tolerance development.     

Endogenous prostaglandin E2 metabolite levels, renin-angiotensin system and catecholamines versus acute hemodynamic response to captopril in chronic congestive heart failure

Hemodynamic and hormonal responses to captopril were measured in 10 patients with severe chronic heart failure poorly controlled by digitalis and diuretics. After administration of a 25-mg dose, stroke volume (SV) increased from 53 +/- 7 to 63 +/- 9 ml (p less than 0.05), while pulmonary wedge pressure (PWP) decreased from 20 +/- 2 to 14 +/- 2 mm Hg (p less than 0.01). The hemodynamic changes were associated with increases in plasma renin activity (PRA; p less than 0.05) and in plasma levels of a novel bicyclo-prostaglandin E2 metabolite (bicyclo-PGE-m; p less than 0.01), whereas norepinephrine (NE) showed a falling tendency. In general, basal hemodynamic and basal hormonal levels did not correlate. Captopril-induced changes in mean artery pressure (MAP) and mean pulmonary artery pressure (mPAP) were positively correlated to pre-captopril PRA (r = 0.74, p less than 0.01; r = 0.64, p less than 0.05) and to changes in PRA (r = 0.85, p less than 0.01; r = 0.80, p less than 0.01) with a similar trend for angiotensin II (AII); decreases of systemic vascular resistance were more pronounced in patients with higher control NE levels (r = 0.62, p less than 0.05), the reduction of NE levels being highest in patients with higher basal concentrations (p less than 0.001); the captopril-induced decreases of mPAP and PWP were inversely related to basal bicyclo-PGE-m levels (r = 0.60, p less than 0.05; r = 0.61, p less than 0.05), and changes in mPAP were closely related to basal ratios of AII/bicyclo-PGE-m (r = 0.67, p less than 0.01). Thus, captopril exerts its acute beneficial hemodynamic effect by inhibiting the generation of AII, associated with toning down of sympathetic stimulation and increased production of vasodilating prostaglandins, such as PGE2. The relation between AII and PGE2-counteracting substances-might determine the hemodynamic response to captopril in the patients.     

Regulation of aldosterone secretion in patients with chronic congestive heart failure by endothelins

We studied acute (day 1) and long-term (day 14) effects of endothelin (ET) receptor blockade with the mixed ET(A/B) antagonist bosentan (1 g twice daily; n = 18) or placebo (n = 12) on plasma angiotensin II and aldosterone in 30 patients with symptomatic chronic heart failure taking angiotensin-converting enzyme inhibitors, diuretics, and digoxin. Hormones were determined before and 3 hours after morning doses of diuretics and digoxin and the double-blind study drug, respectively, on days 1 and 14. On day 1, angiotensin II increased from 16.1+/-17.9 to 27.6+/-5.6 ng/L (p <0.05) with bosentan and similarly with placebo (15.5+/-9.3 and 36.0+/-49.1 ng/L, p = 0.06) after the morning dose of diuretics and digoxin. Aldosterone tended to increase from 322+/-239 to 362+/-254 pmol/L (bosentan) and from 271+/-70 to 297+/-136 pmol/L (placebo). On day 14, before drug intake, angiotensin II was unchanged compared with day 1 in both groups. However, aldosterone was lower than on day 1 with bosentan (213+/-124 vs. 322+/-239 pmol/L, p<0.05) and remained below baseline values 3 hours after drug intake, whereas it was unchanged with placebo. Thus, short-term ET(A/B) receptor antagonism decreases basal aldosterone secretion independently of angiotensin II, suggesting that ET participates in the regulation of aldosterone in patients already treated with angiotensin-converting enzyme inhibitors and diuretics.     

Early and late prognosis after valve replacement in aortic regurgitation. Preoperative risk stratification and reasons for a more aggressive surgical approach

From 1965 through 1986 136 patients underwent valve replacement for aortic regurgitation. Mean age was 50 years and male:female ratio 3.7:1. Hospital mortality (HM, less than or equal to 30 days) varied with NYHA classes and digitalis/diuretics treatment (D/D):I (n = 80) 0%, II without D/D (n = 17) 0%, II with D/D (n = 21) 5%, III (n = 55) 7%; and IV (n = 35) 29% (p less than 0.01). Long-term survival was examined for 121 patients who were alive 30 days postoperatively. Five- and 10-year cumulative survival +/- SE were 80 +/- 4% and 66 +/- 6%, respectively. No late deaths were noted for NYHA class I and NYHA class II without D/D; NYHA class II with D/D had survival characteristics comparable to NYHA class III with 10-year survivals of 60%. Patients with acute regurgitation (endocarditis, n = 35) had a 10-year survival +/- SE of 88 +/- 5% compared to 57 +/- 7% for chronic regurgitation (p = 0.05). A Cox regression analysis revealed that ventricular ectopic beats, chronic regurgitation, left ventricular failure, and right ventricular failure were independent risk factors. Presence and different combination of these risk factors identified 5 risk groups (A-E) with 10-year survivals of:A (n = 16) 100%; B (n = 50) 75%; C (n = 37) 63%; D (n = 15) 27%; and E (n = 3) 0% (p less than 0.0001). Minimally symptomatic patients without preoperative medical treatment for congestive heart failure had superior survival characteristics compared to those who received treatment.(ABSTRACT TRUNCATED AT 250 WORDS)     

Acute hemodynamic and neurohumoral effects of moxonidine in congestive heart failure secondary to ischemic or idiopathic dilated cardiomyopathy.

Elevated plasma norepinephrine (PNE) has been shown to be an important predictor of morbidity and mortality in patients with congestive heart failure (CHF). Moxonidine selectively stimulates imidazoline receptors located in the medulla, which centrally inhibit sympathetic outflow. PNE is suppressed and peripheral vasodilation reduces systemic blood pressure. This study evaluated the acute neurohumoral and hemodynamic effects of a single dose of oral moxonidine in 32 patients (22 men, mean ± SD age 66 ± 10 years) with CHF. All patients were in New York Heart Association functional class III and stabilized on chronic therapy with diuretics, digitalis, and angiotensin-converting enzyme inhibitors. The mean PNE concentration was 509 ± 304 pg/ml at baseline. Patients underwent invasive hemodynamic monitoring after double-blind randomization to either placebo (n = 12), moxonidine 0.4 mg (n = 9), or moxonidine 0.6 mg (n = 11). Moxonidine produced a dose-dependent, vasodilator response compared with placebo. Analysis of the time-averaged change from baseline over 6 hours demonstrated that moxonidine 0.6 mg caused significant reductions in mean systemic arterial pressure (p <0.0001), mean pulmonary arterial pressure (p <0.005), systemic vascular resistance (p <0.05), pulmonary vascular resistance (p <0.01), and heart rate (p <0.05). Stroke volume was unchanged. PNE was reduced substantially (−180 pg/ml at 4 hours, p <0.005) and the reduction was highly correlated with the baseline level (r = −0.968). Moxonidine was well tolerated in this single-dose study and resulted in a modest, dose-dependent, vasodilator response, with substantial reductions in systemic and pulmonary arterial blood pressure. Trials designed to evaluate the clinical efficacy of chronic moxonidine therapy in CHF added to conventional therapy would be appropriate.     

Hemodynamic and clinical effects of captopril in congestive heart failure

The acute and chronic effects of Captopril were evaluated in 8 patients (5 males and 3 females, age 49 +/- 17 years) with chronic severe congestive heart failure. Acute hemodynamic effects were studied according to a randomized, double blind, placebo controlled protocol, by using two doses of Captopril (25 and 50 mg). The usual diuretic and digitalis treatment was kept unchanged throughout the trial. The acute administration of placebo associate with the usual doses of diuretic and digitalis was followed after 2 hours by a significant reduction of mean pulmonary wedge pressure (-23%, p less than 0.05). One hour following a single administration of Captopril, the following significant (p less than 0.05) changes were observed, respectively for the doses of 25 and 50 mg: heart rate -9% and -6%, cardiac index +13% and +10%, mean pulmonary wedge pressure -27% and -35%, mean pulmonary arterial pressure -29% and -26%, systemic vascular resistances -20% and -17%. A longer duration of effects on heart rate and cardiac index was noted after the 50 mg dose. All patients received long-term treatment with Captopril 75 or 150 mg daily. The NYHA functional class improved in all cases and there was a significant decrease of the cardio-thoracic ratio (from 0.61 +/- 0.05 to 0.55 +/- 0.09, p less than 0.01). A repeated hemodynamic study after a mean period of 6.5 months (range 2.5-22 months) revealed in 7 cases a sustained effect of the drug.(ABSTRACT TRUNCATED AT 250 WORDS)     

Clinical and hemodynamic evaluation of 6-week treatment of pulmonary hypertension in chronic obstructive lung diseases (COLD) with low dose of prazosin

The value of vasodilatatory treatment of pulmonary hypertension due to chronic obturative pulmonary disease (c.o.p.d.) is still controversial. However in patients with c.o.p.d. causal treatment as well as chronic domestic oxygen therapy have a wide range of limitations. Among vasodilator alpha-1 blockers show less vasodilator-related adverse effects, and as known from acute trials they exert a potent effect on pulmonary circulation in patients with pulmonary hypertension and c.o.p.d. Prazosin was studied in 11 patients (10 men, 1 women) aged 63 +/- 7 years with advanced c.o.p.d. (FVC 1.8 +/- 0.41, FEV1 0.99 +/- 0.55 l) (s) after their clinical stabilisation. In 4 of them prazosin was added to the maintenance dose of diuretics and digitalis. Subjective status, NYHA functional class, spirometric (FVC, FEV1) and gaseous (PaO2, PCO2) parameters, weight, systemic blood pressure, and heart rate were noted. During Swan-Ganz catheterization mean pulmonary artery pressure (MPAP), right ventricular end-diastolic pressure (RVEDP), pulmonary wedge pressure (PCWP), cardiac output (CO), systemic (SVR) and pulmonary (PVR) vascular resistance were measured. The acute trial with 1 mg prazosin taken orally was followed by 2- and 6-week of 3 mg prazosin treatment assessment. After a single dose of 1 mg prazosin there was a significant decrease in MPAP from 36 +/- 9 to 28 +/- 10 (p = 0.001) and 44% decrease in RVEDP (p = 0.05). CO increased by 16% (p = 0.01). The fall in PVR (30%, p = 0.01) exceeded that in SVR (17%, NS). No adverse effects were observed. During 2-week 3 mg a day prazosin therapy 2 patients were excluded following dyspnea and systemic hypotonia.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of oral milrinone on end-systolic relations in patients with severe congestive heart failure

The new inotropic agent milrinone has both vasodilator and inotropic cardiovascular effects, but the importance of these effects in patients with severe congestive heart failure (CHF) is controversial. The left ventricular (LV) end-systolic pressure-diameter relation was used to determine the independent inotropic effect of milrinone. Seven patients with New York Heart Association class III CHF were invasively monitored with right-sided heart catheters and radial arterial lines. M-mode echocardiography was used to measure LV dimensions. The effect of a 10-mg oral dose of milrinone on hemodynamic, echocardiographic and end-systolic variables was determined. End-systolic pressure was measured at the dicrotic notch of the arterial pressure tracing and end-systolic LV dimensions at the time of aortic valve closure. Methoxamine (n = 6) or nitroprusside (n = 1) was used to alter afterload so that the end-systolic pressure-diameter relation could be determined. Arterial vasodilation from milrinone was evidenced by a decrease in mean arterial blood pressure (88 +/- 5 to 77 +/- 2 mm Hg, p less than 0.025) and an increase in cardiac index (from 2.7 +/- 0.2 to 3.2 +/- 0.2 liters/min/m2, p less than 0.025), with no change in heart rate (80 +/- 5 beats/min). Milrinone decreased preload as assessed by the pulmonary artery wedge pressure (from 17 +/- 2 to 10 +/- 2 mm Hg, p less than 0.01) and end-diastolic LV diameter (from 7.4 +/- 0.4 to 7.0 +/- 0.4 cm, p less than 0.025).(ABSTRACT TRUNCATED AT 250 WORDS)     

Exercise performance in patients with uncomplicated essential hypertension. Effects of nifedipine-induced acute blood pressure reduction.

In untreated patients with uncomplicated essential hypertension, exercise induces an abnormal increase in blood pressure; the influences of this increase on exercise were evaluated by a cardiopulmonary exercise test (CPX) performed in control conditions (step 1) and during acute blood pressure reduction (step 2). Patients were classified as (1) normotensive (resting diastolic blood pressure [BPd] less than 90 mm Hg; n = 14), (2) mildly hypertensive (BPd of 90 to 104 mm Hg; n = 9), and (3) moderately to severely hypertensive (BPd greater than or equal to 105 mm Hg; n = 16). For the three groups, peak mean blood pressure during exercise was 125 +/- 5 mm Hg (mean +/- SEM), 144 +/- 3 mm Hg (p less than 0.01 vs normotensive), and 161 +/- 4 mm Hg (p less than 0.01 vs normotensive and p less than 0.01 vs mild hypertension), respectively. Oxygen consumption (VO2) at peak exercise and at ventilatory anaerobic threshold was 26.1 +/- 1.1 and 17.2 +/- 0.5 ml/min/kg, 25.4 +/- 1.1 and 16.9 +/- 0.8 ml/min/kg, and 26.4 +/- 1.3 and 17.5 +/- 1.2 ml/min/kg in normotensive subjects, those with mild hypertension, and those with moderate to severe hypertension, respectively. Fourteen normotensive subjects, six with mild hypertension, and nine with moderate to severe hypertension participated to step 2 (nifedipine vs placebo, double-blind crossover). Nifedipine reduced blood pressure at rest and at peak exercise in those with hypertension. Peak exercise VO2 was unaffected by nifedipine in both normotensive subjects and those with hypertension. With nifedipine, ventilatory anaerobic threshold occurred earlier and at a lower VO2 in mild and in moderate to severe hypertension (delta VO2 = -1.9 and -2.4 ml/min/kg, respectively). These findings might be due to nifedipine-induced redistribution of blood flow during exercise and might be the reason for the complaint of weakness after blood pressure reduction in hypertensive subjects.     

Efficacy and safety of flosequinan, given over 3 days, evaluated by continuous hemodynamic monitoring

The hemodynamic effects of flosequinan, a new balanced vasodilator, were evaluated in 12 patients with chronic congestive heart failure. The drug was added to diuretics and digitalis and given as an oral dose of 100 mg, once daily in the morning, over 3 days, and hemodynamic monitoring was performed before the first dose and for 72 h thereafter. Hemodynamic improvement, peaking between 1 and 2 h after oral administration, was observed on all 3 days. On day 1 pulmonary capillary wedge pressure (PCWP) was reduced from 27.8 +/- 8.6 to 13.0 +/- 3.1 mm Hg and cardiac output (CO) increased from 3.3 +/- 0.6 to 4.5 +/- 0.9 liters/min (p less than 0.05). After 12-16 h the effect was slightly attenuated but remained significant at 24 h. A similar response was observed after the doses given on days 2 and 3. At 72 h PCWP was 15.5 +/- 4.1 mm Hg and CO 3.8 +/- 1.1 liters/min (p less than 0.05 for the difference from baseline). Heart rate was slightly increased only at 2 h after the dose. Pulmonary arterial and right atrial pressure and systemic and pulmonary vascular resistances were significantly reduced (except for systemic resistance at 72 h). In conclusion, flosequinan produces hemodynamic improvement in patients with chronic congestive heart failure. The response to subsequent doses is similar to the response to the first dose.