OPC-8212 in the treatment of congestive heart failure: Results of a pilot study

Summary To characterize the effects of OPC-8212, a quinolone inotropic agent, in patients with heart failure, we utilized invesive homodynamics, exercise testing, 24-hour ambulatory electrocardiograms, and two patient self-assessment questionnaires, before and after 1 month of treatment with OPC-8212, in 17 patients with moderate to severe congestive heart failure. There were no significant changes from baseline in heart rate (83±8 beats/min), mean arterial pressure (70±15 mmHg), pulmonary wedge pressure (18±7 mmHg), or cardiac index (2.3±0.4 L/min/m²) following treatment with OPC-8212. Both exercise duration (5.3±1.6 min) and peak oxygen consumption (12.0±2.9 mL/kg/min) were unchanged by OPC-8212. Two independent patient self-assessment scores, the Sickness Impact Profile and the Minnesota Living with Heart Failure Questionnaire, showed improvements from 6.8 to 5.4 and 49 to 38, respectively (both p<.05), suggesting that the patients reported an improvement in daily functioning. The median ventricular premature contraction count and frequency were reduced from 1,118 beats to 243 beats (p<0.05) and 11/1,000 beats to 2,4/1,000 beats (0.05<p<0.10), respectively. Two patients developed agranulocytosis during longer-term treatment following this 1-month study. These data demonstrate that OPC-8212 did not have significant effects on hemodynamics or exercise tolerance. However, the improvement in patient self-assessment scores and the trend for improvement in ventricular arrhythmia profiles suggest that OPC-8212 may have some benefit for patients with congestive heart failure, but additional placebo-controlled, double-blind studies are necessary.     

Oral OPC-8212 for the treatment of congestive heart failure: Hemodynamic improvement and increased exercise capacity

Summary The chronic effects of the oral administration of OPC-8212 (3,4-DIHYDRO-6-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]-2(1H)-quinolinone) on resting hemodynamics and exercise capacity were assessed in 15 patients with congestive heart failure (NYHA II–IV). Doses of 30 or 60 mg per day were given per os over 3.0 weeks on average (range 2–6 weeks). Multigated radionuclide ventriculography and multistage exercise testing were performed before and during OPC-8212 therapy to assess the changes in left ventricular volume and exercise capacity respectively. Systolic blood pressure showed a slight increase (from 123±3 to 129±4 mmHg) during OPC-8212 therapy, while heart rate was unchanged (69±3 vs 67±3 beats/min). The left ventricular end-diastolic volume index decreased from 127±9 to 107±7 ml/m², and ejection fraction and the P/V index (the ratio of peak systolic pressure to left ventricular end-systolic volume index) increased during OPC-8212 therapy (from 27%±3% to 30%±4% and from 1.5±0.2 to 2.0±0.3 mmHg/ml/m² respectively). NYHA functional class was improved in 9 of 15 patients, and the average peak work load achieved during exercise testing increased from 27±6 to 47±7 W. No significant adverse effect was observed in any patient. These results indicate that OPC-8212 enhances the inotropic state and, hence, reduces heart size with no change in heart rate. Moreover, it increases exercise capacity. Thus, OPC-8212 is an inotropic agent with promise for application in the long-term treatment of congestive heart failure.     

A placebo-controlled,randomized, double-blind study of OPC-8212 in patients with mild chronic heart failure

Summary OPC-8212 is a newly synthesized, orally effective inotropic agent. Previous studies have shown short-term hemodynamic and symptomatic improvement in patients with congestive heart failure. However, the long-term efficacy of this agent remains to be established. Eighty-three patients with chronic heart failure were randomly assigned to treatment with either OPC-8212 (n=45) or matching placebo (n-38).Of the placebo-treated patients, two patients died and another six patients were withdrawn from the study because of a deterioration of heart failure, while only 1 out of 45 OPC-8212-treated patients were withdrawn because of increased congestive symptoms.After 12 weeks of treatment, the OPC-8212 group showed a significant improvement in their numerical scores in sense of well-being as judged by the patients' subscale A (p<0.01) and their physician's general impression of the patients' status (p<0.01). The ejection fraction obtained from echocardiography increased from a mean (±SEM) baseline value of 42.8±2.6% to 46.6±2.9% (p<0.05) in the OPC-8212 group and 44.4±3.7% to 45.5±4.1% in the placebo group. These effects were not associated with an increase in the heart rate. The treatment was well tolerated without any limiting side effects.Thus, OPC-8212 is effective in patients with chronic heart failure, providing significant hemodynamic and symptomatic benefit in chronic treatment, together with a possible improvement of the prognosis of patients with heart failure.     

A new cardiotonic agent,OPC-8212, elevates the myocardial oxygen consumption versus pressure-volume area (PVA) relation in a similar manner to catecholamines and calcium in canine hearts

Summary We studied the effect of a new positive inotropic agent, OPC-8212 (3,4-Dihydro-6-[4-(3,4-dimethoxybenzoyl)-l-piperazinyl]-2(1H)-quinolinone), on the relation between left ventricular oxygen consumption (VO₂) and pressure-volume area (PVA) in excised cross-circulated dog hearts. PVA represents the total mechanical energy generated by ventricular contraction. OPC-8212 increased the contractility index, Emax, by 59%±36% from 7.6±4.3 to 11.1±4.6 mmHg/(ml/100 g LV [leftventricle]). OPC-8212 elevated the VO₂-PVA relation without a significant change in its slope. Namely, OPC-8212 did not affect the mechanical efficiency of the contractile machinery from the PVA-dependent fraction of VO₂ to PVA, but increased the PVA-independent fraction of VO₂ which is related with non-mechanical processes of contraction. This effect suggested an increased energy expenditure for excitation-contraction coupling. These results associated with the enhanced contractile state by OPC-8212 were both qualitatively and quantitatively similar to those obtained with catecholamines and calcium in our previous study. This suggests that OPC-8212, catecholamines, and calcium have similar effects on intracellular Ca²⁺ concentration and enhanced ventricular contractility.Partly supported by a Grant-in-Aid (61480102) for Scientific Research from the Ministry of Education, Science, and Culture, and a Research Grant (60C-3) for Cardiovascular Diseases from the Ministry of Health and Welfare of Japan.     

Hemodynamic predictors of early intoleranceand long-term effects of propranolol in dilated cardiomyopathy

Background:

Fifty-six patients with dilated cardiomyopathy (DCM) (aged 14–68 years) andbackground therapy of angiotensin-converting enzyme inhibitors, diuretics, and digoxin were given an initial challenge of propranolol in gradually increasing doses. These patients were studied noninvasively and hemodynamically and subjected to right ventricle biopsy.

Methods and Results:

Forty-four patients tolerated propranolol and received the drug for 6 months; 12 patients deteriorated after starting the drug with worsening of congestive heart failure and/or hypotension. The patients who did not tolerate propranolol had higher left ventricular end-diastolic dimension (73 ± 8 vs 66 ± 8 mm, P < .05), and severe mitral regurgitation was more common. Hemodynamically these patients had higher heart rate, right ventricular end-diastolic pressure, mean pulmonary artery pressure, mean pulmonary artery wedge pressure, and left ventricular end-diastolic pressure (102 ± 16 vs 89 ± 12 beats/min, 15 ± 7 vs 9 ± 4, 39 ± 16 vs 31 ± 12, 28 ± 8 vs 21 ± 8, 28 ± 8 vs 22 ± 8 mmHg, respectively, P < .01). These patients had a significantly lower cardiac index (1.9 ± 0.6 vs 2.5 ± 0.6 L/min/m², P < .01). Forty patients completed 6 months follow-up evaluation and were further subjected to repeat noninvasive and hemodynamic study. There was a significant improvement in New York Heart Association class, cardiothoracic ratio, and left ventricular end-diastolic dimension (68% vs 62%, 66 ± 8 vs 62 ± 7 mm, respectively, P < .01), while the ejection fraction (EF) rose from 23 to 35% (P < .001). Hemodynamically, there was a significant decrease in heart rate, right ventricular end-diastolic pressure, mean pulmonary artery pressure, mean pulmonary artery wedge pressure, and left ventricular end-diastolic pressure (91 ± 14 vs 71 ± 5 beats/min, 9 ± 4 vs 5 ± 3, 32 ± 11 vs 22 ± 7, 25 ± 9 vs 17 ± 8, 21 ± 7 vs 14 ± 4 mmHg, P < .05). The cardiac index rose from 2.3 ± 0.6 to 3.2 ± 0.7 L/min/m² (P < .01).

Conclusions:

Propranolol in dilated cardiomyopathy is associated with significant intolerance. Those who tolerate propranolol seem to have long-term beneficial effects. This study is limited as it is uncontrolled and nonrandomized.     

Usefulness of OPC-8212, a quinolinone derivative, for chronic congestive heart failure in patients with ischemic heart disease or idiopathic dilated cardiomyopathy

To evaluate the safety and efficacy of the inotropic agent OPC-8212 in patients with chronic congestive heart failure, 76 patients with impaired cardiac function and diminished exercise tolerance were studied. They were randomized to 12 weeks of double-blind therapy with either 60 mg/day of OPC-8212 or placebo. The study drug was added to their baseline medical regimen. The primary study outcome was the combined outcome of the time to either mortality (of all cause) or substantial worsening of heart failure (major morbidity), whichever occurred first. Treatment with OPC-8212 significantly (p less than 0.01) decreased the combination of major morbidity/mortality over 12 weeks of therapy. Quality of life, assessed by the Sickness Impact Profile questionnaire, was significantly improved in patients receiving OPC-8212 (p less than 0.01). Furthermore, ventricular premature contractions as assessed by 24-hour Holter monitoring were not increased with OPC-8212 treatment. Although patients treated with OPC-8212 were able to reach a significantly higher peak oxygen uptake and exercise longer during symptom-limited exercise, when data were analyzed as percent change from baseline, the absolute increases were small. These results suggest that OPC-8212 is beneficial in treating patients with congestive heart failure and that further evaluation of this new inotropic agent is warranted.     

Cardiovascular actions of OPC-18790: A novel positive inotropic agent with little chronotropic action

Summary OPC-18790 [(±)-6-[3-(3,4-dimethoxy-benzylamino)- 2 - hydroxypropoxy] - 2(1H) - quinolinone], a novel positive inotropic agent, was investigated in several in vitro and in vivo experiments to elucidate its cardiovascular effects and its mechanism of action. In isolated blood-perfused dog heart preparations, OPC-18790 increased contractile force at 10 to 1,000 nmol i.a.; increased coronary arterial blood flow at 30 to 1,000 nmol; and deceased sinus rate slightly at 1,000 nmol. Atrio-ventricular nodal conduction was slightly facilitated with OPC-18790 (10 to 1,000 nmol), whereas ventricular automaticity tended to decrease. OPC-18790 (10^–6 to 10^–4 M) increased contractile force in isolated ventricular muscles of dogs, cats, rabbits and guinea pigs but not rats. OPC-18790 increased left ventricular contractile force dosedependently in anesthetized open-chest dogs and in conscious dogs with slight or no changes in heart rate and blood pressure. The positive inotropic effect of OPC-18790 was not affected by -blockade. OPC-18790 (10^–5 to 10^–4 M) prolonged the duration of action potential in guinea pig papillary muscles. Na⁺, K⁺-ATPase was not inhibited, but peak-III phosphodiesterase (low Km cyclic AMP specific fraction, inhibited by cyclic GMP) was inhibited by OPC-18790 (IC₅₀ = 0.41 × 10^–6 M) in dog myocardium. However, such an inhibitory action of phosphodiesterase can hardly be reconciled with the lack of a positive chronotropic effect shown by OPC-18790. Thus, these results suggest that OPC-18790 may have an additional mechanism. The cardiovascular effects revealed by this study suggest that OPC-18790 may exert a beneficial effect in the treatment of congestive heart failure.     

Inhibition of NOS2 ameliorates cardiac remodeling,improves heart function after myocardial infarction in rats

Abstract. Objective: Previous studies have shown increased expression of nitric oxide synthase 2 (NOS2) in rat heart several weeks after myocardial infarction (MI). The aim of this study was to examine the effect of chronic administration of S-methylisothurea (SMT), a selective NOS2 inhibitor, commenced one week after MI on hemodynamic parameters and left ventricular (LV) remodeling in rats. Methods: Rats with MI induced by left coronary ligation were given SMT (0.5 mg/kg/d) or saline by gavage starting one week after MI. After chronic administration for five weeks, hemodynamic and cardiac morphologic studies were performed, and lung water content, plasma NO_x concentration, NOS2 protein level, myocyte size and collagen volume fraction of noninfarct LV area were quantified. Results: The NO_x concentration in plasma and the NOS2 protein level in noninfarct myocardium in MI rats were higher than controls. When compared with the MI rats receiving saline, chronic administration of SMT reduced myocyte size (15.1 ± 1.6 µm vs 16.9 ± 2.3 µm, P < 0.05), collagen volume fraction of noninfarct LV area (4.4% ± 1.1% vs 5.7% ± 1.2%, P < 0.01) and lung water content (77.4% ± 1.4% vs 79.3% ± 0.9%, P < 0.01), without affecting infarct size. Administration of SMT had no significant effect on heart rate and mean arterial pressure, but decreased LV end-diastolic pressure (8.7 ± 2.1 mmHg vs 13.4 ± 3.1 mmHg, P < 0.01), central venous pressure (0.9 ± 0.3 mmHg vs 1.5 ± 0.5 mmHg, P < 0.01) and inner LV diameter (6.9 ± 0.3 mm vs 7.2 ± 0.3 mm, P < 0.05) in the MI rats. Plasma level of NO_x in the MI rats receiving SMT was reduced to control level. Conclusions: Chronic administration of SMT had beneficial effects on LV remodeling and cardiac dysfunction in MI rats, suggesting the possibility that inhibition of NOS2 could be a therapeutic tool for cardiac dysfunction after MI.     

B-type natriuretic peptide levels are not a surrogate marker for invasive hemodynamics during management of patients with severe heart failure

Background

We sought to assess the utility of serial BNP measurements in patients with severe heart failure and attempted to correlate values with invasively derived data.

Methods

In a retrospective study, we analyzed serial BNP levels in patients receiving hemodynamically guided therapy for severe heart failure and sought correlation with invasively derived data.

Results

Thirty-nine patients with New York Heart Association Class III-IV, with an ejection fraction of 35% or less, who had a pulmonary artery catheter inserted for hemodynamically tailored heart failure therapy, were identified and serial BNP measurements reviewed. BNP was estimated on admission, at 12 and 36 hours. Normally distributed variables are expressed as mean ± SD and otherwise as median ± interquartile range. Mean ejection fraction was 16% ± 6%. Mean pulmonary artery occlusion pressures (PAOP) fell with therapy and were 25 ± 7 mmHg, 18 ± 7 mmHg and 19 ± 7 mmHg at admission, 12 hours and 36 hours respectively (P < 0.05). Median BNP levels fell from 1200 ± 641 to 771 ± 803 at 12 hours and to 805 ± 771 at 36 hours (P < .001). There was no correlation between BNP and any hemodynamically derived variable. A change in BNP was not associated with a change in PAOP in any individual patient. Only 42% remained alive on medical therapy at 30 days.

Conclusions

In patients with severe heart failure, BNP levels do not accurately predict serial hemodynamic changes and do not obviate the need for pulmonary artery catheterization.     

Acute resveratrol supplementation improves flow-mediated dilatation in overweight/obese individuals with mildly elevated blood pressure

Background and Aims

Flow-mediated dilatation of the brachial artery (FMD) is a biomarker of endothelial function and cardiovascular health. Impaired FMD is associated with several cardiovascular risk factors including hypertension and obesity. Various food ingredients such as polyphenols have been shown to improve FMD. We investigated whether consuming resveratrol, a polyphenol found in red wine, can enhance FMD acutely and whether there is a dose-response relationship for this effect.

Methods and Results

19 overweight/obese (BMI 25–35 kg m⁻²) men or post-menopausal women with untreated borderline hypertension (systolic BP: 130–160 mmHg or diastolic BP: 85–100 mmHg) consumed three doses of resveratrol (resVida™ 30, 90 and 270 mg) and a placebo at weekly intervals in a double-blind, randomized crossover comparison. One hour after consumption of the supplement, plasma resveratrol and FMD were measured. Data were analyzed by linear regression versus log₁₀ dose of resveratrol. 14 men and 5 women (age 55 ± 2 years, BMI 28.7 ± 0.5 kg m⁻², BP 141 ± 2/89 ± 1 mmHg) completed this study. There was a significant dose effect of resveratrol on plasma resveratrol concentration (P < 0.001) and on FMD (P < 0.01), which increased from 4.1 ± 0.8% (placebo) to 7.7 ± 1.5% after 270 mg resveratrol. FMD was also linearly related to log₁₀ plasma resveratrol concentration (P < 0.01).

Conclusion

Acute resveratrol consumption increased plasma resveratrol concentrations and FMD in a dose-related manner. This effect may contribute to the purported cardiovascular health benefits of grapes and red wine.     

Long-term treatment with nifedipine reduces urinary albumin excretion and glomerular filtration rate in normotensive type 1 diabetic patients with microalbuminuria

The aim of the present study was to investigate the renal effects of long-term treatment with the calcium channel blocker nifedipine in normotensive type 1 diabetic patients with microalbuminuria. In a randomized, double-blind trial, 15 type 1 diabetic patients were treated with either nifedipine (n=8; dosage 30 mg/day) or placebo (n=7) for 12 months. At baseline and after 6 and 12 months of therapy, the albumin excretion rate (UAER, radioimmunoassay), glomerular filtration rate (GFR, chromium 51 ethylenediamine tetra-acetic acid clearance) and renal plasma flow (RPF, iodine 125 hippuran clearance) were determined. Nifedipine treatment caused a significant reduction of UAER after 6 and 12 months (median, Q₁/Q₃ in mg/24 h): baseline 84 (65/163); 6 months 35 (23/90),P<0.02; 12 months 39 (15/79),P<0.05. GFR was significantly decreased by nifedipine treatment (baseline 157±15, 6 months 122±8, 12 months 111±47 ml/min;P<0.05, mean ± SEM), whereas RPF remained constant. Nifedipine treatment did not influence systolic (baseline 121±7, 12 months 124±2 mmHg, mean ± SEM) or diastolic (baseline 72±2, 12 months 74±3 mmHg) arterial blood pressure. With placebo treatment no significant alterations of UAER, GFR, RPF and arterial blood pressure were observed. Metabolic control was constant throughout the whole study period. Thus, 1 year's treatment with nifedipine reduces the UAER and GFR in normotensive type 1 diabetic patients without influencing the systemic arterial blood pressure. The data, however, do not present a recommendation for the general use of nifedipine in these patients as the exact intrarenal mechanism of calcium channel blockers in humans remains to be established.     

Elevated level of erythropoietin in congestive heart failure Relationship to renal perfusion and plasma renin

Abstract. Background. In animal experiments reduction of renal perfusion can stimulate erythropoietin production. The relationship between renal haemodynamics and erythropoietin production is unknown in congestive heart failure. Objective. The aim was to study the relationship between serum erythropoietin and renal haemodynamics, plasma renin activity and haematocrit in patients with congestive heart failure and in healthy control subjects. Patients and methods. Serum erythropoietin, renal plasma flow, glomerular filtration rate and plasma renin activity were determined in 14 patients with acyanotic congestive heart failure, and 36 healthy controls. Results. Serum erythropoietin was significantly elevated in congestive heart failure 26.6 U l^?1 (median) compared with controls 17.0 U l^?1 despite a normal haematocrit, and increased with the severity of congestive heart failure (New York Heart Association class II: 17 U l^?1 [n = 4]; class III: 30 U l^?1 [n = 5]; class IV: 45 U l^?1 [n = 5]). Significant inverse correlations between serum erythropoietin and renal plasma flow (r = ?0.60, P < 0.03), and between serum erythropoietin and glomerular filtration rate, were found in congestive heart failure but not in the control subjects. A significant positive correlation (r = 0.71, P < 0.03) was demonstrated between serum erythropoietin and plasma renin activity in congestive heart failure. Conclusion. A severe reduction in renal perfusion in congestive heart failure appears to cause an increase in serum erythropoietin.     

Cholinergic stimulation with pyridostigmine reduces ventricular arrhythmia and enhances heart rate variability in heart failure

Background

Increased ventricular arrhythmia density and reduced heart rate variability are associated with risk of death in patients with heart failure. Cholinesterase inhibition with pyridostigmine bromide increases heart rate variability in normal subjects, but its effect on patients with heart failure is unknown. In this study, we tested the hypothesis that short-term administration of pyridostigmine bromide, a cholinesterase inhibitor, reduces ventricular arrhythmia density and increases heart rate variability in patients with congestive heart failure.

Methods

Patients with heart failure and in sinus rhythm participated in a double-blind, cross-over protocol, randomized for placebo and pyridostigmine (30 mg orally 3 times daily for 2 days). Twenty-four hour electrocardiographic recordings were performed for arrhythmia analysis and for the measurement of time domain indices of heart rate variability. Patients were separated into 2 groups, according to their ventricular arrhythmia density. The arrhythmia group (n = 11) included patients with >10 ventricular premature beats (VPBs) per hour (VPBs/h), and the heart rate variability group (n = 12) included patients with a number of VPBs in 24 hours not exceeding 1% of the total number of R-R intervals.

Results

For the arrhythmia group, pyridostigmine resulted in a 65% reduction of ventricular ectopic activity (placebo 266 ± 56 VPBs/h vs pyridostigmine 173 ± 49 VPBs/h, P = .03). For the heart rate variability group, pyridostigmine administration increased mean R-R interval (placebo 733 ± 22 ms vs pyridostigmine 790 ± 33 ms, P = .01), and in the time domain indices of heart rate variability root-mean-square of successive differences (placebo 21 ± 2 ms vs pyridostigmine 27 ± 3 ms, P = .01) and percentage of pairs of adjacent R-R intervals differing by >50 ms (placebo 3% ± 1% vs pyridostigmine 6% ± 2%, P = .03).

Conclusion

In patients with heart failure, pyridostigmine reduced ventricular arrhythmia density and increased heart rate variability, most likely due to its cholinomimetic effect. Long-term trials with pyridostigmine in heart failure should be conducted.     

Increased vasopressor responsiveness to angiotensin II in Type 1 (insulin-dependent) diabetic patients without complications

Summary The blood pressure response to infused angiotensin II (0.3 to 3 ng · kg^–1 · min ^–1) was investigated in six normotensive patients with Type 1 (insulin-dependent) diabetes free of complications and in six healthy subjects matched for age, sex and weight. Basal blood pressures (111/68 and 114/72 mmHg) and basal plasma angiotensin II levels (18.0±5.2 and 14.1±2.4 pmol/l; mean + SD) were similar in the diabetic and control groups as were 24 h urinary excretions of sodium (157±88 and 154±84 mmol/24h). Equal increments in plasma angiotensin II were produced during the infusions in the two groups. Increases in both diastolic and systolic blood pressure were significantly greater in the diabetic patients throughout the infusion. Mean diastolic increments were: 6.7 versus 1.3 mmHg (0.3 ng dose), 11.0 versus 6.9 mmHg (1 ng dose) and 16.7 versus 12.3 mmHg (3 ng dose) (p<0.001). Corresponding figures for systolic pressure were: 8.7 versus 1.3mmHg, 10.3 versus 3.7mmHg and 15.3 versus 8.7mmHg (p<0.001). Vasopressor responsiveness to angiotensin II is thus increased in Type 1 diabetic patients without complications; it may, therefore, be a consequence of the diabetes rather than of the presence of microvascular disease or hypertension.     

Atrial natriuretic factor and right atrial pressure in patients undergoing chronic haemodialysis

To quantitate the mutual relationship between central venous pressure (CVP) and circulating atrial natriuretic factor (ANF) during haemodialysis, nine end-stage renal failure patients on chronic haemodialysis underwent ultrafiltration (UF) and biochemical correction (3 h) separated by 1 h (no dialysis, ND). During UF CVP and circulating ANF decreased significantly in all patients from basal levels (0.5±1.0 vs 5.4±2.0 mmHg and 58±16 vs 95±19 pmol/l respectively,P<0.01 for both), while microhaematocrit increased significantly (29.5±1 vs 26.0±1%,P<0.01). During ND, CVP and ANF rose significantly (P<0.05 for both) in seven of the nine patients, while microhaematocrit returned towards basal values. In two patients CVP did not change during ND and circulating ANF remained unchanged. A significant correlation between CVP and circulating ANF was found (end-basal to end-UF,r=0.72,P<0.05; end-UF to end-ND,r=0.77,P=0.025;n=7). As expected, during biochemical correction plasma creatinine and K⁺ decreased significantly and consistently in all the patients (from 875±74 to 400±56 mol/l and from 4.7±0.07 to 4.0±0.04 mEq/l, respectively;n=9,P<0.01 for both) as did body weight during UF (65.6±7 vs 67±5 kg;n=9,P<0.05). No significant changes were seen for systolic and diastolic blood pressure, heart rate and plasma renin activity at any time. Our data provide further evidence that the regulation of circulating ANF is synchronized with changes in CVP. They also quantitate the mutual relationship between CVP and ANF in end-stage renal failure.     

Acute and chronic effects of a diuretic monotherapy with piretanide in congestive heart failure—A placebo-controlled trial

Summary To evaluate the acute and chronic effects of diuretic monotherapy with 3 mg piretanide bid, 46 patients (pts) with congestive heart failure (NYHA II-III) secondary to coronary artery disease were studied. Within 3 weeks of therapy, the patients lost 1.6 kg body weight. Forty-four patients reported a subjective feeling of improvement. Echocardiographically, a highly significant (p<0.001) reduction of diastolic and systolic diameters was found, as well as an increase of fraction shortening. Chest x-ray indicated a reduction of heart volume from 1012±263 ml to 936±233 ml (p<0.001). The serum potassium level remained unchanged. A subgroup of 26 pts underwent invasive hemodynamic examinations. IV injection of 6 mg piretanide resulted in an acute reduction of pulmonary wedge pressure (pc) from 20.2±5.3 mmHg to 11.9±5.0 mmHg (p<0.001); simultaneously a slight decrease of cardiac index from 3.2±0.6 l/min/m² to 3.0±0.4 l/min/m² was observed. Invasive control after 3 weeks of oral therapy showed no decline of the piretanide effect. The exercise tolerance increased clearly from 135±161 Wmin to 249±268 Wmin (p<0.05). A control group of further 14 pts was treated with placebo only and did not show any significant changes of pc (20.0±6.4 mmHg vs. 22.8±19.2 mmHg), exercise tolerance, or other clinical parameters. Thus, the diuretic monotherapy of congestive heart failure with piretanide is highly effective and shows a significant improvement in all clinical and hemodynamic parameters in the absence of any remarkable side effects.     

Peripheral afferent stimulation of decentralized sympathetic neurons activates lipolysis in spinal cord-injured subjects

Spinal cord-injured (SCI) subjects exhibit a normal lipolytic rate despite the failure of centrally mediated sympathoexcitatory stimuli to activate lipolysis. Peripheral afferent stimulation below the lesion level induces an exaggerated autonomic reaction in SCI with lesion levels above T5, ie, so-called autonomic dysreflexia. The metabolic effects of induced dysreflexia were investigated in five SCI subjects (age, 35 ± 8 years; duration of paresis, 15 ± 7.5 years [mean ± SD]; lesion level, T3 to T4, n = 2, C7, n = 3) following bladder stimulation. Subcutaneous glycerol concentrations were measured by microdialysis above and below the lesion level. Diurnal plasma noradrenaline (NA) and adrenaline levels were continuously monitored in seven SCI subjects (lesion level T3 to T4, n = 2; C4 to C7, n = 5). Bladder stimulation resulted in an increased mean arterial pressure ([MAP] 81 ± 8 to 114 ± 11 mm Hg, P < .05), a decreased heart rate (70 ± 3 to 54 ± 4 beats/min, P < .05), and an increased plasma NA (0.70 ± 0.49 v 3.27 ± 1.56 nmol/L, P < .05). Interstitial glycerol was increased in the decentralized region (89 ± 12 to 135 ± 21 μmol/L, P < .05), whereas no reaction was found in the centrally innervated region. Plasma concentrations of glycerol and insulin increased. Diurnal monitoring showed periods of increased plasma NA sufficient to induce lipolysis (>1.4 nmol/L) during 20% of the registration period. The data suggest that peripheral afferent stimulation below the lesion level increases NA release and activates lipolysis and that frequent episodes of activation are found in SCI subjects with tetraplegia or high paraplegia.     

Effect of enoximone alone and in combination with metoprolol on myocardial function and energetics in severe congestive heart failure: Improvement in hemodynamic and metabolic profile

Summary The hemodynamic and myocardial metabolic effects of enoximone (phosphodiesterase III inhibitor), alone or in combination with metoprolol (beta-adrenergic blocker), were studied in patients with congestive heart failure. Ten patients (New York Heart Association Class III–IV) underwent right heart and coronary sinus catheterization, and parameters were assessed at basal condition, at peak enoximone response (mean intravenous loading dose=2.2 mg/kg), and after the combination with metoprolol (mean intravenous dose=8.5 mg). Heart rate tended to increase during enoximone administration (from 102±16 to 107±16 min^–1, ns) and was reduced during enoximone plus metoprolol (to 88±15 min^–1, p<0.05 vs. basal). Cardiac index was increased during enoximone (from 2.2±0.2 to 3.8±0.5 1/min/m², p<0.05) and decreased during enoximone plus metoprolol (to 2.8±0.5 1/min/m², p<0.05 vs. enoximone). Mean pulmonary wedge pressure fell during enoximone and remained reduced during enoximone plus metoprolol (from 27±9 to 9±3 and to 13±4 mmHg, respectively, both p<0.05). Myocardial oxygen consumption did not change during enoximone (from 27±8 to 25±13 ml/min, ns) and was reduced during enoximone plus metoprolol (to 19±8 ml/min, p<0.05 vs. basal). Myocardial lactate extraction tended to be lower during enoximone and during enoximone plus metoprolol conditions (from 38±17% to 26±20% and to 29±24%, respectively), but no statistical significance was found. Myocardial efficiency was increased during enoximone and during enoximone plus metoprolol (from 9±3% to 15±6% and to 14±6%, respectively, both p<0.05). Thus in patients with congestive heart failure enoximone improves hemodynamics and, in most cases, it does not influence energetics. The addition of metoprolol to enoximone reduces heart rate, cardiac index, and myocardial oxygen consumption without any other major changes, producing a more physiologic hemodynamic and metabolic profile.     

Early changes in clinical characteristics after emergency department therapy for acute heart failure syndromes: identifying patients who do not respond to standard therapy

Clinical trials for acute heart failure syndromes (AHFS) have traditionally enrolled patients well after emergency department (ED) presentation. We hypothesized a large proportion of patients would undergo changes in clinical profiles during the first 24 h of hospitalization, and these changes would be associated with adverse events. We evaluated a prospective cohort of patients with clinical data available at ED presentation and 12–24 h after ED treatment for AHFS. Patients were categorized into distinct clinical profiles at these time points based on (1) systolic blood pressure: a—hypertensive (>160 mmHg); b—normotensive (100–159 mmHg); or c—hypotensive (<100 mmHg); (2) moderate-to-severe renal dysfunction (GFR ≤ 60 ml/min/1.73 m²); and (3) presence of troponin positivity. A composite outcome of 30-day cardiovascular events was determined by phone follow-up. In the 370 patients still hospitalized with data available at the 12–24 h time point, 196 (53.0%) had changed their clinical profiles, with 117 (59.7%) improving and 79 (40.3%) worsening. The composite 30-day event rate was 16.9%. Patients whose clinical profile started and stayed abnormal had a significantly greater proportion of events than those who started and stayed normal (26.1% vs. 11.3%; P = 0.03). Patients with abnormal clinical profiles at presentation that remain abnormal throughout the first 12–24 h of hospitalization are at increased risk of 30-day adverse events. Future clinical trials may need to consider targeting these patients, as they may be the most likely to benefit from experimental therapy.     

Echocardiographic predictors of exercise capacity in patients with heart failure and systolic dysfunction: role of mitral regurgitation

Introduction and objectives

Patients with heart failure and similar left ventricular systolic dysfunction have differing exercise capacity. The aim of this study was to identify echocardiographic predictors of exercise capacity in patients with heart failure and systolic dysfunction.

Methods

We included 150 patients with class II (70%) or III (30%) heart failure with left ventricular ejection fraction below 40%. Six-minute walking test and cardiac color Doppler-echo, including tissue Doppler of mitral and tricuspid rings, were performed. Moderate and severe mitral regurgitation were considered as significant. Two groups were divided according to the median walking distance (290 m): Group 1, <290 m and Group 2, ≥290 m.

Results

Mitral regurgitation was detected in 112 patients (75%), which was significant in 40 (27%). Group 1 showed more significant mitral regurgitation (35 vs 18%), increased left atrium area (27±1 vs 24±1 cm²), mitral E amplitude (88±5 vs 72±3 cm/s) and systolic pulmonary pressure (37±1 vs 32±1 mmHg, all P<.05). By logistic regression analysis, only the presence of significant mitral regurgitation was independently associated with less walked distance (odds ratio: 3.44 95% confidence interval 1.02-11.66, P<.05). By multiple linear regression, the only independent predictor of walked distance was left atrium area (r=0.25, beta coefficient: −6.52 ± 2, P<.01).

Conclusions

In patients with class II-III heart failure and left ventricular systolic dysfunction, the main echocardiographic predictors of exercise capacity are related to the presence of significant mitral regurgitation.Full English text available from:www.revespcardiol.org