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(n=45) or matching placebo (n-38).Of the placebo-treated patients, two patients died and another six patients were withdrawn from the study because of a deterioration of heart failure, while only 1 out of 45 OPC-8212-treated patients were withdrawn because of increased congestive symptoms.After 12 weeks of treatment, the OPC-8212 group showed a significant improvement in their numerical scores in sense of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.     

Calcium sensitization with pimobendan: pharmacology, haemodynamic improvement, and sudden death in patients with chronic congestive heart failure

Calcium sensitization increases myocardial contractility byimproving energy utlization of the myocardium, without an increasein intracellular concentrations of cyclic adenosine monophosphate.The calcium sensitizer most extensively studied up to now ispimobendan (UD-CG 115 BS). Vasodilatation results primarilyfrom phosphodiesterase III inhibition Orally administered pimobendan appears rapidly in plasma. Apeak concentration is reached 1.5 h after drug intake; eliminationfrom the plasma compartment has a half-life of 1.5 h. First-passhepatic O-desmethylation of pimobendan produces the active metaboliteUD-CG 212; plasma concentration curves of UD-CG 212 are similarto those of pimobendan, with apeak concentration 1–2 hlater than the peak concentration of the parent compound. In patients with chronic congestive heart failure, pimobendanproduces a dose-dependent and prolonged decrease in pulmonarycapillary wedge pressure and an increase in cardiac output.Maintenance doses ofpimobendan are well tolerated and may leadto lasting symptomatic improvement in patients with heart failure;open and blinded trials show that exercise tolerance increases.No attenuation of these effects is seen during long-term therapywith pimobendan. Patients in chronic congestive heart failure frequently diesuddenly; many inotropic agents increase the incidence of suddendeath in these patients. Although proarrhythmia has never beenobserved with pimobendan, arrhythmia suppression with amiodaroneseems prudent in heart failure patients receiving maintenancedoses of pimobendan.     

Acute hemodynamic effects of a new inotropic agent,OPC-8212, on severe congestive heart failure

Summary The hemodynamic and clinical effects of OPC-8212, a newly synthesized, orally effective inotropic agent, were assessed for the first time in ten patients with severe congestive heart failure by means of right heart catheterization with a Swan-Ganz catheter. Cardiac output was determined by the thermodilution technique. Patients received a single oral dose of 6 mg/kg. To determine the magnitude and time-course of the effects of OPC-8212, measurements were made during an observation period before and 2, 4, 8, and 12 h after administration. Blood was also taken at these times for measurement of the concentration of plasma OPC-8212. No large meals were allowed during the first 4 h. After the single oral dose of OPC-8212, plasma concentrations increased rapidly, reaching an effective level after 8 h and peaking at 12 h. Hemodynamic performance improved as the mean OPC-8212 plasma level increased, with the maximum effect being observed between 8 and 12 h after acute administration of the drug. At 8 h, the cardiac index was increased from the baseline value of 2.4±0.2 (SEM) to 2.8±0.3 l/min/m² (P<0.01). The stroke work index rose from 26.2±5.1 to 31.7±60 g · m/m². The excessive pulmonary artery diastolic pressure fell from 22±2 to 17±3 mmHg at 8 h (P<0.001) and to 16±2 mmHg (P<0.001) at 12 h. The incidence of ventricular premature beats was not increased and no other side effects were observed. These changes were not associated with significant changes in heart rate or systolic blood pressure. Thus, this drug appears to be very promising for the long-term treatment of congestive heart failure.     

Effects of chronic neutral endopeptidase inhibition on the progression of left ventricular dysfunction and remodeling in dogs with moderate heart failure

Background. The diuretic actions of endogenously produced atrial natriuretic factor (ANF) may be beneficial in the treatment of chronic heart failure (CHF). Neutral endopeptidase (NEP) is the primary enzyme responsible for the degradation of ANF. The present study investigates the effects of long-term NEP inhibition on the progression of left ventricular (LV) dysfunction and remodeling in dogs with moderate heart failure. Methods. LV dysfunction was produced in 12 dogs by multiple sequential intracoronary microembolizations. Embolizations were discontinued when LV ejection fraction (EF) was between 30–40%. Two weeks after the last embolization, dogs were randomized to 3 months of oral therapy with the NEP inhibitor ecadotril (100 mg, once daily, n = 6) or to no therapy at all (control, n = 6). Results. During the 3 months of follow-up, LV EF in control dogs decreased from 37 ± 1% to 28 ± 1% (P < 0.01) and LV end-diastolic volume (EDV) and end-systolic volume (ESV) increased (EDV: 72 ± 3 vs. 84 ± 5 ml, P < 0.01); ESV: 45 ± 1 vs. 60 ± 4 ml, P < 0.01). In dogs treated with ecadotril, LV EF (34 ± 1% vs. 37 ± 2%), EDV (79± 5 vs. 78± 6 ml) and ESV (52 ± 3 vs. 49 ± 4) remained essentially unchanged after 3 months of therapy. Histomorphometric measurements at the termination of the study showed that ecadotril was associated with significantly reduced cardiomyocyte hypertrophy compared to control. Conclusion. Early, long-term NEP inhibition with ecadotril prevents the progression of LV dysfunction and attenuates progressive LV remodeling in dogs with moderate heart failure.     

Acute and chronic effects of the dihydropyridine calcium antagonist nisoldipine on the resting and exercise hemodynamics,neurohumoral parameters,and functional capacity of patients with chronic heart failure

Summary The acute and chronic effects of the dihydropyridine calcium antagonist nisoldipine were studied in patients with chronic heart failure (LV EF<.35; peak VO₂<25 ml/kg/min) caused by idiopathic or postinfarction cardiomyopathy. The study group initially consisted of 16 patients; two patients were excluded from the acute study due to side effects of the drug and two more patients were excluded during the chronic part of the study because of excessive tachycardia or worsening heart failure, respectively; therefore, the final study group consisted of 12 patients. Each patient was evaluated at rest, in the supine and sitting positions, and during maximal bicycle exercise, before and after acute and chronic (2–3 months) oral nisoldipine therapy (20 mg bid). Plasma levels of renin activity, aldosterone, norepinephrine, and epinephrine were measured before and 1 hour after nisoldipine in 10 patients. Concomitant therapy with digitalis and diuretics was kept constant throughout the study. At rest, in the supine position, nisoldipine (20 mg orally) induced an acute increase of cardiac index from 2.87±0.52 to 3.93±1.52 1/min/m², with a reduction of mean arterial pressure from 97±7 to 85±9 mmHg and systemic vascular resistance from 1417±201 to 968±257 dynes sec/sec cm⁵ without significant changes of right atrial and pulmonary pressures. Hemodynamic effects peaked 1 hour after its administration and persisted for 6 hours. Similar changes were observed in the resting sitting position. At maximal exercise nisoldipine significantly increased cardiac index from 5.47±2.06 to 6.11±2.14 1/min/m² and reduced mean arterial pressure from 115±13 to 106±16 mmHg, systemic vascular resistances from 1008±333 to 770±234 dynes sec cm⁵, and pulmonary wedge pressure from 37±11 to 30±13 mmHg. Plasma norepinephrine levels showed a slight but significant increase at rest (389±108 to 580±195 pg/ml) but not at peak exercise. Plasma renin activity and aldosterone did not significantly change after nisoldipine. Two patients did not tolerate chronic nisoldipine therapy because of pulmonary edema in one case and excessive tachycardia in the other and were withdrawn from the study. After chronic therapy, the hemodynamics before nisoldipine administration were not significantly changed in comparison with baseline; the hemodynamic changes after nisoldipine were similar to those observed in the acute study. No significant change of exercise duration and peak oxygen consumption was observed after both acute and chronic nisoldipine therapy.     

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.     

Differential Modulation of Cytokine Production by Drugs: Implications for Therapy in Heart Failure

We studied the effects of various phosphodiesterase (PDE) III inhibitors: amrinone, pimobendan and vesnarinone: a PDE IV inhibitor (Ro 20-1724) and a PDE V inhibitor (E-4021) on the production of cytokines which have been shown to depress myocardial function. Recently developed inotropic agents which inhibit PDE III activity have produced short-term hemodynamic benefits in patients with advanced heart failure, but long-term treatment with these agents has an adverse effect on survival. However, vesnarinone, which has been shown to improve survival dramatically, has an immunomodulating effect and inhibits the production of cytokines. Peripheral blood mononuclear cells obtained from healthy human subjects were stimulated with lipopolysaccharide and each PDE inhibitor was added. After 24 h of incubation, tumor necrosis factor alpha (TNF-α), interleukin 1 beta (IL-1β) and IL-6 in the culture supernatants were measured by an enzyme-linked immunosorbent assay. All three PDE III inhibitors, amrinone, pimobendan and vesnarinone, inhibited TNF-αproduction, but vesnarinone's inhibitory effect was the most prominent. Amrinone and pimobendan enhanced IL-1βproduction, whereas vesnarinone had no effect. Vesnarinone inhibited IL-6 production and pimobendan slightly decreased IL-6 production, whereas amrinone had no significant effect on IL-6 production. The PDE IV inhibitor, Ro 20-1724, decreased the production of IL-1βand TNF-αand also tended to inhibit IL-6 production; its modulation of cytokine production was similar to the effects of vesnarinone. Because 8Br-cAMP or 8Br-cGMP did not suppress cytokine production, the modulating effects were not considered to result from an increase in cAMP or cGMP. Differential modulation of cytokine production may play a role in the therapeutic effect in heart failure patients who are treated with drugs that have PDE-inhibitory actions. It may be important to study whether the use of dual inhibitors of PDE III and PDE IV is therapeutically more useful for the treatment of heart failure due to their immunomodulating properties.     

Effects of Long-Term Digoxin Therapy on Heart Rate Variability, Baroreceptor Sensitivity, and Exercise Capacity in Patients with Heart Failure

We evaluated the effects of long-term digoxin therapy on exercise capacity and on physiological parameters reflecting autonomic tone in 23 patients with mild to moderate heart failure. Before and after maintenance digoxin treatment, all patients underwent cardiopulmonary exercise testing and indexes of heart rate variability (HRV) and baroreceptor sensitivity (BRS) were measured. Long-term digoxin therapy significantly (P > 0.05) increased time domain indexes (rMSSD, pNN50) which reflect parasympathetic activity (from 30 ± 16 to 37 ± 14 and from 8 ± 9 to 12 ± 7, respectively). High-frequency (HF) and low-frequency (LF) power spectral components also showed a significant increase (from 4.5 ± 1 to 5.1 ± 1 and from 5.4 ± 1 to 5.8 ± 1, respectively), but the ratio LF/HF decreased, indicating a predominance of vagal activity. The magnitude of these changes exhibited a strong negative Pearson correlation coefficient when compared with initial values before treatment. BRS increased from 2.95 ± 1.2 to 5.32 ± 3 ms/mmHg (P > 0.05). Oxygen consumption at peak exercise and at the anerobic threshold increased significantly (from 17 ± 3 to 19 ± 3 mL/kg/min and from 14.7 ± 3 to 16.5 ± 3 mL/kg/min, respectively). A persistent negative correlation was found between initial values of HRV and the magnitude of changes in exercise capacity. These findings show that long-term digoxin therapy increases vagal activity and improves exercise capacity in patients with mild to moderate heart failure and seems to exert a more marked therapeutic effect on patients with poorer initial autonomic function.     

Effect of flosequinan on exercise capacity and cardiac function in patients with chronic mild heart failure: A double-blind placebo-controlled study

Summary Although beneficial effects of a new vasodilating agent, flosequinan, have been demonstrated in patients with severe heart failure, its efficacy has not been studied in patients with a less severe form of chronic heart failure. In this study, the effects of 4 weeks' administration of flosequinan, 50mg daily, and placebo on exercise capacity, cardiac function, and symptoms of heart failure were investigated in 24 patients with chronic mild heart failure (New York Heart Association functional class, mainly class II) in a double-blind clinical trial. When the parameter changes during the treatment period of the flosequinan and placebo groups were compared, no significant difference was found in any of the measurements except for left ventricular fractional shortening determined from M-mode echocardiograms; it was increased by 2.9 ± 1.3% in the flosequinan group whereas it was decreased by 1.3 ± 0.9% in the placebo group (P < 0.05 vs flosequinan treatment). However, when compared to baseline values, flosequinan significantly increased exercise time in the symptom-limited maximal exercise test (704 ± 103 to 763 ± 107 s,P < 0.05) and the oxygen uptake at the anaerobic threshold (13.8 ± 1.3 to 16.7 ± 1.4ml/min kg,P < 0.05), and improved symptoms assessed with a new heart failure severity classification (a median value of 2.0–1.5,P < 0.05). These improvements were not observed in the placebo group. Serious adverse effects were not observed in either group. These results suggest that flosequinan is useful for the treatment of chronic mild heart failure as well as severe heart failure.Authors for the Osaka Flosequinan Multicenter Trial Group, members of which are listed in the Appendix     

Beneficial effects of low dose amiodarone in patients with congestive cardiac failure: a placebo-controlled trial

The effects of amiodarone in a low dosage (200 mg every 8 h for 2 weeks, then 200 mg/day) was assessed in a double-blind placebo-controlled trial in 34 patients with a history of severe congestive heart failure but no sustained ventricular arrhythmia. Left ventricular ejection fraction, treadmill exercise tolerance and 48 h electrocardiographic monitoring were assessed before and repeatedly after beginning amiodarone or placebo therapy over 6 months, and side effects were monitored. In patients receiving amiodarone, the ejection fraction increased significantly from 19 +/- 7 to 29 +/- 15% at 6 months (p less than 0.01 from baseline), but not significantly in 14 placebo-treated patients (18 +/- 5 to 22 +/- 9%). Exercise tolerance increased significantly in amiodarone-treated patients (median 433 s to 907 s, p less than 0.05), but not significantly in placebo-treated patients (757 to 918 s). Nonsustained ventricular tachycardia was present in 88% of amiodarone-treated patients before, but in only 21% of patients after 6 months of treatment (p = 0.06); it was seen in 43% of placebo-treated patients at baseline and in 50% after 6 months. Fifty percent of amiodarone-treated patients had side effects (principally nausea) and the drug was withdrawn in 28% of cases; no life-threatening effects were seen. Low dose amiodarone appears to have a multifaceted potential to produce benefits in arrhythmia control, exercise tolerance and ventricular function in patients with a history of severe congestive heart failure, but better control of side effects (principally nausea) appears essential. Effects on mortality could not be determined from this study; such assessment requires a larger cohort of patients.     

Estimation of left ventricular contractile performance in atrial fibrillation: Experimental and clinical studies

Summary There are few studies regarding the assessment of left ventricular contractile function in patients with atrial fibrillation (AF). The aim of this study was to assess the left ventricular (LV) contractile function, i.e., the end-systolic pressure-volume relation (Ees) and a recently developed LV systolic myocardial stiffness constant (Ksm), without load manipulation in AF. In an experimental study of acute AF in dogs (n = 5), we were able to assess these indexes of the LV contractile function during acute AF, and found that the values were similar to those obtained during occlusion of the inferior vena cava (IVC) at the baseline state. During rapid ventricular pacing (140 or 160 bpm), the indices of LV contractile function increased due to the forcefrequency relation (4.56 ± 1.85, Ees baseline; 6.42 ± 2.54^*+, Ees pacing; 5.15 ± 2.01 mmHg/ml, Ees AF;^* P < 0.05 vs baseline,⁺ P < 0.05 vs. AF) (4.73 ± 0.48, Ksm baseline; 6.24 ± 1.12^*+, Ksm pacing; 3.99 ± 1.14, Ksm AF;^* P < 0.05 vs baseline,⁺ P < 0.05 vs AF). In a study of chronic clinical AF in patients without heart disease (lone AF,n = 7), the indexes of LV contractile function were preserved compared with those of control patients (CTL,n = 10) obtained during IVC occlusion; the values were decreased in patients with both AF and dilated cardiomyopathy (AFDCM,n = 5) (2.5 ± 1.1, Ees CTL; 2.4 ± 0.4, Ees lone AF; 1.1 ± 0.3 mmHg/ml^*+, Ees AFDCM;^* P < 0.05 vs CTL,⁺ P < 0.05 vs lone AF) (5.3 ± 1.8, Ksm CTL; 4.9 ± 1.6, Ksm lone AF; 2.7 ± 0.2^*+, Ksm AFDCM;^* P < 0.05 vs CTL,⁺ P < 0.05 vs lone AF). Thus, during acute AF in dogs and in chronic AF patients, LV contractile function was assessed without load manipulation. In both the acute AF dogs and the chronic lone AF patients, LV contractile function was preserved, and in the AFDCM patients it was depressed.     

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.     

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.     

Effects of long-term treatment with pimobendan on neurohumoral factors in patients with non-ischemic chronic moderate heart failure.

To evaluate the effects of the addition of pimobendan to an optimal basic regimen on plasma levels of neurohumoral factors in patients with non-ischemic, moderate heart failure during 2-year follow-up. This prospective, observational study involved 16 patients with non-ischemic, moderate heart failure [New York Heart Association (NYHA) functional class IIM-III] receiving an optimal basic regimen of digitalis, diuretics and angiotensin-converting enzyme inhibitor. Eight patients (Group P) were also administered pimobendan at a dose of 2.5 or 5 mg daily, while the other 8 served as controls (Group C). After 3 months of pimobendan administration, the plasma levels of norepinephrine and atrial natriuretic peptide and brain natriuretic peptide decreased and left ventricular ejection fraction improved. After 1 year, the cardiac symptoms, assessed using the Specific Activity Scale as well as the NYHA functional class, improved and the left ventricular end-diastolic diameter decreased. These improvements in Group P were maintained for 2 years. However, in Group C, the cardiac symptoms and the neurohumoral factor levels remained unchanged or deteriorated during this study, and one patient died of heart failure. Long-term combination therapy with the optimal basic regimen and pimobendan has potentially beneficial effects on neurohumoral factor levels and cardiac symptoms in patients with non-ischemic, chronic moderate heart failure.     

Beneficial effects of pimobendan on exercise tolerance and quality of life in patients with heart failure. Results of a multicenter trial. The Pimobendan Multicenter Research Group.

BACKGROUND. This multicenter trial was conducted to determine the efficacy and safety of pimobendan, an inotropic agent with calcium-sensitizing properties and activity as a phosphodiesterase inhibitor, in patients with heart failure. METHODS AND RESULTS. One hundred ninety-eight ambulatory patients with symptoms of moderate to severe heart failure despite therapy with digitalis and diuretics with or without a single vasodilator were randomly assigned to receive either placebo (n = 49) or pimobendan (n = 149) in a double-blind fashion for 12 weeks. A dose range of pimobendan was used including 2.5 (n = 49), 5 (n = 51), or 10 mg/day (n = 49). One hundred fifty-eight (80%) patients were taking a converting enzyme inhibitor (CEI) and 28 (14%) patients were taking a non-CEI vasodilator. At end point, the 5-mg dose of pimobendan significantly increase exercise duration compared with placebo (121.6 +/- 19.1 seconds, p less than 0.001), whereas the 10-mg dose produced an increase of borderline significance (81.1 +/- 19.5 seconds, p = 0.05). Peak VO2 was significantly increased by 2.23 +/- 0.58 ml/kg/min in the 5-mg group (p less than 0.01 versus placebo). Furthermore, quality of life measured with the Minnesota Living With Heart Failure Questionnaire improved by 8.5 +/- 2.3 units in the 5-mg group compared with 1.3 +/- 2.2 units in the placebo group (p less than 0.01). There were a total of 23 all-cause hospitalizations in the placebo group, which was significantly greater compared with 33 in the three groups treated with pimobendan (p less than 0.01). There were no significant differences between the placebo and pimobendan groups with respect to changes in ejection fraction and plasma norepinephrine measured at baseline and at the completion of the 12-week study, proarrhythmic effect, or the number of patients with a significant adjustment in background therapy. Eleven patients died, including three (6%) on placebo and eight (5%) on pimobendan (p = NS). Among all adverse events, headache tended to be more common in the pimobendan groups compared with placebo, with the incidence increasing with dose (p less than 0.05). CONCLUSIONS. These data demonstrate that pimobendan significantly increases exercise duration, peak VO2, and quality of life in patients with heart failure. Pimobendan appears to be useful adjunctive therapy when added to digitalis, diuretics, and vasodilators.     

Patient Sex Does Not Modify Ejection Fraction as a Predictor of Death in Heart Failure: Insights from the APPROACH Cohort

BACKGROUND  Normal and low ejection fraction (EF) heart failure patients appear to have similar outcomes. OBJECTIVE  The object of this study was to determine whether sex modifies the effects of left ventricular EF on prevalent heart failure mortality. DESIGN  Prospective cohort study. PATIENTS  Patients (n = 6, 095) with a diagnosis of heart failure and a measure of EF undergoing cardiac catheterization in Alberta, Canada between April 1999 and December 2004; follow-up continued through October 2005. MEASUREMENTS  All-cause mortality was assessed in analyses stratified by patient sex and EF (≤50% vs. >50%). MAIN RESULTS  Overall, female heart failure patients were older, had more hypertension, valvular disease, less systolic impairment and coronary artery disease. Baseline medication use was similar in the four sex-EF groups. Low EF heart failure mortality over 6.5 years was slightly higher but was not significantly modified by patient sex. This relationship remained unchanged after adjustment for differences in baseline characteristics and process of care (women normal EF, reference group; men normal EF adjusted HR 1.1, 95% CI 0.9–1.3; women low EF adjusted HR 1.5, 95% CI 1.1–2.0; men low EF adjusted HR 1.6, 95% CI 1.2–2.1). CONCLUSIONS  Patient sex did not appear to modify the negative effects of low EF on long-term survival in this prospective study of prevalent heart failure. The small absolute difference in survival between low and normal EF heart failure highlights the need for further research into optimal therapy for the latter, a less well-understood condition. Preliminary findings presented as a poster at the Canadian Society of Internal Medicine Annual Meeting, Calgary, Alberta on November 2, 2006     

Cardiac troponin I: a potential marker of exercise intolerance in patients with moderate heart failure

Background In severe heart failure, increased values of cardiac troponins have been detected during decompensation. In this study, we investigated whether an increase of cardiac troponin I can be observed after symptom-limited exercise and after an exercise training session in patients with moderate heart failure. Methods Twenty-seven patients with moderate heart failure (New York Heart Association II-III, ejection fraction 31% ± 8%) were compared with 9 patients with mild heart failure and 10 subjects without heart failure. They underwent a symptom-limited exercise test and a bicycle exercise training session at >80% of maximal heart rate over 20 to 30 minutes. Plasma cTnI levels were measured at baseline, after symptom-limited exercise (hourly for 5 hours), and after training (4 and 10 hours). Results Patients with moderate heart failure showed an increase of cTnI from 37 ± 49 pg/mL to 73 ± 59 pg/mL (P < .001) after symptom-limited exercise. Four patients with moderate and 1 with mild heart failure and normal cTnI values at rest showed an increase of cTnI above 100 pg/mL after acute exercise but not after training. Subjects without heart failure had lower cTnI levels at rest and significantly lower values after symptom-limited exercise and training (P < .05 for each). Conclusion Patients with symptomatic heart failure reveal an increase of cTnI after symptom-limited exercise at levels that indicate minor myocardial damage. The prognostic impact of this finding should, therefore, be further investigated. (Am Heart J 2002;144:351-8)     

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.     

Iodine-123 metaiodobenzylguanidine scintigraphic analysis of myocardial sympathetic innervation in patients with AL (primary) amyloidosis

Background Although a high incidence of myocardial adrenergic denervation has been reported in patients with familial amyloid polyneuropathy, assessment of cardiac sympathetic nerve function has not been available in patients with AL (primary) amyloidosis. Methods To test the hypothesis that myocardial sympathetic nerve innervation might be impaired and variable according to the presence or absence of clinical autonomic abnormalities and congestive heart failure in AL amyloidosis, we examined 25 patients by use of iodine-123 metaiodobenzylguanidine (MIBG) scintigraphy. Results Ten of the 16 patients without autonomic symptoms and 5 of the 9 patients with autonomic neuropathy showed congestive heart failure. The heart/mediastinal activity (H/M) ratio (1.53 ± 0.06 vs 1.29 ± 0.05 at 3 hours, P < .001) and myocardial washout ratio (41.5% ± 4.8% vs 30.8% ± 4.0%, P < .001) of MIBG were significantly increased in patients without autonomic symptoms compared with patients showing autonomic neuropathy. In patient groups with and without autonomic dysfunction, patients demonstrating congestive heart failure exhibited a significantly decreased H/M ratio and increased washout compared with patients with no heart failure, and left ventricular fractional shortening was positively correlated with the H/M ratio and inversely correlated with the washout ratio. There were significant correlations between the low-frequency component of the heart rate variability and the H/M ratio and washout ratio in the entire patient population. Conclusions Patients with AL amyloidosis and no autonomic dysfunction showed variable degrees of enhanced cardiac adrenergic neuronal activity with presynaptic sympathetic dysfunction. In contrast, patients with AL amyloidosis and autonomic neuropathy exhibited prominent myocardial adrenergic denervation with normal or impaired sympathetic neural function of the heart. This study demonstrates that myocardial uptake and turnover of MIBG in patients with AL amyloidosis are heterogeneous and dependent on the presence or absence of congestive heart failure and cardiac autonomic dysfunction. (Am Heart J 2002;144:122-9.)     

Usefulness of enalapril in congestive heart failure

The usefulness of vasodilating agents in congestive heart failure depends on their ability to diminish left ventricular afterload; this effect does not necessarily persist with long-term treatment. The present study reports the clinical response of 16 patients in heart failure; the trial was double blind with enalapril and/or placebo during 24 weeks. Diagnoses were dilated cardiomyopathy in six, rheumatic heart disease in five, ischemic heart disease in four und hypertensive heart disease in one. Two patients on enalapril died of non cardiac causes and one was withdrawn from the study due to pregnancy. In those patients treated with enalapril the NYHA functional class improved from 2.9/0.8 to 1.1/0.4 (p less than 0.001), and the effort capacity increased from 545/171 to 888/160 seconds (p less than 0.01). Left ventricular systolic function evaluated by echocardiogram and Tc 99 m ventriculogram, radiologic size of the heart and echocardiographic left ventricular diameters showed no significant changes. There were no adverse clinical effects nor laboratory abnormalities. It is concluded that in this study, enalapril produced sustained clinical improvement in patients with heart failure and it was well tolerated during long-term treatment.