Hemodynamic performance during exercise in patients with severe chronic congestive heart failure before and after a single dose of pimobendan.

Duration of symptom-limited exercise on a bicycle ergometer (constant workload of 25 W) was determined in 12 patients with severe chronic congestive heart failure (CHF) due to dilated cardiomyopathy (CMP, 4 patients) or ischemic heart disease (IHD, 8 patients) undergoing hemodynamic monitoring. Mean exercise duration was 214 +/- 124 s and produced severe dyspnea lasting > 5 min in all patients. The next morning, each patient exercised again to the same level; pimobendan (10 mg orally) was then administered, and exercise to the same workload was repeated 4 and 10 h later. Mean +/- SD exercise-induced changes in heart rate (HR, min-1), pulmonary capillary wedge pressure (PCW, mm Hg), cardiac output (CO, L/min-1), and stroke volume index (SVI, ml.min-1) were as follows. At baseline, HR was 85 +/- 17-110 +/- 21 beats/min (p < 0.001), PCW 21 +/- 10-31 +/- 10 mm Hg (p < 0.05), CO 3.7 +/- 1.0-3.9 +/- 1.0 L.min-1 (NS), and SVI, 25 +/- 7-20 +/- 7 ml.m-2 (NS). Four hours after pimobendan administration, HR was 90 +/- 14-113 +/- 21 beats/min (p < 0.001), PCW 11 +/- 7-20 +/- 10 mm Hg (p < 0.05), CO 5.3 +/- 0.7-5.8 +/- 1.0 L.min-1 (NS), and SVI 33 +/- 3-29 +/- 7 ml.m-2 (NS).(ABSTRACT TRUNCATED AT 250 WORDS)

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

Calcium sensitization increases myocardial contractility by improving energy utilization of the myocardium, without an increase in intracellular concentrations of cyclic adenosine monophosphate. The calcium sensitizer most extensively studied up to now is pimobendan (UD-CG 115 BS). Vasodilatation results primarily from phosphodiesterase III inhibition. Orally administered pimobendan appears rapidly in plasma. A peak concentration is reached 1.5 h after drug intake; elimination from the plasma compartment has a half-life of 1.5 h. First-pass hepatic O-desmethylation of pimobendan produces the active metabolite UD-CG 212; plasma concentration curves of UD-CG 212 are similar to those of pimobendan, with a peak concentration 1-2 h later than the peak concentration of the parent compound. In patients with chronic congestive heart failure, pimobendan produces a dose-dependent and prolonged decrease in pulmonary capillary wedge pressure and an increase in cardiac output. Maintenance doses of pimobendan are well tolerated and may lead to 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 therapy with pimobendan. Patients in chronic congestive heart failure frequently die suddenly; many inotropic agents increase the incidence of sudden death in these patients. Although proarrhythmia has never been observed with pimobendan, arrhythmia suppression with amiodarone seems prudent in heart failure patients receiving maintenance doses of pimobendan.

Lack of negative inotropic effects of the new calcium antagonist Ro 40-5967 in patients with stable angina pectoris.

We screened the antiischemic, hemodynamic, and inotropic effects of different dosages of the new calcium channel blocker Ro 40-5967 in 65 patients with stable effort-induced angina pectoris. In a double-blind way, patients were randomized to recieve a single oral dose of 50, 100, or 200 mg Ro 40-5967 or placebo, given as a drinking solution. Left ventricular ejection fraction (LVEF), blood pressure (BP), and heart rate (HR) were measured at rest and during a supine bicycle exercise test on day 0 (baseline) and 2 h after drug intake on day 1. Twenty-four hours later, the bicycle exercise test was repeated. Ro 40-5967 improved exercise duration and resting LVEF. After 200 mg, exercise time increased significantly from 8.4 +/- 0.8 min (mean +/- SEM) to 9.6 +/- 0.7 min (p = 0.018), and LVEF at rest increased from 54.5 +/- 2.2 to 58.1 +/- 2.6% (p = 0.045). Time to 0.1 mV ST-segment depression increased significantly from 4.3 +/- 0.8 to 5.5 +/- 0.9 min in the 100-mg group (p = 0.013) and from 4.3 +/- 1.3 to 5.4 +/- 1.5 min in the 200-mg group (p = 0.027). Maximum ST-segment depression decreased significantly at all dose levels (p = 0.01), with the maximum decrease noted in the 200-mg group (from 0.21 +/- 0.03 to 0.15 +/- 0.02 mV, p = 0.004). BP, HR, and rate-pressure product did not change significantly at rest or at maximum exercise. A single dose of Ro 40-5967 has antiischemic properties in patients with stable angina pectoris, with maximum effects obtained after 200 mg. No signs of negative inotropy were noted, and the drug was well tolerated.

Intractable heart failure despite angiotensin-converting enzyme inhibitors, digoxin, and diuretics: long-term effectiveness of add-on therapy with pimobendan.

In 25 patients whose chronic congestive heart failure (CHF) had recently worsened to New York Heart Association class IV, pimobendan (5 to 20 mg/day) was added to maximum conventional therapy consisting of digoxin, diuretics, angiotensin-converting enzyme inhibitors, coumadin derivatives to prevent thromboembolic complications, and amiodarone to suppress serious ventricular rhythm disturbances. CHF was fatal in less than 1 month in five patients (two had shown some initial improvement). The other 20 had sustained improvement by at least one functional class, interrupted by episodes of CHF that usually responded to intravenous therapy. Median survival was 12 months (range 10 days to greater than 3 years); five patients died suddenly, 12 died of intractable CHF, and two died of other causes. Six patients were alive 3 years after the onset of treatment with pimobendan. Add-on therapy with pimobendan produced a sustained improvement in many patients with severe CHF that was no longer responding to a combination of digoxin, diuretics, and angiotensin-converting enzyme inhibitors.

Cardiovascular effects and plasma level profile of pimobendan (UD-CG 115 BS) and its metabolite UD-CG 212 in patients with congestive heart failure after single and repeated oral dosing.

Pimobendan (10 mg on day 1, then 5 mg twice daily for 28 days) was administered orally to nine patients in class III-IV stable congestive heart failure. On day 1, pimobendan appeared in plasma within 30 min, its plasma concentration peaked at 39 +/- 23 ng/ml after 1.5 h, and then decreased with a half-life of 1.44 +/- 0.94 h. Concentrations of its major metabolite UD-CG 212 peaked 3 h after drug intake, at 24 +/- 7 ng/ml. The time course of plasma concentrations was similar on days 1, 2, and 28. Cardiac index increased from 2.2 +/- 0.5 to 2.8 +/- 0.4 L.min-1.m-2 (p = 0.0001) on day 1, from 2.8 +/- 0.5 to 3.4 +/- 0.4 L.min-1.m-2 (p = 0.0032) on day 2, and stayed at 2.7 +/- 0.6 and 2.7 +/- 0.9 L.min-1.m-2 (p = 0.7895) on day 28. On day 1, pulmonary capillary wedge pressure decreased from 16 +/- 7 to 6 +/- 5 mm Hg (p = 0.0001), from 10 +/- 7 to 7 +/- 8 mm Hg (p = 0.0001) on day 2, and from 9 +/- 7 to 5 +/- 3 mm Hg (p = 0.0275) on day 28. Cardiovascular effects of pimobendan were independent of plasma concentrations. All patients improved by at least one NYHA functional class; exercise tolerance increased. No side effect was observed, but two patients died suddenly: Arrhythmogenicity should be ruled out before pimobendan is recommended for treatment of heart failure.

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.

Correlations between the cardiovascular effects of pimobendan and plasma concentrations of the parent compound and of its major active metabolite, UD-CG 212 CL, in patients with congestive heart failure.

Pimobendan was administered orally (10 mg single dose on day 1, then 5 mg twice daily for 4 weeks) to nine patients with chronic heart failure undergoing hemodynamic monitoring. The time course of changes in plasma concentrations of pimobendan and of its major active metabolite. UD-CG 212 CL, was similar on days 1, 2, and 28. Pimobendan plasma levels peaked 1.5-2.0 h after drug intake: plasma concentrations of UD-CG 212 CL reached a maximum 1 h later; the terminal half-life of pimobendan in plasma varied between 1.44 +/- 0.94 h on day 1 and 1.19 +/- 0.36 h on day 2. Initially, cardiovascular variables changed with increasing plasma drug levels and reached a maximum 4 h after pimobendan intake; later, we found no correlation between plasma concentrations and hemodynamic effects. A steady state of hemodynamic improvement was achieved after 4 weeks of maintenance therapy with pimobendan. Baseline pulmonary capillary wedge pressure dropped from 16 +/- 7 mm Hg on day 1 to 5 +/- 3 mm Hg at noon on day 28 (-69%; p less than 0.001), and baseline cardiac index increased from 2.2 +/- 0.5 L/min/m2 on day 1 to 2.7 +/- 0.9 L/min/m2 on day 28 (+23%; p less than 0.01). Pimobendan is a long-acting drug that effectively improves cardiac performance in patients with chronic congestive heart failure.

Growth rate of left atrial myxoma. Development of a symptomatic left atrial myxoma less than two years after coronary artery bypass grafting.

In April 1984, a left atrial myxoma almost filling the left ventricle was discovered in a patient who had no evidence of myxoma at the time of aortocoronary bypass grafting in September 1982. We conclude that the growth rate of a primary cardiac myxoma may be much faster than expected from previous observations.

[Hemodynamic effects of intravenous perfusion of amrinone in increasing doses in 12 patients with severe heart decompensation]. / Effets hémodynamiques d'une perfusion intraveineuse d'amrinone à doses croissantes chez douze patients en décompensation cardiaque sévère.

Twelve patients with severe heart failure were given amrinone by intravenous infusion in doses rising from 1 to 2, 3 and 4 mg X min-1, the interval between each dose being 30 min. The total cumulative dose was 300 mg over 120 min. Haemodynamic measurements were started the day before treatment to take into account nycthemeral fluctuations in haemodynamics and the possible effects of maintenance treatments and meals, all factors which might influence the baseline values. When given at a rate of more than 2 mg X min-1, amrinone significantly improved cardiac function (p less than 0.001). The mean pulmonary capillary pressure fell from 24.1 +/- 5.3 to 13.7 +/- 8.6 mmHg, and the cardiac index rose from 1.75 +/- 0.40 to 2.51 +/- 0.32 1 X min-1 X m-2. Heart rate and blood pressure were not significantly modified. No adverse reaction was observed during the infusion and the following 24 hours. Thus, intravenous amrinone proved effective in patients with severe heart failure, with maximal effects being obtained in doses of 3 mg X min-1.

Prevalence of retrograde conduction in heart block after DDD pacemaker implantation.

Electrophysiologic studies were performed before DDD pacemaker implantation in 50 patients with symptomatic heart block. The patients were separated into 2 groups. Group I consisted of patients with intact retrograde conduction and group II consisted of patients with blocked retrograde conduction. After pacemaker implantation, postventricular atrial refractory periods in patients in group I were programmed at 50 to 100 ms, in excess of the retrograde conduction times measured during electrophysiologic studies. In group II patients, postventricular atrial refractory periods were routinely programmed at 300 ms. During follow-up, patients visited the outpatient clinic at 3-month intervals for noninvasive assessment of the prevalence of retrograde conduction, and to test the inducibility of pacemaker-mediated tachycardias. The mean follow-up of group I (15 patients) was 27 +/- 10 months, whereas the mean follow-up of group II (35 patients) was 19 +/- 9 months. The mean number of noninvasive tests performed during follow-up was 8 +/- 3 per patient for group I and 5 +/- 3 per patient for group II. In group I, retrograde conduction remained intact in 12 patients (p less than 0.01). In 29 of 31 patients in group II, retrograde conduction remained absent (p less than 0.01). In 4 patients in group II, chronic atrial fibrillation occurred during follow-up. Chronic atrial fibrillation did not occur in any patient in group I. During serial electrophysiologic testing, no pacemaker-mediated tachycardias could be induced in any patient in group I or II.(ABSTRACT TRUNCATED AT 250 WORDS)

Pacemaker electrocardiography of rate smoothing during DDD pacing.

A rate smoothing option is available in a new bipolar AV universal (DDD) pacemaker. In three patients, two with intact retrograde conduction and one with retrograde block, rate smoothing values of 3% and 6% were programmed. Irregular pacemaker-mediated tachycardia occurred in one patient and AV synchrony was temporarily lost in the other two patients. In this report, we describe the pacemaker electrocardiography of rate smoothing during DDD pacing.

Flecainide: one-year efficacy in patients with chronic ventricular arrhythmias.

During a one-week short-term in-hospital period, 60 patients with chronic ventricular arrhythmias were treated with 200 mg flecainide twice a day. Flecainide reduced premature ventricular complexes (PVCs) by more than 85% without causing important side-effects in 47 patients, who entered a one-year follow-up period and were followed with bimonthly 24-h ECGs. Median PVC-frequency remained reduced by more than 99% during the follow-up period. Repetitive ventricular beats and ventricular tachycardia were present in 83% and 42% of patients, respectively, before flecainide. During follow-up, these arrhythmias were seen in less than 32% and less than 10% of patients, respectively, at each 24-h ECG. Furthermore, the mean number of hours with repetitive ventricular beats and ventricular tachycardia remained reduced by more than 76% and more than 79%, respectively, throughout the follow-up period. Ventricular arrhythmias remained suppressed despite a gradual reduction in flecainide dosages (to a median of 300 mg day-1) and flecainide plasma levels. In nine out of 47 patients, an increase in ventricular arrhythmias above baseline values on one or more occasions was observed. During a flecainide withdrawal period, a 65-fold increase in median PVC-frequency was observed and ventricular tachycardia reappeared in 18 patients. Subjective side-effects were acceptable except for two patients. During the follow-up period, one patient developed reversible heart failure and sinus node dysfunction. During the total study period, four patients, with either severe coronary artery disease (2) or cardiomyopathy (2) developed lethal arrhythmias (3) or ischaemic events (1). We conclude that prolonged flecainide treatment is effective in a high proportion of patients with chronic ventricular arrhythmias. In some patients an arrhythmogenic effect may occur.

Serial electrophysiologic studies after single chamber atrial pacemaker implantation in patients with symptomatic sinus node dysfunction.

After single chamber atrial pacemaker implantation, serial electrophysiologic studies were performed noninvasively at intervals of 3 months over a total period of 3 years in 24 patients with symptomatic sinus node dysfunction. All patients underwent invasive electrophysiologic studies before pacemaker implantation and demonstrated intact anterograde AV conduction. Patients were divided into 2 groups: group I did not require antiarrhythmic drugs during follow-up whereas group 2 received antiarrhythmic drugs. In group I (11 patients) the atrial paced heart rate producing AV Wenckebach phenomenon (AVWHR) remained stable during a mean follow-up of 22 +/- 10 months; with a variability not exceeding 10 beats min-1 with respect to the initial AVWHR obtained during preoperative electrophysiologic study. In group 2 (13 patients) with a mean follow-up of 15 +/- 8 months a mean decrease of AVWHR of 19.2 +/- 17.5 beats min-1 was present between AVWHR before and 3 months after initiation of oral antiarrhythmic drugs (P less than 0.01). During chronic (greater than 3 months) antiarrhythmic drug therapy the variability of the AVWHR never exceeded 10 beats min-1 with respect to the AVWHR obtained 3 months after the initiation of oral drug therapy. Deterioration of anterograde AV conduction during long-term follow-up of patients with symptomatic sinus node dysfunction and intact anterograde AV conduction at the time of pacemaker implantation is a consequence of orally taken antiarrhythmic drugs, rather than a consequence of degeneration of the AV conducting system.

Physiological interpretation of the skewness of indicator-dilution curves; theoretical considerations and a practical application.

Indicator-dilution curves can be interpreted and analysed by describing the system between injection- and sampling site with a physical model. Till now mainly compartmental and distributed models have been investigated. One feature of distributed models is the possibility to interpret skewness or asymmetry of the curve in terms of a parameter, proportional with the Peclet number, which is a measure of the relative contribution between convection and diffusion in indicator transport. In patients with and without pulmonary edema, we analyzed a number of curves obtained with an intravascular indicator (131I radioiodinated serum albumin, RISA) and a diffusing indicator (tritiated water, THO) over the pulmonary vascular bed. Edema was measured by indexed extravascular lung water and by critical pressure, defined as the difference between pulmonary capillary wedge pressure and plasma colloid osmotic pressure. The significant decrease of the symmetry of the RISA curves with increasing cardiac output we explained by an increasing labyrinth dispersion and increasing turbulence at higher flows. For normals we found all THO curves to be less skew than albumin curves. This difference diminished and even reversed when the degree of pulmonary edema increased. We suggest a hypothesis for this phenomenon by considering various mechanisms responsible for dispersion and capillary exchange of the indicator during transport from injection to sampling site. In normals the contribution of Taylor diffusion during laminar flow in parts of the circulatory system may be responsible for the greater symmetry of THO curves; with increasing pulmonary edema, transcapillary diffusion of THO causes THO curves to become more skew and even more asymmetric when compared with albumin curves.

Responses of an AV universal (DDD) pulse generator (Cordis 233D) to programmed single ventricular extrastimuli.

To evaluate factors playing a role in initiation and perpetuation of pacemaker-mediated tachycardias (PMTs), 22 consecutive patients with symptomatic conduction disorders were studied after implantation of an AV universal (DDD) pulse generator (Cordis 233D). Patients were divided into two groups, depending upon the presence or absence of ventriculo-atrial (VA) conduction during electrophysiological study (EPS) performed before pacemaker implantation. PMTs could be initiated in six of eight patients of Group I and in none of 14 patients of Group II. Initiation and perpetuation of PMTs during DDD pacing were dependent upon the capacity of the patient to conduct ventricular premature beats (VPBs) and subsequent paced ventricular beats retrogradely to the atria, and upon three programmable parameters of the pulse generator (AV delay period, upper rate limit, tachycardia response). Programmed single ventricular extrastimulation demonstrated that: (1) merely the presence of VA conduction during EPS, although necessary, was not sufficient to induce PMTs after DDD pacemaker implantation; (2) VPBs introduced late rather than early in the cardiac cycle initiated PMTs in a different way; (3) the initiation of PMTs could be prevented during study by adjusting the programmable parameters (AV delay period, upper rate limit, tachycardia response); (4) one of the two available tachycardia responses of the pulse generator (gradual fall-back response) was able to terminate and initiate PMTs consistently. These observations helped in understanding the responses of the Cordis 233D pulse generator to ventricular premature beats. They indicate that additional refinement of the pulse generator is necessary to solve the problem of PMT.

Cardiovascular effects of sulmazol administered intravenously to patients with severe heart failure.

Ten patients with severe heart failure (NYHA class IV) received sulmazol intravenously under haemodynamic and electrocardiographic surveillance. All patients were on maintenance doses of digitalis and diuretics. At 30 min intervals we increased the infusion rate of sulmazol from 1 to 2, 4, 6, and 8 mg min-1, to a total of 630 mg of sulmazol administered over 150 min. Statistically significant changes (P less than 0.001) were found for heart rate (from 97 to 103 min-1); right atrial pressure (from 9.5 to 1.5 mmHg); pulmonary artery diastolic pressure (from 25.0 to 9.0 mmHg); pulmonary capillary wedge pressure (from 22.0 to 9.0 mmHg); aortic diastolic pressure (from 62.5 to 52.5 mmHg); pulmonary artery oxygen saturation (from 53.0 to 68.5%); cardiac output (from 2.83 to 4.38 l min-1), and for indices derived from these measurements. No correlation was found between the improvement in cardiac performance and sulmazol plasma concentrations. Haemodynamic improvement persisted for more than 7.5 h after cessation of sulmazol administration. Renal function was measured before and after sulmazol administration; creatinine clearance (from 47.5 to 52.0 ml min-1) and p-amino hippuric acid clearance (from 146 to 125 ml min-1) were unchanged. Side-effects included yellow-colored vision, ventricular extrasystoles, and possibly sulmazol-induced liver function disturbances. Even in severe heart failure sulmazol improved cardiac performance in patients who were treated with the maximum tolerated dose of digoxin.

Right to left shunt, with severe hypoxemia, at the atrial level in a patient with hemodynamically important right ventricular infarction.

This report describes a patient with a massive right ventricular infarction, complicated by severe hypoxemia. Contrast echocardiography demonstrated a right to left shunt through a previously asymptomatic atrial septal defect. This phenomenon should be considered as a possible cause of hypoxemia in the presence of right ventricular infarction.