Frans Hagemeijer

Sensitivity to digitalis drugs in acute myocardial infarction.

Abstract Tolerance for digitalis during acute myocardial infarction was evaluated by acetyl strophanthidin testing. Fifty-four patients hospitalized in a coronary care unit were studied within 48 hours of admission; continuous electrocardiographic monitoring and the rapid onset in activity of acetyl strophanthidin allowed a precise titration of druginduced arrhythmias. The dose schedule was 0.1 to 0.2 mg every 5 to 6 minutes. Tolerance for 1.0 mg of acetyl strophanthidin or the emergence of gastrointestinal symptoms or electrocardiographic signs of early digitalis intoxication with 1.0 mg or less constituted the test procedure. Forty-eight of the patients (89 percent) tolerated a full dose of acetyl strophanthidin; ventricular ectopic mechanisms developed in only 3 patients (6.0 percent of those receiving 1.0 mg). An increase in blood pressure followed administration of acetyl strophanthidin in 32 (59.3 percent) of the 54 patients. These data suggest that the large majority of patients with acute myocardial infarction and heart failure can safely be treated with digitalis drugs.

Effect of Heart Rate on Electrically Induced Repetitive Ventricular Responses in the Digitalized Dog

After recovery from acetylstrophanthidin-induced ventricular tachycardia, a repetitive ventricular response (RVR) following a single diastolic stimulus could be elicited for 22 minutes. With atrial pacing at the maximum ventricular follow rate, RVR was obtainable for 70 minutes. A pause in pacing also evoked a ventricular ectopic beat; however, this persisted for only 27 minutes. The minimum heart rate required for RVR was always less than the minimum rate required for pause-induced ectopic beats. Extrasystoles following a pause during pacing, RVR in sinus rhythm, and RVR during rapid heart rates represent decreasing levels of ventricular automaticity corresponding to progressive dissipation of digitalis intoxication. The underlying mechanism for RVR probably is due to net loss of intracellular potassium, which can be induced both by digitalization and by rate acceleration.

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.

Comparison of Serum Digoxin Level Measurement with Acetyl Strophanthidin Tolerance Testing

Serum digoxin levels (SDL) were compared with tolerance for the rapidly acting cardiac aglycone, acetyl strophanthidin (AS). AS titration tests were performed on 133 patients with diverse cardiac disorders. All were receiving maintenance digoxin. Both exquisite AS sensitivity and tolerance for a 1.0 mg AS were associated with a wide range of SDL values. Concordance and discordance between the two methods in assessing degree of digitalization were evaluated by considering SDL of 1.4 ng/ml to be the mean value for patients without glycoside-induced cardiac arrhythmia. An SDL of < 1.5 ng/ml with tolerance for 1.0 mg AS and an SDL of > 1.4 ng/ml with sensitivity to 1.0 mg AS or less constituted concordant responses. An SDL of < 1.5 ng/ml with intolerance for 1.0 mg or less AS and an SDL of > 1.4 ng/ml with tolerance for 1.0 mg AS comprised discordant responses. In 60 of 144 (42%) AS titrations discordant results were observed. Severe pulmonic, coronary, and aortic valvular heart disease, as well as old age, contributed to unusual AS sensitivity. Titration with AS clarified pharmacologic quantification of SDL by providing insight into optimum therapeutic glycoside dose.

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.

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)

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 maxiμm 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 maxiμm 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 < 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 < 0.01). Pimobendan is a long-acting drug that effectively improves cardiac performance in patients with chronic congestive heart failure

Anti-arrhythmic efficacy of aprindine in acute myocardial infarction

ULTRASOUND EVALUATION OF SYSTOLIC ANTERIOR SEPTAL MOTION IN PATIENTS WITH AND WITHOUT RIGHT VENTRICULAR VOLUME OVERLOAD Arthur Hagan, MD; Gary Francis, MD; David Sahn, MD; Joel Karliner, MD, FACC; William Friedman, MD, FACC; and Robert O’Rourke, MD, FACC, U. S. Naval Hospital and University of California, San Diego, California Systolic anterior septal motion (SASM) has been proposed as a reliable indicator of right ventricular volume overload (RVVO). Accordingly, we studied 244 patients (pts) without clinical or catheterization evidence of RVVO employing the ultrasound continuous recording technique. At the level of the mitral valve SASM was present in 11 1 pts; in 39 pts the septum did not move during systole while in 74 pts, septal motion was variably anterior and posterior during the same recording. However, at the level of the chordae tendinae, 225 of the 244 pts (92%) had normal posterior septal motion. The other 19 pts had severely impaired left ventricular function. In 30 pts with RVVO, 16 had abnormal septal motion at the level of the chordae tendinae (13 with SASM and 3 with no movement). To evaluate septal motion further, 100 normal subjects were studied using a phased multicrystal ultrasound system (by Bomi which provides a saggital plane image of the cardiac structures. In all 100 subjects the superior septum moved anteriorly in systole with the aortic root, whereas the midportion of the septum acted as a “hinge” for the inferior portion, which moved posteriorly. In 8 of 20 pts with RVVO, the entire septum moved anteriorly during systole; variable patterns occurred in 5 pts, while normal septal motion was present in 7 pts. We conclude: 1) that SASM is usually present when reptal motion is recorded at the mitral valve level in pts with and without RVVO, and 2) that abnormal septal motion is not a constant echocardiographic finding in pts with RVVO even when recordings are performed at the level of the chordae tendinae. ANTI-ARRHYTHMIC EFFICACY OF APRINDINE IN ACUTE MYOCARDIAL INFARCTION. Frans Hagemeijer, MD : Paul G .Hugenholtz, MD, FACC, Thoraxcenter,Erasmus University Rotterdam,Netherlands. Aprindine (A) is a new, lonqacting, orally effective antiarrhythmic drug, with electrophysiologic properties akin to those of Lidocaine (L). In 40 consecutive patients (pts) admitted to the CCU with a diagnosis of acute myocardial infarction (MI) and evidence for ventricular irritability, a double-blind randomized study was undertaken compariq the effectiveness of oral A (200 mg, then 100 mg g 12 h for 60 h) and intravenous L (2 mg/min for 60 h) in preventing ventricular arrhythmias. These were detected by on-line computer monitoring of the ECG, standard monitoring, recording of a 60 set rhythm strip every two hours, and observation by nurses and doctors. 5 pts (lA, 4L) proved not to have MI. Treatment was considered excellent if no ventricular arrhythmias were observed : good if no serious arrhythmia occurred; a failure if VF, VT, doublets, or early VPB’s appeared despite therapy : Excellent Good Failure A 13 2 4 L 5 2 9 Gas chromatographic analysis of serum levels of A gave the following values (mg/l) : 0.6-l. 1 12 h after first dose ; 1.7-2.8 60 h after first dose: 0.9-2.0 48h after last dose. The only possible symptoms of drug toxicity involved the central venous system : nightmares, hallucinations, restlessness. 2 A pts and 3 L pts were so affected. 1 A pt and 2 L pts died during the first 7 days after admission. Oral Aprindine compares favourably with intra venous Lidocaine in preventing ventricular arrhythmias after acute MI. DIAGNOSIS VALUE OF THE ELECTROCARDIOGRAM IN RECURRENT MYOCARDIAL INFARCTION : AN AUTOPSY STUDY. Robert Haiat, MD, Associate Fellow ACC; Christine Halphen, MD; Claude Seban, MD; Paul Chiche, MD FACC; H8pital Tenon, Paris, France. Of 294 consecutive autopsies data of patients (pts) dying of myocardial infarction (MI), 45 with recurrent MI, were selected and correlated to the electrocardiogram (ECG). ECGs were first interpreted without knowledge of pathological findings. Accuracy of the ECG diagnosis was then evaluated. Results were classified into 3 categories : (I) in I4 pts (31,1%) diagnosis was correct as both old and recent MIS were recognized; (2) in 26 pts (57,7%) diagnosis was incomplete due to the lack of ECG signs of either the old (8 pts) or recent (I8 pts) MI; (3) in 5 pts (ll,Z%) MI could not be detected on the ECG. Many factors contribute to obscure the diagnosis : lack of serial tracings especially when ECG have become normal after the previous MI; presence of intraventricular conduction disturbances, left bundle branch block mainly; recurrent MI occurring in the subendocardial region or in an already infarcted area (31 of 45 pts); atypical ECG patterns, the absence of early ST-T changes being quite remarkable. It is concluded that, ECG is inaccurate in recognizing recurrent MI as correct diagnosis was possible in only I4 of 45 pts (3l,l%), the recent MI being twice more often unrecognized than the old one. DETERMINANTS OF REVERSIBILITY OF LEFT VENTRICULAR FUNCTION AFTER AORTOCORONARY BYPASS SURGERY Robert I. Hamby, MD, FACC; Agop Aintablian, MD; Farouk Tabrah, MD; Marvin L. Hartstein, MD; B. George Wisoff, MD, Long Island Jewish-Hillside Medical Center, New Hyde Park, New York. Left ventricular (LV) hemodynamics and contractile patterns were evaluated in 104 patients (pts) before and after aortocoronary bypass surgery. grafts (171). All pts had patent Group I consisted of 44 pts with single grafts. Mean LV end-diastolic pressure (LVedp), volume and ejection fraction (EF) did not change. Twenty-four pts who had asynergy preop revealed 16 with a normal contractile pattern postop. Group II consisted of 47 pts with double vein grafts. Significant decrease in LVedp (p<O.O05) and increase in EF (p ~0.001) postop. Asynergy in 29 pts preop revealed postop IS synergy, 3 improved, 9 no change and 2 became worse. Group III consisted of 10 pts with triple vein grafts. EF significantly increased postop (p<O.Ol). All but 2 of the 8 pts with asynergy preop showed synergy postop. in 43 pts preop, Synergy with one exception, persisted postop. Asyneresis in 41 instances preop revealed postop 38 (93%) had normal wall movement. In 29 instances of preop akine sia of a wall, only 8 (28%) showed a return to normal wall movement. Unstable angina pectoris alone did not influence reversibility of abnormal contractile patterns. Unstable angina pectoris with absence of abnormal Q waves in the EKG was noted in 23 pts with asynergy. All but 1 pt had synergy postop. Pts with infarction pattern on the EKG, when accompanied by asynergy, were unlikely to have a normal contractile pattern postop (b/23). Reversibility of LV function after surgery is common, not related to number of grafts, but is related to type of LV wall abnormality, EKG and clinical state of pt. 142 January 1974 The American Journal 01 CARDIOLOGY Volume 33

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

Summary: 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 ± 1.0L × min-1 (NS), and SVI 33 ± 3–29 × 7 ml × m-2 (NS). Ten h after pimobendan, HR was 89 ± 17–113 ± 21 beats/min (p < 0.05), PCW 14 ± 7–24 ± 7 mm Hg (p < 0.001), CO 5.4 ± 0.7–5.4 ± 1.4 L ± min-1 (NS), and SVI 34 ± 7–27 ± 10 ml · m-2 (NS). Hemodynamic variables at rest improved markedly after pimobendan; the decrease in PCW and the increases in CO and in SVI were highly significant (p < 0.0001). Pimobendan decreased severity and duration of exertional dyspnea. Increases in HR and in PCW during exercise were similar before and after pimobendan; CO and SVI did not increase during ergometry.