Josef Kaliman

Sensitivity of platelets to prostaglandins in coronary heart disease and angina pectoris

The platelet sensitivity to the antiaggregatory prostaglandins (PGI2, PGE1 and PGD2) was studied in patients with angiographically verified coronary heart disease. The sensitivity was tested in vitro by inhibiting the ADP-induced platelet aggregation by various concentrations of these prostaglandins. Beside the age dependent alterations of platelet sensitivity reported earlier, there is a statistically significant decrease in sensitivity for PGI2 and PGE1 in patients with coronary heart disease. In contrast, no significant change for the PGD2-sensitivity could be observed. In angina pectoris a further significant decrease in sensitivity (again only for PGE1 and PGI2) was found which returned back to the starting values within a few hours. In patients with maturity onset diabetes and coronary heart disease the sensitivity was always lower than in those patients with coronary heart disease alone. Changes in platelet sensitivity might play a key role in initiating and progressing atherosclerosis by an immediate disturbance of hemostatic balance. The studies further support the hypothesis that PGI2 and PGE1 share the same receptor on the platelet surface.

Comparable effect of prostaglandin E1 in decreasing in vivo platelet deposition on human lesion sites after intravenous and intraarterial application

It had been claimed that prostaglandin E1 is degraded during first lung passage to a major extent. Clinical results, however, as well as various platelet function tests and coagulation parameters revealed no apparent difference after i.v. and i.a. infusion. Thus, we examined the question what the quantitative difference between i.v. and i.a. PGE1-application would be upon in-vivo platelet function assessed by platelet uptake over active lesion sites as well as platelet half-life monitoring after autologous 111-In-oxine platelet labelling. In patients suffering from peripheral vascular disease stage II according to Fontaine PGE1 was able to decrease platelet uptake after i.v. and i.a. therapy to a comparable extent; similarily, a significant prolongation in platelet half-life was noted, again revealing no difference. As the decrease in platelet uptake is assumed to be predominantly a vascular effect, it is hypothetized that more stable derivatives of PGE1 are active, counterbalancing a lower biological activity with a longer half-life.

Beneficial effect of long-term PGE1-treatment in left ventricular heart failure.

Five male patients aged 34-47 years with congestive heart failure showed an improvement of left ventricular ejection fraction (LVEF) at rather low PGE1-doses (10-30 ng/kg/min) without affecting blood pressure or heart rate. LVEF was estimated by means of radionuclide ventriculography (RNV) prior to and during i.v.-infusion of PGE1 at increasing dose rates (10-100 ng/kg/min). Therefore, we administered to these responders PGE1 at a rate of 20 ng/kg/min i.v. continuously on a long-term basis by means of a portable infusion pump. Until up to 4 months the remarkable benefit in LVEF induced by PGE1 was still present to a comparable extent in all the patients. No rebound desensitization phenomenon occurred either on platelet activity or on LVEF. PGE1, via a more practical route of application or by a stable analogue, may be a promising therapy at this stage of cardiomyopathy (CMP).

Enhanced prostacyclin formation in veins of women under chronical treatment with oral contraceptive drugs.

This study attempted to examine the venous prostacyclin formation, platelet sensitivity, and platelet function in women taking oral contraceptive (OC) pills. All patients and controls were healthy except for varicose veins. 8 pill users (.25 mg Norgestil, .05 mg oestradiol) and 12 controls underwent surgery for varicose veins, and morphologically controlled, unchanged venous tissue (saphenous vein) was removed during the surgery. Blood samples were collected and assayed for platelet tests. In terms of prostacyclin formation, in comparison to age-matched controls the formation in saphenous vein tissue of OC users was statistically significantly enhanced (P .01). This difference held for both age groups studied (aged 21-3 and aged 31-40). No significant difference of the platelet reaction on exogenous PGI2 (prostacyclin) was detected. In addition, neither the dose of PGI2 needed to suppress the aggregation response to half nor the response on different PGI2 doses was different. In OC users, the ADP-induced platelet aggregation was slightly more activated than in controls, but this was not statistically significant.

Diminished platelet residence time on active human atherosclerotic lesions in-vivo — Evidence for an optimal dose of aspirin?

Although aspirin is an old drug, its optimal dose for the treatment of human atherosclerosis has not been finally proven. Various in-vitro and ex-vivo platelet function tests revealed a dose range from 1 to 3000 mg as being optimal. It was thus the goal to examine its in-vivo efficacy in human suffering from peripheral vascular disease in 7 different doses ranging from 1 mg to 1000 mg a day. All these patients have been treated for 3 months. Platelet half-life and platelet uptake ratio show an in part significant improvement being most pronounced at the daily doses of 20 and 1000 mg respectively. No change occurs in the placebo treated controls. These findings indicate, that 20 or 1000 mg aspirin taken daily per os, are superior to the other doses examined concerning the in-vivo platelet function (as measured by platelet half-life) and rendering the arterial surface less thrombogenic (as reflected by platelet uptake ratio-measurements).

Exercise testing after surgical repair of coarctation of the aorta

SummaryAfter repair of coarctation, exercise testing was performed in 20 patients with an isolated coarctation (group I) and in 26 with additional congenital cardiac malformations (group II). Ages at time of operation were significantly different in both groups (7.9±6.0 years in group I; 4.6±3.8 years in group II;p≤0.01). Simultaneous blood pressures were obtained from upper and lower limbs at rest and after exercise. There was no significant difference regarding the systolic blood pressures at rest (122.5±15.6 mmHg in group I versus 119±15.8 mmHg in group II). Seven (14%) of the patients were hypertensive; five of them had blood pressure gradients between arms and legs of 15–45 mmHg. But the gradients at rest were found to be significantly different in both groups (9.0±10.5 mmHg in group I; 18.5±16.1 mmHg in group II;p≤0.05). Six patients, all in group II, had gradients ≥30 mmHg at rest. After exercise there were no significant differences in systolic blood pressure and gradients in both groups. Values for blood pressures and gradients at rest and after exercise showed a positive correlation (blood pressurer=0.76,p≤0.001; gradientr=0.44,p≤0.01). Thus exercise testing can provide valuable information about blood pressure and gradient changes during physical activity, but angiography is required to reveal restenosis or residual stenosis.

Subsidiary pacemaker function in complete heart block after His-bundle ablation.

To investigate the electrophysiological properties of ventricular impulse formation after His-bundle ablation in 11 patients, incremental ventricular overdrive stimulation studies were performed. The studies, which were spread over a follow-up period of up to 601 days, were carried out invasively with temporary leads as well as noninvasively with the implanted pacemakers and chest wall inhibition. The overdrive pacing rate was increased in steps of 10 beats/min, and the pacing duration was 2 minutes at each level. Ten out of 11 patients had a reliable ventricular escape rhythm; in the remaining patient, consistently no subsidiary pacemaker function was observed up to 10 seconds. In 83% of the studies, incremental ventricular overdrive stimulation caused progressive suppression of ventricular impulse formation with exponential increase in ventricular recovery time and progressive postrecovery subsidiary pacemaker depression. In the remaining 17%, ventricular recovery time showed a heterogeneous response to overdrive stimulation--as possible cause alterations in the sympathetic tone and limitations attributable to the method used are discussed. The results of this study demonstrate a rate-dependent overdrive suppression of subsidiary ventricular pacemaker tissue. This can be of clinical importance in patients with complete heart block and rate-adaptive pacemakers because sudden pacemaker failure or temporary pacemaker inhibition at high stimulation rates may cause Stokes-Adams attacks not reproducible at lower pacing rates.

Electrophysiologic Findings in Carotid Sinus Massage

Thirty patients with carotid sinus syndrome were electrophysiologically studied. In 14 patients carotid sinus massage was performed during atrial and ventricular stimulation, and the conduction times were measured. The AH‐time was prolonged by more than 120ms in 6 patients(20%); the HV‐time was prolonged in 6 patients by more than 55 ms (20%); 5 patients had bundle branch block (16.7%); The sinus node recovery time was prolonged in 7 out of 27 patients (26%). Ten patients (33%) did not have additional electrophysiologic abnormalities. There was a predominance of carotid sinus syndrome on the right side. During carotid sinus massage there was a significant increase of the AH‐time, but there were no significant changes of the HV‐time or the width of the QRS‐complexes. Twenty‐one patients developed an atrial asystole and 9 patients an atrial bradycardia and an additional AV‐block. There was a longer AH‐time and a longer prolongation of the AH‐time in the patients who developed an AV‐block. Twelve out of 14 patients (85.7%) developed an AV‐block during carotid sinus massage and atrial pacing. During ventricular pacing 5 of 14 patients (35.7%) revealed a complete retrograde block before carotid sinus massage and 5 of the remaining 9 patients developed a total retrograde block during carotid sinus massage. Consequently, in 71.4% of the patients with carotid sinus syndrome complete retrograde conduction block and atrial asystole can be expected during attacks of ventricular asystole and simultaneous ventricular pacing. In conclusion, there is a high incidence of additional disturbances of the sinus node function and AV‐conduction in patients with carotid sinus syndrome. AAI pacemakers are contraindicateddue to the common development of additional A V‐block during carotid sinus massage. Physiologic pacing might contribute to better hemodynamics, particularly in patients with the mixed type of carotid sinus syndrome.

Determinants of Subsidiary Ventricular Pacemaker Suppression in Man

To investigate the relative contribution of the duration and rate of overdrive to subsidiary ventricular pacemaker suppression, in six patients with complete heart block after His‐bundle ablation, ventricular overdrive stimulation studies were performed. The studies, which were spread over a mean follow‐up period of 745 days, were carried out invasively with a temporary lead (one patient) as well as nonin‐vasively with the implanted pacemakers and chest wall inhibition (five patients). The overdrive pacing rate was increased in steps of 10 beats/min, and the pacing duration was 15, 30, 60, 90, and 120 seconds at each level. A recovery period of 2 minutes was allowed after each overdrive stimulation. Incremental ventricular overdrive stimulation at increasing pacing durations consistently caused progressive suppression of ventricular impulse formation. Nonparamelric variance analysis demonstrated a significant (P < 0.0001) influence of both the pacing rate and duration on ventricular recovery time. Nonlinear regression showed an exponential increase in recovery time with incremental pacing rate and a biphasic increase in recovery time with incremental pacing duration. Beyond a pacing duration of 60 seconds ventricular impulse suppression was primarily dependent upon the pacing rate. A nonlinear regression model was applied to predict the number of heals required for return of the escape rhythm toward prepacing control values. The predicted maximum mean number of beats was 15.4 ± 5.9 and independent of the rate and duration of pacing, although, the initial temporary instability of the escape rhythm was directly related to the degree of overdrive.

Rate Dependent Depression of Subsidiary Ventricular Impulse Formation—Cause of Stokes‐Adams Attacks in a Patient with Rate Modulated Pacing

Following His bundle ablation and implantation of a rate adaptive pacemaker (Vitatron TX 911) a 52‐year‐old gentleman experienced several presyncopal attacks while driving a car. On examination pectoralis muscle contraction caused temporary pacemaker inhibition. Incremental overdrive stimulation demonstrated progressive depression idioventricular automaticity and was associated with similar symptoms following overdrive at high pacing rates. Following appropriate pacemaker programming the patient remained symptom free.