Kunio Akahane

Long‐Term Follow‐Up of Patients with Sick Sinus Syndrome: A Comparison of Clinical Aspects Among Unpaced, Ventricular Inhibited Paced, and Physiologically Paced Groups

To analyze the prognosis of the sick sinus syndrome (SSS), we compared the clinical aspects among unpaced, ventricular paced, and physiologically paced patients who were followed over a long period. Unpaced intrinsic SSS was not always progressive and patients did not necessarily require permanent pacing. The incidence of concomitant AV conduction disturbance was 65.6% before pharmacologic autonomic block, (PAB), but this was significantly reduced to 31.7% after PAB. Follow‐up study of the physiologically paced groups revealed no development of either new or more than second degree AVB. The VVI group had significantly more complications (68%) than the physiologically paced groups, mainly chronic atrial fibrillation (36%) and thromboembolism (20%). In addition, cardiothoracic ratio (CTR) in the VVI group was significantly greater compared with that in the physiologic groups. Nine deaths occurred during the follow‐up period in the pacing groups, including six with VVI and three with physiologic pacing. In the VVI pacing group, heart failure and thromboembolism were most commonly the causes of death, while in the physiologic pacing groups, the causes of death were noncardiac. Although the survival rate in the ventricular paced group was not significantly different from that in the physiologic pacing groups, cardiac deaths were fewer in the latter group. Considering our clinical data, the decision to use ventricular pacing needs to be carefully weighed in patients with sick sinus syndrome, and physiologic pacing is more highly recommended. (PACE, Vol. 11. November 1988)

Comparison between ventricular inhibited pacing and physiologic pacing in sick sinus syndrome

Abstract Sick sinus syndrome (SSS) causes not only infrequent cardiac dysfunction but also systemic complication, and pacemaker implantation has been applied to prevent such an episode. Several kinds of pacemakers have been available for clinical use. However, the selection of these pacemakers has been controversial depending on the severity and character of the conduction system impairment accompanying SSS. We have already reported the long-term follow-up results in patients with SSS who had not had a pacemaker or had implanted pacemakers of various modes. 1 In that report, we found that the ventricular inhibited paced (VVI) group had significantly more complications and a greater cardiothoracic ratio after pacing in the follow-up period than the physiologically paced groups. We concluded that the decision to use VVI pacing needed to be carefully assessed in patients with SSS, and that physiologic pacing is more highly recommended. However, the study population in that report was small and the follow-up period was short. In this article, we report the results of our further study with a larger population and longer follow-up.

Different antagonism of the positive chronotropic and inotropic responses of the isolated, blood-perfused dog atrium to Bay k 8644 by nicardipine and verapamil

The effects of Bay k 8644, a dihydropyridine calcium agonist, on sinoatrial (SA) node pacemaker activity and atrial contractility and its interaction with the calcium antagonists, nicardipine and verapamil, were investigated in the isolated, blood-perfused dog atrium. Bay k 8644 (0.03-30 micrograms) increased sinus rate and atrial contractility dose dependently. Norepinephrine (NE) and CaCl2 dose dependently increased the sinus rate and contractility but the positive chronotropic effect of CaCl2 was much less than that of the other drugs. The positive chronotropic effect of Bay K 8644 (0.3-1 microgram) was dose dependently depressed by nicardipine at doses of 1-10 micrograms but the inotropic effect was depressed only by a large dose of 10 micrograms. After sinus arrest induced by nicardipine (10-30 micrograms), SA node pacemaker activity was readily restored by Bay k 8644 or NE. Verapamil (1-3 micrograms) also depressed the positive chronotropic effect of Bay k 8644 more effectively than the inotropic effect although it did not attenuate the chronotropic effect of NE. The inotropic interaction could not be evaluated at higher doses of antagonists because of sinus arrest. Propranolol (3 micrograms) suppressed both positive chronotropic and inotropic effects of NE but did not depress the Bay k 8644-induced responses. These results show that the antagonism between Bay k 8644 and calcium antagonists is predominant on SA node pacemaker activity in cardiac tissues.

K+ channel blocking and anti-muscarinic effects of a novel piperazine derivative, INO 2628, on the isolated dog atrium

The effects of a novel piperazine derivative, INO 2628, on the negative inotropic and chronotropic responses to intracardiac parasympathetic nerve stimulation and carbachol, to adenosine and to the K+ channel openers, pinacidil and nicorandil, were investigated in isolated, blood-perfused dog heart preparations. INO 2628 (0.1-10 mumol) injected into the sinus node artery of the isolated atrium induced negative chronotropic and small positive inotropic responses in a dose-dependent manner. INO 2628 antagonized the negative chronotropic and inotropic responses to intracardiac vagus stimulation and carbachol in a dose-dependent manner, whereas INO 2628 did not antagonize the negative cardiac responses to adenosine. Pinacidil and nicorandil caused dose-dependent negative inotropic and small negative chronotropic responses in isolated atria and ventricles, suggesting that pinacidil-related K+ channels are much sparser in SA nodal pacemaker cells than in cardiac muscle cells. INO 2628 dose dependently antagonized the negative inotropic responses to pinacidil and nicorandil, but it did not modify the nicardipine-, pentobarbital- or G-strophanthin-induced cardiac responses. These results suggest that INO 2628 inhibits the negative cardiac effects of acetylcholine at muscarinic receptors and directly inhibits K+ channels in the isolated dog heart.

Differential vagal inhibition of the positive chronotropic and inotropic responses to cardiotonics in the isolated dog atrium.

The effects of vagal nerve stimulation on the chronotropic and inotropic responses to norepinephrine (NE), dobutamine, forskolin, 3-isobutyl-1-methylxanthine (IBMX) and Bay k 8644 were investigated in the isolated, blood-perfused right atrium of the dog. Electrical stimulation of intramural vagal nerves evoked decreases in the sinus rate and atrial contractile force, which were maintained at almost constant levels during stimulation. Vagal stimulation consistently attenuated both the positive chronotropic and inotropic responses to NE, dobutamine, forskolin and IBMX. The vagal inhibition of the chronotropic response to each substance was greater than that of the inotropic one except that to Bay k 8644. Vagal stimulation did not depress the positive chronotropic and inotropic responses to Bay k 8644. These results, therefore, suggest that, under parasympathetic tonic conditions, NE, dobutamine, forskolin and IBMX induce a positive chronotropic effect much less than a positive inotropic effect in the isolated dog atrium. Our results also suggest that the vagal inhibition of the chronotropic response to a beta-adrenoceptor agonist is induced at intracellular sites in the cyclic AMP cascade proximal to the Ca channel activation and also at a site proximal to the catalytic unit of adenylate cyclase.

β‐Adrenoceptor blocking effects of a selective β2‐agonist, mabuterol, on the isolated, blood‐perfused right atrium of the dog

1 Effects of (±)−1‐(4‐amino‐3‐chloro‐5‐trifluoromethyl‐phenyl)−2‐tert.‐butylamino‐ethanol hydrochloride (mabuterol) on pacemaker activity and atrial contractility were investigated in the isolated and blood‐perfused right atrium of the dog. 2 Mabuterol, injected into the sinus node artery of the isolated atrium, dose‐dependently increased atrial rate and contractile force at doses of 0.01–10 nmol but the responses to over 10 nmol of mabuterol gradually decreased and mabuterol at higher doses induced biphasic cardiac responses, i.e., negative followed by positive cardiac responses. 3 The maximal increases in atrial rate and contractile force induced by mabuterol were 41.4% and 12.9%, respectively, of the maximal chronotropic and inotropic effects of isoprenaline. 4 Positive chronotropic and inotropic responses to mabuterol were dose‐dependently inhibited by a selective β2‐adrenoceptor antagonist, ICI 118,551. These responses were only slightly attenuated by atenolol. 5 Mabuterol (1–300 nmol) dose‐dependently inhibited both dobutamine‐ and procaterol‐induced positive chronotropic and inotropic responses. 6 These results indicate that mabuterol causes weak positive chronotropic and inotropic effects on the perfused canine right atrium by activating β2‐adrenoceptors, and that higher concentrations non‐selectively block both β1‐ and β2‐adrenoceptors.