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The action of nifedipine given first intravenously and then orally was studied in nine patients undergoing investigation for angina pectoris who were already receiving atenolol (100-200 mg/daily) and who had been shown to be fully beta blocked (reduction in maximal heart rate by greater than 25%). Intravenous nifedipine 7.5 micrograms/kg reduced both systolic blood pressure and left ventricular pressure (dP/dt) transiently; both values were significantly lower five and 10 minutes after the infusion of nifedipine but were not significantly different from control values at 20 minutes. There was minimal but pronounced depression of atrioventricular nodal function after giving intravenous nifedipine, though this was detected only when sensitive tests of atrioventricular nodal function were used. These effects were also transient, showing no significant change from control values at 20 minutes. Atrioventricular nodal conduction time and sinus rate were unchanged. Radionuclide angiography of patients taking the oral combination of atenolol and nifedipine for chronic angina showed no change in ejection fraction compared with those taking atenolol alone, but there was a small increase in peak ejection rate. Resting blood pressure and heart rate were unchanged and the PR interval did not lengthen. Peak heart rate and systolic blood pressure showed no alteration on exercise testing when the drugs were combined compared with the response with atenolol alone. Despite the negative inotropic influence when nifedipine was given intravenously, the absence of haemodynamic deterioration when oral nifedipine is combined with atenolol has confirmed that this combination can be used safely in patients with normal left ventricular function. The minimal changes in atrioventricular nodal function cannot be detected on the surface electrocardiogram and are not of clinical importance in patients with normal conduction.

The names of Russian physicians do not often spring to mind when recalling the advances of the past century, though a quick glance discloses many contributions, including those of Anitschkow in the pathogenesis of arteriosclerosis, Korotkoff in the measurement of blood pressure, and Elie Metchnikoff, the bacteriologist. Few, however, realise that James Herrick's diagnosis of coronary occlusion in the living patient1 had been anticipated by two years by two physicians from Kiev, Obrastzow and Straschesko. Their original description in Russki Vrach was republished almost simultaneously in German and was cited by Herrick.2 Even before this, however, a Russian physiologist, Alexander Filipovich Samojloff, had written the first book on electro cardiography, which should have been easily accessible to Western physicians because it was written in German and had been issued by a leading German publisher.3 The book is not, however, listed in two important EngUsh bibliographies,45 though it and several other publications by Samojloff were cited by Western contemporaries, and his contributions are proudly acknowledged in the Soviet Union. Who was Samojloff and what was his role in Russian and indeed international physiology?

A randomised controlled crossover trial was performed to assess the anti-anginal effects of nifedipine and propranolol separately and together. The effects of these treatments on blood pressure and heart rate were assessed at rest and after the cold pressor and mental arithmetic tests. Nifedipine and propranolol together produced the greatest reduction in supine and erect systolic and diastolic blood pressures. Propranolol (480 mg daily) lowered resting systolic/diastolic blood pressures by 7/6 mm Hg and nifedipine (60 mg daily) lowered it by 10/8 mm Hg, while in the erect position the hypotensive effect of these agents averaged 9/8 mm Hg. During the cold pressor test propranolol lowered the maximum pressure by an average of 11/6 mm Hg and nifedipine by 19/10 mm Hg. For the mental arithmetic test, the results were 7/2 mm Hg and 16/7 mm Hg respectively. Propranolol (480 mg daily)reduced supine and erect heart rate by 19 and 25 beats/minute respectively, while nifedipine did not alter heart rate significantly. The favourable haemodynamic responses to nifedipine suggest that it may be of value in the management of hypertension.

In a double-blind clinical trial the antianginal effects of nifedipine (30 and 60 mg/day) and propranolol 240 and 480 mg/day) and a combination of both drugs were compared with those of placebo in 16 patients with severe exertional angina pectoris. Response to treatment was assessed by the objective criteria of 16-point precordial exercise mapping and 48-hour ambulatory electrocardiographic monitoring and subjectively by analysis of patients' daily diaries of episodes of angina and consumption of glyceryl trintrate. The incidence of pain and consumption of glyceryl trinitrate were significantly decreased by each drug compared with placebo, and the combination produced a further significant improvement. Objectively the total area and amount of ST depression on the precordial exercise map and the total number of episodes of ST depression detected on ambulatory monitoring confirmed the efficacy of each treatment regimen; the combination was significantly better than either drug alone (p

In 25 outpatients taking digoxin for chronic atrial fibrillation (established for at least six months) a prospective study identified only one case in which rapid availability of the results of a plasma digoxin assay altered the dose which had already been selected on the basis of simple clinical assessment. No patient received more than 375 micrograms digoxin per day and none showed clinical evidence of toxicity even though seven had renal impairment. Six other patients had poorly controlled ventricular rates requiring larger doses of digoxin, but even in these patients the dose could be selected on clinical grounds alone. Despite the availability of a very rapid fluorescence polarisation immunoassay for digoxin, simple but careful clinical monitoring is an adequate basis for the selection of a suitable dose in most patients taking digoxin for atrial fibrillation.

One hundred years ago, Augustus Desiré Waller recorded the human electrocardiogram for the first time, using a capillary electrometer. Electrocardiography only became clinically relevant in 1901 when Willem Einthoven devised his string galvanometer for this purpose. Sir Thomas Lewis was the key figure in showing the value of the electrocardiography for the diagnosis of disorders of cardiac rhythm and conduction, but many others amplified the technique to encompass the assessment of structural heart disease, especially when due to ischemia. Knowledge of their role and work gives us a better perspective when considering the development of surface electrocardiography.

We present clinical and electrophysiological data on 9 patients with paroxysmal reciprocating sinus tachycardia (PRST) of whom only 6 described palpitations. Sinus node disease was present in 5 and cardiac ischemia and/or hypertension in another 3; the remaining case had apparently coincidental Wolff-Parkinson-White (WPW) syndrome. PRST could be initiated in all cases, and terminated in the 4 in whom it was sustained, by suitably timed atrial premature beats over a zone that was dependent on the effective atrial extrastimulus coupling interval (A1-A2) in the high right atrium (HRA). The sequence of atrial depolarization during PRST was similar to that of sinus beats although minor changes in both the P wave and the configuration of the HRA electrogram were observed in half the cases. During paroxysms, cycle length variation and sensitivity to alterations in vagal tone were common. In 6, paroxysms could be initiated by moderately rapid atrial pacing. Repetitive attacks were usually initiated by increases in the sinus rate and not be an antecedent premature atrial extrasystole. Verapamil suppressed sinus node reentry in 5 patients while small doses of atropine favored initiation in 3. PRST was seen in association with AV reentry tachycardias in the patient who had the WPW syndrome.

Verapamil is a novel antiarrhythmic agent which appears to act as a calcium-ion antagonist, blocking calcium transport across the myocardial cell membrane. It was given intravenously, in a dose of 10 mg, to thirty-two patients suffering from paroxysmal supraventricular tachycardia, and sinus rhythm was achieved promptly in all. Identical results were obtained in a further ten patients with supraventricular tachycardias associated with the Wolff-Parkinson-White or other pre-excitation syndromes. In a separate group of eighteen patients in whom A-V junctional tachycardias were induced during intracardiac electrography, conversion to sinus rhythm was achieved in fifteen patients, with prolongation of the cycle length in the others. Circus-movement tachycardias were induced in eight patients with the Wolff-Parkinson-White syndrome, and conversion to sinus rhythm was achieved in seven. The results were less consistent in patients with other supraventricular arrhythmias including ectopic atrial tachycardia and atrial flutter, and, in the single patient with supraventricular and ventricular tachycardias, only the former was controlled. In the single patient with atrial fibrillation complicating the wolff-Parkinson-White syndrome who received Verapamil, sinus rhythm was restored. Side effects were few and mild, with rare exceptions of profound hypotension, bradycardia and asystole; their management is discussed, and reasons are advanced why their occurrence is likely to be related either to the concomitant administration of beta-adrenergic blockers or to the presence of sinoatrial disease. It appears that Verapamil is particularly suitable for the treatment of supraventricular tachycardias due to a circus movement as calcium antagonism is likely to be most effective in the N region of the atrioventricular node.

Oral amiodarone has been used to treat 21 patients with various supraventricular arrhythmias; 13 had Wolff-Parkinson-White syndrome, which was complicated by atrial fibrillation and re-entry atrioventricular tachycardia in four, and re-entry tachycardia alone in the other nine. The remaining eight patients had paroxysmal atrial fibrillation or flutter without pre-excitation. All were refractory to conventional treatment and had undergone intracardiac electrophysiological study. Fifteen have been controlled with amiodarone, this treatment proving most effective in atrial fibrillation or flutter with or without pre-excitation. Amiodarone was successful in only four of the nine patients with re-entry atrioventricular tachycardia. In two patients who responded well the drug had to be discontinued because of side effects.

Myocardial histamine(H)2 receptor stimulation has been studied in six normal men. Since histamine is a potent vasodilator, the haemodynamic effects of histamine infusion were compared with those of nitroprusside at equihypotensive doses, to identify changes in myocardial contractility attributable to vasodilatation. After H1 receptor blockade with mepyramine, subjects received, in single blind crossover fashion, either histamine alone and with the H2 receptor antagonist cimetidine, or nitroprusside alone and with cimetidine. Echocardiographic left ventricular dimensions, plasma catecholamines, blood pressure, and heart rate were measured. The rise in catecholamines suggested similar baroreflex activation by both histamine and nitroprusside. Echo ejection phase indices did not alter significantly after nitroprusside, but histamine caused an increase in percentage fractional shortening from 38.2 +/- 4.1 to 53.5 +/- 3-6% and in mean fibre shortening velocity from 1.31 +/- 0.19 to 1.99 +/- 0.22 cm/s. These changes were both greatly reduced by cimetidine and suggest that H2 receptor stimulation in man causes a direct positive inotropic response.

Bepridil (2 mg/kg intravenously) was given to 20 patients with atrioventricular (AV) reentrant tachycardia and its effects were compared with those of verapamil (0.15 mg/kg intravenously) in 8 patients and ajmaline (0.75 mg/kg intravenously) in 12. After baseline electrophysiologic measurements, the drugs were given during sustained AV reentrant tachycardia (8 patients had dual AV nodal pathways and 12 had an accessory AV pathway). Verapamil terminated AV reentrant tachycardia in 7 patients and bepridil terminated it in 6. In 8 of the patients who received ajmaline, AV reentrant tachycardia was terminated and in 6 of this group bepridil did so. Bepridil was more successful in terminating AV reentrant tachycardia in those with dual AV nodal pathways than in those with an accessory AV pathway. Bepridil slowed sinus rate by 10% (p less than 0.0001), whereas verapamil did not change it significantly. Both verapamil and bepridil administration prolonged AV nodal conduction (39% and 44%, respectively), lengthened AV nodal effective refractory period (18% and 17% respectively) and increased the Wenckebach cycle length of the AV node (24% and 25%, respectively) to a significant degree (p less than 0.05). Bepridil also lengthened atrial and ventricular effective refractory periods (p less than 0.01) and QT interval (p less than 0.0001) in the group as a whole; in those receiving ajmaline and bepridil only atrial refractoriness was significantly altered (p less than 0.05). After treatment for 3 to 5 days with oral bepridil, 19 patients underwent repeat study.(ABSTRACT TRUNCATED AT 250 WORDS)

In the century since calcium was shown to be essential in the normal function of the myocardium (1) little further information on the importance was available until Fleckenstein and colleagues (2) proposed the concept of calcium antagonism. A variety of substances were shown to be capable of inhibiting the transmembrane passage of calcium ions. Although this work had concentrated on the role of calcium in the myocardium the profound influence of these compounds was evident in the cells of the specialised conducting system. It has become apparent that the transmembrane flux of calcium is a fundamental but complex procedure: additionally this calcium transfer subserves different purposes in different types of cells. In the myocardium calcium is of fundamental importance in excitation-contraction coupling but of limited importance is electrical depolarisation. The contrast, calcium is of profound importance in the generation and propagation of electrical activity in the SA and AV nodes. Although, in both the transitional cells of the SA node and the N cells of the AV node, sodium ions have a role in the initial generation of the action potential it is calcium which determines to a greater extent the upstroke velocity and the speed of repolarisation. Thus substances which impair the transmembrane movement of calcium ions may have electrophysiological actions throughout the action potential. Translating these influences from the single cell to the intact heart would suggest that an influence on the upstroke velocity of the action potential will slow conduction while a prolongation of repolarisation will lengthen the refractory period and slow the slope of spontaneous distolic depolarisation. Where calcium antagonists have clinical electrophysiological actions these are the fundamental effects although our ability to observe changing SA nodal function in man is very limited.

Bepridil is an anti-anginal agent with a novel chemical structure. Its main pharmacological effects are an increase in coronary blood flow, a reduction in myocardial oxygen demand, reduction in cardiac work, primarily by a decrease in after-load and a dose-dependent negative chronotropic effect, and anti-arrhythmic properties. These are mainly due to a calcium-antagonistic action. There is evidence that fast sodium channels in heart muscle are also inhibited. Trials have shown that bepridil is effective in the prophylactic treatment of various forms of angina pectoris and accompanying arrhythmias. Pharmacokinetic data justify once-daily administration. The evidence suggests that bepridil is generally well tolerated. This paper reviews already published studies and the results of recent investigations on the pharmacological and clinical efficacy of bepridil.

The antiarrhythmic effects of verapamil noted clinically [1, 2] were postulated on experimental grounds [3, 4] to reflect a previously unrecognized therapeutic mechanism, selective inhibition of the transmembrane passage of calcium ions. Singh and Vaughan Williams [4] indicated that verapamil differed in its mode of action from substances that slowed the upstroke of the action potential (their class I, the paradigm of which is quinidine) as well as from beta-adrenergic blockers, with their antisympathetic action; however, part of the action of beta-blockers, predominantly in the class II of Singh and Vaughan Williams [4], was also shown to be due to an effect on calcium handling by the myocardial cell. “Calcium-antagonism„, perhaps more precisely expressed as inhibition of the slow inward channel of the cell membrane (SIC-inhibition), has both practical and theoretical importance as regards the generation and treatment of cardiac arrhythmias. A new class of agents is thus available for the treatment of arrhythmias, but its role must be defined; and the relationship of such activity to the mechanisms, whereby certain arrhythmias arise; for example if the slow (rather than the fast) inward channel becomes responsible for depolarization [6]. Nevertheless, the caution expressed by Coumel [7] is wise: extrapolation from observed behaviour does not necessarily provide firm rules for therapeutic action and precise classifications depending on them can be premature.

The electrophysiological effects of diltiazem (0.25 mg/kg), administered by intravenous bolus, have been assessed during intracardiac investigation in 10 patients. Effects on both sinus node and atrioventricular nodal function were measured, as was the influence on reentry atrioventricular tachycardia. There was a tendency for the sinus rate to increase after both diltiazem and verapamil, although with neither drug was this uniform. There was, however, a consistent depression of atrioventricular nodal function with diltiazem which was similar in magnitude to the changes seen after verapamil. With neither drug was there an alteration in His-Purkinje conduction. The drugs had similar effects when given during reentry tachycardia. In six of eight patients, termination occurred, whereas, in the others, both drugs slowed the arrhythmia but failed to terminate it. Diltiazem shows a range of electrophysiological and antiarrhythmic properties similar to those of verapamil. These make it potentially useful for both the acute and chronic treatment of arrhythmias where depression of atrioventricular nodal function is desired.

One can make few useful generalizations about the clinical features of tachyarrhythmias, but the basic clinical tool used in their elucidation is the electrocardiogram; and, as we have heard during previous presentations, this is by no means the final diagnostic tool. Nevertheless it is the one that we most often use, and provided we have the necessary reservations about interpretation, it is a highly practical and indeed essential instrument. What we are here concerned with today are tachyarrhythmias, which can be irregular or regular, and which can be associated with two consequential features that may influence the clinical findings: atrioventricular block in the case of some supraventricular tachycardias, and atrioventricular dissociation as the hallmark, if not the invariable one, of ventricular tachycardias. Atrioventricular dissociation can of course occur in its own right under certain circumstances where the pulse rate is fast, but AV block in the presence of a normal sinus rate will require no further consideration because it will present as bradycardia.

An atrial aneurysm gave rise to incessant atrial tachycardia in a 21 year old Seychellian soldier. This arrhythmia was suppressed by intravenous adenosine triphosphate and ajmaline. Resection of the aneurysm abolished the arrhythmia and re-established sinus rhythm.

In 9 patients with paroxysmal supraventricular tachycardia the effects of tilting the body on the blood pressure and on responses during tachycardia or pacing revealed important effects that could influence the clinical presentation and the treatment required. Assessment of these reflex responses adds a major dimension to the understanding of the patient with supraventricular tachycardia.

Although supraventricular arrhythmias usually lack the frequently malignant implication of rhytnm disturbances arising in the ventricles, their incidence is considerable and their chronicity often profound. The young person with paroxysmal supraventricular tachycardia may not be in grave danger but he may well face years of discomfort in the absence of effective treatment. The paroxysmal nature of many supraventricular arrhythmias, together with their occurrence, frequently in the absence of organic heart disease, often enables the afflicted patient to enjoy long spells of normal health which are interrupted abruptly by disabling and distressing symptoms. These may be particularly severe when there is associated valvular, ischemic or myopathic heart disease. In addition, the presence of supraventricular arrhythmia may add its own contribution to tne prognosis of the associated heart disease and thus contribute significantly to the patient’s outlook. In rare instances, such as persistent atrial fibrillation in the presence of mitral stenosis, embolie complications make the arrhythmia life-threatening and ideal therapy should achieve the return and persistence of sinus rhythm.