Potential arrhythmogenic role of cyclic adenosine monophosphate (AMP) and cytosolic calcium overload: implications for prophylactic effects of beta-blockers in myocardial infarction and proarrhythmic effects of phosphodiesterase inhibitors.

Activation of the adrenergic nervous system appears to play a crucial role in the genesis of fatal arrhythmias associated with the very early stages of acute myocardial infarction. The second messenger of beta-adrenergic catecholamine stimulation, cyclic adenosine monophosphate (AMP), has established arrhythmogenic qualities, acting by an increase in cytosolic calcium, which potentially has three adverse electrophysiologic effects. First, stimulation of the transient inward current by excess oscillations of cytosolic calcium can invoke delayed afterdepolarizations, so that triggered automaticity can develop in otherwise quiescent ventricular muscle. Second, cyclic AMP can evoke calcium-dependent slow responses in depolarized fibers, so that conditions for reentry are favored. Third, excess cytosolic calcium can cause intercellular uncoupling with conduction slowing. Focal changes in cyclic AMP and cytosolic calcium promote the development of ventricular fibrillation. Beta-adrenergic blockade can limit the formation of cyclic AMP in ischemic tissue. Furthermore, by reducing sinus tachycardia it can lessen cytosolic calcium overload. Hence, beta-adrenergic blockade helps to prevent ventricular fibrillation in the early stages of acute myocardial infarction and protects from sudden death in the postinfarction phase. In congestive heart failure, abnormalities of cytosolic calcium patterns exist with cytosolic calcium overload. It is proposed that the adverse effects of phosphodiesterase inhibitors on the mortality rate in patients with congestive heart failure can be explained by increased rates of formation of cyclic AMP and the development of calcium-dependent arrhythmias. Because calcium is the ultimate messenger of cyclic AMP-induced arrhythmias and because cytosolic calcium is increased in heart failure, it will be difficult to develop positive inotropic agents that are free of the risk of sudden death.

Treatment of hypertension in pregnancy.

A better understanding of the hemodynamic abnormalities in gestational hypertension together with the use of effective antihypertensive agents have resulted in more rational therapeutic approaches and a substantial improvement in maternal and fetal welfare. In normal pregnancy, there is reduced vascular reactivity with peripheral pooling and decreased circulatory responses to pressor agents. These are prostacyclin-dependent processes. In gestational hypertension, the normal increase in plasma volume and cardiac output with pregnancy is attenuated and prostacyclin-dependent processes are impaired, resulting in persistent vasoconstriction, enhanced responses to pressor agonists, and failure to develop adequate uteroplacental interchange. Among the modern antihypertensive agents, alpha- and beta-adrenergic antagonists and calcium ion entry blockers have permitted safe and effective long-term blood pressure control with sustained fetal growth. The development of proteinuria that can occur in chronic hypertension or in previously normotensive women (toxemia of pregnancy) can be prevented by the use of beta-adrenergic blocking agents and possibly by low-dose aspirin (75 mg/day). Maternal prostacyclin-thromboxane imbalance, important in the pathogenesis of gestational hypertension, is corrected by low-dose aspirin treatment. With the prevention of pre-eclampsia, the adverse maternal and fetal prognosis in gestational hypertension has been improved.

Adenine nucleotides and ventricular fibrillation.

The isolated perfused rat heart was used to study the influence of adenine nucleotides and their metabolites on vulnerability to ventricular fibrillation. In this model the incidence of ventricular arrhythmias after coronary artery ligation is determined by the extracellular K+ concentration; with perfusate K+ of 2.0 and 3.0 mmol/l hearts develop a high incidence of ventricular arrhythmias and fibrillation while arrhythmias are not encountered with perfusate K+ of 9.0 mmol/l. Assay of adenine nucleotides in uninvolved and ischaemic myocardium of these hearts showed a direct relationship between incidence of ventricular fibrillation and tissue levels of cyclic AMP but not tissue levels of lactate, high energy phosphates, adenosine, inosine and hypoxanthine/xanthine. Administration of dibutyryl cyclic AMP to isolated rat hearts reduced the ventricular fibrillation threshold; this action of cyclic AMP was effectively antagonized by adenosine and its N-ethylcarboxamido analogue but not by 2-chloroadenosine, phenylisopropyladenosine, cyclohexyladenosine and the adenosine deaminase inhibitor, EHNA. 2-Chloroadenosine, like adenosine, inhibited the increase in heart rate caused by DBcAMP. All the adenosine analogues had antiarrhythmic activity against spontaneously occurring ventricular arrhythmias during coronary artery occlusion. Adenosine analogues also antagonized the effect of dibutyryl cyclic AMP whereby it prolongs the QT interval. Adenosine, by as yet incompletely defined mechanisms, may act as an antagonist to the cyclic AMP mediated increase in vulnerability which contributes to the genesis of ventricular fibrillation in the early phase of myocardial ischaemia.

Anticardiolipin antibodies: their presence as a marker for lupus anticoagulant in pregnancy.

A solid phase ELISA was developed to investigate the association between anticardiolipin antibodies and lupus anticoagulant in pregnancy. Twenty-seven pregnant women with a history of recurrent fetal losses or systemic lupus erythematosus (SLE) were tested for the presence of lupus anticoagulant, anticardiolipin antibodies, antinuclear antibodies (ANA) and anti-single-stranded DNA antibodies. Nineteen women with a total of 49 previous unsuccessful pregnancies were found to have lupus anticoagulant and anticardiolipin antibodies. Three women who had suffered four fetal deaths from six pregnancies had anticardiolipin antibodies without lupus anticoagulant. Cardiolipin antibodies were not detected in the remaining five patients. This assay for measuring anticardiolipin antibodies appears to provide a simple and inexpensive method of identifying women at risk of fetal death from the adverse effects of lupus anticoagulant.

Hypertension in pregnancy: whom and how to treat.

1. Elucidation of some of the mechanisms responsible for blood pressure elevation in pregnancy has permitted therapy to be based on more rational principles. The decreased arterial reactivity encountered in normotensive pregnancy is most likely mediated by prostaglandins; preventive therapy using low dose aspirin is an option to prevent development of proteinuria in pre-existing hypertension and provide prophylaxis against pregnancy-induced hypertension. 2. Antihypertensive therapy utilizing sympathetic inhibition with either methyldopa or alpha- and beta-adrenoceptor blockade yields the most promising results. Vasodilation with hydralazine, calcium entry blockers (nifedipine), intravenous labetalol or diazoxide is primarily used in severely hypertensive patients. The use of orally administered nifedipine in severely hypertensive women is associated with encouraging results. 3. It is clear that women with blood pressure levels greater than 170/110 mm Hg need antihypertensive therapy for maternal safety; it remains to be proven to what extent foetal growth and welfare can be improved in women with diastolic pressure levels 85-110 mm Hg when adrenoceptor blocking agents are used for blood pressure control. Initial studies are suggestive of improved foetal growth, prevention of proteinuria and the respiratory distress syndrome but more long-term controlled studies are required. 4. In a recent study, at our institution, of foetal growth during long term antihypertensive therapy, treatment with pindolol yielded better foetal growth than therapy with atenolol. It is as yet unclear whether the ISA or beta 2-mediated vasodilation associated with pindolol was responsible for the improved foetal growth. Further controlled studies are indicated in hypertension in pregnancy to confirm the suggested benefits of beta-adrenoceptor blocker therapy.

Permissive action of potassium on arrhythmogenesis in the rat heart.

The isolated perfused rat heart was used to assess the influence of extracellular potassium ([K+]0) on vulnerability of the heart to ventricular fibrillation (VF). The VF threshold is reduced when [K+]0 is lowered from 5.9 to 2.0 and 3.0 mmol/l. The vulnerable period is not only widened but VF can be obtained by stimuli on the R wave. The opposite effects are encountered when [K+]0 is increased to 9.0 mmol/l. These alterations in vulnerability to VF are accompanied by an increased incidence of tachyarrhythmias and spontaneous VF during coronary artery ligation and following reperfusion on reduction of [K+]0, with elimination of these arrhythmias on increasing [K+]0 to 9.0 mmol/l. The cellular biochemical responses that accompanied the altered electrical behaviour on alterations of [K+]0 involved the tissue levels of cyclic AMP in both non-ischaemic and ischaemic myocardium and tissue levels of Ca2+ whereas tissue levels of high energy phosphates, adenosine, inosine, hypoxanthine, lactate, Na+, K+ and Mg2+ did not discriminate between hearts vulnerable and hearts resistant to VF. In this model the extracellular K+ level is a determinant of vulnerability to ventricular fibrillation while ischaemic tissue levels of Ca2+ provide the best correlation with alterations in vulnerability.

A community-based trial of transdermal antihypertensive therapy with clonidine (Catapres-TTS).

The effectiveness of transdermally administered clonidine using Catapres-TTS patches applied once a week was assessed in the control of mild to moderate hypertension by 16 general practitioners in 135 subjects. Following two weeks on placebo patches, subjects with mean seated diastolic pressures 90 to 104 mmHg were titrated to one, two or three patches and blood pressure responses measured at monthly intervals for three months. Satisfactory response of blood pressure to 90 mmHg or lower was obtained in 85% of patients who completed the maintenance phase; in 20 patients whose blood pressure responses did not reach 90 mmHg, a significantly higher blood pressure (mean 158/103 mmHg) occurred at entry into the trial (145/96 mmHg). Withdrawal from the trial was mainly for reasons of inadequate blood pressure control (15%) or localised skin reactions (15%). Dryness of the mouth was the only systemic side effect encountered with significant frequency and resulted in the withdrawal of three patients. Localised skin reactions were encountered in 51% of subjects, in the majority these were mild and subjects elected to continue with transdermal clonidine because of the convenience of once a week administration. Severe or generalised skin reactions were not encountered. Serum biochemical measurements, including serum lipid levels, remained unaltered. Transdermal clonidine therapy provided satisfactory blood pressure control in the majority of subjects and apart from the localised skin reactions which were largely of nuisance value, proved safe and acceptable to patients.

Long-term tolerance of amiodarone treatment for cardiac arrhythmias.

For the 5-year period 1979 to 1983, 242 patients were followed up who had received amiodarone treatment, 156 for supraventricular tachycardia (SVT) and 86 for ventricular arrhythmias. Five patients were lost to follow-up overseas; the rest were followed to cessation of therapy, death or recent review for a mean of 24 +/- 15 months. Male/female incidence was 1.8:1 and mean age was 58 years (range 4 to 88). Half the group had impaired left ventricular function. Adverse effects were recorded in 59% of the patients and led to drug withdrawal in 26% of the total group. In contrast, unsuccessful treatment was the cause of drug withdrawal in only 5% of the patients, although an additional 25% stopped taking the drug for various reasons. Actuarial survival for the whole group, and subgroups with SVT and ventricular tachycardia/fibrillation were 66%, 74% and 52%, respectively, at 50 months. For the whole group, the actuarial probability of being alive and continuing with amiodarone therapy was only 19% at 50 months. Thus, although amiodarone was effective, few patients tolerated the drug on a long-term basis. Although amiodarone remains a valuable treatment for patients with ventricular tachycardia, its long-term effectiveness for patients with SVT is less certain.

Amiodarone-induced torsades de pointes.

Five cases of amiodarone-induced syncope due to torsades de pointes or ventricular fibrillation are described. Amiodarone was used for recurrent supraventricular tachycardia in four cases and frequent ventricular extra systoles complicating congenital QT prolongation in the remaining case. Each was associated with a marked prolongation in the QTc interval following amiodarone. Three cases had had a previous history of life-threatening ventricular arrhythmias secondary to anti-arrhythmic drugs. Hypokalemia may have been a contributory factor in two. The clinical features, predisposing factors, and treatment are discussed.

Lupus anticoagulant and pregnancy.

A subset of women with a high rate of fetal wastage is identifiable among those with serologic but not necessarily clinical evidence of connective tissue disease. The presence of lupus anticoagulant in the plasma of a pregnant woman serves as a marker for a high rate of fetal wastage and risk of thrombosis. Lupus anticoagulant is best identified by the activated partial thromboplastin time or kaolin clotting time and can be specifically confirmed by the platelet neutralization procedure. Review of the obstetric literature indicates a total of 49 women with 160 unsuccessful pregnancies and 13 live births. Prednisone in immunosuppressive doses (40 to 60 mg/day) combined with low-dose aspirin (75 mg/day) has been demonstrated to be effective in suppressing activity of lupus anticoagulant in pregnant women and successful pregnancies have been obtained with this treatment. Lupus anticoagulant should be excluded in women with suspected collagen disease, with repeated early abortions and all unexpected late fetal losses.

Extensive pulmonary embolism associated with lupus anticoagulant.

A female patient with extensive pulmonary emboli associated the lupus anticoagulant is described. She made a good recovery with heparin treatment.