Heart Rate Slowing by If Current Inhibition

Abstract

I shall never forget the excitement in my laboratory and that of Dario DiFrancesco in Milan around 1980 when he performed the critical experiment that showed that the ‘pacemaker current’ in cardiac Purkinje fibres was not a pure potassium current, as Dick Tsien and I had described it in 1968, but the same hyperpolarizing-activated mixed cation current, If, that had already been found in the sinus node, in my laboratory and by Irisawa's in Japan. We had dubbed it the ‘funny’ current because, at that time, its properties did seem to be curious. The critical discovery was so unexpected that the telephone call between Milan and Oxford was subsequently referred to in a review as a ‘publication’. Now, as this beautifully produced volume shows, the If channel has become the successful target of drug therapy. Ivabradine is a specific blocker of If. Had this channel been the‘pacemaker current’ in the sinus node, as it is in Purkinje fibres, the therapeutic value would have been questionable. If you remove If in Purkinje fibres, rhythm stops completely. Stopping heart rhythm is hardly a risk worth taking! But in the sinus node the channel is a regulator of frequency, not the only generator, so that inhibition produces only a modest reduction in frequency. Moreover, when frequency is elevated, as in exercise, the reduction is greater. The result is an intervention that can have great therapeutic value by reducing and limiting the oxygen demand by the heart. The volume begins with a convincing review of the evidence that reducing heart rate is a good predictor of longevity. One of the chapters shows also that heart rate is a major determinant of oxygen usage. The specificity of Ivabradine is then assessed, as also is the evidence that it binds to the channel in its open state. The clinical evidence is reviewed, revealing that more than 4000 patients have now been studied in angina prevention trials. The results of comparative studies (with atenolol) show that one of the advantages of Ivabradine is the absence of intrinsic negative inotropic effects. An important result, expected from the biophysical studies referred to above, is that severe sinus bradycardia is very rare. It is fortunate too that the drug does not cross the blood–brain barrier, so that actions on hyperpolarizing-activated channels in the brain are avoided. A concluding chapter by one of the editors then points the way to future research that may extend the range of applicability of If inhibiting drugs. The book appears in the series Advances in Cardiology and succeeds in documenting a major advance all the way from discovery of basic physiological and biochemical mechanisms through to application in the clinic.