Michiel J. Janse

The potential for QT prolongation and pro-arrhythmia by non-anti-arrhythmic drugs: clinical and regulatory implications. Report on a Policy Conference of the European Society of Cardiology

The Policy Conference on The Potential for QT Prolongation and Pro-arrhythmia by Non-anti-arrhythmic Drugs. Clinical and Regulatory Implications was held at the European Heart House in Sophia Antipolis, France, on the initiative of Gunter Breithardt, FESC, FACC, on June 24th and 25th, 1999 after formal approval by the Board of the European Society of Cardiology (ESC).nnThe conference was organised under the auspices of the ESC Committee for Scientific and Clinical Initiatives by Gunter Breithardt and Wilhelm Haverkamp, Munster, Germany, with participation of representatives of the Working Group on Arrhythmias of the ESC, the American College of Cardiology, the American Heart Association, the World Heart Federation, the European Agency for the Evaluation of Medicinal Products, the Medicines Control Agency (UK), the Food and Drug Administration (USA), the National Heart, Lung and Blood Institute (USA), the Federal Institute for Drugs and Medical Devices (Germany), and the Medical Products Agency (Sweden).nnThe scientific and clinical basis of drug-induced QT prolongation and pro-arrhythmia was summarised by formal presentations. The speakers were chosen for their particular competence in the relevant field. Furthermore, selected topics were discussed in detail in separate workshops. This document represents the executive summary of the conference. It is based on written reports composed by the speakers and the chairs of the workshops. Before preparation of the final version of the document, a draft was circulated to all participants of the conference for suggestions and comments. The opinions expressed in this document are those of the participants and do not necessarily reflect the official position of their organisations or agencies. The meeting was made possible by unrestricted educational grants to the Committee for Scientific and Clinical Initiatives of the ESC from several companies listed in the Appendix A.nnQT interval prolongation, and possibly increased QT dispersion, are risk factors in a …

Biological pacemaker implanted in canine left bundle branch provides ventricular escape rhythms that have physiologically acceptable rates.

Background—We hypothesized that administration of the HCN2 gene to the left bundle-branch (LBB) system of intact dogs would provide pacemaker function in the physiological range of heart rates. Methods and Results—An adenoviral construct incorporating HCN2 and green fluorescent protein (GFP) as a marker was injected via catheter under fluoroscopic control into the posterior division of the LBB. Controls were injected with an adenoviral construct of GFP alone or saline. Animals were monitored electrocardiographically for up to 7 days after surgery, at which time they were anesthetized and subjected to vagal stimulation to permit emergence of escape pacemakers. Hearts were then removed and injection sites visually identified and removed for microelectrode study of action potentials, patch clamp studies of pacemaker current, and/or immunohistochemical studies of HCN2. For 48 hours postoperatively, 7 of 7 animals subjected to 24-hour ECG monitoring showed multiple ventricular premature depolarizations and/or ventricular tachycardia attributable to injection-induced injury. Thereafter, sinus rhythm prevailed. During vagal stimulation, HCN2-injected dogs showed rhythms originating from the left ventricle, the rate of which was significantly more rapid than in the controls. Excised posterior divisions of the LBB from HCN2-injected animals manifested automatic rates significantly greater than the controls. Isolated tissues showed immunohistochemical and biophysical evidence of overexpressed HCN2. Conclusions—A gene-therapy approach for induction of biological pacemaker activity within the LBB system provides ventricular escape rhythms that have physiologically acceptable rates. Long-term stability and feasibility of the approach remain to be tested.

New approaches to antiarrhythmic therapy: Emerging therapeutic applications of the cell biology of cardiac arrhythmias

UNLABELLEDnCardiac arrhythmias complicate many diseases affecting the heart and the circulation, and incorporate a multiplicity of underlying mechanisms. The evolution of scientific knowledge has made the complex changes produced by cardiovascular disease sufficiently understood at the organ, cellular, and molecular levels such that there is a diversity of therapeutic targets for pharmacological therapy and/or prevention. Moreover, the approach of rational drug design in mechanism-specific and disease-specific fashion facilitates targeting of therapy via the methods of molecular, structural and translational biology. Additional approaches, employing similar drug design strategies but based on gene therapy and transcriptional and translational modification are on the horizon. Hence, there is reason to be optimistic regarding the design, testing and clinical availability of novel antiarrhythmic therapies.nnnCONDENSED ABSTRACTnThe evolution of scientific knowledge has made the effects of cardiovascular disease sufficiently understood at the organ, cellular, and molecular levels such that there is a diversity of therapeutic targets for pharmacological therapy and/or prevention. Moreover, the approach of rational drug design facilitates targeting of therapy via the methods of molecular, structural and translational biology. Additional approaches, employing similar drug design strategies but based on gene therapy and transcriptional and translational modification are on the horizon. Hence, there is reason to be optimistic regarding the design, testing and clinical availability of novel antiarrhythmic therapies.

A brief history of sudden cardiac death and its therapy.

At the end of the 19th century, there was both experimental and clinical evidence that coronary artery obstruction causes ventricular fibrillation and sudden death and that fibrillation could be terminated by electric shocks. The dominant figure at that time was McWilliam, who in 1923 complained that little attention was given to the new view for many years. This remained so for many decades. It was not until the 1960s that the medical profession became aware of the magnitude of the problem of sudden death and began to install coronary care units where arrhythmias could be monitored and prompt defibrillation could be delivered. This approach was pioneered by Julian in 1961. Milestones that allowed this development were open-chest defibrillation by Beck, closed-chest defibrillation by Zoll, cardiac massage by Kouwenhoven et al., and development of the DC defibrillator by Lown. In 1980, Mirowski et al. implanted the first implantable cardioverter defibrillator (ICD) in a patient. Thereafter, the use of the ICD increased exponentially. Several randomized trials, largely in patients with coronary artery disease and left ventricular dysfunction or in patients with documented lethal arrhythmias, showed beyond doubt that the ICD is superior to antiarrhythmic drug therapy in preventing sudden death, although a number of trials showed no effect. Trials on antiarrhythmic drugs were disappointing. Sodium channel blockers and pure potassium channel blockers actually increase mortality, calcium channel blockers have no effect, and, although amiodarone reduces arrhythmic death, it had no effect on total mortality in the 2 largest trials. Only the beta-blockers have been proven to reduce the incidence of sudden death, but their effect appears not to be related to the suppression of arrhythmias but rather to the reduction in sinus rate. Drugs that prevent ischemic events, or lessen their impact, such as anticoagulants, statins, angiotensin-converting enzyme inhibitors, and aldosteron antagonists, all reduce the incidence of sudden death.

The Rear Mirror

I vividly remember how pleased I was when Circulation Research published my first papers, one on the ventricular refractory period following changes in heart rate and another on the dual inputs into the atrioventricular node, in 1969. I thought then that Circulation Research was the top journal for basic research in the cardiovascular field, and I still think so today.nnMany things have changed since then, and much progress has been made. Still, it is wise to remember the words of the Austrian writer Robert Musil: “Progress could be wonderful, if only it would stop.” I often felt like that when trying to follow the explosive developments in molecular biology, and I am very happy that Circulation Research now has a section on Integrative Physiology. I feel at home there.nnBrowsing through the 1969 volumes, I came across an Editorial by Julius H. Comroe, Jr, in the October issue: “Answers to a Congressman’s Questions.” After reading it, I realized that in some areas things have not changed much. The issue at hand was a reduction in NIH funding for medical research, and some questions had emerged: “Can’t we fire the 16% who receive ALL their salary from research grants without influencing the teaching …