QT Prolongation, Sudden Death, and Sympathetic Imbalance: The Pendulum Swings

Waxing and waning have characterized the medical interest in the role of the autonomic nervous system, particularly its sympathetic limb, in the genesis of life-threatening cardiac arrhythmias. From the early days, the focus was on the attempt to provide protection by preventing deleterious sympathetic in uences. This was accomplished by removing either one or both stellate ganglia, which represent the main relay station between brain and heart. This “protection,” aimed initially at reducing attacks of angina pectoris, was pioneered in 1916 by Thomas Jonnesco who, following a suggestion by Francois Franck, removed the left stellate ganglion (left stellectomy) in a patient with incapacitating angina accompanied by arrhythmias. Relevant here is that, after surgery, the arrhythmias as well the attacks of angina disappeared.1 Jonnesco’s intervention and subsequent statements in 1929 by Leriche and Fontaine2 that the left stellate ganglion (LSG) played a major role in the re exes that initiate anginal attacks and that the sympathetic nerves had vasoconstrictive effects on the coronary arteries stirred one of the most violent controversies in the history of cardiology. Indeed, Danielopolu3 initiated a relentless and venomous assault that spanned over 30 years. It began with his labeling this surgical procedure as “physiologically inadmissible” because it severed the sympathetic  bers innervating the coronary arteries that then were thought to have vasodilatory effects. Danielopolu went on to claim that relief of pain during the anginal episodes might be detrimental by “removing the alarm signal which allows the patients to stop and rest their hearts. ” He also warned that stellectomy could favor the occurrence of pump failure, myocardial infarction (MI), and sudden death.4 Despite his dire predictions, favorable results in anginal patients treated with stellectomy continued to be reported by numerous investigators.5 -9 Indeed, the decline in the use of stellate ganglionectomy was not due to lack of ef cacy but rather to the advent of beta-blockers. Despite a wealth of encouraging results in experimental animals, it took a long period of time before sympathetic denervation was considered for the treatment or prevention of cardiac arrhythmias in man.1 0 -1 4 A valid reason for this slow transition was the absence of a sound rationale for this unconventional intervention, but, as we will see later, this situation was destined to change. In this issue of the Journal, Zhou et al.15 report an interesting observation that, curiously, is in direct line with the early pioneering studies and with another series of experimental and clinical studies performed in the 1970s and 1980s that led to the concept of “sympathetic imbalance” and its role in arrhythmogenesis.1 6 By adding some new experiments and performing an ECG analysis not previously reported, Zhou et al. expand upon an intriguing series of studies performed recently by Chen and colleagues.1 7 ,18 Chen et al. moved from the concept that when a nerve is damaged, as may occur with MI, regeneration is triggered by re-expression of nerve growth factor (NGF), which induces nerve sprouting in an effort to reinnervate the end organ.19 -2 1 In the area of arrhythmogenesis and QT prolongation, NGF and antiserum to NGF had already been used by Malfatto et al.2 2 to enhance or interrupt sympathetic nerve growth in newborn rats. The initial study was performed in native hearts of transplant recipients1 7 and provided two main  ndings: (1) in ventricles with myocardial injury, there is an inhomogeneous distribution of sympathetic nerve  bers that is characterized by areas of regional hyperinnervation and regional denervation; and (2) the density of these nerve  bers is signi cantly higher in patients with a history of tachyarrhythmias than in patients without tachyarrhythmias. The authors proposed that the increased quantity of sympathetic nerves might be secondary to injury-related nerve sprouting and that regional hyperinnervation may play a role in arrhythmogenesis in patients with chronic severe congestive heart failure. Their second step was to test the hypothesis that augmented sympathetic nerve regeneration (nerve sprouting) increases the probability of life-threatening ventricular arrhythmias.23 Cardiac sympathetic nerve sprouting was induced by infusing NGF into the LSG of nine dogs with MI and complete AV block. Six other dogs that were similarly prepared but without NGF infusion served as controls.18 The frequency of phase 2 ventricular tachycardia (VT), which appears several days after MI, was 10-fold higher in the LSG group compared with the control group. Moreover, four dogs in the LSG group and none in the control group died suddenly of spontaneous ventricular  brillation (VF). These results suggest a direct relationship between sympathetic nerve sprouting and sudden cardiac death in this model. Finally, in the present report by Zhou et al., a comparison was made between the two groups of post-MI dogs previously studied and another group in which NGF was infused in the right stellate ganglion (RSG) of six post-MI dogs. Two parameters were examined: changes in QT interval and incidence of ventricular tachyarrhythmias. In a time-dependent manner, with the peak at week 5 after surgery at the end of NGF infusion, QT and QTc were increased in the LSG group and decreased in the RSG group. No dog in the RSG group developed VF; the RSG group was the same as the control group and different from the LSG group in which 4 of 9 dogs died suddenly of VF. The authors note J Cardiovasc Electrophysiol, Vol. 12, pp. 1074-1077, September 2001.