Clin Auton Res (2008) 18:3–5 DOI 10.1007/s10286-008-0455-2
Research highlights from the literature Jens Jordan, MD
j Abstract Atrial
fibrillation is considered a relatively benign condition; however, hemodynamic compromise and excessive embolism and stroke risk are major concerns. Pulmonary vein ablation close to the left atrium using radiofrequency catheters is becoming increasingly popular in the treatment of atrial fibrillation. A recent study suggests that the therapeutic response to pulmonary vein ablation is explained by modulation of adjacent autonomic structures rather than interruption of ‘‘electrical circuits’’ within the artery wall. Two independent studies in patients who survived a myocardial infarction further support the idea that impaired cardiac autonomic function may have utility in predicting risk of future cardiovascular events or death. Perhaps, patients identified in this fashion may benefit from more aggressive treatment—a hypothesis needs to be tested in prospective trials.
j Key words autonomic Æ atrial fibrillation Æ cardiac death Æ heart rate variability Æ heart rate turbulence Æ baroreflex sensitivity Æ pulmonary vein Æ ablation
Fried ganglia and fibrillations
The prevalence increases with advancing age and may exceed 10% in subjects above the age of 70 years. Patients with structural heart disease are at an even greater risk. Atrial fibrillation is considered a relatively benign condition; however, hemodynamic compromise and excessive embolism and stroke risk are major concerns. The financial burden to society associated with atrial fibrillation is considerable. Better means to prevent and to treat atrial fibrillation are needed. The autonomic nervous system may be important in this regard—a fact that has largely been neglected in recent years. Clinical observations suggested that changes in autonomic tone may set off atrial fibrillation in susceptible individuals. Some patients develop atrial fibrillation during psychological or physiological stress as sympathetic activity is raised. In others, atrial fibrillation occurs at rest presumably through parasympathetic mechanisms. Indeed, previous animal studies suggested that sympathetic stimulation is less effective than vagal stimulation in promoting atrial fibrillation. Arrhythmogenic foci within the pulmonary veins may initiate atrial fibrillations. Hence, circular pulmonary vein ablation close to the left atrium is becoming increasingly popular in the treatment of atrial fibrillation, especially in patients with vagal atrial fibrillations. During the procedure, a radiofrequency catheter is applied to pulmonary vein ostia to create a circular lesion, which may alter the vascular wall as well as surrounding structures. Autonomic innervation is particulary dense in this region and may directly affect arrhythmogenic foci. Therefore, Lemola et al. [3] tested
the hypothesis that the therapeutic response to pulmonary vein ablation is explained by modulation of adjacent autonomic structures rather than interruption of ‘‘electrical circuits’’ within the artery wall. The authors conducted their studies in anesthetized adult dogs. They elicited atrial fibrillation through electrical stimulation of the vagus nerve. They repeated the procedure after various interventions. In some dogs, they ablated pulmonary veins only. Surrounding autonomic ganglia remained intact. In another group, the investigators ablated autonomic ganglia surrounding pulmonary veins but left the vascular wall intact. In addition, they conducted various control experiments. In the event, pulmonary vascular wall ablation did not prevent atrial fibrillation. In contrast, autonomic ganglia ablation was quite effective. To substantiate these findings, the authors conducted in vitro studies. They prepared the left atria with the attached pulmonary veins and recorded atrial electrical activity. Then, they simulated vagal activation through pharmacological stimulation of muscarinergic cholinergic receptors with carbachol. Rapid electrical stimulation of the preparation elicited atrial fibrillation, particularly during cholinergic stimulation. The response was largely unchanged when pulmonary veins were excised. Together, the in vivo and in vitro experiments suggest that autonomic ganglia adjacent to the pulmonary vein may be more important in vagally mediated atrial fibrillation than pulmonary veins. Furthermore, the beneficial response of patients with atrial fibrillation to catheter ablation may be explained in part by modulation of these ganglia.
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Atrial fibrillation is a particularly common cardiac dysrhythmia.
AUTONOMIC NEWS
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Autonomic regulation and prognosis Clinicians specialized in autonomic nervous system disorders apply various cardiovascular tests including heart variability and baroreflex tests in the diagnostic work up of their patients. Studies in recent years suggest that these methods may also have utility in predicting risk of future cardiovascular events or death in patients with cardiovascular conditions, such as congestive heart failure and myocardial infarction. Presumably, impaired cardiac function leads to reflex mediated activation of the sympathetic nervous system while suppressing parasympathetic tone. It is likely that genetic and environmental factors modulate the sympathetic response. Autonomic imbalance is known to promote life threatening cardiac arrhythmias. Furthermore, sympathetic activation may further worsen cardiac function. The success of beta blockers in post myocardial infarction and heart failure patients firmly supports these ideas. Thus, measurements of autonomic nervous system regulation may identify patients at particularly high cardiovascular risk. Exner et al. [2] reported data from the so called REFINE study, which stands for Risk Estimation Following Infarction, Noninvasive Evaluation—a very fine acronym, indeed. The investigators recruited 322 patients with myocardial infarction and mildly reduced left ventricular function. Patients were submitted to a battery of tests 2– 4 weeks and again 10–14 weeks after myocardial infarction. In all patients, left ventricular ejection fraction was assessed using radionuclide ventriculography. The evaluation also included submaximal exercise testing, recording of high-resolution electrocardiograms, and baroreflex testing using
a phenylephrine bolus dose. Phenylephrine raises blood pressure, which leads to a compensatory baroreflex mediated decrease in heart rate or an increase in the R–R wave interval in the surface electrocardiogram. The authors considered a change of the R–R interval by less than 6.1 milliseconds for each 1 mmHg increment in blood pressure as abnormal. Finally, heart rate variability and heart rate turbulence were determined in holter electrocardiograms. The concept of heart rate turbulence as a risk marker was put forward approximately 10 years ago. After a premature ventricular complex (PVC), heart rate speeds up and then decreases below the baseline value for a brief period, at least in healthy subjects. The response is mediated through baroreflex adjustment of cardiac autonomic tone and is quantified as heart rate turbulence. The sicker you are, the less heart rate varies after a PVC—heart rate turbulence is decreased. Did any of these measurements make a difference over the median 47 months follow-up period? During the follow-up period, 29 patients reached the specified primary outcome measure, which was defined as cardiac death or resuscitated cardiac arrest. When data from the initial 2–4 week assesment were analyzed, only left ventricular function and history of diabetes mellitus predicted cardiac arrest or death. All autonomic measurements were not predictive. Measurements obtained 10–14 weeks after myocardial infarction were more helpful. For example, patients with baroreflex sensitivity below 6.1 milliseconds per mmHg had a 2.7 fold greater risk for experiencing the primary outcome measure compared with patients having better baroreflex sensitivity. The authors achieved an even better risk prediction when several measurements were combined. For example, patients
with repolarization abnormalities in the holter electrocardiogram, reduced heart rate turbulence and left ventricular ejection fraction below 50% had a more than sixfold greater risk compared with patients in whom all these measurements were normal. The authors suggested a relatively simple screening strategy. Exercise testing and 24-hour holter monitoring may have utility in clinical practice; however, they acknowledged that further studies are required to confirm this strategy. Another study by De Ferrari et al. [1] tested a similar strategy in patients with preserved left ventricular function. Thank god there is no acronym. The authors enrolled 244 patients who had experienced myocardial infarction. They had to have a left ventricular ejection fraction above 35%. Approximately one month after myocardial infarction, patients presented at the clinic and underwent echocardiography as well as cardiovascular autonomic testing. Autonomic testing included determination of heart rate variability in the time domain and baroreflex testing with phenylephrine. In this study, baroreflex sensitivity below 3 milliseconds per mm Hg was considered abnormal. The average follow-up period in this study was 61 months. Cardiovascular death, the primary endpoint of the study, occurred in 5.7% of the patients. The authors compared patients who died with patients who survived. Interestingly, left ventricular ejection fraction was identical in both groups. However, patients who died were on average six years older, had slightly lower heart rate variability and markedly suppressed baroreflex sensitivity. Baroreflex sensitivity was 2.6 milliseconds per mmHg in patients who died during follow up and 7.0 milliseconds per mm Hg in survivors. Then, authors performed multivariate analysis entering age, gender, left ventricu-
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lar function and baroreflex sensitivity into the model. In this model, only baroreflex sensitivity was a statistically significant predictor of cardiovascular death. The relative risk for cardiovascular death in patients with reduced baroreflex sensitivity exceeded eleven. Both studies may have important clinical implications. Impaired baroreflex function predicts cardiovascular events even in post myocardial infarction patients with normal left ventricular function. This group is usually considered to be at a relatively low risk. One caveat is the large variability of autonomic test results and the susceptibility to artifacts. The concern is particularly relevant when these technologies are used in a routine setting rather than specialized laboratories. Moreover, it remains unclear what to do with all this information.
Perhaps, patients identified in this fashion may benefit from more aggressive treatment. The hypothesis needs to be tested in prospective trials. Moreover, the autonomic nervous system may be a target for treatment in the post infarction period. Adrenergic drive to the heart can be attenuated with beta adrenoreceptor blockade. We do not have a good remedy for impaired parasympathetic function.
Shibata MA, Gulamhussein S, McMeekin J, Tymchak W, Schnell G, Gillis AM, Sheldon RS, Fick GH, Duff HJ (2007) Noninvasive risk assessment early after a myocardial infarction the REFINE study. J Am Coll Cardiol 50(24):2275–2284 3. Lellouche N, Buch E, Celigoj A, Siegerman C, Cesario D, De DC, Mahajan A, Boyle NG, Wiener I, Garfinkel A, Shivkumar K (2007) Functional characterization of atrial electrograms in sinus rhythm delineates sites of parasympathetic innervation in patients with paroxysmal atrial fibrillation. J Am Coll Cardiol 50(14):1324–1331
References
J. Jordan, MD (&) Franz Volhard Clinical Research Center (Haus 129) Charite´ Campus Buch Wiltbergstr. 50 13125 Berlin, Germany Tel.: +49-30/9417-2220 Fax: +49-30/9417-2265 E-Mail
[email protected]
1. De Ferrari GM, Sanzo A, Bertoletti A, Specchia G, Vanoli E, Schwartz PJ (2007) Baroreflex sensitivity predicts long-term cardiovascular mortality after myocardial infarction even in patients with preserved left ventricular function. J Am Coll Cardiol 50(24):2285–2290 2. Exner DV, Kavanagh KM, Slawnych MP, Mitchell LB, Ramadan D, Aggarwal SG, Noullett C, Van SA, Mitchell RT,
