Autonomic imbalance in patients with takotsubo cardiomyopathy: cause or association?
Sir,In a recent paper, Akashi et al.1 examined cardiac autonomic functions in patients with reversible takotsubo cardiomyopathy (TC), and suggested that this disorder might be caused by neurogenic stunning of the myocardium due to acute autonomic dysfunction. While these findings are very interesting, and may provide useful insight into the pathogenesis of this poorly understood disorder, certain ethical issues and suggested interpretations of the study deserve attention.
In their study, the diagnosis of TC was made based upon acute-onset myocardial-infarction-like symptoms and EKG changes, elevated cardiac enzymes in most patients, normal coronaries on coronary angiography and typical apical ballooning seen on left ventriculogram and/or echocardiography. All their patients fulfil the joint European Society of Cardiology/American College of Cardiology committee diagnostic criteria for acute myocardial infarction (AMI),2 which is not only much more common than TC but is also associated with adverse short and long-term prognosis. It is only the reversible nature of the left ventricular dysfunction that differentiates TC from AMI. This means that the diagnosis of TC can only be made retrospectively, and patients with a clinical suspicion of TC should be treated similar to that of AMI until their left ventricular function returns to normal. In the present study, however, no patient seems to have received any medication, including aspirin, beta-blockers or ACE inhibitors, during the study period, assuming TC as the cause of LV dysfunction. This appears to be a potentially dangerous approach. Although one may argue that typical LV apical ballooning on left ventriculogram makes AMI an unlikely cause of LV dysfunction, this might not be true. A few authors have shown typical apical ballooning in patients with AMI with occlusion of a large wrap around LAD, which was indistinguishable from that seen in TC.3 Therefore, patients suspected to have TC should be treated as AMI until there is complete resolution of LV dysfunction, and depriving these patients of appropriate pharmacological interventions should be discouraged.
The authors also reported that the pattern of heart rate variability (HRV) in patients with TC was very different than that seen in patients with impaired coronary blood flow in AMI. However, this comparison may have some limitations. Patients with TC do not suffer permanent myocardial damage. If the pathogenesis of TC is secondary to ‘intermittent coronary occlusion with spontaneous reperfusion', as suggested by Ibanez et al.,4 then HRV parameters in these patients, although not yet studied, would not be expected to be similar to that of AMI. Therefore the pattern of HRV observed by Akashi et al. does not rule out the possibility of the above theory in the pathogenesis of TC. More importantly, HRV parameters are significantly altered by pharmacological and other non-pharmacological interventions, including ACE inhibitors and beta-blocker therapy, commonly used in patients after AMI.5,6 None of the patients in this study received such medication, which might account for the differences seen.
Finally, as mentioned by the authors, the evaluation of HRV, especially frequency domain analyses, may be more an indicator of strength of the modulation of autonomic nervous system rather than the intensity of the regional or global cardiac sympathetic outflow.7 HRV parameters are altered by a variety of clinical conditions, such as heart failure and acute coronary syndrome, and the presence of these autonomic imbalances in patients with TC does not imply causality. This would make HRV an inferior, rather than ‘the only’ choice (as stated by the authors) for assessing the role of cardiac sympathetic function in the pathogenesis of TC. Moreover, studies have shown conflicting results between the measurement of HRV and other measures of cardiac sympathetic activation in both normal individuals and patients with heart failure.8,9 Therefore, presence of cardiac autonomic imbalance in patients with TC may be merely an association rather than the cause. While we have also proposed catecholamine cardiotoxicity as one of the mechanisms in the pathogenesis of TC,10 it is possible that TC may result from a spectrum of clinical conditions with varying combinations of 'ischaemic' and 'neurogenic' stunning in certain susceptible individuals.
Western Pennsylvania Hospital
Temple University Program
Department of Cardiovascular Diseases
4800 Friendship Avenue Pittsburgh, PA 15224
email: sandeeparora24{at}hotmail.com
References
1. Akashi YJ, Barbaro G, Sakurai T, Nakazawa K, Miyake F. Cardiac autonomic imbalance in patients with reversible ventricular dysfunction takotsubo cardiomyopathy. Q J Med (2007) 100:335–43.[Web of Science]
2. The Joint European Society of Cardiology/American College of Cardiology Committee. Myocardial infarction redefined—a consensus document of the Joint European Society of Cardiology/American College of Cardiology Committee for the redefinition of myocardial infarction. Eur Heart J (2000) 21:1502–13.
3. Ibanez B, Navarro F, Farre J, et al. Tako-tsubo transient left ventricular apical ballooning is associated with a left anterior descending coronary artery with a long course along the apical diaphragmatic surface of the left ventricle. Rev Esp Cardiol (2004) 57:209–16.[CrossRef][Web of Science][Medline]
4. Ibanez B, Navarro F, Cordoba M, M-Alberca P, Farre J. Tako-tsubo transient left ventricular apical ballooning: is intravascular ultrasound the key to resolve the enigma? Heart (2005) 91:102–4.
5. Zhang Y, Song Y, Zhu J, Hu T, Wan L. Effects of enalapril on heart rate variability in patients with congestive heart failure. Am J Cardiol (1995) 76:1045–8.[CrossRef][Web of Science][Medline]
6. Lin JL, Chan HL, Du CC, et al. Long-term beta-blocker therapy improves autonomic nervous regulation in advanced congestive heart failure: a longitudinal heart rate variability study. Am Heart J (1999) 137:658–65.[CrossRef][Web of Science][Medline]
7. Notarius CF, Floras JS. Limitations of the use of spectral analysis of heart rate variability for the estimation of cardiac sympathetic activity in heart failure. Europace (2001) 3:29–38.
8. Kingwell BA, Thompson JM, Kaye DM, McPherson GA, Jennings GL, Esler MD. Heart rate spectral analysis, cardiac norepinephrine spillover, and muscle sympathetic nerve activity during human sympathetic nervous activation and failure. Circulation (1994) 90:234–40.
9. Pagani M, Montano N, Porta A, et al. Relationship between spectral components of cardiovascular variabilities and direct measures of muscle sympathetic nerve activity in humans. Circulation (1997) 95:1441–8.
10. Arora S, Alfayoumi F, Srinivasan V. Transient left ventricular apical ballooning in a patient after cocaine use. Is catecholamine cardiotoxicity the pathological link? Mayo Clin Proc (2006) 81:829–32.
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