Nauman , Sarah Aftab , and Affan: Mechanisms of Takotsubo Cardiomyopathy; Role of Microcirculatory Dysfunction.

Introduction

Since its first description in Japan in the 1990s, Takotsubo cardiomyopathy (TCM) has garnered significant scientific interest and media attention. We have seen a dramatic increase in research on the subject in the past two decades which has led to somewhat improved understanding of the disease process. Various pathophysiologic mechanisms have been proposed for its development: these include multivessel epicardial coronary artery spasm, catecholamine spillover with resultant cardiotoxicity, neurogenic stunned myocardium but the true cause of TCM still remains elusive. Another causative factor that has been described in recent literature is the microcirculatory or endothelial dysfunction or coronary slow flow (CSF) especially in the acute phase of the illness.1-9 It has been suggested that the neurogenic stunning of the myocardium or catecholamine spillover (which are central to the syndrome’s etiology) may lead to impairment of microcirculation. Alternatively, it has also been postulated that these coronary flow abnormalities may be present before the acute episode in susceptible individuals. Whether these disturbances represent a preceding event or sequelae of the catecholaminergic storm raises an important cause vs. consequence question. It is certainly possible that in a small subset of these patients, coronary slow flow may be a related bystander phenomenon; nevertheless, it still remains a strong contender for the causative pathophysiology of Takotsubo cardiomyopathy.1-9,11-13

TIMI frame count a novel technique:

Takotsubo cardiomyopathy is an acute cardiac syndrome characterized by transient systolic dysfunction of the apical and/or mid segments of the left ventricle that mimics myocardial infarction but without significant obstructive coronary artery disease.1-13 Several invasive and non-invasive modalities have been utilized to assess myocardial perfusion both during the acute and recovery phase of TCM.8,9,14-23 These techniques include Doppler guidewire technique, Thrombolysis In Myocardial Infarction (TIMI) frame count (TFC) and TIMI myocardial perfusion grade (TMPG) calculation.8,9,14-23 Gibson et al. introduced a novel method in 1996 called ‘TIMI frame count’ for measuring coronary flow velocity from coronary angiograms.8-10 Since then TFC has been used as a quantitative index to determine microcirculatory function in patients with acute coronary syndrome after primary coronary angioplasty as a predictor of functional recovery. Few studies have employed this method in Takotsubo cardiomyopathy as well for indirect assessment of microcirculation.8,9,14-18 TIMI frame count is defined as ‘the number of frames required for the contrast material to travel from coronary ostium to the standardized distal landmark’.8-10 TFC is a simple, objective, reproducible and inexpensive test for calculation of the coronary flow reserve. The term ‘corrected TIMI frame count’ (CTFC) is applied when a correction factor is applied to account for the longer length of the left anterior descending artery (LAD) compared with the circumflex (Cx) and the right coronary arteries (RCA).8-10

Studies favoring the role of microcirculatory dysfunction in Takotsubo Cardiomyopathy:

Utilizing TIMI Frame Count:

We recently conducted a microcirculatory analysis in a retrospective cohort of sixteen patients with Takotsubo cardiomyopathy by computing TIMI frame counts in the three main coronary arteries (the LAD, Cx and RCA) and compared it with age matched controls (n=15).8,9 Our results showed that the mean corrected TFC values were elevated by a total of three frames (reaching statistical significance) in the LAD of patients with Takotsubo cardiomyopathy compared with LAD of control individuals, with no difference observed between the two groups in other vessels.8,9 The exact reason for this selective distribution of microvascular dysfunction in the left anterior descending artery territory is unclear although it may explain the predisposition for apical involvement in Takotsubo cardiomyopathy patients.8, 9

At least three studies have been previously performed which show a similar correlation between abnormal TIMI frame count and microvascular dysfunction.14-16 Bybee et al. noted abnormal TIMI frame counts during acute phase of Takotsubo cardiomyopathy in sixteen patients in all three coronary vessels suggesting that diffuse impairment of coronary microcirculatory function may play a role in underlying pathogenesis although it remained unclear if microvascular dysfunction was the primary cause or a secondary phenomenon.14 Similarly Kurisu et al. found significantly higher TFCs in 28 patients with TCM when compared with controls both during the acute phase and follow-up.15 Fazio et al. also noted abnormalities in all three vessels in their cohort of 24 patients suggesting a pathological slowdown of the general coronary flow.16

Utilizing other modalities:

We found at least four studies and one case report in literature utilizing techniques other than TIMI frame count that support the presence of microvascular dysfunction in Takotsubo cardiomyopathy.17-21 Kume et al. recorded coronary flow velocity spectrum and coronary flow velocity reserve (CFVR) by using Doppler guidewire technique in the acute phase and three weeks later in the three main coronary vessels along with assessment of deceleration time of diastolic velocity (DDT).17 They noted that both the CFVR and DDT decreased during the acute phase of the illness with normalization noted at three weeks.17 These findings suggested that microvascular dysfunction may play a role in the acute phase of Takotsubo cardiomyopathy.17

Yoshida et al. described coronary perfusion abnormalities and severe myocardial metabolic disturbances in patients with Takotsubo cardiomyopathy based on the results of thallium-201 myocardial single-photon emission computed tomography (SPECT) and F-18 fluorodeoxyglucose myocardial positron emission tomography (FDG PET).18 They noticed markedly decreased uptake at the apical region on F-18 FDG PET images whereas thallium 201 images showed only mildly reduced uptake.18 The affinity for decreased uptake may possibly be related to increased density of beta receptors noted in apex[18]. The metabolic disturbance was likely linked to the sudden preceding stress and this resulted in corresponding perfusion abnormalities.18

Elesber et al. calculated Thrombolysis In Myocardial Infarction (TIMI) myocardial perfusion grade (TMPG) via angiograms in a cohort of 42 patients.19 TMPG is an index of myocardial perfusion and was noted to be in 29 (69%) of the patients suggesting impaired microcirculation.19 Interestingly patients with abnormal TMPG had higher peak troponin levels and greater propensity to have electrocardiographic changes (ST-segment elevation or deep T-wave inversion) compared with patients with normal TMPG.19 These findings suggested that the disturbed myocardial perfusion correlated with the degree of myocardial injury.19

Ito et al. assessed myocardial perfusion via 99mTc-tetrofosmin myocardial SPECT in the acute, subacute and chronic phases of Takotsubo cardiomyopathy.20 They noticed that the myocardial perfusion scores were impaired at admission and showed improvement in the subacute and chronic phases of TCM. They supported their findings with nuclear imaging findings of diminished myocardial perfusion in the absence of obstructive coronary artery disease.20 Similarly, Nishikawa et al. employed (99m) Tc-tetrofosmin myocardial single photon emission computed tomography (SPECT) showed severely decreased uptake in the apex.21 Additionally they noticed that coronary flow reserve measured with a Doppler guide wire was also severely reduced. The reduced apical uptake, and the reduced coronary flow reserve returned to normal over two weeks and one month respectively.21 These studies suggest that microvascular dysfunction plays a key role in the development of Takotsubo cardiomyopathy.

Studies not favoring the role of microcirculatory dysfunction in Takotsubo Cardiomyopathy:

In contrast, some other studies suggest a limited role of microvascular dysfunction in Takotsubo cardiomyopathy.22-23 Sharkey et al. evaluated 59 patients (all women aged 32–90 years) with Takotsubo cardiomyopathy and noted that patients with or without ST-segment elevation didn’t differ with regard to clinical outcome, ejection fraction, abnormal left ventricular contraction patterns (including the apical sparing variant) or TFC.22 Abe et al. investigated 17 patients utilizing Technetium-99m tetrofosmin tomographic imaging and noted decreased uptake at the left ventricular apical region in 11 patients (85%) that later returned to normalcy.23 No significant stenosis or angiographic slow flow in epicardial coronary arteries was observed. Furthermore, no significant abnormality in the coronary microcirculation was detected by Doppler guidewire technique.23 In summary, there is some evidence (albeit limited) that does not support the role of microcirculation in etiopathogenesis of TCM, however given the smaller sample size, limited data many clinicians still support the microcirculatory disorder hypothesis as one of the contributors towards Takotsubo cardiomyopathy.

Conclusion

Taken together, these studies suggest that coronary microcirculatory abnormalities may play a key role in the evolution of Takotsubo cardiomyopathy. Various invasive and non-invasive techniques support the presence of disturbances in microcirculation especially in the acute phase of Takotsubo cardiomyopathy. However, the association may not indicate a cause and effect relationship. TIMI frame count can be utilized as a diagnostic marker and clinical indicator in assessment of microvascular function or coronary flow in patients with Takotsubo cardiomyopathy.

Declarations of Interest

The authors declare no conflicts of interest.

Acknowledgements

The authors state that they abide by the “Requirements for Ethical Publishing in Biomedical Journals”.24

References

1. 

Khalid N, Ikram S Coronary flow assessment in Takotsubo cardiomyopathy with TIMI frame count. Int J Cardiol 2015; 30197: 208 10.1016/j.ijcard.2015.06.078

2. 

Khalid N, Chhabra L Takotsubo cardiomyopathy and microcirculatory dysfunction. Nat Rev Cardiol 2015; 12497: 10.1038/nrcardio.2015.88

3. 

Khalid N Microcirculatory disorder hypothesis in Takotsubo cardiomyopathy. Int J Cardiol 2015; 195: 29 10.1016/j.ijcard.2015.05.095

4. 

Khalid N, Ikram S Microvascular dysfunction in Takotsubo cardiomyopathy; prognostic implications. Int J Cardiol 2015; 201: 58–59 10.1016/j.ijcard.2015.08.018

5. 

Khalid N, Ahmad SA, Umer A Coronary flow reserve assessment via invasive and noninvasive means in Takotsubo cardiomyopathy. Int J Cardiol 2016; 202: 573 10.1016/j.ijcard.2015.09.109

6. 

Khalid N, Ahmad SA, Umer A, Chhabra L Role of microcirculatory disturbances and diabetic autonomic neuropathy in Takotsubo cardiomyopathy. Crit Care Med 2015; 43: e527 10.1097/CCM.0000000000001183

7. 

Khalid N, Ahmad SA, Chhabra L, Spodick DH Autonomic dysfunction and Takotsubo cardiomyopathy. Am J Med 2015; 128: e45–6 10.1016/j.amjmed.2015.06.013

8. 

Khalid N, Iqbal I, Coram R, Raza T, Fahsah I, Ikram S Thrombolysis In Myocardial Infarction Frame Count in Takotsubo Cardiomyopathy. Int J Cardiol 2015; 191: 107–8 10.1016/j.ijcard.2015.04.192

9. 

Khalid N, Iqbal I, Ikram S Thrombolysis in myocardial infarction frame count in takotsubo cardiomyopathy. J Am Coll Cardiol 291912015; pp.107–108 10.1016/S0735-1097(13)60051-0

10. 

Gibson CM, Cannon CP, Daley WL et al TIMI frame count: a quantitative method of assessing coronary artery flow. Circulation 1996; 93: 879–88

11. 

Chhabra L, Khalid N, Kluger J, Spodick DH Lupus myopericarditis as a preceding stressor for takotsubo cardiomyopathy. Proc (Bayl Univ Med Cent) 2014; 27: 327–30

12. 

Khalid N, Ahmad SA, Umer A, Chhabra L Takotsubo cardiomyopathy and myopericarditis: Unraveling the inflammatory hypothesis. Int J Cardiol 2015; 196: 168–9 10.1016/j.ijcard.2015.05.175

13. 

Khalid N, Chhabra L Takotsubo Cardiomyopathy and Viral Myopericarditis: An Association Which Should be considered in the Differential Diagnosis. Angiology 2015; May120003319715585665s 10.1177/0003319715585665

14. 

Bybee KA, Prasad A, Barsness GW et al Clinical characteristics and thrombolysis in myocardial infarction frame counts in women with transient left ventricular apical ballooning syndrome. Am J Cardiol 2004; 94: 343–6 10.1016/j.amjcard.2004.04.030

15. 

Kurisu S, Inoue I, Kawagoe T et al Myocardial perfusion and fatty acid metabolism in patients with tako-tsubo-like left ventricular dysfunction. J Am Coll Cardiol 2003; 41: 743–8 10.1016/S0735-1097(02)02924-8

16. 

Fazio G, Sarullo FM, Novo G et al Tako-tsubo cardiomyopathy and microcirculation. J Clin Monit Comput 2010; 24: 101–5 10.1007/s10877-009-9217-5

17. 

Kume T, Akasaka T, Kawamoto T et al Assessment of coronary microcirculation in patients with takotsubo-like left ventricular dysfunction. Circ J 2005; 69: 934–939 10.1253/circj.69.934

18. 

Yoshida T, Hibino T, Kako N et al A pathophysiologic study of tako-tsubo cardiomyopathy with F-18 fluorodeoxyglucose positron emission tomography. Eur Heart J 2007; 28: 2598–2604 10.1093/eurheartj/ehm401

19. 

Elesber A, Lerman A, Bybee KA et al Myocardial perfusion in apical ballooning syndrome correlate of myocardial injury. Am Heart J 2006; 152: 469.e9–469.e13 10.1016/j.ahj.2006.06.007

20. 

Ito K, Sugihara H, Katoh S, Azuma A, Nakagawa M Assessment of Takotsubo (ampulla) cardiomyopathy using 99mTc-tetrofosmin myocardial SPECT--comparison with acute coronary syndrome. Ann Nucl Med 2003; 17: 115–22

21. 

Nishikawa S, Ito K, Adachi Y, Katoh S, Azuma A, Matsubara H Ampulla (‘takotsubo’) cardiomyopathy of both ventricles: evaluation of microcirculation disturbance using 99mTc-tetrofosmin myocardial single photon emission computed tomography and doppler guide wire. Circ J 2004; 68: 1076–80 10.1253/circj.68.1076

22. 

Sharkey SW, Lesser JR, Menon M, Parpart M, Maron MS, Maron BJ Spectrum and significance of electrocardiographic patterns, troponin levels, and thrombolysis in myocardial infarction frame count in patients with stress (tako-tsubo) cardiomyopathy and comparison to those in patients with ST-elevation anterior wall myocardial infarction. Am J Cardiol 2008; 101: 1723–8 10.1016/j.amjcard.2008.02.062

23. 

Abe Y, Kondo M, Matsuoka R, Araki M, Dohyama K, Tanio H Assessment of clinical features in transient left ventricular apical ballooning. J Am Coll Cardiol 2003; 41: 737–42 10.1016/S0735-1097(02)02925-X

24. 

Shewan LG, Coats AJS, Henein M Requirements for ethical publishing in biomedical journals. International Cardiovascular Forum Journal 2015; 2: 2 10.17987/icfj.v2i1.4



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