Pathophysiology of Takotsubo Cardiomyopathy: Reopened Debate

Abstract

Takotsubo cardiomyopathy (TTC), a persistently obscure dysfunctional condition of the left ventricle, is uniquely transient but nevertheless dangerous. It features variable ventricular patterns and is predominant in women. For 30 years, pathophysiologic investigations have progressed only slowly and with inadequate focus. It was initially proposed that sudden-onset spastic obliteration of coronary flow induced myocardial ischemia with residual stunning and thus TTC. Later, it was generally accepted without proof that, in the presence of pain or emotional stress, the dominant mechanism for TTC onset was a catecholamine surge that had a direct, toxic myocardial effect. We think that the manifestations of TTC are more dynamic and complex than can be assumed from catecholamine effects alone. In addition, after reviewing the recent medical literature and considering our own clinical observations, especially on spasm, we theorize that atherosclerotic coronary artery disease modulates and physically opposes obstruction during spasm. This phenomenon may explain the midventricular variant of TTC and the lower incidence of TTC in men. We continue to recommend and perform acetylcholine testing to reproduce TTC and to confirm our theory that coronary spasm is its initial pathophysiologic factor. An improved understanding of TTC is especially important because of the condition's markedly increased incidence during the ongoing COVID-19 pandemic.

Keywords: Acetylcholine; catecholamines/metabolism; coronary artery disease/complications; coronary vasospasm/complications/physiopathology; plaque, atherosclerotic/physiopathology; risk factors; sex differences; takotsubo cardiomyopathy/blood/etiology/physiopathology; ventricular function, left/drug effects.

Fig. 1

International Takotsubo Registry data show accumulated incidence of takotsubo cardiomyopathy by age and sex in 1,750 patients. Relative incidence peaks at age 60 to 64 years in men and at 75 to 79 years in women. Reprinted with permission from Templin C, Ghadri JR, Diekmann J, Napp LC, Bataiosu DR, Jaguszewski M, et al. Clinical features and outcomes of takotsubo (stress) cardiomyopathy. N Engl J Med 2015;373(10):929–38.

Fig. 2

Drawings (left panels) show A) apical and B) mid left ventricular locations of akinesia in takotsubo cardiomyopathies. The different arterial spastic behavior during acetylcholine testing (right panels) is probably related to atherosclerotic intimal disease, assumed present in the epicardial left anterior descending coronary artery (LAD) in B). The intramural septal branches (free of coronary artery disease) become severely obstructed from spasm (asterisks). Arrows indicate phasic left ventricular systolic motion, assuming similar end-diastolic volumes in all cases (continuous line). Diag = diagonal coronary branch; LCx = left circumflex coronary artery; RCA = right coronary artery Adapted and reprinted with permission from Angelini P, Monge J, Simpson L. Biventricular takotsubo cardiomyopathy: case report and general discussion. Tex Heart Inst J 2013;40(3):312–5.

Fig. 3

In a 70-year-old woman, left ventricular angiograms at A) end-systole and B) end-diastole show a hypercontractile apex (bullet) and akinetic midventricular ballooning (asterisks) during end-systole, a case of midventricular takotsubo cardiomyopathy. Subsequent left coronary artery angiograms show the same mechanism when C) acetylcholine reproduces critical spastic narrowing of the LCx–OM1, LCx–OM2, diagonal, and septal branches amid preserved apical flow, and D) nitroglycerin enlarges the vessels, exposing minimal residual irregularities in the left anterior descending coronary artery that are likely evidence of nonobstructive coronary artery disease not properly quantifiable on angiograms. LCx = left circumflex coronary artery; OM = obtuse marginal branch

Fig. 4

Diagram illustrates the interrelationship between coronary artery disease (CAD) and takotsubo cardiomyopathy (TTC). When CAD is absent (upper panel), occasional spasm can induce luminal narrowing followed by dependent myocardial TTC; conversely, substantial CAD (lower panel) resists severe arterial spasm, preventing luminal narrowing and TTC by means of a stenting effect. Because all-vessel CAD occurs earlier in life and more frequently in men than in women, men would be comparatively more protected from TTC.

Fig. 5

Diagram shows dynamic mechanisms during an episode of takotsubo cardiomyopathy: the degree of endothelial dysfunction (dotted red line) and its threshold for spasm inducibility (gray line), the time courses of spontaneous spasm (dashed blue line), left ventricular (LV) dysfunction (broken green line), and the inducibility window for reproducing spasm with use of acetylcholine (ACh) (dashed purple line and shaded area). Adapted and reprinted with permission from Angelini P, Uribe C. Is transient takotsubo syndrome associated with cancer? Why, and with what implications for oncocardiology? J Am Heart Assoc 2019;8(15):e013201.

Fig. 6

Diagram shows different left ventricular (LV) conditions: normal, apical takotsubo cardiomyopathy (TTC), and midventricular TTC. At end-systole, the normal heart is shown (light blue, 1S); apical TTC corresponds with diffuse coronary spasm (dotted green line, 2); and midventricular TTC (intermittent red line, 3) has preserved apical contraction because left anterior descending coronary artery disease prevents apical akinesia. For simplicity, the end-diastolic outline is shown as identical in the 3 conditions (dark blue line, 1D).

Fig. 7

The International Takotsubo Registry (InterTAK) Diagnostic Score, a point system, relies on clinical factors for diagnosing takotsubo cardiomyopathy (TTC) at varying levels of certainty. The variables are not well quantifiable; also, for example, no male could be diagnosed to have TTC without exhibiting emotional stress: male sex + stress = 49 of the required 71 points. Adapted and reprinted with permission from Ghadri JR, Wittstein IS, Prasad A, Sharkey S, Dote K, Akashi YJ, et al. International expert consensus document on takotsubo syndrome (part II): diagnostic workup, outcome, and management. Eur Heart J 2018;39(22):2047–62.