Takotsubo cardiomyopathy

In this issue of Journal of Hypertension, Thomas et al.[1] update their studies on hypertension with respect to sex, metabolic, hereditary and ethnic factors on the basis of early wave reflection distorting the ideal ventricular/vascular interaction that is seen in youth [2,3]. This is an extension of the work conducted by Safar's group over a lifetime and provides a basis for the modern therapy of hypertension and its complications, especially heart disease. It considers different expression of arterial stiffness and wave reflection in men and women, in different ethnic groups, and with different dietary and lifestyle risk factors. In seeking relevance of this work, one needs look no further than the June 2018 edition of European Heart Journal, which contains consensus documents on Takotsubo (acute ‘Stress’) cardiomyopathy [4,5]. This condition was first described in Japan [6] and only recently recognized in the USA and Europe [7]. It is a dramatic acute clinical syndrome that mimics acute myocardial infarction, with typical ischemic chest pain, typical troponin and ECG changes of ST segment elevation myocardial infarction (STEMI), has typical complications of early STEMI including arrhythmias and left ventricular failure. But coronary angiography typically shows normal coronary arteries [4,5]. In the acute stage, it can be lethal [8], but recovery can be complete with reversion of all ECG changes, even ST segment elevation and Q waves, and return of left ventricular contractility to normal [4,5]. Takotsubo cardiomyopathy is characterized by ischaemia involving the apex of the ventricle, with basal contraction preserved (or enhanced) so that the ventriculogram in systole looks like a Japanese octopus trap (‘Takotsubo’) [9]. In contrast to the other coronary syndromes that show male dominance, this condition is 10 times more common in women than men [4,5], and most are postmenopausal. It is most commonly precipitated by stress (emotional or physical) such as a threat to life or loved ones, unaccustomed exertion, intraoperative or postoperative stress. It is usually associated with adrenal and sympathetic nerve stimulation and rapid tachycardia. The cause of this condition is not agreed. It is often attributed to ‘spasm’ and can be relieved by nitrate, but localized spasm is not documented at coronary angiography, as in Prinzmetal (variant) angina [10]. The most curious feature of the condition is the anatomical confinement of ischaemia to noncontractile myocardium at the cardiac apex, not in the distribution of any coronary artery, and not at the base of the ventricle closest to the origin of coronary arteries from the aorta. We propose that the features of this condition are an extreme manifestation of the abnormalities described by Thomas et al.[1], as these affect blood flow to the heart during a catecholamine surge and independent of the coronary arteries (which are normal or trivially narrowed, as noted above). Carefully conducted studies such as those undertaken by Ferro et al.[11] over 20 years ago (Fig. 1) show that angina on exertion can be caused by impairment of the time available for coronary perfusion during diastole, as well as by coronary narrowing, and even with no coronary narrowing at all. Buckberg et al. showed in animals [12], and in cardiac surgical patients [13], that myocardial ischemia can be induced by increasing the systolic left ventricular pressure or the left ventricular ejection time, or by decreasing the diastolic time available for coronary perfusion, or the pressure gradient across the coronary vascular bed. Buckberg et al.[12,13] showed how subendocardial myocardial ischaemia can be predicted by an index that relates diastolic pressure-time integral to systolic pressure-time integral, and called this the subendocardial viability index. Myocardial ischaemia is likely to be provoked when this index is less than 70–80%, even in the absence of coronary disease [12,13], and at a higher level (80–100%) when coronary lesions are present.FIGURE 1: Relationship between heart rate and coronary artery diameter in nine patients with single vessel coronary disease, with heart rate increased by upright stress test, supine bicycle stress test and transoesophageal atrial pacing. In upper section, heart rate is expressed as R-R interval (ordinate), while in lower section, heart rate is expressed as diastolic perfusion time (ordinate). Abscissa is minimal stenosis diameter (left) and percentage diameter stenosis (right) for top and bottom graphs. Figure strongly suggests that the relationship between heart rate and coronary stenosis at onset of angina is determined by diastolic time and severity of stenosis. Adapted with permission [10].Thomas et al.[1] point out the factors that are likely to impair coronary blood flow in the absence of coronary narrowing. These include increase in aortic stiffening, with early return of wave reflection from the lower body. Both aortic stiffening and early wave reflection increase pressure in the aorta during systole, so adding to myocardial oxygen requirement while decreasing pressure in the aorta during diastole, so reducing coronary flow. These two factors, increased blood requirement and reduced capacity for flow, predispose to myocardial ischaemia. Left ventricular hypertrophy further predisposes to ischaemia by increasing left ventricular systolic ejection duration and decreasing left ventricular diastolic time available for perfusion. These changes are worsened by tachycardia, which further increases relative ejection time and reduces diastolic coronary perfusion time. We have shown [14] that these factors can be used to extend the concept of the Cardiovascular Continuum by Dzau et al. [15]. One further issue remains. Why is the apex of the left ventricle (LV) affected specifically, and not the base of the LV? The work by Buckberg et al. [12,13] provides the explanation. Their subendocardial viability index is so termed because the subendocardial region of the left ventricular myocardial wall is more susceptible than the subepicardial region of the LV, being further away from the source of blood in the epicardial arteries. In Takotsubo cardiomyopathy, the haemodynamic gradient is longitudinal rather than radial (i.e. worse distally at the apex, remote from the source of blood in the epicardial coronary arteries at the left ventricular base). This problem is likely worsened by another factor. The myocardium closest to the base demands and receives more coronary flow because it is made to contract more vigorously, during cathecolamine surge. Myocardium at the apex is starved of blood because of this massive upstream ‘steal’, becomes ischaemic, dilates and fails to contract, with the LV during systole coming to resemble a Takotsubo trap. Functionally, the mechanism can manifest as Takotsubo cardiomyopathy or as subendocardial infarction (NSTEMI, non-STEMI). Both syndromes are caused by increased myocardial blood requirement in the presence of no or minor coronary narrowing. Subendocardial infarction or ‘NSTEMI’ is usually less extensive than STEMI and carries a lower mortality. The severity of Takotsubo syndrome is almost certainly due to the vicious circle of intensive ischaemia and cardiac failure caused by the diversion (steal) of blood from the apical coronary arteries to the hypercontractile basal myocardium. Anatomically, clinically and pathologically, however, the syndromes of NSTEMI and Takotsubo syndrome are completely different. We have here provided mechanisms to explain the syndrome of Takotsubo on the basis of Safar's description of abnormalities of blood flow to the myocardium that occur independently of coronary narrowing [1]. These are supported by the Women Ischemia Syndrome Evaluation (WISE) study results [16,17] and by our group analysis of McEniery's population data [7]. The syndrome of Takotsubo cardiomyopathy is an extreme manifestation of the supply/demand process, as it enters a vicious circle. Whether these explanations are correct will depend on future studies, which must focus on noncoronary factors responsible for myocardial ischaemia. The explanation fits the wide view of cardiac hypertrophy and failure described by Thomas et al.[1] and the views of Victor Dzau and ourselves on the Cardiovascular Continuum [14]. It takes the focus off the anatomical coronary arteries, which currently are in the spotlight of most other approaches [4,5], despite agreement that coronary arteries are usually clear. It provides logic for medical treatment: reduction of heart rate, avoidance of adrenaline, care with drugs that enhance ‘steal’, use of intra-aortic balloon counterpulsation in the worst cases. It suggests how the condition can be monitored and treatment optimized, by the same methods and pulse waveform analysis as employed by Thomas and colleagues in France, by Hoffman and Buckberg in California, and by Nichols and Pepine in the US WISE study. This issue is yet another possibility for consideration by the NHBLI Task Force on sex [18], currently under consideration in the USA. ACKNOWLEDGEMENTS Conflicts of interest M.O’R is a founding director of Aortamate and AtCor Medical, companies formed to aid measurement of central aortic pressure, development of software for pulse wave analyses and methods to reduce aortic stiffness. The other authors report no disclosure.