Author + information
- Received August 7, 2017
- Revision received September 6, 2017
- Accepted September 6, 2017
- Published online November 27, 2017.
- Guido Tavazzi, MD, PhDa,b,∗ (, )
- Marinella Zanierato, MDa,
- Gabriele Via, MDc,
- Giorgio Antonio Iottia and
- Francesco Procaccio, MDd
- aAnesthesia and Intensive Care, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo, Pavia, Italy
- bDepartment of Surgical, Pediatric, and Diagnostic Sciences, University of Pavia, Pavia, Italy
- cCardiac Anesthesia and Intensive Care, Cardiocentro Ticino, Lugano, Switzerland
- dCentro Nazionale Trapianti, Istituto Superiore di Sanità, Rome, Italy
- ↵∗Address for correspondence:
Dr. Guido Tavazzi, Anesthesia and Intensive Care, Fondazione IRCCS Policlinico San Matteo, Piazzale Golgi 19, Pavia 27110, Italy.
The imbalance between the number of organ donors and the demand is currently a major health care problem, although improved technology and experience with long-term mechanical support are increasingly providing alternative solutions to end-stage heart disease.
There are strict criteria to assess the heart suitability for transplantation (1). Among those criteria, the echocardiographic presence of wall motion abnormalities or left ventricular ejection fraction <40%, despite optimization of hemodynamics with inotropic support, makes the heart unsuitable for transplantation. Wall motion abnormalities (either global or regional) account for approximately 30% of patients with severe brain damage without a known history of cardiac disease (2).
The primary purpose of this report was to briefly review the features of neurogenic stress cardiomyopathy and Takotsubo syndrome with a focus on the potential reversibility of cardiac dysfunction in candidates to heart donation.
Hormonal Changes During Brain Death
Patients with dramatic brain hemorrhage suffer from profound endocrine derangements. Sympathetic and parasympathetic activation (the former exceeding the latter) are mediated first by the “mass effect” due to hematoma (3) as a consequence of an unabated rise in intracranial pressure and, eventually, brain stem herniation. Deregulation of intracranial pressure and elicitation of the Cushing reflex cause a catecholamine surge and the consequent “autonomic storm,” with an increase in systemic vascular resistance and disproportionate systemic arterial hypertension. Such a severe vasocontraction associated with an abrupt increase of ventricular afterload may lead to a coronary perfusion mismatch triggering the ischemic cascade. The catecholamine secretion peaks in the first hours following brain death, to abruptly decrease in the following hours, when preload optimization and vasopressor drugs become then indispensable to maintain adequate cardiac index and organ perfusion. The same effect impacts the pulmonary vascular arterial bed, increasing its resistance but with earlier reduction in comparison with the systemic vascular resistance. This determines an imbalance between systemic and pulmonary circulation, one of the underlying mechanisms of neurogenic pulmonary edema (Online Ref. 3).
At the same time, a disruption of blood supply to the hypothalamus and pituitary gland occurs, causing a significant decrease of plasma level of ACTH, cortisol, vasopressin, and tri-iodothyronine, thus eliciting the panpituitarism syndrome (3).
The catecholamine storm along with these hormonal deficiencies are mutually responsible for cardiac stunning and for the altered vascular reactivity, finally causing a deranged hemodynamic profile, which may range from acute heart failure to cardiogenic shock.
The complex pathophysiology of Takotsubo syndrome has been largely investigated in the last decades. A catecholamine rise (either endogenously triggered by external stressors or tumors, or exogenously triggered) play a central role, leading to multiple relevant effects on the brain, on systemic and coronary vasculature, and on the myocardium (4,5).
Massive release of epinephrine and norepinephrine through the activation of the hypothalamic-pituitary-adrenal axis in response to a given stress causes an increase in peripheral arterial vasoconstriction, inducing a sudden left ventricle (LV) afterload increase and an increase in LV end-systolic pressure. At the same time, acute artery vasospasm is responsible for myocardial ischemia, determining systemic hypotension. This, together with a direct negative effect on α and β ventricular receptors, produces a subsequent cardiac output reduction. The role of catecholamine surge on the β2 receptors has been debated over the years. Lyon et al. (5) speculated that the typical distribution of LV wall motion abnormalities was due to the increased density of receptors in the apex rather than in the basal segment (Online Ref. 4). However, in mammalian hearts, higher sympathetic nerve density is normally seen in the base rather than in the apex. Nevertheless, rat and preclinical computational models used to investigate the effect of varying β-adrenoreceptor gradients across the LV under different hemodynamic scenarios have demonstrated an apical dysfunction after a massive release of epinephrine and isoprenaline when a higher density of β-adrenoreceptors was concentrated at the apex (5). In any case, because distributions of the receptors may differ among individuals, Takotsubo presentation may either be consistent with apical or apical-sparing wall motion abnormalities (4).
In both syndromes, only a mild increase in cardiac-related enzymes is observed, disproportionate to the magnitude of LV dysfunction. Electrocardiography changes occur that mimic LV myocardial infraction (4), although ST-segment elevation is more typical in Takotsubo than in potential brain-dead donor patients (these more frequently exhibit ST-segment depression) (2). Such ST-segment depressions are thought to be due to sympathetically mediated intramyocardial electrolyte disturbances, which lead to myocardial cell calcium overload, enhanced cellular efflux of potassium ions, and subsequently catecholamine-induced contraction band necrosis (4). In cohorts of both syndromes, contraction band myocyte necrosis has been found in histological studies (4) (Online Ref. 5).
Conversely, LV wall motion abnormal distribution is generally different: apical hypokinesis is more frequent in Takotsubo, whereas basal hypokinesis is typical in patient with severe brain damage (2).
The most significant, and prognostically relevant similarity is that both syndromes show remarkable recovery of the LV systolic function over time. Few case reports and series have already been published describing patients receiving heart transplantation from organ donors with “neurogenic stress cardiomyopathy,” who exhibit excellent results (6) (Online Refs. 6,7).
It is key to consider that pharmacological treatment of potential organ donors during the hemodynamic instability phase is likely to significantly affect this form of LV failure. Inotropes and vasopressors should not be used in order not to further elicit the catecholamine detrimental effect on myocardial cells. In addition to preload optimization, the use of vasopressin as an alternative vasopressor is now advocated. Vasopressin acts at different levels: mediating a vasopressor effect (through V1-receptor), an anti-diuretic effect (V2-receptors), and stimulating ACTH release (V3-receptors). In a study of early goal-directed treatment in organ donors, the possibility of replacing norepinephrine with vasopressin was associated with improvements in hemodynamics and in function of donor hearts (Online Ref. 8).
Moreover, the use of T3 hormone has been suggested because of the secretion reduction and because it increases the expression of mRNAs encoding acutely regulated T3 responsive cardiac genes, including the sarcoplasmic reticulum, although an effective benefit has not been demonstrated yet (3).
Possible Step Forward
Optimal hemodynamic treatment of possible organ donor patients has yet to be completely defined. Although the replacement of exogenous hormones has a strong pathophysiological background, results are still controversial, most probably due to methodological limitations of the studies conducted so far, which included doses and time modulation of the drugs used.
Echocardiography is presently increasingly available in intensive care units and plays a key role in the assessment of cardiac morphological/dynamic function and screening of pre-existing diseases. Nevertheless, specific strategies defining the suitability for heart donation during the acute phase of heart failure are still lacking. Dobutamine stress echocardiography is used to assess the contractility reserve, although this contradicts the pathophysiological underpinning this LV failure phenotype (i.e., to avoid inotropes in those patients in order not to worsen myocardial dysfunction), has been proposed (Online Ref. 9). A strict echocardiographic monitoring over days waiting until the beginning of LV recovery is an ex adiuvantibus strategy, but it would be hardly feasible in intensive care units not dedicated to the management of such patients (Online Ref. 10).
The application of Takotsubo diagnostic criteria (Online Ref. 11), including coronary angiography study results to rule out potential coronary culprit lesions, dissection, thrombosis, or spasm, should be applied to brain death patients in order to differentiate between “stress cardiomyopathy,” therefore, recoverable in a specific time-frame, and acute heart failure due to primary cardiac disease.
However, considering the strong pathophysiological mechanistic evidence shared by Takotsubo and “neurogenic stress cardiomyopathy,” and the promising preliminary experiences described in literature, further research addressing the best ways to assess cardiac reserve and suitability for donation is advocated.
Considering the lack of donor hearts, the identification of strategies to optimize the hemodynamic profile and to identify potential hearts with on-going but temporary cardiac failure would have a clinical impact. Further research to test the application of Takotsubo diagnostic criteria to brain death patients with suspected “stress cardiomyopathy” would represent an important step forward. Transplantation of those hearts would represent a clinical challenge, but the results of the published reports seem promising. The kind of hormone and the dosage of hormone replacement therapy must also be better delineated.
The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Received August 7, 2017.
- Revision received September 6, 2017.
- Accepted September 6, 2017.
- 2017 American College of Cardiology Foundation
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