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Is stress cardiomyopathy the underlying cause of ventricular dysfunction associated with brain death?

2010; Elsevier BV; Volume: 29; Issue: 9 Linguagem: Inglês

10.1016/j.healun.2010.04.008

1557-3117

Marius Berman, Ayyaz Ali, Euan A. Ashley, Darren H. Freed, Kieran Clarke, Steven Tsui, J. Parameshwar, Stephen Large,

Cardiac Structural Anomalies and Repair

Most deaths in the first 30 days after cardiac transplantation are due to failure of the donor heart, often with the clinical picture of right ventricular failure. Indeed, there is a significant reduction in contractility of the human donor heart and loss of contractile reserve before and soon after transplantation. This myocardial insult appears in association with brain death in the donor and follows a “catecholamine storm” associated with a rapidly rising intracranial pressure. Microscopy of the myocardium in organ donors shows a picture typical of catecholamine-induced injury and similar to changes found in endomyocardial specimens of stress cardiomyopathy (catecholamine-induced cardiomyopathy, or Takotsubo cardiomyopathy). There are 3 common features between stress cardiomyopathy and the heart of a brain-dead donor: exposure of the heart to unusually high catecholamine levels, ventricular dysfunction, and prompt recovery.Stress cardiomyopathy is a temporary myocardial dysfunction that has been described after sub-arachnoid hemorrhage, traumatic head injury, pheochromocytoma, acute emotional distress, exogenous administration of catecholamines, and non-related surgery. Given the common features of this catecholamine-mediated myocardial insult, we ask if brain-dead donor heart dysfunction is an extreme variant of stress cardiomyopathy? And, if so is it, like stress cardiomyopathy, reversible? Can we therefore expect recovery of the dysfunctional donor heart over time, thereby permitting increased use of hearts offered for transplantation? Most deaths in the first 30 days after cardiac transplantation are due to failure of the donor heart, often with the clinical picture of right ventricular failure. Indeed, there is a significant reduction in contractility of the human donor heart and loss of contractile reserve before and soon after transplantation. This myocardial insult appears in association with brain death in the donor and follows a “catecholamine storm” associated with a rapidly rising intracranial pressure. Microscopy of the myocardium in organ donors shows a picture typical of catecholamine-induced injury and similar to changes found in endomyocardial specimens of stress cardiomyopathy (catecholamine-induced cardiomyopathy, or Takotsubo cardiomyopathy). There are 3 common features between stress cardiomyopathy and the heart of a brain-dead donor: exposure of the heart to unusually high catecholamine levels, ventricular dysfunction, and prompt recovery. Stress cardiomyopathy is a temporary myocardial dysfunction that has been described after sub-arachnoid hemorrhage, traumatic head injury, pheochromocytoma, acute emotional distress, exogenous administration of catecholamines, and non-related surgery. Given the common features of this catecholamine-mediated myocardial insult, we ask if brain-dead donor heart dysfunction is an extreme variant of stress cardiomyopathy? And, if so is it, like stress cardiomyopathy, reversible? Can we therefore expect recovery of the dysfunctional donor heart over time, thereby permitting increased use of hearts offered for transplantation? Recently, there has been increased interest in both stress cardiomyopathy and human donor heart dysfunction. To date no association has been made between these 2 conditions. However, they share 3 characteristics:1exposure of the heart to unusually high catecholamine levels,2ventricular dysfunction, and3prompt recovery. The “catecholamine storm” is a characteristic of brain death. The levels of intrinsic catecholamines appear directly related to the speed of rise of intracranial pressure.1Shivalkar B. Van Loon J. Wieland W. et al.Variable effects of explosive or gradual increase of intracranial pressure on myocardial structure and function.Circulation. 1993; 87: 230-239Crossref PubMed Scopus (286) Google Scholar Depression of ventricular function, to a greater or lesser extent, has been demonstrated in all hearts taken for clinical transplantation.2Stoica S.C. Satchihananda D.K. White P.A. et al.Brain death leads to abnormal contractile properties of the human donor right ventricle.J Thorac Cardiovasc Surg. 2006; 132: 116-123Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar However, it appears that the right ventricle (RV) fares worse than the left in human donor hearts and animal models,3Novitzky D. Detrimental effects of brain death on the potential organ donor.Transplant Proc. 1997; 29: 3770-3772Abstract Full Text PDF PubMed Scopus (99) Google Scholar with up to 50% of heart transplant recipients expressing some degree of RV dysfunction. Mortality after transplantation parallels the degree of ventricular dysfunction with most deaths occurring in the first 30 days post transplantation.2Stoica S.C. Satchihananda D.K. White P.A. et al.Brain death leads to abnormal contractile properties of the human donor right ventricle.J Thorac Cardiovasc Surg. 2006; 132: 116-123Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar Dysfunction appears to be temporary in clinical practice, resolving in a matter of days or weeks. Ventricular dysfunction occurs uncommonly in patients after conventional cardiac procedures, but accounts for 50% of all complications and 19% of early deaths after orthotopic heart transplantation.4Taylor D.O. Edwards L.B. Aurora P. et al.Registry of the International Society for Heart and Lung Transplantation: Twenty-fifth Official Adult Heart Transplant Report—2008.Heart Lung Transplant. 2008; 27: 943-956Abstract Full Text Full Text PDF PubMed Scopus (357) Google Scholar There is no doubt that heart transplantation is effective in treating advanced, drug-resistant heart failure through relief of symptoms and improvement in prognosis. Unfortunately, donor hearts are scarce, and only about 1 in 8 offered hearts are accepted for transplantation. Poor cardiac function is the most common reason for declining an offer. A comparable picture to the dysfunction seen in the donor heart has been reported after sub-arachnoid hemorrhage, pheochromocytoma, acute emotional distress, and exogenous administration of catecholamines. We have been impressed by the similar pattern of injury and recovery between stress cardiomyopathy and the dysfunctional human donor heart. If the donor heart is a florid example of stress cardiomyopathy can we expect:•the clinically unsuitable dysfunctional donor heart to recover given time?•the donor heart to recover sufficiently to become of clinical use? If this is so and realizable, the limited numbers of useable donor hearts for transplantation could be increased. With this in mind, we have reviewed and compared the recent literature of donor heart dysfunction and stress cardiomyopathy. To understand these two problems and their possible relationship this review falls into four parts:1A review of brainstem death, associated catecholamine surge, and the pattern of ventricular dysfunction.2A review of catecholamine-induced myocardial stunning and stress cardiomyopathy.3A comparison between stress cardiomyopathy and the brain-dead donor's heart.4Suggestions for possible mechanisms of ventricular dysfunction and its recovery. Brainstem death follows cerebral herniation through the tentorium as a result of raised intracranial pressure. As intracranial pressure rises, brainstem ischemia progresses. Mean arterial pressure rises, maintaining some cerebral perfusion.1Shivalkar B. Van Loon J. Wieland W. et al.Variable effects of explosive or gradual increase of intracranial pressure on myocardial structure and function.Circulation. 1993; 87: 230-239Crossref PubMed Scopus (286) Google Scholar Mid-brain ischemia results in parasympathetic activation with sinus bradycardia. Subsequent pontine ischemia leads to sympathetic stimulation with superimposed hypertension, the Cushing reflex.1Shivalkar B. Van Loon J. Wieland W. et al.Variable effects of explosive or gradual increase of intracranial pressure on myocardial structure and function.Circulation. 1993; 87: 230-239Crossref PubMed Scopus (286) Google Scholar, 2Stoica S.C. Satchihananda D.K. White P.A. et al.Brain death leads to abnormal contractile properties of the human donor right ventricle.J Thorac Cardiovasc Surg. 2006; 132: 116-123Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar It is proposed that further ischemia of the vagal cardiomotor nucleus in the medulla oblongata occurs, resulting in unopposed sympathetic stimulation and loss of baroreceptor control, the “autonomic storm.”2Stoica S.C. Satchihananda D.K. White P.A. et al.Brain death leads to abnormal contractile properties of the human donor right ventricle.J Thorac Cardiovasc Surg. 2006; 132: 116-123Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar In an animal model, this is accompanied by an elevation of systemic vascular resistance, adding to systemic hypertension and leading to a fall in cardiac output, acute left ventricular (LV) failure, acute transient mitral valvular regurgitation, and left atrial hypertension.3Novitzky D. Detrimental effects of brain death on the potential organ donor.Transplant Proc. 1997; 29: 3770-3772Abstract Full Text PDF PubMed Scopus (99) Google Scholar These events are believed to lead to pulmonary congestion.4Taylor D.O. Edwards L.B. Aurora P. et al.Registry of the International Society for Heart and Lung Transplantation: Twenty-fifth Official Adult Heart Transplant Report—2008.Heart Lung Transplant. 2008; 27: 943-956Abstract Full Text Full Text PDF PubMed Scopus (357) Google Scholar Electrocardiography in an animal model demonstrated myocardial ischemic changes with multiple arrhythmias.5Novitzky D. Horak A. Cooper D.K. et al.Electrocardiographic and histopathologic changes developing during experimental brain death in the baboon.Transplant Proc. 1989; 21: 2567PubMed Google Scholar The vasoconstrictive effect of the autonomic storm further compromises end organ blood flow, its magnitude correlating with the rate of rise of intracranial pressure.1Shivalkar B. Van Loon J. Wieland W. et al.Variable effects of explosive or gradual increase of intracranial pressure on myocardial structure and function.Circulation. 1993; 87: 230-239Crossref PubMed Scopus (286) Google Scholar Donor hearts are rejected most commonly on grounds of poor function in addition to coronary artery disease, immunologic and physical barriers believed to stand in the way of clinical success. When identified, RV dysfunction is associated with both early mortality and morbidity. RV dysfunction after cardiac transplantation may complicate a raised pulmonary vascular resistance in the recipient, cold and warm ischemic time, and the handling necessary for recipient implantation.6Bhatia S.J.S. Kirshenbaum J.M. Shemin R.J. et al.Time course of resolution of pulmonary hypertension and right ventricular remodelling after orthotopic cardiac transplantation.Circulation. 1987; 76: 819-826Crossref PubMed Scopus (162) Google Scholar We recognize that the human donor circulation is labile and tends to deteriorate with time. Added to this, the multiorgan procurement operation is a further challenge to donor hemodynamics. It has all the features of major surgery: fluid imbalance, electrolyte and acid-base disturbances, high inotropic load, and hypoxia due to pulmonary congestion, atelectasis, or aspiration. We found that the combination of brain death and noradrenalin appears detrimental to the RV.7Stoica S.C. Satchihananda D.K. White P.A. et al.Noradrenaline use in human donor and relationship with load-independent right ventricular contractility.Transplantation. 2004; 78: 1193-1197Crossref PubMed Scopus (43) Google Scholar It would seem that at any point in the management of the brainstem-dead donor, a noradrenalin dose of more than 0.07 μg/kg/min acts as a marker for impairment of donor heart function. Brainstem-dead donors showed higher end-diastolic volume index, lower end-systolic pressure volume relationship, reduced contractility, and elevated end-diastolic pressure-volume relationship than did patients with normal LV function, undergoing coronary artery bypass grafting. Thus, there is evidence for both systolic and diastolic impairment of the human donor heart. Inotropic reserve was lost and an increased stroke volume was related to a paradoxical increase in RV diastolic volume. Several authors described biventricular dysfunction after cardiac transplantation, with the degree of RV dysfunction being more pronounced than that of the LV (Figure 1, Figure 2, Figure 3). Talaj et al8Talaj J.A. Kirklin J.A. Brown R.N. et al.Post-heart transplant diastolic dysfunction is a risk factor for mortality.J Am Coll Cardiology. 2007; 50: 1064-1069Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar reported an elevated right atrial pressure (RAP)/stroke volume (SV) ratio to be a strong predictor of death after heart transplantation. These observations may reflect RV dysfunction, pulmonary vascular bed dysfunction, or a combination of both.Figure 2Brain death causes a significant decrease in left (LV) and right ventricular (RV) function. The injury to the RV is more prominent than the LV. Pressure volume loops plotted for (A) the LV and (B) RV in consecutive cardiac cycles during occlusion of both vena cava. Left graph; x-axis shows the intracavitary ventricular volume (ml); y-axis shows the intracavitary pressure (mm Hg). Right graph; x-axis shows the intracavitary ventricular volume (ml); y-axis shows the stroke work (area of pressure volume loop) plotted for each cardiac cycle (erg 103). The slope of this graph equals the pre-load independent recruitable stroke volume (PRSW).(Reprinted with permission, Kendall, et al. Right ventricular function in the donor heart. Eur J Cardiothorac Surg 1997;11:609–11.)View Large Image Figure ViewerDownload Hi-res image Download (PPT)Figure 3Relationship of brain death and left (LV) and right ventricular (RV) function. Pre-load-recruitable stroke work increased acutely from baseline values (LV, 74.5 ± 4.1 erg 103; RV, 21.9 ± 1.4 erg 103) at time 0 immediately after induction of brain death. On average, LR and RV function decreased significantly, by 19% and 35%, respectively, after induction of brain death and over the course of 2 to 6 hours after brain death. No recovery potential of LV or RV function was observed. Data are presented with the standard deviation.(Reprinted with permission, Bittner, et al. The combined effects of brain death and cardiac graft preservation on cardiopulmonary hemodynamics and function before and after subsequent heart transplantation. J Heart Lung Transplant 1996;15:764–77.)View Large Image Figure ViewerDownload Hi-res image Download (PPT) Approximately 20 years ago, Takotsubo cardiomyopathy was first described in Japan9Sato M. Fujita S. Saito A. et al.Increased incidence of transient left ventricular apical ballooning (so-called “Takotsubo” cardiomyopathy) after the mid-mitigata Prefecture earthquake.Circ J. 2006; 70: 947-953Crossref PubMed Scopus (89) Google Scholar and named after a traditional gourd-shaped contraption used for catching octopus. The problem is also known as LV apical ballooning, broken heart syndrome, ampulla cardiomyopathy, and more recently, stress cardiomyopathy (SC). Despite the recent spate of publications, the mechanism of injury is still unclear.10Akashi Y.J. Goldstein D.S. Barbaro G. et al.Takotsubo cardiomyopathy—a new form of acute, reversible heart failure.Circulation. 2008; 118: 2754-2762Crossref PubMed Scopus (615) Google Scholar SC may include basal hypokinesis with a hyperdynamic apex11Riera M. Llompart-Pou J.A. Carrillo A. Blanco C. Head injury and inverted Takotsubo cardiomyopathy.J Trauma. 2010; 68: E13-E15Crossref PubMed Scopus (31) Google Scholar, 12Van de Walle S.O. Gevaert S.A. Gheeraet P.J. et al.Transient stress-induced cardiomyopathy with an “inverted takotsubo” contractile pattern.Mayo Clin Proc. 2006; 81: 1499-1502Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar, 13Hurst R.T. Askew J.W. Reuss C.S. et al.Transient midventricular ballooning syndrome: a new variant.J Am Coll Cardiol. 2006; 48: 579-583Abstract Full Text Full Text PDF PubMed Scopus (232) Google Scholar and is biventricular, also being shown to be present in the RV14Elseber A.A. Prasad A. Bybee K.A. et al.Transient cardiac apical ballooning syndrome: prevalence and clinical implications of right ventricular involvement.J Am Coll Cardiol. 2006; 47: 1082-1083Abstract Full Text Full Text PDF PubMed Scopus (187) Google Scholar (Figure 4, Figure 5).Figure 5Right ventricular (RV) involvement in Takotsubo cardiomyopathy. (A) End-diastolic and (B) end-systolic frames of the left ventricle (LV) and (C) end-diastolic and (D) end-systolic frames of the RV demonstrate the extent of LV and RV dysfunction (arrows).(Reprinted from; Haghi, et al. Right ventricular involvement in Takotsubo cardiomyopathy. Eur Heart J 2006;27:2433–9 by permission of Oxford University Press.)View Large Image Figure ViewerDownload Hi-res image Download (PPT) In the past decade, abnormalities of cardiac contractility and heart failure have been reported after acute emotional stress.15Brandspiegel H.Z. Marinchak R.A. Rials S.J. et al.A broken heart.Circulation. 1998; 98: 1349Crossref PubMed Scopus (78) Google Scholar Wittstein et al16Wittstein I.S. Thiemann D.R. Lima J.A. et al.Neurohumoral features of myocardial stunning due to sudden emotional stress.N Engl J Med. 2005; 352: 539-548Crossref PubMed Scopus (2358) Google Scholar described 19 patients admitted with symptomatic heart failure precipitated by acute emotional stress. Patients presented with chest pain, pulmonary edema, and cardiogenic shock. Diffuse T-wave inversion and prolonged QT interval was seen in most patients. Severe LV dysfunction was present on admission (median ejection fraction, 20%) but resolved rapidly in all patients within 2 weeks (ejection fraction, 60%). Plasma catecholamine levels at presentation were markedly higher in patients with stress-induced cardiomyopathy than among those with Killip class 3 myocardial infarction. Endomyocardial specimens were compatible with catecholamine cardiomyopathy. Sub-arachnoid hemorrhage (SAH)-induced cardiac dysfunction has often been referred to as “neurogenic stunned myocardium.” Lee et al17Lee V.H. Connolly H.M. Fulgham J.R. et al.Takotsubo cardiomyopathy in aneurismal subarachnoid haemorrhage: an underappreciated ventricular dysfunction.J Neurosurg. 2006; 105: 264-270Crossref PubMed Scopus (193) Google Scholar described the largest patient cohort to date, with SAH complicated by Takotsubo cardiomyopathy. Cardiac complications after SAH are well described.18Mayer S.A. LiMandri G. Sherman D. et al.Electrocardiographic markers of abnormal left ventricular wall motion in acute subarachnoid haemorrhage.J Neurosurg. 1995; 83: 889-896Crossref PubMed Scopus (152) Google Scholar Electrocardiographic (ECG) abnormalities, including prolonged QTc, T-wave, and ST segment abnormalities,19Yoshikawa D. Hara T. Takahashi K. et al.An association between QTc prolongation and left ventricular hypokinesis during sequential episodes of subarachnoid haemorrhage.Anest Analg. 1999; 89: 962-964PubMed Google Scholar have been reported. SAH patients with elevated cardiac enzymes and changes on ECG are more likely to manifest echocardiographic and clinical evidence of LV dysfunction.20Pollick C. Cujec B. Parker S. et al.Left ventricular wall motion abnormalities in subarachnoid haemorrhage: an echocardiographic study.J Am Coll Cardiol. 1988; 12: 600-605Abstract Full Text PDF PubMed Scopus (192) Google Scholar Troponin has been reported to be elevated in a fifth of patients with SAH and appears to be a more sensitive and specific indication of LV dysfunction than creatine kinase-MB.21Parekh N. Venkatesh B. Cross D. et al.Cardiac Troponin I predicts myocardial dysfunction in aneurismal subarachnoid haemorrhage.J Am Coll Cardiol. 2000; 36: 1328-1335Abstract Full Text Full Text PDF PubMed Scopus (190) Google Scholar A myriad of abnormal wall motion patterns after SAH include hypokinesis consistently involving the ventricular apex,22Dujardin K.S. McCully R.B. Wijdicks E.F. et al.Myocardial dysfunction associated with brain death: clinical, echocardiographic, and pathological features.J Heart Lung Tansplant. 2001; 20: 350-357Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar although an apex-sparing pattern of LV dysfunction has been reported. Most series of Takotsubo cardiomyopathy specifically exclude patients with SAH, however, and some have proposed that diagnostic criteria for apical ballooning syndrome require the exclusion of head trauma and intracranial bleeding.23Bybee K.A. Kara T. Prasad A. et al.Systemic review: transient left ventricular apical ballooning: a syndrome that mimics ST-segment elevation myocardial infarction.Ann Intern Med. 2004; 141: 858-865Crossref PubMed Scopus (1219) Google Scholar Ako et al24Ako J. Sudhir K. Farouque O. et al.Transient left ventricular dysfunction under severe stress: Brain-heart relationship revisited.Am J Med. 2006; 119: 10-17Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar were the first to recognize that Takotsubo cardiomyopathy has similarities to the cardiac dysfunction seen in SAH and proposed that the 2 entities shared a similar mechanism of origin, namely a preceding and acute catecholamine excess. The term “norepinephrine endocarditis,” associated with pheochromocytoma, was coined almost 50 years ago.25Van Vliet P.D. Burchell H.B. Titus J.L. Focal myocarditis associated with phheochromocytoma.N Engl J Med. 1966; 274: 1102-1108Crossref PubMed Scopus (321) Google Scholar Clinical findings similar to other catecholamine-induced cardiomyopathies occur early and are associated with exposure to catecholamine. The electrocardiogram shows elevation of ST segments, T-wave changes, and a prolonged QTc. Echocardiography shows global or localized LV hypokinesia, an inverted Takotsubo pattern, and an obstructive cardiomyopathy with high pulmonary artery pressures.26Sanchez-Recalde A. Costero O. Oliver J.M. et al.Pheochromocytoma-related cardiomyopathy; inverted takotsubo contractile pattern.Circulation. 2006; 113: e738-e739Crossref PubMed Scopus (110) Google Scholar LV end-diastolic pressure is raised in patients with cardiogenic pulmonary edema. The pathology is similar to that described after catecholamine infusion.27Abraham J. Mudd J.O. Kapur N. et al.Stress cardiomyopathy after intravenous administration of catecholamines and beta-receptor agonists.J Am Coll Cardiol. 2009; 53: 1320-1325Abstract Full Text Full Text PDF PubMed Scopus (316) Google Scholar Contraction band necrosis, ruptured myocardial muscle fibers, inflammatory cell infiltration with monocytes and lymphocytes, and eventually, myocytolysis has been reported. Electron microscopic findings show cardiomyocytes with over-contracting sarcomeres. Takotsubo cardiomyopathy features reverse within 14 days after removal of the catecholamine-secreting adrenal tumor.27Abraham J. Mudd J.O. Kapur N. et al.Stress cardiomyopathy after intravenous administration of catecholamines and beta-receptor agonists.J Am Coll Cardiol. 2009; 53: 1320-1325Abstract Full Text Full Text PDF PubMed Scopus (316) Google Scholar Abraham et al27Abraham J. Mudd J.O. Kapur N. et al.Stress cardiomyopathy after intravenous administration of catecholamines and beta-receptor agonists.J Am Coll Cardiol. 2009; 53: 1320-1325Abstract Full Text Full Text PDF PubMed Scopus (316) Google Scholar described an experience of stress-cardiomyopathy in 9 patients immediately after the intravenous administration of epinephrine or dobutamine. Specific patterns of regional wall motion abnormalities included apical and mid-ventricular akinesis with sparing of the base. However, mid-ventricular akinesis with preserved contraction of the apex and base, or mid-ventricular and basal akinesis with normal apical contractility, was also seen. Minimal elevation of cardiac isoenzymes and ECG abnormalities (diffuse T-wave inversion and prolonged QTc), absence of coronary lesions, and rapid improvement of the LV characterized the picture. A direct comparison between SC and brainstem-dead donor hearts is reported in Table 1. Overall, we believe that the human donor heart demonstrates many, if not all, of the features of SC. RV dysfunction has been described in the context of the brain death and SC. It is clear from reports that biventricular dysfunction is present in both conditions.Table 1Main Features of Stress Cardiomyopathy and Brainstem Dead DonorsFeaturesStress cardiomyopathyaThe term stress cardiomyopathy includes Takotsubo cardiomyopathy, neurogenic (sub arachnoid haemorrhage, ischemic stroke, head injury) stunned myopathy, after infusion of catecholamines and β-receptor agonists, and pheochromocytoma (early features).Brainstem deadCatecholamineYesCatecholamine stormTimingAcute dysfunctionAcute dysfunctionAbsence of coronary lesionYesYesElectrocardiogramSinus tachycardia, elevation of ST segments, prolonged QTc, T-wave changesIdemSegments affectedLeft ventricle typical (apical and middle hypokinesis combined with basal hyperkinesis) or invertedLeft ventricleBiventricularBiventricularRight ventricleRight ventricleRegion affected beyond single coronary vessel supplyYesYesMicroscopic findingsContraction band with or without overt myocyte necrosisContraction bands, mitochondrial injury, intracellular edemaInterstitial infiltrates consisting of mononuclear lymphocytes, macrophagesExtra cardiac featuresPulmonary edemaPulmonary edemaCirculating biomarkersHigher BNP levels in stress cardiomyopathy than STEMIHigher BNP levels than normal; ongoing studies about levels and predictive impactReversibility7–14 days7–14 daysBNP, Brain natriuretic peptide; STEMI, ST elevation myocardial infarction.a The term stress cardiomyopathy includes Takotsubo cardiomyopathy, neurogenic (sub arachnoid haemorrhage, ischemic stroke, head injury) stunned myopathy, after infusion of catecholamines and β-receptor agonists, and pheochromocytoma (early features). Open table in a new tab BNP, Brain natriuretic peptide; STEMI, ST elevation myocardial infarction. The mechanism underlying the association between circulating catecholamines and myocardial stunning is unknown. Such proposed mechanisms of catecholamine-induced cardiac dysfunction are those arising through high catecholamine-mediated injury, those through injury to adrenergic signalling, and miscellaneous. High levels of catecholamine may lead to vascular spasm and so to reduced coronary flow in the absence of obstructive disease in SC.28Aretz H.T. Billingham M.E. Edwards W.D. et al.Myocarditis: a histopathologic definition and classification.Am J Cardiovasc Pathol. 1987; 1: 3-14PubMed Google Scholar Ischemia due to epicardial spasm seems unlikely and would not readily explain the various ballooning patterns seen with this syndrome. Decreased coronary flow velocity and higher thrombolysis in myocardial infarction in patients with SC suggest the possibility of catecholamine-mediated microvascular dysfunction. These findings, however, may be secondary to myocardial stunning. Epicardial coronary arterial spasm has been demonstrated with mental stress in patients without coronary disease.29Mann D.L. Kent R.L. Parsons B. et al.Adrenergic effects on the biology of the adult mammalian cardiocyte.Circulation. 1992; 85: 790-804Crossref PubMed Scopus (764) Google Scholar These features maybe found in patients with SC. Elevated catecholamine levels decrease the viability of myocytes through cyclic-adenosine monophosphate-mediated calcium overload. Ellison et al30Ellison G.M. Torella D. Karakikes I. et al.Acute beta-adrenergic overload produces myocyte damage through calcium leakage from the ryanodine receptor 2 but spares cardiac stem cells.J Biol Chem. 2007; 282: 11397-11409Crossref PubMed Scopus (133) Google Scholar showed that phosphorylation of ryanodine receptors caused diffuse myocyte death through calcium leakage. Interestingly, the same study observed that cardiac stem cells were resistant to the induced acute hyperadrenergic state. Catecholamines are also a potential source of oxygen-derived free radicals, and cause myocyte injury in animal models that is attenuated by antioxidants. Free radicals may interfere with sodium and calcium transport, possibly resulting in myocyte dysfunction through increase trans-sarcolemmal calcium influx and cellular calcium overload. The argument for sympathetic over-activation is further substantiated by a rat model of stress-induced cardiac apical ballooning. Cardiac dysfunction was prevented by pre-treatment with combined α- and β-adrenoreceptor blockade. Novitzky et al31Novitzky D. Wicomb W.N. Cooper K.C. et al.Prevention of myocardial injury during brain death by total cardiac sympathectomy in the Chacma baboon.Ann Thorac Surg. 1986; 41: 520-524Abstract Full Text PDF PubMed Scopus (184) Google Scholar demonstrated in a baboon model of catastrophic cerebral insult that contraction band necrosis could be blocked by cardiac sympathectomy or cardiac denervation but not vagotomy. The crucial mediator of neurogenic cardiac injury may be endogenous release of catecholamines from myocardial sympathetic terminals rather than circulating catecholamines. Supporting this theory is the observation that contraction band necrosis still occurs after bilateral adrenalectomy, suggesting that protecting the heart from local release of norepinephrine, rather than systemic release, may be the key to preventing cardiac injury. Central sympathetic blockade significantly reduced hemodynamic instability, adverse ECG changes, and myocellular injury, and suppressed an increase in myocardial gene expression (Figure 6). Szabo et al32Szabo G. Sebening C. Hagl C. et al.Right ventricular function after brain death: Response to an increased afterload.Eur J Cardiothorac Surg. 1998; 13: 449-459Crossref PubMed Scopus (34) Google Scholar has shown that uncoupling the catecholamine storm from the catecholamine-induced increase in afterload prevents ventricular dysfunction. Adrenoreceptor variability may cause individuals to be more susceptible to catecholamine-mediated myocardial dysfunction than others. The apical myocardium in the canine heart has a greater density of β-adrenergic receptors and an increased response to sympathetic stimulation compared with the base.33Mori H. Ishikawa S. Kojima S. et al.Increased responsiveness of left ventricular apical myocardium to adrenergic stimuli.Cardiovasc Res. 1993; 27: 192-198Crossref PubMed Scopus (312) Google Scholar This may explain the apical ballooning pattern, although a similar gradient in receptor density has not been demonstrated in humans. Zaroff et al34Zaroff J.G. Pawlikowska L. Miss J.C. et al.Adrenoreceptor polymorphism and the risk of cardiac injury and dysfunction after subarachnoid haemorrhage.Stroke. 2006; 37: 1680-1685Crossref PubMed Scopus (109) Google Scholar assessed adrenoreceptor polymorphism and the risk of cardiac injury and dysfunction after sub-arachnoid hemorrhage. The combination of the β1AR 389 CC and α2AR-deletion genotypes resulted in a marked increase in the chance of LV dysfunction, supporting the suggestion that some individuals may be more susceptible to SC than others. In patients with acute myocardial dysfunction related to brain injury, White at al35White M. Wiechmann R.J. Roden R.L. et al.Cardiac beta-adrenergic neuroeffector systems in acute myocardial dysfunction related to brain injury.Circulation. 1995; 92: 2183-2189Crossref PubMed Scopus (131) Google Scholar assessed components of the β-receptor–G-protein–adrenal cyclase complex and contractile response. It appeared that the brain-dead donor RV and LV had uncoupling of the β1-adrenergic receptors, a more profound uncoupling of β2-receptors from adenyl cyclase. There was a significant decrease in β1 and β2-receptor agonist binding affinity, as deduced from the position of isoproterenol-adenyl cyclase and muscle contraction dose-response curves. Van Trigt et al36Van Trigt P. Bittner H.B. Kendall S.W. et al.Mechanism of transplant right ventricular dysfunction.Ann Surg. 1995; 221: 666-676Crossref PubMed Scopus (23) Google Scholar found no significant changes in the RV myocardial β-adrenergic receptor sensitivity or adenyl cyclase activity. The predominance of women with SC suggests a gender susceptibility to stress-related myocardial dysfunction. Women appear to be more vulnerable to sympathetically mediated myocardial stunning, as evidenced by increased catecholamine production and transient LV dysfunction after sub-arachnoid hemorrhage. Men, however, have higher levels of basal sympathetic activity than women, produce higher levels of catecholamine in response to emotional stress,37Kneale B.J. Chowienczyk P.J. Brett S.E. Gender differences in sensitivity to adrenergic agonists of forearm resistance vasculature.J Am Coll Cardiol. 2000; 36 (at al): 1233-1238Abstract Full Text Full Text PDF PubMed Scopus (256) Google Scholar and are more sensitive to catecholamine-mediated vasoconstriction. There is a difference in high-energy phosphate (HEP) metabolism between the 2 ventricles.38Stoica S.C. Satchithananda D.K. Atkinson C. et al.The energy metabolism in the right and left ventricles of human donor hearts across transplantation.Eur J Cardiothorac Surg. 2003; 23: 503-512Crossref PubMed Scopus (26) Google Scholar Our group found that the RV was prone to HEP depletion at retrieval. Recipients with impaired function showed marked variation in HEP at reperfusion, and those with RV dysfunction failed to replenish their energy stores. However, no brain injury was seen in 18% of patients with SAH who developed SC.39Kothavale A. Banki N.M. Kopelnik A. et al.Predictors of left ventricular regional wall motion abnormalities after subarachnoid haemorrhage.Neurocrit Care. 2006; 4: 199-205Crossref PubMed Scopus (88) Google Scholar In conclusion, cardiac injury may complicate neurologic insult. It may be that these 2 injuries are associated through raised catecholamines that reflect the speed of development of intracranial injury. We believe that brain-dead donors might have a cardiomyopathy that is similar to that of SC. If the dysfunctional human donor heart is indeed secondary to SC, we in heart transplantation would be wise to:1work to better understand the phenomenon of catecholamine-associated ventricular dysfunction,2accept that the unusable, poorly functioning, human donor heart is likely to improve in function with time (reverse remodelling), and3seek ways to buy time for the dysfunctional human heart offered for transplantation to improve and become of clinical use. If we are correct in drawing a parallel between SC and donor heart dysfunction, recovery can be expected in both conditions over two or so weeks. Creative thinking is going to be required to find time for the dysfunctional donor heart to recover. If we can achieve this, we may find ourselves a step closer to reducing the enormous and widening gap between the demand for the donor heart and its available supply for transplantation. None of the authors has a financial relationship with a commercial entity that has an interest in the subject of the presented manuscript or other conflicts of interest to disclose.