Journal of Cardiac Failure Vol. 20 No. 3 2014
Review Article
Neurogenic Stress Cardiomyopathy in Heart Donors BURHAN MOHAMEDALI, MD, GEETHA BHAT, MD, PhD, ANTONE TATOOLES, MD, AND ALLAN ZELINGER, MD Chicago and Oak Lawn, Illinois
ABSTRACT Cardiac transplantation is severely restricted by donor availability. Left ventricular dysfunction due to neurogenic stress cardiomyopathy is often seen during donor evaluation and often presents a clinical dilemma for procurement. We report a case of a 23-year-old man with severe left ventricular dysfunction whose heart was successfully procured for transplantation. The brief case report is followed by an extensive review of neurogenic stress cardiomyopathy as well as donor evaluation for cardiac transplantation in the setting of such cardiomyopathy. (J Cardiac Fail 2014;20:207e211) Key Words: Neurogenic stress cardiomyopathy, cardiac transplant, donor evaluation, heart transplant.
Case Report
intubation and phenylephrine for hemodynamic support. After stabilization, the patient was declared brain dead. He was a registered organ donor and subsequently evaluated for organ donation. A transthoracic echocardiogram (TTE) was ordered to evaluate the heart. TTE revealed a large area of apical LV dysfunction with an ejection fraction (EF) of 30%. The wall motion abnormalities were not representative of any single coronary artery distribution. Given the overall young age and lack of any cardiac history, the LV dysfunction was thought likely a result of acute NSC. A decision was made to temporize patient’s status for a few hours and repeat imaging before organ donation was made. On repeated TTE 10 hours later, the patient’s EF was noted to be 50%. The heart was successfully procured and transplanted. Immediate postoperative echocardiogram showed an EF of 60%. All serial follow-up imaging demonstrated a preserved EF.
A previously healthy 23-year-old man was brought to the emergency room with a gunshot wound to the head. On arrival, his Glasgow Coma Scale rating was 3. He required
Discussion
From the Division of Cardiology and Cardiovascular Surgery, Advocate Christ Medical Center, University of Illinois Hospitals and Health Sciences System, Chicago and Oak Lawn, Illinois. Manuscript received July 31, 2013; revised manuscript received December 15, 2013; revised manuscript accepted December 18, 2013. Reprint requests: Burhan Mohamedali, MD, Department of Cardiology, University of Illinois Hospitals and Health Sciences System, 840 S Wood St, MC 715, Chicago, IL 60612. Tel: 312-839-0896; Fax 708-684-7040. E-mail: [email protected] See page 210 for disclosure information. 1071-9164/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.cardfail.2013.12.017
Cardiac transplantation is the treatment of choice for qualified candidates with end-stage cardiomyopathy. Unfortunately, it is hampered by a paucity of acceptable donor hearts. On any given day, O3,000 patients are on the waiting list for heart transplantation in the U.S.1 However, the number of hearts transplanted per year has remained relative constant at w2,200.2 Interestingly, among deceased organ donors, only 28% of hearts are recovered for transplantation.3 Many potential donor hearts may be rejected owing to LV systolic dysfunction seen on initial procurement evaluation.4 In this paper we discuss cardiac
Cardiac transplantation is presently limited by a scarcity of donors. Many potential donors are evaluated in the setting of an acute fatal brain injury. Left ventricular (LV) dysfunction in this setting is found in about one-third of the patients and appears to be the result of neurogenic stress cardiomyopathy (NSC) rather than primary cardiomyopathy. Such cardiac dysfunction in potential heart transplant donors often presents a clinical dilemma of whether or not the heart should be procured for transplantation. In this review, we discuss the clinical entity of NSC, its clinical presentation, pathophysiology, diagnosis, and evaluations for donation. We begin by examining the case of a young male patient suffering from acute brain injury and LV dysfunction, whose heart was successfully procured for transplantation.
207
208 Journal of Cardiac Failure Vol. 20 No. 3 March 2014 dysfunctions noted with acute brain injury and its implications toward heart transplantation. Acute Brain Injury and Cardiac Dysfunction
Acute brain injury (ABI) is the most common cause of death in potential heart transplant donors, and LV dysfunction is a well reported abnormality in these patients.5e7 Systolic dysfunction has an incidence of up to 23%e45% in patients with subarachnoid hemorrhage (SAH) and brain death, respectively.6,8 Usually about one-third of patients with ABI manifest LV dysfunction.9 LV dysfunction in such a setting is thought to be due to a transient catecholamine surge that accompanies the acute brain injury rather than coronary artery disease or anatomic myocardial damage.5e8 In a recently published study, we reported a single-center series assessing the frequency and pattern of LV systolic dysfunction in potential heart donors, where 34 consecutive adult organ donors were evaluated for LV systolic dysfunction by screening echocardiography or angiography. The results indicated that 32% of potential donors had LV dysfunction. All patients with repeated assessment of their LV function had improvement in their EF. This improvement was seen as early as 3 hours after initial assessment.9 Catecholamine surge in brain-death patients has been extensively reported.5e10 It is postulated that either the surge in serum levels of catecholamines or direct stimulation of intramyocardial nerve fiber endings results in the release of excess catecholamine leading to sustained sympathetic stimulation. This sustained stimulation induces prolonged sarcomere contraction, resulting in a pathologic subendocardial pattern of necrosis.7,11 Autopsy data has confirmed myocardial band necrosis, also known as myocytolysis, without ischemic necrosis in patients with catecholamine-induced ventricular dysfunction.5,6,10 At a cellular level, adrenergic hyperstimulation is thought to lead to pathologic myocyte calcium influx through myocardial 30 ,5ecyclic adenosine monophosphate production. This may lead to prolonged actin-myocin interaction and adenosine triphosphate depletion, which culminates in myocardial injury and subsequent contraction band necrosis.6,10 Electrocardiographic and Rhythm Abnormalities
Electrocardiographic abnormalities are often seen in up to 50% of patients with ABI.12 These abnormalities range from prolonged QT interval, peaked T waves, deep inverted or large upright T waves, ST-segment depression or elevation, and prominent U waves.13e15 These changes are thought to resolve with clinical recovery of the index neurologic event.16 Here too, these abnormalities result from excess catecholamines.13 Additionally, many arrhythmias are reported in the acute period in patients with ABI. These may range from benign premature ventricular and atrial complexes and supraventricular tachycardias, to the more serious atrioventricular blocks and complete heart blocks.14,15 Life-threatening ventricular
tachycardia and ventricular fibrillation also have been reported.14,15 The mechanisms for such arrhythmias are postulated to range from electrolyte derangement, intracranial hypertension, catecholamine excess, impaired vagal nerve function, cerebral vasospasm, and preexisting heart disease.14,15 Laboratory Abnormalities
Owing to ABI-induced localized ischemia in susceptible patients, cardiac biomarkers are often elevated.17 However, their role in donor evaluation remains unclear.18 Cardiac troponins are generally elevated in w20%e34% of patients with SAH.19 However, these elevations are generally below the threshold value for significant myocardial infarction.7 Troponin levels in such patients are thought to peak within the first 24 hours.20 Higher values are generally indicative of adverse outcomes and may be associated with development of NSC, pulmonary edema, hypotension, or cerebral vasospasm.21 Occasionally, patients with electrocardiographic changes together with elevated cardiac enzymes suggesting myocardial damage present a diagnostic dilemma to treating physicians.22 Bulsara et al, from their cohort of 350 patients with SAH, concluded that a cardiac troponin T value of !2.8 ng/mL in patients with EF !40% was consistent with NSC and can be reliable to distinguish myocardial infarction from NSC.17 Myocardial-band creatine kinase (CKMB) is also elevated during ABI. Elevations of CKMB in these patients may be noncardiac in origin. Ay et al demonstrated that in their cohort of patients with SAH and elevated troponin levels, only a minority of patients had elevated CKMB levels. None of the patients with normal troponin had an elevated CKMB level.23 B-Type natriuretic peptide (BNP) as a surrogate marker of LV dysfunction in patients has been theorized. However, such correlation in patients with NSC is lacking. Data on BNP in other similar reversible cardiomyopathies are controversial. In a Mayo clinic cohort of 205 patients with takotsubo cardiomyopathy (TKCM) whose BNP levels were measured during index hospitalization, BNP was elevated in 95% of the patients but did not correlate with EF, hemodynamic parameters, peak troponin, or peak CKMB.24 On the other hand, Nguyen et al, in a smaller study of 56 patients, demonstrated that peak N-terminal pro-BNP correlated with extent of impairment of LV EF.25 Forms of Neurogenic Stress Cardiomyopathy
The catecholamine-induced cardiac dysfunction is often termed neurogenic stress cardiomyopathy (NSC) and bears many similarities to the reversible stress-induced cardiomyopathy known as takotsubo cardiomyopathy (TKCM).6,8,26 Although frequently described as separate entities, their pathophysiology and clinical course from onset to resolution are almost identical.27 TKCM is a well known phenomenon that is thought to occur with stress. It may also be induced by catecholamine excess
NSC and Heart Transplantation
and manifests itself mainly with apical wall-motion abnormalities that do not correlate with a single coronary distribution.6 The Mayo clinic criteria for diagnosis of TKCM exclude head trauma or intracranial bleed. Although the pathophysiologies of these 2 entities are thought to be similar, the exclusion from Mayo Clinic criteria was due to variable distribution of wall-motion abnormalities in these patients.6 NSC has been reported in patients with a vast array of neurologic symptoms, including: stroke, SAH, and brain death.5e8 In contrast to classic TKCM, with an apical ‘‘ballooning’’ pattern, global hypokinesis and basal patterns of regional LV dysfunction predominate in NSC.6 The basal pattern consists of a hypokinetic to akinetic base with hyperkinetic apex. This form of NSC is also called inverted TKCM, and has been reported in brain-dead patients.6,28 The inverted TKCM pattern is thought to be due to decreased sympathetic nerve terminal density and reduced myocardial norepinephrine content in the LV apex, rendering it relatively resistant to the catecholamine storm.6,29 In addition, other patterns of wall motion abnormalities in these patients have been reported as well and may be a result of heterogeneity in myocardial norepinephrine receptor expression.6,9,30
Mohamedali et al
209
Diagnosing Neurogenic Stress Cardiomyopathy
It is often difficult to distinguish between ventricular dysfunction due to transient NSC and primary cardiomyopathy in donor hearts. In addition to the standard evaluation with the use of cardiac biomarkers and TTE, as described in the present case report, some authors in such cases have advocated the use of dobutamine echocardiography to determine augmentation of LV as a quick screening tool to distinguish the entities.31 Zaroff et al demonstrated that the use of serial echocardiography showed improvement in LV EF in a majority of potential donors.32 In such donor evaluations, improvement in LV function is seen in as early as 3 hours, and EF may completely normalize within a few days or up to a week.9,10 In potential transplant brain-dead donors, waiting such a length of time is unreasonable. In our patient, marked improvement in EF occurred within 10 hours and the heart was procured. Other centers have demonstrated similar results.33 Current Donor Evaluation and Neurogenic Stress Cardiomyopathy
The United Network for Organ Sharing has established guidelines for donor evaluation. The recommendations
Hemodynamic and Metabolic Stabilization As per United Network for Organ Sharing guidelines
Fig. 1. Evaluation of donor with suspected neurogenic stress cardiomyopathy.
210 Journal of Cardiac Failure Vol. 20 No. 3 March 2014 dictate that hearts with EF O45% should be accepted for donation, whereas donors with EF !45% should undergo hemodynamic management to achieve euvolemia and adjustment of vasoconstrictors and vasodilators to normalize afterload before the organ is declined.18,34 Metabolic management to correct acid-base balance and evaluation of the need for insulin, corticosteroids, and thyroid hormone therapy are also recommended.18,34 In addition to the above management, coronary angiography is generally recommended for all men O46 and women O51 years of age. Angiography is indicated in younger patients O35 years with cocaine use or O3 cardiac risk factors.18 Although the above-mentioned hemodynamic and metabolic treatments should be carried out, we additionally recommend a concurrent integrative approach to be undertaken to determine the etiology of the cardiomyopathy in patients presenting with ABI (Fig. 1). Certainly a very young patient without any cardiac history would point toward NSC as an etiology of the patient’s heart dysfunction. It is the older patient that represents a significant difficulty in determining etiology of the cardiac dysfunction. Features suggestive of a reversible neurogenic cause of cardiomyopathy may include the atypical wall-motion abnormalities that are not in the distribution of a single coronary artery, only modest peak elevation of cardiac troponin relative to LV dysfunction, and the temporal improvement in LV function with serial echocardiography over 3e12 hours. Conclusion It is important to recognize that LV dysfunction after fatal ABI is likely due to NSC and may be transient. We suggest that if LV dysfunction is discovered during initial heart donor evaluation, serial imaging assessment should be undertaken before excluding cardiac procurement. Reassessment over time and possibly temporizing organ procurement may permit LV function to improve enough to allow procurement (Fig. 1). Alternatively, if improvement in EF is not seen over 12e24 hours after hemodynamic and metabolic stabilization, a trial of low-dose dobutamine may be attempted to look for augmentation of EF. Such an approach could dramatically increase the pool of hearts available for transplantation. Further research into the mechanisms and means of speeding amelioration of the transient LV dysfunction in potential heart donors should be undertaken. Disclosures None.
References 1. US Department of Health and Human Services: Organ Procurement and Transplantation Network. Data 2013. Available at: http://optn.trans plant.hrsa.gov/latestData/rptData.asp. Accessed December 13, 2013.
2. Scientific Registry of Transplant Recipients. U.S. organ donors by organ and donor type, 2002 to 2011 2012. Available at: http://www.srtr.org/ annual_reports/2011/101_dh.aspx. Accessed December 10, 2013. 3. Scientific Registry of Transplant Recipients. Deceased donor organ utilization, 2002 to 2011. Available at: http://www.srtr.org/annual_re ports/2011/217_dc.pdf. Accessed October 13, 2013. 4. Zaroff JG, Babcock WD, Shiboski SC. The impact of left ventricular dysfunction on cardiac donor transplant rates. J Heart Lung Transplant 2003;22:334e7. 5. Banki NM, Kopelnik A, Dae MW, et al. Acute neurocardiogenic injury after subarachnoid hemorrhage. Circulation 2005;112:3314e9. 6. Bybee KA, Prasad A. Stress-related cardiomyopathy syndromes. Circulation 2008;118:397e409. 7. Tung P, Kopelnik A, Banki N, et al. Predictors of neurocardiogenic injury after subarachnoid hemorrhage. Stroke 2004;35: 548e51. 8. Trio O, de Gregorio C, Ando G. Myocardial dysfunction after subarachnoid haemorrhage and tako-tsubo cardiomyopathy: a differential diagnosis? Ther Adv Cardiovasc Dis 2010;4:105e7. 9. Mohamedali B, Bhat G, Zelinger A. Frequency and pattern of left ventricular dysfunction in potential heart donors: implications regarding use of dysfunctional hearts for successful transplantation. J Am Coll Cardiol 2012;60:235e6. 10. Berman M, Ali A, Ashley E, et al. Is stress cardiomyopathy the underlying cause of ventricular dysfunction associated with brain death? J Heart Lung Transplant 2010;29:957e65. 11. Brouwers PJ, Westenberg HG, van Gijn J. Noradrenaline concentrations and electrocardiographic abnormalities after aneurysmal subarachnoid haemorrhage. J Neurol Neurosurg Psychiatry 1995;58: 614e7. 12. Solenski NJ, Haley EC Jr, Kassell NF, et al. Medical complications of aneurysmal subarachnoid hemorrhage: a report of the multicenter, cooperative aneurysm study. Participants of the Multicenter Cooperative Aneurysm Study. Crit Care Med 1995;23:1007e17. 13. Mayer SA, Lin J, Homma S, et al. Myocardial injury and left ventricular performance after subarachnoid hemorrhage. Stroke 1999;30:780e6. 14. di Pasquale G, Pinelli G, Andreoli A, Manini G, Grazi P, Tognetti F. Holter detection of cardiac arrhythmias in intracranial subarachnoid hemorrhage. Am J Cardiol 1987;59:596e600. 15. Lanzino G, Kongable GL, Kassell NF. Electrocardiographic abnormalities after nontraumatic subarachnoid hemorrhage. J Neurosurg Anesthesiol 1994;6:156e62. 16. Gascon P, Ley TJ, Toltzis RJ, Bonow RO. Spontaneous subarachnoid hemorrhage simulating acute transmural myocardial infarction. Am Heart J 1983;105:511e3. 17. Bulsara KR, McGirt MJ, Liao L, et al. Use of the peak troponin value to differentiate myocardial infarction from reversible neurogenic left ventricular dysfunction associated with aneurysmal subarachnoid hemorrhage. J Neurosurg 2003;98:524e8. 18. Zaroff JG, Rosengard BR, Armstrong WF, et al. Consensus conference report: maximizing use of organs recovered from the cadaver donor: cardiac recommendations, March 28e29, 2001, Crystal City, Va. Circulation 2002;106:836e41. 19. Murthy SB, Shah S, Rao CP, Bershad EM, Suarez JI. Neurogenic stunned myocardium following acute subarachnoid hemorrhage: pathophysiology and practical considerations. J Intensive Care Med. 2013 Nov 7. [Epub ahead of print]. 20. Lee VH, Oh JK, Mulvagh SL, Wijdicks EF. Mechanisms in neurogenic stress cardiomyopathy after aneurysmal subarachnoid hemorrhage. Neurocrit Care 2006;5:243e9. 21. Saritemur M, Akoz A, Kalkan K, Emet M. Intracranial hemorrhage with electrocardiographic abnormalities and troponin elevation. Am J Emerg Med 2013;31:271.e5ee7. 22. Kerr G, Ray G, Wu O, Stott DJ, Langhorne P. Elevated troponin after stroke: a systematic review. Cerebrovasc Dis 2009;28:220e6. 23. Parekh N, Venkatesh B, Cross D, et al. Cardiac troponin I predicts myocardial dysfunction in aneurysmal subarachnoid hemorrhage. J Am Coll Cardiol 2000;36:1328e35.
NSC and Heart Transplantation 24. Ahmed KA, Madhavan M, Prasad A. Brain natriuretic peptide in apical ballooning syndrome (takotsubo/stress cardiomyopathy): comparison with acute myocardial infarction. Coron Artery Dis 2012;23: 259e64. 25. Nguyen TH, Neil CJ, Sverdlov AL, et al. N-Terminal proebrain natriuretic protein levels in takotsubo cardiomyopathy. Am J Cardiol 2011; 108:1316e21. 26. de Gregorio C, Ando G, Lentini C, Carerj S. Transient left ventricular dysfunction and stroke: an intriguing mystery still far from being fully elucidated. Int J Cardiol 2010;145:217e9. 27. Guglin M, Novotorova I. Neurogenic stunned myocardium and takotsubo cardiomyopathy are the same syndrome: a pooled analysis. Congest Heart Fail 2011;17:127e32. 28. Marechaux S, Fornes P, Petit S, et al. Pathology of inverted takotsubo cardiomyopathy. Cardiovasc Pathol 2008;17:241e3. 29. Banki N, Kopelnik A, Tung P, et al. Prospective analysis of prevalence, distribution, and rate of recovery of left ventricular systolic dysfunction in patients with subarachnoid hemorrhage. J Neurosurg 2006;105:15e20.
Mohamedali et al
211
30. Yamaguchi K, Wakatsuki T, Kusunose K, et al. A case of neurogenic myocardial stunning presenting transient left ventricular mid-portion ballooning simulating atypical takotsubo cardiomyopathy. J Cardiol 2008;52:53e8. 31. Kono T, Nishina T, Morita H, Hirota Y, Kawamura K, Fujiwara A. Usefulness of low-dose dobutamine stress echocardiography for evaluating reversibility of brain deatheinduced myocardial dysfunction. Am J Cardiol 1999;84:578e82. 32. Zaroff JG, Babcock WD, Shiboski SC, Solinger LL, Rosengard BR. Temporal changes in left ventricular systolic function in heart donors: results of serial echocardiography. J Heart Lung Transplant 2003;22: 383e8. 33. Hernandez-Caballero C, Martin-Bermudez R, Revuelto-Rey J, Aguilar-Cabello M, Villar-Gallardo J. Neurogenic stunned myocardium and cardiac transplantation: a case report. Transplant Proc 2012;44: 2106e10. 34. Wood KE, Becker BN, McCartney JG, d’Alessandro AM, Coursin DB. Care of the potential organ donor. N Engl J Med 2004; 351:2730e9.
Review Article
Neurogenic Stress Cardiomyopathy in Heart Donors BURHAN MOHAMEDALI, MD, GEETHA BHAT, MD, PhD, ANTONE TATOOLES, MD, AND ALLAN ZELINGER, MD Chicago and Oak Lawn, Illinois
ABSTRACT Cardiac transplantation is severely restricted by donor availability. Left ventricular dysfunction due to neurogenic stress cardiomyopathy is often seen during donor evaluation and often presents a clinical dilemma for procurement. We report a case of a 23-year-old man with severe left ventricular dysfunction whose heart was successfully procured for transplantation. The brief case report is followed by an extensive review of neurogenic stress cardiomyopathy as well as donor evaluation for cardiac transplantation in the setting of such cardiomyopathy. (J Cardiac Fail 2014;20:207e211) Key Words: Neurogenic stress cardiomyopathy, cardiac transplant, donor evaluation, heart transplant.
Case Report
intubation and phenylephrine for hemodynamic support. After stabilization, the patient was declared brain dead. He was a registered organ donor and subsequently evaluated for organ donation. A transthoracic echocardiogram (TTE) was ordered to evaluate the heart. TTE revealed a large area of apical LV dysfunction with an ejection fraction (EF) of 30%. The wall motion abnormalities were not representative of any single coronary artery distribution. Given the overall young age and lack of any cardiac history, the LV dysfunction was thought likely a result of acute NSC. A decision was made to temporize patient’s status for a few hours and repeat imaging before organ donation was made. On repeated TTE 10 hours later, the patient’s EF was noted to be 50%. The heart was successfully procured and transplanted. Immediate postoperative echocardiogram showed an EF of 60%. All serial follow-up imaging demonstrated a preserved EF.
A previously healthy 23-year-old man was brought to the emergency room with a gunshot wound to the head. On arrival, his Glasgow Coma Scale rating was 3. He required
Discussion
From the Division of Cardiology and Cardiovascular Surgery, Advocate Christ Medical Center, University of Illinois Hospitals and Health Sciences System, Chicago and Oak Lawn, Illinois. Manuscript received July 31, 2013; revised manuscript received December 15, 2013; revised manuscript accepted December 18, 2013. Reprint requests: Burhan Mohamedali, MD, Department of Cardiology, University of Illinois Hospitals and Health Sciences System, 840 S Wood St, MC 715, Chicago, IL 60612. Tel: 312-839-0896; Fax 708-684-7040. E-mail: [email protected] See page 210 for disclosure information. 1071-9164/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.cardfail.2013.12.017
Cardiac transplantation is the treatment of choice for qualified candidates with end-stage cardiomyopathy. Unfortunately, it is hampered by a paucity of acceptable donor hearts. On any given day, O3,000 patients are on the waiting list for heart transplantation in the U.S.1 However, the number of hearts transplanted per year has remained relative constant at w2,200.2 Interestingly, among deceased organ donors, only 28% of hearts are recovered for transplantation.3 Many potential donor hearts may be rejected owing to LV systolic dysfunction seen on initial procurement evaluation.4 In this paper we discuss cardiac
Cardiac transplantation is presently limited by a scarcity of donors. Many potential donors are evaluated in the setting of an acute fatal brain injury. Left ventricular (LV) dysfunction in this setting is found in about one-third of the patients and appears to be the result of neurogenic stress cardiomyopathy (NSC) rather than primary cardiomyopathy. Such cardiac dysfunction in potential heart transplant donors often presents a clinical dilemma of whether or not the heart should be procured for transplantation. In this review, we discuss the clinical entity of NSC, its clinical presentation, pathophysiology, diagnosis, and evaluations for donation. We begin by examining the case of a young male patient suffering from acute brain injury and LV dysfunction, whose heart was successfully procured for transplantation.
207
208 Journal of Cardiac Failure Vol. 20 No. 3 March 2014 dysfunctions noted with acute brain injury and its implications toward heart transplantation. Acute Brain Injury and Cardiac Dysfunction
Acute brain injury (ABI) is the most common cause of death in potential heart transplant donors, and LV dysfunction is a well reported abnormality in these patients.5e7 Systolic dysfunction has an incidence of up to 23%e45% in patients with subarachnoid hemorrhage (SAH) and brain death, respectively.6,8 Usually about one-third of patients with ABI manifest LV dysfunction.9 LV dysfunction in such a setting is thought to be due to a transient catecholamine surge that accompanies the acute brain injury rather than coronary artery disease or anatomic myocardial damage.5e8 In a recently published study, we reported a single-center series assessing the frequency and pattern of LV systolic dysfunction in potential heart donors, where 34 consecutive adult organ donors were evaluated for LV systolic dysfunction by screening echocardiography or angiography. The results indicated that 32% of potential donors had LV dysfunction. All patients with repeated assessment of their LV function had improvement in their EF. This improvement was seen as early as 3 hours after initial assessment.9 Catecholamine surge in brain-death patients has been extensively reported.5e10 It is postulated that either the surge in serum levels of catecholamines or direct stimulation of intramyocardial nerve fiber endings results in the release of excess catecholamine leading to sustained sympathetic stimulation. This sustained stimulation induces prolonged sarcomere contraction, resulting in a pathologic subendocardial pattern of necrosis.7,11 Autopsy data has confirmed myocardial band necrosis, also known as myocytolysis, without ischemic necrosis in patients with catecholamine-induced ventricular dysfunction.5,6,10 At a cellular level, adrenergic hyperstimulation is thought to lead to pathologic myocyte calcium influx through myocardial 30 ,5ecyclic adenosine monophosphate production. This may lead to prolonged actin-myocin interaction and adenosine triphosphate depletion, which culminates in myocardial injury and subsequent contraction band necrosis.6,10 Electrocardiographic and Rhythm Abnormalities
Electrocardiographic abnormalities are often seen in up to 50% of patients with ABI.12 These abnormalities range from prolonged QT interval, peaked T waves, deep inverted or large upright T waves, ST-segment depression or elevation, and prominent U waves.13e15 These changes are thought to resolve with clinical recovery of the index neurologic event.16 Here too, these abnormalities result from excess catecholamines.13 Additionally, many arrhythmias are reported in the acute period in patients with ABI. These may range from benign premature ventricular and atrial complexes and supraventricular tachycardias, to the more serious atrioventricular blocks and complete heart blocks.14,15 Life-threatening ventricular
tachycardia and ventricular fibrillation also have been reported.14,15 The mechanisms for such arrhythmias are postulated to range from electrolyte derangement, intracranial hypertension, catecholamine excess, impaired vagal nerve function, cerebral vasospasm, and preexisting heart disease.14,15 Laboratory Abnormalities
Owing to ABI-induced localized ischemia in susceptible patients, cardiac biomarkers are often elevated.17 However, their role in donor evaluation remains unclear.18 Cardiac troponins are generally elevated in w20%e34% of patients with SAH.19 However, these elevations are generally below the threshold value for significant myocardial infarction.7 Troponin levels in such patients are thought to peak within the first 24 hours.20 Higher values are generally indicative of adverse outcomes and may be associated with development of NSC, pulmonary edema, hypotension, or cerebral vasospasm.21 Occasionally, patients with electrocardiographic changes together with elevated cardiac enzymes suggesting myocardial damage present a diagnostic dilemma to treating physicians.22 Bulsara et al, from their cohort of 350 patients with SAH, concluded that a cardiac troponin T value of !2.8 ng/mL in patients with EF !40% was consistent with NSC and can be reliable to distinguish myocardial infarction from NSC.17 Myocardial-band creatine kinase (CKMB) is also elevated during ABI. Elevations of CKMB in these patients may be noncardiac in origin. Ay et al demonstrated that in their cohort of patients with SAH and elevated troponin levels, only a minority of patients had elevated CKMB levels. None of the patients with normal troponin had an elevated CKMB level.23 B-Type natriuretic peptide (BNP) as a surrogate marker of LV dysfunction in patients has been theorized. However, such correlation in patients with NSC is lacking. Data on BNP in other similar reversible cardiomyopathies are controversial. In a Mayo clinic cohort of 205 patients with takotsubo cardiomyopathy (TKCM) whose BNP levels were measured during index hospitalization, BNP was elevated in 95% of the patients but did not correlate with EF, hemodynamic parameters, peak troponin, or peak CKMB.24 On the other hand, Nguyen et al, in a smaller study of 56 patients, demonstrated that peak N-terminal pro-BNP correlated with extent of impairment of LV EF.25 Forms of Neurogenic Stress Cardiomyopathy
The catecholamine-induced cardiac dysfunction is often termed neurogenic stress cardiomyopathy (NSC) and bears many similarities to the reversible stress-induced cardiomyopathy known as takotsubo cardiomyopathy (TKCM).6,8,26 Although frequently described as separate entities, their pathophysiology and clinical course from onset to resolution are almost identical.27 TKCM is a well known phenomenon that is thought to occur with stress. It may also be induced by catecholamine excess
NSC and Heart Transplantation
and manifests itself mainly with apical wall-motion abnormalities that do not correlate with a single coronary distribution.6 The Mayo clinic criteria for diagnosis of TKCM exclude head trauma or intracranial bleed. Although the pathophysiologies of these 2 entities are thought to be similar, the exclusion from Mayo Clinic criteria was due to variable distribution of wall-motion abnormalities in these patients.6 NSC has been reported in patients with a vast array of neurologic symptoms, including: stroke, SAH, and brain death.5e8 In contrast to classic TKCM, with an apical ‘‘ballooning’’ pattern, global hypokinesis and basal patterns of regional LV dysfunction predominate in NSC.6 The basal pattern consists of a hypokinetic to akinetic base with hyperkinetic apex. This form of NSC is also called inverted TKCM, and has been reported in brain-dead patients.6,28 The inverted TKCM pattern is thought to be due to decreased sympathetic nerve terminal density and reduced myocardial norepinephrine content in the LV apex, rendering it relatively resistant to the catecholamine storm.6,29 In addition, other patterns of wall motion abnormalities in these patients have been reported as well and may be a result of heterogeneity in myocardial norepinephrine receptor expression.6,9,30
Mohamedali et al
209
Diagnosing Neurogenic Stress Cardiomyopathy
It is often difficult to distinguish between ventricular dysfunction due to transient NSC and primary cardiomyopathy in donor hearts. In addition to the standard evaluation with the use of cardiac biomarkers and TTE, as described in the present case report, some authors in such cases have advocated the use of dobutamine echocardiography to determine augmentation of LV as a quick screening tool to distinguish the entities.31 Zaroff et al demonstrated that the use of serial echocardiography showed improvement in LV EF in a majority of potential donors.32 In such donor evaluations, improvement in LV function is seen in as early as 3 hours, and EF may completely normalize within a few days or up to a week.9,10 In potential transplant brain-dead donors, waiting such a length of time is unreasonable. In our patient, marked improvement in EF occurred within 10 hours and the heart was procured. Other centers have demonstrated similar results.33 Current Donor Evaluation and Neurogenic Stress Cardiomyopathy
The United Network for Organ Sharing has established guidelines for donor evaluation. The recommendations
Hemodynamic and Metabolic Stabilization As per United Network for Organ Sharing guidelines
Fig. 1. Evaluation of donor with suspected neurogenic stress cardiomyopathy.
210 Journal of Cardiac Failure Vol. 20 No. 3 March 2014 dictate that hearts with EF O45% should be accepted for donation, whereas donors with EF !45% should undergo hemodynamic management to achieve euvolemia and adjustment of vasoconstrictors and vasodilators to normalize afterload before the organ is declined.18,34 Metabolic management to correct acid-base balance and evaluation of the need for insulin, corticosteroids, and thyroid hormone therapy are also recommended.18,34 In addition to the above management, coronary angiography is generally recommended for all men O46 and women O51 years of age. Angiography is indicated in younger patients O35 years with cocaine use or O3 cardiac risk factors.18 Although the above-mentioned hemodynamic and metabolic treatments should be carried out, we additionally recommend a concurrent integrative approach to be undertaken to determine the etiology of the cardiomyopathy in patients presenting with ABI (Fig. 1). Certainly a very young patient without any cardiac history would point toward NSC as an etiology of the patient’s heart dysfunction. It is the older patient that represents a significant difficulty in determining etiology of the cardiac dysfunction. Features suggestive of a reversible neurogenic cause of cardiomyopathy may include the atypical wall-motion abnormalities that are not in the distribution of a single coronary artery, only modest peak elevation of cardiac troponin relative to LV dysfunction, and the temporal improvement in LV function with serial echocardiography over 3e12 hours. Conclusion It is important to recognize that LV dysfunction after fatal ABI is likely due to NSC and may be transient. We suggest that if LV dysfunction is discovered during initial heart donor evaluation, serial imaging assessment should be undertaken before excluding cardiac procurement. Reassessment over time and possibly temporizing organ procurement may permit LV function to improve enough to allow procurement (Fig. 1). Alternatively, if improvement in EF is not seen over 12e24 hours after hemodynamic and metabolic stabilization, a trial of low-dose dobutamine may be attempted to look for augmentation of EF. Such an approach could dramatically increase the pool of hearts available for transplantation. Further research into the mechanisms and means of speeding amelioration of the transient LV dysfunction in potential heart donors should be undertaken. Disclosures None.
References 1. US Department of Health and Human Services: Organ Procurement and Transplantation Network. Data 2013. Available at: http://optn.trans plant.hrsa.gov/latestData/rptData.asp. Accessed December 13, 2013.
2. Scientific Registry of Transplant Recipients. U.S. organ donors by organ and donor type, 2002 to 2011 2012. Available at: http://www.srtr.org/ annual_reports/2011/101_dh.aspx. Accessed December 10, 2013. 3. Scientific Registry of Transplant Recipients. Deceased donor organ utilization, 2002 to 2011. Available at: http://www.srtr.org/annual_re ports/2011/217_dc.pdf. Accessed October 13, 2013. 4. Zaroff JG, Babcock WD, Shiboski SC. The impact of left ventricular dysfunction on cardiac donor transplant rates. J Heart Lung Transplant 2003;22:334e7. 5. Banki NM, Kopelnik A, Dae MW, et al. Acute neurocardiogenic injury after subarachnoid hemorrhage. Circulation 2005;112:3314e9. 6. Bybee KA, Prasad A. Stress-related cardiomyopathy syndromes. Circulation 2008;118:397e409. 7. Tung P, Kopelnik A, Banki N, et al. Predictors of neurocardiogenic injury after subarachnoid hemorrhage. Stroke 2004;35: 548e51. 8. Trio O, de Gregorio C, Ando G. Myocardial dysfunction after subarachnoid haemorrhage and tako-tsubo cardiomyopathy: a differential diagnosis? Ther Adv Cardiovasc Dis 2010;4:105e7. 9. Mohamedali B, Bhat G, Zelinger A. Frequency and pattern of left ventricular dysfunction in potential heart donors: implications regarding use of dysfunctional hearts for successful transplantation. J Am Coll Cardiol 2012;60:235e6. 10. Berman M, Ali A, Ashley E, et al. Is stress cardiomyopathy the underlying cause of ventricular dysfunction associated with brain death? J Heart Lung Transplant 2010;29:957e65. 11. Brouwers PJ, Westenberg HG, van Gijn J. Noradrenaline concentrations and electrocardiographic abnormalities after aneurysmal subarachnoid haemorrhage. J Neurol Neurosurg Psychiatry 1995;58: 614e7. 12. Solenski NJ, Haley EC Jr, Kassell NF, et al. Medical complications of aneurysmal subarachnoid hemorrhage: a report of the multicenter, cooperative aneurysm study. Participants of the Multicenter Cooperative Aneurysm Study. Crit Care Med 1995;23:1007e17. 13. Mayer SA, Lin J, Homma S, et al. Myocardial injury and left ventricular performance after subarachnoid hemorrhage. Stroke 1999;30:780e6. 14. di Pasquale G, Pinelli G, Andreoli A, Manini G, Grazi P, Tognetti F. Holter detection of cardiac arrhythmias in intracranial subarachnoid hemorrhage. Am J Cardiol 1987;59:596e600. 15. Lanzino G, Kongable GL, Kassell NF. Electrocardiographic abnormalities after nontraumatic subarachnoid hemorrhage. J Neurosurg Anesthesiol 1994;6:156e62. 16. Gascon P, Ley TJ, Toltzis RJ, Bonow RO. Spontaneous subarachnoid hemorrhage simulating acute transmural myocardial infarction. Am Heart J 1983;105:511e3. 17. Bulsara KR, McGirt MJ, Liao L, et al. Use of the peak troponin value to differentiate myocardial infarction from reversible neurogenic left ventricular dysfunction associated with aneurysmal subarachnoid hemorrhage. J Neurosurg 2003;98:524e8. 18. Zaroff JG, Rosengard BR, Armstrong WF, et al. Consensus conference report: maximizing use of organs recovered from the cadaver donor: cardiac recommendations, March 28e29, 2001, Crystal City, Va. Circulation 2002;106:836e41. 19. Murthy SB, Shah S, Rao CP, Bershad EM, Suarez JI. Neurogenic stunned myocardium following acute subarachnoid hemorrhage: pathophysiology and practical considerations. J Intensive Care Med. 2013 Nov 7. [Epub ahead of print]. 20. Lee VH, Oh JK, Mulvagh SL, Wijdicks EF. Mechanisms in neurogenic stress cardiomyopathy after aneurysmal subarachnoid hemorrhage. Neurocrit Care 2006;5:243e9. 21. Saritemur M, Akoz A, Kalkan K, Emet M. Intracranial hemorrhage with electrocardiographic abnormalities and troponin elevation. Am J Emerg Med 2013;31:271.e5ee7. 22. Kerr G, Ray G, Wu O, Stott DJ, Langhorne P. Elevated troponin after stroke: a systematic review. Cerebrovasc Dis 2009;28:220e6. 23. Parekh N, Venkatesh B, Cross D, et al. Cardiac troponin I predicts myocardial dysfunction in aneurysmal subarachnoid hemorrhage. J Am Coll Cardiol 2000;36:1328e35.
NSC and Heart Transplantation 24. Ahmed KA, Madhavan M, Prasad A. Brain natriuretic peptide in apical ballooning syndrome (takotsubo/stress cardiomyopathy): comparison with acute myocardial infarction. Coron Artery Dis 2012;23: 259e64. 25. Nguyen TH, Neil CJ, Sverdlov AL, et al. N-Terminal proebrain natriuretic protein levels in takotsubo cardiomyopathy. Am J Cardiol 2011; 108:1316e21. 26. de Gregorio C, Ando G, Lentini C, Carerj S. Transient left ventricular dysfunction and stroke: an intriguing mystery still far from being fully elucidated. Int J Cardiol 2010;145:217e9. 27. Guglin M, Novotorova I. Neurogenic stunned myocardium and takotsubo cardiomyopathy are the same syndrome: a pooled analysis. Congest Heart Fail 2011;17:127e32. 28. Marechaux S, Fornes P, Petit S, et al. Pathology of inverted takotsubo cardiomyopathy. Cardiovasc Pathol 2008;17:241e3. 29. Banki N, Kopelnik A, Tung P, et al. Prospective analysis of prevalence, distribution, and rate of recovery of left ventricular systolic dysfunction in patients with subarachnoid hemorrhage. J Neurosurg 2006;105:15e20.
Mohamedali et al
211
30. Yamaguchi K, Wakatsuki T, Kusunose K, et al. A case of neurogenic myocardial stunning presenting transient left ventricular mid-portion ballooning simulating atypical takotsubo cardiomyopathy. J Cardiol 2008;52:53e8. 31. Kono T, Nishina T, Morita H, Hirota Y, Kawamura K, Fujiwara A. Usefulness of low-dose dobutamine stress echocardiography for evaluating reversibility of brain deatheinduced myocardial dysfunction. Am J Cardiol 1999;84:578e82. 32. Zaroff JG, Babcock WD, Shiboski SC, Solinger LL, Rosengard BR. Temporal changes in left ventricular systolic function in heart donors: results of serial echocardiography. J Heart Lung Transplant 2003;22: 383e8. 33. Hernandez-Caballero C, Martin-Bermudez R, Revuelto-Rey J, Aguilar-Cabello M, Villar-Gallardo J. Neurogenic stunned myocardium and cardiac transplantation: a case report. Transplant Proc 2012;44: 2106e10. 34. Wood KE, Becker BN, McCartney JG, d’Alessandro AM, Coursin DB. Care of the potential organ donor. N Engl J Med 2004; 351:2730e9.
