The Journal of Heart and Lung Transplantation
Volume 29, Issue 9 , Pages 957-965, September 2010

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

  • Marius Berman, MD

      Affiliations

    • Department of Cardiothoracic Surgery, Papworth Hospital, Cambridge, United Kingdom
    • ,
  • Ayyaz Ali, MRCS

      Affiliations

    • Department of Cardiothoracic Surgery, Papworth Hospital, Cambridge, United Kingdom
    • ,
  • Euan Ashley, PhD, MD, FRCP

      Affiliations

    • Stanford University School of Medicine, Palo Alto California
    • ,
  • Darren Freed, PhD, MD

      Affiliations

    • Department of Surgery, University of Manitoba Medical School, Winnipeg, Manitoba, Canada
    • ,
  • Kieran Clarke, PhD

      Affiliations

    • Department of Physiology, University of Oxford, Oxford, United Kingdom
    • ,
  • Steven Tsui, MD, FRCS

      Affiliations

    • Department of Cardiothoracic Surgery, Papworth Hospital, Cambridge, United Kingdom
    • ,
  • Jayan Parameshwar, FRCP

      Affiliations

    • Department of Cardiothoracic Surgery, Papworth Hospital, Cambridge, United Kingdom
    • ,
  • Stephen Large, FRCP, FRCS

      Affiliations

    • Department of Cardiothoracic Surgery, Papworth Hospital, Cambridge, United Kingdom
    • Corresponding Author InformationReprint requests: Stephen Large, FRCP, FRCS, Consultant Cardiothoracic Surgeon, Papworth Hospital, Papworth Everard, Cambridge CB23 3RE, UK. Telephone: ++44-1480-830541. Fax: ++44-1480-364334

published online 07 June 2010.

Article Outline

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?

Keywords: heart transplantation, graft dysfunction, RV dysfunction, stress cardiomyopathy, Takotsubo cardiomyopathy

 

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:

1.exposure of the heart to unusually high catecholamine levels,

2.ventricular dysfunction, and

3.prompt 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.1 Depression of ventricular function, to a greater or lesser extent, has been demonstrated in all hearts taken for clinical transplantation.2 However, it appears that the right ventricle (RV) fares worse than the left in human donor hearts and animal models,3 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.2 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.4

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:

1.A review of brainstem death, associated catecholamine surge, and the pattern of ventricular dysfunction.

2.A review of catecholamine-induced myocardial stunning and stress cardiomyopathy.

3.A comparison between stress cardiomyopathy and the brain-dead donor's heart.

4.Suggestions for possible mechanisms of ventricular dysfunction and its recovery.

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Brainstem death, associated catecholamine surge, and the pattern of ventricular dysfunction 

Brainstem death and catecholamine storm 

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.1 Mid-brain ischemia results in parasympathetic activation with sinus bradycardia. Subsequent pontine ischemia leads to sympathetic stimulation with superimposed hypertension, the Cushing reflex.1, 2 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.”2

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.3 These events are believed to lead to pulmonary congestion.4 Electrocardiography in an animal model demonstrated myocardial ischemic changes with multiple arrhythmias.5 The vasoconstrictive effect of the autonomic storm further compromises end organ blood flow, its magnitude correlating with the rate of rise of intracranial pressure.1

Heart dysfunction in the brain-dead donor and recipient 

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.6

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.7 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 al8 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.

  • View full-size image.
  • Figure 1. 

    Brain death causes significant right ventricular (RV) dysfunction and power loss, which further deteriorates after graft preservation and transplantation. (A) RV pre-load-recruitable stroke work (PRSW) and (B) total power (TP) changes in controls (CTL), brain-dead donor transplant group (BD-Tx), and the chronic pulmonary hypertension recipient group (PHTN-Tx) before and 4 hours after induction of brain death (Post-BD) and after cardiac transplantation (Post-Tx). Compared with the control group, RV PRSW and TP decreased significantly after brain death and transplantation. In the group with a normal donor heart and recipients with pulmonary hypertension, there was a significant increase in RV PRSW and TP. Data are presented with the standard deviation.

(Reprinted with permission, Bittner HB, et al. Right ventricular dysfunction after cardiac transplantation: primarily related to the status of donor heart. Ann Thorac Surg 1999;68:1605–11.)

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  • Figure 2. 

    Brain 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.)

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  • Figure 3. 

    Relationship 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.)

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Catecholamine-induced myocardial stunning and stress cardiomyopathy 

Nomenclature and distribution 

Approximately 20 years ago, Takotsubo cardiomyopathy was first described in Japan9 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.10 SC may include basal hypokinesis with a hyperdynamic apex11, 12, 13 and is biventricular, also being shown to be present in the RV14 (Figure 4, Figure 5).

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  • Figure 4. 

    Right ventricular involvement is shown in Takotsubo cardiomyopathy. (A) Diastolic and (B) systolic cine cardiographic magnetic resonance images in the horizontal long axis-axis view demonstrate right and left ventricular ballooning (arrows). Mild right-sided pleural effusion (asteric) and significant left-sided pleural effusion (hash) are also present.

(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 full-size image.
  • Figure 5. 

    Right 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.)

Triggers of SC 

Sudden emotional stress (broken heart syndrome) 

In the past decade, abnormalities of cardiac contractility and heart failure have been reported after acute emotional stress.15 Wittstein et al16 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.

Traumatic and non-traumatic sub-arachnoid hemorrhage 

Sub-arachnoid hemorrhage (SAH)-induced cardiac dysfunction has often been referred to as “neurogenic stunned myocardium.” Lee et al17 described the largest patient cohort to date, with SAH complicated by Takotsubo cardiomyopathy. Cardiac complications after SAH are well described.18 Electrocardiographic (ECG) abnormalities, including prolonged QTc, T-wave, and ST segment abnormalities,19 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.20 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.21 A myriad of abnormal wall motion patterns after SAH include hypokinesis consistently involving the ventricular apex,22 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.23 Ako et al24 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.

Catecholamine-induced cardiomyopathy associated with pheochromocytoma 

The term “norepinephrine endocarditis,” associated with pheochromocytoma, was coined almost 50 years ago.25 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.26 LV end-diastolic pressure is raised in patients with cardiogenic pulmonary edema.

The pathology is similar to that described after catecholamine infusion.27 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.27

SC after intravenous catecholamine 

Abraham et al27 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.

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Comparison between SC and the brain-dead donor's heart 

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 1. Main Features of Stress Cardiomyopathy and Brainstem Dead Donors
FeaturesStress cardiomyopathyaBrainstem dead
CatecholamineYesCatecholamine storm
TimingAcute dysfunctionAcute dysfunction
Absence of coronary lesionYesYes
ElectrocardiogramSinus tachycardia, elevation of ST segments, prolonged QTc, T-wave changesIdem
Segments affectedLeft ventricle typical (apical and middle hypokinesis combined with basal hyperkinesis) or invertedLeft ventricle
BiventricularBiventricular
Right ventricleRight ventricle
Region affected beyond single coronary vessel supplyYesYes
Microscopic findingsContraction band with or without overt myocyte necrosisContraction bands, mitochondrial injury, intracellular edema
Interstitial infiltrates consisting of mononuclear lymphocytes, macrophages
Extra cardiac featuresPulmonary edemaPulmonary edema
Circulating biomarkersHigher BNP levels in stress cardiomyopathy than STEMIHigher BNP levels than normal; ongoing studies about levels and predictive impact
Reversibility7–14 days7–14 days

BNP, Brain natriuretic peptide; STEMI, ST elevation myocardial infarction.

aThe 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).

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Suggestions for possible mechanisms of ventricular dysfunction and its recovery 

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 catecholamine-mediated injury 

High levels of catecholamine may lead to vascular spasm and so to reduced coronary flow in the absence of obstructive disease in SC.28 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.29 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 al30 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.

Injury through adrenergic signalling 

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 al31 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 al32 has shown that uncoupling the catecholamine storm from the catecholamine-induced increase in afterload prevents ventricular dysfunction.

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  • Figure 6. 

    (A) Effect of increased intracranial pressure (ICP) and brain death on left ventricular myocardial histologic features. Increased ICP resulted in pronounced contraction band necrosis and myocytolysis. (B) In contrast, brain death ameliorated with central sympathetic blockade (ICP-CSB) abrogates these effects with sparse lesions and minimal contraction banding. Hematoxylin and eosin stain, original magnification 300x.

(Reprinted with permission; Yeh, et al. Central sympathetic blockade ameliorates brain death—induced cardiotoxicity and associated changes in myocardial gene expression. J Thorac Cardiovasc Surg 2002;124:1087–98.)

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.33 This may explain the apical ballooning pattern, although a similar gradient in receptor density has not been demonstrated in humans.

Zaroff et al34 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 al35 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 al36 found no significant changes in the RV myocardial β-adrenergic receptor sensitivity or adenyl cyclase activity.

Miscellaneous causes 

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,37 and are more sensitive to catecholamine-mediated vasoconstriction.

There is a difference in high-energy phosphate (HEP) metabolism between the 2 ventricles.38 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.39

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:

1.work to better understand the phenomenon of catecholamine-associated ventricular dysfunction,

2.accept that the unusable, poorly functioning, human donor heart is likely to improve in function with time (reverse remodelling), and

3.seek 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.

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Disclosure statement 

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.

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PII: S1053-2498(10)00240-8

doi:10.1016/j.healun.2010.04.008

The Journal of Heart and Lung Transplantation
Volume 29, Issue 9 , Pages 957-965, September 2010

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