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Neurogenic stress cardiomyopathy associated with subarachnoid hemorrhage Wilbert S Aronow*

ABSTRACT Cardiac manifestations are recognized complications of subarachnoid hemorrhage. Neurogenic stress cardiomyopathy is one complication that is seen in acute subarachnoid hemorrhage. It can present as transient diffuse left ventricular dysfunction or as transient regional wall motion abnormalities. It occurs more frequently with neurologically severe-grade subarachnoid hemorrhage and is associated with increased morbidity and poor clinical outcomes. Managing this subset of patients is challenging. Early identification followed by a multidisciplinary team approach can potentially improve outcomes. Cardiac abnormalities in subarachnoid hemorrhage (SAH) have been described in the medical literature since 1947 [1] . These abnormalities include echocardiographic (ECG) changes, cardiac biomarker release, diffuse left ventricular dysfunction (LVD) and regional wall motion abnormalities (RWMAs). The pathophysiological mechanism appears to be massive catecholamine release by the cardiac sympathetic nerves, which leads to myocardial injury rather than coronary artery occlusion [2] . Myocardial injury in SAH manifests as cardiac troponin elevation and LVD. Terms such as ‘Takotsubo-like cardiomyopathy’ and ‘neurogenic stunned myocardium’ have been used to describe the various imaging findings of the left ventricle. The term ‘neurogenic stress cardiomyopathy’ (NSC) most appropriately describes LVD in SAH [3] . The early diagnosis and treatment of NSC may improve clinical outcomes in SAH. This article will focus on patterns of left ventricular wall motion abnormalities and management in SAH.

KEYWORDS 

• neurogenic stress

cardiomyopathy • neurogenic stunned myocardium • stress cardiomyopathy • subarachnoid hemorrhage • Takotsubo’s cardiomyopathy

Cardiac manifestations of SAH ●●ECG abnormalities

The earliest sign of a link between the brain and the heart was the recognition of ECG abnormalities found in SAH [4] . ECG changes include morphological abnormalities such as ST-segment changes, T wave inversion, U waves, prolongation of the QT interval and abnormal Q waves [5] . ST-segment elevation, mimicking acute myocardial injury, is usually seen with LVD involving apical and midventricular walls [6] . Arrhythmias also occur in SAH. The most common rhythm abnormality is sinus bradycardia, followed by sinus tachycardia, atrial arrhythmias, supraventricular tachycardias, sinoatrial block and ventricular arrhythmias [7] . Although they are usually benign, life-threatening arrhythmias such as ventricular tachycardia and torsades de pointes may also occur, leading to sudden death (Box 1) [8,9] . Prevalence

ECG abnormalities are seen in approximately 50–100% of SAHs [9] . Clinically significant arrhythmias such as ventricular or atrial arrhythmias occur in only 1–4%. They are more often *The Cardiology Division, Department of Medicine, Westchester Medical Center/New York Medical College, Valhalla, NY 10595, USA; Tel.: +1 914 493 5311; Fax: +1 914 235 6274; [email protected]

10.2217/FCA.14.73 © 2015 Future Medicine Ltd

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Review Aronow Box 1. Echocardiographic abnormalities encountered in subarachnoid hemorrhage-induced neurogenic stress cardiomyopathy. Morphological ECG changes ●● Prolonged QTc interval ●● T wave abnormalities ●● Abnormal Q waves ●● ST-segment changes ●● Large U waves Rhythm abnormalities ●● Sinus bradycardia ●● Sinus tachycardia ●● Atrial fibrillation ●● Atrioventricular block ●● Supraventricular tachycardia ●● Ventricular tachycardia

seen within the first 48 h after the acute onset of SAH [8,10] . In a study of 101 patients with SAH conducted at our institution, 44% had normal ECGs, 17% had ST-segment depression, 16% had sinus tachycardia and 5% had deep T inversions. Significant arrhythmias such as ventricular tachycardia were seen in 5% and supraventricular tachyarrhythmias were seen in 2% [11] . Pathophysiology

The pathophysiology of ECG abnormalities is incompletely understood. Significant adrenergic release may cause cardiomyopathy, which results in ECG abnormalities [12] . However, the changes do not always reflect structural changes in the heart muscle [12,13] . The ECG changes in SAH can also be attributed to autonomic dysregulation from hypothalamic stimulation and increased intracranial pressure [4,5] .

these biomarkers, cardiac troponin I is a highly sensitive marker for myocardial injury (Box 2) [18] . Prevalence

Cardiac troponin I may be elevated in 20–40% of SAH patients [19–21] . Troponin levels peak within 1–2 days of the onset of SAH and then taper [22] . Elevated troponin levels are associated with diastolic dysfunction, pulmonary congestion and LVD. Tanabe et al. reported the presence of RWMAs of the left ventricle in 50% of SAH patients with elevated troponin [23] . Pathophysiology

Proposed mechanisms for myocardial injury include coronary artery spasm, microvascular dysfunction and the direct effects of catechol­ amines on cardiomyocytes. Catecholaminemediated cardiotoxcity is a widely accepted theory of myocardial injury [2,3] . Prognosis

Troponin levels, when elevated, are a powerful prognostic marker [24] . In our study of 96 patients with SAH, the in-hospital mortality was 40% in patients with increased troponin I compared with 11% for patients with normal troponin I (p < 0.005) [25] . A study of 253 SAH patients reported that peak troponin levels are predictive of an increased risk of hypotension requiring pressors, pulmonary edema, left ventricular systolic dysfunction and delayed cerebral ischemia from vasospasm [25] . Elevated troponins also independently predict mortality and severe disability at discharge or 14 days after SAH, but could not predict mortality at 3 months [24] . Highly positive troponin I levels >1 ng/ml are associated with severe neurological injury [23] . ●●Brain natriuretic peptide

Prognosis

ECG changes are associated with more severe neurological injury and do not independently predict all-cause mortality [14,15] . In patients with SAH, the presence of deep T wave inversions and prolonged QT intervals correlate with existing LVD [16] . Clinically significant arrhythmias are associated with an increased risk of cardio­ vascular comorbidity, prolonged hospital stay and poor clinical outcomes after SAH [17] . ●●Serum cardiac markers

Cardiac troponin I, creatine kinase and creatine kinase MB can all be elevated in SAH. Among

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Plasma brain natriuretic peptide (BNP) can also be elevated in SAH. The levels increase soon after SAH and return to baseline in 1–2 weeks [26,27] . Increased levels of BNP are seen in patients with high-grade SAH due to the rupture of an anterior communicating artery aneurysm [26] . Pathophysiology

In patients with SAH, plasma BNP is two- to three-fold higher than levels in cerebrospinal fluid, which indicates a noncerebral source of BNP [27] . The possible mechanisms that have been hypothesized are hypoxia of the hypothalamus, endothelin-1 release and excess catecholamine release that

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Neurogenic stress cardiomyopathy associated with subarachnoid hemorrhage  increases the load on the cardiac ventricles [28] . Prognosis

Plasma BNP elevation is associated with RWMAs, LVD, diastolic dysfunction, pulmonary edema and troponin elevation [26,27] . Elevated BNP levels after SAH are more likely to suggest vasospasm or cerebral infarction, and these patients have poor neurological outcomes at 14 days [26–31] . Hence, BNP may be used as a prognostic biomarker in detecting patients who are at risk for adverse outcomes. However, BNP levels do not correlate well with myocardial injury [31] . ●●Left ventricular dysfunction

In 1988, Pollick and colleagues first documented the presence of LVD in SAH [32] . In SAH, the term ‘transient left ventricular apical ballooning cardiomyopathy’ was used to describe apical hypokinesis, and ‘neurogenic stunned myocardium’ was used to describe RWMAs of the apical, basal and mid ventricular walls [3,33] . Both conditions appear to have the same pathophysiology and clinical course [2,3] . Ako et al. proposed that SAH-induced cardiomyopathy and Takotsubo’s cardiomyopathy have common pathophysiological mechanisms [34] . The term ‘NSC’ was introduced by Lee et al. as a more appropriate description of myocardial dysfunction associated with SAH (Box 3) [2] . Prevalence

The prevalence of LVD in SAH ranges from 8 to 27% (Table 1) [35,36] . In a meta-analysis by van der Bilt et al., RWMAs varied from 13 to 31% [37] . Diastolic dysfunction was reported in 71% of patients [38] . Mean left ventricular ejection fraction (LVEF) varied from 32 to 45.2% [39] . The prevalence of transthoracic ECG abnormalities as reported in a study by Amin et al. of 30 patients with SAH showed that five patients (17%) had left ventricular hypertrophy, one patient (3%) had abnormal LVEF and 20 patients (67%) had no abnormalities [40] . RWMAs are seen within the first 2 days in the course of SAH [41] . RWMAs resolve within days or weeks in almost all patients who survived the acute phase. A follow-up ECG typically reveals a normal LVEF [33,35] . Risk factors

Risk factors for LVD are poor-grade SAH, advanced age and female sex [14,21,42] . Patients with Hunt–Hess grade >3 have a higher risk of

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Review

Box 2. Biomarkers seen in subarachnoid hemorrhage-induced neurogenic stress cardiomyopathy. ●● Cardiac troponin I ●● Creatine kinase ●● Creatine kinase MB ●● Brain natriuretic peptide

LVD [14] . The precise role of sex hormones in SAH-induced RWMAs is not known [43] . Patterns of LVD

The abnormal wall motion patterns seen in SAH include diffuse left ventricular hypokinesis [44] , apical hypokinesis or akinesis [18,22] or midventricular or basal hypokinesis (apex-sparing pattern) [45,46] . The patterns of RWMAs do not match single coronary artery distributions and are usually transient [36] . In their study of 173 SAH patients, Banki et al. reported that the most common left ventricular segments involved basal portions of the anteroseptal and anterior walls and the middle ventricular portions of the anteroseptal, inferoseptal, anterior and anterolateral walls. These segments were hypokinetic or akinetic in 54–63% of patients with RWMAs [41] . The prevalences of RWMAs at the left ventricular apex and the basal portions of the inferior and posterolateral walls were relatively low compared with the frequencies of abnormalities of the basal septum and anterior wall [41] . In a retrospective study by Zaroff et al. in 30 patients with SAH, regional and global wall motion patterns were observed in 21 and nine patients, respectively. Preservation of apical function relative to the base level was seen in 57% [46] . Predominance of the apical pattern of wall motion abnormalities with a apical to nonapical distribution in a 3:1 ratio was seen only in a few studies [47] . The various patterns of wall motion abnormalities can be explained by the distribution and sensitivity of adrenergic receptors within the myocardium [48] . The density and location of adrenergic receptors in the myocardium varies among individuals and also with age in the same individual [49,50] . Younger patients present more often with the apical-sparing variant and older patients have more apical hypokinesis due to the redistribution of adrenoceptors with age [51] . Zaroff et al. reported that specific genetic polymorphisms of β- and α-adrenergic receptors are associated with increased sensitivity to catecholamines and an increased risk of cardiac dysfunction [52] .

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Review Aronow Table 1. Summary of some of the studies in patients with subarachnoid hemorrhage and their echocardiographic findings. Study (year)

Patients Echocardiographic findings (n)

Follow-up period Patients with recovery of EF (%)

Kilbourn et al. (2013) Sugimoto et al. (2008) Mayer et al. (1999) Parekh et al. (2000) Banki et al. (2006) Tanabe et al. (2008)

299 47 72 39 173 103

RWMAs or EF