Hypoperfusion-related cerebral ischemia and cardiac left ventricular systolic dysfunction

Hypoperfusion-Related Cerebral Ischemia and Cardiac Left Ventricular Systolic Dysfunction Patrick Pullicino, MD, Victoria Mifsud, MD, Edward Wong, MBBS, Susan Graham, MD, Ishani Ali, MD, and Dzevdet Smajlovic, MD

Background: Cardiomyopathy and low ejection fraction (EF) are associated with cardiac thrombi and cardiogenic embolism but may also be risk factors for hypoperfusion-related cerebral ischemia (HRCI). Current stroke subtype criteria do not include an HRCI category. Method: To look for evidence of HRCI, we compared mean infarct volume between serial patients with EF ⱕ35% and high-grade (ⱖ 70%) carotid stenosis and serial patients with normal EF and high-grade carotid stenosis. We matched serial stroke patients with EF ⱕ35% with stroke patients with normal EF and compared the number and type of ischemic lesion (symptomatic or asymptomatic) and mean infarct volume on magnetic resonance imaging. We blindly compared stroke subtype in these groups using modified Trial of ORG 10172 in Acute Stroke Treament (TOAST) criteria, including an HRCI category. Results: In patients with carotid stenosis, ipsilateral infarct volume was greater with EF ⱕ 35% (74.7mL, 95% CI, 17.3-132.1 mL) than in controls (17.1mL, 95% Cl, 9.4-24.8 mL) (P ⬍ .05). There was no difference in the mean number of HRCI-compatible infarcts on computed tomography scan between patients with low EF and controls. Symptomatic HRCI occurred in 4 of 15 patients with low EF and in 0 of 15 controls. Conclusions: Symptomatic HRCI occurs in patients with low EF. Severe arterial stenosis may interact with left ventricular systolic dysfunction to cause cerebral hypoperfusion. Modification of the TOAST criteria to include an HRCI subtype is feasible and HRCI should be included as a stroke subtype. Key Words: Left ventricular systolic dysfunction—Cerebral ischemia—Hypoperfusion. Copyright © 2001 by National Stroke Association

Low cardiac ejection fraction (EF) is a known risk factor for cerebral infarction. Two large studies found the rate of stroke inversely proportional to EF.1,2 In the Survival and Ventricular Enlargement (SAVE) study,1 there was an 18% increment in the risk of stroke for every 5% decline in EF. A retrospective analysis of data from the Studies of Left Ventricular Dysfunction (SOLVD), which excluded patients with atrial fibrillation, found a 58% increase in

From the Departments of Neurology and Cardiology, State University of New York at Buffalo, Buffalo, NY. Received February 15, 2001; accepted May 22, 2001. Address reprint requests to Patrick Pullicino, MD, Stroke Program, Department of Neurology, Buffalo General Hospital/Kaleida Health, 100 High St, Buffalo NY 14203. Copyright © 2001 by National Stroke Association 1052-3057/01/1004-0007$35.00/0 doi:10.1053/jscd.2001.26870

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risk of thromboembolic events for every 10% decrease in EF among women (P ⫽ .01).2 Abnormally low EF is caused by left ventricular systolic dysfunction (LVSD) secondary to ischemic or nonischemic causes. LVSD causes an increased left ventricular end diastolic volume and left ventricular stasis, which may predispose to thrombus formation. Current stroke subtype criteria3 classify the mechanism of stroke in patients with cardiomyopathy as cardiogenic embolism. Peripheral embolism is well documented in patients with LVSD secondary to cardiomyopathy and probably results from left ventricular thrombus. Twelve percent of patients with cardiomyopathy have left ventricular thrombus formation, and EF is the factor most associated with ventricular thrombus formation.4 Cardiac disease is often cited as a cause of cerebral hypoperfusion and hypoperfusion-related cerebral isch-

Journal of Stroke and Cerebrovascular Diseases, Vol. 10, No. 4 (July-August), 2001: pp 178-182

HYPOPERFUSION-RELATED CEREBRAL ISCHEMIA 5,6

emia (HRCI). The presumed mechanism of cerebral hypoperfusion secondary to cardiac disease is an episode of severe systemic hypotension secondary to arrhythmia.7 Patients with LVSD have an elevated left ventricular filling pressure and a reduced stroke volume, and this causes a reduction of systemic blood flow. However, systemic blood pressure is usually well maintained by peripheral vasoconstriction, and patients with low EF may even be hypertensive.8 Because autoregulation maintains cerebral blood flow through a wide range of systemic blood pressures in a patient with intact autoregulation, a reduction in EF should not affect cerebral blood flow. Patients with LVSD may easily decompensate hemodynamically, however, and may become hypotensive secondary to cardiac ischemia or arrhythmia. Patients with LVSD, who have impaired autoregulation caused by recent stroke or severe carotid occlusive disease, may be at risk for HRCI. Hypoperfusion may also be the cause of ejection fraction-related cognitive impairment in the elderly.9 The frequency of HRCI cannot be established by using currently available stroke subtype criteria3 because they do not include an HRCI stroke subtype. This study was initiated to look for evidence of HRCI in patients with LVSD.

Patients and Methods We reviewed the echocardiographic reports of serial patients with a clinical diagnosis of stroke or transient ischemic attack who had undergone transesophageal or transthoracic echocardiography over a 3-year period and selected patients with EF ⱕ 35%. The Institutional Review Board of the Buffalo General Hospital, Buffalo, NY, approved the study protocol. First, we compared mean infarct volume on computed tomography scan (CT) or magnetic resonance imaging (MRI) hard-copy images between serial patients with cardiac EF ⱕ 35% who had high-grade (ⱖ 70%) carotid artery stenosis and a control group of serial patients with normal cardiac EF and ⱖ 70% carotid artery stenosis. The control group was made up of serial patients admitted with recent stroke over the same 3-year period as the patients with low EF, who had high-grade carotid stenosis on magnetic resonance angiography, carotid doppler, or both and whose echocardiogram showed a normal EF. The volume of each infarct was measured on hard-copy images by a method previously validated for inter-rater reliability.10 MRI infarct volume measurements showed a strong correlation (r ⫽ 0.88) with CT infarct volume measurements, using this method. Second, we individually matched patients with recent stroke and EF ⱕ 35% who had a cranial MRI scan with patients with normal EF with recent stroke who had a cranial MRI for age within 10 years, sex, presence of

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hypertension, and presence of carotid disease (ⱖ 50% stenosis). The matching was performed blind to the MRI scan findings. Patients with atrial fibrillation were excluded. The MRI scans were reviewed in random order by 2 observers, blind to cardiac EF and other clinical data. The following were noted: (1) number of infarcts “compatible with HRCI” (see below); (2) number of small, deep infarcts (deep cerebral, brainstem, or cerebellar infarcts ⬍ 1.5cm in diameter); (3) pial territory infarcts (cortical cerebral or cerebellar infarcts11); (4) the severity of periventricular white matter disease12; and (5) the volume of each infarct was measured on hard-copy images.10 We compared the mean number of infarcts per scan, the severity of white matter disease, and the mean infarct volume per group between these matched groups. We also determined stroke subtype in these matched groups using a modification of the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) criteria.3 We modified the TOAST criteria3 by adding an HRCI subtype. We defined as probable HRCI the combination of a symptomatic infarct “compatible with HRCI” on imaging with a potential cardiac or arterial cause of hypoperfusion. Possible HRCI is evidence of a symptomatic infarct “compatible with HRCI” on imaging alone. Infarction “compatible with HRCI” includes the following: 1. Cortical watershed infarcts5 that are located at the junction of the usual territories of major cerebral arteries that are in free anastomosis (anterior, middle, and posterior cerebral).13 2. Distal field infarcts that are confined to a location at the most distal field of supply of an artery that has few or no collaterals (e.g., the upper lateral margin of the lateral ventricle [distal field of the lenticulostriate arteries]).14 3. Internal borderzone infarcts are deep infarcts that lie between the territories of 2 arteries that do not freely anastomose (e.g., white matter infarcts [lying between territories supplied by long penetrators of anterior, middle, or posterior cerebral artery]).15 Potential cardiac or arterial causes of hypoperfusion are (1) high-grade (ⱖ 70%) stenosis of artery supplying territory of symptomatic infarct,16 (2) cardiac disease including left ventricular systolic dysfunction with cardiac failure or reduced (ⱕ 35%) ejection fraction,1 and (3) ⬎ 25% reduction in mean systemic arterial pressure.17,18 When the HRCI subtype was added to the TOAST criteria, cardiomyopathy and congestive cardiac failure became criteria for both cardioembolism and HRCI, and high-grade carotid stenosis became a criterion for both large-artery atherosclerosis and HRCI. Under our modified criteria, if cardiomyopathy, cardiac failure, or highgrade carotid stenosis were present, the finding of infarction “compatible with HRCI” on CT scan or MRI

P. PULLICINO ET AL.

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Table 1. Comparison of ipsilateral infarct volumes in patients with high-grade carotid stenosis between patients with low ejection fraction and controls Low EF

All infarcts Pial infarcts

Controls

No. of infarcts

Mean volume (mL)

95% Cl (mL)

No. of infarcts

Mean volume (mL)

95% CI (mL)

P value

7 6

74.7 84.8

17.3-132.1 20.3-148.5

38 13

17.1 32.3

9.4-24.8 17.5-47.1

⬍.05 .09

controls. Small deep infarcts were less frequent (P ⫽ .04), and periventricular white-matter hyperintensity tended to be less severe (P ⫽ .09) in scans of patients with reduced EF than controls. The mean infarct volume for all infarct types was not significantly different between these matched groups. Patients with reduced EF tended to have larger pial infarcts (52.71 mL; 95% CI, 7.79 - 97.62 mL) than patients with normal EF (20.26 mL; 95% CI, 11.39 - 29.13 mL) (P ⫽ .12) (Table 3). Stroke subtype in the 15 patients with reduced EF and matched controls with normal EF is shown in Figure 1. Symptomatic probable HRCI was only diagnosed in the group with reduced EF.

determined that the stroke was classified as HRCI rather than cardioembolic or atherosclerotic. Student’s t tests, chi-square tests or Fisher exact tests were used for comparisons as appropriate. A P level of ⬍.05 was taken to be significant.

Results Over a 3-year period, 673 (58%) of 1159 patients with acute stroke had echocardiograms within 3 months of the stroke. Forty-seven (7%) of the 673 patients with stroke had an EF ⱕ 35% Eight of these patients had no cranial CT scan or MRI. The remaining 39 patients were included in the study. In patients with high-grade carotid stenosis, the mean volume of infarcts ipsilateral to the stenosis was greater in patients with low EF (74.7mL, 95% CI, 17.3 - 132.1mL) than in patients with normal EF (17.1 mL; 95% CI, 9.4 24.8mL) using all infarct types (P ⬍ .05). The volume of pial infarcts ipsilateral to the stenosis tended to be greater in patients with low EF (84.4 mL; 95% CI; 20.3 -148.5 mL) than in patients with normal EF (32.3 mL; 95% CI, 17.5 47.1 mL) (P ⫽ .09) (Table 1). No patients with HRCIcompatible infarction had documented ⬎ 25% drop in mean arterial pressure. Results of the MRI comparison of 15 patients with reduced EF and normal EF controls is shown in Table 2. There was no difference in the mean number of infarcts, HRCI-compatible infarcts, or pial infarcts per scan between the MRI scans of patients with reduced EF and

Discussion Our finding that infarct volume is greater ipsilateral to a high-grade carotid stenosis in patients with low EF than in patients with normal EF is presumptive evidence for HRCI and suggests that cerebral perfusion secondary to low EF may increase the size of an infarct. The trend to a larger volume of pial (presumed cardioembolic) infarcts in patients with low EF than in patients with normal EF in both of our case-control groups also supports this finding. Caplan and Hennerici19 recently hypothesized that hypoperfusion and embolism often interact and that reduced perfusion may exacerbate ischemia resulting from embolism. In macaques, cerebral blood flow varies directly with cardiac output in ischemic brain regions.20 Autoregulation is impaired adjacent to an acute infarct,21

Table 2. Comparison of mean infarct numbers per scan in 15 patients with low ejection fraction and 15 matched controls Low EF

Pial infarcts HRCI-compatible infarcts Small deep Infarcts WMS

Controls

Mean

SD

Mean

SD

P value

0.60 0.87 0.53 0.87

0.63 0.74 0.92 0.92

0.67 0.67 1.20 1.60

0.90 0.82 1.10 1.35

.8 .4 .04 .09

NOTE. Mean equals mean number of infarcts per scan. Abbreviation: SD, standard deviation; WMS, white matter score.12

HYPOPERFUSION-RELATED CEREBRAL ISCHEMIA

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Table 3. Comparison of infarct volumes between 15 patients with low ejection fraction and 15 matched controls Low EF

All infarcts Pial infarcts

Controls

No. of infarcts

Mean volume (mL)

95% CI (mL)

No. of infarcts

Mean volume (mL)

95% CI (mL)

P value

32 8

14.6 52.7

11.2 - 28.1 7.8 - 97.6

39 12

7.1 20.2

2.9 - 11.3 11.4 - 29.1

.3 .1

and the ischemic penumbra may be more vulnerable in patients with reduced EF than in patients with normal EF. The fact that infarct volume was significantly greater with low EF only in patients with high-grade carotid stenosis suggests a hemodynamic interaction between arterial stenosis and LVSD. An interaction between arterial stenosis and reduced cardiac output is often cited as a cause of focal cerebral ischemia22,23 but is difficult to prove. A reduction of volume flow proximal to a critical stenosis does not decrease the flow across the stenosis unless the proximal blood pressure is also reduced. It is possible that episodes of systemic hypotension caused by hemodynamic decompensation or overmedication in patients with cardiomyopathy could result in a reduction of blood flow and in HRCI distal to a critically stenosed artery. It is uncertain whether patients with occlusive carotid disease who have low EF are at increased risk of HRCI-related stroke or if low EF only enlarges an area of existing ischemia. The fact that low EF did not increase the number of symptomatic or asymptomatic infarcts “compatible with HRCI” suggests that LVSD by itself does not initiate a new infarct. Because symptomatic HRCI infarcts were only seen in patients with low EF, this suggests that

border-zone or watershed infarcts may be larger and more likely to be symptomatic in patients with low EF. This is supported by our finding of larger infarct volume in patients with high-grade stenosis and low EF and by the trend to larger infarct size in our other matched group. By using our modified TOAST stroke subtype criteria, we were able to classify strokes into an HRCI subtype. By using these criteria, we found HRCI to be responsible for as many as 25% of strokes in patients with cardiomyopathy or low EF. Cardioembolism has been assumed to be the sole stroke subtype in patients with cardiomyopathy,3 but our findings support the findings of a recent autopsy series24 that HRCI may be misdiagnosed as cardioembolic stroke. Although cardiac disease has been found to be a risk factor for watershed infarction,5,18 it is not possible to determine the frequency of HRCI using current stroke subtype criteria because this stroke subtype is not currently included. There is need to modify current stroke subtype criteria to include an HRCI category. Our criteria for HRCI are based on the presence of an infarct in a recognized watershed territory or vascular border zone. Although it has been argued25 that watershed infarction is an unreliable sign of hemodynamic stroke, positron emission tomographic studies have shown that border-zone locations are selectively vulnerable to HRCI,26 and the majority of infarcts in these regions are likely to be at least partly of hemodynamic origin. Definitive ascertainment of cerebral hypoperfusion probably requires positron emission tomographic scanning, which cannot be used for subtyping of routine strokes.

References Figure 1. Stroke subtype by modified TOAST criteria comparing patients with low EF and controls. The percentage of the total number (n ⫽ 15) of strokes in each subtype is shown on the y axis. Numbers of patients are shown above each bar. HRCI, hypoperfusion-related cerebral infarction; C/E, cardioembolic infarct; LA, infarct secondary to large artery disease; Lac, lacunar infarct; 2 et, infarct with two causes identified; Neg, infarct with undetermined etiology due to negative evaluation; Low EF, patients with reduced ejection fraction; N EF, patients with normal ejection fraction.

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