Tachycardia evoked from insular stroke in rats is dependent on glutamatergic neurotransmission in the dorsomedial hypothalamus.

BACKGROUND AND PURPOSE: Damage to the insula results in cardiovascular complications. In rats, activation of N-methyl-d-aspartate receptors (NMDARs) in the intermediate region of the posterior insular cortex (iIC) results in sympathoexcitation, tachycardia and arterial pressure increases. Similarly, focal experimental hemorrhage at the iIC results in a marked sympathetic-mediated increase in baseline heart rate. The dorsomedial hypothalamic region (DMH) is critical for the integration of sympathetic-mediated tachycardic responses. Here, whether responses evoked from the iIC are dependent on a synaptic relay in the DMH was evaluated. METHODS: Wistar rats were prepared for injections into the iIC and DMH. Anatomical (tracing combined with immunofluorescence) and functional experiments (cardiovascular and sympathetic recordings) were performed. RESULTS: The iIC sends dense projections to the DMH. Approximately 50% of iIC neurons projecting to the DMH express NMDARs, NR1 subunit. Blockade of glutamatergic receptors in the DMH abolishes the cardiovascular and autonomic responses evoked by the activation of NMDARs in the iIC (change in mean arterial pressure 7 ± 1 vs. 1 ± 1 mmHg after DMH blockade; change in heart rate 28 ± 3 vs. 0 ± 3 bpm after DMH blockade; change in renal sympathetic nerve activity 23% ± 1% vs. -1% ± 4% after DMH blockade). Experimental hemorrhage at the iIC resulted in a marked tachycardia (change 89 ± 14 bpm) that was attenuated by 65% ± 5% (p = 0.0009) after glutamatergic blockade at the DMH. CONCLUSIONS: The iIC-induced tachycardia is largely dependent upon a glutamatergic relay in the DMH. Our study reveals the presence of an excitatory glutamatergic pathway from the iIC to the DMH that may be involved in the cardiovascular alterations observed after insular stroke.

Autonomic and cardiovascular consequences resulting from experimental hemorrhagic stroke in the left or right intermediate insular cortex in rats.

Damage to the insular cortex (IC) results in serious cardiovascular consequences and evidence indicates that the characteristics are lateralized. However, a study comparing the effects of focal experimental hemorrhage between IC sides was never performed. We compared the cardiovascular, autonomic and cardiac changes produced by focal experimental hemorrhage (ICH) into the left (L) or right (R) IC. Wistar rats were submitted to microinjection of autologous blood (ICH) or saline (n = 6 each side/group) into the R or L IC. Blood pressure (BP), heart rate (HR) and renal sympathetic activity (RSNA) were recorded. Measurements of calcium transient and sarcoplasmic Ca2+ ATPase expression in cardiomyocytes were performed. ICH increased baseline HR (Δ:L-ICH 452 ± 13 vs saline 407 ± 11 bpm; R-ICH 450 ± 7 vs saline 406 ± 8 bpm, P < 0.05) without changing BP. HR was restored to baseline levels after i.v. atenolol. Strikingly, ICH rats presented a reduced baseline RSNA (Δ:L-ICH 122 ± 4 vs saline 148 ± 11 spikes/s; R-ICH 112 ± 5 vs saline 148 ± 7 spikes/s, P < 0.05). After 24 h of ICH we observed a marked increase in cardiac ectopies and this number was greater after ICH R-IC. Heart weight, calcium amplitude and SERCA expression were reduced only in ICH R-IC. Focal stroke into IC can alter the cardiac and renal autonomic control. Damage to the R-IC produces a greater number of arrhythmias and changes in calcium dynamics in cardiac cells indicating that the cardiovascular consequences are hemisphere-dependent. These findings confirm asymmetry for cardiac autonomic control at the IC and help to understand the cardiac and renal implications observed after specific side cortical damage.

Functional topography of cardiovascular regulation along the rostrocaudal axis of the rat posterior insular cortex.

Cardiovascular (CV) representation has been identified within the insular cortex (IC) and a lateralization of function previously suggested. In order to further understand the role of IC on cardiovascular control, the present study compared the CV responses evoked by stimulation of N-metil-D-aspartate (NMDA) receptors in the right and left posterior IC at different rostrocaudal levels. Intracortical microinjections of NMDA were performed into the IC of male Wistar rats anaesthetized with urethane (1.4 g/kg) prepared for blood pressure, heart rate and renal sympathetic nerve activity. Gene expression of NMDA receptor subunits NR2A and NR2B in the IC was confirmed by RT-PCR. Immunofluorescence for the NMDA receptor NR1 subunit was demonstrated in the IC (coordinates anteroposterior (AP) +1.5, 0.0 and -1.5 mm). A cardiac sympathoinhibitory site was identified, more rostrally located than identified in previous studies. A site of sympathoexcitatory cardiac control was identified more caudal to this region in agreement with earlier work. Under the experimental conditions, no lateralization of cardiovascular function was identified with chemical stimulation eliciting the same responses from either left or right insular cortices. No tonic role of the insula on cardiovascular control was identified with the use of the NMDA antagonist, AP-5. Peri-insular microinjection of NMDA was without cardiovascular effect indicating the specificity of the insula as a cardiovascular regulatory site. The current study reveals a functional topography for autonomic cardiovascular control along the rostrocaudal axis of the posterior IC.

Cerebral hemodynamic changes after wartime traumatic brain injury.

Traumatic brain injury (TBI) is associated with the severest casualties from Operation Iraqi Freedom (OIF) and Operation Enduring Freedom (OEF). From October 1, 2008, the U.S. Army Medical Department initiated a transcranial Doppler (TCD) ultrasound service for TBI; included patients were retrospectively evaluated for TCD-determined incidence of post-traumatic cerebral vasospasm and intracranial hypertension after wartime TBI. Ninety patients were investigated with daily TCD studies and a comprehensive TCD protocol, and published diagnostic criteria for vasospasm and increased intracranial pressure (ICP) were applied. TCD signs of mild, moderate, and severe vasospasms were observed in 37%, 22%, and 12% of patients, respectively. TCD signs of intracranial hypertension were recorded in 62.2%; 5 patients (4.5%) underwent transluminal angioplasty for post-traumatic clinical vasospasm treatment, and 16 (14.4%) had cranioplasty. These findings demonstrate that cerebral arterial spasm and intracranial hypertension are frequent and significant complications of combat TBI; therefore, daily TCD monitoring is recommended for their recognition and subsequent management.

Bedside assessment of stroke and stroke mimics.

Following ischemic stroke, interventions to bring about reperfusion must be implemented within the recognized timeframe; this means that timely clinical recognition of this condition is vital. The process of diagnosis begins with the initial bedside assessment of the patient to be followed by appropriate imaging studies. However, because reperfusion therapy may be attended by significant adverse consequences, and since imaging may be negative for many hours after stroke onset, the clinician must be aware of conditions that mimic cerebral ischemia. Depending on the timing and nature of ancillary testing, stroke mimics can be identified in 3-30% of patients presenting with the acute onset of a neurological deficit. These mimics include metabolic, traumatic, migrainous, neoplastic, endocrine, convulsive, and psychiatric disorders. Interestingly, the nature of these mimics, their frequency of occurrence, and presentation may vary between different geographical regions; however, detailed information regarding such variations is not available at present. This review provides an overview of the conditions that can masquerade as stroke, and includes information that may aid in their early detection or, at the very least, serve to warn the clinician that the patient is presenting with something other than cerebral ischemia.

Association of leukocyte count with progression of aortic atheroma in stroke/transient ischemic attack patients.

BACKGROUND AND PURPOSE: Leukocyte count is an independent predictor of stroke. We investigated the association between leukocyte count and progression of aortic atheroma over 12 months in stroke/transient ischemic attack (TIA) patients. METHODS: Consecutive ischemic stroke and transient ischemic attack patients underwent 12-month sequential transesophageal echocardiography and were assessed for total and differential leukocyte counts on admission. Paired aortic plaque images were assessed for several parameters, including changes in grade, intimal-medial thickness (IMT), and cross-sectional area. Multivariate linear and logistic regressions were used to calculate the effect of leukocyte count on the change in aortic atheromas over 12 months. RESULTS: Of the 115 participants (mean+/-SD age, 64.6+/-11.9 years; 53.1% men; 73.4% white, 24.2% black, and 2.3% Asian), 45 (35%) showed clinically significant progression of aortic atheromas (maximal change in IMT >0.70 mm over 12 months). The mean admission leukocyte count was higher in the progression group compared with the no-progression group (8.6+/-2.2 vs 7.3+/-2.2 x 10(9)/L respectively, P=0.002). Each unit increase in leukocyte count was associated with a 0.26-mm increase in aortic arch IMT over 12 months (P=0.006). After adjustment for other atherosclerosis risk factors, the relation persisted (mean increase in aortic arch IMT per unit increase in leukocyte count=0.27 mm, P=0.007). Each unit increase in leukocyte count was associated with an increased risk of significant progression of aortic atheromas (adjusted odds ratio=1.33; 95% CI, 1.09 to 1.61). CONCLUSIONS: In stroke/transient ischemic attack patients, leukocyte count is independently associated with the progression of aortic atheroma over 12 months (>0.70 mm), which is associated with cardiovascular risk.

Aortic arch atheroma progression and recurrent vascular events in patients with stroke or transient ischemic attack.

BACKGROUND: It is not known whether progression of aortic arch (AA) atheroma is associated with vascular events in patients with stroke or transient ischemic attack (TIA). METHODS AND RESULTS: AA atheroma was detected on baseline transesophageal echocardiogram in 167 consecutive patients who had prevalent stroke or TIA. Of these, 125 consented to a follow-up transesophageal echocardiogram at 12 months. Adequate paired AA images were obtained in 117 (78 with strokes, 39 with TIAs), which allowed detailed measurements of plaques. On admission for their index stroke or TIA, patients were assessed for stroke risk factors, stroke subtypes, baseline AA plaque characteristics, and laboratory parameters. Progression of AA atheroma was observed in 33 patients (28%) on 12-month follow-up transesophageal echocardiogram. It was determined that the progression group had significantly higher adjusted homocysteine levels (P<0.0001) and neutrophil counts (P<0.0001) than the no-progression group. These patients were followed up for a median of 1.7 years from the index stroke/TIA (range 0.5 to 4.5 years) for vascular events including stroke, TIA, myocardial infarction, and death due to vascular causes. Kaplan-Meier curves showed fewer patients with AA atheroma progression remained free of the composite vascular end point (49% compared with 89% in the no-progression group; P<0.0001). AA atheroma progression was associated with composite vascular events (hazard ratio 5.8, 95% confidence interval 2.3 to 14.5, P=0.0002) after adjustment for a propensity score based on confounders. CONCLUSIONS: In this preliminary study of stroke/TIA patients with AA atheroma on transesophageal echocardiogram, AA atheroma progression was associated with recurrent vascular events.

Protective effects of beta-blockers in cerebrovascular disease.

OBJECTIVE: Because activated sympathetic tone is associated with poorer outcome after stroke, we investigated whether beta-blocker treatment was associated with lesser stroke severity and improved outcome. METHOD: We prospectively studied 111 patients with stroke. Stroke severity on presentation gauged by Canadian Neurologic Scale (CanNS) and medication use verified from medical records. Power spectral analysis of heart rate variability estimated cardiac sympathovagal tone. Coagulation and inflammatory activity were assessed. RESULTS: On multiple linear regression, beta-blocker use was the sole independent predictor of less severe stroke on presentation (95% CI: 0.12 to 1.86: p = 0.03). When CanNS was dichotomized, multiple logistic regression revealed that beta-blocker use (odds ratio [OR] 3.70, 95% CI: 1.24 to 11.01, p = 0.02) and female gender (OR 2.96, 95% CI: 1.14 to 7.69, p = 0.03) were independent predictors of CanNS score >8.5. There was no difference in blood pressure and blood glucose between these two groups. Beta-blocker treatment was associated with lower sympathovagal tone (p = 0.001), thrombin (p = 0.009), hemoglobin A(1)C levels (p = 0.02), and erythrocyte sedimentation rate (p = 0.003). CONCLUSION: Beta-blocker use is associated with less severe stroke on presentation and may be cerebroprotective due to a sympatholytic effect associated with decreased thrombin, inflammation, and hemoglobin A(1)C.

Changes in cardiac thrombus status after cerebral ischemia.

BACKGROUND AND PURPOSE: Intracardiac thrombi are a potential source of cerebral embolism. The disposition of intracardiac thrombi in ischemic stroke/transient ischemic attack (TIA) patients was investigated over a 10-month period using omniplanar transesophageal echocardiography (TEE). METHODS: One hundred and five patients underwent TEE examination at <1 month and again at 9-12 months (mean 10 months) after symptom onset. TEEs were evaluated for thrombi in the left atrium, left atrial appendage and left ventricle. Stroke risk factors and TEE findings were compared between patients with and without new thrombi on follow-up TEE. Similar comparisons were made in patients with and without disappearance of thrombi on the follow-up TEE. The effect of anticoagulants was evaluated. RESULTS: Intracardiac thrombi were found initially in 18% (95% CI 11-25%) of patients in 79% (95% CI 61-97%) of whom the thrombi disappeared on the follow-up TEE; this significantly correlated with warfarin anticoagulation (p = 0.037). In the remainder 82% (95% CI 75-89%) patients, new thrombi were detected on the follow-up TEE in 8% (2-14%). These were older (p = 0.009), and not on anticoagulation. Patients with aortic atheroma >/=4 mm were also more likely to develop new intracardiac thrombi (p = 0.001). CONCLUSIONS: Anticoagulation with warfarin for 10 months is associated with conditions leading to disappearance of intracardiac thrombi after a cerebral ischemic event and hence has a probable therapeutic role. Older patients, not anticoagulated, and those with significant aortic atheroma >/=4 mm may have increased probability for de novo thrombus development. These patients may be at risk of cardiac embolization and could be considered for prophylactic anticoagulation.

Risk factors for progression of aortic atheroma in stroke and transient ischemic attack patients.

BACKGROUND AND PURPOSE: Aortic atheroma is an independent risk factor for stroke and undergoes temporal progression. Clinical and risk factor associations of such progression are unknown. Hyperhomocysteinemia has been linked with atherosclerosis, including that in the cerebral vasculature. This study investigated associations between elevated homocysteine levels and other stroke vascular risk factors and the risk of aortic atheroma progression in patients with cerebrovascular disease. METHODS: Fifty-seven stroke and 21 transient ischemic attack patients underwent multiplanar transesophageal echocardiograms within 1 month of symptom onset and again at 9 months. Aortic atheroma was graded and stratified by use of existing criteria. Stroke risk factors; use of anticoagulant, antiplatelet, and hypolipidemic drugs; and clinical and etiological subtypes of stroke were recorded and compared in patients stratified for the presence or absence of aortic atheroma progression. RESULTS: Of the 78, 29 (37%) progressed, 32 (41%) remained unchanged, and 17 (22%) regressed. Progression was most marked at the aortic arch (P=0.005), followed by the ascending segment (P<0.04). In nearly two thirds of the patients in whom aortic atheroma remained unchanged over 9 months, no atheroma was evident on baseline transesophageal echocardiogram. Only homocysteine levels > or =14.0 micromol/L (P=0.02), total anterior cerebral infarct (P=0.02), and large-artery atherosclerosis (P=0.005) significantly correlated with progression. CONCLUSIONS: Among vascular risk factors, elevated homocysteine levels are associated with aortic atheroma progression. Stroke and transient ischemic attack patients with aortic atheroma should undergo assessment of homocysteine levels, which, if elevated, may be treated with vitamins in an effort to arrest aortic atheroma progression.