During the past decade, technological advances have made it possible to measure regional cerebral hemodynamics in individual patients. Studies performed with these techniques have demonstrated that the degree of carotid stenosis correlates poorly with the hemodynamic status of the ipsilateral cerebral circulation. The primary determinant of cerebral perfusion pressure and blood flow under these circumstances is the adequacy of collateral circulatory pathways. Since collateral circulation varies from patient to patient, there is no critical degree of carotid stenosis that consistently produces hemodynamic compromise of the cerebral circulation. It is, thus, time to abandon the concept of the hemodynamically significant carotid stenosis as it relates to the pathogenesis and treatment of cerebrovascular disease. Measurement of regional cerebral hemodynamics have provided new insight into the pathogenesis of tranisent ischemic attacks and generated some preliminary data on the prognostic and therapeutic importance of chronic reductions in regional cerebral perfusion pressure. Further investigations into the importance of hemodynamic factors in ischemic stroke can now be based on accurate assessment of cerebral (not carotid or vertebrobasilar) hemodynamics in the context of other coexisting epidemiological, clinical, hematological, and angiographic risk factors.

Cerebral hemodynamics in ischemic cerebrovascular disease.

Sickle-cell anaemia is the most common cause of stroke in children, and stroke is one of the most devastating complications of sickle-cell disease. Overt strokes are typically due to large-artery vasculopathy affecting the intracranial internal carotid arteries and proximal middle cerebral arteries, whereas silent strokes typically occur in the territory of penetrating arteries. The sickled red blood cell can contribute to the pathogenesis of stroke via abnormal adherence to the vascular endothelium and by haemolysis, which results in endothelial cell activation, a hypercoaguable state, and alterations in vasomotor tone. Red-blood-cell transfusion, the most common preventive measure for stroke in sickle-cell disease, is associated with iron overload in chronic disease. Therefore, interventions directed towards the potential mechanisms that promote vasculopathy and occlusion in sickle-cell anaemia should be investigated. Here we review the epidemiology, clinical spectrum, and pathophysiology of stroke in sickle-cell disease to identify potential therapeutic targets.

https://www.thelancet.com/pdfs/journals/laneur/PIIS1474-4422(06)70469-0.pdf

Pathophysiology and treatment of stroke in sickle-cell disease: present and future

The genetic cause of sickle cell disease has been known for decades, yet the reasons for its clinical variability are not fully understood. The neurological complications result from one point mutation that causes vasculopathy of both large and small vessels. Anemia and the resultant cerebral hyperemia produce conditions of hemodynamic insufficiency. Sickled cells adhere to the endothelium, contributing to a cascade of activated inflammatory cells and clotting factors, which result in a nidus for thrombus formation. Because the cerebrovascular reserve becomes exhausted, the capacity for compensatory cerebral mechanisms is severely limited. There is evidence of small-vessel sludging, and a relative deficiency of nitric oxide in these vessels further reduces compensatory vasodilatation. Both clinical strokes and silent infarcts occur, affecting motor and cognitive function. New data suggest that, in addition to sickle cell disease, other factors, both environmental (eg, hypoxia and inflammation) and genetic (eg, mutations resulting in thrombogenesis), may contribute to a patient's stroke risk. The stroke risk is polygenic, and sickle cell disease can be considered a model for all cerebrovascular disease. This complex disease underscores the potential intellectual and practical distance between the determination of molecular genetics and effective clinical application and therapeutics.

Sickle cell disease: the neurological complications.

The present paper aims to review the main pathophysiological links between red blood cell disorders and cardiovascular diseases, provides a brief description of the latest studies in this area, and considers implications for clinical practice and therapy. Anemia is associated with a special risk in proatherosclerotic conditions and heart disease and became a new therapeutic target. Guidelines must be updated for the management of patients with red blood cell disorders and cardiovascular diseases, and targets for hemoglobin level should be established. Risk scores in several cardiovascular diseases should include red blood cell count and RDW. Complete blood count and hemorheological parameters represent useful, inexpensive, widely available tools for the management and prognosis of patients with coronary heart disease, heart failure, hypertension, arrhythmias, and stroke. Hypoxia and iron accumulation cause the most important cardiovascular effects of sickle cell disease and thalassemia. Patients with congenital chronic hemolytic anemia undergoing splenectomy should be monitored, considering thromboembolic and cardiovascular risk.

/pdf/mechanisms-linking-red-blood-cell-disorders-and-11xkqz0lgp.pdf

Mechanisms Linking Red Blood Cell Disorders and Cardiovascular Diseases

To investigate cerebral hemodynamics in sickle cell disease (SCD), we used the 133Xenon inhalation technique of quantifying cerebral blood flow (CBF) in 67 patients. Clinical examinations and cerebral magnetic resonance imaging also were performed in all patients. Compared with age-matched healthy controls, CBF was elevated by 68% in patients, and inversely related to hematocrit. An experimental index of cerebral blood volume, pr4, was also elevated in the patients in a similar manner. Cerebral blood volume was positively correlated to CBF in SCD patients but not in controls. History of stroke and current neurologic symptoms were associated with lower flow and higher cerebral blood volume. Transfusion therapy reduced the hyperemia, the reduction being greater than expected by hematocrit elevation alone. These findings document a vasodilatory hyperemia in SCD. This dilatation may be a risk factor for ischemic distal-field infarctions, as visualized by MRI, due to a limitation of cerebrovascular reserve capacity.

Cerebral hyperemia, stroke, and transfusion in sickle cell disease.

Regional cerebral blood flow, blood volume, fractional oxygen extraction and oxygen consumption were measured by positron emission tomography in six patients with sickle cell disease to see how oxygen delivery to the brain is maintained in the presence of both anemia and a low oxygen affinity hemoglobin. Both regional cerebral blood flow and blood volume were found to be markedly increased compared to values obtained from 14 normal subjects in the same age range. The mean fractional oxygen extraction was not significantly different in the two groups. Mean oxygen consumption in the two groups was also not significantly different but low values in individual patients with sickle cell disease and the presence of atrophy on the CT-scans of three of them were suggestive of some neuronal loss in patients without any history of nervous system involvement. In view of the known high values of cerebral blood flow and metabolism in childhood, it is suggested that when compounded by anemia and abnormal red cells, a hypercirculatory state may make patients in this age-group particularly prone to ischemic infarction.

Measurement of regional cerebral blood flow, blood volume and oxygen metabolism in patients with sickle cell disease using positron emission tomography.

Sepsis is a devastating complication of infection and injury that, through widespread endothelial dysfunction, can cause perfusion deficits and multi-organ failure. To address the recognised need for therapeutics targetting the endothelial barrier, a topical formulation (CUR; VASCEPTOR™; Vascarta Inc, Summit, NJ) was developed to transdermally deliver bio-active concentrations of curcumin-an anti-inflammatory and nitric oxide promoter. Male, Sprague Dawley rats were treated daily with lipopolysaccharide (LPS, 10 mg/kg, IP) to induce endotoxemia, and topical applications of Vehicle Control (LPS + VC; N = 7) or Curcumin (LPS + CUR; N = 7). A third group received neither LPS nor treatment (No-LPS; N = 8). After 72 h, animals were surgically prepared for measurements of physiology and endothelial dysfunction in the exteriorised spinotrapezius muscle through the extravasation of 67 kDa TRITC-BSA (albumin) and 500 kDa FITC-dextran (dextran). At 72 h, LPS + VC saw weight loss, and increases to pulse pressure, lactate, pCO2, CXCL5 (vs No-LPS) and IL-6 (vs 0 h; p < 0.05). LPS + CUR was similar to No-LPS, but with hypotension. Phenylephrine response was increased in LPS + CUR. Regarding endothelial function, LPS + CUR albumin and dextran extravasation were significantly reduced versus LPS + VC suggesting that Curcumin mitigated endotoxemic endothelial dysfunction. The speculated mechanisms are nitric oxide modulation of the endothelium and/or an indirect anti-inflammatory effect.

Novel transdermal curcumin therapeutic preserves endothelial barrier function in a high-dose LPS rat model.

INTRODUCTION
Pulmonary dysfunction (PD) and its associated hypoxia present a complication to the care of many service members and can arise intrinsically via comorbidities or extrinsically by infection or combat-related trauma (burn, smoke inhalation, and traumatic acute lung injury). Current supportive treatments (e.g., ventilation and supplemental oxygen) relieve hypoxia but carry a significant risk of further lung injury that drives mortality. Ox66 is a novel, solid-state oxygenating compound capable of delivering oxygen via intravenous infusion.


MATERIALS AND METHODS
Male Sprague Dawley rats (N = 21; 250-300 g) were surgically prepared for cardiovascular monitoring, fluid infusion, mechanical ventilation, and intravital and phosphorescence quenching microscopy (interstitial oxygen tension; PISFO2) of the spinotrapezius muscle. Baselines (BL) were collected under anesthesia and spontaneous respiration. PD was simulated via hypoventilation (50% tidal volume reduction) and was maintained for 3 hours. Groups were randomized to receive Ox66, normal saline (NS; vehicle control), or Sham (no treatment) and were treated immediately following PD onset. Arterial blood samples (65 µL) and intravital images were taken hourly to assess blood gases and chemistry and changes in arteriolar diameter, respectively. Significance was taken at P < .05.


RESULTS
PD reduced PISFO2 for all groups; however, by 75 minutes, both NS and Sham were significantly lower than Ox66 and remained so until the end of PD. Serum lactate levels were lowest in the Ox66 group-even decreasing relative to BL-but only significant versus Sham. Furthermore, all Ox66 animals survived the full PD challenge, while one NS and two Sham animals died. No significant vasoconstrictive or vasodilative effect was noted within or between experimental groups.


CONCLUSION
Treatment with intravenous Ox66 improved interstitial oxygenation in the spinotrapezius muscle-a recognized bellwether for systemic capillary function-suggesting an improvement in oxygen delivery. Ox66 offers a novel approach to supplemental oxygenation that bypasses lung injury and dysfunction.

Evaluation of an Injectable, Solid-State, Oxygen-Delivering Compound (Ox66) in a Rodent Model of Pulmonary Dysfunction-Induced Hypoxia.

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Papers

Measurement of regional cerebral blood flow, blood volume and oxygen metabolism in patients with sickle cell disease using positron emission tomography.

Novel transdermal curcumin therapeutic preserves endothelial barrier function in a high-dose LPS rat model.

Evaluation of an Injectable, Solid-State, Oxygen-Delivering Compound (Ox66) in a Rodent Model of Pulmonary Dysfunction-Induced Hypoxia.