Yoshiyasu Tsuda

Effects of pravastatin sodium and simvastatin on plasma fibrinogen level and blood rheology in type II hyperlipoproteinemia

Elevated plasma fibrinogen level is known to progress atherosclerosis and to be one of the risk factors for the occurrence of cardiovascular diseases. The objective of this study is to evaluate the changes in plasma fibrinogen level and blood rheology in patients with type II hyperlipoproteinemia before and after random administrations of HMG-CoA (3-hydroxy-e-methylglutaryl-cocarboxylase-A) reductase inhibitors, pravastatin sodium and simvastatin, and compare with results in normal subjects. Of a total of 28 patients with type II primary hyperlipoproteinemia with > 230 mg/dl fasting total plasma cholesterol, 16 patients (mean, 59.7 years old) were administered 10-15 mg/day of pravastatin sodium for an average of 10.2 weeks, and 12 patients (mean, 62.0 years old) were administered 5-10 mg/day of simvastatin for an average of 13.9 weeks. Patients were evaluated before and after drug administration and results were compared with those of 16 normal subjects of similar age (mean, 56.9 years old). Blood viscosities were measured using a cone-plate viscometer (Biorheolizer, BRL-1000, Japan). The following were measured before and after drug administration: whole blood viscosity at shear rates of 75-375 s-1, corrected blood viscosity at low (112.5 s-1) and high (225.0 s-1) shear rates for the standard hematocrit of 45%, plasma viscosity, hematocrit, total protein, serum albumin, and plasma fibrinogen. Total cholesterol level was significantly decreased (from 270 to 225, mg/dl, mean values; P < 0.0007) an average of 10.2 weeks after start of pravastatin sodium administration. In addition to the reductions of whole blood viscosity, at every shear rate examined, corrected blood viscosity, and plasma viscosity, plasma fibrinogen levels were significantly decreased (from 354 to 309 mg/dl, mean values; P < 0.0007) after start of pravastatin sodium administration. Fibrinogen level and blood rheology were not significantly changed after start of simvastatin administration despite similar significant reductions in total cholesterol level (from 260 to 207 mg/dl, mean values; P < 0.0001) to those in the case of pravastatin sodium. From the results, we conclude that administration of pravastatin sodium, but not simvastatin, reduced the plasma fibrinogen level and blood viscosities to normal levels in type II hyperlipoproteinemic patients while both drugs reduced total cholesterol level. The hydrophilicity and a small binding capacity with plasma protein of pravastatin sodium may be responsible in part for the beneficial hemorheologic effects observed in the patients with type II hyperlipoproteinemia. Further investigations should be conducted to confirm the findings observed.

Hemorheologic profiles of plasma fibrinogen and blood viscosity from silent to acute and chronic cerebral infarctions

Hemorheologic changes from silent to acute and chronic cerebral infarction have seldom been reported. We evaluated hemorheologic profiles of the whole blood viscosity, plasma viscosity and fibrinogen level in stroke at-risk patients with silent cerebral infarction, patients with acute or chronic cerebral lacunar infarction, and subjects at low risk for stroke. Hemorheologic profiles were measured in 88 subjects: (1) 36 patients with silent cerebral infarction (mean 64.7 years), who provided no clinical history of having had definitive stroke but showing > 5 mm lesions of cerebral infarction or periventricular hyperintensity (PVH) observed in magnetic resonance imaging (MRI) T2-weighted images; (2) 12 patients with acute cerebral lacunar infarction (mean 69.1 years), measured within 3 days and repeated 1 month after onset; (3) 25 patients with chronic cerebral lacunar infarction (mean 66.2 years), measured 12.5 months after onset; and (4) 15 subjects at low risk for stroke (mean 65.8 years) without cardiovascular risk factors or lesions on MRI. Patients with silent cerebral infarction were subdivided into two groups of less advanced and more advanced grades, based on the number of infarctions or the grade of PVH. Whole blood viscosity (shear rates: 22.5-225.0 s-1), corrected blood viscosity for 45% standard hematocrit (Hct), plasma viscosity, fibrinogen, serum total protein, albumin, and Hct were measured. Plasma fibrinogen levels were lower in silent cerebral infarctions than in chronic cerebral infarctions (P < 0.01), and patients with more advanced grades of silent cerebral infarction showed higher levels of plasma fibrinogen than those with less advanced grades (P < 0.01 and P < 0.05). Whole blood viscosity, corrected blood viscosity (Hct 45%), plasma viscosity and fibrinogen levels in acute cerebral infarction within 3 days after onset were higher significantly than those in subjects at low risk for stroke. Plasma fibrinogen level persisted to be elevated up to 1 month after onset, which continued as well in patients with chronic cerebral infarction. Advanced grades of silent cerebral infarction in stroke at-risk patients are accompanied by elevations of plasma fibrinogen level, which increases further after onset of cerebral infarction; such abnormalities persist up to the chronic stage. Elevated plasma fibrinogen level might reflect progression of atherogenesis in patients with advanced grades of silent cerebral infarction, resulted in an increased probability as to be a risk factor for cerebral infarction.

Effects of Defibrination on Hemorheology, Cerebral Blood Flow Velocity, and CO2 Reactivity During Hypocapnia in Normal Subjects

BACKGROUND AND PURPOSE Plasma fibrinogen is reported to be an independent risk factor for stroke and cardiovascular diseases. The effects of defibrination on hemorheology, middle cerebral artery (MCA) blood flow velocity, and CO2 reactivity during hypocapnia were evaluated in normal subjects. METHODS Twenty-five healthy subjects (mean age, 31.8 +/- 5.7 years) were included in the study. Measurements were done at rest and repeated 24 hours after administration of 10 batroxobin units. Plasma fibrinogen, plasma viscosity, and whole blood viscosity were measured as hemorheological factors. MCA blood flow velocity was measured with a transcranial Doppler flowmeter. Blood flow velocity was corrected to 40 mm Hg of end-tidal CO2 partial pressure (PETCO2), and expressed as CV40. CO2 reactivity was measured as percent change in mean blood flow velocity per millimeter of mercury PETCO2. RESULTS Plasma fibrinogen (from 7.04 to 2.29 mumol/L; P < .001), whole blood viscosity, and plasma viscosity decreased after administration of batroxobin. Mean MCA blood flow velocity at rest, CV40. and CO2 reactivity during hypocapnia increased significantly (from 67.4 to 73.6 cm/s, from 71.7 to 77.7 cm/s, and from 2.9%/mm Hg to 3.2%/mm Hg, respectively; P < .01) after defibrination. Mean arterial blood pressure and PETCO2 at rest were constant before and 24 hours after administration of batroxobin. There was a significant positive correlation between CV40 and CO2 reactivity (r = .623, P < .0001). CONCLUSIONS The increase in MCA blood flow velocity was associated with improved CO2 reactivity and reduced blood viscosity after defibrination. The data may suggest that defibrination increases cerebral blood flow by reducing blood viscosity.

Improvement of cerebral blood flow and/or CO2 reactivity after superficial temporal artery-middle cerebral artery bypass in patients with transient ischemic attacks and watershed-zone infarctions

The effect of extracranial-intracranial bypass anastomosis on cerebral blood flow and CO2 reactivity during hypocapnia was investigated in ten patients with transient ischemic attacks or watershed infarctions due to carotid occlusive diseases. Six patients had occlusion and four had stenosis (greater than 50%) of the internal carotid artery. Those with infarctions had increased cerebral blood flow and CO2 reactivity postoperatively, and improved clinically. Those with transient ischemic attacks due to stenosis (greater than 50%) of the internal carotid artery had increased CO2 reactivity postoperatively but constant normal regional blood flow. Cerebral blood flow improved in those with poorer flow, CO2 reactivity increased in those with better reactivity, and better CO2 reactivity preoperatively brought about a greater flow increase. The pre- and postoperative evaluation of cerebral blood flow and CO2 reactivity is believed to be useful in evaluating the effectiveness of bypass anastomosis. Preoperative evaluation might be informative in selecting candidates for bypass.

A Controlled Study on the Effect of Pentoxifylline and an Ergot Alkaloid Derivative on Regional Cerebral Blood Flow in Patients with Chronic Cerebrovascular Disease

Regional cerebral blood flow (rCBF) in 90 patients with CBF decreased due to vascular diseases was studied by using the xenon 133 inhalation technique and a 32-detector setup. Whereas 30 patients received their standard basic ther apy only and were regarded as controls, 30 others received 3 x 2 mg/day of an ergot alkaloid (co-dergocrine mesylate), and 30 others received 3 x 400 mg pen toxifylline (slow-release formulation)/day orally. Therapy was performed for eight weeks and CBF measured before start of treatment, after a four-week treatment period, and at the end of the study. CBF did not change significantly in the control group; both the pentoxifylline and the ergot alkaloid group pre sented with a significant increase in the CBF. This positive effect was signifi cantly more pronounced in the pentoxifylline group and affected more ischemic than other brain tissues. In addition, symptoms like sleep disturbances, vertigo, and tinnitus improved significantly during the pentoxifylline observation peri od.

Duration threshold of induced hypertension on cerebral blood flow, energy metabolism, and edema after transient forebrain ischemia in gerbils

We have investigated whether there is a duration threshold for the effects of phenylephrine-induced hypertension on CBF, brain energy metabolism, and cerebral parenchymal specific gravity (SG) following transient forebrain ischemia in gerbils. Sixty gerbils were randomly assigned to one of the four treatment groups: one control group and three groups subjected to an increase of 25 mm Hg in MABP induced by treatment, 30 min after reperfusion, with phenylephrine for 15 min, 30 min, or 60 min. The local CBF was measured continuously, and the SG was evaluated 120 min after reperfusion. Sequential changes in brain energy metabolism, as shown by the ratio of phosphocreatine to inorganic phosphate (Pi), the β-ATP/Pi ratio, and intracellular pH, were also measured. The 15-min induced hypertension regimen was most suited to the recovery of brain energy metabolism, which was associated with an increase in local CBF and a decrease in cerebral edema. These results demonstrate that a suitable duration can be chosen to optimize the beneficial effects of phenylephrine-induced hypertension on ischemic brain injury following transient forebrain ischemia.

Nimodipine improves brain energy metabolism and blood rheology during ischemia and reperfusion in the gerbil brain

Whether nimodipine improves cerebral blood flow (CBF) and metabolism in cerebral ischemia remains a controversial issue. We investigated the effect of nimodipine on CBF, brain energy metabolism, using a laser-Doppler flowmeter and in vivo 31phosphorus nuclear magnetic resonance (31P NMR) spectroscopy, and blood rheology during forebrain ischemia and reperfusion in gerbils. Eighty-three adult gerbils received nimodipine (1 micrograms/kg/min), or an equal volume of the vehicle, or saline, over 60 min prior to a transient forebrain ischemia for 60 min. We measured sequential changes in phosphocreatine (PCr) / inorganic phosphate (Pi) ratio, beta-ATP/Pi ratio, and intracellular pH (pHi) during ischemia and reperfusion by 31P NMR spectroscopy, and the measurement of whole blood viscosity (WBV) at 60 min after reperfusion. CBF was measured continuously throughout the study by a laser-Doppler flowmeter. During forebrain ischemia, PCr/Pi and beta-ATP/Pi ratios were higher significantly in the nimodipine-treated group (p < 0.05 and 0.01) than in the vehicle- or saline-treated groups. During reperfusion, PCr/Pi and beta-ATP/Pi ratios recovered significantly only in the nimodipine-treated group (p < 0.05 and 0.01). The WBV at high shear rate (562.5 s-1) lowered significantly in the nimodipine-treated group (p < 0.05) compared with the vehicle- or saline-treated group. CBF was higher significantly only during administration of nimodipine in the nimodipine-treated group (p < 0.01) than other groups. Nimodipine improved brain energy metabolism and blood rheology during forebrain ischemia and reperfusion in the gerbil brain.

Comparison of the effects of infusion with hydroxyethyl starch and low molecular weight dextran on cerebral blood flow and hemorheology in normal baboons

Cerebral blood flow (CBF) and hemorheological parameters, such as hematocrit, plasma viscosity, and erythrocyte aggregation, were measured before and up to 7 h after 60-min infusions with 10% hydroxyethyl starch (HES), or 0.9% NaCl solution and 10% low molecular weight dextran (LMWD) in a total of 12 normal baboons. Infusion of HES increased CBF up to 48% from the resting level, and decreased hematocrit without an increase in plasma viscosity. Infusion of LMWD decreased hematocrit with an increase in CBF of up to 9.6%, but increased plasma viscosity at the same time. The disaggregating effect for erythrocytes was rather more obvious with LMWD than with HES but without significant difference between them. These data show different rheological effects with infusions of HES and LMWD on the physiological conditions of normal baboons.

Cerebral blood flow and CO2 reactivity in transient ischemic attacks: comparison between TIAs due to the ICA occlusion and ICA mild stenosis.

Hemispheric mean cerebral blood flow (CBF), together with its CO2 reactivity in response to hyperventilation, was investigated in 18 patients with transient ischemic attacks (TIAs) by intraarterial 133Xe injection method in a subacute-chronic stage of the clinical course. In 8 patients, the lesion responsible for symptoms was regarded as unilateral internal carotid artery (ICA) occlusion, and in 10 patients, it was regarded as unilateral ICA mild stenosis (less than 50% stenosis in diameter). Resting flow values were significantly (P less than 0.05) decreased in the affected hemisphere of TIA due to the ICA occlusion as compared with the unaffected hemisphere of the same patient, regarded as the relative control. It was not decreased in the affected hemisphere of TIA due to the ICA mild stenosis as compared with the control. With respect to the responsiveness of CBF to changes in PaCO2, it was preserved in both TIAs, due to the ICA occlusion and ICA mild stenosis. Vasoparalysis was not observed in either types of TIAs in the subacute-chronic stage. However, in the relationship of blood pressure and CO2 reactivity, expressed as delta CBF(%)/delta PaCO2, pressure-dependent CO2 reactivity as a group was observed with significance (P less than 0.05) in 8 cases of TIA due to the ICA occlusion, while no such relationship was noted in 10 cases of TIA due to the ICA mild stenosis. Moreover, clinical features were different between TIAs due to the ICA occlusion and ICA mild stenosis, i.e., more typical, repeatable TIA (6.3 +/- 3.7 times) with shorter duration (less than 30 minutes) was observed in TIAs due to the ICA mild stenosis, while more prolonged, less repeatable TIA (2.4 +/- 1.4 times) was observed in TIAs due to fixed obstruction of the ICA. From these observations, two different possible mechanisms as to the pathogenesis of TIA might be expected, e.g., TIA of microembolic origin due to the ICA mild stenosis, and TIA of hemodynamic origin due to fixed obstruction of the ICA, for whom the bypass surgery might be beneficial, i.e., all TIAs are not based on the same mechanism.

Bi-hemispheric CBF and its CO2 reactivity of TIAs and completed strokes in ICA occlusions.

Bi-hemispheric cerebral blood flow (CBF) measurements during rest and hyperventilation, with intra-arterial 133Xe injection method, were investigated in 19 cases, angiographically diagnosed as unilateral internal carotid artery (ICA) occlusion, including 8 cases with TIAs and 11 cases with completed strokes as the onset. Indices of cerebral vascular resistance and CO2 reactivity with decreasing arterial PCO2 were also investigated. A significant decrease (P less than 0.05) of hemispheric mean CBF was noted in the ischemic hemisphere, but normal flow values in the unaffected hemisphere and preserved CO2 responsiveness during hyperventilation were observed in both the affected and unaffected hemispheres in patients with TIAs. Moreover, a direct relationship between CBF and blood pressure, observed in 11 cases with completed strokes, was not recognized in 8 cases with TIAs. A degree of the abnormalities of the affected hemisphere in cerebral circulation was suggested to be somewhat different between TIAs and completed strokes in ICA occlusions, and bi-hemispheric CBF measurements would be an useful method for evaluating the various indices of the CBF in ICA occlusions.