Task-oriented aerobic exercise in chronic hemiparetic stroke: training protocols and treatment effects.

Stroke is the leading cause of disability in older Americans. Each year 750,000 Americans suffer a stroke, two thirds of whom are left with neurological deficits that persistently impair function. Principal among them is hemiparetic gait that limits mobility and increases fall risk, promoting a sedentary lifestyle. These events propagate disability by physical deconditioning and "learned non-use," with further functional declines accelerated by the sarcopenia and fitness decrements of advancing age. Conventional rehabilitation care typically provides little or no structured therapeutic exercise beyond the subacute stroke recovery period, based on natural history studies showing little or no further functional motor recovery beyond 6 months after stroke. Emerging evidence suggests that new models of task-oriented exercise have the potential to improve motor function even years after stroke. This article presents treadmill as a task-oriented training paradigm to optimize locomotor relearning while eliciting cardiovascular conditioning in chronic stroke patients. Protocols for exercise testing and longitudinal aerobic training progression are presented that provide fundamental formulas that safely approach the complex task of customizing aerobic training to gait deficit severity in the high CVD risk stroke population. The beneficial effects of 6 months task-oriented treadmill exercise on cardiovascular-metabolic fitness, energy cost of hemiparetic gait, ADL mobility task performance, and leg strength are discussed with respect to the central and peripheral neuromuscular adaptations targeted by the training. Collectively, these findings constitute one initial experience in a much broader neuroscience and exercise rehabilitation development of task-oriented training paradigms that offer a multisystems approach to improving both neurological and cardiovascular health outcomes in the chronic stroke population.

Cardiovascular health and fitness after stroke.

Stroke patients have profound cardiovascular and muscular deconditioning, with metabolic fitness levels that are about half those found in age-matched sedentary controls. Physical deconditioning, along with elevated energy demands of hemiparetic gait, define a detrimental combination termed diminished physiological fitness reserve that can greatly limit that can greatly limit performance of activities of daily living. The physiological features that underlie worsening metabolic fitness in the chronic phase of stroke include gross muscular atrophy, altered muscle molecular phenotype, increased intramuscular area fat, elevated tissue inflammatory markers, and diminished peripheral blood flow dynamics. Epidemiological evidence further suggests that the reduced cardiovascular fitness and secondary biological changes in muscle may propagate components of the metabolic syndrome, conferring added morbidity and mortality risk. This article reviews some of the consequences of poor fitness in chronic stroke and the potential biological underpinnings that support a rationale for more aggressive approaches to exercise therapy in this population.

Repetitive bilateral arm training with rhythmic auditory cueing improves motor function in chronic hemiparetic stroke.

BACKGROUND AND PURPOSE: Chronic upper extremity hemiparesis is a leading cause of functional disability after stroke. We investigated the hypothesis that bilateral arm training with rhythmic auditory cueing (BATRAC) will improve motor function in the hemiparetic arm of stroke patients. METHODS: In this single group pilot study we determined the effects of 6 weeks of BATRAC on 14 patients with chronic hemiparetic stroke (median time after stroke, 30 months) immediately after training and at 2 months after training. Four 5-minute periods per session (3 times per week) of BATRAC were performed with the use of a custom-designed arm training machine. RESULTS: The patients showed significant and potentially durable increases in the following: Fugl-Meyer Upper Extremity Motor Performance Test of impairment (P<0.0004), Wolf Motor Function Test (performance time measure, P<0.02), and University of Maryland Arm Questionnaire for Stroke measuring daily use of the hemiparetic arm (P<0.002). Isometric strength improved in elbow flexion (P<0.05) and wrist flexion (P<0.02) for the paretic arm and in elbow flexion (P<0.02) and wrist extension (P<0.02) for the nonparetic arm. Active range of motion improved for paretic-side shoulder extension (P<0.01), wrist flexion (P<0.004), and thumb opposition (P<0.002), and passive range of motion improved for paretic wrist flexion (P<0.03). CONCLUSIONS: -Six weeks of BATRAC improves functional motor performance of the paretic upper extremity as well as a few changes in isometric strength and range of motion. These benefits are largely sustained at 8 weeks after training cessation.

Alcohol intake, type of beverage, and the risk of cerebral infarction in young women.

BACKGROUND AND PURPOSE: The relationship between alcohol consumption and cerebral infarction remains uncertain, and few studies have investigated whether the relationship varies by alcohol type or is present in young adults. We examined the relationship between alcohol consumption, beverage type, and ischemic stroke in the Stroke Prevention in Young Women Study. METHODS: All 59 hospitals in the greater Baltimore-Washington area participated in a population-based case-control study of stroke in young women. Case patients (n=224) were aged 15 to 44 years with a first cerebral infarction, and control subjects (n=392), identified by random-digit dialing, were frequency matched by age and region of residence. The interview assessed lifetime alcohol consumption and consumption and beverage type in the previous year, week, and day. ORs were obtained from logistic regression models controlling for age, race, education, and smoking status, with never drinkers as the referent. RESULTS: Alcohol consumption, up to 24 g/d, in the past year was associated with fewer ischemic strokes (<12 g/d: OR 0.57, 95% CI 0. 38 to 0.86; 12 to 24 g/d: OR 0.38, 95% CI 0.17 to 0.86; >24 g/d: OR 0.95, 95% CI 0.43 to 2.10) in comparison to never drinking. Analyses of beverage type (beer, wine, liquor) indicated a protective effect for wine consumption in the previous year (<12 g/wk: OR 0.58, 95% CI 0.35 to 0.97; 12 g/wk to <12 g/d: OR 0.55, 95% CI 0.28 to 1.10; >/=12 g/d: OR 0.92, 95% CI 0.23 to 3.64). CONCLUSIONS: Light to moderate alcohol consumption appears to be associated with a reduced risk of ischemic stroke in young women.

The fibrinolytic system is not impaired in older men with hypertension.

The fibrinolytic system is thought to be impaired in older hypertensive adults, thus contributing to the elevated risk of atherothrombosis, stroke, and acute myocardial infarction in this population. However, studies that have examined the fibrinolytic system in hypertensive individuals have failed to control for the confounding effects of other metabolic risk factors, making it difficult for one to determine the independent effect of hypertension on the fibrinolytic system. The purpose of the present study was to test the hypothesis that the fibrinolytic system is not impaired in older sedentary hypertensive men when the confounding effects of cardiovascular disease, diabetes, and dyslipidemia are controlled. Plasma concentrations of tissue-type plasminogen activator antigen and activity as well as plasminogen activator inhibitor-1 antigen and activity were measured under resting conditions in 12 hypertensive (69.4 +/- 1.4 years) and 11 normotensive 65.2 +/- 1.3 years) older men. The hypertensive and normotensive subjects had similar anthropometric and metabolic characteristics. There were no significant differences between the hypertensive and normotensive men in tissue-type plasminogen antigen (7.3 +/- 0.5 versus 6.1 +/- 0.6 ng/mL) and activity (1.8 +/- 0.3 versus 1.7 +/- 0.2 IU/mL) or plasminogen activator inhibitor-1 antigen (14.1 +/- 2.3 versus 10.8 +/- 2.2 ng/mL) and activity (17.4 +/- 1.2 versus 17.5 +/- 1.8 arbitrary units [AU]/mL) levels. In addition, the molar concentration ratio of active tissue type plasminogen activator to active plasminogen activator inhibitor-1 did not differ between the hypertensive (1:9.7 +/- 2.3) mmol/L) and normotensive (1:10.5 +/- 2.2 mmol/L) subjects, indicative of no impairment in fibrinolytic potential in either group. These results support the hypothesis that hypertension does not directly result in impaired fibrinolytic function in older adults. Furthermore, our findings suggest that abnormalities in fibrinolytic function in older hypertensive men are likely due to the primary effects of other metabolic disorders that usually accompany hypertension, such as hyperinsulinemia and dyslipidemia.

Traditional risk factors and ischemic stroke in young adults: the Baltimore-Washington Cooperative Young Stroke Study.

OBJECTIVE: To determine the association of hypertension, diabetes, and cigarette smoking with incidence of ischemic stroke in young adults. DESIGN: Case-control study. SETTING: Population-based sample of cases and controls. SUBJECTS: The study included 296 cases of incident ischemic stroke among black and white adults aged 18 to 44 years in central Maryland counties from the Baltimore-Washington Cooperative Young Stroke Study and 1220 black and white adults aged 18 to 44 years from the Maryland Behavioral Risk Factor Survey, a telephone survey of a random sample of the same region, to serve as controls. MAIN OUTCOME MEASURES: Logistic regression models were developed to determine the age-adjusted odds ratios for each risk factor. Population-attributable risk percent were computed based on the odds ratios and prevalence of each risk factor. RESULTS: The age-adjusted odds ratios (95% confidence intervals) for white men (WM), white women (WW), black men (BM), and black women (BW) were as follows: current cigarette smoking: WM, 2.0 (1.1-3.8), WW, 2.1 (1.1-4.3), BM, 3.3 (1.6-6.6), and BW, 2.2 (1.3-3.9); history of diabetes mellitus: WM, 22.9 (5.8-89.6), WW, 6.2 (1.9-20.2), BM, 4.2 (0.8-21.9), and BW, 3.3 (1.4-7.7); and history of hypertension: WM, 1.6 (0.7-3.2), WW, 2.5 (1.1-5.9), BM, 3.8 (1.8-7.9), and BW, 4.2 (2.4-7.5). The population-attributable risk percent (95% confidence intervals) were as follows: current cigarette smoking: WM, 22.6 (3.1-38.2), WW, 17.2 (4.0-34.0), BM, 40.5 (23.1-54.0), and BW, 29.1 (13.5-41.9); history of diabetes mellitus: WM, 19.0 (8.2-28.5), WW, 15.8 (3.8-26.3), BM, 13.2 (5.3-20.4), and BW, 22.1 (12.5-30.7); and history of hypertension: WM, 21.7 (6.2-34.6), WW, 21.3 (5.4-34.5), BM, 53.5 (39.0-64.4), and BW, 50.5 (37.1-61.1). CONCLUSIONS: Hypertension, diabetes mellitus, and current cigarette smoking are important risk factors in a biracial young adult population. Cigarette smoking and hypertension, the 2 most modifiable risk factors, were particularly important risk factors in young blacks.

Cerebral infarction in young adults: the Baltimore-Washington Cooperative Young Stroke Study.

BACKGROUND: Few reports on stroke in young adults have included cases from all community and referral hospitals in a defined geographic region. METHODS: At 46 hospitals in Baltimore City, 5 central Maryland counties, and Washington, DC, the chart of every patient 15 to 44 years of age with a primary or secondary diagnosis of possible cerebral arterial infarction during 1988 and 1991 was abstracted. Probable and possible etiologies were assigned following written guidelines. RESULTS: Of 428 first strokes, 212 (49.5%) were assigned at least one probable cause, 80 (18.7%) had no probable cause but at least one possible cause, and 136 (31.8%) had no identified probable or possible cause. Of the 212 with at least one probable cause, the distribution of etiologies was cardiac embolism (31.1%), hematologic and other (19.8%), small vessel (lacunar) disease (19.8%), nonatherosclerotic vasculopathy (11.3%), illicit drug use (9.4%), oral contraceptive use (5.2%), large artery atherosclerotic disease (3.8%), and migraine (1.4%). There were an additional 69 recurrent stroke patients. CONCLUSIONS: In this hospital-based registry within a region characterized by racial/ethnic diversity, cardiac embolism, hematologic and other causes, and lacunar stroke were the most common etiologies of cerebral infarction in young adults. Nearly a third of both first and recurrent strokes had no identified cause.

Stroke in children and sickle-cell disease: Baltimore-Washington Cooperative Young Stroke Study.

BACKGROUND/PURPOSE: The Baltimore-Washington Cooperative Young Stroke Study is the largest biracial urban-suburban population-based study to examine the etiology of strokes in children. METHODS: We identified all children aged 1 to 14 years discharged from all 46 hospitals in central Maryland and Washington, DC with a diagnosis of ischemic stroke and intracerebral hemorrhage in the years 1988 and 1991. Each medical record was reviewed by two neurologists for appropriateness of the diagnosis of stroke and for information on the patient's history, clinical presentation, pertinent investigations, hospital stay, and outcome at time of discharge. RESULTS: Eighteen children with ischemic infarction and 17 with intracerebral hemorrhage were identified. The most common cause of ischemic stroke was sickle-cell disease (39%), followed by vasculopathic (33%) and indeterminate (28%) causes. Causes of intracerebral hemorrhages were arteriovenous malformation (29%), hematologic (23%), vasculopathy (18%), surgical complication (12%), coagulopathy (6%), and indeterminate (12%). The overall incidence for childhood stroke was 1.29 per 100,000 per year, with ischemic stroke occurring at a rate of 0.58 per 100,000 and intracerebral hemorrhage occurring at a rate of 0.71 per 100,000. The incidence of stroke among children with sickle-cell disease was estimated to be 0.28% or 285 per 100,000 per year. CONCLUSION: Sickle-cell disease plays a disproportionately high role in childhood stroke when a biracial population is surveyed.

Illicit drug-associated ischemic stroke in the Baltimore-Washington Young Stroke Study.

BACKGROUND: Limited information exists on the frequency, trends in occurrence, risk factors, mechanisms, and outcome of ischemic stroke associated with illicit drug use among young adults in a geographically defined population. METHODS: We reviewed ischemic stroke in young adults (aged 15 to 44 years) in 46 regional hospitals for 1988 and 1991. We examined stroke mechanisms and outcome in patients with recent drug use. RESULTS: Recent illicit drug use was noted in 51/422 (12.1%) stroke patients. Patients with drug use were more likely than other stroke patients to be black (p=0.01), aged 25 to 39 years (p=0.004), and smokers (p=0.006), and were less likely to have hypertension (p=0.004) or diabetes mellitus (p=0.004). Drug use was the probable cause of stroke in 20 (4.7%) patients. Among 31 (7.3%) patients with drug use as a possible stroke mechanism, more likely diagnoses included cardioembolic stroke in 18, hematologic/collagen vascular in 6, nonatherosclerotic vasculopathy in 5, and atherosclerosis in 3. There was no difference in outcome between drug-associated and non-drug associated stroke. CONCLUSIONS: Recent illicit drug use occurs in 12.1% of young adult stroke patients. Drug-associated young adult stroke seems to relate to vascular mechanisms other than those related to hypertension or diabetes. Case-control studies are needed.

Lipoprotein (a) and the risk of ischemic stroke in young women.

BACKGROUND AND PURPOSE: lipoprotein (a) (lp (a)) is a lipid-containing particle similar to LDL which has been found in atherosclerotic plaque. The role of lp (a) in ischemic stroke remains controversial, but some studies suggest lp (a) is particularly important as a risk factor for stroke in young adults. We investigated the role of lp (a) as a risk factor for stroke in young women enrolled in the Stroke Prevention in Young Women Study. METHODS: subjects were participants in a population-based, case-control study of risk factors for ischemic stroke in young women. Cases were derived from surveillance of 59 regional hospitals in the central Maryland, Washington DC, Pennsylvania and Delaware area. Lp (a) was measured in 110 cases and 216 age-matched controls. Demographics, risk factors, and stroke subtype were determined by interview and review of medical records. RESULTS: lp (a) values were higher in blacks than whites, but within racial groups, the distribution of lp (a) values was similar between cases and controls. After adjustment for age, race, hypertension, diabetes, cigarette smoking, coronary artery disease, total cholesterol and HDL cholesterol, the odds ratio for an association of lp (a) and stroke was 1.36 (95% CI 0.80-2.29). There was no dose-response relationship between lp (a) quintile and stroke risk. Among stroke subtypes, only lacunar stroke patients had significantly elevated lp (a) values compared to controls. CONCLUSIONS: we found no association of lp (a) with stroke in a population of young women with ischemic stroke. Small numbers of patients limit conclusions regarding risk in ischemic stroke subtypes, but we could not confirm previous suggestions of an association of lp (a) with atherosclerotic stroke in young adults.

Distribution and correlates of elevated total homocyst(e)ine: the Stroke Prevention in Young Women Study.

PURPOSE: To determine the distribution and correlates of elevated total homocyst(e)ine (tHcy) concentration in a population of premenopausal black and white women. METHODS: Data from the Stroke Prevention in Young Women Study (N = 304), a population-based study of risk factors for stroke in women aged 15-44 years of age, were used to determine the distribution and correlates of elevated tHcy in black (N = 103) and white women (N = 201). RESULTS: The mean tHcy level for the population was 6.58 micromol/L (range 2.89-26.5 micromol/L). Mean tHcy levels increased with age, cholesterol level, alcohol intake, and number of cigarettes smoked (all: p < 0.05). There were no race differences (mean tHcy 6.72 micromol/L among blacks and 6.51 micromol/L among whites; p = 0.4346). Regular use of multivitamins and increasing education was associated with significant reductions in tHcy concentration. Approximately 13% of the sample had elevated tHcy levels, defined as a tHcy concentration > or = 10.0 micromol/L. Multivariate-adjusted correlates of elevated tHcy included education > 12 vs. < or = 12 (odds ratio [OR] = 0.4, 95% confidence interval [CI] = 0.2-0.8); smoking > or = 20 cigarettes/day vs. nonsmokers (OR = 2.8, 95% CI = 1.1-7.3); and the regular use of multivitamins (OR = 0.4, 95% CI = 0.2-0.9). CONCLUSIONS: These results suggest that a substantial proportion of healthy young premenopausal women have tHcy levels that increase their risk for vascular disease. A number of potentially modifiable behavioral and environmental factors appear to be significantly related to elevated tHcy levels in young women.

Elevated levels of circulating cell adhesion molecules in uncomplicated essential hypertension.

Elevated levels of circulating soluble cell adhesion molecules are associated with the development of cardiovascular disease. We tested the hypothesis that circulating levels of soluble cell adhesion molecules are elevated in older men with uncomplicated essential hypertension, which may contribute to the increased risk of atherosclerosis in this population. Circulating levels of soluble intercellular adhesion molecule-1, vascular adhesion molecule-1, and E-selectin were measured in 11 hypertensive (69+/-1 years) and ten normotensive (65+/-1 years) older men who were free of overt atherosclerotic disease, diabetes, and dyslipidemia. The hypertensive subjects had higher (P < .05) circulating levels of soluble intercellular adhesion molecule-1 (232.4+/-16.5 v 189.8+/-11.1 ng/mL) and vascular adhesion molecule-1 (737.3+/-65.6 v 565.7+/-46.8 ng/mL) compared with their normotensive peers. However, there was no difference in the levels of soluble E-selectin between the hypertensive (51.1+/-3.9 ng/ mL) and normotensive (48.8+/-6.6 ng/mL) subjects. Univariate analysis revealed a positive correlation between soluble intercellular adhesion molecule-1 and both systolic (r = 0.50, P = .02) and diastolic (r = 0.49, P = .03) blood pressure. In addition, soluble vascular adhesion molecule-1 was positively correlated with age (r = 0.60, P = .004) and systolic blood pressure (r = 0.43, P = .05). The results of this study support the hypothesis that circulating levels of soluble cell adhesion molecules are elevated in older men with uncomplicated essential hypertension.

Fibrinolytic responses to acute physical activity in older hypertensive men.

We tested the hypothesis that the fibrinolytic response to acute physical activity is impaired in sedentary older hypertensive men, which may contribute to the risk of exertion-triggered acute myocardial infarction in this population. Tissue-type plasminogen activator (t-PA) antigen and activity and plasminogen activator inhibitor-1 (PAI-1) antigen and activity were measured in 12 hypertensive (69 +/- 1 yr) and 11 normotensive (64 +/- 1 yr) men before and after an acute bout of submaximal exercise. Contrary to our hypothesis, there were no differences between the two groups in the fibrinolytic response to exercise. t-PA antigen and activity were significantly elevated in both the hypertensive (38 and 172%, respectively) and normotensive (45 and 130%, respectively) groups immediately after exercise but they returned to resting levels within 30 min. There was no change in PAI-1 antigen levels immediately after exercise in either group; however, PAI-1 antigen was significantly lower at 30 and 60 min postexercise in both the hypertensive (31 and 16%, respectively) and normotensive (35 and 20%, respectively) groups. PAI-1 activity was significantly lower immediately after exercise in both the hypertensive (25%) and normotensive (22%) groups and remained lower than preexercise levels at 30 min (23 and 26%, respectively) and 60 min (16 and 12%, respectively) postexercise in both groups. The results of this study demonstrate that the fibrinolytic response to an acute bout of moderate physical activity is not impaired in sedentary older hypertensive men.

Hemiparetic gait parameters in overground versus treadmill walking.

OBJECTIVE: Hemiparetic gait is characterized by high stride-cycle variability, diminished stance time, single-limb stance time, and stance/swing ratio in the paretic limb. Recent studies suggest treadmill (TM) training may improve the motor control underlying these variables, but supporting evidence is sparse. METHODS: This study compared gait patterns of untrained chronic hemiparetic stroke patients (n = 18; mean, 39.5 months poststroke) during overground (OG) and TM walking at matched velocities. Variables included relative stance time, relative single-limb stance time, stance/swing ratio, peak force, and impulse. Within-subject variability of these measures (CV) was used to assess gait pattern stability. RESULTS: OG and TM cycle durations were similar, but CVs differed (TM < OG, p < 0.05). In the paretic limb, differences were seen in relative stance time, relative single-limb stance time, and stance/swing ratio, respectively (TM > OG, p < 0.05). These variables decreased in the nonparetic limb during TM walking (p < 0.05 for all). Improved interlimb symmetry and coordination were evidenced by decreased between-limb differences and improved relative temporal phasing, respectively, in the TM condition (p < 0.05). CONCLUSIONS: Collectively, these results demonstrate that the TM induces an immediate alteration toward a more consistent and symmetric gait pattern. Further investigation is needed to determine whether TM training leads to motor relearning and neuroplasticity in chronic hemiparetic subjects.

Effects of aerobic treadmill training on gait velocity, cadence, and gait symmetry in chronic hemiparetic stroke: a preliminary report.

It is widely assumed that only limited improvement in functional mobility is possible beyond the subacute period following ischemic stroke. Contrary to this notion, we studied "neurologically plateaued" stroke patients with chronic hemiparesis to assess whether a "task-oriented" treadmill-training regimen would improve walking speed, cadence, and gait cycle symmetry on a modified "Get-Up and Go" task. Five male patients with a mean age of 60.4 +/- 2.7 years (mean +/- S.D.) status post ischemic stroke (> 6 months prior) participated in this nonrandomized low-intensity treadmill exercise pilot study three times/week for 3 months. All patients had mild to moderate gait asymmetries due to residual hemiparesis. Patients were videotaped before and after 3 months of treadmill aerobic exercise (AEX) while performing a functional task consisting of arising from a chair, walking 3.1 m without an assistive device as fast as safely possible, and returning to sit. Gait events were timed using a 2-D Peak Motus video analysis system. After 3 months AEX training, times for the overall "get-up and return-to-sit" (GURS) task and the "straight-away walk" (SAW) segment decreased from 8.2 +/- 1.4 sec to 6.5 +/- 0.8 sec (mean +/- SEM) (p < 0.05), and from 3.7 +/- 1 sec to 2.8 +/- 0.7 sec (p < 0.05), respectively. These data represent improvements of 21% and 24% for the GURS and SAW segments, respectively. Mean velocity increased from 0.9 +/- 0.2 to 1.2 +/- 0.21 m/sec, a 33% improvement (p < 0.01). Mean cadence (steps/min) increased from 89 +/- 9 to 97 +/- 8, a 9% increase (p < 0.05). Mean stance and swing duration diminished for both paretic (P) and nonparetic (NP) limbs, and the intralimb stance/swing ratio values moved toward normal for both the paretic and nonparetic limbs. However, these latter changes reached significance only for the P limb. Interlimb stance symmetry was unchanged. The more impaired subjects experienced the greatest gains in gait velocity and temporal measures. Collectively, these findings indicate that treadmill exercise improves functional overground mobility in individuals with chronic, stable hemiparesis.

The impact of angiotensin II receptor blockade and the DASH diet on markers of endogenous fibrinolysis.

Hypertension is associated with impaired fibrinolysis. Both angiotensin receptor blockers (ARB) and the DASH (Dietary Approaches to Stop Hypertension) diet effectively lower blood pressure in hypertensive patients. Some evidence suggests that treatment with ARBs could increase fibrinolysis, however, data is conflicting. The impact of the DASH diet on fibrinolytic parameters is not known. Fifty-five hypertensive participants (35 African-American, 20 white) were randomly assigned to receive 8 weeks of either a control diet or the DASH diet. The diets did not differ in sodium content (approximately 3 g/day). Within each diet, individuals were randomly assigned to receive losartan or placebo for 4 weeks in double-blind, cross-over fashion. Tissue plasminogen activator (t-PA) antigen, t-PA activity, plasminogen activator inhibitor-1 (PAI-1) activity and plasma renin activity (PRA) were measured at the end of a 2-week run-in period on the control diet and after each treatment period. The DASH diet did not affect markers of fibrinolysis. Losartan significantly lowered t-PA antigen levels (-1.8 ng/mL, P = 0.045), but had no effect on t-PA or PAI-1 activities. This effect was more pronounced in whites (-4.1 ng/mL (P = 0.003)) compared with African-Americans (-0.3 ng/mL (P = 0.7), P-interaction = 0.03). Results were not materially affected by adjustment for basline values or changes in blood pressure. This study demonstrates that losartan reduces t-PA antigen levels in white, but not African-American hypertensive individuals. In contrast, the DASH diet had no significant effect on markers of fibrinolysis in whites or African-Americans.

Chronic reversible cerebral ischemia: evaluation of a new baboon model.

The authors describe their experience with a baboon model of reversible cerebral ischemia. Middle cerebral artery occlusion was achieved by external compression with an implantable, inflatable balloon cuff in awake, unanesthetized baboons. Selective cerebral angiography confirmed consistent, reliable occlusion. Computed tomography demonstrated early density changes after ischemia, which were reversible with reperfusion. Neurological evaluation demonstrated a "recruitment response" of increasingly persistent deficit with repeated occlusion. Permanent deficits were noted after extensive angiography during periods of occlusion. This was accompanied by the dropout of small vessels in the middle cerebral artery distribution. The results of pathological examinations were consistent with the clinical examinations. No gross or microscopic changes were noted after repeated occlusions that caused deficits like those of transient ischemic attacks. Consistent infarctions were noted in animals with permanent deficits after permanent occlusion or after repeated occlusion and extensive angiography.

Barbiturate coma in focal cerebral ischemia. Relationship of protection to timing of therapy.

The therapeutic application of barbiturate-induced coma was evaluated in a primate model of focal cerebral ischemia. A standardized regimen of pentobarbital was used, and the times of initiation of administration were varied following a 6-hour middle cerebral artery occlusion in baboons. Three groups of five animals were treated at 30, 120, and 240 minutes after occlusion, while one group of five animals received no barbiturate therapy. Complete protection from intracranial pressure (ICP) elevation and ischemic damage was seen only in the group treated at 30 minutes. Those treated at 120 minutes, while doing better than untreated animals, still had ICP elevation and a marked neuropathological deficit. Animals treated at 240 minutes suffered a detrimental effect, in that malignant ICP and marked ischemic damage occurred earlier than in the untreated animals. The safe "therapeutic window" for barbiturate-induced coma in this animal model does not extend beyond 2 hours. Delayed administration results in a deleterious response and not merely a lack of protection.

Fibrinolytic response to acute exercise in patients with peripheral arterial disease.

PURPOSE: Elevations in tissue plasminogen activator (tPA) are postulated to protect against atherothrombotic events during exercise. However, fibrinolytic response to repetitive bouts of symptom-limited exercise is unknown in peripheral arterial disease (PAD) patients, a population with impaired fibrinolysis and increased risk for ischemic events. The purpose of the present study was to evaluate the fibrinolytic response to repetitive bouts of symptom-limited exercise in PAD patients. METHODS: Nine (8 male, 1 female) patients with Fontaine State II PAD were studied. Fasting blood samples for determination of tPA and plasminogen activator inhibitor (PAI-1) were obtained into an acidified citrate solution via an indwelling venous catheter before, immediately after, 30 min after, and 60 min after submaximal treadmill walking. Patients walked intermittently at 65% of maximal intensity achieved on a previous graded exercise test until 30 min of exercise was achieved. RESULTS: Exercise increased tPA activity by 180% (0.5 +/- 0.16 IU.mL(-1) baseline, 1.4 +/- 1.2 IU.mL(-1) postexercise), and decreased PAI-1 activity by 40% (20.6 +/- 5.5 AU.mL(-1) baseline, 11.8 +/- 6.2 AU.mL(-1) postexercise), without changing tPA or PAI-1 antigen. Notably, plasma tPA activity levels 1 h after exercise remained elevated by 80%, whereas PAI-1 activity remained decreased by 49%. The decrease in PAI-1 significantly (P < 0.05) correlated with oxygen uptake (VO(2)) during submaximal exercise (r = -0.77). CONCLUSION: These findings demonstrate that repetitive bouts of symptom-limited exercise produce a substantial improvement in the fibrinolytic profile of PAD patients, which persists at least 1 h after exercise cessation.

Thermolabile methylenetetrahydrofolate reductase polymorphism (C677T) and total homocysteine concentration among African-American and white women.

A polymorphism associated with a thermolabile variant (C677T) of the enzyme methylenetetrahydrofolate reductase has been associated with both elevated total homocysteine (tHcy) levels and risk for cardiovascular disease. Data from the Stroke Prevention in Young Women Study were used to determine the prevalence of the C677T genotype and to assess whether environmental factors modified the association between genotype and tHcy concentration. The C677T genotype prevalence was 80% -/-, 20% +/-, and 0% +/+ among 46 African-American women; and 39% -/-, 53% +/-, and 8% +/+ among 77 white women (P < 0.01). There was a trend toward higher tHcy levels in African-American women with the +/- genotype when compared with the -/- genotype (6.9 mumol/L vs 5.3 mumol/L respectively, p = 0.10); no association was found among the white women (6.0 mumol/L, -/-; 4.5 mumol/L, +/-; and 6.2 mumol/L, +/+; p = 0.67). Among African American women, those who smoked and were +/- genotype had the highest tHcy levels (8.0 mumol/L); while among white women, those who smoked and were -/- had the highest tHcy levels (8.1 mumol/L). Despite being hampered by a limited sample size, the thermolabile allele is significantly less common among African-American than white women. The association between genotype and tHcy concentration is influenced by smoking and multivitamin use.