Genetic markers of fibrinolytic responses of older persons to exercise training.

We assessed the interactive effect of genetic polymorphisms and exercise training on fibrinolysis in 50 - 75 yr old men (n = 17) and women (n = 28). Subjects had tissue plasminogen activator (t-PA) antigen levels and activity and plasminogen activator inhibitor-1 (PAI-1) activity measured before and after 6 mo of endurance-exercise training. Subject's DNA was typed for the PAI-1 4 G/5 G and t-PA I/D variants. Baseline PAI-1 activity, t-PA activity, and t-PA antigen levels were not different among PAI-1 or t-PA genotype groups. Overall, exercise training did not change PAI-1 activity (- 0.43 +/- 0.81 IU/mL, p = NS), increased t-PA activity (0.37 +/- 0.16 IU/mL, p = 0.02), and decreased t-PA antigen levels (- 0.88 +/- 0.20 ng/mL, p < 0.001). Although the differences in changes with training were not significant among genotype groups, significant t-PA antigen level improvements were evident only in PAI-1 4 G allele carriers and significant t-PA activity increases only in PAI-1 4 G homozygotes. t-PA genotype affected the training-induced t-PA antigen level improvements (p = 0.033) after covarying for gender and baseline t-PA antigen levels, with the smallest and largest reductions in the D homozygotes and I/D heterozygotes, respectively. These findings could have important treatment implications for the use of exercise training to reduce CV disease and thrombotic risk in older men and women.

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.

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.

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.

Treadmill training improves fitness reserve in chronic stroke patients.

OBJECTIVE: To investigate the hypothesis that treadmill training will improve peak fitness, while lowering the energy cost of hemiparetic gait in chronic stroke patients. DESIGN: Noncontrolled exercise intervention study with repeated-measures analysis. SETTING: Hospital-based senior exercise research center. PARTICIPANTS: Twenty-three patients (mean age +/- standard deviation [SD] 67 +/- 8 yr) with chronic hemiparetic gait after remote (>6 mo) ischemic stroke. INTERVENTION: Three 40-minute sessions of treadmill exercise weekly for 6 months. MAIN OUTCOME MEASURES: Peak exercise capacity (VO2peak) and rate of oxygen consumption during submaximal effort treadmill walking (economy of gait) by open circuit spirometry and ambulatory workload capacity before and after 3 and 6 months of training. RESULTS: Patients who completed 3 months of training (n = 21) increased their VO2peak +/- SD from 15.4 +/- 2.9 mL x kg(-1) x min(-1) to 17.0 +/- 4.4 mL x kg(-1) x min(-1) (p <.02) and lowered their oxygen demands of submaximal effort ambulation from 9.3 +/- 2 mL x kg(-1) x min(-1) to 7.9 +/- 1.5 mL x kg(-1) x min(-1) (p =.002), which enabled them to perform the same constant-load treadmill task using 20% less of their peak exercise capacity (62.3% +/- 17.2% vs 49.9% +/- 19.3%, p <.002). Gains in VO2peak and economy of gait plateaued by 3 months, while peak ambulatory workload capacity progressively increased by 39% (p <.001) over 6 months. CONCLUSIONS: Treadmill training improves physiologic fitness reserve in chronic stroke patients by increasing VO2peak while lowering the energy cost of hemiparetic gait, and increases peak ambulatory workload capacity. These improvements may enhance functional mobility in chronic stroke patients.

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.

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.

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.

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.

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.

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.

Cardiovascular fitness after stroke: Role of muscle mass and gait deficit severity.

Functional disability after hemiparetic stroke may be compounded by physical deconditioning and muscular wasting, factors related to disuse and advancing age. However, the role of body composition, severity, and chronicity of gait deficits as determinants of exercise fitness after stroke is unknown. The purpose of this study was to determine whether oxygen consumption during peak exercise (VO2 peak) is associated with body composition, the severity, or duration of gait deficits in chronic (>6 months) hemiparetic stroke patients. Twenty-six patients (22 men, 4 women), aged 66 ± 9 years (mean ± standard deviation [SD]), completed a progressive graded treadmill test until fatigue to measure VO2 peak (1.3 ± 0.4 L/minute). Timed 30-foot walks were used to determine self-selected floor walking velocity (0.63 ± 0.31 m/s), an index of gait deficit severity. Percent body fat (30.4% ± 10.6%), total lean mass (52.0 ± 9.3 kg), lean mass of the paretic and nonaffected legs (17.2 ± 3.7 kg), and lean mass of the paretic and nonaffected thighs (13.2 ± 2.7 kg) were determined by dual-energy x-ray absorptiometry. Total lean mass (r = 0.60), lean mass of both legs (r = 0.58), paretic leg lean mass (r = 0.55), lean mass of both thighs (r = 0.64), and self-selected floor walking velocity (r = 0.53, all P < .01) correlated with VO2 peak. In contrast, percent body fat and latency since index stroke were unrelated to VO2 peak. In a stepwise regression analysis, lean mass of both thighs (r = 0.64, P < .001) and self-selected walking velocity (cumulative r = 0.78, P < .001) were independent predictors of VO2 peak and explained 61% of the variance. These results suggest that hemiparetic stroke patients are profoundly deconditioned, regardless of the latency since stroke, and that lower lean thigh mass and greater gait deficit severity predict even poorer peak exercise capacity.

"Task-oriented" exercise improves hamstring strength and spastic reflexes in chronic stroke patients.

BACKGROUND AND PURPOSE: Despite the belief that after cerebral infarction only limited functional gains are possible beyond the subacute period, we tested the hypothesis that a 12-week program of "task-oriented" treadmill exercise would increase muscle strength and decrease spastic reflexes in chronic hemiparetic patients. METHODS: Fourteen subjects, aged 66+/-3 (mean+/-SEM) years, with residual gait deviations due to remote stroke (>6 months), underwent repeated measures of reflexive and volitional (concentric and eccentric) torque with use of isokinetic dynamometry on the hamstring musculature bilaterally. Torque output was measured at 4 angular velocities (30(o), 60(o), 90(o), and 120(o)/s). RESULTS: After 3 months of 3 times/wk low-intensity aerobic exercise, there were significant main effects (2 legs [P<0.01]x2 times [P<0. 01]x4 angular velocities [P<0.05]) for concentric torque production. Torque/time production in the concentric mode also improved significantly in the paretic (50%, P<0.01) and nonparetic hamstrings (31%, P<0.01). Eccentric torque/time production increased by 21% (P<0.01) and 22% (P<0.01) in the paretic and nonparetic hamstrings, respectively. Passive (reflexive) torque/time generation in the paretic hamstrings decreased by 11% (P<0.027). Reflexive torque/time was unchanged in the nonparetic hamstrings (P=0.45). CONCLUSIONS: These findings provide evidence that progressive treadmill aerobic exercise training improves volitional torque and torque/time generation and reduces reflexive torque/time production in the hemiparetic limb. Strength changes associated with improved functional mobility in chronic hemiparetic stroke survivors after treadmill training will be reported in future articles.

Homocyst(e)ine and risk of cerebral infarction in a biracial population : the stroke prevention in young women study.

BACKGROUND AND PURPOSE: Genetic enzyme variation and vitamin intake are important determinants of blood homocyst(e)ine levels. The prevalence of common genetic polymorphisms influencing homocyst(e)ine levels varies by race, and vitamin intake varies by socioeconomic status. Therefore, we examined the effect of vitamin intake, race, and socioeconomic status on the association of homocyst(e)ine with stroke risk. METHODS: All 59 hospitals in the greater Baltimore-Washington area participated in a population-based case-control study of stroke in young women. One hundred sixty-seven cases of first ischemic stroke among women aged 15 to 44 years were compared with 328 controls identified by random-digit dialing from the same region. Risk factor data were collected by standardized interview and nonfasting phlebotomy. Plasma homocyst(e)ine was measured by high-performance liquid chromatography and electrochemical detection. RESULTS: Blacks and whites did not differ in median homocyst(e)ine levels, nor did race modify the association between homocyst(e)ine and stroke. After adjustment for cigarettes per day, poverty status, and regular vitamin use, a plasma homocyst(e)ine level of >/=7.3 micromol/L was associated with an odds ratio for stroke of 1.6 (95% CI, 1.1 to 2.5). CONCLUSIONS: The association between elevated homocyst(e)ine and stroke was independent not only of traditional vascular risk factors but also of vitamin use and poverty status. The degree of homocyst(e)ine elevation associated with an increased stroke risk in young women is lower than that previously reported for middle-aged men and the elderly and was highly prevalent, being present in one third of the control group.

Brain-specific protein C activation during carotid artery occlusion in humans.

BACKGROUND AND PURPOSE: Activation of plasma protein C (PC) zymogen by thrombin-thrombomodulin at the endothelial surface is an important endogenous antithrombotic mechanism. It is unknown whether activated protein C (APC) is generated in vivo in the cerebrovasculature, because there is only limited thrombomodulin expression in human brain vascular endothelium. Therefore, we tested the hypothesis that carotid occlusion produces brain-specific PC activation. METHODS: Blood samples were simultaneously collected from the ipsilateral internal jugular vein and radial artery before and during carotid cross-clamping and on "de-occlusion" in 8 awake patients undergoing routine carotid endarterectomy. Plasma PC zymogen and circulating APC levels were measured using enzyme immunocapture assay and expressed as percent of pooled plasma controls. RESULTS: Internal jugular vein APC levels increased 28% exclusively during carotid occlusion and then decreased 32% with de-occlusion (F=8.1, P<0.005). PC zymogen increased only 5.9% with occlusion (F=6.3, P<0.02), consistent with hemoconcentration. There were no changes in radial artery PC or APC levels. CONCLUSIONS: These findings demonstrate brain-specific protein C activation in humans during carotid occlusion and suggest a protective role for endogenous APC generation during cerebrovascular occlusion.

Elevated tissue plasminogen activator antigen and stroke risk: The Stroke Prevention In Young Women Study.

BACKGROUND AND PURPOSE: Abnormalities in endogenous fibrinolysis are associated with an increased risk for stroke in men and older adults. We tested the hypothesis that elevated plasma tissue plasminogen activator (tPA) antigen, a marker for impaired endogenous fibrinolysis, is an independent risk factor for stroke in young women. METHODS: Subjects were 59 nondiabetic females ages 15 to 44 years with cerebral infarction from the Baltimore-Washington area and 97 control subjects frequency-matched for age who were recruited by random-digit dialing from the same geographic area. A history of cerebrovascular disease risk factors was obtained by face-to-face interview. Plasma tPA antigen was measured by enzyme-linked immunosorbent assay. RESULTS: Mean plasma tPA antigen levels were significantly higher in stroke patients than control subjects (4. 80+/-4.18 versus 3.23+/-3.67 ng/mL; P=0.015). After adjustment for age, hypertension, cigarette smoking, body mass index, and ischemic heart disease, there was a dose-response association between tPA antigen and stroke with a 3.9-fold odds ratio of stroke (95% CI, 1.2 to 12.4; P=0.03) for the upper quartile (>4.9 ng/mL) of tPA antigen compared with the lowest quartile. The dose-response relationship between tPA antigen and stroke was equally present in white and nonwhite women, and further adjustment for total and HDL cholesterol levels only modestly attenuated this association. CONCLUSIONS: This population-based case-control study shows that elevated plasma tPA antigen level is independently associated with an increased risk for ischemic stroke in nondiabetic females 15 to 44 years of age. These findings support the hypothesis that impaired endogenous fibrinolysis is an important risk factor for stroke in young women.

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.

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.

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.