Roger Sherwin

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.

Effect of Postmenopausal Hormone Therapy on Lipoprotein(a) Concentration

BACKGROUND Postmenopausal hormone therapy has been reported to decrease levels of lipoprotein (Lp)(a) in cross-sectional studies and small or short-term longitudinal studies. We report findings from a large, prospective, placebo-controlled clinical trial that allows a broad characterization of these effects for four regimens of hormone therapy. METHODS AND RESULT The Postmenopausal Estrogen/Progestin Interventions study was a 3-year, placebo-controlled, randomized clinical trial to assess the effect of hormone regimens on cardiovascular disease risk factors in postmenopausal women 45 to 65 years of age. The active regimens were conjugated equine estrogens therapy at 0.625 mg daily, alone or in combination with each of three regimens of progestational agents: medroxyprogesterone acetate (MPA) at 2.5 mg daily (ie, continuous MPA), MPA at 10 mg days 1 to 12 (ie, cyclical MPA), and micronized progesterone at 200 mg days 1 to 12. Plasma levels of Lp(a) were measured at baseline (n = 366), 12 months (n = 354), and 36 months (n = 342). Assignment to hormone therapy resulted in a 17% to 23% average drop in Lp(a) concentrations relative to placebo (P<.0001), which was maintained across 3 years of follow-up. No significant differences were observed among the four active arms. Changes in Lp(a) associated with hormone therapy were positively correlated with changes in LDL cholesterol, total cholesterol, apolipoprotein B, and fibrinogen levels and were similar across subgroups defined by age, weight, ethnicity, and prior hormone use. CONCLUSIONS Postmenopausal estrogen therapy, with or without concomitant progestin regimens, produces consistent and sustained reductions in plasma Lp(a) concentrations.

Antiphospholipid antibodies and stroke in young women.

Background and Purpose— Antiphospholipid antibodies have been associated with ischemic stroke in some but not all studies. Methods— We performed a population-based case-control study examining antiphospholipid antibodies (anticardiolipin antibodies and lupus anticoagulants) using stored frozen sera and plasma in 160 cases and 340 controls enrolled in the Stroke Prevention in Young Women study. We evaluated for the presence of anticardiolipin antibody (IgG, IgM, and IgA isotypes) by an enzyme-linked immunosorbent assay and for the lupus anticoagulant using several phospholipid-dependent coagulation tests (activated partial thromboplastin time, dilute Russell’s viper venom time) with mixing studies. If mixing studies were prolonged, confirmatory tests were performed. Results— A positive anticardiolipin antibody level of any isotype was seen in 43 cases (26.9%) and 62 controls (18.2%) (P =0.03), lupus anticoagulant in 29 cases (20.9%) and 38 controls (12.8%) (P =0.03), and either anticardiolipin antibody or lupus anticoagulant in 61 cases (42.1%) and 86 controls (27.9%) (P =0.003). After adjustment for age, current cigarette smoking, hypertension, diabetes, angina, ethnicity, body mass index, and high-density lipoprotein levels, the relative odds of stroke for women with anticardiolipin antibody immunoreactivity of any isotype or a lupus anticoagulant was 1.87 (95% confidence interval, 1.24 to 2.83;P =0.0027). Conclusions— The results from this study support the importance of antiphospholipid antibodies as an independent risk factor for stroke in young women.

The multiple risk factor intervention trial (MRFIT).: II. The development of the protocol

Abstract The detailed development of the MRFIT protocol is discussed, beginning with the general plan outlined by the National Heart and Lung Institute in the initial solicitation of contract proposals. The protocol is designed to test the hypothesis that lowering serum cholesterol by diet, reducing high blood pressure by diet and drugs, and cessation of cigarette smoking will result in a reduced risk of (a) death from coronary heart disease (CHD), (b) combined fatal CHD and nonfatal myocardial infarction, (c) deaths from all cardiovascular disease, and (d) death from all causes, over a period of 6 years among men aged 35–57 without initial evidence of CHD. After screening 361,662 men, from 1974 to early 1976, 12,866 from the upper end of the risk spectrum of CHD on the basis of serum cholesterol, blood pressure, and smoking habits, were randomly assigned either to a program of Special Intervention (SI) directed toward altering these risk factors or to their usual source of medical care (UC). Men in the UC group have been evaluated once each year in the clinic without direct intervention on the risk factors. Men in the SI group participated in an initial intensive series of group sessions designed to assist in modification of behavior relating to the three risk factors. The SI men have since been invited to the clinic at least three times each year to maintain and increase risk factor change. Changes in the intervention protocol have resulted mainly from difficulty in achieving the expected response in serum cholesterol. These changes have included greater emphasis on control of body weight, the recommendation of more rigorous dietary specifications for those with persistently elevated levels of serum cholesterol, and advice to increase physical activity.

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.

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.

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.

The association of birth weight with arterial stiffness at mid-adulthood: the Bogalusa Heart Study

Background: Birth weight has been found to predict cardiovascular morbidity and mortality. Pulse wave velocity (PWV), a marker of arterial stiffness, has been associated with cardiovascular risk factors. An association between birth weight and blood pressure (BP) has previously been reported. In this study, the association of birth weight with PWV, and the relationship between birth weight, pulse wave velocity and BP in mid-adulthood were investigated. Methods: The Bogalusa Heart Study (BHS) is a population-based longitudinal study to investigate the natural development of cardiovascular risk factors. In the 2001 survey, brachial-ankle PWV (baPWV) was measured as an indicator of arterial stiffness. Of the 1203 participants in that survey, 707 had complete data on birth weight and PWV, which were utilised for this study. Results: In this study, birth weight was inversely correlated with baPWV, pulse pressure, and systolic and diastolic BP (r = −0.10; r = −0.10; r = −0.13 and r = −0.09, respectively; p⩽0.01 for all). After adjustment, birth weight was inversely associated with baPWV. On average, baPWV decreased by 0.23 m/s (95% CI −0.44 to −0.03 m/s) for each 1 kg increase in birth weight. Birth weight (inversely) and baPWV were independently associated with systolic BP (B = −2.05; 95% CI −3.27 to −0.84 and B = 2.99; 95% CI 2.58 to 3.40 respectively). Conclusions: Lower birth weight is associated with higher baPWV. The link between birth weight and systolic BP may be partially explained by the association of birth weight with PWV.

Rationale, design, and conduct of the PEPI trial

Abstract There is growing and consistent evidence that estrogen use in postmenopausal women is associated with a substantial reduction in the occurrence of cardiovascular disease. However, remarkably little is known about the biological mechanisms by which estrogen therapy may influence risk. Even less information is available on the cardiovascular effects of combined estrogen-progestin use. PEPI was not designed to test whether estrogen and estrogen-progestin therapy is efficacious in the prevention of cardiovascular disease, as a much larger trial with clinical disease outcomes is needed to answer that question. However, PEPI will provide critical evidence regarding the potential effectiveness of the various estrogen and estrogen-progestin regimens in altering risk factors for cardiovascular disease in women. Detailed information on factors such as adherence, side effects, and general patient acceptability will also be ascertained.

Sudden Death in Men with Increased Risk of Myocardial Infarction

SummaryThe Multiple Risk Factor Intervention Trial (MRFIT) was a randomised clinical trial of the preventability of fatal first heart attacks among middle-aged men at high risk of coronary heart disease (CHD). After screening 361,662 men aged 35 to 57 years, 12,866 men currently free of CHD at the upper end of the risk spectrum on the basis of their levels of serum cholesterol, diastolic blood pressure and cigarette smoking were randomised either to ‘special intervention’ (SI) or to ‘usual care’ (UC). Those SI men with a sustained diastolic blood pressure ⩾ 90mm Hg (following attempted weight loss, if indicated) received pharmacological treatment in the form of a protocol of ‘stepped care’. UC men were referred to their usual source of medical care.At the termination of the study —after 6 to 8 years of intervention —no significant differences in overall deaths from CHD or from all causes were observed between the SI and UC groups. However, among the subgroup of individuals who had both a diastolic blood pressure ⩾ 90mm Hg and abnormalities of the resting electrocardiogram at baseline there was an excess of deaths from CHD in the SI group compared with the UC group (36 vs 21), and most of the excess deaths were sudden (20 vs 8).RésuméLe Multiple Risk Factor Intervention Trial (MRFIT), essai clinique randomisé, avait pour objectif d’étudier la possibilité de prévenir les premières crises cardiaques fatales chez des hommes d’âge mûr à haut risque de maladie coronarienne. Ainsi 12.866 hommes ont été sélectionnés parmi 361.662 hommes âgés de 35 à 57 ans parce qu ’ils n ’avaient pas de signes d’insuffisance coronarienne mais se situaient en revanche au plus haut niveau de risque d’en avoir, ceci sur la base de leurs taux de cholestérol sérique, de leur pression diastolique et de leur habitude de fumer. Ils ont été répartis au hasard soit en ‘traitement particulier’ (Special Intervention, SI) soit en ‘traitement médical habituel’ (usual care’, UC).Le groupe SI, dont la pression diastolique était égale ou supérieure à 90 mm Hg a suivi, si nécessaire, un traitement amaigrissant et a reçu un traitement médicamenteux progressif par paliers en fonction des résultats. Les sujets du groupe UC ont suivi leur traitement habituel.A la fin de l’étude —6 à 8 ans d’intervention —on n’a pas trouvé de différence significative entre les deux groupes du point de vue des décès par insuffisance coronarienne d’une part et des décès par toute autre cause d’autre part. Par contre, dans le sous-groupe d’individus chez lesquels on retrouvait à la fois une pression diastolique égale ou supérieure à 90 mm Hg et des anomalies de l’électrocardiogramme de repos, on a observé plus de décès par insuffisance coronarienne dans le groupe SI que dans le groupe UC (36 contre 21), la plupart des décès supplémentaires correspondant à une mort subite (20 contre 8).ZusammenfassungDer Multiple Risk Factor Intervention Trial (MRFIT) war eine randomisierte klinische Studie zur Verhütung der ersten tödlichen Herzanfälle bei Männern im mittleren Alter mit einem hohen Risiko einer koronaren Herzkrankheit (KHK). Nach einer Untersuchung von 361662 Männern im Alter zwischen 35 und 57 Jahren wurden 12866 ohne KHK aufgrund ihrer Cholesterin-Serumspiegel, ihres diastolischen Blutdrucks und Zigarettenrauchens am oberen Ende des Risikospektrums stehende Männer entweder einer ‘speziellen Intervention’ (SI) oder einer gewöhnlichen Behandlung (UC) zugeordnet. Die SI-Gruppe mit einem diastolischen Blutdruck ⩾ 90 mm Hg (nach versuchter Gewichtsreduktion, wenn angezeigt) wurde pharmakologisch nach dem Protokoll eines ‘Stufenplans’ behandelt; die UC-Gruppe einer üblichen medizinischen Betreuung zugewiesen.Bei Beendigung der Studie —nach 6-bis 8-jähriger Behandlung —wurden keine signifikanten Unterschiede in bezug auf die Gesamttodesfälle durch KHK oder alle Ursachen zwischen den SI-und UC-Gruppen beobachtet. In der Subgruppe von Personen, die zu Beginn sowohl einen diastolischen Blutdruck von ⩾ 90 mm Hg als auch Anomalien des Ruheelektrokardiogramms aufwiesen, ergab sich eine höhere Zahl von Todesfällen durch KHK in der SI-Gruppe im Vergleich zur UC-Gruppe (36 vs 21). Die meisten dieser überzähligen Fälle waren durch plötzlichen Herztod bedingt (20 vs 8).SommarioIl Multiple Risk Factor Intervention Trial (MRFIT) è stato uno studio clinico randomizzato sulla prevedibilità del primo attacco cardiaco in soggetti di sesso maschile di età intermedia ad alto rischio per cardiopatia ischemica (CI). Dopo uno screening su 361.662 soggetti di sesso maschile, di età compresa fra i 35 e 57 anni, vennero selezionati 12.866 soggetti in quel momento senza segni clinici di CI, che si trovavano all’estremità superiore dello spettro dei fattori di rischio, sulla base dei loro livelli plasmatici colesterolo, della pressione arteriosa diastolica e della abitudine al fumo di sigaretta. Questi soggetti vennero randomizzati in due gruppi un gruppo venne sottoposto ad un speciale programma terapeutico (special intervention, SI), Valtro venne affidato per l’assistenza alle usuali strutture sanitarie (usual care, UC). I soggetti del gruppo SI con pressione arteriosa diastolica costantemente ⩾ 90mmHg (dopo un tentativo di riduzione del peso corporeo, ove indicato) furono sottoposti a terapia farmacologica secondo uno schema ‘a gradini’. I soggetti del gruppo UC vennero rinviati alla loro usuale fonte di assistenza sanitaria.Al termine dello studio —dopo 6—8 anni di partecipazione —non si osservarono differenze significative nella mortalità globale, da CI o da altre cause, tra i gruppi SI e UC. Tuttavia nel sottogruppo di soggetti che avevano sia una pressione arteriosa diastolica ⩾ 90mmHg sia anomalie nell’elettrocardiogramma di base a riposo, ci fu un numero maggiore di decessi da CI nel gruppo SI rispetto al gruppo UC (36 contro 21), e la maggior parte dei decessi in più era dovuta a morte improvvisa (20 contro 8).ResumenEl Estudio de Intervención de Factores de Riesgo Múltiples (Multiple Risk Factor Intervention Trial) (MRFIT) fue un estudio clinico aleatorio que in vestigó la posibilidad de prevention del primer ataque cardiaco entre varones de edad media con elevado riesgo de cardiopatia coronaria (CC). De entre 361.662 varones entre la edad de 35 y 57 anõs, se seleccionaron 12.886 libres por entonces de CC, pero en situación de elevadísimo riesgo sobre la base de sus concentraciones séricas de colesterol, tension arterial diastólica y consumo de tabaco. Los sujetos se distribuyeron al azar en grupos llamados de ‘intervention especial’ (IE) o ‘cuidados habituates’ (CH), respectivamente. Los sujetos del grupo IE con una presión arterial diastolica mantenida superior o igual a 90 mm Hg (tras haber seguido cura de adelgazamiento en caso de que estuviera indicada), se sometieron a tratamiento farmacológico según un proiocoio de ‘pasos escalonados’. Los sujetos de CH se siguieron tratando como hasta el momento.Al término del estudio, al cabo de un período de 6–8 años segün los casos, las tasas globales de mortalidad tanto debidas a CC como a otras causas de ambos grupos no presentaban diferencias significativas. Sin embargo, en el subgrupo de sujetos con presión diastólica ⩾ 90 mm Hg y anomalías del ECG de reposo a valores base se observó un exceso de muertes por CC en el grupo de IE en comparación con el de CH (36 frente a 21), y la mayor parte de estas muertes excesivas fueron subitas (20 frente a 8).ResumoO Teste de Intervenção de Fator de Riscos Múitiplos (TIFRM) teve como objetivo testar clinicamente a possibilidade de se prevenir um primeiro ataque cardiaco junto a homens de meia-idade com alto risco de doença coronária (DC). Após consideração de 361 662 indivíduos com idades entre 35 e 57 anos, selecionou-se 12 866 sujeitos naquele momento livres de DC e estando situados na faixa superior do espectro de riscos, com base nas suas concentrações de colesterol no sero, na pressao sanguínea diastólica e no consumo de cigarros. Aqueles foram distribuidos ao acaso em dois grupos: o sob ‘intervenção especial’ (IE) e o sob ‘tratamento usual’ (TU). Os indivíduos do grupo IE com uma pressão arterial diastólica mantida ⩾ 90mm Hg (depots de uma tentativa de perda de peso, caso indicado) receberam tratamento farmacológico na forma de um procedimento ‘faseado’. Os individuos do grupo TU foram encaminhados à sua fonte habitual de cuidados médicos.Ao término do estudo —após 6 a 8 anos de participação —não se verificaram diferenças significativas no número global de mortes por DC nem por qualquer outra causa entre os grupos IE e TU. Contudo, no seio do sub-grupo de individuos que tinham tanto pressão arterial diastólica ⩾ 90mm Hg quanto anormalidades eletrocardiográficas em descanso na linha de base, houve um excesso de mortes por DC no grupo IE, em relação ao grupo TU (36 versus 21), sendo que a maior parte do excesso foi constituída por mortes súbitas (20 versus 8).