Association of Hyperhomocysteinemia with Stroke Recurrence after Initial Stroke.

BACKGROUND AND PURPOSE: Homocysteine (Hcy) is closely associated with stroke. Despite the fact that Hcy has consistently been shown to predict development of recurrent stroke, prior studies on the association of Hcy and stroke subtypes have been inconclusive. METHODS: Data from the Ege Stroke Registry were examined and 5-year follow-up data were analyzed. Multivariate survival analyses were undertaken using Cox proportional hazards models to determine the prognostic value of Hcy in different ischemic stroke subtypes. RESULTS: Of the 9522 patients with stroke, 307 (27%) with hyperhomocysteinemia (hHcy) had recurrent stroke. Univariate Cox regression model showed that hHcy group was associated with recurrent stroke (crude hazard ratio [HR] 1.16; 95% CI 1.02-1.30). But there was no such association in multivariate regression models (adjusted HR 1.11; 95% CI .97-1.26). hHcy was not associated with any ischemic stroke subtypes at 5 years. Univariate Cox regression model showed that hHcy group was associated with overall cardiovascular events (crude HR 1.44; 95% CI 1.32-1.57). However, this association no longer existed in multivariate regression models (adjusted HR 1.01; 95% CI .93-1.12). Higher plasma Hcy group was significantly associated with higher mortality compared with normal plasma Hcy group (OR 1.83; 95% CI .45-2.32). CONCLUSIONS: Our results showed that elevated Hcy is not associated independently with stroke recurrence and overall cardiovascular events in patients with ischemic stroke. There was no association between the hHcy and stroke recurrence in the stroke subtypes within 5 years.

Homocysteine as a predictor of early neurological deterioration in acute ischemic stroke.

BACKGROUND AND PURPOSE: Hyperhomocysteinemia is a well-known risk factor for vascular disease. However, its action, mechanism, and role in the acute phase of stroke have not been determined. We tried to determine whether an association existed between elevated serum homocysteine levels and early neurological deterioration (END) in patients with acute ischemic stroke. METHODS: We performed a secondary analysis from the Cilostazol in Acute Ischemic Stroke Treatment (CAIST) trial, which was a double-blinded, randomized, multicenter trial, assessing the noninferiority of cilostazol over aspirin within 48 hours of an acute ischemic stroke. END was defined as an increase of ≥1 point in motor power or an increase of ≥2 points in the total National Institute of Health Stroke Scale score within 7 days. RESULTS: The mean (±SD) serum homocysteine level was 11.4±4.7 µmol/L. Of the 396 patients studied, 57 (14.4%) patients worsened during the 7 days after inclusion. Most (68%) of the END cases occurred within the first 24 hours after treatment. High levels (>10.3 µmol/L) of serum homocysteine were independent predictors for END (third quartile odds ratio, 3.45; 95% confidence intervals, 1.25-9.50; P=0.016; fourth quartile odds ratio, 3.36; 95% confidence intervals 1.18-9.52; P=0.023) in multivariate analysis. CONCLUSIONS: Patients with acute stroke with elevated serum homocysteine levels are at an increased risk for END.

Determination of cysteine, homocysteine, cystine, and homocystine in biological fluids by HPLC using fluorosurfactant-capped gold nanoparticles as postcolumn colorimetric reagents.

We have demonstrated for the first time the suitability of fluorosurfactant-capped spherical gold nanoparticles as HPLC postcolumn colorimetric reagents for the direct assay of cysteine, homocysteine, cystine, and homocystine. The success of this work was based on the use of an on-line tris(2-carboxyethyl)phosphine reduction column for cystine and homocystine. Several parameters affecting the separation efficiency and the postcolumn colorimetric detection were thoroughly investigated. Under the optimized conditions, cysteine, homocysteine, cystine, and homocystine in human urine and plasma samples were determined. Detection limits for cysteine, homocysteine, cystine, and homocystine ranged from 0.16-0.49 µM. The accuracy in terms of recoveries ranged between 94.0-102.1%. This proposed method was rapid, inexpensive, and simple.

Complementary effects of multivitamin and omega-3 fatty acid supplementation on indices of cardiovascular health in individuals with elevated homocysteine.

Homocysteine (HCY), C-reactive protein (hsCRP), and triglycerides (TG) are risk factors for cardiovascular disease (CVD). While multivitamins (MVit) may reduce HCY and hsCRP, omega-3 fatty acids (N3) reduce TG; yet, they are seldom studied simultaneously. We randomly assigned 100 participants with baseline HCY (> 8.0 umol/L) to the daily ingestion of: (1) placebo, (2) MVit (VitC: 200 mg; VitE: 400 IU; VitB6: 25 mg; Folic Acid: 400 ug; VitB12: 400 ug) + placebo, (3) N3 (2 g N3, 760 mg EPA, 440 mg DHA)+placebo, or (4) MVit + N3 for 12 weeks. At follow-up, we observed significant reductions in HCY (umol/L) for the MVit (- 1.43, 95 %CI, - 2.39, - 0.47) and MVit + N3 groups (- 1.01, 95 %CI, - 1.98, - 0.04) groups, both being significant (p < 0.05) vs. placebo (- 0.57, 95 %CI, - 1.49, 0.35) and N3 (1.11, 95 % CI, 0.07, 2.17). hsCRP (nmol/L) was significantly reduced in the MVit (- 6.00, 95 %CI, - 1.04, - 0.15) and MVit + N3 (- 0.98, 95 %CI, - 1.51, - 0.46) groups, but not vs. placebo (- 0.15, 95 %CI, - 0.74, 0.43) or N3 (- 0.53, 95 %CI, - 1.18, 0.12). Lastly, we observed significant reductions in TG for the N3 (- 0.41, 95 %CI, - 0.69, - 0.13) and MVit + N3 (- 0.71, 95 %CI, - 0.93, - 0.46) groups, both significant vs. placebo (- 0.10, 95 %CI, - 0.36, 0.17) and MVit groups (0.15, 95 %CI, - 12, 0.42). The co-ingestion of MVit + N3 provides synergistic affects on HCY, hsCRP, and plasma TG.

Does maternal Helicobacter pylori infection increase the risk of occurrence of neural tube defects in newborns in Northern Iran?

OBJECTIVE: To determine the relation between maternal Helicobacter pylori (H. pylori) infection and the occurrence of neural tube defects (NTDs) in newborns. METHODS: This hospital-based case-control study was carried out in Dezyani Teaching Hospital, Gorgan, Northern Iran from April 2007 to March 2009. Thirty-five mothers with NTD-affected newborns, and 53 mothers with healthy newborns were considered the cases and controls. A peripheral blood sample was obtained from all subjects, and H. pylori infections were tested by H. pylori serum antibody. The serum folic acid, vitamin B12, ferritin, and homocysteine concentrations were measured by laboratory tests. Data were analyzed using odds ratio (OR) and logistic regression. RESULTS: Forty-three percent of cases, and 26% of controls were positive for H. pylori IgG antibody, and this difference was not significant. The H. pylori seropositivity non significantly increased the risk of NTD-affected pregnancies (OR: 2.08; 95% confidence interval [CI]: 0.84-5.17, p=0.11). Serum vitamin B12 deficiency was detected in 17% of cases and 13% of controls, and folic acid deficiency in 17% of cases and 13% of controls (p=0.61). The H. pylori seropositivity was non significantly associated with low serum folate (OR 1.93 CI: 0.58-6.4, p=0.34) and ferritin (OR 1.24; CI: 0.42-3.60, p=0.68). CONCLUSION: Maternal H. pylori infection can increase the risk of occurrence of NTDs in newborns.

Metabolic syndrome and serum homocysteine in patients with bipolar disorder and schizophrenia treated with second generation antipsychotics.

There is accumulating evidence for an increased prevalence of metabolic syndrome (MetS) in bipolar patients, which is comparable to the prevalence of MetS in patients with schizophrenia. Hyperhomocysteinaemia has emerged as an independent and graded risk factor for the development of cardiovascular disease (CVD), which is, at the same time, the primary clinical outcome of MetS. The aim of this study was to ascertain if the presence of MetS was associated with hyperhomocysteinaemia in patients with bipolar disorder (N=36) and schizophrenia (N=46) treated with second-generation antipsychotics (SGA). MetS was defined according to the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP-III) criteria and the cut-off point for hyperhomocysteinaemia was set up at 15 µmoll(-1). Results of the study indicated that the presence of the MetS is statistically significantly associated with the elevated serum homocysteine in all participants. As hyperhomocysteinaemia has emerged as an independent risk factor for psychiatric disorder and CVD, it could be useful to include fasting homocysteine serum determination in the diagnostic panels of psychiatric patients to obtain a better assessment of their metabolic risk profile.

[The relationship between plasma homocysteine levels and diabetic peripheral neuropathy].

OBJECTIVE: To explore the relationship between plasma homocysteine levels and diabetic peripheral neuropathy (DPNP). METHODS: A crossectional analysis was conducted on 227 patients with type 2 diabetes. Peripheral neuropathy was confirmed using electromyography (EMG). The risk factors possibly associated with diabetic neuropathy or plasma homocysteine levels were analyzed in relation to likelihood of occurrence of DPNP. RESULTS: Eighty patients with neuropathy and 147 patients without neuropathy were included. Plasma homocysteine levels were significantly higher in patients with diabetic neuropathy [(12.6 ± 3.6) µmol/L] than without diabetic neuropathy [(8.2 ± 0.9) µmol/L] (P < 0.001), and the relationship remained significant after adjusting for duration of diabetes, glycosylated hemoglobin A1c (HbA1c), age, renal status, serum folate acid and vitamin B(12), and metformin [OR 1.15 (1.02 - 1.28), P < 0.05]. In addition, per increase of 4.0 µmol/L plasma homocysteine was closely related to the occurrence of neuropathy after controlling for per unit increase of other confounding factors [OR 1.17 (0.94 - 1.33), P < 0.05]. CONCLUSIONS: Hyperhomocysteinemia was an independent risk factor for the occurrence of diabetic peripheral neuropathy.

[Cardiovascular disease prevention: results from Programma FASEN - H San Raffaele]. / La prevenzione delle malattie cardiovascolari: l'esperienza del Programma FASEN - H San Raffaele.

We studied 9145 workers allocated among Italian country employed in the same factory. Most of them were male, mean age 47,6 (20,2

Can high-sensitivity C-reactive protein and plasma homocysteine levels independently predict the prognosis of patients with functional disability after first-ever ischemic stroke?

BACKGROUND: The prognosis of functional disability in patients with cerebrovascular disease has not been well established. Therefore, we conducted this study to determine the prognostic significance of high-sensitivity C-reactive protein (hs-CRP) and homocysteine (Hcy) levels in patients with functional disability after acute first-ever ischemic stroke. METHOD: A total of 309 patients with first-ever stroke were examined within 24 h after symptom onset. Hcy was measured at admission, and hs-CRP measurements were made at admission and on the seventh hospital day. The correlations between the concentration of hs-CRP or Hcy and functional disability at 1, 3, 6 and 12 months after stroke onset were analyzed. RESULTS: The present study showed that both hs-CRP values on admission and on the seventh hospital day were significantly correlated with modified Rankin Scale (mRS) scores obtained at 4 times after the onset of stroke. These results also demonstrated that mRS scores are more closely associated with hs-CRP values on the seventh hospital day than on admission. However, there was no significant relationship between Hcy and mRS scores during the 12-month follow-up period. CONCLUSION: According to the present study, we cautiously suggest that hs-CRP values on the subacute phase have sufficient value as a predictor of the prognosis of functional disability after first-ever stroke.

Hypoxia tolerance and retinal vein occlusion: a pilot evaluation.

PURPOSE: To determine if hypoxia tolerance in patients with retinal vein occlusion (RVO) following exposure to transient hypoxia is different from the hypoxia tolerance of healthy patients without retinal vein occlusion. METHODS: Consecutive patients presenting with RVO following exposure to transient hypoxia (Group I) were compared with healthy subjects (Group II). In addition to cardiovascular and plasma tests, functional respiratory evaluation was performed at rest and during exercise at both normal oxygen levels (21% O2) and in hypoxia (11.6% O2). We used the Wilcoxon test for statistical analysis. RESULTS: Both groups of eight males had similar mean ages: Group I, 47.5 years and Group II, 53 years. In Group I, three patients had glucose or lipid abnormalities, one had hypertension, and one minor thalassanemia. In Group II, one patient had hypertension. At rest in hypoxia, the oxyhemoglobinic desaturation was significantly different (p=0.03) in Group I in comparison with Group II (-13.8 versus -9.3). At exercise in hypoxia, the oxyhemoglobinic desaturation was similar in both groups but there was a statistically significant increase in both systolic (189 versus 155 mmHg; p=0.01) and diastolic (94 versus 77 mmHg; p=0.03) blood pressure in Group I. Ventilation rate and increased heart rate during hypoxia were higher in Group I compared with Group II but were not statistically significant. CONCLUSIONS: In our pilot study, patients with RVO following exposure to transient hypoxia demonstrated intolerance to hypoxia and were significantly different from healthy subjects in their response to hypoxia. A larger study is required to confirm these preliminary results.

Homocystine levels, polymorphisms and the risk of ischemic stroke in young Asian Indians.

BACKGROUND: Homocysteine has been for a fairly long time been debated to be a risk factor for stroke. Opinions are divided as to whether raised levels of homocysteine seen in stroke patients are the cause or consequence of stroke. A large number of studies have been conducted in the Caucasian as well as on the Oriental population, which tend to suggest contradictory findings at many times. However, there have been no reports forthcoming from the Asian Indian population, which is a genetically different population than the previously studied populations. SUBJECTS AND METHODS: In our present study, we looked at homocysteine levels and four commonly seen polymorphisms of homocysteine metabolizing enzymes and their respective prevalence in 120 acute onset ischemic stroke patients compared with an equal number of age and gender matched healthy population. We also tested the influence of folic acid dosage (5 mg OD) on the levels of homocysteine and the allied vitamin supplements, vitamin B12 and folate in smaller groups selected from the larger group. RESULTS AND CONCLUSIONS: We found homocysteine levels to be significantly raised in the stroke population compared with healthy controls [patients: 12 micromol/L (range: 5.3-39.1 micromol/L), controls: 11.2 micromol/L (range: 6.2-14.2 micromol/L); P =0.001]. There was an almost total response to folic acid dosage as all hyperhomocysteinemic patients showed lowering of homocysteine levels in response to the dosage. The MTHFR 677 C > T polymorphisms showed association with both homocysteine levels as well as stroke (P < 0.001). Nutritional deficiency plays a dominant role in hyperhomocysteinemic conditions in our stroke population, however. Genetic determinants of homocysteine level may also have some part in determining hyperhomocysteinemic conditions in the Asian Indian populations.

Elevated homocysteine is associated with reduced regional left ventricular function: the Multi-Ethnic Study of Atherosclerosis.

BACKGROUND: An elevated homocysteine (Hcy) level has been reported to be a risk factor for the development of congestive heart failure in individuals free of myocardial infarction. In this study, we aim to investigate the relationship between Hcy levels and regional left ventricular function in an asymptomatic population. METHOD AND RESULTS: Regional peak systolic midwall circumferential strains were calculated from 1178 tagged magnetic resonance imaging studies in participants in the Multi-Ethnic Study of Atherosclerosis (MESA). Left ventricular regions were defined by coronary territories (left anterior descending, left circumflex, right coronary artery). For the 1178 study participants (66+/-10 years of age, 58% males), the median (interquartile range) of Hcy was 9.1 (9.0 to 9.3). After adjustment for traditional risk factors, race, height, weight, left ventricular end-diastolic mass/volume, serum creatinine, and measures of atherosclerosis, reduced regional myocardial circumferential shortening across sex-specific quartiles of plasma Hcy in the left anterior descending (P=0.038) and left circumflex (P=0.009) regions persisted, which indicated an important association of reduced function with elevated Hcy. Multiple linear regression analyses confirmed that circumferential systolic dysfunction was associated with log transformed Hcy levels in the left anterior descending (P=0.004) and left circumflex (P=0.0002) regions. In the fully adjusted model, the odds ratio for left ventricular strains below the 10th percentile with 1 SD increases in log-transformed Hcy was 1.33 (95% confidence interval, 1.04 to 1.70; P=0.022) for the left anterior descending, 1.28 (95% confidence interval, 1.00 to 1.64; P=0.046) for the left circumflex, and 1.32 (95% confidence interval, 1.03 to 1.69; P=0.025) for the right coronary artery region. CONCLUSIONS: In this asymptomatic population, an elevated Hcy level is associated with reduced regional left ventricular systolic function detected by tagged magnetic resonance imaging.

Cognitive impairment in folate-deficient rats corresponds to depleted brain phosphatidylcholine and is prevented by dietary methionine without lowering plasma homocysteine.

Poor folate status is associated with cognitive decline and dementia in older adults. Although impaired brain methylation activity and homocysteine toxicity are widely thought to account for this association, how folate deficiency impairs cognition is uncertain. To better define the role of folate deficiency in cognitive dysfunction, we fed rats folate-deficient diets (0 mg FA/kg diet) with or without supplemental L-methionine for 10 wk, followed by cognitive testing and tissue collection for hematological and biochemical analysis. Folate deficiency with normal methionine impaired spatial memory and learning; however, this impairment was prevented when the folate-deficient diet was supplemented with methionine. Under conditions of folate deficiency, brain membrane content of the methylated phospholipid phosphatidylcholine was significantly depleted, which was reversed with supplemental methionine. In contrast, neither elevated plasma homocysteine nor brain S-adenosylmethionine and S-adenosylhomocysteine concentrations predicted cognitive impairment and its prevention by methionine. The correspondence of cognitive outcomes to changes in brain membrane phosphatidylcholine content suggests that altered phosphatidylcholine and possibly choline metabolism might contribute to the manifestation of folate deficiency-related cognitive dysfunction.

Elevated homocysteine reduces apolipoprotein A-I expression in hyperhomocysteinemic mice and in males with coronary artery disease.

Hyperhomocysteinemia, a risk factor for cardiovascular disease, is caused by nutritional or genetic disturbances in homocysteine metabolism. A polymorphism in methylenetetrahydrofolate reductase (MTHFR) is the most common genetic cause of mild hyperhomocysteinemia. To examine mechanisms by which an elevation in plasma homocysteine leads to vascular disease, we first performed microarray analyses in livers of Mthfr-deficient mice and identified differentially expressed genes that are involved in lipid and cholesterol metabolism. Microarrays and RT-PCR showed decreased mRNA for apolipoprotein A (ApoA)-IV and for ApoA-I and increased mRNA for cholesterol 7alpha hydroxylase (Cyp7A1) in Mthfr(+/-) mice compared with Mthfr(+/+) mice. Western blotting revealed that ApoA-I protein levels in liver and plasma of Mthfr(+/-) mice were 52% and 62% of levels in the respective tissues of Mthfr(+/+) mice. We also performed Western analysis for plasma ApoA-I protein levels in 60 males with coronary artery disease and identified a significant (P<0.01) negative correlation (-0.33) between ApoA-I and plasma homocysteine levels. This cohort also displayed a negative correlation (-0.24, P=0.06) between high-density lipoprotein cholesterol and plasma homocysteine. Treatment of HepG2 cells with supraphysiological levels of 5 mmol/L homocysteine reduced peroxisome proliferator-activated receptor (PPAR) alpha and ApoA-I protein levels and decreased ApoA-I promoter activity. Transfection with a PPARalpha construct upregulated ApoA-I and MTHFR. Our results suggest that hyperhomocysteinemia may increase risk of atherosclerosis by decreasing expression of ApoA-I and increasing expression of CYP7A1.

Effect of the methylenetetrahydrofolate reductase gene polymorphisms on homocysteine, folate and vitamin B12 in patients with bipolar disorder and relatives.

We investigated the effect of polymorphic variants of c.1298A>C (Glu429Ala) and c.677C>T (Ala222Val) in methylenetetrahydrofolate (MTHFR) gene on the total homocysteine (tHcy), folate and B12 levels in patients with bipolar disorder, first-degree relatives of patients, and controls. The c.677C>T and c.1298A>C polymorphisms in MTHFR were determined by polymerase chain reaction-restriction fragment length polymorphism in 197 bipolar patients, 278 relatives and 238 controls. tHcy and folate and vitamin B12 levels were measured by Fluorescence Polarization Immunoassay and Electrochemiluminescence, respectively. The tHcy was significantly increased in patients and relatives. In contrast, folate and B12 were significantly lower in patients and relatives. Gender was not considered as a significant determinant in the multivariate analysis. Genotypes of c.1298A>C and c.677C>T were correlated with tHcy, folate and B12. Patients and relatives carrying TT and/or AA and AC genotypes had elevated tHcy and reduced folate and B12 levels. High tHcy but low folate and vitamin B12 levels may be a risk factor for development of bipolar disorder.

Effect of dietary soybean protein level on the plasma homocysteine concentration in rats.

There was an inverse correlation between the plasma homocysteine concentration and dietary protein level or protein intake when a soybean protein isolate (SPI) was used as a protein source for rats. The hepatic cystathionine beta-synthase activity increased in response to the dietary SPI level. The results suggest that a high-protein diet might be an effective means to lower the plasma homocysteine concentration, probably through enhancement of the homocysteine-metabolizing activity.

Homocysteine activates platelets in vitro.

The mechanism of thrombogenicity in hyperhomocysteinemia remains controversial. The authors investigated the association between elevated plasma homocysteine levels, platelet function, and blood coagulation. Blood was collected from healthy subjects and patients with critical limb ischemia. Basal platelet counts and platelet aggregation as well as flow cytometry were performed to assess spontaneous- and agonist-induced platelet aggregation as well as P-selectin and Glycoprotein IIb/IIIa expression at different homocysteine concentrations. Thromboelastography was performed, and platelet shape change was assessed, using a channelyzer, by measuring median platelet volume. Lactate dehydrogenase was measured, to indirectly assess red blood cell membrane integrity, after homocysteine exposure. The study results suggest that platelet activation and hypercoagulability occur after exposure to homocysteine, especially in patients with critical limb ischemia. Homocysteine concentrations of approximately 50 micromol/L appear to be the level at which these changes occur in vitro, and this effect on platelets appears to be indirect.

Protein-bound homocyst(e)ine. A possible risk factor for coronary artery disease.

The development of atherosclerotic changes and thromboembolism are common features in homocystinurics. Hence, we postulate a positive correlation between the level of homocyst(e)ine in the blood and the occurrence of coronary artery disease. Homocysteine is found either as free homocystine, cysteine-homocysteine mixed disulfide, or protein-bound homocyst(e)ine. In nonhomocystinuric subjects, most homocysteine molecules are detectable in the protein-bound form. Thus, protein-bound homocyst(e)ine in stored plasma which reflected total plasma homocyst(e)ine was determined in 241 patients with coronary artery disease (173 males and 68 females). The mean +/- SD total plasma homocyst(e)ine was 5.41 +/- 1.62 nmol/ml in male patients, 4.37 +/- 1.09 nmol/ml in male controls, 5.66 +/- 1.93 nmol/ml in female patients, and 4.16 +/- 1.62 nmol/ml in female controls. The differences between the patients with coronary artery disease and the controls were statistically significant (P less than 0.0005).

Vascular dysfunction in monkeys with diet-induced hyperhomocyst(e)inemia.

Elevated plasma homocyst(e)ine may predispose to complications of vascular disease. Homocysteine alters vasomotor regulatory and anticoagulant properties of cultured vascular endothelial cells, but little is known about effects of hyperhomocyst(e)inemia on vascular function in vivo. We tested the hypothesis that diet-induced moderate hyperhomocyst(e)inemia is associated with vascular dysfunction in cynomolgus monkeys. Plasma homocyst(e)ine increased from 4.O +/- O.2 microM when monkeys were fed normal diet to 10.6 +/- 2.6 microM when they were fed modified diet (mean +/- SE; P = 0.02). Vasomotor responses were assessed in vivo by quantitative angiography and Doppler measurement of blood flow velocity. In response to activation of platelets by intraarterial infusion of collagen, blood flow to the leg decreased by 42 +/- 9% in monkeys fed modified diet, compared with 14 +/- 11% in monkeys fed normal diet (P = 0.008), Responses of resistance vessels to the endothelium-dependent vasodilators acetylcholine and ADP were markedly impaired in hyperhomocyst(e)inemic monkeys, which suggests that increased vasoconstriction in response to collagen may be caused by decreased vasodilator responsiveness to platelet-generated ADP. Relaxation to acetylcholine and, to a lesser extent, nitroprusside, was impaired ex vivo in carotid arteries from monkeys fed modified diet. Thrombomodulin anticoagulant activity in aorta decreased by 34 +/- 15% in hyperhomocyst(e)inemic monkeys (P = 0.03). We conclude that diet-induced moderate hyperhomocyst(e)inemia is associated with altered vascular function.

Homocystine-induced arteriosclerosis. The role of endothelial cell injury and platelet response in its genesis.

The atherogenic mechanism of homocystinemia has been defined by measuring endothelial cell loss and regeneration, platelet consumption, and intimal lesion formation in a primate model. Three groups of baboons were studied: (a) 8 control animals; (b) 15 animals after 3 mo of continuous homocystinemia; and (c) 11 animals after 3 mo of combined homocystinemia and oral treatment with dipyridamole. Experimental homocystinemia caused patchy endothelial desquamation comprising about 10% of the aortic surface despite a 25-fold increase in endothelial cell regeneration. Neither endothelial cell loss nor regeneration was changed significantly by dipyridamole. Homocystine-induced vascular deendothelialization produced a threefold increase in platelet consumption that was interrupted by dipyridamole inhibition of platelet function. All homocystinemic animals developed typical arteriosclerotic or preatherosclerotic intimal lesions composed of proliferating smooth muscle cells averaging 10-15 cell layers surrounded by large amounts of collagen, elastic fibers, glycosaminoglycans, and sometimes lipid. Intimal lesion formation was prevented by dipyridamole therapy. We conclude that homocystine-induced endothelial cell injury resulted in arteriosclerosis through platelet-mediated intimal proliferation of smooth muscle cells that can be prevented by drug-induced platelet dysfunction.