Consequences of hyperhomocyst(e)inemia on vascular function in atherosclerotic monkeys

Moderate elevation of plasma homocyst(e)ine is associated with increased risk for atherosclerotic vascular disease. In a previous study, we observed impaired vascular function in nonatherosclerotic monkeys with moderate hyperhomocyst(e)inemia. In this study, we tested the hypothesis that dietary intervention to lower plasma homocyst(e)ine corrects vascular dysfunction in atherosclerotic monkeys. Cynomolgus monkeys were fed an atherogenic diet that produces both hypercholesterolemia and moderate hyperhomocyst(e)inemia. After 17 months, the atherogenic diet was supplemented with B vitamins (5 mg folic acid, 400 micrograms vitamin B-12, and 20 mg vitamin B-6 daily) for 6 months. Total plasma homocyst(e)ine decreased from 12.8 +/- 2.8 to 3.5 +/- 0.3 mumol/L (n = 9; mean +/- SE; P < .01) after vitamins were added to the diet, but plasma cholesterol remained elevated (522 +/- 63 versus 514 +/- 41 mg/dL; P > .05). In response to intra-arterial infusion of collagen, blood flow to the leg decreased by 30 +/- 3% and 38 +/- 5%, respectively, before and after vitamin supplementation (P > .05). In vivo responses of resistance vessels to endothelium-dependent vasodilators (acetylcholine or ADP) were impaired at baseline and did not improve after vitamin supplementation. In carotid artery studied ex vivo, relaxation to low doses of acetylcholine improved after vitamin supplementation, but maximal relaxation remained impaired. Ex vivo thrombomodulin anticoagulant activity was threefold higher in monkeys fed the atherogenic diet (with or without B vitamins) than in normal monkeys (P < .05). We conclude that normalization of plasma homocyst(e)ine is insufficient to restore normal vascular function in atherosclerotic monkeys with persistent hypercholesterolemia and that atherosclerosis, with or without hyperhomocyst(e)inemia, is associated with elevated thrombomodulin activity.     

Hyperhomocyst(e)inemia and endothelial dysfunction in IDDM

OBJECTIVE: While elevated blood levels of homocyst(e)ine represent an independent risk factor for macrovascular disease, we assessed the link between hyperhomocyst(e)inemia and diabetic microvascular diseases. RESEARCH DESIGN AND METHODS: Plasma levels of homocyst(e)ine and thrombomodulin (TM), markers of endothelial cell damage, were measured before and 3 h after oral methionine loading in 75 patients with IDDM and 40 healthy control subjects matched for sex and age. Exclusion criteria were hyperlipidemia, hypertension, smoking, or positive family history for cardiovascular disease. RESULTS: IDDM patients had higher pre- and postload plasma levels of homocyst(e)ine than did healthy control subjects (12.0 vs. 7.7 mumol/l and 27.6 vs. 16.0 mumol/l; P < 0.001). Of 75 IDDM patients, 26 had plasma homocyst(e)ine levels above the normal range (means +/- 2 SD of values obtained in the control group). These IDDM patients with hyperhomocyst(e)inemia had higher plasma TM levels (62.2 vs. 38.2 ng/ml, P < 0.001), higher albumin excretion rates (485 vs. 115 mg/l, P < 0.005), and a higher prevalence of late diabetic complications (nephropathy, 76 vs. 33%; retinopathy, 69 vs. 51%; neuropathy, 57 vs. 41%; and macroangiopathy, 57 vs. 33%) compared with IDDM patients with normal plasma homocyst(e)ine. In vitro experiments with human umbilical vein cells showed an increased release of TM into the culture supernatant only when endothelial cells were pretreated with advanced glycation end product (AGE)-albumin before L-homocystine was added. A synergistic action of homocyst(e)ine and AGEs might contribute to vascular complications in patients with diabetes. CONCLUSIONS: Hyperhomocyst(e)inemia is common in nephropathic diabetic patients and may contribute to the enhanced morbidity and mortality from cardiovascular diseases characteristically observed in IDDM patients with diabetic nephropathy.     

Fasting and post-methionine load homocyst(e)ine values are correlated with microalbuminuria and could contribute to worsening vascular damage in non-insulin-dependent diabetes mellitus patients

The study aim was to assess the relationship between homocyst(e)inemia and microalbuminuria in non-insulin-dependent diabetes mellitus (NIDDM) patients. The study was performed on 33 NIDDM patients (16 males and 17 females), and 16 healthy control subjects (seven males and nine females). Plasma fasting and post-methionine load homocyst(e)ine (tHcy), together with other parameters that could modify tHcy levels, were assessed. There were no significant differences between NIDDM patients and controls for fasting tHcy (8.12 +/- 3.17 v 7.19 +/- 2.40 micromol/L) and post-methionine load tHcy (26.51 +/- 11.50 v 25.06 +/- 10.76 micromol/L). Moreover, there was a significant correlation between urinary albumin excretion (UAE) and fasting tHcy (r = .340, P = .05) and post-methionine load tHcy (r = .502, P = .004) in NIDDM patients. Fasting tHcy was correlated both with post-methionine load tHcy (r = .429, P = .01) and with vitamin B12 (r = -.349, P = .04) in NIDDM patients. Microalbuminuric NIDDM patients had higher fasting tHcy (9.05 +/- 3.83 micromol/L) than normoalbuminurics (7.12 +/- 1.95 micromol/L). In addition, NIDDM patients with complications presented higher fasting tHcy values than the group without complications (9.61 +/- 3.34 v 6.53 +/- 2.09 micromol/L, Kolmogorov-Smirnov two-sample test for nonparametric data [KS] = 1.794, P = .003), without any other significant differences in the parameters considered. tHcy could be an important risk factor worsening the prognosis in NIDDM patients, especially microalbuminuric patients. Microalbuminuric NIDDM patients could be particularly prone to hyperhomocyst(e)inemia, probably due to endothelial or renal dysfunction with a reduction in the scavenging of tHcy.     

The role of vitamins in the pathogenesis and treatment of hyperhomocyst(e)inaemia

The relation between vitamin nutritional status and circulating plasma homocyst(e)ine concentrations is reviewed. Several studies have shown that plasma concentrations of folate, vitamin B12 and pyridoxal 5'-phosphate are inversely associated with plasma total homocyst(e)ine concentrations. Of the three vitamins mentioned above, folate is the most powerful homocyst(e)ine lowering agent and a daily supplement of 0.65 mg/day is sufficient to normalize moderate hyperhomocyst(e)inaemia in most individuals with normal renal function. In patients with severe renal failure, high doses of folate are required to treat hyperhomocyst(e)inaemia. Folic acid is ineffective in reducing plasma total homocyst(e)ine concentrations in patients with a vitamin B12 deficiency. Vitamin B6 supplementation has no effect on fasting plasma total homocyst(e)ine concentrations, but attenuates the post-methionine load plasma homocyst(e)ine peak. At least one report has shown that some individuals appear to be unable to maintain plasma total homocyst(e)ine concentrations in the normal reference range by a dietary intake of folic acid only. Long-term vitamin supplementation may be indicated in these individuals. However, the clinical benefit of vitamin supplementation has not yet been demonstrated and controlled trials are urgently required.     

Hyperhomocyst(e)inemia and a common methylenetetrahydrofolate reductase mutation (Ala223Val MTHFR) in patients with inherited thrombophilic coagulation defects

To assess whether certain abnormalities of the sulfated amino acid metabolism are associated with the occurrence of thromboembolic events in patients with inherited thrombophilic conditions, the levels of homocyst(e)ine, before or after methionine load, and the presence of the Ala223Val substitution in the 5,10-methylenetetrahydrofolate reductase (MTHFR) were evaluated in 119 subjects with a congenital single thrombophilic condition (type I deficiency of antithrombin n = 10, protein C n = 24, protein S n = 16; activated protein C resistance due to factor V Leiden mutation n = 69). Sixty-three subjects had experienced at least one documented thrombotic event, while the remaining 56 subjects were still free from any thrombotic symptom. Our results show that (1) high homocyst(e)ine levels, either in fasting condition or after methionine load, were not more frequent in subjects with inherited thrombophilic alterations (14.4%) than in normal control subjects (10% by definition) and (2) the frequency of hyperhomocyst(e)inemia was similar in thrombophilic subjects, who already have (14.3%) or have not (14.6%) experienced thrombotic events. As regards the MTHFR mutation, the homozygous condition was present in 23.2% of the thrombophilic patients versus 17.5% in the control subjects, a nonsignificant difference. The mutation was slightly more frequent in those thrombophilic subjects who had suffered a thrombotic episode (25.5%) versus those with no thrombosis (20.8%), with odds ratios of 1.61 (confidence interval (CI) = 0.58-4.52) and 1.24 (CI = 0.42-3.43), respectively. These differences were also nonsignificant. It is concluded that in subjects with inherited thrombophilias, a condition of hyperhomocyst(e)inemia "per se" is not a factor increasing the risk of thrombosis. The risk enhancement conferred by the MTHFR mutation, if any, seems to be slight or limited, and its significance could be ascertained only in a large multicenter trial.     

Methylenetetrahydrofolate reductase gene polymorphism and ischemic stroke in Japanese

Hyperhomocyst(e)inemia has been identified as an independent risk factor for atherosclerotic and thromboembolic diseases such as coronary artery disease, cerebral artery disease, and venous thrombosis. Recently, the alanine/valine (A/V) gene polymorphism of 5,10-methylenetetrahydrofolate reductase (MTHFR), one of the key enzymes that catalyzes the remethylation of homocysteine, was reported. The VV genotype is correlated with increased plasma homocyst(e)ine levels as a result of the reduced activity and increased thermolability of this enzyme. In this study, we examined the association between the V allele of the MTHFR gene and ischemic stroke in an elderly Japanese population. The diagnosis of cerebral infarction of all study patients was confirmed by CT of the brain. The MTHFR genotype was analyzed by polymerase chain reaction followed by HinfI digestion. In 256 stroke patients and 325 control subjects, the frequencies of the V allele were 0.45 and 0.32, respectively. The odds ratios and 95% confidence intervals adjusted for the other risk factors were, respectively, 1.51 (1.02 to 2.23) for the AV genotype and 3.35 (1.94 to 5.77) for the VV genotype compared with the AA genotype. Both of these effects were statistically significant (P=0.041 and P<0.001, respectively). In patients with multiple infarcts in particular, the allele frequency of the V mutation was 0.56, and the association between the V allele and stroke was highly significant. Plasma homocyst(e)ine levels were significantly higher in patients with the VV genotype than in patients with the AA or AV genotype, especially those with low plasma folate levels. The V allele of the MTHFR gene was significantly associated with cerebral infarction in an elderly Japanese population in a codominant manner. The VV genotype may contribute to risk for ischemic stroke through a predisposition to increased plasma homocyst(e)ine levels, and dietary folate supplementation may be of benefit, particularly to patients with this genotype.     

Plasma folic acid cutoff value, derived from its relationship with homocyst(e)ine

We established the cutoff value for plasma folic acid, using plasma homocyst(e)ine as the functional marker. To do this, we investigated the relationship of the plasma folic acid of 103 apparently healthy adults with their fasting plasma homocyst(e)ine and with their plasma homocyst(e)ine 6 h after oral methionine challenge (100 mg/kg). We also studied the relationship of their plasma folic acid with the decline of fasting plasma homocyst(e)ine after 7 days of folic acid supplementation (5 mg/day). The three approaches suggested a cutoff value of 10 nmol/L. The chances of individuals to significantly (P <0.05) lower their plasma homocyst(e)ine after folic acid supplementation proved significantly higher at plasma folic acid concentrations < or = 10 nmol/L, as compared with folic acid concentrations above this value (odds ratio, 5.02; 95% confidence interval, 1.87-13.73). We suggest adopting a 10 nmo/L plasma folic acid cutoff value on functional grounds.     

Splenic artery embolization before laparoscopic splenectomy. An update

Several studies have indicated that plasma viscosity contributes to cardiovascular risk in men. So far, a significant relationship between plasma viscosity and the severity of coronary heart disease has not been found. Thus, the present study is the first to report on the relationship of plasma viscosity and the severity of coronary heart disease. In a collective of 1142 male myocardial infarction patients, plasma viscosity and additional laboratory parameters were determined. Atherosclerotic changes were quantified by coronary angiography. Patients were divided into groups without any, and with one to three stenosed vessels. We found a positive relationship between plasma viscosity and the severity of coronary heart disease, even after adjusting groups for age, fibrinogen, and use of diuretics. Mean plasma viscosity ranged from 1.141+/-0.035 mPa s in patients without stenosed vessels to 1.162+/-0.044 mPa s in patients who had three coronary vessels with stenoses >50%. Differences between the groups were significant (P<0.001 to 0.05), with two exceptions: differences between patients without any and with one stenosed vessel, as well as between patients with one and two stenosed vessels, did not reach the significance level. On the whole, we can give further support to the hypothesis that cardiovascular risk factors and coronary heart disease may be linked by plasma viscosity.     

Increased expression of P-selectin on platelets is a risk factor for silent cerebral infarction in patients with atrial fibrillation: role of nitric oxide

BACKGROUND: Platelet activation and decreased levels of nitrite and nitrate (NOx), stable end products of nitric oxide (NO), are reported in patients with atrial fibrillation (AF). We examined the time-course changes in plasma NOx levels and the expression of P-selectin on platelets after the onset of AF in a canine model and determined whether these parameters could be risk factors for silent cerebral infarction in patients with AF. METHODS AND RESULTS: AF was induced by rapid atrial pacing in the canine model of AF. Plasma NOx levels were significantly decreased and the levels of P-selectin on platelets and of neutrophil/platelet conjugates were significantly increased after the onset of AF in this model. The in vitro experiments demonstrated that the inhibition of NO synthesis increased the expression of P-selectin on platelets. Plasma NOx levels (19.7+/-2.4 versus 27.5+/-2.8 micromol/L) were significantly lower in 25 patients with AF compared with age- (+/-2 years) and sex-matched control subjects. Conversely, the levels of P-selectin on platelets (7.6+/-0.8% versus 4.8+/-0.7%) and of neutrophil/platelet conjugates (14.8+/-0.9% versus 8.1+/-0.6%) were significantly higher in patients with AF. Multiple regression analysis revealed that increased P-selectin on platelets and advanced age were associated with the number of foci of silent cerebral infarction. CONCLUSIONS: An irregular heart rate that is characteristic of AF appeared to blunt NO synthesis. The increased expression of P-selectin on platelets associated with the reduced NO levels was a risk factor for silent cerebral infarction in patients with AF.     

Correction of erythrocyte shape abnormalities in familial hypercholesterolemia after LDL-apheresis: does it influence cerebral hemodynamics?

It is well known that red blood cells incubated in low-density lipoprotein (LDL)-rich medium show shape abnormalities that revert to normal after reincubation in normal plasma. Patients with homozygous familial hypercholesterolemia (HFH) have an increased percentage of abnormally-shaped erythrocytes (mostly stomatocytes, knisocytes, and crenated cells) compared to normocholesterolemic controls: 7.73+/-0.96 versus 3.52+/-0.52 (mean+/-SEM; P = 0.001). To confirm the role of high LDL concentration in inducing red cell shape abnormalities we determined the percentage of abnormally shaped erythrocytes in seven HFH patients 1 day after the procedure of LDL-apheresis with a 40% cholesterol decrease. A reduction in kniscocytes, stomatocytes, and crenated cells was observed in the patients treated by LDL-apheresis (P < 0.01). To investigate the possible benefit of a reduction in erythrocyte shape abnormality on cerebral hemodynamics, cerebral flow velocity, as evaluated by transcranial Doppler, was evaluated concomitantly and found to be remarkably increased after apheresis (P < 0.01). No significant change in hematocrit, plasma viscosity, blood viscosity, mean pressure, or cardiac output was detected, 1 day after apheresis. An inverse correlation was demonstrated (r = 0.55; P = 0.04) between changes in the percentage of knisocytes+stomatocytes +crenated cells and percent changes in middle cerebral artery peak systolic velocity. The correction of erythrocyte shape abnormalities after LDL-apheresis might be related to dramatic changes in plasma phospholipid concentration and proportion occurring after this procedure in HFH patients. The reduction of erythrocyte shape abnormalities could contribute, together with other hemorheological factors, to the improvement of cerebral hemodynamics after LDL-apheresis.     

Independent impact of thrombolytic therapy and vessel patency on left ventricular dilation after myocardial infarction. Serial echocardiographic follow-up

BACKGROUND: It has been shown that successful reperfusion of the infarct-related artery by thrombolysis can prevent left ventricular dilation after acute myocardial infarction; these beneficial effects were detected from several days to several months after infarction. To date, however, no study has shown that these effects can be demonstrated within hours after the onset of infarction. Furthermore, data are scarce on the independent impact of thrombolytic therapy and late vessel patency on ventricular volume and function. The aim of this study was to assess separate effects of thrombolysis and patency of the infarct-related artery on left ventricular size and function by serial two-dimensional echocardiographic examinations. METHODS AND RESULTS: We evaluated 131 consecutive patients with first acute myocardial infarction by two-dimensional echocardiography in the following sequence: days 1, 2, 3, 7, and after 3 and 6 weeks. Intravenous streptokinase was administered in 81 patients, and 50 patients were treated without thrombolysis. Left ventricular end-diastolic volume, end-systolic volume, and ejection fraction were determined from apical two- and four-chamber views using the Simpson biplane formula and normalized to body surface area. Coronary angiography was performed in 107 patients after a mean of 26.0 +/- 20.2 (mean +/- SD) days after infarction. Patency of the infarct-related artery was assessed using TIMI criteria, with 54 considered patent (TIMI 3) and 53 with TIMI grade < 3. On day 1, end-systolic volume was significantly higher in patients not receiving thrombolysis (37.7 +/- 15.3 versus 33.0 +/- 10.6 mL/m2, P = .045). End-systolic volume (ESVi) was significantly higher in patients treated without thrombolysis throughout the study, whereas significant differences in end-diastolic volume (EDVi) were detected from day 3 (P = .041) onward and in ejection fraction (EF) from day 2 (P = .025) onward, all differences becoming progressively more significant with time (6-week values: EDVi, 78.8 +/- 25.4 versus 65.9 +/- 15.7 mL/m2, P = .001; ESVi, 45.4 +/- 22.6 versus 33.9 +/- 15.1 mL/m2, P = .002; EF, 45.1 +/- 11.6% versus 50.2 +/- 10.1%, P = .018). Patients with an occluded infarct-related artery (TIMI < 3) demonstrated highly significant differences at 6 weeks compared with patients with patent vessels (EDVi, 76.8 +/- 24.7 versus 65.2 +/- 15.6 mL/m2, P = .006; ESVi, 44.6 +/- 23.3 versus 31.9 +/- 12.2 mL/m2, P = .001; EF, 45.0 +/- 11.6% versus 52.1 +/- 9.0%, P < .001), but these differences developed more slowly than that seen among the thrombolytic subgroups. Indeed, multivariate analysis demonstrated that thrombolysis was the major determinant of initial volumes (P = .08, .02, and .08 for EDVi, ESVi, and EF, respectively), while vessel patency was the overwhelming determinant of subsequent changes (P = .0033, .0002, and .0024 for EDVi, ESVi, and EF, respectively). Additionally, ventricular volumes were significantly higher and ejection fractions lower in patients with anterior versus inferior infarction, but even adjusting for these differences as well as those associated with age, sex, and initial ventricular volume, the additive and independent impact of thrombolysis and infarct vessel patency persisted. CONCLUSIONS: These data indicate that the beneficial effect of thrombolysis on left ventricular size and function can be demonstrated in the earliest phases of acute myocardial infarction and that subsequent changes are mediated primarily through patency of the infarct-related artery. Thrombolytic therapy and late vessel patency thus have an additive and complementary impact in reducing ventricular dilation after myocardial infarction.     

Linear growth velocity in children with cerebral palsy

Retrospective analysis of an anthropometric database collected prospectively in children with cerebral palsy (CP) was carried out to evaluate linear growth velocity and identify risk factors for poor linear growth. Growth velocity measures were compared with published norms for prepubertal growth velocity and z scores were calculated. Mean growth velocity z score (Gvz) was -0.97+/-1.9. Boys grew more slowly than girls (mean Gvz = -1.5+/-1.9 versus -0.3+/-1.7 P = 0.003). Gvz did not correlate with type of CP or presence/absence of microcephaly. Young age was a risk factor for poor linear growth (mean Gvz = -2.40+/-2.6 for children under 2 years of age versus -0.76+/-1.9 ages 2 to 6 and -0.77+/-1.6 ages 6 to 10, P = 0.04). Children at nutritional risk (triceps skinfold thickness < or =55%) grew poorly (mean Gvz = -1.46+/-1.5 versus -0.30+/-1.8, P = 0.01). For children over 2 years, those with cognitive impairments grew more slowly than those with normal cognition (mean Gvz = -1.25+/-1.9 versus -0.12+/-1.8, P = 0.02) and non-ambulatory children grew more slowly than ambulatory children (mean Gvz = -1.20+/-1.5 versus -0.35+/-1.9, P = 0.03). Prepubertal children with CP grow more slowly than expected compared with age- and sex-based standards. Sex, age, cognitive impairment, ambulatory status, and nutritional state are factors which may contribute to slow growth. These results add to the growing data that children with CP have unique growth patterns. Further study is needed to clarify the factors which contribute to poor linear growth in this population.     

Regional cerebral blood volume after severe head injury in patients with regional cerebral ischemia

OBJECTIVE: Recent early cerebral blood flow (CBF) studies in cases of severe head injury have revealed ischemia in a substantial number of patients with a variety of computed tomographically demonstrated diagnoses. The underlying derangements causing this early ischemia are unknown, but cerebral blood volume (CBV) measurements might offer some insight into this pathological abnormality. METHODS: For this purpose, stable xenon-enhanced computed tomography was used for assessment of CBF, and a dynamic computed tomographic imaging technique was used for determining CBV. Based on the occurrence of regional ischemia (CBF < 20 ml/100 g/min), seven patients with varying anatomic lesions revealed by computed tomography were identified for comparison between CBF and CBV in ischemic and nonischemic areas. RESULTS: Both CBF (15+/-4.3 versus 34+/-11 g/min, P < 0.002) and CBV (2.5+/-1.0 versus 4.9+/-1.9 ml/100 g) exhibited significantly lower values in the ischemic zones than in the nonischemic zones (means+/-standard deviations). Among 26 patients with or without ischemia observed during their initial follow-up studies, which were conducted between Days 2 and 8, all patients showed CBF and CBV values within the low-normal range. CONCLUSION: These data evidently support the suggestion that compromise of the microvasculature is the cause of early ischemia, rather than vasospasm of the larger conductance vessels.     

Isolation of hMRE11B: failure to complement yeast mre11 defects due to species-specific protein interactions

Hyperhomocyst(e)inemia in patients with coronary and peripheral arterial occlusion has been demonstrated by others. Redox-state of homocyst(e)ine causes dysfunction of endothelial cells and promote growth of vascular smooth muscle cells. The role of tissue, protein bound and unbound, oxidative mixed disulfides in the development of fibrous plaque in atherosclerotic lesion is not known. Redox-state around the fibroblasts and vascular smooth muscle cells modulates the expression of extracellular matrix (ECM) components (Tyagi et al. 1996, J Cell Biochem, 61: 139-151). To determine the role of tissue homocystine in fibrotic atherosclerotic plaque development, coronary arteries were isolated from ischemic explanted hearts (n = 10). Apparently normal vascular tissue was obtained from idiopathic cardiomyopathic explanted hearts (n = 10). Tissue extract were prepared from atherosclerotic lesions and from normal arteries devoid of adventitia. Interaction of homocystine with Ellman's reagent (5, 5'-dithio-bis-2-nitro benzoic acid) catalyzed by limiting amount of reducing agent (catalyst) generated change in optical density (OD) at 412 nm in dose dependent fashion. We have generated a standard curve between change at 412 nm and amount of homocystine. The change in OD at 412 nm with increasing amount (0-25 microg) of homocystine demonstrated linearity. The protein-bound oxidized disulfides were precipitated by trichloroacetic acid (TCA) and free-oxidative disulfides in the supernatant were collected. The pathophysiological amount of protein-bound disulfide in atherosclerotic tissue (1.0 +/- 0.2 microg/mg total protein) was 10 times that in normal tissue (0.1 +/- 0.01 microg/mg, p < 0.001). The amount of free oxidative disulfide in atherosclerotic tissue (1.5 +/- 0.3 microg/mg) was 15 times that in normal tissue (0.12 +/- 0.02 microg/mg, p < 0.001). To determine the role of homocystine in ECM expression, ECM collagenase activity in the presence and absence of homocystine was measured by zymography. The effect of homocysteine on collagenase activity was biphasic, increased at < [0.01 mM] and inhibited at > [0.1 mM]. To determine whether homocystine regulates vascular tone, isometric measurements were carried out using normal coronary rings. Results suggested that homocystine induced endothelial-modulated vasoconstriction in coronary vessels. Tissue oxidative disulfides and the homocystine may contribute to the development of fibrotic atherosclerotic lesions and vascular dysfunction.     

Use of hypertonic (3%) saline/acetate infusion in the treatment of cerebral edema: Effect on intracranial pressure and lateral displacement of the brain

OBJECTIVE: To determine the effect of continuous hypertonic (3%) saline/acetate infusion on intracranial pressure (ICP) and lateral displacement of the brain in patients with cerebral edema. DESIGN: Retrospective chart review. SETTINGS: Neurocritical care unit of a university hospital. PATIENTS: Twenty-seven consecutive patients with cerebral edema (30 episodes), including patients with head trauma (n = 8), postoperative edema (n = 5), nontraumatic intracranial hemorrhage (n = 8), and cerebral infarction (n = 6). INTERVENTION: Intravenous infusion of 3% saline/acetate to increase serum sodium concentrations to 145 to 155 mmol/L. MEASUREMENTS AND MAIN RESULTS: A reduction in mean ICP within the first 12 hrs correlating with an increase in the serum sodium concentration was observed in patients with head trauma (r2 = .91, p = .03), and postoperative edema (r2 = .82, p = .06), but not in patients with nontraumatic intracranial hemorrhage or cerebral infarction. In patients with head trauma, the beneficial effect of hypertonic saline on ICP was short-lasting, and after 72 hrs of infusion, four patients required intravenous pentobarbital due to poor ICP control. Among the 21 patients who had a repeat computed tomographic scan within 72 hrs of initiating hypertonic saline, lateral displacement of the brain was reduced in patients with head trauma (2.8 +/- 1.4 to 1.1 +/- 0.9 [SEM]) and in patients with postoperative edema (3.1 +/- 1.6 to 1.1 +/- 0.7). This effect was not observed in patients with nontraumatic intracranial bleeding or cerebral infarction. The treatment was terminated in three patients due to the development of pulmonary edema, and was terminated in another three patients due to development of diabetes insipidus. CONCLUSIONS: Hypertonic saline administration as a 3% infusion appears to be a promising therapy for cerebral edema in patients with head trauma or postoperative edema. Further studies are required to determine the optimal duration of benefit and the specific patient population that is most likely to benefit from this treatment.     

Atherogenic, hemostatic, and other potential risk markers in subjects with previous isolated myocardial infarction compared with long-standing uncomplicated stable angina

BACKGROUND: Several atherogenic, hemostatic, inflammatory, and genetic parameters and markers have been implicated as risk factors in coronary artery disease, although whether they are risk factors for acute as opposed to chronic coronary disease is unclear. METHODS AND RESULTS: Fifty subjects with an isolated myocardial infarction >3 months previously were compared with 50 subjects with a minimum 3-year history of stable angina, documented coronary artery disease, normal electrocardiogram and normal ventricular wall motion, and no episode suggesting infarction or unstable angina. Biologic variables analyzed included apolipoprotein B (apo B), lipoprotein (a), C-reactive protein (CRP), fibrinogen, factor VII, tissue plasminogen activator (TPA) and inhibitor (PAI-1), thrombin-antithrombin (TAT), fragment 1+2 (F1+2), von Willebrand factor (vWF), activated protein C resistance, homocyst(e)ine, anticardiolipin antibodies, blood group, and the angiotensin-converting enzyme insertion/deletion (I/D) and angiotensin II receptor gene polymorphisms. There were no significant differences between the 2 groups for any of the variables studied, although fibrinogen and F 1+2 tended to be slightly higher in the angina group (P = .09 for each). These significant correlations were present: age with fibrinogen, homocyst(e)ine, and vWF; factor VII with apo B, homocyst(e)ine, and TPA; apo B with TPA and CRP; CRP with fibrinogen, TPA, PAI-1, and factor VII; fibrinogen with vWF. CONCLUSIONS: Examination of atherogenic, hemostatic, inflammation, and genetic variables in the clinically quiescent state permitted no distinction between subjects with a previous isolated myocardial infarction in contrast to those with long-standing uncomplicated stable angina, favoring the notion that acute coronary events occur at random on a varying background of atherosclerosis. The multiple correlations found among these variables also underscore their complex interaction in the atherosclerotic process.     

Impaired dynamic cerebral autoregulation in carotid artery stenosis

BACKGROUND AND PURPOSE: If it could be determined whether cerebral blood flow can be maintained (autoregulated) during transient falls in arterial blood pressure, we might be able to identify patients with carotid stenosis who are at risk of stroke. However, conventional methods of determining autoregulation in such patients are invasive and/or expensive. METHODS: We used a new noninvasive method to estimate dynamic cerebral autoregulation in 27 patients with carotid stenosis and 21 age-matched normal controls. After a stepwise fall in arterial blood pressure, we determined the rate of rise of middle cerebral artery blood flow velocity compared with that of arterial blood pressure. We compared the method with a conventional method of determining cerebral hemodynamics, CO2 reactivity. RESULTS: Autoregulatory index (ARI) was significantly reduced in middle cerebral arteries ipsilateral to a stenosed/ occluded carotid artery: mean +/- SD 3.3 +/- 2.2 compared with normal controls (6.3 +/- 1.1; P < .0001) and nonstenosed carotid arteries in patients (5.9 +/- 2.1; P < .002). A subgroup of patients with severe impairment was identified. ARI returned to normal after carotid endarterectomy was performed. In a number of cases, ARI was impaired in the presence of CO2 reactivity. CONCLUSIONS: This simple technique allows identification of impaired autoregulation in patients with carotid artery disease. It may allow identification of patients at risk from transient falls of blood pressure as may occur at the onset of antihypertensive therapy and during surgery. It may allow a subgroup of patients with asymptomatic carotid stenosis who are at risk of hemodynamic stroke to be identified.     

A study of cardiovascular risk in heterozygotes for homocystinuria

Early atherosclerotic-like lesions and thromboemobolic problems are prominent in homocystinuric patients. Recent evidence suggested that mild homocyst(e)inemia, such as is present in heterozygotes for homocystinuria due to cystathionine synthase deficiency, may cause a marked excess in early ischemic heart disease. To evaluate the risk due to mild homocyst(e)inemia, the frequencies of heart attacks and strokes in parents and grandparents of homocystinuric children were assessed in the present study. No statistically significant increases in the incidence of heart attacks or strokes were consistently detected. The data available are sufficient to virtually exclude an increase in the cardiovascular risk for homocystinuria heterozygotes of as much as fivefold compared to controls, and to make very improbable a relative risk of as much as threefold. Less than 5% of homocystinuria heterozygotes are likely to have a fatal or nonfatal heart attack by age 50. These results fail to suggest that mild homecyst(e)inemia is an important contributory factor in the overall incidence of cardiovascular disease.     

Postischemic application of lipid peroxidation inhibitor U-101033E reduces neuronal damage after global cerebral ischemia in rats

BACKGROUND AND PURPOSE: The lipid peroxidation inhibitor U-101033E was examined for effects on cerebral blood flow (CBF), cortical tissue hemoglobin oxygen saturation (HbSo2), and neuronal damage. METHODS: Fifteen minutes of global cerebral ischemia was induced by two-vessel occlusion and hypobaric hypotension. Wistar rats (n = 25) were randomized to receive vehicle (n = 9) or 40 mg/kg U-101033E (n = 9) intraperitoneally during 2 hours of reperfusion. A sham group (n = 7) had neither ischemia nor therapy. Histology was evaluated 7 days after ischemia. RESULTS: During late hyperperfusion (at 17 minutes), vehicle-treated animals had a higher (P = 0.044) cortical tissue HbSo2 (72.0 +/- 1.4%) than did U-101033E-treated animals (65.8 +/- 2.5%). Neuronal counts in the superficial cortex layer found after 7 days correlated negatively with rCBF (r = -0.76; P < 0.001) or cortical tissue HbSo2 (r = -0.56; P = 0.028) assessed during the late hyperperfusion phase. U-101033E reduced neuronal damage in hippocampal CA1 from 64.3 +/- 9.2% to 31.2 +/- 8.4% (P = 0.020), as well as in the superficial cortical layer from 53.5 +/- 14.6% to 12.8 +/- 11.7% (P = 0.046). While animals in the vehicle group had reduced counts in all four examined cortex layers (P < 0.05 versus sham group), there was significant cortical neuron loss in the U-101033E group in only one of four areas. U-101033E had no effect on resting CBF or CO2 reactivity. CONCLUSIONS: Postischemic application of U-101033E protects hippocampal CA1 and cortical neurons after 15 minutes of global cerebral ischemia. The results indicate that free radical-induced lipid peroxidation contributes to reperfusion injury, a process that can be inhibited by antioxidants such as U-101033E.     

Gene therapy for myocardial angiogenesis: initial clinical results with direct myocardial injection of phVEGF165 as sole therapy for myocardial ischemia

BACKGROUND: We initiated a phase 1 clinical study to determine the safety and bioactivity of direct myocardial gene transfer of vascular endothelial growth factor (VEGF) as sole therapy for patients with symptomatic myocardial ischemia. METHODS AND RESULTS: VEGF gene transfer (GTx) was performed in 5 patients (all male, ages 53 to 71) who had failed conventional therapy; these men had angina (determined by angiographically documented coronary artery disease). Naked plasmid DNA encoding VEGF (phVEGF165) was injected directly into the ischemic myocardium via a mini left anterior thoracotomy. Injections caused no changes in heart rate (pre-GTx=75+/-15/min versus post-GTx=80+/-16/min, P=NS), systolic BP (114+/-7 versus 118+/-7 mm Hg, P=NS), or diastolic BP (57+/-2 versus 59+/-2 mm Hg, P=NS). Ventricular arrhythmias were limited to single unifocal premature beats at the moment of injection. Serial ECGs showed no evidence of new myocardial infarction in any patient. Intraoperative blood loss was 0 to 50 cm3, and total chest tube drainage was 110 to 395 cm3. Postoperative cardiac output fell transiently but increased within 24 hours (preanesthesia=4.8+/-0.4 versus postanesthesia=4.1+/-0.3 versus 24 hours postoperative=6. 3+/-0.8, P=0.02). Time to extubation after closure was 18.4+/-1.4 minutes; average postoperative hospital stay was 3.8 days. All patients had significant reduction in angina (nitroglycerin [NTG] use=53.9+/-10.0/wk pre-GTx versus 9.8+/-6.9/wk post-GTx, P<0.03). Postoperative left ventricular ejection fraction (LVEF) was either unchanged (n=3) or improved (n=2, mean increase in LVEF=5%). Objective evidence of reduced ischemia was documented using dobutamine single photon emission computed tomography (SPECT)-sestamibi imaging in all patients. Coronary angiography showed improved Rentrop score in 5 of 5 patients. CONCLUSIONS: This initial experience with naked gene transfer as sole therapy for myocardial ischemia suggests that direct myocardial injection of naked plasmid DNA, via a minimally invasive chest wall incision, is safe and may lead to reduced symptoms and improved myocardial perfusion in selected patients with chronic myocardial ischemia.