Robert R. Sciacca

Effect of medical treatment in stroke patients with patent foramen ovale: patent foramen ovale in Cryptogenic Stroke Study.

Background—Patent foramen ovale (PFO) is associated with stroke, but there are no randomized studies to evaluate the efficacy of antithrombotic therapies. Methods and Results—The PFO in Cryptogenic Stroke Study was a 42-center study that evaluated transesophageal echocardiographic findings in patients randomly assigned to warfarin or aspirin in the Warfarin-Aspirin Recurrent Stroke Study. In this study, 630 stroke patients were enrolled, of whom 312 (49.5%) were randomized to warfarin and 318 (50.5%) to aspirin. Of these, 265 patients experienced cryptogenic stroke and 365 experienced known stroke subtypes. End points were recurrent ischemic stroke or death. PFO was present in 203 patients (33.8%). There was no significant difference in the time to primary end points between those with and those without PFO in the overall population (P =0.84; hazard ratio 0.96; 95% CI 0.62 to 1.48; 2-year event rates 14.8% versus 15.4%) or in the cryptogenic subset (P =0.65; hazard ratio 1.17; 95% CI 0.60 to 2.37; 2-year event rates 14.3% versus 12.7%). There was no significant difference among those with no, small, or large PFO (P =0.41 for small PFO and P =0.16 for large PFO; 2-year event rates for no, small, and large PFO, 15.4%, 18.5%, and 9.5%, respectively). There was no significant difference between patients with isolated PFO and those with PFO in association with atrial septal aneurysm (P =0.84; 2-year event rates 14.5% versus 15.9%). In patients with PFO, there was no significant difference in the time to primary end points between those treated with warfarin and those treated with aspirin (P =0.49; hazard ratio 1.29; 95% CI 0.63 to 2.64; 2-year event rates 16.5% versus 13.2%). Conclusions—On medical therapy, the presence of PFO in stroke patients did not increase the chance of adverse events regardless of PFO size or the presence of atrial septal aneurysm.

Predictors of hemorrhage in patients with untreated brain arteriovenous malformation

Background: Intracranial hemorrhage is a serious possible complication in patients with brain arteriovenous malformation (AVM). Several morphologic factors associated with hemorrhagic AVM presentation have been established, but their relevance for the risk of subsequent AVM hemorrhage remains unclear. Methods: The authors analyzed follow-up data on 622 consecutive patients from the prospective Columbia AVM database, limited to the period between initial AVM diagnosis and the start of treatment (i.e., any endovascular, surgical, or radiation therapy). Univariate and multivariate logistic regression and Cox proportional hazard models were applied to analyze the effect of patient age, gender, AVM size, anatomic location, venous drainage pattern, and associated arterial aneurysms on the risk of intracranial hemorrhage at initial presentation and during follow-up. Results: The mean pretreatment follow-up was 829 days (median: 102 days), during which 39 (6%) patients experienced AVM hemorrhage. Increasing age (hazard ratio [HR] 1.05, 95% CI 1.03 to 1.08), initial hemorrhagic AVM presentation (HR 5.38, 95% CI 2.64 to 10.96), deep brain location (HR 3.25, 95% CI 1.30 to 8.16), and exclusive deep venous drainage (HR 3.25, 95% CI 1.01 to 5.67) were independent predictors of subsequent hemorrhage. Annual hemorrhage rates on follow-up ranged from 0.9% for patients without hemorrhagic AVM presentation, deep AVM location, or deep venous drainage to as high as 34.4% for those harboring all three risk factors. Conclusions: Hemorrhagic arteriovenous malformation (AVM) presentation, increasing age, deep brain location, and exclusive deep venous drainage appear to be independent predictors for AVM hemorrhage during natural history follow-up. The risk of spontaneous hemorrhage may be low in AVMs without these risk factors.

Ventriculostomy-related infections: a critical review of the literature

OBJECTIVE To provide a critical evaluation of the published literature describing risk factors for ventriculostomy-related infections (VRIs) and the efficacy of prophylactic catheter exchange. METHODS A MEDLINE literature search was performed, and data were extracted from studies published from 1941 through 2001. RESULTS Published criteria for diagnosing VRIs are highly variable. Intraventricular hemorrhage, subarachnoid hemorrhage, cranial fracture with cerebrospinal fluid leak, craniotomy, systemic infections, and catheter irrigation all predispose patients to the development of VRIs. Extended duration of catheterization is correlated with an increasing risk of cerebrospinal fluid infections during the first 10 days of catheterization. Prophylactic catheter exchange does not modify the risk of developing later VRIs in retrospective studies. CONCLUSION Categorizing suspected cerebrospinal fluid infections as contaminants, colonization, suspected or confirmed VRIs, or ventriculitis more accurately describes the patients clinical condition and may indicate different management strategies. A prospective, randomized clinical trial is required to further evaluate the efficacy of prophylactic catheter exchange in limiting the incidence of VRIs during prolonged catheterization. Although prophylactic catheter exchange remains a practice option, the available data suggest that this procedure is not currently justified.

Risk of spontaneous haemorrhage after diagnosis of cerebral arteriovenous malformation

BACKGROUND A small proportion of strokes are caused by cerebral arteriovenous malformations (AVM). Treatment to prevent intracranial haemorrhage itself carries risks, and untreated AVM may in many cases have a good prognosis. We investigated the risk of subsequent symptomatic bleeding in the clinical course of AVM in patients with and without an initial haemorrhage. METHODS 281 unselected, consecutive, prospectively enrolled patients with cerebral AVM were grouped according to their initial clinical presentation--142 presented with and 139 without haemorrhage. The frequency of AVM haemorrhages during the subsequent clinical course (before the start of endovascular, surgical, or radiation treatment) in the two groups was compared by means of Kaplan-Meier life-tables, log-rank test, and multivariate proportional-hazards regression models. Haemorrhage was defined as a clinically symptomatic event with signs of acute bleeding on computed tomography or magnetic resonance brain imaging. FINDINGS During mean follow-up of 8.5 months for the haemorrhage group and 11.9 months for the non-haemorrhage group, haemorrhages occurred in 18 (13%) of the former patients and in three (2%) of the latter (p=0.0002). The annual risk of haemorrhage was 17.8% and 2.2%, respectively. In the multivariate regression model, the adjusted hazard ratio for haemorrhage at initial presentation was 13.9 (95% CI 2.6-73.8; p=0.002). Deep venous drainage (hazard ratio 4.1 [1.2-14.9], p=0.029) and male sex (9.2 [2.1-41.3], p=0.004) were also significantly associated with subsequent haemorrhage, but no significant association was found for age or AVM size. The annual rate of spontaneous haemorrhage was 32.6% for men and 10.4% for women in the haemorrhage group compared with 3.3% for men and 1.3% for women in the non-haemorrhage group. Among patients with haemorrhage at initial presentation, the risk of haemorrhage fell from 32.9% in year 1 to 11.3% in subsequent years (34.2% to 31.0% in men; 31.1% to 5.5% in women). INTERPRETATION In AVM, patients initially presenting with haemorrhage have a higher risk of subsequent bleeding than those presenting with other symptoms. The risk is higher in men than in women.

The lethal effects of cytokine-induced nitric oxide on cardiac myocytes are blocked by nitric oxide synthase antagonism or transforming growth factor beta.

Inducible nitric oxide (NO) produced by macrophages is cytotoxic to invading organisms and has an important role in host defense. Recent studies have demonstrated inducible NO production within the heart, and that cytokine-induced NO mediates alterations in cardiac contractility, but the cytotoxic potential of nitric oxide with respect to the heart has not been defined. To evaluate the role of inducible nitric oxide synthase (iNOS) on cardiac myocyte cytotoxicity, we exposed adult rat cardiac myocytes to either cytokines alone or to activated J774 macrophages in coculture. Increased expression of both iNOS message and protein was seen in J774 macrophages treated with IFN gamma and LPS and cardiac myocytes treated with TNF-alpha, IL-1 beta, and IFN gamma. Increased NO synthesis was confirmed in both the coculture and isolated myocyte preparations by increased nitrite production. Increased NO synthesis was associated with a parallel increase in myocyte death as measured by CPK release into the culture medium as well as by loss of membrane integrity, visualized by trypan blue staining. Addition of the competitive NO synthase inhibitor L-NMMA to the culture medium prevented both the increased nitrite production and the cytotoxicity observed after cytokine treatment in both the isolated myocyte and the coculture experiments. Because transforming growth-factor beta modulates iNOS expression in other cell types, we evaluated its effects on cardiac myocyte iNOS expression and NO-mediated myocyte cytotoxicity. TGF-beta reduced expression of cardiac myocyte iNOS message and protein, reduced nitrite production, and reduced NO-mediated cytotoxicity in parallel. Taken together, these experiments show the cytotoxic potential of endogenous NO production within the heart, and suggest a role for TGF-beta or NO synthase antagonists to mute these lethal effects. These findings may help explain the cardiac response to sepsis or allograft rejection, as well as the progression of dilated cardiomyopathies of diverse etiologies.

The New York Islands AVM Study Design, Study Progress, and Initial Results

Background and Purpose— Prospective population-based data on the incidence of brain arteriovenous malformation (AVM) hemorrhage are scarce. We studied lifetime detection rates of brain AVM and incident AVM hemorrhage in a defined population. Methods— The New York islands (ie, Manhattan Island, Staten Island, and Long Island) comprise a 9 429 541 population according to the 2000 census. Since March 15, 2000, all major New York islands hospitals have prospectively reported data on consecutive patients living in the study area with a diagnosis of brain AVM and whether the patient had suffered AVM hemorrhage. Patients living outside the ZIP code–defined study area were excluded from the study population. Results— As of June 14, 2002, 284 prospective AVM patients (mean±SD age, 35±18 years; 49% women) were encountered during 21 216 467 person-years of observation, leading to an average annual AVM detection rate of 1.34 per 100 000 person-years (95% CI, 1.18 to 1.49). The incidence of first-ever AVM hemorrhage (n=108; mean age, 31±19 years; 45% women) was 0.51 per 100 000 person-years (95% CI, 0.41 to 0.61). The estimated prevalence of AVM hemorrhage among detected cases (n=144; mean age, 33±19 years; 50% women) was 0.68 per 100 000 (95% CI, 0.57 to 0.79). Conclusions— Our prospective data, spanning 27 months, suggest stable rates for AVM detection and incident AVM hemorrhage. Approximately half of AVM patients may suffer intracranial hemorrhage.

Induction of myocardial nitric oxide synthase by cardiac allograft rejection.

Cardiac transplantation, effective therapy for end-stage heart failure, is frequently complicated by allograft rejection, the mechanisms of which remain incompletely understood. Nitric oxide (NO), a vasodilator which is cytotoxic and negatively inotropic, can be produced in large amounts by an inducible NO synthase (iNOS) in response to cytokines. To investigate whether iNOS is induced during cardiac allograft rejection, hearts from Lewis or Wistar-Furth rats were transplanted into Lewis recipients. At day 5, allogeneic grafts manifested reduced contractility and histologic evidence of rejection (inflammatory infiltrate, edema, necrosis of myocytes). The mRNA for iNOS and iNOS protein were detected in ventricular homogenates and in isolated cardiac myocytes from rejecting allogeneic grafts but not in tissue and myocytes from syngeneic control grafts. Immunocytochemistry showed increased iNOS staining in infiltrating macrophages and in microvascular endothelial cells and cardiac muscle fibers and also in isolated purified cardiac myocytes from the rejecting allografts. Using a myocardial cytosolic iNOS preparation, nitrite formation from L-arginine and [3H] citrulline formation from [3H]L-arginine were increased significantly in the rejecting allogeneic grafts (P < 0.01). Myocardial cyclic GMP was also increased significantly (P < 0.05). The data indicate myocardial iNOS mRNA, protein and enzyme activity are induced in infiltrating macrophages and cardiac myocytes of the rejecting allogeneic grafts. Synthesis of NO by iNOS may contribute to myocyte necrosis and ventricular failure during cardiac allograft rejection.

Acute Elevations of Plasma Asymmetric Dimethylarginine and Impaired Endothelial Function in Response to a High-Fat Meal in Patients With Type 2 Diabetes

Asymmetric dimethylarginine (ADMA), a compound detectable in human plasma, is an endogenous inhibitor of NO synthase. Endothelial dysfunction is an early event in atherogenesis, and large-vessel atherosclerosis is a major cause of morbidity and mortality in patients with type 2 diabetes mellitus. Fifty patients with type 2 diabetes mellitus were studied at baseline and 5 hours after ingestion of a high-fat meal. Plasma ADMA measured by using high-performance liquid chromatography increased from 1.04±0.99 to 2.51±2.27 &mgr;mol/L (P <0.0005). Brachial arterial vasodilation after reactive hyperemia, a NO-dependent function, measured by high-resolution ultrasound, decreased from 6.9±3.9% at baseline to 1.3±4.5% (P <0.0001). These changes occurred in association with increased plasma levels of triglycerides and very low density lipoprotein triglycerides, with reduced low density lipoprotein cholesterol and high density lipoprotein cholesterol, and with no changes in total cholesterol. The increase in plasma ADMA in response to a high-fat meal was significantly and inversely related to the decrease in percent vasodilation. In 10 of the subjects studied with a similar protocol on another day, no significant changes in the brachial artery flow responses or in plasma ADMA were observed 5 hours after ingestion of a nonfat isocaloric meal. The data suggest that ADMA may contribute to abnormal blood flow responses and to atherogenesis in type 2 diabetics.

The influence of hemodynamic and anatomic factors on hemorrhage from cerebral arteriovenous malformations.

The physiological and anatomical aberrations that result in hemorrhage from cerebral arteriovenous malformations (AVMs) remain unclear. In an attempt to clarify which conditions may predispose to hemorrhage, we examined clinical and physiological indices on presentation groups of either hemorrhage or nonhemorrhage in a large cohort of patients (n = 449). Variables examined included AVM size, type of venous drainage, transcranial Doppler (TCD) velocities, feeding mean arterial pressure (FMAP), and draining vein pressure. TCD and pressure data were obtained before any treatment. Age (mean +/- standard deviation) at the time of presentation was 33 +/- 13 years and did not differ between groups. Patients with small (< or = 2.5 cm) AVMs presented more frequently with hemorrhage (90%) than did patients with medium (> 2.5 and < or = 5.0 cm; 52%) or large (> 5.0 cm; 50%) AVMs (P = 0.0001). The 48 of 94 AVMs (51%) with deep venous drainage were more likely to have hemorrhage (P = 0.0219) than were those with superficial drainage (24 of 73 [33%]). Deep drainage was a predictor of hemorrhage even in the subgroup of medium and large supratentorial AVMs (P = 0.005). There was no difference in draining vein pressure (n = 18) between groups (21 +/- 10 and 19 +/- 11 mm Hg, respectively; P = 0.7812). FMAP (n = 52) was higher in the hemorrhage than in the nonhemorrhage group (44 +/- 13 versus 34 +/- 10 mm Hg; P = 0.0007) but was only weakly related to the size of the lesion (largest dimension) (y = -0.74x + 40; r = 0.09).(ABSTRACT TRUNCATED AT 250 WORDS)

Apoptosis of Cardiac Myocytes During Cardiac Allograft Rejection: Relation to Induction of Nitric Oxide Synthase

BACKGROUND Apoptosis is a distinct form of programmed cell death characterized by activation of endonucleases that cleave nuclear DNA, condensation and fragmentation of nuclear chromatin, blebbing of intact membranes, and cell shrinkage and fragmentation. The mechanisms responsible are unclear, but nitric oxide (NO) generated by inducible NO synthase (iNOS) has been demonstrated to induce apoptosis in macrophages in vitro. This study investigated whether apoptosis occurs during cardiac allograft rejection and examined the relationship of apoptosis to iNOS expression. METHODS AND RESULTS Heterotopic abdominal transplantation from Lewis to Wistar-Furth rats was used as a model of cardiac allograft rejection; Lewis-to-Lewis grafts served as controls. Apoptosis was identified by DNA ladders after electrophoresis on agarose gels and by in situ labeling of DNA fragments; cell types were determined by immunohistochemistry. The number of apoptotic cardiac myocytes increased sharply from day 3 (0.31/mm2 ventricular tissue) to day 5 (1.27/mm2) after transplantation. At day 5, allografts showed a significant increase (P < .01) in apoptotic cardiac myocytes, macrophages, and endothelial cells compared with syngeneic grafts. The expression of iNOS mRNA, protein, and enzyme activity paralleled in time and extent the apoptosis of cardiac myocytes. iNOS immunostaining of infiltrating macrophages and cardiac muscle fibers increased significantly in the allografts at days 3 to 5 and was accompanied by immunostaining of both cell types for nitrotyrosine, which is indicative of peroxynitrite formation. CONCLUSIONS Apoptosis of myocardial cells occurs during cardiac allograft rejection. Apoptosis during rejection parallels the expression of iNOS, which suggests that apoptosis may be triggered by NO and peroxynitrite.