Jorge Luna

Infectious Burden and Carotid Plaque Thickness: The Northern Manhattan Study

Background and Purpose— The overall burden of prior infections may contribute to atherosclerosis and stroke risk. We hypothesized that serological evidence of common infections would be associated with carotid plaque thickness in a multiethnic cohort. Methods— Antibody titers to 5 common infectious microorganisms (ie, Chlamydia pneumoniae, Helicobacter pylori, cytomegalovirus, and herpesvirus 1 and 2) were measured among stroke-free community participants and a weighted index of infectious burden was calculated based on Cox models previously derived for the association of each infection with stroke risk. High-resolution carotid duplex Doppler studies were used to assess maximum carotid plaque thickness. Weighted least squares regression was used to measure the association between infectious burden and maximum carotid plaque thickness after adjusting for other risk factors. Results— Serological results for all 5 infectious organisms were available in 861 participants with maximum carotid plaque thickness measurements available (mean age, 67.2±9.6 years). Each individual infection was associated with stroke risk after adjusting for other risk factors. The infectious burden index (n=861) had a mean of 1.00±0.35 SD and a median of 1.08. Plaque was present in 52% of participants (mean, 0.90±1.04 mm). Infectious burden was associated with maximum carotid plaque thickness (adjusted increase in maximum carotid plaque thickness 0.09 mm; 95% CI, 0.03 to 0.15 mm per SD increase of infectious burden). Conclusion— A quantitative weighted index of infectious burden, derived from the magnitude of association of individual infections with stroke, was associated with carotid plaque thickness in this multiethnic cohort. These results lend support to the notion that past or chronic exposure to common infections, perhaps by exacerbating inflammation, contributes to atherosclerosis. Future studies are needed to confirm this hypothesis and to define optimal measures of infectious burden as a vascular risk factor.

High-sensitivity C-reactive protein predicts mortality but not stroke The Northern Manhattan Study

Objective: To determine whether high-sensitivity C-reactive protein (hsCRP) and serum amyloid A (SAA) predict stroke, vascular events, and mortality in a prospective cohort study. Background: Markers of inflammation have been associated with risk of myocardial infarction (MI). Their association with stroke is controversial. Methods: The Northern Manhattan Study includes a stroke-free community-based cohort study in participants aged ≥40 years (median follow-up 7.9 years). hsCRP and SAA were measured using nephelometry. Cox proportional hazards models were used to calculate hazard ratios (HR) and 95% confidence intervals (CI) for the association of markers with risk of ischemic stroke and other outcomes after adjusting for demographics and risk factors. Results: hsCRP measurements were available in 2,240 participants (mean age 68.9 ± 10.1 years; 64.2% women; 18.8% white, 23.5% black, and 55.1% Hispanic). The median hsCRP was 2.5 mg/L. Compared with those with hsCRP <1 mg/L, those with hsCRP >3 mg/L were at increased risk of ischemic stroke in a model adjusted for demographics (HR = 1.60, 95% CI 1.06–2.41), but the effect was attenuated after adjusting for other risk factors (adjusted HR = 1.20, 95% CI 0.78–1.86). hsCRP >3 mg/L was associated with risk of MI (adjusted HR = 1.70, 95% CI 1.04–2.77) and death (adjusted HR = 1.55, 95% CI 1.23–1.96). SAA was not associated with stroke risk. Conclusion: In this multiethnic cohort, high-sensitivity C-reactive protein (hsCRP) was not associated with ischemic stroke, but was modestly associated with myocardial infarction and mortality. The value of hsCRP and serum amyloid A may depend on population characteristics such as age and other risk factors.

High-Sensitivity C-Reactive Protein and Interleukin-6–Dominant Inflammation and Ischemic Stroke Risk The Northern Manhattan Study

Background and Purpose— Interleukin-6 (IL-6) is a proinflammatory cytokine with known autoregulatory feedback mechanisms. We hypothesized that elevated high-sensitivity C-reactive protein (hsCRP) relative to IL-6 confers an increased risk of ischemic stroke (IS), and low hsCRP relative to IL-6 a decreased risk, for individuals in the prospective, multiethnic, population-based Northern Manhattan Study (NOMAS). Methods— Serum hsCRP and IL-6 were measured in NOMAS participants at baseline. We created a trichotomized predictor based on the dominant biomarker in terms of quartiles: hsCRP-dominant, IL-6–dominant, and codominant groups. Cox proportional hazards models were used to calculate hazard ratios and 95% confidence intervals for the association between inflammatory biomarker group status and risk of incident IS. Results— Of 3298 participants, both hsCRP and IL-6 were available in 1656 participants (mean follow-up, 7.8 years; 113 incident IS). The hsCRP-dominant group had increased risk of IS (adjusted hazard ratio, 2.62; 95% confidence interval, 1.56–4.41) and the IL-6–dominant group had decreased risk (adjusted hazard ratio, 0.38; 95% confidence interval, 0.18–0.82) when compared with the referent group, after adjusting for potential confounders. Model fit was improved using the inflammation-dominant construct, over either biomarker alone. Conclusions— In this multiethnic cohort, when hsCRP-quartile was higher than IL-6 quartile, IS risk was increased, and conversely when IL-6 quartiles were elevated relative to hsCRP, IS risk was decreased. Construct validity requires confirmation in other cohorts.

C-Reactive Protein as a Prognostic Marker After Lacunar Stroke Levels of Inflammatory Markers in the Treatment of Stroke Study

Background and Purpose— Inflammatory biomarkers predict incident and recurrent cardiac events, but their relationship to stroke prognosis is uncertain. We hypothesized that high-sensitivity C-reactive protein (hsCRP) predicts recurrent ischemic stroke after recent lacunar stroke. Methods— Levels of Inflammatory Markers in the Treatment of Stroke (LIMITS) was an international, multicenter, prospective ancillary biomarker study nested within Secondary Prevention of Small Subcortical Strokes (SPS3), a phase III trial in patients with recent lacunar stroke. Patients were assigned in factorial design to aspirin versus aspirin plus clopidogrel, and higher versus lower blood pressure targets. Patients had blood samples collected at enrollment and hsCRP measured using nephelometry at a central laboratory. Cox proportional hazard models were used to calculate hazard ratios (HRs) and 95% confidence intervals (95% CIs) for recurrence risks before and after adjusting for demographics, comorbidities, and statin use. Results— Among 1244 patients with lacunar stroke (mean age, 63.3±10.8 years), median hsCRP was 2.16 mg/L. There were 83 recurrent ischemic strokes (including 45 lacunes) and 115 major vascular events (stroke, myocardial infarction, and vascular death). Compared with the bottom quartile, those in the top quartile (hsCRP >4.86 mg/L) were at increased risk of recurrent ischemic stroke (unadjusted HR, 2.54; 95% CI, 1.30–4.96), even after adjusting for demographics and risk factors (adjusted HR, 2.32; 95% CI, 1.15–4.68). hsCRP predicted increased risk of major vascular events (top quartile adjusted HR, 2.04; 95% CI, 1.14–3.67). There was no interaction with randomized antiplatelet treatment. Conclusions— Among recent lacunar stroke patients, hsCRP levels predict the risk of recurrent strokes and other vascular events. hsCRP did not predict the response to dual antiplatelets. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00059306.

The Levels of Inflammatory Markers in the Treatment of Stroke study (LIMITS): inflammatory biomarkers as risk predictors after lacunar stroke.

Background Inflammation is increasingly recognised as playing a central role in atherosclerosis, and peripheral blood markers of inflammation have been associated with incident and recurrent cardiac events. The relationship of these potentially modifiable risk markers to prognosis after ischaemic stroke is less clear. The Levels of Inflammatory Markers in the Treatment of Stroke (LIMITS) study will address hypotheses related to the role of inflammatory markers in secondary stroke prevention in an efficient manner using the well-established framework of the Secondary Prevention of Small Subcortical Strokes (SPS3) trial (NCT00059306). Methods SPS3 is an ongoing Phase III multicentre secondary prevention trial focused on preventing recurrent stroke in patients with small vessel ischaemic stroke, or lacunes. In SPS3, patients are assigned in a factorial design to aspirin vs. aspirin plus clopidogrel, and to usual vs. aggressive blood pressure targets. The purpose of LIMITS is to determine whether serum levels of inflammatory markers – including high-sensitivity C-reactive protein, serum amyloid A, CD40 ligand, and monocyte chemoattractant protein-1 – predict recurrent stroke and other vascular events among lacunar stroke patients. The project will also determine whether these markers predict which people will respond best to dual antiplatelet therapy with clopidogrel and aspirin, as well the relationship to cognitive function. Analysis plan Multivariate Cox proportional hazard regression modeling will be used to estimate hazard ratios for the effect of marker levels on risk of recurrent stroke and other outcomes after adjusting for additional potential risk factors, including age, gender, ethnicity, treatment arm, and traditional stroke risk factors. Interactions between marker levels and treatment assignment for both arms of the SPS3 study will be assessed. Observations will be censored at the time of last follow-up visit. Conclusions LIMITS represents an efficient approach to the identification of novel inflammatory biomarkers for use in risk prediction and treatment selection in patients with small vessel disease.

Tumour necrosis factor receptor 1 and mortality in a multi-ethnic cohort: the Northern Manhattan Study

OBJECTIVE to study the association between soluble tumour necrosis factor receptor 1 (sTNFR1) levels and mortality in the population-based Northern Manhattan Study (NOMAS). METHODS NOMAS is a multi-ethnic, community-based cohort study with mean 8.4 years of follow-up. sTNFR1 was measured using ELISA. Cox proportional hazards models were used to calculate hazard ratios and 95% confidence intervals (HR, 95% CI) for the association of sTNFR1 with risk of all-cause mortality after adjusting for relevant confounders. RESULTS sTNFR1 measurements were available in 1,862 participants (mean age 69.2 ± 10.2 years) with 512 all-cause deaths. Median sTNFR1 was 2.28 ng/ml. Those with sTNFR1 levels in the highest quartile (Q4), compared with those with sTNFR1 in the lowest quartile (Q1), were at an increased risk of all-cause mortality (adjusted HR: 1.8, 95% CI: 1.4-2.4) and non-vascular mortality (adjusted HR: 2.5, 95% CI: 1.5-3.6), but not vascular mortality (adjusted HR: 1.3, 95% CI: 0.9-1.9). There were interactions between sTNFR1 quartiles and medical insurance-status [likelihood ratio test (LRT) with 3 degrees of freedom, Pinteraction = 0.02] and alcohol consumption (LRT with 3 degrees of freedom, Pinteraction < 0.01) for all-cause mortality. In participants with no insurance or Medicaid, those with sTNFR1 in the top quartile had nearly a threefold increased risk of total mortality than the lowest quartile (adjusted HR: 2.9, 95% CI: 1.9-4.4). CONCLUSION in this multi-ethnic cohort, sTNFR1 was associated with all-cause and non-vascular mortality, particularly among those of a lower socioeconomic status.

Inflammatory Markers and Outcomes After Lacunar Stroke: Levels of Inflammatory Markers in Treatment of Stroke Study.

Background and Purpose— We hypothesized that concentrations of interleukin 6 (IL-6), serum amyloid A, tumor necrosis factor-&agr; receptor 1, CD40 ligand, and monocyte chemoattractant protein 1 would predict recurrent ischemic stroke and major vascular events after recent lacunar stroke. Methods— Levels of Inflammatory Markers in the Treatment of Stroke (LIMITS) was an international, multicenter, prospective ancillary biomarker study nested within the Secondary Prevention of Small Subcortical Strokes (SPS3) study, a Phase III trial in patients with recent lacunar stroke. Crude and Adjusted Cox proportional hazards models were used to calculate hazard ratios (HRs) and 95% confidence intervals (95% CI) for recurrence risks. Results— Among 1244 patients with lacunar stroke (mean age, 63.3±10.8 years), there were 115 major vascular events (stroke, myocardial infarction, and vascular death). The risk of major vascular events increased with elevated concentrations of both tumor necrosis factor-&agr; receptor 1 (adjusted HR per SD, 1.21; 95% CI, 1.05–1.41; P=0.01) and IL-6 (adjusted HR per SD, 1.10; 95% CI, 1.02–1.19; P=0.008). Compared with the bottom quartile (tumor necrosis factor-&agr; receptor 1 <2.24 ng/L), those in the top quartile of tumor necrosis factor-&agr; receptor 1 (>3.63 ng/L) were at twice the risk of major vascular events after adjusting for demographics (partially adjusted HR, 1.98; 95% CI, 1.11–3.52), though the effect attenuated after adjusting for other risk factors and statin use (adjusted HR, 1.68; 95% CI, 0.93–3.04). Serum amyloid A, CD40 ligand, and monocyte chemoattractant protein 1 were not associated with prognosis. Conclusions— Among recent lacunar stroke patients, IL-6 and TNF receptor concentrations predict risk of recurrent vascular events, and they are associated with the effect of antiplatelet therapies. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00059306.

Risk of Acute Stroke After Hospitalization for Sepsis: A Case-Crossover Study

Background and Purpose— Infections have been found to increase the risk of stroke over the short term. We hypothesized that stroke risk would be highest shortly after a sepsis hospitalization, but that the risk would decrease, yet remain up to 1 year after sepsis. Methods— This case-crossover analysis utilized data obtained from the California State Inpatient Database of the Healthcare Cost and Utilization Project. All stroke admissions were included. Exposure was defined as hospitalization for sepsis or septicemia 180, 90, 30, or 15 days before stroke (risk period) or similar time intervals exactly 1 or 2 years before stroke (control period). Conditional logistic regression was used to calculate the odds ratio (OR) and 95% confidence interval (95% CI) for the association between sepsis/septicemia and ischemic or hemorrhagic stroke. Results— Ischemic (n=37 377) and hemorrhagic (n=12 817) strokes that occurred in 2009 were extracted where 3188 (8.5%) ischemic and 1101 (8.6%) hemorrhagic stroke patients had sepsis. Sepsis within 15 days before the stroke placed patients at the highest risk of ischemic (OR, 28.36; 95% CI, 20.02–40.10) and hemorrhagic stroke (OR, 12.10; 95% CI, 7.54–19.42); however, although the risk decreased, it remained elevated 181 to 365 days after sepsis for ischemic (OR, 2.59; 95% CI, 2.20–3.06) and hemorrhagic (OR, 3.92; 95% CI 3.29–4.69) strokes. There was an interaction with age (P=0.0006); risk of developing an ischemic stroke within 180 days of hospitalization for sepsis increased 18% with each 10-year decrease in age. Conclusions— Risk of stroke is high after sepsis, and this risk persists for up to a year. Younger sepsis patients have a particularly increased risk of stroke after sepsis.

Parvovirus B19 Infection in Children With Arterial Ischemic Stroke

Background and Purpose— Case–control studies suggest that acute infection transiently increases the risk of childhood arterial ischemic stroke. We hypothesized that an unbiased pathogen discovery approach utilizing MassTag–polymerase chain reaction would identify pathogens in the blood of childhood arterial ischemic stroke cases. Methods— The multicenter international VIPS study (Vascular Effects of Infection in Pediatric Stroke) enrolled arterial ischemic stroke cases, and stroke-free controls, aged 29 days through 18 years. Parental interview included questions on recent infections. In this pilot study, we used MassTag–polymerase chain reaction to test the plasma of the first 161 cases and 34 controls enrolled for a panel of 28 common bacterial and viral pathogens. Results— Pathogen DNA was detected in no controls and 14 cases (8.7%): parvovirus B19 (n=10), herpesvirus 6 (n=2), adenovirus (n=1), and rhinovirus 6C (n=1). Parvovirus B19 infection was confirmed by serologies in all 10; infection was subclinical in 8. Four cases with parvovirus B19 had underlying congenital heart disease, whereas another 5 had a distinct arteriopathy involving a long-segment stenosis of the distal internal carotid and proximal middle cerebral arteries. Conclusions— Using MassTag–polymerase chain reaction, we detected parvovirus B19—a virus known to infect erythrocytes and endothelial cells—in some cases of childhood arterial ischemic stroke. This approach can generate new, testable hypotheses about childhood stroke pathogenesis.

Influenza‐like illness as a trigger for ischemic stroke

We hypothesized that ILI is associated with risk of incident stroke, and that the risk would be highest closest in time to the event.