Fibroblast growth factor 23 is associated with risk of intracerebral hemorrhage.

BACKGROUND AND PURPOSE: Fibroblast growth factor 23 (FGF23) is an osteogenic hormone associated with chronic kidney disease and is an emerging risk factor for several cardiovascular diseases. The association of FGF23 with stroke is unclear. The aim of this study was to investigate the association of FGF23 with incident intracerebral hemorrhage (ICH). METHODS: This was a nested case-control study of 220 ICH cases and 244 age- and sex-matched controls from the population-based Malmö Diet and Cancer Study (n = 28,449). Incident ICH cases were ascertained using national registers and classified by bleeding location. Logistic regression was used to study the association of plasma levels of FGF23 with incident ICH, adjusting for potential ICH risk factors. Subgroup analyses were performed for lobar and non-lobar ICH, fatal ICH, ICH with large volume and ICH with poor functional outcome, respectively. RESULTS: Higher FGF23 levels at baseline were significantly associated with incident ICH. After multivariable adjustment, the odds ratio for the association with all ICH was 1.84 (95% confidence interval [CI] 1.25-2.71, p = 0.002) per doubling of FGF23 concentration. For lobar and non-lobar ICH, odds ratios were 1.73 (95% CI 1.04-2.87, p = 0.035) and 2.13 (95% CI 1.32-3.45, p = 0.002), respectively. FGF23 was also significantly associated with fatal ICH, ICH with large volume and ICH with poor functional outcome. CONCLUSIONS: Higher FGF23 was associated with incident ICH in this nested case-control study. Further studies are required to explore whether the association is causal.

Circulating Growth Differentiation Factor 15 Levels Are Associated With Risk of Both Intracerebral and Subarachnoid Hemorrhage.

Background: Growth differentiation factor 15 (GDF-15) has been associated with the risk of developing major bleedings, including but not restricted to intracranial hemorrhages, in patients on oral anticoagulants or dual antiplatelet therapy. We hypothesized that there may be an association of GDF-15 with incidence of hemorrhagic strokes in the general population, which has not been investigated before. Methods: Two different case-control studies, one for intracerebral hemorrhage (ICH) and one for subarachnoid hemorrhage (SAH), nested within the population-based Malmö Diet and Cancer cohort, were defined using the incidence density sampling method. GDF-15 was analyzed in frozen blood samples taken at the baseline examination in 1991-1996. The associations between GDF-15 and incident ICH (220 cases, 244 controls) and incident SAH (79 cases, 261 controls), respectively, were explored using conditional logistic regression adjusting for risk factors. Results: GDF-15 levels at baseline were higher in both incident ICH and SAH cases, compared with their respective control subjects. After adjustment for risk factors, significant relationships with high GDF-15 concentrations were observed both for incident ICH (odds ratio (OR) per 1 log2 unit: 2.27, 95% confidence interval (CI): 1.52-3.41; P = 7.1 × 10-5) and incident SAH (OR: 2.16, 95% CI: 1.29-3.59; P = 0.0032). Conclusions: High circulating GDF-15 levels were associated with incident ICH and incident SAH, independently of the main risk factors.

Risk factors for intracerebral haemorrhage - Results from a prospective population-based study.

INTRODUCTION: While the relationship between hypertension and incident intracerebral haemorrhage is well established, other risk factors are less clear. This study examined risk factors for primary intracerebral haemorrhage, separately for lobar and non-lobar intracerebral haemorrhage. PATIENTS AND METHODS: Incidence of intracerebral haemorrhage was studied among 28,416 individuals from the population-based Malmö Diet and Cancer cohort. Intracerebral haemorrhage cases were ascertained using the Swedish Hospital Discharge Register and the Stroke Register of Malmö, validated by review of hospital records and images, and classified by location by a neuroradiologist. Multivariable Cox regression was used. RESULTS: Three hundred and thirty-three intracerebral haemorrhages occurred, mean follow-up time was 18.4 years. Systolic blood pressure (hazard ratio per 10 mmHg 1.19 [95% confidence interval 1.13-1.26], diastolic blood pressure (hazard ratio 1.42 [1.27-1.59]), oral anticoagulants (hazard ratio 4.26 [2.17-8.38]), smoking (hazard ratio 1.45 [1.14-1.87]), living alone (hazard ratio 1.32 [1.04-1.69]) and low apolipoprotein B (hazard ratio per 10 mg/dL: 0.94 [0.90-0.99]) were significantly associated with incident intracerebral haemorrhage after multivariable adjustment. Systolic blood pressure, smoking and oral anticoagulants were associated with lobar intracerebral haemorrhage. Systolic blood pressure, diastolic blood pressure, living alone and diabetes were associated with non-lobar intracerebral haemorrhage. Diabetes and diastolic blood pressure showed significantly different relationships with lobar and non-lobar intracerebral haemorrhage. Alcohol, apolipoprotein A1, body mass index, waist circumference, physical activity and education were not independently associated with intracerebral haemorrhage.Discussion and conclusions: Blood pressure, smoking, low apolipoprotein B, oral anticoagulants and living alone were associated with intracerebral haemorrhage. Diabetes was associated with non-lobar intracerebral haemorrhage only. Further research is required on differences between lobar and non-lobar intracerebral haemorrhage.

Tumor Necrosis Factor Receptor 1 and 2 Are Associated With Risk of Intracerebral Hemorrhage.

BACKGROUND AND PURPOSE: Raised plasma concentrations of tumor necrosis factor receptors (TNFR) have been linked to arterial stiffness, cerebral microbleeds, and vascular events. The aim of this study was to investigate the association of circulating levels of TNFR1 and TNFR2 with risk for future intracerebral hemorrhage (ICH). METHODS: The population-based MDCS cohort (Malmö Diet and Cancer Study; n=28 449) was conducted in 1991 to 1996. A nested case-control study was performed in the MDCS, including 220 cases who experienced ICH during the follow-up period (mean age at inclusion 62 years, 48% men) and 244 matched controls. Of the 220 ICH cases, 68 died within 28 days. Conditional logistic regression was used to study the association between plasma levels of TNFR1 and TNFR2 and incident ICH, adjusting for known ICH risk factors. RESULTS: Concentrations of both TNFR1 and TNFR2 were significantly higher in subjects who developed ICH during the follow-up. The associations remained after adjustment for ICH risk factors (TNFR1: odds ratio [OR], 2.28; 95% confidence interval [CI], 1.26-4.11; P=0.006; TNFR2: OR, 1.77; CI, 1.16-2.70; P=0.008). ORs were somewhat higher for nonlobar ICH (3.04; CI, 1.29-7.14 and 2.39; CI, 1.32-4.32, respectively) than for lobar ICH (2.03; CI, 0.93-4.41 and 1.35; CI, 0.78-2.37, respectively). TNFR1 and TNFR2 were also associated with increased risk of fatal ICH (TNFR1: OR, 4.42; CI, 1.67-11.6; TNFR2: OR, 2.90; CI, 1.50-5.58) and with poor functional outcome according to the modified Rankin Scale. CONCLUSIONS: High plasma levels of TNFR1 and TNFR2 were associated with incident ICH, most clearly with ICH of nonlobar location. The results suggest that tumor necrosis factor-mediated inflammation could be associated with vascular changes preceding ICH.