Association of Cardiovascular Risk Factors with Disease Severity in Cerebral Cavernous Malformation Type 1 Subjects with the Common Hispanic Mutation

Abstract

Background: Cerebral cavernous malformations (CCM) are enlarged vascular lesions affecting 0.1-0.5% of the population worldwide and causing hemorrhagic strokes, seizures, and neurological deficits. Familial CCM type 1 (CCM1) is an autosomal dominant disease caused by mutations in the Krev Interaction Trapped 1 (KRIT1/CCM1) gene, and is characterized by multiple brain lesions whose number and size increase with age. The number of lesions varies widely for unknown reasons, even among carriers of similar ages with the same mutation. The purpose of this study was to investigate whether cardiovascular (CV) risk factors influence potential markers of familial CCM1 disease severity, such as lesion count and history of intracerebral hemorrhage. Methods: We analyzed baseline data from 185 Hispanic subjects, enrolled in the Brain Vascular Malformation Consortium study between June 2010 and March 2013. All subjects were carriers of the founder Q455X ‘Common Hispanic Mutation' (CHM) in the KRIT1 gene, and had a clinical diagnosis of CCM or had an affected first- or second-degree relative with CCM. We performed a cross-sectional study, collecting detailed clinical information of CCM1-CHM subjects and cerebral susceptibility-weighted magnetic resonance imaging to assess lesion count. Linear or logistic regression analysis of log-lesion count or history of intracerebral hemorrhage and CV risk factors (age, gender, obesity, diabetes, hypertension, hyperlipidemia and smoking status) and related quantitative traits (body mass index, glycosylated hemoglobin levels, blood pressure, lipids levels and pack-years of cigarette smoking) was performed accommodating familial clustering. Results: CCM1-CHM subjects were mainly female (63.8%) and symptomatic at presentation (63.2%). Lesion count was highly variable (mean ± SD: 57.7 ± 110.6; range: 0-713); 90% of CCM1-CHM subjects had multiple lesions at enrollment. Age (p < 0.001) was positively correlated with lesion count and male gender (p = 0.035) was associated with a greater number of lesions. Obesity (p = 0.001) and higher body mass index (p = 0.002) were associated with fewer lesions. No association with hypertension was detected, however, systolic blood pressure (p = 0.002) was associated with fewer lesions. No significant association with lesion count was observed for diabetes, hyperlipidemia, smoking status or for related quantitative traits. History of intracerebral hemorrhage was not significantly associated with any CV risk factors, however, we found borderline associations of hemorrhage with obesity (p = 0.062), systolic blood pressure (p = 0.083) and pack-years of cigarette smoking (p = 0.055). After correction for multiple testing, age and obesity remained significantly associated with lesion count in CCM1-CHM subjects. Conclusions: These results suggest that several CV risk factors explain some of the variability in lesion count in Hispanic CCM1-CHM subjects. Although age, gender, obesity, body mass index and systolic blood pressure may influence familial CCM1 disease severi...

Peripheral Plasma Vitamin D and Non-HDL Cholesterol Reflect the Severity of Cerebral Cavernous Malformation Disease

“…Notably, the mean value of 158 mg/dl in the nonaggressive group is considered to be 'borderline high.' This is in-line with a recent study by Choquet et al reporting that obese CCM patients with higher BMI harbored a lower CCM lesion burden than lean subjects [14]. BMI is positively correlated with non-HDL cholesterol values [36].…”

“…BMI is positively correlated with non-HDL cholesterol values [36]. Choquet et al failed to find a correlation between hyperlipidemia and CCM severity [14], but the discrepancy might be due to our use of continuous variables in lipid levels, while Choquet et al considered a clinical history of hyperlipidemia as a categorical variable. Similarly, a lack of correlation of CRP levels with CCM disease aggressiveness in our subjects may reflect the categorical reporting of clinical laboratory CRP results.…”

“…Patients' histories and previously adjudicated relevant disease parameters were obtained during their clinical visit and stored prospectively in a secure database for subsequent analysis [1,9,14].…”

“…A relevant disease biomarker might reflect chronic disease aggressiveness over the patient's lifetime, or more acute clinical activity [3,9,14]. We considered validated features of chronic disease aggressiveness including a history of multiple adjudicated clinically overt hemorrhages, early age of clinical onset or high lesion burden in familial cases.…”

“…Another study indicated that proinflammatory genotypes [9] and low BMI [14] may be associated with greater aggressiveness of familial CCM cases harboring a common CCM1 muta- Research Article Girard, Khanna, Shenkar et al tion. Additionally, the inflammatory cells and their cytokines are modulated by vitamin D [15].…”