A clinical risk score of myocardial fibrosis predicts adverse outcomes in aortic stenosis.

AIMS: Midwall myocardial fibrosis on cardiovascular magnetic resonance (CMR) is a marker of early ventricular decompensation and adverse outcomes in aortic stenosis (AS). We aimed to develop and validate a novel clinical score using variables associated with midwall fibrosis. METHODS AND RESULTS: One hundred forty-seven patients (peak aortic velocity (Vmax) 3.9 [3.2,4.4] m/s) underwent CMR to determine midwall fibrosis (CMR cohort). Routine clinical variables that demonstrated significant association with midwall fibrosis were included in a multivariate logistic score. We validated the prognostic value of the score in two separate outcome cohorts of asymptomatic patients (internal: n = 127, follow-up 10.3 [5.7,11.2] years; external: n = 289, follow-up 2.6 [1.6,4.5] years). Primary outcome was a composite of AS-related events (cardiovascular death, heart failure, and new angina, dyspnoea, or syncope). The final score consisted of age, sex, Vmax, high-sensitivity troponin I concentration, and electrocardiographic strain pattern [c-statistic 0.85 (95% confidence interval 0.78-0.91), P < 0.001; Hosmer-Lemeshow χ(2) = 7.33, P = 0.50]. Patients in the outcome cohorts were classified according to the sensitivity and specificity of this score (both at 98%): low risk (probability score <7%), intermediate risk (7-57%), and high risk (>57%). In the internal outcome cohort, AS-related event rates were >10-fold higher in high-risk patients compared with those at low risk (23.9 vs. 2.1 events/100 patient-years, respectively; log rank P < 0.001). Similar findings were observed in the external outcome cohort (31.6 vs. 4.6 events/100 patient-years, respectively; log rank P < 0.001). CONCLUSION: We propose a clinical score that predicts adverse outcomes in asymptomatic AS patients and potentially identifies high-risk patients who may benefit from early valve replacement.

Fibrinogen production is enhanced in an in-vitro model of non-alcoholic fatty liver disease: an isolated risk factor for cardiovascular events?

BACKGROUND: Cardiovascular disease (CVD) remains the major cause of excess mortality in patients with non-alcoholic fatty liver disease (NAFLD). The aim of this study was to investigate the individual contribution of NAFLD to CVD risk factors in the absence of pathogenic influences from other comorbidities often found in NAFLD patients, by using an established in-vitro model of hepatic steatosis. METHODS: Histopathological events in non-alcoholic fatty liver disease were recapitulated by focused metabolic nutrient overload of hepatoblastoma C3A cells, using oleate-treated-cells and untreated controls for comparison. Microarray and proteomic data from cell culture experiments were integrated into a custom-built systems biology database and proteogenomics analysis performed. Candidate genes with significant dysregulation and concomitant changes in protein abundance were identified and STRING association and enrichment analysis performed to identify putative pathogenic pathways. RESULTS: The search strategy yielded 3 candidate genes that were specifically and significantly up-regulated in nutrient-overloaded cells compared to untreated controls: fibrinogen alpha chain (2.2 fold), fibrinogen beta chain (2.3 fold) and fibrinogen gamma chain (2.1 fold) (all rank products pfp <0.05). Fibrinogen alpha and gamma chain also demonstrated significant concomitant increases in protein abundance (3.8-fold and 2.0-fold, respectively, p <0.05). CONCLUSIONS: In-vitro modelling of NAFLD and reactive oxygen species formation in nutrient overloaded C3A cells, in the absence of pathogenic influences from other comorbidities, suggests that NAFLD is an isolated determinant of CVD. Nutrient overload-induced up-regulation of all three fibrinogen component subunits of the coagulation cascade provides a possible mechanism to explain the excess CVD mortality observed in NAFLD patients.