Excess Mortality for Abdominal Aortic Aneurysms and the Potential of Strict Implementation of Cardiovascular Risk Management: A Multifaceted Study Integrating Meta-Analysis, National Registry, and PHAST and TEDY Trial Data.

OBJECTIVE: Previous studies imply a profound residual mortality risk following successful abdominal aorta aneurysm (AAA) repair. This excess mortality is generally attributed to increased cardiovascular risk. The aim of this study was (1) to quantify the excess residual mortality for patients with AAA, (2) to evaluate the cross sectional level of cardiovascular risk management, and (3) to estimate the potential of optimised cardiovascular risk management to reduce the excess mortality in these patients. METHODS: Excess mortality was estimated through a systematic review and meta-analysis, and through data from the Swedish National Health Registry. Cardiovascular risk profiles were individually assessed during eligibility screening of patients with AAA for two multicentre pharmaceutical AAA stabilisation trials. The potential of full implementation of cardiovascular risk management was estimated through the validated Second Manifestations of ARTerial disease (SMART) risk scores algorithm. RESULTS: The meta-analysis showed a similarly impaired survival for patients who received early repair (small AAA) or regular repair (≥ 55 mm), and a further impaired survival for patients under surveillance for a small AAA. Excess mortality was further quantified using Swedish population data. The data revealed a more than quadrupled and doubled five year mortality rate for women and men who had their AAA repaired, respectively. Evaluation of the level of risk management of 358 patients under surveillance in 16 Dutch hospitals showed that the majority of patients with AAA did not meet therapeutic targets set for risk management in high risk populations, and indicated a more pronounced prevention gap in women. Application of the SMART risk score algorithm predicted that optimal implementation of risk management guidelines would reduce the 10 year risk of major adverse cardiovascular events from 43% to 14%. CONCLUSION: Independent of the rupture risk, AAA is associated with a worryingly compromised life expectancy with a particularly poor prognosis for women. Optimal implementation of cardiovascular risk prevention guidelines is predicted to profoundly reduce cardiovascular risk.

Correlation of the tumour-stroma ratio with diffusion weighted MRI in rectal cancer.

OBJECTIVE: This study evaluated the correlation between intratumoural stroma proportion, expressed as tumour-stroma ratio (TSR), and apparent diffusion coefficient (ADC) values in patients with rectal cancer. METHODS: This multicentre retrospective study included all consecutive patients with rectal cancer, diagnostically confirmed by biopsy and MRI. The training cohort (LUMC, Netherlands) included 33 patients and the validation cohort (VHIO, Spain) 69 patients. Two observers measured the mean and minimum ADCs based on single-slice and whole-volume segmentations. The TSR was determined on diagnostic haematoxylin & eosin stained slides of rectal tumour biopsies. The correlation between TSR and ADC was assessed by Spearman correlation (rs). RESULTS: The ADC values between stroma-low and stroma-high tumours were not significantly different. Intra-class correlation (ICC) demonstrated a good level of agreement for the ADC measurements, ranging from 0.84-0.86 for single slice and 0.86-0.90 for the whole-volume protocol. No correlation was observed between the TSR and ADC values, with ADCmeanrs= -0.162 (p= 0.38) and ADCminrs= 0.041 (p= 0.82) for the single-slice and rs= -0.108 (p= 0.55) and rs= 0.019 (p= 0.92) for the whole-volume measurements in the training cohort, respectively. Results from the validation cohort were consistent; ADCmeanrs= -0.022 (p= 0.86) and ADCminrs = 0.049 (p= 0.69) for the single-slice and rs= -0.064 (p= 0.59) and rs= -0.063 (p= 0.61) for the whole-volume measurements. CONCLUSIONS: Reproducibility of ADC values is good. Despite positive reports on the correlation between TSR and ADC values in other tumours, this could not be confirmed for rectal cancer.

Hypomorphic MKS1 mutation in a Pakistani family with mild Joubert syndrome and atypical features: Expanding the phenotypic spectrum of MKS1-related ciliopathies.

Postaxial polydactyly (PAP) is one of the most common congenital malformations observed in the general population. However, it can also occur as part of a syndrome. Unbiased genetic screening techniques such as exome sequencing are highly appropriate methods to provide a molecular diagnosis in patients with polydactyly due to the large number of mutated genes associated with it. The present study describes a consanguineous family of Pakistani origin with PAP, speech impairment, hearing impairment of variable degree, and proportionate short stature with no prominent intellectual disability or ophthalmological abnormalities. One affected individual of the family was subjected to exome sequencing which resulted in the identification of four homozygous variants including an in-frame deletion (c.1115_1117delCCT; p.(Ser372del) in MKS1, which was later shown to be the only variant segregating with the phenotype. In silico predictions supported the potential pathogenicity of the identified mutation. Additional clinical tests and MRI features of a patient in the family showed a molar tooth sign, which is a hallmark of Joubert syndrome. In conclusion, we have described a pathogenic variant in the MKS1 resulting in a mild Joubert syndrome phenotype, which broadens the spectrum of mutations in the MKS1. © 2016 Wiley Periodicals, Inc.

Prognostic and predictive biomarkers of abdominal aortic aneurysm growth rate.

OBJECTIVES: To test the utility of clinical and circulating biomarkers to predict abdominal aortic aneurysm (AAA) growth rate and response to doxycycline therapy. METHODS: Plasma samples were obtained in the Pharmaceutical Aneurysm Stabilization Trial that tested the effect of doxycycline (n = 44) vs. placebo (n = 49) in patients with a 35-50 mm AAA. Approximately 200 biomarkers were evaluated in a candidate approach that included markers of matrix turnover and cathepsin S activity and a broad-based approach of predominantly inflammation-related and clinical biomarkers. RESULTS: In a recursive partitioning based analysis, total cholesterol, baseline AAA size, and apolipoprotein B were prognostic of AAA growth in the placebo group whereas elastin and biglycan degradation products were predictive of AAA growth with doxycycline treatment. Univariate analysis of these biomarkers showed that baseline total cholesterol (r = 0.38, unadjusted P = 0.011), apolipoprotein B (r = 0.41, unadjusted P = 0.005), and baseline AAA size (r = 0.35, unadjusted P = 0.013) correlated with AAA growth in the placebo but not the doxycycline group. Elastin fragments were associated with 18 month AAA growth (r = 0.33, unadjusted P = 0.031) in the doxycycline group. LIMITATIONS: Limitations of this study include small sample size, a retrospective growth analysis, and translatability of the method used to measure the analytes. CONCLUSIONS: This study implies that total cholesterol, baseline AAA size, and apolipoprotein B are predictors of AAA growth. Levels of elastin and biglycan fragments are predictive of doxycycline effects on AAA growth and provide a clue towards this unexpected negative effect.

ACE inhibitors potently reduce vascular inflammation, results of an open proof-of-concept study in the abdominal aortic aneurysm.

BACKGROUND: Independent of their blood pressure lowering effect, ACE inhibitors are thought to reduce vascular inflammation. The clinical relevance of this effect is unclear with the current knowledge. Abdominal aortic aneurysms (AAA) are characterized by a broad, non-specific inflammatory response, and thus provide a clinical platform to evaluate the anti-inflammatory potential of ACE inhibitors. METHODS AND RESULTS: Eleven patients scheduled for open AAA repair received ramipril (5 mg/day) during 2-4 weeks preceding surgery. Aortic wall samples were collected during surgery, and compared to matched samples obtained from a biobank. An anti-inflammatory potential was evaluated in a comprehensive analysis that included immunohistochemistry, mRNA and protein analysis. A putative effect of ACE inhibitors on AAA growth was tested separately by comparing 18-month growth rate of patients on ACE inhibitors (n = 82) and those not taking ACE inhibitors (n = 204). Ramipril reduces mRNA expression of multiple pro-inflammatory cytokines such as IL-1ß, IL-6, IL-8, TNF -α, Interferon-[Formula: see text], and MCP-1, as well as aortic wall IL-8 and MCP-1 (P = 0.017 and 0.008, respectively) protein content. The is followed by clear effects on cell activation that included a shift towards anti-inflammatory macrophage (M2) subtype. Evaluation of data from the PHAST cohort did not indicate an effect of ACE inhibitors on 18-month aneurysm progression (mean difference at 18 months: -0.24 mm (95% CI: -0.90-0.45, P = NS). CONCLUSIONS: ACE inhibition quenches multiple aspects of vascular inflammation in AAA. However, this does not translate into reduced aneurysm growth. TRIAL REGISTRATION: Nederlands Trial Register 1345.

A clinical evaluation of statin pleiotropy: statins selectively and dose-dependently reduce vascular inflammation.

Statins are thought to reduce vascular inflammation through lipid independent mechanisms. Evaluation of such an effect in atherosclerotic disease is complicated by simultaneous effects on lipid metabolism. Abdominal aortic aneurysms (AAA) are part of the atherosclerotic spectrum of diseases. Unlike atherosclerotic occlusive disease, AAA is not lipid driven, thus allowing direct evaluation of putative anti-inflammatory effects. The anti-inflammatory potency of increasing doses (0, 20 or 40 mg/day) simvastatin or atorvastatin was evaluated in 63 patients that were at least 6 weeks on statin therapy and who underwent open AAA repair. A comprehensive analysis using immunohistochemistry, mRNA and protein analyses was applied on aortic wall samples collected during surgery. The effect of statins on AAA growth was analyzed in a separate prospective study in incorporating 142 patients. Both statins equally effectively and dose-dependently reduced aortic wall expression of NFκB regulated mediators (i.e. IL-6 (P<0.001) and MCP-1 (P<0.001)); shifted macrophage polarization towards a M2 phenotype (P<0.0003); selectively reduced macrophage-related markers such as cathepsin K and S (P<0.009 and 0.0027 respectively), and ALOX5 (P<0.0009), and reduced vascular wall NFκB activity (40 mg/day group, P<0.016). No effect was found on other cell types. Evaluation of the clinical efficacy of statins to reduce AAA progression did not indicate an effect of statins on aneurysm growth (P<0.337). Hence, in the context of AAA the clinical relevance of statins pleiotropy appears minimal.

Doxycycline for stabilization of abdominal aortic aneurysms: a randomized trial.

BACKGROUND: Doxycycline inhibits formation and progression of abdominal aortic aneurysms (AAAs) in preclinical models of the disease, but it is unclear whether and how this observation translates to humans. OBJECTIVE: To test whether doxycycline inhibits AAA progression in humans. DESIGN: Randomized, placebo-controlled, double-blind trial. (Dutch Trial Registry: NTR 1345) SETTING: 14 Dutch hospitals. PATIENTS: 286 patients with small AAAs between October 2008 and June 2011. INTERVENTION: Daily dose of 100 mg of doxycycline (n = 144) or placebo (n = 142) for 18 months. MEASUREMENTS: The primary outcome measure was aneurysm growth at 18 months, as estimated by repeated single-observer ultrasonography. Secondary outcomes included growth at 6 and 12 months and the need for elective surgery. RESULTS: Mean aneurysm diameter (approximately 43 mm) and other baseline characteristics were similar in both groups. Doxycycline treatment was associated with increased aneurysm growth (4.1 mm in the doxycycline group vs. 3.3 mm in the placebo group at 18 months; difference, 0.8 mm [95% CI, 0.1 to 1.4 mm]; P = 0.016 mm). Twenty-one patients receiving doxycycline and 22 patients receiving placebo had elective surgical repair (Kaplan­Meier estimates were 16.1% for those receiving doxycycline and 16.5% for those receiving placebo; difference, -0.4% [CI, -9.3% to 8.5%]; P = 0.83). Time to repair was similar in the groups (P = 0.92). LIMITATIONS: This study focuses on patients with small AAAs. As such, whether the data can be extrapolated to larger AAAs (>55 mm) is unclear. The high number of elective repairs (n = 43) was unanticipated. Moreover, the study did not follow patients who withdrew because of an adverse effect. CONCLUSION: This trial found that 18 months of doxycycline therapy did not reduce aneurysm growth and did not influence the need for AAA repair or time to repair. PRIMARY FUNDING SOURCE: The Netherlands Organisation for Health Research and Development, and the NutsOhra Fund.

Activator protein-1 (AP-1) signalling in human atherosclerosis: results of a systematic evaluation and intervention study.

Animal studies implicate the AP-1 (activator protein-1) pro-inflammatory pathway as a promising target in the treatment of atherosclerotic disease. It is, however, unclear whether these observations apply to human atherosclerosis. Therefore we evaluated the profile of AP-1 activation through histological analysis and tested the potential benefit of AP-1 inhibition in a clinical trial. AP-1 activation was quantified by phospho-c-Jun nuclear translocation (immunohistochemistry) on a biobank of aortic wall samples from organ donors. The effect of AP-1 inhibition on vascular parameters was tested through a double blind placebo-controlled cross-over study of 28 days doxycycline or placebo in patients with symptomatic peripheral artery disease. Vascular function was assessed by brachial dilation as well as by plasma samples analysed for hs-CRP (high-sensitivity C-reactive protein), IL-6 (interleukin-6), IL-8, ICAM-1 (intercellular adhesion molecule-1), vWF (von Willebrand factor), MCP-1 (monocyte chemoattractant protein-1), PAI-1 (plasminogen activator inhibitor-1) and fibrinogen. Histological evaluation of human atherosclerosis showed minimal AP-1 activation in non-diseased arterial wall (i.e. vessel wall without any signs of atherosclerotic disease). A gradual increase of AP-1 activation was found in non-progressive and progressive phases of atherosclerosis respectively (P<0.044). No significant difference was found between progressive and vulnerable lesions. The expression of phospho-c-Jun diminished as the lesion stabilized (P<0.016) and does not significantly differ from the normal aortic wall (P<0.33). Evaluation of the doxycycline intervention only revealed a borderline-significant reduction of circulating hs-CRP levels (-0.51 µg/ml, P=0.05) and did not affect any of the other markers of systemic inflammation and vascular function. Our studies do not characterize AP-1 as a therapeutic target for progressive human atherosclerotic disease.