Urinary proteomic biomarkers in coronary artery disease

Urinary proteomics is emerging as a powerful non-invasive tool for diagnosis and monitoring of variety of human diseases. We tested whether signatures of urinary polypeptides can contribute to the existing biomarkers for coronary artery disease (CAD). We examined a total of 359 urine samples from 88 patients with severe CAD and 282 controls. Spot urine was analyzed using capillary electrophoresis on-line coupled to ESI-TOF-MS enabling characterization of more than 1000 polypeptides per sample. In a first step a "training set" for biomarker definition was created. Multiple biomarker patterns clearly distinguished healthy controls from CAD patients, and we extracted 15 peptides that define a characteristic CAD signature panel. In a second step, the ability of the CAD-specific panel to predict the presence of CAD was evaluated in a blinded study using a "test set." The signature panel showed sensitivity of 98% (95% confidence interval, 88.7-99.6) and 83% specificity (95% confidence interval, 51.6-97.4). Furthermore the peptide pattern significantly changed toward the healthy signature correlating with the level of physical activity after therapeutic intervention. Our results show that urinary proteomics can identify CAD patients with high confidence and might also play a role in monitoring the effects of therapeutic interventions. The workflow is amenable to clinical routine testing suggesting that non-invasive proteomics analysis can become a valuable addition to other biomarkers used in cardiovascular risk assessment.

The role of monocytes in atherosclerotic coronary artery disease

Inflammation plays a key role in the pathogenesis of atherosclerosis. The more we discover about the molecular pathways involved in atherosclerosis, the more we perceive the importance of monocytes in this process. Circulating monocytes are components of innate immunity, and many pro-inflammatory cytokines and adhesion molecules facilitate their adhesion and migration to the vascular endothelial wall. In addition to the accumulation of lipids and formation of atherogenic 'foam' cells, monocytes may promote atherosclerotic plaque growth by production of inflammatory cytokines, matrix metalloproteinases, and reactive oxidative species. However, the contribution of monocytes to atherogenesis is not only limited to tissue destruction. Monocyte subsets are also involved in intraplaque angiogenesis and tissue reparative processes. The aim of this overview is to discuss the mechanisms of monocyte activation, the pivotal role and importance of activated monocytes in atherosclerotic coronary artery disease, their implication in the development of acute coronary events, and their potential in cardiovascular reparative processes such angiogenesis.

Monocytes in coronary artery disease and atherosclerosis:where are we now?

Despite improvements in interventional and pharmacological therapy of atherosclerotic disease, it is still the leading cause of death in the developed world. Hence, there is a need for further development of effective therapeutic approaches. This requires better understanding of the molecular mechanisms and pathophysiology of the disease. Atherosclerosis has long been identified as having an inflammatory component contributing to its pathogenesis, whereas the available therapy primarily targets hyperlipidemia and prevention of thrombosis. Notwithstanding a pleotropic anti-inflammatory effect to some therapies, such as acetyl salicylic acid and the statins, none of the currently approved medicines for management of either stable or complicated atherosclerosis has inflammation as a primary target. Monocytes, as representatives of the innate immune system, play a major role in the initiation, propagation, and progression of atherosclerosis from a stable to an unstable state. Experimental data support a role of monocytes in acute coronary syndromes and in outcome post-infarction; however, limited research has been done in humans. Analysis of expression of various cell surface receptors allows characterization of the different monocyte subsets phenotypically, whereas downstream assessment of inflammatory pathways provides an insight into their activity. In this review we discuss the functional role of monocytes and their different subpopulations in atherosclerosis, acute coronary syndromes, cardiac healing, and recovery with an aim of critical evaluation of potential future therapeutic targets in atherosclerosis and its complications. We will also discuss technical difficulties of delineating different monocyte subpopulations, understanding their differentiation potential and function.

Individual Proton Pump Inhibitors and Outcomes in Patients With Coronary Artery Disease on Dual Antiplatelet Therapy: A Systematic Review.

BACKGROUND: Observational studies evaluating the possible interaction between proton pump inhibitors (PPIs) and clopidogrel have shown mixed results. We conducted a systematic review comparing the safety of individual PPIs in patients with coronary artery disease taking clopidogrel. METHODS AND RESULTS: Studies performed from January 1995 to December 2013 were screened for inclusion. Data were extracted, and study quality was graded for 34 potential studies. For those studies in which follow-up period, outcomes, and multivariable adjustment were comparable, meta-analysis was performed.The adjusted odds or hazard ratios for the composite of cardiovascular or all-cause death, myocardial infarction, and stroke at 1 year were reported in 6 observational studies with data on individual PPIs. Random-effects meta-analyses of the 6 studies revealed an increased risk for adverse cardiovascular events for those taking pantoprazole (hazard ratio 1.38; 95% CI 1.12-1.70), lansoprazole (hazard ratio 1.29; 95% CI 1.09-1.52), or esomeprazole (hazard ratio 1.27; 95% CI 1.02-1.58) compared with patients on no PPI. This association was not significant for omeprazole (hazard ratio 1.16; 95% CI 0.93-1.44). Sensitivity analyses for the coronary artery disease population (acute coronary syndrome versus mixed) and exclusion of a single study due to heterogeneity of reported results did not have significant influence on the effect estimates for any PPIs. CONCLUSIONS: Several frequently used PPIs previously thought to be safe for concomitant use with clopidogrel were associated with greater risk of adverse cardiovascular events. Although the data are observational, they highlight the need for randomized controlled trials to evaluate the safety of concomitant PPI and clopidogrel use in patients with coronary artery disease.

Long-term outcomes following “presumed” total parathyroidectomy for secondary hyperparathyroidism of chronic kidney disease

Aim. The most efficacious surgical treatment for renal hyperparathyroidism is still subject of research. Considering its low incidence rate of long-term relapse, “presumed” total parathyroidectomy without autotrasplantation (TP) may be indicated for secondary hyperparathyroidism (2HPT) in patients with chronic kidney disease (CKD), not eligible for kidney transplantation. The aim of this study was to analyse the TP long-term results in 2HPT haemodialysis (HD) patients. Method. Between January 2004 and October 2009, 25 2HPT HD patients, not eligible for kidney transplantation, underwent TP of at least four parathyroid glands. Clinical status and intact parathyroid hormone (iPTH) serum levels were assessed intraoperatively and during a 36-month follow-up. Results. TP improved the typical clinical symptoms and a significant reduction of iPTH serum levels was achieved in each patient. Aparathyroidism was never observed; in case of severe postoperative hypocalcemia, hypocalcemic seizures were never reported and the long-term recurrence rate was 8%. Only one patient received a kidney transplantation. Postoperative cardiovascular events (hypertension, peripheral artery disease, arrhythmia, coronary or cerebrovascular disease) were observed in 32% of cases and mortality rate was 16%. Conclusions. Considering its low long-term relapse rate and the absence of postoperative aparathyroidism, TP may still be considered the treatment of choice in patients with aggressive forms of 2HPT or of advanced dialytic vintage, with no access to renal transplantation. In case of postoperative hypoparathyroidism, hypocalcaemia can be effectively managed by medical treatment.