Renin and aldosterone are not associated with vulnerable plaque characteristics in patients with carotid artery disease.

BACKGROUND: The renin-angiotensin-aldosterone system is increasingly being recognized to play an important role in the development and clinical course of cardiovascular diseases. Renin-angiotensin-aldosterone system activation is associated with clinical outcome in various populations of cardiovascular patients, such as patients with coronary artery, peripheral artery, and cerebrovascular disease. In this study, we investigated the associations between plasma renin and aldosterone concentrations and atherosclerotic plaque characteristics and secondary vascular events in patients undergoing carotid endarterectomy. METHODS AND RESULTS: Baseline plasma renin and aldosterone concentrations from 506 subjects undergoing carotid endarterectomy (mean age, 67 ± 9 years; 65% male) were correlated with histopathologic characteristics and inflammatory protein concentrations of the excised atherosclerotic plaque. Ordinal logistic regression (for ordinal outcome parameters) or linear regression (for linear outcome) analysis did not show a statistically significant relationship between plasma renin or aldosterone concentrations and plaque fat, thrombus, calcifications, collagen, smooth muscle cells, or macrophage content. Neither could any association be found with intraplaque inflammatory mediators. During a median follow-up of 3 years, 102 (20%) patients experienced a major secondary vascular event (composite of stroke, myocardial infarction, leg amputation, vascular death, or coronary revascularization or peripheral intervention). In multivariable Cox regression analysis, including both renin and aldosterone, baseline renin concentrations were associated with the occurrence of secondary events. CONCLUSIONS: In patients with established atherosclerotic disease undergoing carotid endarterectomy, plasma renin and aldosterone concentrations were not associated with atherosclerotic plaque characteristics. Plasma renin concentration was positively associated with the occurrence of major secondary vascular events.

Aldosterone, mortality, and acute ischaemic events in coronary artery disease patients outside the setting of acute myocardial infarction or heart failure.

BACKGROUND: Recent studies have demonstrated that aldosterone levels measured in patients with heart failure or acute myocardial infarction (MI) are associated with long-term mortality, but the association with aldosterone levels in patients with coronary artery disease (CAD) outside these specific settings remains unknown. In addition, no clear mechanism has been elucidated to explain these observations. The present study was designed to evaluate the relationship between the level of aldosterone and the risk of death and acute ischaemic events in CAD patients with a preserved left ventricular (LV) function and no acute MI. METHODS AND RESULTS: In 799 consecutive CAD patients referred for elective coronary angioplasty measurements were obtained before the procedure for: aldosterone (median = 25 pg/mL), brain natriuretic peptide (BNP) (median = 35 pg/mL), hsC-reactive protein (median = 4.17 mg/L), and left ventricular ejection fraction (mean = 58%). Patients with acute MI or coronary syndrome (ACS) who required urgent revascularization were not included in the study. The primary endpoint, cardiovascular death, occurred in 41 patients during a median follow-up period of 14.9 months. Secondary endpoints-total mortality, acute ischaemic events (acute MI or ischaemic stroke), and the composite of death and acute ischaemic events-were observed in 52, 54, and 94 patients, respectively. Plasma aldosterone was found to be related to BMI, hypertension and NYHA class, and inversely related to age, creatinine clearance, and use of beta-blockers. Multivariate Cox model analysis demonstrated that aldosterone was independently associated with cardiovascular mortality (P = 0.001), total mortality (P = 0.001), acute ischaemic events (P = 0.01), and the composite of death and acute ischaemic events (P = 0.004). Reclassification analysis, using integrated discrimination improvement (IDI) and net reclassification improvement (NRI), demonstrated incremental predictive value of aldosterone (P < 0.0001). CONCLUSION: Our results demonstrate that, in patients with CAD but without heart failure or acute MI, the level of aldosterone is strongly and independently associated with mortality and the occurrence of acute ischaemic events.

Measuring and targeting aldosterone and renin in atherosclerosis-a review of clinical data.

Our understanding of the development and progression of atherosclerosis has increased substantially over the past decades. A significant role for the renin-angiotensin-aldosterone system (RAAS) in this process has gained appreciation in recent years. Preclinical and clinical studies have associated components of the RAAS with various cardiovascular disease conditions. Classically known for its contribution to hypertension, dysregulation of the system is now also believed to promote vascular inflammation, fibrosis, remodeling, and endothelial dysfunction, all intimately related to atherosclerosis. The reduction in cardiovascular mortality and morbidity, as seen with the use of angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers, supports the concept that RAAS is involved in the pathogenesis of atherosclerotic disease. However, the underlying molecular mechanisms of the pathophysiology remain to be completely understood. Evidence points toward additional benefit from therapeutic approaches aiming at more complete inhibition of the system and the possible utility of renin or aldosterone in the prediction of cardiovascular outcome. This review will summarize the current knowledge from clinical studies regarding the presumptive role of renin and aldosterone in the prediction and management of patients with atherosclerosis. For this purpose, a literature search was performed, focusing on available clinical data regarding renin or aldosterone and cardiovascular outcome.

The relationship between fractional flow reserve, platelet reactivity and platelet leukocyte complexes in stable coronary artery disease.

BACKGROUND: The presence of stenoses that significantly impair blood flow and cause myocardial ischemia negatively affects prognosis of patients with stable coronary artery disease. Altered platelet reactivity has been associated with impaired prognosis of stable coronary artery disease. Platelets are activated and form complexes with leukocytes in response to microshear gradients caused by friction forces on the arterial wall or flow separation. We hypothesized that the presence of significantly flow-limiting stenoses is associated with altered platelet reactivity and formation of platelet-leukocyte complexes. METHODS: One hundred patients with stable angina were studied. Hemodynamic significance of all coronary stenoses was assessed with Fractional Flow Reserve (FFR). Patients were classified FFR-positive (at least one lesion with FFR≤0.75) or FFR-negative (all lesions FFR>0.80). Whole blood samples were stimulated with increasing concentrations of ADP, TRAP, CRP and Iloprost with substimulatory ADP. Expression of P-selectin as platelet activation marker and platelet-leukocyte complexes were measured by flowcytometry. Patients were stratified on clopidogrel use. FFR positive and negative patient groups were compared on platelet reactivity and platelet-leukocyte complexes. RESULTS: Platelet reactivity between FFR-positive patients and FFR-negative patients did not differ. A significantly lower percentage of circulating platelet-neutrophil complexes in FFR-positive patients and a similar non-significant decrease in percentage of circulating platelet-monocyte complexes in FFR-positive patients was observed. CONCLUSION: The presence of hemodynamically significant coronary stenoses does not alter platelet reactivity but is associated with reduced platelet-neutrophil complexes in peripheral blood of patients with stable coronary artery disease.

Aldosterone, atherosclerosis and vascular events in patients with stable coronary artery disease.

BACKGROUND AND AIMS: Plasma aldosterone has been associated with all-cause and cardiovascular mortality in high-risk cardiovascular populations, including patients with heart failure, myocardial infarction and high-risk coronary artery disease (CAD) patients. In the present study, we evaluated the association of plasma aldosterone levels with vascular events in a large prospective cohort of stable CAD patients recruited in an outpatient setting. Moreover, we investigated the relationship between aldosterone and atherosclerotic burden. METHODS AND RESULTS: Baseline plasma aldosterone levels were measured in 2699 subjects with CAD (mean age 60 ± 10 years, 82% male). During a median follow-up of 4.7 years, 308 (11%) patients died, of which 203 were from a vascular cause. Vascular endpoints of myocardial infarction, ischemic stroke or vascular death occurred in 355 (13%) patients. Multivariable Cox regression analysis was performed, adjusting for multiple confounders. Aldosterone (median 96 pg/mL, interquartile range 70-138 pg/mL, normal range 58-362 pg/mL) was independently associated with major vascular events (hazard ratio (HR) 1.56, 95% confidence interval (CI) 1.13-2.15) and vascular mortality (HR 1.95, 95% CI 1.27-3.00). By multivariable regression analysis, aldosterone was also associated with the presence of atherosclerosis in additional vascular territories (cerebrovascular disease and/or peripheral artery disease) (p=0.026). CONCLUSIONS: In patients with stable coronary artery disease, plasma aldosterone is independently associated with the risk of major vascular events and vascular mortality and with atherosclerotic burden.

Toll-Like Receptor induced CD11b and L-selectin response in patients with coronary artery disease.

Toll-Like Receptor (TLR) -2 and -4 expression and TLR-induced cytokine response of inflammatory cells are related to atherogenesis and atherosclerotic plaque progression. We examined whether immediate TLR induced changes in CD11b and L-selectin (CD62L) expression are able to discriminate the presence and severity of atherosclerotic disease by exploring single dose whole blood TLR stimulation and detailed dose-response curves. Blood samples were obtained from 125 coronary artery disease (CAD) patients and 28 controls. CD11b and L-selectin expression on CD14+ monocytes was measured after whole blood stimulation with multiple concentrations of the TLR4 ligand LPS (0.01-10 ng/ml) and the TLR2 ligand P3C (0.5-500 ng/ml). Subsequently, dose-response curves were created and the following parameters were calculated: hillslope, EC50, area under the curve (AUC) and delta. These parameters provide information about the maximum response following activation, as well as the minimum trigger required to induce activation and the intensity of the response. CAD patients showed a significantly higher L-selectin, but not CD11b response to TLR ligation than controls after single dose stimulations as well as significant differences in the hillslope and EC50 of the dose-response curves. Within the CAD patient group, dose-response curves of L-selectin showed significant differences in the presence of hypertension, dyslipidemia, coronary occlusion and degree of stenosis, whereas CD11b expression had the strongest discriminating power after single dose stimulation. In conclusion, single dose stimulations and dose-response curves of CD11b and L-selectin expression after TLR stimulation provide diverse but limited information about atherosclerotic disease severity in stable angina patients. However, both single dose stimulation and dose-response curves of LPS-induced L-selectin expression can discriminate between controls and CAD patients.

A prospective "oversizing" strategy of the Edwards SAPIEN bioprosthesis: results and impact on aortic regurgitation.

OBJECTIVE: Moderate to severe aortic regurgitation is occurring in 20% to 30% of cases after transcatheter aortic valve implantation. METHODS: The purpose of the study was to investigate the impact of a prospective policy of "oversizing" the Edwards SAPIEN bioprosthesis (Edwards Lifesciences LLC, Irvine, Calif) relative to the diameter of the aortic annulus on the rate and severity of aortic regurgitation in 28 consecutive patients initially considered eligible for transcatheter aortic valve implantation on the basis of angiography, multislice computed tomography, and transthoracic echocardiography. This policy included the systematic use of transesophageal echocardiography to exclude borderline patients and the modification of the procedure to use the larger device possible. The results were studied on an individual patient basis. RESULTS: Because 6 of 28 patients (21%) had an annulus diameter greater than 24 mm by transesophageal echocardiography, 22 patients underwent implantation of the Edwards SAPIEN prosthesis. In 6 of 22 patients, the procedure was adapted to follow our "oversizing" policy. As a result, the "prosthesis/annulus cover index" was 12.4% ± 4.3%. The procedure was successful in 21 of 22 patients (95%), and 18 patients were available for echocardiography at 1 month. Although a moderate to severe aortic regurgitation was observed pretreatment in 4 of 18 patients (22%), it was no longer the case at 1 month (0/18, 0%; P = .03). The improvement was secondary to a disappearance of the aortic regurgitation in all 7 patients with a significant aortic regurgitation at pretreatment, whereas the new aortic regurgitations appearing in 5 of the 11 patients with no aortic regurgitation at pretreatment were only mild aortic regurgitations. CONCLUSIONS: In patients with a successful implantation of an Edwards SAPIEN valve, a simple "oversizing" policy based on a systematic use of transesophageal echocardiography and modification of the procedure may prevent the occurrence of moderate and severe aortic regurgitations.

Circulating cells as predictors of secondary manifestations of cardiovascular disease: design of the CIRCULATING CELLS study.

Biomarkers for primary or secondary risk prediction of cardiovascular disease (CVD) are urgently needed to improve individual treatment and clinical trial design. The vast majority of biomarker discovery studies has concentrated on plasma/serum as an easily accessible source. Although numerous markers have been identified, their added predictive value on top of traditional risk factors has been limited, as the biological specimen does not specifically reflect expression profiles related with CVD progression and because the signal is often diluted by marker release from other organs. In contrast to serum markers, circulating cells serve as indicators of the actual disease state due to their active role in the pathogenesis of CVD and are responsible for the majority of secreted biomarkers. Therefore, the CIRCULATING CELLS study was initiated, focusing on the cellular effectors of atherosclerosis in the circulation. In total, 714 patients with coronary artery disease (CAD) symptoms were included. Blood cell fractions (monocytes, T-lymphocytes, platelets, granulocytes, PBMC) of all individual patients were isolated and stored for analysis. Concomitantly, extensive flow cytometric characterization of these populations was performed. From each patient, a detailed clinical profile together with extensive questionnaires about medical history and life style was obtained. Various high-throughput -omics approaches (protein, mRNA, miRNA) are currently being undertaken. Data will be integrated with advanced bioinformatics for discovery and validation of secondary risk markers for adverse events. Overall, the CIRCULATING CELLS study grants the interesting possibility that it will both identify novel biomarkers and provide useful insights into the pathophysiology of CAD in patients.