Abstract There is compelling experimental and clinical evidence suggesting a crucial role for inflammation in the initiation and also the progression of atherosclerosis. Numerous biomarkers involved ...at various levels of the inflammation cascade have been shown to be associated with adverse cardiovascular outcomes. Yet, to date, it is not clear whether inflammation simply accompanies the atherosclerotic process or represents a major driver. Among all blood biomarkers, C-reactive protein (CRP), the classical acute phase reactant that can be measured with high-sensitivity (hs) assays seems to be the most promising candidate. It has already found its way into the guidelines in primary prevention. Hs-CRP can also be used to identify a high-risk group for recurrent events in patients with manifest atherosclerosis. Several post hoc analyses of large-scale randomized clinical trials testing various statins have indicated that, besides low density lipoprotein (LDL) cholesterol, hs-CRP levels might also further aid in tailoring statin treatment. The large JUPITER trial has prospectively confirmed these findings in primary prevention in patients with elevated hs-CRP but normal LDL cholesterol levels. Still, statin therapy is not a specific anti-inflammatory regime acting on the inflammation cascade. Thus, to directly test the inflammation hypothesis, a novel, more proximally located cytokine-based approach is needed. Canakinumab, a fully human monoclonal antibody against interleukin-1β, might represent a promising compound in this regard and provide a proof of concept. If successful, this may become a novel strategy to treat high-risk patients with stable atherosclerotic disease to prevent recurrent events on top of standard medical care.
Basic research over the last two decades has identified a large number of molecules pertinent to the atherosclerotic process, which have clearly improved our understanding of the underlying ...pathology. It is now well established that inflammation represents a major feature which is present in the vessel wall throughout all stages of the disease until the final pathophysiologic steps, representing plaque destabilization and eventually plaque rupture. Several cells typical for the atherosclerotic plaque, like monocyte-derived macrophages and T-lymphocytes are able to produce and secrete such mediator molecules, like cytokines, chemokines, growth-factors, enzymes, and disintegrins, which lead to activation of endothelial cells, proliferation of smooth muscle cells, lesion progression, and finally to the weakening of a vulnerable plaque by matrix degradation of its fibrous cap. Today, many of these molecules involved can be measured systemically by sensitive assays, and elevated concentrations in the circulation have been shown to be associated with future cardiovascular events. Determination of several of these molecules carries important prognostic information, independent of traditional risk factors, and may turn out to be useful in improving risk stratification. However, for most of these biomarkers the clinical utility has not yet been established.
The notion that fibrinogen is strongly, consistently, and independently related to cardiovascular risk has been widely accepted. The evidence is based on numerous prospective epidemiological studies ...and clinical observations. In meta-analysis, an association between even modest increases (10%) in fibrinogen and future coronary heart disease (CHD) endpoints has been found with an odds ratio for CHD of 1.8; 95% CI, 1.6 to 2.0, if the top tertile of the fibrinogen distribution was compared to the bottom tertile; but fibrinogen levels were also associated with unstable and stable coronary artery disease, and coronary complications after interventions. Similar results have been obtained for incident stroke, progression of peripheral arterial disease, and finally for total mortality. The reasons however, why fibrinogen is elevated in cardiovascular disease and in atherosclerosis in general, are only incompletely understood; but all cells involved in the atherogenetic process are able to produce cytokines which induce an acute phase reaction, and thus increase fibrinogen plasma levels. The potential pathophysiological mechanisms by which elevated fibrinogen levels mediate cardiovascular risk are manyfold: It forms the substrate for thrombin and represents the final step in the coagulation cascade; it is essential for platelet aggregation; it modulates endothelial function; it promotes smooth muscle cell proliferation and migration; it interacts with the binding of plasmin with its receptor, and finally it represents a major acute phase protein. Whether or not fibrinogen is causally involved in atherothrombogenesis still remains to be determined, and even though other unsolved issues await conclusive answers, fibrinogen has emerged as an important additional marker of cardiovascular risk.
Cystatin C and Cardiovascular Risk Taglieri, Nevio; Koenig, Wolfgang; Kaski, Juan Carlos
Clinical chemistry (Baltimore, Md.),
11/2009, Volume:
55, Issue:
11
Journal Article
Peer reviewed
Open access
Patients with chronic kidney disease (CKD) are at high risk for developing cardiovascular disease (CVD) and cardiovascular events. Cystatin C, a protease inhibitor synthesized in all nucleated cells, ...has been proposed as a replacement for serum creatinine for the assessment of renal function, particularly to detect small reductions in glomerular filtration rate.
This report presents a review of the role of cystatin C as a predictor of cardiovascular risk.
Patients with higher circulating cystatin C concentrations appear to have an increased cardiovascular risk profile, i.e., they are older and have a higher prevalence of systemic hypertension, dyslipidemia, documented CVD, increased body mass index, and increased concentrations of C-reactive protein. Prospective studies have shown, in various clinical scenarios, that patients with increased cystatin C are at a higher risk of developing both CVD and CKD. Importantly, cystatin C appears to be a useful marker for identifying individuals at a higher risk for cardiovascular events among patients belonging to a relatively low-risk category as assessed by both creatinine and estimated glomerular filtration rate values. Of interest, elastolytic proteases and their inhibitors, in particular cystatin C, have been shown to be directly involved in the atherosclerotic process. Increased concentrations of cystatin C appear to be indicative of preclinical kidney disease associated with adverse outcomes. Clinical studies involving direct glomerular filtration rate measurements are required to ascertain both the true role of this promising marker in renal disease and whether atherogenic factors like inflammation can account for increases in cystatin C concentrations, thus explaining its predictive value in CVD.
Psoriasis increases the risk of cardiovascular (CV) disease. Secukinumab, a fully human monoclonal antibody against IL-17A, shows significant efficacy in psoriasis, but effects on CV markers are ...unknown. CARIMA (Evaluation of Cardiovascular Risk Markers in Psoriasis Patients Treated with Secukinumab) was a 52-week, randomized, double-blind, placebo-controlled, exploratory trial in patients with moderate to severe plaque psoriasis without clinical CV disease. Patients were randomly assigned to receive 300 mg or 150 mg secukinumab until week 52 or to receive placebo until week 12 and then 300 mg or 150 mg secukinumab until week 52. The primary outcome was endothelial function measured by flow-mediated dilation (FMD). Baseline FMD was significantly lower in psoriasis patients than healthy volunteers (4.4 ± 3.9% vs. 6.1 ± 3.3%, P = 0.01). At week 12, baseline-adjusted mean FMD was numerically higher in patients receiving secukinumab versus those receiving placebo, but this difference (300-mg group, +1.2%; 150-mg group, +0.76%; P = 0.223 and P = 0.403 by analysis of covariance) did not reach significance. At week 52, FMD increased across groups. FMD was significantly higher than baseline in patients receiving the label dose of 300 mg secukinumab for 52 weeks (+2.1%, 95% confidence interval = 0.8–3.3; P = 0.0022). Other relevant CV markers were unchanged. CARIMA indicates that secukinumab might have a beneficial effect on CV risk by improving the endothelial function of patients with plaque psoriasis.
Summary Background Statins lower high-sensitivity C-reactive protein (hsCRP) and cholesterol concentrations, and hypothesis generating analyses suggest that clinical outcomes improve in patients ...given statins who achieve hsCRP concentrations less than 2 mg/L in addition to LDL cholesterol less than 1·8 mmol/L (<70 mg/dL). However, the benefit of lowering both LDL cholesterol and hsCRP after the start of statin therapy is controversial. We prospectively tested this hypothesis. Methods In an analysis of 15 548 initially healthy men and women participating in the JUPITER trial (87% of full cohort), we prospectively assessed the effects of rosuvastatin 20 mg versus placebo on rates of non-fatal myocardial infarction, non-fatal stroke, admission for unstable angina, arterial revascularisation, or cardiovascular death (prespecified endpoints) during a maximum follow-up of 5 years (median 1·9 years), according to on-treatment concentrations of LDL cholesterol (≥1·8 mmol/L or <1·8 mmol/L) and hsCRP (≥2 mg/L or <2 mg/L). We included all events occurring after randomisation. This trial is registered with ClinicalTrials.gov , number NCT00239681. Findings Compared with placebo, participants allocated to rosuvastatin who achieved LDL cholesterol less than 1·8 mmol/L had a 55% reduction in vascular events (event rate 1·11 vs 0·51 per 100 person-years; hazard ratio HR 0·45, 95% CI 0·34–0·60, p<0·0001), and those achieving hsCRP less than 2 mg/L a 62% reduction (event rate 0·42 per 100 person-years; HR 0·38, 95% CI 0·26–0·56, p<0·0001). Although LDL cholesterol and hsCRP reductions were only weakly correlated in individual patients ( r values <0·15), we recorded a 65% reduction in vascular events in participants allocated to rosuvastatin who achieved both LDL cholesterol less than 1·8 mmol/L and hsCRP less than 2 mg/L (event rate 0·38 per 100 person-years; adjusted HR 0·35, 95% CI 0·23–0·54), versus a 33% reduction in those who achieved one or neither target (event rate 0·74 per 100 person-years; HR 0·67, 95% CI 0·52–0·87) (p across treatment groups <0·0001). In participants who achieved LDL cholesterol less than 1·8 mmol/L and hsCRP less than 1 mg/L, we noted a 79% reduction (event rate 0·24 per 100 person-years; HR 0·21, 95% CI 0·09–0·52). Achieved hsCRP concentrations were predictive of event rates irrespective of the lipid endpoint used, including the apolipoprotein B to apolipoprotein AI ratio. Interpretation For people choosing to start pharmacological prophylaxis, reduction in both LDL cholesterol and hsCRP are indicators of successful treatment with rosuvastatin. Funding AstraZeneca.
Elevated lipoprotein-associated phospholipase A2 activity promotes the development of vulnerable atherosclerotic plaques, and elevated plasma levels of this enzyme are associated with an increased ...risk of coronary events. Darapladib is a selective oral inhibitor of lipoprotein-associated phospholipase A2.
In a double-blind trial, we randomly assigned 15,828 patients with stable coronary heart disease to receive either once-daily darapladib (at a dose of 160 mg) or placebo. The primary end point was a composite of cardiovascular death, myocardial infarction, or stroke. Secondary end points included the components of the primary end point as well as major coronary events (death from coronary heart disease, myocardial infarction, or urgent coronary revascularization for myocardial ischemia) and total coronary events (death from coronary heart disease, myocardial infarction, hospitalization for unstable angina, or any coronary revascularization).
During a median follow-up period of 3.7 years, the primary end point occurred in 769 of 7924 patients (9.7%) in the darapladib group and 819 of 7904 patients (10.4%) in the placebo group (hazard ratio in the darapladib group, 0.94; 95% confidence interval CI, 0.85 to 1.03; P=0.20). There were also no significant between-group differences in the rates of the individual components of the primary end point or in all-cause mortality. Darapladib, as compared with placebo, reduced the rate of major coronary events (9.3% vs. 10.3%; hazard ratio, 0.90; 95% CI, 0.82 to 1.00; P=0.045) and total coronary events (14.6% vs. 16.1%; hazard ratio, 0.91; 95% CI, 0.84 to 0.98; P=0.02).
In patients with stable coronary heart disease, darapladib did not significantly reduce the risk of the primary composite end point of cardiovascular death, myocardial infarction, or stroke. (Funded by GlaxoSmithKline; STABILITY ClinicalTrials.gov number, NCT00799903.).
Circulating biomarkers are associated with the development of coronary heart disease (CHD) and its complications by reflecting pathophysiological pathways and/or organ dysfunction. We explored the ...associations between 157 cardiovascular (CV) and inflammatory biomarkers and CV death using proximity extension assays (PEA) in patients with chronic CHD.
The derivation cohort consisted of 605 cases with CV death and 2,788 randomly selected non-cases during 3-5 years follow-up included in the STabilization of Atherosclerotic plaque By Initiation of darapLadIb TherapY (STABILITY) trial between 2008 and 2010. The replication cohort consisted of 245 cases and 1,042 non-cases during 12 years follow-up included in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study between 1997 and 2000. Biomarker levels were measured with conventional immunoassays and/or with the OLINK PEA panels CVD I and Inflammation. Associations with CV death were evaluated by Random Survival Forest (RF) and Cox regression analyses. Both cohorts had the same median age (65 years) and 20% smokers, while there were slight differences in male sex (82% and 76%), hypertension (70% and 78%), and diabetes (39% and 30%) in the respective STABILITY and LURIC cohorts. The analyses identified 18 biomarkers with confirmed independent association with CV death by Boruta analyses and statistical significance (all p < 0.0001) by Cox regression when adjusted for clinical characteristics in both cohorts. Most prognostic information was carried by N-terminal prohormone of brain natriuretic peptide (NTproBNP), hazard ratio (HR for 1 standard deviation SD increase of the log scale of the distribution of the biomarker in the replication cohort) 2.079 (95% confidence interval CI 1.799-2.402), and high-sensitivity troponin T (cTnT-hs) HR 1.715 (95% CI 1.491-1.973). The other proteins with independent associations were growth differentiation factor 15 (GDF-15) HR 1.728 (95% CI 1.527-1.955), transmembrane immunoglobulin and mucin domain protein (TIM-1) HR 1.555 (95% CI 1.362-1.775), renin HR 1.501 (95% CI 1.305-1.727), osteoprotegerin (OPG) HR 1.488 (95% CI 1.297-1.708), soluble suppression of tumorigenesis 2 protein (sST2) HR 1.478 (95% CI 1.307-1.672), cystatin-C (Cys-C) HR 1.370 (95% CI 1.243-1.510), tumor necrosis factor-related apoptosis-inducing ligand receptor 2 (TRAIL-R2) HR 1.205 (95% CI 1.131-1.285), carbohydrate antigen 125 (CA-125) HR 1.347 (95% CI 1.226-1.479), brain natriuretic peptide (BNP) HR 1.399 (95% CI 1.255-1.561), interleukin 6 (IL-6) HR 1.478 (95% CI 1.316-1.659), hepatocyte growth factor (HGF) HR 1.259 (95% CI 1.134-1.396), spondin-1 HR 1.295 (95% CI 1.156-1.450), fibroblast growth factor 23 (FGF-23) HR 1.349 (95% CI 1.237-1.472), chitinase-3 like protein 1 (CHI3L1) HR 1.284 (95% CI 1.129-1.461), tumor necrosis factor receptor 1 (TNF-R1) HR 1.486 (95% CI 1.307-1.689), and adrenomedullin (AM) HR 1.750 (95% CI 1.490-2.056). The study is limited by the differences in design, size, and length of follow-up of the 2 studies and the lack of results from coronary angiograms and follow-up of nonfatal events.
Profiles of levels of multiple plasma proteins might be useful for the identification of different pathophysiological pathways associated with an increased risk of CV death in patients with chronic CHD.
ClinicalTrials.gov NCT00799903.
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