Therapy For Atherosclerotic Disease Research Articles

Anti-Inflammatory Drugs in Patients with Ischemic Heart Disease.

Inflammation has long been known to play a role in atherogenesis and plaque complication, as well as in some drugs used in therapy for atherosclerotic disease, such as statins, acetylsalicylic acid, and modulators of the renin-angiotensin system, which also have anti-inflammatory effects. Furthermore, inflammatory biomarkers have been demonstrated to predict the incidence of cardiovascular events. In spite of this, and with the exception of acetylsalicylic acid, non-steroidal anti-inflammatory drugs are unable to decrease the incidence of cardiovascular events and may even be harmful to the cardiovascular system. In recent years, other anti-inflammatory drugs, such as canakinumab and colchicine, have shown an ability to reduce the incidence of cardiovascular events in secondary prevention. Colchicine could be a potential candidate for use in clinical practice given its safety and low price, although the results of temporary studies require confirmation in large randomized clinical trials. In this paper, we discuss the evidence linking inflammation with atherosclerosis and review the results from various clinical trials performed with anti-inflammatory drugs. We also discuss the potential use of these drugs in routine clinical settings.

Galectin-9: A Suppressor of Atherosclerosis?

It is no longer controversial that atherosclerosis is a vascular wall chronic inflammatory disease mediated by cells of innate and adaptive immunity. Galectin-9 (Gal-9) seems to be a crucial regulator of T-cell immunity by inducing apoptosis in specific T-cell subpopulations associated with autoimmunity and inflammatory disease. Accumulating evidence showed that galectin-9 signaling via T-cell immunoglobulin mucin 3 (TIM-3) is concerned with different regulatory functions in autoimmunity, including direct depletion of pro-inflammatory T-cells, expanding the number of regulatory T cells, altering macrophages to an anti-inflammatory state and the induction of repressive myeloid-derived suppressor cells. In addition, anti-Tim-3-Ab administration increased atherosclerotic plaque formation by blocking Tim-3–galectin-9 interaction. Hence, we hypothesize that galectin-9 may be a novel therapy for atherosclerotic disease. Further researches are needed to investigate the precise effect of galectin-9 in the process of atherosclerosis.

Abstract 279: Eligibility and Cost Estimates for Anti-inflammatory Therapy for Atherosclerotic Disease: Implications of the CANTOS Trial for the US Adult Population

Background: The CANTOS trial supports the use of canakinumab to target residual inflammatory risk for secondary cardiovascular prevention. To better understand the potential impact of these findings, we use nationally representative data to estimate the number of US adults who qualify for therapy with canakinumab and the projected cost burden on the US health system based on its current pricing. Methods: In National Health and Nutrition Examination Survey (NHANES) 2005-10, we identified all adults with a prior MI and elevated hsCRP ≥2 mg/L, and fulfilling all eligibility criteria for CANTOS. Further, we also assessed the number of individuals not receiving statins who might be potentially eligible. Statin non-users were considered potentially eligible if they would have had hsCRP ≥2mg/L even after assuming a maximal hsCRP lowering of 50% with statin therapy in all patients. We used survey methods to obtain weighted estimates for the eligible adults in the US population. Annual costs were estimated at $60000/year for canakinumab therapy. Results: Of the 17689 adults sampled in NHANES during 2005-2010, 16608 (94%) had hsCRP testing. Of these, 684 (3.0%), representing an estimated 6.8 million (95% CI 5.7-7.8 million) US adults, had a history of MI (Figure 1). Among those with a prior MI, 42% did not report using a statin. Among statin-users, 44% had an hsCRP<2 mg/L (32% overall). After applying CANTOS inclusion and exclusion criteria, 21% (unweighted n=128) of adults with a prior MI on statin therapy, representing 1.4 million (95% CI 1.1-1.8 million) US adults, were canakinumab-eligible. A further 9% of AMI patients would be eligible after accounting for statin-associated hsCRP lowering in statin non-users (Figure 1). Cumulatively, 31% (unweighted n=207) of adults with a prior MI, representing 2.1 million (95% CI 1.6-2.5 million) US adults would potentially qualify for canakinumab therapy. The treatment of 5% to 100% of all CANTOS-eligible US adults would cost payers $6-$124 billion/year. Conclusion: Nearly 1 in 3 or 2.1 million US adults with a prior MI are potential treatment candidates. Assuming current canakinumab prices would incur an annual financial burden of up to 124 billion dollars in the United States. Further work is needed to define the population that achieves favorable value with treatment.

The Role of Inflammatory Biomarkers in the Detection and Therapy of Atherosclerotic Disease.

The estimation of risk for atherosclerotic cardiovascular (CV) events based only on the presence of classical risk factors is often insufficient. Therefore, efforts have been made to find markers that indicate the presence of preclinical or clinical disease. Inflammation mediates all stages of the disease, from initiation to the thrombotic complications of atherosclerosis. Raised levels of several circulating markers, particularly inflammatory mediators, have been reported in subjects with atherosclerosis. Increased risk for CV events is associated with increased levels of cytokines, celladhesion molecules, P-selectin and E-selectin, and acute phase reactants, such a highsensitivity C-reactive protein and serum amyloid-A. Elevation of some of these markers predicts the outcomes of patients with acute coronary syndromes. However, because of their non-specificity, these biomarkers represent only a moderate added predicting value after considering conventional CV risk factors. Consequently, recent research has focused on the detection of vulnerable plaque, using vascular bed-specific biomarkers that can help identify individuals at highest risk and help guide how to intervene to prevent CV events. Considerable progress in the understanding of the role of the inflammation in atherogenesis has opened new possibilities for the management of atherosclerosis. Recently new drugs mediating the direct inhibition of circulating markers of inflammation were developed. These drugs could provide a novel therapeutic approach and further enhance the understanding of the role of inflammation in atherosclerosis.

Effectiveness of antiplatelet therapy in atherosclerotic disease: comparing the ASA low-response prevalence in CVD, CAD and PAD

Although acetylsalicylic acid (ASA, aspirin) reduces the risk of ischemic events in patients with atherosclerosis, a substantial number of incidents continue to occur. As only limited data exist we evaluated the antiplatelet effectiveness of ASA in patients with different manifestations of atherosclerosis as in cerebrovascular, coronary artery and peripheral arterial disease (CVD, CAD, PAD). For the evaluation of the antiplatelet effectiveness of ASA we used whole blood aggregometry (Chrono-log Model 590). The patients in the different subgroups received ASA 100, 200 or 500mg daily. We analysed 737 consecutive patients: 47.5% with CVD, 33.6% with CAD, and 18.9% with PAD. We identified 28.0% of the CVD, 18.1% of the CAD and 21.6% of the PAD patients to be ASA low-responder (ALR). Comparing subgroups treated with 100mg ASA, 36.4% were ALR in the CVD group as were 13.1% of the CAD and 21.6% of the PAD patients. Multivariate regression analysis revealed an odds ratio for being ALR of 4.50 (95% confidence interval (CI) 1.70-11.9) when 100mg and of 2.97 (95% CI 1.58-5.60) when 200mg ASA was taken compared to a dose of 500mg. Despite the proven benefits of antiplatelet therapy in the secondary prevention of atherosclerotic disease, current antiplatelet management is suboptimal as up to 36% of patients failed to achieve an adequate platelet inhibitory effect. Our findings may explain, at least in part, the high rates of cardiovascular events observed in the course of atherothrombotic disease and support the need to improve antiplatelet therapy.

Low level natural antibodies against phosphorylcholine: A novel risk marker and potential mechanism in atherosclerosis and cardiovascular disease

Atherosclerosis is an inflammatory condition characterised by an abundance of activated immunocompetent cells in plaques which cause cardiovascular disease (CVD) when they rupture. Oxidized forms of low density lipoprotein (OxLDL) are a major constituent of atherosclerotic plaques and have proinflammatory effects, making oxLDL a candidate factor promoting atherosclerosis. In previous studies we and others demonstrated that platelet-activating factor (PAF)-like lipids in oxLDL may cause oxLDL-induced immune-stimulatory effects. A common denominator is phosphorylcholine (PC), a hapten-like epitope which is exposed on OxLDL and some microorganisms. We recently demonstrated that anti-PC has anti-inflammatory properties and that low levels of anti-PC predict the development of stroke and myocardial infarction. We hypothesize that low anti-PC represents a novel paradigm as a cause of chronic inflammatory diseases such as atherosclerosis where oxidized and/or inflammatory phospholipids play a role. It is possible that anti-PC can be used as a novel diagnostic tool and therapy in atherosclerotic disease.

Statin treated patients have reduced intraplaque angiogenesis in carotid endarterectomy specimens

Background Treatment with statins is considered a first line therapy in atherosclerotic disease. Intraplaque angiogenesis is involved in plaque progression and instability. It remains unclear whether the beneficial effect of statin treatment in humans is achieved through reduced intraplaque angiogenesis. The aim of this study was to evaluate the capillaries density in carotid plaques removed from patients treated with statin versus untreated patients. Methods and results We studied 102 patients who underwent carotid endarterectomy: 98 of them met the inclusion criteria and entered the study; 75 men and 23 women; mean age 66 ± 8 years (range 42–83 years). Forty-three patients (44%) were on statin treatment at least 3 months before endarterectomy and 55 (56%) had never received statin treatment. The intensity of intraplaque angiogenesis was evaluated with immunohistochemistry using the antibody CD34. The number of capillaries per mm 2 was measured with a custom designed image tool analysis. With the exception of serum total cholesterol levels and serum low-density cholesterol levels, the two groups of patients did not vary significantly in cardiovascular risk factors and in parameters pertaining to the procedure profile. Patients on statin treatment had less capillaries per mm 2 than patients not receiving this kind of drugs (0.97 ± 0.61 per mm 2 versus 1.39 ± 0.98 per mm 2, p = 0.031). Univariate associations between possible explanatory variables and number of capillaries per mm 2 were tested using Spearman rank R. Variables associated with a p-value <0.20 (age, serum creatinine, serum total cholesterol, serum low-density lipoprotein, serum homocysteine, presence of diabetes mellitus and statin treatment) were entered in a multivariable model. Multivariate analysis showed that statin treatment was the only independent predictor ( t = −5.39, p < 0.001) of intraplaque angiogenesis. Conclusions Statin therapy is associated with reduced intraplaque angiogenesis in the carotid arteries. This could provide an explanation for the beneficial effects of this kind of drug on patients with atherosclerotic disease.

Angiotensin II promotes the inflammatory response to CD40 ligation via TRAF-2

A plethora of evidence supports a link between inflammation and atherogenesis. Both the vasoactive peptide angiotensin II (ANG II) as well as the CD40/CD154 signaling pathway exhibit proinflammatory properties with a direct influence on atherogenesis. We therefore tested the hypothesis that ANG II interacts with CD40/CD154 in human vascular smooth muscle cells (SMC). ANG II did not increase expression of CD40 in human SMC. However, when SMC were prestimulated with ANG II and thereafter stimulated with CD154, the ligand for CD40, the release of IL-6 as a marker of inflammatory activation was augmented compared to cells not primed with ANG II. TNF receptor-associated factor 2 (TRAF-2), an important adaptor protein involved in CD40 signaling, but not TRAF-5 or -6, was increased by ANG II via activation of the angiotensin II type 1 (AT1) receptor subtype. These results suggest that a signaling pathway downstream of CD40 may be altered by ANG II prestimulation. Thus, ANG II can also indirectly cause inflammatory activation of vascular SMC. The data show a novel link between the proatherogenic vasoactive peptide ANG II and cell-cell contact-mediated inflammatory pathways and implicate options for the prevention and therapy of atherosclerotic disease.

Applications of Site-Targeted Perfluorocarbon Nanoparticles in Diagnosis and Therapy of Atherosclerotic Disease

Applications of Site-Targeted Perfluorocarbon Nanoparticles in Diagnosis and Therapy of Atherosclerotic Disease

Accurate magnetic resonance imaging of atherosclerotic plaques: Change future strategies for the diagnosis and therapy of atherosclerotic disease

In recent years, magnetic resonance imaging (MRI) have been developed to image atherosclerosis and is emerging as a useful tool to assess the burden of atherosclerosis, whereas the potential influence on the diagnosis and therapy of atherosclerotic disease have not been fully determined. MRI allows for three-dimensional evaluation of vascular structures and outstanding depiction of various components of the atherosclerotic plaque. The self-contained intravascular MRI probe appears to hold promise in the identification of high-risk coronary and peripheral atherosclerotic lesions. Molecular and targeted contrast MRI can offer exciting possibilities of direct visualization of biologic processes within atherosclerotic tissue. The addition of quantitative hydrogen 1 magnetic resonance spectroscopy and diffusion weighted imaging within atherosclerotic plaques can provide important data on the biological activity of potentially vulnerable lesions. Therefore, we hypothesized that accurate magnetic resonance imaging of atherosclerotic plaques maybe further affect and change future strategies for the diagnosis and therapy of atherosclerotic disease.

Risk reduction with long-term clopidogrel following percutaneous coronary intervention

Only recently have we begun to appreciate that the mechanical treatment of a haemodynamically significant coronary lesion does not represent conclusive therapy for atherosclerotic disease, but rather serves as a warning for a heightened risk of future events and the need for aggressive preventative therapies. A recently published analysis attempted to quantify the benefit of long-term clopidogrel therapy in such patients.1 We do not feel the conclusions of the author are supported when the results from the CREDO trial and the subset analysis of PCI patients from the CURE trial are accurately analysed. PCI-CURE was a pre-specified observational subset analysis of the much larger …

Intravascular radiation therapy in atherosclerotic disease: promises and premises.

Since its introduction in 1977, coronary angioplasty has become an established technique for the treatment of atherosclerotic coronary disease. Currently, more than 500 000 procedures are performed each year worldwide. However, two major problems remain unresolved. The first, post-angioplasty acute vessel closure, occurs in about 5% of cases. In this setting, intracoronary stenting has been very useful for the management of postangioplasty dissections'. The second problem, restenosis, occurs in 30 to 50% of cases. Thus far, drug therapy has shown little benefit in reducing the extent of this phenomenon. Recently, however, the STRESS trial showed that intracoronary stents could reduce restenosis rates from 42% to 32%, and the BENESTENT trial had an even greater reduction: from 32% to 22%. The beneficial effect of stenting is presumably due to better vessel geometry since it induces more neointima formation than balloon angioplasty.

A secondary prevention trial of antioxidant vitamins and cardiovascular disease in women: Rationale, design, and methods

The evidence for a potential benefit of antioxidant vitamins in the prevention and therapy of atherosclerotic disease is derived from laboratory, clinical, and observational epidemiologic studies but remains inconclusive. Data from randomized clinical trials are sparse, particularly for women. Therefore, it is both timely and important to conduct large-scale primary and secondary prevention trials of antioxidants and cardiovascular disease (CVD). The Women's Antioxidant and Cardiovascular Study (WACS) is a randomized, double-blind, placebo-controlled secondary prevention trial of the balance of benefits and risks of antioxidant vitamins (vitamins E and C, and beta-carotene) among 8000 women with preexisting CVD. This secondary prevention trial will be conducted as a companion to the recently started Women's Health Study, a primary prevention trial of vitamin E and betacarotene, as well as aspirin. In the WACS, US female health professionals aged 40 years and older with a history of myocardial infarction, angina pectoris, coronary revascularization, stroke, transient cerebral ischemia, carotid endarterectomy, or peripheral artery surgery will be randomly assigned, utilizing a 2 × 2 × 2 factorial design, to receive vitamin E, vitamin C, beta-carotene, and/or placebo. Cardiovascular end points include nonfatal myocardial infarction, nonfatal stroke, coronary revascularization procedures, and total CVD mortality. The present article describes the rationale, design, and methods of the trial.