Rationale and design of the Cardiovascular Inflammation Reduction Trial: a test of the inflammatory hypothesis of atherothrombosis.
TL;DR: If low-dose methotrexate reduces cardiovascular events, CIRT would provide a novel therapeutic approach for the secondary prevention of heart attack, stroke, and cardiovascular death.
About: This article is published in American Heart Journal.The article was published on 2013-08-01 and is currently open access. It has received 347 citations till now. The article focuses on the topics: Myocardial infarction & Rheumatoid arthritis.
Citations
More filters
TL;DR: Whether therapies to modulate inflammageing can reduce the age-related decline in health is discussed, and the hypothesis that inflammation affects CVD, multimorbidity, and frailty is supported by mechanistic studies but requires confirmation in humans.
Abstract: Most older individuals develop inflammageing, a condition characterized by elevated levels of blood inflammatory markers that carries high susceptibility to chronic morbidity, disability, frailty, and premature death. Potential mechanisms of inflammageing include genetic susceptibility, central obesity, increased gut permeability, changes to microbiota composition, cellular senescence, NLRP3 inflammasome activation, oxidative stress caused by dysfunctional mitochondria, immune cell dysregulation, and chronic infections. Inflammageing is a risk factor for cardiovascular diseases (CVDs), and clinical trials suggest that this association is causal. Inflammageing is also a risk factor for chronic kidney disease, diabetes mellitus, cancer, depression, dementia, and sarcopenia, but whether modulating inflammation beneficially affects the clinical course of non-CVD health problems is controversial. This uncertainty is an important issue to address because older patients with CVD are often affected by multimorbidity and frailty — which affect clinical manifestations, prognosis, and response to treatment — and are associated with inflammation by mechanisms similar to those in CVD. The hypothesis that inflammation affects CVD, multimorbidity, and frailty by inhibiting growth factors, increasing catabolism, and interfering with homeostatic signalling is supported by mechanistic studies but requires confirmation in humans. Whether early modulation of inflammageing prevents or delays the onset of cardiovascular frailty should be tested in clinical trials. Inflammageing is a chronic, pro-inflammatory state that develops with age and is a risk factor for cardiovascular disease, comorbidities, frailty, and death. In this Review, Ferrucci and Fabbri discuss whether therapies to modulate inflammageing can reduce the age-related decline in health.
1,428 citations
01 Nov 2009
903 citations
TL;DR: Among patients with stable atherosclerosis, low‐dose methotrexate did not reduce levels of interleukin‐1β, interleUKin‐6, or C‐reactive protein and did not result in fewer cardiovascular events than placebo and was associated with elevations in liver‐enzyme levels, reductions in leukocyte counts and hematocrit levels, and a higher incidence of non–basal‐cell skin cancers than placebo.
Abstract: Background Inflammation is causally related to atherothrombosis. Treatment with canakinumab, a monoclonal antibody that inhibits inflammation by neutralizing interleukin-1β, resulted in a lower rate of cardiovascular events than placebo in a previous randomized trial. We sought to determine whether an alternative approach to inflammation inhibition with low-dose methotrexate might provide similar benefit. Methods We conducted a randomized, double-blind trial of low-dose methotrexate (at a target dose of 15 to 20 mg weekly) or matching placebo in 4786 patients with previous myocardial infarction or multivessel coronary disease who additionally had either type 2 diabetes or the metabolic syndrome. All participants received 1 mg of folate daily. The primary end point at the onset of the trial was a composite of nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. Near the conclusion of the trial, but before unblinding, hospitalization for unstable angina that led to urgent revas...
802 citations
TL;DR: This review examines some of the currently proposed molecular mechanisms for statin pleiotropy and discusses whether they could have any clinical relevance in cardiovascular disease.
Abstract: The statins have been used for 30 years to prevent coronary artery disease and stroke. Their primary mechanism of action is the lowering of serum cholesterol through inhibiting hepatic cholesterol biosynthesis thereby upregulating the hepatic low-density lipoprotein (LDL) receptors and increasing the clearance of LDL-cholesterol. Statins may exert cardiovascular protective effects that are independent of LDL-cholesterol lowering called pleiotropic effects. Because statins inhibit the production of isoprenoid intermediates in the cholesterol biosynthetic pathway, the post-translational prenylation of small GTP-binding proteins such as Rho and Rac, and their downstream effectors such as Rho kinase and nicotinamide adenine dinucleotide phosphate oxidases are also inhibited. In cell culture and animal studies, these effects alter the expression of endothelial nitric oxide synthase, the stability of atherosclerotic plaques, the production of proinflammatory cytokines and reactive oxygen species, the reactivity of platelets, and the development of cardiac hypertrophy and fibrosis. The relative contributions of statin pleiotropy to clinical outcomes, however, remain a matter of debate and are hard to quantify because the degree of isoprenoid inhibition by statins correlates to some extent with the amount of LDL-cholesterol reduction. This review examines some of the currently proposed molecular mechanisms for statin pleiotropy and discusses whether they could have any clinical relevance in cardiovascular disease.
744 citations
Cites background from "Rationale and design of the Cardiov..."
...Agents that target inflammation alone, such as anti-IL-1β therapy (canakinumab) and methotrexate, are currently being tested in secondary prevention trials as adjunctive therapy to lipid lowering.(185,186) Furthermore, the ROCK inhibitors, fasudil and ripasudil, which are currently approved in Japan for the treatment of cerebral vasospasm after subarachnoid hemorrhage and to treat glaucoma, respectively, may be of interest as novel therapies for reducing cardiovascular diseases....
[...]
TL;DR: This review considers the mechanisms, history, controversies, new pharmacological agents, and recent evidence for current guidelines for cardiovascular management in the patient with diabetes mellitus to support evidence-based care outside of the acute care setting.
Abstract: Cardiovascular disease remains the principal cause of death and disability among patients with diabetes mellitus. Diabetes mellitus exacerbates mechanisms underlying atherosclerosis and heart failure. Unfortunately, these mechanisms are not adequately modulated by therapeutic strategies focusing solely on optimal glycemic control with currently available drugs or approaches. In the setting of multifactorial risk reduction with statins and other lipid-lowering agents, antihypertensive therapies, and antihyperglycemic treatment strategies, cardiovascular complication rates are falling, yet remain higher for patients with diabetes mellitus than for those without. This review considers the mechanisms, history, controversies, new pharmacological agents, and recent evidence for current guidelines for cardiovascular management in the patient with diabetes mellitus to support evidence-based care in the patient with diabetes mellitus and heart disease outside of the acute care setting.
707 citations
References
More filters
TL;DR: In this paper, the authors investigated whether intensive therapy to target normal glycated hemoglobin levels would reduce cardiovascular events in patients with type 2 diabetes who had either established cardiovascular disease or additional cardiovascular risk factors.
Abstract: BACKGROUND Epidemiologic studies have shown a relationship between glycated hemoglobin levels and cardiovascular events in patients with type 2 diabetes. We investigated whether intensive therapy to target normal glycated hemoglobin levels would reduce cardiovascular events in patients with type 2 diabetes who had either established cardiovascular disease or additional cardiovascular risk factors. METHODS In this randomized study, 10,251 patients (mean age, 62.2 years) with a median glycated hemoglobin level of 8.1% were assigned to receive intensive therapy (targeting a glycated hemoglobin level below 6.0%) or standard therapy (targeting a level from 7.0 to 7.9%). Of these patients, 38% were women, and 35% had had a previous cardiovascular event. The primary outcome was a composite of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes. The finding of higher mortality in the intensive-therapy group led to a discontinuation of intensive therapy after a mean of 3.5 years of follow-up. RESULTS At 1 year, stable median glycated hemoglobin levels of 6.4% and 7.5% were achieved in the intensive-therapy group and the standard-therapy group, respectively. During follow-up, the primary outcome occurred in 352 patients in the intensive-therapy group, as compared with 371 in the standard-therapy group (hazard ratio, 0.90; 95% confidence interval [CI], 0.78 to 1.04; P=0.16). At the same time, 257 patients in the intensive-therapy group died, as compared with 203 patients in the standard-therapy group (hazard ratio, 1.22; 95% CI, 1.01 to 1.46; P=0.04). Hypoglycemia requiring assistance and weight gain of more than 10 kg were more frequent in the intensive-therapy group (P<0.001). CONCLUSIONS As compared with standard therapy, the use of intensive therapy to target normal glycated hemoglobin levels for 3.5 years increased mortality and did not significantly reduce major cardiovascular events. These findings identify a previously unrecognized harm of intensive glucose lowering in high-risk patients with type 2 diabetes. (ClinicalTrials.gov number, NCT00000620.)
6,621 citations
TL;DR: Although ATP III identified CVD as the primary clinical outcome of the metabolic syndrome, most people with this syndrome have insulin resistance, which confers increased risk for type 2 diabetes, when diabetes becomes clinically apparent, CVD risk rises sharply.
Abstract: The National Cholesterol Education Program’s Adult Treatment Panel III report (ATP III)1 identified the metabolic syndrome as a multiplex risk factor for cardiovascular disease (CVD) that is deserving of more clinical attention. The cardiovascular community has responded with heightened awareness and interest. ATP III criteria for metabolic syndrome differ somewhat from those of other organizations. Consequently, the National Heart, Lung, and Blood Institute, in collaboration with the American Heart Association, convened a conference to examine scientific issues related to definition of the metabolic syndrome. The scientific evidence related to definition was reviewed and considered from several perspectives: (1) major clinical outcomes, (2) metabolic components, (3) pathogenesis, (4) clinical criteria for diagnosis, (5) risk for clinical outcomes, and (6) therapeutic interventions.
ATP III viewed CVD as the primary clinical outcome of metabolic syndrome. Most individuals who develop CVD have multiple risk factors. In 1988, Reaven2 noted that several risk factors (eg, dyslipidemia, hypertension, hyperglycemia) commonly cluster together. This clustering he called Syndrome X , and he recognized it as a multiplex risk factor for CVD. Reaven and subsequently others postulated that insulin resistance underlies Syndrome X (hence the commonly used term insulin resistance syndrome ). Other researchers use the term metabolic syndrome for this clustering of metabolic risk factors. ATP III used this alternative term. It avoids the implication that insulin resistance is the primary or only cause of associated risk factors. Although ATP III identified CVD as the primary clinical outcome of the metabolic syndrome, most people with this syndrome have insulin resistance, which confers increased risk for type 2 diabetes. When diabetes becomes clinically apparent, CVD risk rises sharply. Beyond CVD and type 2 diabetes, individuals with metabolic syndrome seemingly are susceptible to other conditions, notably polycystic ovary syndrome, fatty liver, cholesterol gallstones, asthma, sleep disturbances, and some …
6,238 citations
TL;DR: The addition of the measurement of C-reactive protein to screening based on lipid levels may provide an improved method of identifying persons at risk for cardiovascular events.
Abstract: Background Since inflammation is believed to have a role in the pathogenesis of cardiovascular events, measurement of markers of inflammation has been proposed as a method to improve the prediction of the risk of these events. Methods We conducted a prospective, nested case–control study among 28,263 apparently healthy postmenopausal women over a mean follow-up period of three years to assess the risk of cardiovascular events associated with base-line levels of markers of inflammation. The markers included high-sensitivity C-reactive protein (hs-CRP), serum amyloid A, interleukin-6, and soluble intercellular adhesion molecule type 1 (slCAM-1). We also studied homocysteine and several lipid and lipoprotein measurements. Cardiovascular events were defined as death from coronary heart disease, nonfatal myocardial infarction or stroke, or the need for coronay-revascularization procedures. Results Of the 12 markers measured, hs-CRP was the strongest univariate predictor of the risk of cardiovascular events; the relative risk of events for women in the highest as compared with the lowest quartile for this marker was 4.4 (95 percent confidence interval, 2.2 to 8.9). Other markers significantly associated with the risk of cardiovascular events were serum amyloid A (relative risk for the highest as compared with the lowest quartile, 3.0), slCAM-1 (2.6), interleukin-6 (2.2), homocysteine (2.0), total cholesterol (2.4), low-density lipoprotein (LDL) cholesterol (2.4), apolipoprotein B-100 (3.4), high-density lipoprotein (HDL) cholesterol (0.3), and the ratio of total cholesterol to HDL cholesterol (3.4). Prediction models that incorporated markers of inflammation in addition to lipids were significantly better at predicting risk than models based on lipid levels alone (P<0.001). The levels of hs-CRP and serum amyloid A were significant predictors of risk even in the subgroup of women with LDL cholesterol levels below 130 mg per deciliter (3.4 mmol per liter), the target for primary prevention established by the National Cholesterol Education Program. In multivariate analyses, the only plasma markers that independently predicted risk were hs-CRP (relative risk for the highest as compared with the lowest quartile, 1.5; 95 percent confidence interval, 1.1 to 2.1) and the ratio of total cholesterol to HDL cholesterol (relative risk, 1.4; 95 percent confidence interval, 1.1 to 1.9). Conclusions The addition of the measurement of C-reactive protein to screening based on lipid levels may provide an improved method of identifying women at risk for cardiovascular events.
5,895 citations
TL;DR: In this trial of apparently healthy persons without hyperlipidemia but with elevated high-sensitivity C-reactive protein levels, rosuvastatin significantly reduced the incidence of major cardiovascular events.
Abstract: Increased levels of the inflammatory biomarker high-sensitivity C-reactive protein predict cardiovascular events. Since statins lower levels of high-sensitivity C-reactive protein as well as cholesterol, we hypothesized that people with elevated high-sensitivity C-reactive protein levels but without hyperlipidemia might benefit from statin treatment. Methods We randomly assigned 17,802 apparently healthy men and women with low-density lipoprotein (LDL) cholesterol levels of less than 130 mg per deciliter (3.4 mmol per liter) and high-sensitivity C-reactive protein levels of 2.0 mg per liter or higher to rosuvastatin, 20 mg daily, or placebo and followed them for the occurrence of the combined primary end point of myocardial infarction, stroke, arterial revascularization, hospitalization for unstable angina, or death from cardiovascular causes. Results The trial was stopped after a median follow-up of 1.9 years (maximum, 5.0). Rosuvastatin reduced LDL cholesterol levels by 50% and high-sensitivity C-reactive protein levels by 37%. The rates of the primary end point were 0.77 and 1.36 per 100 person-years of follow-up in the rosuvastatin and placebo groups, respectively (hazard ratio for rosuvastatin, 0.56; 95% confidence interval [CI], 0.46 to 0.69; P<0.00001), with corresponding rates of 0.17 and 0.37 for myocardial infarction (hazard ratio, 0.46; 95% CI, 0.30 to 0.70; P = 0.0002), 0.18 and 0.34 for stroke (hazard ratio, 0.52; 95% CI, 0.34 to 0.79; P = 0.002), 0.41 and 0.77 for revascularization or unstable angina (hazard ratio, 0.53; 95% CI, 0.40 to 0.70; P<0.00001), 0.45 and 0.85 for the combined end point of myocardial infarction, stroke, or death from cardiovascular causes (hazard ratio, 0.53; 95% CI, 0.40 to 0.69; P<0.00001), and 1.00 and 1.25 for death from any cause (hazard ratio, 0.80; 95% CI, 0.67 to 0.97; P = 0.02). Consistent effects were observed in all subgroups evaluated. The rosuvastatin group did not have a significant increase in myopathy or cancer but did have a higher incidence of physician-reported diabetes. Conclusions
5,547 citations
TL;DR: The reduction associated with the use of aspirin in the risk of a first myocardial infarction appears to be directly related to the level of C-reactive protein, raising the possibility that antiinflammatory agents may have clinical benefits in preventing cardiovascular disease.
Abstract: Background Inflammation may be important in the pathogenesis of atherothrombosis. We studied whether inflammation increases the risk of a first thrombotic event and whether treatment with aspirin decreases the risk. Methods We measured plasma C-reactive protein, a marker for systemic inflammation, in 543 apparently healthy men participating in the Physicians' Health Study in whom myocardial infarction, stroke, or venous thrombosis subsequently developed, and in 543 study participants who did not report vascular disease during a follow-up period exceeding eight years. Subjects were randomly assigned to receive aspirin or placebo at the beginning of the trial. Results Base-line plasma C-reactive protein concentrations were higher among men who went on to have myocardial infarction (1.51 vs. 1.13 mg per liter, P<0.001) or ischemic stroke (1.38 vs. 1.13 mg per liter, P = 0.02), but not venous thrombosis (1.26 vs. 1.13 mg per liter, P = 0.34), than among men without vascular events. The men in the quartile wit...
5,489 citations