Person:

Libby, Peter

Background Using a transcriptional profiling approach, we recently identified myeloid-related protein 8/14 (MRP-8/14) to be expressed by platelets during acute myocardial infarction (MI). Elevated concentrations of MRP-8/14 are associated with a higher risk for future cardiovascular events in apparently healthy individuals but have not been assessed with respect to prognosis in patients with acute coronary syndrome. Methods We performed a nested case-control study (n = 237 case-control pairs) among patients enrolled in the Pravastatin or Atorvastatin Evaluation and Infection Theraphy: Thrombolysis in Myocardial Infarction 22 (PROVE IT-TIMI 22) trial (mean follow-up 24 months) to investigate the risk of cardiovascular death or MI associated with MRP-8/14 measured at 30 days after an acute coronary syndrome. Results Patients with cardiovascular death or MI after 30 days (cases) had higher median [25th, 75th percentile] MRP-8/14 levels than patients who remained free of recurrent events (5.6 [2.8, 13.5] mg/L vs 4.0 [1.9, 10.1] mg/L, P = .020). The risk of a recurrent cardiovascular event increased with each increasing quartile of MRP-8/14 ( P-trend = 0.007) such that patients with the highest levels had a 2.0-fold increased odds (95% CI 1.1-3.6, P = .029) of a recurrent event after adjusting for standard risk indicators, randomized treatment, and C-reactive protein. Patients with elevated levels of MRP-8/14 and high-sensitivity C-reactive protein showed significantly increased risk of cardiovascular death or MI compared with patients with the lowest levels of both markers (adjusted odds ratio 2.1, 95% CI 1.2-3.8). Conclusions Myeloid-related protein 8/14 may be a useful biomarker of platelet and inflammatory disease activity in atherothrombosis and may serve as a novel target for therapeutic intervention.

Physicians have traditionally viewed ischemic heart disease in a cardiocentric manner: plaques grow in arteries until they block blood flow, causing acute coronary and other ischemic syndromes. Recent research provides new insight into the integrative biology of inflammation as it contributes to ischemic cardiovascular disease. These results have revealed hitherto unsuspected inflammatory signaling networks at work in these disorders that link the brain, autonomic nervous system, bone marrow, and spleen to the atherosclerotic plaque and to the infarcting myocardium. A burgeoning clinical published data indicates that such inflammatory networks—far from a mere laboratory curiosity—operate in our patients and can influence aspects of ischemic cardiovascular disease that determine decisively clinical outcomes. These new findings enlarge the circle of the traditional “cardiovascular continuum” beyond the heart and vessels to include the nervous system, the spleen, and the bone marrow.

Background—Myocardial infarction (MI) is an ischemic wound that recruits millions of leukocytes. MI-associated blood leukocytosis correlates inversely with patient survival, yet the signals driving heightened leukocyte production after MI remain incompletely understood.

Methods and Results—With the use of parabiosis surgery, this study shows that soluble danger signals, among them interleukin-1β, increase bone marrow hematopoietic stem cell proliferation after MI. Data obtained in bone marrow reconstitution experiments reveal that interleukin-1β enhances hematopoietic stem cell proliferation by both direct actions on hematopoietic cells and through modulation of the bone marrow’s hematopoietic microenvironment. An antibody that neutralizes interleukin-1β suppresses these effects. Anti-interleukin-1β treatment dampens the post-MI increase in hematopoietic stem cell proliferation. Consequently, decreased leukocyte numbers in the blood and infarct reduce inflammation and diminish post-MI heart failure in ApoE–/– mice with atherosclerosis.

Conclusions—The presented insight into post-MI bone marrow activation identifies a mechanistic target for muting inflammation in the ischemically damaged heart.

Background—Healing after myocardial infarction (MI) involves the biphasic accumulation of inflammatory Ly-6Chigh and reparative Ly-6Clow monocytes/macrophages. Excessive inflammation disrupts the balance between the 2 phases, impairs infarct healing, and contributes to left ventricle remodeling and heart failure. Lipoprotein-associated phospholipase A2 (Lp-PLA2), a member of the phospholipase A2 family of enzymes, produced predominantly by leukocytes, participates in host defenses and disease. Elevated Lp-PLA2 levels associate with increased risk of cardiovascular events across diverse patient populations, but the mechanisms by which the enzyme elicits its effects remain unclear. This study tested the role of Lp-PLA2 in healing after MI.

Methods and Results—In response to MI, Lp-PLA2 levels markedly increased in the circulation. To test the functional importance of Lp-PLA2, we generated chimeric mice whose bone marrow–derived leukocytes were Lp-PLA2–deficient (bmLp-PLA2−/−). Compared with wild-type controls, bmLp-PLA2−/− mice subjected to MI had lower serum levels of inflammatory cytokines tumor necrosis factor-α, interleukin (IL)-1β, and IL-6, and decreased number of circulating inflammatory myeloid cells. Accordingly, bmLp-PLA2−/− mice developed smaller and less inflamed infarcts with reduced numbers of infiltrating neutrophils and inflammatory Ly-6Chigh monocytes. During the later, reparative phase, infarcts of bmLp-PLA2−/− mice contained Ly-6Clow macrophages with a skewed M2-prone gene expression signature, increased collagen deposition, fewer inflammatory cells, and improved indices of angiogenesis. Consequently, the hearts of bmLp-PLA2−/− mice healed more efficiently, as determined by improved left ventricle remodeling and ejection fraction.

Conclusions—Lp-PLA2 augments the inflammatory response after MI and antagonizes healing by disrupting the balance between inflammation and repair, providing a rationale for focused study of ventricular function and heart failure after targeting this enzyme acutely in MI.

Background— Healing after myocardial infarction (MI) involves the biphasic accumulation of inflammatory Ly-6Chigh and reparative Ly-6Clow monocytes/macrophages. Excessive inflammation disrupts the balance between the 2 phases, impairs infarct healing, and contributes to left ventricle remodeling and heart failure. Lipoprotein-associated phospholipase A2 (Lp-PLA2), a member of the phospholipase A2 family of enzymes, produced predominantly by leukocytes, participates in host defenses and disease. Elevated Lp-PLA2 levels associate with increased risk of cardiovascular events across diverse patient populations, but the mechanisms by which the enzyme elicits its effects remain unclear. This study tested the role of Lp-PLA2 in healing after MI. Methods and Results— In response to MI, Lp-PLA2 levels markedly increased in the circulation. To test the functional importance of Lp-PLA2, we generated chimeric mice whose bone marrow–derived leukocytes were Lp-PLA2–deficient (bmLp-PLA2−/−). Compared with wild-type controls, bmLp-PLA2−/− mice subjected to MI had lower serum levels of inflammatory cytokines tumor necrosis factor-α, interleukin (IL)-1β, and IL-6, and decreased number of circulating inflammatory myeloid cells. Accordingly, bmLp-PLA2−/− mice developed smaller and less inflamed infarcts with reduced numbers of infiltrating neutrophils and inflammatory Ly-6Chigh monocytes. During the later, reparative phase, infarcts of bmLp-PLA2−/− mice contained Ly-6Clow macrophages with a skewed M2-prone gene expression signature, increased collagen deposition, fewer inflammatory cells, and improved indices of angiogenesis. Consequently, the hearts of bmLp-PLA2−/− mice healed more efficiently, as determined by improved left ventricle remodeling and ejection fraction. Conclusions— Lp-PLA2 augments the inflammatory response after MI and antagonizes healing by disrupting the balance between inflammation and repair, providing a rationale for focused study of ventricular function and heart failure after targeting this enzyme acutely in MI.