The effect of the timing of invasive management on cardiac function in patients with nste-acs, insights from the optima-2 randomized controlled trial

The timing of coronary angiography in patients with non-ST-elevation acute coronary syndrome (NSTE-ACS) remains a matter of debate. The relationship between the timing of invasive management and left ventricular function (LVF) is largely unknown. The An Immediate or Early Invasive Strategy in Non-ST-Elevation Acute Coronary Syndrome trial (OPTIMA-2) was a randomized controlled prospective open-label multicenter trial that randomized 249 NSTE-ACS patients to either an immediate (<3 h) invasive treatment strategy or an early strategy (12–24 h). Patients were pre-treated with a combination of aspirin, ticagrelor and fondaparinux. The aim of this prespecified sub-analysis was to assess (the recovery of) left ventricular function by analysing echocardiography data obtained <72 h after admission and at 30-day follow-up, for patients with a confirmed diagnosis of acute coronary syndrome. LVF was determined using ejection fraction (EF) and global longitudinal strain (GLS). Inter-observer variability was tested. No difference in the recovery of EF was found between an immediate and early strategy if the follow-up echocardiograms were compared to baseline: 2.5% (standard deviation (SD): 7.9) and 3.3% (SD: 8.5), p = 0.51, nor was there any difference in GLS recovery between the study groups: −0.8% (SD: 2.5) vs. −0.7% (SD 2.8) p = 0.82. If baseline and follow-up echocardiograms were compared, there was a similar but significant improvement in both EF and GLS in both separate study groups. An immediate invasive strategy in NSTE-ACS patients did not result in an improved left ventricular EF or GLS recovery compared with an early strategy

Impact of the B Cell Growth Factor APRIL on the Qualitative and Immunological Characteristics of Atherosclerotic Plaques.

Studies on the role of B lymphocytes in atherosclerosis development, have yielded contradictory results. Whereas B lymphocyte-deficiency aggravates atherosclerosis in mice; depletion of mature B lymphocytes reduces atherosclerosis. These observations led to the notion that distinct B lymphocyte subsets have different roles. B1a lymphocytes exert an atheroprotective effect, which has been attributed to secretion of IgM, which can be deposited in atherosclerotic lesions thereby reducing necrotic core formation. Tumor necrosis factor (TNF)-family member 'A Proliferation-Inducing Ligand' (APRIL, also known as TNFSF13) was previously shown to increase serum IgM levels in a murine model. In this study, we investigated the effect of APRIL overexpression on advanced lesion formation and composition, IgM production and B cell phenotype. We crossed APRIL transgenic (APRIL-Tg) mice with ApoE knockout (ApoE-/-) mice. After a 12-week Western Type Diet, ApoE-/-APRIL-Tg mice and ApoE-/- littermates showed similar increases in body weight and lipid levels. Histologic evaluation showed no differences in lesion size, stage or necrotic area. However, smooth muscle cell (α-actin stain) content was increased in ApoE-/-APRIL-Tg mice, implying more stable lesions. In addition, increases in both plaque IgM deposition and plasma IgM levels were found in ApoE-/-APRIL-Tg mice compared with ApoE-/- mice. Flow cytometry revealed a concomitant increase in peritoneal B1a lymphocytes in ApoE-/-APRIL-Tg mice. This study shows that ApoE-/-APRIL-Tg mice have increased oxLDL-specific serum IgM levels, potentially mediated via an increase in B1a lymphocytes. Although no differences in lesion size were found, transgenic ApoE-/-APRIL-Tg mice do show potential plaque stabilizing features in advanced atherosclerotic lesions

Lesion size and stage of ApoE^-/- and ApoE^-/-APRIL-Tg mice.

<p>After 12 weeks of WTD lesion size (A) was quantified and lesion stage (B) was determined in the aortic roots of ApoE^-/- (n = 13) and ApoE^-/-APRIL-Tg mice (n = 10). Representative photomicrographs are shown with original magnification x25. Data are represented as mean±SEM; Scale bars represent 1mm.</p

Lesion characteristics of ApoE^-/- and ApoE^-/-APRIL-Tg mice.

<p>ApoE^-/- (n = 13) and ApoE^-/-APRIL-Tg mice (n = 10). After 12 weeks of WTD macrophage content (A) and the percentage of collagen deposition (B) were quantified. Representative photomicrographs and quantification of Smooth muscle cell content (C), necrosis (D), and IgM deposition (E) are shown. Original magnification x50 (C+D) and x25 (E). Data are represented as mean±SEM; *p<0.05; Scale bars represent 1mm.</p

Bodyweight, lipid levels and blood cell counts of ApoE^-/- and ApoE^-/-APRIL-Tg mice.

<p>ApoE^-/- (n = 13) and ApoE^-/-APRIL-Tg mice (n = 10). Every week body weight was determined (A), plasma cholesterol and triglycerides were measured before the start of diet and after 12 weeks of WTD (B). After 12 weeks of WTD the number of blood cells were measured by a cell counter (C). Data are represented as mean±SEM. Chol (cholesterol); WBC (white blood cells); RBC (red blood cells); Htc (hematocrit).</p

Immunoglobulins of ApoE^-/- and ApoE^-/-APRIL-Tg mice.

<p>After 12 weeks WTD both plasma IgM (A) and IgG (B) were measured. In ApoE^-/- (n = 13) and ApoE^-/-APRIL-Tg mice (n = 10) IgG deposition was quantified as a % of total lesion size (C). Specific antibodies to copper-oxidized (CuOx) or malondialdehyde (MDA)-modified LDL (quantified as relative light units (RLU)) were determined for both IgM (<b>D</b>) and IgG (<b>E</b>) before start of the WTD and at harvest (after 12 weeks WTD). F, percentage of CD19⁺ cells, as well as the percentages of each subset are shown. Data are represented as mean±SEM; **p<0.01 ***p<0.001.</p

Peritoneal B cell subsets of ApoE^-/- and ApoE^-/-APRIL-Tg mice.

<p>Peritoneal B cell subsets were quantified by FACS analysis after 12 weeks of WTD in ApoE^-/- (n = 13) and ApoE^-/-APRIL-Tg mice (n = 10). The cells were gated (A) for Lymphocytes in the FSC/SSC plot and B cells were selected on the basis of CD19 positivity. Subsets were identified as follows: CD5⁺CD11b⁺B1a cells, CD5^-CD11b⁺ B1b cells, and CD5^-CD11b- B2 cells. The percentages (B) and concentration (C) of CD19⁺ cells, as well as for each B cell subset are shown. Data are represented as mean±SEM; *p<0.05 **p<0.01 ***p<0.001.</p