Aims: During the first 6–12 h of intensive care unit (ICU) stay, post-cardiac arrest (CA) patients treated with a mean arterial pressure (MAP) 65 mmHg target experience a drop of the cerebral oxygenation that may cause additional cerebral damage. Therefore, we investigated whether an early goal directed haemodynamic optimization strategy (EGDHO) (MAP 85–100 mmHg, SVO2 65–75%) is safe and could improve cerebral oxygenation, reduce anoxic brain damage, and improve outcome when compared with a MAP 65 mmHg strategy. Methods and results: A total of 112 out-of-hospital CA patients were randomly assigned to EGDHO or MAP 65 mmHg strategies during the first 36 h of ICU stay. The primary outcome was the extent of anoxic brain damage as quantified by the percentage of voxels below an apparent diffusion coefficient (ADC) score of 650.10−6 mm2/s on diffusion weighted magnetic resonance imaging (at day 5 ± 2 post-CA). Main secondary outcome was favourable neurological outcome (CPC score 1–2) at 180 days. In patients assigned to EGDHO, MAP (P < 0.001), and cerebral oxygenation during the first 12 h of ICU stay (P = 0.04) were higher. However, the percentage of voxels below an ADC score of 650.10−6 mm2/s did not differ between both groups [16% vs. 12%, odds ratio 1.37, 95% confidence interval (CI) 0.95–0.98; P = 0.09]. Also, the number of patients with favourable neurological outcome at 180 days was similar (40% vs. 38%, odds ratio 0.98, 95% CI 0.41–2.33; P = 0.96). The number of serious adverse events was lower in patients assigned to EGDHO (P = 0.02). Conclusion: Targeting a higher MAP in post-CA patients was safe and improved cerebral oxygenation but did not improve the extent of anoxic brain damage or neurological outcome.

Extracellular vesicles (EVs) are small bilayer lipid membrane vesicles that can be released by most cell types and detected in most body fluids. EVs exert key functions for intercellular communication via transferring their bioactive cargos to recipient cells or activating signaling pathways in target cells. Increasing evidence has shown the important regulatory effects of EVs in cardiovascular diseases (CVDs). EVs secreted by cardiomyocytes, endothelial cells, fibroblasts, and stem cells play essential roles in pathophysiological processes such as cardiac hypertrophy, cardiomyocyte survival and apoptosis, cardiac fibrosis, and angiogenesis in relation to CVDs. In this review, we will first outline the current knowledge about the physical characteristics, biological contents, and isolation methods of EVs. We will then focus on the functional roles of cardiovascular EVs and their pathophysiological effects in CVDs, as well as summarize the potential of EVs as therapeutic agents and biomarkers for CVDs. Finally, we will discuss the specific application of EVs as a novel drug delivery system and the utility of EVs in the field of regenerative medicine.

Optimal healing after myocardial infarction requires not only the induction of inflammation, but also its timely resolution. In patients, 30 days post myocardial infarction, circulating monocytes have increased expression of Semaphorin3A (Sema3A) as compared to directly after admission. This increased expression coincides with increased expression of Cx3CR1—a marker of non-classical monocytes that are important for immune resolution hence proper wound healing. In mice, the expression of Sema3A also increases in response to myocardial ischemia being expressed by infiltrating leukocytes. Comparing Sema3A heterozygote (HZ) and wild type (WT) mice post myocardial infarction, revealed increased presence of leukocytes in the cardiac tissues of HZ mice as compared to WT, with no differences in capillary density, collagen deposition, cardiomyocyte surface area, chemokine—or adhesion molecules expression. Whilst infarct sizes were similar 14 days after myocardial infarction in both genotypes, Sema3A HZ mice had thinner infarcts and reduced cardiac function as compared to their WT littermates. In vitro experiments were conducted to study the role of Sema3A in inflammation and resolution of inflammation as a potential explanation for the differences in leukocyte recruitment and cardiac function observed in our in vivo experiments. Here, recombinant Sema3A protein was able to affect the pro-inflammatory state of cultured bone marrow derived macrophages. First, the pro-inflammatory state was altered by the induced apoptosis of classical macrophages in the presence of Sema3A. Second, Sema3A promoted the polarization of classical macrophages to resolution-phase macrophages and enhanced their efferocytotic ability, findings that were reflected in the infarcted cardiac tissue of the Sema3A HZ mice. Finally, we demonstrated that besides promoting resolution of inflammation, Sema3A was also able to retard the migration of monocytes to the myocardium. Collectively our data demonstrate that Sema3A reduces cardiac inflammation and improves cardiac function after myocardial infarction by promoting the resolution of inflammation.

Background: The identification of patients with acute myocardial infarction (MI) at risk of subsequent left ventricular (LV) dysfunction remains challenging, but it is important to optimize therapies. The aim of this study was to determine the unbiased RNA profile in peripheral blood of patients with acute MI and to identify and validate new prognostic markers of LV dysfunction. Methods: We prospectively enrolled a discovery cohort with acute MI (n=143) and performed whole-blood RNA profiling at different time points. We then selected transcripts on admission that related to LV dysfunction at follow-up and validated them by quantitative polymerase chain reaction in the discovery cohort, in an external validation cohort (n=449), and in a representative porcine MI model with cardiac magnetic resonance–based measurements of infarct size and postmortem myocardial pathology (n=33). Results: RNA profiling in the discovery cohort showed upregulation of genes involved in chemotaxis, IL (interleukin)-6, and NF-κB (nuclear factor-κB) signaling in the acute phase of MI. Expression levels of the majority of these transcripts paralleled the rise in cardiac troponin T and decayed at 30 days. RNA levels of QSOX1 , PLBD1 , and S100A8 on admission with MI correlated with LV dysfunction at follow-up. Using quantitative polymerase chain reaction, we confirmed that QSOX1 and PLBD1 predicted LV dysfunction (odds ratio, 2.6 [95% CI, 1.1–6.1] and 3.2 [95% CI, 1.4–7.4]), whereas S100A8 did not. In the external validation cohort, we confirmed QSOX1 and PLBD1 as new independent markers of LV dysfunction (odds ratio, 1.41 [95% CI, 1.06–1.88] and 1.43 [95% CI, 1.08–1.89]). QSOX1 had an incremental predictive value in a model consisting of clinical variables and cardiac biomarkers (including NT-proBNP [N-terminal pro-B-type natriuretic peptide]). In the porcine MI model, whole-blood levels of QSOX1 and PLBD1 related to neutrophil infiltration in the ischemic myocardium in an infarct size–independent manner. Conclusions: Peripheral blood QSOX1 and PLBD1 in acute MI are new independent markers of LV dysfunction post-MI.

Background: Acute myocardial infarction (MI) invokes a large inflammatory response, which contributes to myocardial repair.Hypothesis: We investigated whether C‐reactive protein (CRP) measured during MI vs at 1 month follow‐up improves the prediction of left ventricular (LV) function.Methods: We prospectively enrolled 131 consecutive patients with acute MI and without non‐cardiovascular causes of inflammation. We correlated admission and peak levels of CRP during hospitalization and high‐sensitivity (hs) CRP at 1 month follow‐up with markers of cardiac injury. Clinical follow‐up and echocardiography for LV function were performed at a mean of 17 months.Results: Median CRP levels were 1.89 mg/L on admission with MI, peaked to 12.10 mg/L during hospitalization and dropped to 1.24 mg/L at 1 month. Although admission CRP levels only weakly correlated with ejection fraction in the acute phase of MI (coefficient −0.164, P = 0.094), peak CRP was significantly related to ejection fraction (coefficient −0.4, P < 0.001), hsTroponin T (0.389, P < 0.001), and white blood cell count (0.389, P < 0.001). hsCRP at 1 month was not related to the extent of acute cardiac injury. These findings were replicated in an independent cohort of 57 patients. Peak CRP predicted LV dysfunction at follow‐up (OR 11.0, 3.1‐39.5 per log CRP, P < 0.001), persisting after adjustment for infarct size (OR 5.1, 1.1‐23.6, P = 0.037), while hsCRP at 1 month was unrelated to LV function at follow‐up.Conclusions: hsCRP 1 month post‐MI does not relate to acute cardiac injury or LV function at follow‐up, but we confirm that peak CRP is an independent predictor of LV dysfunction at follow‐up.