In its classic hormonal role, erythropoietin (EPO) is produced by the kidney and regulates the number of erythrocytes within the circulation to provide adequate tissue oxygenation. EPO also mediates other effects directed towards optimizing oxygen delivery to tissues, e.g. modulating regional blood flow and reducing blood loss by promoting thrombosis within damaged vessels. Over the past 15 years, many unexpected nonhaematopoietic functions of EPO have been identified. In these more recently appreciated nonhormonal roles, locally-produced EPO signals through a different receptor isoform and is a major molecular component of the injury response, in which it counteracts the effects of pro-inflammatory cytokines. Acutely, EPO prevents programmed cell death and reduces the development of secondary, pro-inflammatory cytokine-induced injury. Within a longer time frame, EPO provides trophic support to enable regeneration and healing. As the region immediately surrounding damage is typically relatively deficient in endogenous EPO, administration of recombinant EPO can provide increased tissue protection. However, effective use of EPO as therapy for tissue injury requires higher doses than for haematopoiesis, potentially triggering serious adverse effects. The identification of a tissue-protective receptor isoform has facilitated the engineering of nonhaematopoietic, tissue-protective EPO derivatives, e.g. carbamyl EPO, that avoid these complications. Recently, regions within the EPO molecule mediating tissue protection have been identified and this has enabled the development of potent tissue-protective peptides, including some mimicking EPO's tertiary structure but unrelated in primary sequence.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1365-2796.2008.02024.x

Erythropoietin-mediated tissue protection: reducing collateral damage from the primary injury response.

Signals from the intestinal microbiota are important for normal host physiology; alteration of the microbiota (dysbiosis) is associated with multiple disease states. We determined the effect of antibiotic-induced intestinal dysbiosis on circulating cytokine levels and severity of ischemia/reperfusion injury in the heart. Treatment of Dahl S rats with a minimally absorbed antibiotic vancomycin, in the drinking water, decreased circulating leptin levels by 38%, resulted in smaller myocardial infarcts (27% reduction), and improved recovery of postischemic mechanical function (35%) as compared with untreated controls. Vancomycin altered the abundance of intestinal bacteria and fungi, measured by 16S and 18S ribosomal DNA quantity. Pretreatment with leptin (0.12 μg/kg i.v.) 24 h before ischemia/reperfusion abolished cardioprotection produced by vancomycin treatment. Dahl S rats fed the commercially available probiotic product Goodbelly, which contains the leptin-suppressing bacteria Lactobacillus plantarum 299v, also resulted in decreased circulating leptin levels by 41%, smaller myocardial infarcts (29% reduction), and greater recovery of postischemic mechanical function (23%). Pretreatment with leptin (0.12 μg/kg i.v.) abolished cardioprotection produced by Goodbelly. This proof-of-concept study is the first to identify a mechanistic link between changes in intestinal microbiota and myocardial infarction and demonstrates that a probiotic supplement can reduce myocardial infarct size.—Lam, V., Su, J., Koprowski, S., Hsu, A., Tweddell, J. S., Rafiee, P., Gross, G. J., Salzman, N. H., Baker, J. E. Intestinal microbiota determine severity of myocardial infarction in rats.

https://faseb.onlinelibrary.wiley.com/doi/pdf/10.1096/fj.11-197921

Intestinal microbiota determine severity of myocardial infarction in rats

Plasma concentrations of inflammatory cytokines rise rapidly during ECMO-related SIRS due to the release of preformed stores in the intestine

Preconditioning is hormesis part I: Documentation, dose-response features and mechanistic foundations.

Background—Thrombosis, usually considered a serious but rare complication of pediatric cardiac surgery, has not been a major clinical and/or research focus in the past. Methods and Results—We noted 444 thrombi (66% occlusive, 60% symptomatic) in 171 of 1542 surgeries (11%). Factors associated with increased odds of thrombosis were age <31 days (odds ratio [OR], 2.0; P=0.002), baseline oxygen saturation <85% (OR, 2.0; P=0.001), previous thrombosis (OR, 2.6; P=0.001), heart transplantation (OR, 4.1; P<0.001), use of deep hypothermic circulatory arrest (OR, 1.9 P=0.01), longer cumulative time with central lines (OR, 1.2 per 5-day equivalent; P<0.001), and postoperative use of extracorporeal support (OR, 5.2; P<0.001). Serious complications of thrombosis occurred with 64 of 444 thrombi (14%) in 47 of 171 patients (28%), and were associated with thrombus location (intrathoracic, 45%; extrathoracic arterial, 19%; extrathoracic venous, 8%; P<0.001), symptomatic thrombi (OR, 8.0; P=0.02), and partially/fully occl...

Risk, Clinical Features, and Outcomes of Thrombosis Associated With Pediatric Cardiac Surgery

Characterizing the inflammatory response to cardiopulmonary bypass in children.

Erythropoietin is known to stimulate red cell production and has recently been shown to protect the heart against injury from ischemia/reperfusion. However, it is unknown whether darbepoetin alfa (Dpa), a long-acting analog of erythropoietin, can play a protective role against myocardial infarction. We assessed the potential protective role of Dpa in an in vivo rat model of myocardial ischemia/reperfusion and the underlying mechanisms. We found that a single intravenous Dpa treatment immediately before 30 minutes of regional ischemia reduced myocardial necrosis following 120 minutes of reperfusion in a dose-dependent manner. Optimal protection with Dpa against myocardial infarction was manifest at a dose of 2.5 microg/kg. Dpa conferred cardioprotection when administered after the onset of ischemia and at the start of reperfusion. Dpa (2.5 microg/kg) also reduced infarct size and Troponin I leakage 24 hours after reperfusion. Inhibition of p42/44 MAPK (PD98059), p38 MAPK (SB203580), mitochondrial ATP-dependent potassium (KATP) channels (5-HD), sarcolemmal KATP channels (HMR 1098), but not phosphatidylinositol-3 (PI3) kinase/Akt (Wortmannin and LY 294002) abolished Dpa-induced cardioprotection. Dpa confers immediate and sustained cardioprotection in rats, suggesting a potential therapeutic role of this long-acting erythropoietin analog for the treatment of acute myocardial infarction.

Darbepoetin alfa protects the rat heart against infarction: dose-response, phase of action, and mechanisms.

Outcomes of Heart Transplantation in Children with Previously Palliated Hypoplastic Left Heart Syndrome

Pediatric mechanical circulatory support — a review

Purpose Infants awaiting pediatric heart transplantation (PHT) experience long waitlist duration and high mortality due to donor shortage. Using UNOS database, we explored if increasing donor-recipient weight ratio (DRWR) >2.0 (recommended cutoff) was associated with adverse outcomes. Methods Between 2007-20, 1392 infants received PHT. We divided cohort to 3 groups: A (DRWR ≤1.0,n=239,17%), B (DRWR 1.0-2.0,n=947,68%), C (DRWR >2.0,n=206,15%). Group characteristics and PHT outcomes were analyzed. Results DRWR ranged between 0.5-4.1. Underlying pathology (congenital vs. cardiomyopathy), gender, race, renal function, and mechanical circulatory support were comparable between groups. Group C patients were more likely to be ventilated, to receive ABO incompatible heart, and to have longer donor ischemic time. Waitlist duration was significantly shorter for Group C (33 vs. 50 days,p<0.1). Early outcomes for groups A,B,C were the following (respectively): operative death (6%,4%,3%,p=0.29), primary graft dysfunction (5%,3%,3%,p=0.30), renal failure (10%,7%,7%,p=0.42), stroke (3%,4%,1%,p=0.36). DRWR group was not associated with mortality in either congenital (OR=0.819,95%CI=0.523-1.282) or cardiomyopathy (OR=1.221,95%CI=0.780-1.912) patients and only pre-PHT ECMO was associated with mortality (OR=4.400,95%CI=2.761-7.010). Additionally, survival at 1 year (87%,87%,85%,p=0.80) and 5 years (76%,78%,77%,p=0.80) was comparable between the DRWR groups. Conclusion Infants who received PHT with DRWR >2.0 (up to 4.1) experienced shorter waitlist duration with no demonstrable increase in peritransplant complications, operative or late mortality. Historic practice to avoid DRWR>2.0 due to complications (e.g. hypertension-related stroke, graft dysfunction, death) is not currently supported in infants and stretching DRWR acceptance criteria would decrease PHT waitlist duration and potentially improve waitlist complications and mortality. Infants awaiting pediatric heart transplantation (PHT) experience long waitlist duration and high mortality due to donor shortage. Using UNOS database, we explored if increasing donor-recipient weight ratio (DRWR) >2.0 (recommended cutoff) was associated with adverse outcomes. Between 2007-20, 1392 infants received PHT. We divided cohort to 3 groups: A (DRWR ≤1.0,n=239,17%), B (DRWR 1.0-2.0,n=947,68%), C (DRWR >2.0,n=206,15%). Group characteristics and PHT outcomes were analyzed. DRWR ranged between 0.5-4.1. Underlying pathology (congenital vs. cardiomyopathy), gender, race, renal function, and mechanical circulatory support were comparable between groups. Group C patients were more likely to be ventilated, to receive ABO incompatible heart, and to have longer donor ischemic time. Waitlist duration was significantly shorter for Group C (33 vs. 50 days,p<0.1). Early outcomes for groups A,B,C were the following (respectively): operative death (6%,4%,3%,p=0.29), primary graft dysfunction (5%,3%,3%,p=0.30), renal failure (10%,7%,7%,p=0.42), stroke (3%,4%,1%,p=0.36). DRWR group was not associated with mortality in either congenital (OR=0.819,95%CI=0.523-1.282) or cardiomyopathy (OR=1.221,95%CI=0.780-1.912) patients and only pre-PHT ECMO was associated with mortality (OR=4.400,95%CI=2.761-7.010). Additionally, survival at 1 year (87%,87%,85%,p=0.80) and 5 years (76%,78%,77%,p=0.80) was comparable between the DRWR groups. Infants who received PHT with DRWR >2.0 (up to 4.1) experienced shorter waitlist duration with no demonstrable increase in peritransplant complications, operative or late mortality. Historic practice to avoid DRWR>2.0 due to complications (e.g. hypertension-related stroke, graft dysfunction, death) is not currently supported in infants and stretching DRWR acceptance criteria would decrease PHT waitlist duration and potentially improve waitlist complications and mortality. 

Deborah J. Kozik

Papers

Characterizing the inflammatory response to cardiopulmonary bypass in children.

Darbepoetin alfa protects the rat heart against infarction: dose-response, phase of action, and mechanisms.

Outcomes of Heart Transplantation in Children with Previously Palliated Hypoplastic Left Heart Syndrome

Pediatric mechanical circulatory support — a review

Increasing Donor-Recipient Weight Mismatch is Associated with Shorter Waitlist Duration and No Increased Morbidity or Mortality