Troponin T and N-Terminal Pro-Brain Natriuretic Peptide Are Associated with Long-Term All-Cause Mortality in Patients with Post-Sternotomy Mediastinitis following Coronary Artery Bypass Grafting: A 15-Year Follow-Up Study.

BACKGROUND: Deep sternal wound/mediastinitis is a rare but feared complication in coronary artery bypass grafting (CABG) patients and seems to increase the risk of cardiac death, and is also associated with the risk of early internal mammary artery (IMA) graft obstruction. The pathological mechanism explaining the link between mediastinitis and IMA graft obstruction and the impact on mortality is complex, multifactorial, and not fully investigated. OBJECTIVES: Mediastinitis has been associated with increased concentrations of N-terminal pro-brain natriuretic peptide (NT-proBNP) and troponin T (TnT) at mid-term follow-up, representing persistent low-grade myocardial injury and impaired cardiac function. However, whether mediastinitis is associated with all-cause mortality, or whether the association is driven by these cardiac-specific biomarkers (NT-proBNP and TnT), is not investigated. METHODS: The present study provides the longest and most complete follow-up data in 82 patients undergoing CABG, including 41 with post-sternotomy mediastinitis. RESULTS: The annualized incidence rate of mediastinitis was 0.14%/year and remained stable at 0.14% throughout the study period. During a mean follow-up of 12.7 ± 3.5 years, a total of 42 deaths occurred (27 [65.9%] in mediastinitis and 15 [36.6%] in non-mediastinitis group, p = 0.008). No association was found between IMA or saphenous vein graft obstruction with all-cause mortality. Mediastinitis was associated with a 1.9-fold increased risk of all-cause mortality. However, in the multivariable-adjusted models, age and higher TnT and NT-proBNP levels, but not mediastinitis per se were associated with all-cause mortality. CONCLUSIONS: Mediastinitis after CABG surgery was associated with a poor prognosis during a 15-year follow-up, showing a nearly two-fold higher frequency of all-cause mortality compared with non-mediastinitis group, with the differences in mortality rate occurring primarily after 10 years. The association between mediastinitis and all-cause mortality was modulated by subclinical myocardial damage and stretch, reflected by elevated TnT and NT-proBNP, measured at 2.7-year follow-up, underscoring that these could represent prognostic markers in CABG patients.

Deficiency of miR-409-3p improves myocardial neovascularization and function through modulation of DNAJB9/p38 MAPK signaling.

Angiogenesis is critical for tissue repair following myocardial infarction (MI), which is exacerbated under insulin resistance or diabetes. MicroRNAs are regulators of angiogenesis. We examined the metabolic regulation of miR-409-3p in post-infarct angiogenesis. miR-409-3p was increased in patients with acute coronary syndrome (ACS) and in a mouse model of acute MI. In endothelial cells (ECs), miR-409-3p was induced by palmitate, while vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) decreased its expression. Overexpression of miR-409-3p decreased EC proliferation and migration in the presence of palmitate, whereas inhibition had the opposite effects. RNA sequencing (RNA-seq) profiling in ECs identified DNAJ homolog subfamily B member 9 (DNAJB9) as a target of miR-409-3p. Overexpression of miR-409-3p decreased DNAJB9 mRNA and protein expression by 47% and 31% respectively, while enriching DNAJB9 mRNA by 1.9-fold after Argonaute2 microribonucleoprotein immunoprecipitation. These effects were mediated through p38 mitogen-activated protein kinase (MAPK). Ischemia-reperfusion (I/R) injury in EC-specific miR-409-3p knockout (KO) mice (miR-409ECKO) fed a high-fat, high-sucrose diet increased isolectin B4 (53.3%), CD31 (56%), and DNAJB9 (41.5%). The left ventricular ejection fraction (EF) was improved by 28%, and the infarct area was decreased by 33.8% in miR-409ECKO compared with control mice. These findings support an important role of miR-409-3p in the angiogenic EC response to myocardial ischemia.

Increased levels of NT-proBNP and troponin T 2 years after coronary artery bypass grafting complicated by mediastinitis.

Background: Mediastinitis after coronary bypass grafting (CABG) increases the risk of the internal mammary artery (IMA) graft obstruction, and has a detrimental effect on long-term survival. The pathogenesis for this increased mortality is poorly understood. In the present study, we aimed to investigate the relationship between mediastinitis and persistently elevated cardiac-specific biomarkers [troponin T (TnT) and N-terminal pro-brain natriuretic peptide (NT-proBNP)] and C-reactive protein (CRP) at mid-term follow-up following CABG. Material and methods: The epidemiologic design was of an exposed (mediastinitis, n = 41) vs. randomly selected non-exposed (non-mediastinitis) controls (n = 41) cohort. Serum samples for measurements of NT-proBNP, TnT, and CRP were obtained at a median follow up time of 2.7 (range 0.5-5.2) years after CABG surgery. Results: NT-proBNP (mean 65.0 pg/ml vs. 34.8 pg/ml, p = 0.007) and TnT levels (mean 14.7 ng/L vs. 11.2 ng/L, p = 0.004) were significantly higher in the mediastinitis group than in the control group. Patients with mediastinitis had also higher body mass index (BMI) and were more likely to have diabetes and previous myocardial infarction. There was no difference in serum CRP level between the groups. After controlling for potential confounders (previous myocardial infarction, age, and BMI), the presence of mediastinitis was associated with higher levels of log NT-proBNP (p = 0.02) and log TnT (p = 0.04). Conclusion: Mediastinitis increases the concentrations of cardiac-specific biomarkers NT-proBNP and TnT at mid-term follow-up, representing persistent myocardial injury and impaired cardiac function.

MicroRNA-615-5p Regulates Angiogenesis and Tissue Repair by Targeting AKT/eNOS (Protein Kinase B/Endothelial Nitric Oxide Synthase) Signaling in Endothelial Cells.

Objective- In response to tissue injury, the appropriate progression of events in angiogenesis is controlled by a careful balance between pro and antiangiogenic factors. We aimed to identify and characterize microRNAs that regulate angiogenesis in response to tissue injury. Approach and Results- We show that in response to tissue injury, microRNA-615-5p (miR-615-5p) is rapidly induced and serves as an antiangiogenic microRNA by targeting endothelial cell VEGF (vascular endothelial growth factor)-AKT (protein kinase B)/eNOS (endothelial nitric oxide synthase) signaling in vitro and in vivo. MiR-615-5p expression is increased in wounds of diabetic db/db mice, in plasma of human subjects with acute coronary syndromes, and in plasma and skin of human subjects with diabetes mellitus. Ectopic expression of miR-615-5p markedly inhibited endothelial cell proliferation, migration, network tube formation in Matrigel, and the release of nitric oxide, whereas miR-615-5p neutralization had the opposite effects. Mechanistic studies using transcriptomic profiling, bioinformatics, 3' untranslated region reporter and microribonucleoprotein immunoprecipitation assays, and small interfering RNA dependency studies demonstrate that miR-615-5p inhibits the VEGF-AKT/eNOS signaling pathway in endothelial cells by targeting IGF2 (insulin-like growth factor 2) and RASSF2 (Ras-associating domain family member 2). Local delivery of miR-615-5p inhibitors, markedly increased angiogenesis, granulation tissue thickness, and wound closure rates in db/db mice, whereas miR-615-5p mimics impaired these effects. Systemic miR-615-5p neutralization improved skeletal muscle perfusion and angiogenesis after hindlimb ischemia in db/db mice. Finally, modulation of miR-615-5p expression dynamically regulated VEGF-induced AKT signaling and angiogenesis in human skin organoids as a model of tissue injury. Conclusions- These findings establish miR-615-5p as an inhibitor of VEGF-AKT/eNOS-mediated endothelial cell angiogenic responses and that manipulating miR-615-5p expression could provide a new target for angiogenic therapy in response to tissue injury. Visual Overview- An online visual overview is available for this article.

MicroRNA-135a-3p regulates angiogenesis and tissue repair by targeting p38 signaling in endothelial cells.

Angiogenesis is a critical process in repair of tissue injury that is regulated by a delicate balance between pro- and antiangiogenic factors. In disease states associated with impaired angiogenesis, we identified that miR-135a-3p is rapidly induced and serves as an antiangiogenic microRNA (miRNA) by targeting endothelial cell (EC) p38 signaling in vitro and in vivo. MiR-135a-3p overexpression significantly inhibited EC proliferation, migration, and network tube formation in matrigel, whereas miR-135-3p neutralization had the opposite effects. Mechanistic studies using transcriptomic profiling, bioinformatics, 3'-UTR reporter and miRNA ribonucleoprotein complex -immunoprecipitation assays, and small interfering RNA dependency studies revealed that miR-135a-3p inhibits the p38 signaling pathway in ECs by targeting huntingtin-interacting protein 1 (HIP1). Local delivery of miR-135a-3p inhibitors to wounds of diabetic db/db mice markedly increased angiogenesis, granulation tissue thickness, and wound closure rates, whereas local delivery of miR-135a-3p mimics impaired these effects. Finally, through gain- and loss-of-function studies in human skin organoids as a model of tissue injury, we demonstrated that miR-135a-3p potently modulated p38 signaling and angiogenesis in response to VEGF stimulation by targeting HIP1. These findings establish miR-135a-3p as a pivotal regulator of pathophysiological angiogenesis and tissue repair by targeting a VEGF-HIP1-p38K signaling axis, providing new targets for angiogenic therapy to promote tissue repair.-Icli, B., Wu, W., Ozdemir, D., Li, H., Haemmig, S., Liu, X., Giatsidis, G., Cheng, H. S., Avci, S. N., Kurt, M., Lee, N., Guimaraes, R. B., Manica, A., Marchini, J. F., Rynning, S. E., Risnes, I., Hollan, I., Croce, K., Orgill, D. P., Feinberg, M. W. MicroRNA-135a-3p regulates angiogenesis and tissue repair by targeting p38 signaling in endothelial cells.

Differential expression of vitamin D associated genes in the aorta of coronary artery disease patients with and without rheumatoid arthritis.

BACKGROUND: Vitamin D has an important role in the immune system, and has been linked to rheumatoid arthritis (RA) and coronary artery disease (CAD). The exact mechanisms by which vitamin D is involved in these processes are still unclear. Therefore, we wanted to search for differences in expression of genes involved in the vitamin D receptor (VDR) activation pathway and genes that are known to alter upon vitamin D stimulation, in the aortic adventitia of CAD patients with and without RA. METHODS: Affymetrix microarray was used to determine gene expression profile in surgical specimens from the adventitia of the ascending aorta of CAD patients with RA (n = 8) and without RA (n = 8) from the Feiring Heart Biopsy Study. RESULTS: We identified three vitamin D associated genes that were differentially expressed between RA and non-RA patients: Growth arrest and DNA-damage-inducible protein 45 alpha (GADD45A) (FC = 1.47; p = 0.006), Nuclear Receptor Co-repressor 1 (NCOR1) (FC = 1,21; p = 0.005) and paraoxonases 2 (PON2) (FC = -1.37; p = 0.01). High expression of GADD45A in RA tissues was confirmed by real-time qRT-PCR. GADD45A expression correlated with plasma levels of 1,25(OH)2D3 (rs = 0.69; p = 0.003). CONCLUSIONS: Microarray analyses revealed higher expression of GADD45A and NCOR1; and lower expression of PON2 in the aortic adventitia of RA than non-RA patients. Further studies are needed to elucidate if and how GADD45A, NCOR1 and PON2 are involved in the development of accelerated atherosclerosis in RA. In theory, some of these factors might have proatherogenic effects whereas others might reflect an underlying vascular pathology promoting atherogenesis (such as vascular stress).

Expression of High Mobility Group Protein B1 in Cardiac Tissue of Elderly Patients with Coronary Artery Disease with or without Inflammatory Rheumatic Disease.

BACKGROUND: It is known from clinical practice and observational studies that elderly patients with a diagnosis of inflammatory rheumatic diseases (IRD) bear a significantly increased risk for cardiovascular diseases such as coronary artery disease (CAD) and heart failure. The molecular mechanism, however, is still not known. Recently, high mobility group protein B1 (HMGB1), a ubiquitous, highly conserved single polypeptide expressed in all mammal eukaryotic cells, has been identified to mediate myocardial dysfunction in vitro once released from the nuclei of cardiomyocytes. OBJECTIVE: To investigate whether HMGB1 and its receptors are expressed in cardiac muscles of elderly patients with CAD with or without IRD. METHODS: HMGB1 and its 3 well-known receptors, receptor for advanced glycation end products, Toll-like receptor 2 (TLR2), and TLR4, were examined by immunohistochemistry on myocardial biopsy specimens from 18 elderly patients with CAD (10 with IRD, 8 without IRD). Furthermore, total HMGB1 protein levels were measured by Western blot from the cardiac biopsies in 5 patients with and 5 without IRD. RESULTS: Pathologic cytosolic HMGB1 in cardiomyocytes was massively recorded in all patients with IRD, but only slightly expressed in 1 patient without IRD. Total HMGB1 levels were also consistently lower in myocardial muscle biopsies of patients with IRD compared to those without IRD. Furthermore, all 3 HMGB1 receptors were expressed in cardiomyocytes of all patients. CONCLUSION: The increased cytosolic expression of HMGB1 in cardiomyocytes and the lower total amount of HMGB1 in the cardiac specimens of IRD patients is consistent with a greater release of HMGB1 from the myocardial nuclei in IRD than non-IRD individuals. Thus, the HMGB1 signaling pathways may be more easily activated in elderly CAD patients with concomitant IRD and trigger a detrimental inflammatory process causing severe cardiovascular problems. Therefore, targeting HMGB1 in IRD patients might reduce the risk for cardiovascular events.

Postoperatively increased serum alanine aminotransferase level is closely associated with mortality after cardiac surgery.

BACKGROUND: Hepatic biomarkers are often not assessed routinely after cardiac surgery. Alanine aminotransferase (ALT) has become the primary biomarker of any type of liver injury. Our purpose was to study the prognostic value of serum ALT in early and late mortality. METHODS: Patients subjected to any type of cardiac operation from January 1999 through December 2010 were studied. According to postoperative maximum ALT level, four groups were created: group 1 = ALT ≤ 50 U/L (n = 8,669), group 2 = ALT 50 to 150 U/L (n = 3,055), group 3 = ALT 151 to 500 U/L (n = 248), and group 4 = ALT > 500 U/L (n = 50). Cox multivariate modeling was used for survival analysis. RESULTS: Patients in groups 3 and 4 had increased 30-day mortality (hazard ratio [HR] = 8.07 [4.15-15.69], p < 0.001 and HR = 19.07 [9.88-36.80], p < 0.001, respectively). Late mortality was increased for group 4 after final adjustments (HR = 1.87 [1.18-2.95], p = 0.007). CONCLUSION: Elevated postoperative ALT level (above 150 U/L) is closely associated with early mortality after cardiac surgery. ALT level above 500 U/L implies a substantial liver dysfunction with a considerable negative association on both early and late survival.

Mediastinitis after coronary artery bypass grafting: the effect of vacuum-assisted closure versus traditional closed drainage on survival and re-infection rate.

Mediastinitis is treated with either vacuum-assisted closure (VAC) or traditional closed drainage (TCD) with irrigation. The aim of the study was to determine the effect of the two treatments on mortality and re-infection rate in a source population, using 21 314 consecutive patients undergoing isolated coronary artery bypass grafting (CABG) from January 1997 to October 2010. Median observation time was 2·9 years in the VAC group and 8·0 years in the TCD group. The epidemiological design was of an exposed (VAC, n = 64) versus non-exposed (TCD, n = 66) cohort with two endpoints: (1) mortality and (2) failure of sternal wound healing or re-infection. The crude effect of treatment technique versus endpoint was estimated by univariate analysis. Stratification analysis by the Mantel-Haenszel method was performed to quantify confounders and to pinpoint effect modifiers. Adjustment for confounders was performed using Cox regression analysis. Mediastinitis was diagnosed 6-105 (median 14) days after primary operation in the VAC group and 13 (5-29) days in the TCD group. There was no difference between groups in long-term survival. Failure of sternal wound healing or re-infection occurred less frequently in the VAC group (6%) than in the TCD group (21%; relative risk = 0·29, 95% CI = 0·06-0·88, P = 0·01). There are concerns for increase in right ventricle rupture in VAC compared with TCD. There was no difference in survival after VAC therapy and TCD therapy of post-CABG mediastinitis. Failure of sternal wound healing or re-infection was more common after TCD therapy.

Mediastinitis after coronary artery bypass grafting increases the incidence of left internal mammary artery obstruction.

Mediastinitis after coronary artery bypass grafting (CABG) gives a longstanding chronic inflammation and has a detrimental negative effect on long-term survival. For this reason, we aimed to study the effect of mediastinitis on graft patency after CABG. The epidemiologic design was of an exposed (mediastinitis, n = 41) versus non-exposed (non-mediastinitis, controls, n = 41) cohort with two endpoints: (i) obstruction of saphenous vein grafts (SVG) and (ii) obstruction of the internal mammary artery (IMA) grafts. The graft patency was evaluated with coronary CT-angiography examination at a median follow-up of 2·7 years. The number of occluded SVG in the mediastinitis group was 18·9% versus 15·5% in the control group. Using generalized estimating equations model with exchangeable matrix, and confounding effect of ischaemic time and patients age, we found no significant association between presence of mediastinitis and SVG obstruction [rate ratio (RR) = 0·96, 95% CI (0·52-2·67), P = 0·697]. The number of occluded IMA grafts was 10·5% in the mediastinitis group and 2·4% in the control group. Using the Poisson regression model, we estimated RR = 5·48, 95% CI (1·43-21·0) and P = 0·013. There was a significant association between mediastinitis and IMA graft obstruction, when controlling for the confounding effect of ischaemic time, body mass index, presence of diabetes mellitus and the number of diseased vessels. Presence of mediastinitis increases the risk of IMA graft obstruction. This may confirm the importance of inflammation as a major contributor to the pathogenesis of atherosclerosis and explain the negative effect of mediastinitis on a long-term survival.

Immediate rescue operations after failed diagnostic or therapeutic cardiac catheterization procedures.

OBJECTIVES: Although rare, life-threatening complications requiring emergency cardiac surgery do occur after diagnostic and therapeutic cardiac catheterization procedures. The operative mortality has been persistently reported to remain high. The purpose of this observational study was to evaluate and report the outcomes, with particular emphasis on early mortality, of these risky operations that were performed in a single highly specialized cardiac centre. METHODS: Between June 1997 and August 2007, 100 consecutive patients, 13 after diagnostic complicated cardiac catheterization (0.038% of 34,193 angiographies) and 87 after crashed percutaneous coronary intervention (PCI; 0.56% of 15,544 PCIs), received emergency operations at the Feiring Heart Center. In the same period, 10,192 other patients underwent open cardiac surgery. Early outcome data were analysed and compared between the cohorts. Follow-up was 100% complete. RESULTS: The preoperative status of the 100 patients was that 4 had ongoing external cardiac massage, 24 were in cardiogenic shock, 32 had frank enduring ST-segment infarction but without shock and 40 had threatened acute myocardial infarction. There was 1% (1 patient) 30-day mortality in the study group, which is equal (0.9%, P=0.60) to that of all other operations. Postoperative myocardial infarction and prolonged ventilator use were significantly higher in the crash group, whereas the rate of stroke, renal failure, reopening for bleeding and mediastinitis were similar between the groups. CONCLUSIONS: With rapid transfer to an operation room, minimizing the time of warm myocardial ischaemia, and by performing complete coronary revascularization, it is possible to obtain equally low operative mortality in patients with life-threatening cardiac catheterization-associated complications, as is the case with open cardiac operations in general.

Avoidance of noninfectious sternal dehiscence: figure-of-8 wiring is superior to straight wire closure.

OBJECTIVES: Comparison of figure-of-8 wiring or simple straight-wiring technique assessed by the frequency of early noninfectious sternal dehiscence. DESIGN: Observational register study with 7835 patients having sternal closure with figure-of-8 steel wires was compared with 2122 patients, where the sternotomy was closed by simple interrupted straight wires. The endpoint was the rate of early (within 30 days) sterile sternal dehiscence. RESULTS: Fourteen patients (0.66%) with single wires and five patients (0.06%) with figure-of-8 wires underwent re-operation for nonmicrobial sternal disruption (p < 0.0001). The median time-point for re-intervention was 6 days for both groups. In more than 6000 patients, the sternotomy was closed with five figure-of-8 wires without dehiscence in any of them. CONCLUSION: In a large cohort of consecutive cardiac operations, it was found that sternal closure with figure-of-8 wires is better than closure with simple interrupted wires.

Long-term survival after aortic valve replacement in octogenarians and high-risk subgroups.

OBJECTIVES: The increasing age in the population and improvements in the treatment options for aortic valvular disease have resulted in a considerable rise in the number of elderly patients being admitted for conventional aortic valve surgery. Recently, transcatheter aortic valve implantation (TAVI) has been developed as a less invasive treatment option. However, both open heart surgery and transcatheter treatment have serious complications. Thus, the knowledge of contemporary results of conventional surgery is important in guiding treatment allocation. METHODS: From the database at Feiring Heart Clinic, 1525 patients were identified who had undergone aortic valve replacement from 1999 to 2010; of these, 361 patients were more than 80 years of age. The population was followed for all-cause mortality until March 2011, with special reference to the age group older than 80 years and other high-risk subsets. RESULTS: The short-term mortality was 2.2% in the whole population and 3.9% in octogenarians. Five-year survival was 83.1 and 68.1%, respectively. In the high-risk subgroup of patients with a logistic EuroSCORE above 20%, the equivalent figures were 4.2 and 72.7%. CONCLUSIONS: Contemporary results after conventional aortic valve surgery are excellent in both short- and long-term survival and should not be withheld in the elderly or otherwise high-risk populations. The logistic EuroSCORE grossly overestimates the operative risk and should be used with caution in allocating patients to TAVI instead of conventional surgery.

Fluid overload during cardiopulmonary bypass is effectively reduced by a continuous infusion of hypertonic saline/dextran (HSD).

OBJECTIVE: Cardiopulmonary bypass (CPB) is associated with fluid overload. We examined how a continuous infusion of hypertonic saline/dextran (HSD) influenced fluid shifts during CPB. MATERIALS AND METHODS: Fourteen animals were randomized to a control-group (CT-group) or a hypertonic saline/dextran-group (HSD-group). Ringer's solution was used as CPB-prime and as maintenance fluid at a rate of 5 ml/kg/h. In the HSD group, 1 ml/kg/h of the maintenance fluid was substituted with HSD. After 60 min of normothermic CPB, hypothermic CPB was initiated and continued for 90 min. Fluid was added to the CPB-circuit as needed to maintain a constant level in the venous reservoir. Fluid balance, plasma volume, total tissue water (TTW), intracranial pressure (ICP) and fluid extravasation rates (FER) were measured/calculated. RESULTS: In the HSD-group the fluid need was reduced with 60% during CPB compared with the CT-group. FER was 0.38(0.06) ml/kg/min in the HSD-group and 0.74 (0.16) ml/kg/min in the CT-group. TTW was significantly lower in the heart and some of the visceral organs in the HSD-group. In this group ICP remained stable during CPB, whereas an increase was observed in the CT-group (p<0.01). CONCLUSIONS: A continuous infusion of HSD reduced the fluid extravasation rate and total fluid gain during CPB. TTW was reduced in the heart and some visceral organs. During CPB ICP remained normal in the HSD-group, whereas an increase was present in the CT-group. No adverse effects were observed.

Mean arterial pressure about 40 mmHg during CPB is associated with cerebral ischemia in piglets.

OBJECTIVE: To investigate if a mean arterial pressure below 50 mmHg during CPB may lead to cerebral ischemia. MATERIAL AND METHODS: Piglets with low mean arterial pressure by nitroprusside (LP-group) (n=6) were compared with piglets given norepinephrine to obtain high pressure (HP-group) (n=6) during normothermic and hypothermic CPB. Intracranial pressure, flow and markers of cerebral energy metabolism (microdialysis) were recorded. RESULTS: Mean arterial pressure differed significantly between the groups and stabilized about 40-45 mmHg in the LP-group. Cerebral perfusion pressure decreased to 21.3 (7.7) mmHg in the LP-group and increased to 51.8 (11.2) mmHg in the HP-group at 150 min of CPB (P<0.001, between groups). During bypass the intracerebral glucose concentration decreased significantly in the LP-group. In this group the lactate/pyruvate ratio increased from 15.5 (5.3) to 64.5 (87.6) at 90 min and 45.0 (36.5) at 150 min (P<0.05) with no such changes in the HP-group. Similarly the cerebral glycerol concentration increased significantly in the LP-group, whereas glycerol remained stable in the HP-group. CONCLUSION: Mean arterial pressure about 40 mmHg during CPB is associated with cerebral ischemia.