Stress Biomarkers Do Not Correlate With Risk Factors for Kidney Injury After Cardiac Surgery.

BACKGROUND: The urinary cell cycle arrest biomarkers (UBs) insulin-like growth factor-binding protein-7 and tissue inhibitor of metalloproteinases-2 provide early detection of kidney stress, and elevations may predict cardiac surgery-associated acute kidney injury (CS-AKI). We sought to determine whether known clinical risk factors for CS-AKI correlated with increased UB values. METHODS: UBs were measured over a 12-month period the morning after on-pump cardiac surgery. Patients with a preoperative serum creatinine level greater than 2.0 mg/dL or patients undergoing dialysis were excluded. Known clinical AKI risk factors in patients with elevated UB (>0.3 (ng/mL)2/1000), that is known to correlate with kidney stress, were compared with patients with low scores (≤0.3 (ng/mL)2/1000) by using logistic regression; the analysis was repeated with UB as a continuous variable. RESULTS: A total of 412 patients met inclusion criteria. Unadjusted results demonstrated a clinically similar CS-AKI risk profile in patients with either elevated or low UB values. The Pearson correlation between preoperative estimated glomerular filtration rate and UB was low (r = 0.16). Clinical risk factors for CS-AKI were not associated with elevated UB values in the logistic regression model, thus producing an area under the receiver operating characteristic curve of 0.63. Linear regression analysis also found few associations between CS-AKI clinical risk factors and UB when measured as a continuous variable, (R2) = 0.15. CONCLUSIONS: Traditional CS-AKI clinical risk factors do not differ between patients with normal or elevated UB values. This UB test may identify patients at increased risk for AKI who otherwise would appear to be at low risk by traditional metrics.

Using urinary biomarkers to reduce acute kidney injury following cardiac surgery.

BACKGROUND: Prediction of acute kidney injury (AKI) following cardiac surgery is unreliable through the use of serum creatinine or urinary output alone. Cell cycle arrest urinary biomarkers insulin-like growth factor-binding protein 7 (IGFBP7) and tissue inhibitor of metalloproteinases-2 (TIMP2) provide early detection of kidney stress and possibly AKI. We sought to determine whether therapeutic interventions driven by elevated urinary biomarkers (UB) reduces post-cardiac surgery stage 2/3 AKI. METHODS: A quality improvement initiative based on UB was undertaken in all adult on-pump cardiac surgical patients with a preoperative serum creatinine level ≤2.0 mg/dL. A UB score the morning after cardiac surgery that was considered positive for kidney stress (≥0.3 [ng/mL]2/1000) triggered activation of a multidisciplinary acute kidney response team (AKRT) with implementation of a predefined staged protocol, including targeted goal-directed fluid management, liberalized transfusion thresholds, continued invasive hemodynamic monitoring and its optimization in the intensive care unit, and avoidance of nephrotoxins. We compared the incidence of stage 2/3 AKI before (pre-UB) versus after (post-UB) implementation of the Kidney Disease: Improving Global Outcomes quality improvement initiative. Standardized, protocolized, evidence-based care pathways were used pre-UB. RESULTS: The incidence of stage 2/3 AKI was compared in 435 pre-UB patients and 412 post-UB patients. Fifty-five percent of the post-UB patients had a moderate or high UB score (≥0.3 [ng/mL]2/1000). Ten patients (2.30%) had stage 2/3 AKI pre-UB, compared with 1 patient (0.24%) post-UB, a relative reduction of 89% (P = .01). The total and postoperative lengths of stay, cost, mortality, and readmissions were similar in the 2 groups. The negative predictive value for AKI of UB <0.3 [ng/mL]2/1000 was 100%. CONCLUSIONS: The routine measurement of UB and subsequent activation of an AKRT are useful post-cardiac surgery therapeutic adjuncts. They are associated with early detection of kidney stress, allowing for targeted proactive intervention, and a significant decrease in postoperative stage 2/3 AKI without increases in cost or length of stay.

Guidelines for Perioperative Care in Cardiac Surgery: Enhanced Recovery After Surgery Society Recommendations.

Enhanced Recovery After Surgery (ERAS) evidence-based protocols for perioperative care can lead to improvements in clinical outcomes and cost savings. This article aims to present consensus recommendations for the optimal perioperative management of patients undergoing cardiac surgery. A review of meta-analyses, randomized clinical trials, large nonrandomized studies, and reviews was conducted for each protocol element. The quality of the evidence was graded and used to form consensus recommendations for each topic. Development of these recommendations was endorsed by the Enhanced Recovery After Surgery Society.

Hemoadsorption to Reduce Plasma-Free Hemoglobin During Cardiac Surgery: Results of REFRESH I Pilot Study.

Generation of plasma-free hemoglobin (pfHb) and activated complement during complex cardiac surgery contributes to end-organ dysfunction. This prospective, multicenter REFRESH I (REduction in FREe Hemoglobin) randomized controlled trial evaluated the safety and feasibility of CytoSorb hemoadsorption therapy to reduce these factors during prolonged cardiopulmonary bypass (CPB). Eligible patients underwent elective, nonemergent complex cardiac surgery with expected CPB duration ≥3 hours. Exclusions included single procedures including primary coronary artery bypass graft, single valves, transplant, and left ventricular assist device extraction. TREATMENT used 2 parallel 300 mL CytoSorb hemoadsorption cartridges in a side circuit during CPB. CONTROL was standard of care. Of 52 enrolled patients, 46 underwent surgery (Safety group, n = 23 vs Control, n = 23), and 38 were evaluated for pfHb reduction (EFFICACY group, n = 18 vs CONTROL, n = 20). Type and number of serious adverse events (44 vs 43 CONTROL) were similar, as was 30-day mortality. Transient reduction in platelets during CPB was observed in both groups, especially TREATMENT, but returned to pretreatment levels after CPB without bleeding. Peak pfHb was positively correlated with CPB length (P = 0.01) but the high variability of pfHb, due to the broad surgical procedure mix, prevented detection of changes in pfHb in the overall EFFICACY population. However, the valve replacement surgery subgroup (8 vs 10 CONTROL) had the highest peak pfHb levels, and TREATMENT demonstrated significant pfHb reductions vs CONTROL (P ≤ 0.05) in CPB ≥3 hours. In the EFFICACY group, C3a and C5a were significantly reduced by treatment throughout surgery. Intraoperative hemoadsorption with CytoSorb was safe and feasible in this randomized, controlled pilot study during complex cardiac surgery. Treatment with CytoSorb resulted in significant reductions in pfHb during valve replacement surgery and reductions in C3a and C5a in the overall EFFICACY group. Future studies will target complex cardiac surgery patients with prolonged CPB to assess hemoadsorption effect on end-organ dysfunction and outcomes.

Strategies and Devices to Minimize Stroke in Adult Cardiac Surgery.

Stroke after cardiac surgery is a devastating complication with a frequency of 1%-3% and a potential mortality risk of >20%. The approaches that one should consider to minimize the risk of stroke associated with cardiac surgery involve preoperative, intraoperative, and postoperative interventions, which are described in detail.

Sildenafil-mediated neovascularization and protection against myocardial ischaemia reperfusion injury in rats: role of VEGF/angiopoietin-1.

Sildenafil citrate (SC), a drug for erectile dysfunction, is now emerging as a cardiopulmonary drug. Our study aimed to determine a novel role of sildenafil on cardioprotection through stimulating angiogenesis during ischaemia (I) reperfusion (R) at both capillary and arteriolar levels and to examine the role of vascular endothelial growth factor (VEGF) and angiopoietin-1 (Ang-1) in this mechanistic effect. Rats were divided into: control sham (CS), sildenafil sham (SS), control+IR (CIR) and sildenafil+IR (SIR). Rats were given 0.7 mg/kg, (i.v) of SC or saline 30 min. before occlusion of left anterior descending artery followed by reperfusion (R). Sildenafil treatment increased capillary and arteriolar density followed by increased blood flow (2-fold) compared to control. Treatment with sildenafil demonstrated increased VEGF and Ang-1 mRNA after early reperfusion. PCR data were validated by Western blot analysis. Significant reduction in infarct size, cardiomyocyte and endothelial apoptosis were observed in SC-treated rats. Increased phosphorylation of Akt, eNOS and expression of anti-apoptotic protein Bcl-2, and thioredoxin, hemeoxygenase-1 were observed in SC-treated rats. Echocardiography demonstrated increased fractional shortening and ejection fraction following 45 days of reperfusion in the treatment group. Stress testing with dobutamine infusion and echocardiogram revealed increased contractile reserve in the treatment group. Our study demonstrated for the first time a strong additional therapeutic potential of sildenafil by up-regulating VEGF and Ang-1 system, probably by stimulating a cascade of events leading to neovascularization and conferring myocardial protection in in vivo I/R rat model.

Protection against myocardial ischemia-reperfusion injury by the angiogenic Masterswitch protein PR 39 gene therapy: the roles of HIF1alpha stabilization and FGFR1 signaling.

PR-39, a proline-arginine-rich angiogenic response peptide, has been implicated in myocardial ischemic reperfusion injury. The present study examined the cardioprotective abilities of PR39 gene therapy. Male C57Bl/J6 mice were randomized to intramyocardial injecton of 10(9) p.f.u. adenovirus encoding PR39 (PR39), FGFR1 dominant negative signaling construct (FGFR1-dn), empty vector (EV), or PR39 adenovirus plus 4 microg of plasmid endcoding a HIF1alpha dominant negative construct (PR39 + HIF1alpha-dn). Seven days later, hearts were subjected to 20 min of ischemia (I) and 2 h. reperfusion (R) ex vivo and aortic and coronary flow, left ventricular developed pressure (LVDP), and LVdp/dt were measured. Myocardial infarct (MI) size and cardiomyocyte apoptosis were measured by TTC staining and TUNEL, respectively. PR39 expression was robust up to 14 days after gene transfer and was absent after EV and FGFR1-dn. Hemodynamics showed no differences at baseline, and heart rate remained unchanged in all groups throughout the experiment. After I-R, hemodynamics remained unchanged in PR39 hearts, but deteriorated significantly in the other groups, except for aortic flow, which remained significantly higher in FGFR1-dn than in EV and PR39 + HIF1alpha-dn (p < 0.05), although it was lower than in PR39 (p < 0.05). MI was 8.7 +/- 0.9 % in PR39, 23.8 +/- 1.1% in FGFR1-dn, 29.9 +/- 2.2% in EV, and 30.8 +/- 2.7 % in PR39 + HIF1alpha-dn (PR39 vs. other groups: p < 0.05; FGFR1-dn vs. EV and PR39 + HIF1alpha-dn: p < 0.05). In PR39, HIF-1alpha protein was higher than in FGFR1-dn and EV. Importantly, cotransfection of HIF1alpha-dn with PR39 completely abolished cardioprotection by PR39. Cardioprotection by PR39 is likely conveyed by protective metabolic and survival responses through HIF1-alpha stabilization and not by angiogenesis, because baseline coronary flow was the same in all groups. Abrogation of FGFR1 signaling conveyed an intermediate degree of cardioprotection.

Angiotensin preconditioning of the heart: evidence for redox signaling.

Angiotensin II (Ang II) has been found to exert preconditioning-like effect on mammalian hearts. Diverse mechanisms are known to exist to explain the cardioprotective abilities of Ang II preconditioning. The present study hypothesized, based on the recent report that Ang II generates reactive oxygen species (ROS) through NADPH oxidase, that Ang II preconditioning occurs through redox cycling. To test this hypothesis, a group of rat hearts was treated with Ang II in the absence or presence of an NADPH oxidase inhibitor, apocynin; or a cell-permeable ROS scavenger, N-acetyl cysteine (NAC). Ang II pretreatment improved postischemic ventricular recovery; reduced myocardial infarction; and decreased the number of cardiomyocyte apoptosis, indicating its ability to precondition the heart against ischemic injury. Both apocynin and NAC almost abolished the preconditioning ability of Ang II. Ang II resulted in increase in ROS activity in the heart, which was reduced by either NAC or apocynin. Ang II also increased both the NADPH oxidase subunits gp91 phox and p22phox mRNA expression, which was abolished with apocynin and NAC. Our results thus demonstrate that the Ang II preconditioning was associated with enhanced ROS activities and increased NADPH oxidase subunits p22phox and gp91phox expression. Both NAC and apocynin reduced ROS activities simultaneously abolishing preconditioning ability of Ang II, suggesting that Ang II preconditioning occurs through redox cycling. That both NAC and apocynin reduced ROS activities and abolished Ang II-mediated increase in p22phox and gp91phox activity further suggest that such redox cycling occurs via both NADPH oxidase-dependent and -independent pathways.

Role of Akt signaling in mitochondrial survival pathway triggered by hypoxic preconditioning.

BACKGROUND: The signaling pathways that control ischemia/reperfusion-induced cardiomyocyte apoptosis in heart have not been fully defined. In this study, we investigated whether Akt signaling has a role in the antiapoptotic pathways of preconditioning against hypoxia/reoxygenation (H/R). METHODS AND RESULTS: Primary cultures of adult rat ventricular myocytes (ARVMs) were subjected to preconditioning (PC) by exposing the cells to 10 minutes of hypoxia followed by 30 minutes of reoxygenation. Non-PC and PC myocytes were subjected to 90 minutes of hypoxia followed by 120 minutes of reoxygenation. Hypoxic-PC protected the myocytes from subsequent H/R injury, as evidenced by decreased apoptosis and LDH release and increased cell viability. H/R-induced cytochrome c release and activation of caspase-3 and -9 were blocked by PC. This protective effect was inhibited by treating the cells with LY294002 (50 micromol/L), a PI3 kinase inhibitor, for 10 minutes before and during PC. PC also induced phosphorylation of Akt and BAD. Protein levels of Bcl-2 in mitochondria were maintained in PC. ARVMs were infected with either a control adenovirus (Adeno lac-Z), an adenovirus expressing dominant-negative Akt, or an adenovirus expressing constitutively active Akt. Ectopic overexpression of constitutively active Akt protected ARVMs from apoptosis induced by hypoxia/reoxygenation compared with Adeno lac-Z. In contrast, dominant negative Akt overexpression abolished the antiapoptotic effect of PC. CONCLUSIONS: Our data demonstrated that in adult cardiomyocytes, the antiapoptotic effect of PC against H/R requires Akt signaling leading to phosphorylation of BAD, inhibition of cytochrome c release, and prevention of caspase activation.

Role of ceramide in ischemic preconditioning.

BACKGROUND: A recent study showed increased myocardial content of ceramide and sphingosine during preconditioning (PC). Because sphingosine-1-phosphate, a metabolite of ceramide, may function as an antiapoptotic factor, we hypothesized the increased ceramide during PC may be heart's effort to harness its own protection. STUDY DESIGN: The isolated hearts were divided into five groups: 1) perfused for 3 hours 45 minutes with KHB buffer (control); 2) perfused with buffer for 45 minutes followed by 30 minutes of ischemia and 2 hours of reperfusion; 3) perfused for 15 minutes with desipramine followed by 30 minutes of perfusion with buffer, 30 minutes of ischemia, and 2 hours of reperfusion; 4) preconditioned followed by 30 minutes of ischemia and 2 hours of reperfusion; and 5) the same as 4), but preperfused for 15 minutes with desipramine. Myocardial preservation was assessed by examining left ventricular function, infarct size, and cardiomyocyte apoptosis. RESULTS: Ischemia/reperfusion-mediated cardiac dysfunction was partially restored with desipramine. PC improved postischemic ventricular recovery and reduced myocardial infarct size and cardiomyocyte apoptosis. The cardioprotective abilities of PC were abolished with desipramine, which also downregulated a PC-mediated increase in antiapoptotic protein Bcl-2. The apparent paradoxical results of desipramine can be explained by the increase in proapoptotic ceramide content in the ischemic reperfused heart that was blocked with desipramine and an increase in antiapoptotic sphingosine-1-p content in the preconditioned heart that was inhibited with desipramine. CONCLUSIONS: The results suggested for the first time that sphingolipid can induce the expression of Bcl-2 warranting its clinical use as a pharmacologic PC agent.

Redox regulation of angiotensin II signaling in the heart.

A large number of studies have demonstrated the role of angiotensin II in cardiac preconditioning against ischemic reperfusion injury. Generally, angiotensin II is a detrimental factor for the heart, and its inhibition with an ACE inhibitor provides cardioprotection. This review provides an explanation for such paradoxical behavior of angiotensin II. Angiotensin II can potentiate the induction of the expression of a variety of redox-sensitive factors including p38 MAPK, JNK and Akt, IGF-IR, EGF-R, and HO-1 as well as redox-regulated genes and transcription factors such as NFkappaB. It becomes increasingly apparent that during the earlier phase, the heart attempts to adapt itself against the detrimental effects of angiotensin II by upregulating several cardioprotective genes and proteins. These genes and proteins are redox-regulated and the antioxidants or ROS scavengers block their expressions. Interestingly, an identical pattern of cardioprotective proteins and genes are expressed in the preconditioned heart, which are also inhibited with ROS scavengers. It is tempting to speculate that the induction of the expression of the redox-sensitive cardioprotective proteins is the results of adaptation of the heart against the oxidative stress resulting from angiotensin II; and preconditioning is the net result of harnessing its own protection during ischemic and/or oxidative stress through its ability to trigger redox signaling.

Thioredoxin redox signaling in the ischemic heart: an insight with transgenic mice overexpressing Trx1.

This study examined if thioredoxin, the major redox-regulator in the mammalian system, plays any role in the redox signaling of ischemic myocardium. Isolated working rat hearts were made globally ischemic for 30 min followed by 2 h of reperfusion. Another group of hearts was rendered tolerant to ischemia by four cyclic episodes of 5 min ischemia each followed by another 10 min of reperfusion. Reperfusion of ischemic myocardium resulted in the downregulation of thioredoxin 1 (Trx1) expression, which was upregulated in the adapted myocardium. The increased expression of Trx1 was completely blocked with cis-diammine-dichloroplatinum (CDDP), an inhibitor of Trx1. CDDP also abolished cardioprotection afforded by ischemic adaptation as evidenced by a reduction of post-ischemic ventricular recovery, increase in myocardial infarct size and cardiomyocyte apoptosis. The decreased amount of reactive oxygen species in the adapted heart was increased significantly, when Trx1 was blocked with CDDP. The cardioprotective role of Trx1 was further confirmed with transgenic mouse hearts overexpressing Trx1. The Trx1 mouse hearts displayed significantly improved post-ischemic ventricular recovery and reduced myocardial infarct size as compared to the corresponding wild-type mouse hearts. Taken together, the results of this study implicate a crucial role of Trx1 in redox signaling of the ischemic myocardium.

Hypoxic preconditioning triggers myocardial angiogenesis: a novel approach to enhance contractile functional reserve in rat with myocardial infarction.

A modern experimental strategy for treating myocardial ischemia is to induce neovascularization of the heart by the use of "angiogens", mediators that induce the formation of blood vessels, or angiogenesis. Studies demonstrated that coronary collateral vessels protect ischemic myocardium after coronary obstruction; therefore we sought to examine a novel method of stimulating myocardial angiogenesis through hypoxic preconditioning at both capillary (using anti-CD31) and arteriolar (using anti- alpha smooth muscle actin) levels and also investigate whether such treatments could preserve left ventricular contractile functional reserve and regional blood flow by increasing vascular endothelial growth factor (VEGF). Male Sprague-Dawley rats were randomly divided into four groups: normoxia+sham surgery (CS), normoxia+permanent left anterior descending coronary artery (LAD) occlusion (CMI), hypoxic preconditioning+sham surgery (HS) and hypoxic preconditioning+permanent LAD occlusion (HMI). Rats in the preconditioned groups were subjected to systemic hypoxemic hypoxic exposure (10+/-0.4% O(2)) for 4 h followed by a 24 h period of normoxic reoxygenation prior to undergoing LAD occlusion. Rats in the normoxia group were time matched with the preconditioned group and maintained under normoxic conditions for a 28 h period prior to LAD occlusion. Western blot analysis was performed to measure VEGF expression and TUNEL staining with endothelial cell-specific antibody, anti-VWF, was used to examine endothelial apoptosis. One, two and three weeks after the LAD occlusion, baseline left ventricular pressures were monitored and recorded. Pharmacological stress tests with dobutamine infusion in progressively increasing doses revealed significantly elevated contractile reserve at each dose point in the HMI group compared to the CMI group. The HMI group displayed statistically significant increases in capillary as well as arteriolar density after 1, 2 and 3 weeks post-operation. Blood flow was also significantly elevated in the HMI groups when compared to the CMI group. The extent of endothelial cell apoptosis was found to be inversely proportional to VEGF expression. It was concluded that hypoxic preconditioning stimulates myocardial angiogenesis to an extent sufficient to exert significant cardioprotection in a rat model of myocardial infarction progressing to heart failure as evidenced by increased capillary/arteriolar density and enhanced ventricular contractile functional reserve.

Nonobstructive membranes of the left atrial appendage cavity: report of three cases.

A membranous structure causing functional stenosis at the mouth of the left atrial appendage (LAA) has been reported. In this study we describe the presence of nonobstructive membranes traversing the cavity of the LAA found incidentally on transesophageal echocardiography (TEE).

Diagnosis of Partial Anomalous Pulmonary Venous Connection with Intact Interatrial Septum by Echocardiography.

This case illustrates the complementary use of transthoracic echocardiography and transesophageal echocardiography in the diagnosis of partial anomalous pulmonary venous connection. The transthoracic echocardiogram suggested the presence of anomalous pulmonary venous return by demonstrating right heart volume overload and evidence of an intact atrial septum. Transesophageal echocardiography was required to confirm these findings and provide a firm anatomic diagnosis before surgery. This case also emphasizes that a high degree of clinical suspicion for this condition should occur in situations in which apparent right heart volume overload is otherwise unexplained.