Lower preoperative hematocrit, longer hospital stay, and neurocognitive decline after cardiac surgery.

BACKGROUND: Cardiopulmonary bypass may be associated with postoperative neurocognitive dysfunction; however, risk factors have not been clearly identified. We hypothesize that lower hematocrit levels are correlated with postoperative neurocognitive dysfunction. METHODS: A total of 30 patients underwent cardiac operations utilizing cardiopulmonary bypass and screening for neurocognitive dysfunction preoperatively and on postoperative day 4. Patients were analyzed according to hematocrit preoperatively, 6 hours postoperatively, and on postoperative day 4, and whether they received intra or postoperative transfusions of packed red blood cells. Neurocognitive data is presented as a difference in Repeatable Battery for the Assessment of Neuropsychological Status standardized score from baseline to postoperative day 4 and analyzed by unpaired two-tailed Spearman test and unpaired Mann-Whitney U test. RESULTS: There was a significant correlation between patients with lower hematocrit before surgery and a decline in neurocognitive function at postoperative day 4 (P < .05). All patients experienced a decrease in hematocrit during their hospital stay, but the hematocrit 6 hours postoperatively and postoperative day 4 did not impact cognition. Receiving a transfusion was also not associated with neurocognitive dysfunction. Patients with low hematocrit preoperatively had a consistently lower hematocrit throughout their stay. Prolonged total length of stay was also significantly associated with neurocognitive decline. CONCLUSION: A lower preoperative hematocrit and prolonged length of hospital stay are correlated with neurocognitive decline after cardiac surgery utilizing cardiopulmonary bypass.

Calpain inhibition modulates glycogen synthase kinase 3ß pathways in ischemic myocardium: A proteomic and mechanistic analysis.

BACKGROUND: Calpain inhibition has an enhancing effect on myocardial perfusion and improves myocardial density by inhibiting glycogen synthase kinase 3ß (GSK-3ß) and up-regulating downstream signaling pathways, including the insulin/PI3K and WNT/ß-catenin pathways, in a pig model of chronic myocardial ischemia in the setting of metabolic syndrome. METHODS: Pigs were fed a high-fat diet for 4 weeks, then underwent placement of an ameroid constrictor to the left circumflex artery. Three weeks later, the animals received no drug (high-cholesterol controls [HCC]), a high-dose calpain inhibitor (HCI), a low-dose calpain inhibitor (LCI), or a GSK-3ß inhibitor (GSK-3ßI). The diets and drug regimens were continued for 5 weeks and the myocardial tissue was harvested. RESULTS: Calpain and GSK-3ß inhibition caused an increase in myocardial perfusion ratios at rest and during pacing compared with controls. Pigs in the LCI and HCI groups had increased vessel density in the ischemic myocardium, and pigs in the GSK-3ßI group had increased vessel density in the ischemic and nonischemic myocardium compared with the HCC group. Calpain inhibition modulates proteins involved in the insulin/PI3K and WNT/ß-catenin pathways. Quantitative proteomics revealed that calpain and GSK-3ß inhibition significantly modulated the expression of proteins enriched in cytoskeletal regulation, metabolism, respiration, and calcium-binding pathways. CONCLUSIONS: In the setting of metabolic syndrome, calpain or GSK-3ß inhibition increases vessel density in both ischemic and nonischemic myocardial tissue. Calpain inhibition may exert these effects through the inhibition of GSK-3ß and up-regulation of downstream signaling pathways, including the insulin/PI3K and WNT/ß-catenin pathways.

Atorvastatin impairs the myocardial angiogenic response to chronic ischemia in normocholesterolemic swine.

OBJECTIVE: Statins, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, used routinely in patients with coronary disease, can improve endothelial function but can have biphasic and dose-dependent effects on angiogenesis. In vitro evidence suggests that the proangiogenic effects of statins are linked to activation of Akt, a mediator of endothelial cell survival and an activator of endothelial nitric oxide synthase. We investigated the functional and molecular effects of atorvastatin supplementation on microvascular function and the endogenous angiogenic response to chronic myocardial ischemia in normocholesterolemic swine. METHODS: Yucatan miniswine were fed a normal diet with (ATOR, n = 7) or without (control, n = 8) atorvastatin (1.5 mg/kg/d) for 20 weeks. Chronic ischemia was induced by ameroid constrictor placement around the circumflex artery. Myocardial perfusion was assessed at 3 and 7 weeks using isotope-labeled microspheres. In vitro microvessel relaxation responses and myocardial protein expression were evaluated. RESULTS: Endothelium-dependent relaxation to adenosine diphosphate and endothelium-independent relaxation to sodium nitroprusside were intact in both groups. The ATOR group demonstrated impaired microvessel relaxation to vascular endothelial growth factor (53% +/- 3% vs 70% +/- 7%, ATOR vs NORM at 10(-10) mol/L, P = .05) and fibroblast growth factor-2 (35% +/- 3% vs 57% +/- 5%, ATOR vs NORM at 10(-10) mol/L, P = .04). Baseline-adjusted myocardial perfusion in the ischemic circumflex territory was significantly reduced in the ATOR group (-0.29 +/- 0.10 mL/min/g vs NORM, P = .009). Phosphorylation of Akt was significantly increased in the ATOR group (+235% +/- 72%, P = .009 vs NORM), as was the myocardial expression of endostatin, an antiangiogenic protein (+51% +/- 9%, P < .001 vs NORM). Expression of vascular endothelial growth factor, Tie-2, fibroblast growth factor receptor-1, and endothelial nitric oxide synthase was similar in both groups. CONCLUSIONS: Atorvastatin supplementation is associated with impaired growth factor-mediated microvessel relaxation and a significant reduction in collateral-dependent perfusion. Chronic Akt activation, increased myocardial expression of endostatin, and impaired growth factor signaling may account for the diminished endogenous angiogenic response observed with atorvastatin treatment.

Biologically based myocardial regeneration: is there a role for the surgeon?

PURPOSE OF REVIEW: Despite advances in medical, percutaneous, and surgical treatment, there is an increasing burden of ischemic cardiovascular disease and heart failure. Over the past decade, a large number of preclinical and clinical studies have evaluated various biologic agents to treat these diseases. RECENT FINDINGS: Although the safety and feasibility of growth factor therapy, using vascular endothelial growth factors and fibroblast growth factors, for myocardial angiogenesis has been well established in a number of clinical trials, their ability to induce clinically significant improvements in symptoms remains uncertain. Numerous candidates have been proposed for cell-based therapies to improve myocardial perfusion and function and have demonstrated efficacy in preclinical studies. These cell types include skeletal myoblasts, bone-marrow derived cells, endothelial progenitors, and mesenchymal stem cells. Early clinical trials have demonstrated feasibility of cell harvest and implantation. SUMMARY: Biologic myocardial regeneration is a new and rapidly evolving area for the treatment of cardiovascular disease. Translation of these biologic entities into clinically useful therapeutic agents will require a better mechanistic understanding of their effects on the myocardium and the coronary circulation, optimization of delivery techniques, and systematic evaluation in large, randomized, placebo-controlled studies.