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A porcine model was used to study diastolic dysfunction in hibernating myocardium (HM) and recovery with coronary artery bypass surgery (CABG).HM was induced in Yorkshire-Landrace juvenile swine (n = 30) by placing a c-constrictor on left anterior descending artery causing chronic myocardial ischemia without infarction. At 12 weeks, animals developed the HM phenotype and were either killed humanely (HIB group; n = 11) or revascularized with CABG and allowed 4 weeks of recovery (HIB+CABG group; n = 19). Control pigs were matched for weight, age, and sex to the HIB group. Before the animals were killed humanely, cardiac magnetic resonance imaging (MRI) was done at rest and during a low-dose dobutamine infusion. Tissue was obtained for histologic and proinflammatory biomarker analyses.Diastolic peak filling rate was lower in HIB compared with control (5.4 ± 0.7 vs 6.7 ± 1.4 respectively, P = .002), with near recovery with CABG (6.3 ± 0.8, P = .06). Cardiac MRI confirmed preserved global systolic function in all groups. Histology confirmed there was no transmural infarction but showed interstitial fibrosis in the endomysium in both the HIB and HIB+CABG groups compared with normal myocardium. Alpha-smooth muscle actin stain identified increased myofibroblasts in HM that were less apparent post-CABG. Cytokine and proteomic studies in HM showed decreased peroxisome proliferator-activator receptor gamma coactivator 1-alpha (PGC1-α) expression but increased expression of granulocyte-macrophage colony-stimulating factor and nuclear factor kappa-light-chain enhancer of activated B cells (NFκB). Following CABG, PGC1-α and NFκB expression returned to control whereas granulocyte-macrophage colony-stimulating factor, tumor necrosis factor-α, and interferon gamma remained increased.In porcine model of HM, increased NFκB expression, enhanced myofibroblasts, and collagen deposition along with decreased PGC1-α expression were observed, all of which tended toward normal with CABG. Estimates of impaired relaxation with MRI within HM during increased workload persisted despite CABG, suggesting a need for adjuvant therapies during revascularization.

BACKGROUND: Among patients with stable coronary disease and moderate or severe ischemia, whether clinical outcomes are better in those who receive an invasive intervention plus medical therapy than in those who receive medical therapy alone is uncertain. METHODS: We randomly assigned 5179 patients with moderate or severe ischemia to an initial invasive strategy (angiography and revascularization when feasible) and medical therapy or to an initial conservative strategy of medical therapy alone and angiography if medical therapy failed. The primary outcome was a composite of death from cardiovascular causes, myocardial infarction, or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest. A key secondary outcome was death from cardiovascular causes or myocardial infarction. RESULTS: Over a median of 3.2 years, 318 primary outcome events occurred in the invasive-strategy group and 352 occurred in the conservative-strategy group. At 6 months, the cumulative event rate was 5.3% in the invasive-strategy group and 3.4% in the conservative-strategy group (difference, 1.9 percentage points; 95% confidence interval [CI], 0.8 to 3.0); at 5 years, the cumulative event rate was 16.4% and 18.2%, respectively (difference, -1.8 percentage points; 95% CI, -4.7 to 1.0). Results were similar with respect to the key secondary outcome. The incidence of the primary outcome was sensitive to the definition of myocardial infarction; a secondary analysis yielded more procedural myocardial infarctions of uncertain clinical importance. There were 145 deaths in the invasive-strategy group and 144 deaths in the conservative-strategy group (hazard ratio, 1.05; 95% CI, 0.83 to 1.32). CONCLUSIONS: Among patients with stable coronary disease and moderate or severe ischemia, we did not find evidence that an initial invasive strategy, as compared with an initial conservative strategy, reduced the risk of ischemic cardiovascular events or death from any cause over a median of 3.2 years. The trial findings were sensitive to the definition of myocardial infarction that was used. (Funded by the National Heart, Lung, and Blood Institute and others; ISCHEMIA ClinicalTrials.gov number, NCT01471522.).

Background NT-Pro BNP levels provide incremental value in perioperative risk assessment prior to major noncardiac surgery. Whether they can be pharmacologically modified in patients prior to an elective vascular operation is uncertain. Methods A double-blind, randomized controlled trial was implemented at a single institution. Patients were screened during their preoperative vascular clinic appointment and randomly assigned to CoQ10 (400 mg per day) versus Placebo for 3 days prior to surgery. Biomarkers, including NT-Pro BNP, troponin I and C-reactive protein were obtained prior to and following surgery for up to 48 hours. The primary endpoint was postoperative NT-Pro BNP levels, and secondary endpoint measures included myocardial injury, defined by an elevated cardiac troponin level and length of stay. Results One hundred and twenty-three patients were randomized to receive either CoQ10 (N = 62) versus Placebo (N = 61) for 3 days before vascular surgery. Preoperative cardiac risks included ischemic heart disease (N = 52), CHF (N = 12), stroke (N = 23), and diabetes mellitus (N = 48) and the planned vascular procedures were infrainguinal (N = 78), carotid (N = 36), and intraabdominal (N = 9). There were no intergroup differences in these clinical variables. NT-Pro BNP levels (median; IQs) in the CoQ10 and Placebo groups were 179 (75–347) and 217 (109–585) pg/ml, respectively, (P = 0.08) preoperatively, and 397 (211–686) and 591 (288–1,433) pg/ml respectively, (P = 0.01) at 24 hours following surgery. Patients with an elevated NT-Pro BNP had a higher incidence of myocardial injury, (58% vs. 20%; P Conclusions NT-Pro BNP levels predict adverse events post-vascular surgery and are lowered in those patients assigned to preoperative administration of CoQ10. Trial Registration clinicaltrials.gov Identifier: NCT03956017 . Among patients undergoing elective vascular surgery, 123 patients were randomized to either CoQ10 (400 mg/day) versus placebo for three days preoperatively. NT-Pro BNP levels (median; IQs) in the CoQ10 and Placebo groups were 179 (75–347) and 217 (109–585) pg/ml, respectively, (P = 0.08) preoperatively, and 397 (211–686) and 591 (288–1,433) pg/ml, respectively, (P = 0.01) post-surgery. Patients with an elevated NT-Pro BNP had a higher incidence of myocardial injury (58% vs. 20%; P

Patients presenting to the Emergency Room with consideration of an acute coronary syndrome (ACS) are risk-stratified with sensitive troponin assays. Among many patients who present with symptoms other than chest pain, they are admitted for observation if the troponin assay is above the upper reference limit of that specific assay. With the advent of high sensitivity troponin assays, it is estimated that the prevalence of admissions for secondary myocardial infarctions, termed Type 2 Myocardial Infarctions and Myocardial Injury, will increase by 100%. This is a heterogeneous population and although adverse outcomes such as readmission and death are high, outcome-based therapies with Guideline-Directed Treatments have not been advanced in this subset. As such, the clinician is often confused about the optimal treatment at hospital discharge. More studies should address the value of specific known therapies in this cohort, that have been shown to improve outcomes in patients with an acute coronary syndrome or Type 1 Myocardial Infarction.

Saphenous vein grafts (SVGs) have high rates of in-stent restenosis (ISR). We compared the baseline clinical and angiographic characteristics of patients and lesions that did develop ISR with those who did not develop ISR during a median follow-up of 2.7 years in the DIVA study (NCT01121224). We also examined the ISR types using the Mehran classification. ISR developed in 119 out of the 575 DIVA patients (21%), with similar incidence among patients with drug-eluting stents and bare-metal stents (BMS) (21% vs 21%, p = 0.957). Patients in the ISR group were younger (67 ± 7 vs 69 ± 8 years, p = 0.04) and less likely to have heart failure (27% vs 38%, p = 0.03) and SVG lesions with Thrombolysis In Myocardial Infarction 3 flow before the intervention (77% vs 83%, p0.01), but had a higher number of target SVG lesions (1.33 ± 0.64 vs 1.16 ± 0.42, p0.01), more stents implanted in the target SVG lesions (1.52 ± 0.80 vs 1.31 ± 0.66, p0.01), and longer total stent length (31.37 ± 22.11 vs 25.64 ± 17.42 mm, p = 0.01). The incidence of diffuse ISR was similar in patients who received drug-eluting-stents and BMS (57% vs 54%, p = 0.94), but BMS patients were more likely to develop occlusive restenosis (17% vs 33%, p = 0.05).

Background: Over the past three decades, there has been a 900% increase in the number of women experiencing incarceration in Minnesota. We wished to test whether handwriting, as creative visual art expression for women in jail, would be a positive experience for them as well as for individuals viewing the artwork during expositions. Methods: Over a 2-year period, the principal artist invited women residents from four separate county jails in Minnesota, to handwrite their thoughts on a sheet of paper. Two hundred twenty-three women residents participated in the artist-led handwriting/visual art sessions and gave permission to use their authentic script, anonymously, for presentation in a 3-D visual art form. At the conclusion of the sessions, a survey was offered at each venue, which asked three questions relative to the participation in the handwriting art project: (1) Did it have a positive impact on me? (2) Would you recommend it to other women who are incarcerated? (3) Do you want to participate in more projects such as this during your incarceration? The resulting artwork of more than 1,000 sculptures, each exhibiting a portion of the women's original script, was displayed at several public showings and a survey was offered at each venue, which asked: (1) Did the exhibition increase awareness of mass incarceration of women? (2) Did it help the viewer see women who are incarcerated? (3) Did it make the viewer realize that action is needed to reduce incarceration of women? Survey questions were graded from 1 to 5, with a sliding scale from strongly disagree to strongly agree. Results: The impact of this project of art activism has been very positive on both participants and the larger audience. The vast majority of women residents responding to the survey either agreed or strongly agreed that their participation in the project (1) had a positive effect on them (94%), (2) would recommend it to other incarcerated women (94%), and (3) would want to participate in more projects such as this (93%). A total of 425 surveys were collected among the audience at several sites: the law school (N = 87), open studios (N = 268), and a public library (N = 62). The vast majority of individuals responding to the survey either agreed or strongly agreed that the exhibited work (1) increased awareness of the problem (93%), (2) showed the humanity behind the script (88%), and (3) suggested that interventions were needed to address the problem (86%). Conclusions: Women under incarceration in county jails, who participated in a visual art handwriting program, as part of a collaborative visual art project led by principal artist, found great value in the sessions and agreed that such programs should be available to other women in detention. The overwhelming majority of the audience of the resulting exhibitions in public venues strongly agreed that interventions are needed to address the mass incarceration of women in Minnesota, suggesting the importance of art as a vehicle for increasing awareness about social problems and perhaps social change.

Background: Direct stenting without pre-dilation or post-dilation has been advocated for saphenous vein graft percutaneous coronary intervention to decrease the incidence of distal embolization, periprocedural myocardial infarction, and target lesion revascularization. Methods: We performed a post hoc analysis of patients enrolled in the DIVA (Drug-Eluting Stents Versus Bare Metal Stents in Saphenous Vein Graft Angioplasty; NCT 01121224) prospective, double-blind, randomized controlled trial. Patients were stratified into stent-only and balloon-stent groups. Primary end point was 12-month incidence of target vessel failure (defined as the composite of cardiac death, target vessel myocardial infarction, or target vessel revascularization). Secondary end points included all-cause death, stent thrombosis, myocardial infarction, and target lesion revascularization during follow-up. Results: Of the 575 patients included in this substudy, 185 (32%) patients underwent stent-only percutaneous coronary intervention. Patients in the stent-only versus balloon-stent group had similar baseline characteristics and similar incidence of target vessel failure at 12-months (15% versus 19%; hazard ratio, 1.34 [95% CI, 0.86–2.08]; P =0.19). During long-term follow-up (median of 2.7 years), the incidence of definite stent thrombosis (1% versus 5%; hazard ratio, 9.20 [95% CI, 1.23–68.92]; P =0.0085), the composite of definite or probable stent thrombosis (5% versus 11%; hazard ratio, 2.52 [95% CI, 1.23–5.18]; P =0.009), and target vessel myocardial infarction (8% versus 14%; hazard ratio, 1.92 [95% CI, 1.08–3.40]; P =0.023) was lower in the stent-only group. Multivariable analysis showed that a higher number of years since coronary artery bypass grafting and >1 target saphenous vein graft lesions were associated with increased target vessel failure during entire follow-up, while preintervention Thrombolysis in Myocardial Infarction-3 flow was protective. Conclusions: In patients undergoing percutaneous coronary intervention of de novo saphenous vein graft lesions, there was no difference in target vessel failure at 12 months and long-term follow-up in the stent-only versus the balloon-stent group; however, the incidence of stent thrombosis was lower in the stent-only group, as was target vessel myocardial infarction. Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT 01121224.

Background Early MPI after CABG is currently considered rarely appropriate in asymptomatic patients. This study aimed to identify prognostic value of nuclear stress-imaging post-CABG. Methods This was a single center prospective study looking at long-term outcomes post-CABG. Per protocol participants underwent SPECT-MPI stress testing and coronary angiogram on the same day, 1-year following CABG. Defect size was semi-quantified. The primary outcomes were the composite of death and congestive heart failure. Results Eighty-four participants underwent nuclear stress-imaging and angiography, with a median follow-up of 11.1 years. Three separate stress findings predicted the primary outcome: inability to reach stage 3 of a Bruce protocol (OR 7.3, CI 2.4-22.1, P Conclusion In clinically stable patients early after revascularization with CABG, SPECT-MPI can identify patients at higher risk of heart failure and death.

Background Expression of mitochondrial proteins is reduced within hibernating myocardium (HM). It is unclear whether dietary supplementation with CoQ10 can increase expression of mitochondrial electron transport chain (ETC) and antioxidant proteins within this tissue. In a swine model of HM, we tested whether dietary administration of CoQ10 for four weeks enhances the expression of ETC and antioxidant proteins within the mitochondria via increased PGC1α signaling. Methods 12 swine were instrumented with a fixed constrictor around the LAD artery to induce gradual stenosis. At three months, transthoracic ECHO was performed to confirm the presence of a wall motion abnormality in the anterior wall. Animals were then randomly assigned to receive daily dietary supplements of either CoQ10 (10 mg/kg/day) or placebo for four weeks. At this time, animals underwent a final ECHO and terminal procedure. Expression of nuclear-bound PGC1α (Western blots) and mitochondrial proteins (Tandem Mass Tag) were determined. Results Mitochondrial and nuclear membranes were isolated from the LAD region. Nuclear-bound PGC1α levels were > 200-fold higher with administration of four weeks of CoQ10 treatment (p = 0.016). Expression of ETC proteins was increased in those animals that received CoQ10. Compared with mitochondria in the LAD region from placebo-treated pigs, CoQ10-treated pigs had higher levels of Complex I (p = 0.03), Complex IV (p = 0.04) and Complex V (p = 0.028) peptides. Conclusions Four weeks of dietary CoQ10 in HM pigs enhances active, nuclear-bound PGC1α and increases the expression of ETC proteins within mitochondria of HM tissue.

Quality of care utilization measures for patients admitted to the hospital with an acute myocardial infarction (AMI) include length of stay (LOS) and 30-day readmission rates. Our aim was to test whether efforts resulting in reduced LOS in patients diagnosed as having AMI would result in a higher risk of readmission within 30 days of hospital discharge and whether specific interventions could be targeted to reduce readmissions.Using data supplied by the Veterans Affairs Inpatient Evaluation Center, we analyzed both the readmissions within 30 days of an AMI and LOS and determined the timing of readmissions and associated diagnoses.During 2013-2015, 35 (13.3%) of 263 patients with AMI were readmitted within 30 days of discharge compared with 19 (13.4%) of 142 patients during 2016 (not significant). During the same time, LOS was3 days in most patients. From 2013 to 2015, the initial hospital time was 6 ± 6 days, whereas time out of the hospital before readmission was 11 ± 8 days; these times did not differ from 2016. Initial therapeutic decisions were based on coronary anatomy in90% of patients with a decision to proceed with revascularization in most patients. Diagnoses during readmission to the hospital were also similar during early and later time periods and most frequently were a result of either coronary artery bypass grafting-related complications from the initial hospitalization or elective coronary artery bypass grafting. Acute coronary syndrome-related diagnoses and recurrent noncardiac causes of chest pain also were common diagnoses during both time periods and did not involve extensive workup during the readmission.Readmissions for patients with AMI were stable during a 4-year period, at a time that efforts to reduce LOS were emphasized. Because a significant proportion of readmissions involved noncardiac sources of chest pain, improved communication between the emergency department and in-patient cardiology services at the time of triage may be a feasible way to improve efficiency of utilization.

Objectives The study examined the frequency in which a right coronary artery (RCA) anomaly resulting in intra-atrialization of the vessel might increase risk of RCA damage during routine radiofrequency ablation in the right atrium even with low power or temperature. Background Right coronary artery (RCA) injury with endocardial RF ablation of the right atrium is a rare complication. Methods This prospective observational study comprised an analysis of coronary artery anatomies in 331 patients who underwent autopsies at our institution from 2005 to 2014. The presence of intra-atrial RCA including the number and length of intra-atrial RCA segments with accompanying atherosclerosis and coronary anomalies were evaluated. Results The authors report a case series of 6 of 331 (1.8%) patients in whom autopsies showed evidence of an intra-atrial RCA. The patients were all men (average 69 ± 12 years of age). They observed 3 variations of the intra-atrial RCA course. In 2 similar variations, the RCA entered the anterolateral aspect of the right atrium, returning to its normal distribution to supply the distal RCA (case 4 of 6) and the atrioventricular nodal artery (case 1 of 6). In the sixth case, the atrialized artery was an anterior branch of the RCA, in which the artery similarly coursed across the pectinate muscles, extending to the region of the anterior crista terminalis, before diving into the muscle. Conclusions The prevalence and variants of the intra-atrial RCA have not been reported before. In the presence of an intra-atrial artery, RCA damage may occur due to direct injury rather than collateral injury due to transmural extension of an ablation lesion.

Objective Clinical studies demonstrate delayed recovery of hibernating myocardium (HM) following coronary artery bypass graft (CABG) surgery. Cardiac magnetic resonance (CMR) imaging is effective in identifying HM in clinical settings. Our animal model of HM shows partial but incomplete functional recovery 1 month following CABG using echocardiography. This study uses CMR imaging to determine completeness of recovery 3 months post-CABG. Methods Swine (N = 12) underwent left anterior descending artery (LAD) 1.5-cm constrictor placement creating a territory of HM over 12 weeks. CMR at 12 weeks confirmed hibernation without infarction (N = 12). Off-pump left internal thoracic artery (LITA) to the LAD was performed in 9 animals. Three animals were killed as HM controls. CMR imaging was repeated in revascularized animals before death at 1 (n = 4) or 3 months (n = 5). CMR imaging was performed at baseline and with dobutamine infusion (5 μg/kg/min). Results Twelve weeks after constrictor placement, CMR imaging confirmed viability in LAD region and LAD stenosis in all animals. In HM, wall thickening is reduced at baseline but with contractile reserve present during dobutamine infusion. Following revascularization, CMR imaging confirmed patent LITA graft (n = 9). Analysis of baseline regional function shows incomplete recovery of HM following CABG, with reduced contractile reserve at both 1 and 3 months post-CABG. Conclusions CMR imaging provides accurate spatial resolution of regional contractile function and confirms the presence of HM at 12 weeks following instrumentation of the LAD. Three months following CABG, partial recovery of HM with contractile reserve is present in the single LAD territory.

The purpose of this study was to determine the incidence and correlates of QT prolongation or ventricular tachycardia (VT) resulting in discontinuation of dofetilide in a real-world setting.Dofetilide is a class III antiarrhythmic agent approved for achieving and maintaining sinus rhythm in patients with symptomatic atrial fibrillation. Because of a risk of QT prolongation and VT, patients starting dofetilide need to be hospitalized for 3 days to closely monitor telemetry and electrocardiography. In large clinical trials, 3% of patients had to discontinue dofetilide because of QT prolongation, but data from real-world experience are lacking.We examined 114 consecutive patients with atrial fibrillation who were hospitalized for starting dofetilide at the Minneapolis Veterans Affairs Health Care System from 2011 to 2014.The mean age of the patients was 64 ± 8 years. Dofetilide was discontinued in 22 (19%) patients because of QT prolongation (17%) or VT (2%). A total of 32 (28%) patients were taking other QT-prolonging drugs. Of these, 10 (31%) had to discontinue dofetilide versus 12 (15%) of the 82 patients who were not taking any other QT-prolonging drugs (p = 0.04). Patients who were taking concomitant QT-prolonging drugs were 1.9 times more likely to discontinue dofetilide (95% confidence interval: 1.1 to 3.4; p = 0.04) compared with those who were not taking any other QT-prolonging drugs.The incidence of QT prolongation or VT that lead to discontinuation of dofetilide is remarkably higher in the real-world setting than in clinical trials. Concomitant use of other QT-prolonging drugs was associated with discontinuation of dofetilide.

NT-Pro BNP levels provide incremental value in perioperative risk assessment prior to major noncardiac surgery. Whether they can be pharmacologically modified in patients prior to an elective vascular operation is uncertain.A double-blind, randomized controlled trial was implemented at a single institution. Patients were screened during their preoperative vascular clinic appointment and randomly assigned to CoQOne hundred and twenty-three patients were randomized to receive either CoQNT-Pro BNP levels predict adverse events post-vascular surgery and are lowered in those patients assigned to preoperative administration of CoQclinicaltrials.gov Identifier: NCT03956017. Among patients undergoing elective vascular surgery, 123 patients were randomized to either CoQ

Hibernating myocardium is a subset of ischemic cardiac disease characterized by viable but dysfunctional tissue. Standard treatment for hibernating myocardium is coronary artery bypass graft, which reduces arrhythmias and improves survival but does not fully restore function, presenting a gap in currently available treatments. Large animal studies of hibernating myocardium have identified impaired mitochondrial dynamics as a root cause of persistent cardiac dysfunction despite surgical revascularization. This study presents a novel in vitro model of hibernating myocardium cardiomyocytes to study active mitochondrial respiration in hibernating myocardium cells, and to test the paracrine effect of mesenchymal stem cells on impaired mitochondrial function. Exposure of cardiomyocytes to hypoxic conditions of 1% oxygen for 24 hours resulted in a phenotype consistent with hibernating myocardium cardiac tissue, including decreased respiratory capacity under high work states, decreased expression of mitochondrial proteins, and preserved cellular viability. Co-culture of hibernating myocardium cardiomyocytes with mesenchymal stem cells restored mitochondrial respiratory function, potentially via an increase in proliferator-activated receptor gamma coactivator 1-alpha-driven mitochondrial biogenesis. Co-culture treatment of hibernating myocardium cardiomyocytes with mesenchymal stem cells shows improvement in both mitochondrial function and ATP production, both of which are critical for effectively functioning cardiac tissue. These results suggest that mesenchymal stem cell therapy as an adjunct treatment to revascularization may address the current gap in treatment for hibernating myocardium patients.

Cardiac arrest after cardiac procedures has a case fatality rate of approximately 60%. However, the long-term risk of death and outcomes among survivors of postoperative cardiac arrest is less clear.We examined the mortality and outcomes of 6,979 consecutive patients who underwent cardiac operations from 1991 to 2014 in the Minneapolis Veterans Affairs Health Care System.Cardiac arrest occurred in 182 patients (2.6%) at a median of 3 days (range, 0 to 39 days) after the operation. Of these, 93 (51%) died during the same hospitalization, and an additional 24 (13%) died within 1 year. Mortality at 30 days (51% vs 1.9%; p0.0001), at 1 year (64% vs 6%; p 0.0001), and after a mean follow-up of 7.5 ± 5.5 years (81% vs 34%; p0.0001), was higher in those with vs without cardiac arrest. After adjusting for age, sex, year, and type of operation, an in-hospital cardiac arrest was associated with a 4.7-times (95% confidence interval [CI], 3.9 to 5.6; p 0.0001) higher risk of long-term death in the entire cohort, 2.0-times (95% CI, 1.6 to 2.7; p0.0001) higher risk among those who survived 30 days, and 1.3-times (95% CI, 0.9 to 1.9; p = 0.14) higher risk among those who survived 1 year after the operation. Being discharged to a facility (hazard ratio, 3.97; 95% CI, 1.52 to 10.32; p = 0.005) and renal dysfunction (hazard ratio, 3.35; 95% CI, 1.42 to 7.89; p = 0.006) were independent predictors of death amongst cardiac arrest survivors.Long-term mortality remains high in patients discharged alive after postoperative cardiac arrest. Discharge disposition and renal dysfunction after cardiac arrest have important prognostic implications.

Chronic cardiac ischemia that impairs cardiac function, but does not result in infarct, is termed hibernating myocardium (HM). A large clinical subset of coronary artery disease (CAD) patients have HM, which in addition to causing impaired function, puts them at higher risk for arrhythmia and future cardiac events. The standard treatment for this condition is revascularization, but this has been shown to be an imperfect therapy. The majority of pre-clinical cardiac research focuses on infarct models of cardiac ischemia, leaving this subset of chronic ischemia patients largely underserved. To address this gap in research, we have developed a well-characterized and highly reproducible model of hibernating myocardium in swine, as swine are ideal translational models for human heart disease. In addition to creating this unique disease model, we have optimized a clinically relevant treatment model of coronary artery bypass surgery in swine. This allows us to accurately study the effects of bypass surgery on heart disease, as well as investigate additional or alternate therapies. This model surgically induces single vessel stenosis by implanting a constrictor on the left anterior descending (LAD) artery in a young pig. As the pig grows, the constrictor creates a gradual stenosis, resulting in chronic ischemia with impaired regional function, but preserving tissue viability. Following the establishment of the hibernating myocardium phenotype, we perform off-pump coronary artery bypass graft surgery to revascularize the ischemic region, mimicking the gold-standard treatment for patients in the clinic.

Hibernating myocardium is characterized by viable yet dysfunctional myocardium secondary to chronic ischemia, with studies demonstrating incomplete early recovery after coronary artery bypass graft (CABG). We tested whether mitochondrial fusion proteins, an indicator of mitochondrial biogenesis, are increased in hibernating myocardium post-CABG.A constrictor was placed on the left anterior descending (LAD) artery of nine pigs. Four of these pigs additionally underwent CABG 12 wk later with a left internal mammary artery graft to the LAD distal to the constrictor. Five pigs had a constrictor placed but did not undergo CABG (Hib). Five pigs did not have a constrictor placed (control). Computerized tomography angiography was used to confirm stenosis at the site of constrictor placement and patency of left internal mammary artery grafts. Regional blood flows were determined at baseline and during 40 μg/kg/min dobutamine infusion. Mitochondrial proteins were quantified by Western blot.Blood flow in the LAD region after CABG was lower than remote regions during dobutamine infusion (2.54 ± 0.24 versus 3.46 ± 0.33 mL/min/g; P 0.05). Electron transport chain proteins were ∼70% lower in Hib compared with those in control and failed to normalize after CABG. Post-CABG, PGC1α nuclear-bound content was increased compared with Hib (9.02 ± 0.48 versus 5.54 ± 0.98 arbitrary units, respectively; P 0.05), and expression of mitofusins-1 and 2 and optic atrophy-1 more than doubled.PGC1α and mitochondrial fusion proteins are increased 4 wk post-CABG in hibernating hearts, indicating mitochondrial fusion has begun to occur and signaling early mitochondrial recovery. Future studies should address changes in maximal myocardial oxygen consumption relative to mitochondrial protein expression.

We have previously shown that mitochondrial uncoupling protein-2 (UCP-2) is increased in a swine model of hibernating myocardium (HM). Although UCP-2 reduces oxidant stress, it can promote inefficiency of the electron transport chain. In this study, we tested whether UCP-2 remains increased in revascularized HM (RHM) after coronary artery bypass grafting (CABG).Seven swine underwent thoracotomy with placement of a constrictor on the left anterior descending artery (LAD). Twelve weeks later, a left internal mammary artery graft was placed on the distal LAD. Four weeks post-CABG, computed tomography angiography documented patent grafts and function. At the terminal study, blood flow to the LAD and remote territories were assessed during high dose dobutamine and mitochondria isolated from both regions for analysis. Comparisons were made to a group of swine with HM who underwent constrictor placement without bypass grafting (n = 4).During dobutamine infusion, RHM demonstrated lower blood flows (2.44 ± 0.23 versus 3.43 ± 0.30 mL/min/g; P 0.05) and reduced wall thickening (33 ± 9% versus 52 ± 13%; P 0.05) compared with remote regions. RHM had lower respiratory control indices (3.7 ± 0.3 versus 4.3 ± 0.4; P 0.05) with persistently increased UCP-2 content.Despite patent grafts, RHM demonstrates a submaximal response to dobutamine infusion and increased mitochondrial UCP-2 expression. These data support the notion that recovery of the mitochondria in RHM is delayed early post-CABG and may contribute to impaired oxygen consumption and contractile reserve during catecholamine challenges.

Myocardial responses to chronic ischemia represent a continuum of adaptations resulting, over time, in a stress-resistant phenotype. One such adaptation, hibernating myocardium (HM), has increased antioxidant capacity that protects against ischemia-induced oxidative stress. Studies have suggested that revascularization alone may not fully restore cardiac function, highlighting the need for targeted therapies to serve as adjuncts to the innate healing process following revascularization. In our review, we discuss current understanding of HM and the recovery process following surgical revascularization, focusing on animal models of HM to understand implications for human patients.

Intravenous sodium bicarbonate and oral acetylcysteine are widely used to prevent acute kidney injury and associated adverse outcomes after angiography without definitive evidence of their efficacy.Using a 2-by-2 factorial design, we randomly assigned 5177 patients at high risk for renal complications who were scheduled for angiography to receive intravenous 1.26% sodium bicarbonate or intravenous 0.9% sodium chloride and 5 days of oral acetylcysteine or oral placebo; of these patients, 4993 were included in the modified intention-to-treat analysis. The primary end point was a composite of death, the need for dialysis, or a persistent increase of at least 50% from baseline in the serum creatinine level at 90 days. Contrast-associated acute kidney injury was a secondary end point.The sponsor stopped the trial after a prespecified interim analysis. There was no interaction between sodium bicarbonate and acetylcysteine with respect to the primary end point (P=0.33). The primary end point occurred in 110 of 2511 patients (4.4%) in the sodium bicarbonate group as compared with 116 of 2482 (4.7%) in the sodium chloride group (odds ratio, 0.93; 95% confidence interval [CI], 0.72 to 1.22; P=0.62) and in 114 of 2495 patients (4.6%) in the acetylcysteine group as compared with 112 of 2498 (4.5%) in the placebo group (odds ratio, 1.02; 95% CI, 0.78 to 1.33; P=0.88). There were no significant between-group differences in the rates of contrast-associated acute kidney injury.Among patients at high risk for renal complications who were undergoing angiography, there was no benefit of intravenous sodium bicarbonate over intravenous sodium chloride or of oral acetylcysteine over placebo for the prevention of death, need for dialysis, or persistent decline in kidney function at 90 days or for the prevention of contrast-associated acute kidney injury. (Funded by the U.S. Department of Veterans Affairs Office of Research and Development and the National Health and Medical Research Council of Australia; PRESERVE ClinicalTrials.gov number, NCT01467466 .).

This study hypothesizes that post-extrasystolic potentiation reflects left ventricle contractile reserve and therefore may predict an improvement of premature ventricular contraction (PVC)-induced cardiomyopathy after PVC ablation.Post-extrasystolic potentiation is a physiologic phenomenon of blood pressure accentuation after a PVC beat.We performed a retrospective study of patients with a PVC burden of ≥10% PVC/24 h and left ventricular ejection fraction (LVEF) of 50% who underwent successful ablation between January 1, 2009, to June 30, 2015. Subjects were classified as having reversible (a final LVEF ≥50%) or irreversible (final LVEF 50%) LV dysfunction on a follow-up echocardiogram. A reference (control) group with ≥10% PVC but normal LV function was also identified.Sixty-one patients (age 68 ± 11 years, 98% male) were studied: 30 with preserved and 31 with reduced LVEF. During median follow-up of 9.4 months, the LVEF of 17 of 31 reduced EF patients improved (reversible) but 14 did not (irreversible). The post-PVC beat systolic blood pressure (SBP) (mm Hg) increase ranged from 12.1 in control subjects (LVEF50%) to 11.5 in reversible patients to 5 in irreversible patients. In multivariate analysis, the independent predictors of reversible LV function were post-PVC SBP rise (odds ratio [OR]: 4.61; 95% confidence interval [CI]: 1.45 to 15.83 per 5-mm Hg increase; p 0.001), post-PVC pulse pressure change (OR: 5.2; 95% CI: 2.3 to 18.6 per 5-mm Hg increase; p 0.001), and PVC QRS duration (OR: 2.78; 95% CI: 1.63 to 10.94 per 10-ms increase; p 0.001).In patients with LV dysfunction and frequent PVC, post-PVC SBP accentuation may be a marker for subsequent recovery of LVEF after ablation in presumed PVC-induced cardiomyopathy.

Background Remote ischemic preconditioning ( RIPC ) has been shown to reduce infarct size in animal models. We hypothesized that RIPC before an elective vascular operation would reduce the incidence and amount of a postoperative rise of the cardiac troponin level. Methods and Results Cardiac Remote Ischemic Preconditioning Prior to Elective Vascular Surgery ( CRIPES ) was a prospective, randomized, sham‐controlled phase 2 trial using RIPC before elective vascular procedures. The RIPC protocol consisted of 3 cycles of 5‐minute forearm ischemia followed by 5 minutes of reperfusion. The primary endpoint was the proportion of subjects with a detectable increase in cardiac troponin I ( cTnI ) and the distribution of such increases. From June 2011 to September 2015, 201 male patients (69±7, years) were randomized to either RIPC (n=100) or a sham procedure (n=101). Indications for vascular surgery included an expanding abdominal aortic aneurysm (n=115), occlusive peripheral arterial disease of the lower extremities (n=37), or internal carotid artery stenosis (n=49). Of the 201 patients, 47 (23.5%) had an increase in cTnI above the upper reference limit within 72 hours of the vascular operation, with no statistically significant difference between those patients assigned to RIPC (n=22; 22.2%) versus sham procedure (n=25; 24.7%; P =0.67). Among the cohort with increased cTnI , the median peak values (interquartile range) in the RIPC and control group were 0.048 (0.004–0.174) and 0.017 (0.003–0.105), respectively ( P =0.54). Conclusions In this randomized, controlled trial of men with increased perioperative cardiac risks, elevation in cardiac troponins was common following vascular surgery, but was not reduced by a strategy of RIPC . Clinical Trial Registration URL : https://www.clinicaltrials.gov . Unique identifier: NCT 01558596.

The utility of measuring cardiac troponins (cTn) in asymptomatic patients during the perioperative period has been controversial. In the present substudy of the Cardiac Remote Ischemic Preconditioning Prior to Elective Vascular Surgery Trial (NCT01558596), we hypothesized that surveillance of myocardial injury with cTnI in the perioperative period would lead to initiation or intensification of medical therapies for coronary artery disease. Increases in cTnI ≥0.01 μg/l in the perioperative period were considered clinically significant. Intensification of medical therapy was defined as initiation of aspirin or initiation or increases in the dose of angiotensin-converting-enzyme inhibitors or angiotensin-receptor blockers, statins, or β blockers and was left to the discretion of treating physicians. From June 2011 to April 2015, a total of 185 patients (mean age 68 ± 7 years, 100% men) were enrolled in the trial. A total of 28 patients (15%) had significant increases in cTnI after vascular surgery, and 38 (20.5%) had their medical therapies intensified in the perioperative period. Among patients with increases in cTnI, 11 (39%) had intensification of medical therapy versus 27 patients (17%) with no or smaller increases in cTnI (p = 0.02). Among those patients with ΔcTnI ≥0.01 μg/l, hospital readmissions at 3 to 6 months were 7.6% for the intensification group versus 25% for the no intensification group (p = 0.18). Mortality rate at 6 months was low in both groups (2.6% vs 0%, respectively, p = 0.13). In conclusion, among patients undergoing vascular surgery, perioperative increases in cTn were associated with initiation or intensification of medical therapies for coronary artery disease at the time of discharge.

There is conflicting clinical evidence whether administration of coenzyme Q10 (CoQ10) improves function following coronary artery bypass graft surgery (CABG). Using a swine model of hibernating myocardium, we tested whether daily CoQ10 would improve contractile function by MRI at 4-week post-CABG. Twelve pigs underwent a thoracotomy and had a constrictor placed on the left anterior descending (LAD). At 12 weeks, they underwent off-pump bypass and received daily dietary supplements of either CoQ10 (10 mg/kg/day) or placebo. At 4-week post-CABG, circumferential strain measurements in the hibernating LAD region from placebo and CoQ10 groups were not different and increased to a similar extent with dobutamine (-14.7 ± 0.6 versus -14.8 ± 0.1, respectively (NS)). Post-sacrifice, oxidant stress markers were obtained in the mitochondrial isolates and protein carbonyl in the placebo, and CoQ10 groups were 6.14 ± 0.36 and 5.05 ± 0.32 nmol/mg, respectively (NS). In summary, CoQ10 did not improve contractile reserve or reduce oxidant stress at 4-week post-CABG.

Background The utility of postoperative troponins as an independent predictor of long-term mortality after vascular surgery is unknown. Methods One hundred sixty-four consecutive patients underwent vascular surgery and postoperative mortality was determined at 2.5 years. Troponins were drawn within 48 hours postsurgery and the peak levels, defined by the upper reference limit (URL), were categorized as negative ( Results Mortality in the high positive (n = 44), low positive (n = 41), and negative (n = 79) troponin groups was 46%, 17%, and 6%, respectively ( P P P = .043), and use of statins (OR, 0.19; 95% CI, 0.07-0.49; P c index for peak troponin levels was 0.75 (95% CI, 0.68-0.82; P Conclusions Among patients undergoing vascular surgery, an elevated postoperative troponin level provides incremental value in predicting long-term outcomes, when compared with standard preoperative cardiac and surgical risks.

Cabrera JA, Ziemba EA, Colbert R, Anderson LB, Sluiter W, Duncker DJ, Butterick TA, Sikora J, Ward HB, Kelly RF, McFalls EO. Altered expression of mitochondrial electron transport chain proteins and improved myocardial energetic state during late ischemic preconditioning. Am J Physiol Heart Circ Physiol 302: H1974-H1982, 2012. First published March 2, 2012; doi: 10.1152/ajpheart.00372.2011.-Altered expression of mitochondrial electron transport proteins has been shown in early preconditioned myocardial tissue. We wished to determine whether these alterations persist in the Second Window of Protection (SWOP) and if so, whether a favorable energetic state is facilitated during subsequent ischemia. Fourteen pigs underwent a SWOP protocol with ten 2-minute balloon inflations in the LAD artery, each separated by 2 minutes reperfusion. Twenty-four hours later, mitochondria were isolated from SWOP and SHAM pig hearts and analyzed for uncoupling protein (UCP)-2 content by western blot analysis, proteomic changes by iTRAQ (R) and respiration by an oxygen electrode. In parallel in vivo studies, high-energy nucleotides were obtained by transmural biopsy from anesthetized SWOP and SHAM pigs at baseline and during sustained low-flow ischemia. Compared with SHAM mitochondria, ex vivo SWOP heart tissue demonstrated increased expression of UCP-2, Complex IV (cytochrome c oxidase) and Complex V (ATPase) proteins. In comparison with SHAM pigs during in vivo conditions, transmural energetics in SWOP hearts, as estimated by the free energy of ATP hydrolysis (Delta G(0)), were similar at baseline but had decreased by the end of low-flow ischemia (-57.0 +/- 2.1 versus -51.1 +/- 1.4 kJ/mol; P < 0.05). In conclusion, within isolated mitochondria from preconditioned SWOP hearts, UCP-2 is increased and in concert with enhanced Complex IV and V proteins, imparts a favorable energetic state during low-flow ischemia. These data support the notion that mitochondrial adaptations that may reduce oxidant damage do not reduce the overall efficiency of energetics during sustained oxygen deprivation.

Myocardial uncoupling protein (UCP)-2 is increased with chronic peroxisome proliferator-activated receptor gamma (PPAR gamma) stimulation, but the effect on membrane potential and superoxide is unclear. Wild-type (WI) and UCP-2 knockout (KO) mice were given a 3-week diet of control (C) or the PPAR gamma agonist pioglitazone (PIO; 50 mu g/g-chow per day). In isolated mitochondria, UCP-2 content by Western blots, membrane potential (Delta Psi(m)) by tetraphenylphosphonium (TPP), and relative superoxide levels by dihydroethidium (DHE) were measured. Oxygen respiration was determined at base-line and after 10 min anoxia-reoxygenation. PIO induced a 2-fold increase in UCP-2 and nuclear-bound PGC1 alpha in WT mice with no UCP-2 expression in KO mice. Mitochondria! Delta Psi(m) from WT mice on C and PIO diets was -166 +/- 4 mV and -147 +/- 6 mV, respectively (P < 0.05). These values were lower than in UCP-2 KO mice on C and PIO (-180 +/- 4 mV and -180 +/- 4 mV, respectively; P < 0.05). Maximal complex III inhibitable superoxide from WT mice on C and PIO diets was 22.5 +/- 1.3 and 17.8 +/- 1.1 AU, respectively (P < 0.05), and were lower than UCP-2 KO on C and PIO (32.9 +/- 2.3 and 29.2 +/- 1.9 AU, respectively; P < 0.05). Postanoxia, the respiratory control index (RCI) in mitochondria from wr mice with and without PIO was 2.5 +/- 0.3 and 2.4 +/- 0.2, respectively, and exceeded that of UCP-2 KO mice on C and PIO (1.2 +/- 0.1 and 1.4 +/- 0.1, respectively; P < 0.05). In summary, chronic PPARy stimulation leads to depolarization of the inner membrane and reduced superoxide of isolated heart mitochondria, which was critically dependent on increased expression of UCP-2. Thus, UCP-2 expression affords resistance to brief anoxia-reoxygenation. (Translational Research 2012;159:383-390)

The peroxisome proliferator-activated receptor (PPAR)-γ drug pioglitazone (PIO) has been shown to protect tissue against oxidant stress. In a swine model of chronic myocardial ischemia, we tested whether PIO increases PGC1-α signaling and the expression of mitochondrial antioxidant peptides. Eighteen pigs underwent a thoracotomy with placement of a fixed constrictor around the LAD artery. At 8 weeks, diet was supplemented with either PIO (3 mg/kg) or placebo for 4 weeks. Regional myocardial function and blood flow were determined at the time of the terminal study. PGC1-α expression was quantified from nuclear membranes by gels and respiration, oxidant stress markers and proteomics by iTRAQ were determined from isolated mitochondria. In the chronically ischemic LAD region, wall thickening from the PIO and control groups was 42 ± 6 and 45 ± 5 %, respectively (NS) with no intergroup differences in basal blood flow (0.72 ± 0.04 versus 0.74 ± 0.04 ml/min g, respectively; NS). In the PIO group, the expression of nuclear bound PGC1-α was higher (11.3 ± 2.6 versus 4.4 ± 1.4 AU; P < 0.05) and the content of mitochondrial antioxidant peptides including superoxide dismutase 2, aldose reductase, glutathione S-transferase and thioredoxin reductase were greater than controls. Although isolated mitochondria from the PIO group showed lower state 3 respiration (102 ± 13 versus 161 ± 22 nmol/min mg; P < 0.05), no differences in oxidant stress were noted by protein carbonyl (1.7 ± 0.7 versus 1.1 ± 0.1 nmol/mg). Chronic pioglitazone does not reduce regional myocardial blood flow or function in a swine model of chronic myocardial ischemia, but may have an important role in increasing expression of antioxidant proteins through PGC1-α signaling.

Objective Cardiac troponin levels help risk-stratify patients presenting with an acute coronary syndrome. Although cardiac troponin levels may be elevated in patients presenting with non-acute coronary syndrome conditions, specific diagnoses and long-term outcomes within that cohort are unclear. Methods By using the Veterans Affairs centralized databases, we identified all hospitalized patients in 2006 who had a troponin assay obtained during their initial reference hospitalization. On the basis of the diagnostic codes of the International Classification of Diseases, 9th Revision, primary diagnoses were categorized as acute coronary syndrome or non-acute coronary syndrome conditions. Results Of a total of 21,668 patients with an elevated troponin level who were discharged from the hospital, 12,400 (57.2%) had a non-acute coronary syndrome condition. Among that cohort, the most common diagnostic category involved the cardiovascular system, and congestive heart failure (N=1661) and chronic coronary artery disease (N=1648) accounted for the major classifications. At 1 year after hospital discharge, mortality in patients with a non-acute coronary syndrome condition was 22.8% and was higher than in the acute coronary syndrome cohort (odds ratio 1.39; 95% confidence interval, 1.30-1.49). Despite the high prevalence of cardiovascular diseases in patients with a non-acute coronary syndrome diagnosis, use of cardiac imaging within 90 days of hospitalization was low compared with that in patients with acute coronary syndrome (odds ratio 0.25; 95% confidence interval, 0.23-0.27). Conclusions Hospitalized patients with an elevated troponin level more often have a primary diagnosis that is not an acute coronary syndrome. Their long-term survival is poor and justifies novel diagnostic or therapeutic strategy-based studies to target the highest risk subsets before hospital discharge.

Background There is uncertainty regarding the prognostic value of troponin and creatine kinase muscle and brain isoenzyme measurements after noncardiac surgery. Methods The current study undertook a systematic review and meta-analysis. The study used six search strategies and included noncardiac surgery studies that provided data from a multivariable analysis assessing whether a postoperative troponin or creatine kinase muscle and brain isoenzyme measurement was an independent predictor of mortality or a major cardiovascular event. Independent investigators determined study eligibility and abstracted data in duplicate. Results Fourteen studies, enrolling 3,318 patients and 459 deaths, demonstrated that an increased troponin measurement after surgery was an independent predictor of mortality (odds ratio [OR] 3.4, 95% confidence interval [CI] 2.2-5.2), but there was substantial heterogeneity (I(2) = 56%). The independent prognostic capabilities of an increased troponin value after surgery in the 10 studies that assessed intermediate-term (≤ 12 months) mortality was an OR = 6.7 (95% CI 4.1-10.9, I(2) = 0%) and in the 4 studies that assessed long-term (more than 12 months) mortality was an OR = 1.8 (95% CI 1.4-2.3, I(2) = 0%; P < 0.001 for test of interaction). Four studies, including 1,165 patients and 202 deaths, demonstrated an independent association between an increased creatine kinase muscle and brain isoenzyme measurement after surgery and mortality (OR 2.5, 95% CI 1.5-4.0, I(2) = 4%). Conclusions An increased troponin measurement after surgery is an independent predictor of mortality, particularly within the first year; limited data suggest an increased creatine kinase muscle and brain isoenzyme measurement also predicts subsequent mortality. Monitoring troponin measurements after noncardiac surgery may allow physicians to better risk stratify and manage their patients.

Background Acute kidney injury (AKI) after cardiac surgery is associated with increased morbidity and mortality. Methods We assessed whether statin treatment is associated with a lower incidence of postoperative AKI in 2,104 consecutive patients who underwent coronary artery bypass graft or valve surgery at the Minneapolis Veterans Administration Medical Center. Acute kidney injury was defined as absolute increase greater than 0.3 mg/dL or relative increase greater than 50% in serum creatinine from baseline, within 48 hours after surgery or requiring postoperative hemodialysis per AKI network. Propensity scores were utilized to adjust for the differences between the statin and the no-statin treatment groups. All statins were converted to equivalent-dose simvastatin and divided at the median to construct high-dose (≥40 mg) and low-dose ( Results Of the 2,104 patients, 1,435 (68%) were taking statins (638 high-dose) and 495 (24%) developed AKI (25% high-dose vs 40% low-dose vs 35% no-statin; p = 0.014). Estimated preoperative glomerular filtration rate ( p = 0.003), diabetes mellitus (p=0.02), valve surgery with or without coronary artery bypass graft ( p = 0.024), cardiopulmonary bypass time ( p = 0.001), and intraaortic balloon pump ( p = 0.055) were independent predictors of AKI. After propensity adjustment statin treatment was not associated with postoperative AKI (odds ratio 0.79; 95% confidence interval 0.59 to 1.06; p = 0.11 for high-dose v. no-statin). After full adjustment for all independent predictors of AKI, the results did not change. Statins also had no effect on the incidence of postoperative hemodialysis (0.8% high-dose vs 1.9% low-dose vs 1% no-statin; p = 0.15). Conclusions Statin treatment is not associated with a lower incidence of AKI after cardiac surgery.

Objectifs L’histoire naturelle de la maladie coronarienne (CAD) apres la chirurgie vasculaire reste mal definie. Le but de cette etude etait de determiner l’evolution des lesions de l’artere coronaire necessitant une revascularisation par une intervention coronaire percutanee (PCI) apres chirurgie vasculaire elective, et de determiner l’utilite des biomarqueurs preoperatoires sur la prediction des patients a risque de nouvelles lesions coronaires. Methodes L’etude Coronary Artery Revascularization Prophylaxis Trial a examine l’avantage a long terme sur la survie de la revascularisation des arteres coronaires avant chirurgie vasculaire elective. Parmi les patients randomises qui ont plus tard eu besoin de PCI apres chirurgie, la stenose de la lesion cible a l’angiographie de suivi a ete comparee a la stenose preoperatoire au meme site sur l’angiographie de depart. Resultats Un total de 30 patients ont subi une PCI pour des symptomes progressifs sur une mediane de 11,5 mois (de 4,5 a 18,5) apres chirurgie. Parmi les 30 patients, 16 (53%) avaient une CAD non obstructive en pre-operatoire (groupe 1) avec une stenose qui a augmente de 17 ± 6% a 91 ± 2% ( P P = 0,15). Le seul biomarqueur qui etait un temoin de la formation precoce de lesion de l’artere coronaire dans le groupe 1 compare aux patients du groupe 2 etait un taux plus eleve d’homocysteine (14,6 ± 1,4 contre 10,6 ± 0,7 mg/dl ; P = 0,02). Conclusions Les lesions de l’artere coronaire symptomatique exigeant une PCI apres une operation vasculaire elective se compliquent souvent de restenose. Les therapies visant a stabiliser les plaques existantes ou a empecher la restenose, en particulier chez les patients avec une homocysteinemie elevee, devraient permettre d’ameliorer les resultats postoperatoires.

The natural history of coronary artery disease (CAD) after vascular surgery is poorly defined. The aim of this study was to determine the temporal change of coronary artery lesions requiring revascularization with a percutaneous coronary intervention (PCI) after elective vascular surgery and to determine the utility of preoperative biomarkers on predicting those patients at risk for new coronary lesions.The Coronary Artery Revascularization Prophylaxis Trial tested the long-term survival benefit of coronary artery revascularization before elective vascular surgery. Among randomized patients who subsequently required PCI after surgery, the stenosis of the culprit lesion from the follow-up angiogram was compared with the preoperative vessel stenosis at the identical site on the baseline angiogram.A total of 30 patients underwent PCI for progressive symptoms at a median of 11.5 (interquartiles: 4.5-18.5) months postsurgery. Of 30 patients, 16 (53%) had nonobstructive CAD preoperatively (group 1) with a stenosis that increased from 17 +/- 6% to 91 +/- 2% (P0.01) and 14 (47%) had severe CAD at the culprit site preoperatively (group 2), with a stenosis that increased 89 +/- 2% (P = 0.15). The only biomarker that was an identifier of early coronary artery lesion formation in group 1 compared with group 2 patients was a higher baseline homocysteine level (14.6 +/- 1.4 vs. 10.6 +/- 0.7 mg/dL; P = 0.02).Culprit coronary artery lesions requiring PCI after an elective vascular operation often arise from in-stent restenosis. Therapies that either stabilize existing plaques or prevent restenosis, particularly among patients with elevated homocysteine levels, have the greatest promise for improving postoperative outcomes.

The Coronary Artery Revascularization Prophylaxis (CARP) study showed no survival benefit with preoperative coronary artery revascularization before elective vascular surgery. The generalizability of the trial results to all patients with multivessel coronary artery disease (CAD) has been questioned. The objective of this study was to determine the impact of prophylactic coronary revascularization on long-term survival in patients with multivessel CAD. Over a 4-year period, 1,048 patients underwent coronary angiography before vascular surgery during screening into the CARP trial. The cohort was composed of registry (n = 586) and randomized (n = 462) patients, and their survival was determined at 2.5 years after vascular surgery. High-risk coronary anatomy without previous bypass surgery included 2-vessel disease (n = 204 [19.5%]), 3-vessel disease (n = 130 [12.4%]), and left main coronary artery stenosis > or = 50% (n = 48 [4.6%]). By log-rank test, preoperative revascularization was associated with improved survival in patients with a left main coronary artery stenoses (0.84 vs 0.52, p

The expanded ability to detect myocardial injury using very sensitive and specific biomarker assays has been a major factor in the evolution of the definition of acute myocardial infarction (MI). This is clearly evident in the ‘Universal Definition of Myocardial Infarction’ recently developed by a joint task force of experts on behalf of the ESC, ACCF, AHA, and WHF (European Society of Cardiology, American College of Cardiology Foundation, American Heart Association, and World Heart Federation).1 In a clinical setting consistent with myocardial ischaemia, criteria are presented for defining acute MI that include a rise and/or fall in cardiac biomarkers together with symptoms of ischaemia, and/or appropriate ECG changes, and/or imaging evidence of a new regional wall motion abnormality or loss of myocardium. The task force developed a clinical classification of different types of MI that can be briefly summarized as: This multi-component scheme appears to add complexity in an area that can be quite confounding because of the multiple terms used to describe myocardial ischaemia/infarction in all of its various manifestations. This includes differentiating myocardial damage associated with ST elevation (STEMI) from that occurring without ST elevation (non-STEMI). Patients with a sudden change in cardiac status are often admitted to the hospital with a diagnosis of acute coronary syndrome (ACS), but ACS is not included in the ICD-9-CM codes.2 Intermediate coronary syndrome (code 411.1), which includes impending infarction, preinfarction angina, or unstable angina, can be used as a …

Aims The predictors and outcomes of patients with a peri-operative elevation in cardiac troponin I above the 99th percentile of normal following an elective vascular operation have not been studied in a homogeneous cohort with documented coronary artery disease. Methods and results The Coronary Artery Revascularization Prophylaxis (CARP) trial was a randomized trial that tested the benefit of coronary artery revascularization prior to vascular surgery. Among 377 randomized patients, core lab samples for peak cardiac troponin I concentrations were monitored following the vascular operation and the blinded results were correlated with outcomes. A peri-operative myocardial infarction (MI), defined by an increase in cardiac troponin I greater than the 99th percentile reference (> or =0.1 microg/L), occurred in 100 patients (26.5%) and the incidence was not dissimilar in patients with and without pre-operative coronary revascularization (24.2 vs. 28.6%; P = 0.32). By logistic regression analysis, predictors of MI (odds risk; 95%CI; P-value) were age >70 (1.84; 1.14-2.98; P = 0.01), abdominal aortic surgery (1.82; 1.09-3.03; P = 0.02), diabetes (1.86; 1.11-3.11; P = 0.02), angina (1.67; 1.03-2.64; P = 0.04), and baseline STT abnormalities (1.62; 1.00-2.6; P = 0.05). At 2.5 years post-surgery, the probability of survival in patients with and without the MI was 0.73 and 0.84, respectively (P = 0.03, log-rank test). Using a Cox proportional hazards regression analysis, a peri-operative MI in diabetic patients was a strong predictor of long-term mortality (hazards ratio: 2.43; 95% CI: 1.31-4.48; P Conclusion Among patients with coronary artery disease who undergo vascular surgery, a peri-operative elevation in cardiac troponin levels is common and in combination with diabetes, is a strong predictor of long-term mortality. These data support the utility of cardiac troponins as a means of stratifying high-risk patients following vascular operations.

We tested in the in vivo rat heart the hypothesis that although ischemic preconditioning can employ different signal transduction pathways, these pathways converge ultimately at the level of the mitochondrial respiratory chain. Infarct size produced by a 60-min coronary artery occlusion (69% +/- 2% of the area at risk) was limited by a preceding 15-min coronary occlusion (48% +/- 4%). Cardloprotection by this stimulus was triggered by adenosine receptor stimulation, which was followed by protein kinase C and tyrosine kinase activation and then mitochondrial K-ATP(+)-channel opening. In contrast, cardioprotection by 3 cycles of 3-min coronary occlusions (infarct size 27% +/- 5% of the area at risk) involved the release of reactive oxygen species, which was followed by protein kinase C and tyrosine kinase activation, but was independent of adenosine receptor stimulation and K-ATP(+)-channel activation. However, both pathways decreased respiratory control index (RCl; state-3/state-2, using succinate as complex-II substrate) from 3.1 +/- 0.2 in mitochondria from sham-treated hearts to 2.4 +/- 0.2 and 2.5 +/- 0.1 in hearts subjected to a single 15-min and triple 3-min coronary occlusions, respectively (both P < 0.05). The decreases in RCl were due to an increase in state-2 respiration, whereas state-3 respiration was unchanged. Abolition of cardioprotection by blockade of either signal transduction pathway was paralleled by a concomitant abolition of mitochondrial uncoupling. These observations are consistent with the concept that mild mitochondrial uncoupling contributes to infarct size limitation by various ischemic preconditioning stimuli, despite using different signal transduction pathways. In conclusion, in the in vivo rat heart, different ischemic preconditioning (IPC) stimuli can activate highly different signal transduction pathways, which seem to converge at the level of the mitochondria where they increase state-2 respiration. (Translational Research 2008; 151:17-26).

This study was designed to investigate the developmental expression of endothelial nitric oxide synthase (eNOS) during stem cell differentiation into endothelial cells and to examine the functional status of the newly differentiated endothelial cells. Mouse adult multipotent progenitor cells (MAPCs) were used as the source of stem cells and were induced to differentiate into endothelial cells with vascular endothelial growth factor (VEGF) in serum-free medium. Expression of eNOS in the cells during differentiation was evaluated with real-time PCR, nitric oxide synthase (NOS) activity, and Western blot analysis. It was found that eNOS, but no other NOS, was present in undifferentiated MAPCs. eNOS expression disappeared in the cells immediately after induction of differentiation. However, eNOS expression reoccurred at day 7 during differentiation. Increasing eNOS mRNA, protein content, and activity were observed in the cells at days 14 and 21 during differentiation. The differentiated endothelial cells formed dense capillary networks on growth factor-reduced Matrigel. VEGF-stimulated phosphorylation of extracellular signal-regulated kinase (ERK)-1 and ERK-2 occurred in these cells, which was inhibited by NOS inhibitor N(G)-nitro-L-arginine methyl ester. In conclusion, these data demonstrate that eNOS is present in MAPCs and is dynamically expressed during the differentiation of MAPCs into endothelial cells in vitro. ispartof: American Journal of Physiology. Heart and Circulatory Physiology vol:293 issue:3 pages:H1760-H1765 ispartof: location:United States status: published

Cardiac troponin I (cTnI) measured after heart surgery has been associated with operative mortality. We sought to determine whether measuring cTnI after heart surgery provides additional prognostic information beyond that provided by validated preoperative risk scores, the Veterans Affairs (VA) risk score and the European System for Cardiac Operative Risk Evaluation (EuroSCORE).We retrospectively collected cTnI levels measured 24 hours after surgery in 1,186 patients who underwent coronary artery bypass graft surgery (n = 696) or valve surgery (n = 490). The outcomes were operative death and perioperative myocardial infarction. The ability of the cTnI and the risk scores to discriminate patients who did or did not have the study outcomes was assessed by the area under the receiver operating curve (c-index).Mean age was 66 +/- 10 years. Median cTnI was 38 ng/mL after valve surgery versus 18 ng/mL after coronary artery bypass graft surgery (p0.0001). There were 51 operative deaths (4.3%) and 142 perioperative myocardial infarctions (12%). For every 50 ng/mL increase in cTnI, the odds of operative death increased by 40% (odds ratio, 1.4; 95% confidence interval: 1.2 to 1.6) after coronary artery bypass graft surgery and by 30% (odds ratio, 1.3; 95% confidence interval: 1.1 to 1.5) after valve surgery. Cardiac troponin I was a significant independent correlate of perioperative myocardial infarction and death (p0.0001) with a c-index of 0.70 for death. Addition of cTnI improved the c-indexes of the risk scores for predicting death (from 0.75 to 0.79 for the VA risk score; p = 0.1; and from 0.69 to 0.77 for the EuroSCORE; p = 0.005).Postoperative cTnI measured 24 hours after heart surgery is independently associated with operative death and perioperative myocardial infarction and improves the ability to predict operative mortality in comparison with preoperative risk scores alone.