Surgical Porcine Model of Chronic Myocardial Ischemia Treated by Exosome-laden Collagen Patch and Off-pump Coronary Artery Bypass Graft.

Chronic myocardial ischemia resulting from progressive coronary artery stenosis leads to hibernating myocardium (HIB), defined as myocardium that adapts to reduced oxygen availability by reducing metabolic activity, thereby preventing irreversible cardiomyocyte injury and infarction. This is distinct from myocardial infarction, as HIB has the potential for recovery with revascularization. Patients with significant coronary artery disease (CAD) experience chronic ischemia, which puts them at risk for heart failure and sudden death. The standard surgical intervention for severe CAD is coronary artery bypass graft surgery (CABG), but it has been shown to be an imperfect therapy, yet no adjunctive therapies exist to recover myocytes adapted to chronic ischemia. To address this gap, a surgical model of HIB using porcine that is amenable to CABG and mimics the clinical scenario was used. The model involves two surgeries. The first operation involves implanting a 1.5 mm rigid constrictor on the left anterior descending (LAD) artery. As the animal grows, the constrictor gradually causes significant stenosis resulting in reduced regional systolic function. Once the stenosis reaches 80%, the myocardial flow and function are impaired, creating HIB. An off-pump CABG is then performed with the left internal mammary artery (LIMA) to revascularize the ischemic region. The animal recovers for one month to allow for optimal myocardial improvement prior to sacrifice. This allows for physiologic and tissue studies of different treatment groups. This animal model demonstrates that cardiac function remains impaired despite CABG, suggesting the need for novel adjunctive interventions. In this study, a collagen patch embedded with mesenchymal stem cell (MSC)-derived exosomes was developed, which can be surgically applied to the epicardial surface distal to LIMA anastomosis. The material conforms to the epicardium, is absorbable, and provides the scaffold for the sustained release of signaling factors. This regenerative therapy can stimulate myocardial recovery that does not respond to revascularization alone. This model translates to the clinical arena by providing means of physiological and mechanistic explorations regarding recovery in HIB.

Stem cell-derived exosome patch with coronary artery bypass graft restores cardiac function in chronically ischemic porcine myocardium.

OBJECTIVE: This study aimed to investigate whether or not the application of a stem cell-derived exosome-laden collagen patch (EXP) during coronary artery bypass grafting (CABG) can recover cardiac function by modulating mitochondrial bioenergetics and myocardial inflammation in hibernating myocardium (HIB), which is defined as myocardium with reduced blood flow and function that retains viability and variable contractile reserve. METHODS: In vitro methods involved exposing H9C2 cardiomyocytes to hypoxia followed by normoxic coculture with porcine mesenchymal stem cells. Mitochondrial respiration was measured using Seahorse assay. GW4869, an exosomal release antagonist, was used to determine the effect of mesenchymal stem cells-derived exosomal signaling on cardiomyocyte recovery. Total exosomal RNA was isolated and differential micro RNA expression determined by sequencing. In vivo studies comprised 48 Yorkshire-Landrace juvenile swine (6 normal controls, 17 HIB, 19 CABG, and 6 CABG + EXP), which were compared for physiologic and metabolic changes. HIB was created by placing a constrictor on the proximal left anterior descending artery, causing significant stenosis but preserved viability by 12 weeks. CABG was performed with or without mesenchymal stem cells-derived EXP application and animals recovered for 4 weeks. Before terminal procedure, cardiac magnetic resonance imaging at rest, and with low-dose dobutamine, assessed diastolic relaxation, systolic function, graft patency, and myocardial viability. Tissue studies of inflammation, fibrosis, and mitochondrial morphology were performed posttermination. RESULTS: In vitro data demonstrated improved cardiomyocyte mitochondrial respiration upon coculture with MSCs that was blunted when adding the exosomal antagonist GW4869. RNA sequencing identified 8 differentially expressed micro RNAs in normoxia vs hypoxia-induced exosomes that may modulate the expression of key mitochondrial (peroxisome proliferator-activator receptor gamma coactivator 1-alpha and adenosine triphosphate synthase) and inflammatory mediators (nuclear factor kappa-light-chain enhancer of activated B cells, interferon gamma, and interleukin 1ß). In vivo animal magnetic resonance imaging studies demonstrated regional systolic function and diastolic relaxation to be improved with CABG + EXP compared with HIB (P = .02 and P = .02, respectively). Histologic analysis showed increased interstitial fibrosis and inflammation in HIB compared with CABG + EXP. Electron microscopy demonstrated increased mitochondrial area, perimeter, and aspect ratio in CABG + EXP compared with HIB or CABG alone (P < .0001). CONCLUSIONS: Exosomes recovered cardiomyocyte mitochondrial respiration and reduced myocardial inflammation through paracrine signaling, resulting in improved cardiac function.

An Adjuvant Stem Cell Patch with Coronary Artery Bypass Graft Surgery Improves Diastolic Recovery in Porcine Hibernating Myocardium.

Diastolic dysfunction persists despite coronary artery bypass graft surgery (CABG) in patients with hibernating myocardium (HIB). We studied whether the adjunctive use of a mesenchymal stem cells (MSCs) patch during CABG improves diastolic function by reducing inflammation and fibrosis. HIB was induced in juvenile swine by placing a constrictor on the left anterior descending (LAD) artery, causing myocardial ischemia without infarction. At 12 weeks, CABG was performed using the left-internal-mammary-artery (LIMA)-to-LAD graft with or without placement of an epicardial vicryl patch embedded with MSCs, followed by four weeks of recovery. The animals underwent cardiac magnetic resonance imaging (MRI) prior to sacrifice, and tissue from septal and LAD regions were collected to assess for fibrosis and analyze mitochondrial and nuclear isolates. During low-dose dobutamine infusion, diastolic function was significantly reduced in HIB compared to the control, with significant improvement after CABG + MSC treatment. In HIB, we observed increased inflammation and fibrosis without transmural scarring, along with decreased peroxisome proliferator-activated receptor-gamma coactivator (PGC1α), which could be a possible mechanism underlying diastolic dysfunction. Improvement in PGC1α and diastolic function was noted with revascularization and MSCs, along with decreased inflammatory signaling and fibrosis. These findings suggest that adjuvant cell-based therapy during CABG may recover diastolic function by reducing oxidant stress-inflammatory signaling and myofibroblast presence in the myocardial tissue.

Persistent diastolic dysfunction in chronically ischemic hearts following coronary artery bypass graft.

OBJECTIVE: A porcine model was used to study diastolic dysfunction in hibernating myocardium (HM) and recovery with coronary artery bypass surgery (CABG). METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Novel Therapeutic Approaches Enhance PGC1-alpha to Reduce Oxidant Stress-Inflammatory Signaling and Improve Functional Recovery in Hibernating Myocardium.

Ischemic heart disease affects millions of people around the world. Current treatment options, including coronary artery bypass grafting, do not result in full functional recovery, highlighting the need for novel adjunctive therapeutic approaches. Hibernation describes the myocardial response to prolonged ischemia and involves a set of complex cytoprotective metabolic and functional adaptations. PGC1-alpha, a key regulator of mitochondrial energy metabolism and inhibitor of oxidant-stress-inflammatory signaling, is known to be downregulated in hibernating myocardium. PGC1-alpha is a critical component of cellular stress responses and links cellular metabolism with inflammation in the ischemic heart. While beneficial in the acute setting, a chronic state of hibernation can be associated with self-perpetuating oxidant stress-inflammatory signaling which leads to tissue injury. It is likely that incomplete functional recovery following revascularization of chronically ischemic myocardium is due to persistence of metabolic changes as well as prooxidant and proinflammatory signaling. Enhancement of PGC1-alpha signaling has been proposed as a possible way to improve functional recovery in patients with ischemic heart disease. Adjunctive mesenchymal stem cell therapy has been shown to induce PGC1-alpha signaling in hibernating myocardium and could help improve clinical outcomes for patients undergoing bypass surgery.

The Troponin Complex: Discriminating the Signal from the Noise.

Patients presenting to the emergency department 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.

In-Stent Restenosis in Saphenous Vein Grafts (from the DIVA Trial).

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%, p <0.01), but had a higher number of target SVG lesions (1.33 ± 0.64 vs 1.16 ± 0.42, p <0.01), more stents implanted in the target SVG lesions (1.52 ± 0.80 vs 1.31 ± 0.66, p <0.01), 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).

Preventing Myocardial Injury Following Non-Cardiac Surgery: A Potential Role for Preoperative Antioxidant Therapy with Ubiquinone.

Over 240 million non-cardiac operations occur each year and are associated with a 15-20% incidence of adverse perioperative cardiovascular events. Unfortunately, preoperative therapies that have been useful for chronic ischemic heart diseases, such as coronary artery revascularization, antiplatelet agents, and beta-blockers have failed to improve outcomes. In a pre-clinical swine model of ischemic heart disease, we showed that daily administration of ubiquinone (coenzyme Q10, CoQ10) enhances the antioxidant status of mitochondria within chronically ischemic heart tissue, potentially via a PGC1α-dependent mechanism. In a randomized controlled trial, among high-risk patients undergoing elective vascular surgery, we showed that NT Pro-BNP levels are an important means of risk-stratification during the perioperative period and can be lowered with administration of CoQ10 (400 mg/day) for 3 days prior to surgery. The review provides background information for the role of oxidant stress and inflammation during high-risk operations and the potential novel application of ubiquinone as a preoperative antioxidant therapy that might reduce perioperative adverse cardiovascular outcomes.

Recovery of hibernating myocardium using stem cell patch with coronary bypass surgery.

OBJECTIVE: This study aims to investigate the utility of mesenchymal stem cells (MSCs) applied as an epicardial patch during coronary artery bypass graft (CABG) to target hibernating myocardium; that is, tissue with persistently decreased myocardial function, in a large animal model. METHODS: Hibernating myocardium was induced in juvenile swine (n = 12) using a surgically placed constrictor on the left anterior descending artery, causing stenosis without infarction. After 12 weeks, single-vessel CABG was performed using left internal thoracic artery to left anterior descending artery graft. During CABG, an epicardial patch was applied to the hibernating myocardium region consisting either of MSCs grown onto a polyglactin mesh (n = 6), or sham polyglactin mesh without MSCs (n = 6). Four weeks after CABG and patch placement, cardiac magnetic resonance imaging was performed and cardiac tissue was examined by gross inspection, including coronary dilators for vessel stenosis and patency, electron microscopy, protein assays, and proteomic analysis. RESULTS: CABG + MSC myocardium showed improvement in contractile function (78.24% ± 19.6%) compared with sham patch (39.17% ± 5.57%) during inotropic stimulation (P < .05). Compared with sham patch control, electron microscopy of CABG + MSC myocardium showed improvement in mitochondrial size, number, and morphology; protein analysis similarly showed increases in expression of the mitochondrial biogenesis marker peroxisome proliferator-activated receptor gamma coactivator 1-alpha (0.0022 ± 0.0009 vs 0.023 ± 0.009) (P < .01) along with key components of the electron transport chain, including succinate dehydrogenase (complex II) (0.06 ± 0.02 vs 0.14 ± 0.03) (P < .05) and adenosine triphosphate synthase (complex V) (2.7 ± 0.4 vs 4.2 ± 0.26) (P < .05). CONCLUSIONS: In hibernating myocardium, placement of a stem cell patch during CABG shows promise in improving myocardial function by improving mitochondrial morphology and function.

Myocardial Infarction in the ISCHEMIA Trial: Impact of Different Definitions on Incidence, Prognosis, and Treatment Comparisons.

BACKGROUND: In the ISCHEMIA trial (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches), an initial invasive strategy did not significantly reduce rates of cardiovascular events or all-cause mortality in comparison with a conservative strategy in patients with stable ischemic heart disease and moderate/severe myocardial ischemia. The most frequent component of composite cardiovascular end points was myocardial infarction (MI). METHODS: ISCHEMIA prespecified that the primary and major secondary composite end points of the trial be analyzed using 2 MI definitions. For procedural MI, the primary MI definition used creatine kinase-MB as the preferred biomarker, whereas the secondary definition used cardiac troponin. Procedural thresholds were >5 times the upper reference level for percutaneous coronary intervention and >10 times for coronary artery bypass grafting. Procedural MI definitions included (1) a category of elevated biomarker only events with much higher biomarker thresholds, (2) new ST-segment depression of ≥1 mm for the primary and ≥0.5 mm for the secondary definition, and (3) new coronary dissections >National Heart, Lung, and Blood Institute grade 3. We compared MI type, frequency, and prognosis by treatment assignment using both MI definitions. RESULTS: Procedural MIs accounted for 20.1% of all MI events with the primary definition and 40.6% of all MI events with the secondary definition. Four-year MI rates in patients undergoing revascularization were more frequent with the invasive versus conservative strategy using the primary (2.7% versus 1.1%; adjusted hazard ratio [HR], 2.98 [95% CI, 1.87-4.73]) and secondary (8.2% versus 2.0%; adjusted HR, 5.04 [95% CI, 3.64-6.97]) MI definitions. Type 1 MIs were less frequent with the invasive versus conservative strategy using the primary (3.40% versus 6.89%; adjusted HR, 0.53 [95% CI, 0.41-0.69]; P<0.0001) and secondary (3.48% versus 6.89%; adjusted HR, 0.53 [95% CI, 0.41-0.69]; P<0.0001) definitions. The risk of subsequent cardiovascular death was higher after a type 1 MI than after no MI using the primary (adjusted HR, 3.38 [95% CI, 2.03-5.61]; P<0.001) or secondary MI definition (adjusted HR, 3.52 [2.11-5.88]; P<0.001). CONCLUSIONS: In ISCHEMIA, type 1 MI events using the primary and secondary definitions during 5-year follow-up were more frequent with an initial conservative strategy and associated with subsequent cardiovascular death. Procedural MI rates were greater in the invasive strategy and with the use of the secondary MI definition. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01471522.

Inside Out: Change Through Art.

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.

Utility of nuclear stress imaging in predicting long-term outcomes one-year post CABG Surgery.

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 < 0.001), LVEF < 45% (OR 4.0, CI 1.1-15.3, P = 0.041) and a moderate-large stress defect size (HR 2.31, CI 1.1-1.5, P = 0.04). These findings appear to be additive and strongest among patients who underwent exercise stress testing (HR 10.6, CI 3.6-30.6, P < 0.001). Graft disease was identified in 39 (46%) patients and compared to those individuals with no graft disease, did not predict long-term adverse outcomes (P = 0.29). CONCLUSION: In clinically stable patients early after revascularization with CABG, SPECT-MPI can identify patients at higher risk of heart failure and death.

NT-Pro BNP Predicts Myocardial Injury Post-vascular Surgery and is Reduced with CoQ10: A Randomized Double-Blind Trial.

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 < 0.01) and a longer hospital stay (4.4 ± 3.8 vs. 2.8 ± 3.2 days; P < 0.02) compared with individuals without an elevated NT-Pro BNP level. 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 < 0.01) and a longer hospital stay (4.4 ± 3.8 vs. 2.8 ± 3.2 days; P < 0.02) compared with individuals without an NT-Pro BNP elevation. In conclusion, BNP predicts adverse outcomes and can be reduced with preoperative CoQ10.

Mitochondrial Respiratory Capacity is Restored in Hibernating Cardiomyocytes Following Co-Culture with Mesenchymal Stem Cells.

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.

CoQ10 enhances PGC1α and increases expression of mitochondrial antioxidant proteins in chronically ischemic swine myocardium.

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.

Surgical Swine Model of Chronic Cardiac Ischemia Treated by Off-Pump Coronary Artery Bypass Graft Surgery.

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.

Hospital Readmission Rates Following AMI: Potential Interventions to Improve Efficiency.

OBJECTIVES: 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. METHODS: 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. RESULTS: 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 was <3 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 in >90% 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. CONCLUSIONS: 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.