Analysis of racial disparities in acute type A aortic dissection repair at a rural tertiary academic medical center.

BACKGROUND: To determine if racial disparities exist between African Americans (AA) and Non-Hispanic Whites (NHW) for patients undergoing repair of acute type A aortic dissection (ATAAD) at a rural tertiary academic medical center. METHODS: There were 215 consecutive AA and NHW patients who underwent ATAAD repair at our institution from 1999 to 2019 included in a retrospective analysis of our Society of Thoracic Surgeons Adult Cardiac Surgery Database. Statistical analysis was performed with a p value of less than .05 considered statistically significant. RESULTS: Patients undergoing ATAAD repair were 47% AA despite comprising only 27% of the total population in our region. AAs were significantly younger (54.0 vs. 61.2 years), were more likely to be hypertensive (94.1% vs. 79.7%), had higher creatinine levels (1.7 vs. 1.1 mg/dL), and higher body mass index (30.8 vs. 28.1 kg/m2 ) (all p values < .006). There were no significant differences in type of repair or intraoperative variables. A logistic regression analysis showed AAs had an increased rate of postoperative acute renal failure not requiring hemodialysis when compared to NHWs (20.8% vs. 10.6%, p value = .042). Thirty-day mortality was not significantly different (15.7% vs. 13.4%) nor was 1-year survival (78% vs. 79%) in AAs and NHWs, respectively. CONCLUSIONS: Despite AAs having more medical comorbidities at presentation, there were no differences in short- and intermediate-term survival. In our catchment of 1.8 million people, AAs appear to undergo ATAAD repair at a disproportionate rate versus NHWs. These findings may alter strategies for surveillance and prevention of aortic disease in this high-risk population.

Natural history of the proximal aorta in patients with descending thoracic aortic disease.

OBJECTIVE: This study investigated the growth and behavior of the ascending aorta in patients with descending thoracic aortic disease. METHODS: We examined 200 patients with descending thoracic aortic disease including acute type B dissection (n = 95), chronic type B dissection (n = 38), intramural hematoma (n = 23), and thoracoabdominal aortic aneurysms (n = 44). Images from computed tomography and magnetic resonance imaging were evaluated after three-dimensional reconstruction to examine the growth rate in those with >1 year of imaging follow-up (n = 108). Survival data were derived from all 200 patients in this study. RESULTS: Average proximal aortic dimensions at the index image were relatively small, measuring 3.65 ± 0.51 cm in the root, 3.67 ± 0.48 cm in the ascending aorta, and 3.50 ± 0.44 cm in the proximal arch. Average growth rate was low for the aortic root, ascending aorta, and proximal arch at 0.36 ± 0.64 mm/y, 0.26 ± 0.44 mm/y, and 0.25 ± 0.44 mm/y, respectively. There was no difference in baseline proximal aortic dimensions and growth rate between the four subgroups. An index aortic diameter ≥4.1 cm grew faster than those <4.1 cm at the ascending aorta (P = .028) and proximal arch (P = .019). There was no difference in aortic growth rates at the aortic root (P = .887). After the index scan, five patients underwent six ascending aortic replacement procedures, leading to a 3% ascending aortic intervention rate. Overall median life expectancy was 86.15 years. CONCLUSIONS: Native ascending aortic growth in patients with descending thoracic aortic disease is slow. We suggest regular follow-up for index ascending aorta ≥4.1 cm because of its larger initial size and more rapid growth.

Inhibition of Postinfarction Ventricular Remodeling by High Molecular Weight Polyethylene Glycol.

BACKGROUND: Myocardial infarction (MI) is a major etiology for the development of heart failure. We have previously shown that high molecular weight polyethylene glycol (PEG) can protect cardiac myocytes from hypoxia-reoxygenation injury in vitro. In this study, we investigated the potential protective effects of 15-20 kD PEG postinfarction without reperfusion. METHODS: One milliliter of PEG 15-20 was delivered intravenously following permanent left anterior descending ligation in adult male rats with phosphate buffer saline (PBS) as control (n = 9 in each group). Echocardiography was performed at baseline and at 8 wk post-MI. Left ventricles (LVs) were harvested to quantify fibrosis, apoptosis, cell survival signaling, regulation of ß-adrenergic signaling, and caveolin (Cav) expression. RESULTS: The PEG group had significant recovery of LV function at 8 wk compared with the PBS group. There was less LV fibrosis in both the infarct and remote territory. Cell survival signaling was upregulated in the PEG group with increased Akt and ERK phosphorylation. PEG inhibited apoptosis as measured by terminal deoxynucleotidyl transferase [TdT]-mediated dUTP nick-end labeling positive nuclei and caspase-3 activity. There was maintenance of Cav-1, Cav-2, and Cav-3 expression following PEG treatment versus a decline in the PBS group. Negative regulators of ß-adrenergic signaling, G protein-coupled receptor kinase-2, and ß-arrestin 1 and 2 were all upregulated in PBS-treated samples compared to normal control; however, PEG treatment led to decreased expression. CONCLUSIONS: These data suggest that PEG 15-20 may have significant protective effects post-MI even in the setting of no acute reperfusion. Upregulation of Cav expression appears to be a key mechanism for the beneficial effects of PEG on ventricular remodeling and function.

Acute retrograde type A aortic dissection: morphologic analysis and clinical implications.

BACKGROUND: This study compares the morphology and outcomes of acute retrograde type A dissections (RTADs) with acute antegrade type A dissections (ATADs), and acute type B dissections. MATERIALS AND METHODS: From 2000 to 2016, there were 12 acute RTADs, 96 ATADs, and 92 type B dissections with available imaging. Dissections were characterized using computerized tomography angiography images. We examined clinical features, tear characteristics, and various morphologic measurements. RESULTS: Compared with acute type B dissections, RTAD primary tears were more common in the distal arch (75% versus 43%, P = 0.04), and the false-to-true lumen contrast intensity ratio at the mid-descending thoracic aorta was lower (0.46 versus 0.71, P = 0.020). RTAD had less false lumen decompression because there were fewer aortic branch vessels distal to the subclavian that were perfused through the false lumen (0.40 versus 2.19, P < 0.001). Compared with ATAD, RTAD had less root involvement where root true-to-total lumen area ratio was higher (0.88 versus 0.76, P = 0.081). Furthermore, RTAD had a lower false-to-true lumen contrast intensity ratio at the root (0.25 versus 0.57, P < 0.05), ascending aorta (0.25 versus 0.72, P < 0.001), and proximal arch (0.39 versus 0.67, P < 0.05). RTAD were more likely to undergo aortic valve resuspension (100% versus 74%, P = 0.044). CONCLUSIONS: RTAD tends to occur when primary tears occur in close proximity to the aortic arch and when false lumen decompression through the distal aortic branches are less effective. Compared with ATAD, RTAD has less root involvement, and successful aortic valve resuspension is more likely.

Outpatient air leak management after lobectomy: a CMS cost analysis.

BACKGROUND: Air leaks after lobectomy are associated with increased length of stay (LOS) and protracted resource utilization. Portable drainage systems (PDS) allow for outpatient management of air leaks in patients otherwise meeting discharge criteria. We evaluated the safety and cost efficiency of a protocol for outpatient management of air leaks with a PDS. METHODS: We retrospectively assessed patients who underwent lobectomy for non-small-cell lung cancer at our institution between 2004 and 2014. All patients discharged with a PDS for air leak were included in the analysis. The study group was compared to an internally matched cohort of patients undergoing lobectomy for non-small-cell lung cancer managed without the need for outpatient PDS. Study end points included resource utilization, postoperative complications, and readmission. RESULTS: A total of 739 lobectomies were performed during the study period, 73 (10%) patients with air leaks were discharged with a PDS after fulfilling postoperative milestones. Shorter LOS was observed in the study group (3.88 ± 2.4 versus 5.68 ± 5.7 d, P = 0.014) without significant differences in 30-d readmission (11.7% versus 9.0%, P = 0.615). PDS-related complications occurred in 6.8% of study patients (5/73), and 2.7% (2/73) required overnight readmission. PDSs were used for 8.30 ± 4.5 outpatient days. A CMS-based cost analysis predicted an overall savings of $686.72/patient (4.9% of Medicare reimbursement for a major thoracic procedure), associated with significantly fewer hospital days and resources used. CONCLUSIONS: In patients otherwise meeting discharge criteria, outpatient management of air leaks is safe and effective. This strategy is associated with improved efficiency of postoperative care and a modest reduction in hospital costs. This model may be applicable to other thoracic procedures associated with protracted LOS.

ß-Arrestins regulate human cardiac fibroblast transformation and collagen synthesis in adverse ventricular remodeling.

Cardiac fibroblasts (CFs) produce and degrade the myocardial extracellular matrix and are critical in maladaptive ventricular remodeling that can result in heart failure (HF). ß-Arrestins are important signaling molecules involved in ß-adrenergic receptor (ß-AR) desensitization and can also mediate signaling in a G protein-independent fashion. We hypothesize that ß-arrestins play an important role in the regulation of adult human CF biology with regard to myofibroblast transformation, increased collagen synthesis, and myocardial fibrosis which are important in the development of HF. ß-Arrestin1 & 2 expression is significantly upregulated in adult human CF isolated from failing left ventricles and ß-AR signaling is uncoupled with loss of ß-agonist-mediated inhibition of collagen synthesis versus normal control CF. Knockdown of either ß-arrestin1 or 2 restored ß-AR signaling and ß-agonist mediated inhibition of collagen synthesis. Overexpression of ß-arrestins in normal CF led to a failing phenotype with increased baseline collagen synthesis, impaired ß-AR signaling, and loss of ß-agonist-mediated inhibition of collagen synthesis. ß-Arrestin knockdown in failing CF diminished TGF-ß stimulated collagen synthesis and also inhibited ERK phosphorylation. Overexpression of ß-arrestins in normal CF increased basal ERK1/2 and Smad2/3 phosphorylation and enhanced TGF-ß-stimulated collagen synthesis. This was prevented by pre-treatment with a MEK1/2 inhibitor. Enhanced ß-arrestin signaling appears to be deleterious in CF by promoting a pro-fibrotic phenotype via uncoupling of ß-AR signaling as well as potentiating ERK and Smad signaling. Targeted inhibition of ß-arrestins in CF may represent a therapeutic strategy to prevent maladaptive myocardial fibrosis.

Acute kidney injury and mortality following ventricular assist device implantation.

BACKGROUND: Ventricular assist devices (VADs) are increasingly common, and their surgical implantation predisposes patients to an increased risk of acute kidney injury (AKI). We sought to evaluate the incidence, risk factors and short- and long-term all-cause mortality of patients with AKI following VAD implantation. METHODS: We identified all patients who underwent VAD implantation at the University of Chicago between January 1, 2008, and January 31, 2012. We evaluated the incidence of AKI, defined as a ≥50% increase in serum creatinine over the first 7 postoperative days (RIFLE Risk-Creatinine). A logistic regression model was used to identify risk factors for the development of AKI, and a Cox proportional hazards model was used to examine factors associated with 30-day and 365-day all-cause mortality. RESULTS: A total of 157 eligible patients had VAD implantations with 44 (28%) developing postimplantation AKI. In a multivariate analysis, only diabetes mellitus [odds ratio = 2.25 (1.03-4.94), p = 0.04] was identified as a significant predictor of postoperative AKI. Using a multivariable model censored for heart transplantation, only AKI [hazard ratio, HR = 3.01 (1.15-7.92), p = 0.03] and cardiopulmonary bypass time [HR = 1.01 (1.001-1.02), p = 0.02] were independent predictors of 30-day mortality. Preoperative body mass index [HR = 0.95 (0.90-0.99), p = 0.03], preoperative diabetes mellitus [HR = 1.89 (1.07-3.35), p = 0.03] and postimplantation AKI [HR = 1.85 (1.06-3.21), p = 0.03] independently predicted 365-day mortality. CONCLUSION: AKI is common following VAD implantation and is an independent predictor of 30-day and 1-year all-cause mortality.

GRK2-mediated inhibition of adrenergic and dopaminergic signaling in right ventricular hypertrophy: therapeutic implications in pulmonary hypertension.

BACKGROUND: The cause and consequences of impaired adrenergic signaling in right ventricular failure/hypertrophy (RVH) are poorly understood. We hypothesized that G protein-coupled receptor kinase-2 (GRK2)-mediated uncoupling of ß-adrenergic receptor signaling impairs inotropic reserve. The implications of right ventricular (RV) adrenergic remodeling for inotrope selection and the therapeutic benefit of interrupting Gßγ-GRK2 interaction, using gallein, were tested. METHODS AND RESULTS: Chamber-specificity and cellular localization of adrenergic remodeling were compared in rodent RVH associated with pulmonary arterial hypertension (PAH-RVH; SU5416+chronic-hypoxia or Monocrotaline) versus pulmonary artery banding-induced RVH (PAB-RVH). Results were corroborated in RV arrays from 10 PAH patients versus controls. Inotropic reserve was assessed in RV- and left ventricular-Langendorff models and in vivo. Gallein therapy (1.8 mg/kg/day ×2-weeks) was assessed. Despite similar RVH, cardiac output (58.3±4.9 versus 82.9±4.8 mL/min; P<0.001) and treadmill distance (41.5±11.6 versus 244.1±12.4 m; P<0.001) were lower in PAH-RVH versus PAB-RVH. In PAH-RVH versus PAB-RVH there was greater downregulation of ß1-, α1- and dopamine-1 receptors, more left ventricular involvement, and greater impairment of RV contractile reserve. RV GRK2 activity increased in parallel with a reduction in both adrenergic receptor expression and inotrope-stimulated cAMP levels (P<0.01). ß1-receptor downregulation also occurred in human PAH-RVH. Dobutamine was superior to dopamine as an RV inotrope, both ex vivo and in vivo. CONCLUSIONS: GRK2-mediated desensitization-downregulation of adrenergic and dopaminergic receptors impairs inotropic reserve in PAH-RVH. Acute inotropic support in RVH is best accomplished by dobutamine, reflecting its better coupling to adenylyl cyclase and the reliance of dopamine on dopamine-1-receptor signaling, which is impaired in RVH. Inhibiting Gßγ-GRK2 interactions has therapeutic benefit in RVH.

Impact of timing of urgent coronary artery bypass grafting following coronary angiography on acute kidney injury.

OBJECTIVES: Prior studies have examined the association between timing of cardiac surgery after coronary angiography with risk of acute kidney injury, but this remains controversial. The purpose of this study was to investigate the association between interval from coronary angiography to urgent coronary artery bypass grafting with acute kidney injury, and to examine this possible effect in patients with preexisting kidney disease. METHODS: Patients from a single institution undergoing urgent, isolated coronary artery bypass grafting within 7 days of coronary angiography were included. Patients were subdivided by chronic kidney disease stage and angiography-to-surgery interval. Locally estimated scatterplot smoothing was used to evaluate the functional relationship of the probability of acute kidney injury and time interval. Adjusted odds ratios were calculated for each time interval group compared against the Day 0 to 1 interval group, controlling for multiple covariates. Analyses were repeated for each chronic kidney disease subgroup. RESULTS: A total of 2249 patients were included in this study. There were 271 (12.0%) patients with postoperative acute kidney injury. Plots demonstrated a decreasing risk of kidney injury from Day 0 to 1 to Day 3 following coronary angiography. Adjusted odds ratios also showed a significant decrease in risk of kidney injury on Day 3 compared with Day 0 to 1. Analyses repeated for each chronic kidney disease stage showed similar trends. CONCLUSIONS: For patients undergoing urgent coronary artery bypass grafting, there is a decreased risk of kidney injury in those having surgery on day 3 after coronary angiography compared with those having surgery on Day 0 to 1, regardless of preexisting kidney disease.

G protein-coupled receptor kinase-2 is a novel regulator of collagen synthesis in adult human cardiac fibroblasts.

Cardiac fibroblasts (CF) make up 60-70% of the total cell number in the heart and play a critical role in regulating normal myocardial function and in adverse remodeling following myocardial infarction and the transition to heart failure. Recent studies have shown that increased intracellular cAMP can inhibit CF transformation and collagen synthesis in adult rat CF; however, mechanisms by which cAMP production is regulated in CF have not been elucidated. We investigated the potential role of G protein-coupled receptor kinase-2 (GRK2) in modulating collagen synthesis by adult human CF isolated from normal and failing left ventricles. Baseline collagen synthesis was elevated in failing CF and was not inhibited by ß-agonist stimulation in contrast to normal controls. ß-adrenergic receptor (ß-AR) signaling was markedly uncoupled in the failing CF, and expression and activity of GRK2 were increased 3-fold. Overexpression of GRK2 in normal CF recapitulated a heart failure phenotype with minimal inhibition of collagen synthesis following ß-agonist stimulation. In contrast, knockdown of GRK2 expression in normal CF enhanced cAMP production and led to greater ß-agonist-mediated inhibition of basal and TGFß-stimulated collagen synthesis versus control. Inhibition of GRK2 activity in failing CF by expression of the GRK2 inhibitor, GRK2ct, or siRNA-mediated knockdown restored ß-agonist-stimulated inhibition of collagen synthesis and decreased collagen synthesis in response to TGFß stimulation. GRK2 appears to play a significant role in regulating collagen synthesis in adult human CF, and increased activity of this kinase may be an important mechanism of maladaptive ventricular remodeling as mediated by cardiac fibroblasts.

A Genotype-Phenotype Analysis of Glutathione Peroxidase 4 in Human Atrial Myocardium and Its Association with Postoperative Atrial Fibrillation.

Heterogeneity in the incidence of postoperative atrial fibrillation (POAF) following heart surgery implies that underlying genetic and/or physiological factors impart a higher risk of this complication to certain patients. Glutathione peroxidase-4 (GPx4) is a vital selenoenzyme responsible for neutralizing lipid peroxides, mediators of oxidative stress known to contribute to postoperative arrhythmogenesis. Here, we sought to determine whether GPX4 single nucleotide variants are associated with POAF, and whether any of these variants are linked with altered GPX4 enzyme content or activity in myocardial tissue. Sequencing analysis was performed across the GPX4 coding region within chromosome 19 from a cohort of patients (N = 189) undergoing elective coronary artery bypass graft (−/+ valve) surgery. GPx4 enzyme content and activity were also analyzed in matching samples of atrial myocardium from these patients. Incidence of POAF was 25% in this cohort. Five GPX4 variants were associated with POAF risk (permutated p ≤ 0.05), and eight variants associated with altered myocardial GPx4 content and activity (p < 0.05). One of these variants (rs713041) is a well-known modifier of cardiovascular disease risk. Collectively, these findings suggest GPX4 variants are potential risk modifiers and/or predictors of POAF. Moreover, they illustrate a genotype−phenotype link with this selenoenzyme, which will inform future mechanistic studies.

Thromboelastography-Platelet Mapping Allows Safe and Earlier Urgent Coronary Artery Bypass Grafting.

BACKGROUND: The Society of Thoracic Surgeons current (STS) guidelines recommend delaying coronary artery bypass graft surgery (CABG) for several days or performing platelet function testing in stable patients who received P2Y12 inhibitors. Our program routinely uses thromboelastography-platelet mapping (TEG-PM) to expedite CABG in P2Y12 nonresponders. We hypothesize that P2Y12 nonresponders had no difference in length of stay to surgery and blood product transfusion compared with patients undergoing urgent inpatient CABG not treated with a P2Y12 inhibitor. METHODS: A total of 221 patients from 2015 to 2019 were P2Y12 nonresponders based on TEG-PM result of less than 50% adenosine diphosphate inhibition. The control group was 232 consecutive patients who also had urgent inpatient CABG but were not treated preoperatively with a P2Y12 inhibitor. Exclusion criteria were identical between groups. RESULTS: Sixty-seven percent of inpatient CABG patients who were treated preoperatively with a P2Y12 inhibitor were nonresponders. The mean number of days from cardiac surgical consultation to CABG in the TEG-PM nonresponders group was 1.6 ± 0.1 vs 2.1 ± 0.1 in the control group (P < .01). The mean total number of blood product units transfused was 1.6 ± 0.2 in the TEG-PM nonresponders group vs 1.6 ± 0.4 in the control group (P = .91). CONCLUSIONS: Our results demonstrate a very high incidence of P2Y12 nonresponders among patients undergoing urgent CABG at our program. These patients underwent surgery at least 3 days earlier than STS recommendations and common practice with no difference in transfusion requirement. Routine use of TEG-PM to identify P2Y12 nonresponders can safely decrease preoperative hospital length of stay and associated cost and improve resource utilization and patient satisfaction.

G alpha(q)-mediated activation of GRK2 by mechanical stretch in cardiac myocytes: the role of protein kinase C.

G protein-coupled receptor kinase-2 (GRK2) is a critical regulator of beta-adrenergic receptor (beta-AR) signaling and cardiac function. We studied the effects of mechanical stretch, a potent stimulus for cardiac myocyte hypertrophy, on GRK2 activity and beta-AR signaling. To eliminate neurohormonal influences, neonatal rat ventricular myocytes were subjected to cyclical equi-biaxial stretch. A hypertrophic response was confirmed by "fetal" gene up-regulation. GRK2 activity in cardiac myocytes was increased 4.2-fold at 48 h of stretch versus unstretched controls. Adenylyl cyclase activity was blunted in sarcolemmal membranes after stretch, demonstrating beta-AR desensitization. The hypertrophic response to mechanical stretch is mediated primarily through the G alpha(q)-coupled angiotensin II AT(1) receptor leading to activation of protein kinase C (PKC). PKC is known to phosphorylate GRK2 at the N-terminal serine 29 residue, leading to kinase activation. Overexpression of a mini-gene that inhibits receptor-G alpha(q) coupling blunted stretch-induced hypertrophy and GRK2 activation. Short hairpin RNA-mediated knockdown of PKC alpha also significantly attenuated stretch-induced GRK2 activation. Overexpression of a GRK2 mutant (S29A) in cardiac myocytes inhibited phosphorylation of GRK2 by PKC, abolished stretch-induced GRK2 activation, and restored adenylyl cyclase activity. Cardiac-specific activation of PKC alpha in transgenic mice led to impaired beta-agonist-stimulated ventricular function, blunted cyclase activity, and increased GRK2 phosphorylation and activity. Phosphorylation of GRK2 by PKC appears to be the primary mechanism of increased GRK2 activity and impaired beta-AR signaling after mechanical stretch. Cross-talk between hypertrophic signaling at the level of PKC and beta-AR signaling regulated by GRK2 may be an important mechanism in the transition from compensatory ventricular hypertrophy to heart failure.

Molecular and functional characterization of a novel cardiac-specific human tropomyosin isoform.

BACKGROUND: Tropomyosin (TM), an essential actin-binding protein, is central to the control of calcium-regulated striated muscle contraction. Although TPM1alpha (also called alpha-TM) is the predominant TM isoform in human hearts, the precise TM isoform composition remains unclear. METHODS AND RESULTS: In this study, we quantified for the first time the levels of striated muscle TM isoforms in human heart, including a novel isoform called TPM1kappa. By developing a TPM1kappa-specific antibody, we found that the TPM1kappa protein is expressed and incorporated into organized myofibrils in hearts and that its level is increased in human dilated cardiomyopathy and heart failure. To investigate the role of TPM1kappa in sarcomeric function, we generated transgenic mice overexpressing cardiac-specific TPM1kappa. Incorporation of increased levels of TPM1kappa protein in myofilaments leads to dilated cardiomyopathy. Physiological alterations include decreased fractional shortening, systolic and diastolic dysfunction, and decreased myofilament calcium sensitivity with no change in maximum developed tension. Additional biophysical studies demonstrate less structural stability and weaker actin-binding affinity of TPM1kappa compared with TPM1alpha. CONCLUSIONS: This functional analysis of TPM1kappa provides a possible mechanism for the consequences of the TM isoform switch observed in dilated cardiomyopathy and heart failure patients.

High-molecular-weight polyethylene glycol protects cardiac myocytes from hypoxia- and reoxygenation-induced cell death and preserves ventricular function.

Apoptosis plays a significant role in maladaptive remodeling and ventricular dysfunction following ischemia-reperfusion injury. There is a critical need for novel approaches to inhibit apoptotic cell death following reperfusion, as this loss of cardiac myocytes can progressively lead to heart failure. We investigated the ability and signaling mechanisms of a high-molecular-weight polyethylene glycol-based copolymer, PEG 15-20, to protect cardiac myocytes from hypoxia-reoxygenation (H-R)-induced cell death and its efficacy in preserving ventricular function following extended hypothermic ischemia and warm reperfusion as relevant to cardiac transplantation. Pretreatment of neonatal rat ventricular myocytes with a 5% PEG solution led to a threefold decline in apoptosis after H-R relative to untreated controls. There was a similar decline in caspase-3 activity in conjunction with inhibition of cytochrome c release from the inner mitochondrial membrane. Treatment with PEG also reduced reactive oxygen species production after H-R, and sarcolemmal lipid-raft architecture was preserved, consistent with membrane stabilization. Cell survival signaling was upregulated after H-R with PEG, as demonstrated by increased phosphorylation of Akt, GSK-3ß, and ERK1/2. There was also maintenance of cardiac myocyte ß-adrenergic signaling, which is critical for myocardial function. PEG 15-20 was very effective in preserving left ventricular function following prolonged hypothermic ischemia and warm reperfusion. PEG 15-20 has a potent protective antiapoptotic effect in cardiac myocytes exposed to H-R injury and may represent a novel therapeutic strategy to decrease myocardial cell death and ventricular dysfunction at the time of reperfusion during acute coronary syndrome or following prolonged donor heart preservation.

The heart and pericardium.

This article describes the normal anatomy of the heart and pericardium. Included is a detailed description of the pericardium, mediastinal nerves, cardiac chambers, valves, coronary arteries and veins, and the conduction tissues. As cardiac and thoracic surgery continue to get more specialized and the procedures become less invasive, it is essential for the cardiothoracic surgeon to have a thorough working knowledge of cardiothoracic anatomy.

Enhanced Catecholamine Flux and Impaired Carbonyl Metabolism Disrupt Cardiac Mitochondrial Oxidative Phosphorylation in Diabetes Patients.

Aims: Catecholamine metabolism via monoamine oxidase (MAO) contributes to cardiac injury in models of ischemia and diabetes, but the pathogenic mechanisms involved are unclear. MAO deaminates norepinephrine (NE) and dopamine to produce H2O2 and highly reactive "catecholaldehydes," which may be toxic to mitochondria due to the localization of MAO to the outer mitochondrial membrane. We performed a comprehensive analysis of catecholamine metabolism and its impact on mitochondrial energetics in atrial myocardium obtained from patients with and without type 2 diabetes. Results: Content and maximal activity of MAO-A and MAO-B were higher in the myocardium of patients with diabetes and they were associated with body mass index. Metabolomic analysis of atrial tissue from these patients showed decreased catecholamine levels in the myocardium, supporting an increased flux through MAOs. Catecholaldehyde-modified protein adducts were more abundant in myocardial tissue extracts from patients with diabetes and were confirmed to be MAO dependent. NE treatment suppressed mitochondrial ATP production in permeabilized myofibers from patients with diabetes in an MAO-dependent manner. Aldehyde dehydrogenase (ALDH) activity was substantially decreased in atrial myocardium from these patients, and metabolomics confirmed lower levels of ALDH-catalyzed catecholamine metabolites. Proteomic analysis of catechol-modified proteins in isolated cardiac mitochondria from these patients identified >300 mitochondrial proteins to be potential targets of these unique carbonyls. Innovation and Conclusion: These findings illustrate a unique form of carbonyl toxicity driven by MAO-mediated metabolism of catecholamines, and they reveal pathogenic factors underlying cardiometabolic disease. Importantly, they suggest that pharmacotherapies targeting aldehyde stress and catecholamine metabolism in heart may be beneficial in patients with diabetes and cardiac disease. Antioxid. Redox Signal. 35, 235-251.

Combined surgical treatment of symptomatic carotid, coronary and mesenteric occlusive disease.

The surgical management of advanced symptomatic atherosclerotic disease in multiple distributions including the coronary circulation presents unique challenges due to the high risk of perioperative ischemic complications in the setting of coronary artery bypass grafting. We present a novel case of the combined surgical management of symptomatic carotid, coronary and mesenteric ischemic disease. The patient underwent carotid endarterectomy followed by combined coronary and mesenteric revascularization using cardiopulmonary bypass during the same hospital admission. He had an uncomplicated post-operative course and was discharged to home on post-operative day 7 after the combined procedure. Ninety-day follow-up was also unremarkable with the patient having no recurrent symptoms of ischemia. This case demonstrates the feasibility and safety of our approach for this rare clinical presentation.