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Ischemic preconditioning (Pre-con) is an adaptive response triggered by a brief ischemia applied before a prolonged coronary occlusion. We tested the hypothesis that repetitive ischemia applied during early reperfusion, i.e., postconditioning (Post-con), is cardio-protective by attenuating reperfusion injury. In anesthetized open-chest dogs, the left anterior descending artery (LAD) was occluded for 60 min and reperfused for 3 h. In controls (n = 10), there was no intervention. In Pre-con (n = 9), the LAD was occluded for 5 min and reperfused for 10 min before the prolonged occlusion. In Post-con (n = 10), at the start of reperfusion, three cycles of 30-s reperfusion and 30-s LAD reocclusion preceded the 3 h of reperfusion. Infarct size was significantly less in the Pre-con (15 [+ or -] 2%, P < 0.05) and Post-con (14 [+ or -] 2%, P < 0.05) groups compared with controls (25 [+ or -] 3%). Tissue edema (% water content) in the area at risk was comparably reduced in Pre-con (78.3 [+ or -] 1.2, P < 0.05) and Post-con (79.7 [+ or -] 0.6, P < 0.05) versus controls (81.5 [+ or -] 0.4). Polymorphonuclear neutrophil (PMN) accumulation (myeloperoxidase activity, [DELTA]absorbance*[min.sup.-1]*g [tissue.sup.-1]) in the area at risk myocardium was comparably reduced in Post-con (10.8 [+ or -] 5.5, P < 0.05) and Pre-con (13.4 [+ or -] 3.4, P < 0.05) versus controls (47.4 [+ or -] 15.3). Basal endothelial function measured by PMN adherence to postischemic LAD endothelium (PMNs/[mm.sup.2]) was comparably attenuated by Post-con and Pre-con (15 [+ or -] 0.6 and 12 [+ or -] 0.6, P < 0.05) versus controls (37 [+ or -] 1.5), consistent with reduced expression of P-selectin on coronary vascular endothelium in Post-con and Pre-con. Endothelial function assessed by the maximal vasodilator response of postischemic LAD to acetylcholine was significantly greater in Post-con (104 [+ or -] 6%, P < 0.05) and Pre-con (109 [+ or -] 5%, P < 0.05) versus controls (71 [+ or -] 8%). Plasma malondialdehyde ([micro]M/ml), a product of lipid peroxidation, was significantly less at 1 h of reperfusion in Post-con (2.2 [+ or -] 0.2, P < 0.05) versus controls (3.2 [+ or -] 0.3) associated with a decrease in superoxide levels revealed by dihydroethidium staining in the myocardial area at risk. These data suggest that Post-con is as effective as Pre-con in reducing infarct size and preserving endothelial function. Post-con may be clinically applicable in coronary interventions, coronary artery bypass surgery, organ transplantation, and peripheral revascularization where reperfusion injury is expressed. infarct size; neutrophils

Current approaches to stratify the risk for disease progression in thoracic aortic aneurysm (TAA) lack precision, which hinders clinical decision making. Connective tissue phenotyping of children with TAA previously identified the association between skin striae and increased rate of aortic dilation. The objective of this study was to analyze associations between connective tissue abnormalities and clinical endpoints in adults with aortopathy. Participants with TAA or aortic dissection (TAD) and trileaflet aortic valve were enrolled from 2016 to 2019 in the setting of cardiothoracic surgical care. Data were ascertained by structured interviews with participants. The mean age among 241 cases was 61 ± 13 years. Eighty (33%) had history of TAD. While most participants lacked a formal syndromic diagnosis clinically, connective tissue abnormalities were identified in 113 (47%). This included 20% with abdominal hernia and 13% with skin striae in atypical location. In multivariate analysis, striae and hypertension were significantly associated with TAD. Striae were associated with younger age of TAD or prophylactic aortic surgery. Striae were more frequent in TAD cases than age- and sex-matched controls. Thus, systemic features of connective tissue dysfunction were prevalent in adults with aortopathy. The emerging nexus between striae and aortopathy severity creates opportunities for clinical stratification and basic research. [ABSTRACT FROM AUTHOR]

Objective: We previously showed that brief intermittent ischemia applied during the onset of reperfusion (i.e., postconditioning) is cardioprotective in a canine model of ischemia–reperfusion. This study tested the hypothesis that the early minutes of reperfusion (R) during which postconditioning (Post-con) is applied are critical to its cardioprotection. Methods: In anesthetized open-chest rats, the left coronary artery (LCA) was occluded for 30 min and reperfused for 3 h. All rats were randomly divided into six groups: Control (n=8): no intervention at R; Ischemic preconditioning (IPC) (n=8): the LCA was occluded for 5 min followed by 10 min of R before the index occlusion; Post-con 1 (n=8): after LCA occlusion, three cycles of 10 s R followed by 10 s LCA re-occlusion were applied during the first minute of R; Post-con 2 (n=8): Six cycles of 10 s R and 10 s re-occlusion were applied during the first 2 min of R; Delayed Post-con (n=8): the ligature was loosened for full reflow for the first minute of R, after which the three-cycle Post-con algorithm was applied; Sham (n=6): the surgical procedure was identical to other groups, but the LCA ligature was not ligated. Results: Infarct size (TTC staining) was 23% smaller in Post-con 1 (40±2%*) than in Control (52±3%), confirmed by plasma creatine kinase activity (18±2* vs. 46±6 IU/g protein). There was no further reduction in infarct size with 6 cycles of Post-con (40±2.9%, p>0.05 vs. Post-con 1). Meanwhile, infarct size reduction was significantly greater in the IPC group (17±3%) than in Post-con1 (p<0.01). The plasma lipid peroxidation product malondialdehyde (MDA, μM/ml) was less after R in IPC and Post-con 1 (0.8±0.07* and 0.8±0.06*) vs. Control (1.21±0.08), consistent with a visual decrease in superoxide anion generation (dihydroethidium staining) in the AAR myocardium after 3 h of reperfusion. Neutrophil accumulation (myeloperoxidase activity, MPO, U/100 g tissue) in the AAR was less in IPC (1.4±0.3*) and Post-con 1 (2.5±0.3*) vs. Control (5.5±0.6). The reductions in infarct size, creatine kinase, MDA and DHE staining were lost with delayed Post-con, while MPO activity remained lower than in Control (3.2±0.4*). Conclusions: (1) Post-con at onset of R reduces myocardial injury; (2) cardioprotection may be mediated, in part, by inhibiting oxidant generation and oxidant mediated injury; (3) the first minute of R in the rat model is critical to cardioprotection by Post-con; and (4) cardioprotection by Post-con may be independent of neutrophil accumulation in AAR. *p<0.05 Post-con vs. Control. [Copyright &y& Elsevier]

Ischemic preconditioning (Pre-con) is an adaptive response triggered by a brief ischemia applied before a prolonged coronary occlusion. We tested the hypothesis that repetitive ischemia applied during early reperfusion, i.e., postconditioning (Post-con), is cardioprotective by attenuating reperfusion injury. In anesthetized open-chest dogs, the left anterior descending artery (LAD) was occluded for 60 min and reperfused for 3 h. In controls (n = 10), there was no intervention. In Pre-con (n = 9), the LAD was occluded for 5 min and reperfused for 10 min before the prolonged occlusion. In Post-con (n = 10), at the start of reperfusion, three cycles of 30-s reperfusion and 30-s LAD reocclusion preceded the 3 h of reperfusion. Infarct size was significantly less in the Pre-con (15 ± 2%, P < 0.05) and Post-con (14 ± 2%, P < 0.05) groups compared with controls (25 ± 3%). Tissue edema (% water content) in the area at risk was comparably reduced in Pre-con (78.3 ± 1.2, P < 0.05) and Post-con (79.7 ± 0.6, P < 0.05) versus controls (81.5 ± 0.4). Polymorphonuclear neutrophil (PMN) accumulation (myeloperoxidase activity, Δabsorbance·min[sup -1]·g tissue[sup -1]) in the area at risk myocardium was comparably reduced in Post-con (10.8 ± 5.5, P < 0.05) and Pre-con (13.4 ± 3.4, P < 0.05) versus controls (47.4 ± 15.3). Basal endothelial function measured by PMN adherence to post-ischemic LAD endothelium (PMNs/mm²) was comparably attenuated by Post-con and Pre-con (15 ± 0.6 and 12 ± 0.6, P < 0.05) versus controls (37 ± 1.5), consistent with reduced expression of P-selectin on coronary vascular endothelium in Post-con and Pre-con. Endothelial function assessed by the maximal vasodilator response of post-ischemic LAD to acetylcholine was significantly greater in Post-con (104 ± 6%, P < 0.05) and Pre-con (109 ± 5%, P < 0.05) versus controls (71 ± 8%).... [ABSTRACT FROM AUTHOR]

Introduction: Thoracic aortic aneurysm (TAA) predisposes to aortic dissection and sudden death. Dysfunction of aortic smooth muscle cells (AoSMCs) is a key component of TAA pathogenesis, but precise mechanisms leading to AoSMC dysfunction are incompletely understood. In a previous exome study of patients with extreme TAA phenotypes, we identified the gene COQ8B , which is important for biosynthesis of coenzyme Q, as a candidate modifier of TAA severity. Hypothesis: We hypothesized that there is metabolic dysregulation of AoSMCs in TAA and that altered COQ8B expression causes AoSMC abnormalities. Methods: We compared levels of the oxidative stress marker nitrotyrosine in formalin-fixed aortic root or ascending aorta tissues acquired from patients with TAA (N=51) or healthy aorta (N=11). Using AoSMCs cultured directly from human tissues, mRNA expression of COQ8B was compared between TAA (N=6) and healthy aorta (N=4). The effects of siRNA targeting COQ8B on AoSMC oxidative metabolism were determined using the Seahorse XFp Analyzer and Amplex Red H2O2 Assay. Results: Nitrotyrosine levels were increased in the aortic medial layer of TAA tissues in univariate analysis (p=0.02) and an ordinal regression model (p=0.005) including the covariates age, sex, and vascular risk factors such as hypertension. Expression levels of COQ8B in cultured AoSMCs were decreased in TAA compared with healthy aorta (p=0.02) and inversely correlated with expression of the smooth muscle contractile gene ACTA2. Correspondingly, siRNA knockdown of COQ8B in healthy AoSMCs resulted in increased expression of smooth muscle contractile genes ACTA2 (p<0.05) and CNN1 (p=0.008). Decreased COQ8B expression caused approximately two-fold reduction in maximal respiration (p=0.01) and spare respiratory capacity (p<0.05) and approximately 1.5 fold increased level of the reactive oxygen species H2O2(p<0.05). Conclusions: Increased oxidative stress and decreased COQ8B expression are seen in AoSMCs in TAA. Decreased oxidative metabolism and increased generation of reactive oxygen species resulting from knockdown of COQ8B expression suggest a mechanism by which genetic variants in COQ8B influence TAA phenotype severity. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Current treatments for conduit vessel vasospasm are short-acting and do not inhibit all vasospastic stimuli. This study tests the hypothesis that irreversible inactivation of myosin light chain kinase provides sustained inhibition of arterial vasoconstriction stimulated by a spectrum of vasopressors. Methods: Canine radial artery segments were soaked for 60min in control buffer or buffer with wortmannin, an irreversible inhibitor of myosin light chain kinase. The vessels were then thoroughly washed and contractile responses were quantified in response to a spectrum of vasopressors at 2 and 48h after treatment. After 48h, selected vessels were examined for morphologic changes and development of apoptosis. Results: Two hours after treatment, wortmannin-soaked vessels contracted significantly less than controls in response to norepinephrine (0.19±0.07g vs. 7.22±0.37g, P<0.001), serotonin (0.92±0.35g vs. 9.64±0.67g, P<0.001), thromboxane-mimetic U46619 (1.25±0.17g vs. 10.99±0.50g, P<0.001), and KCl (1.98±0.27g vs.15.00±0.48g, P<0.001). At 48h, vasoconstriction remained significantly inhibited in wortmannin-treated vessels compared to control vessels in response to norepinephrine (2.36±0.17 vs. 6.95±0.47g, P<0.001), serotonin (4.67±0.39 vs. 12.42±0.70g, P<0.001), U46619 (5.42±0.34 vs. 9.29±0.74g, P=0.008), and KCl (7.49±0.48 vs. 13.32±0.60g, P<0.001). Histology of wortmannin-treated vessels revealed no overt smooth muscle or endothelial cell damage. TUNEL staining revealed a significantly greater proportion of apoptotic smooth muscle and endothelial cells in wortmannin-treated vessels as compared to controls. Conclusions: Disengaging the smooth muscle contractile apparatus by irreversibly binding myosin light chain kinase with wortmannin significantly attenuates radial artery vasoconstriction up to 48h after brief treatment. This novel strategy may prevent vasospasm of arterial grafts from all causes for several postoperative days. [Copyright &y& Elsevier]

Objective: A number of factors limit the effectiveness of current aortic arch studies in assessing optimal neuroprotection strategies, including insufficient patient numbers, heterogenous definitions of clinical variables, multiple technical strategies, inadequate reporting of surgical outcomes and a lack of collaborative effort. We have formed an international coalition of centres to provide more robust investigations into this topic., Methods: High-volume aortic arch centres were identified from the literature and contacted for recruitment. A Research Steering Committee of expert arch surgeons was convened to oversee the direction of the research., Results: The International Aortic Arch Surgery Study Group has been formed by 41 arch surgeons from 10 countries to better evaluate patient outcomes after aortic arch surgery. Several projects, including the establishment of a multi-institutional retrospective database, randomized controlled trials and a prospectively collected database, are currently underway., Conclusions: Such a collaborative effort will herald a turning point in the surgical management of aortic arch pathologies and will provide better powered analyses to assess the impact of varying surgical techniques on mortality and morbidity, identify predictors for neurological and operative risk, formulate and validate risk predictor models and review long-term survival outcomes and quality-of-life after arch surgery.

Objective: : Historically, success of surgical treatment of atrial fibrillation (AF) has been measured by electrocardiograms (ECGs) at various intervals. However, continuous monitoring of cardiac rhythms by "autocapture" devices has recently become more available and convenient. The concordance of measurements of freedom from AF by these two techniques has not been reported after surgical ablation., Methods: : Between August 2005 and May 2006, 47 patients at a single academic center underwent surgical ablation procedures for AF and had recurrence of AF assessed by both "spot" 12-lead ECG and autocapture event monitoring. Forty-one ablation procedures were concomitant with other cardiac surgery and six were stand alone, nonsternotomy procedures. Agreement between these diagnostic modes was measured using the κ statistic at 3, 6, and 12 months (κ of 1 is perfect agreement, 0 is no agreement). McNemar test was employed to determine whether agreement significantly changed from 3 to 12 months., Results: : At 3 months follow-up, spot ECGs suggested that 81% (38 of 47) of surgical patients were free of any AF, whereas 1-week event recordings found only 70% (31 of 44) of patients were free of any AF. At 6 months, spot ECGs estimated that 87% (40 of 46) of surgical patients were free of AF; 1-week event recordings found only 74% (34 of 46) of patients were free of AF. At 12 months, spot ECGs estimated that 84% (26 of 31) of surgical patients were free of AF compared with only 68% (19 of 28) as measured by the 1-week event recorder. The κ measures (with 95% confidence interval) at 3, 6, and 12 months were 0.52 (0.24-0.80), 0.60 (0.32-0.87), and 0.63 (0.32-0.94) respectively, showing only moderate agreement. McNemar test showed no significant shift in agreement from 3 to 6 months (P = 0.7055), 3 to 12 months (P = 1.000), or 6 to 12 months (P = 1.000). There were no deaths or strokes, but one myocardial infarction among these 47 patients during 12 months follow-up., Conclusions: : "Spot" ECGs underestimate the incidence of recurrent AF after surgical ablation for AF and show poor agreement with the more reliable 1-week autocapture event recordings.

Background: : Cardiac resynchronization therapy (CRT) improves symptoms, quality of life, and ejection fraction in selected patients with congestive heart failure (CHF) and interventricular conduction delay. Transvenous insertion of left ventricular (LV) pacing leads via the coronary sinus is unsuccessful in 8-10% of patients. This study describes intermediate-term follow up of minimally invasive surgical techniques for CRT as a viable alternative after failed transvenous lead insertion., Methods: : From March 2001 to October 2005, fifty-four patients with NYHA Class III-IV symptoms, QRS duration 181 ± 40 milliseconds, and LV ejection fraction 19.7 ± 8.0% underwent a total of 56 minimally invasive LV lead placements via thoracoscopic video assistance (n = 38) or minithoracotomy (n = 17). One patient required full thoracotomy after a previous video-assisted thoracoscopic procedure. Intraoperative transesophageal echocardiography was used to assess changes in LV function., Results: : Acute thresholds for the active lead measured 1.10 ± 0.62 V, with R-wave amplitude of 12.3 ± 6.6 mV and impedance of 631 ± 185 Ohm. Thirty-day mortality was 5%. There were no perioperative myocardial infarctions or strokes. Five patients required transfusion, 3 had exacerbation of prior renal insufficiency, 5 had pulmonary complications, and 8 required inotropic support for more than 48 hours. Intermediate-term follow up (mean 20 ± 16 months, range 11 days to 55 months) revealed 3 patients with lead failure requiring additional surgical intervention. Hospitalization due to worsening CHF occurred in 5 patients, and 2 of these patients required intravenous inotropic support. QRS duration decreased to 146 ± 36 milliseconds postoperatively (P < 0.001)., Conclusion: : Minimally invasive surgical lead placement safely and effectively accomplishes cardiac resynchronization using either thoracoscopic or minithoracotomy techniques.

Background: Although the radial artery bypass conduit has excellent intermediate-term patency, it has a proclivity to vasospasm. We tested the hypothesis that brief pretreatment of a radial artery graft with the irreversible adrenergic antagonist phenoxybenzamine attenuates the vasoconstrictor response to the vasopressors phenylephrine and norepinephrine compared with the currently used papaverine/lidocaine., Methods: Segments of human radial artery grafts were obtained after a 30-minute intraoperative pretreatment with a solution containing 20 mL of heparinized blood, 0.4 mL of papaverine (30 mg/mL), and 1.6 mL of lidocaine (1%). The segments were transported to the laboratory and placed into a bath containing Krebs-Henseleit solution and 10, 100, or 1000 micromol/L phenoxybenzamine or vehicle. The segments were tested in organ chambers for contractile responses to increasing concentrations of phenylephrine and norepinephrine (0.5-15 micromol/L)., Results: Contractile responses to 15 micromol/L phenylephrine in control radial artery segments averaged 44.2% +/- 9.1% of the maximal contractile response to 30 mmol/L KCl. Papaverine/lidocaine modestly attenuated contraction to 15 micromol/L phenylephrine (32.1% +/- 5.9%; P =.22), but 1000 micromol/L phenoxybenzamine completely abolished radial artery contraction (-7.2% +/- 4.4%; P <.001). The effect of 10 and 100 micromol/L phenoxybenzamine on attenuating vasocontraction was intermediate between 1000 micromol/L phenoxybenzamine and papaverine/lidocaine. Responses to 15 micromol/L norepinephrine in control radial artery segments averaged 54.7% +/- 7.5% of maximal contraction to 30 mmol/L KCl. Papaverine/lidocaine modestly attenuated the contraction response of radial artery segments (35.6% +/- 5.1%; P =.04). In contrast, 1000 micromol/L phenoxybenzamine showed the greatest attenuation of norepinephrine-induced contraction (-10.5% +/- 2.0%; P <.001)., Conclusions: A brief pretreatment of the human radial artery bypass conduit with 1000 micromol/L phenoxybenzamine completely attenuates the vasoconstrictor responses to the widely used vasopressors norepinephrine and phenylephrine. Papaverine/lidocaine alone did not block vasoconstriction to these alpha-adrenergic agonists.