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Objectives: To identify novel predictors for coronary artery bypass grafting failure, we probed for associations with known clinical and biochemical risk factors for atherosclerosis. We also used microarray analysis to identify novel single nucleotide polymorphisms to better understand the genetics and pathogenesis of graft occlusion., Methods: The present study was a nested case-control substudy of the Radial Artery Patency Study 5-year follow-up data. From 1996 to 2001, 87 patients underwent coronary artery bypass grafting. Of these, 26 patients (29.9%) had an occluded study graft (saphenous vein or radial artery) at 8.0 ± 1.1 years. The clinical parameters, late angiography, blood biomarker levels, and surgical outcomes data were included in a multivariate analysis to determine the independent predictors of graft failure., Results: The risk factors of graft failure were fibrinogen (odds ratio [OR], 3.94; 95% confidence interval [CI], 1.33-11.63; P = .01), creatinine (OR, 1.06; 95% CI, 1.02-1.10; P = .006), and diabetes mellitus (OR, 5.15; 95% CI, 1.08-24.59; P = .04). High-density lipoprotein (OR, 0.74; 95% CI, 0.53-1.02; P = .06) was weakly protective; however, low-density lipoprotein and total cholesterol were not predictors. We then identified the association of several human single nucleotide polymorphisms with graft failure, including mutations in glutathione-S-transferase α3. Human coronary arteries and bypass grafts demonstrated increased protein expression of glutathione-S-transferase α3, a known cardioprotective factor, in the atherosclerotic regions and surrounding adventitial tissues., Conclusions: We identified diabetes as a potential clinical predictor and plasma fibrinogen, creatinine, and high-density lipoprotein as potential novel biomarkers. These might help risk stratify patients for the development of graft failure. We also demonstrated a novel association between glutathione-S-transferase α3 and graft failure., (Copyright © 2014 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.)

Objective: Neointimal hyperplasia secondary to vascular smooth muscle cell (VSMC) activation limits the long-term patency of saphenous vein grafts (SVGs). We compared markers of vascular injury and VSMC activation in SVGs harvested using the pedicled 'no-touch' (NT) vs the conventional (CON) technique., Methods: Patients undergoing coronary artery bypass surgery were enrolled in the PATENT SVG trial (clinicaltrials.gov NCT01488084). Patients were randomly allocated to have SVGs harvested with the NT technique from one leg and the CON method from the other. SVG segments underwent morphometry, histological and electron microscopy assessments and transcript measurements of VSMC activation and differentiation markers. Leg wound functional recovery and harvest site complications were assessed using a quality-of-life questionnaire., Results: A total of 17 patients (65.3 ± 7.3 years) were enrolled. SVGs harvested using the NT vs CON technique exhibited preserved intimal, medial and adventitial architecture. CON harvest was associated with greater medial Kruppel-like factor 4 transcript levels (0.26 ± 0.05 vs 0.11 ± 0.02, P < 0.05). CON samples had significantly lower medial serum response factor (0.53 ± 0.11 vs 1.44 ± 0.50, P < 0.05) and myocardin (0.59 ± 0.08 vs 1.33 ± 0.33, P < 0.05) transcript levels. MicroRNA-145, an inhibitor of VSMC activation and differentiation, was higher in the NT vs CON samples (1.84 ± 1.03 vs 0.50 ± 0.19, P < 0.05). Leg assessment scores were worse in the NT legs at 3 months, but similar to CON scores at 12 months., Conclusions: SVGs harvested using the 'NT' technique exhibit an early molecular and morphological pattern consistent with decreased VSMC activation compared with CON harvesting. Functional leg recovery was similar in both groups at 12 months. Larger studies are required to corroborate these findings.

Objective: The benefit of stentless valves remains in question. In 1999, a randomized trial comparing stentless and stented valves was unable to demonstrate any hemodynamic or clinical benefits at 1 year after implantation. This study reviews long-term outcomes of patients randomized in the aforementioned trial., Methods: Between 1996 and 1999, 99 patients undergoing aortic valve replacement were randomized to receive either a stented Carpentier-Edwards pericardial valve (CE) (Edwards Lifesciences, Irvine, Calif) or a Toronto Stentless Porcine Valve (SPV) (St Jude Medical, Minneapolis, Minn). Among these, 38 patients were available for late echocardiographic follow-up (CE, n = 17; SPV, n = 21). Echocardiographic analysis was undertaken both at rest and with dobutamine stress, and functional status (Duke Activity Status Index) was compared at a mean of 9.3 years postoperatively (range, 7.5-11.1 years). Clinical follow-up was 82% complete at a mean of 10.3 years postoperatively (range, 7.5-12.2 years)., Results: Preoperative characteristics were similar between groups. Effective orifice areas increased in both groups over time. Although there were no differences in effective orifice areas at 1 year, at 9 years, effective orifice areas were significantly greater in the SPV group (CE, 1.49 +/- 0.59 cm(2); SPV, 2.00 +/- 0.53 cm(2); P = .011). Similarly, mean and peak gradients decreased in both groups over time; however, at 9 years, gradients were lower in the SPV group (mean: CE, 10.8 +/- 3.8 mm Hg; SPV, 7.8 +/- 4.8 mm Hg; P = .011; peak: CE, 20.4 +/- 6.5 mm Hg; SPV, 14.6 +/- 7.1 mm Hg; P = .022). Such differences were magnified with dobutamine stress (mean: CE, 22.7 +/- 6.1 mm Hg; SPV, 15.3 +/- 8.4 mm Hg; P = .008; peak: CE, 48.1 +/- 11.8 mm Hg; SPV, 30.8 +/- 17.7 mm Hg; P = .001). Ventricular mass regression occurred in both groups; however, no differences were demonstrated between groups either on echocardiographic, magnetic resonance imaging, or biochemical (plasma B-type [brain] natriuretic peptide) assessment (P = .74). Similarly, Duke Activity Status Index scores of functional status improved in both groups over time; however, no differences were noted between groups (CE, 27.5 +/- 19.1; SPV, 19.9 +/- 12.0; P = .69). Freedom from reoperation at 12 years was 92% +/- 5% in patients with CEs and 75% +/- 5% in patients with SPVs (P = .65). Freedom from valve-related morbidity at 12 years was 82% +/- 7% in patients with CEs and 55% +/- 7% in patients with SPVs (P = .05). Finally, 12-year actuarial survival was 35% +/- 7% in patients with CEs and 52% +/- 7% in patients with SPVs (P = .37)., Conclusion: Although offering improved hemodynamic outcomes, the SPV did not afford superior mass regression or improved clinical outcomes up to 12 years after implantation., (Copyright 2010 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.)

Background: Left internal thoracic artery (LITA) grafts to the left anterior descending coronary artery (LAD) during coronary bypass surgery (CABG) have greater patency rates than saphenous vein grafts and reduce long-term cardiac morbidity and mortality rates. The benefits of multiple versus single arterial grafts and the role of different arterial conduits with respect to short- and medium-term outcome remains controversial. The purpose of this study was to compare the perioperative and intermediate-term results of: (1) patients receiving 2 arterial grafts versus 1 arterial graft and (2) patients receiving a right internal thoracic artery (RITA) versus a radial artery (RA) as the second arterial graft., Methods and Results: Retrospective analysis of prospectively gathered data on consecutive patients undergoing isolated CABG at our institution between 1989 and 1996 was conducted. The first section of the study compared outcomes for 1 arterial graft (LITA to LAD, n = 2333) versus 2 arterial grafts (LITA + RA or LITA + RITA, n = 378). The second section of the study compared outcomes for the RITA (n = 132) versus the RA (n = 171) as second arterial grafts since 1992, when the radial series was initiated. Part I: By multivariable stepwise logistic regression, the use of 1 arterial graft was associated with an increased incidence of perioperative cardiac morbidity and mortality (odds ratio 2.2, 95% confidence interval 1.4 to 3.3), with the use of our current patient selection criteria. Double-arterial graft patients had a nonsignificant trend toward increased intermediate-term actuarial survival (P = 0.12) and cardiac event-free survival (P = 0.09). Part II: Comparison of preoperative demographics revealed a higher incidence of diabetes (27% vs 11%, P < 0.001), peripheral vascular disease (16% vs 8%, P = 0.03), and elderly age (13% vs 2%, P = 0.001) in patients receiving an RA versus those receiving a RITA as the second arterial graft. Perioperative outcome analysis revealed a decreased intensive care unit stay in the RA versus RITA group (median 30.4 vs 36.2 hours, respectively, P = 0.005) but no significant difference in hospital length of stay. There was no significant difference in perioperative mortality or cardiac morbidity rates. RITA patients had a higher incidence of sternal wound infection (5.3% vs 0.6%, P = 0.01), however, and tended to have increased blood product transfusion rates (51% vs 40%, P = 0.06)., Conclusions: The use of 2 arterial grafts is safe, with a reduction in perioperative cardiac morbidity or mortality rates compared with 1 arterial graft after adjustment for other risk variables. When comparing RITA to RA as second arterial grafts, patients receiving an RA have a lower incidence of sternal wound infection and decreased transfusion requirements, with no difference in perioperative or intermediate-term cardiac morbidity or mortality rates.

Background: Laboratory evidence supports the use of adenosine-supplemented cardioplegia. An initial phase 1 dose-ranging clinical evaluation demonstrated that an adenosine concentration of 15 mumol/L could be safely administered with warm blood cardioplegia and suggested that phase 2 studies were warranted., Methods and Results: Two separate double-blind, randomized, placebo-controlled trials were performed in patients undergoing primary, isolated, nonemergent coronary artery bypass graft surgery. Patients were randomized to receive adenosine 15 mumol/L versus placebo in the first study (n = 200) and adenosine 50 or 100 mumol/L versus placebo in the second study (n = 128). Adenosine was infused with both initial and final doses of warm antegrade blood cardioplegia. The data from the 2 trials were combined using the methods of Mantel and Haenszel, and the results of the meta-analysis are presented as the relative risk with their associated 95% confidence intervals (CI). The different study groups were comparable with respect to all preoperative clinical characteristics, angiographic findings, and intraoperative variables. In both trials 1 and 2, no differences were found between groups in the incidence of the individual primary or secondary outcomes. Similarly, when both studies were combined, there was no significant evidence of any consistent treatment benefit (primary: death: relative risk [RR] = 1.02, 95% CI = 0.06, 16.6; myocardial infarction by CK-MB: RR = 0.84, CI = 0.54, 1.31; low output syndrome: RR = 1.38, CI = 0.29, 6.42; any of the above: RR = 0.98, CI = 0.78, 1.25; secondary: Q-wave myocardial infarction: RR = 1.30, CI = 0.41, 4.13; myocardial infarction by troponin T: RR = 0.7, CI = 0.40, 1.21; inotrope requirement: RR = 0.9, CI = 0.46, 1.79; intra-aortic balloon pump requirement: RR = 0.6, CI = 0.07, 4.81; P > 0.20)., Conclusions: Despite promising experimental data, adenosine supplementation of warm blood cardioplegia did not demonstrate any statistically significant benefit in patients undergoing elective coronary artery bypass graft surgery. Although sample sizes were relatively small, based on our interim analyses, it is unlikely that increased patient enrollment would reveal any substantive clinical differences between groups.

Background: The cardioprotective role of adenosine in various models of ischemia-reperfusion, including adenosine supplementation to cardioplegic formulations, has been studied extensively. The appropriate dose of adenosine in humans is uncertain and could be limited by systemic hypotension or AV block., Methods and Results: An open-label, nonrandomized phase 1 adenosine dose-ranging study was performed. Patients scheduled for primary isolated coronary bypass surgery were eligible for the study. Antegrade warm blood potassium cardioplegia (ratio, 4:1, blood to crystalloid) was administered in the routine fashion, with adenosine added to the initial 1000-mL dose and final 500-mL dose. Patients were studied in blocks of 4 per concentration. An escalating adenosine dosage schedule was planned to produce blood cardioplegia concentrations from 0 to 250 mumol/L, and the blocks were tested sequentially. Stopping rules were defined for systemic hypotension (phenylephrine dose during cardiopulmonary bypass > or = 5.0 mg; phenylephrine dose during cardioplegic induction > or = 800 micrograms) and AV block (permanent pacemaker insertion; temporary pacing dependency for > 90 minutes after cardiopulmonary bypass). Doses of 1, 2.5, 5, 10, and 25 mumol/L were well tolerated. With 50 mumol/L, systemic hypotension occurred during cardioplegic induction in 3 of 4 patients versus 1 of 24 (P < .005) at all lower concentrations (880 +/- 217 versus 297 +/- 286 micrograms phenylephrine per patient). The studies were repeated with an 8:1 blood-to-crystalloid cardioplegia delivery system. Adenosine concentrations of 0 (n = 4), 15 (n = 12), 20 (n = 8), and 25 mumol/L (n = 4) were tested. Hypotension during cardioplegic induction was more prevalent (P = .05) with the higher doses (15 mumol/L, 394 +/- 189 micrograms, 1 of 12 patients; 20 mumol/L, 360 +/- 355 micrograms, 2 of 8 patients; 25 mumol/L, 600 +/- 478 micrograms, 2 of 4 patients). There were no differences with respect to systemic hypotension during cardiopulmonary bypass or for pacing > 90 minutes after discontinuation of cardiopulmonary bypass, and no patient required permanent pacing. There have been no deaths, Q-wave myocardial infarctions, intra-aortic balloon pump insertions, or cerebral infarctions in the total sample of 56 patients., Conclusions: Our initial investigations have shown that adenosine can be safely administered during cardiopulmonary bypass. The authors recommend that further studies are warranted using adenosine 15 to 25 mumol/L, depending on the delivery system.

Certain antiarrhythmic drugs that inhibit myocardial repolarizing currents decrease defibrillation energy, but the effect of blocking particular currents on defibrillation is not well understood. We therefore investigated the effect of barium, a relatively selective blocker of inwardly rectifying potassium current (Ik1) on voltage and energy requirements for defibrillation in an open-chest dog model. Defibrillation energy and voltage requirements were assessed by delivering monophasic shocks through epicardial electrode patches at varying voltages to construct a dose-dependent curve of energy and voltage versus success in defibrillation. The energy and voltage for 50% success in defibrillation (E50 and V50, respectively) were determined by logistic regression. Monophasic action potential duration at 90% repolarization (MAPD90) was measured with a contact electrode, and ventricular refractory period (VERP) was measured. After baseline measurements were obtained of E50, V50, MAPD90, and VERP, saline (control) (n = 6) or barium (1.1 mg/kg/min for 5 min followed by 0.25 mg/kg/min) (n = 11) was administered. Defibrillation voltage and energy requirements and electrophysiologic measures were repeated after 30 and 120 min of barium or saline infusion. In control animals, there was no significant change with time in V50 (2.0 +/- 12.4 and -0.2 +/- 16.0% at 30 and 120 min, respectively), VERP (+3 +/- 5 and -2 +/- 3% at 30 and 120 min, respectively) or MAPD90 (+1 +/- 4 and -2 +/- 6, at 30 and 120 min, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of an isoproterenol infusion on the duration of the human right ventricular endocardial monophasic action potential at 90% repolarization were recorded in the absence and in the presence of an antiarrhythmic drug regimen containing class III effects in two similar groups of patients. The drugs used were amiodarone (N = 3, 300 +/- 50 mg), sotalol plus quinidine (N = 11, 156 +/- 13 mg sotalol, 1688 +/- 594 mg quinidine), and sotalol alone (N = 3, 300 +/- 20 mg). All patients had underlying coronary disease but no evidence of inducible ischemia. In the absence of antiarrhythmic drug, isoproterenol did not significantly change the relationship of action potential duration at 90% repolarization to cycle length; there was a linear decrease in action potential duration by 19.8% between a paced cycle length of 600 and 300 ms. Isoproterenol did not significantly shorten the action potential duration at any cycle length. However, isoproterenol decreased the ventricular effective refractory period at 400 ms drive from 240 +/- 5.0 to 225 +/- 6.0 ms (p < 0.05) accompanied by no change in the ratio of refractory period to steady-state action potential duration. In the presence of class III drug effects, the action potential duration was increased by an average of 9.2% at all paced cycle lengths longer than 300 ms (p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Sotalol is unique among beta-adrenergic blocking drugs in possessing significant class III antiarrhythmic actions. The present study was designed to assess the relative concentration dependence of beta-blocking and class III actions of sotalol and to relate the findings to concentrations achieved during oral sotalol therapy in humans. Measurements were made in anesthetized dogs under control conditions, and then in the presence of a series of stable sotalol plasma concentrations produced by sequential loading and maintenance infusions. Beta-blocking effects of sotalol, determined by attenuation of the chronotropic actions of isoproterenol, were seen at the lowest dose used. Increases in atrial and ventricular refractory periods (observed in dogs with autonomic blockade to exclude beta-receptor-mediated or reflex autonomic effects) required much larger doses of sotalol. Half-maximal beta-blocking effects occurred at an average sotalol concentration of 0.8 +/- 0.3 mg/liter, an order of magnitude lower than the concentrations required for half-maximal effects on atrial (6.9 +/- 1.2 mg/liter, p less than 0.01) and ventricular (6.8 +/- 2.8 mg/liter, p less than 0.05) refractoriness. These results show that substantially higher concentrations are needed for the class III effects of sotalol than for its beta-blocking action. These pharmacodynamic differences need to be considered in evaluating the antiarrhythmic efficacy and mechanisms of this unusual drug.