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Objective: Cardiac surgery demands highly effective cardioprotective regimens. We previously demonstrated improved cardioprotection with "polarized" compared with "depolarized" arrest. This study uses a clinically relevant porcine model of cardiopulmonary bypass to compare the efficacy of blood-based St Thomas' Hospital polarizing cardioplegia (STH-Pol-B) with blood-based St Thomas' Hospital hyperkalemic cardioplegia (STH2-B)., Methods: Pigs were monitored and subjected to normothermic cardiopulmonary bypass, cardiac arrest via antegrade cold (4°C) blood cardioplegia (STH2-B, control group: n = 6 or STH-Pol-B, study group: n = 7), and global ischemia (60 minutes) followed by on-pump reperfusion (60 minutes) and subsequent off-pump reperfusion (90 minutes). At termination, tissue samples were taken for analysis of high-energy phosphates, ultrastructure, and microRNAs. The primary endpoint of this study was creatine kinase-muscle/brain release during reperfusion., Results: Creatine kinase-muscle/brain was comparable in both groups. After pigs were weaned from cardiopulmonary bypass, hemodynamic parameters such as mean arterial pressure (P = .007), left ventricular systolic pressure (P < .001), external heart work (P = .012), stroke volume (P = .015), as well as dp/dt max (P = .027), were improved with polarizing cardioplegia. Wedge pressure was significantly lower in the study group (P < .01). Energy charge was comparable between groups. MicroRNA-708-5p was significantly lower (P = .019) and microRNA-122 expression significantly (P = .046) greater in STH-Pol-B hearts., Conclusions: Polarized cardiac arrest offers similar myocardial protection and enhances functional recovery in a porcine model of cardiopulmonary bypass. Differential expression of microRNAs may indicate possible new ischemia-reperfusion markers. These results confirm the noninferiority and potential of polarized versus depolarized arrest., (Copyright © 2018 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Background: Pulmonary hypertension (PH) is a life-threatening complication in patients with chronic kidney disease on hemodialysis (CKD-HD)., Objectives: To determine whether subcutaneous infusion of treprostinil was effective and tolerable CKD-PH., Methods and Results: A 57-year-old man was admitted to our hospital due to presyncope and dyspnea during exercise with a history of CKD-HD. Cardiac catheterization revealed high pulmonary arterial pressure (PAP) of 53/24/32 mmHg and pulmonary vascular resistance (PVR) of 11.2 w.u. Upfront combination therapy with bosentan and sildenafil was started. However, 6-month therapy did not attenuate his symptoms, probably due to the high PAP and PVR (60/19/30 mmHg and 5.9 w.u.). We added subcutaneous treprostinil. Surprisingly, 9-month treprostinil (50 ng/kg/min) normalized hemodynamics (PAP: 25/4/13 mmHg and PVR: 1.9 w.u.). His symptoms during excise disappeared without any adverse effects., Conclusion: This is the first report that subcutaneous treprostinil was very effective and tolerable in a PH patient with CKD-HD., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Takotsubo cardiomyopathy can occur at the early phase of severe acute brain injuries. In the case of cardiac output decrease or shock, the optimal treatment is still a matter of debate. Due to massive stress hormone release, the infusion of catecholamines may have limited effects and may even aggravate cardiac failure. Other inotropic agents may be an option. Levosimendan has been shown to have potential beneficial effects in this setting, although milrinone has not been studied., Methods: We report a case of a young female presenting with inverted Takotsubo cardiomyopathy syndrome after severe traumatic brain injury., Results: Due to hemodynamic instability and increasing levels of infused norepinephrine, dobutamine infusion was begun but rapidly stopped due to tachyarrhythmia. Milrinone infusion stabilized the patient's hemodynamic status and improved cardiac output without deleterious effects., Conclusion: Milrinone could be a good alternative when inotropes are required in Takotsubo cardiomyopathy and when dobutamine infusion is associated with tachyarrhythmia., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Nonocclusive mesenteric ischemia (NOMI) can evolve in a variety of low-flow states. Although the mechanisms leading to NOMI-related intestinal necrosis are largely unknown, circumstantial evidence suggests that excessive vasoconstriction and complement activation both play important roles in this process. Because targeting of the circulatory malfunction of the splanchnic area could be of therapeutic relevance, we set out to investigate the long-term effects of treatment with a complement C5a antagonist in a rat model of partial aortic occlusion (PAO)-induced transient mesenteric hypoperfusion., Methods: The mean arterial pressure of the splanchnic area was kept between 30 and 40 mm Hg by 60 minutes of PAO in anesthetized male Sprague-Dawley rats. C5a inhibitor acetyl-peptide-A (AcPepA; 4 mg kg(-1) intravenously) or vehicle administration was initiated at the 45th minute of PAO. After 24 hours, the animals were reanesthetized to record the macrohemodynamics and ileal microcirculation, and plasma and tissue samples were taken for determination of high-mobility group box protein-1 (HMGB-1), endothelin-1, tumor necrosis factor (TNF)-α levels, and small intestinal leukocyte infiltration. Epithelial structural changes were visualized by in vivo confocal laser scanning endomicroscopy., Results: At 24 hours after PAO, mean arterial pressure, heart rate, and cardiac output were significantly greater, the intestinal intramural microcirculation was significantly impaired, and plasma HMGB-1, endothelin-1, TNF-α levels, the degree of epithelial damage and leukocyte infiltration was increased. The AcPepA treatment moderated the hemodynamic and microcirculatory changes, and decreased inflammatory activation and histologic signs of mucosal damage., Conclusion: C5a inhibition ameliorated the potentially harmful local mesenteric hypoperfusion and global long-term inflammatory consequences of PAO. This approach is of promise for use in NOMI-associated situations., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Intestinal ischemia-reperfusion injury (IRI) is a clinical challenge with high morbidity and mortality, leading to intestine damage, systemic inflammation, and multiorgan failure. Previous research has shown that the inhaled anesthetic sevoflurane protects various organs from IRI. However, whether sevoflurane protects against intestinal IRI and which application condition is the most effective are not completely clear. Thus, we investigated the effects of sevoflurane on intestinal IRI with sevoflurane given before, during or after intestinal ischemia, and the role of phosphatidylinositol 3 kinases (PI3K)/Akt pathway in these effects., Methods: Rat model of intestinal ischemia-reperfusion (IR) was used in this study. The superior mesenteric artery was clamped for 60 minutes followed by 120 minutes of reperfusion. Sevoflurane at 0.25, 0.5, and 1.0 minimum alveolar concentration (MAC) was inhaled for 30 minutes before, during, or after ischemic insult. LY294002, a PI3K inhibitor, was injected intraperitoneally before sevoflurane inhalation., Results: Intestinal IR caused a significant decrease of mean arterial blood pressure, severe intestinal mucosa injury and epithelial cell apoptosis, downregulation of the levels of phospho-Akt and phospho-Bad proteins. Exposure to 0.5 or 1.0 MAC sevoflurane before or after intestinal ischemia or 0.5 MAC during intestinal ischemia significantly ameliorated IR-induced histopathologic changes and decreased Chiu's scores. Pretreatment with 0.5 MAC sevoflurane also inhibited intestinal IR-induced increase of terminal deoxyribonucleotide transferase-mediated dUTP nick end labeling-positive cells and activation of caspase-3 and restored expression of phospho-Akt and phospho-Bad. LY294002 partly blocked the protective effects induced by 0.5 MAC sevoflurane pretreatment., Conclusion: Our results suggest that sevoflurane inhalation at clinical related concentration before, during, or after ischemia protects against IR-induced intestinal injury. The pretreatment-induced protection was partly mediated by inhibiting intestinal mucosal epithelial apoptosis via activation of the PI3K/Akt pathway., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Although the introduction of novel medical and invasive therapies in recent years has led to a significant reduction in mortality from heart failure, the same cannot be said for mortality due to cardiogenic shock. Drug therapy with inotropic agents and catecholamines has the disadvantage of causing increased myocardial oxygen consumption resulting in increased heart rate which may lead to the widening of the ischemic area. A reduction in heart rate with the administration of β-blockers is contraindicated due to negative inotropic and blood pressure lowering effects, typical of this group of drugs. Thus the theoretical possibility of ivabradine administration for an isolated reduction in heart rate, associated with the absence of a negative inotropic effect, could favorably influence hemodynamics in patients with cardiogenic shock. We report a case of cardiogenic shock treated by adding ivabradine to the currently used therapy., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objectives: Pulmonary vein stenosis (PVS) is a relentless disease with a poor prognosis. Although surgical repair can effectively treat "downstream" (near left atrial junction) PVS, residual "upstream" (deep in lung parenchyma) PVS commonly dictates long-term survival. Our initial studies revealed an association between PVS and transforming growth factor-β signaling, which led us to investigate the effect of losartan on upstream pulmonary vein vasculopathy in a piglet model of PVS., Methods: Neonatal Yorkshire piglets underwent sham surgical banding (sham, n = 6), staged bilateral pulmonary vein banding of all pulmonary veins except the right middle pulmonary vein (banded, n = 6), and staged pulmonary vein banding with losartan treatment (losartan, 1 mg/kg/d, n = 7). After 7 weeks, the hemodynamic data were obtained and the piglets killed., Results: Pulmonary vein banding (compared with sham) was associated with continuous turbulent flow in banded pulmonary veins, pulmonary hypertension (pulmonary artery/systemic blood pressure ratio 0.51 ± 0.06 vs 0.23 ± 0.02, P < .001), and diffuse pulmonary vein intimal hyperplasia in the upstream pulmonary veins (P < .001). Losartan administration decreased the pulmonary artery/systemic blood pressure ratios compared with those in the banded piglets (0.36 ± 0.08 vs 0.51 ± 0.06, P = .007) but it remained greater than those in the sham group (P = .001). Losartan was also associated with diminished pulmonary vein intimal hyperplasia compared with that in the banded piglets (P < .001) but still remained more than that in the sham group (P = .035). Pulmonary vein banding reduced vascular endothelial-cadherin expression, indicative of diminished endothelial integrity, which was restored with losartan., Conclusions: Losartan treatment improved PVS-associated pulmonary hypertension and intimal hyperplasia and might be a beneficial prophylactic therapy for patients at high risk of developing PVS after pulmonary vein surgery., (Copyright © 2014 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Study Objective: Hydroxocobalamin is a Food and Drug Administration-approved antidote for cyanide poisoning. Cobinamide is a potential antidote that contains 2 cyanide-binding sites. To our knowledge, no study has directly compared hydroxocobalamin with cobinamide in a severe, cyanide-toxic large-animal model. Our objective is to compare the time to return of spontaneous breathing in swine with acute cyanide-induced apnea treated with intravenous hydroxocobalamin, intravenous cobinamide, or saline solution (control)., Methods: Thirty-three swine (45 to 55 kg) were intubated, anesthetized, and instrumented (continuous mean arterial pressure and cardiac output monitoring). Anesthesia was adjusted to allow spontaneous breathing with FiO2 of 21% during the experiment. Cyanide was continuously infused intravenously until apnea occurred and lasted for 1 minute (time zero). Animals were then randomly assigned to receive intravenous hydroxocobalamin (65 mg/kg), cobinamide (12.5 mg/kg), or saline solution and monitored for 60 minutes. A sample size of 11 animals per group was selected according to obtaining a power of 80%, an α of .05, and an SD of 0.17 in mean time to detect a 20% difference in time to spontaneous breathing. We assessed differences in time to death among groups, using Kaplan-Meier estimation methods, and compared serum lactate, blood pH, cardiac output, mean arterial pressure, respiratory rate, and minute ventilation time curves with repeated-measures ANOVA., Results: Baseline weights and vital signs were similar among groups. The time to apnea and cyanide dose required to achieve apnea were similar. At time zero, mean cyanide blood and lactate concentrations and reduction in mean arterial pressure from baseline were similar. In the saline solution group, 2 of 11 animals survived compared with 10 of 11 in the hydroxocobalamin and cobinamide groups (P<.001 between the 2 treated groups and the saline solution group). Time to return of spontaneous breathing after antidote was similar between hydroxocobalamin and cobinamide (1 minute 48 seconds versus 1 minute 49 seconds, respectively). Blood cyanide concentrations became undetectable at the end of the study in both antidote-treated groups, and no statistically significant differences were detected between the 2 groups for mean arterial pressure, cardiac output, respiratory rate, lactate, or pH., Conclusion: Both hydroxocobalamin and cobinamide rescued severely cyanide-poisoned swine from apnea in the absence of assisted ventilation. The dose of cobinamide was one fifth that of hydroxocobalamin., (Copyright © 2014 American College of Emergency Physicians. Published by Elsevier Inc. All rights reserved.)

Background: Alpha-blockade is the standard management preoperatively to prevent intraoperative hemodynamic instability (IHD) during resection of a pheochromocytoma. Calcium channel blockers also have been shown to lessen the risk of IHD. We aim to determine differences between these classes of antihypertensive agents in minimizing IHD., Methods: This was a retrospective analysis from a tri-institutional database. Inclusion criteria were unilateral transabdominal adrenalectomy for pheochromocytomas between 2002 and 2012. IHD was defined as at least one systolic blood pressure (SBP) measurement >160 mm Hg and at least one episode of mean arterial pressure 60 mm Hg., Results: A total of 155 patients were included: 110 receiving calcium channel blockers, 41 alpha-blockade, and 4 no medication. Intraoperatively, mean maximal SBP was less after alpha-blockade (P < .0001) as well as the incidence and duration of episodes of SBP >200 mm Hg (P < .01); however, severe hypotensive episodes (MAP <60 mm Hg) were more frequent (P < .001) and longer (P < .0001) with alpha-blockade. Consequently, intraoperative vasoactive drugs were used more frequently (P = .03), and mean fluid volume infused was larger (P < .001). Fifty-four patients had IHD, but these were independent of type of preoperative medication used. Familial disease was the only independent predictor of IHD., Conclusion: IHD was independent of type of preoperative medical management but was dependent on familial disease. These findings broaden options for clinicians in the preoperative management of pheochromocytoma., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Study Objective: We compare the effects of intravenous lipid emulsion and normal saline solution pretreatment on mortality and hemodynamic changes in a rat model of cocaine toxicity. We hypothesize that intravenous lipid emulsion will decrease mortality and hemodynamic changes caused by cocaine administration compared with saline solution., Methods: Twenty male Sprague-Dawley rats were sedated and randomized to receive intravenous lipid emulsion or normal saline solution, followed by a 10 mg/kg bolus of intravenous cocaine. Continuous monitoring included intra-arterial blood pressure, pulse rate and ECG tracing. Endpoints included a sustained undetectable mean arterial pressure (MAP) or return to baseline MAP for 5 minutes. The log-rank test was used to compare mortality. A mixed-effect repeated-measures ANOVA was used to estimate the effects of group (intravenous lipid emulsion versus saline solution), time, and survival on change in MAP, pulse rate, or pulse pressure., Results: In the normal saline solution group, 7 of 10 animals died compared with 2 of 10 in the intravenous lipid emulsion group. The survival rate of 80% (95% confidence interval 55% to 100%) for the intravenous lipid emulsion rats and 30% (95% confidence interval 0.2% to 58%) for the normal saline solution group was statistically significant (P=.045)., Conclusion: Intravenous lipid emulsion pretreatment decreased cocaine-induced cardiovascular collapse and blunted hypotensive effects compared with normal saline solution in this rat model of acute lethal cocaine intoxication. Intravenous lipid emulsion should be investigated further as a potential adjunct in the treatment of severe cocaine toxicity., (Copyright © 2013 American College of Emergency Physicians. Published by Mosby, Inc. All rights reserved.)

Objective: To assess the ability of vasopressin to stabilize hemodynamics in infants with systemic hypotension secondary to congenital diaphragmatic hernia (CDH)., Study Design: A retrospective chart review was performed to identify 13 patients with CDH treated with vasopressin for refractory hypotension to assess the effect of vasopressin on pulmonary and systemic hemodynamics and gas exchange in this setting. Data collected included demographics, respiratory support, inotropic agents, pulmonary and systemic hemodynamics, urine output, and serum and urine sodium levels during vasopressin therapy., Results: Vasopressin therapy increased mean arterial pressure and decreased pulmonary/systemic pressure ratio, heart rate, and fraction of inspired oxygen. In 6 of 13 patients, extracorporeal membrane oxygenation therapy was no longer indicated after treatment with vasopressin. Improvement in left ventricular function and oxygenation index after vasopressin initiation was associated with a decreased need for extracorporeal membrane oxygenation therapy. Prolonged vasopressin treatment was associated with hyponatremia, increased urine output, and increased urine sodium., Conclusions: Vasopressin stabilized systemic hemodynamics without adverse effects on pulmonary hemodynamics in a subset of infants with CDH. Our results suggest a potential role for vasopressin therapy in patients with CDH with catecholamine-resistant refractory hypotension., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: In patients with severe aortic stenosis (AS), treatment with angiotensin-converting enzyme inhibitors has previously been considered contraindicated. However, there is a lack of clinical evidence to confirm these potential hemodynamic risks and benefits., Methods: Forty-four patients with severe AS (aortic valve area <1 cm(2)) were randomized to treatment with trandolapril 22 mg daily/placebo (1:1). Right heart catheterization and echocardiography were performed at rest and during exercise at baseline and on day 3. Follow-up was performed before valve replacement or after a maximum of 8 weeks, when exercise echocardiography was repeated., Results: Compared with placebo, systolic blood pressure and systemic arterial compliance significantly changed at day 3 (-14 ± 11 vs -5 ± 13 mm Hg, P = .02, and 0.08 ± 0.16 vs -0.05 ± 0.86 mL/m(2) per mm Hg, P = .03, respectively). Changes in left ventricular end systolic volume (LVESV) was nonsignificant (-8 ± 9 vs -3 ± 11 mL, P = .17). At a median of 49 days of follow-up, changes in LVESV and N-terminal pro-brain natriuretic peptide were even lower revealing significant differences between the groups (-7.8 ± 2.6 vs -0.5 ± 2.5 mL, P = .04, and -19 ± 7 vs 0.8 ± 6 pmol/L, P = .04, respectively). No episodes of symptomatic hypotension were noted, and other hemodynamic parameters remained unchanged., Conclusion: Angiotensin-converting enzyme inhibition in severe AS caused a decrease in LVESV and N-terminal pro-brain natriuretic peptide with other hemodynamic parameters preserved both at rest and during exercise implying hemodynamic improvement with left ventricular unloading., (© 2014.)

Background: Continuous infusion of epoprostenol is the treatment of choice in patients with pulmonary arterial hypertension in functional classes III to IV. However, this treatment's limitations include instability at room temperature. A new epoprostenol formulation offers improved storage conditions and patient convenience., Methods: The EPITOME-2 trial was an open-label, prospective, multicenter, single-arm, phase IIIb study. Patients with pulmonary arterial hypertension on long-term, stable epoprostenol therapy were transitioned from epoprostenol with glycine and mannitol excipients (Flolan; GlaxoSmithKline, Durham, NC) to epoprostenol with arginine and sucrose excipients (Veletri; Actelion Pharmaceuticals Ltd, Allschwil, Switzerland). Patients were followed up for 3 months, and dose adjustments were recorded. Efficacy measures included the 6-minute walk distance, hemodynamics assessed by right heart catheterization, and New York Heart Association functional class. Safety and tolerability of the transition were also evaluated. Quality of life was assessed using the Treatment Satisfaction Questionnaire for Medication., Results: Forty-two patients enrolled in the study, and 1 patient withdrew consent before treatment; thus, 41 patients received treatment and completed the study. Six patients required dose adjustments. There were no clinically relevant changes from baseline to month 3 in any of the efficacy end points. Adverse events were those previously described with intravenous prostacyclin therapy. Treatment Satisfaction Questionnaire for Medication scores showed an improvement from baseline to month 3 in the domain of treatment convenience., Conclusions: Transition from epoprostenol with glycine and mannitol excipients to epoprostenol with arginine and sucrose excipients did not affect treatment efficacy, raised no new safety or tolerability concerns, and provided patients with an increased sense of treatment convenience., (© 2014.)

Background: Epoprostenol sodium with arginine-mannitol excipients (epoprostenol AM; Veletri [Actelion Pharmaceuticals Ltd, Allschwil, Switzerland]) and epoprostenol sodium with glycine-mannitol excipients (epoprostenol GM; Flolan [GlaxoSmithKline, Triangle Park, NC]) are intravenous treatments for pulmonary arterial hypertension (PAH). Epoprostenol AM contains different inactive excipients, resulting in greater stability at room temperature compared with epoprostenol GM., Methods: In this prospective, multicenter, open-label, randomized, phase IV exploratory study, epoprostenol-naïve patients in need of injectable prostanoid therapy were randomized 2:1 to open-label epoprostenol AM or epoprostenol GM. The study period was 28 days, followed by a 30-day safety follow-up. Study aims were to descriptively compare the safety, tolerability, drug metabolite levels, and treatment effects of epoprostenol AM and epoprostenol GM in PAH. Statistical analysis was descriptive only because of the exploratory nature of the study., Results: Thirty patients with PAH (18-70 years, 24 women, 20 idiopathic PAH) were randomized to epoprostenol AM (n = 20) or epoprostenol GM (n = 10). Most frequently reported adverse events included jaw pain, headache, nausea, and flushing. Two deaths occurred during the study period, and 1 death occurred during the 30-day safety follow-up period, all in patients receiving epoprostenol AM. All deaths were classified by the treating physician as unrelated to epoprostenol AM. The median (range) change from baseline to day 28 in 6-minute walk distance was 36 m (-127 to 210 m) and 49 m (-44 to 110 m) for the epoprostenol AM and epoprostenol GM groups, respectively., Conclusions: In this randomized clinical study of epoprostenol AM in PAH, use of this novel preparation with greater room temperature stability was well tolerated., (© 2014.)

Objective: Systemic effects of carbon dioxide (CO2) insufflation during left-sided cardiac surgery were evaluated in a prospective randomized study, with regard to acid-base status, gas exchange, cerebral hemodynamics, and red blood cell morphology., Methods: Twenty patients undergoing elective left-sided cardiac surgery were randomized to de-airing procedure either by CO2 insufflation technique (CO2 group, n = 10) or by Lund technique without CO2 insufflation (Lund group, n = 10). Groups underwent assessment of acid-base status by intermittent arterial blood gases and in-line blood gas monitoring. Capnography was used to determine volume of CO2 produced. Cerebral hemodynamics was measured by transcranial Doppler sonography and near-infrared spectroscopy. Red cell morphology from cardiotomy suction and vent tubing was studied by scanning electron microscopy., Results: Patients in the CO2 group consequently developed significantly higher levels of hypercapnia with a concomitant increase in the volume of CO2 produced despite significantly higher oxygenator gas flows compared with the Lund group. Effects on cerebral hemodynamics were observed in the CO2 group with significantly higher blood flow velocities in the middle cerebral artery and higher regional cerebral saturation. Red blood cell damage was observed in the CO2 group by scanning electron microscopy (97% in CO2 group vs 18% in Lund group)., Conclusions: Insufflation of CO2 into the cardiothoracic wound cavity during left-sided cardiac surgery can induce hypercapnic acidosis and increased cerebral blood flow and local blood cell damage. These systemic effects should be monitored by in-line capnography and acid-base measurements for early and effective correction by increase in gas flows to the oxygenator., (Copyright © 2014 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.)

Objective: Vasoactive medications improve hemodynamics after cardiac surgery but are associated with high metabolic and arrhythmic burdens. The vasoactive-inotropic score was developed to quantify vasoactive and inotropic support after cardiac surgery in pediatric patients but may be useful in adults as well. Accordingly, we examined the time course of this score in a substudy of the Biventricular Pacing After Cardiac Surgery trial. We hypothesized that the score would be lower in patients randomized to biventricular pacing., Methods: Fifty patients selected for increased risk of left ventricular dysfunction after cardiac surgery and randomized to temporary biventricular pacing or standard of care (no pacing) after cardiopulmonary bypass were studied in a clinical trial between April 2007 and June 2011. Vasoactive agents were assessed after cardiopulmonary bypass, after sternal closure, and 0 to 7 hours after admission to the intensive care unit., Results: Over the initial 3 collection points after cardiopulmonary bypass (mean duration, 131 minutes), the mean vasoactive-inotropic score decreased in the biventricular pacing group from 12.0 ± 1.5 to 10.5 ± 2.0 and increased in the standard of care group from 12.5 ± 1.9 to 15.5 ± 2.9. By using a linear mixed-effects model, the slopes of the time courses were significantly different (P = .02) and remained so for the first hour in the intensive care unit. However, the difference was no longer significant beyond this point (P = .26)., Conclusions: The vasoactive-inotropic score decreases in patients undergoing temporary biventricular pacing in the early postoperative period. Future studies are required to assess the impact of this effect on arrhythmogenesis, morbidity, mortality, and hospital costs., (Copyright © 2013 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.)

Objective: We aimed to evaluate the efficacy and safety of a cold crystalloid cardioplegic solution with adenosine (1.2 mmol/L) instead of supranormal potassium., Methods: Sixty low-risk patients scheduled for elective coronary artery bypass grafting (CABG) were randomized to receive standard cold crystalloid hyperkalemic cardioplegia (hyperkalemic group) or normokalemic cardioplegia in which supranormal potassium was replaced with 1.2 mmol/L adenosine (adenosine group). End points were postoperative release of troponin T and creatine kinase MB, hemodynamics measured by PiCCO arterial thermodilution catheters, perioperative release of markers of endothelial activation and injury, and clinical course., Results: The adenosine group had a significantly shorter time to arrest than did the hyperkalemic group (mean ± standard deviation, 11 ± 5 vs 44 ± 18 seconds; P < .001). Three hearts in the adenosine group were probably not adequately drained and received additional hyperkalemic cardioplegia to maintain satisfactory cardioplegic arrest. There were no differences between groups with respect to perioperative release of markers of endothelial activation or injury and no differences between groups in postoperative release of troponin T or creatine kinase MB. Postoperative hemodynamics including cardiac index were similar between groups. The incidence of postoperative atrial fibrillation was significantly lower in the adenosine group than in the hyperkalemic group (4 vs 15; P = .01)., Conclusions: Adenosine instead of hyperkalemia in cold crystalloid cardioplegia is safe, gives more rapid cardiac arrest, and affords similar cardioprotection and maintenance of hemodynamic parameters, together with a marked reduction in the incidence of postoperative atrial fibrillation., (Copyright © 2013 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.)

Background: We previously performed a trial of intravenous landiolol hydrochloride during and after cardiac surgery (the PASCAL trial) and demonstrated a preventive effect on postoperative atrial fibrillation (AF). In the present study, we investigated the efficacy of increasing the dose and administration period of landiolol for prevention of postoperative AF, as well as the effect of oral bisoprolol in the early postoperative period., Patients and Methods: A total of 105 patients who underwent coronary artery bypass grafting were randomized to 3 groups: a group receiving intravenous landiolol perioperatively at 5 μg/kg/min for 3 days (group L), a group receiving oral bisoprolol postoperatively together with landiolol (group LB), and a control group without beta-blocker therapy (group C). The primary end point was the presence/absence of postoperative AF. Secondary end points were (1) the early clinical outcome, (2) hemodynamics, (3) cardiac enzymes (creatine kinase isoenzyme MB, troponin-I, and human heart fatty acid-binding protein), (4) high-sensitivity C-reactive protein (hs-CRP) and pentraxin-3, (5) asymmetric dimethylarginine (ADMA), and (6) brain natriuretic peptide., Results: Postoperative AF occurred in 14.5% of group L, 9.1% of group LB, and 35.3% of group C. A significant difference was observed between groups LB and C. Significantly higher levels of troponin-I, human heart fatty acid-binding protein, hs-CRP, pentraxin-3, and ADMA were noted in group C than in groups L and LB., Conclusions: Landiolol and bisoprolol prevented postoperative AF. The anti-ischemic, anti-inflammatory, and anti-oxidant effects of these beta-blockers presumably inhibited the onset of AF., (Copyright © 2012 The American Association for Thoracic Surgery. All rights reserved.)

Objective: To determine whether "early" ibuprofen treatment, at the onset of subtle patent ductus arteriosus (PDA) symptoms, would improve respiratory outcome in premature infants compared with "expectant" management, with ibuprofen treatment only when the PDA becomes hemodynamically significant (HS)., Study Design: We conducted a randomized double-blind controlled trial of infants with gestational ages 23 to 32 weeks and birth weights 500 to 1250 g who had echocardiography for subtle PDA symptoms (metabolic acidosis, murmur, bounding pulses). Infants were then randomized to "early" treatment (blinded ibuprofen; n = 54) or "expectant management" (blinded placebo, n = 51). If the PDA became HS (pulmonary hemorrhage, hypotension, respiratory deterioration), infants received open label ibuprofen. Infants with HS PDA at enrollment were excluded from the study. Respiratory outcomes and mortality and major morbidities were determined., Results: "Early" treatment infants received ibuprofen at median age of 3 days; infants in the "expectant group" in whom HS symptoms developed (20%) received ibuprofen at median of 11 days. A total of 49% of "expectant" infants never required ibuprofen or ligation. No significant differences were found in the primary outcome (days on oxygen [O(2)] during the first 28 days), death, O(2) at 36 weeks, death or O(2) at 36 weeks, intestinal perforation, surgical necrotizing enterocolitis, grades III and IV intracranial hemorrhage, periventricular leukomalacia, sepsis or retinopathy of prematurity., Conclusion: Infants with mild signs of PDA do not benefit from early PDA treatment compared with delayed treatment., (Copyright © 2012 Mosby, Inc. All rights reserved.)

Objectives: We previously reported that patients with preoperative B-type natriuretic peptide levels of 30 pg/mL or more have increased risk of postoperative atrial fibrillation after pulmonary resection. This study evaluated the effects of human atrial natriuretic peptide on postoperative atrial fibrillation in patients undergoing pulmonary resection for lung cancer., Methods: A prospective, randomized study was conducted with 40 patients who had preoperative elevated B-type natriuretic peptide (≥ 30 pg/mL) and underwent a scheduled pulmonary resection for lung cancer. Results were compared between patients who received low-dose human atrial natriuretic peptide and those who received a placebo. The primary end point was the incidence of postoperative atrial fibrillation during the first 4 days after surgery., Results: The incidence of postoperative atrial fibrillation was significantly lower in the human atrial natriuretic peptide group than in the placebo group (10% vs 60%; P < .001). Patients in the human atrial natriuretic peptide group also showed significantly lower white blood cell counts and C-reactive protein levels after surgery., Conclusions: Continuous infusion of low-dose human atrial natriuretic peptide during lung cancer surgery had a prophylactic effect against postoperative atrial fibrillation after pulmonary resection in patients with preoperative elevation of B-type natriuretic peptide levels. A larger sample size is needed to establish the safety and efficacy of this intervention., (Copyright © 2012 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.)

Objective: Resistance arteries remain subject to pulsatility, a potent regulator of large elastic artery tone and structure, but the effect is incompletely understood. Extracorporeal circulation during cardiac surgery is often associated with absence of pulsatility, which may affect vascular tone. To define the role of the vascular wall in the inflammatory process that may occur with or without pulsatility, we studied resistance arteries functions ex vivo. We measured vascular reactivity, oxidative stress, and inflammation in the arterial wall., Methods: Isolated rat mesenteric resistance arteries were mounted in an arteriograph and subjected to pulsatility or not in vitro. Arteries were perfused with a physiologic salt solution without circulating cells., Results: After 180 minutes, flow-mediated dilation was higher and pressure-induced myogenic tone lower in arteries subjected to pulsatility. Without pulsatility, reactive oxygen species and markers of inflammation (monocyte chemotactic protein 1 and tumor necrosis factor α) were higher than baseline. In perfused mesenteric beds under similar conditions, tumor necrosis factor α was higher in perfusate after 180 minutes of nonpulsatility (5.7 ± 1.6 pg/mL vs 1.1 ± 0.4 pg/mL; P < .01). In arteries treated with the antioxidant 4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl (tempol), flow-mediated dilation and myogenic tone were similar in nonpulsatile and pulsatile arteries; monocyte chemotactic protein 1 and nuclear factor κB expression levels were not increased in tempol-treated nonpulsatile arteries., Conclusions: Absence of pulsatility in resistance arteries increased oxidative stress, which in turn induced inflammation and preferentially altered pressure and flow-dependent tone, which play a key role in control of local blood flow., (Copyright © 2011 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.)

Objective: Cyclooxygenase-2 inhibitors have been implicated in adverse cardiac events. We hypothesize that hypercholesterolemia and ischemia may alter the myocardial response to the cyclooxygenase-2 inhibitor celecoxib., Methods: Yorkshire swine fed normal chow (CX, n = 6) or high-cholesterol diet (HCX, n = 6) underwent placement of an Ameroid constrictor on the left circumflex artery and were started on celecoxib (200 mg/day). After 7 weeks, ischemic and nonischemic myocardium was analyzed for thrombogenic ratio (thromboxane content divided by prostacyclin content), total protein oxidative stress, and expression of prostacyclin synthase, thromboxane synthase, myeloperoxidase, and superoxide dismutase. Cardiac function, tissue perfusion, and vessel density were measured., Results: HCX animals were significantly hypercholesterolemic compared with CX animals. Thrombogenic ratio was significantly higher in the HCX group than in the CX group, but prostacyclin and thromboxane synthase expression was similar in all tissues. Myocardial perfusion was decreased in the HCX group compared with the CX group. Total oxidative stress, myeloperoxidase, and superoxide dismutase were increased in ischemic tissue compared with nonischemic tissues, but there was no diet-induced difference between groups. There was no difference in capillary or arteriolar density between groups. Left ventricular contractility was greater in the HCX group than in the CX group, but there was no significant difference in heart rate, mean arterial pressure, or left ventricular pressure., Conclusions: Hypercholesterolemic patients using celecoxib may be at higher risk for thrombotic events than those with normal cholesterol, but the relationship between dyslipidemia, ischemia, and cyclooxygenase-2 inhibition is likely much more complicated than originally thought., (Copyright © 2011 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.)

Background: Progressive heart failure and sudden cardiac death are the common causes of death in Eisenmenger syndrome. β-Bockers may be useful in Eisenmenger syndrome, but the safety and efficacy are not proven. The objective of the study was to evaluate the hemodynamic effects and safety of metoprolol in Eisenmenger syndrome., Methods: Fifteen patients of Eisenmenger syndrome with a mean age of 22.6 (±8.9) years were studied. Hemodynamic parameters were measured at baseline, after 15 mg of intravenous metoprolol and 6 weeks after oral metoprolol (25 mg/d for 2 weeks and 50 mg/d for 4 weeks)., Results: Intravenous metoprolol was well tolerated, although there was a significant decrease in pulmonary and systemic blood flows. The calculated pulmonary vascular resistance index (23.3 ± 8.6 to 27.4 ± 10.6 Wood U, P = .005) and systemic vascular resistance index (34.9 ± 9.9 to 41.9 ± 13.5 Wood U, P = .005) increased significantly. After 6 weeks of oral metoprolol, the pulmonary artery mean pressure declined significantly (79.9 ± 12.9 to 73.4 ± 14.0 mm Hg, P = .04), which was associated with a slight decrease in mean aortic pressures as compared with baseline. The 6-minutes walk distance increased (401.2 ± 99.9 to 462.5 ± 81.7 m, P = .005)., Conclusions: Preliminary observations suggest that metoprolol is safe and well tolerated in selected patients with Eisenmenger syndrome. Acute hemodynamic worsening recovers in the short term, and the exercise capacity improves in most patients. Larger studies are warranted., (Copyright © 2011 Mosby, Inc. All rights reserved.)

Objective: Left ventricular assist device (LVAD) implantation is an established option for treatment of patients with end-stage heart failure, but outcome may be worsened by right ventricular failure. The aim of this study was to evaluate the acute effect of LVAD on right ventricular geometry and function and the pulmonary circulation. The effect of inhaled nitric oxide (iNO) was assessed., Methods: We evaluated pre- and postoperatively obtained transesophageal echocardiography images and hemodynamics of patients participating in a randomized trial on the effect of inhaled nitric oxide during LVAD implantation. Twenty-four patients were randomized to the iNO group and 23 to the placebo group., Results: After LVAD implantation marked decreases in pulmonary capillary wedge pressure (P < .01) and mean pulmonary artery pressure (P < .01) were observed in both groups. Pulmonary vascular resistance decreased only in the iNO group (311 ± 35 to 225 ± 17, P < .01). Transesophageal echocardiography measurements show significant improvement of right ventricular geometry (right ventricular end-diastolic diameter: 50 ± 2 to 45 ± 2, P < .01 and 48 ± 2 to 44 ± 2 mm, P < .05 in iNO and placebo groups) and function (right ventricular fractional area change: 24% ± 2% to 31% ± 2%, P < .05 and 23% ± 2% to 29% ± 2%, P < .05 in iNO and placebo groups) without any difference between the iNO and placebo groups. The overall incidence of postoperative right ventricular failure was 4 of 47 (8.5%)., Conclusions: LVAD implantation markedly improved right ventricular geometry and function in most of the patients, probably by resolving left ventricular congestion and thus reducing right ventricular afterload. Beneficial effects of iNO may have been masked by more pronounced consequences of left ventricular unloading on right ventricular function., (Copyright © 2011 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.)

Objectives: Stromal cell-derived factor (SDF)-1α is a potent endogenous endothelial progenitor cell (EPC) chemokine and key angiogenic precursor. Recombinant SDF-1α has been demonstrated to improve neovasculogenesis and cardiac function after myocardial infarction (MI) but SDF-1α is a bulky protein with a short half-life. Small peptide analogs might provide translational advantages, including ease of synthesis, low manufacturing costs, and the potential to control delivery within tissues using engineered biomaterials. We hypothesized that a minimized peptide analog of SDF-1α, designed by splicing the N-terminus (activation and binding) and C-terminus (extracellular stabilization) with a truncated amino acid linker, would induce EPC migration and preserve ventricular function after MI., Methods: EPC migration was first determined in vitro using a Boyden chamber assay. For in vivo analysis, male rats (n = 48) underwent left anterior descending coronary artery ligation. At infarction, the rats were randomized into 4 groups and received peri-infarct intramyocardial injections of saline, 3 μg/kg of SDF-1α, 3 μg/kg of spliced SDF analog, or 6 μg/kg spliced SDF analog. After 4 weeks, the rats underwent closed chest pressure volume conductance catheter analysis., Results: EPCs showed significantly increased migration when placed in both a recombinant SDF-1α and spliced SDF analog gradient. The rats treated with spliced SDF analog at MI demonstrated a significant dose-dependent improvement in end-diastolic pressure, stroke volume, ejection fraction, cardiac output, and stroke work compared with the control rats., Conclusions: A spliced peptide analog of SDF-1α containing both the N- and C- termini of the native protein induced EPC migration, improved ventricular function after acute MI, and provided translational advantages compared with recombinant human SDF-1α., (Copyright © 2010 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.)

Objectives: In patients with chronic thromboembolic pulmonary hypertension, high flow in unobstructed lung regions may induce small-vessel damage responsible for persistent pulmonary hypertension after pulmonary thromboendarterectomy. In piglets, closure of an experimental aortopulmonary shunt reverses the flow-induced vascular lesions and diminishes the elevated levels of messenger RNA (mRNA) expression for endothelin-1 and endothelin receptor A (ETA). We wanted to study the effect of the ETA antagonist TBC 3711 on reversal of flow-induced pulmonary vascular lesions., Methods: Twenty piglets were studied. In 15 piglets, pulmonary vasculopathy was induced by creating an aortopulmonary shunt. After 5 weeks of shunting, some animals were studied (n = 5); others underwent shunt closure for 1 week with (n = 5) or without (n = 5) TBC3711 treatment. Anti-ETA treatment started 1 week before and ended 1 week after the shunt closure. The controls were sham-operated animals (n = 5)., Results: High blood flow led to medial hypertrophy of the distal pulmonary arteries (54.9% +/- 1.3% vs 35.3% +/- 0.9%; P < .0001) by stimulating smooth muscle cell proliferation (proliferating cell nuclear antigen) and increased the expression of endothelin-1, ETA or endothelin receptor type A or endothelin receptor A, angiopoietin 1, and Tie2 (real-time polymerase chain reaction). One week after shunt closure, gene expression levels were normal and smooth muscle cells showed increased apoptosis (terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling) without proliferation. However, pulmonary artery wall thickness returned to control values only in the group given TBC3711 (33.2% +/- 8% with and 50.3% +/- 1.3% without; P < .05)., Conclusions: Anti-ETA therapy accelerated the reversal of flow-induced pulmonary arterial disease after flow correction. In patients with chronic thromboembolic pulmonary hypertension and severe distal pulmonary vasculopathy, anti-ETA agents may prove useful for preventing persistent pulmonary hypertension after pulmonary thromboendarterectomy., (2010 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.)

Objective: To investigate the efficacy of bosentan in patients with single-ventricle physiology who were unable to undergo right-sided heart bypass surgery because of high pulmonary vascular resistance and pulmonary artery pressure., Methods: Eight patients with single-ventricle physiology (2 male and 6 female; aged 7 months to 5 years, median 1 year) were enrolled. Prior surgical interventions included pulmonary artery banding in 4 patients, Blalock-Taussig shunt operation in 2 patients, and bidirectional Glenn operation in 5 patients. Right-sided heart bypass surgery was contraindicated for all patients because of high pulmonary vascular resistance and pulmonary artery pressure., Results: Bosentan therapy successfully reduced pulmonary artery pressure and pulmonary vascular resistance in all patients. Mean pulmonary artery pressure at baseline and after bosentan therapy was 21.1 +/- 7.2 mm Hg and 11.9 +/- 4.1 mm Hg, respectively (P < .01). Mean pulmonary vascular resistance index at baseline and after bosentan therapy was 5.7 +/- 3.3 U/m(2) and 1.3 +/- 0.4 U/m(2), respectively (P < .01). Mean pulmonary vascular resistance/systemic vascular resistance at baseline and after bosentan therapy was 0.25 +/- 0.11 and 0.07 +/- 0.03, respectively (P < .01). All patients had improved clinical symptoms and underwent successful Fontan operations., Conclusion: Bosentan induces mid-term clinical and hemodynamic improvement in patients with single-ventricle physiology and elevated pulmonary vascular resistance and pulmonary artery pressure. Bosentan therapy may increase the surgical options and improve outcomes in candidates for right-sided heart bypass surgery., (Copyright 2010 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.)

Study Objective: Severe beta-blocker intoxication remains a clinical challenge despite a variety of treatment options. Because of its unique mechanism of action, the new calcium sensitizer levosimendan may provide more prominent cardiac support compared with current medications used to reverse negative inotropy. We hypothesize that levosimendan could reverse propranolol-induced severe negative inotropy in a porcine model of beta-blocker intoxication., Methods: Twenty-four pigs were anesthetized and monitored. After severe propranolol intoxication was completed, animals were randomized into 3 groups. With a double-blind procedure, 9 animals received a 1.25-mg levosimendan bolus, followed by saline solution infusion, 9 animals received mean arterial pressure-targeted dobutamine infusion after saline solution bolus, and 6 animals received a saline solution bolus followed by saline solution infusion. Hemodynamic and laboratory data were collected during a follow-up period of 120 minutes., Results: All 9 pigs in the levosimendan group survived. In contrast, 4 of 6 (67%) and 7 of 9 (78%) pigs died during the experiment in the placebo and the dobutamine groups, respectively. The levosimendan group showed improved change in the maximum positive slope of the left ventricular pressure, cardiac output, stroke volume, and mean arterial pressure compared with the dobutamine and the placebo groups., Conclusion: Levosimendan improved hemodynamic function and survival in this animal model of severe propranolol intoxication. The potential clinical application of levosimendan in propranolol intoxication warrants further investigation.

Objective: Inhaled nitric oxide has been shown to reduce pulmonary vascular resistance in patients undergoing cardiothoracic surgery, but it is limited by toxicity, the need for special monitoring, and cost. Inhaled prostacyclin also decreases pulmonary artery pressure, is relatively free of toxicity, requires no specific monitoring, and is less expensive. The objective of this study was to compare nitric oxide and prostacyclin in the treatment of pulmonary hypertension, refractory hypoxemia, and right ventricular dysfunction in thoracic transplant recipients in a prospective, randomized, crossover pilot trial., Methods: Heart transplant and lung transplant recipients were randomized to nitric oxide or prostacyclin as initial treatment, followed by a crossover to the other agent after 6 hours. Pulmonary vasodilators were initiated in the operating room for pulmonary hypertension, refractory hypoxemia, or right ventricular dysfunction. Nitric oxide was administered at 20 ppm, and prostacyclin was administered at 20,000 ng/mL. Hemodynamic and oxygenation parameters were recorded before and after initiation of pulmonary vasodilator therapy. At 6 hours, the hemodynamic and oxygenation parameters were recorded again, just before discontinuing the initial agent. Crossover baseline parameters were measured 30 minutes after the initial agent had been stopped. The crossover agent was then started, and the hemodynamic and oxygenation parameters were measured again 30 minutes later., Results: Heart transplant and lung transplant recipients (n = 25) were randomized by initial treatment (nitric oxide, n = 14; prostacyclin, n = 11). Nitric oxide and prostacyclin both reduced pulmonary artery pressure and central venous pressure, and improved cardiac index and mixed venous oxygen saturation on initiation of therapy. More importantly, at the 6-hour crossover trial, there were no significant differences between nitric oxide and prostacyclin in the reduction of pulmonary artery pressures or central venous pressure, or in improvement in cardiac index or mixed venous oxygen saturation. Nitric oxide and prostacyclin did not affect the oxygenation index or systemic blood pressure. There were no complications associated with nitric oxide or prostacyclin., Conclusion: In heart transplant and lung transplant recipients, nitric oxide and prostacyclin similarly reduce pulmonary artery pressures and central venous pressure, and improve cardiac index and mixed venous oxygen saturation. Inhaled prostacyclin may offer an alternative to nitric oxide in the treatment of pulmonary hypertension in thoracic transplantation.

Despite the increased mortality and morbidity in patients with acute decompensated heart failure (ADHF), its management has been based primarily on anecdotal experiences and physiologic assumptions rather than on prospective randomized controlled trials. The data on diuretics have been conflicting. Routine use of inotropes in ADHF has been clearly associated with increased mortality and morbidity, although inotropes seem to cause short-term clinical improvement. The safety of the different vasoactive medications has never been adequately confirmed in prospective trials despite their use for a long time in heart failure. Good evidence that supports the safety and efficacy of the different medications that are routinely used in ADHF is lacking. Unless properly designed prospective clinical trials are done to evaluate the safety of the various ADHF regimens, clinicians might continue to be misguided by the beneficial short-term effects at the expense of long-term mortality and morbidity.

Background: Selective beta adrenergic antagonists are commonly used to reduce myocardial demise in patients at risk for cardiac-related death. The purpose of this study was to examine the hemodynamic and metabolic effects of cardiac selective beta adrenergic blockade in patients., Methods: Muscle protein kinetics were quantified using isotopic tracer methodology in 6 moderately septic, mechanically ventilated patients with pneumonia before and then at the conclusion of a 3-hour infusion of esmolol of sufficient dose to reduce heart rate by 20% from baseline. A battery of hemodynamic measurements as facilitated by a thermodilution pulmonary artery catheter and indirect calorimetry were also measured before and after the 3-hour selective beta adrenergic blockade., Results: Selective beta adrenergic blockade was associated with the 20% reduction in heart rate and a comparable decrease in cardiac output. Esmolol administration failed to affect systemic or pulmonary vascular resistance, oxygen consumption, hepatic or leg blood flow, energy expenditure, or ATP availability/energy charge within muscle. Esmolol infuse did incite a shift in fuel oxidation toward an increase in palmitate oxidation and with a decrease in the oxidation of glucose. There was no demonstrable influence beta1 adrenergic blockade on muscle protein kinetics., Conclusions: Cardiac selective beta adrenergic blockade with esmolol reduces cardiac output in proportion to the percentage decreases in heart rate in moderately severe septic patients without adversely affecting oxygen utilization or hepatic, peripheral blood flow.

Background: The effects of angiotensin antagonists on coronary circulation in type 2 diabetes are unclear. We aimed to assess whether 4 weeks of treatment with angiotensin-converting enzyme inhibitor or angiotensin II type 1 receptor antagonist improves coronary flow velocity reserve (CFVR) in patients with type 2 diabetes., Methods: Twenty-four asymptomatic patients with type 2 diabetes were randomly assigned to temocapril (2 mg/d) or candesartan (8 mg/d). Coronary flow velocity reserve, calculated as the ratio of adenosine-induced hyperemic to basal coronary flow velocity, was measured with transthoracic Doppler echocardiography. Coronary flow velocity reserve measurement and venous blood sampling were performed before and after 4 weeks of treatment. We also obtained CFVR and venous blood data in the 8 healthy controls., Results: Coronary flow velocity reserve was significantly lower in patients than controls (temocapril group 2.74 +/- 0.28, candesartan group 2.65 +/- 0.30, controls 3.53 +/- 0.23, P < .0001 for both, respectively). Blood pressure was reduced in both diabetic groups (n = 12 each) similarly 4 weeks after treatment. There were no significant differences between the 2 groups in venous blood data before or after treatment. However, CFVR increased significantly in the temocapril group (2.74 +/- 0.28 to 3.31 +/- 0.36, P < .0001), but not in the candesartan group (2.65 +/- 0.30 to 2.71 +/- 0.43, P = ns)., Conclusions: Coronary flow velocity reserve in patients with type 2 diabetes improved after treatment with temocapril but not with candesartan, suggesting that angiotensin-converting enzyme inhibitor, but not angiotensin II type 1 receptor antagonist, might have beneficial effects on coronary microangiopathy associated with type 2 diabetes.

Background: Endothelin-1 (ET-1), a very potent mediator of vasoconstriction, leads to microcirculatory disturbances and release of proinflammatory cytokines under pathophysiologic conditions. Our aim was to evaluate the effect of a selective ET(A)-receptor antagonist (ET(A)-RA) on cold ischemia/reperfusion (I/R) injury in a pig model., Methods: Twenty pigs revealed orthotopic liver transplantation. The animals were randomized into 2 groups: control pigs received isotonic saline; the treated group received the selective ET(A)-RA BSF 208075 at the beginning of reperfusion. On postoperative days 4 and 7, animals were re-laparotomized to obtain tissue specimens. Liver tissue samples were collected and quantitative mRNA expression for prepro-ET-1, ET(A) receptor, pro-IL-1beta, pro-IL-6, pro-TNF-alpha, and endothelial nitric oxide synthase was analyzed using the TaqMan system. Additionally, immunohistochemical analysis for ET-1 was performed. Hepatic microcirculation was evaluated by laser Doppler flow measurement and partial pressure of oxygen and carbon dioxide measurements with the Paratrend sensor. Postischemic liver damage was monitored by measurement of liver enzymes and by histologic analysis using a semiquantitative scoring classification., Results: Treatment with the ET(A)-RA significantly reduced the severity of I/R injury evidenced by lower serum AST, ALT and GLDH. Analysis of partial pressure of oxygen and blood flow revealed a significant improvement of capillary perfusion and blood flow in the treated group and was associated with a relevant reduction of tissue injury. One hour after reperfusion, quantitative RT-PCR revealed significantly lower expression of prepro-ET-1, ET(A) receptor, endothelial nitric oxide synthase, pro-TNF-alpha, pro-IL-1beta and pro-IL-6 in the therapy group. Immunohistochemical analysis demonstrated significantly reduced ET-1 immunostaining after therapy. Histologic investigation suggested less tissue damage in treated animals., Conclusions: Treatment with the selective ET(A)-RA BSF 208075 has protective effects on microcirculation after liver transplantation. ET(A)-RA not only affects the expression of vasoactive genes, but also decreases gene expression of proinflammatory cytokines such as TNF-alpha, IL-1beta and IL-6.

Background: Assessment of pulmonary vasodilator responsiveness is important in determining the prognosis and management of patients with pulmonary hypertension. Many patients, however, are already on vasodilators at the time of testing. It is unclear if these agents should be temporarily discontinued to improve the sensitivity of testing., Methods: We examined the hemodynamic effects of nitric oxide (NO) inhalation in 60 patients with pulmonary arterial hypertension. Thirty-one of these patients were receiving medications with vasodilating properties. Vasodilator testing was performed with invasive measurement of pressure of the right side of the heart at baseline and during inhalation of 40 ppm NO., Results: No significant demographic differences were seen between patients receiving and not receiving vasodilators. Similar reductions in mean pulmonary artery pressure (19 +/- 12% vs 20 +/- 12%, P = .734) and pulmonary vascular resistance (31 +/- 18 vs 32 +/- 16, P = .967) were seen in patients receiving and not receiving vasodilators. Using the definition of positive vasodilator response (> or = 20% drop in mean pulmonary artery pressure), 55% (17/31) of patients in the baseline vasodilator group had a positive response compared with 62% (18/29) of the patients not on vasodilators (P = .570)., Conclusions: Concurrent use of oral vasodilators does not appear to mask a significant response to inhaled NO on the pulmonary vasculature. Therefore, routine discontinuation of pulmonary vasodilators is likely unnecessary before vasodilator testing in patients with pulmonary arterial hypertension.

Background: Positive inotropic agents may be associated with increasing myocardial ischemia or malignant arrhythmias. Levosimendan, a new calcium sensitizer, with its little effect on myocardial oxygen demand is better tolerated by patients with acute coronary syndromes. We evaluated the acute effects of levosimendan on hemodynamics and coronary flow velocities in patients with left ventricular (LV) dysfunction undergoing percutaneous coronary interventions (PCIs) for an acute myocardial infarction (AMI)., Methods: Patients with AMI and LV dysfunction undergoing primary PCI were randomized to intravenous infusion of levosimendan (10 minutes bolus with 12 microg/kg followed by 0.1 microg/kg per minute for 24 hours) or placebo, 10 minutes after a primary PCI. Evaluation of hemodynamics and of coronary flow reserve (CFR) were performed at baseline and after bolus., Results: Twenty-six consecutive patients (mean age 57 +/- 5.4 years, 18 males) were included into the study. At baseline, mean values of hemodynamics and coronary flow velocities were comparable between groups. After bolus, patients with levosimendan (n = 12) showed a significant decrease of pulmonary capillary wedge pressure (from 24 to 19 mm Hg) and a significant increase of cardiac index (from 1.8 to 2.4 L/m2 per minute) resulting in a significant decrease of systemic vascular resistance (from 1366 to 1075 [dyne . s]/cm2). Moreover, CFR on infarct-related artery and on reference vessel significantly improved in patients treated with levosimendan (from 1.6 to 2.0 and from 2.1 to 2.4, respectively). On the other hand, no statistically significant changes have been observed in the placebo group (n = 14)., Conclusions: Levosimendan, given intravenously after a PCI procedure in patients with AMI and LV dysfunction, significantly improves hemodynamics and CFR, compared with placebo.

Objective: Nitrate-stimulated tilt testing may be used to diagnose vasovagal syncope or to guide therapy. To date, the reproducibility of the test in patients with clinically suspected vasovagal syncope and healthy controls is undetermined. A high reproducibility is a prerequisite for correct interpretation of the test result. This study investigates the reproducibility of a nitrate-stimulated tilt test in patients with clinically suspected vasovagal syncope and a healthy control group., Methods and Results: We studied 43 patients (24 women, 19 men) with a typical history of vasovagal syncope and 18 healthy controls (3 women, 15 men). We used a combined tilt protocol with a 30-minute passive and 15-minute nitrate-stimulated phase. The second tilt test was performed 16 +/- 12 days after the first. In both patients and controls, overall positive tilt responses were reproduced in the second test in 100%. In contrast to this, the reproducibility of an overall negative test was 50% in patients but 93% in controls. Overall hemodynamic responses to tilt were reproducible in 80%., Conclusion: Nitrate-stimulated tilt testing in both patients with suspected vasovagal syncope and controls has an excellent reproducibility of positive results but a moderate reproducibility of negative results. Importantly, these results are still valid at a repeat interval of 2 weeks and longer. These data suggest that in patients with suspected vasovagal syncope, a nitrate-stimulated tilt test may provide a suitable tool to evaluate the efficacy of a therapeutic approach.

Background: Smoking cessation is an important factor in the primary and secondary prevention of cardiac events. Although multiple clinical trials have examined the efficacy of various smoking cessation aids, a systematic review of the efficacy and safety of smoking cessation aids has not been done., Methods: This paper reviews the effects of smoking on coronary artery disease. In addition, we identify randomized controlled trials examining the efficacy and safety of smoking cessation aids from the years 1970 to 2004. We then pooled the trial results for 6- and 12-month rates of continuous smoking abstinence., Results: The 4 principal mechanisms of cardiovascular damage caused by cigarette smoking are induction of a hypercoagulable state, reduction of oxygen delivery because of carbon monoxide, coronary vasoconstriction, and nicotine-induced hemodynamic effects. Our review of clinical trials suggests that each smoking cessation aid improved continuous smoking abstinence rates at both 6 and 12 months compared with placebo. The 12-month abstinence rates for the active versus placebo treatments were the following: nicotine patch 11.1% versus 5.5%, nicotine gum 27.3% versus 16.5%, nicotine inhaler 16.9% versus 9.1%, bupropion 18.5% versus 6.6%, and behavioral therapy 20.0% versus 13.9%., Conclusions: Several smoking-related mechanisms are responsible for the development of atherosclerosis and the induction of cardiac events. Smoking cessation aids effect a modest increase in smoking abstinence at 12 months compared with placebo. In spite the apparent success of cessation aids, smoking relapse rates are quite high.

Background: Enhanced central hypercapnic chemosensitivity is known to mediate excessive exercise ventilation and to indicate a poor prognosis in patients with chronic heart failure. The present study was designed to elucidate the role of central sympathetic activity in the enhancement of hypercapnic chemosensitivity., Methods: Central hypercapnic chemosensitivity and plasma norepinephrine were measured in 99 patients with chronic heart failure. In 40 patients, the alpha index was derived from simultaneous analysis of R-R interval and systolic blood pressure variability. The effects of a central sympatholytic agent, guanfacine (0.25 mg/day), on hypercapnic chemosensitivity and exercise ventilatory response were studied in 20 of these patients., Results: Hypercapnic chemosensitivity was enhanced in 76% of the patients and correlated significantly with plasma norepinephrine levels (r = 0.49, P < .01) at rest. There was a significant inverse relationship between central chemosensitivity and the alpha index (r = -0.41, P < .01). Guanfacine significantly reduced plasma norepinephrine levels by 29% (P < .01) and chemosensitivity by 31% (P < .01). The beneficial effect of central sympathoinhibition with guanfacine was observed specifically in patients who had enhanced chemosensitivity prior to drug administration. Similarly, the patients with excessive exercise ventilation showed a greater reduction in exercise ventilation with this agent., Conclusions: The present findings suggest that central sympathoexcitation could play an important role in the pathogenesis of enhanced hypercapnic chemosensitivity and a resultant increase in exercise ventilation in chronic heart failure.

Background: Cardiomyocytes produce opioid peptides and receptors. beta-Endorphin is increased in the plasma of patients with congestive heart failure (CHF). We evaluated whether an intravenous infusion of beta-endorphin exerted any effect on cardiovascular function and on the neurohormonal milieu in patients with mild to moderate CHF., Methods: According to a double-blind, placebo-controlled design, 10 patients (5 men, age 46.9 +/- 8.2 years [mean +/- SD]) with CHF and New York Heart Association functional class II to III received, in random order, 1-hour intravenous infusion of beta-endorphin (500 microg/h) and, on a separate occasion, received placebo and underwent echocardiographic and laboratory measurements at baseline and during infusions., Results: beta-Endorphin significantly increased left ventricular ejection fraction (LVEF) (P =.0001) and stroke volume (P =.0001), and reduced systemic vascular resistance (P =.031) in patients with CHF. These changes were paralleled by a significant increase in plasma levels of glucagon (P =.0001), GH (P =.0001), and IGF-1 (P =.0001), and a significant decrease in plasma levels of endothelin (P =.0001) and catecholamines (P =.01). No hemodynamic and neurohormonal changes were observed during the placebo study in any patient., Conclusions: We conclude that a short-term, high dose infusion of beta-endorphin improves LVEF, reduces systemic vascular resistance, blunts the neurohormonal activation, and stimulates the GH/IGF-1 axis in patients with mild to moderate CHF.

Background: Inhaled nitric oxide produces potent pulmonary vasodilation by activating soluble guanylate cyclase and increasing smooth muscle cell concentrations of cyclic guanosine monophosphate. However, responses are often nonsustained, and clinically significant increases in pulmonary vascular resistance have been noted on its acute withdrawal. In vitro and in vivo data suggest that inhaled nitric oxide decreases endogenous nitric oxide synthase activity. The effects of inhaled nitric oxide on the downstream mediators of the nitric oxide/cyclic guanosine monophosphate cascade, soluble guanylate cyclase and phosphodiesterase 5, have not been investigated. We sought to determine the effects of inhaled nitric oxide on endogenous cyclic guanosine monophosphate levels, soluble guanylate cyclase, and phosphodiesterase 5 protein levels in the intact lamb., Methods: Eleven 1-month-old lambs were mechanically ventilated. In 7 lambs, inhaled nitric oxide (40 ppm) was administered for 24 hours and then acutely withdrawn. Intermittent lung biopsy samples were obtained for cyclic guanosine monophosphate concentrations and soluble guanylate cyclase and phosphodiesterase 5 protein levels (Western blot analysis)., Results: Initiation of nitric oxide decreased left pulmonary vascular resistance by 26.2%, and withdrawal rapidly increased pulmonary vascular resistance by 77.8% (P <.05). Tissue cyclic guanosine monophosphate concentrations initially increased during nitric oxide therapy but were not maintained during the 24-hour exposure. In addition, cyclic guanosine monophosphate concentrations rapidly decreased after nitric oxide withdrawal (P <.05). The alpha soluble guanylate cyclase (-45.7%) and beta soluble guanylate cyclase (-48.4%) protein levels decreased during nitric oxide therapy (P <.05), whereas phosphodiesterase 5 proteins levels were unchanged., Conclusions: These data suggest a role for decreased soluble guanylate cyclase and its resulting decrease in cyclic guanosine monophosphate concentrations in the nonsustained response to nitric oxide and the rebound pulmonary hypertension noted on its acute withdrawal. Phosphodiesterase 5 inhibitors may be a useful adjunct therapy during inhaled nitric oxide to preserve cyclic guanosine monophosphate levels and thereby preserve nitric oxide responsiveness and prevent rebound pulmonary hypertension.

Background: H(1)-antihistamines are widely used for symptom relief in allergic disorders in infants and children; however, there are few prospective, randomized, double-blind, controlled studies of these medications in young children, and to date, no such studies have been conducted in infants., Objective: This prospective, randomized, parallel-group, double-blind, placebo-controlled study was designed to evaluate the safety of the H(1)-antihistamine cetirizine, particularly with regard to central nervous system and cardiac effects, in infants age 6 to 11 months, inclusive., Methods: Infants who met the entry criteria for age and had a history of treatment with an H(1)-antihistamine for an allergic or other disorder were randomized to receive 0.25 mg/kg cetirizine orally or matching placebo twice daily orally for 1 week., Results: The mean daily dose in cetirizine-treated infants was 4.5 +/- 0.7 mg (SD). No differences in all-cause or treatment-related adverse events were observed between the cetirizine- and placebo-treated groups. A trend was observed toward fewer adverse events and sleep-related disturbances in the cetirizine group compared with the placebo group. No prolongation in the linear corrected QT interval was observed in cetirizine-treated infants compared with either baseline values or with values in placebo-treated infants., Conclusions: We have documented the safety of cetirizine in this short-term investigation, the first randomized, double-blind, placebo-controlled study of any H(1)-antihistamine in infants. Additional prospective, randomized, double-blind, placebo-controlled, long-term studies of cetirizine and other H(1)-antihistamines are needed in this population.

Objectives: We tested whether nitric oxide scavenging with a ruthenium-based compound (AMD6221) would improve hemodynamics and alter nitric oxide synthase and matrix metalloproteinase activities in a canine model of cardiopulmonary bypass., Methods: Dogs were randomized to either cardiopulmonary bypass (n = 12) or control (n = 12) groups. They were further randomized to receive a continuous infusion of AMD6221 or placebo. Cardiopulmonary bypass was maintained for 90 minutes, and then, 4 hours later, dogs were killed. Cardiac, lung, and brain sections were snap frozen in liquid nitrogen for determination of nitric oxide synthase, matrix metalloproteinase 2, and matrix metalloproteinase 9 activities., Results: After cardiopulmonary bypass, 3 of 6 placebo-treated (cardiopulmonary bypass-placebo) and 0 of 6 AMD6221-treated (cardiopulmonary bypass-6221) animals required phenylephrine infusion to maintain a predetermined blood pressure (P <.05). Total fluid administration was lower in the cardiopulmonary bypass-6221 group compared with that in the cardiopulmonary bypass-placebo group (983 +/- 134 vs 1617 +/- 254 mL, respectively; P <.005). After cardiopulmonary bypass, matrix metalloproteinase 2 and matrix metalloproteinase 9 activities in the lung, left ventricle, and left atrium were decreased in the cardiopulmonary bypass-6221 group compared with that in the cardiopulmonary bypass-placebo group (P <.05). Ca(2+)-independent nitric oxide synthase activity and matrix metalloproteinase 2 activity in the brain were also lower (P <.05) in the cardiopulmonary bypass-SCV group. Finally, neutrophil expression of CD18, an adhesion complex, was lower at 4 hours after cardiopulmonary bypass in the cardiopulmonary bypass-6221 group compared with that in the cardiopulmonary bypass-placebo group (38 +/- 27 vs 81 +/- 11; P <.05)., Conclusions: We found that (1) infusion of an nitric oxide scavenger, AMD6221, was associated with improved predefined hemodynamics; (2) cardiopulmonary bypass increased activities of Ca(2+)-independent nitric oxide synthase and matrix metalloproteinases in multiple organs; and (3) AMD6221 could ameliorate the increased generation of nitric oxide and increased matrix metalloproteinase activities.

Background: Global and regional shape changes that occur within the left ventricular wall after myocardial infarction have been termed infarct expansion. A potential mechanism for this postinfarction remodeling is activation of the matrix metalloproteinases. Accordingly, the present study examined the effects of matrix metalloproteinase inhibition on left ventricular global geometry after myocardial infarction in pigs., Methods: Myocardial infarction was created in pigs by means of occlusion of the first and second obtuse marginal branches of the circumflex coronary artery, resulting in a uniform left ventricular free wall infarct size of 21% +/- 2%. At 5 days after infarction, the pigs were randomized to undergo broad-spectrum matrix metalloproteinase inhibition (n = 9; PD166793, 20 mg. kg(-1). d(-1) by mouth) or myocardial infarction alone (n = 8). Ten pigs served as noninfarction control animals. Left ventricular end-diastolic area, determined by means of echocardiography, was measured 8 weeks after infarction., Results: Left ventricular end-diastolic area increased in both the myocardial infarction plus broad-spectrum matrix metalloproteinase inhibition and myocardial infarction only groups compared to reference control animals (3.7 +/- 0.2 cm(2)), but was reduced with broad-spectrum matrix metalloproteinase inhibition compared to myocardial infarction alone (4.5 +/- 0.2 vs 4.9 +/- 0.2 cm(2), respectively; P <.05). Regional radial stress within the infarct region increased in both infarction groups when compared to values obtained from reference control animals (599 +/- 152 g/cm(2)), but was attenuated in the myocardial infarction plus broad-spectrum matrix metalloproteinase inhibition group compared to the myocardial infarction alone group (663 +/- 108 vs 1242 +/- 251 g/cm(2), respectively; P <.05). Similarly, regional myocardial stiffness increased in both the myocardial infarction plus broad-spectrum matrix metalloproteinase inhibition and the myocardial infarction only groups compared with that observed in reference control animals (14 +/- 1 rkm, P <.05) but was lower with broad-spectrum matrix metalloproteinase inhibition than with myocardial infarction alone (42 +/- 6 vs 68 +/- 10 rkm, respectively; P <.05)., Conclusions: Matrix metalloproteinase inhibition reduced postinfarction left ventricular dilation, reduced regional myocardial wall stress, and modified myocardial material properties. These unique findings suggest that increased myocardial matrix metalloproteinase activation after infarction contributes directly to the left ventricular remodeling process.

Background: This study evaluated the short-term and long-term effects of the angiotensin II type 1 receptor antagonist candesartan cilexetil on hemodynamics, neurohormones, and clinical symptoms in patients with congestive heart failure (CHF)., Methods: In this multicenter, double-blind, parallel-group study, 218 patients with CHF (New York Heart Association class II or III) with impaired left ventricular function (ejection fraction < or =40%) and pulmonary capillary wedge pressure > or =13 mm Hg were randomly assigned to 12 weeks of treatment with placebo (n = 44) or candesartan cilexetil (2 mg [n = 45], 4 mg [n = 46], 8 mg [n = 39], or 16 mg [n = 44]) once daily after a 2-week placebo run-in period. Hemodynamic measurements were performed by right heart catheterization over a 24-hour period after single (day 1) and repeated (3-month) treatment with the study drug., Results: On regression analysis of the time-response curves, single and multiple doses of candesartan cilexetil produced sustained, significant, and dose-dependent reductions in pulmonary capillary wedge pressure (short-term effect P =.036, long-term effect P =.035) and mean pulmonary arterial pressure (short-term effect P =.031, long-term effect P =.042). Systemic vascular resistance showed a trend toward decreasing with dose on short-term and long-term treatments. No consistent changes were seen in cardiac index. Compensatory increases in plasma renin activity and angiotensin II levels with decreases in aldosterone and atrial natriuretic peptide were dose-dependent and significant. Candesartan cilexetil improved clinical symptoms, stabilized patient New York Heart Association status compared with placebo, and was judged to be an efficacious treatment by the investigators. More patients receiving placebo stopped the trial prematurely because of an adverse event than in any candesartan cilexetil group, and there was no excess of deaths in any treatment group. Candesartan was safe and well tolerated at all dosages., Conclusions: Candesartan cilexetil demonstrated significant short-term and long-term improvements in hemodynamic, neurohormonal, and symptomatic status and was well tolerated in patients with CHF.

Objectives: This study was designed to assess whether testing of potential reversibility of pulmonary hypertension (PHT) may be a useful means of defining the short-term prognosis of patients with advanced heart failure and elevated pulmonary artery pressure. In such patients, the reversibility of PHT after acute vasodilator administration is associated with a low early mortality rate after heart transplantation. However, its short-term prognostic value has not yet been determined., Methods and Results: Between 1994 and 1998, 76 patients with advanced heart failure and PHT underwent right heart cathetherization. The hemodynamic measurements, including thermodilution-derived right ventricular ejection fraction, were repeated after an intravenous bolus of nitroglycerin (NTG). During a median follow-up period of 8.2 months (25% and 75% centiles, 3.3 and 18.9 months), 47 patients had a cardiac event (death or urgent heart transplantation). With Cox survival analysis, a multivariate model that included the New York Heart Association class and the hemodynamic variables obtained after NTG administration allowed a better assessement of the short-term prognosis of the patients than a model including the baseline variables. The evaluation of right ventricular function during the acute NTG-induced pulmonary vasodilation was of critical importance in obtaining such a refinement in the prognostic stratification., Conclusions: The prognostic evaluation of patients with advanced heart failure and PHT should include the assessment of the changes of right ventricular ejection fraction after acute afterload reduction.

Background: Nitrates are often administrated with a variety of other pharmacologic agents in the management of chronic heart failure (CHF). However, limited information is available concerning the long-term effects in patients with evidence of left ventricular (LV) dysfunction after acute myocardial infarction (AMI) already treated with standard heart failure therapy., Methods: In a randomized, double-blind, placebo-controlled trial, we evaluated the effects of a 60 mg dose of isosorbide-5-mononitrate (IS-5-MN) given daily for 11 months to 47 patients with clinical or echocardiographic evidence of left ventricular dysfunction after acute myocardial infarction. Forty-five patients received a placebo., Results: Invasive hemodynamic measurements did not show any difference between the treatment regimens. Overall changes in echocardiographic measurements were not significantly different between IS-5-MN therapy and the placebo groups. However, in a prespecified subgroup with left ventricular ejection fraction < or =40% at baseline, IS-5-MN therapy resulted in a lesser increase of end-diastolic volume index than the placebo (P =.047). IS-5-MN significantly reduced the serum concentration of atrial natriuretic peptide (mean 20.0 pmol/L, 95% CI 7.7-32.3, P =.002), whereas the placebo did not (P =.041 for the difference between the groups). The proportion of patients taking diuretics was significantly reduced in the IS-5-MN group, from 30 of 44 to 20 of 44 (P =.02), but not with placebo, which remained at 27 of 43 (P = 1.0, with P =.048 for the difference between the regimens)., Conclusions: Oral, long-term IS-5-MN therapy resulted in lower atrial natriuretic peptide levels and reduced the need for additional diuretics. Less LV dilatation was observed in patients with more severe LV dysfunction at baseline.

Background: The immune-enhancing diet (IED) (Impact, Novartis Corp, Minneapolis, Minn) initiates a delayed and sustained increase in blood flow to the ileum and gut-associated lymphoid tissue. The immune-enhancing benefits of Impact (Novartis Corp) are attributed to the addition of L-arginine, fish oil (FO), and RNA fragments to a standard enteral diet. The sustained increase in blood flow to the gut-associated lymphoid tissue during IED exposure might account for these immune effects. We hypothesized that the increase in ileal blood flow with IED might be a result of ileal omega-3 fatty acid absorption in the ileum by a bile-dependent mechanism., Methods: Male Sprague-Dawley rats (200 g-230 g) were anesthetized and cannulated for microsphere measurement of whole organ blood flow. Rats received gastric gavage (2 mL) with either IED, an isocaloric, isonitrogenous control diet (CD) (Boost, Mead-Johnson, Evansville, Ind), CD plus menhaden FO (CD+FO), or CD+FO plus bile duct ligation (BDL). Blood flow was determined at baseline and 30, 60, and 120 minutes after short-term gavage., Results: Baseline blood flow and central hemodynamics were comparable in all groups. In the ileum, at 120 minutes postgavage, blood flow was increased by IED and CD+FO compared with baseline and CD. BDL prevented the increase in blood flow in the CD+FO+BDL rats. All groups exhibited differences in splanchnic blood flow distribution after gavage: CD and CD+FO+BDL increased blood flow compared with baseline early in the proximal gut and spleen. IED and CD+FO produced a delayed, sustained hyperemia to the distal gut., Conclusions: Gastrointestinal blood flow distribution after feeding is dependent on nutrient composition. These findings suggest that omega-3 fatty acids are the components of the enteral IED, Impact (Novartis Corp), which produce the increased blood flow to the terminal ileum and its contiguous gut-associated lymphoid tissue. Our data suggests that an intact enterohepatic bile pathway is needed for the IED blood flow effect.