Skeletal muscle microvasculature response to ß-adrenergic stimuli is diminished with cardiac surgery.

BACKGROUND: Cardiac surgery and cardiopulmonary bypass are associated with alterations in blood pressure in the perioperative period, which, if uncontrolled, can result in end organ damage or dysfunction. Microvessels, significant contributors to blood pressure, both in the myocardium and peripheral skeletal muscle, have diminished responsiveness to major mediators of vascular tone, including thromboxane and serotonin after cardiopulmonary bypass. Responsiveness of these vessels to ß-adrenergic stimulation, a major mediator of vascular tone, has not yet been studied. In this report, we investigated the role of ß-adrenergic receptors in vascular tone regulation in human skeletal muscle microvessels before and after ß-adrenergic stimulation. METHODS: Skeletal muscle microvessels were isolated from patients undergoing cardiac surgery before and after cardiopulmonary bypass. Vessels were exposed in an ex vivo model to the ß-adrenergic agonist isoproterenol, or the direct adenylyl cyclase activator, forskolin, and the selective ß-receptor antagonist ICI18.551 hydrochloride plus isoproterenol. Immunofluorescence of ß receptors and Western blotting were also performed. RESULTS: Microvessels showed diminished responsiveness to isoproterenol (10-6 to 10-4M) after cardiopulmonary bypass (n = 8/group, P = .01). Pretreatment with the selective ß-2 blocker ICI18.551 (10-6M) prevented isoproterenol-induced microvascular relaxation (P = .001). Forskolin-induced relaxation response was also significantly diminished after cardiopulmonary bypass (n = 4/group, P < .05 versus before cardiopulmonary bypass). No significant changes in the total protein expression of ß-1, ß-2, and ß-3 receptors were detected by western blotting or immunofluorescence. CONCLUSION: Microvessels isolated from human skeletal muscle show diminished responsiveness to isoproterenol and its downstream activator forskolin after cardiopulmonary bypass, suggesting there is an alteration in ß-adrenergic receptor responsive in adenylate cyclase. The relaxation response to isoproterenol was via activation ß-2 receptors without changes in ß-adrenergic receptor abundance.

Sequence analysis of capnography waveform abnormalities during nurse-administered procedural sedation and analgesia in the cardiac catheterization laboratory.

Identifying common patterns in capnography waveform abnormalities and the factors that influence these patterns could yield insights to optimize responses to sedation-induced respiratory depression. Respiratory state sequences for 102 patients who had a procedure in a cardiac catheterisation laboratory with procedural sedation and analgesia were developed by classifying each second of procedures into a state of normal breathing or other capnography waveform abnormalities based on pre-specified cut-offs for respiratory rate and end-tidal CO2 concentration. Hierarchical clustering identified four common patterns in respiratory state sequences, which were characterized by a predominance of the state assigned normal breathing (n = 42; 41%), hypopneic hypoventilation (n = 38; 38%), apnea (n = 15; 15%) and bradypneic hypoventilation (n = 7; 7%). A multivariable distance matrix regression model including demographic and clinical variables explained 28% of the variation in inter-individual differences in respiratory state sequences. Obstructive sleep apnea (R2 = 2.4%; p = 0.02), smoking status (R2 = 2.8%; p = 0.01), Charlson comorbidity index score (R2 = 2.5%; p = 0.021), peak transcutaneous carbon dioxide concentration (R2 = 4.1%; p = 0.002) and receiving an intervention to support respiration (R2 = 5.6%; p = 0.001) were significant covariates but each explained only small amounts of the variation in respiratory state sequences. Oxygen desaturation (SpO2 < 90%) was rare (n = 3; 3%) and not associated with respiratory state sequence trajectories.

Impaired coronary contraction to phenylephrine after cardioplegic arrest in diabetic patients.

BACKGROUND: We have previously found that hyperkalemic cardioplegic arrest in the setting of cardiopulmonary bypass (CP/CPB) is associated with impairment of the coronary arteriolar response to phenylephrine in nondiabetic (ND) patients. We hypothesized that diabetes may alter coronary arteriolar response to alpha-1 adrenergic agonist in the setting of CP/CPB. In this study, we further investigated the effects of diabetes on the altered coronary arteriolar response to phenylephrine in patients undergoing cardiac surgery. METHODS: Coronary arterioles (90-150 µm in diameter) were harvested pre- and post-CP/CPB from the ND and diabetic mellitus (DM) patients (n = 8/group) undergoing cardiac surgery. In-vitro microvascular reactivity was examined in response to phenylephrine. The protein expression/localization of the alpha-1 adrenergic receptors in the atrial myocardium was measured by Western blotting and immunohistochemistry. RESULTS: Phenylephrine (10-9 to 10-4 M) induced a dose-dependent contractile response in both ND and DM vessels pre- and post-CP/CPB. There was no significant difference in the pre-CP/CPB contractile responses to phenylephrine between ND and DM groups. The post-CP/CPB contractile response was significantly diminished in both ND and DM groups compared with the respective pre-CP/CPB response (P < 0.05 versus pre-CP/CPB). This diminished contractile response was more pronounced in vessels from DM patients compared with vessels from ND patients (P < 0.05 versus ND). There were no significant differences in the protein expression of alpha-1A and alpha-1B receptors in the atrial myocardium between the ND and DM groups or tissue harvested pre- or post-CP/CPB. CONCLUSIONS: Diabetes is associated with a decreased contractile response of coronary arterioles to phenylephrine in the setting of CP/CPB versus that observed in ND patients. This alteration may contribute to the vasomotor dysfunction of coronary microcirculation seen early after CP/CPB in patients with diabetes.

Serum periostin levels following small bone fractures, long bone fractures and joint replacements: an observational study.

BACKGROUND: In asthma, serum periostin may potentially be used as a biomarker in the management of patients with Type-2 eosinophilic airway inflammation. However, serum periostin may be influenced by factors other than Type 2 inflammation, potentially confounding its interpretation. We aimed to measure change in periostin following bone injury. METHODS: 102 adults without asthma were recruited into three groups: joint replacement surgery, long bone fracture, short bone fracture. Participants underwent seven measurements of serum periostin over 26 weeks after bone injury, and prior to surgery in the joint replacement group. Differences in periostin were measured using a ratio of geometric mean (RGM), with comparison made with pre-surgery (joint replacement) or 26 week (long and short fracture) reference measurements. RESULTS: In the joint replacement group, periostin fell within 48 h (RGM 0.80, 95% CI 0.75-0.86), then increased to a maximum at 8 weeks (RGM 1.89, 1.77-2.02) and by 26 weeks remained above the reference measurement (RGM 1.27, 1.19-1.36). In the long bone fracture group, periostin was reduced at 48 h (RGM 0.76, 0.71-0.83) and then progressively increased to a maximum at 8 weeks (RGM 1.15, 1.06-1.23) compared with the reference measurement. In the short bone fracture group, periostin was reduced at 48 h (RGM 0.9, 0.85-0.95) but was not different from after week 1 compared with the reference measurement. CONCLUSIONS: Serum periostin levels are influenced by bone injury. The timing and extent of bone injury needs consideration if periostin is used as a biomarker in the management of eosinophilic asthma.Trial registration This trial was prospectively registered with the Australia New Zealand Trials Registry on Feb 7 2014, (ACTRN12614000151639: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=363881).

Phenotypes of symptomatic airways disease in China and New Zealand.

It is uncertain whether phenotypes of asthma and chronic obstructive pulmonary disease (COPD) vary between populations with different genetic and environmental characteristics. Here, our objective was to compare the phenotypes of airways disease in two separate populations.This was a cross-sectional observational study in adult populations from New Zealand and China. Participants aged 40-75 years who reported wheeze and breathlessness in the last 12 months were randomly selected from the general population and underwent detailed characterisation. Complete data for cluster analysis were available for 345 participants. Hierarchical cluster analysis was undertaken, based on 12 variables: forced expiratory volume in 1 s (FEV1), FEV1/forced vital capacity ratio, bronchodilator reversibility, peak expiratory flow variability, transfer coefficient of the lung for carbon monoxide, exhaled nitric oxide fraction, total IgE, C-reactive protein, age of symptom onset, body mass index, health status and cigarette smoke exposure.Cluster analysis of the combined dataset described five phenotypes: "severe late-onset asthma/COPD overlap group", "moderately severe early-onset asthma/COPD overlap group", "moderate to severe asthma group with type 2 predominant disease", and two groups with minimal airflow obstruction, differentiated by age of onset. Separate analyses by country showed similar patterns; however, a distinct obese/comorbid group was observed in the New Zealand population.Cluster analysis of adults with symptomatic airways disease suggests the presence of similar asthma/COPD overlap phenotypes within populations with different genetic and environmental characteristics, and an obese/comorbid phenotype in a Western population.

RCT of the effect of berryfruit polyphenolic cultivar extract in mild steroid-naive asthma: a cross-over, placebo-controlled study.

OBJECTIVE: There is preclinical evidence that consumption of berryfruit extract may reduce chronic airways inflammation and modify airway remodelling in allergen-induced models of lung inflammation. We investigated the effect of berryfruit extract on the fractional expired nitric oxide (FeNO), a biomarker of eosinophilic airways inflammation, in adults with steroid-naïve asthma. DESIGN: Randomised placebo-controlled cross-over double-blind trial. SETTING: Single-centre community-based trial. PARTICIPANTS: 28 steroid-naïve mild asthmatics with Feno >40 ppb, of whom 25 completed both study interventions. INTERVENTIONS: Participants were randomised to receive, according to the cross-over design, 100 mg berryfruit polyphenolic extract (BFPE) or placebo for 4 weeks, with a 4-week washout period between the interventions. PRIMARY OUTCOME MEASURE: The primary outcome variable was FeNO at 4 weeks, analysed by a mixed linear model, with a random effect for participant and baseline FeNo as a covariate. RESULTS: The mean (SD) natural logarithm transformed (ln) FeNO after 4 weeks of treatment for the BFPE and placebo groups was 4.28 (0.47) and 4.22 (0.47), respectively. The paired change from baseline mean (SD) BFPE minus placebo ln FeNO was -0.03 (0.39), N=25. The mixed linear model estimate, with baseline covariate adjustment, difference in ln FeNO, was -0.002 (95% CI -0.15 to 0.14), p=0.98. This is equivalent to a ratio of geometric mean FeNO of 1.0 (95% CI 0.86 to 1.15). CONCLUSIONS: In steroid-naïve participants with mild asthma and elevated FeNO, there was no effect of BFPE on FeNO, a biomarker of eosinophilic airways inflammation. Caution is required in the extrapolation of apparent benefit in murine models of lung eosinophilia to clinical efficacy in patients with asthma. TRIAL REGISTRATION NUMBER: ANZCTR: 12613000451707; Results.

Long-Term Outcomes of External Repair as a Rescue Operation for Atrioventricular Groove Disruption.

BACKGROUND: Atrioventricular groove disruption (AVGD) is an uncommon but lethal complication of mitral valve operations associated with mortality approaching 90%. Traditionally, an "internal" repair is performed requiring prosthesis explantation, complete atrioventricular groove reconstruction using a patch positioned from within the cardiac cavity, and subsequent prosthesis reimplantation. This is a massive undertaking that is usually unsuccessful. We examine the utility of an alternative, "external" approach for rescue of AVGD. METHODS: A retrospective review was conducted of consecutive patients with AVGD after mitral operations at 3 North American medical centers. All patients underwent external repair as a rescue procedure. The external repair technique was conducted on cardiopulmonary bypass using direct suturing or felt-reinforced suturing, or both, of the atrioventricular groove. This was supplemented as needed with applications of BioGlue (CryoLife, Kennesaw, GA), external bovine pericardial patch, left atrial buttress, and coronary bypass grafting of the circumflex circulation. RESULTS: Between 1995 and 2015, 3,071 mitral valve operations resulted in 13 AVGDs (incidence, 0.42%). Average patient age was 75.2 years (range, 59-90 years), and 77% (10 of 13) were women. The 30-day mortality was 15.4% (2 of 13), and hospital mortality was 23.1% (3 of 13). Survival rates at 1, 3, and 5 years were 72.7%, 72.7%, and 44.4%, respectively. Seven patients are currently still alive and remain in no greater than New York Heart Association Functional Classification II. A stable pseudoaneurysm subsequently developed in 2 patients. CONCLUSIONS: The incidence of AVGD after mitral operations is low. Despite an older population with more tissue fragility, the external approach represents an effective, alternative repair technique for rescue of AVGD with encouraging results.

Long-term survival after use of internal thoracic artery in octogenarians is gender related.

OBJECTIVE: The goal of this study is to assess the benefits of a left internal thoracic artery as a bypass conduit in octogenarians undergoing elective coronary artery bypass grafting. We hypothesize that there is no survival advantage and that outcome may be gender related. METHODS: In a retrospective analysis of 1141 octogenarians (aged >80 years) undergoing isolated coronary artery bypass grafting from 1996 to 2012, patients were divided into 2 groups: Group I (coronary artery bypass grafting-left internal thoracic artery) included 870 patients (339 female/531 male), and group II (coronary artery bypass grafting-saphenous vein graft) included 271 patients (131 female/140 male). RESULTS: The overall 30-day mortality was 5.7%: 4.3% in group I and 7.0% in group II (P = .1). Group II had a lower trend of any postoperative complication (P = .05) and pneumonia (P = .05). When analyzed by gender, there were no discernable differences in long-term survival for male patients in group I (65% at 5 years and 29% at 10 years) versus male patients in group II (65% at 5 years and 31% at 10 years) (P = .2). However, survival was significantly greater for female patients in group I (70% at 5 years and 35% at 10 years) versus female patients in group II (63% at 5 years and 21% at 19 years) (P = .01). Multiple logistic and Cox regression analysis showed that left internal thoracic artery use is associated with improved survival in female patients (hazard ratio [HR], 0.72; confidence interval [CI], 0.56-0.93) but not in male patients (HR, 1.14; CI, 0.9-1.4). Advanced age was associated with an increased risk of mortality (HR, 1.08 per year; CI, 1.05-1.1). Both patient age (P = .01) and Society of Thoracic Surgeons-predicted 30-day mortality (P = .03) remain in the final model for 30-day mortality. The benefit of the left internal thoracic artery after coronary artery bypass grafting in octogenarians may be gender related. CONCLUSIONS: This study shows that the benefit of the left internal thoracic artery in the octogenarian population undergoing coronary artery bypass grafting may be gender related. For elderly female patients, the use of the left internal thoracic artery as a bypass conduit was associated with better long-term survival, whereas no significant difference was found among the male population. The use of the left internal thoracic artery was associated with a greater postoperative pulmonary morbidity for the study population as a whole. The present study does not refute the benefit of the left internal thoracic artery-left anterior descending graft, but instead distinguishes a subset who might benefit more.

Randomised controlled trial of topical kanuka honey for the treatment of rosacea.

OBJECTIVE: To investigate the efficacy of topical 90% medical-grade kanuka honey and 10% glycerine (Honevo) as a treatment for rosacea. DESIGN: Randomised controlled trial with blinded assessment of primary outcome variable. SETTING: Outpatient primary healthcare population from 5 New Zealand sites. PARTICIPANTS: 138 adults aged ≥ 16, with a diagnosis of rosacea, and a baseline blinded Investigator Global Assessment of Rosacea Severity Score (IGA-RSS) of ≥ 2. 69 participants were randomised to each treatment arm. 1 participant was excluded from the Honevo group, and 7 and 15 participants withdrew from the Honevo and control groups, respectively. INTERVENTIONS: Participants were randomly allocated 1:1 to Honevo or control cream (Cetomacrogol), applied twice daily for 8 weeks. MAIN OUTCOME MEASURES: The primary outcome measure was the proportion of participants who had a ≥ 2 improvement in the 7-point IGA-RSS at week 8 compared to baseline. Secondary outcomes included change in IGA-RSS and subject-rated visual analogue score of change in severity (VAS-CS) on a 100 mm scale (0 mm 'much worse', 100 mm 'much improved') at weeks 2 and 8. RESULTS: 24/68 (34.3%) in the Honevo group and 12/69 (17.4%) in the control group had a ≥ 2 improvement in IGA-RSS at week 8 compared to baseline (relative risk 2.03; 95% CI 1.11 to 3.72, p=0.020). The change in IGA-RSS for Honevo compared to control at week 2 minus baseline was -1 (Hodges-Lehman estimate, 95% CI -1 to 0, p=0.03), and at week 8 minus baseline was -1 (Hodges-Lehman estimate, 95% CI -1 to 0, p=0.005). The VAS-CS at week 2 was 9.1 (95% CI 3.5 to 14.7), p=0.002, and at week 8 was 12.3 (95% CI 5.7 to 18.9)¸ p<0.001 for Honevo compared to control. CONCLUSIONS: Honevo is an effective treatment for rosacea. TRIAL REGISTRATION NUMBER: This trial was registered in the Australian and New Zealand Clinical Trials Registry ACTRN12614000004662.

Changes in microvascular reactivity after cardiopulmonary bypass in patients with poorly controlled versus controlled diabetes.

BACKGROUND: We investigated the effects of cardiopulmonary bypass (CPB) on peripheral arteriolar reactivity and associated signaling pathways in poorly controlled (UDM), controlled (CDM), and case-matched nondiabetic (ND) patients undergoing coronary artery bypass grafting (CABG). METHODS AND RESULTS: Skeletal muscle arterioles were harvested before and after CPB from the UDM patients (hemoglobin A1c [HbA1c]=9.0 ± 0.3), the CDM patients (HbA1c=6.3 ± 0.15), and the ND patients (HbA1c=5.2 ± 0.1) undergoing CABG surgery (n=10/group). In vitro relaxation responses of precontracted arterioles to endothelium-dependent vasodilators adenosine 5'-diphosphate (ADP) and substance P and the endothelium-independent vasodilator sodium nitroprusside (SNP) were examined. The baseline responses to ADP, substance P, and SNP of arterioles from the UDM patients were decreased as compared with microvessels from the ND or CDM patients (P<0.05). The post-CPB relaxation responses to ADP and substance P were significantly decreased in all 3 groups compared with pre-CPB responses (P<0.05). However, these decreases were more pronounced in the UDM group (P<0.05). The post-CPB response to SNP was significantly decreased only in the UDM group, not in the other 2 groups compared with pre-CPB. The expression of protein kinase C (PKC)-α, PKC-ß, protein oxidation, and nitrotyrosine in the skeletal muscle were significantly increased in the UDM group as compared with those of ND or CDM groups (P<0.05). CONCLUSIONS: Poorly controlled diabetes results in impaired arteriolar function before and after CPB. These alterations are associated with the increased expression/activation of PKC-α and PKC-ß and enhanced oxidative and nitrosative stress.

Midterm outcomes of patients undergoing aortic valve replacement after previous coronary artery bypass grafting.

OBJECTIVES: Redo cardiac surgery for aortic valve replacement (AVR) after previous coronary artery bypass grafting (CABG) is technically challenging and carries a high incidence of peri-operative complications. However, experience in the field continues to evolve generating reproducible, and increasingly safer results. We anticipate an increased future role for catheter-based valve procedures and review our operative results to maintain current surgical outcomes for comparison. METHODS: A retrospective review was conducted from 1996 through 2010 of patients undergoing AVR as a re-operation after previous CABG. Data were obtained through query of the Society of Thoracic Surgeons (STS) database and chart review. Patient outcomes were compared with STS-predicted risk scores. RESULTS: One hundred and thirty-two patients met inclusion criteria (male 83%, female 17%). Average age was 76 (± 7). Thirty-seven patients (28%) required concomitant CABG. Average ejection fraction was 45 (± 14). Comorbid conditions included: diabetes 37% (49/132), hypertension 87% (115/132), NYHA class III/IV 83% (110/132), smoking 51% (67/132), chronic obstructive pulmonary disease 21% (27/132), history of myocardial infarction 61% (80/132), renal failure 16% (21/132) and peripheral arterial disease 38% (50/132).Operative (30-day + hospital) mortality was 6.1% (8/132; 95% CI = 2.9-12.0%), and 30-day mortality was 3.8% (5/132; 95% CI = 1.4-9.1%). One, three and five-year survival rates were 86, 74 and 62%, respectively. Complication rates were as follows: re-operation for bleeding 2.3% (3/132), permanent stroke 0.8% (1/132), prolonged ventilator requirement 18.2% (24/132), deep sternal wound infection 0% (0/132; CI = 0.0-3.5%) and renal failure 9.1% (12/132; none required dialysis). The mean STS-predicted mortality risk score was 7.8% for 111 (applicable) patients for whom actual operative (30-day + hospital) mortality was 3.6%. CONCLUSIONS: Low initial operative mortality suggests that surgery is safe and reproducible. However, older age and multiple comorbidities in this patient population may significantly influence late outcomes. The data reported in this study: (i) support open surgical technique as a safe, reliable approach for redo AVR in patients who have undergone previous CABG, and (ii) add to the large body of evidence suggesting that STS scores overestimate risk.