Cell therapy for heart disease: Trial sequential analyses of two Cochrane reviews.

Meta-analyses of cell therapy trials for heart disease have yielded discrepant results. To resolve limitations associated with meta-analyses, such as imprecision and accumulation of random errors, we conducted trial sequential analysis (TSA). Randomized controlled trials that administered autologous bone marrow-derived cells to patients who suffered acute myocardial infarction (AMI) or heart failure (HF) were included. TSA has been applied to two clinical outcomes, all-cause mortality and hospitalization for HF, and to left ventricular ejection fraction (LVEF), as a surrogate of heart function. The results suggest that there is evidence of reduction of the risk of mortality and hospitalization in HF, but insufficient evidence to determine treatment effect in AMI. Moreover, the treatment does not improve LVEF by more than a mean difference of 4% when administered to either AMI or HF patients. The required number of participants to include in a meta-analysis to detect treatment effect was also estimated.

Polycyclic aromatic hydrocarbons in residential dust and risk of childhood acute lymphoblastic leukemia.

Several polycyclic aromatic hydrocarbons (PAHs) are known or probable human carcinogens. We evaluated the relationship between PAH exposure and risk of childhood acute lymphoblastic leukemia (ALL) using concentrations in residential dust as an exposure indicator. We conducted a population-based case-control study (251 ALL cases, 306 birth-certificate controls) in Northern and Central California from 2001 to 2007. We collected residential dust using a high volume small surface sampler (HVS3) (n=185 cases, 212 controls) or by sampling from participants' household vacuum cleaners (n=66 cases, 94 controls). We evaluated log-transformed concentrations of 9 individual PAHs, the summed PAHs, and the summed PAHs weighted by their carcinogenic potency (the toxic equivalence). We calculated odds ratios (ORs) and 95% confidence intervals (CI) using logistic regression adjusting for demographic characteristics and duration between diagnosis/reference date and dust collection. Among participants with HVS3 dust, risk of ALL was not associated with increasing concentration of any PAHs based on OR perln(ng/g). Among participants with vacuum dust, we observed positive associations between ALL risk and increasing concentrations of benzo[a]pyrene (OR perln[ng/g]=1.42, 95% CI=0.95, 2.12), dibenzo[a,h]anthracene (OR=1.98, 95% CI=1.11, 3.55), benzo[k]fluoranthene (OR=1.71, 95% CI=0.91, 3.22), indeno[1,2,3-cd]pyrene (OR=1.81, 95% CI=1.04, 3.16), and the toxic equivalence (OR=2.35, 95% CI=1.18, 4.69). The increased ALL risk among participants with vacuum dust suggests that PAH exposure may increase the risk of childhood ALL; however, reasons for the different results based on HVS3 dust samples deserve further study.

The impact of off-pump coronary artery bypass surgery on postoperative renal function.

OBJECTIVES: A number of risk factors have been recognised for postoperative renal dysfunction following on-pump coronary artery bypass surgery (CABG). There are, however, few studies that have evaluated the potential reno-protective effects of off-pump CABG in the presence of other confounding risk factors. The aim of this study was to determine if off-pump CABG reduces the risk of renal injury. METHODS: Serum creatinine values (preoperatively and day 1, 2 and 4 postoperatively) and other clinical data were prospectively collected on 1580 consecutive patients who underwent first-time CABG from 2002 to 2005. Creatinine clearance was calculated using the Cockcroft and Gault equation. The effect of on-pump vs. off-pump CABG on renal function was analysed, adjusting for age, gender, diabetes mellitus, left ventricular (LV) function and preoperative creatinine clearance, using multiple regression analysis. RESULTS: One thousand one hundred and forty-five (73%) patients underwent on-pump CABG and 435 (27%) underwent off-pump CABG. The two groups were similar with respect to age, gender and diabetes. Two hundred and seventy-four (17%) patients were females and 274 (17%) patients had diabetes. Multivariate analysis demonstrated significantly lower creatinine clearance postoperatively in patients with diabetes (P<0.001) and advanced age (P<0.001). The on-pump group had significantly lower postoperative creatinine clearance in comparison to the off-pump group (P= 0.01). The effect remained consistent after adjusting for potential risk factors (age, diabetes, gender, LV function and preoperative creatinine clearance) in the multivariate analysis. CONCLUSION: Off-pump surgery is associated with a reduction in postoperative renal injury.

Prognostic value of coronary revascularisation-related myocardial injury: a cardiac magnetic resonance imaging study.

AIMS: Myocardial revascularisation improves outcomes in patients with coronary artery disease. However, these procedures may themselves cause irreversible myocardial injury. The prognostic value of procedural myocardial injury is uncertain. METHODS AND RESULTS: We quantified procedural myocardial necrosis using delayed enhancement cardiovascular magnetic resonance imaging (DE-CMR) in 152 consecutive patients before and shortly after percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG). The primary endpoint was defined as death, non-fatal myocardial infarction, sustained ventricular arrhythmia, unstable angina or heart failure requiring hospitalisation. During a median follow-up of 2.9 years, 27 patients (18%) reached the primary endpoint. 49 patients (32%) had evidence of new procedure-related myocardial hyperenhancement with a median mass of 5.0 g (interquartile range 2.7-9.8). After adjustment for age and sex, these patients had a 3.1-fold (95% confidence interval 1.4 to 6.8; p = 0.004) higher risk of adverse outcome than patients without new hyperenhancement. Cardiac troponin levels and quantitative measures of left ventricular function after procedure did not show any significant independent association with the primary endpoint and they did not alter the independent association of new hyperenhancement. CONCLUSIONS: Myocardial injury during PCI or CABG, identified by DE-CMR, adversely affects clinical outcome. This suggests the benefits from revascularisation could partially be offset by new myocardial injury caused by the intervention itself.

Radiolabeled metaiodobenzylguanidine for imaging and therapy of neuroblastoma.

Neuroblastoma is an embryonic tumor of the peripheral sympathetic nervous system, and is able to take up, store and secrete catecholamine metabolites. Neuro-blastoma is metastatic or otherwise high risk for relapse in nearly 50% of cases, with a long-term survival of <40%, necessitating new approaches to therapy. The tumor cells express the norepinephrine transporter, which makes metaiodobenzylguanidine (MIBG), an analogue of norepinephrine, an ideal tumor specific agent for imaging and therapy, when labeled with (123)I or (131)I. This article will briefly review the use of [(123)I]MIBG imaging for monitoring therapy in neuroblastoma, and concentrate on the past, current and planned clinical trials using [(131)I]MIBG as targeted radiotherapy. The administration guidelines, toxicity, response and survival are discussed. Various therapeutic approaches include MIBG monotherapy, sequential infusion, and combination therapy. Treatment with MIBG has been tested as induction therapy, part of consolidation, and as treatment for relapse. The high response rates of 30-40% using MIBG monotherapy in relapsed neuroblastoma, and the low non-hematologic toxicity make this an ideal agent for incorporation into standard therapy of high-risk neuroblastoma.

Oestrous cycle of captive southern hairy-nosed wombats (Lasiorhinus latifrons) in South Australia, Australia.

There is limited information available on the oestrous cycle of female southern hairy-nosed wombats (Lasiorhinus latifrons). This is mainly due to an extremely poor breeding success in captivity and the difficulty in routine recapturing of these cryptic, semi-fossorial animals in the wild. The aim of this study was to characterise the oestrous cycle of this species by monitoring peripheral plasma concentrations of progesterone and oestradiol, assessing changes in vaginal cytology, pouch condition and the urogenital sinus. Eight adult female wombats were monitored during the breeding season (July-December) over 2 years (2002-2003). Samples were collected up to three times a week. Vaginal smears contained several cell types, categorised by morphology, as either superficial epithelial cells or parabasal-intermediate cells. Leucocytes were also counted. Plasma progesterone profiles showed a mean oestrous cycle length of 36.33+/-0.67 days with a peak progesterone concentration of 139.53+/-10.62nmol/L. Levels of oestradiol peaked at a mean level of 467.33+/-44.32pmol/L on average 5 days before a rise in plasma progesterone values. The proportion of epithelial cells in vaginal smears varied throughout the cycle, with a high percentage of superficial epithelial cells observed during the follicular phase. During periods when progesterone concentrations were high, a greater percentage of parabasal-intermediate cells was observed. In conclusion, this study has characterised the oestrous cycle of the southern hairy-nosed wombat and confirmed that changes in vaginal smears together with pouch and urogenital sinus details could be used to determine signs of oestrus in this species.

Postoperative hypoxia is a contributory factor to cognitive impairment after cardiac surgery.

OBJECTIVE: Cognitive dysfunction and postoperative hypoxia are common sequelae of coronary artery bypass grafting, but there has been no study to determine whether there is any relationship between them. METHODS: Arterial blood gas measurements were performed before surgical intervention and on the second and fifth postoperative day, and neuropsychological assessments were performed before surgical intervention and 5 days and 3 months postoperatively by using a battery of 10 psychometric tests in 175 patients undergoing coronary artery bypass grafting. An estimate of overall performance on the battery at each assessment point was provided by a simple aggregate cognitive index score calculated from the mean z scores of 4 normally distributed test variables. Multiple regression analysis was performed by using the cognitive index score at day 5 as the dependent variable, with age, sex, duration of the operation, presence or absence of cardiopulmonary bypass, preoperative cognitive index score, and arterial oxygenation and percentage of saturation at day 5 as independent variables. RESULTS: The mean cognitive index score decreased significantly in 115 (66%) patients who agreed to neuropsychological test battery assessment on the fifth postoperative day but improved significantly beyond baseline at 3 months. Mean arterial oxygen tension and percentage of saturation decreased significantly 2 days after the operation and, although improving over the following 3 days, remained decreased at day 5. Decreased cognitive index scores at day 5 strongly predicted cognitive impairment at 3 months (r = 0.36). The only significant independent predictors of the day 5 cognitive index score in the multiple regression analysis were preoperative cognitive index score and arterial oxygenation tension at day 5 (r = 0.24, P <.03). CONCLUSIONS: We report a significant correlation between postoperative cognitive dysfunction and hypoxia 5 days after coronary artery bypass grafting. This finding might have therapeutic implications because early postoperative cognitive dysfunction influences long-term impairment.

Neuroprotection during cardiac surgery: a randomised trial of a platelet activating factor antagonist.

OBJECTIVE: To assess platelet activating factor (PAF) antagonists, potent neuroprotective agents in experimental cerebral dysfunction, in clinical practice. DESIGN: Double blind, minimised, placebo controlled trial of low and high dose PAF antagonist (lexipafant). SETTING: Cardiac surgery unit. PATIENTS: 150 patients undergoing coronary artery bypass graft (CABG) surgery using cardiopulmonary bypass. INTERVENTIONS: Randomisation to placebo, low dose (10 mg) or high dose (100 mg) lexipafant. MAIN OUTCOME MEASURES: Incidence of impairment on four established cognitive tests, undertaken before, five days, and three months after CABG, examined by three methods for defining impairment. RESULTS: The three groups were similar with respect to preoperative and intraoperative factors. Observed levels of cognitive impairment were less than had been predicted from previous studies. There was no difference in the groups in cognitive change scores at five days or three months. Group mean analysis showed significant time factors for all four tests but not for interactions or for the lexipafant group. A composite cognitive index, based on the aggregate of four normally distributed tests, showed a significant effect for timing of the test but not for the lexipafant group or interaction. Age, but not duration of bypass, was the most important determinant of postoperative cognitive impairment. CONCLUSIONS: The neuroprotective PAF antagonist lexipafant did not differentially reduce the level of cognitive impairment after CABG as determined by power estimates derived from published studies. The strongest predictors of cognitive impairment were age and timing of the test after operation.

Total arterial revascularisation as a primary strategy for coronary artery bypass grafting.

BACKGROUND: Bilateral internal thoracic arteries confer improved survival benefit after coronary artery bypass grafting (CABG). Despite increasing evidence, the use of arterial conduits has not been accepted as a primary practice in most of the centres in the UK for various reasons. A series of patients has been analysed to assess the feasibility of total arterial revascularisation as a primary strategy in patients requiring first time CABG. METHODS: Altogether 245 patients undergoing first time CABG by one surgeon, from June 1999 to October 2000, were studied. Group 1 consisted of 165 patients undergoing total arterial revascularisation (using bilateral internal thoracic and radial arteries) and group 2 consisted of 80 patients undergoing conventional CABG (using one internal thoracic artery and supplemental veins). Thirty day mortality and early morbidity with particular reference to resternotomy for bleeding, cerebrovascular accidents, renal failure, and sternal dehiscence were the main outcome measures. RESULTS: Patients in group 1 were younger (mean (SD) 60 (10) v 65 (9) years; p<0.001), had lower Parsonnet scores (mean (SD) 5 (5) v 11 (7); p<0.001), and better left ventricular function. Both groups received a similar number of grafts. The percentage of patients undergoing total arterial revascularisation rose from 44% in the first three months to over 75% in the three latter three month periods. Overall 30 day mortality was 1.3%, one patient (0.6%) in group 1 and two patients (2.5%) in group 2. There was a similar incidence of postoperative complications and length of median postoperative stay in both groups. CONCLUSION: Total arterial revascularisation can be adopted as a primary strategy in most patients undergoing CABG with no increase in mortality or morbidity.

Neurological and cognitive disorders after coronary artery bypass grafting.

Cerebral injury is a major cause of mortality and morbidity of coronary artery bypass grafting. Stroke occurs in 3% of patients and is largely caused by embolization of atheromatous debris during manipulation of the diseased aorta. Cognitive impairment, which is predominantly caused by microembolization of gaseous and particulate matter, mainly generated by cardiotomy suction, is more common. Demonstration of similar cognitive impairment in patients operated on without cardiopulmonary bypass indicates that other pathophysiological mechanisms, such as anaesthesia and hypoperfusion, are also involved. Advances in medical, anesthetic, and surgical management have resulted in a reduction in the incidence of neurological injury in CABG patients over the past decade. On the other hand, an increasingly elderly population with more severe comorbidity, who are more prone to cerebral injury, are increasingly being referred for CABG. Possible mechanisms to reduce overt and subtle cerebral injury are discussed. The use of composite arterial grafts performed on the beating heart may be the most effective way of minimizing the risk of cerebral injury associated with CABG.

Effect of arterial revascularisation on survival: a systematic review of studies comparing bilateral and single internal mammary arteries.

BACKGROUND: Coronary artery bypass grafting (CABG) is the commonest major operation in most developed countries. A single internal mammary artery (IMA) graft has proven survival benefits, but the additional survival advantage of a second graft is unknown. We systematically reviewed published studies of bilateral versus single IMA grafts in CABG to assess any differences in survival. METHODS: We identified from Medline all studies in which single and bilateral IMA grafts were compared. We included studies in which at least 100 patients in each group had been followed up for at least 4 years. We assessed study quality on the basis of patient selection, comparability of intervention groups (especially for age, sex, ventricular function, and diabetes status), outcome assessment, and completeness of follow-up. Our primary outcome was survival. Estimates of treatment effect (single versus bilateral) expressed as hazard ratios were pooled across studies. FINDINGS: None of the studies was a randomised trial, but nine cohort studies met our inclusion criteria. Seven studies yielded survival data for meta-analysis, and included 15962 patients: 11269 single and 4693 bilateral IMA grafts. The bilateral group had significantly better survival than the single group (hazard ratio for death 0.81; 95% CI 0.70-0.94). Exclusion of methodologically weak studies improved survival rates with bilateral IMA grafts. INTERPRETATION: Because no study was a randomised trial, our results are more uncertain than is indicated by the 95% CI. Nevertheless, bilateral IMA grafts seem to give better survival rates than single grafts.

Skeletonization of the radial artery: advantages over the pedicled technique.

The radial artery is usually harvested as a pedicle with surrounding veins, perivascular fat, and areolar tissue. We describe an alternative technique of skeletonization of the radial artery and its potential advantages over the pedicled technique.

Phenoxybenzamine is more effective and less harmful than papaverine in the prevention of radial artery vasospasm.

OBJECTIVES: There is an increasing use of arterial conduits for coronary artery bypass grafting, and the radial artery is commonly used as the third graft. The major drawback of the radial artery is its proclivity to spasm. Both papaverine and phenoxybenzamine have been recommended as topical vasodilators in clinical practice. We compared the efficacy of both drugs to prevent radial artery spasm and their ability to preserve endothelial function. METHODS: The ability of both drugs to prevent alpha-adrenoreceptor mediated constriction was tested in vitro in an organ bath in radial artery segments obtained from 20 patients. Vessel viability was determined by potassium (K(+)) constriction, and endothelial function was assessed by observing endothelium-dependent relaxation by a synthetic analogue of acetylcholine, carbachol. RESULTS: Papaverine consistently abolished and prevented spasm for up to a maximum of 30 min in all segments. In contrast, phenoxybenzamine consistently abolished and prevented radial artery spasm in all segments for at least 6 h. Whereas papaverine damaged the endothelium of 70% of vessels, there was no evidence of endothelial damage in any arterial segments after exposure to phenoxybenzamine. CONCLUSIONS: Phenoxybenzamine more effectively prevents alpha-adrenoreceptor mediated spasm of the human radial artery than papaverine. It is also less harmful to the endothelium.