Surgical epicardial left ventricular lead versus coronary sinus lead placement in biventricular pacing.

OBJECTIVE: Biventricular pacing has demonstrated improvement in cardiac function in treating congestive heart failure (CHF). Two different operative strategies (coronary sinus vs. epicardial stimulation) for left ventricular (LV) pacing were compared. METHODS: Since April 1999, a total of 86 patients (pts, age: 63+/-10 years) with depressed systolic LV function (mean ejection fraction 24+/-9%), left bundle-branch-block (mean QRS 182+/-22 ms) and congestive heart failure NYHA III or higher were enrolled. For biventricular stimulation coronary sinus (CS) leads were placed in 79 pts. Nine of these devices were converted to surgical epicardial LV-leads, because of CS-lead failure. In 7 patients epicardial LV-leads were initially implanted surgically, accounting for a total of 16 pts with surgical placed epicardial steroid-eluting LV-leads. For these, a limited left-lateral thoracotomy (7+/-4 cm) was used. Thirty-three (38%) pts had an indication for a defibrillator. The mean follow-up time was 16.4+/-15.4 months (0.1-45 months), representing 107.1 patient-years. RESULTS: In the biventricular pacing mode, QRS duration decreased to 143+/-16 ms (P<0.001). Threshold capture of the CS-leads increased significantly compared to surgically placed epicardial leads (18 month control: 2.2+/-1.4V/0.5 ms vs. 0.7+/-0.3V/0.5 ms), which had no increase in threshold (P<0.001). At the 18 month follow-up 7 CS-leads had a threshold of >4V/0.5 ms vs. epicardial leads which were under 1.1V/0.5 ms, except for one (1.8V/0.5 ms). After CS-lead implantation 25 LV-lead related complications occurred, (failed implantation, CS-dissection, loss of pacing capture, diaphragm stimulation or lead dislodgment), vs. one dislodgement after surgical epicardial lead placement (P<0.05). Correct lead positioning (obtuse marginal branch area) was achieved in all surgical epicardial placements but only in 70% with CS-leads (P<0.03). In the follow up period, 9 pts died (4 cardiac related). Heart transplantation was necessary in 4 pts due to deterioration of the cardiomyopathy. CONCLUSIONS: Surgical epicardial lead placement revealed excellent long-term results and a lower LV-related complication rate compared to CS-leads. Although, the approach via limited thoracotomy for biventricular pacing is associated with 'more surgery', it is a safe and reliable technique and should be considered as an equal alternative.     

Adjustment of metabolism,catecholamines and β-adrenoceptors to 90 min of cycle ergometry

Adrenaline infusion of 0.1 g · kg^–1 · min^–1 in healthy volunteers results in an increase of hepatic glucose production, an increase of the absolute number of occupied -adrenoceptors and specific changes in metabolism. To compare these effects with the changes induced by an endogenous catecholamine release, we investigated healthy volunteers during cycle ergometry. After fasting at least 14 h seven healthy subjects exercised for 90 min at an intensity of 20% below their individual anaerobic threshold. The rate of glucose production as well as the turnover rates of alanine and leucine were calculated using stable isotope tracers. High and low affinity -adrenergic binding sites on lymphocytes were determined by an equilibrium binding assay with (–)¹²⁵ Iodocyanopindolol. After 90 min of cycling the rate of appearance of glucose increased significantly from means of 2.0 (SD 0.2) to 2.65 (SD 0.50) mg · kg^–1 · min^–1 with unchanged blood concentrations of glucose and lactate. The flux of the amino acids alanine and leucine decreased significantly from means of 0.91 (SD 0.21) to 0.62 (SD 0.14) mg · kg^–1 · min^–1 and from 0.40 (SD 0.05) to 0.32(SD 0.04) mg · kg^–1 · min^–1, respectively. The mean free fatty acid concentration increased significantly from 0.65 (SD 0.33) to 1.27 (SD 0.45) mmol · l^–1 during the endurance trial. The increase of glucose turnover and the decrease of amino acid flux point to a metabolic shift towards enhanced utilization of free fatty acids. Adrenaline and noradrenaline concentrations showed a moderate but significant increase from means of 0.61 (SD 0.20) to 0.99 (SD 0.36) nmol · l^–1 and from 2.27 (SD 0.75) to 3.46 (SD 0.38) nmol · 1^–1, respectively. The number of high affinity -adrenergic binding sites per cell (-adrenoceptors) nearly doubled from 770 (SD 130) to 1490 (SD 150) during 90 min of cycling. The observed endogenous plasma catecholamine concentrations were not sufficient to change significantly the relative receptor occupancy. This would seem to indicate that the aerobic exercise induced effects depended more on the absolute number of occupied -adrenoceptors than on their relative receptor occupancy. When compared to the results of the adrenaline infusion experiment the increases of the hepatic glucose production and the increase of -adrenoceptors were very similar in both groups despite ten times higher adrenaline plasma concentrations in the infusion group. This would seem to indicate that -adrenoceptors mediated effects do not correlate with catecholamine plasma concentrations.     

The MDR1 polymorphisms at exons 21 and 26 predict steroid weaning in pediatric heart transplant patients

Various polymorphisms of the MDR1 gene that encodes for P-glycoprotein (P-gp), a transmembrane pump, have been identified. A silent mutation C3435T in exon 26 and a G2677T mutation in exon 21 have been correlated with P-gp expression and function in humans. The objectives of this study were (a) to determine whether the MDR1 exon 21 and exon 26 polymorphisms were related to steroid weaning in a pediatric heart transplant (HTx) population, and (b) to determine whether an association exist between the MDR1 exon 21 and exon 26 polymorphisms in these patients. Sixty-nine pediatric HTx patients were studied. MDR1 genotyping was determined by polymerase chain reaction amplification, sequencing the DNA, and sequence evaluation using Polyphred software (University of Washington) to identify genotypes. The steroid dose at 1 year post-transplantation was recorded. For steroid weaning at one year post-HTx for MDR1 C3435T, 12 of 18 (67%) patients in the CC genotype were still on prednisone, whereas only 18 of 47 (38%) of the CT/TT group were still receiving prednisone (p = 0.04). Similar results were observed for the MDR1 G2677T genotyping and steroid weaning. Forty-three of 46 patients (93.5%) who have MDR1 C3435T allele also have a mutant G2677T allele (p < 0.001). We conclude that (a) a significantly larger number of MDR1 3435 CC HTx patients remain on steroids at 1 year after transplantation, and (b) the MDR1 C3435T genotype is associated with the G2677 genotype in pediatric HTx patients.     

Refeeding Syndrome: A Critical Reality in Patients with Chronic Disease

Malnutrition is one of the most frequent metabolic challenges in the population of chronically ill patients. This results in increased administration of nutritional therapy in inpatient settings, which poses the risk of side effects, in particular, the development of refeeding syndrome. If not managed accordingly, it leads to a significant rise in morbidity and mortality. However, despite its importance, evidence-based recommendations on the management of refeeding syndrome are largely lacking, and only a few randomized controlled trials have been conducted. In light of this, the aim of this review is to raise awareness of refeeding syndrome in chronically ill patients by critically reviewing recent literature and providing a short overview as well as diagnosis and treatment algorithms of this underreported metabolic condition. In summary, recent findings suggest undergoing risk assessment and stratification for every patient receiving nutritional therapy. According to this, adaptation of energy and fluid support during the replenishment phase should be implemented in the nutritional therapy for patients at high risk. Additionally, continuous monitoring should take place, and appropriate actions should be initiated when necessary.     

Adoptive immunotherapy of metastatic breast cancer: present and future

Breast cancer is a systemic disease with a primarily local component. Besides surgical resection and irradiation of the locoregional tumor setting, central therapeutic aim is the elimination of disseminated micrometastatic tumor cells using cytostatic and/or hormonal treatment. Nevertheless, in the course of time a majority of patients suffer from systemic recurrence in the form of distant metastases. Intriguingly, in this connection, intratumoral cytotoxic T lymphocytes might serve as independent predictors of treatment efficacy and clinical outcome. Loss of immune balance (tumor dormancy) during intensive cross talk between T cells and tumor cells in the bone marrow microenvironment is suggested one reason for distant metastatic relapse. In this clinical context, further supportive therapies become increasingly attractive, taking immunological features of breast cancer cells into special account. The present review aims to dissect bone marrow-derived cellular antitumor immune responses and translational immunologic treatment options regarding their actual relevance to patients’ clinical benefit and their future directions in breast cancer management.     

Polycaprolactone scaffold and reduced rhBMP-7 dose for the regeneration of critical-sized defects in sheep tibiae

The transplantation of autologous bone graft as a treatment for large bone defects has the limitation of harvesting co-morbidity and limited availability. This drives the orthopaedic research community to develop bone graft substitutes. Routinely, supra-physiological doses of bone morphogenetic proteins (BMPs) are applied perpetuating concerns over undesired side effects and cost of BMPs. We therefore aimed to design a composite scaffold that allows maintenance of protein bioactivity and enhances growth factor retention at the implantation site. Critical-sized defects in sheep tibiae were treated with the autograft and with two dosages of rhBMP-7, 3.5 mg and 1.75 mg, embedded in a slowly degradable medical grade poly(ε-caprolactone) (PCL) scaffold with β-tricalcium phosphate microparticles (mPCL–TCP). Specimens were characterised by biomechanical testing, microcomputed tomography and histology. Bridging was observed within 3 months for the autograft and both rhBMP-7 treatments. No significant difference was observed between the low and high rhBMP-7 dosages or between any of the rhBMP-7 groups and autograft implantation. Scaffolds alone did not induce comparable levels of bone formation compared to the autograft and rhBMP-7 groups. In summary, the mPCL–TCP scaffold with the lower rhBMP-7 dose led to equivalent results to autograft transplantation or the high BMP dosage. Our data suggest a promising clinical future for BMP application in scaffold-based bone tissue engineering, lowering and optimising the amount of required BMP.     

Deletion of MCL-1 causes lethal cardiac failure and mitochondrial dysfunction

MCL-1 is an essential BCL-2 family member that promotes the survival of multiple cellular lineages, but its role in cardiac muscle has remained unclear. Here, we report that cardiac-specific ablation of Mcl-1 results in a rapidly fatal, dilated cardiomyopathy manifested by a loss of cardiac contractility, abnormal mitochondria ultrastructure, and defective mitochondrial respiration. Strikingly, genetic ablation of both proapoptotic effectors (Bax and Bak) could largely rescue the lethality and impaired cardiac function induced by Mcl-1 deletion. However, while the overt consequences of Mcl-1 loss were obviated by combining with the loss of Bax and Bak, mitochondria from the Mcl-1-, Bax-, and Bak-deficient hearts still revealed mitochondrial ultrastructural abnormalities and displayed deficient mitochondrial respiration. Together, these data indicate that merely blocking cell death is insufficient to completely overcome the need for MCL-1 function in cardiomyocytes and suggest that in cardiac muscle, MCL-1 also facilitates normal mitochondrial function. These findings are important, as specific MCL-1-inhibiting therapeutics are being proposed to treat cancer cells and may result in unexpected cardiac toxicity.