Effects of autologous bone marrow stem cell transplantation on beta-adrenoceptor density and electrical activation pattern in a rabbit model of non-ischemic heart failure

BACKGROUND: Since only little is known on stem cell therapy in non-ischemic heart failure we wanted to know whether a long-term improvement of cardiac function in non-ischemic heart failure can be achieved by stem cell transplantation. METHODS: White male New Zealand rabbits were treated with doxorubicine (3 mg/kg/week; 6 weeks) to induce dilative non-ischemic cardiomyopathy. Thereafter, we obtained autologous bone marrow stem cells (BMSC) and injected 1.5–2.0 Mio cells in 1 ml medium by infiltrating the myocardium via a left anterolateral thoracotomy in comparison to sham-operated rabbits. 4 weeks later intracardiac contractility was determined in-vivo using a Millar catheter. Thereafter, the heart was excised and processed for radioligand binding assays to detect β(1)- and β(2)-adrenoceptor density. In addition, catecholamine plasma levels were determined via HPLC. In a subgroup we investigated cardiac electrophysiology by use of 256 channel mapping. RESULTS: In doxorubicine-treated animals β-adrenoceptor density was significantly down-regulated in left ventricle and septum, but not in right ventricle, thereby indicating a typical left ventricular heart failure. Sham-operated rabbits exhibited the same down-regulation. In contrast, BMSC transplantation led to significantly less β-adrenoceptor down-regulation in septum and left ventricle. Cardiac contractility was significantly decreased in heart failure and sham-operated rabbits, but was significantly higher in BMSC-transplanted hearts. Norepinephrine and epinephrine plasma levels were enhanced in heart failure and sham-operated animals, while these were not different from normal in BMSC-transplanted animals. Electrophysiological mapping revealed unaltered electrophysiology and did not show signs of arrhythmogeneity. CONCLUSION: BMSC transplantation improves sympathoadrenal dysregualtion in non-ischemic heart failure

Cardiovascular development: towards biomedical applicability: Regulation of cardiomyocyte differentiation of embryonic stem cells by extracellular signalling

Investigating the signalling pathways that regulate heart development is essential if stem cells are to become an effective source of cardiomyocytes that can be used for studying cardiac physiology and pharmacology and eventually developing cell-based therapies for heart repair. Here, we briefly describe current understanding of heart development in vertebrates and review the signalling pathways thought to be involved in cardiomyogenesis in multiple species. We discuss how this might be applied to stem cells currently thought to have cardiomyogenic potential by considering the factors relevant for each differentiation step from the undifferentiated cell to nascent mesoderm, cardiac progenitors and finally a fully determined cardiomyocyte. We focus particularly on how this is being applied to human embryonic stem cells and provide recent examples from both our own work and that of others

Stem Cell Therapy: Pieces of the Puzzle

Acute ischemic injury and chronic cardiomyopathies can cause irreversible loss of cardiac tissue leading to heart failure. Cellular therapy offers a new paradigm for treatment of heart disease. Stem cell therapies in animal models show that transplantation of various cell preparations improves ventricular function after injury. The first clinical trials in patients produced some encouraging results, despite limited evidence for the long-term survival of transplanted cells. Ongoing research at the bench and the bedside aims to compare sources of donor cells, test methods of cell delivery, improve myocardial homing, bolster cell survival, and promote cardiomyocyte differentiation. This article reviews progress toward these goals

ACT variation after a weight-based heparin bolus before CPB is not predictable in infant

BackgroundIn pediatric cardiac surgery, anticoagulation protocols are derived from adult protocols. Age, Antithrombin III level, and capacity to generate thrombin are factors that affect unfractionated heparin (UFH) action in children. A starting UFH dose of 400 UI/kg is recommended to get an Activated Clotting Time (ACT) target over 400seconds. In our daily practice, we noticed a wide range of ACT increase (ΔACT) after this standardized weight based bolus of UFH.ObjectiveTo define factors affecting UFH effectiveness based on ΔACT before CPB initialization in pediatric cardiac surgery.MethodsA retrospective chart review of patient undergoing cardiac surgery requiring CPB in a single university hospital was performed. Patients receiving preoperative anticoagulation therapy or platelet aggregation inhibitors were excluded. We searched predictive factors for ΔACT. We defined 2 groups: hyperrespondents (HR; ΔACT>500) and normorespondents (NR; ΔACT<500).ResultsSeventy-nine charts were reviewed. Median [25–75] age and weight were respectively 13.8 [5–72] months and 8.7 kg [5.5–18.8]. UFH pre CPB bolus was 384 [358–410] to increase pre operative ACT from 124 [115–137] to 536 s[463–582]. HR are younger (4.9 [3.7–13] vs 24.6 [5.7–76] months, P<0.05) and have smaller weight (6,1 [4.6–7.8] vs 10 kg[5,8–19.5], P<0,05) than NR. ΔACT is correlated to UFH dose for patients>5 months (r=0.59 P=0.00001) and>5kg (r=0.54 P=0.00001) for with a predictive ΔACT of 386 s [325–443]. There is no correlation between ΔACT and UFH dose for patients<5 months and<5kg.ConclusionA dose UFH of 400 UI/kg before starting CPB in pediatrics is overestimated, especially for children<5 months and<5kg. Accurate dose for ACT target>400 s in this specific population should be calculated using other method that still needs to be developed to avoid complications associated to excessive dose of UFH

Make use of time, let not advantage slip – How this William Shakespeare (1564–1616) quote lead us to optimize occlusion time for balloon dilatations –

IntroductionNeuro-developmental impairment which follows management of complex congenital heart disease is a major issue. Balloon dilation is a frequent procedure, which can lead to brain injury. Whereas the pressure and diameter of balloon for inflation are quite normalized, there are no written guidelines for time of inflation. Our aim was to study the brain perfusion with the NIRS (Near Infra Red Spectroscopy) during catheter procedure.MethodsWe prospectively enrolled 20 consecutive children (mean±SD: age=2.8±3.4y.o.; weight=15.6±13.6kg) who underwent transcatheter balloon dilation of pulmonary valve, trunk or conduit stenosis. Procedure was done under general anesthesia with regular monitoring. SpO2 was used by physician for patient safety. Cerebral oxygen saturation (Rso2) was monitored by NIRS. Each brain desaturation events were collected. 40% of rSO2 was considered as the cut-off limit below which brain injury may occurs. Time to reach this limit (TTR40), time to recover (TTR95), area under curve and deepness of the events were extracted (Appendix 1).ResultsThe total number of inflation was 56, with a mean of 2,8 inflations per patient (min=2; max=10). The NIRS curve had two parts: it decreased during balloon inflation due to CO interruption and then increased during the reperfusion. Both were easily detected (Se=100%) whereas the SpO2 remained wrongfully high. Near 36% of desaturation were under the cut-off (NIRS<40%). TTR40 was 56.76s and TTR95 was 34.85s for the whole group. The linear regression based on NIRS shows two significant (P<0.0001) slopes: −0.68rSO2%/s for TTR40 and +0.70 rSO2%/s for TTR95. Our results suggest that a cumulative time over 44s (95% CI) of multiples occlusions without recovery may cause brain injury. A recovery delay of 40s (95% CI) after each set of balloon inflation is therefore mandatory.ConclusionPulmonary valve, trunk or conduit dilatation requires short occlusion and total recovery before any new inflation