Cardiomyocyte Ca2+ handling and structure is regulated by degree and duration of mechanical load variation

Cardiac transverse (t)-tubules are altered during disease and may be regulated by stretch-sensitive molecules. The relationship between variations in the degree and duration of load and t-tubule structure remains unknown, as well as its implications for local Ca2+-induced Ca2+ release (CICR). Rat hearts were studied after 4 or 8 weeks of moderate mechanical unloading [using heterotopic abdominal heart–lung trans-plantation (HAHLT)] and 6 or 10 weeks of pressure overloading using thoracic aortic constriction. CICR, cell and t-tubule structure were assessed using confocal-microscopy, patch-clamping and scanning ion conductance microscopy. Moderate unloading was compared with severe unloading [using heart-only transplantation (HAHT)]. Mechanical unloading reduced cardiomyocyte volume in a time-dependent manner. Ca2+ release synchronicity was reduced at 8 weeks moderate unloading only. Ca2+ sparks increased in frequency and duration at 8 weeks of moderate unloading, which also induced t-tubule disorganization. Overloading increased cardiomyocyte volume and disrupted t-tubule mor-phology at 10 weeks but not 6 weeks. Moderate mechanical unloading for 4 weeks had milder effects compared with severe mechanical unloading (37 % reduction in cell volume at 4 weeks compared to 56 % reduction after severe mechanical unloading) and did not cause depres-sion and delay of the Ca2+ transient, increased Ca2+ spark frequency or impaired t-tubule and cell surface structure. These data suggest that variations in chronic mechanical load influence local CICR and t-tubule structure in a time- and degree-dependent manner, and that physiologi-cal states of increased and reduced cell size, without pathological changes are possible

Factors associated with unplanned reinterventions and their relation to early mortality after pediatric cardiac surgery

Objective: Unplanned reintervention (uRE) is used as an indicator of patient morbidity and quality of care in pediatric cardiac surgery. We investigated associated factors and early mortality after uREs. / Methods: Morbidity data were prospectively collected in 5 UK centers between 2015 and 2017; uRE included surgical cardiac, interventional transcatheter cardiac, permanent pacemaker, and diaphragm plication procedures. Mortality (30-day and 6-month) in uRE/no-uRE patients was reported before and after matching. Predicted 30-day mortality was calculated using the Partial Risk Adjustment in Surgery score. / Results: A total of 3090 procedures (2861 patients) were included (median age, 228 days). There were 146 uREs, resulting in an uRE rate of 4.7%. Partial Risk Adjustment in Surgery score, 30-day mortality and 6-month mortality in uRE and no-uRE groups were 2.4% versus 1.3%, 8.9% versus 1%, and 17.1% versus 2.4%, respectively. After matching, mortality at 6 months remained higher in uRE compared with no-uRE (12.2% vs 1.4%; P = .02; 74 pairs). In the uRE group, 21 out of 25 deaths at 6 months occurred when at least 1 additional postoperative complication was present. In multivariable analysis, neonatal age (P = .002), low weight (P = .009), univentricular heart (P < .001), and arterial shunt (P < .001) were associated with increased risk of uRE, but Partial Risk Adjustment in Surgery score was not (only in univariable analysis). / Conclusions: uREs are a relatively frequent complication after pediatric cardiac surgery and are associated with some patient characteristics, but not the Partial Risk Adjustment in Surgery risk score. Early mortality was higher after uRE, independent of preoperative factors, but linked to other postoperative complications

Right Ventricle Has Normal Myofilament Function But Shows Perturbations in the Expression of Extracellular Matrix Genes in Patients With Tetralogy of Fallot Undergoing Pulmonary Valve Replacement

BACKGROUND: Patients with repair of tetralogy of Fallot (rToF) who are approaching adulthood often exhibit pulmonary valve regurgitation, leading to right ventricle (RV) dilatation and dysfunction. The regurgitation can be corrected by pulmonary valve replacement (PVR), but the optimal surgical timing remains under debate, mainly because of the poorly understood nature of RV remodeling in patients with rToF. The goal of this study was to probe for pathologic molecular, cellular, and tissue changes in the myocardium of patients with rToF at the time of PVR. METHODS AND RESULTS: We measured contractile function of permeabilized myocytes, collagen content of tissue samples, and the expression of mRNA and selected proteins in RV tissue samples from patients with rToF undergoing PVR for severe pulmonary valve regurgitation. The data were compared with nondiseased RV tissue from unused donor hearts. Contractile performance and passive stiffness of the myofilaments in permeabilized myocytes were similar in rToF‐PVR and RV donor samples, as was collagen content and cross‐linking. The patients with rToF undergoing PVR had enhanced mRNA expression of genes associated with connective tissue diseases and tissue remodeling, including the small leucine‐rich proteoglycans ASPN (asporin), LUM (lumican), and OGN (osteoglycin), although their protein levels were not significantly increased. CONCLUSIONS: RV myofilaments from patients with rToF undergoing PVR showed no functional impairment, but the changes in extracellular matrix gene expression may indicate the early stages of remodeling. Our study found no evidence of major damage at the cellular and tissue levels in the RV of patients with rToF who underwent PVR according to current clinical criteria

Rapid desensitization through immunoadsorption during cardiopulmonary bypass. A novel method to facilitate human leukocyte antigen incompatible heart transplantation

Background: Anti-human leukocyte antigen (HLA)-antibody production represents a major barrier to heart transplantation, limiting recipient compatibility with potential donors and increasing the risk of complications with poor waiting-list outcomes. Currently there is no consensus to when desensitization should take place, and through what mechanism, meaning that sensitized patients must wait for a compatible donor for many months, if not years. We aimed to determine if intraoperative immunoadsorption could provide a potential desensitization methodology. Methods: Anti-HLA antibody-containing whole blood was added to a Cardiopulmonary bypass (CPB) circuit set up to mimic a 20 kg patient undergoing heart transplantation. Plasma was separated and diverted to a standalone, secondary immunoadsorption system, with antibody-depleted plasma returned to the CPB circuit. Samples for anti-HLA antibody definition were taken at baseline, when combined with the CPB prime (on bypass), and then every 20 min for the duration of treatment (total 180 min). Results: A reduction in individual allele median fluorescence intensity (MFI) to below clinically relevant levels (4000 was demonstrated. Reduction occurred in all cases within 120 min, demonstrating efficacy in a time period usual for heart transplantation. Flowcytometric crossmatching of suitable pseudo-donor lymphocytes demonstrated a change from T cell and B cell positive channel shifts to negative, demonstrating a reduction in binding capacity. Conclusions: Intraoperative immunoadsorption in an ex vivo setting demonstrates clinically relevant reductions in anti-HLA antibodies within the normal timeframe for heart transplantation. This method represents a potential desensitization technique that could enable sensitized children to accept a donor organ earlier, even in the presence of donor-specific anti-HLA antibodies

Midterm results of the Ross procedure in children: an appraisal of the subannular implantation with interrupted sutures technique

OBJECTIVES: The support of the pulmonary autograft root by the fibromuscular left ventricular outflow tract is emphasized to address the concern related to the dilatation of the pulmonary autograft structures in the paediatric population. METHODS: This retrospective study analyses the outcomes of 75 children who were operated between 1998 and 2012 with the subannular interrupted sutures technique at a median age of 10.2 years (range, 5.3 months–18.0 years). Median follow-up time was 5.2 years (range, 3 days–13.2 years). RESULTS: There were no deaths, but there were 3 reinterventions on the autograft for regurgitation and 2 resections of left ventricular outflow tract obstruction. There was no significant autograft stenosis, and freedom from moderate-to-severe regurgitation was 95% (95% confidence interval: 89–100) and 88% (95% confidence interval: 77–99) at 5 and 10 years, respectively. Median z-scores at the latest follow-up examination were, at the annulus, 0.31 [interquartile range (IQR) = −0.81 to 1.2]; at the sinus of Valsalva, 2.7 (IQR = 1.5–3.5); and at the sinotubular junction, 3.1 (IQR = 1.7–4.2). The correlation between z-scores and time after the operation was negative at the level of the annulus (r = −0.29, P = 0.034) but positive at the level of the sinus (r = +0.37, P = 0.005) and the sinotubular junction (r = +0.26, P = 0.068). The median rate of change in the z-score at the annulus was low, 0.065 z-score/year (IQR = −0.13 to 0.43). CONCLUSIONS: The subannular interrupted sutures implantation technique is associated with acceptable risks and, in the midterm, delivers limited annular dilatation, autograft regurgitation and delayed need for autograft reintervention

Incidence and risk factors for important early morbidities associated with pediatric cardiac surgery in a UK population

Objective Given excellent 30-day survival for pediatric cardiac surgery, other outcome measures are important. We aimed to study important early postoperative morbidities selected by stakeholders following a rigorous and evidenced-based process, with a view to identifying potential risk factors. Methods The incidence of selected morbidities was prospectively measured for 3090 consecutive pediatric cardiac surgical admissions in 5 UK centers between October 2015 and June 2017. The relationship between the candidate risk factors and the incidence of morbidities was explored using multiple regressions. Patient survival, a secondary outcome, was checked at 6 months. Results A total of 675 (21.8%) procedure episodes led to at least 1 of the following: acute neurologic event, unplanned reoperation, feeding problems, renal replacement therapy, major adverse events, extracorporeal life support, necrotizing enterocolitis, surgical infection, or prolonged pleural effusion. The highest adjusted odds ratio of morbidity was in neonates compared with children, 5.26 (95% confidence interval, 3.90-7.06), and complex heart diseases (eg, hypoplastic left heart), 2.14 (95% confidence interval, 1.41-3.24) compared with low complexity (eg, atrial septal defect, P < .001 for all). Patients with any selected morbidity had a 6-month survival of 88.2% (95% confidence interval, 85.4-90.6) compared with 99.3% (95% confidence interval, 98.9-99.6) with no defined morbidity (P < .001). Conclusions Evaluation of postoperative morbidity provides important information over and above 30-day survival and should become a focus for audit and quality improvement. Our results have been used to initiate UK-based audit for 5 of these 9 morbidities, co-develop software for local monitoring of these morbidities, and parent information about these morbidities

Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes

BACKGROUND: Data are lacking on the long-term effect on cardiovascular events of adding sitagliptin, a dipeptidyl peptidase 4 inhibitor, to usual care in patients with type 2 diabetes and cardiovascular disease. METHODS: In this randomized, double-blind study, we assigned 14,671 patients to add either sitagliptin or placebo to their existing therapy. Open-label use of antihyperglycemic therapy was encouraged as required, aimed at reaching individually appropriate glycemic targets in all patients. To determine whether sitagliptin was noninferior to placebo, we used a relative risk of 1.3 as the marginal upper boundary. The primary cardiovascular outcome was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina. RESULTS: During a median follow-up of 3.0 years, there was a small difference in glycated hemoglobin levels (least-squares mean difference for sitagliptin vs. placebo, -0.29 percentage points; 95% confidence interval [CI], -0.32 to -0.27). Overall, the primary outcome occurred in 839 patients in the sitagliptin group (11.4%; 4.06 per 100 person-years) and 851 patients in the placebo group (11.6%; 4.17 per 100 person-years). Sitagliptin was noninferior to placebo for the primary composite cardiovascular outcome (hazard ratio, 0.98; 95% CI, 0.88 to 1.09; P<0.001). Rates of hospitalization for heart failure did not differ between the two groups (hazard ratio, 1.00; 95% CI, 0.83 to 1.20; P = 0.98). There were no significant between-group differences in rates of acute pancreatitis (P = 0.07) or pancreatic cancer (P = 0.32). CONCLUSIONS: Among patients with type 2 diabetes and established cardiovascular disease, adding sitagliptin to usual care did not appear to increase the risk of major adverse cardiovascular events, hospitalization for heart failure, or other adverse events

Spatial and temporal trends of the Stockholm Convention POPs in mothers’ milk — a global review

Persistent organic pollutants (POPs) have been of environmental and health concern for more than half a century and have their own intergovernmental regulation through the Stockholm Convention, from 2001. One major concern is the nursing child’s exposure to POPs, a concern that has led to a very large number of scientific studies on POPs in mothers’ milk. The present review is a report on the assessment on worldwide spatial distributions of POPs and of their temporal trends. The data presented herein is a compilation based on scientific publications between 1995 and 2011. It is evident that the concentrations in mothers’ milk depend on the use of pesticides and industrial chemicals defined as POPs. Polychlorinated biphenyls (PCBs) and “dioxins” are higher in the more industrialized areas, Europe and Northern America, whereas pesticides are higher in Africa and Asia and polybrominated diphenyl ethers (PBDEs) are reported in higher concentrations in the USA. POPs are consequently distributed to women in all parts of the world and are thus delivered to the nursing child. The review points out several major problems in the reporting of data, which are crucial to enable high quality comparisons. Even though the data set is large, the comparability is hampered by differences in reporting. In conclusion, much more detailed instructions are needed for reporting POPs in mothers’ milk. Temporal trend data for POPs in mothers’ milk is scarce and is of interest when studying longer time series. The only two countries with long temporal trend studies are Japan and Sweden. In most cases, the trends show decreasing concentrations of POPs in mothers’ milk. However, hexabromocyclododecane is showing increasing temporal concentration trends in both Japan and Sweden

Effects of Once-Weekly Exenatide on Cardiovascular Outcomes in Type 2 Diabetes.

Abstract BACKGROUND: The cardiovascular effects of adding once-weekly treatment with exenatide to usual care in patients with type 2 diabetes are unknown. METHODS: We randomly assigned patients with type 2 diabetes, with or without previous cardiovascular disease, to receive subcutaneous injections of extended-release exenatide at a dose of 2 mg or matching placebo once weekly. The primary composite outcome was the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. The coprimary hypotheses were that exenatide, administered once weekly, would be noninferior to placebo with respect to safety and superior to placebo with respect to efficacy. RESULTS: In all, 14,752 patients (of whom 10,782 [73.1%] had previous cardiovascular disease) were followed for a median of 3.2 years (interquartile range, 2.2 to 4.4). A primary composite outcome event occurred in 839 of 7356 patients (11.4%; 3.7 events per 100 person-years) in the exenatide group and in 905 of 7396 patients (12.2%; 4.0 events per 100 person-years) in the placebo group (hazard ratio, 0.91; 95% confidence interval [CI], 0.83 to 1.00), with the intention-to-treat analysis indicating that exenatide, administered once weekly, was noninferior to placebo with respect to safety (P<0.001 for noninferiority) but was not superior to placebo with respect to efficacy (P=0.06 for superiority). The rates of death from cardiovascular causes, fatal or nonfatal myocardial infarction, fatal or nonfatal stroke, hospitalization for heart failure, and hospitalization for acute coronary syndrome, and the incidence of acute pancreatitis, pancreatic cancer, medullary thyroid carcinoma, and serious adverse events did not differ significantly between the two groups. CONCLUSIONS: Among patients with type 2 diabetes with or without previous cardiovascular disease, the incidence of major adverse cardiovascular events did not differ significantly between patients who received exenatide and those who received placebo. (Funded by Amylin Pharmaceuticals; EXSCEL ClinicalTrials.gov number, NCT01144338 .)