Prevalence and prognostic significance of atrial arrhythmias after orthotopic cardiac transplantation

Objectives. We studied the duration and prognostic significance of atrial arrhythmias in the denervated transplanted heart, specifically the occurrence of atrial fibrillation in the absence of vagal modulation.

Background. Substantial animal data indicate that vagally induced dispersion of atrial refractoriness plays a central role in the induction and maintenance of atrial fibrillation.

Methods. We studied the occurrence of atrial arrhythmias in the denervated hearts of 88 consecutive orthotopic transplantations in 85 patients by means of continuous telemetry and all available electrocardiographic tracings.

Results. Fifty percent of recipients (44 of 88) developed at least one atrial arrhythmia. Atrial fibrillation occurred 23 times (21 recipients), atrial flutter 39 times (26 recipients), ectopic atrial tachycardia 3 times (3 recipients) and supraventricular tachycardia 18 times (11 recipients). The number of atrial fibrillation and atrial flutter episodes did not differ (23 vs. 39, p = 0.072), but the fibrillation (37.0 ± 10 vs. 6.6 ± 3.6 h, p = 0.014). Atrial fibrillation was associated with an increased risk of subsequent death (10 of 21 recipients with vs. 15 of 67 without atrial fibrillation, risk ratio 3.15 ± 0.18, p = 0.005 by Cox proportional hazards model). All 5 recipients who developed “late” atrial fibrillation (>2 weeks after transplantation) died versus 5 of 16 who developed atrial fibrillation within the first 2 weeks (p = 0.007). Causes of death included rejection (three recipients), allograft failure (two recipients), infection (three recipients) and multiorgan failure (two recipients). Atrial fibrillation was not associated with age, gender, ischemic time, reason for transplantation, echocardiographic variables, invasive hemodynamic variables or biopsy grade. Mean time from atrial arrhythmia to echocardiography was 2.7 ± 3.3 days; that to biopsy was 4.8 ± 6.3 days. Atrial flutter was not associated with subsequent death. Only 7 (15.9%) of 44 recipients demonstrated moderate or severe allograft rejection at the time of the arrhythmia.

Conclusions. Atrial arrhythmias occur frequently in the denervated transplanted heart, often in the absence of significant rejection. Late atrial fibrillation may be associated with an increased all-cause mortality.     

Circulating delta‐like Notch ligand 1 is correlated with cardiac allograft vasculopathy and suppressed in heart transplant recipients on everolimus‐based immunosuppression

Cardiac allograft vasculopathy (CAV) causes heart failure after heart transplantation (HTx), but its pathogenesis is incompletely understood. Notch signaling, possibly modulated by everolimus (EVR), is essential for processes involved in CAV. We hypothesized that circulating Notch ligands would be dysregulated after HTx. We studied circulating delta‐like Notch ligand 1 (DLL1) and periostin (POSTN) and CAV in de novo HTx recipients (n = 70) randomized to standard or EVR‐based, calcineurin inhibitor‐free immunosuppression and in maintenance HTx recipients (n = 41). Compared to healthy controls, plasma DLL1 and POSTN were elevated in de novo (P < .01; P < .001) and maintenance HTx recipients (P < .001; P < .01). Use of EVR was associated with a treatment effect for DLL1. For de novo HTx recipients, a change in DLL1 correlated with a change in CAV at 1 (P = .021) and 3 years (P = .005). In vitro, activation of T cells increased DLL1 secretion, attenuated by EVR. In vitro data suggest that also endothelial cells and vascular smooth muscle cells (VSMCs) could contribute to circulating DLL1. Immunostaining of myocardial specimens showed colocalization of DLL1 with T cells, endothelial cells, and VSMCs. Our findings suggest a role of DLL1 in CAV progression, and that the beneficial effect of EVR on CAV could reflect a suppressive effect on DLL1. Trial registration numbers— SCHEDULE trial: ClinicalTrials.gov NCT01266148; NOCTET trial: ClinicalTrials.gov NCT00377962.     

ENIGMA-DTI: Translating reproducible white matter deficits into personalized vulnerability metrics in cross-diagnostic psychiatric research

The ENIGMA-DTI (diffusion tensor imaging) workgroup supports analyses that examine the effects of psychiatric, neurological, and developmental disorders on the white matter pathways of the human brain, as well as the effects of normal variation and its genetic associations. The seven ENIGMA disorder-oriented working groups used the ENIGMA-DTI workflow to derive patterns of deficits using coherent and coordinated analyses that model the disease effects across cohorts worldwide. This yielded the largest studies detailing patterns of white matter deficits in schizophrenia spectrum disorder (SSD), bipolar disorder (BD), major depressive disorder (MDD), obsessive–compulsive disorder (OCD), posttraumatic stress disorder (PTSD), traumatic brain injury (TBI), and 22q11 deletion syndrome. These deficit patterns are informative of the underlying neurobiology and reproducible in independent cohorts. We reviewed these findings, demonstrated their reproducibility in independent cohorts, and compared the deficit patterns across illnesses. We discussed translating ENIGMA-defined deficit patterns on the level of individual subjects using a metric called the regional vulnerability index (RVI), a correlation of an individual's brain metrics with the expected pattern for a disorder. We discussed the similarity in white matter deficit patterns among SSD, BD, MDD, and OCD and provided a rationale for using this index in cross-diagnostic neuropsychiatric research. We also discussed the difference in deficit patterns between idiopathic schizophrenia and 22q11 deletion syndrome, which is used as a developmental and genetic model of schizophrenia. Together, these findings highlight the importance of collaborative large-scale research to provide robust and reproducible effects that offer insights into individual vulnerability and cross-diagnosis features.     

Fluids in septic shock: too much of a good thing?

In a recent issue of Critical Care, Brandt and colleagues report the effects of a 'liberal' fluid loading protocol compared to a more 'restrictive' protocol on hemodynamics and mortality in pigs in which septic shock had been induced. It appears that the former protocol was associated with higher mortality in spite of improved hemodynamics compared to the latter. The results of the paper are discussed here in view of the scope and mechanisms of these findings. With regard to fluid resuscitation, they indicate that too much of an otherwise good thing is harmful, even if overhydration and edema formation seem to have been prevented. They also do not exclude a specific toxic effect of the larger volumes of hydroxyethyl starch in the 'liberal' strategy. The precise nature of a toxic effect remains obscure, however, but may involve the kidneys.     

A pilot methodology study for the photographic assessment of post‐inflammatory hyperpigmentation in patients treated with tretinoin

Background Post‐inflammatory hyperpigmentation (PIH) is a common occurrence in patients with acne vulgaris, particularly in those with skin of colour. Aims A previous study has demonstrated the benefit of tretinoin (retinoic acid) in the treatment of PIH; however, there is currently no standard protocol to evaluate change in PIH following treatment. Based on these findings, we performed a pilot, exploratory, blinded, intraindividual‐controlled methodology study that consisted of a photographic assessment protocol with facial mapping. Materials and methods The study was based on a secondary analysis of a phase 4, community‐based trial of 544 acne patients who were treated with tretinoin gel microsphere 0.04% or 0.1%. Only patients with Fitzpatrick types III–V (skin of colour) were included in the study; subjects with Fitzpatrick skin type VI were excluded because the photographic assessment did not allow for proper evaluation. Results Despite the small number of subjects evaluated (n = 25), the results revealed consistent assessment of improvement in PIH between two independent graders (weighted κ = 0.84). Conclusion Further study with a larger population is recommended to validate the accuracy of this method.     

The effectiveness of adding cognitive behavioural therapy aimed at changing lifestyle to managed diabetes care for patients with type 2 diabetes: design of a randomised controlled trial

Background  

In patients with type 2 diabetes, the risk for cardiovascular disease is substantial. To achieve a more favourable risk profile, lifestyle changes on diet, physical activity and smoking status are needed. This will involve changes in behaviour, which is difficult to achieve. Cognitive behavioural therapies focussing on self-management have been shown to be effective. We have developed an intervention combining techniques of Motivational Interviewing (MI) and Problem Solving Treatment (PST). The aim of our study is to investigate if adding a combined behavioural intervention to managed care, is effective in achieving changes in lifestyle and cardiovascular risk profile.     

Growth hormone and mild exercise in combination increases markedly muscle mass and tetanic tension in old rats

OBJECTIVE: A decline of skeletal muscle mass and strength is seen with aging and immobilization. Growth hormone (GH) has been shown to increase muscle mass. In the present study the effects of a combination of mild exercise and GH on skeletal musculature tetanic tension, dry defatted weight (DDW), volume, water, fat and collagen concentrations were investigated in old rats. DESIGN: Recombinant human GH (2.7mg/kg per day) was injected subcutaneously for 73 days in 21-month-old female rats. Exercised rats ran on a treadmill, 8 m/min for 1 h/day. The in vivo maximal tetanic tension of the calf musculature (m. soleus, m. plantaris, m. gastrocnemius together) was analysed in anaesthetized rats by stimulating the ischiadic nerve. RESULTS: The maximal tetanic tension was increased by 23% in GH-injected compared to saline-injected rats. Mild exercise + GH in combination resulted in a further 18% increase in maximal tetanic tension. The mild exercise by itself did not influence the maximal tetanic tension significantly when compared with saline injected rats. The GH administration and/or mild exercise did not change skeletal muscle endurance, measured as tetanic tension during 30s of stimulation. Serum IGF-I concentration was increased twofold in GH-injected rats. CONCLUSION: The increased muscle mass induced by GH + mild exercise was associated with a corresponding increase in maximal tetanic tension. Combination of GH + mild exercise resulted in a substantial further increase of muscle mass and maximal tension compared with GH injections alone in these old rats.