Outcomes in Dutch DPP6 risk haplotype for familial idiopathic ventricular fibrillation:a focused update

Background: The genetic risk haplotype DPP6 has been linked to familial idiopathic ventricular fibrillation (IVF), but the associated long-term outcomes are unknown. Methods: DPP6 risk haplotype-positive family members (DPP6 cases) and their risk haplotype-negative relatives (DPP6 controls) were included. Clinical follow-up data were collected through March 2023. Implantable cardioverter-defibrillator (ICD) indication was divided in primary or secondary prevention. Cumulative survival and event rates were calculated. Results: We included 327 DPP6 cases and 315 DPP6 controls. Median follow-up time was 9 years (interquartile range: 4–12). Of the DPP6 cases, 129 (39%) reached the composite endpoint of appropriate ICD shock, sudden cardiac arrest or death, at a median age of 45 years (range: 15–97). Median overall survival was 83 years and 87 years for DPP6 cases and DPP6 controls, respectively (p &lt; 0.001). In DPP6 cases, median overall survival was shorter for males (74 years) than females (85 years) (p &lt; 0.001). Of the DPP6 cases, 97 (30%) died, at a median age of 50 years. With a prophylactic ICD implantation advise based on risk haplotype, sex and age, 137 (42%) of DPP6 cases received an ICD, for primary prevention (n = 109) or secondary prevention (n = 28). In the primary prevention subgroup, 10 patients experienced a total of 34 appropriate ICD shocks, and there were no deaths during follow-up. DPP6 cases with a secondary prevention ICD experienced a total of 231 appropriate ICD shocks.Conclusion: Patients with the DPP6 risk haplotype, particularly males, are at an increased risk of IVF and sudden cardiac death. Using a risk stratification approach based on risk haplotype, sex and age, a substantial proportion of patients with a primary prevention ICD experienced appropriate ICD shocks, showing the benefit of prophylactic ICD implantation with this strategy.</p

Interobserver variability in target definition for stereotactic arrhythmia radioablation

BackgroundStereotactic arrhythmia radioablation (STAR) is a potential new therapy for patients with refractory ventricular tachycardia (VT). The arrhythmogenic substrate (target) is synthesized from clinical and electro-anatomical information. This study was designed to evaluate the baseline interobserver variability in target delineation for STAR.MethodsDelineation software designed for research purposes was used. The study was split into three phases. Firstly, electrophysiologists delineated a well-defined structure in three patients (spinal canal). Secondly, observers delineated the VT-target in three patients based on case descriptions. To evaluate baseline performance, a basic workflow approach was used, no advanced techniques were allowed. Thirdly, observers delineated three predefined segments from the 17-segment model. Interobserver variability was evaluated by assessing volumes, variation in distance to the median volume expressed by the root-mean-square of the standard deviation (RMS-SD) over the target volume, and the Dice-coefficient.ResultsTen electrophysiologists completed the study. For the first phase interobserver variability was low as indicated by low variation in distance to the median volume (RMS-SD range: 0.02–0.02 cm) and high Dice-coefficients (mean: 0.97 ± 0.01). In the second phase distance to the median volume was large (RMS-SD range: 0.52–1.02 cm) and the Dice-coefficients low (mean: 0.40 ± 0.15). In the third phase, similar results were observed (RMS-SD range: 0.51–1.55 cm, Dice-coefficient mean: 0.31 ± 0.21).ConclusionsInterobserver variability is high for manual delineation of the VT-target and ventricular segments. This evaluation of the baseline observer variation shows that there is a need for methods and tools to improve variability and allows for future comparison of interventions aiming to reduce observer variation, for STAR but possibly also for catheter ablation

Cardiac output measured by uncalibrated arterial pressure waveform analysis by recently released software version 3.02 versus thermodilution in septic shock

To evaluate the 3.02 software version of the FloTrac/Vigileo™ system for estimation of cardiac output by uncalibrated arterial pressure waveform analysis, in septic shock. Nineteen consecutive patients in septic shock were studied. FloTrac/Vigileo™ measurements (COfv) were compared with pulmonary artery catheter thermodilution-derived cardiac output (COtd). The mean cardiac output was 7.7 L min-1 and measurements correlated at r = 0.53 (P 10 % in both COtd and COfv (n = 46) were in the same direction. Eighty-five percent of the measurements were within the 30 -330 of the polar axis. COfv with the latest software still underestimates COtd at low SVR in septic shock. The tracking capacities of the 3.02 software are moderate-good when clinically relevant changes are considered

Arginase-1 deficiency regulates arginine concentrations and NOS2-mediated NO production during endotoxemia

Arginase-1 is an important component of the intricate mechanism regulating arginine availability during immune responses and nitric oxide synthase (NOS) activity. In this study Arg1(fl/fl)/Tie2-Cre(tg/-) mice were developed to investigate the effect of arginase-1 related arginine depletion on NOS2- and NOS3-dependent NO production and jejunal microcirculation under resting and endotoxemic conditions, in mice lacking arginase-1 in endothelial and hematopoietic cells. Arginase-1-deficient mice as compared with control mice exhibited higher plasma arginine concentration concomitant with enhanced NO production in endothelial cells and jejunal tissue during endotoxemia. In parallel, impaired jejunal microcirculation was observed in endotoxemic conditions. Cultured bone-marrow-derived macrophages of arginase-1 deficient animals also presented a higher inflammatory response to endotoxin than control littermates. Since NOS2 competes with arginase for their common substrate arginine during endotoxemia, Nos2 deficient mice were also studied under endotoxemic conditions. As Nos2(-/-) macrophages showed an impaired inflammatory response to endotoxin compared to wild-type macrophages, NOS2 is potentially involved. A strongly reduced NO production in Arg1(fl/fl)/Tie2-Cre(tg/-) mice following infusion of the NOS2 inhibitor 1400W further implicated NOS2 in the enhanced capacity to produce NO production Arg1(fl/fl)/Tie2-Cre(tg/-) mice. Reduced arginase-1 activity in Arg1(fl/fl)/Tie2-Cre(tg/-) mice resulted in increased inflammatory response and NO production by NOS2, accompanied by a depressed microcirculatory flow during endotoxemia. Thus, arginase-1 deficiency facilitates a NOS2-mediated pro-inflammatory activity at the expense of NOS3-mediated endothelial relaxatio

Impaired nitrite, TNF, IL-10 and IL-12p40 production in cultured <i>Nos2^−/−</i> bone marrow-derived macrophages after LPS stimulation.

<p>(A) LPS-treated bone marrow-derived macrophages from <i>Nos2^−/−</i> mice (n = 3) produced less nitrite (A; P<0.001), TNF (B; P<0.01), and IL-12p40 (D; P<0.01) in 24 hrs than macrophages from control mice (n = 3). IL-10 production after LPS treatment did not differ between control and <i>Nos2^−/−</i> macrophages (C).</p

Plasma arginine, citrulline and ornithine amino-acid concentrations in control and <i>Arg1^fl/fl/Tie2-Cre^tg/−</i> mice under basal and endotoxemic conditions.

<p>Plasma concentrations are displayed in µmol/L. Values are represented as mean ± SEM. Significance: *p<0.05 vs. control during basal conditions; $p<0.001 vs. <i>Arg1^fl/fl/Tie2-Cre^tg/−</i>during basal conditions; ^#p<0.001 vs. <i>Arg1^fl/fl/Tie2-Cre^tg/−+ LPS</i>.</p