Mechanisms of ventricular arrhythmogenesis in the age dependent Pgc-1β -/- model of mitochondrial dysfunction.

Sudden cardiac death is a leading cause of mortality worldwide. Ventricular arrhythmias, both ventricular tachycardia and ventricular fibrillation, are the primary arrhythmias that lead to sudden cardiac death. A large proportion of ventricular arrhythmias are ischaemic in origin. However, increasing clinical and experimental evidence links metabolic disease, mitochondrial dysfunction and ageing as independent risk factors for arrhythmogenesis beyond the risk they confer to coronary artery disease. To date, researchers have focused upon investigation of monogenic ion channel disorders as well circumscribed diseases to investigate the principles of arrhythmogenesis. This has given insight into the basic theories of arrhythmogenesis as well as the tools needed to dissect them. In this study, we use Pgc-1β-/- mice as a murine model of mitochondrial dysfunction, to further investigate the link between mitochondrial and energetic insufficiency and arrhythmias. The study uses electrocardiographic data to characterise the phenotype at the whole animal level, revealing significant age related abnormalities in ventricular activation and abnormal nodal tissue phenotypes. Single cell action potential characteristics in intact Langendorff perfused whole hearts were then used both in programmed electrical stimulation studies and at incrementally paced steady states to investigate the electrophysiological characteristics that give rise to arrhythmia. These experiments revealed a significant deficit in maximal rate of depolarisation and consequent effects on conduction wavelengths, accompanied by instabilities in activation characteristics as evidenced by the presence of electrical alternans. Finally, patch-clamp studies are performed to confirm the hypotheses of the earlier experiments and their effect on cellular currents in a physiological environment which show a physiological deficit in sodium current density. At all stages care was taken to perform experiments in the least disruptive manner, maintaining as much physiological relevance as possible. The series of experiments reveal that not only is mitochondrial dysfunction related to arrhythmias in an age dependant manner, but that it leads to altered sodium current density with a plausible role of Ca2+ as a central mediator of this, allowing future studies to build on this.Funded by the MRC clinical training research fellowship (CRTF

Hand Injuries in the Oil Fields of Brunei Darussalam

Hands are essential organs and their agility and dexterity are vital to our daily lives. In the present study, we analysed 107 patients who presented at the local hospital with hand injuries sustained in the oil fields, oil industries and related employment sectors from the surrounding regions. All the patients were male and the mean age was 37.89 years (range,21-61y). Forty-seven (43.93%) patients had simple cut injuries, 14 patients (13.08%) had tendon injuries, 13 patients (12.14%) had amputation of the digit (30.84%) had bone fractures (including 20 (66.66%) open fractures). Only 19 (17.75%) patients were admitted in hospital for further treatment. Ninety-one (85.04%) patients injured within one year of employment and 57(53.27%) patients were not satisfied with instructions and orientation before starting their job. Hand injury is one of the most common injuries in the oil industry and overtime work further increases incidence of this injury

IoT Based Real Time Early Age Concrete Compressive Strength Monitoring

Concrete Strength determination has been an expensive and hectic job due to its orthodox methodology of measuring concrete strength where cylinders are filled with concrete. Its strength is measured using the crushing of concrete (Compression Test). A significant amount of waste is generated while performing this test multiple times during the execution of the project. The present study proposes a new IoT-based framework comprising a low-cost sensor and a window dashboard to estimate and monitor the real-time early-age concrete strength. This system will significantly help the construction industry to avoid the onsite laboratory testing of concrete for strength. In this study, a temperature sensor, along with an ESP32 microprocessor, is used to acquire and transmit the recorded temperature in real time to a cloud database. The window application developed load data from the cloud database and presented it as figures and graphs related to concrete strength with time. The strength calculated using the developed sensor was compared with the actual strength determined using a compression test for the same mix design, which showed a significant match. The project is a contribution toward the non-destructive testing of concrete. By knowing the concrete strength of any structural member in advance, the practitioners can make decisions well before time to avoid delays in the project

Pro-arrhythmic atrial phenotypes in incrementally paced murine Pgc1β-/- hearts: effects of age.

What is the central question of this study? Can we experimentally replicate atrial pro-arrhythmic phenotypes associated with important chronic clinical conditions, including physical inactivity, obesity, diabetes mellitus and metabolic syndrome, compromising mitochondrial function, and clarify their electrophysiological basis? What is the main finding and its importance? Electrocardiographic and intracellular cardiomyocyte recording at progressively incremented pacing rates demonstrated age-dependent atrial arrhythmic phenotypes in Langendorff-perfused murine Pgc1β-/- hearts for the first time. We attributed these to compromised action potential conduction and excitation wavefronts, whilst excluding alterations in recovery properties or temporal electrophysiological instabilities, clarifying these pro-arrhythmic changes in chronic metabolic disease. Atrial arrhythmias, most commonly manifesting as atrial fibrillation, represent a major clinical problem. The incidence of atrial fibrillation increases with both age and conditions associated with energetic dysfunction. Atrial arrhythmic phenotypes were compared in young (12-16 week) and aged (>52 week) wild-type (WT) and peroxisome proliferative activated receptor, gamma, coactivator 1 beta (Ppargc1b)-deficient (Pgc1β-/- ) Langendorff-perfused hearts, previously used to model mitochondrial energetic disorder. Electrophysiological explorations were performed using simultaneous whole-heart ECG and intracellular atrial action potential (AP) recordings. Two stimulation protocols were used: an S1S2 protocol, which imposed extrasystolic stimuli at successively decremented intervals following regular pulse trains; and a regular pacing protocol at successively incremented frequencies. Aged Pgc1β-/- hearts showed greater atrial arrhythmogenicity, presenting as atrial tachycardia and ectopic activity. Maximal rates of AP depolarization (dV/dtmax ) were reduced in Pgc1β-/- hearts. Action potential latencies were increased by the Pgc1β-/- genotype, with an added interactive effect of age. In contrast, AP durations to 90% recovery (APD90 ) were shorter in Pgc1β-/- hearts despite similar atrial effective recovery periods amongst the different groups. These findings accompanied paradoxical decreases in the incidence and duration of alternans in the aged and Pgc1β-/- hearts. Limiting slopes of restitution curves of APD90 against diastolic interval were correspondingly reduced interactively by Pgc1β-/- genotype and age. In contrast, reduced AP wavelengths were associated with Pgc1β-/- genotype, both independently and interacting with age, through the basic cycle lengths explored, with the aged Pgc1β-/- hearts showing the shortest wavelengths. These findings thus implicate AP wavelength in possible mechanisms for the atrial arrhythmic changes reported here

Major septal defects: Comparative study of down syndrome and non-down syndrome infants, before and after surgery

Objective: To compare pre-operative, intra-operative, and post-operative parameters in Down syndrome (DS) and non-DS patients with atrioventricular septal defects (AVSD) and inlet ventricular septal defects (VSD) in a tertiary care hospital in Pakistan.Methods: We conducted a retrospective study at Aga Khan University, Pakistan. All complete atrioventricular septal defect (CAVSD), partial atrioventricular septal defect (PAVSD), and VSD with inlet extension surgical cases from January 2007 to January 2019 were included. Patients with congenital heart diseases other than those listed above were excluded.Results: In 61 cases, 18 had DS. Median age, mean body surface area (BSA), and height were lower in DS patients compared to non-DS patients: 7.0 vs 23.0 months, 0.311 vs 0.487 m2, and 63 vs 82 cm, respectively. Bypass duration, aortic cross clamp time, post-operative ventilator hours, dose of inotropes, CICU stay, and total hospital stay were all significantly higher in the DS group. The odds ratio (955% CI) for mortality in DS babies was 6.2 (1.4, 27.1), p=0.015, after adjusting for age, weight, and height. The overall morbidity was comparable between the two groups, demonstrating no significant difference after adjusting for confounders.Conclusion: DS babies with AVSD and inlet VSD are at a greater risk of mortality compared to non-DS babies, particularly those with CAVSD. Furthermore, DS babies undergo surgery at a younger age and require more aggressive post-operative therapy and monitoring due to the development of complications

Systematic review of renal denervation for the management of cardiac arrhythmias

Background In the wake of the controversy surrounding the SYMPLICITY HTN-3 trial and data from subsequent trials, this review aims to perform an updated and more comprehensive review of the impact of renal sympathetic denervation on cardiac arrhythmias. Methods and results A systematic search was performed using the Medline, Scopus and Embase databases using the terms “Renal Denervation” AND “Arrhythmias or Atrial or Ventricular”, limited to Human and English language studies within the last 10 years. This search yielded 19 relevant studies (n = 6 randomised controlled trials, n = 13 non-randomised cohort studies) which comprised 783 patients. The studies show RSD is a safe procedure, not associated with increases in complications or mortality post-procedure. Importantly, there is no evidence RSD is associated with a deterioration in renal function, even in patients with chronic kidney disease. RSD with or without adjunctive pulmonary vein isolation (PVI) is associated with improvements in freedom from atrial fibrillation (AF), premature atrial complexes (PACs), ventricular arrhythmias and other echocardiographic parameters. Significant reductions in ambulatory and office blood pressure were also observed in the majority of studies. Conclusion This review provides evidence based on original research that ‘second generation’ RSD is safe and is associated with reductions in short-term blood pressure and AF burden. However, the authors cannot draw firm conclusions with regards to less prominent arrhythmia subtypes due to the paucity of evidence available. Large multi-centre RCTs investigating the role of RSD are necessary to comprehensively assess the efficacy of the procedure treating various arrhythmias

Cardiomyocyte ionic currents in intact young and aged murine Pgc-1β-/- atrial preparations.

INTRODUCTION: Recent studies reported that energetically deficient murine Pgc-1β-/- hearts replicate age-dependent atrial arrhythmic phenotypes associated with their corresponding clinical conditions, implicating action potential (AP) conduction slowing consequent upon reduced AP upstroke rates. MATERIALS AND METHODS: We tested a hypothesis implicating Na+ current alterations as a mechanism underlying these electrophysiological phenotypes. We applied loose patch-clamp techniques to intact young and aged, WT and Pgc-1β-/-, atrial cardiomyocyte preparations preserving their in vivo extracellular and intracellular conditions. RESULTS AND DISCUSSION: Depolarising steps activated typical voltage-dependent activating and inactivating inward (Na+) currents whose amplitude increased or decreased with the amplitudes of the activating, or preceding inactivating, steps. Maximum values of peak Na+ current were independently influenced by genotype but not age or interacting effects of genotype and age on two-way ANOVA. Neither genotype, nor age, whether independently or interactively, influenced voltages at half-maximal current, or steepness factors, for current activation and inactivation, or time constants for recovery from inactivation following repolarisation. In contrast, delayed outward (K+) currents showed similar activation and rectification properties through all experimental groups. These findings directly demonstrate and implicate reduced Na+ in contrast to unchanged K+ current, as a mechanism for slowed conduction causing atrial arrhythmogenicity in Pgc-1β-/- hearts

Molecular basis of arrhythmic substrate in ageing murine peroxisome proliferator-activated receptor γ co-activator deficient hearts modelling mitochondrial dysfunction.

INTRODUCTION: Ageing and chronic metabolic disorders are associated with mitochondrial dysfunction and cardiac pro-arrhythmic phenotypes which were recently attributed to slowed atrial and ventricular action potential (AP) conduction in peroxisome proliferator-activated receptor γ co-activator deficient (Pgc-1β-/-) mice. METHODS: We compared expression levels of voltage-gated Na+ channel (NaV1.5) and gap junction channels, Connexins 40 and 43 (Cx40 and Cx43) in the hearts of young and old, and wild-type (WT) and Pgc-1β-/- mice. This employed Western blotting (WB) for NaV1.5, Cx40 and Cx43 in atrial/ventricular tissue lysates, and immunofluorescence (IF) from Cx43 was explored in tissue sections. Results were analysed using two-way analysis of variance (ANOVA) for independent/interacting effects of age and genotype. RESULTS: In atria, increased age and Pgc-1β-/- genotype each independently decreased both Cx40 and Cx43 expression without interacting effects. In IF experiments, both age and Pgc-1β deletion independently reduced Cx43 expression. In ventricles, age and genotype exerted interacting effects in WB studies of NaV1.5 expression. Young Pgc-1β-/- then showed greater NaV1.5 expression than young WT ventricles. However, neither age nor Pgc-1β deletion affected Cx43 expression, independently or through interacting effects in both WB and IF studies. CONCLUSION: Similar pro-arrhythmic atrial/ventricular phenotypes arise in aged/Pgc-1β-/- from differing contributions of altered protein expression and functional effects that may arise from multiple acute mechanisms