Normal cardiac function requires that intracellular Ca concentration be reduced to low levels in diastole so that the ventricle can relax and refill with blood. Heart failure is often associated with ...impaired cardiac relaxation. Little, however, is known about how diastolic intracellular Ca concentration is regulated. This article first discusses the reasons for this ignorance before reviewing the basic mechanisms that control diastolic intracellular Ca concentration. It then considers how the control of systolic and diastolic intracellular Ca concentration is intimately connected. Finally, it discusses the changes that occur in heart failure and how these may result in heart failure with preserved versus reduced ejection fraction.
The first experimental TE-mode silicon-on-insulator (SOI) isolators using Faraday Rotation are here realized to fill the 'missing link' in source-integrated near infrared photonic circuits. The ...isolators are simple 1D 2-element waveguides, where garnet claddings and longitudinal magnetic fields produce nonreciprocal mode conversion, the waveguide equivalent of Faraday Rotation (FR). Quasi-phase matched claddings are used to overcome the limitations of birefringence. Current experimental SOI isolators use nonreciprocal phase shift (NRPS) in interferometers or ring resonators, but to date NRPS requires TM-modes, so the TE-modes normally produced by integrated lasers cannot be isolated without many ancillary polarisation controls. The presented FR isolators are made via lithography and sputter deposition, which allows facile upscaling compared to the pulsed laser deposition or wafer bonding used in the fabrication of NRPS devices. Here, isolation ratios and losses of 11 dB and 4 dB were obtained, and future designs are identified capable of isolation ratios >30 dB with losses <6 dB.
Faraday rotators in optical isolators, typically composed of iron garnets, are photonic analogues of electrical diodes in that they do not allow reciprocal transmission of light. Isolators are ...especially important for blocking back-reflected light from reaching source lasers, as such feedback gives rise to unwanted noise and instabilities. In commonly implemented photonic integrated circuits (PICs), isolation is the only critical function that cannot yet be achieved by direct integration. While several techniques have been explored for integrating high-gyrotropy garnets into silicon-on-insulator PICs, this article focuses on sputter deposition, which is the most up-scalable process. High-gyrotropy Ce-doped yttrium iron garnet on nongarnet substrates can be made by sputter deposition with the use of garnet seed layers. Because these seed layers can compromise device performance, seed layer-free terbium iron garnet (TIG) has also recently been developed. Careful doping of TIG can produce Faraday rotations with opposite chiralities, which enable new device designs. Most optical isolator designs involve two-dimensional transverse magnetic-mode structures, such as interferometers or ring resonators, which employ nonreciprocal phase shift. One-dimensional Faraday rotation waveguides with quasi-phase matching have been shown to enable direct integration of isolators for all modes, including the transverse electric mode of lasers currently available for fully integrated PICs.
Experimental evidence has shown potential cardioprotective actions of phosphodiesterase type-5 inhibitors (PDE5is). We investigated whether PDE5i use in patients with type 2 diabetes, with ...high-attendant cardiovascular risk, was associated with altered mortality in a retrospective cohort study.
Between January 2007 and May 2015, 5956 men aged 40-89 years diagnosed with type 2 diabetes before 2007 were identified from anonymised electronic health records of 42 general practices in Cheshire, UK, and were followed for 7.5 years. HRs from multivariable survival (accelerated failure time, Weibull) models were used to describe the association between on-demand PDE5i use and all-cause mortality.DC1SM110.1136/heartjnl-2015-309223.supp1Supplementary appendix RESULTS: Compared with non-users, men who are prescribed PDE5is (n=1359) experienced lower percentage of deaths during follow-up (19.1% vs 23.8%) and lower risk of all-cause mortality (unadjusted HR=0.69 (95% CI: 0.64 to 0.79); p<0.001)). The reduction in risk of mortality (HR=0.54 (0.36 to 0.80); p=0.002) remained after adjusting for age, estimated glomerular filtration rate, smoking status, prior cerebrovascular accident (CVA) hypertension, prior myocardial infarction (MI), systolic blood pressure, use of statin, metformin, aspirin and β-blocker medication. PDE5i users had lower rates of incident MI (incidence rate ratio (0.62 (0.49 to 0.80), p<0.0001) with lower mortality (25.7% vs 40.1% deaths; age-adjusted HR=0.60 (0.54 to 0.69); p=0.001) compared with non-users within this subgroup.
In a population of men with type 2 diabetes, use of PDE5is was associated with lower risk of overall mortality and mortality in those with a history of acute MI.
Ventricular arrhythmias can cause death in heart failure (HF). A trigger is the occurrence of Ca2+ waves which activate a Na+‐Ca2+ exchange (NCX) current, leading to delayed after‐depolarisations and ...triggered action potentials. Waves arise when sarcoplasmic reticulum (SR) Ca2+ content reaches a threshold and are commonly induced experimentally by raising external Ca2+, although the mechanism by which this causes waves is unclear and was the focus of this study. Intracellular Ca2+ was measured in voltage‐clamped ventricular myocytes from both control sheep and those subjected to rapid pacing to produce HF. Threshold SR Ca2+ content was determined by applying caffeine (10 mM) following a wave and integrating wave and caffeine‐induced NCX currents. Raising external Ca2+ induced waves in a greater proportion of HF cells than control. The associated increase of SR Ca2+ content was smaller in HF due to a lower threshold. Raising external Ca2+ had no effect on total influx via the L‐type Ca2+ current, ICa‐L, and increased efflux on NCX. Analysis of sarcolemmal fluxes revealed substantial background Ca2+ entry which sustains Ca2+ efflux during waves in the steady state. Wave frequency and background Ca2+ entry were decreased by Gd3+ or the TRPC6 inhibitor BI 749327. These agents also blocked Mn2+ entry. Inhibiting connexin hemi‐channels, TRPC1/4/5, L‐type channels or NCX had no effect on background entry. In conclusion, raising external Ca2+ induces waves via a background Ca2+ influx through TRPC6 channels. The greater propensity to waves in HF results from increased background entry and decreased threshold SR content.
Key points
Heart failure is a pro‐arrhythmic state and arrhythmias are a major cause of death.
At the cellular level, Ca2+ waves resulting in delayed after‐depolarisations are a key trigger of arrhythmias. Ca2+ waves arise when the sarcoplasmic reticulum (SR) becomes overloaded with Ca2+.
We investigate the mechanism by which raising external Ca2+ causes waves, and how this is modified in heart failure.
We demonstrate that a novel sarcolemmal background Ca2+ influx via the TRPC6 channel is responsible for SR Ca2+ overload and Ca2+ waves.
The increased propensity for Ca2+ waves in heart failure results from an increase of background influx, and a lower threshold SR content.
The results of the present study highlight a novel mechanism by which Ca2+ waves may arise in heart failure, providing a basis for future work and novel therapeutic targets.
figure legend Raising external Ca2+ (1) leads to a background Ca2+ influx via TRPC6 channels (2). This Ca2+ is pumped into the sarcoplasmic reticulum via SERCA leading to a rise in SR Ca2+ content (3). When SR Ca2+ content reaches a threshold, spontaneous Ca2+ release leads to propagating Ca2+ waves (4). In heart failure, the background Ca2+ influx is increased and SR threshold decreased, resulting in a greater propensity to Ca2+ waves.
Supplemental Digital Content is available in the text.
PDE5 (phosphodiesterase 5) inhibition reduces the occurrence of ventricular arrhythmias following myocardial ischemia. However, the mechanisms ...of the antiarrhythmic effects of PDE5 inhibition are unknown. Diastolic calcium (Ca
2+
) waves lead to arrhythmias by inducing delayed afterdepolarizations (DADs). Ca
2+
waves are initiated when sarcoplasmic reticulum (SR) Ca
2+
content reaches a threshold level and the SR releases Ca
2+
spontaneously and generates a depolarizing inward sodium-calcium exchange current.
Ventricular arrhythmias can cause death in heart failure (HF). A trigger is the occurrence of Ca
waves which activate a Na
-Ca
exchange (NCX) current, leading to delayed after-depolarisations and ...triggered action potentials. Waves arise when sarcoplasmic reticulum (SR) Ca
content reaches a threshold and are commonly induced experimentally by raising external Ca
, although the mechanism by which this causes waves is unclear and was the focus of this study. Intracellular Ca
was measured in voltage-clamped ventricular myocytes from both control sheep and those subjected to rapid pacing to produce HF. Threshold SR Ca
content was determined by applying caffeine (10 mM) following a wave and integrating wave and caffeine-induced NCX currents. Raising external Ca
induced waves in a greater proportion of HF cells than control. The associated increase of SR Ca
content was smaller in HF due to a lower threshold. Raising external Ca
had no effect on total influx via the L-type Ca
current, I
, and increased efflux on NCX. Analysis of sarcolemmal fluxes revealed substantial background Ca
entry which sustains Ca
efflux during waves in the steady state. Wave frequency and background Ca
entry were decreased by Gd
or the TRPC6 inhibitor BI 749327. These agents also blocked Mn
entry. Inhibiting connexin hemi-channels, TRPC1/4/5, L-type channels or NCX had no effect on background entry. In conclusion, raising external Ca
induces waves via a background Ca
influx through TRPC6 channels. The greater propensity to waves in HF results from increased background entry and decreased threshold SR content. KEY POINTS: Heart failure is a pro-arrhythmic state and arrhythmias are a major cause of death. At the cellular level, Ca
waves resulting in delayed after-depolarisations are a key trigger of arrhythmias. Ca
waves arise when the sarcoplasmic reticulum (SR) becomes overloaded with Ca
. We investigate the mechanism by which raising external Ca
causes waves, and how this is modified in heart failure. We demonstrate that a novel sarcolemmal background Ca
influx via the TRPC6 channel is responsible for SR Ca
overload and Ca
waves. The increased propensity for Ca
waves in heart failure results from an increase of background influx, and a lower threshold SR content. The results of the present study highlight a novel mechanism by which Ca
waves may arise in heart failure, providing a basis for future work and novel therapeutic targets.
Novel cardioprotective agents are needed in both heart failure (HF) and myocardial infarction. Increasing evidence from cellular studies and animal models indicate protective effects of ...phosphodiesterase-5 (PDE5) inhibitors, drugs usually reserved as treatments of erectile dysfunction and pulmonary arterial hypertension. PDE5 inhibitors have been shown to improve contractile function in systolic HF, regress left ventricular hypertrophy, reduce myocardial infarct size and suppress ischaemia-induced ventricular arrhythmias. Underpinning these actions are complex but increasingly understood cellular mechanisms involving the cyclic GMP activation of protein kinase-G in both cardiac myocytes and the vasculature. In clinical trials, PDE5 inhibitors improve symptoms and ventricular function in systolic HF, and accumulating epidemiological data indicate a reduction in cardiovascular events and mortality in PDE5 inhibitor users at high cardiovascular risk. Here, we focus on the translation of underpinning basic science to clinical studies and report that PDE5 inhibitors act through a number of cardioprotective mechanisms, including a direct myocardial action independent of the vasculature. We conclude that future clinical trials should be designed with these mechanisms in mind to identify patient subsets that derive greatest treatment benefit from these novel cardioprotective agents.
Cigarette smoking (CS) is the main risk factor for the development of chronic obstructive pulmonary disease (COPD) and most COPD exacerbations are caused by respiratory infections including ...influenza. Influenza infections are more severe in smokers. The mechanism of the increased risk and severity of infections in smokers is likely multifactorial, but certainly includes changes in immunologic host defenses.
We investigated retinoic acid-inducible protein I (RIG-I) and interferon (IFN) induction by influenza A virus (IAV) in human bronchial epithelial cells (HBEC) isolated from smokers or nonsmokers. Subcultured HBEC cells were infected with A/Puerto Rico/8/1934 (PR8) IAV at an MOI of 1. After 24 h of infection, cells and supernatants were collected for qRT-PCR, immunoblot or ELISA to determine RIG-I, Toll-like receptor3 (TLR3) and IFN expression levels.
IAV exposure induced a vigorous IFN-β, IFN-λ 1 and IFN-λ 2/3 antiviral response in HBEC from nonsmokers and significant induction of RIG-I and TLR3. In cells from smokers, viral RIG-I and TLR3 mRNA induction was reduced 87 and 79 % compared to the response from nonsmokers. CS exposure history was associated with inhibition of viral induction of the IFN-β, IFN-λ1 and IFN-λ 2/3 mRNA response by 85, 96 and 95 %, respectively, from that seen in HBEC from nonsmokers. The demethylating agent 5-Aza-2-deoxycytidine reversed the immunosuppressive effects of CS exposure in HBEC since viral induction of all three IFNs was restored. IFN-β induction of RIG-I and TLR3 was also suppressed in the cells from smokers.
Our results suggest that active smoking reduces expression of antiviral cytokines in primary HBEC cells. This effect likely occurs via downregulation of RIG-I and TLR3 due to smoke-induced epigenetic modifications. Reduction in lung epithelial cell RIG-I and TLR3 responses may be a major mechanism contributing to the increased risk and severity of viral respiratory infections in smokers and to viral-mediated acute exacerbations of COPD.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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