Zfhx3 decreases expression of cardiac Nav1.5 channels and inhibits sodium current

Abstract Background Zfhx3 (zinc finger homeobox 3) is a transcription factor (TF) encoded by the ZFHX3 gene. GWAS and gene-based association studies showed that ZFHX3 is one of the major atrial fibrillation (AF) susceptibility-conferring genes. The sodium current (INa), carried by Nav1.5 channels encoded by SCN5A, is responsible for atrial and ventricular action potential depolarization and determines cardiac excitability. Zfhx3 interacts with other TFs, such as Tbx5 and Pitx2c that increase and decrease INa, respectively. However, the effects of Zfhx3 on cardiac INa are currently unknown. Purpose We aimed to determine the effects of Zfhx3 on the INa on HL-1 cardiomyocytes. Methods cDNAs encoding human Zfhx3 together or not with Pitx2c or Tbx5 were transfected in HL-1 cells. Endogenous Zfhx3 expression in HL-1 cells was silenced by means of siRNAs. INa was recorded at room temperature using the whole-cell patch-clamp and luciferase reporter assays, qPCR and Western-blot (WB) analyses were also conducted. Results Expression analysis of RNA-seq data from human ventricular (n=432) samples (GTEx) demonstrated that Zfhx3 mRNA can be detected in the adult working myocardium. Transfection of Zfhx3 strongly reduced peak INa density (from −75.0±6.6 to −30.9±2.9 pA/pF; n≥26, P<0.001). In contrast, Zfhx3 silencing augmented INa density compared to cells transfected with scrambled siRNA (from −65.9±8.9 to −104.6±10.8 pA/pF; n≥8, P<0.05). Neither Zfhx3 expression nor silencing modified time and voltage dependence of activation and inactivation or the reactivation kinetics. Zfhx3 significantly reduced transcriptional activity of human SCN5A, PITX2 and TBX5 minimal promoters and, consequently, the mRNA and protein expression levels of Nav1.5, Pitx2c, and Tbx5 were diminished (n≥6, P<0.05). In cells transfected with Zfhx3 together with Pitx2c, but not with Tbx5, INa density was significantly smaller than in cells expressing WT Zfhx3 alone (n≥15, P<0.05). Further WB experiments demonstrated that Zfhx3 increased the expression of Nedd4–2 ubiquitin-protein ligase, which ubiquitinates Nav1.5 channels and favors their proteasomal degradation. Conclusions Zfhx3 inhibits INa as a result of a direct repressor effect on the SCN5A promoter, the modulation of Tbx5-increasing and Pitx2-decreasing effects on the INa, and the enhancement of Nav1.5 channel degradation. We propose a novel and complex mechanism that regulates the expression of sodium channels and the density of the INa, which are critical for the control of cardiac excitability. FUNDunding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Ministerio de Economía y CompetitividadComunidad Autόnoma de Madrid

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Piezo1 and BKCa channels in human atrial fibroblasts: interplay and remodelling in atrial fibrillation

EP Europace ◽

10.1093/europace/euab116.581 ◽

2021 ◽

Vol 23 (Supplement_3) ◽

Author(s):

D Jakob ◽

A Klesen ◽

B Allegrini ◽

E Darkow ◽

D Aria ◽

...

Keyword(s):

Atrial Fibrillation ◽

Sinus Rhythm ◽

Calcium Influx ◽

Primary Cultures ◽

Science Research ◽

Bkca Channels ◽

National Budget ◽

Funding Sources ◽

Public Grant ◽

In Cells

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Ministry of Science, Research and Arts Baden-Württemberg (MWK-BW Sonderlinie Medizin) Atrial Fibrillation (AF) is an arrhythmia of increasing prevalence. One of the important indicators for AF is sustained atrial dilatation, highlighting the importance of mechanical overload in the pathophysiology of AF. The mechanisms by which atrial cells, including fibroblasts, sense and react to such changing mechanical forces, are not fully elucidated. Here, we characterise stretch-activated ion channels (SAC) in human atrial fibroblasts and changes in their expression and activity associated with AF. Using primary cultures of human atrial fibroblasts, isolated from patients in sinus rhythm or with sustained AF, we combine electrophysiological, molecular and pharmacological tools to identify SAC. Two electrophysiological SAC-signatures were detected, indicative of cation-nonselective and potassium-selective channels. Using siRNA-mediated knockdown, we identified the nonselective SAC as Piezo1. Biophysical properties of the potassium-selective channel and its pharmacology indicated presence of ‘big potassium channels’, BKCa. In cells from AF patients, Piezo1 activity and mRNA expression levels were higher than in cells from sinus rhythm patients, while BKCa activity (but not expression) was downregulated. Both Piezo1-knockdown and removal of extracellular calcium from the patch pipette resulted in a significant reduction of stretch-induced BKCa current. No co-immunoprecipitation of Piezo1 and BKCa was detected. Human atrial fibroblasts express functional Piezo1 and BKCa channels. While Piezo1 is directly stretch-activated, the increase in BKCa activity during mechanical stimulation appears to be mainly secondary to calcium influx via SAC such as Piezo1. During sustained AF, Piezo1 is increased, while BKCa activity is reduced, highlighting differential regulation of both channels. Our data show the presence and activity of Piezo1 and BKCa in human atrial fibroblasts and suggest an interplay between the two in the absence of direct physical interactions.

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Anatomical localization and classification of bundle branch blocks using novel CineECG

EP Europace ◽

10.1093/europace/euab116.039 ◽

2021 ◽

Vol 23 (Supplement_3) ◽

Author(s):

MJ Boonstra ◽

BN Hilderink ◽

ET Locati ◽

FW Asselbergs ◽

P Loh ◽

...

Keyword(s):

Time Interval ◽

Heart Model ◽

National Budget ◽

Funding Sources ◽

Conduction Disorders ◽

Bundle Branch Blocks ◽

Anatomical Localization ◽

The Mean ◽

Diagnostic Work ◽

Public Grant

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): This work was supported by the Dutch Heart Foundation Background Ventricular conduction disorders can induce arrhythmias and impair cardiac function. Bundle branch blocks are diagnosed by 12-lead ECG, but discrimination between complete bundle branch blocks, incomplete bundle branch blocks and normal tracings can be challenging. CineECG computes the mean temporo-spatial isochrone (mTSI) trajectory of activation waveforms in a 3D-heart model from 12-lead ECGs. This trajectory represents the mean trajectory of the ventricular electrical activation at any time interval directly related to ventricular anatomy. In Brugada patients, CineECG has localized the terminal components of ventricular depolarization to right ventricle outflow tract (RVOT). Also, for the localization of bundle branch blocks, the region of latest activation contains the most information. Using CineECG, subject specific anatomically related information about the location of bundle branch blocks is obtained. Purpose This study aimed at exploring whether CineECG can improve the discrimination between complete left/right bundle branch blocks (LBBB/RBBB), and incomplete RBBB (iRBBB). Methods We utilized 400 12-lead ECGs from the online Physionet-XL-PTB-Diagnostic ECG Database with a certified ECG diagnosis. The mTSI trajectory was calculated and projected into the anatomical 3D-heart model. Five CineECG classes were established: "Normal", "iRBBB", "RBBB", "LBBB" and "Undetermined", to which each tracing was allocated. We determined the accuracy of CineECG classification with the gold standard diagnosis. Results A total of 391 ECGs were analyzed (9 ECGs were excluded for noise) and 240/266 were correctly classified as "normal", 14/17 as "iRBBB", 55/55 as "RBBB", 51/51 as "LBBB" and 31 as "undetermined". Average mTSI trajectories were calculated according to ECG diagnosis (Figure). The terminal mTSI contained most information about the BBB localization, as that part directs to the site of latest activation (Figure, red arrow). Conclusion CineECG provided the anatomical localization of different BBBs and accurately differentiated between normal, LBBB and RBBB, and iRBBB. CineECG may aid clinical diagnostic work-up, potentially also contributing to the difficult discrimination between normal, iRBBB and Brugada patients. Abstract Figure. Average CineECG trajectories

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Rotational activity presence and its impact in persistent atrial fibrillation follow-up

European Heart Journal ◽

10.1093/eurheartj/ehab724.0375 ◽

2021 ◽

Vol 42 (Supplement_1) ◽

Author(s):

G R Rios-Munoz ◽

N Soto ◽

P Avila ◽

T Datino ◽

F Atienza ◽

...

Keyword(s):

Atrial Fibrillation ◽

Treatment Success ◽

Persistent Atrial Fibrillation ◽

Recurrence Rates ◽

National Budget ◽

Funding Sources ◽

Cycle Lengths ◽

Public Grant ◽

Af Recurrence

Abstract Introduction Treatment of atrial fibrillation (AF) remains sub-optimal, with low success in pulmonary vein isolation (PVI) ablation procedures in long-standing-persistent AF patients. The maintenance mechanisms of AF are still under debate. Rotational activity (RA) events, also known as rotors, may play a role in perpetuating AF. The characterisation of these drivers during electroanatomical (EA) guided ablation procedures in relationship with follow-up and recurrence ratios in AF patients is necessary to design new ablation strategies to improve the AF treatment success. Purpose We report an AF patient cohort of endocardial mapping and PVI ablation procedures with additional RA events detected during the EA study. We aim to study the presence and distribution of RA in AF patients and its impact on AF recurrence when only PVI ablation is performed. Methods 75 persistent consecutive AF patients (age 60.7±9.8, 74.7% men) underwent EA mapping and RA detection with an automatic algorithm. The presence of RA was annotated on the EA map based on the unipolar electrograms (EGMs) registered with a 20-pole catheter. RA presence was analysed at different left atrial locations (37.2±14.8 sites per patient). AF recurrence was evaluated in follow-up after treatment. Results At follow-up (9±5 months), 50% of the patients presented AF recurrence. Patients with RA had more dilated atria in terms of volumes (p=0.002) and areas (p=0.001). Patients with RA exhibited higher mean voltage EGMs 0.6±0.3 mV vs 0.5±0.2 mV (p=0.036), with shorter cycle lengths 169.1±26.0 ms vs. 188.4±44.2 ms (p=0.044). Finally, patients with RA presented more AF recurrence rates than patients with no RA events (p=0.007). No significant differences were found in terms of comorbidities, e.g., heart failure, hypertension, COPD, stroke, SHD, or diabetes mellitus. Conclusions The results show that patients with more RA events and those with RA outside the PVI ablated regions presented higher AF recurrence episodes than those with no RA or events inside the areas affected by radio-frequency ablation. The study suggests that further ablation treatment of the areas harboring RA might be necessary to reduce the recurrence ratio in AF patients. FUNDunding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Instituto de Salud Carlos III; Sociedad Española de Cardiología

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CT-based cardiovascular risk stratification benefits in asymptomatic patients

European Heart Journal - Cardiovascular Imaging ◽

10.1093/ehjci/jeab111.021 ◽

2021 ◽

Vol 22 (Supplement_3) ◽

Author(s):

AN Rozhkov ◽

DY Shchekochikhin ◽

PYU Kopylov

Keyword(s):

Computed Tomography ◽

Roc Analysis ◽

Basic Research ◽

Cardiovascular Risks ◽

Diagnostic Significance ◽

National Budget ◽

Funding Sources ◽

Asymptomatic Patients ◽

Outpatient Practice ◽

Public Grant

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Russian Foundation for Basic Research Background Cardiovascular risks (CVR) stratification and assessment of atherosclerotic plaques vulnerability in asymptomatic patients are serious challenges in outpatient practice. The use of modern CT techniques can help to personalize stratification. Methods The study included ambulatory patients with suspected coronary heart disease, who underwent computed tomography coronary angiography (CTA) in 2019-2020. CVR was estimated via Score, ACC/AHA, Framingham, MESA scales, CTA was performed on 640-slice computed tomography station. The patients were divided into two groups: patent arteries and atherosclerotic lesions (30-99%). We analyzed of the estimated CVR distribution, using coronary arteries visualization as the cut-off. Then ROC analysis of the scales, and Agatson Index was performed. Results The study included 60 patients, mean age is 61,5 years (65% female). 36,7% had no atherosclerosis; 56,7% had 30-99% coronary artery stenosis. Our results showed risks overestimation using the SCORE and Framingham scales (+33.33% and +52.38%) and underestimation using ACC/AHA and MESA (-33.33% and -9.52%) in patients without coronary atherosclerosis. The ROC analysis showed that the "standard" scales have no diagnostic significance for zero atherosclerosis (p > 0.05) or for >30% plaques (p > 0.05). Conclusion Our data shows a significant predictive superiority of CTA. Asymptomatic patients with zero or low coronary calcium with low estimated CVR may have a REAL high risk based on morphological plaque criteria.

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Cardiovascular benefit of lowering LDL-C below 1 mmol/L (40 mg/dl)

European Heart Journal ◽

10.1093/eurheartj/ehab724.2585 ◽

2021 ◽

Vol 42 (Supplement_1) ◽

Author(s):

N A Marston ◽

R P Giugliano ◽

J G Park ◽

A Ruzza ◽

P S Sever ◽

...

Keyword(s):

Statin Therapy ◽

Clinical Benefit ◽

Recurrent Events ◽

Pcsk9 Inhibitors ◽

National Budget ◽

Funding Sources ◽

Lower Baseline ◽

The Difference ◽

Public Grant

Abstract Background The 2019 ESC/EAS Dyslipidemia Guidelines recommend an LDL-C goal of <1.4 mmol/L (∼55 mg/dl) for patients with very high-risk ASCVD, and <1 mmol/L (∼40 mg/dl) for those with recurrent events within 2 years despite taking maximally tolerated statin therapy. The addition of PCSK9 inhibitors to statin therapy can achieve LDL-C levels well below 1 mmol/L in many patients, yet the clinical benefit of LDL-C lowering beyond this level has recently been questioned. Methods FOURIER was a cardiovascular outcomes trial comparing evolocumab vs. placebo in patients with stable ASCVD on optimized statin therapy with a median follow-up of 2.2 years. We performed an exploratory analysis to determine the consistency of CV risk reduction with LDL-C lowering below ∼1 mmol/L (40 mg/dl) with evolocumab. We modeled the achieved LDL-C at 48 weeks in the two treatment arms as well as the percentage of LDL-C difference between the two arms that was due to LDL-C below ∼1 mmol/L (40 mg/dl) as a function of baseline LDL-C. We then modeled the hazard ratio (HR) for the composite of CV death, MI or stroke (per 1 mmol/L reduction in LDL-C) with evolocumab vs. placebo as a function of baseline LDL-C. Results All 27,564 patients from FOURIER were included in this analysis. Patients with lower baseline LDL-C achieved lower LDL-C levels following evolocumab therapy, with achieved LDL-C typically being below 1 mmol/L (40 mg/dl) once the baseline LDL-C was below 2.4 mmol/L (94 mg/dl) and reaching levels approaching 0.5 mmol/L (∼20 mg/dl). Accordingly, the further baseline LDL-C levels were below 2.4 mmol/L (94 mg/dl), the greater the proportion of the difference in achieved LDL-C between the evolocumab and placebo arms was due to LDL-C levels below ∼1 mmol/L (40 mg/dl), reaching nearly 40% of the difference in LDL-C between treatment arms (Upper Panel). Despite this, the clinical benefit of LDL-C lowering was not attenuated (p=0.78) (and even appeared greater), with robust reductions in risk of CV death, MI or stroke even when LDL-C was lowered to nearly 0.5 mmol/L (∼20 mg/dl) and having close to 40% of the LDL-C difference between treatment arms due to LDL-C lowering below ∼1 mmol/L (40 mg/dl) (Lower Panel). Conclusion PCSK9 inhibitors added to statin therapy can achieve LDL-C well below 1 mmol/L (40 mg/dl). There is no evidence for attenuation of the clinical benefit of lowering LDL-C below this threshold. These data support lowering LDL-C to below 1 mmol/L (40 mg/dl) in patients with ASCVD. FUNDunding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): National Institute of Health

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Sex differences in cardiovascular research

European Heart Journal ◽

10.1093/eurheartj/ehab724.3167 ◽

2021 ◽

Vol 42 (Supplement_1) ◽

Author(s):

D N Millenaar ◽

M Dillmann ◽

T Fehlmann ◽

A Flohr ◽

R Mehran ◽

...

Keyword(s):

Senior Author ◽

Cardiovascular Research ◽

National Budget ◽

Female Authors ◽

Funding Sources ◽

Research Activities ◽

Average Impact ◽

Female Authorship ◽

Public Grant ◽

Number Of Citations

Abstract Background Women are underrepresented in cardiovascular publications. We sought to investigate sex-specific differences in cardiovascular research over the last decade. Methods and results All 387,463 cardiovascular publications between 2010–2019 were retrieved from Web-of-Science and analyzed regarding the authors' sex, the average impact factor (IF), the number of citations, co-authors per article, and international collaborations. The number of cardiovascular research articles increased between 2010–2019 from 19,960 to 29,604 articles per year. The number of articles written by female first authors increased by 48.3% (6434 articles in 2010 and 11,343 articles in 2019) and by 35.0% for male first authors (13,526 articles in 2010 and 18,261 articles in 2019). The last/senior author was more likely to be female in articles with female first authors compared with male first authors (28.2% vs. 14.1%; odds ratio 2.48, 95% confidence interval 2.43–2.53, p<0.001). The average IF for articles by female first authors was lower compared to male (3.1±3.8 vs. 3.5±4.9, p<0.001). Likewise, the H-Index was lower for female than male first authors (1.07±0.74 vs. 1.25±0.98, p<0.001), as was the number of citations per articles (14.0±31.1 vs. 18.0±68.8 citations, p<0.001). Female first authors had fewer co-authors per article than their male peers (7.4±19.6 vs. 8.2±35.2; p<0.001) and were less represented in articles with >15 co-authors (3,623 articles by female and 8,941 by male first authors; ratio female to male 0.41). Scientific advancement as the ratio between female to male first authorships was highest in publications from Latin America (ratio 0.92) and lowest in Asia (ratio 0.40). Female authorship articles reached the highest IF in North America (average IF 3.7), the lowest Africa (average IF 1.8). Conclusions Publications in cardiovascular research have increased over the last decade, particularly by female authors. Female researchers are cited less often compared with their male peers and publish with fewer co-authors. The IF remains lower for articles by female researchers. Efforts to further increase women-led research activities are needed FUNDunding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): German Cardiac SocietyGerman Research Foundation (DFG)

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A slowly inactivating sodium current contributes to spontaneous diastolic depolarization of atrial myocytes

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00444.2009 ◽

2009 ◽

Vol 297 (4) ◽

pp. H1254-H1262 ◽

Cited By ~ 33

Author(s):

Yejia Song ◽

John C. Shryock ◽

Luiz Belardinelli

Keyword(s):

Sodium Current ◽

Slow Inward Current ◽

Resting Membrane Potential ◽

Atrial Myocytes ◽

Patch Clamp Technique ◽

Whole Cell Patch Clamp ◽

Diastolic Depolarization ◽

Ramp Voltage ◽

Spontaneous Action ◽

In Cells

Diastolic depolarization (DD) of atrial myocytes can lead to spontaneous action potentials (APs) and, potentially, atrial tachyarrhythmias. This study examined the hypotheses that 1) a slowly inactivating component of the Na+ current (referred to as late INa) may contribute to DD and initiate AP firing and that 2) blocking late INa will reduce spontaneous and induced firing of APs by atrial myocytes. Guinea pig atrial myocytes without or with DD and spontaneous AP firing were studied using the whole cell patch-clamp technique. In experiments using cells with a stable resting membrane potential (no spontaneous DD or firing), hydrogen peroxide (H2O2, 50 μmol/l) caused DD and AP firing. The H2O2-induced activity was suppressed by the late INa inhibitors tetrodotoxin (TTX, 1 μmol/l) and ranolazine (5 μmol/l). In cells with DD but no spontaneous APs, the late INa enhancer anemone toxin II (ATX-II, 10 nmol/l) accelerated DD and induced APs. In cells with DD and spontaneous AP firing, TTX and ranolazine (both, 1 μmol/l) significantly reduced the slope of DD by 81 ± 12% and 75 ± 11% and the frequency of spontaneous firing by 70 ± 15% and 74 ± 9%, respectively. Ramp voltage-clamp simulating DD elicited a slow inward current. TTX at 1, 3, and 10 μmol/l inhibited this current by 41 ± 4%, 73 ± 2%, and 91 ± 1%, respectively, suggesting that a slowly inactivating INa underlies the DD. ATX-II and H2O2 increased the amplitude of this current, and the effects of ATX-II and H2O2 were attenuated by ranolazine or TTX. In conclusion, late INa can contribute to the DD of atrial myocytes and the inhibition of this current suppresses atrial DD and spontaneous APs.

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Impact of pregnancy and risk factors for ventricular arrhythmias in women operated for tetralogy of Fallot

European Heart Journal - Cardiovascular Imaging ◽

10.1093/ehjci/jeaa356.402 ◽

2021 ◽

Vol 22 (Supplement_1) ◽

Author(s):

A Quattrone ◽

ØH Lie ◽

E Nestaas ◽

C De Lange ◽

K Try ◽

...

Keyword(s):

Tetralogy Of Fallot ◽

Ventricular Arrhythmias ◽

Holter Monitoring ◽

National Database ◽

High Survival ◽

National Budget ◽

Funding Sources ◽

Mechanical Dispersion ◽

Preconception Counselling ◽

Public Grant

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): South-Eastern Norway Regional Health Authority Background Patients with tetralogy of Fallot (TOF) have a high survival rate 30 years after surgical repair, and generally enjoy a satisfactory quality of life. Many female patients experience pregnancy during adulthood, however the effects of pregnancy on the long-term cardiovascular outcome in this group of patients are not well known. Purpose We aimed to investigate the association of pregnancy and cardiac function with occurrence of ventricular arrhythmia (VA) in women operated for TOF. Methods We included 80 patients recruited from the national database for patients diagnosed for TOF. All were examined with echocardiography, including strain echocardiography. We assessed mechanical dispersion of right ventricle (RV) as measure of heterogeneous contraction. Holter monitoring or implanted devices detected ventricular arrhythmias (VA), defined as non-sustained or sustained ventricular tachycardia or aborted cardiac arrest. Blood tests included N-terminal pro-brain natriuretic peptide (NT-proBNP). Results In all, 55 (69%) women had experienced pregnancy (age 40 ± 9 years, parity median 1, range 1-4), while 25 (31%) women were nulliparous. The mean age was lower in nulliparous compared to those with children (30 ± 9 vs 40 ± 9, p < 0.01). VA was more prevalent in women who had experienced pregnancy (n = 16, 94%) compared to nulliparous (n = 1, 6%) (p = 0.02), and importantly also when adjusted for age [adjusted OR 9.8 (95% CI 1.2-79.1), p = 0.02]. RV mechanical dispersion was more pronounced in patients with VA [39.2 ± 14 ms vs. 49.6 ± 8 ms, p = 0.009, adjusted OR 2.1 (95% CI 1.3 - 7.5), p = 0.01 adjusted for age]. Higher NT-proBNP was also a marker of VA [211 ng/L (127-836) vs. 139 ng/L (30-465), p = 0.007, adjusted OR 1.4 (95% CI 1.1 - 1.8) p = 0.017 adjusted for age]. NT-proBNP >182 ng/L (normal values < 170 ng/L) optimally detected women with VA (p = 0.019), also independent of age [OR 7.2 (95% CI 1.7-30.1), p = 0.007]. Conclusion History of pregnancy was associated with higher prevalence of VA among women with surgically corrected TOF. Right ventricular mechanical dispersion and NT-proBNP were age independent markers of VA. These findings may have importance for risk stratification and preconception counselling of these patients.

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miR-190a-5p Partially Represses the Abnormal Electrical Activity of SCN3B in Cardiac Arrhythmias by Downregulation of IL-2

Frontiers in Cardiovascular Medicine ◽

10.3389/fcvm.2021.795675 ◽

2022 ◽

Vol 8 ◽

Author(s):

Qianqian Li ◽

Ziguan Zhang ◽

Shanshan Chen ◽

Zhengrong Huang ◽

Mengru Wang ◽

...

Keyword(s):

Cardiac Arrhythmias ◽

Protective Factor ◽

Sodium Current ◽

Interleukin 2 ◽

Pathological Process ◽

Cardiac Conduction ◽

Luciferase Reporter ◽

Cardiac Tissues ◽

Whole Cell Patch Clamp ◽

Gated Channel

Cardiac arrhythmias (CAs) are generally caused by disruption of the cardiac conduction system; interleukin-2 (IL-2) is a key player in the pathological process of CAs. This study aimed to investigate the molecular mechanism underlying the regulation of IL-2 and the sodium channel current of sodium voltage-gated channel beta subunit 3 (SCN3B) by miR-190a-5p in the progression of CAs. ELISA results suggested the concentration of peripheral blood serum IL-2 in patients with atrial fibrillation (AF) to be increased compared to that in normal controls; fluorescence in situ hybridization indicated that the expression of IL-2 in the cardiac tissues of patients with AF to be upregulated and that miR-190a-5p to be downregulated. Luciferase reporter assay, quantitative real-time-PCR, and whole-cell patch-clamp experiments confirmed the downregulation of IL-2 by miR-190a-5p and influence of the latter on the sodium current of SCN3B. Overall, miR-190a-5p suppressed the increase in SCN3B sodium current caused by endogenous IL-2, whereas miR-190a-5p inhibitor significantly reversed this effect. IL-2 was demonstrated to be directly regulated by miR-190a-5p. We, therefore, concluded that the miR-190a-5p/IL-2/SCN3B pathway could be involved in the pathogenesis of CAs and miR-190a-5p might acts as a potential protective factor in pathogenesis of CAs.

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Keeping the plates spinning: a qualitative study of the multifaceted role of caregiving in HFpEF

European Journal of Cardiovascular Nursing ◽

10.1093/eurjcn/zvab060.042 ◽

2021 ◽

Vol 20 (Supplement_1) ◽

Author(s):

CR Pearson ◽

E Khair ◽

F Forsyth ◽

E Sowden ◽

C Deaton

Keyword(s):

Heart Failure ◽

Qualitative Study ◽

Informal Caregivers ◽

Healthcare Providers ◽

Support Network ◽

Structured Interviews ◽

National Budget ◽

Funding Sources ◽

Public Grant ◽

Caregiver Role

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): National Institutes of Health Research School for Primary Care Research OnBehalf Optimise HFpEF Background Heart failure with preserved ejection fraction (HFpEF) accounts for 50% of all heart failure cases yet remains poorly understood, diagnosed and managed, which can add complexity to the caregiver role. No study to date has explicitly investigated the experiences of informal caregivers of people with HFpEF. Objective The aim of this study was to explore and understand the role and experiences of informal caregivers of people with HFpEF. Methods and design A qualitative study using semi-structured interviews involving caregivers alone, patients alone or caregiver/patient dyads. The interviews were performed as part of a larger programme of research in HFpEF. Participants were recruited from three regions of England. Interviews were transcribed verbatim and analysed thematically. Results 22 interviews were conducted with a total of 38 participants, 17 of which were informal caregivers. Three inter-related themes were identified: (1) ‘spinning plates’ - the multifaceted nature of informal caregiving: household manager, health manager and motivator; (2) ‘the spinning falters’- the barriers to caregiving: lack of HFpEF awareness, information and support, the burden of multimorbidity, caregiver stress and the caregiver’s health status; (3) ‘keeping the plates spinning’- the facilitators of caregiving: being informed, being appreciated, having a champion (a health care professional that is key to managing the patient’s HFpEF), and engaging a wider support network. Conclusions Informal caregivers play an important role in supporting people with HFpEF. The experience of caregiving to people with HFpEF is similar to HFrEF, but complicated by challenges of poor HFpEF information and support, and the burden of multimorbidity. Healthcare providers should assess the needs of informal caregivers as part of patient care in HFpEF. Caregivers and patients would both benefit from improved information and management of HFpEF and associated multi-morbidities. Helping caregivers ‘keep the plates spinning’ will require innovative approaches and coordination across the care continuum.

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