Noninvasive unipolar electrogram T-wave upslope is an accurate marker of local refractoriness in explanted hearts with drug-induced repolarization dispersion

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): French National Research Agency Matthijs Cluitmans is supported by a Veni grant from the Netherlands Organization for Scientific Research Background The relationship between T-wave morphology in local unipolar electrograms (UEGs) as mapped with noninvasive electrocardiographic imaging (ECGI) and local repolarization time (RT) has not been validated in pronounced RT dispersion. Purpose To study the time of upslope of the T-wave (Tup) in epicardial UEGs mapped with ECGI as a marker of time of local refractoriness (trefr, a surrogate for RT) in intact hearts with RT dispersion. Methods Six pig hearts were Langendorff-perfused with selective perfusion of the LAD artery and submersed in a torso-shaped tank containing 256 electrodes on the torso surface (panel A). RT was prolonged in the non-LAD regions by infusing dofetilide (‘Dof’) and shortened in the LAD region using pinacidil (‘Pin’). Tup was determined in both invasive UEGs (recorded with epicardial electrodes) and in noninvasive UEGs (reconstructed with ECGI). Programmed stimulation was used to determine trefr, defined as the shortest coupling interval with capture. Both metrics were determined relative to the common pacing spike. Results In all six hearts, selective dofetilide and pinacidil infusion resulted in delayed trefr and Tup in the non-LAD region, and shortened invasive trefr and noninvasive Tup in the LAD region, respectively (panel B and C). Over all 59 observations, Tup showed high agreement with trefr (values close to line of identity, panel D) with strong correlation (r = 0.91). This finding was independent of T-wave polarity (positive, negative or biphasic). Conclusion The moment of steepest upslope of the T-wave in a noninvasively reconstructed UEG accurately reflects end of local refractoriness in intact hearts, in case of pronounced RT dispersion. Under these circumstances, when local RT is defined by moment of re-excitability (allowing to link it to conduction block and re-entry), ECGI T-wave upslope can be taken as a truthful marker for local RT. Abstract Figure. Results

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An explainable algorithm for detecting drug-induced QT-prolongation at risk of torsades de pointes (TdP) regardless of heart rate and T-wave morphology

Computers in Biology and Medicine ◽

10.1016/j.compbiomed.2021.104281 ◽

2021 ◽

Vol 131 ◽

pp. 104281

Author(s):

Alaa Alahmadi ◽

Alan Davies ◽

Jennifer Royle ◽

Leanna Goodwin ◽

Katharine Cresswell ◽

...

Keyword(s):

At Risk ◽

Heart Rate ◽

Torsades De Pointes ◽

Qt Prolongation ◽

Drug Induced ◽

T Wave ◽

Wave Morphology

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Sensitivity of QTc and T-wave morphology to small drug-induced electrocardiographic changes

Journal of Electrocardiology ◽

10.1016/j.jelectrocard.2008.08.026 ◽

2008 ◽

Vol 41 (6) ◽

pp. 644

Author(s):

C. Graff ◽

J. Matz ◽

M.P. Andersen ◽

J.K. Kanters ◽

E. Toft ◽

...

Keyword(s):

Drug Induced ◽

T Wave ◽

Wave Morphology ◽

Electrocardiographic Changes

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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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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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A novel trigger-substrate mechanism based on clinically concealed repolarization abnormalities underlies idiopathic ventricular fibrillation

European Heart Journal ◽

10.1093/ehjci/ehaa946.3684 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

M Cluitmans ◽

L Bear ◽

U Nguyen ◽

B Van Rees ◽

J Stoks ◽

...

Keyword(s):

Ventricular Fibrillation ◽

Sudden Cardiac Arrest ◽

Funding Source ◽

Drug Infusion ◽

National Budget ◽

Coupling Interval ◽

Temporal Coupling ◽

Structural Disease ◽

Public Grant ◽

Repolarization Abnormalities

Abstract Background Sudden cardiac arrest (SCA) is most often due to ventricular fibrillation (VF). When no cause is found during diagnostic follow-up, fibrillation is classified as idiopathic (iVF). We hypothesize that a critical functional substrate-trigger interaction underlies iVF. Purpose To study electrophysiological triggers and substrate for iVF in a clinical cohort; and seek mechanistic explanations in explanted pig hearts and computer models mimicking trigger-substrate interactions. Methods Repolarization time (RT) isochrones on the epicardium were studied with electrocardiographic imaging (ECGI) in patients with iVF, patients with frequent monomorphic premature ventricular complexes (fmPVC) but no structural disease or SCA, and controls without cardiovascular disease. RT gradients were created in explanted, Langendorff-perfused pig hearts by local infusion of dofetilide (“dof”, 250 nM, delaying RT) and pinacidil (“pin”, 30 μM, shortening RT) in adjacent regions of the heart. Arrhythmia inducibility was tested by programmed stimulation (8 atrial stimuli [S1] followed by one ventricular stimulus [S2] paced at regions of early or late RT). A computational ventricular monodomain model was used to study the location-dependency of trigger-substrate interaction; RT gradients were created by local changes in potassium channel conductance. Results Although QTc values were similar, iVF survivors (n=11) displayed significantly steeper RT gradients than controls (n=10) or fmPVC individuals (n=7): 269±111 vs 179±40 vs 171±76 ms/cm respectively (panel A). Unipolar electrograms (EGMs) at the gradients displayed a change in polarity of the local T wave (B). In iVF, PVCs originated more often from regions with early RT than in fmPVC individuals (yellow circles in A; 64% vs 14%). In the explanted hearts (C), drug infusion resulted in similar RT gradients and polarity changes of EGM T waves (D-E). VF inducibility by pacing of the early RT region (D) increased significantly with steeper RT gradients (baseline: 3/6 hearts inducible, dof+pin: 3/3). Pacing of late RT regions (E) did not induce arrhythmias in baseline (0/6) nor with RT gradients (0/3). For similar pacing intervals at the early RT region, the 12-lead ECG R-on-T morphology was similar but VF only occurred in the presence of RT gradients (F). In the computer model, the number of inducible pacing intervals critically depended on the stimulus location (G). Conclusion Combined, these results demonstrate that R-on-T superposition per se is insufficient to explain arrhythmogenesis. Rather, not only the temporal coupling interval but also the spatial origin of PVCs in relationship to the degree of local repolarization abnormalities are critical elements. In iVF, a substrate of RT gradients (panel H1) with triggers from early RT regions (H2) precipitate reentry (H3). Noninvasive ECGI can uncover these substrate and trigger characteristics in (at least a subset of) iVF survivors. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Netherlands Organization for Scientific Research Veni grant TTW 16772, French National Research Agency (ANR-10-IAHU04-LIRYC)

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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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