Pub Date : 2024-09-27DOI: 10.1152/ajpheart.00705.2023
Anastasia Adella, Faris Tengku, Francisco J Arjona, Sanne Broekman, Erik de Vrieze, Erwin van Wijk, Joost G J Hoenderop, Jeroen H F de Baaij
The Ras-related GTP-binding protein D (RRAGD) gene plays a crucial role in cellular processes. Recently, RRAGD variants found in patients have been implicated in a novel disorder with kidney tubulopathy and dilated cardiomyopathy. Currently, the consequences of RRAGD variants at organismal level is unknown. Therefore, this study investigated the impact of RRAGD variants on cardiac function using zebrafish embryo model. Furthermore, the potential usage of rapamycin, an mTOR inhibitor, as a therapy was assessed in this model. Zebrafish embryos were injected with RRAGD p.S76L and p.P119R cRNA and the resulting heart phenotypes were studied. Our findings reveal that overexpression of RRAGD mutants resulted in decreased ventricular fractional shortening, ejection fraction, and pericardial swelling. In RRAGD S76L-injected embryos, lower survival and heartbeat were observed, while survival was unaffected in RRAGD P119R embryos. These observations were reversible following therapy with the mTOR inhibitor rapamycin. Moreover, no effects on electrolyte homeostasis were observed. Together, these findings indicate a crucial role of RRAGD for cardiac function. In the future, the molecular mechanisms by which RRAGD variants result in cardiac dysfunction, and if the effects of rapamycin are specific for RRAGD-dependent cardiomyopathy should be studied in clinical studies.
{"title":"<i>RRAGD</i> variants cause cardiac dysfunction in a zebrafish model.","authors":"Anastasia Adella, Faris Tengku, Francisco J Arjona, Sanne Broekman, Erik de Vrieze, Erwin van Wijk, Joost G J Hoenderop, Jeroen H F de Baaij","doi":"10.1152/ajpheart.00705.2023","DOIUrl":"https://doi.org/10.1152/ajpheart.00705.2023","url":null,"abstract":"<p><p>The Ras-related GTP-binding protein D (<i>RRAGD</i>) gene plays a crucial role in cellular processes. Recently, <i>RRAGD</i> variants found in patients have been implicated in a novel disorder with kidney tubulopathy and dilated cardiomyopathy. Currently, the consequences of <i>RRAGD</i> variants at organismal level is unknown. Therefore, this study investigated the impact of <i>RRAGD</i> variants on cardiac function using zebrafish embryo model. Furthermore, the potential usage of rapamycin, an mTOR inhibitor, as a therapy was assessed in this model. Zebrafish embryos were injected with <i>RRAGD</i> p.S76L and p.P119R cRNA and the resulting heart phenotypes were studied. Our findings reveal that overexpression of <i>RRAGD</i> mutants resulted in decreased ventricular fractional shortening, ejection fraction, and pericardial swelling. In <i>RRAGD</i> S76L-injected embryos, lower survival and heartbeat were observed, while survival was unaffected in <i>RRAGD</i> P119R embryos. These observations were reversible following therapy with the mTOR inhibitor rapamycin. Moreover, no effects on electrolyte homeostasis were observed. Together, these findings indicate a crucial role of <i>RRAGD</i> for cardiac function. In the future, the molecular mechanisms by which <i>RRAGD</i> variants result in cardiac dysfunction, and if the effects of rapamycin are specific for <i>RRAGD</i>-dependent cardiomyopathy should be studied in clinical studies.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142339445","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-27DOI: 10.1152/ajpheart.00660.2024
Carmen De Miguel
{"title":"Constipation as a new non-traditional significant contributor to cardiovascular disease.","authors":"Carmen De Miguel","doi":"10.1152/ajpheart.00660.2024","DOIUrl":"https://doi.org/10.1152/ajpheart.00660.2024","url":null,"abstract":"","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142339446","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-20DOI: 10.1152/ajpheart.00624.2024
Vincenzo Lionetti, Fabio A Recchia
{"title":"Sexual dimorphism of psychological stress-induced susceptibility to ischemic heart disease: is the king naked?","authors":"Vincenzo Lionetti, Fabio A Recchia","doi":"10.1152/ajpheart.00624.2024","DOIUrl":"https://doi.org/10.1152/ajpheart.00624.2024","url":null,"abstract":"","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142279130","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-20DOI: 10.1152/ajpheart.00536.2024
Maria Knierim, Thea Bommer, Michael Paulus, Dominic Riedl, Sarah Fink, Arnold Pöppl, Florian Reetz, Peter Wang, Lars Maier, Niels Voigt, Matthias Nahrendorf, Samuel Sossalla, Katrin Streckfuss-Bömeke, Steffen Pabel
Electric pacing of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) has been increasingly used to simulate cardiac arrhythmias in vitro and to enhance cardiomyocyte maturity. However, the impact of electric pacing on cellular electrophysiology and Ca2+-handling in differentiated hiPSC-CM is less characterized. Here we studied the effects of electric pacing for 24h or 7d at a physiological rate of 60 bpm on cellular electrophysiology and Ca2+-cycling in late-stage, differentiated hiPSC-CM (>90% troponin+, >60d post differentiation). Electric culture pacing for 7d did not influence cardiomyocyte cell size, apoptosis or generation of reactive oxygen species in differentiated hiPSC-CM compared to 24h pacing. However, epifluorescence measurements revealed that electric pacing for 7d improved systolic Ca2+-transient amplitude and Ca2+-transient upstroke, which could be explained by elevated sarcoplasmic reticulum Ca2+-load and SERCA activity. Diastolic Ca2+-leak was not changed in line-scanning confocal microscopy suggesting that the improvement in systolic Ca2+-release was not associated with a higher open probability of RyR2 during diastole. While bulk cytosolic Na+-concentration and NCX activity were not changed, patch-clamp studies revealed that chronic pacing caused a slight abbreviation of the action potential duration (APD) in hiPSC-CM. We found in whole-cell voltage-clamp measurements that chronic pacing for 7d led to a decrease in late Na+-current, which might explain the changes in APD. In conclusion, our results show that chronic pacing improves systolic Ca2+-handling and modulates the electrophysiology of late-stage, differentiated iPSC-CM. This study might help to understand the effects of electric pacing and its numerous applications in stem cell research including arrhythmia simulation.
{"title":"Cellular calcium handling and electrophysiology are modulated by chronic physiological pacing in human induced pluripotent stem cell-derived cardiomyocytes.","authors":"Maria Knierim, Thea Bommer, Michael Paulus, Dominic Riedl, Sarah Fink, Arnold Pöppl, Florian Reetz, Peter Wang, Lars Maier, Niels Voigt, Matthias Nahrendorf, Samuel Sossalla, Katrin Streckfuss-Bömeke, Steffen Pabel","doi":"10.1152/ajpheart.00536.2024","DOIUrl":"https://doi.org/10.1152/ajpheart.00536.2024","url":null,"abstract":"<p><p>Electric pacing of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) has been increasingly used to simulate cardiac arrhythmias in vitro and to enhance cardiomyocyte maturity. However, the impact of electric pacing on cellular electrophysiology and Ca<sup>2+</sup>-handling in differentiated hiPSC-CM is less characterized. Here we studied the effects of electric pacing for 24h or 7d at a physiological rate of 60 bpm on cellular electrophysiology and Ca<sup>2+</sup>-cycling in late-stage, differentiated hiPSC-CM (>90% troponin<sup>+</sup>, >60d post differentiation). Electric culture pacing for 7d did not influence cardiomyocyte cell size, apoptosis or generation of reactive oxygen species in differentiated hiPSC-CM compared to 24h pacing. However, epifluorescence measurements revealed that electric pacing for 7d improved systolic Ca<sup>2+</sup>-transient amplitude and Ca<sup>2+</sup>-transient upstroke, which could be explained by elevated sarcoplasmic reticulum Ca<sup>2+</sup>-load and SERCA activity. Diastolic Ca<sup>2+</sup>-leak was not changed in line-scanning confocal microscopy suggesting that the improvement in systolic Ca<sup>2+</sup>-release was not associated with a higher open probability of RyR2 during diastole. While bulk cytosolic Na<sup>+</sup>-concentration and NCX activity were not changed, patch-clamp studies revealed that chronic pacing caused a slight abbreviation of the action potential duration (APD) in hiPSC-CM. We found in whole-cell voltage-clamp measurements that chronic pacing for 7d led to a decrease in late Na<sup>+</sup>-current, which might explain the changes in APD. In conclusion, our results show that chronic pacing improves systolic Ca<sup>2+</sup>-handling and modulates the electrophysiology of late-stage, differentiated iPSC-CM. This study might help to understand the effects of electric pacing and its numerous applications in stem cell research including arrhythmia simulation.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142279127","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-20DOI: 10.1152/ajpheart.00648.2024
Marie Billaud, Julie Phillippi
{"title":"Only the strong (aorta) survives: The female edge in a mouse model of severe Marfan syndrome.","authors":"Marie Billaud, Julie Phillippi","doi":"10.1152/ajpheart.00648.2024","DOIUrl":"https://doi.org/10.1152/ajpheart.00648.2024","url":null,"abstract":"","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142279129","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-06DOI: 10.1152/ajpheart.00481.2024
Marius Reto Bigler, Andrea Kieninger-Gräfitsch, Miklos Rohla, Noé Corpataux, Frédéric Waldmann, Reto Wildhaber, Jonas Häner, Christian Seiler
Background-Fractional flow reserve (FFR) measurements are recommended for assessing hemodynamic coronary stenosis severity. Intracoronary ECG (icECG) is easily obtainable and highly sensitive in detecting myocardial ischemia due to its close vicinity to the myocardium. We hypothesized that the remission time of myocardial ischemia on icECG after a controlled coronary occlusion accurately detects hemodynamically relevant coronary stenosis. Methods-This retrospective, observational study included patients with chronic coronary syndrome undergoing hemodynamic coronary stenosis assessment immediately following a strictly 1-minute proximal coronary artery balloon occlusion with simultaneous icECG recording. IcECG was used for a beat-to-beat analysis of the ST-segment shift during reactive hyperemia immediately following balloon deflation. The time from coronary balloon deflation until the ST-segment shift reached 37% of its maximum level, i.e., icECG ST-segment shift remission time(τ-icECG in seconds,s) was obtained by an automatic algorithm. τ-icECG was tested against the simultaneously obtained reactive hyperemia FFR at a threshold of 0.80 as reference parameter. Results-One hundred and thirty-nine icECGs from 120 patients (age 68±10 years) were analysed. Receiver operating characteristic (ROC) analysis of τ-icECG for the detection of hemodynamically relevant coronary stenosis at an FFR of ≤0.80 was performed. The area under the ROC curve was equal to 0.621(p=0.0363) at an optimal τ-icECG threshold of 8s(sensitivity 61%, specificity 67%). τ-icECG correlated inversely and linearly with FFR(p=0.0327). Conclusion-This first proof-of-concept study demonstrates that τ-icECG, a measure of icECG ST segment-shift remission after a 1-minute coronary artery balloon occlusion accurately detects hemodynamically relevant coronary artery stenosis according to FFR at a threshold of ≥8seconds.
{"title":"Intracoronary ECG ST-Segment Shift Remission Time During Reactive Myocardial Hyperemia (Τ-icECG): A New Method to Assess Hemodynamic Coronary Stenosis Severity.","authors":"Marius Reto Bigler, Andrea Kieninger-Gräfitsch, Miklos Rohla, Noé Corpataux, Frédéric Waldmann, Reto Wildhaber, Jonas Häner, Christian Seiler","doi":"10.1152/ajpheart.00481.2024","DOIUrl":"https://doi.org/10.1152/ajpheart.00481.2024","url":null,"abstract":"<p><p>Background-Fractional flow reserve (FFR) measurements are recommended for assessing hemodynamic coronary stenosis severity. Intracoronary ECG (icECG) is easily obtainable and highly sensitive in detecting myocardial ischemia due to its close vicinity to the myocardium. We hypothesized that the remission time of myocardial ischemia on icECG after a controlled coronary occlusion accurately detects hemodynamically relevant coronary stenosis. Methods-This retrospective, observational study included patients with chronic coronary syndrome undergoing hemodynamic coronary stenosis assessment immediately following a strictly 1-minute proximal coronary artery balloon occlusion with simultaneous icECG recording. IcECG was used for a beat-to-beat analysis of the ST-segment shift during reactive hyperemia immediately following balloon deflation. The time from coronary balloon deflation until the ST-segment shift reached 37% of its maximum level, i.e., icECG ST-segment shift remission time(<i>τ</i>-icECG in seconds,s) was obtained by an automatic algorithm. <i>τ</i>-icECG was tested against the simultaneously obtained reactive hyperemia FFR at a threshold of 0.80 as reference parameter. Results-One hundred and thirty-nine icECGs from 120 patients (age 68±10 years) were analysed. Receiver operating characteristic (ROC) analysis of <i>τ</i>-icECG for the detection of hemodynamically relevant coronary stenosis at an FFR of ≤0.80 was performed. The area under the ROC curve was equal to 0.621(p=0.0363) at an optimal <i>τ</i>-icECG threshold of 8s(sensitivity 61%, specificity 67%). <i>τ</i>-icECG correlated inversely and linearly with FFR(p=0.0327). Conclusion-This first proof-of-concept study demonstrates that τ-icECG, a measure of icECG ST segment-shift remission after a 1-minute coronary artery balloon occlusion accurately detects hemodynamically relevant coronary artery stenosis according to FFR at a threshold of ≥8seconds.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142139042","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-06DOI: 10.1152/ajpheart.00551.2023
Stephanie L Samani, Shayne C Barlow, Lisa A Freeburg, Grayson M Catherwood, Amelia M Churillo, Traci L Jones, Diego Altomare, Hao Ji, Michael Shtutman, Michael R Zile, Tarek Shazly, Francis G Spinale
Background: Left ventricular pressure overload (LVPO) can lead to heart failure with a preserved ejection fraction (HFpEF) and LV chamber stiffness (LV Kc) is a hallmark. This project tested the hypothesis that the development of HFpEF due to an LVPO stimulus, will alter post-transcriptional regulation, specifically microRNAs (miRs). Methods: LVPO was induced in pigs (n=9) by sequential ascending aortic cuff and age and weight matched pigs (n=6) served as controls. LV function was measured by echocardiography and LV Kc by speckle tracking. LV myocardial miRs were quantified using an 84 miR array. Treadmill testing and natriuretic peptide-A (NPPA) mRNA levels in controls and LVPO were performed (n=10, n=9, respectively). LV samples from LVPO and controls (n=6, respectively) were subjected to RNA sequencing. Results: LV mass and Kc increased by over 40% with LVPO (p<0.05). A total of 30 miRs shifted with LVPO of which 11 miRs correlated to LV Kc (p<0.05) which mapped to functional domains relevant to Kc such as fibrosis and calcium handling. LVPO resulted in reduced exercise tolerance (oxygen saturation, respiratory effort) and NPPA mRNA levels increased by 4-fold (p<0.05). RNA analysis identified several genes which mapped to specific miRs that were altered with LVPO. Conclusion: A specific set of miRs are changed in a large animal model consistent with the HFpEF phenotype, were related to LV stiffness properties and several miRs mapped to molecular pathways which may hold relevance in terms of prognosis and therapeutic targets.
{"title":"Heart failure with preserved ejection fraction in pigs causes shifts in post-transcriptional checkpoints.","authors":"Stephanie L Samani, Shayne C Barlow, Lisa A Freeburg, Grayson M Catherwood, Amelia M Churillo, Traci L Jones, Diego Altomare, Hao Ji, Michael Shtutman, Michael R Zile, Tarek Shazly, Francis G Spinale","doi":"10.1152/ajpheart.00551.2023","DOIUrl":"https://doi.org/10.1152/ajpheart.00551.2023","url":null,"abstract":"<p><p><i>Background:</i> Left ventricular pressure overload (LVPO) can lead to heart failure with a preserved ejection fraction (HFpEF) and LV chamber stiffness (LV Kc) is a hallmark. This project tested the hypothesis that the development of HFpEF due to an LVPO stimulus, will alter post-transcriptional regulation, specifically microRNAs (miRs). <i>Methods:</i> LVPO was induced in pigs (n=9) by sequential ascending aortic cuff and age and weight matched pigs (n=6) served as controls. LV function was measured by echocardiography and LV Kc by speckle tracking. LV myocardial miRs were quantified using an 84 miR array. Treadmill testing and natriuretic peptide-A (NPPA) mRNA levels in controls and LVPO were performed (n=10, n=9, respectively). LV samples from LVPO and controls (n=6, respectively) were subjected to RNA sequencing. <i>Results:</i> LV mass and Kc increased by over 40% with LVPO (p<0.05). A total of 30 miRs shifted with LVPO of which 11 miRs correlated to LV Kc (p<0.05) which mapped to functional domains relevant to Kc such as fibrosis and calcium handling. LVPO resulted in reduced exercise tolerance (oxygen saturation, respiratory effort) and NPPA mRNA levels increased by 4-fold (p<0.05). RNA analysis identified several genes which mapped to specific miRs that were altered with LVPO. Conclusion: A specific set of miRs are changed in a large animal model consistent with the HFpEF phenotype, were related to LV stiffness properties and several miRs mapped to molecular pathways which may hold relevance in terms of prognosis and therapeutic targets.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142139041","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Mitochondrial dysfunction contributes significantly to the development of atrial fibrillation (AF). Conflicting data regarding the atrial pacing and the risk of AF existed and the impact of atrial pacing on mitochondrial function remains unknown. Therefore, we sought to examine the association between atrial pacing percentage and mitochondrial function in patients with cardiovascular implantable electronic devices (CIED) with atrial pacing capability. This is a cross-sectional study involving 183 patients with CIED with atrial pacing capability. The oxidative stress and mitochondrial function were determined in peripheral blood mononuclear cells (PBMCs). Among 183 patients, 55.7% had permanent pacemakers, 7.7% had defibrillators and 36.6% had cardiac resynchronization therapy. Mean age was 67.5±14.7 years with 51% being male. Mean left ventricular ejection fraction (LVEF) was 53.9 ± 16.8%. We demonstrated that the presence of atrial pacing above 50% correlated with higher levels of mitochondrial spared respiratory capacity (P=0.043) and coupling efficiency (P=0.045). After adjusting with multiple linear regression for age, sex, LVEF, history of AF, sick sinus syndrome, co-morbidities, eGFR, CRT, and percentage of ventricular pacing, our findings revealed a statistically significant association between a higher percentage of atrial pacing and increased spared respiratory capacity (β 0.217, P=0.046), lower non-mitochondrial respiration (β -0.230, P=0.023) and proton leak (β -0.247, P=0.022). We demonstrated that atrial pacing enhances mitochondrial performance in PBMCs and left ventricular contractile performance in patients with CIED. This observation may serve as additional support for the preventive effect of atrial pacing in the prevention of atrial arrhythmia.
{"title":"Atrial Pacing Improves Mitochondrial Function in Peripheral Blood Mononuclear Cells in Patients with Cardiac Implantable Electronic Devices.","authors":"Teerapat Nantsupawat, Pawut Gumrai, Nattayaporn Apaijai, Arintaya Prommintikul, Narawudt Prasertwitayakij, Siriporn C Chattipakorn, Nipon Chattipakorn, Wanwarang Wongcharoen","doi":"10.1152/ajpheart.00537.2024","DOIUrl":"https://doi.org/10.1152/ajpheart.00537.2024","url":null,"abstract":"<p><p>Mitochondrial dysfunction contributes significantly to the development of atrial fibrillation (AF). Conflicting data regarding the atrial pacing and the risk of AF existed and the impact of atrial pacing on mitochondrial function remains unknown. Therefore, we sought to examine the association between atrial pacing percentage and mitochondrial function in patients with cardiovascular implantable electronic devices (CIED) with atrial pacing capability. This is a cross-sectional study involving 183 patients with CIED with atrial pacing capability. The oxidative stress and mitochondrial function were determined in peripheral blood mononuclear cells (PBMCs). Among 183 patients, 55.7% had permanent pacemakers, 7.7% had defibrillators and 36.6% had cardiac resynchronization therapy. Mean age was 67.5±14.7 years with 51% being male. Mean left ventricular ejection fraction (LVEF) was 53.9 ± 16.8%. We demonstrated that the presence of atrial pacing above 50% correlated with higher levels of mitochondrial spared respiratory capacity (P=0.043) and coupling efficiency (P=0.045). After adjusting with multiple linear regression for age, sex, LVEF, history of AF, sick sinus syndrome, co-morbidities, eGFR, CRT, and percentage of ventricular pacing, our findings revealed a statistically significant association between a higher percentage of atrial pacing and increased spared respiratory capacity (β 0.217, P=0.046), lower non-mitochondrial respiration (β -0.230, P=0.023) and proton leak (β -0.247, P=0.022). We demonstrated that atrial pacing enhances mitochondrial performance in PBMCs and left ventricular contractile performance in patients with CIED. This observation may serve as additional support for the preventive effect of atrial pacing in the prevention of atrial arrhythmia.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142139039","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-01Epub Date: 2024-07-19DOI: 10.1152/ajpheart.00425.2024
Luisa Wirth, Elias Erny, Markus Krane, Harald Lahm, Lutz Hein, Ralf Gilsbach, Achim Lother
Chronic heart failure is associated with adverse remodeling of the heart that is typically characterized by cardiomyocyte hypertrophy. This requires the formation of new capillaries to maintain oxygen supply. Insufficient angiogenesis promotes the transition from compensated hypertrophy into heart failure. The aim of this study was to identify angiogenesis-related gene networks and corresponding regulatory hubs in endothelial cells from failing human hearts. We isolated left ventricular endothelial cells from patients with advanced heart failure undergoing left ventricular assist device surgery (n = 15) and healthy organ donors (n = 2) and performed RNA sequencing. Subgroup analysis revealed no impact of comorbidities on gene expression. In a weighted gene coexpression network analysis, we found 26 gene clusters, of which 9 clusters showed a significant positive or negative correlation with the presence of heart failure. We identified the transcription factors CASZ1 (castor zinc finger 1), ZNF523 (zinc finger protein 523), and NFE2L1 (nuclear factor erythroid 2-related factor 1) as hub genes of a cluster related to angiogenesis. Knockdown of CASZ1, ZNF523, or NFE2L1 in human umbilical vein endothelial cells led to a downregulation of genes from the respective cluster, including CD34 and platelet-derived growth factor-β, confirming their regulatory function. In conclusion, we assessed gene networks in endothelial cells and identified transcription factors CASZ1, ZNF532, and NFE2L1 as potential regulators of angiogenesis in failing human hearts. Our study provides insights into the transcriptional regulation of angiogenesis beyond the classical vascular endothelial growth factor signaling pathway.NEW & NOTEWORTHY Gene coexpression network analysis defined 26 gene clusters expressed in endothelial cells from failing human hearts. Transcription factors CASZ1, ZNF523, and NFE2L1 were identified as hub genes of a cluster related to angiogenesis. Knockdown of CASZ1, ZNF523, or NFE2L1 in human umbilical vein endothelial cells led to a downregulation of genes from the respective cluster, confirming their regulatory function. This provides insights into the transcriptional regulation of angiogenesis in heart failure beyond classical signaling pathways.
{"title":"Gene expression networks in endothelial cells from failing human hearts.","authors":"Luisa Wirth, Elias Erny, Markus Krane, Harald Lahm, Lutz Hein, Ralf Gilsbach, Achim Lother","doi":"10.1152/ajpheart.00425.2024","DOIUrl":"10.1152/ajpheart.00425.2024","url":null,"abstract":"<p><p>Chronic heart failure is associated with adverse remodeling of the heart that is typically characterized by cardiomyocyte hypertrophy. This requires the formation of new capillaries to maintain oxygen supply. Insufficient angiogenesis promotes the transition from compensated hypertrophy into heart failure. The aim of this study was to identify angiogenesis-related gene networks and corresponding regulatory hubs in endothelial cells from failing human hearts. We isolated left ventricular endothelial cells from patients with advanced heart failure undergoing left ventricular assist device surgery (<i>n</i> = 15) and healthy organ donors (<i>n</i> = 2) and performed RNA sequencing. Subgroup analysis revealed no impact of comorbidities on gene expression. In a weighted gene coexpression network analysis, we found 26 gene clusters, of which 9 clusters showed a significant positive or negative correlation with the presence of heart failure. We identified the transcription factors CASZ1 (castor zinc finger 1), ZNF523 (zinc finger protein 523), and NFE2L1 (nuclear factor erythroid 2-related factor 1) as hub genes of a cluster related to angiogenesis. Knockdown of <i>CASZ1</i>, <i>ZNF523</i>, or <i>NFE2L1</i> in human umbilical vein endothelial cells led to a downregulation of genes from the respective cluster, including <i>CD34</i> and platelet-derived growth factor-β, confirming their regulatory function. In conclusion, we assessed gene networks in endothelial cells and identified transcription factors CASZ1, ZNF532, and NFE2L1 as potential regulators of angiogenesis in failing human hearts. Our study provides insights into the transcriptional regulation of angiogenesis beyond the classical vascular endothelial growth factor signaling pathway.<b>NEW & NOTEWORTHY</b> Gene coexpression network analysis defined 26 gene clusters expressed in endothelial cells from failing human hearts. Transcription factors CASZ1, ZNF523, and NFE2L1 were identified as hub genes of a cluster related to angiogenesis. Knockdown of CASZ1, ZNF523, or NFE2L1 in human umbilical vein endothelial cells led to a downregulation of genes from the respective cluster, confirming their regulatory function. This provides insights into the transcriptional regulation of angiogenesis in heart failure beyond classical signaling pathways.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141722824","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-01Epub Date: 2024-08-02DOI: 10.1152/ajpheart.00506.2024
Delphine O Okoye, Benard O Ogola
{"title":"Hypertension and oxidative stress: it takes two to tango.","authors":"Delphine O Okoye, Benard O Ogola","doi":"10.1152/ajpheart.00506.2024","DOIUrl":"10.1152/ajpheart.00506.2024","url":null,"abstract":"","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141873966","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}