B. Weber, Dana Weisenfeld, Thany Seyok, Sicong Huang, E. Massarotti, Leanne Barrett, C. Bibbo, D. H. Solomon, J. Plutzky, M. Bolster, M. D. Di Carli, K. Liao
will be prevalent in patients with RA who have low estimated ASCVD risk and that CMD will be associated with higher levels of IL- 6. We analyzed baseline data from the LIIRA (Lipids, Inflammation and Cardiovascular Risk in RA) study, NCT02714881. The data that support the findings of this study are available from the corresponding author upon reasonable request. LIIRA included individuals with RA, age>35 years with active RA, not on a statin or biologic therapy. All subjects underwent assessment of cardiovascular risk factors, as well as the validated RA Disease Activity Score- 28- C- reactive protein (CRP3), which includes tender, swollen joints, and hsCRP (high-sensitivity CRP); a stress myocardial perfusion positron emission tomography scan was performed to quantify CFR. Standard positron emission tomography imaging protocols were performed as previously described. 3 CFR was calculated as the ratio of myocardial blood flow (mL/min per g) at peak stress over that at rest; CMD was defined as CFR<2.5. Attenuation correction computed tomography scans were reviewed for semi-quantitative assessment of coronary artery calcium. HsCRP and IL- 6 levels were measured in the clinical laboratory. A Wilcoxon rank- sum test was performed
{"title":"Relationship Between Risk of Atherosclerotic Cardiovascular Disease, Inflammation, and Coronary Microvascular Dysfunction in Rheumatoid Arthritis","authors":"B. Weber, Dana Weisenfeld, Thany Seyok, Sicong Huang, E. Massarotti, Leanne Barrett, C. Bibbo, D. H. Solomon, J. Plutzky, M. Bolster, M. D. Di Carli, K. Liao","doi":"10.1161/JAHA.121.025467","DOIUrl":"https://doi.org/10.1161/JAHA.121.025467","url":null,"abstract":"will be prevalent in patients with RA who have low estimated ASCVD risk and that CMD will be associated with higher levels of IL- 6. We analyzed baseline data from the LIIRA (Lipids, Inflammation and Cardiovascular Risk in RA) study, NCT02714881. The data that support the findings of this study are available from the corresponding author upon reasonable request. LIIRA included individuals with RA, age>35 years with active RA, not on a statin or biologic therapy. All subjects underwent assessment of cardiovascular risk factors, as well as the validated RA Disease Activity Score- 28- C- reactive protein (CRP3), which includes tender, swollen joints, and hsCRP (high-sensitivity CRP); a stress myocardial perfusion positron emission tomography scan was performed to quantify CFR. Standard positron emission tomography imaging protocols were performed as previously described. 3 CFR was calculated as the ratio of myocardial blood flow (mL/min per g) at peak stress over that at rest; CMD was defined as CFR<2.5. Attenuation correction computed tomography scans were reviewed for semi-quantitative assessment of coronary artery calcium. HsCRP and IL- 6 levels were measured in the clinical laboratory. A Wilcoxon rank- sum test was performed","PeriodicalId":17189,"journal":{"name":"Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"72867921","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
R. Gopinathannair, N. Pothineni, J. Trivedi, H. Roukoz, J. Cowger, Mustafa M. Ahmed, A. Bhan, Ashwin K Ravichandran, G. Bhat, Amin Al Ahmad, A. Natale, L. Di Biase, M. Slaughter, D. Lakkireddy
Background Atrial and ventricular arrhythmias are commonly encountered in patients with advanced heart failure, with amiodarone being the most commonly used antiarrhythmic drug in continuous‐flow left ventricular assist device (CF‐LVAD) recipients. The purpose of this study was to assess the impact of amiodarone use on long‐term all‐cause mortality in ptients with a CF‐LVAD. Methods and Results A retrospective multicenter study of CF‐LVAD was conducted at 5 centers including all CF‐LVAD implants from 2007 to 2015. Patients were stratified based on pre–CF‐LVAD implant amiodarone use. Additional use of amiodarone after CF‐LVAD implantation was also evaluated. Primary outcome was all‐cause mortality during long‐term follow‐up. Kaplan‐Meier curves were used to assess survival outcomes. Multivariable Cox regression was used to identify predictors of outcomes. Propensity matching was done to address baseline differences. A total of 480 patients with a CF‐LVAD (aged 58±13 years, 81% men) were included. Of these, 170 (35.4%) were on chronic amiodarone therapy at the time of CF‐LVAD implant, and 310 (64.6%) were not on amiodarone. Rate of all‐cause mortality over the follow‐up period was 32.9% in the amiodarone group compared with 29.6% in those not on amiodarone (P=0.008). Similar results were noted in the propensity‐matched group (log‐rank, P=0.04). On multivariable Cox regression analysis, amiodarone use at baseline was independently associated with all‐cause mortality (hazard ratio, 1.68 [95% CI, 1.1–2.5]; P=0.01). Conclusions Amiodarone use was associated with significantly increased rates of all‐cause mortality in CF‐LVAD recipients. Earlier interventions for arrhythmias to avoid long‐term amiodarone exposure may improve long‐term outcomes in CF‐LVAD recipients and needs further study.
{"title":"Amiodarone Use and All‐Cause Mortality in Patients With a Continuous‐Flow Left Ventricular Assist Device","authors":"R. Gopinathannair, N. Pothineni, J. Trivedi, H. Roukoz, J. Cowger, Mustafa M. Ahmed, A. Bhan, Ashwin K Ravichandran, G. Bhat, Amin Al Ahmad, A. Natale, L. Di Biase, M. Slaughter, D. Lakkireddy","doi":"10.1161/JAHA.121.023762","DOIUrl":"https://doi.org/10.1161/JAHA.121.023762","url":null,"abstract":"Background Atrial and ventricular arrhythmias are commonly encountered in patients with advanced heart failure, with amiodarone being the most commonly used antiarrhythmic drug in continuous‐flow left ventricular assist device (CF‐LVAD) recipients. The purpose of this study was to assess the impact of amiodarone use on long‐term all‐cause mortality in ptients with a CF‐LVAD. Methods and Results A retrospective multicenter study of CF‐LVAD was conducted at 5 centers including all CF‐LVAD implants from 2007 to 2015. Patients were stratified based on pre–CF‐LVAD implant amiodarone use. Additional use of amiodarone after CF‐LVAD implantation was also evaluated. Primary outcome was all‐cause mortality during long‐term follow‐up. Kaplan‐Meier curves were used to assess survival outcomes. Multivariable Cox regression was used to identify predictors of outcomes. Propensity matching was done to address baseline differences. A total of 480 patients with a CF‐LVAD (aged 58±13 years, 81% men) were included. Of these, 170 (35.4%) were on chronic amiodarone therapy at the time of CF‐LVAD implant, and 310 (64.6%) were not on amiodarone. Rate of all‐cause mortality over the follow‐up period was 32.9% in the amiodarone group compared with 29.6% in those not on amiodarone (P=0.008). Similar results were noted in the propensity‐matched group (log‐rank, P=0.04). On multivariable Cox regression analysis, amiodarone use at baseline was independently associated with all‐cause mortality (hazard ratio, 1.68 [95% CI, 1.1–2.5]; P=0.01). Conclusions Amiodarone use was associated with significantly increased rates of all‐cause mortality in CF‐LVAD recipients. Earlier interventions for arrhythmias to avoid long‐term amiodarone exposure may improve long‐term outcomes in CF‐LVAD recipients and needs further study.","PeriodicalId":17189,"journal":{"name":"Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85302557","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Le Ni, Bowen Lin, Lingjie Hu, Ruoyu Zhang, Fengmei Fu, Meiting Shen, Jian Yang, Dan Shi
Background Heart failure, caused by sustained pressure overload, remains a major public health problem. PKM (pyruvate kinase M) acts as a rate‐limiting enzyme of glycolysis. PKM2 (pyruvate kinase M2), an alternative splicing product of PKM, plays complex roles in various biological processes and diseases. However, the role of PKM2 in the development of heart failure remains unknown. Methods and Results Cardiomyocyte‐specific Pkm2 knockout mice were generated by crossing the floxed Pkm2 mice with α‐MHC (myosin heavy chain)‐Cre transgenic mice, and cardiac specific Pkm2 overexpression mice were established by injecting adeno‐associated virus serotype 9 system. The results showed that cardiomyocyte‐specific Pkm2 deletion resulted in significant deterioration of cardiac functions under pressure overload, whereas Pkm2 overexpression mitigated transverse aortic constriction‐induced cardiac hypertrophy and improved heart functions. Mechanistically, we demonstrated that PKM2 acted as a protein kinase rather than a pyruvate kinase, which inhibited the activation of RAC1 (rho family, small GTP binding protein)‐MAPK (mitogen‐activated protein kinase) signaling pathway by phosphorylating RAC1 in the progress of heart failure. In addition, blockade of RAC1 through NSC23766, a specific RAC1 inhibitor, attenuated pathological cardiac remodeling in Pkm2 deficiency mice subjected to transverse aortic constriction. Conclusions This study revealed that PKM2 attenuated overload‐induced pathological cardiac hypertrophy and heart failure, which provides an attractive target for the prevention and treatment of cardiomyopathies.
{"title":"Pyruvate Kinase M2 Protects Heart from Pressure Overload‐Induced Heart Failure by Phosphorylating RAC1","authors":"Le Ni, Bowen Lin, Lingjie Hu, Ruoyu Zhang, Fengmei Fu, Meiting Shen, Jian Yang, Dan Shi","doi":"10.1161/JAHA.121.024854","DOIUrl":"https://doi.org/10.1161/JAHA.121.024854","url":null,"abstract":"Background Heart failure, caused by sustained pressure overload, remains a major public health problem. PKM (pyruvate kinase M) acts as a rate‐limiting enzyme of glycolysis. PKM2 (pyruvate kinase M2), an alternative splicing product of PKM, plays complex roles in various biological processes and diseases. However, the role of PKM2 in the development of heart failure remains unknown. Methods and Results Cardiomyocyte‐specific Pkm2 knockout mice were generated by crossing the floxed Pkm2 mice with α‐MHC (myosin heavy chain)‐Cre transgenic mice, and cardiac specific Pkm2 overexpression mice were established by injecting adeno‐associated virus serotype 9 system. The results showed that cardiomyocyte‐specific Pkm2 deletion resulted in significant deterioration of cardiac functions under pressure overload, whereas Pkm2 overexpression mitigated transverse aortic constriction‐induced cardiac hypertrophy and improved heart functions. Mechanistically, we demonstrated that PKM2 acted as a protein kinase rather than a pyruvate kinase, which inhibited the activation of RAC1 (rho family, small GTP binding protein)‐MAPK (mitogen‐activated protein kinase) signaling pathway by phosphorylating RAC1 in the progress of heart failure. In addition, blockade of RAC1 through NSC23766, a specific RAC1 inhibitor, attenuated pathological cardiac remodeling in Pkm2 deficiency mice subjected to transverse aortic constriction. Conclusions This study revealed that PKM2 attenuated overload‐induced pathological cardiac hypertrophy and heart failure, which provides an attractive target for the prevention and treatment of cardiomyopathies.","PeriodicalId":17189,"journal":{"name":"Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90887197","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Lucas Hollanda Oliveira, M. Viana, C. Luize, Ricardo Sobral de Carvalho, C. Cirenza, Cristiano de Oliveira Dietrich, L. C. Correia, Cláudio Marcelo Bittencourt das Virgens, Juliana Medeiros Filgueiras, M. Barreto, E. Porto, E. Coutinho, Â. de Paola
Background Catheter ablation (CA) is a safe, effective, cost‐effective technique and may be considered a first‐line strategy for the treatment of symptomatic supraventricular tachycardias (SVT). Despite the high prospect of cure and the recommendations of international guidelines in considering CA as a first‐line treatment strategy, the average time between diagnosis and the procedure may be long. The present study aims to evaluate predictors related to non‐referral for CA as first‐line treatment in patients with SVT. Methods and Results The model was derived from a retrospective cohort of patients with SVT or ventricular pre‐excitation referred for CA in a tertiary center. Clinical and demographical features were used as independent variables and non‐referral for CA as first‐line treatment the dependent variable in a stepwise logistic regression analysis. Among 20 clinical‐demographic variables from 350 patients, 10 were included in initial logistic regression analysis: age, women, presence of pre‐excitation on ECG, palpitation, dyspnea and chest discomfort, number of antiarrhythmic drugs before ablation, number of concomitant symptoms, symptoms’ duration and evaluations in the emergency room due to SVT. After multivariable adjusted analysis, age (odds ratio [OR], 1.2; 95% CI 1.01–1.32; P=0.04), chest discomfort during supraventricular tachycardia (OR, 2.7; CI 1.6–4.7; P<0.001) and number of antiarrhythmic drugs before ablation (OR, 1.8; CI 1.4–2.3; P<0.001) showed a positive independent association for non‐referral for CA as SVT first‐line treatment. Conclusions The independent predictors of non‐referral for CA as first‐line treatment in our logistic regression analysis indicate the existence of biases in the decision‐making process in the referral process of patients who would benefit the most from catheter ablation. They very likely suggest a skewed medical decision‐making process leading to catheter ablation underuse.
导管消融(CA)是一种安全、有效、经济的技术，可能被认为是治疗症状性室上性心动过速(SVT)的一线策略。尽管有很高的治愈前景，并且国际指南建议将CA作为一线治疗策略，但从诊断到手术的平均时间可能很长。本研究旨在评估与非转诊CA作为SVT患者一线治疗相关的预测因素。方法和结果该模型来源于一个三级中心的室性心动过速或心室预兴奋患者的回顾性队列。在逐步logistic回归分析中，临床和人口统计学特征作为自变量，非转诊CA作为一线治疗的因变量。在来自350例患者的20个临床人口学变量中，有10个变量被纳入了初始logistic回归分析:年龄、女性、ECG上的预兴奋、心悸、呼吸困难和胸部不适、消融前抗心律失常药物的数量、伴随症状的数量、症状持续时间和因SVT在急诊室的评估。经多变量调整分析，年龄(优势比[OR]， 1.2;95% ci 1.01-1.32;P=0.04)，室上性心动过速时胸部不适(OR, 2.7;可信区间1.6 - -4.7;P<0.001)和消融前抗心律失常药物的数量(OR, 1.8;可信区间1.4 - -2.3;P<0.001)显示非转诊CA作为SVT一线治疗的独立正相关。结论:在我们的logistic回归分析中，不转诊CA作为一线治疗的独立预测因素表明，在转诊过程中，哪些患者将从导管消融中获益最多，在决策过程中存在偏差。它们很可能表明，一个扭曲的医疗决策过程导致导管消融使用不足。
{"title":"Underuse of Catheter Ablation as First‐Line Therapy for Supraventricular Tachycardia","authors":"Lucas Hollanda Oliveira, M. Viana, C. Luize, Ricardo Sobral de Carvalho, C. Cirenza, Cristiano de Oliveira Dietrich, L. C. Correia, Cláudio Marcelo Bittencourt das Virgens, Juliana Medeiros Filgueiras, M. Barreto, E. Porto, E. Coutinho, Â. de Paola","doi":"10.1161/JAHA.121.022648","DOIUrl":"https://doi.org/10.1161/JAHA.121.022648","url":null,"abstract":"Background Catheter ablation (CA) is a safe, effective, cost‐effective technique and may be considered a first‐line strategy for the treatment of symptomatic supraventricular tachycardias (SVT). Despite the high prospect of cure and the recommendations of international guidelines in considering CA as a first‐line treatment strategy, the average time between diagnosis and the procedure may be long. The present study aims to evaluate predictors related to non‐referral for CA as first‐line treatment in patients with SVT. Methods and Results The model was derived from a retrospective cohort of patients with SVT or ventricular pre‐excitation referred for CA in a tertiary center. Clinical and demographical features were used as independent variables and non‐referral for CA as first‐line treatment the dependent variable in a stepwise logistic regression analysis. Among 20 clinical‐demographic variables from 350 patients, 10 were included in initial logistic regression analysis: age, women, presence of pre‐excitation on ECG, palpitation, dyspnea and chest discomfort, number of antiarrhythmic drugs before ablation, number of concomitant symptoms, symptoms’ duration and evaluations in the emergency room due to SVT. After multivariable adjusted analysis, age (odds ratio [OR], 1.2; 95% CI 1.01–1.32; P=0.04), chest discomfort during supraventricular tachycardia (OR, 2.7; CI 1.6–4.7; P<0.001) and number of antiarrhythmic drugs before ablation (OR, 1.8; CI 1.4–2.3; P<0.001) showed a positive independent association for non‐referral for CA as SVT first‐line treatment. Conclusions The independent predictors of non‐referral for CA as first‐line treatment in our logistic regression analysis indicate the existence of biases in the decision‐making process in the referral process of patients who would benefit the most from catheter ablation. They very likely suggest a skewed medical decision‐making process leading to catheter ablation underuse.","PeriodicalId":17189,"journal":{"name":"Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86731696","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Min Hye Kang, Weon Kim, J. S. Kim, K. Jeong, M. Jeong, J. Hwang, S. Hur, H. Hwang
Background Hydrophilic and lipophilic statins have similar efficacies in treating coronary artery disease. However, specific factors relevant to renal impairment and different arterial pathogeneses could modify the clinical effects of statin lipophilicity, and create differences in protective effects between statin types in patients with renal impairment. Methods and Results A total of 2062 patients with acute myocardial infarction with an estimated glomerular filtration rate <60 mL/min per 1.73 m2 were enrolled from the Korea Acute Myocardial Infarction Registry between November 2011 and December 2015. The primary end point was a composite of 2‐year major adverse cardiac and cerebrovascular events (MACEs) after acute myocardial infarction occurrence. MACEs were defined as all‐cause death, recurrent myocardial infarction, revascularization, and stroke. Propensity‐score matching and Cox proportional hazards regression were performed. A total of 529 patients treated with hydrophilic statins were matched to 529 patients treated with lipophilic statins. There was no difference in the statin equivalent dose between the 2 statin groups. The cumulative event rate of MACEs, all‐cause mortality, and recurrent myocardial infarction were significantly lower in patients treated with hydrophilic statins in the propensity‐score matched population (all P<0.05). In the multivariable Cox regression analysis, patients treated with hydrophilic statins had a lower risk for composite MACEs (hazard ratio [HR], 0.70 [95% CI, 0.55–0.90]), all‐cause mortality (HR, 0.67 [95% CI, 0.49–0.93]), and recurrent myocardial infarction (HR, 0.40 [95% CI, 0.21–0.73]), but not for revascularization and ischemic stroke. Conclusions Hydrophilic statin treatment was associated with lower risk of MACEs and all‐cause mortality than lipophilic statin in a propensity‐score matched observational cohort of patients with renal impairment following acute myocardial infarction.
{"title":"Hydrophilic Versus Lipophilic Statin Treatments in Patients With Renal Impairment After Acute Myocardial Infarction","authors":"Min Hye Kang, Weon Kim, J. S. Kim, K. Jeong, M. Jeong, J. Hwang, S. Hur, H. Hwang","doi":"10.1161/JAHA.121.024649","DOIUrl":"https://doi.org/10.1161/JAHA.121.024649","url":null,"abstract":"Background Hydrophilic and lipophilic statins have similar efficacies in treating coronary artery disease. However, specific factors relevant to renal impairment and different arterial pathogeneses could modify the clinical effects of statin lipophilicity, and create differences in protective effects between statin types in patients with renal impairment. Methods and Results A total of 2062 patients with acute myocardial infarction with an estimated glomerular filtration rate <60 mL/min per 1.73 m2 were enrolled from the Korea Acute Myocardial Infarction Registry between November 2011 and December 2015. The primary end point was a composite of 2‐year major adverse cardiac and cerebrovascular events (MACEs) after acute myocardial infarction occurrence. MACEs were defined as all‐cause death, recurrent myocardial infarction, revascularization, and stroke. Propensity‐score matching and Cox proportional hazards regression were performed. A total of 529 patients treated with hydrophilic statins were matched to 529 patients treated with lipophilic statins. There was no difference in the statin equivalent dose between the 2 statin groups. The cumulative event rate of MACEs, all‐cause mortality, and recurrent myocardial infarction were significantly lower in patients treated with hydrophilic statins in the propensity‐score matched population (all P<0.05). In the multivariable Cox regression analysis, patients treated with hydrophilic statins had a lower risk for composite MACEs (hazard ratio [HR], 0.70 [95% CI, 0.55–0.90]), all‐cause mortality (HR, 0.67 [95% CI, 0.49–0.93]), and recurrent myocardial infarction (HR, 0.40 [95% CI, 0.21–0.73]), but not for revascularization and ischemic stroke. Conclusions Hydrophilic statin treatment was associated with lower risk of MACEs and all‐cause mortality than lipophilic statin in a propensity‐score matched observational cohort of patients with renal impairment following acute myocardial infarction.","PeriodicalId":17189,"journal":{"name":"Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"91457414","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
M. Ribeiro, Carlos M Campos, Lucio T. Padilla, A. C. B. da Silva, J. E. T. de Paula, Marco A. Alcántara, Ricardo Santiago, Franklin Hanna, Franciele R da Silva, Karlyse C Belli, L. Azzalini, P. P. de Oliveira, G. Araujo, V. Sucato, K. Mashayekhi, A. Galassi, A. Abizaid, A. Quadros
Background Coronary perforation is a life‐threatening complication of acute percutaneous coronary intervention (PCI) for chronic total occlusions (CTO), but data on midterm outcomes are limited. Methods and Results Data from LATAM (Latin American)‐CTO Registry (57 centers; 9 countries) were analyzed. We assessed the risk of 30‐day, 1‐year major adverse cardiac events of coronary perforation using time‐to‐event and weighted composite end point analysis having CTO PCI without perforation as comparators. Additionally, we studied the independent predictors of perforation in these patients. Of 2054 patients who underwent CTO PCI between 2015 and 2018, the median Multicenter CTO Registry in Japan and Prospective Global Registry for the Study of Chronic Total Occlusion Intervention‐Chronic total occlusions scores were 2.0 (1.0–3.0) and 1.0 (0.0–2.0), respectively. The perforation rate was 3.7%, of which 55% were Ellis class 1. After 1‐year coronary perforation had higher major adverse cardiac events rates (24.9% versus 13.3%; P<0.01). Using weighted composite end point, perforation was associated with increased bleeding and ischemic events at 6 months (P=0.04) and 1 year (P<0.01). We found as independent predictors associated with coronary perforation during CTO PCI: maximum activated clotting time (P<0.01), Multicenter CTO Registry in Japan score ≥2 (P=0.05), antegrade knuckle wire (P=0.04), and right coronary artery CTO PCI (P=0.05). Conclusions Coronary perforation was infrequent and associated with anatomical and procedural complexity, resulting in higher risk of hemorrhagic and ischemic events. Landmark and weighted analysis showed a sustained burden of major events between 6 months and 1 year follow‐up.
{"title":"Risk Burden of Coronary Perforation in Chronic Total Occlusion Recanalization: Latin American CTO Registry Analysis","authors":"M. Ribeiro, Carlos M Campos, Lucio T. Padilla, A. C. B. da Silva, J. E. T. de Paula, Marco A. Alcántara, Ricardo Santiago, Franklin Hanna, Franciele R da Silva, Karlyse C Belli, L. Azzalini, P. P. de Oliveira, G. Araujo, V. Sucato, K. Mashayekhi, A. Galassi, A. Abizaid, A. Quadros","doi":"10.1161/JAHA.121.024815","DOIUrl":"https://doi.org/10.1161/JAHA.121.024815","url":null,"abstract":"Background Coronary perforation is a life‐threatening complication of acute percutaneous coronary intervention (PCI) for chronic total occlusions (CTO), but data on midterm outcomes are limited. Methods and Results Data from LATAM (Latin American)‐CTO Registry (57 centers; 9 countries) were analyzed. We assessed the risk of 30‐day, 1‐year major adverse cardiac events of coronary perforation using time‐to‐event and weighted composite end point analysis having CTO PCI without perforation as comparators. Additionally, we studied the independent predictors of perforation in these patients. Of 2054 patients who underwent CTO PCI between 2015 and 2018, the median Multicenter CTO Registry in Japan and Prospective Global Registry for the Study of Chronic Total Occlusion Intervention‐Chronic total occlusions scores were 2.0 (1.0–3.0) and 1.0 (0.0–2.0), respectively. The perforation rate was 3.7%, of which 55% were Ellis class 1. After 1‐year coronary perforation had higher major adverse cardiac events rates (24.9% versus 13.3%; P<0.01). Using weighted composite end point, perforation was associated with increased bleeding and ischemic events at 6 months (P=0.04) and 1 year (P<0.01). We found as independent predictors associated with coronary perforation during CTO PCI: maximum activated clotting time (P<0.01), Multicenter CTO Registry in Japan score ≥2 (P=0.05), antegrade knuckle wire (P=0.04), and right coronary artery CTO PCI (P=0.05). Conclusions Coronary perforation was infrequent and associated with anatomical and procedural complexity, resulting in higher risk of hemorrhagic and ischemic events. Landmark and weighted analysis showed a sustained burden of major events between 6 months and 1 year follow‐up.","PeriodicalId":17189,"journal":{"name":"Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73884229","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
M. Segar, Kershaw V. Patel, A. Hellkamp, M. Vaduganathan, Y. Lokhnygina, Jennifer B. Green, S. Wan, A. Kolkailah, R. Holman, E. Peterson, V. Kannan, D. Willett, D. McGuire, A. Pandey
Background The WATCH‐DM (weight [body mass index], age, hypertension, creatinine, high‐density lipoprotein cholesterol, diabetes control [fasting plasma glucose], ECG QRS duration, myocardial infarction, and coronary artery bypass grafting) and TRS‐HFDM (Thrombolysis in Myocardial Infarction [TIMI] risk score for heart failure in diabetes) risk scores were developed to predict risk of heart failure (HF) among individuals with type 2 diabetes. WATCH‐DM was developed to predict incident HF, whereas TRS‐HFDM predicts HF hospitalization among patients with and without a prior HF history. We evaluated the model performance of both scores to predict incident HF events among patients with type 2 diabetes and no history of HF hospitalization across different cohorts and clinical settings with varying baseline risk. Methods and Results Incident HF risk was estimated by the integer‐based WATCH‐DM and TRS‐HFDM scores in participants with type 2 diabetes free of baseline HF from 2 randomized clinical trials (TECOS [Trial Evaluating Cardiovascular Outcomes With Sitagliptin], N=12 028; and Look AHEAD [Look Action for Health in Diabetes] trial, N=4867). The integer‐based WATCH‐DM score was also validated in electronic health record data from a single large health care system (N=7475). Model discrimination was assessed by the Harrell concordance index and calibration by the Greenwood‐Nam‐D’Agostino statistic. HF incidence rate was 7.5, 3.9, and 4.1 per 1000 person‐years in the TECOS, Look AHEAD trial, and electronic health record cohorts, respectively. Integer‐based WATCH‐DM and TRS‐HFDM scores had similar discrimination and calibration for predicting 5‐year HF risk in the Look AHEAD trial cohort (concordance indexes=0.70; Greenwood‐Nam‐D’Agostino P>0.30 for both). Both scores had lower discrimination and underpredicted HF risk in the TECOS cohort (concordance indexes=0.65 and 0.66, respectively; Greenwood‐Nam‐D’Agostino P<0.001 for both). In the electronic health record cohort, the integer‐based WATCH‐DM score demonstrated a concordance index of 0.73 with adequate calibration (Greenwood‐Nam‐D’Agostino P=0.96). TRS‐HFDM score could not be validated in the electronic health record because of unavailability of data on urine albumin/creatinine ratio in most patients in the contemporary clinical practice. Conclusions The WATCH‐DM and TRS‐HFDM risk scores can discriminate risk of HF among intermediate‐risk populations with type 2 diabetes.
{"title":"Validation of the WATCH‐DM and TRS‐HFDM Risk Scores to Predict the Risk of Incident Hospitalization for Heart Failure Among Adults With Type 2 Diabetes: A Multicohort Analysis","authors":"M. Segar, Kershaw V. Patel, A. Hellkamp, M. Vaduganathan, Y. Lokhnygina, Jennifer B. Green, S. Wan, A. Kolkailah, R. Holman, E. Peterson, V. Kannan, D. Willett, D. McGuire, A. Pandey","doi":"10.1161/JAHA.121.024094","DOIUrl":"https://doi.org/10.1161/JAHA.121.024094","url":null,"abstract":"Background The WATCH‐DM (weight [body mass index], age, hypertension, creatinine, high‐density lipoprotein cholesterol, diabetes control [fasting plasma glucose], ECG QRS duration, myocardial infarction, and coronary artery bypass grafting) and TRS‐HFDM (Thrombolysis in Myocardial Infarction [TIMI] risk score for heart failure in diabetes) risk scores were developed to predict risk of heart failure (HF) among individuals with type 2 diabetes. WATCH‐DM was developed to predict incident HF, whereas TRS‐HFDM predicts HF hospitalization among patients with and without a prior HF history. We evaluated the model performance of both scores to predict incident HF events among patients with type 2 diabetes and no history of HF hospitalization across different cohorts and clinical settings with varying baseline risk. Methods and Results Incident HF risk was estimated by the integer‐based WATCH‐DM and TRS‐HFDM scores in participants with type 2 diabetes free of baseline HF from 2 randomized clinical trials (TECOS [Trial Evaluating Cardiovascular Outcomes With Sitagliptin], N=12 028; and Look AHEAD [Look Action for Health in Diabetes] trial, N=4867). The integer‐based WATCH‐DM score was also validated in electronic health record data from a single large health care system (N=7475). Model discrimination was assessed by the Harrell concordance index and calibration by the Greenwood‐Nam‐D’Agostino statistic. HF incidence rate was 7.5, 3.9, and 4.1 per 1000 person‐years in the TECOS, Look AHEAD trial, and electronic health record cohorts, respectively. Integer‐based WATCH‐DM and TRS‐HFDM scores had similar discrimination and calibration for predicting 5‐year HF risk in the Look AHEAD trial cohort (concordance indexes=0.70; Greenwood‐Nam‐D’Agostino P>0.30 for both). Both scores had lower discrimination and underpredicted HF risk in the TECOS cohort (concordance indexes=0.65 and 0.66, respectively; Greenwood‐Nam‐D’Agostino P<0.001 for both). In the electronic health record cohort, the integer‐based WATCH‐DM score demonstrated a concordance index of 0.73 with adequate calibration (Greenwood‐Nam‐D’Agostino P=0.96). TRS‐HFDM score could not be validated in the electronic health record because of unavailability of data on urine albumin/creatinine ratio in most patients in the contemporary clinical practice. Conclusions The WATCH‐DM and TRS‐HFDM risk scores can discriminate risk of HF among intermediate‐risk populations with type 2 diabetes.","PeriodicalId":17189,"journal":{"name":"Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74530878","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
B. Shahim, B. Redfors, B. Lindman, Shmuel Chen, T. Dahlén, Tamim Nazif, S. Kapadia, Z. Gertz, Aaron Crowley, Ditian Li, V. Thourani, S. Kodali, A. Zajarías, V. Babaliaros, R. Guyton, S. Elmariah, H. Herrmann, D. Cohen, M. Mack, Craig R. Smith, M. Leon, I. George
Background The neutrophil‐to‐lymphocyte ratio (NLR) as a marker of systemic inflammation has been associated with worse prognosis in several chronic disease states, including heart failure. However, few data exist on the prognostic impact of elevated baseline NLR or change in NLR levels during follow‐up in patients undergoing transcatheter or surgical aortic valve replacement (TAVR or SAVR) for aortic stenosis. Methods and Results NLR was available in 5881 patients with severe aortic stenosis receiving TAVR or SAVR in PARTNER (Placement of Aortic Transcatheter Valves) I, II, and S3 trials/registries (median [Q1, Q3] NLR, 3.30 [2.40, 4.90]); mean NLR, 4.10; range, 0.5–24.9) and was evaluated as continuous variable and categorical tertiles (low: NLR ≤2.70, n=1963; intermediate: NLR 2.70–4.20, n=1958; high: NLR ≥4.20, n=1960). No patients had known baseline infection. High baseline NLR was associated with increased risk of death or rehospitalization at 3 years (58.4% versus 41.0%; adjusted hazard ratio [aHR], 1.39; 95% CI, 1.18–1.63; P<0.0001) compared with those with low NLR, irrespective of treatment modality. In both patients treated with TAVR and patients treated with SAVR, NLR decreased between baseline and 2 years. A 1‐unit observed decrease in NLR between baseline and 1 year was associated with lower risk of death or rehospitalization between 1 year and 3 years (aHR, 0.86; 95% CI, 0.82–0.89; P<0.0001). Conclusions Elevated baseline NLR was independently associated with increased subsequent mortality and rehospitalization after TAVR or SAVR. The observed decrease in NLR after TAVR or SAVR was associated with improved outcomes. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT00530894, NCT0134313, NCT02184442, NCT03225001, NCT0322141.
{"title":"Neutrophil‐to‐Lymphocyte Ratios in Patients Undergoing Aortic Valve Replacement: The PARTNER Trials and Registries","authors":"B. Shahim, B. Redfors, B. Lindman, Shmuel Chen, T. Dahlén, Tamim Nazif, S. Kapadia, Z. Gertz, Aaron Crowley, Ditian Li, V. Thourani, S. Kodali, A. Zajarías, V. Babaliaros, R. Guyton, S. Elmariah, H. Herrmann, D. Cohen, M. Mack, Craig R. Smith, M. Leon, I. George","doi":"10.1161/JAHA.121.024091","DOIUrl":"https://doi.org/10.1161/JAHA.121.024091","url":null,"abstract":"Background The neutrophil‐to‐lymphocyte ratio (NLR) as a marker of systemic inflammation has been associated with worse prognosis in several chronic disease states, including heart failure. However, few data exist on the prognostic impact of elevated baseline NLR or change in NLR levels during follow‐up in patients undergoing transcatheter or surgical aortic valve replacement (TAVR or SAVR) for aortic stenosis. Methods and Results NLR was available in 5881 patients with severe aortic stenosis receiving TAVR or SAVR in PARTNER (Placement of Aortic Transcatheter Valves) I, II, and S3 trials/registries (median [Q1, Q3] NLR, 3.30 [2.40, 4.90]); mean NLR, 4.10; range, 0.5–24.9) and was evaluated as continuous variable and categorical tertiles (low: NLR ≤2.70, n=1963; intermediate: NLR 2.70–4.20, n=1958; high: NLR ≥4.20, n=1960). No patients had known baseline infection. High baseline NLR was associated with increased risk of death or rehospitalization at 3 years (58.4% versus 41.0%; adjusted hazard ratio [aHR], 1.39; 95% CI, 1.18–1.63; P<0.0001) compared with those with low NLR, irrespective of treatment modality. In both patients treated with TAVR and patients treated with SAVR, NLR decreased between baseline and 2 years. A 1‐unit observed decrease in NLR between baseline and 1 year was associated with lower risk of death or rehospitalization between 1 year and 3 years (aHR, 0.86; 95% CI, 0.82–0.89; P<0.0001). Conclusions Elevated baseline NLR was independently associated with increased subsequent mortality and rehospitalization after TAVR or SAVR. The observed decrease in NLR after TAVR or SAVR was associated with improved outcomes. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT00530894, NCT0134313, NCT02184442, NCT03225001, NCT0322141.","PeriodicalId":17189,"journal":{"name":"Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"91212986","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
M. Nelson, Olivia N. Gilbert, P. Duncan, D. Kitzman, G. Reeves, D. Whellan, R. Mentz, Haiying Chen, L. Hewston, Karen M Taylor, A. Pastva
Background The REHAB‐HF (Rehabilitation Therapy in Older Acute Heart Failure Patients) trial showed that a novel, early, transitional, tailored, progressive, multidomain physical rehabilitation intervention improved physical function and quality of life in older, frail patients hospitalized for acute decompensated heart failure. This analysis examined the relationship between intervention adherence and outcomes. Methods and Results Adherence was defined as percent of sessions attended and percent of sessions attended adjusted for missed sessions for medical reasons. Baseline characteristics were examined to identify predictors of session attendance. Associations of session attendance with change in physical function (Short Physical Performance Battery [primary outcome], 6‐minute walk distance, quality of life [Kansas City Cardiomyopathy Questionnaire], depression, and clinical events [landmarked postintervention]) were examined in multivariate analyses. Adherence was 67%±34%, and adherence adjusted for missed sessions for medical reasons was 78%±34%. Independent predictors of higher session attendance were the following: nonsmoking, absence of myocardial infarction history and depression, and higher baseline Short Physical Performance Battery. After adjustment for predictors, adherence was significantly associated with larger increases in Short Physical Performance Battery (parameter estimate: β=0.06[0.03–0.10], P=0.001), 6‐minute walk distance (β=1.8[0.2–3.5], P=0.032), and Kansas City Cardiomyopathy Questionnaire score (β=0.62[0.26–0.98], P=0.001), and reduction in depression (β=−0.08[−0.12 to 0.04], P<0.001). Additionally, higher adherence was significantly associated with reduced 6‐month all‐cause rehospitalization (rate ratio: 0.97 [0.95–0.99], P=0.020), combined all‐cause rehospitalization and death (0.97 [0.95–0.99], P=0.017), and all‐cause rehospitalization days (0.96 [0.94–0.99], P=0.004) postintervention. Conclusions In older, frail patients with acute decompensated heart failure, higher adherence was significantly associated with improved patient‐centered and clinical event outcomes. These data support the efficacy of the comprehensive adherence plan and the subsequent intervention‐related benefits observed in REHAB‐HF. Registration URL: https://clinicaltrials.gov/; Unique identifier: NCT02196038.
{"title":"Intervention Adherence in REHAB‐HF: Predictors and Relationship With Physical Function, Quality of Life, and Clinical Events","authors":"M. Nelson, Olivia N. Gilbert, P. Duncan, D. Kitzman, G. Reeves, D. Whellan, R. Mentz, Haiying Chen, L. Hewston, Karen M Taylor, A. Pastva","doi":"10.1161/JAHA.121.024246","DOIUrl":"https://doi.org/10.1161/JAHA.121.024246","url":null,"abstract":"Background The REHAB‐HF (Rehabilitation Therapy in Older Acute Heart Failure Patients) trial showed that a novel, early, transitional, tailored, progressive, multidomain physical rehabilitation intervention improved physical function and quality of life in older, frail patients hospitalized for acute decompensated heart failure. This analysis examined the relationship between intervention adherence and outcomes. Methods and Results Adherence was defined as percent of sessions attended and percent of sessions attended adjusted for missed sessions for medical reasons. Baseline characteristics were examined to identify predictors of session attendance. Associations of session attendance with change in physical function (Short Physical Performance Battery [primary outcome], 6‐minute walk distance, quality of life [Kansas City Cardiomyopathy Questionnaire], depression, and clinical events [landmarked postintervention]) were examined in multivariate analyses. Adherence was 67%±34%, and adherence adjusted for missed sessions for medical reasons was 78%±34%. Independent predictors of higher session attendance were the following: nonsmoking, absence of myocardial infarction history and depression, and higher baseline Short Physical Performance Battery. After adjustment for predictors, adherence was significantly associated with larger increases in Short Physical Performance Battery (parameter estimate: β=0.06[0.03–0.10], P=0.001), 6‐minute walk distance (β=1.8[0.2–3.5], P=0.032), and Kansas City Cardiomyopathy Questionnaire score (β=0.62[0.26–0.98], P=0.001), and reduction in depression (β=−0.08[−0.12 to 0.04], P<0.001). Additionally, higher adherence was significantly associated with reduced 6‐month all‐cause rehospitalization (rate ratio: 0.97 [0.95–0.99], P=0.020), combined all‐cause rehospitalization and death (0.97 [0.95–0.99], P=0.017), and all‐cause rehospitalization days (0.96 [0.94–0.99], P=0.004) postintervention. Conclusions In older, frail patients with acute decompensated heart failure, higher adherence was significantly associated with improved patient‐centered and clinical event outcomes. These data support the efficacy of the comprehensive adherence plan and the subsequent intervention‐related benefits observed in REHAB‐HF. Registration URL: https://clinicaltrials.gov/; Unique identifier: NCT02196038.","PeriodicalId":17189,"journal":{"name":"Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76077024","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Xiaonan Chen, Hao Lin, Weiyao Xiong, Jia-Yu Pan, Shuying Huang, Shan Xu, Shufang He, Ming Lei, A. C. Chang, Huili Zhang
Background Heart failure with preserved ejection fraction (HFpEF) accounts for 50% of patients with heart failure. Clinically, HFpEF prevalence shows age and gender biases. Although the majority of patients with HFpEF are elderly, there is an emergence of young patients with HFpEF. A better understanding of the underlying pathogenic mechanism is urgently needed. Here, we aimed to determine the role of aging in the pathogenesis of HFpEF. Methods and Results HFpEF dietary regimen (high‐fat diet + Nω‐Nitro‐L‐arginine methyl ester hydrochloride) was used to induce HFpEF in wild type and telomerase RNA knockout mice (second‐generation and third‐generation telomerase RNA component knockout), an aging murine model. First, both male and female animals develop HFpEF equally. Second, cardiac wall thickening preceded diastolic dysfunction in all HFpEF animals. Third, accelerated HFpEF onset was observed in second‐generation telomerase RNA component knockout (at 6 weeks) and third‐generation telomerase RNA component knockout (at 4 weeks) compared with wild type (8 weeks). Fourth, we demonstrate that mitochondrial respiration transitioned from compensatory state (normal basal yet loss of maximal respiratory capacity) to dysfunction (loss of both basal and maximal respiratory capacity) in a p53 dosage dependent manner. Last, using myocardial‐specific p53 knockout animals, we demonstrate that loss of p53 activation delays the development of HFpEF. Conclusions Here we demonstrate that p53 activation plays a role in the pathogenesis of HFpEF. We show that short telomere animals exhibit a basal level of p53 activation, mitochondria upregulate mtDNA encoded genes as a mean to compensate for blocked mitochondrial biogenesis, and loss of myocardial p53 delays HFpEF onset in high fat diet + Nω‐Nitro‐L‐arginine methyl ester hydrochloride challenged murine model.
背景:保留射血分数(HFpEF)的心力衰竭占心力衰竭患者的50%。临床上，HFpEF患病率存在年龄和性别差异。虽然大多数HFpEF患者是老年人，但也出现了年轻的HFpEF患者。迫切需要更好地了解潜在的致病机制。在这里，我们旨在确定衰老在HFpEF发病机制中的作用。方法与结果采用HFpEF饮食方案(高脂饮食+ Nω -硝基- L -精氨酸甲酯盐酸盐)诱导野生型和端粒酶RNA敲除小鼠(第二代和第三代端粒酶RNA成分敲除)衰老小鼠模型HFpEF。首先，雄性和雌性动物同样会患上HFpEF。其次，在所有HFpEF动物中，心脏壁增厚先于舒张功能障碍。第三，与野生型(8周)相比，第二代端粒酶RNA成分敲除组(6周)和第三代端粒酶RNA成分敲除组(4周)观察到HFpEF的加速发作。第四，我们证明了线粒体呼吸以p53剂量依赖的方式从代偿状态(正常的基础呼吸能力和最大呼吸能力的丧失)过渡到功能障碍(基础呼吸能力和最大呼吸能力的丧失)。最后，使用心肌特异性p53敲除动物，我们证明p53激活的丧失会延迟HFpEF的发展。结论p53的激活在HFpEF的发病机制中起作用。我们发现，短端粒动物表现出基础水平的p53激活，线粒体上调mtDNA编码基因作为补偿线粒体生物发生受阻的手段，心肌p53的缺失延迟了高脂肪饮食+ Nω -硝基- L -精氨酸甲酯盐化物挑战小鼠模型的HFpEF发病。
{"title":"p53‐Dependent Mitochondrial Compensation in Heart Failure With Preserved Ejection Fraction","authors":"Xiaonan Chen, Hao Lin, Weiyao Xiong, Jia-Yu Pan, Shuying Huang, Shan Xu, Shufang He, Ming Lei, A. C. Chang, Huili Zhang","doi":"10.1161/JAHA.121.024582","DOIUrl":"https://doi.org/10.1161/JAHA.121.024582","url":null,"abstract":"Background Heart failure with preserved ejection fraction (HFpEF) accounts for 50% of patients with heart failure. Clinically, HFpEF prevalence shows age and gender biases. Although the majority of patients with HFpEF are elderly, there is an emergence of young patients with HFpEF. A better understanding of the underlying pathogenic mechanism is urgently needed. Here, we aimed to determine the role of aging in the pathogenesis of HFpEF. Methods and Results HFpEF dietary regimen (high‐fat diet + Nω‐Nitro‐L‐arginine methyl ester hydrochloride) was used to induce HFpEF in wild type and telomerase RNA knockout mice (second‐generation and third‐generation telomerase RNA component knockout), an aging murine model. First, both male and female animals develop HFpEF equally. Second, cardiac wall thickening preceded diastolic dysfunction in all HFpEF animals. Third, accelerated HFpEF onset was observed in second‐generation telomerase RNA component knockout (at 6 weeks) and third‐generation telomerase RNA component knockout (at 4 weeks) compared with wild type (8 weeks). Fourth, we demonstrate that mitochondrial respiration transitioned from compensatory state (normal basal yet loss of maximal respiratory capacity) to dysfunction (loss of both basal and maximal respiratory capacity) in a p53 dosage dependent manner. Last, using myocardial‐specific p53 knockout animals, we demonstrate that loss of p53 activation delays the development of HFpEF. Conclusions Here we demonstrate that p53 activation plays a role in the pathogenesis of HFpEF. We show that short telomere animals exhibit a basal level of p53 activation, mitochondria upregulate mtDNA encoded genes as a mean to compensate for blocked mitochondrial biogenesis, and loss of myocardial p53 delays HFpEF onset in high fat diet + Nω‐Nitro‐L‐arginine methyl ester hydrochloride challenged murine model.","PeriodicalId":17189,"journal":{"name":"Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75233013","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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