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Fei C, Zhao C, Ma Y, Liu Y, Chen R, Zhang H. Factors influencing early recurrence of atrial fibrillation among elderly patients following radiofrequency catheter ablation and the impact of different antiarrhythmic regimens. Front Med (Lausanne) 2024; 11:1393208. [PMID: 38994337 PMCID: PMC11236554 DOI: 10.3389/fmed.2024.1393208] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Accepted: 06/17/2024] [Indexed: 07/13/2024] Open
Abstract
Background Patients with atrial fibrillation (AF) who undergo radiofrequency catheter ablation (RFCA) necessitate the administration of antiarrhythmic drugs to prevent early recurrence. The clinical outcomes among these patients may be influenced by varying antiarrhythmic regimens. Objectives To identify the risk factors associated with early recurrence and compare the clinical outcomes among different antiarrhythmic regimens in elderly patients with AF following radiofrequency catheter ablation (RFCA) during a 3-month period. Methods A retrospective observational study encompassed 420 elderly patients with AF following RFCA. Baseline data were collected during the initial postoperative visit and clinical outcomes were carefully monitored over a 3-month follow-up period. Logistic regression and Cox-proportional hazard regression analyses were performed to investigate the relationship between various antiarrhythmic regimens and the clinical outcomes. Results Multivariate logistic regression analysis revealed that age (p = 0.001), left atrial diameter (p < 0.001), left ventricular diameter (p = 0.015), reactive hyperemia index (RHI) (p < 0.001), antiarrhythmic drug (p < 0.001) and hs-cTnI (p = 0.017) were independent risk factors of early recurrence. Furthermore, in cox survival regression analysis model, survival rate of early recurrence in the amiodarone group was higher than in the propafenone group (HR 2.30, 95%CI 1.17-4.53, p = 0.016) and in the sotalol group (HR 3.60, 95%CI 2.17-5.95, p < 0.001). Compared to the amiodarone group, the incidence of liver dysfunction was lower in the dronedarone group (p = 0.046) and the propafenone group (p = 0.021). The incidence of bradyarrhythmia (p = 0.003), QT interval prolongation (p = 0.035) and atrioventricular transmission block (p = 0.021) were higher in the sotalol group than in the amiodarone group. Conclusion RHI was identified as an independent risk factor for early recurrence among elderly AF patients after RFCA. Compared to amiodarone, propafenone and sotalol exhibited an elevated risk of early recurrence. Although there was no significant difference in early recurrence between amiodarone and dronedarone, dronedarone emerged as the preferred option due to its lower frequency of adverse drug reactions than amiodarone.
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Affiliation(s)
- Changdong Fei
- Department of Health Management Center, The 967th Hospital of Joint Logistics Support Force of Chinese PLA, Dalian, China
| | - Caitong Zhao
- Department of Quality Control, General Hospital of Northern Theater Command, Shenyang, China
| | - Yan Ma
- National Clinical Research Center of Geriatric Diseases, The Second Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Yupeng Liu
- Department of Critical Care Medicine, The 967th Hospital of Joint Logistics Support Force of Chinese PLA, Dalian, China
| | - Renzheng Chen
- National Clinical Research Center of Geriatric Diseases, The Second Medical Center, Chinese PLA General Hospital, Beijing, China
- Department of Emergency, The 967th Hospital of Joint Logistics Support Force of Chinese PLA, Dalian, China
| | - Hualin Zhang
- Department of Emergency, The 967th Hospital of Joint Logistics Support Force of Chinese PLA, Dalian, China
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Kourek C, Karatzanos E, Raidou V, Papazachou O, Philippou A, Nanas S, Dimopoulos S. Effectiveness of high intensity interval training on cardiorespiratory fitness and endothelial function in type 2 diabetes: A systematic review. World J Cardiol 2023; 15:184-199. [PMID: 37124974 PMCID: PMC10130888 DOI: 10.4330/wjc.v15.i4.184] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2023] [Revised: 02/22/2023] [Accepted: 03/29/2023] [Indexed: 04/20/2023] Open
Abstract
BACKGROUND Type 2 diabetes mellitus (T2DM) is a chronic metabolic syndrome characterized by insulin resistance and hyperglycemia that may lead to endothelial dysfunction, reduced functional capacity and exercise intolerance. Regular aerobic exercise has been promoted as the most beneficial non-pharmacological treatment of cardiovascular diseases. High intensity interval training (HIIT) seems to be superior than moderate-intensity continuous training (MICT) in cardiovascular diseases by improving brachial artery flow-mediated dilation (FMD) and cardiorespiratory fitness to a greater extent. However, the beneficial effects of HIIT in patients with T2DM still remain under investigation and number of studies is limited. AIM To evaluate the effectiveness of high intensity interval training on cardiorespiratory fitness and endothelial function in patients with T2DM. METHODS We performed a search on PubMed, PEDro and CINAHL databases, selecting papers published between December 2012 and December 2022 and identified published randomized controlled trials (RCTs) in the English language that included community or outpatient exercise training programs in patients with T2DM. RCTs were assessed for methodological rigor and risk of bias via the Physiotherapy Evidence Database (PEDro). The primary outcome was peak VO2 and the secondary outcome was endothelial function assessed either by FMD or other indices of microcirculation. RESULTS Twelve studies were included in our systematic review. The 12 RCTs resulted in 661 participants in total. HIIT was performed in 310 patients (46.8%), MICT to 271 and the rest 80 belonged to the control group. Peak VO2 increased in 10 out of 12 studies after HIIT. Ten studies compared HIIT with other exercise regimens (MICT or strength endurance) and 4 of them demonstrated additional beneficial effects of HIIT over MICT or other exercise regimens. Moreover, 4 studies explored the effects of HIIT on endothelial function and FMD in T2DM patients. In 2 of them, HIIT further improved endothelial function compared to MICT and/or the control group while in the rest 2 studies no differences between HIIT and MICT were observed. CONCLUSION Regular aerobic exercise training has beneficial effects on cardiorespiratory fitness and endothelial function in T2DM patients. HIIT may be superior by improving these parameters to a greater extent than MICT.
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Affiliation(s)
- Christos Kourek
- Clinical Ergospirometry, Exercise and Rehabilitation Laboratory, 1 Critical Care Medicine Department, Evangelismos Hospital, Athens 10676, Greece
- Department of Cardiology, 417 Army Share Fund Hospital of Athens, Athens 11521, Greece
| | - Eleftherios Karatzanos
- Clinical Ergospirometry, Exercise and Rehabilitation Laboratory, 1 Critical Care Medicine Department, Evangelismos Hospital, Athens 10676, Greece
| | - Vasiliki Raidou
- Clinical Ergospirometry, Exercise and Rehabilitation Laboratory, National and Kapodistrian University of Athens, Athens 10676, Greece
| | - Ourania Papazachou
- Department of Cardiology, "Helena Venizelou" Hospital, Athens 10676, Greece
| | - Anastassios Philippou
- Clinical Ergospirometry, Exercise and Rehabilitation Laboratory, 1 Critical Care Medicine Department, Evangelismos Hospital, Athens 10676, Greece
- Department of Physiology, School of Medicine, National and Kapodistrian University of Athens, Athens 11527, Greece
| | - Serafim Nanas
- Clinical Ergospirometry, Exercise and Rehabilitation Laboratory, 1 Critical Care Medicine Department, Evangelismos Hospital, Athens 10676, Greece
| | - Stavros Dimopoulos
- Clinical Ergospirometry, Exercise and Rehabilitation Laboratory, 1 Critical Care Medicine Department, Evangelismos Hospital, Athens 10676, Greece
- Cardiac Surgery Intensive Care Unit, Onassis Cardiac Surgery Center, Athens 17674, Greece.
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3
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Wu J, Hou Q, Han Q, Mao R, Yue B, Yu J, Chen S, Wu S, Li K. Atrial fibrillation is an independent risk factor for new-onset myocardial infarction: a prospective study. Acta Cardiol 2022; 78:341-348. [PMID: 36251263 DOI: 10.1080/00015385.2022.2129184] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/01/2022]
Abstract
BACKGROUND Atrial fibrillation (AF) and myocardial infarction (MI) share common cardiovascular risk factors, therefore coexistence of AF and MI is very common, in addition, both AF and MI aggravate and exacerbate each other through multiple pathological processes. The aim of this study is to investigate whether AF increases the risk of new-onset MI. METHODS In total 171,086 participants from an industrial city in North China were selected and enrolled in this prospective cohort study, participants were divided into the AF group or the non-AF group according to their medical history. 1542 participants from the AF group were propensity-matched with 4626 participants from the non-AF group. All the participants were followed up every 2 years from June 2006 to December 2020, the median follow-up was 14.25 years and the endpoint of this study was new-onset MI. The association between AF and new-onset MI was analysed by using both univariate and multivariate Cox proportional hazards regression analysis. RESULTS New-onset MI was documented in 56 cases from the AF group and 98 cases from the non-AF group, respectively, the cumulative incidence of new-onset MI in the AF group (3.73%) was significantly higher than that in the non-AF group (2.23%) (p < 0.01). In a univariate analysis, AF was associated with an increased risk of new-onset MI (hazard ratio: 1.73, 95% confidence interval: 1.24-2.40), in two multivariable-adjusted analyses, AF was still associated with an increased risk of new-onset MI (hazard ratio: 1.78, 95% confidence interval, 1.28-2.47). CONCLUSIONS AF is an independent risk factor for new-onset MI in an industrial population of North China.
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Affiliation(s)
- Jianmei Wu
- Department of Cardiovascular Surgery, Tangshan Gongren Hospital, Tangshan, China
| | - Qiqi Hou
- Department of Cardiology, Tangshan Gongren Hospital, Tangshan, China.,Graduate School, Hebei Medical University, Shijiazhuang, China
| | - Quanle Han
- Department of Cardiology, Tangshan Gongren Hospital, Tangshan, China.,Graduate School, Hebei Medical University, Shijiazhuang, China.,School of Clinical Medicine, North China University of Science and Technology, Tangshan, China
| | - Ruiying Mao
- Department of Cardiology, Tangshan Gongren Hospital, Tangshan, China
| | - Bocheng Yue
- Department of Cardiology, Tangshan Gongren Hospital, Tangshan, China
| | - Jing Yu
- Department of Intervention, Tangshan Gongren Hospital, Tangshan, China
| | - Shuohua Chen
- Department of Cardiology, Kailuan General Hospital, Tangshan, China
| | - Shouling Wu
- School of Clinical Medicine, North China University of Science and Technology, Tangshan, China.,Department of Cardiology, Kailuan General Hospital, Tangshan, China
| | - Kangbo Li
- School of Clinical Medicine, North China University of Science and Technology, Tangshan, China
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Heshmat-Ghahdarijani K, Jangjoo S, Amirpour A, Najafian J, Khosravi A, Heidarpour M, Hekmat M, Shafie D. Endothelial dysfunction in patients with lone atrial fibrillation. ARYA ATHEROSCLEROSIS 2021; 16:278-283. [PMID: 34122581 PMCID: PMC8172232 DOI: 10.22122/arya.v16i6.2095] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
BACKGROUND Atrial fibrillation (AF) is the most common tachyarrhythmia in patients with cardiovascular diseases (CVDs) and may have significant complications such as stroke. The present study aims to evaluate endothelial dysfunction in patients with lone atrial fibrillation (LAF) through flow-mediated dilation (FMD) in the brachial artery, as a non-invasive method for evaluating functional and structural markers of endothelial dysfunction. METHODS In this case-control study, 43 patients with LAF were selected. 51 age and sex-matched healthy individuals were selected as the control group. The brachial artery diameter of the subjects in both groups was measured through FMD. The obtained data were analyzed by SPSS software. RESULTS Patients with LAF and healthy subjects did not have any difference in terms of gender, heart rate (HR), and systolic blood pressure (SBP) (P > 0.05 for all). FMD of the patients with AF was significantly lower (P = 0.04) than FMD of the healthy controls. CONCLUSION Our findings showed that LAF was associated with systemic endothelial dysfunction. AF plays an important and independent role in reducing FMD.
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Affiliation(s)
- Kiyan Heshmat-Ghahdarijani
- Heart Failure Research Center, Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Shahrzad Jangjoo
- Resident, Isfahan Cardiovascular Research Center, Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Afshin Amirpour
- Cardiac Rehabilitation Research Center, Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Jamshid Najafian
- Isfahan Cardiovascular Research Center, Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Alireza Khosravi
- Hypertension Research Center, Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Maryam Heidarpour
- Isfahan Endocrine and Metabolism Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mostafa Hekmat
- Heart Failure Research Center, Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Davood Shafie
- Heart Failure Research Center, Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran
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Główczyńska R, Piotrowicz E, Szalewska D, Piotrowicz R, Kowalik I, Pencina MJ, Zaręba W, Banach M, Orzechowski P, Pluta S, Irzmański R, Kalarus Z, Opolski G. Effects of hybrid comprehensive telerehabilitation on cardiopulmonary capacity in heart failure patients depending on diabetes mellitus: subanalysis of the TELEREH-HF randomized clinical trial. Cardiovasc Diabetol 2021; 20:106. [PMID: 33985509 PMCID: PMC8120915 DOI: 10.1186/s12933-021-01292-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Accepted: 04/27/2021] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Type 2 diabetes mellitus (DM) is one of the most common comorbidities among patients with heart failure (HF) with reduced ejection fraction (HFrEF). There are limited data regarding efficacy of hybrid comprehensive telerehabilitation (HCTR) on cardiopulmonary exercise capacity in patients with HFrEF with versus those without diabetes. AIM The aim of the present study was to analyze effects of 9-week HCTR in comparison to usual care on parameters of cardiopulmonary exercise capacity in HF patients according to history of DM. METHODS Clinically stable HF patients with left ventricular ejection fraction [LVEF] < 40% after a hospitalization due to worsening HF within past 6 months were enrolled in the TELEREH-HF (The TELEREHabilitation in Heart Failure Patients) trial and randomized to the HCTR or usual care (UC). Cardiopulmonary exercise tests (CPET) were performed on treadmill with an incremental workload according to the ramp protocol. RESULTS CPET was performed in 385 patients assigned to HCTR group: 129 (33.5%) had DM (HCTR-DM group) and 256 patients (66.5%) did not have DM (HCTR-nonDM group). Among 397 patients assigned to UC group who had CPET: 137 (34.5%) had DM (UC-DM group) and 260 patients (65.5%) did not have DM (UC-nonDM group). Among DM patients, differences in cardiopulmonary parameters from baseline to 9 weeks remained similar among HCTR and UC patients. In contrast, among patients without DM, HCTR was associated with greater 9-week changes than UC in exercise time, which resulted in a statistically significant interaction between patients with and without DM: difference in changes in exercise time between HCTR versus UC was 12.0 s [95% CI - 15.1, 39.1 s] in DM and 43.1 s [95% CI 24.0, 63.0 s] in non-DM, interaction p-value = 0.016. Furthermore, statistically significant differences in the effect of HCTR versus UC between DM and non-DM were observed in ventilation at rest: - 0.34 l/min [95% CI - 1.60, 0.91 l/min] in DM and 0.83 l/min [95% CI - 0.06, 1.73 l/min] in non-DM, interaction p value = 0.0496 and in VE/VCO2 slope: 1.52 [95% CI - 1.55, 4.59] for DM vs. - 1.44 [95% CI - 3.64, 0.77] for non-DM, interaction p value = 0.044. CONCLUSIONS The benefits of hybrid comprehensive telerehabilitation versus usual care on the improvement of physical performance, ventilatory profile and gas exchange parameters were more pronounced in patients with HFrEF without DM as compared to patients with DM. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT02523560. Registered 3rd August 2015. https://clinicaltrials.gov/ct2/show/NCT02523560?term=NCT02523560&draw=2&rank=1 . Other Study ID Numbers: STRATEGME1/233547/13/NCBR/2015.
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Affiliation(s)
- Renata Główczyńska
- 1st Chair and Department of Cardiology, Medical University of Warsaw, Warsaw, Poland
| | - Ewa Piotrowicz
- Telecardiology Center, National Institute of Cardiology, Alpejska Str. 42, 04-828, Warsaw, Poland.
| | - Dominika Szalewska
- Clinic of Rehabilitation Medicine, Faculty of Health Sciences, Medical University of Gdańsk, Gdańsk, Poland
| | - Ryszard Piotrowicz
- National Institute of Cardiology, Warsaw, Poland
- Warsaw Academy of Medical Rehabilitation, Warsaw, Poland
| | | | | | | | - Maciej Banach
- Department of Hypertension, Medical University of Łódź, Lodz, Poland
| | - Piotr Orzechowski
- Telecardiology Center, National Institute of Cardiology, Alpejska Str. 42, 04-828, Warsaw, Poland
| | - Sławomir Pluta
- Department of Cardiology, Congenital Heart Diseases and Electrotherapy, Silesian Center for Heart Diseases, Silesian Medical University, Zabrze, Poland
| | - Robert Irzmański
- Department of Internal Medicine and Cardiac Rehabilitation, Medical University of Łódź, Lodz, Poland
| | - Zbigniew Kalarus
- Department of Cardiology, Congenital Heart Diseases and Electrotherapy, Silesian Center for Heart Diseases, Silesian Medical University, Zabrze, Poland
| | - Grzegorz Opolski
- 1st Chair and Department of Cardiology, Medical University of Warsaw, Warsaw, Poland
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Zhou L, Liu Y, Wang Z, Liu D, Xie B, Zhang Y, Yuan M, Tse G, Li G, Xu G, Liu T. Activation of NADPH oxidase mediates mitochondrial oxidative stress and atrial remodeling in diabetic rabbits. Life Sci 2021; 272:119240. [PMID: 33600862 DOI: 10.1016/j.lfs.2021.119240] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Revised: 02/05/2021] [Accepted: 02/13/2021] [Indexed: 01/05/2023]
Abstract
AIMS The mechanisms of atrial fibrillation (AF) in diabetes mellitus (DM) involve a complex interplay between increased oxidative stress, mitochondrial dysfunction and atrial remodeling. In this study, we examined the effects of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation on mitochondrial oxidative stress and atrial remodeling in a rabbit model of diabetes mellitus (DM). MAIN METHODS Healthy rabbits were selected and randomly divided into control, diabetic and apocynin administration group. Parameters of echocardiography, atrial electrophysiology, oxidative stress and mitochondrial function were compared between the different groups. KEY FINDINGS Compared to the control group, the DM group showed higher activity of NADPH oxidase, increased oxidative stress, larger left atrial diameter, a reduction in atrial mean conduction velocity. These findings were associated with increased interstitial fibrosis of the atria and higher atrial fibrillation (AF) inducibility. Moreover, atrial ultrastructure and mitochondrial function such as the mitochondrial respiratory control rate (RCR) were impaired. NADPH oxidase inhibition using the pharmacological agent apocynin improved these changes. SIGNIFICANCE NADPH oxidase activity plays an important role in mitochondrial oxidative stress, which is associated with AF inducibility by promoting adverse atrial remodeling. The NADPH oxidase inhibitor apocynin can prevent these pathological changes and may be a potential drug for AF treatment.
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Affiliation(s)
- Lingling Zhou
- Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin 300211, People's Republic of China
| | - Yang Liu
- Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin 300211, People's Republic of China; Department of Cardiology, Tianjin Fourth Central Hospital, The Fourth Central Hospital Affiliated to Nankai University, The Fourth Center Clinical College of Tianjin Medical University, Tianjin 300140, People's Republic of China
| | - Zhaojia Wang
- Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin 300211, People's Republic of China
| | - Daiqi Liu
- Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin 300211, People's Republic of China
| | - Bingxin Xie
- Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin 300211, People's Republic of China
| | - Yue Zhang
- Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin 300211, People's Republic of China
| | - Meng Yuan
- Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin 300211, People's Republic of China
| | - Gary Tse
- Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin 300211, People's Republic of China
| | - Guangping Li
- Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin 300211, People's Republic of China
| | - Gang Xu
- Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin 300211, People's Republic of China.
| | - Tong Liu
- Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin 300211, People's Republic of China.
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Nesti L, Pugliese NR, Sciuto P, Natali A. Type 2 diabetes and reduced exercise tolerance: a review of the literature through an integrated physiology approach. Cardiovasc Diabetol 2020; 19:134. [PMID: 32891175 PMCID: PMC7487838 DOI: 10.1186/s12933-020-01109-1] [Citation(s) in RCA: 90] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Accepted: 08/29/2020] [Indexed: 12/14/2022] Open
Abstract
The association between type 2 diabetes mellitus (T2DM) and heart failure (HF) is well established. Early in the course of the diabetic disease, some degree of impaired exercise capacity (a powerful marker of health status with prognostic value) can be frequently highlighted in otherwise asymptomatic T2DM subjects. However, the literature is quite heterogeneous, and the underlying pathophysiologic mechanisms are far from clear. Imaging-cardiopulmonary exercise testing (CPET) is a non-invasive, provocative test providing a multi-variable assessment of pulmonary, cardiovascular, muscular, and cellular oxidative systems during exercise, capable of offering unique integrated pathophysiological information. With this review we aimed at defying the cardiorespiratory alterations revealed through imaging-CPET that appear specific of T2DM subjects without overt cardiovascular or pulmonary disease. In synthesis, there is compelling evidence indicating a reduction of peak workload, peak oxygen assumption, oxygen pulse, as well as ventilatory efficiency. On the contrary, evidence remains inconclusive about reduced peripheral oxygen extraction, impaired heart rate adjustment, and lower anaerobic threshold, compared to non-diabetic subjects. Based on the multiparametric evaluation provided by imaging-CPET, a dissection and a hierarchy of the underlying mechanisms can be obtained. Here we propose four possible integrated pathophysiological mechanisms, namely myocardiogenic, myogenic, vasculogenic and neurogenic. While each hypothesis alone can potentially explain the majority of the CPET alterations observed, seemingly different combinations exist in any given subject. Finally, a discussion on the effects -and on the physiological mechanisms-of physical activity and exercise training on oxygen uptake in T2DM subjects is also offered. The understanding of the early alterations in the cardiopulmonary response that are specific of T2DM would allow the early identification of those at a higher risk of developing HF and possibly help to understand the pathophysiological link between T2DM and HF.
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Affiliation(s)
- Lorenzo Nesti
- Metabolism, Nutrition and Atherosclerosis Lab, Dietologia Universitaria, Pisa, Italy. .,Cardiopulmonary Test Lab, Department of Clinical and Experimental Medicine, University of Pisa, Via Savi 10, 56126, Pisa, Italy.
| | - Nicola Riccardo Pugliese
- Cardiopulmonary Test Lab, Department of Clinical and Experimental Medicine, University of Pisa, Via Savi 10, 56126, Pisa, Italy
| | - Paolo Sciuto
- Metabolism, Nutrition and Atherosclerosis Lab, Dietologia Universitaria, Pisa, Italy
| | - Andrea Natali
- Metabolism, Nutrition and Atherosclerosis Lab, Dietologia Universitaria, Pisa, Italy
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8
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Noninvasive peripheral vascular function and atrial fibrillation in the general population. J Hypertens 2019; 37:928-934. [DOI: 10.1097/hjh.0000000000002000] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Elshazly MB, Senn T, Wu Y, Lindsay B, Saliba W, Wazni O, Cho L. Impact of Atrial Fibrillation on Exercise Capacity and Mortality in Heart Failure With Preserved Ejection Fraction: Insights From Cardiopulmonary Stress Testing. J Am Heart Assoc 2017; 6:JAHA.117.006662. [PMID: 29089343 PMCID: PMC5721762 DOI: 10.1161/jaha.117.006662] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Background Atrial fibrillation (AF) has been objectively associated with exercise intolerance in patients with heart failure with reduced ejection fraction; however, its impact in patients with heart failure with preserved ejection fraction has not been fully scrutinized. Methods and Results We identified 1744 patients with heart failure and ejection fraction ≥50% referred for cardiopulmonary stress testing at the Cleveland Clinic (Cleveland, OH), 239 of whom had AF. We used inverse probability of treatment weighting to balance clinical characteristics between patients with and without AF. A weighted linear regression model, adjusted for unbalanced variables (age, sex, diagnosis, hypertension, and β‐blocker use), was used to compare metabolic stress parameters and 8‐year total mortality (social security index) between both groups. Weighted mean ejection fraction was 58±5.9% in the entire population. After adjusting for unbalanced weighted variables, patients with AF versus those without AF had lower mean peak oxygen consumption (18.5±6.2 versus 20.3±7.1 mL/kg per minute), oxygen pulse (12.4±4.3 versus 12.9±4.7 mL/beat), and circulatory power (2877±1402 versus 3351±1788 mm Hg·mL/kg per minute) (P<0.001 for all comparisons) but similar submaximal exercise capacity (oxygen consumption at anaerobic threshold, 12.0±5.1 versus 12.4±6.0mL/kg per minute; P =0.3). Both groups had similar peak heart rate, whereas mean peak systolic blood pressure was lower in the AF group (150±35 versus 160±51 mm Hg; P<0.001). Moreover, AF was associated with higher total mortality. Conclusions In the largest study of its kind, we demonstrate that AF is associated with peak exercise intolerance, impaired contractile reserve, and increased mortality in patients with heart failure with preserved ejection fraction. Whether AF is the primary offender in these patients or merely a bystander to worse diastolic function requires further investigation.
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Affiliation(s)
- Mohamed B Elshazly
- Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic, Cleveland, OH.,Division of Cardiology, Department of Medicine, Weill Cornell Medical College-Qatar, Education City, Doha, Qatar
| | - Todd Senn
- Department of Cardiovascular Medicine, Columbia Heart, Columbia, SC
| | - Yuping Wu
- Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic, Cleveland, OH.,Department of Mathematics, Cleveland State University, Cleveland, OH
| | - Bruce Lindsay
- Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic, Cleveland, OH
| | - Walid Saliba
- Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic, Cleveland, OH
| | - Oussama Wazni
- Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic, Cleveland, OH
| | - Leslie Cho
- Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic, Cleveland, OH
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Triposkiadis F, Pieske B, Butler J, Parissis J, Giamouzis G, Skoularigis J, Brutsaert D, Boudoulas H. Global left atrial failure in heart failure. Eur J Heart Fail 2016; 18:1307-1320. [DOI: 10.1002/ejhf.645] [Citation(s) in RCA: 71] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2016] [Revised: 07/21/2016] [Accepted: 07/24/2016] [Indexed: 01/08/2023] Open
Affiliation(s)
- Filippos Triposkiadis
- Department of Cardiology; Larissa University Hospital; PO Box 1425 411 10 Larissa Greece
| | - Burkert Pieske
- Department of Internal Medicine and Cardiology, Charité University Medicine Berlin-Campus Virchow Klinikum, and Department of Internal Medicine and Cardiology, German Heart Centre; Berlin Centre for Heart Failure; Berlin Germany
| | - Javed Butler
- Cardiology Division, School of Medicine; Stony Brook University; Stony Brook NY USA
| | - John Parissis
- Department of Cardiology; Athens University Hospital Attikon; Athens Greece
| | - Gregory Giamouzis
- Department of Cardiology; Larissa University Hospital; PO Box 1425 411 10 Larissa Greece
| | - John Skoularigis
- Department of Cardiology; Larissa University Hospital; PO Box 1425 411 10 Larissa Greece
| | - Dirk Brutsaert
- Laboratory of Physiopharmacology (Building T2); University of Antwerp; Universiteitsplein 1 Antwerp 2610 Belgium
| | - Harisios Boudoulas
- Ohio State University; Columbus Ohio USA
- Biomedical Research Foundation Academy of Athens; Athens, and Aristotelian University of Thessaloniki; Thessaloniki Greece
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11
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Alves-Cabratosa L, García-Gil M, Comas-Cufí M, Martí R, Ponjoan A, Parramon D, Blanch J, Ramos R. Diabetes and new-onset atrial fibrillation in a hypertensive population. Ann Med 2016; 48:119-27. [PMID: 26939743 DOI: 10.3109/07853890.2016.1144930] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
AIM The association of diabetes with new-onset atrial fibrillation (AF) remains controversial. Hypertension may partly explain the risk association ascribed to diabetes. We studied the role and characteristics of diabetes in hypertensive patients with no ischemic vascular disease. METHODS Records of 262,892 persons from the Information System for the Development of Research in Primary Care in Catalonia (Spain) were examined from July 2006 to December 2011. Included participants were ≥55-years-old and hypertensive with no ischemic heart disease, stroke, or peripheral artery disease. We used Cox proportional hazards regression to model incidences in the diabetic and non-diabetic subgroups of our population, and among diabetic patients, diabetes duration and pharmacological treatment, hemoglobin A1C, and body mass index. RESULTS New-onset AF incidence in diabetic patients was 13.3 per 1000 person-years (mean follow-up: 4.3 years). In non-diabetic patients, it was 10.4 per 1000 person-years (mean follow-up: 4.1 years). Diabetes hazard ratio (HR) for new-onset AF was 1.11 (95% confidence interval (CI): 1.06-1.16). Diabetic patients also diagnosed with obesity had an HR of 1.41 (95% CI: 1.22-1.64). CONCLUSION Diabetes was modestly associated with new-onset AF in hypertensive patients with no ischemic vascular disease. Among diabetic patients, only obesity reached significance in its association with this arrhythmia.
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Affiliation(s)
- Lia Alves-Cabratosa
- a Vascular Health Research Group (ISV)-Girona, Jordi Gol Institute for Primary Care Research (IDIAP Jordi Gol) , Catalonia , Spain
| | - Maria García-Gil
- a Vascular Health Research Group (ISV)-Girona, Jordi Gol Institute for Primary Care Research (IDIAP Jordi Gol) , Catalonia , Spain ;,b Translab Research Group, Department of Medical Sciences , School of Medicine, University of Girona , Girona , Spain
| | - Marc Comas-Cufí
- a Vascular Health Research Group (ISV)-Girona, Jordi Gol Institute for Primary Care Research (IDIAP Jordi Gol) , Catalonia , Spain
| | - Ruth Martí
- a Vascular Health Research Group (ISV)-Girona, Jordi Gol Institute for Primary Care Research (IDIAP Jordi Gol) , Catalonia , Spain ;,c Girona Biomedical Research Institute (IdibGi), Dr. Trueta University Hospital , Catalonia , Spain
| | - Anna Ponjoan
- a Vascular Health Research Group (ISV)-Girona, Jordi Gol Institute for Primary Care Research (IDIAP Jordi Gol) , Catalonia , Spain ;,c Girona Biomedical Research Institute (IdibGi), Dr. Trueta University Hospital , Catalonia , Spain
| | - Dídac Parramon
- a Vascular Health Research Group (ISV)-Girona, Jordi Gol Institute for Primary Care Research (IDIAP Jordi Gol) , Catalonia , Spain ;,d Primary Care Services, Girona, Catalan Institute of Health (ICS) , Catalonia , Spain
| | - Jordi Blanch
- a Vascular Health Research Group (ISV)-Girona, Jordi Gol Institute for Primary Care Research (IDIAP Jordi Gol) , Catalonia , Spain
| | - Rafel Ramos
- a Vascular Health Research Group (ISV)-Girona, Jordi Gol Institute for Primary Care Research (IDIAP Jordi Gol) , Catalonia , Spain ;,b Translab Research Group, Department of Medical Sciences , School of Medicine, University of Girona , Girona , Spain ;,d Primary Care Services, Girona, Catalan Institute of Health (ICS) , Catalonia , Spain
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12
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Corrêa APDS, Antunes CF, Figueira FR, de Castro MA, Ribeiro JP, Schaan BD. Effect of acute inspiratory muscle exercise on blood flow of resting and exercising limbs and glucose levels in type 2 diabetes. PLoS One 2015; 10:e0121384. [PMID: 25803283 PMCID: PMC4372446 DOI: 10.1371/journal.pone.0121384] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2014] [Accepted: 01/31/2015] [Indexed: 11/19/2022] Open
Abstract
To evaluate the effects of inspiratory loading on blood flow of resting and exercising limbs in patients with diabetic autonomic neuropathy. Ten diabetic patients without cardiovascular autonomic neuropathy (DM), 10 patients with cardiovascular autonomic neuropathy (DM-CAN) and 10 healthy controls (C) were randomly assigned to inspiratory muscle load of 60% or 2% of maximal inspiratory pressure (PImax) for approximately 5 min, while resting calf blood flow (CBF) and exercising forearm blood flow (FBF) were measured. Reactive hyperemia was also evaluated. From the 20 diabetic patients initially allocated, 6 wore a continuous glucose monitoring system to evaluate the glucose levels during these two sessions (2%, placebo or 60%, inspiratory muscle metaboreflex). Mean age was 58 ± 8 years, and mean HbA1c, 7.8% (62 mmol/mol) (DM and DM-CAN). A PImax of 60% caused reduction of CBF in DM-CAN and DM (P<0.001), but not in C, whereas calf vascular resistance (CVR) increased in DM-CAN and DM (P<0.001), but not in C. The increase in FBF during forearm exercise was blunted during 60% of PImax in DM-CAN and DM, and augmented in C (P<0.001). Glucose levels decreased by 40 ± 18.8% (P<0.001) at 60%, but not at 2%, of PImax. A negative correlation was observed between reactive hyperemia and changes in CVR (Beta coefficient = -0.44, P = 0.034). Inspiratory muscle loading caused an exacerbation of the inspiratory muscle metaboreflex in patients with diabetes, regardless of the presence of neuropathy, but influenced by endothelial dysfunction. High-intensity exercise that recruits the diaphragm can abruptly reduce glucose levels.
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Affiliation(s)
- Ana Paula dos Santos Corrêa
- Exercise Pathophysiology Research Laboratory, Hospital de Clínicas de Porto Alegre, Porto Alegre, Rio Grande do Sul, Brasil
- Faculty of Health Sciences, University of Sydney, Lidcombe, NSW, Australia
| | - Cristiano Fetter Antunes
- Exercise Pathophysiology Research Laboratory, Hospital de Clínicas de Porto Alegre, Porto Alegre, Rio Grande do Sul, Brasil
| | - Franciele Ramos Figueira
- Exercise Pathophysiology Research Laboratory, Hospital de Clínicas de Porto Alegre, Porto Alegre, Rio Grande do Sul, Brasil
- Postgraduate Program in Endocrinology and Department of Internal Medicine, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brasil
| | - Marina Axmann de Castro
- Postgraduate Program in Pneumology Science, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brasil
| | - Jorge Pinto Ribeiro
- Exercise Pathophysiology Research Laboratory, Hospital de Clínicas de Porto Alegre, Porto Alegre, Rio Grande do Sul, Brasil
- Postgraduate Program in Cardiology, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brasil
| | - Beatriz D’Agord Schaan
- Exercise Pathophysiology Research Laboratory, Hospital de Clínicas de Porto Alegre, Porto Alegre, Rio Grande do Sul, Brasil
- Postgraduate Program in Endocrinology and Department of Internal Medicine, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brasil
- * E-mail:
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13
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Magrì D, Agostoni P, Corrà U, Passino C, Scrutinio D, Perrone-Filardi P, Correale M, Cattadori G, Metra M, Girola D, Piepoli MF, Iorio A, Emdin M, Raimondo R, Re F, Cicoira M, Belardinelli R, Guazzi M, Limongelli G, Clemenza F, Parati G, Frigerio M, Casenghi M, Scardovi AB, Ferraironi A, Di Lenarda A, Bussotti M, Apostolo A, Paolillo S, La Gioia R, Gargiulo P, Palermo P, Minà C, Farina S, Battaia E, Maruotti A, Pacileo G, Contini M, Oliva F, Ricci R, Sinagra G. Deceptive meaning of oxygen uptake measured at the anaerobic threshold in patients with systolic heart failure and atrial fibrillation. Eur J Prev Cardiol 2014; 22:1046-55. [DOI: 10.1177/2047487314551546] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2014] [Accepted: 08/26/2014] [Indexed: 01/23/2023]
Affiliation(s)
- Damiano Magrì
- Department of Clinical and Molecular Medicine, “La Sapienza” University of Rome, Italy
- Centro Cardiologico Monzino, IRCCS, Italy
| | - Piergiuseppe Agostoni
- Centro Cardiologico Monzino, IRCCS, Italy
- Department of Clinical Sciences and Community Health, University of Milano, Italy
| | - Ugo Corrà
- Divisione di Cardiologia Riabilitativa, Fondazione Salvatore Maugeri, IRCCS, Istituto Scientifico di Veruno, Italy
| | - Claudio Passino
- Fondazione Gabriele Monasterio, CNR-Regione Toscana, Italy
- Scuola Superiore S. Anna, Italy
| | - Domenico Scrutinio
- Division of Cardiology, “S. Maugeri” Foundation, IRCCS, Institute of Cassano Murge, Italy
| | | | | | | | - Marco Metra
- Cardiology, Department of Medical and Surgical Specialities, Radiological Sciences, and Public Health, University of Brescia, Italy
| | - Davide Girola
- Dipartimento Cardiologico “A. De Gasperis”, Ospedale Cà Granda- A.O. Niguarda, Italy
| | | | - AnnaMaria Iorio
- Cardiovascular Department, Ospedali Riuniti and University of Trieste, Italy
| | - Michele Emdin
- Fondazione Gabriele Monasterio, CNR-Regione Toscana, Italy
| | - Rosa Raimondo
- Fondazione Salvatore Maugeri, IRCCS, Istituto Scientifico di Tradate, Italy
| | - Federica Re
- Cardiology Division, Cardiac Arrhythmia Center and Cardiomyopathies Unit, San Camillo-Forlanini Hospital, Italy
| | | | | | - Marco Guazzi
- Heart Failure Unit, IRCCS Policlinico San Donato, Italy
| | - Giuseppe Limongelli
- Cardiologia SUN, Ospedale Monaldi (Azienda dei Colli), Seconda Università di Napoli, Italy
| | - Francesco Clemenza
- Mediterranean Institute for Transplantation and Advanced Specialized Therapies, Italy
| | | | - Maria Frigerio
- Dipartimento Cardiologico “A. De Gasperis”, Ospedale Cà Granda- A.O. Niguarda, Italy
| | - Matteo Casenghi
- Department of Clinical and Molecular Medicine, “La Sapienza” University of Rome, Italy
| | | | | | | | - Maurizio Bussotti
- Division of Cardiology, Salvatore Maugeri Foundation, IRCCS, Institute of Milan, Italy
| | | | - Stefania Paolillo
- Department of Advanced Biomedical Sciences, “Federico II” University, Italy
| | - Rocco La Gioia
- Division of Cardiology, “S. Maugeri” Foundation, IRCCS, Institute of Cassano Murge, Italy
| | - Paola Gargiulo
- SDN Foundation, Institute of Diagnostic and Nuclear Development, Napoli, Italy
| | | | - Chiara Minà
- Mediterranean Institute for Transplantation and Advanced Specialized Therapies, Italy
| | | | - Elisa Battaia
- Section of Cardiology, Department of Medicine, University of Verona, Italy
| | - Antonello Maruotti
- Southampton Statistical Sciences Research Institute & School of Mathematics, University of Southampton, United Kingdom
- Department of Politic Sciences, Università “Roma Tre”, Italy
| | - Giuseppe Pacileo
- Cardiologia SUN, Ospedale Monaldi (Azienda dei Colli), Seconda Università di Napoli, Italy
| | | | - Fabrizio Oliva
- Dipartimento Cardiologico “A. De Gasperis”, Ospedale Cà Granda- A.O. Niguarda, Italy
| | | | - Gianfranco Sinagra
- Cardiovascular Department, Ospedali Riuniti and University of Trieste, Italy
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14
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Zakeri R, Borlaug BA, McNulty SE, Mohammed SF, Lewis GD, Semigran MJ, Deswal A, LeWinter M, Hernandez AF, Braunwald E, Redfield MM. Impact of atrial fibrillation on exercise capacity in heart failure with preserved ejection fraction: a RELAX trial ancillary study. Circ Heart Fail 2013; 7:123-30. [PMID: 24162898 DOI: 10.1161/circheartfailure.113.000568] [Citation(s) in RCA: 116] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
BACKGROUND Atrial fibrillation (AF) is common among patients with heart failure and preserved ejection fraction (HFpEF), but its clinical profile and impact on exercise capacity remain unclear. RELAX (Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in HFpEF) was a multicenter randomized trial testing the impact of sildenafil on peak VO2 in stable outpatients with chronic HFpEF. We sought to compare clinical features and exercise capacity among patients with HFpEF who were in sinus rhythm (SR) or AF. METHODS AND RESULTS RELAX enrolled 216 patients with HFpEF, of whom 79 (37%) were in AF, 124 (57%) in SR, and 13 in other rhythms. Participants underwent baseline cardiopulmonary exercise testing, echocardiogram, biomarker assessment, and rhythm status assessment before randomization. Patients with AF were older than those in SR but had similar symptom severity, comorbidities, and renal function. β-blocker use and chronotropic indices were also similar. Despite comparable left ventricular size and mass, AF was associated with worse systolic (lower EF, stroke volume, and cardiac index) and diastolic (shorter deceleration time and larger left atria) function compared with SR. Pulmonary artery systolic pressure was higher in AF. Patients with AF had higher N-terminal pro-B-type natriuretic peptide, aldosterone, endothelin-1, troponin I, and C-telopeptide for type I collagen levels, suggesting more severe neurohumoral activation, myocyte necrosis, and fibrosis. Peak VO2 was lower in AF, even after adjustment for age, sex, and chronotropic response, and VE/VCO2 was higher. CONCLUSIONS AF identifies an HFpEF cohort with more advanced disease and significantly reduced exercise capacity. These data suggest that evaluation of the impact of different rate or rhythm control strategies on exercise tolerance in patients with HFpEF and AF is warranted. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00763867.
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15
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Jover E, Marín F, Roldán V, Montoro-García S, Valdés M, Lip GYH. Atherosclerosis and thromboembolic risk in atrial fibrillation: focus on peripheral vascular disease. Ann Med 2013; 45:274-90. [PMID: 23216106 DOI: 10.3109/07853890.2012.732702] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Atrial fibrillation (AF) is the most common cardiac arrhythmia in clinical practice. It results in a 5-fold increased risk for stroke and thromboembolism and is associated with a high morbidity and mortality. AF shares several risk factors and pathophysiological features with atherosclerosis. Hence AF is often complicated by a variety of other cardiovascular conditions. Indeed, peripheral vascular disease (PVD) is highly prevalent among AF patients and associates with increased mortality. Inclusion of PVD within stroke risk scoring systems such as the CHA2DS2-VASc score improves risk stratification of AF patients. Of note, PVD has not been previously well documented nor looked for in observational studies or clinical trials. The aim of this present review article is to provide an overview of the association between atherosclerosis (with particular focus on PVD) and AF as well as its complications.
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Affiliation(s)
- Eva Jover
- Department of Cardiology, Hospital Universitario Virgen de la Arrixaca, Murcia, Spain
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16
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Mechanism of and therapeutic strategy for atrial fibrillation associated with diabetes mellitus. ScientificWorldJournal 2013; 2013:209428. [PMID: 23576900 PMCID: PMC3612491 DOI: 10.1155/2013/209428] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2013] [Accepted: 02/19/2013] [Indexed: 12/28/2022] Open
Abstract
Diabetes mellitus (DM) is one of the most important risk factors for atrial fibrillation (AF) and is a predictor of stroke and thromboembolism. DM may increase the incidence of AF, and when it is combined with other risk factors, the incidence of stroke and thromboembolism may also be higher; furthermore, hospitalization due to heart failure appears to increase. Maintenance of well-controlled blood glucose and low levels of HbA1c in accordance with guidelines may decrease the incidence of AF. The mechanisms of AF associated with DM are autonomic remodeling, electrical remodeling, structural remodeling, and insulin resistance. Inhibition of the renin-angiotensin system is suggested to be an upstream therapy for this type of AF. Studies have indicated that catheter ablation may be effective for AF associated with DM, restoring sinus rhythm and improving prognosis. Catheter ablation combined with hypoglycemic agents may further increase the rate of maintenance of sinus rhythm and reduce the need for reablation.
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17
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The Role of Ascorbic Acid Supplementation in the Prevention of Atrial Fibrillation After Coronary Artery Bypass Surgery. TOP CLIN NUTR 2013. [DOI: 10.1097/tin.0b013e31827dfa63] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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18
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RAVIELE ANTONIO, RONCO FEDERICO. Endothelial Dysfunction and Atrial Fibrillation: What is the Relationship? J Cardiovasc Electrophysiol 2010; 22:383-4. [DOI: 10.1111/j.1540-8167.2010.01954.x] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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Hadi HA, Alsheikh-Ali AA, Mahmeed WA, Suwaidi JMA. Inflammatory cytokines and atrial fibrillation: current and prospective views. J Inflamm Res 2010; 3:75-97. [PMID: 22096359 PMCID: PMC3218735 DOI: 10.2147/jir.s10095] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
Atrial fibrillation (AF) is the most common sustained arrhythmia and a challenging clinical problem encountered in daily clinical practice. There is an increasing body of evidence linking inflammation to a broad spectrum of cardiovascular conditions including AF. Historical evidence supports an association between AF and inflammation and is consistent with the association of AF with inflammatory conditions of the heart, such as myocarditis and pericarditis. AF has been associated with myocardial oxidative stress, and antioxidant agents have demonstrated antiarrhythmic benefit in humans. Increased plasma interleukin (IL)-6, C-reactive protein (CRP), and plasma viscosity support the existence of an inflammatory state among "typical" populations with chronic AF. These indexes of inflammation are related to the prothrombotic state and may be linked to the clinical characteristics of the patients (underlying vascular disease and comorbidities), rather than simply to the presence of AF itself. It has been suggested that inflammation may have a role in the development of atrial arrhythmias after cardiac surgery, and that a genetic predisposition to develop postoperative complications exists. Cytokines can have a prognostic significance; IL-6 levels, CRP, and other cytokines may have prognostic value in AF. Cytokine lowering therapies, statins, angiotensin converting enzyme inhibitors and other anti-inflammatory agents may have a role in the treatment of AF. The present article provides an overview of the evidence linking inflammatory cytokines to AF and their therapeutic and prognostic implications.
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Affiliation(s)
- Hadi Ar Hadi
- Institute of Cardiac Sciences, Sheikh Khalifa Medical City, Abu Dhabi, United Arab Emirates
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20
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Balady GJ, Arena R, Sietsema K, Myers J, Coke L, Fletcher GF, Forman D, Franklin B, Guazzi M, Gulati M, Keteyian SJ, Lavie CJ, Macko R, Mancini D, Milani RV. Clinician's Guide to cardiopulmonary exercise testing in adults: a scientific statement from the American Heart Association. Circulation 2010; 122:191-225. [PMID: 20585013 DOI: 10.1161/cir.0b013e3181e52e69] [Citation(s) in RCA: 1431] [Impact Index Per Article: 95.4] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
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Abstract
1. We believe that the ultimate goal of cardiovascular regulatory mechanisms is not the regulation of arterial blood pressure (BP), but the maintenance of tissue blood flows commensurate with metabolic requirements. Thus, elevated BP can potentially contribute to optimizing tissue blood flows under select circumstances; for example, when there are primary defects in autoregulation of tissue blood flows. 2. The hypothesis that a primary defect in autoregulation of tissue blood flows may be responsible for the development of hypertension is presented. It is argued that, in this context, at least part of the rise in BP may be reflexly driven by a 'metaboreflex', a homeostatic mechanism acting to regulate tissue blood flows. 3. We argue that in the context of primary defects in autoregulation of tissue blood flows, the ability to generate and sustain a hypertensive phenotype increases the lifespan of species (i.e. if it were not for this adaptive hypertensive phenotype, death due to circulatory failure would occur much earlier). 4. Experimental and clinical evidence that indirectly supports the hypothesis is reviewed briefly and a means for testing this hypothesis is suggested.
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Affiliation(s)
- E S Prakash
- Faculty of Medicine, AIMST University, Bedong, Kedah, Malaysia.
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22
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Reactive oxidative metabolites are associated with atrial conduction disturbance in patients with atrial fibrillation. Heart Rhythm 2009; 6:935-40. [PMID: 19560081 DOI: 10.1016/j.hrthm.2009.03.012] [Citation(s) in RCA: 64] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2008] [Accepted: 03/03/2009] [Indexed: 12/15/2022]
Abstract
BACKGROUND Oxidative stress is associated with atrial fibrillation (AF). However, little is known about the relationship between serum markers of oxidation and electrical activity in patients with AF. OBJECTIVE The purpose of this study was to investigate the possible association between serum markers of reactive oxidative metabolism and atrial remodeling in paroxysmal and persistent AF. METHODS Derivatives of reactive oxidative metabolites (DROM), an index of oxidative stress, were measured in 306 consecutive patients with AF (225 paroxysmal, 81 persistent) undergoing radiofrequency (RF) catheter ablation. Filtered P-wave duration by P-wave signal-averaged ECG and levels of high-sensitivity C-reactive protein (CRP) as an inflammatory marker also were measured. RESULTS Patients were followed up for 1.2 +/- 0.8 years. DROM levels in patients with persistent AF were significantly higher than in patients with paroxysmal AF (341.6 +/- 85.5 Carratelli [Carr] units vs 305.0 +/- 77.7 Carr units, P <.001). DROM levels showed a tighter, positive correlation with filtered P-wave duration in persistent AF patients (r = 0.56, P <.001) than in all AF patients (r = 0.13, P <.05). DROM levels also showed a weaker but significant correlation with high-sensitivity CRP in patients with AF. Kaplan-Meier analysis revealed that the highest quartile of basal DROM levels exhibited a significantly higher AF recurrence rate after RF catheter ablation in patients with paroxysmal AF (P <.01). CONCLUSION Serum markers of oxidative stress reflect atrial conduction disturbance and predict AF recurrence after RF catheter ablation in paroxysmal AF patients. DROM could serve as a biomarker for predicting risk of AF recurrence after RF catheter ablation.
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Guazzi M, Reina G, Gripari P, Tumminello G, Vicenzi M, Arena R. Prognostic value of flow-mediated dilatation following myocardial infarction. Int J Cardiol 2009; 132:45-50. [DOI: 10.1016/j.ijcard.2007.10.036] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2007] [Revised: 07/12/2007] [Accepted: 10/27/2007] [Indexed: 11/26/2022]
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Agostoni P, Emdin M, Corra U, Veglia F, Magri D, Tedesco CC, Berton E, Passino C, Bertella E, Re F, Mezzani A, Belardinelli R, Colombo C, La Gioia R, Vicenzi M, Giannoni A, Scrutinio D, Giannuzzi P, Tondo C, Di Lenarda A, Sinagra G, Piepoli MF, Guazzi M. Permanent atrial fibrillation affects exercise capacity in chronic heart failure patients. Eur Heart J 2008; 29:2367-72. [DOI: 10.1093/eurheartj/ehn361] [Citation(s) in RCA: 57] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
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25
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Long-term use of sildenafil in the therapeutic management of heart failure. J Am Coll Cardiol 2007; 50:2136-44. [PMID: 18036451 DOI: 10.1016/j.jacc.2007.07.078] [Citation(s) in RCA: 231] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2007] [Revised: 07/06/2007] [Accepted: 07/23/2007] [Indexed: 12/16/2022]
Abstract
OBJECTIVES This study sought to test the functional exercise capacity and endothelial function in a cohort of chronic heart failure (CHF) patients treated with chronic type 5 phosphodiesterase (PDE5) inhibitor. BACKGROUND In CHF, endothelial dysfunction is involved in muscle underperfusion, ergoreflex oversignaling, and exercise ventilation inefficiency. Inhibition of PDE5 by improving endothelial dysfunction might be beneficial. METHODS Stable CHF patients were randomly assigned to placebo (23 patients) or sildenafil at the dose of 50 mg twice per day (23 patients) in addition to their current drug treatment for 6 months, with assessments (at 3 and 6 months) of endothelial function by brachial artery flow-mediated dilatation (FMD), cardiopulmonary exercise testing, and ergoreflex response. RESULTS In the sildenafil group only, at 3 and 6 months we observed reduction of systolic pulmonary artery pressure (from 33.7 to 25.2 mm Hg and 23.9 mm Hg), ergoreflex effect on ventilation (from 6.9 to 2.3 l x min(-1) and 1.9 l x min(-1)), ventilation to CO2 production slope (V(E)/VCO2, from 35.5 to 32.1 and 29.8), and breathlessness (score) (from 23.6 to 16.6 and 17.2), and an increase of FMD (from 8.5% to 13.4% and 14.2%), peak VO2 (from 14.8 to 18.5 ml x min(-1) x kg(-1) and 18.7 ml x min(-1) x kg(-1)), and ratio of VO2 to work rate changes (from 7.7 to 9.3 and 10.1). All changes were significant at p < 0.01. In the sildenafil group, a significant correlation was found at 3 and 6 months between changes in FMD and those in ergoreflex. Changes in ergoreflex correlated with those in peak VO2 and V(E)/VCO2 slope. No adverse effects were noted except for flushing in 3 patients. CONCLUSIONS In CHF, improvement in exercise ventilation and aerobic efficiency with sildenafil is sustained and is significantly related with an endothelium-mediated attenuation of exercising muscle oversignaling. Chronic sildenafil seems to be a remedy based on CHF pathophysiology and devoid of remarkable adverse effects.
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Neuman RB, Bloom HL, Shukrullah I, Darrow LA, Kleinbaum D, Jones DP, Dudley SC. Oxidative stress markers are associated with persistent atrial fibrillation. Clin Chem 2007; 53:1652-7. [PMID: 17599958 PMCID: PMC3158654 DOI: 10.1373/clinchem.2006.083923] [Citation(s) in RCA: 166] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Atrial fibrillation (AF) has been associated with myocardial oxidative stress, and antioxidant agents have demonstrated antiarrhythmic benefit in humans. We compared serum markers of oxidation and associated inflammation in individuals with or without AF. METHODS Serum markers of oxidative stress and inflammation were compared in a cross-sectional, case-control design study of 40 male individuals, with or without persistent or permanent AF, who were matched for age, sex, diabetes, and smoking status, known confounding variables for the measurement of oxidative stress. We used derivatives of reactive oxidative metabolites (DROMs) and ratios of oxidized to reduced glutathione (E(h) GSH) and cysteine (E(h) CySH) to quantify oxidative stress. We also measured inflammatory markers, including high-sensitivity C-reactive protein, interleukins 1beta and 6, and tumor necrosis factor alpha. RESULTS Univariate, conditional logistical regression analysis showed that oxidative stress but not inflammatory markers were statistically associated with AF (P <0.05). The increase in the odds ratios for AF for E(h) GSH, E(h) CySH, and DROMs were 6.1 (95% CI, 1.3-28.3; P = 0.02), 13.6 (95% CI, 2.5-74.1; P = 0.01), and 15.9 (95% CI, 1.7-153.9; P = 0.02), respectively. There was a stronger correlation between E(h) GSH and E(h) CySH (r = 0.66) than between E(h) GSH and DROMs (r = 0.41). In multivariate analysis corrected for statins and other AF risk factors differing between the groups, the association of AF and oxidative stress remained significant. CONCLUSIONS These data suggest that oxidative stress markers may have predictive value in AF management.
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Affiliation(s)
- Robert B. Neuman
- Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, GA
| | - Heather L. Bloom
- Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, GA
- Division of Cardiology, Atlanta Veterans Affairs Medical Center, Atlanta, GA
| | - Irfan Shukrullah
- Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, GA
- Division of Cardiology, Atlanta Veterans Affairs Medical Center, Atlanta, GA
| | | | - David Kleinbaum
- Rollins School of Public Health, Emory University, Atlanta, GA
| | - Dean P. Jones
- Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Emory University School of Medicine, Atlanta, GA
| | - Samuel C. Dudley
- Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, GA
- Division of Cardiology, Atlanta Veterans Affairs Medical Center, Atlanta, GA
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Guazzi M, Casali M, Berti F, Rossoni G, Colonna VD, Guazzi MD. Endothelium-mediated modulation of ergoreflex and improvement in exercise ventilation by acute sildenafil in heart failure patients. Clin Pharmacol Ther 2007; 83:336-41. [PMID: 17653139 DOI: 10.1038/sj.clpt.6100306] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Reflex neural oversignaling sensitive to muscle by-products (ergoreflex) causes exercise hyperventilation in heart failure (HF). We probed whether an improved endothelial function with sildenafil intake may prevent this effect. In 16 chronic heart failure patients and 16 normal subjects, before and after sildenafil intake (50 mg) or placebo, we measured ergoreflex, flow-mediated brachial artery dilation (FMD, an index of endothelial function), and, during maximal exercise, the slope of ventilation to carbon dioxide production (VE/VCO2, an index of ventilatory efficiency), the ratio of changes in O2 uptake (VO2) versus work rate (WR) (deltaVO2/deltaWR, an index of aerobic efficiency). After sildenafil intake, patients, unlike controls, showed a significant decrease in ergoreflex and VE/VCO2 slope and an increase in FMD and deltaVO2/deltaWR. Ergoreflex changes with sildenafil intake correlated with those in FMD and VE/VCO2. Phosphodiesterase-5 inhibition, by improving endothelial activity and muscle perfusion, modulates signaling and improves ventilatory and aerobic efficiencies, potentially indicating a novel pathway in the HF therapeutic management.
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Affiliation(s)
- M Guazzi
- Cardiopulmonary Unit, Cardiology Division, University of Milano, San Paolo Hospital, Milano, Italy.
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Guazzi M, Tumminello G, Reina G, Vicenzi M, Guazzi MD. Atorvastatin therapy improves exercise oxygen uptake kinetics in post-myocardial infarction patients. Eur J Clin Invest 2007; 37:454-62. [PMID: 17537152 DOI: 10.1111/j.1365-2362.2007.01805.x] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
BACKGROUND Statins represent a modern mainstay of the drug treatment of coronary artery disease and acute coronary syndromes. Reduced aerobic work performance and slowed VO(2) kinetics are established features of the clinical picture of post-myocardial infarction (MI) patients. We tested the hypothesis that statin therapy improves VO(2) exercise performance in normocholesterolaemic post-MI patients. MATERIALS AND METHODS According to a double-blinded, randomized, crossover and placebo-controlled study design, in 18 patients with uncomplicated recent (3 days) MI we investigated the effects of atorvastatin (20 mg day(-1)) on gas exchange kinetics by calculating VO(2) effective time constant (tau) during a 50-watt constant workload exercise, brachial artery flow-mediated dilatation (FMD) as an index of endothelial function, left ventricular function (echocardiography) and C-reactive protein (CRP, as an index of inflammation). Atorvastatin or placebo was given for 3 months each. RESULTS Atorvastatin therapy significantly improved exercise VO(2) tau and FMD, and reduced CRP levels. We did not observe changes in cardiac contractile function and relaxation properties during all study periods in either group. CONCLUSIONS In post-MI patients exercise performance is a potential additional target of benefits related to statin therapy. Endothelial function improvement is very likely implicated in this newly described therapeutic property.
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Affiliation(s)
- M Guazzi
- Cardiopulmonary Unit, Cardiology Division, University of Milan, San Paolo Hospital, 20142 Milan, Italy.
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Guazzi M, Belletti S, Lenatti L, Bianco E, Guazzi MD. Effects of cardioversion of atrial fibrillation on endothelial function in hypertension or diabetes. Eur J Clin Invest 2007; 37:26-34. [PMID: 17181564 DOI: 10.1111/j.1365-2362.2007.01744.x] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
BACKGROUND Cardioversion (CV) to sinus rhythm corrects endothelial dysfunction secondary to atrial fibrillation (AF). As AF often complicates hypertension and diabetes (disorders associated with impaired endothelial function) the study probed whether these comorbidities to AF produced an additive effect and to what extent CV might be advantageous. MATERIALS AND METHODS Brachial artery flow-mediated dilatation (FMD) was evaluated before and after CV in 17 lone AF patients (group 1), 16 patients with AF + hypertension (group 2) and 17 patients with AF + diabetes type II (group 3), while in supine and head-up tilting (HUT) positions, as this is when endothelial vasodilation is emphasized as a counterbalance to neurogenic vasoconstriction. RESULTS After 2 weeks, CV in group 1 increased (P < 0.01) supine FMD (from 7.22-->9.50%) and restored its HUT potentiation (from 9.31-->17.22%). In group 2, FMD also improved significantly with CV (supine from 4.92-->7.11% and HUT from 5.29-->11.83%; P < 0.01). In group 3, CV did not promote significant FMD changes (supine from 5.12-->4.92% and HUT from 4.98-->4.73%). After 3 months, FMD improvement persisted in groups 1 and 2 with enduring sinus rhythm, but not in those with AF relapse. In group 3, FMD remained unchanged regardless of cardiac rhythm. CONCLUSIONS Cardioversion persistently increases supine shear stress endothelial responsiveness and restores the orthostatic modulation in AF alone or in association with hypertension, but not with diabetes. Differences in background endothelial impairment may explain the presence (hypertension) or the absence (diabetes) of an additive AF effect in comorbidities, as well as CV results.
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Affiliation(s)
- M Guazzi
- University of Milan, San Paolo Hospital, Milan, Italy.
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Guazzi M, Berti M, Belletti S, Reina G, Guazzi MD. Exercise metaboreflex activation and endothelial function impairment in atrial fibrillation. Am J Physiol Heart Circ Physiol 2006; 291:H2396-402. [PMID: 16815988 DOI: 10.1152/ajpheart.00437.2006] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Exercising muscle hypoperfusion stimulates afferents (metaboreceptors) involved in the regulation of ventilation. Atrial fibrillation (AF), particularly when combined with diseases causing endothelial (ED) impairment, such as hypertension (HP) and diabetes mellitus (DM), depresses the ED activity and enhances exercise hyperventilation. The relationship between these two functions and the underlying mechanisms have not been explored previously. In lone AF or AF associated with HP or DM (12 subjects in each cohort), we investigated the brachial artery flow-mediated dilatation (ED function) and ventilation during the recovery phase of handgrip (metaboreflex) exercise for subjects receiving placebo or oral vitamin C (double-blind crossover), both before and after cardioversion (CV) to sinus rhythm. Baseline ED impairment was increasingly more severe and the ergoreflex activity more pronounced in AF + HP and AF + DM compared with lone AF. Vitamin C and CV significantly improved both flow-mediated dilatation and metaboreflex activity in lone AF and AF + HP, and vitamin C did not produce any additive effect when administered after CV. In AF + DM, neither vitamin C nor CV was effective. This study provides the following information: AF generates oxidative injury, which is less when the arrhythmia is lone AF and greater when the arrhythmia is associated with HP. In DM, the oxidative injury generated by AF is refractory to a rather weak antioxidant, like vitamin C, or the baseline damage is such as to prevent any additive influence of AF. In AF, a cause-effect link exists between ED dysfunction and metaboreflex activity. Ventilatory advantages of CV seem to be inversely related with the extension of the underlying ED oxidative impairment.
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Affiliation(s)
- Marco Guazzi
- Endothelial Function and Cardiopulmonary Unit, Cardiology Division, Univ. of Milano, San Paolo Hospital, Via A. di Rudinì 8, 20142 Milan, Italy.
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