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Aims: The aim of this study was to assess the effect of granulocyte colony-stimulating factor (G-CSF) on left ventricular (LV) function and volumes in patients with anterior ST-elevation myocardial infarction (STEMI) and depressed LV ejection fraction (EF). Methods and Results: Sixty consecutive patients with anterior STEMI, undergoing primary angioplasty percutaneous coronary intervention (PCI), with symptom-to-reperfusion time of 2-12 h and EF ≤45% after PCI, were randomized to G-CSF 5 μg/kg b.i.d. subcutaneously (n = 24) or placebo (n = 25) for 5 days, starting <12 h after PCI. The primary endpoint was an increase from baseline to 6 months of 5% in left ventricular ejection fraction (LVEF), as measured by magnetic resonance imaging (MRI). Co-primary endpoint was a ≥20 mL difference in end-diastolic volume (EDV). Infarct size and perfusion were evaluated with late gadolinium enhancement (LGE) and gated (99m)Technetium Sestamibi single-photon emission computed tomography (SPECT). Left ventricular EDV and end-systolic volume (ESV) increased from baseline to 6 months in the placebo group (81.7 ± 24.4 to 94.4 ± 26.0 mL/m(2), P < 0.00005 and 45.2 ± 20.0 to 53.2 ± 23.8 mL/m(2), P = 0.016) but were unchanged in the G-CSF group (82.2 ± 20.3 to 85.7 ± 23.7 mL/m(2), P = 0.40 and 46.0 ± 18.2 to 48.4 ± 20.8 mL/m(2), P = 0.338). There were no significant differences in EF or perfusion between groups. A significant reduction in transmural LGE segments was seen at 6 months in the G-CSF vs. placebo groups (4.38 ± 2.9 to 3.3 ± 2.6, P = 0.04 and 4.2 ± 2.6 to 3.6 ± 2.7, P = 0.301, respectively). Significantly more placebo patients had a change in left ventricular end-diastolic volume abovethe median (9.3 mL/m(2)) when reperfusion time exceeded 180 min (median time-to-reperfusion) (P = 0.0123). Severe adverse events were similar between groups. Conclusion: Early G-CSF administration attenuates ventricular remodelling in patients with anterior STEMI and EF ≤45% after successful PCI. [ABSTRACT FROM AUTHOR]

An abstract of the study "Sildenafil improves alveolar gas diffusion and exercise ventilation efficiency in heart failure patients," by C. Fiorentini et al. is presented.

Background: Chronic kidney disease is common in patients admitted with acute coronary syndrome and its prevalence dramatically increases with age. Understanding the determinants of adverse outcomes in this extremely high-risk population may be useful for the development of specific treatment strategies and planning of secondary prevention modalities., Aim: The aim of this study was to assess the impact of baseline renal function and acute kidney injury on one-year outcome of elderly patients with acute coronary syndrome treated with percutaneous coronary intervention., Methods: Patients aged 75 years and older with acute coronary syndrome undergoing successful percutaneous coronary intervention were selected among those enrolled in three Italian multicentre studies. Based on the baseline estimated glomerular filtration rate (eGFR) calculated using the Cockcroft-Gault formula ([(140-age) × body weight × 0.85 if female]/(72 × serum creatinine)* 1.73 m 2 of body surface area), patients were classified as having none or mild (eGFR ≥60 ml/min/1.73 m 2 ), moderate (eGFR 30-59 ml/min/1.73 m 2 ) or severe (eGFR <30 ml/min/1.73 m 2 ) renal dysfunction. Acute kidney injury was defined according to the Acute Kidney Injury Network classification. All-cause and cardiovascular mortality, non-fatal myocardial infarction, rehospitalisation for cardiovascular causes, stroke and type 2, 3 and 5 Bleeding Academic Research Consortium bleedings were analysed up to 12 months., Results: A total of 1904 patients were included. Of these, 57% had moderate and 11% severe renal dysfunction. At 12 months, patients with renal dysfunction had higher rates ( P  < 0.001) of all-cause (4.5%, 7.5% and 17.8% in patients with none or mild, moderate and severe renal dysfunction, respectively) and cardiovascular mortality (2.8%, 5.2% and 10.2%, respectively). After multivariable adjustment, severe renal dysfunction was associated with a higher risk of all-cause (hazard ratio (HR) 2.86, 95% confidence interval (CI) 1.52-5.37, P  = 0.001) and cardiovascular death (HR 3.11, 95% CI 1.41-6.83, P  = 0.005), whereas non-fatal events were unaffected. Acute kidney injury incidence was significantly higher in ST-elevation myocardial infarction versus non-ST-elevation acute coronary syndrome patients (11.7% vs. 7.8%, P  = 0.036) and in those with reduced baseline renal function ( P  < 0.001), and it was associated with increased mortality independently from baseline renal function and clinical presentation., Conclusions: Baseline renal dysfunction is highly prevalent and is associated with higher mortality in elderly acute coronary syndrome patients undergoing percutaneous coronary intervention. Acute kidney injury occurs more frequently among ST-elevation myocardial infarction patients and those with pre-existing renal dysfunction and is independently associated with one-year mortality., (© The European Society of Cardiology 2020.)

Background: Worse outcomes have been reported for women, compared with men, after an acute coronary syndrome (ACS). Whether this difference persists in elderly patients undergoing similar invasive treatment has not been studied. We investigated sex-related differences in 1-year outcome of elderly acute coronary syndrome patients treated by percutaneous coronary intervention (PCI)., Methods: Patients 75 years and older successfully treated with PCI were selected among those enrolled in 3 Italian multicenter studies. Cox regression analysis was used to assess the independent predictive value of sex on outcome at 12-month follow-up., Results: A total of 2035 patients (44% women) were included. Women were older and most likely to present with ST-elevation myocardial infarction (STEMI), diabetes, hypertension, and renal dysfunction; men were more frequently overweight, with multivessel coronary disease, prior myocardial infarction, and revascularizations. Overall, no sex disparity was found about all-cause (8.3% vs 7%, P = .305) and cardiovascular mortality (5.7% vs 4.1%, P = .113). Higher cardiovascular mortality was observed in women after STEMI (8.8%) vs 5%, P = .041), but not after non ST-elevation-ACS (3.5% vs 3.7%, P = .999). A sensitivity analysis excluding patients with prior coronary events (N = 1324, 48% women) showed a significantly higher cardiovascular death in women (5.4% vs 2.9%, P = .025). After adjustment for baseline clinical variables, female sex did not predict adverse outcome., Conclusions: Elderly men and women with ACS show different clinical presentation and baseline risk profile. After successful PCI, unadjusted 1-year cardiovascular mortality was significantly higher in women with STEMI and in those with a first coronary event. However, female sex did not predict cardiovascular mortality after adjustment for the different baseline variables., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The prognostic role of previous coronary artery bypass (CABG) in elderly patients admitted to hospital for an acute coronary syndrome (ACS) is unclear. Therefore, the aim of this study was to compare the prognosis of patients aged ≥75 years admitted for an ACS with or without previous history of CABG. The primary outcome of the study was a composite of overall mortality, recurrent nonfatal myocardial infarction, nonfatal stroke, and rehospitalization for heart failure at 1-year follow-up. We included 2,253 ACS patients, aged 81 (78 to 85) years enrolled in 3 multicenter studies (the Italian Elderly ACS study, the LADIES ACS study, and the Elderly ACS 2 randomised trial) - 178 (7.9%) with previous CABG, 2,075 (92.1%) without. Patients with previous CABG had a higher burden of cardiovascular risk factors, lower ejection fraction, and higher creatinine values on admission. However, both at univariate analysis and after adjustment for the most relevant covariates (sex, age, previous myocardial infarction, type of ACS, left ventricular ejection fraction, and serum creatinine on admission), previous CABG did not show any statistically significant association with 1-year outcome (adjusted hazard ratio 0.85; 95% confidence interval 0.61 to 1.19; p = 0.353). In conclusion, our study suggests that elderly ACS patients with previous CABG have worse basal clinical characteristics. Nevertheless, in a broad cohort of patients mostly treated with percutaneous coronary intervention during the index event, previous CABG did not confer independent additional risk of major adverse cardiovascular events at 1-year follow-up., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Central venous catheterization is essential for careful administration of fluids and drugs in cardiac critical care patients. The axillary vein might represent an alternative to subclavian and jugular vein accesses, with the advantage of being extra-thoracic, more distal from the pleural space and with more likehood of comfort for the patient. Conventional ultrasound-guided cannulation of the axillary vein is technically demanding and does not guarantee precise visualization of the needle tip., Methods: We describe a new in-plane technique with a dedicated bracket support for the needle, giving full tip control and continuous visualization of the tip and vessel, making the maneuver easier and safer. In a prospective observational study we also report the feasibility and safety of the novel procedure in a series of 35 cardiac critical care patients, also receiving non-invasive ventilatory support and/or being fully anti-coagulated., Results: With the novel technique, we obtained 97% success with procedural times comparable to other insertion sites and without complications., Conclusions: Placement of a central line catheter in the axillary vein using a novel ultrasound-guided bracket-assisted technique may be a feasible, safe and rapid alternative to the conventional jugular and subclavian approaches.

Objective: Vasomotor symptoms (VMS) during menopausal transition have been linked to a higher burden of cardiovascular risk factors, subclinical vascular disease, and subsequent vascular events. We aim to investigate the association of VMS with the extent of coronary disease and their prognostic role after an acute coronary syndrome., Methods: The Ladies Acute Coronary Syndrome study enrolled consecutive women with an acute coronary syndrome undergoing coronary angiography. A menopause questionnaire was administered during admission. Angiographic data underwent corelab analysis. Six out of 10 enrolling centers participated in 1-year follow-up. Outcome data included the composite endpoint of all-cause mortality, recurrent myocardial infarction, stroke, and rehospitalization for cardiovascular causes within 1 year., Results: Of the 415 women with available angiographic corelab analysis, 373 (90%) had complete 1-year follow-up. Among them, 202 women had had VMS during menopausal transition. These women had the same mean age at menopause as those without VMS (50 years in both groups), but were younger at presentation (median age 71 vs 76 years; P < 0.001), despite a more favorable cardiovascular risk profile (chronic kidney dysfunction 4.5% vs 15.9%; P = 0.001; prior cerebrovascular disease 4.5 vs 12.2%; P = 0.018). Extent of coronary disease at angiography was similar between groups (mean Gensini score 49 vs 51; P = 0.6; mean SYNTAX score 14 vs 16; P = 0.3). Overall cardiovascular events at 1 year did not differ between groups (19% vs 22%; P = 0.5)., Conclusions: In postmenopausal women with an acute coronary syndrome, a history of VMS was associated with younger age at presentation, despite a lower vascular disease burden and similar angiographically defined coronary disease as compared with women without VMS. No difference could be found in terms of overall clinical outcomes. These results should be interpreted cautiously as all analyses were unadjusted and did not account for risk factor differences between women with and without a history of VMS.

Background: Early menopause has been associated with increased cardiovascular mortality, but prospective studies investigating outcomes of postmenopausal women with acute coronary syndromes (ACS) in relation to menopausal age are lacking., Methods: We analyzed the 1-year outcome of 373 women with acute myocardial infarction enrolled in the Ladies ACS study. All patients underwent coronary angiography, with corelab analysis. Menopause questionnaires were administered during admission. Menopausal age below the median of the study population (50 years) was defined as "early menopause". The composite 1-year outcome included all-cause mortality, recurrent myocardial infarction and stroke., Results: The mean age at index ACS was 73 years (IQR 65-83) for women with early menopause, and 74 (IQR 65-80) for those with late menopause. Patients with early menopause had more prevalent chronic kidney disease (12.8% vs 5.9%, p = 0.03), whereas there were no differences in all other clinical characteristics, extent of coronary disease at angiography (as assessed by Gensini and SYNTAX scores), as well as interventional treatments. Within 1 year, women with late menopause had significantly better outcome as compared with those with early menopause (6.5% vs 15.3%, p = 0.007). At logistic regression analysis, late menopause was independently associated with better outcome (OR 0.28; 95% CI 0.12-0.67; p = 0.004). With each year's delay in the menopause the adjusted risk decreased by 12% (OR 0.88, 0.77-0.99, p = 0.040)., Conclusion: Despite comparable clinical and angiographic characteristics, women with late menopausal age experience better outcomes after an ACS as compared with those with early menopause., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Age- and sex-specific differences exist in the treatment and outcome of ST-elevation myocardial infarction (STEMI). We sought to describe age- and sex-matched contemporary trends of in-hospital management and outcome of patients with STEMI., Methods and Results: We analyzed data from 5 Italian nationwide prospective registries, conducted between 2001 and 2014, including consecutive patients with STEMI. All the analyses were age- and sex-matched, considering 4 age classes: <55, 55 to 64, 65 to 74, and ≥75 years. A total of 13 235 patients were classified as having STEMI (72.1% men and 27.9% women). A progressive shift from thrombolysis to primary percutaneous coronary intervention occurred over time, with a concomitant increase in overall reperfusion rates (P for trend <0.0001), which was consistent across sex and age classes. The crude rates of in-hospital death were 3.2% in men and 8.4% in women (P<0.0001), with a significant increase over age classes for both sexes and a significant decrease over time for both sexes (all P for trend <0.01). On multivariable analysis, age (odds ratio 1.09, 95% CI 1.07-1.10, P<0.0001) and female sex (odds ratio 1.44, 95% CI 1.07-1.93, P=0.009) were found to be significantly associated with in-hospital mortality after adjustment for other risk factors, but no significant interaction between these 2 variables was observed (P for interaction=0.61)., Conclusions: Despite a nationwide shift from thrombolytic therapy to primary percutaneous coronary intervention for STEMI affecting both sexes and all ages, women continue to experience higher in-hospital mortality than men, irrespective of age., (© 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)

Background: Epidemiological studies have shown a higher risk of cardiovascular mortality associated with early menopause, but the relation between menopausal age and extent of coronary artery disease after menopause is unknown. We assessed the relation between menopausal age and extent of coronary disease in postmenopausal women with an acute coronary syndrome., Methods: A prospective study was conducted in patients ≥55 years old undergoing coronary angiography for an acute coronary syndrome. Enrollment was stratified by sex (women/men ratio 2:1) and age (55-64, 65-74, 75-85, and >85 years). Women were administered menopause questionnaires during admission. An independent core lab quantified coronary artery disease extent using the Gensini Score, which classifies both significant (>50%) and nonsignificant lesions. Linear correlation was used to appraise the association between the Gensini score and menopausal age., Results: We enrolled 675 patients, 249 men and 426 women (mean age 74 years). The mean Gensini score was 60 ± 36 in men vs 50 ± 32 in women (P <.001), being higher among men at any age. The median menopausal age of women was 50 years. Risk factors and age at first acute coronary syndrome were identical among women below and above the median menopausal age. The Gensini score in women showed a weak association with age (R = 0.127; P = .0129), but not with menopausal age (R = 0.063; P = .228). At multivariable analysis, ejection fraction, female sex, and ST elevation myocardial infarction were independent predictors of the Gensini score in the overall population., Conclusions: Menopausal age was not associated with the extent of coronary artery disease. Age at first acute coronary syndrome presentation, risk factors, and prior cardiovascular events were not affected by menopausal age. (The LADIES ACS study: NCT01997307)., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Pericardiocentesis is useful in the diagnosis and treatment of pericardial effusive disease. To date, a number of methods have been developed to reduce complications and increase the success rate of the procedure. The aim of the present study was to evaluate the efficacy and the safety of echocardiography-guided pericardiocentesis under continuous echocardiographic monitoring in the management of pericardial effusion. We prospectively performed 161 pericardiocentesis procedures in 141 patients admitted from 1993 to 2015 in 3 centers. This procedure was performed for tamponade or large pericardial effusion in 157 cases and for diagnosis in 4 cases. A percutaneous puncture was performed where the largest amount of fluid was detected. To perform a real-time echo-guided procedure, a multi-angle bracket was mounted on the echocardiographic probe to support the needle and enable its continuous visualization during the puncture. The procedure was successful in 160 of 161 cases (99%). Two major complications occurred (1.2%): 1 mediastinal hematoma that required surgical drainage in a patient on anticoagulant therapy and 1 pleuropericardial shunt requiring thoracentesis. Seven minor complications occurred (4.3%): 1 pleuropericardial shunt, 1 case of transient AV type III block, 3 vasovagal reactions (1 with syncope), and 2 cases of acute pulmonary edema managed with medical therapy. No punctures of any cardiac chamber occurred, and emergency surgical drainage was not required in any case. In conclusion, echocardiography-guided pericardiocentesis under continuous visualization is effective, safe, and easy to perform, even in hospitals with low volumes of procedures with or without cardiac surgery., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Aims: To compare time to active pacing and complication rates associated with temporary transvenous pacemaker (TTVPM) insertion between a fully echo-guided approach of vein access and lead placement, and standard placement of TTVPM under fluoroscopic guidance., Methods and Results: We performed a prospective single-center observational study enrolling all consecutive patients from 1 January 2008 to 31 December 2012 needing emergent TTVPM placement. According to personal experience and clinical setting, the operators could choose between a fully echo-guided approach of TTVPM placement through the jugular vein and a standard fluoro-guided approach through the femoral vein. Safety and efficacy endpoints were pre-specified, registered, and compared. A total of 113 patients were treated using the echo-guided approach, and 90 via the fluoro-guided approach. The two groups differed with regard to clinical setting at presentation: an acute coronary syndrome was more frequent in the fluoro-guided approach group (39.7% vs. 16.8%, p<0.001), whereas asystole was more frequent in the echo-guided approach group (9.7 vs. 0%). Median time from decision to active pacing was significantly shorter in the echo-guided approach group (22 vs. 43 minutes, p<0.01). The overall complication rates were significantly lower in the echo-guided approach group (15.0% vs. 28.8%, p 0.02), because of lower rates of infections (2.7% vs. 11.1%, p 0.02) and puncture-related hematomas (0 vs. 3.3%, p=0.08). There were no deaths related to TTVPM, but one heart perforation requiring emergent pericardiocentesis occurred in the fluoro-guided approach group. One pneumothorax treated conservatively occurred in the echo-guided approach group, while no differences were observed with regard to sustained tachyarrhythmias (1.8% vs. 2.2%) or malfunctions requiring reposition of the catheter (8.8 vs. 8.9%). Overall, complications delaying permanent pacemaker implant for >48 hours were observed less often in the echo-guided approach group (6.8 vs. 20.7%, p = 0.03)., Conclusion: Echo-guided insertion of TTVPM through the jugular vein is a feasible and safe alternative to fluoroscopic guidance and may reduce complications and time to active pacing in patients who are not candidates for emergent cardiac catheterization., (© The European Society of Cardiology 2015.)

Background: Granulocyte-colony stimulating factor (G-CSF) has been clinically tested in ST-elevation myocardial infarction (STEMI) with mixed results. Our 3-year follow-up data from STEM-AMI trial documented a sustained benefit of G-CSF on adverse ventricular remodeling after large anterior STEMI, when administered early and at a high-dose in patients with left ventricular (LV) dysfunction. The Aim of the present trial is to establish whether G-CSF improves hard clinical long-term outcomes., Methods: The STEM-AMI OUTCOME is a prospective, multicenter, randomized, open-label, phase III trial. It will include 1,530 patients with anterior STEMI undergoing primary percutaneous coronary intervention 2 to 24 hours after symptoms onset and with LV ejection fraction ≤45% after successful reperfusion. Patients will be randomized 1:1 to G-CSF and/or standard treatment. The primary end point is a reduced occurrence of all-cause death, recurrence of myocardial infarction, or hospitalization due to heart failure in G-CSF-treated patients. Left ventricular remodeling will be assessed via cardiac ultrasound and a substudy with cardiac magnetic resonance will be carried out in 120 subjects. Accrual and follow-up periods will last 3 and 2 years, respectively., Conclusions: The STEM-AMI OUTCOME study is designed to be a rigorous controlled phase III trial with adequate statistical power to conclusively assess efficacy of G-CSF treatment in STEMI., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objective: To assess whether granulocyte colony-stimulating factor (G-CSF) treatment induces a sustained benefit on adverse remodelling in patients with large anterior ST-elevation myocardial infarction (STEMI) and left ventricular (LV) dysfunction after successful reperfusion., Methods: The STEM-AMI Trial was a prospective, placebo-controlled, multicentre study. Sixty consecutive patients with a first anterior STEMI, who underwent primary percutaneous coronary intervention 2-12 h after symptom onset, with LV ejection fraction (LVEF) ≤45% measured by echocardiography within 12 h after successful revascularisation (TIMI flow score ≥2), were randomised 1:1 to G-CSF (5 µg/Kg body weight b.i.d.) or placebo. Clinical events and Major Adverse Cardiac and Cerebrovascular Event (MACCE) were monitored, and LVEF, LV end-diastolic (LVEDV) and end-systolic (LVESV) volumes, and infarct size were evaluated by MRI at the final 3-year follow-up., Results: Fifty-four patients completed the study, of whom 35 with MRI. No significant differences were found in mortality and MACCE between G-CSF and placebo-treated groups. The 3-year infarct size was not different between groups, whereas LVEDV was significantly lower in G-CSF (n=20) than in placebo (n=15) patients (170.1±8.1 vs 197.2±8.9 mL, respectively; p=0.033 at analysis of covariance). A significant inverse correlation was detected in G-CSF patients between the number of circulating CD34 cells at 30 days after reperfusion and the 3-year absolute and indexed LVEDV (ρ=-0.71, 95% CI -0.90 to -0.30, and ρ=-0.62, -0.86 to -0.14, respectively), or their change over time (r=-0.59, -0.85 to -0.11, and r=-0.55, -0.83 to -0.06, respectively)., Conclusions: G-CSF therapy may be beneficial in attenuating ventricular remodelling subsequent to a large anterior STEMI in the long term. No differences have been detected in clinical outcome.

Background: Substantial changes have occurred over time in the diagnoses, procedures and characteristics of patients admitted to coronary care units (CCU). Following the introduction of cardiac surgery activity in our hospital in December 2009, the aim of this study was to evaluate the changes in activity, processes of care and outcomes of patients consecutively admitted to our CCU after the reorganization of the Cardiovascular Department., Methods: All 1674 consecutive patients admitted to the CCU from January 2009 to December 2010 were enrolled in this retrospective registry., Results: In 2010, the number of patients referred from other hospitals or wards significantly increased (from 17.2% to 28.3%; p<0.001). Significant was also the increase of patients with ST-elevation myocardial infarction (n=190 to n=230, p<0.001), shock (n=20 to n=50, p<0.001), pulmonary edema (n=47 to n=64, p<0.05), cardiac arrest (n=2 to n=8, p<0.05), aortic dissection (n=0 to n=12; p<0.001). Conversely, the number of patients admitted for acute coronary syndromes without ST-segment elevation and GRACE risk score <140 significantly decreased (n=169 to n=52, p<0.001). In parallel, a significant increase in the use of intra-aortic balloon pump (2.0% to 5.6%, p<0.001), continuous hemofiltration (0.3% to 3.1%, p>0.001), non-invasive ventilation (5.6% to 10.5%, p<0.001) and mechanical ventilation (0% to 4.1%, p<0.001) was observed. Intensive care devices were more frequently used in the subgroups affected by shock, acute coronary syndromes without ST-segment elevation and GRACE risk score >200, and heart failure. Interestingly, despite the increase in high-risk clinical conditions the intra-CCU mortality did not change (3.1 vs 2.9%)., Conclusions: Patients admitted to the CCU have high-risk acute clinical conditions. A model based on the sharing of cardiological, cardiac anesthesiological and surgical expertise is effective in increasing admission appropriateness and improving standards of care in a short period of time.

Endothelial dysfunction and underperfusion of exercising muscle contribute to exercise intolerance, hyperventilation, and breathlessness in atrial fibrillation (AF). Cardioversion (CV) improves endothelial function and exercise performance. We examined whether CV is equally beneficial in diabetes and hypertension, diseases that cause endothelial dysfunction and are often associated with AF. Cardiopulmonary exercise and pulmonary and endothelial (brachial artery flow-mediated dilation) function were tested before and after CV in patients with AF alone (n = 18, group 1) or AF with hypertension (n = 19, group 2) or diabetes (n = 19, group 3). Compared with group 1, peak exercise workload, O2 consumption (Vo2), O2 pulse, aerobic efficiency (Delta Vo2/Delta WR), and ratio of brachial diameter changes to flow changes (Delta D/Delta F) were reduced in group 2 and, to a greater extent, in group 3; exercise ventilation efficiency (Ve/Vco2 slope) and dead space-to-tidal volume ratio (Vd/Vt) were similar among groups. CV had less effect on peak workload (+7% vs. +18%), peak Vo2 (+12% vs. +17%), O2 pulse (+33% vs. +50%), Delta Vo2/Delta WR (+7% vs. +12%), Ve/Vco2 slope (-6% vs. -12%), Delta D/Delta F (+7% vs. +10%), and breathlessness (Borg scale) in group 2 than in group 1 and was ineffective in group 3. The antioxidant vitamin C, tested in eight additional patients in each cohort, improved flow-mediated dilation in groups 1 and 2 before, but not after, CV and was ineffective in group 3, suggesting that the oxidative injury is least in lone AF, greater in hypertension with AF, and greater still in diabetes with AF. Comorbidities that impair endothelial activity worsen endothelial dysfunction and exercise intolerance in AF. The advantages of CV appear to be inversely related to the extent of the underlying oxidative injury.