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Cardiac involvement has been frequently reported in COVID-19 as responsible of increased morbidity and mortality. Given the importance of right heart function in acute and chronic respiratory diseases, its assessment in SARS-CoV-2 infected patients may add prognostic accuracy. Transthoracic echocardiography has been proposed to early predict myocardial injury and risk of death in hospitalized patients. This systematic review presents the up-to-date sum of literature regarding right ventricle ultrasound assessment. We evaluated commonly used echocardiographic parameters to assess RV function and discussed their relationship with pathophysiological mechanisms involved in COVID-19. We searched Medline and Embase for studies that used transthoracic echocardiography for right ventricle assessment in patients with COVID-19.

Objectives The DETECT algorithm has been developed to identify SSc patients at risk for pulmonary arterial hypertension (PAH) yielding high sensitivity but low specificity, and positive predictive value. We tested whether cardiopulmonary exercise testing (CPET) could improve the performance of the DETECT screening strategy. Methods Consecutive SSc patients over a 30-month period were screened with the DETECT algorithm and positive subjects were referred for CPET before the execution of right-heart catheterization. The predictive performance of CPET on top of DETECT was evaluated and internally validated via bootstrap replicates. Results Out of 314 patients, 96 satisfied the DETECT application criteria and 54 were positive. PAH was ascertained in 17 (31.5%) and pre-capillary pulmonary hypertension in 23 (42.6%) patients. Within CPET variables, the slope of the minute ventilation to carbon dioxide production relationship (VE/VCO2 slope) had the best performance to predict PAH at right-heart catheterization [median (interquartile range) of specificity 0.778 (0.714–0.846), positive predictive value 0.636 (0.556–0.750)]; exploratory analysis on pre-capillary yielded a specificity of 0.714 (0.636–0.8) and positive predictive value of 0.714 (0.636–0.8). Conclusion In association with the DETECT algorithm, CPET may be considered as a useful tool in the workup of SSc-related pulmonary hypertension. The sequential determination of the VE/VCO2 slope in DETECT-positive subjects may reduce the number of unnecessary invasive procedures without any loss in the capability to capture PAH. This strategy had also a remarkable performance in highlighting the presence of pre-capillary pulmonary hypertension.

Background During COVID‐19 outbreak, Italy was the first country in Europe to be heavily affected with an intensive care unit mortality of 26%. In order to reduce this percentage, physicians should establish clear and objective criteria to stratify COVID‐19 patients at high risk of in‐hospital death. Thus, the aim has been to test a large spectrum of variables ranging from clinical evaluation to laboratory biomarkers to identify which parameter would best predict all‐cause in‐hospital mortality in COVID‐19 patients. Design observational study. Results Multivariate Cox regression analysis showed that each 5 years of increase in age corresponded to a hazard ratio (HR) of 1.28 (95% CI 1.00‐1.65, P = .050); each increment of 803 ng/L of N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) corresponded to a HR of 1.24 (95% CI 1.11‐1.39, P

ObjectivesIn Italy, the pandemic of COVID-19 resulted in congestion of hospitals and laboratories and probably determined an underestimation of the number of infected subjects, as the molecular diagnosis of SARS-CoV-2 infection was mainly performed on hospitalised patients. Therefore, limited data are available about the number of asymptomatic/paucisymptomatic subjects in the general population across time. To understand SARS-CoV-2 infection in the general population, we have developed a cross-sectional study (the ‘UNIversity against CORoNavirus study’) to investigate infection trends in asymptomatic/paucisymptomatic subjects in Milan (Italy), between March and June 2020.ParticipantsThe study population included 2023 subjects asymptomatic at the enrolment.Primary outcome measuresA nasal mid-turbinate swab for the detection of SARS-CoV-2 RNA and blood specimen for testing serum antibodies (immunoglobulin M (IgM) and IgG) were collected.ResultsSubjects showing positivity for the SARS-CoV-2 RNA and/or for anti-SARS-CoV-2 Ig is 237 (11.7%). Only 1.2% (n=25) of the total population had a positive nasal swab for SARS-CoV-2 and the large majority (21/25) of them were observed in March. A total of 226 subjects (11%) had IgM (n=19; 0.9%), IgG (n=155; 7.7%) or both (n=52; 2.6%) against SARS-CoV-2. Subjects with a present or past SARS-CoV-2 infection did not differ from other subjects as regards the number of cohabiting family members, travels, fever and upper and lower respiratory infection episodes.ConclusionsResults from the present study support the hypothesis that the actual spread of the virus in Lombardy was underestimated in the official records. However, as it is not known how long Ig persist, numbers should be taken cautiously.

Early risk stratification for complications and death related to Coronavirus disease 2019 (COVID-19) infection is needed. Because many patients with COVID-19 who developed acute respiratory distress syndrome have diffuse alveolar inflammatory damage associated with microvessel thrombosis, we aimed to investigate a common clinical tool, the CHA(2)DS(2)-VASc, to aid in the prognostication of outcomes for COVID-19 patients. We analyzed consecutive patients from the multicenter observational CORACLE registry, which contains data of patients hospitalized for COVID-19 infection in 4 regions of Italy, according to data-driven tertiles of CHA(2)DS(2)-VASc score. The primary outcomes were inpatient death and a composite of inpatient death or invasive ventilation. Of 1045 patients in the registry, 864 (82.7%) had data available to calculate CHA(2)DS(2)-VASc score and were included in the analysis. Of these, 167 (19.3%) died, 123 (14.2%) received invasive ventilation, and 249 (28.8%) had the composite outcome. Stratification by CHA(2)DS(2)-VASc tertiles (T1: ≤1; T2: 2 to 3; T3: ≥4) revealed increases in both death (8.1%, 24.3%, 33.3%, respectively; p

Introduction: Myocardial injury is commonly observed in patients (pts) with Coronarvirus disease 2019 (Covid-19) but its anatomical correlate has not been elucidated. We evaluated the association between presence of transthoracic echocardiographic (TTE) left ventricular (LV) regional wall motion abnormalities (RWMA), myocardial injury and outcomes in Covid-19 pts. Methods: We conducted a cohort study including 7 hospitals in New York City (US) and Milan (Italy) of hospitalized pts with confirmed Covid-19 who had a TTE during their index hospitalization. Myocardial injury was defined as any elevation in cardiac troponin (cTn) during the hospitalization. Using multivariable logistic regression, we analyzed the association between RWMA, myocardial injury and in-hospital death. Results: Among 305 total pts included in the study, 49 (16%) had RWMA and 44 (14%) had global LV systolic dysfunction. Among those with RWMA, 31/49 (63%) had LV ejection fraction Figure 1 ). Conclusion: In Covid-19 pts, RWMA are associated with typical ACS presentation: chest pain, ST changes and cTn elevations. Accordingly, a large proportion of pts with RWMA who underwent LHC had confirmed ACS warranting PCI. Though myocardial injury was associated with increased risk of in-hospital death regardless of the presence of RWMA, LHC should be considered for pts with RWMA and myocardial injury to rule-out obstructive disease.

Background Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) utilizes the angiotensin‐converting enzyme‐2 (ACE‐2) receptor to enter human cells. Angiotensin‐converting enzyme inhibitors (ACEI) and angiotensin II receptor antagonists (ARB) are associated with ACE‐2 upregulation. We hypothesized that antecedent use of ACEI/ARB may be associated with mortality in coronavirus disease 2019 (COVID‐19). Methods and Results We used the Coracle registry, which contains data of patients hospitalized with COVID‐19 in 4 regions of Italy, and restricted analyses to those ≥50 years of age. The primary outcome was in‐hospital mortality. Among these 781 patients, 133 (17.0%) used an ARB and 171 (21.9%) used an ACEI. While neither sex nor smoking status differed by user groups, patients on ACEI/ARB were older and more likely to have hypertension, diabetes mellitus, and congestive heart failure. The overall mortality rate was 15.1% (118/781) and increased with age ( P Trend P =0.9333, and 1.13, 95% CI, 0.67–1.91, P =0.6385, respectively. After adjusting for age, hypertension, diabetes mellitus, and congestive heart failure, antecedent ACEI administration was associated with reduced mortality (OR, 0.55; 95% CI, 0.31–0.98, P =0.0436); a similar, but weaker trend was observed for ARB administration (OR, 0.58; 95% CI, 0.32–1.07, P =0.0796). Conclusions In those aged ≥50 years hospitalized with COVID‐19, antecedent use of ACEI was independently associated with reduced risk of inpatient death. Our findings suggest a protective role of renin‐angiotensin‐aldosterone system inhibition in patients with high cardiovascular risk affected by COVID‐19.

Introduction: Myocardial injury is common amongst patients hospitalized with Covid-19 and is associated with a poor prognosis. It is unknown whether its incidence and its mechanisms differ by race and ethnicity. Methods: We conducted a multicenter, international cohort study at 7 hospitals in New York (United States) and Milan (Italy) between March and May 2020. All patients were hospitalized, had laboratory-confirmed Covid-19, and received a transthoracic echocardiogram (TTE) during their hospitalization. We evaluated the association between race/ethnicity and myocardial injury in multivariable logistic regression models. Myocardial injury was defined as any cardiac troponin elevation above the upper limit of normal at each enrolling site. Results: A total of 305 consecutive patients were included, of whom 280 had self-reported race/ethnicity. Key demographic, laboratory and echocardiographic characteristics are presented in the Table. All minority groups had higher incidence of a composite of major echocardiographic abnormalities compared to whites, and Asian and Hispanic patients had increased incidence of RV dysfunction. In multivariable models, compared with Whites, Black (adjOR 2.7 [1.1-6.4]), Asian (adjOR 3.3 [1.1-10.2]), and Hispanic (adjOR 2.8 [1.4-5.8]) patients had increased odds of myocardial injury. After adjusting for baseline demographic and clinical variables, both Asian (adjOR 9.9 [2.6-38.6]) and Hispanic (adjOR 5.7 [2.1-15.6]) patients had increased odds of in-hospital mortality compared with White, but not Black (adjOR 2.0 [0.6-7.0]) patients. Conclusions: Among hospitalized patients with Covid-19 who received a TTE, minority groups had higher incidence of echocardiographic abnormalities and increased risk of myocardial injury. After adjustment for baseline confounders, only Asian and Hispanic patients remained at increased risk for in-hospital mortality.

Background Myocardial injury is frequent among patients hospitalized with coronavirus disease-2019 (COVID-19) and is associated with a poor prognosis. However, the mechanisms of myocardial...

Background: In COVID-19 patients, aldosterone via angiotensin-converting enzyme-2 deregulation may be responsible for systemic and pulmonary vasoconstriction, inflammation, and oxidative organ damage. Aim: To verify retrospectively the impact of the mineralcorticoid receptor antagonist canrenone i.v. on the need of invasive ventilatory support and/or all-cause in-hospital mortality. Methods: Sixty-nine consecutive COVID-19 patients, hospitalized for moderate to severe respiratory failure at Fondazione Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS) Ca&rsquo, Granda Ospedale Maggiore Policlinico of Milan, received two different therapeutic approaches in usual care according to the personal skills and pharmacological management experience of the referral medical team. Group A (n = 39) were given vasodilator agents or renin&ndash, angiotensin&ndash, aldosterone system (RAAS) inhibitors and group B (n = 30) were given canrenone i.v. Results: Among the 69 consecutive COVID-19 patients, those not receiving canrenone i.v. (group A) had an event-free rate of 51% and a survival rate of 64%. Group B (given a mean dose of 200 mg/q.d. of canrenone for at least two days of continuous administration) showed an event-free rate of 80% with a survival rate of 87%. Kaplan&ndash, Meier analysis for composite outcomes and mortality showed log rank statistics of 0.0004 and 0.0052, respectively. Conclusions: The novelty of our observation relies on the independent positive impact of canrenone on the all-cause mortality and clinical improvement of COVID-19 patients ranging from moderate to severe diseases.

Objectives: The combination of Lumacaftor and Ivacaftor (LUM/IVA) has been approved for treatment of cystic fibrosis (CF) patients homozygous for the Phe508del mutation. Only one report is available detailing the positive effects of LUM/IVA on physical activity (PA) and exercise tolerance. The aim of this study is to assess the long-term impact of this therapy on daily PA and exercise tolerance. Methods: In this 12 month-long multicenter study, lung function and exercise tolerance will be prospectively evaluated through spirometry and cardiopulmonary exercise testing (CPET) in a cohort of CF patients candidate to treatment with LUM/IVA. CPET-related measurements will include: minute ventilation, oxygen uptake (V9O2), indices of ventilatory efficiency, oxygen saturation, registered at peak exercise and throughout the test. Daily PA will be monitored using a multi-sensor armband (SenseWear Pro3 Armband, SWA) that patients will wear at home for seven full consecutive typical days. Health-related quality of life will be assessed by the adult version of the revised Italian CFQ-R questionnaire. All the procedures will be performed at baseline and at 6 and 12 months after initiation of LUM/IVA therapy. Results: Five adults with CF (median age 30 years (range 28 – 43 years); median FEV1 75(68–113)% pred; median BMI 22.1(17.1–24.2)kg/m2) were recruited between June and October 2019. Baseline median V’O2 peak value was 27.0(24.9–38.4)ml/min/kg, corresponding to 67.0(59.7–110.1)% predicted. Conclusions: Preliminary data collected after 6 months on LUM/IVA therapy will be presented at the ERS 2020 event.

Objectives: To describe patients according to the maximum degree of respiratory support received and report their inpatient mortality due to coronavirus disease 2019. Design: Analysis of patients in the Coracle registry from February 22, 2020, to April 1, 2020. Setting: Hospitals in the Piedmont, Lombardy, Tuscany, and Lazio regions of Italy. Patients: Nine-hundred forty-eight patients hospitalized for coronavirus disease 2019. Interventions: None. Measurements and Main Results: Among 948 patients, 122 (12.87%) received invasive ventilation, 637 (67.19%) received supplemental oxygen only, and 189 (19.94%) received no respiratory support. The median (quartile 1–quartile 3) age was 65 years (54–76.59 yr), and there was evidence of differential respiratory treatment by decade of life (p = 0.0046); patients greater than 80 years old were generally not intubated. There were 606 men (63.9%) in this study, and they were more likely to receive respiratory support than women (p < 0.0001). The rate of in-hospital death for invasive ventilation recipients was 22.95%, 12.87% for supplemental oxygen recipients, and 7.41% for those who received neither (p = 0.0004). A sensitivity analysis of the 770 patients less than 80 years old revealed a lower, but similar mortality trend (18.02%, 8.10%, 5.23%; p = 0.0008) among the 14.42%, 65.71%, and 19.87% of patients treated with mechanical ventilation, supplemental oxygen only, or neither. Overall, invasive ventilation recipients who died were significantly older than those who survived (median age: 68.5 yr [60–81.36 yr] vs 62.5 yr [55.52–71 yr]; p = 0.0145). Conclusions: Among patients hospitalized for coronavirus disease 2019, 13% received mechanical ventilation, which was associated with a mortality rate of 23%.

Pulmonary capillary stress failure is potentially involved in exercise-induced hypoxemia i.e. a significant fall in hemoglobin O2 saturation (SpO2) during sea level exercise in endurance-trained athletes. Whether there may be specific properties of the pulmonary vascular function in athletes exhibiting O2 desaturation is unknown., info:eu-repo/semantics/published

Coronavirus disease 2019 (COVID-19) is a pandemic that has affected more than 1.8 million people worldwide, overwhelmed health care systems owing to the high proportion of critical presentations, and resulted in more than 100,000 deaths. Since the first data analyses in China, elevated cardiac troponin has been noted in a substantial proportion of patients, implicating myocardial injury as a possible pathogenic mechanism contributing to severe illness and mortality. Accordingly, high troponin levels are associated with increased mortality in patients with COVID-19. This brief review explores the available evidence regarding the association between COVID-19 and myocardial injury.

Knowledge of preoperative right heart function of adult patients with cystic fibrosis (CF) awaiting lung transplant (LUTX) is limited. The echocardiography of adult patients with CF enlisted for LUTX was retrospectively analyzed and compared with standards and invasive analyses (right heart catheterization, multigated radionuclide ventriculography). We included 49 patients (reported as mean ± standard deviation; 29 ± 9 years of age; forced expiratory volume in first second of expiration, 31% ± 11% predicted; lung allocation score, 36 ± 5; invasive mean pulmonary artery pressure, 17 ± 5 mm Hg; multigated radionuclide ventriculography right ventricle [RV] ejection fraction, 50% ± 9%). Patients had increased RV end-diastolic area, RV wall thickness, and increased pulmonary artery acceleration time with subnormal tricuspid annular plane systolic excursion, tissue Doppler positive peak systolic velocity, and fraction area change. Subnormal tricuspid annular plane systolic excursion (23 mm), tissue Doppler positive peak systolic velocity (14 cm/s), and fraction area change (49%) had high sensitivity and negative predictive value in predicting impaired RV. EJECTION FRACTION: A good correlation between echocardiographic estimated and invasively measured systolic pulmonary artery pressure was observed (R

Expanding from China around the World, COVID-19 is the disease caused by the Severe Acute Respiratory Syndrome Related Coronavirus 2 (SARS-CoV-2). COVID-19 primarily manifests by hypoxic normo-hypocapnia with preserved lung compliance [1]. In the absence of targeted treatment, sub-intensive clinicians support patients with non-invasive ventilation and anti-inflammatory/anti-viral agents waiting for status improvement. Angiotensin-converting enzyme 2 (ACE2), highly expressed on the external membrane of lungs, heart, kidney and gastrointestinal tract cells, displays the binding site for the spike protein of SARS-CoV-2 [2]. ACE2, identified as counterpart of the Renin-Angiotensin-Aldosterone System (RAAS), converts Angiotensin (Ang) II to Ang-(1-7) and Ang I to Ang-(1-9). ACE2 activity induces vasodilatation and reduces cell growth and inflammatory response. In experimental models that mimic the viral acute respiratory distress syndrome (ARDS), the absence of Ace2 led to inflammation, vascular permeability and lung injury via activation of Ang II pathway [3, 4]. The decrease in ACE2 activity by SARS-CoV-2 can unleash a cascade of injurious effects through a heightened imbalance in the actions of the products of ACE versus ACE2. Moving to a clinical setting, the ACE2 downregulation may be one of the pathways sustaining arterial hypertension [5] and pulmonary arterial hypertension [6]. Therefore, it is conceivable that in COVID-19 a cleavage of membrane ACE2 along with its circulatory levels could impact on the disease progression and clinical worsening [7]. Thus, to support a pathophysiological role of ACE2, the present report shares clinical data from an observational study conducted on 40 patients with a diagnosis of COVID-19, hospitalised in the Cardiorespiratory Sub-Intensive COVID-19 Unit at the Fondazione IRCCS Ca' Granda Policlinico Hospital of Milan., In COVID-19 patients respiratory failure is associated with increase systemic blood pressure conceivably due to the modulation of renin-angiotensin-aldosterone system by SARS-CoV-2 infection.

Uncertainties remain about the diagnostic and therapeutic strategy to prevent left ventricular thrombus formation after myocardial infarction. In particular, the roles of predisposing factors and prophylactic anticoagulation have not been sufficiently considered. We propose an ‘uncertainties flowchart’ with the aim of stimulating research on the topic.

There has been suggestion that a greater "pulmonary vascular reserve" defined by a low pulmonary vascular resistance (PVR) and a high lung diffusing capacity (DL) allow for a superior aerobic exercise capacity. How pulmonary vascular reserve might affect exercise capacity at moderate altitude is not known.Thirty-eight healthy subjects underwent an exercise stress echocardiography of the pulmonary circulation, combined with measurements of DL for nitric oxide (NO) and carbon monoxide (CO) and a cardiopulmonary exercise test at sea level and at an altitude of 2250 m.At rest, moderate altitude decreased arterial oxygen content (CaO2) from 19.1 ± 1.6 to 18.4 ± 1.7 mL·dL, P0.001, and slightly increased PVR, DLNO, and DLCO. Exercise at moderate altitude was associated with decreases in maximum O2 uptake (V˙O2max), from 51 ± 9 to 43 ± 8 mL·kg⋅min, P0.001, and CaO2 to 16.5 ± 1.7 mL·dL, P0.001, but no different cardiac output, PVR, and pulmonary vascular distensibility. DLNO was inversely correlated to the ventilatory equivalent of CO2 (V˙E/V˙CO2) at sea level and at moderate altitude. Independent determinants of V˙O2max as determined by a multivariable analysis were the slope of mean pulmonary artery pressure-cardiac output relationship, resting stroke volume, and resting DLNO at sea level as well as at moderate altitude. The magnitude of the decrease in V˙O2max at moderate altitude was independently predicted by more pronounced exercise-induced decrease in CaO2 at moderate altitude.Aerobic exercise capacity is similarly modulated by pulmonary vascular reserve at moderate altitude and at sea level. Decreased aerobic exercise capacity at moderate altitude is mainly explained by exercise-induced decrease in arterial oxygenation.

INTRODUCTION: Pulmonary hypertension (PH) is a well documented clinical complication in Non-Transfusion Dependent Thalassemia (NTDT) patients, and it is associated with poor outcome [1]. PH prevalence is extremely variable among studied cohorts, ranging from 4.8% to 59% [2, 3]. Nevertheless, in the majority of the studies, the diagnosis is based on echocardiography, whereas the gold standard for PH definition is right heart catheterization (RHC). Thus, PH real prevalence, its pathophysiological mechanisms and risk factors still need to be elucidated. AIM:The aim of this study is to define the prevalence of PH in a cohort of NTDT patients through the application of the PH diagnostic work-up of the European Society of Cardiology Guidelines (ESC) [4]. We also aimed to investigate the involved pathophysiological mechanisms, to define risk factors, and to identify a potential role for cardiopulmonary exercise testing (CPET) in the risk stratification. MATERIALS AND METHODS: We planned a screening program for all NTDT patients referring to Rare Disease Center, in collaboration with the Dyspnea Lab of the Cardiology Unit, at Fondazione IRCCS Ca' Granda Policlinico in Milan. Following the systematic approach of ESC PH algorithm, together with an echocardiogram and cardiological evaluation, our patients underwent cardiopulmonary exercise testing (CPET) and the dosage of NT-proBNP. Patients were stratified according to PH probability (low vs intermediate-high) and further investigations (including V/Q lung scan and RHC) to confirm PH were performed in those with intermediate-high risk. RESULTS AND DISCUSSION:48 NTDT patients (18 females and 30 males) were consecutively enrolled over a period of 10 months. The mean age at enrollment was 46±12 years (median 45, range 25-72 years) and a wide spectrum of thalassemia genotypes was observed. 38 out of 48 (79%) had a low PH probability according to NYHA class and echocardiogram, thus they were addressed to regular follow-up. 10 patients presented intermediate-high PH probability and underwent further tests. So far, 6 out of 10 intermediate-high risk underwent RHC: PH was confirmed in 5 cases, allowing to identify 2 post-capillary PH, 1 pre-capillary PH (due to pulmonary embolism detected with V/Q scan) and 2 forms of PH due to high cardiac output (CO). The sixth patient showed a condition of high CO but with a mean arterial pulmonary pressure just below the value needed to diagnose PH. Thus, PH was confirmed in 5 out of 48 patients, with a prevalence of 10.4%. The four remaining patients with high PH probability are planned to be tested. Comparing those with high and low PH probability, the first were older (58.4 ±8.9 vs 42.6 ±10.7 years, p=0.0002) and presented higher NT-proBNP (450±442 vs 92±99 ng/mL, p=0.0001). Hemoglobin, erythroblasts, and platelet count were similar. Patients with high PH probability on CPET reached a lower maximal workload (87.9 W ±32.1 vs 126.9 ±41.6W) and lower O2 consumption (1207.7 ±284.5 vs 1594 ±454.8 mL/min), together with worse ventilation efficiency (VE/VCO2 slope 40.9 ±6.9 vs 29.4 ±3.85). CONCLUSIONS: In our cohort, according to these preliminary data, PH prevalence in NTDT is 10.4% and older patients seem to be at higher risk. Thus, cardiac evaluation programs are required, considering the increased life span. RHC is mandatory to confirm the diagnosis, to identify the underlying mechanisms and consequently a proper treatment. CPET may have an essential role in detecting predictive and prognostic parameters of PH and in defining different hemodynamic mechanisms (pre- or post-capillary) to select patients requiring RHC. Together with pulmonary embolism, which needs to be excluded with imaging, high CO due to chronic anemia seems to play an important role. This hypothesis could have significant treatment implications, giving more importance to increase Hb levels, either with blood transfusions or new therapies. Sleiman J, Int J Mol Sci 2018 2 Derchi G, Circulation 2014 3 Aessopos E., Blood 2001 4 Galiè N, Eur Heart J 2016 Disclosures Motta: Sanofi Genzyme:Honoraria.Cappellini:Genzyme/Sanofi:Honoraria, Membership on an entity's Board of Directors or advisory committees;CRISPR Therapeutics, Novartis, Vifor Pharma:Membership on an entity's Board of Directors or advisory committees;BMS:Honoraria.

AIMS The efficacy of a telephone support program in chronic heart failure has been questioned particularly when considering short-term follow-up. This study is aimed to assess the impact of the HeartNetCare telephone support program in chronic heart failure within 18 months of observation and to verify a possible effect of a learning-to-care curve on outcome. METHODS We retrospectively compared a cohort of 269 chronic heart failure patients included in HeartNetCare program with 200 patients receiving usual care as a control group. All-cause death and hospitalization for heart failure or implantation of left ventricular assist device were the primary composite outcome. Secondary endpoints were the changes in left ventricular ejection fraction and in New York Heart Association (NYHA) functional class. Outcome data were also analyzed in relation to the time of enrollment from program initiation. RESULTS At baseline, HeartNetCare group showed lower ejection fraction and higher NYHA class. At the follow-up, 59 HeartNetCare patients (21.9%) and 49 usual care patients (24.5%) reached the primary endpoint (P = 0.51). After 18 months of follow-up, HeartNetCare patients improved ejection fraction and NYHA class compared with the usual care patients (P

Introduction: β-Thalassemia syndromes are among the most common monogenic disorders worldwide. Clinically, on the basis of the severity of the phenotype, β-thalassemias are classified into two grou...

Introduction: The presence of pulmonary hypertension (PH) before lung transplantation (LuTx) is a well known risk factor for primary graft dysfunction (PGD). However, the role of the comprehensive cardiopulmonary hemodynamic assessed before LuTx is limited. We aimed to explore if other hemodynamic variables may have a role in PGD, besides absolute PH. Methods: a retrospective study was conducted at Policlinico Hospital of Milan (Italy) on adults who underwent LuTx for any indication other than cystic fibrosis from 2011 to 2017. PGD was defined as PaO2/FIO2 Results: among 67 patients (57% male, median age 58 years), 28 (42%) had PGD. PH was prevalent in PGD+ group (57% vs 33%, p=0.045). PAWP showed the strongest difference (PAWP: 13.0 vs 10.0 mmHg, p=0.036), while RAP was slightly higher in PGD+ group (RAP: 7.0 vs 5.5 mmHg, p=0.048). No differences were observed between PVR or IC (PVR: 2.61 vs 2.62 UW, p=0.622; CI: 3.13 vs 3.07 l/min/mq, p=0.760). Conclusion: our data confirm that PH is an important factor in PGD. However normal median values of PVR together with a higher median PAWP may suggest a predominant role of the post capillary component in this disease. From this point of view, RAP may reflect the overload of the right ventricle caused by higher total afterload. Thus, PAWP should be considered in PGD’s development.

Essential hypertension is the leading preventable cause of death in the world. Epidemiological studies have shown that physical training can reduce blood pressure (BP), both in hypertensive and healthy individuals. Increasing evidence is emerging that DNA methylation is involved in alteration of the phenotype and of vascular function in response to environmental stimuli. We evaluated repetitive element and gene-specific DNA methylation in peripheral blood leukocytes of 68 volunteers, taken before (T0) and after (T1) a three-month intervention protocol of continuative aerobic physical exercise. DNA methylation was assessed by bisulfite-PCR and pyrosequencing. Comparing T0 and T1 measurements, we found an increase in oxygen consumption at peak of exercise (VO2peak) and a decrease in diastolic BP at rest. Exercise increased the levels of ALU and Long Interspersed Nuclear Element 1 (LINE-1) repetitive elements methylation, and of Endothelin-1 (EDN1), Inducible Nitric Oxide Synthase (NOS2), and Tumour Necrosis Factor Alpha (TNF) gene-specific methylation. VO2peak was positively associated with methylation of ALU, EDN1, NOS2, and TNF, systolic BP at rest was inversely associated with LINE-1, EDN1, and NOS2 methylation, diastolic BP was inversely associated with EDN1 and NOS2 methylation. Our findings suggest a possible role of DNA methylation for lowering systemic BP induced by the continuative aerobic physical training program.

Previous studies showed that transcutaneous vagus nerve stimulation (tVNS) modulates the autonomic nervous system (ANS) in resting condition. However, the autonomic regulation in response to an orthostatic challenge during tVNS in healthy subjects remains unknown. We tested the hypothesis that tVNS reduces heart rate (HR) and alters the responsivity of ANS to orthostatic stress in healthy subjects. In a randomized and cross-over trial, thirteen healthy subjects underwent two experimental sessions on different days: (1) tVNS and (2) control. Using a tVNS device, an auricular electrode was placed on the left cymba conchae of the external ear, an electric current with a pulse frequency of 25 Hz and amplitude between 1 and 6 mA was applied. For the assessment of ANS, the beat-to-beat HR and systolic arterial pressure (SAP) were analyzed using linear and nonlinear approaches during clinostatic and orthostatic conditions. In clinostatic conditions, tVNS reduced HR (p &lt, 0.01), SAP variability (p &lt, 0.01), and cardiac and peripheral sympathetic modulation (p &lt, 0.01). The responsivity of the peripheral sympathetic modulation to orthostatic stress during tVNS was significantly higher when compared to the control session (p = 0.03). In conclusion, tVNS reduces the HR and affects cardiac and peripheral autonomic control and increases the responses of peripheral autonomic control to orthostatic stress in healthy subjects.

Traditional echocardiography is unable to detect neither the early stages of iron overload cardiomyopathy nor myocardial iron deposition. The aim of the study is to determine myocardial systolic strain indices in thalassemia major (TM), and assess their relationship with T2*, a cardiac magnetic resonance index of the severity of cardiac iron overload. 55 TM cases with recent cardiac magnetic resonance (CMR-T2*) underwent speckle tracking analysis to assess regional myocardial strains and rotation. The results were compared with a normal control group (n = 20), and were subsequently analyzed on the basis of the CMR-T2* values. Two TM groups were studied: TM with significant cardiac iron overload (“low” T2*, ≤20 ms; n = 21), and TM with normal T2* values (“normal” T2*, >20 ms; n = 34). TM patients show significant, uniform decrease in circumferential and radial strain (P

Background— The prevalence of heart failure with preserved ejection fraction is increasing. The prognosis worsens with pulmonary hypertension and right ventricular (RV) failure development. We targeted pulmonary hypertension and RV burden with the phosphodiesterase-5 inhibitor sildenafil. Methods and Results— Forty-four patients with heart failure with preserved ejection fraction (heart failure signs and symptoms, diastolic dysfunction, ejection fraction ≥50%, and pulmonary artery systolic pressure >40 mm Hg) were randomly assigned to placebo or sildenafil (50 mg thrice per day). At 6 months, there was no improvement with placebo, but sildenafil mediated significant improvements in mean pulmonary artery pressure (−42.0±13.0%) and RV function, as suggested by leftward shift of the RV Frank-Starling relationship, increased tricuspid annular systolic excursion (+69.0±19.0%) and ejection rate (+17.0±8.3%), and reduced right atrial pressure (−54.0±7.2%). These effects may have resulted from changes within the lung (reduced lung water content and improved alveolar-capillary gas conductance, +15.8±4.5%), the pulmonary vasculature (arteriolar resistance, −71.0±8.2%), and left-sided cardiac function (wedge pulmonary pressure, −15.7±3.1%; cardiac index, +6.0±0.9%; deceleration time, −13.0±1.9%; isovolumic relaxation time, −14.0±1.7%; septal mitral annulus velocity, −76.4±9.2%). Results were similar at 12 months. Conclusions— The multifaceted response to phosphodiesterase-5 inhibition in heart failure with preserved ejection fraction includes improvement in pulmonary pressure and vasomotility, RV function and dimension, left ventricular relaxation and distensibility (structural changes and/or ventricular interdependence), and lung interstitial water metabolism (wedge pulmonary pressure decrease improving hydrostatic balance and right atrial pressure reduction facilitating lung lymphatic drainage). These results enhance our understanding of heart failure with preserved ejection fraction and offer new directions for therapy. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT01156636.

Background Cardiopulmonary exercise testing (CPET) provides powerful information on risk of death in heart failure (HF). We sought to define the relative and additive contribution of the 3 landmark (CPET) prognostic markers—peak oxygen consumption (VO 2 ), minute ventilation/carbon dioxide production (VE/VCO 2 ) slope, and exercise periodic breathing (EPB)—to the overall risk of cardiac death and to develop a prognostic score for optimizing risk stratification in HF patients. Methods and Results A total of 695 stable HF patients (average LVEF: 25 ± 8%) underwent a symptom-limited CPET maximum test after familiarization and were prospectively tracked for cardiac mortality. At multivariable Cox analysis EPB emerged as the strongest prognosticator. Using a statistical bootstrap technique (5000 data resamplings), point estimates, and 95% confidence intervals were obtained. Thirty-two configurations were adopted to classify patients into a given cell, according to EPB presence or absence and values of the 2 other covariates. Configurations without EPB and with VE/VCO 2 slope ≤30 were not significantly different from 0 (reference value). Statistical power of configurations increased with higher VE/VCO 2 slope and lower peak VO 2 . This prompted us to formulate a score including EPB as a discriminating variable, the (P)e(R)i(O)dic (B)reathing during (E)xercise (PROBE), which ranges between -1 and 1, with zero as reference configuration, that would help to optimize the prognostic accuracy of CPET-derived variables. The greatest PROBE score impact was provided by EPB, followed by VE/VCO 2 slope, whereas peak VO 2 added minimal prognostic power. Conclusions EPB with an elevated VE/VCO 2 slope leads to the highest and most precise PROBE score, whereas no additional risk information emerges when EPB is present with a peak VO 2 ≤10 mL O 2 ·kg −1 ·min −1 . PROBE score appears to provide a step forward for optimizing CPET use in HF prognostic definition.

ObjectivesThe purpose of this study was to test the ability of cardiopulmonary exercise testing (CPET)-derived variables as sudden cardiac death (SCD) predictors.BackgroundThe CPET variables, such as peak oxygen uptake (VO2), ventilatory requirement to carbon dioxide (CO2) production (VE/VCO2) slope, and exercise oscillatory breathing (EOB), are strong predictors of overall mortality in chronic heart failure (CHF) patients. Even though up to 50% of CHF patients die from SCD, it is unknown whether any of these variables predicts SCD.MethodsOne hundred fifty-six CHF patients (mean age: 60.9 ± 9.4 years; mean ejection fraction: 34.9 ± 10.6%) underwent CPET. Subjects were tracked for sudden versus pump-failure cardiac mortality over 27.8 ± 25.2 months.ResultsSeventeen patients died from SCD, and 17 died from cardiac pump failure. Survivors showed significantly higher peak VO2(16.8 ± 4.5 ml·kg−1·min−1) and lower VE/VCO2slope (32.8 ± 6.4) and prevalence of EOB (20.3%), compared with subjects who experienced arrhythmic (13.5 ± 3.2 ml·kg−1·min−1; 41.5 ± 11.4; 100%) or nonarrhythmic (14.1 ± 4.7 ml·kg−1·min−1; 38.1 ± 7.3; 47.1%) deaths (p < 0.05). At Cox regression analysis, all variables were significant univariate predictors of both sudden and pump failure death (p < 0.01). Multivariate analysis, including left ventricular (LV) ejection fraction, LV end systolic volume, and LV mass selected EOB, was the strongest predictor of both overall mortality (chi-square: 38.7, p < 0.001) and SCD (chi-square: 44.7, p < 0.001), whereas VE/VCO2slope was the strongest ventilatory predictor of pump failure death (chi-square: 11.8, p = 0.001).ConclusionsExercise oscillatory breathing is an independent predictor of SCD in patients with CHF and might help as an additional marker for prioritization of antiarrhythmic strategies.

Background Statins represent a modern mainstay of the drug treatment of coronary artery disease and acute coronary syndromes. Reduced aerobic work performance and slowed VO2 kinetics are established features of the clinical picture of post-myocardial infarction (MI) patients. We tested the hypothesis that statin therapy improves VO2 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 VO2 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 VO2 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.

Patients with pulmonary arterial hypertension (PAH) and with heart failure (HF) have increased ventilatory responses to exercise in proportion to disease severity. Exercise-associated oscillatory ventilation (EOV) predicts poor outcome in HF. Whether EOV occurs in PAH is unknown.We analyzed the initial cardiopulmonary exercise tests (CPETs) and right heart catheterization data of 109 patients with PAH and in 107 patients with HF consecutively referred to our center.The PAH patients were aged 54±16 years and their NYHA functional class was 2.8±0.5. The HF patients were aged 53±13 years and NYHA 2.4±0.6. Hemodynamic data were obtained in only 36 of them. The patients with PAH compared to those with HF had a lower peak VO2 (13±5 vs 17±5 mL/kg/min, p0.001) and a higher ventilatory equivalent for CO2 (VE/VCO2) slope (55±21 vs 34±7, p0.001). Mean pulmonary artery pressure was higher (50±10 vs 29±11 mmHg) and wedge pressure lower (10±3 vs 19±5 mmHg) in PAH patients, but cardiac output was not different (4.0±1.3 vs 4.2±1.2L/min). EOV was present in 22 patients (21%) with HF and in no patient with PAH.Patients with PAH compared to HF with slightly better functional class have a lower aerobic exercise capacity and higher ventilatory responses, but no EOV. An increase in pulmonary artery wedge pressure rather than a low cardiac output may be necessary condition of EOV in HF.

Air pollution has recently been associated with the development of acute decompensated heart failure, but the underlying biological mechanisms remain unclear. A pulmonary vasoconstrictor effect of air pollution, combined with its systemic effects, may precipitate decompensated heart failure. The aim of the present study was to investigate the effects of acute exposure to diesel exhaust (DE) on pulmonary vascular resistance (PVR) under resting and stress conditions but also to determine whether air pollution may potentiate acquired pulmonary hypertension. Eighteen healthy male volunteers were exposed to ambient air (AA) or dilute DE with a particulate matter of 3for 2 h in a randomized, crossover study design. The effects of DE on PVR, on the coefficient of distensibilty of pulmonary vessels (α), and on right and left ventricular function were evaluated at rest ( n = 18), during dobutamine stress echocardiography ( n = 10), and during exercise stress echocardiography performed in hypoxia ( n = 8). Serum endothelin-1 and fractional exhaled nitric oxide were also measured. At rest, exposure to DE did not affect PVR. During dobutamine stress, the slope of the mean pulmonary artery pressure-cardiac output relationship increased from 2.8 ± 0.5 mmHg·min·l−1in AA to 3.9 ± 0.5 mmHg·min·l−1in DE ( P < 0.05) and the α coefficient decreased from 0.96 ± 0.15 to 0.64 ± 0.12%/mmHg ( P < 0.01). DE did not further enhance the hypoxia-related upper shift of the mean pulmonary artery pressure-cardiac output relationship. Exposure to DE did not affect serum endothelin-1 concentration or fractional exhaled nitric oxide. In conclusion, acute exposure to DE increased pulmonary vasomotor tone by decreasing the distensibility of pulmonary resistive vessels at high cardiac output.

We appreciate Dr Jamous' interest in our article1 and his query as to how pulmonary hemodynamics may have changed after vasodilating challenge. This was not a prespecified end point or a quest for testing our hypotheses. Nonetheless, it remains intriguing to understand whether pulmonary capillary wedge pressure and pulmonary vascular resistance under acute challenge may predict benefit. According to Melenowski et al,2 an acute test with sildenafil can be very appropriate in left-sided pulmonary hypertension (PH), given the high responsiveness rate in heart failure (HF) patients with elevated pulmonary vascular resistance who are unresponsive to standard challenge with prostacyclin. As to mean pulmonary artery pressure differences between our study and the Sildenafil Use in Pulmonary Arterial Hypertension (SUPER-1) trial, performed in patients with pulmonary arterial hypertension, we would avoid, according to current literature, the comparison of pulmonary arterial hypertension with nonpulmonary forms, such as group 2 PH.3 Differences in pathobiology and drug dose may, per se, explain variability in outcomes. We agree that changes in the precapillary contribution to the pulmonary artery pressure rise are attributable to mechanisms other than vasodilation. Indeed, in a transaortic constriction rat model of left ventricular (LV) hypertrophy and diastolic HF, a clear biological activity of sildenafil on lung arterial microvasculature and endothelial function has been documented.4 This fully supports our findings and may represent …

Background— In heart failure (HF), a defective nitric oxide signaling is involved in left ventricular (LV) diastolic abnormalities and remodeling. PDE5 inhibition, by blocking degradation of nitric oxide second-messenger cyclic guanosine monophosphate, might be beneficial. In a cohort of systolic HF patients, we tested the effects of PDE5 inhibition (sildenafil) on LV ejection fraction, diastolic function, cardiac geometry, and clinical status. Methods and Results— Forty-five HF patients (New York Heart Association class II-III) were randomly assigned to placebo or sildenafil (50 mg three times per day) for 1 year, with assessment (6 months and 1 year) of LV ejection fraction, diastolic function, geometry, cardiopulmonary exercise performance, and quality of life. In the sildenafil group only, at 6 months and 1 year, LV ejection fraction, early diastolic tissue Doppler velocities (E′) at the mitral lateral (from 4.62 to 5.20 and 5.19 m/s) and septal (from 4.71 to 5.23 and 5.24 m/s) annuli significantly increased, whereas the ratio of early transmitral (E) to E′ lateral decreased (from 13.1 to 9.8 to 9.4) ( P 2 ; P 2 ; P o 2 ), ventilation efficiency (ventilation to CO 2 production slope), and quality of life ( P Conclusions— Findings confirm that in HF, sildenafil improves functional capacity and clinical status and provide the first human evidence that LV diastolic function and cardiac geometry are additional targets of benefits related to chronic PDE5 inhibition. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00975494.

The assessment of aerobic exercise capacity is an important component in the clinical management of patients with heart failure (HF). Although a significant percentage of patients diagnosed with HF also present with chronic obstructive pulmonary disease (COPD) comorbidity, the combined impact of these chronic conditions on the aerobic exercise response is unknown and is therefore the purpose of the present investigation.Sixty-nine subjects with HF and COPD were matched to 69 subjects solely diagnosed with HF according to age, sex, and HF etiology. All subjects underwent resting pulmonary function and diffusion capacity testing, echocardiography with tissue Doppler imaging, and cardiopulmonary exercise testing (CPX).Subjects with COPD comorbidity had significantly lower pulmonary function testing and diffusion capacity values versus HF alone (P.05). In addition, subjects with both HF and COPD had significantly higher pulmonary artery systolic pressures (51.9 ± 9.0 vs 37.0 ± 7.8 mm Hg, P.001) as assessed by pulsed Doppler echocardiography. Cardiopulmonary exercise testing revealed a significantly poorer response in subjects with HF and COPD by all variables that were analyzed, including peak oxygen consumption (12.1 ± 4.3 vs 16.3 ± 4.3 mL kg⁻¹ min⁻¹, P.001), minute ventilation/carbon dioxide production slope (42.7 ± 7.4 vs 33.3 ± 6.6, P.001) and heart rate recovery at 1 minute (12.1 ± 2.5 vs 14.2 ± 2.9 beats, P.001).Patients with HF and the comorbidity of COPD have significantly impaired CPX responses. This novel finding may impact the clinical interpretation of CPX data in patients with HF who also present with this chronic pulmonary condition.

Background— The six-minute walk test (6MWT) and cardiopulmonary exercise testing (CPET) are the 2 testing modalities most broadly used for assessing functional limitation in patients with heart failure (HF). A comprehensive comparison on clinical and prognostic validity of the 2 techniques has not been performed and is the aim of the present investigation. Methods and Results— Two hundred fifty-three patients diagnosed with systolic (n=211) or diastolic (n=42) HF (age: 61.9�10.1 years; New York Heart Association Class: 2.2�0.78) underwent a 6MWT and a symptom-limited CPET evaluation and were prospectively followed up. During the 4-year tracking period, there were 43 cardiac-related deaths with an annual cardiac mortality rate of 8.7%. The 6MWT distance correlated with CPET-derived variables (ie, peak V o 2 , V o 2 at anaerobic threshold, and V e /V co 2 slope) and was significantly reduced in proportion with lower peak V o 2 and higher V e /V co 2 slope classes and presence of an exercise oscillatory breathing (EOB) pattern ( P P =NS). At univariate and multivariate Cox proportional analyses, the association of the 6MWT distance with survival was not significant either as a continuous or dicotomized variable (≤300 m). Conversely, CPET-derived variables emerged as prognostic with the strongest association found for EOB (systolic HF) and V e /V co 2 slope (entire population with HF and patients with a 6MWT≤300 m). Conclusions— The 6MWT is confirmed to be a simple and reliable first-line test for quantification of exercise intolerance in patients with HF. However, there is no supportive evidence for its use as a prognostic marker in alternative to or in conjunction with CPET-derived variables.

Some studies suggest that the sympathetic nervous system and the renin-angiotensin system are activated in patients with chronic obstructive pulmonary disease (COPD), potentially resulting in negative cardiopulmonary and muscular effects. The aim of this pilot study was to evaluate the efficacy of an angiotensin converting enzyme (ACE) inhibitor on cardiopulmonary exercise performance in COPD patients. Primary outcome was the effect of treatment on the ventilatory response to exercise (VE/VCO(2) slope). Secondary outcomes were exercise variables evaluated by the cardiopulmonary exercise test, and pulmonary function according to ACE genotyping.4 weeks treatment with enalapril (10 mg od) or placebo was evaluated in 21 COPD patients (FEV(1)60%) and without cardiovascular disease in a double-blind, cross-over study.18 patients completed the study. Enalapril did not exert a significant effect on exercise VE/VCO(2) slope or on peak O(2) consumption. However enalapril significantly improved peak O(2) pulse and work rate compared to placebo. A mild but significant worsening of the diffusion capacity of the lung was observed. ACE genotype did not significantly affect patients' response to treatment, except for a trend toward a more evident effect of treatment in patients with II ACE genotype in terms of O(2) pulse and gas diffusion.In this pilot study, ACE inhibition did not affect the ventilatory response to exercise in COPD patients. However, treatment resulted in improvement in work rate and O(2) pulse, suggesting that ACE inhibitor therapy warrants consideration and may provide beneficial effect on the cardiovascular response to exercise in COPD.

Aim: Nitric oxide (NO) is a mediator of the pulmonary vessel tone and permeability. We hypothesized that it may also regulate the alveolar-capillary membrane gas conductance and lung diffusion capacity. Methods: In 20 healthy subjects (age = 23 ± 3 years) we measured lung diffusion capacity for carbon monoxide (DLco), its determinants (membrane conductance, D m , and pulmonary capillary blood volume, V c ), systolic pulmonary artery pressure (PAPs) and pulmonary vascular resistance (PVR). Measurements were performed before and after administration of N G -monomethyl-L-arginine (L-NMMA, 0.5 mg kg -1 min -1 ), as a NO production inhibitor, and L-arginine (L-Arg, 0.5 mg kg -1 mini) as a NO pathway activator. The effects of L-NMMA were also tested in combination with active L-Arg and inactive stereoisomer D-Arg vehicled by 150 mL of 5% D-glucose solution. For L-Arg and L-NMMA, saline (150 mL) was also tested as a vehicle. Results: L-NMMA reduced D m (-41% P < 0.01), DLco (-20%, P < 0.01) and cardiac output (CO), and increased PAPs and PVR. In 10 additional subjects, a dose of L-NMMA of 0.03 mg kg -1 min 1 infused in the main stem of the pulmonary artery was able to lower D m (-32%, P < 0.01) despite no effect on PVR and CO. D m depression was significantly greater when L-NMMA was vehicled by saline than by glucose. L-Arg but not D-Arg abolished the effects of L-NMMA. L-Arg alone increased D m (+14%, P < 0.01). Conclusion: The findings indicate that NO mediates the respiratory effects of L-NMMA and L-Arg, and is involved in the physiology of the alveolar-capillary membrane gas conductance in humans. NO deficiency may cause an excessive endothelial sodium exchange/water conduction and fluid leakage in alveolar interstitial space, lengthening the air-blood path and depressing diffusion capacity.

Aims The influence of permanent atrial fibrillation on exercise tolerance and cardio-respiratory function during exercise in heart failure (HF) is unknown. Methods and results We retrospectively compared the results of 942 cardiopulmonary exercise tests, performed consecutively at seven Italian laboratories, in HF patients with atrial fibrillation ( n = 180) and sinus rhythm ( n = 762). By multivariable logistic regression analysis, peak VO2 (OR 0.376, 95% CI 0.240–0.588, P < 0.0001), O2pulse (VO2/heart rate, HR) (OR 0.236, 95% CI 0.152–0.366, P < 0.0001), VCO2 (OR 3.97, 95% CI 2.163–7.287, P < 0.0001), and ventilation (OR 1.38, 95% CI 1.045–1.821, P = 0.0231) were independently associated with atrial fibrillation. Anaerobic threshold (AT) was identified in 132 of 180 (73%) atrial fibrillation and in 649 of 762 (85%) sinus rhythm patients ( P = 0.0002). By multivariable logistic regression analysis, only peak VO2 (OR 0.214, 95% CI 0.155–0.296, P < 0.0001) was independently associated with unidentified AT. At AT, atrial fibrillation HF patients had higher HR ( P < 0.0001) and higher VO2 ( P < 0.001) compared with sinus rhythm HF patients. Among AT variables, by multivariable logistic regression analysis, only HR was an independent predictor of atrial fibrillation. Conclusion In HF patients with permanent atrial fibrillation, exercise performance is reduced as reflected by reduced peak VO2. The finding of unidentified AT is associated with a poor performance. In atrial fibrillation patients, VO2 is higher at AT whereas lower at peak. This last observation raises uncertainties about the use of AT data to define performance and prognosis of HF patients with atrial fibrillation.

Background Risk stratification for subsequent cardiovascular events following a myocardial infarction (MI) is an important area of research. Previous findings indicate flow-mediated dilatation (FMD) may be a valuable prognostic indicator. This study investigates the prognostic value of FMD in patients suffering an uncomplicated MI. Methods One hundred and seventy nine post-MI patients [110male/69 female, mean age: 64.8±10.0 years, ejection fraction: 51.9±12.2%] were included in this analysis. Ultrasound images of the brachial artery were used to determine FMD following reactive hyperemia. Subjects were tracked for subsequent cardiovascular events [myocardial infarction, heart failure, additional interventions (percutaneous coronary intervention, coronary artery bypass)] following data collection via medical chart review. Results There were 45 subsequent cardiovascular events during a mean tracking period of 13.7 (±9.5) months. Receiver operating characteristic (ROC) curve analysis revealed a diagnosis of diabetes (ROC area: 0.67, p =0.001, 95% confidence interval: 0.58–0.77) and percent change in arterial diameter (ROC area: 0.63, p =0.01, 95% confidence interval: 0.53–0.73, optimal threshold: ≤/>4.5%) were prognostically significant. Kaplan–Meier analysis revealed the event-free survival rate for subjects without diabetes and an arterial diameter change >4.5%, without diabetes and percent change in arterial diameter ≤4.5%, with diabetes and percent change in arterial diameter >4.5% and with diabetes and percent change in arterial diameter ≤4.5% was 88.7%, 78.4%, 67.7% and 38.5%, respectively (Log-rank: 24.9, p Conclusions Non-invasive FMD is a potential risk factor after MI and may add information to conventional risk stratification. This will need to be tested in further studies.

Background Ventilatory efficiency, commonly assessed by the minute ventilation (VE)-carbon dioxide production (VCO 2 ) slope, has proven to be a strong prognostic marker in the heart failure (HF) population. Recently, the oxygen uptake efficiency slope (OUES) has demonstrated prognostic value, but additional comparisons to established cardiopulmonary exercise test (CPET) variables are required. Methods and Results A total of 341 subjects were diagnosed with HF participated in this analysis. The VE/VCO 2 slope and the OUES were calculated using 50% (VE/VCO 2 slope 50 or OUES 50 ) and 100% (VE/VCO 2 slope 100 or OUES 100 ) of the exercise data. Peak oxygen consumption (VO 2 ) was also determined. There were 47 major cardiac-related events during the 3-year tracking period. Receiver operating characteristic (ROC) curve analysis demonstrated the classification schemes for both VE/VCO 2 slope and OUES calculations as well as peak VO 2 were statistically significant (all areas under the ROC curve: ≥0.74, P 2 slope 100 was, however, significantly greater than OUES 50 , OUES 100 , and peak VO 2 ( P Conclusions Although the OUES was a significant predictor of mortality, the VE/VCO 2 slope maintained optimal prognostic value. An elevated VE/VCO 2 slope may be the single best indicator of increased risk for adverse events.