Pharmacological rationale for the very early treatment of acute coronary syndrome with monoclonal antibodies anti-PCSK9.

Immediate and aggressive lipid lowering therapies after acute coronary syndromes (ACS) and percutaneous coronary interventions (PCI) are supported by the ESC/EAS dyslipidemia guidelines, recommending the initiation of high-intensity statin therapy within the first 1-4 days of hospitalization. However, whether non statin lipid-lowering agents, added to statin treatment, could produce a further reduction in the risk of major adverse cardiovascular events (MACE) is still unknown. Thus, the efficacy of early treatment post-ACS with monoclonal antibodies (mAbs) anti PCSK9, evolocumab and alirocumab, is under investigation. The rationale to explore the rapid and aggressive pharmacological intervention with PCSK9 mAbs is supported by at least five confirmatory data in ACS: 1) circulating PCSK9 levels are raised during ACS 2) PCSK9 may stimulate platelet reactivity, this last being pivotal in the recurrence of ischemic events; 3) PCSK9 is associated with intraplaque inflammation, macrophage activation and endothelial dysfunction; 4) PCSK9 concentrations are associated with inflammation in the acute phase of ACS; and 5) statins raise PCSK9 levels promptly and, at times, dramatically. In this scenario, appropriate pharmacodynamic characteristics of anti PCSK9 therapies are a prerequisite for an effective response. Monoclonal antibodies act on circulating PCSK9 with a direct and rapid binding by blocking the interaction with the low-density lipoprotein receptor (LDLR). Evolocumab and alirocumab show a very rapid (within 4 h) and effective suppression of circulating unbound PCSK9 (- 95 % ÷ - 97 %). This inhibition results in a significant reduction of LDL-cholesterol (LDL-C) after 48 h (- 35 %) post injection with a full effect after 7-10 days (55-75 %). The complete and swift inhibitory action by evolocumab and alirocumab could have a potential clinical impact in ACS patients, also considering their potential inhibition of PCSK9 within the atherosclerotic plaque. Thus, administration of evolocumab or alirocumab is effective in lowering LDL-C levels in ACS, although the efficacy to prevent further cardiovascular (CV) events is still undetermined. The answer to this question will be provided by the ongoing clinical trials with evolocumab and alirocumab in ACS. In the present review we will discuss the pharmacological and biological rationale supporting the potential use of PCSK9 mAbs in ACS patients and the emerging evidence of evolocumab and alirocumab treatment in this clinical setting.

Left Ventricular Thrombus Management After Acute Myocardial Infarction in Clinical Practice: Results from LEVITATION Survey and Narrative Review.

PURPOSE: Left ventricular thrombus (LVT) after ST-elevation myocardial infarction still presents diagnostic and therapeutic challenges. The LEVITATION survey was designed to take a picture of LVT management in current clinical practice. METHODS: The survey covered diagnostic, therapeutic, and prophylactic issues and was completed by 104 European cardiac centers. Most of them (59%) were university or tertiary centers. RESULTS: The survey showed anterior apical a-/dyskinesia, large MI, spontaneous echo-contrast, late presentation with delayed PCI, and TIMI flow 0-1 as the most important perceived risk factors for LVT formation. Serial ultrasound imaging is the most used tool to diagnose LVT (88% of the centers), with contrast-enhanced ultrasound and cardiac MR performed in case of poor apex visualization or spontaneous echo-contrast. One third (34%) of the centers uses prophylactic anticoagulation to prevent LVT formation. In the presence of LVT, low molecular weight heparin is the most used in-hospital therapy. At discharge, vitamin K antagonist and direct oral anticoagulants are used in 67 and 32% of the cases, respectively. Triple antithrombotic therapy with aspirin plus clopidogrel and VKA is the most used strategy at discharge (55%), whereas a single antiplatelet therapy is preferred only in the case of moderate-to-high risk of bleeding. To assess LVT total regression, half of the centers use contrast-enhanced ultrasound and/or cardiac-MR. The duration of anticoagulation is usually 3-6 months (55%), with long-term prolongation in case of LVT persistence or recurrence. CONCLUSION: The survey has depicted for the first time the current real-world management of this neglected topic and has highlighted several grey zones that are still present and not supported by evidence.

Prognostic parameters of in-hospital mortality in COVID-19 patients-An Italian experience.

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 < .001); each increment of 58 ng/L of interleukin (IL)-6 corresponded to a HR of 1.23 (95% CI 1.09-1.40, P < .001), and each increment of 250 U/L of lactate dehydrogenase (LDH) corresponded to a HR of 1.23 (95% CI 1.10-1.37, P < .001). According to the calculated cut-points for age (≥70 years), NT-proBNP (≥803 ng/L), IL-6 (≥58 ng/L) and LDH (≥371 U/L) when 2 out of these 4 were overcome, the HR was 2.96 (95% CI 1.97-4.45, P < .001). Conclusion In COVID-19 patients, besides age, the evaluation of three biochemical parameters, available in few hours after hospital admission can predict in-hospital mortality regardless of other comorbidities.

Cardiopulmonary exercise testing in a combined screening approach to individuate pulmonary arterial hypertension in systemic sclerosis.

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.

Elevated Troponin in Patients With Coronavirus Disease 2019: Possible Mechanisms.

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.

COVID-19 multidisciplinary high dependency unit: the Milan model.

COVID-19 is a complex and heterogeneous disease. The pathogenesis and the complications of the disease are not fully elucidated, and increasing evidence shows that SARS-CoV-2 causes a systemic inflammatory disease rather than a pulmonary disease. The management of hospitalized patients in COVID-19 dedicated units is advisable for segregation purpose as well as for infection control. In this article we present the standard operating procedures of our COVID-19 high dependency unit of the Policlinico Hospital, in Milan. Our high dependency unit is based on a multidisciplinary approach. We think that the multidisciplinary involvement of several figures can better identify treatable traits of COVID-19 disease, early identify patients who can quickly deteriorate, particularly patients with multiple comorbidities, and better manage complications related to off-label treatments. Although no generalizable to other hospitals and different healthcare settings, we think that our experience and our point of view can be helpful for countries and hospitals that are now starting to face the COVID-19 outbreak.

At high cardiac output, diesel exhaust exposure increases pulmonary vascular resistance and decreases distensibility of pulmonary resistive vessels.

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 <2.5 µm concentration of 300 µg/m(3) for 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 (-1) in AA to 3.9 ± 0.5 mmHg · min · l (-1) in 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.

SGLT2-i prevent left ventricular dysfunction induced by anthracycline in mouse model: A systematic-review and meta-analysis.

CLINICAL QUESTION: Could SGLT2-i be helpful for the prevention of left ventricular dysfunction induced by anthracycline? WHAT IS THE MAIN FINDING?: SGLT2-i appear effective for the prevention of left ventricular dysfunction induced by anthracycline in mouse model.

Right Heart Catheterization: An Antecubital Vein Approach to Reduce Fluoroscopy Time, Radiation Dose, and Guidewires Need.

Antecubital access for right heart catheterization (RHC) is a widespread technique, even though there is a need to clarify if there are differences and significant advantages compared to proximal vein access. To pursue this issue, we retrospectively identified patients who underwent RHC in our clinic over a 7 year period (between January 2015 and December 2022). We revised demographic, anthropometric, and procedural data, including the fluoroscopy time, the radiation exposure, and the use of guidewires. The presence of any complications was also assessed. In patients with antecubital access, the fluoroscopy time and the radiation exposure were lower compared to proximal vein access (6 vs. 3 min, mean difference of 2 min, CI 95% 1-4 min, p < 0.001 and 61 vs. 30 cGy/m2, mean difference 64 cGy/m2, CI 95% 50-77, p < 0.001). The number of patients requiring the use of at least one guidewire was lower in the group undergoing RHC through antecubital access compared to proximal vein access (55% vs. 43%, p = 0.01). The feasibility was optimal, as just 0.9% of procedures switched from antecubital to femoral access, with a negligible rate of complications. The choice of the antecubital site exhibits advantages, e.g., a shorter fluoroscopy time, a reduced radiation dose, and a lower average number of guidewires used compared to proximal vein access.

Case report: Sodium-glucose cotransporter 2 inhibitors induce left ventricular reverse remodeling in anthracycline-related cardiac dysfunction-a case series.

Purpose: To describe the efficacy and safety of sodium-glucose cotransporter 2 inhibitors as a specific treatment for anthracycline-related cardiac dysfunction in a small real-world population. Methods: Seven patients with anthracycline-related cardiac dysfunction were clinically and echocardiographically evaluated before and after the introduction of sodium-glucose cotransporter 2 inhibitors. Results: After a median period of 24 weeks with uninterrupted sodium-glucose cotransporter 2 inhibitors treatment, a significant clinical improvement was observed with at least one New York Heart Association Functional Class (NHYA FC) improvement in all patients (median NYHA FC: I vs. III, p < 0.010). A noteworthy left ventricular reserve remodeling (median left ventricular end diastolic volume indexed: 53 vs. 82.5 ml/m2, p = 0.018; median left ventricular ejection fraction: 50% vs. 40%, p = 0.17) was also observed. Sodium-glucose cotransporter 2 inhibitors therapy was well tolerated by every patients; no cases of discontinuation or relevant side effects were observed. Conclusion: Sodium-glucose cotransporter 2 inhibitors induce a significant clinical improvement and left ventricular reserve remodeling in patients affected by anthracycline-related cardiac dysfunction.

Melatonin mitigates oxidative damage induced by anthracycline: a systematic-review and meta-analysis of murine models.

Background: Oxidative stress induced by the excessive production of reactive oxygen species is one of the primary mechanisms implicated in anthracycline (ANT)-induced cardiotoxicity. There is a strong clinical need for a molecule capable of effectively preventing and reducing the oxidative damage caused by ANT. In vitro and in vivo studies conducted in mice have shown that melatonin stimulates the expression of antioxidative agents and reduces lipid peroxidation induced by ANT. Methods: We investigated this issue through a meta-analysis of murine model studies. The outcome of the meta-analysis was to compare oxidative damage, estimated by products of lipid peroxidation (MDA = Malondialdehyde) and markers of oxidative stress (SOD = Superoxide Dismutase, GSH = Glutathione), along with a marker of cardiac damage (CK-MB = creatine kinase-myocardial band), assessed by measurements in heart and/or blood samples in mice undergoing ANT chemotherapy and assuming melatonin vs. controls. The PubMed, OVID-MEDLINE and Cochrane library databases were analysed to search English-language review papers published from the inception up to August 1st, 2023. Studies were identified by using Me-SH terms and crossing the following terms: "melatonin", "oxidative stress", "lipid peroxidation", "anthracycline", "cardiotoxicity". Results: The metanalysis included 153 mice administered melatonin before, during or immediately after ANT and 153 controls from 13 studies. Compared with controls, the levels of all oxidative stress markers were significantly better in the pooled melatonin group, with standardized mean differences (SMD) for MDA, GSH and SOD being -8.03 ± 1.2 (CI: -10.43/-5.64, p < 0.001), 7.95 ± 1.8 (CI: 4.41/11.5, p < 0.001) and 3.94 ± 1.6 (CI: 0.77/7.12, p = 0.015) respectively. Similarly, compared with controls, CK-MB levels reflecting myocardial damage were significantly lower in the pooled melatonin group, with an SMD of -4.90 ± 0.5 (CI: -5.82/-3.98, p < 0.001). Conclusion: Melatonin mitigates the oxidative damage induced by ANT in mouse model. High-quality human clinical studies are needed to further evaluate the use of melatonin as a preventative/treatment strategy for ANT-induced cardiotoxicity.

The "Woggle" Technique for Venous Access Site Management: An Old Technique for a New Need.

BACKGROUND: Several closure devices are routinely used for percutaneous arterial access, while a relatively low number is available for the management of large bore venous accesses. The Woggle technique is a modification of the purse-string suture which was introduced several years ago in patients undergoing hemodialysis. METHODS: A population of 45 patients who underwent transvenous femoral structural heart interventions was retrospectively evaluated. The Woggle technique consists of a purge string suture with a collar to maintain the tension as stable over time and a suture lock to tighten the suture. RESULTS: Sheaths magnitude ranged from 8 French (F) to 14 F. A rapid post-procedural hemostasis was achieved in the whole population, and in 95% of cases, definite hemostasis was obtained after the first single release; the mean time of release was 302 ± 83 min. Although no relevant bleedings were reported, a significant reduction in hemoglobin levels was found in the whole population. This decrement was statistically significant only in the group with sheaths higher than 12 F. A single mild local hematoma was recorded in the group in which smaller sheaths were used. Seventy-two percent of patients were pre-treated with a dual antiplatelet therapy. CONCLUSIONS: The Woggle technique has shown to be a simple, effective, and safe approach for the management of large bore venous in percutaneous structural heart interventions.

Haemodynamic validation of the three-step HFA-PEFF algorithm to diagnose heart failure with preserved ejection fraction.

AIMS: The HFA-PEFF algorithm (Heart Failure Association-Pre-test assessment, Echocardiography and natriuretic peptide score, Functional testing in cases of uncertainty, Final aetiology) is a three-step algorithm to diagnose heart failure with preserved ejection fraction (HFpEF). It provides a three-level likelihood of HFpEF: low (score < 2), intermediate (score 2-4), or high (score > 4). HFpEF may be confirmed in individuals with a score > 4 (rule-in approach). The second step of the algorithm is based on echocardiographic features and natriuretic peptide levels. The third step implements diastolic stress echocardiography (DSE) for controversial diagnostic cases. We sought to validate the three-step HFA-PEFF algorithm against a haemodynamic diagnosis of HFpEF based on rest and exercise right heart catheterization (RHC). METHODS AND RESULTS: Seventy-three individuals with exertional dyspnoea underwent a full diagnostic work-up following the HFA-PEFF algorithm, including DSE and rest/exercise RHC. The association between the HFA-PEFF score and a haemodynamic diagnosis of HFpEF, as well as the diagnostic performance of the HFA-PEFF algorithm vs. RHC, was assessed. The diagnostic performance of left atrial (LA) strain < 24.5% and LA strain/E/E' < 3% was also assessed. The probability of HFpEF was low/intermediate/high in 8%/52%/40% of individuals at the second step of the HFA-PEFF algorithm and 8%/49%/43% at the third step. After RHC, 89% of patients were diagnosed as HFpEF and 11% as non-cardiac dyspnoea. The HFA-PEFF score resulted associated with the invasive haemodynamic diagnosis of HFpEF (P < 0.001). Sensitivity and specificity of the HFA-PEFF score for the invasive haemodynamic diagnosis of HFpEF were 45% and 100% for the second step of the algorithm and 46% and 88% for the third step of the algorithm. Neither age, sex, body mass index, obesity, chronic obstructive pulmonary disease, or paroxysmal atrial fibrillation influenced the performance of the HFA-PEFF algorithm, as these characteristics were similarly distributed over the true positive, true negative, false positive, and false negative cases. Sensitivity of the second step of the HFA-PEFF score was non-significantly improved to 60% (P = 0.08) by lowering the rule-in threshold to >3. LA strain alone had a sensitivity and specificity of 39% and 14% for haemodynamic HFpEF, increasing to 55% and 22% when corrected for E/E'. CONCLUSIONS: As compared with rest/exercise RHC, the HFA-PEFF score lacks sensitivity: Half of the patients were wrongly classified as non-cardiac dyspnoea after non-invasive tests, with a minimal impact of DSE in modifying HFpEF likelihood.

Cardiac magnetic resonance predictors of left ventricular remodelling following acute ST elevation myocardial infarction: The VavirimS study.

BACKGROUND: Left ventricular (LV) remodelling (REM) ensuing after ST-elevation myocardial infarction (STEMI), has typically been studied by echocardiography, which has limitations, or cardiac magnetic resonance (CMR) in early phase that may overestimate infarct size (IS) due to tissue edema and stunning. This prospective, multicenter study investigated LV-REM performing CMR in the subacute phase, and 6 months after STEMI. METHODS AND RESULTS: patients with first STEMI undergoing successful primary angioplasty were consecutively enrolled. CMR was done at 30-days and 6-months. Primary endpoint was prevalence at 6 months of LV-REM [≥12% increase in LV end-diastolic volume index (LV-REMEDV)]; LV-REM by end-systolic volume index increase ≥12% (LV-REMESV) was also calculated. Of 325 patients enrolled, 193 with a full set of research-quality CMR images were analyzed. LV-REMEDV and LV-REMESV were present in 36/193 (19%) and 34/193 (18%) patients, respectively. At follow up, LV ejection fraction (EF) improved in patients with or without LV-REMEDV, whilst it decreased in those with LV-REMESV (p < 0.001 for interaction). Considering predictors of LV-REM, IS in the highest tertile was clearly separated from the two lower tertiles. In LV-REMEDV, the highest tertile was associated with significantly higher LV-EDV, LV-ESV, and lower EF. CONCLUSIONS: In a contemporary cohort of STEMI patients studied by CMR, prevalence of LV-REMEDV was lower than previously reported. Importantly, our data indicate that LV-REMEDV might not be "adverse" per se, but rather "compensatory", being associated with LV-EF improvement at follow-up. Conversely, LV-REMESV might be an "adverse" phenomenon associated with decreased LV-EF, driven by IS.

Induced myocardial ischemia in candidates to liver transplantation without evidence of heart disease.

BACKGROUND: Coronary artery disease (CAD) is associated with perioperative liver transplantation (LT) mortality. In absence of a defined risk algorithm, we aimed to test whether stress echocardiography and coronary computed tomography angiography (CCTA) could detect CAD in end-stage liver disease (ESLD) patients without previous evidence of heart disease. METHODS: LT candidates ≥30 years underwent a cardiovascular (CV) assessment through stress echocardiography. CCTA was performed in patients ≥50 years with two or more CV risk factors (e.g. diabetes, CAD family history, dyslipidaemia). Coronary angiography (CAG) was scheduled when stress echocardiography and/or CCTA were positive. Sensibility, specificity, positive and negative predictive values of stress echocardiography and CCTA were assessed by numbers of coronary revascularization (true positives) and lack of acute coronary events over a mean follow-up of 3 years (true negatives). RESULTS: Stress echocardiography was performed in 273 patients, CCTA in 34 and CAG in 41. Eight patients had critical coronary lesions, and 19 not-critical lesions. Sensitivity, specificity, positive and negative predictive values were 50.0%, 90.2%, 13.3% and 98.4% for stress echocardiography and 100%, 76.7%, 36.4% and 100% for CCTA. Among 163 patients who underwent LT (57.6%), 16 died and 5 had major adverse CV events over a mean follow-up of 3 years. CONCLUSIONS: A very low prevalence of CAD in a selected population of ESLD at intermediate to high CV risk was found. A screening based on stress echocardiography and CCTA resulted in low incidence of post-LT acute coronary events in ELSD patients. CAD has no impact on mid-term survival.

Pulmonary hypertension in heart failure with preserved ejection fraction: a target of phosphodiesterase-5 inhibition in a 1-year study.

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.

Salmeterol improves fluid clearance from alveolar-capillary membrane in COPD patients: a pilot study.

UNLABELLED: The cardiovascular component associated with chronic obstructive pulmonary disease (COPD) plays a major role in disease prognosis, accounting for 25% of the deaths. Experimental and initial clinical data suggest that beta-adrenergic agonists accelerate fluid clearance from the alveolar airspace, with potentially positive effects on cardiogenic and noncardiogenic pulmonary oedema. This pilot study investigated the acute effects of the long-acting beta-2 agonist, salmeterol, on alveolar fluid clearance after rapid saline intravenous infusion by evaluating diffusive and mechanical lung properties. Ten COPD and 10 healthy subjects were treated with salmeterol or placebo 4 h before the patient's mechanical and diffusive lung properties were measured during four non consecutive days, just before and after a rapid saline infusion, or during a similar period without an infusion. RESULTS: In both COPD and healthy subjects, rapid saline infusion with placebo or salmeterol premedication lead to a significant decrease in diffusion capacity for carbon monoxide (DLCO) and forced expiratory volume in 1 s (FEV1). Nonetheless, salmeterol pretreatment lead to a significantly reduced gas exchange impairment caused by saline infusion (-64% of DLCO reduction compared with placebo), whereas it did not affect changes in FEV1. In the control setting with no infusion, we found no significant change in either DLCO or mechanical properties of the lung. CONCLUSIONS: Salmeterol appears to provide a protective effect, not related to bronchodilation, against an acute alveolar fluid clearance challenge secondary to lung fluid overload in COPD patients.

The added value of right ventricular function normalized for afterload to improve risk stratification of patients with pulmonary arterial hypertension.

BACKGROUND: Risk stratification is central to the management of pulmonary arterial hypertension (PAH). For this purpose, multiparametric tools have been developed, including the ESC/ERS risk score and its simplified versions derived from large database analysis such as the COMPERA and the French Pulmonary Hypertension Network (FPHN) registries. However, the distinction between high and intermediate-risk profiles may be difficult as the latter lacks granularity. In addition, neither COMPERA or FPHN strategies included imaging-derived markers. We thus aimed at investigating whether surrogate echocardiographic markers of right ventricular (RV) to pulmonary artery (PA) coupling could improve risk stratification in patients at intermediate-risk. MATERIAL AND METHODS: A single-center retrospective analysis including 102 patients with a diagnosis of PAH was performed. COMPERA and FPHN strategies were applied to stratify clinical risk. The univariate linear regression was used to test the influence of the echo-derived parameters qualifying the right heart (right ventricle basal diameter, right atrial area, and pressure, tricuspid regurgitation velocity, tricuspid annular plane systolic excursion -TAPSE-). Among these, the TAPSE and tricuspid regurgitation velocity ratio (TAPSE/TRV) as well as the TAPSE and systolic pulmonary artery pressure ratio (TAPSE/sPAP) were considered as surrogate of RV-PA coupling. RESULTS: TAPSE/TRV and TAPSE/sPAP resulted the more powerful markers of prognosis. Once added to COMPERA, TAPSE/TRV or TAPSE/sPAP significantly dichotomized intermediate-risk group in intermediate-to-low-risk (TAPSE/TRV≥3.74 mm∙nm/s)-1 or TAPSE/sPAP≥0.24 mm/mmHg) and in intermediate-to-high-risk subgroups (TAPSE/TRV<3.74 mm∙(m/s)-1 or TAPSE/sPAP<0.24 mm/mmHg). In the same way, TAPSE/TRV or TAPSE/sPAP was able to select patients at lower risk among those with 2, 1, and 0 low-risk criteria of both invasive and non-invasive FPHN registries. CONCLUSIONS: Our results suggest that adopting functional-hemodynamic echo-derived parameters may provide a more accurate risk stratification in patients with PAH. In particular, TAPSE/TRV or TAPSE/sPAP improved risk stratification in patients at intermediate-risk, that otherwise would have remained less characterized.