Effect of Migalastat on cArdiac InvOlvement in FabRry DiseAse: MAIORA study.

BACKGROUND: A small but significant reduction in left ventricular (LV) mass after 18 months of migalastat treatment has been reported in Fabry disease (FD). This study aimed to assess the effect of migalastat on FD cardiac involvement, combining LV morphology and tissue characterisation by cardiac magnetic resonance (CMR) with cardiopulmonary exercise testing (CPET). METHODS: Sixteen treatment-naïve patients with FD (4 women, 46.4±16.2 years) with cardiac involvement (reduced T1 values on CMR and/or LV hypertrophy) underwent ECG, echocardiogram, troponin T and NT-proBNP (N-Terminal prohormone of Brain Natriuretic Peptide) assay, CMR with T1 mapping, and CPET before and after 18 months of migalastat. RESULTS: No change in LV mass was detected at 18 months compared to baseline (95.2 g/m2 (66.0-184.0) vs 99.0 g/m2 (69.0-121.0), p=0.55). Overall, there was an increase in septal T1 of borderline significance (870.0 ms (848-882) vs 860.0 ms (833.0-875.0), p=0.056). Functional capacity showed an increase in oxygen consumption (VO2) at anaerobic threshold (15.50 mL/kg/min (13.70-21.50) vs 14.50 mL/kg/min (11.70-18.95), p=0.02), and a trend towards an increase in percent predicted peak VO2 (72.0 (63.0-80.0) vs 69.0 (53.0-77.0), p=0.056) was observed. The subset of patients who showed an increase in T1 value and a reduction in LV mass (n=7, 1 female, age 40.5 (28.6-76.0)) was younger and at an earlier disease stage compared to the others, and also exhibited greater improvement in exercise tolerance. CONCLUSION: In treatment-naïve FD patients with cardiac involvement, 18-month treatment with migalastat stabilised LV mass and was associated with a trend towards an improvement in exercise tolerance. A tendency to T1 increase was detected by CMR. The subset of patients who had significant benefits from the treatment showed an earlier cardiac disease compared to the others. TRIAL REGISTRATION NUMBER: NCT03838237.

Abdominal obesity phenotype is associated with COVID-19 chest X-ray severity score better than BMI-based obesity.

PURPOSE: Chest X-ray (CXR) severity score and BMI-based obesity are predictive risk factors for COVID-19 hospital admission. However, the relationship between abdominal obesity and CXR severity score has not yet been fully explored. METHODS: This retrospective cohort study analyzed the association of different adiposity indexes, including waist circumference and body mass index (BMI), with CXR severity score in 215 hospitalized patients with COVID-19. RESULTS: Patients with abdominal obesity showed significantly higher CXR severity scores and had higher rates of CXR severity scores ≥ 8 compared to those without abdominal obesity (P < 0.001; P = 0.001, respectively). By contrast, patients with normal weight, with overweight and those with BMI-based obesity showed no significant differences in either CXR severity scores or in the rates of CXR severity scores ≥ 8 (P = 0.104; P = 0.271, respectively). Waist circumference and waist-to-height ratio (WHtR) correlated more closely with CXR severity scores than BMI (r = 0.43, P < 0.001; r = 0.41, P < 0.001; r = 0.17, P = 0.012, respectively). The area under the curves (AUCs) for waist circumference and WHtR were significantly higher than that for BMI in identifying a high CXR severity score (≥ 8) (0.68 [0.60-0.75] and 0.67 [0.60-0.74] vs 0.58 [0.51-0.66], P = 0.001). A multivariate analysis indicated abdominal obesity (risk ratio: 1.75, 95% CI: 1.25-2.45, P < 0.001), bronchial asthma (risk ratio: 1.73, 95% CI: 1.07-2.81, P = 0.026) and oxygen saturation at admission (risk ratio: 0.96, 95% CI: 0.94-0.97, P < 0.001) as the only independent factors associated with high CXR severity scores. CONCLUSION: Abdominal obesity phenotype is associated with a high CXR severity score better than BMI-based obesity in hospitalized patients with COVID-19. Therefore, when visiting the patient in a hospital setting, waist circumference should be measured, and patients with abdominal obesity should be monitored closely. Level of evidence Cross-sectional descriptive study, Level V.

Altered Hemodynamics and End-Organ Damage in Heart Failure: Impact on the Lung and Kidney.

Heart failure is characterized by pathologic hemodynamic derangements, including elevated cardiac filling pressures ("backward" failure), which may or may not coexist with reduced cardiac output ("forward" failure). Even when normal during unstressed conditions such as rest, hemodynamics classically become abnormal during stressors such as exercise in patients with heart failure. This has important upstream and downstream effects on multiple organ systems, particularly with respect to the lungs and kidneys. Hemodynamic abnormalities in heart failure are affected by processes that extend well beyond the cardiac myocyte, including important roles for pericardial constraint, ventricular interaction, and altered venous capacity. Hemodynamic perturbations have widespread effects across multiple heart failure phenotypes, ranging from reduced to preserved ejection fraction, acute to chronic disease, and cardiogenic shock to preserved perfusion states. In the lung, hemodynamic derangements lead to the development of abnormalities in ventilatory control and efficiency, pulmonary congestion, capillary stress failure, and eventually pulmonary vascular disease. In the kidney, hemodynamic perturbations lead to sodium and water retention and worsening renal function. Improved understanding of the mechanisms by which altered hemodynamics in heart failure affect the lungs and kidneys is needed in order to design novel strategies to improve clinical outcomes.

Exercise-induced mitral regurgitation and right ventricle to pulmonary circulation uncoupling across the heart failure phenotypes.

Exercise-induced mitral regurgitation (Ex-MR) is one of the mechanisms that contribute to reduced functional capacity in heart failure (HF). Its prevalence is not well defined across different HF subtypes. The aim of the present study was to describe functional phenotypes and cardiac response to exercise in HFrEF, HFmrEF, and HFpEF, according to Ex-MR prevalence. A total of 218 patients with HF [146 men, 68 (59-78) yr], 137 HFrEF, 41 HFmrEF, 40 HFpEF, and 23 controls were tested with cardiopulmonary exercise test combined with exercise echocardiography. Ex-MR was defined as development of at least moderate (≥2+/4+) regurgitation during exercise. Ex-MR was highly prevalent in the overall population (52%) although differed in the subgroups as follows: 82/137 (60%) in HFrEF, 17/41 (41%) in HFmrEF, and 14/40 (35%) in HFpEF (P < 0.05). Ex-MR was associated with a high rate of ventilation (VE) to carbon dioxide production (VCO2) in all HF subtypes [31.2 (26.6-35.6) vs. 33.4 (29.6-40.5), P = 0.004; 28.1 (24.5-31.9) vs. 34.4 (28.2-36.7), P = 0.01; 28.8 (26.6-32.4) vs. 32.2 (29.2-36.7), P = 0.01] and with lower peak VO2 in HFrEF and HFmrEF. Exercise right ventricle to pulmonary circulation (RV-PC) uncoupling was observed in HFrEF and HFpEF patients with Ex-MR [peak TAPSE/SPAP: HFrEF 0.40 (0.30-0.57) vs. 0.29 (0.23-0.39), P = 0.006; HFpEF 0.44 (0.28-0.62) vs. 0.31 (0.27-0.33), P = 0.05]. HFpEF with Ex-MR showed a distinct phenotype characterized by better chronotropic reserve and peripheral O2 extraction.NEW & NOTEWORTHY Ex-MR is a common mechanism across the spectrum of HF subtypes and combines with ventilatory inefficiency and RV-PC uncoupling. Interestingly, in HFpEF, Ex-MR emerged as unexpectedly prevalent and peculiarly associated with increased chronotropic response and peripheral O2 extraction as potential adaptive mechanisms to backward flow redistribution.

Nonresponse to Acute Vasodilator Challenge and Prognosis in Heart Failure With Pulmonary Hypertension.

BACKGROUND: An acute vasodilator challenge is recommended in patients with heart failure and pulmonary hypertension during heart transplant evaluation. The aim of the study was to assess which hemodynamic parameters are associated with nonresponsiveness to the challenge. METHODS AND RESULTS: This study is a retrospective analysis of 402 patients with heart failure with pulmonary hypertension who underwent right heart catheterization and a pulmonary vasodilator challenge. Among the 140 who fulfilled the transplant guidelines eligibility criteria for the vasodilator challenge, 38 were responders and 102 nonresponders. At multivariable analysis, a diastolic blood pressure of <70 mm Hg, pulmonary vascular resistance of >5 Woods units, and pulmonary artery compliance of <1.2 mL/mm Hg were independently associated with poor response to vasodilator challenge (all P < .001). The presence of any 2 of these 3 conditions was associated with a 90% probability of being a nonresponder. The covariate-adjusted hemodynamic predictors of death in the entire population were a low baseline systolic blood pressure (P = .0017) and a low baseline right ventricular stroke work index (P = .0395). CONCLUSIONS: In patients with heart failure and pulmonary hypertension, low pulmonary arterial compliance, high pulmonary vascular resistance, and low diastolic blood pressure predict the nonresponsiveness to acute vasodilator challenge whilst a poor right ventricular function predicts a dismal prognosis.

A right ventricular state of mind in the progression of heart failure with reduced ejection fraction: implications for left ventricular assist device therapy.

Right ventricular (RV) function in patients with preexisting left ventricular (LV) systolic dysfunction is key to determining prognosis and identifying appropriate candidates for cardiac replacement therapy. This becomes particularly relevant during selection for left ventricular assist device (LVAD) therapy, since adequate cardiac output, differently from heart transplantation, still relies on native RV function. Importantly, accumulating evidence indicates that RV failure (RVF) carries detrimental consequences of progressive end-organ dysfunction due to systemic venous congestion-mediated inflammation and oxidative stress. Therefore, it is crucial to detect RVF early on in the disease state through heightened clinical suspicion and noninvasive and/or invasive modalities before the RV fails and organ damage ensues, precluding patients from life saving measures such as LVAD therapy. The purpose of this review is to discuss the pathogenesis of RVF, its systemic consequences, implications for pre- and post-LVAD management, and its impact on clinical outcomes.

Implications of atrial fibrillation on the clinical course and outcomes of hospitalized COVID-19 patients: results of the Cardio-COVID-Italy multicentre study.

AIMS: To assess the clinical relevance of a history of atrial fibrillation (AF) in hospitalized patients with coronavirus disease 2019 (COVID-19). METHODS AND RESULTS: We enrolled 696 consecutive patients (mean age 67.4 ± 13.2 years, 69.7% males) admitted for COVID-19 in 13 Italian cardiology centres between 1 March and 9 April 2020. One hundred and six patients (15%) had a history of AF and the median hospitalization length was 14 days (interquartile range 9-24). Patients with a history of AF were older and with a higher burden of cardiovascular risk factors. Compared to patients without AF, they showed a higher rate of in-hospital death (38.7% vs. 20.8%; P < 0.001). History of AF was associated with an increased risk of death after adjustment for clinical confounders related to COVID-19 severity and cardiovascular comorbidities, including history of heart failure (HF) and increased plasma troponin [adjusted hazard ratio (HR): 1.73; 95% confidence interval (CI) 1.06-2.84; P = 0.029]. Patients with a history of AF also had more in-hospital clinical events including new-onset AF (36.8% vs. 7.9%; P < 0.001), acute HF (25.3% vs. 6.3%; P < 0.001), and multiorgan failure (13.9% vs. 5.8%; P = 0.010). The association between AF and worse outcome was not modified by previous or concomitant use of anticoagulants or steroid therapy (P for interaction >0.05 for both) and was not related to stroke or bleeding events. CONCLUSION: Among hospitalized patients with COVID-19, a history of AF contributes to worse clinical course with a higher mortality and in-hospital events including new-onset AF, acute HF, and multiorgan failure. The mortality risk remains significant after adjustment for variables associated with COVID-19 severity and comorbidities.

A multicentric quality-control study of exercise Doppler echocardiography of the right heart and the pulmonary circulation. The RIGHT Heart International NETwork (RIGHT-NET).

PURPOSE: This study was a quality-control study of resting and exercise Doppler echocardiography (EDE) variables measured by 19 echocardiography laboratories with proven experience participating in the RIGHT Heart International NETwork. METHODS: All participating investigators reported the requested variables from ten randomly selected exercise stress tests. Intraclass correlation coefficients (ICC) were calculated to evaluate the inter-observer agreement with the core laboratory. Inter-observer variability of resting and peak exercise tricuspid regurgitation velocity (TRV), right ventricular outflow tract acceleration time (RVOT Act), tricuspid annular plane systolic excursion (TAPSE), tissue Doppler tricuspid lateral annular systolic velocity (S'), right ventricular fractional area change (RV FAC), left ventricular outflow tract velocity time integral (LVOT VTI), mitral inflow pulsed wave Doppler velocity (E), diastolic mitral annular velocity by TDI (e') and left ventricular ejection fraction (LVEF) were measured. RESULTS: The accuracy of 19 investigators for all variables ranged from 99.7 to 100%. ICC was > 0.90 for all observers. Inter-observer variability for resting and exercise variables was for TRV = 3.8 to 2.4%, E = 5.7 to 8.3%, e' = 6 to 6.5%, RVOT Act = 9.7 to 12, LVOT VTI = 7.4 to 9.6%, S' = 2.9 to 2.9% and TAPSE = 5.3 to 8%. Moderate inter-observer variability was found for resting and peak exercise RV FAC (15 to 16%). LVEF revealed lower resting and peak exercise variability of 7.6 and 9%. CONCLUSIONS: When performed in expert centers EDE is a reproducible tool for the assessment of the right heart and the pulmonary circulation.

Echocardiographic phenotype and prognosis in transthyretin cardiac amyloidosis.

AIMS: Transthyretin amyloidosis cardiomyopathy (ATTR-CM) is an increasingly recognized cause of heart failure. We sought to characterize the structural and functional echocardiographic phenotype across the spectrum of wild-type (wtATTR-CM) and hereditary (hATTR-CM) transthyretin cardiomyopathy and the echocardiographic features predicting prognosis. METHODS AND RESULTS: We studied 1240 patients with ATTR-CM who underwent prospective protocolized evaluations comprising full echocardiographic assessment and survival between 2000 and 2019, comprising 766 with wtATTR-CM and 474 with hATTR-CM, of whom 314 had the V122I variant and 127 the T60A variant. At diagnosis, patients with V122I-hATTR-CM had the most severe degree of systolic and diastolic dysfunction across all echocardiographic parameters and patients with T60AhATTR-CM the least; patients with wtATTR-CM had intermediate features. Stroke volume index, right atrial area index, longitudinal strain, and E/e' were all independently associated with mortality (P < 0.05 for all). Severe aortic stenosis (AS) was also independently associated with prognosis, conferring a significantly shorter survival (median survival 22 vs. 53 months, P = 0.001). CONCLUSION: The three distinct genotypes present with varying degrees of severity. Echocardiography indicates a complex pathophysiology in which both systolic and diastolic function are independently associated with mortality. The presence of severe AS was independently associated with significantly reduced patient survival.

Exercise Intolerance in Heart Failure with Preserved Ejection Fraction.

Exercise intolerance represents a typical feature of heart failure with preserved ejection fraction (HFpEF), and is associated with a poor quality of life, frequent hospitalizations, and increased all-cause mortality. The cardiopulmonary exercise test is the best method to quantify exercise intolerance, and allows detection of the main mechanism responsible for the exercise limitation, influencing treatment and prognosis. Exercise training programs improve exercise tolerance in HFpEF. However, studies are needed to identify appropriate type and duration. This article discusses the pathophysiology of exercise limitation in HFpEF, describes methods of determining exercise tolerance class, and evaluates prognostic implications and potential therapeutic strategies.

Redistribution of cardiac output during exercise by functional mitral regurgitation in heart failure: compensatory O2 peripheral uptake to delivery failure.

Functional mitral regurgitation (MR) is prognostic in heart failure (HF). MR favors an nonphysiological exercise central cardiac output (CO) redistribution which adds to oxygen (O2) delivery failure. The consequences of this redistribution in O2 supply have not been explored previously. We aimed at evaluating the putative role of cardiac output (CO) and O2 arteriovenous [C(a-v)O2] difference in the attained peak V̇o2 in advanced HF with reduced ejection fraction (HFrEF) and MR. 134 HFrEF patients and 80 controls with no HF underwent exercise gas exchange combined with CO and C(a-v)O2 estimated by echo-Doppler technique. The HF population was divided into two groups: HF with severe rest MR (MR+ group; n = 36) and no to mild MR (MR- group; n = 98). HF groups did not differ in rest CO (MR+ vs. MR- 3.4 ± 1.8 vs. 3.8 ± 1.0 L/min; P = 0.32) and showed a trend for a higher C(a-v)O2 at rest (9.0 ± 4.0 vs. 8.0 ± 2.0 mL O2/100 mL; P = 0.14). In HF, CO and C(a-v)O2 at rest were significantly lower and higher compared with controls. At peak exercise, MR+ compared with MR- exhibited a significant reduction in peak V̇o2 11.6 ± 3.0 vs. 13.7 ± 3.6 ml O2·kg-1·min-1; P < 0.01) with a lower O2 delivery (CO: 5.2 ± 3.3 vs. 7.0 ± 2.0 L/min; P < 0.01), which was partially compensated by a significantly greater O2 extraction [C(a-v)O2, 18 ± 5 vs. 15 ± 4 mL O2/100 mL; P < 0.01]. In HFrEF, severe MR is associated with impaired O2 delivery due to CO redistribution to the pulmonary circulation. C(a-v)O2 is maximalized to compensate for the reduced O2 delivery. This novel information is relevant to phenotyping and targeting mediators of functional response in HF. Specifically, findings provide directions in the understanding at which extent mitral valve repair would restore an efficient cardiac reserve by enhancing O2 delivery during exercise, likely contributing to symptom relief and hopefully impacting the clinical trajectory of HF syndrome with secondary MR.NEW & NOTEWORTHY This is an analysis involving 134 heart failure patients with reduced ejection fraction versus 80 controls investigated during functional evaluation with gas exchange and hemodynamic, addressing the severe MR phenotype and testing the hypothesis that the backward cardiac output redistribution to the lung during exercise impairs delivery and overexpresses peripheral extraction. This information is new and has important implications in the management of heart failure.

Cardiovascular Death Risk in Recovered Mid-Range Ejection Fraction Heart Failure: Insights From Cardiopulmonary Exercise Test.

BACKGROUND: Heart failure with midrange ejection fraction (HFmrEF) represents a heterogeneous category where phenotype, as well as prognostic assessment, remains debated. The present study explores a specific HFmrEF subset, namely those who recovered from a reduced EF (rec-HFmrEF) and, particularly, it focuses on the possible additive prognostic role of cardiopulmonary exercise testing. METHODS AND RESULTS: We analyzed data from 4535 patients with HFrEF and 1176 patients with rec-HFmrEF from the Metabolic Exercise combined with Cardiac and Kidney Indexes database. The end point was cardiovascular death at 5 years. The median follow-up was 1343 days (25th-75th range 627-2403 days). Cardiovascular death occurred in 552 HFrEF and 61 rec-HFmrEF patients. The multivariate analysis confirmed an independent role of the MECKI score's variables in HFrEF (C-index = 0.744) whereas, in the rec-HFmrEF group, only age and peak oxygen uptake (pVO2) remained associated to the end point (C-index = 0.745). A peak oxygen uptake of ≤55% of predicted and a ventilatory efficiency of ≥31 resulted as the most accurate cut-off values in the outcome prediction. CONCLUSIONS: Present data support the cardiopulmonary exercise test and, particularly, the peak oxygen uptake, as a useful tool in the rec-HFmrEF prognostic assessment. A peak VO2 of ≤55% predicted and ventilatory efficiency of ≥31 might help to identify a high-risk rec-HFmrEF subgroup.

Pre-existing type 2 diabetes is associated with increased all-cause death independently of echocardiographic predictors of poor prognosis only in ischemic heart disease.

BACKGROUND AND AIMS: It is unknown whether the prognostic role of diabetes (T2DM) in outpatients with chronic heart failure (CHF) is independent of the most important echocardiographic markers of poor prognosis. The aims of this analysis were to evaluate whether T2DM modifies the risk of mortality in CHF patients stratified by etiology of disease or by right-ventricular to pulmonary arterial coupling at echocardiography and to evaluate how T2DM interacts with the prognostic role of cardiac plasma biomarkers. METHODS AND RESULTS: This is a retrospective analysis of 1627 CHF outpatients who underwent a complete echocardiographic examination. During a median follow-up period of 63 months 255 patients died. Poor right-ventricular to pulmonary arterial coupling and reduced left ventricular ejection fraction were independent predictors of outcome, whereas ischemic etiology and T2DM were not. T2DM interacted with etiology increasing the risk of mortality by 32% among patients with ischemic disease (p = 0.003). Elevated hsTNI plasma levels were associated with poor survival in T2DM but not in non-diabetic patients. CONCLUSION: T2DM signals a worse outcome in ischemic CHF patients regardless of the echocardiographic phenotype. High plasma levels of hsTNI are stronger predictors of mortality in CHF patients with T2DM than in patients without diabetes.

How to diagnose heart failure with preserved ejection fraction: the HFA-PEFF diagnostic algorithm: a consensus recommendation from the Heart Failure Association (HFA) of the European Society of Cardiology (ESC).

Making a firm diagnosis of chronic heart failure with preserved ejection fraction (HFpEF) remains a challenge. We recommend a new stepwise diagnostic process, the 'HFA-PEFF diagnostic algorithm'. Step 1 (P=Pre-test assessment) is typically performed in the ambulatory setting and includes assessment for HF symptoms and signs, typical clinical demographics (obesity, hypertension, diabetes mellitus, elderly, atrial fibrillation), and diagnostic laboratory tests, electrocardiogram, and echocardiography. In the absence of overt non-cardiac causes of breathlessness, HFpEF can be suspected if there is a normal left ventricular ejection fraction, no significant heart valve disease or cardiac ischaemia, and at least one typical risk factor. Elevated natriuretic peptides support, but normal levels do not exclude a diagnosis of HFpEF. The second step (E: Echocardiography and Natriuretic Peptide Score) requires comprehensive echocardiography and is typically performed by a cardiologist. Measures include mitral annular early diastolic velocity (e'), left ventricular (LV) filling pressure estimated using E/e', left atrial volume index, LV mass index, LV relative wall thickness, tricuspid regurgitation velocity, LV global longitudinal systolic strain, and serum natriuretic peptide levels. Major (2 points) and Minor (1 point) criteria were defined from these measures. A score ≥5 points implies definite HFpEF; ≤1 point makes HFpEF unlikely. An intermediate score (2-4 points) implies diagnostic uncertainty, in which case Step 3 (F1: Functional testing) is recommended with echocardiographic or invasive haemodynamic exercise stress tests. Step 4 (F2: Final aetiology) is recommended to establish a possible specific cause of HFpEF or alternative explanations. Further research is needed for a better classification of HFpEF.

TAPSE/PASP use in heart failure: Implementing the evidence for simplicity.

Commentary to: "Assessment of right ventricular-arterial coupling by echocardiography in patients with heart failure with reduced to mid-range ejection fraction: impact on survival" by Rosa et al.

Pulmonary hypertension due to left heart disease.

Pulmonary hypertension (PH) is frequent in left heart disease (LHD), as a consequence of the underlying condition. Significant advances have occurred over the past 5 years since the 5th World Symposium on Pulmonary Hypertension in 2013, leading to a better understanding of PH-LHD, challenges and gaps in evidence. PH in heart failure with preserved ejection fraction represents the most complex situation, as it may be misdiagnosed with group 1 PH. Based on the latest evidence, we propose a new haemodynamic definition for PH due to LHD and a three-step pragmatic approach to differential diagnosis. This includes the identification of a specific "left heart" phenotype and a non-invasive probability of PH-LHD. Invasive confirmation of PH-LHD is based on the accurate measurement of pulmonary arterial wedge pressure and, in patients with high probability, provocative testing to clarify the diagnosis. Finally, recent clinical trials did not demonstrate a benefit in treating PH due to LHD with pulmonary arterial hypertension-approved therapies.

2016 focused update: clinical recommendations for cardiopulmonary exercise testing data assessment in specific patient populations.

In the past several decades, cardiopulmonary exercise testing (CPX) has seen an exponential increase in its evidence base. The growing volume of evidence in support of CPX has precipitated the release of numerous scientific statements by societies and associations. In 2012, the European Association for Cardiovascular Prevention & Rehabilitation and the American Heart Association developed a joint document with the primary intent of redefining CPX analysis and reporting in a way that would streamline test interpretation and increase clinical application. Specifically, the 2012 joint scientific statement on CPX conceptualized an easy-to-use, clinically meaningful analysis based on evidence-vetted variables in color-coded algorithms; single-page algorithms were successfully developed for each proposed test indication. Because of an abundance of new CPX research in recent years and a reassessment of the current algorithms in light of the body of evidence, a focused update to the 2012 scientific statement is now warranted. The purposes of this update are to confirm algorithms included in the initial scientific statement not requiring revision, to propose revisions to algorithms included in the initial scientific statement, to propose new algorithms based on emerging scientific evidence, to further clarify the application of oxygen consumption at ventilatory threshold, to describe CPX variables with an emerging scientific evidence base, to describe the synergistic value of combining CPX with other assessments, to discuss personnel considerations for CPX laboratories, and to provide recommendations for future CPX research.

Pulmonary Hypertension and Heart Failure: A Dangerous Liaison.

Pulmonary hypertension (PH) is a common hemodynamic evolution of heart failure (HF) with preserved or reduced ejection fraction, responsible for congestion, symptoms worsening, exercise limitation, and negative outcome. In HF of any origin, PH develops in response to a passive backward pressure transmission as result of increased left atrial pressure. Sustained pressure injury and chronic venous congestion can trigger pulmonary vasoconstriction and vascular remodeling, leading to irreversible pulmonary vascular disease, right ventricular hypertrophy, and failure. In this article, the key determinants of this "dangerous liaison" are analyzed with some digressions on related "leitmotiv" at the horizon.

The Right Heart International Network (RIGHT-NET): Rationale, Objectives, Methodology, and Clinical Implications.

The Right Heart International Network is a multicenter international study aiming to prospectively collect exercise Doppler echocardiography tests of the right heart pulmonary circulation unit (RHPCU) in large cohorts of healthy subjects, elite athletes, and individuals at risk of or with overt pulmonary hypertension. It is going to provide standardization of exercise stress echocardiography of RHPCU and explore the full physiopathologic response.