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Background: The role of risk scores in heart failure (HF) management has been highlighted by international guidelines. In contrast with HF, which is intrinsically a dynamic and unstable syndrome, all its prognostic studies have been based on a single evaluation. We investigated whether time-related changes of a well-recognized risk score, the MECKI score, added prognostic value. MECKI score is based on peak VO2, VE/VCO2 slope, Na+, LVEF, MDRD and Hb. Methods: A multi-centre retrospective study was conducted involving 660 patients who performed MECKI re-evaluation at least 6 months apart. Based on the difference between II and I evaluation of MECKI values (MECKI II - MECKI I = ∆ MECKI) the study population was divided in 2 groups: those presenting a score reduction (∆ MECKI 0, clinical deterioration). Results: The prognostic value of MECKI score is confirmed also when re-assessed during follow-up. The group with improved MECKI (366 patients) showed a better prognosis compared to patients with worsened MECKI (294 patients) (p < 0.0001). At 1st evaluation, the two groups differentiated by LVEF, VE/VCO2 slope and blood Na+ concentration, while at 2nd evaluation they differentiated in all 6 parameters considered in the score. The patients who improved MECKI score, improved in all components of the score but hemoglobin, while patients who worsened the score, worsened all parameters. Conclusions: This study shows that re-assessment of MECKI score identifies HF subjects at higher risk and that score improvement or deterioration regards several MECKI score generating parameters confirming the holistic background of HF.

Background and purpose The impact of non-cardiac comorbidities on left ventricular (LV) diastolic properties in HFrEF and HFmrEF patients is still uncertain. Aim of the study was to determine how comorbidities affect LV relaxation and diastolic compliance in patients with HFrEF and HFmrEF. Methods Consecutive patients diagnosed with HFrEF or HFmrEF were enrolled. Non-cardiac comorbidity were recorded: diabetes, chronic kidney disease (CKD), chronic obstructive pulmonary disease (COPD), obstructive sleep apnea syndrome (OSAS), dyslipidemia and active or previous cancer. Patients underwent laboratory tests, including NT-pro-BNP. The following diastolic properties were evaluated non-invasively by echocardiography using previously validated methods: the time constant of isovolumetric relaxation (τ) and the diastolic stiffness index (β). Left atrial volume index (LAVi) was also recorded. Patients were divided in two groups: a) ≥2 comorbidities and b) Results Seventy-five patients were enrolled of whom 73% reported dyslipidaemia, 26% diabetes, 20% CKD, 18% COPD, 8% cancer, 4% OSAS. Thirty-five patients (47%) presented with ≥2 comorbidities showing higher values of τ (62±15ms vs 48±15ms, p Conclusion Among patients with HFrEF e HFmrEF the presence of multiple non-cardiac comorbidities was associated with more impaired proto-diastolic relaxation reflected by higher τ values. No significant differences were found in diastolic stiffness (β) and imaging and laboratory characteristics suggestive of increased end-diastolic LV filling pressure.

Rationale Demographic characteristics of pulmonary arterial hypertension (PAH) patients have changed over time, but the effects of cardiovascular risk factors on risk status and pulmonary vascular resistance (PVR) reduction with initial oral combination therapy are not known. Therefore, we tested the relevance of cardiovascular comorbidities in this setting. Methods The study enrolled 181 treatment-naive PAH patients with a 6- months (IQR 144-363 days) right heart catheterization and risk assessment after initial oral combination therapy. Results Group-A, 96 (53.0%) patients without cardiac comorbidities; Group-B, 54 (29.8%) patients with one cardiac comorbidity; Group-C, 31 (17.1%) patients with ≥2 cardiac comorbidities. Group-C patients were older with a balanced gender distribution. There was a significant difference in PVR reduction moving from the absence to one or ≥2 cardiac comorbidities, respectively, median -45.0%, -30.3%, -24.3%. A ERS/ESC low-risk status was present at first follow-up in 50 (52.0%) patients in Group-A, 19 (35.1%) in Group-B, and 9 (29.0%) in Group-C; a REVEAL 2.0 low-risk status was present at first follow-up in 41 (42.0%) patients in Group-A, 15 (27.7%) in Group-B, and 7 (22.6%) in Group-C. Group-A patients were 2.3 times more likely to achieve/maintain a low risk status compared with Group-B and -C (OR 2.27, 95% C.I. 1.15-4.54, p=0.02). No significant difference was observed between patients with non-cardiac comorbidities and those without comorbidities. Conclusion Initial oral combination therapy seems associated with a less effective response for patients with cardiovascular comorbidities compared with the others, related to the magnitude of treatment- induced decrease in PVR.

Background Chronic Thromboembolic Pulmonary Hypertension (CTEPH) is the most serious long-term complication of acute pulmonary embolism (PE) though it is the only potentially reversible form of Pulmonary Hypertension (PH). Its incidence is mainly limited to the first 2 years following the embolic event, however it is often underdiagnosed or misdiagnosed. Methods This is a multicenter observational cross-sectional and prospective study. Patients with a prior diagnosis of PE will be enrolled and undergo baseline evaluation for prevalent PH detection through a clinical examination and an echocardiogram as first screening exam. All cases of intermediate-high echocardiographic probability of PH will be confirmed by right heart catheterization and then identified as CTEPH through appropriate imaging and functional examinations in order to exclude other causes of PH. A CTEPH Risk Score will be created using retrospective data from this prevalent cohort of patients and will be then validated on an incident cohort of patients with acute PE. Results 1000 retrospective and 218 prospective patients are expected to be enrolled and the study is expected to be completed by the end of 2021. Up to now 841 patients (620 retrospective and 221 prospective) have been enrolled. Conclusions This study is the first large prospective study for the prediction of CTEPH development in patients with PE. It aims to create a comprehensive scoring tool that includes echocardiographic data which may allow early detection of CTEPH and the application of targeted follow up screening programs in patients with PE.

This review is devoted to presenting the history of the CARDIOSIM

Rationale: An initial oral combination of drugs is being recommended in pulmonary arterial hypertension (PAH), but the effects of this approach on risk reduction and pulmonary vascular resistance (PVR) are not known.Objectives: To test the hypothesis that a low-risk status would be determined by the reduction of PVR in patients with PAH treated upfront with a combination of oral drugs.Methods: The study enrolled 181 treatment-naive patients with PAH (81% idiopathic) with a follow-up right heart catheterization at 6 months (interquartile range, 144-363 d) after the initial combination of endothelin receptor antagonist + phosphodiesterase-5 inhibitor drugs and clinical evaluation and risk assessments by European guidelines and Registry to Evaluate Early and Long-Term PAH Disease Management scores.Measurements and Main Results: Initial combination therapy improved functional class and 6-minute-walk distance and decreased PVR by an average of 35% (median, 40%). One-third of the patients had a decrease in PVR

Objectives The purpose of this study was to explore speckle tracking echocardiographic right ventricular (RV) post-systolic strain patterns and their clinical relevance in idiopathic pulmonary arterial hypertension (PAH). Background The imaging of RV diastolic function in PAH remains incompletely understood. Methods Speckle tracking echocardiography of RV post-systolic strain recordings were examined in 108 consecutive idiopathic patients with PAH. Each of them underwent baseline clinical, hemodynamic, and complete echocardiographic evaluation and follow-up. Results In total, 3 post-systolic strain patterns derived from the mid-basal RV free wall segments were identified. Pattern 1 was characterized by prompt return of strain-time curves to baseline after peak systolic negativity, like in normal control subjects. Pattern 2 was characterized by persisting negativity of strain-time curves well into diastole, before an end-diastolic returning to baseline. Pattern 3 was characterized by a slow return of strain-time curves to baseline during diastole. The 3 patterns corresponded respectively to mild PH, more advanced PH but with still preserved RV function, and PH with obvious end-stage right heart failure. Patterns were characterized by optimal reproducibility when complementary to quantitative measurement of right ventricular longitudinal early diastolic strain rate (RVLSR-E), and right ventricular longitudinal late diastolic strain rate (RVLSR-A) (Cohen's κ = 0.88; p = 0.0001). Multivariable models for clinical worsening prediction demonstrated that the addition of RV post-systolic patterns to clinical and hemodynamic variables significantly increased their prognostic power (0.78 vs. 0.66; p Conclusions Speckle tracking echocardiography allows for the identification of 3 phenotypically distinct, reproducible, and clinically meaningful RV strain-derived post-systolic patterns.

Heart failure is a complex syndrome affecting several organs including kidney, lungs, liver, brain muscles and sympathetic system. Each of these organs might contribute to its severity and prognosis. The prognosis assessment is critical for a correct heart failure management. It has already been demonstrated that a single parameter is weaker for prognosis than different parameters combined. The Metabolic Exercise test data combined with Cardiac and Kidney Indexes (MECKI) score has been built and validated for heart failure with reduced ejection fraction (HFrEF) patients by considering cardiopulmonary exercise test data combined with clinical, laboratory and echocardiographic measurements. The betablockers treatment is a milestone in the HFrEF management. In the MECKI score database, the association of betablockers treatment with outcome has been investigated in different settings.

BACKGROUND: Upfront combination therapy with ambrisentan and tadalafil has been reported to improve the condition of patients with pulmonary arterial hypertension (PAH) more than with either drug alone. However, little is known about the long-term associated changes in hemodynamics and risk assessment scores. METHODS: This was a multicenter, retrospective analysis of clinical data in 106 patients with newly diagnosed PAH. Clinical evaluations, including demographics, medical history, World Health Organization (WHO) functional class (FC) and 6-minute walk distance (6MWD), right heart catheterization, and Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL) risk score 2.0, were assessed over 48 months of ambrisentan‒tadalafil therapy. RESULTS: At baseline, 9 patients (9%) showed a low (8) REVEAL risk score. At a median follow-up of 2 years, 45 patients (43%) showed a low, 47 patients (44%) showed an intermediate, and 14 patients (13%) showed a high REVEAL score, along with improvements in WHO FC, 6MWD and a decrease in mean pulmonary artery pressure and N-terminal pro brain natriuretic peptide (all p < 0.001). Pulmonary vascular resistance (PVR) decreased by 37% from 11.5 ± 6.5 to 7.2 ± 4.1 Wood units (p < 0.001). A total of 61 patients (57%) remained in intermediate-risk or high-risk categories. Low-risk patients had either a decrease in PVR of >50% or a stroke volume within the limits of normal. CONCLUSIONS: Initial combination therapy with ambrisentan and tadalafil in PAH improves the REVEAL risk score in proportion to decreased PVR and preserved stroke volume but still insufficiently so in approximately 50% of the patients.

Systemic sclerosis (SSc) is a connective tissue disease characterized by immune-system alterations, fibrosis involving the skin and internal organs and diffuse microangiopathy. Pulmonary arterial hypertension (PAH) is a severe complication of SSc affecting about 10–15% of the patients and it is a leading cause of mortality. Due to the devastating nature of SSc-PAH, there is a clear need to systematically adopt appropriate screening programs. Nail fold videocapillaroscopy (NVC) studies have shown a more severe peripheral microvascular dysfunction in SSc patients with PAH suggesting that abnormalities in peripheral microcirculation may correlate with pulmonary microangiopathy. This is a cross-sectional study involving four tertiary University Rheumatology Units in the Center-North of Italy. Seventy patients, 35 adults with SSc and PAH confirmed by RHC (F/M 34/1; median age 65.2 ± 8.9 SD yrs), and 35 SSc patients without PAH were enrolled (F/M 3471; median age 63.3 ± 10.3 SD yrs). Clinical, laboratoristic and instrumental data were collected and NVC was performed in all patient. Specific NVC parameters were evaluated and a semi-quantitative rating scale was adopted to score these changes. Finally, patients were distributed into the suitable NVC pattern belonging to the scleroderma pattern. Our aim was to compare the peripheral microangiopathy changes in SSc patients with and without PAH, and to investigate the relationship between NVC findings and the main hemodynamic parameters of pulmonary vasculopathy. Patients with SSc-PAH+ showed a significant higher frequency of interstitial lung disease (ILD). No significant differences regarding clinical and laboratoristic parameters were observed. NVC abnormalities, avascular areas were more frequent in SSc patients with PAH, respect to those without (p = 0.03), and capillary density was significantly lower when considering grade 3 (p = 0.02). A higher NVC semiquantitative mean was found in SSc-PAH+ patients and a greater rate of the “late” pattern was detected in SSc-PAH+ subjects in respect to PAH- (57.1% vs. 25.7%) (p = 0.03). A significant correlations between pulmonary pressure values (sPAP by TTE and mPAP by RHC) and the capillary density (Spearman's rho 0.35, p = 0.04 for both). Our findings provide additional evidence to the literature data, confirming that a higher degree of peripheral nailfold microangiopathy is more common in SSc-PAH patients, and further strengthening the concept that NVC changes may run parallel with similar abnormalities inside pulmonary microcirculation.

Pulmonary hypertension is a clinical syndrome that may include multiple clinical conditions and can complicate the majority of cardiovascular and respiratory diseases. Pulmonary hypertension secondary to left heart disease is the prevalent clinical condition and accounts for two-thirds of all cases. Type 2 diabetes mellitus, which affects about 422 million adults worldwide, has emerged as an independent risk factor for the development of pulmonary hypertension in patients with left heart failure. While a correct diagnosis of pulmonary hypertension secondary to left heart disease requires invasive hemodynamic evaluation through right heart catheterization, several scores integrating clinical and echocardiographic parameters have been proposed to discriminate pre- and post-capillary types of pulmonary hypertension. Despite new emerging evidence on the pathophysiological mechanisms behind the effects of diabetes in patients with pre- and/or post-capillary pulmonary hypertension, no specific drug has been yet approved for this group of patients. In the last few years, the attention has been focused on the role of antidiabetic drugs in patients with pulmonary hypertension secondary to left heart failure, both in animal models and in clinical trials. The aim of the present review is to highlight the links emerged in the recent years between diabetes and pre- and/or post-capillary pulmonary hypertension and new perspectives for antidiabetic drugs in this setting.

ObjectiveThe coronavirus disease 2019 (COVID-19) outbreak has led to significant restrictions on routine medical care. We conducted a multicentre nationwide survey of patients with pulmonary arterial hypertension (PAH) to determine the consequences of governance measures on PAH management and risk of poor outcome in patients with COVID-19.Materials and methodsThe present study, which included 25 Italian centres, considered demographic data, the number of in-person visits, 6-min walk and echocardiographic test results, brain natriuretic peptide/N-terminal pro-brain natriuretic peptide test results, World Health Organization functional class assessment, presence of elective and non-elective hospitalisation, need for treatment escalation/initiation, newly diagnosed PAH, incidence of COVID-19 and mortality rates. Data were collected, double-checked and tracked by institutional records between March 1 and May 1, 2020, to coincide with the first peak of COVID-19 and compared with the same time period in 2019.ResultsAmong 1922 PAH patients, the incidences of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and COVID-19 were 1.0% and 0.46%, respectively, with the latter comparable to that in the overall Italian population (0.34%) but associated with 100% mortality. Less systematic activities were converted into more effective remote interfacing between clinicians and PAH patients, resulting in lower rates of hospitalisation (1.2% versus 1.9%) and related death (0.3% versus 0.5%) compared with 2019 (pConclusionA cohesive partnership between healthcare providers and regional public health officials is needed to prioritise PAH patients for remote monitoring by dedicated tools.

Aims Significant concern has been raised about the effect of pre-existing cardiovascular diseases (CVD), cardiovascular (CV) risk factors and CV therapies on COVID-19 course. On the other hand, COVID-19 could worse pre-existing CVD or trigger the development of new-onset CVD. The aim of this study was to evaluate the relationship between pre-existing CVD, CV risk factors, and CV therapy with the clinical course of hospitalized COVID-19 patients. Methods and results Consecutive hospitalized COVID-19 patients admitted to the Cardiovascular COVID-19 Unit at Policlinico Umberto I of Rome between December 2020 and April 2021 were enrolled. All patients underwent a cardiovascular evaluation including troponin, electrocardiogram (ECG), and echocardiogram. Data on medical history, pre-existing CVD, CV risk factors, and therapy were collected. Admission to the Intensive Care Unit (ICU) or Cardiac Intensive Care Unit (CICU), as well as the development of new-onset CVD, were considered as endpoint of the study. Among n = 229 patients enrolled, 22 (10%) died. Nearly half of patients (112, 49%) were admitted to the ICU/CICU. The presence of prior ischaemic heart disease nearly doubled the probability of hospitalization in the ICU/CICU (HR: 2.09, 95% CI: 1.132–3.866, P 0.018). In regards of therapy, beta blockers reduced the likelihood of admission in the ICU/CICU (HR: −1016, 95% CI: 0.192–10.682, P 0.002). However, neither the use of RAAS blockers, heparin or dexamethasone influenced the risk of ICU/CICU admission (respectively, HR: 0.85, 95% CI: 0.498–1.450, P 0.551; HR: 0.768, 95% CI: 0.435–1.356, P 0.363; HR: 0.861, 95% CI: 0.453–1.635, P 0.647). N = 89 patients (39%) experienced a new onset CVD including arrythmias (18.3%) with nearly half experiencing atrial fibrillation, acute coronary syndrome (10.9%), acute pulmonary embolism (5.3%), heart failure (HF) (3%), and myocarditis and pericarditis (1.3%). A pre-existing diagnosis of HF substantially increased the likelihood of new onset CVD (HR: 2.380, 95% CI: 1.004–5.638, P 0.049). However, treatment with heparin or dexamethasone reduced the risk of new onset CVD (HR: 0.482 95% CI: 0.268–0.867, P 0.015; HR: 0.487, 95% CI: 0.253–0.937, P 0.031, respectively). Conclusions Our study found that hospitalized COVID-19 patients who have at least one CV risk factor or pre-existing CVD had a greater likelihood of being admitted to the ICU/CICU and experiencing new onset CVD.

Aims Risk assessment in pulmonary arterial hypertension (PAH) is essential for prognostication. However, the majority of patients end-up in an intermediate risk status despite targeted-therapy, offering insufficient guidance in clinical practice. The added value of cardiopulmonary exercise testing (CPET) in this setting remains undefined. Methods and results Two independent cohorts with idiopathic PAH at intermediate risk were used to develop (n = 124) and externally validate (n = 143) the prognostic model. Risk assessment was based on the simplified version of the ESC/ERS guidelines score. The same definition of clinical worsening (CW) was used for both cohorts. Discrimination and calibration were assessed. Seventy-four derivation cohort patients experienced CW (51.2%) during a median of 34 months. Stroke volume index (SVI) and 6-min walk-distance (6MWD) were independent predictors of CW. With addition of CPET variables, SVI and VO2 peak independently improved the power of the prognostic model, determined by the integrated discrimination integral (IDI) index. ROC-derived cut-off values for SVI and VO2 peak were 34 and 14 ml/kg/min, respectively. Forty-eight validation cohort patients experienced CW (33.5%) during a median of 27 months follow-up. Different combinations of cut-off values of SVI and VO2 peak defined three meaningful groups showing good discrimination and calibration. The event-free survival rates at 1, 2, and 3 years were, respectively, 96%, 89%, and 89% for high SVI/high VO2 peak combination; 85%, 73%, and 61% for high SVI/low VO2 peak; and 80%, 70%, and 56% for low SVI/low VO2 peak. Conclusions Combinations of VO2 peak and SVI during follow-up is important in the prognostication of intermediate-risk prevalent patients with idiopathic PAH.

Precision medicine, providing the right therapeutic strategy for the right patient, could revolutionize management and prognosis of patients affected by cardiovascular diseases. Big data and artificial intelligence are pivotal for the realization of this ambitious design. In the setting of pulmonary arterial hypertension (PAH), the use of computational models and data derived from ambulatory implantable hemodynamic monitors could provide useful information for tailored treatment, as requested by precision medicine.

The several randomized controlled trials (RCTs) conducted in the last 25 years in the field of pulmonary arterial hyper- tension (PAH) have led to the approval of over 10 drugs, which seek to restore the right balance between vasoconstrictor and vasodilator factors, and to the consequent increase of the median survival. However, no medical treatment is currently curative. Ongoing research is focusing on how to preserve right ventricle (RV) function, curbing the inexorable progres- sion of the disease towards right heart failure and death. Below, we provide a comprehensive review of the current available PAH specific therapies and briefly report the therapeutic strategies adopted by PH specialists in clinical practice.

COVID-19 pandemic severely affected national health systems, altering the modality and the type of care of patients with acute and chronic diseases. To minimize the risk of exposure to SARS-CoV2 for patients and health professionals, face-to-face visits were cancelled or postponed and the use of telemedicine was strongly encouraged. This reorganization involved especially patients with rare diseases needing periodic comprehensive assessment, such as pulmonary arterial hypertension (PAH).The paper reports a proposal of strategy adopted for patients followed at our PAH center in Rome, where patients management was diversified based on clinical risk according to the European Society of Cardiology/European Respiratory Society PH guidelines-derived score and the REVEAL 2.0 score. A close monitoring and support of these patients were made possible by policy changes reducing barriers to telehealth access and promoting the use of telemedicine. Synchronous/asynchronous modalities and remote monitoring were used to collect and transfer medical data in order to guide physicians in therapeutic-decision making. Conversely, the use of implantable monitors providing hemodynamic information and echocardiography-mobile devices wirelessly connecting was limited by the poor experience existing in this setting. Large surveys and clinical trials are welcome to test the potential benefit of the optimal balance between traditional PAH management and telemedicine opportunities.Italy was found unprepared to manage the dramatic effects caused by COVID-19 on healthcare systems. In this emergency situation telemedicine represented a promising tool especially in rare diseases as PAH, but was limited by its scattered availability and legal and ethical issues. Cohesive partnership of health care providers with regional public health officials is needed to prioritize PAH patients for telemedicine by dedicated tools.

Chronic thromboembolic pulmonary hypertension (CTEPH) is a severe and under-recognized complication of acute pulmonary embolism (PE). Forty consecutive patients with acute PE (Group 1), predominantly female (22, 55%) with a mean age of 69 ± 15 years, were matched for demographic data with 40 healthy subjects (Group 2), 40 systemic hypertension patients (Group 3) and 45 prevalent idiopathic pulmonary arterial hypertension (IPAH) patients (Group 4). The baseline evaluation included physical examination, NYHA/WHO functional class, right heart catheterization (RHC) limited to IPAH patients, echocardiographic assessment and systemic arterial stiffness measurement by cardio-ankle vascular index (CAVI). Patients with PE underwent an echocardiographic evaluation within 1 month from hospital discharge (median 27 days, IQR 21–30) to assess the echo-derived probability of PH. The CAVI values were significantly higher in the PE and IPAH groups compared with the others (Group 1 vs. Group 2, p &lt, 0.001, Group 1 vs. Group 3, p &lt, Group 1 vs. Group 4, p = ns, Group 4 vs. Group 2, p &lt, Group 4 vs. Group 3, p &lt, Group 2 vs. Group 3, p = ns). The predicted probability of echocardiography-derived high-risk criteria of PH increases for any unit increase of CAVI (OR 9.0, C.I.3.9–20.5, p = 0.0001). The PE patients with CAVI ≥ 9.0 at the time of hospital discharge presented an increased probability of PH. This study highlights a possible positive predictive role of CAVI as an early marker for the development of CTEPH.

Risk assessment in pulmonary arterial hypertension (PAH) is essential for prognostication. However, the majority of patients end-up in an intermediate risk status, offering insufficient guidance in clinical practice. The added value of cardiopulmonary exercise testing in this setting remains undefined.Two independent cohorts with idiopathic PAH at intermediate risk were used to develop (n = 124) and externally validate (n = 143) the prognostic model. Cross-validation on the overall population was used to strengthen the results of the analysis. Risk assessment was based on the simplified version of the ESC/ERS guidelines score. Discrimination and calibration were assessed.A risk score was constructed based on the beta-coefficient of the cross-validated model, including the stroke volume index (SVI) and the peak oxygen uptake (VOCombinations of VO

Pulmonary arterial hypertension (PAH) is a rare, progressive disease with a poor prognosis. The pathophysiologic model is mainly characterized by an afterload mismatch in which an increased right ventricle afterload, driven by increased pulmonary vascular resistance (PVR), leads to right heart failure. International guidelines recommend optimization of treatment based on regular risk assessments to achieve or maintain a low-risk status. Current risk scores are based on a multi-modality approach, including demographic, clinical, functional, exercise, laboratory, and hemodynamic parameters, which lack significant echocardiographic parameters. The originality of echocardiography relies on the opportunity to assess in a non-invasive way a physiologically meaningful combination of easy to measure variables tightly related to right ventricle adaptation/maladaptation to increased afterload, the main determinant of a patient’s prognosis. Echo-derived morphological and functional parameters have been investigated in PAH, proving to have prognostic relevance. Different therapeutic strategies proved to have different effects in reducing PVR. An upfront combination of drugs, including a parenteral prostacyclin, has shown to be associated with right heart reverse remodeling in a greater proportion of patients than other treatment strategies as a function of PVR reduction. Adding echocardiographic data to current risk scores would allow better identification of right ventricle (RV) adaptation in PAH patients’ follow-up. This additional information would allow better stratification of the patient, leading to optimized and personalized therapeutic management.

Background In pulmonary arterial hypertension (PAH) upfront oral therapy represents the standard of care for naive patients at low and intermediate risk. However little is known about associated changes in risk assessment and prediction of low risk status achievement. Purpose To evaluate determinants of PVR reduction in patients treated with upfront oral therapy and to create a score to predict PVR reduction after upfront oral treatment and compared its additive value on top of the European and REVEAL scoring system in predicting treatment response. Methods One-hundred-eighty-one consecutive naive PAH patients treated with upfront therapy at 11 italian centers were retrospectively evaluated. Evaluation included clinical, hemodynamic and simple echocardiographic parameters, together with European and REVEAL 2.0 risk scores. Results At the time of diagnosis, the majority of the patients was idiopathic PAH (80.6%), female (66.3%), at intermediate risk, 71.8% and 55.2%, respectively, according to the European (average method) and the REVEAL 2.0 risk scores. Ambrisentan-Tadalafil was the most frequent combination used (62%). The median PVR reduction obtained after 180 days (IQR 79–394) was −40.4% (IQR −25.8; −45.3). Age ≥60 years, male-sex, baseline mPAP 48 mmHg associated with low CI (1 associated with low TAPSE ( At second evaluation 78 (43.1%) patients achieved or remained at European-derived low risk status, while 63 (34.8%) considering the REVEAL 2.0 score. Multivariate analysis for the prediction of treatment failure, defined as the absence of low-risk status at follow-up, demonstrated the incremental prognostic power of the models incorporating the treatment response score (≥3) on top of the European and REVEAL 2.0 scores, improving risk discrimination by 63.2% (IDI index 0.056) and 36.8% (IDI index 0.080), respectively. Conclusions A significant proportion of PAH patients treated with upfront oral combination are not able to achieve a low-risk status. The treatment response score helps clinicians in predicting treatment failure at the time of diagnosis. Funding Acknowledgement Type of funding source: None

Highlights • The paper “Intra-Aortic Balloon Counterpulsation Timing: A New Numerical Model for Programming and Training in the Clinical Environment.”, is original research from our ongoing program on numerical simulation applied to the clinical environment. • In this work we present a new numerical model of the intraaortic balloon pump (IABP). The new model also allows us to simulate patient weaning from IABP assistance. • Furthermore, the cardiovascular network model in which the IABP is inserted, allows us to simulate also a mechanical ventilatory assistance that is very important in patients affected by COVID-19., Background and Objective : The intra-aortic balloon pump (IABP) is the most widely available device for short-term mechanical circulatory support, often used to wean off cardiopulmonary bypass or combined with extra-corporeal membrane oxygenation support or as a bridge to a left ventricular assist device. Although based on a relatively simple principle, its complex interaction with the cardiovascular system remains challenging and open to debate. The aim of this work was focused on the development of a new numerical model of IABP. Methods : The new module was implemented in CARDIOSIM©, which is a modular software simulator of the cardiovascular system used in research and e-learning environment. The IABP is inserted into the systemic bed divided in aortic, thoracic and two abdominal tracts modelled with resistances inertances and compliances. The effect induced by the balloon is reproduced in each tract of the aorta by the presence of compliances connected to PIABP generator and resistances. PIABP generator reproduces the balloon pressure with the option to change IABP timing.We have used literature data to validate the potential of this new numerical model. Results : The results have shown that our simulation reproduced the typical effects induced during IABP assistance. We have also simulated the effects induced by the device on the hemodynamic variables when the IABP ratio was set to 1:1, 1:2, 1:4 and 1:8. The outcome of these simulations is in accordance with literature data measured in the clinical environment. Conclusions : The new IABP module is easy to manage and can be used as a training tool in a clinical setting. Although based on literature data, the outcome of the simulations is encouraging. Additional work is ongoing with a view to further validate its features. The configuration of CARDIOSIM© presented in this work allows to simulate the effects induced by mechanical ventilatory assistance. This facility may have significant importance in the management of patients affected by COVID-19 when they require mechanical circulatory support devices.

Combinations of therapies are currently recommended for patients with severe pulmonary arterial hypertension (PAH), and excellent results have been reported with triple upfront combination of these drugs. We evaluated the effects of this approach on right ventricular (RV) function and outcome in patients with severe PAH.Twenty-one patients (age, 44 ± 15 years) with newly diagnosed high-risk idiopathic PAH that was nonreversible by the inhalation of nitric oxide were treated upfront with a combination of ambrisentan, tadalafil, and subcutaneous treprostinil between 2014 and 2018. Clinical evaluation, World Health Organization functional class, 6-min walk distance, biomarkers, echocardiography, and right-sided heart catheterization data were recorded at baseline and during follow-up.At a median follow-up of 2 years, all patients were still alive. The Registry to Evaluate Early and Long-term Pulmonary Arterial Hypertension Disease Management score decreased from 10 ± 1 to 5 ± 1, right-sided atrial pressure decreased from 13 ± 3 to 5 ± 2 mm Hg, mean pulmonary artery pressure decreased from 60 ± 9 to 42 ± 5 mm Hg, pulmonary vascular resistance (PVR) decreased from 16.4 ± 4.4 to 5.5 ± 1.3 Wood units, N-terminal pro-brain natriuretic peptide decreased from 3,379 ± 1,921 to 498 ± 223 pg/mL, and World Health Organization functional class decreased from 3.4 ± 0.5 to 2.0 ± 0.4 (all P .001). Cardiac index increased from 1.8 ± 0.3 to 3.5 ± 0.8 L/min/mTriple upfront combination therapy with ambrisentan, tadalafil, and subcutaneous treprostinil in severe nonreversible PAH is associated with considerable clinical and hemodynamic improvement and right-sided heart reverse remodeling.

Pulmonary arterial hypertension (PAH) is a progressive, life-threatening, and incurable disease. Its prognosis is based on right ventricular (RV) function. Therefore, adequate assessment of RV function is mandatory. Areas covered: This article presents the case of a patient with PAH in which the traditional diagnostic approach did not provide a complete assessment of RV function. The authors show how the analysis of other parameters yielded additional information that improved the management of this patient. Expert commentary: Despite current treatments, PAH often worsens due to progressive RV dysfunction. Appropriate assessment of RV function may facilitate the early identification of patients at risk of RV function impairment. More aggressive treatment of PAH might delay progression of the disease. Traditional risk stratification, which is based on New York Heart Association/World Health Organization (NYHA/WHO) functional class evaluation, the 6-minute walk test, and right heart catheterization, proves insufficient in many PAH patients, as it does not provide complete information about RV function. Thus, further parameters are required. Analysis of RV function, in addition to echocardiography and cardiopulmonary exercise testing, may add relevant prognostic information and improve therapy.

Background Right ventricular (RV) failure is a major determinant of symptoms and shortened survival in pulmonary arterial hypertension (PAH). This study assessed the prognostic relevance of increased right heart (RH) dimensions determined by echocardiography and RH reverse remodeling (RHRR) with targeted therapies in idiopathic PAH (IPAH). Methods The study prospectively monitored 102 therapy-naive IPAH patients for the presence of clinical worsening. Baseline evaluation included RH catheterization and echocardiography. RHRR at the 1-year follow-up was defined by a decrease in RV end-diastolic area, right atrial area, and the left ventricular systolic eccentricity index. Results At the 1-year follow-up, 18 of 102 patients (17.6%) presented with RHRR. A decrease in pulmonary vascular resistance was the only independent determinant of RHRR. The 94 surviving patients were monitored for 995 ± 529 days. RHRR was an independent prognostic factor and significantly improved the power of the prognostic model based on traditional clinical and hemodynamic parameters. The respective event-free survival rates at 1, 3, and 5 years were 94%, 94%, and 94% in patients with RHRR and 75%, 55%, and 24% in those without RHRR (p = 0.0001). Interestingly, RHRR was able to further stratify patients’ risk assessment through the Registry to Evaluate Early And Long-term PAH Disease Management risk score. Conclusions RHRR after 1 year of treatment is an independent predictor of prognosis in IPAH. The likelihood of RHRR is proportional to decreased pulmonary vascular resistance.

The right ventricle (RV) adapts in pulmonary arterial hypertension (PAH) by an increased contractility to preserve its coupling to the pulmonary circulation but relies on increased dimensions when this homeometric adaptation gets exhausted ([1][1]). We therefore investigated on the added value of

Aim Current treatments strategies for high-risk patients with pulmonary arterial hypertension (PAH) are based on the use of parenteral prostanoids. The evidence to support triple upfront combination therapy remains largely based on expert consensus or small studies. Aim of this study was to evaluate the efficacy and safety of an upfront triple combination therapy with ambrisentan, tadalafil and subcutaneous (sc) treprostinil in patients with severe PAH. Methods This is a multi-center retrospective analysis of patients with newly diagnosed severe PAH treated with upfront triple combination therapy with ambrisentan, tadalafil and sc treprostinil between 2014 and 2018. Clinical evaluations, WHO functional class (FC), 6-min walk distance, biomarkers and right heart catheterization were collected from the patients' medical records at baseline and during the follow-up. Results Overall, 20 patients (mean age 44±15 years, 15 female) were included. Over a median follow-up of 12 months, all patients were still alive on triple combination therapy. At baseline 11 patients were in WHO-FC 3 and 9 patients in WHO-FC 4. At follow-up, WHO-FC (2.0±0.5 vs 3.5±0.5, p Conclusions Triple upfront combination therapy with ambrisentan, tadalafil and sc treprostinil is safe and offers clinical and heamodynamics benefits in incident patients with severe PAH.

Pulmonary arterial hypertension is an obstructive pulmonary vasculopathy that leads to increased pulmonary vascular resistance, right ventricular overload and failure, and death. Patients' clinical status and prognosis depend mostly on the capability of the right ventricle to adapt to the increased afterload, maintain function, and preserve cardiac output. As a result, reducing the hemodynamic burden of the right ventricle should be a key target of current treatments, along with improvement in WHO functional class, 6-minute walk distance, and rates of hospitalization. However, physicians still find it challenging to integrate the evaluation of right ventricular function into widely accepted clinical parameters in order to stratify patients more accurately. This limitation is very relevant, since higher-risk patients are more likely to benefit from a more aggressive therapeutic approach. We analyzed the hemodynamic burden in pulmonary arterial hypertension, the importance of echocardiographic evaluation of the right ventricle, the impact of current treatments on hemodynamic parameters, and the identification of patients who are more likely to benefit from a more aggressive therapeutic approach.

BACKGROUND >Despite advances in drug development, life expectancy in idiopathic pulmonary arterial hypertension (IPAH) remains unacceptable. Contemporary IPAH characterization is based on criteria that may not adequately capture disease heterogeneity and may be proposed as a possible explanation for why patient outcome is still unfavorable. The aim of this study was to apply cluster analysis to improve phenotyping of patients with IPAH and analyze long-term clinical outcome of derived clusters. METHODS Patients with IPAH from 2 referral centers (n = 252) were evaluated with clinical, hemodynamic, and echocardiographic assessment and cardiopulmonary exercise test. Patients were classified according to cluster analysis and followed for clinical worsening occurrence. RESULTS The cluster analysis identified 4 IPAH phenotypes. Cluster 1 was characterized by young patients, mild pulmonary hypertension (PH), mild right ventricular (RV) dilation and high oxygen (O2) pulse; Cluster 2 by severe PH and RV dilation and high O2 pulse; and Cluster 3 by male patients, severe PH and RV dilation, and low O2 pulse. Cluster 4 patients were older and overweight, with mild PH and RV dilation and low O2 pulse. After a mean follow-up of 995 ± 623 days, 123 (48.8%) patients had clinical worsening. Cluster 1 patients presented the best prognosis, whereas Cluster 3 had the highest rates of clinical worsening. Compared with Cluster 1, risk of clinical worsening ranged from 4.12 (confidence interval [CI] 1.43–11.92; p = 0.009) for Cluster 4 to 7.38 (CI 2.80–19.40) for Cluster 2 and 13.8 (CI 5.60–34.0; p = 0.0001) for Cluster 3. CONCLUSIONS Cluster analysis of clinical variables identified 4 distinct phenotypes of IPAH. Our findings underscore the high degree of disease heterogeneity that exists within patients with IPAH and the need for advanced clinical testing to define phenotypes to improve treatment strategy decision-making. CONDENSED ABSTRACT Idiopathic pulmonary arterial hypertension (IPAH) characterization is based on criteria that may not adequately capture disease heterogeneity. The aim of this study was to apply cluster analysis to improve phenotyping of IPAH. Patients with IPAH (n = 252) were evaluated with clinical, hemodynamic, and echocardiographic assessment and cardiopulmonary exercise test. Within the umbrella category of IPAH, it was the combination of mean pulmonary arterial pressure, right ventricular size, and oxygen pulse that further stratified patients into novel IPAH phenotypes that significantly associate with clinical worsening. These findings underscore the need for novel multidimensional IPAH phenotyping for improved patient care and trial quality.

Patient with idiopathic pulmonary hypertension (IPAH) develop peripheral inefficiency which could lead to an increase total energy expenditure and that could have a significant prognostic impact. To test the hypothesis, fifty-five consecutive stable IPAH patients (mean age 51±17 years) and 24 matched controls underwent an incremental exercise test and followed for a 5 years’ period. Total energy expenditure was assessed as the ratio between total V O 2 uptake (during both effort and recovery) and total external work ( V O 2 T O T / W T O T ). Patients with IPAH had a lower exercise capacity and a significantly higher V O 2 T O T / W T O T than controls ( V O 2 T O T / W T O T 0.33 ± 0.09 ml/j vs 0.22 ± 0.04 ml/j, p V O 2 T O T / W T O T was higher in whom died during follow up compared to survivors (0.41 ± 0.11 ml/j vs 0.30 ± 0.06 ml/j, p In multivariate Cox regression analysis V O 2 T O T / W T O T , gender, PETCO2 peak, V ˙ O 2 p e a k were independent risk factors for death. Patients with IPAH have shown a less efficient muscular oxygen utilization than controls. Notably the high energy expenditure has a relevant independent prognostic impact.

BACKGROUND The added value of cardiopulmonary exercise testing (CPET) in the follow-up of patients with stable pulmonary arterial hypertension (PAH) remains undefined. METHODS Idiopathic, heritable, and drug-induced PAH patients free from clinical worsening (CW) after 1 year of treatment were enrolled in derivation (n = 80) and validation (n = 80) cohorts at an interval of 6 years and followed for 3 years. Prognostic models were constructed and validated in low-risk patients in World Health Organization (WHO) Functional Class I or II with cardiac index (CI) ≥2.5 liters/min/m2 and right atrial pressure (RAP)

Mortality following an admission for acute decompensated heart failure (ADHF) is high and risk stratification in this context remains a challenge. The objective of the present study was to assess whether a simple echocardiographic assessment of pulmonary hypertension (PH) and/or of right ventricular (RV) dysfunction is associated with cardiovascular events in a 1-year follow-up after hospital discharge.The present prospective longitudinal study included 214 patients admitted to hospital with a cardiologist-adjudicated diagnosis of ADHF and a left ventricular ejection fraction (LVEF) at echocardiography 40%. Echocardiography was performed at admission and at discharge and included pulmonary artery systolic pressure (PASP) and RV function as defined by the tricuspid annular plane systolic displacement (TAPSE). The primary end-point was the combination of all-cause mortality and re-hospitalization for worsening heart failure at 1 year after hospital discharge. During an average follow-up period of 230 ± 130 days, 40 patients died and 41 patients underwent re-hospitalization due to ADHF. At multivariate analysis the independent predictors were LVEF, PASP at discharge and creatinine plasma levels (all p 0.001). At ROC analysis the best threshold of PASP to discriminate low-risk from high-risk patients was 40 mm Hg.In ADHF patients with reduced LVEF, PH at discharge is a pivotal prognostic feature to predict morbidity/mortality within the first year after the acute episode.

Objectives: The aim of this study was to determine the prevalence of right intraventricular dyssynchrony, its determinants and prognostic impact in idiopathic, heritable, and anorexigen-ind...

Background Although increased pulmonary pressure is caused by changes in the pulmonary vasculature, prognosis in idiopathic pulmonary arterial hypertension (IPAH) is strongly associated with right ventricular (RV) function. The aim of this study was to describe the best RV adaptive remodeling pattern to increased afterload in IPAH. Methods In 60 consecutive patients with IPAH, RV morphologic and functional features were evaluated by echocardiography and cardiac magnetic resonance imaging. To address the question of the best RV adaptation pattern, we divided the study population into two groups by the median value of RV mass/volume ratio (0.46) because this parameter allows the distinction between RV eccentric (≤0.46) and concentric hypertrophy (>0.46). The two groups were compared for RV remodeling and systolic function parameters, World Health Organization class, pulmonary hemodynamics, and 6-minute walk test. Results Despite similar pulmonary vascular resistance, mean pulmonary pressure, and compliance, patients with eccentric hypertrophy had advanced World Health Organization class and worse 6-minute walk test, hemodynamics, RV remodeling, and systolic function parameters compared with patients with concentric hypertrophy. The group with concentric hypertrophy had higher RV to pulmonary arterial coupling compared with the group with eccentric hypertrophy (1.24 ± 0.26 vs 0.83 ± 0.33, p = 0.0001), indicating higher RV efficiency. A significant correlation was found between pulmonary vascular resistance and RV to pulmonary arterial coupling ( r = −0.55, r 2 = 0.31, p = 0.0001), with patients with RV mass/volume ratio > 0.46 at the higher part of the scatterplot, confirming more adequate RV function. Conclusions Concentric hypertrophy might represent a more favorable RV adaptive remodeling pattern to increased afterload in IPAH because it is associated with more suitable systolic function and mechanical efficiency.

Survival in patients with pulmonary arterial hypertension (PAH) is determined by right ventricular (RV) function adaptation to afterload. How altered RV function impacts on exercise capacity in PAH is not exactly known.104 idiopathic PAH (IPAH) patients aged 52±14 years underwent a diagnostic right heart catheterisation, a comprehensive echocardiography including two-dimensional speckle tracking for RV dyssynchrony evaluation and a cardiopulmonary exercise test. Multivariate analyses were performed to identify independent predictors of peak oxygen uptake (peakV′O2).A first multivariate analysis of only resting haemodynamic variables identified cardiac index, right atrial (RA) pressure and pulmonary arterial compliance as independent predictors, with low predictive capacity (r2=0.31; p2=0.35; p2=0.48; pV′O2(r2=0.53; p=0.001).A comprehensive echocardiography with speckle tracking-derived assessment of the heterogeneity of RV contraction improves the prediction of aerobic exercise capacity in IPAH.

Purpose Aim of this study was to describe strain-derived right ventricular (RV) diastolic patterns by speckle-tracking echocardiography (STE) and its clinical impact in idiopathic pulmonary arterial hypertension (IPAH).STE of the RV has been extensively described in PAH. However, diastolic function has been yet underlooked (neglected) for no reason. Methods In 108 consecutive IPAH patients we identified three distinct strain-derived patterns from the mid-basal RV free wall segments. Each patient underwent baseline clinical, hemodynamic and complete echocardiographic evaluation and followed-up for clinical worsening occurrence. Results The three strain-derived diastolic patterns were characterized by high reproducibility (Cohen's κ=0.64, p=0.0001). Pattern 1 was associated with mild pulmonary hypertension and preserved clinical and RV function (preserved RV phenotype). This pattern was repetitively found in a cohort of 30 healthy subjects. Pattern 2 was associated with moderate to severe pulmonary hypertension, WHO functional class II and III, still preserved RV function (RV adaptive phenotype). Pattern 3 was associated with advanced stage of IPAH, characterized by high right atrial pressure, low cardiac index and severe RV remodeling (RV maladaptive phenotype). Multivariable models for clinical worsening (CW) prediction demonstrated that the addition of RV diastolic patterns to clinical and hemodynamic variables significantly increased the prognostic power of the model (0.79 vs 0.66; p Conclusion The results of the present study suggest that using speckle tracking echocardiography we can identify three phenotypically distinct, reproducible and clinically meaningful RV strain-derived diastolic patterns.

article i nfo Objectives: To address if baseline endothelin-1 (ET-1) plasma levels might predict clinical worsening (CW) in patients with idiopathic pulmonary hypertension (IPAH) treated with bosentan. Methods: Forty-four consecutive patients with IPAH (WHO classes II-III) were included in this study. After an initial assessment (clinical status, pulmonary hemodynamics, samples for adrenomedullin (ADM), ET-1 and brain natriuretic peptide (BNP) plasma levels), patients were treated with bosentan and followed-up for CW. Results: We observed CW in 24 patients. Actuarial rates of freedom from CW were 74% at 1 year, 56% at 2 years, and 43% at 3 years. Patients with CW had a worse WHO functional class (II/III; no-CW 14/6 vs CW 5/19, p=0.002), six- minute walk-test distance (no-CW 439+94 m vsCW 385+82 m, p=0.04), mean pulmonary artery pressure (no- CW 47.4+10.6 mm Hg vs CW 56+12.6 mm Hg, p=0.02) and pulmonary vascular resistance (PVR no-CW 12.5+ 4.8 WU vs CW 16.4+6.3 WU, p=0.03) than the no-CW group. Moreover ET-1 (no-CW 14.1+4.2 pg/ml vs CW 21.3+6.3 pg/ml, p=0.0001), ADM (no-CW 14.9+7 pg/ml vs CW 21.5+10.4 pg/ml p=0.002) and BNP (no- CW 82.8+35.3 pg/ml vs CW 115.4+39.6 pg/ml, p=0.007) plasma levels were significantly higher in the CW group than in the no-CW group. The multivariate Cox proportional hazards model identified WHO class III (RR 4.6, 95%CI 14.6-1.45), ET-1 plasma levels (RR 1.1, 95%CI 2.05-1.01) and PVR (RR 1.2, 95%CI 1.3- 1.03) as indepen- dent risk factors for CW. Conclusions: These data confirm the high rate of CW in patients with IPAH treated with bosentan and document the impact of the endothelin system on CW of these patients. © 2011 Published by Elsevier Ireland Ltd.

Background Because the pathophysiology of idiopathic pulmonary arterial hypertension (IPAH) is an afterload mismatch, wall stress represents the most important feature affecting the overloaded right ventricle (RV). Thus, the RV mass/volume (M/V) ratio may reflect more adequately the suitability of the remodeling pattern in minimizing RV wall stress compared with the lone RV volume. This study investigated the prognostic effect of the RV M/V ratio in IPAH. Methods Enrolled in our center were 74 therapy-naive IPAH patients who were prospectively monitored for the presence of clinical worsening (CW). Baseline evaluation included clinical, hemodynamic, and echocardiographic parameters. Cardiac magnetic resonance was used for RV M/V ratio determination. Results During 541 ± 283 days of follow-up, 31 of 74 patients (42%) presented with CW. Actuarial rates of CW were 14%, 28%, and 46%, at 6, 12, and 24 months, respectively. The RV M/V ratio significantly improved the power of the prognostic model based on traditional clinical, hemodynamic, and imaging parameters (area under the curve: 0.74 vs 0.66, respectively; p = 0.01). When the cutoff values of the RV M/V ratio and cardiac index (CI) derived from receiver operating characteristic curve analysis were combined, patients with a low RV M/V ratio/low CI, low RV M/V ratio/high CI, and high RV M/V ratio/low CI showed a 28.8, 8.8, and 6.1 increase in the hazard ratio, respectively, compared with high RV M/V ratio/high CI patients ( p = 0.0001). Conclusions The RV M/V ratio is an independent predictor of prognosis in IPAH and may allow clinicians to better stratify patients with normal CI, identifying at an early stage those patients at higher risk of right heart failure development before hemodynamic instability appears.

Background Right ventricular (RV) function is a major determinant of exercise intolerance and outcome in idiopathic pulmonary arterial hypertension. The aim of the study was to evaluate the incremental prognostic value of echocardiography of the right ventricle and cardiopulmonary exercise testing (CPET) on long-term prognosis in these patients. Methods One hundred and thirty treatment-naive patients with idiopathic pulmonary arterial hypertension were enrolled and prospectively followed. Clinical worsening (CW) was defined by a reduction in 6-min walk distance plus an increase in functional class, or nonelective hospitalization for PAH, or death. Baseline evaluation included clinical, hemodynamic, echocardiographic, and CPET variables. Cox regression modeling with c-statistic and bootstrapping validation methods were done. Results During a mean period of 528 ± 304 days, 54 patients experienced CW (53%). Among demographic, clinical, and hemodynamic variables at catheterization, functional class and cardiac index were independent predictors of CW (model 1). With addition of echocardiographic and CPET variables (model 2), peak O 2 pulse (peak V ˙ o 2 /heart rate) and RV fractional area change (RVFAC) independently improved the power of the prognostic model (area under the curve, 0.81 vs 0.66, respectively; P = .005). Patients with low RVFAC and low O 2 pulse (low RVFAC + low O 2 pulse) and high RVFAC + low O 2 pulse showed a 99.8 and 29.4 increase in the hazard ratio, respectively (relative risk, 41.1 and 25.3, respectively), compared with high RVFAC + high O 2 pulse ( P = .0001). Conclusions Echocardiography combined with CPET provides relevant clinical and prognostic information. A combination of low RVFAC and low O 2 pulse identifies patients at a particularly high risk of clinical deterioration.