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Anabolic deficiencies play a pivotal role in left-sided heart failure. Little is known about their impact on idiopathic pulmonary arterial hypertension (iPAH). Therefore, the aim of this study was to assess the impact of multiple hormone-metabolic deficiencies on clinical features and outcomes in idiopathic pulmonary arterial hypertension. We have demonstrated that the assessment of anabolic hormone levels in patients with iPAH allows the identification of a subpopulation with worse exercise capacity, pulmonary hemodynamics, right ventricular size, and function generating the hypothesis about the potential role of hormonal replacement therapy. These data should be confirmed by larger studies.

Pulmonary hypertension (PH) is a risk factor for morbidity and mortality in patients undergoing surgery and anesthesia. This document represents the first international consensus statement for the perioperative management of patients with pulmonary hypertension and right heart failure. It includes recommendations for managing patients with PH being considered for surgery, including preoperative risk assessment, planning, intra- and postoperative monitoring and management strategies that can improve outcomes in this vulnerable population. This is a comprehensive document that includes common perioperative patient populations and surgical procedures with unique considerations.

Genetic susceptibility may influence ischemic heart disease (IHD) predisposition and affect coronary blood flow (CBF) regulation mechanisms. The aim of this study was to investigate the association among single nucleotide polymorphisms (SNPs) of genes encoding for proteins involved in CBF regulation and IHD. A total of 468 consecutive patients were enrolled and divided into three groups according to coronary angiography and intracoronary functional tests results: G1, patients with coronary artery disease (CAD); G2, patients with coronary microvascular dysfunction (CMD); and G3, patients with angiographic and functionally normal coronary arteries. A genetic analysis of the SNPs rs5215 of the potassium inwardly rectifying channel subfamily J member 11 (KCNJ11) gene and rs1799983 of the nitric oxide synthase 3 (NOS3) gene, respectively encoding for the Kir6.2 subunit of ATP sensitive potassium (KATP) channels and nitric oxide synthase (eNOS), was performed on peripheral whole blood samples. A significant association of rs5215_G/G of KCNJ11 and rs1799983_T/T of NOS3 genes was detected in healthy controls compared with CAD and CMD patients. Based on univariable and multivariable analyses, the co-presence of rs5215_G/G of KCNJ11 and rs1799983_T/T of NOS3 may represent an independent protective factor against IHD, regardless of cardiovascular risk factors. This study supports the hypothesis that SNP association may influence the crosstalk between eNOS and the KATP channel that provides a potential protective effect against IHD.

Contains fulltext : 291541.pdf (Publisher’s version ) (Closed access) BACKGROUND: Right atrial (RA) imaging has emerged as a promising tool for the evaluation of patients with pulmonary hypertension (PH), albeit without systematic validation. METHODS: PubMed, Web of Science and the Cochrane library were searched for studies investigating the prognostic value of RA imaging assessment in patients with PH from 2000 to June 2021 (PROSPERO Identifier: CRD42020212850). An inverse variance-weighted meta-analysis of univariable hazard ratios (HRs) was performed using a random effects model. RESULTS: Thirty-five studies were included (3,476 patients with PH; 74% female, 86% pulmonary arterial hypertension). Risk of bias was low/moderate (Quality of Prognosis Studies checklist). RA area (HR 1.06; 95% confidence interval [CI] 1.04-1.08), RA indexed area (HR 1.09; 95% CI 1.04-1.14), RA peak longitudinal strain (PLS; HR 0.94; 95% CI 0.91-0.97) and RA total emptying fraction (HR 0.96; 95% CI 0.94-0.98) were significantly associated with combined end-points including death, clinical worsening and/or lung transplantation; RA volume and volume index showed marginal significant associations. RA area (HR 1.06; 95% CI 1.04-1.07), RA indexed area (HR 1.12; 95% CI 1.07-1.17) and RA PLS (HR 0.98; 95% CI 0.97-0.99) showed significant associations with mortality; RA total emptying fraction showed a marginal association. CONCLUSIONS: Imaging-based RA assessment qualifies as a relevant prognostic marker in PH. RA area reliably predicts composite end-points and mortality, which underscores its clinical utility. RA PLS emerged as a promising imaging measure, but is currently limited by the number of studies and different acquisition methods. 01 april 2023

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.

Background The multiorgan involvement of heart failure is similar to the spread observed in cancer. We proposed a new score, named HLM, analogous to TNM classification used in oncology. HLM refers to (i) H: heart damage, instead of “T” for tumor; (ii) L: lung involvement, instead of “N” for lymph nodes; (iii) M: systemic multiorgan involvement, instead of “M” for metastasis. Objectives to compare HLM score to NYHA class, ACC/AHA stages and left ventricular ejection fraction (LVEF) classification, to assess the most accurate prognostic tool for HF patients. Methods We performed a multicentric, observational, prospective study of consecutive patients admitted for HF, or at risk for HF. Parameters for heart, lungs and organs’ function were collected. Each patient was classified according to HLM, NYHA, ACC/AHA stages and LVEF classification. Patients were followed up for 12 months. The primary composite endpoint was all-cause death and rehospitalization due to HF. Results We enrolled 1720 patients who completed the 12-month follow-up. As shown by Kaplan Meier curves, HLM was the most accurate score to predict primary endpoint at 12- month. The area under the ROC curve (AUC) was greater for HLM score than NYHA, ACC/AHA stages and LVEF classification, regarding the composite endpoint (HLM=0.645; NYHA=0.580; ACC/AHA=0.589; LVEF=0.572) (Figure 1). HLM score related AUC showed statistically significant differences compared to LVEF (p=0.002), ACC/AHA (p=0.029) and NYHA (p=0.009). Conclusions HLM score has a greater prognostic power compared to other nosologies, in terms of the composite endpoint of all-cause death and rehospitalization due to HF, at 12-month follow-up. Key words: heart failure; HLM score; prognosis; mortality; rehospitalization. Figure 1.

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 Pulmonary hypertension (PH) in COPD is a poorly investigated clinical condition. Research Question Which factors determine the outcome of PH in COPD? Study Design and Methods We analyzed the characteristics and outcome of patients enrolled in the Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA) with moderate or severe PH in COPD as defined during the 6th PH World Symposium who received medical therapy for PH and compared them with patients with idiopathic pulmonary arterial hypertension (IPAH). Results The population included incident patients with moderate PH in COPD (n = 68), with severe PH in COPD (n = 307), and with IPAH (n = 489). Patients with PH in COPD were older, predominantly male, and treated mainly with phosphodiesterase-5 inhibitors. Despite similar hemodynamic impairment, patients with PH in COPD achieved a worse 6-min walking distance (6MWD) and showed a more advanced World Health Organization functional class (WHO FC). Transplant-free survival rates at 1, 3, and 5 years were higher in the IPAH group than in the PH in COPD group (IPAH: 94%, 75%, and 55% vs PH in COPD: 86%, 55%, and 38%; P = .004). Risk factors for poor outcomes in PH in COPD were male sex, low 6MWD, and high pulmonary vascular resistance (PVR). In patients with severe PH in COPD, improvements in 6MWD by ≥ 30 m or improvements in WHO FC after initiation of medical therapy were associated with better outcomes. Interpretation Patients with PH in COPD were functionally more impaired and had a poorer outcome than patients with IPAH. Predictors of death in the PH in COPD group were sex, 6MWD, and PVR. Our data raise the hypothesis that some patients with severe PH in COPD may benefit from PH treatment. Randomized controlled studies are necessary to explore this hypothesis further. Trial Registry ClinicalTrials.gov; No.: NCT01347216 ; URL: www.clinicaltrials.gov

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.

BACKGROUND: The prognostic value of improvement endpoints that have been used in clinical trials of treatments for pulmonary arterial hypertension (PAH) needs to be further investigated. METHODS: Using the COMPERA database, we evaluated the prognostic value of improvements in functional class (FC) and absolute or relative improvements in 6-min walking distance (6MWD) and N-terminal fragment of pro-brain natriuretic peptide (NT-proBNP). In addition, we investigated multicomponent endpoints based on prespecified improvements in FC, 6MWD and NT-proBNP that have been used in recent PAH trials. Finally, we assessed the predictive value of improvements determined by risk stratification tools. The effects of changes from baseline to first follow-up (3-12 months after initiation of PAH therapy) on consecutive survival were determined by Kaplan-Meier analysis with Log-Rank testing and Cox proportional hazard analyses. RESULTS: All analyses were based on 596 patients with newly diagnosed PAH for whom complete data were available at baseline and first follow-up. Improvements in FC were associated with improved survival, whereas absolute or relative improvements in 6MWD had no predictive value. For NT-proBNP, absolute declines conferred no prognostic information while relative declines by ≥35% were associated with better survival. Improvements in multicomponent endpoints were associated with improved survival and the same was found for risk stratification tools. CONCLUSION: While sole improvements in 6MWD and NT-proBNP had minor prognostic relevance, improvements in multicomponent endpoints and risk stratification tools based on FC, 6MWD, and NT-proBNP were associated with improved survival. These tools should be further explored as outcome measures in PAH trials. ispartof: JOURNAL OF HEART AND LUNG TRANSPLANTATION vol:41 issue:7 pages:971-981 ispartof: location:United States status: published

BackgroundRisk stratification plays an essential role in the management of patients with pulmonary arterial hypertension (PAH). The current European guidelines propose a three-stratum model to categorise risk as low, intermediate or high, based on the expected 1-year mortality. However, with this model, most patients are categorised as intermediate risk. We investigated a modified approach based on four risk categories, with intermediate risk subdivided into intermediate-low and intermediate-high risk.MethodsWe analysed data from the Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA), a European pulmonary hypertension registry, and calculated risk at diagnosis and first follow-up based on World Health Organization functional class, 6-min walk distance (6MWD) and serum levels of brain natriuretic peptide (BNP) or N-terminal pro-BNP (NT-proBNP), using refined cut-off values. Survival was assessed using Kaplan–Meier analyses, log-rank testing and Cox proportional hazards models.ResultsData from 1655 patients with PAH were analysed. Using the three-stratum model, most patients were classified as intermediate risk (76.0% at baseline and 63.9% at first follow-up). The refined four-stratum risk model yielded a more nuanced separation and predicted long-term survival, especially at follow-up assessment. Changes in risk from baseline to follow-up were observed in 31.1% of the patients with the three-stratum model and in 49.2% with the four-stratum model. These changes, including those between the intermediate-low and intermediate-high strata, were associated with changes in long-term mortality risk.ConclusionsModified risk stratification using a four-stratum model based on refined cut-off levels for functional class, 6MWD and BNP/NT-proBNP was more sensitive to prognostically relevant changes in risk than the original three-stratum model.

Among the most common causes of death worldwide, ischemic heart disease (IHD) is recognized to rank first. Even if atherosclerotic disease of the epicardial arteries is known as the leading cause of IHD, the presence of myocardial infarction with non-obstructive coronary artery disease (MINOCA) is increasingly recognized. Notwithstanding the increasing interest, MINOCA remains a puzzling clinical entity that can be classified by distinguishing different underlying mechanisms, which can be divided into atherosclerotic and non-atherosclerotic. In particular, coronary microvascular dysfunction (CMD), classifiable in non-atherosclerotic mechanisms, is a leading factor for the pathophysiology and prognosis of patients with MINOCA. Genetic susceptibility may have a role in primum movens in CMD. However, few results have been obtained for understanding the genetic mechanisms underlying CMD. Future studies are essential in order to find a deeper understanding of the role of multiple genetic variants in the genesis of microcirculation dysfunction. Progress in research would allow early identification of high-risk patients and the development of pharmacological, patient-tailored strategies. The aim of this review is to revise the pathophysiology and underlying mechanisms of MINOCA, focusing on CMD and actual knowledge about genetic predisposition to it.

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.

BACKGROUND: A diagnosis of idiopathic pulmonary arterial hypertension (IPAH) is frequently made in elderly patients who present with comorbidities, especially hypertension, coronary heart disease, diabetes mellitus, and obesity. It is unknown to what extent the presence of these comorbidities affects the response to PAH therapies and whether risk stratification predicts outcome in patients with comorbidities. METHODS: We assessed the database of COMPERA, a European pulmonary hypertension registry, to determine changes after initiation of PAH therapy in WHO functional class (FC), 6-minute walking distance (6MWD), brain natriuretic peptide (BNP) or N-terminal fragment of probrain natriuretic peptide (NT-pro-BNP), and mortality risk assessed by a 4-strata model in patients with IPAH and no comorbidities, 1-2 comorbidities and 3-4 comorbidities. RESULTS: The analysis was based on 1,120 IPAH patients (n = 208 [19%] without comorbidities, n = 641 [57%] with 1-2 comorbidities, and n = 271 [24%] with 3-4 comorbidities). Improvements in FC, 6MWD, BNP/NT-pro-BNP, and mortality risk from baseline to first follow-up were significantly larger in patients with no comorbidities than in patients with comorbidities, while they were not significantly different in patients with 1-2 and 3-4 comorbidities. The 4-strata risk tool predicted survival in patients without comorbidities as well as in patients with 1-2 or 3-4 comorbidities. CONCLUSIONS: Our data suggest that patients with IPAH and comorbidities benefit from PAH medication with improvements in FC, 6MWD, BNP/NT-pro-BNP, and mortality risk, albeit to a lesser extent than patients without comorbidities. The 4-strata risk tool predicted outcome in patients with IPAH irrespective of the presence of comorbidities. ispartof: JOURNAL OF HEART AND LUNG TRANSPLANTATION vol:42 issue:1 pages:102-114 ispartof: location:United States status: published

This review is devoted to presenting the history of the CARDIOSIM

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.

A comprehensive PAH echocardiographic examination of patients with pulmonary arterial hypertension (PAH) should include a set of parameters resembling the pathophysiological changes occurring in the course of the disease. This approach could help clinicians build a complete picture of the patient, test the effects of targeted therapies and identify patients who need a more aggressive therapeutic approach to achieve a low risk-status.

In Europe, liver cirrhosis represents the fourth-most common cause of death, being responsible for 170,000 deaths and 5500 liver transplantations per year. The main driver of its decompensation is portal hypertension, whose progression radically changes the prognosis of affected patients. Transjugular intrahepatic portosystemic shunt (TIPS) is one of the main therapeutic strategies for these patients as it reverts portal hypertension, thus improving survival. However, the coexistence of portal hypertension and pulmonary hypertension or heart failure is considered a contraindication to TIPS. Nevertheless, in the latest guidelines, the definition of heart failure has not been specified. It is unclear whether the contraindication concerns the presence of clinical signs and symptoms of heart failure or hemodynamic changes in the right heart-pulmonary circulation. Moreover, data about induced right heart volume overload after TIPS and the potential development of heart failure and pulmonary hypertension is currently scanty and controversial. In this article we revise this issue in finding predictors of cardiac performance after TIPS procedure. Performing a fluid challenge during right heart catheterization might be a promising expedient to test the adaptation of the right ventricle to a sudden increase in preload in the first few months after TIPS. This test may unmask a potential cardiac inability to sustain the hemodynamic load after TIPS, allowing for a clearer definition of heart failure and, consequently, a more robust indication to TIPS.

BackgroundSince 2015, the European pulmonary hypertension guidelines recommend the use of combination therapy in most patients with pulmonary arterial hypertension (PAH). However, it is unclear to what extent this treatment strategy is adopted in clinical practice and if it is associated with improved long-term survival.MethodsWe analysed data from COMPERA, a large European pulmonary hypertension registry, to assess temporal trends in the use of combination therapy and survival of patients with newly diagnosed PAH between 2010 and 2019. For survival analyses, we looked at annualised data and at cumulated data comparing the periods 2010–2014 and 2015–2019.ResultsA total of 2531 patients were included. The use of early combination therapy (within 3 months after diagnosis) increased from 10.0% in patients diagnosed with PAH in 2010 to 25.0% in patients diagnosed with PAH in 2019. The proportion of patients receiving combination therapy 1 year after diagnosis increased from 27.7% to 46.3%. When comparing the 2010–2014 and 2015–2019 periods, 1-year survival estimates were similar (89.0% (95% CI 87.2–90.9%) and 90.8% (95% CI 89.3–92.4%), respectively), whereas there was a slight but nonsignificant improvement in 3-year survival estimates (67.8% (95% CI 65.0–70.8%) and 70.5% (95% CI 67.8–73.4%), respectively).ConclusionsThe use of combination therapy increased from 2010 to 2019, but most patients still received monotherapy. Survival rates at 1 year after diagnosis did not change over time. Future studies need to determine if the observed trend suggesting improved 3-year survival rates can be confirmed.

Despite numerous therapeutic advances in pulmonary arterial hypertension, patients continue to suffer high morbidity and mortality, particularly considering a median age of 50 years. This article explores whether early, robust reduction of right ventricular afterload would facilitate substantial improvement in right ventricular function and thus whether afterload reduction should be a treatment goal for pulmonary arterial hypertension. The earliest clinical studies of prostanoid treatment in pulmonary arterial hypertension demonstrated an important link between lowering mean pulmonary arterial pressure (or pulmonary vascular resistance) and improved survival. Subsequent studies of oral monotherapy or sequential combination therapy demonstrated smaller reductions in mean pulmonary arterial pressure and pulmonary vascular resistance. More recently, retrospective reports of initial aggressive prostanoid treatment or initial combination oral and parenteral therapy have shown marked afterload reduction along with significant improvements in right ventricular function. Some data suggest that reaching threshold levels for pressure or resistance (components of right ventricular afterload) may be key to interrupting the self-perpetuating injury of pulmonary vascular disease in pulmonary arterial hypertension and could translate into improved long-term clinical outcomes. Based on these clues, the authors postulate that improved clinical outcomes might be achieved by targeting significant afterload reduction with initial oral combination therapy and early parenteral prostanoids.

A comprehensive PAH echocardiographic examination of patients with pulmonary arterial hypertension (PAH) should include a set of parameters resembling the pathophysiological changes occurring in the course of the disease. This approach could help clinicians build a complete picture of the patient, test the effects of targeted therapies and identify patients who need a more aggressive therapeutic approach to achieve a low risk-status.

Risk scores integrate clinical variables emphasizing symptoms, exercise capacity, and measures of cardiac strain to predict clinical outcome better than any single value in pulmonary arterial hypertension (PAH). Risk scores have demonstrated prognostic utility for outcomes in registries, and recent studies have suggested that they are also therapy-responsive in controlled trials.FREEDOM-EV, a global, placebo-controlled, event-driven study, randomized 690 PAH participants 1:1 to oral treprostinil (TRE) or placebo. Clinical assessments were performed every 12 weeks to calculate the non-invasive French risk assessment (FRA), 4-strata COMPERA, REVEAL 2.0, and REVEAL Lite 2; median follow-up was 58 weeks. The Week 12 risk scores were used to predict time to clinical worsening (from Week 12) with Kaplan-Meier product-limit estimates. Log-rank test was used to calculate the statistical difference among risk categories, and mediation analysis tested the hypothesis that improvements in risk score contributed to reduced likelihood for clinical worsening. We assessed the previously proposed "net clinical benefit" (achievement of FRA low-risk status and absence of clinical worsening).Both REVEAL scores, COMPERA, and FRA at Week 12 predicted subsequent clinical worsening better than baseline risk. Mediation analysis demonstrated that Week 12 risk score reduction explained part of TRE's effect on clinical worsening, especially for those with higher baseline risk. TRE assigned participants were more likely to achieve the previously proposed "net clinical benefit" at Weeks 24 and beyond. Few participants who achieved 'net clinical benefit' had subsequent clinical worsening.Contemporary risk scores were therapy responsive in FREEDOM-EV and early improvements predicted subsequent outcomes. This post hoc analysis suggests that risk scores may be a surrogate for clinical worsening.