Medical Management of Right Ventricular Dysfunction in Pulmonary Arterial Hypertension.

PURPOSE OF REVIEW: The purpose of this review is to overview the most relevant and recent knowledge regarding medical management in pulmonary arterial hypertension (PAH). RECENT FINDINGS: Evidence has shown that PAH patients' quality of life and prognosis depend on the capability of the RV to adapt to increased afterload and to fully recover in response to substantially reduced pulmonary vascular resistance obtained with medical therapy. Data from recent clinical studies show that more aggressive treatment strategies, especially in higher risk categories, determine larger afterload reductions, consequentially increasing the probability of achieving right heart reverse remodeling, therefore improving the patients' survival and quality of life. Remarkable progress has been observed over the past decades in the medical treatment of PAH, related to the development of drugs that target multiple biological pathways, strategies for earlier and more aggressive treatment interventions. New hopes for treatment of patients who are unable to achieve low-risk status have been derived from the phase 2 trial PULSAR and the phase 3 trial STELLAR, which show improvement in the hemodynamic status of patients treated with sotatercept on top of background therapy. Promising results are expected from several ongoing clinical trials targeting new pathways involved in the pathophysiology of PAH.

Fixed-dose combination therapy in pulmonary arterial hypertension: Pros & cons.

Quality of life of patients suffering from chronic diseases is inevitably conditioned by the number of pills taken during the day. To improve patients' tolerability, compliance and quality of life and reduce healthcare costs, pharmaceutical companies are focusing on the commercialization of fixed-dose combination (FDC) therapies. The last ESC/ERS guidelines for the treatment of pulmonary arterial hypertension (PAH) recommend initial dual combination therapy for newly diagnosed patients at low or intermediate mortality risk. In this regard, polypills including an endothelin receptor antagonist (ERA) and a phosphodiesterase 5 inhibitor (PDE5-i) could represent an useful therapeutic strategy, although with some limitations. To date, evidence about the use of FDCs in PAH is limited but future studies evaluating their safety and efficacy are welcome.

Long-Term Functional Limitations on Cardiopulmonary Exercise Testing in Emotion-Triggered Takotsubo Syndrome.

Background: In patients with prior Takotsubo syndrome (TTS), long-lasting functional cardiac limitations were described as compared with normal subjects. Emotion-triggered Takotsubo syndrome (E-TTS) has more favorable outcomes than TTS preceded by a physical trigger or by no identifiable factors. The aim of the present study was to assess long-term cardiac functional limitations in a cohort of asymptomatic E-TTS patients. Methods: We enrolled n = 40 asymptomatic patients with a diagnosis of E-TTS. Cardiopulmonary exercise tests (CPET) were performed at 30 (12-40) months median follow-up from the acute event. A cohort of n = 40 individuals matched for age, sex, body mass index and comorbidities served as control. Results: Despite recovery of left ventricular ejection fraction, patients with prior E-TTS had lower peak VO2 and percentage of predicted peak VO2 (17.8 ± 3.6 vs. 22.1 ± 6.5; p < 0.001 and 75.2 ± 14.1% vs. 100.6 ± 17.1%, p < 0.001), VO2 at anaerobic threshold (AT) (11.5 [10.1-12.9] vs. 14.4 [12.5-18.7]; p < 0.001), peak O2 pulse (9.8 ± 2.5 vs. 12.9 ± 3.5; p < 0.001) and higher VE/VCO2 slope (30.5 ± 3.7 vs. 27.3 ± 3.5; p < 0.001) compared with matched controls. We found no statistically significant differences in heart rate reserve (HRR), respiratory equivalent ratio (RER), mean blood pressure and peak PetCO2 between patients and controls. Conclusions: Despite its favorable outcome, patients with E-TTS in our population were found to have subclinical long-term functional cardiac limitations as compared with a control cohort.

Comparative effectiveness of oral therapies targeting the prostacyclin pathway in pulmonary arterial hypertension: A systematic review and network meta-analysis.

BACKGROUND: Oral prostanoids are recommended in patients with pulmonary arterial hypertension (PAH) and an unsatisfactory response to first-line therapy. OBJECTIVE: To compare the effectiveness of oral therapies targeting the prostacyclin pathway in PAH patients. METHODS: An online search of Medline, Cochrane Registry, Scopus and EMBASE libraries (from inception to May, 12,020) was conducted. Eight randomized controlled studies were included in the meta-analysis involving 3023 patients, with 828 receiving oral treprostinil, 607 patients receiving selexipag, 125 patients receiving beraprost, and 1463 patients receiving placebo. RESULTS: Compared to placebo, oral treprostinil (WMD 9.05, 95% CI 3.0280-15.0839, p = 0.0032) and beraprost (WMD 21.98, 95% CI 5.0536-38.9063, p = 0.0109) were associated with a significant increase in 6-min walking distance (6MWD) at follow-up from baseline, whereas selexipag use was associated with a non-significant increase in 6MWD (WMD 15.41, 95% CI -0.6074; 31.4232, p = 0.0593). Compared to placebo, the risk of clinical worsening was significantly lowered by selexipag (RR 0.47, 95% CI 0.35-0.65, p < 0.001) and oral treprostinil (RR 0.65, 95% CI 0.46-0.90, p 0.012), whereas a non-significant reduction of the outcome was related to beraprost use (RR 0.70, 95% CI 0.36-1.38, p 0.31). No significant difference in 6MWD change and clinical worsening reduction were found among oral treprostinil and selexipag. Beraprost use less frequently caused adverse events as compared to selexipag and oral treprostinil. CONCLUSIONS: No differences in 6MWD change, clinical worsening reduction and adverse events rates were found among oral treprostinil and selexipag, resulting in similar efficacy and safety profiles.

Prognostic value of deep echocardiographic phenotyping in pulmonary arterial hypertension.

Background: A novel approach to derive prognostic information from echocardiography in pulmonary arterial hypertension (PAH) is to define a phenotype of right heart function combining standard echocardiographic parameters which describe right ventricular pump function and systemic venous congestion. We tested the hypothesis that the combination of advanced strain imaging parameters could yield high prognostic accuracy. Methods: This was a prospective observational study with a single centre derivation cohort and a second centre validation cohort. The derivation cohort included 49 naive PAH patients who underwent right heart catheterisation and echocardiographic evaluation at baseline and 4-12 months after diagnosis. The validation cohort included 83 prevalent PAH patients who underwent the same examinations at 12 months after diagnosis. We stratified the risk of the derivation cohort according to three models: Model 1, based on haemodynamic parameters; Model 2, based on standard echocardiographic parameters; and Model 3, based on advanced echocardiographic parameters. The median follow-up period was 21 months; the end point of the analysis was clinical worsening. Results: In the derivation cohort, haemodynamic and echocardiographic parameters obtained at diagnosis were not associated with outcome, whereas a significant association was observed at first reassessment. Model 3 yielded a better predictive accuracy (Harrell's C index 0.832) as compared to Model 2 (Harrell's C index 0.667), and to Model 1 (Harrell's C index 0.713). The validation cohort confirmed the accuracy of Model 3. Conclusions: A comprehensive assessment of right heart function using right ventricular strain, right atrial reservoir strain and degree of tricuspid regurgitation provides accurate prognostic information in prevalent PAH patients.

Right ventricular phenotyping in incident patients with idiopathic pulmonary arterial hypertension.

BACKGROUND: Right ventricular (RV) imaging has not a definite role in risk stratification of pulmonary arterial hypertension (PAH) patients. We tested the hypothesis that echocardiography-derived phenotypes, depicting different degrees of RV remodeling and dysfunction, may provide additional prognostic information to current risk stratification tools. METHODS: Consecutive incident PAH patients aged ≥18 years, diagnosed between January 2005 and December 2021, underwent clinical assessment, right heart catheterization, standard echocardiography. Simple echocardiographic variables were combined in order to define a priori four phenotypes representing different degrees of RV dilatation and RV-pulmonary arterial (PA) coupling: Phenotype 1 with mildy dilated right ventricle and preserved RV-PA coupling (n = 152 patients); phenotype 2 with mildly dilated right ventricle and poor RV-PA coupling (n = 143 patients); phenotype 3 with severely dilated right ventricle and preserved RV-PA coupling (n = 201 patients); phenotype 4 with severely dilated right ventricle and poor RV-PA coupling, with or without severe tricuspid regurgitation (n = 519 patients). Risk stratification was based on the European Society of Cardiology/European Respiratory Society (ESC/ERS) 3-strata model and Registry to Evaluate Early and Long-Term PAH disease Management (REVEAL) 2.0 score. RESULTS: These phenotypes were present in all risk groups. Notably, regardless of the ESC/ERS risk stratum assigned to the patient, phenotype 4 was associated with a 2-fold increase of the odds of death (HR 2.1, 95% CI 1.6-2.8, p < 0.001), while phenotype 1 was associated with a 71% reduction in the odds of dying (HR 0.29, 95% CI 0.18-0.47, p < 0.001). CONCLUSIONS: Echocardiography-derived phenotypes describing RV remodeling and dysfunction may provide prognostic information which is independent of and additional to the clinically defined risk in incident PAH patients.

Biobanks: The unmet need in heart failure management.

Heart failure (HF) represents a major health and economic issue, with increasing morbidity and mortality in spite of novel therapeutic weapons. The disappointing results of HF management may be due to the current therapeutic approach based on the paradigm "one fits all", that cannot apply to a complex and multifaceted syndrome as HF. At this regard, the European Union is developing policies to move from reductionism to precision medicine, in order to identify specific disease biomarkers and develop targeted therapeutic strategies. The institution of biobanks may represent the game changer in HF scenario, providing a collection of human biological materials with the related medical and epidemiological data fueling the development of personalized therapeutic approach and fostering current and/or future research projects.

Comparative effectiveness of oral therapies targeting the prostacyclin pathway in pulmonary arterial hypertension: A systematic review and network meta-analysis.

BACKGROUND: Oral prostanoids are recommended in patients with pulmonary arterial hypertension (PAH) and a unsatisfactory response to first-line therapy. OBJECTIVE: To compare effectiveness of oral therapies targeting the prostacyclin pathway in PAH patients. METHODS: An online search of Medline, Cochrane Registry, Scopus and EMBASE libraries (from inception to May, 12020) was performed. Eight randomized controlled studies were included in the meta-analysis involving 3023 patients, of whom 828 receiving oral treprostinil, 607 patients receiving selexipag, 125 patients receiving beraprost, and 1463 patients received placebo. RESULTS: As compared to placebo, oral treprostinil (WMD 9.05, 95% CI 3.0280-15.0839, p = 0.0032) and beraprost (WMD 21.98, 95% CI 5.0536-38.9063, p = 0.0109) arms significantly increased 6 min walking distance (6MWD) at follow-up from baseline, whereas selexipag use was associated with a non-significant increase in 6MWD (WMD 15.41, 95% CI -0.6074; 31.4232, p = 0.0593). Compared to placebo, the risk of clinical worsening was significantly lowered by selexipag (RR 0.47, 95% CI 0.35-0.65, p < 0.001) and oral treprostinil (RR 0.65, 95% CI 0.46-0.90, p 0.012), whereas a non-significant reduction of the outcome was related to beraprost use (RR 0.70, 95% CI 0.36-1.38, p 0.31). No significant difference in 6MWD change and clinical worsening reduction were found among oral treprostinil and selexipag. Beraprost use less frequently caused adverse events as compared to selexipag and oral treprostinil. CONCLUSIONS: No differences in 6MWD change, clinical worsening reduction and adverse events rates were found among oral treprostinil and selexipag, resulting in similar efficacy and safety profile.

Impact of Parenteral Prostanoids in Pulmonary Arterial Hypertension: The Relevance of Timing.

Parenteral prostanoids are being recommended in pulmonary arterial hypertension (PAH) treatment, but the prognostic relevance of delayed treatment initiation is still debated. This study assessed the impact of the timing of prostacyclin treatment initiation on reducing PVR and achieving a low-risk profile in PAH patients. The study enrolled 151 patients who started on parenteral prostanoids with different treatment strategies. All patients underwent right heart catheterization, clinical evaluation, and risk assessments at baseline and after 1-year follow-up. Patients with an upfront strategy including parenteral prostanoid plus one oral drug had -5.3 ± 6.2 WU (-50 ± 19%) reduction in PVR, patients with an upfront strategy including parenteral prostanoid plus double oral drug had -12.8 ± 5.9 WU (-68 ± 17%) reduction in PVR, while patients with an add-on strategy including parenteral prostanoid after oral drugs had -3.9 ± 3.5 WU (-23 ± 19%) reduction in PVR. An upfront strategy including parenteral prostanoids was independently associated with an increased likelihood of achieving the greater reduction of PVR compared with an add-on strategy. Additionally, the greater the severity of PH at the time of diagnosis, in terms of PVR and RV reverse remodeling, the higher the probability of treatment failure. An upfront strategy including a parenteral prostanoid is associated with the highest likelihood of achieving a low-risk profile and a greater reduction of PVR compared with parenteral prostanoid as an add-on to oral treatment.

Telehealth: A winning weapon to face the COVID-19 outbreak for patients with pulmonary arterial hypertension.

BACKGROUND: 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). MAIN BODY: 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. CONCLUSION: 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.