Transthoracic echocardiography of right ventricular (RV) to pulmonary artery coupling by TAPSE/sPAP predicts outcome in heart failure (HF). This study aims at investigating the thresholds for the increase in mortality risk of tricuspid annular plane systolic excursion (TAPSE), of systolic pulmonary artery pressure (sPAP) and of their ratio (TAPSE/sPAP), in HF patients with reduced (HFrEF) or preserved (HFpEF) left ventricular ejection fraction, of ischemic or nonischemic etiology, and in subjects with cardiovascular risk factors (CVRF). TAPSE and sPAP were obtained in 1,660 patients with HFrEF, 718 with HFpEF, 210 subjects with CVRF and 216 healthy controls. Cox proportional hazards regression was used to assess the association between sPAP, TAPSE and TAPSE/sPAP ratio with mortality. Mortality at follow-up increased nonlinearly with increased sPAP and decreased TAPSE or TAPSE/sPAP, with cut-off values of 33 mmHg, 19 mm and 0.68 mm/mmHg respectively. The results were essentially the same in HF of different etiologies or categories, and in subjects with CVRF except for the absence of significant impact of TAPSE alone on outcome in HFpEF. The prediction of outcome by TAPSE/sPAP was more robust than by sPAP or TAPSE alone as assessed by different metrics. The TAPSE/sPAP ratio better than TAPSE or sPAP alone predicts outcome in HF patients regardless of etiology and category and in asymptomatic subjects with CVRF. The prognostic thresholds are positioned at the upper limits of normal for sPAP and within normal limits for TAPSE/sPAP.

BACKGROUND:The Venous Excess Ultrasound (VExUS) score is increasingly used to assess systemic venous congestion, yet direct validation against invasively measured right atrial pressure (RAP) in pulmonary hypertension (PH) remains limited. RESEARCH QUESTION:How accurate is the VExUS score to predict RAP in patients with established or suspected PH? METHODS:We conducted a multicenter observational study across 7 Italian reference centers including patients referred for PH and undergoing a VExUS assessment and right heart catheterization within 1 hour. A VExUS score was calculated with a 0 to 3 grading based on inferior vena cava (IVC) diameter and collapsibility, and Doppler assessment of hepatic, portal, and intrarenal venous flow patterns. The diagnostic performance of VExUS for identifying elevated RAP thresholds was compared with echocardiographic estimates based on IVC diameter and inspiratory collapse and RA surface areas using a multivariable analysis followed by receiver operator curves (ROC) calculations. Subgroup analyses were performed across pulmonary hemodynamic phenotypes (normal hemodynamics vs pre- vs postcapillary PH). RESULTS:The study included 145 patients with pre-capillary PH, most of whom with pulmonary arterial hypertension (PAH), 21 with post-capillary PH, and 21 with no PH. The VExUS score showed a strong graded association with RAP, with mean RAP increasing across VExUS grades (0: 3.9 mmHg; 1: 8.4 mmHg; 2: 13.5 mmHg; 3: 15.8 mmHg; p<0.001). The VExUS score demonstrated excellent discrimination for elevated RAP >12 mmHg (AUC 0.97, 95% CI 0.94-0.99), with higher diagnostic performance than isolated echocardiographic markers and performance comparable to echocardiographic RAP estimation. These findings were consistent across hemodynamic phenotypes.

Normal limits for exercise Doppler echocardiography (ex-TTE) measurements of the right ventricle (RV), pulmonary artery (PA) and left atrial (LA) unit remain inadequately defined. This meta-analysis aims to establish normal limits for measurements of the RV-PA-LA unit. A comprehensive literature search of Medline, Web of Science and Scopus (1 January 1999-December 2024) was performed. We included ex-TTE studies performed using a supine/semi-recumbent cycle ergometer in healthy subjects that reported the following parameters: tricuspid regurgitation velocity (TRV), systolic pulmonary artery pressure (sPAP), mean pulmonary artery pressure (mPAP), mPAP/cardiac output (CO) slope, mitral Doppler E to tissue Doppler e' ratio (E/e'), tricuspid annular plane excursion (TAPSE) and TAPSE/sPAP. Summary mean estimates were calculated using a restricted maximum-likelihood random-effects model. Lower and upper limits of normal (LLN and ULN) were defined as the 5th and 95th percentiles. Between-study heterogeneity was assessed using the Q-statistic and quantified with the inconsistency index. Data on 1122 healthy subjects (mean±sd age: 42.8±18.3 years) across 19 eligible studies were analysed. The pooled mean estimates and limits of normal for ex-TTE measurements were as follows: TRV 2.5 m·s-1 (ULN 3.4), sPAP 38.5 mmHg (ULN 57.8), mPAP 29.8 mmHg (ULN 43.0), mPAP/CO slope 1.4 mmHg·min·L-1 (ULN 3.0), E/e' 7.1 (ULN 11.5), TAPSE 31.8 mm (LLN 24.6), TAPSE/sPAP 0.8 mm·mmHg-1 (LLN 0.4). Despite notable heterogeneity for several measurements, the present meta-analysis provides a robust framework for defining normal reference limits for ex-TTE measurements of the RV-PA-LA unit.

Background Combination therapy is recommended for pulmonary arterial hypertension (PAH), part of which generally includes prostanoids, which affect both the vascular tone and vessel remodeling seen in PAH. This study tested whether a dual prostacyclin treatment strategy (oral esuberaprost + inhaled treprostinil and oral background PAH therapies) would provide additional clinical benefit. Methods 271 World Health Organization functional class (FC) III/IV patients with PAH received placebo or 28.4 µg oral esuberaprost 4 times daily, in addition to newly initiated or ongoing inhaled treprostinil and background therapies. Results There was no difference between treatment groups in time to clinical worsening (primary endpoint); 49 (36.0%) patients on esuberaprost and 51 (37.8%) on placebo had a clinical worsening event. No favorable esuberaprost treatment effects were observed for the secondary or exploratory endpoints (6-minute walk distance [6MWD], Borg dyspnea score, and N-terminal pro-brain natriuretic peptide [NT-proBNP]). There were 21 all-cause deaths (esuberaprost: 8 [5.9%]; placebo: 13 [9.6%]). Post hoc exploratory analyses to investigate the effect of inhaled treprostinil on treprostinil-naïve patients (n = 151) found that the addition of inhaled treprostinil resulted in improvements in multiple components of risk status, NT-proBNP, and 6MWD from screening through week 52, irrespective of background therapy. Notably, these improvements were also seen in patients on dual background therapy. Conclusion While the study did not meet its primary endpoint, it suggested that monitoring patients based on proven risk scores may be highly beneficial. Trial Registration: Beraprost-314d Added-on to Tyvaso® (BEAT) NCT01908699; Registered 2013-07-26

BACKGROUND:The precise impact of cardiovascular risk factors (CVRFs) on the right ventricle-pulmonary circulation unit remains unclear. RESEARCH QUESTION:Are there any differences regarding resting and exercise right ventricular function in patients with CVRFs but without overt cardiovascular disease when compared with healthy control patients? STUDY DESIGN AND METHODS:We extracted from the RIGHT Heart International NETwork registry the data of 362 patients with at least 1 CVRF but no overt cardiovascular disease and 375 healthy control patients. All patients and control patients had undergone resting and exercise echocardiographic evaluations on a semirecumbent cycle ergometer. Right ventricular-pulmonary arterial coupling was assessed using the ratio of tricuspid annular plane systolic excursion (TAPSE) to pulmonary arterial systolic pressure (sPAP) and pulmonary vascular function through the slope of mean pulmonary arterial pressure (mPAP) to cardiac output (CO) relationship, or dynamic total pulmonary vascular resistance. All-cause mortality and hospitalization events at follow-up were analyzed. RESULTS:Patients with CVRFs had lower TAPSE/sPAP (P < .001) and a steeper mPAP/CO slope (P < .001) than control patients. A substantial proportion of patients with ≥ 2 CVRFs (38.2%) had mPAP/CO slopes ≥ 3 mm Hg/min/L. Patients with CVRFs also had worse exercise capacity with chronotropic incompetence. The presence of ≥ 2 CVRFs was associated with an additional negative impact on right ventricular systolic function as assessed by TAPSE. The presence of CVRFs affected outcome, with 1 event in healthy control patients compared with 12 events in patients with CVRFs (P < .001). However, no independent effect of TAPSE/sPAP or mPAP/CO was observed, likely due to the limited number of events. INTERPRETATION:Patients with CVRFs exhibited echocardiographic evidence of right ventricular-pulmonary arterial uncoupling at rest and during exercise, along with elevated dynamic pulmonary vascular resistance, all of which are relevant to exercise capacity. CLINICAL TRIAL REGISTRATION:ClinicalTrials.gov; No.: NCT03041337; URL: www. CLINICALTRIALS:gov.

PURPOSE OF REVIEW:Left heart disease (LHD) is the commonest cause of pulmonary hypertension (PH). The differential diagnosis between PH associated with LHD (PH-LHD) and pulmonary arterial hypertension (PAH) may be difficult. PH associated with LHD is causally related to chronically increased pulmonary artery wedge pressure (PAWP). However, PAWP may be "falsely" normal or high-normal at the time of diagnostic right heart catheterization. RECENT FINDINGS:Updated guidelines for step-by-step diagnosis of PAH and LHD leave nevertheless a proportion of patients with PH and diagnostic uncertainty. In these patients, several studies have shown that a PAWP >18 mmHg after a rapid infusion of 500 ml saline is associated with a high likelihood of LHD. Evidence has been accumulated that patients with PH, cardiovascular risk factors and a high-normal PAWP should have LHD excluded by a fluid challenge. Preliminary studies suggest that the test may be performed noninvasively by combining Doppler echocardiography and lung ultrasound showing respectively a ratio of trans-mitral flow E wave to mitral annulus tissue velocity e' (E/e') ≥12 and ≥5 B-lines. SUMMARY:A fluid challenge has a place in the step-by-step diagnostic work-up of patients referred for PH for the differential diagnosis between PH-LHD and PAH.

Rationale: Echocardiographic indicators of pulmonary hypertension have been reported to predict decreased survival in patients with lung cancer. Objectives: We tested the hypothesis that this may be associated with impaired right ventricular (RV)-systolic pulmonary arterial pressure (sPAP) coupling. Methods: This prospective observational study included 220 outpatients with non-small cell lung cancer examined using Doppler, strain, and three-dimensional echocardiography before starting therapy. Of the included patients, 41% were women, and the median age was 68 years (interquartile range, 61-74 yr). Prediction of one-year overall survival was assessed using univariable analysis followed by multivariate Cox regression, receiver operating characteristic curves and Kaplan-Meier analyses. Results: Median sPAP was within the limits of normal (31 mm Hg [interquartile range, 26-36 mm Hg]); 30% of the patients had sPAP ≥ 35 mm Hg. In univariable analysis, one-year overall survival was associated with RV systolic function and probability of pulmonary hypertension. In multivariate Cox regression, only RV global longitudinal strain (GLS):sPAP ratio (hazard ratio [HR], 8.76 [95% confidence interval (CI), 1.24-61.82]; P = 0.03), forced expiratory volume in 1 second (HR, 0.98 [95% CI, 0.96-1.00]; P = 0.03) and Eastern Cooperative Oncology Group performance status <2 (HR, 0.34 [95% CI, 0.17-0.68]; P = 0.003) independently predicted survival. The optimal receiver operating characteristic curve-derived RV GLS:sPAP cutoff to predict survival was -0.54%/mm Hg. Among patients in Union for International Cancer Control (UICC) stage 4, those with impaired RV-arterial coupling (RV GLS:sPAP > -0.54%/mm Hg) had worse survival than those with maintained RV-arterial coupling (HR, 2.89 [95% CI, 1.55-5.42]; P < 0.001); the latter subgroup had similar survival compared with patients in UICC stage 3 (HR, 0.65 [95% CI, 0.35-1.20]; P = 0.17). Conclusions: RV GLS:sPAP ratio as an echocardiographic measure of RV-arterial coupling adds to prognostication by UICC status in non-small cell lung cancer. Clinical trial registered with www.clinicaltrials.gov (NCT04467333).

BACKGROUND:Pulmonary hypertension is a contraindication to correction of tricuspid regurgitation. CASE SUMMARY:A 75-year-old Italian woman with previous episodes of right heart failure was diagnosed with World Health Organization (WHO) functional class IV pulmonary arterial hypertension (PAH) complicated by torrential tricuspid regurgitation. After 6 months of treatment with diuretic agents, macitentan, and tadalafil, she improved to WHO functional class III, with a pulmonary vascular resistance (PVR) decreasing from 5.4 to 3 Wood units. She then underwent transcatheter valve repair. One year later, she was in WHO functional class I with a PVR of 2.2 Wood units. DISCUSSION:Right heart failure with a moderate increase in PVR in PAH may be caused by severe tricuspid insufficiency. Transtricuspid valve repair under optimized medical treatment may then be successful. TAKE-HOME MESSAGE:Severe tricuspid regurgitation in PAH may be the dominant cause of right heart failure and is amenable to transcatheter repair under optimal medical therapy.

BACKGROUND:Right ventricular functional adaptation to afterload is a major determinant of outcome in pulmonary arterial hypertension (PAH). We aimed to investigate if right ventricular-pulmonary artery (PA) coupling evaluated by the ratio of tricuspid annular plane systolic excursion (TAPSE) to systolic pulmonary artery pressure (sPAP) improves risk assessment scores for survival prediction. METHODS:A total of 677 consecutive patients with PAH (55% idiopathic) were prospectively enrolled with follow-up clinical, right heart catheterization, and echocardiographic evaluations within 12 months (interquartile range, 180-344 days) after initiation of targeted therapies in 11 Italian centers. European Society of Cardiology/European Respiratory Society guidelines-derived risk scores and REVEAL 2.0 (US Registry to Evaluate Early and Long-Term PAH Disease Management 2.0) risk scores were collected at baseline and follow-up. 254 consecutive patients with PAH retrospectively enrolled in a German reference center served as a validation cohort. RESULTS:A low-risk status at a median of 3.7 years (interquartile range, 1.2-6.8) follow-up was significantly associated with each unit (0.1 mm/mm Hg) increase in TAPSE/sPAP under targeted therapies (European Society of Cardiology/European Respiratory Society score: odds ratio, 1.78; P≤0.001; REVEAL 2.0 score: odds ratio, 1.43; P≤0.001). At follow-up, the TAPSE/sPAP ratio increased the prognostic information of each risk stratum of the European Society of Cardiology/European Respiratory Society risk score, except the highest risk stratum, with 0.5 mm/mm Hg, 0.35 mm/mm Hg, and 0.30 mm/mm Hg, from the lowest to the intermediate-high risk score, identified as the best cutoff value. TAPSE/sPAP ratio increased the prognostic information of the REVEAL 2.0 score at follow-up, with 0.35 mm/mm Hg identified as the best cutoff value to discriminate within a score of 5 to 8, with no added value for scores <5 and >8. These results were confirmed in the validation cohort. CONCLUSIONS:Assessment of right ventricular-PA coupling by the TAPSE/sPAP ratio in PAH improves risk assessment scores except in the lowest or most advanced stage of the disease.

Aims:Outcome in pulmonary arterial hypertension (PAH) is determined by right ventricular (RV) function adaptation to increased afterload. Echocardiography is easily available to assist bedside evaluation of the RV. However, no agreement exists about the feasibility and most relevant measurements. We therefore examined the feasibility, quality, and clinical correlations of standard echocardiographic variables in the evaluation of PAH. Methods and results:The present multicentric study collected echocardiographic examinations with centralized reading in 401 patients with prevalent PAH. Clinical variables, as World Health Organization (WHO) functional class (FC), 6 min walk distance (6MWD), brain natriuretic peptide (BNP)/NT-proBNP, invasive haemodynamics, the European Society of Cardiology (ESC)/European Respiratory Society (ERS) guidelines-derived four-strata score, and the United States Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management (REVEAL) 2.0 score, were also collected. Echocardiographic measurements showed variable degrees of dilation of the right heart as assessed by right atrial and RV areas, altered indices of systolic function such as tricuspid annular plane systolic excursion (TAPSE), fractional area change, or 2D strain, and derived estimates of RV to pulmonary artery (PA) coupling by referring these measurements to systolic PA pressure (sPAP). All these measurements were feasible. All measurements of right heart dimensions and function, particularly TAPSE/sPAP, were correlated with WHO-FC, 6MWD, BNP/NT-proBNP, invasive haemodynamics, and ESC/ERS and REVEAL 2.0 scores. Conclusion:The present quality-controlled data from a network of PAH referral centres offer the background needed for further evaluation of the added value of echocardiography to currently recommended risk assessments in PAH.

The impact of classical cardiovascular risk factors (CVRF) such as arterial hypertension, hypercholesterolemia, and type 2 diabetes mellitus on resting and exercise right ventricular (RV) function and hemodynamics is a poorly explored area. To clarify the impact of CVRF, we compared resting and exercise RV function in patients with CVRF but without overt cardiovascular disease vs. healthy controls. Of 2,228 subjects enrolled in the RIGHT-NET database, we compared 362 patients with at least one CVRF but not overt cardiovascular disease with 375 healthy controls. All subjects underwent resting and exercise echocardiography on a semi-recumbent cycle ergometer. All-cause mortality and hospitalizations were collected at follow-up. CVRF patients displayed a lower peak exercise tricuspid annular plane systolic excursion/ pulmonary arterial systolic pressure (TAPSE/PASP) (p<0.001) and steeper mean pulmonary arterial pressure / cardiac output (mPAP/CO) slope (p<0.001) than controls. A substantial proportion of patients with ≥2 CVRF (38.2%) had mPAP/CO >3 mmHg/L/min. CVRF patients also had worse exercise capacity with chronotropic incompetence. The presence of >1 CVRF was associated with an additive negative effect on the right heart. Patients with CVRF without overt cardiovascular disease exhibit signs of resting as well as exercise RV pulmonary artery uncoupling, and a steeper mPAP/CO slope. Such abnormalities are more pronounced in patients with concomitant (>1) risk factors.