Circulating sLR11 levels predict severity of pulmonary hypertension due to left heart disease

Background Heart failure is a severe condition often involving pulmonary hypertension (PH). Soluble low-density lipoprotein receptor with 11 ligand-binding repeats (sLR11) has been associated with pulmonary artery hypertension. We examined whether sLR11 correlates with PH in left heart disease and can be used as a predictive marker. Method We retrospectively analyzed patients with severe mitral regurgitation who underwent right heart catheterization before surgery for valve replacement or valvuloplasty from November 2005 to October 2012 at Juntendo University. We measured sLR11 levels before right heart catheterization and analyzed correlations with pulmonary hemodynamics. We compared prognoses between a group with normal sLR11 (≤9.4 ng/ml) and a group with high sLR11 (>9.4 ng/ml). Follow-up was continued for 5 years, with end points of hospitalization due to HF and death due to cardiovascular disease. Results Among 34 patients who met the inclusion criteria, sLR11 correlated with mean pulmonary artery pressure (r = 0.54, p<0.001), transpulmonary pressure gradient (r = 0.42, p = 0.012), pulmonary vascular resistance (r = 0.36, p<0.05), and log brain natriuretic peptide (BNP). However, logBNP did not correlate with pulmonary vascular resistance (p = 0.6). Levels of sLR11 were significantly higher in the 10 patients with PH (14.4±4.3 ng/ml) than in patients without PH (9.9±3.9 ng/ml; p = 0.002). At 5 years, the event rate was higher in the high-sLR11 group than in the normal-sLR11 group. The high-sLR11 group showed 5 hospitalizations due to HF (25.0%) and 2 deaths (10.0%), whereas the normal-sLR11 group showed no hospitalizations or deaths. Analyses using receiver operating characteristic curves showed a higher area under the concentration-time curve (AUC) for sLR11 level (AUC = 0.85; 95% confidence interval (CI) = 0.72–0.98) than for BNP (AUC = 0.80, 95%CI = 0.62–0.99) in the diagnosis of PH in left heart disease. Conclusions Concentration of sLR11 is associated with severity of PH and offers a strong predictor of severe mitral regurgitation in patients after surgery.

380 Left heart disease phenotype and use of pulmonary vasodilators in elderly patients with pulmonary arterial hypertension: the Patriarca registry

Aims The prevalence of occult left heart disease (LHD) and the feasibility of vasodilator therapy in the progressively growing population of elderly subjects with pulmonary arterial hypertension (PAH) are under scrutiny. We evaluated the presence of a LHD phenotype and the patterns of vasodilator treatment in such patients. Methods and results The PATRIARCA registry collected cross-sectional data from 180 subjects with PAH or chronic thromboembolic pulmonary hypertension and ≥70 years of age in 11 Italian centres between 1 December 2019 and 15 September 2020. After excluding patients with CTEPH or incomplete follow-up haemodynamic parameters, 77 individuals with PAH diagnosed at ≥ 65 years of age according to current guidelines were included in the analysis. A LHD phenotype was defined as follows, expanding the criteria adopted in the AMBITION trial: (i) ≥3 among body mass index ≥30 kg/m2, systemic hypertension, diabetes, and significant coronary artery disease; (ii) 2 of the risk factors for LHD above and ≥1 among permanent atrial fibrillation, left ventricular (LV) hypertrophy, LV ejection fraction &lt;50%, at least moderate mitral or aortic valve disease, and left atrial dilation; (iii) pulmonary vascular resistance (PVR) between 3 and 3.75 WU or PVR between 3.75 and 6.25 WU in the presence of a pulmonary artery wedge pressure (PAWP) of 13–15 mmHg. Forty-one (53%) patients had a LHD phenotype according to the most recent clinical and haemodynamic evaluation, which was performed 16 (4–35) months after diagnosis (Figure). As per definition, they had higher rates of comorbidities and more often echocardiographic signs of LHD (not shown). The frequency of NYHA classes I–II was comparable between the two groups, while the 6 min-walking distance tended to be lower in subjects with a LHD phenotype than in those without (Figure, left panel). Furthermore, these latter had lower PVR and higher PAWP. No differences were seen in treatment with pulmonary vasodilators, with around 50% of patients receiving double oral combination therapy in both groups (Figure, right panel). During the study period, 7 (17%) and 4 (11%) patients died in the LHD and no-LHD groups, respectively (P = 0.40). Conclusions In this real-world cohort of elderly patients, a LHD phenotype was common despite an initial haemodynamic diagnosis of PAH. However, it did not appear to cause simplification or discontinuation of pulmonary vasodilator therapy. Longitudinal studies are needed to determine whether and how a LHD phenotype affects the use and effects of PAH drugs in the elderly.

Role of echocardiography to avoid misclassification of pulmonary hypertension associated with left heart disease as precapillary pulmonary hypertension

Background The proportion of patients (pts) diagnosed with pulmonary arterial hypertension (PAH) at a more advanced age and/or with more risk factors for left ventricular diastolic dysfunction is increasing. Therefore, it can be challenging to differentiate PH associated with left heart disease (PH-LHD, PHpost) from other precapillary forms of PH (PHpre). Purpose We analyzed the performance of the Opotowsky (OS), D'Alto (DS), and simplified D'Alto (sDS) echocardiographic scores according to the pretest probability (before right heart catheterization – RHC) of PH-LHD in pts with suspected PH submitted to RHC to identify the hemodynamic phenotype. Methods 37 consecutive stable pts (3/2018–3/2020) with a tricuspid regurgitation peak velocity &gt;2.8 m/s were prospectively included (21F, 49±17 yrs). Blinded transthoracic echocardiography was performed within 2 hours of RHC. We assessed OS (−2 to 2 points) and DS/sDS (0 to 34/7 points). We estimated cardiac index (thermodilution) and hemodynamic parameters using standard formulas. If PA occlusion pressure (PAOP) cannot properly be measured at end-expiration, we assessed left ventricular end-diastolic pressure (LVEDP). PH was defined as a mean PA pressure (mPAP) ≥25 mmHg. PAOP/LVEDP &gt;15 mmHg defined PHpost. If the PAOP/LVEDP was between 13–15 mmHg in an I pt, a volume challenge was done. We categorized pts according to the pretest probability of PH-LHD proposed in the 6th WSPH based on the combination of 7 noninvasive variables (age, presence of CV comorbidities, presence of current or paroxysmal atrial fibrillation, prior cardiac intervention, presence of structural LHD, presence of left bundle branch/LV hypertrophy or RV strain in ECG, presence of left atrial dilatation/grade &gt;2 mitral flow in Echo). The individual average probability was calculated by assigning a score of 1, 2, and 3 for each variable (1 = low (L), 2 = intermediate (I), and 3 = high (H) probability) rounding the average of the sum of values allocated for each variable to the nearest integer. Nonparametric ROC plots assessed the performance of echo-scores. Results All pts had PH. 19 pts showed PHpost, 10/19 with PVR &gt;3Wu (Combined PHpost). All scores were lower in PHpost compared to PHpre pts (p&lt;0.05) (Table 1). ROC area was &gt;0.9 with a similar Youden index (0.83) among the three scores (p&lt;0.05) (Figure 1). 17 PHpost with H pts were correctly identified by all scores (94–100%). In 15 PHpre with L pts OS performed better than DS/sDS (93 vs. 80%). In 3 PHpre and 2 PHpost with I pts, DS/sDS performed better than OS (100 vs. 80%). Conclusion The use of simple echo-scores could facilitate the screening of the hemodynamic phenotype in pts with PH, regardless of the pretest probability of PH-LHD. D'Alto scores might have some advantage compared to OS to classify the intermediate pretest probability of PH pts correctly. FUNDunding Acknowledgement Type of funding sources: Public hospital(s). Main funding source(s): Centro Cardiovascular Universitario. Hospital de Clínicas. Facultad de Medicina. Universidad de la República Table 1. Echo & Hemodynamic Data Figure 1. ROC curves of Echo scores

Impact of left heart disease risk factors on risk stratification and treatment response in pulmonary arterial hypertension

Background Contemporary registries have documented a change in the epidemiology of PAH patients displaying increasing co-morbidities associated with left heart disease (LHD). These patients are often excluded from randomized clinical trials. It is unclear whether the presence of LHD comorbidities may adversely impact the accuracy of risk stratification and response to PAH therapy. Method Data was extracted from the Pulmonary Hypertension Society of Australia and New Zealand registry for incident patients with a diagnosis with idiopathic/heritable/toxin-induced (I/H/D)-PAH and connective tissue disease (CTD) associated PAH from 2011 - 2020. Patients without available medication and follow up data were excluded. We used the AMBITION trial exclusion criteria to define the subpopulation with LHD risk factors and haemodynamic phenotype (PAH-rLHD). Results 489 patients (I/H/D-PAH=251, CTD-PAH=238) were included in our analysis, with 103 (21.0%) fulfilling the definition of PAH-rLHD (34 had ≥3 risk factors for left heart disease (rLHD-hypertension, diabetes, obesity or ischaemic heart disease) and 76 had borderline haemodynamics (mean capillary wedge pressure 13–15 with pulmonary vascular resistance &lt;500 dynes sec/cm5) including 7 who met both criteria). Compared to classical PAH, patients with PAH-rLHD were older at diagnosis (66±13 vs 58±19, p&lt;0.001), had lower pulmonary vascular resistance (PVR: 393±266 vs 708±391, p=0.031) but worse exercise capacity (6MWD: 286±130m vs 327±136m, p=0.005). PAH-rLHD were more likely to be started on initial monotherapy, compared with “classical” PAH (73% vs 56%, p=0.002). In the monotherapy groups, endothelin receptor antagonists (ERA) were used in 73% PAH-rLHD, compared with 66% in classical PAH group. Both groups exhibited similar response to both mono- and combination therapy with commensurate improvements in WHO functional class (mean change 0.3±0.6 vs 0.3±0.8, p=0.443) and 6-minute walk distance (mean change 44±82 vs 48±101, p=0.723). There was no difference in survival between classical PAH and PAH-rLHD (log rank, p=0.29). The REVEAL 2.0 risk score effectively discriminated risk in both populations at baseline and first follow up (classical PAH: baseline C statistic 0.750, follow up 0.774 and PAH-rLHD: baseline C statistic 0.756, follow up 0.791). Conclusion Despite lower PVR at diagnosis, PAH-rLHD patients and “classical” PAH demonstrate similar response to first-line therapy with similar long term survival. The REVEAL 2.0 risk score can be effectively applied to the subpopulation of PAH-rLHD in real life clinical practice. FUNDunding Acknowledgement Type of funding sources: None.