Clinical application of pulmonary vascular resistance in patients with pulmonary arterial hypertension

Pulmonary arterial hypertension is a type of malignant pulmonary vascular disease, which is mainly caused by the increase of pulmonary vascular resistance due to the pathological changes of the pulmonary arteriole itself, which eventually leads to right heart failure and death. As one of the diagnostic indicators of hemodynamics, pulmonary vascular resistance plays an irreplaceable role in the pathophysiology, diagnosis and treatment of pulmonary arterial hypertension. It provides more references for the evaluation of pulmonary arterial hypertension patients. This article summarizes the clinical application of pulmonary vascular resistance in patients with pulmonary arterial hypertension.

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 <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<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.

Mendelian randomisation and experimental medicine approaches to IL-6 as a drug target in PAH

Inflammation and dysregulated immunity are important in the development of pulmonary arterial hypertension. Compelling preclinical data supports the therapeutic blockade of interleukin-6 signalling.We conducted an open-label phase-II study of intravenous tocilizumab (8 mg·kg−1) over 6 months in group 1 pulmonary arterial hypertension. Co-primary endpoints were safety, defined by incidence and severity of adverse events, and change in pulmonary vascular resistance. Separately, a Mendelian randomisation study was undertaken on 11,744 individuals with European ancestry including 2085 patients with idiopathic/heritable disease for the IL6R variant (rs7529229), known to associate with circulating IL6R levels.Twenty-nine patients (M/F 10/19; mean age 54.9[SD11.4]) were recruited. Nineteen had heritable/idiopathic and ten connective tissue disease associated pulmonary arterial hypertension. Six were withdrawn prior to drug administration. Twenty-three patients received at least one dose of tocilizumab. Tocilizumab was discontinued in 4 patients due to serious adverse events. There were no deaths. Despite evidence of target engagement in plasma interleukin-6 and C-reactive protein levels, both intention-to-treat and modified intention-to-treat analyses demonstrated no change in pulmonary vascular resistance. Inflammatory markers did not predict treatment response. Mendelian randomisation did not support an effect of the lead IL6R variant on risk of pulmonary arterial hypertension (OR 0.99, p=0.88).Adverse events were consistent with the known safety profile of tocilizumab. Tocilizumab did not show any consistent treatment effect.

Inaccuracy of a non-invasive estimation of pulmonary vascular resistance assessed by cardiovascular magnetic resonance in heart failure patients

Pulmonary vascular resistance (PVR) is a marker of pulmonary vascular remodeling. A non-invasive model assessed by cardiovascular magnetic resonance (CMR) has been proposed to estimate PVR. However, its accuracy has not yet been evaluated in patients with heart failure. We prospectively included 108 patients admitted with acute heart failure (AHF), in whom a right heart catheterization (RHC) and CMR were performed at the same day. PVR was estimated by CMR applying the model: PVR = 19.38 − [4.62 × Ln pulmonary artery average velocity (in cm/s)] − [0.08 × right ventricle ejection fraction (in %)], and by RHC using standard formulae. The median age of the cohort was 67 years (interquartile range 58–73), and 34% were females. The median of PVR assessed by RHC and CMR were 2.2 WU (1.5–4) and 5 WU (3.4–7), respectively. We found a weak correlation between invasive PVR and PVR assessed by CMR (Spearman r = 0.21, p = 0.02). The area under the ROC curve for PVR assessed by CMR to detect PVR ≥ 3 WU was 0.57, 95% confidence interval (CI): 0.47–0.68. In patients with AHF, the non-invasive estimation of PVR using CMR shows poor accuracy, as well as a limited capacity to discriminate increased PVR values.

A Simple and Novel Noninvasive Method of Estimating Markedly Elevated Pulmonary Vascular Resistance in Patients with Pre-capillary Pulmonary Hypertension

Background: Several echocardiographic methods to estimate pulmonary vascular resistance (PVR) in patients with pulmonary hypertension (PH) have been proposed. So far, most studies have focused on relatively low PVR. We aimed to clarify the clinical usefulness of our new echocardiographic index of evaluating markedly elevated PVR in pre-capillary PH patients. Methods: We studied 129 consecutive patients with pre-capillary PH. We estimated the mean pulmonary artery pressure using echocardiography (mPAPEcho) and measured LV internal diameter at end diastole (LVIDd). The ratio of mPAPEcho / LVIDd was then correlated with invasive PVR. Using receiver operating characteristic curve analysis, a cutoff value for the index was generated to identify patients with PVR > 15 Wood units (WU). Results: mPAPEcho / LVIDd correlated well with PVR (r = 0.70, P < 0.0001). There was a better correlation between PVR and mPAPEcho / LVIDd in patients with PVR > 15 WU compared with TRV2 /TVIRVOT and sPAPEcho / LVIDd. A cut-off value of 1.14 had an 80.0% sensitivity and 74.7% specificity to determine PVR > 15 WU (AUC=0.840, p<0.0001). Conclusions: The index of mPAPEcho / LVIDd could be a valuable noninvasive and simple method of estimating markedly elevated PVR in pre-capillary PH patients.