By Fabio Dardi, M.D. of the Scientific Board Secretariat of WSPHA
A) Pulmonary Hypertension new definition
The new haemodynamic definition of PH proposed during the last world symposium (mean pulmonary arterial pressure, mPAP, >20 mmHg + PVR > 3 WU instead of mPAP ³ 25 mmHg) is surely more strongly evidence based. In fact, the risk of death appears to increase from a value of 19 mmHg independently from the value of PVR and PAWP. Anyway some controversies remain open: 1) the vast majority of patients with a mPAP between 21 and 24 mmHg have a high prevalence of comorbidities and most of them have group 2 or group 3 PH; 2) actually there are no evidences about the treatment in patients with a mPAP between 21 and 24 mmHg; 3) according to different registries, only 1-2% of patients would be reclassified as having PAH so the impact of the new definition seems limited; 4) also the cut-off value of PVR > 3 WU seems to be not appropriate as mortality starts to rise from a value of 2 WU (independently from the PAWP). A particular case is PAH associated with CTD. In these patients, the diagnosis, thanks to the screening, is more and more done in an early stage and frequently they may have a mPAP between 21 and 24 mmHg. These patients with CTD and mildly elevated mPAP appear to be younger and with better WHO-FC and up to 1/3 of these patients may develop a mPAP>25 mmHg in 3 years but some of them may develop group 2 or group 3 PH.
B) Right ventricular function
Some new studies of RV function have outlined that: 1) RVEF (at MRI) improvement is mainly due to an improvement of arterial elastance and coupling and RV diastolic function and that the most important predictor of survival at MRI seems to be RVESVi (227% of the predicted for age and sex distinguish between low and high risk) both at baseline and at follow-up (RVEF and LVEDVi also emerge but they were not significant in the validation cohort of the study). These results can be important as current trial consider less and less haemodynamic as an endpoint but consider survival and RV function is related to survival even if some drugs may reduce function but improve survival (i.e. beta-blockers in heart failure); 2) considering RV-PA coupling a newer single-beat approach using a multi-harmonic sine function has been proposed and seems superior to the single-harmonic technique in humans; 3) RV fibrosis in PH is associated with increased ACh levels (inhibition of nAChR prevents nicotine- and ACh-induced fibroblast proliferation and collagen production that may be mediated by the EGFR pathway); 4) Ceramide accumulation in the PAH RV has been described in experimental models and human PAH in the context of altered fatty acid metabolism due to underlying mutation of BMPR2 receptor; 5) Inflammation has been proposed as a potential target for PAH but as IL6 promotes microtubule-mediated t-tubule remodeling and its signaling is activated in the right ventricle of MCT rats it can be a potential target also for RV dysfunction.
Anyway, should RV be a therapeutic target in PAH? The main target of PAH treatment should be the pulmonary vasculature to unload the RV and improve both RV systolic and diastolic function (diastolic dysfunction mainly due to hypertrophy and lengthening of the sarcomere rather than fibrosis). Anyway, in scleroderma, there may be a reduced contractility that can be addressed, especially in an ICU setting (calcium sensitizers? Pro-angiogenetics to increased myocardial microcirculation?)
C) Pulmonary Arterial Hypertension risk stratification
The REVEAL risk score seems to predict better the risk that other validated tools but at the expense of a larger number of parameters compared to European guideline risk table and considering also non-modifiable parameter that may limit its connection with the treatment algorithm. A Bayesian model for PAH prognosis was also presented (PHORA) and it has a better accuracy and sensitivity than REVEAL 2.0 model; using this model patients at low risk seem to not benefit from combination therapy versus monotherapy. An important risk parameter considered in each risk tool is 6MWT anyway some centers use the ISWT that is able to stratify the risk of death for incident and prevalent patients and in a wide range of subgroups and the cutoffs proposed are 130 and 420 m.
D) Registries data
Early data from the PVDOMICS cohort suggests that additional risk factors for left heart disease in group 1 and 3 PH were associated with greater mPAP and lower cardiac output (CO) in Group 3 instead additional risk factors for lung disease in group 1 or 2 PH were associated with lower mPAP and, in group 2, lower CO. There is also a higher prevalence of obesity in group 2 PH, a male predominance in group 5 PH and a higher elevated mortality in group 3 PH despite less severe elevation in pulmonary arterial pressure. Data from PVDOMICS initiative highlight also the high prevalence of mild lung disease and elevation of PAWP with provocation in patients classified in group 1 PH, especially with increasing age.
For what concern obesity in registries: it is correlated to a worst quality of life but, paradoxically, to a lower mortality in PH anyway it can be simply associated with a lower risk phenotype rather than be protective itself. Age instead (in particular in the PHAR registry) is associated to both a worse baseline functional impairments and quality of life and a worse survival.
E) Pulmonary Arterial Hypertension treatment
Some new data on prostanoids were presented. In particular, consistently with known Literature, it seems that earlier initiation of treatment for PAH results in a more pronounced treatment effect. As a matter of fact in a subanalysis of the GRIPHON trial outcome was better in patients who were treated with selexipag closer to the time of diagnosis (independently from the background PAH therapy). Real-world data confirm this for all prostacyclins. Real world data on Selexipag in the SPHERE registry in particular show that at 1 year 85% of patients remained in the same risk group (63%) or improved to a less severe risk group (22%). For what concern Ralinepag, the open-label extension study of its phase 2 trial showed that long-term improvements in hemodynamics and 6MWD were maintained at 2 years of follow-up and that patients who switched from placebo trended toward improvements in PVR and 6MWD.
Some data on humans were presented about the efficacy of: 1) initial triple combination therapy with a parenteral prostanoids: after adjustment for age, gender, FC, 6MWD, RAP, and cardiac index, it reduced the risk of death compared to mono- or dual combination therapy; 2) BPA that, in a meta-analysis, led to a greater improvement in exercise tolerance and pulmonary hemodynamics than riociguat therapy; 3) oral treprostinil: according to the results of FREEDOM-EV trial, when adjusted for baseline risk, oral treprostinil reduced the risk of clinical worsening and improve exercise capacity, FC and NT-proBNP; 4) metformin that, in a pilot open label single arm trial, appears to improve RV function, reduced RV triglyceride content and increased the efficiency of fatty acid oxidation and of other pathways of interest in PAH.
F) New potential Pulmonary Arterial Hypertension treatment targets
A lot of studies were presented suggesting new possible PAH medication target. In particular: 1) stimulation vagal nerve can induce pulmonary vascular remodeling in different murine animal models with PH induced by Hypoxia and Sugen; 2) a pilot echocardiographic study showed that a short-acting inhaled β2-adrenergic agonist lowers mPAP and PVR significantly in patients with group 1 PAH who are on oral pulmonary vasodilator therapy; 3) higher serum HDGF predicts survival, and is associated with measures of disease severity and it is highly expressed by the liver so it can be used for the association with porto-pulmonary PAH and as a potential target for treatment; 4) spermine is associated with the severity of PAH, it promotes proliferation and migration of PASMC and its inhibition suppressed PDGF-mediated proliferation of PASMC; 5) MAO-A inhibitors can act both on pulmonary vascular remodeling and on RV function; 6) PINK1 can blunt pulmonary arterial smooth muscle cells hyperproliferation in hypoxic conditions; 7) MTH1 has a protective role against oxidative DNA damage and its inhibition reduces pulmonary arterial smooth muscle cells proliferation and apoptosis resistance associated with genome instability and loss of mitochondrial function; 8) oxidative stress can be potentially implicated in PH as documented in hypoxia animal models: a) an oxidative DNA damage and repair pathway regulates gene expression in hypoxic cells; b) base damage and repair is likely important for governing expression of genes in the hypoxic transcriptome; c) methamphetamine and HIV-Tat protein work synergistically to induce oxidative stress and endothelial cells apoptosis; 9) xanthine metabolism was taken into account in PAH associated with scleroderma: some SNPs of xanthine dehydrogenase gene have been associated with the occurrence and the severity of PAH.
Some important questions about new potential PAH medications are: do novel genes discovered will help in PAH treatment? Is precision medicine applicable to PAH? Are animal models still crucial in PAH? 23 genes have been discovered up to now and gene mutations can be found in 16% of patients with “idiopathic” PAH so they can be considered potential candidates for precision medicine in PAH. Anyway there should be a second hit in gene carriers as the penetrance of the disease is not 100%. Moreover the presence of a gene mutation was considered a risk factor for a more severe disease course but more recent data in patients optimally treated with PAH specific therapies don’t confirm this assumption. Genetics, anyway, may be helpful in precision medicine especially considering the fact that testing PAH drugs taking into account all different characteristics of patients would necessitate a too huge sample size for a rare disease trial. For what concern animal models we can say that they are not perfect, are heterogeneous and frequently with a different pathobiology than cannot be translated to humans anyway they have led to the development of currently available effective PAH specific drugs and still facilitate an ethical research. Moreover they can become relevant in the setting of precision medicine.
G) Pulmonary Hypertension due to left heart disease
Some particular issues were addressed:
– the distinction between PAH and PH-HFpEF (and also between IpcPH vs CpcPH). These parameters were proposed: the biomarker NEBI (quantification of bcl-2 in pulmonary artery endothelial cells harvested from the balloon tips of Swan-Ganz catheters following right heart catheterization), RA/PAWP ratio (ratio ≥ 1 identified also patients with a worse right heart function) and eccentricity index at echo. The differentiation between group 1, 2 and 3 instead, can be done according to different patterns of regional gas exchange and hemodynamics detected with 129Xenon MR Imaging and Spectroscopy.
– in HFpEF hyperventilation during exercise is associated with low cardiac index, low oxygen delivery and low maximum oxygen uptake, but not with high PAWP (this suggest that dynamic hyperventilation in HFpEF is likely primarily determined by “forward failure” rather than “backwards failure”);
– pulmonary arterial stiffening in PH due left heart disease in associated with increased collagen/elastin ratio, diameters of the pulmonary trunk and PA-wall thickness;
– some possible therapeutic targets: 1) in a metabolic syndrome-associated PH-HFpEF model treprostinil improves glucose tolerance and, combined with metformin, also improves cardiac function; 2) administration of oral nitrite acutely improve right ventricular and left ventricular filling pressures without any significant reduction in cardiac index or mean arterial pressure (moreover, there seems to be a diminished ability to reduce nitrate to nitrite in PH-HFpEF suggesting nitrites as a potential therapy);
– new data from experimental models of HFpEF: a) RV maladaptive remodeling occur early in the pathogenesis of PH-HFpEF prior to left heart remodeling so there can be a possible role for metabolic gene dysregulation underlying these morphologic changes; b) transgenic mice with purine metabolism that recapitulates the human uric acid levels develop, with age, systemic hypertension, LV concentric hypertrophy, LV fibrosis and diastolic disfunction, chronic kidney disease and metabolic syndrome; moreover PNPase (Inosine degradating enzime) inhibition has been demonstrated beneficial in the metabolic syndrome and associated pulmonary hypertension emphasizing the role of purine metabolism in metabolic syndrome and PH; c) in beef cattle models obesity can induced PH independently from hypoxemia even if pre-existing alveolar hypoxia combined with obesity may exacerbate PH and adverse cardiopulmonary outcomes.