In Search of Markers of Pulmonary Vascular Remodelling in Pulmonary Hypertension Due to Left Heart Disease
Year: 2018
Type: editorial
Abstract: This article refers to ‘Haemodynamic effects of an acute vasodilator challenge in heart failure patients with reduced ejection fraction and different forms of post-capillary pulmonary hypertension’ by S. Ghio et al., published in this issue on pages XXX. All left ventricular cardiomyopathies irrespective of their aetiology can cause pulmonary disease, a blow that adds insult to injury and worsens prognosis. Initially, elevated left-sided filling pressures are transmitted to the pulmonary vasculature leading to capillary congestion and then endothelial damage with interstitial and alveolar oedema. Thus, patients with left heart disease (LHD) first develop pulmonary hypertension [PH, defined as mean pulmonary artery pressure ≥ 25 mmHg and pulmonary capillary wedge pressure (PCWP) >15 mmHg] due to increased stiffness of the pulmonary vasculature. This can be reversed with the reduction of post-capillary pressure and is otherwise known as isolated post-capillary PH (IpcPH). However, prolonged exposure to elevated post-capillary pressures will result in endothelial dysfunction with reduced nitric oxide availability, increased production of endothelin-1, angiotensin II, transforming growth factor-β, leucocyte infiltration and release of inflammatory cytokines as well as further hypoxia-mediated vasoconstriction.1 Activation of these pathways will trigger proliferation of vascular myofibroblasts causing thickening of the alveolar membrane, medial hypertrophy, interstitial and intimal fibrosis and occasionally occlusion of small arterioles, ultimately resulting in irreversible changes of the pulmonary vasculature.2-4 Therefore, pulmonary artery pressures remain ‘fixed’ or ‘out of proportion’ for their respective PCWP, which is defined as combined post- and pre-capillary PH (CpcPH). Differentiating CpcPH from IpcPH has significant implications in the management and outcomes of patients with PH-LHD and has been a matter of ongoing debate.3, 5, 6 This led to a recent update in the guidelines proposed by the European Society of Cardiology (ESC) and the European Respiratory Society (ERS) where CpcPH patients were defined as having a diastolic pulmonary gradient (DPG, defined as diastolic pulmonary artery pressure minus PCWP) ≥7 mmHg and/or pulmonary vascular resistance (PVR, defined as mean pulmonary artery pressure minus PCWP divided by cardiac output) >3 Wood units.7 Thus far no prior study has specifically tested if CpcPH patients have actually reduced or diminished response to vasodilators suggestive of irreversible physiology. In the current issue of the Journal, Ghio and colleagues8 attempt for the first time to address whether patients with CpcPH due to heart failure with reduced ejection fraction (HFrEF) have actually remodelled pulmonary vasculature using acute vasodilatory testing. The authors retrospectively analysed the haemodynamic recordings of 156 patients with PH-LHD and end-stage HFrEF from three different referral centres. The patients were evaluated for cardiac transplantation with a right heart catheterization and underwent acute vasodilatory testing with intravenous nitrates (nitroglycerin or sodium nitroprusside). Given the relative uncertainty and ongoing debate regarding the best haemodynamic measure of CpcPH,2, 3 the authors used three different definitions of CpcPH. First, they defined CpcPH using the most recent guidelines issued by ESC/ERS.7 In addition, they defined CpcPH as DPG ≥7 mmHg as previously recommended at the 5th World Symposium on PH held in Nice in 2013.1 Finally, the authors specified CpcPH by a transpulmonary gradient (TPG) ≥12 mmHg. Individuals with CpcPH (according to the most recent guidelines) had at baseline lower tricuspid annular plane systolic excursion (TAPSE) to systolic pulmonary artery pressure ratio suggestive of worse right ventricular to pulmonary circulation coupling2 and worse haemodynamics including lower pulmonary arterial compliance (PAC) and cardiac output and as expected higher TPG, DPG and PVR. Interestingly, the right ventricular stroke work index was higher in CpcPH subjects consistent with slightly better right ventricular function. After vasodilatation, PVR, DPG and TPG improved significantly more in CpcPH patients as defined by the latest guidelines and the 2013 Nice criteria. This was likely and at least in part due to the fact that the absolute baseline values of PVR, DPG and TPG were significantly higher in CpcPH compared to IpcPH. Notably, the only haemodynamic parameter that increased more in IpcPH patients was PAC. When IpcPH was defined by TPG <12 mmHg, PVR and TPG decreased more with vasodilatation. However, despite the greater change in most of the haemodynamic markers in CpcPH patients, the product of the inverse relationship between PVR and PAC (resistance–compliance constant) remained on the steeper part of the hyperbolic curve (where any change in PVR has a minimal effect on compliance) suggestive of a persistently higher right ventricular load. Finally, a very similar percentage of patients (∼25%) with CpcPH normalized their PVR values (<2.5 Wood units) after vasodilatation irrespective of the definition of CpcPH. In an attempt to perform survival analysis, the authors followed the patients for a median period of 23 months and, as previously described,9 individuals with CpcPH according to the 2015 ESC/ERS guidelines, had higher mortality rates. Not surprisingly, non-survivors in the CpcPH group had lower right ventricular stroke work index and systolic pulmonary artery pressure both consistent with worse right ventricular function, which undoubtedly is the most important predictor of outcomes in PH-LHD.2, 10 There was no reported difference in survival based on high DPG or TPG, as this study included a small number of patients and was likely underpowered to detect any significant mortality difference in these groups. Finally, as expected, patients with PH-LHD who responded to vasodilators had lower mortality rates. The authors should be commended for their attempt to study for the first time the latest recommended haemodynamic markers of CpcPH and their association with potential remodelling of the pulmonary vessels based on vasoreactivity testing. Pulmonary vasoreactivity testing is not standardized for patients with PH-LHD and the definition of reversibility to nitrates in this study was arbitrary and based solely on PVR. However, according to the current guidelines by the International Society for Heart and Lung Transplantation, this test is recommended for heart transplant evaluation of patients with PVR >3 Wood units or TPG ≥15 mmHg and the response is assessed by a decrease in PVR.11 In spite of the haemodynamic and biological similarities of CpcPH with pulmonary arterial hypertension (PAH),12 it has recently become more obvious that pulmonary vascular remodelling is less common, at least in HFrEF patients with PH. As it was demonstrated by Masri and colleagues,13 left ventricular assist device (LVAD) implantation normalized all pre-capillary haemodynamic markers within 72 h. A slightly later reversibility effect was also shown in a small, single centre study where LVAD implantation improved significantly all haemodynamic parameters (including DPG) within 3 months. Additionally, in a recent large retrospective analysis of 1016 patients with end-stage HFrEF and PH-LHD with very high PVR (mean 5.7 ± 2.4 Wood units) and TPG (mean 19.3 ± 5.3 mmHg), LVAD implantation or inotropes reversed all haemodynamics and in approximately one-third of the patients normalized their PVR.14 Thus, most patients with PH as a result of HFrEF develop reversible pulmonary artery disease from vessel over-distension, which could explain the failure of several PAH therapies in these patients.3 As there is still ongoing disagreement regarding the best haemodynamic classification of patients with CpcPH, this study highlights that even though the latest definition of CpcPH has a better association with prognosis, its relationship with the actual pulmonary vascular pathology is still unclear. Indeed, considering the heterogeneity of diseases leading to elevated left atrial pressures and PH-LHD, the differences in the extent and severity of the pulmonary vasculature involvement and duration of disease as well as the variable increase in right ventricular load, it is almost impossible to actually study the pathogenesis of this disease without more research on histology patterns and the molecular mechanisms involved. Thus, more translational studies based on biomarkers, human autopsy samples and animal models are needed to clarify and more accurately phenotype PH-LHD patients. This will provide significant insight and definitely help us differentiate, treat and prognosticate better this diverse group of patients. Regarding the haemodynamic definitions of CpcPH, more prospective, large and multicentre studies with long-term follow-up are necessary to clarify the controversy in the field. Importantly, in this analysis PAC was the only parameter that increased more in IpcPH than in CpcPH with vasodilatation in spite of no difference in PCWP between the two groups. Therefore, it is possible that PAC, which as a measure of total right ventricular afterload incorporates resistive, pulsatile and passive components, possibly reflects better any potential irreversible remodelling of the pulmonary vasculature.15 This further strengthens the recognized role of PAC as an important prognosticator in patients with PH-LHD.2, 3 In conclusion, the study by Ghio et al. casts doubt on the presence of irreversible pulmonary vascular remodelling in patients with PH-LHD and HFrEF. It also highlights that even though the new haemodynamic definition of CpcPH has a good prognostic capability, its association with non-vasoreactive PH remains uncertain. Therefore the search for truly irreversible PH in HFrEF patients and better markers for its characterization should continue… Conflict of interest: none declared.
DOI: 10.1002/ejhf.1137
Author: Emmanouil Tampakakis
Institutions: Johns Hopkins University, Johns Hopkins Medicine
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2783786763