Short-Term Effect of Levosimendan in Acute Right Heart Failure Caused by Pulmonary Hypertension: A Pilot Study

World Health Organization Pulmonary Hypertension Group 2: Pulmonary hypertension due to left heart disease in the adult—a summary statement from the Pulmonary Hypertension Council of the International Society for Heart and Lung Transplantation

Pulmonary Hypertension in Heart Failure With Preserved Ejection Fraction: A Community-Based Study

PROGNOSTIC VALUE OF EXERCISE RIGHT VENTRICULAR FREE WALL STRAIN IN PATIENTS WITH SICKLE CELL DISEASE

Peripheral Venous Pressure: An Important but Neglected Contributor to Echocardiographic Estimation of Pulmonary Artery Pressure With Exercise.

This article refers to ‘Pulmonary hypertension due to left heart disease: analysis of survival according to the haemodynamic classification of the 2015 ESC/ERS guidelines and insights for future changes’ by M. Palazzini et al., published in this issue on pages 248–255. Pulmonary hypertension (PH) is a common condition, affecting approximately 10% of the elderly population.1 Left heart disease (LHD) by far represents the most common cause of PH.1, 2 In fact, the majority of patients with LHD have some degree of PH,2, 3 and several studies have shown that any degree of PH impacts morbidity and mortality in patients with various forms of LHD, including heart failure and valvular disease.2, 3 Despite the clinical importance of PH in these patients, our understanding of the range of pulmonary vascular responses to LHD remains very limited. From a pathophysiological point of view, PH caused by LHD initially results from pulmonary congestion and backward transmission of elevated left-sided filling pressure [commonly measured as pulmonary artery wedge pressure (PAWP)], which causes post-capillary PH. However, over time, some patients may develop additional pulmonary vascular disease (PVD), thereby adding a pre-capillary component to their PH2, 3 which may be associated with a worse outcome but may represent a potentially treatable target. How PVD in patients with LHD can be best defined and diagnosed remains a matter of debate. Based on the recommendations of the Fifth World Symposium on PH,3 the 2015 European PH guidelines proposed that post-capillary PH be subclassified into ‘isolated post-capillary PH’ (Ipc-PH) and ‘combined post- and pre-capillary PH’ (Cpc-PH).4 The distinction between these entities is based on two haemodynamic criteria: the diastolic pressure gradient (DPG), defined by the difference between diastolic pulmonary artery pressure (PAP) and PAWP, and pulmonary vascular resistance (PVR), calculated as the difference between mean PAP and PAWP divided by cardiac output (CO). This definition of Cpc-PH was recently challenged by several studies with findings that have stimulated discussions among experts. In particular, the role of the DPG in predicting survival in PH-LHD as shown by some groups5-7 is subject to controversy as the analyses of other cohorts have failed to show the prognostic value of this variable.8-11 In this issue of the Journal, Palazzini et al. add another piece to the puzzle.12 They present a retrospective, single-centre analysis of 276 patients with LHD who underwent invasive haemodynamic assessment between 1997 and 2015, in whom post-capillary PH (mean PAP ≥25 mmHg; mean PAWP >15 mmHg) was diagnosed. According to current guidelines,4 the authors defined a group of patients with Cpc-PH [DPG ≥7 mmHg, PVR >3 Wood units (WU)], a group with Ipc-PH (DPG <7 mmHg; PVR ≤3 WU), and an ‘intermediate’ group in which only one of the two variables was elevated. They then estimated survival rates in the three groups using the Kaplan–Meier method and log-rank test with the aim of elucidating the prognostic values of PVR and DPG alone and in combination, as well as those of other haemodynamic indices. They found that patients with Ipc-PH had better survival than both patients with Cpc-PH (P = 0.026) and those in the intermediate group (P = 0.025). Furthermore, although patients with normal PVR had better survival compared with those with elevated PVR (P = 0.013), there were no differences in survival according to the level of DPG (P = 0.254) or level of transpulmonary pressure gradient (TPG; defined as the difference between mean PAP and PAWP) (P = 0.147). The authors also showed that, in addition to PVR, pulmonary arterial compliance (PAC), calculated as stroke volume divided by pulse pressure (difference between systolic and diastolic PAP), was also predictive of survival. In fact, a low PAC turned out to be the strongest predictor of death when analysed as a continuous variable (P = 0.001).12 These data must be interpreted in relation to the findings of a number of other studies that have assessed the prognostic values of haemodynamic variables in PH-LHD and unfortunately yielded quite heterogeneous results5-14 (Table 1). The distinct and in part contradictory findings may be explained by differences in methodology, definitions and threshold levels,2, 3 lack of standardization for optimized LHD treatment and volume load, as well as the fact that some studies investigated PH caused by LHD in general, whereas others focused on specific LHDs [i.e. heart failure with reduced ejection fraction (HFrEF), heart failure with preserved ejection fraction (HFpEF), valvular disease] at various stages.5-14 Moreover, the potential bias induced by the retrospective nature of most studies must be acknowledged. Despite these limitations, we may conclude that the overall amount and quality of available data are insufficient to support any judgements on the prognostic value of haemodynamic variables in PH-LHD. Nevertheless, the fog may be lifting as we collect more data, and the work by Palazzini et al.12 adds important information. Firstly, it shows that a substantial number of patients with LHD and PH display an elevated PVR, which may or may not be associated with an increased DPG, whereas an isolated elevation of the DPG with normal PVR appears to be very rare, which is consistent with the findings of other groups.15 Secondly, the subgrouping of post-capillary PH into Ipc-PH and Cpc-PH predicted survival in patients with PH-LHD, which is also in line with the results of several other studies.5-7, 9-14 Thirdly, the ‘intermediate’ group was mainly driven by elevated PVR with normal DPG, and outcomes in this group did not differ from those in the group with Cpc-PH (i.e. elevated levels of PVR and DPG). Fourthly, pressure gradients (i.e. DPG, TPG) appeared to be of minor importance, whereas variables incorporating cardiac function (i.e. PVR, PAC) were superior in predicting outcome in PH-LHD, which is consistent with the majority of recent studies.8-11 The main limitations of the study by Palazzini et al.,12 as well as of most other studies evaluating the role of pulmonary vascular indices for predicting survival in patients with LHD,5-11 concern the limited numbers of patients in many of the studies, the single-centre approach and the retrospective nature of the analyses. Furthermore, most studies have grouped together all types of LHD on the assumption that the consequences on pulmonary haemodynamics and right ventricular (RV)–pulmonary artery (PA) coupling are the same for various types and degrees of heart failure (HFpEF, HF with mid-range EF, HFrEF) and valvular disease (mitral stenosis/mitral regurgitation, aortic stenosis/aortic regurgitation), or other left heart conditions. However, this may not be the case. Hence, the available evidence remains limited and the existing data should be interpreted with caution. The heterogeneity of published data and the uncertainty about the diagnostic and/or prognostic value of single haemodynamic indices raise two key questions. Firstly, do we need a subclassification of PH-LHD and, if so, why? Given that the presence of PH and particularly a pre-capillary component of PH as well as impaired RV–PA coupling are associated with adverse outcomes, this question must be answered in the affirmative. However, future adjustments of the classification must be more precise about the diagnostic vs. the prognostic value of haemodynamic measures (which are certainly not the same), as improvement of our pathophysiological understanding and proper risk stratification in PH-LHD are warranted. Current work provides novel insights into the clinical, genetic and pathophysiological features of Ipc-PH vs. Cpc-PH.11, 16 The key question concerns whether we can improve morbidity and mortality in selected patients with PH-LHD by targeting the pulmonary circulation and unloading the right ventricle. To this end, we have preliminary evidence at best.17-19 Secondly, based on pathophysiological considerations, which pulmonary vascular indices would be expected to indicate PVD and a higher likelihood of death? The pathophysiological interplay between the left heart, pulmonary circulation and right heart is well established.2 Indeed, several studies have shown that RV dysfunction is a strong and independent predictor of survival in patients with heart failure.20-22 Furthermore, impaired RV–PA coupling appears to be of particular importance to outcomes in HFpEF,23 especially in patients with Cpc-PH.24 It should be noted that RV workload is defined by pressures, rather than gradients, and that the adaptation of the right ventricle to an increased afterload is of key importance.25 In that sense, RV afterload is composed of a steady (PVR) and a pulsatile (PAC) vascular load. Consistently, in several recent studies PVR and PAC outperformed the DPG in predicting mortality10, 12, 13 and, hence, PVD in LHD may be best defined by measures incorporating RV function (i.e. PVR, PAC).25 This claim, however, must be confirmed in larger trials. Furthermore, our current understanding and the classification of PH-LHD are based mainly on haemodynamics at rest, whereas impaired RV–PA coupling during moderate exercise is detected even in early stages of HFpEF,26 and the increase in CO during exercise rather than CO at rest may be more relevant.27 In this context, an abnormal pulmonary haemodynamic response during exercise is characterized by an excessive increase of PAP in relation to flow, and a currently proposed definition of ‘exercise PH’ is based on the relationship between Δmean PAP and ΔCO.28 In summary, the current classification of PH-LHD needs to be refined and measures should be indicative of PVD, RV dysfunction and RV–PA coupling at rest and potentially during exercise, so that a combination of variables rather than a single parameter may be suitable for proper haemodynamic phenotyping. In 2018, the Sixth World Symposium on Pulmonary Hypertension will be held in Nice, France; it will be a challenging goal to summarize current knowledge and adjust definitions in preparation for this. The current evidence is incomplete, preliminary in nature rather than definite, and partly contradictory. Hence, the belief that we are close to making conclusions may be illusory. As Palazzini et al.12 point out, what we need are prospective, multicentre, adequately sized studies with pre-specified endpoints, inclusion criteria, subgroup definitions and uniform baseline assessments and follow-up strategies. Such studies should be based on our pathophysiological understanding and subclassification of PH-LHD, and conducted separately in patients with specific underlying LHDs. The final answers may come from therapeutic interventions, which may or may not be safe and efficacious in distinct subgroups of patients with PH attributable to LHD. Only then will we be ready to draw conclusions. Conflict of interest: none declared.

Pulmonary hypertension (PH) has long been recognized as a complication of interstitial lung disease (ILD). It contributes significantly to morbidity and mortality and thus is of key importance in prognostication and deciding the timing of referral for lung transplant. There is increasing evidence of the complexity of its pathogenesis beyond simple fibrosis and hypoxemic vasoconstriction. The pathophysiologic overlap with pulmonary arterial hypertension (PAH) has led to trials of pulmonary vasodilatory therapy in PH-ILD. While prior trials of pulmonary vasodilatory therapy in ILD have presented mixed results, a recent trial of inhaled pulmonary vasodilator therapy in this group has shown positive effect.1 As a result, the early recognition of the development of PH in ILD may have a greater implication for patients than just prognostication and assessment during considerations for transplant, and may contribute to better outcomes.In this paper we review the current understanding of the pathogenesis of PH in patients with ILD and what is known about the clinical impact of PH in the context of ILD. We then review the importance of hemodynamic assessment to the diagnosis of PH in ILD. Lastly, we review different symptoms, physical exam findings and studies that raise the index of suspicion for the presence of PH in ILD and considerations for incorporating these into initial and subsequent evaluations for patients with ILD.While PH can occur in many different contexts in a patient who also has ILD, the implications of labeling an individual as having PH-ILD suggests that ILD is the primary driver of the presence of PH. This can be a subtle distinction: many patients with group 1 PH (PAH), and in particular those with connective tissue disease (CTD), may have a mild form of ILD while also having PAH. Similarly, patients with sarcoidosis may have both ILD and PH while still not being considered as group 3 PH. The understanding of these distinctions is crucial for interpretation of results of clinical studies, which often use such definitions for inclusion or exclusion.Significant history exists in classification of patients with ILD into group 3 PH (PH associated with chronic lung disease) using a combination of hemodynamics and the degree of lung disease. The hemodynamic definition of PH, in the context of chronic lung disease (group 3 PH) was updated in the 6th World Symposium on Pulmonary Hypertension to include a resting mean pulmonary artery pressure of &gt;20 mm Hg, a pulmonary artery occlusion pressure ≤15 mm Hg, and a pulmonary vascular resistance of &gt;3 Wood units.2 It is important, however, to note hemodynamic definitions do not create a distinction between group 3 and group 1 PH, rather the distinction relies on defining chronic lung disease as the primary driver of precapillary PH.2,3 This is done through a combination of pulmonary function testing and imaging—evidence of significant decrement in lung volumes or evidence of significant ILD burden on imaging moves the patient from group 1 to a group 3 designation. The challenge then becomes to define “significant ILD burden”. This is particularly difficult in conditions such as CTD where PH can exist with and without the presence of ILD. If we look at most PAH trials, a lower limit of forced vital capacity (FVC) of close to 70% or total lung capacity (TLC) of 60% is used as a hard cutoff, suggesting that of the patient with higher ILD burden should be classified as group 3.Special note must be made about sarcoidosis, which leads to the development of both ILD and PH through multiple mechanisms. Currently PH due to sarcoidosis remains categorized as group 5 disease and is excluded from many studies and discussions of PH-ILD.3Direct hypoxic vasoconstriction and tissue fibrosis have been long been postulated to underlie the development of PH in ILD.4 While these mechanisms are an important driver of pulmonary vascular disease in ILD, there is increasing appreciation of the complex combined tissue and vascular remodeling leading to PH in ILD.3–6In areas of fibrosis, there is significant narrowing of the lumen of the arteries,7 which is associated with a degree of fibrosis in the surrounding tissue.8 On the other hand, that direct fibrosis is not solely responsible for PH-ILD. This is supported by the presence of vascular changes in patients with idiopathic pulmonary fibrosis (IPF) in areas without significant architectural distortion.7 Furthermore, the presence of PH is not well associated with lung volume loss as measured by pulmonary function testing (PFT)9 or the degree of fibrosis on imaging.10 While low diffusing capacity for carbon monoxide (DLCO) and oxygenation are associated with PH-ILD, it is not clear whether this implicates hypoxemia as a causal pathway in the development of PH. Nevertheless, histologic studies of PH in the context of ILD do show significant vascular remodeling reminiscent of that found in PAH.3,4 For example, in a study of explants from advanced fibrotic ILD undergoing transplantation, severe arterial vasculopathy, including plexiform lesions thought to be classically associated with PAH, were noted in 16 of the 38 subjects studied, regardless of the presence or severity of PH.11Alterations in markers commonly indicative of PAH have been reported in patients with IPF. For example, the expression of endothelin, a well described peptide implicated in the pathology of PAH,12 have been noted in ILD.13,14 Additional data also supports that many inflammatory mediators known to be abnormally expressed in PAH are also altered in ILD.15 For example, TGFβ is an inflammatory mediator that is heavily involved in both IPF16 and PAH.17 Alterations in VEGF levels,18 IL-6,19 as well tumor necrosis factor α3 have also been reported. Thus it is likely that the emergence of PH in ILD is a complex interplay of tissue destruction, inflammation, and hypoxia, leading to pulmonary vascular remodeling through multiple pathways.Prevalence of ILD is estimated to be between 0.0672%20 (females)/0.0809% (males) and 0.071%21 in 2 cohort studies. The estimation of the prevalence of PH-ILD is difficult given the variable admixture of causes of ILD, and the inherent bias of the presence of retrospective hemodynamic data only in those patients already suspected of having PH or undergoing transplant work-up. As a result, a wide range of estimates of prevalence of PH in ILD exist. For example, a review of 126 studies in IPF revealed a range of prevalence of PH between 3% and 86%.22 Illustrating the temporal prevalence of PH-ILD, in a study of 44 IPF patients with serial right heart catheterization (RHC) at initial evaluation and prior to transplantation, 39% of the patients were found to have PH-ILD, whereas at the time of transplant evaluation, 86.4% of patients had PH-ILD.23 A study of 340 ILD patients undergoing RHC showed 96 (28%) of patients with PH, of which 56 were considered to be severe.24 In a study of 135 patients with IPF being evaluated for lung transplantation, 39 patients (29%) had PH-ILD.25 Evaluation of 488 IPF patients with mild or moderate restrictive disease showed that 14% of subjects met the criteria for PH-ILD.26CTD such as the systemic sclerosis/scleroderma spectrum are highly associated with development of progressive PH. As mentioned previously, many such patients are classified as having group 1 disease (PAH) based on the degree of ILD involvement, particularly in comparison to the degree of PH. Nonetheless, PH remains a major complication of CTDs in the presence of ILD. In one study of patients with systemic sclerosis with interstitial lung disease (SSc-ILD), 31% had PH while 16% met the definitions of group 3 PH.27 In another study, the prevalence of PH-ILD in patients with idiopathic interstitial pneumonias was 29% vs 64% in those with CTD-ILD.28While PH-ILD in the context of CTD-ILD and IPF have been the most thoroughly studied, PH has also been documented in the context of other forms of ILD including nonspecific interstitial pneumonias (NSIP) (31.4%)29 and chronic hypersensitivity pneumonitis (44%).30Of note, most of the data used in prior studies in this and other reviews have included a previous definition with a resting mean pulmonary artery pressure cutoff of 25 mm Hg. The impact of the new definition on the prevalence of PH-ILD in IPF was recently studied in 15 563 subjects undergoing RHC in the United Network for Organ Sharing database. This analysis revealed that that the threshold of 20 mm Hg increased the number of patients considered to have PH from 47.6% to 73.6%. However, the new hemodynamic definition also imposes a pulmonary vascular resistance limitation not present in the previous definitions, which together with the pulmonary artery occlusion pressure requirements leads to a prevalence of 36.8% for precapillary PH in this cohort.The presence of PH-ILD is generally believed to be a poor prognostic indicator in patients with ILD. Initially, this was thought to reflect the relationship between advanced disease and presence of PH. However, an alternate explanation is the impact of pulmonary vascular disease and right ventricular dysfunction on exercise capacity and eventual progression to heart failure. Supporting this explanation is data relating hemodynamics with exercise impairment and mortality. For example, in an analysis of 124 patients with IPF, resting mean pulmonary artery pressure was shown to be the best predictor of 6-minute walk distance (6MWD) in multivariable analysis including pulmonary function testing. Elevated resting mean pulmonary artery pressure has been shown to predict mortality in patients with IPF,31 even when not meeting the criteria for PH-ILD.31 Additionally, in a study of patients with IPF being evaluated for lung transplantation, increased pulmonary vascular resistance, evidence of right ventricle dilation and dysfunction were associated with increased mortality.25 The importance of hemodynamics in predicting mortality in IPF has also been demonstrated using exercise hemodynamics in IPF.33 Findings similar to those in IPF have been reproduced in more general ILD population with reduced 6MWD and survival noted in patients with PH-ILD.24,34The severity of PH in the context of ILD is believed to generally be biased toward mild to moderate elevations in pulmonary arterial pressures.3 In addition to fundamental pathophysiologic differences, other explanations for this include classification bias (patients with severe PH are classified as group 1) and survivorship bias (patients with advanced PH and ILD do not survive or are transplanted). Nonetheless, outcomes in PH-ILD are fairly poor. In an analysis of the COMPERA registry, an international registry of PH patients on pulmonary vasodilatory therapy, significantly lower 3-year survival rates were noted in patients with PH associated with idiopathic interstitial pneumonias (34.0%) compared to idiopathic PAH (68.6%). In the analysis of the Giessen PH registry, 3-year survival rates in patients with PH-ILD were noted to be 40.3% compared to 72.2% in PAH.35RHC is necessary for the diagnosis and the consideration of treatment of PH in patients with ILD, a statement supported by society and group recommendations.2 The rationale for this requirement is many-fold. As discussed below, noninvasive methods to diagnose PH in the context of ILD have significant limitations and as a result, initiation of treatment requires hemodynamic confirmation. Additionally, postcapillary PH is not an uncommon finding in patients with ILD, requiring a very different approach to management. For example, in a study of 157 patients with ILD-PH, 20% were diagnosed with postcapillary PH.36 In another study of 8991 patients undergoing transplant for IPF, 11.3% had postcapillary PH, of which 4% were combined precapillary and postcapillary disease. Lastly the hemodynamic severity and circulatory impact of ILD-PH can better be quantified by RHC, which then in turn is part of the critical decision making and application of clinical evidence in the decision to treat with pulmonary vasodilatory therapy.Because RHC is needed for the diagnosis and assessment of PH prior to therapy, both screening at initial evaluation and subsequent monitoring rest on the index of suspicion for PH. Assessment of symptoms, physical examination, pulmonary function tests and computed tomography (CT) imaging are a part of the routine assessment and monitoring of patients with ILD and can provide information that can be used to risk-stratify patients.In general, there are 2 groups of findings that signal the presence of pulmonary vascular disease in ILD: those related to out-of-proportion impairment of gas exchange resulting from increase in pulmonary vascular resistance, and those related to right ventricular dysfunction. Both these mechanisms then feed into increased shortness of breath and decreased exercise tolerance. Thus, increased dyspnea on exertion, worsening oxygenation, and decreased exercise tolerance in the context of stable disease markers of ILD should raise concerns for PH-ILD. Physical exam findings associated with PH-ILD are also related to increased PA pressure (pronounced P2) or related to right ventricle dysfunction: pulmonary edema, jugular venous distension and cardiac exam suggestive of right ventricle dysfunction (such as parasternal heave).It is important to note that the traditional markers of disease severity in ILD such as reduction of lung volume on PFTs have not been associated the presence of PH-ILD.4,9 On the other hand, multiple studies have demonstrated that low DLCO is a predictor of the presence of PH in ILD.9,31,37–39 Steen and colleagues observed that an FVC:DLCO ratio of &gt;1.4 was an excellent predictor of development of isolated PAH.40 Seibold reported that an FVC:DLCO ratio of ≥1.8 was a good predictor of death in SSc, while Trad and colleagues found a ratio of ≥2 to predict survival.41,42 Associated with this finding is the observation that hypoxemia itself may be a predictor of PH in ILD.38,39As mentioned earlier, patients with PH-ILD have decreased exercise tolerance as measured by 6MWD.34 Though 6MWD is not routinely part of the ILD follow-up protocols, when performed, a decrease in exercise capacity, particularly if not associated with progression of the underlying ILD, can be a signal of progression of pulmonary vascular disease. Other measurements obtained during 6MWT may also be telling: abnormal heart rate recovery at 1 minute has also been found to be predictive of both the presence of PH and survival in patients with IPF.43 Oxygenation measured in the context of exercise is also predictive of PH in ILD.44Brain natriuretic peptide (BNP) and N-terminal pro-brain natriuretic peptide (NT-proBNP), well-known markers of heart failure, have been investigated as a tool for screening for PH in ILD. In 2 studies, a low NT-proBNP (&lt;95 ng/L) in ILD patients had a negative predictive value of &gt;94% for the presence of PH.45,46 These studies used echocardiography as a gold standard of diagnosis.45Echocardiography and specifically findings suggestive of elevated pulmonary circulatory pressures, volume overload, and right ventricular dysfunction are commonly used as a final touchstone before the decision to proceed to RHC. While many different advanced metrics have been proposed and shown to be promising as markers of PH in ILD, standardization particularly across performing sites remains a challenge in broad acceptance. The tricuspid regurgitant velocity, which is often used to estimate a right ventricular systolic pressure (RVSP) or pulmonary arterial systolic pressure, is the most well studied and employed method of screening for PH on PAH as well as PH-ILD. Unfortunately, this measure in isolation has significant limitations. For example, in a study of 265 ILD patients being investigated for PH, 86% of patients with a tricuspid regurgitant velocity &gt;3.4 m/s were found to have to have PH on RHC, whereas only 40% of those with a tricuspid regurgitant velocity &lt;2.8 m/s were found to have PH.47 Similarly, a cross-sectional study of 110 IPF patients found that while higher RVSP was associated with increased likelihood of PH in ILD, without consideration of additional testing such as PFT and 6MWT, no clear optimal cutoff for classification was present.48 Other smaller or more focused studies have confirmed the conclusion that while elevated tricuspid regurgitant velocity or derived measures such as RVSP are helpful in risk stratification, they cannot be used in isolation.49,50CT imaging is widely available on presentation and for monitoring of progression in patients with ILD. As pressures in the pulmonary circulation increase, the main pulmonary artery dilates. The pulmonary artery diameter can be used as a marker of PH either on its own or normalized by the diameter of aorta in the same CT slice. One study found that a pulmonary artery diameter of &gt;25 mm in patients with ILD had a sensitivity of 86.4% but only a specificity of 41.2% in identifying RHC-proven PH in ILD patients. When using pulmonary artery diameters of &gt;29 mm as compared to echocardiography evidence of PH, this criteria had a 63% sensitivity and 41.5% specificity in identifying high pulmonary artery pressure on echocardiograms.51 Additionally, pulmonary arterial size is a predictor for mortality in IPF.52 While most CT imaging in ILD is not cardiac gated, the size of the right ventricle as compared to the left ventricle, particularly visible in contrast imaging, is also suggestive of PH (See Figure). CT imaging may also be used for the detection of the presence of both fibrosis and emphysema on CT imaging has been proposed a distinct entity, which has been associated with increased prevalence of PH.53,54The results of the studies reviewed above and others have led to the general agreement that no single noninvasive diagnostic modality should be used in isolation in the screening and monitoring of patients with ILD for PH-ILD. In particular, multivariable analysis has generally led to the verification of this observation and to multiple algorithms incorporating a selected set of measurements (BNP, DLCO, echocardiography),55 (Ratio of FVC/DLCO, PAA, RVSP)56 (TLC/DLCO index, age, 6MWD, room air oxygen saturation at 6MW).57 In absence of established research, a combination of these methods could be used to lead clinicians from routine history, examinations, and laboratory findings to a primary workup for PH with echocardiography, 6MWD measurements, and BNP/NT-proBNP, with a low threshold for RHC in the right clinical setting. (See Table)The appearance of increased pulmonary pressures is uniformly a harbinger of poor outcomes, and so is the case in PH-ILD. Advances in therapeutic options has led to an urgency to look for PH in our ILD patients. Certain symptoms, physical exam signs, and laboratory and imaging findings in the routine care of ILD patients can suggest the need for a deeper dive with further testing including echocardiography. Presence of elevated RVSP and a clinical picture consistent with PH should result in a low threshold to obtain a RHC. Further research in years to come should help better identify the patients that need to be screened and then sent for confirmation with a RHC.

This article refers to 'Different correlates but similar prognostic implications for right ventricular dysfunction in heart failure patients with reduced or preserved ejection fraction' by S. Ghio et al., published in this issue on pages 873-879.

Since the last World Symposium on Pulmonary Hypertension in 2008, we have witnessed numerous and exciting developments in chronic thromboembolic pulmonary hypertension (CTEPH). Emerging clinical data and advances in technology have led to reinforcing and updated guidance on diagnostic approaches to pulmonary hypertension, guidelines that we hope will lead to better recognition and more timely diagnosis of CTEPH. We have new data on treatment practices across international boundaries as well as long-term outcomes for CTEPH patients treated with or without pulmonary endarterectomy. Furthermore, we have expanded data on alternative treatment options for select CTEPH patients, including data from multiple clinical trials of medical therapy, including 1 recent pivotal trial, and compelling case series of percutaneous pulmonary angioplasty. Lastly, we have garnered more experience, and on a larger international scale, with pulmonary endarterectomy, which is the treatment of choice for operable CTEPH. This report overviews and highlights these important interval developments as deliberated among our task force of CTEPH experts and presented at the 2013 World Symposium on Pulmonary Hypertension in Nice, France.

Impact of Aging on Pulmonary Hemodynamics in the General Population

Oxygen consumption trajectory flattening-yet another cardiopulmonary exercise testing parameter in chronic heart failure.

Background The diagnostic pathway of pulmonary hypertension (PH) is complex and requires several parameters. Differential diagnosis between left heart disease (group 2) and pulmonary disease (group 3) as PH etiology is also challenging. The latest European guidelines recommend a comprehensive echocardiographic evaluation for suspected PH, and the use of several basic echocardiographic indices to assess cardiac etiology of PH. Speckle tracking echocardiography (STE) has emerged as a more sensitive technique to evaluate myocardial performance in different clinical settings and is recommended for the diagnosis of HFpEF. Purpose Our ai was to assess the potential value of STE to predict left heart disease in patients presenting with dyspnoea and PH. Methods Consecutive outpatients with dyspnoea with efforts and subsequent diagnosis of PH were retrospectively enrolled. Inclusion criteria were New York heart association (NYHA) class≥II, LV ejection fraction≥50%, echocardiographic evidence of systolic pulmonary artery pressure≥35 mmHg and tricuspid regurgitant velocity≥2.8 ms, known diagnosis of PH with relative etiology (heart failure with preserved ejection fraction, HFpEF or lung diseases i.e. sarcoidosis, idiopathic pulmonary fibrosis, chronic obstructive lung disease). Patients underwent clinical, biohumoral and echocardiographic evaluation, STE was performed offline. Primary endpoint was the prediction of HFpEF. Results Overall, 145 patients were enrolled (80 with HFpEF, 65 with lung disease). Mean age was 75±12 years, 53% were female. Patients with HFpEF were older (77±10 vs. 68±14 years, p&amp;lt;0.0001) and had higher LA volume (93±37 vs. 64±31 ml, p&amp;lt;0.0001), E/E’ by tissue Doppler imaging (TDI) (15±5 vs. 9±3, p&amp;lt;0.0001), mitral regurgitation (MR) grading (p=0.002), lower tricuspid regurgitation (TR) grading (p=0.004). Regarding STE, patients with HFpEF had lower peak atrial longitudinal strain (PALS) (15 ± 8 vs. 24 ± 11%, p&amp;lt;0.0001) and LV global longitudinal strain (-13 ± 9 vs. -17 ± 6%, p=0.009). LA stiffness, calculated as the ratio between E/E’ and PALS, an index of LA dysfunction and fibrosis, was higher in patients with HFpEF (median LA stiffness = 1.09 [CI = 0.64-1.73] 0. Vs.0.35 [CI = 0.20-0.59], p&amp;lt;0.0001). With ROC curves, both E/E’ and global PALS provided a good prediction for HFpEF (AUC 0.73 and 0.79 respectively), but LA stiffness significantly enhanced the predictive power (AUC = 0.83) with an optimal cutoff value ≥0.53. With multivariate analysis including age, LA volume, LV GLS, LA stiffness, mitral and tricuspid regurgitation grade, LA stiffness≥0.53 (RR = 19.14, CI 5.86-62.55) was the only independent predictor of HFpEF in our cohort of patients with PH (Fig.1). Conclusions STE may aid differential diagnosis of etiology between left heart disease and pulmonary disease in patients with PH. The combination of TDI E/E’ and PALS to calculate LA stiffness offers the most accurate prediction of PH with cardiac etiology.

Background Pulmonary hypertension (PH) complicated with heart failure (HF) is associated with increased morbidity and mortality. Vascular endothelial growth factor D (VEGF-D), one of key regulators of lymphangiogenesis, was reported to be higher in HF patients with pulmonary congestion on chest X-ray. Furthermore, we previously reported that HF patients with high VEGF-D had higher incidence of major adverse cardiovascular events (MACE), defined as cardiovascular death or heart failure hospitalization. Purpose To investigate the association of VEGF-D with pulmonary hypertension in patients with HF. Methods The PREHOSP-CHF study is a multicenter prospective cohort study to determine the predictive value of angiogenesis-related biomarkers in HF. A total of 1,024 patients (mean age 75.5±12.6 years; 58.7% male) admitted to acute decompensated HF were included in the analyses. Serum levels of VEGF-D, as well as N-terminal pro B-type natriuretic peptide (NT-proBNP), high sensitivity cardiac troponin-I (hs-cTnI), high sensitivity C reactive protein (hs-CRP), were measured at the time of discharge. PH was assessed by tricuspid regurgitation velocity (TRV) in echocardiography. Patients were followed-up over two years. Results Data on PH was obtained in 932 patients. Of these, 44 (4.7%) and 223 (23.9%) patients showed PH (TRV&amp;gt;3.4 m/s) and borderline PH (TRV&amp;gt;2.8 m/s), respectively. Patients with PH/borderline PH were significantly older and had lower body mass index. Prevalence of prior HF hospitalization, HF with preserved ejection fraction, atrial fibrillation, anemia, and chronic kidney disease were higher in patients with PH/borderline PH. Levels of NT-proBNP and VEGF-D, but not hs-cTnI or hs-CRP, were higher in patients with PH/borderline PH (Figure). Levels of NT-proBNP and VEGF-D had weak but significant correlation with TRV (NT-proBNP, R2=0.04, P&amp;lt;0.001; VEGF-D, R2=0.05, P&amp;lt;0.001). After adjustment for these factors, VEGF-D levels were significantly correlated with TRV (β, 3.29; SEM, 0.85, P&amp;lt;0.001). During the follow-up, 12 in PH, 34 in borderline PH, and 53 in no PH patients developed MACE. Unadjusted Hazard ratios [95% confidence intervals] for MACE compared to no PH were 2.44 [1.58-3.60] in PH, and 1.62 [1.26-2.05] in borderline PH. When we divided each PH group into two groups based on the median of VEGF-D levels of each group (no PH, 387 pg/ml; borderline PH, 479 pg/ml; PH, 549 pg/ml), patients with high VEGF-D showed significantly higher incidence of MACE in no PH (unadjusted hazard ratio, 1,70; 95% confidence intervals, 1.29-2.26), and tended to show high incidence of MACE in borderline PH group (unadjusted hazard ratio, 1,39; 95% confidence intervals, 0.93-2.09) and PH group (unadjusted hazard ratio, 1,83; 95% confidence intervals, 0.84-4.18). Conclusions VEGF-D levels were independently associated with PH in patients with HF, and might serve as a predictive biomarker for PH, as well as prognostic biomarker for MACE among patients with HF.

Objective To investigate the outcome of fetus with abnormal increase of pulmonary artery systolic pressure at second and third trimester by color Doppler ultrasound. Methods Ninety-five fetuses with a little or mild tricuspid regurgitation (control group) and 60 fetuses with moderate and severe tricuspid regurgitation (observation group) were included. The degree, velocity, and differential pressure of tricuspid regurgitation were measured and the variations of baseline information and the measured value of pulmonary systolic pressure between the two groups were compared. As for the follow-up on observation group, the pressure of fetus with high pulmonary systolic pressure (>20 mmHg) was repeatedly measured every 4 weeks until it return to normal. Results There were significant differences in terms of gestational weeks, velocity and pressure of tricuspid regurgitation, as well as pulmonary systolic pressure between the two groups (P<0.001). Pulmonary systolic pressure was positively correlated with gestational weeks, velocity and pressure of tricuspid regurgitation (r=0.442, 0.998, 0.999; all P<0.001), but had no correlations with the age of pregnant women (r=-0.001, P=0.674). The follow-up revealed that, in observation group, 47 cases (78.3%, systolic pressure <50 mmHg) presented with the decreased pulmonary systolic pressure, the disappeared or the slight appeared regurgitation before birth, meanwhile, 13(21.7%, systolic pressure ≥50 mmHg) exhibited severe tricuspid regurgitation and persistent pulmonary elevation, with the highest of more than 70 mmHg accompanying the varying degrees of right heart failure. Only one of 13 fetuses died due to persistent pulmonary hypertension and hypoxia (oxygen saturation <45%). The fetal pulmonary artery systolic pressure of the remaining 12 cases recovered from 5 to 105 days after birth, with normal heart function. Conclusions The majority of fetal pulmonary arterial hypertension complicated with obvious tricuspid regurgitation is reversible functional alteration, which can restore normality in most cases before or after birth. Key words: Echocardiography, Doppler; Artery systolic pressure; Second and third trimester fetus; Tricuspid value insufficiency

Jumping down the rabbit hole: unravelling the right ventricle in heart failure.

Echocardiography in Pulmonary Arterial Hypertension: An Essential Tool