What Is the Prognostic Significance of Pulmonary Hypertension in Heart Failure?

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

40-Year-Old Woman With Breathlessness and Fatigue

We hypothesized that pulmonary venous hypertension in heart failure (HF) leads to predominate remodeling of pulmonary veins and that the severity of venous remodeling is associated with the severity of pulmonary hypertension (PH) in HF. Patients with HF (n=108; 53 preserved and 55 reduced ejection fraction) with PH (HF-PH; pulmonary artery systolic pressure [PASP] ≥40 mm Hg) were compared to normal controls (n=12) and patients with primary pulmonary veno-occlusive disease (PVOD; n=17). In lung specimens from autopsy (control, HF-PH, and 7 PVOD) or surgery (10 PVOD), quantitative histomorphometry was performed in all analyzable arteries (n=4949), veins (n=7630), and small indeterminate vessels (IV; n=2168) to define percent medial thickness (arteries) and percent intimal thickness (%IT) (arteries, veins, and IV) relative to external diameter. The average arterial percent medial thickness (control, 6.9; HF-PH, 11.0; PVOD, 15.0), arterial %IT (control, 4.9; HF-PH, 14.9; PVOD, 31.1), venous %IT (control, 14.0; HF-PH, 24.9; PVOD, 43.9), and IV %IT (control, 10.6; HF-PH, 25.8; PVOD, 50.0) in HF-PH were higher than controls (P<0.0001 for all) but lower than PVOD (P≤0.005 for all). PASP (mm Hg) was lower in HF-PH (median, 59 [interquartile range, 50-70]) than in PVOD (median, 91 [interquartile range, 82-103]). PASP correlated with arterial percent medial thickness (r=0.41) and arterial %IT (r=0.35) but more strongly with venous %IT (r=0.49) and IV %IT (r=0.55) (P<0.0001 for all). Associations between PASP and venous or IV %IT remained significant after adjusting for arterial percent medial thickness and %IT and did not vary by HF type. In patients with right heart catheterization (30 HF-PH, 14 PVOD), similar associations between the transpulmonary gradient and pulmonary vascular remodeling existed, with numerically stronger associations for venous and IV %IT. Although the PASP was slightly higher in patients with HF-PH with right ventricular dysfunction, pulmonary vascular remodeling was not more severe. Pulmonary vascular remodeling severity was associated with reductions in the diffusing capacity of the lungs. In HF, PH is associated with global pulmonary vascular remodeling, but the severity of PH correlates most strongly with venous and small IV intimal thickening, similar to the pattern observed in PVOD. These findings expand our understanding of the pathobiology of PH in HF.

Background Heart failure (HF) with preserved ejection fraction (HFpEF) can develop pulmonary hypertension (PH), which can result from pre-capillary PH as well as post-capillary PH. However, the prevalence and clinical significance of pre-capillary component of PH in HFpEF remain unknown. Purpose We aimed to investigate prevalence, clinical features, and prognostic impact of pre-capillary and/or post capillary PH associated with HFpEF. Methods From the PURSUIT-HFpEF (Prospective Multicenter Observational Study of Patients with Heart Failure with Preserved Ejection Fraction) registry, 204 patients (men: 46%, age: 79±9 years) who were hospitalized with HF and underwent right heart catheterization were divided into 4 groups according to the PH guidelines: non-PH, isolated post-capillary PH (Ipc-PH), pre-capillary PH, and combined pre- and post-capillary PH (Cpc-PH). Patients who had been diagnosed with idiopathic pulmonary arterial hypertension were excluded from the analysis. Results The prevalence of PH was 31% (Ipc-PH: 22%, pre-capillary PH: 3%, Cpc-PH: 6%). The prevalence of subcategories of PH was significantly different depending on mean right atrial pressure (RAP) (figure). Echocardiography at discharge showed no significant differences in RV diameter or TAPSE, but smaller LV diameter and higher E/e' in pre-capillary PH and Cpc-PH, which resulted in a higher operant diastolic elastance (Ed). Composite endpoint of all-cause mortality and HF hospitalization at 1 year occurred 13% in non-PH, 25% in Ipc-PH, 49% in pre-capillary PH, and 63% in Cpc-PH, respectively (p=0.001 by log-rank test). Conclusions Distinct prevalence of PH was observed in the groups with different RAP levels. Pre-capillary component of PH was associated with impaired LV diastolic function and worse outcomes in HFpEF. Figure 1 Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Roche Diagnostics K.K.; Fuji Film Toyama Chemical Co. Ltd

steps that will be taken if the initial laryngoscopy or other technique fails so there is a rational plan in place.Implementing this approach should dramatically decrease the incidence of lifethreatening complications that commonly occur during the endotracheal intubation of critically ill patients.Expertise in the use of video laryngoscopy, intubating supraglottic airway devices, and awake fiberoptic intubation may facilitate difficult airway management as well (16)(17)(18).What is next?As we await external validation of this approach, the question we ask is how to reduce complications and mortality during intubations in the ICU.Preexisting hypoxia, hypotension, myocardial ischemia, and cardiopulmonary resuscitation may make it unlikely that severe complications can be completely eliminated, but we need to strive to minimize them.There is a paucity of research on this issue.The MACOCHA score (maybe as part of a structured checklist used with every patient undergoing endotracheal intubation) will provide a standardized evaluation to facilitate conducting the much-needed intervention trials by objectively identifying the patients at low risk for difficult endotracheal intubation.

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

Introduction: The proposed revision of hemodynamic definition of pulmonary hypertension (PH) adopts a lower threshold of mean pulmonary artery pressure (mPAP) &gt; 20 mmHg. In addition, pulmonary vascular resistance (PVR) ≥ 3 Wood units (WU) is included as the definition of pre-capillary component of PH. Heart failure (HF) with preserved ejection fraction (HFpEF) can develop pre-capillary PH as well as post-capillary PH. We aimed to investigate the impact of the proposed definition of PH on clinical diagnosis of PH associated with HFpEF. Methods: From the PURSUIT-HFpEF (Prospective Multicenter Observational Study of Patients with Heart Failure with Preserved Ejection Fraction) registry, 225 patients who were hospitalized with HF and underwent right heart catheterization were categorized according to the current guidelines and the proposed definition of PH: non-PH, isolated post-capillary PH (Ipc-PH), pre-capillary PH, and combined pre- and post-capillary PH (Cpc-PH). In the proposed definition, patients with mPAP &gt; 20 mmHg, PVR &lt; 3 WU, and pulmonary artery wedge pressure ≤ 15 mmHg do not meet criteria for any of the above categories and are categorized as “unclassified PH”. Results: Prevalence of PH was significantly increased in the proposed definition compared to that in the current definition (51% vs 29%, p&lt;0.0001), with a doubled frequency of pre-capillary PH (Fig A). Furthermore, 24 patients (11%) were diagnosed as unclassified PH and accounted for 22% of those with PH by the proposed definition. Among the PH categories in the proposed definition, Cpc-PH category was significantly relevant for worse prognosis at 1 year after discharge in patients with HFpEF (p=0.03 vs non-PH by log-rank test with Bonferroni's correction) (Fig 2). Conclusions: The new definition of PH resulted in a remarkable increase of prevalence of PH in HFpEF with a quite a few patients with unclassified PH and doubled frequency of pre-capillary PH.

Case Presentation: A 71-year-old man with coronary artery disease, left ventricular (LV) systolic dysfunction (ejection fraction, 30%), and recent admission for heart failure presented with acute dyspnea and hypoxemia. A pro-brain–type natriuretic peptide level was elevated at 2450 pg/mL (normal <350 pg/mL). Chest x-ray demonstrated cardiomegaly and small bilateral pleural effusions. After an hour of diuresis, the patient developed systemic arterial hypotension and worsened hypoxemia, prompting cardiology consultation. Based on the absence of rales on physical examination and lack of pulmonary edema on chest x-ray, an alternative diagnosis of pulmonary embolism (PE) was suggested, and contrast-enhanced chest tomography (CT) was obtained. Chest CT demonstrated large bilateral proximal PE. Venous thromboembolism (VTE), which encompasses deep vein thrombosis and PE, is an increasingly common and challenging complication of heart failure. The relative risk of PE is at least double that of patients without heart failure and increases as LV systolic function declines.1 PE patients with heart failure have a higher overall mortality rate than those without heart failure (17% versus 10%).2 In addition, PE is an independent predictor of death or rehospitalization among heart failure patients.3 ### Risk Factors Heart failure patients often have a high medical acuity and multiple risk factors that amplify the risk of VTE.4 The increased risk of VTE observed with heart failure itself has been attributed to reduced flow caused by low cardiac output and abnormalities of hemostasis, platelet function, and endothelial function. Central venous catheters and leads from implantable cardiac defibrillators and pacemakers are common among heart failure patients and have been shown to increase the risk of upper-extremity deep vein thrombosis. Heart failure patients tend to be older, and VTE in the elderly is problematic.5 ### Hemodynamics Acute PE increases pulmonary vascular resistance and right ventricular (RV) afterload through direct physical obstruction, hypoxemia, and pulmonary …

should decrease pulmonary artery pressure (PAP) and pulmonary vascular resistance (PVR), without affecting systemic arterial pressure (SAP), and potentially improve oxygenation by redistributing pulmonary blood flow to ventilated areas of lung. INO (INO Therapeutics Inc., Clinton NJ) possesses these properties and has gained approval from the Food and Drug Administration (FDA) for the care of neonates with acute lung injury and pulmonary hypertension (PH), and widespread clinical acceptance (but not FDA approval) for adults with PH with or without lung injury. Delivered as a gas, INO is preferentially distributed to the ventilated areas of the lung, where it produces relaxation of pulmonary vascular smooth muscle via activation of guanylate cyclase and the conversion of guanosine-5-triphosphate to cyclic guanosine monophosphate. 1 Absorbed INO is rapidly inactivated by hemoglobin, thereby preventing systemic effects and confining its vasodilator properties to the pulmonary circulation. 1 The search for inhaled selective pulmonary vasodilators was an active area of research, particularly in Europe and Australia, before the widespread publicity and testing of INO in the early 1990s. However, research on this subject appears to have declined inversely with the growing acceptance and use of INO. Until FDA approval had been granted, INO had been supplied free of charge in the United States on an investigational-drug basis. However, after FDA approval, the cost of treatment with INO became very expensive. This prompted a search at our institution for alternative agents to INO. The purpose of this article is to review the published experience concerning alternative inhaled vasodilators and, when possible, compare their reported efficacy with that of INO.

A Possible Role for Systemic Hypoxia in the Reactive Component of Pulmonary Hypertension in Heart Failure

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.

Background/Introduction Pulmonary hypertension (PH) due to left heart disease worsens the clinical status and the prognosis of heart failure (HF) patients [1]. It is important to diagnose it, as combined post- and pre-capillary PH (CpcPH) with severe pre-capillary component requires an individualized approach to the treatment (I C class recommendation) [1]. Purpose The study aimed to assess the prevalence of PH due to left heart disease and its types: isolated postcapillary PH (IpcPH) and CpcPH in patients undergoing right heart catheterization (RHC). Methods The study sample consists of 564 patients with HF with reduced ejection fraction (HFrEF) undergoing elective RHC. PH was diagnosed according to the ESC 2022 guidelines: mean pulmonary artery pressure (mPAP) &amp;gt;=20 mmHg [1]. IpcPH was diagnosed when pulmonary arterial wedge pressure (PAWP) was &amp;gt; 15 mmHg and pulmonary vascular resistance (PVR) &amp;lt;=2 Wood units; CpcPH was diagnosed when PAWP was &amp;gt; 15 mmHg and a PVR &amp;gt; 2 Wood units [1]. In the case of PH and PAWP below 15 mmHg and PVR ≤2 Wood units, unclassified PH was diagnosed [1]. Results The study group included 15.4% women, a mean age was 51.9 ± 11.3 years, and a mean left ventricular ejection fraction (LVEF) was 21.0 ± 7.0%. Considering the NYHA class, 29.6% were in the I or II class, 55.9% in the III class, and 14.5% in the IV class. More than two-thirds of the patients had PH - 68.4%. Patients with CpcPH constituted 45.9% of the enrolled cohort, and 21.4% had IpcPH. Unclassified PH was diagnosed in 1.1% of patients. CpcPH with severe pre-capillary component (PVR&amp;gt;5 Wood units) was recognized in 9.9% of the group. Conclusion PH is a prevalent comorbidity in HFrEF. The majority of patients with PH had combined post- and pre-capillary PH. CpcPH with severe pre-capillary component was relatively common with an incidence of 1 for 10 HFrEF patients – according to ESC guidelines, an individualized approach to treatment is recommended in this group (I C class recommendation). It underlines the importance of RHC as the gold standard for PH diagnosing in managing HFrEF patients.

Kussmaul's Sign in Pulmonary Hypertension Corresponds With Severe Pulmonary Vascular Pathology Rather Than Right Ventricular Diastolic Dysfunction.

Systemic right ventricular (RV) failure may progress necessitating referral for orthotropic heart transplantation (OHT). Pulmonary hypertension (PH) frequently coexists in adult congenital heart disease and can complicate the assessment for OHT. Single-center case series of six patients (median age 34.9years [IQR, 31.9-42.4]) with systemic RV physiology with PH referred for OHT evaluation from 2008 to 2017. One-third (n=6) of 18 patients with systemic RV physiology referred for OHT evaluation had pulmonary arterial hypertension (PAH) defined as mean pulmonary artery pressure (mPAP)>25mm Hg and pulmonary vascular resistance (PVR)>3 Wood Units. Two of the six patients were considered OHT-ineligible due to PH and comorbidities. Of the remaining four, two had pre-capillary PH and underwent heart-lung transplant (HLTx). The other two demonstrated reversibility of PVR with vasodilator testing and underwent OHT alone, one of whom died post-transplant from PH crisis. Pulmonary arterial hypertension is common in systemic RV patients referred for OHT. Systemic RV dysfunction places these patients at risk for post-capillary PH but pre-capillary PH can exist. Despite management with selective pulmonary vasodilators and afterload reduction, criteria for listing patients for HLTx vs OHT are not known and need further elucidation.

Pulmonary hypertension secondary to chronic pulmonary venous hypertension in patients with congestive heart failure may become relatively fixed over time due to structural changes in the pulmonary vasculature [1]. An acute decrease in left atrial pressure (Pia) after cardiac transplantation in these patients may therefore be associated with high pulmonary arterial pressures (Ppa), persistent at levels known to be poorly tolerated by a normal right ventricle [2]. Accordingly, high preoperative pulmonary vascular resistance (PVR) has been found associated with a significant risk of fatal right ventricular (RV) failure after orthotopic cardiac transplantation [3–6]. In order to limit the frequency of this complication, patients with a PVR of more than 480 to 640 dynes.s.cm5 (6 to 8 Wood units) are generally excluded from the potential benefits of the surgical procedure [3–6]. Most recently, testing for a pharmacological reversal of elevated PVR at preoperative evaluation has been reported [6,7], and the results of these manipulations contended to be helpful for the prediction of postoperative pulmonary hemodynamics [6].