Passive Pulmonary Hypertension Research Articles

Transition from post-capillary pulmonary hypertension to combined pre- and post-capillary pulmonary hypertension in swine: a key role for endothelin.

Key points Passive, isolated post‐capillary pulmonary hypertension (PH) secondary to left heart disease may progress to combined pre‐ and post‐capillary or ‘active’ PHThis ‘activation’ of post‐capillary PH significantly increases morbidity and mortality, and is still incompletely understood.In this study, pulmonary vein banding gradually produced post‐capillary PH with structural and functional microvascular remodelling in swine.Ten weeks after banding, the pulmonary endothelin pathway was upregulated, likely contributing to pre‐capillary aspects in the initially isolated post‐capillary PH.Inhibition of the endothelin pathway could potentially stop the progression of early stage post‐capillary PH. Passive, isolated post‐capillary pulmonary hypertension (IpcPH) secondary to left heart disease may progress to combined pre‐ and post‐capillary or ‘active’ PH (CpcPH) characterized by chronic pulmonary vascular constriction and remodelling. The mechanisms underlying this ‘activation’ of passive pulmonary hypertension (PH) remain incompletely understood. Here we investigated the role of the vasoconstrictor endothelin‐1 (ET) in the progression from IpcPH to CpcPH in a swine model for post‐capillary PH. Swine underwent pulmonary vein banding (PVB; n = 7) or sham‐surgery (Sham; n = 6) and were chronically instrumented 4 weeks later. Haemodynamics were assessed for 8 weeks, at rest and during exercise, before and after administration of the ET receptor antagonist tezosentan. After sacrifice, the pulmonary vasculature was investigated by histology, RT‐qPCR and myograph experiments. Pulmonary arterial pressure and resistance increased significantly over time. mRNA expression of prepro‐endothelin‐1 and endothelin converting enzyme‐1 in the lung was increased, while ETA expression was unchanged and ETB expression was downregulated. This was associated with increased plasma ET levels from week 10 onward and a more pronounced vasodilatation to in vivo administration of tezosentan at rest and during exercise. Myograph experiments showed decreased endothelium‐dependent vasodilatation to Substance P and increased vasoconstriction to KCl in PVB swine consistent with increased muscularization observed with histology. Moreover, maximal vasoconstriction to ET was increased whereas ET sensitivity was decreased. In conclusion, PVB swine gradually developed PH with structural and functional vascular remodelling. From week 10 onward, the pulmonary ET pathway was upregulated, likely contributing to pre‐capillary activation of the initially isolated post‐capillary PH. Inhibition of the ET pathway could thus potentially provide a pharmacotherapeutic target for early stage post‐capillary PH.

French National observatory on pulmonary hypertension measured by right heart catheterism in heart failure. First report of PHHF observatory. A study from GICC

The physiopathology, prevalence, characteristics and prognostic impact of the different type of pulmonary hypertension (PH) in CHF are unknown. The gold standard to measure PH is the right heart catheterism. Echocardiography allows just an estimate of pulmonary artery pressure. The main objective of PHHF is to compare the mortality between CHF patients with reactive and passive PH in CHF determined by right heart catheterization. The secondary objectives are to study the prevalence of the two types of PH, to identify their clinical, biological, cardiac and pulmonary determinants. PHHF is a prospective, multicenter, observational, open-lapel observatory of CHF patients. The target population constituted of CHF patients necessitating right heart catheterization for their medical care. Five hundred patients with PH and HF and 120 HF without PH will be included before the 31st of December 2017. The primary endpoint will be death and/or urgent heart transplant and/or urgent ventricular assist device implant. The secondary endpoints will be hospitalizations for acute heart failure. The inclusion criteria are: (1) patients with CHF (LV systolic dysfunction, HFPEF, cardiac valvular disease) having a right heart catheterism; (2) written informed consent; (3) age ≥ 18 years; (4) optimal medical CHF treatment. The baseline characteristics of the patients (March 2017) are showed here. Five hundred and twenty-one patients are included of who 414 are in PH groups. Sixty-one percent are men. The mean (sd) age is 62 ± 13%. Fifty percent have LV systolic failure, 43% preserved LV ejection fraction and 6.5% valvular heart failure. Thirty-eight percent have a ischemic cardiopathy. Forty-three percent are in NYHA class II and 46% in III. The average of the mean pulmonary artery pressure (mPAP) was 35 ± 12 mmHg. The mean PCWP was 22 ± 7 mmHg. Pulmonary artery pressure is severe and frequent in the three type of HF. More analysis will be provided at the end of the study (December 2017) for the JESFC Congress.

Vasopressors induce passive pulmonary hypertension by blood redistribution from systemic to pulmonary circulation.

Vasopressors are widely used in resuscitation, ventricular failure, and sepsis, and often induce pulmonary hypertension with undefined mechanisms. We hypothesize that vasopressor-induced pulmonary hypertension is caused by increased pulmonary blood volume and tested this hypothesis in dogs under general anesthesia. In normal hearts (model 1), phenylephrine (2.5μg/kg/min) transiently increased right but decreased left cardiac output, associated with increased pulmonary blood volume (63%±11.8, P=0.007) and pressures in the left atrium, pulmonary capillary, and pulmonary artery. However, the trans-pulmonary gradient and pulmonary vascular resistance remained stable. These changes were absent after decreasing blood volume or during right cardiac dysfunction to reduce pulmonary blood volume (model 2). During double-ventricle bypass (model 3), phenylephrine (1, 2.5 and 10μg/kg/min) only slightly induced pulmonary vasoconstriction. Vasopressin (1U and 2U) dose-dependently increased pulmonary artery pressure (52±8.4 and 71±10.3%), but did not cause pulmonary vasoconstriction in normally beating hearts (model 1). Pulmonary artery and left atrial pressures increased during left ventricle dysfunction (model 4), and further increased after phenylephrine injection by 31±5.6 and 43±7.5%, respectively. In conclusion, vasopressors increased blood volume in the lung with minimal pulmonary vasoconstriction. Thus, this pulmonary hypertension is similar to the hemodynamic pattern observed in left heart diseases and is passive, due to redistribution of blood from systemic to pulmonary circulation. Understanding the underlying mechanisms may improve clinical management of patients who are taking vasopressors, especially those with coexisting heart disease.

Prognostic significance of reactive pulmonary hypertension in patients with chronic heart failure listed for elective heart transplantation.

Pulmonary hypertension (PH) is recognised in about 60% of patients referred for heart transplantation (HTx), and it influences the patient's prognosis. To assess the prognostic value of reactive PH in patients listed for elective HTx. A total of 522 patients were enlisted from the Polish National Registry (POLKARD), listed for HTx, in whom complete haemodynamic data were reported. The endpoint was all-cause death before HTx. Heart transplantation, elective or urgent, was considered as an end of the follow-up (mean follow-up 1.47 ± 1.26 years). Patients were divided into three subgroups: no PH, passive PH, reactive PH taking into account mean pulmonary artery pressure (PAP) of 25 mm Hg, pulmonary capillary wedge pressure (PCWP) 15 mm Hg, and pulmonary vascular resistance (PVR) 3.0 Wood units. Haemodynamic, clinical, echocardiographic, and biochemical assessments (including NT-proBNP, hs-CRP) were performed. The Heart Failure Survival Score (HFSS) was calculated. Estimated death rate was comparable between patients with no PH, passive PH, and reactive PH, despite the fact that the patients with reactive PH had the worst pulmonary haemodynamic scores (mean PAP 38.4 ± 7.8, PCWP 27 ± 7.4 mm Hg and PVR 4.8 ± 1.7 Wood units). In patients with reactive PH, in multifactor Cox analysis only the serum Na level influenced survival. According to the Kaplan-Meier method, patients with reactive PH, with mean PAP ≥ 41.4 mm Hg had the worst prognosis, estimated survival was: one year - 83%, two years - 65%. Reactive PH is common among patients with chronic HF listed to HTx (28%). It has no further influence on short-term prognosis as compared with patients with no PH and passive PH. Serum Na concentration and mean PAP ≥ 41.4 mm Hg influence the prognosis of patients with reactive PH.

Abstract 16622: Plasma Metabolomic Profiles Differentiate Hemodynamic Subtypes of Pulmonary Hypertension

Introduction: Pulmonary hypertension (PH) is defined as a mean pulmonary artery pressures (mPAP) ≥ 25 mmHg. Within PH, there are distinct hemodynamic subgroups based on the presence of hypertension in the precapillary or postcapillary beds of the pulmonary vasculature: pulmonary arterial hypertension (PAH - precapillary PH), passive PH secondary to left heart disease (postcapillary PH) and mixed PH with both precapillary and postcapillary components. Hypothesis: As metabolic abnormalities have been noted in PAH and heart failure, we hypothesized that different hemodynamic subtypes of PH would be associated with distinct plasma metabolomic profiles. Methods: The CATHGEN biorepository consists of biological samples collected on over 9000 individuals undergoing cardiac catheterization at Duke University Medical Center. Of those subjects who had targeted metabolomics studies performed, 282 were identified with mPAP ≥ 25 mmHg. Of these 282 subjects, 133 met criteria for passive PH (PCWP > 15 mmHg, PVR 15 mmHg, PVR ≥ 3 WU) and 67 for PAH (PCWP ≤ 15 mmHg). Tandem flow injection mass spectrometry (MS) with isotope-labeled internal standards were used for targeted quantitative measurements of ~ 60 metabolites (including free fatty acids, acylcarnitines, amino acids, lipids and ketones). Multivariable logistic regression adjusted for age, presence of coronary artery disease, sex, race, diabetes and ejection fraction were used to determine differences in metabolites between the pulmonary HTN subgroups and with a matched cohort of CATHGEN subjects free from PH (N=280, matched on 282). Results: All PH subgroups demonstrated significantly different levels of long chain acylcarnitines from controls (p < 0.01). Compared to controls, subjects with mixed PH also had significant differences in long chain dicarboxyl acylcarnitines (p < 0.01) and C3-C5s (p < 0.028), passive PH had significant differences in ketone related metabolites (p < 0.04), and PAH had significant differences in branched chain amino acids (p < 0.01). Conclusions: Passive, mixed and PAH subtypes of PH were associated with distinct plasma metabolomics profiles compared to matched controls. These finding demonstrate that specific metabolic changess develop in the distinct subtypes of PH.

Abstract 18874: Prognostic Importance of Pulmonary Hypertension Etiology by Invasive Hemodynamics in Patients With Severe Aortic Stenosis

Introduction: Pulmonary hypertension (PH) may arise from both pre-capillary and post-capillary etiologies which can be evaluated and quantified by invasive hemodynamics (CATH). The impact of PH etiology on all-cause mortality of patients with severe aortic stenosis (AS) is unknown. Hypothesis: CATH classification of PH etiology allows for identification of severe AS patients with combined pre and post-capillary PH that would have the highest mortality risk. Methods: Retrospective data collection of patients with severe AS (AV area index ≤ 0.6 cm2/m2) and CATH with invasive hemodynamics was performed. Patients were classified as having: a) no PH (PAmean<25mmHg), b) pre-capillary PH (PAH, PAmean≥25mmHg and pulmonary capillary wedge pressure, PCWP15mmHg). Multivariate Cox-proportional hazard model was used for risk-adjustment comparisons. Results: A total of 187 patients were identified with mean age of 77 ± 10 years, 62% male and 38% diabetic. After a median follow-up of 18 months (IQR: 5-27 months), there were 66 deaths (35%). According to the etiology, 54 patients (29%) had no PH, 18 (10%) had PAH, 78 (42%) had passive PH, and 37 (20%) had combined PH. After adjustments for AVR (HR=0.14, 95% CI 0.05-0.35,p<0.01), age, gender, BMI, diabetes, and NYHA class, presence of combined PH by CATH was independently associated with increased risk (HR vs. no PH=2.49, 95% CI 1.09- 5.73, P=0.03). (Figure 1) Conclusion: Post-capillary PH is very common in severe AS (62%). Ascertainment of PH etiology by CATH is important as combined pre-post capillary PH is associated with increased short-term mortality despite adjustments for AVR and other comorbidities. Whether this risk can be decreased by further interventions needs to be investigated in future studies.

0337 : Echocardiographic findings in passive and reactive postcapillary pulmonary hypertension

Left heart diseases are the most common cause of pulmonary hypertension (PH). The reactive form of PH confers a worse prognosis than the passive one. Therapeutic intervention are going on investigating vasodilation drugs. The aim of this study was to seek for echocardiographic differences between passive and reactive postcapillary pulmonary hypertension in patients with heart failure and preserved ejection fraction. This study enrolled 58 patients who were assigned both to pulmonary artery catheterization and standard echocardiographic examination. Patients were classified into 2 groups: reactive PH (mean pulmonary artery pressure >25mmHg, pulmonary capillary wedge pressure >15 mmHg, and transpulmonary gradient >12 mmHg) and passive PH (mean pulmonary artery pressure >25mmHg, pulmonary capillary wedge pressure >15 mmHg, and transpulmonary gradient < 12 mmHg). Despite similar wedge pressure (p = 0.67), patients with reactive PH showed significantly higher systolic pulmonary artery pressure (p < 0.05) and pulmonary arterial resistance (p < 0.05). There was a trend of correlation with a better contractility measured by the lateral tricuspid annulus motion in tissue Doppler imaging (10,2±2,1 vs. 8,3±1,9m/s, p = 0,094) and lower values on the right ventricle long axis (73,8±12,4 vs. 80,1±23,5mm p = 0,05) in patients with reactive PH compared with passive PH. Despite higher pressure and resistance, patients with reactive PH showed better right ventricular function and less remodeling.

Right ventricular function quantified by two-dimensional speckle tracking imaging in patients with left heart disease related pulmonary hypertension

Objective To quantify the right ventricular (RV) function in patients with left heart disease (LHD) related pulmonary hypertension (PH) by two-dimensional speckle tracking imaging (2D-STI), and explore its potential value in diagnosis of reactive PH. Methods Forty healthy volunteers and 65 patients with LHD related PH were enrolled. PH patients were further divided into two subgroups according to pulmonary vascular resistance(PVR): passive PH group and reactive PH group. A complete 2D-STI derived longitudinal strain of RV free wall was performed, and the basal, middle, apical longitudinal peak systolic strain (LS) and RV free wall global LS (RVLSbas, RVLSmid, RVLSapi and RVLSfw) were measured. Results Compared to control group, RVLSbas and RVLSfw in reactive PH group decreased significantly (all P 0.05). No significant differences in etiology and left ventricular ejection fraction (LVEF) were observed between PH subgroups (all P>0.05). The area under the ROC curve of RVLSbas in predicting reactive PH was 0.93, the cut-off value was -21.86, and the sensitivity and specificity were 83% and 89%, respectively. The area under the ROC curve of RVLSfw was 0.79, the cut-off value was -13.84, and the sensitivity and specificity were 59% and 89%, respectively. Conclusions 2D-STI can realize quantitative assessment of RV function in patients with LHD related PH. RVLSbas and RVLSfw may have important clinical value in diagnosing patients with reactive PH, and differential diagnosis value between patients with passive PH and patients with reactive PH. Key words: Echocardiography; Ventricular function, right; Hypertension, pulmonary; Two-dimensional speckle tracking imaging

Clinical evaluation and management of pulmonary hypertension in the adult with congenital heart disease.

Pulmonary hypertension (PH) refers to elevated pulmonary artery (PA) pressure (PAP), defined as mean PAP≥25 mm Hg. PH is not synonymous with pulmonary arterial hypertension (PAH), which specifies resistive PH characterized by elevated pulmonary vascular resistance (PVR) and normal pulmonary venous pressure. Approximately 5% to 10% of adults with congenital heart disease (CHD) have PH, and this subset of CHD patients is at higher risk of hospitalization and death.1–3 Understanding the epidemiology of PH associated with CHD (PH-CHD) is not straightforward, however, because definitions of PH-CHD and diagnostic techniques vary. Appropriate diagnosis and the management of PH-CHD rest on identifying the cause of elevated PAP: high pulmonary venous pressure, high pulmonary vascular resistance, high pulmonary flow, or some combination of these factors, which are referred to throughout this review as passive, resistive, hyperkinetic, and polygenic PH, respectively (Table 1). View this table: Table 1. Modified Wood Classification of Pulmonary Hypertension Prognosis in PH-CHD depends on the underlying cause, pulmonary vascular pathophysiology, and the interaction between the right heart and pulmonary circulation. Adult CHD is heterogeneous, with myriad permutations of underlying defects, previous interventions, and associated comorbidities. Although comprehensive understanding of clinical context is a prerequisite, identifying the optimal therapy for a patient with PH-CHD depends more heavily on an understanding of pathophysiology than it does on the underlying diagnosis. Therefore, the goal of this review is to frame an understanding of PH-CHD in terms of fundamental cardiopulmonary hemodynamic pathophysiology and to emphasize the clinical assessment and management of situations commonly encountered by adult cardiologists caring for patients with PH-CHD. Classification schemes in PH represent clinical perspectives of underlying pathophysiology and tend to parallel fundamental hemodynamic relationships of the pulmonary circulation. PVR is defined: ![Graphic][1] . Pulmonary artery occlusion pressure (PAOP) approximates pulmonary venous pressure and Qp is pulmonary blood flow. Rearranging this … [1]: /embed/inline-graphic-1.gif

The Diastolic Pulmonary Gradient Does Not Predict Survival in Patients With Pulmonary Hypertension Due to Left Heart Disease

ObjectivesThis study sought to evaluate if diastolic pulmonary gradient (DPG) can predict survival in patients with pulmonary hypertension due to left heart disease (PH-LHD). BackgroundPatients with combined post- and pre-capillary PH-LHD have worse prognosis than those with passive pulmonary hypertension. The transpulmonary gradient (TPG) and pulmonary vascular resistance (PVR) have commonly been used to identify high-risk patients. However, these parameters have significant shortcomings and do not always correlate with pulmonary vasculature remodeling. Recently, it has been suggested that DPG may be better a marker, yet its prognostic ability in patients with cardiomyopathy has not been fully assessed. MethodsA retrospective cohort of 1,236 patients evaluated for unexplained cardiomyopathy at Johns Hopkins Hospital was studied. All patients underwent right heart catheterization and were followed until death, cardiac transplantation, or the end of the study period (mean time 4.4 years). The relationships between DPG, TPG, or PVR and survival in subjects with PH-LHD (n = 469) were evaluated with Cox proportional hazards regression and Kaplan-Meier analyses. ResultsDPG was not significantly associated with mortality (hazard ratio [HR]: 1.02, p = 0.10) in PH-LHD whereas elevated TPG and PVR predicted death (HR: 1.02, p = 0.046; and HR: 1.11, p = 0.002, respectively). Similarly, DPG did not differentiate survivors from non-survivors at any selected cut points including a DPG of 7 mm Hg. ConclusionsIn this retrospective study of patients with cardiomyopathy and PH-LHD, an elevated DPG was not associated with worse survival.

Pulmonary arterial capacitance in patients with heart failure and reactive pulmonary hypertension.

Reactive pulmonary hypertension (PH) is a severe form of PH secondary to left-sided heart failure (HF). Given the structural and functional abnormalities in the pulmonary vasculature that occur in reactive PH, we hypothesized that pulmonary artery capacitance (PAC) may be profoundly affected, with implications for clinical outcome. We studied 393 HF patients of whom 124 (32%) were classified as having passive PH and 140 (36%) as having reactive PH, and 91 patients with pulmonary arterial hypertension (PAH). Mean PAC was highest in patients without PH (4.5 ± 2.1 mL/mmHg), followed by the passive PH group (2.8 ± 1.4 mL/mmHg) and was lowest in those with reactive PH (1.8 ± 0.7 mL/mmHg) (P = 0.0001). PAC and pulmonary vascular resistance (PVR) fitted well to a hyperbolic inverse relationship (PAC = 0.25/PVR, R(2) = 0.70), with reactive PH patients dispersed almost predominantly on the flat part of the curve where a reduction in PVR is associated with a small improvement in PAC. Elevated PCWP was associated with a significant lowering of PAC for any PVR (P = 0.036). During a median follow-up of 31 months, both reactive PH [hazard ratio (HR) 2.59, 95% confidence interval (CI) 1.14-4.46, P = 0.02] and reduced PAC (HR 0.72 per 1 mL/mmHg increase, 95% CI 0.59-0.88, P = 0.001) were independent predictors of mortality. The development of reactive PH is associated with a marked reduction in PAC. PAC is a strong independent haemodynamic marker of mortality in HF and may contribute to the increased mortality associated with reactive PH.

Pathophysiology and potential treatments of pulmonary hypertension due to systolic left heart failure

Pulmonary hypertension (PH) due to left heart failure is becoming increasingly prevalent and is associated with poor outcome. The precise pathophysiological mechanisms behind PH due to left heart failure are, however, still unclear. In its early course, PH is caused by increased left ventricular filling pressures, without pulmonary vessel abnormalities. Conventional treatment for heart failure may partly reverse such passive PH by optimizing left ventricular function. However, if increased pulmonary pressures persist, endothelial damage, excessive vasoconstriction and structural changes in the pulmonary vasculature may occur. There is, at present, no recommended medical treatment for this active component of PH due to left heart failure. However, as the vascular changes in PH due to left heart failure may be similar to those in pulmonary arterial hypertension (PAH), a selected group of these patients may benefit from PAH treatment targeting the endothelin, nitric oxide or prostacyclin pathways. Such potent pulmonary vasodilators could, however, be detrimental in patients with left heart failure without pulmonary vascular pathology, as selective pulmonary vasodilatation may lead to further congestion in the pulmonary circuit, resulting in pulmonary oedema. The use of PAH therapies is therefore currently not recommended and would require the selection of suitable patients based on the underlying causes of the disease and careful monitoring of their progress. The present review focuses on the following: (i) the pathophysiology behind PH resulting from systolic left heart failure, and (ii) the current evidence for medical treatment of this condition, especially the role of PAH-targeted therapies in systolic left heart failure.

Prognostic value of the pre-transplant diastolic pulmonary artery pressure–to–pulmonary capillary wedge pressure gradient in cardiac transplant recipients with pulmonary hypertension

Although the transpulmonary gradient (TPG) and pulmonary vascular resistance (PVR) are commonly used to differentiate heart failure patients with pulmonary vascular disease from those with passive pulmonary hypertension (PH), elevations in TPG and PVR may not always reflect pre-capillary PH. Recently, it has been suggested an elevated diastolic pulmonary artery pressure-to-pulmonary capillary wedge pressure gradient (DPG) may be a better indicator of pulmonary vascular remodeling, and therefore, may be of added prognostic value in patients with PH being considered for cardiac transplantation. Using the United Network for Organ Sharing (UNOS) database, we retrospectively reviewed all primary adult (age > 17 years) orthotropic heart transplant recipients between 1998 and 2011. All patients with available pre-transplant hemodynamic data and PH (mean pulmonary artery pressure ≥ 25 mm Hg) were included (n = 16,811). We assessed the prognostic value of DPG on post-transplant survival in patients with PH and an elevated TPG and PVR. In patients with PH and a TPG > 12 mm Hg (n = 5,827), there was no difference in survival at up to 5 years post-transplant between high DPG (defined as ≥3, ≥5, ≥7, or ≥10 mm Hg) and low DPG (<3, <5, <7, or <10 mm Hg) groups. Similarly, there was no difference in survival between high and low DPG groups in those with a PVR > 3 Wood units (n = 6,270). Defining an elevated TPG as > 15 mm Hg (n = 3,065) or an elevated PVR > 5 (n = 1,783) yielded similar results. This large analysis investigating the prognostic value of DPG found an elevated DPG had no effect on post-transplant survival in patients with PH and an elevated TPG and PVR.

Pressure reflection in the pulmonary circulation by echocardiography in patients with left heart disease indicates reactive pulmonary hypertension

The two hemodynamic profiles in left heart disease (LHD) with pulmonary hypertension (PH), passive PH with increased pulmonary venous pressure and reactive PH with increased pulmonary vascular resistance (PVR > 3 Wood units, WU), are difficult to distinguish non-invasively. We hypothesized that echocardiographic signs of pressure reflection (PR) in the pulmonary circulation can be used to diagnose reactive PH. The study comprised 122 patients divided into three groups: patients without PH (No PH, n = 61), patients with LHD, PH and normal PVR (passive PH, n = 29) and patients with LHD, PH and increased PVR (reactive PH, n = 32). Echocardiography and right heart catheterization were performed within 24 h. Three parameters were selected related to PR [the acceleration of flow in the right ventricular outflow tract (RVOT), the interval and the augmentation of pressure between peak RVOT flow and peak RV pressure]. Cutoff values aiming at ruling in (high positive likelihood ratio, PLR) and ruling out (low negative likelihood ratio, NLR) increased PVR were determined using receiver operator characteristic (ROC) curves. The proportions of the patients with PH and PVR > 3 WU were 50% and 29%. Twenty-one percent had both increased pulmonary capillary wedge pressure and PVR. The area under the ROC curve for the PR parameters was 0.82-0.89. The PLR with ruling in cutoff values ranged from 4.7 to 9.4. The NLR with ruling out cutoff values ranged from 0.20 to 0.12. Echocardiographic assessment of PR in patients with LHD can be used to identify or exclude reactive PH.

Pressure reflection in the pulmonary circulation by echocardiography in patients with left heart disease indicates reactive pulmonary hypertension

Background and aims: The two hemodynamic profiles in Left Heart Disease (LHD) with Pulmonary Hypertension (PH), passive PH with increased pulmonary venous pressure and reactive PH with increased Pulmonary Vascular Resistance (PVR), cannot be distinguished non-invasively. We hypothesized that echocardiographic signs of Pressure Reflection (PR) in the pulmonary circulation can be used to diagnose reactive PH. Methods: The study comprised 122 patients that were divided into three groups: patients without PH (No PH, n=61), patients with PH (pulmonary artery mean pressure, PAMP≥25 mmHg) and normal PVR (Passive PH, n=29) and patients with increased PVR (Reactive PH, n=32). Echocardiography and Right Heart Catheterization (RHC) was performed within 24 hours. Three PR variables were selected: the acceleration time in the Right Ventricular Outflow Tract (RVOT), the time interval between RVOT peak velocity and peak tricuspid regurgitant velocity and the right ventricular pressure increase after peak RVOT velocity. Separate cutoff values indicating either high likelihood (major criteria) or low likelihood (minor criteria) for PVR>3WU were investigated using Receiver Operator Characteristic (ROC) curves. Results: The mean±SD age was 50±14 years, and the percentage of males was 63%. Sixty-eight patients (56%) underwent RHC due to known or suspected LHD whereof 23 patients had dilated cardiomyopathy. Thirty-one patients (25%) were heart transplant recipients, 8 patients (7%) had cardiac amyloidosis and 15 patients (12%) were miscellaneous. No patient included in the study had PH or increased PVR due to other causes than left ventricular dysfunction. Sixty-six percent of patients with Reactive PH had mild to moderate PH (PAMP 25-40 mmHg). The proportion of patients with pulmonary capillary wedge pressure>15 mmHg was 14% in No PH, 97% in Passive PH and 74% in Reactive PH. The area under the ROC curve for PR variables was 0.82 to 0.89. With three major criteria present the likelihood of PVR>3 WU increases 27.3 fold (positive likelihood ratio) and absence of minor criteria decreases the likelihood 8.3 fold (negative likelihood ratio). Conclusions: Echocardiographic assessment of PR in patients with LHD can be used to identify or exclude reactive PH. Patients with reactive PH often have mild to moderate rather than severe PH.

Pulmonary vascular reactivity in pulmonary hypertension due to left heart disease

Purpose: Pulmonary hypertension (PH) due to left heart disease (LHD) is the most common subset of PH. It is defined by an increase of mean pulmonary artery pressure (mPAP) ≥25mmHg in the presence of a mean pulmonary capillary wedge pressure (mPCWP) >15mmHg. In the current guidelines PH due to LHD with a TPG >12mmHg is labeled as out-of-proportion PH, as opposed to what is labeled as passive PH, i.e. PH as the consequence of elevated left ventricular filling pressures. Recent data have shown that patients with out-of-proportion PH and a diastolic pulmonary vascular pressure gradient (DPG) ≥7mmHg have an increased mortality and significant pulmonary vascular disease. We hypothesize that these patients may benefit from vasodilator treatment. The aim of this study was to compare the degree of acute vasoreactivity to inhaled nitric oxide (NO) in out-of-proportion PH with a DPG ≥7mmHg to that of passive PH and out-of-proportion PH with a DPG <7mmHg. Methods: A prospective data set of 73 patients with PH due to LHD undergoing first diagnostic right and left heart catheterizations at rest and after inhalation of 40ppm NO was analyzed. 22 patients were classified as passive PH, 25 as out-of-proportion PH with a DPG <7mmHg and 26 as out-of-proportion PH with a DPG ≥7mmHg. Changes were expressed as the differences between hemodynamics at baseline and after vasoreactivity testing. Results: The strongest decrease of mPAP was observed in patients with out-of-proportion PH and a DPG ≥7mmHg (-4.1±5.9mmHg, p=0.003). In contrast there was no significant change in mPAP in patients with out-of-proportion PH and a DPG <7mmHg (-2.1±5.3mmHg, p=0.07). In passive PH a significant increase in mPAP could be observed (2.3±4.8mmHg, p=0.045) upon NO inhalation. View this table: Table 1. Hemodynamics at rest and after Conclusion: DPG identifies patients with out-of-proportion PH who have significant pulmonary vascular disease that is reactive to inhaled NO.

Clinical Features, Hemodynamics, and Outcomes of Pulmonary Hypertension Due to Chronic Heart Failure With Reduced Ejection Fraction: Pulmonary Hypertension and Heart Failure

The purpose of this study was to assess the clinical, functional, and hemodynamic characteristics of passive and mixed pulmonary hypertension (PH), compare outcomes, and contrast conventional and novel hemodynamic partition values in patients with chronic heart failure of reduced left ventricular ejection fraction (HFREF). PH in HFREF may develop from left-sided venous congestion (passive PH) or the combination of pulmonary arterial disease and venous congestion (mixed PH). Subgroup outcomes are not well defined, and the partition values used to define risk are based largely on consensus opinion rather than outcome data. Ambulatory patients referred for hemodynamic catheterization were analyzed retrospectively (N = 463). Comparing patients with no PH to those with passive PH and mixed PH, a progressive gradient of more severely deranged hemodynamics, diastolic dysfunction, and mitral regurgitation was observed. In multivariate analysis, the presence of any PH or mixed PH was associated with older age, diuretic use, atrial fibrillation, and lower pulmonary artery compliance (PAC). Over a median follow-up of 2.1 years, patients with PH displayed greater risk of death (hazard ratio [HR]: 2.24; confidence limits [95% CL]: 1.39, 3.98; p < 0.001) with mixed PH demonstrating greater risk than passive PH (HR: 1.55; 95% CL: 1.11, 2.20; p < 0.001). Partition values identifying highest risk were pulmonary vascular resistance >4 Wood units, systolic pulmonary artery pressure >35 mm Hg, pulmonary wedge pressure >25 mm Hg, and PAC <2.0 ml/mm Hg. Among stable HFREF outpatients, PH was associated with markers of greater disease severity and risk of death. However, the presence of pulmonary arterial disease (mixed PH) carries incremental risk. Abnormalities in pulmonary vascular resistance and compliance may serve as novel therapeutic targets.

Management of pulmonary hypertension in left heart disease

Pulmonary hypertension (PH) due to left heart disease is classified as group II according to the Dana Point classification, which includes left ventricular systolic and/or diastolic left heart failure, and left-sided valvular disease. PH due to left heart disease is the most common cause and when present, especially with right ventricular dysfunction, is associated with a worse prognosis. Left heart disease with secondary PH is associated with increased left atrial pressure, which causes a passive increase in pulmonary pressure. Passive PH could be superimposed by an active protective, and in some patients by an 'out of proportion', elevated precapillary pulmonary vasoconstriction and vascular remodelling which leads to greater or lesser further increase of the pulmonary artery pressure. In this review, epidemiological and pathophysiologic mechanisms for the development of group II PH are summarized. The conflicting data about the haemodynamic and possible parameters to diagnose passive versus reactive and 'out of proportion' PH are presented. The different therapeutic concepts, along with novel treatment strategies, are reviewed in detail and critically discussed regarding their effectiveness and safety.

Exercise pulmonary gas exchange differentiates type and severity of pulmonary hypertension in heart failure

BackgroundHeart failure (HF) is associated with impaired exercise pulmonary gas exchange (PGX) that is likely related to the development and severity of pulmonary hypertension (PH).PurposeTo determine whether PGX measures differentiate HF patients with reactive PH from patients with passive PH or no PH.Methods/ResultsPulmonary arterial pressure (PAP), pulmonary wedge pressure (PWP), transpulmonary pressure gradient (TPG) and PGX indices [end‐tidal CO2 (PETCO2), ventilatory efficiency (VE/VCO2), O2pulse, estimated pulmonary arterial capacitance (GXCAP)] were assessed simultaneously at rest and during cycle exercise in 38 HF patients undergoing right heart catheterization. Post hemodynamic evaluation, patients were classified as having no PH (n = 12), passive PH (n = 10) or reactive PH (n = 16). TPG increased during exercise in all groups but was greater at end exercise in the reactive PH vs. the passive PH and no PH patients (21±9 vs. 14±7 vs. 12±7 mmHg). At an equivalent VO2, PETCO2, O2pulse and GXCAP were higher and VE/VCO2 ratio lower in the no PH and, to a lesser extent, in the passive PH vs. the reactive PH subjects (Figure 1).ConclusionNoninvasive measures of PGX during exercise appear to differentiate HF patients with reactive PH from patients with passive PH or no PH and may be a useful adjunct to invasive catheterization in assessing PH type and severity. HL71478, AHA12POST12070084, Gilead Science

Hemodynamic Benefits of Chronic Sildenafil Therapy in Advanced Heart Failure (HF): A Multi-Center Experience

Purpose Type II pulmonary hypertension (PH) is frequent in advanced HF patients. Initially passive, secondary to elevated left side filling pressures, PH can evolve to a reactive profile involving the pulmonary arterial vasculature, defined at right heart catheterization (RHC). When reactive PH remains fixed despite an aggressive reversibility protocol, heart transplantation is contraindicated. This study reports the experience of two cardiac transplant centres of open-label 3-months (3M) sildenafil (S) therapy, a selective phosphodiesterase inhibitor (PDE-5), in HF patients with PH, focusing on pulmonary hemodynamics at rest. Methods and Materials We conducted a retrospective review of HF patients evaluated for cardiac transplantation who received sildenafil therapy because of severe PH despite optimal medical therapy. We compared hemodynamic findings, including trans-pulmonary gradient (TPG), cardiac index (CI) and pulmonary vascular resistance(PVR) at baseline and after 3M of S. Results 37 advanced HF patients (NYHA III-IV, 86% male) with a mean age of 50±12 years and depressed LVEF (23±5%), received S for severe PH (mPAP 41±11mmHg). Compared to baseline, RHC resting values at 3M showed 19% increase in CI (1.6, 1.4–1.9 to 1.9, 1.6–2.6 l/min/m2, p=0.002) and 23% decrease in PVR (4.6, 3.2-6.0 to 3.2, 2.4–5.4 WU, p=0.01), without TPG change (−12%, 16 to 13 mmHg, p=0.09). sPAP, dPAP and PCWP were also unchanged. Amongst the patients with reactive PH at baseline (32/37), six evolved toward a passive PH profile at 3M and 14/18 of the fixed PH patients, had a reversible profile at 3M. Conclusions In advanced HF patients with type II PH, 3M of sildenafil therapy increased CI and decreased PVR on resting RHC. An aggressive reversibility protocol was able to modify reactive or fixed PH to a passive profile, leading to potential transplant candidacy for these patients. These results suggest a strong implication of NO and PDE pathway in severePH secondary to HF.