Combined Precapillary And Postcapillary PH Research Articles

3-Year Outcome in Patients With Combined Precapillary and Postcapillary Pulmonary Hypertension: Results From PADN-5 Trial

BackgroundLong-term benefits of pulmonary artery denervation (PADN) for patients with combined precapillary and postcapillary pulmonary hypertension (CpcPH) secondary to left heart failure are unknown. ObjectivesThe authors sought to report the 3-year clinical results of PADN for patients with CpcPH. MethodsA total of 98 patients with CpcPH, defined as having mean pulmonary arterial pressure of ≥25 mm Hg, pulmonary capillary wedge pressure of >15 mm Hg, and pulmonary vascular resistance of >3.0 WU, were randomly assigned to receive the sham + sildenafil or PADN. The primary endpoint was the occurrence of clinical worsening defined as cardiopulmonary death, rehospitalization or heart/lung transplantation at 3-year follow-up. Changes in the 6-minute walk distance and N-terminal pro–B-type natriuretic peptide served as secondary points. ResultsAt the 3-year follow-up, clinical worsening was reported in 49 (50.0%) patients, with 31 (62.0%) in the sham + sildenafil group and 18 (37.5%) in the PADN group (HR: 2.13 [95% CI: 1.19-3.81]; P = 0.011), largely driven by a higher rate of rehospitalization in the sham + sildenafil group (56.2% vs 35.4%; HR: 1.96 [95% CI: 1.07-3.58]; P = 0.029) by Cox proportional hazards regression. At the end of the study, cardiopulmonary-related deaths occurred in 16 (32.0%) patients in the sham and 9 (18.8%) (P = 0.167) patients in the PADN group. PADN also resulted in a more profound increase in the 6-minute walk distance and reduction in N-terminal pro–B-type natriuretic peptide. ConclusionsPADN is associated with significant improvements in exercise capacity, cardiac function, and clinical outcomes. Further study without approved drugs for pulmonary arterial hypertension is required to confirm the benefits of PADN for patients with CpcPH. (Pulmonary Arterial Denervation in Patients With Pulmonary Hypertension Associated With the Left Heart Failure [PADN-5]; NCT02220335)

Characteristics of cardiopulmonary exercise testing in patients with combined post- and pre-capillary pulmonary hypertension due to left heart disease.

Pulmonary hypertension (PH) is a common and morbid complication of left heart disease (LHD), comprising two subtypes: (1) isolated post-capillary pulmonary hypertension (Ipc-PH) and (2) combined post-capillary and pre-capillary pulmonary hypertension (Cpc-PH). Knowledge regarding the physiological characteristics that distinguish Cpc-PH, which has a worse prognosis, from Ipc-PH remains limited. Therefore, this study aimed to assess the utility of cardiopulmonary exercise testing (CPET) variables in detecting Cpc-PH. Among 105 consecutive patients with LHD (age: 55 ± 13 years; male/female = 79/26) who underwent right heart catheterization and CPET, 45 (43%) were classified as PH-LHD (mean pulmonary artery pressure >20 mmHg). Ipc-PH (n = 24) was defined as pulmonary vascular resistance (PVR) ≤ 3 WU and Cpc-PH (n = 21) as PVR > 3 WU. Patients with Cpc-PH had a significantly lower peak partial pressure of carbon dioxide (PETCO2) (Non-PH/Ipc-PH/Cpc-PH = 38.2 ± 6.6 vs. 38.3 ± 6.0 vs 33.0 ± 4.4 mmHg, p = 0.006), higher VE vs. VCO2 slope (Non-PH/Ipc-PH/Cpc-PH = 33.0 [28.3, 36.6] vs. 32.5 [28.1, 37.8] vs. 40.6 [33.6, 46.1], p = 0.007), and lower ΔVO2/ΔWR (Non-PH/Ipc-PH/Cpc-PH = 8.5 ± 1.4 vs. 8.0 ± 1.7 vs. 6.8 ± 2.0 mL/min/watt, p = 0.001) than those with Ipc-PH and non-PH. Using multivariable logistic regression analysis, CPET variables were found to be independent predictors of Cpc-PH (lower peak PETCO2: odds ratio, 0.728 [95% confidence interval {CI}: 0.616-0.840], p = 0.003 and lower ΔVO2/ΔWR: odds ratio, 0.747 [95% CI: 0.575-0.872], p = 0.003). From our exploratory analysis, CPET variables, especially in the lower peak PETCO2 and lower ΔVO2/ΔWR, were associated with Cpc-PH in patients with left heart disease.

2022 ESC/ERS guidelines on the diagnostics and treatment of pulmonary hypertension : Afocussed review

Pulmonary hypertension (PH) is ahemodynamic state that can be caused by avariety of underlying conditions. The pathophysiology is complex and can involve several organ systems, requiring amultidisciplinary approach to differential diagnostics and management. This review article provides acomprehensive overview of the most important changes in the updated 2022 European Society of Cardiology (ESC)/European Respiratory Society (ERS) guidelines on the diagnostics and treatment of pulmonary hypertension, as compared to the previous 2015 version. A special focus is on (i)updated hemodynamic definitions of PH, including general definition, precapillary vs. postcapillary PH, isolated postcapillary PH (IpcPH), combined postcapillary and precapillary PH (CpcPH), (ii)the clinical presentation and classification of PH, (iii)the diagnostic approach as well as (iv)specific aspects of pulmonary arterial hypertension (PAH, group1), including risk assessment, treatment and PAH with comorbidities, PH associated with left heart (group2) or lung disease (group3), and chronic thromboembolic pulmonary hypertension (CTEPH, group4). Regarding the latter, the specific diagnostic algorithm and the multimodal approach to treatment are presented. Finally, for each of the PH groups, clinically relevant aspects and innovations are briefly and concisely presented.

Pulmonary hypertension with a precapillary component in heart failure with preserved ejection fraction

ObjectivesHeart failure with preserved ejection fraction (HFpEF) is often complicated by pulmonary hypertension (PH), which is mainly characterised by postcapillary PH and occasionally accompanied by a precapillary component of PH....

Abstract 12949: Altered Fatty Acids and Oxylipins Metabolism Differentiate Isolated Post-Capillary versus Combined Pre- and Post-Capillary Pulmonary Hypertension

Introduction: Pulmonary hypertension due to left heart disease (Group 2) is the most common type of pulmonary hypertension and has two subtypes: isolated post-capillary pulmonary hypertension (Ipc-PH) and combined post-capillary and pre-capillary pulmonary hypertension (Cpc-PH). Little is known about the molecular characteristics that distinguish these two subphenotypes or if Cpc-PH shares molecular similarities to pulmonary arterial hypertension (PAH), as has previously been suggested. Many lipid metabolites, including a diverse group of bioactive lipid mediators known as oxylipins, have been associated with cardiovascular disease and other inflammatory conditions. Therefore, we sought to characterize oxylipin and other bioactive lipid profiles among patients with Ipc-PH and Cpc-PH, as well as those with PAH. Methods: We studied 129 patients with Ipc-PH (n=38), Cpc-PH (n=52), or PAH (n=39) between June 2006 and March 2012. Liquid chromatography-mass spectrometry was used to assess 350 lipid metabolite analytes in each patient. Results: In multivariable analyses adjusting for age, sex, BMI, and pulmonary hypertension medications, we observed 34 metabolites were significantly increased and 10 were decreased in Ipc-PH compared to Cpc-PH (Figure). Among these same metabolites, only 9 were significantly different between Cpc-PH and PAH. Compared to patients with Ipc-PH, those with Cpc-PH had elevated levels of fatty acyl esters of hydroxy fatty acids and polyunsaturated fatty acids as well as lower levels of anti-inflammatory and pulmonary vascular relaxant oxylipins. Conclusions: Overall, these findings suggest that Cpc-PH may diverge from Ipc-PH and share some molecular similarities with PAH. Identifying key molecular targets involved in Cpc-PH pathophysiology may be critical for diagnostic purposes and in the development of novel therapeutic avenues for patients with Cpc-PH.

Update in approaches to pulmonary hypertension because of left heart disease.

Left heart disease is the most common cause of pulmonary hypertension. This review summarizes the current care of patients with pulmonary hypertension caused by left heart disease (PH-LHD) and discusses recent and active clinical trials in this patient population. The primary focus of interventions aimed at treating PH-LHD address the treatment of left heart disease. Significant advancements in the treatment of heart failure with preserved ejection fraction (HFpEF), a frequent cause of PH-LHD, are supported in the current literature. Patients with residual pulmonary hypertension despite optimal treatment of left heart disease have poor outcomes. Yet, interventions targeting the pulmonary vasculature in PH-LHD patients have not demonstrated significant benefits in studies to date. Current work focuses on differentiating isolated postcapillary pulmonary hypertension (IpcPH) from combined precapillary and postcapillary pulmonary hypertension (CpcPH) in a clinically consistent manner. It is hopeful that thorough phenotyping of PH-LHD patients will translate into effective treatment strategies addressing pulmonary vascular disease. Referral to centers of excellence, considerations for enrollment in clinical trials, and evaluation for transplant is recommended for patients with residual pulmonary hypertension despite optimal treatment of left heart disease, particularly those with CpcPH.

Prevalence and haemodynamic profiles of pulmonary hypertension in cardiac amyloidosis

ObjectivesWhile cardiac amyloidosis (CA) classically involves the left ventricle (LV), less is known about its impact on the right ventricle (RV) and pulmonary vasculature. We performed a retrospective analysis to identify the prevalence and types of pulmonary hypertension (PH) profiles in CA and to determine haemodynamic and cardiovascular magnetic resonance (CMR) predictors of major adverse cardiovascular events (MACE).MethodsPatients with CA who underwent CMR and right heart catheterisation (RHC) within 1 year between 2010 and 2019 were included. Patients were assigned the following haemodynamic profiles based on RHC: no PH, precapillary PH, isolated postcapillary PH (IPCPH), or combined precapillary and postcapillary PH (CPCPH). The relationship between PH profile and MACE (death, heart failure hospitalisation) was assessed using survival analysis. CMR and RV parameters were correlated with MACE using Cox-regression analysis.ResultsA total of 52 patients were included (age 69±9 years, 85% men). RHC was performed during biopsy in 44 (85%) and for clinical indications in 8 (15%) patients. Rates of no PH, precapillary PH, IPCPH and CPCPH were 5 (10%), 3 (6%), 29 (55%) and 15 (29%), respectively. Haemodynamic PH profile did not correlate with risk of death (p=0.98) or MACE (p=0.67). Transpulmonary gradient (TPG) (HR 0.88, CI 0.80 to 0.97), RV, (HR 0.95, CI 0.92 to 0.98) and LV ejection fraction (HR 0.95, CI 0.92 to 0.98) were significantly associated with MACE.ConclusionsPH is highly prevalent in CA, even at the time of diagnosis. While IPCPH was most common, CPCPH is not infrequent. TPG and RV ejection fraction (RVEF) are prognostic markers in this population.

Cardiac acoustic biomarkers as surrogate markers to diagnose the phenotypes of pulmonary hypertension: an exploratory study

Pulmonary hypertension (PH) is commonly associated with left heart disease. In this retrospective study, using the database of a clinical study conducted between January 2008 and July 2008, the phenotypes of PH were classified using non-invasive cardiac acoustic biomarkers (CABs) and compared with classification by echocardiography. Records with same-day measurement of acoustic cardiography and right heart catheterization (RHC) parameters were included; cases with congenital heart disease were excluded. Using the RHC measurements, PH was classified as pre-capillary PH (Prec-PH), isolated post-capillary PH (Ipc-PH), and combined pre-capillary and post-capillary PH (Cpc-PH). The first, second, third, and fourth heart sounds (S1, S2, S3, and S4) were quantified as CABs (intensity, complexity, and strength). Forty subjects were selected: 5 had Prec-PH, 5 had Ipc-PH, 8 had Cpc-PH, and 22 had No-PH. CABs were significantly correlated with RHC measurements, with significant differences among phenotypes. Phenotype classification was performed using various CABs, and the diagnostic performance as assessed by the area under the receiver operating characteristic curve was 0.674–0.720 for Prec-PH, 0.657–0.807 for Ipc-PH, and 0.742 for Cpc-PH. High negative and low positive predictive values for phenotype identification were observed. CABs may provide an ambulatory measurement method with home-monitoring friendliness which is more convenient than standard examinations to identify presence of PH and its phenotypes.

Clinical significance of pulmonary hypertension in patients with constrictive pericarditis

ObjectivesWe investigated haemodynamics and clinical outcomes according to type of pulmonary hypertension (PH) in patients with constrictive pericarditis (CP).BackgroundAs the prevalence of CP with concomitant myocardial disease (mixed CP) grows,...

Metabolic Syndrome Mediates ROS-miR-193b-NFYA-Dependent Downregulation of Soluble Guanylate Cyclase and Contributes to Exercise-Induced Pulmonary Hypertension in Heart Failure With Preserved Ejection Fraction.

Many patients with heart failure with preserved ejection fraction have metabolic syndrome and develop exercise-induced pulmonary hypertension (EIPH). Increases in pulmonary vascular resistance in patients with heart failure with preserved ejection fraction portend a poor prognosis; this phenotype is referred to as combined precapillary and postcapillary pulmonary hypertension (CpcPH). Therapeutic trials for EIPH and CpcPH have been disappointing, suggesting the need for strategies that target upstream mechanisms of disease. This work reports novel rat EIPH models and mechanisms of pulmonary vascular dysfunction centered around the transcriptional repression of the soluble guanylate cyclase (sGC) enzyme in pulmonary artery (PA) smooth muscle cells. We used obese ZSF-1 leptin-receptor knockout rats (heart failure with preserved ejection fraction model), obese ZSF-1 rats treated with SU5416 to stimulate resting pulmonary hypertension (obese+sugen, CpcPH model), and lean ZSF-1 rats (controls). Right and left ventricular hemodynamics were evaluated using implanted catheters during treadmill exercise. PA function was evaluated with magnetic resonance imaging and myography. Overexpression of nuclear factor Y α subunit (NFYA), a transcriptional enhancer of sGC β1 subunit (sGCβ1), was performed by PA delivery of adeno-associated virus 6. Treatment groups received the SGLT2 inhibitor empagliflozin in drinking water. PA smooth muscle cells from rats and humans were cultured with palmitic acid, glucose, and insulin to induce metabolic stress. Obese rats showed normal resting right ventricular systolic pressures, which significantly increased during exercise, modeling EIPH. Obese+sugen rats showed anatomic PA remodeling and developed elevated right ventricular systolic pressure at rest, which was exacerbated with exercise, modeling CpcPH. Myography and magnetic resonance imaging during dobutamine challenge revealed PA functional impairment of both obese groups. PAs of obese rats produced reactive oxygen species and decreased sGCβ1 expression. Mechanistically, cultured PA smooth muscle cells from obese rats and humans with diabetes or treated with palmitic acid, glucose, and insulin showed increased mitochondrial reactive oxygen species, which enhanced miR-193b-dependent RNA degradation of nuclear factor Y α subunit (NFYA), resulting in decreased sGCβ1-cGMP signaling. Forced NYFA expression by adeno-associated virus 6 delivery increased sGCβ1 levels and improved exercise pulmonary hypertension in obese+sugen rats. Treatment of obese+sugen rats with empagliflozin improved metabolic syndrome, reduced mitochondrial reactive oxygen species and miR-193b levels, restored NFYA/sGC activity, and prevented EIPH. In heart failure with preserved ejection fraction and CpcPH models, metabolic syndrome contributes to pulmonary vascular dysfunction and EIPH through enhanced reactive oxygen species and miR-193b expression, which downregulates NFYA-dependent sGCβ1 expression. Adeno-associated virus-mediated NFYA overexpression and SGLT2 inhibition restore NFYA-sGCβ1-cGMP signaling and ameliorate EIPH.

Transcatheter pulmonary denervation in patients with left heart failure with reduced ejection fraction and combined precapillary and postcapillary pulmonary hypertension: A prospective single center experience.

The present study was a prospective, single-center, single-arm study to investigate the efficacy of transcatheter pulmonary artery denervation (TPADN) in patients with combined postcapillary and precapillary PH (Cpc-PH) associated with left heart failure with reduced ejection fraction (HF-rEF). Pulmonary hypertension (PH) in patients with left ventricular systolic dysfunction has a negative impact on outcome. The combination of pulmonary artery systolic pressure (PAPs) ≥60 mmHg, transpulmonary pressure gradient (TPG) ≥12 mmHg, nonreversible mean PAP, and pulmonary vascular resistance (PVR) ≥3.5 Wood Units was considered as too high risk for heart transplantation (HTx). The clinical efficacy endpoint was an improvement in 6-min walking test and the hemodynamic endpoints were changes in PAPs, PVR, and TPG between baseline and 6months. Circumferential radiofrequency applications were delivered around distal main, left and right pulmonary arteries. At each ablation point temperature was 45°C and energy 10W. TPADN was performed in 10 patients. At 6-month in 5 patients we observed reduction in PAP, PVR, TPG, and DPG and then 1 had successful HTx, 2 are on HTx waiting list, 2 received LVADs, 2 patients did not improve, and 3 patients died. TPADN may be beneficial in selected patients with HF-rEF and Cpc-PH.

METASTATIC PULMONARY CALCIFICATION: A RARE CAUSE OF PULMONARY HYPERTENSION

SESSION TITLE: Fellows Pulmonary Vascular Disease Posters SESSION TYPE: Fellow Case Report Posters PRESENTED ON: October 18-21, 2020 INTRODUCTION: Metastatic calcification is seen at autopsy in 60-75% of CKD patients on hemodialysis (HD) due to increased calcium phosphate product (normal 40 mg2/dl2; MPC >70 mg2/dl2) (1,2). Metastatic pulmonary calcification associated with pulmonary hypertension (PH) is rare. We present a case of MPC associated combined postcapillary and precapillary PH (CpcPH). CASE PRESENTATION: A 58-year-old woman with SLE, CTD-ILD (FVC 64%, TLC 56 %), ESRD on HD since 2008 and diastolic heart failure was admitted to the hospital with worsening dyspnea, leg edema and orthopnea. Her calcium phosphate product was 61. CT chest showed diffuse ground glass opacity with mosaic perfusion, enlarged pulmonary artery (PA 4.3 cm) and chest wall calcifications. Echocardiogram showed grade 3 diastolic dysfunction, severely dilated left atrium and elevated right ventricular systolic pressure. Heart catheterization showed mean PA pressure 62 mm Hg, PA wedge pressure 29 mm Hg, transpulmonary gradient (TPG) 33, diastolic pulmonary gradient (DPG) 11, pulmonary vascular resistance 9 WU, LV end diastolic pressure 27 mm Hg, cardiac output 3.6, cardiac index 2.1. Given her severe PH, low CI and NYHA functional class IV, she was started on inhaled treprostinil with improvement in leg edema and orthopnea at 6-month follow up. DISCUSSION: Hyperphosphatemia in ESRD causes increased calcium phosphate product leading to calcium crystallization. Metastatic calcifications are usually seen in lamina propria of stomach, lung alveoli, renal tubules and interstitium(2). Acidosis between HD sessions causes leaching of calcium from bone, leading to deposition during post dialysis alkalosis. Uremia alters the configuration of tissue protein, rendering them more calcifiable. Three main CT patterns of MPC include centrilobular ground glass nodules, dense consolidation and small dense nodules(1). It is usually peripheral in distribution with upper lung zone dominance due to increased alkalinity (higher V/Q ratio causing low PaCO2) causing calcium salt deposition. Vascular calcification in chest and abdominal wall is a common finding as noted in our case. 30-50% of CKD and ESRD patients have PH. Vascular calcification can affect pulmonary arterial capacitance (low PAC in our case 0.81) and increase RV afterload. In this case, contributing factors to her PH are elevated LVEDP, ILD and ESRD (WHO group II, III and V). TPG >12 and DPG >7 suggested pulmonary vascular remodeling from shear stress and downstream pressure. This is an interesting case of MPC with associated PH. Initiation of the pulmonary vasodilator treprostinil reduced her PVR allowing for a better coupling of the RV-PA system. CONCLUSIONS: Treatment of MPC includes intensification of HD sessions and use of calcium and phosphate binders. In this case, inhaled pulmonary vasodilators for treatment of CpcPH after medical treatment optimization of other co-morbidities led to symptomatic improvement. Reference #1: Metastatic pulmonary calcification: HRCT findings in 23 cases, Radiol Bras.2017 Jul-Aug; 50(4): 231–236 Reference #2: Metastatic pulmonary calcification: State-of-the-art review focused on imaging findings, Respiratory Medicine Feb 2014 (108): 668-676 Reference #3: Pulmonary hypertension with extensive calcification in small pulmonary vessels and alveolar capillary wall in a chronic hemodialysis patient, Journal of Cardiology Cases 8 (Feb 2013) e13–e16 DISCLOSURES: No relevant relationships by Moises Cossio, source=Web Response No relevant relationships by Domingo Franco-Palacios, source=Web Response No relevant relationships by Kushagra Gupta, source=Web Response No relevant relationships by Shahzad Hussain, source=Web Response No relevant relationships by Venkateswara Kollipara, source=Web Response No relevant relationships by Toribiong Uchel, source=Web Response

Relationship between B-type natriuretic peptide and invasive haemodynamics in patients with severe aortic valve stenosis.

AimsIn patients with aortic stenosis (AS), B‐type natriuretic peptide (BNP) is a prognostic marker. However, there is little information on the association between BNP and invasive haemodynamics in AS. The aim of the present study was to assess the hitherto not well‐defined relationship between BNP and invasive haemodynamics in patients with severe AS undergoing aortic valve replacement (AVR) with a view to understand the link between high BNP and poor prognosis in these patients. In particular, we were interested in the association between BNP and combined pre‐capillary and post‐capillary pulmonary hypertension (CpcPH).Methods and resultsBNP was measured in 252 patients (age 74 ± 10 years, 58% male patients) with severe AS [indexed aortic valve area 0.4 ± 0.1 cm2/m2 and left ventricular ejection fraction (LVEF) 57 ± 12%] the day before cardiac catheterization. Patients were followed for a median (interquartile range) period of 3.1 (2.3–4.3) years after surgical (n = 157) or transcatheter (n = 95) AVR. The prevalence of CpcPH (mean pulmonary artery pressure ≥ 25 mmHg, mean pulmonary artery wedge pressure > 15 mmHg, and pulmonary vascular resistance > 3 Wood units) was 13%. The median BNP plasma concentration was 188 (78–452) ng/L. The indexed aortic valve area was similar across BNP quartiles (P = 0.21). Independent predictors of higher BNP (ln transformed) included lower haemoglobin (beta = −0.18; P < 0.001), lower LVEF (beta = −0.20; P < 0.001), more severe mitral regurgitation (beta = 0.20; P < 0.001), higher mean pulmonary artery wedge pressure (beta = −0.37; P < 0.001), and higher pulmonary vascular resistance (beta = 0.21; P < 0.001). In a multivariate model with CpcPH rather than its haemodynamic components, CpcPH was independently associated with higher BNP (0.21; P < 0.001). Higher ln BNP was associated with higher mortality [hazard ratio 1.90 (95% confidence interval 1.33–2.71); P < 0.001] in the univariate analysis. Patients in the third and fourth BNP quartiles had a more than six‐fold risk of death compared with patients in the first and second quartiles [hazard ratio 6.29 (95% confidence interval 1.86–21.27); P = 0.003]. In the multivariate analysis, lower LVEF [hazard ratio 0.96 (95% confidence interval 0.94–0.99) per 1% increase; P = 0.01] and CpcPH [hazard ratio 4.58 (95% confidence interval 1.89–11.09); P = 0.001] but not BNP were independently associated with mortality. The areas under the receiver operator characteristics curve for BNP for the prediction of CpcPH and mortality were 0.88 and 0.74, respectively.ConclusionsIn patients with severe AS, higher BNP is a marker of the presence of CpcPH and its contributors. The association between BNP and such an adverse haemodynamic profile at least in part explains the ability of BNP to predict long‐term post‐AVR mortality.

Correction: Persistent abnormalities in pulmonary arterial compliance after heart transplantation in patients with combined post-capillary and pre-capillary pulmonary hypertension

[This corrects the article DOI: 10.1371/journal.pone.0188383.].

Pulmonary Artery Denervation Significantly Increases 6-Minute Walk Distance for Patients with Pulmonary Hypertension Associated with Left-Side Heart Failure: A Prospective, Randomized, and Sham-Controlled PADN-5 Study

Background: Heart failure (HF) is associated with sympathetic overactivation. Combined pre-capillary and post-capillary pulmonary hypertension (CpcPH) bears the same pathology as pulmonary arterial hypertension (PAH). Benefits of targeted-PAH medications for CpcPH patients are unknown. Pulmonary artery denervation (PADN), which showed benefit for both PAH and PH patients in a previous consecutive registry study, has not been studied in CpcPH patients using a randomized design. We therefore sought to assess the benefits of PADN for CpcPH patients. Methods: Of 865 patients with HF who were stable for ≥ 3 months and were admitted due to recent worsening of symptoms were enrolled, 387 patients after at least 3 days of treatment had a systolic pulmonary arterial pressure (PAP) ≥ 45 mmHg measured by echocardiography. Among them, 98 CpcPH patients (mean PAP≥25 mmHg, pulmonary capillary wedge pressure >15 mmHg, and pulmonary vascular resistance [PVR] > 3·0 Wood units) were randomly assigned to receive sildenafil plus anti-HF medication and sham PADN or PADN plus anti-HF medication without sildenafil. The primary endpoint was an increase in the 6-minute walk distance (6MWD) at the 6-month followup. PVR and clinical worsening were secondary endpoints. Pulmonary embolism was a safety endpoint. Findings: At the 6-month follow-up, the mean increases in the 6MWD were 83 m in the PADN group and 15 m in the sildenafil group ((least square mean difference 66 m, 95% confidence interval= 38·2-98·8; p<0·001). A 1-SD decrease in the 6MWD was strongly correlated with clinical worsening (corresponding hazard ratio [95% confidence interval] =3·02[ 1·05-8·74]; p=0·04). PADN treatment was associated with significant reduction (29·8%) in PVR and lower rate (16·7%) of clinical worsening, compared with 3·4% (hazard ratio [95% confidence interval] =4·73 [2·05-10·89]; p<0·001) and 40% (hazard ratio [95% confidence interval] =3·33 [1·29-8·59]; p=0·014) in the sildenafil group. At the end of the study, there were 7 all-cause deaths (5 in the sildenafil and 2 in the PADN group) and 2 embolisms (1 in each group). Interpretation: PADN is associated with significant improvements in hemodynamic parameters, cardiac function, and clinical outcomes, when compared with those after 6-month sildenafil treatment. Further studies are warranted to confirm the reduction of CpcPH-related events by PADN. Clinical Trial Number: Registration at clinicaltrials.com; identifier: NCT02220335 Funding Statement: National Science Foundation of China (NSFC 91639303 and NSFC 81770441). Declaration of Interests: CSL is the inventor of PADN patent, but not the owner. The remaining authors have nothing to disclosure. Ethics Approval Statement: The PADN-5 trial is a 4-center, randomized, and sham-controlled clinical trial, which was approved by the ethics committee at each participating center. All patients provided written informed consent. Sponsors had no access to the trial data and no role in the design, conduct, or reporting of the results. Clinical events were adjudicated by an independent committee.

Characteristics of Cardiopulmonary Exercise Testing in Patients with Combined Post-capillary and Pre-capillary Pulmonary Hypertension (Cpc-PH) Due to Left Heart Disease

Characteristics of Cardiopulmonary Exercise Testing in Patients with Combined Post-capillary and Pre-capillary Pulmonary Hypertension (Cpc-PH) Due to Left Heart Disease

Baseline diastolic pressure gradient and pressure reduction in chronic heart failure patients implanted with the CardioMEMS™ HF sensor

AimsRemote haemodynamic monitoring (RHM) decreases hospitalization rates in patients with chronic heart failure (HF). Many patients with chronic HF develop pulmonary hypertension (PH) secondary to left heart disease with some acquiring combined pre‐capillary and post‐capillary PH (Cpc‐PH). The efficacy of RHM in achieving pulmonary pressure reductions in patients with Cpc‐PH vs. isolated post‐capillary PH (Ipc‐PH) is unknown. The purpose of this study is to evaluate whether a higher baseline diastolic pressure gradient (DPGbaseline) measured at the time of CardioMEMS™ HF sensor implantation is associated with lower reductions in pulmonary artery diastolic pressures (PADP).Methods and resultsThis was a retrospective analysis of 32 patients meeting clinical indications for CardioMEMS™ implantation. DPGbaseline categorized patients as Cpc‐PH (DPG ≥ 7 mmHg) or Ipc‐PH (DPG < 7 mmHg). Minimum achievable PADP (PADPmin) and ∆PADP (PADPbaseline − PADPmin) were determined. Pearson's correlation analysis and comparison of mean pressure changes were assessed. Median age was 69 years, and median left ventricular ejection fraction (LVEF) was 25%. Eight patients (25%) had a LVEF ≥40%. Twenty‐five patients (78%) met criteria for Ipc‐PH and seven (22%) for Cpc‐PH. Neither PADPmin (ρ = 0.27; P = 0.13) nor ΔPADP (ρ = 0.07; P = 0.72) was correlated with DPGbaseline. A trend towards higher ΔPADP was seen in Cpc‐PH vs. Ipc‐PH patients (15.2 vs. 9.88 mmHg; P = 0.12). There was a moderate positive correlation between baseline PADP and ΔPADP [ρ = 0.55 (0.26–0.76); P < 0.001].ConclusionsDecreased PADP reduction was not seen in Cpc‐PH vs. Ipc‐PH patients. Higher PADPbaseline was associated with greater ΔPADP. Larger studies are needed to elaborate our findings.

Persistent abnormalities in pulmonary arterial compliance after heart transplantation in patients with combined post-capillary and pre-capillary pulmonary hypertension.

BackgroundThe hemodynamic definitions of pulmonary hypertension (PH) in left heart disease have recently been refined to better match the characteristics required to reflect the presence of pulmonary vascular disease. Accordingly, we tested the hypothesis that abnormalities in the stiffness of pulmonary circulation would persist after heart transplantation in patients with combined post-capillary and pre-capillary PH (Cpc-PH) in contrast to those with isolated post-capillary PH (Ipc-PH).MethodsWe retrospectively analyzed right heart hemodynamics in a cohort of 295 consecutive patients with heart failure and advanced left ventricular systolic dysfunction (LVSD) before and 1 year after heart transplantation.ResultsAccording to their baseline hemodynamic profile, patients were classified as: 75 Cpc-PH, 111 Ipc-PH, and 98 without PH (no-PH), and 11 pre-capillary PH. One year after heart transplantation, pulmonary artery pressures, pulmonary vascular resistance and cardiac index normalized in all patients regardless of the baseline hemodynamic profile. However, pulmonary arterial compliance remained lower in Cpc-PH patients (from 1.6±1.2 at baseline to 3.7±1.4 ml/mmHg at 1 year) than in Ipc-PH (from 1.2±2.0 to 4.4±2.3 ml/mmHg) and no-PH patients (from 3.7±2.0 to 4.5±1.8 ml/mmHg); (adjusted p = 0.03 Ipc-PH vs. Cpc-PH INT<0.001).ConclusionsIn heart failure patients with advanced LVSD, a hemodynamic profile characterized by Cpc-PH predicts the persistence of a stiffer pulmonary circulation at 1 year after heart transplantation.

Haemodynamic effects of an acute vasodilator challenge in heart failure patients with reduced ejection fraction and different forms of post-capillary pulmonary hypertension.

The most recent European guidelines have proposed new definitions of pulmonary hypertension (PH) in left heart disease, to better approach the characteristics required to reflect the presence of pulmonary vascular disease. The purpose of this study was to assess whether different haemodynamic definitions of post-capillary PH imply a different reversibility of PH in response to acute vasodilator administration in heart failure patients with reduced ejection fraction and PH (HFrEF-PH). Right heart catheterization and reversibility testing was performed in 156 HFrEF-PH patients. Patients were classified as combined post-capillary and pre-capillary pulmonary hypertension (Cpc-PH) vs. isolated post-capillary pulmonary hypertension (Ipc-PH) and on the basis of diastolic pulmonary gradient (DPG) ≥ 7 vs. < 7 mmHg or of transpulmonary gradient (TPG) >12 vs. ≤12 mmHg. After vasodilator administration, Cpc-PH patients showed a greater per cent improvement in pulmonary vascular resistance (PVR), DPG and TPG as compared with Ipc-PH patients (all Pint < 0.001); only pulmonary compliance (PCa) improved less in Cpc-PH than in Ipc-PH patients (Pint = 0.007). However, despite vasodilatation, Cpc-PH patients remained in an unfavourable portion of the inverse hyperbolic relationship between PVR and PCa. The number of patients in whom PVR was reduced below 2.5 wood units was similar in Cpc-PH, DPG ≥7 mmHg and TPG >12 mmHg groups (28.3, 26.7 and 18.9%, respectively). Although substantial improvements in PVR, DPG and TPG were observed in Cpc-PH patients after acute vasodilator administration, this response was associated with persistent abnormalities in the PVR vs. PCa relationship. The link between baseline right heart haemodynamics and pulmonary vascular disease remains elusive.

A simple echocardiographic score for the diagnosis of pulmonary vascular disease in heart failure.

A simple echocardiographic score was designed for diagnosing precapillary vs postcapillary pulmonary hypertension and for discriminating between isolated postcapillary pulmonary hypertension (Ipc-PH) and combined precapillary and postcapillary pulmonary hypertension (Cpc-PH). The score comprised 7 points (2 for E/e' ratio ≤10, 2 for a dilated non-collapsible inferior vena cava, 1 for a left ventricular eccentricity index ≥1.2, 1 for a right-to-left heart chamber dimension ratio >1 and 1 for the right ventricle forming the heart apex) and was applied to 230 consecutive patients referred for evaluation of pulmonary hypertension. Precapillary pulmonary hypertension and postcapillary pulmonary hypertension were diagnosed in 160 and 70 patients, respectively. In the latter, Ipc-PH was found in 51 and Cpc-PH in 19. The echo score was higher in precapillary vs postcapillary pulmonary hypertension patients (4.2 ± 1.7 vs 1.6 ± 1.7, P < 0.001) and in patients with Cpc-PH vs Ipc-PH (2.7 ± 2.1 vs 1.2 ± 1.3, P = 0.001). The sensitivity and specificity of the echo score at least 2 for precapillary pulmonary hypertension were 99 and 54%, respectively (area under the curve 0.85). In patients with postcapillary pulmonary hypertension, the sensitivity and specificity of the echo score at least 2 for Cpc-PH were 63 and 82% (area under the curve 0.73). A simple echocardiographic score helps in the differential diagnosis between precapillary and postcapillary pulmonary hypertension, and between Ipc-PH and Cpc-PH.