Combined Pre- And Post-capillary PH Research Articles

Pathobiological characterization of pulmonary hypertension associated with heart failure with preserved ejection fraction

Abstract Introduction Heart failure with preserved ejection fraction (HFpEF) is an age-related cardiometabolic disease associated with vascular inflammation in cardiac tissue, pulmonary congestion and right ventricular dysfunction. Patients with HFpEF often develop pulmonary hypertension (PH) and right ventricular (RV) hypertrophy. Pulmonary vascular remodeling contributes to combined post- and precapillary PH (CpcPH), which is associated with worse outcome in humans. A recently developed meta-inflammatory murine HFpEF model approximates the characteristics of human HFpEF. Herein, HFpEF is induced by metabolic (high-fat diet (HFD)) and hypertensive stress (inhibition of constitutive NO synthase by Nω-nitro-1-arginomethyl ester (L-NAME)) over a 12-week period of time. With a focus on PH, we have developed a 'three-hit' model based on this model with a supplementary 21- or 42-day hypoxia phase (HFpEF-CpcPH). Methods Adult C57BL/6N mice were fed HFD for 15 or 18 weeks and supplied with L-NAME (0,5g/L or 1g/L) via drinking water, including a final period of 21 or 42 days, respectively, of hypoxia (normobaric, 10 % oxygen) or normoxia. Transthoracic echocardiography was performed using a small animal ultrasound device (Vevo 3100, Visual Sonics) and measurement of right ventricular systolic pressure (RVSP) using a Millar® pressure catheter (Mil-SPR-1000) inserted into the right ventricle. Right ventricular hypertrophy was measured as the ratio of the wet weight of the right ventricle to the left ventricle including the septum (RV/LV+S). Results Administration of HFD and L-NAME had no significant effect on RVSP in either HFpEF-normoxia group (15 weeks (n=8) or 18 weeks (n=5)) compared to the control group (n=8, n=5). 21 days of hypoxia increased RV systolic pressure (RVSP) to 37.05±1.6 (PH, n=8) and 40.33±0.87 mmHg (HFpEF-CpcPH, n=8) respectively, while 42 days of hypoxia caused no further increase (35.1±3.5 mmHg (PH, n=5) and 35.24±3.47 mmgHg (HFpEF-CpcPH, n=4)), respectively. RV hypertrophy (RV/LV+S) was significantly increased after 21 days of hypoxia in HFpEF-CpcPH compared to HFpEF (n=8) (34.42±1.75 vs. 24.93±1.1). Again, 42 days of hypoxia did not lead to a further increase in RV hypertrophy (35.2±3.9 vs. 25.80±4.39) in HFpEF-CpcPH, even though there was a significant difference compared to the HFpEF group. As expected, the heart weight/body weight ratio was significantly increased in HFpEF-CpcPH compared to HFpEF at both time points. However, mice under the prolonged hypoxia phase showed a significantly greater decrease in body weight, which complicates the interpretation of the results. Conclusion In summary, we could show that in the meta-inflammatory HFpEF model no significant PH can be observed within the investigated periods of time. However, a 21 day hypoxia phase was sufficient to induce a HFpEF-CpcPH phenotype. This model provides an important basis to develop new therapeutic approaches.

Long-term Efficacy of Pulmonary Artery Desnervation Treatment in Heart Failure With Preserved Ejection Fraction: A Subgroup Analysis of 3-year Results From the PADN-5 Study

Objective: The Pulmonary Arterial Denervation in Patients With Pulmonary Hypertension Associated With the Left Heart Failure (PADN-5) study proved that pulmonary artery denervation (PADN) is associated with significant improvements in hemodynamic and clinical outcomes in patients with combined pre- and post-capillary pulmonary hypertension (CpcPH). This study aimed to assess the 3-year clinical results of PADN in patients who had heart failure with preserved ejection fraction (HFpEF) developing into CpcPH (HFpEF-CpcPH). Methods: In this post hoc analysis of the PADN-5 trial, 38 patients with HFpEF were included in screening out of 98 patients with CpcPH who were randomly assigned to treatment with sildenafil and sham PADN (sham PADN (plus sildenafil) group, abbreviated as sham group) or PADN (PADN group). HFpEF in the PADN-5 trial was defined as a left ventricular ejection fraction ≥50%, and CpcPH was defined as a mean pulmonary arterial pressure ≥25 mmHg, a pulmonary arterial wedge pressure >15 mmHg, and a pulmonary vascular resistance >3.0 WU. The changes in the 6-minute walk distance (6-MWD) and the plasma concentration of N-terminal pro-brain natriuretic peptide (NT-proBNP) at 6-month and 3-year follow-up, as well as the clinical endpoint of the occurrence of clinical worsening, defined as cardiopulmonary-related death, rehospitalization, or heart or lung transplantation at 3-year follow-up were examined. Results: Thirty-eight patients with HFpEF-CpcPH were assigned to the PADN group (n = 19) or the sham group (n = 19). At the 6-month follow-up, 6-MWD (433 (275, 580)m vs. 342 (161, 552)m), and reductions in NT-proBNP (−47% (−99%, 331%) vs. −12% (−82%, 54%)) were significantly improved in the PADN group (all P < 0.05). Over the 3-year follow-up period, PADN treatment resulted in marked increases in 6-MWD (450 (186, 510)m vs. 348 (135, 435)m) and reductions in NT-proBNP (−55% (−99%, 38%) vs. −10% (−80%, 95%)) (all P < 0.05). Clinical worsening was experienced by 12 patients (63%) in the sham group, but by only 5 patients (26%) in the PADN group (hazard ratio = 0.149, 95% confidence interval: 0.038–0.584, P = 0.006). The 6-MWD and PADN treatments were independent predictors of clinical deterioration in patients with HFpEF-CpcPH. Conclusions: PADN therapy is associated with improvements in exercise capacity and clinical outcomes. PADN therapy may have a potential role in patients with HFpEF-CpcPH for whom current treatment options are limited.

Impact of the 2022 pulmonary hypertension definition on haemodynamic classification and mortality in patients with aortic stenosis undergoing valve replacement.

With the 2022 pulmonary hypertension (PH) definition, the mean pulmonary artery pressure (mPAP) threshold for any PH was lowered from ≥25 to >20 mmHg, and the pulmonary vascular resistance (PVR) value to differentiate between isolated post-capillary PH (IpcPH) and combined pre- and post-capillary PH (CpcPH) was reduced from >3 Wood units (WU) to >2 WU. We assessed the impact of this change in the PH definition in aortic stenosis (AS) patients undergoing aortic valve replacement (AVR). Severe AS patients (n = 503) undergoing pre-AVR cardiac heart catheterization were classified according to both the 2015 and 2022 definitions. The post-AVR mortality [median follow-up 1348 (interquartile range 948-1885) days] was assessed. According to the 2015 definition, 219 (44% of the entire population) patients had PH: 63 (29%) CpcPH, 125 (57%) IpcPH, and 31 (14%) pre-capillary PH. According to the 2022 definition, 321 (+47%) patients were diagnosed with PH, and 156 patients (31%) were re-classified: 26 patients from no PH to IpcPH, 38 from no PH to pre-capillary PH, 38 from no PH to unclassified PH, 4 from pre-capillary PH to unclassified PH, and 50 from IpcPH to CpcPH (CpcPH: +79%). With both definitions, only the CpcPH patients displayed increased mortality (hazard ratios ≈ 4). Among the PH-defining haemodynamic components, PVR was the strongest predictor of death. In severe AS, the application of the 2022 PH definition results in a substantially higher number of patients with any PH as well as CpcPH. With either definition, CpcPH patients have a significantly increased post-AVR mortality.

Effect of Acute Vasodilator Testing Using Oxygen in Pulmonary Hypertension Due to Left Heart Disease.

Pulmonary vasodilators, including oxygen, have not shown consistent beneficial effects on pulmonary hypertension due to valvular heart disease (PH-VHD). Therefore, the study aimed to assess the effect of 100% fractional inspiration of oxygen (FiO2) on pulmonary and systemic hemodynamics in patients with combined pre- and post-capillary pulmonary hypertension (CpcPH) and isolated post-capillary pulmonary hypertension (IpcPH) due to PH-VHD. This prospective study was conducted among patients with PH-VHD undergoing mitral or aortic valve replacement or repair. The study was conducted after induction of anesthesia and pulmonary artery catheterization. Cardiac output was obtained using thermodilution and all direct, and derived hemodynamic variables were obtained at 30% and 100% FiO2. The patients were stratified a priori into responders {(≥10mmHg fall in mean pulmonary artery pressure (MPAP)} and non-responders. Fifty-seven patients completed the acute vasodilator test. The mean age and body mass index of the study population was 41.8 ± 14.1years and 21.4 ± 4.6kg/m2, respectively. There was a significant decrease in MPAP (40.77 ± 12.07mmHg vs 36.74 ± 13.3mmHg; P < .001) and pulmonary vascular resistance (PVR) {(median; Interquartile range (IQR); 388; 371 vs 323; 362dynes sec.cm-5; P < .001) at 100% FiO2. Transpulmonary gradient (TPG) and diastolic pulmonary gradient (DPG) also decreased significantly (P < .001 and P < .001). Cardiac output did not change significantly. The magnitude of decrease in MPAP, PVR, TPG, DPG, and pulmonary artery compliance (PAC) between CpcPH and IpcPH was comparable. Responders did not show a significantly greater fall in MPAP, PVR, TPG, DPG, and PAC after surgery. Hyperoxia may lead to reduction in MPAP and PVR in both hemodynamic phenotypes of PH-VHD. A larger sample size is required to support or refute the findings of this study.

Omics and Extreme Phenotyping Reveal Longitudinal Association Between Left Atrial Size and Pulmonary Vascular Resistance in Group 2 Pulmonary Hypertension.

Left heart disease is the most common cause of pulmonary hypertension (PH) and is frequently accompanied by increases in pulmonary vascular resistance. However, the distinction between phenotypes of PH due to left heart disease with a normal or elevated pulmonary vascular resistance-isolated postcapillary PH (IpcPH) and combined pre- and postcapillary PH (CpcPH), respectively-has been incompletely defined using unbiased methods. Patients with extremes of IpcPH versus CpcPH were identified from a single-center record of those who underwent right heart catheterization. Individuals with left ventricular ejection fraction <40% or with potential causes of PH beyond left heart disease were excluded. Medication usage in IpcPH and CpcPH was compared across Anatomical Therapeutic Chemical classes and identified vitamin K antagonists as the only medication with pharmacome-wide significance, being more commonly used in CpcPH and for an indication of atrial fibrillation in ≈90% of instances. Accordingly, atrial fibrillation prevalence was significantly higher in CpcPH in a phenome-wide analysis. Review of echocardiographic data most proximal to right heart catheterization revealed that left atrial diameter indexed to body surface area-known to be associated with atrial fibrillation-was increased in CpcPH regardless of the presence of atrial fibrillation. An independent cohort with serial right heart catheterizations and PH-left heart disease showed a significant positive correlation between change in left atrial diameter indexed to body surface area and change in pulmonary vascular resistance. Guided by pharmacomic and phenomic screens in a rigorously phenotyped cohort, we identify a longitudinal association between left atrial diameter indexed to body surface area and pulmonary vascular resistance with implications for the future development of diagnostic, prognostic, and therapeutic tools.

By using the new hemodynamic definition of pulmonary hypertension in patients with left heart disease the prognostic value of different phenotypes might be lost

Abstract Background and aims In the 2022 ECS/ERS pulmonary hypertension (PH) guidelines the threshold for increased pulmonary vascular resistance (PVR) was lowered from 3 to 2 Wood Units (WU). Consequently, in patients with PH due to left heart disease, the proportions of patients with combined pre- and postcapillary PH (CpcPH) will increase while the proportion with isolated post-capillary PH (IpcPH) will decrease. In the present study we investigate in patients with left heart disease the impact of this revision in terms of hemodynamic profile, right ventricular (RV) function and prognostication. Methods. Two-hundred and two patients consecutively referred for heart transplant or heart failure work-up were included with right heart catheterization and echocardiography within 48 hours. RV dysfunction was graded using a novel echocardiographic score allocating one point each for (1) systolic pulmonary artery pressure (PAP) &amp;gt;40 mmHg, (2) reduced tricuspid annular plane systolic excursion (TAPSE&amp;lt;17 mm), (3) RV area dilatation, (4) moderate/severe tricuspid regurgitation and (5) reduced inferior cava collapsibility. For assessment of prognostication, we studied the end-point of all-cause mortality. Results. One-hundred and seventy-three patients (86%) had left ventricular ejection fraction &amp;lt;40%. Eighty-nine patients (44%) underwent heart transplantation and the median (25%; 75% percentile) follow-up time (years) was 1.8 (0.35; 6.7). Sixty patients (30%) had mean PAP&amp;lt;20 mmHg, thus no PH. Ninety-six patients (48%) had IpcPH using PVR 3 WU as threshold. Lowering the threshold to PVR 2 WU decreased the corresponding proportion to 24%. The degree of backward failure (PA wedge pressure), forward failure (cardiac index) or RV dysfunction (RVD score) did not significantly differ by the change in hemodynamic definition (Table). With the previous hemodynamic definition, the Kaplan-Meier curves demonstrated increased mortality in CpcPH patients compared with IpcPH (Figure B). Using the new definition this difference was not present (Figure B). Conclusions. The revised hemodynamic definition of PH significantly increases the proportion with CpcPH, but does not significantly alter the hemodynamic or RV function profiles in left heart disease patients with IpcPH or CpcPH phenotype. However, our findings indicate that by using the new hemodynamic definition of IpcPH and CpcPH phenotype the prognostic value of this hemodynamic classification might be lost.Table

Abstract 15769: Ventricular Interdependent Phenotype of CPC-Pulmonary Hypertension With Normal Left Atrium and Pericardial Restraint: Impact on CPET Metrics and Clinical Outcomes

Background: Combined pre- and post-capillary pulmonary hypertension (Cpc-PH) has overlapping pathophysiology due to left heart disease and pulmonary vascular disease, which may vary in an individual patient. Hypothesis: While the majority of CpcPH patients have left heart disease with abnormal left atrium, a minority of CpcPH patients have normal left atrium and develop elevated left-sided pressures due to exaggerated ventricular interdependence and pericardial restraint. Aim: to define ventricular interdependent sub-phenotype of CpcPH. Methods: 30 CpcPH patients undergoing invasive cardiopulmonary exercise test with complete echocardiographic data were identified. Abnormal left atrium group was defined as left atrial volume index ≥40mL/m 2 and E/E' ≥10, and rest was defined as normal left atrium group. p-value &lt;0.05* Results: Key metrics of abnormal (n=23) vs normal (n=7) left atrium subjects are shown in Figure. In the same order (abnormal vs normal), age was 65±15 vs 61±16, female gender 6 (26%) vs 4 (57%), BMI 34±8 vs 38±10, H2FpEF score 5.8±2.3 vs 5.3±1.7, BNP 514±406 vs 191±280, eccentricity index 1.12±0.25 vs 1.24±0.38, RV:LV ratio 0.9±0.3 vs 0.9±0.2, E' medial 5.6±1.7 vs 9.7±4.0*, E' lateral 6.8±2.2 vs 9.2±1.9*, TAPSE/PASP 0.33±0.12 vs 0.41±0.18, epicardial fat 6±2 vs 6±3, delta ETCO 2 -1.9±2.0 vs +1.7±2.1. Rest hemodynamics: mPAP 42±6 vs 37±11, PAWP 21±3 vs 18±3*, CO 4.9±1.4 vs 5.4±0.8, PVR 4.6±2.2 vs 3.4±1.5. With exercise: mPAP/CO slope 9.2±6.5 vs 6.1±4.5 and PVR 3.8±2.5 vs 2.7±1.2. Comorbidity burden between the two groups did not have a statistically significant difference. On one-year follow-up, incidence of mortality and heart failure hospitalizations were: 16 (69%) vs 1 (14%)*. Conclusions: A subset of CpcPH with normal left atrium have increased pericardial restraint and lower left ventricular transmural pressure. This likely leads to LV compression and Cpc-PH physiology. This sub-cohort has better exercise capacity and clinical outcomes.

Diagnosing post-capillary hypertension in patients with left heart disease: impact of new guidelines.

In 2022, the definition of pulmonary hypertension (PH) in the presence of left heart disease was updated according to the new joint guidelines of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS). The impact of the new ESC/ERS definition on the prevalence of post-capillary PH (pc-PH) and its subgroups of isolated post-capillary (Ipc-PH) and combined pre- and post-capillary PH (Cpc-PH) in patients with left heart disease is unclear. We retrospectively identified N = 242 patients with left heart disease with available data on right heart catheterisation (RHC) and cardiac magnetic resonance imaging (CMR). The proportion of pc-PH and its subgroups was calculated according to the old and new ESC/ERS PH definition. As the old definition did not allow the exact allocation of all patients with pc-PH into a respective subgroup, unclassifiable patients (Upc-PH) were regarded separately. Seventy-six out of 242 patients had pc-PH according to the new ESC/ERS definitions, with 72 of these patients also meeting the criteria of the old definition. Using the old definition, 50 patients were diagnosed with Ipc-PH, 4 with Cpc-PH, and 18 with Upc-PH. Applying the new definition, Ipc-PH was diagnosed in 35 patients (4 newly), and Cpc-PH in 41 patients. No CMR parameter allowed differentiating between Ipc-PH and Cpc-PH, regardless of which guideline version was used. Applying the new ESC/ERS 2022 guideline definitions mildly increased the proportion of patients diagnosed with pc-PH (+ 5.5%) but markedly increased Cpc-PH diagnoses. This effect was driven by the allocation of patients with formerly unclassifiable forms of post-capillary PH to the Cpc-PH subgroup and a significant shift of patients from the Ipc-PH to the Cpc-PH subgroup. Distribution of post-capillary pulmonary hypertension (pc-PH) subgroups according to the European Society of Cardiology/European Respiratory Society (ESC/ERS) PH guidelines from 2015 and 2022 in N = 242 patients with left heart disease.

Long-term outcome of patients with combined post- and pre-capillary pulmonary hypertension.

Pulmonary hypertension (PH) is a complex clinical condition, and left heart disease is the leading cause. Little is known about the epidemiology and prognosis of combined post- and pre-capillary PH (CpcPH). This retrospective analysis of the Swiss PH Registry included incident patients with CpcPH registered from January 2001 to June 2019 at 13 Swiss hospitals. Patient baseline characteristics [age, sex, mean pulmonary artery pressure (mPAP), pulmonary artery wedge pressure (PAWP), pulmonary vascular resistance (PVR), and risk factors, including World Health Organization (WHO)-functional class (FC), 6 min walk distance (6MWD), and N-terminal pro-brain natriuretic peptide (NT-proBNP), treatment, days of follow-up, and events (death or loss to follow-up) at last visit] were analysed by Kaplan-Meier and Cox regression analyses. Two hundred and thirty-one patients (59.3% women, age 65 ± 12 years, mPAP 48 ± 11 mmHg, PAWP 21 ± 5 mmHg, PVR 7.2 ± 4.8 WU) were included. Survival analyses showed a significantly longer survival for women [hazard ratio (HR) 0.58 (0.38-0.89); P = 0.01] and a higher mortality risk for mPAP > 46 mmHg [HR 1.58 (1.03-2.43); P = 0.04] but no association with age or PVR. Patients stratified to high risk according to four-strata risk assessment had an increased mortality risk compared with patients stratified to low-intermediate risk [HR 2.44 (1.23-4.84); P = 0.01]. A total of 46.8% of CpcPH patients received PH-targeted pharmacotherapy; however, PH-targeted medication was not associated with longer survival. Among patients with CpcPH, women and patients with an mPAP ≤46 mmHg survived longer. Furthermore, risk stratification by using non-invasively assessed risk factors, such as WHO-FC, 6MWD, and NT-proBNP, as proposed for pulmonary arterial hypertension, stratified survival in CpcPH, and might be helpful in the management of these patients.

Pulmonary hypertension associated with left heart disease.

Pulmonary hypertension (PH) is acommon condition in patients with left heart disease (LHD) that is highly relevant for morbidity and mortality. While post-capillary in nature, the pathophysiology of PH in patients with LHD (heart failure/cardiomyopathy, valvular heart disease; other: congenital/acquired) is complex, and decisions about management strategies are challenging. Recently, the updated European Society of Cardiology/European Respiratory Society guidelines on the diagnosis and treatment of PH revisited hemodynamic definitions and the sub-classification of post-capillary PH, and provided numerous new recommendations on the diagnosis and management of PH associated with various types of LHD. Here, we review several novel aspects that focus on: (a)updated hemodynamic definitions, including the distinction between isolated post-capillary PH (IpcPH) and combined post- and pre-capillary PH (CpcPH); (b)the pathogenesis of PH-LHD, considering various components contributing to PH, such as pulmonary congestion, vasoconstriction, and vascular remodeling; (c)the prognostic relevance of PH and hemodynamic markers; (d)the diagnostic approach to PH-LHD; (e)management strategies in PH-LHD, distinguishing between targeting the underlying left heart condition, the pulmonary circulation, and/or impaired right ventricular function. In conclusion, precise clinical and hemodynamic characterization and detailed phenotyping are essential for prognostication and the management of patients with PH-LHD.

Clinical features do not identify risk of progression from isolated postcapillary pulmonary hypertension to combined pre- and postcapillary pulmonary hypertension.

Pulmonary hypertension is a common sequelae of left heart failure and may present as isolated postcapillary pulmonary hypertension (Ipc-PH)or combined pre- and postcapillary pulmonary hypertension (Cpc-PH).Clinical features associated with progression from Ipc-PH to Cpc-PHhave not yet been described. We extracted clinical data from patients who underwent right heart catheterizations (RHC)on two separate occasions. Ipc-PH was defined as mean pulmonary pressure >20 mmHg, pulmonary capillary wedge pressure >15 mmHg, and pulmonary vascular resistance (PVR) < 3 WU. Progression to Cpc-PHrequired an increase in PVR to ≥3 WU. We performed a retrospective cohort study with repeated assessments comparing subjects that progressed to Cpc-PHto subjects that remained with Ipc-PH.Of 153 patients with Ipc-PHat baseline who underwent a repeat RHC after a median of 0.7 years (IQR0.2, 2.1), 33% (50/153) had developed Cpc-PH.In univariate analysis comparing the two groups at baseline, body mass index (BMI)and right atrial pressure were lower, while the prevalence of moderate or worse mitral regurgitation (MR)was higher among those who progressed. In age- and sex-adjusted multivariable analysis, only BMI (OR0.94, 95% CI 0.90-0.99, p = 0.017, C = 0.655) and moderate or worse MR (OR3.00, 95% CI 1.37-6.60, p = 0.006, C = 0.654) predicted progression, but with poor discriminatory power. This study suggests that clinical features alone cannot distinguish patients at risk for development of Cpc-PH and support the need for molecular and genetic studies to identify biomarkers of progression.

Pulmonary Hypertension Phenotype Can Be Identified in Heart Failure With Reduced Ejection Fraction Using Echocardiographic Assessment of Pulmonary Artery Pressure With Supportive Use of Pressure Reflection Variables

Pulmonary hypertension (PH) is frequent in patients with heart failure and reduced ejection fraction (HFrEF) with 2 different phenotypes: isolated postcapillary PH (IpcPH) and, with the worst prognosis, combined pre- and postcapillary PH (CpcPH). The aims of the present echocardiography study were to investigate (1) the ability to identify PH phenotype in patients with HFrEF using the newly adopted definition of PH (mean pulmonary artery pressure >20mm Hg) and (2) the relationship between PH phenotype and right ventricular (RV) function. One hundred twenty-four patients with HFrEF consecutively referred for heart transplant or heart failure workup were included with echocardiography and right heart catheterization within 48hours. We estimated systolic pulmonary artery pressure (sPAPDoppler) and used a method to detect increased pulmonary vascular resistance (>3 Wood units) based on predefined thresholds of 3 pressure reflection (PRefl) variables (the acceleration time in the RV outflow tract [RVOT], the interval between peak RVOT and peak tricuspid regurgitant velocity, and the RV pressure augmentation following peak RVOT velocity). Using receiver operator characteristic analysis in a derivation group (n=62), we identified sPAPDoppler ≥35mm Hg as a cutoff that in a test group (n=62) increased the likelihood of PH 6.6-fold. The presence of sPAPDoppler >40mm Hg and 2 or 3 positive PRefl variables increased the probability of CpcPH 6- to 8-fold. A 2-step approach with primarily assessment of sPAPDoppler and the supportive use of PRefl variables in patients with mild/moderate PH (sPAPDoppler 41-59mm Hg) showed 76% observer agreement and a weighted kappa of 0.63. The steady-state (pulmonary vascular resistance) and pulsatile (compliance, elastance) vascular loading are increased in both IpcPH and CpcPH with a comparable degree of RV dysfunction. The PH phenotype can be identified in HFrEF using standard echocardiographic assessment of pulmonary artery pressure with supportive use of PRefl variables in patients with mild to moderate PH.

Lung diffusion capacity correlates with pre-implant pulmonary hypertension and predicts outcome after LVAD implantation.

Diffusing capacity of the lung for carbon monoxide (DLCO ) reduction is common in heart failure (HF) and is associated with a worse prognosis. Correlations between DLCO and pulmonary hypertension (PH) are unclear, and published data are conflicting; it has been shown that DLCO impairment may persist or even worsen after normalization of pulmonary pressures following left ventricle assist device (LVAD) implantation, maybe reflecting persistent pulmonary damage. We aimed to investigate the impact of pre-implant DLCO and central haemodynamics on outcome in patients with advanced HF implanted with a LVAD. We retrospectively analysed pre-implant and post-implant data from 42 patients implanted with a LVAD at our institution. Out of 42 patients, 35 had post-capillary PH before implantation, including 17 with combined post- and pre-capillary PH (Cpc-PH). Median DLCO was 59% (IQR 47-68%), and it inversely correlated with pulmonary vascular resistance (PVR) (P 0.037) and diastolic pulmonary gradient (DPG) (P 0.042). Compared with baseline, LVAD resulted in improvement in LV diameter (LVDd, P<0.001), mitral regurgitation (P 0.022), and PH (mPAP 24 vs. 36mmHg, P<0.001; PAWP 12 vs. 23mmHg, P 0.001; pulmonary artery compliance, CPA 3.1 vs. 1.9mL/mmHg, P 0.021). Lower DLCO and Cpc-PH at baseline were associated with a better LV reverse remodelling post-implantation (P 0.027 for LVDd) but also with a smaller gain in CPA (P 0.049). Before LVAD implantation, DLCO impairment is associated with higher PVR and DPG, suggesting that it might be an expression of persistent pulmonary damage occurring in Cpc-PH. After LVAD implantation, both LV dimension and haemodynamics improve. Lower pre-implant DLCO is associated with better LV reverse remodelling.

β3 adrenergic agonist treatment in chronic pulmonary hypertension associated with heart failure (SPHERE-HF): a double blind, placebo-controlled, randomized clinical trial.

Pulmonary hypertension (PH) associated with left heart disease is an increasingly prevalent problem, orphan of targeted therapies, and related to a poor prognosis, particularly when pre- and post-capillary PH combine. The current study aimed to determine whether treatment with the selective β3 adrenoreceptor agonist mirabegron improves outcomes in patients with combined pre- and post-capillary PH (CpcPH). The β3 Adrenergic Agonist Treatment in Chronic Pulmonary Hypertension Secondary to Heart Failure (SPHERE-HF) trial is a multicentre, randomized, parallel, placebo-controlled clinical trial that enrolled stable patients with CpcPH associated with symptomatic heart failure. A total of 80 patients were assigned to receive mirabegron (50 mg daily, titrated till 200 mg daily, n=39) or placebo (n=41) for 16 weeks. Of them, 66 patients successfully completed the study protocol and were valid for the main analysis. The primary endpoint was the change in pulmonary vascular resistance (PVR) on right heart catheterization. Secondary outcomes included the change in right ventricular (RV) ejection fraction by cardiac magnetic resonance or computed tomography, other haemodynamic variables, functional class, and quality of life. The trial was negative for the primary outcome (placebo-corrected mean difference of 0.62 Wood units, 95% confidence interval [CI] -0.38, 1.61, p=0.218). Patients receiving mirabegron presented a significant improvement in RV ejection fraction as compared to placebo (placebo-corrected mean difference of 3.0%, 95% CI 0.4, 5.7%, p=0.026), without significant differences in other pre-specified secondary outcomes. SPHERE-HF is the first clinical trial to assess the potential benefit of β3 adrenergic agonists in PH. The trial was negative since mirabegron did not reduce PVR, the primary endpoint, in patients with CpcPH. On pre-specified secondary outcomes, a significant improvement in RV ejection fraction assessed by advanced cardiac imaging was found, without differences in functional class or quality of life.

Thirty-year trends and outcome of isolated versus combined group 2 pulmonary hypertension after cardiac transplantation.

To investigate the effect of the new definition of pulmonary hypertension (PH) and new pulmonary vascular resistance (PVR) thresholds on the prevalence, clinical characteristics, and events following cardiac transplantation (CTx) over 30 years. Patients who underwent CTx between 1983 and 2014 for whom invasive hemodynamic data was available were analyzed (n = 342). Patients transplanted between 1983 and 1998 were classified as early era and those transplanted between 1999 and 2014 were classified as recent era. Group 2 PH was diagnosed in the presence of a mean pulmonary artery pressure (mPAP) > 20 mmHg and pulmonary capillary wedge pressure (PCWP) > 15 mmHg. Isolated post capillary PH (Ipc-PH) was defined as PVR ≤ 2 wood units and combined pre and post capillary PH (Cpc-PH) was defined PVR > 2 wood units. Moderate to severe PH was defined as mPAP ≥ 35 mmHg. The primary outcome was 30-day mortality and long-term mortality according to type and severity of PH. Proportions were analyzed using the chi-square test, and survival analyses were performed using Kaplan-Meier curves and compared using the logrank test. The prevalence of PH in patients transplanted in the early era was 89.1%, whilst 84.2% of patients transplanted in the recent era had PH (p = 0.3914). There was no difference in the prevalence of a pre-capillary component according to era (p = 0.4001), but severe PH was more common in the early era (51.1% [early] vs 38.0% [recent] p = 0.0151). Thirty-day and long-term mortality were not significantly associated with severity or type of PH. There was a trend toward increased 30-day mortality in mild PH (10.1%), compared to no PH (4.4%) and moderate to severe PH (6.6%; p = 0.0653). Long-term mortality did not differ according to the severity of PH (p = 0.1480). There were no significant differences in 30-day or long-term mortality in IpcPH compared to CpcPH (p = 0.3974 vs p = 0.5767, respectively). Over 30 years, PH has remained very prevalent before CTx. The presence, severity, and type (pre- vs post-capillary) of PH is not significantly associated with short- or long-term mortality.

Effects of remote haemodynamic-guided heart failure management in patients with different subtypes of pulmonary hypertension: insights from the MEMS-HF study.

The CardioMEMS European Monitoring Study for Heart Failure (MEMS-HF) investigated safety and efficacy of pulmonary artery pressure (PAP)-guided remote patient management (RPM) in New York Heart Association (NYHA) class III outpatients with at least one heart failure hospitalization (HFH) during the previous 12 months. This pre-specified subgroup analysis investigated whether RPM effects depended on presence and subtype of pulmonary hypertension (PH). In 106/234 MEMS-HF participants, Swan-Ganz catheter tracings obtained during sensor implant were available for off-line manual analysis jointly performed by two experts. Patients were classified into subgroups according to current PH definitions. Isolated post-capillary PH (IpcPH) and combined post- and pre-capillary PH (CpcPH) were present in 38 and 36 patients, respectively, whereas 31 patients had no PH. Clinical characteristics were comparable between subgroups, but among patients with PH pulmonary vascular resistance was higher (p= 0.029) and pulmonary artery compliance lower (p= 0.003) in patients with CpcPH. During 12 months of PAP-guided RPM, all PAPs declined in IpcPH and CpcPH subgroups (all p< 0.05), whereas only mean and diastolic PAP decreased in patients without PH (both p< 0.05). Improvements in post- versus pre-implant HFH rates were similar in CpcPH (0.639 events/patient-year; hazard ratio [HR] 0.37) and IpcPH (0.72 events/patient-year; HR 0.45) patients. Participants without PH benefited most (0.26 events/patient-year; HR 0.17, p= 0.04 vs. IpcPH/CpcPH patients). Quality of life and NYHA class improved significantly in all subgroups. Outpatients with NYHA class III symptoms with at least one HFH during 1 year pre-implant benefitted significantly from PAP-guided RPM during post-implant follow-up irrespective of presence or subtype of PH at baseline.

Heart Failure with Preserved Ejection Fraction and Pulmonary Hypertension: Focus on Phosphodiesterase Inhibitors.

Pulmonary hypertension (PH) is common in patients with heart failure with preserved ejection fraction (HFpEF). A chronic increase in mean left atrial pressure leads to passive remodeling in pulmonary veins and capillaries and modest PH (isolated postcapillary PH, Ipc-PH) and is not associated with significant right ventricular dysfunction. In approximately 20% of patients with HFpEF, “precapillary” alterations of pulmonary vasculature occur with the development of the combined pre- and post-capillary PH (Cpc-PH), pertaining to a poor prognosis. Current data indicate that pulmonary vasculopathy may be at least partially reversible and thus serves as a therapeutic target in HFpEF. Pulmonary vascular targeted therapies, including phosphodiesterase (PDE) inhibitors, may have a valuable role in the management of patients with PH-HFpEF. In studies of Cpc-PH and HFpEF, PDE type 5 inhibitors were effective in long-term follow-up, decreasing pulmonary artery pressure and improving RV contractility, whereas studies of Ipc-PH did not show any benefit. Randomized trials are essential to elucidate the actual value of PDE inhibition in selected patients with PH-HFpEF, especially in those with invasively confirmed Cpc-PH who are most likely to benefit from such treatment.

Prognostic Implications of the Novel Pulmonary Hypertension Definition in Patients with Aortic Stenosis after Transcatheter Valve Replacement.

Introduction: Pulmonary hypertension (PH), traditionally defined as a mean pulmonary artery pressure (PAP) ≥ 25 mmHg, is associated with poor outcomes in patients undergoing a transcatheter aortic valve replacement (TAVR) for severe aortic stenosis (AS). Recently, a novel definition for PH has been proposed, placing the cut-off value of mean PAP at 20 mmHg, and introducing pulmonary vascular resistance as an exclusive indicator for the pre-capillary involvement. In light of the novel criteria, whether PH still preserves its prognostic significance remains unknown. Methods: The study population consisted of 380 patients with AS, who underwent a right heart catheterization before TAVR. The cohort was divided according to the presence of PH (n = 174, 45.7%) or not. Patients with PH were further divided into the following groups: (1) Pre-capillary PH ((Pre-capPH), n = 46, 12.1%); (2) Isolated post-capillary PH ((IpcPH), n = 78, 20.5%); (3) Combined pre and post-capillary PH ((CpcPH), n = 82, 21.6%). The primary endpoint was all-cause mortality at 1 year. Results: A total of 246 patients (64.7%) exhibited mean PAP > 20 mmHg. Overall, the presence of PH was associated with higher 1-year mortality rates (hazard ratio (HR) 2.8, 95% CI: 1.4–5.8, p = 0.004). Compared to patients with no PH, Pre-capPH and CpcPH (but not IpcPH) were related to higher 1-year mortality (HR 2.7, 95% CI: 1.0–7.2, p = 0.041 and HR 3.9, 95% CI: 1.8–8.5, p = 0.001, respectively). This remained significant even after the adjustment for baseline comorbidities. Conclusions: Pre-interventional PH according to the novel hemodynamic criteria, is linked with poor outcomes in patients undergoing TAVR for severe AS. However, this is mainly driven by patients with mean PAP ≥ 25 mmHg. Patients with a pre-capillary PH component as defined by increased PVR present an even worse prognosis as compared to patients with isolated post-capillary or no PH who present comparable 1-year mortality rates.

Beneficial Effects of Pulmonary Vasodilators on Pre-Capillary Pulmonary Hypertension in Patients with Chronic Kidney Disease on Hemodialysis.

Background: In patients with chronic kidney disease (CKD) on hemodialysis, comorbid pulmonary hypertension (PH) aggravates exercise tolerance and eventually worsens the prognosis. The treatment strategy for pre-capillary PH, including combined pre- and post-capillary PH (Cpc-PH), has not been established. Objectives: This study aimed to evaluate the impact of pulmonary vasodilators on exercise tolerance and pulmonary hemodynamics in patients with CKD on hemodialysis. Methods and Results: The medical records of 393 patients with suspected PH who underwent right heart catheterization were reviewed. Of these, seven patients had isolated pre-capillary PH and end-stage CKD on hemodialysis. Pulmonary vasodilators decreased pulmonary vascular resistance from 5.9 Wood units (interquartile range (IQR), 5.5–7.6) at baseline to 3.1 Wood units (IQR, 2.6–3.3) post-treatment (p = 0.02) as well as increased pulmonary capillary wedge pressure from 10 mmHg (IQR, 7–11) to 11 mmHg (IQR, 8–16) (p = 0.04). Pulmonary vasodilators increased the World Health Organization functional class I or II from 0% to 100% (p = 0.0002) and the 6 min walk distance from 273 m (IQR, 185–365) to 490 m (IQR, 470–550) (p = 0.03). Conclusions: Pulmonary vasodilators for PH in patients with CKD on hemodialysis decrease pulmonary vascular resistance and eventually improve exercise tolerance. Pulmonary vasodilators may help hemodialysis patients with pre-capillary PH, although careful management considering the risk of pulmonary edema is required.

Pulmonary Vascular Load Impairs Dynamic Right Ventricular-pulmonary Artery Coupling And Increases Lung Congestion During Exercise In Left Heart Disease

Background Pulmonary hypertension (PH) is common complication of left heart disease (LHD) and associated with poor outcomes. Exertional dyspnea and fatigue are frequently reported symptoms among patients with PH due to LHD, and these symptoms are more severely observed in patients with combined post- and pre-capillary PH (CpcPH) as compared with isolated post-capillary PH (IpcPH). However, the pathophysiologic mechanisms underlying exercise intolerance in this setting remain poorly understood. Methods Subjects with elevated both mean pulmonary artery pressure (>20 mmHg) and pulmonary capillary wedge pressure (PCWP) (>15 mmHg) at rest were classified into two groups: CpcPH (pulmonary vascular resistance [PVR]≥3.0 WU, n=32), IpcPH (PVR<3.0 WU, n=54), and controls (n=52) underwent cardiopulmonary exercise testing with invasive hemodynamics and simultaneous echocardiography and lung ultrasound in a prospective study. Results As compared with controls and IpcPH-LHD, subjects with CpcPH-LHD displayed poorer LV diastolic function, lower left atrial (LA) reservoir and booster strain with greater LA volume and more severe right ventricular systolic dysfunction at rest. With exercise, subjects with CpcPH-LHD displayed more severe exercise-induced pulmonary hypertension, higher right atrial pressure (RAP) and more pronounced right ventricular-pulmonary vascular uncoupling. Peak oxygen consumption was lowest in patients with CpcPH-LHD, coupled with greater limitations in cardiac output reserve and more severe increases in lung congestion, arterial hypoxia and pulmonary vascular resistance (Figure 1). Dynamic ventricular interaction was greatest in CpcPH-LHD, evidenced by greater LV eccentricity index and RAP/PCWP and less increase in LV transmural pressure compared with IpcPH-LHD (Figure 2). Conclusions : Patients with CpcPH-LHD display more severe abnormalities in pulmonary vascular reserve with exercise leading to greater lung congestion and enhanced exertional ventricular interdependence compared to patients with IpcPH-LHD. Further study is required to identify therapies targeting pulmonary vascular disease or ventricular interdependence to improve outcomes in people with CpcPH-LHD. Pulmonary hypertension (PH) is common complication of left heart disease (LHD) and associated with poor outcomes. Exertional dyspnea and fatigue are frequently reported symptoms among patients with PH due to LHD, and these symptoms are more severely observed in patients with combined post- and pre-capillary PH (CpcPH) as compared with isolated post-capillary PH (IpcPH). However, the pathophysiologic mechanisms underlying exercise intolerance in this setting remain poorly understood. Subjects with elevated both mean pulmonary artery pressure (>20 mmHg) and pulmonary capillary wedge pressure (PCWP) (>15 mmHg) at rest were classified into two groups: CpcPH (pulmonary vascular resistance [PVR]≥3.0 WU, n=32), IpcPH (PVR<3.0 WU, n=54), and controls (n=52) underwent cardiopulmonary exercise testing with invasive hemodynamics and simultaneous echocardiography and lung ultrasound in a prospective study. As compared with controls and IpcPH-LHD, subjects with CpcPH-LHD displayed poorer LV diastolic function, lower left atrial (LA) reservoir and booster strain with greater LA volume and more severe right ventricular systolic dysfunction at rest. With exercise, subjects with CpcPH-LHD displayed more severe exercise-induced pulmonary hypertension, higher right atrial pressure (RAP) and more pronounced right ventricular-pulmonary vascular uncoupling. Peak oxygen consumption was lowest in patients with CpcPH-LHD, coupled with greater limitations in cardiac output reserve and more severe increases in lung congestion, arterial hypoxia and pulmonary vascular resistance (Figure 1). Dynamic ventricular interaction was greatest in CpcPH-LHD, evidenced by greater LV eccentricity index and RAP/PCWP and less increase in LV transmural pressure compared with IpcPH-LHD (Figure 2). : Patients with CpcPH-LHD display more severe abnormalities in pulmonary vascular reserve with exercise leading to greater lung congestion and enhanced exertional ventricular interdependence compared to patients with IpcPH-LHD. Further study is required to identify therapies targeting pulmonary vascular disease or ventricular interdependence to improve outcomes in people with CpcPH-LHD.