Post-capillary Pulmonary Hypertension Research Articles

Left atrial deformation in estimating left atrial pressure

Abstract Background In the absence of mitral valve disease, elevated left atrial (LA) pressure reflects reduced left ventricular (LV) compliance and raised diastolic pressures, hence an important explanation for exertional breathlessness. Methods We studied 145 symptomatic patients, age 63±14 years, 55 males, using conventional transthoracic echocardiography guidelines protocol, including LA and LV myocardial deformation investigations along with simultaneous right heart catheterization using conventional techniques. From invasive measurements, pulmonary artery pressure (PAP), pulmonary capillary wedge pressure (PCWP) were measured and pulmonary vascular resistance (PVR) calculated. No patient had more than mild mitral or aortic valve disease. Results LA strain rate during atrial systole (LASRa) was the strongest correlate with PCWP (r2=−0.39, p<0.001), over and above LASR during LV systole (LASRs) and peak LA longitudinal strain (PALS) (r2=−0.21 and −0.19, respectively, p<0.001 for both). Both LASRa and PALS predicted elevated PCWP >15 mmHg but only modestly (AUC= 0.55 and 0.52). The relationship between LASRa and PCWP was stronger in patients with post-capillary pulmonary hypertension compared to those with pre-capillary pulmonary hypertension (r2=0.21 vs. r2=0.02). However, the strongest relationship between LASRa and PCWP was in patients with LA volume >34 ml/m2 (r2=0.59, p<0.001, see figure) but other strain relationships did not improve after only including patients with increased LA volume. Finally, LASRa correlated modestly with the respective LVSRa (r=0.53, P<0.01), and to lesser extent with other cavity interaction correlations (r=0.26–0.48, p<0.01). Conclusion Despite being somehow related to ventricular function, left atrial strain rate during atrial contraction is the closest correlate to PCWP, particularly in patients with dilated LA cavity. These data should be of significant clinical value in daily management of symptomatic patients. LASRaecho and PCWPrhc in patients with d Funding Acknowledgement Type of funding source: None

The assessment of right ventricular structure and function in patients with different cardiovascular diseases using modern echocardiographic technologies and magnetic resonance imaging

To perform comparative analysis of right ventricular (RV) structure and function in patients with various cardiovascular diseases using modern echocardiographic technologies in comparison with magnetic resonance imaging (MRI). The study included 85 patients. Group 1 consisted of 32 patients with idiopathic pulmonary hypertension (IPH) (mean age 35.910.2 years). Group 2 included 27 patients with arterial hypertension (AH) grade 3 (mean age 58.612.3 years). Group 3 consisted of 26 patients with chronic heart failure (CHF) (mean age 56.115.3 years). Control group included 28 healthy volunteers (mean age 38.710.9 years). The main method was transthoracic echocardiography (TTE) using modern technologies, such as three-dimensional echocardiography (3DE), tissue Doppler imaging (TDI), and speckle tracking echocardiography (STE). In some patients and healthy volunteers 3DE data were compared with MRI data. Patients with IPH and CHF had minimal RV ejection fraction (EF) both according to 3DE and MRI. Correlation analysis revealed close correlation between RV volumes and EF according to 3DE and MRI. Minimal values of systolic indicator STV according to TDI were observed in patients with CHF. In all groups, including control group, the highest values of STV were obtained at the level of the basal segments and the lowest values at the level of apical segments. STE revealed the same pattern as TDI. According to STE minimal RV strain was observed in IPH and CHF groups and significantly differed not only from control group, but also from AH group. The lowest values of RV EF and strain were observed in IPH and CHF groups. There were no significant differences in these indicators between the groups, that dictates the need for thorough assessment of RV structure and function not only in patients with precapillary, but also with postcapillary pulmonary hypertension. The results of the study confirm good comparability of 3DE and MRI in assessing RV volumes and EF.

Problematic aspects of pulmonary hypertension due to left heart disease: focus on combined postcapillary and precapillary pulmonary hypertension

Рulmonary hypertension (PH) is a common complication of left heart diseases. In addition to a passive increase of pressure in the venous bed of the pulmonary circulation, leading to an increase of mean pulmonary pressure, signs of precapillary PH could be detected in some patients. Since 2013, a hemodynamic subtype of PH due to left heart diseases combined post/precapillary PH has been identified, with a more unfavorable prognosis and high mortality.

Diagnostic utility of sub-maximum cardiopulmonary exercise testing in the ambulatory setting for heart failure with preserved ejection fraction.

Pulmonary hypertension is commonly associated with heart failure with preserved ejection fraction. In heart failure with preserved ejection fraction, the elevated left-sided filling pressures result in isolated post-capillary pulmonary hypertension or combined pre- and post-capillary pulmonary hypertension. Although right heart catheterization is the gold standard for diagnosis, it is an invasive test with associated risks. The ability of sub-maximum cardiopulmonary exercise test as an adjunct diagnostic tool in pulmonary hypertension-associated heart failure with preserved ejection fraction is not known. Forty-six patients with heart failure with preserved ejection fraction and pulmonary hypertension (27 patients with combined pre- and post-capillary pulmonary hypertension and 19 patients with isolated post-capillary pulmonary hypertension) underwent sub-maximum cardiopulmonary exercise test followed by right heart catheterization. The study also included 18 age- and gender-matched control subjects. Several sub-maximum gas exchange parameters were examined to determine the ability of sub-maximum cardiopulmonary exercise test to distinguish between isolated post-capillary pulmonary hypertension and combined pre- and post-capillary pulmonary hypertension. Conventional echocardiogram measures did not distinguish between isolated post-capillary pulmonary hypertension and combined pre- and post-capillary pulmonary hypertension. Compared to isolated post-capillary pulmonary hypertension, combined pre- and post-capillary pulmonary hypertension had greater ventilatory equivalent for carbon dioxide (VE/VCO2) slope, reduced delta end-tidal CO2 change during exercise, reduced oxygen uptake efficiency slope, and reduced gas exchange determined pulmonary vascular capacitance. The latter was significantly associated with right heart catheterization determined pulmonary artery compliance (r = 0.5; p = 0.0004). On univariate analysis, sub-maximum VE/VCO2, delta end-tidal carbon dioxide, and gas exchange determined pulmonary vascular capacitance emerged as independent predictors of the extrapolated maximum oxygen uptake (%predicted) (β-coefficient values of –7.32, 95% CI: –13.3 – (–1.32), p = 0.01; 8.01, 95% CI: 1.96–14.05, p = 0.01; 8.78, 95% CI: 2.26–15.29, p = 0.01, respectively). Sub-maximum gas exchange parameters obtained during cardiopulmonary exercise test in an ambulatory setting allows for discrimination between isolated post-capillary pulmonary hypertension and combined pre- and post-capillary pulmonary hypertension. Additionally, sub-maximum cardiopulmonary exercise test derived VE/VCO2, delta end-tidal carbon dioxide, and gas exchange determined pulmonary vascular capacitance influences aerobic capacity in heart failure with preserved ejection fraction.

Right ventricular dysfunction and long-term risk of death.

Sudden cardiac death (SCD), or sudden loss of life-sustaining systemic and cerebral perfusion, is most often due to left ventricular (LV) dysfunction secondary to ischemic or structural cardiac disease or channelopathies. Degeneration of sinus rhythm into ventricular tachycardia and ultimately ventricular fibrillation is the final common pathway for most heart failure patients. Right ventricular (RV) dysfunction is recognized as an independent contributor to worsening heart failure. There is emerging evidence that RV dysfunction may also be an independent predictor of SCD. This review examines the role of RV dysfunction on modifying long term risk of SCD, and explores possible mechanisms that may underlie SCD. The RV has unique anatomy and physiology compared to the LV. Subsequently, we begin with a review of cardiac embryology, focusing on the chambers, valves, coronary arteries, and cardiac conduction system to understand the origins of RV dysfunction. Static and dynamic physiology of the RV is contrasted with that of the LV. Particular emphasis is placed on ventriculo-arterial coupling, mechanical cardiac constraint, and ventricular interdependence. The epidemiology of SCD is briefly reviewed to highlight how causes of SCD are age-specific. In turn, the age-specific causes of RV dysfunction are presented, including those which predominate in childhood and adolescence [arrhythmogenic RV dysplasia (ARVD) and hypertrophic cardiomyopathy (HCM)] and older adulthood (cardiac ischemia, chronic congestive heart failure and post-capillary pulmonary hypertension, and pulmonary hypertension). There is a clear need for additional studies on the independent contribution of RV dysfunction to overall functional capacity, SCD-associated mortality, and non-SCD-associated mortality. Discovery would be aided by the development of prospective cohorts with excellent RV phenotyping, coupled with deeper biologic measurements linking mechanisms to clinically relevant outcomes.

HEMODYNAMIC PHENOTYPES OF PULMONARY HYPERTENSION IN PVDOMICS

SESSION TITLE: Pulmonary Vascular Disease Posters SESSION TYPE: Original Investigation Posters PRESENTED ON: October 18-21, 2020 PURPOSE: PVDOMICS (Redefining Pulmonary Hypertension through Pulmonary Vascular Disease Phenomics) is a NIH-funded initiative that aims to re-examine the current pulmonary hypertension (PH) classification based on shared biological features. The study enrolled 1198 subjects comprised of patients with PH and comparators with heart, lung and sleep comorbidities without PH and healthy controls from six centers in the United States. We sought to describe clinical phenotypes of enrollees based on hemodynamic profiles of isolated pre-capillary PH (PrePH), isolated post-capillary PH (PostPH), and combined pre- and post-capillary PH (CpcPH) defined by the 2013 WSPH statement used at the time of protocol development. METHODS: Enrollees including incident or prevalent diagnoses, underwent deep phenotyping including history and physical examination, cardiac imaging, pulmonary function testing, six-minute walk testing and right heart catheterization. Enrollees were assigned to WSPH categories by the center investigator with a secondary diagnosis allowed based on clinical context including imaging and provocative testing. PrePH (mean PA pressure (mPAP) >25mmHg, wedge pressure <15mmHg), PostPH (mPAP>25mmHg, wedge pressure >15mmHg, diastolic pressure gradient (DPG) <7mmHg) and CpcPH (mPAP >25mmHg, wedge pressure >15mmHg, DPG≥7mmHg). p<0.05 was considered significant. RESULTS: In the 709 enrollees whose hemodynamics were in one of the above categories, 474 (66%) had PrePH, 116 (16%) had CpcPH and 119 (17%) had PostPH. CpcPH hemodynamics were found in 43 (13%) of Group 1, 44 (33%) Group 2, 16 (11%) Group 3, and 7 (13%) of Group 4 enrollees. In the 338 patients with Group 1, Group 2 and combined 1 and 2 (Group 1,2) PH, there were 220 enrollees with PrePH, 52 with CpcPH, and 66 with PostPH. CpcPH included 23 Group 1, 14 Group 1,2, 14 Group 2 PH and 1 Group 2 comparator patients. CpcPH patients had higher BMI than PrePH, but similar age. Six minute walk distance was lower in CpcPH compared to PrePH. On cardiac MRI, there were no differences in RV ejection fraction between PrePH and CpcPH, and both were lower than PostPH. Compared with PrePH, CpcPH patients had higher resting right atrial pressure, higher mPAP though PVR was similar. Wedge pressure was intermediate between PrePH and PostPH. CONCLUSIONS: Resting CpcPH hemodynamics are present in all WSPH Groups and most common in Group 2 PH. There was modest agreement between physician’s judgement of mixed group 1,2 PH and CpcPH hemodynamics, suggesting that resting hemodynamics alone cannot fully account for clinically assigned phenotype. CpcPH patients had similar degree of RV dysfunction by cardiac MRI and echocardiogram compared with PrePH, however they had evidence of more significant right heart failure on right heart catheterization. CLINICAL IMPLICATIONS: CpcPH hemodynamics are prevalent in all WSPH groups of PH. How this impacts outcomes and treatment is unknown. DISCLOSURES: No relevant relationships by Erika Berman Rosenzweig, source=Web Response Advisory Committee Member relationship with Liquidia Please note: $1001 - $5000 Added 03/19/2020 by Robert Frantz, source=Web Response, value=Consulting fee Advisory Committee Member relationship with Altavant Please note: $1001 - $5000 Added 03/19/2020 by Robert Frantz, source=Web Response, value=Consulting fee Advisory Committee Member relationship with Actelion Please note: $5001 - $20000 Added 07/16/2020 by Robert Frantz, source=Web Response, value=Consulting fee No relevant relationships by Paul Hassoun, source=Web Response Advisory Committee Member relationship with actelion Please note: $1001 - $5000 Added 06/01/2020 by Anna Hemnes, source=Web Response, value=Consulting fee Advisory Committee Member relationship with bayer Please note: $1001 - $5000 Added 06/01/2020 by Anna Hemnes, source=Web Response, value=Consulting fee Advisory Committee Member relationship with Complexa Please note: $1-$1000 Added 06/01/2020 by Anna Hemnes, source=Web Response, value=Consulting fee Advisory Committee Member relationship with United Therapeutics Please note: $1001 - $5000 Added 06/01/2020 by Anna Hemnes, source=Web Response, value=Consulting fee Scientific Medical Advisor relationship with PHPrecisionMed Please note: $1-$1000 Added 06/01/2020 by Anna Hemnes, source=Web Response, value=Ownership interest no disclosure on file for Evelyn Horn; No relevant relationships by Miriam Jacob, source=Web Response My spouse/partner as a Consultant relationship with Cellectis Please note: >$100000 Added 05/28/2020 by Jane Leopold, source=Web Response, value=Consulting fee No relevant relationships by Milena Radeva, source=Web Response no disclosure on file for Franz Rischard

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

Non-compliant Left Atrium Due to Scarring From Atrial Fibrillation Ablation Leads to Discordance of PAWP-LVEDP and Severe Post-Capillary Pulmonary Hypertension

Introduction Atrial fibrillation (AF) is one etiology of WHO group II post-capillary pulmonary hypertension (PH). Higher left atrial pressure, estimated as pulmonary artery wedge pressure (PAWP) out of proportion to left ventricular end-diastolic pressure (LVEDP), has been reported in AF. However, the impact of atrial scarring associated with AF ablation (ABL) on these pressure differences remains unclear. Hypothesis Extensive AF ABL leads to scarring of the left atrial wall, decreasing atrial compliance, which leads to elevated left atrial pressure in the presence of a lower LVEDP creating a PAWP-LVEDP gradient. Methods We selected all patients who were diagnosed with PH (n=4,945) between 2009 and 2019 at the University of Wisconsin-Madison who underwent simultaneous right and left heart catheterization and had an EP procedure (n=27), after excluding patients with significant mitral valve disease and amyloid. We then divided them into 3 groups: group 1 (AF-ABL) n=5, group 2 (AF) n=16, group 3 (no AF) n=6. Results The PAWP-LVEDP gradient among three groups was (AF-ABL vs AF vs No AF): +6.8±3.42 vs -0.2±4.4 vs -1.8±4.0 mm Hg (Figure). Among the overall cohort, we further analyzed the patients with PAWP-LVEDP gradient >2 (discordant) vs ≤2 (concordant). PAWP-LVEDP gradient between the discordant group (n=12) vs the concordant group (n=15) was +5.0±2.7 vs -2.7±3.6*. Among the discordant group, 5 had AF ABL and 6 had AF. Among the concordant group, 5 had no AF, 10 had AF and no patients had AF ABL. The characteristics between discordant (DIS) vs concordant (CON) groups were: Age 68.2 ± 10 vs 67.0 ± 19.3, BMI 33.6 ± 4.55 vs 30.8 ± 11.2, diabetes 33% vs 47%, hypertension 75% vs 67%, OSA 91% (11/12) vs 40% (6/15)*, systolic pulmonary artery pressure (PAP) 55±19 vs 41±11*, mean PAP 37±12 vs 29±8*, PAWP 20±6 vs 18±7*, LVEDP 15±6 vs 20±7*. All patients who underwent ablation had persistent type AF and had extensive ablation beyond PVI (4 of 5 with PVI). Among the 16 patients with AF (without ABL - 6 in DIS, 10 in CON groups), 8 had paroxysmal (3 in DIS, 5 in CON) and 8 had persistent AF (3 in DIS, 5 in CON). While age, BMI, HTN and DM were similar among DIS vs CON groups, the incidence of OSA was higher. However, given the patients with elevated PAWP-LVEDP gradient have worse PH, we suspect they were more likely to be tested for OSA (referral bias). Conclusion AF ablation is associated with an increased PAWP-LVEDP gradient likely from atrial scarring and non-compliance of the left atrium. Patients with elevated PAWP-LVEDP gradient have worse pulmonary hypertension and are more likely to be diagnosed with OSA.

Pulmonary hypertension associated with left-sided heart failure.

Pulmonary hypertension is a common phenomenon in heart failure patients that is highly relevant for morbidity and outcome. Although postcapillary in nature, the pathophysiology of pulmonary hypertension in patients with heart failure with reduced or preserved ejection fraction is complex, and decisions about management strategies remain challenging. Recently, the hemodynamic definitions and subclassification of postcapillary pulmonary hypertension have been revisited. The distinction between isolated postcapillary pulmonary hypertension (IpcPH) and combined post and precapillary pulmonary hypertension (CpcPH) and their definition are essential. Novel data on the prognostic impact of hemodynamic variables and right ventricular function highlight the importance of cardiopulmonary interaction in patients with left-sided heart failure (LHF). Furthermore, the impact of management strategies including medical therapy, remote hemodynamic monitoring, and interventional approaches on hemodynamics and outcome has recently been investigated. Here, we critically review recent developments and future considerations in this field, and highlight distinct treatment strategies targeting the underlying left heart condition, the pulmonary circulation, and/or impaired right ventricular function. Detailed hemodynamic characterization and proper phenotyping are essential for prognostication and the management of patients with pulmonary hypertension associated with LHF, both in clinical practice and when addressing research questions.

Phosphodiesterase 5 inhibitor sildenafil in patients with heart failure with preserved ejection fraction and combined pre- and postcapillary pulmonary hypertension: a randomized open-label pilot study

BackgroundHeart failure with preserved ejection fraction (HFpEF) is frequently complicated by pulmonary hypertension (PH). A pulmonary vascular contribution could be considered as a substantial therapeutic target in HFpEF and PH and combined pre- and postcapillary PH (Cpc-PH).MethodsWe enrolled 50 patients with HFpEF and Cpc-PH who were determined by echocardiography to have pulmonary artery systolic pressure (PASP) > 40 mmHg, pulmonary vascular resistance > 3 Wood units, and/or transpulmonary gradient > 15 mmHg.ResultsThe patients were assigned to the phosphodiesterase 5 (PDE5) inhibitor sildenafil group (25 mg TID for 3 months followed by 50 mg TID for 3 months; n = 30) or the control group (n = 20). In the sildenafil group after 6 months, the 6-min walk distance increased by 50 m (95% CI, 36 to 64 m); substantial improvement in NYHA functional class and exercise capacity during diastolic stress test were revealed; decreases in early mitral inflow to mitral annulus relaxation velocities ratio by 2.4 (95% CI, − 3.3 to − 1.4) and PASP by 17.0 mmHg (95% CI, 20.4 to 13.5) were observed; right ventricular systolic function (M-mode tricuspid annular plane systolic excursion) increased by 0.42 cm (95% CI, 0.32 to 0.52 cm; P < 0.01 for all). No changes occurred in the control group.ConclusionsIn a subset of patients with HFpEF and Cpc-PH assessed by echocardiography, PDE5 inhibition was associated with an improvement in exercise capacity, pulmonary haemodynamic parameters, and right ventricular function. The role of sildenafil needs to be considered in randomized trials in selected patients with HFpEF with invasively confirmed Cpc-PH.Trial registrationRussian National Information System of Research, Development and Technology Data of Civilian Usage (NIS, https://rosrid.ru), registration number 01201257849. Registered 20 April 2012.This manuscript adheres to the CONSORT guidelines.

Effect of sildenafil on right ventricular performance in an experimental large-animal model of postcapillary pulmonary hypertension

Right ventricle (RV) dysfunction is a main determinant of morbidity and mortality in postcapillary pulmonary hypertension (PH). However, currently there are not available therapies. Since reduced nitric oxide (NO) availability and cyclic guanylate monophosphate (cGMP) levels are central in this disease, therapies targeting the NO pathway might have a beneficial effect on RV performance. In this regard, sildenafil has shown contradictory results. Our objective was to evaluate the effect of sildenafil on RV performance in an experimental pig model of postcapillary PH induced by a fixed banding of the venous pulmonary confluent. Animals were evaluated by right heart catheterization and cardiac magnetic resonance before randomization and after 8 weeks on sildenafil (n = 8) or placebo (n = 8), and myocardial tissues were analyzed with histology and molecular biology. At the end of the study, animals receiving sildenafil showed better RV performance as compared with those on placebo (improvement in RV ejection fraction of 7.3% ± 5.8% versus -0.6% ± 5.0%, P= 0.021) associated with less apoptotic cells and gene expression related with reduced oxidative stress and increased anti-inflammatory activity in the myocardium. No differences were observed in pulmonary hemodynamics. In conclusion, in a translational large animal model of chronic postcapillary PH, sildenafil improved RV systolic function independently of afterload. Further research with pharmacological approaches able to manipulate the NO-cGMP axis are needed to confirm this potential cardioprotective effect.

Pulmonary artery hemodynamics are associated with duration of nocturnal desaturation but not apnea-hypopnea index.

Sleep-disordered breathing and nocturnal hypoxia are prevalent among patients with precapillary pulmonary hypertension (PAH). The rationale for these associations remains unclear and these relationships have not been well studied in other forms of pulmonary hypertension (PH). We hypothesized that severity of sleep-disordered breathing and nocturnal hypoxia are associated with worsening pulmonary hemodynamics, regardless of hemodynamic profile. Four hundred ninety-three patients were divided into 4 groups: 1) no PH, 2) postcapillary pulmonary hypertension, 3) PAH, and 4) mixed PAH/postcapillary pulmonary hypertension. The relationship between right heart catheterization measurements and apnea-hypopnea index or the percentage of sleep time spent with oxygen saturation < 90% (T90) was calculated using multiple linear regression. Analysis of variance was used for between-group comparisons. Statistical models were adjusted for known confounders. Apnea-hypopnea index did not differ between hemodynamic subgroups (P = .27) and was not associated with right atrial pressure (.11 ± .19, P = .55), cardiac index (.25 ± 1.64, P = .88), mean pulmonary artery pressure (-.004 ± .09, P = .97), or pulmonary artery occlusion pressure (.16 ± .14, P = .26). While patients with PH had a higher T90 than those without (mean 24.2% vs 11.7%, P < .001), there was no difference in T90 between individual PH subgroups (P = .70). T90 was associated with mean pulmonary artery pressure (.55 ± .10, P < .0001), PVR (1.61 ± .49, P = .001), and right atrial pressure (.50 ± .20, P = .01), but not cardiac index (-.76 ± 1.73, P = .66), or pulmonary artery occlusion pressure (.23 ± .15, P = .13). Increased PH severity was associated with longer duration of nocturnal hypoxia regardless of hemodynamic subgroup.

Noninvasive Prediction of Elevated Wedge Pressure in Pulmonary Hypertension Patients Without Clear Signs of Left-Sided Heart Disease: External Validation of the OPTICS Risk Score.

BackgroundAlthough most newly presenting patients with pulmonary hypertension (PH) have elevated pulmonary artery wedge pressure, identification of so‐called postcapillary PH can be challenging. A noninvasive tool predicting elevated pulmonary artery wedge pressure in patients with incident PH may help avoid unnecessary invasive diagnostic procedures.Methods and ResultsA combination of clinical data, ECG, and echocardiographic parameters was used to refine a previously developed left heart failure risk score in a retrospective cohort of pre‐ and postcapillary PH patients. This updated score (renamed the OPTICS risk score) was externally validated in a prospective cohort of patients from 12 Dutch nonreferral centers the OPTICS network. Using the updated OPTICS risk score, the presence of postcapillary PH could be predicted on the basis of body mass index ≥30, diabetes mellitus, atrial fibrillation, dyslipidemia, history of valvular surgery, sum of SV1 (deflection in V1 in millimeters) and RV6 (deflection in V6 in millimeters) on ECG, and left atrial dilation. The external validation cohort included 81 postcapillary PH patients and 66 precapillary PH patients. Using a predefined cutoff of >104, the OPTICS score had 100% specificity for postcapillary PH (sensitivity, 22%). In addition, we investigated whether a high probability of heart failure with preserved ejection fraction, assessed by the H2 FPEF score (obesity, atrial fibrillation, age >60 yrs, ≥2 antihypertensives, E/e' >9, and pulmonary artery systolic pressure by echo >35 mmHg), similarly predicted the presence of elevated pulmonary artery wedge pressure. High probability of heart failure with preserved ejection fraction (H2 FPEF score ≥6) was less specific for postcapillary PH.ConclusionsIn a community setting, the OPTICS risk score can predict elevated pulmonary artery wedge pressure in PH patients without clear signs of left‐sided heart disease. The OPTICS risk score may be used to tailor the decision to perform invasive diagnostic testing.

Echocardiographic Diagnosis of Postcapillary Pulmonary Hypertension: A RIGHT1 Substudy

Background: Pulmonary hypertension is observed in 70% of patients with left ventricular (LV) dysfunction. Right heart catheterization is the gold standard for a complete evaluation of Pulmonary Hypertension (PH); however, echocardiography represents a powerful initial diagnostic tool. The aim of our study was to evaluate the accuracy of echocardiography for the diagnosis of postcapillary PH, i.e., due to increased left ventricular filling pressures. Methods and Results: We recruited patients with a diagnosis of PH from the RIGHT1 study (Right heart invasive and echocardiographic hemodynamic evaluation in Turin 1). Transthoracic echocardiography was performed within 60 min of cardiac catheterization. High LV filling pressures were defined by a pulmonary arterial wedge pressure (PAWP) greater than 15 mmHg. We assessed numerous morphological and functional features of LV, and their association with PAWP. 128 patients were diagnosed with PH. We observed a significant association between PAWP, the left atrial volume indexed by BSA (LAVi, R2 = 0.27; p &lt; 0.0001) and the E/e’ ratio (R2 = 0.27; p &lt; 0.0001). With these parameters, we implemented a diagnostic algorithm to identify high ventricular filling pressures in PH patients. The application of this algorithm could help identify patients with a diagnosis of postcapillary PH due to high ventricular filling pressures (E/E’ &gt; 15). Conclusions: The echocardiographic parameters with the best association with PAWP in PH patients are E/e’ and LAVi. For these patients, our diagnostic algorithm could improve the diagnostic precision for the definition of subgroups.

The dangerous and contradictory prognostic significance of PVR

AimsIn 2019, pulmonary vascular resistance (PVR) < 3WU was adopted to stratify patients at low risk in pulmonary hypertension due to left heart disease (PH‐LHD) as well those with isolated PH‐LHD. We sought to evaluate whether supervised machine learning with decision tree analysis, which provides more information than Cox Proportional analysis by forming a hierarchy of multiple covariates, confirms this risk stratification.Methods and resultsTwo hundred two consecutive patients (mean age: 69 ± 11 years, female: 42%) with mean pulmonary artery pressure ≥ 20 mmHg and wedge pressure > 15 mmHg were recruited. Transpulmonary pressure gradient ⩾̸ 12 mmHg, PVR ⩾̸ 3WU, diastolic pressure gradient ⩾̸ 7 mmHg, pulmonary arterial capacitance < 1.1 mL/mmHg, tricuspid annular plane systolic excursion (TAPSE) < 16 mm, peak systolic tissue Doppler velocity < 10 cm/s, right ventricular end‐diastolic area ⩾̸ 25 cm2 were the seven categorical values entered into the model due to their prognostic significance in PH. We used the chi‐squared automatic interaction detection method to predict mortality. Each node and branch were compared using survival analysis at 6‐year follow‐up. Mean pulmonary artery pressure, wedge pressure, cardiac index, and PVR were 40.3 ± 10.0 mmHg, 22.3 ± 7.1 mmHg, 2.9 ± 0.8 L/min/m2, and 3.6 ± 2.1WU, respectively. Among the seven dichotomous, TAPSE was first selected following by PVR. Compared with patients with PVR < 3WU and TAPSE ⩾̸ 16 mm, patients with PVR ⩾̸ 3WU and TAPSE ⩾̸ 16 mm, or patients with PVR ⩾̸ 3WU and TAPSE<16 mm had significantly increased mortality, HR = 3.0, 95% CI = [1.4–6.4], P = 0.006 and HR = 3.3, 95% CI = [1.6–6.9], P = 0.002, respectively, while patients with PVR < 3WU and TAPSE < 16 mm exhibited the worst prognosis, HR = 7.2, 95% CI = [3.3–15.9], P = 0.0001.ConclusionsUsed for solving regression and classification problems, decision tree analysis confirms that PVR and TAPSE have to be analysed together in PH‐LHD and revealed the dangerous and contradictory prognostic significance of PVR < 3WU when TAPSE<16 mm.

Impact of the updated hemodynamic definitions on diagnosis rates of pulmonary hypertension.

We evaluated whether updated pulmonary hypertension definitive criteria proposed in sixth World Symposium on Pulmonary Hypertension had an impact on diagnosis of overall pulmonary hypertension and pre-capillary and combined pre- and post-capillary phenotypes as compared to those in European Society of Cardiology/European Respiratory Society 2015 pulmonary hypertension Guidelines. Study group comprised the retrospectively evaluated 1300 patients (age 53.1 ± 18.8 years, female 807, 62.1%) who underwent right heart catheterization with different indications between 2006 and 2018. Mean pulmonary arterial pressure ≥25 mmHg (European Society of Cardiology) and PAMP (mean pulmonary arterial pressure) >20 mmHg (World Symposium on Pulmonary Hypertension) right heart catheterization definitions criteria were used, respectively. For pre-capillary pulmonary hypertension, pulmonary artery wedge pressure ≤15 mmHg and pulmonary vascular resistance ≥3 Wood units criteria were included in the both definitions. Normal mean pulmonary arterial pressure (<21 mmHg), borderline mean pulmonary arterial pressure elevation (21–24 mmHg), and overt pulmonary hypertension (≥25 mmHg) were documented in 21.1, 9.8, and 69.1% of the patients, respectively. The pre-capillary and combined pre- and post-capillary pulmonary hypertension were noted in 2.9 and 1.1%, 8.7 and 2.5%, and 34.6 and 36.6% of the patients with normal mean pulmonary arterial pressure, borderline, and overt pulmonary hypertension subgroups, respectively. The World Symposium on Pulmonary Hypertension versus European Society of Cardiology/European Respiratory Society definitions resulted in a net 9.8% increase in the diagnosis of overall pulmonary hypertension whereas increases in the pre-capillary pulmonary hypertension and combined pre- and post-capillary pulmonary hypertension diagnosis were only 0.8 and 0.3%, respectively. The re-definition of mean pulmonary arterial pressure threshold seems to increase the frequency of the overall pulmonary hypertension diagnosis. However, this increase was mainly originated from those in post-capillary pulmonary hypertension subgroup whereas its impact on pre-capillary and combined pre- and post-capillary pulmonary hypertension was negligible. Moreover, criteria of pre-capillary pulmonary vascular disease and combined pre- and post-capillary phenotypes were still detectable even in the presence of normal mean pulmonary arterial pressure. The obligatory criteria of pulmonary vascular resistance ≥3 Wood units seems to keep specificity for discrimination between pre-capillary versus post-C pulmonary hypertension after lowering the definitive mean pulmonary arterial pressure threshold to 20 mmHg.

Impact of Combined Pre and Postcapillary Pulmonary Hypertension on Survival after Transcatheter Aortic Valve Implantation

We aimed to evaluate the association between pulmonary hypertension (PH) hemodynamic classification and all-cause mortality in patients with symptomatic severe aortic stenosis (AS) undergoing transcatheter aortic valve implantation (TAVI). PH is common and associated with post-TAVI outcomes in patients with severe AS. Although PH in these patients is primarily driven by elevated left-sided pressures (postcapillary PH), some patients develop increased pulmonary vascular resistance (PVR) configuring the combined pre- and postcapillary PH (CpcPH). We analyzed severe AS patients with mean pulmonary artery pressure (mPAP) measured by right heart catheterization (RHC) before TAVI between 2011 and 2017. PH hemodynamic classification was defined as: No PH (mPAP < 25 mm Hg); precapillary PH (mPAP ≥ 25 mm Hg, pulmonary capillary wedge pressure (PCWP) ≤15 mm Hg); isolated postcapillary PH (IpcPH; mPAP ≥ 25 mm Hg, PCWP > 15 mm Hg, PVR ≤ 3 Wood units (WU); CpcPH (mPAP ≥ 25 mm Hg, PCWP > 15 mm Hg, PVR > 3 WU). Kaplan-Meier and Cox regression analyses were used to test the association of PH hemodynamic classification with post-TAVI all-cause mortality. We examined 561 patients (mean age 82 ± 8 years, 51% men, mean LVEF 54 ± 14%). The prevalence of no PH was 201 (36%); precapillary PH, 59 (10%); IpcPH, 189 (34%); and CpcPH, 112 (20%). During a median follow-up of 30 months, 240 all-cause deaths occurred. Patients with CpcPH had higher mortality than those with no-PH even after adjustment for baseline characteristics (Hazard ratio 1.56, 95% confidence interval 1.06 to 2.29, p = 0.025). There was no survival difference among patients with non-PH, precapillary PH and IpcPH. In conclusion, for patients with symptomatic severe AS treated with TAVI, CcpPH is independently associated with long-term all-cause mortality despite successful TAVI.

Machine learning for the diagnosis of pulmonary hypertension.

Objective This paper aims to investigate whether machine learning (ML) can be used to predict the state of pulmonary hypertension (PH), including pre-capillary and post-capillary, from echocardiographic data.Methods Two hundred and seventy-five patients with PH who underwent both echocardiography and right heart catheterization were included in the study. Mean pulmonary artery pressure, pulmonary artery wedge pressure measured by right heart catheterization were used as criteria for judging pre-capillary PH and post-capillary PH. Thirteen echocardiographic indicators were used to predict whether the PH was pre-capillary or post-capillary. Nine ML models were used to make predictions. Accuracy was used as the primary reference standard, and the performance of classification model is observed in conjunction with area under curve (AUC), specificity (Sp), sensitivity (Se), Positive Prediction Value (PPV), Negative Prediction Value (NPV), Positive Likelihood Ratio (PLR) and Negative Likelihood Ratio (NLR) and other assessment protocols.Results By comparing the accuracy (ACC), recall rate (Recall) and other model effect evaluation index of the classification under the nine ML models, it can be found that the ML model can effectively identify the pre-capillary PH and the post-capillary PH. LogitBoost performed best in nine ML models (ACC=0.87, Recall=0.83, F1score=0.85, AUC=0.87, Se=0.90, NPV=0.88, PPV=0.87, PLR=8.61 and NLR=0.18, AUC=0.83), it showed good results in identification of the pre-capillary PH (ACC=0.83, Recall=0.87, F-score=0.85); Post-vascular PH (ACC=0.90, Recall=0.88, F-score=0.89). Decision Tree (ACC=0.75, Recall=0.77, F1score=0.78, AUC=0.75, Se=0.72, NPV=0.78, PPV=0.77, PLR=3.66 and NLR=0.29, AUC=0.79) performed worst, and the accuracy of the other seven models was greater than 0.82.Conclusion The classification results of the nine ML models in this paper indicate that the ML method can effectively identify the pre-capillary PH and post-capillary PH from echocardiographic data. Compared with medical diagnosis, ML methods can distinguish between pre-capillary PH and the post-capillary PH under non-invasive conditions.

Associations of 2D speckle tracking echocardiography-based right heart deformation parameters and invasively assessed hemodynamic measurements in patients with pulmonary hypertension

BackgroundWe aimed to evaluate associations of right atrial (RA) and right ventricular (RV) strain parameters assessed by 2D speckle tracking echocardiography (2D STE) with invasively measured hemodynamic parameters in patients with and without pulmonary hypertension (PH).MethodsIn this study, we analyzed 78 all-comer patients undergoing invasive hemodynamic assessment by left and right heart catheterization. Standard transthoracic echocardiographic assessment was performed under the same hemodynamic conditions. RA and RV longitudinal strain parameters were analyzed using 2D STE. PH was defined as invasively obtained mean pulmonary arterial pressure (mPAP) ≥25 mmHg at rest and was further divided into pre-capillary PH (pulmonary capillary wedge pressure [PCWP] ≤ 15 mmHg), post-capillary PH (PCWP > 15 mmHg) and combined PH (PCWP > 15 mmHg and difference between diastolic PAP and PCWP of ≥7 mmHg). Correlation analyses between variables were calculated with Pearson’s or Spearman’s correlation coefficient as applicable.ResultsOut of 78 patients, 45 presented with PH. Within the PH group, 39 had post-capillary, five had combined pre- and post-capillary PH, and one had pre-capillary PH. Patients with PH had a significantly increased RA area (PH 22.0 ± 9.2 cm2, non-PH 17.3 ± 10.7 cm2; p = 0.003) and end-systolic RV area (PH 14.7 ± 6.1, non-PH 11.9 ± 4.8 cm2; p = 0.022). RV mid strain was significantly reduced in PH (PH -17.4 ± 7.8, non-PH: − 21.6 ± 5.5; p = 0.019). Average peak systolic RA strain (RAS) and average peak systolic RV strain (RVS) showed a significant association with mPAP (r = − 0.470, p = 0.001 and r = 0.490, p = 0.001, respectively) and with PCWP (r = − 0.296, p = 0.048 and r = 0.365, p = 0.015, respectively) in patients with PH. Furthermore, RV apical, mid and basal strain as well as RV free wall strain showed moderate associations with mPAP. In patients without PH, there were no associations detectable between RA or RV strain parameters and mPAP and PCWP.ConclusionIn an all-comer cohort, RA and RV strain parameters showed significant associations with invasively assessed mPAP and PCWP in patients with predominantly post-capillary PH. These associations may be useful in clinical practice to assess the impact of post-capillary PH on myocardial right heart function.

Pulmonary Hypertension Due to Left Heart Disease: Diagnosis, Pathophysiology, and Therapy.

Pulmonary hypertension (PH) due to left heart disease (LHD) is the most common type of PH and is defined as mean pulmonary artery systolic pressure of >20 mm Hg and pulmonary capillary wedge pressure >15 mm Hg during right heart catheterization. LHD may lead to elevated left atrial pressure alone, which in the absence of intrinsic pulmonary vascular disease will result in PH without changes in pulmonary vascular resistance. Persistent elevation in left atrial pressure may, however, also be associated with subsequent pulmonary vascular remodeling, vasoconstriction, and an increase in pulmonary vascular resistance. Hence, there are 2 subgroups of PH due to LHD, isolated postcapillary PH and combined post- and precapillary PH, with these groups have differing clinical implications. Differentiation of pulmonary arterial hypertension and PH due to LHD is critical to guide management planning; however, this may be challenging. Older patients, patients with metabolic syndrome, and patients with imaging and clinical features consistent with left ventricular dysfunction are suggestive of LHD etiology rather than pulmonary arterial hypertension. Hemodynamic measures such as diastolic pressure gradient, transpulmonary gradient, and pulmonary vascular resistance may assist to differentiate pre- from postcapillary PH and offer prognostic insights. However, these are influenced by fluid status and heart failure treatment. Pulmonary arterial hypertension therapies have been trialed in the treatment with concerning results reflecting disease heterogeneity, variation in inclusion criteria, and mixed end point criteria. The aim of this review is to provide an updated definition, discuss possible pathophysiology, clinical aspects, and the available treatment options for PH due to LHD.