Precapillary Pulmonary Hypertension Research Articles

Cardiac Arrhythmias in Pulmonary Arterial Hypertension and Chronic Thromboembolic Pulmonary Hypertension: Mechanistic Insights, Pathophysiology, and Outcomes.

Arrhythmias are increasingly recognized as severe complications of precapillary pulmonary hypertension, encompassing pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH). Despite their significant contribution to symptoms, morbidity, in-hospital mortality, and potentially sudden death in PAH/CTEPH, there remains a lack of comprehensive data on epidemiology, pathophysiology, and outcomes to inform the management of these patients. This review provides an overview of the latest evidence on this subject, spanning from the molecular mechanisms underlying arrhythmias in the hypertrophied or failing right heart to the clinical aspects of epidemiology, diagnosis, and treatment.

Cardiac biomarker profiles in dogs with naturally occurring precapillary pulmonary hypertension

Introduction/ObjectivesThis study evaluated circulating amino-terminal pro-B-type natriuretic peptide (NT-proBNP), amino-terminal pro-A-type natriuretic peptide (NT-proANP), and cardiac troponin I (cTnI) concentrations in dogs with precapillary pulmonary hypertension (Pre-PH) and control dogs with respiratory clinical signs but no Pre-PH. AnimalsTwenty-six dogs (17 affected, and 9 controls) were involved in the study. Materials and MethodsThis was a sub-study of a large prospective single-center observational study. Dogs underwent blood sample collection, physical examination, and echocardiographic evaluation. Pre-PH was diagnosed when a calculated right ventricular-to-right atrial pressure gradient (RV:RA PG) measuring ≥40 mmHg was identified echocardiographically, barring right ventricular outflow obstruction and/or left-sided cardiac disease. ResultsTwo, nine, and six dogs had mild, moderate, and severe Pre-PH, respectively. Plasma concentrations of NT-proBNP, NT-proANP, and cTnI were significantly higher in the affected group than in the control group (P=0.020, P=0.009, P=0.011, respectively). There was a positive correlation between RV:RA PG and NT-proBNP (r = 0.52), NT-proANP (r = 0.54), and cTnI (r = 0.67) concentrations. DiscussionPre-PH should be included in the differential diagnosis list of elevated cardiac biomarker concentrations in dogs with respiratory signs. Study LimitationsStrict selection criteria reduced group sizes. There were rare missing data points. The diagnosis of Pre-PH was obtained from Doppler echocardiographic RV:RA PG. The disease process causing Pre-PH was not evaluated histopathologically. ConclusionsCirculating cardiac biomarker concentrations are increased in dogs with Pre-PH and there is a positive correlation between RV:RA PG and NT-proBNP, NT-proANP, and cTnI concentrations.

Definition, classification and diagnosis of pulmonary hypertension.

Pulmonary hypertension (PH) is a haemodynamic condition characterised by elevation of mean pulmonary arterial pressure (mPAP) >20 mmHg, assessed by right heart catheterisation. Pulmonary arterial wedge pressure (PAWP) and pulmonary vascular resistance (PVR) distinguish pre-capillary PH (PAWP ≤15 mmHg, PVR >2 Wood Units (WU)), isolated post-capillary PH (PAWP >15 mmHg, PVR ≤2 WU) and combined post- and pre-capillary PH (PAWP >15 mmHg, PVR >2 WU). Exercise PH is a haemodynamic condition describing a normal mPAP at rest with an abnormal increase of mPAP during exercise, defined as a mPAP/cardiac output slope >3 mmHg/L/min between rest and exercise. The core structure of the clinical classification of PH has been retained, including the five major groups. However, some changes are presented herewith, such as the re-introduction of "long-term responders to calcium channel blockers" as a subgroup of idiopathic pulmonary arterial hypertension, the addition of subgroups in group 2 PH and the differentiation of group 3 PH subgroups based on pulmonary diseases instead of functional abnormalities. Mitomycin-C and carfilzomib have been added to the list of drugs with "definite association" with PAH. For diagnosis of PH, we propose a stepwise approach with the main aim of discerning those patients who need to be referred to a PH centre and who should undergo invasive haemodynamic assessment. In case of high probability of severe pulmonary vascular disease, especially if there are signs of right heart failure, a fast-track referral to a PH centre is recommended at any point during the clinical workup.

Pulmonary hypertension associated with left heart disease.

Left heart disease (LHD) is the most common cause of pulmonary hypertension (PH), which may be classified further as isolated post-capillary (ipcPH) or combined post- and pre-capillary PH (cpcPH). The 7th World Symposium on Pulmonary Hypertension PH-LHD task force reviewed newly reported randomised clinical trials and contemplated novel opportunities for improving outcome. Results from major randomised clinical trials reinforced prior recommendations against the use of pulmonary arterial hypertension therapy in PH-LHD outside of clinical trials, and suggested possible harm. Greater focus on phenotyping was viewed as one general strategy by which to ultimately improve clinical outcomes. This is potentially achievable by individualising ipcPH versus cpcPH diagnosis for patients with pulmonary arterial wedge pressure within a diagnostic grey zone (12-18 mmHg), and through a newly developed PH-LHD staging system. In this model, PH accompanies LHD across four stages (A=at risk, B=structural heart disease, C=symptomatic heart disease, D=advanced), with each stage characterised by progression in clinical characteristics, haemodynamics and potential therapeutic strategies. Along these lines, the task force proposed disaggregating PH-LHD to emphasise specific subtypes for which PH prevalence, pathophysiology and treatment are unique. This includes re-interpreting mitral and aortic valve stenosis through a contemporary lens, and focusing on PH within the hypertrophic cardiomyopathy and amyloid cardiomyopathy clinical spectra. Furthermore, appreciating LHD in the profile of PH patients with chronic lung disease and chronic thromboembolic pulmonary disease is essential. However, engaging LHD patients in clinical research more broadly is likely to require novel methodologies such as pragmatic trials and may benefit from next-generation analytics to interpret results.

Left ventricular diastolic dysfunction in non-myocardial disorders.

This article reviews and discusses non-myocardial disorders which represent diagnostic challenges when evaluating patients for suspected heart failure with preserved left ventricular ejection fraction. This includes pre-capillary pulmonary hypertension, which is important to differentiate from post-capillary hypertension caused by left sided heart disease. The impact of electrical disorders on LV diastolic function is also reviewed, and includes a discussion of left bundle branch, which has both a direct effect on LV diastolic function, as well as a long-term effect due to remodeling. Furthermore, evaluation of diastolic function in patients with atrial fibrillation is discussed. Pericardial diseases are reviewed as well as effects of a normal pericardium on diastolic function in failing hearts. Finally, the article reviews how valvular diseases impact LV diastolic function.

The effects of bolus isosorbide dinitrate on pulmonary hypertension with cardiopulmonary comorbidities.

Lowering mean pulmonary arterial pressure (mPAP) without reducing cardiac output is essential in treating pulmonary hypertension (PH). Isosorbide dinitrate (ISDN) potentially achieves this in post-capillary PH but can decrease cardiac output and blood pressure (BP), especially in pre-capillary PH. However, post-capillary PH and pre-capillary PH can overlap, and their clear discrimination is difficult. The aim of the study was to examine to what extent bolus ISDN injection reduces mPAP and BP, and changes mixed venous oxygen saturation (SvO2), an indicator of cardiac output in PH with various cardiopulmonary comorbidities in the context of treatment modifications. We retrospectively examined the hemodynamic effects of bolus ISDN injection in patients with PH who underwent right heart catheterization and their subsequent treatment modification. Our sample comprised 13 PH patients. In seven with pre-capillary PH, ISDN significantly lowered mPAP from the median 34 (interquartile range 32-39) to 28 (28-30) mmHg and the mean BP (mBP) from 90 (79-92) to 72 (68-87) mmHg. In six with post-capillary PH, ISDN lowered mPAP from 40 (29-44) to 27 (23-31) mmHg and mBP from 91 (87-110) to 87 (82-104) mmHg. There was a significant decrease in SvO2 from 69.8% (64.9%-78.1%) to 63.9% (60.5%-71.5%) in pre-capillary PH, but not in post-capillary PH including combined post- and pre-capillary PH and some patients showed a large increase in SvO2. In all patients showing an SvO2 increase, diuretics or hemodialysis were up-titrated or continued. Bolus ISDN injection lowered mPAP. However, in pre-capillary PH, it caused a significant decrease in SvO2 and a notable reduction in blood pressure. In post-capillary PH, including combined post- and pre-capillary PH, it clarified whether systemic preload and afterload reduction increased or decreased SvO2 in each patient, which may aid in treatment modification.

Kidney Dysfunction, Hepatic Impairment, and Lipid Metabolism Abnormalities in Patients with Precapillary Pulmonary Hypertension.

Pulmonary hypertension (PH) is a global health issue that has profound medical and research implications. This retrospective study examined changes in renal and liver function, as well as lipid metabolism, over a 12-month period in 49 adult patients with pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH). All cases were admitted, managed, and followed up with in the PH Center, County Emergency Clinical Hospital of Targu Mures, Romania. Kidney dysfunction was observed in 12.24% of cases at baseline, decreasing to 8.16% at 12 months, and CTEPH patients were more affected. In particular, CTEPH patients exhibited an improvement in renal function, confirmed by an increase in their glomerular filtration rates. Hepatic impairment was present in 57.14% of subjects at baseline, declining to 42.86% at 12 months, with significant improvements noted in the PAH group. Lipid metabolic dysregulations were experienced by 22.45% of all patients at baseline, decreasing to 16.33% at 6 months, with a slow elevation to 24.49% at 12 months, but with no statistically significant differences. Pharmacological regimens were adjusted in accordance with the PH groups, a patient's functional and clinical response, and laboratory tests. Our results demonstrate the multi-organ damage in PH and the importance of individualized treatment approaches.

Tadalafil for Treatment of Combined Postcapillary and Precapillary Pulmonary Hypertension in Patients With Heart Failure and Preserved Ejection Fraction: A Randomized Controlled Phase 3 Study.

We assessed the efficacy and safety of tadalafil, a phosphodiesterase type 5 inhibitor, in patients with heart failure with preserved ejection fraction and combined postcapillary and precapillary pulmonary hypertension. In the double-blind PASSION study (Phosphodiesterase-5 Inhibition in Patients With Heart Failure With Preserved Ejection Fraction and Combined Post- and Pre-Capillary Pulmonary Hypertension), patients with heart failure with preserved ejection fraction and combined postcapillary and precapillary pulmonary hypertension were randomized 1:1 to receive tadalafil at a target dose of 40 mg or placebo. The primary end point was the time to the first composite event of adjudicated heart failure hospitalization or all-cause death. Secondary end points included all-cause mortality and improvements in New York Heart Association functional class or ≥10% improvement in 6-minute walking distance from baseline. Initially targeting 372 patients, the study was terminated early because of disruption in study medication supply. At that point, 125 patients had been randomized (placebo: 63; tadalafil: 62,). Combined primary end-point events occurred in 20 patients (32%) assigned to placebo and 17 patients (27%) assigned to tadalafil (hazard ratio, 1.02 [95% CI, 0.52-2.01]; P=0.95). There was a possible signal of higher all-cause mortality in the tadalafil group (hazard ratio, 5.10 [95% CI, 1.10-23.69]; P=0.04). No significant between-group differences were observed in other secondary end points. Serious adverse events occurred in 29 participants (48%) in the tadalafil group and 35 (56%) in the placebo group. The PASSION trial, terminated prematurely due to study medication supply disruption, does not support tadalafil use in patients with heart failure with preserved ejection fraction and combined postcapillary and precapillary pulmonary hypertension, with potential safety concerns and no observed benefits in primary and secondary end points. URL: https://www.clinicaltrialsregister.eu/; Unique identifier: 2017-003688-37. URL: https://drks.de; Unique identifier: DRKS -DRKS00014595.

Association of arteriovenous fistulae with precapillary pulmonary hypertension – A single center retrospective analysis of invasive hemodynamic parameters

BackgroundPulmonary hypertension (pH) is a well-known complication among patients with chronic kidney disease (CKD). Arteriovenous fistulae (AVF) have been associated with pH mainly by increasing cardiac output. However, the burden of precapillary pH in individuals with CKD and an AVF is unclear. ObjectivesTo better and more fully understand the mechanism and development of precapillary pH in patients with AVF, as well as the consequences of precapillary pH in these patients. MethodsThis was a large retrospective study of patients with CKD stage 4 or 5 who underwent right heart catheterization (RHC) from 2018 to 2023. The data were stratified according to the presence of AVF. To determine if AVF was independently associated with precapillary pH, we used a multivariable logistic regression analysis adjusting for demographics and potential comorbidities associated with precapillary pH, including diagnosis of chronic lung disease, obstructive sleep apnea, connective tissue disease, history of venous thromboembolism, chronic anemia, and heart failure. ResultsOf 651 patients with CKD4 or CKD5, 145 (22 %) had AVF and 506 (78 %) did not have AVF. Within the AVF group, the median age was 64 years (IQR 54–71), and they were predominantly males (61 %, n = 88) and African American (77 %, n = 111). A total of 31 % (n = 45) had evidence of precapillary pH, 30 % (n = 43) of combined pH, and 14 % (n = 20) of isolated postcapillary pH. Compared to the non-AVF group, precapillary pH was more likely in the AVF group (31% vs 17 %, p < 0.0001). On multivariable analysis, AVF was independently associated with precapillary pH (OR 2.47, CI 1.56–3.89; p < 0.0001). The median time from dialysis initiation to RHC date (and precapillary pH diagnosis) was 6 years (IQR 3–8). ConclusionBased on RHC findings, almost one-third of patients with CKD and AVF had precapillary pH. The presence of AVF was independently associated with precapillary pH.

Association of Cardiopulmonary Hemodynamics and Outcomes in Pulmonary Hypertension Following Kidney TransplantationA: A Multicenter Retrospective Cohort Study

BackgroundPulmonary Hypertension (PH) frequently complicates the evaluation of kidney transplant (KT) candidates, and is associated with increased adverse outcomes (mortality, delayed graft function (DGF), and major adverse cardiovascular events (MACE)) following KT. Research QuestionWhat is the relationship between cardiopulmonary hemodynamics and post-KT outcomes? Study Design and MethodsWe conducted a multicenter retrospective cohort study of adults undergoing KT between 10/1/11 and 10/1/21, who underwent right heart catheterization (RHC) to assess cardiopulmonary hemodynamics within a year of transplantation. Frailty models and logistic regression models were used to evaluate the association between cardiopulmonary hemodynamics and outcomes (mortality, DGF, MACE) following KT. ResultsA total of 117 patients were included in the final analysis, predominantly male (72%), with a median age of 57 years. PH, defined as mean pulmonary artery pressure (mPAP) > 20mmHg, was present in the majority of the cohort (N=93, 79%). The cohort was followed for a median of 29.9 months post-KT, during which about one-fourth experienced mortality (23%) or DGF (25%) events, and approximately one-third (34%) experienced MACE. Though echocardiographic measures of pulmonary artery pressure failed to identify post-KT outcomes, a mPAP of ≥ 30mmHg on RHC was associated with post-KT MACE (Hazard Ratio 2.60, 95% Confidence Interval [1.10, 6.10]) and more prevalent in those experiencing post-KT mortality (63% vs 32%, p=0.001). Pre-capillary pulmonary hypertension was also associated with post-KT mortality (Hazard Ratio 3.71, 95% Confidence Interval [1.07, 12.90]). InterpretationPre-capillary pulmonary hypertension and a mPAP of ≥ 30mmHg on RHC, but not echocardiographic evidence of PH, was associated with mortality and MACE following KT. These data suggest that RHC hemodynamics are superior to echocardiographic measures of PH in associating with outcomes following KT, and RHC-derived mPAP in particular may have value in predicting MACE and mortality post-KT.

Non-invasive prediction of pulmonary vascular disease-related exercise intolerance and survival in non-group 1 pulmonary hypertension.

The clinical utility of pulmonary hypertension (PH) risk scores in non-group 1 PH with pulmonary vascular disease (PVD) remains unresolved. We utilized the prospective multicenter PVDOMICS cohort with group 2, 3, 4 or 5 PH-related PVD and calculated group 1 PH risk scores (REVEAL 2.0, REVEAL Lite 2, French registry score and COMPERA 2). The c-statistic to predict death was compared separately in (i) pre-capillary PH groups 3/4/5, and (ii) combined post- and pre-capillary PH group 2. Exercise right heart catheterization reserve, ventricular interdependence and right ventricular-pulmonary artery (RV-PA) coupling were compared across risk categories. Among 449 individuals with group 3/4/5 PH, the REVEAL 2.0 risk score had the highest c-statistic for predicting death (0.699, 95% confidence interval [CI] 0.660-0.737, p < 0.0001) with comparable performance using the simpler REVEAL Lite 2 score (0.695, 95% CI 0.656-0.734, p < 0.0001). The French and COMPERA 2 risk scores were also predictive of mortality, but performance of both was statistically inferior to REVEAL 2.0 (c-statistic difference -0.072, 95% CI -0.123 to -0.020, p = 0.006, and -0.043, 95% CI -0.067 to -0.018, p = 0.0007, respectively). RV function and RV-PA coupling measures were prognostic in isolation, but did not add incremental value to REVEAL (p > 0.50 for all). Findings were similar in patients with group 2 PH (n = 239). Stratification by the REVEAL Lite 2 score non-invasively identified non-group 1 PH with more advanced PVD with worse exercise capacity, RV-PA uncoupling, ventricular interdependence and impaired cardiac output reserve (p < 0.05 for all). Non-invasive REVEAL risk predicts mortality in non-group 1 PH without incremental prognostic value from detailed RV function or RV-PA coupling assessment. Baseline REVEAL Lite 2 risk stratification non-invasively identifies greater pulmonary vascular dysfunction and right heart-related exercise limitation, which may help guide patient selection for targeted pulmonary vascular therapies in non-group 1 PH.

Predicting high-risk pre-capillary pulmonary hypertension: an echocardiographic multiparameter scoring index

BackgroundThe risk stratification of pulmonary arterial hypertension proposed by the European Society of Cardiology /European Respiratory Society guidelines in 2015 and 2022 included two to three echocardiographic indicators. However, the specific value of echocardiography in risk stratification of pre-capillary pulmonary hypertension (pcPH) has not been efficiently demonstrated. Given the complex geometry of the right ventricular (RV) and influencing factors of echocardiographic parameter, there is no single echocardiographic parameter that reliably informs about PH status. We hypothesize that a multi-parameter comprehensive index can more accurately evaluate the severity of the pcPH. The purpose of this study was to develop and validate an echocardiographic risk score model to better assist clinical identifying high risk of pcPH during initial diagnosis and follow-up.MethodsWe studied 197 consecutive patients with pcPH. A multivariable echocardiographic model was constructed to predict the high risk of pcPH in the training set. Points were assigned to significant risk factors in the final model based on β-coefficients. We validated the model internally and externally.ResultsThe echocardiographic score was constructed by multivariable logistic regression, which showed that pericardial effusion, right atrial (RA) area, RV outflow tract proximal diameter (RVOT-Prox), the velocity time integral of the right ventricular outflow tract (TVIRVOT) and S’ were predictors of high risk of pcPH. The area under curve (AUC) of the training set of the scoring model was 0.882 (95%CI: 0.809–0.956, p < 0.0001). External validation was tested in a test dataset of 77 patients. The AUC of the external validation set was 0.852. A 10-point score risk score was generated, with scores ranging from 0 to 10 in the training cohort. The estimate risk of high risk of pcPH ranged from 25.1 to 94.6%.ConclusionsThe echocardiographic risk score using five echocardiographic parameters could be comprehensive and useful to predict the high risk of pcPH for initial assessment and follow-up.

Haemolytic Anaemia-Related Pulmonary Hypertension.

Haemolytic anaemia represents a risk factor for the development of pulmonary hypertension (PH), currently classified as World Health Organization group 5 PH, and data regarding appropriate therapeutic strategy are limited. A total of 28 patients, 85.7% with thalassaemia and 14.3% with sickle cell disease, with a diagnosis of PH confirmed by right heart catheterization were included in the study. The patients were divided into three groups according to the PH haemodynamic definition and overall diagnostic approach: 42.9% had precapillary PH (pulmonary arterial hypertension-PAH group), 25% had post-capillary PH, and 32.1% had chronic thromboembolic PH (CTEPH) (29% of b-thalassemia and 50% of SCD patients). The therapeutic approach in each group and its impact on the outcome and haemodynamics were recorded. PAH-specific drug therapy received 82.1% of patients, and balloon pulmonary angioplasty (BPA) was performed in six patients with CTEPH. There were statistically significant differences in baseline mPAP and PVR values between the CTEPH-haemolytic anaemia group and other groups. PAH-specific drug therapy resulted in haemodynamic improvement for the PAH group. Patients who underwent BPA had improved pulmonary haemodynamics. The median survival time was 162 months, and the survival rate was 1 year-100%; 2, 3, 4, 5, and 6 years-96%; 9 years-90%; and 13 years-78%. In patients with haemolytic anaemia, the wide spectrum of induced PH highlighted the importance of a correct predominant diagnosis. BPA in CTEPH patients and specific-PAH drug therapy for PAH patients represent potential therapeutic strategies; however, the management should be offered in expert PH centres under individualized approaches for patients.

Pulmonary Hypertension Induced by Right Pulmonary Artery Occlusion: Hemodynamic Consequences of Bmpr2 Mutation.

The primary genetic risk factor for heritable pulmonary arterial hypertension is the presence of monoallelic mutations in the BMPR2 gene. The incomplete penetrance of BMPR2 mutations implies that additional triggers are necessary for pulmonary arterial hypertension occurrence. Pulmonary artery stenosis directly raises pulmonary artery pressure, and the redirection of blood flow to unobstructed arteries leads to endothelial dysfunction and vascular remodeling. We hypothesized that right pulmonary artery occlusion (RPAO) triggers pulmonary hypertension (PH) in rats with Bmpr2 mutations. Male and female rats with a 71 bp monoallelic deletion in exon 1 of Bmpr2 and their wild-type siblings underwent acute and chronic RPAO. They were subjected to full high-fidelity hemodynamic characterization. We also examined how chronic RPAO can mimic the pulmonary gene expression pattern associated with installed PH in unobstructed territories. RPAO induced precapillary PH in male and female rats, both acutely and chronically. Bmpr2 mutant and male rats manifested more severe PH compared with their counterparts. Although wild-type rats adapted to RPAO, Bmpr2 mutant rats experienced heightened mortality. RPAO induced a decline in cardiac contractility index, particularly pronounced in male Bmpr2 rats. Chronic RPAO resulted in elevated pulmonary IL-6 (interleukin-6) expression and decreased Gdf2 expression (corrected P value<0.05 and log2 fold change>1). In this context, male rats expressed higher pulmonary levels of endothelin-1 and IL-6 than females. Our novel 2-hit rat model presents a promising avenue to explore the adaptation of the right ventricle and pulmonary vasculature to PH, shedding light on pertinent sex- and gene-related effects.

Relationship between changes in the electrical axis of the heart during inspiration and the structural and functional state of the heart according to echocardiography in patients with precapillary pulmonary hypertension

Introduction. A deep breath causes a whole range of physiological effects that are reflected in the electrocardiogram. The purpose of the study is to assess the position of the electrical axis of the heart during deep inspiration compared to quiet breathing in patients with precapillary pulmonary hypertension and compare these data with echocardiographic characteristics of the structural and functional state of the heart. Materials and methods. The study included 40 patients with idiopathic pulmonary hypertension and 40 patients with chronic thromboembolic pulmonary hypertension. Echocardiography assessed the size of the heart chambers, systolic and diastolic function of the right and left ventricles, pulmonary artery pressure, pulmonary vascular resistance and indicators of cardiovascular coupling. Results. The values of the electrical axis of the heart during free breathing were 106° [84°; 123°], on inspiration – 89° [87°; 120°] (p = 0.68). In 50 (62.5 %) patients, during a deep inspiration, the electrical axis of the heart shifted to the left from the original one, and in 30 (37.5 %) patients – to the right. In patients with a displacement of the electrical axis of the heart to the left from the original, compared with the others, the end-diastolic size of the left ventricle, end-diastolic and end-systolic volumes of the left ventricle, stroke volume, cardiac output were statistically significantly lower, and the eccentricity index, pulmonary vascular resistance and effective aortic stiffness – significantly larger. Conclusion. In patients with precapillary pulmonary hypertension, two variants of changes of the heart electrical axis during deep inspiration were identified: a shift to the right from the original and to the left from the original. Patients with a displacement of the electrical axis to the left from the original were characterized by a significantly greater increase in pulmonary vascular resistance, a decrease in left ventricular volumes, stroke volume and cardiac output.

Clinical Characteristics and Outcomes Associated With Distinct Hemodynamic Patterns in End-stage Liver Disease: A Retrospective Cohort Analysis

IntroductionDespite advances in the diagnosis and therapeutics strategies for pulmonary hypertension (PH) in patients with end-stage liver disease (ESLD), the impact of hemodynamic patterns among ESLD patients identified through right heart catheterization (RHC) on clinical outcomes remains poorly understood. MethodsThis single-center retrospective cohort study identified patients diagnosed with ESLD who underwent RHC from August 2018 to June 2023. Demographic and clinical data, including comorbidities, transthoracic echocardiography, and RHC findings, were obtained. Our outcomes of interest were all-cause mortality and the chance of receiving orthotopic liver transplantation (OLT) within a year after RHC. Kaplan-Meier with log-rank test was employed to generate survival curves. ResultsWe identified 415 ESLD patients with the RHC results. The median (IQR) age was 59 years (52-66), and 62% were male. Caucasians accounted for 43%, followed by African Americans (30%). Up to 89% had a diagnosis of portal hypertension. Median MELD-Na score was 30 (19-36). The etiology of ESLD was mainly from alcohol use (55%). Patients were classified based on RHC results as pre-capillary PH (19%), post-capillary PH (28%), and non-PH (53%) groups. Overall, one-year mortality post-RHC was 22%, with no significant difference in mortality regardless of hemodynamic group. However, the pre-capillary PH group was less likely to receive OLT compared to other groups (p<0.001). ConclusionWe observed no difference in all-cause mortality among hemodynamic groups. However, pre-capillary PH group were less likely to undergo OLT compared to others. Further investigations are necessary to determine how this should be addressed in clinical practice.

Increased bone morphogenetic protein 10 in precapillary pulmonary hypertension patients

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Netherlands Organization for Scientific Research: NWO-VICI num. 918.16.610 and NWO-VIDI num. 917.18.338. Dutch Heart Foundation Dekker senior post-doc grant num. 2018T059 and the Netherlands CardioVascular Research Initiative: CVON-2017-10 DOLPHIN-GENESIS and CVON-2018-29 PHAEDRA-IMPACT. Fundació La Marató de TV3 num.202038. The Spanish Ministry of Science through the Ramón y Cajal grant num.RYC2021-030866-I. Introduction Precapillary pulmonary hypertension (PH) results in increased right atrial (RA) stretch and pressure. The right atrium is the major source of bone morphogenetic protein (BMP) 10 (BMP10) in adults, mostly produced by RA cardiomyocytes. The major predisposing risk factor for PH involves loss-of-function mutations in the bone morphogenetic protein receptor type 2 (BMPR2) gene, through which BMP10 and BMP9 transduce signals. Purpose The aim of this study was to investigate if BMP10 expression is altered in PH, and whether BMP10 signaling activity associates with right ventricular (RV) adaptation, RA function and disease progression. Methods We investigated BMP10 gene and protein expressions in RA tissue. We determined BMP10 and BMP9 plasma levels by ELISA. We studied BMP10 signaling activity in PH and CTEPH patients before and after pulmonary endarterectomy (PEA). Results BMP10 mRNA, protein and activity were significantly increased in the PH right atrium. While circulating levels of BMP10 and BMP9 proteins were increased, no significant changes were observed in BMP10 signaling activity between PH and controls. In a cohort of CTEPH patients, BMP10 signaling activity was reduced after PEA which coincided with improved hemodynamics and RV function. Interestingly, high BMP10 activity was associated with reduced RV function and adaptation, increased RA dilation and decreased RA function. No associations were observed with hemodynamics or general disease markers. Conclusions RA BMP10 expression and plasma levels are increased in precapillary PH. High BMP10 transcriptional activity was associated with worse RV function, RV adaptation, RA dilation and RA function. Future studies are needed to further understand the mechanism underlying BMP10 secretion and function in PH.

Retrospective evaluation of a right heart parameter score in the assessment of precapillary pulmonary hypertension in dogs (2017-2021): 135 cases.

To determine if emergency and critical care residents can identify moderate to severe precapillary pulmonary hypertension on cardiologist-obtained cineloops using a pulmonary hypertension score (PHS) and report the interobserver variability of the PHS. Multicenter, retrospective, case-control study from 2017 to 2021. Private referral center and veterinary teaching hospital. One hundred and thirty-five client-owned dogs that underwent diagnostic echocardiography. None. Medical records of dogs with stage B1 myxomatous mitral valve disease (MMVD) and dogs diagnosed with precapillary pulmonary hypertension (PCPH) via echocardiograms were reviewed. Dogs were categorized by a cardiologist into 5 groups (normal, B1 MMVD, mild, moderate, and severe PCPH) based on Doppler pulmonary pressure gradients and right heart morphology. Cineloops from each case were subjectively evaluated by emergency and critical care residents for the presence of right atrial and ventricular enlargement, right ventricular hypertrophy, interventricular septal flattening, and pulmonary artery and trunk enlargement to form a composite pulmonary hypertension score out of 8 (PHS8). When available, signs of peritoneal effusion and distention of the caudal vena cava were subjectively assessed to generate a pulmonary hypertension score out of 10 (PHS10). There was excellent discrimination of moderate to severe PCPH versus grouped absent to mild PCPH using PHS8 (area under the receiver operator curve [AUC] [95% confidence interval, CI]=0.90 [0.84-0.95], P<0.0001) and PHS10 (AUC [95% CI]=0.89 [0.81-0.97], P<0.0001). PHS8≥3 was 64% sensitive and 98% specific for moderate to severe PCPH (positive likelihood ratio [LR+] 32, negative likelihood ration [LR-] 0.37). PHS10≥3.3 was 64% sensitive and 92% specific for moderate to severe PCPH (LR+ 8, LR- 0.39). Interobserver agreement was good to excellent (intraclass correlation coefficient [ICC]=0.74 [95% CI: 0.66-0.80], n=135). Residents identified moderate to severe PCPH in dogs using PHS on cineloops previously obtained by a cardiologist. The interrater agreement was good to excellent with limited training. Prospective studies to determine if residents can obtain diagnostic images for PHS are warranted.

PULMONARY VENO–OCCLUSIVE DISEASE ASSOCIATED WITH METHAMPHETAMINE ABUSE: A FIRST CASE DESCRIPTION

Abstract Background Recreational methamphetamine is widely used worldwide (about 35 million people), mainly as 3,4–Methylenedioxymethamphetamine (MDMA). A definite association has been established between methamphetamine and pulmonary arterial hypertension (PAH). This drug–associated form of PAH shares histological, clinical and hemodynamic characteristics, prognosis and treatment strategies with idiopathic PAH. However, the association between MDMA and a rarer and devasting form of PAH with concomitant venous involvement (pulmonary veno–occlusive disease, PVOD), has never been reported. Notably, initiation of PAH–specific treatment in PVOD may lead to catastrophic consequences. Case Description A 32–year–old man was fast–track referred to our PH Centre in December 2023, due to high echocardiographic probability of pulmonary hypertension (PH). After interrogation, he admitted the regular use of MDMA. No other risk factor for PAH was found. Right heart catheterization showed a pre–capillary PH (mean pulmonary artery pressure 35 mmHg; wedge pressure 12 mmHg; pulmonary vascular resistance 5.9 WU) with low cardiac output (2.2 L/min/m2) and no acute response to vasoreactivity testing. Exercise capacity was severely reduced (oxygen consumption 19.6 mL/Kg/min, 50% of predicted) due to absent stroke volume reserve, accompanied by augmented exercise hyperventilation (VE/VCO2 slope 60) and exercise–induced desaturation (SaO2 94 à 77%), this latter not explained by a right–to–left shunt. Diffusion capacity of the lung was severely reduced (DLCO 28%). Chest CT and perfusion scan excluded both thromboembolic etiology and parenchymal lung disease. A diagnosis of PVOD was made, based on the presence of pre–capillary PH, oxygen desaturation, extreme exercise hyperventilation and very low DLCO, even in the absence of pathognomonic CT features. Counselling for stopping MDMA abuse was offered. Cautious monotherapy with macitentan was started and was well tolerated. A genetic testing for EIF2AK4 is ongoing. Contact with transplant center has been performed. A follow–up RHC has been planned before careful therapy up–titration. Conclusions This is the first case reported of the potential association between methamphetamines and PVOD. Due to the large worldwide use of MDMA, this link should be considered because of its prognostic and therapeutic implications. The diagnosis of PVOD is a clinical one, needing a high index of suspicion especially in the absence of chest CT findings.

A CASE OF PULMONARY HYPERTENSION ASSOCIATED WITH MYELOFIBROSIS: THERAPEUTICAL CHALLENGES FROM ACUTE TO CHRONIC SETTING

Abstract A 85–year–old female was transferred to our ICCU for acute heart failure from one of our spoke hospitals. The patient had a long history of chronic myelofibrosis, treated with fedratinib as a second–line agent after ruxolitinib failure. During a recent hospital admission, transthoracic echocardiography already showed signs of severe pulmonary hypertension (PH) with right ventricular (RV) dysfunction, so diuretic was started. On admission the patient presented showed consistent with acute on chronic kidney injury (serum Cr 3.2 mg/dl), stable anemia (Hb 9.2 mg/dl) and markedly elevated Nt–proBNP. A pulmonary CT–scan excluded acute pulmonary embolism and lung parenchymal alterations, with a clear dilation of main pulmonary artery. Transthoracic echocardiography (figure 1) confirmed precapillary PH phenotype diagnosis. Electrocardiogram (figure 2) showed sinus rhythm; incomplete RBBB, T wave inversion in V2 to V4. The patient was initially treated with high dose furosemide, low flow oxygen; but later she needed multiple cycles of inotropes, vasopressors and combined diuretic therapy (metolazone and acetazolamide) to stabilize the clinical setting. The patient also experienced episodes of paroxysmal high ventricular rate atrial flutter. After resolution of volume overload, a right heart catheterization was performed and findings were consistent with severe precapillary pulmonary hypertension: PA pressure 90/58/40 mmHg, normal PCWP, high PVR, mild cardiac index reduction. Due to critical clinical situation, Sildenafil 20 mg was started as an off–label therapy for PH (group 5). Subsequently, the patient experienced gradual but constant hemodynamic and clinical improvement and was discharged in NYHA class II. At 1 month control, patient was stable, echocardiogram revealed improvement in right ventricle dimension, systolic function and right atrial enlargement. At three months, patient is still in an intermediate risk class for PH, so we are evaluating a combination therapy (either endothelin receptor antagonist or prostanoids), taking into account anemia and thrombocytopenia. Take home message: PH can be a complication of hematological disorders as myelofibrosis, included in “mixed” forms (group 5) of PH. In our patient, after a challenging management for acute right heart failure, an off–label PDE–5 inhibitor stabilized the clinical scenario: more data are needed on PH drugs use in this setting where up to now therapeutic strategies are lacking.