Elevated Pulmonary Vascular Resistance Research Articles

Circulating Biomarkers in Pulmonary Arterial Hypertension: An Update.

Pulmonary arterial hypertension (PAH) is a rare subtype of group 1 pulmonary hypertension (PH) diseases, characterized by high pulmonary artery pressure leading to right ventricular dysfunction and potential life-threatening consequences. PAH involves complex mechanisms: vasoconstriction, vascular remodeling, endothelial dysfunction, inflammation, oxidative stress, fibrosis, RV remodeling, cellular hypoxia, metabolic imbalance, and thrombosis. These mechanisms are mediated by several pathways, involving molecules like nitric oxide and prostacyclin. PAH diagnosis requires clinical evaluation and right heart catheterization, confirming a value of mPAP ≥ 20 mmHg at rest and often elevated pulmonary vascular resistance (PVR). Even if an early and accurate diagnosis is crucial, PAH still lacks effective biomarkers to assist in its diagnosis and prognosis. Biomarkers could contribute to arousing clinical suspicion and serve for prognosis prediction, risk stratification, and dynamic monitoring in patients with PAH. The aim of the present review is to report the main novelties on new possible biomarkers for the diagnosis, prognosis, and treatment monitoring of PAH.

(1374) - Isolated Heart Transplantation Needing Mechanical Circulatory Support in Elevated Pulmonary Vascular Resistance

(1374) - Isolated Heart Transplantation Needing Mechanical Circulatory Support in Elevated Pulmonary Vascular Resistance

Reversibility of precapillary pulmonary hypertension and outcomes after heart transplantation bridged with left ventricular assist devices: Insight from the United Network for Organ Sharing

BackgroundIn light of the updated lowered threshold for diagnosing pulmonary hypertension (PH), the reversibility of precapillary PH with left ventricular assist device (LVAD) and the associated post-heart transplantation (HT) outcomes remain unclear. MethodsUsing data from the United Network for Organ Sharing database, we aimed to investigate predictors of persistent precapillary PH in HT recipients bridged with LVAD and examine the interrelated post-HT survival using the updated pulmonary vascular resistance (PVR) cutoff of >2 Wood units for precapillary PH. ResultsAmong 2169 HT recipients bridged with LVAD, 1299 had PVR >2 at baseline; 551 (42.4%) of whom normalized their PVR ≤2 and 748 (57.6%) remained with elevated PVR >2 after LVAD implantation. Female sex (adjusted odds ratio [aOR]; 2.22, 95% confidence interval [CI], 1.61-3.07; P < .001) and inotrope treatment at listing (aOR, 1.31; 95% CI, 1.03-1.66; P = .028) were associated with persistently elevated PVR after LVAD. Conversely, longer duration of LVAD support (aOR, 0.74; 95% CI, 0.65-0.84; P < .001) and use of HeartMate II (aOR, 0.74; CI, 0.59-0.93; P = .011) were found to be protective against persistently elevated PVR after LVAD. Persistently elevated PVR >2 after LVAD was associated with increased risk of death compared with those who normalized their PVR (adjusted hazard ratio [aHR], 1.26; 95% CI, 1.01-1.57; P = .037). However, the normalized PVR post-LVAD group had comparable survival with those with PVR ≤2 at baseline (aHR, 0.76; 95% CI, 0.57-1.02; P = .07). ConclusionsMany recipients of HT bridged with LVAD remain with PVR >2 after LVAD implantation, which is associated with increased risk of death after HT compared with patients with normalized PVR after LVAD.

Male Sex Is Associated With Worse Right Ventricular Function and Survival in Pulmonary Hypertension in the Redefining Pulmonary Hypertension Through Pulmonary Vascular Disease Phenomics Cohort

BackgroundSex-based differences are important in the development and progression of pulmonary arterial hypertension (PAH). However, it is not established whether these differences are generalizable to all forms of pulmonary hypertension (PH). Research QuestionTo assess sex-based differences in right ventricular (RV) function and transplant-free survival in subjects with PH from the PVDOMICS cohort. Study Design and MethodsSubjects with PH enrolled in PVDOMICS cohort study underwent right heart catheterization, cardiac MRI, and echocardiogram. A multivariable linear regression model was used to investigate the interactive effect between sex and pulmonary vascular resistance (PVR) on RV ejection fraction (EF). Effects of sex, RVEF, and PVR on transplant-free survival were assessed using a Cox proportional hazards model. Results750 subjects with PH (62.8% female) were enrolled, including 397 subjects with Groups 2-5 PH. Group 1 was most predominantly female (73.4%). Men had multiple markers of worse RV function with significantly lower RVEF (Adjusted difference 5.5%, 95% CI: 3.2-7.8%, P<0.001) on cardiac MRI and lower RV fractional shortening (Adjusted difference 4.0%, 95% CI: 2.3 to 5.8%, P<0.001) and worse RV free wall longitudinal strain (Adjusted difference 2.4%, 95% CI: 1.2 to 3.6%, P<0.001) on echocardiogram. There was significant interaction between PVR and sex on RVEF with largest sex-based differences in RVEF noted at mild to moderate PVR elevation. Male sex was associated with decreased transplant-free survival (adjusted HR 1.46, 95% CI: 1.07 to 1.98, P=0.02), partially mediated by differences in RVEF (P=0.003). InterpretationIn subjects with PH in PVDOMICS, female sex is more common, while male sex is associated with worse RV function and decreased transplant-free survival, most notably at mild to moderate elevation of PVR.

Elevated pulmonary vascular resistance is associated with increased lung transplant waitlist mortality among patients with chronic obstructive pulmonary disease and pulmonary hypertension: a retrospective cohort analysis

BackgroundThe latest European Society of Cardiology and European Respiratory Society guidelines have changed the definition of both pre-capillary pulmonary hypertension (PH) and severe PH in chronic lung disease. The clinical significance of these new criteria are unclear among patients with chronic obstructive pulmonary disease (COPD)-PH. We aim to examine the clinical significance of the new PH definitions with regards to lung transplant waitlist mortality amongst patients with COPD-PH.MethodsThis was a retrospective cohort study of adult patients with COPD-PH listed for lung transplantation. Kaplan–Meier survival analyses were performed comparing patients with newly defined pre-capillary PH to those without pre-capillary PH and comparing patients with severe PH, defined as pulmonary vascular resistance (PVR) > 5 WU, to those without severe PH. Both mean pulmonary artery pressure (mPAP) and PVR were analyzed for potential cut-off points associated with increased waitlist mortality. Predictors of waitlist mortality were identified via Cox regression.ResultsAmong 6495 patients with COPD-PH listed for lung transplantation, pre-capillary PH was not associated with increased waitlist mortality (logrank p = 0.43), while severe PH was (logrank p < 0.001). Both severe PH (HR 1.79, 95% CI 1.22–2.60, p = 0.003) and PVR > 3.9 WU (HR 1.49, 95% CI 1.14–1.95, p = 0.004) were independently and significantly associated with increased waitlist mortality.ConclusionsPVR may serve as a strong predictor of lung transplant waitlist mortality among patients with COPD-PH as compared to other pulmonary hemodynamic parameters when predicting transplant waitlist mortality.

Mild elevation of pulmonary vascular resistance predicts mortality regardless of mean pulmonary artery pressure in mild interstitial lung disease

BackgroundPulmonary hypertension (PH) is defined by elevated mean pulmonary arterial pressure (MPAP), and elevated pulmonary vascular resistance (PVR) reflects pulmonary vascular abnormalities. The clinical significance of non-severe PH in patients...

Inhaled Pulmonary Vasodilators for the Treatment of Right Ventricular Failure in Cardio-Thoracic Surgery: Is One Better than the Others?

Right ventricular failure (RFV) is a potential complication following cardio-thoracic surgery, with an incidence ranging from 0.1% to 30%. The increase in pulmonary vascular resistance (PVR) is one of the main triggers of perioperative RVF. Inhaled pulmonary vasodilators (IPVs) can reduce PVR and improve right ventricular function with minimal systemic effects. This narrative review aims to assess the efficacy of inhaled nitric oxide and inhaled prostacyclins for the treatment of perioperative RVF. The literature, although statistically limited, supports the clinical similarity between them. However, it failed to demonstrate a clear benefit from the pre-emptive use of inhaled nitric oxide in patients undergoing left ventricular assist device implantation or early administration during heart-lung transplants. Additional concerns are related to cost safety and IPV use in pathologies associated with pulmonary venous congestion. The largest ongoing randomized controlled trial on adults (INSPIRE-FLO) is addressing whether inhaled Epoprostenol and inhaled nitric oxide are similar in preventing RVF after heart transplants and left ventricular assist device placement, and whether they are similar in preventing primary graft dysfunction after lung transplants. The preliminary analysis supports their equivalence. Several key points may be achieved by the present narrative review. When RVF occurs in the setting of elevated PVR, IPV should be the preferred initial treatment and they should be preventively used in patients at high risk of postoperative RVF. If severe refractory postoperative RVF occurs, IPVs should be combined with complementary pharmacology (inotropes and inodilators). If unsuccessful, right ventricular mechanical support should be established.

Analyzing Short and Medium-Term Morbidity and Mortality in Patients with Heart Failure and Borderline Ejection Fraction (EF: 40-49%).

Introduction: Heart failure with moderately impaired ejection fraction (HFmEF) has garnered increasing attention in recent years. However, understanding this new phenotype, particularly concerning morbidity and mortality, remains limited. Materials and Methods: A prospective, observational, and single-center study spanning 26 months was conducted on 204 patients with HFmEF selected from 447 patients with chronic heart failure (CHF) categorized based on their left ventricular ejection fraction (LVEF): HF with reduced ejection fraction (HFrEF) if LVEF ≤ 40% (n = 173) and HF with preserved ejection fraction (HFpEF) if LVEF ≥ 50% (n = 70). This study included a detailed evaluation of factors precipitating cardiovascular (CV) death and rehospitalizations in patients with HFmEF. Results: After a mean follow-up of 431 days in the HFmEF patient group, our results indicated that CV mortality at six months was 2.5%, and at one year, it was 5.9%. Prognostic factors for survival included chronic kidney disease, blood glucose level &gt; 1.4g/l, presence of moderate to severe secondary mitral insufficiency, sphericity index &lt; 1.7, elevated pulmonary vascular resistance, and resistance to diuretic treatment. HF rehospitalization rates at 6 and 12 months were 2.5% and 8.3%, respectively. Predictive factors for HF rehospitalizations included diabetes, hemoglobin level &lt; 13g/dl, left atrial volume &gt; 34 ml/m3-, mitral S-wave &lt; 0.05cm/s, non-improvement of global longitudinal strain, and resistance to diuretic treatment. Conclusion: This category of HF remains underrecognized and neglected by practitioners, and its prognosis is formidable, especially in the presence of adverse prognostic factors.

Pulmonary vascular dysfunction without pulmonary hypertension: A distinct phenotype in idiopathic pulmonary fibrosis.

Pulmonary vascular dysfunction in the absence of pulmonary hypertension (PH) has been observed in patients with idiopathic pulmonary fibrosis (IPF). We describe the prevalence and etiology of elevated pulmonary vascular resistance (PVR) without PH among patients with IPF. Hemodynamic, echocardiographic, and functional respiratory imaging (FRI) data was compared between patients with IPF without PH with normal (<3 wood units) and elevated PVR (≥3 wood units). Mortality between these two groups were compared to patients with IPF and PH. Of 205 patients with IPF, there were 146 patients without PH, of whom 114 (78.1%) had a normal PVR and 32 (21.9%) who had a high PVR. Functional testing and hemodynamics were similar in the two groups, except for the cardiac index which was significantly lower in patients with a high PVR (2.3 vs. 2.6 L/min/m2; p = 0.004). Echocardiographic comparison demonstrated a higher tricuspid regurgitant velocity in those with a high PVR (3.4 vs 3.0 m/s; p = 0.046). FRI revealed proportionately fewer large vessels as a proportion of the vasculature in the patients without PH and elevated PVRs. Among patients without PH, PVR was associated with increased mortality. In conclusion, patients with IPF without PH but a high PVR appear to be a distinct phenotype with a prognosis between those with and without PH, likely reflecting the continuum of vascular dysfunction. The basis for this unique hemodynamic profile could not be definitively discerned although FRI suggested an aberrant anatomical vascular response.

Promising dawn in the management of pulmonary hypertension: The mystery veil of gut microbiota

AbstractThe gut microbiota is a complex community of microorganisms inhabiting the intestinal tract, which plays a vital role in human health. It is intricately involved in the metabolism, and it also affects diverse physiological processes. The gut–lung axis is a bidirectional pathway between the gastrointestinal tract and the lungs. Recent research has shown that the gut microbiome plays a crucial role in immune response regulation in the lungs and the development of lung diseases. In this review, we present the interrelated factors concerning gut microbiota and the associated metabolites in pulmonary hypertension (PH), a lethal disease characterized by elevated pulmonary vascular pressure and resistance. Our research team explored the role of gut‐microbiota‐derived metabolites in cardiovascular diseases and established the correlation between metabolites such as putrescine, succinate, trimethylamine N‐oxide (TMAO), and N, N, N‐trimethyl‐5‐aminovaleric acid with the diseases. Furthermore, we found that specific metabolites, such as TMAO and betaine, have significant clinical value in PH, suggesting their potential as biomarkers in disease management. In detailing the interplay between the gut microbiota, their metabolites, and PH, we underscored the potential therapeutic approaches modulating this microbiota. Ultimately, we endeavor to alleviate the substantial socioeconomic burden associated with this disease. This review presents a unique exploratory analysis of the link between gut microbiota and PH, intending to propel further investigations in the gut–lung axis.

Autonomic nervous modulation: early treatment for pulmonary artery hypertension.

Pulmonary artery hypertension (PAH) is a chronic vascular disease defined by the elevation of pulmonary vascular resistance and mean pulmonary artery pressure, which arises due to pulmonary vascular remodelling. Prior research has already established a link between the autonomic nervous system (ANS) and PAH. Therefore, the rebalancing of the ANS offers a promising approach for the treatment of PAH. The process of rebalancing involves two key aspects: inhibiting an overactive sympathetic nervous system and fortifying the impaired parasympathetic nervous system through pharmacological or interventional procedures. However, the understanding of the precise mechanisms involved in neuromodulation, whether achieved through medication or intervention, remains insufficient. This limited understanding hinders our ability to determine the appropriate timing and scope of such treatment. This review aims to integrate the findings from clinical and mechanistic studies on ANS rebalancing as a treatment approach for PAH, with the ultimate goal of identifying a path to enhance the safety and efficacy of neuromodulation therapy and improve the prognosis of PAH.

Rescuing the Right Ventricle: Mechanical Support After Pediatric Heart Transplantation

BackgroundRight ventricular (RV) failure after heart transplantation (HT) is common in those with pretransplantation elevated pulmonary vascular resistance (PVR). Mechanical circulatory support has been used as a bridge to recovery, with mixed outcomes. We describe a patient with failed single-ventricle palliation in whom severe RV failure developed after HT. We review the current literature and outline our post-HT strategy. MethodsAn infant with trisomy 21, severely unbalanced right dominant atrioventricular septal defect, and hypoplastic aortic arch was palliated with a hybrid procedure. At 6 months of age, cardiac catheterization measured PVR index of 5.47 Wood units × m2 on maximal medical therapy. The patient was deemed unsuitable for second-stage palliation and underwent HT at 18 months of age. Despite preemptive medical therapies, acute RV failure developed, necessitating extracorporeal membrane oxygenation. He was quickly converted to main pulmonary artery to left atrial cannulation. Unloaded RV function normalized; he was weaned from support and discharged home 5 weeks after HT. ResultsFailure of medical therapy in RV failure after HT requires escalation to mechanical circulatory support. We review the literature on RV failure and support after HT. We also describe a novel cannulation strategy to provide a reliable way to directly reduce RV afterload, to allow physiologic training of the right ventricle to a higher PVR, and to maintain normal left ventricular coupling and loading. ConclusionsIn pediatric patients with elevated PVR undergoing HT, advanced therapies can be used effectively to treat acute RV failure. Unique cannulation strategies may play a role in improving survival of similar patients.

Development of KER-012, a modified ActRIIB ligand trap, for the treatment of pulmonary arterial hypertension

Abstract Background Pulmonary Arterial Hypertension (PAH) is a debilitating disorder characterized by elevated pulmonary vascular resistance (PVR) due to severe constriction obliteration of pulmonary vessels (Tielemans 2019). The pathology of PAH is driven by endothelial dysfunction and vascular remodeling that leads to increased wall thickening and resistance to blood flow. Dysregulated TGF-β, specifically SMAD signaling, is a key molecular defect in proliferative thickening of pulmonary arterioles in PAH leading to increased arterial pressure and compensatory right ventricular hypertrophy, ultimately resulting in decompensated right heart failure. Increased levels of activin A, a TGF-β superfamily ligand, have been found in PAH patients, and in the lungs of hypoxia-induced pulmonary hypertensive mice (Yndestad 2009). KER-012 is an investigational modified ActRIIB ligand trap designed to bind and inhibit activin A, activin B, GDF8 and GDF11 to maximally inhibit SMAD2/3 (pro proliferative), while permitting SMAD1/5/9 (anti-proliferative) signaling. This profile is expected to rebalance defective SMAD signaling in PAH and potentially delay or reverse disease progression. Aim To evaluate safety and tolerability of KER-012 in healthy post-menopausal women (PMW) and present the planned design of a Phase 2 trial in participants with PAH. Methods A two-part Phase 1 study has been conducted with KER-012 in healthy PMW. Participants received either placebo or a single dose of KER-012 ranging between 0.75 and 5.0 mg/kg in Part 1 or multiple doses between 0.75 and 4.5 mg/kg in Part 2 subcutaneously once every 4 weeks over a 12-week period. Safety, PK and biomarkers of activin target engagement were assessed. Results KER-012 was generally well tolerated at dose levels up to 5 mg/kg as a single dose and at dose levels up to 4.5 mg/kg administered Q4W for a total of 3 doses (Table 1). Maximal target engagement of KER-012, as demonstrated by changes in biomarkers of activin inhibition, namely follicle stimulating hormone (FSH) and bone specific alkaline phosphatase (BSAP), was observed in this study. As previous studies with activin receptor type II ligand traps have shown a potentially dose-limiting increase in erythropoiesis, changes in red blood cells (RBC) were closely monitored in this study. KER-012 did not elicit any changes in hemoglobin or RBC count in the Phase 1 study (Figure 1). Summary KER-012 was generally well tolerated in healthy participants. The observed biomarker changes are consistent with inhibition of activins, suggestive of a balance shift in favor of signaling via the anti-proliferative SMAD 1/5/9 pathway. Based on this mechanism, administration of KER-012 could potentially result in reverse vascular remodeling and clinical cardiopulmonary improvements in patients with PAH, without targeting erythropoietic pathways. Given this profile, KER-012 is being advanced for development in patients with PAH in an upcoming Ph2 clinical trial (Figure 2).

High-Soluble-Fiber Diet Attenuates Hypoxia-Induced Vascular Remodeling and the Development of Hypoxic Pulmonary Hypertension.

Hypoxic pulmonary hypertension is a difficult disease to manage that is characterized by sustained elevation of pulmonary vascular resistance and pulmonary artery pressure due to vasoconstriction, perivascular inflammation, and vascular remodeling. Consumption of soluble-fiber is associated with lower systemic blood pressure, but little is known about its ability to affect the pulmonary circulation. Mice were fed either a low- or high-soluble-fiber diet (0% or 16.9% inulin) and then exposed to hypoxia (FiO2, 0.10) for 21 days to induce pulmonary hypertension. The impact of diet on right ventricular systolic pressure and pulmonary vascular resistance was determined in vivo or in ex vivo isolated lungs, respectively, and correlated with alterations in the composition of the gut microbiome, plasma metabolome, pulmonary inflammatory cell phenotype, and lung proteome. High-soluble-fiber diet increased the abundance of short-chain fatty acid-producing bacteria, with parallel increases in plasma propionate levels, and reduced the abundance of disease-related bacterial genera such as Staphylococcus, Clostridioides, and Streptococcus in hypoxic mice with parallel decreases in plasma levels of p-cresol sulfate. High-soluble-fiber diet decreased hypoxia-induced elevations of right ventricular systolic pressure and pulmonary vascular resistance. These changes were associated with reduced proportions of interstitial macrophages, dendritic cells, and nonclassical monocytes. Whole-lung proteomics revealed proteins and molecular pathways that may explain the effect of soluble-fiber supplementation. This study demonstrates for the first time that a high-soluble-fiber diet attenuates hypoxia-induced pulmonary vascular remodeling and the development of pulmonary hypertension in a mouse model of hypoxic pulmonary hypertension and highlights diet-derived metabolites that may have an immuno-modulatory role in the lung.

Comprehensive analyses of m6A RNA methylation patterns and related immune microenvironment in idiopathic pulmonary arterial hypertension.

Idiopathic pulmonary arterial hypertension (IPAH) is a life-threatening disease with a poor prognosis and high heritability, characterized by elevated pulmonary vascular resistance (PVR) and pulmonary artery pressure. N6-methyladenosine (m6A) RNA modification influences many RNA metabolism pathways. However, the position of m6A methylation regulators in IPAH remains unknown. Therefore, the study aims to disclose the function m6A regulators exert in the pathological mechanisms of IPAH and the immune microenvironment involved. The GSE117261 dataset was downloaded from the Gene Expression Omnibus (GEO) to screen the differentially expressed genes (DEGs) between normal and IPAH samples. Functional and pathway enrichment analyses of DEGs were then conducted by Gene ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG). We also identified the differentially-expressed m6A (DEm6A) regulators between normal and IPAH samples. Key m6A regulators related to the prediction of IPAH were selected using the random forest model. The results showed that FMR1, RBM15, HNRNPA2B1 and IGFBP3 were upregulated in IPAH. In contrast, LRPPRC was downregulated. The single sample gene set enrichment analysis (ssGSEA) method was then adopted to estimate the immune microenvironment in distinct m6A clusters and m6A phenotype-related genes (PRGs) clusters, respectively. Furthermore, we calculated the m6A score via principal component analysis (PCA), and the Sankey diagram was selected to present the correlation among the m6A clusters, m6A PRGs clusters and m6A score. Finally, quantitative RT-PCR and Western blotting were used to validate the key genes in human pulmonary artery smooth muscle cells (HPASMCs) treated by human platelet-derived growth factor-BB (PDGF-BB). The relative mRNA and protein expression levels of FMR1 were significantly elevated, however, the relative mRNA and protein expression levels of LRPPRC were downregulated. Besides, the relative mRNA level of HNRNPA2B1 was increased. Generally, this bioinformatics analysis might provoke more insights into diagnosing and treating IPAH.

Management of systemic to pulmonary shunts and elevated pulmonary vascular resistance.

Repair of systemic to pulmonary shunts is timed to prevent the development of irreversible pulmonary vascular disease, including in patients with other factors contributing to pulmonary hypertension. This study assessed outcomes of an individualised strategy for managing patients with mild-moderately elevated pulmonary vascular resistance (PVR) deemed borderline eligible for repair. A retrospective chart review was conducted of patients with systemic to pulmonary shunts and baseline indexed PVR (PVRi) ≥3 WU·m2 treated at a single centre from 1 January 2005 to 30 September 2019. Data included demographics, World Health Organization functional class (WHO FC), medications and haemodynamic data at baseline and serial follow-up. 30 patients (18 females) met criteria for inclusion. Median age at diagnosis of pulmonary arterial hypertension was 1.3 years (range 0.03-54 years) and at surgery was 4.1 years (range 0.73-56 years). Median follow-up time was 5.8 years (range 0.2-14.6 years) after repair. Most patients received at least one targeted pulmonary arterial therapy prior to repair and the majority (80%) underwent fenestrated shunt closure. There was a significant decrease in mean pulmonary arterial pressure (mPAP) (p<0.01), PVRi (p=0.0001) and PVR/systemic vascular resistance (p<0.01) between baseline and preoperative catheterisation and a decrease in PVRi (p<0.005), mPAP (p=0.0001) and pulmonary to systemic flow ratio (p<0.03) from baseline to most recent catheterisation. WHO FC improved from FC II-III at baseline to FC I post repair in most patients (p<0.003). In carefully selected patients with systemic to pulmonary shunts and elevated PVR considered borderline for operability, the use of preoperative targeted therapy in conjunction with fenestrated or partial closure of intracardiac shunts is associated with improvement in WHO FC and clinical outcomes.

Predictors of outcomes in mild pulmonary hypertension according to 2022 ESC/ERS Guidelines: the EVIDENCE-PAH UK study.

Interventional studies in pulmonary arterial hypertension completed to date have shown to be effective in symptomatic patients with significantly elevated mean pulmonary artery pressure (mPAP) (≥25 mmHg) and pulmonary vascular resistance (PVR) > 3 Wood Unit (WU). However, in health the mPAP does not exceed 20 mmHg and PVR is 2 WU or lower, at rest. The ESC/ERS guidelines have recently been updated to reflect this. There is limited published data on the nature of these newly defined populations (mPAP 21-24 mmHg and PVR >2-≤3 WU) and the role of comorbidity in determining their natural history. With the change in guidelines, there is a need to understand this population and the impact of the ESC/ERS guidelines in greater detail. A retrospective nationwide evaluation of the role of pulmonary haemodynamics and comorbidity in predicting survival among patients referred to the UK pulmonary hypertension (PH) centres between 2009 and 2017. In total, 2929 patients were included in the study. Patients were stratified by mPAP (<21 mmHg, 21-24 mmHg, and ≥25 mmHg) and PVR (≤2 WU, > 2-≤3 WU, and >3 WU), with 968 (33.0%) in the mPAP <21 mmHg group, 689 (23.5%) in the mPAP 21-24 mmHg group, and 1272 (43.4%) in the mPAP ≥25 mmHg group. Survival was negatively correlated with mPAP and PVR in the population as a whole. Survival in patients with mildly elevated mPAP (21-24 mmHg) or PVR (>2-≤3WU) was lower than among those with normal pressures (mPAP <21 mmHg) and normal PVR (PVR ≤ 2WU) independent of comorbid lung and heart disease [hazard ratio (HR) 1.36, 95% confidence interval (CI) 1.14-1.61, P = .0004 for mPAP vs. HR 1.28, 95% CI 1.10-1.49, P = .0012 for PVR]. Among patients with mildly elevated mPAP, a mildly elevated PVR remained an independent predictor of survival when adjusted for comorbid lung and heart disease (HR 1.33, 95% CI 1.01-1.75, P = .042 vs. HR 1.4, 95% CI 1.06-1.86, P = .019). 68.2% of patients with a mPAP 21-24 mmHg had evidence of underlying heart or lung disease. Patients with mildly abnormal haemodynamics were not more symptomatic than patients with normal haemodynamics. Excluding patients with heart and lung disease, connective tissue disease was associated with a poorer survival among those with PH. In this subpopulation evaluating those with a mPAP of 21-24 mmHg, survival curves only diverged after 5 years. This study supports the change in diagnostic category of the ESC/ERS guidelines in a PH population. The newly included patients have an increased mortality independent of significant lung or heart disease. The majority of patients in this new category have underlying heart or lung disease rather than an isolated pulmonary vasculopathy. Mortality is higher if comorbidity is present. Rigorous phenotyping will be pivotal to determine which patients are at risk of progressive vasculopathic disease and in whom surveillance and recruitment to studies may be of benefit. This study provides an insight into the population defined by the new guidelines.

Pulmonary Vasodilator Therapy in Pediatric Patients on Ventricular Assist Device Support: A Single-Center Experience and Proposal for Use.

Pediatric precapillary pulmonary hypertension can develop in response to systemic atrial hypertension. Systemic atrial decompression following ventricular assist device (VAD) implantation may not sufficiently lower pulmonary vascular resistance (PVR) to consider heart transplant candidacy. Prostacyclins have been used in adult VAD patients with success, but pediatric data on safety and efficacy in this population are limited. We sought to describe our center's experience to show its safety and to present our current protocol for perioperative use. We reviewed our use of prostacyclin therapy in pediatric patients on VAD support with high PVR from 2016 to 2021. Of the 17 patients who met inclusion, 12 survived to transplant and 1 is alive with VAD in situ. All patients survived posttransplant. With continuous intravenous (IV) epoprostenol or treprostinil therapy, there were no bleeding complications or worsening of end-organ function. A significant reduction was observed in vasoactive inotropic scores by 49% in the first 24 hours post-prostacyclin initiation. The proportion of patients surviving to transplant in this high-risk cohort is favorable. In conclusion, prostacyclins may be safe to use in patients with elevated PVR as part of their VAD and transplant course and may provide a transplant option in those otherwise not candidates.

Group 2 pulmonary hypertension: from diagnosis to treatment.

Pulmonary hypertension associated with left heart disease (PHLHD) is common and associated with adverse prognosis. Proper diagnosis is critical to avoid inappropriate treatment. Practical approaches to noninvasive diagnosis are available, though invasive hemodynamics including volume loading or exercise are often necessary for definitive diagnosis. Treatment strategies and research in the field is rapidly evolving. Combined pre and post capillary pulmonary hypertension is associated with remodeling of the pulmonary vasculature that is proportional to the severity of the pulmonary hypertension. Even quite mild elevation of pulmonary vascular resistance (PVR), (greater than 2.0 Wood units (WU)) is associated with adverse outcome. Guideline-directed medical therapy (GDMT) for left heart failure has rapidly evolved, including approval of SGLT2 inhibitors for treatment of heart failure with preserved ejection fraction (HFpEF). However, full implementation of GDMT is lagging. Utilization of implanted pulmonary artery pressure monitoring can facilitate patient management in selected patient phenotypes and has been utilized to demonstrate improvement in pulmonary pressures with emerging therapies in HFpEF including SGLT2 inhibitors and sacubitril/valsartan. A variety of shunt devices to create a left-to-right shunt in order to decompress the left heart are available or undergoing clinical trials. There is concern that there could be adverse response to such devices in patients who have even mild elevation of pulmonary vascular resistance. Sleep disordered breathing is common in PHLHD and should be aggressively sought out and treated. Even mild elevation in pulmonary vascular resistance is associated with adverse outcome. A systematic approach to diagnosis of PHLHD is essential. Guideline-directed medical therapy for PHLHD prioritizes optimal management of the left heart disease. Pulmonary artery pressure sensors are useful in selected patients.

Association of Size Matching Using Predicted Heart Mass With Mortality in Heart Transplant Recipients With Obesity or High Pulmonary Vascular Resistance

Pretransplant obesity and higher pulmonary vascular resistance (PVR) are risk factors for death after heart transplant. However, it remains unclear whether appropriate donor-to-recipient size matching using predicted heart mass (PHM) is associated with lower risk. To investigate the association of size matching using PHM with risk of death posttransplant among patients with obesity and/or higher PVR. All adult patients (>18 years) who underwent heart transplant between 2003 and 2022 with available information using the United Network for Organ Sharing cohort database. Multivariable Cox models and multivariable-adjusted spline curves were used to examine the risk of death posttransplant with PHM matching. Data were analyzed from October 2022 to March 2023. Recipient's body mass index (BMI) in categories (<18.0 [underweight], 18.1-24.9 [normal weight, reference], 25.0-29.9 [overweight], 30.0-34.9 [obese 1], 35-39.9 [obese 2], and ≥40.0 [obese 3]) and recipient's pretransplant PVR in categories of less than 4 (29 061 participants), 4 to 6 (2842 participants), and more than 6 Wood units (968 participants); and less than 3 (24 950 participants), 3 to 5 (6115 participants), and 5 or more (1806 participants) Wood units. All-cause death posttransplant on follow-up. The mean (SD) age of the cohort of 37 712 was 52.8 (12.8) years, 27 976 (74%) were male, 25 342 were non-Hispanic White (68.0%), 7664 were Black (20.4%), and 3139 were Hispanic or Latino (8.5%). A total of 12 413 recipients (32.9%) had a normal BMI, 13 849 (36.7%) had overweight, and 10 814 (28.7%) had obesity. On follow-up (median [IQR] 5.05 [0-19.4] years), 12 785 recipients (3046 female) died. For patients with normal weight, overweight, or obese 2, receiving a PHM-undermatched heart was associated with an increased risk of death (normal weight hazard ratio [HR], 1.20; 95% CI, 1.07-1.34; overweight HR, 1.12; 95% CI, 1.02-1.23; and obese 2 HR, 1.07; 95% CI, 1.01-1.14). Moreover, patients with higher pretransplant PVR who received an undermatched heart had a higher risk of death posttransplant in multivariable-adjusted spline curves in graded fashion until appropriately matched. In contrast, risk of death among patients receiving a PHM-overmatched heart did not differ from the appropriately matched group, including in recipients with an elevated pretransplant PVR. In this cohort study, undermatching donor-to-recipient size according to PHM was associated with higher posttransplant mortality, specifically in patients with normal weight, overweight, or class II obesity and in patients with elevated pretransplant PVR. Overmatching donor-to-recipient size was not associated with posttransplant survival.