Phenotypes in Pulmonary Hypertension.

The clinical classification of pulmonary hypertension (PH) has guided diagnosis and treatment of patients with PH for several decades. Discoveries relating to underlying mechanisms, pathobiology, and responses to treatments for PH have informed the evolution in this clinical classification to describe the heterogeneity in PH phenotypes. In more recent years, advances in imaging, computational science, and multi-omic approaches have yielded new insights into potential phenotypes and sub-phenotypes within the existing clinical classification. Identification of novel phenotypes in pulmonary arterial hypertension (PAH) with unique molecular profiles, for example, could lead to new precision therapies. Recent phenotyping studies have also identified groups of patients with PAH that more closely resemble patients with left heart disease (group 2 PH) and lung disease (group 3 PH), which has important prognostic and therapeutic implications. Within group 2 and group 3 PH, novel phenotypes have emerged that reflect a persistent and severe pulmonary vasculopathy that is associated with worse prognosis but still distinct from PAH. In group 4 PH (chronic thromboembolic pulmonary disease) and sarcoidosis (group 5 PH) the current approach to patient phenotyping integrates clinical, hemodynamic and imaging characteristics to guide treatment but applications of multi-omic approaches to sub-phenotyping in these areas are sparse. The next iteration of the PH clinical classification is likely to reflect several emerging PH phenotypes and improve the next generation of prognostication tools, clinical trial design, and improve treatment selection in clinical practice.

Medical Emergencies in Pulmonary Hypertension.

The management of acute medical emergencies in patients with pulmonary hypertension (PH) can be challenging. Patients with preexisting PH can rapidly deteriorate due to right ventricular decompensation when faced with acute physiological challenges that would usually be considered low-risk scenarios. This review considers the assessment and management of acute medical emergencies in patients with PH, encompassing both pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH), acknowledging these comprise the more severe groups of PH. Management protocols are described in a systems-based approach. Respiratory emergencies include pulmonary embolism, airways disease, and pneumonia; cardiac emergencies including arrhythmia and chest pain with acute myocardial infarction are discussed, alongside PH-specific emergencies such as pulmonary artery dissection and extrinsic coronary artery compression by a dilated proximal pulmonary artery. Other emergencies including sepsis, severe gastroenteritis with dehydration, syncope, and liver failure are also considered. We propose management recommendations for medical emergencies based on available evidence, international guidelines, and expert consensus. We aim to provide advice to the specialist alongside the generalist, and emergency doctors, nurses, and acute physicians in nonspecialist centers. A multidisciplinary team approach is essential in the management of patients with PH, and communication with local and specialist PH centers is paramount. Close hemodynamic monitoring during medical emergencies in patients with preexisting PH is vital, with early referral to critical care recommended given the frequent deterioration and high mortality in this setting.

Phosphodiesterase 5 inhibitor treatment and survival in interstitial lung disease pulmonary hypertension: A Bayesian retrospective observational cohort study.

BACKGROUND AND OBJECTIVE: Pulmonary hypertension is a life-limiting complication of interstitial lung disease (ILD-PH). We investigated whether treatment with phosphodiesterase 5 inhibitors (PDE5i) in patients with ILD-PH was associated with improved survival. METHODS: Consecutive incident patients with ILD-PH and right heart catheterisation, echocardiography and spirometry data were followed from diagnosis to death, transplantation or censoring with all follow-up and survival data modelled by Bayesian methods. RESULTS: The diagnoses in 128 patients were idiopathic pulmonary fibrosis (n = 74, 58%), hypersensitivity pneumonitis (n = 17, 13%), non-specific interstitial pneumonia (n = 12, 9%), undifferentiated ILD (n = 8, 6%) and other lung diseases (n = 17, 13%). Final outcomes were death (n = 106, 83%), transplantation (n = 9, 7%) and censoring (n = 13, 10%). Patients treated with PDE5i (n = 50, 39%) had higher mean pulmonary artery pressure (median 38 mm Hg [interquartile range, IQR: 34, 43] vs. 35 mm Hg [IQR: 31, 38], p = 0.07) and percentage predicted forced vital capacity (FVC; median 57% [IQR: 51, 73] vs. 52% [IQR: 45, 66], p=0.08) though differences did not reach significance. Patients treated with PDE5i survived longer than untreated patients (median 2.18 years [95% CI: 1.43, 3.04] vs. 0.94 years [0.69, 1.51], p = 0.003) independent of all other prognostic markers by Bayesian joint-modelling (HR 0.39, 95% CI: 0.23, 0.59, p < 0.001) and propensity-matched analyses (HR 0.38, 95% CI: 0.22, 0.58, p < 0.001). Survival difference with treatment was significantly larger if right ventricular function was normal, rather than abnormal, at presentation (+2.55 years, 95% CI: -0.03, +3.97 vs. +0.98 years, 95% CI: +0.47, +2.00, p = 0.04). CONCLUSION: PDE5i treatment in ILD-PH should be investigated by a prospective randomized trial.

Percutaneous oxygenated right ventricular assist device for pulmonary embolism: A case series.

Acute right ventricular (RV) failure following massive pulmonary embolism (PE) can have significant hemodynamic consequences and is the mode of death. Temporary mechanical circulatory support can provide tissue perfusion required while thrombectomy or lysis-aimed therapies act to relieve the thrombotic obstruction. Veno-arterial extracorporeal membrane oxygenation (V-A ECMO) has conventionally been the first line MCS. A more selective approach to RV support has been advocated in the form of an extracorporeal right ventricular assist device (RVAD) as it mitigates some of the shortcomings of V-A ECMO. We present the first case series of four patients who received fully percutaneous RVAD, with an integrated oxygenator forming an Oxy-RVAD, for selective right heart support following massive PE, including the application of single-access dual-lumen right atrium to pulmonary artery cannula. All patients achieved RV recovery and were successfully weaned from oxy-RVAD support within 5-10 days demonstrating the feasibility of selective percutaneous right heart support in managing these challenging patients.

The Effect of Borderline Pulmonary Hypertension on Survival in Chronic Lung Disease.

BACKGROUND: The impact of the new "borderline" hemodynamic class for pulmonary hypertension (PH) (mean pulmonary artery pressure [mPAP], 21-24 mm Hg and pulmonary vascular resistance, [PVR], ≥3 wood units, [WU]) in chronic obstructive pulmonary disease (COPD) and interstitial lung disease (ILD) is unclear. OBJECTIVES: The aim of this study was to assess the effect of borderline PH (BLPH) on survival in COPD and ILD patients. METHOD: Survival was analyzed from retrospective data from 317 patients in 12 centers (Italy, Spain, UK) comparing four hemodynamic groups: the absence of PH (NoPH; mPAP <21 mm Hg or 21-24 mm Hg and PVR <3 WU), BLPH (mPAP 21-24 mm Hg and PVR ≥3 WU), mild-moderate PH (MPH; mPAP 25-35 mm Hg and cardiac index [CI] ≥2 L/min/m2), and severe PH (SPH; mPAP ≥35 mm Hg or mPAP ≥25 mm Hg and CI <2 L/min/m2). RESULTS: BLPH affected 14% of patients; hemodynamic severity did not predict survival when COPD and ILD patients were analyzed together. However, survival in the ILD cohort for any PH level was worse than in NoPH (3-year survival: NoPH 58%, BLPH 32%, MPH 28%, SPH 33%, p = 0.002). In the COPD cohort, only SPH had reduced survival compared to the other groups (3-year survival: NoPH 82%, BLPH 86%, MPH 87%, SPH 57%, p = 0.005). The mortality risk correlated significantly with mPAP in ILD (hazard ratio [HR]: 2.776, 95% CI: 2.057-3.748, p < 0.001) and notably less in COPD patients (HR: 1.015, 95% CI: 1.003-1.027, p = 0.0146). CONCLUSIONS: In ILD, any level of PH portends worse survival, while in COPD, only SPH presents a worse outcome.

EmPHasis-10 health-related quality of life score predicts outcomes in patients with idiopathic and connective tissue disease-associated pulmonary arterial hypertension: results from a UK multicentre study.

Health-related quality of life (HRQoL) scores assess symptom burden in pulmonary arterial hypertension (PAH) but data regarding their role in prognostication and risk stratification are limited. We assessed these relationships using the emPHasis-10 HRQoL measure.1745 patients with idiopathic PAH (IPAH), drug-induced PAH (DPAH), heritable PAH (HPAH) (collectively "(I/D/H)PAH"), or connective tissue disease-associated PAH (CTD-PAH), who had completed emPHasis-10 questionnaires at one of six UK referral centres between 2014 and 2017, were identified. Correlations with exercise capacity and World Health Organization (WHO) functional class were assessed, and exploratory risk stratification thresholds were tested.Moderate correlations were seen between emPHasis-10 scores and 6-min walk distance (r=-0.546), incremental shuttle walk distance (r=-0.504) and WHO functional class (r=0.497) (all p<0.0001). Distribution of emPHasis-10 score differed significantly between each WHO functional class (all p<0.0001). On multivariate analysis, emPHasis-10 score, but not WHO functional class, was an independent predictor of mortality. In a risk stratification approach, scores of 0-16, 17-33 and 34-50 identified incident patients with 1-year mortality of 5%, 10% and 23%, respectively. Survival of patients in WHO functional class III could be further stratified using an emPHasis-10 score ≥34 (p<0.01). At follow-up, patients with improved emPHasis-10 scores had improved exercise capacity (p<0.0001) and patients who transitioned between risk groups demonstrated similar survival to patients originally in those risk groups.The emPHasis-10 score is an independent prognostic marker in patients with (I/D/H)PAH or CTD-PAH. It has utility in risk stratification in addition to currently used parameters. Improvement in emPHasis-10 score is associated with improved exercise capacity.

Sarcoidosis associated pulmonary hypertension: an update.

PURPOSE OF REVIEW: Sarcoidosis associated pulmonary hypertension (SAPH) is a well-recognised complication, associated with a seven-fold increase in mortality. This comprehensive review will summarise these recent developments and proposes the use of a phenotype-based management approach in SAPH. RECENT FINDINGS: Recent registry-based studies have highlighted the adverse outcomes associated with SAPH and shown that reduced 6-min walk distance and diffusion capacity for carbon monoxide are predictive of poor prognosis. There is increasing interest in methods for early detection of SAPH, although whether early diagnosis impacts on survival remains uncertain. The pathophysiology underpinning SAPH is complex and often incorporates multiple mechanisms. Once the diagnosis is confirmed, understanding the underlying phenotypes of SAPH is key to providing the most effective management plan. There is some evidence that treating patients with precapillary PH with pulmonary vasodilators may improve some haemodynamic and quality life measures. However, more work is needed to determine whether mortality is affected. SUMMARY: SAPH is associated with worsened survival. A range of phenotypes are recognised in SAPH. Multimodality risk assessment in patients with SAPH is likely to be important and is an area that requires further work. Published evidence for pulmonary vasodilator therapies in SAPH with a Pulmonary arterial hypertension-like phenotype is encouraging so far, but multiple confounding factors affects the quality of the evidence. The role of immunosuppressive agents for improving pulmonary pressures is unclear. Urgent controlled trials are needed.

Perioperative management of patients with pulmonary hypertension undergoing non-cardiothoracic, non-obstetric surgery: a systematic review and expert consensus statement.

BACKGROUND: The risk of complications, including death, is substantially increased in patients with pulmonary hypertension (PH) undergoing anaesthesia for surgical procedures, especially in those with pulmonary arterial hypertension (PAH) and chronic thromboembolic PH (CTEPH). Sedation also poses a risk to patients with PH. Physiological changes including tachycardia, hypotension, fluid shifts, and an increase in pulmonary vascular resistance (PH crisis) can precipitate acute right ventricular decompensation and death. METHODS: A systematic literature review was performed of studies in patients with PH undergoing non-cardiac and non-obstetric surgery. The management of patients with PH requiring sedation for endoscopy was also reviewed. Using a framework of relevant clinical questions, we review the available evidence guiding operative risk, risk assessment, preoperative optimisation, and perioperative management, and identifying areas for future research. RESULTS: Reported 30 day mortality after non-cardiac and non-obstetric surgery ranges between 2% and 18% in patients with PH undergoing elective procedures, and increases to 15-50% for emergency surgery, with complications and death usually relating to acute right ventricular failure. Risk factors for mortality include procedure-specific and patient-related factors, especially markers of PH severity (e.g. pulmonary haemodynamics, poor exercise performance, and right ventricular dysfunction). Most studies highlight the importance of individualised preoperative risk assessment and optimisation and advanced perioperative planning. CONCLUSIONS: With an increasing number of patients requiring surgery in specialist and non-specialist PH centres, a systematic, evidence-based, multidisciplinary approach is required to minimise complications. Adequate risk stratification and a tailored-individualised perioperative plan is paramount.

Consumer Safety Considerations of Skin and Oral Microbiome Perturbation.

Microbiomes associated with human skin and the oral cavity are uniquely exposed to personal care regimes. Changes in the composition and activities of the microbial communities in these environments can be utilized to promote consumer health benefits, for example, by reducing the numbers, composition, or activities of microbes implicated in conditions such as acne, axillary odor, dandruff, and oral diseases. It is, however, important to ensure that innovative approaches for microbiome manipulation do not unsafely disrupt the microbiome or compromise health, and where major changes in the composition or activities of the microbiome may occur, these require evaluation to ensure that critical biological functions are unaffected. This article is based on a 2-day workshop held at SEAC Unilever, Sharnbrook, United Kingdom, involving 31 specialists in microbial risk assessment, skin and oral microbiome research, microbial ecology, bioinformatics, mathematical modeling, and immunology. The first day focused on understanding the potential implications of skin and oral microbiome perturbation, while approaches to characterize those perturbations were discussed during the second day. This article discusses the factors that the panel recommends be considered for personal care products that target the microbiomes of the skin and the oral cavity.

Physiological predictors of survival in patients with sarcoidosis-associated pulmonary hypertension: results from an international registry.

INTRODUCTION: Sarcoidosis-associated pulmonary hypertension (SAPH) is associated with reduced survival in single-centre studies. The international Registry for SAPH (ReSAPH) with long-term follow-up was established to enrich our knowledge of this complication of sarcoidosis. This analysis aims to elucidate factors associated with reduced transplant-free survival in SAPH patients. METHODS: ReSAPH contains prospectively collected outcomes of SAPH patients since the time of registry enrolment. Information analysed includes right heart catheterisation data, pulmonary function testing, chest radiography, Scadding stage and 6-min walk distance (6MWD), among others. Cox regression models were used to identify independent predictors of transplant-free survival. RESULTS: Data from 215 patients followed for a mean±sd 2.5±1.9 years were available for analysis. In the 159 precapillary patients, the Kaplan-Meier-adjusted 1-, 3- and 5-year transplant-free survival was 89.2%, 71.7% and 62.0%, respectively. Kaplan-Meier-adjusted 1-, 3- and 5-year transplant-free survival in the incident group was 83.5%, 70.3% and 58.3%, respectively, and in the prevalent group was 94.7%, 72.2% and 66.3%, respectively. Patients with reduced diffusing capacity of the lung for carbon monoxide (D LCO) (<35% predicted) and 6MWD <300 m in the precapillary cohort had significantly worse transplant-free survival. Reduced 6MWD and preserved forced expiratory volume (FEV1)/forced vital capacity (FVC) ratio were identified as independent risk factors for reduced transplant-free survival in the precapillary cohort. CONCLUSION: Reduced D LCO (<35% pred) and 6MWD (<300 m) at the time of registry enrolment were associated with reduced transplant-free survival in the overall precapillary cohort. Preserved FEV1/FVC ratio was identified as an independent risk factor for worsened outcomes.

Predictors of obstetric anal sphincter injury during waterbirth: a secondary analysis of a prospective observational study.

INTRODUCTION AND HYPOTHESIS: Obstetric anal sphincter injury (OASI) during childbirth is associated with urino-genital pain and dysfunction. Waterbirth is a popular birth choice for women, but controversy remains around the risk of OASI during waterbirth. This study reports on the incidence of OASI, and factors associated with OASI, for a cohort of women who gave birth in water. METHODS: This secondary analysis used prospectively collected data from 2,908 women who gave birth in water in a hospital setting. The incidence of OASI was calculated. Univariable and multivariable logistic regression analysis evaluated factors associated with OASI. RESULTS: The incidence of OASI was 1.9% (95% confidence interval (CI) 1.4, 2.4) for all women. In nulliparae it was higher (3.2%, 95% CI 2.3, 4.3) than in multiparae (0.9%, 95% CI 0.5, 1.4). In the multivariable analysis, two variables were associated with OASI; multiparity was negatively associated with OASI (adjusted odds ratio [aOR] 0.24, 95% CI 0.12, 0.50, p < 0.001), and birth weight was positively associated with OASI (aOR 1.001, 95% CI 1.000, 1.002, p = 0.02). A "hands-on" technique was used during only 13% of births. A birth position supporting a flexible sacrum did not influence OASI risk. CONCLUSIONS: A low incidence of OASI was found for this cohort of women. The low proportion of midwives using a hands-on technique suggests that it may not be required in waterbirth.

Challenging the patient and therapist during evolving phases of a veteran's treatment within a strong public-private partnership.

Veterans Health Administration (VA) Medical Centers provide excellent care for many veterans. However, there are a number of veterans who are ineligible or choose not to access mental health treatment at the VA. To meet the needs of those veterans and of military family members, private centers have emerged to fill in gaps where care is unavailable or scarce. This paper describes how one such center, the Steven A. Cohen Military Family Center at NYU Langone Health, partnered with the local VA hospital to give one veteran ineligible for free mental health services the care he desperately needed. The case demonstrates the transformative work that can take place when public-private partnerships are forged and evidence-based treatments can be provided in a flexible way. It also illustrates the complexity of many veterans' presentations, which in this case required the therapist to continually challenge her conceptualization as she and the patient navigated different phases of his treatment.

Mending broken bonds in military couples using emotionally focused therapy for couples: Tips and discoveries.

Military families face specific challenges related to military service, deployments, separations, and coming together. The process of reintegration back to civilian life can be challenged by posttraumatic stress and other readjustment difficulties that can affect not only the veteran but the family as a whole. Strengthening bonds and relationships is an important step in recovery. In this paper, the authors review the application of emotionally focused therapy to couples therapy with military couples and identify factors that can facilitate the therapeutic process with this unique population.

Traffic exposures, air pollution and outcomes in pulmonary arterial hypertension: a UK cohort study analysis.

While traffic and air pollution exposure is associated with increased mortality in numerous diseases, its association with disease severity and outcomes in pulmonary arterial hypertension (PAH) remains unknown.Exposure to particulate matter with a 50% cut-off aerodynamic diameter ≤2.5 µm (PM2.5), nitrogen dioxide (NO2) and indirect measures of traffic-related air pollution (distance to main road and length of roads within buffer zones surrounding residential addresses) were estimated for 301 patients with idiopathic/heritable PAH recruited in the UK National Cohort Study of Idiopathic and Heritable PAH. Associations with transplant-free survival and pulmonary haemodynamic severity at baseline were assessed, adjusting for confounding variables defined a prioriHigher estimated exposure to PM2.5 was associated with higher risk of death or lung transplant (unadjusted hazard ratio (HR) 2.68 (95% CI 1.11-6.47) per 3 µg·m-3; p=0.028). This association remained similar when adjusted for potential confounding variables (HR 4.38 (95% CI 1.44-13.36) per 3 µg·m-3; p=0.009). No associations were found between NO2 exposure or other traffic pollution indicators and transplant-free survival. Conversely, indirect measures of exposure to traffic-related air pollution within the 500-1000 m buffer zones correlated with the European Society of Cardiology/European Respiratory Society risk categories as well as pulmonary haemodynamics at baseline. This association was strongest for pulmonary vascular resistance.In idiopathic/heritable PAH, indirect measures of exposure to traffic-related air pollution were associated with disease severity at baseline, whereas higher PM2.5 exposure may independently predict shorter transplant-free survival.

A portal to healing: Treating military families and veterans through telehealth.

This paper explores the triumphs and challenges of providing free, integrative treatment to veterans and military families through secure video connections into their homes. Two case studies of telemental health treatment conducted through the Greater NYC Military Family Consortium in conjunction with the Steven A. Cohen Military Family Center at NYU Langone Health in New York City illustrate the complexities and opportunities that emerge in the course of treatment, most of which was conducted remotely. The access to people's lives through a portal adds new wrinkles to evidence-based practice in military settings while underscoring the overall need to broaden a network of care in partnership with Veterans Affairs hospital (VAs), Vet Centers, and community providers to reach those who might otherwise not seek help.

T-type Ca2+ channels elicit pro-proliferative and anti-apoptotic responses through impaired PP2A/Akt1 signaling in PASMCs from patients with pulmonary arterial hypertension.

Idiopathic pulmonary arterial hypertension (iPAH) is characterized by obstructive hyperproliferation and apoptosis resistance of distal pulmonary artery smooth muscle cells (PASMCs). T-type Ca2+ channel blockers have been shown to reduce experimental pulmonary hypertension, although the impact of T-type channel inhibition remains unexplored in PASMCs from iPAH patients. Here we show that T-type channels Cav3.1 and Cav3.2 are present in the lung and PASMCs from iPAH patients and control subjects. The blockade of T-type channels by the specific blocker, TTA-A2, prevents cell cycle progression and PASMCs growth. In iPAH cells, T-type channel signaling fails to activate phosphatase PP2A, leading to an increase in ERK1/2, P38 activation. Moreover, T-type channel signaling is redirected towards the activation of the kinase Akt1, leading to increased expression of the anti-apoptotic protein survivin, and a decrease in the pro-apoptotic mediator FoxO3A. Finally, in iPAH cells, Akt1 is no longer able to regulate caspase 9 activation, whereas T-type channel overexpression reverses PP2A defect in iPAH cells but reinforces the deleterious effects of Akt1 activation. Altogether, these data highlight T-type channel signaling as a strong trigger of the pathological phenotype of PASMCs from iPAH patients (hyper-proliferation/cells survival and apoptosis resistance), suggesting that both T-type channels and PP2A may be promising therapeutic targets for pulmonary hypertension.