Approach to the hospitalized patient with pulmonary arterial hypertension.

PURPOSE OF REVIEW: Hospitalization in pulmonary arterial hypertension (PAH) patients is an important clinical worsening event significantly associated with subsequent mortality. Furthermore, irrespective of the cause of hospitalization, the overall outcome is closely related to the severity of the right ventricular (RV) dysfunction. Therefore, understanding the pathophysiology of pulmonary hypertension and RV failure is paramount in successfully managing PAH patients requiring hospitalization. This review highlights diagnostic and therapeutic approaches in various clinical scenarios that might be encountered during hospitalization of the World Health Organization group I PAH patient. RECENT FINDINGS: This article covers recent literature describing risk factors, predictors of outcome and state-of the art management approach to a hospitalized PAH patients with a special focus on management of RV failure and common complications in PAH requiring hospitalization. SUMMARY: The review highlights the importance of multidisciplinary approach to a hospitalized PAH patient and highlight important implications in clinical practice and knowledge gaps for potential future research.

Undiagnosed ventricular septal defect with resultant Eisenmenger syndrome presenting with diplopia.

Ventricular septal defect (VSD) is the most common congenital heart lesion among children. In most cases, however, it is identified and corrected in childhood, before long-term sequelae such as pulmonary hypertension develop. In this case report, we present a young man with an undiagnosed VSD with consequent Eisenmenger syndrome who initially presented to medical attention with diplopia found to be caused by cerebral infarcts.

A retrospective study on the effects of pulmonary rehabilitation in patients with pulmonary hypertension.

A retrospective analysis of 23 patients was undertaken to evaluate the outcome of pulmonary rehabilitation (PR) in patients with pulmonary hypertension (PH) over a preceding 6-year time frame. Chart review and data analyses were undertaken evaluating pulmonary arterial hypertension pharmacotherapy versus the same therapy with the addition of PR. Analysis included 23 patients who had a mean pulmonary artery pressure of 36.6 while on therapy and who had initial six-minute walk tests (6MWTs) ranging between 54 and 396 meters. Outcomes included 6MWTs and Saint George's Respiratory Questionnaire. There was no improvement in 6MWT postpharmacotherapy. Patients with low 6MWT <250 meters had substantial gains in 6MWT postrehabilitation (average of 86 meters). As well, those with initial 6MWT >250 meters had a significant improvement of 52.55 meters, documenting the utility of PR in patients with PH. PH patients are increasingly seen in PR clinics as they share many characteristics present in chronic respiratory disease states. There is increasing literature supporting the utility of PR in this population. We have found that patients with 6MWTs as low as <250 meters are also candidates for PR and can demonstrate substantial benefits as measured using the 6MWTs.

Pericardiocentesis in Severe Pulmonary Arterial Hypertension Guided by a Pulmonary Artery Catheter.

Patients, often with underlying rheumatologic disease, may present with pericardial effusions in the setting of pulmonary hypertension (PHTN). Pericardial drainage in PHTN is associated with significant morbidity and mortality. We describe a patient with PHTN who developed cardiac tamponade that was managed safely and effectively with pulmonary artery catheter-guided pericardiocentesis.

Long-term impact of add-on sequential triple combination therapy in pulmonary arterial hypertension: real world experience.

BACKGROUND: Sequential triple combination therapy is recommended for pulmonary arterial hypertension (PAH) patients who are not at therapeutic goal on dual therapy, but long-term data on efficacy and safety is scarce. OBJECTIVE: To assess the long-term impact of sequential triple combination therapy in patients with PAH who are not at goal on dual combination therapy. STUDY DESIGN AND METHODS: We performed a retrospective observational study in a racially/ethnically diverse cohort of consecutive PAH patients on a stable dual therapy regimen who remained in intermediate- or high-risk category and were subsequently initiated on sequential triple combination therapy. We studied interval change in functional, echocardiographic, and hemodynamic parameters, REVEAL 2.0 risk category and ERS/ESC 2022 simplified four-strata risk category. Multivariate logistic regression analysis was performed to identify independent predictors of successful risk reduction (achievement or maintenance of REVEAL 2.0 low-risk category). Kaplan-Meier survival curves were created to assess the effect of risk reduction on survival. RESULTS: Out of 414 PAH patients seen in our program, 55 patients received add-on sequential triple combination regimen and had follow-up hemodynamic data. The mean age was 57 years, with 85% women. The most common etiology of PAH was idiopathic/heritable (41.8%). Most patients were WHO functional class III (76.4%), and 34.5% of patients were in high-risk category (REVEAL 2.0). On a median follow-up of 68 weeks, there was a significant improvement in WHO Functional Class (p < 0.001), six-minute walk distance (35 m) with 61.8% of patients achieving low-risk status by REVEAL 2.0, and a 28% of patients' improvement in pulmonary vascular resistance. Female gender was identified as a strong predictor of successful risk reduction, whereas Hispanic ethnicity estimated right atrial pressure on echocardiogram and pericardial effusion predicted lower probability of risk reduction. Patients who achieved or maintained low-risk status had significantly improved survival. CONCLUSION: Add-on sequential triple combination therapy significantly increased functional, echocardiographic, and hemodynamic parameters with improvement in risk category and survival.

Pulmonary Vasodilator Therapy in Severe Pulmonary Hypertension Due to Chronic Obstructive Pulmonary Disease (Severe PH-COPD): A Systematic Review and Meta-Analysis.

Background: Chronic obstructive pulmonary disease-associated pulmonary hypertension (PH-COPD) results in a significant impact on symptoms, quality of life, and survival. There is scant and conflicting evidence about the use of pulmonary hypertension (PH) specific therapy in patients with PH-COPD. Study Design and Methods: PubMed, OVID, CINAHL, Cochrane, Embase, and Web of Science were searched using various MESH terms to identify randomized controlled trials (RCTs) or observational studies investigating PH-specific therapies in patients with severe PH-COPD, defined by mean pulmonary artery pressure (mPAP) of more than 35 mm Hg or pulmonary vascular resistance (PVR) of more than 5 woods units on right heart catheterization. The primary outcome was a change in mPAP and PVR. Secondary outcomes were changes in six-minute walk distance (6MWD), changes in the brain-natriuretic peptide (BNP), New York Heart Association (NYHA) functional class, oxygenation, and survival. Results: Thirteen studies satisfied the inclusion criteria, including a total of 328 patients with severe PH-COPD. Out of these, 308 patients received some type of specific therapy for PH. There was a significant reduction in mPAP (mean difference (MD) -3.68, 95% CI [-2.03, -5.32], p < 0.0001) and PVR (MD -1.40 Wood units, 95% CI [-1.97, -0.82], p < 0.00001). There was a significant increase in the cardiac index as well (MD 0.26 L/min/m2, 95% CI [0.14, 0.39], p < 0.0001). There were fewer patients who had NYHA class III/lV symptoms, with an odds ratio of 0.55 (95% CI [0.30, 1.01], p = 0.05). There was no significant difference in the 6MWD (12.62 m, 95% CI [-8.55, 33.79], p = 0.24), PaO2 (MD -2.20 mm Hg, 95% CI [-4.62, 0.22], p = 0.08), or BNP or NT-proBNP therapy (MD -0.15, 95% CI [-0.46, 0.17], p = 0.36). Conclusion: The use of PH-specific therapies in severe PH-COPD resulted in a significant reduction in mPAP and PVR and increased CI, with fewer patients remaining in NYHA functional class III/IV. However, no significant difference in the 6MWD, biomarkers of right ventricular dysfunction, or oxygenation was identified, demonstrating a lack of hypoxemia worsening with treatment. Further studies are needed to investigate the use of PH medications in patients with severe PH-COPD.

Delphi consensus recommendation for optimization of pulmonary hypertension therapy focusing on switching from a phosphodiesterase 5 inhibitor to riociguat.

Dual combination therapy with a phosphodiesterase-5 inhibitor (PDE5i) and endothelin receptor antagonist is recommended for most patients with intermediate-risk pulmonary arterial hypertension (PAH). The RESPITE and REPLACE studies suggest that switching from a PDE5i to a soluble guanylate cyclase (sGC) activator may provide clinical improvement in this situation. The optimal approach to escalation or transition of therapy in this or other scenarios is not well defined. We developed an expert consensus statement on the transition to sGC and other treatment escalations and transitions in PAH using a modified Delphi process. The Delphi process used a panel of 20 physicians with expertise in PAH. Panelists answered three questionnaires on the management of treatment escalations and transitions in PAH. The initial questionnaire included open-ended questions. Later questionnaires consolidated the responses into statements that panelists rated on a Likert scale from -5 (strongly disagree) to +5 (strongly agree) to determine consensus. The Delphi process produced several consensus recommendations. Escalation should be considered for patients who are at high risk or not achieving treatment goals, by adding an agent from a new class, switching from oral to parenteral prostacyclins, or increasing the dose. Switching to a new class or within a class should be considered if tolerability or other considerations unrelated to efficacy are affecting adherence. Switching from a PDE5i to an SGC activator may benefit patients with intermediate risk who are not improving on their present therapy. These consensus-based recommendations may be helpful to clinicians and beneficial for patients when evidence-based guidance is unavailable.

Advances in the management of pulmonary arterial hypertension.

The management of pulmonary arterial hypertension (PAH) has significantly evolved over the last decades in the wake of more sensitive diagnostics and specialized clinical programs that can provide focused medical care. In the current era of PAH care, 1-year survival rates have increased to 86%-90% from 65% in the 1980s, and average long-term survival has increased to 6 years from 2.8 years. The heterogeneity in the etiology and disease course has opened doors to focusing research in phenotyping the disease and understanding the pathophysiology at a cellular and genetic level. This may eventually lead to precision medicine and the development of medications that may prevent or reverse pulmonary vascular remodeling. With more insight, clinical trial designs and primary end-points may change to identify the true survival benefit of pharmacotherapy. Identifying responders from non-responders to therapy may help provide individualized patient-centered care rather than an algorithm-based approach. The purpose of this review is to highlight the latest advances in screening, diagnosis, and management of PAH.

COVID-19 in Pulmonary Artery Hypertension (PAH) Patients: Observations from a Large PAH Center in New York City.

Information on outcomes of COVID-19 in pulmonary arterial hypertension (PAH) patients is limited to a few case series and surveys. Here, we describe our experience at a large Pulmonary Hypertension Center in New York City at the height of the pandemic. We performed a retrospective chart review of eleven consecutive PAH patients who were diagnosed with SARS-CoV-2 infection. We analyzed demographics, PAH severity, risk factors for COVID-19, and COVID-19 severity and outcomes. We found in our sample that 63.6% of patients required intensive care, and there was a 45.45% overall mortality. Most patients had a known COVID-19 contact and mean duration of symptoms prior to presentation was 12 days. Only 4/11 (36%) patients presented to a center with pulmonary hypertension expertise, all of whom survived. Most patients had at least moderate pulmonary hypertension with an average REVEAL score of 7.81 despite double or triple PAH therapy. Our cases series underscores the gravity of SARS-CoV-2 infection in patients with PAH. It also suggests possible interventions to prevent unfavorable outcomes such as preserving social distancing, PAH management optimization, and early and preferential presentation to a center with specialized expertise in PAH.

Sarcoidosis-associated pulmonary hypertension: assessment and management.

Pulmonary hypertension (PH) is a recognized complication of sarcoidosis, with increased morbidity and poor prognosis. Sarcoidosis-associated pulmonary hypertension (SAPH) is typically seen in advanced cases, with pulmonary fibrosis, destruction and obliteration of the pulmonary vasculature, and chronic hypoxemia. PH can, however, occur in the absence of pulmonary fibrosis, suggesting alternative pathophysiological mechanisms. Diverse processes may coexist in the pathogenesis of SAPH, and there is an overlap with mechanisms of pulmonary arterial hypertension (PAH). This has encouraged the study of PAH-specific therapeutic agents in the treatment of SAPH. In small series, prostacyclin analogues, endothelin receptor antagonists, and phosphodiesterase-5 inhibitors have been shown to improve hemodynamics, functional status, and outcomes. This article reviews the most recent data available in the epidemiology, pathophysiology, diagnosis, and treatment of SAPH.

Clinical and hemodynamic benefit of macitentan and riociguat upfront combination in patients with pulmonary arterial hypertension.

In this open-label study, we evaluated the effect of upfront macitentan and riociguat combination in newly diagnosed pulmonary arterial hypertension (PAH) patients. In 15 consecutive PAH patients, we collected clinical and hemodynamic data at baseline, visit 1 (median 4 months) and visit 2 (median 12 months). Survival and transplantation status were analyzed over 36 months. Statistical analysis included student t-test and 95% confidence interval (CI) ( t-statistic or Clopper-Pearson). Kaplan-Meier was used to estimate survival rate. There were 11/15 women (mean age 56 years), in World Health Organization (WHO) functional class (FC) III ( n = 14) or IV ( n = 1). The 6 min walk distance increased from 281.6 m (baseline) to 315.7 m (visit 1) and visit 2 (313.9 m), representing a 34- and 32-m change ( P < 0.05), respectively, associated with Borg score improvements. Brain natriuretic peptide decreased: 318.2 pg/mL (baseline) to 122.0 pg/mL (visit 1) and 98.6 pg/mL (visit 2) ( P < 0.05). WHO FC improved in eight patients (53%, 95% CI 27%-79%). Pulmonary vascular resistance (9.2 to 5.7 Wood Units) and mean pulmonary artery pressure (47.3 to 38.9 mmHg) decreased; cardiac index increased (2.3 to 3.0 L/min/m2) (baseline to visit 2, all P < 0.05). All patients had intermediate and high risk score (baseline); at 1-year follow-up, dual therapy led to reduction to low risk score in 7/15 (47%) patients. There were no unexpected or serious side effects. Three patients died due to unrelated causes; one patient received a lung transplant. Transplant-free survival rate (36 months) was 85%. Preliminary evidence is provided for effectiveness of initial macitentan and riociguat combination therapy in PAH.

Imaging of Pulmonary Hypertension: Pictorial Essay.

Pulmonary hypertension (PH) is an end result of a diverse array of complex clinical conditions that invoke hemodynamic and pathophysiological changes in the pulmonary vasculature. Many patients' symptoms begin with dyspnea on exertion for which screening tests such as chest roentgenograms and more definitive noninvasive tests such as CT scans are ordered initially. It is imperative that clinicians are cognizant of subtle clues on these imaging modalities that alert them to the possibility of PH. These clues may serve as a stepping stone towards more advanced noninvasive (echocardiogram) and invasive (right heart catheterization) testing. On the CT scan, the signs are classified into mediastinal and lung parenchymal abnormalities. In addition to suspecting the diagnosis of PH, this paper provides a pictorial essay to guide health care professionals in identifying the etiology of PH. This paper also provides concrete definitions, wherever possible, of what constitutes abnormalities in PH, such as dilated pulmonary arteries, pruning of vessels, and increased thickness of free wall of the right ventricle. The sensitivities and specificities of each sign are enumerated. The common radiographic and clinical features of many different etiologies of PH are tabulated for the convenience of the readers. Some newer imaging modalities such as dual-energy CT of the chest that hold promise for the future are also described.

Prevalence and correlates of septal delayed contrast enhancement in patients with pulmonary hypertension.

Using cardiac magnetic resonance, the presence of myocardial delayed contrast enhancement (DCE) has been described in the ventricular septum at the level of the right ventricular insertion points in patients with pulmonary hypertension (PH). The aim of this study was to investigate the prevalence, extent, and correlates of this finding. Septal DCE was evaluated in 55 patients with known or suspected PH of various causes. The extent of DCE was estimated visually with an insertion enhancement score (range 0 to 4) and quantified as DCE mass. The results were correlated with cine magnetic resonance and right-sided cardiac catheterization. Predictors of DCE were investigated using multivariate analysis. PH at rest was present in 42 patients (group 1) and absent in 13 (group 2). DCE was noted in 41 patients (97%) in group 1 and 3 (23%) in group 2 (p <0.0001). The extent of DCE was higher in group 1 than group 2 (median insertion enhancement score 3 vs 0, median DCE mass 8.7 vs 0 g, respectively; p <0.0001 for both). The extent of DCE showed moderate to good univariate correlations (r = 0.5 to 0.73) with pulmonary pressures and with right ventricular volumes, mass, and ejection fractions. In multivariate analysis, systolic pulmonary pressure was the only predictor of DCE. In conclusion, the presence of septal DCE at the right ventricular insertion points is common in PH of different causes, and the level of systolic pulmonary pressure elevation appears to be the main determinant of this finding.

Exercise-induced pulmonary hypertension by stress echocardiography: Prevalence and correlation with right heart hemodynamics.

OBJECTIVES: The aim of this study was to determine the prevalence of exercise-induced pulmonary hypertension (EIPH) in consecutive subjects referred for stress echocardiography for chest pain or shortness of breath and correlate echocardiographic diagnosis of EIPH with hemodynamics at right heart catheterization (RHC). BACKGROUND: Elevated pulmonary pressure can lead to significant morbidity and mortality. EIPH by ehocardiography has been described in patients with connective tissue disease. It's prevalence in the setting of routine clinically indicated stress echocardiography unknown. METHODS: In a retrospective analysis of 4068 consecutive stress subjects undergoing stress echocardiography, 479 subjects with EIPH were identified. All 479 subjects with EIPH were compared to 479 age and sex matched subjects with normal pulmonary artery pressures post exercise. EIPH was defined as PASP>50mmHg or peak tricuspid regurgitation velocity>3.2m/s. Of 100 patients with EIPH who underwent RHC we identified variables which predicted abnormal hemodynamic findings on RHC. RESULTS: The prevalence of EIPH in subjects referred for stress echocardiography was 11.7%. A greater proportion of subjects with EIPH were obese or had lung disease or connective tissue disease. Of 100 subjects who underwent RHC, 65 had abnormal results. Age>55years (OR 5.1, p<0.01]) or dilated left atrium (OR 4.4, p=0.02]) were independently associated with abnormal right heart hemodynamics. CONCLUSIONS: The results demonstrate that 11.7% of patients undergoing clinically indicated stress echocardiography have EIPH. Of those who underwent RHC abnormal hemodynamics were significantly associated with a dilated left atrium or age older than 55years.

Pulmonary Hypertension Due to Common Respiratory Conditions: Classification, Evaluation and Management Strategies.

Pulmonary hypertension (PH) due to chronic respiratory disease and/or hypoxia is classified as World Health Organization (WHO) Group III pulmonary hypertension. The patients most commonly encountered in clinical practice with group III PH include those with chronic obstructive lung disease (COPD), diffuse parenchymal lung disease, and sleep-disordered breathing. The purpose of this review is to outline the variable clinical significance of pulmonary hypertension in the most common pulmonary disease states and how a clinician may approach the management of these patients.

Distinctive clinical, radiographic, and functional characteristics of patients with sarcoidosis-related pulmonary hypertension.

STUDY OBJECTIVE: To differentiate the clinical, radiographic, and physiologic profile in patients with sarcoidosis with and without pulmonary hypertension. DESIGN: Retrospective survey. SETTING: Tertiary care center. PATIENTS: One hundred six patients with sarcoidosis were classified by two-dimensional echocardiography into two groups: group 1, 54 patients with pulmonary hypertension; group 2, 52 patients without pulmonary hypertension. INTERVENTIONS: Patients underwent two-dimensional and Doppler echocardiography, chest radiography (CXR), pulmonary function testing, and arterial oxygen saturation determination, and the test results were compared between the two groups. Statistical analysis was performed using independent-sample t test and chi2 test, as appropriate; p < 0.05 was considered to be significant. RESULTS: Predicted spirometric values and lung diffusing capacity were significantly lower in patients in group 1 compared to patients in group 2: FVC, 54% vs 64% (p = 0.0065), FEV(1), 47% vs 61% (p = 0.0005), forced expiratory flow, midexpiratory phase, 35% vs 52% (p = 0.0363), and single-breath diffusing capacity of the lung for carbon monoxide (D(LCO)sb), 39% vs 54% (p = 0.0001). Sixty percent of patients in group 1 had radiographic Scadding stage 4 sarcoidosis, while no radiographic stage predominated in group 2. Arterial oxygen saturation, need for oxygen supplementation, and degree of desaturation after exercise did not differ between groups. CONCLUSIONS: The presence of pulmonary hypertension in patients with sarcoidosis is associated with higher prevalence of stage 4 sarcoidosis by CXR and lower predicted spirometric and D(LCO)sb measurements.

The acute hemodynamic effect of IV nitroglycerin and dipyridamole in patients with pulmonary arterial hypertension: comparison with IV epoprostenol.

Nitroglycerin and dipyridamole are two commonly available and well tolerated vasoactive medications. Their acute hemodynamic effects in patients with pulmonary arterial hypertension are not well defined in the current literature. The authors retrospectively analyzed the acute hemodynamic effects of IV nitroglycerin, dipyridamole, and epoprostenol in 59 patients with pulmonary arterial hypertension as determined by changes from baseline in systemic and pulmonary hemodynamic parameters. Statistical analysis was performed using the independent sample t test. A p value <0.05 was considered significant. Nitroglycerin is predominantly a vasodilator of the pulmonary vasculature with moderate systemic vasodilator effect, while dipyridamole is primarily a positive inotropic agent. Epoprostenol is a potent vasodilator of both pulmonary and systemic vessels and a strong positive inotropic agent. Nitroglycerin and dipyridamole may be useful in the acute management of pulmonary arterial hypertension.

Pulmonary artery sarcoma misdiagnosed as chronic thromboembolic pulmonary hypertension.

Pulmonary artery sarcomas are rare neoplasms of the pulmonary artery that are often confused with chronic thromboembolic disease, as both diseases have similar presentations. In patients with presumed chronic thromboembolic pulmonary hypertension, certain clinical and imaging characteristics may suggest the alternative diagnosis of pulmonary artery sarcoma. In this article we present a case of a man initially diagnosed with chronic thromboembolic pulmonary hypertension, but who was later found to have pulmonary artery sarcoma. We review the distinguishing characteristics of the two diseases and discuss possible treatment strategies.

Early Observations on the Use of Riociguat in a Large, Metropolitan Pulmonary Arterial Hypertension/Chronic Thromboembolic Pulmonary Hypertension Treatment Center.

INTRODUCTION: Pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) are rare, life-threatening diseases in which chronically elevated pressure in the pulmonary arteries results in vascular remodeling and right heart failure. Treatment goals are to improve patient functioning, exercise capacity, and symptoms; delay disease progression; normalize the right ventricular function; and, ultimately, improve survival. Therapeutic management centers on the affected physiologic pathways and includes endothelin receptor antagonists, phosphodiesterase-5 inhibitors, and prostacyclins. Recently, riociguat, a novel therapeutic agent that stimulates soluble guanylate cyclase via the nitric oxide pathway, was approved for the treatment of both PAH and CTEPH. Clinical trial data show that riociguat significantly improves exercise capacity as well as hemodynamic parameters in PAH/CTEPH. METHODS: We report on the early use of riociguat at our center-a large, metropolitan pulmonary hypertension treatment facility that cares for >250 patients with PAH/CTEPH. Through our initial clinical experience, we offer evidence on the benefits of riociguat in three patients with PAH associated with different etiologies, symptoms, and treatment goals. RESULTS: Overall, patients at our center who have received riociguat have experienced clinical benefits, including improvement in symptomatic and hemodynamic parameters, increase in 6-min walk distance, and improvement or stabilization of World Health Organization functional class. In several cases, initial response to riociguat has been encouraging and has helped patients reach their treatment goals. Riociguat appears to be well tolerated, with only one patient experiencing mild, self-limiting side effects. CONCLUSION: Novel agents are continuously being introduced into the PAH/CTEPH armamentarium, and clinicians must decide how best to integrate them into their existing treatment algorithms. This case series offers initial evidence from our practice on the benefits of riociguat in optimizing hemodynamic and functional parameters. These benefits have been observed in PAH associated with different etiologies and functional status, and in both first-line and combination use. FUNDING: Bayer HealthCare Pharmaceuticals.