Therapeutic Potential of Treprostinil Inhalation Powder for Patients with Pulmonary Arterial Hypertension: Evidence to Date.

Pulmonary arterial hypertension (PAH) is a complex and incurable disease for which pulmonary vasodilators remain the core therapy. Of the three primary pathways that vasodilators target, the prostacyclin pathway was the earliest to be used and currently has the largest number of modalities for drug delivery. Inhaled treprostinil has been introduced as a treatment option in PAH and, more recently, pulmonary hypertension (PH) due to interstitial lung disease (PH-ILD), and the earlier nebulized form has been joined by a dry powder form allowing for more convenient use. In this review, we discuss inhaled treprostinil, focusing on the dry powder inhalation (DPI) formulation, and explore its dosing, applications, and evidence to support patient tolerance and acceptance. Recent trials underpinning the evidence for use of inhaled treprostinil and the most recent developments concerning the drug are discussed. Finally, the review looks briefly into premarket formulations of inhaled treprostinil and relevant early studies suggesting efficacy in PAH treatment.

Diagnosis and management of chronic thromboembolic pulmonary hypertension (CTEPH) in sickle cell disease: A review.

Pulmonary hypertension in sickle cell disease (SCD) is a complex phenomenon resulting from multiple overlapping etiologies, including pulmonary vasoconstriction in the setting of chronic hemolytic anemia, diastolic dysfunction, and chronic thromboembolic disease. The presence of pulmonary hypertension of any cause in SCD confers a significant increase in mortality risk. Evidence to guide the management of patients with sickle cell disease and chronic thromboembolic pulmonary hypertension (CTEPH) is scant and largely the realm of case reports and small case series. Centered on a discussion of a complex young patient with hemoglobin hemoglobin SC who ultimately underwent treatment with pulmonary thromboendarterectomy, we review the available literature to guide management and discuss and overview of treatment of CTEPH in SCD, considering the unique considerations and challenges facing patients suffering from this multisystem disease.

BREEZE: Open-label clinical study to evaluate the safety and tolerability of treprostinil inhalation powder as Tyvaso DPI™ in patients with pulmonary arterial hypertension.

Inhaled treprostinil is an approved therapy for pulmonary arterial hypertension (PAH) and pulmonary hypertension associated with interstitial lung disease in the United States. Studies have confirmed the robust benefits and safety of nebulized inhaled treprostinil, but it requires a time investment for nebulizer preparation, maintenance, and treatment. A small, portable treprostinil dry powder inhaler has been developed for the treatment of PAH. The primary objective of this study was to evaluate the safety and tolerability of treprostinil inhalation powder (TreT) in patients currently treated with treprostinil inhalation solution. Fifty-one patients on a stable dose of treprostinil inhalation solution enrolled and transitioned to TreT at a corresponding dose. Six-minute walk distance (6MWD), device preference and satisfaction (Preference Questionnaire for Inhaled Treprostinil Devices [PQ-ITD]), PAH Symptoms and Impact (PAH-SYMPACT®) questionnaire, and systemic exposure and pharmacokinetics for up to 5 h were assessed at baseline for treprostinil inhalation solution and at Week 3 for TreT. Adverse events (AEs) were consistent with studies of inhaled treprostinil in patients with PAH, and there were no study drug-related serious AEs. Statistically significant improvements occurred in 6MWD, PQ-ITD, and PAH-SYMPACT. Forty-nine patients completed the 3-week treatment phase and all elected to participate in an optional extension phase. These results demonstrate that, in patients with PAH, transition from treprostinil inhalation solution to TreT is safe, well-tolerated, and accompanied by statistically significant improvements in key clinical assessments and patient-reported outcomes with comparable systemic exposure between the two formulations at evaluated doses (trial registration: clinicaltrials.gov identifier: NCT03950739).

Case Report: An Atypical Case of Carney Complex.

BACKGROUND Intracardiac tumors are a rare entity, with myxomas being the most common among them (approximately 50% of intracardiac tumors). Up to 80% of myxomas originate within the left atrium and while most are incidental or isolated findings in asymptomatic patients, others may result in clinical manifestations of heart failure or emboli. Moreover, in some cases, myxomas can be part of a genetically inherited syndrome known as Carney complex (CNC), and present with varied phenotypes, including skin, endocrine, and neuroendocrine tumors. CASE REPORT We present a case of a 54-year-old male patient who presented with a several-month history of non-specific cough, dyspnea on exertion, and palpitations along with several skin tags, nevi, and nodules. He was found to have a retrocardiac density on chest X-ray, which was revealed to be a large left atrial myxoma on echocardiography. The myxoma was surgically excised and genetic testing for a mutation of the PRKAR1A gene (the most common mutation underlying CNC) was negative. However, 2 major clinical criteria for diagnosis of CNC were fulfilled based on cardiac myxoma and spotty skin pigmentation. In this report, we focus on the clinical manifestations of CNC, including guidance on tumor surveillance and genetic variants of CNC. CONCLUSIONS While CNC is most commonly associated with an inactivating mutation of the PRKAR1A gene, it can be diagnosed clinically in the absence of an identifiable genetic mutation. In patients presenting with atypical cardiac tumors, the early recognition of cutaneous manifestations can raise the index of suspicion for CNC, which can facilitate early diagnosis, treatment, and initiation of surveillance for neoplasia development.

Comparing Diuresis Patterns in Hospitalized Patients With Heart Failure With Reduced Versus Preserved Ejection Fraction: A Retrospective Analysis.

BACKGROUND: Congestion predominates in exacerbations of heart failure with reduced ejection fraction (HFrEF) or preserved ejection fraction (HFpEF), but evidence suggests that excess volume may be distributed differently in these 2 subgroups. METHODS AND RESULTS: In this retrospective study, diuretic efficiency (DE, or net urine output per 40-mg of intravenous furosemide equivalent) during the first 72 hours was compared between patients hospitalized with HFrEF (n = 121) versus HFpEF (n = 120). Multivariate analysis was used to compare the 2 groups based on expected baseline differences (e.g., demographics, heart failure etiology, concomitant therapy). During the first 72 hours, mean daily diuretic doses were higher in patients with HFpEF versus HFrEF (172.0 vs. 159.9 mg, respectively, P = 0.026) but urine output was not significantly different (2603.3 mL vs. 2667.5 mL, respectively, adjusted P = 0.100). Similarly, mean cumulative DE did not differ (-673.5 vs. -637.8 mL/40-mg in the HFrEF and HFpEF groups, respectively, adjusted P = 0.884). An exploratory analysis of propensity-matched cohorts yielded similar findings. Correlations between the components of DE varied considerably and only became weak to moderately correlated toward the end of the observation period. CONCLUSIONS: Although cumulative DE did not differ between patients with HFrEF and HFpEF, variable correlations in the components of DE suggest there may be differences in diuretic response that warrant future analysis.

Right Heart Failure in Pulmonary Hypertension.

Right heart failure is a major cause of morbidity and mortality in pulmonary hypertension. Its pathophysiology is complex and involves both adaptive and maladaptive patterns of right ventricular change. In addition to the gold standard of right heart catheterization, noninvasive imaging such as echocardiography is useful in diagnosis and risk assessment. Management focuses on optimizing preload, reducing afterload, and supporting the function of the right ventricle with vasopressors and inotropes, if necessary. If required, mechanical support is increasingly used to facilitate recovery or as a bridge to transplant.

Management of Pulmonary Artery Aneurysms in Pulmonary Hypertension: A Single-Center Review of 3 Cases.

Pulmonary artery aneurysms (PAAs) are defined as having pulmonary artery diameter of greater than 40 mm. PAAs are rare and can occur in various pulmonary diseases. There are no clear-cut guidelines regarding the management of PAAs, and recommendations for management are made based on expert consensus opinion, case reports, and institutional experience. This series highlights three patients with pulmonary hypertension (PH) and PAA. The clinical course and diagnostic findings and the decision-making involved in the treatment are reviewed. An overview of three distinct management strategies including medical management, heart/lung transplant, and surgical aneurysm repair is presented.

Sarcoidosis-associated hypercalcemia potentiating calcific uremic arteriolopathy in a patient with a left ventricular assist device.

Calcific uremic arteriolopathy is a rare, life-threatening syndrome of vascular calcification characterized by occlusion of microvessels that results in extremely painful skin necrosis. We present a case of sarcoidosis-associated hypercalcemia potentiating calcific uremic arteriolopathy in a patient with a left ventricular assist device. The patient's calcific uremic arteriolopathy was successfully treated with sodium thiosulfate. Clinicians should be vigilant in diagnosing calcific uremic arteriolopathy early since it is especially life-threatening in patients with multiple risk factors.

Aortic Root Abscess with Aorta to Right Atrium Fistula due to Vancomycin-Intermediate Staphylococcus aureus (VISA).

We present a case of root abscess with aorta to right atrium fistula due to vancomycin-intermediate Staphylococcus aureus (VISA) after limb amputation and cardiac surgery. Patient underwent redo aortic valve replacement, patch repair of aorta to right atrial fistula, and tricuspid valve repair with a ring. Fistula formation is a rare complication of prosthetic valve endocarditis (PVE). This is the first case to discuss aortocavitary fistula (ACF) formation due to VISA. Transesophageal echocardiogram (TEE) is the preferred imaging modality to diagnose ACF.

Echo is a good, not perfect, measure of cardiac output in critically ill surgical patients.

BACKGROUND: Compared with a pulmonary artery catheter (PAC), transthoracic echocardiography (TTE) has been shown to have good agreement in cardiac output (CO) measurement in nonsurgical populations. Our hypothesis is that the feasibility and accuracy of CO measured by TTE (CO-TTE), relative to CO measured by PAC thermodilution (CO-PAC), is different in surgical intensive care unit patients (SP) and nonsurgical patients (NSP). METHODS: Surgical patients with PAC for hemodynamic monitoring and NSP undergoing right heart catheterization were prospectively enrolled. Cardiac output was measured by CO-PAC and CO-TTE. Pearson coefficients were used to assess correlation. Bland-Altman analysis was used to determine agreement. RESULTS: Over 18 months, 84 patients were enrolled (51 SP, 33 NSP). Cardiac output TTE could be measured in 65% (33/51) of SP versus 79% (26/33) of NSP; p = 0.17. Inability to measure the left ventricular outflow tract diameter was the primary reason for failure in both groups; 94% (17/18) in SP versus 86% (6/7) NSP; p = 0.47. Velocity time integral could be measured in all patients. In both groups, correlation between PAC and TTE measurement was strong; SP (r = 0.76; p < 0.0001), NSP (r = 0.86; p < 0.0001). Bland-Altman analysis demonstrated bias of -0.1 L/min, limits of agreement of -2.5 and +2.3 L/min, percentage error (PE) of 40% for SP, and bias of +0.4 L/min, limits of agreement of -1.8 and +2.5 L/min, and PE of 40% for NSP. CONCLUSION: There was strong correlation and moderate agreement between TTE and PAC in both SP and NSP. In both patient populations, inability to measure the left ventricular outflow tract diameter was a limiting factor. LEVEL OF EVIDENCE: Diagnostic tests or criteria, level III.

Cardiologist perceptions of family-centred rounds in cardiovascular clinical care.

Objective: Few data exist regarding physician attitudes and implementation of family-centred rounds (FCR) in cardiovascular care. This study aimed to assess knowledge and attitudes among cardiologists and cardiology fellows regarding barriers and benefits of FCRs. Methods: An electronic, web-based questionnaire was nationally distributed to cardiology fellows and attending cardiologists. Results: In total, 118 subjects were surveyed, comprising cardiologists (n=64, 54%) and cardiology fellows (n=54, 46%). Overall, 61% of providers reported participating in FCRs and 64% felt family participation on rounds benefits the patient. Both fellows and cardiologists agreed that family rounds eased family anxiety (fellows, 63%; cardiologists, 56%; p=0.53), improved communication between the medical team and the patient and family (fellows, 78%; cardiologists, 61%; p=0.18) and improved patient safety (fellows, 59%; cardiologists, 47%; p=0.43). Attitudes regarding enhancement of trainee education were similar (fellows, 69%; cardiologists, 55%; p=0.19). Fellows and cardiologists felt that family increased the duration of rounds (fellows, 78%; cardiologists, 80%; p=0.18) and led to less efficient rounds (fellows, 54%; cardiologists, 58%; p=0.27). Conclusion: The majority of cardiologists and fellows believed that FCRs benefited families, communication and patient safety, but led to reduced efficiency and longer duration of rounds.

Anomalous Left-sided Superior Vena Cava with Cephalad Flow.

The case of a 24-year-old male with complaints of migraine headaches was referred for echocardiography. The rest of medical history was unremarkable. Agitated saline contrast bubble study showed evidence of a right to left intracardiac shunt, probably secondary to a patent foramen ovale. Results of a transesophageal echocardiogram suggested the possibility of an anomalous venous circulation and eventually identified as anomalous left-sided superior vena cava with cardiac magnetic resonance imaging.

Clinical Outcomes for Peripartum Cardiomyopathy in North America: Results of the IPAC Study (Investigations of Pregnancy-Associated Cardiomyopathy).

BACKGROUND: Peripartum cardiomyopathy (PPCM) remains a major cause of maternal morbidity and mortality. OBJECTIVES: This study sought to prospectively evaluate recovery of the left ventricular ejection fraction (LVEF) and clinical outcomes in the multicenter IPAC (Investigations of Pregnancy Associated Cardiomyopathy) study. METHODS: We enrolled and followed 100 women with PPCM through 1 year post-partum. The LVEF was assessed by echocardiography at baseline and at 2, 6, and 12 months post-partum. Survival free from major cardiovascular events (death, transplantation, or left ventricular [LV] assist device) was determined. Predictors of outcome, particularly race, parameters of LV dysfunction (LVEF), and remodeling (left ventricular end-diastolic diameter [LVEDD]) at presentation, were assessed by univariate and multivariate analyses. RESULTS: The cohort was 30% black, 65% white, 5% other; the mean patient age was 30 ± 6 years; and 88% were receiving beta-blockers and 81% angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. The LVEF at study entry was 0.35 ± 0.10, 0.51 ± 0.11 at 6 months, and 0.53 ± 0.10 at 12 months. By 1 year, 13% had experienced major events or had persistent severe cardiomyopathy with an LVEF <0.35, and 72% achieved an LVEF ≥0.50. An initial LVEF <0.30 (p = 0.001), an LVEDD ≥6.0 cm (p < 0.001), black race (p = 0.001), and presentation after 6 weeks post-partum (p = 0.02) were associated with a lower LVEF at 12 months. No subjects with both a baseline LVEF <0.30 and an LVEDD ≥6.0 cm recovered by 1 year post-partum, whereas 91% with both a baseline LVEF ≥0.30 and an LVEDD <6.0 cm recovered (p < 0.00001). CONCLUSIONS: In a prospective cohort with PPCM, most women recovered; however, 13% had major events or persistent severe cardiomyopathy. Black women had more LV dysfunction at presentation and at 6 and 12 months post-partum. Severe LV dysfunction and greater remodeling at study entry were associated with less recovery. (Investigations of Pregnancy Associated Cardiomyopathy [IPAC]; NCT01085955).

Pharmacologic treatment of pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a rare, incurable disease characterized by adverse remodeling of the pulmonary vasculature, leading to increased pulmonary arterial pressures and right ventricular failure. Contemporary pharmacotherapy targets 3 distinct molecular pathways that are abnormal in PAH: deficient production of nitric oxide and prostacyclin, and over production of endothelin. Risk assessment is critical in guiding therapeutic decision making and in disease surveillance following treatment initiation. Patients with more advanced disease are best treated with continuous infusion therapy, while those less symptomatic patients may respond to oral or inhaled therapies. Combination therapy is being increasingly utilized in patients who fail to achieve treatment goals.

Assessment and management of cardiogenic shock in the emergency department.

Cardiogenic shock remains a major cause of morbidity and mortality in patients hospitalized with myocardial infarction, severe valvular disease, and other causes of cardiomyopathy. Emergency physicians play a pivotal role in the initial management of these patients, as they are most often the point of first contact with the medical system. This review discusses the initial assessment and management of cardiogenic shock, emphasizing the importance and role of the emergency physician.

Pharmacotherapy for pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a disabling, progressive disease. The past decade has seen an explosion in the available therapies for the management of PAH. Choosing appropriate pharmacotherapy can be a daunting task for the practitioner, as no head-to-head comparisons between drugs have been published. This article aims to assist the practitioner in developing an evidence-based, rational pharmacologic treatment algorithm for the management of patients with PAH. Currently approved pharmacotherapy and the pivotal trials that led to approval for the respective agents are reviewed. Common dilemmas in the treatment of PAH for which strong evidence is lacking are discussed.