Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by formation of chronic, organized thrombus in pulmonary arteries resulting in development of pulmonary hypertension. We describe the favorable recovery of a patient with inoperable CTEPH treated with combination riociguat and inhaled treprostinil.The patient is a 77 year old female who presented with bilateral pulmonary emboli and was anticoagulated with warfarin for six months. One year later the patient developed recurrent dyspnea and multiple bilateral pulmonary emboli were again noted. Pulmonary arterial pressure (PAP) was estimated at 91 mmHg by echocardiography. The patient was treated with warfarin and sildenafil. Eighteen months later the PAP was estimated at 106 mmHg with significant right ventricular enlargement. The patient was referred to our center for pulmonary hypertension consultation. Right heart catheterization confirmed severe pulmonary hypertension with preserved cardiac output. The patient was not a candidate for thromboendarterectomy due to the peripheral location of chronic obstructing thrombi. Systemic prostacyclin therapy was declined by the patient. Inhaled treprostinil was added to sildenafil and warfarin. The patient maintained good performance status for 2 years, but then developed progressive activity limitation with depressed cardiac output on right heart catheterization. Systemic prostacyclin therapy was declined again. Sildenafil was replaced with riociguat, and 1 year later the patient demonstrated significant recovery of functional capacity and improved hemodynamic profile.We describe significant recovery in a patient with inoperable, progressive CTEPH treated with riociguat and inhaled treprostinil after failing sequential addition of sildenafil and inhaled treprostinil to warfarin. The reported benefits may relate to riociguat's ability to directly stimulate production of cyclic GMP independent of nitric oxide levels in pulmonary artery smooth muscle. There may also be a unique interaction between riocguat and treprostinil that enhanced treatment outcome. Further investigation of this combination of agents may be warranted.

Type II pulmonary epithelial cells (T2P) in primary culture assemble a biologically active extracellular matrix (ECM) from endogenously synthesized components, including fibronectin. Fibronectin is a well-recognized attachment protein that mediates cell adhesion, migration, and cytodifferentiation. In some cell types, exogenous fibronectin also is incorporated into ECM. The latter pathway of ECM assembly was thus investigated in T2P. Cells were cultured for 3-days in Dulbecco's modified Eagle's medium (DMEM) with or without 10% fetal calf serum (FCS), a source of exogenous fibronectin. Cell and matrix fractions were harvested on culture days 1, 2, and 3 to determine synthesis of cell and matrix proteins and matrix fibronectin content. During 3 days in DMEM containing 10% FCS, T2P flattened and spread to confluence more rapidly than cells in DMEM; they also produced ECM with higher fibronectin content than did cells in DMEM alone. On culture days 2 and 3, 10% FCS doubled (on average) synthesis of ECM fibronectin; in contrast, ECM fibronectin content increased nearly 10-fold. These observations suggest that cultured type II cells incorporate exogenous fibronectin into newly assembled ECM to a greater extent than the newly synthesized glycoprotein. Components of both endogenous and exogenous origin may therefore contribute to T2P assembly of a biologically active ECM.

Oral treprostinil (ORE) is approved to delay disease progression and improve exercise capacity in pulmonary arterial hypertension (PAH). The ongoing ADAPT registry (NCT03045029) collects real-world use and tolerability of ORE. This analysis reports patient-reported incidence and treatment of five common adverse events (headache, diarrhea, nausea, extremity pain and flushing) associated with oral prostacyclin-class (PCY) therapy to better understand adverse event (AE) management and tolerability.

Pulmonary hypertension may develop as a disease process specific to pulmonary arteries with no identifiable cause or may occur in relation to other cardiopulmonary and systemic illnesses. The World Health Organization (WHO) classifies pulmonary hypertensive diseases on the basis of primary mechanisms causing increased pulmonary vascular resistance. Effective management of pulmonary hypertension begins with accurately diagnosing and classifying the disease in order to determine appropriate treatment. Pulmonary arterial hypertension (PAH) is a particularly challenging form of pulmonary hypertension as it involves a progressive, hyperproliferative arterial process that leads to right heart failure and death if untreated. Over the last two decades, our understanding of the pathobiology and genetics behind PAH has evolved and led to the development of several targeted disease modifiers that ameliorate hemodynamics and quality of life. Effective risk management strategies and more aggressive treatment protocols have also allowed better outcomes for patients with PAH. For those patients who experience progressive PAH with medical therapy, lung transplantation remains a life-saving option. More recent work has been directed at developing effective treatment strategies for other forms of pulmonary hypertension, such as chronic thromboembolic pulmonary hypertension (CTEPH) and pulmonary hypertension due to other lung or heart diseases. The discovery of new disease pathways and modifiers affecting the pulmonary circulation is an ongoing area of intense investigation.

Background: Oral treprostinil (ORE) is approved for the treatment of pulmonary arterial hypertension (PAH) to delay disease progression and improve exercise capacity. ADAPT is an ongoing registry (NCT03045029) following patients after ORE initiation to collect real-world use and tolerability, including site-and patient-reported data. This analysis reports characteristics and dosing data on patients transitioning from inhaled, parenteral, or oral prostacyclin class therapies (PCY) to ORE. Methods: As of July 26, 2019, interim data are reported for eligible patients who newly or previously (within 182 days) initiated ORE. Baseline data include the most recent variables collected the 182 days prior to ORE initiation. Data was prospectively collected for up to 78 weeks after ORE initiation. Analyses represent data from transition patients (receiving another PCY within 3 days prior to initiating ORE) and non-transition patients. Adverse event (AE) and dosing data were reported by patients in the online portal; if dosing data was provided without accompanying AE data at a given timepoint, it was assumed no AE occurred. Data were analyzed using descriptive statistics. Results: Data for 76 patients who initiated ORE, 27 (36%) of which transitioned from PCY, are reported. In transition patients, the median [IQR] time since diagnosis was 4.2 [2.3,8.7] years and median duration of previous PCY was 29.9 [9.9,59.5] months. Reasons for transition included convenience (n=10), tolerability (n=2), efficacy (n=4), worsening of disease (n=5), and other (n=6). At ORE initiation, 11%, 37%, and 52% were on none, one, or two PAH-specific background therapies, respectively. 56% of patients transitioned from parenteral treprostinil, 22% from inhaled treprostinil, 19% from selexipag, and 4% from epoprostenol. Of those with available patient-reported data, transition patients reported higher median [IQR] total daily dose (TDD) of ORE at initiation (3 [0.4,12] mg vs. 0.4 [0.4,0.9] mg),

Myocardial nucleic acid responses were analysed in New Zealand White rabbits 20 min-1 h and 6-8 h following single subcutaneous injections of soman (20, 30, or 40 micrograms kg-1). Scanning-integrating microdensitometry was used to quantify Azure B-RNA and Feulgen-DNA (F-DNA) levels, and changes in the susceptibility of chromatin to Feulgen acid hydrolysis (F-DNA reactivity) of individual ventricular myocardial cells. With a dosage of 20 micrograms kg-1 soman, no RNA alterations were evidenced at 1 h whereas at 6-8 h myocardial cells exhibited higher RNA levels and an increase in F-DNA reactivity of chromatin. With dosages of 30 and 40 micrograms kg-1 soman there was an augmentation in RNA levels and in the acid hydrolysability of nuclear chromatin at both 20 min-1 h and 6-8 h. It is postulated that the observed cellular transformations represent a compensatory augmentation in myocardial metabolic functioning presumably in response to an increased functional demand on the ventricular myocardium. The absence of cytopathic or cytochemical evidence of impairment in nucleic acid metabolism is inconsistent with the premise that soman exerts direct cytotoxic effects on rabbit myocardium.

Pulmonary hypertension is a well-known complication of systemic sclerosis. Patients with systemic sclerosis may develop a pulmonary arteriopathy characterized by vascular remodeling, increased pulmonary vascular resistance, and right ventricular failure. Pulmonary hypertension may also arise in systemic sclerosis as a consequence of interstitial lung disease or left ventricular dysfunction. Vascular remodeling is more prevalent than other forms of pulmonary hypertension in systemic sclerosis. The pathogenesis of pulmonary vascular remodeling in this disease state is not completely understood; however, there is evidence of a complex process involving genetic susceptibility, risk factors, vascular injury, and endothelial dysfunction. In those patients with pulmonary arterial hypertension, survival prognosis is extremely poor if the diagnosis is delayed or goes undetected and untreated. In recent years, a number of disease-targeted therapies have been developed that improve functional capacity, hemodynamics, and survival. Early detection and treatment with one or more targeted therapies are essential to improving survival when systemic sclerosis is complicated by pulmonary arterial hypertension.

No abstract