Toshihiro Sarashina

epoprostenol sodium for treatment of pulmonary arterial hypertension

The release of endogenous prostacyclin (PGI2) is depressed in patients with pulmonary arterial hypertension (PAH). PGI2 replacement therapy by epoprostenol infusion is one of the best treatments available for PAH. Here, we provide an overview of the current clinical data for epoprostenol. Epoprostenol treatment improves symptoms, exercise capacity, and hemodynamics, and is the only treatment that has been shown to reduce mortality in patients with idiopathic PAH (IPAH) in randomized clinical trials. We have reported that high-dose epoprostenol therapy (>40 ng/kg/min) also results in marked hemodynamic improvement in some patients with IPAH. High-dose epoprostenol has a pro-apoptotic effect on PAH-PASMCs via the IP receptor and upregulation of Fas ligand (FasL) in vitro. However, long-term intravenous administration of epoprostenol is sometimes associated with catheter-related infections and leads to considerable inconvenience for the patient. In the future, the development of new routes of administration or the development of powerful PGI2 analogs, IP-receptor agonists, and gene and cell-based therapy enhancing PGI2 production with new routes of administration is required.

Histological Changes of Pulmonary Arteries Treated by Balloon Pulmonary Angioplasty in a Patient With Chronic Thromboembolic Pulmonary Hypertension

A 41-year-old man was referred to our hospital for the treatment of chronic thromboembolic pulmonary hypertension (CTEPH). On admission, he was in World Health Organization functional class III. Right heart catheterization demonstrated that pulmonary arterial pressure (systolic/diastolic/mean) was 140/42/71 mm Hg, cardiac index was 1.6 L/min/m2 and pulmonary vascular resistance was 1663 dyn ·s·cm–5. The patient had severe pulmonary hypertension and was considered inoperable because of peripheral organized thrombi and coexisting seminoma; therefore, balloon pulmonary angioplasty (BPA) was performed. After BPA, pulmonary angiography showed improvement of pulmonary arterial flow (Figure 1A). Pulmonary arterial pressure was 108/42/67 mm Hg and cardiac index was 2.5 L/min/m2 when he returned to the cardiac care unit after BPA. His condition temporarily improved; however, 2 hours later, it deteriorated because of reperfusion pulmonary injury and gastrointestinal bleeding. He required mechanical ventilation and percutaneous cardiopulmonary support. To improve hemodynamics, another session of BPA was tried 9 days later (Figures 2A and 3A) and pulmonary arterial pressure seemed to improve to 83/48/58 mm Hg. However, he died from right heart failure on day 26 after BPA despite intensive care. Figure 1. Representative images of pulmonary angiography and histology of pulmonary arteries of the upper lobe of the right lung. A , Angiographic images before (a) and after (b) BPA. A web lesion of the right pulmonary artery (arrow) was treated by BPA. Angiography after BPA showed a dilated vessel and increased flow in the distal arteries. Arrows indicate the areas where specimen for B was obtained. B , Histology of a pulmonary artery treated by BPA (arrow in A ). This lesion was treated by BPA at the initial session and second session (26 and 17 days before death). (a) Hematoxylin–eosin stain, low magnification. A large …

Reverse Right Ventricular Remodeling After Lung Transplantation in Patients With Pulmonary Arterial Hypertension Under Combination Therapy of Targeted Medical Drugs

BACKGROUND Patients with pulmonary arterial hypertension (PAH) are currently treated with combination therapy of PAH-targeted drugs. Reverse right ventricular (RV) remodeling after lung transplantation (LTx) in patients with end-stage PAH despite combination therapy of PAH-targeted drugs has not been fully elucidated.Methods and Results:A total of 136 patients, including 32 with PAH, underwent LTx from 1998 to 2014. We enrolled 12 consecutive patients with PAH treated with combination therapy of PAH-targeted drugs who underwent LTx and retrospectively analyzed the temporal and serial changes in hemodynamics and echocardiography before LTx and at 3 and 12 months after LTx. Before LTx, the RV was markedly dilated with substantially reduced RV fractional area change (RVFAC). At 3 months after LTx, pulmonary artery pressure, pulmonary vascular resistance and RV stroke work index were significantly decreased, while left ventricular stroke work index was increased. RV size assessed by echocardiography also significantly decreased and RVFAC improved. At 12 months after LTx, RVFAC was further increased and RV wall thickness was decreased significantly. CONCLUSIONS Although severe RV dysfunction and dilation were observed in patients with end-stage PAH despite combination therapy of PAH-targeted drugs, RV function and morphology were improved after reduction of RV pressure load by LTx.

Nanoparticle-Mediated Drug Delivery System for Pulmonary Arterial Hypertension

Nanoparticles have been used as a novel drug delivery system. Drug-incorporated nanoparticles for local delivery might optimize the efficacy and minimize the side effects of drugs. The efficacy and safety of intratracheal administration of prostacyclin analog (beraprost) -incorporated nanoparticles and imatinib (a PDGF-receptor tyrosine kinase inhibitor) -incorporated nanoparticles in Sugen-hypoxia-normoxia or monocrotaline rat models of pulmonary arterial hypertension (PAH) and in human PAH-pulmonary arterial smooth muscle cells have been reported. The use of inhaled drug-incorporated nanoparticles might be a novel approach for the treatment of PAH.

Enhanced EP4 Expression in a Pulmonary Artery Aneurysm With Dissection in a Patient With Pulmonary Arterial Hypertension

Pulmonary artery (PA) aneurysm is sometimes found in patients with pulmonary arterial hypertension (PAH), and PA dissection is a rare but life-threatening complication. The pathological background of PA aneurysms and dissection remains poorly understood. A 29-year-old man was diagnosed with PAH associated with patent ductus arteriosus (PDA; Movie I in the Data Supplement) and was in World Health Organization functional class II. Chest radiography showed an enlargement of the PA (Figure 1A). Contrast-enhanced computed tomography demonstrated large PA aneurysm with a diameter of 72 mm (Figure 1B). His PA pressure was 58/33 (44) mm Hg, and PA wedge pressure was 6 mm Hg. We closed the PDA with a coil. Seven years after the diagnosis, he was transported to our hospital with sudden chest pain and deteriorating consciousness. Systemic blood pressure was 92/63 mm Hg, heart rate was 83/min, and oxygen saturation was 98% with 3 L/min of oxygen administered. A chest radiography showed marked enlargement …

Treat-and-repair strategy is a feasible therapeutic choice in adult patients with severe pulmonary arterial hypertension associated with a ventricular septal defect: case series

Abstract Introduction Recent advances in pulmonary arterial hypertension (PAH)-specific drugs have dramatically changed the therapeutic strategy for PAH. A strategy that includes ‘treatment’ with PAH-specific drugs initially and then ‘repair’ by closure of the cardiac defect (i.e. ‘treat and repair’) was devised, and has been attempted, in patients with PAH associated with a cardiac defect. Case presentation We present three cases of severe PAH associated with a ventricular septal defect (VSD) in adult patients who were initially treated with PAH-specific drugs followed by VSD closure. Two of the patients were treated with a combination of an endothelin receptor antagonist (ERA), phosphodiesterase type 5 inhibitor, and intravenous prostacyclin before VSD closure. The third patient was treated with an ERA and pulmonary artery banding before VSD closure. After 12 months of anti-PAH treatment, the pulmonary vascular resistance index and the ratio of the pulmonary vascular index to the systemic vascular resistance index decreased to levels that allowed VSD closure. At the mid- and long-term follow-up measurements after surgical closure of the VSD, the mean pulmonary artery pressure had markedly decreased. Discussion Our case series suggests that the treat-and-repair strategy is a promising approach for adult patients with severe PAH associated with VSD.

Suppression of Wnt Signaling and Osteogenic Changes in Vascular Smooth Muscle Cells by Eicosapentaenoic Acid

Vascular medial calcification is often observed in patients with arteriosclerosis. It is also associated with systolic hypertension, wide pulse pressure, and fluctuation of blood pressure, which results in cardiovascular events. Eicosapentaenoic acid (EPA) has been shown to suppress vascular calcification in previous animal experiments. We investigated the inhibitory effects of EPA on Wnt signaling, which is one of the important signaling pathways involved in vascular calcification. Intake of food containing 5% EPA resulted in upregulation of the mRNA expression of Klotho, an intrinsic inhibitor of Wnt signaling, in the kidneys of wild-type mice. Expression levels of β-catenin, an intracellular signal transducer in the Wnt signaling pathway, were increased in the aortas of Klotho mutant (kl/kl) mice compared to the levels in the aortas of wild-type mice. Wnt3a or BIO, a GSK-3 inhibitor that activates β-catenin signaling, upregulated mRNA levels of AXIN2 and LEF1, Wnt signaling marker genes, and RUNX2 and BMP4, early osteogenic genes, in human aorta smooth muscle cells. EPA suppressed the upregulation of AXIN2 and BMP4. The effect of EPA was cancelled by T0070907, a PPARγ inhibitor. The results suggested that EPA could suppress vascular calcification via the inhibition of Wnt signaling in osteogenic vascular smooth muscle cells via PPARγ activation.

Progression of pulmonary artery dilatation in patients with pulmonary hypertension coexisting with a pulmonary artery aneurysm

BACKGROUND Pulmonary artery (PA) dilatation is usually observed in patients with pulmonary hypertension (PH), but a PA aneurysm (PA diameter > 40mm) is rare. The difference between characteristics of patients with and those without progression of PA diameter remains poorly understood. We assessed the changes in PA diameter in patients with PH coexisting with and without a PA aneurysm. METHODS We investigated the changes in PA diameter by multi-detector computed tomography performed twice with an interval of more than one year in 44 patients with PH. Seventeen patients had a PA aneurysm and 27 patients did not have a PA aneurysm at baseline. RESULTS The median follow-up period was 3.6 years. All patients received medical or invasive treatment for PH. At baseline, main PA diameters were 52±15mm in patients with a PA aneurysm and 33±3mm in patients without a PA aneurysm. Mean PA pressure was higher in patients with a PA aneurysm than in those without a PA aneurysm (61±15mmHg vs. 51±16mmHg, p=0.04). At follow-up, mean PA pressure significantly decreased in both patients with a PA aneurysm (44±11mmHg) and patients without a PA aneurysm (41±18mmHg). Main PA diameter significantly increased in patients with a PA aneurysm (65±28mm, change ratio: 23.3%), while it did not increase in patients without a PA aneurysm (32±3mm, change ratio: -3.1%). CONCLUSIONS PA dilatation progressed in patients with a PA aneurysm despite treatment of PH. The progression of PA dilatation is independent of reduction of PA pressure by PH treatment.

High Frequency of Acute Adverse Cardiovascular Events After Lung Transplantation in Patients With Pulmonary Arterial Hypertension Receiving Preoperative Long-Term Intravenous Prostacyclin

Adverse cardiovascular events after lung transplantation (LT) increase the mortality in patients with pulmonary arterial hypertension (PAH). Long-term intravenous prostacyclin is the usual treatment in severe patients with PAH, but it may increase the risk of hemorrhage due to its antiplatelet aggregation effect or thrombocytopenia. We investigated the impact of length of intravenous prostacyclin therapy on acute adverse cardiovascular events including hemorrhagic complication after LT. We retrospectively compared the incidence of adverse events (death, intrathoracic hematoma and bleeding, cardiac congestion or shock, cerebral infarction and pulmonary embolism) within 30 days after LT between no/short-term (median 0.6 years, n = 13) and long-term (median 3.7 years, n = 15) intravenous prostacyclin groups. There were no differences in the dose of intravenous prostacyclin and pulmonary artery pressure between the two groups. Among 22 adverse events (0.8 ± 1.1 events/patient), 4 events occurred in the no/short-term intravenous prostacyclin group and 18 occurred in the long-term intravenous prostacyclin group. The event rate per patient in the long-term intravenous prostacyclin group (1.2 ± 1.3 events/patient) was significantly higher than that in the no/short-term intravenous prostacyclin group (0.3 ± 0.5 events/patient) (P < 0.05). Intrathoracic hematoma and bleeding was the most frequent adverse event (9 events, 41%). Preoperative long-term intravenous prostacyclin therapy increases acute adverse cardiovascular events after LT in patients with PAH.

Crucial role of RAGE in inappropriate increase of smooth muscle cells from patients with pulmonary arterial hypertension

Background Pulmonary vascular remodeling of pulmonary arterial hypertension (PAH) is characterized by an inappropriate increase of vascular cells. The receptor for advanced glycation end products (RAGE) is a type I single-pass transmembrane protein belonging to the immunoglobulin superfamily and is involved in a broad range of hyperproliferative diseases. RAGE is also implicated in the etiology of PAH and is overexpressed in pulmonary artery smooth muscle cells (PASMCs) in patients with PAH. We examined the role of RAGE in the inappropriate increase of PASMCs in patients with PAH. Methods and results PASMCs were obtained from 12 patients with PAH including 9 patients with idiopathic PAH (IPAH) and 3 patients with heritable PAH (HPAH) (2 patients with BMPR2 mutation and one patient with SMAD9 mutation) who underwent lung transplantation. Western blot analysis and immunofluorescence staining revealed that RAGE and S100A8 and A9, ligands of RAGE, were overexpressed in IPAH and HPAH-PASMCs in the absence of any external growth stimulus. PDGF-BB (10 ng/mL) up-regulated the expression of RAGE in IPAH and HPAH-PASMCs. PAH-PASMCs are hyperplastic in the absence of any external growth stimulus as assessed by 3H-thymidine incorporation. This result indicates overgrowth characterized by continued growth under a condition of no growth stimulation in PAH-PASMCs. PDGF-BB stimulation caused a higher growth rate of PAH-PASMCs than that of non-PAH-PASMCs. AS-1, an inhibitor of TIR domain-mediated RAGE signaling, significantly inhibited overgrowth characterized by continued growth under a condition of no growth stimulation in IPAH and HPAH-PASMCs (P<0.0001). Furthermore, AS-1 significantly inhibited PDGF-stimulated proliferation of IPAH and HPAH-PASMCs (P<0.0001). Conclusions RAGE plays a crucial role in the inappropriate increase of PAH-PASMCs. Inhibition of RAGE signaling may be a new therapeutic strategy for PAH.