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Background Transition to pulmonary arterial hypertension (PAH)-specific drugs is considered in patients with PAH and chronic thromboembolic pulmonary hypertension who do not respond to combination therapy or who experience side effects to the combination drugs. Riociguat directly stimulates soluble guanylate cyclase independently of nitric oxide. Therefore, transition from a phosphodiesterase type 5 inhibitor (PDE5i), which requires nitric oxide to exert its effects, to riociguat might be effective. The length of time of washout periods for transition is important because haemodynamic instability sometimes occurs during these periods or during transition with no washout period. Method We investigated the feasibility of transitioning from a PDE5i to riociguat without washout periods by monitoring haemodynamics under right heart catheterisation in six patients with PAH and one with chronic thromboembolic pulmonary hypertension who had already received dual- or triple-combination therapy. Results Reasons for transition were headache caused by a PDE5i in three patients, and an inadequate response to combination therapy in four. Transition was successful in all patients, with no haemodynamic instability observed. Pulmonary vascular resistance (from 797 ± 241 to 518 ± 230 dyne/s/cm–5) and systemic blood pressure (from 121 ± 13 to 100 ± 15 mmHg) were significantly reduced immediately after transition. There were no significant differences in the tricuspid regurgitation pressure gradient or systemic blood pressure during the post-transition and follow-up periods. Headaches caused by a PDE5i were diminished after transition to riociguat. Conclusions Transition from a PDE5i to riociguat without a washout period is safe. This transition may be a viable option for patients with headaches caused by a PDE5i, or who have an inadequate response to combination therapy that includes a PDE5i.

Chronic-active Epstein-Barr virus infection (CAEBV) is a rare disease that can lead to pulmonary arterial hypertension (PAH). However, the treatment for CAEBV-associated PAH has not been established. We discuss a case of improved pulmonary hypertension after chemotherapy in a patient with CAEBV-associated PAH. A 44-year old man was admitted to our hospital because of an abnormal electrocardiogram and liver dysfunction detected by annual medical examination. Echocardiography showed a dilated right ventricle and an estimated right ventricular systolic pressure of 92 mmHg. Right heart catheterization revealed a mean pulmonary arterial pressure of 45 mmHg and pulmonary vascular resistance of 9.8 Wood units. Laboratory examination showed granular lymphocytes and 91% natural killer cells in lymphocyte subsets in peripheral blood. We diagnosed the patient as having CAEBV-associated PAH. After two cycles of chemotherapy without PAH-specific drugs, echocardiography showed improvement in the dilated right ventricle and an estimated right ventricular systolic pressure of 59 mmHg. Right heart catheterization revealed a mean pulmonary arterial pressure of 27 mmHg and pulmonary vascular resistance of 2.4 Wood units. Chemotherapy may improve pulmonary hypertension in patients with CAEBV-associated PAH.

Background Arterial stiffness is an important predictor of cardiovascular events; however, indexes for measuring arterial stiffness have not been widely incorporated into routine clinical practice. This study aimed to determine whether the cardio‐ankle vascular index (CAVI), based on the blood pressure–independent stiffness parameter β and reflecting arterial stiffness from the origin of the ascending aorta, is a good predictor of cardiovascular events in patients with cardiovascular disease risk factors in a large prospective cohort. Methods and Results This multicenter prospective cohort study, commencing in May 2013, with a 5‐year follow‐up period, included patients (aged 40‒74 years) with cardiovascular disease risks. The primary outcome was the composite of cardiovascular death, nonfatal stroke, or nonfatal myocardial infarction. Among 2932 included patients, 2001 (68.3%) were men; the mean (SD) age at diagnosis was 63 (8) years. During the median follow‐up of 4.9 years, 82 participants experienced primary outcomes. The CAVI predicted the primary outcome (hazard ratio, 1.38; 95% CI, 1.16‒1.65; P 2 value increased from 33.8 to 45.2 ( P P =0.024). Conclusions This large cohort study demonstrated that the CAVI predicted cardiovascular events. Registration URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01859897.

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.

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.

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.

Background Pulmonary artery (PA) dilatation is usually observed in patients with pulmonary hypertension (PH), but a PA aneurysm (PA diameter > 40 mm) 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 ± 15 mm in patients with a PA aneurysm and 33 ± 3 mm 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 ± 15 mmHg vs. 51 ± 16 mmHg, p = 0.04). At follow-up, mean PA pressure significantly decreased in both patients with a PA aneurysm (44 ± 11 mmHg) and patients without a PA aneurysm (41 ± 18 mmHg). Main PA diameter significantly increased in patients with a PA aneurysm (65 ± 28 mm, change ratio: 23.3%), while it did not increase in patients without a PA aneurysm (32 ± 3 mm, 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.

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 …

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 …

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

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.

There were few reports regarding arrhythmias with idiopathic pulmonary arterial hypertension (IPAH). A 37-year-old woman was presented with a 6-year history of palpitations. She was diagnosed as IPAH at 25 years old and introduced continuous intravenous administration of PGI2 at 27 years old. Her electrocardiogram revealed paroxysmal supraventricular tachycardia (PSVT) and was referred for catheter ablation. The electrophysiological study revealed dual pathway in AV and VA conduction. PSVT was induced by programmed atrial stimuli with jump up phenomenon under a small amount of isoproterenol. The tachycardia cycle length was from 460 ms to 560 ms, but earliest atrial potential was recorded at His and intra-atrial propagation was similar in any cycle lengths. The single-extra ventricular stimuli did not reset the tachycardia, so we diagnosed as common type AV nodal reentrant tachycardia. Fractionated potential so called slow pathway potential were recorded in broad postero-septal area and junctional tachycardia was immediately obtained during the applications of radiofrequency current, but it was hard to eliminate the PSVT. After 12 deliveries of radiofrequency current, PSVT could not be induced by any programmed stimuli.