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A 45-year-old man, who was implanted with an inferior vena cava (IVC) filter in his infrarenal IVC, had a complication of deep vein thrombosis (DVT) propagation from the IVC, beyond the IVC filter, to the right calf and left external iliac veins. The entire IVC filter was covered with a massive thrombus. We first decided to retrieve the IVC filter itself, which was suspected of causing metallic allergy. The thrombotic IVC filter was successfully retrieved using multi-step catheter intervention. To our knowledge, this is the first case report to describe successful multi-step catheter intervention for retrieval of an IVC filter covered with a massive thrombus.

Systemic right ventricular (RV) failure in patients with congenitally corrected transposition of the great arteries (ccTGA), a major cause of mortality in the long-term follow-up, is usually induced by concomitant severe morphologically tricuspid regurgitation (TR) with/without Ebstein's anomaly or progressive conduction tissue disturbances. However, whether or not myocardial fibrosis is a common cause of systemic RV failure in patients with ccTGA remains unclear. Here, we describe an 82-year-old man who had been diagnosed previously as having uncomplicated ccTGA and situs inversus and recently developed systemic RV failure, which was neither associated with severe TR nor advanced conduction tissue abnormalities. Cardiovascular magnetic resonance (CMR) with delayed-enhancement imaging clearly detected extensive myocardial scars (presumably fibrosis) in the RV wall as well as prominent dilatation, hypertrophy, and systolic dysfunction of the systemic RV. These findings suggest that myocardial fibrosis can cause systemic RV failure in elderly patients with uncomplicated ccTGA despite the absence of severe TR or advanced conduction tissue abnormalities and that CMR may be a useful examination to accurately detect systemic RV failure associated with myocardial fibrosis and to subsequently clarify the prognosis in these patients.

Objective To determine safety and efficacy of cardiac rehabilitation (CR) initiated immediately following balloon pulmonary angioplasty (BPA) in patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH) who presented with continuing exercise intolerance and symptoms on effort even after a course of BPA; 2–8 sessions/patient. Methods Forty-one consecutive patients with inoperable CTEPH who underwent their final BPA with improved resting mean pulmonary arterial pressure of 24.7±5.5 mm Hg and who suffered remaining exercise intolerance were prospectively studied. Participants were divided into two groups just after the final BPA (6.8±2.3 days): patients with (CR group, n=17) or without (non-CR group, n=24) participation in a 12-week CR of 1-week inhospital training followed by an 11-week outpatient programme. Cardiopulmonary exercise testing, haemodynamics, and quality of life (QOL) were assessed before and after CR. Results No significant between-group differences were found for any baseline characteristics. At week 12, peak oxygen uptake (VO2), per cent predicted peak VO2 (70.7±9.4% to 78.2±12.8%, p

Chronic thromboembolic pulmonary hypertension (CTEPH) is a complication of pulmonary embolism and a major cause of chronic PH leading to right heart failure and death. Lung ventilation/perfusion scintigraphy is the screening test of choice; a normal scan rules out CTEPH. In the case of an abnormal perfusion scan, a high-quality pulmonary angiogram is necessary to confirm and define the pulmonary vascular involvement and prior to making a treatment decision. PH is confirmed with right heart catheterisation, which is also necessary for treatment determination. In addition to chronic anticoagulation therapy, each patient with CTEPH should receive treatment assessment starting with evaluation for pulmonary endarterectomy, which is the guideline recommended treatment. For technically inoperable cases, PH-targeted medical therapy is recommended (currently riociguat based on the CHEST studies), and balloon pulmonary angioplasty should be considered at a centre experienced with this challenging but potentially effective and complementary intervention., State of the art and research perspectives in chronic thromboembolic pulmonary hypertension, including treatment algorithm http://ow.ly/C3Iy30mfUly

Coronary microvessel endothelial dysfunction and nitric oxide (NO) depletion contribute to elevated passive tension of cardiomyocytes, diastolic dysfunction and predispose the heart to heart failure with preserved ejection fraction. We examined if diastolic dysfunction at the level of the cardiomyocytes precedes coronary endothelial dysfunction in prediabetes. Further, we determined if myofilaments other than titin contribute to impairment. Utilizing synchrotron microangiography we found young prediabetic male rats showed preserved dilator responses to acetylcholine in microvessels. Utilizing synchrotron X-ray diffraction we show that cardiac relaxation and cross-bridge dynamics are impaired by myosin head displacement from actin filaments particularly in the inner myocardium. We reveal that increased PKC activity and mitochondrial oxidative stress in cardiomyocytes contributes to rho-kinase mediated impairment of myosin head extension to actin filaments, depression of soluble guanylyl cyclase/PKG activity and consequently stiffening of titin in prediabetes ahead of coronary endothelial dysfunction.

Although several tissue-Doppler imaging (TDI) models for pulmonary capillary wedge pressure (PCWP) estimation have been reported, their reliability remains uncertain. Our previous theoretical and experimental analyses suggest that right atrial pressure (RAP) corrected by tissue-Doppler imaging tricuspid/mitral annular peak systolic velocities (ST/SM) (RAP × ST/SM) reliably predicts elevated PCWP. We sought to investigate its clinical usefulness for predicting elevated PCWP in heart failure (HF) patients. Ninety-eight patients admitted with HF who underwent right heart catheterization were prospectively studied. RAP and PCWP were measured by right heart catheterization. Simultaneously, ST/SM, early diastolic transmitral flow velocity to mitral annular velocity ratio (E/Ea), and diameter of inferior vena cava at inspiration (IVCDi), a noninvasive surrogate for RAP, were measured by echocardiography. RAP correlated with IVCDi (R2 = 0.57). A significantly stronger correlation was observed between IVCDi corrected by ST/SM (IVCDi × ST/SM) and PCWP than between E/Ea and PCWP (R2 = 0.47 vs 0.18). Receiver-operating characteristic analyses indicated that IVCDi × ST/SM >16 mm predicted PCWP >18 mm Hg with 90% sensitivity and 77% specificity, and the area under the curve was 0.86, which was significantly larger than that of E/Ea (area under the curve=0.72). In conclusions, IVCDi × ST/SM is a new useful noninvasive model to predict elevated PCWP in HF patients.

Background: Riociguat is approved in Japan for treatment of pulmonary arterial hypertension and inoperable or persistent/recurrent CTEPH after pulmonary endarterectomy. Aim: Obtain post-marketing information on riociguat safety in treatment of CTEPH in routine clinical practice in Japan. Methods: Multicentre, prospective, non-interventional study in patients treated with riociguat for inoperable or persistent/recurrent CTEPH (NCT02117791). Primary outcomes: treatment-emergent adverse events (AEs) and adverse drug reactions over mandatory 12 months’ observation and up to 7 years thereafter. Results: Interim data are available for 684 patients (median age 69.0 years; 75.3% female; 89.6% inoperable; 9.8% persistent/recurrent). Median treatment duration with riociguat 358 (range 2–1128) days; median dose 5.8 mg/day. Prior use of an ERA in 29.8% of patients, PCA in 29.8%, PDE5i in 23.2% and balloon pulmonary angioplasty (BPA) in 27.2%. Concomitant ERA in 29.7%, PCA in 27.5%, PDE5i in 1.5%. AEs were reported in 188 patients (27.5%), drug-related AEs in 118 (17.3%; Table) and serious drug-related AEs in 15 (2.2%): 24 (3.5%) withdrew because of BPA and 44 (6.4%) because of AEs. Conclusions: The AE profile of riociguat in clinical practice in Japan appears consistent with clinical trials globally and in Japan. The most common AEs are consistent with the vasodilating action of riociguat.

Background: It is reported that there is no benefit of pulmonary hypertensive medical therapy (PHT) in patients undergoing pulmonary endarterectomy (PEA), except improved total pulmonary resistance with epoprostenol (Kurt W et al. Circulation 2009). They cautioned that the use of PHT delayed the time to referral for PEA. However, the effects of PHT on long-term prognosis after PEA remain to be examined. Methods: We retrospectively studied 149 patients (57±16 years) with chronic thromboembolic pulmonary hypertension undergoing PEA at Bologna University Hospital. The prevalence of PHT and its impact on haemodynamics and long-term outcomes were studied. Results: Sixty-one patients were untreated (non-tp), whereas 88 (59%) were treated with some PHT, consisting of monotherapy in 73; sildenafil in 47 (sil) and bosentan in 26 (bos), and combination therapy in 15 (combo). At baseline, there were no significant changes in age, sex, mean pulmonary arterial pressure (mPAP) or exercise capacity among 4 groups. During a mean follow-up of 60±44 months, 27 patients died. Five-year survival from PEA was 80, 87, 96 and 80% in non-tp, sil, bos and combo groups (P=0.36). Pre-PEA treatments with sil and combo significantly improved mPAP (50.0±8.9 to 46.0±9.7, 53.1±10.7 to 47.4±8.7 mmHg, P Conclusions: Pre-PEA treatments with sildenafil did not affect the long-term prognosis after PEA, but may be effective for stabilising haemodynamics before PEA without delaying the time to surgery.

Pulmonary arterial hypertension (PAH) is a rare, devastating disease, characterized by elevated pulmonary arterial pressure due to pulmonary microvascular obstruction, which can result in heart failure and death. PAH can be associated with exposure to certain drugs or toxins. We herein report a case in which PAH developed in a patient with refractory ulcerative colitis during treatment with "Qing-Dai," a Chinese herbal medicine. The patient's PAH improved after the discontinuation of Qing-Dai.

Chronic thromboembolic pulmonary hypertension (CTEPH) is a debilitating but potentially reversible complication of chronic pulmonary thromboembolic disease characterized by progressive right heart dysfunction secondary to pulmonary arterial stenosis or occlusion. Balloon pulmonary angioplasty (BPA) has recently emerged as an alternative intervention for non-surgical candidates with CTEPH. Modern reperfusion angioplasty techniques relieve sequela of chronic pulmonary hypertension, ameliorate right ventricular failure, and improve functional status. This article will discuss the diagnosis and treatment of patients with CTEPH and the current state of endovascular management with BPA.

BACKGROUND Post-thrombotic syndrome (PTS), the most common complication of deep venous thrombosis (DVT), develops in ≥50% of patients with iliofemoral DVT. However, the benefit of endovascular treatment in Japanese patients with chronic DVT and PTS remains unclear. Methods and Results: Between June 2014 and May 2016, endovascular treatment was performed in 11 consecutive Japanese patients with chronic iliofemoral DVT and PTS refractory to anticoagulant therapy and elastic compression stockings. We evaluated the technical success rate, complications, patency, Villalta score, calf circumference, and popliteal vein reflux in both the acute stage (the day following endovascular treatment) and chronic stage (after 6 months). Imaging follow-up included venous duplex scanning and/or magnetic resonance venography. The technical success rate was 81.8%, without complications. In patients with successful intervention, the Villalta score improved significantly, from 9.0±3.7 preoperatively to 3.6±2.5 in the acute phase (P

Caspase recruitment family member 14 (CARD14, also known as CARMA2), is a scaffold protein that mediates NF-κB signal transduction in skin keratinocytes. Gain-of-function CARD14 mutations have been documented in familial forms of psoriasis vulgaris (PV) and pityriasis rubra pilaris (PRP). More recent investigations have also implicated CARD14 in the pathogenesis of pustular psoriasis. Follow-up studies, however, have been limited, so that it is not clear to what extent CARD14 alleles account for the above conditions. Here, we sought to address this question by carrying out a systematic CARD14 analysis in an extended patient cohort (n=416). We observed no disease alleles in subjects with familial PV (n=159), erythrodermic psoriasis (n=23), acral pustular psoriasis (n=100), or sporadic PRP (n=29). Conversely, our analysis of 105 individuals with generalized pustular psoriasis (GPP) identified a low-frequency variant (p.Asp176His) that causes constitutive CARD14 oligomerization and shows a significant association with GPP in Asian populations (P=8.4 × 10−5; odds ratio=6.4). These data indicate that the analysis of CARD14 mutations could help stratify pustular psoriasis cohorts but would be mostly uninformative in the context of psoriasis and sporadic PRP.

Chronic thromboembolic pulmonary hypertension (CTEPH), especially when severe in patients unsuited for pulmonary endarterectomy, has a poor prognosis. Balloon pulmonary angioplasty (BPA) is a new catheter-based alternative treatment option for patients with inoperable CTEPH. BPA has not been widely accepted, however, primarily because of possible fatal complications, although effects described in 2001 were encouraging. Recent studies about BPA from Japan and Norway are promising. However, this emerging catheter-based intervention is still considered to be experimental because of a number of concerns and unanswered questions. This review describes the recent progress in BPA at the dawn of a new CTEPH treatment era.Recent studies about BPA show consistently beneficial effects in haemodynamics, symptoms, 6-minute walking distance, and biomarkers. Exercise capacity and right ventricular function are also improved by BPA. However, this new technique still has potentially fatal complications, including reperfusion oedema and pulmonary artery perforation, even in recent studies. There remain a number of concerns and unanswered questions about BPA, including indications, best procedural approach, and long-term outcomes.Recent advances in BPA for inoperable CTEPH are promising. Further investigation by multidisciplinary CTEPH teams is mandatory before BPA's role in CTEPH treatment strategies is determined.

Inferior vena cava (IVC) stenosis is a well-known complication of the IVC filter. However, there are no previous reports of IVC stenosis caused by a temporary IVC filter. In this case report, we describe the case of a 35-year-old man who was referred to our center for the treatment of recurrent proximal deep vein thrombosis (DVT) and severe IVC stenosis that occurred after retrieval of a temporary IVC filter. We performed a catheter-directed thrombolysis and balloon angioplasty. DVT resolved effectively, and his leg symptoms resolved. .

To assess the usefulness of cone-beam CT (CBCT) during pulmonary angiography for the evaluation of organized thrombus at segmental or subsegmental arteries in patients with chronic thromboembolic pulmonary hypertension (CTEPH). The segmental and/or subsegmental pulmonary arteries of 13 patients with CTEPH were evaluated by CBCT. We classified representative forms of organized thrombus into 4 types (type 1: webs, type 2: web and slits, type 3: slits, and type 4: narrowing or complete occlusion), and the distribution and frequency of the organized thrombus were evaluated. The relative detectability of these lesions using CBCT was compared with that in contrast-enhanced CT pulmonary angiography (CTPA). Type 1 lesions were most frequently observed in both segmental (30/65 = 46 %) and subsegmental branches (72/156 = 46 %). Type 2 lesions were relatively less frequent than type 1, but subsegmental branches were frequently involved (29/156 = 19 %). Type 3 lesions observed as a thin flap in 9/156 subsegmental branches (6 %). Comparing with CTPA, all 40 lesions in segmental branches were detectable in CTPA, whereas only 62 lesions among 90 lesions (69 %) in subsegmental branches could be observed by CTPA. CBCT is found to be useful for the treatment planning of balloon pulmonary angioplasty distal to segmental arteries.

Chronic thromboembolic pulmonary hypertension (CTEPH) is thought to result from incomplete resolution of pulmonary thromboemboli that undergo organisation into fibrous tissue within pulmonary arterial branches, filling pulmonary arterial lumina with collagenous obstructions. The treatment of choice is pulmonary endarterectomy (PEA) in CTEPH centres, which has low post-operative mortality and good long-term survival. For patients ineligible for PEA or who have recurrent or persistent pulmonary hypertension after surgery, medical treatment with riociguat is beneficial. In addition, percutaneous balloon pulmonary angioplasty (BPA) is an emerging option, and promises haemodynamic and functional benefits for inoperable patients. In contrast to conventional angioplasty, BPA with undersized balloons over guide wires exclusively breaks intraluminal webs and bands, without dissecting medial vessel layers, and repeat sessions are generally required. Observational studies report that BPA improves haemodynamics, symptoms and functional capacity in patients with CTEPH, but controlled trials with long-term follow-up are needed. Complications include haemoptysis, wire injury, vessel dissection, vessel rupture, reperfusion pulmonary oedema, pulmonary parenchymal bleeding and haemorrhagic pleural effusions. This review summarises the available evidence for BPA, patient selection, recent technical refinements and periprocedural imaging, and discusses the potential future role of BPA in the management of CTEPH.

Systemic right ventricular (RV) failure in patients with congenitally corrected transposition of the great arteries (ccTGA), a major cause of mortality in the long-term follow-up, is usually induced by concomitant severe morphologically tricuspid regurgitation (TR) with/without Ebstein's anomaly or progressive conduction tissue disturbances. However, whether or not myocardial fibrosis is a common cause of systemic RV failure in patients with ccTGA remains unclear. Here, we describe an 82-year-old man who had been diagnosed previously as having uncomplicated ccTGA and situs inversus and recently developed systemic RV failure, which was neither associated with severe TR nor advanced conduction tissue abnormalities. Cardiovascular magnetic resonance (CMR) with delayed-enhancement imaging clearly detected extensive myocardial scars (presumably fibrosis) in the RV wall as well as prominent dilatation, hypertrophy, and systolic dysfunction of the systemic RV. These findings suggest that myocardial fibrosis can cause systemic RV failure in elderly patients with uncomplicated ccTGA despite the absence of severe TR or advanced conduction tissue abnormalities and that CMR may be a useful examination to accurately detect systemic RV failure associated with myocardial fibrosis and to subsequently clarify the prognosis in these patients.

Background Chronic thromboembolic pulmonary hypertension (CTEPH) is a disease characterized by chronic obstructive thrombus and pulmonary hypertension. Balloon pulmonary angioplasty (BPA), an emerging alternative catheter-based treatment for inoperable patients with CTEPH, has not yet been standardised, especially for lesion assessment in distal pulmonary arteries. Recent advancement in computed tomography enables distal CTEPH lesions to be visualized. Methods We retrospectively studied 80 consecutive patients with inoperable CTEPH who received BPA guided by cone-beam computed tomography (CT) (CBCT) or electrocardiogram (ECG)-gated area detector CT (ADCT) for target lesion assessment. We collected clinical and hemodynamic data, including procedural complications, before BPA and at 3 months and 1 year after BPA. Results Three hundred eight-five BPA sessions (4.8 sessions/patient) were performed for the lesions of subsegmental arteries (1155 lesions), segmental arteries (738 lesions), and lobar arteries (4 lesions) identified by CBCT or ECG-gated ADCT. Significant improvements in the symptoms, 6-min walk distance, brain natriuretic peptide level, exercise capacity, and haemodynamics were observed 3 months and 1 year after BPA. No cases of death or cardiogenic shock with a low rate of severe wire perforation (0.3%) and severe reperfusion oedema (0.3%) were observed. Conclusions BPA guided by CBCT or ECG-gated ADCT is effective and remarkably safe in patients with CTEPH . These new advanced CT techniques may be useful in pre-BPA target lesion assessment.

Pulmonary arterial hypertension (PAH) is a rare cardiovascular disorder caused by narrowing of blood vessels in the lung and in the absence of therapy leads to right heart failure and death. No cure for this devastating disorder is known. The major objective of the current treatments is to improve symptoms and these therapies were developed prior to the discovery that this disease has substantial genetic components. In this review, we discuss molecular genetic basis of PAH together with pathobiology, current and future therapeutic interventions. DOI: http://dx.doi.org/10.3329/akmmcj.v3i2.11691 AKMMC J 2012; 3(2): 30-33

Pulmonary arterial hypertension (PAH) is a cardiovascular disorder associated with enhanced proliferation and suppressed apoptosis of pulmonary arterial smooth muscle cells (PASMCs). Heterozygous mutations in the type II receptor for bone morphogenetic protein (BMPR2) underlie the majority of the inherited and familial forms of PAH. The transforming growth factor β (TGFβ) pathway is activated in both human and experimental models of PAH. However, how these factors exert pro-proliferative and anti-apoptotic responses in PAH remains unclear. Using mouse primary PASMCs derived from knock-in mice, we demonstrated that BMPR-II dysfunction promotes the activation of small mothers against decapentaplegia-independent mitogen-activated protein kinase (MAPK) pathways via TGFβ-associated kinase 1 (TAK1), resulting in a pro-proliferative and anti-apoptotic response. Inhibition of the TAK1-MAPK axis rescues abnormal proliferation and apoptosis in these cells. In both hypoxia and monocrotaline-induced PAH rat models, which display reduced levels of bmpr2 transcripts, this study further indicates that the TGFβ-MAPK axis is activated in lungs following elevation of both expression and phosphorylation of the TAK1 protein. In ex vivo cell-based assays, TAK1 inhibits BMP-responsive reporter activity and interacts with BMPR-II receptor. In the presence of pathogenic BMPR2 mutations observed in PAH patients, this interaction is greatly reduced. Taken together, these data suggest dysfunctional BMPR-II responsiveness intensifies TGFβ-TAK1-MAPK signalling and thus alters the ratio of apoptosis to proliferation. This axis may be a potential therapeutic target in PAH.

Background: We have recently shown that balloon pulmonary angioplasty (BPA) improves peak oxygen uptake (peak VO2) early after the procedure, along with hemodynamics, in patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH), without postprocedural deconditioning. However, the combined effects of BPA and the following cardiac rehabilitation (CR) on exercise capacity and quality of life (QOL) remain to be examined. Methods: We prospectively enrolled 35 consecutive patients (68±10 years) with inoperable CTEPH who underwent a series of BPA (3.7±2.0 procedures). Just after the final BPA (6.4±2.5 days), 13 out of 35 patients participated in 12-week CR program, consisting of walking, bicycle, and resistance training. Serial changes of cardiopulmonary exercise testing (CPX), hemodynamics, and QOL were assessed before the first BPA, after the final BPA (the beginning of CR), and the end of CR. Results: In 35 patients, BPA significantly improved hemodynamics (mean pulmonary arterial pressure, 35±11 to 24±6 mmHg), heart failure (HF) symptoms and signs, exercise intolerance (normalized peak VO2, 64±13 to 72±11%, P

We previously demonstrated the usefulness of temporary inferior vena cava filters (t-IVCFs) to prevent pulmonary thromboembolism in pregnant women with deep venous thrombosis (DVT). However, there is currently no consensus on the indications for intrapartum t-IVCF in pregnant women with DVT. In this study, we re-evaluated the safety and usefulness of t-IVCF inserted in this condition.A retrospective evaluation in a single center was performed of 45 Japanese patients (54 pregnancies) with DVT between 1989 and 2014. Intrapartum t-IVCF insertion was indicated in patients who had or might have had extensive DVT located in iliofemoral veins and who had floating thrombi in the veins of their lower limbs.Eighteen patients (40%) had thrombophilias. Onset of DVT and delivery occurred at 17 ± 9 weeks and 37 ± 2 weeks of gestation, respectively. Twenty pregnant women underwent placement of an intrapartum t-IVCF. All t-IVCFs were successfully placed in the suprarenal inferior vena cava before delivery. Filter-related complications occurred in two cases (10%). One was an allergic reaction to the lidocaine used at the insertion, and another was dislocation of the t-IVCF to the right atrium. The t-IVCFs were placed for more acute DVT compared with the 34 pregnancies without t-IVCF; the onset of DVT with t-IVCF was significantly later (22 vs 12 weeks; P = .002), and the duration of unfractionated heparin therapy was significantly shorter (16 vs 28 weeks; P.001). There was no case of clinical pulmonary embolism in the perinatal period. Thrombus was detected macroscopically at the removed t-IVCF in 15 cases; however, almost all were minute pieces. In only one case with protein S deficiency and placental abruption was a large thrombus captured in the t-IVCF, which was considered to have prevented a clinically relevant pulmonary embolus.Placement of a t-IVCF appears to be safe for pregnant women. However, intrapartum t-IVCF insertion is considered to be unnecessary for pregnant women with DVT who have received anticoagulation therapy at early onset of gestation and long term before delivery. Patients with thrombophilia and at high risk of hemorrhage may represent a subgroup of women who would benefit from t-IVCF placement, but larger prospective multicenter evaluations are required to establish that fact.

Balloon pulmonary angioplasty (BPA) has been reported to improve haemodynamics and functional capacity, with an acceptable risk, in patients with chronic thromboembolic pulmonary hypertension (CTEPH) who are not candidates for pulmonary endarterectomy. However, right ventricular (RV) function, an important predictor in CTEPH, remains to be elucidated. We aimed to examine the impact of BPA on RV remodelling and dysfunction relative to haemodynamic improvements in patients with inoperable CTEPH. 20 consecutive patients with inoperable CTEPH who underwent BPA with cardiovascular magnetic resonance before and after BPA were retrospectively studied. BPA led to significant amelioration of the mean pulmonary arterial pressure, cardiac index and pulmonary vascular resistance (PVR), without death or major complications. Furthermore, BPA significantly ameliorated right-sided heart failure symptoms and signs, and exercise capacity. Cardiovascular magnetic resonance revealed a marked improvement in RV end-diastolic and end-systolic volume index, with concomitant improvements in RV ejection fraction, mass and interventricular septal bowing after BPA. Changes in RV volumes strongly correlated with changes in cardiac index and PVR. BPA induced RV reverse remodelling and improved systolic dysfunction safely by ameliorating haemodynamics in patients with inoperable CTEPH. Evaluating RV function with cardiovascular magnetic resonance may be effective for noninvasively monitoring BPA efficacy.

Pulmonary endarterectomy (PEA) is the standard therapy for chronic thromboembolic pulmonary hypertension (CTEPH). Balloon pulmonary angioplasty (BPA) is an alternative therapy for such patients. Here we report the case of a 60-year-old woman who presented with severe CTEPH resulting in low cardiac output and liver failure. Her clinical status rapidly deteriorated after she developed a respiratory infection that was refractory to antibiotic treatment. PEA was risky because of her unstable hemodynamics, uncontrolled infection, and liver failure with jaundice. We thus performed rescue BPA. After 3 BPA procedures, her cardiac symptoms improved from World Health Organization functional class IV to II, and her jaundice resolved. The day after her final BPA procedure, her hemodynamics dramatically improved, and she continued to show improvement 3 months later. We thus suggest that BPA is a good treatment option in CTEPH patients with rapidly deteriorating heart failure and uncontrolled comorbidities.

The heterozygous loss of function mutations in the Type II bone morphogenetic protein receptor (BMPR-II), a member of the transforming growth factor (TGF-β) receptor family, underlies the majority of familial cases of pulmonary arterial hypertension (PAH). The TGF-β1 pathway is activated in PAH, and inhibitors of TGF-β1 signaling prevent the development and progression of PAH in experimental models. However, the effects of currently used therapies on the TGF-β pathway remain unknown. Prostacyclin analogs comprise the first line of treatment for clinical PAH. We hypothesized that these agents effectively decrease the activity of the TGF-β1 pathway. Beraprost sodium (BPS), a prostacyclin analog, selectively inhibits proliferation in a dose-dependent manner in murine primary pulmonary arterial smooth muscle cells (PASMCs) harboring a pathogenic BMPR2 nonsense mutation in both the presence and absence of TGF-β1 stimulation. Our study demonstrates that this agent inhibits TGF-β1-induced SMAD-dependent and SMAD-independent signaling via a protein kinase A-dependent pathway by reducing the phosphorylation of SMADs 2 and 3 and p38 mitogen-activated protein kinase proteins. Finally, in a monocrotaline-induced rat model of PAH, which is associated with increased TGF-β signaling, this study confirms that treprostinil, a stable prostacyclin analog, inhibits the TGF-β pathway by reducing SMAD3 phosphorylation. Taken together, these data suggest that prostacyclin analogs inhibit dysregulated TGF-β signaling in vitro and in vivo, and reduce BMPR-II-mediated proliferation defects in mutant mice PASMCs.

Heterozygous germline mutations of BMPR2 contribute to familial clustering of pulmonary arterial hypertension (PAH). To further explore the genetic basis of PAH in isolated cases, we undertook a candidate gene analysis to identify potentially deleterious variation. Members of the bone morphogenetic protein (BMP) pathway, namely SMAD1, SMAD4, SMAD5, and SMAD9, were screened by direct sequencing for gene defects. Four variants were identified in SMADs 1, 4, and 9 among a cohort of 324 PAH cases, each not detected in a substantial control population. Of three amino acid substitutions identified, two demonstrated reduced signaling activity in vitro. A putative splice site mutation in SMAD4 resulted in moderate transcript loss due to compromised splicing efficiency. These results demonstrate the role of BMPR2 mutation in the pathogenesis of PAH and indicate that variation within the SMAD family represents an infrequent cause of the disease.

It had been reported that BPA significantly improved pulmonary artery hypertension, New York Heart Association (NYHA) class and 6-minute walk distances (6MWD), in patients whose mean pulmonary arterial pressure (mPAP) >30mmHg. However, CTEPH patients with mPAP ≤30mmHg still have the symptom such