Background Balloon pulmonary angioplasty (BPA) techniques have been refined and increasingly adopted for chronic thromboembolic pulmonary hypertension. Objectives This study aimed to evaluate the temporal trends in BPA safety, with a focus on outcomes in older patients. Methods Using the Japanese Cardiovascular Disease All-Case Registry (2013-2022), we retrospectively analyzed 14,429 BPA procedures performed on 3,700 patients (median age, 68 years). The study period was divided into early (2013-2017) and late (2018-2022) periods. Patient characteristics and major complication rates were evaluated for each period. Complications were defined as a composite of major adverse events occurring within 30 days: death, mechanical ventilation, extracorporeal membrane oxygenation, continuous hemodiafiltration, transfusion, cardiac tamponade, or surgery. Results Patients treated in the late period were older (P < 0.001). The complication rate decreased from 7.8% in the early period to 4.2% in the late period (P < 0.001). In multivariable analysis, the adjusted OR of complications was lower in the late period (OR: 0.411; 95% CI: 0.247-0.675). The adjusted complication risk decreased across all age categories in the late period. An age-dependent increase in the adjusted complication risk was observed across all periods (trend P = 0.002), significant in the early (trend P = 0.015) but not in the late (trend P = 0.085) period. Conclusions BPA safety has improved over time. Despite higher complication risks in older patients, the narrowing gap with younger patients in recent years suggests that BPA is a safe and feasible option for this population.

BACKGROUND:Acute right heart failure (RHF) is life threatening in patients with pulmonary hypertension (PH). This study investigated the efficacy and safety of inhaled nitric oxide (iNO; INOflo®for inhalation 800 ppm), a rapid pulmonary vasodilator, in patients with acute severe RHF due to PH. METHODS AND RESULTS:In this Phase 2 randomized controlled trial, 30 patients with acute severe RHF due to PH (pulmonary arterial hypertension or chronic thromboembolic PH) were randomized 1 : 1 to either an iNO or control group (which did not receive iNO). The primary endpoint was the change in pulmonary vascular resistance (PVR) from baseline to 30 min after either iNO initiation or patient registration and assignment (control group), which differed significantly between the iNO and control groups (mean [±SD] -2.41±2.47 vs. 0.8±1.03 Wood units, respectively; between group difference -3.21 [95% confidence interval -4.633, -1.785] Wood units). Serum B-type natriuretic peptide (BNP) levels and inferior vena cava diameter (secondary endpoints) decreased significantly in the iNO group over the 7-day study period. No serious adverse events, including methemoglobinemia, were observed. CONCLUSIONS:iNO significantly reduced PVR in patients with acute severe RHF due to PH, without serious adverse events. Serum BNP levels and inferior vena cava diameter improved in the iNO group. These findings suggest that iNO is a promising acute treatment option for RHF due to PH.

Pulmonary arterial hypertension (PAH) complicates a subset of patients with atrial septal defects (ASD). Although patients with ASD-PAH and high pulmonary vascular resistance (PVR) generally do not benefit, those who demonstrate a favorable response to PAH-specific therapy, particularly a PVR of < 5 Wood units (WU) post-treatment, may be considered for shunt closure. We aimed to examine the hemodynamic characteristics of patients with severe ASD-PAH who achieved a PVR of < 5 WU with PAH-specific therapy. This retrospective study evaluated 15 patients with severe ASD-PAH (PVR ≥ 5.0 WU) who underwent PAH-specific therapy. The effects of PAH-specific therapy and acute vasoreactivity testing (AVT) were examined. Patients who achieved PVR < 5 WU post-therapy were classified into the low-PVR group, and others into the high-PVR group. The PVR significantly decreased from 10.7 ± 5.5 to 7.0 ± 5.2 WU after oral PAH-specific therapy (p < 0.05). The maximum baseline PVR in the low-PVR group (n = 7, 47

Background: Acute right heart failure (RHF) is a syndrome characterized by sudden right ventricular dysfunction leading to systemic hypoperfusion, which carries a poor prognosis, particularly in patients with pulmonary hypertension (PH). Early reduction of pulmonary vascular resistance (PVR) is crucial for improving RHF and reducing acute mortality. Compared with pulmonary vasodilators approved for pulmonary arterial hypertension (PAH) and chronic thromboembolic PH (CTEPH), inhaled nitric oxide (iNO) therapy has the advantages of being fast acting, an excellent selective pulmonary vasodilation, and has less effect on systemic blood pressure. Methods and Results: We describe a phase II, investigator-initiated, randomized, open-label trial (Japan Registry of Clinical Trials ]RCT2051220042) to evaluate the efficacy and safety of iNO therapy (INOflo (R) for inhalation 800 ppm), as an acute-phase treatment for severe RHF associated with PAH or CTEPH over a 1-week course. Thirty patients will be enrolled and randomized to receive the study drug, or not, in addition to conventional therapy. The primary endpoint is the change in PVR from baseline to 30 min after the start of inhalation, measured using right heart catheterization. Secondary endpoints include changes in hemodynamic parameters, arterial blood tests, and echocardiography findings, and the safety of iNO therapy, assessed through blood methemoglobin concentration, blood pressure, and adverse events. Conclusions: iNO therapy is expected to play a significant role in rapidly improving acute severe RHF associated with PH.

Manual aspiration thrombectomy (MAT) is a catheter intervention for cases with a high risk of bleeding. It is a rapid, simple, inexpensive, and single-session intervention for patients with proximal deep vein thrombosis (DVT). We evaluated the long-term outcome of MAT for patients with proximal DVT. All consecutive patients with acute proximal DVT treated at our center from April 2012 to December 2022 were retrospectively screened. Twenty-one patients who underwent MAT were enrolled. We evaluated the incidence and clinical characteristics of post-thrombotic syndrome (PTS) post-MAT in the chronic phase. The venous clot burden extent was assessed using the venographic segment (VS) score during catheter intervention. We evaluated the pre- and post-treatment total VS score. PTS was evaluated by PTS onset at any time between 6 and 24 months. We compared the clinical characteristics of patients with and without PTS (PTS and non-PTS groups, respectively). PTS onset at any time between 6 and 24 months post-MAT was 33

BACKGROUND:Balloon pulmonary angioplasty (BPA) improves haemodynamics in patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH). Previous studies on BPA have set the treatment objective to achieve a mean pulmonary arterial pressure (mPAP) of <30 mm Hg. However, the clinical impact of mPAP after BPA remains unclear. This study aimed to stratify patients according to their mPAP after BPA and evaluate its association with clinical status and long-term outcomes. METHODS:We retrospectively reviewed 304 patients with inoperable CTEPH (median age, 72 (61 to 79) years) who underwent BPA and follow-up right heart catheterisation. Patients were categorised by mPAP after BPA: ≤20, >20-<30 and ≥30 mm Hg groups. RESULTS:The WHO functional classification, 6 min walk distance and right ventricular ejection fraction were significantly better in the group with a lower mPAP (trend test p=0.007, p<0.001 and p=0.002, respectively). Additionally, the proportions of patients who required pulmonary vasodilators or oxygen therapy were significantly lower in the group with a lower mPAP (trend test p<0.001 and p<0.001, respectively). Across all multivariable models, the mPAP ≥30 mm Hg group had a significantly poorer prognosis compared with the mPAP ≤20 mm Hg group. In contrast, no significant difference was observed between the mPAP ≤20 mm Hg and >20-<30 mm Hg groups. CONCLUSIONS:In patients with CTEPH after BPA, an mPAP of <30 mm Hg was associated with a favourable prognosis, and patients with an mPAP of ≤20 mm Hg presented with better symptoms, exercise capacity, right ventricular function and more withdrawal from oxygen therapy and pulmonary vasodilators. The BPA treatment goal may require individual adaptation.

BACKGROUND:Treatment options for patients with chronic thromboembolic hypertension (CTEPH) have increased over the past decade. However, it is unknown whether the outcomes of patients with CTEPH have changed as well. METHODS:This retrospective study analysed the data of 834 patients with CTEPH, categorised into early (April 1980-December 1999), middle (January 2000-September 2010) and current (October 2010-December 2023) eras. The primary end-point was all-cause mortality. Multivariable Cox proportional hazards models were used to assess changes in all-cause mortality after adjusting for confounding variables. RESULTS:95, 210 and 529 patients were from the early, middle and current eras, respectively. The proportion of patients who did not receive CTEPH therapy decreased from 65% in the early era to 36% and 3% in the middle and current eras, respectively. Meanwhile, the adoption of multimodal treatment increased from 0% to 58% over time. The Kaplan-Meier analysis revealed significant improvements in overall survival (log-rank p<0.001). The 5-year survival rates improved from 68% in the early era to 85% and 93% in the middle and current eras, respectively. The adjusted hazard ratios for mortality were 0.291 (95% CI 0.154-0.550; p<0.001) for the early versus middle era, 0.447 (95% CI 0.249-0.804; p=0.007) for the middle versus current era and 0.130 (95% CI 0.067-0.254; p<0.001) for the early versus current era. CONCLUSION:The long-term prognosis of patients with CTEPH has significantly improved in recent decades.

Background: Despite the development of effective pulmonary vasodilators, the prognosis for patients with pulmonary hypertension (PH) remains poor, particularly in medication-refractory patients. Catheter-based pulmonary artery denervation (PADN) is an emerging therapeutic strategy targeting the sympathetic nervous system in various types of PH. However, data on its safety and efficacy in refractory patients with PH who truly require non-pharmacotherapy are lacking. Here, we describe a phase II, investigator- initiated, open-label, single-arm trial (Japan Registry of Clinical Trials jRCTs052200017) to evaluate the efficacy and safety of PADN over a 2-year observation period. Methods and Results: Twenty participants will be enrolled and will undergo PADN. The primary endpoint is the time from PADN to the first occurrence of the composite events of death, lung transplantation, and worsening of PH. The safety endpoints are the occurrence of adverse events related to PADN and bradycardia requiring treatment. The exploratory endpoints include right ventricular function evaluated using cardiac magnetic resonance imaging and Short Form-36 score. Conclusions: The findings of this study will lead to the adoption of PADN for patients with limited treatment options.

A subset of peripheral pulmonary artery stenosis (PPS) is associated with ring finger protein 213 (R1VF213) p.Arg 4810Lys variant and may show intimal/medial hyperplasia with abnormal waving of the internal elastic lamina. Although stent deployment and balloon angioplasty are valuable treatment options for PPS, the specific impact of endovascular treatment on pulmonary vascular morphology remains unclear. In this case report, we present the pathologic findings after endovascular therapy for PPS in a patient harbouring a homozygous R1VF213 p.Arg4810Lys variant.

Pulmonary endarterectomy (PEA) is the gold standard treatment for chronic thromboembolic pulmonary hypertension (CTEPH). While balloon pulmonary angioplasty (BPA) is an emerging treatment for distal CTEPH, a standard therapeutic strategy for CTEPH with unilateral central lesions has yet to be established. Herein, we describe the successful treatment of a patient with CTEPH who underwent BPA for left distal lesions, followed by PEA for unilateral right central lesions, without serious complications. BPA before PEA may reduce perioperative complications by improving hemodynamics and contribute to a better clinical course by shortening deep hypothermic circulatory arrest time through reduction of the PEA treatment area. Depending on the anatomical characteristics of the lesions, this combination therapy should be discussed by a multidisciplinary CTEPH team.

We present the case of a patient who developed severe pre-capillary pulmonary hypertension 7 years after heart transplantation. The transplantation was performed due to the dilated phase of hypertrophic cardiomyopathy with combined post- and pre-capillary pulmonary hypertension (CpcPH), which had initially improved. This case highlights the potential underlying factors contributing to pulmonary arterial hypertension in patients with CpcPH and the importance of careful long-term follow-up after heart transplantation.

Background The heterozygous ring finger protein 213 (RNF213) p.Arg4810Lys variant has been identified in patients with chronic thromboembolic pulmonary hypertension (CTEPH). This study aimed to clarify the influence of the RNF213 p.Arg4810Lys variant on the response to balloon pulmonary angioplasty (BPA) in patients with CTEPH. Methods We retrospectively analyzed 93 patients with CTEPH who underwent BPA by analyzing the RNF213 p.Arg4810Lys variant. Clinical parameters and hemodynamics following BPA were compared between RNF213 p.Arg4810Lys variant carriers and noncarriers, along with BPA‐related complications. Results Among 93 patients, 7 (8%) were heterozygous RNF213 p.Arg4810Lys variant carriers and 86 (92%) were noncarriers. Both groups showed significant improvements in mean pulmonary artery pressure and pulmonary vascular resistance following BPA. However, the 6‐minute walk distance, symptoms, cardiac index, and right ventricular function did not significantly improve in heterozygous RNF213 variant carriers, whereas noncarriers showed notable improvements. Group differences in mean change from baseline to follow‐up were significant in cardiac index (0.4 L/min per m2 [95% CI, 0.1–0.8]; P=0.019), 6‐minute walk distance (70 m [95% CI, 6–135]; P=0.036), and right ventricular ejection fraction (9% [95% CI, 5–12]; P<0.001), all favoring noncarriers. Of the 515 BPA procedures, complications were significantly higher in variant carriers than in noncarriers (25% versus 8%; P<0.001). Multivariate logistic regression analysis indicated a significant association between the RNF213 p.Arg4810Lys variant and BPA complications (adjusted odds ratio, 7.0 [95% CI, 1.1–44.4]; P=0.038). Conclusions Heterozygous RNF213 p.Arg4810Lys variant carriers exhibited a poor response to BPA, suggesting that the RNF213 p.Arg4810Lys variant could be a risk factor for BPA complications.

BACKGROUND:The clinical impact of acute vasoreactivity testing with inhaled nitric oxide (NO testing) in severe pulmonary hypertension associated with lung disease (LD-PH) remains unknown. METHODS:We retrospectively reviewed 48 consecutive patients with severe LD-PH (73 ± 9 years; male: 81%) who underwent NO testing between 2014 and 2022. We conducted an exploratory analysis of the association between the response to NO testing and both the efficacy of pulmonary vasodilators and prognosis. RESULTS:NO testing demonstrated a significant improvement in hemodynamics, with an average reduction of 1.8 wood units in pulmonary vascular resistance (PVR) without a decrease of oxygen saturation. Patients were divided into the vasoreactive and non-vasoreactive groups based on the median PVR response (-15%) to NO testing. The vasoreactive group had a higher proportion of patients who initiated pulmonary vasodilators and had better long-term prognosis than that of the non-vasoreactive group (P = 0.03). Among the 36 patients (75%) who initiated pulmonary vasodilators after NO testing, the vasoreactive group demonstrated a significant improvement in the symptom, brain natriuretic peptide level, and hemodynamics at the first follow-up (median 4 months), whereas the non-vasoreactive group did not. Moreover, a correlation was observed between the change in PVR at NO testing and the change in PVR after initiation of pulmonary vasodilators (r = 0.42, P = 0.02). CONCLUSIONS:The PVR response to NO testing associated with short-term efficacy of pulmonary vasodilators in patients with severe LD-PH. Prospective studies of PVR response to NO testing on the clinical efficacy in large-scale LD-PH cohorts are warranted.

Takayasu arteritis (TAK) is classified as a large vessel vasculitis and often causes vascular stenosis, occlusion, and aneurysm formation. Although the principal treatment for TAK involves suppressing inflammation with glucocorticoids, the emergence of biological disease-modifying antirheumatic drugs has considerably changed the treatment landscape of TAK in recent years. Several biological disease-modifying antirheumatic drugs, such as tocilizumab (TCZ), have shown promising effects on TAK in clinical studies. Cardiologists and cardiovascular surgeons encounter patients receiving these drugs who require catheterization, endovascular treatment, or cardiovascular surgery. However, in patients treated with glucocorticoids and TCZ, there needs to be greater awareness of more complications than usual after surgery, such as delayed wound healing, systemic infection, and surgical site infection. In addition, in patients receiving TCZ, inflammatory markers, such as C-reactive protein, may not increase when complications arise from infection. Unfortunately, there are no guidelines or solid evidence that have clearly defined the optimal perioperative treatment strategy for patients with TAK who require cardiovascular surgery. This article reviews the evidence and our recent experience supporting the perioperative use of TCZ, and proposes a protocol that can reduce complications in patients with TAK undergoing invasive cardiovascular treatment.

Background:Limited data exists on upfront combination therapy for portopulmonary hypertension. We evaluated the clinical efficacy, long-term outcomes, and safety of upfront combination therapy in patients with portopulmonary hypertension. Methods:We performed a retrospective, single-center cohort study involving a final analysis of 33 consecutive patients diagnosed with portopulmonary hypertension who were taking pulmonary arterial hypertension-specific medication. We compared hemodynamic parameters, risk profiles, composite clinical worsening events, and safety between monotherapy (n = 23) and upfront combination therapy (n = 10). Results:Twenty-seven patients (82 %) were classified into the Child-Pugh A stage. The change ratios of pulmonary vascular resistance (-32 % vs. -57 %, P = 0.006) were significantly better with upfront combination therapy. Upfront combination therapy also showed significant improvement in risk profiles. Kaplan-Meier analysis showed that the composite event-free rate was significantly lower in patients who received upfront combination therapy than in those who received monotherapy (P = 0.016), although no statistical differences were observed in all-cause death. In the univariate Cox proportional hazards analysis, upfront combination therapy was a factor for decreasing composite clinical worsening outcomes (hazard ratio 0.190, 95 % confidence interval 0.042-0.854; P = 0.030). No significant hepatic impairments were observed over 2 years of follow-up in the upfront combination group. Conclusions:In patients with portopulmonary hypertension, upfront combination therapy significantly improved symptoms and short-term hemodynamics, and reduced long-term clinical worsening events without serious adverse effects. This study's findings suggest that patients with portopulmonary hypertension presenting with mild hepatic impairment benefit from upfront combination therapy.

Balloon pulmonary angioplasty (BPA) is beneficial for patients with chronic thromboembolic pulmonary disease (CTEPD) with pulmonary hypertension (PH). However, the clinical benefit of BPA for the patients with CTEPD without PH remains unknown. In this study, we aimed to evaluate the efficacy, safety, and long-term outcomes of BPA in patients with CTEPD without PH. We retrospectively analyzed the data from 84 CTEPD patients with mean pulmonary artery pressure (mPAP) < 25 mmHg and 39 CTEPD patients with mPAP ≤ 20 mmHg (without PH). Among the 39 patients with CTEPD without PH, 14 underwent BPA (BPA-treated group), and the remaining 25 received no treatment (untreated group). In the patients with CTEPD without PH, BPA led to improvements in symptoms, pulmonary vascular resistance (3.6 ± 1.6 to 2.6 ± 1.1 Wood units, p < 0.001), peak oxygen consumption (16.1 ± 4.0 to 18.8 ± 4.3 mL/kg/min, p = 0.033), minute ventilation versus carbon dioxide production slope (41.4 ± 12.2 to 35.1 ± 6.7, p = 0.026), and mPAP/cardiac output slope (7.0 ± 2.6 to 4.4 ± 2.0 mmHg/L/min, p = 0.004) and facilitated the discontinuation of home oxygenation therapy, with no serious complications. Kaplan-Meier analysis showed no significant difference in all-cause mortality between the untreated and BPA-treated groups. BPA may be a safe treatment option for the patients with CTEPD without PH that can alleviate symptoms, improve exercise capacity, and facilitate weaning from home oxygen therapy. Further prospective randomized trials are needed to confirm these findings.

Background Ring finger protein 213 ( RNF213 ) p.Arg4810Lys is a susceptibility gene for moyamoya disease, peripheral pulmonary artery stenosis (PPS), and other vascular diseases and thrombosis. We investigated the prevalence and clinical characteristics of RNF213 variant carriers diagnosed with chronic thromboembolic pulmonary hypertension (CTEPH). Methods and Results We retrospectively analyzed the prevalence of the RNF213 p.Arg4810Lys variant in patients diagnosed with CTEPH (n=112) and PPS (n=10). Clinical and angiographic characteristics were evaluated between RNF213 variant carriers diagnosed with CTEPH and noncarriers with CTEPH and homozygous variant carriers with PPS. Eight heterozygous RNF213 p.Arg4810Lys variant carriers (7.1%) were identified among patients diagnosed with CTEPH, while 5 patients with PPS (50%) carried the homozygous variant. The clinical characteristics of heterozygous variant carriers with CTEPH were not remarkably different from those of noncarriers with CTEPH. All heterozygous variant carriers with CTEPH showed webs/bands lesions at the segmental/subsegmental level, with 75% showing distal tortuous vessels. None of the heterozygous variant carriers with CTEPH exhibited the string‐of‐beads pattern or elongated stenosis. Homozygous variant carriers with PPS showed the string‐of‐beads pattern, elongated stenosis, and distal tortuous vessels without webs/bands lesions. Conclusions A subset of patients diagnosed with CTEPH (7.1%) carried the heterozygous RNF213 p.Arg4810Lys variant. Clinical and angiographic characteristics of heterozygous variant carriers were not remarkably different from those of noncarriers of CTEPH. However, both heterozygous variant carriers with CTEPH and homozygous variant carriers with PPS showed tortuous vessels on angiography.