Takeshi Ogo

Extract Beyond the established treatment goal of low-risk status in pulmonary arterial hypertension (PAH) [1], haemodynamic thresholds for complete and partial remission have recently been proposed as deeper treatment targets [2, 3]. Upfront triple therapy including intravenous (IV) epoprostenol has yielded marked haemodynamic improvement [4] and should be considered in treatment-naïve patients at high or intermediate risk with severe haemodynamic impairment [1]. These haemodynamic effects suggest that this may represent a strategy for achieving haemodynamic remission.

Pulmonary arterial hypertension (PAH) harboring the heterozygous ring finger protein 213 (RNF213) p.Arg4810Lys variant responds poorly to PAH treatment and has a poor prognosis. Here, we present a case of severe PAH and moyamoya disease (MMD) harboring a heterozygous RNF213 p.Arg4810Lys variant that responded well to PAH monotherapy. A 23‐year‐old woman with cerebral infarction due to MMD was referred to our center for MMD bypass surgery and treatment of severe PAH. Genetic analysis revealed a heterozygous RNF213 p.Arg4810Lys variant. We initiated PAH‐targeted therapy before MMD bypass surgery, as bypass surgery was considered high‐risk in the presence of severe PAH. Despite a positive response to acute vasoreactivity testing with nitric oxide (NO) inhalation, calcium channel blockers were avoided due to the risk of hypotension‐induced cerebral ischemia. We initiated endothelin receptor antagonist (macitentan, 10 mg/day) monotherapy because upfront combination therapy may also cause hypotension. Endothelin receptor antagonist monotherapy improved symptoms and pulmonary hemodynamics, reducing vascular resistance from 11.4 to 7.1 Wood Units after 1 month. Bilateral cerebral bypass surgery was performed after hemodynamic improvement. The clinical spectrum of RNF213‐associated PAH may be broader than previously reported. This case highlights the importance of personalized medicine that considers patient conditions and comorbidities when selecting treatment options for patients with PAH harboring the RNF213 p.Arg4810Lys variant.

Background: Methamphetamine-associated pulmonary arterial hypertension (Meth-PAH) is increasingly recognized in Western countries, but Japanese data remain limited.Methods and Results: Of 363 patients with PAH, we identified 5 patients with Meth-PAH (1.4%); 4 were women, with a mean age of 37.6±7.2 years. Patients receiving PAH-specific therapy showed favorable hemodynamic responses, although 40% of patients experienced treatment discontinuation and methamphetamine reuse.Conclusions: In this case series of 5 Japanese patients with Meth-PAH, there was a high rate of treatment discontinuation and methamphetamine reuse, which suggests possible underdiagnosis of Meth-PAH and barriers to sustained care in Japan.

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.

Connective tissue disease‐associated pulmonary arterial hypertension (CTD‐PAH) has a poorer prognosis than idiopathic PAH, potentially attributable to pulmonary veno‐occlusive disease (PVOD)‐like involvement. The diffusing capacity for carbon monoxide (DLco) may reflect small pulmonary venous obliteration. Whether severely reduced DLco reflects the severity of venous remodelling in CTD‐PAH remains incompletely characterised, particularly with quantitative morphometric assessment. Thus, we evaluated the association of reduced DLco with clinical characteristics and venous vasculopathy in patients with CTD‐PAH. We retrospectively reviewed patients with CTD‐PAH without interstitial pneumonia. Patients were categorised into two groups based on %DLco (< 45%: severely reduced DLco or ≥ 45%: non‐severely reduced DLco). Clinical characteristics and survival rates were compared. Histopathological characteristics of the pulmonary vasculature were analysed in eight autopsy cases. Of the 86 patients (mean age, 49.2 ± 16.8 years), 25 (29.1%) were classified into the severely reduced DLco group. They were older, showed a higher prevalence of systemic sclerosis, and exhibited lower arterial oxygen saturation and mean pulmonary arterial pressure compared with the other group. The severely reduced DLco group had a worse survival in unadjusted analysis ( p = 0.048). Histopathological analysis revealed that the severity of small pulmonary venous stenosis was inversely correlated with %DLco ( R ² = 0.537, p = 0.039; 95% CI, −0.69 to −0.03). Patients with CTD‐PAH and a severely reduced DLco demonstrated a poorer prognosis than those without. Reduced DLco was associated with the severity of small pulmonary venous stenosis, consistent with a PVOD‐like venous remodelling spectrum in CTD‐PAH. DLco may serve as a clinically accessible marker of venous involvement within the PVOD‐like spectrum of CTD‐PAH.

BACKGROUND: Over the past decade, balloon pulmonary angioplasty (BPA) for chronic thromboembolic pulmonary hypertension has shown improved outcomes with procedural refinement in expert hospitals with high procedural volume. Whether the outcomes of BPA are reproducible in hospitals with limited procedural volumes remains unknown. The Japan BPA registry was designed to assess the outcomes of contemporary BPA from a nationwide perspective, including hospitals with low treatment volume. METHODS: This prospective multicenter registry enrolled 1202 consecutive patients with chronic thromboembolic pulmonary hypertension who underwent BPA at 44 hospitals between April 2018 and March 2023. We assessed the efficacy and safety of BPA and survival rates, comparing high- and low-volume hospitals based on the BPA center definition (≥50 procedures per year) from the seventh World Symposium on Pulmonary Hypertension. RESULTS: A total of 5207 procedures were performed. Thirty-five low-volume hospitals (79.5%) performed 40.8% of all BPA procedures. BPA significantly improved symptoms, clinical parameters, and hemodynamics (55.6% reduction in pulmonary vascular resistance), with 0.2% periprocedural BPA-related mortality. Severe lung injury (0.3%), balloon overdilatation (0.67%), and mechanical ventilation (0.3%) were less common in high-volume hospitals than in low-volume hospitals (1.3%, 1.7%, and 1.5%, respectively; P <0.001). In the Kaplan-Meier analysis, the survival rate of all patients at 3 years was 94.7% (95% CI, 92.5%–96.3%). Multivariable Cox regression analysis showed an increased mortality risk with higher right atrial pressure, and high-volume hospitals were associated with a reduced mortality risk. CONCLUSIONS: This nationwide registry demonstrated the outcomes of contemporary BPA in patients with chronic thromboembolic pulmonary hypertension. No significant differences were observed in efficacy and periprocedural mortality between low- and high-volume hospitals. However, the significantly lower rate of severe complications in high-volume hospitals indicates that BPA may be safer in high-volume hospitals.