BackgroundSelexipag, an oral IP prostacyclin receptor agonist, improves outcomes in pulmonary arterial hypertension (PAH); however, real-world hemodynamic data and the relationship between adverse events (AEs) and treatment response are limited.ObjectivesThe aims of this study were to evaluate the efficacy and safety of selexipag in a Japanese cohort and assess whether treatment-emergent adverse events, particularly headache and diarrhea, were associated with subsequent hemodynamic responses.DesignWe conducted a retrospective observational study at the National Cerebral and Cardiovascular Center in Japan.MethodsWe retrospectively analyzed consecutive patients with PAH initiating selexipag at our institution between 2016 and 2022. Baseline and follow-up right heart catheterization, 6-minute walk distance (6MWD), and B-type natriuretic peptide (BNP) were assessed at 26, 52, and 104 weeks. AEs requiring treatment were recorded.ResultsOf the 97 included patients, 94% received dual or triple PAH therapies at baseline. At 52 weeks, selexipag was associated with reductions in pulmonary vascular resistance (-1.36±4.70 Wood units; p=0.036) and mean pulmonary artery pressure (mPAP; -4.27±9.61 mmHg; p=0.001) and an increase in 6MWD (+26.6±53.8 m; p=0.003), without significant changes in cardiac index or BNP. The proportion of patients at low ESC/ERS 3-strata risk increased from 63% to 78% (p=0.017). AEs occurred in 62% of patients, most commonly headache (42%) and diarrhea (29%). Headaches, typically developing during dose escalation, might be associated with a better prognosis through greater mPAP reduction.ConclusionSelexipag initiation improved pulmonary hemodynamics, exercise capacity, and risk profile, without new safety signals. Headache, a common prostacyclin-related AE, may indicate treatment responsiveness and predict therapeutic outcomes. Careful titration to the maximally tolerated dose with vigilant AE management may optimize outcomes.

Although immune checkpoint inhibitors (ICIs) have improved oncological outcomes, they can cause a myriad of inflammatory conditions known as immune-related adverse events (irAEs). Raynaud's phenomenon (RP) is a rare rheumatologic irAE that may arise de novo or present as an exacerbation of preexisting disease. This case series aims to describe ICI-induced RP in patients without a rheumatological diagnosis seen at a large, specialized cancer center. Our case series describes five patients with ICI-induced RP who were evaluated by rheumatology at a cancer center during the past 3 years where their cancers, type of ICIs, diagnostic tests, and treatments are discussed in detail. Among our five patients, one patient had preexisting psoriatic arthritis, and one had preexisting RP. The outcome of our patients' ICI-induced RP varied widely. Although three patients had significant digital ischemia resulting in ulceration requiring epoprostenol infusions, the remaining two patients had mild digital ischemia that were controlled conservatively. However, none of our patients had clinical features to suggest systemic sclerosis (SSc), where RP is often the first symptom. Interestingly, interferon-γ and interleukin-6 were the most frequently elevated cytokines when checked in these patients. This is the first case series, to the authors' knowledge, to describe ICI-induced RP, which may occur without other clinical features of an autoimmune rheumatological disease. The severity of the disease may vary, but it warrants increased awareness and prompt initiation of appropriate treatment.

Pulmonary arterial hypertension (PAH), a progressive disease, is characterized by increased pulmonary vascular resistance (PVR) and leads to right ventricular failure and premature death. PAH therapies aim to reduce PVR; however, these treatments as vasodilators may also result in reduced systemic vascular resistance and mean arterial pressure (MAP), leading to clinical or symptomatic hypotension. Low MAP can limit the administration of optimal dosage of PAH drugs. Midodrine, an oral alpha-1 adrenergic agonist, as a promising intervention, can potentially increase mean MAP and improve tolerance to PAH therapies.

Pulmonary hypertension (PH) is a progressive disorder associated with substantial morbidity and mortality, and its diagnosis may be delayed in older adults with multiple cardiopulmonary comorbidities because symptoms frequently overlap with more common cardiovascular and pulmonary conditions. Combined post- and pre-capillary pulmonary hypertension (CpcPH) is a severe phenotype characterized by pulmonary vascular remodeling superimposed on elevated left-sided filling pressures and is associated with worse outcomes than isolated post-capillary PH. We report the case of a 77-year-old man with chronic hypoxic respiratory failure, heart failure with preserved ejection fraction (HFpEF), chronic atrial fibrillation, coronary artery disease, and obstructive sleep apnea who presented with progressive exertional dyspnea, syncope, and increasing oxygen requirements. His symptoms were initially attributed to HFpEF and coexisting cardiopulmonary conditions. Serial transthoracic echocardiography demonstrated progressive right ventricular enlargement, worsening right ventricular systolic function, interventricular septal flattening, and progressively increasing right ventricular systolic pressure (RVSP) from 46.6 to 87 mmHg. Right heart catheterization confirmed severe combined post- and pre-capillary pulmonary hypertension with a pulmonary capillary wedge pressure of 16 mmHg and pulmonary vascular resistance of 10.7 Wood units. Comprehensive evaluation excluded alternative causes of pre-capillary pulmonary hypertension. Because the severity of pulmonary vascular disease appeared disproportionate to isolated HFpEF-related pulmonary hypertension, the patient underwent multidisciplinary evaluation at a specialized pulmonary hypertension center, where an individualized treatment strategy with intravenous epoprostenol and sildenafil was initiated, resulting in improvement in functional status and oxygen requirements during hospitalization. This case highlights the diagnostic challenges of CpcPH in patients with HFpEF and multiple cardiopulmonary comorbidities. Progressive right ventricular remodeling, syncope, and worsening oxygen requirements should prompt consideration of pulmonary hypertension when clinical deterioration appears disproportionate to the underlying cardiopulmonary disease. Early recognition, serial echocardiographic assessment, timely right heart catheterization, and referral to specialized pulmonary hypertension centers are essential for establishing an accurate diagnosis and guiding individualized management.

Cardiovascular disease risk accelerates in women after the menopausal transition, coinciding with the cessation of endogenous oestrogen production. The accompanying decline in vascular function is considered a key driver of this shift. However, longitudinal studies investigating the impact and time course of changes in cardiovascular and skeletal muscle function during the menopausal transition and in the subsequent years are warranted.

Prostacyclin analogues are effective treatments in pulmonary arterial hypertension (PAH), especially in advanced stages. Treprostinil, a stable prostacyclin analogue, can be administered as subcutaneous and intravenous infusions, oral extended-release tablets and inhalation. Inhalation offers several advantages over other routes of administration, including direct access to the lungs for localized therapy, reduced infection risk, and a painless, convenient mode of delivery. However, small lipophilic molecules like treprostinil are absorbed into the bloodstream within minutes after inhalation, resulting in a short duration of action in the lungs and systemic side effects. To address these limitations, we developed a novel strategy involving a double treprostinil prodrug tailored for pulmonary delivery. The prodrug consists of treprostinil di-esterified at its carboxylic acid with a polyethylene glycol (PEG) chain, and at its C11 hydroxyl group with butyric acid. The prodrug exhibited sustained treprostinil release in bronchoalveolar lavage fluid and serum, supporting its suitability for pulmonary delivery. It was cleaved by initial hydrolysis of the PEG chain, followed by subsequent cleavage of the short-chain fatty acid. Ex vivo studies in isolated pulmonary artery rings showed a delayed and prolonged vasorelaxation effect of the conjugate compared to the free drug. In vivo studies demonstrated significant lung retention, with detectable quantities of the compound remaining in the lungs 24 h after administration, and a markedly reduced peak serum concentration following inhalation. This double-prodrug approach represents a promising strategy for improving PAH treatment by optimizing local, sustained treprostinil delivery while minimizing systemic exposure.

Pulmonary arterial hypertension (PAH) is a progressive illness that may require therapy with parenteral prostacyclin pathway agents (PPA) (epoprostenol and treprostinil). These parenteral PPA's are continuous ambulatory infusions that require a high level of skill and knowledge to maintain safety and effectiveness. Depending on the clinical context, transition to oral prostacyclin receptor agonist therapy (selexipag) is sometimes pursued. To prevent abrupt withdrawal from parenteral PPA's, overlap transitions are typically used. This report describes 35 inpatient, rapid transitions from parenteral PPA's to oral selexipag. Planned hospital admissions for transition were common (n = 27, 77%), and all patients successfully transitioned without a return to parenteral PPA's in the immediate post-transition period. Most patients transitioned due to difficulties with current parenteral PPA therapy (n = 20, 57%), followed by an improved clinical status on parenteral PPA therapy (n = 8, 23%). The median length of transition was 36 h (IQR 24-48 h) and hospital stay was 3 days (IQR 2-6 days). Following transition, the cohort demonstrated stability in PAH-specific risk scores and functional status. All patients survived to outpatient pulmonary hypertension follow up (median 5.5 weeks, IQR 1.4-9.6 weeks), and the majority were alive at 1-year post-transition (n = 32, 91%). Based on these results, we conclude that transition from parenteral PPA's to selexipag can be done in the inpatient setting safely, quickly, and effectively.

Pulmonary hypertension (PH) is a hemodynamic and pathophysiologic condition associated with increased perioperative morbidity and mortality, particularly in patients undergoing cardiac or high-risk non-cardiac surgery. Inhaled pulmonary vasodilators (iPVs) offer a targeted strategy to reduce pulmonary vascular resistance (PVR) and improve right ventricular (RV) function while minimizing systemic hypotension. Traditional vasodilators such as nitroglycerin and sodium nitroprusside lack pulmonary specificity and can exacerbate systemic hypotension. Inhaled agents including nitric oxide (NO), epoprostenol (iEPO), iloprost, milrinone (iMIL) and levosimendan provide selective pulmonary vasodilation with more favorable hemodynamic profiles. This narrative review summarizes current evidence and clinical considerations for the use of iPVs in the perioperative management of PH and discusses pharmacokinetics, delivery mechanisms, adverse effects, and logistical considerations for these agents. New emerging PH therapies are included based on early clinical trial data as they have the potential to impact perioperative care in the future. Overall, iPVs represent a valuable tool in the perioperative care of patients with PH. Continued research is needed to refine clinical protocols, evaluate emerging agents, and establish outcome-based evidence for their routine use.

Orphan GPCRs of the GPRC5 family regulate macrophage activity and vascular contractility by dimerizing with other GPCRs, but pharmacological modulation of this process has not been explored. We previously identified the dimerization interface of receptor GPRC5B and show here that both its mutation and inhibition by a decoy peptide disturbed the interaction with the prostaglandin E2 receptor EP2 in macrophages, resulting in reduced EP2 signaling, enhanced migration and phagocytosis, and protection from bacterial peritonitis in mice. Furthermore, we show that a similar interface exists in related receptor GPRC5C, and, the same as in GPRC5B, mutation or inhibition by decoy peptide improved host defense. Through a virtual docking screen, we identified a small molecule inhibitor of both GPRC5B and GPRC5C dimerization, K303MP20, and showed that it reduced EP2 signaling, enhanced macrophage activity, and improved host defense in bacterial peritonitis and influenza A infection. Interestingly, K303MP20 not only blocked dimerization between GPRC5B/C and EP2, but also with prostacyclin receptor IP and angiotensin II receptor AT1, resulting in reduced AT1-dependent contraction and enhanced IP-dependent relaxation in human and murine smooth muscle cells. In vivo, K303MP20 did not affect basal blood pressure, but protected mice from angiotensin II-induced hypertension. Taken together, inhibition of orphan GPCR dimerization by small molecules is feasible and improves infection control and arterial hypertension.