Evaluating the Impact of Pulmonary Arterial Hypertension Therapies on Pericardial Effusion and Patient Survival.

Objectives: To evaluate the impact of Pulmonary Arterial Hypertension (PAH) therapies on the incidence of pericardial effusion and its prognostic implications for patient survival. Methods: This retrospective cohort study included 60 patients diagnosed with PAH at a high-volume tertiary care center, treated with intravenous or subcutaneous prostanoids. Data were collected from 2015 to 2019, including echocardiographic assessments, right heart catheterization, World Health Organization functional class evaluations, six-minute walk distance tests, and biomarkers such as brain natriuretic peptide and N-terminal prohormone of brain natriuretic peptide. Follow-up was conducted at least 90 days post-treatment initiation. Results: Pericardial effusion was observed in 31.7% of patients before therapy. Patients with moderate to large effusions had a significantly higher mortality risk (HR = 1.92; 95% CI 1.1-44.78; p =0.0044), while small effusions appeared protective (HR = 0.27; 95% CI 0.15-0.48; p =0.006). Survival rates declined from 89% at one year to 71% at three years post-therapy, with effusion presence correlating with more severe PAH manifestations. Conclusions: Initial pericardial effusion severity is a critical predictor of mortality in PAH patients. Early assessment and stratified management of pericardial effusion are essential for optimizing therapeutic outcomes in PAH management. Future research should explore targeted interventions for managing pericardial effusion to improve patient prognosis.

Association between Postoperative Adjuvant Vasodilator Therapy and In-Hospital Mortality for Non-Occlusive Mesenteric Ischemia: A Nationwide Observational Study.

BACKGROUND: Although several clinical guidelines recommend vasodilator therapy for non-occlusive mesenteric ischemia (NOMI) and immediate surgery when bowel necrosis is suspected, these recommendations are based on limited evidence. METHODS: In this retrospective nationwide observational study, we used information from the Japanese Diagnosis Procedure Combination inpatient database from July 2010 to March 2018 to identify patients with NOMI who underwent abdominal surgeries on the day of admission. We compared patients who received postoperative vasodilator therapy (vasodilator group) with those who did not (control group). Vasodilator therapy was defined as venous and/or arterial administration of papaverine and/or prostaglandin E1 within 2 days of admission. The primary outcome was in-hospital mortality. Secondary outcomes included the prevalence of additional abdominal surgery performed ≥3 days after admission and short bowel syndrome. RESULTS: We identified 928 eligible patients (149 in the vasodilator group and 779 in the control group). One-to-four propensity score matching yielded 149 and 596 patients for the vasodilator and control groups, respectively. There was no significant difference in in-hospital mortality between the groups (control vs. vasodilator, 27.5% vs. 30.9%; risk difference, 3.4%; 95% confidence interval, -4.9 to 11.6; p=0.42) and no significant difference in the prevalences of abdominal surgery, bowel resection ≥3 days after admission, and short bowel syndrome. CONCLUSIONS: Postoperative vasodilator use was not significantly associated with a reduction in in-hospital mortality or additional abdominal surgery performed ≥3 days after admission in surgically treated NOMI patients.

Efficacy of endovascular therapy for cerebral vasospasm following aneurysmal subarachnoid hemorrhage: a systematic review and meta-analysis.

Background: Cerebral vasospasm (CV) is a common complication of aneurysmal subarachnoid hemorrhage (aSAH), leading to increased morbidity and mortality rates. Endovascular therapy, particularly intra-arterial vasodilator infusion (IAVI), has emerged as a potential alternative treatment for CV. Methods: A systematic review and meta-analysis were conducted to compare the efficacy of endovascular therapy with standard treatment in patients with CV following aSAH. The primary outcomes assessed were in-hospital mortality, discharge favorable outcome, and follow-up favorable outcome. Secondary outcomes included major infarction on CT, ICU stay duration, and total hospital stay. Results: Regarding our primary outcomes of interest, patients undergoing intervention exhibited a significantly lower in-hospital mortality compared to the standard treatment group, with the intervention group having only half the mortality risk (RR = 0.49, 95% CI [0.29, 0.83], p = 0.008). However, there were no significant differences between the two groups in terms of discharge favorable outcome (RR = 0.99, 95% CI [0.68, 1.45], p = 0.963) and follow-up favorable outcome (RR = 1.09, 95% CI [0.86, 1.39], p = 0.485). Additionally, there was no significant difference in major infarction rates (RR = 0.79, 95% CI [0.34, 1.84], p = 0.588). It is important to note that patients undergoing endovascular treatment experienced longer stays in the ICU (MD = 6.07, 95% CI [1.03, 11.12], p = 0.018) and extended hospitalization (MD = 5.6, 95% CI [3.63, 7.56], p < 0.001). Subgroup analyses based on the mode of endovascular treatment further supported the benefits of IAVI in lowering in-hospital mortality (RR = 0.5, 95% CI [0.27, 0.91], p = 0.023). Conclusion: Endovascular therapy, particularly IAVI, holds promising potential in reducing in-hospital mortality for patients with CV following aSAH. However, it did not show significant improvement in long-term prognosis and functional recovery. Further research with larger sample sizes and randomized controlled trials is necessary to validate these findings and optimize the treatment strategy for cerebral vasospasm in aSAH patients. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/, identifier: CRD42023451741.

Increased Responsiveness of Stored Platelets after Short-Term Refrigeration.

Introduction: Refrigeration of platelets is considered to provide advantages in therapy of acute hemorrhage due to increased platelet responsiveness. The alleviation of inhibitory signaling caused by cold temperature (CT) has been identified as an important mechanism contributing to enhanced platelet reactivity, detectable in freshly prepared platelets within 1 h of cold storage. The aim of this study was to confirm the effects of short-term refrigeration in platelets from apheresis-derived platelet concentrates (APC). Methods: APC were stored under standardized conditions for 1 day or for 2 days at room temperature and then refrigerated for 1 h, followed by sampling of platelets for analysis. Platelet reactivity was measured by aggregation studies using threshold concentrations of different agonists and by detection of fibrinogen binding using flow cytometry. The exploration of inhibitory signaling comprised the detection of VASP phosphorylation using flow cytometry or Western blot and the measurement of cyclic nucleotide levels. Results: Aggregation responses induced with ADP, collagen, or thrombin receptor-activating peptide-6 (TRAP-6) were increased in APC after cold storage for 1 h, associated with elevated TRAP-6-induced fibrinogen binding. VASP phosphorylation levels were decreased after cold exposition, detectable in 1-day- and 2-day-stored APC with flow cytometry, and in 2-day-stored APC with Western blot technique. Induced cGMP levels were lower after storage at CT in APC on day 1 and on day 2, whereas cAMP levels were reduced on 2-day-stored APC. Conclusion: Short-term refrigeration for 1 h is sufficient to induce an attenuation of inhibitory signaling, accompanied with increased aggregation responses in APC stored for up to 2 days. The "on demand" refrigeration of PC may be a reasonable approach for the preparation of platelets with enhanced responsiveness to treat patients with hemorrhage more effectively, which should be further addressed in consecutive studies.

Predictors and prognosis of pulmonary hypertension complicating interstitial lung disease in systemic sclerosis.

OBJECTIVE: To identify those with concurrent pulmonary hypertension (PH) and interstitial lung disease (ILD) in systemic sclerosis (SSc) and determine their disease severity, therapeutic approach, and survival. METHODS: Consecutive SSc patients enrolled in the Australian Scleroderma Cohort Study (ASCS) who were diagnosed on right heart catherisation with pulmonary hypertension were included. Logistic regression was used to determine the associations of ILD with PH hemodynamic parameters and therapeutic approach. Kaplan-Meier survival curves were used to estimate survival. RESULTS: Of 1,883 SSc patients, 164 (8.7%) developed incident PH over a median follow up of 4.3 (1.7-7.9) years. Of these, 43.9% had concurrent ILD at PH diagnosis (PH-ILD) and 56.1% had Group 1 PAH. Extensive ILD was present at PH diagnosis in 40.3%. Despite these distinct PH cohorts, a similar frequency of each PH cohort was treated with vasodilatory therapy at PH diagnosis, regardless of the presence or severity of ILD. The majority (87.5%) of those with extensive ILD and PH received upfront vasodilatory therapy at PH diagnosis with no difference in its tolerability or therapy cessation compared with Group 1 PAH. Although vasodilator therapy was not associated with a survival advantage in those with extensive ILD, its use was associated with an improvement in symptoms, physical function, and quality of life (QoL). CONCLUSION: Despite vasodilator therapy, survival in SSc-PH is poor, with the presence of concurrent ILD associated with worse survival. Although vasodilator therapy commenced at PH diagnosis does not portray an improved survival in PH with extensive ILD, it appears well tolerated and may improve symptoms, physical function, and QoL.

Pulmonary Hypertension in Adult Congenital Heart Disease-Related Heart Failure.

Already a challenging condition to define, adult congenital heart disease (ACHD) -associated heart failure (HF) often incorporates specific anatomies, including intracardiac and extracardiac shunts, which require rigorous diagnostic characterization and heighten the importance of clinicians proactively considering overall hemodynamic impacts of using specific therapies. The presence of elevated pulmonary vascular resistance dramatically increases the complexity of managing patients with ACHD-HF. Total circulatory management in patients with ACHD-HF requires input from multidisciplinary care teams and thoughtful and careful utilization of medical, interventional, and surgical approaches.

How to assess nonresponsiveness to vasodilator stress.

Myocardial perfusion imaging (MPI) is a powerful tool for the functional assessment of ischemia in patients with suspected or known coronary artery disease (CAD). Given that the diagnostic accuracy and prognostic value of MPI and post-test management are highly dependent on achieving an adequate stress vasodilatory response, it is critical to identify those who may not have adequately responded to vasodilator pharmacological stress agents such as adenosine, dipyridamole, and regadenoson. Caffeine, a potent inhibitor of the adenosine receptor, is a compound that can affect vasodilatory hemodynamics, result in false negative studies, and potentially alter management in cases of inaccurate test results. Vasodilator non-responsiveness can be suspected by examining hemodynamics, quantitative positron emission tomography (PET) metrics such as myocardial flow reserve (MFR), and splenic response to stress. Quantitative MFR values of 1-1.2 should raise suspicion for nonresponsiveness in the setting of normal perfusion, along with the absence of a splenic switch off. Newer metrics, such as splenic response ratio, can be used to aid in the identification of potential nonresponders to pharmacologic vasodilators.

Randomized Controlled Trials of Pulmonary Vasodilator Therapy Adjunctive to Inhaled Nitric Oxide for Persistent Pulmonary Hypertension of the Newborn: A Systematic Review.

Inhaled nitric oxide (iNO) is a pulmonary vasodilator considered standard of care to treat persistent pulmonary hypertension of the newborn. However, not all infants respond to iNO. The authors performed a systematic review to examine methodology, outcomes, and challenges of randomized controlled trials testing pulmonary vasodilator medications adjunctive to iNO. The 5 trials identified showed heterogeneity in eligibility criteria and outcomes assessed. No trial achieved recruitment goals, limiting conclusions regarding efficacy, safety, and pharmacology. Trial design consensus and alternative methodologic strategies such as deferred consent, real-world controls, nonrandomized database assessments, and Bayesian statistical approaches are needed.

Effect of amlodipine on the circulating renin-angiotensin-aldosterone system in healthy cats.

BACKGROUND: Systemic hypertension (SH) is a common cardiovascular disease in older cats that is treated primarily with the calcium channel blocker amlodipine besylate (AML). The systemic effect of AML on the classical and alterative arms of the renin-angiotensin-aldosterone system (RAAS) in cats is incompletely characterized. HYPOTHESIS/OBJECTIVES: To determine the effect of AML compared to placebo on circulating RAAS biomarkers in healthy cats using RAAS fingerprinting. ANIMALS: Twenty healthy client-owned cats. METHODS: Cats were administered amlodipine besylate (0.625 mg in toto) or placebo by mouth once daily for 14 days in a crossover design with a 4-week washout period. Plasma AML concentrations and RAAS biomarker concentrations were measured at multiple timepoints after the final dose in each treatment period. Time-weighted averages for RAAS biomarkers over 24 hours after dosing were compared between treatment groups using Wilcoxon rank-sum testing. RESULTS: Compared to placebo, AML treatment was associated with increases in markers of plasma renin concentration (median 44% increase; interquartile range [IQR] 19%-86%; P = .009), angiotensin I (59% increase; IQR 27-101%; P = .006), angiotensin II (56% increase; IQR 5-70%; P = .023), angiotensin IV (42% increase; -19% to 89%; P = .013); and angiotensin 1-7 (38% increase; IQR 9-118%; P = .015). CONCLUSIONS AND CLINICAL IMPORTANCE: In healthy cats, administration of AML resulted in nonspecific activation of both classical and alternative RAAS pathways.

Treatment of pulmonary arterial hypertension in patients with connective tissue diseases: a systematic review and meta-analysis.

The evidence for the treatment of connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH) mostly depends on subgroup or post hoc analysis of randomized controlled trials (RCTs). Thus, we performed a meta-analysis of RCTs that reported outcomes for CTD-PAH. PubMed and EMBASE were searched for CTD-PAH treatment. The selected outcomes were functional class (FC) change, survival rates, 6-min walk distance (6-MWD), clinical worsening (CW), N-terminal prohormone BNP (NT-proBNP), pulmonary vascular resistance (PVR), mean pulmonary arterial pressure (mPAP), right atrial pressure (RAP), and cardiac index (CI). The meta-analysis was conducted according to the PRISMA guidelines and registered in PROSPERO (CRD42020153560). Twelve RCTs conducted with 1837 patients were included. The diagnoses were systemic sclerosis in 59%, SLE in 20%, and other CTDs in 21%. The pharmacological interventions were epoprostenol, treprostinil, sildenafil, tadalafil, bosentan, macitentan, ambrisentan, riociguat, and selexipag. There was a significant difference between interventions and placebo in FC, 6MWD, CW, PVR, RAP, and CI that favored intervention. Our analysis showed a 39% reduction in the CW risk with PAH treatment. The short-term survival rates and mean serum NT-proBNP changes were similar between the study and control groups. Treatment for CTD-PAH had favorable effects on clinical and hemodynamic outcomes but not on survival and NT-proBNP levels. Different from the previous meta-analyses that focused on 6-MWD, time to clinical worsening, and CW as outcomes, this meta-analysis additionally reports the pooled analysis of change in FC, hemodynamic measurements (RAP, PVR, CI), and NT-proBNP, some of which have prognostic value for PAH.

Short term effect of intravenous treprostinil in term and preterm infants with pulmonary hypertension.

BACKGROUND: Pulmonary hypertension (PH) is a life-threatening condition in newborns. We aimed to assess the clinical and echocardiographic responses of term and preterm infants to treprostinil. METHODS: This retrospective study included newborns diagnosed with PH and treated with treprostinil as additional therapy after inhaled nitric oxide administration in the neonatal intensive care unit of a tertiary center. Term and preterm infants were compared in terms of echocardiographic findings and clinical findings 4 weeks after treprostinil treatment. RESULTS: During the study period, 11 term and 18 preterm infants were diagnosed with PH and received treprostinil. There were no differences in the echocardiographic findings of interventricular septal deviation, direction of shunt, and ratio of estimated pulmonary artery pressure over systolic blood pressure. Congenital diaphragmatic hernia was the most common condition occurring upon PH diagnosis among term infants, while severe bronchopulmonary dysplasia was the most common in preterm infants. Improvements in echocardiographic findings were more pronounced in term infants than in preterm infants (100% vs. 55.6%, P = 0.012). The inhaled nitric oxide dose was gradually tapered for term infants and was lower than that for preterm infants at 1, 2, and 3 weeks after treprostinil. CONCLUSION: Intravenous treprostinil could be an adjuvant therapy option for term and preterm infants with PH, especially for those who cannot receive oral medication. The efficacy and safety of treprostinil in this population with PH should be investigated further.

Effect of Acute Vasodilator Testing Using Oxygen in Pulmonary Hypertension Due to Left Heart Disease.

BACKGROUND: Pulmonary vasodilators, including oxygen, have not shown consistent beneficial effects on pulmonary hypertension due to valvular heart disease (PH-VHD). Therefore, the study aimed to assess the effect of 100% fractional inspiration of oxygen (FiO2) on pulmonary and systemic hemodynamics in patients with combined pre- and post-capillary pulmonary hypertension (CpcPH) and isolated post-capillary pulmonary hypertension (IpcPH) due to PH-VHD. METHODS: This prospective study was conducted among patients with PH-VHD undergoing mitral or aortic valve replacement or repair. The study was conducted after induction of anesthesia and pulmonary artery catheterization. Cardiac output was obtained using thermodilution and all direct, and derived hemodynamic variables were obtained at 30% and 100% FiO2. The patients were stratified a priori into responders {(≥10 mmHg fall in mean pulmonary artery pressure (MPAP)} and non-responders. RESULTS: Fifty-seven patients completed the acute vasodilator test. The mean age and body mass index of the study population was 41.8 ± 14.1 years and 21.4 ± 4.6 kg/m2, respectively. There was a significant decrease in MPAP (40.77 ± 12.07 mmHg vs 36.74 ± 13.3 mmHg; P < .001) and pulmonary vascular resistance (PVR) {(median; Interquartile range (IQR); 388; 371 vs 323; 362 dynes sec.cm-5; P < .001) at 100% FiO2. Transpulmonary gradient (TPG) and diastolic pulmonary gradient (DPG) also decreased significantly (P < .001 and P < .001). Cardiac output did not change significantly. The magnitude of decrease in MPAP, PVR, TPG, DPG, and pulmonary artery compliance (PAC) between CpcPH and IpcPH was comparable. Responders did not show a significantly greater fall in MPAP, PVR, TPG, DPG, and PAC after surgery. CONCLUSION: Hyperoxia may lead to reduction in MPAP and PVR in both hemodynamic phenotypes of PH-VHD. A larger sample size is required to support or refute the findings of this study.

Prostaglandin-E1 infusion in persistent pulmonary hypertension of the newborn.

BACKGROUND: Neonates with persistent pulmonary hypertension of the newborn (PPHN) can present with hypoxia and right ventricular dysfunction with resultant inadequate oxygen delivery and end-organ damage. This study describes the use of prostaglandin-E1 (PGE) for ductal patency to preserve right ventricular systolic function and limit afterload in newborns with PPHN. METHODS: This is a retrospective cohort study that follows the hemodynamics, markers of end-organ perfusion, length of therapeutics, and echocardiographic variables of 57 newborns who used prostglandin-E1 in the setting of PPHN. RESULTS: Tachycardia, lactic acidosis, and supplemental oxygen use improved following PGE initiation. Fractional area change (FAC), to assess right ventricular systolic function, and pulmonary arterial acceleration time indexed to right ventricular ejection time (PAAT/RVET), to assess right ventricular afterload, also improved over three time points relative to PGE use (before, during, and after). CONCLUSIONS: Overall, we described the safety and utility of PGE in newborns with severe PPHN for stabilization while allowing natural disease progression.

Reassessing the role of milrinone in the treatment of heart failure and pulmonary hypertension in neonates and children: a systematic review and meta-analysis.

To evaluate milrinone's impact on pediatric cardiac function, focusing on its specific role as an inotrope and lusitrope, while considering its systemic and pulmonary vasodilatory effects. Search of PubMed, EMBASE, and the Cochrane Library up to August 2023. We included all studies that evaluated milrinone in children under 18 years old in neonatal, pediatric, or cardiac intensive care units. We excluded case reports, studies that did not provide tabular information on milrinone's outcomes, and studies focused on non-intensive care populations. We extracted data on the research design, objectives, study sample, and results of each study, including the impact of milrinone and any associated factors. We screened a total of 9423 abstracts and 41 studies were ultimately included. Milrinone significantly improved left ventricular ejection fraction (WMD 3.41 [95% CI 0.61 - 6.21]), left ventricle shortening fraction (WMD 4.25 [95% CI 3.43 - 5.08]), cardiac index (WMD 0.50 [95% CI 0.32 to 0.68]), left ventricle output (WMD 55.81 [95% CI 4.91 to 106.72]), serum lactate (WMD -0.59 [95% CI -1.15 to -0.02]), and stroke volume index (WMD 2.95 [95% CI 0.09 - 5.82]). However, milrinone was not associated with improvements in ventricular myocardial performance index (WMD -0.01 [95% CI -0.06 to 0.04]) and ventricular longitudinal strain (WMD -2.14 [95% CI -4.56 to 0.28]). Furthermore, milrinone was not associated with isovolumetric relaxation time reduction (WMD -8.87 [95% CI -21.40 to 3.66]). CONCLUSION: Our meta-analysis suggests potential clinical benefits of milrinone by improving cardiac function, likely driven by its systemic vasodilatory effects. However, questions arise about its inotropic influence and the presence of a lusitropic effect. Moreover, milrinone's pulmonary vasodilatory effect appears relatively weaker compared to its systemic actions. Further research is needed to elucidate milrinone's precise mechanisms and refine its clinical applications in pediatric practice. WHAT IS KNOWN: • Milrinone is a phosphodiesterase III inhibitor that has been used to treat a variety of pediatric and neonatal conditions. • Milrinone is believed to exert its therapeutic effects by enhancing cardiac contractility and promoting vascular relaxation. WHAT IS NEW: • Milrinone may not have a significant inotropic effect. • Milrinone's pulmonary vasodilatory effect is less robust than its systemic vasodilatory effect.

Ultrastructural changes of vascular smooth muscle cells and resistance to vasospasm treatment in femoral arteries of an arteriosclerotic rat model.

The objective of this study was to establish an animal model of arteriosclerosis for assessing vasospasm and to investigate the relationship between arteriosclerosis and vasospasm. Twelve-week-old male Sprague-Dawley rats were fed a diet supplemented with adenine and vitamin D (adenine/vitD). Body weight, blood, and femoral artery histopathology were assessed at 2, 4, and 6 weeks. Change in the femoral artery was examined by transmission electron microscope (TEM). Vasospasm was induced by administering epinephrine extravascularly into the femoral artery and released by the treatment with lidocaine as a vasodilator. During this period, the extravascular diameter and blood flow were measured. The rats in the adenine/vitD group developed renal dysfunction, uremia, hyperphosphatemia, and elevated serum alkaline phosphatase. Histological and TEM analyses of the femoral arteries in the treated rats revealed the degeneration of elastic fibers and extensive calcification of the tunica media and intima. Vascular smooth muscles were degenerated and osteoblasts were developed, resulting in calcified arteriosclerosis. Vasospasm in arteriosclerotic arteries was detected; however, vasodilation as well as an increase in the blood flow was not observed. This study revealed the development of vasospasm in the femoral arteries of the arteriosclerotic rats and, a conventional vasodilator did not release the vasospasm.

The Role of Vasodilator-stimulated Phosphoproteins in the Development of Malignant Tumors.

Vasodilator-stimulated phosphoprotein (VASP) is an actin-binding protein that includes three structural domains: Enabled/VASP homolog1 (EVH1), EVH2, and proline-rich (PRR). VASP plays an important role in various cellular behaviors related to cytoskeletal regulation. More importantly, VASP plays a key role in the progression of several malignant tumors and is associated with malignant cell proliferation, invasion, and metastasis. Here, we have summarized current studies on the impact of VASP on the development of several malignant tumors and their mechanisms. This study provides a new theoretical basis for clinical molecular diagnosis and molecular targeted therapy.

Targeting the apelin system for the treatment of cardiovascular diseases.

Cardiovascular disease is the leading cause of death worldwide. Its prevalence is rising due to ageing populations and the increasing incidence of diseases such as chronic kidney disease, obesity, and diabetes that are associated with elevated cardiovascular risk. Despite currently available treatments, there remains a huge burden of cardiovascular disease-associated morbidity for patients and healthcare systems, and newer treatments are needed. The apelin system, comprising the apelin receptor and its two endogenous ligands apelin and elabela, is a broad regulator of physiology that opposes the actions of the renin-angiotensin and vasopressin systems. Activation of the apelin receptor promotes endothelium-dependent vasodilatation and inotropy, lowers blood pressure, and promotes angiogenesis. The apelin system appears to protect against arrhythmias, inhibits thrombosis, and has broad anti-inflammatory and anti-fibrotic actions. It also promotes aqueous diuresis through direct and indirect (central) effects in the kidney. Thus, the apelin system offers therapeutic promise for a range of cardiovascular, kidney, and metabolic diseases. This review will discuss current cardiovascular disease targets of the apelin system and future clinical utility of apelin receptor agonism.

Predictors of the response to phosphodiesterase-5 inhibitors in pulmonary arterial hypertension: an analysis of the Spanish registry.

BACKGROUND: Achieving and maintaining a low-risk profile is associated with favorable outcome in pulmonary arterial hypertension (PAH). The effects of treatment on risk profile are variable among patients. OBJECTIVE: To Identify variables that might predict the response to treatment with phosphodiesterase-5 inhibitors (PDE-5i) in PAH. METHODS: We carried out a cohort analysis of the Spanish PAH registry in 830 patients diagnosed with PAH that started PDE5i treatment and had > 1 year follow-up. 644 patients started PDE-5i either in mono- or add-on therapy and 186 started combined treatment with PDE-5i and endothelin receptor antagonist (ERA). Responders were considered when at 1 year they: (1) were alive; (2) did not present clinical worsening; and (3) improved European Society of Cardiology/European Respiratory Society (ESC/ERS) risk score or remained in low-risk. Univariate and multivariate logistic regression models were used to analyze variables associated with a favorable response. RESULTS: Two hundred and ten patients (33%) starting PDE-5i alone were classified as responders, irrespective of whether it was mono- or add-on therapy. In addition to known predictors of PAH outcome (low-risk at baseline, younger age), male sex and diagnosis of portopulmonary hypertension (PoPH) or HIV-PAH were independent predictors of favorable response to PDE-5i. Diffusing capacity for carbon monoxide (DLco) ≤ 40% of predicted was associated with an unfavorable response. When PDE-5i were used in upfront combination, 58% of patients were responders. In this group, diagnosis of idiopathic PAH (IPAH) was an independent predictor of favorable response, whereas connective tissue disease-PAH was associated with an unfavorable response. CONCLUSION: Male sex and diagnosis of PoPH or HIV-PAH are predictors of favorable effect of PDE-5i on risk profile when used as mono- or add-on therapy. Patients with IPAH respond more favorably to PDE-5i when used in upfront combination. These results identify patient profiles that may respond favorably to PDE-5i in monotherapy and those who might benefit from alternative treatment strategies.

Hesperetin-7-O-glucoside/ß-cyclodextrin Inclusion Complex Induces Acute Vasodilator Effect to Inhibit the Cold Sensation Response during Localized Cold-Stimulate Stress in Healthy Human Subjects: A Randomized, Double-Blind, Crossover, and Placebo-Controlled Study.

Hesperetin, a citrus flavonoid, exerts vasodilation and is expected to improve endothelial function and alleviate cold sensation by activating nervous system thermal transduction pathways. In this randomized, double-blind, crossover, and placebo-controlled study, the purpose was to assess the effect of an orally administered highly bioavailable soluble inclusion complex of hesperetine-7-O-glucoside with ß-cyclodextrin (HEPT7G/ßCD; SunActive® HES/HCD) on cold sensation response during localized cold-stimulated stress in healthy humans. A significant (p ≤ 0.05) dose-dependent increase in skin cutaneous blood flow following relatively small doses of HEPT7G/ßCD inclusion complex ingestion was confirmed, which led to a relatively effective recovery of peripheral skin temperature. The time delay of an increase in blood flow during rewarming varied significantly between low- and high-dose HEPT7G/ßCD inclusion complex consumption (e.g., 150 mg and 300 mg contain 19.5 mg and 39 mg of HEPT7G, respectively). In conclusion, the substantial alteration in peripheral skin blood flow observed during local cooling stress compared to placebo suggested that deconjugated hesperetin metabolites may have a distinct capacity for thermoregulatory control of human skin blood flow to maintain a constant body temperature during cold stress exposure via cutaneous vasodilation and vasoconstriction systems.

Differential inhibition of platelet function by cilostazol in combination with clopidogrel.

PURPOSE: To assess the antiplatelet effect of cilostazol clinically, we compared the effects of cilostazol in combination with clopidogrel on various platelet function tests. METHODS: We recruited patients with ischemic stroke at high risk of recurrence who were treated with clopidogrel alone within 180 days after stroke onset. Subjects underwent baseline platelet function tests, and were then randomly assigned to receive dual antiplatelet therapy (DAPT) comprising clopidogrel and cilostazol or clopidogrel monotherapy (SAPT). After 6 months, platelet function was measured again and compared to that at baseline in each group, and the rate of change was compared between groups. RESULTS: Thirty-four patients were enrolled, but 4 patients were excluded for various reasons. In total, 30 subjects (13 in DAPT and 17 in SAPT group) were analyzed. Adenosine diphosphate- and collagen-induced aggregation, VerifyNow P2Y12 reaction units, vasodilator-stimulated phosphoprotein (platelet reactivity index: PRI) and plasma p-selectin concentration were significantly lower (P = 0.004, 0.042, 0.049, 0.003 and 0.006 respectively), while VerifyNow % inhibition was significantly higher at 6 months compared to baseline (P = 0.003) in the DAPT group only. Comparison of the rate of change in each parameter from baseline to 6 months showed that while PRI decreased at a greater rate (P = 0.012), VerifyNow % inhibition increased at a greater rate (P = 0.003) in the DAPT group than the SAPT group. CONCLUSIONS: The inhibitory effects of adjunctive cilostazol added to clopidogrel on platelet function differed by type of platelet function test. VerifyNow % inhibition and PRI were more inhibited than the other platelet function tests. TRIAL REGISTRATION: CSPS.com substudy in TWMU (UMIN000026672), registered on April 1, 2017. This study was performed as a substudy of CSPS.com (UMIN000012180, registered on October 31, 2013) and was retrospectively registered.