Risultati per: Long COVID: principali risultati, meccanismi e raccomandazioni

Circulation, Volume 150, Issue Suppl_1, Page A4147606-A4147606, November 12, 2024. Introduction:Long QT syndrome (LQTS) is a potentially life-threatening genetic heart disease. Patients with LQTS may also have co-existent mental health illnesses that may benefit from psychiatric medications. However, because many of these medications have QT-prolonging potential (www.crediblemeds.org), many of these patients receive suboptimal mental health care.Objective:To evaluate the frequency, management, and incidence of breakthrough cardiac events (BCEs) in patients with LQTS and concomitant mental health issues treated with psychiatric medications.Methods:A retrospective review was conducted on patients cared for in Mayo Clinic’s Windland Smith Rice Genetic Heart Rhythm Clinic between 2000 and 2024 focusing on patients with LQTS and a concomitant psychiatric diagnosis requiring medication with known, possible or conditional risk of torsades de pointes (TdP). Electronic medical records were reviewed for data. BCEs were defined as LQTS-triggered syncope, seizures, appropriate ICD therapy, sudden cardiac arrest (SCA), or sudden cardiac death (SCD). Patients with missing information were excluded.Results:Overall, 195 /1899 LQTS patients [10%, 86 (43%) with LQT1, 83 (42%) with LQT2, and 16 (8%) with LQT3] had a concomitant psychiatric diagnosis requiring medication [150 female (76%), mean age at diagnosis 27 ± 18 years, median follow-up time 6.6 years (IQR 2.9-13)]. The most common psychiatric conditions were depression (71%), anxiety (62%), and ADHD (9%). The mean duration of therapy was 3.36 +/- 3.48 years and the most common medications used were fluoxetine (26%), sertraline (14%), and escitalopram (11%). There was no significant difference in QTc after starting the first psychiatric medication when compared to baseline (473 ± 33 vs 474 ± 35 ms, p=0.6). Prior to their LQTS diagnosis and while therefore untreated, 61/195 (31%) had at least 1 LQTS-associated cardiac event. This occurred in the setting of a psychiatric drug in 7 patients (11%). Following LQTS diagnosis and treatment, 14/195 patients (7%) have experienced a non-lethal BCE of which only 3/14 (21%) while on psychiatric medications.Conclusions:Although avoidance of medications with known QT-prolonging potential is prudent, attention to patient’s overall well-being besides just their LQTS must be given. After correct diagnosis and treatment, LQTS patients with concomitant mental health issues may be safely and effectively treated with medications known to prolong QTc.

Circulation, Volume 150, Issue Suppl_1, Page A4136963-A4136963, November 12, 2024. Background:There is increasing evidence of a strong association between obstructive sleep apnea (OSA) and ischemic heart disease. Previous studies have demonstrated OSA to be a significant predictor of incident CAD, while recent studies have confirmed individuals with OSA to have 3.9 times greater incidence of major adverse cardiac and cerebrovascular events (MACCE) at one year following acute myocardial infarction (AMI) than individuals without OSA. Whether treatment with continuous positive airway pressure (CPAP) after AMI in OSA patients reduces MACCE is not known. This study investigated the long-term cardiovascular outcomes associated with CPAP therapy after AMI in OSA patients, and is the first study to evaluate the effect of CPAP on secondary prevention after AMI.Methods:This retrospective study was conducted from 2015 to 2019 and included adults with AMI. Patients with at least moderate OSA (n=180) were followed for at least 1 year and categorized as either AMI and compliant to CPAP (54 patients) or AMI and non-compliant to CPAP (126 patients). We estimated the incidence of MACCE (early rehospitalization, re-catheterization, CABG, recurrent MI, CHF, arrhythmia, stroke, and death) in each group during follow-up from the index event. Continuous and categorical variables were analyzed for significance with Wilcoxon’s test and Fisher’s exact test respectively. Multivariate analyses were performed to adjust for confounders.Results:Most participants were male, the average age was 66 years old, and no significant demographic difference was identified between the two groups. Compared with non-compliant patients, CPAP-compliant patients exhibited significantly lower overall MACCE incidence (22.2% vs 40.5%, p=0.03) and repeat catheterization rate (1.9% vs 11.1%, p=0.04) after AMI.Conclusion:Long-term, compliant CPAP therapy, as compared with non-compliant CPAP therapy, significantly reduces recurrent cardiovascular events and provides effective secondary prevention after AMI in patients with at least moderate OSA.

Circulation, Volume 150, Issue Suppl_1, Page A4147601-A4147601, November 12, 2024. Background:The consequences of cancer and anti-cancer treatments are often described as representing an “accelerated aging” phenotype. However, little is known about how the “accelerated aging” phenotype affects mortality risks in long-term cancer survivors.Purpose:To investigate the association between accelerated aging phenotype and cause-specific mortality in a sample of long-term cancer survivorsMethods:Data for cancer survivors (CS) were extracted from the National Health and Nutrition Examination Survey between the years 1999-2010. Participants missing vital data and those diagnosed with multiple cancers, childhood cancers, cancer within the previous 5 years, or skin cancer were excluded. Mortality outcomes were collected from the National Death Index through December 2019. The Phenotype Age score was derived from blood biochemistry measures such as albumin, creatinine, and c-reactive protein. Accelerated Aging (AA) was defined as a Phenotype Age greater than the participants’ chronological age. CS were grouped by time since diagnosis: 5-10, 10-15, 15-20, and ≥20 years. Within each group, hazard ratios (HR) were derived from competing-risk hazard regression for the AA phenotype association with cancer-specific and cardiovascular-specific mortality. Regressions were modeled with participant age as the time-scale to account for the predictive nature of chronological age.Results:A total of 875 CS (65.6±12.9 years, 62% female, 31% non-white, 15.6±9.4 years from cancer diagnosis) were included. The most common cancer types were prostate (16%) and breast (21%) cancer. There were 107 cancer and 113 cardiovascular deaths over a 10.8±4.6 year follow-up. The AA phenotype was significantly associated with cardiovascular-specific mortality in each survivor group (all p

Circulation, Volume 150, Issue Suppl_1, Page A4117180-A4117180, November 12, 2024. Introduction:Patients receiving renin-angiotensin-aldosterone system inhibitors (RAASi) are at increased risk of developing hyperkalemia (HK). Sodium zirconium cyclosilicate (SZC) is used to treat HK, but the impact of duration of SZC on healthcare resource utilization (HRU) in RAASi users is unknown. The GALVANIZE Outcome study compared HK-related HRU among RAASi users between long-term and short-term SZC users.Methods:Adults with ≥1 outpatient prescription for SZC (index date) and ≥1 RAASi prescription spanning the index date were identified from a large US insurance claims database (7/2018-12/2022) and were stratified based on duration of SZC use. Long-term SZC users ( >90 days) and short-term SZC users (≤30 days) were exactly and propensity score matched on key baseline characteristics. Rates of HK-related hospitalizations or emergency department (ED) visits, HK-related ED visits, and HK-related hospitalizations were compared during follow-up from index to the earliest of 6 months post-index, end of data availability, other potassium binder use, or re-initiation of SZC post-discontinuation.Results:Among 1,586 matched pairs, the mean age was 65.5 years, 41.0% of patients were female, and most patients had any stage chronic kidney disease (91.9%), hypertension (90.8%), and diabetes (73.4%). Also, 30.0% of patients had heart failure. The most used RAASi therapies at index were angiotensin-converting enzyme inhibitors (57.3%) and angiotensin-receptor blockers (56.3%). Patients with long-term SZC use had a 44% lower rate of HK-related hospitalizations or ED visits, a 41% lower rate of HK-related hospitalizations and a 52% lower rate of HK-related ED visits than patients with short-term SZC use during follow-up (all p

Circulation, Volume 150, Issue Suppl_1, Page A4125636-A4125636, November 12, 2024. Background:Postural orthostatic tachycardia syndrome (POTS) is a prevalent cardiovascular disorder after COVID-19 infection. Although POTS is characterized by the presence of sinus tachycardia, other hemodynamic disturbances including blood pressure (BP) regulation, remain largely unexplored.Aims:We investigated BP changes using 24-hour ambulatory-BP-monitoring in patients with new-onset POTS after COVID-19 compared with pre-pandemic healthy controls.Methods:We performed a case-control study in 100 verified COVID-19 patients with new-onset POTS (mean age 40.0±12.9 years, 85% women) diagnosed by positive head-up tilt-testing versus 100 healthy controls (mean age 45.0±14.6 years, 70% women) from a population-based cohort with negative active standing test, no history of syncope, orthostatic intolerance, or endocrine disease. We analyzed 24-hour Systolic BP (SBP) and hypotensive SBP episodes (

Circulation, Volume 150, Issue Suppl_1, Page A4140218-A4140218, November 12, 2024. Background:Prior data indicated a reduction in mortality among STEMI (ST-elevation myocardial infarction) patients with COVID-19 from 2020 to 2021 in the United States.Objective:To describe national trends and determinants of outcomes among STEMI patients with COVID-19 from 2020-2021.Methods:A retrospective cohort study was conducted using the 2020-2021 Nationwide Inpatient Sample of adults diagnosed with STEMI and COVID-19, assessing in-hospital mortality and the use of percutaneous coronary intervention (PCI), mechanical ventilation, and mechanical circulatory support (MCS).Results:The study included 6,195 STEMI patients with COVID-19 and revealed stable mortality (18% in 2020 to 21% in 2021,p=0.06). Demographic shifts occurred, with White patients increasing from 52% in 2020 to 66% in 2021 (p

Circulation, Volume 150, Issue Suppl_1, Page A4143186-A4143186, November 12, 2024. Introduction:Statins are lipid-lowering agents with anti-inflammatory effects. Data surrounding the benefits of statins in patients with coronavirus disease 2019 (Covid-19) are conflicting. We sought to better understand the impact of statins in the context of Covid-19-related inflammation.Methods:We leveraged the International Study of Inflammation in Covid-19, a prospective multicenter cohort study of patients hospitalized specifically for Covid-19 between February 1, 2020 and October 30, 2022. Participants underwent systematic assessment of biomarkers of inflammation. We used logistic regression modeling and inverse probability-of-treatment weighting (IPTW) to examine the association between prior statin use and the composite outcome of in-hospital death, need for mechanical ventilation, and need for renal replacement therapy.Results:A total of 4,464 patients were included in the study, of whom 1,364 (27.5%) were taking a statin prior to admission. There were 1,061 primary outcome events, including 540 deaths, 854 mechanical ventilation and 313 renal replacement therapy. Amongst biomarkers of inflammation, statin use was associated solely with lower levels of soluble urokinase plasminogen activator receptor (suPAR) after adjusting for known confounders. In multivariable logistic regression analysis, statin use was associated with lower odds of the composite outcome (adjusted odds ratio (aOR) 0.63, 95%CI[0.53-0.76]) compared to patients not on statins. Findings were consistent with IPTW (aOR 0.92, 95%CI [0.89- 0.95]). The proportion of the effect of statin on the primary outcome mediated by suPAR was estimated at 31.5%.Conclusion:Prior statin use is associated with improved outcomes and lower inflammation as measured by suPAR levels in patients hospitalized for Covid-19.

Circulation, Volume 150, Issue Suppl_1, Page A4143314-A4143314, November 12, 2024. Objectives:Improve clinical pathways to impact atherosclerotic cardiovascular disease (ASCVD) management of Veterans through a Learning Healthcare System model of quality improvement designed to improve the management of dyslipidemia among those with high-risk ASCVD.Methodology:Long Beach VA (LBVA) is one of 50 VA sites participating in a national quality improvement initiative called the VALOR QI: VA Lipid Optimization Reimagined Quality Improvement Project. VALOR-QI is a collaborative project between the U.S. Department of Veterans Affairs (VA) and the American Heart Association (AHA) with the goal of positively impacting Veterans’ cardiovascular (CV) health. As part of the program, VA sites work with an AHA QI Consultant develop and deploy a local quality improvement plan to help overcome site specific barriers preventing Veterans from achieving optimal cholesterol levels.At the LBVA, patients with LDL-C >70 and an ASCVD diagnosis are screened from a list generated by the health care provider. If a patient meets criteria, the health coach approaches the patient and begins working with them once a month over the phone or in person. During these meetings medication compliance and refills are reviewed, lifestyle goals or progress are reevaluated, and patients are reminded of upcoming appointments and labs.Results:Since October 2022, the LBVA VALOR-QI program has directly interacted with 277 patients who have a high ASCVD risk and LDL-C >70. Of those 277 patients, 84 patients (30%) have reached an LDL-C

Circulation, Volume 150, Issue Suppl_1, Page A4145209-A4145209, November 12, 2024. Background:Acute decompensated heart failure accounts for an increasing proportion of hospitalizations in the United States and is linked to high readmission and 30-day mortality rates. Prior studies suggest up to 17% mortality rate within 30 days for patients admitted with heart failure.Research Questions/Hypothesis:We present an analysis characterizing patients who experienced mortality within 30 days of admission at a large safety net hospital following the COVID-19 pandemic.Methods/Approach:A retrospective review was conducted for all heart failure admissions of patients >18 years of age admitted to the coronary care unit (CCU) at Los Angeles General Medical Center from January to December 2021 after the peak of the COVID-19 pandemic. Demographics, insurance information, drug use, medication use, heart failure etiology, and CCU interventions were indexed. The primary outcome was all-cause mortality.Results/Data:172 patients were identified during the study period. 10% of patients died within 30 days of admission, of which 94% died during the same admission. Of patients who died during index admission, 88% had heart failure with reduced EF. None of these patients were on all four pillars of guideline-directed medical therapy (GDMT), with 33% on one or no GDMT medications.There was not a statistically significant difference in mortality rate when comparing those with active stimulant use 5/60 (8%) to those without active illicit drug use 12/112 (11%) (RR 0.79, 95% CI, p= 0.64).9/17 (53%) patients died of refractory cardiogenic shock, 5/17 (29%) were found in cardiopulmonary arrest of unknown etiology while undergoing treatment for acute decompensated heart failure. Two patients (12%) died of septic shock while 1/17 (5%) died of hemorrhagic shock related to chronic liver disease.Conclusion(s)The COVID-19 pandemic exacerbated significant healthcare inequalities, especially for urban underserved populations leading to late presentations of disease and worse outcomes, however, based on our data the overall inpatient mortality rate remained largely similar to pre-pandemic values.

Circulation, Volume 150, Issue Suppl_1, Page A4142982-A4142982, November 12, 2024. Introduction:Preeclampsia, a pregnancy-specific complication, is an established risk factor for long-term cardiovascular complications, including heart failure with preserved ejection fraction (HFpEF), however, the exact mechanism of this cardiovascular dysfunction remains unclear. This study aimed to characterize the cardiac structure and myocardial tissue using cardiac magnetic resonance imaging (CMR) in women with a long-term history of preeclampsia. We hypothesized that prior preeclampsia is associated with myocardial fibrosis or scarring.Methods:Women with singleton pregnancies delivered between 2004 and 2019 were identified and prospectively enrolled to undergo CMR (1.5T Signa Artist GE HealthCare) with cine imaging, tissue multiparametric quantitative mapping and late gadolinium enhancement (LGE) imaging.Results:Twenty-three subjects (41.0±6 years, 12.7±5 years post-partum) were included. Women with a history of preeclampsia (n=11) were compared to a healthy control group of women with prior normotensive, uncomplicated pregnancy (n=12). There was no significant difference in LV systolic function, LV mass, T1 and T2 mapping, or LGE between the preeclamptic group versus controls, although right ventricular (RV) systolic function was significantly higher (65±7.5% vs 58±7.7%; p=0.04) in individuals with preeclampsia (Panel A). Notably, global extracellular volume fraction (ECV) was significantly higher in women with preeclampsia versus normotensive pregnancies (47.2±21.2% vs 31.0±4.8% respectively; p=0.02) (Panel B).Conclusions:Global myocardial ECV appears to be increased with preeclampsia, many years after the index pregnancy, potentially reflecting diffuse interstitial fibrosis. Diffuse fibrosis may stiffen the myocardium and reduce myocardial compliance, resulting in loss of diastolic function. Further research is needed to determine whether these alterations in cardiac structure and increased myocardial fibrosis contribute to preeclampsia-associated HFpEF and cardiovascular outcomes.

Circulation, Volume 150, Issue Suppl_1, Page A4135741-A4135741, November 12, 2024. Background:Although recent studies have showed improved outcomes, aortic valve replacement (AVR) for chronic aortic regurgitation (AR) in the presence of reduced left ventricular ejection fraction (LVEF) is associated with a higher surgical risk. Contemporary long-term outcome remains poorly investigated.Methods:Between January 2004 and August 2019, we identified 122 patients who underwent AVR for pure chronic severe AR with LVEF less than 50%. Patients with severe reduced LVEF (

Circulation, Volume 150, Issue Suppl_1, Page A4138793-A4138793, November 12, 2024. Background:Previous studies have indicated that diabetes mellitus (DM) is linked to the severity and mortality of both pulmonary thromboembolism and pulmonary arterial hypertension. But the relationships between diabetes and chronic thromboembolic pulmonary hypertension (CTEPH) have not been discussed. This study aims to investigate the relationships of DM with disease severity and clinical worsening events in patients with CTEPH.Methods:We analysed data of patients with CTEPH from the National Center for Cardiovascular Diseases in China between January 1, 2013 and August 31, 2023. A 2-group propensity score matching was conducted to adjust for differences between CTEPH patients with and without DM, employing a 1:1 pairing algorithm. The association between DM and long-term adverse outcomes was appraised utilizing multivariable Cox regression models. Subgroup analyses, predicated on age, sex, World Health Organization functional class (WHO-FC) and body mass index, were carried out to evaluated interaction effects.Results:In total, 489 consecutive CTEPH patients were included in the study, with 25.97% diagnosed with DM. Subsequent matched analysis comprised 127 patients with DM and 127 without DM. CTEPH patients with DM exhibited inferior WHO-FC as well as cardiac index, elevated N-terminal pro–brain natriuretic peptide levels, pericardial effusion, tricuspid annular plane systolic excursion / systolic pulmonary arterial pressure ratio and pulmonary vascular resistance. After adjusting for confounding factors, DM remained independently associated with adverse outcomes in patients with CTEPH. In addition, further subgroup analyses disclosed a more robust association in patients without overweight or obesity.Conclusions:DM correlates with heightened severity of CTEPH and serves as an autonomous predictor of long-term prognosis in CTEPH. Moreover, this correlation is more pronounced in individuals devoid of overweight or obesity.

Circulation, Volume 150, Issue Suppl_1, Page A4140290-A4140290, November 12, 2024. Background:We evaluated the efficacy of a digital health program integrating self-measured blood pressure (BP) monitoring and lifestyle coaching in managing hypertension (HTN). Conducted from 2019 to 2022 across 39 healthcare facilities in 10 US states, using Bluetooth-enabled devices, mobile apps, and a care coordination platform, longitudinal BP data was collected.Methods:Linear mixed models with patient-specific random intercepts assessed within-subject BP changes. Causal modeling evaluated BP improvement by adherence level, measured by the regularity and frequency of BP measurements in the first 6 months, adjusting for covariates including age, gender, BMI, and medication compliance. To assess the patient adherence to the impact on BP outcomes in the long term we also analyzed those with data at baseline and endpoints from 6 to 24 months.Results:We analyzed 5520 patients with baseline HTN II (SBP/DBP: 152.6 ± 12.7 / 87.6 ± 10.5 mmHg, mean± SD), 51.3% female, 43.3% in 65-80yr and 34.9% in 46-65yr. BP change at 6 months was -12.5 ± 16.9 / -6.9 ± 10.0 (N = 4171, p

Circulation, Volume 150, Issue Suppl_1, Page A4141571-A4141571, November 12, 2024. Background:Although ambient air pollution exposure has been linked with increased mortality in many cardiovascular or pulmonary diseases, its relationship with pulmonary arterial hypertension (PAH) is still unknown. The present study aims to investigate the association of ambient particulate matter (PM) exposure with pulmonary hemodynamics and long-term survival in patients with PAH in China.Methods:This retrospective multi-center cohort study included 1511 participants who underwent invasive right heart catheterization and were eventually diagnosed with PAH from January 2014 to December 2020. The primary outcome was transplant-free survival from the time of diagnosis. The association of PM2.5and PM10with all-cause death or lung transplantation was assessed by fitting Cox proportional risk models. Generalized linear models were used to examine the relationship between PM exposure and pulmonary hemodynamic severity at baseline. Restricted cubic splines were used to describe exposure-response curves. Mediation analysis with bootstrap method was used to explore whether potential variables mediated the associations.Results:During a median follow-up of 36.7 months, all-cause death or lung transplantation occurred in 149 patients. Per 10 µg/m3increase of PM2.5and PM10were associated with 14.5% and 7.9% increased risk of primary outcomes adjusting for potential confounding variables, respectively. PM2.5and PM10were associated with European Society of Cardiology risk stratification and with pulmonary hemodynamics at baseline, in particular pulmonary vascular resistance (PVR), mean pulmonary artery pressure (mPAP), cardiac index, and mixed venous oxygen saturation (SVO2). Effect of PM may be mediated in part by impaired glucolipid metabolism and inflammation-associated lymphocyte.Conclusions:Particulate matter exposure was associated with disease severity and pulmonary hemodynamics at baseline in patients with PAH, and higher chronic exposure to PM2.5and PM10independently predicted shorter transplant-free survival.

Circulation, Volume 150, Issue Suppl_1, Page A4113573-A4113573, November 12, 2024. Introduction/Background:Cardiovascular and neurological diseases develop in a significant proportion of COVID-19 patients. Minimally invasive tools to predict outcome after SARS-CoV-2 infection would enable personalized healthcare, potentially easing the disease burden. We showed that blood levels of the long noncoding RNA lymphoid enhancer-binding factor-1 antisense 1 (LEF1-AS1) predict COVID-19 in-hospital mortality.Hypothesis:LEF1-AS1 is associated with long-term clinical outcomes of COVID-19.Aim:Test the capacity of LEF1-AS1 to predict neuro-cardio-vascular outcomes post-SARS-CoV-2 infection.Methods/Approach:We enrolled 104 primo-infected COVID-19 patients aged 18+ recruited from April to December 2020 in the PrediCOVID national cohort for which 12-month follow-up data were available (Ethics Committee approvals 202003/07 and 202310/02-SU-202003/07). Whole blood samples were collected at baseline and expression levels of LEF1-AS1 were assessed by quantitative PCR.Results/Data:Of the 104 patients, 35 had at least one neurological symptom and one cardiovascular symptom at month 12. Levels of LEF1-AS1 at baseline were lower (p=0.019) in patients who developed neurological and cardiovascular symptoms as compared to patients who did not. Lower LEF1-AS1 was associated with symptoms development with an odds ratio of 0.48 (95% CI 0.28-0.83) from logistic regression model adjusted for age, sex, comorbidities and disease severity at baseline. Addition of LEF1-AS1 to a clinical model including age, sex, comorbidities and baseline severity yielded an incremental predictive value as attested by an increased AUC from 0.79 to 0.83 (likelihood ratio test p=0.005), a net reclassification index of 0.54 (p=0.007) and an integrated discrimination improvement of 0.08 (p=0.009).Conclusion:Blood levels of LEF1-AS1 predict 12-month neurological and cardiovascular outcomes of COVID-19 patients. This needs to be validated in larger populations.

Circulation, Volume 150, Issue Suppl_1, Page A4139216-A4139216, November 12, 2024. Introduction:TX000045 (TX45) is a long-acting Fc-relaxin fusion protein with vasodilatory, anti-fibrotic and anti-inflammatory activity due to selective agonism of the G protein-coupled relaxin family peptide receptor 1 (RXFP1). It is being developed for Group 2 pulmonary hypertension associated with heart failure with preserved ejection fraction (HFpEF). This first-in-human study evaluated the safety/tolerability, pharmacokinetic and pharmacodynamic profile of TX45 in healthy volunteers after single doses.Methods:This phase 1a, randomized, double-blind, placebo-controlled single ascending dose study was performed in seven cohorts of healthy volunteers. Six cohorts consisted of eight patients receiving intravenously (IV) or subcutaneously (SC) one of several doses of TX45 (n=6 on treatment) or placebo (n=2), including 0.3 mg/kg IV, 1 mg/kg IV, 3 mg/kg IV, 150 mg SC (x2 cohorts), and 300 mg SC. One cohort consisted of seven patients receiving 600 mg SC TX45 (n=5 patients) or placebo (n=2 patients). The goals of the study were to assess the tolerability and safety, immunogenicity, pharmacokinetic (PK) and pharmacodynamic (PD = renal plasma flow, RPF) properties of TX45 in healthy volunteers after single doses. RPF was determined by analysis of steady-state para-aminohippurate (PAH) blood levels in response to a PAH IV infusion.Results:55 healthy volunteers were randomized. TX45 was well tolerated. Most adverse events were mild to moderate in intensity. The most common treatment emergent adverse event was transient orthostatic tachycardia, not associated with hypotension. TX45 demonstrated linear pharmacokinetics across the dose range with a terminal half-life estimated to be 13-23 days. Treatment with TX45, across dose levels, increased renal plasma flow by 16-42%, consistent with known relaxin effects. Leveraging repeated measures of renal plasma flow post dose, TX45 demonstrated prolonged maintenance of a pharmacodynamic effect. There was no evidence of immune mediated clearance of TX45.Conclusions:TX45 was generally well tolerated with a safety, pharmacokinetic and pharmacodynamic profile to support further clinical development. Its maximum effect on RPF is similar to previously described effects of native relaxin. Its half-life will support a prolonged dosing interval. These findings support further evaluation of TX45 in patients with Group 2 pulmonary hypertension associated with HFpEF.