Peripheral Arterial Disease Research Articles

The incidence of death and risk factors for mortality following major bleeding in patients anticoagulated with factor Xa inhibitors: an observational study in the UK clinical setting (AXIOM UK)

Abstract Background Major bleeding (MB) in association with anticoagulant use results in significant mortality. Mortality can be directly attributed to bleeding, or may follow bleeding complications such acute kidney injury, myocardial infarction, stroke and other cardiovascular events. Most real-world data relating to bleeding mortality is derived from cohorts receiving vitamin-K antagonists. We investigated all-cause mortality (ACM) after MB in a large cohort anticoagulated with Factor Xa inhibitors (FXai), e.g. direct oral anticoagulants (DOAC) rivaroxaban, apixaban and low-molecular-weight heparins (LMWH). Purpose To describe incidence rates of and risk factors for ACM following MB in patients receiving FXai. To investigate MB related ACM by bleeding site, treatment indication, treatment subgroups and individual and cumulative time periods. Methods Retrospective cohort analysis of new users of FXai, between 2012-2020, for therapeutic indications including atrial fibrillation (AF), venous thromboembolism, bioprosthetic cardiac valves or adult congenital heart disease was conducted. MB was defined by the International Society on Thrombosis and Haemostasis (ISTH) criteria. Incidence rates were reported per 100 person-years. Sub-distribution hazard ratios with 95% confidence intervals (95% CI) were estimated from Fine and Gray regression models accounting for competing risks. Results In 240,357 new users of FXai, 88% used an oral FXai. The most common FXai indication was AF (72%). There were 10,163 patients (4.2%) hospitalised for bleeding events during FXai use. Of these, 3,873 MB events (38%) fulfilled the ISTH definition of MB and 1312 died during 3,542 person years of follow-up (Table 1). ACM incidence rates varied by time, indication, bleeding subtype, and drug type. ACM occurred in 926 patients (23.9%) in the first month. Mortality rates were highest in the first month 607 (95% CI 568-647) per 100 person years, the rates then decreased over the year but remained elevated throughout the first year compared with subsequent years. Those receiving LMWH had higher ACM than those receiving a DOAC, but this was not significant in the adjusted risk factor analysis. Risk factors for ACM following bleeding included age ≥80, and a history of current smoking, myocardial infarction, congestive heart failure, peripheral artery disease, Stage 4 or 5 kidney disease, metastatic cancer, and intracranial haemorrhage. Age<60, bleeding following major trauma, and a history of anaemia were associated with lower risk of ACM (Table 2). Conclusions There is a significant incidence of ACM following MB among FXai users. The incidence rate of ACM in patients treated with FXai was highest in the first month after FXai initiation, declined during the first year and then plateaued. Multiple risk factors associated with ACM have been recognised and these could guide urgent therapies such as antidotes.

Restoration of autophagy reduces diabetes-induced endothelial dysfunction

Abstract Introduction Diabetes leads to endothelial dysfunction, a main determinant of several cardiovascular diseases. The molecular mechanisms underlying the effects of hyperglycemia in endothelial cells are not fully characterized. Autophagy, the intracellular process by which the cell digests and recycles senescent or damaged cytoplasmic elements, exerts cardiovascular protective effects, limiting cardiac and vascular injury in the presence of stress. However, it is unclear how hyperglycemia modulates autophagy in endothelial cells. Purpose In this study, we elucidated the role of autophagy in vascular damage induced by diabetes. We also tested whether the restoration autophagy attenuates diabetes-induced endothelial damage. Methods We evaluated the effects of high-glucose (HG, 30 mM for 6 and 24 hours) on markers of endothelial function, autophagy, autophagic flux, and mitophagy in human umbilical endothelial cells (HUVEC) in vitro and in mesenteric arteries from wild-type mice (WT) ex vivo. We tested the effects of autophagy reactivation using the natural polyamine spermidine or ATG7 overexpression (ATG7ov) on apoptosis and angiogenesis in HUVEC treated with HG. Vascular reactivity experiments in the presence of autophagy activation were performed in HG-treated mouse mesenteric arteries and human saphenous veins from patients with peripheral artery disease. Finally, we evaluated the level of autophagy in the mammary arteries of newly discovered diabetic patients undergoing coronary artery bypass graft surgery. Results We found that HG reduces autophagy (0.6 fold p<0.05) and mitophagy (1.5 fold p<0.001) in HUVECs. We also demonstrated that endothelial cells undergoing hyperglycemia fail to activate autophagy under hypoxic conditions (0.6 fold p<0.05). Reactivation of autophagy by ATG7ov rescues apoptosis (0.52 fold p<0.05) and angiogenesis (2.3 fold p<0.05) in HUVEC treated with HG. We further observed that HG exacerbates endothelial dysfunction in a mouse model of genetic inhibition (Beclin 1 +/- mice), compared to WT mice (-19.16 % +-4.97 SEM vs -48.39 % +-2.18 SEM p<0.001). Mechanistically, HG increases cellular acetylation status (0.7 fold p<0.05) and activates p300 (1 fold p<0.05), an autophagy inhibitor. ATG7ov or spermidine, a p300 inhibitor, rescue endothelial-dependent relaxation in mesenteric arteries of WT mice treated with HG (ATG7ov -62.48 % +-5.16 SEM; SP -63.01 +-3.22 SEM; HG -40.67 % +-3.82 p<0.001). Finally, we observed reduced levels of autophagy in mammary arteries from diabetic patients and demonstrated that SP improves vascular function in human saphenous veins (-37.6 % +-12.76 SEM vs -12.52 % +-5.6 SEM p<0.001). Conclusion Our results suggest that the impairment of autophagy is a strong contributor of diabetes induced-endothelial dysfunction. Targeting autophagy may represent a valid therapeutic strategy to counteract the cardiovascular consequences of metabolic stress.

Effect of alirocumab on coronary plaque stratified by atherothrombotic risks

Abstract Background Previous clinical studies have shown that high-risk subgroups including patients with major atherosclerotic cardiovascular disease (ASCVD) events and multiple atherothrombotic risk factors derive enhanced cardiovascular benefit from proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition. To date, the effect of alirocumab on coronary plaque regression stratified by the number of atherothrombotic risk factors remains unknown. Purpose To investigate the utility of atherothrombotic risk stratification to identify patients with acute myocardial infarction (AMI) who have the greatest potential for benefit on plaque regression as assessed by intracoronary imaging from the addition of alirocumab to high-intensity statin therapy. Methods This was a substudy of the PACMAN trial, a randomized, double-blind trial comparing biweekly alirocumab (150 mg) versus placebo in AMI patients undergoing percutaneous coronary intervention. Intravascular ultrasound (IVUS) was serially performed in non-infarct-related coronary arteries at baseline and after 52 weeks. Atherothrombotic risk factors defined in the 2018 ACC/AHA cholesterol guidelines include myocardial infarction, ischemic stroke, peripheral artery disease, age ≥65 years, familial hypercholesterolemia, coronary revascularization, diabetes, hypertension, chronic kidney disease, current smoking, LDL-C ≥100 mg/dL despite maximum tolerated statin therapy, and history of heart failure. The key endpoint was the change in IVUS-derived percent atheroma volume (PAV) from baseline to 52 weeks. Results A total of 263 patients available for serial IVUS data were analyzed for the current study. The most prevalent atherothrombotic risk factors were current smoking (49%), hypertension (43%), and age ≥65 years (24%). Patients were divided into 3 groups according to the number of risk factors (0 risk factor: n=52, 1 risk factor: n=101, ≥2 risk factors: n=100). Patients with risk factors had greater PAV at baseline compared with those with 0 risk factor (39.0% vs. 42.6% vs. 42.8%, P=0.008). The addition of Alirocumab to high-intensity statin therapy demonstrated a significant reduction in PAV among patients with 0 risk factor (-2.66% vs. -1.02%, P=0.009) and those with 1 risk factor (-2.36% vs. -0.76%, P<0.001) (Figure 1). In contrast, patients with ≥2 risk factors had no significant PAV reduction by alirocumab (-1.72% vs. -1.12%, P=0.076, P for interaction=0.009). Conclusions Among AMI patients with no or 1 atherothrombotic risk factor, the addition of alirocumab to high-intensity statin therapy demonstrated greater coronary plaque regression. Patients with fewer risk factors thus appear to be more susceptible for atheroma regression.Change in PAV stratified by risk factors

Edoxaban for stroke prevention in routine practice patients with atrial fibrillation with and without atherosclerotic disease: a post-hoc sub-study of ETNA-AF-Europe

Abstract Background Patients with atrial fibrillation (AF) and concomitant coronary and peripheral artery disease (CAD and/or PAD) have an increased risk of adverse health events compared to those without such atherosclerotic disease. The annual risks of major adverse cardiovascular outcomes for these patients treated with edoxaban in routine clinical practice remain uncertain. Purpose To determine the clinical characteristics and rates of key adverse events over multiple years of follow-up in patients with and without atherosclerotic disease (defined as CAD and/or PAD). Methods This is a post-hoc sub-study of ETNA-AF-Europe, a multinational, prospective cohort study on unselected patients with AF treated with edoxaban. In total, 13,164 (97%) of the 13,632 patients who provided informed consent were included in this substudy. The included patients were followed for a total of 48 months. Data were collected at baseline and yearly thereafter (±2 months). The present analysis compared baseline clinical characteristics (n [%] or mean [SD]) and clinical outcomes (events per 100 patient-years [%/year] with 95% confidence intervals [95% CI]) by CAD/PAD status at baseline. Results Of the 13,164 patients included in the analysis, 2973 had CAD and/or PAD (n=2762 CAD only). Patients with atherosclerotic disease were older (75.3 years vs 73.2 years), had higher CHA2DS2-VASc scores (3.8 vs 3.0) and HAS-BLED scores (2.8 vs 2.4), and more frequently received the reduced dose of 30 mg edoxaban than those without CAD/PAD (30.2% vs 21.0%) (Table). Cardiovascular comorbidities were in general more prevalent in those with atherosclerotic disease vs those without. Rates of stroke or systemic embolism (0.89%/year, 95%-CI 0.72–1.09 vs 0.59%/year, 95%-CI 0.52–0.68), myocardial infarction (0.73%/year, 95%-CI 0.58–0.92 vs 0.25%/year, 95%-CI 0.20–0.30), and cardiovascular (1.56%/year, 95%-CI 1.33–1.83 vs 0.85%/year, 95%-CI 0.76–0.95) as well as all-cause death (5.96%/year, 95%-CI 5.50–6.46 vs 3.56%/year, 95%-CI 3.37–3.77) were higher for patients with CAD/PAD vs those without such atherosclerotic disease (Figure). Conclusion Annual rates of thromboembolic and bleeding events were low for AF patients treated with edoxaban in routine practice. The higher rates of thrombotic and bleeding events in patients with CAD/PAD are most likely caused by differences in baseline intrinsic risks. Nonetheless, these differences, particularly the threefold higher rate of myocardial infarction, warrants further investigation.Baseline Characteristics

Association of the lipoprotein(a) gene (LPA) p.Ile4399Met variant with lipoprotein(a) level and cardiovascular events in patients following coronary artery bypass grafting under 65 years of age

Abstract Introduction Lipoprotein(a) (Lp[a]), a well-known risk factor for atherosclerotic cardiovascular disease, is largely determined by variation in the Lp(a) gene (LPA) locus encoding apolipoprotein(a). The LPA gene Ile4399Met (rs3798220) variant has been previously reported to have a strong association with the Lp(a) level in patients with coronary artery disease (CAD), however, its prevalence in the middle-age patients after coronary artery bypass grafting (CABG) has not been investigated. Purpose To assess the frequency of the LPA gene c.5673A>G variant (p.Ile4399Met; rs3798220) in Polish patients with CAD following CABG under 65 years of age and determined its association with laboratory and clinical variables. Materials and Methods We studied 215 patients with stable CAD, aged 59.5±4.9 years, who underwent primary and isolated CABG surgery (at age of 57.8±5.4 years), including 195 (90.8%) male. Clinical characteristics and analysis of the LPA c.5673A>G variant were performed. Results The genotype distribution was as follows: AA – 192 (89.3%), AG – 19 (8.8%), and GG – 4 (1.9%). The c.5673G allele carriers had higher Lp(a) level (106.5 [IQR 77.9-149.7] vs 10.4 [IQR 4.4-43.0] mg/dL, p<0.001) compared with non-carriers. Among the c.5673G allele carriers, Lp(a) correlated positively with pack-years of smoking (r=0.563, p=0.045) and fibrinogen (r=0.431, p=0.040), but not with low-density lipoprotein cholesterol (r=0.202, 0.368). There were no other genotype-associated differences with regard to demographic and clinical variable between carriers and non-carriers, including myocardial infarction (56.5% vs 47.9%, p=0.511), peripheral artery disease (21.7% vs 15.1%, p=0.377) and cerebrovascular events (13.0% vs 6.7%, p=0.389). Conclusions To our knowledge, this is the first report on the prevalence of LPA rs3798220 variant in patients with advanced CAD following CABG surgery under 65 years of age. We showed a relatively high (10.7%) percentage of c.5673G allele carriers who have ten times higher Lp(a) levels compared to the wild type, however, its impact on cardiovascular events requires further studies.

Prognostic significance of pre-procedure wall shear stress in the ascending aorta in patients with aortic stenosis undergoing transcatheter aortic valve replacement

Abstract Background Accurate prognostication before the procedure is challenging in patients with aortic stenosis (AS) undergoing transcatheter aortic valve replacement (TAVR). Recently, blood flow dynamics assessed by four-dimensional flow cardiovascular magnetic resonance imaging (4D-flow CMR) showed a significant reduction in average wall shear stress (WSS) in the ascending aorta (AAo) after TAVR. However, the prognostic value of pre-procedure average WSS in the AAo is controversial. Purpose We aimed to investigate whether pre-procedure average WSS was associated with clinical outcomes in patients with AS undergoing TAVR. Methods We prospectively examined 159 consecutive AS patients who underwent TAVR (57 males, mean age 83.6 ± 4.7 years, median left ventricular ejection fraction 63.4%) between May 2018 and May 2022. We assessed average WSS in the AAo before TAVR using 4D-flow CMR. We divided the patients into high WSS (≥6.60 Pa, n = 79) and low WSS (<6.60 Pa, n = 80) groups according to the median value of pre-TAVR WSS. The primary outcome of interest was a composite of all-cause death and hospitalization for worsening heart failure. Results Patients with high WSS had lower age compared to those with low WSS. There were no significant differences on sex, body mass index, systolic blood pressure, hemoglobin, serum albumin, N-terminal pro b-type natriuretic peptide, left ventricular ejection fraction, mean transaortic valvular gradient, annulus area in aortic valve and AAo diameter between the groups. During a median follow-up period of 19.8 months (interquartile range 6.0-37.1), the primary outcome more frequently occurred in patients with low WSS than in those with high WSS (28% vs 5%, P <0.001) (Figure 1). A multivariable Cox regression showed that lower WSS independently associated with increased risk of the primary outcome (hazard ratio 0.69, 95% confidence interval [CI] 0.53-0.91, P <0.001), even after adjustment for significant prognostic covariates including age, sex, serum albumin, history of chronic obstructive pulmonary disease, peripheral artery disease and malignancy, and estimated glomerular filtration rate. Predictive performance for the primary outcome was improved when adding the value of WSS in the AAo to representative prognostic factors (c-index 0.81 95%CI 0.72-0.90 vs. 0.77 95%CI 0.67-0.88) (Figure 2). Conclusions In patients with AS who underwent TAVR, lower average WSS in the AAo before procedure was associated with higher risk of worse clinical outcomes, suggesting that pre-TAVR average WSS in the AAo would be a surrogate marker and useful for the risk stratification.Survival analysis for primary outcomePredictive performance

Differences in non-flow limiting non-culprit plaque characteristics after myocardial infarction in patients with versus without chronic kidney disease

Abstract Background Patients with chronic kidney disease (CKD) are at increased risk for recurrent cardiovascular events after myocardial infarction compared to patients with preserved renal function. This disparity may be related to differences in plaque morphology. Purpose To compare non-flow limiting non-culprit (NC) plaque characteristics as assessed by optical coherence tomography in patients with versus without chronic kidney disease presenting with myocardial infarction. Methods 438 patients presenting with myocardial infarction with additional non-flow limiting (defined as a fractional flow reserve >0.80) NC lesions were included in the prospective observational PECTUS-obs study after treatment of the infarct related artery. An independent core laboratory performed all quantitative and qualitative OCT analyses. For the present subgroup analysis, patients were grouped according to the presence or absence of CKD, which was defined as an estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m². Baseline characteristics were compared between groups on a patient-level and OCT characteristics were compared on a lesion-level while accounting for within-patient clustering. Results Out of 420 patients with at least one analyzable OCT, baseline renal function was known in 416. Among them, there were 55 patients with and 361 patients without CKD (mean eGFR 47.4 ± 9.2 vs 84.7 ± 15.0 ml/min/1.73 m², p<0.001). Patients with CKD were older (mean age 73 ± 9 vs 62 ± 10 years, p<0.001), more frequently were female (29.1% vs 17.2%, p=0.035) and predominantly presented with a non-ST-segment elevation myocardial infarction (72.2% vs 44.9%, p<0.001). Comorbid disease was more prevalent among patients with CKD, including a higher prevalence of hypertension (p=0.010), hypercholesterolemia (p=0.020), diabetes (p<0.001), history of myocardial infarction (p<0.001), carotid artery disease (p=0.019) and peripheral artery disease (p=0.002). Coronary lesions in patients with CKD on average had a larger maximal calcium arc (188 ± 114 vs 137 ± 87º, p=0.003) and length (11.9 ± 10.3 vs 8.4 ± 7.4 mm, p=0.021). Lipid plaques were less prevalent among lesions in patients with CKD (63.6% vs 78.0%, p=0.016) and less frequently had a lipid arc ≥90º (60.6% vs 76.1%, p=0.018). Although the mean minimal fibrous cap thickness was lower in patients with CKD (p=0.025), no difference was observed in the prevalence of thin-cap fibroatheromas (p=0.984) or high-risk plaques according to the PECTUS-obs criteria (p=0.665). Conclusion Non-flow limiting NC lesions in patients with CKD differ from those in patients without CKD in a cohort of patients presenting with myocardial infarction. Overall, plaques in patients with CKD show more extensive calcification, whereas lesions in patients without CKD more often consist of lipid plaques, but the prevalence of high-risk plaques was comparable.

Cardiovascular disease burden and risk factor management in cancer survivors: insights from a large-scale East London cohort

Abstract Introduction Improvements in cancer survival have led to an urgent need to address long-term health issues among survivors, notably increased risk of cardiovascular disease (CVD). Shared risk factors may underpin at least part of this excess risk. Aims To investigate differences in cardiovascular risk profile between cancer survivors and controls; and to assesses the management of hypertension and statin use among cancer survivors compared with controls in a multi-ethnic and socio-economically diverse population. Methods The data were obtained from electronic health records of 1.2 million people registered with general practices in East London. It provides a snapshot of health records at the time of data extraction (01/01/2023). We identify individuals with record of past cancer (grouped into 20 cancer types) and their cardiovascular profile. Each cancer-exposed patient was age- and sex-matched to four non-cancer comparators. Multivariable logistic regression, with extensive adjustment for demographic and health-related variables, was used to elucidate the independent associations of past cancer with a range of cardiovascular outcomes. Patterns of guideline-directed risk factor control among cancer patients with hypertension and ischaemic CVDs (vs non-cancer controls) were assessed. Results The study consisted of 18,839 cancer survivors and 75,356 matched controls (64±15 years, 43% male), with marked ethnic diversity (cancer survivors: 48% White, 24% Black and 22% Asian) and socio-economic deprivation. Compared to matched controls, patients with past cancer had a higher prevalence of hypertension (44% vs. 41%) and chronic kidney disease (18% vs. 14%). We observed a higher prevalence of CVDs including venous thromboembolism (VTE) (5.6% vs. 2.8%), atrial fibrillation (AF) (6.5% vs. 5%), and heart failure (HF) (4.4% vs. 3.4%) among cancer survivors. Regression models fully adjusted for shared risk factors demonstrated an increased risk of a range of CVDs in patients with (any) past cancer, including VTE (OR 2.01), HF (OR 1.31) and AF (OR 1.27). CVD risk varied across cancer types (Figure 1). For example, lung cancer survivors had an elevated risk of VTE (OR 4.02), AF (OR 2.47), IHD (OR 1.45) and peripheral artery disease (OR 1.67) while colorectal cancer survivors had increased risks of VTE (OR 2.68), HF (OR 1.4) and AF (OR 1.32). In subgroup analyses, control of blood pressure and cholesterol did not differ significantly across cancer survivors and matched controls with hypertension and ischaemic CVDs, respectively. Conclusion We show higher burden of VRFs and an increased risk of CVDs among cancer survivors compared with non-cancer controls, with notable variation across cancer types. The lack of difference in control of blood pressure and cholesterol between cancer survivors and controls suggests that these risk factors did not explain the increased risk. Suggesting that an individualised approach to risk management is likely to be warranted.Risk of CVDs in Cancer Survivors

Dual pathway inhibition in patients with atherosclerosis with and without heart failure: insights from the XATOA Registry

Abstract Introduction Patients with atherosclerotic cardiovascular disease (ASCVD) are at a high-risk of experiencing a major adverse cardiovascular event, with 1 in 10 individuals experiencing an event within four years (1). To address this risk of secondary cardiovascular events, there have been renewed efforts to enhance secondary prevention therapies through the application of guideline-directed medical therapy. One secondary prevention strategy is the use of dual pathway inhibition (DPI) therapy with aspirin and vascular-dose rivaroxaban (2.5mg twice daily), which simultaneously targets both the platelet activation and thrombin generation pathways. Patients with concomitant ASCVD and heart failure (HF) are a subgroup with a higher risk for ischemic events, but have not been adequately represented in recent clinical trials. Purpose To explore the risks and benefits of DPI therapy in a generalizable population of patients with concomitant ASCVD and HF. Methods The Xarelto plus Acetylsalicylic acid Treatment patterns and Outcomes in patients with Atherosclerosis (XATOA) registry is a prospective, multicentre registry of patients with either coronary artery or peripheral artery disease that were initiated on DPI (2). The primary endpoint was a composite of cardiovascular death, myocardial infarction or stroke and the safety outcome was major bleeding. Multivariable logistic regression was performed to assess the association of HF status and ejection fraction (EF) on the outcomes of interest. Results Of 5532 participants, 4022 (72.7%) had documentation of HF status. Of those 873 (21.5%) had a history of heart failure (EF >40% - 461; EF ≤40% - 181, EF unknown – 231). Over a median follow-up of 465 days (IQR – 372-576), the primary outcome occurred in 4.9% of participants with HF compared to 2.4% in those without HF (aHR 1.57 95% CI 1.02-2.41). The safety outcome was similar in patients with and without HF (0.9% versus 1.11%; aHR 0.7 95% CI 0.31-1.67). Among patients with HF, those with an EF of ≤40% demonstrated a non-significant trend towards higher rates of adverse events including MACE (8.8% versus 3.5%; aHR 1.38; 95% CI 0.59-3.22) compared to those with an EF of > 40%. Conclusion In a generalizable cohort of patients with atherosclerotic disease and HF, the use of DPI is associated with similar outcomes to those observed in recent randomised controlled clinical trials.Table 1 - Demographics by HF statusFigure 1 - MACE by HF status

Revascularization strategies in elderly patients with acute coronary syndromes and multivessel disease: comparative analysis of culprit-only vs complete revascularization

Abstract Background Acute coronary syndromes (ACS) are more challenging in elderly patients, particularly when related to multivessel disease (MVD). Concerns about outcomes, and the lack of evidence, lead to more conservative treatment. While benefits of complete revascularization are well established among the youngest, doubts persist in older patients. Despite FIRE trial having showed superiority of complete revascularization with coronary physiology, in older patients with ACS and MVD, more evidence is needed. Methods Multicenter retrospective cohort of 629 patients, older than 75 years, with ACS and MVD, was divided into complete or culprit-only revascularization groups. In-hospital outcome of death and major adverse cardiovascular events (MACE) and follow-up outcome of death and cardiovascular hospital admission were assessed. Results From the 629 patients, 383 (61%) were submitted to PCI, of which 66% (n=254) were submitted to culprit-only revascularization and 34% (n=129) to complete revascularization. Culprit-only group's mean age was 83±5 years and median age in complete revascularization group was 81 (IQ 78-84) years. There was similar number of female patients in both groups (42% and 37%, p=0,26), and the culprit only group was significantly older (p=0,006). There were more ST-segment elevation myocardial infarctions in culprit- only group (p<0,001). Regarding diabetes, previous ACS, Killip classification, heart failure, stroke, peripheral artery disease, and chronic kidney disease, there were no statistically significant differences between groups (p>0,05). Complete revascularization was associated with lower in-hospital events, with 36% against 48% in culprit-only (p=0,025 OR 0,62 [0,4-0,9]), mainly due to lower in-hospital deaths, with 3% against 13% (p<0,01 OR 0,3 [0,15-0,67]) but also due to lower in-hospital MACE with 29% against 27% (p=0,02 OR 0,6 [0,4-0,9]). The mean follow-up was 13±7 months, during which, in complete revascularization group, there was non-statistically significant decrease of deaths, with 13% against 15% (p=0,4), hospital readmissions, with 21,8%, in comparison with 24,9% (p=0,2), and composite outcome, with 35% and 40% (p=0,16) of composite events in the culprit-only group There was a non-statistically significant decrease of the mean for survival time for culprit only group which was 10±8 months comparing with complete group of 13±8 months (p=0,16). Conclusion In older patients with ACS and MVD the ideal strategy is yet to be determined. Still complete revascularization strategy showed a statistically significant decrease of in-hospital death and MACE, and non-statistically significant decrease in follow-up mortality and readmissions. This study suggests, like FIRE trial, that when clinically and anatomically feasible, it seems legit to attempt complete revascularization in elderly patients with ACS and MVD.

Prognostic impact of intravascular imaging in percutaneous coronary intervention according to procedural complexity

Abstract Background/Introduction Few randomized controlled trials have shown reduction of adverse cardiac events with intravascular imaging (IVI)-guided percutaneous coronary intervention (PCI) compared with conventional angiography. However, data for IVI in complex PCI remains scarce. Purpose Current study investigated whether optimization of stent implantation in the IVI-guided PCI could improve the efficacy of PCI across various degrees of PCI procedural complexity. Methods This study was post-hoc analysis of the RENOVATE-COMPLEX-PCI (Randomized Controlled Trial of Intravascular Imaging Guidance Versus Angiography-Guidance on Clinical Outcomes After Complex Percutaneous Coronary Intervention) trial. Study population was stratified according to PCI procedural complexity assessed by the ESC criteria into low-, moderate-, or high-procedural complexity group. The high-procedural complexity group consisted of patients meeting at least one of the clinical risk criteria [diabetes mellitus, chronic kidney disease, defined as glomerular filtration rate between 15 and 60 mL/min, prior myocardial infarction (MI), peripheral artery disease, age < 45 years, multivessel coronary artery disease] and at least one of the procedural risk criteria (≥3 stents implanted, ≥3 lesions treated, total stent length >60 mm, left main PCI, chronic total occlusion, bifurcation lesion treated with 2 stents). The primary endpoint was target vessel failure (TVF), a composite of cardiac death, target vessel-related MI, or clinically driven target vessel revascularization. Results At a median follow-up of 2.1 years (interquartile range 1.4 to 3.0 years), the risk of TVF significantly increased in a stepwise fashion from the low- (reference group) to the moderate- (adjusted hazard ratio [HR]: 3.530; 95% confidence interval [CI]: 1.226-10.163, p=0.019) and high-procedural complexity group (adjusted HR: 3.951; 95% CI: 1.576-9.908; p=0.003). The effect of IVI-guided PCI was heterogeneous per PCI procedural complexity, with a significant benefit in patients who underwent high-procedural complexity PCI (adjusted HR: 0.598; 95% CI: 0.370-0.966) compared with those who had low-procedural complexity PCI (adjusted HR: 1.969; 95% CI: 0.217-17.881). Importantly, the magnitude of the benefit with IVI-guided PCI was progressively greater per increase in procedural complexity (p for interaction=0.026). Conclusions In patients who underwent complex PCI, compared with a conventional angiography, IVI-guided PCI significantly reduced the risk of adverse cardiac events with a magnitude that was greater for higher procedural complexity.

Monocyte response to mitochondrial DAMPs in elderly subjects: a possible contribution to chronic inflammation and atherosclerosis

Abstract Background Aging is an important risk factor for atherosclerosis and persists as an independent contributor when all other known factors are controlled. Circulating free mitochondrial DNA (cf-mtDNA) can activate immune cells, including monocytes, that promote plaque formation and produce proinflammatory cytokines [1]. Several receptors, including TLR9, AIM2, NLRP3, cGAS can bind cf-mtDNA and activate downstream pathways, leading to the activation of proinflammatory genes [2]. We previously showed that mtDNA increases with age, and at the highest concentrations observed in plasma, can enhance the pro-inflammatory effect of bacterial PAMPs [3]. Nevertheless, it is unknown if the pathways triggered by mtDNA are functionally preserved in elderly, and if it can synergize with oxidized low-density lipoproteins (ox-LDL), which are known to interact with TLR4 and TLR2, in concert with scavenger receptors to regulate the inflammatory microenvironment in atherosclerosis. Purpose This study aims to understand if and how the cf-mtDNA activates monocytes triggering an inflammatory response, if monocyte from young and old donors present a different response to mtDNA if age-related difference in the functional activity of these cells. Methods We selected 10 old subjects (74.4 ± 2.4 y.o.; 2M:8F) without a history of cardiovascular or peripheral arterial diseases, 4 ultranonagenarians (98.3 ± 4.7 y.o.; 1M:3F) and 9 sex-matched young controls (28.4 ± 7.3 y.o.; 0M:9F). Monocytes were isolated from blood samples, and inflammatory response to mtDNA alone or in combination with LPS was assessed, by analyzing TLR9 expression, NF-kB activation and the release in the supernatants of a panel of proinflammatory cytokines. Results Monocyte expression of the mtDNA receptor TLR9 showed a slight reduction with aging, and is similar in old subjects and ultranonagenarians. mtDNA was internalized only in cells pre-treated with LPS and co-localized with TLR9. When internalization occurred, monocytes treated with mtDNA+LPS, released pro-inflammatory cytokines at higher levels than cells treated with LPS alone. Monocytes from elderly subjects showed a partial impairment in mtDNA uptake, and a lower capability to activate TLR9 downstream pathway. However, the capability to secrete pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) was not compromised, and NF-kB translocation into the nucleus after treatment with mtDNA is preserved, suggesting that compensatory mechanisms allowed mtDNA-driven activation of monocytes in elderly people. Conclusions The capability of mtDNA to promote an inflammatory response is preserved in elderly people and is still present in ultranonagenarians subjects. As mtDNA plasma levels increase with aging, mtDNA likely act as proinflammatory agents in aged people and can contribute to maintain inflammation in the atherosclerotic plaques. Further studies will clarify if mtDNA can act synergistically with ox-LDL to promote monocyte activation.

Rurality and outcomes in prostate cancer: role of socioeconomic status and educational attainment

Abstract Background/Introduction Patients diagnosed with prostate cancer (PC) have a higher cardiovascular disease (CVD) prevalence and mortality risk. Rurality have been associated with up to 33% higher CVD risk and 44% higher all-cause mortality risk in patients with PC. Purpose Analyze the impact of rurality (from both patient and provider perspectives) on the development of adverse outcomes after a PC diagnosis according to socioeconomic and educational status. Methods We included men aged ≥66 with a new primary PC diagnosis (defined as ICD-10 = C61) from 2009-2017 from the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database. The primary outcomes were CVD (comprising heart failure, atrial fibrillation, acute myocardial infarction, peripheral artery disease, and ischemic stroke), PC-specific mortality (PCsm), cardiovascular disease mortality (CVDm), and all-cause mortality. Patients living in areas with a population of <2,500 or <20,000, not adjacent to a metropolitan area, were considered to have a positive rural status. The provider status (metropolitan vs. non-metropolitan) was defined according to the 2013 National Center for Health Statistics' Urban-Rural Classification Scheme for Counties. Low socioeconomic status (SES) was defined according to Yost Index quintiles. Low educational status was defined according to percentiles of people >25 years old with less than a high school diploma. Multivariable Fine-Gray models, accounting for competing mortality/type of mortality, and Cox regression models were applied. Results We included 75,221 patients with PC (Picture 1), of which 1,828 were from rural areas and 362 were from rural areas with providers from non-metropolitan areas. Among patients from rural areas under the care of non-metropolitan providers, 82.6% had low SES (Yost Index ≤ 2). In this subgroup, patients from rural areas with non-metropolitan providers had 30% higher CVD risk (sHR 1.30; 95% CI 1.04-1.62) and 44% higher all-cause mortality risk (sHR 1.44; 95% CI 1.14-1.83; Picture 2) when compared to patients with low SES from urban or rural areas with providers from metropolitan areas. Additionally, within patients from rural areas with non-metropolitan providers, the median % of people with only high school diploma was 38.3 (IQR 36.2-40.9). Among those with low educational status (≤41% of high school county-rate), patients from rural areas with non-metropolitan providers had a 35% higher associated CVD risk (sHR 1.35; 95% CI 1.06-1.71), 54% higher associated CVDm risk (sHR 1.54; 95% CI 1.01-2.36), and a 32% higher associated all-cause mortality risk (sHR 1.32; 95% CI 1.04-1.66). Conclusion Patients with PC from rural areas with non-metropolitan providers have higher rates of low SES and low educational status and suffer from up to 54% higher associated risks of adverse outcomes, emphasizing the role of multiple domains of the Social Determinants of Health in health outcomes.

MELD-albumin score is strongly associated with all-cause mortality in patients with acute myocardial infarction complicated by cardiogenic shock

Abstract Background Kidney and liver injury are frequent complications in patients with acute myocardial infarction complicated by cardiogenic shock (AMICS) because of hypoperfusion and venous congestion. Model of End-Stage Liver Disease replacing INR with albumin (MELD-Albumin) score quantifies liver and kidney function and has been associated with mortality in acute heart failure. Higher MELD-albumin score indicates particularly more severe hepatic dysfunction. The predictive value of MELD-albumin score has yet to be assessed in AMICS. Methods This is a retrospective, multicenter observational cohort study of 1,716 patients admitted with AMICS at two tertiary facilities in Denmark between 2010 and 2017. MELD-albumin was calculated for each patient individually from 0–72-hour peak s-albumin, s-creatinine and s-bilirubin values in patients alive beyond day 2. Patients were stratified into groups according to score (Low: 1-10, Intermediate: 11-25, High: >25). Using national health registries, we performed follow-up until a maximum of 5 years (median 3.4 years). The primary outcome was all-cause mortality. Results Of 1716 patients in the cohort, 1284 (75%) were alive beyond admission day 2. Albumin, creatinine, and bilirubin measurements were available in 764 patients (60%). The median MELD-albumin score was 17. In the comparison across high vs. intermediate vs. low score groups, the high score group revealed a significantly higher prevalence of hypertension (61 vs. 49 vs. 39%, p=0.038), diabetes mellitus (33 vs. 18 vs. 13%, p=0.003), and history of acute myocardial infarction (24 vs. 13 vs. 17%, p=0.026). Fewer had suffered out-of-hospital cardiac arrest (34 vs. 52 vs. 48%, p=0.014) and revascularization attempts (82 vs. 93 vs. 92%, p=0.007) in the high score group. No significant differences were observed in the initial hemodynamic pressures, lactate levels, left ventricular ejection fraction (LVEF), number of diseased vessels and culprit lesions between the three groups. Patients in the high score group had a 30-day mortality rate of 58%, which was higher compared to 40% in the medium- and 17% in the low score group (Figure 1, p<0.001, using the log-rank test). These findings were still significant when excluding s-creatinine from the calculations. In a Cox Regression analysis, a MELD-albumin score of >25 was associated with a hazard ratio (HR) of 4.34 for 5-year mortality (p < 0.001), whereas a score of 11-25 was associated with a HR of 2.52 (p < 0.001). When adjusting for age, diabetes, hypertension, dyslipidemia, peripheral arterial disease, STEMI, left ventricular ejection fraction and baseline lactate, scores of >25 and 11-25 were still associated with similar 4- to 2.5-fold increases in 5-year mortality risks. Conclusions This study revealed a strong association between MELD-albumin score and all-cause mortality among patients with AMICS, supporting kidney and liver function inclusion in future risk stratification models.

Educational attainment and cardiovascular outcomes in prostate cancer: observations from 3700 men in 6 countries in the RADICAL PC study

Abstract Background Educational attainment has been associated with improved cardiovascular outcomes in individuals with or at high risk for cardiovascular disease (CVD). There is little information on the relationship between education and CVD outcomes in individuals with cancer. Also, we have limited understanding of what mediates the relationship between education and these outcomes. Purpose To evaluate the relationship between educational attainment in patients with PC and CVD event (CVE) or all-cause mortality. Methods We prospectively studied 3,778 men with PC from 55 sites in 7 countries (median age 69 years), 46% on ADT. Inclusion criteria were one of: PC diagnosed in the past 12 months; started ADT within the past 6 months; or plan to start ADT in the next month. Educational attainment was classified as those who attained primary school education vs. those who attained high school education vs. those who attained greater than high school education. Participants were followed for a median of 2.5 years from enrolment to document CVE: myocardial infarction, angina, stroke, cerebrovascular disease, peripheral arterial disease, arterial revascularization, heart failure, venous thromboembolism, and atrial fibrillation. The primary outcome for this analysis was CVE or death. All outcomes were evaluated by Cox proportional hazards models adjusted sequentially for age, race, physical activity levels, tobacco use, and alcohol use. Results Among 3,778 participants, 726 (19%) achieved primary school education, 1,001 (27%) high school, and 2,051 (54%) greater than high school education. On univariate analysis, as compared with participants with greater than high school education, those with high school education and primary school education had respective HR (95% CI) of 1.33 (1.05-1.69) and 2.19 (1.71-2.83). Adding age, race, tobacco, and alcohol use to the Cox model progressively attenuated the association between education and the primary outcome. Eventually, after adjustment for these characteristics and physical activity levels, the relationship between education and the primary outcome was no longer significant (Table). Conclusion This finding suggests that patterns of tobacco and alcohol use and physical activity, which are modifiable behaviors, account for the relationship between education and death or CVE in patients with prostate cancer.Table

Elderly patients with decompensated heart failure: prospective analysis from the LECRA-HF registry

Abstract Background/Introduction Heart failure (HF) presents as a clinical syndrome associated with an adverse prognosis, increased mortality risk, and recurrent hospitalizations for HF (HHF). In Poland, there has been a persistent increase in the overall prevalence and hospitalizations of HF among patients. Each subsequent HHF is associated with progressively worsening prognosis. In Europe, HF is most prevalent in elderly individuals, rendering this patient group particularly susceptible to HF exacerbations. Purpose The aim of this study was to conduct a comprehensive analysis of the oldest patients (≥80 years) hospitalized due to HF decompensation, compared to the rest of the evaluated cohort, including overall mortality after median 46 months of observation. Methods The prospective registry of patients with HF decompensation (LECRA-HF) is an ongoing registry conducted at a tertiary cardiology center specializing in HF treatment. Patients enrolled in the registry (n=1394) were evaluated for the presence of cardiovascular risk factors, HF phenotype, laboratory, and echocardiographic findings, as well as overall mortality. Due to the frequent occurrence of HF in elderly patients, we arbitrarily chose to compare two cohorts of patients: those above (n=306) vs. below 80 years of age (n=1088). Results Median age of elderly patients was 84 [82-86] years, of which only 7.8% were >90 years of age. HFrEF was the most common HF phenotype, which, occurred less frequently in the elderly (54.4 vs 74.4%, P<0.001). In turn, HFpEF was more prevalent in elderly group (39.2 vs 17.7%, P<0.001). Elderly patients were more often female (45.1 vs 30.2%, P<0.001) and had more comorbidities: arterial hypertension (85.6 vs 78.6%, P=0.007), atrial fibrillation (61.1 vs 45.7%, P<0.001), renal failure (49.7 vs 28.5%, P<0.001) as well as peripheral arterial disease (17 vs 9.8%, P=0.005). Those patients had more frequently implanted cardiac pacemakers (28.6 vs 12.6%, P<0.001), but less often implantable cardioverter-defibrillators (7.9 vs 14.3%, P=0.003). During HHF they were less often qualified to elective coronary angiography (24.2 vs 31.5%, P=0.039). At discharge mineralocorticoid receptor antagonist were less often prescribed in that group (42.4 vs 50.3%, P=0.010). During long-term observation patients ≥80 years had a higher all-cause mortality (81 vs 67.4%, P<0.001, Panel A). Moreover, it was also higher elderly with NT-proBNP>4497 pg/mL (P<0.001) and LVEF<41% (P=0.014) (Panel B). Conclusion(s) Patients aged ≥80 years were characterized by a higher burden of comorbidities. They were more often qualified to cardiac pacemakers, but less often to implantable cardioverter-defibrillators and invasive coronary procedures. The most common HF phenotype was HFrEF, however with a significant increase in HFpEF. They exhibited significantly higher overall mortality compared to those <80 years old, which was associated with both LVEF and NT-proBNP levels.

Sex differences in cardiovascular-related hospital readmissions, adverse events and interventions within 1 year after ST-elevation myocardial infarction

Abstract Introduction Reducing cardiovascular (CV)-related hospital readmissions as well as adverse events following ST- elevation myocardial infarction (STEMI) is a critical goal to improve outcomes as well as quality of life and reduce healthcare costs. We aimed to study the rates of CV-related readmissions, adverse events and interventions after STEMI in women and men. Methods We included STEMI patients from the Acute Myocardial Infarction in Switzerland (AMIS) Plus registry, who underwent percutaneous coronary intervention (PCI) between 2013 and 2022 and participated in a telephone-based follow-up (FU) interview 1-year after hospital admission. Patients were asked if they had hospital readmissions (if yes: planned/emergency/both) during FU for any CV reason, if they suffered a reinfarction or stroke and if they had any or several of the following interventions: PCI, coronary artery bypass graft, pacemaker and/or defibrillator implantation. These self-reported data were analysed using descriptive statistics and logistic regression models were used to study the relationship between patient characteristics and hospital readmissions. Results Of 4388 PCI-treated STEMI patients contacted for FU, 275 (6.3%) were unreachable, 118 (2.7%) died, and 223 (5.1%) had no data on readmissions; therefore 3772 patients (78.4% men, 21.6% women) were analysed. Women were older (mean (SD) age at event: 68.4 (12.0) vs. 62.5 (11.5) years) while the Charlson Comorbidity Index (CCI) was similar (CCI>1: 14.0% vs. 12.1%, n.s.). The mean rate of patients readmitted for CV reasons was 22.1%; 20.4% for women and 22.6% for men (p=0.198). Overall, 8.8% had at least one emergency and 13.9% at least one planned readmission. The occurrence of a planned readmission was significantly lower in women (11.1% vs. 14.7%, p=0.008). Patients with a readmission had during the index hospitalisation higher rates of in-hospital complications (18% vs. 14%), heart failure (NYHA III+IV) (2.2% vs. 0.8%), diabetes (18% vs. 14%) and peripheral arterial disease (3.9% vs. 2.5%). A multivariable adjusted model that included these factors together with age and sex identified heart failure (OR: 2.5, CI 1.34-4.66, p=0.004) and in-hospital complications (OR:1.4, CI 1.12-1.70, p=0.003) as independent predictors of hospital readmission. The rates of the analysed adverse events and interventions were similar between sexes except that women had less often a PCI during the FU period (13.2% vs. 16.6%, p=0.026). Conclusion Over the last 10 years, on average 1 in 5 patients had at least one CV-related readmission within 1 year after PCI-treated STEMI, while no overall sex-difference was found. Heart failure and in-hospital complications were independent predictors of readmission. Women had less often planned hospital readmissions and additional PCIs.

Impact of a clinician-to-clinician electronic consultation program in heart failure patients with previous hospitalization. Implications for heart failure multidisciplinary management

Abstract Background A clinician-to-clinician electronic consultation (e-consultation) programme may not only improve the accessibility to care but may also impact patient outcomes, particularly in heart failure (HF) patients with a previous episode of hospitalization (HFH), group of patients associated with a worse outcome. Purpose To evaluate the impact of an outpatient care management programme that includes a clinician-to-clinician e-consultation on delay time in care, hospital admissions, and mortality in a high-risk group of patients with heart failure (HF) and previous episodes of HF hospitalization (HFH). Materials and methods We selected 6444 HF patients who visited the cardiology service at least once between 2010 and 2021. Of these, 4146 were attended in e-consultation, and 2230 had previous HFH (Fig 1a). Using an interrupted time series regression model, we analysed the impact of incorporating e-consultation into the healthcare model in the group of patients with HFH and evaluated the elapsed time to cardiology care, HF, cardiovascular (CV), and all-cause hospital admissions and mortality, calculating the incidence relative risk (iRR). We performed a multivariate logistic regression for each of these outcomes in both groups. Results Patients with HFH had a higher prevalence of men (P < 0.001) but had a similar age (P = 0.267) compared to patients without HFH. Patients with HFH had a higher prevalence of diabetes (P < 0.001), ischaemic heart disease (P = 0.036), and peripheral arterial disease (P = 0.008) (Fig 1b). In the group of patients with HFH, the introduction of e-consult substantially decreased waiting times to cardiology care (8.6 [8.7] vs. 55.4 [79.9] days, P < 0.001) (Fig 2a). In that group of patients, after e-consult implantation, hospital admissions for HF were reduced (iRR [95%CI]: 0.837 [0.840–0.833]), 0.900 [0.862–0.949] for CV and 0.699 [0.678–0.726] for all-cause hospitalizations (Fig 2b). There was also lower mortality (iRR [95%CI]: 0.715 [0.657–0.798] due to HF, 0.737 [0.764–0.706] for CV and 0.687 [0.652–0.718] for all-cause) (Fig 2c). The improved outcomes after e-consultation implementation were significantly higher in the group of patients with previous HFH. The multivariate analyses showed a higher risk of hospitalizations in men, patients with HFH, and those who required more emergency department assistance (Fig 2d). Conclusions In patients with HFH, an outpatient care programme that includes an e-consultation significantly reduced waiting times to cardiology care and was safe, with a lower rate of hospital admissions and mortality in the first year. Our results may have implications for optimize the heart failure care organization.Figure 1Figure 2

Use and associations with mortality/morbidity of guideline-directed medical therapy use in heart failure with improved ejection fraction: a PS-matched analysis from the swedish heart failure registry

Abstract Background Guideline-directed medical therapy reduces mortality/morbidity in heart failure (HF) with reduced ejection fraction (EF). However, evidence about its use and prognostic role once EF has improved is limited. Purpose To assess use and associations with mortality/morbidity of renin-angiotensin system inhibitors (RASi), angiotensin-receptor neprilysin inhibitors (ARNi), beta-blockers (BBL), and mineralocorticoid receptor antagonists (MRA) in patients with HF and improved EF (HFimpEF). Methods We analyzed patients with HFimpEF, defined as a first recorded EF <40% and a subsequent EF ≥40%, registered in the Swedish HF registry between 2004 and 2021. Index date was the SwedeHF registration reporting the second (i.e. improved) EF assessment. To reduce the bias related to the initial recommendation for MRA limited to more severe HF (NYHA III-IV), the assessment of MRA was restricted to patients with index date 2016 or later, when Swedish guidelines on HF included a recommendation for MRA in patients with NYHA class II–IV. The association between treatment use and the composite outcome cardiovascular mortality (CVM)/HF hospitalization (HHF) (with censoring >3 years) was assessed by Cox proportional hazard models in a 2:1 propensity score-matched cohort. Propensity scores for treatment use were calculated by a logistic regression model including 38 variables, achieving a standardized mean difference <0.1 for all evaluated variables. Since matching reduces the sample size and may limit generalizability, a Cox proportional hazard model was fitted in the overall cohort adjusting, rather than matching, for the propensity score (Overall HR). Results Of 4700 patients with HFimpEF (mean age 68±12 yrs, 70% male), 94%, 95%, and 50% received RASi/ARNi, BBL, and MRA, respectively. Regardless of the specific treatment, non-users had lower BMI, education level and use of other HF medications, but older age, higher EF at improvement, higher NT-proBNP, and more likely peripheral artery disease, anemia, and valvular disease. In the matched cohorts, RASi/ARNi use was associated with a statistically significant lower risk of CVM/HHF [hazard ratio (HR) 0.71, 95% confidence interval (CI) 0.53–0.95] (Figure). There was no statistically significant association between CVM/HHF and beta-blockers (HR 0.75, (95% CI 0.53-1.08), and MRA (HR 1.16, 95% CI 0.90-1.49). These results were consistent after adjustment for the propensity score in the overall cohort (Figure). Conclusion In patients with HFimpEF use of GDMT was high. Treatment with RASi/ARNi was associated with lower morbidity and mortality, whereas no statistically significant association was observed with beta-blockers which might be explained by limited statistical power.Composite outcome.

Ambrisentan reverses the prosenescent and anti-autophagic effect of high glucose on human pulmonary artery endothelial cells exposed to hypoxia

Abstract Background Cardiovascular (CV) comorbidities (systemic hypertension, hyperlipidemia, obesity, diabetes mellitus, peripheral arterial disease, coronary artery disease) are associated with reduced treatment response to specific drugs for group 1 pulmonary arterial hypertension (PAH). Often this epidemiological evidence is the result of misdiagnosis of group 2 PH associated with left heart disease, but it can also be explained as the intrinsic loss of the ability of pulmonary endothelial cells to respond to specific antiremodeling drugs. Aims To evaluate the impact of high glucose and hyperosmolar stress on the responsiveness of human pulmonary artery endothelial cells (hPAECs) to the endothelin receptor antagonist ambrisentan in terms of senescence, autophagic activity, viability and expression of some microRNAs involved in pulmonary arterial remodeling. Methods We incubated hPAECs with high glucose (HG, 30.5 mM) or high mannitol (HM, 25 mM), with/without ambrisentan (0.02 nM) in normoxia (N) or hypoxia (H) for 24 h and tested them for cell viability (MTT assay), protein and miRNA levels, autophagy and senescence (β-Gal assay) in vitro. Results H induced cell death as compared to N (752 ± 44 vs 701 ± 45 Abs units, p = 0.03). H reduced autophagy (Figure 1A-C) and induced senescence (Figure 1D), an effect further potentiated by HG and HM. Treatment with A in N and H significantly reversed the effect of HG but not HM on autophagy (Figure 1A-C) and senescence (Figure 1D). H increased the abundance of antiapoptotic miR124-3, compared to N in vehicle (V)-treated hPAEC (p=0.008) (Figure 2A), and induced a similar effect on antiapoptotic and proliferative miR191-3p, although not statistically significant (Figure 2B). In N, A potentiated the expression of both miR124-3p (p=0.007) and miR191-3p (p=0.02) in HG-treated hPAEC, and only miR191-3p in HM-treated hPAEC (p=0.01). A induced a similar effect on miR191-3p in hPAEC exposed to H+HG (p=0.02), with a non-statistically significant trend on miR124-3p. Conclusions In hPAEC exposed to H, A retains its pro-autophagic and antisenescent effects in an in vitro model mimicking diabetes. miR124-3p and miR191-3p may act as biomarkers of disease and treatment response to specific drugs in patients with PAH.Figure 1:autophagy and senescenceFigure 2:miRNA expression