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Abstract Background Cardiovascular disease remains the leading cause of death and burden globally, warranting the need to explore novel predictors of major adverse cardiovascular events (MACE) using new technologies. Artificial Intelligence (AI)-enhanced ECG (AI-ECG) algorithms can provide information on cardiovascular health of individuals, independent of conventional risk factors. Purpose The current study aimed to understand whether a previously described AI-ECG sex estimation algorithm could be applied for risk stratification of major adverse cardiovascular events (MACE), with a focus on a population without previous history of MACE. Methods Patients having 12-lead ECGs between 2018-2019 were included and followed up until August 2023. Exclusion criterion was a prior history of MACE. AI-ECG sex estimation was determined using a previously described algorithm predicting sex based on 12-lead ECGs. The algorithm generates outputs ranging from 0 to 1, representing the estimated probability of being male. Outputs above 0.5 were considered as AI-ECG-estimated male, and below as AI-ECG-estimated female. This was compared with biological sex to determine whether the two matched. Inconsistency between AI-ECG estimated sex and biological sex was defined as discordance. MACE was defined as myocardial infarction, coronary revascularization, non-fatal stroke, and all-cause death. Results Among 80,578 subjects (mean age 59.1 ± 16.1 years, 52.4% female), 9.7% exhibited sex discordance in AI-ECG estimation. Discordance was associated with a 56% higher risk of MACE (HR, 1.56, 95% CI 1.46-1.65, p <0.001), and remained significant in multivariable analysis with traditional risk factors (HR 1.35, 95% CI 1.27-1.43, p <0.001) (Figure 1). Sex-specific analysis showed increased MACE risk in both discordant males and females (Figure 2). Conclusion In patients with no history of MACE, discordance in AI-ECG sex estimation is associated with increased risk of MACE. These findings suggest the potential of AI-ECG sex estimation algorithm for risk assessment, especially in patients with no history of MACE.Figure 1.Cox proportional hazard modelFigure 2.Kaplan-Meier of MACE by sex

Abstract Background Patients with carotid artery disease undergoing carotid endarterectomy (CEA) appear to be at high risk of all-cause mortality during their follow-up. However, the possible predictors of this adverse outcome are not elucidated yet. Purpose We aimed to test cardiovascular (CV) risk factors as possible predictors of all-cause mortality in patients undergoing CEA and to determine whether there is a difference between the mortality rate of our study cohort and the general population. We hypothesize that CEA-treated patients have a higher mortality rate during follow-up after surgery than the general population, which is not related to the presence of CV risk factors. Methods We prospectively enrolled and followed up patients undergoing CEA. Univariate and multivariable Cox regression were performed to test whether common CV risk factors (demographics, laboratory values, comorbidities, and events before CEA) were predictive of all-cause mortality. We then compared the standardized mortality ratio (SMR) of our population and the age-sex-matched Minnesota (MN) general population at 5,10, and 21 years of follow-up after CEA. Results A total of 710 patients were followed for a median of 7.1 [2.9-11.9] years after CEA. Mortality occurred in 198 (27.0%) patients during the follow-up. The median time to event was 11.0 [10.0-12.0] years. Age was the only predictor of all-cause mortality in CEA-treated patients in multivariable models adjusted for known CV risk factors (Model 1: HR 1.03 [95%CI 1.01-1.06]; p=0.004; Model 2: HR 1.02 [95%CI 1.00-1.04]; p=0.023) (Table 1). However, the CEA-treated group had a higher mortality rate than would have been expected in the MN population (log-rank p<0.001) (Fig.1A). Compared to the MN population, at 5 years of follow-up only patients <60 years old had a higher SMR (4.53 [1.95-8.92]; p=0.001), whereas, at 10 years and 21 years of follow-up, our study population had a higher mortality rate at any age (Fig.1B). Conclusions The elevated mortality risk post-CEA in our cohort cannot be solely attributed to chronological aging. The underlying process of atherosclerosis likely contributes to all-cause mortality, and plaque characteristics may offer additional insight into the risk stratification of this patient group.All cause mortality predictors after CEAStudy population vs. MN population SMR

Abstract Background Patients with carotid artery disease undergoing carotid endarterectomy (CEA) have a high risk of experiencing Major Adverse Cardiovascular Events (MACE) after surgery. The occurrence of MACE in CEA-treated patients is not predicted by common cardiovascular (CV) risk factors. Purpose We aimed to identify the association between plasma and plaque inflammatory cytokines and the incidence of MACE in the follow-up after CEA. We hypothesized that MACE is related to a higher level of circulating inflammatory cytokines at the time of surgery. Methods We prospectively enrolled patients with carotid artery disease undergoing CEA. Plasma and carotid plaques were collected during the surgery. Inflammatory cytokines (MCP-1/CCL2, IL-8/CXCL8, IFN-gamma, IL-10, IL-1beta/IL-1F2, IL-6, PDGF-AA, PDGF-AB/BB, TNF-alpha, VEGF) were measured in plasma and tissue homogenates using a customized 10-plex Luminex assay. Baseline demographics and clinical data for all the patients were extracted from electronic health records. MACE after CEA was defined as a composite measure of nonfatal cardiac events such as myocardial infarction with or without revascularization, cerebrovascular events (ischemic stroke, TIA, and amaurosis fugax), and all-cause mortality. Results Of 107 patients who underwent CEA with a median age of 73 (67-78) years, 57 (53.2%) experienced MACE during a median follow-up of 5.2 [2.2-9.3] years: 23 (40.3%) cardiac events, 9 (15.7%) CVA, and 25 (43.8%) all-cause mortality. Plaque cytokines levels did not differ between the groups with and without MACE in the follow-up after CEA. Instead, plasma cytokines were associated with MACE in the follow-up after CEA, as summarized in Figure 1. In the logistic regression analysis, plasma levels of MCP-1/CCL2, IFN-gamma, and TNF-alpha were independent predictors of MACE in follow-up post-CEA in univariate and multivariable models adjusted for CV risk factors such as age, BMI, systolic and diastolic blood pressure, low-density lipoprotein, high-density lipoprotein, and glucose level: MCP1/CCL2 (HR 1.009 [1.002-1.015]; p=0.007), IFN-gamma (HR 1.368 [1.014-1.845]; p=0.040), and TNF-alpha (HR 1.121 [1.022-1.228]; p=0.015) (Table 1). Conclusions Plasma levels of CCL2, IFN-gamma, and TNF-alpha are associated with the high incidence of MACE in the follow-up after CEA, indicating that these are potential biomarkers of MACE in this patient population and potential therapeutic targets in patients' progression of systemic atherosclerosis.Plasma cytokines and MACE after CEACytokines logistic regression analysis

Abstract Background One of the main features of vulnerability in atherosclerotic carotid plaques is intraplaque hemorrhage (IPH), which is related to a higher incidence of cerebrovascular events in patients with carotid artery disease. Additionally, inflammation plays a pivotal role in the progression of atherosclerotic disease. Purpose We aimed to determine plasma and tissue levels of inflammatory cytokines in patients with carotid artery disease hypothesizing that plaques with IPH are characterized by the presence of a more inflamed environment. Methods We retrospectively enrolled 104 consecutive patients undergoing carotid endarterectomy (CEA) with symptomatic (ischemic stroke, TIA, amaurosis fugax) or asymptomatic ipsilateral carotid artery disease. Plasma and carotid plaque specimens were collected at CEA. The tissue samples were stained with H&E to identify IPH and classified as specimens with and without IPH. Frozen homogenates of both plasma and tissue were analyzed using a customized 10-plex Luminex assay to determine the levels of inflammatory cytokines such as MCP-1/CCL2, IL-8/CXCL8, IFN-gamma, IL-10, IL-1beta/IL-1F2, IL-6, PDGF-AA, PDGF-AB/BB, TNF-alpha, and VEGF. Results IPH was identified in 53 patients (51.0 %). Cytokine levels in plasma and tissue from patients with and without IPH are reported in Table 1. In the univariate logistic regression MCP-1/CCL2, IL-8/CXCL8, IFN-gamma, IL-10, IL6, PDGF-AA, and PDGF-AB/BB were associated with IPH (Table 2). In the multivariate logistic regression, IL-6 was an independent predictor of IPH (HR 1.026 [95% CI 1.005-1.047]; p=0.014) after adjusting for cardiovascular risk factors such as age, BMI, sex, hypertension, diabetes mellitus, hyperlipidemia, ipsilateral carotid stenosis %. Conclusions Carotid plaques with IPH have an elevated inflammatory burden, potentially impacting adverse outcomes in this patient cohort. The local inflammatory cytokines in carotid plaques with IPH might serve as biomarkers and therapeutic targets in patients with carotid artery disease.

Abstract Background Patients with ischemia and nonobstructive coronary arteries (INOCA) suffer from a broad range of anginal symptoms that may differ depending on the biologic sex of the patient, the underlying coronary vasomotor disorder, or the type of presentation. Purpose We sought to characterize the symptom description and angina classification of patients referred for invasive coronary function testing (CFT) in the DISCOVER INOCA multicenter registry, stratified by type of presentation (stable vs unstable), biologic sex, and underlying diagnosis, including coronary microvascular dysfunction (CMD), vasospastic angina (VSA), or other disorders such as symptomatic myocardial bridging. Methods DISCOVER INOCA is a prospective, multicenter registry in the United States that includes patients who are referred for clinically indicated coronary angiography and found to have INOCA. All patients underwent protocol-guided angiography, acetylcholine provocation, coronary thermodilution, and intravascular imaging. Symptom characteristics were compared between groups. Results From September 2022 until February 2024, 104 patients were enrolled, 78% were female, and mean age was 57 ± 11 years. The post-procedure diagnosis was CMD in 19%, VSA in 41%, a mixed syndrome in 15%, or other diagnosis in 26%. The average coronary flow reserve (CFR) was 2.9 ± 1.1 in the CMD group and 5.3 ± 3.0 in the VSA group, (p < 0.001). 53% of patients presented with stable angina and 47% with unstable or progressive symptoms. Symptoms included chest pain (89%), chest tightness (42%), chest pressure (39%), shortness of breath (53%), and fatigue (16%), and no significant differences were reported when stratified by diagnostic phenotype. Female patients were more likely to report arm/neck/back/jaw pain (25% vs 5% in men, p = 0.038). Symptom triggers included exertion/activity in 73%, emotional stress in 12%, and resting symptoms in 58%. In female patients 4% reported catamenial symptoms. Of patients with stable angina, the Canadian Cardiovascular Society (CCS) Angina Classification was Grade I in 25%, Grade II in 52%, Grade III in 21%, and Grade IV in 2%. In patients with unstable angina, the Braunwald Angina Classification was Class I in 9%, Class II in 73%, and Class III in 18%. Conclusions Patients with INOCA referred for clinically indicated coronary angiography and CFT were predominantly female and most commonly reported chest pain as a presenting symptom. Female patients were more likely to report arm/neck/back/jaw pain than male patients. Over half of patients reported resting symptoms with no differences between the diagnostic phenotypes (CMD, VSA, or other). The CCS and Braunwald angina classification indicated that most patients had moderate intensity symptoms. Patient-reported outcome measures will be used to systematically categorize the symptom burden in these patients.

Abstract Background Six percent of patients presenting with acute myocardial infarction (MI) have MI with non-obstructed coronary artery disease (MINOCA). Coronary microvascular disease (CMD) is common in angina with non-obstructive coronary artery disease (ANOCA), but its prevalence and severity in MINOCA is undefined. Purpose Patients with CMD may have elevated risk of myocardial infarction despite no significant stenosis. We tested the hypothesis that patients with MINOCA have more significant burden of CMD than patients with ANOCA. Methods A retrospective case-control study was performed on patients who underwent invasive testing for signs of coronary ischemia and found to have non-obstructive disease (stenoses< 50%). Cases of MI were classified as MINOCA (n=87) and compared to patients with ANOCA (n=552). Patients with spontaneous coronary artery dissection, myocarditis, Takotsubo cardiomyopathy or prior atherothrombotic MI were excluded. Coronary catheterization was performed followed by invasive provocation testing with adenosine and acetylcholine using a Doppler flow wire. CMD was subdivided into endothelium-independent, defined as coronary flow reserve (CFR) < 2.5 with intra-coronary adenosine, and endothelium dependent, defined as < 50% increase in coronary blood flow with acetylcholine. Epicardial vasoconstriction > 90% with typical anginal symptoms was classified as epicardial vasospasm. Results There was no difference in age, sex or traditional coronary risk factors between the MINOCA and ANOCA groups (Table 1). Fifty (57%) of patients with MINOCA had type 2 MI secondary to supply-demand mismatch. Both MINOCA and suspected ANOCA patients had a high prevalence of CMD (71% vs 67%) and endothelium-independent CMD is more prevalent in MINOCA (64.5% vs 50.4%). Although odds of endothelium-dependent CMD were similar, the CFR within this group and CMD overall was worse in MINOCA patients (Figure 1). There was no difference in epicardial spasm. Conclusion Coronary microvascular disease and vasomotor dysfunction are common in patients with MINOCA, with a higher prevalence of endothelium-independent CMD and more severe CMD overall compared to patients with ANOCA. Treatment of CMD in patients with MINOCA may help reduce recurrence and warrants further investigation.

Abstract Kidney injury is a major medical burden and one of the most common reasons for hospitalization and poor life quality. Kidney injury can include acute kidney injury, chronic kidney disease, and immune-mediated kidney diseases most of which have no definitive therapy. The spleen is a secondary lymphoid organ in the reticuloendothelial system that plays an important role in protecting the body from various diseases. Notably, spleen tyrosine kinase, a non-receptor tyrosine kinase, is a crucial player that aids in immunity and protection and is highly expressed in the kidney and hematopoietic cells. It has been shown that alterations in spleen tyrosine kinase function or expression could lead to a wide range of diseases and abnormalities. Over the past decade, the role of spleen and spleen tyrosine kinase in multiple kidney diseases has emerged. Evidence suggests that modulating the spleno-renal connection through activation of the cholinergic anti-inflammatory pathway can be a promising strategy for protecting against kidney injury. Imitating the protective function of the spleen through interleukin-10-extracellular vesicles can also be of therapeutic value. In addition, evidence showed that inhibition of the spleen tyrosine kinase leads to amelioration of the kidney injury. However, further exploration and long-term studies are needed to unravel the spleno-renal connection, as well as the efficacy of spleen tyrosine kinase inhibitors, before they can be used as means for treatment of kidney injury. Graphical Abstract

Background Myocardial bridging (MB) is accompanied by the dynamic extravascular compression of epicardial coronary arteries, leading to intracoronary hemodynamic disturbance with abnormal coronary flow profiles. We aimed to evaluate the prognostic implications of resistive reserve ratio (RRR), a composite measure of flow and pressure parameters that represents the vasodilatory capacity of the coronary arteries, in patients with angina with nonobstructive coronary artery disease (ANOCA) and MB, in comparison with coronary flow reserve (CFR). Methods and Results In this retrospective cohort study, we included patients with ANOCA who underwent coronary reactivity testing, where MB was identified by transient constriction in coronary artery segments between systole and diastole. Abnormal CFR and RRR were defined as <2.5 and <2.62, respectively. Major adverse cardiac events, including cardiovascular death, stroke, myocardial infarction, heart failure, and late revascularization, served as outcomes. Among 1251 patients with ANOCA, 191 (15.3%) had MB. The prevalence of abnormal CFR or RRR was not significantly different between patients with and without MB ( P =0.144 and P =0.398, respectively). Over a median follow‐up time of 6.9 years, abnormal RRR predicted major adverse cardiac events in patients with MB (hazard ratio [HR], 4.38 [95% CI, 1.71–11.21]; P =0.002) and without MB (HR, 1.91 [95% CI, 1.38–2.64]; P <0.001). Abnormal CFR predicted major adverse cardiac events in patients without MB (HR, 2.15 [95% CI, 1.54–3.00]; P <0.001), whereas it was not predictive of major adverse cardiac events in patients with MB (HR, 2.29 [95% CI, 0.93–5.65]; P =0.073). Conclusions In patients with ANOCA and MB, impaired RRR was superior to impaired CFR in distinguishing patients at a higher risk of future adverse events, suggesting that RRR may serve as a risk stratification tool in patients with MB and ANOCA.

Key Points Renovascular disease impairs the capacity of human adipose tissue–derived mesenchymal stem/stromal cells to repair ischemic murine kidneys. miR-378h modulated the capacity of renovascular disease adipose tissue–derived mesenchymal stem/stromal cells to repair ischemic kidneys in vivo . Background Renovascular disease leads to renal ischemia, hypertension, and eventual kidney failure. Autologous transplantation of adipose tissue–derived mesenchymal stem/stromal cells (MSCs) improves perfusion and oxygenation in stenotic human kidneys, but associated atherosclerosis and hypertension might blunt their effectiveness. We hypothesized that renovascular disease alters the human MSC transcriptome and impairs their reparative potency. Methods MSCs were harvested from subcutaneous abdominal fat of patients with renovascular disease and healthy volunteers ( n =3 each), characterized and subsequently injected (5×10 5 /200 μ l) into mice 2 weeks after renal artery stenosis or sham surgery ( n =6/group). Two weeks later, mice underwent imaging and tissue studies. MSCs from healthy volunteers and in those with renovascular disease were also characterized by mRNA/microRNA (miRNA) sequencing. Based on these, MSC proliferation and mitochondrial damage were assessed in vitro before and after miRNA modulation and in vivo in additional renal artery stenosis mice administered with MSCs from renovascular disease pretreated with miR-378h mimic ( n =5) or inhibitor ( n =4). Results MSCs engrafted in stenotic mouse kidneys. Healthy volunteer MSCs (but not renovascular disease MSCs) decreased BP, improved serum creatinine levels and stenotic-kidney cortical perfusion and oxygenation, and attenuated peritubular capillary loss, tubular injury, and fibrosis. Genes upregulated in renovascular disease MSCs versus healthy volunteer MSCs were mostly implicated in transcription and cell proliferation, whereas those downregulated encoded mainly mitochondrial proteins. Upregulated miRNAs, including miR-378h, primarily target nuclear-encoded mitochondrial genes, whereas downregulated miRNAs mainly target genes implicated in transcription and cell proliferation. MSC proliferation was similar, but their mitochondrial structure and reparative function both in vivo and in vitro improved after miR-378h inhibition. Conclusions Renovascular disease impaired the reparative capacity of human MSCs, possibly by dysregulating miR-378h that targets mitochondrial genes. Podcast This article contains a podcast at https://dts.podtrac.com/redirect.mp3/www.asn-online.org/media/podcast/JASN/2024_08_21_ASN0000000000000440.mp3

Objective: Arterial hypertension (HTN) coexisting with chronic kidney disease (CKD) presents a significant global healthcare challenge, with limited effective clinical interventions. Electro-Hydraulic Acoustic Therapy (eHAT), a lower-energy modality vs. lithotripsy, emerges as a promising technique for relieving ischemia and promoting tissue regeneration. We hypothesized that eHAT would reduce blood pressure (BP) and preserve renal function in patients with hypertension and CKD. Design and method: Twenty medically treated patients with HTN and Stage IIIa/b CKD enrolled in this prospective, single-arm study were treated over 3-weeks with six eHAT sessions (2400 shockwaves/kidney; 0.09 mJ/mm2 at 2.66Hz; NephrospecTM, Curespec, Yehud, Israel). Follow-up (FU) visits at 1, 3, 6, and 12 months involved measurements of attended and unattended office BP, ambulatory BP and estimated glomerular filtration rate (eGFR). Results: The treatment was well tolerated. All BP measurements strongly tended to decline over 12 months and showed a similar pattern.(Table 1, Figs. 1-3), whereas eGFR was well preserved (Table 1, Fig. 4). Conclusions: Conclusion. eHAT is a tolerable and safe procedure and, moreover, a 3-week regimen tends to reduce BP and preserve eGFR in patients with HTN and CKD. Therefore, eHAT may constitute a novel, safe, and non-invasive alternative therapeutic approach in the management of HTN in the context of CKD.