Lerman, Lilach O.

Background α‐Klotho is a multifunctional protein implicated in vascular aging. Declining Klotho levels are associated with arterial stiffness, endothelial dysfunction, and vascular calcification. We investigated the associations between circulating klotho, aortoiliac calcification, endothelial progenitor cells, and 10‐year survival. Methods In this retrospective cohort, blinded clinicians scored calcification on computed tomography (0–10 scale: aorta 6 points, iliac 4 points). Plasma klotho was measured by ELISA; endothelial progenitor cell subsets were quantified via flow cytometry. Mortality data were obtained from the Minnesota Death Registry. Results This study included 148 participants (mean age 72.4±9.6 years; 41% female). Median calcification score was 3 (interquartile range, 1–5). Patients with low calcification had higher Klotho levels (669 [567–841] versus 556 [457–678] pg/mL; P <0.01), with Klotho inversely correlated with calcification (r=−0.315, P <0.01). Stratified by calcification location and severity, the highest Klotho levels were seen in patients without aortic or iliac calcification ( P =0.015). Over 10 years, low Klotho was independently associated with higher mortality (hazard ratio [HR], 3.056 [95% CI 1.288–7.878]; P =0.014). Klotho inversely correlated with mature osteocalcin‐positive EPCs; B=−0.16 (95% CI, −0.29 to −0.02; P =0.027). Immunohistochemistry and immunofluorescence confirmed endothelial Klotho expression in internal mammary artery. Conclusions Lower circulating Klotho levels are associated with increased aortoiliac calcification and higher 10‐year mortality, supporting a role for Klotho in vascular aging.

Introduction: Blood pressure (BP) is a complex physiological marker. Cuffless devices, often based on photoplethysmography (PPG), enable frequent or continuous BP monitoring without arterial occlusion, enhancing comfort and usability in both inpatient and outpatient settings. Various devices have received regulatory clearance, but they are not yet included in clinical guidelines due to evolving validation standards. Aim: To evaluate accuracy of the Biobeat WP613 device for continuous BP monitoring using invasive intra-arterial pressure (IAP) monitoring in ICCU patients. Methods: This prospective, single-center study enrolled adults undergoing cardiac surgery at Chaim Sheba Medical Center (June 2020–January 2023) who had radial artery catheters for standard BP monitoring. Severe shock patients were excluded. Demographics and Fitzpatrick skin tone were recorded. ClinicalTrials.gov NCT04071015. Post-op, patients were simultaneously monitored with the standard IAP system and the Biobeat device. Continuous BP and HR were collected for up to five days. Data analyzed post hoc. Tested device The WP613 (Biobeat, Israel) is FDA-cleared, chest-worn, PPG-based device that uses multi-wavelength light and a sensor to monitor vital signs. It wirelessly transmits data to a cloud based algorithms to measure BP, cardiac output, stroke volume, and more. It also records a single-lead ECG and has a 5-day battery life. Results: A total of 96 patients were enrolled, with 88 included in the final BP analysis after excluding 8 due to technical issues. Of those, 80 received inotropic support. The average age was 63.2±12.2 years, with 33% female. Monitoring lasted an average of 25.6±17.2 hours, yielding over 78000 readings for each BP parameter and over 92000 HR readings (Fig 1) . Patients represented the full range of skin tones, classified using the Fitzpatrick scale I–VI. The Biobeat device showed excellent correlation with IAP monitoring: r=0.959 for SBP, 0.973 DBP, and 0.962 HR. Bland-Altman showed minimal bias (e.g., 0.1±4.8 for SBP) (Fig 2) . Correlation remained strong across BP ranges and skin tones. Heatmaps and representative cases confirmed close tracking between Biobeat and IAP (Fig 3) . Conclusion: The tested cuffless device (Biobeat) offers a high level of accuracy and agreement for BP and HR compared to data obtained by IAP monitoring in post-cardiac surgery patients. Further studies are needed to validate these findings in various populations and clinical settings.

Background: An increasing recognition of angina and nonobstructive coronary artery disease (ANOCA) underscores the importance of this patient group. While inflammation is a well-established key driver in the initiation and progression of atherosclerosis, its role in early stage is less clear. The current study was designed to assess the predictive value of monocyte-lymphocyte ratio(MLR) in comparison with hs-CRP in these patients. Method: This observational cohort study included patients with chest pain and nonobstructive coronary artery disease <40% stenosis in major coronary arteries on clinically indicated elective coronary angiography who underwent invasive physiological coronary reactivity testing for evaluation of coronary vasomotor function between 1997-2021. Preprocedural MLR was categorized as high (≥0.30) or low (<0.30) using the best cutoff value for predicting major adverse cardiovascular and cerebrovascular events (MACCE) determined by ROC curves. Preprocedural Hs-CRP levels ≥1 and <1 mg/L were classified as high or low, respectively. MACCE comprised cardiovascular death, nonfatal myocardial infarction, heart failure, stroke, and late revascularization. Kaplan-Meier plots, Log-rank test, and Cox regression analysis were used for analysis. Result: Among 892 patients (median age 52 [IQR: 43- 61] years, 69% females), 40% had high MLR and 49% had high hs-CRP, respectively. Over a 10-year follow-up, 125 patients (14%) experienced MACCE. In univariable analysis, high MLR level ( p < 0.001 ) and high hs-CRP ( p = 0.045) were associated with worse outcomes. (Figure 1) In multivariate Cox regression after adjusting for age, body mass index, creatinine, hypertension, hyperlipidemia, and diabetes mellitus, MLR remained a significant predictor of MACCE (HR=1.75, 95% CI=1.20- 2.55, p = 0.004), whereas hs-CRP lost its significance (HR=1.26, 95% CI=0.857- 1.848, p=0.241). Stratifying patients into four groups of high MLR/high hs-CRP (21%), high MLR/low hs-CRP (19%), low MLR/high hs-CRP (28%), and low MLR/low hs-CRP (32%) revealed that high MLR was associated with increased MACCE in both groups with high and low hs-CRP, while in both high MLR and low MLR groups, hs-CRP levels made no difference in MACCE incidences. (Figure 2). Conclusion: elevated MLR is a strong independent predictor of MACCE in patients with ANOCA, superior to hs-CRP. These findings highlight the potential of MLR as a valuable, readily available marker for risk stratification in early atherosclerosis.

Background: Sex differences in coronary physiology have been reported, particularly with regard to higher resting coronary flow in women. Resting flow is independently associated with clinical outcomes, irrespective of the presence of coronary microvascular dysfunction (CMD), but its sex-specific prognostic significance remains unclear. Aims: This study aimed to compare the prognostic implications of resting flow and CMD between sexes among patients with angina and non-obstructive coronary arteries (ANOCA). Methods: We studied 1194 patients with ANOCA undergoing coronary reactivity testing. Endothelium-independent microvascular function was assessed by coronary flow reserve (CFR) during adenosine-induced hyperemia, and endothelium-dependent function by coronary blood flow (CBF) increase during intracoronary acetylcholine infusion. Endothelium-dependent CMD was defined as <50% CBF increase, and endothelium-independent CMD as CFR <2.5. Cardiovascular events were defined as a composite of all-cause death, myocardial infarction and heart failure. Results: The median age of the study population was 52 years, and 71.1% were women. Resting average peak velocity (rAPV) and baseline CBF (bCBF) were significantly higher in women (p<0.001 and p=0.006, respectively). Survival analysis revealed that both elevated rAPV and bCBF were significantly associated with worse outcomes in men (p<0.001 and p=0.036, respectively, Figure 1), whereas no such associations were observed in women. In Cox proportional hazard analysis, sex showed a significant interaction effect with elevated rAPV (interaction p=0.014). Furthermore, endothelium-independent CMD was significantly associated with adverse outcomes in both men and women (p=0.011 and p=0.004, respectively), whereas endothelium-dependent CMD was significantly associated with prognosis only in men (p=0.006). Among men with endothelium-dependent CMD, the subtype characterized by higher bCBF was particularly associated with worse prognosis (p=0.001, Figure 2). Conclusions: In patients with ANOCA, men had lower resting coronary flow than women. However, its association with adverse outcomes was observed only in men, especially in those with impaired endothelial function. These results suggest that coronary physiology should be interpreted differently by sex, and that clinical decisions should be adjusted accordingly.

Introduction: Renal accessory arteries originate at the aorta and deliver renal blood flow independent of the main renal artery, while renal artery branches originate from and their flow depends on the main renal artery. However, the clinical significance of accessory arteries remains unclear. We tested the hypothesis that characteristics of renal accessory and/or branching arteries morphology are linked to resistant hypertension (RH). Methods: In a case-control study we compared the presence and characteristics of renal accessory and branching arteries (exposures) in individuals with RH (cases) vs. healthy kidney donors (normotensive controls) (Figure 1). Using MR angiography we calculated the length, diameter, tortuosity, and resistance (8*Length*blood viscosity)/(πr 4 )) of each artery (Figure 2). In separate logistic regression analyses we compared cases and controls for each of the following accessory or branching artery parameters: number of vessels, smallest diameter, length of longest vessel, greatest tortuosity, and greatest resistance. Results: We compared 89 unique RH cases to 248 unique normotensive controls (Table 1). For accessory arteries, their number was inversely related with RH (OR 0.38, 95% CI: 0.21 to 0.69, p<0.01), while length was mildly associated with RH (OR 1.06, 95% CI 1.00 to 1.13, p=0.04). Diameter and tortuosity were not associated in either direction. For branching arteries, RH was strongly associated with their diameter (OR 12.86, 95% CI 2.89 to 57.13, p<0.01), but more mildly and inversely with their resistance (OR 0.99, 95% CI: 0.97 to 1.00, p=0.01). The number and length of branching arteries were not associated in either direction. Conclusion: RH is strongly associated with a reduced number of accessory renal arteries and wider branching arteries, both being novel findings. Future longitudinal studies should determine if these changes are causally related to development of hypertension. Elucidation of this relationship may open new avenues for management of RH.

Abstract Endothelial dysfunction can be regarded as the earliest feature of vascular aging and may occur in individuals without traditional risk factors for cardiovascular disease. Once present, endothelial dysfunction is known to increase the risk for atherosclerosis, cardiovascular diseases and complications such as stroke or death. Identification of individuals with early features of vascular aging remains challenging and has fuelled investigative efforts to associated biologic, imaging, and digital markers with endothelial dysfunction. This review highlights emerging and traditional methods to identify patients with early endothelial dysfunction and summarizes available and experimental therapies aimed at mitigating the vascular aging process.

Purpose of review This paper reviews the current understanding of coronary vascular dysfunction (CVDys) in patients with angina and no obstructive coronary artery disease (ANOCA), based on recent findings from a comprehensive, large-scale study. It also discusses potential future directions for research and clinical practice. Recent findings CVDys involves enhanced vasoconstriction or impaired vasodilation caused by endothelium-dependent and/or -independent dysfunction in the epicardial or microvascular coronary arteries. It is classified into four subtypes based on anatomical location and underlying mechanisms, and can be assessed using coronary reactivity testing (CRT). Previous studies have evaluated their prognostic implications separately or in limited populations. A recent study assessed all subtypes within a single ANOCA cohort and confirmed that endothelium-dependent epicardial dysfunction and both types of microvascular dysfunction are associated with worse prognosis. Moreover, it demonstrated that microvascular function – both endothelium-dependent and -independent – serves as an independent prognostic factor for major adverse cardiovascular events. These findings emphasize the value of CRT-based comprehensive evaluation for risk stratification. Summary While evidence regarding the prognostic impact of CVDys has become increasingly robust, effective treatment strategies remain undefined. Future efforts should focus on developing CRT-guided interventions targeting coronary dysfunction, with the goal of improving clinical outcomes.

Abstract Importance Mesenchymal stromal cells (MSCs) possess therapeutic properties that mediate repair. Obesity impairs MSC functionality and therapeutic efficacy, possibly by eliciting dynamic modifications of epigenetic markers, like 5-hydroxymethylcytosine (5hmC). Objective We hypothesized that human obesity alters the 5hmC landscape and anti-inflammatory capacity of adipose tissue-derived MSCs to activate the prominent inflammatory signaling mediator Interleukin (IL)-1β. Design, Setting, Participants, Intervention Adipose tissue samples were collected from obese and lean individuals (body mass index ≥30 or &lt;30 kg/m2, respectively, n = 11 each) during weight-loss or kidney donation surgery. Main Outcomes and Measures MSCs were harvested and analyzed for 5hmC profiles (MeDIP-seq) and mRNA expression (RNA-seq) (n = 5 each). Subsequently, MSCs or a vehicle were injected into mice, (n = 6 each) and two-weeks later, kidneys were evaluated using in-vivo magnetic resonance imaging and ex vivo studies. The role of IL-1β was then studied in-vitro in MSC-induced immunomodulation using siRNA in macrophages. Results Compared to MSC from lean patients, obese-MSC genes showed 2087 differential 5hmC modifications and 175 differential mRNA expression. Among them, 14 genes with overlapping alterations were involved in regulation of cytokine production, prominently IL-1β. Injecting obese MSCs elevated renal expression of IL-1β and M1 macrophage count but lowered kidney perfusion. Silencing IL-1β in obese-MSCs in vitro reduced M1 phenotype switching in co-incubated macrophages. Conclusions and Relevance Obesity induces epigenetic and gene expression changes in MSCs, particularly in IL-1β, associated with impaired anti-inflammatory functionality of MSCs. Targeting IL-1β could be a useful therapeutic approach to modulate the decline in MSC functionality resulting from obesity.