Lerman, Amir

Background: Coronary microvascular disease (CMD) may be endothelium-independent (coronary flow reserve, CFR < 2.5) or endothelium-dependent (<50% increase in coronary blood flow in response to acetylcholine). CMD has been implicated in abnormal myocardial relaxation and impaired diastolic function. Wave intensity analysis (WIA) is a hemodynamic method that quantifies the energy of pressure-flow waves driving coronary blood flow. The backward expansion wave (BEW) is the dominant distally originating wave, generated by microvascular suction during ventricular relaxation. Thus, the BEW may offer mechanistic insight into the link between CMD and diastolic dysfunction. Hypothesis: We hypothesized that diastolic dysfunction would be more common in patients with CMD, and that the backward expansion wave (BEW) intensity would be lower in those with diastolic dysfunction compared to those without. Methods: Patients with non-obstructive coronary artery disease undergoing invasive coronary physiology assessment of the left anterior descending artery were included (n = 113). Pressure and Doppler flow were recorded at rest, with adenosine, and with acetylcholine for categorization of CMD as endothelium-independent (CMD-Ei) and/or endothelium-dependent (CMD-Ed). Wave intensity analysis was used to calculate cumulative BEW (J×m -2 ) at rest in CMD, CMD-Ei (endothelium-independent), and CMD-Ed (endothelium-dependent) subgroups. Diastolic dysfunction was diagnosed by transthoracic echocardiogram using the 2016 American Society of Echocardiography (ASE) guidelines. Results: Of the 113 study patients, 88 (77.9%) had CMD and 25 (22.1%) did not. Among those with CMD, 39 patients (44.3%) had diastolic dysfunction (Figure 1). In the patients with CMD, the BEW intensity was significantly lower in patients with diastolic dysfunction compared to those without (6.5 vs. 9.0 × 10 3 W×m -2 ×s -1 , p < 0.05). The same trend was observed for the CMD-Ei (7.2 vs. 9.7 × 10 3 W×m -2 ×s -1 , p < 0.05) and CMD-Ed (6.2 vs. 9.1 × 10 3 W×m -2 ×s -1 , p < 0.05) subtypes. Conclusions: Diastolic dysfunction is frequent in patients with invasively diagnosed CMD. Patients with CMD who have diastolic dysfunction have comparatively lower BEW intensity, regardless of endothelial subtype. Since the BEW is the major driver of coronary flow during diastole, this suggests a mechanism by which CMD may lead to diastolic dysfunction.

Background: Coronary wave intensity analysis (WIA) provides a mechanistic view of coronary hemodynamics and has been increasingly used to phenotype coronary microvascular disease (CMD). Standard WIA requires simultaneous pressure and flow measurements within the same vessel, but intra-coronary pressure measurement may be limited by hardware availability. In patients with non-obstructive coronary arteries, aortic pressure may serve as a surrogate for intra-coronary pressure to enable broader feasibility of WIA. We aimed to determine whether wave profiles derived from intra-aortic and intra-coronary pressure measurements are comparable when paired with intracoronary Doppler flow in patients with non-obstructive coronary artery disease. Methods: Patients undergoing invasive coronary physiology assessment of the left anterior descending artery were included. Intracoronary flow velocity and intra-coronary pressure were simultaneously recorded using a ComboWire (Philips Volcano) in the proximal LAD. Aortic pressure was concurrently measured via the guide catheter to allow comparison of pressure sources. In the intra-aortic pressure group, pressure and flow data were aligned using the R wave of the ECG trace. WIA was performed using conventional methods to quantify the dominant waves: forward compression wave (FCW), backward compression wave (BCW), and backward expansion wave (BEW). Agreement between wave intensity was assessed using Bland-Altman analysis and Pearson correlation. Results: A total of 14 paired waveforms were analyzed with a total of 42 coronary waves compared. Wave intensities calculated using intra-coronary versus intra-aortic pressure showed excellent agreement across all wave types. Mean bias between methods was −0.07 x 10 3 W×m -2 ×s -1 with limits of agreement from −0.63 to +0.49. The correlation between intra-coronary and intra-aortic wave intensities was strong (r = 0.997, p < 0.001), with minimal dispersion and consistent agreement across the full range of wave intensities ( Figure 1 ). Conclusions: In patients with non-obstructive coronary arteries, wave intensity analysis using guide-catheter aortic pressure yields results nearly identical to those obtained with intra-coronary pressure. These findings support the use of aortic pressure as a reliable surrogate for intra-coronary pressure in WIA for the calculation of microvascular coronary hemodynamics, reducing technical barriers and enabling broader clinical and research utilization.

Introduction: Photoplethysmography-based (PPG) devices represent a significant advancement in noninvasive cardiovascular monitoring. These cuffless technologies enable assessment of hemodynamic parameters with improved comfort, usability and compliance. Modern PPG systems have expanded their capabilities to include advanced metrics such as systemic vascular resistance (SVR) and cardiac output (CO). Many antihypertensive drugs lower blood pressure by reducing SVR through vasodilatation of the systemic and renal vasculature. Limited data is available on SVR during ambulatory monitoring. PPG devices become more common as they allow us to assess SVR in real life, in ambulatory blood pressure monitoring (ABPM) patients. Aim: To evaluate and compare SVR using the Biobeat (WP613) device across patient groups. Methods: Adults from the Hypertension Clinic at University of Miami, Florida, from Aug. 2023–Jan. 2025 underwent 24-h ABPM monitoring using Biobeat device. Patient data was matched with Biobeat. PPG data was available every 15 minutes; The raw data included SBP and DBP, the heart rate, stroke volume, CO and SVR. Results: A total of 539 patients underwent PPG ABPM during the study period. The median was 62 (IQR 54, 71) years, with 57% females (Tab 1) . Patients were defined as hypertensive per AHA 2017 guidelines [SBP≥130 and DBP≥80 mmHg]. Overall, 265 patients were classified as having normal BP, 95 as having isolated systolic hypertension, and 179 as having mixed hypertension. Within the Mix-HTN group, 42 patients had isolated diastolic hypertension and the remaining 137 systolic and diastolic hypertension (Fig 2) . In subgroup analysis (Fig 3); SVR was significantly different between the groups: lowerst in No/C-HTN and highest in Mix-HTN. particularly among the mixed-hypertension group, SVR was higher in the Systolic and Diastolic HTN compared to the Isolated diastolic HTN group. Among the No/C-HTN group, 60 patients were not hypertensives and 205, were hypertensives on at least 1 drug. The SVR was not statistically significant between these 2 subgroups, suggesting that SVR may be a helpful target biomarker used to up-titrate antihypertensives. Conclusion: PPG devices offer a valuable enhancement to conventional ABPM by providing additional physiological measurements such as SVR that can help differentiate between various hypertension phenotypes and potentially provide personalized therapy that target the driver of hypertension.

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.

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.

Abstract Background and Aims Invasive coronary function testing (CFT) identifies coronary vasomotor disorders in up to 90% of patients with angina with non-obstructive coronary arteries (ANOCA). The ILIAS ANOCA trial hypothesized that routine ad hoc CFT would be feasible, safe, and effective in providing an early, comprehensive diagnosis. Additionally, it was anticipated that combining CFT with a disease-specific treatment protocol would significantly improve quality of life in ANOCA patients compared with standard care. Methods After excluding patients with obstructive coronary artery disease (CAD) during clinically indicated invasive coronary angiography (ICA), eligible patients underwent CFT and were randomized to either the standard care group, where CFT results remained blinded, or the intervention group, where CFT results were disclosed along with a tailored medical therapy protocol. The primary outcome was the mean difference in the within-subject change in Seattle Angina Questionnaire summary score (SAQSS) between groups from baseline to a follow-up of 6 months. The trial is registered with the International Clinical Trials Registry Platform (NL-OMON20739). Results A total of 255 patients consented, of whom 153 patients (60%) without CAD underwent CFT and were randomized 1:1 to the standard care (n = 76) or intervention group (n = 77). All CFT procedures were successful without adverse events. A vasomotor disorder was identified in 120 patients (78%). At 6-month follow-up, the SAQSS improved significantly in the intervention group compared with the control group, with an intervention effect of 9.4 units (95% confidence interval 3.9–14.9, P = .001). There were no major adverse cardiac events at the 6-month follow-up. Conclusions Routine CFT during the initial ICA was feasible, safe, and had high diagnostic yield. Implementing a pragmatic CFT protocol combined with a disease-specific treatment protocol significantly improved disease-related quality of life in patients with ANOCA compared with standard care.

Introduction: Atherosclerosis, the underlying cause of cardiovascular disease (CVD), is a lipid-driven chronic inflammatory disease. We have identified the co-stimulatory CD40-CD40L immune checkpoint dyad as a key driver of inflammation during atherosclerosis. CD40 and CD40L exert cell-type divergent functions via different signaling pathways. Hypothesis: We hypothesize that CD40 on endothelial cell (ECs) induces endothelial-to-mesenchymal transition (EndMT)-mediated vascular inflammation in atherosclerosis. Methods & Results: Using single cell RNAseq, we found that CD40 (TNFRSF5) is expressed on PDE3A + GJA5 + and KDR + COL15A1 + ECs of advanced human carotid atherosclerotic plaques. CD40 is highly expressed in the endothelial lining of human and mouse atherosclerotic plaques, and colocalizes with the EndMT markers fibronectin and collagen and adhesion molecule ICAM-1. CD40L activation of human aortic endothelial cells (HAECs) results in expression of the EndMT markers fibronectin, vimentin, sm22α, FSP1 and snail. Activation of CD40 in EC induces filamin A dependent translocation of CD40 into lipid rafts, increases TNF-receptor associated factor (TRAFs) -2, -3 and 6 levels, induces Akt signaling and increases expression of VCAM1 and CCL2. Conclusions: The endothelial cell has been more and more regarded as a cell type that plays a major role in driving inflammation. Our data suggest that the CD40-CD40L axis plays a significant role in EC-mediated inflammation in atherosclerosis by driving EndMT.

Endothelial progenitor cells (EPCs) constitute a promising focus for research in regenerative medicine. These cells originate from the bone marrow and other circulating hematopoietic cells and regulate tissue regeneration and vascular integrity. EPC mobilization serves for neovascularization and re-endothelialization after injury in multiple organ systems, including the renal and cardiovascular systems. Both their number and function may vary in disease states such as CKD, depending on severity, comorbid conditions, and other factors. Therefore, circulating EPC count and function have been proposed as markers for vascular health, and their mobilization or replenishment may offer a potential therapy. Delivery of EPCs has shown success in repairing injured kidneys in animal models of both chronic and AKIs. This approach may be limited by EPC heterogeneity and incomplete characterization that may be addressed by standardization, engineering, or combination with other therapies. The aim of this article was to review the current state and recent advances in our understanding of the role of EPCs in homeostasis and conditions that may lead to their dysregulation in kidney diseases.