Lerman, Lilach O.

Scattered tubular-like cells (STCs) are dedifferentiated renal tubular cells that repair other damaged kidney cells. This study shows that renovascular disease (RVD) induces site-specific 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) modifications in DNA associated with transcriptional changes and impaired proliferative capacity of swine STCs, which could be mitigated in RVD-STCs treated with an epigenetic modulator. Therefore, our observations may contribute to the development of novel approaches to preserve the reparative capacity of STCs in individuals with RVD.

Abstract Aims Social isolation (SI) is associated with a higher risk of cardiovascular disease (CVD). One mechanism linking SI and CVD is accelerated biological ageing, which can be assessed using artificial intelligence-enabled electrocardiography (AI-ECG). We investigated whether longitudinal changes in SI status are associated with changes in biological ageing patterns. Methods and results A retrospective longitudinal cohort study including 17 663 individuals without significant CVD who completed ≥2 Berkman and Syme Social Network Index and had paired ECGs within 1 year of each questionnaire. Longitudinal SI status was defined by comparing baseline and follow-up SI status. Ageing trends were assessed using Δage-gap, defined as the change in the gap between AI-ECG-predicted age and chronological age from baseline to follow-up. Linear regression models predicting Δage-gap and survival analyses with Kaplan–Meier and multivariable Cox regression for all-cause mortality were performed. Persistently connected individuals were older [63.1 (52.1, 70.6) years] and had a higher prevalence of hyperlipidaemia and hypertension, yet demonstrated more favourable ageing trajectories. Similarly, those who became connected showed a non-significant attenuation of accelerated ageing. In multivariable linear regression, being persistently isolated [β = +0.412 years, P < 0.001] or becoming isolated [β = +0.438 years, P = 0.012] was associated with accelerated ageing compared to being persistently connected. In survival analyses, becoming isolated (aHR = 1.94, 95% CI = 1.53–2.46, P < 0.001) and being persistently isolated (aHR = 1.66, 95% CI = 1.40–1.96, P < 0.001) were associated with significantly higher all-cause mortality, independent of chronological age and comorbidities. Conclusion Persistent social connection is associated with slower biological ageing and lower mortality. The effects of SI on ageing and survival appear to be potentially reversible, calling for a prospective study to evaluate interventions aimed at improving both the social and biological burden of SI.

Background Coronary flow reserve reflects microvascular function, whereas filling pressure indicates myocardial hemodynamic burden. In angina with nonobstructive coronary arteries, abnormalities in either could contribute to a supply–demand mismatch; however, their combined prognostic significance remains unclear. Methods Patients with angina with nonobstructive coronary arteries who underwent invasive coronary reactivity tests were studied retrospectively. Coronary microvascular dysfunction (CMD) was coronary flow reserve <2.5. An artificial intelligence–enabled ECG marker of elevated filling pressure (AIEFP) was applied as a scalable prognostic marker of myocardial hemodynamic stress. Associations with major adverse cardiovascular events were evaluated using Cox regression and propensity score overlap weighting. Results Among 1957 patients with angina with nonobstructive coronary arteries (median age, 51.8 years; 67.2% women), CMD+ was identified in 26.4% and AIEFP+ in 6.6%. Over 8 years, 204 patients (10.4%) experienced major adverse cardiovascular events. In nested models, both CMD (hazard ratio [HR]=1.42 [95% CI=1.13–1.78]; P =0.002) and AIEFP (HR=2.28 [95% CI=1.67–3.11]; P <0.001) remained associated with major adverse cardiovascular events after adjustment. Adding AIEFP to the base model improved model fitness (Δχ 2 =23.65, P <0.001; ΔAkaike Information Criterion=−21.7) and modestly improved discrimination (ΔHarrell concordance index=0.02, P =0.02). In a 4‐group model, adjusted risks increased in a graded manner. Overlap‐weighted analysis after covariate balance demonstrated distinct temporal risk trajectories: CMD+/AIEFP+ had the highest 1‐year risk (12.7%), and AIEFP+ had the highest cumulative 8‐year risk (57% in CMD− and 51.8% in CMD+). Conclusions CMD and AIEFP provide complementary prognostic information, with AIEFP remaining significantly associated with outcomes after multivariable adjustment. A dual‐axis framework integrating myocardial hemodynamic stress (AIEFP) and microvascular function (coronary flow reserve) may enhance risk stratification and enable identification of clinically distinct angina with nonobstructive coronary arteries phenotypes with divergent trajectories.

Background Studies have demonstrated an association between endothelial dysfunction and major depressive disorder (MDD). However, the link between coronary endothelial dysfunction (CED) and an incident diagnosis of MDD across sexes is unclear. Methods Patients with nonobstructive coronary artery disease (stenosis <40%) underwent an invasive assessment of CED. Macrovascular CED was defined as a percentage change in coronary diameter in response to acetylcholine of ≤−10% compared with baseline. Microvascular CED was defined as a percentage change in coronary blood flow in response to acetylcholine of ≤−50% compared with baseline. In the period after the index procedure, patients were followed up for developing a diagnosis of MDD, and logistic regression was performed to assess the association between baseline CED and incident MDD. Results In total, 2280 patients underwent invasive testing for CED. A total of 516 patients (23%) underwent an evaluation for MDD at a date after the index procedure (mean±SD age, 53±12 years; 72% women). A total of 160 (31%) were diagnosed with MDD. The percentage change in coronary diameter in response to acetylcholine was lower in those diagnosed with MDD in all patients (−10.8% versus −5.3%; P =0.008), and in men (−19.0% versus −4.8%; P =0.001). In men, a higher proportion of those with macrovascular CED were diagnosed with MDD compared with those not diagnosed with MDD (59% versus 38%; P =0.035). In multivariable analyses, macrovascular CED was associated with MDD in men (odds ratio: 2.99 [95% CI, 1.26–7.45]; P =0.015). Conclusions Macrovascular CED is significantly associated with incident MDD in men with nonobstructive coronary artery disease. Endothelial dysfunction in the coronary arteries could thus be a helpful biomarker to identify patients at risk of MDD.

Background Inadequate preventive dental care may contribute to inflammatory conditions such as periodontitis, increasing cardiovascular disease risk. Artificial intelligence–enabled electrocardiography (AI‐ECG) algorithms accurately estimate cardiovascular disease risk. We investigated the association between inadequate preventive dental care and the AI‐ECG–estimated risk of atrial fibrillation, aortic stenosis, low ejection fraction, cardiac amyloid, cardiovascular aging, and all‐cause mortality. Methods We retrospectively analyzed 266 637 Mayo Clinic patients (2018–2024) who completed a Social Determinants of Health Survey and had an ECG performed within 1 year of survey completion. AI‐ECG algorithms generated continuous risk scores (0 or 1) for atrial fibrillation, aortic stenosis, low ejection fraction, and amyloid. Cardiac aging was assessed by delta age, calculated as AI‐ECG–estimated physiological age minus the chronological age. Associations with preventive dental care were analyzed using logistic regression. Cox regression evaluated dental care predictiveness on all‐cause mortality. Results Among 266 637 individuals (mean age, 59.5±16.4 years; 51.1% women), 49 918 (18.7%) reported inadequate preventive dental care. These individuals had higher delta age and increased AI‐ECG–predicted risks of atrial fibrillation, aortic stenosis, amyloid, and reduced ejection fraction (all P <0.001). In multivariable logistic regression models including all AI‐ECG scores, inadequate preventive dental care was associated with higher probabilities of low ejection fraction (odds ratio [OR], 1.80 [95% CI, 1.69–1.91]), atrial fibrillation (OR, 1.10 [95% CI, 1.04–1.17]), aortic stenosis (OR, 1.90 [95% CI, 1.64–2.20]), amyloid (OR, 1.18 [95% CI, 1.12–1.25]), and higher delta age (OR, 1.03 [95% CI, 1.02–1.03]) (all P <0.001). Inadequate preventive dental care predicted all‐cause mortality after adjusting for demographics, risk factors, and AI‐ECG algorithms (HR, 1.45 [95% CI, 1.38–1.53], P <0.001). Conclusions Inadequate preventive dental care is associated with subclinical cardiovascular disease. AI‐ECG algorithms may facilitate cardiovascular risk stratification among individuals with limited preventive dental care access.

Abstract Background Coronary flow augmentation occurs through the simultaneous interaction and regulation of both endothelium-dependent and endothelium-independent mechanisms. A decrease in coronary flow reserve (CFR) secondary to either mechanism is associated with poor prognosis. However, at the individual level, the integrated impact of these two mechanisms has not been thoroughly investigated. Purpose This study investigated the prognostic implications of an integrated metric, CFRsum, combining endothelium-dependent and -independent CFR. Methods A total of 1441 patients with angina with non-obstructive coronary artery (ANOCA) undergoing coronary reactivity testing were studied. Endothelium-independent CFR was measured during adenosine-induced hyperemia, and endothelium-dependent CFR during intracoronary acetylcholine infusion. CFRsum was calculated by summing these components. Cardiovascular event was defined as composite of cardiovascular death, myocardial infarction, heart failure, and cerebral infarction. Results Our patients had a median age of 51.7 years, 69.0% of whom were female, and their CFRsum was 4.57 [3.88, 5.37]. Patients were divided into three tertile-based groups, and Cox proportional hazards analysis demonstrated that all CFR classes were independent predictors of prognosis, with CFRsum providing the best model fit (Likelihood ratio: 54.62, degrees of freedom: 7, P &lt; 0.001). The Kaplan-Meier curve (Figure) demonstrated a stepwise deterioration in prognosis across CFRsum tertile groups, with lower CFRsum being associated with progressively worse outcomes (p &lt; 0.001). Stratification by follow-up duration (3 years) revealed that patients with middle-range CFRsum exhibited comparable outcomes to those with the highest CFRsum during the early phase (&lt;3y) but significantly worse outcomes in the late phase (≥3y) (P = 0.459 and P &lt; 0.001, respectively). Conclusion CFRsum showed superior prognostic value over traditional CFR metrics in patients with ANOCA, identifying a compensated group with time-varying outcomes. This novel metric improves the assessment of microvascular function and supports better clinical management.

Objective: This study aims to develop a contrast-free, high-sensitivity ultrasound method, denoted as Radon transform-based flow measurement (R-Flow), for in vivo mapping of microvascular flow vectors and for establishing R-Flow-derived vector-field metrics to noninvasively quantify microcirculatory patterns in liver cirrhosis. Impact Statement: R-Flow enables robust, contrast-free imaging of microvascular dynamics and demonstrates translational feasibility in the human liver. Its direction-aware indices offer pilot in vivo quantification of flow redistribution and remodeling, providing unique insights into hepatic flow dynamics. Introduction: Microvascular dysfunction is a hallmark of many diseases, yet noninvasive visualization and quantitative assessment of abnormal microcirculation remain limited. Methods: R-Flow leverages Radon transform to decode red blood cell dynamics from the spatiotemporal domain of ultrasound flow signals, reconstructing velocity vectors at microvascular scale. From these vector maps, unique direction-aware indices are further derived to characterize flow distribution and heterogeneity. Results: Validated across simulations, phantoms, and in vivo studies, R-Flow provides robust velocity estimation across a wide range (1 to 60 mm/s). Notably, it enables high-sensitivity microvascular flow vector mapping of human liver, showing strong agreement with references ( r > 0.9). In a rat model, these direction-aware indices revealed a shift from healthy multipath perfusion in control livers to directionally biased vascular pattern in cirrhotic livers, demonstrating significant correlation with pathological indicators. Conclusion: R-Flow enables noninvasive, contrast-free mapping of microvascular blood flow velocity and offers a promising approach for high-resolution assessment of microvascular flow characteristics.

Key Points The kidney microvasculature was quantified reliably in human autosomal dominant polycystic kidney disease early on, using super-resolution ultrasound localization microscopy. Microvascular parameters correlated with structural and functional indices, constituting promising biomarkers to evaluate noncystic parenchyma. Microvascular parameters may serve to assess disease severity and monitor progression from the early stages of the disease. Background In vitro studies in individuals with autosomal dominant polycystic kidney disease (ADPKD) have shown extensive intrarenal microvascular remodeling. However, analyses have been limited to the time of kidney failure because of the invasive nature of current methodologies to assess the intrarenal microvasculature. We hypothesized that super-resolution ultrasound microvascular imaging, known as ultrasound localization microscopy, enabled by high-framerate ultrasound imaging and microbubble localization and tracking postprocessing techniques, would safely, reliably, and reproducibly assess the intrarenal microvasculature in individuals with ADPKD at an early stage of the disease. Methods We prospectively enrolled young (<40 years of age), well-characterized, early-stage (eGFR >90 ml/min per 1.73 m 2 ) individuals with ADPKD, and sex–age 1:1 matched controls ( n =17 each) and assessed the intrarenal microvasculature using ultrasound localization microscopy. We determined the intersonographer reliability, intraobserver repeatability, and interobserver reproducibility of microvascular parameters in both groups, and the day-to-day variability in the control group. Microvascular parameters were correlated with structural (total kidney volume) and functional (eGFR) markers in individuals with ADPKD. Results Ultrasound localization microscopy provided a super-resolved map of the intrarenal microvasculature in ADPKD and matched controls. Intrarenal microvascular parameters ( e.g ., vessel density) were quantified in a safe, reliable (intraclass correlation coefficients, 0.96; 95% confidence interval, 0.91 to 0.98), reproducible (intraclass correlation coefficient, 0.96; 95% confidence interval, 0.93 to 0.98), and repeatable (coefficient of variations, 3.6%) manner. In control individuals, the day-to-day variability of most parameters was low, with coefficient of variation ranging from 1.8% to 10.7%. Microvascular parameters differed in individuals with ADPKD compared with controls, despite preserved eGFR. Interestingly, cortical vessel density and its derived perfusion correlated directly with eGFR, whereas tortuosity indices presented an inverse correlation. Conclusions Ultrasound localization microscopy provided a safe and reliable in vivo assessment of the human intrarenal microvasculature.