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Background Elevated plasma ceramides are independent predictors of cardiovascular disease and mortality in patients with advanced epicardial coronary artery disease. Our understanding of plasma ceramides in early epicardial coronary artery disease, however, remains limited. We examined the role of plasma ceramides in early coronary atherosclerosis characterized by coronary endothelial dysfunction. Methods and Results Participants presenting with chest pain and nonobstructive epicardial coronary artery disease underwent coronary endothelial function. Patients (n=90) demonstrated abnormal coronary endothelial function with acetylcholine (≥20% decrease in coronary artery diameter or ≤50% increase in coronary blood flow). A total of 30 controls had normal coronary endothelial function. Concentrations of plasma ceramide 18:0 ( P =0.038), 16:0 ( P =0.021), and 24:0 ( P =0.019) differed between participants with normal and abnormal coronary endothelial function. Ceramide 24:0 (odds ratio [OR], 2.23 [95% CI, 1.07–4.66]; P =0.033) and 16:0 (OR, 1.91×10 6 [95% CI, 11.93–3.07×10 11 ]; P =0.018) were independently associated with coronary endothelial dysfunction. Among participants with endothelium‐dependent coronary dysfunction (n=78), ceramides 16:0 (OR, 5.17×10 5 [95% CI, 2.83–9.44×10 10 ]; P =0.033), 24:0 (OR, 2.98 [95% CI, 1.27–7.00]; P =0.012), and 24:1/24:0 (OR, 4.39×10 −4 [95% CI, 4×10 −7 –0.48]; P =0.030) were more likely to be elevated. Conclusions The current study demonstrated an association between increased circulating ceramide levels and coronary endothelial dysfunction in the absence of epicardial coronary artery disease. This study supports the role of plasma ceramides as a potential biomarker or a therapeutic target for early coronary atherosclerosis in humans.

Extracellular vesicles are important vectors for cell-cell communication and show potential value for diagnosis and treatment of kidney diseases. The pathologic diagnosis of kidney diseases relies on kidney biopsy, whereas collection of extracellular vesicles from urine or circulating blood may constitute a less invasive diagnostic tool. In particular, urinary extracellular vesicles released mainly from resident kidney cells might provide an alternative tool for detection of kidney injury. Because extracellular vesicles mirror many features of their parent cells, cargoes of several populations of urinary extracellular vesicles are promising biomarkers for disease processes, like diabetic kidney disease, kidney transplant, and lupus nephritis. Contrarily, extracellular vesicles derived from reparative cells, such as mesenchymal stem cells, tubular epithelial progenitor cells, and human umbilical cord blood represent promising regenerative tools for treatment of kidney diseases. Furthermore, induced pluripotent stem cells–derived and engineered extracellular vesicles are being developed for specific applications for the kidney. Nevertheless, some assumptions regarding the specificity and immunogenicity of extracellular vesicles remain to be established. This review focuses on the utility of extracellular vesicles as therapeutic and diagnostic (theranostic) tools in kidney diseases and future directions for studies.

Background: There are limited data on uninsured patients presenting with acute myocardial infarction-cardiogenic shock (AMI-CS). This study sought to compare the management and outcomes of AMI-CS between uninsured and privately insured individuals. Methods: Using the National Inpatient Sample (2000–2016), a retrospective cohort of adult (≥18 years) uninsured admissions (primary payer—self-pay or no charge) were compared with privately insured individuals. Interhospital transfers were excluded. Outcomes of interest included in-hospital mortality, temporal trends in admissions, use of cardiac procedures, do-not-resuscitate status, palliative care referrals, and resource utilization. Results: Of 402 182 AMI-CS admissions, 21 966 (5.4%) and 93 814 (23.3%) were uninsured and privately insured. Compared with private insured individuals, uninsured admissions were younger, male, from a lower socioeconomic status, had lower comorbidity, higher rates of acute organ failure, ST-segment elevation AMI-CS (77.3% versus 76.4%), and concomitant cardiac arrest (33.8% versus 31.9%; all P <0.001). Compared with 2000, in 2016, there were more uninsured (adjusted odds ratio, 1.15 [95% CI, 1.13–1.17]; P <0.001) and less privately insured admissions (adjusted odds ratio, 0.85 [95% CI, 0.83–0.87]; P <0.001). Uninsured individuals received less frequent coronary angiography (79.5% versus 81.0%), percutaneous coronary intervention (60.8% versus 62.2%), mechanical circulatory support (54% versus 55.5%), and had higher palliative care (3.8% versus 3.2%) and do-not-resuscitate status use (4.4% versus 3.2%; all P <0.001). Uninsured admissions had higher in-hospital mortality (adjusted odds ratio, 1.62 [95% CI, 1.55–1.68]; P <0.001) and resource utilization. Conclusions: Uninsured individuals have higher in-hospital mortality and lower use of guideline-directed therapies in AMI-CS compared with privately insured individuals.

Object We sought to determine the safety and efficacy in secondary stroke prevention of carotid endarterectomy (CEA) in patients with symptomatic non-stenotic carotid artery disease (SyNC). Methods This was a single-centre retrospective case series. All patients who underwent CEA for unilateral anterior circulation cerebrovascular events with ipsilateral <50% carotid stenosis from 2002 to 2020 were included. Imaging hallmarks including the degree of luminal stenosis and the presence of various vulnerable plaque characteristics (eg, intraplaque haemorrhage (IPH) on MR angiography, ulceration or low-density plaque on CT angiography) were assessed. The presence of vulnerable plaque characteristics was compared between arteries ipsilateral to the ischaemic event and contralateral arteries. The prevalence of perioperative/intraoperative complications, as well as recurrent ischaemic events at follow-up was determined. Results Thirty-two patients were included in the analysis, of which 25.0% were female. Carotid arteries ipsilateral to an ischaemic event had a significantly higher prevalence of IPH when compared with contralateral arteries (80.0% vs 0.0%; p<0.001). There were no intraoperative complications. One patient (3.1%) developed symptoms of transient ipsilateral ischaemia 1 day following CEA which resolved without treatment. In a median follow-up of 18.0 months (IQR 5.0–36.0), only one patient (3.1%) experienced a transient neurologic deficit with complete resolution (annualised rate of recurrent stroke after CEA of 1.5% for a total follow-up of 788 patient-months following CEA). All other patients (31/32, 96.9%) were free of recurrent ischaemic events. Conclusion CEA appears to be safe and well-tolerated in patients with SyNC. Additional studies with larger cohorts and longer follow-up intervals are needed in order to determine the role of CEA in this patient population.

The collateral circulation can adapt to bypass major arteries with limited flow and serves a crucial protective role in coronary, cerebral, and peripheral arterial disease. Emerging evidence indicates that the renal collateral circulation can similarly adapt and thereby limit kidney ischemia in atherosclerotic renovascular disease. These adaptations predominantly include recruitment of preexisting microvessels for arteriogenesis, with de novo vessel formation playing a limited role. Yet, adaptations of the renal collateral circulation in renovascular disease are often insufficient to fully compensate for the limited flow within an obstructed renal artery and may be hampered by the severity of obstruction or patient comorbidities. Experimental strategies have attempted to circumvent limitations of collateral formation and improve the prognosis of patients with various ischemic vascular territories. These have included pharmacological approaches such as endothelial growth factors, renin-angiotensin-aldosterone system blockade, and I f channel-blockers, as well as interventions like preconditioning, exercise, enhanced external counter-pulsation, and low-energy shock-wave therapy. However, few of these strategies have been implemented in atherosclerotic renovascular disease. This review summarizes current understanding regarding the development of renal collateral circulation in atherosclerotic renovascular disease. Studies are needed to apply lessons learned in other vascular beds in the setting of atherosclerotic renovascular disease to develop new treatment regimens for this patient group.

Introduction: Uric acid (UA) level within carotid plaque specimens and its association with cerebrovascular events has not been detected or quantified. Systemically, serum uric acid (SUA) is a marker of inflammation and risk factor for atherosclerosis. However, its association with carotid plaque instability and subsequent cerebrovascular events remains unclear. Hypothesis: We hypothesized that UA may play a role in carotid artery atherosclerosis and stroke pathogenesis. In patients undergoing carotid endarterectomy (CEA), we aimed to determine whether UA is present differentially in carotid plaques of symptomatic versus asymptomatic patients and whether SUA is associated with cerebrovascular symptoms before surgery and major adverse cardiovascular events (MACE) in the follow-up to CEA. Methods: We prospectively collected 32 carotid plaques during CEA. We qualitatively assessed the presence of UA by using Gomori methenamine silver (GMS) staining and immunohistochemistry with anti-UA antibodies. We extracted and measured the quantity of UA in carotid plaques by using an enzymatic colorimetric assay. A retrospective analysis of a clinical database of 534 consecutive patients who underwent CEA was performed. We defined as symptomatic those patients with history of stroke, TIA and amaurosis fugax. Results: UA positive staining was detected in higher number of carotid plaques from symptomatic compared to asymptomatic patients on both staining, GMS [20 (86.9%) vs 2 (22.2%); p=0.001] and immunohistochemistry anti-UA [16 (69.5%) vs 1 (11.1%); p=0.004]. Moreover, we found a significantly higher concentration of UA in carotid plaque from symptomatic compared to asymptomatic patients [25.1 (9.5) μg/g vs 17.9 (3.8) μg/g; p=0.021]. SUA level in patients prior to CEA was significantly higher in the symptomatic compared to the asymptomatic group [6.0 (4.8-7.1) mg/dL vs 5.2 (4.4-6.3) mg/dL; p<0.001] and it was significantly higher in patients who developed MACE after CEA versus those that did not [6.0 (4.8-7.1) mg/dL vs 5.4 (4.5-6.6) mg/dL; p=0.021]. Conclusions: UA may provide a mechanistic explanation as systemic biomarker and potential tissue contributor for carotid plaque instability and subsequent cerebrovascular and cardiovascular symptoms.

Background Pulse pressure (PP), a raw index of arterial stiffness, is inversely related to coronary microvascular function, even among patients with non-obstructive coronary artery disease (CAD), as per non-invasive studies. We aimed to determine whether invasive aortic PP is associated with coronary microvascular endothelial dysfunction (CMED) and/or coronary microvascular endothelial independent dysfunction (CMEID) in patients with non-obstructed CAD. Methods We retrospectively analysed a cohort of 1894 patients (mean age, 51.2 years; 1261 (66.6%) women) who presented with chest pain and non-obstructive CAD (angiographic stenosis <50%); coronary vasoreactivity was assessed in the mid-left anterior descending artery. The patients were classified based on whether aortic PP was high (≥50 mm Hg). CMEID was defined as abnormal coronary flow reserve (<2.5) or hyperaemic myocardial resistance (>2.0 mm Hg/cm/s), CMED was defined as abnormal acetylcholine-induced per cent change of coronary blood flow (≤50%). Results Patients with high aortic PP had a higher rate of CMEID than those with low aortic PP (40.9 vs 25.2%, p<0.001). Conversely, aortic PP was not associated with CMED. On multivariate analysis, high aortic PP was associated with CMEID occurrence (OR 1.42, 95% CI 1.13 to 1.78; p=0.003). On follow-up (median, 150 months), all-cause death was more frequent among patients with vs without high aortic PP (20.1% vs 7.3%, log-rank p<0.001) and HR was 2.08 (95% CI 1.34 to 3.32, p=0.002) on multivariate cox regression analysis. Furthermore, among patients with low aortic PP, CMEID was an independent risk factor for all-cause mortality (HR 2.04, 95% CI 1.01 to 4.16, p=0.048). Conclusion In patients with non-obstructive CAD, invasive aortic PP was significantly associated with CMEID, but not with CMED. High aortic PP was an independent predictor of all-cause mortality, but CMEID was an independent risk factor in patients with low aortic PP.

Background: Coronary microvascular dysfunction results in angina and adverse outcomes in patients with evidence of ischemia and nonobstructive coronary artery disease; however, no specific therapy exists. CD34+ cell therapy increases microvasculature in preclinical models and improves symptoms, exercise tolerance, and mortality in refractory angina patients with obstructive coronary artery disease. The objective of this research was to evaluate the safety, tolerability, and efficacy of intracoronary CD34+ cell therapy in patients with coronary microvascular dysfunction. Methods: We conducted a 2-center, 20-participant trial of autologous CD34+ cell therapy (protocol CLBS16-P01; NCT03508609) in patients with ischemia and nonobstructive coronary artery disease with persistent angina and coronary flow reserve ≤2.5. Efficacy measures included coronary flow reserve, angina frequency, Canadian Cardiovascular Society angina class, Seattle Angina Questionnaire, SF-36, and modified Bruce exercise treadmill test obtained at baseline and 6 months after treatment. Autologous CD34+ cells (CLBS16) were mobilized by administration of granulocyte-colony stimulating factor 5µg/kg/day for 5 days and collected by leukapheresis. Participants received a single intracoronary left anterior descending infusion of isolated CD34+ cells in medium that enhances cell function. Results: Coronary flow reserve improved from 2.08±0.32 at baseline to 2.68±0.79 at 6 months after treatment ( P <0.005). Angina frequency decreased ( P <0.004), Canadian Cardiovascular Society class improved ( P <0.001), and quality of life improved as assessed by the Seattle Angina Questionnaire ( P ≤0.03, all scales) and SF-36 ( P ≤0.04, all scales). There were no cell-related serious adverse events. Conclusions: In this pilot clinical trial of microvascular angina, patients with ischemia and nonobstructive coronary artery disease receiving intracoronary infusion of CD34+ cell therapy had higher coronary flow reserve, less severe angina, and better quality of life at 6 months. The current study supports a potential therapeutic role for CD34+ cells in patients with microvascular angina. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03508609.

Introduction Obesity is a global health issue that impacts quality of life. A calorie-restricted diet with high-intensity consultation provided via the internet may be an effective way to lose weight. The objective of this study was to assess the effectiveness of a practitioner-guided, mobile internet-based low-energy dietary intervention in overweight and obese populations in China. Methods and analysis This open-label randomised controlled trial enrolled 220 overweight and obese adults aged 18–70 years who met the inclusion criteria. Participants were assigned to the control group (n=110) or trial group (n=110). The trial group will be enrolled in the MetaWell programme, a weight loss programme using diet replacement products, wireless scales and a mobile phone app. Participants in the control group will receive paper material containing a sample diet for weight loss. The follow-up period will be 1 year, and measurements will occur at 3, 6 and 12 months. Dual-emission X-ray absorptiometry and abdominal quantitative CT will be performed to estimate the percentage of overall body fat and areas of visceral and subcutaneous fat, alongside several cardiometabolic measurements. The primary outcome of this study is the change in body mas index (BMI) at 6 months after enrolment. A mixed-effects model will be used to compare BMI and body fat changes between the two groups. Ethics and dissemination This study was approved by the ethics committee of the Hospital of Chengdu Office of the People’s Government of the Tibetan Autonomous Region. Advertisements for recruitment will be sent via official accounts using WeChat. The results will be disseminated via publications in academic journals and our clinic. Our study group will maintain contact with the participants to inform them of the study findings. Trial registration number ChiCTR1900021630.

Background: Coronary endothelial dysfunction (CED) causes angina/ischemia in patients with nonobstructive coronary artery disease (NOCAD). Patients with CED have decreased number and function of CD34+ cells involved in normal vascular repair with microcirculatory regenerative potential and paracrine anti-inflammatory effects. We evaluated safety and potential efficacy of intracoronary autologous CD34+ cell therapy for CED. Methods: Twenty NOCAD patients with invasively diagnosed CED and persistent angina despite maximally tolerated medical therapy underwent baseline exercise stress test, GCSF (granulocyte colony stimulating factor)-mediated CD34+ cell mobilization, leukapheresis, and selective 1×10 5 CD34+ cells/kg infusion into left anterior descending. Invasive CED evaluation and exercise stress test were repeated 6 months after cell infusion. Primary end points were safety and effect of intracoronary autologous CD34+ cell therapy on CED at 6 months of follow-up. Secondary end points were change in Canadian Cardiovascular Society angina class, as-needed sublingual nitroglycerin use/day, Seattle Angina Questionnaire scores, and exercise time at 6 months. Change in CED was compared with that of 51 historic control NOCAD patients treated with maximally tolerated medical therapy alone. Results: Mean age was 52±13 years; 75% were women. No death, myocardial infarction, or stroke occurred. Intracoronary CD34+ cell infusion improved microvascular CED (%acetylcholine-mediated coronary blood flow increased from 7.2 [−18.0 to 32.4] to 57.6 [16.3–98.3]%; P =0.014), decreased Canadian Cardiovascular Society angina class (3.7±0.5 to 1.7±0.9, Wilcoxon signed-rank test, P =0.00018), and sublingual nitroglycerin use/day (1 [0.4–3.5] to 0 [0–1], Wilcoxon signed-rank test, P =0.00047), and improved all Seattle Angina Questionnaire scores with no significant change in exercise time at 6 months of follow-up. Historic control patients had no significant change in CED. Conclusions: A single intracoronary autologous CD34+ cell infusion was safe and may potentially be an effective disease-modifying therapy for microvascular CED in humans. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03471611.