A Road Map to Understanding Cardiovascular Disease in Diabetes: From the AHA Strategically Focused Research Network in Cardiometabolic Health and Type 2 Diabetes

Circulation Research · 2026-01-15

Despite major advances in medical therapies and prevention strategies, the risk of cardiovascular complications in patients with both type I and type II diabetes remains substantially elevated. In 2019, the American Heart Association sought applications for a Strategically Focused Research Network on Cardiometabolic Health and Type 2 Diabetes. In 2020, 4 centers were named, including Brigham and Women's Hospital, Johns Hopkins University, New York University, and the University of Iowa. These centers performed basic, translational, and clinical studies to provide insights to explain the over 2-fold risk of cardiovascular complications in diabetes. Clinical studies and studies in cells and animals aimed to uncover new mechanisms responsible for disease development. Studies using human populations sought to uncover new biomarkers to prognosticate risk. In this review, we discuss several key issues and current and developing methods to understand why diabetes drives atherosclerotic cardiovascular disease and heart failure. Both human data and experimental models are considered. We integrate a review of these topics with work from the Strategically Focused Research Network and conclude with suggestions for identifying novel risk factors and future experimental research.

Precision Antiplatelet Therapy: The Promise and Complexity of Pharmacogenomic Antiplatelet Therapy

Circulation Cardiovascular Interventions · 2026-04-27

Melanocortin receptor 4 agonist setmelanotide treats opioid-induced respiratory depression

bioRxiv (Cold Spring Harbor Laboratory) · 2026-03-10

Abstract Background The primary cause of death associated with opioids is opioid-induced respiratory depression (OIRD). Naloxone is used to reverse OIRD, but this drug is a competitive antagonist of µ-opioid receptor (MOR) and reverses analgesia, which limits its therapeutic use. Alternative non-opioid receptor antagonist-based approaches to OIRD treatment and prevention are needed. The aim of this study was to evaluate if setmelanotide (SET) is capable of reversing OIRD in a mouse model. Methods C57BL/6J male and female mice and Sprague-Dawley rats were given IP morphine or fentanyl and then treated 15 min later with either SET or vehicle VEH (IP) in a random order. Breathing was recorded by barometric plethysmography, and pain sensitivity was measured by the tail-flick test. Results In mice with OIRD, SET induced a 3-fold reduction of the apnea index, and decreased apnea duration as compared to the VEH treatment. SET increased respiratory rate and did not affect opioid-induced analgesia. Photostimulation of MC4R+ ChR2-expressing fibers in the parafacial region of MC4R-Cre mice elicited short-latency excitatory postsynaptic current in rostral ventral respiratory group (rVRG) pre-motoneurons projecting to the phrenic nucleus in the C3-C4 ventral horns of the spinal cord. Fentanyl inhibited the activity of rVRG neurons and SET reversed this effect. Conclusions SET effectively treated OIRD by increasing respiratory rate and inducing a significant decrease in the number of apneas without decreasing analgesia.

Stellate Ganglion Block in the Treatment of Long COVID: A Systematic Review

Current Pain and Headache Reports · 2026-04-13

OBJECTIVES: This review evaluates stellate ganglion block as a treatment for long COVID, seeking to evaluate the treatment's efficacy by various symptoms and the limitations of the current literature. STUDY DESIGN: Systematic Review. SETTING: Ambulatory or Outpatient Setting. METHODS, SUBJECTS: A systematic review of the current literature regarding use of stellate ganglion block in patients with long COVID was conducted. 2 databases were searched on August 28th, 2025. Search terms were "long COVID" and "stellate ganglion block", yielding 45 results. Studies examining patient outcomes after stellate ganglion block were included. Case reports, case series, basic science studies and previous reviews were excluded. Seven studies met inclusion criteria. RESULTS: Patients received a single stellate ganglion block in some studies and multiple stellate ganglion blocks in others. All studies reported symptomatic improvement without control groups. Response rates ranged from 55.8% to 100%. The most robust improvements (> 80% patients reporting relief) were seen in cough, dyspnea, headache, joint pain, pain interference/intensity, pins/needles, subjective relief. CONCLUSION: Stellate ganglion block is a promising treatment that appears to generate substantive benefit for many of the symptoms seen in long COVID. However, the current literature has small, uncontrolled studies with heterogenous study designs and follow-up periods. Standardized research with larger sample sizes, control groups, and longer-term follow up is necessary to elucidate the degree of benefit. IRB approval and clinical trial registration not required.

Platelets induce endothelial cell mitochondrial dysfunction in myocardial infarction

Science Advances · 2025-11-14 · 4 citations

Coronary endothelial dysfunction plays a key role in the pathogenesis of acute coronary syndromes. During myocardial infarction (MI), activated platelets release prothrombotic and proinflammatory factors, contributing to vascular injury and dysfunction. To investigate platelet-mediated endothelial dysfunction, endothelial cells (ECs) were treated with platelet-released factors from patients with MI and non-MI controls undergoing coronary angiography. RNA sequencing revealed that MI platelets induced EC mitochondrial dysfunction, confirmed by reduced mitochondrial membrane potential and disrupted mitochondrial networks. Integrating platelet transcriptomic data, we identified the C-C motif chemokine ligand 3 (CCL3) as significantly up-regulated in MI platelets and a key mediator of EC mitochondrial dysfunction. Blocking its receptor, CCR5, attenuated CCL3 effects. In an independent cohort of 261 patients with established cardiovascular disease, higher circulating CCL3 levels were associated with incident major adverse cardiovascular events. Together, these findings establish a mechanistic link between platelet activation and coronary endothelial dysfunction in MI.

Coronary perivascular adipose tissue fat attenuation index in patients with ischemia with no obstructive coronary arteries and coronary microvascular dysfunction

Coronary Artery Disease · 2025-11-03

BACKGROUND: Coronary microvascular dysfunction (CMD) is present in approximately 40% of patients with ischemia with no obstructive coronary arteries (INOCA) and has been associated with inflammation. We investigated associations between measures of inflammation of the coronary perivascular adipose tissue assessed by coronary computed tomography angiography (CCTA) and results of invasive coronary function testing (CFT) to diagnose CMD. METHODS: Adults referred for clinically indicated invasive coronary angiography who had less than 50% stenosis in all epicardial arteries were prospectively enrolled. CMD was defined as a coronary flow reserve (CFR) less than 2.5 or index of microvascular resistance (IMR) greater than or equal to 25 using bolus thermodilution in the left anterior descending (LAD) coronary artery. Coronary perivascular fat attenuation index was assessed by CCTA in the right coronary artery (RCA) and LAD. T tests were used to evaluate differences in perivascular FAI by CMD status. RESULTS: A total of 31 participants underwent CFT and CCTA. The mean age was 58 ± 11.7 years, 77% were female, and 61% were white. CMD was present in 15 participants (48%). No differences in perivascular FAI were observed in patients with and without CMD, either in the RCA [-74.2 ± 9.8 vs. -69.9 ± 10.3 Hounsfield units (HU), P = 0.24] or LAD (-76.4 ± 10.2 vs. -74.8 ± 12.7 HU, P = 0.69). Perivascular FAI was not correlated with CFR or IMR measurements in the RCA or LAD. CONCLUSION: There were no associations between CMD diagnosed by invasive CFT and perivascular FAI by CCTA in patients with INOCA. Further research is needed to understand the relationship between vascular inflammation and CMD in INOCA.

Angiography-Derived Versus Coronary Guidewire-Derived Index of Microcirculatory Resistance in Patients With Ischemia With Nonobstructive Coronary Arteries

Journal of the Society for Cardiovascular Angiography & Interventions · 2025-10-15

Background: compared with the conventional index of microcirculatory resistance (IMR) in a cohort of individuals with INOCA. Methods: was calculated retrospectively, blinded to CFT results. CMD was defined by IMR ≥25 or CFR <2.5. Results: and IMR. Conclusions: appears unreliable for identifying CMD in patients with INOCA.

ENDOTHELIAL PROFILING IN PSORIASIS REVEALS A PRO-INFLAMMATORY GENE SIGNATURE ASSOCIATED WITH CORONARY PLAQUE BURDEN

Journal of the American College of Cardiology · 2025-03-29

Abstract 4370745: Aggressive Lipid Lowering Differentially Impacts the Vascular Endothelium in Diabetic vs Healthy Individuals. Findings from the American Heart Association Cardiometabolic Health Strategically Focused Research Network

Circulation · 2025-11-03

Background: Vascular endothelial cell (EC) damage and subsequent cardiovascular (CV) events occur in patients with type 2 diabetes (T2D) despite aggressive medical therapy. This study investigated the key vascular EC pathways in T2D vs controls at baseline and after aggressive lipid lowering therapy (LLT) to improve our mechanistic understanding of CV risk reduction strategies in T2D. Methods: CHORD (CHOlesterol lowering and Residual Risk in Diabetes) is a clinical trial of LLT with PCSK9 inhibitor plus high-intensity statin or ezetimibe for 1-month to evaluate mechanisms of CV risk in T2D and non-T2D (controls) free of clinical CV disease with an LDL-C &gt; 100 mg/dL. In a subset of participants, EC harvesting was performed at baseline and follow-up by inserting a J-wire through an angiocatheter into the brachial vein. ECs were isolated with magnetic beads directed against CD146, and transcript expression assessed using next generation RNA sequencing. Results: We performed EC harvesting in 15 participants with DM (median age 55 years, 60% male, HbA1c 6.7%, LDL-C 131 mg/dL) and 25 controls (median age 37 years, 56% male, HbA1c 5.2%, LDL-C 142 mg/dL). After adjustment for age and sex, EC RNA sequencing in T2D (vs controls) demonstrated 1126 upregulated and 204 downregulated genes (nominal p&lt;0.05) with dysregulated pathways in T2D (vs controls) involved in lipid metabolic process, apoptosis, interferon signaling, and leukocyte vascular adhesion. After lipid-lowering (LDL-C decreased by 70% in both T2D and controls), 839 genes were upregulated, and 1271 genes were downregulated (nominal p&lt;0.05) with upregulated EC pathways related to EC health, nitric oxide, and IL-10 signaling. Downregulated EC pathways after LLT included interferon production, inflammasome signaling and NFkB production (Figure). When compared to controls, T2D showed preferential reduction in endothelial inflammatory pathways yet upregulation in those related to platelet activation and hemostasis (Figure). Following LLT, the dysregulated pathways between T2D and controls at baseline (lipid process, apoptosis, interferon signaling, leukocyte vascular adhesion) were no longer significantly different between groups. Conclusion: While individuals with and without T2D derive improvement in vascular endothelial function, aggressive lipid lowering appears to have a more robust anti-inflammatory impact in T2D yet no impact on those related to hemostasis.

Coronary Artery Calcium Burden May Stratify Distinct Phenotypes of Carotid Artery Stenosis

Journal of Vascular Surgery · 2025-05-23