Macroscopic loss of extracellular matrix (ECM) can lead to chronic defects in skin wound healing, but supplementation of ECM holds promise for facilitating wound closure, particularly in diabetic wound healing. We recently showed that the ECM proteoglycan agrin accelerates cutaneous wound healing by improving mechanoperception of migrating keratinocytes and allowing them to respond to mechanical stresses via matrix metalloproteinase-12 (MMP12). RNA-sequencing analysis revealed that in addition to a disorganized ECM, agrin-depleted skin cells have impaired YAP/TAZ transcriptional outcomes, leading us to hypothesize that YAP/TAZ, as central mechanosensors, drive the functionality of agrin-MMP12 signaling during cutaneous wound repair. Herein, we demonstrate that agrin activates YAP/TAZ during migration of keratinocytes post-wounding in vitro and in vivo. Mechanistically, YAP/TAZ sustain agrin and MMP12 protein expression during migration post-wounding through positive feedback. YAP/TAZ silencing abolishes agrin-MMP12 mediated force-recognition and geometrical constraints. Importantly, soluble agrin (sAgrin) therapy accelerates wound closure in diabetic mouse models by engaging MMP12-YAP. Because patients with diabetic foot ulcers and impaired wound healing have reduced expression of agrin-MMP12 that correlates with YAP/TAZ inactivation, we propose that timely activation of YAP/TAZ by sAgrin therapy can accentuate mechanobiological microenvironments for efficient wound healing, under normal and diabetic conditions.

Peripheral artery disease (PAD) is a common and debilitating condition characterized by the narrowing of the limb arteries, primarily due to atherosclerosis. Non-invasive multi-modality imaging approaches using computed tomography (CT), magnetic resonance imaging (MRI), and nuclear imaging have emerged as valuable tools for assessing PAD atheromatous plaques and vessel walls. This review provides an overview of these different imaging techniques, their advantages, limitations, and recent advancements. In addition, this review highlights the importance of molecular markers, including those related to inflammation, endothelial dysfunction, and oxidative stress, in PAD pathophysiology. The potential of integrating molecular and imaging markers for an improved understanding of PAD is also discussed. Despite the promise of this integrative approach, there remain several challenges, including technical limitations in imaging modalities and the need for novel molecular marker discovery and validation. Addressing these challenges and embracing future directions in the field will be essential for maximizing the potential of molecular and imaging markers for improving PAD patient outcomes.

There is an unmet need for new pathways to evaluate therapeutic targets and drugs for coronary artery disease (CAD). The use of major adverse cardiovascular events as a primary outcome is advantageous for rigor, but challenges related to large sample size requirements, long study durations, and associated costs and risks remain major disincentives for key stakeholders. Until now, a robust, well-validated surrogate biomarker for cardiovascular events that reflects atherosclerosis itself has been lacking. This is particularly important as new therapeutic candidates targeting inflammation and factors downstream of low-density lipoprotein and other well-recognized factors continue to emerge. Coronary computed tomography angiography (CTA) has emerged as an ideal modality to image, characterize, and quantify specific plaque components, with potential for a more formal role in the CAD drug development pipeline. This review examines both morphological (high-risk plaque) and quantitative (specific plaque components) measures, considering their pathophysiological correlation with other imaging measures of atherosclerosis, evidence for the association of each component with major adverse cardiovascular events, and their responsiveness to effective drug treatments. Given the rapid advancement in coronary CTA acquisition and analysis technology, there is an urgent need for coordination and collaboration among key stakeholders, including imaging hardware and software companies, pharmaceutical companies, as well as clinicians, patients, regulators, and payers. Progress in this area, and the opportunities that may follow for the broader cardiovascular community if standardized coronary CTA endpoints are validated as surrogates for clinical drug trials, could accelerate innovation and enhance efficiency in CAD drug development.

Background: The comparison of coronary computed tomography angiography plaques and perivascular adipose tissue (PVAT) between patients with acute myocardial infarction (AMI) posttreatment and patients with stable coronary artery disease is poorly understood. Our objective was to evaluate the differences in coronary computed tomography angiography–quantified plaque and PVAT characteristics in patients post‐AMI and identify signs of residual inflammation. Methods and Results: We analyzed 205 patients (age, 59.77±9.24 years; 92.20% men) with AMI ≤1 month and matched them with 205 patients with stable coronary artery disease (age, 60.52±10.04 years; 90.24% men) based on age, sex, and cardiovascular risk factors. Coronary computed tomography angiography scans were assessed for nonculprit plaque and vessel characteristics, plaque volumes by composition, high‐risk plaques, and PVAT mean attenuation. Both patient groups exhibited similar noncalcified plaque volumes (383.35±313.23 versus 378.63±426.25 mm ³ , P =0.899). However, multivariable analysis revealed that patients post‐AMI had a greater patient‐wise noncalcified plaque volume ratio (estimate, 0.089 [95% CI, 0.053–0.125], P <0.001), largely attributed to a higher fibrofatty and necrotic core volume ratio, along with higher peri‐lesion PVAT mean attenuation (estimate, 3.968 [95% CI, 2.556–5.379], P <0.001). When adjusted for vessel length, patients post‐AMI had more high‐risk plaques (estimate, 0.417 [95% CI, 0.298–0.536], P <0.001) per patient. Conclusions: Patients post‐AMI displayed heightened noncalcified plaque components, largely due to fibrofatty and necrotic core content, more high‐risk plaques, and increased PVAT mean attenuation on a per‐patient level, highlighting the necessity for refined risk assessment in patients with AMI after treatment.

Aims: To identify differences in CT-derived perivascular adipose tissue (PVAT) and epicardial adipose tissue (EAT) characteristics that may indicate inflammatory status differences between post-treatment acute myocardial infarction (AMI) and stable coronary artery disease (CAD) patients. Methods and results: A cohort of 205 post-AMI patients (age 59.8 ± 9.2, 92.2% male) was propensity-matched with 205 stable CAD patients (age 60.5 ± 10.0, 90.2% male). Coronary CT angiography and non-contrast CT scans were performed to assess PVAT mean attenuation across major coronary segments and EAT mean attenuation and volumes, respectively. For post-AMI patients, CT scans were conducted 28.6 ± 13.8 days after the AMI incidence. Post-AMI patients showed higher non-culprit PVAT and EAT mean attenuation than stable CAD patients (8.01 HU, 95% CI 5.90–10.11 HU, P < 0.001, 2.48 HU, 95% CI 0.83–4.13 HU, P = 0.003, respectively). The EAT volume percentage at higher attenuation levels was higher in post-AMI patients compared with stable CAD (33.93 cm3, 95% CI 16.86–51.00 cm3, P < 0.001), with the difference maximized at the −70 HU threshold (4.75%, 95% CI 3.64%–5.87%, P < 0.001). PVAT mean attenuation positively correlated with EAT mean attenuations and the percentage of EAT volume > −70 HU (P < 0.001 for both). Conclusion: Post-AMI patients showed higher PVAT and EAT attenuation than stable CAD patients, potentially indicating AMI-associated inflammatory cardiac adipose tissue changes. A total of −70 HU can act as a potential cut-off for inflamed EAT. These findings highlight the potential of using CT-derived adipose tissue characteristics to assess inflammation and guide post-AMI management strategies.