Background: Atherosclerosis and consequent risk of cardiovascular events or mortality can be accurately assessed by quantifying coronary artery calcium score (CACS) derived from computed tomography. HMG-CoA-reductase inhibitors (statins) are the primary pharmacotherapy used to reduce cardiovascular events, yet there is growing data that support statin use may increase coronary calcification. We set out to determine the likelihood of severe CACS in the context of chronic statin therapy. Methods: We established a retrospective, case-control study of 1,181 U.S. veterans without coronary artery disease (CAD) from a single site, the Providence VA Medical Center. Duration of statin therapy for primary prevention was divided into 5-year categorical increments. The primary outcome was CACS derived from low-dose lung cancer screening computed tomography (LCSCT), stratified by CACs severity (none = 0; mild = 1–99; moderate = 100–399; and severe ≥400 AU). Statin duration of zero served as the referent control. Ordinal logistic regression analysis determined the association between duration of statin use and CACS categories. Proportional odds assumption was tested using likelihood ratio test. Atherosclerotic cardiovascular disease (ASCVD) risk score, body mass index, and CKD (glomerular filtration rate of <60 ml/min/1.73 m²) were included in the adjustment models. Results: The mean age of the study population was 64.7±7.2 years, and 706 (60%) patients were prescribed a statin at baseline. Duration of statin therapy was associated with greater odds of having increased CACS (>0–5 years, OR: 1.71 [CI: 1.34–2.18], p5–10 years, OR: 2.80 [CI: 2.01–3.90], p10 years, OR: 5.30 [CI: 3.23–8.70], p0–5 years, OR: 1.49 [CI: 1.16–1.92], p = 0.002; >5–10 years, OR: 2.38 [CI: 1.7–3.35], p10 years, OR: 4.48 [CI: 2.7–7.43], p<0.001). Conclusions: Long-term use of statins is associated with increased likelihood of severe CACS in patients with significant smoking history. The use of CACS to interpret cardiovascular event risk may require adjustment in the context of chronic statin therapy.

Coronary artery disease caused by atherosclerosis is a major cause of morbidity and mortality around the world. Data from preclinical and clinical studies support the belief that atherosclerosis is an inflammatory disease that is mediated by innate and adaptive immune signaling mechanisms. This review sought to highlight the role of Rac-mediated inflammatory signaling in the mechanisms driving atherosclerotic calcification. In addition, current clinical treatment strategies that are related to targeting hypercholesterolemia as a critical risk factor for atherosclerotic vascular disease are addressed in relation to the effects on Rac immune signaling and the implications for the future of targeting immune responses in the treatment of calcific atherosclerosis.

Background: There is limited evidence describing the effect of failed rotator cuff repair (RCR), superior capsular reconstruction (SCR), or tendon transfer (TT) before reverse total shoulder arthroplasty (RTSA) on postoperative outcomes. Purpose: (1) To compare patient-reported outcome measure scores, range of motion, and complication rates in patients with previous ipsilateral shoulder surgery to those without previous surgery undergoing RTSA and (2) to compare the outcomes of patients with failed SCR or TT to those with failed RCR. Study Design: Cohort study; Level of evidence, 3. Methods: Patients who underwent RTSA from 2016 to 2021 were retrospectively identified through an institutional database. Patients who underwent RTSA after failed RCR, SCR, or TT (prior surgery [PS] group) were matched by age, sex, body mass index, and concomitant latissimus dorsi TT to patients who underwent RTSA for rotator cuff arthropathy with no prior surgery (NPS group). Primary outcome measures included rates of achieving the minimal clinically important difference (MCID), substantial clinical benefit (SCB), and Patient Acceptable Symptom State (PASS) for the American Shoulder and Elbow Surgeons (ASES) score and Single Assessment Numeric Evaluation (SANE). Secondary outcome measures included Veterans RAND 12-Item Health Survey scores, complication rates, and postoperative range of motion. A subanalysis compared outcomes in patients with prior failed RCR to patients with prior failed SCR or TT. Results: A total of 150 patients (PS: n = 60; NPS: n = 90) met inclusion criteria. The PS group consisted of 33 cases (55.0%) of primary RCR, 10 cases (16.7%) of revision RCR, 10 cases (16.7%) of SCR, and 7 cases (11.7%) of TT. Adjusted analysis showed that the NPS group had higher rates of achieving the MCID (93.3% vs 73.3%, respectively; P = .007), SCB (88.3% vs 56.7%, respectively; P < .001), and PASS (73.3% vs 26.7%, respectively; P < .001) for the ASES and higher rates of achieving the SCB (56.7% vs 20.0%, respectively; P < .001) and PASS (76.7% vs 35.0%, respectively; P < .001) for the SANE. The NPS group had greater forward flexion ( P < .001) at final follow-up. The PS group had higher rates of overall complications (30.0% vs 13.3%, respectively; P = .022) and prosthetic instability or dislocations (10.0% vs 1.1%, respectively; P = .033). Subanalysis showed that the SCR/TT subgroup had significantly lower rates of achieving the SCB (ASES: P = .004; SANE: P = .034) and PASS (ASES: P = .014; SANE: P = .009) compared with the RCR subgroup. Conclusion: Patients with a history of failed RCR, SCR, or TT to address rotator cuff insufficiency before RTSA had greater range of motion deficits, higher complication rates, and lower rates of achieving clinically significant outcomes than those without prior ipsilateral shoulder surgery.

Background: Peripheral artery disease is associated with significant morbidity and mortality. Mechanical revascularization strategies are a mainstay of treatment but are often limited by the anatomic complexity of atherosclerotic lesions. Therapeutic angiogenesis has fallen short of being impactful due to fundamental gaps in our understanding of postdevelopmental angiogenesis. Methods: Using a preclinical model of peripheral artery disease involving acute vascular injury by femoral artery ligation along with cellular and molecular studies of VEGF-A expression, we sought to further understand the early role of macrophages in inflammatory angiogenesis and arteriogenesis. Results: Macrophage depletion studies revealed that the optimal levels of tissue VEGF-A expression, endothelial cell recruitment, and blood flow recovery were dependent on early macrophage recruitment. Proangiogenic VEGF-A expression was highest in macrophages polarized towards an inflammatory phenotype. Myeloid VEGF-A-deletion, while having no impact on the potent inflammatory cytokine, IL-1β, led to reductions in ischemic tissue VEGF-A, endothelial cell recruitment, and blood flow recovery due to impaired angiogenesis and arteriogenesis. Transplant of inflammatory polarized macrophages rescued the myeloid VEGF-A-deletion phenotype, leading to full blood flow recovery. Conclusions: Macrophages are a necessary and sufficient source of tissue VEGF-A during inflammatory-driven angiogenesis and arteriogenesis in response to vascular injury. Although further study is needed, cell-based therapeutic angiogenesis strategies involving the polarization of macrophages toward an inflammatory state, in order to produce high levels of proangiogenic VEGF-A, may be quite effective for improving revascularization in the context of PAD.