Skeletal muscle desmin alterations following revascularization in peripheral artery disease claudicants.

Peripheral artery disease (PAD) is characterized by varying severity of arterial stenosis, exercise induced claudication, malperfused tissue precluding normal healing and skeletal muscle dysfunction. Revascularization interventions improve circulation, but post-reperfusion changes within the skeletal muscle are not well characterized. This study investigates if revascularization enhanced hemodynamics increases walking performance with concurrent improvement of mitochondrial function and reverses abnormal skeletal muscle morphological features that develop with PAD. Fifty-eight patients completed walking performance testing and muscle biopsy before and 6 months after revascularization procedures. Muscle fiber morphology, desmin structure, and mitochondria respiration assessments before and after the revascularization were evaluated. Revascularization improved limb hemodynamics, walking function, and muscle morphology. Qualitatively not all participants recovered normal structural architecture of desmin in the myopathic myofibers after revascularization. Heterogenous responses in the recovery of desmin structure following revascularization may be caused by other underlying factors not reversed with hemodynamic improvements. Revascularization interventions clinically improve patient walking ability and can reverse the multiple subcellular functional and structural abnormalities in muscle cells. Further study is needed to characterize desmin structural remodeling with improvements in skeletal muscle morphology and function.

Sex in cardiovascular disease: Why this biological variable should be considered in in vitro models.

Cardiovascular disease (CVD), the world's leading cause of death, exhibits notable epidemiological, clinical, and pathophysiological differences between sexes. Many such differences can be linked back to cardiovascular sexual dimorphism, yet sex-specific in vitro models are still not the norm. A lack of sex reporting and apparent male bias raises the question of whether in vitro CVD models faithfully recapitulate the biology of intended treatment recipients. To ensure equitable treatment for the overlooked female patient population, sex as a biological variable (SABV) inclusion must become commonplace in CVD preclinical research. Here, we discuss the role of sex in CVD and underlying cardiovascular (patho)physiology. We review shortcomings in current SABV practices, describe the relevance of sex, and highlight emerging strategies for SABV inclusion in three major in vitro model types: primary cell, stem cell, and three-dimensional models. Last, we identify key barriers to inclusive design and suggest techniques for overcoming them.

Evidence-Based Update on Transcatheter Therapies for Pulmonary Embolism.

PURPOSE OF REVIEW: Pulmonary embolism (PE) remains a leading cause of cardiovascular morbidity and mortality. Multiple new therapies are in development and under study to improve our contemporary care of patients with PE. We review and compare here these novel therapeutics and technologies. RECENT FINDINGS: Multiple novel therapeutic devices have been developed and are under active study. This work has advanced the care of patients with intermediate and high-risk PE. Novel therapies are improving care of complex PE patients. These have inspired large multicenter international randomized controlled trials that are actively recruiting patients to advance the care of PE. These studies will work towards advancing guidelines for clinical care of patients with PE.

SARS-CoV-2 spike protein induces endothelial dysfunction in 3D engineered vascular networks.

With new daily discoveries about the long-term impacts of COVID-19, there is a clear need to develop in vitro models that can be used to better understand the pathogenicity and impact of COVID-19. Here, we demonstrate the utility of developing a model of endothelial dysfunction that utilizes human induced pluripotent stem cell-derived endothelial progenitors encapsulated in collagen hydrogels to study the effects of COVID-19 on the endothelium. These cells form capillary-like vasculature within 1 week after encapsulation and treating these cell-laden hydrogels with SARS-CoV-2 spike protein resulted in a significant decrease in the number of vessel-forming cells as well as vessel network connectivity quantified by our computational pipeline. This vascular dysfunction is a unique phenomenon observed upon treatment with SARS-CoV-2 SP and is not seen upon treatment with other coronaviruses, indicating that these effects were specific to SARS-CoV-2. We show that this vascular dysfunction is caused by an increase in inflammatory cytokines, associated with the COVID-19 cytokine storm, released from SARS-CoV-2 spike protein treated endothelial cells. Following treatment with the corticosteroid dexamethasone, we were able to prevent SARS-CoV-2 spike protein-induced endothelial dysfunction. Our results highlight the importance of understanding the interactions between SARS-CoV-2 spike protein and the endothelium and show that even in the absence of immune cells, the proposed 3D in vitro model for angiogenesis can reproduce COVID-19-induced endothelial dysfunction seen in clinical settings. This model represents a significant step in creating physiologically relevant disease models to further study the impact of long COVID and potentially identify mitigating therapeutics.

Outcomes of atherectomy in patients undergoing lower extremity revascularisation.

BACKGROUND: There is a paucity of real-world data on the in-hospital (IH) and post-discharge outcomes in patients undergoing lower extremity peripheral vascular intervention (PVI) with adjunctive atherectomy. AIMS: In this retrospective, registry-based study, we evaluated IH and post-discharge outcomes among patients undergoing PVI, treated with or without atherectomy, in the National Cardiovascular Data Registry PVI Registry. METHODS: The IH composite endpoint included procedural complications, bleeding or thrombosis. The primary out-of-hospital endpoint was major amputation at 1 year. Secondary endpoints included repeat endovascular or surgical revascularisation and death. Multivariable regression was used to identify predictors of atherectomy use and its association with clinical endpoints. RESULTS: A total of 30,847 patients underwent PVI from 2014 to 2019, including 10,971 (35.6%) treated with atherectomy. The unadjusted rate of the IH endpoint occurred in 524 (4.8%) of the procedures involving atherectomy and 1,041 (5.3%) of non-atherectomy procedures (p=0.07). After adjustment, the use of atherectomy was not associated with an increased risk of the combined IH endpoint (p=0.68). In the 6,889 (22.4%) patients with out-of-hospital data, atherectomy was associated with a reduced risk of amputation (adjusted hazard ratio [aHR] 0.67, 95% confidence interval [CI]: 0.51-0.85; p<0.01) and surgical revascularisation (aHR 0.63, 95% CI: 0.44-0.89; p=0.017), no difference in death rates (p=0.10), but an increased risk of endovascular revascularisation (aHR 1.21, 95% CI: 1.06-1.39; p<0.01) at 1 year. CONCLUSIONS: The use of atherectomy during PVI is common and is not associated with an increase in IH adverse events. Longitudinally, patients treated with atherectomy undergo repeat endovascular reintervention more frequently but experience a reduced risk of amputation and surgical revascularisation.

Practical solutions for implementation of blood cholesterol guidelines in clinical practice.

Underutilization of lipid-lowering therapy (LLT) and failure to attain guideline-recommended low-density lipoprotein cholesterol (LDL-C) goals are important quality gaps in cardiovascular risk optimization, especially among patients with atherosclerotic cardiovascular disease (ASCVD). Large database analyses demonstrate an unmet need for improved LDL-C measurement, and that nearly 75% of patients with ASCVD have an LDL-C level above guideline-recommended levels, and greater than 50% are not treated with statins or ezetimibe. Proposed solutions for overcoming these obstacles to optimal lipid management include provider- and patient-facing educational interventions, health information technology strategies, implementation of incentive-based care, advocacy efforts, and systems-based process innovations. While individual interventions may not be enough to overcome the totality of barriers to optimal LLT, comprehensive multifaceted approaches that address barriers at the provider, patient, and healthcare delivery level are likely to offer the greatest likelihood of success and improved patient outcomes.

SARS-CoV-2 spike protein induces endothelial dysfunction in 3D engineered vascular networks.

With new daily discoveries about the long-term impacts of COVID-19 there is a clear need to develop in vitro models that can be used to better understand the pathogenicity and impact of COVID-19. Here we demonstrate the utility of developing a model of endothelial dysfunction that utilizes induced pluripotent stem cell-derived endothelial progenitors encapsulated in collagen hydrogels to study the effects of COVID-19 on the endothelium. We found that treating these cell-laden hydrogels with SARS-CoV-2 spike protein resulted in a significant decrease in the number of vessel-forming cells as well as vessel network connectivity. Following treatment with the anti-inflammatory drug dexamethasone, we were able to prevent SARS-CoV-2 spike protein-induced endothelial dysfunction. In addition, we confirmed release of inflammatory cytokines associated with the COVID-19 cytokine storm. In conclusion, we have demonstrated that even in the absence of immune cells, we are able to use this 3D in vitro model for angiogenesis to reproduce COVID-19 induced endothelial dysfunction seen in clinical settings.

Endovascular Treatment and Outcomes for Femoropopliteal In-Stent Restenosis: Insights from the XLPAD Registry.

Background: There is limited "real-world" evidence examining treatment modalities and outcomes in patients with symptomatic peripheral arterial disease undergoing endovascular treatment of femoropopliteal (FP) in-stent restenosis (ISR). Materials and Methods: We compared outcomes in 2,895 patients from the XLPAD registry (NCT01904851) between 2006 and 2019 treated for FP ISR (n = 347) and non-ISR (n = 2,548) lesions. Primary endpoint included major adverse limb events (MALE) at 1 year, a composite of all-cause death, target limb repeat revascularization, or major amputation. Results: ISR patients were more frequently on antiplatelet (94.5% vs 89.4%, p=0.007) and statin (68.9% vs 60.3%, p=0.003) therapies. Lesion length was similar (ISR: 145 ± 99 mm vs. non-ISR: 142 ± 99 mm, p=0.55). Fewer treated ISR lesions were chronic total occlusions (47.3% vs. 53.7%, p=0.02) and severely calcified (22.4% vs. 44.7%, p < 0.001). Atherectomy (63.5% vs. 45.0%, p < 0.001) and drug-coated balloons (DCB; 4.7% vs. 1.7%, p < 0.001) were more frequently used in ISR lesions. The distal embolization rate was higher in ISR lesions (2.4% vs. 0.9%, p=0.02). Repeat revascularization (21.5% vs. 16.7%, p=0.04; Figure) was higher and freedom from MALE at 1 year was significantly lower (87% vs. 92.5%, p < 0.001) in the ISR group. Conclusion: Atherectomy and DCB are more frequently used to treat FP ISR lesions. Patients with FP ISR have more intraprocedural distal embolization, higher repeat revascularization procedures, and lower freedom from MALE at 1 year.

Safety and Efficacy of Ultra Short-duration Dual Antiplatelet Therapy After Percutaneous Coronary Interventions: A Meta-analysis of Randomized Controlled Trials.

Dual antiplatelet therapy (DAPT) is required after percutaneous coronary intervention (PCI) to reduce stent thrombosis, but DAPT increases bleeding risks. The optimal duration of DAPT that provides the maximum protective ischemic effect along with the minimum bleeding risk is unclear. This is the first meta-analysis comparing outcomes for 1-month versus longer DAPT strategies following PCI.We searched PubMed, Cochrane, and ClinicalTrials.gov databases (from inception to October 2021) for randomized controlled trials that compared 1-month duration vs > 1-month duration of DAPT following PCI. We used a random-effects model to calculate risk ratio (RR) with 95% confidence interval (CI). The co-primary outcomes for study selection were all-cause mortality, major bleeding, and stent thrombosis. Secondary outcomes included myocardial infarction (MI), cardiovascular mortality, ischemic stroke and target vessel revascularization. A total of five randomized controlled trials were included [n = 29,355; 1-month DAPT(n = 14,662) vs > 1-month DAPT (n = 14,693)]. There was no statistically significant difference between the two groups in terms of all-cause mortality (RR 0.89; 95% CI 0.78-1.03; P = 0.12) and stent thrombosis (RR 1.07; 95% CI 0.80-1.43; P = 0.65). Similarly, there were no significant differences in MI, cardiovascular mortality, ischemic stroke, and target vessel revascularization. The rate of major bleeding was significantly lower in the group treated with DAPT for 1-month (RR 0.74; 95% CI 0.56-0.99, P = 0.04).There is no difference in all-cause mortality, cardiovascular mortality, MI, stent thrombosis, ischemic stroke, and target vessel revascularization with 1-month of DAPT following PCI with contemporary drug eluting stents compared to longer DAPT duration.

ACGME Interventional Cardiology Milestones 2.0-an overview: Endorsed by the Accreditation Council for Graduate Medical Education.

This document provides an overview of the rationale, development, interpretation, and practical suggestions for implementation of the new Accreditation Council for Graduate Medical Education (ACGME) Interventional Cardiology (IC) Milestones 2.0. Previously, IC programs used the general ACGME Milestones for internal medicine. The IC Milestones version 2.0 updates the ACGME competencies to be specific to training in IC. In 2019 an ACGME working group consisting of IC program directors, a lay representative, and representatives from the American Board of Internal Medicine met to develop the IC Milestones version 2.0. The ACGME IC Milestones 2.0 establishes a framework for formative feedback for trainees within domains of patient care, medical knowledge, systems-based practice, practice-based learning and improvement, professionalism, and interpersonal and communication skills. The 2021 IC Milestones 2.0 provides a framework for IC mentors and trainees to identify areas for improvement or commendation help stimulate meaningful educational discussions, and provide the basis for self-reflection and self-improvement.

Differences Between Patients With Intermittent Claudication and Critical Limb Ischemia Undergoing Endovascular Intervention: Insights From the Excellence in Peripheral Artery Disease Registry.

BACKGROUND: There are limited data on differences in angiographic distribution of peripheral artery disease and endovascular revascularization strategies in patients presenting with intermittent claudication (IC) and critical limb ischemia (CLI). We aimed to compare anatomic features, treatment strategies, and clinical outcomes between patients with IC and CLI undergoing endovascular revascularization. METHODS: We examined 3326 patients enrolled in the Excellence in Peripheral Artery Disease registry from 2006 to 2019 who were referred for endovascular intervention for IC (n=1983) or CLI (n=1343). The primary outcome was 1-year major adverse limb events, which included death, repeat target limb revascularization, or target limb amputation. RESULTS: Patients with CLI were older and more likely to have diabetes and chronic kidney disease and less likely to receive optimal medical therapy compared with IC. Patients with IC had higher femoropopliteal artery interventions (IC 87% versus CLI 65%; P<0.001), while below the knee interventions were more frequent in CLI (CLI 47% versus IC 12%; P<0.001). Patients with CLI were more likely to have multilevel peripheral artery disease (CLI 32% versus IC 15%, P<0.001). Patients with IC were predominantly revascularized with stents (IC 48% versus CLI 37%; P<0.001) while balloon angioplasty was more frequent in CLI (CLI 37% versus IC 25%; P<0.001). All-cause mortality was higher in patients with CLI (CLI 4% versus IC 2%; P=0.014). Major adverse limb event rates for patients with IC and CLI were 16% and 26%, respectively (P<0.001) and remained higher in CLI after multivariable adjustment of baseline risk factors. CONCLUSIONS: Patients with IC and CLI have significant anatomic, lesion, and treatment differences with significantly higher mortality and adverse limb outcomes in CLI. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01904851. Graphic Abstract: A graphic abstract is available for this article.

Characteristics of clinical trials evaluating cardiovascular therapies for Coronavirus Disease 2019 Registered on ClinicalTrials.gov: a cross sectional analysis.

Morbidity and mortality associated with COVID-19 has increased exponentially, and patients with cardiovascular (CV) disease are at risk for poor outcomes. Several lines of evidence suggest a potential role for CV therapies in COVID-19 treatment. Characteristics of clinical trials of CV therapies related to COVID-19 registered on ClinicalTrials.gov have not been described. METHODS: ClinicalTrials.gov was queried on August 7, 2020 for COVID-19 related trials. Studies evaluating established CV drugs, other fibrinolytics (defibrotide), and extracorporeal membrane oxygenation were included. Studies evaluating anti-microbial, convalescent plasma, non-colchicine anti-inflammatory, and other therapies were excluded. Trial characteristics were tabulated from study-specific entries. RESULTS: A total of 2,935 studies related to COVID-19 were registered as of August 7, 2020. Of these, 1,645 were interventional studies, and the final analytic cohort consisted of 114 studies evaluating 10 CV therapeutic categories. Antithrombotics (32.5%; n = 37) were most commonly evaluated, followed by pulmonary vasodilators (14.0%; n = 16), renin-angiotensin-aldosterone system-related therapies (12.3%; n = 14), and colchicine (8.8%; n = 10). Trials evaluating multiple CV therapy categories and CV therapies in combination with non-CV therapies encompassed 4.4% (n = 5) and 9.6% (n = 11) of studies, respectively. Most studies were designed for randomized allocation (87.7%; n = 100), enrollment of less than 1000 participants (86.8%; n = 99), single site implementation (55.3%; n = 63), and had a primary outcome of mortality or a composite including mortality (56.1%; n = 64). Most study populations consisted of patients hospitalized with COVID-19 (81.6%; n = 93). At the time of database query, 28.9% (n = 33) of studies were not yet recruiting and the majority were estimated to be completed after December 2020 (67.8%; n = 78). Most lead sponsors were located in North America (43.9%; n = 50) or Europe (36.0%; n = 41). CONCLUSIONS: A minority (7%) of clinical trials related to COVID-19 registered on ClinicalTrials.gov plan to evaluate CV therapies. Of CV therapy studies, most were planned to be single center, enroll less than 1000 inpatients, sponsored by European or North American academic institutions, and estimated to complete after December 2020. Collectively, these findings underscore the need for a network of sites with a platform protocol for rapid evaluation of multiple therapies and generalizability to inform clinical care and health policy for COVID-19 moving forward.

The Market Reacts Quickly: Changes in Paclitaxel Vascular Device Purchasing Within the Ascension Healthcare System.

BACKGROUND: A meta-analysis of trials in endovascular therapy suggested an increased mortality associated with treatment exposure to paclitaxel. Multiple publications and corrections of prior data were performed, and the United States Food and Drug Administration has issued multiple advisories regarding paclitaxel use. We analyzed how this controversy impacted device purchasing and related utilization patterns in the period immediately following publication of the meta-analysis. METHODS AND RESULTS: Ascension Healthcare System purchase data over a 14-month period were synthesized across centers for both paclitaxel and non-paclitaxel devices. A fixed-effects regression model and a binary regression model with facility-level controls were used to compare purchasing patterns before and after the meta-analysis. Purchase volumes of each paclitaxel device fell. Pooled purchase volumes of all paclitaxel devices decreased from a 14-month peak of 631 devices in October 2018 to a 14-month nadir of 359 devices in February 2019. An F-test comparing the pooled-month specific fixed effects for the months before vs after the publication of the meta-analysis has an F-statistic of 11.64, suggesting that average purchasing levels in the two periods are statistically different (P<.001). Utilization of non-paclitaxel devices did not decline. CONCLUSIONS: Purchase volumes of paclitaxel devices decreased immediately during the months following publication of the related meta-analysis. Total Ascension-wide paclitaxel device purchase volume in February 2019 demonstrated a 43.1% reduction from peak monthly purchase volume during the assessed period and a 32.5% reduction compared with November 2019, the last month preceding publication of the meta-analysis.

Clinical Decision Support for Peripheral Artery Disease: Answering the Call.

See Article by Arruda-Olson et al.