ABSTRACT
BACKGROUND AND AIMS: The distinct functions of immune cells in atherosclerosis have been mostly defined by preclinical mouse studies. Contrastingly, the immune cell composition of human atherosclerotic plaques and their contribution to disease progression is only poorly understood. It remains uncertain whether genetic animal models allow for valuable translational approaches. METHODS AND RESULTS: Single cell RNA-sequencing (scRNA-seq) was performed to define the immune cell landscape in human carotid atherosclerotic plaques. The human immune cell repertoire demonstrated an unexpectedly high heterogeneity and was dominated by cells of the T-cell lineage, a finding confirmed by immunohistochemistry. Bioinformatical integration with 7 mouse scRNA-seq data sets from adventitial and atherosclerotic vascular tissue revealed a total of 51 identities of cell types and differentiation states, of which some were only poorly conserved between species and exclusively found in humans. Locations, frequencies, and transcriptional programs of immune cells in mouse models did not resemble the immune cell landscape in human carotid atherosclerosis. In contrast to standard mouse models of atherosclerosis, human plaque leukocytes were dominated by several T-cell phenotypes with transcriptional hallmarks of T-cell activation and memory formation, T-cell receptor-, and pro-inflammatory signaling. Only mice at the age of 22 months partially resembled the activated T-cell phenotype. In a validation cohort of 43 patients undergoing carotid endarterectomy, the abundance of activated immune cell subsets in the plaque defined by multi-color flow cytometry associated with the extend of clinical atherosclerosis. CONCLUSIONS: Integrative scRNA-seq reveals a substantial difference in the immune cell composition of murine and human carotid atherosclerosis - a finding that questions the translational value of standard mouse models for adaptive immune cell studies. Clinical associations suggest a specific role for T-cell driven (auto-) immunity in human plaque formation and -instability.
ABSTRACT
Atherosclerosis, the leading cause of cardiovascular disease responsible for the majority of deaths worldwide, cannot be sufficiently explained by established risk factors, including hypercholesterolemia. Elevated plasma homocysteine is an independent risk factor for atherosclerosis and is strongly linked to cardiovascular mortality. However, the role of homocysteine in atherosclerosis is still insufficiently understood. Previous research in this area has been also hampered by the lack of reproducible in vivo models of atherosclerosis that resemble the human situation. Here, we have developed and applied an automated system for vessel wall injury that leads to more homogenous damage and more pronounced atherosclerotic plaque development, even at low balloon pressure. Our automated system helped to glean vital details of cholesterol-independent changes in the aortic wall of balloon-injured rabbits. We show that deficiency of B vitamins, which are required for homocysteine degradation, leads to atherogenic transformation of the aorta resulting in accumulation of macrophages and lipids, impairment of its biomechanical properties and disorganization of aortic collagen/elastin in the absence of hypercholesterolemia. A combination of B vitamin deficiency and hypercholesterolemia leads to thickening of the aorta, decreased aortic water diffusion, increased LDL-cholesterol and impaired vascular reactivity compared to any single condition. Our findings suggest that deficiency of B vitamins leads to atherogenic transformation of the aorta even in the absence of hypercholesterolemia and aggravates atherosclerosis development in its presence.
Subject(s)
Atherosclerosis , Hypercholesterolemia , Hyperlipidemias , Vitamin B Complex , Animals , Aorta/metabolism , Atherosclerosis/metabolism , Cholesterol , Diet, Atherogenic , Homocysteine/metabolism , Humans , Hypercholesterolemia/metabolism , Hyperlipidemias/metabolism , RabbitsABSTRACT
INTRODUCTION: Popliteal artery entrapment syndrome (PAES) is a pathology characterised by anatomical anomalies of the relative position of the popliteal artery (PA) to the medial head of the gastrocnemius muscle (MHGM), resulting in mechanical compression causing damage to and occlusion of the artery. PATIENTS: From 2012 to 2018, we operated on 3 male patients aged 17 to 48 years, who presented with PAES in our department. The first and oldest patient had previously undergone femoro-popliteal bypass surgery in 2003 when aged 23, with the underlying diagnosis of "posttraumatic PAOD IIâb" followed by several reoperations. In 2012, during the preparation of the popliteal fossa for the interposition of the aneurysmatic bypass vein a strong tendinous strand of the MHGM was found intraoperatively to be constricting the vessels. This aberrant part of the MHGM was resected and the vein replaced. The second patient was referred to us in 2014 with the diagnosis "PAOD IIâb with thrombosed popliteal aneurysm" after having undergone intra-arterial lysis at age 33. Due to the remaining wall adherent thrombi and position of the aneurysm, interposition of the PA with a venous graft was planned. Intraoperatively a tendon was found proximal to the aneurysm, causing significant stenosis of the PA. This structure was resected and the interposition performed as planned. The third patient was a 17 year old adolescent, who presented with plantar and calf claudication in his right leg with paleness and pulselessness. Imaging showed occlusion of the popliteal artery in both legs. After initial intra-arterial lysis, HRMRI of the knee showed the atypical course of the PA undercrossing the MHGM from the medial side. Open surgical treatment was performed by myotomy, leading to refixation of the tendon of the MHGM in its physiological position. All patients received individual medical treatment for prophylaxis of rethrombosis. All three patients declined surgical treatment of the asymptomatic contralaterally diagnosed PAES. CONCLUSION: Popliteal artery entrapment syndrome is rare and usually associated with athletic, largely young male patients with pronounced calf muscles. Delayed diagnosis of PAES leads to severe vascular defects, unnecessary reintervention and prolonged illness as is shown in our first case. Therefore, calf and foot claudication in young patients should always bring to mind the differential diagnosis of popliteal entrapment syndrome.
Subject(s)
Aneurysm , Arterial Occlusive Diseases , Popliteal Artery , Vascular Grafting , Adolescent , Adult , Arterial Occlusive Diseases/surgery , Humans , Intermittent Claudication , Male , Middle Aged , Popliteal Artery/pathology , Young AdultABSTRACT
OBJECTIVE: Low psoas muscle area is shown to be an indicator for worse postoperative outcome in patients undergoing vascular surgical. Additionally, it has been associated with longer durations of hospital stay in patients with cancer who undergo surgery and subsequently greater health care costs in Europe and the United States. We sought to evaluate this effect on hospital expenditure for patients undergoing vascular repair in a health care system with universal access. METHODS: Skeletal muscle mass was assessed on preoperative abdominal computed tomography scans of patients undergoing open aortic aneurysm repair in a retrospective fashion. The skeletal muscle index (SMI) was used to define low muscle mass. Health care costs were obtained for all patients and the relationship between a low SMI and higher costs was explored using linear regression and cross-sectional analysis. RESULTS: We included 156 patients (81.5% male) with a median age of 72 years undergoing elective surgery for infrarenal abdominal aortic aneurysm in this analysis. The median SMI for patients with low skeletal muscle mass was 53.21 cm2/kg and for patients without, 70.07 cm2/kg. Hospital duration of stay was 2 days longer in patients with low skeletal muscle mass as compared with patients with normal (14 days vs 11 days; P = .001), as was duration of intensive care stay (3 days vs 1 day; P = .01). The median overall hospital costs were 10,460 higher for patients with a low SMI as compared with patients with a normal physical constitution (53,739 [interquartile range, 45,007-62,471] vs 43,279 [interquartile range, 39,509-47,049]; P = .001). After confounder adjustment, a low SMI was associated with a 14.68% cost increase in overall hospital costs, for a cost increase of 6521. CONCLUSIONS: Low skeletal muscle mass is independently associated with higher hospital as well as intensive care costs in patients undergoing elective aortic aneurysm repair. Strategies to reduce this risk factor are warranted for these patients.
Subject(s)
Aortic Aneurysm, Abdominal/economics , Aortic Aneurysm, Abdominal/surgery , Body Composition , Hospital Costs , Psoas Muscles/physiopathology , Vascular Surgical Procedures/economics , Aged , Aged, 80 and over , Aortic Aneurysm, Abdominal/diagnostic imaging , Aortic Aneurysm, Abdominal/physiopathology , Critical Care/economics , Cross-Sectional Studies , Elective Surgical Procedures/economics , Female , Health Status , Humans , Length of Stay/economics , Male , Middle Aged , Postoperative Complications/economics , Postoperative Complications/therapy , Psoas Muscles/diagnostic imaging , Retrospective Studies , Risk Factors , Time Factors , Treatment Outcome , Vascular Surgical Procedures/adverse effectsABSTRACT
RATIONALE: Cystic medial degeneration Erdheim-Gsell is a vascular pathology mainly of the large vessels, which is mostly associated with Marfan syndrome or Ehlers-Danlos syndrome. The clinical findings of this entity are aneurysms of the aorta or large peripheral arteries which usually present in an acute setting due to rupture of an aneurysm. PATIENT CONCERNS: We present a case of a 43-year-old Caucasian male with histologically proven cystic medial degeneration of the lower limb vessels mimicking peripheral artery occlusive disease. Despite antiplatelet and anticoagulant treatment, the patient suffered multiple vascular stenosis and occlusions. DIAGNOSES: Multiple arterial stenoses and thromboses leading to peripheral artery occlusive disease caused by cystic medial degeneration Erdheim-Gsell. INTERVENTIONS: Multiple surgical and endovascular interventions including bypass graft and intra-arterial thrombolysis as well as oral antiplatelet and anticoagulant therapy. OUTCOME: Despite dual antiplatelet therapy, anticoagulant therapy with rivaroxaban and multiple surgical and endovascular interventions, the patient developed recurrent arterial thromboses. The patient did not suffer further thrombotic events since clopidogrel and phenprocoumon were administered. LESSONS: Clinical presentation of cystic medial degeneration Erdheim-Gsell mimicking peripheral artery occlusive disease is very unusual. Due to the fragile vessel wall, patients with cystic medial degeneration might have a higher risk to develop arterial thromboses, even under antiplatelet therapy or anticoagulant treatment.
Subject(s)
Aortic Aneurysm, Thoracic/complications , Arterial Occlusive Diseases/etiology , Cysts/complications , Thrombosis/etiology , Adult , Humans , MaleABSTRACT
STUDY DESIGN: Test-retest methodological design using a sample of convenience. OBJECTIVE: To determine the criterion-related validity and the reliability of measuring first ray mobility with a ruler. BACKGROUND: Studies have questioned the accuracy of assessing first ray mobility by manual examination. Use of a ruler and adherence to strict guidelines in positioning of the patient may improve the measure. This study investigates the validity, and the intrarater and interrater reliability of measuring dorsal first ray mobility with a ruler while following recent recommendations to standardize the position of measurement. A valid and reliable mechanical device designed to measure first ray mobility was used as the validation criterion of measurement. METHODS: Three clinicians performed ruler measurement of dorsal mobility on 14 subjects. A separate examiner measured dorsal mobility with the mechanical device. Intraclass correlation coefficients (ICCs) and standard error of measurements (SEMs) were computed to quantify the intrarater reliability of both testing procedures and the interrater reliability of the ruler measurement. ICCs of agreement were also computed to determine the concurrent validity of the ruler measurement for each clinician. RESULTS: Mechanical device intrarater reliability ICC was 0.98 (SEM = 0.15 mm). Ruler intrarater ICCs were equal or less than -0.06 (SEMs = 1.1 mm); ruler interrater ICC was 0.05 (SEM = 1.2 mm). The ICCs of agreement between the mechanical device and ruler method ranged from -0.44 to 0.06. CONCLUSION: The ruler method of testing demonstrates poor reliability and validity as a clinical measure.