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Ekim M, Ekim H, Akarsu GD. Diabetic peripheral arterial disease in COVID-19 pandemic. JOURNAL OF RESEARCH IN MEDICAL SCIENCES : THE OFFICIAL JOURNAL OF ISFAHAN UNIVERSITY OF MEDICAL SCIENCES 2024; 29:35. [PMID: 39239073 PMCID: PMC11376723 DOI: 10.4103/jrms.jrms_509_23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Revised: 01/05/2024] [Accepted: 01/31/2024] [Indexed: 09/07/2024]
Abstract
Both diabetes and peripheral arterial disease (PAD) have complex interactions with COVID-19. PAD is one of the most important underlying factors in the development of diabetic foot. The COVID-19 pandemic has also caused an increase in cardiovascular complications in those with chronic diseases, including diabetics, due to both the thrombophilic course of the viral disease and the lockdown measures applied for prevention. Since both COVID-19 and diabetes mellitus predispose to thrombosis, PAD is likely to have a more severe course in diabetic patients with COVID-19. The aim of our study is to discuss the complications, prophylaxis, and treatment of PAD, which is a serious complication of diabetes, during the pandemic period.
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Affiliation(s)
- Meral Ekim
- Department of Nutrition and Dietetics, Yozgat Bozok University Faculty of Health Sciences, Yozgat, Turkey
| | - Hasan Ekim
- Department of Cardiovascular Surgery, Yozgat Bozok University Faculty of Medicine, Yozgat, Turkey
| | - Gökhan Doğukan Akarsu
- Division of Molecular Medicine, Laboratory for Advanced Genomics, Ruder Boskovic Institute, Zagreb, Croatia
- Department of Pharmacy Services, Yozgat Bozok University School of Health Services, Yozgat, Turkey
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Joseph S, Munshi B, Agarini R, Kwok RCH, Green DJ, Jansen S. Near infrared spectroscopy in peripheral artery disease and the diabetic foot: A systematic review. Diabetes Metab Res Rev 2022; 38:e3571. [PMID: 35939767 DOI: 10.1002/dmrr.3571] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Revised: 05/03/2022] [Accepted: 07/01/2022] [Indexed: 11/08/2022]
Abstract
With the need for tools that assess microvascular status in diabetic foot disease (DFD) being clear, near infrared spectroscopy (NIRS) is a putative method for noninvasive testing of the diabetic foot. The use of NIRS in patients with peripheral arterial disease (PAD) has extended to its role in studying the pathophysiology of DFD. NIRS generates metrics such as recovery time, deoxygenation, oxygen consumption (VO2 ), tissue oxygen saturation (StO2 ), total haemoglobin (HbT), and oxyhaemoglobin area under the curve (O2 HbAUC ). NIRS may potentially help the multidisciplinary team stratify limbs as high-risk, especially in diabetic patients with symptoms masked by peripheral neuropathy. NIRS may be useful for assessing treatment effectiveness and preventing deterioration of patients with PAD.
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Affiliation(s)
- Simon Joseph
- Department of Vascular and Endovascular Surgery, Sir Charles Gairdner Hospital, Perth, Western Australia, Australia
| | - Bijit Munshi
- Department of Vascular and Endovascular Surgery, Sir Charles Gairdner Hospital, Perth, Western Australia, Australia
| | - Raden Agarini
- Physiology Department, Faculty of Medicine, Airlangga University, Surabaya, East Java, Indonesia
- School of Human Sciences (Exercise and Sport Sciences), The University of Western Australia, Perth, Western Australia, Australia
| | - Ricky Chi Ho Kwok
- Department of Vascular and Endovascular Surgery, Sir Charles Gairdner Hospital, Perth, Western Australia, Australia
| | - Daniel J Green
- School of Human Sciences (Exercise and Sport Sciences), The University of Western Australia, Perth, Western Australia, Australia
| | - Shirley Jansen
- Department of Vascular and Endovascular Surgery, Sir Charles Gairdner Hospital, Perth, Western Australia, Australia
- Heart and Vascular Research Institute, Harry Perkins Institute of Medical Research, Perth, Western Australia, Australia
- Curtin Medical School, Curtin University, Perth, Western Australia, Australia
- School of Medicine, The University of Western Australia, Perth, Western Australia, Australia
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Characteristics of atherosclerosis in femoropopliteal artery and its clinical relevance. Atherosclerosis 2021; 335:31-40. [PMID: 34547588 DOI: 10.1016/j.atherosclerosis.2021.09.012] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Revised: 08/28/2021] [Accepted: 09/09/2021] [Indexed: 12/12/2022]
Abstract
Atherosclerosis is a systemic disease with different faces. Despite identical or similar pathogenetic mechanisms, atherosclerotic lesions and their clinical manifestations vary in different parts of the vascular system. Peripheral arterial disease (PAD) represents one of the most frequent clinical manifestations of atherosclerosis with predominant location in the superficial femoral artery (SFA). Morphological characteristics of atherosclerotic plaques in peripheral arteries differ from lesions in the coronary and carotid arteries. Plaques in SFA have more fibrotic components, less lipids and inflammatory cells, which makes them more stable and less prone to rupture. Factors that determine the different structure of plaques in SFA compared to coronary arteries include hemodynamic forces, vasa vasorum and calcification. Low shear stress in SFA in the adductor canal is one of the factors which determines frequent atherosclerotic lesions in this region. Lower lipid content and fewer inflammatory cells explain higher stability of SFA plaques. The specific structure of SFA plaques may require preventive and therapeutic measures, which to some extent differ from prevention of coronary atherosclerosis and may include inhibition of fibrotic proliferation in SFA plaques and calcification. Revascularization of PAD differs from procedures used in coronary arteries and requires specific technical expertise and devices.
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Schneble CA, Kahan JB, Burroughs PJ, Nasreddine AY, Sumpio BE, Medvecky MJ. Popliteal Artery Occlusion with Collateral Blood Flow in a Reducible Knee Dislocation During Pregnancy: A Case Report. JBJS Case Connect 2021; 11:01709767-202106000-00016. [PMID: 33835994 DOI: 10.2106/jbjs.cc.20.00516] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022]
Abstract
CASE A 29-year-old healthy woman, 19 weeks pregnant, sustained a right posterolateral knee dislocation with multiligamentous injury and a complete occlusive injury to the right popliteal artery yet had adequate distal perfusion. She declined operative management for both the knee dislocation and the arterial injury, and successful collaboration between obstetrical, vascular, and orthopaedic surgical services resulted in limb preservation and restoration of function. CONCLUSION This is a unique case of traumatic complete popliteal artery occlusion with adequate collateral arterial perfusion after a reducible posterolateral knee dislocation in a pregnant patient that resulted in limb preservation with nonoperative management.
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Affiliation(s)
- Christopher A Schneble
- Department of Orthopaedics & Rehabilitation, Yale School of Medicine, New Haven, Connecticut
| | - Joseph B Kahan
- Department of Orthopaedics & Rehabilitation, Yale School of Medicine, New Haven, Connecticut
| | | | - Adam Y Nasreddine
- Department of Orthopaedics & Rehabilitation, Yale School of Medicine, New Haven, Connecticut
| | - Bauer E Sumpio
- Division of Vascular Surgery, Yale School of Medicine, New Haven, Connecticut
| | - Michael J Medvecky
- Department of Orthopaedics & Rehabilitation, Yale School of Medicine, New Haven, Connecticut
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Tsai S, Vega GL. Coronary and peripheral artery plaques: do differences in plaque characteristics translate to differences in lipid management? J Investig Med 2020; 68:1141-1151. [DOI: 10.1136/jim-2019-001252] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/05/2020] [Indexed: 12/22/2022]
Abstract
Optimal medical management of patients with peripheral arterial disease (PAD) includes statin therapy, which has been shown to decrease the risk of major cardiovascular events. However, the relationship between low-density lipoprotein (LDL) lowering, PAD progression and limb outcomes remains controversial. Although prevention of coronary and cerebrovascular events is a priority, limb outcomes are still important determinants of quality of life and healthcare spending. This review will highlight differences between coronary artery disease (CAD) and PAD, and in particular, the more prevalent role of lipids and LDL cholesterol in CAD versus calcification in PAD. This difference may contribute to the differential impact of LDL cholesterol levels on coronary events and outcomes versus limb outcomes. Beyond LDL lowering, immune modulators have emerged as another agent to treat atherosclerosis in CAD, however similar data in PAD are lacking. Small studies have suggested that other lipids besides LDL cholesterol, such as triglycerides or small dense LDL, may have a greater impact on limb outcomes in patients with PAD. Although statin therapy is central in the management of patients with PAD, current understanding of the distinctions between PAD and CAD suggest that there may be other non-LDL targets for risk reduction that require further study.
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Fadini GP, Albiero M, Bonora BM, Avogaro A. Angiogenic Abnormalities in Diabetes Mellitus: Mechanistic and Clinical Aspects. J Clin Endocrinol Metab 2019; 104:5431-5444. [PMID: 31211371 DOI: 10.1210/jc.2019-00980] [Citation(s) in RCA: 85] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2019] [Accepted: 06/12/2019] [Indexed: 12/25/2022]
Abstract
CONTEXT Diabetes causes severe pathological changes to the microvasculature in many organs and tissues and is at the same time associated with an increased risk of coronary and peripheral macrovascular events. We herein review alterations in angiogenesis observed in human and experimental diabetes and how they contribute to diabetes onset and development of vascular complications. EVIDENCE ACQUISITION The English language medical literature was searched for articles reporting on angiogenesis/vasculogenesis abnormalities in diabetes and their clinical manifestations, mechanistic aspects, and possible therapeutic implications. EVIDENCE SYNTHESIS Angiogenesis is a complex process, driven by a multiplicity of molecular mechanisms and involved in several physiological and pathological conditions. Incompetent angiogenesis is pervasive in diabetic vascular complications, with both excessive and defective angiogenesis observed in various tissues. A striking different angiogenic response typically occurs in the retina vs the myocardium and peripheral circulation, but some commonalities in abnormal angiogenesis can explain the well-known association between microangiopathy and macroangiopathy. Impaired angiogenesis can also affect endocrine islet and adipose tissue function, providing a link to diabetes onset. Exposure to high glucose itself directly affects angiogenic/vasculogenic processes, and the mechanisms include defective responses to hypoxia and proangiogenic factors, impaired nitric oxide bioavailability, shortage of proangiogenic cells, and loss of pericytes. CONCLUSIONS Dissecting the molecular drivers of tissue-specific alterations of angiogenesis/vasculogenesis is an important challenge to devise new therapeutic approaches. Angiogenesis-modulating therapies should be carefully evaluated in view of their potential off-target effects. At present, glycemic control remains the most reasonable therapeutic strategy to normalize angiogenesis in diabetes.
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Affiliation(s)
- Gian Paolo Fadini
- Department of Medicine, University of Padova, Padova, Italy
- Venetian Institute of Molecular Medicine, Padova, Italy
| | - Mattia Albiero
- Department of Medicine, University of Padova, Padova, Italy
- Venetian Institute of Molecular Medicine, Padova, Italy
| | - Benedetta Maria Bonora
- Department of Medicine, University of Padova, Padova, Italy
- Venetian Institute of Molecular Medicine, Padova, Italy
| | - Angelo Avogaro
- Department of Medicine, University of Padova, Padova, Italy
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Fadini GP, Spinetti G, Santopaolo M, Madeddu P. Impaired Regeneration Contributes to Poor Outcomes in Diabetic Peripheral Artery Disease. Arterioscler Thromb Vasc Biol 2019; 40:34-44. [PMID: 31510789 DOI: 10.1161/atvbaha.119.312863] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Diabetes mellitus increases the risk and accelerates the course of peripheral artery disease, making patients more susceptible to ischemic events and infections and delaying tissue healing. Current understanding of pathogenic mechanisms is mainly based on the negative influence of diabetes mellitus on atherosclerotic disease and inflammation. In recent years, the novel concept that diabetes mellitus can impinge on endogenous regenerative processes has been introduced. Diabetes mellitus affects regeneration at the local level, disturbing proper angiogenesis, collateral artery formation, and muscle repair. Recent evidence indicates that an impairment in vascular mural cells, alias pericytes, may participate in diabetic peripheral vasculopathy. Moreover, the bone marrow undergoes a global remodeling, consisting of microvessels and sensory neurons rarefaction and fat accumulation, which creates a hostile microenvironment for resident stem cells. Bone marrow remodeling is also responsible for detrimental systemic effects. In particular, the aid of reparative cells from the bone marrow is compromised: these elements are released in an improper manner and become harmful vectors of inflammatory and antiangiogenic molecules and noncoding RNAs. This new understanding of impaired regeneration is inspiring new therapeutic options for the treatment of ischemic complications in people with diabetes mellitus.
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Affiliation(s)
- Gian Paolo Fadini
- From the Department of Medicine, University of Padova, Italy (G.P.F.).,Veneto Institute of Molecular Medicine, Padova, Italy (G.P.F.)
| | - Gaia Spinetti
- Laboratory of Cardiovascular Research, IRCCS MultiMedica, Milan, Italy (G.S.)
| | - Marianna Santopaolo
- Experimental Cardiovascular Medicine, University of Bristol, United Kingdom (M.S., P.M.)
| | - Paolo Madeddu
- Experimental Cardiovascular Medicine, University of Bristol, United Kingdom (M.S., P.M.)
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Insulin Treatment Forces Arteriogenesis in Diabetes Mellitus by Upregulation of the Early Growth Response-1 (Egr-1) Pathway in Mice. Int J Mol Sci 2019; 20:ijms20133320. [PMID: 31284541 PMCID: PMC6651530 DOI: 10.3390/ijms20133320] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2019] [Revised: 07/01/2019] [Accepted: 07/03/2019] [Indexed: 11/19/2022] Open
Abstract
The process of arteriogenesis is severely compromised in patients with diabetes mellitus (DM). Earlier studies have reported the importance of Egr-1 in promoting collateral outward remodeling. However, the role of Egr-1 in the presence of DM in outward vessel remodeling was not studied. We hypothesized that Egr-1 expression may be compromised in DM which may lead to impaired collateral vessel growth. Here, we investigated the relevance of the transcription factor Egr-1 for the process of collateral artery growth in diabetic mice. Induction of arteriogenesis by femoral artery ligation resulted in an increased expression of Egr-1 on mRNA and protein level but was severely compromised in streptozotocin-induced diabetic mice. Diabetes mellitus mice showed a significantly reduced expression of Egr-1 endothelial downstream genes Intercellular Adhesion Molecule-1 (ICAM-1) and urokinase Plasminogen Activator (uPA), relevant for extravasation of leukocytes which promote arteriogenesis. Fluorescent-activated cell sorting analyses confirmed reduced leukocyte recruitment. Diabetes mellitus mice showed a reduced expression of the proliferation marker Ki-67 in growing collaterals whose luminal diameters were also reduced. The Splicing Factor-1 (SF-1), which is critical for smooth muscle cell proliferation and phenotype switch, was found to be elevated in collaterals of DM mice. Treatment of DM mice with insulin normalized the expression of Egr-1 and its downstream targets and restored leukocyte recruitment. SF-1 expression and the diameter of growing collaterals were normalized by insulin treatment as well. In summary, our results showed that Egr-1 signaling was impaired in DM mice; however, it can be rescued by insulin treatment.
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Safety and Effectiveness of Bone Marrow Cell Concentrate in the Treatment of Chronic Critical Limb Ischemia Utilizing a Rapid Point-of-Care System. Stem Cells Int 2017; 2017:4137626. [PMID: 28194186 PMCID: PMC5282442 DOI: 10.1155/2017/4137626] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2016] [Accepted: 12/14/2016] [Indexed: 01/09/2023] Open
Abstract
Critical limb ischemia (CLI) is the end stage of lower extremity peripheral vascular disease (PVD) in which severe obstruction of blood flow results in ischemic rest pain, ulcers and/or gangrene, and a significant risk of limb loss. This open-label, single-arm feasibility study evaluated the safety and therapeutic effectiveness of autologous bone marrow cell (aBMC) concentrate in revascularization of CLI patients utilizing a rapid point-of-care device. Seventeen (17) no-option CLI patients with ischemic rest pain were enrolled in the study. Single dose of aBMC, prepared utilizing an intraoperative point-of-care device, the Res-Q™ 60 BMC system, was injected intramuscularly into the afflicted limb and patients were followed up at regular intervals for 12 months. A statistically significant improvement in Ankle Brachial Index (ABI), Transcutaneous Oxygen Pressure (TcPO2), mean rest pain and intermittent claudication pain scores, wound/ ulcer healing, and 6-minute walking distance was observed following aBMC treatment. Major amputation-free survival (mAFS) rate and amputation-free rates (AFR) at 12 months were 70.6% and 82.3%, respectively. In conclusion, aBMC injections were well tolerated with improved tissue perfusion, confirming the safety, feasibility, and preliminary effectiveness of aBMC treatment in CLI patients.
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Brownrigg JRW, Hinchliffe RJ, Apelqvist J, Boyko EJ, Fitridge R, Mills JL, Reekers J, Shearman CP, Zierler RE, Schaper NC. Performance of prognostic markers in the prediction of wound healing or amputation among patients with foot ulcers in diabetes: a systematic review. Diabetes Metab Res Rev 2016; 32 Suppl 1:128-35. [PMID: 26342129 DOI: 10.1002/dmrr.2704] [Citation(s) in RCA: 82] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Prediction of wound healing and major amputation in patients with diabetic foot ulceration is clinically important to stratify risk and target interventions for limb salvage. No consensus exists as to which measure of peripheral artery disease (PAD) can best predict outcomes. To evaluate the prognostic utility of index PAD measures for the prediction of healing and/or major amputation among patients with active diabetic foot ulceration, two reviewers independently screened potential studies for inclusion. Two further reviewers independently extracted study data and performed an assessment of methodological quality using the Quality in Prognostic Studies instrument. Of 9476 citations reviewed, 11 studies reporting on 9 markers of PAD met the inclusion criteria. Annualized healing rates varied from 18% to 61%; corresponding major amputation rates varied from 3% to 19%. Among 10 studies, skin perfusion pressure ≥ 40 mmHg, toe pressure ≥ 30 mmHg (and ≥ 45 mmHg) and transcutaneous pressure of oxygen (TcPO2 ) ≥ 25 mmHg were associated with at least a 25% higher chance of healing. Four studies evaluated PAD measures for predicting major amputation. Ankle pressure < 70 mmHg and fluorescein toe slope < 18 units each increased the likelihood of major amputation by around 25%. The combined test of ankle pressure < 50 mmHg or an ankle brachial index (ABI) < 0.5 increased the likelihood of major amputation by approximately 40%. Among patients with diabetic foot ulceration, the measurement of skin perfusion pressures, toe pressures and TcPO2 appear to be more useful in predicting ulcer healing than ankle pressures or the ABI. Conversely, an ankle pressure of < 50 mmHg or an ABI < 0.5 is associated with a significant increase in the incidence of major amputation.
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Affiliation(s)
- J R W Brownrigg
- St George's Vascular Institute, St George's Healthcare NHS Trust, London, UK
| | - R J Hinchliffe
- St George's Vascular Institute, St George's Healthcare NHS Trust, London, UK
| | - J Apelqvist
- Department of Endocrinology, University Hospital of Malmö, Malmö, Sweden
| | - E J Boyko
- Seattle Epidemiologic Research and Information Centre-Department of Veterans Affairs Puget Sound Health Care System and the University of Washington, Seattle, WA, USA
| | - R Fitridge
- Department of Vascular Surgery, The University of Adelaide, Adelaide, South Australia, Australia
| | - J L Mills
- Michael E. Debakey Department of Surgery, Baylor College of Medicine, Houston, USA
| | - J Reekers
- Department of Vascular Radiology, Amsterdam Medical Centre, Amsterdam, The Netherlands
| | - C P Shearman
- Department of Vascular Surgery, Southampton University Hospitals NHS Trust, Hampshire, UK
| | - R E Zierler
- Department of Surgery, University of Washington, Seattle, WA, USA
| | - N C Schaper
- Division of Endocrinology, MUMC+, CARIM Institute, Maastricht, The Netherlands
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Abstract
In 2015, it can be said that the diabetic foot is no longer the Cinderella of diabetic complications. Thirty years ago there was little evidence-based research taking place on the diabetic foot, and there were no international meetings addressing this topic. Since then, the biennial Malvern Diabetic Foot meetings started in 1986, the American Diabetes Association founded their Foot Council in 1987, and the European Association for the Study of Diabetes established a Foot Study Group in 1998. The first International Symposium on the Diabetic Foot in The Netherlands was convened in 1991, and this was soon followed by the establishment of the International Working Group on the Diabetic Foot that has produced useful guidelines in several areas of investigation and the management of diabetic foot problems. There has been an exponential rise in publications on diabetic foot problems in high impact factor journals, and a comprehensive evidence-base now exists for many areas of treatment. Despite the extensive evidence available, it, unfortunately, remains difficult to demonstrate that most types of education are efficient in reducing the incidence of foot ulcers. However, there is evidence that education as part of a multi-disciplinary approach to diabetic foot ulceration plays a pivotal role in incidence reduction. With respect to treatment, strong evidence exists that offloading is the best modality for healing plantar neuropathic foot ulcers, and there is also evidence from two randomized controlled trials to support the use of negative-pressure wound therapy in complex post-surgical diabetic foot wounds. Hyperbaric oxygen therapy exhibits the same evidence level and strength of recommendation. International guidelines exist on the management of infection in the diabetic foot. Many randomized trials have been performed, and these have shown that the agents studied generally produced comparable results, with the exception of one study in which tigecycline was shown to be clinically inferior to ertapenem ± vancomycin. Similarly, there are numerous types of wound dressings that might be used in treatment and which have shown efficacy, but no single type (or brand) has shown superiority over others. Peripheral artery disease is another major contributory factor in the development of ulceration, and its presence is a strong predictor of non-healing and amputation. Despite the proliferation of endovascular procedures in addition to open revascularization, many patients continue to suffer from severely impaired perfusion and exhaust all treatment options. Finally, the question of the true aetiopathogenesis of Charcot neuroarthropathy remains enigmatic, although much work is currently being undertaken in this area. In this area, it is most important to remember that a clinically uninfected, warm, insensate foot in a diabetic patient should be considered as a Charcot foot until proven otherwise, and, as such, treated with offloading, preferably in a cast.
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Affiliation(s)
- K Markakis
- Manchester Royal Infirmary, Manchester, UK
| | - F L Bowling
- Manchester Royal Infirmary, Manchester, UK
- University of Manchester, Manchester, UK
| | - A J M Boulton
- Manchester Royal Infirmary, Manchester, UK
- University of Manchester, Manchester, UK
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Thiruvoipati T, Kielhorn CE, Armstrong EJ. Peripheral artery disease in patients with diabetes: Epidemiology, mechanisms, and outcomes. World J Diabetes 2015; 6:961-969. [PMID: 26185603 PMCID: PMC4499529 DOI: 10.4239/wjd.v6.i7.961] [Citation(s) in RCA: 237] [Impact Index Per Article: 23.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2014] [Revised: 11/20/2014] [Accepted: 04/02/2015] [Indexed: 02/05/2023] Open
Abstract
Peripheral artery disease (PAD) is the atherosclerosis of lower extremity arteries and is also associated with atherothrombosis of other vascular beds, including the cardiovascular and cerebrovascular systems. The presence of diabetes mellitus greatly increases the risk of PAD, as well as accelerates its course, making these patients more susceptible to ischemic events and impaired functional status compared to patients without diabetes. To minimize these cardiovascular risks it is critical to understand the pathophysiology of atherosclerosis in diabetic patients. This, in turn, can offer insights into the therapeutic avenues available for these patients. This article provides an overview of the epidemiology of PAD in diabetic patients, followed by an analysis of the mechanisms by which altered metabolism in diabetes promotes atherosclerosis and plaque instability. Outcomes of PAD in diabetic patients are also discussed, with a focus on diabetic ulcers and critical limb ischemia.
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13
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Brownrigg JRW, Schaper NC, Hinchliffe RJ. Diagnosis and assessment of peripheral arterial disease in the diabetic foot. Diabet Med 2015; 32:738-47. [PMID: 25764390 DOI: 10.1111/dme.12749] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/10/2015] [Indexed: 01/20/2023]
Abstract
Approximately half of all patients with a diabetic foot ulcer have co-existing peripheral arterial disease. Identifying peripheral arterial disease among patients with foot ulceration is important, given its association with failure to heal, amputation, cardiovascular events and increased risk of premature mortality. Infection, oedema and neuropathy, often present with ulceration, may adversely affect the performance of diagnostic tests that are reliable in patients without diabetes. Early recognition and expert assessment of peripheral arterial disease allows measures to be taken to reduce the risk of amputation and cardiovascular events, while determining the need for revascularization to promote ulcer healing. When peripheral arterial disease is diagnosed, the extent of perfusion deficit should be measured. Patients with a severe perfusion deficit, likely to affect ulcer healing, will require further imaging to define the anatomy of disease and indicate whether a revascularization procedure is appropriate.
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Affiliation(s)
| | - N C Schaper
- Division of Endocrinology, Department of Medicine, Maastricht University Medical Centre, The Netherlands
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14
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Metformin stimulates ischemia-induced revascularization through an eNOS dependent pathway in the ischemic hindlimb mice model. J Vasc Surg 2015; 61:489-96. [DOI: 10.1016/j.jvs.2013.09.061] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2013] [Revised: 08/08/2013] [Accepted: 09/17/2013] [Indexed: 11/24/2022]
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15
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Vibrational angioplasty in recanalization of chronic femoropopliteal arterial occlusions: single center experience. Eur J Radiol 2014; 83:155-62. [PMID: 24518192 DOI: 10.1016/j.ejrad.2013.09.026] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2013] [Revised: 09/14/2013] [Accepted: 09/20/2013] [Indexed: 11/22/2022]
Abstract
PURPOSE This prospective study aims to present the overall success rate, safety and long-term outcome of vibrational angioplasty technique, in the treatment of chronic total femoropopliteal occlusions in our institute. METHODS Between October 2000 and December 2008, patients with chronic total femoropoliteal arterial occlusions, treated with vibrational angioplasty during the same session after a failed attempt with conventional recanalization technique, were included. Patient's follow up included serial ankle-brachial index measurements and arterial duplex ultrasound examinations at 1, 3, 6, 12, 24, 36 and 48 months. RESULTS Twenty-seven patients (16 males and 11 females) and twenty-eight lesions were included in our study. Twenty-five lesions (89.3%) were successfully recanalized. Pain relief was noticed in twenty-one cases. From ten lesions with tissue loss (ulcer or gangrene) in successfully recanalized occlusions, six healed without major, or minor amputation. One non-healing amputation stump was healed after recanalization, without further complications. Four limbs underwent amputation (one minor and three major) despite successful recanalization, however all had an excellent healing of the amputation stump without further complications. The Kaplan-Meier test demonstrated 90%, 85% and 70% amputation-free survival rate at 12, 24 and 36 months, respectively. No major or minor complications were encountered. CONCLUSIONS Vibrational angioplasty is a safe, effective and durable endovascular technique for the treatment of chronic total occlusions in patients with limb ischemia that would be difficult to recanalize using conventional intraluminal techniques.
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16
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Chin JA, Sumpio BE. Diabetes mellitus and peripheral vascular disease: diagnosis and management. Clin Podiatr Med Surg 2014; 31:11-26. [PMID: 24296015 DOI: 10.1016/j.cpm.2013.09.001] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
Diabetes mellitus and peripheral artery disease are prevalent diseases throughout the world and often present simultaneously in the same patient, which has direct implications for their diagnosis and management. Refinements of existing and development of new diagnostic and treatment modalities are changing the management of these diseases. This article reviews the significant pathologic basis, history, and physical examination findings with respect to each disease and their presentation together. Advantages and disadvantages of different diagnostic modalities, including noninvasive studies and imaging technologies, are discussed. General medical management principles and indications, techniques, and efficacy of surgical and endovascular interventions are reviewed.
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Affiliation(s)
- Jason A Chin
- Section of Vascular Surgery, Department of Surgery, Yale University School of Medicine, 333 Cedar Street, BB 204, New Haven, CT 06510, USA
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17
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Traupe T, Ortmann J, Stoller M, Baumgartner I, de Marchi SF, Seiler C. Direct quantitative assessment of the peripheral artery collateral circulation in patients undergoing angiography. Circulation 2013; 128:737-44. [PMID: 23817577 DOI: 10.1161/circulationaha.112.000516] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
BACKGROUND Despite the fact that numerous studies have pursued the strategy of improving collateral function in patients with peripheral artery disease, there is currently no method available to quantify collateral arterial function of the lower limb. METHODS AND RESULTS Pressure-derived collateral flow index (CFIp, calculated as (occlusive pressure-central venous pressure)/(aortic pressure-central venous pressure); pressure values in mm Hg) of the left superficial femoral artery was obtained in patients undergoing elective coronary angiography using a combined pressure/Doppler wire (n=30). Distal occlusive pressure and toe oxygen saturation (Sao2) were measured for 5 minutes under resting conditions, followed by an exercise protocol (repetitive plantar-flexion movements in supine position; n=28). In all patients, balloon occlusion of the superficial femoral artery over 5 minutes was painless under resting conditions. CFIp increased during the first 3 minutes from 0.451±0.168 to 0.551±0.172 (P=0.0003), whereas Sao2 decreased from 98±2% to 93±7% (P=0.004). Maximal changes of Sao2 were inversely related to maximal CFIp (r(2)=0.33, P=0.003). During exercise, CFIp declined within 1 minute from 0.560±0.178 to 0.393±0.168 (P<0.0001) and reached its minimum after 2 minutes of exercise (0.347±0.176), whereas Sao2 declined to a minimum of 86±6% (P=0.002). Twenty-five patients (89%) experienced pain or cramps/tired muscles, whereas 3 (11%) remained symptom-free for an occlusion time of 10 minutes. CFIp values were positively related to the pain-free time span (r(2)=0.50, P=0.002). CONCLUSIONS Quantitatively assessed collateral arterial function at rest determined in the nonstenotic superficial femoral artery is sufficient to prevent ischemic symptoms during a total occlusion of 5 minutes. During exercise, there is a decline in CFIp that indicates a supply-demand mismatch via collaterals or, alternatively, a steal phenomenon. CLINICAL TRIAL REGISTRATION-URL: http://www.clinicaltrials.gov. UNIQUE IDENTIFIER: NCT01742455.
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Affiliation(s)
- Tobias Traupe
- Department of Cardiology, University Hospital, CH-3010 Bern, Switzerland
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Abstract
Peripheral arterial disease (PAD) is a common vascular disease that reduces blood flow capacity to the legs of patients. PAD leads to exercise intolerance that can progress in severity to greatly limit mobility, and in advanced cases leads to frank ischemia with pain at rest. It is estimated that 12 to 15 million people in the United States are diagnosed with PAD, with a much larger population that is undiagnosed. The presence of PAD predicts a 50% to 1500% increase in morbidity and mortality, depending on severity. Treatment of patients with PAD is limited to modification of cardiovascular disease risk factors, pharmacological intervention, surgery, and exercise therapy. Extended exercise programs that involve walking approximately five times per week, at a significant intensity that requires frequent rest periods, are most significant. Preclinical studies and virtually all clinical trials demonstrate the benefits of exercise therapy, including improved walking tolerance, modified inflammatory/hemostatic markers, enhanced vasoresponsiveness, adaptations within the limb (angiogenesis, arteriogenesis, and mitochondrial synthesis) that enhance oxygen delivery and metabolic responses, potentially delayed progression of the disease, enhanced quality of life indices, and extended longevity. A synthesis is provided as to how these adaptations can develop in the context of our current state of knowledge and events known to be orchestrated by exercise. The benefits are so compelling that exercise prescription should be an essential option presented to patients with PAD in the absence of contraindications. Obviously, selecting for a lifestyle pattern that includes enhanced physical activity prior to the advance of PAD limitations is the most desirable and beneficial.
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Affiliation(s)
- Tara L Haas
- Angiogenesis Research Group, Muscle Health Research Centre, Faculty of Health, York University, Toronto, Ontario, Canada
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19
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Schiavetta A, Maione C, Botti C, Marino G, Lillo S, Garrone A, Lanza L, Pagliari S, Silvestroni A, Signoriello G, Sica V, Cobellis G. A phase II trial of autologous transplantation of bone marrow stem cells for critical limb ischemia: results of the Naples and Pietra Ligure Evaluation of Stem Cells study. Stem Cells Transl Med 2012. [PMID: 23197862 DOI: 10.5966/sctm.2012-0021] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Critical limb ischemia (CLI) is a vascular disease affecting lower limbs, which is going to become a demanding challenge because of the aging of the population. Despite advances in endovascular therapies, CLI is associated with high morbidity and mortality. Patients without direct revascularization options have the worst outcomes. To date, 25%-40% of CLI patients are not candidates for surgical or endovascular approaches, ultimately facing the possibility of a major amputation. This study aimed to assess the safety and efficacy of autologous bone marrow (BM) transplantation performed in "no-option" patients, in terms of restoring blood perfusion by collateral flow and limb salvage. A multicenter, prospective, not-controlled phase II study for no-option CLI patients was performed. Patients were subjected to intra-arterial infusion of autologous bone marrow and followed for 12 months after the treatment. Variation of blood perfusion parameters, evaluated by laser Doppler flowmetry or transcutaneous oximetry, was set as the primary endpoint at 12 months after treatment and amputation-free survival as the secondary endpoint. Sixty patients were enrolled and treated with BM transplantation, showing improvement in objective and subjective measures of perfusion. Furthermore, survival analysis demonstrated improved amputation-free survival rates (75.2%) at 12 months after the treatment. This study provides further evidence that autologous bone marrow transplantation is well tolerated by CLI patients without adverse effects, demonstrating trends toward improvement in perfusion and reduced amputation rate, confirming the feasibility and safety of the procedure.
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Affiliation(s)
- Alessandro Schiavetta
- Department of Vascular Surgery, Azienda Ospedaliera Santa Corona, Pietra Ligure, Italy.
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20
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Keeling AN, Carroll TJ, McDermott MM, Liu K, Liao Y, Farrelly CT, Pearce WH, Carr J. Clinical correlates of size and number of collateral vessels in peripheral artery disease. Vasc Med 2012; 17:223-30. [PMID: 22738758 DOI: 10.1177/1358863x12446213] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
We studied associations of the number and size of magnetic resonance angiography (MRA)-assessed lower extremity collateral vessels with the ankle-brachial index (ABI), severity of superficial femoral artery (SFA) plaque, and leg symptoms in participants with peripheral artery disease (PAD). A total of 303 participants with PAD underwent time-resolved MRA at the thigh station. Collaterals were categorized by number (Category 1: 0-3 collaterals; Category 2: 4-7 collaterals; Category 3: ≥ 8 collateral vessels) and size (Grade 1: ≤ 5 small collaterals; Grade 2: > 5 small vessels; Grade 3: ≤ 5 large collaterals; Grade 4: > 5 large collaterals). Adjusting for age, sex, race, comorbidities and other covariates, more numerous collateral vessels were associated with lower ABI values (Category 1: 0.79; Category 2: 0.67; Category 3: 0.60; p trend < 0.001). Similarly, larger collateral vessels were associated with lower ABI values (Grade 1: 0.75; Grade 2: 0.65; Grade 3: 0.62; Grade 4: 0.59; p trend < 0.001). More numerous (p < 0.001) and larger (p < 0.001) collateral vessels were associated with greater mean SFA plaque area (p trend < 0.001). More numerous (p trend = 0.007) and larger (p trend = 0.017) collateral vessels were associated with a lower prevalence of asymptomatic PAD. In conclusion, among participants with PAD, larger and more numerous collaterals, measured by MRA, were associated with lower ABI values, greater plaque area in the SFA, and a lower prevalence of asymptomatic PAD. Further study is needed to determine the role of collateral vessels in maintaining functional performance in PAD.
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Affiliation(s)
- Aoife N Keeling
- Department of Cardiovascular Imaging, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
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21
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Lepäntalo M, Apelqvist J, Setacci C, Ricco JB, de Donato G, Becker F, Robert-Ebadi H, Cao P, Eckstein HH, De Rango P, Diehm N, Schmidli J, Teraa M, Moll FL, Dick F, Davies AH. Chapter V: Diabetic foot. Eur J Vasc Endovasc Surg 2012; 42 Suppl 2:S60-74. [PMID: 22172474 DOI: 10.1016/s1078-5884(11)60012-9] [Citation(s) in RCA: 121] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Ulcerated diabetic foot is a complex problem. Ischaemia, neuropathy and infection are the three pathological components that lead to diabetic foot complications, and they frequently occur together as an aetiologic triad. Neuropathy and ischaemia are the initiating factors, most often together as neuroischaemia, whereas infection is mostly a consequence. The role of peripheral arterial disease in diabetic foot has long been underestimated as typical ischaemic symptoms are less frequent in diabetics with ischaemia than in non-diabetics. Furthermore, the healing of a neuroischaemic ulcer is hampered by microvascular dysfunction. Therefore, the threshold for revascularising neuroischaemic ulcers should be lower than that for purely ischaemic ulcers. Previous guidelines have largely ignored these specific demands related to ulcerated neuroischaemic diabetic feet. Any diabetic foot ulcer should always be considered to have vascular impairment unless otherwise proven. Early referral, non-invasive vascular testing, imaging and intervention are crucial to improve diabetic foot ulcer healing and to prevent amputation. Timing is essential, as the window of opportunity to heal the ulcer and save the leg is easily missed. This chapter underlines the paucity of data on the best way to diagnose and treat these diabetic patients. Most of the studies dealing with neuroischaemic diabetic feet are not comparable in terms of patient populations, interventions or outcome. Therefore, there is an urgent need for a paradigm shift in diabetic foot care; that is, a new approach and classification of diabetics with vascular impairment in regard to clinical practice and research. A multidisciplinary approach needs to implemented systematically with a vascular surgeon as an integrated member. New strategies must be developed and implemented for diabetic foot patients with vascular impairment, to improve healing, to speed up healing rate and to avoid amputation, irrespective of the intervention technology chosen. Focused studies on the value of predictive tests, new treatment modalities as well as selective and targeted strategies are needed. As specific data on ulcerated neuroischaemic diabetic feet are scarce, recommendations are often of low grade.
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Affiliation(s)
- M Lepäntalo
- Department of Vascular Surgery, Helsinki University Central Hospital, Helsinki, Finland.
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22
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Schaper NC, Andros G, Apelqvist J, Bakker K, Lammer J, Lepantalo M, Mills JL, Reekers J, Shearman CP, Zierler RE, Hinchliffe RJ. Diagnosis and treatment of peripheral arterial disease in diabetic patients with a foot ulcer. A progress report of the International Working Group on the Diabetic Foot. Diabetes Metab Res Rev 2012; 28 Suppl 1:218-24. [PMID: 22271741 DOI: 10.1002/dmrr.2255] [Citation(s) in RCA: 93] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
The International Working Group on the Diabetic Foot (IWDGF) has produced in 2011 a guideline on the diagnosis and treatment of peripheral arterial disease in patients with diabetes and a foot ulcer. This document, together with a systematic review that provided the background information on management, was produced by a multidisciplinary working group of experts in the field and was endorsed by the IWDGF. This progress report is based on these two documents and earlier consensus texts of the IWDGF on the diagnosis and management of diabetic foot ulcers. Its aim is to give the clinician clear guidance on when and how to diagnose peripheral arterial disease in patients with diabetes and a foot ulcer and when and which treatment modalities should be considered, taking both risks and benefits into account.
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Affiliation(s)
- N C Schaper
- Division of Endocrinology, MUMC+, CARIM and CAPHRI Institute, Maastricht, The Netherlands.
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Significance of ankle brachial index and collaterals for prediction of critical limb ischemia in infrainguinal peripheral arterial occlusive disease. Adv Med Sci 2011; 56:249-54. [PMID: 21940262 DOI: 10.2478/v10039-011-0035-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
PURPOSE Chronic limb ischemia (CLI) is a clinical diagnosis, but should be approved by technical tests like the ankle-brachial index (ABI). Although the ABI is well established, less is known about the influence of collateralization on clinical stage. MATERIAL/METHODS Magnetic resonance angiographies (MRA) of 129 lower extremities were searched for morphological changes and for the number of collateral vessels according to Sorlie. Ankle pressures were recorded as higher (APmax) and lower (APmin) systolic blood pressures of the two ankle arteries with consecutive calculation of ABImax and ABImin. RESULTS In comparisons of ROC curves, APmax (AUC=0.749) did significantly better as a prognostic marker than APmin (AUC=0.642) (p=0.005) and ABImax (AUC=0.744) did significantly better than ABImin (AUC=0.650) (p=0.019). APmax showed a positive likelihood ratio (+LR) of 5.79 and a negative likelihood ratio (-LR) of 0.47 (cutoff ≤55 mmHg). For the number of collateral vessels a +LR 2.27 and a -LR of 0.09 and in patients with an APmax ≤55 mmHg a +LR of 5.50 and a -LR of 0.00 were calculated (cutoff ≤1 collateral vessel). CONCLUSION Whereas APmax is more eligible for verification of CLI, collateral count is better in exclusion of CLI. Both seem to be independent factors for validating the clinical diagnosis of CLI.
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24
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Franz RW, Shah KJ, Johnson JD, Pin RH, Parks AM, Hankins T, Hartman JF, Wright ML. Short- to mid-term results using autologous bone-marrow mononuclear cell implantation therapy as a limb salvage procedure in patients with severe peripheral arterial disease. Vasc Endovascular Surg 2011; 45:398-406. [PMID: 21669864 DOI: 10.1177/1538574411405545] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Short- to mid-term results of a prospective study evaluating dual intramuscular and intra-arterial autologous bone-marrow mononuclear cell (BM-MNC) implantation for the treatment of patients with severe peripheral arterial occlusive disease (PAD) in whom amputation was considered the only viable treatment option are presented. Ankle-brachial indices (ABIs), rest pain, and ulcer healing were assessed at 3 months. Success was defined as improvement in ABI measurements; absence of rest pain; absence of ulcers; and absence of major limb amputations. Twenty patients (21 limbs) have been enrolled. Three-month follow-up evaluation accounting included 18 patients (19 limbs). Four (22.2%) major and 2 (11.1%) minor amputations were performed within 3 months postoperatively. With 17 (94.4%) of 18 limbs demonstrating at least one criterion for success and major amputation avoided in 14 (77.8%) of 18 limbs at the 3-month evaluation, this specific BM-MNC implantation technique is an effective limb salvage strategy for patients with severe PAD.
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Affiliation(s)
- Randall W Franz
- Grant Medical Center, Vascular and Vein Center, Columbus, OH, USA.
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25
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Add-on rosiglitazone therapy improves plasminogen activity and high-density lipoprotein cholesterol in type 2 diabetes mellitus. Blood Coagul Fibrinolysis 2011; 22:512-20. [PMID: 21537159 DOI: 10.1097/mbc.0b013e32834740ba] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Rosiglitazone is an oral hypoglycaemic agent of the thiazolidinedione group. This study aimed to assess changes in the diabetic prothrombotic state via plasminogen activity and changes in surrogate markers of atherosclerotic burden via ankle-brachial pressure index (ABPI) measurements after rosiglitazone was added to a pre-existing type 2 diabetes mellitus treatment regime. A nonblinded interventional study was designed. Fifty-nine patients were enrolled. Rosiglitazone-naïve patients were prescribed oral rosiglitazone 4 mg daily for 10 weeks. ABPI, plasminogen activity, glycosylated haemoglobin (HbA1c) and fasting lipid profile were measured pretreatment and post-treatment. Forty-eight patients completed the study. At the end of this study, mean plasminogen activity improvement was nearly 16% (P<0.05), mean ABPI improvement was 0.01 (P=0.439), mean HbA1c reduction was 0.51% (P<0.05), mean total cholesterol (TC) increase was 0.36 mmol/l (P<0.05), mean high-density lipoprotein cholesterol (HDL-C) increase was 0.15 mmol/l (P<0.05) and mean low-density lipoprotein cholesterol increased by 0.19 mmol/l (P=0.098). Rosiglitazone significantly improved plasminogen activity. There was also significant HbA1c reduction, and rise in both TC and HDL-C. Thus, rosiglitazone potentially improves the atherosclerotic burden and prothrombotic state. In future, more studies are needed to confirm the relationship between rosiglitazone, fibrinolytic system and atheromatous reduction in type 2 diabetes mellitus.
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Diabetes impairs arteriogenesis in the peripheral circulation: review of molecular mechanisms. Clin Sci (Lond) 2010; 119:225-38. [PMID: 20545627 DOI: 10.1042/cs20100082] [Citation(s) in RCA: 80] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Patients suffering from both diabetes and PAD (peripheral arterial disease) are at risk of developing critical limb ischaemia and ulceration, and potentially requiring limb amputation. In addition, diabetes complicates surgical treatment of PAD and impairs arteriogenesis. Arteriogenesis is defined as the remodelling of pre-existing arterioles into conductance vessels to restore the perfusion distal to the occluded artery. Several strategies to promote arteriogenesis in the peripheral circulation have been devised, but the mechanisms through which diabetes impairs arteriogenesis are poorly understood. The present review provides an overview of the current literature on the deteriorating effects of diabetes on the key players in the arteriogenesis process. Diabetes affects arteriogenesis at a number of levels. First, it elevates vasomotor tone and attenuates sensing of shear stress and the response to vasodilatory stimuli, reducing the recruitment and dilatation of collateral arteries. Secondly, diabetes impairs the downstream signalling of monocytes, without decreasing monocyte attraction. In addition, EPC (endothelial progenitor cell) function is attenuated in diabetes. There is ample evidence that growth factor signalling is impaired in diabetic arteriogenesis. Although these defects could be restored in animal experiments, clinical results have been disappointing. Furthermore, the diabetes-induced impairment of eNOS (endothelial NO synthase) strongly affects outward remodelling, as NO signalling plays a key role in several remodelling processes. Finally, in the structural phase of arteriogenesis, diabetes impairs matrix turnover, smooth muscle cell proliferation and fibroblast migration. The review concludes with suggestions for new and more sophisticated therapeutic approaches for the diabetic population.
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Vajanto I, Korpisalo P, Karjalainen J, Hakala T, Mäkinen K, Ylä-Herttuala S. Antegrade flow and peripheral resistance determine the level of endogenous arteriogenesis in patients with superficial femoral artery occlusion. Eur J Clin Invest 2009; 39:1048-54. [PMID: 19807785 DOI: 10.1111/j.1365-2362.2009.02208.x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
OBJECTIVES Occlusion in a limb artery leads to impaired blood supply and ischaemia. Collateral artery growth (arteriogenesis) is one of the most effective natural response mechanisms to compensate this pathologic situation. However, it is unknown if clinically important features, like poor run-off, have an impact on compensatory vessel growth. METHODS Study population of this retrospective study consisted of 70 patients who suffered from lower limb ischaemia and underwent bypass surgery because of an occlusion of the superficial femoral artery. Clinical data were collected and pre- and postoperative angiograms were reviewed. Number of collateral vessels bypassing the occluded segment was counted. Features of inflow and outflow vessels were recorded. RESULTS The mean number of collaterals was 13 + or - 0.5 per patient. In univariate analysis, short daily walking distance, chronic critical leg ischaemia, low ankle brachial index, low number of patent calf arteries and stenosed inflow arteries predicted low number of collateral arteries. In the multivariate analysis, only the quality of inflow and the number of patent calf vessels demonstrated an independent association (P < 0.05) with the number of collaterals. CONCLUSIONS Ankle-brachial index, grade of symptoms and daily walking capacity could be used to predict collateral density. Importantly, a good antegrade flow and peripheral runoff seem to have a significant effect on collateral density, implying an impact on the activation of arteriogenesis.
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Affiliation(s)
- I Vajanto
- Department of Cardiothoracic Surgery, Kuopio University Hospital, Kuopio, Finland
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Amann B, Luedemann C, Ratei R, Schmidt-Lucke JA. Autologous bone marrow cell transplantation increases leg perfusion and reduces amputations in patients with advanced critical limb ischemia due to peripheral artery disease. Cell Transplant 2009; 18:371-80. [PMID: 19500466 DOI: 10.3727/096368909788534942] [Citation(s) in RCA: 130] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Bone marrow cell transplantation has been shown to induce angiogenesis and thus improve ischemic artery disease. This study evaluates the effects of intramuscular bone marrow cell transplantation in patients with limb-threatening critical limb ischemia with a very high risk for major amputation. After failed or impossible operative and/or interventional revascularization and after unsuccessful maximum conservative therapy, 51 patients with impending major amputation due to severe critical limb ischemia had autologous bone marrow cells (BMC) transplanted into the ischemic leg. Patients 1-12 received Ficoll-isolated bone marrow mononuclear cells (total cell number 1.1 +/- 1.1 x 10(9)), patients 13-51 received point of care isolated bone marrow total nucleated cells (3.0 +/- 1.7 x 10(9)). Limb salvage was 59% at 6 months and 53% at last follow-up (mean 411 +/- 261 days, range 175-1186). Perfusion measured with ankle-brachial index (ABI) and transcutaneous oxygen tension (tcpO(2)) at baseline and after 6 months increased in patients with consecutive limb salvage (ABI 0.33 +/- 0.18 to 0.46 +/- 0.15, tcpO(2) 12 +/- 12 to 25 +/- 15 mmHg) and did not change in patients eventually undergoing major amputation. No difference in clinical outcome between the isolation methods were seen. Clinically most important, patients with limb salvage improved from a mean Rutherford category of 4.9 at baseline to 3.3 at 6 months (p = 0.0001). Analgesics consumption was reduced by 62%. Total walking distance improved in nonamputees from zero to 40 m. Three severe periprocedural adverse events resolved without sequelae, and no unexpected long-term adverse events occurred. In no-option patients with end-stage critical limb ischemia due to peripheral artery disease, bone marrow cell transplantation is a safe procedure that can improve leg perfusion sufficiently to reduce major amputations and permit durable limb salvage.
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Affiliation(s)
- Berthold Amann
- Department of Medicine, Franziskuskrankenhaus, Berlin Vascular Center, Berlin, Germany.
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van Golde JM, Ruiter MS, Schaper NC, Vöö S, Waltenberger J, Backes WH, Post MJ, Huijberts MS. Impaired collateral recruitment and outward remodeling in experimental diabetes. Diabetes 2008; 57:2818-23. [PMID: 18633114 PMCID: PMC2551694 DOI: 10.2337/db08-0229] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2008] [Accepted: 07/01/2008] [Indexed: 12/14/2022]
Abstract
OBJECTIVE In this study, the effect of chronic hyperglycemia on acute ligation-induced collateral vasodilation, on monocyte chemotaxis, and on structural outward remodeling of collaterals was investigated. RESEARCH DESIGN AND METHODS Femoral artery ligation was performed 8 weeks after alloxan or saline treatment in New Zealand White rabbits. Angiography was performed directly, 1 and 3 weeks after ligation. These angiographic recordings were used to quantify number of collaterals, lumen, and blood volume index. Reactive hyperemia response was tested by intramuscular laser Doppler measurements. Subsequently, blood was sampled from the aorta for monocyte chemotaxis. RESULTS Ligation resulted in markedly lower acute collateral vasodilation in diabetic compared with control rabbits. Also, hyperemic vasodilatory response to local ischemia was impaired in diabetic rabbits. This difference persisted at 1 and 3 weeks after ligation, with a lower number of visible collaterals. In addition, the collateral lumen was markedly lower in diabetic rabbits after the maturation phase. Likewise, a reduced blood volume index in the region of growing collaterals was observed in diabetic animals. The monocyte migration toward vascular endothelial growth factor-A and monocyte chemotactic protein-1 was strongly reduced in diabetic rabbits. CONCLUSIONS This study demonstrates that chronic hyperglycemia negatively affects the different phases of arteriogenesis: 1) impaired shear induced vasodilatation; 2) impaired outward collateral growth, reflected in the number of collaterals and blood volume index; and 3) inhibition of monocyte chemotaxis. Impairments were most evident in the acute phase of arteriogenesis. Therapies aimed at restoring acute collateral recruitment, such as vasodilators, may be of interest to improve collateral function in diabetes.
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Affiliation(s)
- Jolanda M van Golde
- Department of Internal Medicine, Division of Endocrinology, Maastricht University Medical Centre and Cardiovascular Research Institute Maastricht, Maastricht, the Netherlands.
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