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Peripheral Artery Disease and Diabetic Foot Ulcer: From Bench to...
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Peripheral Artery Disease and Diabetic Foot Ulcer: From Bench to Clinic

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Endocrinology and Metabolism Research".

Deadline for manuscript submissions: closed (31 October 2023) | Viewed by 22104

Special Issue Editors

Prof. Dr. Irene Hinterseher

E-Mail Website
Guest Editor
Berlin Institute of Health, Vascular Surgery Clinic, Charité—Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-Universität zu Berlin, Hindenburgdamm 30, 12203 Berlin, Germany
Interests: revascularization; vascular; endothelial; growth factor; arterial disease
Dr. Racha El Hage

E-Mail Website
Guest Editor
Department of Vascular Surgery, Universitätsklinikum Ruppin-Brandenburg, Fehrbelliner Str. 38, 16816 Neuruppin, Germany
Interests: arterial disease; microbiome; diabetes and endocrinology; gastroenterology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Peripheral artery diseases (PAD) and diabetic foot ulcers (DFU) are life-threatening diseases in the Western world, with crucial importance to the medical field, as they have a major impact on the patient’s quality of life and lead to significant costs for the healthcare system. DFU represent a chronic complication in patients with diabetes; they are often associated with neuropathy and/or peripheral artery disease (PAD) of the lower limb in diabetic patients. PAD is a result of atherosclerosis. The major complication of DFU and PAD is lower limb amputation. Diagnosing PAD is a challenge, as it is asymptomatic in most patients in the early stages and it presents in various ways. Conventional treatments for DFU, including debridement, revascularization, management of infection, and off-loading, have not been shown to be effective enough, and they were not able to reduce the amputation rate. As a result, alternative or additional treatment and new therapeutical approaches in regenerative medicine are required. Furthermore, extra clinical data concerning the risk factors of PAD and DFU, as well as their impact on patients' lives and the healthcare system, are still needed. Molecular inflammatory processes initiating the progress of PAD in diabetics and non-diabetics are still unclear and need to be investigated to create new therapeutical approaches.

Prof. Dr. Irene Hinterseher
Dr. Racha El Hage
Guest Editors

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Keywords

  • peripheral artery diseases
  • diabetic foot ulcer
  • atherosclerosis
  • regenerative medicine
  • inflammatory

Published Papers (16 papers)

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Research

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10 pages, 1048 KiB  
Article
Long-Term Outcome of Lower Extremity Bypass Surgery in Diabetic and Non-Diabetic Patients with Critical Limb-Threatening Ischaemia in Germany
by Johanna Surmann, Philipp Meyer, Jasmin Epple, Thomas Schmitz-Rixen, Dittmar Böckler and Reinhart T. Grundmann
Biomedicines 2024, 12(1), 38; https://doi.org/10.3390/biomedicines12010038 - 22 Dec 2023
Viewed by 685
Abstract
Aim: To present the short- and long-term outcomes of lower extremity bypass (LEB) surgery in patients with critical limb-threatening ischaemia (CLTI), comparing diabetic (DM) and non-diabetic (non-DM) patients. Methods: Retrospective analysis of anonymised data from a nationwide health insurance company (AOK). Data from [...] Read more.
Aim: To present the short- and long-term outcomes of lower extremity bypass (LEB) surgery in patients with critical limb-threatening ischaemia (CLTI), comparing diabetic (DM) and non-diabetic (non-DM) patients. Methods: Retrospective analysis of anonymised data from a nationwide health insurance company (AOK). Data from 22,633 patients (DM: n = 7266; non-DM: n = 15,367; men: n = 14,523; women: n = 8110; mean patient age: 72.5 years), who underwent LEB from 2010 to 2015, were analysed. The cut-off date for follow-up was December 31, 2018 (mean follow-up period: 55 months). Results: Perioperative mortality was 10.0% for DM and 8.2% for non-DM (p < 0.001). Patients with crural/pedal bypasses (n = 8558) had a significantly higher perioperative mortality (10.3%) than those with above-the-knee (n = 7246; 5.8%; p < 0.001) and below-the-knee bypasses (n = 6829; 8.9%; p = 0.003). The 9-year survival rates in DM patients were significantly worse, at 21.5%, compared to non-DM, at 31.1% (p < 0.001). This applied to both PAD stage III (DM: 34.4%; non-DM: 45.7%; p < 0.001) and PAD stage IV (DM: 18.5%; non-DM: 25.0%; p < 0.001). Patients with crural/pedal bypasses had a significantly inferior survival rate (25.5%) compared to those with below-the-knee (27.7%; p < 0.001) and above-the-knee bypasses (31.7%; p < 0.001). Conclusion: Perioperative and long-term outcomes regarding survival and major amputation rate for CLTI patients undergoing LEB are consistently worse for DM patients compared to non-DM patients. Full article
(This article belongs to the Special Issue Peripheral Artery Disease and Diabetic Foot Ulcer: From Bench to Clinic)
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11 pages, 1791 KiB  
Article
Modification of Peripheral Blood Flow and Angiogenesis by CO2 Water-Bath Therapy in Diabetic Skeletal Muscle with or without Ischemia
by Vijayan Elimban, Yan-Jun Xu, Sukhwinder K. Bhullar and Naranjan S. Dhalla
Biomedicines 2023, 11(12), 3250; https://doi.org/10.3390/biomedicines11123250 - 8 Dec 2023
Viewed by 785
Abstract
Previously, it was shown that both blood flow and angiogenesis in the ischemic hind limb of diabetic rats were increased upon CO2 treatment for 4 weeks. In the present study, we have compared the effects of 6 weeks CO2 therapy in [...] Read more.
Previously, it was shown that both blood flow and angiogenesis in the ischemic hind limb of diabetic rats were increased upon CO2 treatment for 4 weeks. In the present study, we have compared the effects of 6 weeks CO2 therapy in diabetic rats with or without peripheral ischemia. Diabetes was induced in rats by a tail vein injection of streptozotocin (65 mg/kg body weight), whereas peripheral ischemia was produced by occluding the femoral artery at 2 weeks of inducing diabetes. Both diabetic and diabetic-ischemic animals were treated with or without CO2 water-bath at 37 °C for 6 weeks (30 min/day; 5 days/week) starting at 2 weeks, after the induction of ischemia. CO2 treatment did not affect heart rate and R-R interval as well as plasma levels of creatine kinase, glucose, cholesterol, triglycerides and high density lipoproteins. Unlike the levels of plasma Ox-LDL, MDA and TNF-α, the levels of NO in diabetic group were increased by CO2 water-bath treatment. On the other hand, the levels of plasma Ox-LDL and MDA were decreased whereas that of NO was increased without any changes in TNF-α level in diabetic-ischemic animals upon CO2 therapy. Treatment of diabetic animals with CO2 increased peak, mean and minimal blood flow by 20, 49 and 43% whereas these values were increased by 53, 26 and 80% in the diabetic-ischemic group by CO2 therapy, respectively. Blood vessel count in diabetic and diabetic-ischemic skeletal muscles was increased by 73 and 136% by CO2 therapy, respectively. These data indicate that peripheral ischemia augmented the increase in blood flow and development of angiogenesis in diabetic skeletal muscle upon CO2 therapy. It is suggested that greater beneficial effects of CO2 therapy in diabetic-ischemic animals in comparison to diabetic group may be a consequence of difference of changes in the redox-sensitive signal transduction mechanisms. Full article
(This article belongs to the Special Issue Peripheral Artery Disease and Diabetic Foot Ulcer: From Bench to Clinic)
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16 pages, 705 KiB  
Article
State-of-the-Art Features for Early-Stage Detection of Diabetic Foot Ulcers Based on Thermograms
by Natalia Arteaga-Marrero, Abián Hernández-Guedes, Jordan Ortega-Rodríguez and Juan Ruiz-Alzola
Biomedicines 2023, 11(12), 3209; https://doi.org/10.3390/biomedicines11123209 - 2 Dec 2023
Cited by 1 | Viewed by 1213
Abstract
Diabetic foot ulcers represent the most frequently recognized and highest risk factor among patients affected by diabetes mellitus. The associated recurrent rate is high, and amputation of the foot or lower limb is often required due to infection. Analysis of infrared thermograms covering [...] Read more.
Diabetic foot ulcers represent the most frequently recognized and highest risk factor among patients affected by diabetes mellitus. The associated recurrent rate is high, and amputation of the foot or lower limb is often required due to infection. Analysis of infrared thermograms covering the entire plantar aspect of both feet is considered an emerging area of research focused on identifying at an early stage the underlying conditions that sustain skin and tissue damage prior to the onset of superficial wounds. The identification of foot disorders at an early stage using thermography requires establishing a subset of relevant features to reduce decision variability and data misinterpretation and provide a better overall cost–performance for classification. The lack of standardization among thermograms as well as the unbalanced datasets towards diabetic cases hinder the establishment of this suitable subset of features. To date, most studies published are mainly based on the exploitation of the publicly available INAOE dataset, which is composed of thermogram images of healthy and diabetic subjects. However, a recently released dataset, STANDUP, provided data for extending the current state of the art. In this work, an extended and more generalized dataset was employed. A comparison was performed between the more relevant and robust features, previously extracted from the INAOE dataset, with the features extracted from the extended dataset. These features were obtained through state-of-the-art methodologies, including two classical approaches, lasso and random forest, and two variational deep learning-based methods. The extracted features were used as an input to a support vector machine classifier to distinguish between diabetic and healthy subjects. The performance metrics employed confirmed the effectiveness of both the methodology and the state-of-the-art features subsequently extracted. Most importantly, their performance was also demonstrated when considering the generalization achieved through the integration of input datasets. Notably, features associated with the MCA and LPA angiosomes seemed the most relevant. Full article
(This article belongs to the Special Issue Peripheral Artery Disease and Diabetic Foot Ulcer: From Bench to Clinic)
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11 pages, 292 KiB  
Article
Examination of Lower Limb Microcirculation in Diabetic Patients with and without Intermittent Claudication
by Katalin Biró, Barbara Sándor, Kinga Tótsimon, Katalin Koltai, Krisztina Fendrik, Dóra Endrei, Judit Vékási, Kálmán Tóth and Gábor Késmárky
Biomedicines 2023, 11(8), 2181; https://doi.org/10.3390/biomedicines11082181 - 3 Aug 2023
Viewed by 1025
Abstract
Intermittent claudication is a frequent complaint in lower extremity artery disease, but approximately two thirds of patients are asymptomatic, most of which are diabetic patients. Non-invasive angiological and microrheological tests on diabetic subjects with and without intermittent claudication were performed in the present [...] Read more.
Intermittent claudication is a frequent complaint in lower extremity artery disease, but approximately two thirds of patients are asymptomatic, most of which are diabetic patients. Non-invasive angiological and microrheological tests on diabetic subjects with and without intermittent claudication were performed in the present study. In total, 98 diabetic patients were included and divided into two groups: 20 patients (63.5 ± 8.8 years, 55% men, 45% women) had intermittent claudication, 78 patients (65.5 ± 9.3 years, 61.5% men, 38.5% women) were asymptomatic. Hand-held Doppler ultrasound examination, transcutaneous tissue partial oxygen pressure (tcpO2) measurement, Rydel–Seiffer tuning fork tests, and 6-min walk tests were performed, and erythrocyte aggregation was investigated. Ankle–brachial index (p < 0.02) and tcpO2, measured during provocation tests (p < 0.003) and the 6-min walk test (p < 0.0001), significantly deteriorated in the symptomatic group. A higher erythrocyte aggregation index and faster aggregate formation was observed in claudication patients (p < 0.02). Despite the statistically better results of the asymptomatic group, 13% of these patients had severe limb ischemia based on the results of tcpO2 measurement. Claudication can be associated with worse hemodynamic and hemorheological conditions in diabetic patients; however, severe ischemia can also develop in asymptomatic subjects. Non-invasive vascular tests can detect ischemia, which highlights the importance of early instrumental screening of the lower limbs. Full article
(This article belongs to the Special Issue Peripheral Artery Disease and Diabetic Foot Ulcer: From Bench to Clinic)
14 pages, 2112 KiB  
Article
Understanding the Impact of COVID-19 on Angioplasty Service and Outcome of Patients Treated for Chronic Limb-Threatening Ischaemia: A Single-Centre Retrospective Cohort Study
by Alexander D. Rodway, Jenny Harris, Lydia Hanna, Charlotte Allan, Felipe Pazos Casal, Ciara Giltinan, Ali Dehghan-Nayeri, Andre Santos, Martin B. Whyte, Nikolaos Ntagiantas, Ivan Walton, Richard Brown, Simon S. Skene, Ajay Pankhania, Benjamin C. T. Field, Gary D. Maytham and Christian Heiss
Biomedicines 2023, 11(7), 2034; https://doi.org/10.3390/biomedicines11072034 - 19 Jul 2023
Cited by 1 | Viewed by 985
Abstract
We evaluated the impact of COVID-19 restriction on the angioplasty service and outcome of chronic limb-threatening ischaemia (CLTI) patients undergoing lower-limb angioplasty in a UK secondary care setting. Consecutive patients were analysed retrospectively. Pre-COVID-19 (08/2018–02/2020), 106 CLTI patients (91% Fontaine 4; 60% diabetes [...] Read more.
We evaluated the impact of COVID-19 restriction on the angioplasty service and outcome of chronic limb-threatening ischaemia (CLTI) patients undergoing lower-limb angioplasty in a UK secondary care setting. Consecutive patients were analysed retrospectively. Pre-COVID-19 (08/2018–02/2020), 106 CLTI patients (91% Fontaine 4; 60% diabetes mellitus) and during COVID-19 (03/2020–07/2021) 94 patients were treated (86% Fontaine 4; 66% diabetes mellitus). While the average monthly number of patients treated did not change, the proportion of day cases significantly increased (53% to 80%), and hospitalised patients decreased. Patients treated in ≤14/5 days after referral significantly increased to 64/63%. Kaplan–Meier survival analysis (30-day/1-year) showed that neither wound healing nor mortality were significantly changed during COVID-19. In day cases, 1-year but not 30-day major amputations significantly increased, and clinically driven target-lesion revascularisation decreased during COVID-19. One-year mortality was significantly worse in hospitalised compared to day cases (14% vs. 43%) at similar wound healing rates (83% vs. 84%). The most frequent known cause of death was infectious disease (64%), while cardiovascular (21%) was less frequent. Despite COVID-19 restrictions, a safe and effective angioplasty service was maintained while shortening waiting times. Very high mortality rates in hospitalised patients may indicate that CLTI patients need to be referred and treated more aggressively earlier. Full article
(This article belongs to the Special Issue Peripheral Artery Disease and Diabetic Foot Ulcer: From Bench to Clinic)
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14 pages, 2673 KiB  
Article
The Effects of Immunosuppressive Drugs on the Characteristics and Functional Properties of Bone Marrow-Derived Stem Cells Isolated from Patients with Diabetes Mellitus and Peripheral Arterial Disease
by Jitka Husakova, Barbora Echalar, Jan Kossl, Katerina Palacka, Vladimira Fejfarova and Michal Dubsky
Biomedicines 2023, 11(7), 1872; https://doi.org/10.3390/biomedicines11071872 - 30 Jun 2023
Viewed by 1186
Abstract
Background: Diabetic patients (DPs) with foot ulcers can receive autologous cell therapy (ACT) as a last therapeutic option. Even DPs who have undergone organ transplantation and are using immunosuppressive (IS) drugs can be treated by ACT. The aim of our study was to [...] Read more.
Background: Diabetic patients (DPs) with foot ulcers can receive autologous cell therapy (ACT) as a last therapeutic option. Even DPs who have undergone organ transplantation and are using immunosuppressive (IS) drugs can be treated by ACT. The aim of our study was to analyze the effects of IS drugs on the characteristics of bone marrow-derived stem cells (BM-MSCs). Methods: The cells were isolated from the bone marrow of DPs, cultivated for 14–18 days, and phenotypically characterized using flow cytometry. These precursor cells were cultured in the presence of various IS drugs. The impact of IS drugs on metabolic activity was measured using a WST-1 assay, and the expression of genes for immunoregulatory molecules was detected through RT-PCR. Cell death was analyzed through the use of flow cytometry, and the production of cytokines was determined by ELISA. Results: The mononuclear fraction of cultured cells contained mesenchymal stem cells (CD45−CD73+CD90+CD105+), myeloid angiogenic cells (CD45+CD146−), and endothelial colony-forming cells (CD45−CD146+). IS drugs inhibited metabolic activity, the expression of genes for immunoregulatory molecules, the production of cytokines, and the viability of the cells. Conclusions: The results indicate that IS drugs in a dose-dependent manner had a negative impact on the properties of BM-MSCs used to treat ischemic diabetic foot ulcers, and that these drugs could affect the therapeutic potential of BM-MSCs. Full article
(This article belongs to the Special Issue Peripheral Artery Disease and Diabetic Foot Ulcer: From Bench to Clinic)
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15 pages, 1579 KiB  
Article
Biomarkers of Neutrophil Activation in Patients with Symptomatic Chronic Peripheral Artery Disease Predict Worse Cardiovascular Outcome
by Giacomo Buso, Elisabetta Faggin, Alessandro Bressan, Silvia Galliazzo, Francesco Cinetto, Carla Felice, Michele Fusaro, Andreas Erdmann, Paolo Pauletto, Marcello Rattazzi and Lucia Mazzolai
Biomedicines 2023, 11(3), 866; https://doi.org/10.3390/biomedicines11030866 - 12 Mar 2023
Cited by 1 | Viewed by 1931
Abstract
Neutrophils play a role in cardiovascular (CV) disease. However, relatively scant evidence exists in the setting of peripheral artery disease (PAD). The aims of this study were to measure biomarkers of neutrophil activation in patients with symptomatic chronic PAD compared with healthy controls, [...] Read more.
Neutrophils play a role in cardiovascular (CV) disease. However, relatively scant evidence exists in the setting of peripheral artery disease (PAD). The aims of this study were to measure biomarkers of neutrophil activation in patients with symptomatic chronic PAD compared with healthy controls, to assess their association with PAD severity, and to evaluate their prognostic value in patients with PAD. The following circulating markers of neutrophil degranulation were tested: polymorphonuclear neutrophil (PMN) elastase, neutrophil gelatinase-associated lipocalin (NGAL), and myeloperoxidase (MPO). Neutrophil extracellular traps (NETs) were quantified by measuring circulating MPO–DNA complexes. Patients with PAD underwent a comprehensive series of vascular tests. The occurrence of 6-month major adverse CV (MACE) and limb events (MALE) was assessed. Overall, 110 participants were included, 66 of which had PAD. After adjustment for conventional CV risk factors, PMN-elastase (adjusted odds ratio [OR]: 1.008; 95% confidence interval [CI]: 1.002–1.015; p = 0.006), NGAL (adjusted OR: 1.045; 95%CI: 1.024–1.066; p < 0.001), and MPO (adjusted OR: 1.013; 95%CI: 1.001–1.024; p = 0.028) were significantly associated with PAD presence. PMN-elastase (adjusted hazard ratio [HR]: 1.010; 95%CI: 1.000–1.020; p = 0.040) and MPO (adjusted HR: 1.027; 95%CI: 1.004–1.051; p = 0.019) were predictive of 6-month MACE and/or MALE. MPO displayed fair prognostic performance on receiver operating characteristic (ROC) curve analyses, with an area under the curve (AUC) of 0.74 (95%CI: 0.56–0.91) and a sensitivity and specificity of 0.80 and 0.65, respectively, for a cut-off of 108.37 ng/mL. MPO–DNA showed a weak inverse correlation with transcutaneous oximetry (TcPO2) on proximal foot (adjusted ρ −0.287; p = 0.032). In conclusion, in patients with symptomatic chronic PAD, enhanced neutrophil activity may be associated with an increased risk of acute CV events, rather than correlate with disease severity. Further research is needed to clarify the role of neutrophils in PAD natural history. Full article
(This article belongs to the Special Issue Peripheral Artery Disease and Diabetic Foot Ulcer: From Bench to Clinic)
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12 pages, 963 KiB  
Article
Overcoming Barriers to Wound Healing in a Neuropathic and Neuro-Ischaemic Diabetic Foot Cohort Using a Novel Bilayer Biodegradable Synthetic Matrix
by Frank P. Guerriero, Robyn A. Clark, Michelle Miller and Christopher L. Delaney
Biomedicines 2023, 11(3), 721; https://doi.org/10.3390/biomedicines11030721 - 27 Feb 2023
Cited by 1 | Viewed by 2595
Abstract
Diabetes-related foot ulceration presents an increasing risk of lower limb amputation globally, driving the search for new treatment technologies. Our single-centre prospective observational study reports on the impact of bilayer biodegradable synthetic matrix technology (NovoSorb® BTM) on the healing and amputation rates [...] Read more.
Diabetes-related foot ulceration presents an increasing risk of lower limb amputation globally, driving the search for new treatment technologies. Our single-centre prospective observational study reports on the impact of bilayer biodegradable synthetic matrix technology (NovoSorb® BTM) on the healing and amputation rates of a diabetic foot ulceration cohort. Consecutive patients with a diabetes-related foot ulceration treated with NovoSorb BTM, between December 2019 and October 2021, were followed for 12 months. Complete wound healing and amputation outcomes were observed. Amputation risk was stratified using the Wound, Ischaemia and foot Infection (WIfI) classification system. Study outcomes were compared with recently published meta-analysis data to evaluate the impact of the synthetic matrix. In total, 25 NovoSorb BTM applications to 23 wounds in 22 patients were observed. Complete wound healing was observed in 15 of the wounds, 3 retained chronic wounds, 3 required minor amputation and 2 required major limb amputation. Further, 12-month WIfI amputation risk analysis saw 18 patients stratified to WIfI stage 4, 4 to WIfI stage 3 and 1 to WIfI stage 1. Our observed 12-month major amputation rates were 11.1% (n = 2) for stage 4 and 0% for stages 3 and 1. Our early experience suggests that NovoSorb BTM is a safe and effective treatment for moderate to severe diabetes-related foot ulceration. While larger-scale data are required, NovoSorb BTM may represent a promising new addition to the armamentarium of clinicians, who strive to achieve limb salvage in this complex cohort of patients. Full article
(This article belongs to the Special Issue Peripheral Artery Disease and Diabetic Foot Ulcer: From Bench to Clinic)
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Review

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15 pages, 1628 KiB  
Review
Therapeutic Potential for Beta-3 Adrenoreceptor Agonists in Peripheral Arterial Disease and Diabetic Foot Ulcers
by Cameron J. F. Evans, Sarah J. Glastras, Owen Tang and Gemma A. Figtree
Biomedicines 2023, 11(12), 3187; https://doi.org/10.3390/biomedicines11123187 - 30 Nov 2023
Viewed by 1286
Abstract
Annually, peripheral arterial disease is estimated to cost over USD 21 billion and diabetic foot disease an estimated at USD 9–13 billion. Mirabegron is a TGA-approved beta-3 adrenoreceptor agonist, shown to be safe and effective in the treatment of overactive bladder syndrome by [...] Read more.
Annually, peripheral arterial disease is estimated to cost over USD 21 billion and diabetic foot disease an estimated at USD 9–13 billion. Mirabegron is a TGA-approved beta-3 adrenoreceptor agonist, shown to be safe and effective in the treatment of overactive bladder syndrome by stimulating bladder smooth muscle relaxation. In this review, we discuss the potential use of beta-3 adrenoreceptor agonists as therapeutic agents repurposed for peripheral arterial disease and diabetic foot ulcers. The development of both conditions is underpinned by the upregulation of oxidative stress pathways and consequential inflammation and hypoxia. In oxidative stress, there is an imbalance of reactive oxygen species and nitric oxide. Endothelial nitric oxide synthase becomes uncoupled in disease states, producing superoxide and worsening oxidative stress. Agonist stimulation of the beta-3 adrenoreceptor recouples and activates endothelial nitric oxide synthase, increasing the production of nitric oxide. This reduces circulating reactive oxygen species, thus decreasing redox modification and dysregulation of cellular proteins, causing downstream smooth muscle relaxation, improved endothelial function and increased angiogenesis. These mechanisms lead to endothelial repair in peripheral arterial disease and an enhanced perfusion in hypoxic tissue, which will likely improve the healing of chronic ulcers. Full article
(This article belongs to the Special Issue Peripheral Artery Disease and Diabetic Foot Ulcer: From Bench to Clinic)
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23 pages, 2062 KiB  
Review
Preventive Therapies in Peripheral Arterial Disease
by Aangi J. Shah, Nicholas Pavlatos and Dinesh K. Kalra
Biomedicines 2023, 11(12), 3157; https://doi.org/10.3390/biomedicines11123157 - 27 Nov 2023
Cited by 1 | Viewed by 1461
Abstract
Atherosclerosis, while initially deemed a bland proliferative process, is now recognized as a multifactorial-lipoprotein-mediated inflammation-driven pathway. With the rising incidence of atherosclerotic disease of the lower extremity arteries, the healthcare burden and clinical morbidity and mortality due to peripheral artery disease (PAD) are [...] Read more.
Atherosclerosis, while initially deemed a bland proliferative process, is now recognized as a multifactorial-lipoprotein-mediated inflammation-driven pathway. With the rising incidence of atherosclerotic disease of the lower extremity arteries, the healthcare burden and clinical morbidity and mortality due to peripheral artery disease (PAD) are currently escalating. With a healthcare cost burden of over 21 billion USD and 200 million patients afflicted worldwide, accurate knowledge regarding the pathophysiology, presentation, and diagnosis of the disease is crucial. The role of lipoproteins and their remnants in atherosclerotic vessel occlusion and plaque formation and progression has been long established. This review paper discusses the epidemiology, pathophysiology, and presentation of PAD. PAD has been repeatedly noted to portend to poor cardiovascular and limb outcomes. We discuss major therapeutic avenues for the prevention of major cardiovascular adverse events and major limb adverse events in patients with PAD. Full article
(This article belongs to the Special Issue Peripheral Artery Disease and Diabetic Foot Ulcer: From Bench to Clinic)
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13 pages, 1505 KiB  
Review
Cardiovascular Prognosis in Patients with Peripheral Artery Disease and Approach to Therapy
by Antonio Curcio, Alessandra Panarello, Carmen Spaccarotella and Ciro Indolfi
Biomedicines 2023, 11(12), 3131; https://doi.org/10.3390/biomedicines11123131 - 24 Nov 2023
Cited by 1 | Viewed by 1065
Abstract
Peripheral artery disease (PAD), the pathophysiologic narrowing of the arterial blood vessels of the lower limbs due to atherosclerosis, is estimated to affect more than 200 million people worldwide and its prevalence ranges from 0.9 to 31.3% in people aged ≥50 years. It [...] Read more.
Peripheral artery disease (PAD), the pathophysiologic narrowing of the arterial blood vessels of the lower limbs due to atherosclerosis, is estimated to affect more than 200 million people worldwide and its prevalence ranges from 0.9 to 31.3% in people aged ≥50 years. It is an established marker of systemic obstructive atherosclerosis, which depicts patients at higher risk of myocardial infarction and stroke, due to the involvement of coronary and cerebral arteries in the atherosclerotic process. Therefore, identifying PAD, particularly in patients with coronary artery disease, is important to assess the cardiovascular risk score and implement specific therapies and prevention strategies. Since PAD emerged as an important clinical cardiovascular predictor, even more than other typical cardiovascular risk factors, an aggressive strategy to identify and treat PAD patients should be pursued by general practitioners, cardiologists, and vascular surgeons; similarly, preventive strategies should be implemented to improve prognosis and outcomes, particularly in patients suffering from both coronary artery disease and PAD. In this review, we describe the pathophysiology, including limb vasoconstriction after coronary angioplasty, the diagnosis of PAD, prognosis according to cardiovascular events, coronary artery disease, and heart failure. Furthermore, a large section of this review is on management, which spans from risk factors’ modification to antithrombotic therapy, and revascularization is provided. Finally, considerations about newer therapeutic options for the “desert foot” are discussed, including gene therapy. Full article
(This article belongs to the Special Issue Peripheral Artery Disease and Diabetic Foot Ulcer: From Bench to Clinic)
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16 pages, 720 KiB  
Review
Unveiling the Genetic Footprint: Exploring Somatic Mutations in Peripheral Arterial Disease Progression
by Amankeldi A. Salybekov and Mehdi Hassanpour
Biomedicines 2023, 11(8), 2288; https://doi.org/10.3390/biomedicines11082288 - 17 Aug 2023
Cited by 1 | Viewed by 1242
Abstract
Peripheral arterial diseases (PADs) are complex cardiovascular conditions influenced by environmental factors and somatic mutations in multiple genes involved in hematopoiesis and inflammation. While traditional risk factors, such as smoking, hypercholesterolemia, and hypertension, have been extensively studied, the role of somatic mutations in [...] Read more.
Peripheral arterial diseases (PADs) are complex cardiovascular conditions influenced by environmental factors and somatic mutations in multiple genes involved in hematopoiesis and inflammation. While traditional risk factors, such as smoking, hypercholesterolemia, and hypertension, have been extensively studied, the role of somatic mutations in PAD progression remains underexplored. The present article intends to provide a comprehensive commentary of the molecular mechanisms, genetic landscape, prognostic significance, and clinical implications of somatic mutations in PADs. The expansion of clonal hematopoiesis of indeterminate potential (CHIP) clones in the circulating blood, named clonal hematopoiesis (CH), leads to the infiltration of these clones into atherosclerotic plaques and the production of inflammatory cytokines, increasing the risk of cardiovascular diseases, including PADs. Furthermore, recent experimental evidence has demonstrated the involvement of somatically mutated TP53 genes with a high variant allele frequency (VAF) in PAD development and prognosis. This review delves into the relationship between CH and PADs, elucidating the prevalence, impact, and underlying mechanisms of this association. This understanding paves the way for novel therapeutic approaches targeting CHIP to promote tissue regeneration and improve outcomes in PAD patients. It emphasizes the need for further research to fully unravel the genetic footprint of the disease and highlights potential clinical implications. The findings presented in this article lay the foundation for personalized medicine approaches and open avenues for the development of targeted therapies based on somatic mutation profiling. Full article
(This article belongs to the Special Issue Peripheral Artery Disease and Diabetic Foot Ulcer: From Bench to Clinic)
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38 pages, 990 KiB  
Review
Micro- and Macrovascular Effects of Inflammation in Peripheral Artery Disease—Pathophysiology and Translational Therapeutic Approaches
by Michael Poledniczek, Christoph Neumayer, Christoph W. Kopp, Oliver Schlager, Thomas Gremmel, Alicja Jozkowicz, Michael E. Gschwandtner, Renate Koppensteiner and Patricia P. Wadowski
Biomedicines 2023, 11(8), 2284; https://doi.org/10.3390/biomedicines11082284 - 17 Aug 2023
Cited by 5 | Viewed by 1666
Abstract
Inflammation has a critical role in the development and progression of atherosclerosis. On the molecular level, inflammatory pathways negatively impact endothelial barrier properties and thus, tissue homeostasis. Conformational changes and destruction of the glycocalyx further promote pro-inflammatory pathways also contributing to pro-coagulability and [...] Read more.
Inflammation has a critical role in the development and progression of atherosclerosis. On the molecular level, inflammatory pathways negatively impact endothelial barrier properties and thus, tissue homeostasis. Conformational changes and destruction of the glycocalyx further promote pro-inflammatory pathways also contributing to pro-coagulability and a prothrombotic state. In addition, changes in the extracellular matrix composition lead to (peri-)vascular remodelling and alterations of the vessel wall, e.g., aneurysm formation. Moreover, progressive fibrosis leads to reduced tissue perfusion due to loss of functional capillaries. The present review aims at discussing the molecular and clinical effects of inflammatory processes on the micro- and macrovasculature with a focus on peripheral artery disease. Full article
(This article belongs to the Special Issue Peripheral Artery Disease and Diabetic Foot Ulcer: From Bench to Clinic)
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13 pages, 1283 KiB  
Systematic Review
Short-Term Outcomes and Efficacy of Percutaneous Deep Vein Arterialization for No-Option Critical Limb Ischemia: A Systematic Review and Meta-Analysis
by Roshanak Roustazadeh, Alexander Gombert, Julia Krabbe, Michael Jacobs and Panagiotis Doukas
Biomedicines 2024, 12(2), 318; https://doi.org/10.3390/biomedicines12020318 - 30 Jan 2024
Viewed by 804
Abstract
Background: Percutaneous deep vein arterialization (pDVA) is considered a treatment modality in patients with no-option critical limb ischemia. However, there is still a paucity of evidence regarding its safety and efficacy. Data sources: MEDLINE (via PubMed), Embase and Web of Science databases as [...] Read more.
Background: Percutaneous deep vein arterialization (pDVA) is considered a treatment modality in patients with no-option critical limb ischemia. However, there is still a paucity of evidence regarding its safety and efficacy. Data sources: MEDLINE (via PubMed), Embase and Web of Science databases as well as the CENTRAL registry up to the end of June 2023. Methods: This review adhered to the PRISMA guidelines (PROSPERO registration no. CRD42023445171). The risk of bias was assessed using the methodological index for non-randomized studies (MINORS). Primary endpoints included technical success, overall survival and limb salvage during the follow-up. Amputation-free survival at 30 days, 6 months and 1 year as well as complete wound healing, major adverse limb events and reintervention were investigated as secondary outcomes. Results: Five observational studies, comprising 208 patients (142 Rutherford class 5/77 Rutherford class 6), were included. MINORS revealed a low risk of bias. The meta-analysis reached a pooled technical success rate of 96.2% (95% CI: 91.5–98.4), an overall survival of 82.8% (95% CI: 70.5–95.2) and a limb salvage rate of 77.2% (95% CI: 65.2–89.1) during the follow-up. The amputation-free survival at 30 days, 6 months and 1 year was 87.8%, 68.7% and 65.6%, respectively. Furthermore, pDVA resulted in a complete wound healing rate of 53.4% (95% CI: 30.3–76.5). The pooled reintervention rate was as high as 46.7% (37.1–56.3%). Conclusions: PDVA seems a feasible bail-out strategy for patients with no option for routine treatment of CLTI. However, due to the small number of studies, the strength of the evidence is low. Full article
(This article belongs to the Special Issue Peripheral Artery Disease and Diabetic Foot Ulcer: From Bench to Clinic)
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7 pages, 249 KiB  
Brief Report
Association between Patients’ Body Mass Index and the Effect of Monophasic Pulsed Microcurrent Stimulation on Pressure Injury Healing
by Yoshiyuki Yoshikawa, Noriaki Maeshige, Atomu Yamaguchi, Mikiko Uemura, Terutaka Hiramatsu, Yoriko Tsuji and Hiroto Terashi
Biomedicines 2023, 11(9), 2379; https://doi.org/10.3390/biomedicines11092379 - 25 Aug 2023
Viewed by 999
Abstract
This secondary analysis study aimed to detect individual variables that influence the efficacy of monophasic pulsed microcurrent on pressure injury healing. Eleven patients with pressure injuries showing delayed healing underwent a microcurrent stimulation period and a placebo period. We analyzed the correlation between [...] Read more.
This secondary analysis study aimed to detect individual variables that influence the efficacy of monophasic pulsed microcurrent on pressure injury healing. Eleven patients with pressure injuries showing delayed healing underwent a microcurrent stimulation period and a placebo period. We analyzed the correlation between the individual variables and the following three outcomes using monophasic pulsed microcurrent: the wound reduction rate in the electrical stimulation period, the reduction rate in the placebo period, and the difference between these two reduction rates. Furthermore, the patients were divided into two groups, one with a wound reduction rate of more than 10% and the other with less than 10%, and the relationship between each variable was compared. As a result, the wound reduction rate in the electrical stimulation period and the difference in the reduction rate between the two periods showed significant positive correlations with patients’ body mass index. In addition, a significant difference was observed in the body mass index between subjects with a reduction rate of 10% or higher and those with a reduction rate of less than 10%. This study found a correlation between the effect of monophasic pulsed microcurrent for pressure injury healing and the level of patients’ body mass index. Full article
(This article belongs to the Special Issue Peripheral Artery Disease and Diabetic Foot Ulcer: From Bench to Clinic)
21 pages, 3002 KiB  
Systematic Review
Effect of Dietary Supplements Which Upregulate Nitric Oxide on Walking and Quality of Life in Patients with Peripheral Artery Disease: A Meta-Analysis
by Shannon A. Wong, Aaron Drovandi, Rhondda Jones and Jonathan Golledge
Biomedicines 2023, 11(7), 1859; https://doi.org/10.3390/biomedicines11071859 - 29 Jun 2023
Viewed by 1421
Abstract
This systematic review pooled evidence from randomised controlled trials (RCTs) on the effectiveness of dietary upregulators of nitric oxide (NO) in improving the walking and quality of life of patients with peripheral artery disease (PAD). RCTs examining the effect of dietary upregulators of [...] Read more.
This systematic review pooled evidence from randomised controlled trials (RCTs) on the effectiveness of dietary upregulators of nitric oxide (NO) in improving the walking and quality of life of patients with peripheral artery disease (PAD). RCTs examining the effect of dietary upregulators of NO in patients with PAD were included. The primary outcome was the maximum walking distance. Secondary outcomes were the initial claudication distance, the six-minute walking distance, quality of life, the ankle-brachial pressure index (ABI), adverse events and risk of mortality, revascularisation or amputation. Meta-analyses were performed using random effects models. The risk of bias was assessed using Cochrane’s ROB-2 tool. Leave-one-out and subgroup analyses were conducted to assess the effect of individual studies, the risk of bias and intervention type on pooled estimates. Thirty-four RCTs involving 3472 participants were included. Seven trials tested NO donors, nineteen tested antioxidants, three tested NO synthase inducers and five tested enhancers of NO availability. Overall, the dietary supplements significantly improved the initial claudication (SMD 0.34; 95%CI 0.04, 0.64; p = 0.03) but not maximum walking (SMD 0.13; 95%CI −0.17, 0.43; p = 0.39) distances. Antioxidant supplements significantly increased both the maximum walking (SMD 0.36; 95%CI 0.14, 0.59; p = 0.001) and initial claudication (SMD 0.58; 95%CI 0.26, 0.90; p < 0.001) distances. The dietary interventions did not improve the physical function domain of the Short Form-36 (SMD −0.16; 95%CI −0.32, 0.00; p = 0.38), ABI or risk of adverse events, mortality, revascularisation or amputation. Dietary NO upregulators, especially antioxidants, appear to improve the initial claudication distance in patients with PAD. Larger high-quality RCTs are needed to fully examine the benefits and risks of these treatments. PROSPERO Registration: CRD42022256653. Full article
(This article belongs to the Special Issue Peripheral Artery Disease and Diabetic Foot Ulcer: From Bench to Clinic)
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