Advertisement

Diabetic Foot Ulcers and Cardiac Autonomic Neuropathy

      Abstract

      Purpose

      Diabetic foot ulcers (DFUs) and cardiac autonomic neuropathy (CAN) are severe complications of diabetes mellitus (DM). Both DFU and CAN are associated with increased risk of major cardiovascular events and mortality. Because of the clinical impact of both these conditions, it is important to establish what effect the presence of CAN has on DFU outcomes.

      Methods

      This is a narrative review of original research articles identified through an electronic search of PubMed, Scopus, and Google scholar databases until June 2021 exploring CAN in individuals with DFUs. We explored prevalence, patient outcomes (DFU healing and amputation), and mortality.

      Findings

      Evidence suggests that the prevalence of CAN is high, ranging from 43% to 66% among those with DFUs. The presence of CAN may also increase the odds of developing DFUs. A single-center, prospective, observational study has suggested that the presence of CAN significantly reduces DFU healing time. The impact on amputation is indeterminate, with conflicting reports from studies reporting either no or increased risk. On the basis of limited evidence, CAN may be associated with increased mortality in individuals with DFUs.

      Implications

      The interplay between CAN and DFUs is poorly understood from current literature. Given the high prevalence of CAN in individuals with DFUs and the potential for suboptimal outcomes, further high-quality studies are required to determine future management approaches when both conditions coexist and to establish whether early CAN screening in individuals with diabetes at high risk of foot ulceration may ultimately improve their outlook.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Clinical Therapeutics
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • van Netten JJ
        • Bus SA
        • Apelqvist J
        • et al.
        Definitions and criteria for diabetic foot disease.
        Diabetes Metab Res Rev. 2020; 36 Suppl 1: e3268
        • Yazdanpanah L
        • Nasiri M
        • Adarvishi S.
        Literature review on the management of diabetic foot ulcer.
        World J Diabetes. 2015; 6: 37-53
        • Campbell IW.
        Epidemiology and clinical presentation of type 2 diabetes.
        Value Health. 2000; 3 Suppl 1: 3-6
        • Alexiadou K
        • Doupis J.
        Management of diabetic foot ulcers.
        Diabetes Ther. 2012; 3: 4
        • Dietrich I
        • Braga GA
        • de Melo FG
        • da Costa Silva
        • Silva ACC.
        The Diabetic Foot as a Proxy for Cardiovascular Events and Mortality Review.
        Curr Atheroscler Rep. 2017; 19: 44
        • Vas PRJ
        • Lucas J
        • Arshad S
        • Edmonds ME.
        Neuropathic Diabetic Foot Ulceration.
        in: Edmonds ME Sumpio BE Limb Salvage of the Diabetic Foot. Springer International Publishing, Cham2019: 53-76
        • Armstrong DG
        • Cohen K
        • Courric S
        • Bharara M
        • Marston W.
        Diabetic Foot Ulcers and Vascular Insufficiency: Our Population Has Changed, but Our Methods Have Not.
        Journal of diabetes science and technology. 2011; 5: 1591-1595
        • Hartling L
        • Hamm M
        • Milne A
        • et al.
        Validity and Inter-Rater Reliability Testing of Quality Assessment Instruments.
        Agency for Healthcare Research and Quality (US), Rockville (MD)2012
        • Lipsky BA
        • Senneville E
        • Abbas ZG
        • et al.
        Guidelines on the diagnosis and treatment of foot infection in persons with diabetes (IWGDF 2019 update).
        Diabetes Metab Res Rev. 2020; 36 Suppl 1: e3280
        • Brownrigg JR
        • Davey J
        • Holt PJ
        • et al.
        The association of ulceration of the foot with cardiovascular and all-cause mortality in patients with diabetes: a meta-analysis.
        Diabetologia. 2012; 55: 2906-2912
        • Pinto A
        • Tuttolomondo A
        • Di Raimondo D
        • et al.
        Cardiovascular risk profile and morbidity in subjects affected by type 2 diabetes mellitus with and without diabetic foot.
        Metabolism. 2008; 57: 676-682
        • Chammas NK
        • Hill RL
        • Edmonds ME.
        Increased Mortality in Diabetic Foot Ulcer Patients: The Significance of Ulcer Type.
        J Diabetes Res. 2016; 20162879809
        • Hicks CW
        • Selvin E.
        Epidemiology of Peripheral Neuropathy and Lower Extremity Disease in Diabetes.
        Curr Diab Rep. 2019; 19: 86
        • Tesfaye S
        • Boulton AJ
        • Dyck PJ
        • et al.
        Diabetic neuropathies: update on definitions, diagnostic criteria, estimation of severity, and treatments.
        Diabetes Care. 2010; 33: 2285-2293
        • Dimitropoulos G
        • Tahrani AA
        • Stevens MJ.
        Cardiac autonomic neuropathy in patients with diabetes mellitus.
        World J Diabetes. 2014; 5: 17-39
        • Ziegler D.
        Diabetic cardiovascular autonomic neuropathy: prognosis, diagnosis and treatment.
        Diabetes Metab Rev. 1994; 10: 339-383
        • Spallone V
        • Ziegler D
        • Freeman R
        • et al.
        Cardiovascular autonomic neuropathy in diabetes: clinical impact, assessment, diagnosis, and management.
        Diabetes Metab Res Rev. 2011; 27: 639-653
        • Gibbons CH
        • Schmidt P
        • Biaggioni I
        • et al.
        The recommendations of a consensus panel for the screening, diagnosis, and treatment of neurogenic orthostatic hypotension and associated supine hypertension.
        J Neurol. 2017; 264: 1567-1582
        • Agashe S
        • Petak S.
        Cardiac Autonomic Neuropathy in Diabetes Mellitus.
        Methodist Debakey Cardiovasc J. 2018; 14: 251-256
        • Vinik AI
        • Maser RE
        • Mitchell BD
        • Freeman R.
        Diabetic autonomic neuropathy.
        Diabetes Care. 2003; 26: 1553-1579
        • Pop-Busui R
        • Low PA
        • Waberski BH
        • et al.
        Effects of prior intensive insulin therapy on cardiac autonomic nervous system function in type 1 diabetes mellitus: the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications study (DCCT/EDIC).
        Circulation. 2009; 119: 2886-2893
        • Braffett BH
        • Gubitosi-Klug RA
        • Albers JW
        • et al.
        Risk Factors for Diabetic Peripheral Neuropathy and Cardiovascular Autonomic Neuropathy in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study.
        Diabetes. 2020; 69: 1000-1010
        • Serhiyenko VA
        • Serhiyenko AA.
        Cardiac autonomic neuropathy: Risk factors, diagnosis and treatment.
        World J Diabetes. 2018; 9: 1-24
        • Maser RE
        • Mitchell BD
        • Vinik AI
        • Freeman R.
        The association between cardiovascular autonomic neuropathy and mortality in individuals with diabetes: a meta-analysis.
        Diabetes Care. 2003; 26: 1895-1901
        • Gerritsen J
        • Dekker JM
        • TenVoorde BJ
        • et al.
        Impaired autonomic function is associated with increased mortality, especially in subjects with diabetes, hypertension, or a history of cardiovascular disease: the Hoorn Study.
        Diabetes Care. 2001; 24: 1793-1798
        • Young LH
        • Wackers FJ
        • Chyun DA
        • et al.
        Cardiac outcomes after screening for asymptomatic coronary artery disease in patients with type 2 diabetes: the DIAD study: a randomized controlled trial.
        JAMA. 2009; 301: 1547-1555
        • Valensi P
        • Sachs RN
        • Harfouche B
        • et al.
        Predictive value of cardiac autonomic neuropathy in diabetic patients with or without silent myocardial ischemia.
        Diabetes Care. 2001; 24: 339-343
        • Ambepityia G
        • Kopelman PG
        • Ingram D
        • Swash M
        • Mills PG
        • Timmis AD.
        Exertional myocardial ischemia in diabetes: a quantitative analysis of anginal perceptual threshold and the influence of autonomic function.
        J Am Coll Cardiol. 1990; 15: 72-77
        • Vinik AI
        • Ziegler D.
        Diabetic cardiovascular autonomic neuropathy.
        Circulation. 2007; 115: 387-397
        • Farrow F
        • Fountoulakis N
        • Cummins K
        • et al.
        Cardiac Autonomic Neuropathy is Associated with Improved Diabetic Foot Ulcer Healing: A Single Centre Prospective Cohort Study.
        Exp Clin Endocrinol Diabetes. 2021; 129: 895-898
        • Menon AS
        • Dixit A
        • Garg MK
        • Girish R.
        Cardiac Autonomic Neuropathy in Patients with Type 2 Diabetes Mellitus at High Risk for Foot Ulcers.
        Indian J Endocrinol Metab. 2017; 21: 282-285
        • Yun JS
        • Cha SA
        • Lim TS
        • et al.
        Cardiovascular Autonomic Dysfunction Predicts Diabetic Foot Ulcers in Patients With Type 2 Diabetes Without Diabetic Polyneuropathy.
        Medicine (Baltimore). 2016; 95: e3128
        • Stevens MJ
        • Edmonds ME
        • Foster AV
        • Watkins PJ.
        Selective neuropathy and preserved vascular responses in the diabetic Charcot foot.
        Diabetologia. 1992; 35: 148-154
        • McFadden JP
        • Corrall RJ
        • O'Brien IA
        Autonomic and sensory nerve function in diabetic foot ulceration.
        Clin Exp Dermatol. 1991; 16: 193-196
        • Tentolouris N
        • Marinou K
        • Kokotis P
        • Karanti A
        • Diakoumopoulou E
        • Katsilambros N.
        Sudomotor dysfunction is associated with foot ulceration in diabetes.
        Diabet Med. 2009; 26: 302-305
        • Bissinger A.
        Cardiac Autonomic Neuropathy: Why Should Cardiologists Care about That?.
        J Diabetes Res. 2017; 20175374176
        • Mayfield JA
        • Caps MT
        • Boyko EJ
        • Ahroni JH
        • Smith DG.
        Relationship of medial arterial calcinosis to autonomic neuropathy and adverse outcomes in a diabetic veteran population.
        J Diabetes Complications. 2002; 16: 165-171
        • Fagher K
        • Londahl M.
        The impact of metabolic control and QTc prolongation on all-cause mortality in patients with type 2 diabetes and foot ulcers.
        Diabetologia. 2013; 56: 1140-1147
        • Pappachan JM
        • Sebastian J
        • Bino BC
        • et al.
        Cardiac autonomic neuropathy in diabetes mellitus: prevalence, risk factors and utility of corrected QT interval in the ECG for its diagnosis.
        Postgrad Med J. 2008; 84: 205-210
        • Ukpabi OJ
        • Onwubere BJ.
        QTc prolongation in Black diabetic subjects with cardiac autonomic neuropathy.
        Afr Health Sci. 2017; 17: 1092-1100
        • Fagher K
        • Katzman P
        • Londahl M.
        Hyperbaric oxygen therapy reduces the risk of QTc interval prolongation in patients with diabetes and hard-to-heal foot ulcers.
        J Diabetes Complications. 2015; 29: 1198-1202
        • Kumar M
        • Chapman A
        • Javed S
        • Alam U
        • Malik RA
        • Azmi S.
        The Investigation and Treatment of Diabetic Gastroparesis.
        Clin Ther. 2018; 40: 850-861
        • Pafili K
        • Trypsianis G
        • Papazoglou D
        • Maltezos E
        • Papanas N.
        Correlation of cardiac autonomic neuropathy with small and large peripheral nerve function in type 2 diabetes mellitus.
        Diabetes Res Clin Pract. 2019; 156107844
        • Pafili K
        • Trypsianis G
        • Papazoglou D
        • Maltezos E
        • Papanas N.
        Cardiovascular Autonomic Neuropathy and Distal Symmetric Sensorimotor Polyneuropathy: These Two Diabetic Microvascular Complications do not Invariably Co-Exist.
        Curr Vasc Pharmacol. 2020; 18: 50-56