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Cardiovascular autonomic neuropathy in diabetes: clinical impact, assessment, diagnosis, and management
Open accessAbstract
The Cardiovascular Autonomic Neuropathy (CAN) Subcommittee of the Toronto Consensus Panel on Diabetic Neuropathy worked to update CAN guidelines, with regard to epidemiology, clinical impact, diagnosis, usefulness of CAN testing, and management. CAN is the impairment of cardiovascular autonomic control in the setting of diabetes after exclusion of other causes. The prevalence of confirmed CAN is around 20%, and increases up to 65% with age and diabetes duration. Established risk factors for CAN are glycaemic control in type 1 and a combination of hypertension, dyslipidaemia, obesity, and glycaemic control in type 2 diabetes. CAN is a risk marker of mortality and cardiovascular morbidity, and possibly a progression promoter of diabetic nephropathy. Criteria for CAN diagnosis and staging are: (1) one abnormal cardiovagal test result identifies possible or early CAN; (2) at least two abnormal cardiovagal test results are required for definite or confirmed CAN; and (3) the presence of orthostatic hypotension in addition to abnormal heart rate test results identifies severe or advanced CAN. Progressive stages of CAN are associated with increasingly worse prognosis. CAN assessment is relevant in clinical practice for (1) diagnosis of CAN clinical forms, (2) detection and tailored treatment of CAN clinical correlates (e.g. tachycardia, orthostatic hypotension, non‐dipping, QT interval prolongation), (3) risk stratification for diabetic complications and cardiovascular morbidity and mortality, and (4) modulation of targets of diabetes therapy. Evidence on the cost‐effectiveness of CAN testing is lacking. Apart from the preventive role of intensive glycaemic control in type 1 diabetes, recommendations cannot be made for most therapeutic approaches to CAN. Copyright © 2011 John Wiley & Sons, Ltd.
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“Timely detection of CAN may help implementation of tailored interventions to prevent its progression and mitigate the risk of associated complications, including CVD, cardiac arrhythmias, myocardial dysfunction leading to congestive heart failure (CHF), CKD, and all-cause mortality.547,614,617–625”
From American Association of Clinical Endocrinology Clinical Practice Guideline: Developing a Diabetes Mellitus Comprehensive Care Plan-2022 Update. (2022) · cites this paper as [622]
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“Autonomic neuropathy can increase the risk of exercise-induced injury or adverse events through decreased cardiac responsiveness to exercise, postural hypotension, impaired thermoregulation, impaired night vision due to impaired papillary reaction, and greater susceptibility to hypoglycemia (277).”
From 5. Facilitating Positive Health Behaviors and Well-being to Improve Health Outcomes:Standards of Care in Diabetes—2023 (2023) · cites this paper as [277]
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“The Deutsche Kardiale Autonome Neuropathie Study demonstrated improved HRV after 4 month of treatment with 800 mg oral ALA per day, suggesting a beneficial effect on CAN [72].”
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“We therefore undertook the present study to investigate the efficacy of normalizing vitamin B12 levels with 1000 μg of methylcobalamin ( C 63 H 91 CoN 13 O 14 P ) daily in DM2 patients with good glycemic control and generalized neuropathy (both DPN and CAN) who were vitamin B12-deficient, partly because they had been…”
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Self-citationAksu, T., Brignole, M., Calò, L., Debruyne, P., Biase, L. D., Deharo, J., Fanciulli, A., Fedorowski, A., Kułakowski, P., Morillo, C. A., et al. (2024) · EP Europace · doi:10.1093/europace/euae206 · Cited by 83
A simple new non‐invasive sweat indicator test for the diagnosis of diabetic neuropathy
Παπάνας, Ν., Boulton, A. J. M., Malik, R. A., Manes, C., Schnell, O., Spallone, V., Tentolouris, N., Tesfaye, S. H., Valensi, P. E., Ziegler, D., et al. (2012) · Diabetic Medicine · doi:10.1111/dme.12000 · Cited by 84
Self-citationCardiac Autonomic Neuropathy: Why Should Cardiologists Care about That?
Bissinger, A. (2017) · Journal of Diabetes Research · doi:10.1155/2017/5374176 · Cited by 86
“The duration of diabetes is an independent factor for developing CAN irrespective of diabetes type [4, 5].”
BackgroundMethodInfluentialLin, Y. K., Fisher, S. J., & Pop‐Busui, R. (2020) · Journal of Diabetes Investigation · doi:10.1111/jdi.13290 · Cited by 82
Self-citationCatechin attenuates diabetic autonomic neuropathy in streptozotocin induced diabetic rats
Addepalli, V., & Suryavanshi, S. V. (2018) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2018.09.179 · Cited by 79
Corneal confocal microscopy for the diagnosis of diabetic autonomic neuropathy
Tavakoli, M., Begum, P., McLaughlin, J. T., & Malik, R. A. (2014) · Muscle & Nerve · doi:10.1002/mus.24553 · Cited by 77
“INTRODUCTION Diabetic autonomic neuropathy (DAN) is associated with a range of debilitating symptoms and deficits, and the presence of cardiac autonomic neuropathy (CAN) in particular has been shown to be an independent risk factor for mortality.(1) Early improved glycemic control clearly has an impact on the developm…”
BackgroundZoppini, G., Cacciatori, V., Raimondo, D., Gemma, M., Trombetta, M., Dauriz, M., Brangani, C., Pichiri, I., Negri, C., Stoico, V., et al. (2015) · Diabetes Care · doi:10.2337/dc15-0081 · Cited by 74
Herder, C., Schamarek, I., Nowotny, B., Carstensen‐Kirberg, M., Straßburger, K., Nowotny, P., Kannenberg, J. M., Strom, A., Püttgen, S., Müssig, K., et al. (2016) · Heart · doi:10.1136/heartjnl-2015-309181 · Cited by 77
Self-citationMoon, J. S., Kang, S., Choi, J. H., Lee, K. A., Moon, J. H., Chon, S., Kim, D. J., Kim, H. J., Seo, J. A., Kim, M. K., et al. (2024) · Diabetes & Metabolism Journal · doi:10.4093/dmj.2024.0249 · Cited by 81
Blood Pressure Variability and Autonomic Dysfunction
Spallone, V. (2018) · Current Diabetes Reports · doi:10.1007/s11892-018-1108-z · Cited by 77
Self-citationDiabetes and cardiovascular disease: inter-relation of risk factors and treatment
Sharma, A., Mittal, S., Aggarwal, R., & Chauhan, M. K. (2020) · Future Journal of Pharmaceutical Sciences · doi:10.1186/s43094-020-00151-w · Cited by 83
“As the ANS is involved in activity modulation of the sinus node (heart rate), end-diastolic and systolic volume, the resistance of systemic vascular, the dysregulation of the autonomic nervous system may result in left ventricular hypertrophy, arterial stiffness, and dysfunction of diastolic of the ventricle [71].”
BackgroundJaiswal, M., McKeon, K., Comment, N., Henderson, J., Swanson, S., Plunkett, C. D., Nelson, P. W., & Pop‐Busui, R. (2014) · Diabetes Care · doi:10.2337/dc14-0445 · Cited by 70
Self-citationDiabetes mellitus and risk of sudden cardiac death: a systematic review and meta-analysis
Zaccardi, F., Khan, H., & Laukkanen, J. A. (2014) · International Journal of Cardiology · doi:10.1016/j.ijcard.2014.08.105 · Cited by 69
“Second, diabetic autonomic neuropathy (DAN) might be another potential mechanism, as subjects with DAN have a high prevalence of electrocardiographic abnormalities and an increased risk of SCD [8].”
BackgroundMathew, A. V., Jaiswal, M., Ang, L. P., Michailidis, G. C., Pennathur, S., & Pop‐Busui, R. (2019) · Diabetes · doi:10.2337/db19-0145 · Cited by 69
Self-citationDidangelos, T., Karlafti, E., Kotzakioulafi, E., Kontoninas, Z., Margaritidis, C., Giannoulaki, P., & Kantartzis, K. (2020) · Nutrients · doi:10.3390/nu12113254 · Cited by 70
“Cardiovascular Reflex Tests (CRT), which are considered to be the gold standard measurement, were used for screening Cardiovascular Autonomic Neuropathy [35].”
BackgroundMethodInfluentialThe prevalence of cardiac autonomic neuropathy in prediabetes: a systematic review
Eleftheriadou, A., Williams, S., Nevitt, S. J., Brown, E. E., Roylance, R., Wilding, J. P. H., Cuthbertson, D. J., & Alam, U. (2020) · Diabetologia · doi:10.1007/s00125-020-05316-z · Cited by 72
“Definite CAN is defined as two or more positive cardiac autonomic tests as per the definitions of the Toronto Diabetic Neuropathy Expert Group [14].”
BackgroundMethodInfluentialDiabetic Autonomic Imbalance and Glycemic Variability
Fleischer, J. (2012) · Journal of Diabetes Science and Technology · doi:10.1177/193229681200600526 · Cited by 69
Corneal Confocal Microscopy: A New Technique for Early Detection of Diabetic Neuropathy
Παπάνας, Ν., & Ziegler, D. (2013) · Current Diabetes Reports · doi:10.1007/s11892-013-0390-z · Cited by 67
“Other evaluation measures have included heart rate variability as an index of cardiovascular autonomic neuropathy [85] in some reports [66, 72, 76•], skin biopsy quantifying intraepidermal nerve fiber density (IENFD) [86] in others [66, 72, 77, 78], the Neuropad indicator test of sudomotor function [5] in 1 study [71]…”
BackgroundSelf-citationBudoff, M. J., Alpert, B. S., Chirinos, J. A., Fernhall, B., Hamburg, N. M., Kario, K., Kullo, I. J., Matsushita, K., Miyoshi, T., Tanaka, H., et al. (2021) · American Journal of Hypertension · doi:10.1093/ajh/hpab178 · Cited by 67
Self-citationCharles, M., Fleischer, J., Witte, D. R., Ejskjær, N., Borch‐Johnsen, K., Lauritzen, T., & Sandbæk, A. (2012) · Diabetologia · doi:10.1007/s00125-012-2744-5 · Cited by 65
“CAN was defined using the ADA criteria and the Toronto Consensus Panel on Diabetic Neuropathy as follows: CAN 0, all tests are normal; CAN early, one test is abnormal signifying the presence of possible or early stage CAN; CAN manifest, two or three abnormal tests signifying definite or late stage CAN [12, 16].”
MethodInfluentialPrediabetic Neuropathy: Does It Exist?
Παπάνας, Ν., & Ziegler, D. (2012) · Current Diabetes Reports · doi:10.1007/s11892-012-0278-3 · Cited by 70
Self-citationDiabetes-Induced Cardiac Autonomic Neuropathy: Impact on Heart Function and Prognosis
Sudo, S. Z., Montagnoli, T. L., Rocha, B., Santos, A. D., de Sá, M. P. L., & Zapata‐Sudo, G. (2022) · Biomedicines · doi:10.3390/biomedicines10123258 · Cited by 62
“As the prevalence of DM increases, a concomitant increase in CAN occurs, which cannot be diagnosed in the early stage, also occurs [18,20].”
Pop‐Busui, R., Hotaling, J., Braffett, B. H., Cleary, P. A., Dunn, R. L., Martin, C. L., Jacobson, A. M., Wessells, H., & Sarma, A. V. (2015) · The Journal of Urology · doi:10.1016/j.juro.2014.12.097 · Cited by 61
Self-citationHilz, M., Liu, M., Koehn, J., Wang, R.-H., Ammon, F., Flanagan, S. R., & Hösl, K. (2016) · BMC Neurology · doi:10.1186/s12883-016-0584-5 · Cited by 60
“, in patients with myocardial infarction [63, 64], congestive heart failure [65], renal failure [66], acute ischemic or hemorrhagic stroke [67–70], and diabetes [71–73].”
BackgroundDiabetic cardiovascular autonomic neuropathy: clinical implications
Karayannis, G., Giamouzis, G., Cokkinos, D. V., Skoularigis, J. S., & Triposkiadis, F. K. (2012) · Expert Review of Cardiovascular Therapy · doi:10.1586/erc.12.53 · Cited by 59
Metadata
- Authors
- Spallone, V., Ziegler, D., Freeman, R., Bernardi, L., Frontoni, S., Pop‐Busui, R., Stevens, M., Kempler, P., Hilsted, J., Tesfaye, S., Low, P., Valensi, P., & Neuropathy, O. B. O. T. T. C. P. O. D.
- Affiliations
- University of Rome Tor Vergata (IT)
- Düsseldorf University Hospital (DE)
- Beth Israel Deaconess Medical Center (US)
- University of Pavia (IT)
- University of Michigan (US)
- University of Birmingham (GB)
- Copenhagen University Hospital (DK)
- Sheffield Teaching Hospitals NHS Foundation Trust (GB)
- Mayo Clinic (US)
- Assistance Publique – Hôpitaux de Paris (FR)
- Corresponding author
- Spallone, Vincenza
- ORCID
- Venue
- Diabetes/Metabolism Research and Reviews
- Publisher
- Wiley
- Published
- 2011-10
- Volume
- 27
- Issue
- 7
- Pages
- 639-653
- ISSN
- 1520-7552 (ISSN-L)
- 1520-7560
- OpenAlex
- W2086516175
- Cited by
- 957
- References
- 67
- Citations by year
- 2026: 65 · 2025: 67 · 2024: 78 · 2023: 63 · 2022: 71 · 2021: 86 · 2020: 93 · 2019: 62 · 2018: 78 · 2017: 54 · 2016: 61 · 2015: 60 · 2014: 52 · 2013: 34 · 2012: 24
- FWCI
- 37.71
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Diabetes/Metabolism Research and Reviews (publishedVersion)
- PubMed (publishedVersion)
- Deep Blue (University of Michigan) (submittedVersion)
- Cineca Institutional Research Information System (Tor Vergata University) (submittedVersion)
- University of Birmingham Research Portal (University of Birmingham) (submittedVersion)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Syncope and Autonomic Disorders
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Heart Rate Variability and Autonomic Control
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
- Keywords
- cardiac autonomic neuropathy, diabetes mellitus, orthostatic hypotension, glycemic control, cardiovascular morbidity and mortality, diabetic nephropathy progression, risk stratification, type 1 diabetes, type 2 diabetes
- MeSH terms
- Autonomic Nervous System, Blood Glucose, Cardiovascular Diseases, Diabetic Neuropathies, Humans, Prognosis, Disease Management
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