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Cardiac Autonomic Neuropathy in Type 1 and 2 Diabetes: Epidemiology, Pathophysiology, and Management

  • Scott Williams
    Affiliations
    Department of Medicine, Aintree University Hospital, Liverpool University Hospitals NHS Foundation Trust, Liverpool, United Kingdom
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  • Siddig Abdel Raheim
    Affiliations
    Department of Medicine, Aintree University Hospital, Liverpool University Hospitals NHS Foundation Trust, Liverpool, United Kingdom
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  • Muhammad Ilyas Khan
    Affiliations
    Department of Medicine, Aintree University Hospital, Liverpool University Hospitals NHS Foundation Trust, Liverpool, United Kingdom
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  • Umme Rubab
    Affiliations
    Department of Medicine, Aintree University Hospital, Liverpool University Hospitals NHS Foundation Trust, Liverpool, United Kingdom
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  • Prathap Kanagala
    Affiliations
    Department of Medicine, Aintree University Hospital, Liverpool University Hospitals NHS Foundation Trust, Liverpool, United Kingdom

    Department of Eye & Vision Sciences, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, United Kingdom
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  • Sizheng Steven Zhao
    Affiliations
    Department of Eye & Vision Sciences, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, United Kingdom

    Centre for Epidemiology Versus Arthritis, Division of Musculoskeletal and Dermatological Sciences, School of Biological Sciences, Faculty of Biology Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, United Kingdom
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  • Anne Marshall
    Affiliations
    Department of Eye & Vision Sciences, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, United Kingdom
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  • Emily Brown
    Affiliations
    Department of Medicine, Aintree University Hospital, Liverpool University Hospitals NHS Foundation Trust, Liverpool, United Kingdom

    Department of Eye & Vision Sciences, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, United Kingdom
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  • Uazman Alam
    Correspondence
    Address correspondence to: Uazman Alam, Department of Medicine, Third Floor Clinical Sciences Centre, Aintree University Hospital, Longmoor Lane, Liverpool, L9 7AL, United Kingdom.
    Affiliations
    Department of Medicine, Aintree University Hospital, Liverpool University Hospitals NHS Foundation Trust, Liverpool, United Kingdom

    Department of Eye & Vision Sciences, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, United Kingdom
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Open AccessPublished:October 19, 2022DOI:https://doi.org/10.1016/j.clinthera.2022.09.002

      Abstract

      Purpose

      Cardiac autonomic neuropathy (CAN) is a serious complication of type 1 and type 2 diabetes and is independently associated with major cardiovascular events, morbidity, and mortality. This narrative review examines the epidemiology, pathophysiology, and management and identifies areas of future research to address the challenge posed by CAN.

      Methods

      We conducted a comprehensive literature search using a range of sources, including the electronic databases PubMed Central, Google Scholar, OVID, and Open Athens, to search for studies on CAN, diabetes mellitus, lifestyle intervention, and cardiovascular risk. We set inclusion criteria to consider review articles or original research published in peer-reviewed journals that examined CAN in diabetes.

      Findings

      Epidemiologic data indicate a varied prevalence of CAN in type 1 and 2 diabetes, with prevalences of 17% to 73%) depending on clinical and demographic factors. Indeed, duration of diabetes and hyperglycemia are the strongest risk factors for CAN development in type 1 diabetes. However, in type 2 diabetes, multifactorial risk factors, including obesity, hypertension, and hyperlipidemia, are associated with the development of CAN. Insulin resistance, which underpins type 2 diabetes and metabolic syndrome, has a direct role in the pathogenesis of CAN. Lifestyle interventions, including dietary measures and tailored exercise programs, have been beneficial in improving cardiac autonomic function primarily measured through heart rate variability. In addition, weight loss through bariatric surgery also improves heart rate variability and may prevent or reduce CAN progression in people living with obesity and concomitant type 2 diabetes. For optimization in type 2 diabetes, both lifestyle and targeted pharmacologic interventions are required to achieve glycemic/metabolic targets, and weight loss is required to prevent or reverse early CAN or prevent the progression to definite and severe CAN.

      Implications

      The focused use of diagnostic testing for CAN, including cardiac autonomic reflex testing in those at high risk of CAN, will enable earlier diagnosis. This testing will allow timely interventions at a reversible stage. Future research should examine targeted early diagnostic testing with subsequent intervention with a combination of lifestyle measures and newer pharmacotherapeutics (eg, sodium-glucose cotransporter 2 inhibitors and glucagon-like peptide 1 receptor agonists), which have produced significant cardiovascular benefit in diabetes.

      Key words

      Introduction

      Cardiac autonomic neuropathy (CAN) is a result of impaired autonomic function and subsequent nervous system imbalance of the cardiovascular system that occurs as a result of diabetes.
      • Spallone V.
      Update on the Impact, Diagnosis and Management of Cardiovascular Autonomic Neuropathy in Diabetes: What Is Defined, What Is New, and What Is Unmet.
      CAN also develops from metabolic derangements in prediabetes and metabolic syndrome (MetS), prior to established diabetes mellitus.
      • Pop-Busui R
      • Boulton AJM
      • Feldman EL
      • Bril V
      • Freeman R
      • Malik RA
      • et al.
      In type 1 diabetes, hyperglycemia acts through multiple cellular mechanisms, resulting in microvascular complications, including CAN.
      • Serhiyenko V
      • Ponomarev A.
      Cardiac Autonomic Neuropathy: Risk Factors, Diagnosis and Treatment.
      In prediabetes, MetS, and type 2 diabetes, a complex relationship exists between increasing insulin resistance and progressive autonomic dysfunction, which results in CAN.
      • Williams SM
      • Eleftheriadou A
      • Alam U
      • Cuthbertson DJ
      • Wilding JPH.
      Cardiac Autonomic Neuropathy in Obesity, the Metabolic Syndrome and Prediabetes: A Narrative Review.
      Asymptomatic abnormalities in autonomic function have been found in approximately 20% of patients with diabetes mellitus from a randomly selected cohort and is therefore considerably underdiagnosed.
      • Dunlay SM
      • Givertz MM
      • Aguilar D
      • et al.
      Type 2 Diabetes Mellitus and Heart Failure: A Scientific Statement From the American Heart Association and the Heart Failure Society of America: This statement does not represent an update of the 2017 ACC/AHA/HFSA heart failure guideline update.
      ,
      • Vinik AI
      • Maser RE
      • Mitchell BD
      • Freeman R.
      Clinical symptoms of CAN include palpitations, dizziness, presyncope, and syncope.
      • Spallone V.
      Update on the Impact, Diagnosis and Management of Cardiovascular Autonomic Neuropathy in Diabetes: What Is Defined, What Is New, and What Is Unmet.
      ,
      • Vinik AI
      • Erbas T.
      Diabetic autonomic neuropathy.
      Unfortunately, symptoms are a late presention and advanced CAN is essentially irreversible with a high 5-year mortality (up to 50%),
      • Balcıoğlu AS
      • Müderrisoğlu H.
      Diabetes and cardiac autonomic neuropathy: Clinical manifestations, cardiovascular consequences, diagnosis and treatment.
      which is worse than a number of common cancers including breast and prostate cancer (5-year mortality of ∼10%)., Cardiac autonomic reflex tests (CARTs) are a universally accepted method for diagnosis and for risk stratification.
      • Williams SM
      • Eleftheriadou A
      • Alam U
      • Cuthbertson DJ
      • Wilding JPH.
      Cardiac Autonomic Neuropathy in Obesity, the Metabolic Syndrome and Prediabetes: A Narrative Review.
      ,
      • Spallone V
      • Bellavere F
      • Scionti L
      • et al.
      Recommendations for the use of cardiovascular tests in diagnosing diabetic autonomic neuropathy.
      Detecting early CAN is vital given that it is reversible and amenable in particular to lifestyle interventions. Multifactorial targeted risk factors intervention by optimising glycemic control, dyslipidemia and hypertension are key components CAN management.
      • Williams SM
      • Eleftheriadou A
      • Alam U
      • Cuthbertson DJ
      • Wilding JPH.
      Cardiac Autonomic Neuropathy in Obesity, the Metabolic Syndrome and Prediabetes: A Narrative Review.
      Early treatment is imperative as CAN is a strong prognostic risk factor for cardiovascular events and mortality.
      • Spallone V
      • Ziegler D
      • Freeman R
      • et al.
      Cardiovascular autonomic neuropathy in diabetes: clinical impact, assessment, diagnosis, and management.
      ,
      • Chowdhury M
      • Nevitt S
      • Eleftheriadou A
      • et al.
      Cardiac autonomic neuropathy and risk of cardiovascular disease and mortality in type 1 and type 2 diabetes: a meta-analysis.
      Pathoalterations in autonomic function result in an increased risk of cardiac arrhythmias and cardiovascular events, including acute myocardial infarction.
      • Serhiyenko V
      • Ponomarev A.
      Cardiac Autonomic Neuropathy: Risk Factors, Diagnosis and Treatment.
      This risk can be observed through abnormal surface measures of cardiac repolarization, including an increase in the corrected QT interval.
      • Imam MH
      • Karmakar CK
      • Khandoker AH
      • Jelinek HF
      • Palaniswami M.
      Heart rate independent QT variability component can detect subclinical cardiac autonomic neuropathy in diabetes.
      • Dimova R
      • Tankova T
      • Chakarova N
      • Grozeva G
      • Dakovska L.
      Main predictors of cardiovascular autonomic dysfunction in early stages of glucose intolerance.
      • Chow E
      • Bernjak A
      • Williams S
      • Fawdry RA
      • Hibbert S
      • Freeman J
      • et al.
      Risk of Cardiac Arrhythmias During Hypoglycemia in Patients With Type 2 Diabetes and Cardiovascular Risk.
      Increases in QT interval in progressive CAN have been correlated to an increased risk for sudden cardiac death.
      • O'Neal WT
      • Singleton MJ
      • Roberts JD
      • Tereshchenko LG
      • Sotoodehnia N
      • Chen LY
      • et al.
      Association Between QT-Interval Components and Sudden Cardiac Death.
      • Straus SMJM
      • Kors JA
      • De Bruin ML
      • van der Hooft CS
      • Hofman A
      • Heeringa J
      • et al.
      Prolonged QTc Interval and Risk of Sudden Cardiac Death in a Population of Older Adults.
      • Ewing DJ
      • Boland O
      • Neilson JM
      • Cho CG
      • Clarke BF.
      Autonomic neuropathy, QT interval lengthening, and unexpected deaths in male diabetic patients.
      Indeed, intraoperative instability and silent myocardial ischemia and infarction are all associated with CAN.
      • Spallone V.
      Update on the Impact, Diagnosis and Management of Cardiovascular Autonomic Neuropathy in Diabetes: What Is Defined, What Is New, and What Is Unmet.
      ,
      • Vinik AI
      • Erbas T.
      Diabetic autonomic neuropathy.
      Therefore, new approaches are required to reduce the mortality and morbidity associated with CAN, which will undoubtedly increase as the prevalence of diabetes mellitus and MetS increases to epidemic proportions globally.
      • Spallone V.
      Update on the Impact, Diagnosis and Management of Cardiovascular Autonomic Neuropathy in Diabetes: What Is Defined, What Is New, and What Is Unmet.
      ,
      • Fisher VL
      • Tahrani AA.
      Cardiac autonomic neuropathy in patients with diabetes mellitus: current perspectives.
      In this article, we critically review the current literature on the epidemiology, diagnosis, and management whilst differentiating the pathoetiology of CAN in type 1 and 2 diabetes.

      Methods

      A comprehensive literature search using a range of sources, including PubMed Central, the US National Institute of Health's National Library of Medicine, Google Scholar, OVID, and Open Athens, was undertaken before writing this narrative review. We used the following search terms: cardiac autonomic neuropathy, diabetes, microvascular complications, and cardiovascular risk. Inclusion criteria were set to include full text review articles or original research published in peer-reviewed journals that examined the epidemiology, pathogenesis, mortality, diagnosis, and management of CAN in diabetes. Articles that were not published in peer-reviewed journals or had not examined CAN in diabetes were excluded from further review.

      Discussion

      Epidemiology of CAN

      Table I summarizes the main prevalence studies of CAN in patients with diabetes, indicating the wide range of CAN prevalence reported in the literature. This wide variability is attributable to the use of different definitions of CAN, diagnostic tests, and variations of population characteristics, including age, duration of diabetes, and cardiovascular risk factor prevalence. As the sensitivity of the diagnostic criteria increases, so does the prevalence. As the specificity of the diagnostic criteria increases, the prevalence decreases.
      • Trevethan R
      Sensitivity, Specificity, and Predictive Values: Foundations, Pliabilities, and Pitfalls in Research and Practice.
      Ziegler et al found the prevalence of CAN to be 7.7% in a sample of patients with newly diagnosed type 1 diabetes (n = 130), suggestive of an excess prevalence.
      • Ziegler D
      • Gries FA
      • Spuler M
      • Lessmann F.
      The epidemiology of diabetic neuropathy. Diabetic Cardiovascular Autonomic Neuropathy Multicenter Study Group.
      In type 1 diabetes the prevalence varies from 17% to 66%, whereas in type 2 diabetes the prevalence is 31% to 73%.
      • Fisher VL
      • Tahrani AA.
      Cardiac autonomic neuropathy in patients with diabetes mellitus: current perspectives.
      CAN is also present in prediabetes at a higher prevalence of 9% to 38%, which is greater than in normal glucose tolerance groups (0%-18%) as detailed in a recent comprehensive systematic review.
      • Eleftheriadou A
      • Williams S
      • Nevitt S
      • Brown E
      • Roylance R
      • Wilding JPH
      • et al.
      The prevalence of cardiac autonomic neuropathy in prediabetes: a systematic review.
      The Cooperative Health Research in the Region of Augsburg (KORA) S4 survey used a population-based sampling strategy with definitive diagnostics for CAN to determine the prevalence of CAN in people with impaired glucose tolerance (5.9%), impaired fasting glycemia (8.1%), and combined impaired fasting glycaemia and impaired glucose tolerance (11.4%). This finding clearly indicates an excess of CAN in prediabetes when compared with the normoglycemic population whose prevalence was approximately 4%.

      Ziegler D, Voss A, Rathmann W, Strom A, Perz S, Roden M, et al. Increased prevalence of cardiac autonomic dysfunction at different degrees of glucose intolerance in the general population: the KORA S4 survey. 2015;58:1118–28.

      Table IPrevalence of cardiac autonomic neuropathy in diabetes.
      StudyType of DiabetesNo. of PatientsDiagnostic Tests UsedCriteria for DiagnosisPopulationPrevalence, %
      O’Brien et al
      • O'Brien IA
      • O'Hare P
      • Corrall RJ
      Heart rate variability in healthy subjects: effect of age and the derivation of normal ranges for tests of autonomic function.
      Type 1506HRV response to resting, E:I ratio, Valsalva maneuver, 30:15 ratio, CV of HRV≥2 Abnormal test resultsMean age, 45 years; duration of diabetes, 15 years17
      Kempler et al
      • Kempler P
      • Tesfaye S
      • Chaturvedi N
      • Stevens LK
      • Webb DJ
      • Eaton S
      • et al.
      Autonomic neuropathy is associated with increased cardiovascular risk factors: the EURODIAB IDDM Complications Study. Diabetic medicine: a journal of the.
      Type 1301030:15 Ratio, SBP postural decrease≥1 Abnormal test resultEuropean populations; mean age, 32.7 years; duration of diabetes, 14.7 years; mean HbA1c, 6.7%36
      Pop-Busui et al
      • Pop-Busui R
      • Low PA
      • Waberski BH
      • Martin CL
      • Albers JW
      • Feldman EL
      • 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).
      Type 1620 in intensive treatment group,

      591 in conventional treatment group
      E:I ratio, Valsalva maneuver, DBP postural decreaseAbnormal HRV combined with abnormal Valsalva ratio or DBP dropPrimary and secondary care; mean age, 47 years; duration of diabetes, 26 years; mean HbA1c 7.9% (intensive), 7.8% (conventional)29 (intensive treatment group) and

      35 (conventional treatment group)
      Tahrani et al
      • Tahrani AA
      • Dubb K
      • Raymond NT
      • et al.
      Cardiac autonomic neuropathy predicts renal function decline in patients with type 2 diabetes: a cohort study.
      Type 2204E:I ratio, Valsalva maneuver, 30:15 ratio, postural decrease≥2 Abnormal test resultsSecondary care; White European population – 43.6%;

      South Asian population – 56.4%; mean age, 59.5 years; duration of

      diabetes, 15 years; male. 60.5%; female, 39.5%; mean HbA1c, 8.2%
      42.2
      Mendivil et al
      • Mendivil CO
      • Kattah W
      • Orduz A
      • et al.
      Neuropad for the detection of cardiovascular autonomic neuropathy in patients with type 2 diabetes.
      Type 2154E:I ratio, Valsalva maneuver,

      30:15 ratio
      ≥1 Abnormal or borderline test resultsSecondary care; Latin American population; mean age, 61.4 years; duration of diabetes, 12.2 years; mean HbA1c, 7.7%68
      Lerner et al
      • Lerner AG
      • et al.
      The CRONICAS Cohort Study Group
      Type 2 diabetes and cardiac autonomic neuropathy screening using dynamic pupillometry.
      Type 2384Valsalva maneuver, SBP postural decrease, 30:15 ratio, E:I ratio≥2 Abnormal test resultsPrimary and secondary care; Peruvian population; mean age, 57.6 years37
      Low et al

      Low PA, Benrud-Larson LM, Sletten DM, et al. Autonomic Symptoms and Diabetic Neuropathy: A population-based study. Diabetes Care. 2004; 27 (12): 2942–2947.

      Type 1 and type 268 patients with type 1 diabetes, 134 patients with type 2 diabetesSudomotor axon-reflex test, HRV during Valsalva maneuver, SBP postural decrease, 30:15 E:I ratioCASS ≥1 in 2 domains or ≥2 in 1 domain (sudomotor, cardiovagal, adrenergic)Community study (recruited from Rochester Diabetic Neuropathy Study); type 1 diabetes – 100% White; type 2 diabetes – 98% White populations; CASS corrected for confounding effects of age and sex; mean age, 59 years; HbA1c, 7.4% (type 1 diabetes) and 7.2% (type 2 diabetes)54 (patients with type 1 diabetes) and 73 (patients with type 2 diabetes)
      Ziegler et al

      Ziegler D, Voss A, Rathmann W, Strom A, Perz S, Roden M, et al. Increased prevalence of cardiac autonomic dysfunction at different degrees of glucose intolerance in the general population: the KORA S4 survey. 2015;58:1118–28.

      NGT, i-IFG, i-IGT, IFG-IGT, n-DM, k-DM565 NGT, 336 IFG, 72 IGT, 151 IFG-IGT, 78 n-DM, 130 k-DM4 HRV measures and QT variability were computed from supine 5 min ECGs≥2 of 4 abnormal HRV indexesPopulation-based cross-sectional KORA S4 study in GermanyNGT. 4.5;

      i-IFG, 8.1;

      i-IGT, 5.9; IFG-IGT, 11.4;

      n-DM, 11.7; k-DM, 17.5

      (P < 0.05 vs NGT, except for i-IGT)
      CASS = composite autonomic severity score; CV = coefficient of variance; DBP = diastolic blood pressure; E:I = excitation/inhibition; HbA1c = glycated hemoglobin A1c; HRV = heart rate variability; i-IFG = isolated impaired fasting glucose; IFG-IGT = impaired fasting glucose and impaired glucose tolerance; i-IGT = isolated impaired glucose tolerance; k-DM = known diabetes; KORA = Cooperative Health Research in the Region of Augsburg; n-DM = newly detected diabetes; NGT = normal glucose tolerance; SBP = systolic blood pressure.

      Risk Factors for CAN

      The established risk factors for CAN are increasing age, duration of diabetes, glycemic control, hypertension, dyslipidemia, obesity, smoking, and the presence of diabetic microvascular complications (neuropathy, nephropathy or microalbuminuria, and retinopathy).
      • Pop-Busui R
      • Boulton AJM
      • Feldman EL
      • Bril V
      • Freeman R
      • Malik RA
      • et al.
      ,
      • Vinik AI
      • Maser RE
      • Mitchell BD
      • Freeman R.
      ,
      • Spallone V
      • Ziegler D
      • Freeman R
      • et al.
      Cardiovascular autonomic neuropathy in diabetes: clinical impact, assessment, diagnosis, and management.
      ,
      • Tesfaye S
      • Boulton AJM
      • Dyck PJ
      • Freeman R
      • Horowitz M
      • Kempler P
      • et al.
      • Braffett BH
      • Gubitosi-Klug RA
      • Albers JW
      • Feldman EL
      • Martin CL
      • White NH
      • 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.

      Dafaalla MD, Nimir MN, Mohammed MI, Ali OA, Hussein A. Risk factors of diabetic cardiac autonomic neuropathy in patients with type 1 diabetes mellitus: a meta-analysis. 2016;3.

      The prevalence of CAN increases with duration of diabetes and age, increasing by approximately 2% per year in patients with type 1 diabetes.
      • Pop-Busui R
      • Low PA
      • Waberski BH
      • Martin CL
      • Albers JW
      • Feldman EL
      • 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).
      In type 2 diabetes, the annual increase in prevalence of CAN has been estimated at 6%.
      • Vinik AI
      • Freeman R
      • Erbas T.
      Diabetic autonomic neuropathy.
      Poor glycemic control, hypertension, and dyslipidemia increase the risk of developing CAN.
      • Spallone V.
      Update on the Impact, Diagnosis and Management of Cardiovascular Autonomic Neuropathy in Diabetes: What Is Defined, What Is New, and What Is Unmet.
      The Action to Control Cardiovascular Risk in Diabetes (ACCORD) study of patients with type 2 diabetes found that women had a greater prevalence (although overall quite low) of severe CAN (2.2%) compared with men (1.4%), and women also had a greater prevalence of moderate to severe CAN (4.7%) compared with men (2.6%).
      • Pop-Busui R
      • Evans GW
      • Gerstein HC
      • Fonseca V
      • Fleg JL
      • Hoogwerf BJ
      • et al.
      Effects of cardiac autonomic dysfunction on mortality risk in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial.
      In type 1 diabetes, the multicenter study EURODIAB IDDM Complications Study found no significant difference in the prevalence of CAN between men (35%) and women (37%).
      • Kempler P
      • Tesfaye S
      • Chaturvedi N
      • Stevens LK
      • Webb DJ
      • Eaton S
      • et al.
      Autonomic neuropathy is associated with increased cardiovascular risk factors: the EURODIAB IDDM Complications Study. Diabetic medicine: a journal of the.
      Therefore, female gender may be a risk factor for CAN in type 2 diabetes but not in type 1 diabetes.
      • Serhiyenko V
      • Ponomarev A.
      Cardiac Autonomic Neuropathy: Risk Factors, Diagnosis and Treatment.
      However, differences in the sample size between ACCORD (n>8000) and the EURODIAB IDDM Complications Study (n=3250) make direct comparisons less reliable.
      • Serhiyenko V
      • Ponomarev A.
      Cardiac Autonomic Neuropathy: Risk Factors, Diagnosis and Treatment.
      When considering ethnic variations, a recent narrative review detailed a similar prevalence of CAN in South Asians compared with White Europeans.
      • Gupta R
      • Misra A.
      Epidemiology of microvascular complications of diabetes in South Asians and comparison with other ethnicities.

      The Natural History of CAN

      Diabetes is the most common cause of CAN globally.
      • Serhiyenko V
      • Ponomarev A.
      Cardiac Autonomic Neuropathy: Risk Factors, Diagnosis and Treatment.
      ,
      • Tesfaye S
      • Boulton AJM
      • Dyck PJ
      • Freeman R
      • Horowitz M
      • Kempler P
      • et al.
      The vagus (parasympathetic) nerve is the longest nerve; it innervates the myocardium and comprises 75% of all parasympathetic nerve fibers.
      • Goldberger JJ
      • Arora R
      • Buckley U
      • Shivkumar K.
      Autonomic Nervous System Dysfunction.
      Vagal efferents originate from the medulla oblongata, and postganglionic fibers innervate the cardiac atria in cardiac fat pads (via ganglia); subsequent neurotransmission is modulated via a nicotinic receptor.
      • Olshansky B
      • Sabbah HN
      • Hauptman PJ
      • Colucci WS.
      Parasympathetic nervous system and heart failure: pathophysiology and potential implications for therapy.
      Similar to the length-dependent nature of diabetic peripheral neuropathy, the distal part of the vagus nerve is affected first in CAN.
      • Boulton AJM
      • Malik RA
      • Arezzo JC
      • Sosenko JM.
      Diabetic Somatic Neuropathies.
      A reduction in parasympathetic autonomic tone is primarily observed in early CAN as measured through CARTs and indicated by a blunted heart rate variability (HRV). As a result, there is a sympathetic predominance, reflected by a higher resting heart rate.
      • Carnethon MR
      • Yan L
      • Greenland P
      • Garside DB
      • Dyer AR
      • Metzger B
      • et al.
      Resting Heart Rate in Middle Age and Diabetes Development in Older Age.
      Imbalance of the autonomic nervous system develops early in CAN pathogenesis and is associated with increased cardiovascular risk prior to definitive CAN development.
      • Vinik AI
      • Casellini C
      • Parson HK
      • Colberg SR
      • Nevoret ML.
      Cardiac autonomic neuropathy in diabetes: A predictor of cardiometabolic events.
      Sympathetic predominance is exacerbated by insulin resistance, a feature of type 2 diabetes, prediabetes, and MetS.
      • Williams SM
      • Eleftheriadou A
      • Alam U
      • Cuthbertson DJ
      • Wilding JPH.
      Cardiac Autonomic Neuropathy in Obesity, the Metabolic Syndrome and Prediabetes: A Narrative Review.
      In addition, ambulatory blood pressure monitoring indicates loss of circadian rhythm in patients with CAN with predominant nocturnal hypertension.
      • Serhiyenko V
      • Ponomarev A.
      Cardiac Autonomic Neuropathy: Risk Factors, Diagnosis and Treatment.
      Untreated, parasympathetic vagal dysfunction continues to worsen with the subsequent development of resting tachycardia (>100 beats/min) attributable to unopposed sympathetic tone.
      • Ziegler D
      • Buchholz S
      • Sohr C
      • Nourooz-Zadeh J
      • Roden M.
      Oxidative stress predicts progression of peripheral and cardiac autonomic nerve dysfunction over 6 years in diabetic patients.
      ,
      • Herder C
      • Schamarek I
      • Nowotny B
      • Carstensen-Kirberg M
      • Straßburger K
      • Nowotny P
      • et al.
      Inflammatory markers are associated with cardiac autonomic dysfunction in recent-onset type 2 diabetes.
      Patients may describe palpitations at this stage but may also remain completely asymptomatic.
      • Vinik AI
      • Ziegler D.
      Diabetic cardiovascular autonomic neuropathy.
      Consequently, autonomic neuropathy develops in the (shorter) sympathetic plexus as advanced CAN ensues, with reduced sympathetic postural responses leading to postural hypotension.
      • Spallone V.
      Update on the Impact, Diagnosis and Management of Cardiovascular Autonomic Neuropathy in Diabetes: What Is Defined, What Is New, and What Is Unmet.
      Finally, both the parasympathetic and sympathetic nerves are effectively abolished in advanced CAN; thus, the denervated heart has a fixed resting tachycardic rate.
      • Duque A
      • Mediano MFF
      • De Lorenzo A
      • Rodrigues Jr, LF
      Cardiovascular autonomic neuropathy in diabetes: Pathophysiology, clinical assessment and implications.
      Table II summarizes these changes.
      Table IISummary of structural and functional changes in CAN.
      Structural Changes in CANFunctional Changes in CAN
      Progressive length–dependent neuropathy predominantly affecting the vagal nerve initiallySympathetic predominance in early CAN with parasympathetic neuropathy
      Full length of vagal nerve affectedLoss of BP circadian rhythm
      CAN progresses to sympathetic plexus of ANSUnopposed sympathetic tone with resting tachycardia and postural BP decrease in advanced CAN
      Both parasympathetic and sympathetic neuropathy with fibrosisSympathetic and parasympathetic neuropathy with denervated heart and fixed HR
      ANS = autonomic nervous system; BP = blood pressure; CAN = cardiac autonomic neuropathy; HR = heart rate.

      CAN Pathogenesis in Patients With Type 1 and 2 Diabetes

      The primary driver for CAN development in type 1 diabetes is hyperglycemia compared with the multifactorial pathogenesis of CAN in type 2 diabetes.
      The Diabetes C, Complications Trial Research G
      The effect of intensive diabetes therapy on measures of autonomic nervous system function in the Diabetes Control and Complications Trial (DCCT).
      Therefore, the foundation of the management of the prevention of CAN (or its progression) in type 1 diabetes is maintaining optimal glycemic control as found in the Diabetes Control and Complications Trial (DCCT) and Epidemiology of Diabetes Interventions and Complications (EDIC) studies.
      • Pop-Busui R
      • Braffett BH
      • Zinman B
      • Martin C
      • White NH
      • Herman WH
      • et al.
      Cardiovascular Autonomic Neuropathy and Cardiovascular Outcomes in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study.
      ,

      The Effect of Intensive Treatment of Diabetes on the Development and Progression of Long-Term Complications in Insulin-Dependent Diabetes Mellitus. 1993;329:977–86.

      In type 2 diabetes, insulin resistance directly increases sympathetic predominance in early CAN.
      • Pop-Busui R
      • Braffett BH
      • Zinman B
      • Martin C
      • White NH
      • Herman WH
      • et al.
      Cardiovascular Autonomic Neuropathy and Cardiovascular Outcomes in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study.
      Patients with type 2 diabetes have varying vascular risk factors, including dyslipidemia and hypertension, which lead to microvascular pathology.
      • Fisher VL
      • Tahrani AA.
      Cardiac autonomic neuropathy in patients with diabetes mellitus: current perspectives.
      ,

      Ziegler D, Voss A, Rathmann W, Strom A, Perz S, Roden M, et al. Increased prevalence of cardiac autonomic dysfunction at different degrees of glucose intolerance in the general population: the KORA S4 survey. 2015;58:1118–28.

      Hyperglycemia

      Peripheral nerves are covered by a sheath of perineurium; thus, there is a paucity of transperineurial arterioles that penetrate into the endoneurium.
      • Yagihashi S
      • Mizukami H
      • Sugimoto K.
      Mechanism of diabetic neuropathy: Where are we now and where to go?.
      Thus, the vascular supply is sparse, with a higher chance of blood flow dysregulation and interruption in flow.
      • Smith DR
      • Kobrine AI
      • Rizzoli HV.
      Absence of autoregulation in peripheral nerve blood flow.
      Hyperglycemia is a key pathogenetic pathway in the development of CAN through toxic glycosylation products and oxidative stress.
      • Fisher VL
      • Tahrani AA.
      Cardiac autonomic neuropathy in patients with diabetes mellitus: current perspectives.
      Together, these effects result in microvascular endothelial damage in the neuronal capillary networks of the autonomic nervous system, which result in cell stress and apoptosis.
      • Agashe S
      • Petak S.
      Cardiac Autonomic Neuropathy in Diabetes Mellitus.
      Hyperglycemia disrupts the tricarboxylic acid (or Krebs cycle) of normal aerobic cell metabolism because of excessive glucose substrate, leading to excessive production of nicotinamide adenine dinucleotide.
      • Pang L
      • Lian X
      • Liu H
      • Zhang Y
      • Li Q
      • Cai Y
      • et al.
      Understanding Diabetic Neuropathy: Focus on Oxidative Stress.
      This leads to the generation of detrimental reactive oxygen species, namely superoxides.
      • Yan L-J.
      Pathogenesis of chronic hyperglycemia: from reductive stress to oxidative stress.
      Subsequent mitochondrial dysfunction ensues with an additional increase in oxidative stress.
      • Yan L-J.
      Pathogenesis of chronic hyperglycemia: from reductive stress to oxidative stress.
      Reactive oxygen species cellular DNA damage results in abnormally glycosylated proteins and lipids collectively known as advanced glycosylation end products (AGE).
      • Spallone V.
      Update on the Impact, Diagnosis and Management of Cardiovascular Autonomic Neuropathy in Diabetes: What Is Defined, What Is New, and What Is Unmet.
      ,
      • Kalopita S
      • Liatis S
      • Thomakos P
      • Vlahodimitris I
      • Stathi C
      • Katsilambros N
      • et al.
      Relationship between autonomic nervous system function and continuous interstitial glucose measurement in patients with type 2 diabetes.
      AGE damage endothelial structures of the microcapillaries that supply the neurones or nerve fascicles and thus alter the microvascular morphology (eg, pericytes hyperplasia, basement membrane thickening, and reduction in endoneurial capillary lumen volume).
      • Goldin A
      • Beckman JA
      • Schmidt AM
      • Creager MA.
      Advanced Glycation End Products.
      This alteration results in vascular occlusion, endothelial leakage of extracellular fluid, and endothelial dysfunction and inflammation, which result in neuronal ischemia (endoneurial hypoxia) and apoptosis.
      • Pop-Busui R
      • Raffel D
      • Rubenfire M
      • Giri A
      • Byun J
      • Ryan K
      • et al.
      Cardiovascular autonomic neuropathy, oxidative stress and lifestyle intervention in subjects with metabolic syndrome.
      ,
      • Østergaard L
      • Finnerup NB
      • Terkelsen AJ
      • Olesen RA
      • Drasbek KR
      • Knudsen L
      • et al.
      The effects of capillary dysfunction on oxygen and glucose extraction in diabetic neuropathy.
      The posttranslational modification of cell proteins from the DNA damage from oxidative stress also reduces synaptic neurotransmitter cycling, which has been implicated in the increased risk of fatal cardiac arrythmias observed in CAN.
      • Spallone V
      • Ziegler D
      • Freeman R
      • et al.
      Cardiovascular autonomic neuropathy in diabetes: clinical impact, assessment, diagnosis, and management.

      Inflammation

      Both type 2 diabetes and MetS are in a proinflammatory state, which increases the risk of vascular complications and subsequent neuronal ischemia, causing CAN.
      • Ormazabal V
      • Nair S
      • Elfeky O
      • Aguayo C
      • Salomon C
      • Zuñiga FA.
      Association between insulin resistance and the development of cardiovascular disease.
      ,
      • Yagihashi S
      • Mizukami H
      • Sugimoto K.
      Mechanism of diabetic neuropathy: Where are we now and where to go?.
      CAN is associated with measurable increases in inflammatory markers, including C-reactive protein, interleukin (IL) 6, and tumor necrosis factor α, and adipose tissue inflammation.
      • Fisher VL
      • Tahrani AA.
      Cardiac autonomic neuropathy in patients with diabetes mellitus: current perspectives.
      The nature of this relationship and whether it is causative or bidirectional are yet to be confirmed. In a cross-sectional study conducted in Germany on recent-onset type 2 diabetes (<1-year duration of diabetes, n = 352), there was a reduction in HRV associated with higher levels of serum inflammatory markers (IL-18).
      • Herder C
      • Schamarek I
      • Nowotny B
      • Carstensen-Kirberg M
      • Straßburger K
      • Nowotny P
      • et al.
      Inflammatory markers are associated with cardiac autonomic dysfunction in recent-onset type 2 diabetes.
      The Whitehall II study conducted in the United Kingdom also found that increased adiponectin levels were a biomarker of preserved autonomic function only in type 2 diabetes.
      • Hansen CS
      • Vistisen D
      • Jørgensen ME
      • Witte DR
      • Brunner EJ
      • Tabák AG
      • et al.
      Adiponectin, biomarkers of inflammation and changes in cardiac autonomic function: Whitehall II study.
      Conversely, Whitehall II also found that increases in a marker of subclinical inflammation, namely, IL-1, can predict increases in resting heart rate at 5 years in type 2 diabetes.
      • Hansen CS
      • Vistisen D
      • Jørgensen ME
      • Witte DR
      • Brunner EJ
      • Tabák AG
      • et al.
      Adiponectin, biomarkers of inflammation and changes in cardiac autonomic function: Whitehall II study.

      Genetic Associations of CAN

      A number of genes, including ACE, APOE, and TCF7L2, as well as single-nucleotide polymorphisms may determine genetic susceptibility for CAN.
      • Politi C
      • Ciccacci C
      • D'Amato C
      • Novelli G
      • Borgiani P
      • Spallone V
      Recent advances in exploring the genetic susceptibility to diabetic neuropathy.
      A recent study of type 2 diabetes (n = 150) used a genotype-phenotype correlation analysis to find that the GG phenotype of the MIR499A gene contributed to the severity of CAN score (P = 0.001) along with the duration of diabetes (P = 0.035).
      • Fisher VL
      • Tahrani AA.
      Cardiac autonomic neuropathy in patients with diabetes mellitus: current perspectives.
      Individuals with the GG mutation were more likely to develop CAN and experience greater severity of CAN.
      • Ciccacci C
      • Latini A
      • Greco C
      • Politi C
      • D'Amato C
      • Lauro D
      • et al.
      Association between a MIR499A polymorphism and diabetic neuropathy in type 2 diabetes.
      However, modifiable environmental factors may have a greater role in the development of CAN through obesity, insulin resistance, and MetS compared with genetic factors alone.
      • Fisher VL
      • Tahrani AA.
      Cardiac autonomic neuropathy in patients with diabetes mellitus: current perspectives.
      A twin study investigating 101 pairs of twins (63 monozygotic and 38 dizygotic) found no genetic effect on cardiovascular autonomic function after a multivariable-adjusted heritability estimate. Of interest, this study found that the unshared environmental influence, including lifestyle, on cardiovascular autonomic function was high at approximately 85% to 96%.
      • Osztovits J
      • Horváth T
      • Littvay L
      • Steinbach R
      • Jermendy A
      • Tárnoki A
      • et al.
      Effects of genetic vs. environmental factors on cardiovascular autonomic function: a twin study.
      It seems that genetic susceptibility may influence the development of CAN when exposed to the relevant risk factors (hyperglycemia, hyperlipidemia, hypertension, and the MetS phenotype).
      • Serhiyenko V
      • Ponomarev A.
      Cardiac Autonomic Neuropathy: Risk Factors, Diagnosis and Treatment.

      Relationship to Other Organ System Disorders

      Obstructive sleep apnea (OSA) is associated with CAN because they share a common risk factor of obesity.
      • Williams SM
      • Eleftheriadou A
      • Alam U
      • Cuthbertson DJ
      • Wilding JPH.
      Cardiac Autonomic Neuropathy in Obesity, the Metabolic Syndrome and Prediabetes: A Narrative Review.
      OSA may also contribute to the pathophysiology of CAN because OSA leads to recurrent nocturnal arousal and chronic intermittent hypoxia, with activation of the sympathetic nervous system.
      • Spallone V.
      Update on the Impact, Diagnosis and Management of Cardiovascular Autonomic Neuropathy in Diabetes: What Is Defined, What Is New, and What Is Unmet.
      ,
      • Williams SM
      • Eleftheriadou A
      • Alam U
      • Cuthbertson DJ
      • Wilding JPH.
      Cardiac Autonomic Neuropathy in Obesity, the Metabolic Syndrome and Prediabetes: A Narrative Review.
      Chronic intermittent hypoxia leads to sympathetic nervous system overactivity through upregulation of carotid chemoreceptors.
      • Carla G
      • Vincenza S.
      Obstructive Sleep Apnoea Syndrome and Diabetes. Fortuitous Association or Interaction?.
      Continuous positive airway pressure is important in the treatment of OSA and has beneficial effects in early CAN by improving autonomic function, including improving baroreceptor sensitivity.
      • Seetho IW
      • Asher R
      • Parker RJ
      • Craig S
      • Duffy N
      • Hardy KJ
      • et al.
      Effect of CPAP on arterial stiffness in severely obese patients with obstructive sleep apnoea.
      ,
      • Coughlin SR
      • Mawdsley L
      • Mugarza JA
      • Wilding JP
      Calverley PM. Cardiovascular and metabolic effects of CPAP in obese males with OSA.

      Nonalcoholic Fatty Liver Disease

      Nonalcoholic fatty liver disease is a major cause of cirrhosis and hepatocellular carcinoma but has a putative role that potentially contributes to abnormal autonomic function by promoting insulin resistance and sympathetic predominance.
      • Williams SM
      • Eleftheriadou A
      • Alam U
      • Cuthbertson DJ
      • Wilding JPH.
      Cardiac Autonomic Neuropathy in Obesity, the Metabolic Syndrome and Prediabetes: A Narrative Review.
      A recent review article discussed the importance of cirrhosis in creating a hepatic cardiomyopathy that contributes to mortality, with CAN being a component.
      • Arya S
      • Kumar P
      • Tiwari B
      • Belwal S
      • Saxena S
      • Abbas H.
      What Every Intensivist should Know about Impairment of Cardiac Function and Arrhythmias in Liver Disease Patients: A Review.
      In a recent study of type 2 diabetes (n = 264), liver fibrosis was associated with diabetic peripheral neuropathy with a higher nonalcoholic fatty liver disease fibrosis score and Fibrosis 4 index.
      • Kim K
      • Oh TJ
      • Cho HC
      • Lee YK
      • Ahn CH
      • Koo BK
      • et al.
      Liver fibrosis indices are related to diabetic peripheral neuropathy in individuals with type 2 diabetes.
      In addition, serum levels of fetuin A, a hepatokine, were decreased in individuals with an abnormal vibration perception or 10-g monofilament tests.
      • Kim K
      • Oh TJ
      • Cho HC
      • Lee YK
      • Ahn CH
      • Koo BK
      • et al.
      Liver fibrosis indices are related to diabetic peripheral neuropathy in individuals with type 2 diabetes.

      Polycystic Ovarian Syndrome

      Polycystic ovarian syndrome is associated with insulin resistance and abnormal HRV indexes of autonomic function.
      • Williams SM
      • Eleftheriadou A
      • Alam U
      • Cuthbertson DJ
      • Wilding JPH.
      Cardiac Autonomic Neuropathy in Obesity, the Metabolic Syndrome and Prediabetes: A Narrative Review.
      This relationship has been found in a study of individuals newly diagnosed with PCOS (n = 31) who were compared to age-matched control participants.
      • Kuppusamy S
      • Pal GK
      • Habeebullah S
      • Ananthanarayanan PH
      Pal P. Association of sympathovagal imbalance with cardiovascular risks in patients with polycystic ovary syndrome.
      PCOS had significant reductions in HRV and a sympathetic nervous system predominance.
      • Kuppusamy S
      • Pal GK
      • Habeebullah S
      • Ananthanarayanan PH
      Pal P. Association of sympathovagal imbalance with cardiovascular risks in patients with polycystic ovary syndrome.

      Cardiovascular Mortality of CAN

      Numerous studies have demonstrated that CAN is a risk factor for cardiovascular events and mortality. Studies indicate that confirmed CAN leads to a 3-fold increase in 5-year mortality risk compared with those without CAN.
      • Balcıoğlu AS
      • Müderrisoğlu H.
      Diabetes and cardiac autonomic neuropathy: Clinical manifestations, cardiovascular consequences, diagnosis and treatment.
      The EURODIAB prospective cohort study of type 1 diabetes suggested that CAN was the strongest predictor of mortality.
      • Soedamah-Muthu SS
      • Chaturvedi N
      • Witte DR
      • Stevens LK
      • Porta M
      • Fuller JH
      • et al.
      Relationship between risk factors and mortality in type 1 diabetic patients in Europe: the EURODIAB Prospective Complications Study (PCS).
      In the ACCORD trial of type 2 diabetes with confirmed CAN, the mortality was 1.5 to 2 times higher compared with those without CAN.

      Pop-Busui R, Evans GW, Gerstein HC, Fonseca V, Fleg JL, Hoogwerf BJ, et al. Effects of Cardiac Autonomic Dysfunction on Mortality Risk in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Trial. 2010.

      Indeed, our recent meta-analysis found a pooled relative risk (RR) of 3.16 (95% CI, 2.42–4.13; P < 0.0001) (n = 16 studies) of future cardiovascular events in favor of CAN.
      • Chowdhury M
      • Nevitt S
      • Eleftheriadou A
      • et al.
      Cardiac autonomic neuropathy and risk of cardiovascular disease and mortality in type 1 and type 2 diabetes: a meta-analysis.
      Again, all-cause mortality data (n = 19 studies) indicated a pooled RR of 3.17 (95% CI, 2.11–4.78; P < 0.0001) in favor of CAN.
      • Chowdhury M
      • Nevitt S
      • Eleftheriadou A
      • et al.
      Cardiac autonomic neuropathy and risk of cardiovascular disease and mortality in type 1 and type 2 diabetes: a meta-analysis.
      These data are consistent with a previous meta-analysis conducted approximately 20 years ago by Maser et al.
      • Maser RE
      • Mitchell BD
      • Vinik AI
      • Freeman R.
      The Association Between Cardiovascular Autonomic Neuropathy and Mortality in Individuals With Diabetes.
      In addition, there is an established link in the increase of baseline resting heart rate with cardiac events and cardiovascular mortality.
      • Aune D
      • Sen A
      • ó'Hartaigh B
      • Janszky I
      • Romundstad PR
      • Tonstad S
      • et al.
      Resting heart rate and the risk of cardiovascular disease, total cancer, and all-cause mortality - A systematic review and dose-response meta–analysis of prospective studies.
      The ONTARGET (Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial)/TRANSEND (Telmisartan Randomised Assessment Study in ACE Intolerant Subjects With Cardiovascular Disease) trials found that mean resting heart rates >75 to 80 beats/min, which included patients with diabetes, were associated with an increased risk of cardiovascular outcomes (except for stroke). Indeed, the authors suggested that future trials are needed to determine whether heart rate–lowering therapy should be used in patients with diabetes to prevent cardiovascular events.
      • Böhm M
      • Schumacher H
      • Teo KK
      • Lonn EM
      • Mahfoud F
      • Ukena C
      • et al.
      Resting heart rate and cardiovascular outcomes in diabetic and non-diabetic individuals at high cardiovascular risk analysis from the ONTARGET/TRANSCEND trials.
      The BEAUTIFUL study also found that an elevated heart rate (>70 beats/min) identifies patients at increased risk of cardiovascular outcomes in patients with coronary artery disease (approximately one-third had diabetes).
      • Fox K
      • Ford I
      • Steg PG
      • Tendera M
      • Robertson M
      • Ferrari R.
      Heart rate as a prognostic risk factor in patients with coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): a subgroup analysis of a randomised controlled trial.
      Myocardial flow reserve is an important predictor of cardiac mortality and nonfatal myocardial infarction in patients with diabetes.
      • Fisher VL
      • Tahrani AA.
      Cardiac autonomic neuropathy in patients with diabetes mellitus: current perspectives.
      CAN is associated with reduced myocardial flow in both type 1 and type 2 diabetes, which may also underpin the increased cardiovascular events described in patients with diabetes and CAN.
      • Bissinger A.
      Cardiac Autonomic Neuropathy: Why Should Cardiologists Care about That?.

      Diagnosis of CAN

      In addition to the clinical symptoms of CAN described, physical signs of CAN include a resting sinus tachycardia and a postural decrease of at least 20 mm Hg in systolic blood pressure or at least 10 mm Hg in diastolic blood pressure within 3 minutes of standing.
      • Williams SM
      • Eleftheriadou A
      • Alam U
      • Cuthbertson DJ
      • Wilding JPH.
      Cardiac Autonomic Neuropathy in Obesity, the Metabolic Syndrome and Prediabetes: A Narrative Review.
      These signs or the presence of any symptoms should prompt formal diagnostic testing for CAN.
      • Spallone V.
      Update on the Impact, Diagnosis and Management of Cardiovascular Autonomic Neuropathy in Diabetes: What Is Defined, What Is New, and What Is Unmet.
      A high index of suspicion that could be guided by screening scores should prompt diagnostic testing for CAN in asymptomatic individuals to allow early treatment.
      • Serhiyenko V
      • Ponomarev A.
      Cardiac Autonomic Neuropathy: Risk Factors, Diagnosis and Treatment.
      Table III summarizes the various tests for CAN.
      Table IIITests for CAN in patients with diabetes.
      TestANS Components AssessedClinical Interpretation
      Cardiovascular reflex tests
      Ewing protocol

      HR response to deep breathing

      HR response to standing

      HR response to Valsalva maneuver

      Systolic blood pressure response to standing

      Diastolic blood pressure response to sustained handgrip
      Assesses parasympathetic ANS components by testing the ability of the vagal nerve to slow the HR; assesses sympathetic ANS components of sympathetic plexus by assessing ability to increase HR and BP in response to stimuliPractical to perform in clinic; simple to replicate; classifies number of abnormal HR and BP responses
      O'Brien protocol

      HR responses to standing, Valsalva maneuver, and a deep breath are compared with age-adjusted reference ranges
      Parasympathetic and sympathetic ANS components adjusted for age range reference valuesClassifies number of abnormal HR responses adjusted for age reference values
      HRV
      HRV time domain analysisHRV time parameters (between RR intervals); parasympatheticClassifies abnormal HRV responses adjusted for age range
      HRV frequency domain analysisParasympathetic and sympatheticClassifies abnormal HRV responses adjusted for age range
      HRV power spectral analysisCombined sympathetic and parasympathetic represented by different frequency bands

      VLF component representing sympathetic

      LF band representing a combination

      Parasympathetic and sympathetic

      HF band corresponding to parasympathetic
      Classifies abnormal HRV responses

      and clarifies parasympathetic and/or sympathetic damage according to type of abnormal HRV responses (VLF/LF/HF) adjusted for age range
      Spontaneous baroreflex sensitivityParasympathetic and sympathetic; requires continuous blood pressure monitoringExpensive and less available; used for research purposes
      Cardiac radionucleotide imaging

      MIBG scan
      Measures sympathetic innervation of the heart (decreased in CAN)Expensive and less available; used for research purposes
      ANS = autonomic nervous system; BP = blood pressure; CAN = cardiac autonomic neuropathy; HF = high frequency; HR = heart rate; HRV = heart rate variability; LF = low frequency; MIBG = metaiodobenzylguanidine; VLF = very low frequency.

      Screening Scores for CAN

      Two studies using HRV to identify early CAN have developed screening scores that may help identify patients with a greater risk of CAN who may benefit from earlier diagnostic testing. The KORA S4 survey included 1332 participants (age range, 55–74 years) (n = 208 with diabetes).

      Ziegler D, Voss A, Rathmann W, Strom A, Perz S, Roden M, et al. Increased prevalence of cardiac autonomic dysfunction at different degrees of glucose intolerance in the general population: the KORA S4 survey. 2015;58:1118–28.

      This study used a combined score calculated from different cardiovascular variables, including the resting heart rate, the presence or absence of hypertension, body mass index, smoking status, use of drugs that alter HRV, and serum creatinine to predict the risk of CAN identified by HRV.

      Ziegler D, Voss A, Rathmann W, Strom A, Perz S, Roden M, et al. Increased prevalence of cardiac autonomic dysfunction at different degrees of glucose intolerance in the general population: the KORA S4 survey. 2015;58:1118–28.

      The score had a good sensitivity (78%–79%), specificity (81%–83%), and negative predictive value (98%), with a low score indicating an excellent discriminatory ability at ruling out CAN.

      Ziegler D, Voss A, Rathmann W, Strom A, Perz S, Roden M, et al. Increased prevalence of cardiac autonomic dysfunction at different degrees of glucose intolerance in the general population: the KORA S4 survey. 2015;58:1118–28.

      A second study in a Chinese population (n = 2092, n = 446 with diabetes) constructed a simple risk score to predict CAN using age, body mass index, the presence or absence of hypertension, and resting heart rate.
      • Ge X
      • Pan S-M
      • Zeng F
      • Tang Z-H
      • Wang Y-W.
      A Simple Chinese Risk Score Model for Screening Cardiovascular Autonomic Neuropathy.
      This study had a lower sensitivity (69%) and specificity (78%) (73). In principle, patients with a high risk score for CAN could be referred for diagnostic testing and thus earlier interventions. However, further large-scale validation of risk scores is required for wider implementation.

      Methods of Diagnostic Testing

      Cardiovascular reflex tests

      In 1982, Ewing and Clarke

      Ewing DJ, Clarke BF. Diagnosis and management of diabetic autonomic neuropathy. 1982;285:916–8.

      proposed 5 CARTs to objectively assess the parasympathetic and sympathetic nerves of the autonomic nervous system. Each participant's heart rate and blood pressure responses are compared to a normal cut-off value. These tests were later updated with age-adjusted reference ranges in the protocol of O'Brien et al.
      • O'Brien IA
      • O'Hare P
      • Corrall RJ
      Heart rate variability in healthy subjects: effect of age and the derivation of normal ranges for tests of autonomic function.

      HRV

      HRV is determined by combined inputs of the sympathetic and parasympathetic branches of the autonomic nervous system. In healthy individuals, the duration of the RR interval changes with a reference range in consecutive heartbeats, which are measured by time and frequency domain analysis of HRV.
      • Vinik AI
      • Erbas T.
      Diabetic autonomic neuropathy.
      Advanced computer processing produces the power spectrum of HRV frequency domains in which there are 3 major peaks: a very low frequency component, representing the sympathetic nervous system division of autonomic function; the low frequency band, representing a combination of parasympathetic and sympathetic nervous system function; and the high frequency band, corresponding to parasympathetic nervous system function (Figure 1).
      • Vinik AI
      • Erbas T.
      Diabetic autonomic neuropathy.
      Age- and sex-adjusted reference ranges allow for detection of abnormal indexes.
      • Agelink MW
      • Malessa R
      • Baumann B
      • Majewski T
      • Akila F
      • Zeit T
      • et al.
      Standardized tests of heart rate variability: normal ranges obtained from 309 healthy humans, and effects of age, gender, and heart rate.
      Figure 1
      Figure 1Power spectrum of heart rate variability diagram. HF = high frequency; LF = low frequency; VLF = very low frequency.

      Baroreflex sensitivity

      The baroreflex is the primary mechanism for maintaining a stable blood pressure despite changes in body positions and fails in CAN. Baroreflex sensitivity (BRS) uses a continuous synchronized measure of the heart rate and blood pressure to assess the function of the parasympathetic and sympathetic components of the autonomic nervous system.
      • Fisher VL
      • Tahrani AA.
      Cardiac autonomic neuropathy in patients with diabetes mellitus: current perspectives.
      ,
      • Tesfaye S
      • Boulton AJM
      • Dyck PJ
      • Freeman R
      • Horowitz M
      • Kempler P
      • et al.
      BRS is widely used to quantify the vagal component of the reflex, a quantitative index of the chronotropic vagal response to alterations in blood pressure.
      • Schrezenmaier C
      • Singer W
      • Swift NM
      • Sletten D
      • Tanabe J
      • Low PA.
      Adrenergic and Vagal Baroreflex Sensitivity in Autonomic Failure.
      BRS can detect early abnormalities consistent with subclinical CAN before the development of any abnormal traditional cardiovascular reflex test results.
      • Kuehl M
      • Stevens MJ.
      Cardiovascular autonomic neuropathies as complications of diabetes mellitus.

      Myocardial scintigraphy

      Myocardial scintigraphy is a nuclear medicine technique that is a useful tool to assess the structural integrity of presynaptic sympathetic nervous system using 123I-metaiodobenzylguanidine, although this is a costly investigation.
      • Didangelos T
      • Moralidis E
      • Karlafti E
      • Tziomalos K
      • Margaritidis C
      • Kontoninas Z
      • et al.
      A Comparative Assessment of Cardiovascular Autonomic Reflex Testing and Cardiac (123)I-Metaiodobenzylguanidine Imaging in Patients with Type 1 Diabetes Mellitus without Complications or Cardiovascular Risk Factors.
      Myocardial scintigraphy assesses the cardiac sympathetic innervation.
      • Serhiyenko V
      • Ponomarev A.
      Cardiac Autonomic Neuropathy: Risk Factors, Diagnosis and Treatment.
      Several studies have found abnormalities in sympathetic innervation in patients with diabetes through myocardial scintigraphy.
      • Fisher VL
      • Tahrani AA.
      Cardiac autonomic neuropathy in patients with diabetes mellitus: current perspectives.
      ,
      • Vinik AI
      • Ziegler D.
      Diabetic cardiovascular autonomic neuropathy.
      The data collected using myocardial scintigraphy correlate with HRV, which is reduced in CAN, but myocardial scintigraphy has a greater sensitivity to detect abnormalities in sympathetic neuronal structure and function.
      • Bernardi L
      • Spallone V
      • Stevens M
      • Hilsted J
      • Frontoni S
      • Pop-Busui R
      • et al.
      Investigation methods for cardiac autonomic function in human research studies.
      However, because of the complexity of this diagnostic modality, it remains primarily used in a research context only.

      Corneal confocal microscopy as a surrogate for CAN

      Corneal confocal microscopy (CCM) is an ophthalmic imaging technique that images corneal nerve fiber (C fibers) length and density in a rapid, quantitative, reiterative, and noninvasive fashion.
      • Yan A
      • Issar T
      • Tummanapalli SS
      • Markoulli M
      • Kwai NCG
      • Poynten AM
      • et al.
      Relationship between corneal confocal microscopy and markers of peripheral nerve structure and function in Type 2 diabetes.
      • Dhage S
      • Ferdousi M
      • Adam S
      • Ho JH
      • Kalteniece A
      • Azmi S
      • et al.
      Corneal confocal microscopy identifies small fibre damage and progression of diabetic neuropathy.
      • Iqbal Z
      • Azmi S
      • Yadav R
      • Ferdousi M
      • Kumar M
      • Cuthbertson DJ
      • et al.
      Diabetic Peripheral Neuropathy: Epidemiology, Diagnosis, and Pharmacotherapy.
      Originally used for research, CCM has rapidly developed into a diagnostic tool for assessing the corneal subbasal nerve plexus.
      • Williams SM
      • Eleftheriadou A
      • Alam U
      • Cuthbertson DJ
      • Wilding JPH.
      Cardiac Autonomic Neuropathy in Obesity, the Metabolic Syndrome and Prediabetes: A Narrative Review.
      Corneal nerve fiber density, measured by CCM, is significantly reduced in CAN and correlates with HRV during deep breathing (r = − 0.55, P = 0.02), and corneal nerve fibre length correlates with the excitation/inhibition ratio during deep breathing (r = 0.68, p = 0.002) in 19 patients with diabetes.
      • Dhage S
      • Ferdousi M
      • Adam S
      • Ho JH
      • Kalteniece A
      • Azmi S
      • et al.
      Corneal confocal microscopy identifies small fibre damage and progression of diabetic neuropathy.
      In a study of type 1 diabetes (n = 89), corneal nerve fiber length quantified by CCM correlates with HRV during deep breathing (r = 1.84, P = 0.0002).
      • Orlov S
      • Bril V
      • Orszag A
      • Perkins BA.
      Heart Rate Variability and Sensorimotor Polyneuropathy in Type 1 Diabetes.
      CCM has also produced promising results with a high-excellent diagnostic sensitivity of 86% to 100% and specificity of 56% to 78% for CAN.
      • Tavakoli M
      • Begum P
      • McLaughlin J
      • Malik RA.
      Corneal confocal microscopy for the diagnosis of diabetic autonomic neuropathy.
      The range in sensitivity and specificity of CCM for the diagnosis of CAN are related to the different parameters of CCM measured, including corneal nerve fiber length, density and branch density.
      • Wang M
      • Zhang C
      • Zuo A
      • Li L
      • Chen L
      • Hou X.
      Diagnostic utility of corneal confocal microscopy in type 2 diabetic peripheral neuropathy.
      CCM is emerging as a useful surrogate for identifying early CAN.
      • Efron N.
      Corneal Confocal Microscopy Is Emerging as a Powerful Diagnostic Tool for Assessing Systemic Neurologic Disease.
      However, further research is required that involves larger studies that incorporate people with a spectrum of CAN compared with sensitive autonomic indexes, including HRV and BRS, to ensure CCM is developed into a reliable outpatient surrogate.
      • Misra SL
      • Craig JP
      • Patel DV
      • McGhee CN
      • Pradhan M
      • Ellyett K
      • et al.
      In Vivo Confocal Microscopy of Corneal Nerves: An Ocular Biomarker for Peripheral and Cardiac Autonomic Neuropathy in Type 1 Diabetes Mellitus.
      ,
      • Lovblom LE
      • Halpern EM
      • Wu T
      • Kelly D
      • Ahmed A
      • Boulet G
      • et al.
      In Vivo Corneal Confocal Microscopy and Prediction of Future-Incident Neuropathy in Type 1 Diabetes: A Preliminary Longitudinal Analysis.

      CAN Diagnostic Criteria

      The CAN Subcommittee of the Toronto Consensus Panel recommends the 4 gold standard tests for CAN are the CARTs of the heart rate response to deep breathing, standing, and Valsalva maneuver and blood pressure response to standing.
      • Spallone V
      • Ziegler D
      • Freeman R
      • et al.
      Cardiovascular autonomic neuropathy in diabetes: clinical impact, assessment, diagnosis, and management.
      Multiple abnormalities in cardiac autonomic function indexes are more reliable and preferable for diagnosis, and there is no superiority of any single test.
      • Spallone V.
      Update on the Impact, Diagnosis and Management of Cardiovascular Autonomic Neuropathy in Diabetes: What Is Defined, What Is New, and What Is Unmet.
      CAN is staged in 3 categories: (1) possible or early CAN (1 abnormal CART result), (2) definite or confirmed CAN (2–3 abnormal CART results), and (3) severe advanced CAN (orthostatic hypotension in addition to ≥2 abnormal cardiovascular reflex test results).
      The Toronto Consensus recommends universal screening for symptoms and signs of CAN in all patients with diabetes.
      • Pop-Busui R
      • Boulton AJM
      • Feldman EL
      • Bril V
      • Freeman R
      • Malik RA
      • et al.
      , The American Association of Clinical Endocrinologists proposes screening for CAN in all patients with type 2 diabetes from diagnosis and in all patients with type 1 diabetes of >5 years’ duration.
      • Spallone V.
      Update on the Impact, Diagnosis and Management of Cardiovascular Autonomic Neuropathy in Diabetes: What Is Defined, What Is New, and What Is Unmet.
      Currently, in the United Kingdom and many other countries, CAN screening is not routinely performed.
      • Duque A
      • Mediano MFF
      • De Lorenzo A
      • Rodrigues Jr, LF
      Cardiovascular autonomic neuropathy in diabetes: Pathophysiology, clinical assessment and implications.
      ,
      • Vinik AI
      • Camacho PM
      • Davidson JA
      • Handelsman Y
      • Lando HM
      • Leddy AL
      • et al.
      American Association of Clinical Endocrinologists and American College of Endocrinology Position Statement on Testing for Autonomic and Somatic Nerve Dysfunction.

      Treatment of CAN

      Early treatment is essential after diagnosis. Treatment should not be delayed until the symptoms and signs of CAN occur because these findings unfortunately indicate the advanced stages of CAN, when there is a lack of reversibility.
      • Spallone V
      • Bellavere F
      • Scionti L
      • et al.
      Recommendations for the use of cardiovascular tests in diagnosing diabetic autonomic neuropathy.
      Early management, including risk factor modification, should be commenced before definitive, irreversible CAN develops. The treatment in type 1 and type 2 diabetes differs because of the divergent underlying pathoetiology in these populations.
      • Spallone V.
      Update on the Impact, Diagnosis and Management of Cardiovascular Autonomic Neuropathy in Diabetes: What Is Defined, What Is New, and What Is Unmet.

      CAN in Type 1 Diabetes

      The primary component of CAN management (prevention) is the optimization of glycemic control using intensive insulin therapy early in the management of type 1 diabetes. This process has been found by the DCCT, which used an intensive insulin therapy arm for a mean period of 6.5 years, and the DCCT-EDIC, which had extended follow-up to 13 to 14 years.
      • Pop-Busui R
      • Braffett BH
      • Zinman B
      • Martin C
      • White NH
      • Herman WH
      • et al.
      Cardiovascular Autonomic Neuropathy and Cardiovascular Outcomes in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study.
      ,
      Intensive Diabetes Treatment and Cardiovascular Disease in Patients with Type 1 Diabetes.
      The DCCT and EDIC found a long-term reduction in CAN prevalence to 28.9% in the intensively treated arm compared with 35.2% in the conventional treatment arm (P = 0.018) which persisted 8 years after the original DCCT intervention.
      • Pop-Busui R
      • Braffett BH
      • Zinman B
      • Martin C
      • White NH
      • Herman WH
      • et al.
      Cardiovascular Autonomic Neuropathy and Cardiovascular Outcomes in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study.
      Both DCCT and EDIC have also found that cardiovascular risk factors, including hypertension, hypercholesterolemia, hypertriglyceridemia, diabetes duration, and history of smoking, increase the risk of cardiac events in type 1 diabetes.
      • Pop-Busui R
      • Braffett BH
      • Zinman B
      • Martin C
      • White NH
      • Herman WH
      • et al.
      Cardiovascular Autonomic Neuropathy and Cardiovascular Outcomes in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study.
      ,
      Risk Factors for Cardiovascular Disease in Type 1 Diabetes.
      In addition, there should be a focus on the optimization of modifiable cardiovascular risk factors in addition to glycemic control in patients with type 1 diabetes.
      • Spallone V.
      Update on the Impact, Diagnosis and Management of Cardiovascular Autonomic Neuropathy in Diabetes: What Is Defined, What Is New, and What Is Unmet.

      CAN in Type 2 Diabetes

      The treatment of CAN in patients with type 2 diabetes requires a multifaceted approach.
      • Williams SM
      • Eleftheriadou A
      • Alam U
      • Cuthbertson DJ
      • Wilding JPH.
      Cardiac Autonomic Neuropathy in Obesity, the Metabolic Syndrome and Prediabetes: A Narrative Review.
      Treatment requires lifestyle interventions with alterations to diet and exercise and pharmacologic interventions in selected patients with type 2 diabetes.
      • Gæde P
      • Oellgaard J
      • Carstensen B
      • Rossing P
      • Lund-Andersen H
      • Parving HH
      • et al.
      Years of life gained by multifactorial intervention in patients with type 2 diabetes mellitus and microalbuminuria: 21 years follow-up on the Steno-2 randomised trial.
      Lifestyle interventions are also important for the prevention of CAN in patients with prediabetes before the onset of type 2 diabetes as found in the Diabetes Prevention Programme study.
      • Carnethon MR
      • Prineas RJ
      • Temprosa M
      • Zhang ZM
      • Uwaifo G
      • Molitch ME.
      The association among autonomic nervous system function, incident diabetes, and intervention arm in the Diabetes Prevention Program.
      In addition, recent data suggest that sodium-glucose cotransporter 2 inhibitors (SGLT2i) may have a modulating effect on the autonomic nervous system as noted by reduced blood pressure without alterations in heart rate, signifying a reduction in sympathetic drive.
      • Lopaschuk GD
      • Verma S.
      Mechanisms of Cardiovascular Benefits of Sodium Glucose Co-Transporter 2 (SGLT2) Inhibitors: A State-of-the-Art Review.

      Lifestyle Interventions

      Dietary Interventions

      Improvement in cardiac autonomic function had been demonstraed through weight loss delivered by two differing calorie restricted diets during 8 weeks in people living with obesity with concomitant type 2 diabetes.
      • Ziegler D
      • Strom A
      • Nowotny B
      • Zahiragic L
      • Nowotny PJ
      • Carstensen-Kirberg M
      • et al.
      Effect of Low-Energy Diets Differing in Fiber, Red Meat, and Coffee Intake on Cardiac Autonomic Function in Obese Individuals With Type 2 Diabetes.
      The first diet used high content of cereal fiber and coffee with no red meat; the second diet was high in red meat and low in fiber with no coffee. Both diets were used to reduce energy intake by a mean of 1198 kJ, leading to 5 to 6 kg of weight loss with associated improvements in cardiac autonomic function.
      • Williams SM
      • Eleftheriadou A
      • Alam U
      • Cuthbertson DJ
      • Wilding JPH.
      Cardiac Autonomic Neuropathy in Obesity, the Metabolic Syndrome and Prediabetes: A Narrative Review.
      ,
      • Ziegler D
      • Strom A
      • Nowotny B
      • Zahiragic L
      • Nowotny PJ
      • Carstensen-Kirberg M
      • et al.
      Effect of Low-Energy Diets Differing in Fiber, Red Meat, and Coffee Intake on Cardiac Autonomic Function in Obese Individuals With Type 2 Diabetes.
      Reduction in energy intake leading to weight loss was more important than the type of diet administered.
      • Sjoberg N
      • Brinkworth GD
      • Wycherley TP
      • Noakes M
      • Saint DA.
      Moderate weight loss improves heart rate variability in overweight and obese adults with type 2 diabetes.

      Exercise Interventions

      A systematic review of exercise interventions in type 2 diabetes found that 15 (of the 18) studies showed improvements in cardiac autonomic function using exercise interventions.
      • Bhati P
      • Shenoy S
      • Hussain ME.
      Exercise training and cardiac autonomic function in type 2 diabetes mellitus: A systematic review.
      All types of physical activity, including lower intensity activity, such as walking, and moderate-intensity endurance activity, including running and aerobic exercise, have demonstrable improvements in measurements of cardiac autonomic function, including HRV.
      • Fisher VL
      • Tahrani AA.
      Cardiac autonomic neuropathy in patients with diabetes mellitus: current perspectives.
      Significant improvements in HRV indexes were found after 6 months of an aerobic exercise training program conducted 3 times per week to an intensity of 70% to 85% of an each individual participant's heart rate reserve.
      • Pagkalos M
      • Koutlianos N
      • Kouidi E
      • Pagkalos E
      • Mandroukas K
      • Deligiannis A.
      Heart rate variability modifications following exercise training in type 2 diabetic patients with definite cardiac autonomic neuropathy.
      A shorter exercise intervention of 8 weeks also improved HRV in a small number of participants (n = 12) using a smartphone application.
      • Stuckey MI
      • Kiviniemi AM
      • Petrella RJ.
      Diabetes and Technology for Increased Activity Study: The Effects of Exercise and Technology on Heart Rate Variability and Metabolic Syndrome Risk Factors.
      Smartphone applications may provide a method of individualized support by allowing patients to monitor their progress, and providing support is important in successful lifestyle interventions.
      • Jeffrey B
      • Bagala M
      • Creighton A
      • Leavey T
      • Nicholls S
      • Wood C
      • et al.
      Mobile phone applications and their use in the self-management of Type 2 Diabetes Mellitus: a qualitative study among app users and non-app users.
      ,
      • Doupis J
      • Festas G
      • Tsilivigos C
      • Efthymiou V
      • Kokkinos A.
      Smartphone-Based Technology in Diabetes Management.

      Combined Diet and Exercise Interventions

      A combined lifestyle intervention in a cohort with prediabetes, including 20 to 30 minutes of activity on at least 5 days per week, with the aim of 7% weight loss and successfully improved cardiac autonomic function in the Diabetes Prevention Program.
      The Diabetes Prevention Program
      Design and methods for a clinical trial in the prevention of type 2 diabetes.
      ,
      The Diabetes Prevention Program (DPP): description of lifestyle intervention.
      This combined lifestyle intervention in a prediabetes population (n = 1079) produced improvements in HRV and was associated with an overall 58% reduction in the incidence of diabetes, which was superior to pharmacotherapy with metformin.
      The Diabetes Prevention Program (DPP): description of lifestyle intervention.

      Bariatric Surgery

      The use of bariatric surgery to achieve weight loss in severely obese patients with type 2 diabetes (n = 17) improves measurements of cardiac autonomic function using HRV and Sudoscan testing (measure of sudomotor function).
      • Casellini CM
      • Parson HK
      • Hodges K
      • Edwards JF
      • Lieb DC
      • Wohlgemuth SD
      • et al.
      Bariatric Surgery Restores Cardiac and Sudomotor Autonomic C-Fiber Dysfunction towards Normal in Obese Subjects with Type 2 Diabetes.
      However, vitamin B12 deficiency caused by malabsorption is common after bariatric surgery and may worsen an autonomic neuropathy and function; therefore, monitoring of and replacement of vitamin B12 (and other micronutrients) after surgery is necessary.
      • Williams SM
      • Eleftheriadou A
      • Alam U
      • Cuthbertson DJ
      • Wilding JPH.
      Cardiac Autonomic Neuropathy in Obesity, the Metabolic Syndrome and Prediabetes: A Narrative Review.
      Unfortunately, orthostatic intolerance may be frequent after bariatric surgery, in 1 study affecting 4.2% of patients within the first 5 years postoperatively.
      • Zhang JB
      • Tamboli RA
      • Albaugh VL
      • Williams DB
      • Kilkelly DM
      • Grijalva CG
      • et al.
      The incidence of orthostatic intolerance after bariatric surgery.
      In 13% of patients with orthostatic intolerance after bariatric surgery, evidence of impaired sympathetic vasoconstriction activity was found; 16.5% with severe symptoms required treatment with vasopressor agents.
      • Zhang JB
      • Tamboli RA
      • Albaugh VL
      • Williams DB
      • Kilkelly DM
      • Grijalva CG
      • et al.
      The incidence of orthostatic intolerance after bariatric surgery.
      However, a recent systematic review and meta-analysis found improvement in overall cardiac autonomic function (sympathetic and parasympathetic) after bariatric surgery with limited or low-quality data on orthostatic intolerance.
      • Al Nou'mani J
      • Al Alawi AM
      • Falhammar H
      • Al Qassabi A
      Orthostatic intolerance after bariatric surgery: A systematic review and meta-analysis.

      Glycemic Control

      Optimizing glycemic control in type 2 diabetes prevents CAN as a part of a multifaceted approach.
      • Martin CL
      • Albers JW
      • Pop-Busui R
      However, it is important to avoid excessively intensive glycemic control in patients with type 2 diabetes with increased cardiovascular risk (eg, ischemic heart disease) because the ACCORD trial found increased cardiovascular mortality in this subgroup, leading to the premature cessation of the trial.
      • Gerstein HC
      • Miller ME
      • Byington RP
      • Goff Jr., DC
      • Bigger JT
      • Buse JB
      • et al.
      Effects of intensive glucose lowering in type 2 diabetes.
      Of interest, a more recent analysis of the ACCORD results found that intensive glycemic control in patients with type 2 diabetes with no previous history of cardiovascular disease reduced the risk of CAN by 16% (P = 0.003) compared with standard glycemic control.
      • Tang Y
      • Shah H
      • Bueno Junior CR
      • Sun X
      • Mitri J
      • Sambataro M
      • et al.
      Intensive Risk Factor Management and Cardiovascular Autonomic Neuropathy in Type 2 Diabetes: The ACCORD Trial.
      A target glycated hemoglobin A1c (HbA1c) of 48 to 58 mmol/mol is appropriate in the absence of other risk factors for cardiovascular disease.
      • Williams SM
      • Eleftheriadou A
      • Alam U
      • Cuthbertson DJ
      • Wilding JPH.
      Cardiac Autonomic Neuropathy in Obesity, the Metabolic Syndrome and Prediabetes: A Narrative Review.
      However, individualized targets are recommended in a risk-benefit decision balanced against the risks of hypoglycemia.
      • Gerstein HC
      • Miller ME
      • Byington RP
      • Goff Jr., DC
      • Bigger JT
      • Buse JB
      • et al.
      Effects of intensive glucose lowering in type 2 diabetes.

      Control of Cardiovascular Risk Factors

      To prevent the development of CAN in patients with diabetes, it is essential to address modifiable cardiovascular risk factors alongside hyperglycemia, including the management of hypertension.
      • Piepoli MF
      • Hoes AW
      • Agewall S
      • Albus C
      • Brotons C
      • Catapano AL
      • et al.
      2016 European Guidelines on cardiovascular disease prevention in clinical practice: The Sixth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of 10 societies and by invited experts)Developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR).
      National Institute for Health and Care Excellence guidance in the United Kingdom recommends that treatment with medication should be considered after lifestyle interventions for patients with diabetes with a blood pressure of ≥140/80 mm Hg.

      NICE. Type 1 diabetes in adults: diagnosis and management [NG17]. 2015.

      ,

      NICE. Type 2 diabetes in adults: management [CG28]. 2015.

      Patients with type 1 diabetes for ≥10 years or those older than 40 years and patients with type 2 diabetes with a QRISK2 score for developing cardiovascular disease of ≥10% for 10 years should receive treatment using lipid modification therapy with statins.

      NICE. Type 1 diabetes in adults: diagnosis and management [NG17]. 2015.

      ,

      NICE. Type 2 diabetes in adults: management [CG28]. 2015.

      Smoking cessation support should be provided.
      • Spallone V
      • Ziegler D
      • Freeman R
      • et al.
      Cardiovascular autonomic neuropathy in diabetes: clinical impact, assessment, diagnosis, and management.

      Combined Lifestyle and Pharmacologic Interventions

      Managing cardiovascular risk factors, including optimizing blood pressure and dyslipidemia, using both lifestyle and pharmacologic interventions in a multifaceted approach is an essential approach.
      • Serhiyenko V
      • Ponomarev A.
      Cardiac Autonomic Neuropathy: Risk Factors, Diagnosis and Treatment.
      The effects of a multifaceted treatment strategy are clearly supported by the significant benefits observed in type 2 diabetes with early microvascular complications (microalbuminuria) noted in the follow-up of the STENO-2 (Intensified Multifactorial Intervention in Patients With Type 2 Diabetes and Microalbuminuria) trial.
      • Neal B
      • Perkovic V
      • Mahaffey KW
      • de Zeeuw D
      • Fulcher G
      • Erondu N
      • et al.
      Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes.
      • Zinman B
      • Wanner C
      • Lachin JM
      • Fitchett D
      • Bluhmki E
      • Hantel S
      • et al.
      Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes.
      • Marso SP
      • Daniels GH
      • Brown-Frandsen K
      • Kristensen P
      • Mann JFE
      • Nauck MA
      • et al.
      This randomized controlled trial used a target-driven intensified lifestyle and multimodal approach, including pharmacologic intervention for 7.8 years that optimized glycemic control, blood pressure, and lipids. The median 7.9 years of life gained at 21.2 years of follow-up were mirrored by a 68% risk reduction for CAN progression and time free from cardiovascular events.
      • Gæde P
      • Oellgaard J
      • Carstensen B
      • Rossing P
      • Lund-Andersen H
      • Parving HH
      • et al.
      Years of life gained by multifactorial intervention in patients with type 2 diabetes mellitus and microalbuminuria: 21 years follow-up on the Steno-2 randomised trial.
      ,
      • Gaede P
      • Vedel P
      • Larsen N
      • Jensen GV
      • Parving HH
      • Pedersen O.
      Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes.

      Pharmacologic Intervention With Effects on the Cardiac Autonomic Nervous System

      Metformin

      Metformin improves insulin sensitivity and reduces hepatic gluconeogenesis, leading to a decrease in the increase of postprandial insulin concentrations. This process leads to a reduction in insulin-mediated sympathetic nervous system activation, which may be beneficial in helping to improve cardiac autonomic function.
      • Kern W
      • Peters A
      • Born J
      • Fehm HL
      • Schultes B.
      Changes in blood pressure and plasma catecholamine levels during prolonged hyperinsulinemia.
      Improvements in HRV indexes, including an increase in mean [SD] total power (2711 [395] msec
      • Pop-Busui R
      • Boulton AJM
      • Feldman EL
      • Bril V
      • Freeman R
      • Malik RA
      • et al.
      at baseline vs 2915 [348] msec
      • Pop-Busui R
      • Boulton AJM
      • Feldman EL
      • Bril V
      • Freeman R
      • Malik RA
      • et al.
      after metformin; P = 0.05) and mean high frequency (22.4 [1.8] nu at baseline vs 23.6 [2.1] nu after metformin; P = 0.05), with a mean reduction in low frequency (68.6 [1.5] nu at baseline vs 52.1 [1.1] after metformin; P = 0.05), representing a reduction in sympathetic predominance, and improved parasympathetic function have been found after commencing use of metformin in the treatment of type 2 diabetes (n = 60).
      • Miles JM
      • Rule AD
      • Borlaug BA.
      Use of metformin in diseases of aging.
      ,
      • Manzella D
      • Grella R
      • Esposito K
      • Giugliano D
      • Barbagallo M
      • Paolisso G.
      Blood pressure and cardiac autonomic nervous system in obese type 2 diabetic patients: Effect of metformin administration*.
      Metformin also improved HRV midway between changes in the lifestyle and placebo groups in QT indexes, the SD of NN intervals, and the root mean square of successive differences between normal heartbeats in the Diabetes Prevention Program study.
      • Carnethon MR
      • Prineas RJ
      • Temprosa M
      • Zhang Z-M
      • Uwaifo G
      • Molitch ME
      • et al.
      The association among autonomic nervous system function, incident diabetes, and intervention arm in the Diabetes Prevention Program.

      SGLT2i

      Data from cardiovascular outcomes trials in SGLT2i reveal several clear themes, including a reduction in admission to hospital with heart failure but also a reduction in heart failure– and arrhythmia-related sudden cardiac deaths.
      • Neal B
      • Perkovic V
      • Mahaffey KW
      • de Zeeuw D
      • Fulcher G
      • Erondu N
      • et al.
      Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes.
      ,
      • Zinman B
      • Wanner C
      • Lachin JM
      • Fitchett D
      • Bluhmki E
      • Hantel S
      • et al.
      Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes.
      ,
      • McMurray JJV
      • Solomon SD
      • Inzucchi SE
      • Køber L
      • Kosiborod MN
      • Martinez FA
      • et al.
      Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction.
      ,
      • Fernandes GC
      • Fernandes A
      • Cardoso R
      • Penalver J
      • Knijnik L
      • Mitrani RD
      • et al.
      Association of SGLT2 inhibitors with arrhythmias and sudden cardiac death in patients with type 2 diabetes or heart failure: A meta-analysis of 34 randomized controlled trials.
      A meta-analysis including 25 placebo randomized controlled trials of canagliflozin, dapagliflozin, empagliflozin, or ertugliflozin found that overall SGLT2i therapy significantly reduced the risk of sudden cardiac death (odds ratio = 0.72; 95% CI, 0.54–0.97; P = 0.03) when compared with the control group.
      • Fernandes GC
      • Fernandes A
      • Cardoso R
      • Penalver J
      • Knijnik L
      • Mitrani RD
      • et al.
      Association of SGLT2 inhibitors with arrhythmias and sudden cardiac death in patients with type 2 diabetes or heart failure: A meta-analysis of 34 randomized controlled trials.
      The mechanisms by which SGLT2is mediate this reduction in cardiovascular death and heart failure is yet to be fully elucidated but clearly extends beyond glycemic control.
      • McMurray JJV
      • Solomon SD
      • Inzucchi SE
      • Køber L
      • Kosiborod MN
      • Martinez FA
      • et al.
      Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction.
      The EMPA-REG outcome trial (BI 10773 (Empagliflozin) Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) of empagliflozin found a modest reduction in blood pressure in the absence of increased heart rate,
      • Zinman B
      • Wanner C
      • Lachin JM
      • Fitchett D
      • Bluhmki E
      • Hantel S
      • et al.
      Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes.
      signaling a reduction in sympathetic tone.
      • Kishi T.
      Heart failure as an autonomic nervous system dysfunction.
      Indeed, dapagliflozin reduces the expression of the sympathetic nervous system neurotransmitter noradrenaline in the kidney and heart, improving renal blood flow independently of its glucose-lowering effect.
      • van Bommel EJM
      • Smits MM
      • Ruiter D
      • Muskiet MHA
      • Kramer MHH
      • Nieuwdorp M
      • et al.
      Effects of dapagliflozin and gliclazide on the cardiorenal axis in people with type 2 diabetes.
      ,
      • Scheen AJ.
      Effect of SGLT2 Inhibitors on the Sympathetic Nervous System and Blood Pressure.
      The EMBODY randomized controlled trial investigated the effects of empagliflozin on cardiac sympathetic and parasympathetic nerve activity (using HRV and heart rate turbulence) in patients with acute myocardial infarction with type 2 diabetes. Significant improvement was noted in heart rate turbulence with empagliflozin (P = 0.01); however, no significant difference was found in change between empagliflozin and placebo groups.
      • Shimizu W
      • Kubota Y
      • Hoshika Y
      • Mozawa K
      • Tara S
      • Tokita Y
      • et al.
      Effects of empagliflozin versus placebo on cardiac sympathetic activity in acute myocardial infarction patients with type 2 diabetes mellitus: the EMBODY trial.
      More recently, the SCAN study

      Sardu C, Massimo Massetti M, Rambaldi P, Gatta G, Cappabianca S, Sasso FC, Santamaria M, Volpicelli M, Ducceschi V, Signoriello G, Paolisso G, Marfella R. SGLT2-inhibitors reduce the cardiac autonomic neuropathy dysfunction and vaso-vagal syncope recurrence in patients with type 2 diabetes mellitus: the SCAN study. Metabolism. 2022 Jun 19:155243. https://doi.org/10.1016/j.metabol.2022.155243. Epub ahead of print. PMID: 35732222.

      demonstrated that SGLT2i reduce cardiac autonomic neuropathy dysfunction and vaso-vagal syncope recurrence in patients with type 2 diabetes mellitus. SGLT2is represent a key pharmacological component of a multifaceted approach for reducing cardiovasular disease events and possibly the development of CAN with the latter requiring further research.
      • Brown E
      • Rajeev SP
      • Cuthbertson DJ
      • Wilding JPH.
      A review of the mechanism of action, metabolic profile and haemodynamic effects of sodium-glucose co-transporter-2 inhibitors.
      Future research needs to evaluate the role of sympathetic control of kidney function and renal afferent nerve and the subsequent response to SGLT2is on blood pressure and HRV.

      Glucagon-like Peptide 1 Receptor Agonists

      Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) have a beneficial weight-lowering effect in type 2 diabetes associated with a reduction in cardiovascular mortality.
      • Marso SP
      • Daniels GH
      • Brown-Frandsen K
      • Kristensen P
      • Mann JFE
      • Nauck MA
      • et al.
      In the LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results) trial, during a median follow-up period of 3.8 years, a reduction in death from cardiovascular causes, nonfatal myocardial infarction, and nonfatal stroke was found in 13% of patients treated with liraglutide compared with 14.9% of the placebo group (P = 0.01 for the superiority of liraglutide).
      • Marso SP
      • Daniels GH
      • Brown-Frandsen K
      • Kristensen P
      • Mann JFE
      • Nauck MA
      • et al.
      However, unlike the putative reduction in sympathetic drive of SGLT2is, GLP-1RAs result in an increase in heart rate with a possible reduction in HRV of uncertain significance.
      • Spallone V.
      Update on the Impact, Diagnosis and Management of Cardiovascular Autonomic Neuropathy in Diabetes: What Is Defined, What Is New, and What Is Unmet.
      ,
      • Valensi P
      • Chiheb S
      • Fysekidis M.
      Insulin- and glucagon-like peptide-1-induced changes in heart rate and vagosympathetic activity: why they matter.
      There is a proven beneficial effect of GLP-1RAs in reducing cardiovascular mortality, which overall suggests that their beneficial effects on weight loss, glycemic control, and improved satiety outweigh any putative promotion of sympathetic predominance.
      • Brown E
      • Wilding JPH
      • Barber TM
      • Alam U
      • Cuthbertson DJ.
      Weight loss variability with SGLT2 inhibitors and GLP-1 receptor agonists in type 2 diabetes mellitus and obesity: Mechanistic possibilities.
      Therefore, GLP-1RAs will remain an important medication in patients with type 2 diabetes with established cardiovascular disease or those at risk. Further research is required to examine the potential benefit of GLP-1RAs in specifically preventing or reversing CAN.

      Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers

      Angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers are the first-line drug class of choice for hypertension and microalbuminuria in diabetes and may have a beneficial role in preventing CAN.

      NICE. Type 1 diabetes in adults: diagnosis and management [NG17]. 2015.

      ,

      NICE. Type 2 diabetes in adults: management [CG28]. 2015.

      ,
      • Didangelos T
      • Veves A.
      Treatment of Diabetic Cardiovascular Autonomic, Peripheral and Painful Neuropathy. Focus on the Treatment of Cardiovascular Autonomic Neuropathy with ACE Inhibitors.
      Enalapril has produced reductions in cardiac neurohormone levels of noradrenaline, which could be protective against CAN.
      • Benedict CR
      • Francis GS
      • Shelton B
      • Johnstone DE
      • Kubo SH
      • Kirlin P
      • et al.
      Effect of long-term enalapril therapy on neurohormones in patients with left ventricular dysfunction. SOLVD Investigators.
      The angiotensin II receptor blocker losartan has also produced improvements in HRV spectral analysis measures of cardiac autonomic function, with an overall increase in HRV attributable to an increase in parasympathetic tone, represented by an increase in high frequency (P < 0.01).
      • Arnold AC
      • Okamoto LE
      • Gamboa A
      • Shibao C
      • Raj SR
      • Robertson D
      • et al.
      Angiotensin II, independent of plasma renin activity, contributes to the hypertension of autonomic failure.
      ,
      • Petretta M
      • Spinelli L
      • Marciano F
      • Apicella C
      • Vicario MLE
      • Testa G
      • et al.
      Effects of losartan treatment on cardiac autonomic control during volume loading in patients with DCM.

      β-Blockers

      β-Adrenoceptor antagonist medication (β-blockers) lowers the resting heart rate and improves the 24-hour ambulatory HRV measures of cardiac autonomic function by improving vagal function.
      • Ebbehøj E
      • Poulsen PL
      • Hansen KW
      • Knudsen ST
      • Mølgaard H
      • Mogensen CE.
      Effects on heart rate variability of metoprolol supplementary to ongoing ACE-inhibitor treatment in Type I diabetic patients with abnormal albuminuria.
      This improvement may provide a cardioprotective effect on mortality in CAN. A separate study found enhanced HRV in patients with coronary artery disease who were given atenolol or metoprolol.
      • Niemelä MJ
      • Airaksinen KEJ
      • Huikuri HV.
      Effect of Beta-blockade on heart rate variability in patients with coronary artery disease.
      Bisoprolol also produced improvements in several HRV measures of parasympathetic activity of the autonomic nervous system in patients with heart failure, including increases in the 24-hour root mean square of successive differences between normal heartbeats (P = 0.04) and daytime high-frequency power (P = 0.03).
      • Pousset F
      • Copie X
      • Lechat P
      • Jaillon P
      • Boissel JP
      • Hetzel M
      • et al.
      Effects of bisoprolol on heart rate variability in heart failure.
      Therefore, bisoprolol has a useful effect in treating CAN by improving parasympathetic autonomic nerve function, but this study did not specifically identify patients with diabetes.
      • Pousset F
      • Copie X
      • Lechat P
      • Jaillon P
      • Boissel JP
      • Hetzel M
      • et al.
      Effects of bisoprolol on heart rate variability in heart failure.
      ,
      • McCarty N
      • Silverman B.
      Cardiovascular autonomic neuropathy.
      Of course, β-blockers are well established for improving prognostic benefit in ischemic heart disease by improving diastolic coronary artery perfusion.
      • Santucci A
      • Riccini C
      • Cavallini C.
      Treatment of stable ischaemic heart disease: the old and the new.
      As previously discussed, the ONTARGET, TRANSEND, and BEAUTIFUL clinical trials found adverse outcomes with a higher baseline heart rate; thus, reduction in ambulatory heart rate may provide additional benefit in CAN.
      • Fitchett D.
      Results of the ONTARGET and TRANSCEND studies: an update and discussion.
      ,
      • Menown IBA
      • Davies S
      • Gupta S
      • Kalra PR
      • Lang CC
      • Morley C
      • et al.
      Resting heart rate and outcomes in patients with cardiovascular disease: where do we currently stand?.

      Statins

      Statins are competitive inhibitors of 3-hydroy-3-methylglutaryl A reductase and reduce cardiovascular risk in diabetes, in both primary and secondary prevention. Of interest, fluvastatin reduces damage to the sympathetic cardiac autonomic nervous system in CAN in a rat model, possibly through reductions in myocardial oxidative stress.
      • Matsuki A
      • Nozawa T
      • Igarashi N
      • Sobajima M
      • Ohori T
      • Suzuki T
      • et al.
      Fluvastatin Attenuates Diabetes-Induced Cardiac Sympathetic Neuropathy in Association With a Decrease in Oxidative Stress.
      This study found that sympathetic nervous function measured by uptake of 131I- and 125I-metaiodobenzylguanidine was reduced in diabetic rats compared with nondiabetic rats, but the reduction was attenuated by approximately 47% by the administration of fluvastatin for 2 weeks. This finding suggests that fluvastatin may improve sympathetic nerve function in CAN, regardless of blood glucose levels.
      • Matsuki A
      • Nozawa T
      • Igarashi N
      • Sobajima M
      • Ohori T
      • Suzuki T
      • et al.
      Fluvastatin Attenuates Diabetes-Induced Cardiac Sympathetic Neuropathy in Association With a Decrease in Oxidative Stress.
      Both simvastatin and atorvastatin also reduce the sympathetic nerve activity in muscles by 12% to 30%.
      • Millar PJ
      • Floras JS.
      Statins and the autonomic nervous system.
      However, statins are already widely used in the management of type 1 and 2 diabetes.

      α-Lipoic Acid

      α-Lipoic acid is a scavenger of free radicals and may have a neuroprotective role by reducing hyperglycemia-driven oxidative stress.
      • Ziegler D
      • Ametov A
      • Barinov A
      • Dyck PJ
      • Gurieva I
      • Low PA
      • et al.
      Oral Treatment With α-Lipoic Acid Improves Symptomatic Diabetic Polyneuropathy.
      The ALADIN (Alpha-Lipoic Acid in Diabetic Neuropathy) I and ALADIN II studies found that α-lipoic acid reduced symptoms of peripheral neuropathy and improved nerve conduction parameters.
      • Ziegler D
      • Hanefeld M
      • Ruhnau KJ
      • Mei\ner HP
      • Lobisch M
      • Schütte K
      • et al.
      Treatment of symptomatic diabetic peripheral neuropathy with the anti-oxidant α-lipoic acid.
      ,
      • Reljanovic M
      • Reichel G
      • Rett K
      • Lobisch M
      • Schuette K
      • Möller W
      • et al.
      Treatment of diabetic polyneuropathy with the antioxidant thioctic acid (alpha-lipoic acid): a two year multicenter randomized double-blind placebo-controlled trial (ALADIN II). Alpha Lipoic Acid in Diabetic Neuropathy.
      Oral α-lipoic acid (600 mg) provided the best risk-benefit ratio for reducing both neuropathic symptoms and deficits during a 5-week period in the Sydney 2 study.
      • Ziegler D
      • Ametov A
      • Barinov A
      • Dyck PJ
      • Gurieva I
      • Low PA
      • et al.
      Oral Treatment With α-Lipoic Acid Improves Symptomatic Diabetic Polyneuropathy.
      A study of patients with type 2 diabetes and CAN in Germany found improvements in 2 of 4 parameters of HRV (root mean square of successive differences between normal heartbeats and low-frequency band of spectral analysis) at rest in the α-lipoic acid groups compared with placebo.
      • Ziegler D
      • Gries FA.
      Alpha-lipoic acid in the treatment of diabetic peripheral and cardiac autonomic neuropathy.
      The DEKAN (Deutsche Kardiale Autonome Neuropathie) study found improvements in HRV in patients with type 2 diabetes and CAN (n = 29 after dropouts) using a well-tolerated dose of α-lipoic acid for 4 months.
      • Ziegler D
      • Schatz H
      • Conrad F
      • Gries FA
      • Ulrich H
      • Reichel G.
      Effects of treatment with the antioxidant alpha-lipoic acid on cardiac autonomic neuropathy in NIDDM patients. A 4-month randomized controlled multicenter trial (DEKAN Study).
      However, a randomized controlled study from Korea did not find improvements in HRV after 24 weeks of oral α-lipoic acid compared with placebo.
      • Lee SJ
      • Jeong SJ
      • Lee YC
      • Lee YH
      • Lee JE
      • Kim CH
      • et al.
      Effects of High-Dose α-Lipoic Acid on Heart Rate Variability of Type 2 Diabetes Mellitus Patients with Cardiac Autonomic Neuropathy in Korea.
      In a recent international expert consensus of diabetic sensorimotor polyneuropathy, α-lipoic acid and benfotiamine were recommended as pathogenetically oriented pharmacotherapy.

      Ziegler D, Tesfaye S, Spallone V, Gurieva I, Al Kaabi J, Mankovsky B, Martinka E, Radulian G, Nguyen KT, Stirban AO, Tankova T, Varkonyi T, Freeman R, Kempler P, Boulton AJ. Screening, diagnosis and management of diabetic sensorimotor polyneuropathy in clinical practice: International expert consensus recommendations. Diabetes Res Clin Pract. 2022 Apr;186:109063. https://doi.org/10.1016/j.diabres.2021.109063. Epub 2021 Sep 20. PMID: 34547367.

      Orthostatic Hypotension

      CAN diagnosed late is typically associated with orthostatic hypotension, which can be symptomatically treated with fludrocortisone or midodrine.
      • Fisher VL
      • Tahrani AA.
      Cardiac autonomic neuropathy in patients with diabetes mellitus: current perspectives.
      Fludrocortisone is a mineralocorticoid that increases blood pressure and expands plasma volume, thereby reducing postural hypotension.
      • Grijalva CG
      • Biaggioni I
      • Griffin MR
      • Shibao CA.
      Fludrocortisone Is Associated With a Higher Risk of All‐Cause Hospitalizations Compared With Midodrine in Patients With Orthostatic Hypotension.
      A recent Cochrane review disappointingly found evidence that a benefit of fludrocortisone in reducing postural symptoms is uncertain.
      • Veazie S
      • Peterson K
      • Ansari Y
      • Chung KA
      • Gibbons CH
      • Raj SR
      • et al.
      Fludrocortisone for orthostatic hypotension.
      Midodrine is a vasopressor that increases standing blood pressure, thereby reducing orthostatic hypotension in two randomized controlled trials.
      • Low PA
      • Gilden JL
      • Freeman R
      • Sheng K-N
      • McElligott MA.
      Efficacy of Midodrine vs Placebo in Neurogenic Orthostatic Hypotension: A Randomized, Double-blind Multicenter Study.
      ,
      • Jankovic J
      • Gilden JL
      • Hiner BC
      • Kaufmann H
      • Brown DC
      • Coghlan CH
      • et al.
      Neurogenic orthostatic hypotension: A double-blind, placebo-controlled study with midodrine.
      The first double-blinded, randomized, placebo-controlled study (n = 97) found that midodrine at 10 mg 3 times daily for 4 weeks increased systolic blood pressure by a mean of 22 mm Hg (P < 0.001 vs placebo).
      • Jankovic J
      • Gilden JL
      • Hiner BC
      • Kaufmann H
      • Brown DC
      • Coghlan CH
      • et al.
      Neurogenic orthostatic hypotension: A double-blind, placebo-controlled study with midodrine.
      Midodrine increases cardiovascular risk by increasing supine hypertension (RR = 5.1) but improves postural symptoms in patients with CAN; therefore, its risks should be weighed up against the benefits.
      • Olshansky B
      • Muldowney J.
      Cardiovascular Safety Considerations in the Treatment of Neurogenic Orthostatic Hypotension.
      Pyridostigmine (60 mg/d) also improves standing blood pressure in patients with neurogenic orthostatic hypotension without worsening supine hypertension.
      • Singer W
      • Sandroni P
      • Opfer-Gehrking TL
      • Suarez GA
      • Klein CM
      • Hines S
      • et al.
      Pyridostigmine Treatment Trial in Neurogenic Orthostatic Hypotension.
      Pyridostigmine augments baroreflex-mediated increases in systemic resistance (through improving BRS), which is proportional to the degree of orthostatic stress, thus improving orthostatic hypotension without causing supine hypertension.
      • Singer W
      • Sandroni P
      • Opfer-Gehrking TL
      • Suarez GA
      • Klein CM
      • Hines S
      • et al.
      Pyridostigmine Treatment Trial in Neurogenic Orthostatic Hypotension.

      Areas for Future Research

      Future research should continue to develop sensitive and specific screening scores for CAN to target diagnostic testing. Improving our understanding of the pathophysiology of CAN offers therapeutic targets for combined lifestyle and pharmacologic interventions. Future research should also investigate the optimum combination and duration of lifestyle and pharmacologic interventions, including newer therapies such as SGLTi and GLP-1RA, particularly early in the natural history.

      Conclusions

      The prevalence of CAN is likely to increase as the prevalence of diabetes mellitus and MetS increases to epidemic proportions globally. CAN is associated with morbidity, high cardiovascular mortality, and sudden cardiac death. Progressive structural and functional changes occur in CAN, which are initially reversible and become permanent over time. Identification of early CAN using focused diagnostic testing is clearly essential to allow the timely provision of multifacted lifestyle and pharmacologic interventions at an early stage where CAN is reversible (Figure 2). Further research should examine the optimal combination of lifestyle measures and newer pharmacotherapeutics (eg, SGLT2is and GLP-1 RAs), which have proven significant cardiovascular benefit in diabetes.
      Figure 2
      Figure 2A putative multifaceted treatment strategy required for the management of cardiac autonomic neuropathy (CAN) in diabetes. This figure highlights the importance of early recognition of CAN at a reversible stage and a multifaceted approach to its management with both lifestyle and pharmacologic interventions.
      • Spallone V.
      Update on the Impact, Diagnosis and Management of Cardiovascular Autonomic Neuropathy in Diabetes: What Is Defined, What Is New, and What Is Unmet.
      ACEis = angiotensin-converting enzyme inhibitors; ARBs = angiotensin II receptor blockers; CV = cardiovascular; GLP-1RAs = glucagon-like peptide 1 receptor agonists; MetS = metabolic syndrome; OSA = obstructive sleep apnea; SGCT2is = sodium-glucose cotransporter 2 inhibitors.

      Acknowledgments

      Scott Williams prepared the manuscript, checked the manuscript and prepared the tables and figures. Siddig Abdel Raheim prepared the manuscript and checked the manuscript. Muhammad Ilyas Khan prepared the manuscript and checked the manuscript. Umme Rubab prepared the manuscript and checked the manuscript. Prathap Kanagala prepared the manuscript and checked the manuscript. Sizheng Steven Zhao prepared the manuscript and checked the manuscript. Anne Marshall prepared the manuscript and checked the manuscript. Emily Brown prepared the manuscript and checked the manuscript. Uazman Alam prepared the manuscript, checked the manuscript and edited the tables and figures.

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