Association Between Cardiovascular Autonomic Neuropathy and Left Ventricular Dysfunction
Open accessAbstract
Objectives The goal of these studies was to determine the association between cardiovascular autonomic neuropathy (CAN) and indices of left ventricle (LV) structure and function in patients with type 1 diabetes (T1DM) in the DCCT/EDIC (Diabetes Control and Complications Trial /Epidemiology of Diabetes Interventions and Complications) study.Background The pathophysiology of LV dysfunction in T1DM remains unclear, especially when the LV ejection fraction (EF) is preserved. Whether CAN is associated with LV dysfunction is unclear.Methods Indices of LV structure and function were obtained by cardiac magnetic resonance imaging (CMRI). CAN was assessed by cardiovascular reflex testing (R-R response to paced breathing, Valsalva ratio, and blood pressure response to standing). Analyses were performed in 966 DCCT/EDIC participants with valid CMRI and CAN data (mean age 51 years, 52% men, mean diabetes duration 29 years, and mean glycosylated hemoglobin 7.9%).Results Systolic function (EF, end-systolic and end-diastolic volumes, stroke volumes) was not different in 371 subjects with CAN compared with 595 subjects without CAN. In multiple-adjusted analyses, participants with either abnormal R-R variation or a composite of abnormal R-R variation, abnormal Valsalva ratio, and postural blood pressure changes had significantly higher LV mass, mass-to-volume-ratio, and cardiac output compared with those with normal tests (p < 0.0001 for all). After further adjustment for traditional cardiovascular risk factors, subjects with abnormal R-R variation had higher LV mass and cardiac output compared with those with a normal R-R variation (p < 0.05).Conclusions In this large cohort of patients with T1DM, CAN is associated with increased LV mass and concentric remodeling as assessed by CMRI independent of age, sex, and other factors. (Diabetes Control and Complications Trial [DCCT]; NCT00360815) (Epidemiology of Diabetes Interventions and Complications [EDIC]; NCT00360893).
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Early detection of CAN may enable tailored interventions that prevent progression and reduce risks of CVD, arrhythmias, myocardial dysfunction leading to CHF, CKD, and all-cause mortality.
“Timely detection of CAN may help implementation of tailored interventions to prevent its progression and mitigate the risk of associated complications, including CVD, cardiac arrhythmias, myocardial dysfunction leading to congestive heart failure (CHF), CKD, and all-cause mortality.547,614,617–625”
From American Association of Clinical Endocrinology Clinical Practice Guideline: Developing a Diabetes Mellitus Comprehensive Care Plan-2022 Update. (2022) · cites this paper as [614]
The Conclusions (page unavailable) say that patients with type 1 diabetes and CAN-associated LV changes may benefit from early, more aggressive risk-factor management, and the paper links this phenotype to CVD risk. It does not show that detecting CAN enables interventions that prevent its progression or reduce the full list of complications; cardiac arrhythmias and CKD are not established as outcomes of such interventions here. (LLM, conf=0.85)
Experimental — accuracy not yet measuredOther evaluations that use expensive devices have low sensitivity and specificity for CAN and are not recommended in clinical care.
“Other evaluations requiring a variety of expensive devices have a low sensitivity and specificity for CAN and are not recommended for use in clinical care.614”
From American Association of Clinical Endocrinology Clinical Practice Guideline: Developing a Diabetes Mellitus Comprehensive Care Plan-2022 Update. (2022) · cites this paper as [614]
The Discussion (page unavailable) says alternative heart-rate-variability measures had only fair agreement with the reference-standard cardiovascular reflex tests. It does not say those evaluations require expensive devices, have low sensitivity and specificity, or are not recommended for clinical care. (LLM, conf=0.76)
Experimental — accuracy not yet measuredSubclinical CAN presents with reduced heart rate variability, often during deep breathing or posture change, and this is considered the earliest clinical indicator of CAN.
“Persons with subclinical CAN present with a decrease in HRV, usually with deep breathing or change in posture, considered the earliest clinical indicator of CAN.547,614”
From American Association of Clinical Endocrinology Clinical Practice Guideline: Developing a Diabetes Mellitus Comprehensive Care Plan-2022 Update. (2022) · cites this paper as [614]
The Methods (Assessment of CAN; page unavailable) define CAN partly by reduced R-R variation during paced breathing. They assess posture change through blood-pressure response, not heart-rate variability. The Discussion describes early autonomic changes but does not identify reduced HRV as the earliest clinical indicator of CAN. (LLM, conf=0.86)
Experimental — accuracy not yet measuredCardiovascular reflex tests that measure heart rate variability changes during deep breathing, Valsalva maneuver, and supine-to-standing remain the gold standard and are available in clinical care.
“Although HRV testing is largely confined to the research setting, the CV reflex tests that assess changes in HRV during standardized clinical challenges such as deep breathing, Valsalva maneuver and supine-to-standing position remain the gold standard tests and are available for clinical care as well.547,614,626”
From American Association of Clinical Endocrinology Clinical Practice Guideline: Developing a Diabetes Mellitus Comprehensive Care Plan-2022 Update. (2022) · cites this paper as [614]
The Methods, Assessment of CAN (page not provided), describes standardized reflex testing with R-R responses to paced breathing, the Valsalva maneuver, and blood-pressure changes on standing. It does not describe the standing test as measuring heart-rate variability, or state that these tests are the gold standard or available in clinical care. (LLM, conf=0.86)
Experimental — accuracy not yet measuredCAN is an independent predictor of cardiovascular disease and mortality in both type 1 and type 2 diabetes.
“Furthermore, CAN is an independent predictor of cardiovascular disease (CVD) and mortality in both T1D and T2D [8–10].”
From Cardiovascular autonomic neuropathy defined by indices of heart rate variability is associated with cardiovascular disease: a longitudinal cohort study of participants with type 1 diabetes (2025) · cites this paper as [9]
The introduction following the Abstract Conclusions states that CAN is an independent predictor of mortality in people with T1DM. The Conclusions report an association between CAN and cardiac remodeling in T1DM and suggest possible CVD risk, but do not establish CAN as an independent predictor of CVD events. The Discussion mentions T2DM only in relation to left ventricular dysfunction, not prediction of CVD or mortality. (LLM, conf=0.88)
Experimental — accuracy not yet measured
CAN is often missed in clinical practice because it presents subtly early in the disease.
“Unfortunately, CAN is frequently overlooked in clinical practice due to its characteristic subtle presentation earlier in disease.547,614”
From American Association of Clinical Endocrinology Clinical Practice Guideline: Developing a Diabetes Mellitus Comprehensive Care Plan-2022 Update. (2022) · cites this paper as [614]
The Discussion describes physiological changes in early CAN, and the Methods explain how CAN was assessed, but neither addresses whether its early presentation is subtle or whether clinicians frequently overlook it. A search for overlooked or asymptomatic CAN found no passage establishing that claim; page numbers were not available in our copy. (LLM, conf=0.72)
Experimental — accuracy not yet measuredThe most frequent CAN symptoms occur on standing and include lightheadedness, weakness, palpitations, faintness, and syncope.
“The most common symptoms of CAN occur upon standing and include lightheadedness, weakness, palpitations, faintness, and syncope.547,614”
From American Association of Clinical Endocrinology Clinical Practice Guideline: Developing a Diabetes Mellitus Comprehensive Care Plan-2022 Update. (2022) · cites this paper as [614]
The Methods section describes blood-pressure testing upon standing, but does not describe symptoms upon standing. The Discussion identifies exercise intolerance as a symptom of CAN, but does not address whether the listed symptoms are the most common; searches for those symptoms and orthostatic symptoms found no supporting passage in our copy. (LLM, conf=0.74)
Experimental — accuracy not yet measured
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Self-citationInsulin–Heart Axis: Bridging Physiology to Insulin Resistance
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Hyperglycemia and Vascular Metabolic Memory: Truth or Fiction?
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Cardiac autonomic neuropathy and risk of incident heart failure among adults with type 2 diabetes
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Cardiorespiratory Fitness and Cardiac Autonomic Function in Diabetes
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Cardiac Organ Damage and Arterial Stiffness in Autonomic Failure
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Pathophysiology and Prevention of Heart Disease in Diabetes Mellitus
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Cardiovascular complications in patients with autonomic failure
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Diabetes mellitus type 1 in adults
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Self-citationPreservation of CGRP in myocardium attenuates development of cardiac dysfunction in diabetic rats
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Oral Semaglutide and Heart Failure Outcomes in Persons With Type 2 Diabetes
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Assessment of autonomic function in a cohort of patients with ANCA-associated vasculitis
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Diabetes and the Nervous System
Vinik, A. I., CASELLINI, C. M., & Neumann, S. A. (2020) · Endocrinology · doi:10.1007/978-3-030-36694-0_10 · Cited by 8 · see citing works
Obesity, Metabolic Health, and Diabetic Complications in People With Type 1 Diabetes
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Self-citationMETABOLIC EFFECTS OF TULBAGHIA VIOLACEA HARV. IN A DIABETIC MODEL.
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Ventricular depolarization and repolarization variability in children with type 1 diabetes mellitus
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Retinopathy, Neuropathy, and Foot Care
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Autonomic dysfunction in systemic diseases: a narrative review
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- Authors
- Pop-Busui, R., Cleary, P. A., Braffett, B. H., Martin, C. L., Herman, W. H., Low, P. A., Lima, J. A. C., & Bluemke, D. A.
- Affiliations
- George Washington University (US)
- University of Michigan (US)
- Mayo Clinic (US)
- National Institutes of Health (US)
- Venue
- Journal of the American College of Cardiology
- Publisher
- Elsevier BV
- Published
- 2013-01
- Volume
- 61
- Issue
- 4
- Pages
- 447-454
- ISSN
- 0735-1097 (ISSN-L)
- PMC
- PMC3616477
- OpenAlex
- W1599042228
- Cited by
- 88
- References
- 50
- Citations by year
- 2026: 7 · 2025: 3 · 2024: 3 · 2023: 4 · 2022: 6 · 2021: 7 · 2020: 6 · 2019: 6 · 2018: 8 · 2017: 7 · 2016: 11 · 2015: 6 · 2014: 9 · 2013: 5
- FWCI
- 4.12
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Journal of the American College of Cardiology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (5r01hl102334-05, n01dk062204-003, UL1TR000439)
- Genentech
- National Heart, Lung, and Blood Institute (R01-HL-102334)
- National Institute of Diabetes and Digestive and Kidney Diseases (N01 DK062204, U01DK094176, P30DK020572)
- National Center for Research Resources
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Function and Risk Factors
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Heart Rate Variability and Autonomic Control
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
- Keywords
- cardiac autonomic neuropathy, left ventricular dysfunction, type 1 diabetes, left ventricular mass, concentric remodeling, Valsalva ratio, postural blood pressure response, cardiac output, preserved ejection fraction, DCCT/EDIC
- MeSH terms
- Adult, Blood Pressure, Diabetes Mellitus, Type 1, Diabetic Neuropathies, Electrocardiography, Female, Heart Function Tests, Humans, Magnetic Resonance Imaging, Male, Middle Aged, Risk Factors, United States, Cohort Studies, Multivariate Analysis, Age of Onset, Ventricular Dysfunction, Left, Ventricular Remodeling
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