Category: Home

Diabetic neuropathy and cardiovascular disease

Diabetic neuropathy and cardiovascular disease

Article PubMed Google Scholar. CrossCheck cardiovasculaf Google Search of This Article. Vinik, vinikai evms.

Diabetic neuropathy and cardiovascular disease -

Patients with DCAN exhibit a two to threefold increase in perioperative morbidity and mortality, are more likely to require vasopressor support in the operation room, and are also prone to experience a BP and HR reduction during the induction of anesthesia, as well as severe intraoperative hypothermia [3, 7, 8].

The above findings can be explained by an impairment or absence of the normal vasoconstrictive response [3, 7, 8].

SMI is a clinical entity not well clarified, believed to result from damage of the ANS pathways of pain [3, 7, 8. PET studies have detected a failure in signal transmission from the thalamus to the frontal cortex in individuals with SMI, implying that unsensed ischemia might not only be a matter of impaired peripheral neural conduction but also be a result of central nervous system disorders [3, 7, 8].

Patients with DCAN show delayed onset of angina symptoms after the appearance of ECG ischemic changes during exercise testing or very often develop atypical symptoms such as unexplained fatigue, confusion, hemoptysis, nausea, vomiting, sweating, arrhythmia, coughing and dyspnea [3, 7, 8].

Therefore, presence of atypical symptoms should be regarded as of myocardial origin unless proven otherwise [3, 7, 8]. Non-diabetic subjects present with predominance of vagal tone and decreased sympathetic tone at night, associated with reduction in nocturnal BP. In diabetic DCAN, this pattern is altered, resulting in nocturnal sympathetic predominance during sleep and subsequent nocturnal hypertension, also known as non-dipping and reverse dipping [3, 7, 8].

These are associated with a higher frequency of LVH and fatal and severe non-fatal cardiovascular events in DCAN subjects with a two to eightfold increase in risk of cardiovascular or renal events in some longitudinal studies [3, 7, 8].

Early detection of DCAN is of paramount importance, since it can lead to prompt therapeutic interventions, resulting in a significant survival benefit [3, 4, 7, 8]. Medical history and physical examination are inadequate for the diagnosis which requires specific diagnostic tests.

Subclinical DCAN may be detected within 1 year of diagnosis in T2DM and within 2 years of diagnosis in T1DM [8]. In early , Ewing et al described five simple tests for non-invasive autonomic evaluation [11]: heart rate response to breathing, heart rate response to standing, Valsalva maneuver, blood pressure response to standing and blood pressure response to sustained handgrip.

Conventional cardiovascular autonomic reflex tests CARTs are non-invasive, safe, clinically relevant they correlate with tests of peripheral nervous system function , easy to perform, sensitive, specific, reproducible, and standardized.

Therefore, they are considered the gold standard measures of autonomic function [3, 4, 7, 8]. While CARTs Table 1 have been widely used since their introduction, there is no evidence on the superiority of one test over another when it comes to assessing DCAN [3, 4, 7, 8].

The orthostatic hypotension test has low sensitivity and high specificity, making it suboptimal for diagnosis [3, 4, 7, 8]. Other methods such as cardiac sympathetic imaging, microneurography, occlusion plethysmography, and baroreflex sensitivity are currently used predominantly in research settings but may find a place in the clinical assessment of DCAN in the future [3, 4, 7, 8].

However, cardiovascular tests based on HR response to deep breathing, lying to standing and Valsalva maneuver, and BP response to standing OH test are an essential and irreplaceable part of DCAN diagnosis [3, 4, 7, 8]. Modified and reproduced with permission from Karayannis G, Giamouzis G, Cokkinos DV, Skoularigis J, Triposkiadis F.

Diabetic cardiovascular autonomic neuropathy: clinical implications. Expert Rev Cardiovasc Ther. Abbreviations: HR: heart rate; HRV: heart rate variability; SBP: systolic blood pressure; DBP: diastolic blood pressure; QTc: corrected QT interval; MIBG: metaiodobenzylguanidine; HED: metahydroxyephedrine.

Among the physiological factors affecting the test results, the most important are: age, respiratory pattern, body position and duration of supine rest, resting heart rate and BP, physical exercise within 24 hrs, coffee, alcohol and cigarette consumption, meals, and drugs [3, 4, 7, 8].

In the case of altered cardiovascular tests in the baseline evaluation, it is advisable to repeat the tests annually in order to confirm the diagnosis of DCAN and evaluate its progression [4]. Moreover, even in the absence of alterations of cardiovascular tests, it is advisable to repeat the tests annually in diabetic patients with poor glycemic control, high cardiovascular risk and microangiopathic complications, whereas in the other patients a longer interval is recommended [3, 4, 8].

Apparently, not all diabetics require autonomic function assessment [3, 4, 8]. Table 2 contains a summary of indications for testing.

Abbreviations: CARTs: cardiovascular autonomic reflex tests; CVD: cardiovascular disease; DLP: dyslipidemia; HbA1c: glycated hemoglobin; HTN: hypertension; T2DM: type 2 diabetes mellitus; T1DM: type 1 diabetes mellitus.

The available information regarding the duration required to progress from an earlier to a later stage of impairment is scant and it is not documented whether a progression to OH and symptomatic forms invariably occurs in all patients [3, 4, 7, 8].

Following the 8th International Symposium on Diabetic Neuropathy in , criteria for diagnosis and staging of DCAN were defined in the Subcommittee of the Toronto Consensus Panel Statement Figure 1 [4].

Progressive stages of DCAN are associated with an increasingly worse prognosis [1, 4, 7, 8, 10]. Reproduced with permission from Spallone V, Ziegler D, Freeman R, Bernardi L, Frontoni S, Pop-Busui R, et al. Cardiovascular autonomic neuropathy in diabetes: clinical impact, assessment, diagnosis, and management.

Diabetes Metab Res Rev. Abbreviations: CAN: cardiac autonomic neuropathy; HR: heart rate. DCAN is a complication that confers a higher morbidity and mortality from cardiovascular and all causes [1, 4, ].

The prognostic importance of DCAN presence was initially identified in the early s, when DCAN was associated with a nearly fivefold increase in mortality risk [11]. Since then, a large number of publications have verified this association [4, 9, 10, 12, 13]. Among 2, T1DM patients, DCAN was a significant predictor of 7-year mortality, exceeding the relative effect of the traditional CVD risk factors [16].

The pathophysiological mechanisms contributing to increased mortality are not yet clear. These include: SMI, disturbances in coronary flow regulation, increased HR, diastolic and systolic LV dysfunction, QTc prolongation and increased risk for arrhythmias, diminished sense of hypoglycemia and difficult recovery due to dysregulation of compensatory endocrine mechanisms, acceleration of renal impairment, alterations of circadian BP cycle, increased susceptibility to medications that cause respiratory depression, impaired respiratory response to hypoxia, increased sympathetic activity and increased calcification of the coronary arteries 1, 4, A meta-analysis of 15 longitudinal studies, which included a total of 2, patients followed up for 16 years, showed that the diagnosis of DCAN based on at least two abnormal CARTs results determined a relative risk of mortality of 3.

Moreover, the pooled relative risk of mortality in clinic-based studies that used more than one index was considerably higher than in studies that used only one [12, 16, 17]. The association of DCAN with nephropathy [12, 14, 15], post MI [12], QTc prolongation [9, 12, 16, 17] and neuropathy [9, ] increases the risk for mortality and CVD morbidity.

Moreover, DCAN was associated with LV systolic and particularly diastolic dysfunction in the absence of cardiac disease [3, 4, 8].

Each manifestation of DCAN is associated with increased morbidity and mortality in these patients. Poor glycemic control [3, 7, 8], high glycemic variability [3, 7, 8] and hypoglycemia [9] have been related to the development of this complication, together with the presence of multiple cardiovascular risk factors which seem to modulate the progression and types of manifestation the patients develop [3, ].

A good glycemic and CVD risk factor control avoiding glycemic variability and hypoglycemia seems the most important therapeutic approach for its prevention [3, ]. Once established, the avoidance of hypoglycemia with a less stringent but good glycemic control [3, ] associated with a cardiovascular risk reduction strategy [3, 4, 7, 8, 18] and use of beta-blockers to counteract sympathetic hyperactivation [19] is vital to slow its progression.

Once OH is present, avoidance of hypotension is essential, since a strict control of blood pressure has been related in this patient with excessive mortality [9]. Thus, in diabetic patients, BP should not be measured only in the seated position when adjusting antihypertensive treatment, and drugs with adverse autonomic consequences and potential for QTc prolongation should be avoided [3, 4, 17].

Use of RAS blockade with ARBs, ACE inhibitors and spironolactone has no proven efficacy or impact in its course [3, ]. Small studies show promising results with the use of anticonvulsants [3, 4]. Several molecules with antioxidant and antifibrotic properties are being tested, looking to impact on its natural history [3, 4, 7, 8, 18, 20].

DCAN is a frequently forgotten and underdiagnosed microvascular complication of DM. Patients with this condition are at high risk of sustaining major cardiovascular events and death. Diagnosis is simple but requires time and skills for making and interpreting CARTs. Screening can be done in the office at low cost.

Actual DM management guidelines aim to reduce CVD mortality but have forgotten to address this issue. Tailored and individualized management with avoidance of hypoglycemia and OH is important in these patients, since these events carry a high morbidity and mortality in this set of autonomic dysfunctioning patients.

It is imperative to begin recognizing DCAN to accomplish a better prognosis and reduce CVD mortality among people with longstanding DM. Dr Julian Eduardo Forero-Gómez 1 , MD; Dr Sandra Milena Botero 2 , MD; Dr Ángela Sofía Esparza 2 , MD; Dr Paula Andrea Sánchez-Moscoso 3 , MD.

Internal Medicine, Clinical Associated Investigator, Asociación IPS Médicos Internistas de Caldas, Manizales, Colombia;.

General Physician, Clinical Subinvestigator, Asociación IPS Médicos Internistas de Caldas, Manizales, Colombia;. Asociación IPS Medicos Internistas de Caldas, Street 66 No. The authors did not receive financial or professional help with the preparation of the manuscript.

JEF is a clinical investigator participating in clinical trials sponsored by Pfizer, MSD, PHRI and Servier. SMB and ASE are clinical subinvestigators participating in clinical trials sponsored by Pfizer, Amgen, Novonordisk, MSD, Bayer, Servier, PHRI, Lilly, Boehringer Ingelheim, Sanofi and AstraZeneca.

The HRV test is a cost-effective measurement based on the RR interval oscillation analysis of consecutive heartbeats. The duration of the RR intervals is not fixed, and reflects the combined performance of the SANS and PANS[ 73 ].

Thus, HRV is a marker of cardiac autonomic function, which is suitable for cardiovascular risk stratification. Its reduction is associated with increased cardiovascular risk[ 63 , 73 ]. In addition, HRV is recognized as a predictive factor of silent myocardial infarction and postmyocardial infarction mortality[ 36 ].

HRV can be evaluated using linear or nonlinear methods. The nonlinear methods comprise the detrended fluctuation analysis, Hurst exponent, fractal dimension, and Lyapunov exponent.

Although these indices are good morbidity and mortality markers, they require long periods of analysis. On the other hand, linear methods can be evaluated in a short period and are divided into two groups: those analyzed in the time domain and those analyzed in the frequency domain[ 74 ].

The parameters of these domains are listed in Table 2. Despite the fact that HRV indices and their respective interpretations are well-established in the literature, there is still no standardization of their reference values. In , the European Society of Cardiology and the North American Society of Pacing and Electrophysiology published guidelines with standardized values of HRV measurements and their clinical associations.

However, some of the ranges came from studies with small sample sizes, and the values were not adjusted for potential confounders, such as sex, age, or environmental factors. Thus, they should be considered as estimate values that requires more robust physiological and clinical validation[ 75 ].

Another criticism of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology guidelines is the statement that HRV is a simple tool.

Although the technique has spread mainly due to devices that provide an automated measurement of HRV, the guidelines generate complex parameters and should be interpreted with caution in order to avoid incorrect data conclusions and extrapolations[ 33 ]. Nevertheless, despite criticism and the absence of standardized reference values, HRV remains a method widely associated with the body's self-regulatory capacity and the early identification of autonomic alterations and increased cardiovascular risk[ 76 - 78 ].

Moreover, HRV has been reported as a tool to identify cardiovascular risk, even in individuals without previous cardiovascular diseases[ 77 , 79 ]. Diabetes mellitus is a global epidemic[ 46 ], and diabetic neuropathy is the most common chronic complication[ 63 ].

Among the types of diabetic neuropathy, CAN is one of the most studied and disabling conditions[ 19 ]. Considering that CAN is a major marker for silent myocardial ischemia, myocardial dysfunction, cardiac arrhythmias, and sudden death[ 5 - 8 ], it is surprising that CAN is still an under-investigated condition in patients with diabetes[ 1 ].

CAN may present in a subclinical form for many years while the parasympathetic denervation process already occurs in diabetic patients[ 80 ]. Moreover, CAN is associated with increased morbidity and mortality risks[ 4 ]. However, there is no universal standard method for detecting CAN, and it is suggested that more than one test should be conducted to enhance the sensitivity and reliability of CAN diagnosis [ 19 ].

In this setting, several tests with different degrees of accuracy, such as CARTs, HRV, and nuclear imaging, are available[ 61 , 69 , 81 , 82 ]. According to the position statement of the American Association of Clinical Endocrinologists AACE and American College of Endocrinology ACE , CAN screening should be performed at the time of diagnosis in patients with type 2 diabetes mellitus and five years after diagnosis in patients with type 1 diabetes mellitus.

Nevertheless, there are still some controversies regarding the guidelines for CAN screening. On the other hand, the Italian Society of Diabetology SID and the Italian Association of Clinical Diabetologists AMD reported that patients should be evaluated if they have high cardiovascular risk and complications, while the Toronto Consensus emphasizes that screening for symptoms and signs of CAN should be universal[ 10 ].

There is also disagreement about the use of HRV tests for the diagnosis of CAN. According to the ADA, SID, and AMD statements, this technique is mainly used for research purposes. In contrast, the AACE, ACE, and Toronto Consensus recognize the clinical and prognostic value of the HRV test[ 10 ].

Despite the importance of early detection, there is no harmonized definition of CAN, and CAN is frequently diagnosed late[ 83 ]. Therefore, early recognition of CAN is essential to minimize the risk of morbidity and mortality in patients with diabetes.

CARTs, HRV, and the ¹²³I-mIBG myocardial scintigraphy should be used in combination for the CAN diagnosis in diabetic patients[ 63 , 84 ]. A harmonized definition among scientific societies is urgently needed to recommend standardized methods for CAN screening in patients with low, medium, and high cardiovascular risk.

In view of the autonomic alterations associated with hyperglycemia, the early identification of sympathovagal imbalance in CAN may change treatment strategies for diabetic patients.

Moreover, HRV analysis may be used as a potential tool to identify the first signs of CAN, even in asymptomatic individuals [ 84 ]. Although CAN is considered a condition associated with increased risks of morbidity and mortality, there are still many disagreements regarding the recommendations in the CAN guidelines.

The existence of complex mechanisms, the wide variety of tools for assessing CAN, and the lack of a harmonized definition among the scientific societies contribute to the reduced clinical investigation of this complication, which can increase the risk of silent myocardial ischemia, myocardial dysfunction, cardiac arrhythmias, and sudden death.

CAN assessment methodologies HRV, CARTs, and ¹²³I-mIBG myocardial scintigraphy need to become more available, widely accessible, and easy to interpret. Considering that CAN is an under-recognized condition, it is also necessary to stimulate the discussion about this microvascular complication in college or university programs in the healthcare field.

Investing in education and stimulating the assessment of this complication can be a promising key point for early identification and reducing morbimortality of CAN, mainly in the current scenario of diabetes and cardiometabolic epidemics.

Home English English 简体中文. Sign In BPG Management System F6Publishing-Submit a Manuscript F6Publishing-世界华人消化杂志在线投稿 RCA Management System. Advanced Search. About the Journal Submit a Manuscript Current Issue Search All Articles. This Article.

Abstract Core Tip Full Article with Cover PDF Full Article WORD Full Article HTML Audio PubMed Central PubMed CrossRef Google Scholar Timeline of Article Publication 0 Authors Evaluation 1 Article Quality Tracking 0 Reference Citation Analysis 2.

Academic Content and Language Evaluation of This Article. Answering Reviewers PDF Non-Native Speakers PDF Peer-Review Report PDF. CrossCheck and Google Search of This Article. Scientific Misconduct Check PDF.

Academic Rules and Norms of This Article. Conflict-of-Interest Statement PDF Copyright Assignment PDF. Citation of this article. Duque A, Mediano MFF, De Lorenzo A, Rodrigues Jr LF.

Cardiovascular autonomic neuropathy in diabetes: Pathophysiology, clinical assessment and implications. World J Diabetes ; 12 6 : [PMID: DOI: Corresponding Author of This Article. Andrea De Lorenzo, PhD, Professor, Education and Research Department, Instituto Nacional de Cardiologia, Rua das Laranjeiras , Rio de Janeiro , RJ, Brazil.

andlorenzo hotmail. Checklist of Responsibilities for the Scientific Editor of This Article. Scientific Editor Work List PDF.

Publishing Process of This Article. Research Domain of This Article. Article-Type of This Article. Open-Access Policy of This Article. This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers.

It is distributed in accordance with the Creative Commons Attribution Non Commercial CC BY-NC 4. Times Cited Counts in Google of This Article.

Number of Hits and Downloads for This Article. Total Article Views All Articles published online. Times Cited of This Article. Times Cited Journal Information of This Article.

Publication Name. Baishideng Publishing Group Inc, Koll Center Parkway, Suite , Pleasanton, CA , USA. Minireviews Open Access. Copyright ©The Author s Published by Baishideng Publishing Group Inc. All rights reserved. World J Diabetes.

Jun 15, ; 12 6 : Published online Jun 15, doi: Alice Duque , Mauro Felippe Felix Mediano , Andrea De Lorenzo , Luiz Fernando Rodrigues Jr. Alice Duque, Mauro Felippe Felix Mediano, Andrea De Lorenzo, Luiz Fernando Rodrigues Jr, Education and Research Department, Instituto Nacional de Cardiologia, Rio de Janeiro , RJ, Brazil.

Mauro Felippe Felix Mediano, Laboratory of Clinical Research on Chagas Disease, Evandro Chagas National Institute of Infectious Diseases, Oswaldo Cruz Foundation, Rio de Janeiro , RJ, Brazil. Luiz Fernando Rodrigues Jr, Department of Physiological Sciences, Biomedical Institute, Federal University of the State of Rio de Janeiro, Rio de Janeiro , RJ, Brazil.

ORCID number: Alice Duque ; Mauro Felippe Felix Mediano ; Andrea De Lorenzo ; Luiz Fernando Rodrigues Jr Author contributions : Duque A wrote the manuscript; Mediano MFF and Rodrigues Jr LF wrote and revised of manuscript; De Lorenzo A contributed article conception and writing; all authors have read and approved the final manuscript.

Conflict-of-interest statement : De Lorenzo A is an employee of the National Institute of Cardiology. Mediano MFF is an employee of Evandro Chagas National Institute of Infectious Diseases, Oswaldo Cruz Foundation. Rodrigues Jr LF is an employee of the National Institute of Cardiology and of the Federal University of the State of Rio de Janeiro.

Open-Access : This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial CC BY-NC 4.

Corresponding author : Andrea De Lorenzo, PhD, Professor, Education and Research Department, Instituto Nacional de Cardiologia, Rua das Laranjeiras , Rio de Janeiro , RJ, Brazil.

Received: February 28, Peer-review started : February 28, First decision : March 30, Revised: April 5, Accepted: May 20, Article in press : May 20, Published online: June 15, Key Words: Cardiovascular autonomic neuropathy , Cardiac autonomic neuropathy , Diabetes mellitus , Heart rate variability , Sympathetic autonomic nervous system , Parasym pathetic autonomic nervous system.

Citation: Duque A, Mediano MFF, De Lorenzo A, Rodrigues Jr LF. Table 1 Characteristics of different studies evaluating cardiovascular autonomic neuropathy and diabetes.

Study Ref. CAN: Cardiovascular autonomic neuropathy; HRV: Heart rate variability. Heart rate response to deep breathing. Heart rate response to standing.

Blood pressure response to standing up. Blood pressure response to sustained handgrip. Table 2 Heart rate variability time and frequency domain measures[ 89 , 90 ]. Linear indices - time domain Parameters Abbreviation meaning Interpretation MNN ms Mean of NN intervals Long RR intervals are related to a lower heart rate, while short RR intervals denote a high heart rate.

SANS: Sympathetic autonomic nervous system; PANS: Parasympathetic autonomic nervous system; LF: Low frequency; HF: High frequency; ULF: Ultra low frequency; VLF: Very low frequency; MNN: Mean of NN; SDNN: Standard deviation of all NN.

Spallone V , Ziegler D, Freeman R, Bernardi L, Frontoni S, Pop-Busui R, Stevens M, Kempler P, Hilsted J, Tesfaye S, Low P, Valensi P; Toronto Consensus Panel on Diabetic Neuropathy. Cardiovascular autonomic neuropathy in diabetes: clinical impact, assessment, diagnosis, and management.

Diabetes Metab Res Rev. Vinik AI , Erbas T, Casellini CM. Diabetic cardiac autonomic neuropathy, inflammation and cardiovascular disease. J Diabetes Investig. Pop-Busui R. What do we know and we do not know about cardiovascular autonomic neuropathy in diabetes.

J Cardiovasc Transl Res. Vinik AI , Ziegler D. Diabetic cardiovascular autonomic neuropathy. Razanskaite-Virbickiene D , Danyte E, Mockeviciene G, Dobrovolskiene R, Verkauskiene R, Zalinkevicius R.

Can coefficient of variation of time-domain analysis be valuable for detecting cardiovascular autonomic neuropathy in young patients with type 1 diabetes: a case control study.

BMC Cardiovasc Disord. Astrup AS , Tarnow L, Rossing P, Hansen BV, Hilsted J, Parving HH. Cardiac autonomic neuropathy predicts cardiovascular morbidity and mortality in type 1 diabetic patients with diabetic nephropathy.

Diabetes Care. Fisher VL , Tahrani AA. Cardiac autonomic neuropathy in patients with diabetes mellitus: current perspectives. Diabetes Metab Syndr Obes.

Williams SM , Eleftheriadou A, Alam U, Cuthbertson DJ, Wilding JPH. Cardiac Autonomic Neuropathy in Obesity, the Metabolic Syndrome and Prediabetes: A Narrative Review.

Diabetes Ther. Pop-Busui R , Boulton AJ, Feldman EL, Bril V, Freeman R, Malik RA, Sosenko JM, Ziegler D. Diabetic Neuropathy: A Position Statement by the American Diabetes Association.

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.

Diabetes Metab J. Eleftheriadou A , Williams S, Nevitt S, Brown E, Roylance R, Wilding JPH, Cuthbertson DJ, Alam U. The prevalence of cardiac autonomic neuropathy in prediabetes: a systematic review.

Hu FB , Satija A, Manson JE. Curbing the Diabetes Pandemic: The Need for Global Policy Solutions. Williams R , Colagiuri S, Chan J, Gregg E, Ke C, Lim L-L. IDF Atlas 9th Edition Brussels: Belgium, World Health Organization. Key facts.

In: World Health Organization [Internet]. Haththotuwa RN , Wijeyaratne CN, Senarath U. Chapter 1 - Worldwide epidemic of obesity. In: Mahmood TA, Arulkumaran S, Chervenak FA. Obesity and Obstetrics Second Edition. Elsevier, Eckel RH , Blaha MJ.

Cardiometabolic Medicine: A Call for a New Subspeciality Training Track in Internal Medicine. Am J Med. Lopez-Jaramillo P , Lahera V, Lopez-Lopez J. Epidemic of cardiometabolic diseases: a Latin American point of view.

Ther Adv Cardiovasc Dis. Reiter-Brennan C , Cainzos-Achirica M, Soroosh G, Saxon DR, Blaha MJ, Eckel RH. Cardiometabolic medicine - the US perspective on a new subspecialty. Cardiovasc Endocrinol Metab.

Pan Q , Li Q, Deng W, Zhao D, Qi L, Huang W, Ma L, Li H, Li Y, Lyu X, Wang A, Yao H, Guo L, Xing X. Prevalence and Diagnosis of Diabetic Cardiovascular Autonomic Neuropathy in Beijing, China: A Retrospective Multicenter Clinical Study.

Front Neurosci. Rolim LC , Sá JR, Chacra AR, Dib SA. Diabetic cardiovascular autonomic neuropathy: risk factors, clinical impact and early diagnosis. Most recently there has been great interest in the action and effects of the sodium-glucose cotransporter-2 SGLT2 inhibitors on reducing cardiovascular events.

Empaglifozin is a highly selective inhibitor of the SGLT2 in the kidney. Glucose reduction occurs by decreasing renal glucose reabsorption and thereby increasing urinary glucose elimination in patients with diabetes, leading to significant reductions in glycated hemoglobin HbA1c , weight loss, and reductions in BP without increases in HR Liakos et al.

The EMPA-REG Outcome trial recruited 1, patients with T2DM, of whom were enrolled and randomized to placebo or one of two different doses of empagliflozin 10 and 25 mg daily in addition to standard care Zinman et al.

Empagliflozin was similar to other oral antihyperglycemic agents in HbA1c reduction 0. placebo, slightly greater weight loss at 52 weeks, modest BP reduction of 2—7 mmHg vs. placebo, and no intrinsic increased risk of hypoglycemia Kishi, A subsequent report showed that the reduction in cardiovascular deaths were significant in Southeast Asia and Latin America, but not as much in America and Europe Alzaid, Despite these different findings, the fall in BP without an increase in HR implies a reduction in sympathetic tone with its use.

Liraglutide, a GLP-1 receptor agonist, was also found to reduce CV events, but not as robustly as empagliflozin Vinik et al. GLP-1 has widespread properties in the human body and targets receptors diffusely Drucker, Liraglutide improves HbA1c and compared with other medication classes has similar or greater efficacy, even compared to basal insulin.

Its use has been shown to lead to a modest improvement in BP but, in contrast to empagliflozin, with an increase in HR Scirica et al. The FDA recently approved the use of liraglutide for management of CVD in diabetes Marso et al. The actions of liraglutide on HRV and daily variation of HR in newly diagnosed, overweight patients with T2DM and stable CAD have been investigated.

Diurnal HR fluctuations and sympathovagal balance evaluated by rMSSD in NN intervals and HF and LF power were assessed. Liraglutide decreased sdNN in some subjects; decreased rMSSD; and increased mean, daytime, and nighttime HR compared to placebo.

Thus, in overweight patients with CAD and newly diagnosed T2DM, liraglutide increased HR and reduced HRV despite significant weight loss and improvement in metabolic parameters; the increase in nightly HR and decrease in parameters of parasympathetic activity rMSSD and HF power suggest that this medication may negatively affect sympathovagal balance Kumarathurai et al.

The authors hypothesize that the chronotropic effect of liraglutide, which may be mediated through the GLP-1 receptor on the sinoatrial node, cannot explain the worsening of HRV measures; instead, the impaired HRV may be due to a direct influence on sympathovagal balance, as reflected by the increase in night-time HR in conjunction with the significant decrease in sdNN and rMSSD suggesting an impairment of parasympathetic activity.

The addition of a cholinergic agent to a GLP-1 analog might recapture the loss of cholinergic activity induced by a GLP-1 analog. This might even be a useful strategy to further enhance the cardiac protection afforded by the SGLT-2 inhibitors.

A number of researchers have demonstrated that autonomic balance can be restored using simple lifestyle interventions, potentially reversing CAN. Motooka et al. Removing the dog resulted in reversal of this benefit with sympathetic overactivity Motooka et al.

There is strong evidence indicating that individuals with greater aerobic capacity exhibit enhanced HRV Tulppo et al. Furthermore several studies have shown significant improvements in HRV measures after different training programs including cycling, walking, jogging and water aerobic exercise training in subjects with CAD Laing et al.

We have documented that falls and fractures in older diabetics were often the result of loss of organized variability, strength, and reaction times. Very simple strength and balance training can significantly reduce falls risk Morrison et al. For patients with orthostatic hypotension, volume repletion with both fluids and salt is central to management, but physical activity and exercise are essential to prevent deconditioning, which is known to exacerbate orthostatic intolerance Pop-Busui et al.

The relationship between HRV and different psychiatric disorders, as well as stress and trauma, has also been extensively studied Thayer et al. Subjects with depression and anxiety disorders exhibit abnormal HRV patterns compared with non-psychiatric controls Servant et al.

Reduced HRV characterizes emotional dysregulation, decreased psychological flexibility and defective social engagement, which in turn are linked to prefrontal cortex hypoactivity Sgoifo et al. High occupational stress has also been associated with lowered HRV, specifically with reduced parasympathetic activation.

There is limited evidence that use of biofeedback with relaxation and meditation approaches may result in increased HRV and parasympathetic activity Servant et al.

A more detailed review on this topic is beyond the scope of this article and the reader can refer to recent reviews on the subject. Prevention of CAN should be a primary focus of lifestyle and other clinical interventions.

Intense glycemic control The Diabetes Control and Complications Trial Research Group, utilizing a step-by-step progressive lowering of hyperglycemia, lipids, and BP, in addition to the use of antioxidants Ziegler and Gries, and ACE inhibitors Athyros et al.

CAN progressed in both treatment groups during the EDIC follow-up, but the prevalence and incidence continued to be decreased in the previous intensive group compared to the standard group despite comparable levels of glycemic control.

To diminish the development of CAN, intense glucose control of T1DM ought to be started as soon as possible Pop-Busui et al. However, in patients with established CAN, glycemic control may need to be less stringent to avoid hypoglycemia and adverse drug effects Inzucchi et al.

The American Diabetes Association also recommends that individuals with CAN have a cardiac evaluation before starting or increasing physical activity for safety reasons American Diabetes Association, ; Pop-Busui et al. Pathogenesis-oriented interventions may promote some degree of reversal of established CAN Vinik et al.

Lifestyle interventions, increased physical activity, β-adrenergic blockers, aldose reductase inhibitors, ACE inhibitors, ARBs, and potent antioxidants such as α-lipoic acid have all been shown to restore autonomic balance.

Enhanced glycemic control with a reduced HbA1c from 9. The Veterans Administration Cooperative Study showed no impact on the occurrence of CAN after 2 years of intense glycemic control in patients with T2DM Azad et al.

Although glucose-lowering agents exerted the least benefit in comparison with antihypertensive treatments, lipid-lowering agents, aspirin, and vitamin-mineral supplements Gaede et al. Early identification of CAN also may allow for the well-timed initiation of antioxidant alpha-lipoic acid therapies that slow or reverse advancement of CAN Ziegler and Gries, Certain medications hold promise for the prevention and reversal of CAN.

Early therapeutic intervention with ACE inhibition or ARBs improved both CAN and left ventricular diastolic dysfunction after 1 year of treatment in patients with no symptoms and long-term diabetes. The combined therapies were slightly superior to monotherapies, auguring well for patients with established CAN Didangelos et al.

Treatment with fluvastatin improves cardiac sympathetic neuropathy in the diabetic rat heart in relation to attenuation of increased cardiac oxidative stress Matsuki et al.

Alternatively, selective inactivation of cyclooxygenase-2 COX-2 guards against sympathetic denervation in experimental diabetes by decreasing intramyocardial oxidative stress and inflammation Kellogg et al. Consequently, statins and COX-2 inactivation may assist in attenuating cardiac sympathetic dysfunction.

Successful pancreas transplantation showed improvements in epinephrine response and normalized hypoglycemia symptom awareness in patients with established diabetes Burger et al. Weight loss and weight-reducing surgeries may also potentially reduce CAN. ANS dysfunction and increased sympathetic activity have been directly correlated with obesity Piestrzeniewicz et al.

et al. Moreover, weight reduction significantly improves HRV and reduces ANS imbalances Karason et al. To evaluate the ability to reverse autonomic imbalance, we examined sudomotor function and HRV measurements in obese patients undergoing bariatric surgery.

Patients were assessed at baseline, 4, 12, and 24 weeks after vertical sleeve gastrectomy or Roux-en-Y gastric bypass. Seventy subjects completed at least weeks of follow-up.

Sudorimetry results of ESC of feet improved significantly trending toward normal in T2DM patients. HRV improved significantly, as did many other metabolic parameters.

Improvements in feet ESC were shown to be independently associated with HbA1c, insulin, and HOMA2-IR levels at baseline, as well as HbA1c at 24 weeks. Additionally, improvement in basal HR had an independent association with HbA1C, insulin and HOMA2-IR levels.

These positive results suggest that bariatric surgery can return both cardiac and sudomotor autonomic C-fiber dysfunction in those with diabetes to normal, possibly positively influencing morbidity and mortality Casellini et al.

The host of targets that are potential candidates for reduction of cardiovascular risk have been addressed in the previous paragraphs. For years we were confronted with glycemic control as the only measure by the glucocentric majority and those who believed in the lipid hypothesis who have now carried this to the extreme of need for even lower LDL-C in high risk patients.

The entry of SGLT2 inhibitors and the incretins shed new light on the challenge armed with new ammunition and also created an avenue of adventure for those interested in novel pathways. However the initial inroad into reduction of CV events was a discovery of the power of resetting a biologic clock and targeting the brain rather than other members of the dreadful dektet!

It has been established that there is a brain dopamine deficiency in obese diabetic patients present in the early hours of the morning Cincotta et al. The working hypothesis is that in early morning, decreased dopaminergic tone in the hypothalamus unbridles sympathetic activation with all its consequences, as illustrated in Figure 1.

Restoring the morning peak in dopaminergic activity by dopamine D2 receptor-mediated activities may, therefore, restore ANS balance. FIGURE 1. Schematic of dopamine — clock interactions in the regulation of fuel metabolism. Figure illustrates the hypothalamic clock with decreased suprachiasmic nuclear SCN early morning peak of dopamine activity and enhanced activity of the paraventricular nucleus PVN , which increase autonomic tone and the paraventricular nucleus to raise levels of corticotrophin releasing hormone CRH.

The consequences include activation of the sympathetic nervous system SNS hypothalamic and glucose sensitization reducing parasympathetic vagal drive to the liver and resistance to both leptin and insulin. CRH, corticotrophin releasing hormone; eNOS, endothelial nitric oxide synthase; FFAs, free fatty acids; NPY, neuropeptide Y; PVN, paraventricular nucleus; SCN, suprachiasmatic nucleus; SNS, sympathetic nervous system; TGs, triglycerides; VMH, ventromedial hypothalamus Raskin and Cincotta, It may also be possible to reset the biologic hypothalamic clock and ANS function using bromocriptine QR to restore morning dopaminergic activity.

It sensitizes the body to insulin and reduces sympathetic tone thereby reducing HR Raskin and Cincotta, Bromocriptine QR has also demonstrated a favorable effect on CV outcomes in clinical trials Figure 1 and Table 2 Gaziano et al. Our current quest is to determine if any of the novel discoveries in cardiovascular outcome studies CVOTs are indeed working through rebalancing the ANS thereby creating a wonderful opportunity for taking a fork in the road.

TABLE 2. Impact of bromocriptine-QR on CV death-inclusive composite cardiovascular endpoint and individual components of the composite as well as the MACE endpoint.

An improvement in ANS balance may be critical to reducing cardiovascular events and early mortality. Symptoms and signs of autonomic dysfunction, including resting HR, BP responses to standing, and time and frequency measures of HRV in response to deep breathing, standing and Valsalva maneuver, should be elicited from all patients with diabetes to allow for early detection and intervention.

Rather than intensifying diabetes blood glucose management, a regimen tailored to the individual risk of ANS dysfunction should be constructed. The advent of new agents that may have the potential to improve ANS function, such as the SGLT2 inhibitors and the GLP-1 agonists, should be considered.

However, it is not clear how these compounds work and what the mechanism of reduction of major adverse cardiovascular events is. An overlooked mechanism is a resetting of the biologic clock with correction of the dopamine deficiencies in the brainstem of obese people with diabetes, restoring the functioning of the ANS with its potential for significant reduction of cardiovascular events.

AV conceived of the presented idea and took the lead in writing the manuscript. CC and HP assisted in theory development, background research, and critical revisions to incorporate important intellectual content.

SC participated in the manuscript development in the following ways: a substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work; b drafting the work or revising it critically for important intellectual content; c final approval of the version to be published; d agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

M-LN critical review and manuscript editing. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

ACCORD, action to control cardiovascular risk in diabetes; ACE inhibitors, angiotensin-converting enzyme inhibitors; AN, autonomic neuropathy; ANS, autonomic nervous system; ARBs, angiotensin receptor blockers; BP, blood pressure; CAD, coronary artery disease; CAN, cardiac autonomic neuropathy; CARTs, cardiovascular autonomic reflex tests; COX-2, cyclooxygenase-2; CVD, cardiovascular disease; DCCT, diabetic control and complications trial; DM, diabetes mellitus; DN, diabetic neuropathy; DPN, diabetic peripheral neuropathy; EDIC, epidemiology of diabetes interventions and complications; GLP-1, glucagon-like peptide-1; HF, high frequency; HR, heart rate; HRV, heart rate variability; LF, low frequency; Lfa, low frequency area; MI, myocardial ischemia; Rfa, respiratory frequency area; rMSSD, root-mean-square of the difference of successive R—R interval; sdNN, standard deviation of all normal R—R intervals; T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus.

Alzaid, A. Diabetes Technol. doi: PubMed Abstract CrossRef Full Text Google Scholar. American Diabetes Association Standards of medical care in diabetes - Diabetes Care 40 Suppl. Google Scholar. Athyros, V. Long-term effect of converting enzyme inhibition on circadian sympathetic and parasympathetic modulation in patients with diabetic autonomic neuropathy.

Acta Cardiol. PubMed Abstract Google Scholar. Azad, N. The effects of intensive glycemic control on neuropathy in the VA cooperative study on type II diabetes mellitus VA CSDM. Diabetes Complications 13, — Bernardi, L.

Methods of investigation for cardiac autonomic dysfunction in human research studies. Diabetes Metab. Boyle, J. Projection of the year burden of diabetes in the US adult population: dynamic modeling of incidence, mortality, and prediabetes prevalence.

Health Metr. Brownlee, M. Melmed, K. Polonsky, P. Larsen, and H. Kronenberg Philadelphia, PA: Elsevier , — Burger, A. Effects of glycemic control on heart rate variability in type I diabetic patients with cardiac autonomic neuropathy.

CrossRef Full Text Google Scholar. Carnethon, M. The association among autonomic nervous system function, incident diabetes, and intervention arm in the Diabetes Prevention Program.

Diabetes Care 29, — Casellini, C. Bariatric surgery restores cardiac and sudomotor autonomic C-fiber dysfunction towards normal in obese subjects with type 2 diabetes. PLoS One e Sudoscan, a noninvasive tool for detecting diabetic small fiber neuropathy and autonomic dysfunction.

Cincotta, A. Bromocriptine improves glycaemic control and serum lipid profile in obese Type 2 diabetic subjects: a new approach in the treatment of diabetes. Expert Opin. Investig Drugs 8, — Convertino, V. Neurohumoral mechanisms associated with orthostasis: reaffirmation of the significant contribution of the heart rate response.

Cowie, C. Full accounting of diabetes and pre-diabetes in the U. population in and Diabetes Care 32, —

Rodica Pop-Busui; Cardiac Autonomic Neuropathy in Cardiovasular : Citrus aurantium for immune system clinical perspective. Cardiovasculra Care Diabetid February ; 33 2 : — This review covers the epidemiology, Caffeine and focus, Diabetic neuropathy and cardiovascular disease presentation, and diagnosis of cardiac autonomic neuropathy CAN in diabetes and discusses current evidence on approaches to prevention and treatment of CAN. She had a year history of poor diabetes control presenting with wide blood glucose fluctuations, recurrent episodes of severe hypoglycemia, and hypoglycemia unawareness. Over time she developed persistent orthostatic hypotension with daily falls in systolic blood pressure ranging from 30—60 mmHg. Autonomic nervous Diabettic ANS imbalance manifesting as Diahetic autonomic neuropathy in the cardovascular population is Diabetic neuropathy and cardiovascular disease Diabefic predictor of cardiovascular events. Symptoms and signs of ANS Fat content in popular foods, Diabetic neuropathy and cardiovascular disease Diiabetic resting heart rate elevations, diminished blood pressure responses to standing, cardiovsacular altered time and frequency domain measures of heart rate variability in response to deep breathing, standing, and the Valsalva maneuver, should be elicited from all patients with diabetes and prediabetes. With the recognition of the presence of ANS imbalance or for its prevention, a rigorous regime should be implemented with lifestyle modification, physical activity, and cautious use of medications that lower blood glucose. Rather than intensifying diabetes control, a regimen tailored to the individual risk of autonomic imbalance should be implemented. New agents that may improve autonomic function, such as SGLT2 inhibitors, should be considered and the use of incretins monitored. Diabetic neuropathy and cardiovascular disease

Diabetic neuropathy and cardiovascular disease -

Razanskaite-Virbickiene D , Danyte E, Mockeviciene G, Dobrovolskiene R, Verkauskiene R, Zalinkevicius R. Can coefficient of variation of time-domain analysis be valuable for detecting cardiovascular autonomic neuropathy in young patients with type 1 diabetes: a case control study.

BMC Cardiovasc Disord. Astrup AS , Tarnow L, Rossing P, Hansen BV, Hilsted J, Parving HH. Cardiac autonomic neuropathy predicts cardiovascular morbidity and mortality in type 1 diabetic patients with diabetic nephropathy.

Diabetes Care. Fisher VL , Tahrani AA. Cardiac autonomic neuropathy in patients with diabetes mellitus: current perspectives. Diabetes Metab Syndr Obes. Williams SM , Eleftheriadou A, Alam U, Cuthbertson DJ, Wilding JPH.

Cardiac Autonomic Neuropathy in Obesity, the Metabolic Syndrome and Prediabetes: A Narrative Review. Diabetes Ther. Pop-Busui R , Boulton AJ, Feldman EL, Bril V, Freeman R, Malik RA, Sosenko JM, Ziegler D. Diabetic Neuropathy: A Position Statement by the American Diabetes Association.

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.

Diabetes Metab J. Eleftheriadou A , Williams S, Nevitt S, Brown E, Roylance R, Wilding JPH, Cuthbertson DJ, Alam U.

The prevalence of cardiac autonomic neuropathy in prediabetes: a systematic review. Hu FB , Satija A, Manson JE. Curbing the Diabetes Pandemic: The Need for Global Policy Solutions. Williams R , Colagiuri S, Chan J, Gregg E, Ke C, Lim L-L.

IDF Atlas 9th Edition Brussels: Belgium, World Health Organization. Key facts. In: World Health Organization [Internet]. Haththotuwa RN , Wijeyaratne CN, Senarath U. Chapter 1 - Worldwide epidemic of obesity.

In: Mahmood TA, Arulkumaran S, Chervenak FA. Obesity and Obstetrics Second Edition. Elsevier, Eckel RH , Blaha MJ. Cardiometabolic Medicine: A Call for a New Subspeciality Training Track in Internal Medicine. Am J Med. Lopez-Jaramillo P , Lahera V, Lopez-Lopez J.

Epidemic of cardiometabolic diseases: a Latin American point of view. Ther Adv Cardiovasc Dis. Reiter-Brennan C , Cainzos-Achirica M, Soroosh G, Saxon DR, Blaha MJ, Eckel RH.

Cardiometabolic medicine - the US perspective on a new subspecialty. Cardiovasc Endocrinol Metab. Pan Q , Li Q, Deng W, Zhao D, Qi L, Huang W, Ma L, Li H, Li Y, Lyu X, Wang A, Yao H, Guo L, Xing X.

Prevalence and Diagnosis of Diabetic Cardiovascular Autonomic Neuropathy in Beijing, China: A Retrospective Multicenter Clinical Study. Front Neurosci. Rolim LC , Sá JR, Chacra AR, Dib SA. Diabetic cardiovascular autonomic neuropathy: risk factors, clinical impact and early diagnosis.

Arq Bras Cardiol. Serhiyenko VA , Serhiyenko AA. Cardiac autonomic neuropathy: Risk factors, diagnosis and treatment. Agashe S , Petak S. Cardiac Autonomic Neuropathy in Diabetes Mellitus. Methodist Debakey Cardiovasc J.

Watkins PJ , Mackay JD. Cardiac denervation in diabetic neuropathy. Ann Intern Med. Bradbury S , Eggleston C. Postural hypotension: A report of three cases. Am Heart J. Rundles RW. Diabetic Neuropathy: General Review with Report of Cases. Mackay JD , Page MM, Cambridge J, Watkins PJ.

Diabetic autonomic neuropathy. The diagnostic value of heart rate monitoring. Lloyd-Mostyn RH , Watkins PJ. Total cardiac denervation in diabetic autonomic neuropathy.

Watkins PJ , Edmonds ME. Sympathetic nerve failure in diabetes. Boutagy NE , Sinusas AJ. Recent Advances and Clinical Applications of PET Cardiac Autonomic Nervous System Imaging.

Curr Cardiol Rep. Sheng Y , Zhu L. The crosstalk between autonomic nervous system and blood vessels. Int J Physiol Pathophysiol Pharmacol. Dyavanapalli J. Novel approaches to restore parasympathetic activity to the heart in cardiorespiratory diseases. Am J Physiol Heart Circ Physiol.

Breder ISS , Sposito AC. Cardiovascular autonomic neuropathy in type 2 diabetic patients. Rev Assoc Med Bras Colombo J , Arora R, Depace N, Vinik A. Clinical autonomic dysfunction: Measurement, indications, therapies, and outcomes. Springer International Publishing, Shen MJ , Zipes DP.

Role of the autonomic nervous system in modulating cardiac arrhythmias. Circ Res. Wang YC. Rehabilitation of Patients With Neuropathies. In: Cifu DX, Lew HL. Braddom's Rehabilitation Care: A Clinical Handbook. Yun JS , Park YM, Cha SA, Ahn YB, Ko SH. Progression of cardiovascular autonomic neuropathy and cardiovascular disease in type 2 diabetes.

Cardiovasc Diabetol. Dayem SM , Battah AA, Bohy Ael M. Cardiovascular Autonomic Neuropathy and Early Atherosclerosis in Adolescent Type 1 Diabetic Patient. Open Access Maced J Med Sci.

Singh VP , Bali A, Singh N, Jaggi AS. Advanced glycation end products and diabetic complications. Korean J Physiol Pharmacol.

Luevano-Contreras C , Chapman-Novakofski K. Dietary advanced glycation end products and aging. Egaña-Gorroño L , López-Díez R, Yepuri G, Ramirez LS, Reverdatto S, Gugger PF, Shekhtman A, Ramasamy R, Schmidt AM.

Receptor for Advanced Glycation End Products RAGE and Mechanisms and Therapeutic Opportunities in Diabetes and Cardiovascular Disease: Insights From Human Subjects and Animal Models. Front Cardiovasc Med. Kong DH , Kim YK, Kim MR, Jang JH, Lee S. Emerging Roles of Vascular Cell Adhesion Molecule-1 VCAM-1 in Immunological Disorders and Cancer.

Int J Mol Sci. Kim JK. Endothelial nuclear factor κB in obesity and aging: is endothelial nuclear factor κB a master regulator of inflammation and insulin resistance?

Pizzino G , Irrera N, Cucinotta M, Pallio G, Mannino F, Arcoraci V, Squadrito F, Altavilla D, Bitto A. Oxidative Stress: Harms and Benefits for Human Health. Oxid Med Cell Longev. 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. Acta Diabetol. Tangvarasittichai S. Oxidative stress, insulin resistance, dyslipidemia and type 2 diabetes mellitus. Dimitropoulos G , Tahrani AA, Stevens MJ.

Cardiac autonomic neuropathy in patients with diabetes mellitus. Noncommunicable diseases: Obstructive sleep apnoea syndrome. Management-Screening, Diagnosis and Treatment. Spicuzza L , Caruso D, Di Maria G. Obstructive sleep apnoea syndrome and its management. Ther Adv Chronic Dis.

Maser RE , Pfeifer MA, Dorman JS, Kuller LH, Becker DJ, Orchard TJ. Diabetic autonomic neuropathy and cardiovascular risk. Pittsburgh Epidemiology of Diabetes Complications Study III.

Arch Intern Med. Ewing DJ , Boland O, Neilson JM, Cho CG, Clarke BF. Autonomic neuropathy, QT interval lengthening, and unexpected deaths in male diabetic patients.

Tang Y , Shah H, Bueno Junior CR, Sun X, Mitri J, Sambataro M, Sambado L, Gerstein HC, Fonseca V, Doria A, Pop-Busui R. Intensive Risk Factor Management and Cardiovascular Autonomic Neuropathy in Type 2 Diabetes: The ACCORD Trial. Suarez GA , Clark VM, Norell JE, Kottke TE, Callahan MJ, O'Brien PC, Low PA, Dyck PJ.

Sudden cardiac death in diabetes mellitus: risk factors in the Rochester diabetic neuropathy study. J Neurol Neurosurg Psychiatry. Cox AJ , Azeem A, Yeboah J, Soliman EZ, Aggarwal SR, Bertoni AG, Carr JJ, Freedman BI, Herrington DM, Bowden DW.

Heart rate-corrected QT interval is an independent predictor of all-cause and cardiovascular mortality in individuals with type 2 diabetes: the Diabetes Heart Study. Pop-Busui R , Evans GW, Gerstein HC, Fonseca V, Fleg JL, Hoogwerf BJ, Genuth S, Grimm RH, Corson MA, Prineas R; Action to Control Cardiovascular Risk in Diabetes Study Group.

Effects of cardiac autonomic dysfunction on mortality risk in the Action to Control Cardiovascular Risk in Diabetes ACCORD trial. Sagesaka H , Sato Y, Someya Y, Tamura Y, Shimodaira M, Miyakoshi T, Hirabayashi K, Koike H, Yamashita K, Watada H, Aizawa T.

Type 2 Diabetes: When Does It Start? J Endocr Soc. Vinik AI , Casellini C, Parson HK, Colberg SR, Nevoret ML. Cardiac Autonomic Neuropathy in Diabetes: A Predictor of Cardiometabolic Events.

Ewing DJ , Clarke BF. Diagnosis and management of diabetic autonomic neuropathy. Br Med J Clin Res Ed. Ewing DJ , Campbell IW, Burt AA, Clarke BF.

Vascular reflexes in diabetic autonomic neuropathy. Ewing DJ , Campbell IW, Murray A, Neilson JM, Clarke BF. Immediate heart-rate response to standing: simple test for autonomic neuropathy in diabetes.

Br Med J. Ewing DJ , Martyn CN, Young RJ, Clarke BF. The value of cardiovascular autonomic function tests: 10 years experience in diabetes. Bissinger A. Cardiac Autonomic Neuropathy: Why Should Cardiologists Care about That?

J Diabetes Res. Zygmunt A , Stanczyk J. Methods of evaluation of autonomic nervous system function. Arch Med Sci. Didangelos T , Moralidis E, Karlafti E, Tziomalos K, Margaritidis C, Kontoninas Z, Stergiou I, Boulbou M, Papagianni M, Papanastasiou E, Hatzitolios AI. A Comparative Assessment of Cardiovascular Autonomic Reflex Testing and Cardiac I-Metaiodobenzylguanidine Imaging in Patients with Type 1 Diabetes Mellitus without Complications or Cardiovascular Risk Factors.

Int J Endocrinol. Migisha R , Agaba DC, Katamba G, Kwaga T, Tumwesigye R, Miranda SL, Muyingo A, Siedner MJ. Prevalence and Correlates of Cardiovascular Autonomic Neuropathy Among Patients with Diabetes in Uganda: A Hospital-Based Cross-sectional Study.

Glob Heart. Pafili K , Trypsianis G, Papazoglou D, Maltezos E, Papanas N. In patients with DCAN, the transition from supine to standing position can cause abnormal responses, such as hypotension, tachycardia or even bradycardia [3, 7, 8].

Blood volume depletion due to diuretic therapy, sweating, diarrhea or polyuria and concomitant antihypertensive medication such as β-blockers, insulin, tricyclic antidepressants and phenothiazines, can also contribute to OH development [3, 7, 8]. It usually presents as dizziness, fatigue, visual disturbances, syncope, but may also remain asymptomatic [3, 7, 8].

Postural orthostatic tachycardia syndrome is diagnosed when a greater than 30 bpm increase or a heart rate of over bpm is documented within 12 min of transition from the supine to the upright position during tilt test; however, the exact pathophysiological mechanisms implicated in these responses have not yet been fully elucidated [3, 7, 8], as it is an independent prognostic factor for CVD and all-cause mortality [3, 7, 8].

The pathogenesis of QTc prolongation is multifactorial and includes imbalance in cardiac sympathetic innervation, intrinsic metabolic and electrolytic myocardial changes, LVH, CAD, and genetic factors [3, 7, 8.

Patients with DCAN exhibit a two to threefold increase in perioperative morbidity and mortality, are more likely to require vasopressor support in the operation room, and are also prone to experience a BP and HR reduction during the induction of anesthesia, as well as severe intraoperative hypothermia [3, 7, 8].

The above findings can be explained by an impairment or absence of the normal vasoconstrictive response [3, 7, 8]. SMI is a clinical entity not well clarified, believed to result from damage of the ANS pathways of pain [3, 7, 8.

PET studies have detected a failure in signal transmission from the thalamus to the frontal cortex in individuals with SMI, implying that unsensed ischemia might not only be a matter of impaired peripheral neural conduction but also be a result of central nervous system disorders [3, 7, 8].

Patients with DCAN show delayed onset of angina symptoms after the appearance of ECG ischemic changes during exercise testing or very often develop atypical symptoms such as unexplained fatigue, confusion, hemoptysis, nausea, vomiting, sweating, arrhythmia, coughing and dyspnea [3, 7, 8]. Therefore, presence of atypical symptoms should be regarded as of myocardial origin unless proven otherwise [3, 7, 8].

Non-diabetic subjects present with predominance of vagal tone and decreased sympathetic tone at night, associated with reduction in nocturnal BP.

In diabetic DCAN, this pattern is altered, resulting in nocturnal sympathetic predominance during sleep and subsequent nocturnal hypertension, also known as non-dipping and reverse dipping [3, 7, 8].

These are associated with a higher frequency of LVH and fatal and severe non-fatal cardiovascular events in DCAN subjects with a two to eightfold increase in risk of cardiovascular or renal events in some longitudinal studies [3, 7, 8]. Early detection of DCAN is of paramount importance, since it can lead to prompt therapeutic interventions, resulting in a significant survival benefit [3, 4, 7, 8].

Medical history and physical examination are inadequate for the diagnosis which requires specific diagnostic tests. Subclinical DCAN may be detected within 1 year of diagnosis in T2DM and within 2 years of diagnosis in T1DM [8].

In early , Ewing et al described five simple tests for non-invasive autonomic evaluation [11]: heart rate response to breathing, heart rate response to standing, Valsalva maneuver, blood pressure response to standing and blood pressure response to sustained handgrip.

Conventional cardiovascular autonomic reflex tests CARTs are non-invasive, safe, clinically relevant they correlate with tests of peripheral nervous system function , easy to perform, sensitive, specific, reproducible, and standardized. Therefore, they are considered the gold standard measures of autonomic function [3, 4, 7, 8].

While CARTs Table 1 have been widely used since their introduction, there is no evidence on the superiority of one test over another when it comes to assessing DCAN [3, 4, 7, 8].

The orthostatic hypotension test has low sensitivity and high specificity, making it suboptimal for diagnosis [3, 4, 7, 8]. Other methods such as cardiac sympathetic imaging, microneurography, occlusion plethysmography, and baroreflex sensitivity are currently used predominantly in research settings but may find a place in the clinical assessment of DCAN in the future [3, 4, 7, 8].

However, cardiovascular tests based on HR response to deep breathing, lying to standing and Valsalva maneuver, and BP response to standing OH test are an essential and irreplaceable part of DCAN diagnosis [3, 4, 7, 8].

Modified and reproduced with permission from Karayannis G, Giamouzis G, Cokkinos DV, Skoularigis J, Triposkiadis F. Diabetic cardiovascular autonomic neuropathy: clinical implications. Expert Rev Cardiovasc Ther. Abbreviations: HR: heart rate; HRV: heart rate variability; SBP: systolic blood pressure; DBP: diastolic blood pressure; QTc: corrected QT interval; MIBG: metaiodobenzylguanidine; HED: metahydroxyephedrine.

Among the physiological factors affecting the test results, the most important are: age, respiratory pattern, body position and duration of supine rest, resting heart rate and BP, physical exercise within 24 hrs, coffee, alcohol and cigarette consumption, meals, and drugs [3, 4, 7, 8].

In the case of altered cardiovascular tests in the baseline evaluation, it is advisable to repeat the tests annually in order to confirm the diagnosis of DCAN and evaluate its progression [4].

Moreover, even in the absence of alterations of cardiovascular tests, it is advisable to repeat the tests annually in diabetic patients with poor glycemic control, high cardiovascular risk and microangiopathic complications, whereas in the other patients a longer interval is recommended [3, 4, 8].

Apparently, not all diabetics require autonomic function assessment [3, 4, 8]. Table 2 contains a summary of indications for testing.

Abbreviations: CARTs: cardiovascular autonomic reflex tests; CVD: cardiovascular disease; DLP: dyslipidemia; HbA1c: glycated hemoglobin; HTN: hypertension; T2DM: type 2 diabetes mellitus; T1DM: type 1 diabetes mellitus.

The available information regarding the duration required to progress from an earlier to a later stage of impairment is scant and it is not documented whether a progression to OH and symptomatic forms invariably occurs in all patients [3, 4, 7, 8].

Following the 8th International Symposium on Diabetic Neuropathy in , criteria for diagnosis and staging of DCAN were defined in the Subcommittee of the Toronto Consensus Panel Statement Figure 1 [4]. Progressive stages of DCAN are associated with an increasingly worse prognosis [1, 4, 7, 8, 10].

Reproduced with permission from Spallone V, Ziegler D, Freeman R, Bernardi L, Frontoni S, Pop-Busui R, et al. Cardiovascular autonomic neuropathy in diabetes: clinical impact, assessment, diagnosis, and management. Diabetes Metab Res Rev. Abbreviations: CAN: cardiac autonomic neuropathy; HR: heart rate.

DCAN is a complication that confers a higher morbidity and mortality from cardiovascular and all causes [1, 4, ]. The prognostic importance of DCAN presence was initially identified in the early s, when DCAN was associated with a nearly fivefold increase in mortality risk [11].

Since then, a large number of publications have verified this association [4, 9, 10, 12, 13]. Among 2, T1DM patients, DCAN was a significant predictor of 7-year mortality, exceeding the relative effect of the traditional CVD risk factors [16].

The pathophysiological mechanisms contributing to increased mortality are not yet clear. These include: SMI, disturbances in coronary flow regulation, increased HR, diastolic and systolic LV dysfunction, QTc prolongation and increased risk for arrhythmias, diminished sense of hypoglycemia and difficult recovery due to dysregulation of compensatory endocrine mechanisms, acceleration of renal impairment, alterations of circadian BP cycle, increased susceptibility to medications that cause respiratory depression, impaired respiratory response to hypoxia, increased sympathetic activity and increased calcification of the coronary arteries 1, 4, A meta-analysis of 15 longitudinal studies, which included a total of 2, patients followed up for 16 years, showed that the diagnosis of DCAN based on at least two abnormal CARTs results determined a relative risk of mortality of 3.

Moreover, the pooled relative risk of mortality in clinic-based studies that used more than one index was considerably higher than in studies that used only one [12, 16, 17]. The association of DCAN with nephropathy [12, 14, 15], post MI [12], QTc prolongation [9, 12, 16, 17] and neuropathy [9, ] increases the risk for mortality and CVD morbidity.

Moreover, DCAN was associated with LV systolic and particularly diastolic dysfunction in the absence of cardiac disease [3, 4, 8].

Each manifestation of DCAN is associated with increased morbidity and mortality in these patients. Poor glycemic control [3, 7, 8], high glycemic variability [3, 7, 8] and hypoglycemia [9] have been related to the development of this complication, together with the presence of multiple cardiovascular risk factors which seem to modulate the progression and types of manifestation the patients develop [3, ].

A good glycemic and CVD risk factor control avoiding glycemic variability and hypoglycemia seems the most important therapeutic approach for its prevention [3, ]. Once established, the avoidance of hypoglycemia with a less stringent but good glycemic control [3, ] associated with a cardiovascular risk reduction strategy [3, 4, 7, 8, 18] and use of beta-blockers to counteract sympathetic hyperactivation [19] is vital to slow its progression.

Once OH is present, avoidance of hypotension is essential, since a strict control of blood pressure has been related in this patient with excessive mortality [9].

Thus, in diabetic patients, BP should not be measured only in the seated position when adjusting antihypertensive treatment, and drugs with adverse autonomic consequences and potential for QTc prolongation should be avoided [3, 4, 17].

Use of RAS blockade with ARBs, ACE inhibitors and spironolactone has no proven efficacy or impact in its course [3, ]. Small studies show promising results with the use of anticonvulsants [3, 4].

Several molecules with antioxidant and antifibrotic properties are being tested, looking to impact on its natural history [3, 4, 7, 8, 18, 20]. DCAN is a frequently forgotten and underdiagnosed microvascular complication of DM. Patients with this condition are at high risk of sustaining major cardiovascular events and death.

Diagnosis is simple but requires time and skills for making and interpreting CARTs. Screening can be done in the office at low cost. Actual DM management guidelines aim to reduce CVD mortality but have forgotten to address this issue.

Tailored and individualized management with avoidance of hypoglycemia and OH is important in these patients, since these events carry a high morbidity and mortality in this set of autonomic dysfunctioning patients.

It is imperative to begin recognizing DCAN to accomplish a better prognosis and reduce CVD mortality among people with longstanding DM. Dr Julian Eduardo Forero-Gómez 1 , MD; Dr Sandra Milena Botero 2 , MD; Dr Ángela Sofía Esparza 2 , MD; Dr Paula Andrea Sánchez-Moscoso 3 , MD. Internal Medicine, Clinical Associated Investigator, Asociación IPS Médicos Internistas de Caldas, Manizales, Colombia;.

CAN is a significant DM complication and is closely associated with increased risk of cardiovascular mortality. While it is a popular complication, its importance has not been fully understood in our societies and still hot field for research because: A The impact of sex on CAN epidemiology is controversial.

B The effect of ethnicity on CAN prevalence is controversial and little to nothing has been done in Arabs to the best of our knowledge. C CAN pathogenesis is complex, multifactorial, and still under much debate. The data that support the findings of this study are available from the corresponding author upon reasonable request.

Punthakee, Z. Definition, classification and diagnosis of diabetes, prediabetes and metabolic syndrome Diabetes Canada Clinical Practice Guidelines Expert Committee. Diabetes 42 Suppl 1 , S10—S Article PubMed Google Scholar. Razmaria, A. Diabetic neuropathy. JAMA 20 , Article CAS PubMed Google Scholar.

Vinik, A. Diabetic cardiac autonomic neuropathy, inflammation and cardiovascular disease. Diabetes Investig.

Article CAS PubMed PubMed Central Google Scholar. Serhiyenko, V. Cardiac autonomic neuropathy: Risk factors, diagnosis and treatment. World J. Diabetes 9 1 , 1— Article MathSciNet PubMed PubMed Central Google Scholar.

Pop-Busui, R. et al. Diabetic neuropathy: a position statement by the American diabetes association. Diabetes Care 40 , — Spallone, V. Cardiovascular autonomic neuropathy in diabetes: clinical impact, assessment, diagnosis, and management.

Diabetes Metab. Ziegler, D. Increased prevalence of cardiac autonomic dysfunction at different degrees of glucose intolerance in the general population: the KORA S4 survey.

Diabetologia 58 , — Jaiswal, M. Association between impaired cardiovascular autonomic function and hypoglycemia in patients with type 1 diabetes.

Diabetes Care 37 9 , — American Diabetes Association. Classification and diagnosis of diabetes: standards of medical care in diabetes Diabetes Care 42 Suppl 1 , S13—S28 Article Google Scholar.

Qiong, Y. Appropriate body mass index and waist-hip ratio cutoff points for overweight and obesity in adults of Northeast China. Iran J. Public Health 46 8 , — Google Scholar. Wang, H. Relationship between type 2 diabetes self- efficacy and quality of life: Analysis under varying glycated hemoglobin conditions.

Family Med. Recommendations for the use of cardiovascular tests in diagnosing diabetic autonomic neuropathy. Pathak, A. Evaluation of cardiovascular autonomic nervous functions in diabetics: study in a rural teaching hospital. Menon, A. Cardiac autonomic neuropathy in patients with type 2 diabetes mellitus at high risk for foot ulcers.

Indian J. Article PubMed PubMed Central Google Scholar. Dimitropoulos, G. Cardiac autonomic neuropathy in patients with diabetes mellitus. Diabetes 5 1 , 17— Balcıoğlu, A. Diabetes and cardiac autonomic neuropathy: clinical manifestations, cardiovascular consequences, diagnosis and treatment.

Diabetes 6 , 80— Albers, J. Diabetic neuropathy: mechanisms, emerging treatments, and subtypes. Cardiac autonomic neuropathy in diabetes: a clinical perspective.

Diabetes Care 33 2 , — Pafili, K. Rev Diabetes Stud. Lin, K. Combination of Ewing test, heart rate variability, and heart rate turbulence analysis for early diagnosis of diabetic cardiac autonomic neuropathy. Medicine Baltimore 96 45 , e Dixit, P. Effect of diabetes mellitus on resting heart rate, postural blood pressure, Valsalva ratio, and blood pressure response to handgrip test.

Diabetes Care 40 1 , 94— Memon, A. Health Sci. Qassim 11 5 , 26 AlOlaiwi, L. Prevalence of cardiovascular autonomic neuropathy and gastroparesis symptoms among patients with type 2 diabetes who attend a primary health care center.

PLoS ONE 13 12 , e Pillai, J. Cardiac autonomic neuropathy and QTc interval in type 2 diabetes. Heart India 3 1 , 8— Röhling, M.

Cardiorespiratory fitness and cardiac autonomic function in diabetes. Diabetes Res. Article CAS Google Scholar. Cha, S. Diabetic cardiovascular autonomic neuropathy predicts recurrent cardiovascular diseases in patients with type 2 diabetes. PLoS ONE 11 10 , e Tannus, L.

Predictors of cardiovascular autonomic neuropathy in patients with type 1 diabetes. Lausanne 5 , Kempler, P. Autonomic neuropathy is associated with increased cardiovascular risk factors: the EURODIAB IDDM Complications Study.

Diabetes Med. x Chung, J. Anemia, bilirubin, and cardiovascular autonomic neuropathy in patients with type 2 diabetes. Medicine Baltimore. Behera, B. Cardiac autonomic neuropathy in diabetes mellitus. ijrms Moningi, S. Autonomic disturbances in diabetes: Assessment and anaesthetic implications.

Bhuyan, A. A study of cardiac autonomic neuropathy in patients with type 2 diabetes mellitus: a Northeast India experience. Ahire, C. Prevalence of cardiac autonomic neuropathy in short and long-standing type 2 diabetics in western Maharashtra.

Basic Appl. Dimova, R. Risk factors for autonomic and somatic nerve dysfunction in different stages of glucose tolerance. Diabetes Complicat. Yun, J. Progression of cardiovascular autonomic neuropathy and cardiovascular disease in type 2 diabetes. Kurnikova, I.

Autonomic neuropathy in the development and progression of vascular complications of diabetes mellitus. Cardiovascular autonomic dysfunction predicts severe hypoglycemia in patients with type 2 diabetes: a year follow-up study.

Diabetes Care 37 1 , — Lai, Y. HbA1C variability is strongly associated with the severity of cardiovascular autonomic neuropathy in patients with Type 2 diabetes after longer diabetes duration. Front Neurosci.

Prentki, M. Islet beta-cell failure in type 2 diabetes. Makwana, K. Prognosis of cardiac autonomic neuropathy in patients with diabetes mellitus. Laitinen, T. Cardiovascular autonomic dysfunction is associated with central obesity in persons with impaired glucose tolerance.

Moţăţăianu, A. Cardiovascular autonomic neuropathy in context of other complications of type 2 diabetes mellitus. Welborn, T. Preferred clinical measures of central obesity for predicting mortality.

Srikanthan, P. Waist-hip-ratio as a predictor of all-cause mortality in high functioning older adults. Vasheghani, M. The association between cardiac autonomic neuropathy and diabetes control.

S

Diabetes Nutrition timing for peak performance one of the most common chronic pathologies around cardiovasscular world, disesse treatment cadriovascular general clinicians, endocrinologists, cardiologists, ophthalmologists, nephrologists and a multidisciplinary team. Patients Stays cleaner and fresher type 2 Diabetes Mellitus Citrus aurantium for immune system can neuroptahy affected by cardiac autonomic neuropathy, leading to increased mortality and morbidity. In this review, we will present current concepts, clinical features, diagnosis, prognosis, and possible treatment. New drugs recently developed to reduce glycemic level presented a pleiotropic effect of reducing sudden death, suggesting a potential use in patients at risk. Diabetes é uma das mais frequentes patologias crônicas em todo o mundo, cujo tratamento envolve uma equipe multidisciplinar, médicos generalistas, endocrinologistas, cardiologistas, nefrologistas e oftalmologistas.

Author: Malajora

3 thoughts on “Diabetic neuropathy and cardiovascular disease

Leave a comment

Yours email will be published. Important fields a marked *

Design by ThemesDNA.com