Cardiac Autonomic Neuropathy Progression Research Articles

#2293 Cardiac autonomic neuropathy: an independent risk factor for renal decline in diabetic kidney disease

Abstract Background and Aims Diabetic kidney disease (DKD) is the leading cause of chronic kidney disease (CKD) and end stage kidney disease (ESKD) in the UK and worldwide. Due to its unpredictability and incurable nature, novel risk factors associated with incidence and progression of DKD need to be identified. One such factor is cardiac autonomic neuropathy (CAN). Many studies over last 30 years had demonstrated a significant relationship between CAN and incidence and progression of DKD using estimated glomerular filtration rate (eGFR) and urinary albumin creatinine ratio (UACR) as end points. However, no prospective studies have looked into relationship between CAN diagnosed by gold standard cardiac autonomic reflex tests (CARTs) and DKD with different prognostic risks as per KDIGO classification. The aim of the study is to examine this relationship further. Method Data from 91 participants (type 1 and type 2 DM) with eGFR >30 ml/min/1.73 m2 who underwent assessment for CAN using CARTs as per O'Brien's and Ewing's criteria during baseline visits performed between 2007 and 2010 were collected. Additional participants (n = 113) were also recruited in 2021 as part of iBEAt study which is an EU-funded, multi-centre renal imaging study to identify novel biomarkers for DKD. Data analysis for 204 participants in total was performed for this study. CAN was defined as 2 or more abnormal CARTs out of 5 (Table 1). The level of prognostic risk was calculated based on eGFR (G1-G5) and UACR (A1-A3), following KDIGO risk table from 2012 CKD guidelines. eGFR was calculated by chronic kidney disease epidemiology collaboration (CKD-EPI) equation and UACR was assessed by early morning urine sample. Participants were categorised as follow: low risk, moderate risk and high risk. Due to limited numbers of participants with G3 in eGFR, we have combined ‘high risk’ and ‘very high risk’ into one group. CAN was divided into 2 groups—with and without CAN. Differences in proportions were examined using chi-square test. The association between baseline CAN and risk of renal decline was assessed using multinominal logistic regression adjusted for baseline age, HbA1c, ACEi/ARBs use, retinopathy status, total cholesterol and triglyceride. If significant differences were found, individual groups were compared by Bonferroni post hoc test. All analyses were performed in SPSS (version 29.0) and correlations were considered significant if p < 0.05. Results We analysed data of 204 participants (130 T1DM, 74 T2DM), 44.6% (n = 91) of them were women, mean (SD) age at baseline visit was 51 (15.7) years, eGFR 82.6 (13) ml/min/1.73 m2, UACR 5.2 (21.8) mg/mmol, duration of diabetes at baseline 19.7 (12.3) years and 36.8% had hypertension. Baseline eGFR and UACR were available for 198 and 193 participants respectively. Of these, 42.9% (85/198) had G1, 47.5 (94/198) had G2 and 9.6 (19/198) had G3. For UACR, 80.8% (156/193) had A1, 15.5% (30/193) had A2 and 3.6% (7/193) had A3. 53.4% (103/204) of participants had CAN and 46.6% (101/204) had no CAN. A higher proportion of participants was in low prognostic risk category 77.8% (154/198), followed by 13.1% (26/198) with moderate risk and 9.8% (18/198) with high risk for CKD progression. The risk of DKD progression was significantly associated with presence of CAN in multinominal logistic regression analysis (p = 0.020). The presence of CAN was closely related to low risk (95% CI: 1.44 to 22.04, p = 0.013) and moderately increased risk (95% CI: 1.03 to 24.7, p = 0.04). The participants with moderate and high risk had lower eGFR (p < 0.001) and higher UACR with increased risk (p < 0.001) (Table 2). This finding was independent of baseline age, HbA1C, retinopathy, ACEI/ARB use, type of diabetes, cholesterol and triglyceride levels at baseline as measured by logistic regression. Conclusion To our knowledge, this is one of the first studies to examine the relationship between presence of CAN in three stages of prognostic risk in DKD. We demonstrated that presence of CAN was an independent risk factor for decline in renal function in DKD. Further large prospective studies are required to confirm the findings of this study and examine the underlying mechanisms how CAN leads to greater risk of DKD.

A study of heart rate variability in diabetic mellitus patients

Background. Heart rate variability (HRV) is reduced in diabetes mellitus (DM) patients, suggesting dysfunction of cardiac autonomic regulation and an increased risk for cardiac events. Cardiac autonomic neuropathy (CAN), which results from damage to autonomic nerve fibers that innervate the heart and blood vessels, is a serious complication of DM. During progression of CAN, the parasympathetic nerve fibers innervating the heart are affected before the sympathetic nerve fibers leading to a reduced heart rate variability. The purpose of this study was to examine type 2 diabetes patients with heart rate variability in order to diagnose autonomic dysfunction and to relate the findings to other complications of diabetes mellitus. Materials and methods. 41 type 2 M patients and 45 age- and sex-matched controls were included. In the time domain we measured the mean R–R interval (NN), the standard deviation of the R–R interval index (SDNN), the standard deviation of the 5-min R–R interval mean (SDANN), the root mean square of successive R–R interval differences (RMSSD) and the percentage of beats with a consecutive R–R interval difference>50 ms (pNN50). In the frequency domain we measured high-frequency power (HF), low-frequency power (LF) and the LF/HF ratio. Results. There was no statistically significant difference between DM patients and controls for age and sex distribution. All time- and frequency-domain parameters except mean R–R interval and the LF/HF ratio were significantly lower in diabetes patients than in controls. When chronic complications of DM were examined, diabetic retinopathy and nephropathy were usually present together. For example, among six patients with nephropathy five also had retinopathy. There were 13 diabetes patients with complications (diabetic nephropathy and/or retinopathy) and nine patients with no diabetic complications. Although the chronological ages of the diabetes patients with and without complications were similar (53±9 and 49±12 years, respectively; P>0.05), the duration of DM in patients with complications was significantly greater than that of those without complications (14±9 versus 5±7 years; P=0.002). Diabetes patients had lower HRV values for time-domain and frequency-domain parameters than controls. Conclusions. Majority of heart rate variability parameters were lower in diabetes patients with chronic complications than in those without complications.

Диабетическая кардиальная автономная нейропатия: каковы перспективы в лечении?

Кардиальная автономная нейропатия (КАН) является серьезным и частым осложнением сахарного диабета. Несмотря на ее связь с повышенным риском сердечно-сосудистой смертности и различными симптомами и нарушениями, значимость КАН сложно переоценить. Изменение образа жизни, интенсивный гликемический контроль позволяют предотвратить развитие или прогрессирование КАН. Патогенетическое лечение КАН включает: сбалансированную диету и физическую активность; оптимизацию гликемического контроля; лечение дислипопротеинемии; коррекцию метаболических нарушений в миокарде; профилактику и лечение тромбоза; применение ингибиторов альдозоредуктазы; применение дигомо-гамма-линоленовой кислоты (ДГЛК); применение ацетил-L-карнитина, антиоксидантов, в первую очередь α-липоевой кислоты (α-ЛК), применение ω-3 и ω-6 полиненасыщенных жирных кислот (ω-3 и ω-6 ПНЖК), вазодилататоров, жирорастворимого витамина B1, аминогуанидина; заместительную терапию ростовыми факторами, в тяжелых случаях — лечение ортостатической гипотензии. Многообещающим является применение средств, которые повышают кровоток в vasa vasorum, в том числе аналогов простациклина, блокаторов тромбоксана А2, а также препаратов, которые способствуют усилению и/или нормализации функции Na+-,К+-АТФазы (ингибиторы фосфодиэстеразы), α-ЛК, ДГЛК, ω-3 ПНЖК, а также одновременное назначение α-ЛК, ω-3 ПНЖК и ДГЛК.

Diffusion Entropy vs. Multiscale and Rényi Entropy to Detect Progression of Autonomic Neuropathy.

We review the literature to argue the importance of the occurrence of crucial events in the dynamics of physiological processes. Crucial events are interpreted as short time intervals of turbulence, and the time distance between two consecutive crucial events is a waiting time distribution density with an inverse power law (IPL) index μ, with μ < 3 generating non-stationary behavior. The non-stationary condition is characterized by two regimes of the IPL index: (a) perennial non-stationarity, with 1 < μ < 2 and (b) slow evolution toward the stationary regime, with 2 < μ < 3. Human heartbeats and brain dynamics belong to the latter regime, with healthy physiological processes tending to be closer to the border with the perennial non-stationary regime with μ = 2. The complexity of cognitive tasks is associated with the mental effort required to address a difficult task, which leads to an increase of μ with increasing task difficulty. On this basis we explore the conjecture that disease evolution leads the IPL index μ moving from the healthy condition μ = 2 toward the border with Gaussian statistics with μ = 3, as the disease progresses. Examining heart rate time series of patients affected by diabetes-induced autonomic neuropathy of varying severity, we find that the progression of cardiac autonomic neuropathy (CAN) indeed shifts μ from the border with perennial variability, μ = 2, to the border with Gaussian statistics, μ = 3 and provides a novel, sensitive index for assessing disease progression. We find that at the Gaussian border, the dynamical complexity of crucial events is replaced by Gaussian fluctuation with long-time memory.

Effect of HMG-Co-A reductase inhibitors on cardiac autonomic neuropathy in diabetic patients

Objective: To observe the effect of statins on cardiac autonomic neuropathy in patients with diabetes and to study the correlation between cardiac autonomic neuropathy as assessed by cardiac autonomic reflex tests (CARTs) and by Composite Autonomic Symptom Scale (COMPASS)-31. Materials and Methods: A cross-sectional observational study was conducted on 62 patients having Type 2 diabetes mellitus for more than 5 years. Patients were randomized into two groups, one group received standard antidiabetic therapy and other group received standard antidiabetic along with statin medication at least for more than 1 year. Each patient underwent CART and heart rate variability to assess autonomic dysfunction. In addition, COMPASS 31 questionnaire was used to evaluate symptoms subjectively. Statin Experience Assessment Questionnaire was used to note adverse effects of statins. Chi-square test, Spearman correlation test, and Mann–Whitney U-test were used for statistical analysis. Results: A significant difference in severity of cardiac autonomic dysfunction was observed between two groups as measured by CART (P = 0.016) and COMPASS-31 questionnaire (P = 0.008). Moreover, COMPASS score of >16 was observed in patients with advanced cardiac autonomic neuropathy. A significant correlation was found between COMPASS 31 score and CART results (r = 0.29, P = 0.02). Conclusion: Our study highlights the potential utility of statins in curbing progression of cardiac autonomic neuropathy and can be safely administered in patients with Type 2 diabetes mellitus. COMPASS 31 questionnaire can be used as an effective screening tool for CART referral, facilitating the early detection of cardiac autonomic neuropathy.

Cardiac Autonomic Neuropathy: A Progressive Consequence of Chronic Low-Grade Inflammation in Type 2 Diabetes and Related Metabolic Disorders.

Cardiac autonomic neuropathy (CAN) is one of the earliest complications of type 2 diabetes (T2D), presenting a silent cause of cardiovascular morbidity and mortality. Recent research relates the pathogenesis of cardiovascular disease in T2D to an ensuing chronic, low-grade proinflammatory and pro-oxidative environment, being the hallmark of the metabolic syndrome. Metabolic inflammation emerges as adipose tissue inflammatory changes extending systemically, on the advent of hyperglycemia, to reach central regions of the brain. In light of changes in glucose and insulin homeostasis, dysbiosis or alteration of the gut microbiome (GM) emerges, further contributing to inflammatory processes through increased gut and blood–brain barrier permeability. Interestingly, studies reveal that the determinants of oxidative stress and inflammation progression exist at the crossroad of CAN manifestations, dictating their evolution along the natural course of T2D development. Indeed, sympathetic and parasympathetic deterioration was shown to correlate with markers of adipose, vascular, and systemic inflammation. Additionally, evidence points out that dysbiosis could promote a sympatho-excitatory state through differentially affecting the secretion of hormones and neuromodulators, such as norepinephrine, serotonin, and γ-aminobutyric acid, and acting along the renin–angiotensin–aldosterone axis. Emerging neuronal inflammation and concomitant autophagic defects in brainstem nuclei were described as possible underlying mechanisms of CAN in experimental models of metabolic syndrome and T2D. Drugs with anti-inflammatory characteristics provide potential avenues for targeting pathways involved in CAN initiation and progression. The aim of this review is to delineate the etiology of CAN in the context of a metabolic disorder characterized by elevated oxidative and inflammatory load.

542-P: Association of Cardiac Autonomic Dysfunction with Plasma Lipid Metabolites in Recent-Onset Type 2 Diabetes

Emerging evidence suggests that obesity and insulin resistance play a role in the development of diabetic cardiac autonomic neuropathy (CAN) characterized by reduced heart rate variability (HRV). In this context we assessed the relationship of 127 biomarkers of lipid metabolism (11 acylcarnitines, 39 free fatty acids, 12 sphingomyelins, 56 phosphatidylcholines, and 9 lysophosphatidylcholines) in plasma using mass spectrometry with HRV indices in individuals with recent-onset type 1 (T1D) or type 2 diabetes (T2D) from the baseline cohort (known diabetes duration (DD) ≤1 year) of the German Diabetes Study (T1D/T2D [mean±SD]: n=126/243; age: 34.5±12.9/53.4±11.0 years; BMI: 24.7±4.3/31.7±6.0 kg/m²; DD: 211±93/198±90 days; HbA1c: 6.8±1.4/6.5±0.9 %). Time domain and frequency domain HRV indices were derived from NN intervals recorded during a 3 h hyperinsulinemic-euglycemic clamp. After adjustment for age, sex, and BMI as well as Bonferroni correction including seven HRV parameters and the number of metabolites of the corresponding lipid class, higher levels of three free fatty acids (myristic acid: β=-0.14, p=0.049; palmitic acid: β=-0.19, p=0.007; palmitoleic acid: β=-0.15, p=0.048), eight phosphatidylcholines (e.g., phosphatidylcholine diacyl (PC aa) C32:0: β=-0.28, p&amp;lt;0.001; phosphatidylcholine acyl-alkyl C34:3: β=-0.20, p&amp;lt;0.004), and two sphingomyelins (sphingomyelin C16:0: β=-0.15, p=0.028; sphingomyelin C16:1: β=-0.18, p=0.020) were inversely associated with the standard deviation of NN intervals (SDNN) in recent-onset T2D but not T1D. PC aa C32:0 was inversely associated with both low (LF) and high frequency (HF) power spectrum in T2D (LF: β=-0.23, p=0.001; HF: β=-0.23, p=0.001). In conclusion, the link between higher plasma levels of specific lipid metabolites and early cardiac autonomic dysfunction in recent-onset type 2 diabetes suggests that plasma lipid panels could be useful to improve the prediction of the development or progression of CAN. Disclosure G.J. Bönhof: None. A. Strom: None. K. Strassburger: None. B. Knebel: None. J. Kotzka: None. H. Al-Hasani: Consultant; Self; Bayer AG. J. Szendroedi: None. O.P. Zaharia: None. Y. Karusheva: None. M. Roden: Advisory Panel; Self; Servier. Board Member; Self; Poxel SA. Consultant; Self; Eli Lilly and Company, Gilead Sciences, Inc., ProSciento, TARGET PharmaSolutions. Research Support; Self; Boehringer Ingelheim International GmbH, Novartis Pharma K.K., Sanofi US. Speaker’s Bureau; Self; Novo Nordisk A/S. D. Ziegler: None.

The association between cardiac autonomic neuropathy and heart function in type 2 diabetic patients

Aim: Cardiac autonomic neuropathy (CAN) is a common and important chronic complication in diabetic patients. Heart failure resulting from cardiomyopathy is also a lethal complication in diabetic patients. However, data showing the exact association between CAN and heart failure in diabetic patients are relatively scarce. Therefore, our study aimed to determine the association between the parameters assessing CAN and heart function in diabetic patients.Method: The medical records of type 2 diabetic patients who underwent an autonomic function test with heart rate variability (HRV) and echocardiography were reviewed from January 2018 to December 2018. A total of 100 type 2 diabetic patients were included, and the association between the parameters assessing CAN and heart function was analysed.Results: Among the 100 analysed patients, 65 were diagnosed with CAN and 26 showed diastolic dysfunction. Moreover, 19 (73.1%) diabetic patients with diastolic dysfunction were complicated with CAN. The occurrence of diastolic dysfunction was higher in diabetic patients with CAN than in diabetic patients without CAN (29.2% vs 20.0%, p < 0.05), and the occurrence of CAN was higher in diabetic patients with diastolic dysfunction than in patients without diastolic dysfunction (73.1% vs 62.2%, p < 0.05). However, there were no significant associations between HRV parameters and heart function.Conclusion: We demonstrated that diastolic dysfunction is more common in diabetic patients complicated with CAN than in diabetic patients without CAN, although several diabetic patients without diastolic dysfunction are also diagnosed with CAN. Moreover, further studies about the long-term serial monitoring of heart function according to the progression of CAN are required to confirm the exact association between CAN and heart function.

Minimal ensemble based on subset selection using ECG to diagnose categories of CAN

Background and objective:Early diagnosis of cardiac autonomic neuropathy (CAN) is critical for reversing or decreasing its progression and prevent complications. Diagnostic accuracy or precision is one of the core requirements of CAN detection. As the standard Ewing battery tests suffer from a number of shortcomings, research in automating and improving the early detection of CAN has recently received serious attention in identifying additional clinical variables and designing advanced ensembles of classifiers to improve the accuracy or precision of CAN diagnostics. Although large ensembles are commonly proposed for the automated diagnosis of CAN, large ensembles are characterized by slow processing speed and computational complexity. This paper applies ECG features and proposes a new ensemble-based approach for diagnosis of CAN progression. MethodsWe introduce a Minimal Ensemble Based On Subset Selection (MEBOSS) for the diagnosis of all categories of CAN including early, definite and atypical CAN. MEBOSS is based on a novel multi-tier architecture applying classifier subset selection as well as the training subset selection during several steps of its operation. Our experiments determined the diagnostic accuracy or precision obtained in 5 × 2 cross-validation for various options employed in MEBOSS and other classification systems. ResultsThe experiments demonstrate the operation of the MEBOSS procedure invoking the most effective classifiers available in the open source software environment SageMath. The results of our experiments show that for the large DiabHealth database of CAN related parameters MEBOSS outperformed other classification systems available in SageMath and achieved 94% to 97% precision in 5 × 2 cross-validation correctly distinguishing any two CAN categories to a maximum of five categorizations including control, early, definite, severe and atypical CAN. ConclusionsThese results show that MEBOSS architecture is effective and can be recommended for practical implementations in systems for the diagnosis of CAN progression.

A Survey of Data Mining Methods for Automated Diagnosis of Cardiac Autonomic Neuropathy Progression

Cardiac autonomic neuropathy (CAN) is a disease that occurs as a result of nerve damage causing an abnormal control of heart rate. CAN is often associated with diabetes and is important, as it can lead to an increased morbidity and mortality of the patients. The detection and management of CAN is important since early intervention can prevent further complications that may lead to sudden death from myocardial infarction or rhythm disturbance. This paper is devoted to a review of work on developing data mining techniques for automated detection of CAN. A number of different categorizations of the CAN progression have been considered in the literature, which could make it more difficult to compare the results obtained in various papers. This is the first review proposing a comprehensive survey of all categorizations of the CAN progression considered in the literature, and grouping the results obtained according to the categorization being dealt with. This novel, thorough and systematic overview of all categorizations of CAN progression will facilitate comparison of previous results and will help to guide future work.

Atypical Cardiac Autonomic Neuropathy Identified with Entropy Measures

Aims: To identify Cardiac Autonomic Neuropathy (CAN) from a range of measures extracted from Heart Rate Variability (HRV), including higher moments of RR intervals and a spectrum of entropy measures of RR intervals. Study Design: Analysis of HRV measured from participants at a diabetes screening clinic. Groups were compared using t-tests to identify variables that provide separation between groups. Place and Duration of Study: Charles Sturt Diabetes Complications Clinic, Albury, NSW Australia. Methodology: Eleven participants with definite CAN, 67 participants with early CAN, and 71 without CAN had their beat-to-beat fluctuations analyzed using two spectra of HRV: the spectrum of moments of RR intervals and the spectrum of Renyi entropy measures. RR intervals were extracted from ECG recordings and were detrended before analysis. Original Research Article Cornforth and Jelinek; CA, 3(1): 1-11, 2015; Article no. CA.2015.001 2 Results: Higher moments of RR intervals identified a previously unnoticed sub-group of patients who are atypical within the definite CAN group. Classification of CAN progression was better with Renyi entropy measures than with moments of RR intervals. Significant differences between early and definite CAN were found with the sixth and eighth moments, (P=.022 and P=.042 respectively), but for entropy measures P values were orders of magnitude smaller. Conclusion: Identification of early CAN provides the opportunity for early intervention and better treatment outcomes, as well as identifying atypical cases. Our findings illustrate the value of exploring a range of different measures when attempting to detect differences in groups of patients with CAN.

Analyzing Systolic-Diastolic Interval Interaction Characteristics in Diabetic Cardiac Autonomic Neuropathy Progression.

Cardiac autonomic neuropathy (CAN), one of the major complications in diabetes, if detected at the subclinical stage allows for effective treatment and avoiding further complication including cardiovascular pathology. Surface ECG (Electrocardiogram)-based diagnosis of CAN is useful to overcome the limitation of existing cardiovascular autonomic reflex tests traditionally used for CAN identification in clinical settings. The aim of this paper is to analyze the changes in the mechanical function of the ventricles in terms of systolic-diastolic interval interaction (SDI) from a surface ECG to assess the severity of CAN progression [no CAN, early CAN (ECAN) or subclinical CAN, and definite CAN (DCAN) or clinical CAN]. ECG signals recorded in supine resting condition from 72 diabetic subjects without CAN (CAN-) and 70 diabetic subjects with CAN were analyzed in this paper. The severity of CAN was determined by Ewing’s Cardiovascular autonomic reflex tests. Fifty-five subjects of the CAN group had ECAN and 15 subjects had DCAN. In this paper, we propose an improved version of the SDI parameter (i.e., TQ/RR interval ratio) measured from the electrical diastolic interval (i.e., TQ interval) and the heart rate interval (i.e., RR interval). The performance of the proposed SDI measure was compared with the performance of the existing SDI measure (i.e., QT/TQ interval ratio). The proposed SDI parameter showed significant differences among three groups (no CAN, ECAN, and DCAN). In addition, the proposed SDI parameter was found to be more sensitive in detecting CAN progression than other ECG interval-based features traditionally used for CAN diagnosis. The modified SDI parameter might be used as an alternative measure for the Ewing autonomic reflex tests to identify CAN progression for those subjects who are unable to perform the traditional tests. These findings could also complement the echocardiographic findings of the left ventricular diastolic dysfunction by providing additional information about alteration in systolic and diastolic intervals in heart failure.

Multi-layer Attribute Selection and Classification Algorithm for the Diagnosis of Cardiac Autonomic Neuropathy Based on HRV Attributes

Cardiac autonomic neuropathy (CAN) poses an important clinical problem, which often remains undetected due difficulty of conducting the current tests and their lack of sensitivity. CAN has been associated with growth in the risk of unexpected death in cardiac patients with diabetes mellitus. Heart rate variability (HRV) attributes have been actively investigated, since they are important for diagnostics in diabetes, Parkinson's disease, cardiac and renal disease. Due to the adverse effects of CAN it is important to obtain a robust and highly accurate diagnostic tool for identification of early CAN, when treatment has the best outcome. Use of HRV attributes to enhance the effectiveness of diagnosis of CAN progression may provide such a tool. In the present paper we propose a new machine learning algorithm, the Multi-Layer Attribute Selection and Classification (MLASC), for the diagnosis of CAN progression based on HRV attributes. It incorporates our new automated attribute selection procedure, Double Wrapper Subset Evaluator with Particle Swarm Optimization (DWSE-PSO). We present the results of experiments, which compare MLASC with other simpler versions and counterpart methods. The experiments used our large and well-known diabetes complications database. The results of experiments demonstrate that MLASC has significantly outperformed other simpler techniques.

Diabetic cardiac autonomic neuropathy: Do we have any treatment perspectives?

Cardiac autonomic neuropathy (CAN) is a serious and common complication of diabetes mellitus (DM). Despite its relationship to an increased risk of cardiovascular mortality and its association with multiple symptoms and impairments, the significance of CAN has not been fully appreciated. CAN among DM patients is characterized review the latest evidence and own data regarding the treatment and the treatment perspectives for diabetic CAN. Lifestyle modification, intensive glycemic control might prevent development or progression of CAN. Pathogenetic treatment of CAN includes: balanced diet and physical activity; optimization of glycemic control; treatment of dyslipoproteinemia; correction of metabolic abnormalities in myocardium; prevention and treatment of thrombosis; use of aldose reductase inhibitors; dihomo-γ-linolenic acid (DGLA), acetyl-L-carnitine, antioxidants, first of all α-lipoic acid (α-LA), use of long-chain ω-3 and ω-6 polyunsaturated fatty acids (ω-3 and ω-6 PUFAs), vasodilators, fat-soluble vitamin B1, aminoguanidine; substitutive therapy of growth factors, in severe cases-treatment of orthostatic hypotension. The promising methods include research and use of tools that increase blood flow through the vasa vasorum, including prostacyclin analogues, thromboxane A2 blockers and drugs that contribute into strengthening and/or normalization of Na(+), K(+)-ATPase (phosphodiesterase inhibitor), α-LA, DGLA, ω-3 PUFAs, and the simultaneous prescription of α-LA, ω-3 PUFA and DGLA.

Decision trees and multi-level ensemble classifiers for neurological diagnostics

Cardiac autonomic neuropathy (CAN) is a well known complication of diabetes leading to impaired regulation of blood pressure and heart rate, and increases the risk of cardiac associated mortality of diabetes patients. The neurological diagnostics of CAN progression is an important problem that is being actively investigated. This paper uses data collected as part of a large and unique Diabetes Screening Complications Research Initiative (DiScRi) in Australia with data from numerous tests related to diabetes to classify CAN progression. The present paper is devoted to recent experimental investigations of the effectiveness of applications of decision trees, ensemble classifiers and multi-level ensemble classifiers for neurological diagnostics of CAN. We present the results of experiments comparing the effectiveness of ADTree, J48, NBTree, RandomTree, REPTree and SimpleCart decision tree classifiers. Our results show that SimpleCart was the most effective for the DiScRi data set in classifying CAN. We also investigated and compared the effectiveness of AdaBoost, Bagging, MultiBoost, Stacking, Decorate, Dagging, and Grading, based on Ripple Down Rules as examples of ensemble classifiers. Further, we investigated the effectiveness of these ensemble methods as a function of the base classifiers, and determined that Random Forest performed best as a base classifier, and AdaBoost, Bagging and Decorate achieved the best outcomes as meta-classifiers in this setting. Finally, we investigated the meta-classifiers that performed best in their ability to enhance the performance further within the framework of a multi-level classification paradigm. Experimental results show that the multi-level paradigm performed best when Bagging and Decorate were combined in the construction of a multi-level ensemble classifier.

Cardiac autonomic neuropathy in patients with diabetes mellitus.

Cardiac autonomic neuropathy (CAN) is an often overlooked and common complication of diabetes mellitus. CAN is associated with increased cardiovascular morbidity and mortality. The pathogenesis of CAN is complex and involves a cascade of pathways activated by hyperglycaemia resulting in neuronal ischaemia and cellular death. In addition, autoimmune and genetic factors are involved in the development of CAN. CAN might be subclinical for several years until the patient develops resting tachycardia, exercise intolerance, postural hypotension, cardiac dysfunction and diabetic cardiomyopathy. During its sub-clinical phase, heart rate variability that is influenced by the balance between parasympathetic and sympathetic tones can help in detecting CAN before the disease is symptomatic. Newer imaging techniques (such as scintigraphy) have allowed earlier detection of CAN in the pre-clinical phase and allowed better assessment of the sympathetic nervous system. One of the main difficulties in CAN research is the lack of a universally accepted definition of CAN; however, the Toronto Consensus Panel on Diabetic Neuropathy has recently issued guidance for the diagnosis and staging of CAN, and also proposed screening for CAN in patients with diabetes mellitus. A major challenge, however, is the lack of specific treatment to slow the progression or prevent the development of CAN. Lifestyle changes, improved metabolic control might prevent or slow the progression of CAN. Reversal will require combination of these treatments with new targeted therapeutic approaches. The aim of this article is to review the latest evidence regarding the epidemiology, pathogenesis, manifestations, diagnosis and treatment for CAN.

Completion report: Effect of Comprehensive Yogic Breathing program on type 2 diabetes: A randomized control trial.

Background:Yoga has been shown to be beneficial in diabetes in many studies, though randomized control trials are few. The aim of this randomized control trial was to see the effect of Sudarshan Kriya and related practices (comprehensive yogic breathing program) on quality of life, glycemic control, and cardiac autonomic functions in diabetes. Diabetes mellitus is a risk factor for sudden cardiac death. Cardiac autonomic neuropathy has been implicated in the causation of sudden cardiac death. Therefore, a maneuver to prevent progression of cardiac autonomic neuropathy holds significance.Materials and Methods:A total of 120 patients of diabetes on oral medication and diet and exercise advice were randomized into two groups: (1) Continued to receive standard treatment for diabetes. (2) Patients administered comprehensive yogic breathing program and monitored to regularly practice yoga in addition to standard treatment of diabetes. At 6 months, quality of life and postprandial plasma glucose significantly improved in the group practicing yoga compared to baseline, but there was no significant improvement in the fasting plasma glucose and glycated hemoglobin.Results:On per protocol analysis, sympathetic cardiac autonomic functions significantly improved from baseline in the group practicing comprehensive yogic breathing.Conclusion:This randomized control trial points towards the beneficial effect of yogic breathing program in preventing progression of cardiac neuropathy. This has important implications as cardiac autonomic neuropathy has been considered as one of the factors for sudden cardiac deaths.

Correlation between arterial wall stiffness, N-terminal prohormone of brain natriuretic peptide, functional and structural myocardial abnormalities in patients with type 2 diabetes mellitus and cardiac autonomic neuropathy

Aim. To assess arterial wall stiffness, plasma levels of of N-terminal prohormone of brain natriuretic peptide (NT-proBNP), as well as functional state and structure of the myocardium in patients with type 2 diabetes mellitus (T2DM) and cardiac autonomic neuropathy (CAN). Materials and Methods. The study involved a total of 65 patients with T2DM. 12 had no evidence of cardiovascular disease (CVD) or CAN, 14 were diagnosed with subclinical stage of CAN, 18 ? with functional stage, and 21 ? with organic stage. We measured aortic pulse wave velocity (PWV), aortic augmentation index (AIx), brachial artery AIx, ambulatory arterial stiffness index (AASI) and plasma levels of NT-proBNP. Clinical examination included ECG, Holter monitoring, ambulatory BP measurement and echocardiography. Results. Patients with isolated T2DM showed a trend for increased vascular wall stiffness. PWV was increased in patients with subclinical stage of CAN. Aortic and brachial AIx, PWV and AASI were elevated in patients with functional stage of CAN, PWV being significantly higher vs. subclinical CAN subgroup. Organic stage was characterized by pathologically increased values of all primary parameters; PWV and AASI were significantly higher compared with other groups. Development and progression of CAN was accompanied by an increase in NT-proBNP plasma levels. Concentration of NT-proBNP was in direct correlation with left ventricular mass (LVM) and PWV. PWV and LVM values also directly correlated between themselves. Conclusion. Development and progression of CAN in patients with T2DM is accompanied by an increase in vascular wall stiffness. The elevation of plasma NT-proBNP in patients with T2DM correlates with the development of CAN and is significantly and independently associated with an increase in LVM and PWV. Our data suggests the pathophysiological interconnection between metabolic, functional and structural myocardial abnormalities in patients with T2DM and CAN.

Natural progression of cardiac autonomic neuropathy in patients with type 1 diabetes: a four-year follow-up study

To determine the prevalence and clinical characteristics of cardiac autonomic neuropathy in type 1 diabetic patients who were followed up for 4 years to shed further light on the natural progression of cardiac autonomic neuropathy. It is a prospective cohort observational study, consisted of 57 patients who were originally studied using the standard tests proposed by Ewing and Clarke (1985). At two years follow up, 46 patients were reevaluated, 55 patients from the original study were reevaluated after another 2 years for the 3rd time using the same protocol. The control group comprised 30 age and sex matched healthy volunteers. McNemar test, ANOVA for repeated measurements, paired t test and unpaired t test were used for statistical analyses. The prevalence of established cardiac autonomic neuropathy (CAN) at the beginning was 14%. Q-Tc intervals were found to be significantly higher in patients with abnormal cardiovascular reflex (CVRs) in the 2nd examination (0.4±0.04 vs 0.5±0.05 sec, p=0.006). Eighteen patients showed deterioration of their CVRs test between 1st and 3rd examination. There was deterioration of their glycemic control guided by glycosylated hemoglobin (8.5±1.4 vs 9.9±1.5%, p=0.05*) and albumin/creatinine ratio (4.4±4.0 vs 28.2±28.0 mg/g creatinine, p=0.04). On the other hand, 12 patients showed regression of their CVRs test. Only their insulin dose showed significant decrease (1.8±1.3 vs 1.1±0.3 dose/kg, p=0.02). The prevalence of established CAN in diabetic patients is high at the beginning of the study. Glycosylated hemoglobin, systolic and diastolic blood pressure were significantly increased in diabetics with deterioration of their CAN. However, the dose of insulin was significantly decreased in diabetics with regression of their CAN.

Regulation of QT indices mediated by autonomic nervous function in patients with type 2 diabetes

Both the QT interval and QT dispersion in diabetic patients have been reported to increase with the progression of cardiac autonomic neuropathy and to have a prognostic value. We assessed the cardiac autonomic influences on QT indices using the measurements of baroreflex sensitivity, heart rate variability, and cardiac 123I-metaiodobenzylguanidine scintigraphic findings in patients with type 2 diabetes mellitus. Forty-two consecutive patients with type 2 diabetes (mean±SD: 54±10 years, 22 women and 20 men) were studied. Baroreflex sensitivity negatively correlated with the maximum and minimum QTc intervals as well as QT/QTc dispersion. However, the high-frequency power and the ratio of low-frequency power to high-frequency power of heart rate variability did not correlate with any QT indices. The percent washout rate of 123I-metaiodobenzylguanidine positively correlated with QT/QTc dispersion, but not with maximum and minimum QTc intervals. Our findings suggest that cardiac vagal dysfunction is related to QT interval prolongation while both sympathetic and vagal dysfunctions are related to increased QT dispersion in type 2 diabetic patients. Baroreflex sensitivity and percent washout rate of 123I-metaiodobenzylguanidine may be useful parameters indicating the abnormalities of the cardiac ventricular repolarization in this population.