Apixaban versus warfarin in patients with atrial fibrillation.

BACKGROUND: Vitamin K antagonists are highly effective in preventing stroke in patients with atrial fibrillation but have several limitations. Apixaban is a novel oral direct factor Xa inhibitor that has been shown to reduce the risk of stroke in a similar population in comparison with aspirin. METHODS: In this randomized, double-blind trial, we compared apixaban (at a dose of 5 mg twice daily) with warfarin (target international normalized ratio, 2.0 to 3.0) in 18,201 patients with atrial fibrillation and at least one additional risk factor for stroke. The primary outcome was ischemic or hemorrhagic stroke or systemic embolism. The trial was designed to test for noninferiority, with key secondary objectives of testing for superiority with respect to the primary outcome and to the rates of major bleeding and death from any cause. RESULTS: The median duration of follow-up was 1.8 years. The rate of the primary outcome was 1.27% per year in the apixaban group, as compared with 1.60% per year in the warfarin group (hazard ratio with apixaban, 0.79; 95% confidence interval [CI], 0.66 to 0.95; P<0.001 for noninferiority; P=0.01 for superiority). The rate of major bleeding was 2.13% per year in the apixaban group, as compared with 3.09% per year in the warfarin group (hazard ratio, 0.69; 95% CI, 0.60 to 0.80; P<0.001), and the rates of death from any cause were 3.52% and 3.94%, respectively (hazard ratio, 0.89; 95% CI, 0.80 to 0.99; P=0.047). The rate of hemorrhagic stroke was 0.24% per year in the apixaban group, as compared with 0.47% per year in the warfarin group (hazard ratio, 0.51; 95% CI, 0.35 to 0.75; P<0.001), and the rate of ischemic or uncertain type of stroke was 0.97% per year in the apixaban group and 1.05% per year in the warfarin group (hazard ratio, 0.92; 95% CI, 0.74 to 1.13; P=0.42). CONCLUSIONS: In patients with atrial fibrillation, apixaban was superior to warfarin in preventing stroke or systemic embolism, caused less bleeding, and resulted in lower mortality. (Funded by Bristol-Myers Squibb and Pfizer; ARISTOTLE ClinicalTrials.gov number, NCT00412984.).

Prevalence of fibromyalgia in vasovagal syncope.

BACKGROUND: Vasovagal syncope is an acute manifestation of autonomic nervous system dysfunction. This type of syncope is often associated with other dysautonomic expressions such as migraine, gastroparesis, or postural tachycardia syndrome. Autonomic nervous system dysfunction has been proposed as a key element in the pathogenesis of fibromyalgia. OBJECTIVES: The objectives of this study were to estimate the frequency of fibromyalgia in a sample of patients with vasovagal syncope and also to correlate the presence of syncope and fibromyalgia with different dysautonomic manifestations. METHODS: We studied 50 consecutive patients with vasovagal syncope seen at the Syncope Unit of the National Cardiology Institute of Mexico between June 2009 and June 2012. All individuals filled out the Composite Autonomic Symptoms and Signs questionnaire and the Fibromyalgia Impact Questionnaire. All cases underwent a head-up tilt test. A rheumatologist examined all participants to assess the presence of fibromyalgia. RESULTS: The median age of the studied population was 21 years. Sixty-eight percent of participants were women. Eight cases (16%) had concomitant fibromyalgia. Significantly, all fibromyalgia cases were female. This subgroup of fibromyalgia subjects had more secretomotor complaints (mainly dry eyes and dry mouth) and more bowel constipation than the remainder of the group. Also in this subgroup of fibromyalgia subjects, several significant associations were found between age, blood pressure, number of syncopal episodes, constipation, insomnia, pupillomotor impairment, and disability. In contrast, no correlations were found in the subgroup of fainters without fibromyalgia. CONCLUSIONS: Fibromyalgia was relatively frequent in these women with vasovagal syncope and could be associated with dysautonomic symptoms. Therefore, it seems important to search for dysautonomic comorbidities in patients with vasovagal syncope and/or fibromyalgia, to provide a patient-centered holistic approach, instead of the often currently used therapeutic partition.

Association of congenital, diffuse electrical disease in children with normal heart: sick sinus syndrome, intraventricular conduction block, and monomorphic ventricular tachycardia.

INTRODUCTION: Rhythm disturbances in children with structurally normal hearts are usually associated with abnormalities in cardiac ion channels. The phenotypic expression of these abnormalities ("channelopathies") includes: long and short QT syndromes, Brugada syndrome, congenital sick sinus syndrome, catecholaminergic polymorphic ventricular tachycardia, Lènegre-Lev disease, and/or different degrees of cardiac conduction disease. METHODS: The study group consisted of three male patients with sick sinus syndrome, intraventricular conduction disease, and monomorphic sustained ventricular tachycardia. Clinical data and results of electrocardiography, Holter monitoring, electrophysiology, and echocardiography are described. RESULTS: In all patients, the ECG during sinus rhythm showed right bundle branch block and long QT intervals. First-degree AV block was documented in two subjects, and J point elevation in one. A pacemaker was implanted in all cases due to symptomatic bradycardia (sick sinus syndrome). Atrial tachyarryhthmias were observed in two patients. The common characteristic ventricular arrhythmia was a monomorphic sustained ventricular tachycardia, inducible with ventricular stimulation and sensitive to lidocaine. In one patient, radiofrequency catheter ablation was successfully performed. No structural abnormalities were found in echocardiography in the study group. CONCLUSION: Common clinical and ECG features suggest a common pathophysiology in this group of patients with congenital severe electrical disease.

Personal exposure to PM2.5 air pollution and heart rate variability in subjects with positive or negative head-up tilt test.

Particulate matter air pollution has been related to an increase in cardiopulmonary morbidity and mortality especially in susceptible subjects with a known cardiopulmonary disease. Recent studies suggest that PM(2.5) air pollution was associated with changes in heart rate variability (HRV). The purpose of this study was to identify and compare changes in HRV in positive or negative head-up tilt (HUT) participants. Fifty two subjects, 31 women and 21 men, 20-40 years old, underwent PM(2.5) personal monitoring and Holter-ECG monitoring in supine and orthostatic position, during active standing, in indoor and outdoor environments. All measurements were made between 8 and 11 AM in the same geographical location (southeast of Mexico City). Frequency domain indexes were estimated in absolute (ms(2)) and in normalized units (nu) (low frequencies (LF), high frequencies (HF) and low/high frequency ratio (LF/HF)) in 5 min periods by standard methods. Data were transformed into natural logarithmic scale (ln). Comparisons were made between genders and positive and negative HUT subjects. LF were larger and HF were smaller in negative HUT males. Multivariate analysis with GEE models, adjusted for each index, showed a significant decrease of HRV (LFln -0.194 95% CI, -0.4509, 0.0627, and HFln -0.298 95% CI, -0.5553, -0.0401) associated to an increase in PM(2.5) air pollution in positive and negative HUT subjects which was larger for HFln in outdoor environments. PM(2.5) air pollution was associated with changes in HRV in positive and negative HUT subjects without cardiopulmonary disease.

[Genetic study of the vasovagal syncope associated to the Arg389Gly polymorphism of the beta1 adrenergic receptor]. / Estudio genético del síncope vasovagal asociado al polimorfismo Arg389Gly del receptor adrenérgico beta1.

The purpose of this study was to evaluate the correlation between the vasovagal syncope (VVS) and the beta1 adrenergic receptor polymorphism at the 389 position. Seventy individuals with VVS were selected. DNA was extracted from peripheral blood by salting out and subjected to the amplification-restriction test. Genotype identification was made by polyacrylamide gel electrophoresis. A higher frequency in genotype and allele frequencies were found in individuals with positive tilted table test respect individuals with negative test, as well as a marked preference of the GlyGly phenotype in women. Genotype Arg389Gly was the most frequent between individuals with positive response in passive phase with respect to those in the induced phase. When the genotype was analyzed based on the hemodynamic response (VASIS) a gradient is observed in the frequency of Arg389Gly with the highest major frequency in the cardio-inhibitory response followed by the mixed response, and finally the vasodepressor response. These results suggest that the SVV has a genetic component associated with the Arg389Gly polymorphism of the adrenergic receptor. The Gly allele has a high risk association and it is maintained in the population through heterozygosis.

Ionic basis of pharmacological therapy in Brugada syndrome.

An implantable cardioverter-defibrillator is considered the only effective therapy to terminate ventricular arrhythmias in symptomatic patients with Brugada syndrome. However, it does not prevent future arrhythmic episodes. Only antiarrhythmic drug therapy can prevent them. There have been several reports of a beneficial effect of oral quinidine in both asymptomatic and symptomatic patients. Other possible beneficial oral agents could be I(to) blockers. Intravenous isoproterenol has been reported to be especially useful in abolishing arrhythmic storms in emergency situations. Also, isolated case reports on the usefulness of cilostazol, sotalol, and mexiletine have been described. The present article reviews the mechanisms by which these drugs may act and their possible role in the pharmacotherapy of this disease.

Value of symptoms to predict tilt testing outcome in patients with clinical suspicion of vasovagal syncope.

Studies to assess the value of clinical symptoms to predict the head-up tilt test (HUT) outcome in patients with suspicion of vasovagal syncope have shown controversial results. We undertook this study to compare the frequency of symptoms between subjects with and without history of syncope, its association with syncopal spells in those with a history of syncope and positive or negative HUT, and to identify clinical predictors of HUT outcome. Sixty seven subjects with a history of unexplained syncope and 26 subjects without a history of syncope were interviewed using a structured questionnaire before undergoing HUT, which was performed first in a passive phase and, if negative, was repeated with pharmacological challenge using 5 mg of sublingual isosorbide. Questionnaire included the 16 symptoms most frequently reported in previous studies. Only five symptoms were reported more frequently by subjects with history of syncope in comparison with subjects without it: visual blurring, dysesthesia, sighing dyspnea, tremor in fingers, and diaphoresis. Comparison of symptom frequency between patients with history of syncope and positive or negative HUT revealed that only two were significantly different: nausea and hot flashes. However, a detailed analysis of the data indicates that only hot flashes occurring just before the syncope were more common in those with a positive HUT. Although some symptoms were found more frequently in patients with a history of syncope than in those without it, the use of a structured questionnaire in the group of patients failed to predict the outcome of the HUT.

[Differences in cardiac autonomic modulation between women and men]. / Diferencias en la modulación autónoma del corazón entre mujeres y hombres.

Gender differences in cardiac autonomic modulation are a controversial topic in several studies. The aim of this study, was to describe and compare the heart rate variability in 30 women and 20 men, Mexicans, between 21 to 36 years of age. A 20 to 24 hours Holter monitoring was performed in all of them. Analysis of time (SDNNN and rMSSD), and frequency domains (HF, LF and LF/HF in absolute values and normalized units) were used. SDNN[IBM1] was significantly higher in men. When adjusted for age, there was a negative correlation in parasympathetic activity indexes (rMSSD and HF) in women. Physical training increased SDNN in men and HF in women. The increased parasympathetic activity found in women with physical training diminishes with age. These results demonstrate differences in cardiovascular autonomic modulation between women and men.

Non-invasive assessment of endothelial function. Intra and inter-observer variability.

BACKGROUND AND OBJECTIVES: Non-invasive evaluation of endothelial function with high resolution ultrasound has become a widely accepted tool in determination of high risk subjects for early atherosclerosis. Despite its simple appearance, ultrasonographic assessment of brachial artery changes, is technically challenging and has a significant learning curve. In the present study, we evaluate the intra and inter-observer variability in assessing peripheral endothelial function with high resolution ultrasound at a tertiary referral center. METHODS: Assessment of endothelial function was performed by 2 physicians in 20 volunteers without evidence of coronary artery disease. Endothelial function is evaluated with a high frequency bidimensional ultrasound with a 10.0-MHz linear-array transducer used for the study. Each volunteer was examined by both observers using an identical protocol, measuring brachial artery diameter on three occasions. RESULTS: Excellent correlation was observed for all brachial artery measures with a Spearman's correlation coefficient > 0.9 (p < 0.0001). Flow-mediated dilation (FMD) in the study population was of 10.45+/-6.9%. Flow independent dilation (FID) was of 24.35+/-7.63%. Intra-observer variability was of 2.1% for observer A and 1.1 % for observer B. CONCLUSIONS: Non-invasive assessment of endothelial function using brachial artery ultrasound is reproducible and can be performed with low intra and inter-observer variability.

Drug therapy in Brugada syndrome.

Sudden cardiac death in healthy individuals with structurally normal hearts and a characteristic morphology of the QRS complex resembling a right bundle branch block with elevation of the ST segment in V1 to V3 is known as Brugada syndrome (BrS). Although placement of an implantable cardioverter-defibrillator is considered the only effective therapy for symptomatic patients, some authors have repeatedly reported a beneficial effect of quinidine and isoproterenol in patients with BrS. Also, isolated case reports on the usefulness of cilostazol, sotalol, and mexiletine have been described. The present article reviews the mechanisms by which these drugs may act and their role in the pharmacotherapy of BrS. Other possible agents, mainly I(2) blockers, are also reviewed.

[Direct cryothermal ablation eliminates conduction of the slow pathway without inducing ectopic rhythms]. / La ablación criotérmica percutánea directa elimina la conducción a través de la vía lenta intranodal sin inducir ritmos ectópicos.

Radiofrequency catheter ablation of atrioventricular nodal reentrant tachycardia is based on the elimination of conduction of slow or fast intranodal pathway. To avoid potential atrioventricular (AV) block, a new technology has been developed, cryothermal ablation. We report a case of AV nodal reentrant tachycardia in whom direct cryoablation, without previous ice mapping, was successfully performed. Interestingly and as previously described, cryotherapy did not induce ectopic rhythms, the conventional surrogate during radiofrequency ablation.

Cardiac Autonomic Response to Active Standing in Adults With Vasovagal Syncope.

PURPOSE: Little is known about the autonomic response to active standing in vasovagal syncope, and most works have focused on children or adolescents. The aim of this work was to study the changes in cardiac autonomic modulation in adult patients with vasovagal syncope through heart rate variability analysis with linear and short-term complexity (alpha-1) indexes during supine position and active standing, in patients with positive or negative head-up tilt test (HUTT). METHODS: Twenty-five patients with vasovagal syncope were included. Heart rate variability linear and short-term complexity (alpha-1) indexes were recorded during an active standing test (15 minutes in each position) and compared among patients grouped by HUTT outcome and between positions. RESULTS: During supine position, positive HUTT (+HUTT) patients had longer mean RR (1016 [850-1051] milliseconds), higher pNN50 (17.7 [9.2-26.2]), lower sympathovagal balance (1.3 [0.5-1.7]), and alpha-1 (0.9 [0.8-1.0]) than negative HUTT (-HUTT) patients (871 [776-969] milliseconds, 8.8 [2.1-14.5], 2.9 [1.3-3.9], and 1.2 [1.0-1.1], respectively). During active standing, heart rate and alpha-1 increased in both groups; in +HUTT patients, pNN50 decreased, whereas sympathovagal balance increased. The magnitude of change between positions of sympathovagal balance and alpha-1 was 6.1 and 4.8 times larger in +HUTT than -HUTT patients, respectively. CONCLUSIONS: The underlying cardiac autonomic mechanism in vasovagal syncope may involve different autonomic patterns in subjects with a history of recurrent syncope and +HUTT or -HUTT.

Common electrocardiographic artifacts mimicking arrhythmias in ambulatory monitoring.

BACKGROUND: Ambulatory electrocardiographic monitoring is used in clinical practice as a means of detecting cardiac arrhythmias during daily activities. Current equipment provides analysis for the detection of arrhythmias, ST-segment deviation, and more sophisticated analyses (late potentials, Q-T behavior, and heart-rate variability). However, despite the system used, a number of artifacts could mislead diagnosis. METHODS AND RESULTS: We prospectively searched for artifacts during ambulatory electrocardiography in patients referred for monitoring to our institution, a tertiary referral center. Patients were ambulatory at home, work, school, or within the hospital. We divided artifacts according to Krasnow and Bloomfield's classification (pseudoarrhythmia, nonarrhythmia), and we added a new category, artifacts in patients with pacemakers. Artifacts encountered mimicked sinus arrest, supraventricular arrhythmias, ventricular arrhythmias, and aberrancy. Examples of each one and diagnostic clues are provided to recognize these artifacts properly. CONCLUSIONS: A substantial amount of invalid data (false-positive findings because of electrocardiographic artifacts) were identified during ambulatory electrocardiographic monitoring that can lead to inappropriate interpretation and may result in severe diagnostic errors.

Vestibular function interferes in cardiovascular reflexes [corrected].

BACKGROUND: Experimental work indicates that the vestibular system participates in autonomic reflexes during body movement and postural changes. However, there are no studies of cardiovascular reflexes during vertigo due to human acute vestibular lesions. METHODS: We assessed the response to active change of posture and hand immersion in cold water in seven patients with unilateral peripheral vestibular failure (vestibular neuritis) and seven age/sex-matched healthy subjects in acute phase (72 h from vertigo onset) and at 2 weeks of follow-up. RESULTS: During acute phase, patients showed decreased blood pressure response during cold hand test (p < 0.05). Upright stance induced deficient decrease of the respiratory component of heart rate variability (p < 0.05) with lack of increase in low frequency/high frequency (LF/HF) ratio. At 2 weeks of follow-up, these abnormalities improved. CONCLUSIONS: Results suggest that acute vestibular lesions can interfere with cardiovascular autonomic responses in humans. This may reflect disruption of normal vestibulo-autonomic reflexes.

Estrogen effect on heart rate variability in hypertensive postmenopausal women.

UNLABELLED: Healthy postmenopausal women and hypertensive patients show an imbalance in the modulation of autonomic nervous control of the cardiovascular system, which may increase the cardiovascular risk. OBJECTIVE: To examine the heart rate variability (HRV) response to estrogen replacement therapy (ERT) and its association with changes in metabolic variables in hypertensive postmenopausal women. METHODS: A double-blind, placebo-controlled clinical trial was conducted in 30 hypertensive postmenopausal women receiving 180 mg/day of verapamil. The experimental group (n=16) received 0.625 mg OD of natural conjugated estrogens during 4 months, while control group (n=14) received a placebo. Lipids, lipoproteins, apolipoproteins, glucose and insulin were measured at 0, 2 and 4 months. HRV was determined in time and frequency domains using a 24-h Holter before and after ERT. RESULTS: Significant higher values of spectral and non-spectral parameters of HRV, associated with a lower LF/HF ratio, were found at the end of 4 months of ERT. Multiple regression analysis revealed that estrogen treatment itself and changes in total cholesterol, LDL-cholesterol, glucose and waist circumference, contributed to the changes observed in indexes reflecting parasympathetic activity in time and frequency domains. CONCLUSIONS: We conclude that ERT partially improves HRV favoring increased parasympathetic drive, and that part of the effect may be mediated by changes in metabolic variables.

Personal exposure to particulate matter less than 2.5 microm in Mexico City: a pilot study.

This study was aimed to describe the personal exposure of permanent residents in Mexico City's Metropolitan Area (MCMA) to particulate matter of less than 2.5 microm diameter (PM(2.5)) during their daily activities. A total of 40 healthy volunteers (30 women and 10 men) with sedentary activities were included. All of them carried a PM(2.5) personal monitor during 13 h and registered their activities in a written diary that classified them in indoor and outdoor microenvironments in each 30 min period. All sample collections started at 0900 hours, and even though measurements were obtained during the rainy season (April-August 2002), the relative humidity was less than 70%. The data were categorized and evaluated under the following criteria: morning and afternoon exposure, indoor and outdoor activities, and geographical location. The descriptive analysis showed that the overall outdoor median concentration of PM(2.5) (89.50 microg/m(3)) was higher than the indoor one (67.55 microg/m(3)). PM(2.5) concentrations in the morning to early afternoon were more elevated than in the late afternoon, suggesting a circadian-like behavior. In the indoor microenvironment, the highest concentration occurred in the subway (106.2 microg/m(3)) followed by school (93.27 microg/m(3)), and the lowest at home (53.1 microg/m(3)). The outdoor microenvironment with the highest concentrations was the public transportation (bus) (99.95 microg/m(3)), while the automobile had the lowest (64.9 microg/m(3)). The geographical zone with the highest concentration was the Center city area (87.87 microg/m(3)), and the one with the lowest concentration was the northeast area of the city (50 microg/m(3)). All the differences were statistically significant (P<0.05). Multivariate analysis corroborated that PM(2.5) concentrations are mainly determined by geographical locations and hour of the day, but not by the type of microenvironment. The inclusion of covariables in the multivariable analysis ensures a more accurate estimation and prediction of the real PM(2.5) concentrations. In conclusion, PM(2.5) personal exposure of healthy adult permanent residents of MCMA is usually higher than recommended by the international standards in outdoor and even in indoor microenvironments. Particulate matter personal exposure varies in relation to hour of the day, daily activities and microenvironments.

Paced breathing can prevent vasovagal syncope during head-up tilt testing.

BACKGROUND: Clinical experience suggests that, through the control of heart rate, paced breathing may prevent syncope. OBJECTIVE: To assess the effect of metronome-paced breathing (0.2 Hz) on the outcome of head-up tilt test (HUT) in patients with vasovagal syncope. PATIENTS AND METHODS: Ten patients (two men), mean +/- SD age 18.4 +/- 5.1 years, with a positive HUT with spontaneous breathing and no evidence of cardiovascular or neurological disease, were exposed to a second HUT under metronome-paced breathing (0.2 Hz). Continuous electrocardiographic recordings were obtained during the two tests, and heart rate variability was analyzed off-line. RESULTS: During HUT with metronome-paced breathing, only one of the 10 patients developed bradycardia, hypotension and syncope (P<0.01, Wilcoxon). Compared with HUT with spontaneous breathing, HUT with paced breathing induced a larger increase in the heart rate in the first minute of tilt (4 +/- 6 beats/min versus 16 +/- 12 beats/min, P<0.05). CONCLUSIONS: The results show that paced breathing can prevent vasovagal syncope induced by HUT. This finding suggests that respiratory training could be useful to prevent vasovagal syncope.

[Syncope of unknown origin in patients with permanent auriculoventricular block with an implanted pacemaker. Usefulness of the tilt table test]. / Síncope de origen desconocido en pacientes con bloqueo auriculoventricular permanente sintomático después del implante de un marcapasos definitivo. Utilidad de la prueba de mesa basculante.

Four female patients aged 26 to 71 years, with permanent complete AV heart block and an implanted pacemaker had syncope or presyncope after the pacemaker implantation. As part of the study protocol the tilt table test was done. Neurological disease, arrhythmias, pacemaker syndrome or dysfunction of the stimulation system were ruled out. A head up tilt was performed, isosorbide was used as pharmacological challenge, since the basal test was negative. In three patients this test was positive: in one patient possibly caused by postural orthostatic tachycardia syndrome, and two with neurally mediated syncope. In one patient it was not possible a diagnosis. The head-up tilt test is a useful procedure to identify the etiology of the appearance of syncope or presyncope after a pacemaker implantation in patients with complete and permanent AV block.

[Effect of angiotensin blockade on the orthostatic response in patients with systemic arterial hypertension]. / Efecto de la inhibición de la acción de la angiotensina sobre la respuesta al ortostatismo en pacientes con hipertensión arterial sistémica.

INTRODUCTION AND OBJECTIVES: The effect of the treatment of arterial hypertension with angiotensin inhibitors on the autonomic response to orthostatism was studied. PATIENTS AND METHOD: In 20 hypertensive patients, enalapril (10 to 20 mg) was administered daily for four weeks. Then, irbesartan (150 to 300 mg) was given for four weeks. Finally, 10 mg of enalapril combined with 150 mg of irbesartan was prescribed for another four weeks. Heart rate variability at rest and during the head-up tilt test with controlled respiration was assessed at the beginning and end of each period. RESULTS: Mean arterial pressure showed a similar reduction in the three treatment periods. There were no changes in heart rate. Heart rate variability at rest showed differences in the spectral high-frequency component between the control and the treatment periods (p = 0.10). There was an increase in the high-frequency component between the control and the third (p = 0.047) and the fourth periods (p = 0.03). In the head-up tilt test there was a decrease in total spectral high-frequency power. CONCLUSIONS: There was no increase in orthostatic intolerance with these drugs in hypertensive patients. The absence of changes in heart rate in spite of a decrease in blood pressure suggests resetting of the baroreflex function. The long-term control of hypertension with these drugs may have a favorable effect on heart rate variability, with an increase in parasympathetic activity.

[Diagnostic evaluation of cardiovascular autonomic function in patients with diabetes mellitus]. / Valoración diagnóstica de la función autónoma cardiovascular en el paciente con diabetes mellitus.

Cardiovascular autonomic neuropathy is a common complication of diabetes mellitus. There are several diagnostic methods currently used. New techniques are described. The purpose of this review paper is to describe and analyze the clinical relevance of all this methods and propose an algorithm for the diagnosis of the cardiovascular autonomic neuropathy at daily medical practice.