Diabetes and cardiac autonomic neuropathy: Clinical manifestations,cardiovascular consequences,diagnosis and treatment

Cardiac autonomic neuropathy (CAN) is a frequent chronic complication of diabetes mellitus with potentially life-threatening outcomes. CAN is caused by the impairment of the autonomic nerve fibers regulating heart rate, cardiac output, myocardial contractility, cardiac electrophysiology and blood vessel constriction and dilatation. It causes a wide range of cardiac disorders, including resting tachycardia, arrhythmias, intraoperative cardiovascular instability, asymptomatic myocardial ischemia and infarction and increased rate of mortality after myocardial infarction. Etiological factors associated with autonomic neuropathy include insufficient glycemic control, a longer period since the onset of diabetes, increased age, female sex and greater body mass index. The most commonly used methods for the diagnosis of CAN are based upon the assessment of heart rate variability (the physiological variation in the time interval between heartbeats), as it is one of the first findings in both clinically asymptomatic and symptomatic patients. Clinical symptoms associated with CAN generally occur late in the disease process and include early fatigue and exhaustion during exercise, orthostatic hypotension, dizziness, presyncope and syncope. Treatment is based on early diagnosis, life style changes, optimization of glycemic control and management of cardiovascular risk factors. Medical therapies, including aldose reductase inhibitors, angiotensin-converting enzyme inhibitors, prostoglandin analogs and alpha-lipoic acid, have been found to be effective in randomized controlled trials. The following article includes the epidemiology, clinical findings and cardiovascular consequences, diagnosis, and approaches to prevention and treatment of CAN.     

Pre-operative measurement of heart rate variability predicts hypotension during general anesthesia

BACKGROUND: Peri-operative hymodynamic instability is one of the major concerns for anesthesiologists when performing general anesthesia for individuals with autonomic dysfunction. The purpose of this study was to examine the potential usage of pre-operative measurement of heart rate variability (HRV) in identifying which individuals, with or without diabetes, may be at risk of blood pressure (BP) instability during general anesthesia. METHODS: We studied 46 patients with diabetes and 87 patients without diabetes ASA class II or III undergoing elective surgery. Participants' cardiovascular autonomic function and HRV were assessed pre-operatively, and hymodynamic parameters were monitored continuously intra-operatively by an independent observer. RESULTS: Only 6% of the participants were classified as having cardiovascular autonomic neuropathy (CAN) based on traditional autonomic function tests whereas 15% experienced hypotension. Total power (TP, P = 0.006), low frequency (LF, P = 0.012) and high frequency (HF, P = 0.028) were significantly lower in individuals who experienced hypotension compared with those who did not. Multivariate logistic regression analysis revealed that TP [odds ratio (OR) = 0.15, 95% confidence interval (CI) = 0.05-0.47, P = 0.001] independently predicted the incidence of hypotension, indicating that each log ms2 increase in total HRV lowers the incidence of hypotension during general anesthesia by 0.15 times. After stepwise multiple linear regression analysis (R2= 11.5%), HF (beta = -11.1, SE = 2.79, P < 0.001) was the only independent determinant of the magnitude of systolic blood pressure (SBP) reduction at the 15th min after tracheal intubation. CONCLUSIONS: Spectral analysis of HRV is a sensitive method for detecting individuals who may be at risk of BP instability during general anesthesia but may not have apparent CAN according to traditional tests of autonomic function.     

Cardiac autonomic neuropathy in patients with diabetes mellitus简

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.     

Is erectile dysfunction a sentinel symptom for cardiovascular autonomic neuropathy in patients with type 2 diabetes?

The study investigated whether there is a significant association between erectile dysfunction (ED) secondary to autonomic failure, and cardiovascular autonomic neuropathy (CAN) in male patients suffering from type 2 diabetes. Twenty-two patients suffering from type 2 diabetes were recruited for this study after satisfying the stringent exclusion criteria used in the first stage. They had no evidence of overt cardiovascular disease, hypertension, neurological, renal or thyroid disease. Each subject was assessed for ED and CAN using standardized tests. Six patients were suffering from CAN while 10 patients were suffering from ED. There was no significant association between CAN and autonomic ED (P = 1). Three patients with normal erectile function had CAN, whilst three patients with ED had CAN. Further analysis demonstrates a significant increase in association between ED and CAN with age (P = 0.036). These results show that ED secondary to autonomic neuropathy is not significantly associated with CAN in this specific group of patients. Nonetheless, the study reveals that ED is a sentinel symptom for future development of CAN.     

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.     

Diabetic heart disease: A clinical update

Diabetes mellitus (DM) significantly increases the risk of heart disease, and DM-related healthcare expenditure is predominantly for the management of cardiovascular complications. Diabetic heart disease is a conglomeration of coronary artery disease (CAD), cardiac autonomic neuropathy (CAN), and diabetic cardiomyopathy (DCM). The Framingham study clearly showed a 2 to 4-fold excess risk of CAD in patients with DM. Pathogenic mechanisms, clinical presentation, and management options for DM-associated CAD are somewhat different from CAD among nondiabetics. Higher prevalence at a lower age and more aggressive disease in DM-associated CAD make diabetic individuals more vulnerable to premature death. Although common among diabetic individuals, CAN and DCM are often under-recognised and undiagnosed cardiac complications. Structural and functional alterations in the myocardial innervation related to uncontrolled diabetes result in damage to cardiac autonomic nerves, causing CAN. Similarly, damage to the cardiomyocytes from complex pathophysiological processes of uncontrolled DM results in DCM, a form of cardiomyopathy diagnosed in the absence of other causes for structural heart disease. Though optimal management of DM from early stages of the disease can reduce the risk of diabetic heart disease, it is often impractical in the real world due to many reasons. Therefore, it is imperative for every clinician involved in diabetes care to have a good understanding of the pathophysiology, clinical picture, diagnostic methods, and management of diabetes-related cardiac illness, to reduce morbidity and mortality among patients. This clinical review is to empower the global scientific fraternity with up-to-date knowledge on diabetic heart disease.     

Performing Only One Cardiovascular Reflex Test Has a High Positive Predictive Value for Diagnosing Autonomic Neuropathy in Patients with Chronic Renal Failure on Hemodialysis

Background. Autonomic neuropathy is an important cause of morbidity and mortality in patients with chronic renal failure (CRF) on hemodialysis. Generally, cardiovascular reflex tests are used to determine autonomic neuropathy. Our purpose in this study was to determine the frequency of autonomic neuropathy in patients with CRF on hemodialysis by using cardiovascular reflex tests and compare the sensitivity of each test. Methods. The authors performed five tests: heart rate response to the Valsalva maneuver, heart rate variation during deep breathing, heart rate response to standing up, blood pressure response to standing up, and blood pressure response to hand grip exercise in order to determine autonomic neuropathy. Each test subject was evaluated as normal, borderline, and abnormal and scored as 0, 1, and 2, respectively. Subjects with a total score ≥ 5 were considered to have autonomic neuropathy. Forty subjects with CRF on hemodialysis were included in this study. None of the subjects had diabetes mellitus or any other etiology that could cause autonomic neuropathy. Results. Thirty-five of 40 subjects (87.5%) had abnormal autonomic tests. In 35 subjects, the relationship between autonomic neuropathy and biochemical parameters, effects of treatment with vitamin D and erythropoietin, and urea reduction rate were studied. No relationship was found between autonomic neuropathy and age, time on hemodialysis, urea reduction rate, albumin, ferritin, calcium, inorganic phosphorus, intact parathyroid hormone, hemoglobin levels, and treatment with vitamin D and erythropoietin. The abnormal test results were as follows: 20 subjects (50%) in the heart rate response to the Valsalva Maneuver, 31 (77.5%) in the heart rate variation during deep breathing, 28 (70%) in the heart rate response to standing up, 6 (15%) in the blood pressure response to standing up, and 31 subjects (77.5%) in the blood pressure response to hand grip exercise tests. Among these five tests, the two most abnormal tests were the heart rate variation during deep breathing and the blood pressure response to hand grip exercise. Conclusion. Patients with CRF on hemodialysis frequently have autonomic neuropathy. For the diagnosis and follow-up of patients, five cardiovascular autonomic reflex tests are generally used. In this study, it was determined that performing only one test instead of all five tests has a high sensitivity and is more practicable in terms of determining autonomic neuropathy.     

Signs of autonomic neuropathy in childhood uremia

To evaluate the presence of autonomic neuropathy in childhood uremia, cardiovascular autonomic reflexes were examined in children with chronic renal failure. Cardiovascular autonomic reflexes of 10 uremic patients on chronic dialysis and 10 transplanted patients were compared to assess the effect of transplantation on autonomic neuropathy. Resting heart rate, heart rate changes induced by deep breathing, by Valsalva maneuver, and following standing up, and blood pressure change induced by handgrip test were examined. Of the 10 uremic children, 4 showed early involvement and 2 had definite involvement of autonomic neuropathy. Only 1 of the 10 transplanted patients showed early signs of autonomic neuropathy. Autonomic tests demonstrated predominantly parasympathetic dysfunction. In conclusion, cardiovascular autonomic neuropathy is not rare in children and adolescents and young adults with chronic renal failure. In contrast, the prevalence is very low in transplanted patients with similar uremic precedents. Efforts should be made to prevent or delay this uremia- related complication. Received: 12 May 2000 / Revised: 9 August 2000 / Accepted: 15 August 2000     

Cardiovascular autonomic neuropathy and subclinical cardiovascular disease in normoalbuminuric type 1 diabetic patients

Cardiovascular autonomic neuropathy (CAN) is associated with increased mortality in diabetes. Since CAN often develops in parallel with diabetic nephropathy as a confounder, we aimed to investigate the isolated impact of CAN on cardiovascular disease in normoalbuminuric patients. Fifty-six normoalbuminuric, type 1 diabetic patients were divided into 26 with (+) and 30 without (-) CAN according to tests of their autonomic nerve function. Coronary artery plaque burden and coronary artery calcium score (CACS) were evaluated using computed tomography. Left ventricular function was evaluated using echocardiography. Blood pressure and electrocardiography were recorded through 24 h to evaluate nocturnal drop in blood pressure (dipping) and pulse pressure. In patients +CAN compared with -CAN, the CACS was higher, and only patients +CAN had a CACS >400. A trend toward a higher prevalence of coronary plaques and flow-limiting stenosis in patients +CAN was nonsignificant. In patients +CAN, left ventricular function was decreased in both diastole and systole, nondipping was more prevalent, and pulse pressure was increased compared with -CAN. In multivariable analysis, CAN was independently associated with increased CACS, subclinical left ventricular dysfunction, and increased pulse pressure. In conclusion, CAN in normoalbuminuric type 1 diabetic patients is associated with distinct signs of subclinical cardiovascular disease.     

Assessment of the cardiovascular and gastrointestinal autonomic complications of diabetes

The global prevalence of diabetes mellitus is increasing; arguably as a consequence of changes in diet, lifestyle and the trend towards urbanization. Unsurprisingly, the incidence of both micro and macrovascular complications of diabetes mirrors this increasing prevalence. Amongst the complications with the highest symptom burden, yet frequently under-diagnosed and sub-optimally treated, is diabetic autonomic neuropathy, itself potentially resulting in cardiovascular autonomic neuropathy and gastrointestinal(GI) tract dysmotility. The aims of this review are fourfold. Firstly to provide an overview of the pathophysiological processes that cause diabetic autonomic neuropathy. Secondly, to discuss both the established and emerging cardiometric methods for evaluating autonomic nervous system function in vivo. Thirdly, to examine the tools for assessing pan-GI and segmental motility and finally, we will provide the reader with a summary of putative non-invasive biomarkers that provide a pathophysiological link between lowgrade neuro inflammation and diabetes, which may allow earlier diagnosis and intervention, which in future may improve patient outcomes.     

Cardiovascular autonomic dysfunction and hemodynamic response to anesthetic induction in patients with coronary artery disease and diabetes mellitus.

Autonomic neuropathy is a major complication of diabetes mellitus and is reported to be associated with increased perioperative hemodynamic instability. We investigated the relationship between autonomic dysfunction and hemodynamic response to anesthetic induction in diabetic and nondiabetic patients with coronary artery disease. We studied 60 patients scheduled for coronary artery surgery, 30 suffering from diabetes mellitus. Preoperative evaluation included traditional cardiovascular autonomic function tests (coefficient of variation of 150 beat-to-beat intervals in heart rate at rest, heart rate response to deep breathing, and heart rate and arterial blood pressure response to standing), spectral analysis of blood pressure and heart rate variability (HRV), and the computation of spontaneous baroreflex sensitivity. After premedication with clorazepate, anesthesia was induced with sufentanil (0.5 microg/kg), etomidate (0.1-0.2 mg/kg), and vecuronium (0.1 mg/kg). Heart rate and blood pressure before anesthetic induction and before and after tracheal intubation were compared between groups. Autonomic function tests, spectral analysis of HRV, and spontaneous baroreflex sensitivity revealed significant differences between patient groups. Most diabetic patients (n = 23) had one or more abnormal test results, in contrast to most nondiabetic patients, who did not show signs of autonomic neuropathy (n = 23). There was no relationship between cardiovascular autonomic function and hemodynamic behavior during anesthetic induction. The blood pressure response to anesthetic induction was not different between patient groups, even when comparing the subgroups with and without abnormal autonomic function tests. These findings indicate that increased hemodynamic instability during anesthetic induction is not obligatory in patients with diabetes mellitus and autonomic dysfunction. IMPLICATIONS: This study indicates that increased hemodynamic instability during anesthetic induction is not obligatory in patients with coronary artery disease and autonomic dysfunction.     

Diabetic cardiomyopathy: Pathophysiology,diagnostic evaluation and management

Diabetes affects every organ in the body and cardiovascular disease accounts for two-thirds of the mortality in the diabetic population. Diabetes-related heart disease occurs in the form of coronary artery disease (CAD), cardiac autonomic neuropathy or diabetic cardiomyopathy (DbCM). The prevalence of cardiac failure is high in the diabetic population and DbCM is a common but underestimated cause of heart failure in diabetes. The pathogenesis of diabetic cardiomyopathy is yet to be clearly defined. Hyperglycemia, dyslipidemia and inflammation are thought to play key roles in the generation of reactive oxygen or nitrogen species which are in turn implicated. The myocardial interstitium undergoes alterations resulting in abnormal contractile function noted in DbCM. In the early stages of the disease diastolic dysfunction is the only abnormality, but systolic dysfunction supervenes in the later stages with impaired left ventricular ejection fraction. Transmitral Doppler echocardiography is usually used to assess diastolic dysfunction, but tissue Doppler Imaging and Cardiac Magnetic Resonance Imaging are being increasingly used recently for early detection of DbCM. The management of DbCM involves improvement in lifestyle, control of glucose and lipid abnormalities, and treatment of hypertension and CAD, if present. The role of vasoactive drugs and antioxidants is being explored. This review discusses the pathophysiology, diagnostic evaluation and management options of DbCM.     

Association and interaction analysis of excess weight and chronic kidney disease for cardiovascular autonomic neuropathy in the general Chinese population

Abstract

Background: The purpose of this study was to evaluate the associations of excess weight (EW) and/or chronic kidney disease (CKD) with cardiovascular autonomic neuropathy (CAN), and to detect the extent to which interaction of EW and CKD has on the outcome in a Chinese sample. Method: We conducted a large-scale, population-based study to analyze the association and interaction of the two factors on CAN in a sample of 2092 Chinese people. Multiple linear regression analysis to include the two main factors and its interaction were employed to detect these relationships. Relative excess risk due to interaction (RERI), the proportion attributable to interaction (AP) and the synergy index (S) were used to estimate the effect of interaction on an additive scale can. Result: Multivariable logistic regression (MLR) indicated that body mass index (BMI) was independently associated with CAN (p?=?0.006). In addition, a significant positive interaction between BMI and CKD on CAN was estimated (p?=?0.042, RETI?=?0.473, 95% CI: 0.0615–0.884, AP?=?0.203, 95% CI: ?0.055 to 0.461 and S?=?1.550, 95% CI: 0.667–2.589). Conclusion: Our findings suggest that BMI is independently associated with CAN and offer evidence to support the hypothesis that excess weight and CKD have significant positive interactions on CAN.     

Psychophysiological characteristics of women suffering from stress‐related fatigue

Stress‐related fatigue has been attributed to excessive sympathetic nervous system and hypothalamic–pituitary–adrenal (HPA) axis activation, but findings have been equivocal as to whether the HPA axis or the autonomic nervous system (ANS) are affected in this condition and how. Whether task performance deficits are associated with this condition is also uncertain. The present study investigated possible differences between women with stress‐related fatigue and healthy women in heart rate variability (HRV) and other autonomic and respiratory measures, task performance and in salivary cortisol response to awakening. Thirty‐six women with stress‐related fatigue were compared with 19 female healthy controls matched in age. Four indices of HRV and other autonomic and respiratory measures were recorded during baseline, task performance and relaxation phases of a laboratory session. Saliva cortisol was measured four times during the hour after awakening. The fatigued group showed less HRV in three measures, higher temperature, lower O₂ saturation at the surface of the finger, lower end‐tidal pCO₂, and greater cortisol response. This group responded faster on the task but with more errors. Women with stress‐related fatigue show signs of hyperarousal on ANS, respiratory and HPA axis measures. The lower HRV may indicate greater cardiovascular risk. Results for task performance confirm subjectively reported deficits. Copyright © 2009 John Wiley & Sons, Ltd.     

Identification of autonomic dysfunction with a pulse oximeter

Chart recordings of the pulse oximeter waveform were taken during the performance of a standard Valsalva manoeuvre, in one subject with and another without autonomic dysfunction. They demonstrate that certain types of pulse oximeter may be used for the rapid pre-operative identification of patients who have an autonomic neuropathy in which the cardiovascular responses to stress are impaired.     

Sudden cardiorespiratory arrest after renal transplantation in a patient with diabetic autonomic neuropathy and prolonged QT interval

A 31–yr male with insulin dependent diabetes mellitus for 20 years underwent general anaesthesia for renal transplantation. During transfer from operating theatre to ICU he developed bradycardia advancing to ventricular fibrillation and had to be resuscitated. Bradycardia did not respond to atropine. Postoperative autonomic nervous function tests showed advanced autonomic neuropathy. He was found to have constantly prolonged QTc interval in his pre– and postoperative ECGs (462–503 ms). Prolongation of QTc interval could be used as a valuable predictor of postoperative cardiac complications in diabetic patients with autonomic neuropathy.     

Influence of angiotensin converting enzyme inhibitor treatment on cardiac autonomic modulation in patients receiving haemodialysis

BACKGROUND: Cardiovascular disease mortality among patients with end stage renal disease (ESRD) exceeds that which is predicted by traditional risk factors. Sudden death accounts for up to 15-38% of patients with ESRD found dead at home. Heart rate variability (HRV) is a reliable measure of autonomic modulation and has a very strong predictive value for ventricular arrhythmias and sudden death. A lower HRV is associated with increased risk. Modifying autonomic tone pharmacologically reduces death from dysrhythmia in the general population but has not been studied in ESRD. METHODS: We examined the effect of ramipril, an angiotensin converting enzyme inhibitor (ACEI) known in the general population to increase HRV, on cardiac function and heart rate variability in patients with renal failure. Eligible subjects on haemodialysis underwent a 2-week washout period free of ACEI or beta blockers, during which time hypertension was treated with amlodipine, which has been shown not to affect HRV. Haemodynamic and HRV measurements were obtained at baseline and after subjects were treated for 4 weeks with an ACEI. RESULTS: Haemodynamics did not differ at 0 and 4 weeks. Baseline HRV values were markedly below those found in the general population, indicating pronounced predominance of sympathetic tone over vagal tone. Actual worsening of HRV with ACEI treatment was evident in several major time domains. The time domain SDNN (the standard deviation of all normal RR intervals) fell from 42.0 +/- 24.8 ms to 20.1 +/- 16.1 ms (P = 0.004) and the triangulation index fell from 178.0 +/- 94.0 to 115 +/- 59.2 (P = 0.01). A trend toward reduced HRV was seen in several other time domains. CONCLUSION: These findings suggest that, unlike the general population, treatment of ESRD patients with an angiotensin converting enzyme inhibitor may cause a deleterious shift toward increased cardiac sympathetic nervous system tone.     

Cardiac autonomic neuropathy in patients with chronic renal failure on hemodialysis

To characterize uremic cardiac autonomic neuropathy, we measured plasma catecholamines, analyzed the 24-hour heart rate variability (HRV), and acquired serial images with (123)I-metaiodobenzylguanidine (MIBG) in 44 patients with chronic renal failure on hemodialysis and in 14 controls. Time-domain measures were calculated using the Marquette HRV program. MIBG clearance rates from the heart and lung were evaluated on planar images, and the regional MIBG uptake in the left ventricular myocardium was evaluated with single-photon emission computed tomography. Compared with controls, plasma dopamine and norepinephrine levels were elevated (p < 0.001 and p = 0.03, respectively), and all the time-domain measures of HRV were reduced in the patients (p < 0.001). The MIBG clearance rate from the heart was higher (p < 0.001), that from the lung was lower (p < 0.001), and the myocardial MIBG distribution was more heterogeneous in patients than in controls (total uptake score p 相似文献