Diabetic cardiovascular autonomic neuropathy: clinical implications

Diabetic cardiovascular autonomic neuropathy (DCAN), the impairment of the autonomic balance of the cardiovascular system in the setting of diabetes mellitus (DM), is frequently observed in both Type 1 and 2 DM, has detrimental effects on the quality of life and portends increased mortality. Clinical manifestations include: resting heart rate disorders, exercise intolerance, intraoperative cardiovascular lability, orthostatic alterations in heart rate and blood pressure, QT-interval prolongation, abnormal diurnal and nocturnal blood pressure variation, silent myocardial ischemia and diabetic cardiomyopathy. Clinical tests for autonomic nervous system evaluation, heart rate variability analysis, autonomic innervation imaging techniques, microneurography and baroreflex analysis are the main diagnostic tools for DCAN detection. Aldose reductase inhibitors and antioxidants may be helpful in DCAN therapy, but a regular, more generalized and multifactorial approach should be adopted with inclusion of lifestyle modifications, strict glycemic control and treatment of concomitant traditional cardiovascular risk factors, in order to achieve the best therapeutic results. In the present review, the authors provide aspects of DCAN pathophysiology, clinical presentation, diagnosis and an algorithm regarding the evaluation and management of DCAN in DM patients.     

Diabetic autonomic neuropathy

Diabetic autonomic neuropathy (DAN) is a serious and common complication of diabetes. Despite its relationship to an increased risk of cardiovascular mortality and its association with multiple symptoms and impairments, the significance of DAN has not been fully appreciated. The reported prevalence of DAN varies widely depending on the cohort studied and the methods of assessment. In randomly selected cohorts of asymptomatic individuals with diabetes, approximately 20% had abnormal cardiovascular autonomic function. DAN frequently coexists with other peripheral neuropathies and other diabetic complications, but DAN may be isolated, frequently preceding the detection of other complications. Major clinical manifestations of DAN include resting tachycardia, exercise intolerance, orthostatic hypotension, constipation, gastroparesis, erectile dysfunction, sudomotor dysfunction, impaired neurovascular function, "brittle diabetes," and hypoglycemic autonomic failure. DAN may affect many organ systems throughout the body (e.g., gastrointestinal [GI], genitourinary, and cardiovascular). GI disturbances (e.g., esophageal enteropathy, gastroparesis, constipation, diarrhea, and fecal incontinence) are common, and any section of the GI tract may be affected. Gastroparesis should be suspected in individuals with erratic glucose control. Upper-GI symptoms should lead to consideration of all possible causes, including autonomic dysfunction. Whereas a radiographic gastric emptying study can definitively establish the diagnosis of gastroparesis, a reasonable approach is to exclude autonomic dysfunction and other known causes of these upper-GI symptoms. Constipation is the most common lower-GI symptom but can alternate with episodes of diarrhea. Diagnostic approaches should rule out autonomic dysfunction and the well-known causes such as neoplasia. Occasionally, anorectal manometry and other specialized tests typically performed by the gastroenterologist may be helpful. DAN is also associated with genitourinary tract disturbances including bladder and/or sexual dysfunction. Evaluation of bladder dysfunction should be performed for individuals with diabetes who have recurrent urinary tract infections, pyelonephritis, incontinence, or a palpable bladder. Specialized assessment of bladder dysfunction will typically be performed by a urologist. In men, DAN may cause loss of penile erection and/or retrograde ejaculation. A complete workup for erectile dysfunction in men should include history (medical and sexual); psychological evaluation; hormone levels; measurement of nocturnal penile tumescence; tests to assess penile, pelvic, and spinal nerve function; cardiovascular autonomic function tests; and measurement of penile and brachial blood pressure. Neurovascular dysfunction resulting from DAN contributes to a wide spectrum of clinical disorders including erectile dysfunction, loss of skin integrity, and abnormal vascular reflexes. Disruption of microvascular skin blood flow and sudomotor function may be among the earliest manifestations of DAN and lead to dry skin, loss of sweating, and the development of fissures and cracks that allow microorganisms to enter. These changes ultimately contribute to the development of ulcers, gangrene, and limb loss. Various aspects of neurovascular function can be evaluated with specialized tests, but generally these have not been well standardized and have limited clinical utility. Cardiovascular autonomic neuropathy (CAN) is the most studied and clinically important form of DAN. Meta-analyses of published data demonstrate that reduced cardiovascular autonomic function as measured by heart rate variability (HRV) is strongly (i.e., relative risk is doubled) associated with an increased risk of silent myocardial ischemia and mortality. The determination of the presence of CAN is usually based on a battery of autonomic function tests rather than just on one test. Proceedings from a consensus conference in 1992 recommended that three tests (R-R variation, Valsalva maneuver, and postural blood pressure testing)or longitudinal testing of the cardiovascular autonomic system. Other forms of autonomic neuropathy can be evaluated with specialized tests, but these are less standardized and less available than commonly used tests of cardiovascular autonomic function, which quantify loss of HRV. Interpretability of serial HRV testing requires accurate, precise, and reproducible procedures that use established physiological maneuvers. The battery of three recommended tests for assessing CAN is readily performed in the average clinic, hospital, or diagnostic center with the use of available technology. Measurement of HRV at the time of diagnosis of type 2 diabetes and within 5 years after diagnosis of type 1 diabetes (unless an individual has symptoms suggestive of autonomic dysfunction earlier) serves to establish a baseline, with which 1-year interval tests can be compared. Regular HRV testing provides early detection and thereby promotes timely diagnostic and therapeutic interventions. HRV testing may also facilitate differential diagnosis and the attribution of symptoms (e.g., erectile dysfunction, dyspepsia, and dizziness) to autonomic dysfunction. Finally, knowledge of early autonomic dysfunction can encourage patient and physician to improve metabolic control and to use therapies such as ACE inhibitors and beta-blockers, proven to be effective for patients with CAN.     

Spectrum of autonomic cardiovascular neuropathy in diabetes

OBJECTIVE: Diabetic patients with incapacitating orthostatic hypotension can have either a "hyperadrenergic" or "hypoadrenergic" presentation. Although the latter is related to overt autonomic neuropathy, the former is proposed to be explained by appropriate autonomic responses. We hypothesize, however, that both conditions are part of a spectrum of autonomic dysfunction. RESEARCH DESIGN AND METHODS: We studied 16 consecutive diabetic patients with preserved renal function referred for incapacitating orthostatic hypotension and characterized their autonomic and neurohumoral cardiovascular regulation. RESULTS: Six patients had a hyperadrenergic orthostatic response: systolic blood pressure fell 42 +/- 15 mmHg, heart rate increased 20 +/- 3 bpm, and plasma norepinephrine increased from 340 +/- 80 to 910 +/- 100 pg/ml. Ten patients had a hypoadrenergic response: systolic blood pressure fell 78 +/- 5 mmHg, heart rate increased only 7 +/- 3 bpm, and norepinephrine increased only from 130 +/- 28 to 230 +/- 40 pg/ml. Vagal (sinus arrhythmia, Valsalva ratio) and sympathetic (response to hyperventilation, postprandial hypotension) responses were impaired in both groups, but to a greater extent in the hypoadrenergic group. Notwithstanding severe orthostatic hypotension, the postural increase in plasma renin was blunted in both groups, more so in the hypoadrenergic group. Despite preserved renal function, patients had mild anemia due to impaired erythropoietin release, as seen in primary cases of autonomic failure. CONCLUSIONS: Our results suggest that diabetic patients presenting with hyperadrenergic orthostatic hypotension have an initial stage of autonomic neuropathy, with overtly abnormal vagal function and early signs of sympathetic impairment. Furthermore, altered renin response can contribute to the patients' orthostatic hypotension.     

Diabetic cardiac autonomic neuropathy and anesthetic management: review of the literature

Cardiac autonomic neuropathy is a serious complication among diabetic patients. It occurs in both type 1 and type 2 diabetes, and its progression results in poor prognosis and increased mortality. During its course, parasympathetic and sympathetic nerve fibers of the cardiovascular system are damaged, resulting in potentially serious cardiac complications and even death. Poor glycemic control is believed to play a pivotal role in the pathogenesis of cardiac autonomic neuropathy. Its underlying etiology is not well understood; however, several potential pathologic mechanisms have been identified. Several clinical manifestations of cardiac autonomic neuropathy have been reported, including resting tachycardia, exercise intolerance, loss of heart rate variability, orthostatic hypotension, prolonged QT interval, silent ischemia, and sudden death. Diabetic patients exhibiting these signs and symptoms are at greater risk of anesthesia-related complications. A series of noninvasive autonomic tests were developed for the diagnosis of cardiac autonomic neuropathy, improving the management of diabetic patients requiring general anesthesia. These patients often experience cardiovascular events that may increase perioperative morbidity and mortality. The presence of cardiac autonomic neuropathy alters the hemodynamic response to induction and tracheal intubation during general anesthesia, resulting in intraoperative hypotension. A thorough preoperative assessment and vigilant monitoring perioperatively ensure successful anesthesia management.     

蹲踞试验对糖尿病心血管自主神经病变的诊断价值——附66例分析

目的：评价蹲踞试验对糖尿病心血管自主神经病变的诊断价值。方法：对６６例２型糖尿病患者和４４名正常对照组同期进行蹲踞经典心电图心血管自主神经功能测定。结果 与对照组同年龄比较,糖尿病踞副交感神经功能比值（ＳｑＴｖ）明显升高,蹲踞交感神经功能比值（ＳｑＴａ）显著降低;与对照组和正常清蛋白尿患者比较,伴清蛋水者,尤其是大量清蛋白尿者。ＳｑＴｖ明显升高,ＳｑＴｓ明显降ｑＴｖ和ＳｑＴｓ和经典心血管自主神经功     

复合自主神经症状评分-31在糖尿病心血管自主神经病变中的诊断价值

目的:探讨复合自主神经症状评分-31(composite autonomic symptom score-31,COMPASS-31)在2型糖尿病心血管自主神经病变(cardiovascular autonomic neuropathy,CAN)中的诊断价值。方法:收集2018年10月至2019年05月河南科技大学第一附属医院内分泌代谢科收治的2型糖尿病患者资料105例。根据心血管反射试验(cardiovascular reflex tests,CARTs)结果将患者分为CAN组(41例)和非CAN组(64例),比较2组间的临床特征及COMPASS-31得分情况。采用Pearson相关分析确定COMPASS-31评分与CARTs的相关性;通过logistic回归模型分析筛选CAN发生的危险因素,并建立多指标联合的诊断模型,运用ROC曲线评价COMPASS-31评分及联合模型对CAN的诊断价值。结果:CAN组患者COMPASS-31总得分明显高于非CAN组(P<0.001)。COMPASS-31总得分与CARTs指标相关性良好(P<0.05)。COMPASS-31总得分升高是CAN的独立危险因素。COMPASS-31总得分诊断CAN的最佳切点为大于19.5分,AUC值为0.788,敏感度为68.3%,特异度为79.7%。将COMPASS-31总得分引入一般危险因素模型后诊断CAN的AUC值显著提高(0.845 vs 0.905,P<0.05)。结论:COMPASS-31评分简便快速、临床操作性强,对2型糖尿病CAN具有一定的诊断价值,可作为一种CAN评估工具。     

糖尿病患者心脏自主神经病变的电生理评估

目的观测心率变异性(heartratevariability,HRV)各频谱参数在糖尿病心脏自主神经病变(cardiovascularautonomicneuropathy,CAN)各阶段的改变,探索糖尿病CAN的早期诊断方法,为有效防止糖尿病CAN的发生、发展提供监测手段。方法根据传统心脏自主神经功能检查将104例糖尿病患者按CAN程度分为4组单纯糖尿病组10例(男8例,女2例),早期CAN组30例(男13例,女17例),肯定CAN组24例(男10例,女14例),严重CAN组40例(男13例,女27例)。每例均检测八项HRV频谱参数,同时检查眼底、尿蛋白、周围神经传导速度及心电图。分析HRV各频谱参数在糖尿病各组间的差异及与正常人群间的差异。结果心率变异性各频谱参数在糖尿病早期CAN组已显著下降,且早于视网膜病变及肌电图改变,与CAN严重程度的相关系数分别为高频-0.43,低频-0.40,总功率-0.38,R-R间隔的方差(varianceofR-Rinterval,Var)-0.35,极低频-0.34,低频百分率-0.32,P均<0.01。极低频、高频、总功率、Var与乏氏指数、深呼吸心率差、卧立位30/15比值显著相关(r=0.30～0.46,P<0.01),低频与乏氏指数、深呼吸心率差、卧立位30/15比值、卧立位血压差、握拳实验显著相关(r=0.20～0.44,P均<0.01)。低频百分率与乏氏指数、卧立位血压差、握拳实验相关(r=0.21～0.30,P<0.05)。结论HRV频     

HIV peripheral neuropathy: pathophysiology and clinical implications

One of the most debilitating neurological complications of human immunodeficiency virus (HIV), affecting nearly one in three patients, is painful peripheral neuropathy. Although HIV infection can cause distal sensory polyneuropathy (DSP), the advent of highly active antiretroviral therapy (HAART) to treat HIV infection has resulted in a significant number of patients developing a clinically indistinguishable form of toxic neuropathy. The predominant symptom, regardless of etiology, is excruciating unremitting pain, resistant to pharmacological treatments, that leads to a reduction in the ability to conduct activities of daily living and, eventually, inability to ambulate. Since withdrawal from nucleoside therapy is not typically recommended, a more thorough understanding of the etiology and pathophysiology underlying nucleoside-induced peripheral neuropathy, through basic and clinical research endeavors, will aid in the development of new therapeutic treatments aimed at alleviating or ameliorating pain. This article provides the latest information regarding the pathophysiology and clinical implications of HIV peripheral neuropathy.     

The association between cardiovascular autonomic neuropathy and mortality in individuals with diabetes: a meta-analysis

OBJECTIVE: To examine by meta-analysis the relationship between cardiovascular autonomic neuropathy (CAN) and risk of mortality in individuals with diabetes. RESEARCH DESIGN AND METHODS: We searched Medline for English-language articles published from 1966 to 2001. Fifteen studies having a baseline assessment of cardiovascular autonomic function and mortality follow-up were identified. The analyses were stratified according to whether a single abnormality or two or more measures of cardiovascular autonomic function were used to define CAN. A global measure of association (i.e., relative risk) was generated for each group by pooling estimates across the studies using the Mantel-Haenszel procedure. RESULTS: CAN was significantly associated with subsequent mortality in both groups, although the magnitude of the association was stronger for those studies for which two or more measures were used to define CAN. The pooled relative risk for studies that defined CAN with the presence of two or more abnormalities was 3.45 (95% CI 2.66-4.47; P < 0.001) compared with 1.20 (1.02-1.41; P = 0.03) for studies that used one measure. CONCLUSIONS: These results support an association between CAN and increased risk of mortality. The stronger association observed in studies defining CAN by the presence of two or more abnormalities may be due to more severe autonomic dysfunction in these subjects or a higher frequency of other comorbid complications that contributed to their higher mortality risk. Future studies should evaluate whether early identification of subjects with CAN can lead to a reduction in mortality.     

糖尿病自主神经病变患者直立倾斜试验特点

目的探讨糖尿病自主神经病变患者直立倾斜试验的特点及其对阳性结果的影响。方法对72例因晕厥就诊的糖尿病自主神经病变患者在安静环境下进行直立倾斜试验,观察其心率、血压变化。结果试验阳性率为87.5%,其中血管抑制型9例,心脏抑制型51例,混合型3例,阴性9例。实验开始后各型心率均呈现逐渐上升的趋势,但心脏抑制型的峰值提前出现,在晕厥前各型心率均明显上升而后在晕厥时快速回落。结论糖尿病自主神经病变患者晕厥主要为心脏抑制型,晕厥前心率变化可以作为直立倾斜试验阳性的预测指标。     

Diabetic neuropathy: clinical and experimental progress in its pathogenesis and treatment

Diabetic symmetrical polyneuropathy have been known to arise from metabolic alteration such as accelerated polyol pathway and/or from neurovascular deficit. Recently, two other hypotheses were confirmed. Decreased neurotrophic supports were reported in diabetic neuropathy. Subcutaneous injection of recombinant human nerve growth factor ameliorated sensory symptoms and cooling detection threshold. The most common adverse effect was injection site hyperalagesia. Brain-derived neurotrophic factor, neurotrophin-3 and insulin-like growth factors are under clinical trials. The excessive oxidative stresses are also associated with diabetic neuropathy. Increased production and decreased scavenge system of free radicals enhance their cytotoxic effects. Alpha-lipoic acid, gliclazide and troglitazone have been reported to be effective for diabetic neuropathy.     

Diabetic neuropathy: mechanisms to management

Neuropathy is the most common and debilitating complication of diabetes and results in pain, decreased motility, and amputation. Diabetic neuropathy encompasses a variety of forms whose impact ranges from discomfort to death. Hyperglycemia induces oxidative stress in diabetic neurons and results in activation of multiple biochemical pathways. These activated pathways are a major source of damage and are potential therapeutic targets in diabetic neuropathy. Though therapies are available to alleviate the symptoms of diabetic neuropathy, few options are available to eliminate the root causes. The immense physical, psychological, and economic cost of diabetic neuropathy underscore the need for causally targeted therapies. This review covers the pathology, epidemiology, biochemical pathways, and prevention of diabetic neuropathy, as well as discusses current symptomatic and causal therapies and novel approaches to identify therapeutic targets.     

Sensitivity of R-R variation and Valsalva ratio in assessment of cardiovascular diabetic autonomic neuropathy

R-R variation and the Valsalva ratio are commonly used to quantitatively assess diabetic autonomic neuropathy (DAN). To assess the sensitivity of these two measures to parasympathetic ablation, 12 nondiabetic subjects were tested before and after graded doses (0.3-4.0 mg i.v.) of atropine. R-R variation was significantly reduced at 0.7 mg, whereas Valsalva ratio was not significantly smaller until the 2.0-mg dose of atropine. R-R variation continued to become progressively smaller during the 0.85-, 1.0-, and 2.0-mg doses. Valsalva ratio, but not R-R variation, was further reduced by the 4.0-mg dose. To further compare these two measures, two groups of diabetic subjects were compared with a group of nondiabetic subjects (n = 22). One group of diabetic subjects had symptoms of DAN (n = 22), and the other diabetic group had no symptoms of DAN (n = 19). In DAN subjects, both R-R variation (nondiabetic 33.2 +/- 4.3 vs. DAN 9.8 +/- 1.2, P less than .001) and the Valsalva ratio (nondiabetic 1.98 +/- 0.07 vs. DAN 1.55 +/- 0.07, P less than .001) were reduced. However, in asymptomatic subjects, R-R variation (23.2 +/- 3.9, P less than .05), but not Valsalva ratio (1.94 +/- 0.13, NS), was less than nondiabetic subjects. Even after beta-blockade, R-R variation was still less in both groups of diabetic subjects (nondiabetic 34.4 +/- 4.2 vs. DAN 7.4 +/- 1.3, P less than .001; asymptomatic 21.8 +/- 3.3, P less than .02).(ABSTRACT TRUNCATED AT 250 WORDS)