Cardiovascular autonomic neuropathy

Incidence and Prevalence

The incidence and prevalence of cardiovascular autonomic neuropathy (CAN) has varied substantially between studies. Such data are highly dependent on the diagnostic criteria, type of tests, definitions of normal, and patient characteristics [1]. The prevalence of CAN, diagnosed using standard cardiovascular reflex tests, was very low ( ~2.5%) in patients with newly diagnosed type 1 diabetes (T1DM) enrolled in the primary prevention cohort of the Diabetes Control and Complications Trial (DCCT) [2]. At DCCT end, CAN was found in less than 10% of the DCCT participants after five years of follow-up [2][3]. Evaluations done after additional 13-14 years of follow-up of the DCCT participants enrolled in the observational Epidemiology of Diabetes Interventions and Complications (EDIC) study, found CAN prevalence rates as high as 35% in the prior conventionally treated DCCT cohort [4]. In the EURODIAB IDDM Complications Study, autonomic dysfunction was present in one-third of T1D subjects at follow-up [5]. These findings contrast with a longitudinal study of new-onset T1D patients in whom heart rate variability was abnormal in 27% at diagnosis and in 56% after 10 years of follow-up [6].

Prevalence rates of 60% and higher were reported in cohorts of patients with long-standing type 2 diabetes (T2DM) [1][7][8] and in patients with long-standing T1DM who were potential candidates for a pancreas transplantation [9]. CAN was found to develop in 35% of subjects with T2D over 7 years in a prospective cohort study in Korea [10].

These data demonstrates that CAN prevalence does increase substantially with the duration of diabetes regardless of diabetes type [1][4][11]. Overall the prevalence of CAN is thought to be approximately 20% [1].

The impact of gender on CAN is unclear. For example, one report suggested that CAN prevalence was similar in 3,250 men and women with diabetes a multi-center, cross sectional study of 3,250 patients with T1D [5]. In contrast, in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial of over 8,000 patients with T2D CAN was more prevalent in women [12].  


Impaired heart rate variability: is considered the earliest sign of CAN and may be completely unassociated with symptoms [1][13][14].

Resting tachycardia: Resting tachycardia is a nonspecific sign for CAN, as it may be present in several other conditions such as anemia, thyroid dysfunction, underlying cardiovascular disease including heart failure, obesity and poor fitness. It is however accepted that a fixed heart rate that is unresponsive to moderate exercise, stress, or sleep indicates almost complete cardiac denervation [14] and is indicative of advanced CAN.

Exercise intolerance: In more advanced cases, patients may present with exercise intolerance due to a reduced response in heart rate and BP, and blunted increases in cardiac output in response to exercise [1][13][14].

Abnormal Blood Pressure Regulation: In normal situations, at night, there is a predominance of vagal tone and a decreased sympathetic tone which is associated with a reduction in nocturnal BP [15]. In diabetic CAN this pattern is altered resulting in nocturnal sympathetic predominance during sleep and subsequent nocturnal hypertension, also known as non-dipping and reverse dipping [16].

Orthostatic hypotension (a fall in systolic or diastolic BP in response to a postural change from supine to standing) occurs in diabetes largely as a consequence of efferent sympathetic vasomotor denervation, causing reduced vasoconstriction of the splanchnic and other peripheral vascular beds. It occurs late in the progression of CAN and is a poor prognostic indicator. Symptoms associated with orthostatic hypotension are shown in Table 3 [1][13][14].

Table 3: Symptoms of Diabetic Autonomic Neuropathies:

Cardiovascular Autonomic Neuropathy Gastrointestinal Urogenital
Impaired Rate Variability Gastroparesis: Nausea, Bloating, Loss of appetite, Early satiety, Postprandial vomiting Bladder dysfunction: Frequency, Urgency, Nocturia, Hesitancy, Weak stream, Dribbling, Urinary incontinence, Urinary retention
Exercise Intolerance Esophageal dysfunction: Heartburn, Dysphagia for solids Male Sexual Dysfunction: Erectile dysfunction, Decreased libido, Abnormal ejaculation
Resting Tachycardia Diabetic Diarrhea: Profuse and watery diarrhea, Fecal incontinence Female Sexual Dysfunction: Decreased sexual desire, Increased pain during intercourse, Decreased sexual arousal, Inadequate lubrication
Abnormal blood pressure regulation: Non-dipping, Reverse dipping Constipation
Orthostatic Hypotension: Lightheadness, Weakness, Faintness, Dizziness, Visual impairment, Syncope (all with standing)


Silent ischemia: In a meta-analysis involving 12 cross-sectional studies CAN was found to be associated with silent ischemia in diabetes (prevalence rate risk of 1.96, 95% CI of 1.53-2.51) [17]. In the Detection of Ischemia in Asymptomatic Diabetics (DIAD) study of 1123 patients with T2DM, CAN was a strong predictor of silent ischemia and subsequent cardiovascular events [18]. A slow heart rate recovery after exercise, which is proposed to indirectly reflect CAN, was also shown to be associated with silent myocardial ischemia [19]. The association between CAN and silent ischemia has important implications, as reduced appreciation for ischemic pain impairs timely recognition of myocardial ischemia or infarction, thereby delaying appropriate therapy.

Myocardial Dysfunction: The presence of CAN was also linked to development of diabetic cardiomyopathy. Diastolic dysfunction, characterized by impairment in LV relaxation and passive filling, was reported as the earliest manifestation of diabetic cardiomyopathy [20][21]. Early in the natural history of CAN isolated diastolic dysfunction may contribute to impaired exercise tolerance [22]. Studies in patients with T1DM reported that left ventricle (LV) dysfunction may precede or occur in the absence of coronary artery disease or hypertension, often seen in the setting of a normal ejection fraction [23][24]. This was confirmed recently in a large cohort ( ~ 900) of patients with T1DM participants in the DCCT/EDIC. In this cohort the presence of CAN, confirmed by comprehensive cardiovascular reflex testing, was associated with increased LV mass and with concentric remodeling as assessed by cardiac MRI independent of age, sex and other factors [25]. Sacre et al reported that in patients with T2DM, measures of both systolic and diastolic function were associated with measures of CAN [26]. In a subgroup analysis of ~ 300 patients with T2DM enrolled in the prospective AdreView Myocardial Imaging for Risk Evaluation in Heart Failure (ADMIRE-HF), the presence of CAN at baseline, as assessed by I-123 metaiodobenzylguanidine imaging, was associated with a significantly greater 2-year rate of heart failure progression, compared with patients with no CAN enrolled in the same trial [27]. Recent studies have also described that patients with T1D may present with increased LV torsion, an early measure of LV dyfunction, which is associated with the presence of CAN [28][29]. The contribution of this abnormality to adverse clinical outcomes remains to be established.

Mortality Risk: One of the most serious consequences of CAN is its relationship with mortality risk. A meta-analysis of 15 studies that included 2,900 subjects with diabetes reported a pooled relative risk of mortality of 3.45 (95% CI 2.66–4.47) in patients with CAN [30].

In a prospective cohort study of T1D patients participating in the EURODIAB IDDM Complications Study, CAN was the strongest predictor for mortality during a 7-year follow-up, [31]. A higher predictive value of increased number of CAN abnormalities was described in patients with both T1DM and T2DM [32][33]. Given that CAN is associated with multiple factors including duration of diabetes, severity of hyperglycemia, the presence of coronary artery disease and other diabetes chronic complications, the exact contribution of CAN to the increased mortality risk has been however difficult to quantify in most studies due to their relatively small sample size that prevented adjustments for multiple covariates. However, recently in a large and carefully characterized cohort of more than 8,000 participants with T2DM enrolled in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, it was confirmed that the presence of CAN strongly predicts all-cause (HR=2.14, 95% CI 1.37-3.37) and CVD mortality (HR=2.62, 95% CI 1.4-4.91) independently of baseline CVD, diabetes duration, multiple traditional CVD risk factors and medications [12].

CAN and Chronic Kidney Disease (CKD): The sympathetic activation associated with CAN may also play a central role in the pathogenesis of CKD, due to changes in glomerular haemodynamics and in the circadian rhythms of BP and albuminuria [34][35][36]. A higher resting HR was reported to be associated with overt nephropathy development in type 1 diabetic patients. In the Atherosclerosis Risk in Communities (ARIC) Study, that included more than 1500 adults with diabetes followed for 16 years, higher resting HR and lower HRV indices were associated with the highest risk of developing end-stage renal disease [37](37).


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