Relationship Between Cardiac Autonomic
Neuropathy and Atherosclerosis in Patients
with Diabetes Mellitus
Sarka Mala1*, Lucie Hoskovcova1, Lucie Riedlbauchova2, Tomas Nedelka3 and Jan Broz1
1Internal Medicine Department, University Hospital Motol, Czech Republic
2Department of Cardiology, University Hospital Motol, Czech Republic
3 Department of Neurology, University Hospital Motol, Czech Republic
Submission: September 28, 2018; Published: October 10, 2018
*Corresponding author: Sarka Mala, Internal Medicine Department, University Hospital Motol, V Uvalu 84, 15006, Prague, Czech Republic.
How to cite this article: Mala S, Hoskovcova L, Riedlbauchova L , Nedelka T, Broz J. Relationship Between Cardiac Autonomic Neuropathy and
Atherosclerosis in Patients with Diabetes Mellitus. Curre Res Diabetes & Obes J. 2018; 9(1): 555753. DOI: 10.19080/CRDOJ.2018.09.555753.
Cardiovascular disease is the major cause of death in diabetic patients. Diabetes mellitus patients have a 4-fold-higher risk of having a cardiovascular event than people without diabetes. Cardiac autonomic neuropathy is a frequent and severe complication of diabetes mellitus. Definite cardiac autonomic neuropathy is present in one fifth of diabetic patients. Cardiac autonomic neuropathy diagnosis is associated with a 5-fold increase in mortality, higher prevalence of silent myocardial ischemia as well as systolic and diastolic left ventricular dysfunction. In the last several years many works described a significant relationship between cardiac autonomic neuropathy and atherosclerotic vascular disease in type 1 and type 2 diabetes mellitus population. Our review focuses on possible pathophysiological pathways binding these two important diabetic complications.
Patients with type 1 and type 2 diabetes mellitus have significantly higher risk of cardiovascular disease including coronary artery disease(CAD), stroke, and peripheral arterial disease comparing to non-diabetic population [1-3]. Cardiovascular disease is the major cause of death in diabetic patients (approximately 70%) [4,5]. Type 2 diabetes mellitus patients have a 4-fold-higher risk of having a cardiovascular event than people without diabetes after adjusting to common risk factors of atherosclerosis, such as age, tobacco smoking, obesity, hyperlipidemia and hypertension. Major cardiovascular event (such as myocardial infarction, coronary revascularization, stroke, acute coronary heart disease death) is 3 times more often in type 1 diabetic men and up to 7 times more often in type 1 diabetic women [5,6].
Prolonged hyperglycemia is considered to be a main cause of diabetic microvascular and macrovascular complications [4,7,8]. Chronic hyperglycemia induces the production of advanced glycation end products (AGEs) through the non-enzymatic glycation process, alters intracellular signaling cascades (protein kinase C activation), and increases oxidative stress. All these mechanisms interact and lead to many structural and functional changes of the vascular wall inducing the atherosclerosis development . Hy
perglycemia also increases platelet aggregation, risk of thrombus formation and atherosclerosis progression .
In patients with type 2 diabetes mellitus, obesity and fatty tissue accumulation lead to lipid metabolism changes and pro-inflammatory markers production. In these subjects, insulin resistance is critically involved in vascular dysfunction [11,12]. Cardiac autonomic neuropathy (CAN) is a frequent and severe complication of diabetes mellitus. Definite CAN is present in one fifth of diabetic patients . CAN diagnosis is associated with a 5-fold increase in mortality comparing to diabetic patients without CAN, and a higher prevalence of silent myocardial ischemia as well as systolic and diastolic left ventricular dysfunction [14-16]. CAN incidence correlates to QT prolongation and increase the risk of malignant arrhythmias and sudden cardiac death . In the last several years many works described a significant relationship between cardiac autonomic neuropathy and atherosclerotic vascular disease in type 1 and type 2 diabetes mellitus population [18-24].
Are cardiac autonomic neuropathy together with accelerated atherosclerosis only products of prolonged unsatisfactory metabolic compensation or is there a pathophysiological mechanism that promotes atherosclerosis development in patients suffering
CAN? We would like to address these questions in our review.
Age, diabetes mellitus, high cholesterol and low density
lipoprotein levels, low level of high density lipoprotein,
hypertension, tobacco smoke, obesity and inactive lifestyle are
now considered to be major risk factors of atherosclerosis .
Some of these factors were also found to be risk markers
of CAN. A meta-analysis of Dafaalla et al. from 2016 found that
age, duration of diabetes, glycated hemoglobin level, BMI, serum
triglycerides, hypertension and incidence of microvascular
complications are directly related to the risk of CAN development
in type 1 diabetes mellitus . Similar findings applies for CAN
in type 2 diabetes mellitus. Reduced heart rate variability(an
indicator of CAN) in type 2 diabetes mellitus patients is also in
association with obesity and smoking . Poor glycemic control
seems to be a major risk for CAN progression in diabetic patient
[27-29]. Many risk factors of atherosclerosis and diabetic CAN
overlap, especially in type 2 diabetes mellitus patients. But what
is the exact mechanism of CAN development? Is it only a result
of vasa nervorum ischemia or do also other pathogenic pathways
take a part?
Pathogenesis of CAN is complex, multifactorial and not
entirely clear. Multiple ethiological hypotheses were proposed
including hyperglycemia induced nerve fibers injury, autoimmune
damage and neurohormonal growth factor deficiency [15,29,30].
Long term hyperglycemia is considered to be a leading cause
of micro and macrovascular complications of diabetes mellitus.
Hyperglycemia leads through the alteration of many metabolic
pathways to endothelial dysfunction, decreased neuronal blood
flow and nerve fiber damage. Excess of glucose activates the polyol
pathway leading to sorbitol accumulation. NADPH is consumed as a
coenzyme in this process. Relative deficiency of NADPH may cause
impaired NO synthesis and decreased nerve blood flow [15,31].
Hyperglycemia induced metabolic changes result in increased
free radicals production and oxidative stress that lead to vascular
endothelium damage . Accelerated advanced glycation end
(AGE) products formation alters the membrane permeability
as well as neuronal and endothelial function . Increased
formation of diacylglycerol lead to the subsequent activation
of protein kinase C(PKC). PKC pathway affects the regulation of
endothelial permeability, vasoconstriction, extracellular matrix
synthesis, abnormal angiogenesis and cytokine activation .
All these mechanisms result in functional and structural changes
of vessels (including vasa nervorum) and nerve fibers.
The role of autoimmunity on diabetic autonomic neuropathy is
also discussed. Several studies proved the independent association
of nervous tissue antibodies and CAN presence in patients with
T1DM [15,29,34-36]. One of the most recent prospective study
with adolescent T1DM patients was published in 2014. Zanone et
al. has followed 66 patients for 16 years. 19 of them had circulating
autobodies(Ab) to autonomic tissues. Prevalence of abnormal
cardiovascular autonomic tests and autonomic symptoms were
higher in Ab-positive (68 and 26%) than Ab-negative (32 and 4%)
patients (P < 0.05) independent of glycemic control . Study of
Shigeta et al. found that the presence of circulating sulfatide and
phospholipid antibodies correlates with diabetic neuropathy in
68 T2DM patients [38,39]. However more studies are needed to
prove the role of autoimmunity on diabetic autonomic neuropathy
in T2DM patients.
Many genes were found to have an association with the
development or progression of diabetic neuropathy (i.e. ACE,
MTHFR, GST, GLO1, APOE, TCF7L2, VEGF, IL-4, GPX1, eNOS,
ADRA2B, GFRA2, MIR146A, MIR128A) . Some of the studies
were focused to find gene polymorphisms correlation with
diabetic autonomic neuropathy. Genes associated with autonomic
dysfunction code for example an antioxidant enzyme (Glutathione
S-transferase), transcription factor (TCF7L2 gene) or autonomic
nervous sysem receptor (alpha2B-adrenergic receptor) [40-42].
It seems that autonomic neuropathy is not only a microvascular
complication, but several pathophysiological mechanisms are
involved in its development. Let‘s have a look from the other side.
How could CAN contribute to atherosclerosis development and
The autonomic nervous system is responsible for the optimal
regulation of the heart rate, strength of cardiac muscle contraction
and vessel tone. The renin-angiotensin-aldosterone system
controls the body fluid volume. Both of these systems interact and
regulate the blood pressure. Blood pressure, along with the heart
rate, physiologically decreases during the sleep period as a result
of the higher tone of the parasympathetic nervous system. This
phenomenon is called nocturnal dipping and it is at least 10%
drop of blood pressure in comparison to average daily values. It
is known that nerve fiber loss is length-dependent. That explains
predominant parasympathetic (vagus nerve) impairment in
early stages of CAN . Vagal nerve dysfunction and relative
hyperactivity of the sympathetic nervous system in early stages
of CAN is the most probable cause of insufficient drop of blood
pressure during the sleep (so called blood pressure „nondipping „)
or even rise of blood pressure during the night (so called „reverse
Nondipping and reverse dipping is associated with left
ventricular hypertrophy and cardiovascular events [45-48]. A
meta-analysis of Cuspidi et al. proved the association between
nondipping and increased risk of subclinical atherosclerosis .
Moreover a prospective study which monitored 75 adolescent T1DM patients found that the abnormal blood pressure
pattern during the night period also precedes the development
of microalbuminuria (marker of glomerular and vascular
dysfunction) . All these studies support a statement of Vinik
and his colleagues from 2003 who suggested that an impaired
circadian pattern of sympathovagal activity with higher blood
pressure values during the night and subsequent complications
could represent an important link between CAN and an increased
risk of mortality in diabetic patients .
Thera are also data indicating that CAN is associated with
arterial stiffness [51-53]. Arterial stiffness leads to higher arterial
wall resistance and increases systolic blood pressure. Higher
systolic blood pressure promotes atherosclerosis development.
Again we are confronted with the question whether CAN and
arterial stiffness are common results of chronic bad diabetic
compensation or whether they interact. As we discussed
above, early stages of CAN are accompanied by prevalent
parasympathetic impairment leading to relative hyperactivity of
sympathetic nervous system. Higher sympathetic tone leads to
tachycardia in rest. In rat animal models, an artificial increase
of heart rate determines the reduction of arterial distensibility
[54-56]. Moreover, vagal denervation is associated with higher
procollagen mRNA levels in the wall of affected vessels .
Sympathetic denervation may cause dedifferentiation of vascular
smooth muscle cells and intima thickening . These findings
suggest that the autonomic nervous system alterations have a
negative trophic effect on arterial wall and could lead to increased
arterial stiffness. This hypothesis seems to be supported by a
prospective study of Prince et al. published in 2010. It showed
that CAN (expressed as decreased heart rate variability in deep
breathing test) is associated with increased arterial stiffness 18
years later in type 1 diabetes mellitus patients .
Experimental studies showed that the autonomic nervous
system modulates the systemic inflammatory response through
the cholinergic anti-inflammatory pathway [60,61]. Rodrigues et
al.  who published in 2010 an interesting study that proved
that reduced heart rate variability(marker of CAN) predicts the
progression of coronary artery calcification in adults with and
without T1DM, suggested that autonomic neuropathy leading to
pro-inflammatory state could represent one pathway leading to
atherosclerosis progression . A study from 2017 found an
association of lower heart rate variability(HRV) and white blood
cells count(WBCC), this study also described an inverse association
of inflammatory markers(WBCC and CRP) with baroreflex
sensitivity and carotid plaque area . Another study described
an association of lower HRV parameters, presence of depression
and higher IMT with CRP and IL6 . Nevertheless more studies
are needed to confirm how could autonomic dysfunction activate
the inflammatory system and promote atherosclerosis.
All mentioned pathophysiological pathways binding CAN and
atherosclerosis are summarized on simplified schema (Figure 1).
Our review focused on the relationship between CAN and
atherosclerosis development in diabetic patients. Although some
risk factors of atherosclerosis overlap with the risk factors of
CAN, it seems that the pathophysiology of CAN is more complex
and multifactorial. Several small studies found a significant
correlation between the presence of circulating autonomic tissue
autobodies and diabetic autonomic neuropathy. The role of
genetic polymorphisms and epigenetic changes of several genes
associated with autonomic function is also discussed.
It seems that both of these diabetic complications interact and
mutually affect the progression of each other. We discussed the
possible pathways (heart rate and blood pressure increase, trophic
changes of arterial wall, arterial stiffness, pro-inflammatory state)
through which CAN may contribute to atherosclerosis progression.
Future prospective studies on young diabetic patients with good glycemic control and free of macrovascular complications
could help to identify the exact pathophysiological mechanisms
between these two units and hopefully find a way how to decrease
cardiovascular mortality in diabetic patients.