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CARDIOVASCULAR AUTONOMIC NEUROPATHY IN DIABETES MELLITUS
Laura Poanta, Simona Clus, Mihai Porojan, Dan L Dumitrascu
University of Medicine and Pharmacy “Iuliu Hatieganu” Cluj Napoca Romania
2nd Department of Internal Medicine
Corresponding author
Laura Poanta
Cluj Napoca, Pascaly Street 9/16 postal code 400431
Romania
[email protected]
Acknowledgement: Research supported from CNCSIS project number 1277 of Ministry
of Education
Abstract
Diabetes mellitus (DM) is a disease of modern world, with a great impact on the
life of the affected individual. Autonomic neuropathy (AN), also called visceral
neuropathy is a disease of the autonomic nervous system affecting mostly the internal
organs. The diagnosis of AN can be made in early stages, and is called sub-clinical
neuropathy. Cardiovascular autonomic neuropathy (CAN) correlates with a lot of signs
and symptoms, which are more or less specific. CAN is associated with poor prognosis
and may result in severe symptomatic diseases, but is also associated with silent
ischemia. In conclusion, CAN is a very important complication of both type 1 and type 2
diabetes which can be early diagnosed by some specific test and should be taken into
account in all the cases, even the asymptomatic ones.
Rezumat
Diabetul zaharat este o boală a lumii moderne, cu un impact deosebit aupra vieţii
individului afectat. Neuropatia vegetativă sau autonomă este o suferinţă a sistemului
nervos vegetativ, afectând în special organele interne. Diagnosticul neuropatiei vegetative
se poate face încă din stadiile precoce de boală, când vorbim de neuropatia sub-clinică.
Neuropatia vegetativă cardiovasculară (NVC) se corelează cu o paletă largă de semne şi
simptome mai mult sau mai puţin specifice. Se asociază, de asemenea, cu un prognostic
mai prost al diabetului zaharat şi cu simptome cardiovasculare severe, dar şi cu episoade
de ischemie miocardică silenţioasă. În concluzie, NVC este o complicaţie redutabilă a
diabetului zaharat atât de tio 1 cât şi de tip 2, ce poate fi diagnosticată precoce prin teste
specifice care ar trebui considerate la toţi pacienţii, chiar şi la cei asimptomatici.
Diabetes mellitus (DM) is a disease of modern world, with a great impact on the
life of the affected individual, regarding the quality of life, work capacity, morbidity and
mortality. On the other hand, DM is a chronic disease which requires treatment on a
lifetime basis, the individual and global costs being also important. WHO showed that for
one diabetic patient there were spent 13.000 dollars in 2002, comparing with a nondiabetic patient were the costs were around 2000 dollars (1). In 2006 there were 264
million diabetics all over the world (1, 2); in 2005 there were 20.8 million persons with
DM in USA and 54 billions with pre-diabetes. In Europe, the number of the persons
affected by DM differs from region to region but is continuingly growing (1, 2, 3).
The American Diabetes Association reported in 2009 that there are 23.6 million
children and adults in the United States - 7.8% of the population, who have diabetes.
While an estimated 17.9 million in the US alone have been diagnosed with diabetes,
nearly one in four (5.7 million) diabetics are unaware that they have the disease (1).
Autonomic neuropathy (AN), also called visceral neuropathy is a disease of the
autonomic nervous system affecting mostly the internal organs such as the bladder
muscles, the cardiovascular system, the digestive tract, and the genital organs. These
nerves are not under a conscious control and function automatically. Most commonly,
autonomic neuropathy is seen in persons with long-standing diabetes mellitus type 1 and
2. AN develops slowly and without significant symptoms at the beginning, and the
prevalence varies widely with the study methods and end-points, reaching 100% in
hospitalized patients in some studies (2, 3).
It is very important to remember that the diagnosis of AN can be made in early
stages, called sub-clinical neuropathy, which are after the first year from the diagnosis for
DM type 2 and after the first 3 years for DM type 1. The most important etiopathogenetic
factors involved are: the gender (females are more affected than the males), a higher body
mass index, the age, and a poor glycemic control. From the diabetic patients with
symptomatic AN, 25 to 50% are prone to die in the next 5 to10 years, which represents
another reason for the early diagnosis and treatment of those complications (2, 3).
The main clinical signs and symptoms of autonomic neuropathy in DM are:
abnormal changes in pupillary diameter, Argyll-Robertson pupil; hypoglycemic episodes
without symptoms; cardiovascular signs and symptoms of AN include: orthostatic
hypotension, abnormal heart rate variability (HRV), abnormal control of heart rate
(expressed by impaired effort adaptation and nocturnal tachycardia), cardiac denervation
syndrome; gastrointestinal signs and symptoms are: dysfagia, abdominal pain, nausea,
vomiting, malabsorption, fecal incontinence, diarrhea and/or constipation (2,3,4);
neurological signs: symmetrical anhidrotic areas, hyperhidrosis; genitor-urinary signs:
erectile dysfunction, retrograde ejaculation, neurogenic bladder. Differential diagnosis
involves a lot of diseases and syndromes like: idiopathic orthostatic hypotension, ShyDrager syndrome, hypopituitarism, pheochromocytoma, Chagas disease, amyloidosis,
hypovolemia of different causes, insulin adverse effects, other drugs adverse effects,
alcoholic neuropathy, heart failure, diarrhea and constipation of various causes, erectile
dysfunction of other causes (organic or psychological)(4, 5, 6).
Diabetes has a great influence on the prevalence of atherosclerosis and coronary
heart disease, and also increases the risk of heart failure. Patients with diabetes are two to
five times more likely to develop heart failure than those without diabetes. Diabetic
cardiomyopathy means that in diabetic patients there is a direct alteration in myocardial
function, but the exact prevalence, nature and cause of cardiac dysfunction is still unclear
because there are other factors common in diabetes, such as hypertension, coronary
atherosclerosis and microvascular dysfunction, which can independently impair
myocardial performance (5, 7, 8, 9). Possible contributors to diabetic cardiomyopathy
are: collagen accumulation leading to decreased myocardial compliance, diastolic
dysfunction due to the accumulation of advanced glycosylation end product-modified
extracellular matrix proteins, direct effect of altered energy substrate supply and
utilization, abnormal myocardial calcium handling, endothelial dysfunction, deposition of
intramyocardial fat, cardiac autonomic neuropathy and genetic abnormalities (8, 9, 10).
Cardiovascular autonomic neuropathy (CAN) correlates with a lot of signs and
symptoms, as we already stated above, which are more or less specific, like:

Orthostatic hypotension, defined as fall of systolic BP over 30 mmHg and
diastolic BP over 10 mmHg in response to a postural change from supine
to standing. Orthostatic hypotension may be completely asymptomatic, or
symptomatic, when it can be confused with hypoglycemia (6, 7, 11, 12).

Imbalanced effort adaptation occurs by reducing the response in heart rate
and blood pressure with incomplete increasing in cardiac output during
exercise.

Increased cardiovascular instability intra and post surgery. Perioperative
cardiovascular morbidity and mortality are increased 2 to 3 fold in patients
with diabetes (6).

Tachycardia / bradycardia. Resting tachycardia and a fixed heart rate are
characteristic late findings in DM patients with vagal impairment, as
opposed to HRV which occurs earlier but is asymptomatic. There is also a
syndrome
called
postural
tachycardia
syndrome
with
obscure
pathogenesis. Some patients have paradoxical bradycardia on standing.

Silent myocardial ischemia; more frequent than in non-diabetic patients,
myocardial infarction, lower survival rates post myocardial infarction (5,
6). This problem is reported in 17% for type 1 DM and 22% for type 2
DM, but in fact the percents are influenced by the study methodology (4).
The impact on mortality is important: a five years meta-analysis showed a
significant lower mortality in patients with DM and normal HRV
compared with DM patients with abnormal HRV (4).

Cardiac denervation syndrome;
The most analyzed signs to asses CAN are the following:

abnormal circadian pattern of the blood pressure (BP), with increased BP
at night;

the lack of beat to beat RR variability in deep inspiration, with the
prevalence increasing with disease duration (from 1.6% at 5 years to 12%
at 9 years) (5);

resting tachycardia; postural or orthostatic tachycardia
(postural
tachycardia syndrome);

long corrected QT with increased risk for sudden death and cardiac
arrhythmias;

standardized stress testing for silent ischemia (12, 13, 14);
A large number of studies (6, 15, 16, 17, 18) compared the prevalence of silent
ischemia in diabetic patients with CAN compared with diabetic patients without CAN.
The presence of silent ischemia was assessed mainly with standardized stress testing. In
some studies (6, 19) there is a significant amount of silent ischemic episodes in diabetic
subjects with CAN.
The ECGs of diabetic patients with chest pain and diabetes mellitus there is a
delay in pain perception, from the moment of significant ST depression, over 1 mm, to
the moment in which the patient feel the pain; this phenomenon is present in subjects
with associated CAN. They are exposed to an increased risk because they will perform
effort despite the presence of myocardial ischemia, as they don’t feel any pain, so the risk
of complications is more important. The explanation for the silent ischemia is the
presence of CAN secondary to DM, the presence of CAN secondary to coronary heart
disease, or both (4, 6).
In Framingham study, unrecognized myocardial infarction rate was 39% in DM
patients and 22% in non-diabetic patients, but the difference wasn’t statistical significant.
The mechanisms of silent myocardial ischemia depend on many factors and are only
partially explained even today (6, 20).
The alterations in pain perception, insuficient ischemia to induce pain, afferent
fibers dysfunction, may be possible explanaitions (6). A large study entitled Detection of
Ischemia in Asymptomatic Diabetics (DIAD) (21), realized in a group of more than 1000
patients with type 2 diabetes mellitus, showed that the presence of autonomic dysfunction
was an significant predictor for ischemic episodes. All the studies performed on this
matter underline the importance of closer surveillance of DM patients with cardiac
autonomic dysfunction, and on the other hand the importance of investigating the
presence of CAN, as an major factor in cardiovascular risk stratification (4, 8, 21, 22).
Some particular clinical aspects in DM patients with CAN are: lack of symptoms,
cough, nausea, dyspnea, and asthenia. Those symptoms, if there are sudden, in a DM
patient should lead to ECG registration which may or may not confirm the diagnosis of
acute coronary syndrome (5, 23).
Effort intolerance is a frequent finding in DM patients with CAN via reduction in
cardiac response to physical exercise (insufficient increasing of heart rate and blood
pressure, with concomitant decrease in cardiac output). Diabetic patients with CAN shoul
be tested for cardiac stress before undertaking an rehabilitation program with physical
exercise. Patients with CAN should rely on their perceived exertion not on heart rate, to
avoid hazardous and dangerous levels of exercise intensity. Exercise test is not routinely
used but may be useful in DM with longer disease duration, with associated
cardiovascular risk factors and known CAN. (6, 8)
In cardiac denervation syndrome, there is a reduced appreciation for ischemic
pain, which may delay the treatment both in chronic cases with silent ischemia and in
acute coronary syndromes without pain.
The evaluation of CAN includes: spectral analysis of heart rate variation during
24 hours and during deep breath, resting heart rate, heart rate ratio with standing and
Valsalva, blood pressure in standing, 24 hours blood pressure monitoring, diastolic blood
pressure during physical exercise; on 24 hours ECG registration and heart rate variability
analysis there are some parameters which are more frequently used: LF (low frequency)
which reflects sympathetic activity and is lower than normal in CAN, HF (high
frequency), which reflects parasympathetic activity and LF/HF rate which reflects
sympathetic / vagal. Therapeutic options are: a good glycemic control in all DM patients,
and medications such as beta blockers (24, 25, 26).
The last decades have witnessed the recognition of a significant relationship
between the autonomic nervous system and cardiovascular mortality, including sudden
cardiac death. Evidence for an association between lethal arrhythmias and signs of either
increased sympathetic or reduced vagal activity has encouraged the development of
quantitative markers of autonomic activity. Heart rate variability (HRV) represents one of
them. Recognition of these problems led the European Society of Cardiology and the
North American Society of Pacing and Electrophysiology to constitute a Task Force
charged with the responsibility of developing appropriate standards (24). There are timedomain and frequency-domain items to be measured for assessing HRV in general. In
neuropathy associated with diabetes mellitus, characterized by alteration of small nerve
fibres, a reduction in time–domain parameters of HRV seems not only to carry negative
prognostic value but also to precede the clinical expression of autonomic neuropathy. In
diabetic patients without evidence of autonomic neuropathy, reduction of the absolute
power of LF and HF during controlled conditions was also reported. However, when the
LF/HF ratio was considered or when LF and HF were analyzed in normalized units, no
significant difference was present. Thus, the initial manifestation of this neuropathy is
likely to involve both efferent limbs of the autonomic nervous system (24, 25, 27).
In conclusion, CAN is a very important complication of both type 1 and type 2
diabetes which can be early diagnosed by some specific test and should be taken into
account in all the cases, even the asymptomatic ones.
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