Key-words:
Cardiovascular autonomic neuropathy - diabetes mellitus - heart rate variability -
orthostatic hypotension - resting tachycardia
Introduction
Diabetes mellitus (DM) is a growing health challenge, and its burden is increasing
on the health-care systems worldwide. This problem is worsened by the association
of DM with several serious and fatal complications, including diabetic autonomic neuropathies.
Cardiac autonomic neuropathy (CAN)[[1]],[[2]] is one of the most severely debilitating forms of these autonomic neuropathies
in DM patients. The autonomic nervous system modulates complex physiological mechanisms
to help preserve blood pressure (BP) and heart rate (HR) within a normal range.
The Toronto Consensus Panel defined CAN as the impairment of cardiovascular autonomic
control in patients with DM after the exclusion of other medical causes.[[3]],[[4]] The diagnosis of CAN involves an evaluation of signs and symptoms for abnormal
cardiovascular autonomic control. Standardized noninvasive cardiovascular autonomic
reflex tests (CARTs) are safe and feasible to administer and have good sensitivity,
specificity, and reproducibility for diagnosing CAN in patients with diabetes.[[4]],[[5]],[[6]],[[7]]
Screening for CAN is recommended in patients with type 2 diabetes (T2D) and type 1
diabetes (T1D) at diagnosis or after 5 years of disease, respectively. CAN is particularly
evident in patients with poor glycemic control (hemoglobin A1c [HbA1c]>7%), at least
one major cardiovascular disease risk factor, or other chronic complications associated
with DM (level B). In asymptomatic patients, screening for CAN may also be required
for preoperative risk assessment for major surgical procedures (level C).[[4]] A classification of CAN is based on “early involvement” (two borderline test results
or one abnormal result on HR test), “definite involvement” (two or more abnormal results
on HR tests), and “severe involvement” (development of orthostatic hypotension).[[8]]
Diabetic CAN is further classified into phases: the subclinical phase is associated
with decreased HR variability (HRV), the early phase with resting tachycardia, and
the advanced phase with exercise intolerance, cardiomyopathy with left ventricular
(LV) systolic dysfunction,[[9]],[[10]] orthostatic hypotension, and silent myocardial ischemia (MI). A meta-analysis of
12 studies identified a higher rate of silent MI in patients with versus without CAN
(20% vs. 10%).[[11]] CAN can independently predict the progression of diabetic nephropathy.[[12]] CAN is also an independent risk factor for all-cause mortality in patients with
T1DM (EURODIAB study) and T2D (ACCORD study).[[4]],[[13]],[[14]] A meta-analysis of 15 longitudinal studies reported an association between CAN
and higher mortality.[[15]]
CAN is also associated with a five-fold increased risk of cardiovascular mortality[[16]] and can be used for cardiovascular risk stratification, including a marker for
a greater risk of intraoperative cardiovascular liability. There are limited data
on CAN in different populations. The present study aims to identify and characterize
CAN and its associated disorders in a sample of Libyan patients with diabetes.
Patients and Methods
Study cohort
Adult patients (18 years and older) diagnosed with DM were seen at the National Diabetes
Hospital outpatient clinic in Tripoli, Libya, between October 2017 and April 2018.
They were prospectively enrolled for diagnostic evaluation after informed consent
for CAN and associated conditions [[Table 1]] and [[Table 2]], highlighting the CARTs. Patients who had any systemic illness (e.g., congestive
heart failure, coronary artery disease, arrhythmia, and thyroid dysfunction) or were
on adrenergic antagonists that could confound the results of the autonomic function
tests were excluded from the final analysis.
Table 1: Distribution of the patients’ sociodemographic characteristics and degree of cardiovascular
autonomic neuropathy severity
Table 2: Distribution of the patients’ clinical characteristics and degree of cardiovascular
autonomic neuropathy severity
Assessment and data acquisition
Baseline demographic data (e.g., age, sex, body mass index (BMI), and history of cardiovascular
risk factors) were taken. Echocardiographic findings and details related to type,
duration, and associated complications of DM were evaluated. Transthoracic echocardiography
(Vivid 7 GE) was used to assess LV systolic function, wall thickness, and ischemic
changes based on the American Society of Echocardiography recommendations.[[17]]
Patients were also evaluated for the diagnosis and staging of CAN and associated conditions
based on Ewing's methodology for autonomic function tests [[Supplementary Material 1]] and [[Supplementary Material 2]]. The existence of one abnormal cardiovagal test result identifies the condition
as possible or early CAN. The presence of at least two abnormal results is necessary
for a definite or confirmed diagnosis of CAN. If orthostatic hypotension is present
in addition to HR test abnormalities, this identifies severe or advanced CAN.
Supplementary Material Appendix 1: Description and definitions of normality and abnormality in the cardiovascular autonomic
reflex tests٭
Supplementary Material Appendix 2: Normal, borderline, and abnormal values in tests of cardiovascular autonomic function٭
Statistical analysis
Analysis was performed using the Statistical Package for the Social Sciences program
version 16 (SPSS Inc. Released 2007. SPSS for Windows, version 16.0. Chicago, SPSS
Inc.). The data are presented as frequency and percentages. Descriptive analysis using
cross-tabs, with the application of Chi-square tests, resulted in Asymp. Sig. (two-sided);
P < 0.05 was taken to indicate statistical significance.
Results
Ninety-nine patients with DM (mean age: 52 ± 1.5 years) were evaluated for CAN. [[Table 1]] highlights the demographics. There were marginally more females (53%), and most
were nonsmokers (70%). Type 2 DM was present in 85% of the cases (based on clinical
classification), 29% were on oral hypoglycemic agents, 27% of the patients were receiving
combined insulin and oral antidiabetic drugs, and 43% were on insulin only. There
were 15% newly diagnosed (<1 year), 43% of their DM duration were <9 years, and about
41% were more than 10 years. The duration of diabetes was 12.7 ± 9.5 years. BMI was
normal (18.5%–24.5%) in 34% of the cases, 43% were overweight (BMI = 25%–29.5%), 17%
were obese (BMI = 30%–39.5%), and 5% with morbid obesity (BMI ≥40%). BMI with mean
± standard deviation was 32.29 ± 7.5. BP was measured for every patient after 15-min
rest, uncontrolled (≥140/90) in 68% of the studied cases. Diabetic microvascular complications
were present in 54% of the cases [[Table 1]].
Cardiac autonomic neuropathy – symptoms and stages
Symptom of CAN (orthostatic symptoms, such as light-headedness, dizziness, blurred
vision, or fainting) was overt in only 16 cases. Six of them had a severe degree of
CAN. Eighty-three percent of the patients were asymptomatic (silent), and 32 of them
had an advanced stage of CAN.
CAN could be detected in 62% of the studied cases. They were classified as (1) subclinical
phase: decreased HR variability and early involvement (two borderline test results
or one abnormal result on HR test) were possible in 18%, (2) early phase: resting
tachycardia and substantial involvement (two or more abnormal results on HR tests)
were in 6% (resting HR: 80.58 ± 1.02), and (3) advanced stage: severe involvement
(development of orthostatic hypotension) was in 38%.
History of hypoglycemic unawareness was present in 76% of the studied cases, with
34% having an advanced CAN stage. A significant association was evident with hypoglycemic
unawareness (P = 0.02), uncontrolled BP (P = 0.006), dyslipidemia (P = 0.012), and
microvascular diabetic complications (P = 0.007) [[Table 2]].
Biochemical associations of cardiac autonomic neuropathy
We meant that out of the total number of the patients who had advanced stage of CAN
( 38 patients ) 19 cases (50% ) of the advanced CAN patients had an average HbA1c
control , whereas 16 cases (42,1% ) of the advanced CAN patients had a poor HbA1c
control. Fasting lipid profiles were abnormal even with described treatment (no compliance)
in 54 cases. There were 22 cases with advanced stage of CAN with abnormal lipid profile,
about 45 cases with an average level under treatment, and 16 cases with advanced CAN
[[Table 3]].
Table 3: Distribution of patients’ biochemical laboratory test and degree of cardiac autonomic
neuropathy severity according to Ewing’s tests
Discussion
This pilot study aimed to evaluate cardiovascular autonomic neuropathy (CAN) by assessing
associated conditions in diabetic patients attending diabetes and cardiac clinics.
CAN was associated with an increase in sudden death in the ACCORD study in which intensive
glycemic control was contemplated.[[14]] In this study, the coexistence of numbness of the feet indicative of exacerbation
of diabetic peripheral neuropathy and fixed HR indicative of CAN provoked the susceptibility
to an incident.[[15]] Similar to the present study, there was a significant association between the presence
of both severe CAN and other microvascular complications (P = 0.04). Seventy-one percent
of the patients have severe CAN and microvascular complications.
Similar results were also found in the EURODIAB study, a large cohort study of T2DM
patients with CAN.[[17]] The presence of retinopathy and albuminuria was associated with severe CAN. EURODIABE
demonstrated that over a 7.5-year follow-up, diabetic retinopathy and higher levels
of microalbuminuria predicted CAN progression.[[17]]
Cardiac autonomic dysfunction leads to many clinical complications, such as orthostatic
tachycardia, orthostatic bradycardia, and hypotension, and can cause arrhythmias and
sudden death.[[6]] The predictive significance of resting HR is a valuable tool for cardiovascular
risk stratification and as a therapeutic target in high-risk patients.[[6]]
Whereas the loss of HRV is the early finding of CAN, resting tachycardia and fixed
HR are typical late features in patients with autonomic dysfunction. Resting HRs of
90–100 b. p. m. and rarely up to 130 b. p. m. arise. The highest resting HRs have
been discovered in patients with vagal nerve dysfunction before sympathetic nerve
injury; in those with a sign for both vagal and sympathetic participation, the rate
resumes near normal but still raised. A fixed HR that is insensitive to moderate exercise,
stress, or sleep signifies nearly complete cardiac denervation. A reduced HR reaction
to adenosine receptor agonists was shown in metabolic syndrome and diabetes, recognized
as earlier stages of CAN.[[18]]
We meant based on large cohort study there are a strong correlation between elevated
resting heart rate and was associated with an increased risk of dying from IHD and
from all causes of death.[[19]]
We found a weak correlation between symptoms and the degree of CAN (P = 0.907) in
agreement with a recent study.[[20]] Patients with orthostatic hypotension classically have light-headedness and presyncopal
symptoms. However, many patients stay asymptomatic even with substantial reductions
in BP and advanced stage of CAN. Orthostatic symptoms can furthermore be misinterpreted
as hypoglycemia and can be provoked by drugs.[[16]] In a small cohort of patients with T2D, there were comparable associations between
loss HRV resulting from 48-h Holter electrocardiography and spontaneous hypoglycemic
events detected by continuous monitoring CGM.[[6]]
On the other hand, the existence of CAN may raise the risk of hypoglycemia through
hypoglycemia unawareness and consequent compromise ability to return euglycemia through
sympathoadrenal dysfunction or delayed gastric emptying.[[18]]
It has been suggested that frequent occurrence of hypoglycemia may diminish the counter-regulatory
hormones and reduce autonomic nervous system responses to succeeding hypoglycemic
episodes.[[19]]. Further studies described that controlled hypoglycemia caused a progressive decrease
in HRV in patients with T1D.[[19]] A current report in adults with T1D showed that a greater rate of spontaneous nocturnal
hypoglycemia was related to a decline in the LF power.[[18]] Our data similarly propose that CAN may increase the risk of hypoglycemic stress
in patients with DM, even though this cannot be established from the present study
due to the cross-sectional nature of this study. We noticed that these relations are
independent of glucose control (HbA1c values) based on an insignificant P = (0.679).
At the same time, we found that uncontrolled hypertension, dyslipidemia, presence
of retinopathy, and history of hypoglycemic unawareness were strongly associated with
a severe form of CAN, suggesting an impaired autonomic function, which was independent
of glycemic control as assessed by the HbA1c. This study found no significant P value
between progressions to the advanced stage of CAN with sex, age, BMI, duration of
DM, orthostatic symptoms, smoke stat, and mode of diabetes treatment [[Table 1]].
This study has some limitations. It is a small and single-center study. Patients were
not followed for the long term to deduce outcome data and link with baseline findings.
Thus, the prognostic implications of our findings remain to be delineated. Nonetheless,
reports on CAN using novel measures for diagnosis and staging are limited, particularly
from different parts of the world.
Conclusions
In this relatively high-risk cardiovascular disease cohort, patients with diabetes,
uncontrolled BP, dyslipidemia, microvascular diabetic complication, and hypoglycemic
unawareness are at increased risk of severe cardiac autonomic neuropathy. Large prospective
studies are warranted to elucidate the complex interplay between hypoglycemia and
cardiac autonomic dysfunction.
Patients with DM who are expected to have CAN should be examined for cardiac autonomic
neuropathy before an exercise program. Patients with CAN must be depending on their
apparent effort, not HR, to avoid dangerous levels of exercise intensity. Silent infarction
can postpone suitable therapy. Thus, patients with CAN necessitate extra caution,
and cardiovascular autonomic function testing might be an essential element in the
risk evaluation of patients with DM and coronary artery disease. Finally, every patient
with DM (T1D after 5 years of diagnosis and T2D at presentation) must be examined
for possible CAN by a cardiologist.
Authors' contributions
All named authors contributed to the study's conception, data collection and analysis,
and drafting and revision of the article. All authors approved the final version of
the manuscript.
Compliance with ethical principles
The Bioethics Committee approved the study at the Biotechnology Center, Tripoli, Libya
(Ref Number 25-2021). Verbal consent was obtained from all participants.
Reviewers:
Ali Ghazil Saad (Jackson, Mississippi, USA)
Alaa Samir Sagar (Texsas, USA)
Editors:
Salem A Beshyah (Abu Dhabi, UAE)
Elmahdi Elkhammas (Columbus, Ohio, USA)
