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Volume 1, ¹4



Art of Medicine
International Medical Scientific journal

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ART of MEDICINE

International Medical Scientific
Journal

Volume 1, ¹4 December 2021



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Volume 1, ¹4

Art of Medicine
International Medical Scientific journal

Founder and Publisher Pascual Izquierdo-Egea
Published science may 2021 year. Issued Quarterly.
Internet address: http://artofmedicineimsj.us
E-mail: info@artofmedicineimsj.us
11931 Barlow Pl  Philadelphia, PA 19116, USA

CHIEF EDITOR

Dr. Pascual Izquierdo-Egea

EDITORIAL BOARD

Prof. Dr. Francesco Albano

Dr. Catherine J. Andersen

Prof. Dr. Sandro Ardizzone

Dr. Dmitriy Atochin

Prof. Dr. Antonio Aversa

Prof. Dr. Tamam Bakchoul

Prof. Dr. Pierre-Gregoire Guinot

Prof. Dr. Rainer Haak

Prof. Henner Hanssen



Art of Medicine
International Medical Scientific journal

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EFFECTS OF INTENSIVE HYPOGLYCEMIC THERAPY FROM THE
POSITION OF THEIR INFLUENCE ON THE DEVELOPMENT OF HEART
RHYTHM DISORDERS

Mirzarahimova Z. H.,
Rakhimova G.N.,

Mullabaeva G. U.,
Yakubov A. A.

Republican Specialized Scientific and Practical Medical Center of Cardiology
Tashkent, Uzbekistan

Abstract: It is known that DM 2-4 times increases the risk of CVD, and mortality when
combined increases 4-5 times. The combination of a cluster of risk factors for the rapid
development and progression of atherosclerosis, which is based on insulin resistance -
hyperglycemia, dyslipidemia, hypertension, allowed the expert Commission of the National
educational program of the United States cholesterol (NCEP) to equate DM2 risk to
coronary heart disease. This article reviews the literature on the relationship of diabetes
and hypoglycemia with the development of cardiac arrhythmias.

Key words: atrial fibrillation, diabetes mellitus, hypoglycemia, prevention

CVDs remain the leading cause of death worldwide, they are responsible for 17.3
million deaths annually - 31.5% of all deaths of the world population and 45% of all
deaths from NCDs, which include 4 groups of diseases, including cardiovascular,
cancer, bronchopulmonary and diabetes mellitus (DM) [2].

However, the XXI century was marked by an epidemic of metabolic risk factors of
CVD, such as obesity, impaired glucose tolerance, diabetes mellitus (DM). According
to the International Diabetes Federation (IDF, 2014) currently 400 million people in
the world suffer from diabetes and by 2035 their number will increase to 600 million
people. In Russia, by 2030, the number of patients with diabetes is predicted to increase
to 14 million. It is known that diabetes 2-4 times increases the risk of CVD, and mortality
when combined increases by 4-5 times [3]. The combination of a cluster of risk factors
for the rapid development and progression of atherosclerosis, based on insulin resistance
- hyperglycemia,  dyslipidemia,  arterial hypertension - allowed the expert committee of
the US National Cholesterol Education Program (NCEP) to equate type 2 diabetes
with coronary heart disease. Today, T2DM is considered the equivalent of having
clinically significant CVD [1].

Well-known prospective studies have confirmed the role of hyperglycemia in the
development of CVDs (DECODE, EPIC-Norfolk, ARIC, ADVANCE). However, a
number of studies have shown that despite improved glycemic control, macrovascular
complications and associated CVDs continue to progress in DM2 patients (UKPDS,
Kumanato Study)

Glycemic control studies have shown that intensive glycemic control in the two types
of diabetes does not always have similar effects. The Diabetes Control and Complications
Trial (DCCT) has convincingly demonstrated the positive role of intensive glycemic
control in reducing the risk of micro- and macrovascular complications in patients with
type 1 diabetes. It was shown that strict and constant glycemic control (average HbA1c
level ~ 7% for 6.5 years) is the main prevention of the development and progression of
microvascular complications and reduces the frequency of microalbuminuria by 39%,
proteinuria - by 54%, neuropathy - by 60% [20].



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The target HbA1c level, according to the current consensus of the European Association

for the Study of Diabetes and the American Diabetes Association, is less than 7.0%
(with normal values less than 6.0%).

Microvascular complications are known to be the cause of early disability in patients
with type 2 diabetes, whereas macrovascular complications in the form of cardiovascular
disease are the cause of death in eight out of ten patients [7, 9]. According to Veterans
Affairs Diabetes Trial (VADT) data, severe hypoglycemic reactions in DM 2 are one
of the main predictors of myocardial infarction, cerebral stroke and death from all
causes [3]. The ambiguous role of intensive glycemic control was demonstrated by a
large-scale multicenter randomized two-factor ACCORD (Action to Control
Cardiovascular Risk in Diabetes) study, the key point of which was to maintain
diabetes compensation with glycosylated hemoglobin (HbA1c) levels less than 6.5%.
The study included 10251 high-risk patients with type 2 DM, randomized into intensive
(HbA1c less than 6%) and traditional (HbA1c 7.0-7.9%) glycemic control groups with
different intensity of control of blood pressure and lipid profile. The study was terminated
early due to high mortality in the intensive treatment group (257 deaths, mean HbA1c
6.4% versus 203 deaths, mean HbA1c 7.5% in the traditional treatment group, i.e., 54
excess deaths in the intensive treatment group) [16]. As a careful review of the study
results showed, episodes of hypoglycemia were significantly more frequent in the intensive
glycemic control group (10.5% vs 3.5%). At the same time, a statistically significant
reduction in myocardial infarction, stroke, and CV mortality was observed in the group
of patients without CVD with baseline HbA1c<8.0% [3]. The effect of intensive glycemic
control on reducing the risk of microvascular (nephropathy and retinopathy) and
macrovascular (myocardial infarction, stroke, CC mortality) complications was
demonstrated in the ADVANCE (The Action in Diabetes and Vascular disease preterAx
and diamicroN-MR Controlled Evaluation) study (OR 0, 9 [95% CI 0.82-0.98] p=0.01),
but it should be noted that the reduction in risk of microvascular events (OR 0.86 [95%
CI 0.77-0.97], p=0.01) was significantly higher, whereas the reduction in risk of
macrovascular events did not reach the level of statistical significance (OR 0.94 [95%
CI 0.84-1.06], p=0.32). However, in contrast to the ACCORD study, no increase in
total or CV mortality was observed in the intensive glycemic control group compared
to the standard glycemic control group [4].

Later, the results of the VADT study confirmed those of the ADVANCE study, where
there were no differences in the incidence of CV events between the intensive and
standard glycemic control groups (OR 0.88 [95% CI 0.74-1.05], p=0.12). CVD mortality
in the intensive glycemic control group was slightly higher than in the standard glycemic
control group (38 versus 29, sudden death 11 versus 4), but this difference did not
reach statistical significance. An in-depth analysis of the results showed the effect of the
duration of diabetes disease on the incidence of endpoints. Thus, when the history of
diabetes was not longer than 12 years, intensive glycemic control did not demonstrate
its negative effect on CV mortality.

At the beginning of the 21st century Nordin C. expressed an opinion about
proarrhythmogenic effect of hypoglycemic reactions due to the direct effect of hypoglycemia
and catecholamine reactions, causing hypokalemia and other disorders [13].

A number of studies have demonstrated an independent role of DM in the development
of sudden death (SD) [5].

Several mechanisms may be involved in the development of sudden death against the
background of hypoglycemia. An important pathogenetic link is the development of the
so-called "autonomic dysregulation disorder associated with hypoglycemia" (NARSH).
NARSH is a form of sympathoadrenal system failure as a result of a recent episode of



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International Medical Scientific journal

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iatrogenic hypoglycemia, which leads to a lower blood glucose threshold level that
triggers the counterinsulatory response necessary to restore normoglycemia [18]. This
contributes to an almost 25-fold increase in the risk of severe hypoglycemia against the
background of intensified insulin therapy and the appearance of repeated episodes of
hypoglycemia.

The Pearson E.C. study found an association between DM and prolongation of the
PQ interval in patients with coronary heart disease (CHD) [15]. Older age and the
presence of comorbidities determine the greatest risk of cardiovascular complications
associated with hypoglycemic states in type 2 DM. At blood glucose levels < 3 mmol/
l for more than 30 min, increased QTc time and ventricular tachycardia occur with an
increased risk of ventricular fibrillation and VS.  Abrupt changes of mean amplitude of
glucose excursion (MAGE) more than 5 mmol/l contribute to greater vulnerability of
electrical stability of the heart, especially in weakened patients with the presence of
coronary heart disease and autonomic dysfunction.

The independent role of diabetes in the development of AF was assessed in the
Fremingham study [21]. Numerous studies since then have found that AF in people with
diabetes is at least twice as common as in people without diabetes, and 3 times as
common if, in addition to diabetes, AH is present [14].

The ADVANCE study demonstrated the role of AF as a strong independent marker
of total and cardiovascular mortality, as well as severe chronic CHF in DM patients
[7], which required more intensive control of blood pressure and other cardiovascular
risk factors in the study population of patients.

So what is the determining role of DM in the development of FP?
Cardiac muscle damage in DM2 is determined not only by atherosclerotic lesions of

the coronary arteries, but also by specific changes peculiar to "late" complications of
diabetes (microangiopathy, neuropathy). Based on pathological anatomical studies Rubler
S. et al. [1972] proposed the term diabetic cardiomyopathy (DC), characterized by the
clinical picture of dilated cardiomyopathy with the development of heart failure with
low ejection fraction in diabetic patients in the absence of arterial hypertension and
coronary artery atherosclerosis. DC is a pathology of the heart muscle, manifested by a
wide range of biochemical and structural abnormalities, mediated by insulin resistance,
hyperglycemia, impaired free fatty acid metabolism and increased free radicals.

Diastolic dysfunction of the left ventricle (LV) is considered as an early marker of
myocardial damage in DM2,  noting the pathogenetic relationship  between LV diastolic
dysfunction and LV hypertrophy (LVH) in the development and progression of chronic
heart failure (CHF), which in turn contributes to the formation of arrhythmogenic
substrate [11].  The pathogenetic role of glycometabolic processes in the development
and progression of diastolic abnormalities is associated with the formation of hypertrophy
under the influence of insulin resistance and activation of fibrosis processes against the
background of hyperglycemia [17].

To date, there are still discussions on the topic - should diastolic dysfunction and
autonomic cardiovascular neuropathy be combined into a single concept, or is there
still a need to distinguish between these mechanisms?

Another key point explaining the high risk of AF in DM is the results of studies of
purely electrophysiological interest. Aleksandrov A.A. et al. [2011] explain the formation
of electrophysiological remodeling of ion channels of myocardiocyte sarcolemmal
membrane in DM patients by the presence of a transmembrane phosphoinositol
mechanism, which normally represents a kind of glucose transport mechanism that is
activated when insulin binds to the cell receptor, or when sulfonylurea derivatives
interact with the cellular  component of phospholi pase C (FLC). The resulting



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Volume 1, ¹4
diacylglycerol (DAG), by stimulating pyruvate kinase C (PKS), increases the availability
of glucose transporters and promotes glucose diffusion inside the cardiomyocyte. At the
same time, electrolyte fluxes of the cardiomyocyte are formed, providing the correct
action potential of the myocardial cell, periods of its electrical refractoriness (KATP-
dependent channels, Ca-balance, Na/H-exchange). Electrophysiological activity of ion
channels is dramatically impaired by the processes of insulin resistance and/or lack of
insulin.

The high risk of electrophysiological abnormalities in DM is associated with the
overload of cardiomyocytes with Ca2+ ions. Against the background of a sharp decrease
in glycolysis, the sarcoplasmic reticulum loses the ability to absorb calcium at the
normal rate. This in turn leads to an imbalance between the mitochondria's need for
ATP to pump out protons as protection against excess calcium and its amount. Thus,
myocardial contracture is formed, conjugation of myocardial electrophysioo logical and
contractile processes is disturbed. In the works of Z.H. Lu et al., high levels of HbA1
were associated with increased risk of atrial fibrillation recurrence in patients with type
2 DM and paroxysmal AF who underwent catheter ablation [12].

At the same time, the effect of hypoglycemia on increased risk of cardiac arrhythmias
is currently not confirmed in randomized clinical trials.

Thus, in the ACCORD study, where 10082 patients were selected, intensive glycemic
control did not demonstrate its effect on the development of AF. Similar results were
obtained by researchers Nicolas G.A. et al. where hypoglycemia was associated with the
development of AF only in female patients.

In later studies, it was demonstrated that DM in need of pharmacological control by
40% increased the risk of PD, as well as the risk of PD was associated with the duration
and lack of adequate glycemic control.

The Chang Sh. study found a positive role of metformin monotherapy in reducing the
risk of AF in patients with diabetes. The authors attribute this effect to a decrease in
tachyinduced cell myolysis and oxidative stress.

In a study by E. Chow et al. studied the effect of hypoglycemic episodes on the
incidence of various types of LDCs. The study included 25 patients with type 2 diabetes
receiving insulin therapy. All patients had atherosclerotic lesions of the cardiovascular
system (CHD, peripheral arterial lesions or  cerebrovascular  disease),  as well as risk
factors in the form of obesity, smoking, and hypodynamia. All patients underwent long-
term glucose-cardiac monitoring for 5 days. Hypoglycemia was established at HbA1c?3.5
mmol/l. During the observation period, 14 patients had episodes of hypoglycemia with
a total duration of 134 hours. At the same time, the duration and frequency of nocturnal
hypoglycemia prevailed over daytime values. A comparative analysis of HRs for eu- and
hypoglycemia showed that bradycardia was 8 times more frequent in nocturnal episodes
of hypoglycemia (OR 8.42 [95% CI 1.40-51.0]). Noteworthy is the fact that despite the
presence of daytime episodes of hypoglycemia, bradycardia was not recorded during
these hours. AF was 4 times more frequently observed in hypoglycemia (3.98 [1.10-
14.4]), but without significant differences between its frequency in daytime and nighttime.
Ventricular extrasystole was recorded with equal frequency during hypoglycemia, both
during the day (1.31 [1.10-1.57]) and at night (3.06 [2.11-4.44]). The analysis of the
heart rhythm variability condition showed its reliable decrease, as well as a decrease in
the total power of the spectrum, an increase in the strength of high-frequency components.
Episodes of hypoglycemia contributed to a significant increase in the corrected QT
interval predominantly in the daytime.

Researchers have concluded that the mechanisms of ventricular tachyarrhythmias
during daytime and nighttime hypoglycemia are different. Thus, prolongation of the QT



Art of Medicine
International Medical Scientific journal

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interval in the daytime may lead to an increase in trigger activity, a form of early
postdepolarization. Sympathetic activity and cytosolic calcium overflow, in turn, leads
to prolongation of postdepolarization and development of ventricular extrasystole. The
two mechanisms described probably explain ventricular HRV predominantly during
daytime hypoglycemia. Nevertheless, the vast majority of LDCs occurred during nocturnal
hypoglycemia, when sympathetic system activity is not pronounced. Researchers found
the answer to this question in experimental hypoglycemia. In response to increased
vagus system activity and decreased sinus node activity, especially in the presence of
NARSH, latent rhythm drivers are activated, which explains the frequent development
of AF and ventricular extrasystole at night. Ventricular extrasystole against a background
of bradycardia is highly likely to be a trigger for Torsade de Pointes, which has been
demonstrated in previous studies in patients with hypoglycemic coma. Summarizing
their results, the authors emphasize that in this study, despite the lack of intensive
glycemic control, episodes of hypoglycemia occurred with approximately the same
frequency as in studies with intensive glycemic control and call for cardiologists and
endocrinologists to more carefully perform risk-stratification of patients with a high risk
of cardiac arrhythmias and, therefore, with the risk of a fatal outcome.

A relatively new study on the effect of hypoglycemia on the risk of AF was the work
of Ko S.H. et al. [9]. Using a retrospective analysis of the case histories of more than 2
thousand patients with type 2 diabetes without prior AF, it was found that hypoglycemia
is an independent predictor of AF within 5 years of follow-up in patients with type 2
diabetes even in the absence of CVD. But it should be noted that this study was retrospective
and studied only cases of documented hypoglycemia, that is, when patients seek medical
care, while the vast majority of episodes of hypoglycemia are asymptomatic. And the
development of AF was also diagnosed when it was detected during a standard ECG, that
is, episodes of paroxysmal AF might have been missed.

The study of the role of hypoglycemia in the increased risk of cardiovascular death is
complicated by the absence of specific anatomical and morphological markers of
hypoglycemia and by the fact that when acute cardiac pain occurs, the patient does not
always determine the glycemic level and/or fix posthypoglycemic hyperglycemia. It is
these factors that limit the analysis of existing studies and make it difficult to design a
study that can prove or disprove the effect of hypoglycemia on arrhythmia risk.

Given the growing incidence of diabetes and associated AF, which in turn increase
the incidence of cardiovascular complications in the form of strokes, heart failure,
inevitably leading to disability and increased mortality, the problem of safe hypoglycemic
therapy and the development of methods for its optimal control will only increase its
relevance. The problem of interaction between antiarrhythmic, hypoglycemic and
antiplatelet drugs also requires detailed coverage,  which will serve as a basis for  new
research in the future.



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