HEART RHYTHM DISTURBANCES IN CONNECTIVE TISSUE DYSPLASIA

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ABSTRACT

The article discusses the association between connective tissue dysplasia (CTD) and arrhythmias, particularly focusing

on mitral valve prolapse as a potential risk factor for life-threatening ventricular arrhythmias and sudden cardiac death.

Various studies emphasize the structural and mechanical abnormalities in the heart that contribute to arrhythmogenic

phenotypes in CTD patients, such as fibrosis, mitral annular disjunction, and accessory chordae. Additionally, the text

explores the role of autoantibodies, cardiac remodeling, and autoimmune processes in mediating rhythm

disturbances and cardiac complications in CTD. The importance of ECG analysis, neural networks, and stress tests in

detecting and monitoring arrhythmias in CTD patients is highlighted. The research underscores the significance of

understanding the morphological basis and pathophysiological mechanisms of arrhythmias in CTD patients to improve

therapeutic strategies and enhance patient outcomes.

KEYWORDS

Connective tissue (CT), Connective tissue dysplasia (CTD), Mechanoelectric feedback (MEFE), heart rhythm disorders,

mitral annular disjunction (MDA), sudden cardiac death (SCD), Stretch-activated channels (SACs).

Research Article

HEART RHYTHM DISTURBANCES IN CONNECTIVE TISSUE DYSPLASIA

Submission Date:

June 05, 2024,

Accepted Date:

June 10, 2024,

Published Date:

June 15, 2024

Crossref doi:

https://doi.org/10.37547/ijmscr/Volume04Issue06-06

Shodikulova Gulandom Zikriyayevna

Professor, Samarkand State Medical University, Samarkand, Uzbekistan

Gulomov Jahongir Ibrokhimovich

Assistant, Samarkand State Medical University, Samarkand, Uzbekistan

Samatov Dilshod Karimovich

Assistant, Samarkand State Medical University, Samarkand, Uzbekistan

Khasanov Oybek Gafurovich

Assistant, Samarkand State Medical University, Samarkand, Uzbekistan

Journal

Website:

https://theusajournals.
com/index.php/ijmscr

Copyright:

Original

content from this work
may be used under the
terms of the creative
commons

attributes

4.0 licence.

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INTRODUCTION

Arrhythmias in connective tissue dysplasia can range

from harmless to life-threatening, and the study of this

aspect of CDT is of interest to researchers. Considering

that the incidence of connective tissue dysplasia,

according to the latest data, Shodikulova G.Z., Mirzaev

O.V., (2020) in the Uzbek population is about 9%,

arrhythmic syndrome with this pathology can be a

serious problem for cardiologists and therapists in our

country.

In case of CTD, the following studies and opinions

explain the relatively high risks of developing

arrhythmias and the substrate for their formation.

Mechanical effects on the myocardium of the left

atrium and ventricle during mitral valve prolapse,

which is a benign disease, may underlie the high risk of

developing life-threatening ventricular arrhythmias

and sudden cardiac death - this new specific phenotype

can be identified as arrhythmogenic MVP. Malignant

arrhythmias in MVP can occur multifactorially under

the influence of abnormal components of the LV

myocardium (fibrosis, scars) and a constant trigger -

mechanical stretching. The presence of focal fibrosis in

the inferolateral wall of the LV is arrhythmogenic, as is

diffuse LV fibrosis, thickening of the mitral annulus and

valve leaflets, elongation and an increased number of

chords [9, 15].

A similar view is shared by Nagata Y et al (2023),

suggesting that basal inferoposterior myocardial

fibrosis in MVP is associated with abnormal mechanical

effects on the myocardium, potentially associated with

ventricular arrhythmia. These associations suggest

pathophysiological

links

between

mechanical

abnormalities associated with MVP and myocardial

fibrosis, which may also be associated with ventricular

arrhythmia and are potential imaging markers of

increased arrhythmia risk. It can be assumed that the

degree of arrhythmogenicity of mitral valve prolapse

may be associated with the severity of mitral

regurgitation and LA hyperextension.

According to Cristina Basso et al. (2019), the origin of

malignant arrhythmias in MVP is likely determined by a

combination of substrate (regional hypertrophy,

myocardial fibrosis and the presence of Purkinje fibers)

and trigger (mechanical stretch) due to primary

morphofunctional abnormalities of the mitral annulus.

According to Chakrabarti AK et al. (2022), mitral valve

prolapses (MVP), a common valvular heart disease

despite a largely benign course, is increasingly

recognized as a representative of the arrhythmic

phenotype, correlated with ventricular arrhythmias

and sudden cardiac death (SCD). Pathophysiological

mechanisms associated with arrhythmias include

cardiac fibrosis, changes in the ventricular refractory

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period

caused

by

mechanical

stress,

and

electrophysiological changes in Purkinje fibers.

Also, among the pathologies of the mitral valve in CTD,

it is worth noting mitral annular disjunction (MDA), a

condition of abnormal displacement of the mitral valve

leaflet to the wall of the left atrium, which is often

found in patients with MVP. According to Wu S and

Siegel RJ (2022), MDA is associated with the risk of

developing malignant ventricular arrhythmias and

sudden cardiac death, so recognizing this diagnosis

and risk stratification is very important. Considering

the above, this anomaly can also be associated with

CTD, which indirectly confirms the presence of a

connection between arrhythmias and the underlying

pathology [14].

An interesting work by Tison GH et al., (2023), involves

the use of a convolutional neural network in the

analysis of a 12-lead ECG. As a result, the neural

network made it possible to identify MVP with a risk of

ventricular arrhythmias, death and/or fibrosis and to

identify new ECG correlates of arrhythmia risk.

According to the authors, this ECG-based neural

network can help select patients with MVP who need

more careful monitoring and/or SM-ECG.

Velthuis S et al. (2021) believe that tension on the LV

wall by accessory chordae and tendinous filaments can

serve as a trigger for ventricular arrhythmias of the

heart, participating in electrocardiographic conduction

and, theoretically, being a source of ventricular

arrhythmias.

According to some studies, additional chords in the left

ventricle can provoke the development of ventricular

extrasystoles, and the likelihood of developing

extrasystoles depended on the shape of the chords

[17].

Recently, studies have appeared to confirm the effect

of cardiac remodeling in supraventricular cardiac

arrhythmias. Mechanoelectric feedback (MEFE) in the

heart operates through several mechanisms that serve

to regulate cardiac function. Stretch-activated

channels (SACs) in the myocyte membrane open in

response to cell elongation, and tension generation

depends on stretch, shortening rate, and calcium

concentration [8, 9]. MEFE is an important aspect of

cardiac function and has the potential to mitigate

activation problems [10]. It is likely that SACs, when

using electrocardiogram and volume-time curves, may

show that each of their patterns has different effects

on the cardiac pattern. In addition, the obtained

models of stretch-activated channels on the

membranes of cardiomyocytes confirmed the role of

MEFE in the occurrence of fibrillation and defibrillation

in the absence of structural damage to the heart [11].

Non-selective stretch-activated channels, as an

additional mechanism of MEFE, contribute to the

deployment

of

heterogeneous

diastolic

transmembrane

voltage,

more

pronounced

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contraction and delayed repolarization in highly

stretched parts of the atria. The differential and

combined effects of these three MEFE mechanisms

during activation of sinus rhythm in a four-chamber

human heart model may have implications in

arrhythmogenesis, both in terms of substrate

(repolarization gradients) and triggers (ectopia) [12].

Myxomatous degeneration, being one of the signs of

CTD, can mediate rhythm disturbances, for example,

provoke bundle branch blocks. When this formation is

localized on the septal cusp of the tricuspid valve, there

is a high probability of blockade of the right bundle

branch [3, 4].

ECG serves as an important tool in searching for the

causes and understanding the process of the

formation of cardiac arrhythmias. This method is also

effective in patients with CTD. In patients with CTD,

prolongation of the QT interval may be associated with

MVP

and

the

arrhythmogenic

effect

of

catecholamines, which are produced more actively

compared to individuals without CTD [3, 4, 5]. The

coexistence of long QT syndrome and arrhythmogenic

biflaflete MVP syndrome can lead to a rare but

malignant clinical presentation characterized by

potentially life-threatening arrhythmias, despite

maximal therapy for long QT interval [16].

The QT interval varies depending on the type of MAS in

patients with CTD. For example, with MVP, as

mentioned above, the Q-T interval is lengthened, and

in 1/3 of patients with abnormally located muscle bands

of the LV, it is shortened.

According to Shodikulova G.Z. et al (2022), [9] a

decrease in the level of Mg+2 and an increase in titers

of

autoantibodies

to

type

I

collagen

are

interconnected, and the dynamics of changes in the

level of antibodies, as well as the level of magnesium,

depending on the severity of the clinical course, can

serve as a method for assessing the progression of the

pathological process and the prognosis of the disease ,

i.e. autoantibodies, as a pathogenetic factor, have a

place.

Autoantibodies are capable of exerting a whole range

of effects that affect the conductivity of the heart,

namely, initiating cell division, vascular constriction,

and indirectly reducing the ability of the myocardium

to contract, provoking necrosis of cardiac muscle cells

[10]. There are studies indicating a relationship

between the degree of autoimmune processes in the

myocardium and the depth of morphological changes

in the heart [11].

Autoimmune diseases are diseases that cause damage

to the div's tissues as a result of immune dysfunction,

often affecting several organs and systems. The heart

is one of the common target organs of autoimmune

diseases. Subsequently, immune dysfunction with

cardiac damage develops microcirculatory disorders,

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arrhythmias,

pericardial

damage,

myocarditis,

myocardial fibrosis and valvular dysfunction [12].

The most important factors underlying rhythm

disturbances are inflammation and fibrosis of the

myocardium. Inflammatory processes and oxidative

stress lead to necrosis of cardiomyocytes followed by

electrical and structural remodeling. In addition,

chronic inflammation is the pathophysiological basis

linking

autoimmune

processes

to

autonomic

dysfunction,

including

excessive

sympathetic

activation and decreased parasympathetic function.

Autoantidiv-mediated inhibitory effects on cellular

events (eg, L-type potassium or calcium currents,

cholinergic or β1

-adrenergic M2muscarinic receptor

signaling) can also lead to cardiac arrhythmias. Drug-

induced arrhythmias caused, for example, by

corticosteroids, methotrexate, chloroquine, are also

observed in patients with autoimmune processes [13].

One of the hypotheses explaining the development of

cardiac complications in DST is an imbalance of the

autonomic system, which mediates disruption of the

functional activity of the SA node through the inclusion

of supra- and ventricular centers of impulse

production.

According to Herring, N. (2019), cardiac autonomic

control is most promising for clinical use in achieving

long-term success in the treatment of arrhythmias. In

their opinion, many primary cardiovascular diseases,

such as hypertension, acute myocardial infarction and

heart failure, are also diseases of the autonomic

nervous system. Sympathetic hyperactivity and vagal

insufficiency are powerful negative predictors of

morbidity and mortality associated with arrhythmias

and sudden cardiac death, and neuromodulation

therapy may be clinically important in the treatment

and prevention of fatal arrhythmias [14].

There are also studies confirming the existence of a

connection between mechanical and autonomic

modulation of heart rate. Stretching the walls of the

heart chamber causes both an increase in heart rate

and a decrease in the response to stimulation of the

vagus nerve in some animals. Conversely, when heart

rate is decreased by vagus nerve stimulation, the

stretch-induced increase in heart rate is enhanced. The

stretch response is similarly enhanced when heart rate

is first decreased by pharmacological parasympathetic

or cholinergic stimulation and decreased when the

heart rate is increased by adrenergic stimulation.

However, whether these changes in the chronotropic

response to stretch are due to the interaction of

mechanical (stretch) and autonomic (sympathetic,

parasympathetic components) components or are

simply the result of HR-dependent differences in the

electrophysiological response to stretch is difficult to

say [several studies have reported that positive

chronotropic the response to stretch increases with a

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decrease in heart rate, regardless of the nature of the

decrease in heart rate [15].

Physical and psycho-emotional stress tests are one of

the important methods for diagnosing heart rhythm

disturbances. These tests promote the release of

neurotransmitters - norepinephrine, dopamine and

hormones - adrenaline, and noradrenaline into the

blood, activate the sympathetic segment of the

autonomic nervous regulation, increasing the

likelihood of arrhythmias. A number emphasize the

importance of stress tests in arrhythmias [17, 18, 19],

and provide information confirming the presence of

certain rhythm disturbances in almost half of the

healthy people after stress tests and in a sample of

patients with morphological changes in the heart (84-

86 %).

CONCLUSION

Thus, studying the cardiovascular system in patients

with DST, in particular rhythm disturbances,

determining

their

morphological

basis,

and

understanding the mechanisms of initiation and

progression of arrhythmias, will allow a deeper

understanding of the problem of cardiovascular

complications, and drawing up further tactics for

managing patients based on the data obtained will

create the opportunity to improve approaches to

therapy patients with arrhythmic syndrome against the

background of DST, improving their quality of life and

prognosis of their existing cardiovascular diseases.

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