Sick sinus syndrome: clinical guidelines

List of Abbreviations

AV – atrioventricular

BP – blood pressure

SNRT – sinus node recovery time

ВПС – congenital heart disease

ICM – implantable cardiac monitor for long-term recording of the electrical activity of the cardiac conduction system

Implantable PM*** – Implantable dual-chamber rate-adaptive pacemaker***, Implantable single-chamber rate-adaptive pacemaker***

cSNRT – corrected sinus node recovery time

SSS – sick sinus syndrome

SA – sinoatrial node

HM – Holter heart rhythm monitoring

TEEPS – transesophageal electrical pacing

HR – heart rate

ECG – electrocardiogram

EP study – electrophysiological study

EchoCG – echocardiography

** – the drug is included in the list of vital and essential drugs

*** – medical device implanted when providing medical care under the state guarantee program for free medical care to citizens

# – off-label use of the drug is possible

Terms and Definitions

Binodal disease – a condition characterized by simultaneous dysfunction of both the sinus and atrioventricular nodes.

Bradyarrhythmia – a disorder of primary pacemaker cells (sinus node) or the structure responsible for conducting the excitation impulse from the atria to the ventricles (atrioventricular conduction).

Sinus node arrest – loss of the ability of pacemaker cells in the sinus node to generate impulses.

Tachycardia-bradycardia syndrome – alternation of bradycardia with tachyarrhythmias (extrasystoles, ectopic tachycardia) on a standard or 24-hour electrocardiogram.

Sinoatrial block – progressive slowing of impulse conduction from the sinus node to the atria, as well as within the conducting tissue of the atria represented by circular and longitudinal muscular bundles, without altering impulse formation function in the sinus node.

Cardiac pacing – a method in which an artificial pacemaker that generates electrical impulses of a specified strength and frequency performs the role of the natural pacemaker (sinus node). Special devices called pacemakers are used as artificial pacemakers.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Sick sinus syndrome (SSS) – a condition caused by a decrease in the functional capacity of the sinus node to act as the primary pacemaker and/or ensure regular impulse conduction to the atria, which leads to pronounced bradycardia and associated ectopic arrhythmias.

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

In most cases in children, SSS develops in the absence of organic cardiovascular pathology. Rhythm-driving disorders in childhood can be caused by various factors: autonomic imbalance with a predominance of parasympathetic influences, drug effects, inflammatory myocardial lesions, metabolic disorders, or autoimmune damage by antibodies against the cardiac conduction system [1, 2, 3, 4]. The etiological factors include:

1. Organic SSS (associated with myocarditis, cardiomyopathies, amyloidosis, sarcoidosis, collagenoses, congenital heart and vascular defects supplying the sinoatrial area, coronary artery disease, cardiac tumors, hormonal-metabolic cardiotoxic disorders, etc., causing the replacement of functioning sinoatrial cells with connective tissue).

2. Regulatory (vagal) sinus node dysfunctions (autonomic dysfunction with a predominance of parasympathetic influences on the heart of hypoxic origin, during athletic overexertion, increased intracranial pressure, cerebral edema, viscerovagal reflexes in pharyngeal, urogenital, and digestive system pathologies).

3. SSS as a consequence of toxic effects (beta-blockers, selective calcium channel blockers with predominant vascular action, cardiac glycosides, antidepressants, hypnotics and sedatives, carbofos and anticholinesterase poisoning, etc.).

4. Sinus node (SN) dysfunction in children after cardiac surgery (correction of congenital heart defects — transposition of the great arteries, atrial septal defect, etc.).

5. Autoimmune SN function disorders.

6. Genetically determined SN function disorders.

7. Idiopathic (cause undetermined).

In the first five cases, there is so-called secondary SSS, the resolution of which is directly dependent on the efficacy of underlying disease therapy. When no disease capable of causing SN dysfunction can be identified, it is customary to refer to the idiopathic variant.

Among pathogenetic mechanisms in the development of idiopathic SSS, the significance of the autonomic nervous system, degenerative changes, apoptosis, and the role of inflammatory myocardial injury are discussed. The importance of insufficient sympathetic influences on the heart in the pathogenesis of progressive sinus node dysfunction in children has been proven, with hypoxic lesions in the perinatal period playing an important role in the formation of autonomic heart regulation disorders [5]. Experimental studies have established a model of SSS development in which the progressive increase in electrocardiographic changes was associated with the attenuation of central nervous system influences on rhythmogenesis [6].

The role of autoimmune mechanisms in the development and progression of SSS is actively debated. The level of anticardiac autoantibodies to the SN and atrioventricular (AV) node [7, 8] may be one of the factors in the pathogenesis of cardiac arrhythmias. The importance of autoimmune processes in the development of atrial fibrillation, which is frequently recorded in patients with SSS, has been demonstrated [9]. Literature sources describe a stable correlation between morphological signs of myocarditis according to biopsy data and autoantibody levels in patients with arrhythmias, and immune activity correlates with the severity of rhythm disorders [10, 11]. To study the autoimmune genesis of inflammatory phenomena in the myocardium, the detection of circulating autoantibodies can be used — both non-selective (against the myocardium) and selective against cardiomyocyte proteins actin and myosin, antifibrillary, antisarcolemmal, and against muscarinic and adrenergic receptors. Elevated titers of anticardiac antibodies in patients, along with autonomic dysfunction, may constitute one of the links in the pathogenesis of SSS in children [12].

To date, a large number of variants and polymorphisms in genes associated with SSS development have been described — SCN5A, HCN4, MYH6, ANK2, TRPM4, NKX2-5, TBX3 and others. [13–17]. Genetic mechanisms underlying sinus bradycardia and SSS can be divided into disorders of ion channels, intercellular junctions, intracellular myosin proteins, ankyrin, regulatory genes, etc. [18]. The presence of mutations may predispose to SN dysfunction or lead to increased sensitivity of SN cells to medications.

1.3 Epidemiology of the Disease or Condition

The prevalence of SSS is difficult to estimate due to the impossibility of accounting for asymptomatic cases and the diagnostic challenges of pathological bradycardia in population studies. The detection rate of SSS increases with age, yet in the group over 50 years old, it is only 5/3000 (0.17%). In the pediatric population, SSS accounts for up to 30% of all arrhythmias [5]. SSS accounts for about half of all pacemaker (PM) implantations, but the number of implantations inadequately reflects the frequency of symptomatic SSS cases. In surgical clinics, about 10% of all cardiac arrhythmias are associated with SSS [19]. The prevalence of electrocardiographic (ECG) phenomena that are part of the SSS symptom complex reaches 0.84% among children with cardiovascular diseases [20]. Among practically healthy children, signs of SN dysfunction on a standard ECG are detected in 2% of children [5]. Sinus bradycardia is the most frequent (up to 85%) type of bradyarrhythmia in children [21]. According to population ECG screening data of children in Russia, the prevalence of rhythm migration is 1.9%, escape and replacement supraventricular rhythms 0.7%, and sinoatrial block 0.3% [22].

Holter rhythm monitoring (HM) reveals a significantly higher prevalence of ECG phenomena included in the SSS symptom complex in practically healthy children. During HM, signs of sinus node dysfunction occur in 2.7% of cases [5]. Single junctional contractions during nighttime are recorded in 13% of children [23], and junctional rhythms in 19% of newborns and 45% of older children [24, 25]. Among children with bradyarrhythmias, sinoatrial blocks are noted in 50% of cases [21].

1.4 Features of Coding the Disease or Condition

I49.5 — Sick sinus syndrome

1.5 Classification of the disease or condition

In children, 4 stable clinical and electrocardiographic variants of sinus node dysfunction are identified (Table 1): the first with minimal manifestations in the form of sinus bradycardia and rhythm migration; the second – escape rhythms, sinus node arrests, sinoatrial blocks against the background of more pronounced depression of the underlying rhythm; the third (tachy-bradycardia syndrome) – a combination of sinus bradycardia with supraventricular heterotopic tachycardia; and the fourth – cardioneuropathy with rigid marked bradycardia, multiple escape rhythms, asystole, and myocardial repolarization abnormalities [5, 26].

Each of the variants is characterized by a fairly high percentage of cases with associated atrioventricular (AV) conduction disorders. There is a staged progression in the formation of sinus node dysfunction in children: from the first to the second (or third, depending on the presence of electrophysiological conditions for the development of tachyarrhythmias) and fourth variants.

Table 1. Clinical and electrocardiographic variants of sick sinus syndrome in children

1.6 Clinical presentation of the disease or condition

Clinical manifestations of SSS in children are non-specific and are often absent. Most commonly, children complain of dizziness, poor exercise tolerance, exertion-induced dyspnea, fatigue, and episodes of weakness. The most threatening manifestations of SSS are arrhythmogenic syncopal states and sudden cardiac death [27], however, the weak correlation between rhythm pause duration and clinical symptoms in children often makes it impossible to predict sudden death.

Syncopal states (Stokes-Adams attacks) – impaired consciousness due to cerebral ischemia resulting from a sudden decrease in cardiac output caused by an acutely developed cardiac rhythm and conduction disorder (sinus arrest, complete AV block, etc.). Patients experience sudden severe weakness and dizziness, loss of consciousness, pallor, cold clammy sweat; tonic and clonic seizures, involuntary urination and defecation may be observed. Arrhythmogenic syncopal states require differential diagnosis with reflex syncopal states and epileptic seizures [28, 29]. Children with initial manifestations of SSS may exhibit reflex syncopal states developing as a result of a sharp drop in total peripheral vascular resistance or blood pressure (BP), whereas arrhythmogenic syncopes are observed more frequently in children with variants IV and III of the disease [12].

2. Diagnostics, medical indications and contraindications for diagnostic methods

Criteria for establishing the diagnosis/condition:

• The diagnosis of SSS is recommended to be established in accordance with the classification presented in section 1.5, based on documented confirmation by any instrumental research method (ECG and/or Holter monitoring) combined with/without clinical symptoms [5, 12, 26, 30-32].

Level of Recommendations Confidence – LRC C (Level of Evidence – LOE 4)

Principles of diagnosis formulation.

The diagnosis indicates the main condition – SSS, the variant of the disease (see classification in 1.5): sinus bradycardia, sinus node arrest, tachy-bradycardia syndrome.

Examples of diagnosis formulation:

ᴑ Sick sinus syndrome (bradycardia, sinus node arrests, supraventricular escape beats, rhythm pauses up to 1850 ms).

ᴑ Sick sinus syndrome (tachy-bradycardia syndrome: junctional tachycardia, bradycardia, sinus node arrests, rhythm pauses up to 2000 ms).

2.1 Complaints and Anamnesis

2.2 Physical Examination

Comment: with long-standing bradycardia, pallor of the skin may be observed. Bradycardia can be detected by palpating the pulse on peripheral arteries, but cardiac auscultation is the most informative method, revealing faint heart sounds.

2.3 Laboratory Diagnostics

There is no specific laboratory diagnostics for SSS. In patients with bradyarrhythmias, laboratory tests based on clinical suspicion of the potential underlying cause of SSS are recommended.

Comment: an increase in anticardiac antibody titers in patients with high degrees of sinus node involvement may be one of the links in the pathogenesis of SSS in children, although there is no conclusive evidence for this fact, or it may indicate the course of autoimmune myocarditis (if other signs of myocarditis are present).

Comment: tests are performed to detect bacterial or viral infections that may be the source of an inflammatory process in the myocardium. Determination of antistreptolysin-O in blood serum, investigation of intestinal microbiocenosis (dysbiosis), and microbiological (culture) examination of mucus from the tonsils and posterior pharyngeal wall for aerobic and facultatively anaerobic microorganisms may also be performed. Detection of a circulating infection may indicate a secondary (inflammatory) genesis of bradyarrhythmia and require antibacterial or other specific therapy.

2.4 Instrumental Diagnostics

Comment: ECG is recommended as the primary diagnostic method for SSS. ECG criteria for sinus bradycardia based on standard ECG data are presented in Table 2. Holter ECG monitoring is more informative, allowing for the detection of abnormalities and signs that strongly indicate the risk of channelopathies and other congenital rhythm and conduction disorders. Resting ECG recording is mandatory before performing procedures such as Holter monitoring, exercise ECG, etc.

Table 2. Minimum allowable HR values according to resting ECG data in healthy children aged 0 to 18 years [22]

Bradycardia in various age groups is traditionally defined as a decrease in HR on a standard ECG below the 5th percentile of the age-specific HR distribution. It is more justified to consider a decrease below the 2nd percentile as a criterion for bradycardia, which in children is associated with a high risk of developing SSS and the onset of syncopal states [12].

• Patients with suspected or established SSS are recommended to undergo Holter ECG monitoring (HM) to record HR and arrhythmias, diagnose metabolic changes in the myocardium, assess heart rate variability and autonomic influences on the heart rhythm, as well as identify risk markers for life-threatening conditions and evaluate treatment efficacy [1, 21, 27–29, 38].

Level of Recommendations Confidence – LRC C (Level of Evidence – LOE 5)

Comment: there are several types of ambulatory ECG monitoring. Holter monitoring allows heart rhythm observation for 24–48 hours; there are also ECG recording device options with a recording duration of up to 7 days. Another type is event-based ECG recording (during syncope or a palpitation episode) using portable recorders, collectively termed "ambulatory event recorders".

An important role in the early diagnosis and prognosis of SSS belongs to the assessment of allowable minimum HR values during HM (Table 3). The degree of reduction in average HR during daytime and nighttime helps differentiate between pathological and physiological bradycardia. Physiological bradycardia is characterized by a decrease in HR at night, whereas the mean daytime and mean 24-hour HR remain within normal limits.

Table 3. Minimum allowable HR values according to HM data in healthy children aged 0–16 years [24, 25, 39–42].

In children with severe bradyarrhythmias, rhythm pauses during HM generally exceed allowable limits, which is an important diagnostic and prognostic criterion. Similarly to HR, the duration of rhythm pauses on HM is evaluated taking into account the child's age (Table 4).

Table 4. Maximum allowable duration of rhythm pauses according to HM data in healthy children aged 0–16 years [24, 40, 41]

In addition to sinus bradycardia, the ECG of children with SSS may show various supraventricular tachyarrhythmias (supraventricular tachycardias, atrial fibrillation, single or paired extrasystoles).

Wandering pacemaker, escape beats and/or rhythms originating from the AV junction occur as a result of depressed pacemaker function of the sinus node and are secondary. Among other rhythm and conduction disorders in SSS, accelerated supraventricular rhythm is encountered. Episodes of supraventricular rhythm in children require the exclusion of tachycardia-bradycardia syndrome.

Sinoatrial block is manifested by a progressive increase in sinoatrial conduction block, while impulse generation function within the sinus node remains unchanged. Sinoatrial block varies in severity. The first degree is characterized by slowed conduction of excitation within the sinus node and is not detected on a standard ECG. The second degree may occur with or without Wenckebach periodicity—whereby some impulses are blocked and fail to conduct to the atria. The third degree is characterized by impaired conduction of normally generated impulses to the right atrial myocardium. This is typically accompanied by the emergence of escape replacement beats from lower-level automaticity centers.

Sinus arrest is the loss of the sinus node's ability to generate impulses in the pacemaker cells of the sinus node. Unlike sinoatrial block, this results in a rhythm pause that exceeds the preceding R–R interval by more than 2 times and is not a multiple of it.

Comment: an implantable cardiac monitor for long-term recording of the electrical activity of the cardiac conduction system (ICM) is capable of capturing recording fragments for up to 3 years [27, 38], however, this technique is currently underutilized in the pediatric population, despite a respectable efficacy of up to 56% in patients with a history of syncopal episodes for recording HR at the moment of clinical symptom onset [43]. The diagnostic value of ICM for detecting rhythm disturbances as a cause of syncope is significantly higher than a single 24-hour HM. Despite the absence of signs of sinus node dysfunction on HM outside of an episode, critical bradycardia or asystole may develop during a faint. The "gold standard" for diagnosing syncopal states of both arrhythmogenic and neurocardiogenic nature remains ECG recording at the moment of typical complaint development, including in triggering situations. If it is necessary to record an ECG at the time of symptoms, one should be guided by the frequency of clinical symptoms presumably associated with bradycardias or conduction disorders [38]. In the case of daily or weekly episodes, preference should be given to single or repeated Holter ECG monitoring, hospital monitoring, or telemetry ECG recording. For monthly loss of consciousness episodes, repeated Holter ECG monitoring, telemetry recording, or other ECG recording devices can be considered [44, 45]. If episodes occur at a frequency of once a month or less, the use of ICM is preferable.

• Patients with established or suspected SSS are recommended to undergo transthoracic echocardiography (TTE) to rule out organic heart disease, assess morphometric parameters, and detect signs of arrhythmogenic cardiomyopathy [1, 21, 28, 29, 46].

Level of Recommendations Confidence – LRC C (Level of Evidence – LOE 5)

Comments: arrhythmogenic cardiomyopathy refers to secondary reversible myocardial dysfunction manifested by dilatation of all chambers, starting with the atrial chambers, followed by decreased myocardial contractility of the ventricles, the onset of relative mitral regurgitation, and the development of congestive heart failure resulting from existing bradycardia. Echocardiography demonstrates maximum diagnostic significance in patients with organic heart diseases [47].

• In selected patients with SSS for advanced visualization, transesophageal echocardiography, cardiac and great vessel magnetic resonance imaging, or other studies are recommended to rule out structural heart disease [21, 28, 29].

Level of Recommendations Confidence – LRC C (Level of Evidence – LOE 5)

• In symptomatic patients with suspected sick sinus syndrome (SSS), an intracardiac electrophysiological study (EPS) to assess sinus node function is recommended to establish a diagnosis if the diagnosis remains uncertain after non-invasive evaluation [21, 48].

Level of Recommendations Confidence – LRC C (Level of Evidence – LOE 5)

• In patients undergoing an EPS for other indications, assessment of sinus node function is recommended to establish the diagnosis of SSS [21, 28, 49].

Level of Recommendations Confidence – LRC C (Level of Evidence – LOE 5)

• In patients with suspected SSS, transesophageal electrical stimulation (TES) is recommended as an alternative to invasive EPS for assessing sinus node function and establishing the diagnosis of SSS if the diagnosis remains uncertain after non-invasive evaluation [21, 48, 50].

Level of Recommendations Confidence – LRC C (Level of Evidence – LOE 5)

Comment: TES is a minimally invasive study that allows the evaluation of sinus node function. The feasibility of cardiac electrical stimulation through the esophagus is determined by its anatomical proximity in the middle third to the left atrium. The test evaluates the sinus node recovery time (SNRT) – the time from the last electrical stimulus to the first sinus P wave in ms, and the corrected sinus node recovery time (CSNRT) – the difference between the SNRT duration and the intrinsic R-R interval in ms. If the SNRT and CSNRT values exceed normal limits, it indicates a decrease in the automatic activity of the sinus node. Reference values for electrophysiological parameters of sinus node function across various pediatric age groups are presented in Table 5.

Table 5. Reference values for electrophysiological parameters of sinus node function [48]

The presence of normal values for transesophageal electrical stimulation parameters, even with the additional elimination of autonomic influences (pharmacological denervation), does not exclude the presence of sinus node dysfunction. Thus, TES lacks sufficient predictive value and can be used in complex cases as an additional diagnostic method.

2.5 Other Procedures

• In patients with a confirmed diagnosis of SSS and suspected hereditary etiology, a geneticist consultation is recommended to rule out or confirm this cause [16, 17, 46, 51].

Level of Recommendations Confidence – LRC C (Level of Evidence – LOE 5)

Comment: a geneticist consultation will determine the necessity, timing, and methodology of molecular genetic testing in the patient to identify mutations and gene polymorphisms associated with the development of SSS, as well as cascade screening of relatives if necessary. [13-17, 46, 51, 52]. Molecular genetic testing may include a panel of studies of the proband with validation of one or more mutations identified by high-throughput sequencing using Sanger sequencing in nuclear family members. First-degree relatives of patients with identified mutations in genes associated with the development of SSS may also be referred for genetic counseling and testing for specific mutations to detect similar conditions [16, 17, 46, 51, 52].

Differential diagnosis

Additional tests are used for the differential diagnosis of SSS and autonomic sinus node dysfunctions.

• Patients with established or suspected SSS are recommended to undergo exercise electrocardiography to assess the sinus node response to exercise or to detect clinical symptoms of bradyarrhythmia provoked by physical exertion [5, 21, 26, 31, 32, 33, 49].

Level of Recommendations Confidence – LRC C (Level of Evidence – LOE 4)

Comment: normally, with minimal physical exertion (10–15 squats), heart rate (HR) increases by 10–15% from baseline [33]. An excessive HR response, when other causes are ruled out, indicates postural orthostatic tachycardia syndrome. An inadequate HR increase during exercise is a sign of chronotropic incompetence, a typical marker of SSS. An HR increase of less than 10% from baseline during the minimal exercise test indicates the presence of SSS and, along with the appearance of cardiac arrhythmias and repolarization abnormalities, is a prognostically unfavorable factor [5].

Methods for dynamic exercise testing include cycle ergometry using a cycle ergometer, treadmill testing, etc. In pediatrics, the most physiological test with a single bout of exercise of varying intensity – the treadmill test – is most commonly used. The Bruce protocol with a baseline stage, warm-up, and recovery period is the most widespread. Protocols with constant load or the 6-minute walk test can also be used in case of reduced exercise tolerance [53]. The maximum diagnostic value of dynamic exercise tests is observed in patients with syncopal episodes during or immediately after exercise [53, 54]. Maximum HR values during the exercise test are calculated using the formula 208 - 0.7 x age in years [55]. The HR increase during a stress test normally reaches 70–85% of the baseline HR [53]. In adult patients, chronotropic incompetence is diagnosed by determining the chronotropic index, calculated as the ratio of the difference between peak HR at maximum load and resting HR (chronotropic response) to the difference between age-predicted maximum HR (formula 220 - age (bpm)) and resting HR (chronotropic reserve, normally ≥ 80%) [56]. As a rule, the maximum heart rate in response to exercise in healthy children and adolescents reaches 170–180 bpm. An HR increase of less than 170 bpm during the exercise test is considered inadequate. However, in patients with SSS, graded exercise increases the HR to a maximum of 120 bpm, and with type III–IV SSS to 100–110 bpm [12, 31]. If sinus bradycardia is associated with increased parasympathetic activity, the HR increase is more pronounced. A criterion for SSS during a graded exercise test in children may be a drop in HR below baseline upon cessation of exercise, as well as an inadequate HR increase during the test [12, 31]. Graded exercise testing in patients with SSS is also characterized by the appearance during the 1st–3rd minutes of the recovery period of arrhythmias not recorded at baseline (accelerated ectopic rhythms, tachy-bradycardia).

• Patients with established or suspected SSS are recommended to undergo an orthostatic test to rule out a possible reflex origin of syncope [5, 12, 31, 33].

Level of Recommendations Confidence – LRC C (Level of Evidence – LOE 4)

Comment: a normal reaction is defined by the absence of complaints, an increase in HR by 20–40% from baseline, a short-term rise in blood pressure by 5–10 mm Hg upon standing and a return to baseline values within 1–3 minutes in the horizontal position, as well as a decrease in pulse pressure during the test by no more than 50% [33]. Pathological variants of the active clino-orthostatic test include hypersympathicotonic and tachycarditic, characterized by excessive autonomic support; asympathicotonic and hyperdiastolic – insufficient autonomic support; and asthenosympathotonic and sympathoasthenic – mixed autonomic support. In children with SSS and syncopal states, insufficient autonomic support (predominantly hyperdiastolic) is more frequently observed during the active clino-orthostatic test, which is further confirmation of the significance of autonomic influences in the pathogenesis of syncope in children with SSS [12, 31].

• Patients with SSS and syncopal episodes of unclear origin are recommended to undergo a passive long-term orthostatic test (tilt test) after ruling out cardiac causes of syncope to exclude a possible reflex origin of syncope [28, 29, 57, 58].

Level of Recommendations Confidence – LRC C (Level of Evidence – LOE 4)

Comment: long-term orthostatic testing (tilt testing) utilizes a specialized tilting table that allows the patient to be moved from a horizontal to a vertical position while continuously recording HR and blood pressure. In pediatric patients, the passive long-term orthostatic test has limited use due to low sensitivity [57–60]; however, the following test features have been identified: the table tilt angle should be 60º, and the optimal test duration should not exceed 30 minutes in children under 12 years of age and 40 minutes in children over 12 years of age [57, 58].

• Patients with established or suspected SSS are recommended to undergo a test with the belladonna alkaloid, tertiary amine drug #Atropine** to eliminate parasympathetic influences on heart rhythm and exclude autonomic sinus node dysfunctions [5, 26, 31-33].

Level of Recommendations Confidence – LRC C (Level of Evidence – LOE 4)

Comment: administer 0.1% solution of #Atropine** intravenously at a dose of 0.02 mg/kg. At 1, 3, and 5 minutes after administration, evaluate the rhythm and heart rate increase compared to baseline, followed by monitoring the return of heart rate to baseline. Normally, after the administration of #Atropine**, a stable sinus rhythm with an age-appropriate heart rate should be observed, and the relative heart rate increase should be at least 30% [26, 33]. If the heart rate increase is insufficient after drug administration, the patient is diagnosed with sick sinus syndrome (SSS).

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

Treatment should be divided into the correction of acute conditions and elective management of bradyarrhythmia. Acute conditions are managed with pharmacotherapy and temporary cardiac pacing. Chronic conditions require permanent cardiac pacing.

• Patients with established SSS are recommended clinical evaluation and management of reversible causes [38].

Level of Recommendations Confidence – LRC C (Level of Evidence – LOE 5)

Comment: section 1.2 presents the causes of secondary SSS, the treatment of which depends on managing the underlying disease that caused the syndrome.

3.1 Conservative Treatment

• In patients with symptomatic SSS or hemodynamic instability, administration of the belladonna alkaloid, tertiary amine drug #Atropine** is recommended to increase heart rate and relieve symptoms [32, 50, 61-64].

Level of Recommendations Confidence – LRC C (Level of Evidence – LOE 5)

Comment: the belladonna alkaloid, tertiary amine drug #Atropine** is administered at a dose of 0.01-0.02 mg/kg intravenously, with a minimum dose of 0.1 mg and a maximum single dose of 0.5 mg for children and 1 mg for adolescents. The dose may be repeated after 5 minutes up to a maximum total dose of 1 mg in children and 2 mg in adolescents [32, 50, 61-64].

• In patients with symptomatic SSS or hemodynamic instability, administration of the adrenergic and dopaminergic agent #Epinephrine** is recommended to increase heart rate and relieve symptoms [32, 50, 61-64].

Level of Recommendations Confidence – LRC C (Level of Evidence – LOE 5)

Comment: the adrenergic and dopaminergic agent #Epinephrine** is administered intramuscularly, intravenously, or intracardially at a dose of 10 mcg/kg (0.01 mg/kg) for the initial and subsequent doses. If necessary, it can be repeated every 3-5 minutes, up to a maximum dose of 1 mg. Age-based calculation is possible using a 0.1% solution at a dose of 0.05 mg × years of age [32, 50, 61-64].

Critical situations involving dizziness and syncopal episodes caused by bradycardia or asystole are managed using belladonna alkaloids, tertiary amines, and adrenergic and dopaminergic agents. Table 6 lists the international nonproprietary names, ATC codes, dosages, and routes of administration for medications used to manage acute situations in patients with SSS. However, belladonna alkaloids, tertiary amines, and adrenergic and dopaminergic agents cannot be used chronically because they suppress intrinsic sinus node activity, increase myocardial oxygen demand, and cause side effects such as hypotension and ventricular arrhythmias. CAppendix A3.2in addition to dosages and treatment regimens, also presents the mechanisms, side effects, and drug interactions of medications used in the emergency management of pediatric patients with SSS.

Table 6. Medications used for the management of acute situations in patients with SSS

• Patients with symptomatic SSS or hemodynamic instability refractory to pharmacotherapy are recommended transcutaneous external or transvenous cardiac pacing [50, 63, 65-66].

Level of Recommendations Confidence – LRC C (Level of Evidence – LOE 4)

Comment: patients with SSS and autonomic dysfunction may be recommended a course of broad-spectrum stimulating therapy to correct excessive autonomic influences:

Nootropic agent #Piracetam** (N06BX03) 0.2-0.4 g 2-3 times daily (0.4-1.2 g daily) for 2-6 months, repeat course in 3-6 months [31, 33], or 20-50 mg/kg/day in 2-3 divided doses for 1-2 months [67].

Nootropic agent #Hopantenic acid (N06BX) 250-500 mg 1-2 times daily (0.75-3 g daily) for 1-3 months, repeat course in 3-6 months [31], or 0.25-1 g 3 times daily for 1-2 months [67].

Other psychostimulants and nootropic agents #Phenibut (N06BX22) from 0.25-0.5 g/day up to 0.05-0.3 g 3 times daily for 4-6 weeks [31, 33] or 0.15-1 g/day in 3 divided doses for 1-2 months [67].

Other psychostimulants and nootropic agents #Cerebrolysin** (N06BX) 1-2 mL intramuscularly for 15-20 days every other day [31].

Antioxidant agent #Sodium polydihydroxyphenylthiosulfonate (N07XX) 1 capsule (250 mg) 3 times daily for 2 months [68].

Antioxidant agent #Ethylmethylhydroxypyridine succinate (N07XX) 2-4 mg/kg/day, not exceeding 4 mL intravenously drip in 100 mL of 0.9% sodium chloride solution for 10 days [67].

General tonic preparations #Eleutherococcus senticosus rhizomes and roots extract (A13A) and #Panax ginseng roots tincture (A13A) 1-2 drops per year of life in the morning and afternoon for 10 days per month for 1 month [31].

In the presence of metabolic changes such as repolarization abnormalities, other cardiac medications are used: #Ubidecarenone (C01EB09) 3 drops 2 times daily in infants under 1 year, 5 drops 2-3 times daily in children aged 1-5 years, 8 drops 2-3 times daily in children aged 5-10 years, 10-15 drops 2-3 times daily in children older than 10 years for 1 month, or 0.5 mL 1-2 times daily for 1 month [69, 70].

Long-term administration (up to 6 months) of a course of these drugs (no more than 4 simultaneously) stimulates redox processes, increases the brain's resistance to hypoxia, and stabilizes cell membranes. Stimulation of the sympathetic nervous system slows the progression of the syndrome and, in a large number of cases in the early stages of SSS, is accompanied by the restoration of normal pacemaking, which is especially important for young children for whom interventional treatment presents certain difficulties.

When replacement heterotopic rhythm with a high heart rate is prominent and arrhythmogenic myocardial dysfunction develops in children with tachycardia-bradycardia syndrome, antiarrhythmic therapy may be required under ECG and Holter monitoring. Antiarrhythmic therapy is contraindicated in children with a history of syncope, severe sinus node depression, numerous marked rhythm pauses, or impaired AV conduction.

3.2 Surgical Treatment

Surgical treatment includes cardiac pacing using a dual-chamber rate-responsive implantable pacemaker***, single-chamber rate-responsive implantable pacemaker*** (implantable pacemaker***)

ISOLATED SICK SINUS SYNDROME

• Permanent cardiac pacing is recommended for children with SSS and symptomatic bradycardia relative to age norms — Class I indication [27, 38, 46, 71-75].

Level of Recommendations Confidence – LRC C (Level of Evidence – LOE 4)

• Permanent cardiac pacing is recommended for children with symptomatic SSS and drug-induced bradycardia when alternative treatments are unavailable — Class IIa indication [38, 46, 75, 76].

Level of Recommendations Confidence – LRC C (Level of Evidence – LOE 4)

• Permanent cardiac pacing is recommended for children with SSS and symptoms related to chronotropic incompetence — Class IIa [38, 75, 78, 79].

Level of Recommendations Confidence – LRC C (Level of Evidence – LOE 4)

• Permanent cardiac pacing is recommended for children with SSS and symptoms likely related to age-inappropriate bradycardia or prolonged pauses after thorough evaluation — Class IIb indication [38, 75].

Level of Recommendations Confidence – LRC C (Level of Evidence – LOE 4)

SICK SINUS SYNDROME ASSOCIATED WITH CONGENITAL HEART DISEASE

• Permanent cardiac pacing is recommended for children with congenital heart disease, SSS, and recurrent atrial tachycardia when surgical or medical treatment is ineffective or unfeasible — Class IIa indication [38, 46, 68, 75, 80-82].

Level of Recommendations Confidence – LRC C (Level of Evidence – LOE 4)

• Permanent cardiac pacing is recommended for children with SSS and congenital heart disease with hemodynamic compromise due to bradycardia or loss of AV synchrony — Class IIa indication [38, 46, 80, 83-85].

Level of Recommendations Confidence – LRC C (Level of Evidence – LOE 4)

• Permanent cardiac pacing is recommended for children with congenital heart disease, sick sinus syndrome, and symptoms associated with pauses or bradycardia — Class IIa indication [38, 75, 80, 86].

Level of Recommendations Confidence – LRC C (Level of Evidence – LOE 4)

• Permanent cardiac pacing is recommended for children with congenital heart disease, sick sinus syndrome, and asymptomatic sinus bradycardia with a resting heart rate of 40 bpm or rhythm pauses greater than 3 seconds — Class IIb indication [27, 38, 71, 75, 84, 87].

Level of Recommendations Confidence – LRC C (Level of Evidence – LOE 4)

Comment: permanent cardiac pacing is the most effective method for managing the manifestations of sick sinus syndrome. The decision regarding the necessity and timing of permanent cardiac pacing, as well as the choice of pacing method and mode, is made individually, with the child's age being of great importance. In the presence of potentially reversible causes of sick sinus syndrome, permanent cardiac pacing is not required. Once indications are established, the choice of pacing mode is addressed. In patients with sick sinus syndrome without evidence of AV nodal conduction abnormalities, isolated single-chamber ventricular pacing should be avoided. In the presence of minimal atrioventricular conduction changes in children with sick sinus syndrome, dual-chamber pacing (atrial and ventricular) must be used. Utilizing pacing functions and algorithms that preserve intrinsic AV conduction will reduce the burden of ventricular pacing in patients with leads in both the atrium and ventricle [85].

One of the most pressing issues in device implantation in children is the need for lifelong pacing. Repeated device replacements and an increasing incidence of lead-related problems necessitate preserving venous access for as long as possible. In newborns and small children, an epicardial approach is preferred [88]. Endocardial lead implantation is acceptable once the child reaches a body weight of 15 kg [89–93]. For a body weight of 15 to 19 kg, a single-chamber, rate-responsive implantable pacemaker*** is implanted. For a body weight of 20 kg or more, a dual-chamber, rate-responsive implantable pacemaker*** is used. The presence of intracardiac shunts may increase the risk of systemic embolism following endocardial implantation and requires their closure before or during the procedure, if possible; otherwise, an epicardial approach must be considered. An epicardial approach is also necessary in patients with congenital heart disease who lack venous access, particularly single-ventricle patients. In patients scheduled for an epicardial approach, lead implantation in the apical position of the left ventricle is recommended, whereas for an endocardial approach, the preferred lead implantation site is the interventricular septum or the cardiac conduction system.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Patients with sick sinus syndrome who have indications for implantable pacemaker*** implantation should undergo psychological rehabilitation before and after surgical treatment. Patients do not require specialized rehabilitation after implantable pacemaker*** implantation and wound healing. In selected cases, a sparing physical activity regimen is advised, restricting large-amplitude movements of the limb on the implantation side for 1 month.

5. Prevention and Dispensary Observation

Regular examinations are required for the timely identification of children with borderline bradycardia, as well as those at risk for syndrome development and early diagnosis of the initial stages of sick sinus syndrome.

• In patients with bradycardia and an ECG heart rate below the 5th percentile relative to age norms, an evaluation by a pediatric cardiologist and heart rate monitoring via ECG at least once a year for at least 5 years are recommended [12, 43].

Level of Recommendations Confidence – LRC C (Level of Evidence – LOE 5)

• If bradycardia with a heart rate below the 2nd percentile relative to age norms is detected on an ECG, an evaluation by a pediatric cardiologist and ECG heart rate monitoring every 3 months are recommended [12, 43].

Level of Recommendations Confidence – LRC C (Level of Evidence – LOE 5)

• Children diagnosed with type I sick sinus syndrome are recommended to be followed up by a pediatric cardiologist once a year, and those with types II–IV sick sinus syndrome, twice a year [12, 43].

Level of Recommendations Confidence – LRC C (Level of Evidence – LOE 5)

Comments: to prevent post-myocarditis bradyarrhythmias, it is necessary to prevent infectious diseases in pregnant women and children, and to promptly prescribe adequate therapy in patients who develop an infectious disease.

In the absence of progression of sick sinus syndrome, annual monitoring of risk factors is recommended via ECG and Holter monitoring, assessing minimum heart rate, rhythm pauses, concomitant rhythm and conduction disorders, and hemodynamic parameters by echocardiography. If the degree of bradycardia worsens, the maximum duration of rhythm pauses increases, or hemodynamic parameters deteriorate, follow-up every 3–6 months is required to determine the indications for cardiac pacing. If indications are present, the patient is hospitalized in a cardiac surgery clinic experienced in implantable pacemaker*** implantation.

Children following implantable pacemaker*** implantation for sick sinus syndrome are recommended to be followed up by a pediatric cardiologist and, if necessary, undergo implantable pacemaker*** interrogation at 6 months, and then at least once a year [27, 38, 71, 94, 95].

Level of Recommendations Confidence – LRC C (Level of Evidence – LOE 5)

• Children following implantable pacemaker*** implantation for sick sinus syndrome are recommended to undergo an ECG at least once a year to assess heart rate, rhythm source, rhythm and conduction disorders, and device function [38].

Level of Recommendations Confidence – LRC C (Level of Evidence – LOE 5)

• Children following implantable pacemaker*** implantation for sick sinus syndrome are recommended to undergo echocardiography at least once a year to evaluate contractile function, detect chamber contraction dyssynchrony, and assess lead status [38, 96].

Level of Recommendations Confidence – LRC C (Level of Evidence – LOE 5)

• In children after implantation of an implantable pacemaker*** for sick sinus syndrome (SSS), to assess the condition and position of the leads, it is recommended to perform targeted chest radiography in two projections every 1–3 years, depending on the child's growth rate and the clinical situation [38].

Level of Recommendations Confidence – LRC C (Level of Evidence – LOE 5)

Comments: the routine follow-up examination of a patient after implantation of an implantable pacemaker*** includes: evaluation of its parameters, ECG recording, echocardiography, targeted chest radiography in two projections; Holter ECG monitoring and exercise ECG testing may also be performed depending on the specific clinical course of SSS in an individual patient. The follow-up schedule and scope of necessary examinations may vary depending on the etiology and specific features of SSS in a particular patient.

Vaccination in children with SSS is performed in the absence of progressive sinus node dysfunction. Preventive vaccinations are contraindicated in children with autoimmune forms of SSS or those of post-myocarditis origin in the acute phase of the disease. In patients with postoperative SSS, vaccination is carried out no earlier than 6 months after correction of congenital heart disease. Inactivated vaccines are preferred when vaccinating patients with SSS. The presence of an implantable pacemaker*** in a patient is not a contraindication to vaccination.

Sports participation

• Athletes with asymptomatic SSS and without limiting structural heart disease or other arrhythmias are recommended to participate in all competitive sports [97].

Level of Recommendations Confidence – LRC C (Level of Evidence – LOE 5)

• Athletes with SSS and symptoms are not recommended to engage in sports during the work-up for structural heart disease and treatment [97].

Level of Recommendations Confidence – LRC C (Level of Evidence – LOE 5)

• Patients with SSS after implantation of an implantable pacemaker*** are recommended to engage in sports provided there is no limiting structural heart disease, other arrhythmias, or symptoms [97].

Level of Recommendations Confidence – LRC C (Level of Evidence – LOE 5)

• Patients with SSS who are completely dependent on an implantable pacemaker*** are not recommended to participate in contact sports where there is a risk of collision that could lead to damage to the implantable pacemaker*** [97].

Level of Recommendations Confidence – LRC C (Level of Evidence – LOE 5)

Patients may have additional restrictions related to the underlying conditions that caused secondary SSS.

6. Organization of Medical Care

Indications for hospital admission to a medical organization:

1) Deterioration of the patient's condition with an established or suspected diagnosis of SSS, the onset of complaints of syncope, dizziness, weakness;

2) Worsening severity of bradycardia or increased duration of rhythm pauses relative to the age norm on the ECG in a patient with an established or suspected diagnosis of SSS;

3) The need to assess the patient's condition and monitor risk factors in a patient with an established diagnosis of SSS;

4) The need to adjust therapy in a patient with an established diagnosis of SSS;

5) The need for scheduled implantation/replacement of an implantable pacemaker*** in a patient with an established diagnosis of SSS;

6) The need for scheduled or emergency assessment and correction of the function of the implantable pacemaker*** in a patient with an established diagnosis of SSS.

Comments: hospitalization is carried out in a specialized pediatric cardiology department of level III medical organizations. In the event of syncope or circulatory arrest, emergency therapeutic measures must be initiated by an ambulance team. The patient must be hospitalized in a medical facility capable of providing resuscitation care. Hospitalization in a hospital with the capabilities and experience of temporary and permanent cardiac pacing is optimal.

Indications for discharging a patient from a medical organization:

1) Disappearance of symptoms, improvement in the patient's condition in a patient with a confirmed or suspected diagnosis of sick sinus syndrome (SSS);

2) No increase in the degree of bradycardia, duration of rhythm pauses, or normalization of heart rate parameters and rhythm pauses on the ECG in a patient with a confirmed or suspected diagnosis of SSS;

3) Successful assessment of the patient's condition and monitoring of risk factors in a patient with a confirmed diagnosis of SSS;

4) Successful correction of therapy in a patient with a confirmed diagnosis of SSS;

5) Successful assessment and correction of the function of the implantable pacemaker*** in a patient with a confirmed diagnosis of SSS.

7. Additional Information

Outcomes and Prognosis

The initial stage in the development of SSS is sinus bradycardia. Persistent (more than 3 years) decrease in heart rate below the 2nd percentile on a standard ECG is associated with the development of progressive impairment of sinus node function in children [5, 12]. Timely detection of borderline bradycardia and age-appropriate assessment of heart rate values can prevent the further development of a generalized degenerative process of the entire cardiac conduction system, where, in the absence of treatment, the syndrome progresses with the appearance of complaints, ECG changes, deterioration of hemodynamic parameters, and the development of atrioventricular and intraventricular conduction abnormalities [3, 5, 12]. To determine the prognosis of the disease in children, a comprehensive assessment of clinical and electrophysiological parameters should be performed, although the presence of clinical symptoms is in some cases of greater value compared to electrophysiological parameters of sinus node function. The principles of evaluating the effectiveness of treatment in children with SSS differ from those for other rhythm disorders. A stable clinical and electrocardiographic picture in the absence of positive dynamics can be regarded as the cessation of the further development of the pathological process. The most unfavorable cases in terms of life-threatening events are those of SSS with multilevel involvement of the cardiac conduction system, onset of syncopal states in preschool age, and familial and congenital manifestations of SSS.

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

1. Polyakova E.B. – Candidate of Medical Sciences (Moscow), Chair of the Working Group, Member of the Association of Pediatric Cardiologists of Russia (APCR), Russian Cardiological Society (RCS), European Heart Rhythm Association (EHRA), European Society of Cardiology (ESC).

2. Chernysheva T.V. – Candidate of Medical Sciences (Tyumen), Secretary of the Working Group, Member of the Association of Pediatric Cardiologists of Russia (APCR), Russian Cardiological Society (RCS).

3. Balykova L.A. – Doctor of Medical Sciences, Professor (Saransk), Member of the Association of Pediatric Cardiologists of Russia (APCR), Russian Cardiological Society (RCS), Russian Society of Holter Monitoring and Noninvasive Electrocardiology (ROHMNE), Union of Pediatricians of Russia, European Pediatric Association (EPA/UNEPSA), European Society of Cardiology (ESC).

4. Batalov R.E.– Doctor of Medical Sciences (Tomsk), Member of the All-Russian Scientific Society of Arrhythmologists (VNOA), Russian Cardiological Society (RCS), European Heart Rhythm Association (EHRA).

5. Shkolnikova M.A. – Doctor of Medical Sciences, Professor (Moscow), Honorary President of the Association of Pediatric Cardiologists of Russia (APCR), Member of the Russian Cardiological Society (RCS), All-Russian Scientific Society of Arrhythmologists (VNOA), European Society of Cardiology (ESC), Association for European Paediatric and Congenital Cardiology (AEPC).

The members of the Working Group confirmed the absence of financial support/conflict of interest. If a conflict of interest was reported, the working group member(s) were excluded from the discussion of sections related to the conflict of interest area.

Appendix A2. Methodology for Developing Clinical Guidelines

Clinical guidelines were developed by expert specialists of the All-Russian Public Organization "Association of Pediatric Cardiologists of Russia" and the All-Russian Scientific Society of Clinical Electrophysiology, Arrhythmology and Pacing – based on the achievements of evidence-based medicine, domestic and foreign clinical experience in the field of cardiac rhythm disorders in children. The basis of this version of the clinical guidelines was Russian and foreign fundamental guidelines and monographs on pediatric cardiology, cardiology, research results, and the latest versions of European and American guidelines. Sources of modern updates were journal publications in authoritative peer-reviewed journals included in Russian and foreign science citation indices.

Target audience for these clinical guidelines:

1. Pediatric cardiologist.

2. Pediatrician.

3. Cardiovascular surgeon.

4. General practitioner (family physician).

5. Medical students.

6. Residents and interns.

During the development, the system of levels of reliability of evidence (LRE) and grades of recommendation (GR) scales for therapeutic, rehabilitation, preventive and diagnostic interventions (Tables PA2-1, PA2-4 and PA2-2) introduced in 2018 by the Center for Healthcare Quality Assessment and Control of the Russian Ministry of Health was used.

Table PA2-1. Scale for assessing the levels of reliability of evidence (LRE) for diagnostic methods (diagnostic interventions)

Table PA2-1. Scale for grading the levels of evidence (LE) for preventive, therapeutic, and rehabilitative methods, including those based on natural therapeutic factors (preventive, therapeutic, and rehabilitative interventions)

Table PA2-1. Scale for grading the grades of recommendation (GR) for preventive, diagnostic, therapeutic, and rehabilitative methods, including those based on natural therapeutic factors (preventive, diagnostic, therapeutic, and rehabilitative interventions)

Procedure for updating clinical guidelines.

The mechanism for updating clinical guidelines provides for their systematic revision at least once every three years, as well as upon the emergence of new evidence-based medicine data on the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or in the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.

Appendix A3. Reference Materials

Appendix A3.1 Regulatory documents and resources used to develop the clinical guidelines

1. Order of the Ministry of Health of the Russian Federation No. 103n dated February 28, 2019, "On approval of the procedure and timeframe for the development of clinical guidelines, their revision, the standard template of clinical guidelines, and requirements for their structure, composition, and scientific validity of the information included in clinical guidelines."

2. Order of the Ministry of Health of the Russian Federation No. 440n dated October 25, 2012, "On approval of the Procedure for the Provision of Medical Care in the Profile 'Pediatric Cardiology'."

3. Order of the Ministry of Health of the Russian Federation No. 203n dated May 10, 2017 "On approval of criteria for assessing the quality of medical care."

4. Methodological recommendations for assessing the validity of evidence and the grades of recommendations. Center for Healthcare Quality Assessment and Control of the Russian Ministry of Health, 2018.

5. Decree of the Government of the Russian Federation No. 3053-r dated December 31, 2018 "On approval of the list of medical devices implanted in the human body when providing medical care under the state guarantee program of free medical care for citizens, as well as the list of medical devices dispensed upon prescriptions for medical devices when providing a set of social services."

6. Decree of the Government of the Russian Federation No. 2406-r dated October 12, 2019, "On approval of the list of vital and essential drugs, as well as lists of drugs for medical use and the minimum assortment of drugs required for the provision of medical care" (as amended by Decrees of the Government of the Russian Federation No. 1142-r dated April 26, 2020, No. 2626-r dated October 12, 2020, No. 3073-r dated November 23, 2020)

Appendix A3.2 Doses, regimens, mechanisms, side effects, and drug interactions of drugs used in emergency care for children with SSS

Appendix B. Physician Action Algorithms

Appendix C. Patient Information

Sick sinus syndrome (SSS) is a condition that develops due to the weakening or cessation of sinus node function. The main manifestation of SSS is a slowed heart rate (bradycardia). Due to marked pulse slowing, a patient with SSS may experience syncopal episodes as well as cardiac arrest, which can lead to sudden cardiac death. Standard ECG and 24-hour Holter rhythm monitoring are most important for diagnosing SSS. Monitoring is more likely to capture ECG changes, track their association with exertion and response to medications, and detect an asymptomatic course. SSS is sometimes characterized by progression, so in the absence of treatment, clinical symptoms may worsen. A more unfavorable prognosis for the course of SSS is noted in patients with organic heart disease. In severe variants of SSS and in the presence of indications, the only treatment method is permanent pacemaker implantation. The decision regarding the necessity and timing of pacemaker implantation, as well as the choice of pacing mode, is made individually, with the patient's age being of great importance.

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

Information is not available.