Pacing for Sinus Node Disease

Cellular Electrophysiology of Sinus Node Disease

The sinoatrial node is an anatomically and electrophysiologically heterogeneous tissue with multiple cell types and a complex structure. The sinus node is located near the junction of the superior vena cava and right atrium extending inferolaterally down the crista terminalis ( Fig. 13-1 ). There is an extensive paranodal area located in the crista terminalis near the sinus node comprising a mixture of nodal and atrial myocytes with a distinct molecular architecture that is intermediate between the characteristics of atrial muscle and sinus node tissue. The role of this paranodal tissue in pacemaking is uncertain. The action potential governing pacemaking usually arises in the center of the sinoatrial node and propagates into the surrounding muscle of the right atrium. A variety of ionic currents contribute to normal sinus node automaticity ( Fig. 13-2 ). These include the repolarizing delayed rectifier current (I _Kr ), three inward currents, I _f , a hyperpolarization-activated inward current and the L- and T-type calcium currents (I _CaL , I _CaT ). There is also activation of inward I _NaCa (the sodium-calcium exchange current) in response to spontaneous Ca ²⁺ release from the sarcoplasmic reticulum mediated via the ryanodine receptor. The Ca ²⁺ clock is reset by uptake of Ca ²⁺ into the sarcoplasmic reticulum. Both the membrane and Ca ²⁺ clocks responsible for cardiac pacemaker activity are regulated by a number of intracellular processes. There is limited or no measurable sodium current (I _Na ) in the center of the node, but it is measurable in the periphery. I _Na may be responsible for activating peripheral cells.

The molecular architecture of the human sinus node has been described in detail. A complex and heterogeneous expression of ion channels is present within the sinus node when compared with the paranodal region within the terminal crest and right atrial tissue. There is a lower expression of Na _v 1.5, K _v 4.3, K _v 1.5, HERG, K _ir 2.1, K _ir 6.2, the cardiac ryanodine receptor, the sarcoplasmic reticulum calcium pump, Connexin 40, and Connexin 43 messenger RNA (mRNA) but a higher expression of Ca _v 1.3, Ca _v 3.1, hyperpolarization-activated cyclic nucleotide-gated channels (HCN1, HCN4) mRNA in the sinus node compared with right atrial tissue. Similar differences in expression of the corresponding ion channel proteins are observed in the sinus node compared with right atrial tissue. The expression pattern of many ion channels in the paranodal area is intermediate between that of the sinus node and right atrium, but greater expression of K _v 4.2, K _ir 6.1, minK-related peptides and other potassium channels (TASK1, SK2) is observed in the paranodal area compared with sinus node or atrial tissue. Estimating conductances of the key ionic currents based on a percentage of the mRNA levels expressed in the sinus node and incorporating these in a mathematical model of the human atrial action potential has successfully produced a model of cardiac pacemaking.

The causes of SND are multifactorial. Abnormalities of one or more ionic channels, transporters, or receptors that are inherited or develop under pathophysiologic states including aging, AF, or HF likely contribute to the substrate for SND. Age-dependent decreases in I _f , I _CaL , I _CaT , and sarcoplasmic reticulum Ca ²⁺ cycling proteins, including the ryanodine receptor, contribute to age-associated decreases in intrinsic sinus node automaticity. Knockout of various ion channels (Na _v 1.5, the sodium channel β ₂ subunit, Ca _v 1.3, Ca _v 3.1, HCN2, HCN4, ankyrin-B) and gap junction subunits (connexin 40) in transgenic mice have produced SND phenotypes characterized by bradycardia, sinus dysrhythmia, and/or sinus node exit block. Mutations of HCN4, the alpha subunit of the sodium channel, ankyrin-B (a protein important in the regulation of ion channel function), and the KCNQ1 gene that encodes the KvLQT1 potassium channel have been reported to be associated with SND. Some experimental models of ventricular hypertrophy, HF, and following myocardial infarction have been reported to be associated with sinus node dysfunction and/or AT/AF. In an experimental model of HF, decreases in the intrinsic sinus rate have been observed in association with significant decreases in I _f . Loss of I _Na in the periphery of the sinus node and decreased expression of connexin 43 within the sinus node have been reported in animal models of aging and may explain abnormalities of sinus node function. Increased interstitial fibrosis in the sinus node and heterogeneity of repolarization have been associated with sinus node reentry following myocardial infarction in a canine model.

Clinical Electrophysiology of Sinus Node Disease

In normal hearts, the sinus node complex displays a dynamic range of activation sites along the posterolateral right atrium. There are multiple origins of sinus activation and exit sites to the atria, demonstrating the multicentricity of the sinus node complex. Electroanatomic mapping has demonstrated that preferential pathways of conduction exist between the sinus node and the exit of sinus activity to the atria. In SND, the sinus node complex has been noted to be more often unicentric and localized to the low crista terminalis. Electroanatomic mapping in patients with SND has also demonstrated significant increases in atrial refractory periods at all right atrial sites, increased atrial conduction times along the lateral right atrium and coronary sinus, and greater number and duration of double potentials along the crista terminalis ( Fig. 13-3 ). Significant regional conduction slowing with double potentials and fractionation associated with areas of low voltage and electrical silence has also been observed in the right atrium. The slow conduction may be caused by increased fibrosis in the atria, although other determinants of conduction velocity (e.g., I _Na or connexin expression) have not been studied in patients with SND. Increased atrial fibrosis detected by late gadolinium enhancement magnetic resonance imaging has been reported to be associated with SND. Areas of low voltage/scarring in the right atrium can be widespread, progressive, and severe. Similar changes are seen in conditions of chronic atrial stretch and increasing age. These results indicate that not only is there disease of the sinus node, but the atrial electrophysiologic abnormalities also involve the right atrial myocardium.

Patients with HF manifest significant sinus node remodeling characterized by anatomic and structural changes along the crista terminalis and a reduction in functional sinus node reserve. Compared with age-matched controls, patients with congestive HF have greater prolongation of the intrinsic sinus cycle length, greater prolongation of sinus node recovery times, caudal origin of sinus activity, prolongation of sinoatrial conduction time, greater number and duration of fractionated electrograms or double potentials along the crista terminalis, loss of voltage amplitude along the crista terminalis, and abnormal and circuitous propagation of the sinus impulse. In addition, atrial refractoriness and regional conduction times are prolonged, and these changes may contribute to the propensity to AF in this setting.

Both AF and atrial flutter cause adverse remodeling of the sinus node. Sinus node activation in patients with persistent atrial flutter is characterized by more caudal activation, slower conduction time along preferential pathways, and modest shifts within the functional pacemaker complex. Prolonged sinus pauses after paroxysms of AF may result from depression of sinus node function that is eliminated by curative ablation of AF. Sinus node recovery times are prolonged immediately following successful cardioversion and shorten over time. In an experimental model of atrial tachyarrhythmias, downregulation of HCN2, HCN3, and minK subunit expression along with the corresponding currents I _f and I _Ks have been reported. These changes were associated with abnormalities of sinus node function, whereas the L- and T-type calcium units and connexin 43 were unaffected. These data suggest that changes in I _f and I _Ks contribute to the abnormalities of sinus node function associated with AF.

The long-term loss of atrioventricular (AV) synchrony induced by ventricular (VVI) pacing is also associated with atrial electrical remodeling that is characterized by nonuniform prolongation of atrial refractoriness, prolongation of atrial conduction time and prolongation of sinus node recovery times. These electrophysiologic changes are reversible after restoration of AV synchrony with dual chamber (DDD) pacing. Together the changes in atrial and sinus node electrophysiology may contribute to the higher incidence of AF that has been observed in patients treated with VVI pacing compared with AV sequential pacing. The cellular mechanisms resulting in the association between sinus node dysfunction and atrial tachyarrhythmias at present remain unknown.

Clinical Presentation

The most common symptoms for which patients with SND seek medical attention include presyncope, syncope, palpitations, decreased exercise tolerance, and fatigue ( Table 13-1 ). Symptoms are usually intermittent and may be of variable duration. Many patients with electrocardiographic evidence of SND may be asymptomatic. Symptoms secondary to systemic thromboembolism may also be observed. Syncope may be secondary to profound sinus bradycardia, asystole, or AT. Syncope may occur without warning or may be heralded by dizziness or palpitations. Symptomatic bradycardia and presyncope or syncope secondary to sinus arrest may be exacerbated in patients with coexisting atrial tachyarrhythmias following initiation of antiarrhythmic drug therapy. The physical examination is frequently unremarkable although sinus bradycardia or AF should raise suspicion of this disorder. However, sinus bradycardia is frequently observed in normal healthy individuals of all age ranges. Clinical correlation with symptoms is important.

Diagnosis of Sinus Node Disease

The diagnostic tools presently available for diagnosing SND are summarized in Table 13-2 . Due to the intermittent nature of this syndrome, the diagnosis is often time-consuming and frustrating. The sensitivity of both noninvasive tests and invasive electrophysiologic studies to identify SND as a potential cause of syncope are low (4%-16%). Implantable loop recorders increase the likelihood of diagnosing bradycardia/sinus arrest as the cause of syncope in patients with SND, and this approach has been shown in selected patients to be more cost-effective than a strategy of serial noninvasive studies followed by invasive studies.

Natural History

The course of SND is unpredictable; periods of symptomatic sinus node dysfunction may be separated by long periods of normal sinus node function. SND disease is believed to evolve over 10 to 15 years commencing with an asymptomatic phase and ultimately progressing to complete failure of sinus node activity and the emergence of subsidiary pacemaker escape rhythms or the development of permanent AF. Menozzi et al prospectively followed 35 untreated patients with SND for up to 4 years (mean 17 ± 15 months). These subjects had a mean sinus rate at rest of ≤50 beats/min and/or intermittent sinoatrial block as well as symptoms attributable to SND. During follow-up, the majority of patients (57%) experienced at least one cardiovascular event that required treatment. Syncope occurred in 23%, symptomatic HF in 17%, permanent AF in 11%, and symptomatic paroxysmal atrial tachyarrhythmias in 6%. The rates of occurrence of cardiovascular events were 35%, 49%, and 63% after 1, 2, and 4 years, respectively. Older age and associated left ventricular (LV) dysfunction were independent predictors of cardiovascular events. The rate of occurrence of syncope was 16%, 31%, and 31% after 1, 2, and 4 years, respectively. Although a favorable outcome was observed in 43% of patients, the cohort studied was small and duration of follow-up was relatively short. Although patients with SND experience higher mortality compared with those without SND, this risk disappears after adjustment for cardiovascular risk factors and the presence of cardiovascular disease.

Pacing and Survival in Sinus Node Disease

One small prospective randomized study reported that atrial (AAI) pacing compared with VVI pacing was associated with improved survival in patients with symptomatic bradycardia secondary to SND. The annual mortality rate was 3.0% in the atrial pacing group compared with 6.4% in the ventricular pacing group. However, these results have not been confirmed in three larger clinical trials. The Pacemaker Selection in the Elderly (PASE) trial randomized 407 patients ≥65 years of age to receive a dual-chamber pacemaker programmed to the dual chamber rate adaptive (DDDR) mode compared with the ventricular rate adaptive (VVIR) mode. Overall mortality was similar in the two pacing groups. Of the 175 patients with SND as the primary indication for pacing in this study, overall mortality was slightly higher in the VVIR group (8.8%/yr) compared with the DDDR group (5.2%/yr; P = 0.09). The Canadian Trial of Physiologic Pacing (CTOPP) investigators randomized 2568 patients from a general pacemaker population but without permanent AF to receive a ventricular ( n = 1474) or atrial-based ( n = 1094) pacemaker. Forty-two percent of the study population had SND as an indication for pacing. Over a mean follow-up period of 3.1 years, overall mortality was similar in both groups (6.3%/yr in the physiologic compared with 6.6%/yr in the ventricular pacing group; P = 0.92). Over extended follow-up of 6.4 years, the primary composite outcome of cardiovascular death or stroke occurred at a rate of 6.1% per year in patients assigned to ventricular pacing and at a rate of 5.5% per year in patients assigned to physiologic pacing. The relative risk reduction was 8.1% with physiologic pacing (95% CI = −6.5 to 20.7; P = 0.26). The Mode Selection Trial (MOST) investigators randomized 2010 patients with SND to VVIR or DDDR pacing. Over a mean follow-up period of 2.76 years, the annual mortality was similar in both groups (7.1%/yr in the DDDR compared with 7.4%/yr in the VVIR group, P = 0.65) ( Fig. 13-4 ). A pooled analysis of five randomized trials did not observe a significant reduction in mortality (HR [hazard ratio] = 0.95; 95% CI = 0.87-1.03) associated with atrial or dual-chamber pacing compared with ventricular pacing.

In a population-based cohort of 8777 patients with SND treated with AAI or DDD pacemakers, a slight increase in the risk of all-cause mortality (HR = 1.12; 95% CI = 1.00-1.25) was reported among DDD patients compared with AAI patients. However, this observation was not confirmed in the DANPACE (Danish Multicenter Randomized Trial on Single Lead Atrial Pacing versus Dual Chamber Pacing in Sick Sinus Syndrome) trial, which randomized 1415 patients with SND and intact AV conduction to AAIR or DDDR pacing. Over 5.4 ± 2.6 years of follow-up, 209 patients (29.6%) in the AAIR group died compared with 193 patients (27.3%) in the DDDR group (HR = 1.06; 95% CI = 0.88-1.29; P = 0.53; Fig. 13-5 ). The DANPACE investigators reported that syncope following pacemaker implantation was associated with higher mortality.

Pacing and Atrial Fibrillation in Sinus Node Disease

Paroxysmal AF, atrial flutter, and AT occur commonly in SND. AT/AF detection and data storage features are present in most dual-chamber pacemakers that facilitate the diagnosis and treatment of AF. Some devices have algorithms developed specifically for the prevention and management of atrial tachyarrhythmias.

Atrial Fibrillation Detection in Pacemakers

Accurate detection of atrial tachyarrhythmias, including atrial flutter and AF, by implantable devices with advanced atrial tachyarrhythmia management features is important for a number of reasons. Accurate detection ensures the appropriateness of automatic mode switching and the appropriateness of atrial antitachycardia pacing (ATP) for termination of atrial flutter. Implantable devices provide a wide range of diagnostic data, including the frequency of AT/AF, time of onset and duration of AT/AF episodes, the quantity of AT/AF (burden expressed as percentage of the day or hours per day), and ventricular rate control during AF ( Fig. 13-6 ). Such information may be valuable for managing antiarrhythmic drug therapy and making decision on the need for antithrombotic drug therapy. With advances in remote monitoring of pacemakers and implantable defibrillators, early detection of atrial tachyarrhythmias facilitates earlier medical intervention. Many clinical device trials have used device-based indices of arrhythmia recurrence, frequency, and burden as surrogates for clinical endpoints. Although measures of AT/AF burden in devices is quite accurate, counts of AT/AF frequency are less accurate because of variations in device-based criteria for detection, termination, and redetection, as well as intermittent atrial undersensing during episodes of AT/AF.

Factors influencing AT/AF underdetection or overdetection are summarized in Table 13-3 . It is important that pacemakers be programmed to optimize detection of AT/AF with careful attention to the atrial sensitivity and postventricular atrial blanking period. Atrial undersensing caused by inappropriate noise reversion when high atrial sensing levels are programmed has been described. Atrial lead position is an important factor for appropriate AT/AF detection because some sites (e.g., near the coronary sinus os and sometimes within the right atrial appendage) are associated with a high incidence of far-field R-wave oversensing that may be inappropriately classified as AF. An example of inappropriate classification due to far-field R-wave oversensing is shown in Figure 13-7 . Interelectrode lead spacing, e.g., 5 mm interelectrode distance, may also minimize far-field R-wave sensing. Attention to these issues permits high sensitivity and specificity of AT/AF detection. In our experience applying these parameters in patients with known AF, the sensitivity of AT/AF detection was 97% for sustained episodes ≥5 minutes' duration. Some devices have incorporated newer detection algorithms that include pattern recognition to facilitate detection of AT/AF and minimize inappropriate detections due to far-field oversensing. Such algorithms have been reported to have high sensitivity (>95%) and specificity for AT/AF detection. In the AF Reduction Atrial Pacing Trial (ASSERT), which included patients with and without AT/AF, 82.7% of adjudicated atrial high rate episodes lasting >6 minutes duration and >190 bpm in duration were classified as appropriate detections ( Fig. 13-8 ). Only 48% of episodes <6 minutes in duration were adjudicated as appropriate detections. However, the positive predictive value increased to over 93% for episodes >30 minutes duration (see Fig. 13-8 ). Most of the inappropriate detections were caused by repetitive nonreentrant ventriculoatrial synchrony which occurs during atrial overdrive AF suppression algorithms.

TABLE 13-3

Factors Influencing Appropriate Device Detection of Atrial Tachycardia (AT)/Atrial Fibrillation (AF)

Sensing	Factors
Undersensing	Low atrial electrogram (AEGM) in sinus rhythm
	AEGM in blanking period
	Programmed atrial rate
	Programmed AT/AF duration
	Programmed atrial sensitivity
	Programmed atrial blanking period
Oversensing	Far-field R-wave detection
Other	Competitive atrial pacing/RNRVAS

RNRVAS, Repetitive nonreentrant ventriculoatrial synchrony.