Anatomy and Physiology of the Sinus Node

The sinus node is a subepicardial, “crescent-” or “tadpole”-shaped structure located laterally within the epicardial groove of the sulcus terminalis of the right atrium (RA) at the junction of the anterior trabeculated appendage with the posterior smooth-walled venous component. The endocardial aspect of the sulcus terminalis is marked by the crista terminalis. Starting epicardially at the junction of the superior vena cava (SVC) and the right atrial appendage, the sinus node courses downward and to the left along the sulcus terminalis, to end subendocardially almost to the inferior vena cava (IVC). In adults, the sinus node measures 8 to 22 mm long and 2 to 3 mm wide and thick. The right phrenic nerve often runs in close proximity to the sinus node, where it lies on the fibrous pericardium immediately overlying the lateral and anterolateral quadrants of the SVC–right atrial junction ( see Fig. 8.1 ).

The sinus node normally is the dominant pacemaker of the heart. Its pacemaker function is determined by its low maximum diastolic membrane potential and steep phase 4 spontaneous depolarization. Importantly, the pacemaker activity is not confined to a single cell in the sinus node; rather, sinus node cells function as electrically coupled oscillators that discharge synchronously because of mutual entrainment. Current evidence suggests a “pacemaker hierarchy” within the sinus node. At faster rates, the sinus impulse originates in the superior portion (head) of the sinus node, whereas at slower rates, the impulse arises from a more inferior part (toward the tail). The hierarchy mediates heart rate changes (in response to physiological stimuli) via a dynamic craniocaudal shift in the “leading pacemaker” site.

Notably, the sinus node is functionally insulated from the surrounding atrial myocytes, except at a limited number of different conduction pathways (exit sites) that allow transmission of sinus impulses to atrial myocardium, likely responsible for the variations in P wave morphology and polarity commonly observed at different sinus rates. Neural and hormonal factors influence both the site of pacemaker activation, likely via shifting points of initial activity, and the point of exit from the sinus node complex.

Pathophysiology

Sinus tachycardia is a physiological response to sympathetic activation and/or parasympathetic withdrawal. Inappropriate sinus tachycardia (IST) is a nonparoxysmal tachyarrhythmia characterized by a persistent increase in resting sinus rate unrelated to, or out of proportion of, the level of physical, emotional, pathological, or pharmacological stress, or an exaggerated heart rate response to minimal exertion or a change in body posture. IST is neither a response to a pathological process (e.g., heart failure, hyperthyroidism, or drug effects) nor a result of physical deconditioning. Crucial to this definition is the presence of associated symptoms.

The underlying mechanism(s) of IST is poorly understood and remains controversial. Potential mechanisms include enhanced automaticity, disorder of autonomic responsiveness of the sinus node, altered sinus nodal intrinsic regulation, and sympathovagal imbalance, with excessive sympathetic drive and/or reduced vagal influence on the sinus node. A primary abnormality of sinus node function has been suggested, as evidenced by a higher intrinsic heart rate (after muscarinic and beta-receptor blockade) than that found in normal controls or a blunted response to adenosine with less sinus CL prolongation than in control subjects (with and without autonomic blockade). In addition, β-adrenergic receptor hypersensitivity, alpha-adrenergic receptor hyposensitivity, M ₂ muscarinic receptor hyposensitivity, brain stem dysregulation, depressed efferent cardiovagal reflex, central and peripheral nociceptive effects, hypothalamic paraventricular nucleus stimulation, and impaired baroreflex control have been offered as likely explanations. Chronic beta-receptor stimulation by autoantibodies and autonomic neuritis or autonomic neuropathy can play a role in some cases. The extent to which each of these mechanisms contributes to tachycardia and associated symptoms is unknown, but the underlying mechanisms are likely multifactorial and complex.

Recently, IST has been linked to sinus node channelopathy. A gain-of-function mutation in the HCN4 gene (which encodes the protein that contributes to formation of I _f channels) has been identified in a cohort of patients with IST. HCN mutations can be associated with IST through increased sensitivity to cyclic adenosine monophosphate-dependent activation.

In some patients, there can be an overlap between IST and disorders, such as chronic fatigue syndrome and neurocardiogenic syncope, and other patients can have a psychological component of hypersensitivity to somatic input. Other groups with similar or overlapping laboratory findings and clinical course include patients with hyperadrenergic syndrome, idiopathic hypovolemia, orthostatic hypotension, and mitral valve prolapse syndrome. It is possible that the phenotype of IST is the result of a number of unrelated disorders (much like ventricular tachycardia is the phenotype of many unrelated causes).

Epidemiology and Natural History

The vast majority of patients afflicted with IST are young women (mean age, 38 ± 12 years), although IST has also been identified in older individuals. IST affects people working in health care in disproportionate numbers, for unknown reasons. The prevalence of IST (symptomatic or asymptomatic) in a middle-aged population (up to 1.2% in one report) appears to be higher than previously assumed.

Despite the chronic nature of the disorder and long-lasting symptoms, the natural course and prognosis of IST are generally benign. IST rarely is associated with tachycardia-induced cardiomyopathy, perhaps due to the frequently observed nocturnal slowing of the heart rate.

Clinical Presentation

The clinical presentation of the arrhythmia is highly variable, ranging from totally asymptomatic patients identified during routine medical examination to those with short, paroxysmal episodes of palpitations to individuals with chronic, incessant, and incapacitating symptoms. The most prominent symptoms are palpitations, fatigue, and exercise intolerance. IST can also be associated with a host of other symptoms, including chest discomfort, dyspnea, orthostatic intolerance, lightheadedness, dizziness, presyncope, and syncope. Symptoms can start abruptly or insidiously, but typically persist for months or years. Importantly, symptoms may not consistently correlate with periods of tachycardia or can be disproportionate to the severity of the tachycardia. In fact, successful treatment of the tachycardia may not lead to improvement of symptoms. Associated psychiatric conditions are not infrequent, but their relationship to IST is uncertain.

Initial Evaluation

IST is an ill-defined clinical syndrome with diverse clinical manifestations. There is no gold standard to make a definitive diagnosis of IST, and the diagnosis remains a clinical one, after exclusion of other causes of symptomatic tachycardia. Clinical examination and routine investigations allow the elimination of secondary causes for the tachycardia but are generally not helpful in establishing the diagnosis of IST.

A thorough history and physical examination is essential to exclude specific physiological, psychological, and pathological causes of appropriate sinus tachycardia ( Box 16.1 ). Blood pressure and heart rate need to be taken in the supine, sitting, immediate standing, and at 2- and 5-minute intervals. Depending on the clinical context, additional work-up can include echocardiography, complete blood count, thyroid function tests, fasting blood sugar, urinary metanephrines, or 24-hour urinary sodium excretion. Evaluation for occult drug abuse (urine and blood drug screening) and psychiatric conditions also need to be considered.

The syndrome of IST is characterized by the following: (1) a relative or absolute increase in sinus rate out of proportion to the physiological demand (a daytime resting sinus rate of more than 100 beats/min, with a mean heart rate more than 90 to 95 beats/min on 24-hour Holter monitor, or an exaggerated heart rate response to minimal physical or emotional stress); (2) P wave axis and morphology during tachycardia that are similar to those noted during normal sinus rhythm; (3) lack of secondary causes of sinus tachycardia; and (4) markedly distressing symptoms of palpitations, fatigue, dyspnea, and anxiety during tachycardia, with an absence of symptoms during normal sinus rates ( Box 16.2 ).

Holter Monitoring

Ambulatory Holter recordings characteristically demonstrate a mean heart rate of more than 90 to 95 beats/min ( Fig. 16.1 ). However, some patients have either a physiological or normal sinus rate at rest (less than 85 beats/min) with an inappropriate tachycardia response to a minimal physiological challenge or a moderately elevated resting heart rate (more than 85 beats/min) with an accentuated (inappropriate) heart rate response to minimal exertion. Importantly, this quantitative definition of ‘inappropriate’ is arbitrary, and validation of the reproducibility of the heart rate and activity correlation can be challenging.

A 24-Hour Trend of the Long-Term Electrocardiogram Showing Inappropriate Sinus Tachycardia Throughout Usual Activity and on Awakening.

Differential Diagnosis

Postural Orthostatic Tachycardia Syndrome

Postural orthostatic tachycardia syndrome (POTS) is a multisystem disorder of the autonomic nervous system, associated with an abnormal response to standing. POTS is characterized by the presence of symptoms of orthostatic intolerance (i.e., the provocation of symptoms on standing that are relieved by recumbence) associated with an exaggerated heart rate increase (30 beats/min or more, or an absolute sinus rate exceeding 120 beats/min) when moving from a recumbent to a standing position held for more than 30 seconds in the absence of orthostatic hypotension (defined as greater than 20 mm Hg drop in systolic blood pressure). For teenagers (12 to 19 years), the required rate increment is at least 40 beats/min).

POTS typically manifests with symptoms of cerebral hypoperfusion (e.g., lightheadedness, presyncope, visual disturbances, cognitive impairment, mental clouding) and excessive sympathetic hyperactivity (e.g., palpitations, chest pain, anxiety, tremulousness), which can cause substantial functional disability. Only a minority of patients with POTS report frank syncope. Importantly, chronic debilitating conditions (e.g., prolonged bed rest), the use of medications known to diminish vascular or autonomic tone, and disorders that might cause tachycardia (e.g., dehydration, anemia) need to be excluded before the diagnosis of POTS is made.

The pathophysiological mechanisms of orthostatic intolerance in POTS are heterogeneous and include impaired regulation of peripheral vascular resistance, hyperadrenergic responses, chronic hypovolemia, and deconditioning. Patients with POTS often have high levels of upright plasma norepinephrine, and many patients have a low blood volume.

POTS has been classified into several subtypes, including neuropathic and hyperadrenergic POTS. “Neuropathic POTS” is likely caused by primary partial dysautonomia (likely related to an autoimmune process) or peripheral autonomic denervation secondary to other diseases (e.g., diabetes, multiple sclerosis, amyloidosis, sarcoidosis, systemic lupus, alcohol, chemotherapy). In this form, peripheral vasoconstriction in response to orthostatic stress is impaired due to peripheral autonomic neuropathy, resulting in excessive peripheral venous pooling in the lower extremities and mesenteric vasculature and a state of “functional” hypovolemia (i.e., low central blood volume) and cerebral hypoperfusion. This, in turn, triggers a sympathetic reflex causing a compensatory increase in both heart rate and myocardial contractility. “Hyperadrenergic POTS” is associated with excessive sympathetic discharge, which can be primary (e.g., norepinephrine reuptake transporter deficiency secondary to genetic mutations), or secondary (precipitated by hypovolemia or drugs). Most patient with hyperadrenergic POTS display exaggerated response to isoproterenol infusion and extremely high plasma levels of norepinephrine (greater than 600 ng/mL) during upright posture.

IST shares several characteristics with POTS. Both IST and POTS appear to have abnormal autonomic modulation, associated with exaggerated sinus rate response to orthostatic stress and a multitude of cardiac and noncardiac symptoms that can be debilitating. In addition, both syndromes occur predominantly in young women. Nonetheless, important differences exist between the two conditions ( Table 16.1 ), and the distinction between IST and POTS is important since IST treatments (including catheter ablation of the sinus node) rarely improve, and can even worsen, symptoms in patients with POTS. On the other hand, treatments for POTS can be useless for IST. If orthostatic vital signs are normal and the clinical suspicion of POTS is high, a tilt-table test might be helpful because it can provide vital signs over more prolonged periods than a simple stand test.

TABLE 16.1

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