Inappropriate sinus tachycardia

Anatomy and physiology of the sinus node

The sinus node is a crescent-shaped, subepicardial specialized muscular structure located posterolaterally in the right atrial (RA) free wall. The sinus node lies within the epicardial groove of the sulcus terminalis, at the junction of the anterior trabeculated RA appendage with the posterior smooth-walled venous component. The endocardial aspect of the sulcus terminalis is marked by the crista terminalis. The sinus node is a tadpole-shaped structure with a head, central body, and tail. The head extends toward the interatrial groove, and the tail extends toward the orifice of the inferior vena cava (IVC). While the head and proximal body portion of the node usually are located subepicardially beneath the fatty tissues at the junction of the superior vena cava (SVC) and the RA appendage, the remaining nodal body and tail portions penetrate inferiorly and obliquely into the musculature of the crista terminalis to end subendocardially almost to the 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-RA junction (see Fig. 9.1 ).

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, disordered 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 cycle length prolongation than in control subjects (with and without autonomic blockade). Other potential mechanisms for IST include beta-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. 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 the formation of channels that carry the funny current [I _f ]) 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).

An initial event may trigger IST, such as a viral infection or toxin exposure. In a recent report, pregnancy was identified as an instigating factor in approximately 8% of patients with IST. While pregnancy is known to be associated with increased sympathetic activity and activation of the renin-angiotensin-aldosterone system, whether dysregulation of these compensatory mechanisms of pregnancy is involved with the development of IST is unclear.

Epidemiology and natural history

The vast majority (>90%) of patients afflicted with IST are young women (mean age, 33 ± 11 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 has been estimated at up to 1.2%.

IST patients often have below-average exercise capacity, and the majority are overweight. Psychiatric disorders, including depression and anxiety, are the most common comorbid conditions, reported in nearly one-quarter of IST patients.

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 they 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 that is made after the 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 ( Table 20.1 ). 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 workup 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 of 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 ( Table 20.2 ). Physical examination is generally normal except that some patients have an unusually dynamic circulation (bounding pulses even at rest).

Holter monitoring

Ambulatory Holter recordings characteristically demonstrate a mean heart rate of more than 90 to 95 beats/min ( Fig. 20.1 ). 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 (>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.