Evaluation of Syncope and Palpitations in Women

Abstract

Syncope and palpitations are common complaints that all physicians confront during daily clinical practice. Single center and multicenter cohort studies have found that syncope accounts for 1%–3% of emergency department evaluations and that palpitations are the primary symptom for approximately 16% of patients who arrive at an outpatient clinic with a cardiac complaint. For both conditions, women make up approximately 60% of the cohorts. In general, the evaluation of both syncope and palpitations can be challenging because of the heterogeneity of causes and, consequently, the variability of clinical outcomes, ranging from a single isolated event with no effect on morbidity and mortality to the first sign of a potentially life-threatening problem and sudden cardiac death. For all women with syncope or palpitations, the history, physical examination, and a baseline electrocardiogram (ECG) form the basis of the initial workup and focus on identifying patients with cardiovascular abnormalities who are at the highest risk for sudden cardiac death. More advanced tests must be chosen using a problem-specific approach, but generally, documentation of the cardiac rhythm during symptoms is critical for all patients with syncope or palpitations. Although the diagnostic testing strategy is generally similar for men and women, gender-related differences in treatment response have been identified. Antiarrhythmic medications, such as dofetilide and sotalol, that prolong the QT interval are more likely to be associated with proarrhythmia in women. In addition, higher complication rates for invasive cardiac procedures, such as device implantation, are observed in women.

Introduction

Syncope and palpitations are problems that are commonly encountered by all clinicians. Patients who have these complaints form a very heterogeneous group, with different etiologies that have very different prognoses. This diversity requires the clinician to take a patient-specific approach to evaluation of syncope and palpitations. The initial goal for evaluation of a patient with syncope or palpitations is to identify those patients who are at risk for sudden death.^1

–4 Once risk for sudden death has been assessed, management shifts to treatment of symptoms. Although there are several comprehensive reviews for the general management of patients with syncope or palpitations, this review focuses on specific issues unique to women (Table 1).

Table 1.

Important Gender Differences for Management of Syncope and Palpitations

Pathophysiology/epidemiology

Women have less orthostatic tolerance compared to men

Reduced sympathetic activity and increased parasympathetic activity

Lower center of gravity

More pelvic blood pooling

Reduced circulating red blood cells

Smaller, stiffer heart

Venous obstruction from the gravid uterus is a pregnancy-specific cause of syncope

Congenital long QT syndrome is more likely in women

Postural orthostatic tachycardia is more commonly observed in women

AV node reentry is the most common etiology for paroxysmal supraventricular tachycardia in women

Diagnosis

No differences in diagnostic strategy between men and women

Identify the presence of cardiac disease

Rhythm correlation with symptoms

Treatment

Different responses to pharmacologic therapy

Increased risk of proarrhythmia with antiarrhythmic medications in women

Possible increased risk of bleeding with anticoagulation in women

Higher complication rates with invasive cardiac procedures in women

Possible reduced benefit from ICD therapy in women

ICD, implantable cardioverter defibrillator.

Pathophysiology of Syncope

Syncope is one cause of transient loss of consciousness. Other reasons for transient loss of consciousness not associated with trauma are seizure and a miscellaneous group that includes alchohol intoxication and other drug/metabolic abnormalities, cataplexy, vertebrobasilar transient ischemic attacks (TIAs), pulmonary embolus, and aortic dissection. Syncope is defined as any disorder that leads to transient loss of consciousness due to cerebral hypoperfusion (Fig. 1). Syncope, in turn, has three common etiologic causes. First, in cardiac syncope, cerebral blood flow is decreased because of an arrhythmia (bradycardia or tachycardia) or obstruction (e.g., aortic stenosis). Second is neurocardiogenic syncope, the most common cause of syncope in all demographic groups, in which a trigger causes a sudden drop in systolic blood pressure that may be accompanied by a sudden decrease in heart rate. The mechanism for this change is complex, but at least in some cases, hyperdynamic left ventricular contraction leads to a reflex arc associated with vasodilation and increased vagal tone (this combination is often referred to as vasovagal syncope or the “common faint”). In addition to orthostatic stress, other triggers that have been described include cough, micturition, and defecation. The third general cause of syncope is orthostatic hypotension, which, unlike neurocardiogenic syncope, is associated with an immediate progressive decline in systolic blood pressure or an immediate increase in heart rate on standing. Orthostatic hypotension may occur as an isolated problem or in conjunction with other neurologic abnormalities.

FIG. 1.

Classification of mechanistic causes for transient loss of consciousness and syncope. TIA, transient ischemic attack.

Multiple studies have demonstrated reduced orthostatic tolerance in women compared to men, although the exact mechanism for this difference is not known. The difference becomes even more pronounced in the setting of hypovolemia.⁵ Sex hormones are an obvious possible explanation for the differences. In a study published over a decade ago, estrogen supplementation in perimenopausal women was found to reduce systolic and diastolic blood pressure by enhancing basal levels of the potent endogenous vasodilator, nitric oxide.⁶ In addition, during the midluteal phase, elevated estrogen levels were associated with increased baroreflex sensitivity.⁷ More recent research, however, suggests that fluctuations in progesterone and estrogen during the normal menstrual cycle do not affect arterial pressures or response to orthostatic stress with tilt table testing.⁸ Similarly, although sympathetic neural input plays an important role in maintaining blood pressure, studies have been mixed, with some suggesting that women have smaller increases in plasma norepinephrine in response to orthostatic challenge, whereas one study reported comparable sympathetic responses to upright tilt table testing in men and women.^9,10 An important difference between men and women is the lower systolic blood pressure in women because of reduced stroke volume. Some investigators have postulated that the smaller and stiffer ventricle in women may lead to a larger decrease in systolic blood pressure in response to orthostatic stress.¹¹ Another possible reason for reduced orthostatic tolerance is a lower center of gravity and more blood pooling in the pelvic region.¹² Large databases have found that females have lower numbers of circulating red blood cells per unit volume compared to matched males, which may contribute to orthostatic intolerance.¹³ Racial differences may also be present, with some preliminary data suggesting that young black women may have better orthostatic tolerance than young white women, with larger increases in norepinephrine and angiotensin II in response to lower negative body pressure.¹⁴ Regardless of the exact mechanism, reduced orthostatic tolerance in women may be associated with palpitations due to an increased heart rate response or syncope in some cases. In addition, orthostatic intolerance may lead to more frequent or severe symptoms in women, with neurocardiogenic syncope or orthostatic hypotension.

Pregnancy is associated with several characteristic changes in cardiovascular physiology. Cardiac output begins increasing in the first trimester and plateaus in the second trimester at approximately 40% more than normal, and at the same time, peripheral vascular resistance decreases throughout pregnancy. Decreased peripheral vascular resistance and decreased preload (caused by obstruction of the inferior vena cava from the gravid uterus) may increase the likelihood of syncope in pregnant patients.^15

–19 Several case reports have described pregnant patients with syncope in the sitting or supine position from obstruction of venous return from the gravid uterus associated with a direct decrease in stroke volume and hypotension or as a trigger for neurocardiogenic syncope and reflex bradycardia and vasodepressor response.^18,19 It is important to remember that transient loss of consciousness in pregnancy may also be due to a diverse collection of problems, such as pulmonary embolism, amniotic fluid embolism, and jugular venous thrombosis, that are not strictly classified as syncope.

Epidemiology

Syncope

Syncope is a common clinical problem, with an estimated incidence of a first self-reported syncope of 6.2/1000 person-years, a cumulative incidence of approximately 3%–6% over 10 years, and a lifetime prevalence of 20%–30%.⁴ The incidence of syncope appears to have a bimodal distribution, with an early peak during the teenage and young adulthood years and a later peak that starts at 50 years old and increases with age.^4,20
–22 Most data suggest that the early peak has a female predominance while the later peak appears independent of gender.^4,20
–22 In a cohort of 62 medical students, 42% of women reported a prior episode of syncope compared to 31% of men.²¹ In a large database registry of more than 300,000 patients admitted to hospitals in the United States over a 5-year period for syncope, women constituted almost 60% of the group and were more likely to have associated symptoms, such as migraine, gastroparesis, or chronic fatigue syndrome (CFS).²³ In another study that specifically evaluated 1051 patients with recurrent neurocardiogenic syncope, women had more frequent episodes over a longer period of time compared to men.

In a cohort study of 174 pregnant women, 4.6% reported a frank syncopal episode, and 28% reported dizziness and near syncope.¹⁷ In this small study, the presence of syncope and presyncope was not associated with other medical problems or increased risk of complications during pregnancy and delivery. There have been several case reports of pregnancies complicated by progressive atrioventricular (AV) block and syncope. In one study, 2 of 4 patients had resolution of complete heart block that developed during pregnancy and during the postpartum period and did not require permanent pacemaker implantation.^24,25 In addition, there is a case report describing a woman with Listeria bacteremia during the latter stages of pregnancy who had two episodes of syncope on the first postpartum day and several days later developed third degree AV block and required implantation of a permanent pacemaker.²⁵

Palpitations

Palpitation, or a sensation of an abnormal heart beat, is a common complaint, accounting for 16% of cardiac complaints from patients evaluated in outpatient clinics.^26,27 In most studies evaluating clinical outcome with palpitations, women make up 60%–70% of the cohorts.^26,27 Clinical studies have reported that approximately 20%–40% of patients who complain of palpitations will have a significant arrhythmia.²⁶ Pregnant women also may complain of palpitations, and one of the typical changes during pregnancy is an increase in heart rate because of sinus tachycardia during the third trimester (probably due to decreased preload and decreased afterload). In addition to sinus tachycardia, with 24-hour ambulatory electrocardiogram (ECG) monitoring in pregnant patients complaining of palpitations, approximately 60% will have isolated premature atrial contractions and 40% will have isolated ventricular contractions. It is important to remember, however, that premature atrial contractions and premature ventricular contractions are almost as common in pregnant women who are not complaining of palpitations.²³ In addition, arrhythmias are an extremely infrequent cause of hospitalization in pregnant women, accounting for <0.2% of admissions in a large retrospective single center study.¹⁹ Importantly, patients with palpitations due to arrhythmias that develop during pregnancy will often have complete resolution of arrhythmias by the sixth postpartum week. Of patients admitted for arrhythmia, paroxysmal supraventricular tachycardia was the most common abnormal rhythm identified. Paroxysmal supraventricular tachycardia was most commonly observed in the third trimester and resolved spontaneously or with standard medical therapy. Isolated atrial fibrillation in pregnant women, not associated with other cardiac disease, has been reported rarely in the literature.^25

–30 In these few patients, most had spontaneous resolution of atrial fibrillation and did not require drug therapy. In any patient who develops atrial fibrillation, pregnant or not, secondary causes of atrial fibrillation, such as hyperthyroidism and pulmonary embolism, should always be considered.

Initial Evaluation

Syncope or palpitations may be the first symptom of a patient at high risk for sudden cardiac death. An episode of syncope can be particularly worrisome as a possible sign of a significant arrhythmia associated with hemodynamic compromise. However, examination of large databases suggests that for patients with syncope, in-hospital mortality is very low (<1%), and subsequent mortality rates are also relatively low, both at 30 days (1%–2%) and at 1 year (7%–8%).^4,26,31 The reason for this difference in perception and outcome is in part due to the varying etiologies and subsequent prognoses for different causes of syncope. In the Framingham data, patients thought to have a cardiac cause of syncope had a 6-month mortality rate of 10%.⁴ In contrast, patients found to have a neurocardiogenic cause for syncope had a similar prognosis to those patients without syncope.⁴ Similarly, although palpitations may represent the first sign of a severe life-threatening arrhythmia, palpitations more commonly will be transient and are most commonly associated with a benign prognosis. In a cohort study of 193 patients with palpitations, approximately one third had complete resolution of their symptoms at 3-month follow-up, and no patient died or required emergent hospitalization. Given the heterogeneous outcomes, a patient-specific approach to diagnostic evaluation that focuses on identification of significant cardiac disease is required for both conditions.

Both the European Society of Cardiology (ESC) Guidelines and the American Heart Association/American College of Cardiology Foundation (AHA/ACCF) Scientific Statement emphasize the importance of a comprehensive history and physical examination for the initial evaluation of syncope (Fig. 2).^1,2 For patients with syncope or palpitations, the history and physical examination should first identify the most likely cause for the symptoms and, second, identify the presence of structural heart disease, which would increase the likelihood of a cardiac cause of syncope and associated worse prognosis. For patients with syncope, syncope with prolonged standing or other orthostatic stress suggests neurocardiogenic syncope or orthostatic hypotension. Conversely, symptoms that occur without changes in position make an arrhythmia (either bradycardia or tachycardia) more likely. For patients with palpitations, questions should focus on the specific description of the palpitations. For some patients palpitations, might be a “pounding and hard sensation” with a normal heart rate, “skips and pauses,” or sudden onset of a fast heart rate. It is very useful to have the patient tap out the rhythm with the fingers. Description of accompanying symptoms (chest pain, dizziness) associated with palpitations is helpful, along with possible triggers (exercise, stress). An accompanying complaint of polyuria, due to release of natriuretic peptides, is more commonly described in patients with supraventricular tachycardias, most commonly atrial fibrillation.³² For patients with syncope or palpitations, the past medical history should be directed toward identifying the presence of heart disease (e.g., prior myocardial infarction) that would increase the likelihood of a severe arrhythmia as the cause of symptoms. Similarly, the physical examination should be focused on identifying heart disease: murmurs, abnormal heart sounds, decreased cardiac upstroke, or increased jugular venous pressure. A comprehensive physical examination for the patient with syncope should include orthostatic blood pressure readings and, in older patients, a carotid sinus massage.

FIG. 2.

Framework for the diagnostic evaluation of a patient with syncope. It is important to remember that as emphasized by the text, an individual approach is required. For example, in the patient with first degree atrioventricular (AV) block and His Purkinje disease where there is a high clinical suspicion for bradycardia as the cause of syncope, electrophysiology (EPI) testing to evaluate AV conduction properties may be the most appropriate first test. Similarly, tilt table testing may be useful for evaluating the orthostatic response in a patient with high clinical suspicion for orthostatic hypotension. In general, however, the first decision point in the evaluation of syncope is to decide whether structural heart disease (prior myocardial infarction [MI] or coronary artery disease [CAD], reduced ventricular function or left ventricular hypertrophy, congenital heart disease, or valvular heart disease) is present. DX, diagnosis; ECG, electrocardiogram; EF, ejection fraction; EPS, electrophysiology study; ICD, implantable cardioverter defibrillator; Sx, symptoms.

The ECG is an important initial diagnostic test for patients with syncope or palpitations. Although a normal ECG does not completely rule out significant heart disease, it is extremely unlikely if the accompanying history and physical examination are also unremarkable. Nonspecific changes in the ST segment and T waves can be seen in 5%–15% of pregnancies. In addition, pregnancy is associated with very subtle leftward and rightward shifts in the frontal axis. However, abnormalities on the ECG, such as left bundle branch block, left ventricular hypertrophy, or abnormal Q waves, suggest the presence of heart disease in both pregnant and nonpregnant patients. The presence of sinus bradycardia, a prolonged PR interval, or bundle branch block on the ECG makes bradycardia a more likely cause of syncope. In women, it is important to evaluate the QT interval in patients with syncope and no apparent heart disease. Almost 70% of patients with congenital long QT syndrome are women.³³ Importantly, women with congenital long QT syndrome have an increased risk of ventricular arrhythmias in the postpartum period, perhaps in part because of the abrupt decline in estrogen and progesterone after delivery. In patients without the congenital long QT syndrome, the QT interval at birth is similar for boys and girls.³⁴ During puberty, however, the QT interval shortens in boys, and throughout adult life, women have longer QT intervals than men. Although there is no specific cutoff point for an abnormally long QT interval, for women any QT interval >480 msec is >2 standard deviations (SD) from the mean and is a worrisome finding, particularly with such associated symptoms as syncope or palpitations. Interestingly, in women with the long QT syndrome, cardiac events during pregnancy are infrequent, although syncope or palpitations due to ventricular arrhythmias are 5-fold more likely in the postpartum period. Although blood tests generally have a low yield in unselected patients with syncope, carefully selected blood tests based on clinical history may be useful. For example, a hemoglobin or hematocrit determination would be a reasonable test in an actively menstruating woman with symptoms suggestive of orthostatic hypotension, and a brain natriuretic peptide level test might be helpful in a patient with associated symptoms suggestive of heart failure.

Additional Diagnostic Testing

Additional directed tests can be useful in certain clinical situations. However, If the patient has a history consistent with vasovagal syncope and a low likelihood for cardiac disease based on the history, physical examination, and ECG, multiple studies have shown that extensive cardiovascular and neurologic testing should not be pursued.^1,2 Similarly, in patients with palpitations, if the initial evaluation does not suggest significant cardiac disease, reassurance without additional testing is often a reasonable first step. For patients for whom the diagnosis is unclear or if heart disease is suggested by the initial evaluation, additional diagnostic testing can be helpful to delineate structural cardiac abnormalities, obtain ECG correlation with symptoms, or provoke symptoms in a controlled setting.

The echocardiogram is often the best initial test for evaluating the patient in whom it is unclear if structural heart disease (valvular abnormalities, congenital heart abnormalities, wall motion abnormalities, ventricular dysfunction, or hypertrophy) is present or for evaluating the severity of abnormalities in patients with known cardiac problems. More advanced imaging techniques, such as magnetic resonance imaging (MRI) or computed tomography (CT), may be helpful in selected patients when more detailed information on cardiac anatomy and function is required.

In patients with syncope and palpitations, it is extremely helpful to assess the cardiac rhythm during symptoms. Depending on the frequency of symptoms, a 24–48-hour ambulatory ECG (Holter) monitor, an external event recorder that the patient uses for 3–4 weeks, or an implantable loop recorder can be used. For patients with daily or weekly symptoms, an external ECG monitor is usually sufficient for obtaining an ECG reading during symptoms. However, it is important for the clinician to remember that the patient will often complain of several types of palpitations, and the length of the ECG monitoring should be determined by the symptom complex that is the least frequent. The external leads required for these systems can be cumbersome if the patient has infrequent symptoms, and generally maximal yield of these devices is achieved after 2 weeks.

Because palpitations often occur daily or weekly, shorter ECG recording periods are typically required than for patients with syncope so that implantable loop recorders are usually not necessary. However, many patients with syncope have very infrequent symptoms, and for these patients, the implantable loop recorder has emerged as the best method for long-term evaluation of cardiac rhythm.^35
–37 Implantable loop recorders are small devices (1×4 cm) that are placed subcutaneously in the anterior left chest. Embedded electrodes at the surface of the device allow continuous ECG recording with a looping memory. The current generation of implantable loop recorders has a functional life span of >1 year. The clinician can program the device to automatically identify tachycardia or bradycardia, and the patient is given an activator the patient or a bystander can place over the device when the patient develops symptoms (Fig. 3). Several randomized trials have found that the implantable loop recorder is the most effective method for evaluating patients with syncope.^35,36 In a large cohort of almost 400 patients with syncope who received an implantable loop recorder, approximately 30% had a recurrent episode of syncope. In patients with recurrent syncope, 50% had specific treatment based on the results from the implantable loop recorder (usually placement of a permanent pacemaker for symptomatic bradycardia), which was associated with an absolute 30% reduction in recurrent syncope (a third episode).³⁵ It is critical to emphasize the importance of obtaining cardiac rhythm correlation with symptoms, perhaps even more so in women. A recently published case series presented 3 women labeled as having “psychogenic syncope” who underwent placement of an implantable loop recorder.³⁸ On follow-up, they were found to have significant bradycardia because of intermittent atrioventricular block; placement of permanent pacemakers eliminated symptoms in all 3 women.

FIG. 3.

Tracings obtained from an implantable loop recorder. Patient with chronic atrial fibrillation (notice the irregular QRS complexes) developed symptoms that correlated with a 12.5-sec period with only two QRS complexes because of transient worsening of atrioventricular conduction.

Several diagnostic tests are designed to monitor the response to stress. For example, tilt table testing is designed to evaluate a patient's hemodynamic response with standing for prolonged periods of time. In selected cases, tilt table testing is useful to define whether the patient has the propensity for neurocardiogenic syncope.^39
–41 Tilt table testing was first applied almost three decades ago for identification of patients with neurocardiogenic syncope. Although protocols vary, generally the patient is placed in a head-up position at an angle of 60–70 degrees for 20–45 minutes. The physiology of standing is complex, but standing leads to accumulation of 300–600 mL of fluid in the legs and a 25%–40% decrease in intravascular volume. Because of activation of several reflex arcs, the normal response to upright tilt table testing is a small increase in heart rate, with a relatively constant blood pressure (Fig. 4). In patients with neurocardiogenic syncope, after an initial stable period, the patient abruptly has a decrease in blood pressure followed by significant bradycardia. In all patient age groups thought to have neurocardiogenic syncope, a mixed response characterized by both hypotension and bradycardia is the most commonly observed finding. In younger patients, however, a bradycardia-only response is the second most common abnormal response, whereas a pure hypotensive or vasodepressor response is the second most common abnormal response in patients >70 years of age. Patients with orthostatic hypotension have an almost immediate gradual decrease in blood pressure until symptoms develop. Another abnormal response, the postural orthostatic tachycardia syndrome (POTS), can also be seen. In this case, it is believed that patients are able to maintain blood pressure on orthostatic stress but only by increasing the heart rate. The POTS is almost exclusively observed in women and is thought to represent a form of autonomic insufficiency. It can occur as syncope but usually is characterized by palpitations and a rapid heart rate. It is covered more extensively in the next section.

FIG. 4.

Tilt table hemodynamic responses in different conditions. Normally in tilt table testing with the upright position, normal baroceptor function maintains a relatively constant heart rate (HR) and systolic blood pressure (SBP). In the vasovagal response after a relatively long period of time, a drop in SBP rapidly followed by a drop in HR is observed. In the orthostatic response, with standing, an almost immediate but gradual drop in SBP is observed, and HR remains unchanged. In the postural orthostatic tachycardia syndrome (POTS), SBP is maintained by a significant increase in HR.

Treatment

Structural heart disease

When significant heart disease is present, a cardiac cause for syncope is more likely. In patients with reduced ejection fraction due to either prior myocardial infarction or nonischemic cardiomyopathy, ventricular arrhythmias may be the cause of syncope. The implantable cardioverter defibrillator (ICD) has become the main treatment option for protecting against sudden cardiac death. Several landmark trials have found that ICD therapy reduces mortality in patients with ejection fraction <30%–35% in the presence of heart failure symptoms regardless of whether or not they have syncope (Fig. 2).^42,43 Thus, many patients with severe cardiac disease are candidates for ICD implantation even in the absence of syncope or palpitations.

Recent data suggest that ICDs are less frequently used in women compared with white men with similar clinical characteristics.⁴⁴ In addition, it is important to note that the benefit of ICD therapy in women may not be equivalent to the benefit observed in men.^45,46 In a meta-analysis of five randomized primary prevention trials, no statistically significant decrease in mortality due to ICD implantation could be detected among women.⁴⁴ In addition, analysis of the national ICD Registry found that women were 70% more likely to have a major adverse event associated with ICD implantation (2.0% in women vs. 1.1% in men).⁴⁴ Although these data generate questions about potential bias and risk of ICD therapy in women, it is important to note that at this time, the decision for ICD therapy should be made independent of gender.

If the patient does not have severe enough structural heart disease to warrant implantation of an ICD, therapy is dependent on the rhythm that correlates with syncope or palpitations during ECG recording with either external ECG recording devices (24°–48° ECG or event recorders) or implantable loop recorders.

Bradycardia

The most common finding in most patient populations with syncope and mild or no structural heart disease is bradycardia caused by sinus node dysfunction or, less commonly, intermittent AV block. Regardless of cause, symptomatic bradycadia is usually treated with a permanent pacemaker. Several studies have demonstrated possible gender differences in permanent pacemaker implantation. Some but not all studies have found that women are more likely than men to receive single chamber pacemakers (which may not preserve AV synchrony), even after adjusting for demographic and clinical characteristics.^47,48 A recently published registry study of German patients receiving pacemakers found that women had higher periprocedural complication rates (women 4.9%–6.4% vs. men 3.7%–5.2%).⁴⁹ It is important to emphasize that permanent pacing generally should be recommended only in symptomatic bradycardia. Bradycardia is generally not found in patients complaining of palpitations.

Premature ventricular contractions/nonsustained ventricular tachycardia

Isolated premature ventricular contractions are present in 50% of people and are more commonly observed with age. The significance of ventricular arrhythmias generally depends on whether structural heart disease or a genetic cardiac abnormality (e.g., long QT syndrome) is present and the severity of symptoms associated with the arrhythmias.

In general, women are less likely to have premature ventricular contractions than men. For example, in the Atheroscerosis Risk in Communities (ARIC) study, in almost 16,000 patients ranging in age from 45 to 65 years old, premature ventricular contractions were observed in 5%–7% of women and in 7%–8% of men.⁵⁰ However, premature ventricular contractions are associated with a greater reduction in quality of life (QOL) indices in women compared to men. In women, premature ventricular contractions appear to be associated with changes in sex hormones, with the highest prevalence observed during the premenopausal period.⁵¹ The most common form of ventricular ectopy arises from the right ventricular outflow tract. Because the ectopy is arising in the superior portion of the right ventricles, the QRS complex of the premature ventricular contraction has a left bundle branch block morphology (as the right ventricle is depolarized than the left ventricle) and an inferior axis with positive QRS complexes in the inferior leads (II, III, and aVF). Generally, this form of ventricular ectopy will be suppressed with exercise and has a benign prognosis and often resolves spontaneously.

In the setting of a normal heart, reassurance is the first step. Pharmacologic therapy using beta-blockers and calcium channel blockers may be effective, and radiofrequency catheter ablation may be an important option for patients with persistent symptomatic ventricular arrhythmias.⁵² A small cohort study has reported a decrease in the frequency of premature ventricular contractions with estrogen therapy in postmenopusal women.⁵³

Paroxysmal supraventricular tachycardia

Paroxysmal supraventricular tachycardia due to reentry in the AV node region (AV node reentry [AVNRT]) is twice as common in women as in men.^54,55 Sex hormones appear to be important for triggering supraventricular tachycardia, with more episodes and symptoms during the luteal phase of the menstrual cycle.⁵⁵ During the luteal phase, higher levels of progesterone have a heterogeneous electrophysiologic effect on different regions of the AV node and increase the likelihood of a stable reentrant circuit developing within the region of the AV node. In addition to being more common, paroxysmal supraventricular tachycardia is associated with a greater reduction in QOL measures in women. In a retrospective study of 107 consecutive patients, criteria for panic disorder according to the DSM-IV criteria were fulfilled in 67% of patients.⁵⁶ When paroxysmal supraventricular tachycardia was unsuspected, 65% of women compared to 32% of men were given the presumptive diagnosis of a psychiatric cause for symptoms. Importantly, after radiofrequency catheter ablation, only 4% of patients continued to have symptoms that met criteria for a panic disorder.⁵⁶ Finally, adenosine is safe for the treatment of supraventricular tachycardia during pregnancy.

Sinus tachycardia

In some cases, palpitations are associated with sinus tachycardia on ECG monitoring. Evaluation of blood pressure during these events is helpful for providing clues to whether the sinus tachycardia is appropriate to maintain blood pressure vs. a heightened sensation of the heartbeat due to hypertension. It is important to evaluate the patient for problems that might be associated with sinus tachycardia, such as anemia, hyperthyroidism, and hypoxia. In some cases, patients may have a focal atrial tachycardia from a region near the sinus node or develop reentry within the sinus node (sinus node reentry) that can mimic sinus tachycardia. Abnormal atrial tachycardias are more likely to have more abrupt onset and offset and tend to be more intermittent than tachycardia caused by more rapid pacemaker activity from the sinus node itself. An example of an incessant atrial tachycardia in a 34-year-old woman who complained of palpitations and fatigue is shown in Figure 5. In the ECG, the P wave is inverted in leads aVL and I, suggesting that the atria are being activated from left to right rather than right to left as would be expected in sinus tachycardia. Careful mapping during an invasive electrophysiology study localized the focus to the junction between the left atrial appendage and left superior pulmonary vein. Radiofrequency catheter ablation eliminated the arrhythmia, with resolution of the patient's symptoms. Finally, it is important to remember that during pregnancy, the heart rate normally increases by 25%.¹⁸

FIG. 5.

ECGs from a patient complaining of chronic fatigue at baseline (top) and after radiofrequncy catheter ablation of an incessant left atrial tachycardia (bottom). Notice that the P waves are negative at baseline in leads I and aVL (arrows), suggesting abnormal left to right atrial activation, and are upright in the same leads (arrows) after ablation, indicating return to sinus rhythm and normal right to left atrial activation. Modified with kind permission from Springer Science and Business Media from ECG interpretation: From Pathophysiology to Clinical Application, 2009, Fred Kusumoto, chapter 11, Figure 4.

Historically, there have been scattered reports of patients complaining of extreme fatigue, palpitations and a rapid heart rate.^57

–61 Two poorly understood conditions associated with sinus tachycardia have been identified: inappropriate sinus tachycardia and POTS. Although often considered separately, these two conditions probably involve overlapping pathophysiologic mechanisms and have similar and often debilitating, symptoms, such as palpitations, extreme fatigue, dizziness, and syncope. Given the complexity of the autonomic nervous system and the physiology of standing, it is not surprising that emerging evidence has identified many different possible etiologies/types for both these syndromes.

The phrase, postural orthostatic tachycardia, was first used in the early 1980s to describe patients with palpitations and rapid heart rate on standing associated with a constellation of symptoms, including exercise intolerance and extreme fatigue.^57
–59 Given the complexity of POTS, it is difficult to assess a true prevalence, although one estimate is 170/100,000.^60
–62 The usual age of presentation is 30 years, and >80% of patients are women.⁵⁹ Symptoms often develop abruptly, and a viral illness precedes development of symptoms in approximately 50% of cases.^60
–62 Studies vary, but approximately 30%–50% of patients with POTS will have a prior episode of syncope, and all will complain of palpitations and an uncomfortably fast heart rate with minimal activity. Recent studies have identified several subsets of POTS that have different responses to tilt table testing, plasma norepinephrine levels, and the presence or absence of an abnormal sweating response. For example, the hyperadrenergic form of POTS is associated with prominent swings in blood pressure with standing and elevated plasma norepinephrine levels (>600 pg/mL). Treatment of POTS is complex and requires a multidisciplinary approach that incorporates a variety of therapies. First, expanding fluid volume with water and salt intake, mineralocortacoids such as fludrocortisones, and in some cases, expanding red cell mass with erythropoietin. Second, maintaining central blood pressure with abdominal binders, stockings, or vasoconstrictors. Third, reversing any secondary deconditioning with a carefully designed and sustainable exercise program. Finally, counseling and open discussion with family members for support and encouragement is critical. Ivadradine, a drug that can dramatically decrease the pacemaker activity of sinus node, was reported in a small study to be an effective treatment.⁶³ As our understanding of this complex condition improves, treatment options directed to the underlying pathophysiologic mechanism for an individual patient will be developed, although efforts at maintaining cerebral perfusion will probably remain the cornerstone of therapy for many patients.

Inappropriate sinus tachycardia occurs with similar symptoms to POTS, but rapid heart rate is the dominant finding on diagnostic testing. Women make up >80% of the reported cases of inappropriate sinus tachycardia in the literature. An immunologic disorder has been suggested as a possible cause for at least some patients, with one study demonstrating circulating anti-beta-receptor antibodies that increased cyclic adenosine monophosphate (cAMP) in over 50% of patients with inappropriate sinus tachycardia that were not present in healthy controls.⁶⁴ In many cases, inappropriate sinus tachycardia probably represents a more generalized autonomic abnormality and can be considered a form of POTS, but at least in some isolated cases, reducing the heart rate with medication or radiofrequency catheter ablation leads to significant improvement in symptoms. Unfortunately, there are no specific tests that can be used to reliably identify this small subset of patients who will benefit from rate slowing therapy, and even worse, rate slowing therapy may exacerbate symptoms in patients with POTS. Ivabradine may be a potential future treatment option for patients with inappropriate sinus tachycardia. In a small cohort of 16 patients, ivabradine decreased the mean heart rate from >100 bpm at initiation of therapy to 70 bpm after 6 months of therapy, with an improvement in exercise tolerance.⁶⁵ Ivabradine is available in Europe, but it is currently not available in the United States.

Atrial fibrillation

Atrial fibrillation is very common in older patients, with a progressive doubling of incidence with every decade.^66
–68 Although more commonly observed in men, women account for >60% of patients >75 years old with atrial fibrillation.^66,67 Women tend to be more symptomatic, in part because of faster heart rates and longer episodes. In the Canadian Trial of Atrial Fibrillation, women reported significant reduction in QOL compared to men, particularly in the role-physical and role-emotional categories of the short form (SF-36) domains.⁶⁹ Even more importantly, atrial fibrillation is associated with an increased annual risk of stroke (women 3.5% vs. men 1.6%) in the Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) study.⁷⁰ The prospective Copenhagen City Heart Study, which evaluated 29,310 patients followed for almost 5 years, found that atrial fibrillation was associated with a 2.5-fold increase in mortality in women compared to men (women 4.4 hazard ratio vs. men 2.2 hazard ratio).⁷¹

Response to therapy for atrial fibrillation also differs between men and women. Some but not all studies suggest that women may be at increased risk of bleeding associated with anticoagulation therapy.^70,72,73 In the Canadian Registry of Atrial Fibrillation (CARAF), women had a more than 3-fold increased risk of major bleeding with warfarin, although the Stroke Prevention in Atrial Fibrillation (SPAF) and ATRIA studies found no differences between men and women.^70,72,73 However, studies have consistently shown that women have a 2-fold increased risk of torsades de pointes with such antiarrhythmic drugs as dofetilide and sotalol that block potassium channels and lead to QT interval prolongation.^74,75 As women have longer QT intervals at baseline, it is not surprising that women are at higher risk with drugs that prolong the QT interval.

Pregnancy

There are several unique issues for treatment of arrhythmias and syncope during pregnancy. In particular, the risk/benefit ratio of antiarrhythmic drugs must be carefully evaluated. Although management strategies need to be individualized, several general recommendations can be made. First, the decision on whether to treat an arrhythmia depends on the frequency and severity of the symptoms. For example, a patient with normal heart and valvular function who has mild palpitations associated with frequent premature ventricular contractions probably does not require any specific treatment. Second, any drug should be started at the lowest amount possible and delayed until after the first trimester. Third, the majority of drugs have a class C recommendation for pregnancy. Class C drugs are designated as “unknown risk” because well-controlled human studies are not available, and animal studies have either shown deleterious effects or are not available. The only class B drugs are sotalol and lidocaine, but it is important to remember that although adenosine is considered class C, small cohort studies and postmarketing surveillance studies have suggested it is safe to use during pregnancy. Finally, the increased volume of distribution associated with pregnancy is at least part of the reason that antiarrhythmic treatment may become less effective during pregnancy.

Conclusions

Cardiac arrhythmias can be associated with either syncope or palpitations. Although there is a general perception that syncope and palpitations are much more frequent in women, large epidemiologic studies have found only a slight female preponderance. With both clinical presentations, the focus should be on determining if the patient has normal cardiac structure and function. In the presence of normal cardiac structure and function, the prognosis generally is excellent. However, unusual causes of symptoms, such as the long QT syndrome, are more commonly observed in women. Palpitations are a common complaint during pregnancy but are not usually severe enough to necessitate hospitalization. Treatment is dependent on the arrhythmia, so diagnostic evaluation focuses on identifying the specific cardiac rhythm associated with symptoms.

Footnotes

Disclosure Statement

The authors have no conflicts of interest to report.

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