Review Article

Carotid Sinus Syndrome Vaibhav Amin, MD* and Behzad B. Pavri, MD*†

Abstract: Carotid sinus hypersensitivity, first described less than 65 years ago, is an important and often undiagnosed cause of syncope in the elderly. Its pathophysiology is complex and certain aspects are not completely understood. The timely diagnosis and treatment of this condition can improve morbidity and prevent complications in the elderly. In this article, the prevalence, risk factors, pathophysiology, diagnosis, aspects of carotid sinus massage, and treatment options for the different kinds of carotid sinus hypersensitivity are discussed. Key Words: carotid sinus syndrome, syncope, unexplained falls (Cardiology in Review 2015;23: 130–134)

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arry1 first described pulse rate slowing from carotid artery pressure in 1799. In 1866, Czermak reported that manual pressure of the carotid artery at the upper margin of the sternocleidomastoid muscle provoked bradycardia and hypotension,2 falsely concluding that direct manipulation of the adjoining vagus nerve was responsible. It was not until 1927, when Hering3 demonstrated cardiac slowing with gentle manipulation of the carotid sinus alone, and not of the vagus nerve, in anesthetized dogs, was Czermak’s theory revised. In the early 1900s, clinical cases of syncope in clergymen with tight neck collars began being reported.4 The term “hypersensitivity” was first used by Roskam5 to describe a prolonged period of asystole associated with loss of consciousness during carotid sinus pressure. In the 1930s, Weiss and Baker6 made the first distinction between those with syncope in daily life and those without, despite both having a positive response to carotid sinus pressure. In 1946, Nathanson7 was the first to emphasize the distinction between carotid sinus hypersensitivity (CSH), a positive response to carotid sinus massage (CSM) in asymptomatic patients, and carotid sinus syndrome (CSS), which was syncope triggered by typical maneuvers in daily life such as shaving.

DEFINITION CSH is defined as a decrease in heart rate and/or blood pressure in response to CSM. Specifically, cardioinhibitory CSH (CICSH) is defined by a ≥3-second pause during CSM. Vasodepressor CSH (VD-CSH) is defined by a drop in blood pressure of at least 50 mm Hg in the absence of significant bradycardia. Finally, the presence of a ≥3-second pause with a decrease in systolic blood pressure of at least 50 mm Hg is termed mixed CSH.8

EPIDEMIOLOGY The reported prevalence of CSH in the literature has been variable. The prevalence of CSH is exceedingly low below age 50 From the *Department of Medicine and †Division of Cardiology, Thomas Jefferson University Hospital, Philadelphia, PA. Disclosure: The authors declare no conflict of interest. The authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation. Correspondence: Vaibhav Amin, MD, 221 South 12th Street, Suite 711 South, Philadelphia, PA 19107. E-mail: [email protected]. Copyright © 2014 Lippincott Williams & Wilkins ISSN: 1061-5377/14/2303-130 DOI: 10.1097/CRD.0000000000000041

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and increases exponentially with increasing age: 2.4% in the 6th decade of life, 9.1% in the 7th decade, 20.7% in 8th decade, and 40.4% in those elder than 80.9 In syncopal patients over the age of 60, an abnormal response to CSM was seen in 22.3% with similar proportions of VD or CI responses.10 However, others have reported a greater percentage of CI-CSH as compared with VD-CSH (39% vs 10%).11 Consistently, CSH is more prevalent in men, with a rate approximately 4 times higher than in women. Thus, the prevalence of CSH in patients with unexplained syncope ranges widely and is likely dependent upon a number of factors, including patient characteristics (age and gender), technique of CSM (5 vs 10 seconds of CSM, supine vs. upright patient positioning, etc.), and definition of a positive result. In asymptomatic, healthy older (>75 years) individuals, the prevalence of an abnormal response to CSM has been reported to be 4.2–35%,12,13 and a smaller proportion may even experience symptoms during the resulting pause. However, it is not clear if clinically asymptomatic individuals who have symptoms produced with CSM should have any intervention performed.

PHYSIOLOGY The carotid sinus is a baroreceptor that responds to stretching of the arterial wall such as provoked by an increase in intra-arterial pressure. This stretch stimulates the baroreceptors leading to increased vagal and decreased sympathetic activity.14 Conversely, a decrease in arterial blood pressure leads to decreased stretch of the arterial wall, decreased baroreceptor firing, and vagal withdrawal.15 The afferent limb of this baroreceptor reflex sends impulses from the carotid sinus via the glossopharyngeal and vagus nerves to the brainstem. These nerves terminate within the nucleus tractus solitarius (NTS), located within the medulla oblongata. The NTS divides into a rostral gustatory nucleus and a caudal region of neurons. Many cardiovascular neurons are positioned within the caudal region, near the midline of the nucleus.16 The efferent limb of the reflex is carried via the sympathetic and parasympathetic (vagus) nerves to the heart and blood vessels, controlling heart rate and vasomotor tone. It is the vagal input to the heart that is likely responsible for CI-CSH. However, VD-CSH is believed to be from rapid withdrawal of sympathetic input to blood vessels.17 Phasic resetting of baroreceptors occurs as the level of blood pressure fluctuates within moments of a change in pressure, such as with change in posture. Chronic (tonic) resetting takes place over weeks or months, and results in a decrease in the sensitivity of the reflex,18 such as with chronic recumbency or in wheelchair-dependent quadriplegics.19

PATHOPHYSIOLOGY Although the physiology of the normal carotid baroreflex is reasonably well established, the pathophysiology of CSH remains relatively obscure. The following pathophysiologic mechanisms have been considered:

Atherosclerotic Noncompliance Advanced aging and atherosclerotic vascular changes (as seen in coronary artery disease, hypertension, stroke, transient ischemic attack, or abdominal aortic aneurysm) are associated with Cardiology in Review  •  Volume 23, Number 3, May/June 2015

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CSH.20 Atherosclerosis diminishes carotid sinus vessel wall compliance, resulting in a reduction in afferent baroreflex impulse traffic, with compensatory brainstem postsynaptic alpha-2 adrenoreceptor upregulation (central “gain”). Vigorous carotid sinus stimulation could then drive an overshoot efferent response resulting in profound hypotension and bradycardia.21 However, the afferent limb of the carotid sinus reflex was shown to be intact in CSH, with a pattern of vasopressin arginine release unchanged from the control group.22 In addition, there was no attenuation of the carotid baroreflex with the administration of yohimbine in 18 patients with CSH, refuting the atherosclerotic hypothesis.23

Sternocleidomastoid Proprioceptive Denervation Another theory suggests a role of peripheral denervation of the sternocleidomastoid muscle, which can be demonstrated by electromyography.24 In health, head turning results in signals from both the sternocleidomastoid muscle and the carotid sinus being relayed to the NTS, and they are correctly integrated by the brainstem centers (gating theory). With aging, sternocleidomastoid denervation occurs, and the NTS receives incomplete minute-tominute proprioceptive information from the sternocleidomastoid; the baroreceptors of the carotid sinus, however, continue to provide signals to the NTS. Thus, unpredictably, head turning may result in afferent signals from the carotid sinus only, interpreted by the NTS as an abrupt increase in blood pressure, resulting in an inappropriate and dramatic decrease in heart rate and/or systolic blood pressure.25

Generalized Autonomic Dysfunction/Conduction System Disease Recent data on heart rate variability and baroreflex sensitivity suggest higher resting sympathetic activity and increased baroreceptor sensitivity in CSH in both symptomatic and asymptomatic subjects. It has been suggested that this finding of sympathetic upregulation may be indicative of a generalized autonomic disorder.26 Some data show that CSH is common in patients with dementia with Lewy bodies, and correlates with deep white matter lesions.27 The complete failure of subsidiary escape pacemakers during CSH is also cited as additional proof of widespread conduction system disease.

CLINICAL PRESENTATION Most commonly, CSH is associated with either syncope, near syncope, or dizziness associated with typical provocation maneuvers such as head turning, shaving, or wearing tight neck collars.4 Typically, the loss of consciousness is sudden, and recovery is spontaneous. Owing to the sudden onset, significant injuries from falls often occur. Elderly patients with CSH may deny syncope but present with recurrent unexplained “falls”.28 The astute clinician will remember that loss of proprioceptive input with aging also affects joints and muscles of the lower extremity, and elderly patients typically use visual cues (by looking down) when negotiating stairs or unfamiliar terrain; this unconscious head flexion may be enough to result in activation of the reflex, but the patient may not report “head turning” before syncope/fall. Poor recall or retrograde amnesia in the elderly can further obfuscate falling versus fainting.29 About one-third of patients elder than 50 with unexplained or recurrent falls will have a positive response to CSM.30 There are numerous case reports of hypotension and/or bradycardia provoked by head and neck positioning during head and neck or shoulder surgery.31,32 Carotid denervation via irradiation or surgery (either direct denervation or due to carotid endarterectomy) has been shown to be a treatment modality for CSH.33,34 Thus, CSH © 2014 Lippincott Williams & Wilkins

Carotid Sinus Syndrome

should not be considered as an etiology of fainting in patients with a history of bilateral carotid endarterectomy.

DIAGNOSIS CSH is diagnosed when CSM elicits a ≥3-second asystole (CI type), a fall in systolic blood pressure ≥50 mm Hg (VD type), or both (mixed). The diagnosis of CSS requires the reproduction of symptoms during 10 seconds of sequential right and left CSM performed supine and erect, under continuous monitoring of heart rate and periodic measurements of blood pressure.35 However, in clinical practice, a far shorter duration (3–5 seconds) of carotid pressure (not true massage) is usually sufficient to elicit a positive response, as discussed below. The heart rate and blood pressure diagnostic criteria for CSH have been questioned.36 It has been observed that for symptoms to occur in CI-CSH, a sinus pause much longer than 3 seconds is usually required; in fact, the average pause required to elicit symptoms was 7.9 seconds in the supine position and 5.5 seconds in the upright position.37,38 In addition, spontaneous episodes of asystole lasting more than 6 seconds caused symptoms of presyncope or syncope in 40% of elderly patients with recurrent syncope; shorter asystolic episodes (3 seconds) were symptomatic in less than 1%.39 Accordingly, it has been proposed that the length of the CI response be extended from 3 to 6 seconds for the diagnosis of CI-CSH.36 Similarly, the first symptoms of retinal and cerebral hypoperfusion occur in the upright posture when systolic pressure drops below 80 mm Hg, and the current working definition (a drop in systolic blood pressure of 50 mm Hg) may be insensitive.40 In a large unselected community sample of elderly subjects, the 95% cutoff for a fall in systolic blood pressure during CSM was 75 mm Hg.41 Accordingly, it has been proposed that a fall of greater than 75 mm Hg and/or an absolute drop in systolic pressure to more than 80 mm Hg should be considered for the diagnosis of VD-CSH.

CAROTID SINUS MASSAGE The technique for performing CSM has evolved significantly over time. It has long been appreciated that manual massage of the carotid sinus is crude and subjective. There is variability in the location of the carotid sinus, and in the duration, force, direction, and modality of the applied pressure (static vs phasic). In the 1930s, digital pressure applied to the carotid sinus for 10–20 seconds in the supine position was the described method42; subsequently, the importance of CSM during the upright position was described.6 In the 1960s, it was appreciated that pressure should not be applied for more than 5–10 seconds to elicit symptoms.43 A formal method of stimulation was described: pressure for 10–30 seconds, but no more than 40 seconds, to be terminated if asystole of 2–3 seconds is induced.4 In 1969, it was suggested that CSM start with light pressure for 20 seconds, and if no response, changing to longitudinal pressure for 15 seconds. The pressure was also distinguished as phasic rubbing with thumb or index finger and middle finger over the carotid sinus insufficient to occlude ipsilateral temporal artery pulse.44 By the 1980s, the general consensus was that external stimulation of the carotid sinus should be by longitudinal massage; the force applied should not occlude the carotid artery, and the duration should not exceed 5 seconds.45 The European Society of Cardiology guidelines detail the currently accepted protocols for CSM.46 The procedure should be performed in both the supine and upright positions with continuous electrocardiography and blood pressure monitoring. Following baseline measurements, carotid massage is performed for 5–10 seconds at the anterior margin of the sternocleidomastoid muscle at the level of the cricoid cartilage. If a positive result is not obtained, the procedure is then repeated on the opposite side after an interval of 1–2 www.cardiologyinreview.com | 131

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minutes. The duration of 5–10 seconds is based on the observed time course of vagal and sympathetic effects. Vagal activation results in almost immediate bradycardia/asystole, which precipitates a fall in cardiac output. Although sympathetic withdrawal starts early along with the fall in heart rate, the nadir in peripheral resistance is only reached after about 10 seconds. This delay in time to a maximal sympathetically-mediated vasodilation can be explained by the relatively slow neural inactivation of vascular smooth muscle by unmyelinated fibers.47 A third of patients will experience symptoms only in the upright position,48 stressing the need to repeat CSM while upright. CSM can be performed safely in the upright position either sitting in a chair or on a tilt table.49 In clinical practice, it is the CI response that is usually assessed with electrocardiographic monitoring, and drives therapy decisions; blood pressure assessment is infrequent. However, if a CI response is elicited, upright CSM may be repeated after atropine administration to identify any underlying vasodepression; this may be clinically relevant, as pacemaker therapy is less effective in the mixed form as opposed to the pure CI type.50 It should be noted that CSM performed in young patients with supraventricular tachycardia to achieve tachycardia termination is safely performed more vigorously.

maneuvers/clothing should be minimized or avoided. Implantation of a permanent pacemaker is the treatment of choice for the CI-CSH and M-CSH, but is ineffective in the pure VD-CSH.

Complications of Carotid Artery Massage Complications of CSM are rare and are mainly neurologic. CSM (5 seconds on left and right in supine and upright positions) was reported in 1000 consecutive patients who presented for syncope or unexplained falls.51 Contraindications to CSM were the presence of a carotid bruit, recent history of stroke or myocardial infarction, or previous ventricular tachyarrhythmia. Nine had neurologic complications, 8 of which resolved within 24 hours; 1 patient had persistent mild right hand weakness. In another study, CSM was performed in 500 patients being evaluated for dizziness, syncope, or unexplained falls. Two patients had neurological complications, 1 pyramidal, and 1 visual field defect.52 Yet another study of CSM in 502 patients in supine and upright positions reported 2 complications such as transient left arm weakness and left homonymous hemianopsia that resolved in 7 days.53 Exclusion criteria were patients with dementia, pacemakers, carotid bruit, and a history of stroke or acute myocardial infarction in the last 3 months. In summary, when aforementioned contraindications are heeded, neurologic complications related to CSM are rare and persistent deficits even rarer, with a rate of 1 case in 1000 patients. Cardiovascular complications are confined to rare case reports.54

TREATMENT Given the natural history of CSH and the propensity for injury,55 a strong case can be made for treatment of patients with frequent and severe symptoms. The decision to implant a pacemaker after a single episode of syncope is, in part, dependent on the consequences of syncope and the severity of injury. However, treatment does not seem to alter mortality.56 If there are obvious causative factors such as vigorous head turning or tight shirt collars, such

Treatment of VD-CSH There are scant data to guide the treatment of VD-CSH, in part because it is infrequently assessed, and no established therapy for this variant exists. The treatment of VD-CSH with pharmacologic agents has generally proven to be unsuccessful. Various pharmacologic agents were tested in patients who developed a VD response after pacemaker implantation for initial CI-CSH57; atropine and propranolol did not diminish the VD response, whereas norepinephrine and ephedrine both attenuated the VD response. The adverse effects of such adrenergic drugs in older patients with comorbidities render them difficult to use. A small (n = 10), prospective, double-blind, randomized crossover study comparing placebo to midodrine for VD-CSH showed that 8 of 10 patients remained symptomatic with CSM on placebo, compared with only 1 on midodrine;58 the mean drop in systolic blood pressure after CSM was smaller and the mean 24-hour ambulatory blood pressure was higher on midodrine. A nonrandomized, uncontrolled study of fludrocortisone in 11 patients with VD-CSH showed a significantly smaller drop in blood pressure and less syncope and presyncope after treatment with fludrocortisone compared with baseline.59

Treatment of CI-CSH The first report of cardiac pacing for CI-CSH was in 197060; a single-chamber (VVI) pacemaker was implanted in an 81-year-old patient with recurrent syncope due to CI-CSH. This report demonstrated that ventricular slowing during CSM was interrupted by pacing with prevention of symptoms. Subsequently, multiple observational series without control arms were published between 1973 and 1982 that demonstrated the ability of demand dual chamber pacing in treating CI-CSH.61,62 Multiple randomized trials of pacing versus no pacing for CICSH have since been reported with varying results, and are summarized in the Table 1.55,63–66 Single-chamber atrial-based (AAI) pacing is not recommended for CSH due to the high rate of atrioventricular block in these patients,67 and the optimal pacing mode is dualchamber pacing. In an acute intrapatient study,68 VVI pacing caused a significant deterioration [greater fall in systolic blood pressure (59 vs 37 mm Hg) and a higher rate of symptom persistence (91% vs 27%)] compared with DVI pacing. In a 2-month randomized crossover study of DVI versus VVI mode in 23 patients affected by mixed CSH,69 syncope occurred in 0 versus 13%, presyncope in 48 versus 74%. In a study of 202 patients, syncope recurred in 9% of DDDpaced versus 18% of VVI-paced patients.70 Finally, carotid sinus denervation has been evaluated as a treatment option for CSH. Surgical carotid sinus denervation was studied in 19 patients with CSH, 5 of whom also underwent carotid endarterectomy. Complete relief of symptoms or marked improvement was noted in all but 1 patient at a follow-up of 5 years.71

TABLE 1.  Randomized Trials of Pacing in Cardioinhibitory Carotid Sinus Hypersensitivity

Study Brignole et al. Blanc et al63 Claesson et al64 Parry et al65 Ryan et al66

55

No. of Patients in Paced Group

No. of Patients in Nonpaced Group

End Point/Symptom Recurrence Rate in Paced Group

Endpoint/Symptom Recurrence Rate in Nonpaced Group

Falls in Paced Group

Falls in Nonpaced Group

Pacing Mode

Blind

32 21 30 25 71

28 33 30 25 70

3 1 3 — —

16 10 12 — —

— — — 12 44

— — — 13 33

VVI VVI DDD DDD DDD

No No No Yes Yes

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In summary, permanent pacing has become a common clinical practice for CI-CSH. Small observational studies and randomizedcontrolled trials have shown an improvement of symptoms in patients with syncope or presyncope and evidence of CI-CSH during CSM. However, blinded studies of DDD versus ODO pacing have failed to show significant improvement in patients with unexplained falls and CI-CSH treated with pacing. As stated earlier, carotid sinus denervation via irradiation or during carotid endarterectomy has been identified as a treatment modality for CSH.33,34 Neither method has been rigorously studied in a clinical trial and has the potential for complications. The 2 largest surgical case series reported include 19 and 8 patients, followed for 15 years and 30 months, respectively.34,72 The procedure resulted in abolishment of syncope in all but 3 patients. However, this form of treatment is not practiced.

PROGNOSIS The natural history of CSH is not well established. A metaanalysis performed of 3 studies in which patients treated with CICSH were followed for a period of up to 3.3 years showed recurrent syncope in 9% treated with implantable pacemakers, compared with 38% in untreated patients.63,64,68 In a registry of 169 consecutive CSH patients treated with permanent pacemakers, 7% had recurrent symptoms at 1 year, 16% at 3 years, and 20% at 5 years.73 One prospective randomized study of 60 patients with CSH compared permanent pacing to no pacing; they reported symptom recurrence in 9% of paced versus 57% of nonpaced patients.46 Some patients with a CI-CSH pattern treated with pacing may demonstrate a VD-CSH response during follow-up, explaining symptom recurrence.74 There are no mortality differences between patients with CSH and age-matched controls56; however, the traumatic consequences of abrupt syncope in the elderly cannot be underestimated. In general, a patient with CI-CSH may be informed that without pacemaker implantation, the likelihood of recurrent syncope is high (about 35–55%), and that implantation of a pacemaker will reduce the chances of recurrent syncope to greater than 10%, even though presyncope and minor symptoms may persist.

SUMMARY CSH and CSS are increasingly encountered with aging, and account for a large proportion of syncope and falls in the elderly. The underlying pathophysiology is not fully elucidated. When the history is classic (syncope with head turning), diagnosis and management are straightforward. However, elderly patients with unexplained “falls” should be screened for CSH, and if the CI form is uncovered, serious consideration should be given to DDD pacing. Without pacing, a substantial proportion of patients will continue to experience recurrent syncope. REFERENCES 1. Parry C. An Inquiry into the Symptoms and Causes of the Syncope Anginosa Commonly Called Angina Pectoris. London, UK: Bath; 1799. 2. Krediet CT, Parry SW, Jardine DL, et al. The history of diagnosing carotid sinus hypersensitivity: why are the current criteria too sensitive? Europace. 2011;13:14–22. 3. Hering H. Die Karotissinusreflexe auf Herz and Gefa¨ sse vom Normalphysiologischen, pathologisch-physiologischen und klinischen standpunkt. Dresden, Germany: Steinkopff; 1927. 4. Franke H. On the hyperactive carotid sinus syndrome. Acta Neuroveg. 1963; 25:187–203. 5. Roskam J. Un syndrome nouveau. Syncopes cardiaques graves et syncope’s repetees par hyperreflexicite sinocarotidienne. Presse Med 1930;38:590–591. 6. Weiss S, Baker JP. The carotid sinus reflex in health and disease: its role in the causation of fainting and convulsions. Medicine. 1933;12:297–354.

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Cardiology in Review  •  Volume 23, Number 3, May/June 2015

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Carotid sinus syndrome.

Carotid sinus hypersensitivity, first described less than 65 years ago, is an important and often undiagnosed cause of syncope in the elderly. Its pat...
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