Post-Exercise Syncope in a Previously Healthy 67-Year-Old Man: The Bezold–Jarisch Reflex and the Role of Autonomic Nervous System Dysfunction

Abstract

A 67-year-old man started treatment due to frequent asymptomatic premature ventricular complexes (PVCs) accidentally being registered during a preventive examination by a specialist, because of which he was referred to cardiologist. During the initial 24-hour (h) ECG monitoring, 4.5% PVCs and one episode of asymptomatic non-sustained ventricular tachycardia (NSVT) with three PVCs in row, at a frequency of 150 beats per minute (bpm), were detected. After the introduction of beta blockers into therapy, a lower number of PVCs, without NSVT, were recorded in the control 24 h Holter ECG, while transthoracic echocardiography (TTE) showed normal left ventricular (LV) systolic function without cardiomyopathy. So, an exercise test was indicated, and it was interrupted in the third minute at 120 beats per minute (bpm) due to fatigue and pain in the hips, without malignant arrhythmias, angina or dyspneic complaints. During the rest period, a significant inferolateral depression of the ST junction was observed, which recovered in the ninth minute. Immediately after the ECG monitoring stopped, the patient lost consciousness; his pulse was not palpable, but breathing was audible, so cardiac massage was started. After he had regained consciousness, the ECG showed alternating sinus and junctional rhythm with the lowest frequency of 33 bpm, which was accompanied by marked hypotension (80/50 mmHg). The patient was immediately hospitalized; coronary angiography and repeated TTE were completely normal, while continuous ECG monitoring did not confirm malignant rhythm disorders or asystole. It was concluded that it was vasovagal syncope (VVS), most likely caused by the Bezold–Jarisch reflex (BJR).

1. Introduction

Although syncope is a frequent medical problem and has a 40% lifetime prevalence [1], it appears very rarely during or post-exercise testing. According to the paper published in 2022 by Csecs I et al., the prevalence of post-exercise syncope is 0.020% per exercise test and 0.023% per individual patient [2]. The Bezold–Jarisch reflex (BJR), first described in the second half of the 19th century, is a subtype of VVS, characterized by bradycardia, hypotension and peripheral vasodilation caused by stimulation of the mechanoreceptors, located mainly in the inferoposterior wall of the left ventricle (LV), that activate unmyelinated C-type vagal afferent nerves, resulting in increased parasympathetic and decreased sympathetic activation [3,4,5,6]. To our knowledge, several cases of post-exercise syncope (either during treadmill or dobutamine stress tests) caused by the BJR have been published in the literature so far [7,8,9,10,11,12,13,14,15,16]. It is interesting that syncope being caused by this reflex after exercise occurs at any age and in both sexes. Although in most cases it is caused by asystole, which in one case lasted as long as 60 s [14], generally, it does not need to be treated with a permanent pacemaker. The BJR has also been described during myocardial ischemia, after reperfusion and rarely after nitroglycerin administration or during spinal anesthesia [17,18,19]. It is now known that, like other types of VVS, the BJR is also one of the manifestations of cardiac autonomic nervous system (CANS) dysfunction [20]. The previously mentioned afferent vagal nerves, which are responsible for clinical manifestation of the BJR, are components of the first level of cardiac autonomic control called the intrinsic cardiac nervous system (ICNS). The ICNS, located in the epicardial fat pads within the ganglion plexi (GPs), contains both cardiac parasympathetic and sympathetic afferent and efferent neurons, as well as local circuit neurons. The second level of the CANS is located within two extracardiac ganglia—the cervical and the stellate ganglia—while the third level involves central neuronal stations (medullary and spinal cord neurons modulated by higher centers) [21]. A multilevel CANS network is responsible for controlling chronotropic, lusitropic, dromotropic and inotropic cardiac function. Therefore, dysfunction, injury or disease at any level of the CANS can lead to cardiac dysfunction. Moreover, in recent years, evidence regarding a bidirectional relationship between cardiac pathology and ICNS dysfunction has accumulated, particularly in the field of myocardial ischemia and heart failure, as well as brady- and tachyarrhythmia [22]. It has been described in the literature that cardiac function can be acutely altered by reflex activation of the CANS in response to inputs from baro-, chemo-, nasopharyngeal and other receptors, as well as by central autonomic responses to stress, physical activity, arousal and sleep. It can also be chronically altered by slowly progressive autonomic failure due to neurodegenerative disorders such as Parkinson’s disease [23,24]. Recently, it was confirmed that the BJR in mice is caused by visceral sensory neurons (VSNs) expressing the Y2 neuropeptide Y receptor (NPY2R), which predominantly connects the wall of the cardiac ventricle to the area postrema. It has also been found that the neural pathway at the heart–brain interface is genetically defined [25]. We present the case of a 67-year old man with frequent asymptomatic but non-trivial PVCs in whom the BJR was stimulated post-exercise test, and it was presented alongside bradycardia and prolonged hypotension.

2. Case Report

A 67-year-old man started treatment in an outpatient cardiology clinic after arterial hypertension and frequent asymptomatic PVCs were accidentally discovered during a preventive examination by a specialist. He was in good health before then. Regarding his symptoms, he complained of occasional, non-specific pain in his left shoulder girdle, which would spread to the left arm and increase when he changed his body position, as well as frequent pain in his hips. He denied anginal complaints and dyspnea on exertion. His appetite was good, and he was not a smoker. His drug allergies were not known, and as for therapy, he occasionally took diazepam in stressful situations, which had occurred significantly more often in the last few months. His family history was negative for sudden cardiac death and early cardiovascular disease. Laboratory findings showed mild dyslipidemia (total cholesterol: 6.6 mmol/L; low-density lipoprotein cholesterol: 4.3 mmol/L; high-density lipoprotein cholesterol: 1.6 mmol/L; triglycerides: 1.6 mmol/L) and a slightly decreased estimated glomerular filtration rate (79 mL/min/1.73 m²), while his red blood count, blood glucose, liver enzymes, urea, creatinine, sodium and potassium were within the reference limits. He was in good condition, was moderately physically active every day and had a body mass index (BMI) of 24 kg/m², no specific skin features (such as Lupus pernio, erythema nodosum, angikeratomas, xanthelasma/xanthomas or palmoplantar keratosis) and no evident neurological disorders. The auscultation findings in his heart and lungs were normal. ECG showed a sinus rhythm with a frequency of 83 bpm, an intermediate electrical axis, mild interventricular conduction disturbances (QRS: 105 ms) and a regular ST segment with two single, monomorphic PVCs, while his blood pressure was 150/90 mmHg. During the initial 24 h ECG monitoring, his sinus rhythm was recorded, with 4.5% PVCs, frequent bigeminy and one episode of NSVT with three PVCs in a row with a frequency of 150 bpm. Nebivolol and perindopril, both at doses of 2.5 mg once a day, plus atorvastatin at a dose of 20 mg were introduced into therapy. Two-dimensional transthoracic echocardiography (TTE) was performed, and all chambers of his heart were of normal diameters. The LV showed normal systolic function, with an ejection fraction (EF) of 62%; the interventricular septum (IVS) was slightly thickened (1.2 cm) and dyskinetic; his left ventricular diastolic function was mildly impaired; and no significant valvular disease was detected. One month after the introduction of beta blockers into therapy, the 24 h ECG monitoring was repeated, during which his sinus rhythm was monitored again, with an average frequency of 68 bpm. A smaller number of single and paired PVCs (1.6%) and 0.2% single premature atrial complexes (PACs) (0.2%) were recorded, without malignant arrhythmia, asystole or atrial fibrillation. In the next step, the Bruce protocol treadmill exercise test was indicated. At the beginning of the stress test, a sinus rhythm with a frequency of 80 bpm and mild disturbances of interventricular conduction (QRS duration: 105 ms) were recorded, without PVCs or ischemia (Figure 1), while his blood pressure was 120/80 mmHg.

The exercise test was interrupted in the third minute (Figure 2) due to fatigue and pain in his hips, without angina or dyspnea. The maximum frequency achieved during exercise was 120 bpm. Rare single and paired PVCs were monitored, not originating from the common site for these arrhythmias (ventricular outflow), and the maximum blood pressure achieved during exercise was 160/90 mmHg.

In the first minute of rest, an ascending, insignificant depression of the ST junction was detected, which progressed in a significant horizontal–descending direction in the inferolateral leads by the sixth minute of rest, with clear isorhythmic competition between his sinus and junctional rhythms (Figure 3), without complaints from the patient at any time.

During the rest period, rare individual PVCs were detected. The patient felt well the whole time, and the ST junction returned to the isoelectric line by the ninth minute of rest (Figure 4). At that time, his blood pressure was 120/80 mmHg.

The patient was told that although he was asymptomatic, the test was positive and he would need to have an additional coronary angiography. Immediately after the ECG monitoring had stopped, the patient complained of weakness and lost consciousness; his pulse was not palpable, but his breathing was audible, so cardiac massage was started. It was stopped after approximately 2 min when the patient regained consciousness. Shortly after the ECG, alternating sinus and junctional rhythms were evident, reaching the lowest frequency of 33 bpm, without recurrent ischemia at any point (Figure 5 and Figure 6).

The bradycardia was short-lived and did not require the administration of atropine or adrenaline. Within a few minutes, a continuous sinus rhythm with a frequency of 60 to 65 bpm was recorded, but significant hypotension was measured (80/50 mmHg), which lasted until the arrival of emergency medical help. For the entire duration, the patient denied experiencing chest pain, and oxygen saturation, measured by a pulse oximeter, was 96%. He was immediately transported to a clinical hospital, where he was hospitalized for several days. Laboratory tests ruled out acute coronary syndrome, a thromboembolic incident or electrolyte and thyroid hormone disorders. Coronary angiography revealed a regular flow in all large epicardial arteries, without stenosis. On repeated TTE, his LV EF was 58%, and no segmental contractility disorders were detected.

Over several days of ECG monitoring, a sinus rhythm of a normal frequency, rare PVCs and one short rhythmic paroxysmal supraventricular tachycardia were recorded, without asystolic pauses or malignant arrhythmias. Hypotension was not detected during his hospitalization. From his subsequent anamnestic statement, it was established that the patient had lost consciousness on several occasions since he was young, usually when he was “scared” and also once when he dislocated his shoulder and felt severe pain. He admitted that on the day on which the exercise test was performed, he was very afraid of positive findings and the recommendation for coronary angiography. Based on the anamnestic data and the findings obtained, the cardiology council decided that it was most likely a case of VVS, probably of the cardioinhibitory subtype, so tilt-table testing (TTT) was recommended, which had not been carried out for the patient yet. As a precaution, beta blocker therapy was stopped, while perindopril and atorvastatin were continued at the same doses after discharge. During a period of four months after his hospitalization, the syncopal episodes did not recur, and the patient felt well. His blood pressure was well regulated, and he did not feel palpitations.

3. Discussion

Syncope is defined as a non-traumatic transient loss of consciousness (TLOC) caused by transient hypoperfusion of the brain due to low peripheral resistance and/or low cardiac output, which is followed by complete recovery. Considering the pathophysiological mechanisms responsible for syncope, the European Society of Cardiology (ESC) distinguishes three main categories of syncope: 1. VVS (as a reflex or neurally mediated); 2. syncope due to orthostatic hypotension (OH); and 3. cardiac syncope (due to arrhythmias, ischemia, structural heart disease or disease of the large blood vessels) [26]. VVS is precipitated by pain, fear and situation (micturition, gastrointestinal stimulation, coughing, sneezing, laughing, playing brass instruments or standing) and is associated with a typical progressive prodrome (pallor, sweating and/or nausea). There are two main pathophysiological mechanisms in VVS: 1. “vasodepression”, in which insufficient sympathetic vasoconstriction results in hypotension [27,28], and 2. “cardioinhibition”, when bradycardia or asystole predominates, reflecting a shift towards parasympathetic predominance. Although cardioinhibition (with or without asystole) predominates in the BJR, also called the cardioinhibitory reflex, hypotension also coexists.

Syncope is common at all ages, with the highest incidence during the adolescent period [29], in which VVS predominates as the first cause and the female sex is more affected [30]. The second peak occurs after the age of 65, with a predominance of males, but regarding the causative factors, the research is quite controversial. Although some researchers have reported that the causes are mainly of cardiac origin and multifactorial at this age [31], data from the Italian Group for the Study of Syncope in the Elderly (GIS) revealed that the prevalence of VVS in the elderly was 70%, and cardiac syncope prevalence was 20% [32], while a group of researchers from Chile announced that in a group of 52 cases of syncope in people over 50 years of age, the main cause was OH (46%), followed by the vasodepression subtype of VVS (21%), while cardioinhibitory VVS was recorded in only 8% of cases [33].

Although syncope and pre-syncope during graded exercise tests are very rare, even in patients at high risk of cardiac syncope [2], post-exercise syncope can be the result of all three classic types of syncope: VVS, OH (due to venous accumulation during exercise) and cardiac syncope (due to arrhythmias, ischemia, severe aortic stenosis, hypertrophic cardiomyopathy, the presence of heart masses, pericardial diseases, congenital anomalies of the coronary arteries and diseases of the large blood vessels, aortic dissection, pulmonary thromboembolism or pulmonary hypertension) [26].

So, the initial assessment of syncope requires the confirmation/exclusion of cardiac syncope, which is acutely life-threatening for a patient. In this context, the first-line assessment includes non-invasive diagnostic methods like a baseline 12-lead ECG, TTE, 24-h Holter ECG and exercise testing. If there is suspicion of structural heart disease (SHD) other than coronary artery disease that cannot be confirmed by TTE (for example, myocarditis or sarcoidosis), cardiac magnetic resonance (CMR) with late gadolinium enhancement (LGE) should be performed. If there is suspicion of disease of the large blood vessels or coronary artery disease (CAD), computed tomography angiography or invasive coronary angiography should be considered. Other diagnostic tests, such as provocative tests (with channel blockers, adenosine or epinephrine) and electrophysiological studies, are reserved for specific cardiomyopathies (such as Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia and long QT syndrome). Although genetic testing is also possible, it is still not widely used [34]. If there is a suspicion of infrequent paroxysmal brady- or tachyarrhythmia as the reason for unexplained syncope, using an implantable loop recorder (ILR) or an external ECG loop recorder should also be considered [26,35]. If a cardiac cause of syncope is confirmed, the therapy includes treatment for the specific cause.

In the absence of cardiac syncope, the prognosis regarding the risk of death and life-threatening events is generally good [36], although in the case of syncope recurrence, a risk of physical injuries may still persist [35]. In these cases, TTT plays a major role regarding further evaluation of syncope as VVS or OH. It also helps to differentiate between VVS subtypes and between syncope and other common conditions, such as epilepsy, and therefore can be useful in guiding treatment [37]. If VVS or OH is confirmed, the current guideline-directed medical therapy (GDMT) includes education; discontinuation of/a reduction in the use of vasoactive or hypotensive drugs; lifestyle modifications, with increased salt and water intake, tilt training or head-up tilt sleeping; physical counterpressure maneuvers; and drug therapy with fludrocortisone or midodrine [26], while dual-chamber permanent pacing should be considered in patients ≥40 years old with severe recurrent reflex syncope in whom a long asystolic pause has been documented [38].

However, despite GDMT, up to 20% of patients have therapy-refractory VVS episodes. For these patients, catheter-based modulation of the ICNS, or cardioneuroablation (CNA), has emerged as a promising therapy in recent decades. CNA is an invasive procedure during which the exact location of the GPs are mapped and subsequently ablated with radiofrequency ablation or cryoablation [39]. Nuclear cardiac imaging with radiopharmaceutical techniques is a newly introduced method for non-invasive evaluation of the functional integrity of cardiac innervation which can be used not only in VVS but also in arrhythmias, cardiomyopathies and ischemia [24]. Although other therapeutic approaches that can significantly reduce ventricular arrhythmias in the setting of severe life-threatening ventricular electrical storm have been described in the literature, such as stimulation of the cervical vagus nerve and the spinal cord, surgical resection and thoracic epidural anesthesia from the stellate ganglion to the T4 paravertebral ganglia, none of them have been adapted for or adopted into clinical practice to date [23].

In our case, we presented a 67-year-old previously healthy man in whom syncope followed stress-induced silent ischemia in the inferolateral leads with post-syncopal bradycardia and without PVCs or residual ischemia, accompanied by persistently low blood pressure. Taking into account everything mentioned above, including the patient’s age and the frequent asymptomatic but non-trivial PVCs recorded before exercise testing, we assumed that the cause was cardiac, most likely ischemic or arrhythmic. After complete hospital cardiology treatment, to our surprise, neither coronary disease nor significant arrhythmias were confirmed. When it was established on the basis of more detailed anamnestic data that the patient had experienced several syncopal episodes potentiated by fear and pain since he was young, the decision was made that the most likely cause was therefore cardioinhibitory VVS, also called the BJR. Considering the coronary angiographic findings in the large epicardial arteries were normal, silent ischemia after exercise could have been caused by microvascular disease or been related to changes in underlying rhythm detected during the post-exercise rest period. Although our patient had no evident neurological symptoms, we did not overlook the fact that neurodegenerative disorders are a possible cause of syncope in the differential diagnosis. The following questions remain open: 1. What was the reason for the frequent occurrence of PVCs? 2. Is it possible that the reason for them was the chronic, intense stress that he mentioned? 3. How should they be treated if they recur in the future while preventing possible bradycardic rhythm disturbances and asystolic pauses? So, strict monitoring of patient, either with Holter ECG or, even better, with continuous monitoring with an ILR, is warranted. CMR is one of the diagnostic tests that we should also consider for excluding underlying SHD, like previous silent myocarditis or initial cardiomyopathy. In cases of frequent and symptomatic PVCs that cannot be suppressed by anti-arrhythmic drugs due to bradycardia or long asystolic pauses, electrophysiological studies, catheter ablation and permanent pacemaker implantation may be considered.

4. Conclusions

Post-exercise syncope without a palpable pulse is a dramatic event that requires a prompt response, as it can be a prelude to sudden cardiac death. Although rare, one possible non-life-threatening cause of post-exercise syncope, even in the elderly, is the cardioinhibitory subtype of VVS called the BJR, caused by autonomic nervous system dysfunction. However, in order to confirm this, it is necessary to rule out cardiac causes first. Although specific therapy is not required in most cases, the implantation of a permanent pacemaker can be considered in patients with more severe forms of recurrent syncope with long asystolic pauses recorded. An invasive procedure like CNA is a promising therapy reserved for patients with refractory VVS.