Long-Term Mortality in Cardioinhibitory Carotid Sinus Hypersensitivity Patient Cohort

Gustavo de Castro Lacerda Andrea Rocha de Lorenzo Bernardo Rangel Tura Marcela Cedenilla dos Santos Artur Eduardo Cotrim Guimarães Renato Côrtes de Lacerda Roberto Coury Pedrosa About the authors

Abstract

Background:

Cardioinhibitory carotid sinus hypersensitivity (CICSH) is defined as ventricular asystole ≥ 3 seconds in response to 5-10 seconds of carotid sinus massage (CSM). There is a common concern that a prolonged asystole episode could lead to death directly from bradycardia or as a consequence of serious trauma, brain injury or pause-dependent ventricular arrhythmias.

Objective:

To describe total mortality, cardiovascular mortality and trauma-related mortality of a cohort of CICSH patients, and to compare those mortalities with those found in a non-CICSH patient cohort.

Methods:

In 2006, 502 patients ≥ 50 years of age were submitted to CSM. Fifty-two patients (10,4%) were identified with CICSH. Survival of this cohort was compared with that of another cohort of 408 non-CICSH patients using Kaplan-Meier curves. Cox regression was used to examine the relation between CICSH and mortality. The level of statistical significance was set at 0.05.

Results:

After a maximum follow-up of 11.6 years, 29 of the 52 CICSH patients (55.8%) were dead. Cardiovascular mortality, trauma-related mortality and the total mortality rate of this population were not statistically different from that found in 408 patients without CICSH. (Total mortality of CICSH patients 55.8% vs. 49,3% of non-CICSH patients; p: 0.38).

Conclusion:

At the end of follow-up, the 52 CICSH patient cohort had total mortality, cardiovascular mortality and trauma-related mortality similar to that found in 408 patients without CICSH.

Keywords:
Carotid Sinus,Massage/mortality; Bradycardia; Syncope; Cardiac Pacing, Artificial

Resumo

Fundamento:

A resposta cardioinibitória (RCI) à massagem do seio carotídeo (MSC) caracteriza-se por assistolia ≥ 3 segundos provocada por 5 a 10 segundos de MSC. Existe uma preocupação de que pacientes com RCI e episódios prolongados de assistolia possam falecer em consequência direta de bradiarritmia, ou em decorrência de lesão cerebral, trauma grave ou arritmia ventricular pausa dependente.

Objetivos:

Determinar a mortalidade total, a mortalidade cardiovascular e a mortalidade relacionada ao trauma de uma coorte de pacientes com RCI à MSC e comparar essas mortalidades com as de uma coorte de pacientes sem RCI à MSC.

Métodos:

Em 2006, 502 pacientes com idade igual ou superior a 50 anos foram submetidos à MSC. Destes, 52 pacientes (10,4%) foram identificados com RCI. A sobrevida desta coorte foi comparada àquela observada em uma coorte de 408 pacientes sem RCI por meio de curvas de Kaplan-Meier. A regressão de Cox foi utilizada para avaliação da relação entre a RCI à MSC e a mortalidade. Variáveis com p < 0,05 foram consideradas estatisticamente significativas.

Resultados:

Após seguimento máximo de 11,6 anos, 29 dos 52 portadores de RCI (55,8%) faleceram. A mortalidade total, a mortalidade cardiovascular e a mortalidade relacionada ao trauma desta coorte de pacientes não foram significativamente diferentes daquelas encontradas nos 408 pacientes sem RCI (mortalidade total com RCI: 55,8% versus 49,3% sem RCI; p: 0,38).

Conclusões:

No fim do seguimento, a mortalidade dos 52 portadores de RCI foi semelhante à observada em uma coorte de pacientes sem RCI. A mortalidade cardiovascular e a relacionada ao trauma também foi semelhante nas duas coortes.

Palavras-chave:
Massagem Seio Carotídeo/mortalidade; Bradicardia; Síncope; Estimulação Cardíaca Artificial

Introduction

Carotid sinus hypersensitivity (CSH) is characterized by ventricular asystole ≥3 seconds, known as cardioinhibitory carotid sinus hypersensitivity (CICSH) or systolic blood pressure fall ≥50 mmHg (vasodepressor carotid sinus hypersensitivity) in response to 5-10 seconds of carotid sinus massage (CSM).11 Brignole M, Moya A, de Lange F, Deharo JC, Elliott PM, Fanciulli A et al. 2018 ESC Guidelines for the diagnosis and management of syncope. Eur Heart J. 2018;39(21):1883-948.,22 Martinelli Filho M, Zimerman LI, Lorga AM, Vasconcelos JTM, Rassi Jr. A. Guidelines for Implantable Electronic Cardiac Devices of the Brazilian Society of Cardiology. Arq Bras Cardiol. 2007;89(6):e210-38. Epidemiologic studies of patients >40 years old have shown that this population have a high prevalence of CSH (10-50%).3,4 This prevalence is even higher among men and in patients with atherosclerosis.33 Kerr SR, Pearce MS, Brayne C, Davis RJ, Kenny RA. Carotid sinus hypersensitivity in asymptomatic older persons implications for diagnosis of syncope and falls. Arch Intern Med. 2006;166(5):515-20.,44 Freitas J, Santos R, Azevedo E, Carvalho M. Prevalência e perfil clínico da hipersensibilidade do seio carotídeo numa população com síncope inexplicada. Rev Port Cardiol. 2004;23(6):835-40.

Carotid sinus hypersensitivity can be present with or without spontaneous symptoms.11 Brignole M, Moya A, de Lange F, Deharo JC, Elliott PM, Fanciulli A et al. 2018 ESC Guidelines for the diagnosis and management of syncope. Eur Heart J. 2018;39(21):1883-948. On the other hand, diagnosis of carotid sinus syncope (CSS) requires the presence of vasodepressor or CICSH and syncope.1,5 Carotid sinus syncope is considered one of the most frequent causes of syncope in the elderly.66 Menozzi C, Brignole M, Tomasi C, Lolli G, Bottoni N, Oddone D, et al. Carotid sinus syncope: the most frequent neurally mediated syncope in the elderly. Arch Gerontol Geriatr. 1995;20(1):7-14. Treatment is generally indicated for CSS patients to reduce recurrence of symptoms.11 Brignole M, Moya A, de Lange F, Deharo JC, Elliott PM, Fanciulli A et al. 2018 ESC Guidelines for the diagnosis and management of syncope. Eur Heart J. 2018;39(21):1883-948.,22 Martinelli Filho M, Zimerman LI, Lorga AM, Vasconcelos JTM, Rassi Jr. A. Guidelines for Implantable Electronic Cardiac Devices of the Brazilian Society of Cardiology. Arq Bras Cardiol. 2007;89(6):e210-38. The concern that a prolonged asystole episode could lead to serious trauma, brain injury, pause-dependent ventricular arrhythmias and death is also used to justify treatment.55 Peretz D, Abdulla A. Management of cardioinhibitory hypersensitive carotid sinus syncope with permanent cardiac pacing: a seventeen year prospective study. Can J Cardiol. 1985;1(2):86-91.,77 Sutton R. 4th European Symposium on Cardiac Pacing. Stockholm, Sweden, May 28-31, 1989. Abstracts.. Pacing Clin Electrophysiol. 1989;12(7 pt 2):1141-308. The main objective of present study is to describe the long-term mortality rate of a cohort of CICSH patients. Secondly, it compares total mortality, cardiovascular mortality, mortality due to ischemic heart disease and trauma-related mortality of this patient cohort with that of a cohort of patients without CICSH.

Methods

In 2006, in the first phase of the present study, 502 patients were randomly selected among 1,686 outpatients ≥50 years of age referred to electrocardiography in a public general hospital in Rio de Janeiro, Brazil. These 502 patients were submitted to CSM, 52 (10,4%) were identified with CICSH (ventricular asystole ≥3) and, in 450, cardioinhibitory reflex was absent. In all cases, CSM was performed in the supine position, initially on the right side, then on the left side for 10 seconds by a single investigator. More patient selection details and more information about CSM can be found in a previous article.88 Lacerda G, Pedrosa R, Santos M, Perez M, Teixeira A, et al. Prevalência e preditores da resposta cardioinibitória massagem do seio carotídeo em 502 pacientes ambulatoriais. Arq Bras Cardiol. 2008;90(3):163-71.

In the present phase of the study, the 502 patients submitted to CSM in 2006 were divided into groups. The first group was formed by the 52 CICSH patients and, for comparison purposes, a second group of 450 patients without CICSH was studied. Survival data was assessed through active follow-up and review of Rio de Janeiro deaths database and the Rio de Janeiro medical admissions database. In the latter, we have searched for all patients who had permanent a pacemaker paid by the state government of Rio de Janeiro. In all cases, we have considered the cause of death described in Rio de Janeiro deaths database. Cardiovascular deaths were those registered under chapter IX of the International Statistical Classification of Diseases and Related Health Problems 10th Revision (ICD-10); ischemic heart disease deaths were those registered under ICD-10 codes I20 - I25, and trauma related deaths were those registered under ICD codes S00 - T14, T66 - T98, V01 - V29, V80 - V94, V98 - W19, W65 - W74, Y85 - Y89.

Ethical approval

The protocol was approved by the local ethics committee (approval statement number 2.383.341) conforming to the standards of the Brazilian National Committee of Research Ethics (resolution 466/2012).

Statistical analysis

All data were analyzed using the R Core Team (2018) software. The Shapiro-Wilk test was used to verify the normality of the data. Normally distributed continuous data are shown as mean and standard deviation and the differences between the two groups are compared using unpaired Student's t-test. Categorical data are presented as absolute and relative frequencies and are compared using x2 or Fisher's exact tests as appropriate. The level of statistical significance was set at 0.05.

Time to event was defined as the time between the date of CSM and death or end of the study; December 31, 2017. The time to event was analyzed using the Kaplan-Meier survival curves, which were compared using the log-rank test. Risk factors associated with mortality were analyzed using the Cox regression analysis. Two models were created, the first adjusted by sex, age and presence of atherosclerosis; the second model made additional adjustments for smoking history, history of hypertension, diabetes and dyslipidemia.

Results

Patients’ characteristics

In the first phase of the study, 52 CICSH patients were identified among the 502 patients submitted to CSM.88 Lacerda G, Pedrosa R, Santos M, Perez M, Teixeira A, et al. Prevalência e preditores da resposta cardioinibitória massagem do seio carotídeo em 502 pacientes ambulatoriais. Arq Bras Cardiol. 2008;90(3):163-71. Only 7 of the 52 CICSH patients had a history of syncope and 40 of them used negative chronotropic drugs. Those 52 patients were advised to avoid inadvertent stimulation of the carotid sinus and, in 12, the dosage of negative chronotropic drugs was reduced. At that time, none of the 52 patients has been submitted to permanent pacemaker implantation.

The baseline characteristics of the patients with and without CICSH are presented in table 1. Patients with CICSH were more likely to be male and had higher prevalence of structural heart disease and atherosclerosis.

Table 1
Baseline characteristics of the patients with and without CICSH

Follow-up of the 52 CICSH patients

Twenty-seven of the 52 CICSH patients were actively followed up. At the end of the study, none of them had been submitted to permanent pacemaker implantation, 19 were alive and 8 had died. Data about the remaining 25 patients were retrieved at Rio de Janeiro databases of death and medical admissions. Twenty-one of those were dead and 4 were alive. None of those patients had been submitted to permanent pacemaker implantation.

Overall, 29 of the 52 patients (55.8%) identified with CICSH had died at the end of the study (maximum follow up time of 11,6 years). Figure 1

Figure 1
Study design and results. CSM: Carotid sinus massage; CICSH: cardioinhibitory carotid sinus hypersensitivity.

Furthermore, the mortality rate of the 7 CICSH patients with history of syncope was 57,1%. This mortality rate was similar to that found in the 45 CICSH patients that did not have this symptom (55,5%).

Follow-up of patients without CICSH

We could not find any information in 42 of the 450 patients without CICSH. One hundred and two patients were actively followed up. Data about the remaining 306 patients without CICSH were retrieved at Rio de Janeiro databases of death and medical admissions. Overall, 201 of the 408 patients without CICSH were dead (49.3%) at the end of follow-up, none had been submitted to permanent pacemaker implantation. One of the 207 patients that was alive at the end of follow-up had been submitted to permanent pacemaker implantation due do complete AV block.

Patients with and without CICSH - Endpoint comparisons

Figure 1 outlines the study design and compares the deathrate of patients with and without CICSH.

Figure 2 shows the distribution of responses to right and left CSM in patients who died during follow-up and in patients who were alive at the end of the study. Median duration of RR intervals observed during CSM were similar in both groups of patients.

Figure 2
Duration of the longest RR interval observed during right and left carotid sinus massage. Boxplots on the left of each square represent patients who died during follow-up. Boxplots on the right represent patients who were alive at the end of the study.

Table 2 compares the total mortality, cardiovascular mortality, mortality due to ischemic heart disease and trauma-related mortality of the 52 CICSH patients with the 408 patients without CICSH. Survival curves are presented in figure 3. The total mortality rate of the 52 CICSH patients was 21.1% at 5 years and 51.9% at 10 years, with median survival time of 10.0 years (95% CI: 7.4 - 12.6 years). The survival curves of patients with and without CICSH were similar without any significant statistical difference. Both Cox regression models failed to reveal any association between CICSH and mortality. In both models, age at the time of CSM, and presence of atherosclerosis were independently associated with mortality. (Table 3)

Figure 3
Survival curves of patients with (in blue) and without CICSH (in red) CICSH: Cardioinhibitory carotid sinus hypersensitivity.

Table 2
Mortality at the end of follow-up of patients with and without CICSH
Table 3
Cox regression results and relation between CICSH and all-cause mortality

Discussion

This study demonstrates, for the first time out of the European continent, that the mortality rate of patients with CICSH is similar to that found in a population without CICSH. Median survival of the 52 CICSH patients was 10.0 years (95% CI: 7.4 - 12.6 years). Cardiovascular mortality and trauma-related mortality, important endpoints in patients with prolonged asystole episodes, were also similar in both cohorts. These results are analogous to that described by Hampton et al.99 Hampton JL, Brayne C, Bradley M, Kenny RA. Mortality in carotid sinus hypersensitivity: a cohort study. BMJ Open. 2011;1(1):e000020. Those authors did not find any association between the presence of CICSH and survival in a cohort of 1,504 English patients with CSH (median age 77 years, 59% female).99 Hampton JL, Brayne C, Bradley M, Kenny RA. Mortality in carotid sinus hypersensitivity: a cohort study. BMJ Open. 2011;1(1):e000020. In that cohort, the median survival of CICSH patients was 8 years (95% CI: 7.3 - 8.7 years).99 Hampton JL, Brayne C, Bradley M, Kenny RA. Mortality in carotid sinus hypersensitivity: a cohort study. BMJ Open. 2011;1(1):e000020. That survival was inferior to the one observed in the 52 CICSH patients described in the present study, but was not different to that found in English elderlies with CSH and pure vasodepressor response (median survival of 7 years; 95% CI: 6.4 - 7.4 years).99 Hampton JL, Brayne C, Bradley M, Kenny RA. Mortality in carotid sinus hypersensitivity: a cohort study. BMJ Open. 2011;1(1):e000020. In the same study, Hampton et al.9 described that the total mortality, cardiac mortality, stroke and trauma-related mortality of the CSH cohort were not different from that found in sex- and age-matched English patients without CSH.99 Hampton JL, Brayne C, Bradley M, Kenny RA. Mortality in carotid sinus hypersensitivity: a cohort study. BMJ Open. 2011;1(1):e000020.

In another European study, the natural history of 262 patients with carotid sinus syncope was described by Brignolle et al.1010 Brignole M, Oddone D, Cogorno S, Menozzi C, Gianfranchi L, Bertulla A. Long-term outcome in symptomatic carotid sinus hypersensitivity. Am Heart J. 1992;123(3):687-92. Eighty-nine patients (34%) died after 46 ± 23 months of follow-up.1010 Brignole M, Oddone D, Cogorno S, Menozzi C, Gianfranchi L, Bertulla A. Long-term outcome in symptomatic carotid sinus hypersensitivity. Am Heart J. 1992;123(3):687-92. This high mortality rate was ascribed to the advanced age of the population and to the presence of important comorbidities.1010 Brignole M, Oddone D, Cogorno S, Menozzi C, Gianfranchi L, Bertulla A. Long-term outcome in symptomatic carotid sinus hypersensitivity. Am Heart J. 1992;123(3):687-92. Similar finding were published by Sutton et al.,77 Sutton R. 4th European Symposium on Cardiac Pacing. Stockholm, Sweden, May 28-31, 1989. Abstracts.. Pacing Clin Electrophysiol. 1989;12(7 pt 2):1141-308. and by Claesson et al.1111 Claesson JE, Kristensson BE, Edvardsson N, Wahrborg P. Less syncope and milder symptoms in patients treated with pacing for induced cardioinhibitory carotid sinus syndrome: a randomized study. Europace. 2007;9(10):932-6. Sutton et al.77 Sutton R. 4th European Symposium on Cardiac Pacing. Stockholm, Sweden, May 28-31, 1989. Abstracts.. Pacing Clin Electrophysiol. 1989;12(7 pt 2):1141-308. reported a 36% mortality rate during 5 years of follow-up.77 Sutton R. 4th European Symposium on Cardiac Pacing. Stockholm, Sweden, May 28-31, 1989. Abstracts.. Pacing Clin Electrophysiol. 1989;12(7 pt 2):1141-308. Claesson et al.1111 Claesson JE, Kristensson BE, Edvardsson N, Wahrborg P. Less syncope and milder symptoms in patients treated with pacing for induced cardioinhibitory carotid sinus syndrome: a randomized study. Europace. 2007;9(10):932-6. surveyed 106 CSH patients (64 with CICSH). After a median follow-up time of 8.6 ± 2.1 years, the mortality rate of the 106 CSH patients was not significantly different from that found in 166 patients without CSH (32% x 22%; p = 0.073).1111 Claesson JE, Kristensson BE, Edvardsson N, Wahrborg P. Less syncope and milder symptoms in patients treated with pacing for induced cardioinhibitory carotid sinus syndrome: a randomized study. Europace. 2007;9(10):932-6.

Hence, until now, no one has been able to prove the presence of any independent relation between the presence of CICSH and mortality. All of these studies evaluated residents of the European Continent and, in all of them, the natural history of CICSH patients may have been altered by pacing therapy.55 Peretz D, Abdulla A. Management of cardioinhibitory hypersensitive carotid sinus syncope with permanent cardiac pacing: a seventeen year prospective study. Can J Cardiol. 1985;1(2):86-91.,77 Sutton R. 4th European Symposium on Cardiac Pacing. Stockholm, Sweden, May 28-31, 1989. Abstracts.. Pacing Clin Electrophysiol. 1989;12(7 pt 2):1141-308.,99 Hampton JL, Brayne C, Bradley M, Kenny RA. Mortality in carotid sinus hypersensitivity: a cohort study. BMJ Open. 2011;1(1):e000020.,1111 Claesson JE, Kristensson BE, Edvardsson N, Wahrborg P. Less syncope and milder symptoms in patients treated with pacing for induced cardioinhibitory carotid sinus syndrome: a randomized study. Europace. 2007;9(10):932-6. In the present study, we have shown that the risk of death was related to population age, to the presence of atherosclerosis and to the presence of risk factors for atherosclerosis. These findings indicate that the presence of CICSH should be interpreted as a risk marker. This hypothesis is supported by our Cox regression results, which showed a relation between the risk of mortality and age at the time of recruitment, and a relation between mortality and the presence of atherosclerosis. Furthermore, the Cox regression results failed to demonstrate any relation between the presence of CICSH and mortality.

Patients with a significant fall in blood pressure after CSM are usually managed with general measures that aim to increase their blood volume, including elastic stockings, physical counterpressure maneuvers, discontinuation/reduction of hypotensive therapy, fludrocortisone and alpha-agonists.11 Brignole M, Moya A, de Lange F, Deharo JC, Elliott PM, Fanciulli A et al. 2018 ESC Guidelines for the diagnosis and management of syncope. Eur Heart J. 2018;39(21):1883-948. Patients with isolated or mixed cardioinhibitory response are usually managed with pacing when syncope is recurrent.11 Brignole M, Moya A, de Lange F, Deharo JC, Elliott PM, Fanciulli A et al. 2018 ESC Guidelines for the diagnosis and management of syncope. Eur Heart J. 2018;39(21):1883-948.,22 Martinelli Filho M, Zimerman LI, Lorga AM, Vasconcelos JTM, Rassi Jr. A. Guidelines for Implantable Electronic Cardiac Devices of the Brazilian Society of Cardiology. Arq Bras Cardiol. 2007;89(6):e210-38.,77 Sutton R. 4th European Symposium on Cardiac Pacing. Stockholm, Sweden, May 28-31, 1989. Abstracts.. Pacing Clin Electrophysiol. 1989;12(7 pt 2):1141-308. However, many studies used to justify pacing were observational, without a control group, or were small randomized open-label trials with no treatment control arm.1010 Brignole M, Oddone D, Cogorno S, Menozzi C, Gianfranchi L, Bertulla A. Long-term outcome in symptomatic carotid sinus hypersensitivity. Am Heart J. 1992;123(3):687-92.

11 Claesson JE, Kristensson BE, Edvardsson N, Wahrborg P. Less syncope and milder symptoms in patients treated with pacing for induced cardioinhibitory carotid sinus syndrome: a randomized study. Europace. 2007;9(10):932-6.
-1212 Kenny RA, Richardson DA, Steen N, Bexton RS, Shaw FE, Bond J. Carotid sinus syndrome: a modifiable risk factor for nonaccidental falls in older adults (SAFE PACE). J Am Coll Cardiol. 2001;38(5):1491-6. Those study results should be regarded with caution. The possibility of spontaneous remission of syncope, the difficulties to document the symptoms used as endpoints and the open-label design of these studies continue to raise doubts about their results. Analogous studies evaluated pacing indications in vasovagal syncope.1313 Connolly SJ, Sheldon R, Roberts RS, Gent M. The North American Vasovagal Pacemaker Study (VPS). a randomized trial of permanent cardiac pacing for the prevention of vasovagal syncope. J Am Coll Cardiol. 1999;33(1):16-20.

14 Romme JJ, Reitsma JB, Black CN, Colman N, Scholten RJ, Wieling W et al. Drugs and pacemakers for vasovagal, carotid sinus and situational syncope. Cochrane Database Syst Rev. 2011 Oct 5;(10):CD004194.
-1515 Varosy PD, Chen LY, Miller AL, Noseworthy PA, Slotwiner DJ, Thiruganasambandamoorthy V. Pacing as a treatment for reflex-mediated (vasovagal, situational, or carotid sinus hypersensitivity) syncope: a systematic review for the 2017 ACC/AHA/HRS Guideline for the Evaluation and Management of Patients With Syncope: a Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol. 2017;70(5):664-79. In an early clinical trial, with an open-label design, pacing was able to reduce syncope recurrence. However, in a later double-blind clinical trial, pacing therapy was not advantageous and failed to have any benefit in reducing syncope recurrence.1616 Connolly SJ, Sheldon R, Thorpe KE, Roberts RS, Ellenbogen KA, Wilkoff BL, et al. Pacemaker therapy for prevention of syncope in patients with recurrent severe vasovagal syncope: Second Vasovagal Pacemaker Study (VPS II): a randomized trial. JAMA. 2003;289(17):2224-9.

Questions about the efficacy of pacing are even stronger in patients with other types of reflex syncope. Those questions are addressed in 2 recent systematic reviews.1515 Varosy PD, Chen LY, Miller AL, Noseworthy PA, Slotwiner DJ, Thiruganasambandamoorthy V. Pacing as a treatment for reflex-mediated (vasovagal, situational, or carotid sinus hypersensitivity) syncope: a systematic review for the 2017 ACC/AHA/HRS Guideline for the Evaluation and Management of Patients With Syncope: a Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol. 2017;70(5):664-79.,1616 Connolly SJ, Sheldon R, Thorpe KE, Roberts RS, Ellenbogen KA, Wilkoff BL, et al. Pacemaker therapy for prevention of syncope in patients with recurrent severe vasovagal syncope: Second Vasovagal Pacemaker Study (VPS II): a randomized trial. JAMA. 2003;289(17):2224-9. Interestingly, in one of them an analysis of mortality is made.1616 Connolly SJ, Sheldon R, Thorpe KE, Roberts RS, Ellenbogen KA, Wilkoff BL, et al. Pacemaker therapy for prevention of syncope in patients with recurrent severe vasovagal syncope: Second Vasovagal Pacemaker Study (VPS II): a randomized trial. JAMA. 2003;289(17):2224-9. In this analysis, which includes 3 studies of patients with CICSH and 1 study of patients with vasovagal syncope, pacing therapy did not reduce mortality.1616 Connolly SJ, Sheldon R, Thorpe KE, Roberts RS, Ellenbogen KA, Wilkoff BL, et al. Pacemaker therapy for prevention of syncope in patients with recurrent severe vasovagal syncope: Second Vasovagal Pacemaker Study (VPS II): a randomized trial. JAMA. 2003;289(17):2224-9.

Only 2 clinical trials evaluated CICSH patients with a double-blind design.1717 Parry SW, Steen N, Bexton RS, Tynan M, Kenny RA. Pacing in elderly recurrent fallers with carotid sinus hypersensitivity: a randomised, doubleblind, placebo controlled crossover trial. Heart. 2009;95(5):405-9.,1818 Ryan DJ, Nick S, Colette SM,Roseanne K. Carotid sinus syndrome, should we pace? a multicentre, randomised control trial (Safepace 2). Heart. 2010;96(5):347-51. The first was a double-blind crossover study1717 Parry SW, Steen N, Bexton RS, Tynan M, Kenny RA. Pacing in elderly recurrent fallers with carotid sinus hypersensitivity: a randomised, doubleblind, placebo controlled crossover trial. Heart. 2009;95(5):405-9. that randomized 32 elderly patients with at least 3 falls attributed to the presence of CICSH. All patients received dual-chamber pacing. The mean age of the population was 77 years. Patients were followed up for 1 year (6 months with DDD pacing turned on, and 6 months without atrial or ventricular pacing).1717 Parry SW, Steen N, Bexton RS, Tynan M, Kenny RA. Pacing in elderly recurrent fallers with carotid sinus hypersensitivity: a randomised, doubleblind, placebo controlled crossover trial. Heart. 2009;95(5):405-9. At the end of follow-up, the reduction in fall burden was similar in both groups.1717 Parry SW, Steen N, Bexton RS, Tynan M, Kenny RA. Pacing in elderly recurrent fallers with carotid sinus hypersensitivity: a randomised, doubleblind, placebo controlled crossover trial. Heart. 2009;95(5):405-9. Those results were affected by a high attrition rate. Seven of the 32 patients did not finish the study, 4 of which died during follow-up (12.5% mortality rate).1717 Parry SW, Steen N, Bexton RS, Tynan M, Kenny RA. Pacing in elderly recurrent fallers with carotid sinus hypersensitivity: a randomised, doubleblind, placebo controlled crossover trial. Heart. 2009;95(5):405-9. Three of these 4 deaths were sudden and occurred at home, 2 of which occurred in patients without pacing.1717 Parry SW, Steen N, Bexton RS, Tynan M, Kenny RA. Pacing in elderly recurrent fallers with carotid sinus hypersensitivity: a randomised, doubleblind, placebo controlled crossover trial. Heart. 2009;95(5):405-9. Autopsy of these patients revealed one death resulting from ischemic stroke, and two from ischemic heart disease.1717 Parry SW, Steen N, Bexton RS, Tynan M, Kenny RA. Pacing in elderly recurrent fallers with carotid sinus hypersensitivity: a randomised, doubleblind, placebo controlled crossover trial. Heart. 2009;95(5):405-9. The fourth patient died after colectomy done after mesenteric infarction.1818 Ryan DJ, Nick S, Colette SM,Roseanne K. Carotid sinus syndrome, should we pace? a multicentre, randomised control trial (Safepace 2). Heart. 2010;96(5):347-51.

The second clinical,1818 Ryan DJ, Nick S, Colette SM,Roseanne K. Carotid sinus syndrome, should we pace? a multicentre, randomised control trial (Safepace 2). Heart. 2010;96(5):347-51. trial recruited 141 elderly patients with a history of syncope or unexplained fall attributed do the presence of CICSH. Patients were randomized to dual-chamber pacing or received an implantable loop recorder. After 2 years of follow-up, fall and syncope recurrence were similar in both groups. This trial has been criticized because the larger RR interval triggered by CSM was 3.1 seconds. Hence, the magnitude of cardioinhibitory response was considered to be small. According to pathophysiological studies, cerebral ischemic anoxia reserve time is around 7 seconds in healthy military personnel,1919 Wieling W, KredietCT, Solari D, de Lange FJ, van Dijk N, Thijs R et al. At the heart of the arterial baroreflex: a physiological basis for a new classification of carotid sinus hypersensitivity. J Intern Med. 2013;273(4):345-58. and a ventricular pause of 3 seconds is not likely to lead to loss of consciousness.2020 Krediet CT, Parry SW, Jardine DL, Benditt DG, Brignole M, Wieling W. The history of diagnosing carotid sinus hypersensitivity: why are the current criteria too sensitive? Europace. 2011;13(1):14-22. So, a ventricular pause of 3 seconds is not likely to produce syncope. Based on this reasoning and based on an epidemiologic study that showed that the 95th percentile for CSM response was 7.3 seconds, Krediet et al.2020 Krediet CT, Parry SW, Jardine DL, Benditt DG, Brignole M, Wieling W. The history of diagnosing carotid sinus hypersensitivity: why are the current criteria too sensitive? Europace. 2011;13(1):14-22. have proposed 6 seconds as a new cut off for the diagnosis of CICSH.2020 Krediet CT, Parry SW, Jardine DL, Benditt DG, Brignole M, Wieling W. The history of diagnosing carotid sinus hypersensitivity: why are the current criteria too sensitive? Europace. 2011;13(1):14-22. In the present study, the largest RR interval triggered by CSM was 10.3 seconds, and the 95th percentile for CSM response was 4.5 seconds. Thirteen of the 502 patients submitted to CSM had an asystole episode ≥6 seconds. (Figure 4) At the end of follow-up, the mortality rate of this small group of patients was 53.8%, which is similar to the percentage found in the 447 patients followed up without a pause ≥6 seconds (53.8% vs. 49.9%; p value: 0.77).

Figure 4
Example of a patient with CICSH. ECG of a 58 year-old male with previous percutaneous coronary intervention. He denied syncope in the past. The ECG reveals normal sinus rhythm with heart rate of 60 bpm and T-wave inversion in Lead 3 and aVF. Right carotid sinus massage triggered 6360 seconds of asystole with concomitant fall in blood pressure and pre-syncope. A few minutes later, he was submitted to left carotid sinus massage, no asystole was observed. RCSM: right carotid sinus massage.

Study limitations

Besides reducing the heart rate and prolonging or blocking atrioventricular conduction, CSM may trigger a fall in blood pressure.11 Brignole M, Moya A, de Lange F, Deharo JC, Elliott PM, Fanciulli A et al. 2018 ESC Guidelines for the diagnosis and management of syncope. Eur Heart J. 2018;39(21):1883-948.,22 Martinelli Filho M, Zimerman LI, Lorga AM, Vasconcelos JTM, Rassi Jr. A. Guidelines for Implantable Electronic Cardiac Devices of the Brazilian Society of Cardiology. Arq Bras Cardiol. 2007;89(6):e210-38. The blood pressure fall observed after CSM is a rapid and transient phenomenon. To be properly observed, this phenomenon must be documented on a beat-by-beat basis using invasive methods or digital pletismography.11 Brignole M, Moya A, de Lange F, Deharo JC, Elliott PM, Fanciulli A et al. 2018 ESC Guidelines for the diagnosis and management of syncope. Eur Heart J. 2018;39(21):1883-948. Furthermore, this blood pressure fall is more commonly observed with the patient in the upright position on a tilt table.11 Brignole M, Moya A, de Lange F, Deharo JC, Elliott PM, Fanciulli A et al. 2018 ESC Guidelines for the diagnosis and management of syncope. Eur Heart J. 2018;39(21):1883-948.,66 Menozzi C, Brignole M, Tomasi C, Lolli G, Bottoni N, Oddone D, et al. Carotid sinus syncope: the most frequent neurally mediated syncope in the elderly. Arch Gerontol Geriatr. 1995;20(1):7-14. In 2006, in the first phase of the present study, devices used to evaluate blood pressure non-invasively on a beat-by-beat basis and tilt tables were not available in Rio de Janeiro public hospitals, so we have evaluated blood pressure response manually with a sphygmomanometer in the supine position. This method lacks sensitivity11 Brignole M, Moya A, de Lange F, Deharo JC, Elliott PM, Fanciulli A et al. 2018 ESC Guidelines for the diagnosis and management of syncope. Eur Heart J. 2018;39(21):1883-948.,66 Menozzi C, Brignole M, Tomasi C, Lolli G, Bottoni N, Oddone D, et al. Carotid sinus syncope: the most frequent neurally mediated syncope in the elderly. Arch Gerontol Geriatr. 1995;20(1):7-14. and, for this reason, we have decided to present only the heart rate response to CSM.

Only 7 of the 52 CICSH patients had a history of unexplained syncope, and none of them had recurrent syncope. This population had CSH, and was not affected by real CSS. It is difficult to conduct a study on the natural history of cardioinhibitory carotid sinus syncope because cardiac pacing is indicated to reduce symptoms in these patients.11 Brignole M, Moya A, de Lange F, Deharo JC, Elliott PM, Fanciulli A et al. 2018 ESC Guidelines for the diagnosis and management of syncope. Eur Heart J. 2018;39(21):1883-948. According to many authors, this treatment could also modify the natural history of CICSH, reducing the mortality of patients with CSS.55 Peretz D, Abdulla A. Management of cardioinhibitory hypersensitive carotid sinus syncope with permanent cardiac pacing: a seventeen year prospective study. Can J Cardiol. 1985;1(2):86-91.,77 Sutton R. 4th European Symposium on Cardiac Pacing. Stockholm, Sweden, May 28-31, 1989. Abstracts.. Pacing Clin Electrophysiol. 1989;12(7 pt 2):1141-308. As we have seen, pacing is also justified by the concern that a prolonged asystole episode could lead to serious trauma, brain injury, pause-dependent ventricular arrhythmias and death.55 Peretz D, Abdulla A. Management of cardioinhibitory hypersensitive carotid sinus syncope with permanent cardiac pacing: a seventeen year prospective study. Can J Cardiol. 1985;1(2):86-91.,77 Sutton R. 4th European Symposium on Cardiac Pacing. Stockholm, Sweden, May 28-31, 1989. Abstracts.. Pacing Clin Electrophysiol. 1989;12(7 pt 2):1141-308. Our results suggest that this concern is excessive. However, we have to emphasize that in their most recent guidelines, the Brazilian Society of Cardiology and the European Society of Cardiology continue to recommend pacing for patients with CICSH and recurrent syncope.11 Brignole M, Moya A, de Lange F, Deharo JC, Elliott PM, Fanciulli A et al. 2018 ESC Guidelines for the diagnosis and management of syncope. Eur Heart J. 2018;39(21):1883-948.,22 Martinelli Filho M, Zimerman LI, Lorga AM, Vasconcelos JTM, Rassi Jr. A. Guidelines for Implantable Electronic Cardiac Devices of the Brazilian Society of Cardiology. Arq Bras Cardiol. 2007;89(6):e210-38. It must be stressed that it is very important to document the association between symptoms and bradycardia because pauses and bradycardias without clinical significance can be easily induced by CSM in elderly individuals, especially when these patients are on negative chronotropic drugs.11 Brignole M, Moya A, de Lange F, Deharo JC, Elliott PM, Fanciulli A et al. 2018 ESC Guidelines for the diagnosis and management of syncope. Eur Heart J. 2018;39(21):1883-948.,22 Martinelli Filho M, Zimerman LI, Lorga AM, Vasconcelos JTM, Rassi Jr. A. Guidelines for Implantable Electronic Cardiac Devices of the Brazilian Society of Cardiology. Arq Bras Cardiol. 2007;89(6):e210-38.

Conclusions

The present study showed that 55.8% of the CICSH patient cohort had died after a maximum follow-up of 11.6 years. This high mortality rate was similar to that found in a cohort of patients without CICSH. Cardiovascular mortality, ischemic heart disease and trauma-related mortalities were also similar in both patient cohorts.

  • Sources of Funding
    There were no external funding sources for this study.
  • Study Association
    This article is part of the thesis of Doctoral submitted by Gustavo de Castro Lacerda, from Faculdade de Medicina da UFRJ - Instituto do Coração Edson Saad.
  • Ethics approval and consent to participate
    This study was approved by the Ethics Committee of the Hospital Geral de Bonsucesso under the protocol number 2.383.341. All the procedures in this study were in accordance with the 1975 Helsinki Declaration, updated in 2013.

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Publication Dates

  • Publication in this collection
    20 Mar 2020
  • Date of issue
    Feb 2020

History

  • Received
    04 Jan 2019
  • Reviewed
    18 Mar 2019
  • Accepted
    15 May 2019
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