Vasovagal Syncope: Hypothesis Focusing on Its Being a Clinical Feature Unique to Humans.

Humans live primarily in the upright position; as a result, there is a constant struggle between gravity and needed supply of blood flow to the brain. In certain circumstances brain blood supply may become temporarily insufficient, resulting in syncope. Among the numerous causes of syncope in humans, vasovagal syncope (VVS) is by far the most common. However, despite intensive research, many aspects of the pathophysiology of VVS remain unknown; among these, one of the least well understood is the basis for why VVS is restricted, among vertebrates, to Homo sapiens. In this manuscript we review proposals that have been offered in an attempt to address the issue of the origin of VVS and, although highly speculative, we suggest a new hypothesis (the "brain theory") to try to address the question of why humans, to the exclusion of other species, remain susceptible to VVS. This theory suggests that VVS evolved to offer protection to the brain's functional integrity under certain conditions of severe threat. Although seemingly a disadvantageous evolutionary adaptation, the faint causes the body to take on a gravitationally neutral position, and thereby provides a better chance of restoring brain blood supply and preserving long-term brain function.

Vasovagal syncope in humans and protective reactions in animals.

Vasovagal syncope (VVS) is not known to occur in animals, although other similar reflex responses are common. This review examines the possible relation of these latter presumably protective reflexes in animals to VVS in humans. The goal is to provide practitioners, and ultimately their patients, a meaningful understanding of the origins and appropriate management of this unpredictable affliction. This report utilized review of computer databases (e.g. PubMed) addressing VVS pathophysiology and origins, spontaneous transient loss of consciousness in animals, and comparative physiology. We also examined articles cited in the publications obtained by computer search and others suggested by colleagues. Articles were chosen based on those providing original observations and/or suggestions of novel mechanisms. In animals self-preservation is directed towards protection of the body through an escalation of behaviours depending on severity and proximity to danger. In humans self-preservation is directed not only to protection of the body, but also to protection of the brain's functional integrity. By virtue of loss of postural tone, the faint causes the body to assume a gravitationally neutral position, thereby offering a better chance of restoring brain blood supply and preserving brain function. Vasovagal syncope may seem to be a disadvantageous evolutionary adaptation. However, it is a reversible condition, that while exposing risk of injury and embarrassment, ultimately favours brain self-preservation in potentially threatening circumstances.

Syncope associated with documented paroxysmal atrioventricular block reproduced by adenosine 5' triphosphate injection.

AIMS: We sought to investigate in patients with syncope the relationship between documented paroxysmal atrioventricular block (AVB) of unknown mechanism and AVB induced by adenosine triphosphate (ATP) injection. METHODS AND RESULTS: We selected patients >45 years free of structural heart disease with syncope related to paroxysmal AVB documented by Holter or in-hospital monitoring, but without any trigger suggestive of vasovagal origin and with normal baseline electrocardiogram. Adenosine triphosphate test was performed according to the usual protocol. Nine patients (all females; mean age 66 ± 14.6 years; range: 48-81 years) matching the abovementioned criteria particularly documented spontaneous complete AVB with long ventricular pauses. Their mean QRS duration was 86.6 ± 14.1 ms and the mean PR interval was 161 ± 21.3 ms. In all patients, ATP induced a long ventricular pause related to AVB (mean duration 13.2 s; range from 7 to 56 s). After a mean follow-up duration of 42 ± 36 months, electrocardiogram (ECG) remained unchanged without progression to permanent AVB or appearance of intraventricular conduction disturbances. CONCLUSION: Some patients, predominantly older females, with 'normal' heart and ECG, have syncope associated with spontaneous AVB of unknown origin reproduced during the ATP test. They do not develop permanent AVB during follow-up. This unusual behaviour could be interpreted as an abnormal susceptibility to ATP and these patients could be considered to have 'ATP-sensitive AVB'. In this subgroup of syncope patients ATP test is useful.

Characteristics of a large sample of candidates for permanent ventricular pacing included in the Biventricular Pacing for Atrio-ventricular Block to Prevent Cardiac Desynchronization Study (BioPace).

AIMS: The general clinical profile of European pacemaker recipients who require predominant ventricular pacing (VP) is scarcely known. We examined the demographic and clinical characteristics of the 1808 participants (out of 1833 randomized patients) of the ongoing Biventricular Pacing for Atrio-ventricular Block to Prevent Cardiac Desynchronization (BioPace) study. METHODS AND RESULTS: BioPace recruited patients between May 2003 and September 2007 predominantly in European medical centres. We analysed demographic data and described clinical characteristics and electrophysiological parameters prior to device implantation in 1808 enrolled patients. The mean age ± standard deviation (SD) of the 1808 patients was 73.5 ± 9.2 years, 1235 (68%) were men, 654 (36%) presented without structural heart disease, 547 (30%) had ischemic, 355 (20%) hypertensive, 146 (8%) valvular, and 102 (6%) non-ischemic dilated cardiomyopathy. Mean left ventricular ejection fraction was 55.4 ± 12.3%. The main pacing indications were (a) permanent and intermittent atrioventricular (AV) block in 973 (54%), (b) atrial fibrillation with slow ventricular rate in 313 (17%), and (c) miscellaneous bradyarrhythmias in 522 (29%) patients. Mean QRS duration was 118.5 ± 30.5 ms, left bundle branch block was present in 316 (17%), and atrial tachyarrhythmias in 426 (24%) patients. CONCLUSION: To the best of our knowledge, this sample is a representative source of description of the general profile of European pacemaker recipients who require predominant VP. Patients' characteristics included advanced age, predominantly male gender, preserved left ventricular systolic function, high-grade AV block, narrow QRS complex, and atrial tachyarrhythmias, the latter being present in nearly one-fourth of the cohort.

Treatment of unexplained syncope: a multicenter, randomized trial of cardiac pacing guided by adenosine 5'-triphosphate testing.

BACKGROUND: The origin of 40% of syncope cases remains unknown even after a complete diagnostic workup. Previous studies have suggested that ATP testing has value in selecting successful therapy. This patient-blinded, multicenter, randomized superiority trial tested whether, in patients with syncope of unknown origin, selecting cardiac pacing in those with a positive ATP test leads to fewer recurrences than those who do not receive pacing. METHODS AND RESULTS: From 2000 to 2005, 80 consenting patients (mean age, 75.9±7.7 years; 81% women; 56% without diagnosed structural heart disease) with syncope of unknown origin and atrioventricular or sinoatrial block lasting >10 seconds (average, 17.9±6.8 seconds) under ATP administration (20-mg IV bolus) were recruited from 10 hospitals, implanted with programmable pacemakers, and randomized to either active pacing (dual-chamber pacing at 70 bpm) or backup pacing (atrial pacing at 30 bpm). Patients were followed up regularly for up to 5 years for any syncope recurrence, the primary outcome. Mean follow-up was 16 months. Syncope recurred in 8 of 39 patients (21%) randomized to active pacing and in 27 of 41 (66%) randomized to backup pacing (control), yielding a hazard ratio of 0.25 (95% confidence interval, 0.12-0.56). After recurrence, the 27 recurrent control patients were reprogrammed to active pacing, and only 1 reported subsequent syncope. CONCLUSION: This study suggests that, in elderly patients with syncope of unknown origin and positive ATP tests, active dual-chamber pacing reduces syncope recurrence risk by 75% (95% confidence interval, 44-88). CLINICAL TRIAL REGISTRATION: URL: http://www.controlled-trials.com/ISRCTN00029383. Unique identifier: ISRCTN00029383.

Pacemaker therapy in patients with neurally mediated syncope and documented asystole: Third International Study on Syncope of Uncertain Etiology (ISSUE-3): a randomized trial.

BACKGROUND: The efficacy of cardiac pacing for prevention of syncopal recurrences in patients with neurally mediated syncope is controversial. We wanted to determine whether pacing therapy reduces syncopal recurrences in patients with severe asystolic neurally mediated syncope. METHODS AND RESULTS: Double-blind, randomized placebo-controlled study conducted in 29 centers in the Third International Study on Syncope of Uncertain Etiology (ISSUE-3) trial. Patients were ≥40 years, had experienced ≥3 syncopal episodes in the previous 2 years. Initially, 511 patients, received an implantable loop recorder; 89 of these had documentation of syncope with ≥3 s asystole or ≥6 s asystole without syncope within 12 ± 10 months and met criteria for pacemaker implantation; 77 of 89 patients were randomly assigned to dual-chamber pacing with rate drop response or to sensing only. The data were analyzed on intention-to-treat principle. There was syncope recurrence during follow-up in 27 patients, 19 of whom had been assigned to pacemaker OFF and 8 to pacemaker ON. The 2-year estimated syncope recurrence rate was 57% (95% CI, 40-74) with pacemaker OFF and 25% (95% CI, 13-45) with pacemaker ON (log rank: P=0.039 at the threshold of statistical significance of 0.04). The risk of recurrence was reduced by 57% (95% CI, 4-81). Five patients had procedural complications: lead dislodgment in 4 requiring correction and subclavian vein thrombosis in 1 patient. CONCLUSIONS: Dual-chamber permanent pacing is effective in reducing recurrence of syncope in patients ≥40 years with severe asystolic neurally mediated syncope. The observed 32% absolute and 57% relative reduction in syncope recurrence support this invasive treatment for the relatively benign neurally mediated syncope. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00359203.

Is "hyper response" to cardiac resynchronization therapy in patients with nonischemic cardiomyopathy a recovery, a remission, or a control?

BACKGROUND AND OBJECTIVES: Some patients treated by cardiac resynchronization therapy (CRT) recover "normal" left ventricular (LV) function and functional status. However, whether this "normalization" persists or reverts over time remains unknown. The aim of the present study was to evaluate the long-term outcomes of LV function in patients hyper responder to CRT. METHODS: Eleven consecutive patients with nonischemic dilated cardiomyopathy, sinus rhythm, left bundle branch block (LBBB), New York Heart Association (NYHA) class III or IV, and optimal pharmacological treatment were hyper responder as they fulfilled concurrently the two following criteria: functional recovery (NYHA class I or II) and normalization of LV ejection fraction (LVEF). RESULTS: After a mean follow-up of 65 ± 30 months between CRT implantation and last evaluation LVEF improved from 26 ± 9 to 59 ± 6% (P < 0.0001). One patient died from pulmonary embolism 31 months after implantation. Three patients exhibited LVEF ≤ 50% at their last follow-up visit (two at 40% and one at 45%). In eight patients, brief cessation of pacing was feasible (three were pacemaker-dependent). Mean QRS duration decreased from 181 ± 23 ms to 143 ± 22 ms (P = 0.006). In one patient, pacing was interrupted for 2 years and LVEF decreased markedly (from 65% to 31%) but returned to normal after a few months when pacing was resumed. CONCLUSION: In hyper responder patients, "normalization" of LV function after CRT persists as long as pacing is maintained with an excellent survival.

Patients with non-ischaemic dilated cardiomyopathy and hyper-responders to cardiac resynchronization therapy: characteristics and long-term evolution.

AIMS: In some patients with non-ischaemic dilated cardiomyopathy (NIDCM), left bundle branch block (LBBB), and severe cardiac failure, cardiac resynchronization therapy (CRT) has been shown to reverse almost completely left ventricular (LV) function. These patients thus eligible to be qualified 'hyper-responders' are exclusively recruited in patients with NIDCM. Evaluate proportion of 'hyper-responders' among patients with NIDCM and try to determine their profile before implantation of CRT. METHODS AND RESULTS: Consecutive patients with DCM [LV ejection fraction (LVEF) <35%, LV end-diastolic diameter >60 mm], sinus rhythm, LBBB, and New York Heart Association (NYHA) class III and IV implanted with a CRT were prospectively followed. Patients were considered 'hyper-responders' if they fulfilled after a minimum period of 6 months the following criteria: functional recovery (NYHA class I or II) and LVEF >or=50%. Among the 51 NIDCM patients, 11 (21.5%) were 'hyper-responders' following CRT (LVEF increased from 26 +/- 9 to 59 +/- 6%, P < 0.01). In the 40 (78.5%) remaining patients, there was no or minimal functional improvement and only a modest increase in LVEF from 21 +/- 9 to 26 +/- 12% (P = 0.03). Comparison between 'hyper-responders' and remaining patients showed that baseline parameters of 'hyper-responders' were less severely deteriorated. CONCLUSION: In a significant subset of patients with CRT for NIDCM, a 'complete' functional recovery associated with normalization of LV function was observed. This observation suggests that LBBB could be the causative factor of DCM in this subgroup of patients. There was not a unique discriminating factor at baseline between 'hyper-responders' and remaining patients.

Edoxaban in atrial fibrillation patients with established coronary artery disease: Insights from ENGAGE AF-TIMI 48.

BACKGROUND:: The relative efficacy and safety profile of the oral Factor Xa inhibitor edoxaban compared with warfarin in patients with atrial fibrillation and established coronary artery disease (CAD) has not been analyzed. MATERIALS AND METHODS:: In the ENGAGE AF-TIMI 48 trial, two edoxaban regimens were compared with warfarin in 21,105 patients with atrial fibrillation and CHADS2 ⩾2. We analyzed the primary trial endpoints (efficacy: stroke or systemic embolic event, safety: International Society on Thrombosis and Haemostasis major bleeding) in patients with versus without CAD, and used interaction testing to assess for treatment effect modification. RESULTS:: The 4510 patients (21.4%) with known CAD were older, more likely male, on aspirin, with lower creatinine clearance and higher CHADS2 and HAS-BLED scores ( p <0.001 for each). Treatment with the higher-dose edoxaban regimen (versus warfarin) in patients with known CAD tended to have a greater reduction in stroke/systemic embolic event compared with patients without CAD (CAD: hazard ratio 0.65 (0.46-0.92) versus no CAD: hazard ratio 0.94 (0.79-1.12), p-INT 0.062) and also in myocardial infarction (CAD: hazard ratio 0.69 (0.49-0.98) versus no CAD: hazard ratio 1.24 (0.89-1.72), p-INT 0.017), while there was a similar reduction in bleeding irrespective of CAD status (hazard ratio 0.81 and 0.80, p-INT 0.97). Presence or absence of CAD did not modify the efficacy or safety profile of the lower-dose edoxaban regimen (versus warfarin). CONCLUSION:: The reduction in ischemic events with the higher-dose edoxaban regimen versus warfarin was greater in patients with CAD, while bleeding was significantly reduced with edoxaban regardless of CAD status. The efficacy and safety profile of the lower-dose edoxaban regimen relative to warfarin was unaffected by CAD status.

Cardiac resynchronization therapy: "nonresponders" and "hyperresponders".

BACKGROUND: Cardiac resynchronization therapy (CRT) is a recognized treatment modality for patients with dilated cardiomyopathy (DCM), left bundle branch block, and severe cardiac failure. However, 30% of patients are "nonresponders." Intriguingly, the opposite case has not been reported until recently: Do some patients treated with CRT have a "complete" recovery and thus can be considered "hyperresponders"? OBJECTIVE: The purpose of this study was to investigate patients treated with CRT who have a "complete" functional recovery, with normalization of left ventricular function after therapy. METHODS: Eighty-four consecutive patients with DCM, sinus rhythm, and left bundle branch block in New York Heart Association functional class III and IV who were implanted with a CRT device were prospectively followed. Patients were considered to be "hyperresponders" if they concurrently fulfilled two criteria: functional recovery and left ventricular ejection fraction > or = 50%. RESULTS: Among the 84 patients with DCM, 11 (13%) were "hyperresponders" within 6 to 24 months after CRT (left ventricular ejection fraction increased from 25% +/- 8% to 60% +/- 6.5%, P = .001). Comparison of baseline parameters between "hyperresponders" and the remaining patients showed that only etiology of the DCM was statistically discriminative. All "hyperresponders" belonged to the group of patients with nonischemic DCM (18% vs 0%, P = .05). CONCLUSION: In a subset of patients successfully implanted with a CRT device, "complete" functional recovery associated with normalization of LV function was observed, giving rise to the concept of "hyperresponders." This finding is observed exclusively in the subgroup of patients with nonischemic DCM and suggests that left bundle branch block may be the causal factor of DCM in this subgroup of patients.

Primary failure of cardiac resynchronization therapy: what are the causes and is it worth considering a second attempt? A single-centre experience.

AIMS: Cardiac resynchronization therapy (CRT) has been validated as an effective treatment for patients with drug-refractory congestive heart failure and left bundle branch block. Failure of implantation of the left ventricular (LV) lead has been reported in 10-15% of patients. The goal of our study was to determine the causes of failure and the success rate following a repeat procedure by the same operators. METHODS AND RESULTS: We reviewed our last 100 consecutive cases of CRT before July 2007. The procedure was considered as unsuccessful if it had to be interrupted before the placement of the LV lead in an appropriate position, because of patient's haemodynamic status or if the procedure duration exceeded 3 h. Cardiac resynchronization therapy was unsuccessful in 10 patients (5 men, mean age: 72 +/- 11 years). The causes of failure of CRT were as follows: no target vein other than the great cardiac vein (n = 5), coronary sinus dissection (n = 1), and a lateral vein too small to provide a stable location for the LV lead (n = 4). A second procedure was attempted in four patients and was successful in all cases. CONCLUSION: In our study results, failure of CRT was observed in 10% of the patients. A second procedure can be attempted in a selected group of patients and is associated with a high success rate.

Cardiac tamponade in medical patients: a 10-year follow-up survey.

OBJECTIVES: Cardiac tamponade represents a life-threatening condition that may complicate almost any cause of pericarditis. We conducted a 10-year prospective survey on patients with cardiac tamponade requiring an emergency drainage. METHODS: From 1996 to 2005, 114 consecutive patients were admitted to the University Hospital of Brest for medical cardiac tamponade. Data on medical history, and volume, characteristics and histology of the pericardial fluid as well as short- and long-term follow-up data were collected. RESULTS: Malignant disease was the primary cause of medical tamponade (74 patients; 65%), followed by viral history (11; 10%) and intra-pericardial bleeding due to anti-coagulation treatment (4; 3%). In 12 cases, aetiology remained unknown (10%). Pericardiocentesis was immediately performed in 80 cases and surgical pericardiotomy in 34. The mean volume drained was 593 +/- 313 ml. In-hospital mortality was 10% without any difference between malignant and non-malignant diseases (p = 0.8). One-year mortality was 76.5% in patients with malignant disease and 13.3% in those without malignant disease (p < 0.0001). Median survival in case of malignant disease was 150 days. CONCLUSION: Compared to previously published data, our survey shows a decrease in some historical causes of tamponade such as tuberculosis, myxoedema or uraemia. The leading cause is currently malignant disease, which carries a very poor prognosis.

Accuracy of 16-detector multislice spiral computed tomography in the initial evaluation of dilated cardiomyopathy.

BACKGROUND: Multislice Computed Tomography (MSCT) recently proved its accuracy in the detection of coronary artery disease (CAD). It can also give information about left ventricular function and venous network anatomy. We here sought to validate a MSCT-based strategy in the initial evaluation of patients with dilated cardiomyopathy (DCM). METHODS: 36 patients with DCM underwent cardiac MSCT before conventional coronary angiography with ventriculography. We analysed arterial calcium score (Agatston score equivalent: ASE), coronary stenosis, left ventricular parameters and venous network. RESULTS: The sensitivity of a MSCT-based strategy in detecting significant CAD was 100% and the specificity 80%. The positive and negative predictive values were respectively 67% and 100%. For ASE <1.000 (75% of patients), MSCT detected all non-CAD patients without one (motion artifacts), enabling conventional angiography to be avoided in 21/27 patients (77.7%). For ASE > or =1000, MSCT enabled conventional angiography to be avoided in only 2/9 patients (22.2%). The ventricle was assessable in 83.4% (30 patients) on MSCT. Correlation coefficient Rs with ventriculography were 0.78 (p<0.0001), 0.77 (p<0.0001) and 0.82 (p<0.0001) respectively for end-diastolic volume, end-systolic volume and EF. The venous network was assessable in all patients both on MSCT and angiography. CONCLUSION: In patients undergoing an initial evaluation of DCM, MSCT appears to be an effective alternative to conventional angiography. The following attitude may be proposed: when ASE >1.000, conventional coronary angiography is mandatory due to MSCT's poor interest in such cases; when ASE <1.000, a contrast-enhanced MSCT may, when normal, replace coronary angiography.

Left ventricular pacing in patients with congestive heart failure.

Cardiac resynchronisation therapy (CRT) using biventricular (BIV) pacing has proved its effectiveness to correct myocardial asynchrony and improve clinical status of patients with severe congestive heart failure (CHF) and widened QRS. Despite a different effect on left ventricular electrical dispersion, left univentricular (LV) pacing is able to achieve the same mechanical synchronisation as BIV pacing in experimental studies and in humans. This results in clinical benefits of LV pacing at mid-term follow-up, with significant improvement in functional class, quality of life and exercise tolerance at the same extent as those observed with BIV stimulation in non randomised studies. Furthermore these benefits are obtained at lesser costs and with conventional dual-chamber devices. However, LV pacing has to be compared to BIV pacing in randomised trials before being definitely considered as a cost-effective alternative to BIV pacing.

Midterm benefits of left univentricular pacing in patients with congestive heart failure.

BACKGROUND: Resynchronization therapy by simultaneous pacing of the right and left ventricles has gained wide acceptance as a useful treatment for patients with severe congestive heart failure. Several short-term hemodynamic studies in humans and animals failed to demonstrate any benefit of biventricular pacing over left univentricular pacing, but long-term studies on this pacing mode are lacking. The objective of this study was to assess the outcome over a 1-year period of patients paced exclusively in the left ventricle. METHODS AND RESULTS: Clinical, angiographic, echocardiographic, and ergometric data were collected at baseline and after 12 months in 22 patients (age, 69.3+/-6.5 years) with NYHA class III or IV (10 patients), sinus rhythm, left bundle-branch block, and no bradycardia indication for pacing. After 12 months, compared with baseline values, NYHA class improved significantly by 40% (P<0.0001), 6-minute walk distance by 30% (P=0.01), peak VO2 by 26% (P=0.01), left ventricular end-diastolic diameter by 5% (P=0.02), ejection fraction by 22% (P=0.07), mitral regurgitation area by 40% (P=0.01), and norepinephrine level by 37% (P=0.04). CONCLUSIONS: In patients with severe congestive heart failure, sinus rhythm, and left bundle-branch block despite optimal pharmacological treatment, left univentricular pacing is feasible and results in significant midterm benefit in exercise tolerance and left ventricular function.

Noninvasive assessment of left main coronary stent patency with 16-slice computed tomography.

We investigated the ability of 16-slice computer tomography (CT) to discriminate any restenosis after left main coronary artery stenting in 29 consecutive patients. CT was able to detect all stents and analyze the lumen properly in 27 of 29 cases. With the exception of arrhythmic or heavily calcified segments, multislice CT provides a noninvasive alternative to conventional coronary angiography in the follow-up of left main angioplasty with stenting.