George N. Theodorakis

METHODOLOGY OF HEAD-UP TILT TESTING IN PATIENTS WITH UNEXPLAINED SYNCOPE

Prolonged 60 degree head-up tilt has been shown to be valuable in the investigation of unexplained syncope, diagnosing neurally mediated bradycardia/hypotension or malignant vasovagal syndrome. To evaluate the methodology of tilt testing, the following were examined: reproducibility of results, tilt duration, angle of tilt, method of tilt support and effect of age in patients and control subjects. Seventy-one patients with recurrent unexplained syncope underwent 60 min of 60 degree tilt; 53 (75%) had an abnormal test with vasovagal syncope at 24 +/- 10 min (mean +/- SD). Tilting to 60 degrees resulted in an abnormal test in only 2 (7%) of 27 control subjects without cardiovascular symptoms (p less than 0.001); and 5 (15%) of 34 patients with syncope and documented conduction tissue disease (p less than 0.001). Of 15 youthful fainters, 3 (20%) had vasovagal reactions as did 1 (8%) of 12 asymptomatic youthful control subjects. These 12 control subjects also underwent tilting with a saddle support and 7 (67%) had vasovagal reactions. It is concluded that the duration of tilting at 60 degrees should be 45 min (mean time to syncope +2 x SD in the 53 patients with abnormal results). Twenty percent of patients with an abnormal tilt test may not demonstrate syncope with repeat tilting. Saddle tilt testing in unexplained syncope may result in a loss of specificity. Tilting at less than 60 degrees results in a loss of sensitivity. Head-up tilt may be less useful in youthful subjects with vasovagal syncope than in other subjects.

Dual Chamber Pacing Aborts Vasovagal Syncope Induced by Head-Up 60° Tilt

To determine if pacing might prevent syncope in cardioinhibitory ‘Malignant Vasovagal Syndrome’ (also known as ‘Neurally‐Mediated Bradycardia/Hypotension’), a study of dual chamber pacing during head‐up 60° tilt was undertaken. Paired invasive tilts were performed in 10 patients who had a history of recurrent syncope, normal routine investigations including electrophysiological study and prior tilt induced vasovagal syncope. Vasovagal reactions of identical severity were produced by prolonged 60° head‐up tilt on consecutive days in seven out of 10 patients. On day 2, without pacing, seven patients had tilt‐induced vasovagal reactions and six became syncopal during the reaction. On day 3, with temporary DVI pacing with rate hysteresis, seven patients had tilt‐induced vasovagal reactions and 1 patient was syncopal. Syncope was aborted in the other five patients. DVI pacing significantly improved cardiac index (CI) (one ± 0.2 to 1.6 ± 0.3 L/min/m2, P < 0.01) and mean arterial blood pressure (MABP) (30 ± 11 to 48 ± 12 mmHg, P < 0.01) during vasovagal reactions on day 3 compared with day 2. The mean period of time that patients could tolerate in the tilted position after the onset of the tilt‐induced vasovagal reaction was significantly prolonged by pacing from 0.9 ± 1.2 to 3.2 ± 1.6 min (P < 0.01). Dual chamber pacing may abort syncope in 85% of patients with cardioinhibitory malignant vasovagal syndrome. Pacing may prolong consciousness sufficiently during a vasovagal reaction to allow injury to be avoided.

The Atrial Fibrillation Ablation Pilot Study: an European Survey on Methodology and results of catheter ablation for atrial fibrillation conducted by the European Heart Rhythm Association

AIMS The Atrial Fibrillation Ablation Pilot Study is a prospective registry designed to describe the clinical epidemiology of patients undergoing an atrial fibrillation (AFib) ablation, and the diagnostic/therapeutic processes applied across Europe. The aims of the 1-year follow-up were to analyse how centres assess in routine clinical practice the success of the procedure and to evaluate the success rate and long-term safety/complications. METHODS AND RESULTS Seventy-two centres in 10 European countries were asked to enrol 20 consecutive patients undergoing a first AFib ablation procedure. A web-based case report form captured information on pre-procedural, procedural, and 1-year follow-up data. Between October 2010 and May 2011, 1410 patients were included and 1391 underwent an AFib ablation (98.7%). A total of 1300 patients (93.5%) completed a follow-up control 367 ± 42 days after the procedure. Arrhythmia documentation was done by an electrocardiogram in 76%, Holter-monitoring in 52%, transtelephonic monitoring in 8%, and/or implanted systems in 4.5%. Over 50% became asymptomatic. Twenty-one per cent were re-admitted due to post-ablation arrhythmias. Success without antiarrhythmic drugs was achieved in 40.7% of patients (43.7% in paroxysmal AF; 30.2% in persistent AF; 36.7% in long-lasting persistent AF). A second ablation was required in 18% of the cases and 43.4% were under antiarrhythmic treatment. Thirty-three patients (2.5%) suffered an adverse event, 272 (21%) experienced a left atrial tachycardia, and 4 patients died (1 haemorrhagic stroke, 1 ventricular fibrillation in a patient with ischaemic heart disease, 1 cancer, and 1 of unknown cause). CONCLUSION The AFib Ablation Pilot Study provided crucial information on the epidemiology, management, and outcomes of catheter ablation of AFib in a real-world setting. The methods used to assess the success of the procedure appeared at least suboptimal. Even in this context, the 12-month success rate appears to be somewhat lower to the one reported clinical trials.

Programmed ventricular stimulation for risk stratification in the Brugada syndrome: A pooled analysis

Background— The role of programmed ventricular stimulation in identifying patients with Brugada syndrome at the highest risk for sudden death is uncertain. Methods and Results— We performed a systematic review and pooled analysis of prospective, observational studies of patients with Brugada syndrome without a history of sudden cardiac arrest who underwent programmed ventricular stimulation. We estimated incidence rates and relative hazards of cardiac arrest or implantable cardioverter-defibrillator shock. We analyzed individual-level data from 8 studies comprising 1312 patients who experienced 65 cardiac events (median follow-up, 38.3 months). A total of 527 patients were induced into arrhythmias with up to triple extrastimuli. Induction was associated with cardiac events during follow-up (hazard ratio, 2.66; 95% confidence interval [CI], 1.44–4.92, P<0.001), with the greatest risk observed among those induced with single or double extrastimuli. Annual event rates varied substantially by syncope history, presence of spontaneous type 1 ECG pattern, and arrhythmia induction. The lowest risk occurred in individuals without syncope and with drug-induced type 1 patterns (0.23%, 95% CI, 0.05–0.68 for no induced arrhythmia with up to double extrastimuli; 0.45%, 95% CI, 0.01–2.49 for induced arrhythmia), and the highest risk occurred in individuals with syncope and spontaneous type 1 patterns (2.55%, 95% CI, 1.58–3.89 for no induced arrhythmia; 5.60%, 95% CI, 2.98–9.58 for induced arrhythmia). Conclusions— In patients with Brugada syndrome, arrhythmias induced with programmed ventricular stimulation are associated with future ventricular arrhythmia risk. Induction with fewer extrastimuli is associated with higher risk. However, clinical risk factors are important determinants of arrhythmia risk, and lack of induction does not necessarily portend low ventricular arrhythmia risk, particularly in patients with high-risk clinical features.

The Ser96Ala variant in histidine-rich calcium-binding protein is associated with life-threatening ventricular arrhythmias in idiopathic dilated cardiomyopathy.

Aims To investigate whether genetic variants of the histidine-rich calcium (HRC)-binding protein are associated with idiopathic dilated cardiomyopathy (DCM) and its progression. Methods and results We screened 123 idiopathic DCM patients and 96 healthy individuals by single-strand conformation polymorphism analysis and direct sequencing for genetic variants in HRC. Six polymorphisms were detected: Leu35Leu (A/G), Ser43Asn (G/A), Ser96Ala (T/G), Glu202_Glu203insGlu (−/GAG), Asp261del (GAT/−), and an in-frame insertion of 51 amino acids at His321. The analysis of their frequencies did not reveal any significant correlation with DCM development. However, the Ser96Ala polymorphism exhibited a statistically significant correlation with the occurrence of life-threatening ventricular arrhythmias. During a follow-up of 4.02 ± 2.4 years, the risk for ventricular arrhythmias was higher (HR, 9.620; 95% CI, 2.183–42.394; P = 0.003) in the Ala/Ala patients, compared with Ser/Ser homozygous patients. On multivariable Cox regression analysis, the Ser96Ala polymorphism was the only significant genetic arrythmogenesis predictor in DCM patients (HR, 4.191; 95% CI, 0.838–20.967; P = 0.018). Conclusion The Ser96Ala genetic variant of HRC is associated with life-threatening ventricular arrhythmias in idiopathic DCM and may serve as an independent predictor of susceptibility to arrhythmogenesis in the setting of DCM.

Provocation of Neurocardiogenic Syncope by Clomipramine Administration During the Head-Up Tilt Test in Vasovagal Syndrome

OBJECTIVES We sought to test the hypothesis that activation of the serotonergic system in patients with vasovagal syndrome during the head-up tilt test provokes syncope. BACKGROUND Central serotonergic activation participates in the pathogenesis of neurocardiogenic syncope. Drugs increasing serotonin (5-HT) in the central nervous system have not been tested as drug challenges during the head-up tilt test with clomipramine (Clom-HUT). METHODS The serotonergic re-uptake inhibitor clomipramine was infused (5 mg in 5 min) at the start of Clom-HUT in 55 patients (mean age 40 +/- 17 years) with a positive history of recurrent neurocardiogenic syncope and in 22 healthy control subjects (mean age 46 +/- 15 years). Blood samples were taken at 0, 5, 10 and 20 min for estimation of plasma prolactin and cortisol as neuroendocrine indicators of central serotonergic responsivity. All subjects had been previously tested with a basic 60 degrees head-up tilt test (B-HUT) for 30 min, and if negative, isoproterenol infusion was given at the end of the test. RESULTS Twenty-nine (53%) of the 55 patients and none of the 22 control subjects had a positive result in the B-HUT. With Clom-HUT, the proportion of patients who experienced a positive response increased to 80% (n = 44), although this happened to only one control subject. Prolactin and cortisol plasma levels increased significantly in the positive Clom-HUT patient group only. CONCLUSIONS The results indicate an increased responsivity of the central serotonergic neural system in subjects with vasovagal syndrome, the activation of which leads to sympathetic withdrawal. The use of clomipramine infusion with the tilt test seems to considerably improve its diagnostic value.

Central Serotonergic Responsiveness in Neurocardiogenic Syncope A Clomipramine Test Challenge

BACKGROUND Central serotonergic mechanisms appear to participate in the pathogenesis of recurrent neurally mediated syncope. The aim of the study was to investigate the responsiveness of the central serotonergic system by measuring the prolactin and cortisol responses to intravenous administration of the serotonin reuptake inhibitor clomipramine. METHODS AND RESULTS Twenty subjects free of any medical treatment were tested. Twelve had a history of recurrent syncopal attacks and positive tilt test (patient group, mean age 47+/-18 years, 8 men); 8 subjects without syncope and a negative tilt test result served as control subjects (mean age 49+/-10 years, 5 men). Twenty-five milligrams of clomipramine was administered intravenously within 15 minutes, and blood samples were taken at 0, 15, 30, 45, and 60 minutes. Two days later, a tilt test was performed at 60 degrees for 30 minutes and blood samples were taken at 0, 10, 20, and 30 minutes. During the clomipramine challenge, plasma prolactin levels increased in both groups. The levels at 30 minutes were higher in the patient group compared with the control group (17.3+/-7.2 vs 9.3+/-7.6 ng/mL, P=0.05). Similar results were observed for cortisol at 30 minutes (172+/-15 vs 118+/-21 ng/mL P=0. 04) and at 45 minutes (189+/-20 vs 116+/-23 ng/mL, P=0.03). The tilt test was positive in 8 (67%) out of 12 of the patient group and negative in all control subjects. In the samples taken during the tilt test, significant increases in prolactin and cortisol were observed only in the subjects with positive tilt test results. CONCLUSIONS Patients with a history of neurocardiogenic syncope show a higher responsiveness of the central serotonergic system to clomipramine challenge. The results support the view that central serotonergic mechanisms are involved in the pathophysiology of the syndrome.

Cardiac denervation after radiofrequency ablation of supraventricular tachycardias.

Inappropriate sinus tachycardia and atrial arrhythmias have been reported after radiofrequency ablation. Previous studies have suggested that cardiac denervation is a possible explanation for these rhythm disturbances. The aim of this study was to investigate possible alterations in autonomic innervation of the heart after ablation using the techniques of heart rate variability (HRV) analysis and metaiodobenzylguanidine (I-123 MIBG) scintigraphy. The subjects of this study were 30 consecutive patients aged 25 to 40 years, without structural heart disease, who underwent radiofrequency ablation of atrioventricular nodal slow pathways, and posteroseptal and left lateral accessory pathways because of symptomatic recurrent reentrant tachycardias. Time and frequency domain analysis of HRV after ablation revealed a significant reduction in the indexes of the mean of all 5-minute standard deviation of RR intervals (p = 0.042), low frequency (p = 0.0005), and total frequency (p = 0.008) compared with preablation values in the group of patients who underwent atrioventricular nodal slow pathway ablation. Patients who underwent ablation of a posteroseptal accessory pathway also had significant attenuation of the indexes of standard deviation about the mean RR interval (p = 0.03), standard deviation of 5-minute mean RR intervals (p = 0.006), and low-frequency (p <0.0001), and high-frequency (p <0.0001) components. Significant I-123 MIBG map defects, indicating efferent cardiac sympathetic denervation, were also found in the same groups of patients: atrioventricular nodal group (p = 0.0024), posteroseptal accessory pathway group (p = 0.0007). None of the above changes in HRV and 123-I MIBG scintigraphy were seen in patients who underwent ablation of left lateral accessory pathways. We conclude that radiofrequency ablation in the anterior, mid-, and posterior regions of the low intraatrial septum may disrupt sympathetic fibers located in these regions, causing cardiac sympathetic denervation. The density of these fibers appear to be less along the left atrioventricular groove.

Hormonal Responses During Tilt-Table Test in Neurally Mediated Syncope

The hormonal profile during tilt testing was examined in syncopal patients. An increase in the growth hormones cortisol and prolactin was found during syncope, suggesting an implication of central serotonergic activation.

Antiinflammatory Effects of Cardiac Resynchronization Therapy in Patients with Chronic Heart Failure

Background: Cardiac resynchronization therapy (CRT) pacing has been proposed as an additional treatment to medical therapy to improve heart failure patients with left ventricular asynchrony. The aim of this study was to evaluate the influence of CRT treatment on proinflammatory cytokines in patients with heart failure.