Self-Organization of Blood Pressure Regulation: Experimental Evidence.

Blood pressure regulation is a prime example of homeostatic regulation. However, some characteristics of the cardiovascular system better match a non-linear self-organized system than a homeostatic one. To determine whether blood pressure regulation is self-organized, we repeated the seminal demonstration of self-organized control of movement, but applied it to the cardiovascular system. We looked for two distinctive features peculiar to self-organization: non-equilibrium phase transitions and hysteresis in their occurrence when the system is challenged. We challenged the cardiovascular system by means of slow, 20-min Tilt-Up and Tilt-Down tilt table tests in random order. We continuously determined the phase between oscillations at the breathing frequency of Total Peripheral Resistances and Heart Rate Variability by means of cross-spectral analysis. We looked for a significant phase drift during these procedures, which signed a non-equilibrium phase transition. We determined at which head-up tilt angle it occurred. We checked that this angle was significantly different between Tilt-Up and Tilt-Down to demonstrate hysteresis. We observed a significant non-equilibrium phase transition in nine healthy volunteers out of 11 with significant hysteresis (48.1 ± 7.5° and 21.8 ± 3.9° during Tilt-Up and Tilt-Down, respectively, p < 0.05). Our study shows experimental evidence of self-organized short-term blood pressure regulation. It provides new insights into blood pressure regulation and its related disorders.

Fetal tachycardia: a role for amiodarone as first- or second-line therapy?

BACKGROUND: Fetal tachycardias result in serious prenatal and postnatal morbidity and mortality. Intrauterine treatment can improve prognosis dramatically and the therapeutic protocol is well defined. Currently, amiodarone is used as third-line therapy and is reserved for refractory cases. AIMS: Our aim was to review the management and outcome of fetal tachycardia, giving particular consideration to the efficacy and safety of amiodarone therapy. METHODS: This was a retrospective study of 24 consecutive cases of sustained fetal tachycardia, treated mainly with digoxin and/or amiodarone administered by the transplacental route. RESULTS: The 24 fetal tachycardias comprised 16 supraventricular tachycardias with 1:1 atrioventricular conduction, seven atrial flutters and one ventricular tachycardia. Seven fetuses were hydropic and eight experienced less severe cardiac failure. Digoxin monotherapy converted 5/12 non-hydropic fetuses and 0/2 hydropic fetuses, with one intrauterine death. Amiodarone monotherapy converted 5/5 fetuses, including two hydropic fetuses: one ventricular tachycardia, two atrial flutters and two supraventricular tachycardias. When administered with digoxin, amiodarone converted all but two fetuses (7/9). No deaths were associated with amiodarone, but there was moderate morbidity, with six transient elevations of thyroid stimulating hormone at birth, two of which required short-term thyroid hormonal substitution therapy. CONCLUSION: Maternal oral amiodarone seems to be effective and relatively safe, even in hydropic fetuses. We suggest that this treatment could be used earlier than is currently advised.

Risk factors related to infections of implanted pacemakers and cardioverter-defibrillators: results of a large prospective study.

BACKGROUND: The Prospective Evaluation of Pacemaker Lead Endocarditis study is a multicenter, prospective survey of the incidence and risk factors of infectious complications after implantation of pacemakers and cardioverter-defibrillators. METHODS AND RESULTS: Between January 1, 2000, and December 31, 2000, 6319 consecutive recipients of implantable systems were enrolled at 44 medical centers and followed up for 12 months. All infectious complications were recorded, and their occurrence was related to the baseline demographic, clinical, and procedural characteristics. Among 5866 pacing systems, 3789 included 2 and 117 had >2 leads; among 453 implantable cardioverter-defibrillators, 178 were dual-lead systems. A total of 4461 de novo implantations occurred and 1858 pulse generator or lead replacements. Reinterventions were performed before hospital discharge in 101 patients. Single- and multiple-variable logistic regression analyses were performed to identify risk factors; adjusted odds ratios (aORs) and 95% confidence intervals (CIs) were calculated. At 12 months, device-related infections were reported in 42 patients (0.68%; 95% CI, 0.47 to 0.89). The occurrence of infection was positively correlated with fever within 24 hours before the implantation procedure (aOR, 5.83; 95% CI, 2.00 to 16.98), use of temporary pacing before the implantation procedure (aOR, 2.46; 95% CI, 1.09 to 5.13), and early reinterventions (aOR, 15.04; 95% CI, 6.7 to 33.73). Implantation of a new system (aOR, 0.46; 95% CI, 0.24 to 0.87) and antibiotic prophylaxis (aOR, 0.4; 95% CI, 0.18 to 0.86) were negatively correlated with risk of infection. CONCLUSIONS: This study identified several factors of risk of device infection and confirmed the efficacy of antibiotic prophylaxis in recipients of new or replacement pacemakers or implantable cardioverter-defibrillators.

Cardiovascular variables do not predict head-up tilt test outcome better than body composition.

Reflex syncope is a well-recognized phenomenon, but the understanding of its underlying pathophysiology remains limited. We hypothesized that patients with a history of syncope and a positive head-up tilt test (HUTT) outcome are in a "not-yet defined" abnormal state even before the head-up position. We performed a 45 min HUTT on 86 patients with a history of syncope. We assessed 19 variables during the supine period before head-up position. Of these variables, 9 were cardiovascular variables (CV) while 8 were body composition variables (BC). The two remaining variables were age and sex. Forty-five patients (41 +/- 15 years, 22 males) have a positive HUTT outcome and 41 a negative one (46 +/- 15 years, 22 males). Statistical tests applied on each of the 19 variables individually did not discriminate patients with a positive and a negative outcome. We used neural networks to screen the sets of variables that allowed for the best predictions of HUTT outcomes. The sensitivity, specificity, positive and negative predictive values (PPV and NPV, respectively) were determined. The best set of predictive values determined from the 19 variables was 76, 81, 78 and 80% for sensitivity, sensibility, PPV, and NPV, respectively. Unexpectedly, the HUTT outcome prediction performed with cardiovascular variables was not better than the prediction performed with body composition variables only. Patients with a positive HUTT outcome are in an abnormal state that can be detected even before the head-up position. Body composition is an important contributor to this abnormal state.

Clinical aspects and prognosis of Brugada syndrome in children.

BACKGROUND: Brugada syndrome is an arrhythmogenic disease characterized by an ECG pattern of ST-segment elevation in the right precordial leads and augmented risk of sudden cardiac death. Little is known about the clinical presentation and prognosis of this disease in children. METHODS AND RESULTS: Thirty children affected by Brugada syndrome who were <16 years of age (mean, 8+/-4 years) were included. All patients displayed a type I ECG pattern before or after drug provocation challenge. Diagnosis of Brugada syndrome was made under the following circumstances: aborted sudden death (n=1), syncope of unexplained origin (n=10), symptomatic supraventricular tachycardia (n=1), suspicious ECG (n=1), and family screening for Brugada syndrome (n=17). Syncope was precipitated by fever in 5 cases. Ten of 11 symptomatic patients displayed a spontaneous type I ECG. An implantable cardioverter-defibrillator was implanted in 5 children; 4 children were treated with hydroquinidine; and 1 child received a pacemaker because of symptomatic sick sinus syndrome. During a mean follow-up of 37+/-23 months, 1 child experienced sudden cardiac death, and 2 children received an appropriate implantable cardioverter-defibrillator shock; all of them were symptomatic and had manifested a type I ECG spontaneously. One child had a cardioverter-defibrillator infection that required explantation of the defibrillator. CONCLUSIONS: In the largest population of children affected by Brugada syndrome described to date, fever represented the most important precipitating factor for arrhythmic events, and as in the adult population, the risk of arrhythmic events was higher in previously symptomatic patients and in those displaying a spontaneous type I ECG.

Increased hydration alone does not improve orthostatic tolerance in patients with neurocardiogenic syncope.

In patients with neurocardiogenic syncope, the beneficial effects of increased daily fluid intake, without an accompanying high dose of salt, are unknown. Our aim was to (1) determine whether plasma volume was low in patients with recurrent neurocardiogenic syncope, and (2) determine how recommendation about increased daily fluid intake, without an accompanying high dose of sodium, effects plasma volume and if this potential therapy improves orthostatic tolerance. Eighty-six patients with neurocardiogenic syncope were recruited in a prospective randomized open study. After an initial head-up tilt test, patients were randomly assigned to either the hydration supplementation group (1500 ml of water + 1500 mg of NaCl/day) or the no treatment (control) group. After ten days a second head-up tilt test was performed. Plasma volume, osmolality, and total body water were measured at baseline, and heart rate, arterial blood pressure, and cardiac transthoracic impedance were monitored during tilting. Hydration treatment did not affect the number of positive tilt tests (52% initial day, 54% after treatment, NS). In both groups, the overall number of positive tilt tests decreased between the initial and final head-up tilt test. There was no association between low plasma volume and positive tilt test. Patients with the lowest plasma volume were equally distributed in both positive and negative tilt response groups. An increased daily intake of fluid, without an accompanying high dose of salt, had no measurable beneficial effect on tolerance to head-up tilting in patients with neurocardiogenic syncope. Moreover in this patient group there was no association between a low plasma volume and a reduced tolerance to orthostatic stress.

Use of a new cardiac pacing mode designed to eliminate unnecessary ventricular pacing.

AIMS: To examine the performance of AAIsafeR2, a new pacing mode to minimize the cumulative proportion of ventricular pacing in patients who do not need regular ventricular support. METHODS AND RESULTS: The safety of AAIsafeR2 was examined in 123 recipients (73 +/- 12 years old, 51% men) of dual chamber pacemakers implanted for sinus node dysfunction, paroxysmal AV block or the bradycardia-tachycardia syndrome. Data were collected from pacemaker diagnostics, and the first 43 patients underwent 24-h Holter recordings before being discharged from the hospital with AAIsafeR2 activated. No adverse event related to AAIsafeR2 was observed. All ventricular pauses detected on Holter tapes triggered immediate back-up ventricular pacing. Appropriate switches to DDD occurred in 97 of 123 patients. In 69 of 123 devices (56%) switches to DDD were non-sustained, and the average % ventricular pacing in this group was 0.2+/-0.5%. CONCLUSION: AAIsafeR2 mode seems to be safe and reliable in patients with infrequent slowing or pauses in ventricular activity, while maintaining ventricular pacing below 1%.

Progressive cardiac conduction defect is the prevailing phenotype in carriers of a Brugada syndrome SCN5A mutation.

INTRODUCTION: Loss-of-function mutations in the SCN5A gene encoding the cardiac sodium channel are responsible for Brugada syndrome (BS) and also for progressive cardiac conduction disease (inherited Lenègre disease). In an attempt to clarify the frontier between these two entities, we have characterized cardiac conduction defect and its evolution with aging in a cohort of 78 patients carrying a SCN5A mutation linked to Brugada syndrome. METHODS AND RESULTS: Families were included in the study if a SCN5A mutation was identified in a BS proband and if at least two family members were mutation carriers. Sixteen families met the study criteria, representing 78 carriers. Resting ECG showed a spontaneous BS ECG pattern in 28 of 78 (36%) gene carriers. Intraventricular conduction anomalies were identified in 59 of 78 gene carriers including complete (17) or incomplete (24) right bundle branch block, right bundle branch block plus hemiblock (6), left bundle branch block (1), hemiblock (1), and parietal block (10). PR and QRS duration were longer in the gene carrier cohort in comparison with their relatives carrying no mutation. Finally, in the gene carrier cohort conduction defect progressively aggravated with aging leading in five occasions to pacemaker implantations. CONCLUSION: The present study shows that the most common phenotype of gene carriers of a BS-type SCN5A mutation is progressive cardiac conduction defects similar to the Lenègre disease phenotype. In consequence, we propose that carriers of a SCN5A mutation need a clinical and ECG follow-up because of the risk associated with severe conduction defects.

Do we need a reflex tachycardia to stand up?

BACKGROUND: Sophisticated atrio-ventricular pacing models are designed to integrate the pacemaker into cardiovascular autonomic control to react appropriately to the cardiovascular demands. Such an approach might be beneficial for patients with vasovagal responses to counterbalance the upright fall in arterial blood pressure by a pacing rate increase. We hypothesized that this approach would improve the cardiovascular response to standing in comparison with a regular pacing mode. METHODS: Two 5-minute tilt tests were performed in a random order in 5 patients with a pacemaker (CLS-INOS(2)) for sinus node disease and atrio-ventricular block. One tilt test was performed in fixed pacing rate (DDD), the other one was performed in close loop stimulation (CLS), which allowed an upright rate-rise pacing. Heart rate, systolic blood pressure, and cardiac output (modelflow) were recorded on a beat-by-beat basis. RESULTS: Changes of systolic blood pressure and cardiac output in response to upright posture were not significantly different between DDD and CLS modes (2.7 +/- 13.2 vs 10.1 +/- 12.9 mmHg and -0.8 +/- 0.3 vs -1.1 +/- 0.4 L/min, respectively). But upright posture led to a tachycardia of more than 30 bpm in 3 patients in CLS mode and to a fall in systolic blood pressure greater than 20 mmHg in 3 patients in CLS mode and only in one patient in DDD mode. CONCLUSION: Systolic blood pressure and cardiac output are not improved by the upright tachycardia and upright blood pressure response is actually worsened when an upright rate-rise pacing is used. Thus, it appears that tachycardia alone cannot compensate for an upright fall in blood pressure.

Late hemodynamic changes during a negative passive head-up tilt predict the symptomatic outcome to a nitroglycerin sensitized tilt.

BACKGROUND: Sublingual nitroglycerin is advocated to sensitize the passive 70 degrees head-upright tilt test (HUTT) of patients with unexplained syncope. We hypothesized that a detailed analysis of hemodynamic responses recorded during a negative HUTT could predict the outcome to a subsequent nitroglycerin sensitized HUTT (NTG-HUTT). METHODS: Thirty-two patients (46 +/- 3 years, 17 males) with recurrent unexplained syncope but a negative HUTT were included. Heart rate, arterial blood pressure, and central hemodynamics assessed by transthoracic impedance (preejection and rapid left ventricular ejection time, slow ejection time, peak amplitude of first derivative, and cardiac index) were recorded during supine rest and 45 minutes HUTT. Changes from supine rest of the variables were retrospectively compared between patients with a negative (n = 15, NTG-HUTT(-)) and positive (n = 17, NTG-HUTT(+)) outcome to 10 minutes subsequent NTG-HUTT. RESULT: Significant differences between groups were observed during the 15th-20th minutes (Italian protocol) and during the last 5 minutes of passive HUTT (Westminster protocol). The combination of cutoff values, determined by receiver operating curves, on hemodynamic variables changes during the last 5 minutes predicted the outcome to a NTG-HUTT with a sensitivity of 76% and a specificity of 87%. The cutoff values determined during 15th-20th minutes gave an attractive sensitivity (85%) but a too weak specificity (53%) to shorten the 45 minutes passive HUTT at 20 minutes. CONCLUSION: Outcome to a NTG-HUTT can be reliably predicted by selected criteria determined from multiple hemodynamic variables recorded during a passive 70 degrees HUTT.

Fever as a precipitant of idiopathic ventricular fibrillation in patients with normal hearts.

INTRODUCTION: Ventricular fibrillation (VF) is the main mechanism of sudden cardiac death. The clinical precipitants of sudden cardiac death due to idiopathic VF are poorly characterized. Emerging evidence implicates triggers originating predominantly from the distal Purkinje arborization and the right ventricular outflow tract. METHODS AND RESULTS: We report three patients without structural heart disease or repolarization abnormalities in whom a febrile illness was the only concurrent disease associated with unexpected sudden cardiac death due to VF storm. An automated defibrillator was implanted in all three patients. In one patient with persistent recurrent VF episodes, mapping demonstrated the origin of these triggers was from the Purkinje arborization of the anterior wall of the right ventricle. Ablation at a site of earliest activation during ectopy, where pace mapping was concordant and Purkinje potential preceded the onset of ventriculogram, resulted in suppression of all arrhythmias. After follow-up of 22, 9, and 18 months in the three patients, no ventricular arrhythmias have been recorded. CONCLUSION: We present a series of patients in whom an apparently benign febrile illness was associated with malignant ventricular arrhythmias in the absence of cardiac disease or other factors known to precipitate sudden cardiac death. Physicians should be aware of this possible phenomenon in cases of febrile illness associated with syncope.

Haemodynamic response to peripheral venous congestion in patients with unexplained recurrent syncope.

In patients with recurrent unexplained syncope, exaggerated peripheral venous pooling and impaired circulatory adjustment is thought to contribute to the outcome of a head-up tilt (HUT) test. The present study investigated the role of leg volume changes during venous congestion in the haemodynamic response of patients with recurrent unexplained syncope and the ability to predict the outcome of a HUT test. Changes in calf volume (strain gauge plethysmography), heart rate and arterial blood pressure were recorded in 60 patients with history of unexplained syncope (without postural tachycardia symptom) during venous congestion provoked by pneumatic thigh cuffs while supine at rest and during the initial 10 min of a 45 min 70 degrees HUT test. Twenty-seven patients [age (mean+/-S.D.), 39+/-16 years] exhibited symptoms [HUT(+)] and 33 patients (45+/-14 years) were asymptomatic [HUT(-)]. During venous congestion, mean+/-S.E.M. calf volume increased in both groups [HUT(-), 4.5+/-0.2; HUT(+), 4.8+/-0.4 ml x 100 ml(-1), not significant), but significantly less during head-upright tilt [HUT(-), 3.3+/-0.2, P <0.01; HUT(+), 2.6+/-0.3 ml x 100 ml(-1), P <0.001] without differences between the groups. During venous congestion, arterial pressure increased significantly in asymptomatic HUT(-) patients, but not in the HUT(+) patients. Calf volume changes did not correlate with a symptomatic outcome to a 70 degrees HUT. The lack of exaggerated venous pooling during venous congestion and the inability of calf volume changes to predict a positive HUT suggest that excessive venous pooling does not contribute to the outcome of HUT. Attenuated changes in arterial pressure during venous congestion while supine suggest impaired adjustment of peripheral resistance to leg venous occlusion.

Programming optimal atrioventricular delay in dual chamber pacing using peak endocardial acceleration: comparison with a standard echocardiographic procedure.

Optimization of programmed atrioventricular delay in dual chamber pacing is essential to the hemodynamic efficiency of the heart. Automatic AV delay optimization in an implanted pacemaker is highly desirable. Variations of peak endocardial acceleration (PEA) with AV delay at rest correlate well with echocardiography derived observations, particularly with end-diastolic filling and mitral valve closure timings. This suggests the possibility of devicing a procedure for the automatic determination of the optimal AV delay. The aim of this study was to compare a proposed algorithm for optimal AV delay determination with an accepted echocardiographic method. Fifteen patients with high degree AV block received BEST-Living pacing systems. Automatic AV delay scans were performed at rest (60-300 ms in 20-ms steps with 60 beats per step) in DDD at 90 ppm, while simultaneously recording cycle-by-cycle PEA values, which were averaged for each AV delay to obtain a PEA versus AV delay curve. Nonlinear regression analysis based on a Boltzmann sigmoid curve was performed, and the optimal AV delay (OAVD) was chosen as the sigmoid inflection point of the regression curve. The OAVD was also evaluated for each patient using the Ritter echocardiographic method. Good sigmoid fit was obtained in 13 of 15 patients. The mean OAVD obtained by the PEA sigmoid algorithm was 146.9 +/- 32.1 ms, and the corresponding result obtained by echocardiography was 156.4 +/- 34.3 ms (range 31.8-39.7 ms). Correlation analysis yielded r = 0.79, P = 0.0012. In conclusion, OAVD estimates obtained by PEA analysis during automatic AV delay scanning are consistent with those obtained by echocardiography. The proposed algorithm can be used for automatic OAVD determination in an implanted pacemaker pulse generator.

Changes in the transthoracic impedance signal predict the outcome of a 70 degrees head-up tilt test.

We determined whether early changes in central haemodynamics, as determined by transthoracic impedance, induced by a 70 degrees head-up tilt (HUT) test could predict syncope. Heart rate, arterial blood pressure and central haemodynamics [pre-ejection period and rapid left ventricular ejection time ( T (1)), slow ejection time ( T (2)) and d Z /d t (max) (where Z is thoracic impedance), assessed by the transthoracic impedance technique], were recorded during supine rest and during a 45 min 70 degrees HUT test in 68 patients (40+/-2 years) with a history of unexplained recurrent syncope. We found that 38 patients (42+/-3 years) had a symptomatic outcome to 70 degrees HUT (fainters) and 30 (39+/-2 years) had a negative outcome (non-fainters). When measured between 5 and 10 min of 70 degrees HUT, T (2) had increased significantly only in the fainters, and a change in T (2) of >40 ms from baseline predicted a positive outcome with a sensitivity of 68% and a specificity of 70%. During supine rest prior to 70 degrees HUT, the fainters exhibited a shorter T (2) than non-fainters (183+/-10 compared with 233+/-14 ms; P <0.01), and a T (2) of <199 ms predicted a positive outcome to 70 degrees HUT with a sensitivity of 68% and a specificity of 63%. Incorporation of the changes that occurred from rest to 70 degrees HUT in other haemodynamic variables (heart rate >11 beats/min, systolic pressure <2 mmHg, diastolic pressure <7 mmHg and pulse pressure <-3 mmHg) increased the specificity to 97% and the positive predictive value to 93%. Thus transthoracic impedance could detect differences in central haemodynamics between fainters and non-fainters during supine rest and during the initial period of 70 degrees HUT with a consistent sensitivity and specificity when combined with peripheral haemodynamic variables.

Comparison between isoproterenol and nitroglycerin sensitized head-upright tilt in patients with unexplained syncope and negative or positive passive head-up tilt response.

It is unknown if the head-upright tilt test in patients who receive isoproterenol and nitroglycerin can identify different populations with vasovagal syncope. The aim of this study was to compare the positive or negative responses to passive tilt between isoproterenol- and nitroglycerin-sensitized upright tilt. Ninety-six patients referred for unexplained recurrent syncope underwent passive tilt (45 minutes at 70 degrees angle), which was then systematically followed, within the same session and in a random order, by a 20-minute tilt at a 70 degrees angle after administration of nitroglycerin (NTG-tilt) and 10-minute tilt at a 70 degrees angle with a continuous infusion of isoproterenol (ISO-tilt). NTG-tilt led to significantly more positive responses than passive tilt or ISO-tilt (55% vs 34% vs 42%, respectively). In the subgroup of patients with a positive response during passive tilt, the percentage of positive responses with NTG-tilt was significantly higher than with ISO-tilt (94% vs 67%). The agreement between NTG-tilt and ISO-tilt was very weak (Kappa coefficient 0.06). In the subgroup of patients with a negative response during passive tilt, the percentage of positive responses between NTG-tilt and ISO-tilt was similar (35% vs 29%). The agreement between NTG-tilt and ISO-tilt was good (Kappa coefficient 0.34). NTG-tilt led to a higher number of positive responses than ISO-tilt, especially when passive tilt outcome was positive. These 2 pharmacologic agents may identify 2 different subpopulations of patients because of their specific pharmacologic actions.

Holter changes resulting from right-sided and bilateral infrastellate upper thoracic sympathectomy.

BACKGROUND: We tested the hypothesis that no right-sided dominance exists after infrastellate surgical upper-thoracic sympathectomy. We aimed to confirm whether a significant bradycardia was constant and only dependent on the right side. METHODS: We performed 24-hour Holter electrocardiographic recordings in 12 patients referred for bilateral sympathectomy. Surgery was performed at two distinct times allowing for the study of the consequences of unilateral right and bilateral sympathectomy. RESULTS: Heart rate was 77 +/- 8 beats per minute before surgery on the 24-hour recording and significantly decreased after bilateral (67.8 +/- 6.5 beats per minute; p < 0.05) but not after unilateral right sympathectomy. Consistently spectral analysis variables significantly changed after bilateral surgery but showed no right-sided dominance. Little effect of sympathectomy was found on the QT interval, which tended to decrease after bilateral sympathectomy. CONCLUSIONS: Patients should be informed of the bradycardia resulting from sympathectomy. No right-sided dominance can be found consistently with the random distribution of substellate cardiac fibers reported in anatomic studies.