Factors Associated With Sinoatrial Reinnervation After Heart Transplantation.

Background: Factors associated with sympathetic and parasympathetic sinoatrial reinnervation after heart transplantation (HTx) are inadequately studied. Methods: Fifty transplant recipients were examined at 7 to 12 wk (index visit), 6, 12, 24, and 36 mo after HTx. Supine rest heart rate variability in the low-frequency (LF) domain (sympathetic and parasympathetic sinoatrial reinnervation) and the high-frequency (HF) domain (parasympathetic sinoatrial reinnervation) were measured repeatedly and related to selected recipient, donor, and perisurgical characteristics. We primarily aimed to identify index visit factors that affect the sinoatrial reinnervation process. Secondarily, we examined overall associations between indices of reinnervation and repeatedly measured recipient characteristics to generate new hypotheses regarding the consequences of reinnervation. Results: LF and HF variability increased time dependently. In multivariate modeling, a pretransplant diagnosis of nonischemic cardiomyopathy (P = 0.038) and higher index visit handgrip strength (P = 0.028) predicted improved LF variability. Recipient age, early episodes of rejection, and duration of extracorporeal circulation were not associated with indices of reinnervation. Study average handgrip strength was positively associated with LF and HF variability (respectively, P = 0.005 and P = 0.029), whereas study average C-reactive protein was negatively associated (respectively, P = 0.015 and P = 0.008). Conclusions: Indices of both sympathetic and parasympathetic sinoatrial reinnervation increased with time after HTx. A pretransplant diagnosis of nonischemic cardiomyopathy and higher index visit handgrip strength predicted higher indices of mainly sympathetic reinnervation, whereas age, rejection episodes, and duration of extracorporeal circulation had no association. HTx recipients with higher indices of reinnervation had higher average handgrip strength, suggesting a link between reinnervation and improved frailty. The more reinnervated participants had lower average C-reactive protein, suggesting an inhibitory effect of reinnervation on inflammation, possibly through enhanced function of the inflammatory reflex. These potential effects of reinnervation may affect long-term morbidity in HTx patients and should be scrutinized in future research.

IV Sotalol Use in Pediatric and Congenital Heart Patients: A Multicenter Registry Study.

Background There is limited information regarding the clinical use and effectiveness of IV sotalol in pediatric patients and patients with congenital heart disease, including those with severe myocardial dysfunction. A multicenter registry study was designed to evaluate the safety, efficacy, and dosing of IV sotalol. Methods and Results A total of 85 patients (age 1 day-36 years) received IV sotalol, of whom 45 (53%) had additional congenital cardiac diagnoses and 4 (5%) were greater than 18 years of age. In 79 patients (93%), IV sotalol was used to treat supraventricular tachycardia and 4 (5%) received it to treat ventricular arrhythmias. Severely decreased cardiac function by echocardiography was seen before IV sotalol in 7 (9%). The average dose was 1 mg/kg (range 0.5-1.8 mg/kg/dose) over a median of 60 minutes (range 30-300 minutes). Successful arrhythmia termination occurred in 31 patients (49%, 95% CI [37%-62%]) with improvement in rhythm control defined as rate reduction permitting overdrive pacing in an additional 18 patients (30%, 95% CI [19%-41%]). Eleven patients (16%) had significant QTc prolongation to >465 milliseconds after the infusion, with 3 (4%) to >500 milliseconds. There were 2 patients (2%) for whom the infusion was terminated early. Conclusions IV sotalol was safe and effective for termination or improvement of tachyarrhythmias in 79% of pediatric patients and patients with congenital heart disease, including those with severely depressed cardiac function. The most common dose, for both acute and maintenance dosing, was 1 mg/kg over ~60 minutes with rare serious complications.

Predictors of Hypertension Development 1 Year After Heart Transplantation.

BACKGROUND: Hypertension after heart transplantation (HTx) is common. We investigated predictors of and mechanisms for hypertension development during the first year after HTx, with particular attention toward immunosuppressive agents, reinnervation processes, and donor/recipient sex. METHODS: Heart transplant recipients (HTxRs) were consecutively enrolled 7 to 12 wk after surgery and followed prospectively for 12 mo. Ambulatory blood pressure recordings and autonomic cardiovascular control assessments were performed at baseline and follow-up. Possible predictors of posttransplant hypertension development were investigated in bivariate linear regression analyses followed by multiple regression modeling. RESULTS: A total of 50 HTxRs were included; 47 attended the follow-up appointment at 12 mo. Mean systolic and diastolic blood pressure increased significantly during the observational period (systolic blood pressure from 133 to 139 mm Hg, P = 0.007; diastolic blood pressure from 81 to 84 mm Hg, P = 0.005). The blood pressure increment was almost exclusively confined to HTxRs with a female donor heart, doubling the cases of systolic hypertension (from 6 to 13/14; 46% to 93%, P = 0.031) and diastolic hypertension (from 7 to 14/14; 54% to 100%, P = 0.031) in this subgroup. Autonomic cardiovascular control assessments suggested tonically constricted resistance and capacitance vessels in recipients with female donor hearts. Immunosuppressive agents and reinnervation markers were not associated with hypertension development. CONCLUSIONS: Blood pressures increase during the first year after HTx, with female donor sex as a strong predictor of recipient hypertension development. The underlying mechanism seems to be enhanced peripheral vasoconstriction caused by attenuated cardiovascular homeostasis capabilities. Further studies are needed to confirm the results.

Relation of Norwood Shunt Type and Frequency of Arrhythmias at 6 Years (from the Single Ventricle Reconstruction Trial).

The Norwood procedure with a right ventricular to pulmonary artery shunt (RVPAS) decreases early mortality, but requires a ventriculotomy, possibly increasing risk of ventricular arrhythmias (VAs) compared with the modified Blalock-Taussig shunt (MBTS). The effect of shunt and Fontan type on arrhythmias by 6 years of age in the SVRII (Single Ventricle Reconstruction Extension Study) was assessed. SVRII data collected on 324 patients pre-/post-Fontan and annually at 2 to 6 years included antiarrhythmic medications, electrocardiography (ECG) at Fontan, and Holter/ECG at 6 years. ECGs and Holters were reviewed for morphology, intervals, atrioventricular conduction, and arrhythmias. Isolated VA were seen on 6-year Holter in >50% of both cohorts (MBTS 54% vs RVPAS 60%), whereas nonsustained ventricular tachycardia was rare and observed in RVPAS only (2.7%). First-degree atrioventricular block was more common in RVPAS than MBTS (21% vs 8%, p = 0.01), whereas right bundle branch block, QRS duration, and QTc were similar. Antiarrhythmic medication usage was common in both groups, but most agents also supported ventricular function (e.g., digoxin, carvedilol). Of the 7 patients with death or transplant between 2 and 6 years, none had documented VAs, but compared with transplant-free survivors, they had somewhat longer QRS (106 vs 93 ms, p = 0.05). Atrial tachyarrhythmias varied little between MBTS and RVPAS but did vary by Fontan type (lateral tunnel 41% vs extracardiac conduit 29%). VAs did not vary by Fontan type. In conclusion, at 6-year follow-up, benign VAs were common in the SVRII population. However, despite the potential for increased VAs and sudden death in the RVPAS cohort, these data do not support significant differences or increased risk at 6 years. The findings highlight the need for ongoing surveillance for arrhythmias in the SVR population.

Heart rate variability and the dawn of complex physiological signal analysis: methodological and clinical perspectives.

Spontaneous beat-to-beat variations of heart rate (HR) have intrigued scientists and casual observers for centuries; however, it was not until the 1970s that investigators began to apply engineering tools to the analysis of these variations, fostering the field we now know as heart rate variability or HRV. Since then, the field has exploded to not only include a wide variety of traditional linear time and frequency domain applications for the HR signal, but also more complex linear models that include additional physiological parameters such as respiration, arterial blood pressure, central venous pressure and autonomic nerve signals. Most recently, the field has branched out to address the nonlinear components of many physiological processes, the complexity of the systems being studied and the important issue of specificity for when these tools are applied to individuals. When the impact of all these developments are combined, it seems likely that the field of HRV will soon begin to realize its potential as an important component of the toolbox used for diagnosis and therapy of patients in the clinic. This article is part of the theme issue 'Advanced computation in cardiovascular physiology: new challenges and opportunities'.

Functional evidence of low-pressure cardiopulmonary baroreceptor reinnervation 1 year after heart transplantation.

PURPOSE: Heart transplantation (HTx) implies denervation of afferent neural connections. Reinnervation of low-pressure cardiopulmonary baroreceptors might impact the development and treatment of hypertension, but little is known of its occurrence. The present prospective study investigated possible afferent reinnervation of low-pressure cardiopulmonary baroreceptors during the first year after heart transplantation. METHODS: A total of 50 heart transplant recipients (HTxRs) were included and were evaluated 7-12 weeks after transplant surgery, with follow-up 6 and 12 months later. In addition, a reference group of 50 healthy control subjects was examined once. Continuous, non-invasive recordings of cardiovascular variables were carried out at supine rest, during 15 min of 20° head-up tilt, during Valsalva maneuver and during 1 min of 30% maximal voluntary handgrip. In addition, routine clinical data including invasive measurements were used in the analyses. RESULTS: During the first year after HTx, the heart rate (HR) response to 20° head-up tilt partly normalized, a negative relationship between resting mean right atrial pressure and HR tilt response developed, low-frequency variability of the RR interval and systolic blood pressure at supine rest increased, and the total peripheral resistance response to Valsalva maneuver became stronger. CONCLUSION: Functional assessments suggest that afferent reinnervation of low-pressure cardiopulmonary receptors occurs during the first year after heart transplantation, partially restoring reflex-mediated responses to altered cardiac filling.

Early Signs of Sinoatrial Reinnervation in the Transplanted Heart.

BACKGROUND: Heart transplantation (HTx) surgically transects all connections to the heart, including the autonomic nerves. We prospectively examined signs, timing and consequences of early sympathetic and parasympathetic sinoatrial reinnervation, as well as explored indirect evidence of afferent cardiopulmonary reinnervation. METHODS: Fifty HTx recipients were assessed at 2.5, 6, and 12 mo after HTx. For comparison, 50 healthy controls were examined once. Continuous, noninvasive recordings of hemodynamic variables and heart rate variability indices were performed at supine rest, 0.2 Hz controlled breathing, 60° head-up-tilt, during the Valsalva maneuver and during handgrip isometric exercise. RESULTS: In HTx recipients, supine low-frequency heart rate variability gradually increased; supine high-frequency variability did not change; heart rate variability indices during controlled breathing remained unaltered; heart rate responses during tilt and isometric exercise gradually increased; the tachycardia response during Valsalva maneuver increased, while the bradycardia response remained unchanged; and indices of baroreflex sensitivity improved. Responses remained low compared to healthy controls. A negative correlation between indices of preload and heart rate response during head-up tilt emerged at 12 mo. CONCLUSIONS: Results suggest that sympathetic reinnervation of the sinoatrial node starts within 6 mo after HTx and strengthens during the first year. No evidence of early parasympathetic reinnervation was found. Indirect signs of afferent reinnervation of cardiopulmonary low-pressure baroreceptors emerged at 12 mo. Better sympathetic sinoatrial control improved heart rate responsiveness to orthostatic challenge and isometric exercise, as well as heart rate buffering of blood pressure fluctuations.

IDeA States Pediatric Clinical Trials Network for Underserved and Rural Communities.

The National Institutes of Health's Environmental Influences on Child Health Outcomes (ECHO) program aims to study high-priority and high-impact pediatric conditions. This broad-based health initiative is unique in the National Institutes of Health research portfolio and involves 2 research components: (1) a large group of established centers with pediatric cohorts combining data to support longitudinal studies (ECHO cohorts) and (2) pediatric trials program for institutions within Institutional Development Awards states, known as the ECHO Institutional Development Awards States Pediatric Clinical Trials Network (ISPCTN). In the current presentation, we provide a broad overview of the ISPCTN and, particularly, its importance in enhancing clinical trials capabilities of pediatrician scientists through the support of research infrastructure, while at the same time implementing clinical trials that inform future health care for children. The ISPCTN research mission is aligned with the health priority conditions emphasized in the ECHO program, with a commitment to bringing state-of-the-science trials to children residing in underserved and rural communities. ISPCTN site infrastructure is critical to successful trial implementation and includes research training for pediatric faculty and coordinators. Network sites exist in settings that have historically had limited National Institutes of Health funding success and lacked pediatric research infrastructure, with the initial funding directed to considerable efforts in professional development, implementation of regulatory procedures, and engagement of communities and families. The Network has made considerable headway with these objectives, opening two large research studies during its initial 18 months as well as producing findings that serve as markers of success that will optimize sustainability.

Autonomic cardiovascular control changes in recent heart transplant recipients lead to physiological limitations in response to orthostatic challenge and isometric exercise.

PURPOSE: Heart transplantation causes denervation of the donor heart, but the consequences for cardiovascular homeostasis remain to be fully understood. The present study investigated cardiovascular autonomic control at supine rest, during orthostatic challenge and during isometric exercise in heart transplant recipients (HTxR). METHODS: A total of 50 HTxRs were investigated 7-12 weeks after transplant surgery and compared with 50 healthy control subjects. Continuous, noninvasive recordings of cardiovascular variables were carried out at supine rest, during 15 min of 60° head-up tilt and during 1 min of 30% of maximal voluntary handgrip. Plasma and urine catecholamines were assayed, and symptoms were charted. RESULTS: At supine rest, heart rate, blood pressures and total peripheral resistance were higher, and stroke volume and end diastolic volume were lower in the HTxR group. During tilt, heart rate, blood pressures and total peripheral resistance increased less, and stroke volume and end diastolic volume decreased less. During handgrip, heart rate and cardiac output increased less, and stroke volume and end diastolic volume decreased less. Orthostatic symptoms were similar across the groups, but the HTxRs complained more of pale and cold hands. CONCLUSION: HTxRs are characterized by elevated blood pressures and total peripheral resistance at supine rest as well as attenuated blood pressures and total peripheral resistance responses during orthostatic challenge, possibly caused by low-pressure cardiopulmonary baroreceptor denervation. In addition, HTxRs show attenuated cardiac output response during isometric exercise due to efferent sympathetic denervation. These physiological limitations might have negative functional consequences.

"A Song of Ice and Fire"-another verse from the world of ablation.

The debate between the use of radiofrequency (RF) or cryoenergy for ablation near the atrioventricular (AV) conducting system or small coronaries has been fueled by the relative efficacies and risks of the two technologies, particularly in smaller hearts. The manuscript by Schneider et al adds another chapter to that ongoing debate.

Closed-Loop Cardiovascular Interactions and the Baroreflex Cardiac Arm: Modulations Over the 24 h and the Effect of Hypertension.

Closed-loop models of the interactions between blood pressure (BP) and heart rate variations allow for estimation of baroreflex sensitivity (feedback effects of BP changes on heart rate) while also considering the feedforward effects of heart rate on BP. Our study is aimed at comparing modulations of feedback and feedforward couplings over 24 h in normotensive and hypertensive subjects, by assessing closed-loop baroreflex models in ambulatory conditions. Continuous intra-arterial BP recordings were performed for 24 h in eight normotensive and eight hypertensive subjects. Systolic BP (SBP) and pulse interval (PI) beat-by-beat series were analyzed by an autoregressive moving average model over consecutive 6-min running windows, estimating closed-loop feedback and feedforward gains in each window. The open-loop feedback gain was estimated for comparison. Normotensive and hypertensive patients were compared during wake (18:00-22:00) and sleep (23:00-5:00) periods by a mixed-effect linear model at p < 0.05. In both groups feedback (feedforward) gain averaged values were higher (lower) in sleep than in wake. Moreover, the closed-loop feedback gain was higher in normotensive subjects both in wake and sleep, whereas the closed-loop feedforward gain was higher in hypertensive subjects during sleep. By contrast, no significant differences were found between the normotensive and hypertensive groups for the open-loop feedback gain. Therefore, the closed-loop SBP-PI model can detect circadian alterations in the feedforward gain of PI on SBP and derangements of spontaneous baroreflex sensitivity in hypertension not detectable with the open-loop approach. These findings may help to obtain a more comprehensive assessment of the autonomic dysfunction underlying hypertension and for the in-depth evaluation of the benefits of rehabilitation procedures on autonomic cardiovascular modulation.

Measures of sympathetic and parasympathetic autonomic outflow from heartbeat dynamics.

Reliable and effective noninvasive measures of sympathetic and parasympathetic peripheral outflow are of crucial importance in cardiovascular physiology. Although many techniques have been proposed to take up this long-lasting challenge, none has proposed a satisfying discrimination of the dynamics of the two separate branches. Spectral analysis of heart rate variability is the most currently used technique for such assessment. Despite its widespread use, it has been demonstrated that the subdivision in the low-frequency (LF) and high-frequency (HF) bands does not fully reflect separate influences of the sympathetic and parasympathetic branches, respectively, mainly due to their simultaneous action in the LF. Two novel heartbeat-derived autonomic measures, the sympathetic activity index (SAI) and parasympathetic activity index (PAI), are proposed to separately assess the time-varying autonomic nervous system synergic functions. Their efficacy is validated in landmark autonomic maneuvers generally employed in clinical settings. The novel measures move beyond the classical frequency domain paradigm through identification of a set of coefficients associated with a proper combination of Laguerre base functions. The resulting measures were compared with the traditional LF and HF power. A total of 236 ECG recordings were analyzed for validation, including autonomic outflow changes elicited by procedures of different nature and temporal variation, such as postural changes, lower body negative pressure, and handgrip tests. The proposed SAI-PAI measures consistently outperform traditional frequency-domain indexes in tracking expected instantaneous autonomic variations, both vagal and sympathetic, and may aid clinical decision making, showing reduced intersubject variability and physiologically plausible dynamics. NEW & NOTEWORTHY While it is possible to obtain reliable estimates of parasympathetic activity from the ECG, a satisfying method to disentangle the sympathetic component from HRV has not been proposed yet. To overcome this long-lasting limitation, we propose two novel HRV-based indexes, the sympathetic and parasympathetic activity indexes.

Epicardial ablation of tachyarrhythmia in children: Experience at two academic centers.

BACKGROUND: Experience with percutaneous epicardial ablation of tachyarrhythmia in pediatrics is limited. This case series addresses the feasibility, safety, and complications of the procedure in children. METHODS: A total of nine patients underwent 10 epicardial ablation procedures from 2002 to 2013 at two academic centers. Activation mapping was performed in all cases, and electroanatomic map was utilized in nine of the 10 procedures. Patients had undergone one to three failed endocardial catheter ablations in addition to medical management, and all had symptoms, a high-risk accessory pathway (AP), aborted cardiac arrest with Wolff-Parkinson-White syndrome (WPW), or ventricular dysfunction. A standard epicardial approach was used for access in all cases, using a 7- or 8- Fr sheath. Epicardial ablation modality was radiofrequency (RF) in seven, cryoablation (CRYO) in one, and CRYO plus RF in one. RESULTS: Median age was 14 (range 8-19) years. INDICATIONS: drug refractory ectopic atrial tachycardia (one), ventricular tachycardia (VT) (five), high-risk AP (two), and aborted cardiac arrest from WPW - (one). Epicardial ablation was not performed in one case despite access due to an inability to maneuver the catheter around a former pericardial scar. VT foci included the right ventricular outflow tract septum, high posterior left ventricle (LV), LV outflow tract, postero-basal LV, and scar from previous rhabdomyoma surgery. WPW foci were in the area of the posterior septum and coronary sinus in all three cases. Overall procedural success was 70% (7/10), with epicardial ablation success in five and endocardial ablation success after epicardial mapping in two. The VT focus was close to the left anterior descending coronary artery in one of the unsuccessful cases in which both RF and CRYO were used. There was one recurrence after a successful epicardial VT ablation, which was managed with a second successful epicardial procedure. There were no other recurrences at more than 1 year of follow-up. Complications were minimal, with one case of inadvertent pleural access requiring no specific therapy. No pericarditis or effusion was seen in any of the patients who underwent epicardial ablation. CONCLUSION: Epicardial ablation in pediatric patients can be performed with low complications and acceptable success. It can be considered for a spectrum of tachycardia mechanisms after failed endocardial ablation attempts and suspected epicardial foci. Success and recurrence may be related to foci in proximity to the epicardial coronaries, pericardial scar, or a distant location from the closest epicardial location. Repeat procedures may be necessary.

Efficacy of Intravenous and Oral Sotalol in Pharmacologic Conversion of Atrial Fibrillation: A Systematic Review and Meta-Analysis.

OBJECTIVES: The role of sotalol is well established for the maintenance of sinus rhythm after successful conversion of atrial fibrillation (AF). However, its role in pharmacologic conversion of AF is poorly defined. The purpose of this study is to compare the efficacy of sotalol to that of other antiarrhythmic agents for AF conversion. METHODS: Standard methods of meta-analysis were employed. Full-text publications of clinical trials in English that compared the efficacy of sotalol to that of other antiarrhythmics or placebo/no treatment were eligible for inclusion. RESULTS: A systematic review revealed 10 eligible publications. Sotalol was superior to placebo and/or no antiarrhythmic therapy in AF conversion, with a relative success of 24 (95% CI 4.7-119, p < 0.001). Sotalol was not significantly different from class IA antiarrhythmic drugs. Similarly, sotalol was not different from class IC antiarrhythmic drugs or amiodarone in terms of conversion efficacy. In one study, sotalol was less effective than high-dose ibutilide (2 mg), with a relative success of 0.248 (95% CI 0.128-0.481, p < 0.001). Ibutilide caused more proarrhythmia. CONCLUSIONS: Sotalol is as effective as class IA and class IC antiarrhythmic agents, and it is also as effective as amiodarone for pharmacologic conversion of AF. Only ibutilide at a high dose showed a greater conversion rate of AF.

Effects of low-dose clonidine on cardiovascular and autonomic variables in adolescents with chronic fatigue: a randomized controlled trial.

BACKGROUND: Chronic Fatigue Syndrome (CFS) is a common and disabling condition in adolescence with few treatment options. A central feature of CFS is orthostatic intolerance and abnormal autonomic cardiovascular control characterized by sympathetic predominance. We hypothesized that symptoms as well as the underlying pathophysiology might improve by treatment with the alpha2A-adrenoceptor agonist clonidine. METHODS: A total of 176 adolescent CFS patients (12-18 years) were assessed for eligibility at a single referral center recruiting nation-wide. Patients were randomized 1:1 by a computer system and started treatment with clonidine capsules (25 µg or 50 µg twice daily, respectively, for body weight below/above 35 kg) or placebo capsules for 9 weeks. Double-blinding was provided. Data were collected from March 2010 until October 2012 as part of The Norwegian Study of Chronic Fatigue Syndrome in Adolescents: Pathophysiology and Intervention Trial (NorCAPITAL). Effect of clonidine intervention was assessed by general linear models in intention-to-treat analyses, including baseline values as covariates in the model. RESULTS: A total of 120 patients (clonidine group n = 60, placebo group n = 60) were enrolled and started treatment. There were 14 drop-outs (5 in the clonidine group, 9 in the placebo group) during the intervention period. At 8 weeks, the clonidine group had lower plasma norepinephrine (difference = 205 pmol/L, p = 0.05) and urine norepinephrine/creatinine ratio (difference = 3.9 nmol/mmol, p = 0.002). During supine rest, the clonidine group had higher heart rate variability in the low-frequency range (LF-HRV, absolute units) (ratio = 1.4, p = 0.007) as well as higher standard deviation of all RR-intervals (SDNN) (difference = 12.0 ms, p = 0.05); during 20° head-up tilt there were no statistical differences in any cardiovascular variable. Symptoms of orthostatic intolerance did not change during the intervention period. CONCLUSIONS: Low-dose clonidine reduces catecholamine levels in adolescent CFS, but the effects on autonomic cardiovascular control are sparse. Clonidine does not improve symptoms of orthostatic intolerance. TRIAL REGISTRATION: Clinical Trials ID: NCT01040429, date of registration 12/28/2009.