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.

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.

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.

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.

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.

Disease mechanisms and clonidine treatment in adolescent chronic fatigue syndrome: a combined cross-sectional and randomized clinical trial.

IMPORTANCE: Chronic fatigue syndrome (CFS) is a disabling condition with unknown disease mechanisms and few treatment options. OBJECTIVE: To explore the pathophysiology of CFS and assess clonidine hydrochloride pharmacotherapy in adolescents with CFS by using a hypothesis that patients with CFS have enhanced sympathetic activity and that sympatho-inhibition by clonidine would improve symptoms and function. DESIGN, SETTING, AND PARTICIPANTS: Participants were enrolled from a single referral center recruiting nationwide in Norway. A referred sample of 176 adolescents with CFS was assessed for eligibility; 120 were included (34 males and 86 females; mean age, 15.4 years). A volunteer sample of 68 healthy adolescents serving as controls was included (22 males and 46 females; mean age, 15.1 years). The CSF patients and healthy controls were assessed cross-sectionally at baseline. Thereafter, patients with CFS were randomized 1:1 to treatment with low-dose clonidine or placebo for 9 weeks and monitored for 30 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. INTERVENTIONS: Clonidine hydrochloride capsules (25 µg or 50 µg twice daily for body weight <35 kg or >35 kg, respectively) vs placebo capsules for 9 weeks. MAIN OUTCOMES AND MEASURES: Number of steps per day. RESULTS: At baseline, patients with CFS had a lower number of steps per day (P < .001), digit span backward score (P = .002), and urinary cortisol to creatinine ratio (P = .001), and a higher fatigue score (P < .001), heart rate responsiveness (P = .02), plasma norepinephrine level (P < .001), and serum C-reactive protein concentration (P = .04) compared with healthy controls. There were no significant differences regarding blood microbiology evaluation. During intervention, the clonidine group had a lower number of steps per day (mean difference, -637 steps; P = .07), lower plasma norepinephrine level (mean difference, -42 pg/mL; P = .01), and lower serum C-reactive protein concentration (mean ratio, 0.69; P = .02) compared with the CFS placebo group. CONCLUSIONS AND RELEVANCE: Adolescent CFS is associated with enhanced sympathetic nervous activity, low-grade systemic inflammation, attenuated hypothalamus-pituitary-adrenal axis function, cognitive impairment, and large activity reduction, but not with common microorganisms. Low-dose clonidine attenuates sympathetic outflow and systemic inflammation in CFS but has a concomitant negative effect on physical activity; thus, sympathetic and inflammatory enhancement may be compensatory mechanisms. Low-dose clonidine is not clinically useful in CFS. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01040429.

Adenosine mapping for adenosine-dependent accessory pathway ablation.

BACKGROUND: This study describes the use of adenosine during ablation procedures to allow conduction through adenosine-dependent accessory pathways (APs), which are inactive at the time of the procedure. The technique allows for successful mapping and ablation of these pathways. METHODS: Retrospective review of all patients undergoing AP ablation from 1998 to 2008 to identify patients with absent or intermittent AP conduction during electrophysiology study. Adenosine boluses were used to activate the AP for the purpose of mapping in each case. RESULTS: Adenosine mapping was utilized in seven patients. One patient had a concealed AP at baseline and six patients had manifest preexcitation at baseline but lost AP conduction during the case. Alternative methods of enhancing AP conduction were attempted in five patients, but failed. Acute ablation results included: four patients with complete elimination of AP conduction, two patients with AP conduction only with adenosine, and one patient with return of baseline preexcitation. Patients with residual antegrade conduction had right superior (anterior) septal APs considered too close to the atrioventricular conduction system for safe ablation. At median follow-up of 2 years, all three patients with residual AP conduction had recurrence of supraventricular tachycardia; the remainder remained free of preexcitation and SVT. CONCLUSION: Adenosine mapping is a useful technique for facilitating AP ablation when pathway conduction is absent or inconsistent, and may enhance conduction in mechanically inhibited or previously ablated APs. Recurrence of AP conduction only during adenosine administration is predictive of late recurrence.

Clonidine in the treatment of adolescent chronic fatigue syndrome: a pilot study for the NorCAPITAL trial.

BACKGROUND: This pilot study (ClinicalTrials.gov ID: NCT01507701) assessed the feasibility and safety of clonidine in adolescent chronic fatigue syndrome (CFS). Specifically, we assessed clonidine dosage in relation to a) plasma concentration levels, b) orthostatic cardiovascular responses, and c) possible adverse effects. FINDINGS: Five adolescent CFS patients (14-19 years old) received 50 µg clonidine twice per day during 14 days in an open, uncontrolled design. Plasma concentration of clonidine was assayed by standard laboratory methods. Changes in orthostatic cardiovascular responses were assessed by a 20o head-up tilt-test (HUT). Adverse effects were mapped by a questionnaire.After 14 days, C0 median (range) of clonidine was 0.21 (0.18-0.36) µg/L, and Cmax median (range) of clonidine was 0.41 (0.38-0.56) µg/L. Also, supine blood pressures and heart rate were lower during clonidine treatment, and the HUT response was closer to the normal response. No serious adverse effects were registered. CONCLUSION: Clonidine 50 µg BID seems to be safe enough to proceed from a pilot study to a controlled trial in a select group of adolescents with CFS (ClinicalTrials.gov ID: NCT01040429).

Safety and results of cryoablation in patients <5 years old and/or <15 kilograms.

Current recommendations discourage elective radiofrequency ablation in patients <5 years old and/or weighing <15 kg, primarily because of the greater complication rate. To describe the current use, complications, and immediate outcomes of cryoablation in this patient population, a multicenter retrospective review of all patients <5 years old and/or weighing <15 kg who were treated with cryoablation for arrhythmia was performed. Eleven centers contributed data for 68 procedures on 61 patients. Of those, 34% were elective and 24% (n = 16) were both cryoablation and radiofrequency ablation. The median age and weight at ablation was 3.5 years (range 8 days to 9.9 years) and 15.2 kg (range 2.3 to 23), respectively. Congenital heart disease was present in 23% of the patients. The immediate success rate of cryoablation alone was 74%. No major complications occurred with cryoablation only; however, 2 of the 16 patients who underwent cryoablation and radiofrequency ablation had major complications. Of the 50 patients receiving cryoablation, 8 (16%) had variable degrees of transient atrioventricular block. The recurrence rate was 20% after cryoablation and 30% after cryoablation plus radiofrequency ablation. In conclusion, cryoablation appears to have a high safety profile in these patients. Compared to older and larger patients, the efficacy of cryoablation in this small, young population was lower and the recurrence rates were higher. Cryoablation's effect on the coronary arteries has not been fully elucidated and requires additional research.

Blood pressure variability and closed-loop baroreflex assessment in adolescent chronic fatigue syndrome during supine rest and orthostatic stress.

Hemodynamic abnormalities have been documented in the chronic fatigue syndrome (CFS), indicating functional disturbances of the autonomic nervous system responsible for cardiovascular regulation. The aim of this study was to explore blood pressure variability and closed-loop baroreflex function at rest and during mild orthostatic stress in adolescents with CFS. We included a consecutive sample of 14 adolescents 12-18 years old with CFS diagnosed according to a thorough and standardized set of investigations and 56 healthy control subjects of equal sex and age distribution. Heart rate and blood pressure were recorded continuously and non-invasively during supine rest and during lower body negative pressure (LBNP) of -20 mmHg to simulate mild orthostatic stress. Indices of blood pressure variability and baroreflex function (α-gain) were computed from monovariate and bivariate spectra in the low-frequency (LF) band (0.04-0.15 Hz) and the high-frequency (HF) band (0.15-0.50 Hz), using an autoregressive algorithm. Variability of systolic blood pressure in the HF range was lower among CFS patients as compared to controls both at rest and during LBNP. During LBNP, compared to controls, α-gain HF decreased more, and α-gain LF and the ratio of α-gain LF/α-gain HF increased more in CFS patients, all suggesting greater shift from parasympathetic to sympathetic baroreflex control. CFS in adolescents is characterized by reduced systolic blood pressure variability and a sympathetic predominance of baroreflex heart rate control during orthostatic stress. These findings may have implications for the pathophysiology of CFS in adolescents.

Acute cardiac resynchronization therapy for the failing left, right, or single ventricle after repaired congenital heart disease.

Use of cardiac resynchronization in children and young adults with congenital heart disease has been described in a variety of anecdotal cases and pooled institutional summaries which report mid-term results. This manuscript addresses use of cardiac resynchronization and/or multisite pacing in children in the acute postoperative period with a failing right, left, or single ventricle.

Cardiac function and circulating cytokines after endotoxin exposure in neonatal mice.

Complications after cardiac surgery in neonates can occur because of activation of the inflammatory system. This study used lipopolysaccharide (LPS) endotoxin exposure to cause cytokine activation in neonatal mice and examine left ventricular (LV) function and the effects of antioxidant treatment on cytokine levels. Neonatal mice (6 d old) were injected with either 25 mg/kg LPS (n = 13) or PBS (n = 14), and LV function (echocardiography) was measured at 4 h. Plasma levels of TNF-α, IL-4, IL-6, and IL-10 were measured at 30 min, 1, 2, and 4 h after injection (n = 5 mice per group). Effects of pretreatment with N-acetylcysteine (NAC, 50 mg/kg) on cytokine levels were examined at 2 and 4 h after PBS or LPS (n = 5 mice per group). Four hours after LPS, heart rate was increased (434 ± 14 versus 405 ± 14 bpm, p < 0.05). LV end-diastolic dimension and ejection time were reduced with LPS (both p < 0.05). LPS exposure increased plasma TNF-α, IL-6, and IL-10 levels. NAC pretreatment attenuated the increases in TNF-α and IL-6 levels, but augmented IL-10 levels at 2 h post-LPS. LPS exposure altered cardiac performance and activated cytokines in neonatal mice, which may be ameliorated using antioxidants.

Long-term outcomes for cryoablation of pediatric patients with atrioventricular nodal reentrant tachycardia.

The long-term efficacy and complications of cryoablation for pediatric atrioventricular nodal reentrant tachycardia (AVNRT) have not been completely defined. We performed a retrospective review of pediatric patients diagnosed with AVNRT and treated with cryoablation therapy. A total of 73 patients underwent cryoablation for AVNRT from 2003 to 2008. Of the 73 patients, 61 were included in the present study. The mean interval from initial successful ablation was 3 + or - 1 years. Of the 61 patients, 4 had documented recurrence of AVNRT after the initially successful ablation, 3 with late recurrence 1 to 2 years after ablation. Procedural complications consisting of transient atrioventricular block developed in 10 patients, and 2 patients were diagnosed with new arrhythmias after AVNRT ablation (1 with junctional ectopic tachycardia and 1 with left ventricular outflow tract tachycardia originating near the region of the atrioventricular node 3 months after ablation). In conclusion, cryoablation is a safe and effective therapy for AVNRT. Recurrences can develop late, up to 2 years after initially successful ablation.

Sudden cardiac death in children and adolescents (excluding Sudden Infant Death Syndrome).

Sudden death in the young is rare. About 25% of cases occur during sports. Most young people with sudden cardiac death (SCD) have underlying heart disease, with hypertrophic cardiomyopathy and coronary artery anomalies being commonest in most series. Arrhythmogenic right ventricular dysplasia and long QT syndrome are the most common primary arrhythmic causes of SCD. It is estimated that early cardiopulmonary resuscitation and widespread availability of automatic external defibrillators could prevent about a quarter of pediatric sudden deaths.

Novel minimally invasive, intrapericardial implantable cardioverter defibrillator coil system: a useful approach to arrhythmia therapy in children.

BACKGROUND: Current approaches to implantable cardioverter defibrillator (ICD) implantation in children remain challenging. Transvenous access may be limited due to patient size or anatomy, while epicardial patches require sternotomy or thoracotomy. We present an alternative approach; minimally invasive placement of a transvenous ICD coil within the pericardial space with active fixation. METHODS: Between August 2005 and October 2008, 7 children meeting indications for ICD therapy for ventricular tachyarrhythmias underwent intrapericardial placement of an ICD coil system. Median age was 5 years (range, 1 to 17), weight was 14 kg (range, 8 to 46), and 4 patients weighed less than 20 kg. The ICD system was composed of a single or dual defibrillation coil, an active can, and either ventricular or dual chamber epicardial sense-pace leads. All implantations were performed through a small subxiphoid incision and pericardial window without sternotomy. The coil lead was actively fixated in the transverse sinus under fluoroscopic guidance, and the generator placed in a subrectus pocket in the upper abdomen through the same incision. RESULTS: There were no perioperative complications, and no early or late deaths. All implants had acceptable defibrillation energies (range, 5 to 15 J) that were successfully tested intraoperatively, and none required energy increase or lead revision during follow-up (range, 1 to 39 months; median, 20 months). Impedance between the active can and the defibrillation coil remained stable in all. There were no inappropriate discharges. Thirty-six successful ICD discharges in 4 patients were recorded. Two patients underwent subsequent orthotopic heart transplantation and ICD system removal. CONCLUSIONS: Intrapericardial placement of an ICD coil system can be safely and successfully carried out through a minimally invasive subxiphoid approach in small infants and children. This novel ICD configuration demonstrates excellent performance, and provides a particularly efficacious approach to ventricular tachyarrhythmia therapy in pediatric patients.