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Biomedical subjects

Andrew J Powell

Publications and source records attributed to Andrew J Powell.

At least 19 recordsLinked to original sources
PubMed2006

Endovascular stenting of obstructed right ventricle-to-pulmonary artery conduits: a 15-year experience.

BACKGROUND: The optimal treatment for dysfunctional right ventricle-to-pulmonary artery (RV-PA) conduits is unknown. Limited follow-up data on stenting of RV-PA conduits have been reported. METHODS AND RESULTS: Between 1990 and 2004, deployment of balloon-expandable bare stents was attempted in 242 obstructed RV-PA conduits in 221 patients (median age, 6.7 years). Acute hemodynamic changes after stenting included significantly decreased RV systolic pressure (89+/-18 to 65+/-20 mm Hg, P<0.001) and peak RV-PA gradient (59+/-19 to 27+/-14 mm Hg, P<0.001). There were no deaths, and, aside from 5 malpositioned stents requiring surgical removal, there were no serious procedural complications. During follow-up of 4.0+/-3.2 years, 9 patients died and 2 underwent heart transplantation, none related to catheterization or stent malfunction. During 155 follow-up catheterizations in 126 patients, the stent was redilated in 83 patients and additional stents were placed in 41. Stent fractures were diagnosed in 56 patients (43%) and associated with stent compression and substernal location but did not cause acute hemodynamic consequences. By Kaplan-Meier analysis, median freedom from conduit surgery after stenting was 2.7 years (3.9 years in patients >5 years), with younger age, homograft conduit, conduit diameter < or =10 mm, diagnosis other than tetralogy of Fallot, Genesis stent, higher prestent RV:aortic pressure ratio, and stent malposition associated with shorter freedom from surgery. Tricuspid regurgitation and RV function did not change between stent implantation and subsequent surgery. CONCLUSIONS: Conduit stenting is an effective interim treatment for RV-PA conduit obstruction and prolongs conduit lifespan in most patients. Stent fractures were common but not associated with significant complications or earlier conduit reoperation.

Adolescent↗
PubMed2006

Determinants of exercise function following univentricular versus biventricular repair for pulmonary atresia/intact ventricular septum.

This study aimed to determine whether the exercise capacity of patients with pulmonary atresia/intact ventricular septum (PA/IVS) who have undergone biventricular repair is superior to that of patients with single ventricle repairs and to account for any differences. PA/IVS is generally treated with either biventricular (outflow tract reconstruction) or univentricular (Fontan) palliation. Although biventricular repair is believed to result in superior exercise function, this theory is untested. Symptom-limited programmed bicycle ergonometry with expiratory gas analysis was prospectively performed on all patients with PA/IVS >7 years old seen over 18 months. Nineteen biventricular and 10 Fontan patients (mean age 16.5 +/- 6.5 vs 12.7 +/- 5.0 years, p = 0.12) were enrolled. The exercise capacity of biventricular patients was not statistically superior to that of Fontan patients (predicted peak VO2 83.5 +/- 21% vs 76.0 +/- 17.5%, p = 0.34), although chronotropic function and ventilatory efficiency were significantly better in the former. The peak exercise capacity varied widely within each group, and there was considerable overlap between biventricular and Fontan patients. Within groups, imaging studies did not reliably predict exercise capacity. Most patients in each group had subnormal peak VO2, and there was a trend toward impaired performance with increasing age regardless of type of repair. In conclusion, biventricular repair may not guarantee superior exercise performance over single-ventricle palliation in PA/IVS. Regardless of repair type, aerobic capacity may deteriorate with age and is not reliably predicted by noninvasive imaging. These findings underscore the need for a quantitative, proactive approach to the assessment and preservation of exercise function.

Adolescent↗
PubMed2006

Faster flow quantification using sensitivity encoding for velocity-encoded cine magnetic resonance imaging: in vitro and in vivo validation.

PURPOSE: To test the agreement between conventional and sensitivity-encoded (SENSE) velocity encoded cine (VEC) MRI in a flow phantom and in subjects with congenital and acquired heart disease. MATERIALS AND METHODS: Flow measurements were performed in a 1.5 T scanner using a segmented k-space VEC MRI sequence and then repeated with a SENSE factor of 2. The flow phantom used a piston pump to generate physiologic arterial waveforms (0.5-4.9 L/min). In the subjects, flow measurements were performed in the ascending aorta (N = 33) and/or the main pulmonary artery (N = 24). RESULTS: Utilization of SENSE reduced the scan time by 50%. In the phantom, measurements without and with SENSE agreed closely with a mean difference of 0.01 +/- 0.08 L/min or 0.12% +/- 3.8% (P = 0.68). In the subjects, measurements without and with SENSE also agreed closely with a mean difference of 0.08 +/- 0.36 L/min or 1.3% +/- 7.2% (P = 0.08). Compared with standard imaging, the use of SENSE reduced the signal-to-noise ratio (SNR) by 28% in the phantom (N = 10) and 27% in vivo (N = 22). CONCLUSION: VEC MRI flow measurements with a SENSE factor of 2 were twice as fast and agreed closely with the conventional technique in vitro and in vivo. VEC MRI with SENSE can be used for rapid and reliable quantification of blood flow.

Adolescent↗
PubMed2006

Simple congenital heart lesions.

Cardiac magnetic resonance imaging (CMR) can provide comprehensive anatomic and physiological information about the cardiovascular system. The review article describes the application of CMR to several simple congenital heart lesions: atrial septal defects and other interatrial communications, ventricular septal defects, patent ductus arteriosus, partially anomalous pulmonary venous connection, and coarctation of the aorta. The anatomy, clinical features, and management of these lesions are discussed. CMR techniques to evaluate patients with these lesions are described and relevant literature is reviewed.

Heart↗
PubMed2005

Upregulation of the voltage-gated sodium channel beta2 subunit in neuropathic pain models: characterization of expression in injured and non-injured primary sensory neurons.

The development of abnormal primary sensory neuron excitability and neuropathic pain symptoms after peripheral nerve injury is associated with altered expression of voltage-gated sodium channels (VGSCs) and a modification of sodium currents. To investigate whether the beta2 subunit of VGSCs participates in the generation of neuropathic pain, we used the spared nerve injury (SNI) model in rats to examine beta2 subunit expression in selectively injured (tibial and common peroneal nerves) and uninjured (sural nerve) afferents. Three days after SNI, immunohistochemistry and Western blot analysis reveal an increase in the beta2 subunit in both the cell body and peripheral axons of injured neurons. The increase persists for >4 weeks, although beta2 subunit mRNA measured by real-time reverse transcription-PCR and in situ hybridization remains unchanged. Although injured neurons show the most marked upregulation,beta2 subunit expression is also increased in neighboring non-injured neurons and a similar pattern of changes appears in the spinal nerve ligation model of neuropathic pain. That increased beta2 subunit expression in sensory neurons after nerve injury is functionally significant, as demonstrated by our finding that the development of mechanical allodynia-like behavior in the SNI model is attenuated in beta2 subunit null mutant mice. Through its role in regulating the density of mature VGSC complexes in the plasma membrane and modulating channel gating, the beta2 subunit may play a key role in the development of ectopic activity in injured and non-injured sensory afferents and, thereby, neuropathic pain.

Animals↗
PubMed2005

Molecular determinants for modulation of persistent sodium current by G-protein betagamma subunits.

Voltage-gated sodium channels are responsible for the upstroke of the action potential in most excitable cells, and their fast inactivation is essential for controlling electrical signaling. In addition, a noninactivating, persistent component of sodium current, I(NaP), has been implicated in integrative functions of neurons including threshold for firing, neuronal bursting, and signal integration. G-protein betagamma subunits increase I(NaP), but the sodium channel subtypes that conduct I(NaP) and the target site(s) on the sodium channel molecule required for modulation by Gbetagamma are poorly defined. Here, we show that I(NaP) conducted by Na(v)1.1 and Na(v)1.2 channels (Na(v)1.1 > Na(v)1.2) is modulated by Gbetagamma; Na(v)1.4 and Na(v)1.5 channels produce smaller I(NaP) that is not regulated by Gbetagamma. These qualitative differences in modulation by Gbetagamma are determined by the transmembrane body of the sodium channels rather than their cytoplasmic C-terminal domains, which have been implicated previously in modulation by Gbetagamma. However, the C-terminal domains determine the quantitative extent of modulation of Na(v)1.2 channels by Gbetagamma. Studies of chimeric and truncated Na(v)1.2 channels identify molecular determinants that affect modulation of I(NaP) located between amino acid residue 1890 and the C terminus at residue 2005. The last 28 amino acid residues of the C terminus are sufficient to support modulation by Gbetagamma when attached to the proximal C-terminal domain. Our results further define the sodium channel subtypes that generate I(NaP) and identify crucial molecular determinants in the C-terminal domain required for modulation by Gbetagamma when attached to the transmembrane body of a responsive sodium channel.

Amino Acid Sequence↗
PubMed2005

Effects of metallic implants on magnetic resonance imaging evaluation of Fontan palliation.

This study examined the effects of endovascular metallic implants on the ability of magnetic resonance imaging to evaluate cardiovascular anatomy and to assess ventricular size and function in 101 consecutive patients with Fontan palliation. Compared with studies in patients without implants, in whom 100% of anatomic segments were adequately visualized and the median image quality grade for ventricular function assessment was 5 of 5, the presence of any implant (54% of studies) reduced the proportion of adequately imaged anatomy to 77% (p <0.001) and the median image quality grade for ventricular function assessment to 3 of 5 (p <0.001).

Adolescent↗
PubMed2005

Magnetic resonance imaging predictors of coarctation severity.

BACKGROUND: MRI is increasingly used for anatomic assessment of aortic coarctation (CoA), but its ability to predict the transcatheter pressure gradient, considered the reference standard for hemodynamic severity, has not been studied in detail. This study evaluated the ability of MRI to distinguish between mild versus moderate and severe CoA as determined by cardiac catheterization. METHODS AND RESULTS: The clinical, MRI, and catheterization data of 31 subjects referred for assessment of native or recurrent CoA were reviewed retrospectively. Patients were divided into 2 groups on the basis of peak coarctation gradient by catheterization: <20 mm Hg (n=12) and > or =20 mm Hg (n=19). Patients with cardiac index <2.2 L x min(-1) x m(-2) by catheterization were excluded. By logistic regression analysis, the following variables simultaneously predicted coarctation gradient > or =20 mm Hg: (1) smallest aortic cross-sectional area (adjusted for body surface area) measured by planimetry from gadolinium-enhanced 3D magnetic resonance angiography (OR 1.71 for 10 mm2/m2 decrease, P=0.005) and (2) heart rate-corrected mean flow deceleration in the descending aorta measured by phase-velocity cine MRI (OR 1.68 for 100 mL/s(1.5) increase, P=0.018). For the combination of these variables, a predicted probability >0.38 had 95% sensitivity, 82% specificity, 90% positive and negative predictive values, and an area under the receiver-operator characteristics curve of 0.938. In a subsequent validation study, the prediction model correctly classified 9 of 10 patients, with no false-negatives. CONCLUSIONS: The combination of anatomic and flow data obtained by MRI provides a sensitive and specific test for predicting catheterization gradient > or =20 mm Hg.

Adolescent↗
PubMed2004

Characterization of the human HCN1 channel and its inhibition by capsazepine.

The human hyperpolarization-activated cyclic nucleotide-gated 1 (hHCN1) subunit was heterologously expressed in mammalian cell lines (CV-1 and CHO) and its properties investigated using whole-cell patch-clamp recordings. Activation of this recombinant channel, by membrane hyperpolarization, generated a slowly activating, noninactivating inward current. The pharmacological properties of hHCN1-mediated currents resembled those of native hyperpolarization-activated currents (I(h)), that is, blockade by Cs(+) (99% at 5 mm), ZD 7288 (98% at 100 microm) and zatebradine (92% at 10 microm). Inhibition of the hHCN1-mediated current by ZD 7288 was apparently independent of prior channel activation (i.e. non-use-dependent), whereas that induced by zatebradine was use-dependent. The VR1 receptor antagonist capsazepine inhibited hHCN1-mediated currents in a concentration-dependent (IC(50)=8 microm), reversible and apparently non-use-dependent manner. This inhibitory effect of capsazepine was voltage-independent and associated with a leftward shift in the hHCN1 activation curve as well as a dramatic slowing of the kinetics of current activation. Elevation of intracellular cAMP or extracellular K(+) significantly enhanced aspects of hHCN1 currents. However, these manipulations did not significantly affect the capsazepine-induced inhibition of hHCN1. The development of structural analogues of capsazepine may yield compounds that could selectively inhibit HCN channels and prove useful for the treatment of neurological disorders where a role for HCN channels has been described.

Animals↗
PubMed2004

Expression of the sodium channel beta3 subunit in injured human sensory neurons.

Voltage-gated sodium channel alpha-subunits play a key role in pain pathophysiology, and are modulated by beta-subunits. We previously reported that beta1- and beta2-subunits were decreased in human sensory neurons after spinal root avulsion injury. We have now detected, by immunohistochemistry, beta3-subunits in 82% of small/medium and 67% of large diameter sensory neurons in intact human dorsal root ganglia: 54% of beta3 small/medium neurons were NGF receptor trkA negative. Unlike beta1- and beta2, beta3-immunoreactivity did not decrease after avulsion injury, and the beta3:neurofilament ratio was significantly increased in proximal injured human nerves. beta3-subunit expression may thus be regulated differently from beta1, beta2 and Nav1.8. Targeting beta3 interactions with key alpha-subunits, particularly Nav1.3 and Nav1.8, may provide novel selective analgesics.

Adult↗
PubMed2004

Clinical role, accuracy, and technical aspects of cardiovascular magnetic resonance imaging in infants.

Cardiovascular magnetic resonance imaging (CMRI) has been shown to be an important alternative to echocardiography and catheterization for diagnostic imaging in older patients with congenital heart disease. However, little information is available on its clinical role, accuracy, and technical aspects in infants. We retrospectively identified all patients <1 year of age who underwent a CMRI examination at our institution over a 4-year period (from 1999 to 2002) and reviewed their medical records. Ninety-nine CMRI examinations were performed in 91 patients (median weight 4.9 kg; range 1.2 to 16.3) at a median age of 102 days (range 1 to 358). Technical modifications were used to improve signal-to-noise ratio and temporal resolution, and specialized personnel and equipment were employed. All CMRI studies were performed under general anesthesia without any complications, and all outpatients (n = 44) were discharged the same day. The primary referral questions for CMRI were delineation of the thoracic vasculature (n = 54), assessment of possible airway compression (n = 25), evaluation of cardiac tumor (n = 6), and other (n = 14). For the thoracic vasculature group, findings at surgery (n = 37) and catheterization (n = 16) were concordant with the CMRI diagnoses. In the airway compression group, findings at surgery (n = 16) were also in agreement with CMRI findings. Tumor types by CMRI in the 3 patients with preoperative studies were confirmed by histologic results. Thus, CMRI has a limited but important diagnostic role in infants with cardiovascular disease. It is an accurate and safe method to delineate the thoracic vasculature, evaluate possible airway compression, and characterize cardiac tumors. CMRI may obviate cardiac catheterization and bronchoscopy in selected cases.

Female↗
PubMed2004

Role of auxiliary beta1-, beta2-, and beta3-subunits and their interaction with Na(v)1.8 voltage-gated sodium channel.

The nociceptive C-fibers of the dorsal root ganglion express several sodium channel isoforms that associate with one or more regulatory beta-subunits (beta1-beta4). To determine the effects of individual and combinations of the beta-subunit isoforms, we co-expressed Nav1.8 in combination with these beta-subunits in Xenopus oocytes. Whole-cell inward sodium currents were recorded using the two-microelectrode voltage clamp method. Our studies revealed that the co-expression beta1 alone or in combination with other beta-subunits enhanced current amplitudes, accelerated current decay kinetics, and negatively shifted the steady-state curves. In contrast, beta2 alone and in combination with beta1 altered steady-state inactivation of Nav1.8 to more depolarized potentials. Co-expression of beta3 shifted steady-state inactivation to more depolarized potentials; however, combined beta1beta3 expression caused no shift in channel availability. The results in this study suggest that the functional behavior of Nav1.8 will vary depending on the type of beta-subunit that expressed under normal and disease states.

Animals↗
PubMed2004

Factors associated with impaired clinical status in long-term survivors of tetralogy of Fallot repair evaluated by magnetic resonance imaging.

OBJECTIVES: The purpose of this study was to identify independent factors associated with impaired clinical status in late survivors of tetralogy of Fallot (TOF) repair. BACKGROUND: Repair of TOF often results in chronic pulmonary regurgitation (PR) and right ventricular (RV) dilation, which have been linked to late morbidity and mortality. However, determinants of clinical status late after TOF repair have not been fully characterized. METHODS: The clinical and laboratory data of 100 consecutive patients with repaired TOF (median 21 years after repair) who completed a cardiac magnetic resonance imaging protocol were analyzed. Impaired clinical status was defined as New York Heart Association (NYHA) functional class > or =III. RESULTS: Of the patients, 88 were in NYHA functional class I or II and 12 were in NYHA functional class III. The degree of PR and indexed RV end-diastolic volume were not associated with impaired clinical status. By multivariate analysis, a lower left ventricular (LV) ejection fraction (EF) (odds ratio [OR] = 3.88 for 10% decrease, p = 0.002) and older age at TOF repair (OR = 1.70 for 5-year increase, p = 0.013) were the strongest independent factors associated with impaired clinical status. Among RV variables, a lower RV EF was the strongest independent factors associated with poor clinical status (OR = 2.41 for 10% decrease, p = 0.01). The LV EF correlated with RV EF (r = 0.58, p < 0.001). CONCLUSIONS: Moderate or severe LV or RV systolic dysfunction, but not PR fraction or RV diastolic dimensions, is independently associated with impaired clinical status in long-term survivors of TOF repair. The close relationship between LV EF and RV EF suggests unfavorable ventricular-ventricular interaction.

Adolescent↗
PubMed2004

Magnetic resonance imaging evaluation of myocardial perfusion and viability in congenital and acquired pediatric heart disease.

This study examined the feasibility and potential clinical utility of magnetic resonance imaging (MRI) evaluation of myocardial perfusion (first-pass contrast enhancement) and viability (myocardial delayed enhancement) in 30 patients with congenital and acquired pediatric heart disease. Good agreement was found between MRI evaluation of myocardial perfusion and viability and analysis of segmental wall motion as well as coronary angiography (n = 10) and single photon emission computed tomography (n = 6).

Adolescent↗
PubMed2004

Heterologous expression and functional analysis of rat Nav1.8 (SNS) voltage-gated sodium channels in the dorsal root ganglion neuroblastoma cell line ND7-23.

The voltage-gated sodium channel NaV1.8 (SNS, PN3) is thought to be a molecular correlate of the dorsal root ganglion (DRG) tetrodotoxin resistant (TTX-R) Na+ current. TTX-R/NaV1.8 is an attractive therapeutic drug target for inflammatory and neuropathic pain on the basis of its specific distribution in sensory neurones and its modulation by inflammatory mediators. However, detailed analysis of recombinant NaV1.8 has been hampered by difficulties in stably expressing the functional protein in mammalian cells. Here, we show stable expression and functional analysis of rat NaV1.8 (rNaV1.8) in the rat DRG/mouse N18Tg2 neuroblastoma hybridoma cell line ND7-23. Rat NaV1.8 Na+ currents were recorded (789 +/- 89 pA, n=62, over 20-cell passages) that qualitatively resembled DRG TTX-R in terms of gating kinetics and voltage-dependence of activation and inactivation. The local anaesthetic drug tetracaine produced tonic inhibition of rNaV1.8 (mean IC50 value 12.5 microM) and in repeated gating paradigms (2-10 Hz) also showed frequency-dependent block. There was a correlation between the ability of several analogues of the anticonvulsant/analgesic compound lamotrigine to inhibit TTX-R and rNaV1.8 (r=0.72, P<0.001). RT-PCR analysis of wild type ND7-23 cells revealed endogenous expression of the beta1 and beta3 accessory Na+ channel subunits-the possibility that the presence of these subunits assists and stabilises expression of rNaV1.8 is discussed. We conclude that the neuroblastoma ND7-23 cell line is a suitable heterologous expression system for rNaV1.8 Na+ channels in that it allows stable expression of a channel with biophysical properties that closely resemble the native TTX-R currents in DRG neurones. This reagent will prove useful in the search for pharmacological inhibitors of rNaV1.8 as novel analgesics.

Animals↗
PubMed2004

Anaesthesia considerations for cardiac MRI in infants and small children.

BACKGROUND: General anaesthesia is frequently necessary in infants and small children undergoing cardiac magnetic resonance imaging (MRI), because of the imaging techniques, MRI environment and potential need for breath-holding to facilitate imaging. Anaesthetizing paediatric patients with congenital heart disease (CHD) for cardiac MRI poses many challenges for the anaesthetist and this report reviews our experience. METHODS: We retrospectively reviewed the anaesthesia and MRI records of all patients who had undergone cardiac MRI between January 2000 and October 2002. RESULTS: A total of 250 children with cardiac disease underwent general anaesthesia for cardiac MRI. ASA classification included class I, 2%; class II; 26%; class III, 60% and class IV, 12%. A total of 168 patients (67%) had undergone previous cardiac surgery, 182 patients (94%) were discharged the same day and 48 patients (19.2%) had cyanotic cardiac defects (SpO2 between 55 and 85%). No scans were interrupted because of low oxygen saturation during breath-hold or haemodynamic instability. No patient was admitted to the hospital from complications related to general anaesthesia, but one inhouse patient from the cardiology ward was admitted to the cardiac intensive care unit (CICU) after the MRI because of cyanosis and low cardiac output. Seven patients from the CICU were on inotropic infusions when they underwent the MRI procedure and two others needed inotropic support after induction of anaesthesia. Five patients had a brief episode of hypotension during the MRI and responded quickly to interventions. CONCLUSION: Our experience demonstrates that general anaesthesia for cardiac MRI can be provided safely in infants and small children with CHD, despite the complexity and pathophysiology of many defects, the frequent breath-holding for image acquisitions and the MRI environment.

Adolescent↗