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Biomedical subjects

Andrew N Redington

Publications and source records attributed to Andrew N Redington.

13 recordsLinked to original sources
PubMed2003

Intravenous sildenafil is a potent pulmonary vasodilator in children with congenital heart disease.

BACKGROUND: Increased pulmonary vascular resistance (PVR) because of congenital heart disease (CHD) may be caused by a dysfunction in endogenous pulmonary endothelial nitric oxide (NO) production. In other forms of pulmonary vascular disease with increased PVR, an elevated activity of a phosphodiesterase type 5 (PDE-5), responsible for the degradation of cyclic guanidine monophosphate (cGMP), the second messenger of endothelially produced NO, has been demonstrated. This study compares the effects of inhaled NO before and after the specific inhibition of the PDE-5 by intravenous sildenafil (Viagra) in pre- and postoperative children with increased PVR because of CHD. METHODS AND RESULTS: 12 children with congenital heart disease (age 0.2 to 15.7 years, median 2.4 years) and increased mean pulmonary arterial pressure, and 12 postoperative children (age 0.11 to 0.65 years, median 0.32 years) with increased PVR (8.3+/-1.0 Wood Units*m2) were studied during cardiac catheterization ("cath laboratory"), or within 2 hours after return from cardiac surgery ("post op"), respectively. All were sedated, tracheally intubated and paralyzed. During alveolar hyperoxygenation (FiO2=0.65), the effects of inhaled NO (20 ppm) were compared before and after the stepwise infusion of sildenafil ("cath laboratory", 1 mg/kg; post op, 0.25 mg/kg). Intravenous sildenafil more effectively reduced PVR than NO (11.5% versus 4.3% in the "cath laboratory" patient group, P<0.05, and 25.8% versus 14.6% in the post op patient group, P=0.09. The increase in cGMP in response to NO was potentiated (2- to 2.4-fold) by PDE-5 inhibition. While the vasodilating effects of sildenafil showed pulmonary selectivity, its infusion was associated with increased intrapulmonary shunting in the postoperative patients (Qs/Qt=16.5+/-4.7% to 25.5+/-18.2% P=0.04). CONCLUSIONS: Intravenous sildenafil is as effective as inhaled NO as a pulmonary vasodilator in children with congenital heart disease. Although clinically insignificant in this study, increased intrapulmonary shunting with sildenafil may be disadvantageous in some patients after CHD surgery.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed2003

Right ventricular myocardial responses to chronic pulmonary regurgitation in lambs: disturbances of activation and conduction.

Patients after repair of tetralogy of Fallot are at increased risk of arrhythmic death. Clinical data suggest that pulmonary regurgitation predisposes to these arrhythmias, although the cellular electrophysiologic effects of pulmonary regurgitation are unknown. We induced pulmonary regurgitation in lambs, and 3 mo later, having quantified the pulmonary regurgitant (PR) fraction, studied right ventricular mechanical and electrophysiologic properties in vivo and in vitro. The PR fraction was greater in PR (75 +/- 10%) than in sham-operated animals (8 +/- 4%; p < 0.01). In vivo, monophasic action potential duration and activation time, at rest and during acute right ventricular stretch, were similar in both groups. However, the dispersion of activation time was greater in PR animals at rest (13 +/- 1.1 versus 8 +/- 1.1 ms; p < 0.05). Furthermore, the dispersion of activation increased during right ventricular stretch in PR, but not in sham-operated animals. In vitro, myocardial force-frequency responses were similar in both groups, indicating preserved systolic performance, but mechanical restitution studies showed a prolonged refractory period (447 +/- 22 versus 370 +/- 26 ms; p < 0.05) and a decreased recovery time constant (184 +/- 19 versus 265 +/- 20 ms; p < 0.001) in PR animals, indicating altered calcium cycling. Furthermore, the myocardial conduction velocity was reduced in PR animals (31 +/- 3.58 versus 47.9 +/- 5.1 cm/s; p < 0.01), resulting from a 2-fold increase in intracellular resistance (437.25 +/- 125.93 versus 194 +/- 43.27 Omega. cm; p = 0.025). Chronic PR leads to inhomogeneity of right ventricular activation, alters myocardial calcium cycling, reduces conduction velocity, and increases intracellular resistivity. These may contribute to the development of arrhythmias associated with PR, including those in patients after tetralogy repair.

Animals↗
PubMed2003

Differential regurgitation in branch pulmonary arteries after repair of tetralogy of Fallot: a phase-contrast cine magnetic resonance study.

BACKGROUND: The importance of pulmonary regurgitation (PR) after repair of tetralogy of Fallot (TOF) is increasingly recognized, but little is known regarding its underlying mechanisms. This phase-contrast cine magnetic resonance (PC MR) study was performed to evaluate the relative contribution of each lung to total regurgitant volume. METHODS AND RESULTS: Twenty-two patients with significant PR underwent a PC MR 3 to 16 years after repair of TOF. Regurgitant fraction of the main pulmonary artery was 39+/-10%. Regurgitant fraction of the left pulmonary artery (LPA; 46+/-18%) was greater than that of the right pulmonary artery (34+/-16%; P=0.002). The average contribution of the LPA to the total regurgitant flow volume was 54+/-19%, whereas its average contribution to the total forward flow volume was 44+/-13% (P=0.002). In 4 patients, regurgitant flow in the LPA accounted for 75% to 100% of the total regurgitant flow. There was a linear relationship between regurgitant fraction and fraction of the regurgitant flow duration in the main pulmonary artery (P<0.001) and right pulmonary artery (P=0.001) but not in the LPA (P=0.129). CONCLUSIONS: PR after repair of TOF is commonly associated with differential regurgitation in the branch pulmonary arteries, which is usually greater in the LPA. Although the cause of this disparity requires further investigation, those patients with a significant unilateral contribution to total PR may be amenable to localized techniques to reduce regurgitation.

Adolescent↗
PubMed2003

Noninvasive assessment of left ventricular force-frequency relationships using tissue Doppler-derived isovolumic acceleration: validation in an animal model.

BACKGROUND: We have demonstrated that myocardial acceleration during isovolumic contraction (IVA) is a sensitive index of right ventricular contractile function. In this study, we assessed the usefulness of IVA to measure left ventricular (LV) contractile function and force-frequency relationships in an experimental preparation. METHODS AND RESULTS: In study 1, we examined 6 pigs by use of tissue Doppler imaging of LV free wall and simultaneous measurements of intraventricular pressure, volume, maximal elastance (Emax), and dP/dtmax by conductance catheterization. Animals were paced via the right atrium at a rate of 130 bpm. IVA was compared with elastance during contractility modulation by esmolol and dobutamine and assessed during preload reduction and afterload increase. In study 2, in 6 more pigs, force-frequency data were obtained during incremental atrial pacing from 120 to 180 bpm. Study 1: Esmolol led to a decrease in IVA and Emax (P<0.03 and <0.02, respectively), both of which increased during dobutamine infusion (P<0.02 and <0.03, respectively). IVA was unaffected by significant (P<0.001) acute reduction of LV volume and a significantly increased LV afterload (systolic pressure increase, P<0.001). Study 2: There was a positive correlation between IVA and dP/dtmax (r2=0.92, P<0.05). As heart rate was increased from 120 to 160 bpm, there were significant increases in both IVA and dP/dtmax (P<0.0004 and P=0.02, respectively). Over the same range of heart rates, there was no significant change in Emax (P=0.22). CONCLUSIONS: IVA is a measurement of LV contractile function that is unaffected by preload and afterload changes within a physiological range and can be used noninvasively to measure LV force-frequency relationships.

Animals↗
PubMed2003

Doppler tissue echocardiography: can transesophageal echocardiography be used to acquire functional data?

BACKGROUND: To date there is no direct comparison of transesophageal and transthoracic Doppler tissue data in patients with cardiac malposition. We compared data acquired from both methods in an animal model. METHOD: We studied 10 15-kg Yorkshire pigs during incremental atrial pacing to modify myocardial responses. Peak isovolumic velocity (IVV) and isovolumic acceleration (IVA) during isovolumic contraction, ejection (S wave), and diastolic velocities (early passive and active filling, E and A wave, respectively) were measured. RESULTS: Bland-Altman plots showed comparable values for IVA, IVV, and E velocity using both methods. Measurements of A velocities were significantly different. S wave velocity measurements were significantly different in animals with cardiac malposition but not in those with levocardia. Malposition did not significantly effect measurements of IVA or IVV by either technique. CONCLUSION: Assessment of systolic function using the indices IVA and IVV by tranesophageal and transthoracic echocardiography are comparable. The tranesophageal assessment of velocities associated with greater degrees of myocardial shortening or lengthening cannot be directly compared with measurements derived from a transthoracic approach in patients with cardiac malposition.

Animals↗
PubMed2003

The energy metabolism in the right and left ventricles of human donor hearts across transplantation.

OBJECTIVE: Brain death appears to predominantly affect the right ventricle (RV) and right ventricular failure is a common complication of clinical cardiac transplantation. It is not clear to what extent myocardial energy stores are affected in the operative sequence. We aimed to describe the time-dependent variation in high energy phosphate (HEP) metabolism of the two ventricles, and the relationship with endothelial activation and postoperative functional recovery. METHODS: Fifty-two human donors had serial biopsies from the RV and the left ventricle (LV) at (1) initial evaluation, (2) after haemodynamic optimisation, (3) end of cold ischaemia, (4) end of warm ischaemia, (5) reperfusion, and (6) at 1 week postoperatively. HEP was measured by chemiluminescence in biopsies 1-5 and adhesion molecules (P-selectin, E-selectin, VCAM-1) and thrombomodulin were analysed by immunohistochemistry in biopsies 5-6. Seventeen donors and five recipients had RV intraoperative pressure-volume recordings by a conductance catheter. Six patients served as live controls. RESULTS: Brain death did not affect HEP metabolism quantitatively. There was no difference between the RV and LV at any time point, but significant time-dependent changes were observed. The RV was prone to HEP depletion at retrieval, with ATP/ADP falling from 3.89 to 3.13, but recovered during cold ischaemia. During warm ischaemia the ATP/ADP ratio fell by approximately 50%, from 5.48 for the RV and 4.26 for the LV, with partial recovery at reperfusion (P<0.005). Hearts with impaired function in the recipient showed marked variations in HEP levels at reperfusion, and those organs with RV dysfunction failed to replenish their energy stores. However, these organs were not different from normally functioning allografts in terms of endothelial activation and clinical risk factors. There was poor correlation between pressure-volume and HEP data in either donor or recipient studies. Hearts followed-up with HEP and pressure-volume studies showed improvement in the recipient, despite functioning against a higher pulmonary vascular resistance. CONCLUSIONS: HEP are preserved over a wide range of contractile performance in the donor heart, with no metabolic difference between the two ventricles. No correlation with endothelial activation was seen either. Preservation efforts should be directed to the vulnerable periods of implantation and reperfusion.

Adult↗
PubMed2003

Measured versus estimated oxygen consumption in ventilated patients with congenital heart disease: the validity of predictive equations.

OBJECTIVE: To determine the validity of predictive equations in calculating oxygen consumption (Vo(2)) in ventilated patients with congenital heart disease. DESIGN: Prospective study. SETTING: Cardiac catheterization laboratories and intensive care units of two university teaching hospitals. PATIENTS: A total of 126 patients with congenital heart disease were studied. Of these, 75 patients received anesthesia in the pediatric cardiac catheterization laboratory, and 51 were deeply sedated in the intensive care unit after open heart surgery. MEASUREMENTS AND MAIN RESULTS: Vo(2) was measured directly in all patients using respiratory mass spectrometry. Estimated values for absolute Vo(2) (mL/min) and indexed Vo(2) (mL.min-1.m-2) were calculated from the four predictive equations published by LaFarge and Miettinen, Lundell et al., Wessel et al., and Lindahl. The agreement between measured and estimated Vo(2) was evaluated by calculating their bias and limits of agreement. A failure of agreement between measured and estimated Vo(2) was noted in both groups of patients, irrespective the equation used, and the agreement was poorer in patients in the intensive care unit. The equation by LaFarge and Miettinen produced the closest estimation in patients at cardiac catheterization with a bias of 4.5 mL/min for absolute Vo(2) and 6.9 mL.min-1.m-2 for indexed Vo(2). A systematic error of overestimating lower and underestimating higher indexed Vo(2) mL.min-1.m-2 was introduced in both groups. CONCLUSION: Predictive equations do not accurately estimate Vo(2) in ventilated patients with congenital heart disease.

Adolescent↗
PubMed2003

Optimal timing of the Ross procedure in the management of chronic aortic incompetence in the young.

UNLABELLED: The appropriate timing of intervention in patients with chronic aortic incompetence allows recovery of ventricular function. We sought to determine the optimal timing of the Ross procedure for chronic aortic incompetence in young patients. We retrospectively analysed case notes, and measured pre- and postoperative echocardiographic indexes of left ventricular function, in patients who had undergone the Ross procedure for chronic aortic incompetence. METHODS AND RESULTS: We found 21 patients with preoperative and postoperative data suitable for analysis. Their age at operation ranged from 5.6 to 26 years, with a median of 13.8 years, and the duration of follow-up was from 0.5 to 6.8 years, with a median of 2.4 years. The preoperative left ventricular end-diastolic dimension was converted to a z-score, and this was used as a threshold to divide the population. Using the threshold of a preoperative left ventricular z-score of more than 3 to divide the population did not show any difference in postoperative parameters of left ventricular function. Significant differences were found postoperatively, however, in both the left ventricular z-score and the ratio of left ventricular end-diastolic radius to posterior wall thickness in diastole, with a cutoff preoperative threshold z-score greater than 4. CONCLUSION: The increase in the ratio of left ventricular end-diastolic radius to the thickness of the posterior wall in diastole would suggest that there is disruption of left ventricular short axis architecture and myocardial contractile function when intervention is postponed. The significantly larger left ventricular dimension at end-diastole, despite the reduction in volume loading post surgery, may also demonstrate irreversible structural changes. Our data would suggest that recovery of left ventricular function is less likely when the left ventricular z-score has reached the value of 4, and that, ideally, intervention should be performed when the z-score approaches or exceeds 3.

Adolescent↗
PubMed2002

Validation of myocardial acceleration during isovolumic contraction as a novel noninvasive index of right ventricular contractility: comparison with ventricular pressure-volume relations in an animal model.

BACKGROUND: We have demonstrated that myocardial acceleration during isovolumic contraction (IVA) is a sensitive index of left ventricular contractile function. In this study, we assessed the utility of IVA to measure right ventricular (RV) contractile function. METHODS AND RESULTS: We examined 8 pigs by using tissue Doppler imaging of the RV free wall and simultaneous measurements of intraventricular pressure, volume, maximal elastance (e(max)), preload recruitable stroke work, and dP/dt(max) by conductance catheterization. Animals were paced in the right atrium at a rate of 130 beats per minute (bpm). IVA was compared with elastance during contractility modulation by esmolol and dobutamine and during preload reduction and afterload increase by transient balloon occlusion of the inferior vena cava and pulmonary artery, respectively. Data were also obtained during incremental atrial pacing from 110 to 210 bpm. Esmolol led to a decrease in IVA and dP/dt(max). During dobutamine infusion, IVA, dP/dt(max), preload recruitable stroke work, and e(max) all increased significantly. During preload reduction and afterload increase, IVA remained constant up to a reduction of RV volume by 54% and an RV systolic pressure increase of 58%. Pacing up to a rate of 190 bpm led to a stepwise increase in IVA and dP/dt(max), with a subsequent fall at a pacing rate of 210 bpm. CONCLUSIONS: IVA is a measurement of RV contractile function that is unaffected by preload and afterload changes in a physiological range and is able to measure the force-frequency relation. This novel index may be ideally suited to the assessment of acute changes of RV function in clinical studies.

Adrenergic beta-Agonists↗
PubMed2002

Right ventricular function.

This article describes the importance of the right ventricle in both the normal circulation, and in the abnormal milieu of previously palliated or corrected congenital heart disease. The latter group represents natural models of abnormal right ventricular loading that do not exist in any other experimental arena, and their study has provided insights into chronic adaptation of the right ventricle, in terms of cardiopulmonary haemodynamics, right-left heart interactions and mechano-electric inter-relationships.

Cardiovascular Physiological Phenomena↗
PubMed2002

Transposition complexes in the adult: a changing perspective.

This study has shown the heterogeneous group of patients with discordant ventricular arterial relations, their management and problems encountered during follow up. Patients after surgery for transposition are still relatively young by cardiology standards and their problems continue to evolve; nevertheless the future is becoming clearer. However there are still important lessons to be learnt by continued and diligent observation and systematic, multicenter research. It is important to maintain a low threshold for thorough re-evaluation of patients whenever new symptoms are discovered. Indeed, patients should undergo regular detailed investigations at timely intervals. It is vital that this evolving group of adult patients, as with most patients emerging from a childhood with other congenital heart malformations, is managed by cardiologists fully trained in congenital heart disease.

Adult↗
PubMed2002

The endothelin antagonist BQ123 reduces pulmonary vascular resistance after surgical intervention for congenital heart disease.

OBJECTIVE: Postoperative pulmonary hypertension in children after surgical intervention for congenital heart disease has been attributed to failure of the pulmonary endothelium to provide adequate vasodilation. Although we have shown that the impaired vasodilatory component attributable to the l-arginine-nitric oxide pathway is almost completely reversible, a nonrestorable component persists, implying an additional vasoconstrictive mechanism in postoperative pulmonary endothelial dysfunction. In this study of children after surgical intervention for congenital heart disease, we measured endothelin-1 levels and used BQ123, a selective endothelin-A receptor antagonist, together with inhaled nitric oxide to discriminate dysfunctional pulmonary endothelial vasodilation from endothelin-mediated pulmonary vasoconstriction. METHODS: All children were examined early after surgical intervention in the intensive care unit. Pulmonary vascular resistance (with respiratory mass spectrometry), as well as arterial and venous endothelin-1 levels (measured by means of a quantitative enzyme-linked immunosorbent assay), were determined in 7 children (age range, 3.3-13.7 months; median age, 6.3 months) with intracardiac shunting defects at baseline and during ventilation with a fraction of inspired oxygen of 0.65, with additional BQ123 (0.1 mg/kg infused over 20 minutes), and with inhaled nitric oxide (20 ppm). RESULTS: Pulmonary vascular resistance decreased from 7.7 +/- 3.4 at baseline to 6.1 +/- 2.8 Woods units. m(-2) (P =.022) at a fraction of inspired oxygen of 0.65 and to 4.7 +/- 2.7 Woods units. m(-2) (P =.013) during BQ123 infusion. Inhaled nitric oxide had no further effect on pulmonary vascular resistance. Left atrial endothelin-1 levels (1.35-5.12 pg/mL; mean, 2.4 pg/mL) correlated significantly with the decrease in pulmonary vascular resistance in response to BQ123 infusion (r(2) = 0.89, P =.003). CONCLUSION: Postoperative elevation of pulmonary vascular resistance in children after surgical intervention for congenital heart disease is responsive to endothelin-A blockade with BQ123. Increased levels of endothelin-1 predict the response to this therapy, which might become an important addition to the clinical armamentarium in postoperative pulmonary hypertensive disease.

Adolescent↗