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Biomedical subjects

Jan M Quaegebeur

Publications and source records attributed to Jan M Quaegebeur.

18 recordsLinked to original sources
PubMed2006

Ventricular diastolic stiffness predicts perioperative morbidity and duration of pleural effusions after the Fontan operation.

BACKGROUND: We validated the clinical relevance of ventricular stiffness by examining surgical morbidity in children with univentricular hearts undergoing Fontan operation. We hypothesized that ventricular stiffness affects Fontan morbidity, particularly duration of pleural effusions. METHODS AND RESULTS: Sixteen children with right ventricular (RV) (n =11) or left ventricular (LV) (n =5) dominance were studied intraoperatively at a median age of 3.3 years (1.8 to 5.1). Transesophageal long-axis echocardiograms and ventricular pressure by micromanometer provided end-diastolic pressure (P) area (A) relations during initiation and conclusion of cardiopulmonary bypass. Curve fitting to the equation P=alphae(betaA) defined the ventricular stiffness constant, beta. Changes in beta and clinical correlations were examined. Ventricular stiffness increased after bypass in patients with complete pre-bypass and post-bypass data (n =11, P=0.023, mixed models methodology). Pre-bypass beta correlated well with duration of chest tube (CT) drainage (r=0.90, n =16), net perioperative fluid balance (r=0.71, n=14), and length of stay (LOS) (r=0.81, n =16). CT duration and LOS also correlated significantly with post-bypass beta (r=0.77 for both, n=11), but insignificantly with preoperative catheterization pressures. CONCLUSIONS: Intraoperative beta predicts duration of CT drainage, net perioperative fluid balance, and LOS after the Fontan operation. These observations could improve risk stratification and clinical management of children at high-risk undergoing the Fontan operation.

Chest Tubes↗
PubMed2006

Surgical management of aortopulmonary window associated with interrupted aortic arch: a Congenital Heart Surgeons Society study.

OBJECTIVE: The objective was to determine outcomes and risk factors of surgical management of patients with aortopulmonary window associated with interrupted aortic arch. METHODS: From 1987 to 1997, 472 neonates with interrupted aortic arch were enrolled prospectively from 33 institutions. Associated aortopulmonary window was present in 20 patients. Competing risk methodology determined the prevalence of reintervention for postrepair pulmonary artery and aortic arch obstruction. RESULTS: Interrupted aortic arch was type A in 17 patients and type B in 3 patients. Aortopulmonary window morphology was type I (n = 10), type II (n = 5), and type III (n = 5). Associated cardiovascular anomalies were common, including atrial septal defect (n = 13) and systemic venous anomalies (n = 3). Overall survival after initial admission was 91%, 86%, and 84% at 1, 5, and 10 years, respectively. Fifteen patients underwent single-stage repair, and 4 patients underwent staged repair. There was an increased prevalence of patch augmentation of the interrupted aortic arch anastomosis in lower-weight infants (2.3 kg vs 3.1 kg, P = .07). Competing risk analysis estimated that 5 years after repair, 51% had initial arch reintervention, 6% had initial pulmonary artery reintervention, and 43% were alive without reintervention. Reintervention for arch obstruction was more likely for those with interrupted aortic arch type B (P = .08) and for those with higher weight at initial repair (P = .003). CONCLUSIONS: Complete correction of aortopulmonary window in the setting of interrupted aortic arch can be performed with low mortality in the neonatal period. Reinterventions for aortic arch obstruction are the most frequent complication after repair, but pulmonary artery stenosis also occurs. Use of patch augmentation may reduce the need for subsequent arch reintervention.

Aorta, Thoracic↗
PubMed2006

Superior outcomes for repair in infants and neonates with tetralogy of Fallot with absent pulmonary valve syndrome.

OBJECTIVE: Primary repair of tetralogy of Fallot with absent pulmonary valve syndrome has been associated with significant mortality, particularly for neonates in respiratory distress. Controversy persists regarding the method of establishing right ventricle-pulmonary artery continuity. METHODS: Anatomic and demographic parameters were evaluated for patients undergoing repair of tetralogy of Fallot with absent pulmonary valve syndrome from 1990 to 2005, as were perioperative and late postoperative parameters (airway complications, reoperation or catheter-based intervention, and mortality). RESULTS: Twenty-three patients underwent repair. Median age was 15 days (range 2-1154 days). Patients were followed up for 5.3 +/- 3.9 years. Seventeen (85%) required preoperative ventilatory assistance. One patient died within 24 hours; 1 patient died 8 months postoperatively. Four patients received valved homografts, and the remainder had valveless connections. All patients underwent reduction pulmonary arterioplasty and mobilization, unifocalization (in 3), and ventricular septal defect closure. Valveless connection recipients had a transannular hood. No patient underwent a Lecompte maneuver. Four patients underwent reoperation for conversion to valveless connection (n = 1), reduction arterioplasty (n = 1), and repair of pulmonary stenosis (n = 2). Three patients required catheter-based intervention, with balloon angioplasty (n = 3) and stent placement (n = 1); 2 now demonstrate equal quantitative lung perfusion. No patient has had significant debility from airway compromise. All patients demonstrate free pulmonary insufficiency and good biventricular function. CONCLUSIONS: We report excellent overall survival (89%) and low postoperative morbidity for neonates and infants undergoing primary repair of tetralogy of Fallot with absent pulmonary valve syndrome. Our recent experience supports the use of a valveless right ventricle-pulmonary artery connection, which, combined with catheter-based intervention, reduces the likelihood of reoperation necessitated by homograft placement.

Child, Preschool↗
PubMed2005

Ross procedure in infants and toddlers followed into childhood.

BACKGROUND: The Ross procedure is commonly used to treat aortic valve disease in pediatric and adult patients. For infants, data are limited regarding survival, reintervention, autograft growth, and function. METHODS AND RESULTS: The Ross procedure was performed in 27 infants <18 months of age (median age 5.7 months). All patients had congenital aortic stenosis (AS); associated lesions included subAS (n=9), supravalvular AS (n=2), coarctation (n=5), and interrupted aortic arch (n=2). Median follow-up was 6.1 years (range 0.2 to 12.9). There were 3 early deaths and no late deaths. Freedom from reintervention for homograft dysfunction was 87% at 8 years; freedom from autograft reintervention was 100%. Follow-up echocardiograms were available in 17 patients. Estimated peak autograft gradient was 55 mm Hg in one patient and <10 mm Hg in 16. Mild autograft insufficiency was seen in 4 patients; 13 had none. Autograft diameter was measured early postoperatively and at latest follow-up. The mean z score increased from 0.63 to 3.2 (P<0.01) at the annulus and from 0.26 to 2.2 (P<0.01) at the sinus. In a subgroup, the mean autograft z score increased significantly from the postoperative period to 1 year for both the annulus (0.72 to 3.2, P<0.01) and the sinus (0.26 to 2.2, P<0.01), but remained unchanged thereafter. CONCLUSIONS: The Ross procedure effectively relieves AS in infants. Homograft reintervention occurred in 13% within 8 years. No patient developed significant autograft insufficiency or required autograft reintervention during the follow-up period. Dilatation of the autograft occurred during the first year after surgery and stabilized thereafter.

Aortic Valve↗
PubMed2005

Successful outcome with extended allograft ischemic time in pediatric heart transplantation.

BACKGROUND: Many cardiac transplant programs have liberalized donor eligibility criteria in an attempt to maximize donor supply and to accommodate increasing demand. Although many studies have evaluated the potential adverse effects of prolonged donor ischemic time (DIT) in adults undergoing cardiac transplantation, relatively few have focused specifically on pediatric recipients that include a substantial number of patients and long-term follow-up. The focus of this study was to examine the effect of extended DIT on mortality after pediatric heart transplantation. METHODS: We conducted a retrospective review of our pediatric cardiac transplant experience in the past 11 years, comparing patients who received allografts and had ischemic times >240 minutes with those who had ischemic times <240 minutes. RESULTS: A total of 129 pediatric patients (<19 years) underwent orthotopic heart transplantation, of whom 78 (60.5%) had DIT <240 minutes and 51 (39.5%) had DIT >240 minutes. We found no statistically significant difference in age, sex, race, height, weight, or donor age between the groups (p = not significant). Post-transplant survival at 1, 5, and 10 years was similar for both groups: 91.2%, 88.0%, and 85.2%, respectively, for patients with DIT <240 minutes vs 89.6%, 87.2%, and 79.8%, respectively, for patients with DIT >240 minutes (p = 0.433). Additionally, using Cox proportional hazard models, extended DIT >240 minutes was not a statistically significant independent predictor of post-transplant mortality (odds ratio, 0.655; 95% confidence interval, 0.518-0.972; p = 0.684; standard error = 0.468). CONCLUSION: Procurement of hearts from distant locations with associated extended DIT is justified in the setting of increased demand and a fixed donor population.

Adolescent↗
PubMed2005

Dysfunction of atrial and B-type natriuretic peptides in congenital univentricular defects.

OBJECTIVE: To examine whether children with univentricular defects have intrinsic dysfunction in the natriuretic peptide system. METHODS: We compared plasma levels of the fluid-regulating hormone vasopressin (antidiuretic hormone), aldosterone, atrial natriuretic peptide, and brain natriuretic peptide in children with congenital univentricular and biventricular defects. We enrolled 27 patients with univentricular defects and 27 patients with biventricular cardiac defects. Children who underwent Fontan and Glenn procedures were considered as patients with univentricular cardiac defects; children who underwent repair of tetralogy of Fallot or subaortic stenosis were considered as controls with biventricular defects. RESULTS: Preoperative plasma atrial natriuretic peptide, brain natriuretic peptide, antidiuretic hormone, and aldosterone were comparable in both groups. Although plasma cyclic guanosine monophosphate levels were comparable between groups, there was a significant correlation between molar concentrations of plasma cyclic guanosine monophosphate and plasma atrial natriuretic peptide ( r = 0.42) and brain natriuretic peptide ( r = 0.44) in the biventricular group, but not in the univentricular group ( r = 0.19 for atrial natriuretic peptide; r = 0.13 for brain natriuretic peptide). All patients had a significant postoperative increase in plasma antidiuretic hormone. A significant postoperative increase in plasma brain natriuretic peptide was found in the patients with biventricular, but not univentricular, defects. In contrast, a significant increase in plasma aldosterone was observed only in the patients with univentricular defects. CONCLUSIONS: There were distinct differences between univentricular and biventricular groups in their perioperative plasma fluid-regulating hormone responses. Specifically, patients with univentricular defects may have abnormal natriuretic peptide secretion and function. The natriuretic dysfunction may be on the basis of hypoplastic ventricular development.

Age Factors↗
PubMed2005

The effect of repair technique on postoperative right-sided obstruction in patients with truncus arteriosus.

OBJECTIVES: We reviewed our experience with repair of truncus arteriosus to assess the effect of type of right ventricular outflow tract reconstruction on perioperative morbidity, survival, and freedom from catheter-based interventions and reoperation. METHODS: Patients undergoing repair of truncus arteriosus from June 1990 through February 2004 were evaluated on the basis of operative procedure regarding preoperative and postoperative variables, the need for postoperative catheter-based intervention or reoperation, and survival on the basis of univariate, multivariable, and actuarial analyses. RESULTS: Of 54 study patients, 15 (28%) received a valved homograft, and 39 (72%) received a direct connection with a variety of hood materials. Five (9.1%) patients died. Valved homograft recipients were more likely to require reoperation than patients receiving direct connections (40% vs 15%, P = .046); however, valved homograft and direct connection recipients had a similar incidence of the combined end point of reoperation or catheter-based intervention (40.0% vs 37.5%, P = .865). Univariate and multivariable modeling demonstrated use of valved homografts or direct connections with an autologous pericardial hood to be predictive of the need for later catheter-based intervention or reoperation. Actuarial analysis demonstrated a trend toward improved outcomes in the direct connection group and within the direct connection cohort, a statistically significant difference on the basis of hood type. CONCLUSIONS: Although the direct connection technique might not prevent later catheter-based intervention, it does reduce the need for reoperation. Outcomes among direct connection recipients were associated with hood type: polytetrafluoroethylene hoods (W. L. Gore & Associates, Inc, Tempe, Ariz) had the lowest rate of reintervention, and untreated autologous pericardial hoods had the highest rate of reintervention. We report excellent outcomes with primary repair of truncus arteriosus. Where anatomically appropriate, we advocate the direct connection technique.

Cardiac Surgical Procedures↗
PubMed2005

Pulmonary position cryopreserved homografts: durability in pediatric Ross and non-Ross patients.

OBJECTIVE: The purpose of this study was to evaluate the outcome and risk factors for implant failure in pediatric patients who underwent pulmonary position homograft placement for right ventricular outflow tract obstruction compared with conduit placement as a component of the Ross operation. Actuarial 5-year survivals for cryopreserved right ventricle-to-pulmonary artery homografts range from 55% to 94% at all ages. It is not known whether there is a difference in homograft durability when utilized for right ventricular outflow tract obstruction or as part of the Ross operation. METHODS: The records of all pediatric patients receiving a right ventricle-to-pulmonary artery homograft from July 1989 through October 2003 were reviewed. Ninety-eight consecutive patients were studied (26 Ross, 72 non-Ross). In addition to Ross versus non-Ross comparisons, other potential risk factors for homograft failure analyzed included age at operation, follow-up time, type of surgery, and homograft type and size. RESULTS: Ross and non-Ross patients were comparable in age at the time of the operation and follow-up time. Homograft failure rates were 12% and 51% for Ross and non-Ross patients, respectively. Freedom from reintervention was 93% in the Ross and 66% in the non-Ross group at 5 years (P = .019). On multivariate analysis, non-Ross operation and age less than 2 years were significant predictors of homograft failure. CONCLUSIONS: 1. Pediatric patients undergoing the Ross operation have longer homograft survival than pediatric patients treated for right ventricular outflow tract obstruction, independent of age. 2. Homografts placed in patients less than 2 years of age have shorter homograft survival.

Blood Vessel Prosthesis↗
PubMed2004

Cardiac transplantation after the Fontan or Glenn procedure.

OBJECTIVES: The purpose of this study was to review the clinical course and outcome of cardiac transplantation after a failed Glenn or Fontan procedure. BACKGROUND: Late complications of the Glenn or Fontan procedure, including ventricular failure, cyanosis, protein-losing enteropathy, thromboembolism, and dysrhythmias often lead to significant morbidity and mortality. If other therapies are ineffective, cardiac transplantation is the only therapeutic recourse. Transplantation in this unique population presents significant challenges in the operative and perioperative periods. METHODS: The anatomic diagnoses, previous operations, clinical status, and indications for transplantation were characterized in patients transplanted after a Glenn or Fontan procedure. Outcomes after transplantation, including postoperative complications and mortality, were reviewed. Comparisons were made between survivors and nonsurvivors. RESULTS: Primary orthotopic cardiac transplantation was performed in 35 patients (mean age 15.7 +/- 8.5 years) with a mean follow-up of 54 +/- 46 months. A total of 11 patients had undergone a Glenn shunt and 24 patients a Fontan procedure. Indications for transplantation were a combination of causes including ventricular dysfunction, failed Fontan physiology, and/or cyanosis. Ten patients died <or=2 months after transplantation; nine of the deaths occurred in the Fontan patients. Overall, one-year survival was 71.5%, and five-year survival was 67.5%. Survival was not significantly different between patients transplanted after a Glenn or Fontan procedure and patients transplanted for other etiologies. CONCLUSIONS: Cardiac transplantation can be performed successfully in patients with end-stage congenital heart disease after a Glenn or Fontan procedure, with outcomes similar to transplantation for end-stage heart failure secondary to other etiologies.

Adolescent↗
PubMed2004

Trends and outcomes in transplantation for complex congenital heart disease: 1984 to 2004.

BACKGROUND: Cardiac transplantation for patients with complex congenital heart disease poses several anatomic and physiologic challenges for the transplant surgeon. We undertook the current single center study to evaluate surgical outcomes and lessons learned through a nearly twenty year experience with cardiac transplantation for complex congenital heart disease. METHODS: A retrospective review was performed to evaluate all patients undergoing cardiac transplantation from January 1, 1984 through January 1, 2004. Donor and recipient demographic and intraoperative and postoperative variables were acquired and correlated with perioperative (30-day) and late mortality in both univariate and multivariate analyses, and with Kaplan-Meier survival estimates. RESULTS: One hundred and six patients underwent transplantation for complex congenital heart disease and were followed for a median of 56 months. Thirty-seven (34.9%) patients died. Male gender and later year of transplantation were protective, and neonatal age and pulmonary artery reconstruction detrimental in multivariable modeling of overall mortality. Transplantation to a physiologic or anatomic single lung did not impact on survival. Patients in the study cohort had comparable survival estimates when compared with all those in the entire cohort without complex congenital heart disease. When comparing patients by era of transplantation, both cohorts demonstrated improved survival with later transplantation. CONCLUSIONS: Outcomes with transplantation for complex congenital heart disease have improved annually over the past twenty years. Transplantation to an anatomic or physiologic single lung did not impair overall survival. Pulmonary artery reconstruction imparted an increase in mortality both short and long term, a finding which merits further investigation.

Adolescent↗
PubMed2004

Regional functional depression immediately after ventricular septal defect closure.

Left ventricular ejection is depressed immediately after repair of ventricular septal defect (VSD). Postrepair functional depression seen after VSD closure could result from a reduction in preload. However, other mechanisms could be at work. Functional depression could also be caused by closure of a low-impedance path for left ventricular ejection, the introduction of a stiff akinetic patch, or the operation itself. We reasoned that functional depression mediated by changes in preload or afterload should symmetrically affect end-diastole and end-systole, whereas depression resulting from changes in septal mechanics should be localized. We, therefore, performed segmental wall-motion analysis on intraoperative echocardiograms from patients undergoing VSD and atrial septal defect repair. After VSD closure, there was an asymmetric change in left ventricular end-systolic segment length and a decrease in fractional segment shortening localized to the septal and lateral walls, whereas patients with atrial septal defect had a symmetric increase in fractional shortening. These results suggest that acute functional depression after VSD repair is a result of localized impairment of septal function.

Cardiac Surgical Procedures↗
PubMed2004

Heart transplantation to a physiologic single lung in patients with congenital heart disease.

BACKGROUND: Heart-lung transplantation has been recommended for patients with end-stage congenital heart disease (CHD) and single-lung physiology due to either discontinuous pulmonary arteries (PAs) and unilateral PA hypertension (HTN) or absence of 1 PA. METHODS: Eleven patients with CHD and single-lung physiology underwent heart transplantation (HT). Diagnoses included: tetralogy of Fallot, absent left PA (n = 4); single-ventricle s/p classic Glenn (n = 7), with absent left PA (n = 1); and severe left PA HTN (n = 6). RESULTS: Mean time from last surgery was 13 +/- 8 years; mean number of operations (op) was 3.2 +/- 1.7. Mean age was 21 +/- 11 years (range 9.5 to 43). Complications and procedures before HT included hemoptysis (n = 2), plastic bronchitis (n = 1) and interventional catheterization (n = 6). Mean cardiopulmonary bypass and ischemic time was 275 +/- 72 and 268 +/- 75 minutes, respectively. Mean time to extubation was 4.6 +/- 3.2 days, and mean length of stay was 19 +/- 7 days. Post-operative morbidity included bleeding (n = 4), vocal cord paralysis (n = 1) and coil embolization of aortopulmonary collaterals (n = 3). Early post-operative survival was 82%. Cause of death was aortic rupture (n = 1) and bleeding (n = 1). Eight patients are alive 4 years (range 0.9 to 7.6) after HT. PA continuity was established in 6 patients; post-HT lung perfusion scan showed no increase in perfusion to the left PA. One patient died from rejection 3 years post-HT. CONCLUSIONS: HT can be performed successfully in patients with single-lung physiology. HT is the procedure of choice in patients with end-stage CHD and a physiologic single lung.

Adolescent↗
PubMed2004

Early and medium-term results for repair of Ebstein anomaly.

OBJECTIVES: We evaluated the early and medium-term single-center results for primary repair of Ebstein anomaly in both adults and children. METHODS: The records were reviewed of patients undergoing repair of Ebstein anomaly at the Children's Hospital of New York from September 1990 to September 2002. Functional, demographic, and echocardiographic parameters were studied both preoperatively and postoperatively, along with functional status and adverse events. The repair technique involved vertical plication of the atrialized ventricle and valve leaflet reimplantation after clockwise rotation. RESULTS: A total of 25 patients (19 children and 6 adults) underwent repair. The average age was 14.2 +/- 15.9 years, and the average follow-up was 4.1 +/- 3.4 years. Three patients required reoperation for right ventricular overload (1 child) and progressive, severe tricuspid regurgitation (2 adults); both adults received tricuspid valve replacements, one at 4 years and the other at 8 years post-repair. Three patients had radiofrequency ablation procedures performed intraoperatively. Ten patients (40%) had moderate-to-severe tricuspid regurgitation perioperatively. However, 18 children (95%) and 5 adults (83%) demonstrated significant improvement in exercise capacity late postoperatively. Two children died suddenly 11 months and 4 years after repair. DISCUSSION: Ebstein repair has good functional outcomes in children despite residual tricuspid regurgitation, likely because of reduction in right ventricular volume loading and relative annular and ventricular plasticity. Adult patients did not demonstrate the same durability of valve repair and frequently required tricuspid valve replacement. Intraoperative radiofrequency ablation represents an important adjunctive treatment for intractable arrhythmias, which may now represent relative indications for operative intervention.

Adolescent↗
PubMed2004

Echocardiographic analysis of ventricular geometry and function during repair of congenital septal defects.

BACKGROUND: This study investigated changes in left ventricular (LV) geometry and systolic function after corrective surgery for atrial (ASD) and ventricular septal defects (VSD). METHODS: Transesophageal LV short-axis echocardiograms were recorded before and after operative repair of ASD (n = 11) and VSD (n = 7). Preload was measured using LV end-diastolic area indexed for body surface area. Measurements of septal-freewall (D1) and anterior-posterior (D2) endocardial diameters were used to assess LV symmetry from D1/D2. Systolic indices included stroke area, area ejection fraction, and fractional shortening. RESULTS: Preload, stroke area, area ejection fraction, and fractional shortening of D1 increased after ASD repair but decreased after VSD repair (p < 0.05). End-diastolic symmetry increased after ASD closure and decreased after VSD closure (p < 0.05). Increases in stroke area and ejection fraction after ASD correction primarily reflected increased shortening of D1. A positive correlation was found overall between percent change in end-diastolic area (EDA) and percent change in area ejection fraction (r(2) = 0.80, p < 0.0001, n = 18). CONCLUSIONS: Preload was the primary determinant of changes in LV function in this series of ASD and VSD repairs. Intraoperative changes in position of the interventricular septum affected systolic and diastolic LV symmetry and septal free wall shortening. Additional studies are needed to define changes in afterload and contractility as well as diastolic compliance and systolic mechanics.

Child↗
PubMed2004

Mitochondrial respiratory abnormalities in patients with end-stage congenital heart disease.

BACKGROUND: Nitric oxide (NO) binds to mitochondrial cytochrome oxidase to decrease myocardial oxygen consumption (MVO(2)). This regulation is disrupted in heart failure (HF) due to reduced NO. The present objective was to evaluate NO-mediated regulation of mitochondrial respiration in the myocardium of patients with congenital heart disease (CHD) and cardiomyopathy (CMP). METHODS: MVO(2) was measured in vitro in explanted human myocardium obtained at transplantation. Seven patients had CHD (5 cyanotic, 2 acyanotic), and 11 had non-ischemic CMP. The effects of the following on MVO(2) were measured: kinin-dependent endothelial NO synthase (eNOS) agonists, bradykinin, ramiprilat and amlodipine; NO donors, nitroglycerin and S-nitroso-N-acetylpenicillamine (SNAP) (10(-7) to 10(-4) mol/liter); and NOS inhibitor, N(omega)-nitro-L-arginine methylester (L-NAME). RESULTS: eNOS agonists caused a smaller decrease in MVO(2) in CHD compared with CMP patients. Changes in MVO(2) at the highest dose in CHD vs CMP were, respectively: bradykinin, -22 +/- 7% vs: -30 +/- 5% (p < 0.05); ramiprilat, -17 +/- 8% vs -26 +/- 2%, (p < 0.001); and amlodipine, -5 +/- 7% vs -29 +/- 6% (p < 0.001). L-NAME attenuated the effect of bradykinin, ramiprilat and amlodipine in both groups, confirming that the drug effect was secondary to eNOS activation. Nitroglycerin and SNAP also caused smaller decreases in MVO(2) in CHD vs CMP (NTG -16 +/- 6% vs -37 +/- 4%, SNAP -37 +/- 4% vs -49 +/- 3%, [p < 0.01]), suggesting altered mitochondrial function in CHD. CONCLUSIONS: Abnormal regulation of MVO(2) in end-stage CMP may be secondary to reduced endogenous NO availability and can be reversed by the use of NO agonists. In end-stage CHD, this abnormality may be related in part to abnormal mitochondrial function.

Adolescent↗
PubMed2002

Endogenous endothelium-derived nitric oxide inhibits myocardial caspase activity: implications for treatment of end-stage heart failure.

BACKGROUND: Apoptosis contributes to ventricular remodeling in heart failure (HF). Nitric oxide (NO) inhibits caspase 3, a key effector apoptotic enzyme. We hypothesized that reduced endogenous NO in HF disinhibits cardiac caspase 3 to promote apoptosis. METHODS: Caspase 3 activity was measured colorimetrically in myocardial cell lysates from endothelial NO synthase (eNOS)-deficient mice (eNOS -/-; n = 18), cardiomyopathic (CMP) hamsters (n = 8), and explanted failing human hearts (n = 10). We stimulated myocardial caspase 3 activity by adding upstream caspase 8 or 9. Cell lysates were incubated with 10(-4) mol/liter NO donor, S-nitroso-N-acetyl penicillamine; NOS inhibitor, nitro-L-arginine-methyl ester (L-NAME); or angiotensin-converting enzyme (ACE) inhibitor, enalaprilat. Hamsters underwent echocardiography so we could study the progression of ventricular dysfunction. RESULTS: Stimulated caspase 3 activity was lower in myocardium of eNOS +/+ compared with eNOS -/- mouse hearts (5.1 +/- 0.5 vs 7.6 +/- 1.0 pmol/10 microg/min, p < 0.05). L-NAME increased enzyme activity only in eNOS +/+ mice, indicating that endogenous NO inhibits caspase 3. Stimulated caspase 3 activity was lower in control hamsters, 3.3 +/- 0.3 pmol/10 microg/min, compared with CMP hamsters, 9.6 +/- 0.7 and 6.9 +/- 0.4 pmol/10 microg/min at 4 and 9 months, respectively. This was associated with progressive ventricular dysfunction, thinning, and dilatation. L-NAME increased enzyme activity in normal but not in CMP hamsters. In failing human myocardium, L-NAME failed to alter caspase activity, indicating reduced NO availability. Enalaprilat inhibited caspase 3, which was reversed by L-NAME. S-nitroso-N-acetyl penicillamine reversed caspase 3 activation in all groups. CONCLUSIONS: Nitric oxide reversibly inhibits myocardial caspase 3 independent of the apoptotic signaling pathway. Reduced NO in HF increases myocardial caspase 3 activity. Agents that promote NO synthesis, including ACE inhibitors, may prevent caspase activation in HF.

Animals↗