Haemodynamic consequences of targeted single- and dual-site right ventricular pacing in adults with congenital heart disease undergoing surgical pulmonary valve replacement.

AIMS: The purpose of this study was to create an epicardial electroanatomic map of the right ventricle (RV) and then apply post-operative-targeted single- and dual-site RV temporary pacing with measurement of haemodynamic parameters. Cardiac resynchronization therapy is an established treatment for symptomatic left ventricular (LV) dysfunction. In congenital heart disease, RV dysfunction is a common cause of morbidity-little is known regarding the potential benefits of CRT in this setting. METHODS AND RESULTS: Sixteen adults (age = 32 ± 8 years; 6 M, 10 F) with right bundle branch block (RBBB) and repaired tetralogy of Fallot (n = 8) or corrected congenital pulmonary stenosis (n = 8) undergoing surgical pulmonary valve replacement (PVR) for pulmonary regurgitation underwent epicardial RV mapping and haemodynamic assessment of random pacing configurations including the site of latest RV activation. The pre-operative pulmonary regurgitant fraction was 49 ± 10%; mean LV end-diastolic volume (EDV) 85 ± 19 mL/min/m(2) and RVEDV 183 ± 89 mL/min/m(2) on cardiac magnetic resonance imaging. The mean pre-operative QRS duration is 136 ± 26 ms. The commonest site of latest activation was the RV free wall and DDD pacing here alone or combined with RV apical pacing resulted in significant increases in cardiac output (CO) vs. AAI pacing (P < 0.01 all measures). DDDRV alternative site pacing significantly improved CO by 16% vs. AAI (P = 0.018), and 8.5% vs. DDDRV apical pacing (P = 0.02). CONCLUSION: Single-site RV pacing targeted to the region of latest activation in patients with RBBB undergoing PVR induces acute improvements in haemodynamics and supports the concept of 'RV CRT'. Targeted pacing in such patients has therapeutic potential both post-operatively and in the long term.

Distal His bundle pacing in a patient with surgically corrected complex Ebstein anomaly and symptomatic second-degree atrioventricular block: a case report.

Background: Ebstein's anomaly occurs when there is an apical displacement of the tricuspid valve with septal and posterior valve leaflets tethering. This condition often occurs in association with other congenital, structural, or conduction system diseases, including intracardiac shunts, valvular lesions, arrhythmias, accessory conduction pathways, and first-degree atrioventricular (AV) block. We present for the first time a case of a patient with Ebstein's anomaly who presented with second-degree Mobitz II AV block and was successfully treated with conduction system pacing (CSP) due to her young age and the likelihood of a long-term high percentage of pacing. Case summary: We present a case of a 42-year-old lady with a background of complex congenital heart disease, including severe pulmonary stenosis, Ebstein anomaly, and atrial septal defect (ASD). She required complex surgical intervention, including tricuspid valve (TV) repair and subsequently replacement, ASD closure, and pulmonary balloon valvuloplasty. She presented to our hospital with symptomatic second-degree Mobitz II AV block (dizziness, shortness of breath, and exercise intolerance) and right bundle branch block (RBBB) on her baseline ECG. Her echocardiogram showed dilated right ventricle (RV) and left ventricle (LV) with low normal LV systolic function. Due to her young age and the likelihood of a long-term high percentage of RV pacing, we opted for CSP after a detailed discussion and patient consent. The distal HIS position is the preferred pacing strategy at our centre. We could not cross the TV with the standard Medtronic C315 HIS catheter, so we had to use the deflectable C304 HIS catheter. Mapping and pacing of the distal HIS bundle were achieved by Medtronic Selectsecure 3830, 69 cm lead. HIS bundle pacing led to the correction of both second-degree Mobitz II AV block and pre-existing RBBB. The implantation was uneventful, and the patient was discharged home the next day without any acute complications. Discussion: Distal HIS pacing is feasible in patients with surgically treated complex Ebstein anomaly and heart block. This approach can normalize the QRS complex with a high probability of preserving or improving LV function.

Contribution of NOTCH1 genetic variants to bicuspid aortic valve and other congenital lesions.

INTRODUCTION: Bicuspid aortic valve (BAV) affects 1% of the general population. NOTCH1 was the first gene associated with BAV. The proportion of familial and sporadic BAV disease attributed to NOTCH1 mutations has not been estimated. AIM: The aim of our study was to provide an estimate of familial and sporadic BAV disease attributable to NOTCH1 mutations. METHODS: The population of our study consisted of participants of the University of Leicester Bicuspid aoRtic vAlVe gEnetic research-8 pedigrees with multiple affected family members and 381 sporadic patients. All subjects underwent NOTCH1 sequencing. A systematic literature search was performed in the NCBI PubMed database to identify publications reporting NOTCH1 sequencing in context of congenital heart disease. RESULTS: NOTCH1 sequencing in 36 subjects from 8 pedigrees identified one variant c.873C>G/p.Tyr291* meeting the American College of Medical Genetics and Genomics criteria for pathogenicity. No pathogenic or likely pathogenic NOTCH1 variants were identified in 381 sporadic patients. Literature review identified 64 relevant publication reporting NOTCH1 sequencing in 528 pedigrees and 9449 sporadic subjects. After excluding families with syndromic disease pathogenic and likely pathogenic NOTCH1 variants were detected in 9/435 (2.1%; 95% CI: 0.7% to 3.4%) of pedigrees and between 0.05% (95% CI: 0.005% to 0.10%) and 0.08% (95% CI: 0.02% to 0.13%) of sporadic patients. Incomplete penetrance of definitely pathogenic NOTCH1 mutations was observed in almost half of reported pedigrees. CONCLUSIONS: Pathogenic and likely pathogenic NOTCH1 genetic variants explain 2% of familial and <0.1% of sporadic BAV disease and are more likely to associate with tetralogy of Fallot and hypoplastic left heart.

Maternal and neonatal outcomes in women with history of coronary artery disease.

BACKGROUND: Pregnancy outcomes in women with pre-existing coronary artery disease (CAD) are poorly described. There is a paucity of data therefore on which to base clinical management to counsel women, with regard to both maternal and neonatal outcomes. METHOD: We conducted a retrospective multicentre study of women with established CAD delivering at 16 UK specialised cardiac obstetric clinics. We included pregnancies of 24 weeks' gestation or more, delivered between January 1998 and October 2018. Data were collected on maternal cardiovascular, obstetric and neonatal events. RESULTS: 79 women who had 92 pregnancies (94 babies including two sets of twins) were identified. 35.9% had body mass index >30% and 24.3% were current smokers. 18/79 (22.8%) had prior diabetes, 27/79 (34.2%) had dyslipidaemia and 21/79 (26.2%) had hypertension. The underlying CAD was due to atherosclerosis in 52/79 (65.8%), spontaneous coronary artery dissection (SCAD) in 11/79 (13.9%), coronary artery spasm in 7/79 (8.9%) and thrombus in 9/79 (11.4%).There were six adverse cardiac events (6.6% event rate), one non-ST elevation myocardial infarction at 23 weeks' gestation, two SCAD recurrences (one at 26 weeks' gestation and one at 9 weeks' postpartum), one symptomatic deterioration in left ventricular function and two women with worsening angina. 14% of women developed pre-eclampsia, 25% delivered preterm and 25% of infants were born small for gestational age. CONCLUSION: Women with established CAD have relatively low rates of adverse cardiac events in pregnancy. Rates of adverse obstetric and neonatal events are greater, highlighting the importance of multidisciplinary care.

Maternal and fetal outcomes in pregnancies complicated by Marfan syndrome.

OBJECTIVES: Information to guide counselling and management for pregnancy in women with Marfan syndrome (MFS) is limited. We therefore conducted a UK multicentre study. METHODS: Retrospective observational study of women with MFS delivering between January 1998 and March 2018 in 12 UK centres reporting data on maternal and neonatal outcomes. RESULTS: In total, there were 258 pregnancies in 151 women with MFS (19 women had prior aortic root replacements), including 226 pregnancies ≥24 weeks (two sets of twins), 20 miscarriages and 12 pregnancy terminations. Excluding miscarriages and terminations, there were 221 live births in 139 women. Only 50% of women received preconception counselling. There were no deaths, but five women experienced aortic dissection (1.9%; one type A and four type B-one had a type B dissection at 12 weeks and subsequent termination of pregnancy). Five women required cardiac surgery postpartum. No predictors for aortic dissection could be identified. The babies of the 131 (65.8%) women taking beta-blockers were on average 316 g lighter (p<0.001). Caesarean section rates were high (50%), particularly in women with dilated aortic roots. In 55 women, echocardiographic aortic imaging was available prepregnancy and postpregnancy; there was a small but significant average increase in AoR size of 0.84 mm (Median follow-up 2.3 months) CONCLUSION: There were no maternal deaths, and the aortic dissection rate was 1.9% (mainly type B). There with no identifiable factors associated with aortic dissection in our cohort. Preconception counselling rates were low and need improvement. Aortic size measurements increased marginally following pregnancy.

Retrospective UK multicentre study of the pregnancy outcomes of women with a Fontan repair.

BACKGROUND: The population of women of childbearing age palliated with a Fontan repair is increasing. The aim of this study was to describe the progress of pregnancy and its outcome in a cohort of patients with a Fontan circulation in the UK. METHODS: A retrospective study of women with a Fontan circulation delivering between January 2005 and November 2016 in 10 specialist adult congenital heart disease centres in the UK. RESULTS: 50 women had 124 pregnancies, resulting in 68 (54.8%) miscarriages, 2 terminations of pregnancy, 1 intrauterine death (at 30 weeks), 53 (42.7%) live births and 4 neonatal deaths. Cardiac complications in pregnancies with a live birth included heart failure (n=7, 13.5%), arrhythmia (n=6, 11.3%) and pulmonary embolism (n=1, 1.9%). Very low baseline maternal oxygen saturations at first obstetric review were associated with miscarriage. All eight women with saturations of less than 85% miscarried, compared with 60 of 116 (51.7%) who had baseline saturations of ≥85% (p=0.008). Obstetric and neonatal complications were common: preterm delivery (n=39, 72.2%), small for gestational age (<10th percentile, n=30, 55.6%; <5th centile, n=19, 35.2%) and postpartum haemorrhage (n=23, 42.6%). There were no maternal deaths in the study period. CONCLUSION: Women with a Fontan circulation have a high rate of miscarriage and, even if pregnancy progresses to a viable gestational age, a high rate of obstetric and neonatal complications.

Trifecta St. Jude medical® aortic valve in pulmonary position.

Introduction: To evaluate an aortic pericardial valve for pulmonary valve (PV) regurgitation after repair of congenital heart defects. Methods: From July 2012 to June 2016 71 patients, mean age 24 ± 13 years (four to years) underwent PV implantation of aortic pericardial valve, mean interval after previous repair = 21 ± 10 years (two to 47 years). Previous surgery at mean age 3.2 ± 7.2 years (one day to 49 years): tetralogy of Fallot repair in 83% (59/71), pulmonary valvotomy in 11% (8/71), relief of right ventricular outflow tract (RVOT) obstruction in 6% (4/71). Pre-operative echocardiography and MRI showed severe PV regurgitation in 97% (69/71), moderate in 3% (2/71) with associated RVOT obstruction. MRI and knowledge-based reconstruction 3D volumetry (KBR-3D-volumetry) showed mean PV regurgitation = 42 ± 9% (20-58%), mean indexed RV end-diastolic volume = 169 ± 33 (130-265) ml m-2 BSA and mean ejection fraction (EF) = 46 ± 8% (33-61%). Cardio-pulmonary exercise showed mean peak O2/uptake = 24 ± 8 ml kg-1 min-1 (14-45 ml kg-1 min-1), predicted max O2/uptake 66 ± 17% (26-97%). Pre-operative NYHA class was I in 17% (12/71) patients, II in 70% (50/71) and III in 13% (9/71). Results: Mean cardio-pulmonary bypass duration was 95 ± 30' (38-190'), mean aortic cross-clamp in 23% (16/71) 46 ± 31' (8-95'), with 77% (55/71) implantations without aortic cross-clamp. Size of implanted PV: 21 mm in seven patients, 23 mm in 33, 25 mm in 23, and 27 mm in eight. The z-score of the implanted PV was -0.16 ± 0.80 (-1.6 to 2.5), effective orifice area indexed (for BSA) of native PV was 1.5 ± 0.2 (1.2 to -2.1) vs. implanted PV 1.2 ± 0.3 (0.76 to -2.5) (p = ns). In 76% (54/71) patients surgical RV modelling was associated. Mean duration of mechanical ventilation was 6 ± 5 h (0-26 h), mean ICU stay 21 ± 11 h (12-64 h), mean hospital stay 6 ± 3 days (three to 19 days). In mean follow-up = 25 ± 14 months (six to 53 months) there were no early/late deaths, no need for cardiac intervention/re-operation, no valve-related complications, thrombosis or endocarditis. Last echocardiography showed absent PV regurgitation in 87.3% (62/71) patients, trivial/mild degree in 11.3% (8/71), moderate degree in 1.45% (1/71), mean max peak velocity through RVOT 1.6 ± 0.4 (1.0-2.4) m s-1. Mean indexed RV end-diastolic volume at MRI/KBR-3D-volumetry was 96 ± 20 (63-151) ml m-2 BSA, lower than pre-operatively (p < 0.001), and mean EF = 55 ± 4% (49-61%), higher than pre-operatively (p < 0.05). Almost all patients (99% = 70/71) remain in NYHA class I, 1.45% = 1/71 in class II. Conclusion: (a) Aortic pericardial valve is implantable in PV position with an easy and reproducible surgical technique; (b) valve size adequate for patient BSA can be implanted with simultaneous RV remodelling; (c) medium-term outcomes are good with maintained PV function, RV dimensions significantly reduced and EF significantly improved; (d) adequate valve size will allow later percutaneous valve-in-valve implantation.

The anti-CD14 antibody IC14 suppresses ex vivo endotoxin stimulated tumor necrosis factor-alpha in patients with chronic heart failure.

BACKGROUND: Activation of the endotoxin (LPS) receptor, CD14, leads to tumor necrosis factor-alpha (TNF) production. Plasma LPS activity is elevated in patients with severe chronic heart failure (CHF). An anti-CD14 antibody, IC14, blocks TNF production in healthy volunteers. It is not known whether IC14 prevents TNF production in CHF patients. METHODS AND RESULTS: Blood from 20 CHF patients (age 64+/-2.1 years, NYHA class 2.2+/-0.1, LVEF 27+/-3%, mean+/-SEM) was pre-incubated with 0.5, 1.0, 5.0, 10 and 50 microg/mL IC14 for 1 h followed by incubation with 1 or 10 ng/mL LPS for 6 h. Fourteen subjects served as controls (58+/-2.4 years). LPS-stimulated TNF release was 76% and 60% greater at 1 and 10 ng/mL LPS, respectively, in CHF patients versus controls (p=0.07 and p=0.008). IC14 at concentrations of 5.0, 10 and 50 microg/mL substantially reduced TNF production in response to stimulation with LPS (all p<0.05). CD14 receptor density was similar in patients and controls. In controls, but not in CHF patients, there was a positive correlation between CD14 receptor density and TNF production (r=0.61, p=0.03). CONCLUSION: IC14 suppresses LPS-stimulated whole blood TNF production in patients with CHF and in normal subjects and therefore may represent a novel therapeutic strategy for CHF patients with systemic immune activation.

Myocardial production of C-type natriuretic peptide in chronic heart failure.

BACKGROUND: C-type natriuretic peptide (CNP) is a vasodilator produced by the vascular endothelium. It shares structural and physiological properties with the cardiac hormones atrial natriuretic peptide and brain natriuretic peptide (BNP), but little is known about its pathophysiological role in chronic heart failure (CHF). We assessed the hypothesis that CNP is produced by the heart in patients with CHF. METHODS AND RESULTS: Myocardial CNP production was determined (difference in plasma levels between the aortic root and coronary sinus [CS]) in 9 patients undergoing right and left heart catheterization as part of their CHF assessment (all male, age 59+/-9 years; New York Heart Association class 2.2+/-0.1; left ventricular ejection fraction 29+/-5%; creatinine 105+/-8 micro mol/L [all values mean+/-SEM]). BNP, established as originating from myocardium, was assessed from the same samples as a positive control. Analyses were performed by a blinded operator using a standard competitive radioimmunoassay kit (Peninsula Laboratories, Bachem Ltd UK). A step-up (29%) in plasma CNP concentration was found from the aorta to the CS (3.55+/-1.53 versus 4.59+/-1.54 pg/mL, respectively; P=0.035). The mean increase in CNP was 0.90+/-0.35 pg/mL (range 0.05 to 2.80 pg/mL). BNP levels increased by 57% from aorta to CS (86.0+/-20.5 versus 135.0+/-42.2 pg/mL; P=0.01). CS CNP levels correlated with mean pulmonary capillary wedge pressure (r=0.82, P=0.007). CONCLUSIONS: We have shown that CNP is produced by the heart in patients with CHF. Although further evaluation is required to define its full pathophysiological role in this condition, CNP may represent an important new local mediator in the heart.

Neurohormonal activation and the chronic heart failure syndrome in adults with congenital heart disease.

BACKGROUND: Neurohormonal activation characterizes chronic heart failure, relates to outcome, and is a therapeutic target. It is not known whether a similar pattern of neurohormonal activation exists in adults with congenital heart disease and, if so, whether it relates to common measures of disease severity or whether cardiac anatomy is a better discriminant. METHODS AND RESULTS: Concentrations of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), endothelin-1 (ET-1), renin, aldosterone, norepinephrine, and epinephrine were determined in 53 adults with congenital heart disease, comprising 4 distinct anatomic subgroups (29 female; 33.5+/-1.5 years of age; New York Heart Association class 2.0+/-0.1, mean+/-SEM) and 15 healthy control subjects (8 female; 32.3+/-1.3 years of age). Systemic ventricular function was graded by a blinded echocardiographer as normal or mildly, moderately, or severely impaired. Adults with congenital heart disease had elevated levels of ANP (56.6 versus 3.1 pmol/L), BNP (35.8 versus 5.7 pmol/L), ET-1 (2.5 versus 0.7 pmol/L, all P<0.0001), renin (147 versus 16.3 pmol/L), norepinephrine (2.2 versus 1.6 pmol/L, both P<0.01) and aldosterone (546 versus 337 pmol/L, P<0.05). There was a highly significant stepwise increase in ANP, BNP, ET-1, and norepinephrine according to New York Heart Association class and systemic ventricular function, with even asymptomatic patients having evidence of significant neurohormonal activation. In contrast, there was no direct relationship between the 4 anatomic subgroups and any of the neurohormones studied. CONCLUSIONS: Neurohormonal activation in adult congenital heart disease bears the hallmarks of chronic heart failure, relating to symptom severity and ventricular dysfunction and not necessarily to anatomic substrate. Neurohormonal antagonism across this large and anatomically diverse population should be considered.

The regulation and measurement of plasma volume in heart failure.

Plasma volume, the intravascular portion of the extracellular fluid volume, can be measured using standard dilution techniques with radiolabeled tracer molecules. In healthy persons, plasma volume remains relatively constant as a result of tight regulation by the complex interaction between neurohormonal systems involved in sodium and water homeostasis. Although chronic heart failure (CHF) is characterized by activation of many of these neurohormonal systems, few studies have evaluated plasma volume in this condition under treatment. Untreated edematous decompensated heart failure (HF) is associated with a significant expansion of plasma volume. Patients with stable CHF, receiving conventional therapy, appear to have a contracted plasma volume, a concept that is in contrast to the widely held belief that CHF is associated with long-term hypervolemia. It is likely that significant changes in plasma volume occur during intensification of medical therapy or during transition from the edematous to the stable state. Clinical assessment of plasma volume may be of particular value during treatment in patients with decompensated HF, in whom the plasma volume is contracted despite an increase in total extracellular fluid volume. Under these circumstances, treatment with inotropes or renal vasodilators may be more appropriate than intravenous diuretics alone. Further studies evaluating plasma volume in HF may help to improve our understanding of the pathophysiologic mechanisms occurring in the development and progression of this complex condition.

Effect of noradrenaline and isoproterenol on lipopolysaccharide-induced tumor necrosis factor-alpha production in whole blood from patients with chronic heart failure and the role of beta-adrenergic receptors.

Increased levels of tumor necrosis factor-alpha (TNF-alpha) correlate with poor prognoses in chronic heart failure (CHF). This study demonstrated that noradrenaline and isoproterenol inhibit TNF-alpha production in patients with CHF in ex vivo whole blood in a dose-dependent fashion. The beta-blocker bisoprolol abolishes this effect.

Cellular endotoxin desensitization in patients with severe chronic heart failure.

BACKGROUND: Increased levels of bacterial lipopolysaccharide (LPS) have been demonstrated in chronic heart failure (CHF). LPS can induce cellular desensitization, with specific down-regulation of LPS-mediated cellular tumor necrosis factor (TNF-alpha) production which does not affect other cytokine parameters. It is not known if LPS desensitization occurs in CHF. METHODS AND RESULTS: Mononuclear cells from 24 CHF patients (mean age 70+/-2 years, age range 58 to 78 years, NYHA class 3.0+/-0.2) and 11 healthy controls (mean age 53+/-3 years, age range 39 to 75 years) were separated from venous blood and cultured for 24 h with LPS (E. coli, 0-10 ng/mL). Culture supernatants were tested for TNF-alpha and interleukin-1 receptor antagonist (IL-1RA). Patients were subgrouped into mild (n=10), moderate (n=5), and severe (n=9) CHF. Independently of age, mononuclear cells from patients with severe heart failure produced less TNF-alpha than controls (p<0.05) and patients with mild (p<0.001) or moderate CHF (p<0.05). IL-1RA release was higher for CHF patients as a group, compared with controls (p<0.05). There was no significant difference in IL-1RA release between CHF patient subgroups. CONCLUSIONS: Mononuclear cells from patients with severe heart failure produce significantly less TNF-alpha than healthy controls or patients with mild to moderate disease. Production of IL-1RA is not affected. This resembles a picture indicative of LPS desensitization occurring in patients with severe CHF.

Whole blood endotoxin responsiveness in patients with chronic heart failure: the importance of serum lipoproteins.

BACKGROUND: Endotoxin [lipopolysaccharide (LPS)] may be an important stimulus for cytokine release in patients with chronic heart failure (CHF). We sought to investigate the relationship between whole blood endotoxin responsiveness and serum lipoprotein concentrations. It is not known if low-dose LPS is sufficient to stimulate immune activation. METHODS AND RESULTS: Whole blood from 32 CHF patients (mean age 66+/-2 years, NYHA class 2.7+/-0.2, five female) and 11 healthy control subjects (mean age 47+/-4 years, six female) was stimulated with LPS at nine different concentrations (0.001 to 10 ng/mL), and tumor necrosis factor (TNF-alpha) release was quantified. Reference standard endotoxin at concentrations of 0, 0.6, 1, and 3 EU/ml was added to whole blood from nine CHF patients (age 64+/-9.1 years, all NYHA class II, eight male) and incubated for 6 h, the TNF-alpha production being measured. Serum lipoproteins were quantified using standard techniques. In CHF patients, there was an inverse relationship between whole blood TNF-alpha release and serum cholesterol which was strongest at 0.6 ng/mL of LPS (r=-0.53, p=0.002). A similar although weaker relationship was found for serum HDL. No such correlation was found in healthy subjects or with serum LDL (all r(2)<0.1). Low concentrations of LPS induced a stepwise increase in TNF-alpha release from whole blood to concentrations well above those seen in CHF. CONCLUSIONS: Serum lipoproteins may play an important role in regulating LPS bioactivity in CHF. Very low LPS activity, at levels seen in vivo in CHF, can induce significant TNF-alpha production ex vivo.

Neurohormonal activation and its relation to outcomes late after repair of tetralogy of Fallot.

BACKGROUND: Brain natriuretic peptide (BNP) levels are elevated in patients with repaired Tetralogy of Fallot (rTOF), the clinical significance of which remains uncertain. METHODS AND RESULTS: Ninety consecutive adults (≥ 16 years) with rTOF (mean age 32.7 ± 11.3 years, 64% men) were prospectively recruited from a single tertiary centre, together with 15 age-matched and gender-matched controls. Patients with rTOF had elevated BNP (8.9 (5.9-14.6) vs 5.4 (2.2-7.5) pmol/L; p<0.01), and BNP activation was common even in asymptomatic patients. Also, atrial natriuretic peptide (6.9 (4.0-9.9) vs 3.3 (1.0-4.0) pmol/L; p<0.01), endothelin-1 (1.14 (0.94-1.48) vs 0.75 (0.44-0.93) pmol/L; p<0.01) and renin (55.0 (45.5-66.5) vs 18.6 (12.0-22.7) pmol/L; p<0.01) were elevated at baseline compared with controls. Interactions between BNP with endothelin-1, cardiothoracic ratio and right atrial area were evident. Eight deaths occurred over a median follow-up of 10 years. On Cox regression analysis, BNP emerged as a strong predictor of death (HR 1.16 per 10 pmol/L, 95% CI 1.05 to 1.29; p<0.01). Survival receiver operating curve analysis revealed an optimum cut-off of BNP ≥ 15 pmol/L (=52 pg/mL), above which BNP was related to significantly increased mortality (HR 5.40, 95% CI 1.29 to 22.6; p<0.01); absolute mortality at 5 years 19% vs 3% in patients with BNP ≤ 15 pmol/L. BNP was also a predictor of sustained arrhythmia (HR 2.06 per 10 pmol/L, 95% CI 1.32 to 3.21; p<0.05). CONCLUSIONS: Neurohormonal activation is present in adults with rTOF including asymptomatic patients. BNP level ≥ 15 pmol/L is associated with a fivefold increased risk of death. These data suggest that BNP measurement in patients with rTOF should be incorporated in the periodic risk stratification assessment of these patients under lifelong follow-up.

Effect of interleukin-10 on the production of tumor necrosis factor-alpha by peripheral blood mononuclear cells from patients with chronic heart failure.

Chronic heart failure (HF) is a state of inflammatory immune activation characterized by elevated circulating levels of tumor necrosis factor-alpha (TNF-alpha). Interleukin-10 (IL-10) is a potent anti-inflammatory cytokine that inhibits TNF-alpha production and lessens endotoxin bioactivity. It is not known whether IL-10 reduces lipopolysaccharide (LPS) stimulated TNF-alpha production of peripheral blood mononuclear cells (PBMCs) from patients with chronic HF. PBMCs were isolated from 15 patients with chronic HF (New York Heart Association functional class 3.0 +/- 0.2, left ventricular ejection fraction 30 +/- 2%, peak oxygen consumption 18.1 +/- 0.8 ml/kg/min) and 15 healthy control subjects and stimulated with 1 and 10 ng/ml LPS for 24 hours with or without prior addition of IL-10 (10 ng/ml). TNF-alpha was quantified in cell-free supernatants by an enzyme-linked immunosorbent assay. TNF-alpha, soluble TNF receptors, IL-10, and LPS were quantified in plasma. LPS stimulated TNF-alpha production was highest in those patients in New York Heart Association class II (p <0.01 vs New York Heart Association class III and IV, p <0.001 vs control subjects). IL-10 reduced PBMC TNF-alpha production in all stimulated samples at 1 and 10 ng/ml LPS (mean reduction 43% at 1 ng/ml, p <0.01 and 55% at 10 ng/ml, p <0.0001). The percentage reduction in TNF-alpha release did not differ significantly between patients and control subjects or with respect to severity of chronic HF or baseline immune parameters. Independently of clinical severity, IL-10 profoundly inhibits TNF-alpha release from PBMCs isolated from patients with chronic HF. IL-10 is, therefore, a potential therapy for use in chronic HF associated with inflammatory immune activation.

Pathophysiologic quantities of endotoxin-induced tumor necrosis factor-alpha release in whole blood from patients with chronic heart failure.

Bacterial endotoxin activity is elevated in patients with decompensated chronic heart failure (HF) and acts as a potent stimulus for immune activation. We sought to determine whether endotoxin, at an activity level seen in vivo (around 0.6 EU/ml), is sufficient to stimulate the secretion of tumor necrosis factor-alpha (TNF-alpha) and TNF-alpha soluble receptor (sTNFR2) in ex vivo whole blood from patients with HF. We studied 15 patients with HF (aged 65 +/- 1.9 years, New York Heart Association class 2.1 +/- 0.3, left ventricular ejection fraction 31 +/- 5%; mean +/- SEM), of whom 5 had cardiac cachexia, and 7 healthy control subjects (59 +/- 5 years, p = NS). Reference endotoxin was added to venous blood at concentrations of 0.6, 1.0, and 3.0 EU/ml, and was incubated for 6 hours. Endotoxin induced a dose-dependent increase in TNF-alpha release (p <0.05 in all groups). Patients with noncachectic HF produced significantly more TNF-alpha compared with controls after stimulation with 0.6, 1.0, and 3.0 EU/ml of endotoxin (113 +/- 46 vs 22 +/- 4 [p = 0.009], 149 +/- 48 vs 34 +/- 4 [p = 0.002], and 328 +/- 88 vs 89 +/- 16 pg/ml [p = 0.002], respectively; mean +/- SEM). Patients with cardiac cachexia produced significantly less TNF-alpha compared with patients without cardiac cachexia for all given concentrations (all p <0.05, analysis of variance p = 0.02). Production of sTNFR2 was greater at all concentrations of endotoxin versus controls (all p <0.05, analysis of variance p = 0.002). Plasma endotoxin levels were higher in patients with cardiac cachexia (4.3 times higher than in control subjects, p <0.005). Thus, low endotoxin activity, at levels seen in vivo in patients with HF, induces significant TNF-alpha and sTNFR2 production ex vivo. These results suggest that elevated plasma endotoxin activity observed in patients with HF is of pathophysiologic relevance.

Elevated circulating levels of inflammatory cytokines and bacterial endotoxin in adults with congenital heart disease.

Chronic heart failure is a state of immune activation, and endotoxin is a potential trigger for cytokine production. Our aim was to study whether immune activation and endotoxemia occur in adults with congenital heart disease. We prospectively measured tumor necrosis factor (TNF)-alpha, soluble TNF receptors (sTNFR-1, sTNFR-2), interleukin-6, interleukin-10, endotoxin, and soluble CD14 levels in 52 consecutive adults with congenital heart disease (age 34 +/- 2 years [mean +/- SEM]) and 18 healthy controls (age 31 +/- 1 years). A variety of congenital heart lesions were studied: single ventricle physiology (n = 15), systemic right ventricle (n = 7), tetralogy of Fallot (n = 20), and "other" congenital heart disease (n = 10). Patients were subgrouped into asymptomatic (New York Heart Association [NYHA] class I, n = 11), mild (NYHA class II, n = 30), and moderate/severe (NYHA class III/IV, n = 11) categories. Patients had elevated TNF and interleukin-6 levels compared with controls (TNF 2.8 vs 2.1 pg/ml, p <0.05; interleukin-6 8.5 vs 5.7 pg/ml, p <0.001). TNF levels were higher in patients with moderate/severe symptoms compared with patients who were asymptomatic or had mild symptoms (p <0.05). Soluble TNFR-1 levels related directly to the degree of systemic ventricular impairment (p <0.05). There were no significant differences in sTNFR-1, sTNFR-2, interleukin-10, or sCD14 levels between patients and controls. Endotoxin levels were greater in patients with congenital heart disease versus controls (0.40 vs 0.26 endotoxin units/ml, p <0.0001). Thus, adults with congenital heart disease have elevated levels of inflammatory cytokines and bacterial endotoxin, which relate to functional status. Congenital heart disease in adults may be amenable to novel anti-inflammatory therapies in selected patients.

Towards defining heart failure in adults with congenital heart disease.

Injury to the myocardium disrupts geometric integrity and results in changes to intracardiac pressure, wall stress and tension, and the pattern of blood flow through the heart. Significant disruption to pump function results in heart failure which is defined in terms of symptoms: breathlessness and fatigue, signs of salt and water retention, and neurohormonal activation. This syndrome most commonly occurs in the context of injury due to ischaemic heart disease and dilated cardiomyopathy but because patients with congenital heart disease (CHD) are born with sometimes gross distortions of cardiac anatomy they too are subject to the forces that drive heart failure. This paper explores the available data relating to the clinical and neurohormonal manifestations of heart failure in patients with congenital heart disease and describes how, by additionally exploring events at a cellular level, we may be able to arrive at a definition of heart failure relevant to this population.

Beta-blockers for chronic heart failure: surviving longer but feeling better?

Beta-blockers, as determined by four landmark placebo-controlled studies, impart a significant survival advantage to the chronic heart failure population. What ancillary benefits might be expected from beta-blockade, in terms of symptom relief and improvement in exercise capacity, is less clear. This situation in part reflects the heterogeneity of tools used to quantify quality of life and exercise performance as well as factors concerning the statistical handling of symptom and exercise data. In this review we explore the methodology and results of over 20 trials of carvedilol, metoprolol and bisoprolol where quality of life and measures of exercise capacity were end-points. A consistent message relating to a benefit from beta-blockade on these outcomes was elusive but the finding that patients on beta-blockers did at least as well as patients prescribed placebo was a unanimous verdict. There remains a dearth of data to help identify those patients that are at high risk of adverse events from beta-blocker therapy.