Right ventricular systolic dysfunction but not dilatation correlates with prognostically significant reductions in exercise capacity in repaired Tetralogy of Fallot.

AIMS: The optimal timing for pulmonary valve replacement in asymptomatic patients with repaired Tetralogy of Fallot (rTOF) and pulmonary regurgitation remains uncertain but is often guided by increases in right ventricular (RV) end-diastolic volume. As cardiopulmonary exercise testing (CPET) performance is a strong prognostic indicator, we assessed which cardiovascular magnetic resonance (CMR) parameters correlate with reductions in exercise capacity to potentially improve identification of high-risk patients. METHODS AND RESULTS: In all, 163 patients with rTOF (mean age 24.5 ± 10.2 years) who had previously undergone CMR and standardized CPET protocols were included. The indexed right and left ventricular end-diastolic volumes (RVEDVi, LVEDVi), right and left ventricular ejection fractions (RVEF, LVEF), indexed RV stroke volume (RVSVi), and pulmonary regurgitant fraction (PRF) were quantified by CMR and correlated with CPET-determined peak oxygen consumption (VO2) or peak work. On univariable analysis, there was no significant correlation between RVEDVi and PRF with peak VO2 or peak work (% Jones-predicted). In contrast, RVEF and RVSVi had significant correlations with both peak VO2 and peak work that remained significant on multivariable analysis. For a previously established prognostic peak VO2 threshold of <27 mL/kg/min, receiver-operating characteristic curve analysis demonstrated a Harrell's c of 0.70 for RVEF (95% confidence interval 0.61-0.79) with a sensitivity of 88% for RVEF <40%. CONCLUSION: In rTOF, CMR indices of RV systolic function are better predictors of CPET performance than RV size. An RVEF <40% may be useful to identify prognostically significant reductions in exercise capacity in patients with varying degrees of RV dilatation.

Randomized Trial of CPAP and Vardenafil on Erectile and Arterial Function in Men With Obstructive Sleep Apnea and Erectile Dysfunction.

Context: Erectile function is important for life satisfaction and often impaired in men with obstructive sleep apnea (OSA). Uncontrolled studies show that treating OSA with continuous positive airway pressure (CPAP) improves erectile function. Phosphodiesterase type 5 inhibitors (e.g., vardenafil) are the first-line therapy for erectile dysfunction (ED), but may worsen OSA. Objective: To assess the effects of CPAP and vardenafil on ED. Design: Sixty-one men with moderate-to-severe OSA and ED were randomized to 12 weeks of CPAP or sham CPAP, and 10 mg daily vardenafil or placebo in a two-by-two factorial design. Main Outcome Measures: International Index of Erectile Function (primary end point), treatment and relationship satisfaction, sleep-related erections, sexual function, endothelial function, arterial stiffness, quality of life, and sleep-disordered breathing. Results: CPAP increased the frequency of sleep-related erections, overall sexual satisfaction, and arterial stiffness but did not change erectile function or treatment or relationship satisfaction. Vardenafil did not alter erectile function, endothelial function, arterial stiffness, or sleep-disordered breathing, but did improve overall self-esteem and relationship satisfaction, other aspects of sexual function, and treatment satisfaction. Adherent CPAP improved erectile function, sexual desire, overall sexual, self-esteem, relationship, and treatment satisfaction, as well as sleepiness, and quality of life. Adherent vardenafil use did not consistently change nocturnal erection quality. Conclusion: CPAP improves overall sexual satisfaction, sleep-related erections, and arterial stiffness. Low-dose daily vardenafil improves certain aspects of sexual function and did not worsen OSA. Adherent CPAP or vardenafil use further improves ED and quality of life.

Sex differences in aortic augmentation index in adolescents.

BACKGROUND: Augmentation index (AIx) is a noninvasive measure of pulse wave reflection. AIx is associated with cardiovascular disease. Adult women have a higher AIx than men, but the factors determining this sex-related difference remain to be determined. METHODS: To examine factors associated with AIx in adolescents, participants in the Childhood Asthma Prevention Study, followed from birth, were assessed at age 14 years, with AIx standardized to a heart rate of 75/min (AIx_75) and pulse wave velocity. Associations of AIx_75 and pulse wave velocity with height, change in height, and measures of puberty were assessed. RESULTS: AIx_75 was higher in women compared to men [-24.5 (12.1) versus -32.3 (12.4)%; P < 0.001]. Lower AIx_75 was significantly related to greater change in height between 8 and 14 years, but not to achieved height. The sex difference in AIx was not independently related to puberty variables. Differences between sexes included early life weight gain, lipids, height, BMI-Z-score, change in height from 8 to 14 years, and age at peak height velocity. Change in AIx_75 from 8 to 14 years was highly associated with change in height (m) from 8 to 14 years (B = -88.8, 95% confidence interval -137.3 to -40.3, P =  < 0.001). The difference between sexes established at 8 years was not amplified from 8 to 14 years. CONCLUSION: AIx is higher in girls than boys at 14 years and is closely associated with change in height between 8 and 14 years. Measures of puberty do not appear to independently influence the sex difference in AIx in adolescents.

Right Ventricular Mass is Associated with Exercise Capacity in Adults with Repaired Tetralogy of Fallot.

The relationship between exercise capacity and right ventricular (RV) structure and function in adult repaired tetralogy of Fallot (TOF) is poorly understood. We therefore aimed to examine the relationships between cardiac MRI and cardiopulmonary exercise test variables in adult repaired TOF patients. In particular, we sought to determine the role of RV mass in determining exercise capacity. Eighty-two adult repaired TOF patients (age at evaluation 26 ± 10 years; mean age at repair 2.5 ± 2.8 years; 23.3 ± 7.9 years since repair; 53 males) (including nine patients with tetralogy-type pulmonary atresia with ventricular septal defect) were prospectively recruited to undergo cardiac MRI and cardiopulmonary exercise testing. As expected, these repaired TOF patients had RV dilatation (indexed RV end-diastolic volume: 153 ± 43.9 mL/m(2)), moderate-severe pulmonary regurgitation (pulmonary regurgitant fraction: 33 ± 14 %) and preserved left (LV ejection fraction: 59 ± 8 %) and RV systolic function (RV ejection fraction: 51 ± 7 %). Exercise capacity was near-normal (peak work: 88 ± 17 % predicted; peak oxygen consumption: 84 ± 17 % predicted). Peak work exhibited a significant positive correlation with RV mass in univariate analysis (r = 0.45, p < 0.001) and (independent of other cardiac MRI variables) in multivariate analyses. For each 10 g higher RV mass, peak work was 8 W higher. Peak work exhibits a significant positive correlation with RV mass, independent of other cardiac MRI variables. RV mass measured on cardiac MRI may provide a novel marker of clinical progress in adult patients with repaired TOF.

Widespread endotheliopathy in adults with cyanotic congenital heart disease.

INTRODUCTION: Cyanotic congenital heart disease is associated with functional limitation and vascular events. The nature and extent of endothelial dysfunction in cyanotic adults is poorly understood. We sought to characterise endothelial function in this setting. METHODS: A total of fourteen adults with cyanotic congenital heart disease (40±3 years) together with age- and sex-matched healthy controls underwent assessment of nitric oxide-dependent vascular responses, including flow-mediated dilatation of the brachial artery and dynamic vessel analysis of the retina in response to flickering light. Plasma levels of the endothelium-derived vasoconstrictor endothelin-1 and the nitric oxide antagonist, asymmetric dimethylarginine, were measured. Circulating endothelial progenitor cells were assessed by flow cytometry. RESULTS: Flow-mediated dilatation was significantly lower in cyanosed adults than controls (4.0±0.8 versus 7.2±1.0%, p=0.019, n=11 per group). Retinal arterial and venous dilatory responses were also impaired (2.9±0.8 versus 5.0±0.6%, p=0.05 and 3.4±0.3 versus 5.2±0.7%, p=0.04, n=13). Serum levels of endothelin-1 and asymmetric dimethylarginine were higher in cyanosed adults (3.0±0.6 versus 1.1±0.1 pg/ml, p=0.004 and 0.68±0.05 versus 0.52±0.02 µmol/L, p=0.03, n=11). Endothelial progenitor cells (CD34+CD45dimCD133+KDR+) were reduced in those with chronic cyanosis (17±4 versus 40±6 per million white blood cells, p=0.005, n=11). CONCLUSIONS: Endothelial function is impaired in the systemic arteries and retinal vessels in adults with cyanotic congenital heart disease, suggesting a widespread endotheliopathy. Diminished numbers of endothelial progenitor cells might potentially contribute to these observations.

Mechanisms of maintained exercise capacity in adults with repaired tetralogy of Fallot.

BACKGROUND: The mechanisms whereby cardiac output is augmented with exercise in adult repaired tetralogy of Fallot (TOF) are poorly characterised. METHODS: 16 repaired TOF patients (25 ± 7 years of age) and 8 age and sex matched controls (25 ± 4 years of age) underwent cardiopulmonary exercise testing and then real-time cardiac MRI (1.5 T) at rest and whilst exercising within the scanner, aiming for 30% heart rate reserve (Level 1) and 60% heart rate reserve (Level 2), using a custom-built MRI compatible foot pedal device. RESULTS: At rest, TOF patients had severely dilated RVs (indexed RV end-diastolic volume: 149 ± 37 mL/m(2)), moderate-severe PR (regurgitant fraction 35 ± 12%), normal RV fractional area change (FAC) (52 ± 7%) and very mildly impaired exercise capacity (83 ± 15% of predicted maximal work rate). Heart rate and RV FAC increased significantly in TOF patients (75 ± 10 vs 123 ± 17 beats per minute, p<0.001; 44 ± 7 vs 51 ± 10%, p=0.025), and similarly in control subjects (70 ± 11 vs 127 ± 12 beats per minute, p<0.001; 49 ± 7 vs 61 ± 9%, p=0.003), when rest was compared to Level 2. PR fraction decreased significantly but only modestly, from rest to Level 2 in TOF patients (37 ± 15 to 31 ± 15%, p=0.002). Pulmonary artery net forward flow was maintained and did not significantly increase from rest to Level 2 in TOF patients (70 ± 19 vs 69 ± 12 mL/beat, p=0.854) or controls (93 ± 9 vs 95 ± 21 mL/beat, p=0.648). CONCLUSIONS: During exercise in repaired TOF subjects with dilated RV and free PR, increased total RV output per minute was facilitated by an increase in heart rate, an increase in RV FAC and a decrease in PR fraction.

Progress of right ventricular dilatation in adults with repaired tetralogy of Fallot and free pulmonary regurgitation.

BACKGROUND: The time course of progressive dilatation of the right ventricle (RV) in adults with pulmonary regurgitation (PR) late after repair of tetralogy of Fallot (TOF) is poorly characterized. METHODS: We analysed cardiac MRI data (1.5 T) from 14 adult repaired TOF patients (26 ± 11 years of age) with dilated RVs and known significant PR, on 2 separate visits with a between MRI period of 2.1 ± 1.0 years. RESULTS: Indexed RV end diastolic volume (RVEDVi) increased over 2 years (142 ± 19 to 151 ± 20 mL/m2, p = 0.005; change = 8.4 ± 9.3 mL/m2, range = - 6 to 26 mL/m2; annual mL/m2 increase = 4.3 ± 4.6; annual percentage increase = 3.1 ± 3.3%), whilst RV ejection fraction decreased (53 ± 8 to 49 ± 7 %, p = 0.039). RV muscular corpus (RVMC) EDVi significantly increased (130 ± 19 to 138 ± 20 mL/m2, p = 0.014), whereas RV outflow tract (RVOT) EDVi did not (12 ± 7 vs 13 ± 6 mL/m2, p = 0.390). No other RV or LV measures significantly changed during the inter-MRI period. The change in RVEDVi correlated significantly with LV end diastolic volume (r = - 0.582, p = 0.029), RVEDVi:LVEDVi (r = 0.6, p = 0.023) and RVMC EDVi (r = 0.9, p < 0.001) but not RVOT EDVi (r = 0.225, p = 0.459). CONCLUSIONS: Adult repaired TOF patients with free PR experienced a mean 3.1%, or 4.3 mL/m2, annual increase in RVEDVi, unrelated to the initial RVEDVi or PR fraction. The increase in RVEDVi was due to RVMC rather than RVOT dilatation. This provides a guide to the frequency of MR surveillance and insights into the natural history of progressive RV dilatation in this setting.

Right ventricular outflow tract enlargement prior to pulmonary valve replacement is associated with poorer structural and functional outcomes, in adults with repaired Tetralogy of Fallot.

BACKGROUND: Pulmonary valve replacement (PVR) is commonly performed late after Tetralogy of Fallot (TOF) repair. We examined the effects of PVR on cardiac structure, function and exercise capacity in adults with repaired TOF. METHODS: Eighteen adult patients with repaired TOF and severe pulmonary regurgitation (PR) with right ventricular (RV) dilatation requiring PVR for clinical reasons (age; 25±8 years) were recruited to undergo cardiac MRI (1.5T) and cardiopulmonary exercise testing before and 14±3 months after PVR. RESULTS: Reduced indexed RV end-diastolic volume (RVEDVi; 186±32mL/m(2) pre-op vs 114±20mL/m(2) post-op, p<0.001) was observed after PVR. "Normalisation" of RVEDVi (≤108mL/m(2)) was achieved in only seven of 18 patients. Pre-PVR RVEDVi correlated with post-operative change in RVEDVi (change=-72.1±20.4mL/m(2), r=-0.815, p<0.001). Exercise capacity remained high-normal post-PVR (% predicted maximal workload: 93±16% vs 91±12%, p=0.5). Regional RV volumes were assessed; RV outflow tract (RVOT) volumes were compared to the RV muscular corpus. Large pre-PVR RVOT volumes correlated negatively with post-surgical RV ejection fraction, peak VO2 and delta VO2 at anaerobic threshold (p<0.05 for all). CONCLUSIONS: Normalisation of RV volume is unlikely to be achieved above a pre-PVR RVEDVi of 165mL/m(2) or more. In particular, an enlarged RVOT prior to PVR predicts suboptimal structural and functional outcomes.

Skeletal muscle abnormalities and exercise capacity in adults with a Fontan circulation.

OBJECTIVES: The peripheral muscle pump is key in promoting cardiac filling during exercise, especially in subjects who lack a subpulmonary ventricle (the Fontan circulation). A muscle-wasting syndrome exists in acquired heart failure but has not been assessed in Fontan subjects. We sought to investigate whether adults with the Fontan circulation exhibit reduced skeletal muscle mass and/or metabolic abnormalities. DESIGN AND PATIENTS: Sixteen New York Heart Association Class I/II Fontan adults (30±2 years) underwent cardiopulmonary exercise testing and lean mass quantification with dual x-ray absorptiometry (DXA); eight had calf muscle (31)P magnetic resonance spectroscopy as did eight healthy age-matched and sex-matched controls. DXA results were compared with Australian reference data. SETTING: Single tertiary referral centre. RESULTS: Peak VO2 was 1.9±0.1 L/min (66±3% of predicted values). Skeletal muscle mass assessed by relative appendicular lean mass index was significantly reduced compared with age-matched and sex-matched reference values (Z-score -1.46±0.22, p<0.0001). Low skeletal muscle mass correlated with poorer VO2 max (r=0.67, p=0.004). Overall, skeletal muscle mass T-score (derived from comparison with young normal reference mean) was -1.47±0.21; 4/16 Fontan subjects had sarcopenic range muscle wasting (T-score <-2.0) and 9/16 had less marked, but clinically significant wasting (T-score <-1.0 but ≥-2.0). Muscle aerobic capacity, measured by the rate constant (k) of postexercise phosphocreatine resynthesis, was significantly impaired in Fontan adults versus controls (1.48±0.13 vs 2.40±0.33 min(-1), p=0.02). CONCLUSIONS: Fontan adults have reduced skeletal muscle mass and intrinsic muscle metabolic abnormalities.

Resistance training improves cardiac output, exercise capacity and tolerance to positive airway pressure in Fontan physiology.

BACKGROUND: Subjects with Fontan-type circulation have no sub-pulmonary ventricle and thus depend exquisitely on the respiratory bellows and peripheral muscle pump for cardiac filling. We hypothesised that resistance training to augment the peripheral muscle pump might improve cardiac filling, reduce inspiratory-dependence of IVC return to the heart and thus improve exercise capacity and cardiac output on constant positive airway pressure (CPAP). METHODS: Eleven Fontan subjects (32+/-2 years, mean+/-SEM) had cardiac magnetic resonance imaging (MRI) and exercise testing (CPET); six underwent 20 weeks of high-intensity resistance training; others were non-exercising controls. After training, CPET was repeated. Four trainers had MRI with real-time flow measurement at rest, exercise and on CPAP in the trained state and following a 12-month detrain. RESULTS: In the trained state, muscle strength increased by 43% (p=0.002), as did total muscle mass (by 1.94 kg, p=0.003) and peak VO2 (by 183 ml/min, p=0.02). After detraining, calf muscle mass and peak workload had fallen significantly (p<0.03 for both) as did peak VO2 (2.72 vs. 2.18 l/min, p<0.001) and oxygen pulse, a surrogate for SV (16% lower, p=0.005). Furthermore after detraining, SV on MRI decreased at rest (by 11 ml, p=0.01) and during moderate-intensity exercise (by 16 ml, p=0.04); inspiratory-dependent IVC blood return during exercise was 40% higher (p=0.02). On CPAP, cardiac output was lower in the detrained state (101 vs. 77 ml/s, p=0.03). CONCLUSIONS: Resistance muscle training improves muscle mass, strength and is associated with improved cardiac filling, stroke volume, exercise capacity and cardiac output on CPAP, in adults with Fontan-type circulation.

Exercise capacity and stroke volume are preserved late after tetralogy repair, despite severe right ventricular dilatation.

OBJECTIVES: To assess if exercise capacity and resting stroke volume are different in tetralogy of Fallot (TOF) repair survivors with indexed RV (right ventricle) end-diastolic volume (RVEDVi) more versus less than 150 ml/m(2), a currently suggested threshold for pulmonary valve replacement (PVR). DESIGN: Cross-sectional study. SETTING: Single-centre adult congenital heart disease unit. PATIENTS: 55 consecutively eligible patients with repaired TOF (age at repair 2.3±1.9 years; age at evaluation 26.2±8.8 years; NYHA Class I or II). INTERVENTIONS: Cardiovascular MRI (1.5T) and cardiopulmonary exercise test. MAIN OUTCOME MEASURES: Biventricular volumes and function; exercise capacity. RESULTS: 20 patients had RVEDVi below, and 35 had RVEDVi above 150 ml/m(2), at time of referral. In the >150 ml/m(2) group, fractional pulmonary regurgitation was higher (41±8 vs 31±8%, p<0.001). Although RV ejection fraction (EF) was lower (47±7 vs 54±6%, p=0.007), indexed RV stroke volume was higher (87±14 vs 64±10 ml/m(2), p<0.001) in the >150 ml/m(2) group. There were no significant differences in LVEF, indexed LV stroke volume or exercise capacity (% predicted peak work: 90±17 vs 89±11% and; % predicted VO(2) peak: 84±17 vs 87±12%). CONCLUSIONS: Exercise capacity and stroke volume are maintained with RVEDVi above compared with below a commonly used cut-off for PVR surgery. Optimal timing for PVR, thus, remains unclear.

The relationship between carotid stiffness and circulating levels of heat shock protein 60 in middle-aged men and women.

OBJECTIVE: There is growing evidence that the presence of the cell stress protein heat shock protein (HSP) 60 in the circulation is associated with risk of coronary heart disease. In this study, we measured the association between plasma HSP60 and carotid arterial stiffness in middle-aged men and women. METHODS: Six hundred and forty-seven men and women aged 50-72 years and free of cardiovascular disease and medication were tested. Carotid artery distensibility coefficient was assessed ultrasonically as a measure of arterial stiffness, and plasma HSP60 was assessed using a sensitive immunoassay. RESULTS: We found a significant, independent association between high plasma levels of HSP60 and increased carotid stiffness. Carotid distensibility coefficient was also related to diabetes, adiposity, blood pressure, lipids, plasma interleukin-6 and C-reactive protein. After adjusting for these factors, the odds of HSP60 concentration of at least 1000 ng/ml were 1.79 (95% confidence intervals 1.06-3.04) for participants in the lowest compared with the highest tertile of the distensibility coefficient. CONCLUSION: HSP60 is a potent activator of vascular endothelial cells and smooth muscle cells. Thus, it is possible that long-term stimulation of these cell populations by blood-borne HSP60 acts to drive blood vessel changes resulting in decreased arterial elasticity.