Randomised trial of ramipril in repaired tetralogy of Fallot and pulmonary regurgitation: the APPROPRIATE study (Ace inhibitors for Potential PRevention Of the deleterious effects of Pulmonary Regurgitation In Adults with repaired TEtralogy of Fallot).

BACKGROUND: Optimal treatment for stable repaired tetralogy of Fallot (rTOF) patients with pulmonary regurgitation (PR) and related right ventricular (RV) dilatation, including timing of valve implantation, remains uncertain. We sought to study tolerability of the angiotensin-converting-enzyme (ACE) inhibitor ramipril and its effects on cardiovascular function in these patients. METHODS: Clinically stable rTOF patients with moderate/severe PR were included. A double-blinded, placebo-controlled study of 6 months of ramipril vs placebo was performed. All patients underwent cardiovascular magnetic resonance (CMR), echocardiography, neurohormonal analysis, and objective cardiopulmonary exercise testing at baseline and follow-up. PRIMARY ENDPOINT: The main aim was to detect changes in RV function (primary endpoint CMR-derived RV ejection fraction). RESULTS: Seventy-two patients were enrolled and 64 qualified for the final analysis. There was no difference in the primary endpoint RV ejection fraction. RV long-axis shortening significantly improved in the ramipril group compared to placebo (RV: 2.3 ± 3.8 vs 0.02 ± 2.7 mm; P=0.017) as did LV long-axis shortening (1.9 ± 4.5 vs -0.2 ± 3.7 mm respectively; P=0.030). No clear differences were detected between ramipril and placebo for other measures. In a subgroup of patients with restrictive RV physiology, ramipril resulted in decrease in LV end-systolic volume index and increase in LVEF (-2.4 ± 5.0 vs 2.7 ± 3.6 mL/m(2); P=0.005, 2.5 ± 5.0 vs -1.3 ± 3.5%; P=0.03). Ramipril did not cause adverse events and was well tolerated. CONCLUSIONS: Ramipril is a well tolerated therapy, improves biventricular function in patients with rTOF and may have a particular role in patients with restrictive RV physiology. Larger, longer-term studies are needed to determine if ACE inhibitors can improve both ventricular remodelling and clinical outcomes. ( ISRCTN: 97515585).

Impaired heart rate response to exercise in adult patients with a systemic right ventricle or univentricular circulation: prevalence, relation to exercise, and potential therapeutic implications.

INTRODUCTION: Exercise limitation is common in patients with a systemic right ventricle or univentricular circulation and may be related to chronotropic incompetence (CI). We aimed to investigate the association of CI with exercise capacity, and evaluate whether CI is causally related to exercise intolerance. PATIENTS AND METHODS: Cardiopulmonary exercise tests were performed in patients with a systemic right ventricle (n=32) or univentricular circulation (n=32). CI was defined as the inability to achieve 80% of age predicted maximal heart rate reserve ([peak heart rate-resting heart rate]/[220-age-resting heart rate]). The linearity of the relation between oxygen consumption (VO(2)) and heart rate (oxygen pulse) was assessed visually and separately quantified by calculating the quadratic regression coefficient (describing departure from linearity). RESULTS: The prevalence of CI was 59% and 84% in patients with a systemic right ventricle or univentricular circulation, respectively. Patients with CI had a lower peak VO(2) (19.8+/-5.5 vs. 24.6+/-6.8 ml/kg/min, P=0.005), and shorter exercise duration (587+/-165 vs. 749+/-176 s, P=0.001) than those without CI. Oxygen pulse kinetics suggested exercise limitation due to CI in 8 of 43 patients (19%). In contrast, 13 of 43 patients (30%) had oxygen pulse kinetics suggestive of exercise limitation due to ventricular dysfunction or cyanosis. DISCUSSION: Chronotropic incompetence is common and associated with exercise limitation in patients with a systemic right ventricle or univentricular circulation. Visual or mathematical assessment of oxygen pulse kinetics identifies patients in whom an attenuated heart-rate response is responsible for poor exercise capacity and may have therapeutic implications.

Heart rate response during exercise predicts survival in adults with congenital heart disease.

OBJECTIVES: To assess the prognostic value of heart rate response to exercise in adult congenital heart disease (ACHD) patients. BACKGROUND: An abnormal heart rate response to exercise is related to autonomic dysfunction and may have prognostic implications in ACHD. METHODS: We identified 727 consecutive ACHD patients (mean age [+/- SD] 33 +/- 13 years) with varying diagnoses and without pacemakers. Peak oxygen consumption (peak VO2), resting heart rate, and the increase in heart rate from resting level to peak exercise ("heart rate reserve") were measured. We also quantified the decrease in heart rate ("heart rate recovery") after cessation of exercise. RESULTS: During a median follow-up of 28 months, 38 patients died. Lower values of heart rate reserve, peak heart rate, heart rate recovery, and peak VO2 (p < 0.01 for each) were associated with increased mortality in univariate analysis. Furthermore, heart rate reserve predicted mortality independently of antiarrhythmic therapy, functional class, and peak VO2. Stratifying patients by diagnostic groups revealed that a lower heart rate reserve was also associated with a greater risk of death in patients with complex anatomy, Fontan circulation, and tetralogy of Fallot (p < 0.05 for each). CONCLUSIONS: An abnormal heart rate response to exercise identifies ACHD patients with a higher risk of mortality in the midterm, even after accounting for antiarrhythmic medication and exercise capacity. Heart rate reserve is a simple and inexpensive way to identify ACHD patients at higher mortality risk.

Blood viscosity and its relationship to iron deficiency, symptoms, and exercise capacity in adults with cyanotic congenital heart disease.

OBJECTIVES: This study sought to determine the relationship between blood viscosity and iron deficiency and their impact on symptoms and exercise function in adults with cyanotic congenital heart disease. BACKGROUND: Iron deficiency is believed to raise whole blood viscosity in cyanotic congenital heart disease, although available data are inconsistent. METHODS: Thirty-nine cyanotic adults were prospectively assessed for iron deficiency (transferrin saturation < or =5%), hyperviscosity symptoms, and exercise capacity. Same-day measurement of whole blood viscosity and hematocrit (Hct) adjusted viscosity (cells resuspended in autologous plasma to Hct of 45%) was performed at shear rates ranging from 0.277 s(-1) to 128.5 s(-1). RESULTS: Viscosity did not differ between patients with iron deficiency (n = 14) and those without (n = 25). Whole blood viscosity correlated with Hct (r = 0.63, p < 0.001 at low shear and r = 0.84, p < 0.001 at high shear) but not with red blood cell size or iron indices. Hyperviscosity symptoms were independent of iron indices but directly correlated with increased Hct-adjusted viscosity (r = 0.41, p = 0.01). Exercise capacity did not differ in iron-deficient patients. However, peak oxygen consumption was higher in those with Hct > or = 65% (12.6 +/- 3.4 ml/kg/m2 vs. 9.8 +/- 2.6 ml/kg/m2, mean +/- SD, p = 0.036) despite higher whole blood viscosity in these same individuals (p < 0.01 for all shear rates). CONCLUSIONS: Iron deficiency is common in cyanotic adults but does not alter viscosity. Hyperviscosity symptoms are associated with a higher Hct-adjusted viscosity independent of cell size or iron stores. Higher Hct is associated with better exercise capacity. Further work to understand the origin of hyperviscosity symptoms is warranted.

Abnormal ventilatory response to exercise in adults with congenital heart disease relates to cyanosis and predicts survival.

BACKGROUND: Limited data exist with which to stratify risk in adult congenital heart disease (ACHD). An increased ventilatory response to exercise, expressed as ventilation per unit of carbon dioxide production (V(E)/V(CO2) slope), is an established predictor of impaired survival in acquired heart disease. We sought to establish the distribution, relation to cyanosis, and prognostic value of the V(E)/V(CO2) slope across a wide spectrum of ACHD patients. METHODS AND RESULTS: Five hundred sixty ACHD patients of varying diagnoses and 50 healthy controls underwent cardiopulmonary exercise testing at a single laboratory between 2001 and 2004. Patient age was 33.2 +/- 12.9 years (mean +/- SD). Peak oxygen consumption was 23.5 +/- 9.0 mL.kg(-1).min(-1).V(E)/V(CO2) slope for all patients was 36.3 +/-15.3. The slope was raised in all ACHD groups compared with controls and was 73% higher in cyanotic patients. Cyanosis, with or without pulmonary arterial hypertension, was the strongest predictor of abnormal V(E)/V(CO2) slope. The V(E)/V(CO2) slope was the most powerful univariate predictor of mortality in the noncyanotic group and the only independent predictor of mortality among exercise parameters on multivariate analysis. In cyanotic patients, no parameter was predictive of death. CONCLUSIONS: Ventilatory response to exercise is abnormal across the spectrum of ACHD. Cyanosis is a powerful stimulus for such exaggerated ventilatory patterns irrespective of the presence of pulmonary arterial hypertension. Increased V(E)/V(CO2) slope is the strongest exercise predictor of death in noncyanotic ACHD patients.

Clinical and haemodynamic effects of sildenafil in pulmonary hypertension: acute and mid-term effects.

AIM: The treatment of patients with pulmonary arterial hypertension remains a challenge. We set out to investigate the use of sildenafil, a selective inhibitor of phosphodiesterase type 5, in patients with this disease. METHODS AND RESULTS: Ten patients (8 females, mean age 34.5+/-3.3 years) with pulmonary hypertension underwent right heart catheterisation with vasodilator testing using incremental doses of intravenous sildenafil without adverse events. All patients were subsequently commenced on oral sildenafil 50 mg t.d.s. Nine patients had repeat right heart catheterisation 3 months after the commencement of oral therapy. There was a significant reduction in mean pulmonary artery pressure (from 55.8+/-5.9 to 50.4+/-6.1 mmHg, p=0.038 ) and pulmonary vascular resistance (from 10.1+/-1.7 to 8.6+/-1.5 Wood units, p=0.009 ), and an increase in cardiac output (from 4.7+/-0.3 to 5.0+/-0.4 l/min, p=0.15 ). Furthermore, there was a significant increase in the 6-minute walk test, a mean of 112 m. In response to a quality-of-life questionnaire, patients indicated marked clinical improvement on sildenafil. Sildenafil was discontinued in 1 patient due to a transient visual disturbance. The only patient previously awaiting transplantation was removed from the active transplantation list. CONCLUSIONS: Sildenafil is well tolerated in its intravenous and oral forms and appears to improve both pulmonary haemodynamics and the clinical status of patients with pulmonary hypertension after 3 months of oral therapy.

Differential contribution of dead space ventilation and low arterial pCO2 to exercise hyperpnea in patients with chronic heart failure secondary to ischemic or idiopathic dilated cardiomyopathy.

In chronic heart failure (CHF), the abnormally large ventilatory response to exercise (VE/VCO(2) slope) has 2 conceptual elements: the requirement of restraining arterial partial pressure of carbon dioxide (pCO(2)) from increasing (because of an increased ratio between increased physiologic dead space and tidal volume [VD/VT]) and the depression of arterial pCO(2) by further increased ventilation, which necessarily implies an important non-carbon dioxide stimulus to ventilation. We aimed to assess the contribution of these 2 factors in determining the elevated VE/VCO(2) slope in CHF. Thirty patients with CHF underwent cardiopulmonary exercise testing (age 65 +/- 11 years, left ventricular ejection fraction 34 +/- 15%, peak oxygen uptake 15.2 +/- 4 ml/kg/min, VE/VCO(2) slope 36.4). At rest and during exercise, arterial pCO(2) was measured and VD was calculated and separated into serial and alveolar components. VD/VT decreased from 0.57 at rest to 0.44 at peak exercise (p <0.01). VE/VCO(2) slope was correlated with peak exercise VD/VT (r = 0.67), the serial VD/VT ratio (r = 0.64), and alveolar VD/VT ratio (r = 0.51) at peak exercise (all p <0.01). VE/VCO(2) slope was also correlated with arterial pCO(2) (r = -0.75, p <0.001). Despite this, arterial pCO(2) was not related to peak oxygen uptake (r = 0.2) or to arterial lactate (r = -0.25) and only weakly to New York Heart Association functional class (F = 3.7). First, the increased VE/VCO(2) slope was caused by both the high VD/VT ratio and by other mechanisms, as shown by low arterial pCO(2) during exercise. Second, this latter component (depression of arterial pCO(2)) was not related to conventional measures of heart failure severity.