Intravenous iron loading improved exercise capacity and symptoms in patients with CHF and evidence of abnormal iron metabolism. Benefits were more evident in anemic patients. (Effect of Intravenous Ferrous Sucrose on Exercise Capacity in Chronic Heart Failure; http://www.clinicaltrials.gov/ct/show/NCT00125996; NCT00125996).

Background-Although some patients with adult congenital heart disease (ACHD) report limitations in exercise capacity, we hypothesized that depressed exercise capacity may be more widespread than superficially evident during clinical consultation and could be a means of assessing risk. Methods and Results-Cardiopulmonary exercise testing was performed in 335 consecutive ACHD patients (age, 33Ϯ13 years), 40 non-congenital heart failure patients (age, 58Ϯ15 years), and 11 young (age, 29Ϯ5 years) and 12 older (age, 59Ϯ9 years) healthy subjects. Peak oxygen consumption (peak V O 2 ) was reduced in ACHD patients compared with healthy subjects of similar age (21.7Ϯ8.5 versus 45.1Ϯ8.6; PϽ0.001). No significant difference in peak V O 2 was found between ACHD and heart failure patients of corresponding NYHA class (PϭNS for each NYHA class). Within ACHD subgroups, peak V O 2 gradually declined from aortic coarctation (28.7Ϯ10.4) to Eisenmenger (11.5Ϯ3.6) patients (PϽ0.001). Multivariable correlates of peak V O 2 were peak heart rate (rϭ0.33), forced expiratory volume (rϭ0.33), pulmonary hypertension (rϭϪ0.26), gender (rϭϪ0.23), and body mass index (rϭϪ0.19). After a median follow-up of 10 months, 62 patients (18.5%) were hospitalized or had died. On multivariable Cox analysis, peak V O 2 predicted hospitalization or death (hazard ratio, 0.937; Pϭ0.01) and was related to the frequency and duration of hospitalization (Pϭ0.01 for each). Conclusions-Exercise capacity is depressed in ACHD patients (even in allegedly asymptomatic patients) on a par with chronic heart failure subjects. Lack of heart rate response to exercise, pulmonary arterial hypertension, and impaired pulmonary function are important correlates of exercise capacity, as is underlying cardiac anatomy. Poor exercise capacity identifies ACHD patients at risk for hospitalization or death. (Circulation. 2005;112:828-835.)

Aims Plasma volume (PV) expansion hallmarks worsening chronic heart failure (CHF) but no non‐invasive means of quantifying volume status exists. Because weight and haematocrit are related to PV, they can be used to calculate relative PV status (PVS). We tested the validity and prognostic utility of calculated PVS in CHF patients. Methods and results First, we evaluated the agreement between calculated actual PV (aPV) and aPV levels measured using 125Iodine‐human serum albumin. Second, we derived PVS as: [(calculated aPV – ideal PV)/ideal PV] × 100%. Third, we assessed the prognostic implications of PVS in 5002 patients from the Valsartan in Heart Failure Trial (Val‐HeFT), and validated this in another 246 routine CHF outpatients. On analysis, calculated and measured aPV values correlated significantly in 119 normal subjects and 30 CHF patients. In the Val‐HeFT cohort, mean (+SD) PVS was –9 ± 8% and related to volume biomarkers such as brain natriuretic peptide (BNP). Over 2 years, 977 (20%) patients died. Plasma volume status was associated with death and first morbid events in a ‘J‐shaped’ fashion with the highest risk seen with a PVS > –4%. Stratification into PVS quartiles confirmed that a PVS > –4% was associated with increased mortality (unadjusted hazard ratio 1.65, 95% confidence interval 1.44–1.88, χ2 = 54, P < 0.001) even after adjusting for 22 variables, including brain natriuretic peptide. These results were mirrored in the validation cohort. Conclusions Relative PVS calculated from simple clinical indices reflects the degree to which patients have deviated from their ideal PV and independently relates to outcomes. The utility of PVS‐driven CHF management needs further evaluation.

Background— Impaired endothelial homeostasis underlies the pathophysiology of pulmonary arterial hypertension (PAH). We speculated that PAH patients are deficient in circulating endothelial progenitor cells (EPCs), potentially contributing to endothelial dysfunction and disease progression. Methods and Results— We recruited 41 patients with Eisenmenger syndrome (13 with Down syndrome), 55 with idiopathic PAH, and 47 healthy control subjects. Flow cytometry and in vitro assays were used to quantify EPCs and to assess cell function. The number of circulating CD34 + , CD34 + /AC133 + , CD34 + /KDR + , and CD34 + /AC133 + /KDR + progenitor cells was low in Eisenmenger patients compared with healthy control subjects, and those with Down syndrome displayed even fewer EPCs. Reductions in EPC numbers correlated with New York Heart Association functional class, 6-minute walk distance, and plasma brain-type natriuretic peptide levels. The capacity of cultured peripheral blood mononuclear cells to form colonies and incorporate into tube-like structures was impaired in Eisenmenger patients. Idiopathic PAH patients had reduced numbers of EPCs, and the number of circulating EPCs correlated with invasive hemodynamic parameters in this cohort. Levels of immune inflammatory markers, cGMP, stable nitric oxide oxidation products, and asymmetric dimethylarginine were abnormal in patients with PAH and related to numbers of EPCs. Within the idiopathic PAH population, treatment with the phosphodiesterase inhibitor sildenafil was associated with a dose-dependent rise in EPC numbers, resulting in levels consistently above those found with other therapies. Conclusions— Circulating EPC numbers are reduced in 2 well-characterized forms of PAH, which also exhibit raised levels of inflammatory mediators. Sildenafil treatment may represent a pharmacological means of increasing circulating EPC numbers long-term.

In patients with CHF, lower S(I) relates to higher mortality, independent of body composition and established prognosticators. Impaired S(I) may have implications in the pathophysiology of CHF disease progression. Therapeutically targeting impaired insulin sensitivity may potentially be beneficial in patients with CHF.

In stable ambulatory CHF patients, development of NOA is frequent and can be predicted by a set of clinical variables. Decreases in Hb over time relate to future increased morbidity and mortality.

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 (V̇ e /V̇ co 2 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 V̇ e /V̇ co 2 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 . V̇ e /V̇ co 2 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 V̇ e /V̇ co 2 slope. The V̇ e /V̇ co 2 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 V̇ e /V̇ co 2 slope is the strongest exercise predictor of death in noncyanotic ACHD patients.

In patients with symptomatic CHF and anemia, darbepoetin alfa increased and maintained hemoglobin concentrations and improved health-related quality of life. A trend toward increased exercise time but not peak VO2 was observed. (Impact of Darbepoetin Alfa on Exercise Tolerance and Left Ventricular Structure in Subjects With Symptomatic Congestive Heart Failure (CHF) and Anemia; http://clinicaltrials.gov/ct/show/NCT00117234?order = 1; NCT00117234).