Darlington O. Okonko

Exercise intolerance in adult congenital heart disease: comparative severity, correlates, and prognostic implication.

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, 33±13 years), 40 non–congenital heart failure patients (age, 58±15 years), and 11 young (age, 29±5 years) and 12 older (age, 59±9 years) healthy subjects. Peak oxygen consumption (peak &OV0312;o2) was reduced in ACHD patients compared with healthy subjects of similar age (21.7±8.5 versus 45.1±8.6; P<0.001). No significant difference in peak &OV0312;o2 was found between ACHD and heart failure patients of corresponding NYHA class (P=NS for each NYHA class). Within ACHD subgroups, peak &OV0312;o2 gradually declined from aortic coarctation (28.7±10.4) to Eisenmenger (11.5±3.6) patients (P<0.001). Multivariable correlates of peak &OV0312;o2 were peak heart rate (r=0.33), forced expiratory volume (r=0.33), pulmonary hypertension (r=−0.26), gender (r=−0.23), and body mass index (r=−0.19). After a median follow-up of 10 months, 62 patients (18.5%) were hospitalized or had died. On multivariable Cox analysis, peak &OV0312;o2 predicted hospitalization or death (hazard ratio, 0.937; P=0.01) and was related to the frequency and duration of hospitalization (P=0.01 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.

Effect of Intravenous Iron Sucrose on Exercise Tolerance in Anemic and Nonanemic Patients With Symptomatic Chronic Heart Failure and Iron Deficiency : FERRIC-HF: A Randomized, Controlled, Observer-Blinded Trial

OBJECTIVES We tested the hypothesis that intravenous iron improves exercise tolerance in anemic and nonanemic patients with symptomatic chronic heart failure (CHF) and iron deficiency. BACKGROUND Anemia is common in heart failure. Iron metabolism is disturbed, and administration of iron might improve both symptoms and exercise tolerance. METHODS We randomized 35 patients with CHF (age 64 +/- 13 years, peak oxygen consumption [pVO2] 14.0 +/- 2.7 ml/kg/min) to 16 weeks of intravenous iron (200 mg weekly until ferritin >500 ng/ml, 200 mg monthly thereafter) or no treatment in a 2:1 ratio. Ferritin was required to be <100 ng/ml or ferritin 100 to 300 ng/ml with transferrin saturation <20%. Patients were stratified according to hemoglobin levels (<12.5 g/dl [anemic group] vs. 12.5 to 14.5 g/dl [nonanemic group]). The observer-blinded primary end point was the change in absolute pVO2. RESULTS The difference (95% confidence interval [CI]) in the mean changes from baseline to end of study between the iron and control groups was 273 (151 to 396) ng/ml for ferritin (p < 0.0001), 0.1 (-0.8 to 0.9) g/dl for hemoglobin (p = 0.9), 96 (-12 to 205) ml/min for absolute pVO2 (p = 0.08), 2.2 (0.5 to 4.0) ml/kg/min for pVO2/kg (p = 0.01), 60 (-6 to 126) s for treadmill exercise duration (p = 0.08), -0.6 (-0.9 to -0.2) for New York Heart Association (NYHA) functional class (p = 0.007), and 1.7 (0.7 to 2.6) for patient global assessment (p = 0.002). In anemic patients (n = 18), the difference (95% CI) was 204 (31 to 378) ml/min for absolute pVO2 (p = 0.02), and 3.9 (1.1 to 6.8) ml/kg/min for pVO2/kg (p = 0.01). In nonanemic patients, NYHA functional class improved (p = 0.06). Adverse events were similar. CONCLUSIONS 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).

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 (&OV0312;e/&OV0312;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 &OV0312;e/&OV0312;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. &OV0312;e/&OV0312;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 &OV0312;e/&OV0312;co2 slope. The &OV0312;e/&OV0312;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 &OV0312;e/&OV0312;co2 slope is the strongest exercise predictor of death in noncyanotic ACHD patients.

Circulating Endothelial Progenitor Cells in Patients With Eisenmenger Syndrome and Idiopathic Pulmonary Arterial Hypertension

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.

Disordered iron homeostasis in chronic heart failure: prevalence, predictors, and relation to anemia, exercise capacity, and survival.

OBJECTIVES The aim of this study was to comprehensively delineate iron metabolism and its implications in patients with chronic heart failure (CHF). BACKGROUND Iron deficiency is an emerging therapeutic target in CHF. METHODS Iron and clinical indexes were quantified in 157 patients with CHF. RESULTS Several observations were made. First, iron homeostasis was deranged in anemic and nonanemic subjects and characterized by diminished circulating (transferrin saturation) and functional (mean cell hemoglobin concentration) iron status in the face of seemingly adequate stores (ferritin). Second, while iron overload and elevated iron stores were rare (1%), iron deficiency (transferrin saturation <20%) was evident in 43% of patients. Third, disordered iron homeostasis related closely to worsening inflammation and disease severity and strongly predicted lower hemoglobin levels independently of age, sex, erythrocyte sedimentation rate, New York Heart Association (NYHA) functional class, and creatinine. Fourth, the etiologies of anemia varied with disease severity, with an iron-deficient substrate (anemia of chronic disease and/or iron-deficiency anemia) evident in 16%, 72%, and 100% of anemic NYHA functional class I or II, III, and IV patients, respectively. Although anemia of chronic disease was more prevalent than iron-deficiency anemia, both conditions coexisted in 17% of subjects. Fifth, iron deficiency was associated with lower peak oxygen consumption and higher ratios of ventilation to carbon dioxide production and identified those at enhanced risk for death (hazard ratio: 3.38; 95% confidence interval: 1.48 to 7.72; p = 0.004) independently of hemoglobin. Nonanemic iron-deficient patients had a 2-fold greater risk for death than anemic iron-replete subjects. CONCLUSIONS Disordered iron homeostasis in patients with CHF relates to impaired exercise capacity and survival and appears prognostically more ominous than anemia.

Prevalence, incidence, and prognostic value of anaemia in patients after an acute myocardial infarction: data from the OPTIMAAL trial

AIMS The prevalence, incidence, and prognostic value of anaemia in patients with an acute myocardial infarction (AMI) complicated by heart failure is unclear. METHODS AND RESULTS We analysed the relationship between haemoglobin (Hb) and outcome in 5010 patients with AMI complicated by heart failure in the OPTIMAAL study. In 3921 patients, follow-up Hb levels were available at 365 (+/-90) days. In a subgroup of 224 patients, iron-related haematinics were assessed at baseline and during follow-up. At baseline, mean Hb was 12.6 +/- 1.3 g/dL in women and 13.7 +/- 1.4 g/dL in men. Hb < 11.5 g/dL was found in 9.3% of patients (women: 18.2%, men: 5.8%). Lower haemoglobin at baseline was clearly associated with female gender and the presence of diabetes, higher age and Killip class, lower body mass index, systolic blood pressure, total cholesterol, and the absence of current smoking (all P < 0.05). Higher Hb [per one standard deviation (SD)] related to lower mortality [adjusted hazard ratios (HR) 0.88; 95% confidence interval (CI) 0.83-0.93], CHF hospitalizations [HR 0.85 (0.77-0.93)], and all-cause hospitalizations [HR 0.96 (0.92-0.99), all P < 0.05]. In patients without anaemia at baseline, the anaemia incidence after 1 year of follow-up was 10.1% in women and 10.0% in men. Of patients with anaemia at baseline, 65% did not have anaemia at 12 months and 46% did not have anaemia at any time during follow-up (median 3.0 years, inter-quartile range, Q1-Q3 = 2.7-3.3 years). At 12 months, an increase in Hb (per SD) was related to lower mortality [HR 0.73 (0.63-0.85; P < 0.0001)] independent of baseline Hb and other clinical characteristics. CONCLUSION In patients with complicated AMIs, anaemia on admission and/or reductions in haemoglobin during follow-up are independent risk factors for mortality and hospitalization. Studies are warranted to determine whether correcting anaemia after a complicated AMI improves outcome.

Expansion of the red cell distribution width and evolving iron deficiency as predictors of poor outcome in chronic heart failure.

BACKGROUND An elevated red cell distribution width (RDW) and iron deficiency (ID) at baseline predict enhanced mortality in chronic heart failure (CHF), but little is known about the prognostic implications of their temporal trends. We sought to determine the survival implications of temporal changes in RDW and evolving ID in patients with CHF. METHODS The relation between red cell indices on first consultation and over time with mortality in 274 stable patients with systolic CHF was analysed. The combination of a rising RDW with a falling mean cell volume (MCV) over time defined evolving ID. RESULTS Over a median 12 month period, 51% and 23% of patients had a rise in RDW and evolving ID, respectively. After a median follow-up of 27 months, 60 (22%) patients died. A rising RDW predicted enhanced all-cause mortality (unadjusted HR for 1% per week rise 9.27, 95% CI 3.58 to 24.00, P<0.0001) independently and incrementally to baseline RDW, with an absolute increase >0.02% per week optimally predictive. Evolving ID also related to higher rates of mortality (HR 2.78, 95% CI 1.64 to 4.73, P<0.001) and was prognostically worse than a rising RDW alone (P<0.005). Patients with evolving ID who maintained their Hb levels over time had a 2-fold greater risk of death than those whose Hb levels declined without evolving ID. CONCLUSIONS An expanding RDW and evolving iron deficiency over time predict an amplified risk of death in CHF and should be utilised for risk stratification and/or therapeutically targeted to potentially improve outcomes.

Effect of pregnancy on clinical status and ventricular function in women with heart disease

BACKGROUND Pregnant women with heart disease (HD) are at an increased risk for maternal and neonatal adverse events. However, the effect of pregnancy on clinical status and ventricular function in women with HD has not been examined in a controlled study. METHODS AND RESULTS Ninety-three women with HD were studied longitudinally. Of these, fifty-three underwent clinical and echocardiographic evaluation before and 1.5+/-1.1 years after pregnancy (pregnancy group), whereas forty served as controls matched for age (28.6+/-4.6 versus 28.5+/-6.6, p=0.88), diagnosis, and length of follow-up (2.9+/-1.4 versus 2.6+/-1.1, p=0.23). NYHA functional class remained unchanged in both groups during follow-up. End diastolic and end systolic dimensions and shortening fraction of the morphologic left ventricle also remained unchanged. Furthermore, systemic and subpulmonary ventricular function remained unchanged in the pregnancy and control groups on semiquantitative analysis. Pregnancy, however, was associated with a persisting increase in subpulmonary ventricular size in patients with tetralogy of Fallot (ToF) which was not present in tetralogy controls. Furthermore, diagnosis of ToF was the only predictor of an increase in subpulmonary ventricular size after pregnancy on univariate logistic regression analysis (OR 8.8[95% CI 1.9-41.1], p=0.006). CONCLUSIONS In this longitudinal controlled study amongst women with HD no deleterious midterm effects of pregnancy on clinical status and right and left ventricular function were found. However, pregnancy was associated with a persisting increase in subpulmonary ventricular size, attributable to patients with repaired ToF. This may have prognostic implications and merits further investigation.

Systematic review of genuine versus spurious side-effects of beta-blockers in heart failure using placebo control: Recommendations for patient information

Background Patients trying life-preserving agents such as beta-blockers may be discouraged by listings of harmful effects provided in good faith by doctors, drug information sheets, and media. We systematically review the world experience of side-effect information in blinded, placebo-controlled beta-blockade in heart failure. We present information for a physician advising a patient experiencing an unwanted symptom and suspecting the drug. Methods We searched Medline for double-blinded randomized trials of beta-blocker versus placebo in heart failure reporting side-effects. We calculated, per 100 patients reporting the symptom on beta-blockade, how many would have experienced it on placebo: the “proportion of symptoms non-pharmacological”. Results 28 of the 33 classically-described side-effects are not significantly more common on beta-blockers than placebo. Of the 100 patients developing dizziness on beta-blockers, 81 (95% CI 73–89) would have developed it on placebo. For diarrhoea this proportion is 82/100 (70–95), and hyperglycaemia 83/100 (68–98). For only two side-effects is this under half (i.e. predominantly due to beta-blocker): bradycardia (33/100, CI 21–44) and intermittent claudication (41/100, 2–81). At least 6 so-called side-effects are less common on beta-blocker than placebo, including depression (reduced by 35%, p < 0.01) and insomnia (by 27%, p = 0.01). Conclusions Clinicians might reconsider whether it is scientifically and ethically correct to warn a patient that a drug might cause them a certain side-effect, when randomized controlled trials show no significant increase, or indeed a significant reduction. A better informed consultation could, in patients taking beta-blockers, alleviate suffering. In patients who might otherwise not take the drug, it might prevent deaths.

Heart failure: Mitochondrial dysfunction and oxidative stress in CHF

The results of the Q-SYMBIO trial showing a reduction in mortality in patients with heart failure treated with coenzyme Q10 have substantial limitations. Nevertheless, they highlight the need to identify effective new therapies targeted at mitochondrial dysfunction and oxidative stress in heart failure.