Beata Ponikowska

Iron deficiency: an ominous sign in patients with systolic chronic heart failure

AIMS Beyond erythropoiesis, iron is involved in numerous biological processes crucial for maintenance of homeostasis. Patients with chronic heart failure (CHF) are prone to develop iron deficiency (ID), and iron supplementation improves their functional status and quality of life. We sought to examine the relationship between ID and survival in patients with systolic CHF. METHODS AND RESULTS In a prospective observational study, we evaluated 546 patients with stable systolic CHF [age: 55 +/- 11 (mean +/- standard deviation) years, males: 88%, left ventricular ejection fraction: 26 +/- 7%, New York Heart Association (NYHA) class (I/II/III/IV): 57/221/226/42]. Iron deficiency was defined as: ferritin <100 microg/L, or 100-300 microg/L with transferrin saturation <20%. The prevalence of ID was 37 +/- 4% [+/-95% confidence intervals (CI)] in the entire CHF population (32 +/- 4 vs. 57 +/- 10%-in subjects without vs. with anaemia defined as haemoglobin level <12 g/dL in women and <13 g/dL in men, P < 0.001). In a multiple logistic model, ID was more prevalent in women, those in the advanced NYHA class, with higher plasma N-terminal pro-type B natriuretic peptide and higher serum high-sensitivity C-reactive protein (all P < 0.05). At the end of follow-up (mean duration: 731 +/- 350 days), there were 153 (28%) deaths and 30 (6%) heart transplantations (HTX). In multivariable models, ID (but not anaemia) was related to an increased risk of death or HTX (adjusted hazard ratio 1.58, 95% CI 1.14-2.17, P < 0.01). CONCLUSION In patients with systolic CHF, ID is common and constitutes a strong, independent predictor of unfavourable outcome. Iron supplementation may be considered as a therapeutic approach in these patients to improve prognosis.

Reduction in Circulating Testosterone Relates to Exercise Capacity in Men With Chronic Heart Failure

BACKGROUND We investigated whether anabolic deficiency was linked to exercise intolerance in men with chronic heart failure (CHF). Anabolic hormones (testosterone, dehydroepiandrosterone sulfate, insulin-like growth factor 1 [IGF1]) contribute to exercise capacity in healthy men. This issue remains unclear in CHF. METHODS AND RESULTS We studied 205 men with CHF (age 60 +/- 11 years, New York Heart Association [NYHA] Class I/II/III/IV: 37/95/65/8; LVEF [left ventricular ejection fraction]: 31 +/- 8%). Exercise capacity was expressed as peak oxygen consumption (peak VO(2)), peak O(2) pulse, and ventilatory response to exercise (VE-VCO(2) slope). In multivariable models, reduced peak VO(2) (and reduced peak O(2) pulse) was associated with diminished serum total testosterone (TT) (P < .01) and free testosterone (eFT; estimated from TT and sex hormone globulin levels) (P < .01), which was independent of NYHA Class, plasma N-terminal pro-brain natriuretic peptide, and age. These associations remained significant even after adjustment for an amount of leg lean tissue. In multivariable models, high VE-VCO(2) slope was related to reduced serum IGF1 (P < .05), advanced NYHA Class (P < .05), increased plasma NT-proBNP (P < .0001), and borderline low LVEF (P = .07). In 44 men, reassessed after 2.3 +/- 0.4 years, a reduction in peak VO(2) (and peak O(2) pulse) was accompanied by a decrease in TT (P < .01) and eFT (P <or= .01). Increase in VE-VCO(2) slope was related only to an increase in plasma NT-proBNP (P < .05). CONCLUSIONS In men with CHF, low circulating testosterone independently relates to exercise intolerance. The greater the reduction of serum TT in the course of disease, the more severe the progression of exercise intolerance. Whether testosterone supplementation would improve exercise capacity in hypogonadal men with CHF requires further studies.

Circulating Estradiol and Mortality in Men With Systolic Chronic Heart Failure

CONTEXT Androgen deficiency is common in men with chronic heart failure (HF) and is associated with increased morbidity and mortality. Estrogens are formed by the aromatization of androgens; therefore, abnormal estrogen metabolism would be anticipated in HF. OBJECTIVE To examine the relationship between serum concentration of estradiol and mortality in men with chronic HF and reduced left ventricular ejection fraction (LVEF). DESIGN, SETTING, AND PARTICIPANTS A prospective observational study at 2 tertiary cardiology centers (Wroclaw and Zabrze, Poland) of 501 men (mean [SD] age, 58 [12] years) with chronic HF, LVEF of 28% (SD, 8%), and New York Heart Association [NYHA] classes 1, 2, 3, and 4 of 52, 231, 181, and 37, respectively, who were recruited between January 1, 2002, and May 31, 2006. Cohort was divided into quintiles of serum estradiol (quintile 1, < 12.90 pg/mL; quintile 2, 12.90-21.79 pg/mL; quintile 3, 21.80-30.11 pg/mL; quintile 4, 30.12-37.39 pg/mL; and quintile 5, > or = 37.40 pg/mL). Quintile 3 was considered prospectively as the reference group. MAIN OUTCOME MEASURES Serum concentrations of estradiol and androgens (total testosterone and dehydroepiandrosterone sulfate [DHEA-S]) were measured using immunoassays. RESULTS Among 501 men with chronic HF, 171 deaths (34%) occurred during the 3-year follow-up. Compared with quintile 3, men in the lowest and highest estradiol quintiles had increased mortality (adjusted hazard ratio [HR], 4.17; 95% confidence interval [CI], 2.33-7.45 and HR, 2.33; 95% CI, 1.30-4.18; respectively; P < .001). These 2 quintiles had different clinical characteristics (quintile 1: increased serum total testosterone, decreased serum DHEA-S, advanced NYHA class, impaired renal function, and decreased total fat tissue mass; and quintile 5: increased serum bilirubin and liver enzymes, and decreased serum sodium; all P < .05 vs quintile 3). For increasing estradiol quintiles, 3-year survival rates adjusted for clinical variables and androgens were 44.6% (95% CI, 24.4%-63.0%), 65.8% (95% CI, 47.3%-79.2%), 82.4% (95% CI, 69.4%-90.2%), 79.0% (95% CI, 65.5%-87.6%), and 63.6% (95% CI, 46.6%-76.5%); respectively (P < .001). CONCLUSION Among men with chronic HF and reduced LVEF, high and low concentrations of estradiol compared with the middle quintile of estradiol are related to an increased mortality.

Bone mineral status and bone loss over time in men with chronic systolic heart failure and their clinical and hormonal determinants

Bone status has not been comprehensively studied in chronic heart failure (CHF). In CHF men, we evaluated bone status, bone loss over time, and their clinical and hormonal determinants.

Identification of chronic heart failure patients with a high 12-month mortality risk using biomarkers including plasma C-terminal pro-endothelin-1.

Objectives We hypothesised that assessment of plasma C-terminal pro-endothelin-1 (CT-proET-1), a stable endothelin-1 precursor fragment, is of prognostic value in patients with chronic heart failure (CHF), beyond other prognosticators, including N-terminal pro-B-type natriuretic peptide (NT-proBNP). Methods We examined 491 patients with systolic CHF (age: 63±11 years, 91% men, New York Heart Association [NYHA] class [I/II/III/IV]: 9%/45%/38%/8%, 69% ischemic etiology). Plasma CT-proET-1 was detected using a chemiluminescence immunoassay. Results Increasing CT-proET-1 was a predictor of increased cardiovascular mortality at 12-months of follow-up (standardized hazard ratio 1.42, 95% confidence interval [CI] 1.04–1.95, p = 0.03) after adjusting for NT-proBNP, left ventricular ejection fraction (LVEF), age, creatinine, NYHA class. In receiver operating characteristic curve analysis, areas under curve for 12-month follow-up were similar for CT-proET-1 and NT-proBNP (p = 0.40). Both NT-proBNP and CT-proET-1 added prognostic value to a base model that included LVEF, age, creatinine, and NYHA class. Adding CT-proET-1 to the base model had stronger prognostic power (p<0.01) than adding NT-proBNP (p<0.01). Adding CT-proET-1 to NT-proBNP in this model yielded further prognostic information (p = 0.02). Conclusions Plasma CT-proET-1 constitutes a novel predictor of increased 12-month cardiovascular mortality in patients with CHF. High CT-proET-1 together with high NT-proBNP enable to identify patients with CHF and particularly unfavourable outcomes.

Deficiencies in circulating testosterone and dehydroepiandrosterone sulphate, and depression in men with systolic chronic heart failure

Elderly men with androgen deficiencies are prone to develop late‐onset depression. We investigated links between circulating androgens and depression, and their combined impact on outcome in men with chronic heart failure (CHF).

Iron Status and Survival in Diabetic Patients With Coronary Artery Disease

OBJECTIVE To investigate the impact of iron status on survival in patients with type 2 diabetes and coronary artery disease (CAD). RESEARCH DESIGN AND METHODS Serum ferritin, transferrin saturation (Tsat), and soluble transferrin receptor (sTfR) were measured in 287 patients with type 2 diabetes and stable CAD (65 ± 9 years of age, 78% men). RESULTS During a mean follow-up of 45 ± 19 months, there were 59 (21%) deaths and 60 (21%) cardiovascular hospitalizations. Both serum ferritin and sTfR strongly predicted 5-year all-cause mortality rates, independently of other variables (including hemoglobin, measures of renal function, inflammation, and neurohormonal activation). There was an exponential relationship between sTfR and mortality (adjusted hazard ratio [HR] per 1 log mg/L: 4.24 [95% CI 1.43–12.58], P = 0.01), whereas the relationship between ferritin and mortality was U-shaped (for the lowest and the highest quintiles vs. the middle quintile [reference group], respectively: adjusted HR 7.18 [95% CI 2.03–25.46], P = 0.002, and adjusted HR 5.12 [1.48–17.73], P = 0.01). Similar patterns were observed for the composite outcome of all-cause mortality or cardiovascular hospitalization, and in these multivariable models, low Tsat was related to unfavorable outcome. CONCLUSIONS Both low and high serum ferritin (possibly reflecting depleted and excessive iron stores, respectively) along with high serum sTfR (reflecting reduced metabolically available iron) identify patients with type 2 diabetes and CAD who have a poor prognosis.

Baroreceptor sensitivity and diabetes mellitus

Diabetes mellitus (DM) is a disease of increasing incidence and prevalence. Arterial baroreceptors are stretch-sensitive receptors, which in a reflex manner are involved in the homeostatic control of arterial blood pressure. Diabetic subjects have depressed baroreflex sensitivity (BRS), although the exact pathomechanisms are unclear. In this review, we discuss the features, clinicaland prognostic implications of reduced BRS for diabetic patients and the potential involvement of cardiovascular autonomic neuropathy and atherosclerosis. Finally, we demonstrate evidence on interventions (e.g. pioglitazone, alpha-lipoic acid, leptin, fluvastatin, physicaltraining etc.) which could improve BRS and ameliorate cardiovascular autonomic dysfunction in diabetic patients.

Circulating testosterone and estradiol, autonomic balance and baroreflex sensitivity in middle-aged and elderly men with heart failure.

Abstract Background: Heart failure (HF) is considered as a cardiogeriatric syndrome. Its fundamental pathophysiological feature is autonomic imbalance (and associated abnormalities within cardiovascular reflex control), but recent evidence suggests the involvement of deranged hormone metabolism. Both these neural and endocrine pathologies have serious clinical and prognostic consequences in patients with HF. We investigated the relations between autonomic status, baroreflex sensitivity (BRS) and hormone status in men with mild systolic HF. Methods: We examined 46 men with stable systolic HF (age: 62 ± 10 years, NYHA class I/II: 10/36 [22%/78%], ischemic aetiology: 72%, left ventricular ejection fraction: 32 ± 8%). Serum hormone levels (i.e. total testosterone [TT], dehydroepiandrosterone sulphate [DHEAS], oestradiol [E2], insulin-like growth factor type 1 [IGF-1] and cortisol) were assessed using immunoassays. Estimated free testosterone (eFT) was estimated using the Vermeulen’s equation. Heart rate variability (HRV) was assessed in time and frequency domains, based on 10-min resting recordings. BRS was estimated using the sequence method (BRS-Seq) and the phenylephrine test (BRS-Phe). Results: Deficiencies in circulating TT, eFT, DHEAS and IGF-1 (defined as a serum hormone ≤the 10th percentile calculated for the adequate age category in the cohort of healthy men) were found in respectively 13%, 30%, 55% and 93% of men with systolic HF. Serum SHBG ≥50 nmol/L and cortisol ≥700 nmol/L characterised, respectively 44% and 29% of men with HF. In multivariable models after the adjustment for clinical variables, the following relationships were found in examined men: DHEAS and SDNN (time domain of HRV defined as a standard deviation of average R–R intervals) (β = 0.29, p = 0.03); E2 and: HRV-LF (ms2) (β = 0.37, p = 0.01), HRV-HF (ms2) (β = 0.44, p = 0.02) and BRS-Phe (β = 0.51, p = 0.008); TT and: HRV-HF (%) (β = 0.35, p = 0.02), HRV-LF/HF ratio (β = −0.35, p = 0.02) and BRS-Seq (β = 0.33, p = 0.04). Conclusions: The observed associations between reduced circulating androgens, oestrogens and lower HRV and depleted BRS, irrespectively of HF severity suggest the pathophysiological links between these two mechanisms. These results constitute the premises to investigate whether the pharmacological supplementation of depleted hormones would enable to restore the autonomic balance and improve the efficacy of reflex control within the cardiovascular system in men with systolic HF.

Anabolic deficiencies in men with systolic heart failure: do co-morbidities and therapies really contribute significantly?

Abstract Background: Deficiencies of anabolic hormones are common in men with heart failure (HF). It remains unclear whether the deranged metabolism of these hormones is the pathophysiological element of HF itself or is the consequence of co-morbidities or/and treatment in HF. Methods: We examined 382 men with systolic HF. Serum hormones (i.e. total testosterone [TT], DHEAS, IGF-1) were assessed using immunoassays, serum free testosterone (eFT) – using the Vermeulen equation. Results: Prevalence of TT and eFT deficiencies was similar in men with HF aged < versus ≥60 years (23% and 32% for TT and eFT deficiencies). Deficiencies in DHEAS and IGF-1 were more common in younger (63% and 92%) than older patients (48% and 73%). In men <60 years, TT deficiency was accompanied by the therapy with digoxin, eFT deficiency – the therapy with digoxin and the presence of diabetes, DHEAS deficiency – the therapy with loop diuretic (all p < 0.05). In men ≥60 years, TT deficiency – the therapy with loop diuretic, DHEAS deficiency – the therapy with spironolactone and digoxin, and hsCRP, IGF-1 deficiency – the high hsCRP (all p < 0.05). Conclusions: Deficiencies in anabolic hormones are common in younger and older men with HF. Some therapies (but not major co-morbidities) may contribute to anabolic deficiencies.