Gülmisal Güder

Complementary and incremental mortality risk prediction by cortisol and aldosterone in chronic heart failure

Background— In patients with systolic heart failure, high levels of circulating aldosterone are associated with an adverse prognosis, and mineralocorticoid receptor blockade improves survival. The prognostic significance of cortisol that may also bind and activate the mineralocorticoid receptor in chronic heart failure is unknown. Methods and Results— Serum levels of cortisol and aldosterone were quantified in a prospective cohort study of 294 consecutive patients with chronic heart failure [48% were in New York Heart Association functional class III or IV; 58% had systolic heart failure]. During a median follow-up of 803 days (interquartile range, 314 to 1098), 79 patients died (27.3% mortality rate). Cortisol and aldosterone were independent predictors of increased mortality risk in Cox regression analyses adjusted for age, sex, New York Heart Association functional class, C-reactive protein, N-terminal pro-brain natriuretic peptide, sodium, and hypercholesterolemia. The hazard ratio for highest versus lowest tertile of cortisol was 2.72 [95% confidence interval [CI], 1.38 to 5.36; P=0.004], and the hazard ratio for aldosterone was 2.19 (95% CI, 1.23 to 3.93; P=0.008). Patients with both cortisol and aldosterone levels above the respective medians had a 3.4-fold higher mortality risk compared with subjects with both corticosteroids below the median (95% CI, 1.54 to 7.46; P=0.0001). Addition of cortisol and aldosterone levels to the fully adjusted model significantly improved the discriminatory power [increase in Harrell’s C-statistic from 0.80 (95% CI, 0.70 to 0.90) to 0.86 (95% CI, 0.79 to 0.94; P<0.001 for change]. Conclusions— In patients with chronic heart failure, higher serum levels of both cortisol and aldosterone were independent predictors of increased mortality risk that conferred complementary and incremental prognostic value.

Reverse Epidemiology in Systolic and Nonsystolic Heart Failure Cumulative Prognostic Benefit of Classical Cardiovascular Risk Factors

Background—Observational studies indicate that classical cardiovascular risk factors as body mass index, total cholesterol, and systolic blood pressure are associated with improved rather than impaired survival in heart failure (“reverse epidemiology”). We estimated the prognostic role of these risk factors in unselected patients with heart failure. Methods and Results—Consecutive subjects with heart failure of any cause and severity were enrolled (n=867), and survivors were followed for a median period of 594 days (25th to 75th percentile, 435 to 840). Mean age was 70±13 years, 41% were female, New York Heart Association class distribution I through IV was 15%/29%/41%/15%, and 49% had preserved left ventricular ejection function. At follow-up, 34% of the patients had died. Low levels of any risk factor (ie, body mass index, total cholesterol, and systolic blood pressure in the low tertile) indicated the highest mortality risk. After adjustment for age, sex, New York Heart Association class, and ejection fraction, ≥2 risk factors in the high tertile indicated a relative reduction in mortality risk of 51% (hazard ratio, 0.49; 95% CI, 0.35 to 0.68; P=0.001) compared with subjects with 3 risk factors in the low tertile. Further adjustment for cause of heart failure, relevant comorbidities, medication, and biomarkers attenuated this association only modestly (hazard ratio, 0.63; 95% CI, 0.45 to 0.89; P=0.009). Conclusion—In patients with heart failure, mortality risk counterintuitively increased on a cumulative scale with lower levels of body mass index, total cholesterol, and systolic blood pressure, irrespective of the type and severity of heart failure. Future studies need to identify whether risk factor control as presently recommended should be advocated in all patients with heart failure.Background— Observational studies indicate that classical cardiovascular risk factors as body mass index, total cholesterol, and systolic blood pressure are associated with improved rather than impaired survival in heart failure (“reverse epidemiology”). We estimated the prognostic role of these risk factors in unselected patients with heart failure. Methods and Results— Consecutive subjects with heart failure of any cause and severity were enrolled (n=867), and survivors were followed for a median period of 594 days (25th to 75th percentile, 435 to 840). Mean age was 70±13 years, 41% were female, New York Heart Association class distribution I through IV was 15%/29%/41%/15%, and 49% had preserved left ventricular ejection function. At follow-up, 34% of the patients had died. Low levels of any risk factor (ie, body mass index, total cholesterol, and systolic blood pressure in the low tertile) indicated the highest mortality risk. After adjustment for age, sex, New York Heart Association class, and ejection fraction, ≥2 risk factors in the high tertile indicated a relative reduction in mortality risk of 51% (hazard ratio, 0.49; 95% CI, 0.35 to 0.68; P =0.001) compared with subjects with 3 risk factors in the low tertile. Further adjustment for cause of heart failure, relevant comorbidities, medication, and biomarkers attenuated this association only modestly (hazard ratio, 0.63; 95% CI, 0.45 to 0.89; P =0.009). Conclusion— In patients with heart failure, mortality risk counterintuitively increased on a cumulative scale with lower levels of body mass index, total cholesterol, and systolic blood pressure, irrespective of the type and severity of heart failure. Future studies need to identify whether risk factor control as presently recommended should be advocated in all patients with heart failure. Received September 29, 2008; accepted August 14, 2009.

Low circulating androgens and mortality risk in heart failure

Objective Deficiency of anabolic sex steroids is common in heart failure (HF). The pathophysiological implications of this phenomenon, however, have not been fully elucidated. This clinical study investigated the significance of low serum androgen levels in HF. Design Prospective cohort study. Patients and Methods In 191 consecutively recruited men with HF (mean age 64 years; New York Heart Association (NYHA) class I–IV 24%/35%/35%/6%) and reduced (ejection fraction (EF) ≤40%, n=96) or preserved (EF >40%, n=95) left ventricular function total and free serum testosterone, dehydroepiandrosterone sulfate (DHEAS) and sex hormone binding globulin (SHBG) were measured. The median observation period was 859 days. Results During follow-up 53 patients (28%) died. Whereas total serum testosterone was normal in most patients (91%), free testosterone and DHEAS were reduced in 79% and 23%, respectively. DHEAS and free testosterone, but not total testosterone, were inversely associated with NYHA class (both p<0.01). Lower free testosterone and DHEAS and higher SHBG predicted all-cause mortality risk (hazard ratio (HR) 0.89, 95% CI 0.82 to 0.96 per 1 ng/dl free testosterone, p=0.004; HR 0.95, 95% CI 0.89 to 1.00 per 10 μg/dl DHEAS, p=0.058; and HR 1.18, 95% CI 1.05 to 1.33 per 10 nmol/l SHBG, p=0.006, respectively; adjusted for age and NYHA class). However, further adjustment for carefully selected confounding factors abolished these associations. Conclusion In male HF patients, low serum levels of androgens are associated with adverse prognosis, but this relation is confounded by indicators of a poor health state. The results suggest that low serum androgens develop as a sequel of this progressive multifaceted systemic disorder.

Reverse Epidemiology in Systolic and Nonsystolic Heart FailureCLINICAL PERSPECTIVE

Background—Observational studies indicate that classical cardiovascular risk factors as body mass index, total cholesterol, and systolic blood pressure are associated with improved rather than impaired survival in heart failure (“reverse epidemiology”). We estimated the prognostic role of these risk factors in unselected patients with heart failure. Methods and Results—Consecutive subjects with heart failure of any cause and severity were enrolled (n=867), and survivors were followed for a median period of 594 days (25th to 75th percentile, 435 to 840). Mean age was 70±13 years, 41% were female, New York Heart Association class distribution I through IV was 15%/29%/41%/15%, and 49% had preserved left ventricular ejection function. At follow-up, 34% of the patients had died. Low levels of any risk factor (ie, body mass index, total cholesterol, and systolic blood pressure in the low tertile) indicated the highest mortality risk. After adjustment for age, sex, New York Heart Association class, and ejection fraction, ≥2 risk factors in the high tertile indicated a relative reduction in mortality risk of 51% (hazard ratio, 0.49; 95% CI, 0.35 to 0.68; P=0.001) compared with subjects with 3 risk factors in the low tertile. Further adjustment for cause of heart failure, relevant comorbidities, medication, and biomarkers attenuated this association only modestly (hazard ratio, 0.63; 95% CI, 0.45 to 0.89; P=0.009). Conclusion—In patients with heart failure, mortality risk counterintuitively increased on a cumulative scale with lower levels of body mass index, total cholesterol, and systolic blood pressure, irrespective of the type and severity of heart failure. Future studies need to identify whether risk factor control as presently recommended should be advocated in all patients with heart failure.Background— Observational studies indicate that classical cardiovascular risk factors as body mass index, total cholesterol, and systolic blood pressure are associated with improved rather than impaired survival in heart failure (“reverse epidemiology”). We estimated the prognostic role of these risk factors in unselected patients with heart failure. Methods and Results— Consecutive subjects with heart failure of any cause and severity were enrolled (n=867), and survivors were followed for a median period of 594 days (25th to 75th percentile, 435 to 840). Mean age was 70±13 years, 41% were female, New York Heart Association class distribution I through IV was 15%/29%/41%/15%, and 49% had preserved left ventricular ejection function. At follow-up, 34% of the patients had died. Low levels of any risk factor (ie, body mass index, total cholesterol, and systolic blood pressure in the low tertile) indicated the highest mortality risk. After adjustment for age, sex, New York Heart Association class, and ejection fraction, ≥2 risk factors in the high tertile indicated a relative reduction in mortality risk of 51% (hazard ratio, 0.49; 95% CI, 0.35 to 0.68; P =0.001) compared with subjects with 3 risk factors in the low tertile. Further adjustment for cause of heart failure, relevant comorbidities, medication, and biomarkers attenuated this association only modestly (hazard ratio, 0.63; 95% CI, 0.45 to 0.89; P =0.009). Conclusion— In patients with heart failure, mortality risk counterintuitively increased on a cumulative scale with lower levels of body mass index, total cholesterol, and systolic blood pressure, irrespective of the type and severity of heart failure. Future studies need to identify whether risk factor control as presently recommended should be advocated in all patients with heart failure. Received September 29, 2008; accepted August 14, 2009.

Airway obstruction in systolic heart failure – COPD or congestion?

BACKGROUND The diagnosis of chronic obstructive pulmonary disease (COPD) in patients with systolic heart failure (SHF) is challenging because symptoms of both conditions overlap. We aimed to estimate the prevalence, correlates and prognostic impact of true COPD in patients with SHF. METHODS To diagnose COPD under stable conditions according to the guidelines, pulmonary function testing (PFT) was performed in 619 patients six months after hospitalization for congestive SHF. In 272 patients, PFT had been also performed prior to discharge. RESULTS In the total cohort, COPD was reported in 23% (144/619). PFT under stable conditions revealed that COPD was absent in 73% (449/619), unconfirmed in 18% (112/619), and proven in 9% (58/619). In 272 patients with serial PFT, initial airway obstruction was found in 19% (51/272) but had resolved in 47% of those (24/51) after six months. Initial hyperinflation detected by bodyplethysmography strongly predicted proven COPD six months later: odds ratio for elevated intrathoracic gas volume 12.8, 95% confidence interval (CI) 2.5-65.9; p=0.002. After a median follow-up of 34 months, 27% of the total cohort (165/619) had died. Only proven COPD was associated with an increased mortality risk after adjustment for age, sex, NYHA functional class, ejection fraction, atrial fibrillation, smoking, renal dysfunction and diabetes: hazard ratio 1.64, 95%CI 1.03-2.63; p=0.039. CONCLUSIONS Airway obstruction is a dynamic phenomenon in SHF. Therefore, a valid diagnosis of COPD in SHF demands serial PFT under stable conditions with special attention to hyperinflation. COPD proven by PFT is associated with an increased all-cause mortality risk.

Nurse‐coordinated collaborative disease management improves the quality of guideline‐recommended heart failure therapy, patient‐reported outcomes, and left ventricular remodelling

Heart failure (HF) pharmacotherapy is often not prescribed according to guidelines. This longitudinal study investigated prescription rates and dosages of angiotensin‐converting enzyme inhibitors/angiotensin receptor blockers (ACEi/ARB), beta‐blockers, and mineralocorticoid receptor antagonists (MRA), and concomitant changes of symptoms, echocardiographic parameters of left ventricular (LV) function and morphology and results of the Short Form‐36 (SF‐36) Health Survey in participants of the Interdisciplinary Network Heart Failure (INH) programme.

Dysnatraemia in heart failure

To investigate in detail the correlates of dysnatremia, and to estimate its differential prognostic relevance in patients with heart failure with reduced or preserved LVEF.

Prognostic impact of subclinical thyroid dysfunction in heart failure

BACKGROUND Therapeutic and prognostic implications of subclinical thyroid dysfunction in patients with heart failure (HF) are unclear. We compared the prognostic impact of euthyroidism, subclinical thyroid dysfunction, and euthyroid sick syndrome (ESS) in systolic HF. METHODS We included 1032 patients hospitalized for systolic HF (left ventricular ejection fraction [LVEF] ≤40%) who participated in a randomized trial assessing the effects of a HF disease management program. Patients with incomplete thyroid function tests or thyrotropic medication were excluded. In the remaining 758 subjects, the risk of all-cause death was estimated based on TSH only, or full thyroid function profile. Changes of thyroid function after six months were assessed in 451 subjects. RESULTS Subclinical thyroid dysfunction was present in 103 patients at baseline (14%). No differences were found between groups regarding NYHA class (P=0.29), and LVEF (P=0.60). After a median follow-up of three years patients with ESS (n=13) had a 3-fold age-adjusted increased risk of death compared to euthyroid patients (P=0.001). However, neither subclinical hyperthyroidism (HR 1.18, 95%CI:0.82-1.70) nor hypothyroidism (HR 1.07, 95%CI:0.58-1.98) were associated with increased age-adjusted mortality risk. Subclinical thyroid dysfunction had normalized spontaneously at follow-up in 77% of patients. However, persistent subclinical thyroid dysfunction was also not associated with worse outcome. CONCLUSIONS In this large well-characterized HF cohort, subclinical thyroid dysfunction did not predict an increased mortality risk. Thus, in patients with moderate to severe HF, further diagnostic and therapeutic procedures for subclinical thyroid dysfunction appear dispensable. ESS was an infrequent but important indicator of a poor prognosis in HF. CLINICAL TRIAL REGISTRATION URL http://www.controlled-trials.com. Unique identifier: ISRCTN23325295.

Prognostic potential of midregional pro-adrenomedullin following decompensation for systolic heart failure: comparison with cardiac natriuretic peptides

Whereas guidelines recommend the routine use of natriuretic peptides (NPs) in heart failure (HF) care, the clinical relevance and prognostic potential of midregional pro‐adrenomedullin (MR‐proADM) is less well established. We aimed to compare the prognostic potential of MR‐proADM after acute decompensation for systolic HF with that of N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) and midregional pro‐atrial NP (MR‐proANP), to investigate the significance of high/rising MR‐proADM, and to evaluate the incremental prognostic yield of repeat measurements.

High evening salivary cortisol is an independent predictor of increased mortality risk in patients with systolic heart failure

AIMS Serum cortisol independently predicts mortality risk in patients with systolic heart failure. Salivary cortisol may provide advantages as it better reflects the biologically active free compound. Furthermore, sampling is non-invasive and may easily be performed in outpatients. We comparatively evaluated associations of morning (MSC) vs. evening salivary cortisol (ESC) and all-cause mortality risk. METHODS AND RESULTS MSC (8 am) and ESC (9 pm) were determined in 229 patients with heart failure participating in the Interdisciplinary Network for Heart Failure program (66 ± 13 years; 21% female; 37% New York Heart Association (NYHA) class III/IV, median left ventricular ejection fraction 33%). The association of cortisol with mortality risk was determined by univariate and Cox multivariable regression analyses adjusting for age, sex, NYHA class, and N-terminal pro-hormone B-type natriuretic peptide. Compared to ESC, MSC was significantly higher and exhibited a higher variance: median 0.59 ng/ml (interquartile range 0.41-0.93) vs. 0.25 ng/ml (0.15-0.48), p<0.001. During 18 months of follow-up, 25 (11%) patients died. In univariate and multivariable models mortality risk was not increased in the highest MSC quartile: crude hazard ratio (HR) 1.81 (95% confidence interval 0.79-4.14, p=0.160), adjusted HR 1.26 (0.51-3.13, p=0.616). However, patients in the highest ESC quartile had a significantly increased mortality risk, suggesting that associations of high ESC and increased mortality were independent of disease severity: crude HR 3.33 (1.50-7.42, p=0.003), adjusted HR 2.49 (1.01-6.14, p=0.047). ESC alone proved the best predictor of mortality. CONCLUSION High ESC but not MSC levels independently predict increased mortality risk in heart failure.