Association of Annual N-Terminal Pro-Brain Natriuretic Peptide Measurements With Clinical Events in Patients With Asymptomatic Nonsevere Aortic Stenosis: A Post Hoc Substudy of the SEAS Trial.

IMPORTANCE: Recent studies have questioned the presumed low-risk status of patients with asymptomatic nonsevere aortic stenosis (AS). Whether annual N-terminal pro-brain natriuretic peptide (NT-proBNP) measurements are useful for risk assessment is unknown. OBJECTIVE: To assess the association of annual NT-proBNP measurements with clinical outcomes in patients with nonsevere AS. DESIGN, SETTING, AND PARTICIPANTS: Analysis of annual NT-proBNP concentrations in the multicenter, double-blind Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) randomized clinical trial was performed. SEAS was conducted from January 6, 2003, to April 1, 2008. Blood samples were analyzed in 2016, and data analysis was performed from February 10 to October 10, 2021. SEAS included 1873 patients with asymptomatic AS not requiring statin therapy with transaortic maximal flow velocity from 2.5 to 4.0 m/s and preserved ejection fraction. This substudy included 1644 patients (87.8%) with available blood samples at baseline and year 1. EXPOSURES: Increased age- and sex-adjusted NT-proBNP concentrations at year 1 and a 1.5-fold or greater relative NT-proBNP concentration change from baseline to year 1. Moderate AS was defined as baseline maximal flow velocity greater than or equal to 3.0 m/s. MAIN OUTCOMES AND MEASURES: Aortic valve events (AVEs), which are a composite of aortic valve replacement, cardiovascular death, or incident heart failure due to AS progression, were noted. Landmark analyses from year 1 examined the association of NT-proBNP concentrations with outcomes. RESULTS: Among 1644 patients, 996 were men (60.6%); mean (SD) age was 67.5 (9.7) years. Adjusted NT-proBNP concentrations were within the reference range (normal) in 1228 of 1594 patients (77.0%) with NT-proBNP values available at baseline and in 1164 of 1644 patients (70.8%) at year 1. During the next 2 years of follow-up, the AVE rates per 100 patient-years for normal vs increased adjusted NT-proBNP levels at year 1 were 1.39 (95% CI, 0.86-2.23) vs 7.05 (95% CI, 4.60-10.81) for patients with mild AS (P < .01), and 10.38 (95% CI, 8.56-12.59) vs 26.20 (95% CI, 22.03-31.15) for those with moderate AS (P < .01). Corresponding all-cause mortality rates were 1.05 (95% CI, 0.61-1.81) vs 4.17 (95% CI, 2.42-7.19) for patients with mild AS (P < .01), and 1.60 (95% CI, 0.99-2.57) vs 4.78 (95% CI, 3.32-6.87) for those with moderate AS (P < .01). In multivariable Cox proportional hazards regression models, the combination of a 1-year increased adjusted NT-proBNP level and 1.5-fold or greater NT-proBNP level change from baseline was associated with the highest AVE rates in both patients with mild AS (hazard ratio, 8.12; 95% CI, 3.53-18.66; P < .001) and those with moderate AS (hazard ratio, 4.05; 95% CI, 2.84-5.77; P < .001). CONCLUSIONS AND RELEVANCE: The findings of this study suggest that normal NT-proBNP concentrations at 1-year follow-up are associated with low AVE and all-cause mortality rates in patients with asymptomatic nonsevere AS. Conversely, an increased 1-year NT-proBNP level combined with a 50% or greater increase from baseline may be associated with high AVE rates. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00092677.

Frequency and Impact of Hyponatremia on All-Cause Mortality in Patients With Aortic Stenosis.

Asymptomatic aortic stenosis (AS) is a frequent condition that may cause hyponatremia due to neurohumoral activation. We examined if hyponatremia heralds poor prognosis in patients with asymptomatic AS, and whether AS in itself is associated with increased risk of hyponatremia. The study question was investigated in 1,677 individuals that had and annual plasma sodium measurements in the SEAS (Simvastatin and Ezetimibe in AS) trial; 1,873 asymptomatic patients with mild-moderate AS (maximal transaortic velocity 2.5 to 4.0 m/s) randomized to simvastatin/ezetimibe combination versus placebo. All-cause mortality was the primary endpoint and incident hyponatremia (P-Na+ <137 mmol/L) a secondary outcome. At baseline, 4% (n = 67) had hyponatremia. After a median follow-up of 4.3 (interquartile range 4.1 to 4.6) years, 140 (9%) of those with initial normonatremia had developed hyponatremia, and 174 (10%) had died. In multiple regression Cox models, both baseline hyponatremia (hazard ratio [HR] 2.1, [95% confidence interval 1.1 to 3.8]) and incident hyponatremia (HR 1.9, [95% confidence interval 1.0 to 3.4], both p ≤ .03) was associated with higher all-cause mortality as compared with normonatremia. This association persisted after adjustment for diuretics as a time-varying covariate. Higher N-terminal pro b-type natriuretic peptide levels and lower sodium levels at baseline was associated with higher risk of incident hyponatremia. Conversely, assignment to simvastatin/ezetimibe protected against incident hyponatremia. In conclusion, both prevalent and incident hyponatremia associate with increased mortality in patients with AS. The prevalence of hyponatremia is around 4% and the incidence about 2% per year, which is comparable to that of older adults without AS.

The Association between Serum Testosterone and Risk Factors for Atherosclerosis.

OBJECTIVE: To study the associations between serum testosterone and risk factors for atherosclerosis in 119 men from general population. METHODS: Systolic pressure, body mass index (BMI), testosterone, fasting glucose, glucose tolerance test, apolipoprotein A-1 (ApoA-1), apolipoprotein B (ApoB), and ApoB/ApoA-1 ratio were assessed. Subjects classified into hypogonadal (testosterone ≤ 12 nmol/l), and eugonadal men (testosterone > 12 nmol/l). RESULTS: BMI (28 vs. 26 kg/ m2, p = 0.01), systolic pressure (129 vs. 123 mmHg, p = 0.03), fasting glucose (5.9 vs. 5.5 mmol/l, p = 0.03), ApoB (1.1 vs. 1.0 g/l, p = 0.03), and ApoB/ApoA-1 ratio (0.8 vs. 0.7, p = 0.03) were higher in hypogonadal compared to eugonadal men, respectively. In adjusted multivariate regression analysis model, testosterone showed negative associations with BMI (ß = -1.832, p = 0.030, 95% CI = -3.485--0.180), fasting glucose (ß = -0.394, p = 0.011, 95% CI = -0.696--0.091), glucose tolerance test (ß = -0.957, p = 0.045, 95% CI = -1.892--0.022), ApoB (ß = -0.157, p = 0.017, 95% CI = -0.286--0.029), and ApoB/ApoA-1 ratio (ß = -0.118, p = 0.046, 95% CI = -0.234--0.002). CONCLUSIONS: These results suggest an inverse association between testosterone levels and risk factors for atherosclerosis.

Association between serum levels of testosterone and biomarkers of subclinical atherosclerosis.

OBJECTIVE: To investigate the association between serum levels of testosterone and biomarkers of subclinical atherosclerosis based on data from 119 middle-aged men of the general population. METHODS: Testosterone, Apolipoprotein A-1 (ApoA-1), Apolipoprotein B (ApoB), Apolipoprotein B-to-Apolipoprotein A-1 ratio (ApoB-to-ApoA-1), high-sensitive C-reactive protein (hsCRP), and fibrinogen levels were measured. Data were also gathered based on age, BMI, waist circumference, smoking, alcohol consumption, and family history of cardiovascular diseases. Men were classified into two groups based on testosterone levels: hypogonadal (testosterone ≤12 nmol/L) and eugonadal men (testosterone >12 nmol/L). RESULTS: When compared to eugonadal, the hypogonadal men were significantly older (56 years vs. 55 years, p = .03), had greater BMI (28 kg/cm2 vs. 26 kg/cm2, p = .01), and higher waist circumference (104 cm vs. 100 cm, p = .01). Moreover, ApoB, ApoB-to-ApoA-1 ratio, and hsCRP were significantly higher in hypogonadal men compared to eugonadal men (1.1 g/L vs. 1.0 g/L, p = .03), (0.8 vs. 0.7, p = .03), (3.3 mg/L vs. 2.0 mg/L, p = .01), respectively. On the other hand, ApoA-1 and fibrinogen levels did not differ significantly between groups (p > .05). In an adjusted multivariate regression analysis model, only ApoB showed a significant negative association with testosterone levels (ß = -0.01; 95% CI = -0.02, -1.50; p = .04). CONCLUSION: Testosterone levels showed an inverse relation to ApoB, a biomarker implicated in subclinical atherosclerosis. These findings support the hypothesis that low testosterone levels play a role in atherosclerosis.

Association Between Erectile Function and Biomarkers of Subclinical Atherosclerosis: A Study Based on Middle-Aged Healthy Men from the General Population.

INTRODUCTION: Epidemiological studies suggest atherosclerosis as a common risk factor between cardiovascular diseases and erectile dysfunction (ED). We aimed to determine the association between erectile function and the biomarkers of subclinical atherosclerosis in 119 middle-aged healthy men from the general population. METHODS: Erectile function was assessed using the International Index of Erectile Function-5 (IIEF-5). Serum levels of biomarkers of atherosclerosis: Apolipoprotein A, Apolipoprotein B, fibrinogen, and C-reactive protein (CRP) were measured. In addition, demographic data was collected. RESULTS: The mean (SD) of age was 55 years (± 4.0). The prevalence of ED was 50%. There was a negative significant correlation between IIEF-5 and CRP levels (r = -0.20, p = 0.02), and BMI (r = -0.20, p = 0.03), respectively. No significant correlations between IIEF-5 and serum levels of Apolipoprotein A, Apolipoprotein B, and fibrinogen were found (p > 0.05). A positive significant correlation was found between BMI and fibrinogen (r = 0.20, p = 0.01), CRP (r = 0.30, p = 0.001). In a multivariate logistic regression model with IIEF-5 as the dependent variable, CRP was the only biomarker that predicted ED (odds ratio = 1.350; 95 % CI: 1.044-1.754). CONCLUSIONS: These results indicate that CRP is a biomarker of subclinical atherosclerosis associated with ED. This association seems to be linked to greater BMI among such men.

Assessing Optimal Blood Pressure in Patients With Asymptomatic Aortic Valve Stenosis: The Simvastatin Ezetimibe in Aortic Stenosis Study (SEAS).

BACKGROUND: Evidence for treating hypertension in patients with asymptomatic aortic valve stenosis is scarce. We used data from the SEAS trial (Simvastatin Ezetimibe in Aortic Stenosis) to assess what blood pressure (BP) would be optimal. METHODS: A total of 1767 patients with asymptomatic aortic stenosis and no manifest atherosclerotic disease were analyzed. Outcomes were all-cause mortality, cardiovascular death, heart failure, stroke, myocardial infarction, and aortic valve replacement. BP was analyzed in Cox models as the cumulative average of serially measured BP and a time-varying covariate. RESULTS: The incidence of all-cause mortality was highest for average follow-up systolic BP ≥160 mm Hg (4.3 per 100 person-years; 95% confidence interval [CI], 3.1-6.0) and lowest for average systolic BP of 120 to 139 mm Hg (2.0 per 100 person-years; 95% CI, 1.6-2.6). In multivariable analysis, all-cause mortality was associated with average systolic BP <120 mm Hg (hazard ratio [HR], 3.4; 95% CI, 1.9-6.1), diastolic BP ≥90 mm Hg (HR, 1.8; 95% CI, 1.1-2.9), and pulse pressure <50 mm Hg (HR, 1.8; 95% CI, 1.1-2.9), with systolic BP of 120 to 139 mm Hg, diastolic BP of 70 to 79 mm Hg, and pulse pressure of 60 to 69 mm Hg taken as reference. Low systolic and diastolic BPs increased risk in patients with moderate aortic stenosis. With a time-varying systolic BP from 130 to 139 mm Hg used as reference, mortality was increased for systolic BP ≥160 mm Hg (HR, 1.7; P=0.033) and BP of 120 to 129 mm Hg (HR, 1.6; P=0.039). CONCLUSIONS: Optimal BP seems to be systolic BP of 130 to 139 mm Hg and diastolic BP of 70 to 90 mm Hg in these patients with asymptomatic aortic stenosis and no manifest atherosclerotic disease or diabetes mellitus. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00092677.

The impact of intravenous ferric carboxymaltose on renal function: an analysis of the FAIR-HF study.

AIMS: Anaemia and iron deficiency are constituents of the cardio-renal syndrome in chronic heart failure (CHF). We investigated the effects of i.v. iron in iron-deficient CHF patients on renal function, and the efficacy and safety of this therapy in patients with renal dysfunction. METHODS AND RESULTS: The FAIR-HF trial randomized 459 CHF patients with iron deficiency (ferritin <100 µg/L, or between 100 and 299 µg/L if transferrin saturation was <20%): 304 to i.v. ferric carboxymaltose (FCM) and 155 to placebo, and followed-up for 24 weeks. Renal function was assessed at baseline and at weeks 4, 12, and 24, using the estimated glomerular filtration rate (eGFR, mL/min/1.73 m(2) ), calculated from the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula. At baseline, renal function was similar between groups (62.4 ± 20.6 vs. 62.9 ± 23.4 mL/min/1.73 m(2) , FCM vs. placebo). Compared with placebo, treatment with FCM was associated with an increase in eGFR [treatment effect: week 4, 2.11 ± 1.21 (P = 0.082); week 12, 2.41 ± 1.33 (P = 0.070); and week 24, 2.98 ± 1.44 mL/min/1.73 m(2) (P = 0.039)]. This effect was seen in all pre-specified subgroups (P > 0.20 for interactions). No interaction between the favourable effects of FCM and baseline renal function was seen for the primary endpoints [improvement in Patient Global Assessment (P = 0.43) and NYHA class (P = 0.37) at 24 weeks]. Safety and adverse event profiles were similar in patients with baseline eGFR <60 and ≥60 mL/min/1.73 m(2) . CONCLUSIONS: Treatment of iron deficiency in CHF patients with i.v. FCM was associated with an improvement in renal function. FCM therapy was effective and safe in CHF patients with renal dysfunction.

High sensitivity C reactive protein as a prognostic marker in patients with mild to moderate aortic valve stenosis during lipid-lowering treatment: an SEAS substudy.

AIMS: To assess the prognostic importance of high-sensitive C reactive protein (hsCRP) in patients with mild to moderate aortic valve stenosis during placebo or simvastatin/ezetimibe treatment in Simvastatin and Ezetimibe in Aortic Stenosis (SEAS). METHODS AND RESULTS: In 1620 SEAS patients, we measured lipids and hsCRP at baseline and after 1 year of treatment and registered during 4 years of follow-up major cardiovascular events (MCE) composed of ischaemic cardiovascular events (ICE) and aortic valve-related events (AVE). Simvastatin/ezetimibe reduced low-density lipoprotein cholesterol (3.49 (2.94 to 4.15) to 1.32 (1.02 to 1.69) vs 3.46 (2.92 to 4.08) to 3.34 (2.81 to 3.92) mmol/L) and hsCRP (2.1 (0.9 to 4.1) to 1.2 (0.6 to 2.4) vs 2.2 (0.9 to 4.9) to 1.8 (0.85 to 4.35) mg/L, all p<0.05) during the first year of treatment. In multivariable Cox regression analysis adjusting for traditional risk factors and baseline hsCRP, ICE was associated with a 1-year increase of hsCRP (HR=1.19 (95% CI 1.12 to 1.25), p<0.001) but not with active treatment (HRTreatment=0.86 (0.67 to 1.13), p=0.28). Patients in the top quartile of baseline hsCRP versus the rest were associated with a higher risk of MCE (HR=1.34(1.09 to 1.64), p=0.02). The prognostic benefit of reduction in hsCRP after 1 year was significantly larger (p<0.01 for interaction) in patients with high versus low baseline hsCRP; hence, a reduction in hsCRP abolished the difference in incidence of MCE between high versus low baseline hsCRP in patients with reduced hsCRP (31.1 vs 31.9%, NS) in contrast to patients with increased hsCRP. CONCLUSIONS: The treatment-associated reduction in ICE was in part related to a reduction in hsCRP but not in lipids. hsCRP reduction was associated with less MCE, especially in patients with high baseline hsCRP. TRIAL REGISTRATION: NCT00092677.

Incidence of cancer and mortality in patients from the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) trial.

The Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) clinical trial, including 1,873 patients found an increased risk for cancer with lipid-lowering therapy with ezetimibe/simvastatin 10/40 mg/day, relative to placebo. In a registry-based follow-up study over 21 months from the conclusion of the SEAS trial, new incident cancer and total mortality were investigated in the SEAS study cohort from Denmark, Finland, Norway, Sweden, and the United Kingdom. Among 1,359 subjects eligible for follow-up (73% of the original total cohort), 1,194 had no history of cancer (primary follow-up cohort). New cancers and deaths were identified in the national cancer and mortality registries and classified by an Expert Review Committee. Data were analyzed using Cox proportional-hazards models of new cancers and mortality during follow-up according to treatment group assigned in the SEAS base study and with age, gender, smoking history, and previous cancers as covariates. The primary follow-up cohort had 12 patients with new cancers in the ezetimibe/simvastatin group and 22 in the placebo group (hazard ratio 0.55, 95% confidence interval 0.27 to 1.11), indicating no significant difference between the treatment groups. During follow-up, 43 patients assigned to ezetimibe/simvastatin and 33 assigned to placebo died (hazard ratio 1.29, 95% confidence interval 0.82 to 2.03). In conclusion, in this registry-based observational follow-up study of the original SEAS study patient population, treatment with ezetimibe/simvastatin was not associated with an increased risk for cancer or mortality in the 21-month period after the completion of the original SEAS study.

Extracellular matrix biomarker, fibulin-1, is closely related to NT-proBNP and soluble urokinase plasminogen activator receptor in patients with aortic valve stenosis (the SEAS study).

BACKGROUND: Fibulin-1, a circulating extracellular matrix glycoprotein, has been associated with arterial disease and elevated N-terminal prohormone B-type natriuretic peptide (NT-proBNP) in diabetes. Soluble urokinase plasminogen activator receptor (suPAR), a marker of inflammation, has been associated with subclinical atherosclerosis. Therefore, we aimed to explore the interplay between these biomarkers and mild to moderate aortic valve stenosis (AS). METHODS: In 374 patients with mild to moderate AS, we investigated the relationship of fibulin-1 with NT-proBNP, levels of suPAR and the degree of AS at baseline and after one and four years of treatment with Simvastatin 40 mg and Ezetimibe 10 mg or placebo. RESULTS: During treatment, fibulin-1 became more closely associated with NT-proBNP (ßyear0 = 0.10, p = 0.08, ßyear1 = 0.16, p = 0.005, ßyear4 = 0.22, p<0.001) and suPAR (ßyear0 = 0.05, p = 0.34, ßyear1 = 0.16, p = 0.006, ßyear4 = 0.13, p = 0.03) at the expense of the association to aortic valve area index (AVAI) (ßyear0 = -0.14, p = 0.005, ßyear1 = -0.08, p = 0.11, ßyear4 = -0.06, p = 0.22) independently of age, gender, creatinine, and serum aspartate aminotransferase (Adj.Ryear02 = 0.19, Adj.Ryear12 = 0.22, Adj.Ryear42 = 0.27). Fibulin-1 was unrelated to aortic regurgitation, left ventricular mass, and ejection fraction. In patients with baseline AVAI<0.58 cm2/m2 (median value), fibulin-1 was more closely associated to NT-proBNP (ßyear0 = 0.25, ßyear1 = 0.21, ßyear4 = 0.22, all p<0.01), and suPAR (ßyear0 = 0.09, p = 0.26, ßyear1 = 0.23, ßyear4 = 0.21, both p<0.01) independently of age, gender, AST and treatment allocation. CONCLUSIONS: Increased levels of fibulin-1 were independently associated with higher levels of suPAR and NT-proBNP especially in patients with lower AVAI, suggesting that fibulin-1 may be an early marker of AS as well as cardiac fibrosis secondarily to elevated left ventricular hemodynamic load.

Adjusting parameters of aortic valve stenosis severity by body size.

BACKGROUND: Adjustment of cardiac dimensions by measures of body size appears intuitively convincing and in patients with aortic stenosis, aortic valve area (AVA) is commonly adjusted by body surface area (BSA). However, there is little evidence to support such an approach. OBJECTIVE: To identify the adequate measure of body size for the adjustment of aortic stenosis severity. METHODS: Parameters of aortic stenosis severity (jet velocity, mean pressure gradient (MPG) and AVA) and measures of body size (height, weight, BSA and body mass index (BMI)) were analysed in 2843 consecutive patients with aortic stenosis (jet velocity ≥2.5 m/s) and related to outcomes in a second cohort of 1525 patients from the Simvastatin/Ezetimibe in Aortic Stenosis (SEAS) study. RESULTS: Whereas jet velocity and MPG were independent of body size, AVA was significantly correlated with height, weight, BSA and BMI (Pearson correlation coefficient (r) 0.319, 0.281, 0.317 and 0.126, respectively, all p<0.001) to the effect that larger patients presented with larger AVA (less severe stenosis). Of the anthropometric measures used for linear adjustment, BSA was most effective in eliminating the correlation between AVA and body size (r=0.007), rivalled only by allometric (non-linear) models, findings that are confirmed in 1525 prospectively followed patients from the SEAS study. Predictive accuracy for aortic valve events and cardiovascular death during 46 months of follow-up was unchanged by adjusting AVA, regardless of measure of body size (area under the receiver operating curve for AVA 0.72 (CI 0.58 to 0.87) versus, for example, AVA/BSA 0.75 (CI 0.61 to 0.88), p=0.22). CONCLUSIONS: In the assessment of aortic stenosis, linear adjustment of AVA by BSA improves comparability between patients with diverging body size without, however, increasing the predictive accuracy for clinical events in a population with mild to moderate stenosis.

Indexing aortic valve area by body surface area increases the prevalence of severe aortic stenosis.

BACKGROUND: To account for differences in body size in patients with aortic stenosis, aortic valve area (AVA) is divided by body surface area (BSA) to calculate indexed AVA (AVAindex). Cut-off values for severe stenosis are <1.0 cm2 for AVA and <0.6 cm2/m2 for AVAindex. OBJECTIVE: To investigate the influence of indexation on the prevalence of severe aortic stenosis and on the predictive accuracy regarding clinical outcome. METHODS: Echocardiographic and anthropometric data from a retrospective cohort of 2843 patients with aortic stenosis (jet velocity >2.5 m/s) and from 1525 patients prospectively followed in the simvastatin and ezetimibe in aortic stenosis (SEAS) trial were analysed. RESULTS: The prevalence of severe stenosis increased with the AVAindex criterion compared to AVA from 71% to 80% in the retrospective cohort, and from 29% to 44% in SEAS (both p<0.001). Overall, the predictive accuracy for aortic valve events was virtually identical for AVA and AVAindex in the SEAS population (mean follow-up of 46 months; area under the receiver operating characteristic curve: 0.67 (95% CI 0.64 to 0.70) vs. 0.68 (CI 0.65 to 0.71) (NS). However, 213 patients additionally categorised as severe by AVAindex experienced significantly less valve related events than those fulfilling only the AVA criterion (p<0.001). CONCLUSIONS: Indexing AVA by BSA (AVAindex) significantly increases the prevalence of patients with criteria for severe stenosis by including patients with a milder degree of the disease without improving the predictive accuracy for aortic valve related events.

Intravenous ferric carboxymaltose in iron-deficient chronic heart failure patients with and without anaemia: a subanalysis of the FAIR-HF trial.

AIMS: Therapy with i.v. iron in patients with chronic heart failure (CHF) and iron deficiency (ID) improves symptoms, functional capacity, and quality of life. We sought to investigate whether these beneficial outcomes are independent of anaemia. METHODS AND RESULTS: FAIR-HF randomized 459 patients with CHF [NYHA class II or III, LVEF ≤40% (NYHA II) or ≤45% (NYHA III)] and ID to i.v. iron as ferric carboxymaltose (FCM) or placebo in a 2:1 ratio. We analysed the efficacy and safety according to the presence or absence of anaemia (haemoglobin ≤120 g/L) at baseline. Of 459 patients, 232 had anaemia at baseline (51%). The effect of FCM on the primary endpoints of self-reported Patient Global Assessment (PGA) and NYHA class at week 24 was similar in patients with and without anaemia [odds ratio (OR) for improvement, 2.48 vs. 2.60, P = 0.97 for PGA and 1.90 vs. 3.39, P = 0.51 for NYHA). Results were also similar for the secondary endpoints, including PGA and NYHA at weeks 4 and 12, 6 min walk test distance, Kansas City Cardiomyopathy Questionnaire overall score, and European Quality of Life-5 Dimensions Visual Analogue Scale at most time points. Regarding safety, no differences were noticed in the rates of death or first hospitalization between FCM and placebo both in anaemic and in non-anaemic patients. CONCLUSIONS: Treatment of ID with FCM in patients with CHF is equally efficacious and shows a similar favourable safety profile irrespective of anaemia. Iron status should be assessed in symptomatic CHF patients both with and without anaemia and treatment of ID should be considered.

Mitral annular plane systolic excursion (MAPSE) in shock: a valuable echocardiographic parameter in intensive care patients.

BACKGROUND: Assessing left ventricular (LV) dysfunction by echocardiography in ICU patients is common. The aim of this study was to investigate mitral annular plane systolic excursion (MAPSE) in critically ill patients with shock and its relation to LV systolic and diastolic function, myocardial injury and to outcome. METHODS: In a prospective, observational, cohort study we enrolled 50 patients with SIRS and shock despite fluid resuscitation. Transthoracic echocardiography (TTE) measuring LV function was performed within 12 hours after admission and daily for a 7-day observation period. TTE and laboratory measurements were related to 28-day mortality. RESULTS: MAPSE on day 1 correlated significantly with LV ejection fraction (LVEF), tissue Doppler indices of LV diastolic function (é, E/é) and high-sensitive troponin T (hsTNT) (p< 0.001, p= 0.039, p= 0.009, p= 0.003 respectively) whereas LVEF did not correlate significantly with any marker of LV diastolic function or myocardial injury. Compared to survivors, non-survivors had a significantly lower MAPSE (8 [IQR 7.5-11] versus 11 [IQR 8.9-13] mm; p= 0.028). Other univariate predictors were age (p=0.033), hsTNT (p=0.014) and Sequential Organ Failure Assessment (SOFA) scores (p=0.007). By multivariate analysis MAPSE (OR 0.6 (95% CI 0.5- 0.9), p= 0.015) and SOFA score (OR 1.6 (95% CI 1.1- 2.3), p= 0.018) were identified as independent predictors of mortality. Daily measurements showed that MAPSE, as sole echocardiographic marker, was significantly lower in most days in non-survivors (p<0.05 at day 1-2, 4-6). CONCLUSIONS: MAPSE seemed to reflect LV systolic and diastolic function as well as myocardial injury in critically ill patients with shock. The combination of MAPSE and SOFA added to the predictive value for 28-day mortality.

The effect of intravenous ferric carboxymaltose on health-related quality of life in patients with chronic heart failure and iron deficiency: a subanalysis of the FAIR-HF study.

AIMS: Patients with chronic heart failure (CHF) show impaired health-related quality of life (HRQoL), an important target for therapeutic intervention. Impaired iron homeostasis may be one mechanism underlying the poor physical condition of CHF patients. This detailed subanalysis of the previously published FAIR-HF study evaluated baseline HRQoL in iron-deficient patients with CHF and the effect of intravenous ferric carboxymaltose (FCM) on HRQoL. METHODS AND RESULTS: FAIR-HF randomized 459 patients with reduced left ventricular ejection fraction and iron deficiency, with or without anaemia, to FCM or placebo (2:1). Health-related quality of life was assessed at baseline and after 4, 12, and 24 weeks of therapy using the generic EQ-5D questionnaire and disease-specific Kansas City cardiomyopathy questionnaire (KCCQ). Baseline mean visual analogue scale (VAS) score was 54.3 ± 16.4 and KCCQ overall summary score was 52.4 ± 18.8. Ferric carboxymaltose significantly improved VAS and KCCQ (mean differences from baseline in KCCQ overall, clinical and total symptom scores, P< 0.001 vs. placebo) at all time points. At week 24, significant improvement vs. placebo was observed in four of the five EQ-5D dimensions: mobility (P= 0.004), self-care (P< 0.001), pain/discomfort (P= 0.006), anxiety/depression (P= 0.012), and usual activity (P= 0.035). Ferric carboxymaltose improved all KCCQ domain mean scores from Week 4 onward (P≤ 0.05), except for self-efficacy and social limitation. Effects were present in both anaemic and non-anaemic patients. CONCLUSIONS: HRQoL is impaired in iron-deficient patients with CHF. Intravenous FCM significantly improved HRQoL after 4 weeks, and throughout the remaining study period. The positive effects of FCM were independent of anaemia status.

Prognostic importance of atrial fibrillation in asymptomatic aortic stenosis: the Simvastatin and Ezetimibe in Aortic Stenosis study.

BACKGROUND: The frequency and prognostic importance of atrial fibrillation (AF) in asymptomatic mild-to-moderate aortic stenosis (AS) has not been well described. METHODS: Clinical examination, electrocardiography and echocardiography were obtained in asymptomatic patients with mild-to-moderate AS and preserved left ventricular (LV) systolic function, randomized to simvastatin/ezetimibe combination vs. placebo in the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) study. At inclusion, AF was categorized as episodic or longstanding. Rhythm change was assessed on annual in-study electrocardiograms. Impact of AF on cardiovascular morbidity and mortality was determined by adjusting for biomarkers, clinical- and echocardiographic covariates. RESULTS: Mean follow-up was 4.3 ± 0.8 years (6,721 patient-years of follow-up). At baseline, episodic AF was present in 87 patients (5.6%), longstanding AF in 55 (3.5%) and no AF in 1,421 (90.9%). Incidence of new-onset AF was 1.2%/year; highest in those with impaired LV function. In multivariable analysis, longstanding AF was compared to no AF at baseline, associated with a 4.1-fold higher risk of heart failure (CI 1.2 to 13.8, p=0.02) and a 4.8-fold higher risk of non-hemorrhagic stroke (CI 1.7 to 13.6, p=0.003). CONCLUSION: Rate of AF is moderate in asymptomatic AS. Longstanding but not episodic AF was, independently predictive of increased risk of heart failure and non-hemorrhagic stroke. New-onset AF was associated with cardiac decompensation.

Aortic stenosis and mitral regurgitation as predictors of atrial fibrillation during 11 years of follow-up.

BACKGROUND: There is limited information about any association between the onset of atrial fibrillation (AF) and the presence of valvular disease. METHODS: We retrospectively examined 940 patients in sinus rhythm, examined by echocardiography in 1996. During 11 years of follow-up, we assessed the incidence of AF and outcome defined as valvular surgery or death, in relation to baseline valvular function. AS (aortic stenosis) severity at baseline examination was assessed using peak transaortic valve pressure gradient. RESULTS: In univariate analysis, the risk of developing AF was related to AS (significant AS versus no significant AS; hazard ratio (HR) 3.73, 95% confidence interval (CI) 2.39-5.61, p<0.0001) and mitral regurgitation (MR) (significant MR versus no significant MR; HR 2.52, 95% CI 1.77-3.51, p<0.0001). Also the risk of valvular surgery or death was related to AS (HR 3.90, 95% CI 3.09-4.88, p<0.0001) and MR (HR 2.07, 95% CI 1.67-2.53, p<0.0001). In multivariate analyses, adjusting for sex, age, other valvular abnormalities, left ventricular ejection fraction and left atrial size - AS was independently related to both endpoints, whereas MR was not independently related to either endpoint. CONCLUSIONS: AS, but not MR, was independently predictive of development of AF and combined valvular surgery or death. In patients with combined AS and MR, the grade of AS, more than the grade of MR, determined the risk of AF and combination of valvular surgery or death. Further studies using contemporary echocardiographic quantification of aortic stenosis are warranted to confirm these retrospective data based on peak transaortic valve pressure gradient.

High-sensitive cardiac Troponin T is superior to echocardiography in predicting 1-year mortality in patients with SIRS and shock in intensive care.

BACKGROUND: Left ventricular (LV) dysfunction is well documented in the critically ill. We assessed 1-year mortality in relation to cardiac biomarkers and LV function parameters by echocardiography in patients with shock. METHODS: A prospective, observational, cohort study of 49 patients. B-natriuretic peptide (BNP), high-sensitive troponin T (hsTNT) and transthoracic echocardiography (TTE) were assessed within 12 h of study inclusion. LV systolic function was measured by ejection fraction (LVEF), mean atrioventricular plane displacement (AVPDm), peak systolic tissue Doppler velocity imaging (TDIs) and velocity time integral in the LV outflow tract (LVOT VTI). LV diastolic function was evaluated by transmitral pulsed Doppler (E, A, E/A, E-deceleration time), tissue Doppler indices (é, á, E/é) and left atrial volume (La volume). APACHE II (Acute Physiology and Chronic Health Evaluation) and SOFA (Sequential Organ Failure Assessment) scores were calculated. RESULTS: hsTNT was significantly higher in non-survivors than in survivors (60 [17.0-99.5] vs 168 [89.8-358] ng/l, p = 0.003). Other univariate predictors of mortality were APACHE II (p = 0.009), E/é (p = 0.023), SOFA (p = 0.024) and age (p = 0.031). Survivors and non-survivors did not differ regarding BNP (p = 0.26) or any LV systolic function parameter (LVEF p = 0.87, AVPDm p = 0.087, TDIs p = 0.93, LVOT VTI p = 0.18). Multivariable logistic regression analysis identified hsTNT (p = 0.010) as the only independent predictor of 1-year mortality; adjusted odds ratio 2.0 (95% CI 1.2- 3.5). CONCLUSIONS: hsTNT was the only independent predictor of 1-year mortality in patients with shock. Neither BNP nor echocardiographic parameters had an independent prognostic value. Further studies are needed to establish the clinical significance of elevated hsTNT in patients in shock.

Impact of QRS duration and morphology on the risk of sudden cardiac death in asymptomatic patients with aortic stenosis: the SEAS (Simvastatin and Ezetimibe in Aortic Stenosis) Study.

OBJECTIVES: The aim of the study was to examine the predictive value of QRS duration and morphology during watchful waiting in asymptomatic patients with aortic stenosis (AS). BACKGROUND: QRS duration and morphology are associated with poor prognosis in many different populations, but the predictive value, particularly of the risk of sudden cardiac death (SCD), in asymptomatic patients with AS has not been well studied. METHODS: Data were obtained in asymptomatic AS patients randomized to simvastatin/ezetimibe combination versus placebo in the SEAS (Simvastatin and Ezetimibe in Aortic Stenosis) study. The impact of QRS duration, evaluated as a categorical variable of <85 ms versus 85 to 99 ms and ≥100 ms (excluding bundle branch block [BBB]) and QRS morphology in those with BBB, on cardiovascular morbidity and mortality was assessed by adjusting for clinical and echocardiographic covariates. RESULTS: QRS data were available in 1,542 patients who were followed for a mean of 4.3 ± 0.8 years (6,631 patient-years of follow-up). There were 68 cardiovascular deaths (4.6%), including 27 SCDs (1.8%). QRS duration was <85 ms in 900 patients (58.4%), 85 to 99 ms in 396 (25.7%), ≥100 ms in those without BBB in 144 (9.3%), and 102 (6.6%) in those with BBB. In multivariable analyses, those with QRS duration ≥100 ms had, compared with those with QRS duration <85 ms, a 5-fold higher risk of SCD (95% confidence interval: 1.8 to 13.7, p = 0.002) and a 2.5-fold higher risk of cardiovascular death (95% confidence interval: 1.2 to 5.1, p = 0.01). CONCLUSIONS: QRS duration and morphology in asymptomatic patients with AS are independently associated with a poor prognosis, particularly the risk of SCD.

A risk score for predicting mortality in patients with asymptomatic mild to moderate aortic stenosis.

BACKGROUND: Prognostic information for asymptomatic patients with aortic stenosis (AS) from prospective studies is scarce and there is no risk score available to assess mortality. OBJECTIVES: To develop an easily calculable score, from which clinicians could stratify patients into high and lower risk of mortality, using data from the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) study. METHOD: A search for significant prognostic factors (p<0.01) among SEAS patients was made by a combined judgemental and statistical elimination procedure to derive a set of three factors (age, gender and smoking) that were forced into the model, and four additional factors captured by the data: left-ventricular mass index, bilirubin, heart rate and natural logarithm of C reactive protein. Calibration was done by comparing observed with calculated number of deaths by tenths of calculated risk using coefficients from the simvastatin + ezetimibe group on placebo group patients. RESULTS: Discrimination was good with ROC area of 0.76 for all patients. Estimated probabilities of death were categorised into thirds. An optimised split point of estimated 5-year risk was about 15% (close to the upper 14% tertile split point), with risk 4 times as high in the upper compared to the two lower thirds. The SEAS score performed better than another established high risk score developed for other purposes. CONCLUSION: A new seven factor model for risk stratification of patients with mild to moderate asymptomatic AS identified a high risk group for total mortality with good discrimination properties. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov, NCT 00092677.