Pulmonary artery pressure monitoring in chronic heart failure: effects across clinically relevant subgroups in the MONITOR-HF trial.

BACKGROUND AND AIMS: In patients with chronic heart failure (HF), the MONITOR-HF trial demonstrated the efficacy of pulmonary artery (PA)-guided HF therapy over standard of care in improving quality of life and reducing HF hospitalizations and mean PA pressure. This study aimed to evaluate the consistency of these benefits in relation to clinically relevant subgroups. METHODS: The effect of PA-guided HF therapy was evaluated in the MONITOR-HF trial among predefined subgroups based on age, sex, atrial fibrillation, diabetes mellitus, left ventricular ejection fraction, HF aetiology, cardiac resynchronization therapy, and implantable cardioverter defibrillator. Outcome measures were based upon significance in the main trial and included quality of life-, clinical-, and PA pressure endpoints, and were assessed for each subgroup. Differential effects in relation to the subgroups were assessed with interaction terms. Both unadjusted and multiple testing adjusted interaction terms were presented. RESULTS: The effects of PA monitoring on quality of life, clinical events, and PA pressure were consistent in the predefined subgroups, without any clinically relevant heterogeneity within or across all endpoint categories (all adjusted interaction P-values were non-significant). In the unadjusted analysis of the primary endpoint quality-of-life change, weak trends towards a less pronounced effect in older patients (Pinteraction = .03; adjusted Pinteraction = .33) and diabetics (Pinteraction = .01; adjusted Pinteraction = .06) were observed. However, these interaction effects did not persist after adjusting for multiple testing. CONCLUSIONS: This subgroup analysis confirmed the consistent benefits of PA-guided HF therapy observed in the MONITOR-HF trial across clinically relevant subgroups, highlighting its efficacy in improving quality of life, clinical, and PA pressure endpoints in chronic HF patients.

Serial cardiac biomarkers, pulmonary artery pressures and traditional parameters of fluid status in relation to prognosis in patients with chronic heart failure: Design and rationale of the BioMEMS study.

AIMS: Heart failure (HF), a global pandemic affecting millions of individuals, calls for adequate predictive guidance for improved therapy. Congestion, a key factor in HF-related hospitalizations, further underscores the need for timely interventions. Proactive monitoring of intracardiac pressures, guided by pulmonary artery (PA) pressure, offers opportunities for efficient early-stage intervention, since haemodynamic congestion precedes clinical symptoms. METHODS: The BioMEMS study, a substudy of the MONITOR-HF trial, proposes a multifaceted approach integrating blood biobank data with traditional and novel HF parameters. Two additional blood samples from 340 active participants in the MONITOR-HF trial were collected at baseline, 3-, 6-, and 12-month visits and stored for the BioMEMS biobank. The main aims are to identify the relationship between temporal biomarker patterns and PA pressures derived from the CardioMEMS-HF system, and to identify the biomarker profile(s) associated with the risk of HF events and cardiovascular death. CONCLUSION: Since the prognostic value of single baseline measurements of biomarkers like N-terminal pro-B-type natriuretic peptide is limited, with the BioMEMS study we advocate a dynamic, serial approach to better capture HF progression. We will substantiate this by relating repeated biomarker measurements to PA pressures. This design rationale presents a comprehensive review on cardiac biomarkers in HF, and aims to contribute valuable insights into personalized HF therapy and patient risk assessment, advancing our ability to address the evolving nature of HF effectively.

Randomized, double-blind, placebo-controlled, multicentre pilot study on the effects of empagliflozin on clinical outcomes in patients with acute decompensated heart failure (EMPA-RESPONSE-AHF).

AIMS: Inhibition of sodium-glucose co-transporter 2 (SGLT2) reduces the risk of death and heart failure (HF) admissions in patients with chronic HF. However, safety and clinical efficacy of SGLT2 inhibitors in patients with acute decompensated HF are unknown. METHODS AND RESULTS: In this randomized, placebo-controlled, double-blind, parallel group, multicentre pilot study, we randomized 80 acute HF patients with and without diabetes to either empagliflozin 10 mg/day or placebo for 30 days. The primary outcomes were change in visual analogue scale (VAS) dyspnoea score, diuretic response (weight change per 40 mg furosemide), change in N-terminal pro brain natriuretic peptide (NT-proBNP), and length of stay. Secondary outcomes included safety and clinical endpoints. Mean age was 76 years, 33% were female, 47% had de novo HF and median NT-proBNP was 5236 pg/mL. No difference was observed in VAS dyspnoea score, diuretic response, length of stay, or change in NT-proBNP between empagliflozin and placebo. Empagliflozin reduced a combined endpoint of in-hospital worsening HF, rehospitalization for HF or death at 60 days compared with placebo [4 (10%) vs. 13 (33%); P = 0.014]. Urinary output up until day 4 was significantly greater with empagliflozin vs. placebo [difference 3449 (95% confidence interval 578-6321) mL; P < 0.01]. Empagliflozin was safe, well tolerated, and had no adverse effects on blood pressure or renal function. CONCLUSIONS: In patients with acute HF, treatment with empagliflozin had no effect on change in VAS dyspnoea, diuretic response, NT-proBNP, and length of hospital stay, but was safe, increased urinary output and reduced a combined endpoint of worsening HF, rehospitalization for HF or death at 60 days.

Drawbacks and prognostic value of formulas estimating renal function in patients with chronic heart failure and systolic dysfunction.

BACKGROUND: Renal function is an important risk marker for morbidity and mortality in chronic heart failure (CHF) and is often estimated with the use of creatinine-based formulas. However, these formulas have never been validated in a wide range of CHF patients. We validated 3 commonly used formulas estimating glomerular filtration rate (GFR) with true GFR in CHF patients. Furthermore, we compared the prognostic value of these formulas for cardiovascular outcome with that of true GFR during 12 months of follow-up. METHODS AND RESULTS: In 110 CHF patients (age, 57+/-11.7 years; left ventricular ejection fraction, 0.27+/-0.09; NYHA class, 2.5+/-0.9), we measured 125I-iothalamate clearance. Cockcroft-Gault (GFR(cg)), Modification of Diet in Renal Disease (MDRD), and simplified MDRD (sMDRD) equations were used as creatinine-based renal function estimations. Furthermore, 24-hour creatinine clearance (CrCl) was determined. CrCl and GFR(cg) were the most accurate. MDRD was most precise formula, although it was also highly biased. All formulas overestimated in the lower ranges and underestimated in the upper ranges of the GFR corrected for body surface area. The predictive performance of the formulas was best in severe CHF (NYHA classes III and IV). The prognostic value of CrCl and MDRD for cardiovascular outcome was comparable to that of GFR, the sMDRD was slightly less, and the GFR(cg) had a significantly worse prognostic value. CONCLUSIONS: In the more severe ranges of CHF, creatinine-based formulas and CrCl corrected for body surface area appeared to be more precise and accurate in estimating true GFR corrected for body surface area. The MDRD formula is the most precise and has a good prognostic value, whereas the sMDRD is slightly less accurate but uses fewer parameters, which makes this formula a practical alternative in clinical practice.

Worsening renal function and prognosis in heart failure: systematic review and meta-analysis.

BACKGROUND: Renal impairment is associated with increased mortality in heart failure (HF). Recently, reports suggest that worsening renal function (WRF) is another predictor of clinical outcome in HF. The present study was designed to establish the proportion of patients with HF that exhibits (WRF) and the associated risk for mortality and hospitalization by conducting a systematic review and meta-analysis. METHODS AND RESULTS: A systematic search of MEDLINE revealed 8 studies on the relationship between WRF and mortality in 18,634 patients with HF. The mortality risk associated with WRF was estimated using random-effects meta-analysis. WRF was defined as an increase in serum creatinine > or = 0.2 mg/dL or a corresponding decrease in estimated glomerular filtration rate > or = 5 mL x min x 1.73 m2. Subgroup analysis included differentiation between in- and out-hospital patients, degree of WRF and time until end point occurrence. WRF developed in 4,734 (25%) patients and was associated with a higher risk for mortality (odds ratio [OR] = 1.62; 95% confidence interval [CI] 1.45-1.82, P < .001) and hospitalization (OR = 1.30, 95% CI 1.04-1.62, P = .022). The severity of WRF was also associated with greater mortality. Patients with impaired renal function at baseline were more prone to progressive renal function loss. CONCLUSIONS: WRF predicts substantially higher rates of mortality and hospitalization in patients with HF.

Serum HER2 levels are increased in patients with chronic heart failure.

BACKGROUND: The use of trastuzumab, an antibody against the human epidermal growth factor receptor 2 (HER2), in patients with HER2 positive metastatic breast cancer, is related to cardiotoxicity. AIMS: To investigate whether serum HER2 is increased in heart failure patients and related to disease severity. METHODS: Serum HER2, plasma tumor necrosis factor (TNF)-alpha and its soluble (s) receptors (sTNF-R1 and 2) were determined with ELISA in chronic heart failure patients and age and gender-matched healthy controls. RESULTS: Serum HER2 was higher (P=0.013) in 50 heart failure patients (18 female; median age 57 (range 33-77) years), mean 12.1+/-S.D. 2.3 ng/mL, than in 15 controls, 10.4+/-2.6 ng/mL. Serum HER2 levels correlated inversely with left ventricular ejection fraction (P=0.037) and were highest among NYHA class III patients, followed by NYHA class II patients and controls (P=0.029, Kruskal-Wallis test). STNF-R1 (P<.001) and sTNF-R2 (P=0.015) were higher in patients than controls, and correlated positively with HER2 (P=0.027 and P=0.036, respectively). CONCLUSIONS: Serum HER2 levels are increased in chronic heart failure patients. Further research is necessary to determine whether HER2 plays a role in the pathophysiology of heart failure.

Decreased cardiac output, venous congestion and the association with renal impairment in patients with cardiac dysfunction.

BACKGROUND: Renal failure in heart failure is related to decreased cardiac output. However, little is known about its association with venous congestion. AIMS: To investigate the relationship between venous congestion and glomerular filtration rate (GFR) in patients with cardiac dysfunction. METHODS AND RESULTS: Right atrial pressure (RAP) and cardiac index (CI) were determined by right heart catheterisation in 51 patients with cardiac dysfunction, secondary to pulmonary hypertension. GFR and renal blood flow (RBF) were measured as (125)I-Iothalamate and (131)I-Hippuran clearances, respectively. Mean age was 40+/-11 years and 69% of patients were female. GFR was 73+/-19 ml/min/1.73 m2 with a CI of 2.1+/-0.7 l/min/m2. In multivariate analysis, RBF (r=0.664, p<0.001) and RAP (r=- 0.367, p=0.020) were independently associated with GFR. In patients in the lower ranges of RBF, venous congestion was an important determinant of renal function. CONCLUSION: RBF is the main factor determining GFR in patients with cardiac dysfunction. Venous congestion, characterised by an increased RAP, adjusted for RBF is also related to GFR. Treatment to preserve GFR should not only focus on improvement of renal perfusion, but also on decreasing venous congestion.

Renal function dependent association of AGTR1 polymorphism (A1166C) and electrocardiographic left-ventricular hypertrophy.

BACKGROUND: The association of renin-angiotensin system (RAS) polymorphisms and left-ventricular hypertrophy (LVH) may depend on the presence of risk factors for LVH, such as renal dysfunction. We studied whether renal function modulates the association between RAS polymorphisms and LVH in a cross-sectional study of 8592 inhabitants of Groningen. METHODS: Left-ventricular hypertrophy was determined with electrocardiograms, using the Cornell voltage-duration product. The following RAS polymorphisms were determined: angiotensin II type-1 receptor (AGTR1 A1166C), angiotensin-converting enzyme (ACE) insertion/deletion (I/D), and angiotensinogen (AGT G-6A). The AGTR1 A1166C and ACE I/D polymorphisms were in Hardy-Weinberg equilibrium. RESULTS: Electrocardiographic LVH was present in 417 (5.0%) subjects. Subjects with LVH were older (53 v 49 years) and overall had more cardiovascular risk factors. Using logistic regression, creatinine clearance interacted with the relationship between the AGTR1 A1166C polymorphism and LVH (beta, -0.19; P = .033). In subjects with the CC genotype, in contrast to carriers of an A allele, the prevalence of LVH increased with more pronounced renal dysfunction. Creatinine clearance also interacted with the relationship between the ACE I/D polymorphism and LVH (beta, 0.12; P = .037), although less strongly, and the other way around. Creatinine clearance did not influence the association between the AGT G-6A polymorphism and LVH (beta, -0.006; P = .491). CONCLUSIONS: In this population-based study, the AGTR1 A1166C polymorphism was associated with LVH, dependent on concomitant renal dysfunction. A weaker renal function dependent association between the ACE I/D polymorphism and LVH was also observed. Renal function should be taken into account as a relevant environmental factor for the pathogenetic effects of RAS polymorphisms.

Vascular function and mild renal impairment in stable coronary artery disease.

OBJECTIVE: In patients with coronary artery disease, the concomitant presence of renal function impairment is associated with decreased survival. We aimed to assess whether in coronary artery diseased patients renal function impairment is associated with systemic vascular function, functional parameters of the renin-angiotensin system, or inflammation as potential mediators for cardiovascular risk. METHODS AND RESULTS: We studied 125 patients, 87% male, with a mean age of 62.2+/-8.2 years; 72% had 3-vessel disease, and mean renal function was 74+/-13 mL/min per 1.73 m2. Internal thoracic artery rings were sampled during coronary bypass surgery and used for in vitro vascular measurements. We could not establish an association between endothelium-dependent vasorelaxation (response to methacholine) and renal function. In addition, vascular response to potassium chloride, phenylephrine, and angiotensin II were not associated with renal function. Finally, serum angiotensin-converting enzyme (ACE) activity, usage of ACE inhibitors, C-reactive protein, and soluble intercellular adhesion molecule 1 were not related to renal function. CONCLUSIONS: In coronary artery disease patients, mild renal function impairment is not associated with systemic vasomotor responsiveness, inflammation, or functional systemic parameters of the renin-angiotensin system. The relation between systemic endothelial dysfunction and mild renal insufficiency might be more complicated than previously thought.

Difference in long-term prognostic value of renal function between ischemic and non-ischemic mild heart failure.

INTRODUCTION: Renal function is one of the strongest prognostic markers in patients with chronic heart failure, but it has been suggested that this might be due to (local, i.e. renal) vascular atherosclerosis. The aim of the present study is to evaluate the prognostic value of renal function in both ischemic and non-ischemic mild chronic heart failure. METHODS: From 161 patients with early chronic heart failure and NYHA class II, who had been enrolled in a multicenter trial, ischemic chronic heart failure was present in 120 patients and non-ischemic chronic heart failure in 41 patients. Estimated glomerular filtration rate was calculated by the Cockcroft-Gault equation (GFRc). RESULTS: Follow-up duration was 13 years (mean 11.7 years). Mean age was 60.5+/-8.0 years, 86% was male and mean left ventricular ejection fraction was 0.29+/-0.08. Baseline characteristics were not statistically different between the groups. Multivariate Cox regression analysis revealed that in non-ischemic chronic heart failure, renal function was an important predictor of all-cause mortality (Relative Risk; 1.65 (1.05-2.58); p=0.029). In contrast, in ischemic chronic heart failure, renal function was not related to all-cause mortality (Relative Risk; 1.07 (0.92-1.23); p=0.40). CONCLUSION: In mild chronic heart failure, renal function is a prognostic risk marker for long-term mortality in non-ischemic chronic heart failure, but not in patients with coronary artery disease. These data suggest that renal vascular abnormalities are not primarily responsible for the prognostic value of renal function in patients with mild chronic heart failure.

Prognostic value of plasma erythropoietin on mortality in patients with chronic heart failure.

OBJECTIVES: This study aimed to investigate the prognostic importance of plasma erythropoietin (EPO) levels in chronic heart failure (CHF) patients. BACKGROUND: Anemia is common and is associated with an impaired survival in patients with CHF. Erythropoietin is a hematopoietic growth factor, upregulated in anemic conditions. Little is known about the pathophysiology of anemia in CHF and the prognostic importance of plasma EPO levels in CHF patients. METHODS: In 74 patients with CHF (age, 61 +/- 2 years; left ventricular ejection fraction, 0.31 +/- 0.01; peak oxygen consumption, 19.1 +/- 0.6 [mean +/- SEM]) and in 15 control patients, hemoglobin levels and plasma concentrations of EPO and brain natriuretic peptide were measured. RESULTS: During a mean follow-up of 3.0 years (range, 2.3 to 5.3 years), 22 patients (30%) died. Anemia was present in 24% of the patients. Multivariate analysis showed that plasma EPO (p = 0.026) and hemoglobin levels (p = 0.005) were independent predictors of survival in this CHF population. We observed only a mild inverse correlation between the logarithm of EPO and hemoglobin levels (r2 = 0.08, p = 0.02) in CHF patients, whereas the control group showed a clear significant inverse correlation (r2 = 0.44, p = 0.007). CONCLUSIONS: Elevated plasma EPO levels are associated with an impaired prognosis independent of hemoglobin levels and other established markers of CHF severity. Furthermore, in the CHF patients, EPO levels poorly correlate with the hemoglobin levels, in contrast with the control group.

Mild preoperative renal dysfunction as a predictor of long-term clinical outcome after coronary bypass surgery.

BACKGROUND: Renal dysfunction is a prognostic marker in patients with cardiovascular disease. However, no long-term follow-up studies on the influence of mild renal dysfunction on mortality in patients undergoing coronary bypass grafting have been reported. Therefore, we aimed to identify the significance of preoperative (mild) renal dysfunction as a long-term predictor of clinical outcome after coronary bypass surgery. METHODS: In 358 patients who underwent isolated saphenous vein aorta-coronary artery bypass grafting, estimated glomerular filtration rates were calculated with the Cockroft-Gault equation (GFRc). Patients were categorized into 2 groups (group 1, GFRc >71.1 mL x min (-1) x 1.73 m (-2) ; group 2, GFRc <71.1 mL x min (-1) x 1.73 m (-2) ). Multivariate Cox proportional hazard analyses were performed to determine the independent prognostic value of GFRc. RESULTS: During a median follow-up of 18.2 years, 233 patients (65.1%) died. Patients who died had lower GFRc and were older. Multivariate analysis demonstrated that total mortality in patients with lower GFRc was significantly increased (lower GFRc group vs normal GFRc group: hazard ratio, 1.44; P = .019). Lower GFRc was also an independent predictor of cardiac mortality (hazard ratio, 1.51; P = .032). No significant differences were observed between groups in the occurrence of myocardial infarction and the need for reintervention. CONCLUSIONS: Our study demonstrates that after long-term follow-up, preoperative mild renal dysfunction is an independent predictor of long-term (cardiac) mortality in patients who undergo coronary artery bypass grafting.

Mild renal dysfunction is associated with electrocardiographic left ventricular hypertrophy.

BACKGROUND: Both renal dysfunction and left ventricular hypertrophy (LVH) are signs of end-organ damage, risk markers of cardiovascular (CV) disease and chronic heart failure. In selected populations such as those with diabetes or hypertension, renal dysfunction was found to be related to LVH. We studied the relation between renal dysfunction and LVH in a cross-sectional study in 8592 inhabitants from Groningen, The Netherlands. METHODS: Standard 12-lead electrocardiograms were recorded, and LVH was classified using the Cornell voltage duration product. Renal dysfunction was defined as creatinine clearance <60 mL/min/1.73 m(2) or microalbuminuria (30 to 300 mg/24 h). RESULTS: Electrocardiographic signs of LVH were present in 396 of subjects (5.3%). Subjects with LVH were older and had a more extensive CV risk profile. We found that LVH was more prevalent in subjects with renal dysfunction than in those without (8% v 4%, P < .001). Multivariate regression analysis demonstrated that renal dysfunction was independently related to a 1.47-fold increased risk of the presence of LVH (95% CI = 1.15 to 1.88, P = .009). In addition, both creatinine clearance (OR = 1.56, 95% CI = 1.07 to 2.2, P = .044) and microalbuminuria (OR = 1.37, 95% CI = 1.04 to 1.80, P = .024) were independently associated with the presence of LVH. CONCLUSION: Subjects with mild renal dysfunction have a substantially higher risk of LVH on electrocardiography than those without renal dysfunction.

Impaired renal function in patients with ischemic and nonischemic chronic heart failure: association with neurohormonal activation and survival.

BACKGROUND: Renal dysfunction is a strong predictor of mortality in chronic heart failure (CHF). Most patients with CHF have atherosclerotic vascular disease, and several authors have suggested that impaired renal function is only a marker of advanced atherosclerosis. We compared renal function in patients with ischemic and nonischemic CHF and examined associations with prognosis and extent of neurohormonal activation. METHODS: In a large survival study (1906 patients), patients with documented coronary artery disease (CAD, n = 995), were compared with patients with idiopathic dilated cardiomyopathy (IDC, n = 429). In a smaller substudy, plasma neurohormones were determined in 270 patients and 37 patients (CAD and IDC, respectively). All patients had advanced CHF (New York Heart Association functional class III-IV). At baseline, the mean patient age was 64 +/- 10 years, and the mean left ventricular ejection fraction was 0.26 +/- 0.08. The baseline glomerular filtration rate was calculated with the Cockcroft-Gault equation (GFRc). RESULTS: GFRc was a strong predictor for mortality in both groups on multivariate analysis. The relative risk was 3.04 for patients with IDC (P < or =.01, for the lowest quartile < or =53 mL/min), and the relative risk for patients with CAD was 1.81 (P =.01 for the lowest quartile < or =42 mL/min). Plasma neurohormones showed a relation with GFRc in both groups. CONCLUSIONS: GFRc is related to survival and plasma neurohormones in both patient groups. In patients with IDC, this association appears to be at least as strong as in patients with CAD.

Prognostic importance of renal function in patients with early heart failure and mild left ventricular dysfunction.

We evaluated the prognostic value of renal function in an initially "untreated" population with mild heart failure and compared the prognosis of this population with a matched controlled population. During a follow-up of 13 years (mean 11.7), 90 patients (56%) died. Mortality was higher compared with a matched controlled population. Multivariate Cox regression analysis demonstrated that beside the well-established risk markers of left ventricular ejection fraction and heart rate, renal function (estimated glomerular filtration rate, hazard ratio 1.16/10 ml/min/1.73 m(2), p = 0.003) was the only additional independent predictor of cardiovascular mortality in patients with early heart failure.

Use of cystatin C levels in estimating renal function and prognosis in patients with chronic systolic heart failure.

BACKGROUND: Estimates of glomerular filtration rate (GFR), including creatinine and creatinine based formulae, are inaccurate in extremes of GFR and substantially biased in patients with chronic heart failure (CHF). OBJECTIVE: To investigate whether serum cystatin C levels would be a better, more accurate and simple alternative for estimation of GFR and prognosis in CHF. DESIGN: Cohort study. SETTING: Chronic heart failure. PATIENTS, INTERVENTIONS AND MAIN OUTCOME MEASURE: In 102 CHF patients, the correlation between GFR as estimated by (125)I-iothalamate clearance (GFR(IOTH)), the modification of diet in renal disease formula (GFR(MDRD)) and cystatin C was investigated. The combined endpoint consisted of the first occurrence of all cause mortality, heart transplantation or admission for CHF within 24 months. RESULTS: Mean age was 58±12 years; 77% were male. Mean left ventricular ejection fraction was 28±9%. Mean GFR(IOTH) was 75±27 ml/min/1.73 m(2), while median cystatin C levels were 0.80 (0.69-1.02) mg/l. GFR(IOTH) was strongly correlated with all renal function estimates, including 1/cystatin C (r=0.867, p<0.001). GFR(IOTH) was better predicted by 1/cystatin C compared to 1/serum creatinine (z=3.12, p=0.002), but equally predicted compared to GFR(MDRD) (z=0.92, p=0.356). Serum 1/cystatin C was a strong independent predictor of prognosis (HR: 2.27 per SD increase, 95% CI 1.12 to 4.63), comparable to GFR(MDRD). CONCLUSIONS: Cystatin C is an accurate and easy estimate of renal function with prognostic properties superior to serum creatinine and similar to creatinine based formulae in patients with CHF.

Tubular damage in chronic systolic heart failure is associated with reduced survival independent of glomerular filtration rate.

BACKGROUND: The prognostic impact of reduced glomerular filtration rate (GFR) in chronic heart failure (CHF) is increasingly recognised, but little is known about tubular damage in these patients. OBJECTIVE: To investigate the prevalence of tubular damage, and its association with GFR, and prognosis in patients with CHF. METHODS AND RESULTS: In 90 patients with CHF, GFR and effective renal plasma flow (ERPF) were measured ([(125)I]iothalamate and [(131)I]hippuran clearances). The tubular markers neutrophil gelatinase-associated lipocalin (NGAL), N-acetyl-beta-D-glucosaminidase (NAG) and kidney injury molecule 1 (KIM-1) as well as urinary albumin excretion were determined in 24 h urine collections. Mean GFR was 78+/-26 ml/min/1.73 m(2). Urinary NGAL (175 (70-346) microg/g creatinine (gCr)), NAG (12 (6-17) U/gCr) and KIM-1 (277 (188-537) ng/gCr) levels were increased compared with 20 healthy controls (all p<0.001). Urinary NAG, but not NGAL or KIM-1 correlated with GFR (r=-0.34, p=0.001) and ERPF (r=-0.29, p=0.006). Both NAG (r=0.21, p=0.048) and KIM-1 (r=0.23, p=0.033) correlated with plasma N-terminal pro-brain natriuretic peptide levels. Both urinary KIM-1 (HR=1.15 (95% CI 1.02 to 1.30) per 100 ng/gCr increase, p=0.025) and NAG (HR=1.42 (95% CI 1.02 to 1.94) per 5 U/gCr increase, p=0.039), were associated with an increased risk of death or heart failure hospitalisations, independent of GFR. CONCLUSION: Tubular damage, as indicated by increased urinary concentrations of NGAL, NAG and KIM-1 is common in patients with CHF and mildly reduced GFR. Both urinary KIM-1 and NAG showed prognostic information additional to GFR. These findings suggest an important role for tubular damage and tubular markers in cardiorenal interaction in heart failure.

Prognostic value of heart rate variability and ventricular arrhythmias during 13-year follow-up in patients with mild to moderate heart failure.

BACKGROUND: In contrast to patients with moderate to severe chronic heart failure (CHF), data regarding long-term outcome in patients with mild CHF are scarce. We examined the place of Holter monitoring to study the prognostic value of ventricular arrhythmias and heart rate variability (HRV) in patients with mild to moderate CHF during long-term follow-up. METHODS: We studied 90 patients with mild to moderate CHF and NYHA class II who had been enrolled in the Dutch Ibopamine Multicenter Trial. At baseline their mean age was 60.5 +/- 8.0 years, left ventricular ejection fraction (LVEF) was 0.29 +/- 0.09, and 85% were males. At the start of the study, patients were only using diuretics, while digoxin, and particularly ACE inhibitors and beta-blockers were initiated later. Univariate and multivariate proportional hazard analyses were performed. RESULTS: At baseline 80% of patients were in NYHA class II, and 20% were in class III; their mean age was 60 years, mean LVEF was 0.29, and 85% were men. During a follow-up of 13 years, 47 patients (53%) died. Cardiovascular (CV) death occurred in 39 patients, of which 28 were sudden cardiac death (SCD). For both CV death and SCD, LVEF <30% and ventricular premature beats/h (>20) were independent risk markers. Of the HRV parameters, total power (>2,500 ms(2)) was an important risk marker for CV death, but not for SCD. CONCLUSION: The present 13-year follow-up study in 90 patients with mild to moderate CHF showed that ventricular premature beats and HRV may have important value in predicting outcome.

Differential associations between renal function and "modifiable" risk factors in patients with chronic heart failure.

BACKGROUND: Reduced glomerular filtration rate (GFR) is strongly associated with reduced survival in patients with chronic heart failure (CHF). Our aim was to determine different pathophysiologic markers that are associated with reduced renal function in CHF. METHODS AND RESULTS: We studied 86 patients with CHF (58+/-12 years, 78% male). GFR and renal blood flow (RBF) were determined by (125)I-Iothalamate and (131)I-Hippuran clearances. Filtration fraction (FF) was calculated. We determined haemoglobin levels, endothelial function, inflammatory status, plasma renin activity (PRA) and N-terminal pro brain natriuretic peptide (NT-proBNP). Urinary albumin excretion (UAE) was measured in 24 h urine. Mean GFR was 74+/-28 ml/min/1.73 m(2). GFR was strongly related to RBF (r=0.915, P<0.001), FF (r=0.546, P<0.001), but only weakly to endothelial function and PRA. In multivariate analysis, RBF (r=0.938, P < 0.001), FF (r=0.786, P < 0.001) and haemoglobin levels (r= -0.520, P<0.001) were independently associated with GFR. UAE was mainly dependent on RBF (r= -0.401, P < 0.001) and increased exponentially with decreasing RBF. RBF was mainly associated with NT-proBNP (r= -0.561, P<0.001) and PRA (r= -0.422, P<0.001). CONCLUSION: Reduced GFR is mainly dependent of decreased RBF in patients with CHF. Endothelial function and neurohormonal activation showed only mild associations with GFR. NT-proBNP showed a strong relationship with RBF, and may be used as a marker of reduced renal perfusion.