Creatinine excretion rate, a marker of muscle mass, is related to clinical outcome in patients with chronic systolic heart failure.

AIMS: In chronic heart failure (CHF), low body mass as a reflection of low muscle mass has been associated with poor outcome. Urinary creatinine excretion rate (CER) is an established marker of muscle mass, but has not been investigated in CHF. This study aims to evaluate urinary CER as a marker of muscle mass in patients with CHF and establish the relationship with clinical outcome. METHODS AND RESULTS: In 120 patients with CHF, we evaluated CER as determined by mean creatinine excretion rate in two consecutive 24-h urine collections. We evaluated the relationship between CER and clinical variables using linear regression. Finally, we evaluated the association between CER and clinical outcome. Mean age was 59 ± 12 years, and 80% were male. Mean CER was 1,383 mg/day (range 412-2,930). Independent predictors of CER were body surface area (BSA) (ß = 0.404, P < 0.001), gender (ß = -0.180, P = 0.029), log N terminal pro-brain natriuretic peptide (NTproBNP) (ß = -0.172, P = 0.048) and age (ß = -0.168, P = 0.035). During three years of follow-up, 33 patients (28%) developed a clinical endpoint, defined as the first occurrence of either all-cause death, heart transplantation, myocardial infarction, or hospitalization for heart failure during three years of follow-up. In Cox regression analyses, log CER was associated with the occurrence of the clinical endpoint independent of age, gender, BSA, glomerular filtration rate and urinary albumin excretion, [hazard ratio 7.67 (1.82-32.3) per log decrease], but not independent of NTproBNP [hazard ratio 3.66 (0.79-17.0), P = 0.098]. CONCLUSIONS: Low urinary CER is associated with smaller body dimensions and more severe heart failure and is associated with an increased risk of adverse outcome.

Usefulness of elevated urine neopterin levels in assessing cardiac dysfunction and exercise ventilation inefficiency in patients with chronic systolic heart failure.

Neopterin is synthesized by macrophages upon stimulation with gamma-interferon, and high neopterin production is associated with cellular immune activation and increased production of reactive oxygen species (oxidant stress), but the clinical utility of urine neopterin levels in patients with heart failure (HF) has not been explored. Fifty-three ambulatory patients with chronic systolic HF (left ventricular [LV] ejection fraction ≤40%) underwent comprehensive echocardiographic evaluation and cardiopulmonary exercise testing. Urine neopterin levels were quantified by liquid chromatography with tandem mass spectrometric analyses and corrected to urine creatinine (Cr) levels. In our study cohort, median urine neopterin level was 60 µmol/mol Cr (interquartile range 40 to 86). There were modest correlations between urine neopterin levels and abnormalities in cardiac structure and function by echocardiography: LV ejection fraction (r = -0.33, p = 0.017), indexed LV end-diastolic volume (r = 0.31, p = 0.029), indexed LV end-systolic volume (r = 0.32, p = 0.024), and E/septal Ea (r = 0.28, p = 0.041). Although there was no significant correlation between urine neopterin and maximal oxygen uptake (peak VO2: r = -0.25, p = 0.07), there was a modest correlation between urine neopterin and maximal ventilation/carbon dioxide production ratio (VE/VCO2 max: r = 0.38, p = 0.005). In conclusion, increase in urine neopterin levels tracks with disease severity in patients with chronic systolic HF.

Urinary 8-hydroxy-2'-deoxyguanosine as a novel biomarker for predicting cardiac events and evaluating the effectiveness of carvedilol treatment in patients with chronic systolic heart failure.

BACKGROUND: The authors recently reported that urinary 8-hydroxy-2'-deoxyguanosine (U8-OHdG) derived from cardiac tissue reflects clinical status and cardiac dysfunction severity in patients with chronic heart failure (CHF). The aim of the present study was to investigate whether U8-OHdG levels can accurately predict cardiac events in CHF patients and their response to ß-blocker treatment. METHODS AND RESULTS: Plasma brain natriuretic peptide (BNP) and U8-OHdG levels were measured in 186 consecutive CHF patients before discharge. Patients were then prospectively followed (median follow-up, 649 days) with endpoints of cardiac death or hospitalization due to progressive heart failure. From receiver operating characteristic curve analysis, cut-offs were 12.4ng/mg creatinine (Cr) for U8-OHdG and 207pg/ml for BNP. On multivariate Cox analysis, U8-OHdG and BNP were independent predictors of cardiac events. Patients were classified into 4 groups according to U8-OHdG and BNP cut-offs. The hazard ratio for cardiac events in patients with BNP ≥207pg/ml and U8-OHdG ≥12.4ng/mg Cr was 16.2 compared with approximately 4 for patients with only 1 indicator above its respective cut-off. Furthermore, carvedilol therapy was initiated in 30 CHF patients. In responders (≥10% increase in left ventricular ejection fraction [LVEF] or ≥1 class decrease in New York Heart Association [NYHA] class), U8-OHdG levels decreased significantly along with improved NYHA class, LVEF, and BNP levels after treatment. CONCLUSIONS: U8-OHdG may be a useful biomarker for predicting cardiac events and evaluating ß-blocker therapy effectiveness in CHF patients.

Impaired natriuretic and renal endocrine response to acute volume expansion in pre-clinical systolic and diastolic dysfunction.

OBJECTIVES: We hypothesized an impaired renal endocrine and natriuretic response to volume expansion (VE) in humans with pre-clinical systolic dysfunction (PSD) and pre-clinical diastolic dysfunction (PDD). We further hypothesized that exogenous B-type natriuretic peptide (BNP) could rescue an impaired natriuretic response in PSD and PDD. BACKGROUND: Recent reports suggest that in early systolic heart failure (HF), there is an impaired natriuretic response to acute VE. METHODS: PSD was defined as left ventricular ejection fraction <40% without HF symptoms. PDD was defined as ejection fraction >50%, moderate to severe diastolic dysfunction by Doppler criteria, and no HF symptoms. A double-blinded, placebo-controlled, crossover study was employed to determine the renal response to VE (0.25 ml/kg/min of normal saline for 60 min) in the presence and absence of exogenous BNP. Twenty healthy control subjects, 20 PSD subjects, and 18 PDD subjects participated. RESULTS: In healthy control subjects, urinary cyclic guanosine monophosphate (cGMP) and natriuresis increased after VE. In contrast, among PSD and PDD subjects, there was a paradoxical decrease in urinary cGMP and attenuated natriuresis. Pre-treatment with subcutaneous BNP resulted in similar increases in both urinary cGMP and natriuresis among healthy normal, PSD, and PDD subjects. CONCLUSIONS: In PSD and PDD, there is impaired renal cGMP activation, which contributes to impaired natriuresis in response to VE. Impaired activation of urinary cGMP and reduced natriuresis may contribute to volume overload and the progression of HF among PSD and PDD subjects. Importantly, the impaired renal excretory response to VE is rescued by exogenous BNP in PSD and PDD.

¹H nuclear magnetic resonance based metabolic urinary profiling of patients with ischemic heart failure.

OBJECTIVES: We sought to identify metabolic pathways characterizing human heart failure (HF) using ¹NMR based urinary metabolomic analysis in conjunction with multivariate statistics. DESIGN AND METHODS: Patients with systolic HF of ischemic origin (n=15) and healthy controls (n=20) participated in this study. Patients with type 2 diabetes mellitus were excluded. RESULTS: The results showed that the urine of the HF patients had higher levels of metabolites for acetate (p<0.05) and acetone (p<0.01) compared to the healthy controls. In addition, there was a perturbation in methylmalonate metabolism as shown by increased urinary levels of methylmalonic acid (p<0.001) in the HF patients. HF patients also had increased urinary levels of cytosine (p<0.01) and phenylacetylglycine (p<0.01) and decreased 1-methylnicotinamide (p<0.05) compared to healthy controls. CONCLUSIONS: TCA cycle metabolites and fatty acid metabolism were modified in the HF patients, indicating altered energy metabolism. Moreover, perturbations of metabolism in nucleotide and methylmalonate were observed.

Urinary 8-hydroxy-2'-deoxyguanosine reflects symptomatic status and severity of systolic dysfunction in patients with chronic heart failure.

AIMS: Oxidative stress is known to play a crucial role in the pathogenesis of heart failure (HF). We investigated whether urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG), a product of oxidative DNA damage, is a clinically useful biomarker of the severity of chronic heart failure (CHF) and oxidative stress levels in failing hearts. METHODS AND RESULTS: We measured 8-OHdG in the serum obtained from the coronary sinus (CS) and aortic root (Ao) in small groups of control subjects and CHF patients. We then measured urinary 8-OHdG and other biomarkers (brain natriuretic peptide, 8-isoplastane, high-sensitivity C-reactive protein, interleukin-6, and tumour necrosis factor-α) in 31 control subjects and 194 patients with CHF [left-ventricular ejection fraction (LVEF): 28.3 ± 8.1%]. Serum 8-OHdG was significantly higher in the CS than the Ao in CHF patients only. Urinary 8-OHdG was also significantly higher in CHF patients than in control subjects, and urinary 8-OHdG became higher as New York Heart Association class increased. Moreover, there was a significant correlation between urinary 8-OHdG and LVEF (r = -0.27), pulmonary capillary wedge pressure (r = 0.31), or left-ventricular end-diastolic volume index (r = 0.22). In contrast, there was poor correlation between the severity of CHF and the other neurohumoral biomarkers. CONCLUSION: In HF, urinary 8-OHdG seems to reflect the level of oxidative stress and various parameters related to symptomatic status and functional severity of CHF.

[Medical management of chronic systolic heart failure]. / Traitement médicamenteux de l'insuffisance cardiaque systolique chronique.

Medical management of systolic heart failure is standardized and based on international guidelines. They promote the use of combination therapy based on neurohormonal blockade targeting both the renin-angiotensin system (with ACE inhibitors or ARB) and sympathetic nervous system (i.e., beta blockers). Drugs have to be titrated at the maximum tolerated level. In symptomatic patients, loop diuretics remain the treatment of choice with dosage adaptation according to symptoms and fluid management. Aldosterone antagonists are indicated in patients with severe heart failure (i.e., NYHA class 3 or 4) and creatinine clearance above 30 ml/min. Their combination with RAS blockers warrants strict biological follow up.

Niveles urinarios de péptido natriurético tipo B (BNP) y disfunción ventricular sistólica en pacientes con insuficiencia cardiaca / Urinary levels of B-type natriuretic peptide (BNP) and ventricular systolic dysfunction in heart failure patients

Introducción. Comparar niveles de péptido urinario tipo B (BNP) en orina según la presenciade disfunción sistólica ventricular izquierda e investigar su valor diagnóstico enpacientes con insuficiencia cardiaca (IC).Material y métodos. Hemos estudiado a 90 pacientes ambulatorios con IC (61 hombres,edad 66 ± 12) y 30 sujetos control apareados por edad y género.Resultados. Se encontró un aumento en los niveles urinarios de BNP en los pacientes con fracciónde eyección (FE) <= 40% comparados con los de FE > 40% (p < 0,0001) y con los controles(p < 0,0001). Se obtuvieron correlaciones signifi cativas entre los niveles urinarios de BNP ylos parámetros funcionales del ventrículo izquierdo. Se realizó un análisis multivariado y elmejor modelo asociado con los niveles urinarios de BNP incluyó a los niveles de BNP en plasma(p < 0,0001), FE (p = 0,02) y volúmenes del ventrículo izquierdo (p < 0,0001). La curvaROC para la detección de FE <= 40% usando BNP urinario mostró un área bajo la curva de0,74 ± 0,05, (p < 0,0001). A partir de la curva ROC, el punto óptimo de corte (2,30 pg/ml)tuvo una sensibilidad del 60% y una especifi cidad del 90%. Finalmente, se realizó unaregresión binaria logística para la detección de FE <= 40%, y los niveles urinarios de BNPmostraron un buen valor predictivo con una odds-ratio de 21.Discusión. Los niveles urinarios de BNP se correlacionan con los parámetros funcionalesdel ventrículo izquierdo, demostrando que este marcador biológico es útil para el diagnósticode la disfunción ventricular izquierda en pacientes con insufi ciencia cardiaca(AU)

Background. It was aimed to compare urine B-type natriuretic peptide (BNP) according toleft ventricular systolic dysfunction and to investigate its diagnostic value in heart failure(HF) patients.Material and methods. A total of 90 HF outpatients (61 men, age 66 ± 12) and 30 age- andgender-matched controls were studied.Results. An increase in urine BNP was observed in patients with EF<= 40% compared toEF> 40% (p < 0.0001), and controls (p < 0.0001). Signifi cant correlations between urinaryBNP and left ventricular functional parameters were obtained. A multivariate regressionanalysis was performed and the best model associated with urine BNP included plasmaBNP (p < 0.0001), EF (p = 0.02) and LV volume indexes (p < 0.0001). The ROC fordetection of EF <= 40% using urine BNP levels showed an area under the curve of 0.74 ±0.05, (p < 0.0001). From the ROC curve, the optimal cut-off value (2.30 ng/l) had a 60%sensitivity and 90% specifi city. Finally, we performed a binary logistic regression fordetection of EF <= 40%, and urine BNP was shown to be a strong predictor with an oddsratioof 21.Discussion. Urine BNP levels correlated with left ventricular functional parameters. Thisbiomarker is a useful tool for detecting and diagnosing left ventricular systolic dysfunctionin heart failure(AU)

Microalbuminuria in systolic and diastolic chronic heart failure patients.

BACKGROUND: Microalbuminuria is considered a major risk factor predisposing to cardiovascular morbidity and mortality. Microalbuminuria levels in patients with or without diabetes have been associated with a higher risk of chronic heart failure (HF). However, there are limited data regarding prevalence of microalbuminuria in chronic heart failure and its prognostic value. The aim of this study was to assess the occurrence of microalbuminuria in chronic heart failure patients as well as its association with clinical, echocardiographic, and body composition markers. METHODS: In a cross-sectional study, we included 72 chronic heart failure patients (NYHA I-III) on standard HF therapy. All patients had an echocardiogram and body composition by vector bioelectric impedance analysis (measured by Body Stat Quad Scan). RESULTS: The studied population consisted of 64% men at mean age of 62.6 +/- 15.1 years. Patients were divided into systolic and diastolic HF groups. Microalbuminuria was observed in 40% of diastolic and 24% systolic HF patients (p = 0.04). Microalbuminuria was present in more patients with volume overload (80 vs. 21.9%, p = 0.002), with a worse phase angle and lower serum albumin (4.7 vs. 5.9 degrees and 3.5 vs. 4.0 mg/dl, p = 0.02) and higher pulmonary arterial pressure compared with patients without microalbuminuria in systolic HF patients. There was no significant association between frequency of microalbuminuria and ejection fraction. In the diastolic HF group, the presence of microalbuminuria was not associated with any known risk factor. CONCLUSIONS: Microalbuminuria was more frequent in diastolic than systolic HF patients. In systolic HF patients microalbuminuria was associated with factors known to be markers of worse prognosis.