Current Role of Blood and Urine Biomarkers in the Clinical Care of Adults with Congenital Heart Disease.

PURPOSE OF REVIEW: There is an increasing number of adult patients with congenital heart disease (CHD). While several biomarkers have been validated and integrated into general cardiology clinical practice, these tests are often applied to adults with CHD in the absence of disease-specific validation. Although these patients are often grouped into a single population, there is heterogeneous pathophysiology, variable disease chronicity, extensive multisystem involvement, and a low event rate relative to acquired heart disease. These stand as challenges to systematic investigation and clinical application of biomarkers for adults with CHD. This paper reviews recent studies investigating the use of biomarkers in this population, with emphasis on biomarkers applied in clinical adult CHD care. RECENT FINDINGS: A handful of biomarkers have been integrated into adult CHD practice, such as iron studies in cyanotic heart disease and stool alpha-1 antitrypsin for diagnosis of protein losing enteropathy in the Fontan circulation. Use of kidney and liver tests has been studied in prognostication of adult CHD patients. A few other biomarkers like natriuretic peptides and troponins seem likely to provide useful information in other ACHD situations based on limited disease-specific data and extrapolation from acquired heart disease. More research is needed to support the robust validity of most existing clinical biomarkers in adult congenital cardiology practice. Until data from larger, prospectively enrolled cohorts are available, clinical use of biomarkers in these patients will require careful interpretation with attention to underlying pathophysiology, as well as detailed understanding of potential pitfalls of specific assays and clinical contexts.

Dietary salt regulates uroguanylin expression and signaling activity in the kidney, but not in the intestine.

The peptide uroguanylin (Ugn) is expressed at significant levels only in intestine and kidney, and is stored in both tissues primarily (perhaps exclusively) as intact prouroguanylin (proUgn). Intravascular infusion of either Ugn or proUgn evokes well-characterized natriuretic responses in rodents. Furthermore, Ugn knockout mice display hypertension and salt handling deficits, indicating that the Na(+) excretory mechanisms triggered when the peptides are infused into anesthetized animals are likely to operate under normal physiological conditions, and contribute to electrolyte homeostasis in conscious animals. Here, we provide strong corroborative evidence for this hypothesis, by demonstrating that UU gnV (the rate of urinary Ugn excretion) approximately doubled in conscious, unrestrained rats consuming a high-salt diet, and decreased by ~15% after salt restriction. These changes in UU gnV were not associated with altered plasma proUgn levels (shown here to be an accurate index of intestinal proUgn secretion). Furthermore, enteric Ugn mRNA levels were unaffected by salt intake, whereas renal Ugn mRNA levels increased sharply during periods of increased dietary salt consumption. Together, these data suggest that diet-evoked Ugn signals originate within the kidney, rather than the intestine, thus strengthening a growing body of evidence against a widely cited hypothesis that Ugn serves as the mediator of an entero-renal natriuretic signaling axis, while underscoring a likely intrarenal natriuretic role for the peptide. The data further suggest that intrarenal Ugn signaling is preferentially engaged when salt intake is elevated, and plays only a minor role when salt intake is restricted.

Neutrophil gelatinase-associated lipocalin as a biomarker of cardiovascular disease: a systematic review.

BACKGROUND: Neutrophil gelatinase-associated lipocalin (NGAL) is a biomarker of acute kidney injury (AKI). Recently, elevated NGAL levels have also been reported in heart failure, coronary heart disease, and stroke. Other studies demonstrate that NGAL is upregulated in failing myocardium and in atherosclerotic plaque. Our aim was to synthesize the current evidence on NGAL and cardiovascular disease (CVD), and to clarify the prognostic significance of systemic NGAL levels in CVD. METHODS: We performed a systematic review to identify experimental and human studies on NGAL and CVD. We excluded articles which specifically dealt with AKI or renal endpoints. RESULTS: We identified 22 studies, including both animal and human data. NGAL is highly expressed in the heart, both in failing myocardium and myocarditis, and is also expressed in atherosclerotic plaques. Areas of co-localization of NGAL and matrix metalloproteinase (MMP)-9 exhibited increased MMP-9 proteolytic activity. Systemic NGAL levels correlated with renal function and severity of CVD in several, but not all, studies. An association between elevated systemic NGAL levels and clinical outcomes (e.g., death, hospital readmissions) were reported in six CVD studies, but these had limited adjustment for potential confounders. CONCLUSIONS: There is ample literature to support a putative role of NGAL in the pathophysiology of CVD, but at present there is insufficient data regarding the clinical utility of systemic NGAL levels in the management of CVD. Available evidence regarding NGAL as a predictor of outcomes in CVD is very limited.

Determinación de péptido natriurético tipo B aminoterminal urinario en pacientes con insuficiencia cardiaca: ¿autopista o carretera secundaria? / Urinary Measurement of N-Terminal B Type Natriuretic Peptide in Patients With Cardiac Failure - Highway or Byway?

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Valor pronóstico comparativo del pro-péptido natriurético tipo B aminoterminal urinario en pacientes con insuficiencia cardiaca aguda descompensada / Comparative Prognostic Value of Plasma and Urinary N-Terminal Pro-B-Type Natriuretic Peptide in Patients With Acute Destabilized Heart Failure

Introducción y objetivos: Se ha sugerido que las concentraciones urinarias de la porción aminoterminal del pro-péptido natriurético tipo B (NT-proBNP) pueden tener valor pronóstico en pacientes con insuficiencia cardiaca estable, pero hasta ahora no se ha realizado una comparación directa con las concentraciones plasmáticas de este marcador en pacientes con una insuficiencia cardiaca aguda descompensada (ICAD). El objetivo de este estudio fue comparar el valor pronóstico de la concentración plasmática de NT-proBNP con el de la concentración urinaria de este marcador en la estratificación del riesgo de los pacientes con ICAD.Métodos: Se estudió prospectivamente a pacientes consecutivos hospitalizados con ICAD. A la llegada al hospital, se obtuvieron simultáneamente muestras de sangre y orina, para determinar las concentraciones de NT-proBNP. Se realizó un seguimiento clínico, y se registraron la mortalidad y la hospitalización por insuficiencia cardiaca.Resultados: Se incluyó un total de 138 pacientes (mediana de edad, 74 años [rango intercuartiles, 67-80]; 54 varones). Durante una mediana de seguimiento de 387 días [rango intercuartiles, 161-559], 65 pacientes (47%) presentaron eventos clínicos adversos. La concentración plasmática de NT-proBNP fue más alta en los pacientes que presentaron eventos clínicos adversos (4.561 pg/ml [2.191-8.631] frente a 2.906 pg/ml [1.643-5.823]; p=0,03), mientras que la concentración urinaria de NT-proBNP fue similar en ambos grupos (p=0,62). En los análisis de regresión de Cox multivariable, la concentración plasmática de NT-proBNP se asoció a un mayor riesgo de eventos clínicos adversos, tanto como variable continua (por 100 pg/ml; razón de riesgos [HR]=1,004; intervalo de confianza [IC] del 95%, 1,001-1,007; p=0,003) o categórica (≥3.345 pg/ml; HR; IC del 95%, 1,41-3,93; p=0,001). En cambio, la concentración urinaria de NT-proBNP no se asoció a una evolución clínica adversa.Conclusiones: La concentración plasmática de NT-proBNP es superior a la concentración urinaria de este marcador en la predicción de los resultados clínicos adversos en pacientes con ICAD (AU)

Introduction and objectives: Urinary concentrations of amino-terminal pro-B type natriuretic peptide (NT-proBNP) may be prognostically meaningful; however, direct comparison to plasma concentrations of this marker have not been performed in patients with acutely decompensated heart failure (ADHF). The aims of this study were to compare the prognostic value of plasma versus urinary NT-proBNP concentration for the risk stratification of patients with ADHF. Methods: Consecutive hospitalized patients with ADHF were prospectively studied. Blood and urine samples were simultaneously collected on hospital arrival to determine NT-proBNP concentrations. Clinical follow-up was obtained, and the occurrence of mortality and heart failure hospitalization was registered. Results: The study included 138 patients (median, 74 years [interquartile range, 67-80]; 54% men). During a median follow-up period of 387 days [interquartile range, 161-559], 65 patients (47%) suffered adverse clinical events. Plasma NT-proBNP concentration was higher among patients who presented adverse events (4561 pg/mL [2191-8631] vs 2906 pg/mL [1643-5823]; P=.03), whereas urinary NT-proBNP was similar in both groups (P=.62). After multivariable Cox regression analyses, plasma NT-proBNP concentration was associated with a higher risk of adverse events, whether considered continuously (per 100 pg/mL; hazard ratio [HR]=1.004; 95% confidence interval [CI], 1.001-1.007; P=.003) or categorically (≥3345 pg/mL; HR=2.35; 95% CI, 1.41-3.93; P=.001). In contrast, urinary NT-proBNP concentration was not associated with adverse outcomes. Conclusions: Plasma NT-proBNP concentration is superior to urinary NT-proBNP concentration for the prediction of adverse clinical outcomes among unselected patients with ADHF (AU)

Natriuretic and antikaliuretic effects of uroguanylin and prouroguanylin in the rat.

The peptide uroguanylin (Ugn) is stored and released as a propeptide (proUgn) by enterochromaffin cells in the intestine, and converted to Ugn and other metabolites in the renal tubules. Both proUgn and Ugn are natriuretic, although the response to proUgn is thought to depend on its conversion to Ugn within nephrons. To assess the efficiency of intrarenal conversion of proUgn to Ugn, we measured urinary Ugn excretion in rats following intravenous infusions of proUgn or Ugn. Infusion of 2 and 10 nmol proUgn/kg body wt increased plasma proUgn concentration from 2.2 ± 0.3 to 5.6 ± 1.3 pmol/ml and to 37 ± 9.6 pmol/ml, respectively. No proUgn was detected in urine before, during, or after proUgn infusions. These two proUgn infusion doses resulted in total Ugn recovery in urine of 162 ± 64 and 206 ± 39 pmol/kg body wt (9 and 2% of the infused amount, respectively). By contrast, the same molar amounts of Ugn resulted in 1,009 ± 477 and 5,352 ± 2,133 pmol/kg body wt of Ugn in urine (recoveries of ∼50%). Unexpectedly, comparisons of natriuretic dose-response curves for each peptide showed proUgn to be about five times more potent than Ugn, despite the relatively modest amount of Ugn generated from infused proUgn. In addition, both peptides were antikaliuretic at low doses, but in this case Ugn showed greater potency than proUgn. These data do not support Ugn as the primary active principle of proUgn for regulation of renal sodium excretion. Instead, an alternative peptide fragment produced from proUgn may be responsible for natriuretic activity in the kidney, whereas Ugn itself may play an antikaliuretic role.

Marcadores pronósticos en la insuficiencia cardíaca. Situación actual / Prognostic markerts in heart failure. Current status

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NT-proBNP urinario. Su valor en la caracterización de pacientes con hipertensión esencial / Urinary NT-proBNP. A valuable marker in the assessment of patients with essential hypertension

El objetivo fue evaluar el poder predictivo para diagnosticar hipertrofia del ventrículo izquierdo (HVI) de la concentración urinaria del fragmento N-terminal del propéptido natriurético tipo B (NT-proBNP) en 160 pacientes asintomáticos diagnosticados de hipertensión esencial (HT). Las concentraciones urinarias de NT-proBNP/creatinina estuvieron incrementadas en pacientes con HVI al compararlos con no hipertróficos (p < 0,0001) y controles (p < 0,0001). El análisis de regresión lineal múltiple mostró que la edad (p = 0,034), el índice de masa del ventrículo izquierdo (IMVI) (p = 0,026) y el NT-proBNP sérico (p = 0,001) predicen la concentración urinaria del péptido. El área bajo la curva de NT-proBNP/creatinina fue 0,71 ± 0,04 (p < 0,0001) para la detección de HVI, y el análisis de regresión logística mostró que NT-proBNP urinario/ creatinina predice la HVI (odds ratio = 4,074; p = 0,009). En conclusión, la concentración de NT-proBNP en orina es un nuevo marcador que puede ser de utilidad para detectar HVI en sujetos con HT esencial (AU)

The aim was to evaluate the usefulness of urinary N-terminal fragment of B-type natriuretic peptide (NT-proBNP) measurement for predicting the presence of left ventricular hypertrophy (LVH) in 160 asymptomatic patients with essential hypertension. The urinary NT-proBNP/creatinine ratio was higher in patients with LVH than in either those without LVH (P < .0001) or control subjects (P < .0001). Multivariate linear regression analysis identified age (P=.034), left ventricular mass index (P=.026) and serum NT-proBNP level (P=.001) as predictors of the urinary peptide level. The area under the curve for the NT-proBNP/creatinine ratio was 0.71±0.04 (P < .0001) for identifying LVH. Logistic regression analysis showed that the NT-proBNP: creatinine ratio was a predictor of LVH (odds ratio=4.074; P=.009). In conclusion, the urinary NT-proBNP concentration is a new marker that could be useful for identifying LVH in subjects with essential hypertension (AU)

Decrease in nocturnal urinary levels of arginine vasopressin in patients with nocturnal polyuria.

OBJECTIVES: To elucidate whether heart function and endocrine levels of arginine vasopressin (AVP) or solute diuresis is associated with the nocturnal voided volume, and whether the urinary AVP could be a parameter for screening for nocturnal polyuria caused by AVP insufficiency. METHODS: A total of 50 patients were enrolled in this study. The blood and urine samples were obtained every 6 hours at 6 pm, 12 am, 6 am, and 12 pm. Atrial natriuretic peptide and brain natriuretic peptide were measured at admission. All voided urine samples were collected every 6 hours for examination. The evaluation items were AVP, osmolarity, sodium, potassium, chloride, and creatinine in blood and urine. RESULTS: The patients were classified into a group with nocturnal polyuria (n = 21) and a group without nocturnal polyuria (n = 25). There was no significant difference in atrial natriuretic peptide, brain natriuretic peptide, electrolytes in blood and urine, and plasma AVP of each sample between the two groups, but urinary AVP/urinary creatinine and urine osmolarity at 12 am and 6 am in the group with nocturnal polyuria were significantly lower than those in the group without nocturnal polyuria. The nocturnal voided volume correlated with urinary AVP/urinary creatinine level in the urine samples obtained at 12 am and 6 am. CONCLUSIONS: The present data have demonstrated that the significant decrease in urinary AVP/urinary creatinine level at 6 am may contribute to the increased nocturnal voided volume followed by nocturia and that the circadian rhythm disorder of AVP can be predicted by a noninvasive test measuring urinary AVP/urinary creatinine in the urine voided early in the morning.

Sleep disordered breathing and nocturnal polyuria: nocturia and enuresis.

Although nocturnal voiding is frequently attributed to urologic disorders, nocturia and enuresis are also important symptoms of sleep-disordered breathing. However, polyuria can be elicited by obstructive sleep apnea as well as bedrest, microgravity and other experimental conditions where the blood volume is shifted centrally to the upper body. The nocturnal polyuria of sleep apnea is an evoked response to conditions of negative intrathoracic pressure due to inspiratory effort posed against a closed airway. The mechanism for this natriuretic response is the release of atrial natriuretic peptide due to cardiac distension caused by the negative pressure environment. This cardiac hormone increases sodium and water excretion and also inhibits other hormone systems that regulate fluid volume, vasopressin and the rennin-angiotensin-aldosterone complex. Treatment of sleep apnea and airway compromise has been shown to reverse nocturnal polyuria and thereby reduce or eliminate nocturia and enuresis. Thus, careful evaluation of nocturia and enuresis for evidence of nocturnal polyuria can increase the diagnostic certainty of referring primary care providers and sleep specialists. In addition, the resolution of these bothersome symptoms after treatment can contribute to patient satisfaction as well as reinforce treatment compliance.