Characterization of Circulating and Urinary Biomarkers in the Fontan Circulation and Their Correlation With Cardiac Imaging.

Several circulating biomarkers have been found to play a role in the surveillance and risk stratification of heart failure without congenital heart disease, but these have not been widely studied in patients with single ventricles palliated with a Fontan operation. Imaging predictors of worse outcomes in this population include ventricular dilation and dysfunction. Patients who weighed >30 kg with a Fontan circulation referred for cardiac magnetic resonance imaging were invited to participate in the study. Blood and urine samples were obtained at the time of imaging and multiple conventional and novel biomarkers were measured. A total of 82 patients with a median age of 18 years were enrolled. Among the novel biomarkers, N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity troponin T had the strongest correlation with ventricular dilation and dysfunction. NT-ProBNP >100 pg/ml has a sensitivity of 91% for the detection of significant ventricular dilation (end-diastolic volume >120 ml/body surface area1.3) and 82% for detection of ejection fraction <50%. The urinary neutrophil gelatinase-associated lipocalin-2 to creatinine ratio correlated with ejection fraction and estimated glomerular filteration rate. In conclusion, abnormalities in biomarkers of heart failure are common in ambulatory, largely asymptomatic patients with Fontan circulation. NT-ProBNP may serve as a sensitive marker for the identification of patients with significant ventricular dilation or dysfunction. Further work is needed to understand how these easily measured circulating biomarkers may be integrated into clinical care.

Urinary Peptidomic Biomarker for Personalized Prevention and Treatment of Diastolic Left Ventricular Dysfunction.

Diastolic heart failure (DHF) is characterized by slow left ventricular (LV) relaxation, increased LV stiffness, interstitial deposition of collagen, and a modified extracellular matrix proteins. Among Europeans, the frequency of asymptomatic diastolic LV dysfunction (DD) is 25%. This constitutes a large pool of people at high risk of DHF. The goal of this review was to describe the discovery and the initial validation of new multidimensional urinary peptidomic biomarkers (UPB) indicative of DD, mainly consisting of collagen fragments, and to describe a roadmap for their introduction into clinical practice. The availability of new drugs creates a window of opportunity for mounting a randomized clinical trial consolidating the clinical applicability of UPB to screen for DD. If successfully completed, such trial will benefit ≈25% of all people older than 50 years and open a large market for a UPB diagnostic tool and the drug tested. Moreover, sequenced peptides making up UPB will generate novel insights in the pathophysiology of DD and facilitate personalized treatment of patients with DHF for whom prevention came too late. If proven cost-effective, the clinical application of UPB will contribute to the sustainability of health care in aging population in epidemiologic transition.

Marinobufagenin and left ventricular mass in young adults: The African-PREDICT study.

Background The endogenous steroidal inhibitor of sodium-potassium-dependent adenosine triphosphate and natriuretic hormone, marinobufagenin, plays a physiological role in ionic homeostasis. Animal models suggest that elevated marinobufagenin adversely associates with cardiac and renal, structural and functional alterations. It remains uncertain whether marinobufagenin relates to the early stages of target organ damage development, especially in young adults without cardiovascular disease. We therefore explored whether elevated 24-hour urinary marinobufagenin excretion was related to indices of subclinical target organ damage in young healthy adults. Design This cross-sectional study included 711 participants from the African-PREDICT study (black 51%, men 42%, 24.8 ± 3.02 years). Methods We assessed cardiac geometry and function by two-dimensional echocardiography and pulse wave Doppler imaging. 24-Hour urinary marinobufagenin and sodium excretion were measured, and the estimated glomerular filtration rate determined. Results Across marinobufagenin excretion quartiles, left ventricular mass ( P < 0.001), end diastolic volume ( P < 0.001), stroke volume ( P = 0.004) and sodium excretion ( P < 0.001) were higher within the fourth compared with the first quartile. Partial regression analyses indicated that left ventricular mass ( r = 0.08, P = 0.043), end diastolic volume ( r = 0.10, P = 0.010) and stroke volume ( r = 0.09, P = 0.022) were positively related to marinobufagenin excretion. In multivariate-adjusted regression analysis, left ventricular mass associated positively with marinobufagenin excretion only in the highest marinobufagenin excretion quartile (adjusted R2 = 0.20; ß = 0.15; P = 0.043). This relationship between left ventricular mass and marinobufagenin excretion was evident in women (adjusted R2 = 0.06; ß = 0.127; P = 0.015) but not in men (adjusted R2 = 0.06; ß = 0.007; P = 0.92). Conclusions Left ventricular mass positively and independently associates with marinobufagenin excretion in young healthy adults with excessively high marinobufagenin excretion. Women may be more sensitive to the effects of marinobufagenin on early structural cardiac changes.

Relationship between intrarenal renin-angiotensin activity and re-hospitalization in patients with heart failure with reduced ejection fraction.

OBJECTIVE: Heart failure (HF) is a clinical syndrome resulting from structural or functional damages. Although clinical trials have shown that the plasma renin-angiotensin system (RAS) activation decreases HF functional status and increases hospitalization for HF patients, the effect of intrarenal RAS activity is still unknown. In this study, we investigated the relationship between the New York Heart Association (NYHA) class, duration, and number of hospitalizations in the previous year and urinary angiotensinogen (UAGT) in patients with HF with reduced ejection fraction (HFrEF). METHODS: This study included 85 patients who had an ejection fraction of <40% and were receiving optimal medical treatment. Among these, 22 were excluded from the study for various reasons. Demographically and biochemically, the remaining 63 patients were compared according to the NYHA functional classes and re-hospitalization status. RESULTS: When the groups were compared in terms of N-terminal pro-B-type natriuretic peptide (NT-proBNP), UAGT, and high-sensitivity C-reactive protein (Hs-CRP), it was found that these parameters were significantly higher in patients who were hospitalized more than two times in the previous year [p<0.001; p=0.007; p<0.001, respectively]. There was a significant correlation between number of hospitalizations and NT-proBNP (r=0.507, p<0.001), Hs-CRP (r=0.511, p<0.001), hemoglobin (r=-0.419, p=0.001), serum sodium (r=-0.26, p=0.04), and systolic blood pressure (r=-0.283, p=0.02). When the independence of multiple correlations was assessed using multiple linear regression analysis, NT-proBNP, Hs-CRP, and hemoglobin levels were independent predictors of re-hospitalization, but this was not the same for UAGT. CONCLUSION: Although UAGT levels are high in patients with poor NYHA functional class and repeated hospitalizations, this marker is not valuable for predicting repeated hospitalization in patients with HFrEF.

Novel Urinary Peptidomic Classifier Predicts Incident Heart Failure.

BACKGROUND: Detection of preclinical cardiac dysfunction and prognosis of left ventricular heart failure (HF) would allow targeted intervention, and appears to be the most promising approach in its management. Novel biomarker panels may support this approach and provide new insights into the pathophysiology. METHODS AND RESULTS: A retrospective comparison of urinary proteomic profiles generated by mass spectrometric analysis from 49 HF patients, 36 patients who progressed to HF within 2.6±1.6 years, and 192 sex- and age-matched controls who did not progress to HF enabled identification of 96 potentially HF-specific peptide biomarkers. Based on these 96 peptides, the classifier called Heart Failure Predictor (HFP) was established by support vector machine modeling. The incremental prognostic value of HFP was subsequently evaluated in urine samples from 175 individuals with asymptomatic diastolic dysfunction from an independent population cohort. Within 4.8 years, 17 of these individuals progressed to overt HF. The area under receiver-operating characteristic curve was 0.70 (95% CI, 0.56-0.82); P=0.0047 for HFP and 0.57 (0.42-0.72; P=0.62) for N-terminal pro b-type natriuretic peptide. Hazard ratios were 1.63 (CI, 1.04-2.55; P=0.032) per 1-SD increment in HFP and 0.70 (CI, 0.35-1.41; P=0.32) for a doubling of the logarithmically transformed N-terminal pro b-type natriuretic peptide. CONCLUSIONS: HFP is a novel biomarker derived from the urinary proteome and might serve as a sensitive tool to improve risk stratification, patient management, and understanding of the pathophysiology of HF.

Prognostic impact of subclinical microalbuminuria in patients with chronic heart failure.

BACKGROUND: Microalbuminuria, traditionally defined as urinary albumin/creatinine ratio (UACR) ≥30 mg/g, is a risk factor for mortality even in patients with preserved glomerular filtration rate (GFR). The prognostic impact of subclinical microalbuminuria, however, remains unknown in patients with chronic heart failure (CHF). METHODS AND RESULTS: In the Chronic Heart Failure Analysis and Registry in the Tohoku District 2 Study, we enrolled 2,039 consecutive symptomatic CHF patients (median age, 67.4 years; 68.9% male) after excluding those on hemodialysis. On classification and regression tree analysis, UACR=10.2 mg/g and 27.4 mg/g were identified as the first and second discriminating points to stratify the risk for composite of death, acute myocardial infarction, HF admission and stroke, therefore subclinical microalbuminuria was defined as UACR ≥10.2 and <27.4 mg/g. There were 506 composite endpoints (24.8%) during the median follow-up of 2.69 years. On Kaplan-Meier analysis and multivariate Cox modeling, subclinical microalbuminuria was significantly associated with increased composite endpoints with hazard ratios of 1.90 (P<0.001) and 2.29 (P<0.001) in patients with preserved (>60 ml·min(-1)·1.73 m(-2), n=1,129) or mildly reduced eGFR (30-59.9 ml·min(-1)·1.73 m(-2), n=789), respectively. In patients with severely reduced GFR (eGFR <30 ml·min(-1)·1.73 m(-2), n=121), >80% had microalbuminuria or macroalbuminuria, and only 9.1% were free from any composite endpoints. CONCLUSIONS: Subclinical microalbuminuria was associated with increased risk of cardiovascular events in CHF patients with mildly reduced or preserved renal function.

Albuminuria is independently associated with cardiac remodeling, abnormal right and left ventricular function, and worse outcomes in heart failure with preserved ejection fraction.

OBJECTIVES: The purpose of this study was to determine the relationship between albuminuria and cardiac structure/function in heart failure with preserved ejection fraction (HFpEF). BACKGROUND: Albuminuria, a marker of endothelial dysfunction, has been associated with adverse cardiovascular outcomes in HFpEF. However, the relationship between albuminuria and cardiac structure/function in HFpEF has not been well studied. METHODS: We measured urinary albumin-to-creatinine ratio (UACR) and performed comprehensive echocardiography, including tissue Doppler imaging and right ventricular (RV) evaluation, in a prospective study of 144 patients with HFpEF. Multivariable-adjusted linear regression was used to determine the association between UACR and echocardiographic parameters. Cox proportional hazards analyses were used to determine the association between UACR and outcomes. RESULTS: The mean age was 66 ± 11 years, 62% were female, and 42% were African American. Higher UACR was associated with greater left ventricular mass, lower preload-recruitable stroke work, and lower global longitudinal strain. Higher UACR was also significantly associated with RV remodeling (for each doubling of UACR, RV wall thickness was 0.9 mm higher [95% confidence interval: 0.05 to 0.14 mm; p = 0.001, adjusted p = 0.01]) and worse RV systolic function (for each doubling of UACR, RV fractional area change was 0.56% lower [95% confidence interval: 0.14 to 0.98%; p = 0.01, adjusted p = 0.03]. The association between UACR and RV parameters persisted after the exclusion of patients with macroalbuminuria (UACR >300 mg/g). Increased UACR was also independently associated with worse outcomes. CONCLUSIONS: In HFpEF, increased UACR is a prognostic marker and is associated with increased RV and left ventricular remodeling and longitudinal systolic dysfunction. (Classification of Heart Failure With Preserved Ejection Fraction; NCT01030991).

Urinary type IV collagen is related to left ventricular diastolic function and brain natriuretic peptide in hypertensive patients with prediabetes.

AIM: Urinary type IV collagen is an early biomarker of diabetic nephropathy. Concomitant prediabetes (the early stage of diabetes) was associated with left ventricular (LV) diastolic dysfunction and increased brain natriuretic peptide (BNP) in hypertensive patients. We hypothesized that urinary type IV collagen may be related to these cardiac dysfunctions. METHODS: We studied hypertensive patients with early prediabetes (HbA1c <5.7% and fasting glucose >110, n=18), those with prediabetes (HbA1c 5.7-6.4, n=98), and those with diabetes (HbA1c>6.5 or on diabetes medications, n=92). The participants underwent echocardiography to assess left atrial volume/body surface area (BSA) and the ratio of early mitral flow velocity to mitral annular velocity (E/e'). Left ventricular diastolic dysfunction (LVDD) was defined if patients had E/e'≥15, or E/e'=9-14 accompanied by left atrial volume/BSA≥32ml/mm(2). Urinary samples were collected for type IV collagen and albumin, and blood samples were taken for BNP and HbA1c. RESULTS: Urinary type IV collagen and albumin increased in parallel with the deterioration of glycemic status. In hypertensive patients with prediabetes, subjects with LVDD had higher levels of BNP and urinary type IV collagen than those without LVDD. In contrast, in hypertensive patients with diabetes, subjects with LVDD had higher urinary albumin and BNP than those without LVDD. Urinary type IV collagen correlated positively with BNP in hypertensive patients with prediabetes, whereas it correlated with HbA1c in those with diabetes. CONCLUSIONS: In hypertensive patients with prediabetes, urinary type IV collagen was associated with LV diastolic dysfunction and BNP.

Left ventricular diastolic function in relation to the urinary proteome: a proof-of-concept study in a general population.

BACKGROUND: In previous studies, we identified two urinary proteomic classifiers, termed HF1 and HF2, which discriminated subclinical diastolic left ventricular (LV) dysfunction from normal. HF1 and HF2 combine information from 85 and 671 urinary peptides, mainly up- or down-regulated collagen fragments. We sought to validate these classifiers in a population study. METHODS: In 745 people randomly recruited from a Flemish population (49.8 years; 51.3% women), we measured early and late diastolic peak velocities of mitral inflow (E and A) and mitral annular velocities (e' and a') by conventional and tissue Doppler echocardiography, and the urinary proteome by capillary electrophoresis coupled with mass spectrometry. RESULTS: In the analyses adjusted for sex, age, body mass index, blood pressure, heart rate, LV mass index and intake of medications, we expressed effect sizes per 1-SD increment in the classifiers. HF1 was associated with 0.204 cm/s lower e' peak velocity (95% confidence interval, 0.057-0.351; p=0.007) and 0.145 higher E/e' ratio (0.023-0.268; p=0.020), while HF2 was associated with a 0.174 higher E/e' ratio (0.046-0.302; p=0.008). According to published definitions, 67 (9.0%) participants had impaired LV relaxation and 96 (12.9%) had elevated LV filling pressure. The odds of impaired relaxation associated with HF1 was 1.38 (1.01-1.88; p=0.043) and that of increased LV filling pressure associated with HF2 was 1.38 (1.00-1.90; p=0.052). CONCLUSIONS: In a general population, the urinary proteome correlated with diastolic LV dysfunction, proving its utility for early diagnosis of this condition.

Association between urine aldosterone and diastolic function in patients with primary aldosteronism and essential hypertension.

OBJECTIVE: To investigate the association between aldosterone and cardiac diastolic dysfunction. DESIGN AND METHODS: We prospectively enrolled 20 patients with primary aldosteronism (PA) and 22 patients with essential hypertension (EH). Plasma aldosterone concentration, plasma renin activity, and 24-h urine aldosterone level were measured. Echocardiography, including tissue Doppler image recordings, was performed. RESULTS: PA patients had a significantly higher left ventricular (LV) mass index and worse LV diastolic function than those in EH patients. Among various measures of aldosterone, log-transformed 24-h urine aldosterone level had the most consistent correlation with diastolic function. CONCLUSIONS: Aldosterone is strongly associated with LV diastolic dysfunction. Twenty-four hour urine aldosterone is a good indicator to evaluate the impact of aldosterone on LV diastolic function.

Accelerated renal fibrosis in cardiorenal syndrome is associated with long-term increase in urine neutrophil gelatinase-associated lipocalin levels.

BACKGROUND: Cardiac events are the main cause of death among patients with end-stage renal failure. Even a mild renal disease is currently considered a major risk factor for cardiovascular complications following myocardial infarction (MI). The aim of the present study was to detect histological, sera and urine characteristics of kidney injury in cardiorenal syndrome (CRS) compared to chronic kidney disease (CKD) with an intact cardiac function. METHODS: We employed a rat model for CRS, in which an acute MI (AMI) was induced 4 weeks after establishment of subtotal nephrectomy. Four weeks later, left ventricular function was assessed by echocardiography and changes in renal performance were examined using histological and biochemical parameters. RESULTS: Increased interstitial fibrosis as well as renal inflammation were observed in renal sections derived from CRS rats, compared to subtotal nephrectomy (CKD)-only animals. Moreover, we found that even though AMI on the background of CKD was not associated with a further decrease in creatinine clearance or a further increase in sera BUN levels compared to CKD only, a significant long-term elevation in urine neutrophil gelatinase-associated lipocalin (Ngal) levels was detectable post-MI induction. CONCLUSIONS: AMI in the CKD setting is associated with accelerated renal fibrosis and long-term elevated urine Ngal values, suggesting that cardiac dysfunction contributes to accelerated intrinsic kidney injury in CKD. The data indicate that elevated urine Ngal may potentially serve as an early non-invasive laboratory parameter for a left ventricular dysfunction-related renal injury.

Adrenergic myocarditis in pheochromocytoma.

The clinical presentation of pheochromocytoma is variable and many biochemical and imaging methods have been suggested to improve the diagnostic accuracy of what has been termed "the great masquerader". This case-report is of a middle-aged woman with a non-specific clinical presentation suggesting acute coronary syndrome or subacute myocarditis. Cardiovascular magnetic resonance (CMR) at presentation showed myocardial edema and intramyocardial late gadolinium enhancement (LGE). An adrenal mass was seen, which was confirmed as pheochromocytoma and surgically removed. Our case shows evidence for acute adrenergic myocarditis, with resolution of both the edema and the LGE after surgical excision.

N-terminal pro-brain natriuretic peptide from fresh urine for the biochemical detection of heart failure and left ventricular dysfunction.

AIMS: Plasma N-terminal pro-brain natriuretic peptide (NT-proBNP) is a strong biochemical marker of heart failure and left ventricular dysfunction (LVD). Due to renal arterio-venous clearance of NT-proBNP and the correlation of plasma concentrations with renal function, we hypothesized that NT-proBNP may have potential as a urinary marker. The objective of this study was to assess urinary concentrations of NT-proBNP and to identify the predictive value of urinary NT-proBNP for detecting LVD and heart failure. METHODS AND RESULTS: N-terminal pro-brain natriuretic peptide (Elecsys proBNP((R)), Roche) was assessed simultaneously in fresh spot urine and plasma from 191 individuals. In patients with heart failure (n = 149), urinary and plasma NT-proBNP concentrations were positively correlated (r = 0.79, P < 0.001), but urinary NT-proBNP was significantly lower than plasma NT-proBNP (42 +/- 25 vs. 1389 +/- 325 pg/mL, P < 0.001). Upon receiver operating curve analysis, urinary NT-proBNP detected LV dysfunction (ejection fraction <40%) with a sensitivity of 91% and a specificity of 98% at a cutpoint of 22 pg/mL [area under the curves (AUC) 0.98]. At the same cutpoint, symptomatic heart failure (NYHA-class > 2) was detected with a sensitivity of 97% and specificity of 98% (AUC 0.99) and clinical signs of fluid retention were detected with a sensitivity and specificity of 98% each (AUC 0.99). CONCLUSION: N-terminal pro-brain natriuretic peptide concentrations were markedly lower in the urine than in the plasma. However, urinary NT-proBNP levels increased stepwise with the severity of heart failure and LVD, and therefore yielded satisfactory predictive values for the detection of significant LVD and symptomatic heart failure. Measurement of urinary NT-proBNP is a novel, promising, and simple method for the biochemical detection of heart failure.

Correlation between increased urinary sodium excretion and decreased left ventricular diastolic function in patients with type 2 diabetes mellitus.

BACKGROUND: Increased salt intake may induce hypertension, lead to cardiac hypertrophy, and exacerbate heart failure. When elderly patients develop heart failure, diastolic dysfunction is often observed, although the ejection fraction has decreased. Diabetes mellitus (DM) is an established risk factor for heart failure. However, little is known about the relationship between cardiac function and urinary sodium excretion (U-Na) in patients with DM. METHODS: We measured 24-hour U-Na; cardiac function was evaluated directly during coronary catheterization in type 2 DM (n = 46) or non-DM (n = 55) patients with preserved cardiac systolic function (ejection fraction > or = 60%). Cardiac diastolic and systolic function was evaluated as - dp/dt and + dp/dt, respectively. RESULTS: The average of U-Na was 166.6 +/- 61.2 mEq/24 hour (mean +/- SD). In all patients, stepwise multivariate regression analysis revealed that - dp/dt had a negative correlation with serum B-type natriuretic peptide (BNP; beta = - 0.23, P = .021) and U-Na (beta = - 0.24, P = .013). On the other hand, + dp/dt negatively correlated with BNP (beta = - 0.30, P < .001), but did not relate to U-Na. In the DM-patients, stepwise multivariate regression analysis showed that - dp/dt still had a negative correlation with U-Na (beta = - 0.33, P = .025). CONCLUSION: The results indicated that increased urinary sodium excretion is associated with an impairment of cardiac diastolic function, especially in patients with DM, suggesting that a reduction of salt intake may improve cardiac diastolic function.

Mineralocorticoid escape by the kidney but not the heart in experimental asymptomatic left ventricular dysfunction.

Unlike healthy subjects, overt congestive heart failure cannot "escape" the sodium- and water-retaining actions of mineralocorticoid excess. It is undefined whether escape occurs in asymptomatic left ventricular dysfunction (ALVD), which is characterized by preserved sodium homeostasis, natriuretic peptide activation, and normal circulating aldosterone. We hypothesized that, in ALVD, mineralocorticoid excess with exogenous deoxycorticosterone acetate (DOCA) would overwhelm renal compensatory mechanisms, resulting in sodium and water retention, and promote renal and cardiac collagen deposition. ALVD was induced in 2 groups (N=5 each) of dogs by tachypacing at 180 bpm. Urine was collected daily and blood drawn at baseline and days 2, 5, 8, and 11. One group served as control (ALVD), and the other received DOCA (ALVD+DOCA) starting at day 2 of pacing. Urine flow and sodium excretion were unchanged in the ALVD group. In ALVD+DOCA, urine flow and sodium excretion decreased on the first 2 days DOCA was given but normalized starting day 4. Urine flow and urinary cGMP excretion increased in ALVD+DOCA after DOCA escape. Plasma atrial natriuretic peptide, B-type natriuretic peptide, and cGMP increased equally in both groups. There were no differences in cardiorenal and hemodynamic parameters in an acute study on day 11. Although renal collagen area fraction was similar, left ventricular collagen area fraction in ALVD+DOCA was significantly higher than in ALVD (3.3+/-0.4% versus 2.0+/-0.2%; P=0.012). We conclude that ALVD can escape the sodium- and water-retaining effects of mineralocorticoid excess. Despite renal escape, increased left ventricular collagen deposition suggests that the heart but not the kidney failed to escape the tissue effects of DOCA.

N-terminal pro-brain natriuretic peptide (NT-proBNP) in Type 2 diabetes with left ventricular dysfunction.

Plasma N-terminal proBNP (NT-proBNP) is released in response to pressure overload, intravascular volume expansion and myocardial ischemia from cardiac ventricles. We studied the relationship between NT-proBNP levels and left ventricular dysfunction and urinary albumin excretion in Type 2 diabetes. The study group consisted of 130 diabetic patients referred for echocardiography. They were divided into four groups according to echocardiographic finding and into three groups according to urinary albumin excretion. NT-proBNP levels were measured by electrochemiluminescence. There were significant differences in NT-proBNP levels among four groups (P=0.012), with a highly significant difference between normal and other groups with left ventricular dysfunction. NT-proBNP levels in diastolic dysfunction were significantly higher than normal group (1491.1 pg/mL versus 232.3 pg/mL, P=0.01), even though there was no difference in ejection fraction (EF) (61.2+/-7.9% versus 60+/-8.4%, P=0.773). NT-proBNP levels showed positive correlation with age (Rs=0.37, P<0.001), creatinine (Rs=0.38, P=0.001), LVIDS (Rs=0.56, P=0.001) and LVIDD (Rs=0.34, P=0.04) and negative correlation with EF (Rs=-0.66, P=0.001). NT-proBNP levels significantly differed among three groups according to urinary albumin excretion (P=0.031). These results suggest that NT-proBNP could be used to identify any impairment of left ventricular function in diabetes.

Diagnostic and prognostic value of urine NT-proBNP levels in heart failure patients.

BACKGROUND: Plasma NT-proBNP levels are sensitive markers of ventricular dysfunction. However, studies of natriuretic peptides in urine are limited. AIMS: To compare urine and plasma NT-proBNP levels and to investigate the diagnostic and prognostic value of urine levels in heart failure (HF). METHODS: Urinary and plasma NT-proBNP levels were measured in 96 HF patients and 20 control subjects. The patients were functionally classified according to the NYHA criteria. RESULTS: Urine NT-proBNP was higher in HF patients than in control subjects (94+/-31 pg/ml vs. 67+/-6 pg/ml, p<0.0001), correlating with plasma NT-proBNP levels (r=0.78, p<0.0001). Urinary levels were elevated in the more severe functional classes and diminished in obese patients. Urine NT-proBNP was a good tool for diagnosis of HF, the area under the curve (AUC) being 0.96+/-0.02 (p<0.0001), and for predicting 12-month cardiac events (p=0.011). To determine the prognostic power of urinary NT-proBNP in detecting 12-month cardiac mortality, we obtained an AUC of 0.75+/-0.10 (p=0.015). CONCLUSION: Urinary NT-proBNP, a relatively simple non-invasive test, is a new candidate marker for the diagnosis and evaluation of prognosis in HF and for the characterization of functional status in these patients.

Microalbuminuria as a marker of cardiac damage in essential hypertension.

A subclinical elevation in urinary albumin excretion (UAE) microalbuminuria is frequently seen in essential hypertension. The level of blood pressure appears to be an important factor in the development of microalbuminuria. Moreover there is some evidence to indicate that microalbuminuria may be an early marker of increased cardiovascular risk. Aim of this study was to evaluate the prevalence of UAE in hypertensives with normal left ventricular mass and to study any association with blood pressure level and with possible modification in left ventricular function. A group of 112 subjects diagnosed as having stage 1-2 essential hypertension were included in the study. Patients underwent urinary collection to evaluate UAE and to 24/hours arterial blood pressure monitoring. Moreover a complete echocardiography was performed. According with UAE levels patients were divided into three groups: A: UAE 0-15 mg/24 h, B: UAE 16-29 mg/24 h, C: UAE 30-300 mg/24 h. We found a significant correlation between 24/h SBP, 24/h DBP and UAE. We observed a significant correlation between impaired diastolic function and UAE. UAE is influenced by BP levels with better correlation with 24/h systolic values. UAE is associated with subclinical decrease of left ventricular function and may be an early marker of cardiac involvement.

Plasma carnitine levels as a marker of impaired left ventricular functions.

L-Carnitine plays a role in the utilization of fatty acids and glucose in the myocardium. Previous studies have indicated carnitine deficiency in patients with congestive heart failure. However, the extent of altered carnitine metabolism and left ventricular function is not fully determined. This study is designed to determine if plasma L-carnitine levels can serve as a marker for impaired left ventricular function in patients with congestive heart failure. To test this hypothesis, plasma and urinary levels of L-carnitine were measured in 30 patients with congestive heart failure (CHF) and in 10 control subjects. CHF was due to dilated cardiomyopathy (DCM) and rheumatic heart disease (RHD). Cardiac functions such as percentage of fractional shortening (%FS), ejection fraction (EF), left ventricular mass index (LVMI), were determined by echocardiography. All patients and control subjects had normal renal functions. Plasma carnitine was significantly higher in patients with DCM (37.05+/-7.62, p < 0.0001) and with RHD (47.2+/-8.04, p < 0.0001) vs. the control subjects (14.4+/-5.30 mg/L). Urinary carnitine was significantly higher in DCM (49.13+/-14.11, p < 0.0001) and in RHD 43.53+/-15.5, p < 0.0001), than the control (25.1+/-5.78 mg/L). Plasma carnitine level correlated significantly with impaired left ventricular systolic functions in these patients: % FS < 25 % (r = -0.38 and p = 0.038), EF < 0.55 (r = -0.502 and p = 0.005) and LMVI > 124 gm/m2 (r = 0.436, and p = 0.016). These data suggest that elevated plasma and urinary carnitine levels in patients with CHF could serve as a marker for myocardial damage and impaired left ventricular functions.

Enalapril prevents clinical proteinuria in diabetic patients with low ejection fraction.

OBJECTIVE: Clinical proteinuria is a risk factor for both end-stage renal disease and cardiovascular disease. The prevalence of clinical proteinuria, its correlates and predictive value, and the effect of ACE inhibitors in preventing clinical proteinuria in diabetic and nondiabetic patients with left ventricular (LV) dysfunction are unknown. RESEARCH DESIGN AND METHODS: The Studies of Left Ventricular Dysfunction (SOLVD) trials were analyzed to determine the baseline distribution of clinical proteinuria and related cardiovascular risk factors, the effect of baseline proteinuria on the risk of hospitalization for congestive heart failure (CHF) and mortality, and the effect of enalapril in preventing new clinical proteinuria. RESULTS: A total of 5,487 out of 6,797 SOLVD participants (81%) were assessed for proteinuria at baseline. A total of 177 patients (3.2%) had baseline proteinuria. These patients had significantly higher systolic (137 vs. 125 mmHg, P < or = 0.001) and diastolic (83 vs. 77 mmHg, P < or = 0.001) blood pressure levels, a higher prevalence of diabetes (41 vs. 18%, P < or = 0.001), a lower ejection fraction (26.2 vs. 27.3%, P < or = 0.05), and greater degree of CHF (New York Heart Association [NYHA] class III/IV in 22 vs. 10%, P < or = 0.001) than patients without baseline proteinuria. Patients with baseline proteinuria also had higher rates of hospitalization for CHF (relative risk 1.81 [95% CI 1.37-2.41], P = 0.0001) and mortality (1.73 [1.34-2.24], P = 0.0001). Enalapril prevented clinical proteinuria in diabetic patients (0.38 [0.17-0.81], P = 0.0123) but not in nondiabetic patients (1.43 [0.77-2.63], P = 0.2622) without baseline proteinuria. CONCLUSIONS: Clinical proteinuria is an independent predictor of hospitalization for CHF and mortality in diabetic and nondiabetic patients with LV dysfunction. Enalapril significantly reduces the risk of clinical proteinuria in diabetic patients with LV dysfunction.