Diagnosis of heart failure using urinary natriuretic peptides

In the present study, we assessed the use of urinary natriuretic peptides [N-terminal proatrial natriuretic peptide (N-ANP) and N-terminal pro-brain natriuretic peptide (N-BNP) and C-type natriuretic peptide (CNP)] in the diagnosis of heart failure. Thirty-four consecutive hospitalized heart failure patients (median age, 75.5 years; 14 female) were compared with 82 age- and gender-matched echocardiographically normal controls. All subjects provided plasma and urine specimens. Plasma was assayed for N-BNP, and urine was assayed for N-ANP, N-BNP and CNP. The diagnostic efficiency of peptides was assessed using receiver operating characteristic (ROC) curve analysis. All three urinary natriuretic peptides were significantly elevated in heart failure patients ( P <0.001). Urine N-BNP was correlated with plasma N-BNP ( r (s)=0.53, P <0.0005). Areas under the ROC curves for urinary N-ANP, N-BNP and CNP were 0.86, 0.93 and 0.70 and for plasma N-BNP was 0.96. Correcting urinary peptide levels using urine creatinine produced ROC areas of 0.89, 0.93 and 0.76 respectively. A urine N-BNP level cut-off point of 11.6 fmol/ml had a sensitivity and specificity for heart failure detection of 97% and 78% respectively, with positive and negative predictive values of 64.7 and 98%. In conclusion, although all three natriuretic peptides were elevated in urine in heart failure, urinary N-BNP had diagnostic accuracy comparable with plasma N-BNP. Use of urinary N-BNP for heart failure diagnosis may be suitable for high-throughput screening, especially in subjects reluctant to provide blood samples.     

N-terminal pro-atrial natriuretic peptide (N-ANP) and N-terminal pro-B-type natriuretic peptide (N-BNP) in the prediction of death and heart failure in unselected patients following acute myocardial infarction

Elevated plasma natriuretic peptide levels after AMI (acute myocardial infarction) are associated with adverse outcome. The aim of the present study was to examine the relationship of plasma N-ANP (N-terminal pro-atrial natriuretic peptide) and N-BNP (N-terminal pro-B-type natriuretic peptide) with mortality and heart failure following AMI. We studied 403 patients with AMI. Blood was sampled for measurement of N-ANP and N-BNP on a single occasion between 72 and 96 h after symptom onset. Natriuretic peptide levels were related to all-cause mortality and heart failure episodes. During follow up (median, 462 days; range 5-764), 43 (10.7%), 25 (6.2%) and 49 (12.2%) patients suffered death, heart failure hospitalization and outpatient heart failure respectively. Only N-BNP (P < 0.0005), N-ANP (P = 0.005) and previous AMI (P = 0.016) were independently predictive of death. N-BNP, but not N-ANP, predicted 30-day mortality. N-ANP, but not N-BNP, predicted mortality after 30 days. N-BNP was the better predictor of heart failure. N-ANP and N-BNP were above the median in 35 and 38 respectively, of 43 patients who later died. N-ANP, N-BNP, or both were above the median in 41 out of 43 patients. Of 25 patients hospitalized with heart failure, N-ANP and N-BNP was above the median in 20 and 24 respectively, and one or other was elevated in all cases. Above-median N-ANP predicted 36 and N-BNP predicted 41 out of 49 episodes of outpatient heart failure. One or other peptide was above the median in 45 out of 49 patients. Our results indicate that N-BNP predicts 30-day and N-ANP >30-day mortality. We conclude that consideration of both N-ANP and N-BNP identifies a greater number of patients at risk of death or heart failure than either peptide alone.     

Brain natriuretic peptide-guided therapy for heart failure

The drug treatment of heart failure, once simple, has become complex. Apart from a loop diuretic and digoxin, most patients should now be receiving an angiotensin-converting enzyme inhibitor (or angiotensin II receptor blocker), a beta-blocker and spironolactone. Newer drugs, such as endothelin-receptor antagonists and combined blockers of converting-enzyme and neutral endopeptidase, might soon become available. When to introduce these drugs and what dose is optimal for any individual, are questions that currently vex clinicians. We proposed that plasma levels of the cardiac hormone brain natriuretic peptide (BNP, or better, its 1-76 amino-acid N-terminal fragment, N-BNP), would provide an objective index for guiding drug treatment in patients with established, stable cardiac failure. In a pilot study, 69 patients were randomized to drug treatment based on clinical criteria, or based on plasma levels of N-BNP. After a median follow-up of 9.6 months, those in the N-BNP group had fewer clinical end-points than those in the group managed by clinical criteria alone (19 vs 54; P= 0.02). These preliminary data encourage the concept that the increasingly complex pharmacotherapy for heart failure, both chronic (as in this trial) and acute, might best be guided by an objective measure such as plasma levels of BNP or N-BNP.     

Brain natriuretic peptide-guided therapy for heart failure

The drug treatment of heart failure, once simple, has become complex. Apart from a loop diuretic and digoxin, most patients should now be receiving an angiotensin-converting enzyme inhibitor (or angiotensin II receptor blocker), a beta-blocker and spironolactone. Newer drugs, such as endothelin-receptor antagonists and combined blockers of converting-enzyme and neutral endopeptidase, might soon become available. When to introduce these drugs and what dose is optimal for any individual, are questions that currently vex clinicians. We proposed that plasma levels of the cardiac hormone brain natriuretic peptide (BNP, or better, its 1-76 amino-acid N-terminal fragment, N-BNP), would provide an objective index for guiding drug treatment in patients with established, stable cardiac failure. In a pilot study, 69 patients were randomized to drug treatment based on clinical criteria, or based on plasma levels of N-BNP. After a median follow-up of 9.6 months, those in the N-BNP group had fewer clinical end-points than those in the group managed by clinical criteria alone (19 vs 54; P= 0.02). These preliminary data encourage the concept that the increasingly complex pharmacotherapy for heart failure, both chronic (as in this trial) and acute, might best be guided by an objective measure such as plasma levels of BNP or N-BNP.     

B-type natriuretic peptide: a diagnostic, prognostic, and therapeutic tool in heart failure.

B-type natriuretic peptide is a neurohormone secreted from the cardiac ventricles in response to ventricular stretch and pressure overload. It counteracts the vasoconstriction that occurs as a compensatory mechanism in heart failure. A new test for measuring plasma levels of B-type natriuretic peptide can help in the diagnosis and treatment of patients with congestive heart failure. Dyspnea associated with cardiac dysfunction is highly unlikely in patients with levels of the peptide less than 100 pg/mL. Whereas most patients with significant congestive heart failure have levels of the peptide greater than 400 pg/mL, in patients with levels of 100 to 400 pg/mL, left ventricular dysfunction without volume overload, pulmonary embolism, and cor pulmonale must be ruled out. Thus, incorporating measurement of B-type natriuretic peptide into clinical evaluation helps physicians and nurses diagnose heart failure more quickly, especially in patients who have multiple comorbid conditions. Elevated levels of B-type natriuretic peptide indicate a poor prognosis in terms of a higher mortality and more hospital readmissions. Levels of B-type natriuretic peptide could be used to guide therapy and discharge planning for patients admitted with decompensated heart failure.     

B-type natriuretic peptide as a marker for heart failure in patients with acute stroke

OBJECTIVE: To determine whether serum N-terminal pro-B-type natriuretic peptide (N-BNP), a biomarker of myocardial wall stress, is specific to acute heart failure (HF) in patients hospitalized with stroke. DESIGN: Case-control study. SETTING: Tertiary hospital, Neurosciences Critical Care Unit and Stroke Unit. PATIENTS: Consecutive patients with acute ischemic or hemorrhagic stroke who were evaluated for HF. INTERVENTION: None. MEASUREMENTS AND RESULTS: Cases and controls were classified, respectively, as patients with or without HF, defined according to modified Framingham criteria. Seventy-two patients were evaluated, 39 with ischemic stroke, 22 with aneurysmal subarachnoid hemorrhage (SAH), and 11 with intracerebral hemorrhage (ICH). Thirty-four patients (47%) met criteria for HF, and 47 patients (65%) had systolic or diastolic left ventricular (LV) dysfunction on echocardiogram. Serum N-BNP was measured a median of 48 h following the onset of stroke and was increased (> 900 pg/ml) in 56 patients (78%), with higher levels in non-survivors (11898 +/- 12741 vs 4073 +/-5691; p = 0.001). In a multiple regression model, N-BNP elevation was not independently associated with HF (OR 5.4, 95% CI 0.8-36.0, p = 0.084). At a cut-off of 900 pg/ml, the sensitivity of N-BNP for HF was 94%, specificity 37%, positive predictive value (PPV) 57%, and negative predictive value (NPV) 88%. For systolic or diastolic LV dysfunction, the sensitivity of N-BNP was 89%, specificity 44%, PPV 75%, and NPV 69%. CONCLUSIONS: These results demonstrate that N-BNP elevation is not specific to HF or LV dysfunction in patients with acute ischemic stroke, SAH, and ICH.     

Prognostic potential of brain natriuretic peptide (BNP) in predialysis chronic kidney disease patients

In the present study, we investigated the potential of N-BNP (N-terminal B-type natriuretic peptide) as a prognostic marker for risk of CV (cardiovascular) events, overall mortality and progression to ESRD (end-stage renal disease) in a cohort of 83 pre-dialysis CKD (chronic kidney disease) patients without clinical evidence of heart failure. During the study, ten patients reached the combined end point of overall mortality and/or CV event. Univariate factors associated with the combined end point were plasma N-BNP (P < 0.0005), creatinine (P < 0.002), systolic blood pressure (P < 0.009) and age (P < 0.015). N-BNP levels were higher in patients with CV events (P < 0.0005). Cox model regression analysis yielded log10 N-BNP (hazard ratio, 9.608; P < 0.007) and pre-existing CV disease (hazard ratio, 4.571; P < 0.029) as independent predictors of overall mortality or CV events. Kaplan-Meier analysis curves for the subgroup with supramedian creatinine levels (225 micromol/l) showed significant separation of the curves stratified for plasma N-BNP levels above and below the group median (291 pmol/l) for all end points. Receiver-operator-characteristic curves for N-BNP (355 pmol/l cut-off) demonstrated a specificity of 65.8% at a sensitivity of 100% for predicting CV events/overall mortality. The measurement of plasma N-BNP may aid in the risk stratification of pre-dialysis CKD patients. The high sensitivity and negative predictive value (100%) may enable the selection of patients who could safely be excluded from further investigations, resulting in better focusing of resources.     

Diastolic heart failure: challenges of diagnosis and treatment

Diastolic heart failure, a major cause of morbidity and mortality, is defined as symptoms of heart failure in a patient with preserved left ventricular function. It is characterized by a stiff left ventricle with decreased compliance and impaired relaxation, which leads to increased end diastolic pressure. Signs and symptoms are similar to those of heart failure with systolic dysfunction. The diagnosis of diastolic heart failure is best made with Doppler echocardiography. Based on current knowledge, pharmacologic treatment of diastolic heart failure should focus on normalizing blood pressure, promoting regression of left ventricular hypertrophy, avoiding tachycardia, treating symptoms of congestion, and maintaining normal atrial contraction when possible. Diuretic therapy is the mainstay of treatment for preventing pulmonary congestion, while beta blockers appear to be useful in preventing tachycardia and thereby prolonging left ventricular diastolic filling time. Angiotensin-converting enzyme inhibitors and angiotensin-receptor blockers may be beneficial in patients with diastolic dysfunction, especially those with hypertension. Evidence from adequately powered randomized controlled trials, however, is not available yet. The outcomes of ongoing clinical trials may provide much-needed information to move from intuitive treatment to therapy based on evidence that matters: decreased morbidity and mortality and improved quality of life.     

Oxygen-regulated protein 150 and prognosis following myocardial infarction

ORP150 (oxygen-regulated protein 150) is a chaperonin expressed in tissues undergoing hypoxic or endoplasmic reticulum stress. In the present study, we investigated plasma levels of ORP150 in patients with AMI (acute myocardial infarction) and its relationship with prognosis, together with a known risk marker N-BNP (N-terminal pro-B-type natriuretic peptide). Plasma from 396 consecutive patients with AMI was obtained for measurement of ORP150 and N-BNP. Mortality and cardiovascular morbidity (acute coronary syndromes/heart failure) was determined during follow-up. A specific ORP150 assay detected the 150 kDa protein in plasma extracts, including 3 and 7 kDa fragments. During follow-up (median, 455 days), 43 (10.9%) patients died. Both N-BNP and ORP150 levels were higher in those who died compared with the survivors [N-BNP, 724 (14.5-28840) compared with 6167 (154.9-33884) pmol/l (P<0.0005); ORP150, 257 (5.9-870.9) compared with 331 (93.3-831.8) pmol/l (P<0.001); values are medians (range)]. In a Cox regression model for mortality prediction, both N-BNP (odds ratio, 5.06; P<0.001) and ORP150 (odds ratio, 2.39; P<0.01) added prognostic information beyond creatinine and the use of thrombolytics. A Kaplan-Meier survival analysis revealed that ORP150 added prognostic information to N-BNP, especially in those with supra-median N-BNP levels. A simplified dual-marker approach with both markers below and either above or both above their respective medians effectively stratified mortality risk (log rank statistic for trend, 32.7; P<0.00005). ORP150 levels were not predictive of other cardiovascular morbidity (acute coronary syndromes or heart failure). In conclusion, ORP150 and peptide fragments derived from it are secreted following AMI and provide independent prognostic information on mortality. High levels associated with endoplasmic reticulum/hypoxic stress predict a poor outcome.     

Systolic and diastolic heart failure are associated with different plasma levels of B-type natriuretic peptide

Previous studies have found that plasma B-type natriuretic peptide (BNP) is elevated during left ventricular systolic or diastolic dysfunction. It is unclear whether the ventricular systolic and diastolic function is associated with different levels of plasma BNP. Plasma BNP was measured in 149 heart failure patients by a rapid point-of-care assay. The patients were divided into left ventricular diastolic dysfunction (n = 48), left ventricular systolic dysfunction (n = 62) and right ventricular systolic dysfunction group (n = 39). The mean BNP level in the left ventricular diastolic dysfunction, left ventricular systolic dysfunction and right ventricular systolic dysfunction was 115 +/- 80 pg/ml, 516 +/- 445 pg/ml and 345 +/- 184 pg/ml, respectively (p < 0.05). We concluded that ventricular systolic and diastolic dysfunction increases plasma BNP levels to a different extent. Left and right ventricular systolic dysfunction is associated with a higher level of plasma BNP than left ventricular diastolic dysfunction.     

Comparative sensitivities between different plasma B-type natriuretic peptide assays in patients with minimally symptomatic heart failure

Plasma B-type natriuretic peptide (BNP) assays have become widely used to diagnose and manage patients with heart failure. However, differences in assay characteristics may have important implications when BNP is used as a screening test for heart failure at a specific cutoff value. We performed a prospective comparison of 2 commercially available assays--one that is a laboratory-based, microparticle enzyme immunoassay (MEIA) that uses EDTA plasma specimens and one that is a point-of-care (POC), single-use fluorescence immunoassay that uses EDTA--anticoagulated whole blood or plasma specimens-in patients with heart failure and healthy controls. Despite the overall concordance between different SNP assays for the diagnosis of heart failure, their sensitivities may differ when compared at the approved diagnostic cutoff value of 100 pg/mL. At this cutoff value, the MEIA on AxSYM demonstrated greater sensitivity than POC Triage BNP assay in minimally symptomatic patients with heart failure. Therefore, for screening purposes, cutoff values for plasma BNP or N-terminal pro-BNP levels should be specific for each assay to optimize test performance. These findings suggest that there is a relationship between the decision statistics used in screening for left ventricular dysfunction and the type of diagnostic assay used.     

Established and emerging cardiovascular magnetic resonance techniques for prognostication and guiding therapy in heart failure

The syndrome of heart failure is prevalent and a cause of significant morbidity and mortality. Cardiovascular magnetic resonance (CMR) offers a unique method to quantify the extent of left ventricular dysfunction and also characterize the myocardium, particularly according to the presence and distribution of late gadolinium enhancement. The prognostic value of late gadolinium enhancement in various etiologies of heart failure has been demonstrated. Newer techniques that non-invasively assess the extracellular volume may also add to the prognostic value of CMR in heart failure. Management decisions in patients with heart failure can often be complex. CMR can provide useful information when planning cardiac device therapy and the CMR assessment of viability is key when planning revascularization.     

Role of diastole in left ventricular function, II: diagnosis and treatment.

Left ventricular diastolic dysfunction plays an important role in congestive heart failure. Although once thought to be lower, the mortality of diastolic heart failure may be as high as that of systolic heart failure. Diastolic heart failure is a clinical syndrome characterized by signs and symptoms of heart failure with preserved ejection fraction (0.50) and abnormal diastolic function. One of the earliest indications of diastolic heart failure is exercise intolerance followed by fatigue and, possibly, chest pain. Other clinical signs may include distended neck veins, atrial arrhythmias, and the presence of third and fourth heart sounds. Diastolic dysfunction is difficult to differentiate from systolic dysfunction on the basis of history, physical examination, and electrocardiographic and chest radiographic findings. Therefore, objective diagnostic testing with cardiac catheterization, Doppler echocardiography, and possibly measurement of serum levels of B-type natriuretic peptide is often required. Three stages of diastolic dysfunction are recognized. Stage I is characterized by reduced left ventricular filling in early diastole with normal left ventricular and left atrial pressures and normal compliance. Stage II or pseudonormalization is characterized by a normal Doppler echocardiographic transmitral flow pattern because of an opposing increase in left atrial pressures. This normalization pattern is a concern because marked diastolic dysfunction can easily be missed. Stage III, the final, most severe stage, is characterized by severe restrictive diastolic filling with a marked decrease in left ventricular compliance. Pharmacological therapy is tailored to the cause and type of diastolic dysfunction.     

Right heart failure due to loss of right ventricular capture in a patient with atrioventricular junction ablation and biventricular pacing

We describe the case of a patient with atrioventricular (AV) junction ablation and chronic biventricular pacing in which intermittent dysfunction of the right ventricular (RV) lead resulted in left ventricular (LV) stimulation alone and onset of severe right heart failure. Restoration of biventricular pacing by increasing device output and then performing lead revision resolved the issue. This case provides evidence that LV pacing alone in patients with AV junction ablation may lead to severe right heart failure, most likely as a result of iatrogenic mechanical dyssynchrony within the RV. Thus, probably this pacing mode should be avoided in pacemaker-dependent patients with heart failure.     

Beneficial effect of replacing of angiotensin-converting enzyme inhibitor with angiotensin II antagonist for heart failure patients

OBJECTIVE: Angiotensin-converting enzyme (ACE) inhibitors and beta-blockers improve prognosis inpatients with chronic heart failure. Some patients, however, show little response to combined treatment with an ACE inhibitor and a beta-blocker. In addition, the ACE inhibitor cannot completely suppress angiotensin II production. Our objective was to examine whether replacing the ACE inhibitor with an angiotensin II antagonist can improve the condition of patients with chronic heart failure. METHODS: In 11 patients with chronic heart failure treated with an ACE inhibitor and a beta-blocker, who have had severe left ventricular dysfunction or high plasma level of natriuretic peptides, left ventricular dimension, and fractional shortening, plasma atrial and brain natriuretic peptide (ANP and BNP) levels were determined before and 3 months after the change of treatment. RESULTS: After substituting the ACE inhibitor with an angiotensin II antagonist, patients showed New York Heart Association functional class improvement, and significant decrease in left ventricular dimension and BNP. CONCLUSION: In patients with severe chronic heart failure treated with an ACE inhibitor and a beta-blocker, replacing the ACE inhibitor with an angiotensin II antagonist may be effective. However, this has to be confirmed by an adequately powered randomized controlled study.     

血浆脑钠素水平与心衰患者左心功能变化的关系

[目的]探讨血浆脑钠素（BNP）水平与心力衰竭患者临床心功能变化之间的关系.[方法] 采用免疫放射分析法（IRMA）测定患者血浆BNP水平,同时采用纽约心脏协会心功能分级（NYHA）心功能分级和超声心动图检查评定患者左心功能.[结果] 随着心功能恶化,血浆BNP水平呈上升趋势,各级心功能间差异均有显著性（P〈0.01）.经抗心衰药物综合治疗后,BNP水平降低（P〈0.01）.BNP水平与左心室射血分数（LVEF）、左心室短轴缩短率（△D%）呈负相关;与左室收缩末内径（LVSd）、左室舒张末内径（LVDd）呈正相关.[结论] 在患者心力衰竭的进展中其血浆BNP水平与心衰程度密切相关,测定患者血浆BNP水平是监测心衰程度的有效手段之一.     

Diagnosis and management of diastolic dysfunction and heart failure

Diastolic heart failure occurs when signs and symptoms of heart failure are present but left ventricular systolic function is preserved (i.e., ejection fraction greater than 45 percent). The incidence of diastolic heart failure increases with age; therefore, 50 percent of older patients with heart failure may have isolated diastolic dysfunction. With early diagnosis and proper management the prognosis of diastolic dysfunction is more favorable than that of systolic dysfunction. Distinguishing diastolic from systolic heart failure is essential because the optimal therapy for one may aggravate the other. Although diastolic heart failure is clinically and radiographically indistinguishable from systolic heart failure, normal ejection fraction and abnormal diastolic function in the presence of symptoms and signs of heart failure confirm diastolic heart failure. The pharmacologic therapies of choice for diastolic heart failure are angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, diuretics, and beta blockers.     

Aldosterone as a target in congestive heart failure

Based upon the results of the RALES trial and accumulating evidence about the role of aldosterone and aldosterone receptor antagonism in various disease states, the authors anticipate that aldosterone receptor antagonists will become standard therapy, along with ACE inhibitors and beta-adrenergic receptor blocking agents, in patients with heart failure that is caused by systolic left ventricular dysfunction. Furthermore, the prospect of the use of these agents in other disease states that have implicated an activated rennin-angiotensin-aldosterone cascade, such as diastolic dysfunction, aging, and atherosclerosis, remains to be tested. Until further data from well-designed, prospective, randomized trials are available, the use of aldosterone receptor antagonists should be restricted to patients with severe or progressive heart failure caused by systolic left ventricular dysfunction in whom serum creatinine level is < or = 2.0 mg/dL and serum potassium levels are < 5.0 meq/L at baseline.     

Circulating levels of non-phosphorylated undercarboxylated matrix Gla protein are associated with disease severity in patients with chronic heart failure

We recently demonstrated that circulating MGP [matrix Gla (γ-carboxylated glutamate) protein] levels were associated with left ventricular dysfunction and increased mortality in patients with symptomatic aortic stenosis. We hypothesized that patients with chronic HF (heart failure) would have dysregulated MGP levels. We examined plasma dp-cMGP (non-phosphorylated carboxylated MGP) and dp-ucMGP (non-phosphorylated undercarboxylated MGP) in 179 patients with chronic HF and matched healthy controls as well as the relationship between MGP and cardiac dysfunction as assessed by echocardiographic measurements, inflammation [CRP (C-reactive protein)] and neurohormonal activation [NT-proBNP (N-terminal proB-type natriuretic peptide)] and the prognostic value of MGP levels in relation to mortality in these patients. We found markedly enhanced plasma dp-cMGP and, in particular, of dp-ucMGP in chronic HF with increasing levels with disease severity. Elevated MGP species were associated with ischaemic aetiology, increased CRP and NT-proBNP levels, as well as systolic and diastolic dysfunction. Finally, dp-ucMGP was associated with long-term heart transplant-free survival (n=48) in univariate, but not in multivariate, analysis. However, plasma dp-ucMGP was markedly higher in patients who died because of progression of HF (n=12) and gave prognostic information also in multivariate analysis. In conclusion, a dysregulated MGP system could be involved in left ventricular dysfunction in patients with chronic HF.