A. Mark Richards

Brain natriuretic peptide and n-terminal brain natriuretic peptide in the diagnosis of heart failure in patients with acute shortness of breath ☆

OBJECTIVES This study sought to compare the utility of measurement of plasma brain natriuretic peptide (BNP) and N-terminal brain natriuretic peptide (N-BNP) in the diagnosis of heart failure (HF) in patients with acute dyspnea. BACKGROUND Plasma BNP is useful in differentiating HF from other causes of dyspnea in the emergency department. The N-terminal component of BNP has a longer half-life, and in HF increases in plasma N-BNP are proportionately greater. METHODS We studied 205 patients (average age 70 +/- 14 years) presenting to the emergency department with acute dyspnea. Brain natriuretic peptide was analyzed using a point-of-care test and two locally developed radioimmunoassays. N-terminal BNP was measured using a locally developed radioimmunoassay and a commercially available assay. Final diagnosis of HF was adjudicated by two cardiologists. RESULTS Patients with HF (n = 70) had higher mean levels of both hormones by all assays (p < 0.001 for all). Results with all assays correlated closely (r values between 0.902 and 0.969). Subjects with left ventricular (LV) dysfunction or left-sided valvular disease but no HF had intermediate levels of BNP and N-BNP (lower than subjects with HF, and higher than subjects without HF with no LV dysfunction or left-sided valvular disease) (p < 0.01 for all). Using optimum cut-offs, specificity for the diagnosis of HF ranged between 70% and 89% (highest for the N-BNP assays). Sensitivity ranged between 80% and 94% (highest for the point-of-care BNP assay). CONCLUSIONS Measurement of BNP or N-BNP is useful in the diagnosis of HF in acute dyspnea. Commercially available assays compare favorably with well-validated laboratory assays. Differences in sensitivity and specificity may influence the assay choice in this setting.

Increased Plasma Natriuretic Peptide Levels Reflect Symptom Onset in Aortic Stenosis

Background—The onset of symptoms is a critical point in the natural history of aortic stenosis and the cardinal indication for valve replacement. This study assessed the associations between natriuretic peptide levels, disease severity, and cardiac symptoms in aortic stenosis. Methods and Results—Seventy-four patients with isolated aortic stenosis underwent independent assessment of symptoms, transthoracic echocardiography, and measurement of plasma levels of atrial natriuretic peptide, brain natriuretic peptide (BNP), and N-BNP. Natriuretic peptide levels were also measured in 100 clinically normal control subjects. The aortic valve area was smaller in symptomatic patients (n=45) than in asymptomatic patients (n=29; mean, 0.71±0.23 cm2 and 0.99±0.31 cm2, respectively;P <0.0001). Plasma natriuretic peptide levels were higher in symptomatic patients than in asymptomatic patients (for N-BNP: median, 112 versus 33 pmol/L; interquartile range, 70 to 193 versus 16 to 58 pmol/L, respectively;P =0.0002). After adjustment for age, sex, serum creatinine, aortic valve area, and left ventricular ejection fraction, N-BNP levels were 1.74 times higher (95% confidence interval, 1.12 to 2.69) for symptomatic than asymptomatic patients with aortic stenosis (P =0.014). Natriuretic peptide levels increased with the New York Heart Association class (for N-BNP median values were 13, 34, 105, and 202 pmol/L for normal control subjects, class I, class II, and class III/IV patients, respectively; interquartile ranges for the same patients were 8 to 21, 16 to 58, 57 to 159, and 87 to 394 pmol/L;P <0.0001). Similar associations were observed for BNP and atrial natriuretic peptide. Conclusions—Plasma natriuretic peptide levels are elevated in symptomatic patients with aortic stenosis. Measurement of natriuretic peptides may complement clinical and echocardiographic evaluation of patients with aortic stenosis.

2-Hour accelerated diagnostic protocol to assess patients with chest pain symptoms using contemporary troponins as the only biomarker: the ADAPT trial.

OBJECTIVES The purpose of this study was to determine whether a new accelerated diagnostic protocol (ADP) for possible cardiac chest pain could identify low-risk patients suitable for early discharge (with follow-up shortly after discharge). BACKGROUND Patients presenting with possible acute coronary syndrome (ACS), who have a low short-term risk of adverse cardiac events may be suitable for early discharge and shorter hospital stays. METHODS This prospective observational study tested an ADP that included pre-test probability scoring by the Thrombolysis In Myocardial Infarction (TIMI) score, electrocardiography, and 0 + 2 h values of laboratory troponin I as the sole biomarker. Patients presenting with chest pain due to suspected ACS were included. The primary endpoint was major adverse cardiac event (MACE) within 30 days. RESULTS Of 1,975 patients, 302 (15.3%) had a MACE. The ADP classified 392 patients (20%) as low risk. One (0.25%) of these patients had a MACE, giving the ADP a sensitivity of 99.7% (95% confidence interval [CI]: 98.1% to 99.9%), negative predictive value of 99.7% (95% CI: 98.6% to 100.0%), specificity of 23.4% (95% CI: 21.4% to 25.4%), and positive predictive value of 19.0% (95% CI: 17.2% to 21.0%). Many ADP negative patients had further investigations (74.1%), and therapeutic (18.3%) or procedural (2.0%) interventions during the initial hospital attendance and/or 30-day follow-up. CONCLUSIONS Using the ADP, a large group of patients was successfully identified as at low short-term risk of a MACE and therefore suitable for rapid discharge from the emergency department with early follow-up. This approach could decrease the observation period required for some patients with chest pain. (An observational study of the diagnostic utility of an accelerated diagnostic protocol using contemporary central laboratory cardiac troponin in the assessment of patients presenting to two Australasian hospitals with chest pain of possible cardiac origin; ACTRN12611001069943).

Plasma natriuretic peptide levels increase with symptoms and severity of mitral regurgitation

OBJECTIVES This paper will describe associations between plasma natriuretic peptide levels and the severity and symptoms of mitral regurgitation (MR). BACKGROUND A biochemical test that assisted grading of the severity of MR and the interpretation of symptoms would be of clinical value. METHODS Forty-nine patients with isolated MR and left ventricular (LV) ejection fractions (EFs) of >55% underwent transthoracic echocardiography, assessment of symptoms, and measurement of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and its amino-terminal portion, N-BNP. RESULTS The level of each natriuretic peptide rose with increasing severity of MR and with increases in left atrial (LA) dimensions (p < 0.001 for all comparisons), but no significant correlation existed between any natriuretic peptide and the LV dimensions or EF. Natriuretic peptide levels were higher in symptomatic MR (n = 16, BNP geometric mean 16.9 [95% confidence interval (CI) 13.3 to 21.4] pmol/l) compared with asymptomatic MR (n = 33, BNP 7.1 [95% CI 6.0 to 8.4] pmol/l, p < 0.001), and higher in asymptomatic MR than in normal controls (n = 100, BNP 5.3 [95% CI 4.8 to 5.8] pmol/l, p < 0.0001). These differences were similar for N-BNP and ANP and remained statistically significant (p < 0.05) after adjustment for echocardiographic measures of LV function and severity of MR. Both the sensitivity and the specificity for symptoms for the natriuretic peptides (area under receiver-operator characteristic curve for BNP = 0.90, N-BNP = 0.89, ANP = 0.89) were similar to the MR score (0.88) and greater than for LA dimension (0.81), vena contracta width (0.82), and LV end-systolic dimension (0.63). CONCLUSIONS Plasma natriuretic peptides levels increase with the severity of MR and are higher in symptomatic compared to asymptomatic patients, even when LV EF is normal.

Biology of the Natriuretic Peptides

The biology of the natriuretic peptide (NP) system is complex, yet highly phylogenetically preserved. It regulates salt and water handling, promotes vasodilatation, and exerts favorable effects on the heart in the context of processes such as heart failure. Prior assumptions about the production of B-type NP (BNP) and its amino-terminal precursor fragment (NT-proBNP) have recently been refuted. It is now recognized that rather than a 1:1 secretion of these 2 NPs, a mixture of cleaved and uncleaved NPs is released by the cardiomyocyte. It is also recognized that BNP is rapidly modified into a mixture of various fragments. Commercial assays for the detection of BNP and NT-proBNP measure a mixture of cleaved and uncleaved NPs as well as varying amounts of degraded BNP. BNP and NT-proBNP are cleared differentially: BNP is actively removed from the bloodstream and also has passive clearance mechanisms, including renal clearance; NT-proBNP is cleared more passively by organs with high rates of blood flow, including the kidney.

Coenzyme Q10: An Independent Predictor of Mortality in Chronic Heart Failure

OBJECTIVES The aim of this study was to investigate the relationship between plasma coenzyme Q(10) (CoQ(10)) and survival in patients with chronic heart failure (CHF). BACKGROUND Patients with CHF have low plasma concentrations of CoQ(10), an essential cofactor for mitochondrial electron transport and myocardial energy supply. Additionally, low plasma total cholesterol (TC) concentrations have been associated with higher mortality in heart failure. Plasma CoQ(10) is closely associated with low-density lipoprotein cholesterol (LDL-C), which might contribute to this association. Therefore we tested the hypothesis that plasma CoQ(10) is a predictor of total mortality in CHF and could explain this association. METHODS Plasma samples from 236 patients admitted to the hospital with CHF, with a median (range) duration of follow-up of 2.69 (0.12 to 5.75) years, were assayed for LDL-C, TC, and total CoQ(10). RESULTS Median age at admission was 77 years. Median (range) CoQ(10) concentration was 0.68 (0.18 to 1.75) micromol/l. The optimal CoQ(10) concentration for prediction of mortality (established with receiver-operator characteristic [ROC] curves) was 0.73 micromol/l. Multivariable analysis allowing for effects of standard predictors of survival--including age at admission, gender, previous myocardial infarction, N-terminal peptide of B-type natriuretic peptide, and estimated glomerular filtration rate (modification of diet in renal disease)--indicated CoQ(10) was an independent predictor of survival, whether dichotomized at the ROC curve cut-point (hazard ratio [HR]: 2.0; 95% confidence interval [CI]: 1.2 to 3.3) or the median (HR: 1.6; 95% CI: 1.0 to 2.6). CONCLUSIONS Plasma CoQ(10) concentration was an independent predictor of mortality in this cohort. The CoQ(10) deficiency might be detrimental to the long-term prognosis of CHF, and there is a rationale for controlled intervention studies with CoQ(10).

Effect of B-type natriuretic peptide-guided treatment of chronic heart failure on total mortality and hospitalization: an individual patient meta-analysis

Aims Natriuretic peptide-guided (NP-guided) treatment of heart failure has been tested against standard clinically guided care in multiple studies, but findings have been limited by study size. We sought to perform an individual patient data meta-analysis to evaluate the effect of NP-guided treatment of heart failure on all-cause mortality. Methods and results Eligible randomized clinical trials were identified from searches of Medline and EMBASE databases and the Cochrane Clinical Trials Register. The primary pre-specified outcome, all-cause mortality was tested using a Cox proportional hazards regression model that included study of origin, age (<75 or ≥75 years), and left ventricular ejection fraction (LVEF, ≤45 or >45%) as covariates. Secondary endpoints included heart failure or cardiovascular hospitalization. Of 11 eligible studies, 9 provided individual patient data and 2 aggregate data. For the primary endpoint individual data from 2000 patients were included, 994 randomized to clinically guided care and 1006 to NP-guided care. All-cause mortality was significantly reduced by NP-guided treatment [hazard ratio = 0.62 (0.45–0.86); P = 0.004] with no heterogeneity between studies or interaction with LVEF. The survival benefit from NP-guided therapy was seen in younger (<75 years) patients [0.62 (0.45–0.85); P = 0.004] but not older (≥75 years) patients [0.98 (0.75–1.27); P = 0.96]. Hospitalization due to heart failure [0.80 (0.67–0.94); P = 0.009] or cardiovascular disease [0.82 (0.67–0.99); P = 0.048] was significantly lower in NP-guided patients with no heterogeneity between studies and no interaction with age or LVEF. Conclusion Natriuretic peptide-guided treatment of heart failure reduces all-cause mortality in patients aged <75 years and overall reduces heart failure and cardiovascular hospitalization.

Beneficial hemodynamic, endocrine, and renal effects of urocortin in experimental heart failure: Comparison with normal sheep

OBJECTIVES The goal of this study was to determine the bioactivity of urocortin (Ucn) in experimental heart failure (HF). BACKGROUND Urocortin may participate in cardiovascular function and pressure/volume homeostasis. Its effects in HF are unknown. METHODS Eight normal sheep and eight sheep with pacing-induced HF received ovine Ucn (10, 50, and 100 mg intravenous boluses at 2-h intervals) in vehicle-controlled studies. RESULTS Urocortin boluses dose-dependently increased plasma Ucn (p < 0.001). Pharmacokinetics were similar in normal and HF sheep with half-lives approximating 1.3 and 19.5 h for the first and second phases, respectively. In HF, cardiac output increased (twofold), while peripheral resistance, left atrial pressure (both 50% falls: p < 0.001), and mean arterial pressure (p < 0.05) fell. In normal sheep, changes in peripheral resistance and atrial pressure were blunted and in arterial pressure were directionally opposite. Urocortin induced persistent, dose-dependent falls (30% to 50%) in plasma vasopressin, renin activity, aldosterone, natriuretic peptides (all p < 0.001), and endothelin-1 (p < 0.05) in HF sheep, while adrenocorticotrophic hormone and cortisol levels rose acutely (both p < 0.001). In comparison, Ucn in normal sheep resulted in a similar rise in cortisol and fall in aldosterone, no significant effects on plasma renin activity and natriuretic peptides, and a rise in vasopressin. Urocortin produced dose-dependent, sustained increases in urine volume (twofold, p < 0.01), sodium excretion (>9-fold rise, p < 0.001), and creatinine clearance (p < 0.001) in HF sheep. No significant renal effects were observed in normal sheep. CONCLUSIONS Urocortin has profound and sustained hemodynamic, hormonal, and renal effects in experimental HF. Urocortin may have a role in pressure/volume homeostasis in HF and may provide a novel therapeutic approach to this disease.

BLOOD-PRESSURE RESPONSE TO MODERATE SODIUM RESTRICTION AND TO POTASSIUM SUPPLEMENTATION IN MILD ESSENTIAL HYPERTENSION

To determine whether moderate restriction of dietary sodium content or supplementation of potassium intake reduces blood-pressure in patients with mild essential hypertension, twelve patients were put on three different diets--a control diet (180 mmol sodium/day), a sodium restricted diet (80 mmol/day). Each diet was taken for at least 4 weeks and the sequence of the regimens was randomised. At the completion of each regimen intra-arterial pressure was recorded continuously, and vasoactive hormones were measured hourly, for 24 h, under standardised conditions, in hospital. Compared with the control diet, sodium restriction was associated with lower blood-pressure readings in seven patients, higher levels in five, and an overall reduction in mean pressures of only 4.0/3.0 mm Hg (not significant). Individual differences in blood-pressure between these two diets correlated closely with concomitant differences in plasma renin activity (r = 0.75). Potassium supplementation also resulted in variable changes in arterial pressure, and the mean difference in pressure recordings (0.1/0.8 mm Hg) was insignificant. The results show that moderate restriction of sodium intake or supplementation of dietary potassium has variable effects on arterial pressure in individuals with mild essential hypertension, and that overall the blood-pressure changes induced are very small. Responsiveness of the renin-angiotensin system may limit the fall in blood-pressure induced by sodium restriction.

Direct Left Atrial Pressure Monitoring in Ambulatory Heart Failure Patients. Initial Experience With a New Permanent Implantable Device

Background— We describe the first human experience with a permanently implantable, direct left atrial pressure (LAP) monitoring system in ambulatory patients with chronic heart failure. Methods and Results— Eight patients with established heart failure and at least 1 heart failure hospitalization or unplanned visit for parenteral therapy in the last year underwent device implantation under fluoroscopic guidance. All subjects received aspirin 150 mg and clopidogrel 75 mg daily. Subjects measured LAP twice daily and attended a clinic regularly for data upload and device calibration. Right heart catheterization was performed at the time of device implantation and at 12 weeks. The device was implanted in all subjects with no procedural complications. At the 12-week follow-up, 87% of device LAP measurements were within ±5 mm Hg of simultaneous pulmonary capillary wedge pressure readings over a wide range of pressures (1.6 to 71 mm Hg). Net drift corrected by calibration was −0.2±1.9 mm Hg/mo. During short-term follow-up, there were no device-related complications or systemic emboli. There were no deaths, no unplanned heart failure clinic visits, and no admissions for heart failure. Conclusions— Ambulatory monitoring of direct LAP with a new implantable device was well tolerated, feasible, and accurate at a short-term follow-up. Further follow-up and investigation are warranted to evaluate the clinical utility of LAP monitoring in patients with heart failure.