R. Troughton

Treatment of heart failure guided by plasma aminoterminal brain natriuretic peptide (N-BNP) concentrations

BACKGROUND There is currently no objective practical guide to intensity of drug treatment for individuals with heart failure. We hypothesised that pharmacotherapy guided by plasma concentrations of the cardiac peptide aminoterminal brain natriuretic peptide (N-BNP) would produce a superior outcome to empirical trial-based therapy dictated by clinical acumen. METHODS 69 patients with impaired systolic function (left-ventricular ejection fraction <40%) and symptomatic heart failure (New York Heart Association class II-IV) were randomised to receive treatment guided by either plasma N-BNP concentration (BNP group) or standardised clinical assessment (clinical group). FINDINGS During follow-up (minimum 6-months, median 9.5 months), there were fewer total cardiovascular events (death, hospital admission, or heart failure decompensation) in the BNP group than in the clinical group (19 vs 54, p=0.02). At 6 months, 27% of patients in the BNP group and 53% in the clinical group had experienced a first cardiovascular event (p=0.034). Changes in left-ventricular function, quality of life, renal function, and adverse events were similar in both groups. INTERPRETATION N-BNP-guided treatment of heart failure reduced total cardiovascular events, and delayed time to first event compared with intensive clinically guided treatment.

B-Type Natriuretic Peptides and Ejection Fraction for Prognosis After Myocardial Infarction

Background—A recent landmark report has demonstrated that plasma B-type natriuretic peptide (BNP) measured in acute coronary syndromes independently predicts mortality, heart failure, and new myocardial infarction. After acute cardiac injury, left ventricular ejection fraction (LVEF) is also of prognostic significance and plays a major role in determining the therapeutic response. Methods and Results—The present report is the first from a substantial (n=666) cohort of patients with acute myocardial infarction to test the prognostic utility of concurrent measurements of BNP, amino-terminal BNP (N-BNP), norepinephrine, and radionuclide LVEF. The B-type peptides and LVEF were predictors of death, heart failure, and new myocardial infarction (all P <0.001) independent of patient age, gender, previous myocardial infarction, antecedent hypertension or diabetes, previous heart failure, plasma norepinephrine, creatinine, cholesterol, drug therapy, and coronary revascularization procedures. The combination of N-BNP (or BNP) with LVEF substantially improved risk stratification beyond that provided by either alone. Elevated N-BNP (or BNP) predicted new myocardial infarction only in patients with LVEF <40%. LVEF <40% coupled to N-BNP over the group median conferred substantial 3-year risks of death, heart failure, and new myocardial infarction of 37%, 18%, and 26%, respectively. N-BNP and BNP were equivalent prognostic markers for these clinical outcomes. Conclusions—Plasma N-BNP (or BNP) and LVEF are complementary independent predictors of major adverse events on follow-up after myocardial infarction. Combined measurement provides risk stratification substantially better than that provided by either alone.

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).

Antecedent hypertension and heart failure after myocardial infarction

OBJECTIVES We sought to assess the relationship of antecedent hypertension to neurohormones, ventricular remodeling and clinical heart failure (HF) after myocardial infarction (MI). BACKGROUND Heart failure is a probable contributor to the increased mortality observed after MI in those with antecedent hypertension. Hence, neurohormonal activation, adverse ventricular remodeling and a higher incidence of clinical HF may be expected in this group. However, no previous report has documented serial postinfarction neurohumoral status, serial left ventricular imaging and clinical outcomes over prolonged follow-up in a broad spectrum of patients with and without antecedent hypertension. METHODS Inpatient events were documented in 1,093 consecutive patients (436 hypertensive and 657 normotensive) with acute MI. In 68% (282 hypertensive, 465 normotensive) serial neurohormonal sampling and radionuclide ventriculography were performed one to four days and three to five months after infarction. Clinical outcomes were recorded over a mean follow-up of two years. RESULTS Plasma neurohormones were significantly higher in hypertensives than in normotensives one to four days and three to five months after infarction. From similar initial values, left ventricular volumes increased significantly in hypertensives, compared with normotensives. Left ventricular ejection fraction rose significantly in normotensive but not hypertensive patients. Together with higher inpatient (8.1% vs. 4.4%, p < 0.002) and post-discharge mortality (9.5% vs. 5.5%, p = 0.043), hypertensive patients incurred more inpatient HF (33% vs. 24%, p < 0.001) and more late HF requiring readmission to hospital (12.4% vs. 5.5%, p < 0.001). Antecedent hypertension predicted late HF in patients >64 years of age with neurohormonal activation and early left ventricular dilation. CONCLUSIONS Antecedent hypertension interacts with age, neurohumoral activation and early ventricular remodeling to confer greater risk of HF after MI.

Hemodynamic, Hormone, and Urinary Effects of Adrenomedullin Infusion in Essential Hypertension

We examined the effects of the vasodilator peptide adrenomedullin (AM) infused intravenously into subjects with essential hypertension. Eight men 39 to 58 years old with uncomplicated hypertension (147/96±5/3 mm Hg at baseline) were studied in a placebo-controlled, crossover design. Each subject received intravenous AM in a low and a high dose (2.9 and 5.8 pmol · kg−1 · min−1 for 2 hours each) or vehicle-control (Hemaccel) infusion in a random order on day 4 of a controlled metabolic diet (80 mmol/d Na+, 100 mmol/d K+). Plasma AM reached pathophysiological levels during infusion (18±4 pmol/L in low dose, 34±9 pmol/L in high dose) with a concurrent rise in plasma cAMP (+8.4±1.2 pmol/L, P <0.05 compared with control). Compared with control, high-dose AM increased peak heart rate (+17.8±2.3 bpm, P <0.01), lowered systolic (−24.6±0.9 mm Hg;P <0.01) and diastolic (−21.9±1.4 mm Hg;P <0.01) blood pressure, and increased cardiac output (+1.0±0.1 L/min in low dose, +2.9±0.2 L/min in high dose;P <0.01 for both). Despite a rise in plasma renin activity during high dose (P <0.05), aldosterone levels did not alter. Plasma norepinephrine levels increased 1295±222 pmol/L (P <0.001) and epinephrine increased 74±15 pmol/L (P <0.05) with high-dose AM compared with control. AM had no significant effect on urine volume and sodium excretion. In subjects with essential hypertension, the intravenous infusion of AM to achieve pathophysiological levels produced significant falls in arterial pressure, increased heart rate and cardiac output, and stimulated the sympathetic system and renin release without concurrent increase in aldosterone. Urinary parameters were unaltered. Although AM has potent hemodynamic and neurohumoral effects in subjects with essential hypertension, the threshold for urinary actions is set higher.

Beneficial Renal and Hemodynamic Effects of Omapatrilat in Mild and Severe Heart Failure

Omapatrilat is a member of the new drug class of vasopeptidase inhibitors that may offer benefit in the treatment of heart failure (HF) through simultaneous inhibition of angiotensin-converting enzyme and neutral endopeptidase. We examined the effects of omapatrilat in a placebo-controlled crossover study using a pacing model of HF. Seven sheep were paced sequentially at 180 bpm (mild HF) and then 225 bpm (severe HF) for 7 days each. Omapatrilat (0.005 mg/kg) or vehicle was administered by intravenous bolus on days 4 to 7 of each paced period. Omapatrilat lowered mean arterial and left atrial pressure and increased cardiac output acutely and chronically in both mild and severe HF (P <0.01 for all). Plasma atrial and brain natriuretic peptide and cGMP levels were stable acutely (P =NS), while brain natriuretic peptide increased after repeated dosing in severe HF (P <0.05). Plasma renin activity rose, whereas angiotensin II and aldosterone levels fell after acute and repeated dosing in both states (P <0.01 for all). Omapatrilat increased urinary sodium excretion by day 7 in both mild and severe HF (P <0.05). Effective renal plasma flow and glomerular filtration rate increased or were stable after omapatrilat in mild and severe HF after both acute and repeated dosing. Omapatrilat exhibited pronounced acute and sustained beneficial hemodynamic and renal effects in both mild and severe heart failure.

B-type natriuretic peptide infusions in acute myocardial infarction

Background: Natriuretic peptides have actions likely to ameliorate cardiac dysfunction. B-type natriuretic peptide (BNP) is indicated as treatment for decompensated cardiac failure. Objective: To determine the utility of BNP in acute myocardial infarction (MI). Design: Double-blind randomised placebo-controlled trial. Setting: Tertiary hospital coronary care unit. Patients: 28 patients with acute MI with delayed or failed reperfusion and moderate left ventricular dysfunction. Interventions: Infusion of BNP or placebo for 60 hours after MI. Main outcome measures: Neurohormonal activation and renal function in response to BNP infusion, secondary end points of echocardiographic measures of left ventricular function and dimension. Results: BNP infusion resulted in a significant rise in BNP (276 pg/l vs 86 pg/l, p = 0.001). NT-proBNP levels were suppressed by BNP infusion (p = 0.002). Atrial natriuretic peptide (ANP) and NT-proANP levels fell with a significant difference in the pattern between BNP infusion and placebo during the first 5 days (p<0.005). C-type natriuretic peptide (CNP) and NT-proCNP levels rose during the infusion with higher levels than placebo at all measurements during the first 3 days (p<0.01). Cyclic guanosine monophosphate (cGMP) was raised during the infusion period showing a peak of 23 pmol/l on day 2 (placebo 8.9 pmol/l, p = 0.002), with a correlation between BNP and cGMP levels (p<0.001). Glomerular filtration rate (GFR) fell with BNP infusion but was not significantly lower than with placebo (71.0 (5.6) vs 75.8 (5.4) ml/min/1.73 m2, p = 0.62). Patients receiving nesiritide exhibited favourable trends in left ventricular remodelling. Conclusions: Nesiritide, given soon after MI, induced increments in plasma cGMP and CNP and decrements in other endogenous cardiac peptides with a neutral effect on renal function and a trend towards favourable ventricular remodelling.

ST2 has diagnostic and prognostic utility for all-cause mortality and heart failure in patients presenting to the emergency department with chest pain.

BACKGROUND Elevated ST2 predicts future heart failure and/or death in patients with pulmonary diseases, heart failure, acute dyspnea, and acute coronary syndromes. This study assesses both diagnostic and prognostic utility of ST2 in patients with chest pain. METHODS AND RESULTS From November 2007 to April 2010, 995 patients attending the Emergency Department with chest pain were prospectively recruited. Troponin I (TnI), B-type natriuretic peptide (BNP), creatine kinase-myocardial band (CKMB), myoglobin, and ST2 were measured at 0 and 2 hours. The diagnostic utility of ST2 for heart failure and prognostic utility for primary outcome of death and/or heart failure by 18 months was assessed. Elevated ST2 had sensitivity 73.5% (55.8%-86.4%) and specificity 79.6% (79.0%-80.1%) for acute heart failure (n = 34) [compared with BNP sensitivity 88.2% (73.6%-95.3%), specificity 66.2% (65.7%-66.4%)]. Elevated ST2 conveyed risk of 18-month primary outcome (n = 110), with an adjusted hazard ratio (HR) of 1.9 (1.2-3.2), compared with BNP HR 2.8 (1.4-5.7), myoglobin HR 1.9 (1.1-3.3), TnI HR 1.7 (1.0-2.7), and CKMB HR 0.9 (0.5-1.7). When ST2 and BNP were both elevated, risk was greater than if either marker was elevated in isolation (P < .001). CONCLUSIONS ST2 was more specific for acute heart failure than BNP. ST2 is independently predictive of future death and/or heart failure and has incremental utility in combination with BNP.

Hypotensive and Natriuretic Actions of Adrenomedullin in Subjects With Chronic Renal Impairment

Abstract—Plasma levels of adrenomedullin are increased in chronic renal failure. The significance of this finding is uncertain, because the biological effects of adrenomedullin in renal impairment are unknown. Therefore, we studied the effects of adrenomedullin infusion in subjects with chronic renal impairment. Eight males with IgA nephropathy and plasma creatinine of 0.19±0.03 mmol/L (mean±SEM) were studied in a vehicle-controlled crossover design. Each subject was studied twice; subjects were administered either adrenomedullin at a low dose and then a high dose (2.9 and 5.8 pmol/kg per minute, respectively, for 2 hours each) or a 4-hour vehicle control (Hemaccel), in random order, on day 4 of controlled metabolic diets. Adrenomedullin infusion achieved plasma adrenomedullin concentrations in the pathophysiological range after the low (31.2±5.1 pmol/L) and high (47.4±4.3 pmol/L) dose, and plasma cAMP was increased. Compared with vehicle control, high-dose adrenomedullin increased peak heart rate (+21.7±3.3 bpm, P <0.01) and cardiac output (+2.9±0.2 L/min, P <0.01) and lowered both systolic and diastolic blood pressures by >10 mm Hg (P <0.05). Plasma renin activity, angiotensin II, and norepinephrine increased by up to 50% above baseline levels (P <0.05 for all), whereas aldosterone and epinephrine were unchanged. Urinary volume and sodium excretion increased significantly (P <0.05) with low-dose adrenomedullin, whereas creatinine clearance was stable, and proteinuria tended to decrease. In subjects with chronic renal impairment due to IgA nephropathy, adrenomedullin infusion lowered blood pressure, stimulated sympathetic activity and renin release, and caused diuresis and natriuresis. Adrenomedullin may have a role in modulating blood pressure and kidney function in renal disease.

High-sensitivity troponin T for early rule-out of myocardial infarction in recent onset chest pain.

Objective To investigate whether a high-sensitivity troponin assay, shown to improve early detection of acute myocardial infarction (AMI), permits accelerated rule-in/rule-out of AMI. Methods Patients who presented to the emergency department within 4 h of the onset of chest pain suggestive of acute coronary syndrome were prospectively recruited from November 2007 to April 2010. Blood samples were taken at 0, 1, 2 and 12–24 h after presentation and were analysed for clinically applied troponin I and for high-sensitivity troponin T (hsTnT). The dynamic change in hsTnT levels between time points was measured. The primary outcome was admission diagnosis of AMI. Results Of the 385 patients recruited, 82 (21.3%) had AMI. The sensitivity of hsTnT by 2 h was 95.1% (88.7–98.1%), specificity 75.6% (73.8–76.5%), positive predictive value 53.8% (50.2–55.5%) and negative predictive value 98.3% (96.0–99.3%). The sensitivity was not statistically different between peak values at 2 h and 24 h. Adding ECG results reduced the false negative rate to 1.2%. The additional application of ≥20% delta criterion over the 2 h period for 0–2 h samples increased specificity to 92.4% (90.2–94.3%) but reduced sensitivity to 56.1% (48.0–63.2%). Conclusion hsTnT taken at 0 and 2 h after presentation, together with ECG results, could identify patients suitable for early stress testing with a false negative rate for AMI of 1.2%. Further trials of such an approach are warranted. The specificity of hsTnT for diagnosing AMI could be improved by the use of a delta of ≥20%, but at the cost of major reductions in sensitivity.