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Aims: In bradycardia patients treated with dual-chamber pacing, we aimed to evaluate whether pacing with atrioventricular (AV) delay management [AV hysteresis (AVH)], compared with standard pacing with fixed AV delays, reduces unnecessary ventricular pacing percentage (VPP) and is associated with better clinical outcomes. Main study endpoints were the incidence of heart failure hospitalizations (HFH), persistent atrial fibrillation (AF), and cardiac death., Methods and Results: Data from two identical prospective observational studies, BRADYCARE I in the USA and BRADYCARE II in Europe, Africa, and Asia, were pooled. Overall, 2592 patients (75 ± 10 years, 45.1% female, 50% with AVH) had complete clinical and device data at 1-year follow-up and were analysed. Primary pacing indication was sinus node disease (SND) in 1177 (45.4%), AV block (AVB) in 974 (37.6%), and other indications in 441 (17.0%) patients. Pacing with AVH, compared with standard pacing, was associated with a lower 1-year incidence of HFH [1.3% vs. 3.1%, relative risk reduction (RRR) 57.5%, P = 0.002] and of persistent AF (5.3% vs. 7.7%, RRR = 31.1%, P = 0.028). Cardiac mortality was not different between groups (1.0% vs. 1.4%, RRR = 27.8%, P = 0.366). Pacing with AVH, compared with standard pacing, was associated with a lower (P < 0.001) median VPP in all patients (7% vs. 75%), in SND (3% vs. 44%), in AVB (25% vs. 98%), and in patients with other pacing indications (3% vs. 47%)., Conclusion: Cardiac pacing with AV delay management via AVH is associated with reduced 1-year incidence of HFH and persistent AF, most likely due to a reduction in VPP compared to standard pacing., Competing Interests: Conflict of interest: M.A. participated in clinical trials sponsored by Abbott and Biotronik; he received speaker honoraria from Biotronik. A.A. participated in clinical trials sponsored by Boston Scientific, Medtronic, EPD Philips, and XSpline; he received consultant or speaker fees from Abbott, Boston Scientific, Cairdac, Corvia, EP Solution, Microport CRM, Philips, Radcliffe Publishers, and XSpline, and he has intellectual properties with Boston Scientific, Biosense Webster, and Microport CRM. A.A. is the review editor of EP Europace and was not involved in the peer review process or publication decision. G.B. received speaker fees from Boston Scientific, Abbott, Daiichi, and Boehringer Ingelheim. A.P., W.L., and A.G. are Abbott employees. All remaining authors have declared no conflicts of interest., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

The approval of new heart failure (HF) therapies has slowed over the past two decades in part due to the high costs of conducting large randomized clinical trials that are needed to adequately power major clinical endpoint studies. Several biomarkers have been identified reflecting different elements of HF pathophysiology, with possible applications in diagnosis, risk stratification, treatment monitoring, and even in the design of clinical trials. Biomarkers could potentially be used to refine study inclusion criteria to enable enrolment of patients who are more likely to respond to a therapeutic intervention, despite being at sufficient risk to meet pre-determined study endpoint rates. When there is a close relationship between biomarker levels and clinical endpoints, changes in biomarker levels after a given treatment can act as a surrogate endpoint, potentially reducing the duration and cost of a clinical trial. Natriuretic peptides have been widely used in clinical trials with a variable amount of added value, which such variation being probably due to the absence of a close pathophysiological connection to the study drug. Notable exceptions to this include sacubitril/valsartan and vericiguat. Future studies should seek to adopt unbiased approaches for discovery of true companion diagnostics; with -omics-based tools, biomarkers might be more precisely selected for use in clinical trials to identify responses that closely reflect the biological effects of the drug under investigation. Finally, biomarkers associated with cardiac damage and remodelling, such as cardiac troponin, could be employed as safety endpoints provided that standardization between different assays is achieved., (© 2022 European Society of Cardiology.)

Background: Heart Rate Score (HrSc), a novel index found to predict mortality in patients with implantable defibrillator (ICD) and cardiac resynchronization defibrillator (CRT-D) devices, is associated with mortality in ICD and CRT-D recipients when HrSc is ≥ 70%. Implantable defibrillator shocks have also been associated with increased mortality in ICD and CRT-D recipients. The objective of this study was to evaluate the relationships between HrSc, shocks, and mortality in ICD and CRT-D patients., Methods: HrSc was calculated from atrial sensed and paced rate histograms collected from the 2006-2011 ALTITUDE remote interrogation database. Shocks were determined in the first year of follow-up. Mortality was assessed over the next 4 years by the Social Security Death Index. Four multivariable models were run: ICD and CRT-D, shock and no shock, with mortality as the outcome and HrS as predictor., Results: Data from 49,358 ICD and 55,953 CRT-D patients were divided into HrSc: ≥ 70%, 30-69%, and < 30%. Shock rates differed between HrSc groups (p < 0.001) for ICD and CRT-D patients. However, the lowest mortality risk HrSc (< 30%) had the highest shock rate. Both highest HrSc (> 70%; p < 0.001) and shocks (p < 0.001) predicted mortality during follow-up. Mortality was unrelated to interactions between HrSc and shocks in ICD patients (p = 0.275) or CRT-D patients (p < 0.079). Comparing HrSc ≥ 70% to HrSc < 30%, HrSc ≥ 70% predicted mortality in CRT-D (HR 1.40; 95% CI 1.29-1.52) and ICD (HR 1.23; 95% CI 1.11-1.36) patients regardless of shocks (P < 0.001 for both)., Conclusions: Patients with ICDs or CRT-Ds having the lowest mortality risk HrSc had the highest shock rate. Shocks and HrSc appear to complement each other as predictors of mortality.

Natriuretic peptide [NP; B-type NP (BNP), N-terminal proBNP (NT-proBNP), and midregional proANP (MR-proANP)] concentrations are quantitative plasma biomarkers for the presence and severity of haemodynamic cardiac stress and heart failure (HF). End-diastolic wall stress, intracardiac filling pressures, and intracardiac volumes seem to be the dominant triggers. This paper details the most important indications for NPs and highlights 11 key principles underlying their clinical use shown below. NPs should always be used in conjunction with all other clinical information. NPs are reasonable surrogates for intracardiac volumes and filling pressures. NPs should be measured in all patients presenting with symptoms suggestive of HF such as dyspnoea and/or fatigue, as their use facilitates the early diagnosis and risk stratification of HF. NPs have very high diagnostic accuracy in discriminating HF from other causes of dyspnoea: the higher the NP, the higher the likelihood that dyspnoea is caused by HF. Optimal NP cut-off concentrations for the diagnosis of acute HF (very high filling pressures) in patients presenting to the emergency department with acute dyspnoea are higher compared with those used in the diagnosis of chronic HF in patients with dyspnoea on exertion (mild increase in filling pressures at rest). Obese patients have lower NP concentrations, mandating the use of lower cut-off concentrations (about 50% lower). In stable HF patients, but also in patients with other cardiac disorders such as myocardial infarction, valvular heart disease, atrial fibrillation or pulmonary embolism, NP concentrations have high prognostic accuracy for death and HF hospitalization. Screening with NPs for the early detection of relevant cardiac disease including left ventricular systolic dysfunction in patients with cardiovascular risk factors may help to identify patients at increased risk, therefore allowing targeted preventive measures to prevent HF. BNP, NT-proBNP and MR-proANP have comparable diagnostic and prognostic accuracy. In patients with shock, NPs cannot be used to identify cause (e.g. cardiogenic vs. septic shock), but remain prognostic. NPs cannot identify the underlying cause of HF and, therefore, if elevated, must always be used in conjunction with cardiac imaging., (© 2019 The Authors. European Journal of Heart Failure © 2019 European Society of Cardiology.)

Aims: Recent international heart failure (HF) guidelines recognize anaemia as an important comorbidity contributing to poor outcomes in HF, based on data mainly from Western populations. We sought to determine the prevalence, clinical correlates, and prognostic impact of anaemia in patients with HF with reduced ejection fraction across Asia., Methods and Results: We prospectively studied 3886 Asian patients (60 ± 13 years, 21% women) with HF (ejection fraction ≤40%) from 11 regions in the Asian Sudden Cardiac Death in Heart Failure study. Anaemia was defined as haemoglobin <13 g/dL (men) and <12 g/dL (women). Ethnic groups included Chinese (33.0%), Indian (26.2%), Malay (15.1%), Japanese/Korean (20.2%), and others (5.6%). Overall, anaemia was present in 41%, with a wide range across ethnicities (33-54%). Indian ethnicity, older age, diabetes, and chronic kidney disease were independently associated with higher odds of anaemia (all P < 0.001). Ethnicity modified the association of chronic kidney disease with anaemia (P interaction  = 0.045), with the highest adjusted odds among Japanese/Koreans [2.86; 95% confidence interval (CI) 1.96-4.20]. Anaemic patients had lower Kansas City Cardiomyopathy Questionnaire scores (P < 0.001) and higher risk of all-cause mortality and HF hospitalization at 1 year (hazard ratio = 1.28, 95% CI 1.08-1.50) compared with non-anaemic patients. The prognostic impact of anaemia was modified by ethnicity (P interaction  = 0.02), with the greatest hazard ratio in Japanese/Koreans (1.82; 95% CI 1.14-2.91)., Conclusions: Anaemia is present in a third to more than half of Asian patients with HF and adversely impacts quality of life and survival. Ethnic differences exist wherein prevalence is highest among Indians, and survival is most severely impacted by anaemia in Japanese/Koreans., (© 2018 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.)

Background: Serial measurement of natriuretic peptides may guide management in heart failure (HF) patients. In previous trials, natriuretic peptides were infrequently monitored, which may undervalue the benefit of this approach., Methods and Results: HOME was an adaptive three-arm randomized clinical study to test whether home monitoring of BNP could reduce HF-related death, hospitalization due to acute decompensated HF (ADHF), and ADHF treated with intravenous diuretics in the emergency department or outpatient setting. Enrolment was terminated early because of slow enrolment, low event rates, and the belief that an algorithm for assessing BNP trends was needed. Justification for pooling data from all study arms was made and analysis as a single observational study was performed. The analysis resulted in 107 patients who were monitored for a median of 172 days with BNP measures on a median of 74% of days. BNP values were highly variable within a patient. Dispersion between serial BNPs was calculated to be 39.3%, 57.7%, and 73.6% for 1, 60, and 120 days between measures, respectively. A moving average filter (fBNP) was calculated to reduce day-to-day fluctuations and track changes from week to week. There were 27 primary events in 17 362 patient days of monitoring; the hazard ratio for time-varying fBNP was 2.22 (95% confidence interval 1.48-3.34) per unit natural log (corresponding to a 2.72-fold change in fBNP level)., Conclusion: The HOME HF study demonstrates the feasibility of home BNP measurement and shows the potential value of fBNP as an index of emerging clinical deterioration. Assessment of the clinical value of this is required., (© 2017 The Authors. European Journal of Heart Failure © 2017 European Society of Cardiology.)

Background: We hypothesized that survival in implantable cardioverter defibrillator (ICD) and cardiac resynchronization therapy defibrillator (CRT-D) patients is predicted by baseline Heart Rate Score., Methods: Heart Rate Score is determined from the atrial paced and sensed histogram of a DDD ICD or CRT-D, and defined as percent of beats in the histogram in the tallest 10 beats/min range bin. It was calculated at initial remote monitoring for patients enrolled in LATITUDE® without persistent atrial fibrillation, and with pulse generators implanted in 2006-2011. Univariate, multivariate, and Kaplan-Meier analyses determined the impact of Heart Rate Score on survival., Results: Of 57,893 ICDs and 67,929 CRT-Ds followed for 2.4 ± 1.5 years, each 10% increase in Heart Rate Score was associated with decreased survival (CRT-D hazard ratio [HR] 1.07 95%, confidence interval 1.06-1.07, P < 0.0001; ICD HR 1.05, 95% confidence interval 1.04-1.06, P < 0.0001). Multivariate analysis showed survival decreased with increasing age, atrial fibrillation, presence of a shock in first-year follow-up, and increasing programmed lower pacing rate in ICD and CRT-D patients. Increased percent right ventricular pacing predicted mortality in ICD patients, while male gender and lower percent left ventricular pacing predicted mortality in CRT patients. Heart Rate Score predicted survival independent of those variables. Heart Rate Score correlates with heart rate variability (standard deviation of average R-R intervals [SDANN]) when both are obtainable, but SDANN was only present in 6% of patients with Heart Rate Score >70%., Conclusion: A simple device histogram measure, Heart Rate Score, predicts survival in ICD and CRT-D patients independent of the available variables, and even when SDANN is unavailable., (© 2017 Wiley Periodicals, Inc.)

Heart failure (HF) is predominantly a disease of older adults and characterized by extensive sympatho-vagal imbalance leading to impaired reflex control of heart rate (HR). However, whether aging influences the development or extent of the autonomic imbalance in HF remains unclear. To address this, we used an ovine model of aging with tachypacing-induced HF to determine whether aging affects the chronotropic and inotropic responses to autonomic stimulation and reduction in heart rate variability (HRV) in HF. We find that aging is associated with increased cardiac dimensions and reduced contractility before the onset of tachypacing, and these differences persist in HF. Additionally, the chronotropic response to β-adrenergic stimulation was markedly attenuated in HF, and this occurred more rapidly in aged animals. By measuring HR during sequential autonomic blockade, our data are consistent with a reduced parasympathetic control of resting HR in aging, with young HF animals having an attenuated sympathetic influence on HR. Time-domain analyses of HR show a reduction in HRV in both young and aged failing animals, although HRV is lowest in aged HF. In conclusion, aging is associated with altered autonomic control and β-adrenergic responsiveness of HR, and these are exacerbated with the development of HF., (© The Author 2015. Published by Oxford University Press on behalf of The Gerontological Society of America.)

Background: Rate-responsive pacing (DDDR) versus nonrate-responsive pacing (DDD) has shown no survival benefit for patients undergoing cardiac resynchronization therapy defibrillator (CRT-D) implants. The heart rate score (HRSc), an indicator of heart rate variation, may predict survival. We hypothesized that high-risk HRSc CRT-D patients will have improved survival with DDDR versus DDD alone., Methods and Results: All CRT-D patients in LATITUDE remote monitoring (2006-2011), programmed DDD, had HRSc calculated at first data upload after implant (median 1.4 months). Patients subsequently reprogrammed to DDDR 7.6 median months later were compared with a propensity-matched DDD group and followed for 21.4 median months by remote monitoring. Data were adjusted for age, sex, lower rate limit, percent atrial pacing, percent biventricular pacing, and implant year. The social security death index was used to identify deaths. Remote monitoring provided programming and histogram data. DDDR programming in CRT-D patients was associated with improved survival (adjusted hazard ratio =0.77; P<0.001). However, only those with baseline HRSc ≥70% (2308/6164) had improved HRSc with DDDR (from 88±9% to 78±15%; P<0.001) and improved survival (hazard ratio =0.74; P<0.001). Patients with a high baseline HRSc and significant improvement over time were more likely to survive (hazard ratio =0.63; P=0.006). For patients with HRSc <70%, DDDR reprogramming increased the HRSc from 46±11% to 50±15% (P<0.001); survival did not change. The HRSc did not change with DDD pacing over time., Conclusions: In CRT-D patients with HRSc ≥70%, DDDR reprogramming improved the HRSc and was associated with survival. Patients with lower HRSc had no change in survival with DDDR programming., (© 2016 American Heart Association, Inc.)

Aim: To investigate the relationship between heart rate and survival in patients with heart failure (HF) and coexisting atrial fibrillation (AF)., Methods and Results: Patients with AF included in the Meta-analysis Global Group in Chronic Heart Failure (MAGGIC) meta-analysis were the main focus of this analysis (3259 patients from 17 studies). The outcome was all-cause mortality at 3 years. Heart rate was analysed as a categorical (tertiles; T1 ≤77 b.p.m., T2 78-98 b.p.m., T3 ≥98 b.p.m.) and continuous variable. Cox proportional hazard models were used to compare the risk of all-cause death between tertiles of baseline heart rate. Patients in the highest tertile were more often female, less likely to have an ischaemic aetiology or diabetes, had a lower ejection fraction but higher blood pressure and New York Heart Association (NYHA) class. Higher heart rate was associated with higher mortality in patients with sinus rhythm (SR) but not in those in AF. In patients with heart failure and reduced ejection fraction (HF-REF) and AF, death rates per 100 patient years were lowest in the highest heart rate tertile (T1 18.9 vs. T3 15.9) but this difference was not statistically significant (P = 0.10). In patients with heart failure and preserved ejection fraction (HF-PEF), death rates per 100 patient years were highest in the highest heart rate tertile (T1 14.6 vs. T3 16.0, P = 0.014). However, after adjustment for other important prognostic variables, higher heart rate was no longer associated with higher mortality in HF-PEF (or HF-REF)., Conclusions: In this meta-analysis of patients with HF, heart rate does not have the same prognostic significance in patients in AF as it does in those in SR, irrespective of ejection fraction or treatment with beta-blocker., (© 2015 The Authors European Journal of Heart Failure © 2015 European Society of Cardiology.)

Heart failure (HF) is commonly associated with reduced cardiac output and an increased risk of atrial arrhythmias particularly during β-adrenergic stimulation. The aim of the present study was to determine how HF alters systolic Ca(2+) and the response to β-adrenergic (β-AR) stimulation in atrial myocytes. HF was induced in sheep by ventricular tachypacing and changes in intracellular Ca(2+) concentration studied in single left atrial myocytes under voltage and current clamp conditions. The following were all reduced in HF atrial myocytes; Ca(2+) transient amplitude (by 46% in current clamped and 28% in voltage clamped cells), SR dependent rate of Ca(2+) removal (kSR, by 32%), L-type Ca(2+) current density (by 36%) and action potential duration (APD90 by 22%). However, in HF SR Ca(2+) content was increased (by 19%) when measured under voltage-clamp stimulation. Inhibiting the L-type Ca(2+) current (ICa-L) in control cells reproduced both the decrease in Ca(2+) transient amplitude and increase of SR Ca(2+) content observed in voltage-clamped HF cells. During β-AR stimulation Ca(2+) transient amplitude was the same in control and HF cells. However, ICa-L remained less in HF than control cells whilst SR Ca(2+) content was highest in HF cells during β-AR stimulation. The decrease in ICa-L that occurs in HF atrial myocytes appears to underpin the decreased Ca(2+) transient amplitude and increased SR Ca(2+) content observed in voltage-clamped cells., (Copyright © 2014. Published by Elsevier Ltd.)

Objectives: The purpose of this study was to assess the impact of atrial fibrillation (AF) on the performance of mid-region amino terminal pro-atrial natriuretic peptide (MR-proANP) in comparison with the B-type peptides (BNP and NT-proBNP) for diagnosis of acute heart failure (HF) in dyspneic patients., Background: The effects of AF on the diagnostic and prognostic performance of MR-proANP in comparison with the B type natriuretic peptides have not been previously reported., Methods: A total of 1,445 patients attending the emergency department with acute dyspnea had measurements taken of MR-proANP, BNP, and NT-proBNP values on enrollment to the BACH trial and were grouped according to presence or absence of AF and HF., Results: AF was present in 242 patients. Plasma concentrations of all three peptides were lowest in those with neither AF nor HF and AF without HF was associated with markedly increased levels (p < 0.00001). HF with or without AF was associated with a significant further increment (p < 0.00001 for all three markers). Areas under receiver operator characteristic curves (AUCs) for discrimination of acute HF were similar and powerful for all peptides without AF (0.893 to 0.912; all p < 0.001) with substantial and similar reductions (0.701 to 0.757) in the presence of AF. All 3 peptides were independently prognostic but there was no interaction between any peptide and AF for prediction of all-cause mortality., Conclusions: AF is associated with increased plasma natriuretic peptide (MR-proANP, BNP and NT-proBNP) levels in the absence of HF. The diagnostic performance of all three peptides is impaired by AF. This warrants consideration of adjusted peptide thresholds for diagnostic use in AF and mandates the continued search for markers free of confounding by AF., (Copyright © 2013 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Serum mid-regional pro-atrial natriuretic peptide (MR-proANP) and pro-adrenomedullin (MR-proADM) are novel biomarkers for acute heart failure (AHF). Like other AFH biomarkers, the performance of these tests are affected by the presence of clinical variables such as renal failure and obesity. In a substudy of the Biomarkers from Acute Heart Failure Study, we show that diabetes did not influence the performance of these markers with regards to AHF diagnosis or 90-day all cause death. However, in patients without AHF, increased MR-proADM alone was associated with the presence of diabetes.

The incidence of heart failure (HF) increases with age. This study sought to determine whether aging exacerbates structural and functional remodeling of the myocardium in HF. HF was induced in young (~18 months) and aged sheep (>8 years) by right ventricular tachypacing. In non-paced animals, aging was associated with increased left ventricular (LV) end diastolic internal dimensions (EDID, P<0.001), reduced fractional shortening (P<0.01) and an increase in myocardial collagen content (P<0.01). HF increased EDID and reduced fractional shortening in both young and aged animals, although these changes were more pronounced in the aged (P<0.05). Age-associated differences in cardiac extracellular matrix (ECM) remodeling occurred in HF with collagen accumulation in young HF (P<0.001) and depletion in aged HF (P<0.05). MMP-2 activity increased in the aged control and young HF groups (P<0.05). Reduced tissue inhibitor of metalloproteinase (TIMP) expression (TIMPs 3 and 4, P<0.05) was present only in the aged HF group. Secreted protein acidic and rich in cysteine (SPARC) was increased in aged hearts compared to young controls (P<0.05) while serum procollagen type I C-pro peptide (PICP) was increased in both young failing (P<0.05) and aged failing (P<0.01) animals. In conclusion, collagen content of the cardiac ECM changes in both aging and HF although; whether collagen accumulation or depletion occurs depends on age. Changes in TIMP expression in aged failing hearts alongside augmented collagen synthesis in HF provide a potential mechanism for the age-dependent ECM remodeling. Aging should therefore be considered an important factor when elucidating cardiac disease mechanisms., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Aims: Biomarkers have proven their ability in the evaluation of cardiopulmonary diseases. We investigated the utility of concentrations of the biomarker procalcitonin (PCT) alone and with clinical variables for the diagnosis of pneumonia in patients presenting to emergency departments (EDs) with a chief complaint of shortness of breath., Methods and Results: The BACH trial was a prospective, international, study of 1641 patients presenting to EDs with dyspnoea. Blood samples were analysed for PCT and other biomarkers. Relevant clinical data were also captured. Patient outcomes were assessed at 90 days. The diagnosis of pneumonia was made using strictly validated guidelines. A model using PCT was more accurate [area under the curve (AUC) 72.3%] than any other individual clinical variable for the diagnosis of pneumonia in all patients, in those with obstructive lung disease, and in those with acute heart failure (AHF). Combining physician estimates of the probability of pneumonia with PCT values increased the accuracy to >86% for the diagnosis of pneumonia in all patients. Patients with a diagnosis of AHF and an elevated PCT concentration (>0.21 ng/mL) had a worse outcome if not treated with antibiotics (P = 0.046), while patients with low PCT values (<0.05 ng/mL) had a better outcome if they did not receive antibiotic therapy (P = 0.049)., Conclusion: Procalcitonin may aid in the diagnosis of pneumonia, particularly in cases with high diagnostic uncertainty. Importantly, PCT may aid in the decision to administer antibiotic therapy to patients presenting with AHF in which clinical uncertainty exists regarding a superimposed bacterial infection.

Aims: Midregional pro atrial natriuretic peptide (MR-proANP) is useful for diagnosing acute heart failure (HF) in patients presenting to the Emergency Department with dyspnoea. Optimal interpretation of MR-proANP requires understanding of how various demographic variables influence its levels and performance as a diagnostic marker. We sought to determine how age, race, sex, and body mass index (BMI) affect the levels and interpretation of MR-proANP for the diagnosis of acute HF., Methods and Results: The Biomarkers in Acute Heart Failure (BACH) study was an international 15-centre study of 1641 patients presenting to the Emergency Department with acute dyspnoea. Of these, 1352 had complete information on age, race, sex, and BMI. MR-proANP levels increased with age and were higher in men and in patients with lower BMI. MR-proANP performed better as a diagnostic marker in younger individuals and in blacks compared with whites. Despite this, MR-proANP at the recommended cut-off point of 120 pmol/L was >90 % sensitive in ruling out the diagnosis of acute HF in all subgroups of patients except white subjects <50 years old., Conclusion: Age, race, sex, and BMI affect MR-proANP levels to various degrees. However, the diagnostic performance of the recommended cut-off point of 120 pmol/L to rule out acute HF was robust across most subgroups. Although both sex and BMI affected MR-proANP levels, they did not alter its overall diagnostic performance. Lower cut-off points for MR-proANP could be considered in younger patients and in patients with a higher BMI, to optimize diagnostic sensitivity.

Objectives: The challenge in management of acute decompensated heart failure (ADHF) is relieving congestion and improving symptoms while preserving renal and systemic perfusion at a level that can tolerate introduction of drugs such as beta-blockers which may have adverse effects acutely yet have proven benefit in the longer term. Urocortin 2 (Ucn2) is a novel peptide with therapeutic potential in heart failure. The present study investigated the effects of combined Ucn2 and beta-blockade in heart failure., Methods: Ucn2 and metoprolol were administered for 3 h, separately and together, in eight sheep with pacing-induced congestive heart failure., Results: Compared with time-matched controls, metoprolol significantly reduced heart rate (HR), left ventricular contractility, cardiac output (CO) and mean arterial pressure (MAP), together with increases in peripheral resistance and left atrial pressure (LAP). In contrast, Ucn2 elevated HR, contractility, CO and MAP, and decreased peripheral resistance and LAP. Combined Ucn2 + metoprolol produced intermediate haemodynamic effects closer to those observed with Ucn2 than with beta-blockade. All three active treatment regimes decreased plasma renin activity, whereas only Ucn2 and Ucn2 + metoprolol significantly reduced plasma aldosterone. Compared with metoprolol alone (which tended to reduce urine output and creatinine excretion/clearance), Ucn2 + metoprolol increased urine volume, sodium and creatinine excretion and clearance., Conclusion: Ucn2 coupled with beta-blockade in experimental heart failure improves CO and MAP, sustains HR, reduces peripheral resistance, LAP and aldosterone and augments renal function. These results suggest a role for Ucn2 as a short-term parenteral therapy in the initial stages of managing ADHF that improves tolerance to introduction of beta-blockers.

Objectives: Few tools exist that provide objective accurate prediction of short-term mortality risk in patients presenting with acute heart failure (AHF). The purpose was to describe the accuracy of several biomarkers for predicting short-term death rates in patients diagnosed with AHF in the emergency department (ED)., Methods: The Biomarkers in ACute Heart failure (BACH) trial was a prospective, 15-center, international study of patients presenting to the ED with nontraumatic dyspnea. Clinicians were blinded to all investigational markers, except troponin and natriuretic peptides, which used the local hospital reference range. For this secondary analysis, a core lab was used for all markers except troponin. This study evaluated patients diagnosed with AHF by the on-site emergency physician (EP)., Results: In the 1,641 BACH patients, 466 (28.4%) had an ED diagnosis of AHF, of whom 411 (88.2%) had a final diagnosis of AHF. In the ED-diagnosed HF patients, 59% were male, 69% had a HF history, and 19 (4.1%) died within 14 days of their ED visit. The area under the curve (AUC) for the 14-day mortality receiver operating characteristic (ROC) curve was 0.484 for brain natriuretic peptide (BNP), 0.586 for N-terminal pro-B-type natriuretic peptide (NT-proBNP), 0.755 for troponin (I or T), 0.742 for adrenomedullin (MR-proADM), and 0.803 for copeptin. In combination, MR-proADM and copeptin had the best 14-day mortality prediction (AUC = 0.818), versus all other markers., Conclusions: MR-proADM and copeptin, alone or in combination, may provide superior short-term mortality prediction compared to natriuretic peptides and troponin. Presented results are explorative due to the limited number of events, but validation in larger trials seems promising., (© 2011 by the Society for Academic Emergency Medicine.)

Background: In patients with heart failure (HF), increased arginine vasopressin concentrations are associated with more severe disease, making arginine vasopressin an attractive target for therapy. However, AVP is difficult to measure due to its in vitro instability and rapid clearance. Copeptin, the C-terminal segment of preprovasopressin, is a stable and reliable surrogate biomarker for serum arginine vasopressin concentrations., Methods and Results: The Biomarkers in Acute Heart Failure (BACH) trial was a 15-center, diagnostic and prognostic study of 1641 patients with acute dyspnea; 557 patients with acute HF were included in this analysis. Copeptin and other biomarker measurements were performed by a core laboratory at the University of Maryland. Patients were followed for up to 90 days after initial evaluation for the primary end point of all-cause mortality, HF-related readmissions, and HF-related emergency department visits. Patients with copeptin concentrations in the highest quartile had increased 90-day mortality (P<0.001; hazard ratio, 3.85). Mortality was significantly increased in patients with elevated copeptin and hyponatremia (P<0.001; hazard ratio, 7.36). Combined end points of mortality, readmissions, and emergency department visits were significantly increased in patients with elevated copeptin. There was no correlation between copeptin and sodium (r=0.047)., Conclusions: This study showed significantly increased 90-day mortality, readmissions, and emergency department visits in patients with elevated copeptin, especially in those with hyponatremia. Copeptin was highly prognostic for 90-day adverse events in patients with acute HF, adding prognostic value to clinical predictors, ser um sodium, and natriuretic peptides., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00537628.

Reduced inotropic responsiveness is characteristic of heart failure (HF). This study determined the cellular Ca2+ homeostatic and molecular mechanisms causing the blunted β-adrenergic (β-AR) response in HF.We induced HF by tachypacing in sheep; intracellular Ca2+ concentration was measured in voltage-clamped ventricular myocytes. In HF, Ca2+ transient amplitude and peak L-type Ca2+ current (ICa-L) were reduced (to 70 ± 11% and 50 ± 3.7% of control, respectively, P <0.05) whereas sarcoplasmic reticulum (SR) Ca2+ content was unchanged. β-AR stimulation with isoprenaline (ISO) increased Ca2+ transient amplitude, ICa-L and SRCa2+ content in both cell types; however, the response of HF cells was markedly diminished (P <0.05).Western blotting revealed an increase in protein phosphatase levels (PP1, 158 ± 17% and PP2A, 188 ± 34% of control, P <0.05) and reduced phosphorylation of phospholamban in HF (Ser16, 30 ± 10% and Thr17, 41 ± 15% of control, P <0.05). The β-AR receptor kinase GRK-2 was also increased in HF (173 ± 38% of control, P <0.05). In HF, activation of adenylyl cyclase with forskolin rescued the Ca2+ transient, SR Ca2+ content and SR Ca2+ uptake rate to the same levels as control cells in ISO. In conclusion, the reduced responsiveness of the myocardium to β-AR agonists in HF probably arises as a consequence of impaired phosphorylation of key intracellular proteins responsible for regulating the SR Ca2+ content and therefore failure of the systolic Ca2+ transient to increase appropriately during β-AR stimulation.

Objectives: Our purpose was to assess the diagnostic utility of mid-regional pro-atrial natriuretic peptide (MR-proANP) for the diagnosis of acute heart failure (AHF) and the prognostic value of mid-regional pro-adrenomedullin (MR-proADM) in patients with AHF., Background: There are some caveats and limitations to natriuretic peptide testing in the acute dyspneic patient., Methods: The BACH (Biomarkers in Acute Heart Failure) trial was a prospective, 15-center, international study of 1,641 patients presenting to the emergency department with dyspnea. A noninferiority test of MR-proANP versus B-type natriuretic peptide (BNP) for diagnosis of AHF and a superiority test of MR-proADM versus BNP for 90-day survival were conducted. Other end points were exploratory., Results: MR-proANP (> or =120 pmol/l) proved noninferior to BNP (> or =100 pg/ml) for the diagnosis of AHF (accuracy difference 0.9%). In tests of secondary diagnostic objectives, MR-proANP levels added to the utility of BNP levels in patients with intermediate BNP values and with obesity but not in renal insufficiency, the elderly, or patients with edema. Using cut-off values from receiver-operating characteristic analysis, the accuracy to predict 90-day survival of heart failure patients was 73% (95% confidence interval: 70% to 77%) for MR-proADM and 62% (95% confidence interval: 58% to 66%) for BNP (difference p < 0.001). In adjusted multivariable Cox regression, MR-proADM, but not BNP, carried independent prognostic value (p < 0.001). Results were consistent using NT-proBNP instead of BNP (p < 0.001). None of the biomarkers was able to predict rehospitalization or visits to the emergency department with clinical relevance., Conclusions: MR-proANP is as useful as BNP for AHF diagnosis in dyspneic patients and may provide additional clinical utility when BNP is difficult to interpret. MR-proADM identifies patients with high 90-day mortality risk and adds prognostic value to BNP. (Biomarkers in Acute Heart Failure [BACH]; NCT00537628)., (Copyright 2010 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Hyponatremia is a well-known predictor of mortality in patients with acutely decompensated heart failure. Associations between hyponatremia and other prognostic variables in acutely decompensated heart failure, such as amino-terminal pro-B type natriuretic peptide remain unclear., Methods and Results: Six hundred twenty-eight patients presenting to the emergency department with acutely decompensated heart failure were studied. All were hospitalized. Serum sodium (Na) concentration at presentation was examined as a function of mortality at 1 year, alone and relative to other predictors of death. Hyponatremia (Na < or =135 mmol/L) was diagnosed in 24%(n=149) patients. Compared with those without hyponatremia, those affected were less likely to be male or to have hypertension or coronary artery disease but were more likely to have severe symptoms, to be anemic, and to have higher amino-terminal pro-B-type natriuretic peptide (NT-proBNP) concentrations (all P< or =0.05). When examined as a function of Na deciles (ranging from Na <132 mmol/L to Na < or =142 mmol/L), a U-shaped association was found between Na level and 1-year mortality. In multivariate Cox proportional hazards analysis, hyponatremia was an independent predictor of 1-year mortality (hazards ratio=1.72; 95% CI=1.22 to 2.37; P=0.001) as was an NT-proBNP concentration above the median value of 4690 pg/mL (hazards ratio=1.49; 95% CI=1.10 to 2.00; P=0.009). Those with hyponatremia and more elevated NT-proBNP were more likely to develop worsening renal function during their hospitalization and had highest rates of 1-year death. Notably, however, hyponatremia predicted only 1-year mortality in those with an elevated NT-proBNP., Conclusion: Hyponatremia is associated with adverse outcome in patients with acutely decompensated heart failure; however, the prognostic value of low Na is mainly evident in those with more pronounced elevation of NT-proBNP concentrations.

Background: Previous studies suggest that management of ambulatory hemodynamics may improve outcomes in chronic heart failure. We conducted a prospective, observational, first-in-human study of a physician-directed patient self-management system targeting left atrial pressure., Methods and Results: Forty patients with reduced or preserved left ventricular ejection fraction and a history of New York Heart Association class III or IV heart failure and acute decompensation were implanted with an investigational left atrial pressure monitor, and readings were acquired twice daily. For the first 3 months, patients and clinicians were blinded as to these readings, and treatment continued per usual clinical assessment. Thereafter, left atrial pressure and individualized therapy instructions guided by these pressures were disclosed to the patient. Event-free survival was determined over a median follow-up of 25 months (range 3 to 38 months). Survival without decompensation was 61% at 3 years, and events tended to be less frequent after the first 3 months (hazard ratio 0.16 [95% confidence interval 0.04 to 0.68], P=0.012). Mean daily left atrial pressure fell from 17.6 mm Hg (95% confidence interval 15.8 to 19.4 mm Hg) in the first 3 months to 14.8 mm Hg (95% confidence interval 13.0 to 16.6 mm Hg; P=0.003) during pressure-guided therapy. The frequency of elevated readings (>25 mm Hg) was reduced by 67% (P<0.001). There were improvements in New York Heart Association class (-0.7+/-0.8, P<0.001) and left ventricular ejection fraction (7+/-10%, P<0.001). Doses of angiotensin-converting enzyme/angiotensin-receptor blockers and beta-blockers were uptitrated by 37% (P<0.001) and 40% (P<0.001), respectively, whereas doses of loop diuretics fell by 27% (P=0.15)., Conclusions: Physician-directed patient self-management of left atrial pressure has the potential to improve hemodynamics, symptoms, and outcomes in advanced heart failure. Clinical Trial Registration Information- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00547729.

Background: In ventricular myocytes, the majority of structures that couple excitation to the systolic rise of Ca(2+) are located at the transverse tubular (t-tubule) membrane. In the failing ventricle, disorganization of t-tubules disrupts excitation contraction coupling. The t-tubule membrane is virtually absent in the atria of small mammals resulting in spatiotemporally distinct profiles of intracellular Ca(2+) release on stimulation in atrial and ventricular cells. The aims of this study were to determine (i) whether atrial myocytes from a large mammal (sheep) possess t-tubules, (ii) whether these are functionally important, and (iii) whether they are disrupted in heart failure., Methods and Results: Sheep left atrial myocytes were stained with di-4-ANEPPS. Nearly all control cells had an extensive t-tubule network resulting in each voxel in the cell being nearer to a membrane (sarcolemma or t-tubule) than would otherwise be the case. T-tubules decrease the distance of 50% of voxels from a membrane from 3.35 + or - 0.15 to 0.88 + or- 0.04 microm. During depolarization, intracellular Ca(2+) rises simultaneously at the cell periphery and center. In heart failure induced by rapid ventricular pacing, there was an almost complete loss of atrial t-tubules. The distance of 50% of voxels from a membrane increased to 2.04 + or - 0.08 microm, and there was a loss of early Ca(2+) release from the cell center., Conclusions: Sheep atrial myocytes possess a substantial t-tubule network that synchronizes the systolic Ca(2+) transient. In heart failure, this network is markedly disrupted. This may play an important role in changes of atrial function in heart failure.

Aims: Brain natriuretic peptide (BNP), left ventricular (LV) systolic function, and mitral filling pattern (MFP) are prognostic indicators in patients with heart failure (HF). This study evaluated the potential role of E/Ea for predicting cardiovascular (CV) events in patients with suspected HF. This non-invasive measure of LV filling pressure has been shown to predict outcome in more advanced HF, but not in mild HF in the community., Methods and Results: Two hundred and twenty-eight elderly symptomatic general practice patients (dyspnoea/oedema) were recruited and underwent clinical evaluation, NT-proBNP assay, and comprehensive echocardiography. The Kaplan-Meier analysis of time to first CV hospitalization or CV death was performed for 1 year after presentation according to nominated thresholds of LV systolic function, NT-proBNP, MFP, and E/Ea ratio. Mean age was 70.3 +/- 7.3 years, mean NT-proBNP was 111.4 +/- 185.8, and 148 (65%) were female. Twenty-six patients (11%) experienced a CV event within 18 months of baseline (6 deaths and 20 admissions). Time to first CV event predicted by NT-proBNP (P < 0.0001), MFP (P = 0.009), and E:Ea (P = 0.0076), but not EF (P = 0.098). When NT-proBNP was elevated, E:Ea >15 identified a group of patients with lower survival (P < 0.0001)., Conclusion: Both E/Ea and NT-proBNP predicted hospitalization and when used in a two-step approach (NT-proBNP first, followed by E/Ea), the combination of both (elevated NT-proBNP and elevated E/Ea) identified those patients at highest risk, thus supporting a complementary approach for echocardiography and NT-proBNP in patients with HF symptoms.

Aims: To document the haemodynamic, neurohormonal, and renal responses to Urocortin 2 (UCN2) infused in human heart failure (HF)., Methods and Results: Eight male patients with HF [left ventricular ejection fraction (LVEF) < 40%, NYHA class II-III] received placebo and 25 [low dose (LD)] and 100 microg [high dose (HD)] of UCN2 intravenously over 1 h in a single-blind, placebo-controlled, dose-escalation design. UCN2 increased cardiac output (CO) (mean peak increments +/- SEM; placebo 0.3 +/- 0.1; LD 1.0 +/- 0.3; HD 2.0 +/- 0.2 L/min; P < 0.001) and LVEF (0.0 +/- 1.5; LD 5.9 +/- 2.1; HD 14.1 +/- 2.7%; P = 0.001) and decreased mean arterial pressure (placebo 6.7 +/- 1.3; LD 11.4 +/- 1.7; HD 19.4 +/- 3.3 mmHg; P = 0.001), systemic vascular resistance (SVR) (placebo 104 +/- 37; LD 281 +/- 64; HD 476 +/- 79 dynes s/cm(5); P < 0.003), and cardiac work (CW) (placebo 48 +/- 12; LD 66 +/- 22; HD 94 +/- 13 mmHg/L/min; P < 0.001). No significant effect on vasoconstrictor/volume-retaining neurohormones was noted. UCN2 decreased urinary volume (P = 0.035) but not creatinine excretion (P = 0.962)., Conclusion: Intravenous UCN2 in HF induced increases in CO and LVEF with falls in SVR and CW. No hormone response occurred. The role of UCN2 in circulatory regulation and its potential therapeutic application in heart disease warrant further investigation.

Background: Hemoglobin and amino-terminal pro-brain natriuretic peptide (NT-proBNP) are both independent predictors of mortality in patients with chronic HF. Their combined predictive power for mortality in the setting of acute HF is uncertain., Methods: In an international prospective cohort design, we evaluated the relationships between hemoglobin, NT-proBNP, and 60-day mortality in 690 patients with acute HF., Results: The median hemoglobin for the entire cohort was 13.0 g/dL (interquartile range 11.6-14.3). The WHO criterion for anemia was met by 44% (n=305). The 60-day mortality rate for anemic patients was 16.4% vs. 8.8% in non-anemic patients (p<0.001). Anemia was an independent predictor of short-term mortality (OR=1.72, 95% CI=1.05-2.80, p=0.03), as was a NT-proBNP concentration >5180 pg/mL (OR=2.32, 95% CI=1.36-3.94 p=0.002). Consideration of four risk groups: not anemic/low NT-proBNP (reference group, n=220), anemic/low NT-proBNP (n=152), not anemic/high NT-proBNP (n=165), and anemic/high NT-proBNP (n=153) revealed respective 60-day mortality rates of 5.0% (referent), 9.2% (OR=1.93, 95% CI=0.85-4.36; p=0.12), 13.9% (OR=3.07, 95% CI=1.45-6.50, p=0.003), and 23.5% (OR=5.84, 95% CI=2.87-11.89, p<0.001)., Conclusions: Anemia was common in this cohort of subjects with acute HF and was related to adverse short-term outcome. Integrated use of hemoglobin and NT-proBNP measurements provides powerful additive information and is superior to the use of either in isolation.

Aims: Experience with amino-terminal pro-brain natriuretic peptide (NT-proBNP) testing for evaluation of dyspnoeic patients with suspected acute heart failure (HF) is limited to single-centre studies. We wished to establish broader standards for NT-proBNP testing in a study involving four sites in three continents., Methods and Results: Differences in NT-proBNP levels among 1256 patients with and without acute HF and the relationship between NT-proBNP levels and HF symptoms were examined. Optimal cut-points for diagnosis and prognosis were identified and verified using bootstrapping and multi-variable logistic regression techniques. Seven hundred and twenty subjects (57.3%) had acute HF, whose median NT-proBNP was considerably higher than those without (4639 vs. 108 pg/mL, P<0.001), and levels of NT-proBNP correlated with HF symptom severity (P=0.008). An optimal strategy to identify acute HF was to use age-related cut-points of 450, 900, and 1800 pg/mL for ages <50, 50-75, and >75, which yielded 90% sensitivity and 84% specificity for acute HF. An age-independent cut-point of 300 pg/mL had 98% negative predictive value to exclude acute HF. Among those with acute HF, a presenting NT-proBNP concentration >5180 pg/mL was strongly predictive of death by 76 days [odds ratio=5.2, 95% confidence interval (CI)=2.2-8.1, P<0.001]., Conclusion: In this multi-centre, international study, NT-proBNP testing was valuable for diagnostic evaluation and short-term prognosis estimation in dyspnoeic subjects with suspected or confirmed acute HF and should establish broader standards for use of the NT-proBNP in dyspnoeic patients.

Background: Sleep-disordered breathing (SDB) has a potential role in the pathogenesis of congestive heart failure (CHF). High rates of central sleep apnea (CSA) are found in patients with severe CHF, and equal proportions of obstructive sleep apnea (OSA) and CSA in are found CHF patients referred to sleep clinics. The prevalence, type, and severity of SDB in unselected stable outpatients with CHF are unknown., Study Objectives: To determine the frequency and type of SDB in stable CHF outpatients and to examine the relationship between indexes of SDB and impaired cardiac function., Participants: Fifty-three of 87 eligible outpatients (left ventricular ejection fraction [LVEF] < 45%) were predominantly male (77%), with an average age of 60.1 +/- 9.8 years, mean body mass index of 27.9 +/- 5.3 kg/m2, and mean LVEF of 34.0 +/- 8.5% (+/- SD)., Measurements: Polysomnography, clinical questionnaire, echocardiography, urinary catecholamines, and amino-terminal fragment of pro-brain natriuretic peptide (NT-BNP)., Results: SDB (apnea-hypopnea index >10 events/h) was demonstrated in 36 patients (68%) including two subgroups: OSA (n = 28, 53%) and CSA (n = 8, 15%). SDB was associated with atrial fibrillation (0% vs 28%, p = 0.02), more severe oxyhemoglobin desaturation (percentage of time with oxygen saturation < 90%: 0.4% vs 7.9%, p = 0.003), sleep disruption (p = 0.003), and higher urinary noradrenaline levels (p = 0.013) in OSA patients and CSA patients, respectively. Subjective sleepiness (Epworth sleepiness scale, 7.5 vs 8.5; p = 0.11), indexes of impaired cardiac function including Minnesota Living With Heart Failure Questionnaire scores, shuttle walk distance, and NT-BNP levels were not related to the presence of SDB (p > 0.05). CSA patients had lower LVEF (p = 0.0013)., Conclusions: SDB is very common in stable outpatients with CHF, and in our sample OSA predominates. Atrial fibrillation and severe left ventricular impairment increased the likelihood of SDB (particularly CSA), whereas symptom severity, subjective daytime sleepiness, exercise capacity, and NT-BNP levels did not. If specific therapy for SDB such as continuous positive airway pressure can be shown to improve major cardiovascular end points, these results support screening of clinically stable CHF patients.

The cardiac natriuretic peptides, and in particular plasma levels of the B-type natriuretic peptides, are acknowledged biomarkers of cardiac function and prognosis in cardiovascular disease. A growing body of evidence confirms plasma BNP and/or NT-proBNP are independent predictors of mortality and/or heart failure events in acute heart failure, established chronic heart failure, acute coronary syndromes and even in asymptomatic but at risk populations. Alongside this large body of associative observational data, there is a growing evidence base from controlled trials which indicates that knowledge of plasma B-type natriuretic peptide levels can be translated into improved clinical outcomes. Measurements of NT-proBNP improve diagnostic accuracy in patients presenting with heart failure in the community. Provision of plasma BNP data improves speed of diagnosis and reduces rates of hospital admission in patients with heart failure presenting with breathlessness (all whilst reducing overall costs). A randomised pilot study demonstrates serial measurements of NT-proBNP can assist in more effective optimisation of heart failure pharmacotherapy with a concomitant improvement in outcome. This finding has been corroborated by a recently reported multicentre study. Screening for left ventricular systolic dysfunction in the general population or in asymptomatic subjects at high risk of cardiovascular events appears to be cost-effective. This developing evidence base from controlled trials encourages further implementation of plasma BNP and/or NT-proBNP in diagnosis, risk stratification and management, not only of acute and chronic heart failure but also in those with coronary disease and asymptomatic subjects with cardiovascular risk factors.

Aims: To document the number of requests by clinicians for plasma brain natriuretic peptide (BNP) measurements and to define which groups of practitioners have made use of the assay over the 7 years since it became available for clinical use., Methods: We reviewed the number and source of requests by clinicians for measurements of plasma BNP in the Christchurch area (from 1995--when the assay became available, until July 2002)., Results: There was an exponential increase in requests for BNP measurements over the 7-year period (1995-2002). Of the 11,308 samples analysed, 47% came from hospital inpatients, 25.9% from patients in general practice, and 14% from hospital emergency departments., Conclusions: There has been a rapidly increasing uptake of the assay for plasma BNP by both hospital and primary care clinicians in the Christchurch area.

With increasing cardiac dysfunction, a complex neurohormonal response results in increasing circulating levels of an array of plasma hormones. Increments in plasma levels of atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) and their amino-terminal congeners are more closely related to cardiac structure and function and to cardiovascular prognosis than changes in other plasma neurohormones. Reports suggest that changes in plasma BNP levels in the course of treatment of acutely decompensated heart failure provide a more powerful prognostic indicator of the likelihood of survival or recurrent decompensation than symptomatic assessment. This observation requires a randomised controlled trial in which changes in peptide levels determine aggression and duration of in-patient therapy in order to establish whether this indicator can improve results from management of acute in-patient heart failure. Plasma BNP or NT-proBNP is a powerful independent predictor of mortality and morbidity in long-term follow-up of heart failure cohorts. In addition, it appears likely to be a good predictor of beneficial response to the addition of beta blockade to anti-heart failure pharmacotherapy. Finally, adjustment of therapy for heart failure according to serial measurements of NT-proBNP promises to improve outcomes in comparison with adjusting therapy according to unassisted clinical acumen.

The levels and pathophysiological role of amino terminal C-type natriuretic peptide in heart failure are unknown. The potential of plasma amino-terminal C-type natriuretic peptide (N-CNP) as a marker of cardiac function was investigated in symptomatic patients. In 305 patients with recent-onset dyspnea and/or peripheral edema, presenting to primary care, assay of plasma amino-terminal C-type natriuretic peptide and other plasma vasoactive hormones was conducted together with echocardiography. Heart failure was diagnosed in 77 (of the 305) patients by rigorous application of predefined criteria. Plasma amino-terminal C-type natriuretic peptide concentrations were elevated in patients with heart failure, and by univariate analysis were related to age, renal function, and other hormones. On multivariate analysis, tertile of plasma N-CNP interacted with tertile of plasma amino-terminal B-type natriuretic peptide to predict heart failure independent of age, gender, renal function, or echocardiographic left ventricular fractional shortening. N-CNP showed significant relations to concurrent plasma CNP, atrial natriuretic peptide (ANP), N-ANP, B-type (or brain) natriuretic peptide (BNP), N-BNP, endothelin-1, and adrenomedullin but not to echocardiographic indicators of left ventricular systolic function. Plasma amino-terminal C-type natriuretic peptide is elevated in heart failure and is related to other plasma hormones in heart failure. These findings suggest a possible compensatory response from the peripheral vasculature to heart failure by an endothelium-based vasodilator peptide and mandate further exploration of the role of C-type natriuretic peptide in this condition.

Objectives: The purpose of this study was to determine the effect of amino-terminal pro-brain natriuretic peptide (N-BNP) on the diagnostic accuracy of heart failure (HF) in primary care., Background: The accurate diagnosis of patients with suspected HF presenting in primary care is difficult. Amino-terminal pro-brain natriuretic peptide is present in high levels in cardiac dysfunction and may improve the diagnostic accuracy of HF in primary care., Methods: The Natriuretic Peptides in the Community Study was a prospective, randomized controlled trial of the effect of N-BNP on the accuracy of HF diagnosis. Patients presenting to their general practitioner (GP) with symptoms of dyspnea and/or peripheral edema were included. The GPs formulated an initial diagnosis based on clinical assessment. All patients underwent a full cardiologic assessment that included echocardiography and N-BNP. Each patient was randomized to the BNP group (GP received the N-BNP result) or the control group (GP did not receive the N-BNP result). Patients were then reviewed by their GP, and their diagnosis was reviewed. The primary end point was the accuracy of the GPs' diagnoses compared with the panel standard., Results: A total of 305 patients were included; mean age was 72 years, 65% were female. Seventy-seven patients met the panel criteria for HF. The diagnostic accuracy improved 21% in the BNP group and 8% in the control group (p = 0.002). The main impact of N-BNP measurement on diagnostic accuracy was the GPs' correctly ruling out HF. The number needed to diagnose by N-BNP measurement was seven patients., Conclusion: This study demonstrates that N-BNP measurement significantly improves the diagnostic accuracy of HF by GPs over and above customary clinical review.

With the increasing prevalence of heart failure, the greater spectrum of proven therapies, the broader spectrum of cardiac dysfunction qualifying for treatment and the recognition that heart failure is difficult to diagnose, the need for an indicator of both the diagnosis and the efficacy of treatment in this condition is clear. Plasma concentrations of the B-type natriuretic peptides are related to cardiac function and cardiovascular prognosis. They parallel hemodynamic indicators of cardiac dysfunction and may therefore act as indicators of the adequacy of therapy. In the one published trial of outpatient treatment of heart failure guided by plasma BNP, 69 patients (LVEF < 40%, NYHA II-IV) were randomised to treatment according to plasma peptide levels or a clinical score. The primary end point of total cardiovascular events was reduced in BNP-guided patients (19 versus 54 events) with p < 0.001 in a multivariate analysis. The natriuretic peptides and particularly plasma BNP and aminoterminal proBNP promised to provide an objective guide for optimising treatment in heart failure.

Aims In bradycardia patients treated with dual-chamber pacing, we aimed to evaluate whether pacing with atrioventricular (AV) delay management [AV hysteresis (AVH)], compared with standard pacing with fixed AV delays, reduces unnecessary ventricular pacing percentage (VPP) and is associated with better clinical outcomes. Main study endpoints were the incidence of heart failure hospitalizations (HFH), persistent atrial fibrillation (AF), and cardiac death. Methods and results Data from two identical prospective observational studies, BRADYCARE I in the USA and BRADYCARE II in Europe, Africa, and Asia, were pooled. Overall, 2592 patients (75 ± 10 years, 45.1% female, 50% with AVH) had complete clinical and device data at 1-year follow-up and were analysed. Primary pacing indication was sinus node disease (SND) in 1177 (45.4%), AV block (AVB) in 974 (37.6%), and other indications in 441 (17.0%) patients. Pacing with AVH, compared with standard pacing, was associated with a lower 1-year incidence of HFH [1.3% vs. 3.1%, relative risk reduction (RRR) 57.5%, P = 0.002] and of persistent AF (5.3% vs. 7.7%, RRR = 31.1%, P = 0.028). Cardiac mortality was not different between groups (1.0% vs. 1.4%, RRR = 27.8%, P = 0.366). Pacing with AVH, compared with standard pacing, was associated with a lower (P < 0.001) median VPP in all patients (7% vs. 75%), in SND (3% vs. 44%), in AVB (25% vs. 98%), and in patients with other pacing indications (3% vs. 47%). Conclusion Cardiac pacing with AV delay management via AVH is associated with reduced 1-year incidence of HFH and persistent AF, most likely due to a reduction in VPP compared to standard pacing. [ABSTRACT FROM AUTHOR]

Myocardial infarction (MI) induced by acute coronary arterial occlusion is usually secondary to atherosclerotic plaque rupture. Dysregulated response of vascular smooth muscle cells (VSMCs) in atherosclerotic plaques may promote plaque rupture. Cadherins (CDHs) form adherens junctions and are known stabilizers of atherosclerotic plaques. To date, the expression patterns of cadherin have not been well investigated in MI aortic VSMCs. We aimed to investigate the expression of cadherin genes in the aortic wall of patients with and without MI. Laser capture microdissected VSMCs were obtained from aortic tissue samples of patients undergoing coronary artery bypass graft surgery. Integrative bioinformatic analysis of the microarray profiles of the VSMCs revealed that MI is discriminated at the whole transcriptome level by hundreds of differentially expressed genes, including genes involved in cell adhesion, of which the cadherin superfamily genes were among the top structural category. Eleven significantly deregulated candidates of the cadherin superfamily were chosen and formed a new classifier that collectively discriminated MI vs. non-MI with ~95% accuracy. Significance validation was performed with an independent cohort by quantitative RT-quantitative PCR, confirming overexpression of CDH2, CDH12, PCDH17, and PCDH18 in MI VSMCs. The dysregulation of these cadherin superfamily genes might be related to an MI-induced remote effect on aortic wall VSMCs and to imbalances in signaling pathways and myocardial repair mechanisms. Although pathophysiological significance of our findings requires functional studies, mRNA upregulation of the identified cadherin superfamily members in VSMCs might be associated with the progression of atherosclerosis and angiogenesis activation in MI [ABSTRACT FROM AUTHOR]

The atria contribute 25% to ventricular stroke volume and are the site of the commonest cardiac arrhythmia, atrial fibrillation (AF). The initiation of contraction in the atria is similar to that in the ventricle involving a systolic rise of intracellular Ca2+ concentration ([Ca2+]i). There are, however, substantial inter-species differences in the way systolic Ca2+ is regulated in atrial cells. These differences are a consequence of a well-developed and functionally relevant transverse (t)-tubule network in the atria of large mammals, including humans, and its virtual absence in smaller laboratory species such as the rat. Where T-tubules are absent, the systolic Ca2+ transient results from a ‘fire-diffuse-fire’ sequential recruitment of Ca2+ release sites from the cell edge to the centre and hence marked spatiotemporal heterogeneity of systolic Ca2+. Conversely, the well-developed T-tubule network in large mammals ensures a near synchronous rise of [Ca2+]i. In addition to synchronizing the systolic rise of [Ca2+]i, the presence of T-tubules in the atria of large mammals, by virtue of localization of the L-type Ca2+ channels and Na+–Ca2+ exchanger antiporters on the T-tubules, may serve to, respectively, accelerate changes in the amplitude of the systolic Ca2+ transient during inotropic manoeuvres and lower diastolic [Ca2+]i. On the other hand, the presence of T-tubules and hence wider cellular distribution of the Na+–Ca2+ exchanger may predispose the atria of large mammals to Ca2+-dependent delayed afterdepolarizations (DADs); this may be a determining factor in why the atria of large mammals spontaneously develop and maintain AF. [ABSTRACT FROM PUBLISHER]

ACADEMIC EMERGENCY MEDICINE 2011; 18:947-958 © 2011 by the Society for Academic Emergency Medicine Abstract Objectives: Few tools exist that provide objective accurate prediction of short-term mortality risk in patients presenting with acute heart failure (AHF). The purpose was to describe the accuracy of several biomarkers for predicting short-term death rates in patients diagnosed with AHF in the emergency department (ED). Methods: The Biomarkers in ACute Heart failure (BACH) trial was a prospective, 15-center, international study of patients presenting to the ED with nontraumatic dyspnea. Clinicians were blinded to all investigational markers, except troponin and natriuretic peptides, which used the local hospital reference range. For this secondary analysis, a core lab was used for all markers except troponin. This study evaluated patients diagnosed with AHF by the on-site emergency physician (EP). Results: In the 1,641 BACH patients, 466 (28.4%) had an ED diagnosis of AHF, of whom 411 (88.2%) had a final diagnosis of AHF. In the ED-diagnosed HF patients, 59% were male, 69% had a HF history, and 19 (4.1%) died within 14 days of their ED visit. The area under the curve (AUC) for the 14-day mortality receiver operating characteristic (ROC) curve was 0.484 for brain natriuretic peptide (BNP), 0.586 for N-terminal pro-B-type natriuretic peptide (NT-proBNP), 0.755 for troponin (I or T), 0.742 for adrenomedullin (MR-proADM), and 0.803 for copeptin. In combination, MR-proADM and copeptin had the best 14-day mortality prediction (AUC = 0.818), versus all other markers. Conclusions: MR-proADM and copeptin, alone or in combination, may provide superior short-term mortality prediction compared to natriuretic peptides and troponin. Presented results are explorative due to the limited number of events, but validation in larger trials seems promising. [ABSTRACT FROM AUTHOR]