Active B-Type Natriuretic Peptide Measured by Mass Spectrometry and Response to Sacubitril/Valsartan.

BACKGROUND: B-type natriuretic peptide (BNP) immunoassays (BNPia) do not differentiate active and inactive forms. Inactive NT-proBNP is used to track heart failure (HF) during treatment with sacubitril/valsartan, which inhibits BNP degradation. Mass spectrometry (MS) may better assess effects of HF treatment on biologically active BNP1-32. METHODS AND RESULTS: We developed a MS assay with immediate protease inhibition to quantify BNP1-32 over a linear range, using labeled recombinant BNP standard. In 4 healthy volunteers, BNP1-32 by MS (BNPMS) increased from below the 5 pg/mL detection limit to 228 pg/mL after nesiritide. In patients with HF, BNPMS was measured in parallel with BNP and NT-proBNP immunoassays before and during sacubitril/valsartan treatment. BNPMS was 4.4-fold lower than BNPia in patients with HF. Among patients not taking sacubitril/valsartan and without end-stage renal disease, BNPMS correlated with BNPia (rs = 0.77, P < .001) and NT-proBNP (rs = 0.74, P < .001). After a median of 8 weeks on sacubitril/valsartan, active BNPMS levels decreased by 50% (interquartile range -98.3% to 41.7%, n = 22, P = .048) and correlated with NT-proBNP (rs = 0.64, P < .001), but not with BNPia (rs = 0.46, P = .057). CONCLUSIONS: Active BNP measured by MS accounts for only a small amount of BNP measured by immunoassays. Although decreased BNP production was anticipated to be masked by inhibition of degradation, levels of active BNP decreased during chronic sacubitril/valsartan treatment.

Risk stratification in acute heart failure: rationale and design of the STRATIFY and DECIDE studies.

BACKGROUND: A critical challenge for physicians facing patients presenting with signs and symptoms of acute heart failure (AHF) is how and where to best manage them. Currently, most patients evaluated for AHF are admitted to the hospital, yet not all warrant inpatient care. Up to 50% of admissions could be potentially avoided and many admitted patients could be discharged after a short period of observation and treatment. Methods for identifying patients that can be sent home early are lacking. Improving the physician's ability to identify and safely manage low-risk patients is essential to avoiding unnecessary use of hospital beds. METHODS: Two studies (STRATIFY and DECIDE) have been funded by the National Heart Lung and Blood Institute with the goal of developing prediction rules to facilitate early decision making in AHF. Using prospectively gathered evaluation and treatment data from the acute setting (STRATIFY) and early inpatient stay (DECIDE), rules will be generated to predict risk for death and serious complications. Subsequent studies will be designed to test the external validity, utility, generalizability and cost-effectiveness of these prediction rules in different acute care environments representing racially and socioeconomically diverse patient populations. RESULTS: A major innovation is prediction of 5-day as well as 30-day outcomes, overcoming the limitation that 30-day outcomes are highly dependent on unpredictable, post-visit patient and provider behavior. A novel aspect of the proposed project is the use of a comprehensive cardiology review to correctly assign post-treatment outcomes to the acute presentation. CONCLUSIONS: Finally, a rigorous analysis plan has been developed to construct the prediction rules that will maximally extract both the statistical and clinical properties of every data element. Upon completion of this study we will subsequently externally test the prediction rules in a heterogeneous patient cohort.

Galectin 3 complements BNP in risk stratification in acute heart failure.

BACKGROUND: Galectin 3 (G3) is a mediator of fibrosis and remodeling in heart failure. METHODS: Patients diagnosed with and treated for Acute Heart Failure Syndromes were prospectively enrolled in the Decision Making in Acute Decompensated Heart Failure multicenter trial. RESULTS: Patients with a higher G3 had a history of renal disease, a lower heart rate and acute kidney injury. They also tended to have a history of HF and 30-day adverse events compared with B-type natriuretic peptide. CONCLUSION: In Acute Heart Failure Syndromes, G3 levels do not provide prognostic value, but when used complementary to B-type natriuretic peptide, G3 is associated with renal dysfunction and may predict 30-day events.

Stem cell therapy for cardiac disease: what can be learned from oncology.

Hematopoietic stem cells (HSCs) are the most well-characterized and studied stem cells. They have been used to treat various benign and malignant hematologic disorders. Most stem cell transplant recipients survive more than 5 years without any evidence of their original clinical disease. Early animal trials have demonstrated the ability to improve cardiac function by transfer of HSCs into the myocardium, and early human studies have demonstrated the feasibility and safety of this approach. Trials in patients after myocardial infarction and with chronic heart failure have seen limited and mixed success, probably because of the various cell types and methods used.

The rationale for an acute heart failure syndromes clinical trials network.

BACKGROUND: Clinical trials involving novel therapies treating acute heart failure syndromes (AHFS) have shown limited success with regard to both efficacy and safety. As a direct result, outcomes have changed little over time and AHFS remains a disease process associated with largely no change in hospitalization rates (80%), hospital length of stay (median 4.5 days), and in-hospital (4-7%) and 60-day mortality (10%). Despite extensive emergency department (ED) involvement during the initial phase of AHFS management, clinical trials have enrolled patients after the ED phase of management, up to 48 hours after initial therapy, long after many patients have experienced significant beneficial effects of standard therapy. As standard therapy has provided symptomatic improvement in up to 70% of patients in these trials, it is not surprising that investigational agents started after 24 to 48 hours of standard therapy have shown limited clinical efficacy when compared with standard therapy. METHODS AND RESULTS: The ability to screen, enroll, and randomize in the emergency setting is fundamental. The unique environment, the ethical complexities of enrollment in emergency-based research, and the need for rapid and standardized study-compliant care represent key challenges to active recruitment in AHFS studies. Specifically, the ability to identify and enroll a large cohort of AHFS patients early (<6 hours) in their presentation has been cited as the primary barrier to the appropriate design of clinical trials that includes this early window. CONCLUSIONS: In response, we have created a network of dedicated academic physicians with experience in clinical trials and acute management of heart failure who together can surmount this barrier and provide a framework for conducting early trials in AHFS.

Eosinophilic myocarditis-an unusual cause of left ventricular hypertrophy.

Eosinophilic myocarditis is a rare condition in which inflammation of the heart results in an infiltrative cardiomyopathy that is often difficult to diagnose in the acute setting. It sometimes presents as left ventricular hypertrophy. The authors present a case of a 79-year-old woman with a history of Non-Hodgkin's lymphoma who presented with acute heart failure with marked left ventricular hypertrophy. Echocardiography demonstrated abnormalities consistent with an infiltrative cardiomyopathy, and endomyocardial biopsy showed findings consistent with eosinophilic myocarditis. The patient was managed with diuresis and glucocorticoid therapy, and within 4 weeks of her admission, her clinical status had improved and her echocardiogram normalized. The prompt diagnosis and treatment of this patient's myocarditis likely resulted in her favorable outcome. This illustrates the need for a broad consideration of all the potential causes of hypertrophy and the necessary diagnostic strategies and therapeutic options.

Identification of Emergency Department Patients With Acute Heart Failure at Low Risk for 30-Day Adverse Events: The STRATIFY Decision Tool.

OBJECTIVES: No prospectively derived or validated decision tools identify emergency department (ED) patients with acute heart failure (AHF) at low risk for 30-day adverse events who are thus potential candidates for safe ED discharge. This study sought to accomplish that goal. BACKGROUND: The nearly 1 million annual ED visits for AHF are associated with high proportions of admissions and consume significant resources. METHODS: We prospectively enrolled 1,033 patients diagnosed with AHF in the ED from 4 hospitals between July 20, 2007, and February 4, 2011. We used an ordinal outcome hierarchy, defined as the incidence of the most severe adverse event within 30 days of ED evaluation (acute coronary syndrome, coronary revascularization, emergent dialysis, intubation, mechanical cardiac support, cardiopulmonary resuscitation, and death). RESULTS: Of 1,033 patients enrolled, 126 (12%) experienced at least one 30-day adverse event. The decision tool had a C statistic of 0.68 (95% confidence interval: 0.63 to 0.74). Elevated troponin (p < 0.001) and renal function (p = 0.01) were significant predictors of adverse events in our multivariable model, whereas B-type natriuretic peptide (p = 0.09), tachypnea (p = 0.09), and patients undergoing dialysis (p = 0.07) trended toward significance. At risk thresholds of 1%, 3%, and 5%, we found 0%, 1.4%, and 13.0% patients were at low risk, with negative predictive values of 100%, 96%, and 93%, respectively. CONCLUSIONS: The STRATIFY decision tool identifies ED patients with AHF who are at low risk for 30-day adverse events and may be candidates for safe ED discharge. After external testing, and perhaps when used as part of a shared decision-making strategy, it may significantly affect disposition strategies. (Improving Heart Failure Risk Stratification in the ED [STRATIFY]; NCT00508638).

Stem cell therapy for chronic heart failure: an updated appraisal.

INTRODUCTION: Significant advances have been made to understand the mechanisms involved in cardiac cell-based therapies. The early translational application of basic science knowledge has led to several animal and human clinical trials. The initial promising beneficial effect of stem cells on cardiac function restoration has been eclipsed by the inability of animal studies to translate into sustained clinical improvements in human clinical trials. AREAS COVERED: In this review, the authors cover an updated overview of various stem cell populations used in chronic heart failure. A critical review of clinical trials conducted in advanced heart failure patients is proposed, and finally promising avenues for developments in the field of cardiac cell-based therapies are presented. EXPERT OPINION: Several questions remain unanswered, and this limits our ability to understand basic mechanisms involved in stem cell therapeutics. Human studies have revealed critical unresolved issues. Further elucidation of the proper timing, mode delivery and prosurvival factors is imperative, if the field is to advance. The limited benefits seen to date are simply not enough if the potential for substantial recovery of nonfunctioning myocardium is to be realized.

Whole exome sequencing identifies a causal RBM20 mutation in a large pedigree with familial dilated cardiomyopathy.

BACKGROUND: Whole exome sequencing is a powerful technique for Mendelian disease gene discovery. However, variant prioritization remains a challenge. We applied whole exome sequencing to identify the causal variant in a large family with familial dilated cardiomyopathy of unknown pathogenesis. METHODS AND RESULTS: A large family with autosomal dominant, familial dilated cardiomyopathy was identified. Exome capture and sequencing were performed in 3 remotely related, affected subjects predicted to share <0.1% of their genomes by descent. Shared variants were filtered for rarity, evolutionary conservation, and predicted functional significance, and remaining variants were filtered against 71 locally generated exomes. Variants were also prioritized using the Variant Annotation Analysis and Search Tool. Final candidates were validated by Sanger sequencing and tested for segregation. There were 664 shared heterozygous nonsense, missense, or splice site variants, of which 26 were rare (minor allele frequency ≤0.001 or not reported) in 2 public databases. Filtering against internal exomes reduced the number of candidates to 2, and of these, a single variant (c.1907 G>A) in RBM20, segregated with disease status and was absent in unaffected internal reference exomes. Bioinformatic prioritization with Variant Annotation Analysis and Search Tool supported this result. CONCLUSIONS: Whole exome sequencing of remotely related dilated cardiomyopathy subjects from a large, multiplex family, followed by systematic filtering, identified a causal RBM20 mutation without the need for linkage analysis.

A comparison of criterion standard methods to diagnose acute heart failure.

The authors sought to compare and contrast the clinical criterion standards currently used in a cohort of emergency department (ED) patients to diagnose acute heart failure syndromes (AHFS). In a prospective observational study of patients with signs and symptoms of AHFS, 3 criterion standards were examined: (1) the treating ED physician's diagnosis; (2) the hospital discharge diagnosis; and (3) a diagnosis based on medical record review by a panel of cardiologists. Using Cohen's kappa (κ) coefficient, the authors assessed agreement and then compared the different standards by repeatedly setting one as the criterion standard and the other two as index tests. A total of 483 patients were enrolled. Across all criterion standards, patients with AHFS were more likely to have a history of AHFS, congestion on physical examination and chest radiography, and elevated natriuretic peptide levels than those without AHFS. The standards agreed well (cardiology review vs hospital discharge diagnosis, κ=0.74; cardiology review vs ED diagnosis, κ=0.66; ED diagnosis vs hospital discharge diagnosis κ=0.59). Each method had similar sensitivity but differing specificities. Different criterion standards identify different patients from among those being evaluated for AHFS. Researchers should consider this when choosing between the various criterion standard approaches when evaluating new index tests.

Benefits of ambulatory axillary intra-aortic balloon pump for circulatory support as bridge to heart transplant.

OBJECTIVE: Axillary intra-aortic balloon pump therapy has been described as a bridge to transplant. Advantages over femoral intra-aortic balloon pump therapy include reduced incidence of infection and enhanced patient mobility. We identified the patients who would benefit most from this therapy while awaiting heart transplantation. METHODS: We conducted a single-center, retrospective observational study to evaluate outcomes from axillary intra-aortic balloon pump therapy. These included hemodynamic parameters, duration of support, and success in bridging to transplant. We selected patients on the basis of history of sternotomy, elevated panel-reactive antibody, and small body habitus. Patients were made to ambulate aggressively beginning on postoperative day 1. RESULTS: Between September 2007 and September 2010, 18 patients underwent axillary intra-aortic balloon pump therapy. All patients had the devices placed through the left axillary artery with a Hemashield side graft (Boston Scientific, Natick, Mass). Before axillary placement, patients underwent femoral placement to demonstrate hemodynamic benefit. Duration of support ranged from 5 to 63 days (median = 19 days). There was marked improvement in ambulatory potential and hemodynamic parameters, with minimal blood transfusion requirements. There were no device-related infections. Some 72% of the patients (13/18) were successfully bridged to transplantation. CONCLUSIONS: Axillary intra-aortic balloon pump therapy provides excellent support for selected patients as a bridge to transplant. The majority of the patients were successfully bridged to transplant and discharged. Although this therapy has been described in previous studies, this is the largest series to incorporate a regimen of aggressive ambulation with daily measurements of distances walked.

Relationship between Uric Acid Levels and Diagnostic and Prognostic Outcomes in Acute Heart Failure.

OBJECTIVES: We evaluated the association of plasma uric acid alone and in combination with b-type natriuretic peptide (BNP) for emergency department (ED) diagnosis and 30-day prognosis in patients evaluated for acute heart failure (AHF). METHODS: We prospectively enrolled 322 adult ED patients with suspected AHF. Wilcoxon rank sum test, multivariable logistic regression and likelihood ratio (LR) tests were used for statistical analyses. RESULTS: Uric acid's diagnostic utility was poor and failed to show significant associations with 30-day clinical outcomes. Uric acid also did not add significantly to BNP results. CONCLUSION: Among ED patients with suspected AHF, uric acid has poor diagnostic and prognostic utility.

Soluble ST2 as a Diagnostic and Prognostic Marker for Acute Heart Failure Syndromes.

OBJECTIVES: We investigated the association of sST2 with diagnostic and prognostic outcomes and assessed whether it aids B-natriuretic peptide (BNP) in diagnosing and predicting outcomes in emergency department (ED) patients with suspected AHFS. METHODS: We recruited patients who presented to the ED of 3 tertiary hospitals with signs or symptoms of AHFS and met modified Framingham criteria for AHFS. Outcome measures were a final diagnosis of AHFS and 5-and 30-day adverse events. RESULTS: In the 295 subjects with sST2 available, the median sST2 was 0.20 ng/ml (IQR=0.10, 0.34). Although unadjusted analyses indicated sST2 was significantly associated with the diagnosis of AHFS (p=0.02), this was not so in the adjusted analysis (p=0.33). Moderately low diagnostic utility was noted with an AUC of 0.62 (95% CI=0.56, 0.69). Similar sST2 test characteristics were seen when BNP was restricted between 100 and 500 pg/ml. While sST2 was associated with AHFS readmission at 30-days (p=0.04), in the adjusted analyses it was not associated with adverse events. CONCLUSION: In patients with signs or symptoms of AHFS, unadjusted analyses indicated that sST2 was significantly associated with the diagnosis of AHFS and with 30-day AHFS recidivism. However, the associations did not carry over to adjusted analyses, and sST2 did not add significant information with regard to explaining the diagnostic and prognostic variability of BNP.

Standardized reporting criteria for studies evaluating suspected acute heart failure syndromes in the emergency department.

Heart failure requiring urgent therapy represents a burgeoning health care burden. Although acute heart failure syndromes are commonly defined as a change in chronic heart failure signs and symptoms requiring urgent therapy, the presentation, development, and response to treatment is highly dependent on individual patient characteristics. This heterogeneity has led to challenges in interpreting widely differing study methods, including eligibility requirements and outcome measures. To improve interpretation of results and translate such information to better patient care, it is essential to present an accurate description of the patient population and study design. Based on existing recommendations and expert consensus, the authors present standardized reporting criteria to improve interpretability of research in this challenging cohort.

Low-risk acute heart failure patients: external validation of the Society of Chest Pain Center's recommendations.

INTRODUCTION: Risk-stratification in acute heart failure syndromes (AHFS) is problematic. A recent set of recommendations describes emergency department (ED) patients with AHFS who do not fulfill high-risk criteria and may be good candidates for observation unit (OU) management. The goal of this analysis was to report on the outcomes experienced by ED patients with AHFS who do not have any of these high-risk criteria. METHODS: We performed a secondary analysis of the HEart failure and Audicor technology for Rapid Diagnosis and Initial Treatment (HEARD-IT) multinational study. HEARD-IT was a multicenter study designed to test the impact of acoustic cardiography on ED decision making in patients with possible AHFS. For the purposes of the current analysis we identified a subset of HEARD-IT patients who did not fulfill any high-risk criteria based on published data. The proportion of these patients who experienced an adverse outcome was determined. RESULTS: The 201 subjects who fulfilled the inclusion criteria had a mean age of 64 years (SD: 13), 61% were male, 34% were Caucasian, and 55% were black. There were a total of 25 (12.4%) cardiac events, including 1 death due to AHFS. The majority of the cardiac events were 30-day readmissions related to AHFS (16/25, 64.0%). CONCLUSION: AHFS patients at low-risk for subsequent morbidity and mortality based on recent consensus guidelines may be good candidates for early discharge after a brief period of observation in the OU or ED. Additional prospective research is needed to determine the impact of implementation of these criteria in ED patients with AHFS.