Sheryl L. Chow

Role of Biomarkers for the Prevention, Assessment, and Management of Heart Failure A Scientific Statement From the American Heart Association

Background and Purpose: Natriuretic peptides have led the way as a diagnostic and prognostic tool for the diagnosis and management of heart failure (HF). More recent evidence suggests that natriuretic peptides along with the next generation of biomarkers may provide added value to medical management, which could potentially lower risk of mortality and readmissions. The purpose of this scientific statement is to summarize the existing literature and to provide guidance for the utility of currently available biomarkers. Methods: The writing group used systematic literature reviews, published translational and clinical studies, clinical practice guidelines, and expert opinion/statements to summarize existing evidence and to identify areas of inadequacy requiring future research. The panel reviewed the most relevant adult medical literature excluding routine laboratory tests using MEDLINE, EMBASE, and Web of Science through December 2016. The document is organized and classified according to the American Heart Association to provide specific suggestions, considerations, or contemporary clinical practice recommendations. Results: A number of biomarkers associated with HF are well recognized, and measuring their concentrations in circulation can be a convenient and noninvasive approach to provide important information about disease severity and helps in the detection, diagnosis, prognosis, and management of HF. These include natriuretic peptides, soluble suppressor of tumorgenicity 2, highly sensitive troponin, galectin-3, midregional proadrenomedullin, cystatin-C, interleukin-6, procalcitonin, and others. There is a need to further evaluate existing and novel markers for guiding therapy and to summarize their data in a standardized format to improve communication among researchers and practitioners. Conclusions: HF is a complex syndrome involving diverse pathways and pathological processes that can manifest in circulation as biomarkers. A number of such biomarkers are now clinically available, and monitoring their concentrations in blood not only can provide the clinician information about the diagnosis and severity of HF but also can improve prognostication and treatment strategies.

Renal Function and Neurohormonal Changes Following Intravenous Infusions of Nitroglycerin Versus Nesiritide in Patients With Acute Decompensated Heart Failure

BACKGROUND Rises in serum creatinine and efficacy have been reported as dose-related effects of nesiritide and nitroglycerin in acute decompensated heart failure (ADHF). However, no study has evaluated the comparative safety, efficacy, and biomarkers of optimally dosed nesiritide versus nitroglycerin in ADHF. METHODS AND RESULTS Eighty-nine ADHF patients were prospectively randomized to receive either nesiritide (0.01 μg kg(-1) min(-1) ± bolus) or nitroglycerin (maximally tolerated doses by standard protocol). Blood urea nitrogen (BUN), and creatinine were obtained during 48 hours of intravenous infusion. B-Type natriuretic peptide (BNP) and N-terminal (NT) proBNP concentrations were measured during hospitalization. There were no significant differences in BUN, serum creatinine, creatinine clearance, or hospitalization and mortality. Although concentrations of BNP and NT-proBNP were significantly decreased over time, the comparative reductions between the 2 vasodilators were similar. CONCLUSIONS Nesiritide and nitroglycerin produce similar hemodynamic effects, do not worsen markers of renal function, and produce significant, yet similar, reductions in neurohormones over time. Both nitroglycerin at maximally titrated doses and nesiritide at standard doses are safe and effective in patients with ADHF who require vasodilator therapy.

Effect of Nesiritide Infusion Duration on Renal Function in Acutely Decompensated Heart Failure Patients

Background: Nesiritide, a synthetic B-type natriuretic peptide, is used for the treatment of patients with acutely decompensated heart failure. Although nesiritide has been reported to worsen renal function, as reflected by significant elevations in serum creatinine (SCr), the impact of infusion duration on renal function has not been evaluated. Objective: To investigate the effect of nesiritide infusion duration (<24 h vs ≥24 h) on worsening renal function in patients with acutely decompensated heart failure. Methods: Medical records of hospitalized patients receiving nesiritide were retrospectively reviewed, and 84 consecutive charts of patients with acute decompensated heart failure and available renal function tests were identified for the study. SCr and blood urea nitrogen (BUN) were documented at baseline and during infusion. Worsening renal function was defined as an increase in SCr of 0.5 mg/dL or more or BUN 10 mg/dL or more from baseline. Results: Univariate analysis showed a significant association between nesiritide infusion duration of 24 hours or more (26.1% vs 2.6%; p = 0.003), high diuretic doses (61.5% vs 32.4%; p = 0.045), and baseline SCr (2.0 ± 0.8 vs 1.5 ± 0.7 mg/dL; p = 0.04) with increases in SCr of 0.5 mg/dL or more. However, only infusion duration of 24 hours or more was statistically significant on multivariate analysis, after adjusting for baseline SCr (OR 10.46; 95% CI 1.26 to 86.72; p = 0.03). Longer duration of infusion was also a consistent variable in both univariate and multivariate analysis when elevated BUN was evaluated (34.8 vs 2.6%; p < 0.001 and OR 19.73; 95% CI 2.47 to 157.46; p = 0.005, respectively). Conclusions: Nesiritide infusion of 24 hours or more appears to be significantly associated with elevated markers of worsening renal function in patients with acutely decompensated heart failure compared with infusion of less than 24 hours; however, prospective studies are needed to corroborate this finding.

Key articles of dietary interventions that influence cardiovascular mortality.

Lifestyle modifications, particularly diet, are a key component to the reduction of cardiovascular events. Diets high in carbohydrates and saturated fat have been shown to negatively affect blood cholesterol, thereby increasing the risk for cardiovascular disease (CVD). Dietary interventions that emphasize the consumption of whole grains, fruits, and vegetables have been shown to be successful in reducing cardiovascular risk. Clinical pharmacist practitioners need to be knowledgeable regarding lifestyle modifications, specifically dietary issues, to develop a comprehensive, effective, and evidence‐based plan for patients who are either at risk for or who have established CVD. Numerous studies have been published over the past few years with regard to the rapidly growing field of dietary interventions that influence cardiovascular risk, and the amount of literature can be overwhelming. Thus we chose to focus our review on articles that assess changes in dietary patterns that affect overall mortality risk from CVD. As such, literature describing the impact of dietary factors that influence weight, lipid changes, or other risk factors alone were not included in this review. A group of practitioners with expertise and interest in CVD were involved in the compilation of this article.

Modulation of Novel Cardiorenal and Inflammatory Biomarkers by Intravenous Nitroglycerin and Nesiritide in Acute Decompensated Heart FailureClinical Perspective

Background—Modulation of novel cardiorenal and inflammatory markers may provide insight into the disease process and outcomes of patients with acute decompensated heart failure. Methods and Results—In this open-labeled, prospective, randomized study, 89 patients received either nesiritide (NES) or nitroglycerin (NTG) infusion by standard protocol. The serum or plasma concentrations of cystatin-C and inflammatory markers (high-sensitivity C-reactive protein, tumor necrosis factor-&agr;, transforming growth factor-&bgr;1, and interleukin-6) were measured in 66 patients with acute decompensated heart failure at baseline and during drug infusion. Mean baseline values for demographics were not significantly different between NTG and NES groups; however, baseline inflammatory markers were elevated on admission. In NES compared with NTG groups, lower cystatin-C (1449 versus 2739 ng/mL, P<0.05) and IL-6 (25 versus 50 pg/mL, P<0.05) were observed. There were no significant differences in concentrations of high-sensitivity C-reactive protein, tumor necrosis factor-&agr;, and transforming growth factor-&bgr;1 between groups over time. Conclusions—The differential modulation effects of cystatin-C and interleukin-6 but not other inflammatory markers, in response to NES compared with NTG therapy, may provide important implications for vasodilator therapy. Further studies are warranted to confirm these findings. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00842023.

Expanding Role of Mineralocorticoid Receptor Antagonists in the Treatment of Heart Failure

Despite numerous pharmacologic and nonpharmacologic treatment strategies, heart failure remains a complex, progressive disorder with significant morbidity and mortality. Angiotensin‐converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), and β‐blockers have been used as routine treatment options for heart failure for the majority of patients with left ventricular systolic dysfunction who tolerate these agents. Mineralocorticoid receptor antagonists (MRAs) have also demonstrated significant benefits in the treatment of heart failure, which include a reduction in sudden cardiac death and ventricular remodeling; however, these agents have not been recommended for most patients with heart failure. In the most recent American College of Cardiology Foundation and American Heart Association guidelines, MRAs are recommended for patients with New York Heart Association class III or IV symptoms or previous acute myocardial infarction, provided an absence of contraindications or risk factors for developing hyperkalemia. Based on more recent evidence, it is likely that future recommendations and guidelines will further expand the use of MRAs to patients with mild heart failure as well. These agents have the potential to be recommended nearly as universally as ACE inhibitors and β‐blockers because of the potential to reduce mortality and hospital admissions for heart failure. The risk of hyperkalemia should be carefully assessed when using these drugs; nonetheless, new strategies being developed may reduce the occurrence of hyperkalemia as well.

Prognostic Value of Insulin-Like Growth Factor-Binding Protein 7 in Patients with Heart Failure and Preserved Ejection Fraction

BACKGROUND The prognostic merit of insulin-like growth factor-binding protein 7 (IGFBP7) is unknown in heart failure and preserved ejection fraction (HFpEF). METHODS AND RESULTS Baseline IGFBP7 (BL-IGFBP7; n = 302) and 6-month change (Δ; n = 293) were evaluated in the Irbesartan in Heart Failure and Preserved Ejection Fraction (I-PRESERVE) trial. Primary outcome was all-cause mortality or cardiovascular hospitalization with median follow-up of 3.6 years; secondary outcomes included HF events. Median BL-IGFBP7 concentration was 218 ng/mL. BL-IGFBP7 was significantly correlated with age (R2 = 0.13; P < .0001), amino-terminal pro-B-type NP (R2 = 0.22; P < .0001), and estimated glomerular filtration rate (eGFR; R2 = 0.14; P < .0001), but not with signs/symptoms of HFpEF. BL-IGFBP7 was significantly associated with the primary outcome (hazard ratio [HR] = 1.007 per ng/mL; P < .001), all-cause mortality (HR = 1.008 per ng/mL; P < .001), and HF events (HR = 1.007 per ng/mL; P < .001). IGFBP7 remained significant for each outcome after adjustment for ln amino-terminal pro-B-type NP and eGFR but not all variables in the I-PRESERVE prediction model. After 6 months, IGFBP7 did not change significantly in either treatment group. ΔIGFBP7 was significantly associated with decrease in eGFR in patients randomized to irbesartan (R2 = 0.09; P = .002). ΔIGFBP7 was not independently associated with outcome. CONCLUSIONS Higher concentrations of IGFBP7 were associated with increased risk of cardiovascular events, but after multivariable adjustment this association was no longer present. Further studies of IGFBP7 are needed to elucidate its mechanism. CLINICAL TRIAL REGISTRATION www.clinicaltrials.gov, NCT00095238.

Predicting therapeutic response in patients with heart failure: the story of C-reactive protein

Heart failure continues to be a major public health burden in the USA. With markedly high rates of morbidity and mortality upon diagnosis, effective treatment and prognosis are critical in the management of chronic heart failure. Growing evidence now supports the hypothesis that inflammation plays a key role in the progression and worsening of heart failure. Of the various inflammatory mediators identified, C-reactive protein, an acute phase inflammatory marker, has been associated with poor prognosis in patients with heart failure. Several interventional studies have been investigated to explore C-reactive protein modulation and potential treatment options and health outcomes; however, further studies are warranted before C-reactive protein–targeted therapy may be recommended in the management of heart failure.

High‐Impact Articles Related to the Management of Heart Failure: 2008 Update

This compilation is part of a series of articles identifying important literature in cardiovascular pharmacotherapy. This bibliography focuses on pharmacotherapeutic management of acute decompensated and chronic heart failure and provides an update of the heart failure bibliography published in Pharmacotherapy in 2004. Most of the cited works present the results of landmark clinical studies that have shaped the management of patients with heart failure. Limited primary literature is available for some topics, thus pertinent review articles are also listed. In addition, consensus documents formed by expert panels are reviewed. This compilation may serve as a teaching tool, reference resource, or update of the literature for pharmacy clinicians, physicians, and students.

Genetic Factors Influencing B-type Natriuretic Peptide-Mediated Production of Cyclic Guanosine Monophosphate and Blood Pressure Effects in Heart Failure Patients

Natriuretic peptides (NPs) represent a critical pathway in heart failure (HF). We explored genetic determinants of pharmacodynamic effects of B-type NP (BNP) and changes in plasma cyclic guanosine monophosphate (cGMP) and blood pressure (BP). HF patients (n = 135) received recombinant human BNP (nesiritide) at standard doses, and plasma cGMP levels were measured at baseline and during infusion. We tested the association of 119 single nucleotide polymorphisms (SNPs) in 4 candidate genes (NPR1, NPR2, NPR3, and membrane metallo-endopeptidase (MME)) with the change in cGMP and BP. Gene-based testing for association of genetic variation with endpoints was significant only for MME. Upon individual SNP testing, two loci in MME were associated with ΔcGMP; another (rs16824656) showed association with BP change. In summary, the pharmacodynamic effects of BNP vary substantially in HF patients and are associated with genetic variation in MME. MME genetic variation may be an important determinant of NP-mediated effects in humans.