How B-Type Natriuretic Peptide (BNP) and Body Weight Changes Vary in Heart Failure With Preserved Ejection Fraction Compared With Reduced Ejection Fraction: Secondary Results of the HABIT (HF Assessment With BNP in the Home) Trial.

BACKGROUND: Heart failure is a common cause of hospitalization and can be divided into types with preserved and reduced ejection fraction (HFpEF and HFrEF, respectively). In this subanalysis of the HABIT (Heart Failure Assessment With BNP in the Home) trial, we examined the differences between home B-type natriuretic peptide (BNP) testing and weight monitoring in patients with HFpEF and with HFrEF before decompensation. METHODS AND RESULTS: This was a retrospective review of patients with HFpEF and HFrEF from the HABIT trial. The HFpEF patients compared with HFrEF patients were older and more obese and had lower baseline BNP values. Intra-individual BNP dispersion (spread of distribution over time) was greater in HFpEF than in HFrEF owing to rapid fluctuations (within 3 days). Slowly varying changes in BNP (estimated by a moving average) were equally predictive of ADHF risk in both HFpEF and HFrEF. However, in HFpEF, a rapid rise in BNP >200 pg/mL within 3 days was associated with an increased risk of acute decompensated heart failure (ADHF; hazard ratio 4.0), whereas a similar association was not observed in HFrEF. Weight gain ≥5 lb in 3 days had a high specificity but low sensitivity for ADHF in both HFpEF and HFrEF, whereas a lower threshold of ≥2 lb weight gain over 3 days in patients with HFpEF (but not HFrEF) was a moderately sensitive cutoff associated with decompensation (60% sensitivity). CONCLUSIONS: Patients with HFpEF and HFrEF have variations in their BNP and weight before decompensation. The rapid time scale behaves differently between the groups. In those with HFpEF, a 3-day period characterized by ≥2 lb weight gain and/or >200 pg/mL BNP rise was significantly associated with decompensation. Future prospective studies investigating different weight and BNP cutoffs for home monitoring of HFpEF and HFrEF patients should be performed to fully learn the value of BNP changes before clinical deompensation.

New Targets in the Drug Treatment of Heart Failure.

Heart failure is a complex syndrome that has been a major contributor to readmissions into hospitals in the USA. Currently, a large number of medications are being used to treat the symptoms of the disease-digoxin, diuretics, renin-angiotensin-aldosterone system inhibitors, ß-blockers, and vasodilators. There is no doubt that the given pharmaceutical therapy has been effective in lowering hospital readmission rates and prolonging life in individual chronic heart failure patients. Despite this, admission rates following heart failure hospitalization remain high, resulting in a substantial financial strain on healthcare institutions. Clearly, there is much room for improvement in heart failure therapy and management in reducing readmission rates. In this review, we address the unmet needs in the current drug treatment of chronic heart failure and describe novel drug targets that are currently under investigation.

Depressive symptoms and spiritual wellbeing in asymptomatic heart failure patients.

Depression adversely predicts prognosis in individuals with symptomatic heart failure. In some clinical populations, spiritual wellness is considered to be a protective factor against depressive symptoms. This study examined associations among depressive symptoms, spiritual wellbeing, sleep, fatigue, functional capacity, and inflammatory biomarkers in 132 men and women with asymptomatic stage B heart failure (age 66.5 years ± 10.5). Approximately 32 % of the patients scored ≥10 on the Beck Depression Inventory, indicating potentially clinically relevant depressive symptoms. Multiple regression analysis predicting fewer depressive symptoms included the following significant variables: a lower inflammatory score comprised of disease-relevant biomarkers (p < 0.02), less fatigue (p < 0.001), better sleep (p < 0.04), and more spiritual wellbeing (p < 0.01) (overall model F = 26.6, p < 0.001, adjusted R square = 0.629). Further analyses indicated that the meaning (p < 0.01) and peace (p < 0.01) subscales, but not the faith (p = 0.332) subscale, of spiritual wellbeing were independently associated with fewer depressive symptoms. Interventions aimed at increasing spiritual wellbeing in patients lives, and specifically meaning and peace, may be a potential treatment target for depressive symptoms asymptomatic heart failure.

Biomarkers in hypertension and their relationship with myocardial target-organ damage.

Essential hypertension is a very common health condition that is associated with an array of long-term end-organ diseases, including premature cardiovascular disease. Currently, there is no effective method to identify high-risk patients who may develop cardiovascular comorbidities in the future. Clinically, it would be beneficial to identify high-risk patients early in the disease process, so they can receive more aggressive blood pressure control and perhaps other specific disease-modifying therapies, thus delaying or avoiding the onset of cardiovascular disease. Cardiac biomarkers may have a unique role in the prognostic evaluation of patients with hypertension as many cardiac biomarker levels become abnormal long before the onset of overt cardiovascular disease. This review will provide an overview of cardiac biomarkers that may be used to predict future cardiovascular disease in patients with hypertension.

Novel biomarkers for heart failure.

Heart failure (HF) has proven to be a major burden on the health system. The continuing prevalence of the condition and its rising associated costs and care, has amplified the need for earlier diagnosis, better risk stratification and cost-effective treatment to cut rates of hospitalization. Biomarkers seem poised to undertake such tasks, with biomarker management of patients with HF quickly evolving over the past several years. Biomarker guided diagnosis and treatment has become vital, especially during the acute setting in which the majority of patients with HF, were initially present. An adequate assessment of risk requires a multi-marker approach to a given HF patient. Established markers including brain natriuretic peptide and NT-proBNP are a significant clinical aid to physicians, though their utility is limited. In the past few years, momentous effort has been put into the discovery of new biomarkers. These endeavors have led to the emergence of several capable and promising biomarkers for HF management including troponins, mid-regional pro-adrenomedullin, GDF-15, C-reactive protein, Galectin-3, IL-6, ST-2, neutrophil gelatinase-associated lipocalin, copeptin and procalcitonin. This review will offer an insight into the novel biomarkers considered as the cutting-edge in the diagnosis and management of HF.

Mid-region pro-adrenomedullin adds predictive value to clinical predictors and Framingham risk score for long-term mortality in stable outpatients with heart failure.

AIMS: The aim of this study was to evaluate the long-term prognostic utility of mid-region prohormone adrenomedullin (MR-proADM) in stable outpatients with heart failure (HF). METHODS AND RESULTS: Echocardiogram and serum for MR-proADM and BNP levels were obtained in 724 stable outpatients. These patients were followed for up to 6 years for the primary endpoint of all-cause mortality. There were 198 stage A patients, 328 stage B patients, and 200 stage C/D patients, with an average age of 68 ± 12 years. There were 195 deaths during the 6-year follow-up period. MR-proADM was predictive of mortality in the overall patient population. The predictive value of MR-proADM for long-term mortality was independent of BNP, echocardiographic indices of structural heart disease, clinical predictors of mortality, and the Framingham risk score. Patients with elevated MR-proADM had significantly increased risk for mortality in stage A and stage C/D HF, with hazard ratio (HR) 3.780, P < 0.001 and HR 2.744, P < 0.001, respectively. There was a trend toward increased mortality in patients with elevated MR-proADM and stage B HF (HR 1.579, P = 0.05005). MR-proADM added incremental predictive value to clinical predictors and the Framingham risk score. CONCLUSIONS: MR-proADM was a potent independent predictor of long-term all-cause mortality in stable outpatients with stage A-D HF, especially in patients in stage A and stage C/D HF. MR-proADM added incremental predictive value to clinical predictors and the Framingham risk score.

Serum methylmalonic acid and holotranscobalamin-II as markers for vitamin B12 deficiency in end-stage renal disease patients.

BACKGROUND: Vitamin replacement, particularly B vitamins, remains an important concern in end-stage renal disease (ESRD) patients undergoing chronic hemodialysis. Serum markers such as methylmalonic acid (MMA) and holoTranscobalamin (holoTC) used to detect vitamin B12 deficiency are affected by impaired renal function which makes the interpretation of these biomarkers difficult in ESRD patients. We investigated the role renal failure has on MMA and holoTC concentrations and evaluated using MMA and/or holoTC to identify B12 deficient patients. MATERIALS AND METHODS: We evaluated the utility of serum MMA and holoTC for its role in the detection of vitamin B12 deficiency in dialysis patients (n=17) by using the reduction of MMA concentrations as a marker of the response to vitamin B12 treatment (1 mg, intramuscular injections once per month for 3 months). Nerve conduction studies (NCS) were done before and after vitamin B12 treatments to evaluate for any alteration in peripheral sensorimotor nerve function within a subset of the cohort. RESULTS: Receiver operating characteristic curves for detection of vitamin B12 deficiency in dialysis patients showed that serum MMA concentrations had the greatest predictive potential (area under the curve = 0.792, p = 0.043) with an optimal cutoff of 750 nmol/L. Dialysis patients (n=10) with pre-MMA > 750 nmol/L and pre-HoloTC < 260 pmol/L showed a significant response to the vitamin B12 treatment (a mean MMA reduction of 461 nmol/L after B12 supplementation; p = 0.006). CONCLUSION: MMA is viable marker of B12 deficiency in ESRD patients. Holo TC has potential as a supplementary marker with MMA to predict the response of vitamin B12 supplementation. Future studies on MMA and B12 should be done to confirm these findings in larger cohorts and to identify individuals who may benefit from vitamin B12 supplementation.

MCP-1 binds to oxidized LDL and is carried by lipoprotein(a) in human plasma.

Lipoprotein oxidation plays an important role in pathogenesis of atherosclerosis. Oxidized low density lipoprotein (OxLDL) induces profound inflammatory responses in vascular cells, such as production of monocyte chemoattractant protein-1 (MCP-1) [chemokine (C-C motif) ligand 2], a key chemokine in the initiation and progression of vascular inflammation. Here we demonstrate that OxLDL also binds MCP-1 and that the OxLDL-bound MCP-1 retains its ability to recruit monocytes. A human MCP-1 mutant in which basic amino acids Arg-18 and Lys-19 were replaced with Ala did not bind to OxLDL. The MCP-1 binding to OxLDL was inhibited by the monoclonal antibody E06, which binds oxidized phospholipids (OxPLs) in OxLDL. Because OxPLs are carried by lipoprotein(a) [Lp(a)] in human plasma, we tested to determine whether Lp(a) binds MCP-1. Recombinant wild-type but not mutant MCP-1 added to human plasma bound to Lp(a), and its binding was inhibited by E06. Lp(a) captured from human plasma contained MCP-1 and the Lp(a)-associated endogenous MCP-1 induced monocyte migration. These results demonstrate that OxLDL and Lp(a) bind MCP-1 in vitro and in vivo and that OxPLs are major determinants of the MCP-1 binding. The association of MCP-1 with OxLDL and Lp(a) may play a role in modulating monocyte trafficking during atherogenesis.

Heart failure biomarkers.

Biomarker testing in patients with heart failure (HF) is rapidly expanding. With high-quality research indicating its diagnostic and prognostic capabilities, biomarkers are excellent adjuncts to manage patients with HF. Their superiority lies mainly in their reflection of ongoing pathophysiological events at a cellular level. Monitoring biomarker levels has been shown to provide incremental information on the progression of disease, thus allowing to better tailor treatment and management. Several biomarkers have gained attention in the past decade and continuing research demonstrates the specificity of each biomarker to be used on its own or in combination to improve diagnostic accuracy. This review will provide an insight into the role of such biomarkers, which are widely studied in the setting of HF so as to delineate their role in diagnosing, prognosticating, and titrating HF therapy.

Neutrophil gelatinase-associated lipocalin as diagnostic and prognostic tool for cardiovascular disease and heart failure.

INTRODUCTION: Cardiovascular disease (CVD) has been a burden on the healthcare system for decades and has increased the need for earlier diagnosis, better risk stratification and cost- effective treatment to reduce the rates of hospitalization. Biomarker research has broadened our knowledge base, shedding more light on the underlying pathophysiological mechanisms associated with the development of heart disorders. Recent technological advances have made it possible to use noninvasive and cost-effective biomarkers for identifying patients who are at risk of developing coronary heart disease and atherosclerosis. AREAS COVERED: In this paper the authors review the development of neutrophil gelatinase-associated lipocalin (NGAL) as a cardiac biomarker, highlighting studies that validate its use in predicting acute changes in patients with an array of cardiac disorders, and stake a case for the use of NGAL as a clinical diagnostic tool to predict outcomes in patients with CVD. EXPERT OPINION: The authors believe that NGAL should be used as a clinical diagnostic tool to predict outcomes in patients with CVD. Growing evidence has illustrated the biological role that neutrophils, such as NGAL, play in inflammation and atherosclerosis. Further studies are needed to determine NGAL's stability in serum and urine, and to substantiate its widespread use, but there are expanding possibilities for this biomarker in clinical practice.

Primary results of the HABIT Trial (heart failure assessment with BNP in the home).

OBJECTIVES: This study was a multicenter, single-arm, double-blinded observational prospective clinical trial designed to monitor daily concentrations of B-type natriuretic peptide (BNP) and to determine how these concentrations correlate with acute clinical heart failure decompensation (ADHF) and related adverse clinical outcomes in at-risk HF patients. BACKGROUND: Although BNP at discharge is predictive of 30-day outcomes, outpatient serial testing may improve the risk of detecting early decompensation. METHODS: A total of 163 patients with HF signs and symptoms of ADHF discharged from the hospital or in an outpatient setting measured their weight and BNP levels daily for 60 days with a finger-stick test. Patients and physicians were blinded to BNP levels. The composite outcome was ADHF events: cardiovascular death, admission for decompensated HF, or clinical HF decompensation requiring either parenteral HF therapy or changes in oral HF medications. RESULTS: A total of 6,934 daily BNP values were recorded, with a median of 46 measures per patient over a monitoring period of 65 days. Forty patients had 56 events. Correlations between BNP measures weakened over time, and the dispersion between BNP measures grew. During 10,035 patient-days, there were 494 (4.9%) days of weight gain (≥5 lbs). The hazard ratio per unit increase of ln BNP was 1.84, and the hazard ratio on a day of weight gain was 3.63. These effects retained significance when controlling for symptoms. When the monitoring period for each subject was broken into intervals based on ADHF events, there were 39 (18.4%) intervals of upward trending BNP corresponding to a risk increase of 59.8% and 64 (30.2%) downward trending intervals corresponding to a risk decrease of 39.0%. There were 94 (44.3%) intervals with 1 or more days of weight gain corresponding to a risk increase of 26.1%. CONCLUSIONS: This pilot study demonstrates that home BNP testing is feasible and that trials using home monitoring for guiding therapy are justifiable in high-risk patients. Daily weight monitoring is complementary to BNP, but BNP changes correspond to larger changes in risk, both upward and downward. (Heart Failure [HF] Assessment with B-type Natriuretic Peptide [BNP] In the Home [HABIT]; NCT00946231).

Biomarkers in acute myocardial injury.

Acute coronary syndrome (ACS) is a significant cause of morbidity and mortality worldwide. The proper diagnosis of ACS requires reliable and accurate biomarker assays to detect evidence of myocardial necrosis. Currently, troponin is the gold standard biomarker for myocardial injury and is used commonly in conjunction with creatine kinase-MB (CK-MB) and myoglobin to enable a more rapid diagnosis of ACS. A new generation of highly sensitive troponin assays with improved accuracy in the early detection of ACS is now available, but the correct interpretation of assay results will require a careful consideration of assay characteristics and the clinical setting prior to incorporation into routine practice. B-type natriuretic peptides, copeptin, ischemia-modified albumin, heart-type fatty-acid-binding protein, myeloperoxidase, C-reactive protein, choline, placental growth factor, and growth-differentiation factor-15 make up a promising group of other biomarkers that have shown the ability to improve prognosis and diagnosis of ACS compared with traditional markers.

Cardiac biomarkers, mortality, and post-traumatic stress disorder in military veterans.

Post-traumatic stress disorder (PTSD) is gaining increasing recognition as a risk factor for morbidity and mortality. The aim of this study was to examine the impact of PTSD and abnormal cardiovascular biomarkers on mortality in military veterans. Eight hundred ninety-one patients presenting for routine echocardiography were enrolled. Baseline clinical data and serum samples for biomarker measurement were obtained and echocardiography was performed at the time of enrollment. Patients were followed for up to 7.5 years for the end point of all-cause mortality. Ninety-one patients had PTSD at the time of enrollment. There were 33 deaths in patients with PTSD and 221 deaths in those without PTSD. Patients with PTSD had a trend toward worse survival on Kaplan-Meier analysis (p = 0.057). Among patients with elevated B-type natriuretic peptide (>60 pg/ml), those with PTSD had significantly increased mortality (p = 0.024). Among patients with PTSD, midregional proadrenomedullin (MR-proADM), creatinine, and C-terminal proendothelin-1 were significant univariate predictors of mortality (p = 0.006, p = 0.024, and p = 0.003, respectively). In a multivariate model, PTSD, B-type natriuretic peptide, and MR-proADM were independent predictors of mortality. In patients with PTSD, MR-proADM was a significant independent predictor of mortality after adjusting for B-type natriuretic peptide, cardiovascular risk factors, cancer, and sleep apnea. Adding MR-proADM to clinical predictors of mortality increased the C-statistic from 0.572 to 0.697 (p = 0.007). In conclusion, this study demonstrates an association among PTSD, abnormal cardiac biomarker levels, and increased mortality.

Cardiac biomarkers: new tools for heart failure management.

The last decade has seen exciting advances in the field of biomarkers used in managing patients with heart failure (HF). Biomarker research has broadened our knowledge base, shedding more light on the underlying pathophysiological mechanisms occurring in patients with both acute and chronic HF. The criterion required by an ideal cardiovascular biomarker has been progressively changing to an era of sensitive assays that can be used to guide treatment. Recent technological advances have made it possible to rapidly measure even minute amounts of these proteins by means of higher sensitivity assays. With a high prevalence of comorbidities associated with HF, an integrated approach utilizing multiple biomarkers have shown promise in predicting mortality, better risk stratification and reducing re-hospitalizations, thus lowering health-care costs. This review provides a brief insight into recent advances in the field of biomarkers currently used in the diagnosis and prognosis of patients with acute and chronic HF.

Prognostic utility of plasma neutrophil gelatinase-associated lipocalin in patients with acute heart failure: the NGAL EvaLuation Along with B-type NaTriuretic Peptide in acutely decompensated heart failure (GALLANT) trial.

AIMS: Neutrophil gelatinase-associated lipocalin (NGAL) is a measure of acute kidney injury. Renal dysfunction portends significant risk after discharge from acute heart failure (AHF). Thus, a sensitive marker of renal injury might also help to risk stratify HF patients. METHODS AND RESULTS: GALLANT [NGAL EvaLuation Along with B-type NaTriuretic Peptide (BNP) in acutely Decompensated Heart Failure] was a multicentre, prospective study to assess the utility of plasma NGAL, alone and in combination with BNP, as an early risk marker of adverse outcomes. We studied 186 patients (61% male). There were 29 events (AHF readmissions and all-cause mortality) at 30 days (16%). Patients with events had higher levels of NGAL than those without (134 vs. 84 ng/mL, P < 0.001). The area under the receiver operating characteristic curve was higher for NGAL (0.72) than BNP (0.65), serum creatinine (0.57), or estimated glomerular filtration rate (eGFR; 0.55). In multivariable analyses, NGAL predicted events (P= 0.001), BNP approached significance (P= 0.052 and 0.070 without creatinine and GFR, respectively) while neither serum creatinine nor eGFR were significant. The addition of discharge NGAL over BNP alone improved classification by a net 10.3% in those with events and 19.5% in those without events, for a net reclassification improvement of 29.8% (P= 0.010). Subjects with both BNP and NGAL elevated were at significant risk [hazard ratio (HR) = 16.85, P= 0.006], as were subjects with low BNP and high NGAL (HR = 9.95, P= 0.036). CONCLUSIONS: Plasma NGAL is a measure of kidney injury that at the time of discharge is a strong prognostic indicator of 30 days outcomes in patients admitted for AHF. CLINICAL TRIAL REGISTRATION NUMBER: NCT 00693745.

Association of ST2 levels with cardiac structure and function and mortality in outpatients.

BACKGROUND: ST2, an interleukin-1 receptor family member up-regulated in the setting of cardiomyocyte strain, has prognostic value in patients with acute myocardial infarction, chronic severe heart failure, and acute heart failure. The predictive value of ST2 levels in outpatients is unknown. We studied the clinical and echocardiographic correlates of ST2 levels and evaluated their prognostic use in outpatients referred for echocardiograms. METHODS: ST2 levels were measured in 588 outpatients referred for echocardiogram. Subjects were analyzed by quartile as well as by optimal ST2 cut-point (28.25 ng/mL) derived from receiver operating characteristic curve analysis. All-cause death at 1 year was the primary outcome. RESULTS: In this cohort with mean age of 68 ± 12 years and median ST2 level of 19.8 ng/mL (interquartile range 15.8-23.7), 25 deaths occurred. Heart rate, creatinine clearance, use of diuretics, and the presence of right ventricular hypokinesis were independently associated with ST2 levels. At 6 months, no patients with ST2 below the median had died. Patients with high ST2 levels had an increased risk of death (adjusted hazard ratio [HR] 2.5, P = .02); those with elevated levels of both ST2 and B-type natriuretic peptide were at even higher risk (adjusted HR 4.3, P = .01 vs none elevated). CONCLUSIONS: ST2 levels reflect right-side heart size and function and are independent predictors of 1-year mortality in outpatients referred for echocardiograms. The optimal cut-point derived in this cohort is comparable with the previously identified prognostic cut-point for sicker patients. ST2 may be an especially strong prognostic marker for short-term mortality risk.