Stromal cell-derived factor 1 as a biomarker of heart failure and mortality risk.

OBJECTIVE: CXCL12 encodes stromal cell-derived factor 1α (SDF-1), which binds to the receptor encoded by CXCR4. Variation at the CXCL12 locus is associated with coronary artery disease and endothelial progenitor cell numbers, whereas variation at the CXCR4 locus is associated with leukocyte telomere length, which has been shown to be associated with coronary artery disease. Therefore, we examined the relationships of plasma SDF-1 levels to cardiovascular disease (CVD)-related outcomes, risk factors, leukocyte telomere length, and endothelial progenitor cells. APPROACH AND RESULTS: SDF-1 was measured in 3359 Framingham Heart Study participants. We used Cox regression to examine relationships of SDF-1 to new-onset CVD, myocardial infarction, heart failure, and all-cause mortality; we used linear regression to evaluate associations of SDF-1 with risk factors, leukocyte telomere length, and CD34+ cell phenotypes. In multivariable models, higher SDF-1 levels were associated with older age, lower levels of high-density lipoprotein-cholesterol and cigarette smoking. Higher SDF-1 levels were associated with lower CD34+ cell frequency (P=0.02) but not with leukocyte telomere length. During follow-up (median, 9.3 years), there were 263 new-onset CVD events, 160 myocardial infarctions, 200 heart failure events, and 385 deaths. After adjusting for clinical risk factors, SDF-1 levels were associated with heart failure (P=0.04) and all-cause mortality (P=0.003) but not with CVD (P=0.39) or myocardial infarction (P=0.10). The association of SDF-1 levels with myocardial infarction was attenuated after adjustment for high-density lipoprotein-cholesterol. CONCLUSIONS: After adjusting for traditional CVD risk factors, SDF-1 is associated with heart failure and all-cause mortality risk. Additional studies are needed to determine whether measurement of SDF-1 levels has clinical use.

Protein biomarkers of new-onset cardiovascular disease: prospective study from the systems approach to biomarker research in cardiovascular disease initiative.

OBJECTIVE: Incorporation of novel plasma protein biomarkers may improve current models for prediction of atherosclerotic cardiovascular disease (ASCVD) risk. APPROACH AND RESULTS: We used discovery mass spectrometry (MS) to determine plasma concentrations of 861 proteins in 135 myocardial infarction (MI) cases and 135 matched controls. Then, we measured 59 markers by targeted MS in 336 ASCVD case-control pairs. Associations with MI or ASCVD were tested in single-marker and multiple-marker analyses adjusted for established ASCVD risk factors. Twelve single markers from discovery MS were associated with MI incidence (at P<0.01), adjusting for clinical risk factors. Seven proteins in aggregate (cyclophilin A, cluster of differentiation 5 molecule [CD5] antigen-like, cell-surface glycoprotein mucin cell surface associated protein 18 [MUC-18], collagen-α 1 [XVIII] chain, salivary α-amylase 1, C-reactive protein, and multimerin-2) were highly associated with MI (P<0.0001) and significantly improved its prediction compared with a model with clinical risk factors alone (C-statistic of 0.71 versus 0.84). Through targeted MS, 12 single proteins were predictors of ASCVD (at P<0.05) after adjusting for established risk factors. In multiple-marker analyses, 4 proteins in combination (α-1-acid glycoprotein 1, paraoxonase 1, tetranectin, and CD5 antigen-like) predicted incident ASCVD (P<0.0001) and moderately improved the C-statistic from the model with clinical covariates alone (C-statistic of 0.69 versus 0.73). CONCLUSIONS: Proteomics profiling identified single- and multiple-marker protein panels that are associated with new-onset ASCVD and may lead to a better understanding of underlying disease mechanisms. Our findings include many novel protein biomarkers that, if externally validated, may improve risk assessment for MI and ASCVD.

Toxicological evaluation of a pumpkin-derived pectin preparation: in vitro genotoxicity studies and a 13-week oral toxicity study in Sprague-Dawley rats.

The safety of a rhamnogalacturonan-I-enriched pectin extract (G3P-01) from pumpkin (Cucurbita moschata var. Dickinson) was evaluated for use as an ingredient in food and dietary supplements. G3P-01 was tested in a battery of genetic toxicity studies including reverse mutagenicity and in vitro micronucleus assay. In addition, Sprague-Dawley rats were randomized and orally dosed with G3P-01 incorporated in animal diet at concentrations of 0, 9000, 18,000, and 36,000 ppm daily for 13-weeks (n=10/sex/group) in line with OECD guidelines (TG 408). The results of the in vitro bacterial reverse mutation assay and micronucleus assay in TK6 cells demonstrated a lack of genotoxicity. The 13-week oral toxicity study in Sprague-Dawley rats demonstrated that the test article, G3P-01 was well tolerated; there were no mortalities and no adverse effects on clinical, gross pathology, hematology, blood chemistry, and histological evaluation of the essential organs of the animals. The present study demonstrates that G3P-01 is non-genotoxic and is safe when ingested in diet at concentrations up to 36, 000 ppm. The subchronic no-observed-adverse-effect level (NOAEL) for G3P-01 was concluded to be 36,000 ppm, equivalent to 1,899 and 2,361 mg/kg/day for male and female rats respectively.

A novel, small-volume subcutaneous furosemide formulation delivered by an abdominal patch infusor device in patients with heart failure: results of two phase I studies.

AIMS: Subcutaneous (SC) furosemide has potential advantages over intravenous (IV) furosemide by enabling self-administration or administration by a lay caregiver, such as facilitating early discharge, preventing hospitalizations, and in palliative care. A high-concentration, pH-neutral furosemide formulation has been developed for SC administration via a small patch infusor pump. We aimed to compare the bioavailability, pharmacokinetic (PK), and pharmacodynamic (PD) profiles of a new SC furosemide formulation with conventional IV furosemide and describe the first use of a bespoke mini-pump to administer this formulation. METHODS AND RESULTS: A novel pH-neutral formulation of SC furosemide containing 80 mg furosemide in ∼2.7 mL (infused over 5 h) was investigated. The first study was a PK/PD study of SC furosemide compared with 80 mg IV furosemide administered as a bolus in ambulatory patients with heart failure (HF). The primary outcome was absolute bioavailability of SC compared with IV furosemide. The second study investigated the same SC furosemide preparation delivered by a patch infusor in patients hospitalized with HF. Primary outcome measures were treatment-emergent adverse events, infusion site pain, device performance, and PK measurements.The absolute bioavailability of SC furosemide in comparison to IV furosemide was 112%, resulting in equivalent diuresis and natriuresis. When SC furosemide was administered via the patch pump, there were no treatment-emergent adverse events and 95% of participants reported no/minor discomfort at the infusion site. CONCLUSION: The novel preparation of SC furosemide had similar bioavailability to IV furosemide. Administration via a patch pump was feasible and well tolerated.

Biomarker-guided therapies in heart failure: a forum for unified strategies.

The complexity of standard medical treatment for heart failure is growing, and such therapy typically involves 5 or more different medications. Given these pressures, there is increasing interest in harnessing cardiovascular biomarkers for clinical application to more effectively guide diagnosis, risk stratification, and therapy. It may be possible to realize an era of personalized medicine for heart failure treatment in which therapy is optimized and costs are controlled. The direct mechanistic coupling of biologic processes and therapies achieved in cancer treatment remains elusive in heart failure. Recent clinical trials and meta-analyses of biomarkers in heart failure have produced conflicting evidence. In this article, which comprises a summary of discussions from the Global Cardiovascular Clinical Trialists Forum held in Paris, France, we offer a brief overview of the background and rationale for biomarker testing in heart failure, describe opportunities and challenges from a regulatory perspective, and summarize current positions from government agencies in the United States and European Union.

Galectin-3 predicts response to statin therapy in the Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA).

AIMS: To investigate whether plasma galectin-3, a mediator of fibrogenesis, can identify patients with chronic heart failure (HF) for whom statins are effective. METHODS AND RESULTS: Patients with ischaemic systolic HF enrolled in the Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA) were randomly assigned to 10 mg/day of rosuvastatin or placebo. Galectin-3 was measured in plasma. The primary outcome was cardiovascular death, myocardial infarction, or stroke. Of 1492 patients, 411 had a primary event during a median follow-up of 32.8 months. There was an interaction between baseline galectin-3 and rosuvastatin on the primary endpoint (P-value for interaction = 0.036). Among patients with below the median plasma concentrations of galectin-3 (≤ 19.0 ng/mL), those assigned to rosuvastatin had a lower primary event rate [hazard ratio (HR) 0.65; 95% confidence interval (CI), 0.46-0.92; P= 0.014], lower total mortality (HR 0.70; 95% CI, 0.50-0.98; P= 0.038), and lower event rate of all-cause mortality and HF hospitalizations (HR 0.72; 95% CI, 0.54-0.98; P= 0.017) compared with placebo, but no benefit was observed in patients with higher levels of galectin-3. The combination of concurrently low concentrations of galectin-3 and N-terminal pro-B-type natriuretic peptide (<102.7 pmol/L) identified patients with a large benefit with rosuvastatin (HR 0.33; 95% CI, 0.16-0.67; P= 0.002). CONCLUSION: Patients with systolic HF of ischaemic aetiology who have galectin-3 values <19.0 ng/mL may benefit from rosuvastatin treatment. However, the data from this post hoc analysis should be interpreted with caution since the overall results of the CORONA study did not show a significant effect on the primary endpoint.

Sex-specific role of galectin-3 in aortic stenosis.

BACKGROUND: Aortic stenosis (AS) is characterized by inflammation, fibrosis, osteogenesis and angiogenesis. Men and women develop these mechanisms differently. Galectin-3 (Gal-3) is a pro-inflammatory and pro-osteogenic lectin in AS. In this work, we aim to analyse a potential sex-differential role of Gal-3 in AS. METHODS: 226 patients (61.50% men) with severe AS undergoing surgical aortic valve (AV) replacement were recruited. In AVs, Gal-3 expression and its relationship with inflammatory, osteogenic and angiogenic markers was assessed. Valve interstitial cells (VICs) were primary cultured to perform in vitro experiments. RESULTS: Proteomic analysis revealed that intracellular Gal-3 was over-expressed in VICs of male AS patients. Gal-3 secretion was also higher in men's VICs as compared to women's. In human AVs, Gal-3 protein levels were significantly higher in men, with stronger immunostaining in VICs with myofibroblastic phenotype and valve endothelial cells. Gal-3 levels in AVs were positively correlated with inflammatory markers in both sexes. Gal-3 expression was also positively correlated with osteogenic markers mainly in men AVs, and with angiogenic molecules only in this sex. In vitro, Gal-3 treatment induced expression of inflammatory, osteogenic and angiogenic markers in male's VICs, while it only upregulated inflammatory and osteogenic molecules in women-derived cells. Gal-3 blockade with pharmacological inhibitors (modified citrus pectin and G3P-01) prevented the upregulation of inflammatory, osteogenic and angiogenic molecules. CONCLUSIONS: Gal-3 plays a sex-differential role in the setting of AS, and it could be a new sex-specific therapeutic target controlling pathological features of AS in VICs.

Aortic stenosis (AS) is a condition that affects the aortic valves (AVs) of the heart and leads to death if untreated. Males and females show clear differences in the onset of AS, both clinically and in valve deterioration. In this study we identified galectin-3 (Gal-3) as a molecule involved in the development of AS alterations with different effects in men and women. We analyzed AVs of 226 patients (139 male and 87 female) with severe AS who underwent surgical AV replacement to study the association of Gal-3 with markers of mechanisms related to AS, such as inflammation, calcification and blood vessels formation. We performed experiments in valvular interstitial cells (VICs) to evaluate the impact of Gal-3 in these cells and its potential use as a therapeutic target. Our results showed that Gal-3 was more expressed in AVs and VICs of men over women. In AVs, Gal-3 levels were associated with inflammatory markers either in male and female, while they correlated with osteogenic markers mainly in men and with angiogenic only in male. The treatment of VICs with Gal-3 produced increased levels of inflammatory and osteogenic molecules by cells of both sexes, but of angiogenic markers only in male's. Pharmacological inhibition of Gal-3 prevented the increase of these pathological markers in VICs. Overall, our study indicates that Gal-3 is a molecule implicated in the setting of AS in a sex-differential way and its targeting may lead to a new sex-specific therapeutic option for AS treatment.

The predictive value of galectin-3 for mortality and cardiovascular events in the Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA).

BACKGROUND: Galectin-3 is a new biomarker involved in inflammation and fibrogenesis and could therefore contribute to myocardial remodeling. We examined the prognostic value of baseline galectin-3 in a substudy involving approximately 30% of participants in the CORONA study. METHODS: Patients (n = 1462) aged >60 years with systolic, ischemic heart failure (HF) were randomized to 10 mg/d rosuvastatin or placebo. The primary composite end point was cardiovascular death, nonfatal myocardial infarction, or stroke (n = 408). RESULTS: In the unadjusted analysis, galectin-3 was associated with all end points considered, except hospitalization for worsening of HF. In multivariable analyses, adjusting for other clinical and biochemical predictor variables, galectin-3 was significantly associated with the primary end point (hazard ratio [HR] 1.53 [1.10-2.12], P = .011) as well as all-cause (HR 1.61 [1.20-2.29], P = .002) and cardiovascular mortality (HR 1.70 [1.19-2.42], P = .003), sudden death (HR 1.83 [1.14-2.94], P = .012), and the coronary end point (HR 1.48 [1.03-2.12], P = .035). However, when N-terminal pro-brain natriuretic peptide was added to the model, galectin-3 association with the end points was markedly attenuated and no longer significant. CONCLUSIONS: Galectin-3 is not associated with outcome in older patients with advanced chronic systolic HF of ischemic etiology when adjusting for N-terminal pro-brain natriuretic peptide and may therefore have limited use in the prognostication of elderly patients with systolic HF in clinical practice.

Pectins from various sources inhibit galectin-3-related cardiac fibrosis.

PURPOSE OF THE STUDY: A major challenge in cardiology remains in finding a therapy for cardiac fibrosis. Inhibition of galectin-3 with pectins attenuates fibrosis in animal models of heart failure. The purpose of this study is to identify pectins with the strongest galectin-3 inhibitory capacity. We evaluated the in vitro inhibitory capacity, identified potent pectins, and tested if this potency could be validated in a mouse model of myocardial fibrosis. METHODS: Various pectin fractions were screened in vitro. Modified rhubarb pectin (EMRP) was identified as the most potent inhibitor of galectin-3 and compared to the well-known modified citrus pectin (MCP). Our findings were validated in a mouse model of myocardial fibrosis, which was induced by angiotensin II (Ang II) infusion. RESULTS: Ang II infusion was associated with a 4-5-fold increase in fibrosis signal in the tissue of the left ventricle, compared to the control group (0•22±0•10 to 1•08±0•53%; P < 0•001). After treatment with rhubarb pectin, fibrosis was reduced by 57% vs. Ang II alone while this reduction was 30% with the well-known MCP (P = NS, P < 0•05). Treatment was associated with a reduced cardiac inflammatory response and preserved cardiac function. CONCLUSION: The galectin-3 inhibitor natural rhubarb pectin has a superior inhibitory capacity over established pectins, substantially attenuates cardiac fibrosis, and preserves cardiac function in vivo. Bioactive pectins are natural sources of galectin-3 inhibitors and may be helpful in the prevention of heart failure or other diseases characterized by fibrosis. FUNDING: Dr. Meijers is supported by the Mandema-Stipendium of the Junior Scientific Masterclass 2020-10, University Medical Center Groningen and by the Netherlands Heart Foundation (Dekkerbeurs 2021)Dr. de Boer is supported by the Netherlands Heart Foundation (CVON SHE-PREDICTS-HF, grant 2017-21; CVON RED-CVD, grant 2017-11; CVON PREDICT2, grant 2018-30; and CVON DOUBLE DOSE, grant 2020B005), by a grant from the leDucq Foundation (Cure PhosphoLambaN induced Cardiomyopathy (Cure-PLaN), and by a grant from the European Research Council (ERC CoG 818715, SECRETE-HF).

The high-risk plaque initiative: primary prevention of atherothrombotic events in the asymptomatic population.

The High-Risk Plaque (HRP) Initiative is a research and development effort to advance the understanding, recognition, and management of asymptomatic individuals at risk for a near-term atherothrombotic event such as myocardial infarction or stroke. Clinical studies using the newest technologies have been initiated, including the BioImage Study in which novel approaches are tested in a typical health plan population. Asymptomatic at-risk individuals were enrolled, including a survey-only group (n = 865), a group undergoing traditional risk factor scoring (n = 718), and a group in which all were assessed for both risk factors and subclinical atherosclerosis (n = 6104). The latter two groups underwent baseline examination in a dedicated mobile facility equipped with advanced imaging tools suitable for noninvasive screening for subclinical atherosclerosis (coronary artery calcium by computed tomography [CT], carotid and aortic disease by ultrasound, and ankle-brachial index). Selected participants were offered advanced imaging (contrast-enhanced CT, magnetic resonance imaging, and positron emission tomography/CT). Plasma, PAXgene RNA, and DNA samples were obtained for biomarker discovery studies. All individuals will be followed until 600 major atherothrombotic events have occurred in those undergoing imaging.

Beneficial Effects of Mineralocorticoid Receptor Pathway Blockade against Endothelial Inflammation Induced by SARS-CoV-2 Spike Protein.

BACKGROUND: Vascular endothelial cells activation and dysfunction mediate inflammation and abnormal coagulation in COVID-19 patients. Mineralocorticoid receptor (MR) signaling and its downstream target Galectin-3 (Gal-3) are known to mediate cardiovascular inflammation and might be involved in the pathogenesis of COVID-19 complications. Accordingly, we aimed to investigate the potential beneficial effects of MR antagonism and Gal-3 inhibition on the inflammatory response induced by SARS-CoV-2 Spike protein in human aortic endothelial cells (HAECs). METHODS: HAECs were treated with recombinant SARS-COV2 Spike (S) protein. MR antagonists (namely spironolactone and eplerenone) or the Gal-3 inhibitor G3P-01 were supplemented before and after S protein challenge. HAECs supernatants were assessed by ELISA or Western blotting. RESULTS: HAECs treated with recombinant S protein resulted in enhanced secretion of inflammatory molecules (interleukin-6, monocyte chemoattractant protein-1, interleukin-18, interleukin-27, and interferon-γ) as well as in the thrombosis marker plasminogen activator inhibitor (PAI)-1. This was prevented and reversed by both MR antagonists and G3P-01. CONCLUSIONS: These findings indicate that MR/Gal-3 pathway blockade could be a promising option to reduce endothelial inflammation in SARS-CoV-2 infection.

Development, validation, and implementation of biomarker testing in cardiovascular medicine state-of-the-art: proceedings of the European Society of Cardiology-Cardiovascular Round Table.

Many biomarkers that could be used to assess ejection fraction, heart failure, or myocardial infarction fail to translate into clinical practice because they lack essential performance characteristics or fail to meet regulatory standards for approval. Despite their potential, new technologies have added to the complexities of successful translation into clinical practice. Biomarker discovery and implementation require a standardized approach that includes: identification of a clinical need; identification of a valid surrogate biomarker; stepwise assay refinement, demonstration of superiority over current standard-of-care; development and understanding of a clinical pathway; and demonstration of real-world performance. Successful biomarkers should improve efficacy or safety of treatment, while being practical at a realistic cost. Everyone involved in cardiovascular healthcare, including researchers, clinicians, and industry partners, are important stakeholders in facilitating the development and implementation of biomarkers. This article provides suggestions for a development pathway for new biomarkers, discusses regulatory issues and challenges, and suggestions for accelerating the pathway to improve patient outcomes. Real-life examples of successful biomarkers-high-sensitivity cardiac troponin, T2* cardiovascular magnetic resonance imaging, and echocardiography-are used to illustrate the value of a standardized development pathway in the translation of concepts into routine clinical practice.

The BioImage Study: novel approaches to risk assessment in the primary prevention of atherosclerotic cardiovascular disease--study design and objectives.

The identification of asymptomatic individuals at risk for near-term atherothrombotic events to ensure optimal preventive treatment remains a challenging goal. In the BioImage Study, novel approaches are tested in a typical health-plan population. Based on certain demographic and risk characteristics on file with Humana Inc, a total of 7,687 men 55 to 80 years of age and women 60 to 80 years of age without evidence of atherothrombotic disease but presumed to be at risk for near-term atherothrombotic events were enrolled between January 2008 and June 2009. Those who met the prespecified eligibility criteria were randomized to a telephonic health survey only (survey only: n = 865), standard risk assessment (Framingham only: n = 718), or comprehensive risk assessment in a dedicated mobile facility equipped with advanced imaging tools (n = 6,104). Baseline examination included assessment of cardiovascular risk factors and screening for subclinical (asymptomatic) atherosclerosis with quantification of coronary artery calcification by computed tomography (CT), measurement of intima-media thickness, presence of carotid atherosclerotic plaques and abdominal aortic aneurysm by ultrasound, and ankle brachial index. Participants with one or more abnormal screening test results underwent advanced imaging with contrast-enhanced magnetic resonance imaging for carotid and aortic plaques, contrast-enhanced coronary CT angiography for luminal stenosis and noncalcified plaques, and 18F-fluorodeoxyglucose-positron emission tomography/CT for carotid and aortic plaque inflammation. Plasma, PAXgene RNA, and DNA samples were obtained, frozen, and stored for future biomarker discovery studies. All individuals will be followed until 600 major atherothrombotic events have occurred in those undergoing imaging. The BioImage Study will help identify those patients with subclinical atherosclerosis who are at risk for near-term atherothrombotic events and enable a more personalized management of care.

Risk factors for near-term myocardial infarction in apparently healthy men and women.

BACKGROUND: Limited information is available regarding risk factors for the near-term (4 years) onset of myocardial infarction (MI). We evaluated established cardiovascular risk factors and putative circulating biomarkers as predictors for MI within 4 years of measurement. METHODS: We conducted a matched, nested case-control study (252 cases and 499 controls) drawing on 45 735 men and women participating in the Copenhagen City Heart Study and the Copenhagen General Population Study. Established risk factors and 17 putative biomarkers, including inflammation-sensitive plasma proteins (C-reactive protein, fibrinogen, alpha(l)-antitrypsin, complement 3), apolipoproteins (A1, B, E, B/A1 ratio), markers of iron overload (iron, transferrin, transferrin saturation), creatinine, alkaline phosphatase, gamma-glutamyl transpeptidase, and leukocytes (lymphocyte count, neutrophil count, neutrophil/lymphocyte ratio) were assessed. RESULTS: Among women and men, only 13% and 50%, respectively, of those with near-term MI were classified as high risk by Framingham risk score at baseline. After adjustment for established risk factors, odds ratios for near-term MI, which compared highest to lowest quintiles, were 2.87(95% CI 1.51-5.48; P = 0.001) for alpha(l)-antitrypsin, 2.84(1.42-5.67; P = 0.003) for C-reactive protein, 1.97(1.09-3.57; P = 0.03) for creatinine, 1.99(1.09-3.65; P = 0.03) for fibrinogen, and 0.37(0.19-0.73; P = 0.004) for iron. The corresponding odds ratio for all biomarkers combined was 7.24 (3.28-16.0; P < 0.001). CONCLUSIONS: We identified 5 biomarkers associated with increased near-term risk of MI independently of established risk factors. All putative biomarkers combined explained a 7-fold increase in the odds of near-term MI.

Negative Risk Markers for Cardiovascular Events in the Elderly.

BACKGROUND: Cardiovascular risk increases dramatically with age, leading to nearly universal risk-based statin eligibility in the elderly population. To limit overtreatment, elderly individuals at truly low risk need to be identified. OBJECTIVES: Discovering "negative" risk markers able to identify elderly individuals at low short-term risk for coronary heart disease and cardiovascular disease. METHODS: In 5,805 BioImage participants (mean age 69 years; median follow-up 2.7 years), the authors evaluated 13 candidate markers: coronary artery calcium (CAC) = 0, CAC ≤10, no carotid plaque, no family history, normal ankle-brachial index, test result <25th percentile (carotid intima-media thickness, apolipoprotein B, galectin-3, high-sensitivity C-reactive protein, lipoprotein(a), N-terminal pro-B-type natriuretic peptide, and transferrin), and apolipoprotein A1 >75th percentile. Negative risk marker performance was compared using patient-specific diagnostic likelihood ratio (DLR) and binary net reclassification index (NRI). RESULTS: CAC = 0 and CAC ≤10 were the strongest negative risk markers with mean DLRs of 0.20 and 0.20 for coronary heart disease (i.e., ≈80% lower risk than expected from traditional risk factor assessment) and 0.41 and 0.48 for cardiovascular disease, respectively, followed by galectin-3 <25th percentile (DLR 0.44 and 0.43, respectively) and absence of carotid plaque (DLR 0.39 and 0.65, respectively). Results obtained by other candidate markers were less impressive. Accurate downward risk reclassification across the Class I statin-eligibility threshold defined by the American College of Cardiology/American Heart Association was largest for CAC = 0 (NRI 0.23) and CAC ≤10 (NRI 0.28), followed by galectin-3 <25th percentile (NRI 0.14) and absence of carotid plaque (NRI 0.08). CONCLUSIONS: Elderly individuals with CAC = 0, CAC ≤10, low galectin-3, or no carotid plaque had remarkable low cardiovascular risk, calling into question the appropriateness of a treat-all approach in the elderly population.

Subcutaneous Furosemide in Heart Failure: Pharmacokinetic Characteristics of a Newly Buffered Solution.

Parenteral diuretics form the cornerstone of decongestion in heart failure. However, parenteral therapy routinely requires emergency room or inpatient care. A novel buffered furosemide formulation with neutral pH was developed to offer "hospital-strength" diuresis for outpatient use, including self-administration at home. Subcutaneous infusion using a biphasic delivery profile resulted in complete bioavailability (99.65%) and equivalent diuresis when compared with intravenous administration. Subcutaneous administration of buffered furosemide was well tolerated with no evidence of any drug-induced skin reactions. Subcutaneous infusion of buffered furosemide in the outpatient setting or home may help to reduce the burden of heart failure.

Limited Added Value of Circulating Inflammatory Biomarkers in Chronic Heart Failure.

OBJECTIVES: This study sought to evaluate whether a panel of biomarkers improved prognostication in patients with heart failure (HF) and reduced ejection fraction of ischemic origin using a systematized approach according to suggested requirements for validation of new biomarkers. BACKGROUND: Modeling combinations of multiple circulating markers could potentially identify patients with HF at particularly high risk and aid in the selection of individualized therapy. METHODS: From a panel of 20 inflammatory and extracellular matrix biomarkers, 2 different biomarker panels were created and added to the Seattle HF score and the prognostic model from the CORONA (Controlled Rosuvastatin Multinational Trial in Heart Failure) study (n = 1,497), which included conventional clinical characteristics and C-reactive protein and N-terminal pro-B-type natriuretic peptide. Interactions with statin treatment were also assessed. RESULTS: The two models-model 1 (endostatin, interleukin 8, soluble ST2, troponin T, galectin 3, and chemokine [C-C motif] ligand 21) and model 2 (troponin T, soluble ST2, galectin 3, pentraxin 3, and soluble tumor necrosis factor receptor 2)-significantly improved the CORONA and Seattle HF models but added only modestly to their Harrell's C statistic and net reclassification index. In addition, rosuvastatin had no effect on the levels of a wide range of inflammatory and extracellular matrix markers, but there was a tendency for patients with a lower level of biomarkers in the 2 panels to have a positive effect from statin treatment. CONCLUSIONS: In the specific HF patient population studied, a multimarker approach using the particular panel of biomarkers measured was of limited clinical value for identifying future risk of adverse outcomes.

Lost in translation? Role of metabolomics in solving translational problems in drug discovery and development.

Too few drug discovery projects generate a marketed drug product, often because preclinical studies fail to predict the clinical experience with a drug candidate. Improving the success of preclinical-to-clinical translation is of paramount importance in optimizing the pharmaceutical value chain. Here, we advance the case for a molecular systems approach to crossing the preclinical-to-clinical translational chasm and for metabolomic analysis of readily accessible bodyfluids as a key technology in translational activities.:

A Simple Disease-Guided Approach to Personalize ACC/AHA-Recommended Statin Allocation in Elderly People: The BioImage Study.

BACKGROUND: The 2013 American College of Cardiology (ACC)/American Heart Association (AHA) guidelines recommend primary prevention with statins for individuals with ≥7.5% 10-year risk for atherosclerotic cardiovascular disease (ASCVD). Everyone living long enough will become eligible for risk-based statin therapy due to age alone. OBJECTIVES: This study sought to personalize ACC/AHA risk-based statin eligibility using noninvasive assessment of subclinical atherosclerosis. METHODS: In 5,805 BioImage participants without known ASCVD at baseline, those with ≥7.5% 10-year ASCVD risk were down-classified from statin eligible to ineligible if imaging revealed no coronary artery calcium (CAC) or carotid plaque burden (cPB). Intermediate-risk individuals were up-classified from optional to clear statin eligibility if CAC was ≥100 (or equivalent cPB). RESULTS: At a median follow-up of 2.7 years, 91 patients had coronary heart disease and 138 had experienced a cardiovascular disease event. Mean age of the participants was 69 years, and 86% qualified for ACC/AHA risk-based statin therapy, with high sensitivity (96%) but low specificity (15%). CAC or cPB scores of 0 were common (32% and 23%, respectively) and were associated with low event rates. With CAC-guided reclassification, specificity for coronary heart disease events improved 22% (p < 0.0001) without any significant loss in sensitivity, yielding a binary net reclassification index (NRI) of 0.20 (p < 0.0001). With cPB-guided reclassification, specificity improved 16% (p < 0.0001) with a minor loss in sensitivity (7%), yielding an NRI of 0.09 (p = 0.001). For cardiovascular disease events, the NRI was 0.14 (CAC-guided) and 0.06 (cPB-guided). The positive NRIs were driven primarily by down-classifying the large subpopulation with CAC = 0 or cPB = 0. CONCLUSIONS: Withholding statins in individuals without CAC or carotid plaque could spare a significant proportion of elderly people from taking a pill that would benefit only a few. This individualized disease-guided approach is simple and easy to implement in routine clinical practice.

Metabolite Signatures of Metabolic Risk Factors and their Longitudinal Changes.

CONTEXT: Metabolic dysregulation underlies key metabolic risk factors­obesity, dyslipidemia, and dysglycemia. OBJECTIVE: To uncover mechanistic links between metabolomic dysregulation and metabolic risk by testing metabolite associations with risk factors cross-sectionally and with risk factor changes over time. DESIGN: Cross-sectional­discovery samples (n = 650; age, 36­69 years) from the Framingham Heart Study (FHS) and replication samples (n = 670; age, 61­76 years) from the BioImage Study, both following a factorial design sampled from high vs low strata of body mass index, lipids, and glucose. Longitudinal­FHS participants (n = 554) with 5­7 years of follow-up for risk factor changes. SETTING: Observational studies. PARTICIPANTS: Cross-sectional samples with or without obesity, dysglycemia, and dyslipidemia, excluding prevalent cardiovascular disease and diabetes or dyslipidemia treatment. Age- and sex-matched by group. INTERVENTIONS: None. MAIN OUTCOME MEASURE(S): Gas chromatography-mass spectrometry detected 119 plasma metabolites. Cross-sectional associations with obesity, dyslipidemia, and dysglycemia were tested in discovery, with external replication of 37 metabolites. Single- and multi-metabolite markers were tested for association with longitudinal changes in risk factors. RESULTS: Cross-sectional metabolite associations were identified with obesity (n = 26), dyslipidemia (n = 21), and dysglycemia (n = 11) in discovery. Glutamic acid, lactic acid, and sitosterol associated with all three risk factors in meta-analysis (P < 4.5 × 10−4). Metabolites associated with longitudinal risk factor changes were enriched for bioactive lipids. Multi-metabolite panels explained 2.5­15.3% of longitudinal changes in metabolic traits. CONCLUSIONS: Cross-sectional results implicated dysregulated glutamate cycling and amino acid metabolism in metabolic risk. Certain bioactive lipids were associated with risk factors cross-sectionally and over time, suggesting their upstream role in risk factor progression. Functional studies are needed to validate findings and facilitate translation into treatments or preventive measures.