Common Variants on FGD5 Increase Hazard of Mortality or Rehospitalization in Patients With Heart Failure From the ASCEND-HF Trial.

BACKGROUND: Heart failure remains a global health burden, and patients hospitalized are particularly at risk, but genetic associates for subsequent death or rehospitalization are still lacking. METHODS: The genetic substudy of the ASCEND-HF trial (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure) was used to perform genome-wide association study and transethnic meta-analysis. The overall trial included the patients of self-reported European ancestry (n=2173) and African ancestry (n=507). The end point was death or heart failure rehospitalization within 180 days. Cox models adjusted for 11 a priori predictors of rehospitalization and 5 genetic principal components were used to test the association between single-nucleotide polymorphisms and outcome. Summary statistics from the 2 populations were combined via meta-analysis with the significance threshold considered P<5×10-8. RESULTS: Common variants (rs2342882 and rs35850039 in complete linkage disequilibrium) located in FGD5 were significantly associated with the primary outcome in both ancestry groups (European Americans: hazard ratio [HR], 1.38; P=2.42×10-6; African ancestry: HR, 1.51; P=4.43×10-3; HR in meta-analysis, 1.41; P=4.25×10-8). FGD5 encodes a regulator of VEGF (vascular endothelial growth factor)-mediated angiogenesis, and in silico investigation revealed several previous genome-wide association study hits in this gene, among which rs748431 was associated with our outcome (HR, 1.20; meta P<0.01). Sensitivity analysis proved FGD5 common variants survival association did not appear to operate via coronary artery disease or nesiritide treatment (P>0.05); and the signal was still significant when changing the censoring time from 180 to 30 days (HR, 1.39; P=1.59×10-5). CONCLUSIONS: In this multiethnic genome-wide association study of ASCEND-HF, single-nucleotide polymorphisms in FGD5 were associated with increased risk of death or rehospitalization. Additional investigation is required to examine biological mechanisms and whether FGD5 could be a therapeutic target. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT00475852.

Evaluation of a New Aptamer-Based Array for Soluble Suppressor of Tumorgenicity (ST2) and N-terminal Pro-B-Type Natriuretic Peptide (NTproBNP) in Heart Failure Patients.

BACKGROUND: Recent advances in multi-marker platforms offer faster data generation, but the fidelity of these methods compared to the ELISA is not established. We tested the correlation and predictive performance of SOMAscan vs. ELISA methods for NTproBNP and ST2. METHODS: Patients ≥ 18 years with heart failure and ejection fraction < 50% were enrolled. We tested the correlation between SOMA and ELISA for each biomarker and their association with outcomes. RESULTS: There was good correlation of SOMA vs. ELISA for ST2 (ρ = 0.71) and excellent correlation for NTproBNP (ρ = 0.94). The two versions of both markers were not significantly different regarding survival association. The two ST2 assays and NTproBNP assays were similarly associated with all-cause mortality and cardiovascular mortality. These associations remained statistically significant when adjusted for MAGGIC risk score (all p < 0.05). CONCLUSION: SOMAscan quantifications of ST2 and NTproBNP correlate to ELISA versions and carry similar prognosis.

Prediction of Survival After Implantation of a Fully Magnetically Levitated Left Ventricular Assist Device.

BACKGROUND: Clinical trials inform on average efficacy, but individualized risk assessments for outcome prediction are important in guiding treatment implementation. OBJECTIVES: The authors developed and validated a patient-specific risk score to predict survival at 1 and 2 years after HeartMate 3 (HM3) left ventricular assist device (LVAD) implantation. METHODS: The MOMENTUM 3 (Multicenter Study of MagLev Technology in Patients Undergoing Mechanical Circulatory Support Therapy with HeartMate 3) trial includes 2,200 HM3 LVAD patients in the pivotal trial and Continued Access Protocol study (2014-2018). The authors randomly assigned all patients to a derivation cohort (n = 1,540) or validation cohort (n = 660). Univariate mortality predictors were screened for potential model inclusion, stepwise selection was used to build the multivariable Cox proportional hazards regression model, and performance (discrimination and calibration) was evaluated. RESULTS: Age, prior cardiac surgery (coronary artery bypass grafting [CABG] or valve procedure), lower serum sodium, higher blood urea nitrogen (BUN), small left ventricular size, and right atrial pressure-to-pulmonary capillary wedge pressure (RAP/PCWP) ratio >0.6 were significant risk factors for mortality. Receiver-operating characteristic (ROC) analysis in the validation cohort demonstrated an area under the curve (AUC) of 0.76 (95% CI: 0.70-0.81) at 1 year and 0.71 (95% CI: 0.66-0.77) at 2 years. Calibration between predicted and observed survival of the risk quintiles was high, with Pearson correlation coefficients of 0.986 and 0.994 at 1 and 2 years, respectively. Patients were successfully stratified into tertiles with higher-than-average, average, and lower-than-average survival, and observed mortality risk increased by 2-fold from one tertile to the next. CONCLUSIONS: A practical, easy-to-use HM3 Survival Risk Score with 6 components was developed to accurately predict 1- and 2-year survival after HM3 LVAD implantation. The survival risk score can be used to provide individual survival estimates to facilitate shared decision making when considering HM3 LVAD therapy. (MOMENTUM 3 Trial Portfolio; NCT02224755, NCT02892955).

Suppression tumorigenicity 2 (ST2) turbidimetric immunoassay compared to enzyme-linked immunosorbent assay in predicting survival in heart failure patients with reduced ejection fraction.

BACKGROUND: Suppressor of tumorigenicity 2 (ST2) is a powerful marker of prognosis and treatment response in heart failure (HF), however, it is an enzyme-linked immunosorbent assay (ELISA) which may be cumbersome and costly. A turbidimetric immunoassay (TIA) that can run on common chemistry analyzers could overcome this. We studied a novel TIA for ST2, comparing it to commercial ST2 (ELISA). METHODS: Patients age ≥ 18 years meeting Framingham definition for HF were enrolled in a prospective registry (Oct 2007 - March 2015) at Henry Ford Hospital and donated blood samples. Participants with reduced ejection fraction (<50%) and available plasma samples were included and valid ST2 measurements were obtained on the same sample using both TIA and ELISA (N = 721). The primary endpoint was all cause death. Correlation between the methods was quantified. The association with survival was tested using unadjusted and adjusted (for MAGGIC score and NTproBNP) Cox models and comparing the Area Under the Curve (AUC). RESULTS: The inter-assay Spearman correlation coefficient was 0.77. Nonparametric regression showed no significant proportional difference (slope = 0.97) and a very small systematic difference (3.2 ng/mL). In univariate analyses, both TIA and ELISA ST2 were significant associates of survival with similar effect sizes (HR 4.46 and 3.50, respectively, both p < 0.001). In models adjusted for MAGGIC score, both ST2 remained significant in Cox models and incrementally improved AUC vs. MAGGIC alone (MAGGIC AUC = 0.757; TIA + MAGGIC AUC = 0.786, p = 0.025; ELISA + MAGGIC AUC = 0.793, p = 0.033). In models with both MAGGIC and NTproBNP included, both ST2 still remained significant but did not improve AUC. CONCLUSIONS: A novel TIA method for ST2 quantification correlates highly with ELISA and offers similarly powerful risk-stratification.

Outcomes on Continuous Flow Left Ventricular Assist Devices: A Single Institutional 9-Year Experience.

BACKGROUND: Continuous-flow left ventricular assist devices (LVADs) have become the standard of care for patients with advanced heart failure. The goal of this study was to review our 9-year institutional experience. METHODS: From March 2006 through May 2015, 231 patients underwent implantation of 240 CF LVADs, HeartMate II LVAD (Thoratec Corp., Pleasanton, CA; n = 205) or HVAD (HeartWare Inc., Framingham, MA; n = 35). Of these, 127 devices (52.9%) were implanted as bridge to transplantation (BTT) and 113 (47.1%) as destination therapy (DT). RESULTS: Mean age was 51.2 ± 11.9 years for BTT patients and 58.2 ± 11.4 years for DT patients (p < 0.001). There was a higher incidence of preoperative diabetes, renal insufficiency, peripheral vascular disease, and previous cardiac operation in DT patients (p < 0.05). Survival was higher for BTT patients, with 1-, 6-, 12-, and 24-month survivals of 91.0%, 90.0%, 88.5%, and 72.1%, respectively, versus 85.3%, 81.1%, 75.6%, and 59.0%, respectively, for DT patients (p = 0.038). Gastrointestinal bleeding was the most common complication (29.6%), followed by right ventricular failure (22.5%) and stroke (15.0%), with a similar incidence for BTT and DT patients. Preoperative liver biopsy (hazard ratio [HR] 2.27, p = 0.036), mechanical support (HR 1.82, p = 0.025), aspartate transaminase (HR 1.07, p = 0.001), and alanine aminotransferase (HR 0.95, p = 0.024) were severe independent predictors of survival in multivariate analysis. CONCLUSIONS: These data indicate excellent survival for BTT and DT patients on long-term LVAD support. However, for LVAD therapy to become a plausible alternative to heart transplantation, we need to further decrease the incidence of postoperative complications.

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.

Effect of Preoperative Albumin Levels on Outcomes in Patients Undergoing Left Ventricular Device Implantation.

Hypoalbuminemia is a well-known predictor of morbidity and mortality in cardiac surgery. Our aim was to establish the impact of serum albumin on outcomes after left ventricular assist device (LVAD) implantation. This was a single-institution retrospective review, including all patients who underwent LVAD implantation between March 2006 and June 2014. Two hundred patients were included in the analysis. Mean serum albumin was 3.27 ± 0.47 g/dl, with 7% in the low albumin group (<2.5 mg/dl), 67.5% in the mid-range (2.5-3.5 mg/dl), and 25.5% in the normal albumin groups (> 3.5 mg/dl). Lower albumin was associated with a significant increase in postoperative renal failure (42.9 vs. 16.5 vs. 17.3%; p = 0.05) and prolonged hospitalization (median 28.5 vs. 16 vs. 15.5 days; p = 0.008). Six month, 1 year, and 5 year survival was 79%, 79%, and 49% with low, 84%, 78%, and 51% with mid-range, and 94%, 88%, and 60% with normal albumin, respectively (p = 0.22). Preoperative hypoalbuminemia is associated with postoperative acute renal failure (ARF) and prolonged hospitalization after LVAD implantation, with no effect on overall survival. Hypoalbuminemia is most likely a marker of advanced disease and should not, in itself, be considered a contraindication to LVAD candidacy.

Future translational applications from the contemporary genomics era: a scientific statement from the American Heart Association.

The field of genetics and genomics has advanced considerably with the achievement of recent milestones encompassing the identification of many loci for cardiovascular disease and variable drug responses. Despite this achievement, a gap exists in the understanding and advancement to meaningful translation that directly affects disease prevention and clinical care. The purpose of this scientific statement is to address the gap between genetic discoveries and their practical application to cardiovascular clinical care. In brief, this scientific statement assesses the current timeline for effective translation of basic discoveries to clinical advances, highlighting past successes. Current discoveries in the area of genetics and genomics are covered next, followed by future expectations, tools, and competencies for achieving the goal of improving clinical care.

Genetic and nongenetic factors influencing pharmacokinetics of B-type natriuretic peptide.

BACKGROUND: Natriuretic peptides (NPs) represent a critical pathway in heart failure (HF). However, there is wide individual variability in NP system activity, which could be partly genetic in origin. We explored genetic and nongenetic contributions to B-type natriuretic peptide (BNP) inactivation. METHODS: Chronic HF patients (n = 95) received recombinant human BNP (nesiritide) at standard doses, and BNP levels were measured at baseline, after 2 hours of infusion, and 30 minutes after discontinuation. Genomic DNA was genotyped for 91 single-nucleotide polymorphisms (SNP) in 2 candidate genes. We tested the association of patient characteristics and genotype with 5 pharmacokinetics (PK) parameters: elimination rate constant, ΔBNP, BNP clearance, adjusted BNP clearance, and half-life. Linear regression with pleiotropic analysis was used to test genotype associations with PK. RESULTS: Participants' mean age was 63 years, 44% were female, and 46% were African American. PK parameters varied widely, some >10-fold. HF type (preserved vs reduced) was associated with PK (P < .01), whereas renal function, demographics, and body mass index and were not. Two SNPs in MME (rs989692, rs6798179) and 2 in NPR3 (rs6880564, rs2062708) also had associations with PK (P < .05). CONCLUSIONS: The pharmacokinetics of BNP varies greatly in HF patients, differs by HF type, and possibly by MME or NPR3 genotype. Additional study is warranted.

Policies and events affecting prescription opioid use for non-cancer pain among an insured patient population.

BACKGROUND: Rising prescription opioid use and abuse have prompted widespread concern. However, to date there have been few rigorous investigations into the policies and events which may have contributed to these trends. OBJECTIVE: This study investigates trends in opioid use and related adverse events among individuals with non-cancer pain before and after implementation of major national policies. STUDY DESIGN: The study used a longitudinal prospective study design. The analysis was limited to adults (age = 18 years) without a recorded cancer diagnosis. Pharmacy claims were used to assess rates of prescription opioid use, the strength of opioids dispensed, the proportion using opioids chronically, and related adverse events. Time trend analysis was used to identify changes in these rates over time. The study was Institutional Review Board approved. SETTING: Study patients were members of a large, health maintenance organization in southeast Michigan, with longitudinal records of prescription opioid use. RESULTS: The analysis comprised 523,623 individuals and 1,066,700 opioid pharmacy fills from January 1, 1997, to December 31, 2011. Contemporaneous with the implementation of health organization accreditation criteria requiring assessment and treatment of pain in all patients beginning January 2001, we observed a consistent and unabated increase in the rate of opioid fills and the proportion of chronic use. A parallel increase in the annual rate of adverse events was also observed. Similarly, we observed a continuous rise in the average strength of opioid fills following January 2001 with the exception of a single drop in December 2010, which was attributable to the withdrawal of propoxyphene from the U.S. market. LIMITATIONS: This was an observational study and not a trial. Other long-term opioid-related benefits or harms, including functional status, quality of life, and substance use disorder, were not assessed. CONCLUSIONS: This study provides temporal evidence for a rise in prescription opioid use after implementation of health organization accreditation criteria requiring standardized management of all individuals with pain.

Dosing of vancomycin in patients with continuous-flow left ventricular assist devices: a clinical pharmacokinetic analysis.

PURPOSE: To describe the pharmacokinetics of vancomycin in patients with continuous-flow left ventricular assist devices (CF-LVADs). METHODS: Eligible patients were ≥18 years old, implanted with a Heart Mate II CF-LVAD during January 2008-April 2012, and treated with vancomycin ≥48 hours for infection. Key exclusion criteria were unstable renal function, acute heart failure exacerbation, hemodynamic instability, and recent surgery. First-order elimination rate constant (Ke) and volume of distribution (Vd) were estimated using ideal (IBW), adjusted (AdjBW), actual (ABW), and fixed body weights. Estimated parameters were compared with measured pharmacokinetic parameters, which were calculated from steady state peak and trough vancomycin levels using one-compartment model equations. RESULTS: Twelve patients were included (age 44.9 ± 15 years, 91.7% male, 58.3% obese, CLcr 79.2 ± 27 mL ∙ min⁻¹). Common treatment indications were health-care associated pneumonia (41.7%), driveline infection (25%), and sepsis (16.7%). All methods of predicting Ke provided overestimates (p<0.05), ranging from 47 to 79%, depending on body habitus. METHODS: of predicting Vd using ABW in obese patients yielded overestimates of 74.5% (p<0.05), where IBW predictive Vd equations provided accurate assessments regardless of body habitus. CONCLUSIONS: General population methods may not accurately estimate the pharmacokinetic parameters of vancomycin for compensated heart failure patients implanted with CF-LVADs.

Acute intravenous infusion of an adenosine regulating agent improves left ventricular function in dogs with advanced heart failure.

PURPOSE: GP531 is a second generation adenosine regulating agent (ARA) that increases concentrations of endogenous adenosine, a natural cardioprotective agent, in ischemic/hypoxic tissue. This study examined the effects of acute intravenous infusions of GP531 on left ventricular (LV) systolic and diastolic function in dogs with advanced chronic heart failure (HF) (LV ejection fraction, EF <30 %). METHODS: Six dogs with intracoronary microembolization-induced HF received a constant intravenous infusion of GP531 (10 µg/kg/min) or vehicle (normal saline) for 6 h in random order 1 week apart. Hemodynamic measurements were made at baseline and at 1, 2, 3, 4, 5 and 6 h after initiating drug infusion. Myocardial oxygen consumption (MVO2) was measured at baseline and 4 and 6 h. LV pressure-volume relationship (PVR) was measured at baseline and 6 h. RESULTS: Vehicle infusions had no effect on indexes of LV systolic and diastolic function. GP531 infusion had no effect on heart rate or mean aortic pressure but significantly decreased LV end-diastolic pressure, end-diastolic volume, end-systolic volume and end-diastolic wall stress. GP531 significantly increased LV EF (27 ± 1 at baseline to 34 ± 1 after 6 h of drug infusion, p < 0.05), deceleration time of early mitral inflow velocity and the slope of end-systolic PVR without increasing MVO2. CONCLUSIONS: Results of the study indicate that approaches which increase the local release of adenosine in failing LV myocardium, such as ARAs, have a favorable impact on LV performance. These observations support the continued development of ARA's for the treatment of acute HF syndromes.

Association of genetic variation with gene expression and protein abundance within the natriuretic peptide pathway.

The natriuretic peptide (NP) system is a critical physiologic pathway in heart failure with wide individual variability in functioning. We investigated the genetic component by testing the association of single nucleotide polymorphisms (SNP) with RNA and protein expression. Samples of DNA, RNA, and tissue from human kidney (n = 103) underwent genotyping, RT-PCR, and protein quantitation (in lysates), for four candidate genes [NP receptor 1 (NPR1), NPR2, and NPR3 and membrane metalloendopeptidase]. The association of genetic variation with expression was tested using linear regression for individual SNPs, and a principal components (PC) method for overall gene variation. Eleven SNPs in NPR2 were significantly associated with protein expression (false discovery rate ≤0.05), but not RNA quantity. RNA and protein quantity correlated poorly with each other. The PC analysis showed only NPR2 as significant. Assessment of the clinical impact of NPR2 genetic variation is needed.

Management of aortic valve insufficiency in patients supported by long-term continuous flow left ventricular assist devices.

Continuous flow (CF) left ventricular assist devices (LVADs) have yielded improved outcomes in patient survival and quality of life compared with first-generation pulsatile pumps; however, they have been associated with an increased incidence of postimplant aortic valve insufficiency (AI), which can have can have serious clinical consequences if not diagnosed and treated expeditiously. We reviewed our experience with AI after LVAD since the start of our CF LVAD program. From March 2006 through July 2011, 94 patients with chronic heart failure underwent implantation of a HeartMate II (HM II) LVAD. Severe AI developed in three patients after CF LVAD implantation. The clinical records of these patients were reviewed to analyze the presenting signs and symptoms of AI, identify the duration of LVAD support when the AI occurred, how the AI was treated, and the outcomes.

Non-cardiac surgery in patients on long-term left ventricular assist device support.

BACKGROUND: An increasing number of patients on left ventricular assist device (LVAD) support are requiring non-cardiac surgical (NCS) procedures. We reviewed our experience with the management of patients on continuous flow (CF) LVAD support undergoing NCS. METHODS: From March 2006 through March 2011, 86 patients with chronic heart failure underwent implantation of a HeartMate II (Thoratec Corp, Pleasanton, CA) LVAD. Clinical records of these patients were reviewed to identify patients who underwent NCS while on LVAD support, with a focus on peri-operative death, bleeding, thrombosis, and device malfunction, as well as management of pre-operative anti-coagulation. RESULTS: While on CF-LVAD support, 20 patients underwent 25 NCSs, comprising 13 major and 12 minor procedures. Operations were performed electively in 22 and as emergencies in 3. No peri-operative deaths, thromboembolic complications, or device malfunctions occurred. The incidence of bleeding requiring transfusion of packed red blood cells was 36.0%, including 25% of patients undergoing minor NCSs and 46.2% undergoing major NCSs (p = 0.004). All bleeding complications occurred in patients on both warfarin and aspirin pre-operatively. The only significant differences between patients who did and did not require transfusion were pre-operative warfarin use and significantly higher pre-operative international normalized ratio in the transfused group (1.9 ± 0.4 vs 1.4 ± 0.3; p = 0.008). CONCLUSIONS: Non-cardiac operations can be performed safely in patients with CF-LVADs. It may possible to reduce peri-operative bleeding by lowering pre-operative anti-coagulation goals, especially before major surgery. However, additional analysis is required to determine if this can be performed safely.

Short term effects of milrinone on biomarkers of necrosis, apoptosis, and inflammation in patients with severe heart failure.

INTRODUCTION: Inotropes are associated with adverse outcomes in heart failure (HF), raising concern they may accelerate myocardial injury. Whether biomarkers of myocardial necrosis, inflammation and apoptosis change in response to acute milrinone administration is not well established. METHODS: Ten patients with severe HF and reduced cardiac output who were to receive milrinone were studied. Blood samples were taken just before initiation of milrinone and after 24 hours of infusion. Dosing was at the discretion of the patient's attending physician (range 0.25-0.5 mcg/kg/min). Plasma measurements of troponin, myoglobin, N-terminal-pro-BNP, interleukin-6, tumor necrosis factor-alpha, soluble Fas, and soluble Fas-ligand were performed at both time points. RESULTS: Troponin was elevated at baseline in all patients (mean 0.1259 +/- 0.17 ng/ml), but there was no significant change after 24 hours of milrinone (mean 0.1345 +/- 0.16 ng/ml, p = 0.44). There were significant improvements in interleukin-6, tumor necrosis factor-alpha, soluble Fas, and soluble Fas-ligand (all p < 0.05) indicative of reduced inflammatory and apoptotic signaling compared to baseline. CONCLUSION: In conclusion, among patients with severe HF and low cardiac output, ongoing myocardial injury is common, and initiation of milrinone did not result in exacerbation of myocardial injury but instead was associated with salutary effects on other biomarkers.