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Rare cases of COVID-19 vaccinated individuals develop anti-platelet factor 4 (PF4) antibodies that cause thrombocytopenia and thrombotic complications, a syndrome referred to as vaccine-induced immune thrombotic thrombocytopenia (VITT). Currently, information on the characteristics and persistence of anti-PF4 antibodies that cause VITT after Ad26.COV2.S vaccination is limited, and available diagnostic assays fail to differentiate Ad26.COV2.S and ChAdOx1 nCoV-19-associated VITT from similar clinical disorders, namely heparin-induced thrombocytopenia (HIT) and spontaneous HIT. Here we demonstrate that while Ad26.COV2.S-associated VITT patients are uniformly strongly positive in PF4-polyanion enzyme-linked immunosorbent assays (ELISAs); they are frequently negative in the serotonin release assay (SRA). The PF4-dependent p-selectin expression assay (PEA) that uses platelets treated with PF4 rather than heparin consistently diagnosed Ad26.COV2.S-associated VITT. Most Ad26.COV2.S-associated VITT antibodies persisted for >5 months in PF4-polyanion ELISAs, while the PEA became negative earlier. Two patients had otherwise unexplained mild persistent thrombocytopenia (140-150 x 10 3 /µL) 6 months after acute presentation. From an epidemiological perspective, differentiating VITT from spontaneous HIT, another entity that develops in the absence of proximate heparin exposure, and HIT is important, but currently available PF4-polyanion ELISAs and functional assay are non-specific and detect all three conditions. Here, we report that a novel un-complexed PF4 ELISA specifically differentiates VITT, secondary to both Ad26.COV2.S and ChAdOx1 nCoV-19, from both spontaneous HIT, HIT and commonly-encountered HIT-suspected patients who are PF4/polyanion ELISA-positive but negative in functional assays. In summary, Ad26.COV2.S-associated VITT antibodies are persistent, and the un-complexed PF4 ELISA appears to be both sensitive and specific for VITT diagnosis., (© 2022 Wiley Periodicals LLC.)

Expansion in blood volume (BV) is a well-recognized response to arterial underfilling secondary to impaired cardiac output in heart failure (HF). However, the effectiveness of this response in terms of outcomes remains inadequately understood. Prospective analysis was undertaken in 110 patients with HF hospitalized and treated for fluid overload. BVs were measured in a compensated state at the hospital discharge using the indicator-dilution methodology. Data were analyzed for composite 1-year HF-related mortality/first rehospitalization. Despite uniform standard of care, marked heterogeneity in BVs was identified across the cohort. The cohort was stratified by BV expansion greater than or equal to +25% above normal (51% of cohort), mild-moderate expansion (22%), and normal BV (27%). Kaplan-Meier (K-M) survival estimates and regression analyses revealed BV expansion (greater than or equal to +25%) to be associated with better event-free survival relative to normal BV ( P = 0.038). Increased red blood cell mass (RBCm; RBC polycythemia) was identified in 43% of the overall cohort and 70% in BV expansion greater than or equal to +25%. K-M analysis demonstrated polycythemia to be associated with better outcomes compared with normal RBCm ( P < 0.002). Persistent BV expansion to include RBC polycythemia is common and, importantly, associated with better clinical outcomes compared with normal total BV or normal RBCm in patients with chronic HF. However, compensatory BV expansion is not a uniform physiological response to the insult of HF with marked variability in BV profiles despite uniform standard of care diuretic therapy. Therefore, recognizing the variability in volume regulation pathophysiology has implications not only for impact on clinical outcomes and risk stratification but also potential for informing individualized volume management strategies. NEW & NOTEWORTHY The novel findings of this study demonstrate that intravascular volume profiles among the patients with chronic heart failure (HF) vary substantially even with similar clinical compensation. Importantly, a profile of blood volume (BV) expansion (compared with a normal BV) is associated with lower HF mortality/morbidity. Furthermore, RBC polycythemia is common and independently associated with improved outcomes. These observations support BV expansion with RBC polycythemia as a compensatory mechanism in chronic HF.

Multiple factors linked to host genetics/inherent biology play a role in interindividual variability in immune response outcomes after rubella vaccination. In order to identify these factors, we conducted a study of rubella-specific humoral immunity before (Baseline) and after (Day 28) a third dose of MMR-II vaccine in a cohort of 109 women of childbearing age. We performed mRNA-Seq profiling of PBMCs after rubella virus in vitro stimulation to delineate genes associated with post-vaccination rubella humoral immunity and to define genes mediating the association between prior immune response status (high or low antibody) and subsequent immune response outcome. Our study identified novel genes that mediated the association between prior immune response and neutralizing antibody titer after a third MMR vaccine dose. These genes included the following: CDC34; CSNK1D; APOBEC3F; RAD18; AAAS; SLC37A1; FAS; and JAK2. The encoded proteins are involved in innate antiviral response, IFN/cytokine signaling, B cell repertoire generation, the clonal selection of B lymphocytes in germinal centers, and somatic hypermutation/antibody affinity maturation to promote optimal antigen-specific B cell immune function. These data advance our understanding of how subjects' prior immune status and/or genetic propensity to respond to rubella/MMR vaccination ultimately affects innate immunity and humoral immune outcomes after vaccination., (© 2021 Wiley-VCH GmbH.)

Aims: Elevated cardiac filling pressures producing clinical congestion in heart failure (HF) patients may be secondary to intravascular volume expansion or abnormalities in cardiac diastolic properties. The objective of this study was to assess the extent to which measures of myocardial function and intravascular volume correlate with haemodynamic abnormalities in chronic HF., Methods and Results: Subjects underwent invasive haemodynamic assessment, measurement of total blood volume (TBV) using radiolabel indicator-dilution methodology, and echocardiography to evaluate cardiac structure and function. Patients were divided into those with hypervolaemia (defined as TBV > +8% above referenced normal volume) and normal volume ('euvolaemia') (TBV ≤ + 8%). Of 66 patients, 39 (59%) were hypervolaemic and 27 (41%) normal TBV. Central venous pressure (CVP, P = 0.01) and pulmonary capillary wedge pressure (PCWP, P < 0.001) were higher in hypervolaemic compared with euvolaemic patients; however, 15% of hypervolaemic patients displayed normal pressures. Of euvolaemic patients, 70% displayed elevated CVP and 63% elevated PCWP. PCWP was moderately correlated with TBV (r = 0.42), left ventricular diastolic function (e' velocity, r = -0.44), and left atrial strain (r = -0.47). In multivariable regression TBV, left ventricular e', and left atrial strain were independently associated with PCWP (all P < 0.05)., Conclusions: While hypervolaemic patients displayed elevations in filling pressures, a substantial proportion (15%) had normal pressures, and of all subjects with elevated filling pressures nearly one third had normal TBVs. Importantly, of patients with normal volumes, a majority (>60%) display elevated filling pressures. Combined analysis of volume, pressure, and cardiac function may be helpful to guide comprehensive assessments of HF status., (© 2021 European Society of Cardiology.)

Background: Findings from heart failure (HF) studies linking diuresis-related weight loss to clinical decongestion and outcomes are mixed. Differential responses of interstitial and intravascular volume compartments to diuretic therapy and heterogeneity in volume profiles may confound the clinical interpretation of weight loss in patients with HF., Methods and Results: Data were prospectively collected in hospitalized patients requiring diuresis. Plasma volume (PV) was measured using I-131-labelled albumin indicator-dilution methodology. The cohort was stratified by tertiles of weight loss and analyzed for interstitial fluid loss relative to changes in PV and HF-related morality or first rehospitalization. Among 92 patients, the admission PV was expanded +42% (4.7 ± 1.2 L) above normal with significant variability (14% normal PV, 18% mild-moderate expansion, and 68% with large PV expansion [>+25% above normal]). With diuresis there were proportional decreases in interstitial volume (-6.5 ± 4.4%) and PV (-7.5 ± 11%); however, absolute decreases in the PV (-254 mL, interquartile range -11 to -583 mL) were less than 10% of interstitial volume loss (-5040 mL, interquartile range -2800 to -7989 mL); greater interstitial fluid loss did not translate into better outcomes (log-rank P = .430)., Conclusions: Diuresis-related decreases in weight reflect fluid loss from the interstitial compartment with only minor changes in the PV and without an impact on outcomes. Further, the degree of PV expansion at hospital admission does not drive the magnitude of the diuresis response, even with a wide spectrum of body weights; interstitial fluid overload is preferentially targeted and PV relatively preserved. Therefore, greater interstitial fluid loss reflects clinical decongestion, but not better outcomes, and a limited association with intravascular volume profiles potentially confounding weight loss as a prognostic metric in HF., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Heparin-induced thrombocytopenia (HIT) is a life-threatening, prothrombotic, antibody-mediated disorder. To maximize the likelihood of recovery, early and accurate diagnosis is critical. Widely available HIT assays, such as the platelet factor 4 (PF4) heparin enzyme-linked immunosorbent assay (ELISA) lack specificity, and the gold-standard carbon 14-labeled serotonin release assay (SRA) is of limited value for early patient management because it is available only through reference laboratories. Recent studies have demonstrated that pathogenic HIT antibodies selectively activate PF4-treated platelets and that a technically simpler assay, the PF4-dependent P-selectin expression assay (PEA), may provide an option for rapid and conclusive results. Based upon predefined criteria that combined 4Ts scores and HIT ELISA results, 409 consecutive adults suspected of having HIT were classified as disease positive, negative, or indeterminate. Patients deemed HIT indeterminate were considered disease negative in the primary analysis and disease positive in a sensitivity analysis. The ability of PEA and SRA to identify patients judged to have HIT was compared using receiver operating characteristic curve statistics. Using these predefined criteria, the diagnostic accuracy of PEA was high (area under the curve [AUC], 0.94; 95% confidence interval [CI], 0.87-1.0) and similar to that of SRA (AUC, 0.91; 95% CI, 0.82-1.0). In sensitivity analysis, the AUCs of PEA and SRA were also similar at 0.88 (95% CI, 0.78-0.98) and 0.86 (95% CI, 0.77-0.96), respectively. The PEA, a technically simple nonradioactive assay that uses ∼20-fold fewer platelets compared with the SRA, had high accuracy for diagnosing HIT. Widespread use of the PEA may facilitate timely and more effective management of patients with suspected HIT., (© 2021 by The American Society of Hematology.)

Background: Identifying the biologic functions of groups of genes identified in high-throughput studies currently requires considerable time and/or bioinformatics experience. This is due in part to each resource housed within separate databases, requiring users to know about them, and integrate across them. Time consuming and often repeated for each study, integrating across resources and merging with data under study is an increasingly common bioinformatics task., Methods: We developed an open-source R software package for assisting researchers in annotating their genesets with functions, pathways, and their interconnectivity across a diversity of network resources., Results: We present rapid integration of term annotation and network resources (RITAN) for the rapid and comprehensive annotation of a list of genes using functional term and pathway resources and their relationships among each other using multiple network biology resources. Currently, and to comply with data redistribution policies, RITAN allows rapid access to 16 term annotations spanning gene ontology, biologic pathways, and immunologic modules, and nine network biology resources, with support for user-supplied resources; we provide recommendations for additional resources and scripts to facilitate their addition to RITAN. Having the resources together in the same system allows users to derive novel combinations. RITAN has a growing set of tools to explore the relationships within resources themselves. These tools allow users to merge resources together such that the merged annotations have a minimal overlap with one another. Because we index both function annotation and network interactions, the combination allows users to expand small groups of genes using links from biologic networks-either by adding all neighboring genes or by identifying genes that efficiently connect among input genes-followed by term enrichment to identify functions. That is, users can start from a core set of genes, identify interacting genes from biologic networks, and then identify the functions to which the expanded list of genes contribute., Conclusion: We believe RITAN fills the important niche of bridging the results of high-throughput experiments with the ever-growing corpus of functional annotations and network biology resources., Availability: Rapid integration of term annotation and network resources is available as an R package at github.com/MTZimmer/RITAN and BioConductor.org., Competing Interests: The authors declare that they have no competing interests.

Background: Although the administration of the measles-mumps-rubella (MMR) vaccine has been widespread in the United States for decades, gaps in vaccine coverage still persist for various reasons. The maintenance of herd immunity against rubella virus (RV) is important to controlling the spread and resurgence of rubella and congenital rubella syndrome., Methods: In this study, we sought to assess the seroprevalence of RV-specific antibodies in an adult population from a defined geographic area in Olmsted County, MN, and the surrounding municipalities, with relatively high vaccine coverage and no documented evidence of circulating RV in the past 24 years. Rubella-specific IgG antibodies were measured by ELISA in a large set of serum samples (n = 1393) obtained from the Mayo Clinic Biobank. This cohort was 80.2% female and ranged from 20 to 44 years of age., Results: In total, 97.8% of subjects were seropositive for rubella-specific IgG antibodies, with a median titer of 40.56 IU/mL, suggesting a high degree of immunization; however, 2.2% of subjects were found to be seronegative. Interestingly, 25.1% of subjects were seropositive but had titers lower than 25 IU/mL, indicating either a population of low responders or individuals that could potentially be at risk of waning immunity. No significant associations or differences were found between RV-specific titers and demographic variables such as age, sex, or body mass index (BMI)., Conclusions: A high rate of seropositivity for rubella was found among this young adult cohort, but a significant percent of the cohort had lower titers that may indicate poor initial vaccine response and potential risk if their antibody titers decline., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Sex differences in immune responses to influenza vaccine may impact efficacy across populations. Methods: In a cohort of 138 older adults (50-74 years old), we measured influenza A/H1N1 antibody titers, B-cell ELISPOT response, PBMC transcriptomics, and PBMC cell compositions at 0, 3, and 28 days post-immunization with the 2010/11 seasonal inactivated influenza vaccine. Results: We identified higher B-cell ELISPOT responses in females than males. Potential mechanisms for sex effects were identified in four gene clusters related to T, NK, and B cells. Mediation analysis indicated that sex-dependent expression in T and NK cell genes can be partially attributed to higher CD4+ T cell and lower NK cell fractions in females. We identified strong sex effects in 135 B cell genes whose expression correlates with ELISPOT measures, and found that cell subset differences did not explain the effect of sex on these genes' expression. Post-vaccination expression of these genes, however, mediated 41% of the sex effect on ELISPOT responses. Conclusions: These results improve our understanding of sexual dimorphism in immunity and influenza vaccine response.

Population-based studies have revealed 2-10% measles vaccine failure rate even after two vaccine doses. While the mechanisms behind this remain unknown, we hypothesized that host genetic factors are likely to be involved. We performed a genome-wide association study of measles specific neutralizing antibody and IFNγ ELISPOT response in a combined sample of 2872 subjects. We identified two distinct chromosome 1 regions (previously associated with MMR-related febrile seizures), associated with vaccine-induced measles neutralizing antibody titers. The 1q32 region contained 20 significant SNPs in/around the measles virus receptor-encoding CD46 gene, including the intronic rs2724384 (p value = 2.64 × 10 -09 ) and rs2724374 (p value = 3.16 × 10 -09 ) SNPs. The 1q31.1 region contained nine significant SNPs in/around IFI44L, including the intronic rs1333973 (p value = 1.41 × 10 -10 ) and the missense rs273259 (His73Arg, p value = 2.87 × 10 -10 ) SNPs. Analysis of differential exon usage with mRNA-Seq data and RT-PCR suggests the involvement of rs2724374 minor G allele in the CD46 STP region exon B skipping, resulting in shorter CD46 isoforms. Our study reveals common CD46 and IFI44L SNPs associated with measles-specific humoral immunity, and highlights the importance of alternative splicing/virus cellular receptor isoform usage as a mechanism explaining inter-individual variation in immune response after live measles vaccine.

To assess gene signatures related to humoral response among healthy older subjects following seasonal influenza vaccination, we studied 94 healthy adults (50-74 years old) who received one documented dose of licensed trivalent influenza vaccine containing the A/California/7/2009 (H1N1)-like virus strain. Influenza-specific antibody (HAI) titer in serum samples and next-generation sequencing on PBMCs were performed using blood samples collected prior to (Day 0) and at two timepoints after (Days 3 and 28) vaccination. We identified a number of uncharacterized genes (ZNF300, NUP1333, KLK1 and others) and confirmed previous studies demonstrating specific genes/genesets that are important mediators of host immune responses and that displayed associations with antibody response to influenza A/H1N1 vaccine. These included interferon-regulatory transcription factors (IRF1/IRF2/IRF6/IRF7/IRF9), chemokine/chemokine receptors (CCR5/CCR9/CCL5), cytokine/cytokine receptors (IFNG/IL10RA/TNFRSF1A), protein kinases (MAP2K4/MAPK3), growth factor receptor (TGFBR1). The identification of gene signatures associated with antibody response represents an early stage in the science for which further research is needed. Such research may assist in the design of better vaccines to facilitate improved defenses against new influenza virus strains, as well as better understanding the genetic drivers of immune responses.

Atrial fibrillation and obesity are two major growing epidemics in the United States and globally. Obese people are at the increased risk of developing atrial fibrillation. The contribution of obesity as an independent risk factor for stroke in the setting of atrial fibrillation remains unclear. We tested the hypothesis that non-valvular atrial fibrillation (NVAF) patients with increased body mass index (BMI) would be at increased risk for the development of left atrial appendage thrombus (LAAT). Consecutive, anticoagulation naïve patients with NVAF referred for a transesophageal echocardiogram (TEE) between January 1, 2007 and October 21, 2009 were approached for study participation. All clinical, laboratory, and TEE measurement data were collected prospectively. Within a group of 400 anticoagulation naïve NVAF patients (mean age 63 ± 15 years, 28 % women; 17 % with LAAT) the prevalence of LAAT was similar across all BMI categories (normal 13 %, overweight 19 %, obese 16 %, morbidly obese 16 %; p = 0.71). Despite a higher CHADS2 score and a higher prevalence of both hypertension and diabetes mellitus, elevated BMI was not an independent predictor of LAAT when analyzed as either a continuous variable, across BMI WHO categories, a dichotomous variable stratified at values above versus below 27 kg/m(2), or BMI stratified on atrial fibrillation duration. Despite a higher prevalence of major risk factors for thromboembolism, the prevalence of LAAT was not increased in overweight, obese, and morbidly obese patients.

Background: B-Type natriuretic peptides (BNP) and cardiac troponin T (cTnT) predict cardiovascular events in heart failure (HF) patients, but additional refinement in risk stratification may be possible by targeting pathways leading to fibrosis. We aimed to assess the value of serial measurements of soluble suppression of tumorigenicity 2 (sST2) and galectin-3 to identify risk for adverse pathophysiologic processes., Methods: New York Heart Association (NYHA) functional class III-IV HF patients (n = 180; LVEF ≤40%) were prospectively evaluated with biomarkers collected every 3 months over 2 years and analyzed regarding a primary end point of death/cardiac transplantation and a secondary end point of HF-related hospitalization or death/transplantation., Results: Time-dependent univariate analyses demonstrated that elevations of sST2 (≥49.3 ng/mL male, ≥33.5 ng/mL female) and galectin-3 (≥22.1 ng/mL) were predictive of the primary and secondary end points. In multivariate models adjusted for BNP, cTnT, and clinical variables, sST2 but not galectin-3 remained an independent predictor (hazard ratio 3.22, 95% confidence interval 1.76-5.89; P < .001). With serial measurements, only sST2 demonstrated incremental value in reclassifying patients to higher risk., Conclusions: Serial monitoring of sST2 (indicating myocardial fibrosis and remodeling) and cTnT (reflecting myocardial injury) identifies highest-risk HF outpatients and may be valuable to guide patient tailored therapy during follow-up evaluations. Serial galectin-3 monitoring in ambulatory HF patients may not be of benefit., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective: To assess the impact of nonvalvular atrial fibrillation (NVAF) and sinus rhythm restoration on the distribution of reticulated platelets (RPs), which are known to be associated with thrombotic propensity and have a greater predilection for thrombus participation., Participants and Methods: The RP content was assessed by flow cytometry (thiazole orange/CD61) in 110 consecutive patients with NVAF before and 3 to 4 months after catheter ablation of the pulmonary veins. Results were compared with those of 55 age- and sex-matched controls with normal sinus rhythm., Results: The mean ± SD percentage of RPs was higher in patients with NVAF compared with controls (28.5%±7.3% vs 6.4%±5.3%; P<.001). The RP content did not vary by CHA2DS2-VASc score. After catheter ablation of the pulmonary veins, 63 patients were available for follow-up assessment. A significant reduction of RPs was observed compared with preintervention values (29.85%±7.1% vs 20.79%±7.6%; P<.001). During follow-up, 19% of patients (12 of 63) had confirmed AF recurrence. The mean ± SD percentage of RPs was higher in this group than in those without a recurrence (24.7%±6.5% vs 18.9%±7.5%; P=.01)., Conclusion: Nonvalvular atrial fibrillation affects the percentage of RPs, independent of the CHA2DS2-VASc score. After ablation, RP content dropped significantly. High RP content in patients with NVAF may explain the potential mechanism of thromboembolic complications and the lack of efficacy of currently available antiplatelet therapy for stroke prevention in this dysrhythmia., (Copyright © 2015 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

Objective: To determine whether blood type affects the risk of thromboembolic complications in patients with atrial fibrillation (AF)., Patients and Methods: The Mayo Clinic electronic medical record was searched (between January 1, 2004, and December 31, 2010) to identify all patients with AF with blood group assessment. Records were analyzed for stroke, transient ischemic attack, left atrium appendage thrombus, cerebral or peripheral embolism, and hemorrhagic stroke. All events were adjusted for Congestive heart failure, Hypertension, Age >75 Years, Diabetes mellitus, and Stroke/transient ischemic attack score., Results: Of the 47,816 patients with AF, 14,462 had blood group type available (40% women; mean age, 73±12 years). These included 12,363 patients with nonvalvular atrial fibrillation (NVAF) (40% women; mean age, 73±12 years) and 2099 patients with valvular AF (41% women, mean age, 73±12 years). Within patients with NVAF, the rate of peripheral embolization was significantly lower in those with blood type O (2.0%) than in those with other blood types (3.0%; odds ratio, 0.66; 95% CI, 0.52-0.84; P<.001). Neither cerebral thromboembolic (8.1% for "O" vs 8.2% for "non-O" blood group for NVAF and 7.29% vs 7.76% for valvular AF) nor cerebral hemorrhage (2.0% each group) events rates differed by blood group., Conclusion: Blood group O may be protective against peripheral cardioembolic complications of NVAF, which may relate, in part, to reduced circulating von Willebrand factor levels. Cerebral thromboembolic event rates did not differ by blood group., (Copyright © 2015 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

Background: The utility of thrombophilia testing in patients with splanchnic vein thrombosis (SpVT) has not previously been rigorously evaluated. The purpose of this study was to characterize differences in the prevalence of thrombophilia in patients with SpVT involving portal (PVT), mesenteric (MVT), splenic (SVT), or hepatic (HVT) veins in isolation or with multisegmental (M-SpVT) involvement compared to patients with lower extremity deep vein thrombosis (DVT)., Methods: An inception cohort of patients with incident SpVT was identified for whom comprehensive thrombophilia testing was performed between 1995 and 2005 and compared to DVT controls., Results: 341 patients with SpVT (mean age 50 ± 16 years, 53 % women) including isolated PVT (n = 112), MVT (n = 67), HVT (n = 22), SVT (n = 11), and M-SpVT (n = 129) involvement and 3621 DVT controls (mean age 55 ± 16 years, 56 % women) had comprehensive thrombophilia testing. The prevalence of abnormal results was similar for SpVT (24.6 %) and DVT (25.9 %) patients. "Strong" thrombophilias were more prevalent among SpVT patients (12.3 vs. 8.5 %, p = 0.0168). Patients with splenic (45.5 %) and mesenteric (41.8 %) thrombosis had the highest thrombophilia prevalence. Protein S deficiency was more common in SpVT patients (3.5 vs. 0.9 %, p < 0.001). In contrast, FV Leiden was more prevalent among DVT patients (15.8 vs. 10.9 %, p = 0.0497)., Conclusion: The prevalence of selected thrombophilia factors differ comparing SpVT and DVT patients. The prevalence is particularly high for patients with splenic and mesenteric vein thrombosis. Whereby the finding of strong thrombophilia impacts duration of anticoagulant therapy, such testing is warranted in the evaluation of patients with unprovoked SpVT.

Baseline values, serial measurements, or both of multiple biomarkers (copeptin, a peptide co-secreted with arginine vasopressin; hyponatremia; B-type natriuretic peptide [BNP]; and cardiac troponin T [cTnT]) may improve risk stratification in outpatients with chronic heart failure. A cohort of 157 patients with class III or IV heart failure was prospectively evaluated every 3 months over 2 years with regard to biomarker levels and risk for death or cardiac transplantation. Copeptin ≥40 pmol/L (cohort fourth quartile value), hyponatremia (≤135 mEq/L), BNP >3 times the upper range limitation of normal adjusted for age and gender, and cTnT ≥0.01 ng/ml were pre hoc determined cut points. After multivariate time-dependent regression analysis, copeptin (hazard ratio [HR] 2.26, 95% confidence interval [CI] 1.2 to 4.3, p = 0.014) and BNP (HR 1.89, 95% CI 1.0 to 3.5, p = 0.047), but not hyponatremia, were associated with the primary end point of death or cardiac transplantation. In contrast to univariate prediction of mortality and transplantation, hyponatremia (HR 1.74, 95% CI 0.9 to 3.4, p = 0.099) and cTnT ≥0.01 ng/ml (HR 1.89, 95% CI 1.0 to 3.7, p = 0.064) were not predictive in multivariate models. Interaction models of copeptin with hyponatremia, adjusted for BNP and cTnT, improved the predictive capacity of serial measurements (HR 4.20, 95% CI 1.6 to 8.9, p = 0.004). In conclusion, marked elevations of copeptin, particularly in serial measurements, are independent predictors of poor outcomes. The combination of elevated copeptin with hyponatremia, when adjusted for BNP and cTnT, is an even stronger predictor. These markers appear to reflect activation of the arginine vasopressin system present even in the absence of overt clinical changes. A strategy of serial monitoring of copeptin in combination with hyponatremia may be valuable in identifying higher risk patients with heart failure., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: Heart failure (HF) progression and outcomes reflect activation of multiple neurohormonal systems. Which biomarkers reflecting these systems contribute incremental information remains unclear. The aim of this study was to determine if serial measurements of pro-BNP(1-108) separately, in combination with standard assay BNP, or with troponin T (cTnT) would enhance risk stratification in ambulatory HF patients., Methods: A cohort of 187 Class III-IV HF patients was prospectively studied. Blood was collected every 3 months over 2 years for biomarker analysis [pro-BNP(1-108), standard assay BNP, troponin T (cTnT)] in relation to the primary endpoint of death or cardiac transplantation., Results: Univariate categorical and continuous variable analyses of single-sample and time-dependent serial values of pro-BNP(1-108) and BNP demonstrated that elevations in both biomarkers were associated with increased risk of death/transplantation. Multivariate analysis of serial measurements adjusted for cTnT revealed cTnT as the independent marker of risk. Combined elevations of either pro-BNP(1-108) or BNP with cTnT, however, were the most significant predictors of outcome., Conclusions: Circulating levels of pro-BNP(1-108) appear to be comparable to mature BNP in ambulatory HF out-patients. Elevated levels of pro-BNP(1-108) or BNP identified by serial monitoring similarly predict events. A strategy of serial monitoring of either pro-BNP(1-108) or BNP alone or particularly in combination with cTnT can serve a valuable role in detecting higher-risk HF patients., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Aims: To characterize mitral medial and lateral annular velocities in constrictive pericarditis or restrictive cardiomyopathy compared with normal subjects., Methods and Results: Tissue Doppler imaging peak systolic velocity (S'), peak early diastolic annular velocity (e'), and timing difference between mitral early flow and early annular movement were measured in 14 patients with constrictive pericarditis, 10 with restrictive cardiomyopathy, and 17 normal subjects using the apical four-chamber view lateral and medial mitral annulus. In controls, mitral lateral e' velocity was 25% higher than medial e' velocity (13.0 +/- 3.1 vs. 10.7 +/- 2.8 cm/s; P = 0.02), whereas with constrictive pericarditis, averaged lateral e' velocity was 2% lower than medial e' velocity (10.7 +/- 2.5 vs. 11.2 +/- 3.1 cm/s; P > 0.05). This relationship represented a reversal of lateral and medial e' velocities compared with normal subjects (P = 0.004). Differences in S', E/e', and timing intervals between normal subjects and patients with constrictive pericarditis were not statistically significant; however, restrictive cardiomyopathy could be distinguished from constrictive pericarditis and controls with all other parameters (S', E/e', medial and lateral e' velocities, and timing interval differences; all P < 0.05)., Conclusion: Practical applications of tissue Doppler imaging for evaluation of possible constrictive pericarditis include reversal of the relationship between lateral and medial e' velocities (i.e. 'annulus reversus').

Objective: To determine whether some adverse outcomes of hemodialysis could be explained by subclinical heparin-induced thrombocytopenia (HIT)., Patients and Methods: Platelet factor 4 (PF4)-heparin antibodies were measured by enzyme-linked immunosorbent assay In a population-based cohort of hemodlalysis patients. Participants were then followed up prospectively for thromboembollc events, cardiovascular events, or death., Results: Of the 59 hemodialysis patients residing In Olmsted County, Minnesota, 57 (97%) agreed to study participation. The mean +/- SD age of the patients was 64 +/- 17 years (median hemodialysis duration, 23 months), and 27 (47%) were women. The enzyme-linked Immunosorbent assay was positive for PF4-heparin antibodies in 2 patients (3.5%). The PF4-heparin antibody content varied over a 10-fold range and was not associated with the duration of hemodialysis (P = .99). During a median follow-up of 798 days, 16 thrombotic events, 37 cardiovascular events, and 23 deaths (Including 13 cardiovascular deaths) occurred. After adjusting for the Framingham risk score, the all-cause mortality rate was significantly higher for patients with the highest tertile of PF4-heparln antibody content compared with patients in the lower tertilles (hazard ratio, 2.47; P = .03). Furthermore, 8 (73%) of deaths in this tertile were due to cardiovascular causes (hazard ratio, 4.14; P = .02)., Conclusions: Despite repetitive heparin exposure, the prevalence of HIT In patients undergoing maintenance hemodialysis is no greater than that anticipated for other patient populations. However, to our knowledge, this is the first study to show an association between elevated PF4-heparin antibodies and Increased mortality rates in hemodlalysis patients.

Motivation: Our goal was to develop a normalization technique that yields results similar to cyclic loess normalization and with speed comparable to quantile normalization., Results: Fastlo yields normalized values similar to cyclic loess and quantile normalization and is fast; it is at least an order of magnitude faster than cyclic loess and approaches the speed of quantile normalization. Furthermore, fastlo is more versatile than both cyclic loess and quantile normalization because it is model-based., Availability: The Splus/R function for fastlo normalization is available from the authors.

Objective: To determine the feasibility, safety, and clinical yield of angiographic screening among hypertensive patients undergoing coronary angiography., Patients and Methods: This study was a prospective cohort analysis of hypertensive patients who underwent cardiac catheterization at a tertiary care referral center from July 1998 to March 1999. Abdominal aortography was performed to screen for renal artery stenosis, the percentage of which was measured., Results: The mean +/- SD age of the 297 study patients was 64.9+/-10.2 years; 58.6% were male, and 98.0% were white. Mean +/- SD systolic/diastolic blood pressure was 142.8+/-22.5/79.6+/-11.4 mm Hg. Aortography required a mean incremental dose of 62+/-9 mL of nonionic contrast agent. No complications were attributable to aortography. Of 680 renal arteries, 611 (90%) were visualized adequately. Also, 53% of patients had normal renal arteries, 28% had stenoses less than 50%, and 19.2% had stenoses of 50% or more. Renal artery stenosis was bilateral in 3.7% of patients and high grade (>70% stenosis) in 7%. Patients with renal artery stenosis were more likely to have had a previous coronary intervention. In multivariate analysis, systolic blood pressure (odds ratio [OR], 1.2; 95% confidence interval [CI], 1.03-138; P=.02), history of stroke or transient ischemic attack (OR, 2.7; 95% CI, 1.27-5.78; P=.01), and cancer (OR, 2.0; 95% CI, 1.02-3.82; P=.04) independently correlated with renal artery stenosis of 50% or more., Conclusion: The prevalence of incidental renal artery stenosis among hypertensive patients undergoing coronary catheterization is significant. Therefore, screening abdominal aortography should be considered in these patients to better define their risk of cardiovascular complications.