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Introduction: Coronary artery calcium (CAC) scans contain useful information beyond the Agatston CAC score that is not currently reported. We recently reported that artificial intelligence (AI)-enabled cardiac chambers volumetry in CAC scans (AI-CAC™) predicted incident atrial fibrillation in the Multi-Ethnic Study of Atherosclerosis (MESA). In this study, we investigated the performance of AI-CAC cardiac chambers for prediction of incident heart failure (HF)., Methods: We applied AI-CAC to 5750 CAC scans of asymptomatic individuals (52% female, White 40%, Black 26%, Hispanic 22% Chinese 12%) free of known cardiovascular disease at the MESA baseline examination (2000-2002). We used the 15-year outcomes data and compared the time-dependent area under the curve (AUC) of AI-CAC volumetry versus NT-proBNP, Agatston score, and 9 known clinical risk factors (age, gender, diabetes, current smoking, hypertension medication, systolic and diastolic blood pressure, LDL, HDL for predicting incident HF over 15 years., Results: Over 15 years of follow-up, 256 HF events accrued. The time-dependent AUC [95% CI] at 15 years for predicting HF with AI-CAC all chambers volumetry (0.86 [0.82,0.91]) was significantly higher than NT-proBNP (0.74 [0.69, 0.77]) and Agatston score (0.71 [0.68, 0.78]) (p ​< ​0.0001), and comparable to clinical risk factors (0.85, p ​= ​0.4141). Category-free Net Reclassification Index (NRI) [95% CI] adding AI-CAC LV significantly improved on clinical risk factors (0.32 [0.16,0.41]), NT-proBNP (0.46 [0.33,0.58]), and Agatston score (0.71 [0.57,0.81]) for HF prediction at 15 years (p ​< ​0.0001)., Conclusion: AI-CAC volumetry significantly outperformed NT-proBNP and the Agatston CAC score, and significantly improved the AUC and category-free NRI of clinical risk factors for incident HF prediction., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Coronary artery calcium (CAC) scans contain actionable information beyond CAC scores that is not currently reported., Methods: We have applied artificial intelligence-enabled automated cardiac chambers volumetry to CAC scans (AI-CAC TM ) to 5535 asymptomatic individuals (52.2% women, ages 45-84) that were previously obtained for CAC scoring in the baseline examination (2000-2002) of the Multi-Ethnic Study of Atherosclerosis (MESA). AI-CAC took on average 21 ​s per CAC scan. We used the 5-year outcomes data for incident atrial fibrillation (AF) and assessed discrimination using the time-dependent area under the curve (AUC) of AI-CAC LA volume with known predictors of AF, the CHARGE-AF Risk Score and NT-proBNP. The mean follow-up time to an AF event was 2.9 ​± ​1.4 years., Results: At 1,2,3,4, and 5 years follow-up 36, 77, 123, 182, and 236 cases of AF were identified, respectively. The AUC for AI-CAC LA volume was significantly higher than CHARGE-AF for Years 1, 2, and 3 (0.83 vs. 0.74, 0.84 vs. 0.80, and 0.81 vs. 0.78, respectively, all p ​< ​0.05), but similar for Years 4 and 5, and significantly higher than NT-proBNP at Years 1-5 (all p ​< ​0.01), but not for combined CHARGE-AF and NT-proBNP at any year. AI-CAC LA significantly improved the continuous Net Reclassification Index for prediction of AF over years 1-5 when added to CHARGE-AF Risk Score (0.60, 0.28, 0.32, 0.19, 0.24), and NT-proBNP (0.68, 0.44, 0.42, 0.30, 0.37) (all p ​< ​0.01)., Conclusion: AI-CAC LA volume enabled prediction of AF as early as one year and significantly improved on risk classification of CHARGE-AF Risk Score and NT-proBNP., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Cardiovascular disease is the leading cause of death in patients receiving hemodialysis. Currently, there is no standardized definition of myocardial infarction (MI) for patients receiving hemodialysis. Through an international consensus process MI was established as the core CVD measure for this population in clinical trials. The Standardised Outcomes in Nephrology Group-Hemodialysis (SONG-HD) initiative convened a multidisciplinary, international working group to address the definition of MI in this population. On the basis of current evidence, the working group recommends using the Fourth Universal Definition of Myocardial Infarction with specific caveats with regard to the interpretation of "ischemic symptoms" and performing a baseline 12-lead electrocardiogram to facilitate interpretation of acute changes on subsequent tracings. The working group does not recommend obtaining baseline cardiac troponin values, though does recommend obtaining serial cardiac biomarkers in settings where ischemia is suspected. The application of an evidence-based uniform definition should increase the reliability and accuracy of trial results., (Copyright © 2023 International Society of Nephrology. All rights reserved.)

Background: Vericiguat reduced the risk of cardiovascular death (CVD) or hospitalization for heart failure (HF) in patients with worsening HF and reduced left ventricular ejection fraction (LVEF)., Objectives: The authors assessed the association of LVEF with biomarker levels, risk of outcome, and whether the effect of vericiguat was homogeneous across LVEF in the VICTORIA (Vericiguat Global Study in Subjects with Heart Failure With Reduced Ejection Fraction) trial., Methods: Patients were grouped by LVEF tertiles (≤24%, 25%-33%, and >33%). Patient characteristics, clinical outcomes, and efficacy and safety of vericiguat were examined by tertile. Prespecified biomarkers including N-terminal pro-B-type natriuretic peptide, cardiac troponin T, growth differentiation factor 15, interleukin 6, high-sensitivity C-reactive protein, and cystatin C were examined., Results: The mean LVEF was 29% ± 8% (range: 5%-45%). A pattern of higher N-terminal pro-B-type natriuretic peptide, high-sensitivity C-reactive protein, and interleukin 6 was evident in patients in the lowest LVEF tertile vs the other tertiles. Patients with lower LVEF experienced higher rates of the composite outcome (41.7%, 36.3%, and 33.4% for LVEF ≤24, 25-33, and >33; P < 0.001). There was no significant treatment effect heterogeneity of vericiguat across LVEF groups (adjusted HR from lowest to highest tertiles: 0.79 [95% CI: 0.68-0.94]; 0.95 [95% CI: 0.82-1.11]; 0.94 [95% CI: 0.79-1.11]; P for interaction = 0.222), although the HR was numerically lower in the lowest tertile. There was also no heterogeneity of effect for CVD and HF hospitalization individually (P interaction for CVD = 0.964; HF hospitalization = 0.438). Discontinuation of treatment because of adverse events, symptomatic hypotension, or syncope was consistent across the range of LVEF., Conclusions: Patients with lower LVEF had a distinctive biomarker profile and a higher risk for adverse clinical outcomes vs those with a higher LVEF. There was no significant interaction for the benefit of vericiguat across LVEF tertiles, although the largest signal for benefit in both the primary outcome and HF hospitalizations was noted in tertile 1 (LVEF ≤24%). (Vericiguat Global Study in Subjects with Heart Failure With Reduced Ejection Fraction [VICTORIA]; NCT02861534)., Competing Interests: Funding Support and Author Disclosures The VICTORIA trial was funded by Merck Sharp and Dohme Corp, a subsidiary of Merck and Co Inc, and Bayer AG. Dr Butler has received consulting fees from Abbott, Adrenomed, Amgen, Array, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, CVRx, G3 Pharmaceutical, Impulse Dynamics, Innolife, Janssen, LivaNova, Luitpold, Medtronic, Merck, Novartis, Novo Nordisk, Roche, and Vifor. Dr Lund is a consultant for Bayer/Merck; has received grants unrelated to the present work from AstraZeneca, Vifor, Boston Scientific, Boehringer Ingelheim, and Novartis; has received consulting fees from Merck, Vifor, AstraZeneca, Bayer, Pharmacosmos, MedScape, Sanofi, Lexicon, Myokardia, Boehringer Ingelheim, and Servier; has received speaker honoraria from Abbott, MedScape, Radcliffe, AstraZeneca, Novartis, and patent AnaCardio; and has stock ownership in AnaCardio. Dr deFilippi has received institutional research grants from Abbott Diagnostics, Roche Diagnostics, Siemens Healthineers, and Ortho Diagnostics; and has received consulting fees from FujiRebio, Roche Diagnostics, Siemens Healthineers, and Ortho Diagnostics. Dr Blaustein is an employee of Merck and Co, Inc. Mr Ezekowitz has received research grants and consulting fees from Bayer, Merck, Servier, Amgen Sanofi, Novartis, Cytokinetics, American Regent, and Applied Therapeutics. Dr Freitas is an employee of Bayer AG. Dr Hernandez has received research grants from Merck, AstraZeneca, Novartis, and Verily; and has received honoraria from Merck, Bayer, Amgen, AstraZeneca, and Novartis. Dr O’Connor has received research grants from Merck; and has received consulting fees from Bayer, Dey LP, and Bristol Myers Squibb Foundation. Dr Voors has received research grants from Boehringer Ingelheim and Roche Diagnostics; and has received consulting fees from Merck, Bayer, Amgen, AstraZeneca, Boehringer Ingelheim, Cytokinetics, Myokardia, Novartis, Servier, and Roche Diagnostics. Dr Westerhout has received consulting fees from Bayer. Dr Lam has received research grants from Bayer and Roche Diagnostics; has received consulting fees from Abbott, Actelion, Alleviant Medical, Allysta Pharma, Amgen, AnaCardio AB, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Cytokinetics, Darma Inc, EchoNous Inc, Impulse Dynamics, Ionis Pharmaceutical, Janssen Research and Development LLC, Medscape/WebMD Global LLC, Merck, Novartis, Novo Nordisk, Prosciento Inc, Radcliffe Group Ltd, Roche Diagnostics, Sanofi, Siemens Healthcare Diagnostics, and Us2.ai; and is a cofounder and nonexecutive director of Us2.ai. Dr Armstrong has received research grants from Merck, Bayer, Sanofi-Aventis Recherche and Développement, Boehringer Ingelheim, and CSL Limited; and has received consulting fees from Merck, Bayer, AstraZeneca, and Novartis., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: The benefits of standardized care for cardiogenic shock (CS) across regional care networks are poorly understood., Objectives: The authors compared the management and outcomes of CS patients initially presenting to hub versus spoke hospitals within a regional care network., Methods: The authors stratified consecutive patients enrolled in their CS registry (January 2017 to December 2019) by presentation to a spoke versus the hub hospital. The primary endpoint was 30-day mortality. Secondary endpoints included bleeding, stroke, or major adverse cardiovascular and cerebrovascular events., Results: Of 520 CS patients, 286 (55%) initially presented to 34 spoke hospitals. No difference in mean age (62 years vs 61 years; P = 0.38), sex (25% vs 32% women; P = 0.10), and race (54% vs 52% white; P = 0.82) between spoke and hub patients was noted. Spoke patients more often presented with acute myocardial infarction (50% vs 32%; P &lt; 0.01), received vasopressors (74% vs 66%; P = 0.04), and intra-aortic balloon pumps (88% vs 37%; P &lt; 0.01). Hub patients were more often supported with percutaneous ventricular assist devices (44% vs 11%; P &lt; 0.01) and veno-arterial extracorporeal membrane oxygenation (13% vs 0%; P &lt; 0.01). Initial presentation to a spoke was not associated with increased risk-adjusted 30-day mortality (adjusted OR: 0.87 [95% CI: 0.49-1.55]; P = 0.64), bleeding (adjusted OR: 0.89 [95% CI: 0.49-1.62]; P = 0.70), stroke (adjusted OR: 0.74 [95% CI: 0.31-1.75]; P = 0.49), or major adverse cardiovascular and cerebrovascular events (adjusted OR 0.83 [95% CI: 0.50-1.35]; P = 0.44)., Conclusions: Spoke and hub patients experienced similar short-term outcomes within a regionalized CS network. The optimal strategy to promote standardized care and improved outcomes across regional CS networks merits further investigation., Competing Interests: Funding Support and Author Disclosures Dr Tehrani has served on the advisory board for Abbott; has received research grants from Boston Scientific and Inari Medical; and has served as a consultant for Boston Scientific. Dr Truesdell has served as a consultant for Abiomed. Dr Ibrahim has received honoraria from Medtronic. Dr Shah is supported by a National Institutes of Health K23 Career Development Award 1K23HL143179; has served as a consultant for Merck, Novartis, and Procyrion; and his institution has received grant support from Abbott, Roche, Merck and Bayer for unrelated research. Dr Batchelor has served as consultant for Boston Scientific, Abbott, Medtronic, and V-Wave. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Noninvasive monitoring of heart allograft health is important to improve clinical outcomes. MicroRNAs (miRs) are promising biomarkers of cardiovascular disease and limited studies suggest they can be used to noninvasively diagnose acute heart transplant rejection., Methods: The Genomic Research Alliance for Transplantation (GRAfT) is a multicenter prospective cohort study that phenotyped heart transplant patients from 5 mid-Atlantic centers. Patients who had no history of rejection after transplant were compared to patients with acute cellular rejection (ACR) or antibody-mediated rejection (AMR). Small RNA sequencing was performed on plasma samples collected at the time of an endomyocardial biopsy. Differential miR expression was performed with adjustment for clinical covariates. Regression was used to develop miR panels with high diagnostic accuracy for ACR and AMR. These panels were then validated in independent samples from GRAfT and Stanford University. Receiver operating characteristic curves were generated and area under the curve (AUC) statistics calculated. Distinct ACR and AMR clinical scores were developed to translate miR expression data for clinical use., Results: The GRAfT cohort had a median age of 52 years, with 35% females and 45% Black patients. Between GRAfT and Stanford, we included 157 heart transplant patients: 108 controls and 49 with rejection (50 ACR and 38 AMR episodes). After differential miR expression and regression analysis, we identified 12 miRs that accurately discriminate ACR and 17 miRs in AMR. Independent validation of the miR panels within GRAfT led to an ACR AUC 0.92 (95% confidence interval [CI]: 0.86-0.98) and AMR AUC 0.82 (95% CI: 0.74-0.90). The externally validated ACR AUC was 0.72 (95% CI: 0.59-0.82). We developed distinct ACR and AMR miR clinical scores (range 0-100), a score ≥ 65, identified ACR with 86% sensitivity, 76% specificity, and 98% negative predictive value, for AMR score performance was 82%, 84% and 97%, respectively., Conclusions: We identified novel miRs that had excellent performance to noninvasively diagnose acute rejection after heart transplantation. Once rigorously validated, the unique clinical ACR and AMR scores usher in an era whereby genomic biomarkers can be used to screen and diagnose the subtype of rejection. These novel biomarkers may potentially alleviate the need for an endomyocardial biopsy while facilitating the initiation of targeted therapy based on the noninvasive diagnosis of ACR or AMR., (Copyright © 2022 International Society for Heart and Lung Transplantation. All rights reserved.)

Introduction: We investigated the associations of high-sensitivity cardiac Troponin T (hs-cTnT) and N-terminal pro B-type natriuretic peptide (NT-proBNP) levels with risk of developing clinical peripheral artery disease (PAD) or a low ankle-brachial index (ABI)., Methods: Hs-cTnT and NT-proBNP were measured in 6692 and 5458 participants respectively without baseline PAD between 2000 and 2002 in the Multi-ethnic Study of Atherosclerosis. A significant number also had repeat biomarker measurement between 2004 and 2005. Incident clinical PAD was ascertained through 2017. Incident low ABI, defined as ABI <0.9 and decline of ≥0.15 from baseline, was assessed among 5920 eligible individuals who had an ABI >0.9 at baseline and at least one follow-up ABI measurement 3-10 years later. Multivariable Cox proportional hazards and logistic regression modeling were used to determine the association of these biomarkers with clinical PAD and low ABI, respectively., Results: Overall, 121 clinical PAD and 118 low ABI events occurred. Adjusting for demographic and clinical characteristics, each log unit increment in hs-cTnT and NT-proBNP was associated with a 30% (adjusted hazard ratio (HR) 1.3, 95% confidence interval (CI): 1.1, 1.6) and 50% (HR) 1.5, 95% CI: 1.2, 1.8) higher risk of clinical PAD respectively. No significant associations were observed for incident low ABI. Change in these biomarkers was not associated with either of the PAD outcomes., Conclusions: NT-proBNP and hs-cTnT are independently associated with the development of clinical PAD. Further study should determine whether these biomarkers can help to better identify those at higher risk for PAD., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objectives: This study sought to evaluate the independent associations and interactions between high-sensitivity cardiac troponin I (hs-cTnI) and physical activity (PA) with risk of heart failure (HF) subtypes, HF with preserved ejection fraction (HFpEF) and HF with reduced ejection fraction (HFrEF)., Background: Black adults are at high risk for developing HF. Physical inactivity and subclinical myocardial injury, as assessed by hs-cTnI concentration, are independent risk factors for HF., Methods: Black adults from the Jackson Heart Study without prevalent HF who had hs-cTnI concentration and self-reported PA assessed at baseline were included. Adjusted Cox models were used to evaluate the independent and joint associations and interaction between hs-cTnI concentrations and PA with risk of HFpEF and HFrEF., Results: Among 3,959 participants, 25.1% had subclinical myocardial injury (hs-cTnI ≥4 and ≥6 ng/l in women and men, respectively), and 48.2% were inactive (moderate-to-vigorous PA = 0 min/week). Over 12.0 years of follow-up, 163 and 150 participants had an incident HFpEF and HFrEF event, respectively. In adjusted analysis, higher hs-cTnI concentration (per 1-U log increase) was associated with higher risk of HFpEF (hazard ratio [HR]: 1.47; 95% confidence interval [CI]: 1.25 to 1.72]) and HFrEF (HR: 1.57; 95% CI: 1.35 to 1.83]). In contrast, higher PA (per 1-U log increase) was associated with a lower risk of HFpEF (HR: 0.93; 95% CI: 0.88 to 0.99]) but not HFrEF. There was a significant interaction between hs-cTnI and PA for risk of HFpEF (p interaction = 0.04) such that inactive participants with subclinical myocardial injury were at higher risk of HFpEF but active participants were not., Conclusions: Among Black adults with subclinical myocardial injury, higher levels of PA were associated with attenuated risk of HFpEF., Competing Interests: Funding Support and Author Disclosures Supported by a Strategically Focused Research Network Grant for Prevention from the American Heart Association to University of Texas Southwestern Medical Center, Dallas, and Northwestern University School of Medicine, Chicago. Dr. Neeland is a consultant for Boehringer Ingelheim/Lilly Alliance and Merck. Dr. deFilippi has received grant support from Roche Diagnostics, Ortho Diagnostics, and Siemens Healthineers; is a consultant for Roche Diagnostics, Abbott Diagnostics, Ortho Clinical Diagnostics, Quidel, FujiRebio, and Siemen’s Health Care Diagnostics; has received royalty payments from UpToDate; co-owns a patent awarded to the University of Maryland (U.S. Patent Application: 15/309,754; Methods for Assessing Differential Risk for Developing Heart Failure); and has received an award, UL1TR003015, from the U.S. National Institutes of Health/Center for Advancing Translational Science. Dr. Seliger has received funding from Roche Diagnostics. Dr. Rodriguez has received research support from Amgen, the American Heart Association, and the National Health Lung and Blood Institute (2R01HL104199). Dr. de Lemos has received grant support from Roche Diagnostics and Abbott Diagnostics; is a consultant for Roche Diagnostics, Abbott Diagnostics, Ortho Clinical Diagnostics, Quidel Cardiovascular, and Siemen’s Health Care Diagnostics; and is a co-owner of a patent awarded to the University of Maryland (U.S. Patent Application: 15/309,754; Methods for Assessing Differential Risk for Developing Heart Failure). Dr. Mentz has received research support and honoraria from Abbott, American Regent, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim/Eli Lilly, Boston Scientific, Cytokinetics, Fast BioMedical, Gilead, Innolife, Medtronic, Merck, Novartis, Relypsa, Respicardia, Roche, Sanofi, Vifor, and Windtree Therapeutics. Dr. Berry has received a grant, 14SFRN20740000, from the American Heart Association prevention network and salary support from Abbott Diagnostics. Dr. Pandey has served on the advisory board of Roche Diagnostics; has received nonfinancial support from Pfizer and Merck; and has received research support from Texas Health Resources Clinical Scholarship, the Gilead Sciences Research Scholar Program, and the National Institute of Aging GEMSSTAR grant (1R03AG067960-01) and Applied Therapeutics., (Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: This study evaluated the application of a biomarker-based risk score to identify individuals with dysglycemia who are at high risk for incident heart failure (HF) and to inform allocation of effective preventive interventions., Background: Risk stratification tools to identify patients with diabetes and pre-diabetes at highest risk for HF are needed to inform cost-effective allocation of preventive therapies. Whether a biomarker score can meaningfully stratify HF risk is unknown., Methods: Participants free of cardiovascular disease from 3 cohort studies (ARIC [Atherosclerosis Risk In Communities], DHS [Dallas Heart Study], and MESA [Multi-Ethnic Study of Atherosclerosis]) were included. An integer-based biomarker score included high-sensitivity cardiac troponin T ≥6 ng/l, N-terminal pro-B-type natriuretic peptide ≥125 pg/ml, high-sensitivity C-reactive protein ≥3 mg/l, and left ventricular hypertrophy by electrocardiography, with 1 point for each abnormal parameter. The 5-year risk of HF was estimated among participants with diabetes and pre-diabetes across biomarker score groups (0 to 4)., Results: The primary analysis included 6,799 participants with dysglycemia (diabetes: 33.2%; pre-diabetes: 66.8%). The biomarker score demonstrated good discrimination and calibration for predicting 5- and 10-year HF risk among pre-diabetes and diabetes cohorts. The 5-year risk of HF among subjects with a biomarker score of ≤1 was low and comparable to participants with euglycemia (0.78%). The 5-year risk for HF increased in a graded fashion with an increasing biomarker score, with the highest risk noted among those with scores of ≥3 (diabetes: 12.0%; pre-diabetes: 7.8%). The estimated number of HF events that could be prevented using a sodium-glucose cotransporter-2 inhibitor per 1,000 treated subjects over 5 years was 11 for all subjects with diabetes and ranged from 4 in the biomarker score zero group to 44 in the biomarker score ≥3 group., Conclusions: Among adults with diabetes and pre-diabetes, a biomarker score can stratify HF risk and inform allocation of HF prevention therapies., Competing Interests: Funding Support and Author Disclosures Dr. Pandey was supported by the Texas Health Resources Clinical Scholarship, Gilead Sciences Research Scholar Program, and the National Institute of Aging GEMSSTAR Grant (1R03AG067960-01). The ARIC study is conducted as a collaborative study supported by National Heart, Lung, and Blood Institute contracts (HHSN268201100005C, HHSN2 68201100006C, HHSN268201100007C, HHSN268201100008C, HHSN26820 1100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201 100012C). The Dallas Heart Study was funded by a grant from the Donald W. Reynolds Foundation. Research reported in this publication was supported by the National Center for Advancing Translational Sciences of the National Institutes of Health (award number UL1TR001105) to the University of Texas Southwestern Medical Center. The Multi-Ethnic Study of Atherosclerosis was supported by the National Heart, Lung, and Blood Institute (R01 HL071739 and contracts N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, and N01-C-95169). Dr. Vaduganathan has been supported by the KL2/Catalyst Medical Research Investigator Training award from Harvard Catalyst (NIH/NCATS Award UL 1TR002541); and has served on advisory boards for Amgen, AstraZeneca, Baxter Healthcare, Bayer AG, Boehringer Ingelheim, Cytokinetics, and Relypsa. Dr. Pandey has served on the advisory board of Roche Diagnostics. Dr. Patel was supported by the National Heart, Lung, and Blood Institute T32 postdoctoral training grant (5T32HL125247-03). Dr. Kosiborod has received research grant support from AstraZeneca and Boehringer Ingelheim; has served as a consultant or on advisory boards for Amgen, Applied Therapeutics, Astra Zeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Janssen, Merck (Diabetes), Novo Nordisk, Sanofi, and Vifor Pharma; has received other research support from AstraZeneca and honorarium from AstraZeneca, Boehringer Ingelheim, and Novo Nordisk. Dr. de Lemos has received grant support from Roche Diagnostics and Abbott Diagnostics; and has received consulting fees from Roche Diagnostics, Abbott Diagnostics, Ortho Clinical Diagnostics, Siemen’s Health Care Diagnostics, Quidel Cardiovascular, Inc, Novo Nordisk, Amgen, Regeneron, Eli Lilly, and Esperion. Drs. DeFilippi and de Lemos hold a patent pending (U.S. Patent Number: 15/309,754) entitled: “Methods for Assessing Differential Risk for Developing Heart Failure.” Dr. McGuire has received personal fees for trial leadership from GlaxoSmithKline, Janssen, Lexicon, AstraZeneca, CSL Behring, Sanofi, Boehringer Ingelheim, Merck & Co, Pfizer, Novo Nordisk, Eisai Inc., Esperion, and Lilly USA; and has received personal consultancy fees from AstraZeneca, Lilly USA, Boehringer Ingelheim, Merck & Co, Novo Nordisk, Metavant, Applied Therapeutics, Sanofi, and Afimmune. Dr. Everett has received personal consultancy fees from Amarin, Amgen, Gilead, FDA, Merck & Co., National Institute of Diabetes and Digestive and Kidney Diseases, and Roche Diagnostics outside the present work; and has received significant investigator-initiated grant funding from the National Institute of Heart, Lung, and Blood Institute outside the present work. A full list of participating MESA investigators and institutions can be found at http://www.mesa-nhlbi.org., (Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Introduction: Subclinical changes to cardiac structure and function detected with echocardiography precede the development of clinical heart failure (HF) in persons with chronic kidney disease (CKD). Circulating cardiac biomarkers may reflect these pathophysiological changes. This study investigated associations between established biomarkers (N-terminal pro-B-type natriuretic peptide [NT-proBNP] and high-sensitivity troponin T [hsTnT]) and novel biomarkers (growth differentiation factor 15 [GDF-15], galectin-3 [Gal-3], and soluble ST-2 [sST-2]), using echocardiographic measurements in persons with CKD., Methods: In cross-sectional analyses among 2101 participants with mild to moderate CKD in the Chronic Renal Insufficiency Cohort (CRIC), biomarker levels measured at baseline were evaluated with echocardiographic measurements 1 year later. These included left ventricular mass index (LVMI), left ventricular end-systolic volume (LVESV), left ventricular end-diastolic volume (LVEDV), left ventricular ejection fraction (LVEF), and left atrial diameter (LAD). Multivariable linear regression analyses tested associations of each biomarker with echocardiographic measurements, adjusting for covariates., Results: GDF-15 was significantly associated with higher LVMI (1.0 g/m 2.7 ; 95% CI, 0.4-1.7), LVESV (0.4 ml/m 2.7 ; 95% CI, 0.0-0.7), and LVEDV (0.6 ml/m 2.7 ; 95% CI, 0.1-1.1), but not with LVEF or LAD. These findings were not significant when adjusting for NT-proBNP and hsTnT. Gal-3 and sST-2 had no significant associations. Higher levels of NT-proBNP and hsTnT were associated with all echocardiographic measurements., Conclusion: In patients with CKD, the novel biomarker GDF-15, a marker of inflammation and tissue injury, and clinical biomarkers NT-proBNP and hsTnT, were associated with echocardiographic measurements of subclinical cardiovascular disease. Collectively, these biomarkers may highlight biological pathways that contribute to the development of clinical HF., (© 2020 International Society of Nephrology. Published by Elsevier Inc.)

Background: Determining diagnostic thresholds for cardiac troponin assays is key to interpreting their clinical performance. We describe the calculation of 99th percentile upper reference limits (URLs) for the Elecsys® Troponin T Gen 5 (TnT Gen 5) assay., Methods: Plasma and serum samples from healthy US participants were prospectively evaluated using TnT Gen 5 Short Turn Around Time and 18-min assays on cobas e 411 and cobas e 601 analyzers (Roche Diagnostics); with, up to 8 TnT Gen 5 results per participant., Results: A total of 10,402 TnT Gen 5 results from 1301 participants were included (50.4% female). Across 9 calculation methods, overall 99th percentile URL was 19.2 ng/l (females, 13.5-13.6 ng/l; males, 21.4-22.2 ng/l). Across different sample/assay/analyzer combinations, overall 99th percentile URLs ranged from 18.4-20.2 ng/l. Median TnT Gen 5 results increased with age, were higher in males, and ranged from 3.0-3.7 ng/l across races/ethnicities and from 3.0-3.6 ng/l across body mass index (BMI) classes. Applying additional exclusion criteria (N-terminal pro-brain natriuretic peptide, BMI and estimated glomerular filtration rate) resulted in lower 99th percentile URLs (overall, 16.9 ng/l; females, 11.8 ng/l; males, 18.5 ng/l)., Conclusion: Our findings facilitate the interpretation of TnT Gen 5 results in US clinical practice., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: We report the analytical performance of the Elecsys® Troponin T Gen 5 STAT (TnT Gen 5 STAT; Roche Diagnostics) assay., Methods: Measuring limits/ranges were determined in lithium-heparin plasma samples per Clinical and Laboratory Standards Institute (CLSI) EP17-A2. Precision was evaluated per CLSI EP05-A2 using lithium-heparin plasma/quality control samples on cobas e 411/cobas e 601 analyzers; two duplicated runs per day for 21 days (n = 84). Cross-reactivity with other troponin forms and interference from endogenous substances/drugs was tested; recovery criterion for no cross-reactivity was within ±10%., Results: Coefficients of variation (CV) for repeatability/intermediate precision were 0.7-5.6%/1.4-10.3% (cobas e 411; mean cardiac troponin T [cTnT]: 7.3-9341 ng/L) and 0.7-3.0%/1.5-6.4% (cobas e 601; mean cTnT: 7.4-9455 ng/L). There was no cross-reactivity with skeletal muscle troponin T (≤ 10,000 ng/L), skeletal muscle troponin I (≤ 100,000 ng/L), cardiac troponin I (≤ 10,000 ng/L), or human troponin C (≤ 80,000 ng/L). No interference was observed with biotin (≤ 20 ng/mL) or 34 drugs., Conclusion: The TnT Gen 5 STAT assay demonstrated a CV of <10% at the 99th percentile upper reference limit, meeting precision requirements (Fourth Universal Definition of Myocardial Infarction) for high-sensitivity troponin assays., (Copyright © 2019. Published by Elsevier B.V.)

The incidence and prevalence of heart failure (HF) and chronic kidney disease (CKD) are increasing, and as such a better understanding of the interface between both conditions is imperative for developing optimal strategies for their detection, prevention, diagnosis, and management. To this end, Kidney Disease: Improving Global Outcomes (KDIGO) convened an international, multidisciplinary Controversies Conference titled Heart Failure in CKD. Breakout group discussions included (i) HF with preserved ejection fraction (HFpEF) and nondialysis CKD, (ii) HF with reduced ejection fraction (HFrEF) and nondialysis CKD, (iii) HFpEF and dialysis-dependent CKD, (iv) HFrEF and dialysis-dependent CKD, and (v) HF in kidney transplant patients. The questions that formed the basis of discussions are available on the KDIGO website http://kdigo.org/conferences/heart-failure-in-ckd/, and the deliberations from the conference are summarized here., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: We aimed to directly compare the diagnostic and prognostic performance of a dual maker strategy (DMS) with combined testing of copeptin and high-sensitivity (hs) cardiac troponin T (cTnT) at time of presentation with other algorithms for rapid rule-out of acute myocardial infarction (AMI)., Methods: 922 patients presenting to the emergency department with suspected AMI and available baseline copeptin measurements qualified for the present TRAPID-AMI substudy. Diagnostic measures using the DMS (copeptin <10, <14 or < 20 pmol/L and hs-cTnT≤14 ng/L), the 1 h-algorithm (hs-cTnT<12 ng/L and change <3 ng/L at 1 h), as well as the hs-cTnT limit-of-blank (LoB, <3 ng/L) and -detection (LoD, <5 ng/L) were compared. Outcomes were assessed as combined end-points of death and myocardial re-infarction., Results: True-negative rule-out using the DMS could be achieved in 50.9%-62.3% of all patients compared to 35.0%, 45.3% and 64.5% using LoB, LoD or the 1 h-algorithm, respectively. The DMS showed NPVs of 98.1%-98.3% compared to 99.2% for the 1 h-algorithm, 99.4% for the LoB and 99.3% for the LoD. Sensitivities were 93.5%-94.8%, as well as 96.8%, 98.7% and 98.1%, respectively. Addition of clinical low-risk criteria such as a HEART-score ≤ 3 to the DMS resulted in NPVs and sensitivities of 100% with a true-negative rule-out to 33.8%-41.6%. Rates of the combined end-point of death/MI within 30 days ranged between 0.2% and 0.3% for all fast-rule-out protocols., Conclusion: Depending on the applied copeptin cut-off and addition of clinical low-risk criteria, the DMS might be an alternative to the hs-cTn-only-based algorithms for rapid AMI rule-out with comparable diagnostic measures and outcomes., (Copyright © 2018. Published by Elsevier B.V.)

Background: The inflammatory biomarker galectin-3 contributes to pathologic conditions such as heart failure and stimulates murine thrombogenesis. Its association with venous thromboembolism (VTE) has been sparsely studied., Objectives: To assess the prospective association of plasma galectin-3 and the LGALS3 rs4644 SNP with VTE incidence., Methods: We measured plasma galectin-3 in 9,916 participants in the Atherosclerosis Risk in Communities (ARIC) study cohort in 1996 - 1998 and identified VTEs through 2013. Using Cox regression, we estimated the hazard ratio associating galectin-3 with incident VTE over a median of 13.9 years. Replication was sought in the Cardiovascular Health Study (CHS)., Results: ARIC included 21.8% blacks and 56.2% females with mean baseline age of 62.7 years. The incidence rate of VTE (n=389 events) increased across quintiles of galectin-3, with hazard ratios (95% CI) of 1 (reference), 1.13 (0.80 - 1.61), 1.00 (0.70 - 1.43), 1.36 (0.96 - 1.91), and 1.55 (1.09 - 2.19) (p-trend = 0.005), adjusted for age, sex, race, body mass index, diabetes status, and renal function. Results did not replicate in the CHS (124 VTE), but meta-analysis of both studies yielded a pooled hazard ratio (95% CI) for 1 SD increment in log galectin-3 of 1.10 (1.00 - 1.22). In ARIC, the C allele of rs4644 in the LGALS3 gene was associated with higher galectin-3 level, and in whites, with an increased rate of VTE., Conclusion: Galectin-3 levels were associated positively with VTE incidence.

Objectives: To evaluate the impact of age- and gender-specific cut-offs for high-sensitivity cardiac troponin T (hs-cTnT) compared to the general 99th percentile hs-cTnT cut-off on diagnosis and prognosis of acute myocardial infarction (AMI)., Methods: 1282 unselected patients presenting to the emergency department with suspected AMI were enrolled as part of the TRAPID-AMI study. In the present sub-analysis, reclassification of AMI diagnosis was performed by comparing the general hs-cTnT cut-off of 14ng/L to previously proposed age- and gender-dependent hs-cTnT 99th percentile cut-offs (28ng/L for ≥65years, 9ng/L for female and 15.5ng/L for male patients). Patients were further clinically adjudicated into acute coronary syndrome (ACS) and non-ACS., Results: For patients ≥65years, application of age-specified cut-offs resulted in a decrease of AMI from 29.8% to 18.3% in the entire cohort (n=557) and 54.7% to 40.9% in the ACS subcohort (n=225). Using gender-specific cut-offs, AMI-rate increased from 16.6% to 22.6% (entire cohort, n=477) and 62.6% to 71.7% (ACS subcohort, n=99) in women, whereas in men, rates decreased from 23.1% to 21.1% (entire cohort, n=805) and 48.8% to 45.9% (ACS, n=281), respectively. Age-specified cut-offs significantly reclassified patients for outcomes of 1-month and 3-month mortality in the entire and ACS cohort (14.2% net reclassification improvement, p<0.001, respectively). Contrary, no significant differences in outcomes could be found using gender-specific cut-offs., Conclusions: While influence of gender-specific hs-cTnT cut-offs on diagnostic and prognostic reclassification was only modest in patients with suspected AMI, age-specific cut-offs showed a significant impact and may be considered for further validation., (Copyright © 2016. Published by Elsevier Ireland Ltd.)

Objectives: This study hypothesized that biomarkers of subclinical myocardial injury (high-sensitivity cardiac troponin T [hs-cTnT]) and hemodynamic stress (N-terminal pro-B-type natriuretic peptide [NT-proBNP]) would differentiate heart failure (HF) risk among older adults with left ventricular hypertrophy (LVH)., Background: The natural history of LVH, an important risk factor for HF, is heterogeneous., Methods: NT-proBNP and hs-cTnT were measured at baseline and after 2 to 3 years in older adults without prior HF or myocardial infarction in the CHS (Cardiovascular Health Study). LVH and left ventricular ejection fraction were determined by echocardiography. HF events were adjudicated over a median of 13.1 years and classified as preserved or reduced left ventricular ejection fraction (heart failure with preserved ejection fraction or heart failure with reduced ejection fraction [HFrEF]). Adjusted risk of HF by LVH and biomarker tertiles, and by LVH and longitudinal increase in each biomarker was estimated using Cox regression., Results: Prevalence of LVH was 12.5% among 2,347 participants with complete measures. Adjusted risk of HF (N = 643 events) was approximately 3.8-fold higher among participants with LVH and in the highest biomarker tertile, compared with those with low biomarker levels without LVH (NT-proBNP, hazard ratio [HR]: 3.78; 95% confidence interval [CI]: 2.78 to 5.15 and hs-cTnT, HR: 3.86; 95% CI: 2.84 to 5.26). The adjusted risk of HFrEF was 7.8 times higher among those with the highest tertile of hs-cTnT and LVH (HR: 7.83; 95% CI: 4.43 to 13.83). Those with LVH and longitudinal increases in hs-cTnT or NT-proBNP were approximately 3-fold more likely to develop HF, primarily HFrEF, compared with those without LVH and with stable biomarkers., Conclusions: The combination of LVH with greater hs-cTnT or NT-proBNP levels, and their longitudinal increase, identifies older adults at highest risk for symptomatic HF, especially HFrEF. These biomarkers may characterize sub-phenotypes in the transition from LVH to HF and suggest modifiable targets for prevention., (Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Various mechanisms in cardiac remodeling related to atrial fibrillation (AF) lead to elevated circulating cardiac troponin levels, but little is known about such elevations upstream to AF onset., Objective: The purpose of this study was to study the association between circulating troponin levels as assessed by a highly sensitive cardiac troponin T (hs-cTnT) assay and incident atrial fibrillation (AF)., Methods: In a large prospective cohort of ambulatory older adults [the Cardiovascular Health Study (CHS)], hs-cTnT levels were measured in sera that were collected at enrollment from 4262 participants without AF (2871 with follow-up measurements). Incident AF was identified by electrocardiograms during CHS visits, hospital discharge diagnoses, and Medicare files, including outpatient and physician claims diagnoses., Results: Over median follow-up of 11.2 years (interquartile range 6.1-16.5), 1363 participants (32.0%) developed AF. Higher baseline levels of hs-cTnT were associated with incident AF in covariate-adjusted analyses accounting for demographics, traditional risk factors, and incident heart failure in time-dependent analyzes (hazard ratio for 3rd tertile vs undetectable 1.75, 95% confidence interval 1.48-2.08). This association was statistically significant in analyses that additionally adjusted for biomarkers of inflammation and hemodynamic strain (hazard ratio for 3rd tertile vs undetectable 1.38, 95% confidence interval 1.16-1.65). Significant associations were also found when hs-cTnT levels were treated as a continuous variable and when examining change from baseline of hs-cTnT levels and incident AF., Conclusion: The findings show a significant association of circulating troponin levels in ambulatory older adults with incident AF beyond that of traditional risk factors, incident heart failure, and biomarkers of inflammation and hemodynamic strain., (Copyright © 2015 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: Inflammation is linked to adverse cardiovascular events, but its association with sudden cardiac death (SCD) has been controversial. Older subjects, who are at particular risk for SCD, were underrepresented in previous studies addressing this issue., Objective: The purpose of this study was to study the association between inflammation and SCD in a community-based population of older adults., Methods: In the Cardiovascular Health Study, 5806 and 5382 participants had measurements of C-reactive protein (CRP) and interleukin-6 (IL6), respectively, and were followed for up to 17 years. SCD risk as a function of baseline IL-6 and CRP was assessed in the overall population and in a group of participants without known prevalent cardiac disease., Results: In univariate analyses, both IL-6 (hazard ratio [HR] 1.79 for 1+ log IL-6, 95% confidence interval [CI] 1.50-2.13; 5th vs 1st quintile HR 3.36, 95% CI 2.24-5.05) and CRP (HR 1.31 for 1+ log CRP, 95% CI 1.18-1.45; 5th vs 1st quintile HR 2.00, 95% CI 1.40-2.87) were associated with SCD risk. In covariate-adjusted analyses, accounting for baseline risk factors, incident myocardial infarction, and heart failure, the association with SCD risk persisted for IL-6 (HR 1.26 for 1+ log IL-6, 95% CI 1.02-1.56; 5th vs 1st quintile HR 1.63, 95% CI 1.03-2.56) but was significantly attenuated for CRP (HR 1.13 for 1+ log CRP, 95% CI 1.00-1.28; 5th vs 1st quintile HR 1.34, 95% CI 0.88-2.05). Similar findings were observed in participants without prevalent cardiac disease., Conclusion: Greater burden of inflammation, assessed by IL-6 levels, is associated with SCD risk beyond traditional risk factors, incident myocardial infarction, and heart failure., (© 2013 Heart Rhythm Society. All rights reserved.)

Objectives: This study sought to determine whether the combined trajectories of cardiac biomarkers identify those older adults with initial low levels who have an increased risk for structural heart disease, incident heart failure (HF), and cardiovascular (CV) death., Background: Initial low levels of high-sensitivity cardiac troponin T (hs-cTnT) and N-terminal pro-brain natriuretic peptide (NT-proBNP) identify older adults at lower risk for CV events., Methods: We performed an observational study among older adults without prevalent HF in the CHS (Cardiovascular Health Study). NT-proBNP and hs-cTnT were measured at baseline and after 2 to 3 years. In those with low baseline levels, a significant increase was defined as cardiac troponin T (cTnT) >50% and NT-proBNP >25% increase to >190 pg/ml. Left ventricular ejection fraction and left ventricular mass were measured by echocardiography at baseline and 5 years. Cox regression was used to estimate the association of change in biomarkers with HF and CV mortality., Results: Among 2,008 participants with initially low biomarker concentrations, significant increases occurred in 14.8% for cTnT only, 13.2% for NT-proBNP only, and 6.1% for both. After 10 years, cumulative HF incidence was 50.4% versus 12.2% among those with both biomarkers versus neither biomarker increased. The adjusted relative risk comparing those with increases in both biomarkers versus neither biomarker was 3.56 for incident HF (95% confidence interval: 2.56 to 4.97) and 2.98 for CV mortality (95% confidence interval: 2.98 to 4.26). Among 1,340 participants with serial echocardiography, the frequency of new abnormal left ventricular ejection fraction was 11.8% versus 4% for those with increases in both biomarkers versus neither biomarker (p = 0.007)., Conclusions: Among older adults without HF with initially low cTnT and NT-proBNP, the long-term trajectory of both biomarkers predicts systolic dysfunction, incident HF, and CV death., (Copyright © 2013 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: The underlying molecular mechanisms of the remodeling after myocardial infarction (MI) remain unclear. The purpose of this study was to investigate the role of a survival pathway (PI3K/Akt) and an apoptosis pathway (calcineurin/BAD) in the remodeling after MI in a large animal model., Methods: Ten Dorset hybrid sheep underwent 25% MI in the left ventricle (LV, n=10). Five sheep were used as sham control. The regional strain was calculated from sonomicrometry. Apoptosis and the activation of the PI3K/Akt and calcineurin/BAD pathways were evaluated in the non-ischemic adjacent zone and the remote zone relative to infarct by immunoblotting, immunoprecipitation, and immunofluorescence staining., Results: Dilation and dysfunction of LV were present at 12 weeks after MI. The regional strain in the adjacent zone was significantly higher than in the remote zone at 12 weeks (36.6 ± 4.0% vs 9.5 ± 3.6%, p<0.05). Apoptosis was more severe in the adjacent zone than in the remote zone. The PI3K/Akt and calcineurin/BAD pathways were activated in the adjacent zone. Dephosphorylation and translocation of BAD were evident in the adjacent zone. Regional correlation between the strain and the expression of calcineurin/BAD indicated that the activation was strain-related (R(2)=0.46, 0.48, 0.39 for calcineurin, BAD, mitochondrial BAD, respectively, p<0.05)., Conclusions: The PI3K/Akt survival and calcineurin/BAD apoptotic pathways were concomitantly activated in the non-ischemic adjacent zone after MI. The calcineurin/BAD pathway is strain related and its imbalanced activation may be one of the causes of progressive remodeling after MI., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Objectives: This study sought to demonstrate that short-term cardiac unloading with a left ventricular (LV) assist device (LVAD) after acute myocardial infarction (MI) can conserve calcium cycling and improve heart function., Background: Heart failure secondary to MI remains a major source of morbidity and mortality. Alterations in calcium cycling are linked to cardiac dysfunction in the failing heart., Methods: Adult Dorsett hybrid sheep underwent acute MI and were mechanically unloaded with an axial-flow LVAD (Impella 5.0) for 2 weeks (n = 6). Six sheep with MI only and 4 sham sheep were used as controls. All animals were followed for 12 weeks post-MI. Regional strains in the LV were measured by sonomicrometry. Major calcium-handling proteins (CHPs), including sarco-/endoplasmic reticulum calcium ATPase-2α (SERCA-2α), Na(+)-Ca(2+) exchanger-1, and phospholamban, and Ca(2+)-ATPase activity were investigated. The electrophysiological calcium cycling in single isolated cardiomyocytes was measured with the patch-clamp technique. The related ultrastructures were studied with electron microscopy., Results: LVAD unloading alleviated LV dilation and improved global cardiac function and regional contractility compared with the MI group. The regional myocardial strain (stretch) was minimized during the unloading period and even attenuated compared with the MI group at 12 weeks. Impaired calcium cycling was evident in the adjacent noninfarcted zone in the MI group, whereas CHP expression was normalized and Ca(2+)-ATPase activity was preserved in the LVAD unloading group. The electrophysiological calcium cycling was also conserved, and the ultrastructural damage was ameliorated in the unloaded animals., Conclusions: Short-term LVAD unloading may conserve calcium cycling and improve heart function during the post-infarct period., (Copyright © 2013 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: The infant Jarvik 2000 heart is a very small, hermetically sealed, intracorporeal, axial-flow ventricular assist device (VAD) designed for circulatory support in neonates and infants. The anatomic fit, short-term biocompatibility and hemodynamic performance of the device were evaluated in a neonate piglet model., Methods: The infant Jarvik 2000 heart with two different blade profiles (low- or high-flow blade design) was tested in 6 piglets (8.8 ± 0.9 kg). Using a median sternotomy, the pump was placed in the left ventricle through the apex without cardiopulmonary bypass. An outflow graft was anastomosed to the ascending aorta. Hemodynamics and biocompatibility were studied for 6 hours., Results: All 6 pumps were implanted without complication. Optimal anatomic positioning was found with the pump body inserted 2.4 cm into the left ventricle. Hemodynamics demonstrated stability throughout the 6-hour duration. The pump flow increased from 0.27 to 0.95 liter/min at increasing speeds from 18 to 31 krpm for the low-flow blade design, whereas the pump flow increased from 0.54 liter/min to 1.12 liters/min at increasing speeds from 16 krpm to 31 krpm for the high-flow blade design. At higher speeds, >80% of flow could be supplied by the device. Blood chemistry and final pathology demonstrated no acute organ injury or thrombosis for either blade design., Conclusions: The infant Jarvik 2000 heart is anatomically and biologically compatible with an short-term neonate piglet model. This in vivo study demonstrates the future feasibility of this device for clinical use., (Copyright © 2012 International Society for Heart and Lung Transplantation. All rights reserved.)

Objectives: This study sought to examine the potential utility of echocardiography and N-terminal pro-B-type natriuretic peptide (NT-proBNP) for heart failure (HF) risk stratification in concert with a validated clinical HF risk score in older adults., Background: Without clinical guidance, echocardiography and natriuretic peptides have suboptimal test characteristics for population-wide HF risk stratification. However, the value of these tests has not been examined in concert with a clinical HF risk score., Methods: We evaluated the improvement in 5-year HF risk prediction offered by adding an echocardiographic score and/or NT-proBNP levels to the clinical Health Aging and Body Composition (ABC) HF risk score (base model) in 3,752 participants of the CHS (Cardiovascular Health Study) (age 72.6 ± 5.4 years; 40.8% men; 86.5% white). The echocardiographic score was derived as the weighted sum of independent echocardiographic predictors of HF. We assessed changes in Bayesian information criterion (BIC), C index, integrated discrimination improvement (IDI), and net reclassification improvement (NRI). We examined also the weighted NRI across baseline HF risk categories under multiple scenarios of event versus nonevent weighting., Results: Reduced left ventricular ejection fraction, abnormal E/A ratio, enlarged left atrium, and increased left ventricular mass were independent echocardiographic predictors of HF. Adding the echocardiographic score and NT-proBNP levels to the clinical model improved BIC (echocardiography: -43, NT-proBNP: -64.1, combined: -68.9; all p < 0.001) and C index (baseline: 0.746; echocardiography: +0.031, NT-proBNP: +0.027, combined: +0.043; all p < 0.01), and yielded robust IDI (echocardiography: 43.3%, NT-proBNP: 42.2%, combined: 61.7%; all p < 0.001), and NRI (based on Health ABC HF risk groups; echocardiography: 11.3%; NT-proBNP: 10.6%, combined: 16.3%; all p < 0.01). Participants at intermediate risk by the clinical model (5% to 20% 5-yr HF risk; 35.7% of the cohort) derived the most reclassification benefit. Echocardiography yielded modest reclassification when used sequentially after NT-proBNP., Conclusions: In older adults, echocardiography and NT-proBNP offer significant HF risk reclassification over a clinical prediction model, especially for intermediate-risk individuals., (Copyright © 2012 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

(Na(+)+K(+))-ATPase (NKA) mediates positive inotropy in the heart. Extensive studies have demonstrated that the reverse-mode Na(+)/Ca(2+)-exchanger (NCX) plays a critical role in increasing intracellular Ca(2+) concentration through the inhibition of NKA-induced positive inotropy by cardiac glycosides. Little is known about the nature of the NCX functional mode in the activation of NKA-induced positive inotropy. Here, we examined the effect of an NKA activator SSA412 antibody on (45)Ca influx in isolated rat myocytes and found that KB-R7943, a NCX reverse-mode inhibitor, fails to inhibit the activation of NKA-induced (45)Ca influx, suggesting that the Ca(2+) influx via the reverse-mode NCX does not mediate this process. Nifedipine, an L-type Ca(2+) channel (LTCC) inhibitor, completely blocks the activation of NKA-induced (45)Ca influx, suggesting that the LTCC is responsible for the moderate increase in intracellular Ca(2+). In contrast, the inhibition of NKA by ouabain induces 4.7-fold (45)Ca influx compared with the condition of activation of NKA. Moreover, approximately 70% of ouabain-induced (45)Ca influx was obstructed by KB-R7943 and only 30% was impeded by nifedipine, indicating that both the LTCC and the NCX contribute to the rise in intracellular Ca(2+) and that the NCX reverse-mode is the major source for the (45)Ca influx induced by the inhibition of NKA. This study provides direct evidence to demonstrate that the activation of NKA-induced Ca(2+) increase is independent of the reverse-mode NCX and pinpoints a mechanistic distinction between the activation and inhibition of the NKA-mediated Ca(2+) influx path ways in cardiomyocytes., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: Sudden cardiac death (SCD), the cause of 250,000-450,000 deaths per year, is a major public health problem. The majority of those affected do not have a prior cardiovascular diagnosis. Elevated B-type natriuretic peptide levels have been associated with the risk of heart failure and mortality as well as with sudden death in women., Objective: The purpose of this study was to examine the relationship between N-terminal pro-B-type natriuretic peptide (NT-proBNP) and SCD in the Cardiovascular Health Study population., Methods: The risk of SCD associated with baseline NT-proBNP was examined in 5,447 participants. Covariate-adjusted Cox model regressions were used to estimate the hazard ratios of developing SCD as a function of baseline NT-proBNP., Results: Over a median follow-up of 12.5 years (maximum 16), there were 289 cases of SCD. Higher NT-proBNP levels were strongly associated with SCD, with an unadjusted hazard ratio of 4.2 (95% confidence interval [2.9, 6.1]; P <.001) in the highest quintile compared with in the lowest. NT-proBNP remained associated with SCD even after adjustment for numerous clinical characteristics and risk factors (age, sex, race, and other associated conditions), with an adjusted hazard ratio for the fifth versus the first quintile of 2.5 (95% confidence interval [1.6, 3.8]; P <.001)., Conclusion: NT-proBNP provides information regarding the risk of SCD in a community-based population of older adults, beyond other traditional risk factors. This biomarker may ultimately prove useful in targeting the population at risk with aggressive medical management of comorbid conditions., (Copyright © 2011 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: Aortic valve bypass (AVB [apicoaortic conduit]) relieves aortic stenosis (AS) by connecting the apex of the left ventricle to the descending thoracic aorta with a valved conduit. AVB is performed through a small left thoracotomy, without cardiopulmonary bypass, aortic cross-clamping, cardiac arrest, or debridement of the native aortic valve. Little is known about hemodynamics, including ventricular performance, relative conduit blood flow, and progression of native AS after AVB., Methods: Forty-seven very high risk patients underwent AVB for AS between 2003 and 2009. The mean age was 82 years. Predismissal and interval transthoracic quantitative two-dimensional and Doppler echocardiography was performed in a core laboratory., Results: No patient had obstruction of the native aortic valve or the conduit during follow-up. The AVB effectively relieved left ventricular outflow tract obstruction (average peak gradient across the conduit was 5.6 +/- 3.8 mm Hg). Native aortic valve stenosis did not progress after AVB (0.63 +/- 0.16 cm(2) before surgery to 0.7 +/- 0.24 cm(2) at latest follow-up more than 6 months; p = 0.16). Total stroke volume increased after AVB from 60 mL +/- 22 mL to 107 mL +/- 27 mL (p < 0.0001). Left ventricular outflow was distributed in a predictable fashion between the conduit and the native aortic valve, with 63% +/- 10% of the flow directed to the conduit. Relative conduit flow remained stable (68% +/- 8%) at latest follow-up more than 6 months (p = 0.17)., Conclusions: Aortic valve bypass effectively relieves the outflow tract obstruction of AS. Placement of an apical valved conduit halts the biologic progression of AS., (Copyright 2010 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)