Biomarkers and Strain Echocardiography for the Detection of Subclinical Cardiotoxicity in Breast Cancer Patients Receiving Anthracyclines.

The optimal surveillance and management strategies for breast cancer patients receiving anthracycline therapy are limited by our incomplete understanding of the role of biomarkers heralding the onset of cardiotoxicity. The purpose of this study was to determine whether there is a temporal correlation between cardiac biomarkers and subclinical left ventricular dysfunction in breast cancer patients receiving anthracycline chemotherapy. Thirty-one females between 46 and 55 years old with breast cancer treated with anthracycline chemotherapy were prospectively enrolled. Cardiac biomarkers were correlated with echocardiography with speckle tracking at baseline, post-anthracycline therapy, and 6 months post-anthracycline chemotherapy. Subclinical cardiotoxicity was defined as ≥ 10% reduction in global longitudinal strain (GLS). There was a relative reduction in left ventricular ejection fraction (LVEF) ≥ 10% in 5/30 (17%) and 7/27 (26%) patients post-anthracycline therapy and 6 months post-anthracycline therapy, respectively. Subclinical cardiotoxicity was noted in 8/30 (27%) and 10/26 (38%) patients post-anthracycline and 6 months post-anthracycline therapy, respectively. Baseline N-terminal pro B-type natriuretic peptide (NT-proBNP) was the strongest predictor of LVEF (ρ = -0.45; p = 0.019), with post-therapy NT-proBNP values illustrating similar predictive value (ρ = -0.40; p = 0.038). Interim changes in suppression of tumorigenicity 2 (ST2) and galectin-3 correlated with a 6-month change in LVEF (ρ = -0.48; p = 0.012 and ρ = -0.45; p = 0.018, for ST2 and galectin-3, respectively). Changes in galectin-3 from baseline to mid-therapy paralleled changes in GLS. NT-proBNP, ST2, and galectin-3 correlate with reduced LVEF among breast cancer patients receiving anthracycline therapy. Additional trials focusing on a cardiac biomarker approach may provide guidance in the early diagnosis and management of anthracycline-induced cardiotoxicity.

Markers of Iron Metabolism and Outcomes in Patients with Heart Failure: A Systematic Review.

Iron deficiency (ID) in conjunction with heart failure (HF) poses a challenge for clinicians and is associated with worse HF outcomes. Treatment of ID with IV iron supplementation for patients with HF has demonstrated benefits in quality of life (QoL) and HF-related hospitalizations. The aim of this systematic review was to summarize the evidence linking iron metabolism biomarkers with outcomes in patients with HF to assist in the optimal use of these biomarkers for patient selection. A systematic review of observational studies in English from 2010 to 2022 was conducted using PubMed, with keywords of "Heart Failure" and respective iron metabolism biomarkers ("Ferritin", "Hepcidin", "TSAT", "Serum Iron", and "Soluble Transferrin Receptor"). Studies pertaining to HF patients, with available quantitative data on serum iron metabolism biomarkers, and report of specific outcomes (mortality, hospitalization rates, functional capacity, QoL, and cardiovascular events) were included, irrespective of left ventricular ejection fraction (LVEF) or other HF characteristics. Clinical trials of iron supplementation and anemia treatment were removed. This systematic review was conducive to formal assessment of risk of bias via Newcastle-Ottawa Scale. Results were synthesized based on their respective adverse outcomes and iron metabolism biomarker(s). Initial and updated searches identified 508 unique titles once duplicates were removed. The final analysis included 26 studies: 58% focused on reduced LVEF; age range was 53-79 years; males composed 41-100% of the reported population. Statistically significant associations of ID were observed with all-cause mortality, HF hospitalization rates, functional capacity, and QoL. Increased risk for cerebrovascular events and acute renal injury have also been reported, but these findings were not consistent. Varying definitions of ID were utilized among the studies; however, most studies employed the current European Society of Cardiology criteria: serum ferritin < 100 ng/mL or the combination of ferritin between 100-299 ng/mL and transferrin saturation (TSAT) < 20%. Despite several iron metabolism biomarkers demonstrating strong association with several outcomes, TSAT better predicted all-cause mortality, as well as long-term risk for HF hospitalizations. Low ferritin was associated with short-term risk for HF hospitalizations, worsening functional capacity, poor QoL, and development of acute renal injury in acute HF. Elevated soluble transferrin receptor (sTfR) levels were associated with worse functional capacity and QoL. Finally, low serum iron was significantly associated with increased risk for cardiovascular events. Considering the lack of consistency among the iron metabolism biomarkers for association with adverse outcomes, it is important to incorporate additional biomarker data, beyond ferritin and TSAT, when assessing for ID in HF patients. These inconsistent associations question how best to define ID to ensure proper treatment. Further research, potentially tailored to specific HF phenotypes, is required to optimize patient selection for iron supplementation therapy and appropriate targets for iron stores replenishment.

Midterm outcomes of mitral valve repair versus replacement in elderly patients: A propensity score-matched analysis.

BACKGROUND: Current literature reports better short-term mortality rates in mitral valve repair over replacement in elderly patients. However, valve durability, postoperative complications, and reintervention rates in these cohorts remain understudied. As such, we aimed to investigate 5-year rates of mortality and reoperation after initial mitral repair or replacement in elderly patients. METHODS: Using the TriNetX Research Network database, we identified patients aged ≥70 who underwent mitral valve repair or replacement for nonrheumatic mitral insufficiency between January 2010 and December 2020. We 1:1 propensity score-matched cohorts for 33 covariates including demographics, comorbidities, and surgical history. After matching, we compared 5-year mortality and reoperation rates between cohorts using Kaplan-Meier estimates and multivariable Cox proportional hazards models. RESULTS: We compared 823 mitral valve repair patients to a propensity score-matched cohort of 823 mitral valve replacement patients over a 5-year follow-up period. All variables of interest were adequately matched. Cumulative 5-year mortality rate was significantly lower among mitral valve repair patients (17.0% vs. 24.9%; hazard ratio [HR]: 0.66, 95% confidence interval [95% CI]: 0.51-0.87, p < 0.0025). Reoperation rates at 5-year did not differ (2.6% vs. 2,1%; HR: 1.34, 95% CI: 0.67-2.68, p = 0.401). CONCLUSIONS: We observed lower 5-year mortality rates and nonsignificantly different reoperation rates among elderly patients with mitral regurgitation undergoing mitral valve repair compared to replacement. Our data support the current understanding that mitral valve repair should be considered as the first treatment line whenever possible, even in elderly patients.

Preliminary study on the diagnostic value of cardiac magnetic resonance feature tracking for malignant ventricular arrhythmias in non-ischemic dilated cardiomyopathy.

Background: Patients with nonischemic dilated cardiomyopathy (NIDCM) and malignant ventricular arrhythmia (MVA) often have a poor prognosis and a high risk of sudden cardiac death. Although the diagnosis of MVA is straightforward by electrocardiogram (ECG), the underlying abnormalities of ventricular mechanics in these patients are unknown. This study aims to preliminarily explore the value of cardiac magnetic resonance feature tracking (CMR-FT) for MVA in dilated cardiomyopathy. Methods: In this retrospective study, patients with NIDCM who met inclusion criteria were divided into an MVA group and a non-MVA group (included from January 2018 to September 2021). The interobserver agreement of myocardial strain parameters, including global longitudinal strain (GLS), global circumferential strain (GCS) and global radial strain (GRS), were tested. The GLS, GCS, GRS, left ventricular ejection fraction (LVEF), Tpeak-Tend interval on ECG and brain natriuretic peptide (BNP) were compared between groups. Single-factor and multifactor receiver operating characteristic (ROC) curve analyses were conducted to calculate the area under the ROC curve (AUC), cut-off point, sensitivity, and specificity of these parameters in predicting MVA in NIDCM. Results: A total of 161 NIDCM patients were included (54 in the MVA group). GLS, GCS, and GRS had good interobserver agreement (all intraclass correlation coefficients >0.80). The absolute GLS and GCS, GRS and LVEF were lower in the MVA group than the non-MVA group (P<0.001), Tpeak-Tend and BNP were higher (P<0.001). Single-factor ROC curve analysis showed that GLS, GCS and GRS had certain diagnostic value for MVA (AUC =0.795, 0.802, and 0.754, respectively). Among them, GCS had higher sensitivity and specificity (GCS 0.796/0.776, GLS 0.778/0.757, GRS 0.741/0.692). Multifactor ROC curve analysis showed the combination of GLS and GCS (AUC =0.810), the combination of GCS and GRS (AUC =0.802), the combination of GLS and GRS (AUC =0.787), the combination of GLS, GCS, and GRS (AUC =0.810). Conclusions: The three-dimensional myocardial strain parameters (especially GLS and GCS) measured by CMR-FT had certain diagnostic value and could reflect the underlying abnormality of ventricular mechanics of NIDCM with MVA.

Cardiac surgeons' perspectives and practices regarding people who use drugs: A scoping review.

BACKGROUND AND AIM OF STUDY: The rising rates of drug use and associated cardiovascular complications, particularly infective endocarditis, have led to poorer health outcomes for people who use drugs (PWUD). The objectives of this scoping review were to identify (1) attitudes of cardiac surgeons toward PWUD and (2) challenges faced in the surgical treatment of drug use-related disease. METHODS: A comprehensive literature search of three databases was performed with this assistance of a medical librarian. Articles were screened and analyzed for common themes by two independent authors. After literature review, a scoping review was conducted according to preferred reporting items for systematic reviews and meta-analyses and Joanna Briggs Institute guidelines, summarizing existing evidence. RESULTS: Analysis of 35 qualified articles revealed eight themes regarding the perspectives and practices of cardiac surgeons toward PWUD: (1) need for multidisciplinary care teams (45.7%); (2) insufficient resources for treatment of underlying substanceuse disorders (40.0%); (3) stigma toward PWUD (37.1%); (4) willingness of surgeons to operate (31.4%); (5) incomplete guidelines for surgical management of drug-use related infective endocarditis (17.1%); (6) recognizing the importance of psychosocial factors (14.3%); (7) use of drug abstinence contracts (14.3%); and (8) use of stigmatizing language to describe PWUD and/or sterile injection (40.0%). CONCLUSIONS: Provision of equitable care for PWUD requires effort from multiple disciplines including cardiothoracic surgeons, infectious disease specialists, addiction medicine specialists, and social workers. Additionally, further research is needed to gather sufficient data for evidence-based guidelines in the treatment of cardiac complications in PWUD.

Biomarker profile in stable Fontan patients.

BACKGROUND: As the population of adults with congenital heart disease (CHD) grows, cardiologists continue to encounter patients with complex anatomies that challenge the standard treatment of care. Single ventricle Fontan palliated patients are the most complex within CHD, with a high morbidity and mortality burden. Factors driving this early demise are largely unknown. METHODS AND RESULTS: We analyzed biomarker expression in 44 stable Fontan outpatients (29.2 ± 10.7 years, 68.2% female) seen in the outpatient Emory Adult Congenital Heart Center and compared them to 32 age, gender and race matched controls. In comparison to controls, Fontan patients had elevated levels of multiple cytokines within the inflammatory pathway including Tumor Necrosis Factor-α (TNF-α) (p < 0.001), Interleukin-6 (IL-6) (p < 0.011), Growth Derived Factor-15 (GDF-15) (p < 0.0001), ß2-macroglobulin, (p = 0.0006), stem cell mobilization: Stromal Derived Factor-1∝ (SDF-1α) (p = 0.006), extracellular matrix turnover: Collagen IV (p < 0.0001), neurohormonal activation: Renin (p < 0.0001), renal dysfunction: Cystatin C (p < 0.0001) and Urokinase Receptor (uPAR) (p = 0.022), cardiac injury: Troponin-I (p < 0.0004) and metabolism: Adiponectin (p = 0.0037). Within 1 year of enrollment 50% of Fontan patients had hospitalizations, arrhythmias or worsening hepatic function. GDF-15 was significantly increased in Fontan patients with clinical events (p < 0.0001). In addition, GDF-15 moderately correlated with longer duration of Fontan (r = 0.55, p = 0.01) and was elevated in atriopulmonary (AP) Fontan circulation. Finally, in a multivariate model, VEGF-D and Collagen IV levels were found to be associated with a change in MELDXI, a marker of liver dysfunction. CONCLUSION: Multiple clinical and molecular biomarkers are upregulated in Fontan patients, suggesting a state of chronic systemic dysregulation.

Serum ST2 and hospitalization rates in Caucasian and African American outpatients with heart failure.

BACKGROUND: Limited data exist on the association between circulating suppression of tumorigenicity 2 (ST2) and recurrent hospitalizations and emergency department (ED) encounters in outpatients with heart failure (HF). In addition, data on ST2 in African American patients with HF are scarce. METHODS: We evaluated 307 outpatients with HF (age, 57 ±â€¯12 years; 64.2% men; 51.5% Caucasian, 45.6% African American; median ejection fraction, 35%; ischemic etiology, 41.4%). Median ST2 was 37.8 ng/mL (29.6-51.4). RESULTS: After a median of 3.1 years, there were 584 hospitalizations (224 for HF) and 335 ED visits (80 for HF). Patients (N = 176; 57.3%) with elevated (>35 ng/mL) ST2 had 2-fold higher hospitalization rates in adjusted models (rate ratio [RR] 1.97; 95% CI 1.38-2.82; P < 0.001), driven by 3.5-fold higher HF hospitalization rates (adjusted RR 3.56; 95% CI 1.69-7.49; P < 0.001). These associations persisted after adjusting for baseline B-type natriuretic peptide levels. Findings were similar for elevated ST2 and ED visit rates. Elevated ST2 was associated with the composite of death or HF hospitalization (109 patients; 3-year estimate: 35.4%); risk was 5-fold higher in the first 6 months but declined gradually. The higher hospitalization rates and composite endpoint risk associated with elevated ST2 was similar in African Americans and Caucasians. In landmark analyses in a subset of patients, 6-month (N = 112) and 12-month (N = 149) changes in ST2 levels from baseline added prognostic information. CONCLUSIONS: Elevated ST2 in outpatients with HF portends higher healthcare resources utilization and higher risk for accelerated disease progression, regardless of race, especially in the first 6 months.

Diastolic Dysfunction in Patients With Human Immunodeficiency Virus Receiving Antiretroviral Therapy: Results From the CHART Study.

BACKGROUND: Diastolic dysfunction (DD) is common and occurs at an earlier age among human immunodeficiency virus-infected (HIV+) individuals, but the mechanisms and consequences of DD among HIV+ individuals are unclear. METHODS AND RESULTS: The Characterization of Heart Function on Antiretroviral Therapy (CHART) study was a multicenter cross-sectional case-control study of treated and virally suppressed HIV+ individuals with (DD+) and without DD (DD-). All patients had normal ejection fraction (>50%), no significant valvular disease, and no history of coronary revascularization or persistent atrial fibrillation. Overall, 94 DD+ and 101 DD- patients were included. DD+ patients were older with higher body mass index (BMI) and more likely to have hypertension, renal dysfunction, and dyslipidemia. Groups were similar with respect to sex, race, CD4 count, and HIV RNA copies. N-terminal pro-B-type natriuretic peptide levels (median 36 [23, 85] vs 26 [12, 49] pg/mL, P < .01) and high-sensitivity troponin I (3.6 [2.6, 5.1] vs 2.5 [1.8, 3.5] pg/mL, P < .01) were higher among DD+ patients. The latter had similar left atrial size, but increased stiffness (conduit strain: 23.5 [17.5, 36.9] vs 30.0 [22.9, 37.0], P < .01) and impaired relaxation (reservoir strain: 39.7 [32.0, 58.0] vs 45.9 [37.0, 60.6], P = .04). On cardiac magnetic resonance, the prevalence of focal fibrosis was higher among DD+ patients (19.0% vs 5.3%, P < .01). DD+ patients demonstrated higher levels of carboxyl-terminal telopeptide of collagen type I (P = .04), and trends toward higher interleukin-6 and oxidized low-density lipoprotein levels (P ≤ .08). Kansas City Cardiomyopathy Questionnaire physical limitation (87.1±21.4 vs 93.1±18.1, P = .01) and symptom frequency scores were lower among DD+ patients (86.0±21.5 vs 92.5±16.8, P = .01). CONCLUSIONS: In this contemporary HIV+ population receiving antiretroviral therapy, DD was associated with multiple alterations in cardiac structure and function, including myocardial fibrosis and left atrial abnormalities, and worse quality of life. Further studies are needed to assess longitudinal changes in these parameters and their potential as therapeutic targets to prevent progressive cardiac remodeling and dysfunction in HIV.

Comorbidities, Sociodemographic Factors, and Hospitalizations in Outpatients With Heart Failure and Preserved Ejection Fraction.

Patients with heart failure and preserved ejection fraction (HFpEF) tend to be older and have a high co-morbidity burden. The impact of co-morbid conditions and sociodemographic risk factors on outcomes in these patients has not been quantified. We evaluated 445 consecutive outpatients with HFpEF, defined as established diagnosis of heart failure (HF) with left ventricular ejection fraction at presentation >40% and no previous left ventricular ejection fraction ≤40%. Patients with specific cardiomyopathies, congenital heart disease, primary right-sided disease, valvular disease, or previous advanced HF therapies were excluded. After 2 years, there were 44 deaths and 609 all-cause hospitalizations; of these, 260 (42.7%) were cardiovascular hospitalizations, including HF, and 173 (28.4%) were specifically for HF. The highest attributable risk for hospitalizations was associated with marital status (single, divorced, and widowed had higher hospitalization rates compared with married patients), hypoalbuminemia, diabetes, atrial fibrillation, and renal dysfunction. The proportion of hospitalizations potentially attributable to these factors was 66.6% (95% confidence interval [CI] 56.4 to 74.4) for all-cause hospitalizations, 76.9% (95% CI 65.2 to 84.6) for cardiovascular hospitalizations, and 83.0% (95% CI 70.3 to 90.3) for HF hospitalizations. For composite end points, the proportion was 46.9% (95% CI 34.0% to 57.3%) for death or all-cause hospitalization, 45.7% (95% CI 29.3% to 58.2%) for death or cardiovascular hospitalization, and 43.7% (95% CI 24.2% to 58.2%) for death or HF-related hospitalization. In conclusion, among outpatients with HFpEF, most hospitalizations could be attributed to co-morbidities and sociodemographic factors. Effects of HF therapies on hospitalizations and related end points may be difficult to demonstrate in these patients. Multidisciplinary approaches are more likely to impact hospitalizations in HFpEF.

Diastolic Dysfunction in Individuals With Human Immunodeficiency Virus Infection: Literature Review, Rationale and Design of the Characterizing Heart Function on Antiretroviral Therapy (CHART) Study.

Antiretroviral therapy (ART) has been associated with a shift in the epidemiology of human immunodeficiency virus (HIV)-associated cardiomyopathy from a phenotype of primarily left ventricular (LV) systolic dysfunction to LV diastolic dysfunction (DD). Patients with HIV receiving ART have higher rates of DD compared with age-matched control subjects and develop DD at a younger age. However, little is known about the natural history and pathogenesis of DD in virally suppressed HIV-infected patients. Current evidence suggests that immune processes modulate the risk for cardiac involvement in HIV-infected persons. Ongoing inflammation appears to have myocardial effects, and accelerated myocardial fibrosis appears to be a key mediator of HIV-induced DD. The Characterizing Heart Function on Antiretroviral Therapy (CHART) study aims to systematically investigate determinants, mechanisms, and consequences of DD in HIV-infected patients. We will compare ART-treated virally suppressed HIV-infected individuals with and without DD and HIV- individuals with DD regarding (1) systemic inflammation, myocardial stress, and subclinical myocardial necrosis as indicated by circulating biomarkers; (2) immune system activation as indicated by cell surface receptors; (3) myocardial fibrosis according to cardiac magnetic resonance examination; (4) markers of fibrosis and remodeling, oxidative stress, and hypercoagulability; (5) left atrial function according to echocardiographic examination; (6) myocardial stress and subclinical necrosis as indicated by circulating biomarkers; (7) proteomic and metabolic profiles; and (8) phenotype signatures derived from clinical, biomarker, and imaging data.

Progenitor Cells and Clinical Outcomes in Patients With Heart Failure.

BACKGROUND: Endogenous regenerative capacity, assessed as circulating progenitor cell (PC) numbers, is an independent predictor of adverse outcomes in patients with cardiovascular disease. However, their predictive role in heart failure (HF) remains controversial. We assessed the relationship between the number of circulating PCs and the pathogenesis and severity of HF and their impact on incident HF events. METHODS AND RESULTS: We recruited 2049 adults of which 651 had HF diagnosis. PCs were enumerated by flow cytometry as CD45med+ blood mononuclear cells expressing CD34, CD133, vascular endothelial growth factor receptor-2, and chemokine (C-X-C motif) receptor 4 epitopes. PC subsets were lower in number in HF and after adjustment for clinical characteristics in multivariable analyses, a low CD34+ and CD34+/CXCR+ cell count remained independently associated with a diagnosis of HF (P<0.01). PC levels were not significantly different in reduced versus preserved ejection fraction patients. In 514 subjects with HF, there were 98 (19.1%) all-cause deaths during a 2.2±1.5-year follow-up. In a Cox regression model adjusting for clinical variables, hematopoietic-enriched PCs (CD34+, CD34+/CD133+, and CD34+/CXCR4+) were independent predictors of all-cause death (hazard ratio 2.0, 1.6, 1.6-fold higher mortality, respectively; P<0.03) among HF patients. Endothelial-enriched PCs (CD34+/VEGF+) were independent predictors of mortality in patients with HF with preserved ejection fraction only (hazard ratio, 5.0; P=0.001). CONCLUSIONS: PC levels are lower in patients with HF, and lower PC counts are strongly and independently predictive of mortality. Strategies to increase PCs and exogenous stem cell therapies designed to improve regenerative capacity in HF, especially, in HF with preserved ejection fraction, need to be further explored.

Renal biomarkers and outcomes in outpatients with heart failure: The Atlanta cardiomyopathy consortium.

BACKGROUND/OBJECTIVES: Cystatin-C and beta-2-microglobulin may be superior to serum creatinine, blood urea nitrogen (BUN), or estimated glomerular filtration rate (eGFR) in patients hospitalized with heart failure (HF). We compared these renal markers in ambulatory HF patients. METHODS: We prospectively evaluated the association of baseline renal markers and eGFR (by 4 different formulas) with (1) the composite of death or HF-related hospitalization and (2) rates of hospitalizations and emergency department (ED) visits in 166 outpatients with HF (57.3±11.6years; 57.2% white, 38.6% black, median left ventricular ejection fraction 27.5% [17.5, 40.0]). RESULTS: After a median of 3.9years, 63 (38.0%) patients met the composite endpoint. There were 458 hospitalizations (177 [38.6%] for HF) and 209 ED visits (51 [24.4%] for HF). Cystatin-based eGFR most consistently predicted (1) the composite endpoint (highest-to-lowest tertile adjusted hazard ratio [HR] 4.92 [95% CI 2.07-11.7; P<0.001]); and (2) hospitalization rates, including HF hospitalizations (highest-to-lowest tertile, adjusted relative rate 5.24 [95% CI 1.61-17.01; P=0.006]). Serum creatinine alone was a strong predictor of the composite endpoint (highest-to-lowest tertile, adjusted HR 3.20 [95% CI, 1.51-6.78; P=0.002]). Only the highest tertile of BUN was associated with rates of ED visits. CONCLUSIONS: In outpatients with HF, cystatin-based eGFR provides consistent prognostication across outcomes, except ED visits. Serum creatinine is an adequate prognosticator of death or HF hospitalization.

The Right Ventricular Function After Left Ventricular Assist Device (RVF-LVAD) study: rationale and preliminary results.

AIMS: Despite improved outcomes and lower right ventricular failure (RVF) rates with continuous-flow left ventricular assist devices (LVADs), RVF still occurs in 20-40% of LVAD recipients and leads to worse clinical and patient-centred outcomes and higher utilization of healthcare resources. Preoperative quantification of RV function with echocardiography has only recently been considered for RVF prediction, and RV mechanics have not been prospectively evaluated. METHODS AND RESULTS: In this single-centre prospective cohort study, we plan to enroll a total of 120 LVAD candidates to evaluate standard and mechanics-based echocardiographic measures of RV function, obtained within 7 days of planned LVAD surgery, for prediction of (i) RVF within 90 days; (ii) quality of life (QoL) at 90 days; and (iii) RV function recovery at 90 days post-LVAD. Our primary hypothesis is that an RV echocardiographic score will predict RVF with clinically relevant discrimination (C >0.85) and positive and negative predictive values (>80%). Our secondary hypothesis is that the RV score will predict QoL and RV recovery by 90 days. We expect that RV mechanics will provide incremental prognostic information for these outcomes. The preliminary results of an interim analysis are encouraging. CONCLUSION: The results of this study may help improve LVAD outcomes and reduce resource utilization by facilitating shared decision-making and selection for LVAD implantation, provide insights into RV function recovery, and potentially inform reassessment of LVAD timing in patients at high risk for RVF.

Elevated Soluble Fms-Like Tyrosine Kinase-1 and Placental-Like Growth Factor Levels Are Associated With Development and Mortality Risk in Heart Failure.

BACKGROUND: Vascular endothelial dysfunction may play an important role in the progression of heart failure (HF). We hypothesize that elevated levels of vascular markers, placental-like growth factor, and soluble Fms-like tyrosine kinase-1 (sFlt-1) are associated with adverse outcomes in patients with HF. We also assessed possible triggers of sFlt-1 elevation in animal HF models. METHODS AND RESULTS: We measured plasma placental-like growth factor and sFlt-1 in 791 HF patients undergoing elective coronary angiogram. Median (interquartile range) placental-like growth factor and sFlt-1 levels were 24 (20-29) and 382 (277-953) pg/mL, respectively. After 5 years of follow-up, and after using receiver operator characteristic curves to determine optimal cutoffs, high levels of sFlt-1 (≥ 280 pg/mL; adjusted hazard ratio, 1.47; 95% confidence interval, 1.03-2.09; P=0.035) but not placental-like growth factor (≥ 25 pg/mL; adjusted hazard ratio, 1.26; 95% confidence interval, 0.94-1.71, P=0.12) were associated with adverse cardiovascular outcomes. In addition, significant elevation of sFlt-1 levels was observed in left anterior descending artery ligation and transverse aortic constriction HF mouse models after 4 and 8 weeks of follow-up, suggesting vascular stress and ischemia as triggers for sFlt-1 elevation in HF. CONCLUSIONS: Circulating sFlt-1 is generated as a result of myocardial injury and subsequent HF development. Elevated levels of sFlt-1 are associated with adverse outcomes in stable patients with HF.

Pulmonary function testing and outcomes in subjects with heart failure listed for heart transplantation.

BACKGROUND: Impaired spirometric parameters have been reported in patients with stage C heart failure and portend worse outcomes in these patients. The impact of spirometric parameters on outcomes in patients with stage D heart failure listed for heart transplantation is unknown. METHODS: We collected data on consecutive subjects listed for heart transplantation and examined the association of FEV1, FVC, and FEV1/FVC with (1) death or left ventricular assist device implantation (primary end point) and (2) death, left ventricular assist device implantation, or urgent transplantation (secondary end point). In a secondary analysis, we examined the association of baseline spirometry with post-transplant outcomes. RESULTS: Among 187 subjects (53 ± 10 y old, 17.1% women, 69.5% white subjects, 28.9% black subjects), there were 19 deaths, 28 left ventricular assist device implantations, and 74 urgent transplantations (primary end point of 25.1%, secondary end point of 64.7%) after a median of 5.5 months (interquartile range of 2.3-15.2). For FEV1, the hazard ratios for the primary and secondary end points were 0.93 (95% CI 0.61-1.41, P = .72) and 0.94 (95% CI 0.72-1.21, P = .62) per L, respectively. The hazard ratios of FVC were 0.90 (95% CI 0.65-1.25, P = .52) and 0.92 (95% CI 0.76-1.13, P = .43) per L, respectively. Impairment patterns (obstructive, restrictive, mixed) were not associated with risk for events. There was no interaction of spirometric parameters with smoking or lung disease for outcomes. Baseline spirometry was not associated with perioperative 30-d mortality (1.4%) and 1-y post-transplant survival (97.1%). CONCLUSIONS: In contrast to stage C subjects with heart failure, spirometric parameters were not associated with outcomes in this homogeneous stage D heart failure population.

Resting heart rate and risk of incident heart failure: three prospective cohort studies and a systematic meta-analysis.

BACKGROUND: The relationship between resting heart rate (RHR) and incident heart failure (HF) has been questioned. METHODS AND RESULTS: RHR was assessed at baseline in 7073 participants in 3 prospective cohorts (Cardiovascular Health Study, Health ABC study and Kuopio Ischemic Heart Disease Study) that recorded 1189 incident HF outcomes during 92 702 person-years of follow-up. Mean age of participants was 67 (9.9) years and mean RHR was 64.6 (11.1) bpm. Baseline RHR correlated (P<0.001) positively with body mass index (r=0.10), fasting glucose (r=0.18), and C-reactive protein (r=0.20); and inversely with serum creatinine (r=-0.05) and albumin (r=-0.05). Baseline RHR was non-linearly associated with HF risk. The age and sex-adjusted hazard ratio for HF comparing the top (>72 bpm) versus the bottom (<57 bpm) quartile of baseline RHR was 1.48 (95% confidence interval [CI] 1.26 to 1.74) and was modestly attenuated (1.30, 95% CI 1.10 to 1.53) with further adjustment for body mass index, history of diabetes, hypertension, smoking status, serum creatinine, and left ventricular hypertrophy. These findings remained consistent in analyses accounting for incident coronary heart disease, excluding individuals with prior cardiovascular events, or those taking beta-blockers; and in subgroups defined by several individual participant characteristics. In a pooled random effects meta-analysis of 7 population-based studies (43 051 participants and 3476 HF events), the overall hazard ratio comparing top versus bottom fourth of RHR was 1.40 (95% CI: 1.19 to 1.64). CONCLUSIONS: There is a non-linear association between RHR and incident HF. Further research is needed to understand the physiologic foundations of this association.

Soluble tumor necrosis factor receptors and heart failure risk in older adults: Health, Aging, and Body Composition (Health ABC) Study.

BACKGROUND: Tumor necrosis factor (TNF) levels are associated with risk for heart failure (HF). The soluble TNF type 1 (sTNF-R1) and type 2 (sTNF-R2) receptors are elevated in patients with manifest HF, but whether they are associated with risk for incident HF is unclear. METHODS AND RESULTS: Using Cox proportional hazard models, we examined the association between baseline levels of sTNF-R1 and sTNF-R2 with incident HF risk among 1285 participants of the Health, Aging, and Body Composition Study (age, 74.0±2.9 years; 51.4% women; 41.1% black). At baseline, median (interquartile range) of TNF, sTNF-R1, and sTNF-R2 levels was 3.14 (2.42-4.06), 1.46 (1.25-1.76), and 3.43 (2.95-4.02) ng/mL, respectively. During a median follow-up of 11.4 (6.9-11.7) years, 233 (18.1%) participants developed HF. In models controlling for other HF risk factors, TNF (hazard ratio [HR], 1.28; 95% confidence interval [CI], 1.02-1.61 per log2 increase) and sTNF-R1 (HR, 1.68; 95% CI, 1.15-2.46 per log2 increase), but not sTNF-R2 (HR, 1.15; 95% CI, 0.80-1.63 per log2 increase), were associated with a higher risk for HF. These associations were consistent across whites and blacks (TNF, sTNF-R1, sTNF-R2; interaction P=0.531, 0.091, and 0.795, respectively) and in both sexes (TNF, sTNF-R1, sTNF-R2; interaction P=0.491, 0.672, and 0.999, respectively). TNF-R1 was associated with a higher risk for HF with preserved versus reduced ejection fraction (HR, 1.81; 95% CI, 1.03-3.18; P=0.038 for preserved versus HR, 0.90; 95% CI, 0.56-1.44; P=0.667 for reduced ejection fraction; interaction P=0.05). CONCLUSIONS: In older adults, elevated levels of sTNF-R1 are associated with increased risk for incident HF. However, addition of TNF-R1 to the previously validated Health ABC HF risk model did not demonstrate material improvement in net discrimination or reclassification.