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Real-life data for vaccination against COVID-19 are sorely needed. This was a population-based analysis aiming at investigating the hospitalization risk for COVID-19 of 98,982 subjects and compare features of vaccinated and unvaccinated patients.Hospitalized patients with COVID-19 between 01/07/2021 and 11/02/2022 were included in the study.582 patients were included in the analysis [males: 58.6% (n=341), vaccinated patients: 28.5% (n=166), unvaccinated patients: 71.5% (n=416)]. Median age of vaccinated patients was significantly higher compared to median age of unvaccinated [74.0 (95% CI: 72.0-77.0) vs. 59.0 (95% CI: 57.0-62.0), p=0.0001]. Mean latency time (±SD) from the second dose to hospitalization was 5.7±2.6 months. Between 01/07/2021 and 01/12/2021, unvaccinated subjects had higher risk for hospitalization compared to vaccinated [HR: 2.82, 95% CI: 2.30-3.45, p0.0001]. Between 02/12/2021 and 11/02/2022, unvaccinated subjects presented with higher risk for hospitalization than subjects that had received booster dose [HR: 2.07, 95% CI: 1.44-2.98, p=0.005], but not than subjects that got two doses. Median value of hospitalization days was higher in unvaccinated patients compared to vaccinated [7.0 (95% CI: 7.0-8.0) vs. 6.0 (95% CI: 5.0-7.0), p=0.02]. Finally, age-adjusted analysis showed that hospitalized unvaccinated patients presented with significantly higher mortality risk compared to hospitalized vaccinated patients [HR: 2.59, 95% CI: 1.69-3.98, p0.0001].Vaccination against COVID-19 remains the best way to contain the pandemic. There is an amenable need for booster dose during the omicron era.

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±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

Background Data on the safety and efficacy profile of tocilizumab in patients with severe COVID-19 needs to be enriched. Methods In this open label, prospective study, we evaluated clinical outcomes in consecutive patients with COVID-19 and PaO2/FiO2 2/FiO2 2/FiO2 at day 5 and change in WHO progression scale at day 10. Findings Overall, 114 patients were included in the analysis (tocilizumab plus usual care: 56, usual care: 58). Allocation to usual care was associated with significant increase in 28-day mortality compared to tocilizumab plus usual care [Cox proportional-hazards model: HR: 3.34, (95% CI: 1.21–9.30), (p = 0.02)]. There was not a statistically significant difference with regards to hospital discharge over the 28 day period for patients receiving tocilizumab compared to usual care [11.0 days (95% CI: 9.0 to 16.0) vs 14.0 days (95% CI: 10.0–24.0), HR: 1.32 (95% CI: 0.84–2.08), p = 0.21]. ΔPaO2/FiO2 at day 5 was significantly higher in the tocilizumab group compared to the usual care group [42.0 (95% CI: 23.0–84.7) vs 15.8 (95% CI: − 19.4–50.3), p = 0.03]. ΔWHO scale at day 10 was significantly lower in the tocilizumab group compared to the usual care group (-0.5 ± 2.1 vs 0.6 ± 2.6, p = 0.005). Conclusion Administration of tocilizumab, at the time point that PaO2/FiO2

Limited data exist on the course of left ventricle ejection fraction (LVEF) among outpatients with heart failure (HF) and preserved ejection fraction (HFpEF) and its impact on outcomes. We evaluated 322 consecutive outpatients with confirmed HF, LVEF40%, no previous LVEF ≤40%, and no specific cardiomyopathies or primary right-sided or valvular heart disease. Median age was 73 years (interquartile range: 63 to 82); 57.1% were women, 50.3% White, and 45.0% Black; median LVEF was 55% (50% to 60%); and 45.6% had coronary artery disease. After a median of 37 months (32 to 38) and 4.5 follow-up echocardiograms (4 to 6) per patient, 11.4% of patients (95% confidence interval [CI] 5.2% to 17.7%) developed LVEF40%. The average drop in LVEF among these patients was 19.4 units (95%CI 15.0 to 23.8) to an average LVEF of 30.3% (95%CI 27.4% to 33.2%). Baseline systolic blood pressure130 mm Hg was associated with more LVEF decline. During follow-up, 50 patients died (3-year mortality 15.3%) and 67 additional patients were hospitalized for HF (3-year death plus HF hospitalization 35.6%). Development of LVEF40% was subsequently followed by 5-fold higher mortality in time-updated models (adjusted HR 4.91; 95%CI 2.00 to 12.0; p = 0.001) and 3.5-fold higher rates of death or HF hospitalization (adjusted HR 3.70; 95%CI 1.67 to 8.19; p = 0.001). Interval coronary events were infrequent (10%) among patients with deteriorated LVEF. The impact of LVEF changes on outcomes was similar in White and Black patients. In conclusion, a proportion of patients with HFpEF will develop reduced LVEF over time. These patients have worse prognosis subsequently.

The recent pandemic caused by the novel coronavirus resulted in the greatest global health crisis since the Spanish flu pandemic of 1918. There is limited knowledge of whether SARS-CoV-2 is physically associated with human metalloproteins. Recently, high-confidence, experimentally supported protein-protein interactions between SARS-CoV-2 and human proteins were reported. In this work, 58 metalloproteins among these human targets have been identified by a structure-based approach. This study reveals that most human metalloproteins interact with the recently discovered SARS-CoV-2 orf8 protein, whose antibodies are one of the principal markers of SARS-CoV-2 infections. Furthermore, this work provides sufficient evidence to conclude that Zn2+ plays an important role in the interplay between the novel coronavirus and humans. First, the content of Zn-binding proteins in the involved human metalloproteome is significantly higher than that of the other metal ions. Second, a molecular linkage between the identified human Zn-binding proteome with underlying medical conditions that might increase the risk of severe illness from the SARS-CoV-2 virus has been found. Likely perturbations of host cellular metal homeostasis by SARS-CoV-2 infection are highlighted., Graphical abstract Unlabelled Image

BACKGROUND: We conducted a pilot study to assess feasibility, on-study retention, trends in natriuretic peptide levels, quality of life (QoL), and safety of a 12-week feeding trial with 1500-mg vs. 3000-mg daily sodium meals in high-risk patients with heart failure (HF). METHODS: Of 196 patients with recent (≤2 weeks) hospitalization for HF, ejection fraction ≤40%, on optimal medical therapy, functionally independent, and able to communicate, 83 (47%) consented to participate. Of these, 27 (age, 62±11 years; 22 men; 20 White; ejection fraction, 26±8%) had 24-h urine sodium ≥3000 mg and agreed to randomly receive either 1500-mg (N=12) or 3000-mg (N=15) sodium meals. RESULTS: On-study retention at 12 weeks was 77% (82% vs. 73%; P=0.53); 6 patients (2 in 1500-mg, 4 in 3000-mg arm) withdrew before study completion. Food satisfaction questionnaires indicated that both diets were well tolerated. QoL improved in the 1500-mg arm at 12 weeks but did not change in the 3000-mg arm. Average compliance with meals was 52% (based on urinary sodium) and was not significantly different between arms (42% vs. 60%; P=0.25). Study meals reduced 24-h urinary sodium by 137±21 mmol (1500-mg arm) and 82±16 mmol (3000-mg arm), both P0.5mg/dL over baseline only occurred in 1 patient in the 3000-mg arm. CONCLUSIONS: Even with prepared meals, investigating optimal dietary sodium in HF comes with challenges, including need for extensive screening, reluctance to participate, and compliance issues. Because both diets reduced urinary sodium without adverse safety or QoL signals, a larger trial, with modifications to improve participation and compliance, would be ethical and feasible. CLINICAL TRIAL REGISTRATION: www.clinicaltrials.gov NCT02467296

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.

Background The Patient Health Questionnaire 9 (PHQ-9) is an effective tool for identification and grading of depression symptoms. Data on PHQ-9 utility for patients with heart failure (HF) are limited. Methods We evaluated the severity of depression by PHQ-9 at baseline and its association with health care resource utilization (HCRU) rates and quality of life (QoL) in 308 outpatients enrolled in a prospective HF cohort study. Depression symptoms were stratified according to PHQ-9 score as minimal (0–4), mild (5–9), or moderate-to-severe (10–27). Results Mean age of patients was 57±11years; 65% were men; 50% were white and 47% black; ejection fraction was 30±15%. Over 24±12months (total: 625person-years), there were 41 (13.3%) major clinical events (34 deaths, 5 transplants, 2 ventricular assist device implantations), 633 all-cause admissions (249 [39.3%] for HF), and 362 emergency department (ED) visits. Moderate-to-severe depressive symptoms were associated with 70% more all-cause admissions compared to patients without depressive symptoms and 2.5 times more HF-related admissions. However, less than 50% of patients with moderate-to-severe symptoms were on antidepressants. In adjusted analyses, even mild depressive symptoms were associated with 57% more all-cause admissions compared to patients without depressive symptoms and more than 2-fold higher rate of HF-related admissions. Depressive symptoms were not associated with ED visits. Increasing PHQ-9 score was associated with progressively worse QoL. PHQ-9 was not associated with major clinical events. Conclusions PHQ-9 effectively identifies HF patients at risk for increased HCRU and lower QoL. Interventions to reduce depression symptoms may help improve HF outcomes.

Background Enrollment criteria used in advanced heart failure (HF) clinical trials might identify a common set of widely accepted quantitative characteristics as the basis of a consensus definition for advanced HF, which is currently lacking. Methods We reviewed all clinical trials investigating interventions in patients with advanced HF as of July 31, 2015. Eligible publications (N = 134) reported original data from clinical trials explicitly defining advanced HF in adults. Results New York Heart Association (NYHA) class was the most common criterion (119 trials, 88.8%; classes ranged from II to IV), followed by left ventricular ejection fraction (LVEF) (84 trials, 62.7%; cutoff range, 20% to 45%; mode 35%). Other criteria included inotrope-dependent status (12.7%), peak oxygen consumption (10.4%), ≥1 previous HF admissions (10.4%), cardiac index (10.4%), pulmonary capillary wedge pressure (9.0%), left ventricular end-diastolic diameter (6.0%), and transplant listing status (5.2%). Cutoff points for quantitative criteria varied considerably. Previous HF admission was more frequently required in recent trials ( P = .007 for temporal trend), whereas use of hemodynamic criteria decreased over time ( P = .050 for temporal trend). Average LVEF among participants increased over time. Conclusions There is considerable variation in the definition of advanced HF for clinical trial purposes. Beyond NYHA and LVEF, a wide array of criteria has been used, with little consistency both in criteria selection and quantitative cutoff points.

Background A systematic assessment of the temporal trends in heart failure (HF) clinical trials is lacking. Methods and Results A total of 154 phase II–IV HF trials including 162,725 patients published from 2001 to 2012 in 8 high-impact-factor journals were reviewed. The median number of participants and sites per trial were 367 (interquartile range [IQR] 133-1450) and 38 (5–101), respectively. Median enrollment duration was 2.2 (1.5–3.3) years. The majority of studies investigated treatment for chronic HF (82.5%) and investigated HF with reduced ejection fraction (EF) (71.4%), whereas 27 trials (17.5%) enrolled patients with mixed EF and 9 (5.8%) enrolled HF with preserved EF patients alone. Enrollment rates did not significantly change over time (median 0.49 patients site −1 month −1 , IQR 0.34–0.98; P = .53). Trials meeting their primary end point decreased over time from 73.5% in 2001–2003 to 52.5% in 2010–2012 ( P = .08) and were more often smaller and used nonmortality end points. Industry trials were larger with shorter enrollment duration, more concentrated in North America, and more likely to be positive. Trials conducted exclusively outside North America and Western Europe had the highest enrollment rates (median 1.95 patients site −1 month −1 , IQR 1.34–4.11). Conclusions Contemporary HF clinical trials display slow enrollment rates and decreased rates of positive outcomes over time. Positive trials tended to be smaller size with a higher proportion of surrogate end points.

An operational consensus definition of Stage D heart failure (HF) is currently lacking.We evaluated 512 outpatients (median age, 63 years; 35.0% women; 45.5% white and 45.9% black; median ejection fraction was 25%; 67.4% had coronary artery disease) with HF and reduced (≤40%) ejection fraction. We applied 3 hypothetical definitions for Stage D: (1) designation as "Stage D" or "advanced" HF by treating physician; (2) INTERMACS profiles, defining Stage D as profiles 2-6; and (3) European Society of Cardiology Heart Failure Association (ESC-HFA) criteria.Physicians, INTERMACS profiles, and ESC-HFA criteria identified 64 (12.5%), 93 (18.2%), and 67 (13.1%) patients, respectively, as Stage D, with modest concordance between definitions (κ = 0.37). After a median of 3.1 years, 97 patients died (3-year mortality 20.4%). Among patients identified as Stage D by physicians, 3-year mortality was 43.7% vs. 17.0% for non-Stage D patients (age-adjusted hazard ratio [HR] 3.17; 95%CI 1.94-5.18; P 0.001). The corresponding mortalities for the INTERMACS-based definition were 41.0% vs. 16.2% (HR 3.28; 95%CI 2.11-5.11; P 0.001) and for ESC-HFA criteria 33.5% vs. 18.6% (HR 2.02; 95%CI 1.22-3.33; P = 0.006); the INTERMACS-based definition provided the best prognostic separation. Results were similar with an alternative INTERMACS-based definition considering only profiles 2-5 as Stage D HF. The INTERMACS-based definition best separated all-cause and HF-specific hospitalization and composite endpoint risk between Stage D and non-Stage D patients also.INTERMACS profiles provide a practical alternative for the identification of Stage D HF in ambulatory populations with systolic HF. The ESC-HFA criteria offer limited prognostic information.

Background Several clinical prediction schemes for right ventricular failure (RVF) risk after left ventricular assist device (LVAD) implantation have been developed in both the pulsatile- and continuous-flow LVAD eras. The performance of these models has not been evaluated systematically in a continuous-flow LVAD cohort. Methods We evaluated 6 clinical RVF prediction models (Michigan, Penn, Utah, Kormos et al, CRITT, Pittsburgh Decision Tree) in 116 patients (age 51 ± 13 years; 41.4% white and 56.0% black; 66.4% men; 56.0% bridge to transplant, 37.1% destination therapy, 17.4% bridge to decision) who received a continuous-flow LVAD (HeartMate II: 79 patients, HeartWare: 37 patients) between 2008 and 2013. Results Overall, 37 patients (31.9%) developed RVF, defined: as pulmonary vasodilator use for ≥48 hours or inotrope use for ≥14 days post-operatively; re-institution of inotropes; multi-organ failure due to RVF; or need for mechanical RV support. Median (Quartile 1 to Quartile 3) time to initial discontinuation of inotropes was 6 (range 4 to 8) days. Among scores, the Michigan score reached significance for RVF prediction but discrimination was modest (C = 0.62 [95% CI 0.52 to 0.72], p = 0.021; positive predictive value [PPV] 60.0%; negative predictive value [NPV] 75.8%), followed by CRITT (C = 0.60 [95% CI 0.50 to 0.71], p = 0.059; PPV 40.5%; NPV 72.2%). Other models did not significantly discriminate RVF. The newer, INTERMACS 3.0 definition for RVF, which includes inotropic support beyond 7 days, was reached by 57 patients (49.1%). The Kormos model performed best with this definition (C = 0.62 [95% CI 0.54 to 0.71], p = 0.005; PPV 64.3%; NPV 59.5%), followed by Penn (C = 0.61), Michigan (C = 0.60) and CRITT (C = 0.60), but overall score performance was modest. Conclusion Current schemes for post-LVAD RVF risk prediction perform only modestly when applied to external populations.

Device uptake and development have progressed over the last decade, but few quantitative data exist examining the overall operating characteristics and temporal trends of these clinical trials. We performed a systematic analysis of all cardiovascular device clinical trials from 2001 to 2012 published in medical and cardiovascular journals with the 8 highest impact factors. Of the 1,224 identified cardiovascular clinical trials, 299 (24.4%) focused specifically on devices. Each trial included a median of 335 patients (162 to 745) recruited from a median of 14 sites (3 to 38) over a median enrollment duration of 1.9 years (1.2 to 3.3). Median enrollment rate was 1.1 patients/site/month (0.5 to 4.2). Most device trials targeted coronary artery disease (55.2%), followed by arrhythmias (17.4%). Most were industry sponsored (53.6%) and included mortality as a primary end point (69.6%). The median number of patients (225 to 499, p0.001 for trend) and enrolling sites (11 to 19, p = 0.07 for trend) increased from 2001 to 2012. During the study period, multinational enrollment grew and approached 50% (p = 0.03), whereas trials enrolling in North America exclusively decreased from 30% to 17% (p = 0.10 for trend). Approximately 70% of device trials met their primary end points; this rate did not significantly change over time. In conclusion, this descriptive study of the contemporary cardiovascular device clinical trials highlights recent trends toward larger, more international trial programs. These aggregate data may help inform future cardiovascular device development.

In the past 2 decades, heart failure (HF) research has focused primarily on drugs and devices. In contrast, evidence remains scarce and mostly observational for dietary sodium restriction,1–3 arguably the most widely recommended self-care measure for patients with HF. In recent studies, patients with HF consumed an average of 3600 to 4200 mg sodium daily by 24-hour urinary sodium excretion,4 with 65% consuming >3000 mg.5 Although the evidence suggests that high-sodium intake worsens outcomes, the level of sodium intake that achieves optimal outcomes for patients with HF is unknown.6–12 All current guidelines emphasize sodium intake restriction; however, there is no consensus on the actual level. Recommendations are either nonspecific or ranging between 2000 and 3000 mg/d,9 largely based on opinions or observational studies. In explicit acknowledgment of the evidence gap, the recent European Society of Cardiology guidelines for HF12 have not assigned a level of evidence to sodium intake recommendations. The recent American College of Cardiology Foundation and American Heart Association guidelines recommend (class IIa) that sodium restriction is reasonable for patients with HF with congestive symptoms, but do not recommend a specific target level.13 The inconsistency of guidelines underlines the weak database that supports this cornerstone treatment. Current data indicate limited adherence with recommended sodium restriction among patients with HF. In a recent interventional study, when instructed to limit sodium intake to 2500 mg/d, patients with HF averaged a daily intake of 2700 to 3900 mg/d by 24-hour urinary sodium, depending on the assigned arm, after 8 months of intervention.4 Sodium intake reduction is difficult to adhere to even among patients with symptomatic HF, with less than one third of patients reporting sodium intake ≤2500 mg/d by 3-day food diaries, which underestimate actual sodium intake.4 Congruent …

Advances in medical therapies leading to improved patient outcomes are in large part related to successful conduct of clinical trials that offer critical information regarding the efficacy and safety of novel interventions. The conduct of clinical trials in the United States, however, continues to face increasing challenges with recruitment and retention. These trends are paralleled by an increasing shift toward more multinational trials where most participants are enrolled in countries outside the United States, bringing into question the generalizability of the results to the American population. This manuscript presents the perspectives and recommendations from clinicians, researchers, sponsors, and regulators who attended a meeting facilitated by the Food and Drug Administration to improve upon the current clinical trial trends in the United States.

Objectives The purpose of this study was to assess the frequency and correlates of documented advance directives (ADs) among patients hospitalized for heart failure (HF). Background Discussing ADs with patients with HF is critical for identifying treatment goals consistent with patients' values and preferences and for facilitating health care team communication. Methods We retrospectively identified electronic medical records of adult patients admitted to 2 large tertiary care hospitals with either the primary or secondary discharge diagnosis of HF from September 2008 to August 2013 to assess the presence of ADs in electronic medical records. We performed analyses including HF as either the primary or secondary admission diagnosis and HF as the primary admission diagnosis only. Multivariable models were constructed to investigate independent predictors of documented ADs. Results Data included 44,768 admissions from 24,291 individual patients over 5 years. Mean age of patients at admission was 64.8 ± 15.9 years; 47.9% of these patients were female, 51.8% were black. The median length of stay for all admissions was 5 (3 to 10) days; 12.7% of patients had documented ADs. Older age, female sex, white race, higher socioeconomic status, higher risk for adverse in-hospital outcomes, length of stay ≥5 days, hospice discharge, palliative care consultation, and a do-not-resuscitate order were all associated with a significantly higher chance of having documented ADs. A significant increase in ADs over time was noted, but more than 80% of patients did not have ADs in medical records at the end of the study period. Conclusions In a diverse population of hospitalized patients with HF, most did not have a documented AD in the medical records. Although several factors were associated with a higher probability, major opportunities exist for all subgroups of patients with HF to improve documentation of ADs.

INTRODUCTION Data on the association between exercise capacity and risk for heart failure (HF) in older adults are limited. METHODS This study examined the association of exercise capacity, and its change over time, with 10-year mortality and incident HF in 2,935 participants of the Health, Aging, and Body Composition Study without HF at baseline (age, 73.6 [SD=2.9] years; 52.1% women; 41.4% black; 58.6% white). This cohort was initiated in 1997-1998 and exercise capacity was evaluated with a long-distance corridor walk test (LDCW) at baseline and Year 4. Outcomes were collected in 2007-2008 and initial analysis performed in 2014. RESULTS Ten-year incident HF for completers (n=2,245); non-completers (n=331); and those excluded from LDCW for safety reasons (n=359) was 11.4%, 19.2%, and 23.0%, respectively. The corresponding 10-year mortality was 27.9%, 41.1%, and 42.4%. In models accounting for competing mortality, the adjusted subhazard ratio for HF was 1.37 (95% CI=1.00, 1.88; p=0.049) in non-completers and 1.41 (95% CI=1.06, 1.89; p=0.020) in those excluded versus completers. Non-completers (adjusted hazard ratio, 1.49; 95% CI=1.21, 1.84; p

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 log 2 increase) and sTNF-R1 (HR, 1.68; 95% CI, 1.15–2.46 per log 2 increase), but not sTNF-R2 (HR, 1.15; 95% CI, 0.80–1.63 per log 2 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.

Renal dysfunction (RD) is a frequent comorbid condition and a major determinant of outcomes in patients with heart failure (HF). It is likely that the etiology of RD in patients with HF is much more complex than we first thought and represents a matrix of independent, albeit interacting, pathophysiological pathways with effects on both the kidney and the heart that share a common denominator: aging and inflammation. Renal dysfunction in HF has been attributed, among others, to biochemical, hormonal, and hemodynamic factors, coupled with pharmacological interventions. Regardless of the cause, the development of RD or worsening renal function is common in patients with HF, and is associated with increased morbidity and mortality. There is increasing evidence, however, that transient increases in creatinine in the setting of acute HF are not prognostically important, whereas persistent deterioration does portend a higher mortality in this patient population. In addition, congestion seems to play an important role in the course of renal deterioration, and the combination of congestion and worsening renal function is the most significant clinical prognosticator in HF patients. This review aims to provide an update on the epidemiology and prognostic significance of RD in HF patients, in both the acute and the chronic setting.

The number of hospitalizations for acute heart failure (HF) continues to increase and it remains the most common discharge diagnosis among Medicare beneficiaries. Prognosis after hospitalization for HF is poor, with high in-hospital mortality and even higher post-discharge mortality and rehospitalization rates. It is a complex clinical syndrome that varies widely with respect to clinical presentation and underlying pathophysiology. This paper reviews what is documented in the literature regarding the known pathophysiologic mechanisms reported in patients hospitalized for HF.

Despite low inpatient mortality and effective symptomatic management, patients hospitalized for heart failure (HHF) experience high postdischarge mortality and rehospitalization rates. HHF represents a widely heterogeneous population with distinct clinical subsets that may require tailored management approaches. Despite this, however, HHF patients are almost uniformly managed with intravenous diuretics, with low uptake of new therapies during hospitalization. This article proposes a practical approach to classifying HHF patients that is focused on guiding individualized inpatient and postdischarge management. HHF is not a single disease but a manifestation of several cardiac and noncardiac processes and thus should be approached as such.

Objectives The objective was to compare readmission rates and hospital bed-days between acute decompensated heart failure (AHF) patients admitted or discharged following accelerated treatment protocol (ATP)-driven care in an emergency department observation unit (OU). Methods This was a retrospective cohort study conducted at two urban university-affiliated hospitals. A total of 358 selected AHF patients received treatment on an ATP in the OU between October 1, 2007, and June 30, 2011. The comparison of interest was admission or discharge following OU treatment. The outcome of interest was readmission within 30 and 90 days of hospital discharge following care in the OU. We also examined resource use (inpatient, inpatient plus outpatient-days) between the admitted and discharged groups. Time to readmission analysis was performed with Cox proportional hazards regression. Results Discharged and admitted patients were similar with respect to age, race, sex, ED length of stay (LOS), and OU LOS. Patients admitted from the OU had a higher median B-type natriuretic peptide (BNP; 1,063 pg/mL [interquartile range {IQR} = 552 to 2,067 pg/mL] vs. 708 pg/mL [IQR = 254 to 1,683 pg/mL]; p = 0.002) and blood urea nitrogen (BUN; 19 mg/dL [IQR = 14 to 26 mg/dL] vs. 17 mg/dL [IQR = 13 to 23 mg/dL]) than those discharged (p = 0.04) and a lower median ejection fraction (EF; 22.5% [15% to 43%] vs. 35% [IQR 20% to 55%]; p = 0.002). In models controlling for age, race, sex, clinical site, BNP, BUN, creatinine, and EF, the 30-day readmission rate (13.8% in the study population as a whole) was not significantly different between the patients discharged or admitted following OU care (hazard ratio [HR] = 0.99; 95% confidence interval [CI] = 0.47 to 2.10). The readmission rates were also not significantly different at 90 days (HR = 1.07; 95% CI = 0.65 to 1.77). Within 30 days of discharge from the OU, patients spent a median of 1.7 days (IQR = 0.0 to 5.1 days) as inpatients, compared to 3.5 days (IQR = 2.3 to 5.8 days) among patients admitted from the OU (p

Pulmonary hypertension (PH) secondary to left-sided heart disease (Group 2 PH) is a frequent complication of heart failure (HF) that worsens exercise capacity, risk for hospitalization, and survival independent of left-ventricular ejection fraction (LVEF) or stage of HF. Increased pulmonary artery pressure (PAP) in patients with HF often represents a combination of increased left-sided filling pressures (passive component) and elevated pulmonary vascular resistance (PVR) attributable to functional and structural abnormalities of the pulmonary vascular bed (reactive component). The latter may be reversible with standard HF treatment in the earlier stages, when remodeling of the pulmonary vasculature has not set in, and abnormalities in pulmonary arterial tone are the major driver for elevated PVR. However, chronic exposure to elevated pulmonary capillary wedge pressure (PCWP) may lead to permanent changes in the pulmonary arterial bed (irreversible or fixed PH).1 Considering that a number of drug classes have successfully modified the natural history of pulmonary arterial hypertension (Group 1 PH) and demonstrated that intervention is possible even after pulmonary vascular remodeling has occurred,2 Group 2 PH is a natural target for screening and potential intervention in patients with HF. In the second part of this 2-part review, we discuss the prognostic impact of PH in HF, the contemporary diagnostic and evaluation approaches, the current evidence from clinical studies in Group 2 PH, the challenges of appropriate patient selection in clinical trials, and potential ways to overcome these challenges in trial designs. ### Echocardiographic Studies Studies using either right heart catheterization (RHC) or echocardiography for determination of PAP have consistently shown that PH considerably worsens prognosis in HF. Abramson et al3 first reported that tricuspid regurgitation jet velocity >2.5 m/s was associated with 3.4 times higher mortality in 108 patients with dilated cardiomyopathy followed for up to 28 months; hospitalization rate for HF was …

This study sought to estimate the rate of progression to Stage D heart failure (HF) among outpatients with Stage C HF and to identify risk factors for progression.The pool of patients who may be candidates for advanced HF therapies is growing.We estimated 3-year progression to clinically determined Stage D HF and competing mortality among 964 outpatients with Stage C heart failure with reduced ejection fraction (HFrEF), where ejection fraction is ≤40%.The mean age of patients was 62 ± 15 years; 35% were women; 47% were white; 46% were black, and 7% were of other races; median baseline ejection fraction was 28% (25th to 75th percentile: 20% to 35%); and 47% had ischemic heart disease. After 3.0 years (25th to 75th percentile: 1.7 to 3.2 years), 112 patients progressed to Stage D (3-year incidence: 12.2%; 95% confidence interval [CI]: 10.2% to 14.6%; annualized: 4.5%; 95% CI: 3.8% to 5.5%), and 116 patients died before progression (3-year competing mortality: 12.9%; annualized: 4.7%; 95% CI: 3.9% to 5.6%). By 3 years, 25.1% of patients (95% CI: 22.2% to 28.1%) had either progressed to Stage D or died (annualized: 9.2%; 95% CI: 8.1% to 10.5%). Annualized progression rates were higher in black versus white patients (6.3% vs. 2.7%, respectively; p 0.001), nonischemic versus ischemic patients (6.1% vs. 2.9%, respectively; p 0.001), and in New York Heart Association functional class III to IV versus I to II patients (7.5% vs. 1.9%, respectively; p 0.001) but were similar for men and women (4.7% vs. 4.2%, respectively; p = 0.53). Lower ejection fraction and blood pressure, renal and hepatic dysfunction, and chronic lung disease rates were additional predictors of progression. Predictors of competing mortality were different from those of disease progression.Among patients with Stage C HFrEF receiving care in a referral center, 4.5% progressed to Stage D HF each year, with earlier progression among black and nonischemic patients. These findings have implications for healthcare planning and resource allocation for these patients.

The burden of heart failure with preserved ejection fraction (HFpEF) is considerable and is projected to worsen. To date, there are no approved therapies available for reducing mortality or hospitalizations for these patients. The pathophysiology of HFpEF is complex and includes alterations in cardiac structure and function, systemic and pulmonary vascular abnormalities, end-organ involvement, and comorbidities. There remain major gaps in our understanding of HFpEF pathophysiology. To facilitate a discussion of how to proceed effectively in future with development of therapies for HFpEF, a meeting was facilitated by the Food and Drug Administration and included representatives from academia, industry, and regulatory agencies. This document summarizes the proceedings from this meeting.

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.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]).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; P0.001]); 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.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.

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.

Diabetes is a chronic metabolic disease that has reached epidemic proportions, affecting millions of individuals worldwide, and the global prevalence of the disease is expected to increase exponentially. Diabetes is associated with substantial mortality, morbidity, and healthcare expenditure. Cardiovascular complications are the major cause of mortality and morbidity in individuals with diabetes and the largest contributor to the overall cost of diabetes. More than 60% of deaths in patients with diabetes have an underlying cardiovascular cause. Patients with diabetes have 2- to 4-fold higher risk of developing cardiovascular disease than individuals without diabetes [1]. Atherosclerosis has long been recognized as the main causative factor for cardiovascular events in patients with diabetes. Emerging evidence suggests that changes in circulating blood (e.g., inflammatory mediators, altered platelet function, hypercoagulability, hypofibrinolysis, and microparticles) and myocardial factors (e.g., altered metabolic state and neural and vascular impairment) may also play equally important roles in the pathophysiologic process underlying the increased propensity for cardiovascular disease in individuals with diabetes. In this special issue, we have invited a few papers that address such issues. Heart Failure and Diabetes. People with diabetes have an increased risk of developing heart failure, both as a consequence of coronary artery disease and as a result of cardiomyopathy, which may be due to a microangiopathy or primary cardiomyocyte dysfunction. Indeed, diastolic left ventricular dysfunction is a consistent observation through all levels of glucose intolerance [2]. Dr. K. Hensel et al. investigated whether speckle tracking echocardiography can be used to detect subclinical alterations of left ventricular myocardial deformation in asymptomatic pediatric patients with uncomplicated T1DM. Furthermore, they combined speckle tracking echocardiography with physical stress testing in order to unmask subtle changes of cardiac contractility that might potentially be occult at rest (for and against the existence of diabetic cardiomyopathy). With their results they provide further evidence for diabetes-associated nonischemic cardiomyopathy in T1DM patients as they describe the early stage of diabetic cardiomyopathy which is initiated by hyperglycemia, has insignificant changes in myocardial structure (normal left ventricular dimensions, wall thickness, and mass), has possible substructural changes in myocytes, and can only be detected by sensitive methods such as strain, strain rate, and myocardial tissue velocity. In another study Dr. L. Leon et al. discuss the current scientific evidences to propose circulating micro-RNA as promising biomarkers for early detection of diabetic cardiomyopathy and then to identify patients at high risk of diabetic cardiomyopathy development. Moreover, they summarize the research strategies to identify micro-RNA as potential biomarkers, the present limitations, challenges, and future perspectives. Volatile anesthetics, like sevoflurane, have cardiodepressive effects and may aggravate cardiovascular complications intraoperatively. Preservation of myocardial perfusion during surgery is particularly important in patients with increased risk for perioperative complications, such as diabetes. As sevoflurane's vasodilatory impact may be more abundant in patients with cardiometabolic disease, like T2DM, Dr. C. E. van den Brom et al. investigated the additional effect of sevoflurane anesthesia on myocardial perfusion and function in diet-induced prediabetic rats. Hyperglycemia is associated with altered myocardial substrate use, a condition that has been hypothesized to contribute to impaired cardiac performance. It is caused to a great extent by change of energy metabolism, which is an additional trigger of functional and structural disorders of heart muscle. In turn, remodeling of the cardiomyocyte membranes with advanced glycation end products and free radical oxidation is essential factor in development of diabetes mellitus. Dr. S. Afanasiev et al. showed that in the experimental conditions induction of DM on the stage of formation of postinfarction remodeling increases adaptive ability of myocardium. It is manifested in inhibition of increase in lipid peroxidation processes activity and maintaining of force-interval reactions of myocardium connected with calcium transport systems of cardiomyocyte sarcoplasmic reticulum. Antiplatelet Therapy in Diabetes. The ADP receptor P2Y12 plays a pivotal role in platelet aggregation [3]. This role is emphasized by the results of clinical trials that demonstrate improvement of long-term clinical outcomes in patients treated with the P2Y12 receptor antagonist clopidogrel. However, a high interindividual variability in platelet response to clopidogrel has been described. The fact that subjects with suboptimal platelet inhibition by clopidogrel are at increased risk of cardiovascular ischemic events represents an alarming clinical problem [4]. T2DM was recently connected with a failure in antiplatelet response to clopidogrel and the presence of high on-treatment platelet reactivity was repeatedly associated with the risk of ischemic adverse events. Patients with T2DM show significantly higher residual platelet reactivity on ADP receptor blocker therapy and are more frequently represented in the group of patients with high on-treatment platelet reactivity. The article by Dr. M. Samos et al. reviews the current knowledge about possible interactions between T2DM and ADP receptor blockers therapy. Heart Rate and Diabetes. Elevated resting heart rate has been associated with increased risk of all-cause mortality and cardiovascular events in healthy subjects as well as those with preexisting cardiovascular disease including hypertension, acute myocardial infarction, and heart failure or left ventricular dysfunction by numerous epidemiological studies [5]. However, limited data are available in T2DM patients. In an interesting study, Dr. V. Bartakova et al. evaluated whether resting heart rate could be a predictor of major cardiovascular events, progression of diabetic kidney disease, and all-cause mortality in a cohort of T2DM patients. Adipose Tissue and Insulin Resistance. Adipose tissue accumulates both within and around internal organs with potential to negatively alter their biological function. Functional abnormalities of the adipose tissue are linked to inflammation, metabolic dysregulation, vascular dysfunction, impaired angiogenesis, and insulin resistance. Interest has focused on the potential role of epicardial adipose tissue as a modulator of cardiovascular function, owing to its immediate anatomic proximity to the coronary vasculature and myocardium with shared microcirculation [6]. Evidence suggests that epicardial adipose tissue could play a role in the pathogenesis of cardiovascular disease and is also potentially involved in the onset and progression of coronary artery disease. Increased expression of receptor for advanced glycation end products (RAGE) in adipose tissue has been associated with inflammation, adipocyte hypertrophy, and impaired insulin signal. The potential role of RAGE in epicardial adipose tissue has not been explored much. The study by Dr. E. Dozio et al. examined the RAGE expression in epicardial adipose tissue and suggests potential involvement in promoting epicardial adipose tissue dysfunction in coronary artery disease patients. We hope that the readers of the journal will find the topics as interesting and important as we did. John Skoularigis Andreas Melidonis Dirk Westermann Vasiliki V. Georgiopoulou Georgios Karagiannis Gregory Giamouzis

Outcomes for heart failure (HF) patients remain suboptimal. No known therapy improves mortality in acute HF and HF with preserved ejection fraction; the most recent HF trial results have been negative or neutral. Improvement in surrogate markers has not necessarily translated into better outcomes. To translate breakthroughs with potential therapies into clinical benefit, a better understanding of the pathophysiology establishing the foundation of benefit is necessary. Vascular function plays a central role in the development and progression of HF. Endothelial function and nitric oxide availability affect myocardial function, systemic and pulmonary hemodynamics, and coronary and renal circulation. Arterial stiffness modulates ventricular loading conditions and diastolic function, key components of HF with preserved ejection. Endothelial function and arterial stiffness may therefore serve as important physiological targets for new HF therapies and facilitate patient selection for improved application of existing agents.

Renal dysfunction is a common, important comorbidity in patients with both chronic and acute heart failure (HF). Chronic kidney disease and worsening renal function (WRF) are associated with worse outcomes, but our understanding of the complex bidirectional interactions between the heart and kidney remains poor. When addressing these interactions, one must consider the impact of intrinsic renal disease resulting from medical comorbidities on HF outcomes. WRF may result from any number of important processes. Understanding the role of each of these factors and their interplay are essential in understanding how to improve outcomes in patients with renal dysfunction and HF.

Heart failure is a growing epidemic that currently affects nearly 6 million people in the USA. Despite the well-documented hemodynamic abnormalities associated with the disease (e.g., elevated systemic vascular resistance), therapies that directly target these derangements have consistently failed to improve important clinical outcomes, unless they also act on the underlying pathophysiology of the disease (e.g., angiotensin-converting enzyme inhibitors). Numerous clinical trials of vasodilators in the treatment of heart failure have resulted in either neutral or negative outcomes suggesting that systemic vascular resistance may be an inappropriate target of therapy. The reasons for failure in these studies are manifold, including a poor understanding of vasodilator agents and their secondary effects, poorly designed studies that include a markedly heterogeneous patient population and a paucity of objective end points that may be used as targets of therapy, to name a few. Future studies of vasodilators will need to consider these issues in trial design.

Dietary sodium restriction is arguably the most frequent self-care behavior recommended to patients with heart failure (HF)1,2 and is endorsed by all HF guidelines.2–10 However, the data on which this recommendation is drawn are modest, and the limited trials conducted have produced inconsistent findings. Americans consume ≈3700 mg sodium daily,11 whereas the US Department of Agriculture and the Department of Health and Human Services recommend 2300 mg daily intake for the general population, with a stricter recommendation of 1500 mg/d for those >50 years of age, blacks, or individuals with hypertension, diabetes mellitus, or chronic kidney disease.12 According to a recent report from the National Health and Nutrition Examination Survey, although 47.6% of persons aged ≥2 years meet the criteria to limit daily sodium intake to 1500 mg, the usual intake for 98.6% of those persons was >1500 mg; in 88.2% of the remaining population, daily intake was greater than the recommended

The recent explosion of scientific knowledge and technological progress has led to the discovery of a large array of circulating molecules commonly referred to as biomarkers. Biomarkers in heart failure research have been used to provide pathophysiological insights, aid in establishing the diagnosis, refine prognosis, guide management, and target treatment. However, beyond diagnostic applications of natriuretic peptides, there are currently few widely recognized applications for biomarkers in heart failure. This represents a remarkable discordance considering the number of molecules that have been shown to correlate with outcomes, refine risk prediction, or track disease severity in heart failure in the past decade. In this article, we use a broad framework proposed for cardiovascular risk markers to summarize the current state of biomarker development for heart failure patients. We utilize this framework to identify the challenges of biomarker adoption for risk prediction, disease management, and treatment selection for heart failure and suggest considerations for future research.

The heart failure epidemic calls for urgent prevention efforts. Hypertension is present in the majority of individuals who develop heart failure and carries the highest population-attributable risk for heart failure together with coronary heart disease. Therefore, hypertension is a natural prime target for prevention interventions. However, a substantial proportion of heart failure develops among individuals with a systolic BP (SBP) level below current therapeutic target recommendations (140 mmHg or 130 mmHg for high-risk groups), which are accepted as 'normal' levels, underlining the importance of prehypertension for heart failure development. Prevalence and incidence of both hypertension and prehypertension are high. Efforts to prevent or attenuate BP rise could lead to a substantial reduction of complications, including heart failure development. Lifestyle modifications play a crucial role in preventing elevation of BP levels and better control of high BP. Weight loss, control of sodium intake and diet, and physical activity are essential steps towards this direction. However, when medications are needed to reduce BP levels, the selection of the appropriate agent is important not only for effective control of BP but also to reduce hypertension-related complications. Diuretics and renin-angiotensin system modulators seem to be the most effective agents for heart failure prevention according to the existing evidence. Patients with heart failure and hypertension should be treated for hypertension based on the same principles, although medication selection should take into account concomitant medications, other risk factors and type of heart failure (reduced vs preserved left ventricular ejection fraction).

Background The prognostic value of deformation parameters of the systemic right ventricle in adults with D-transposition of the great arteries and prior atrial switch has not been reported. Methods Sixty-four adults with D-transposition of the great arteries and prior atrial switch (mean age, 29 ± 6 years; 22 women; mean right ventricular [RV] fractional area change, 22.9 ± 7.5%; 31 with pacemakers at baseline) and no histories of heart failure or ventricular tachycardia were prospectively evaluated. Global longitudinal strain (GS), global systolic strain rate (GSRs), and global early diastolic strain rate (GSRe) of the right ventricle were measured using speckle tracking from apical views and compared with standard parameters of RV function (fractional area change, tricuspid annular plane systolic excursion, tissue Doppler velocities, and isovolumic acceleration) for association with and potential prediction of clinical events, defined as incident stage C heart failure or ventricular tachycardia. Results Baseline RV GS, GSRs, and GSRe were −12.5 ± 3.0%, −0.59 ± 0.14 sec −1 , and 0.68 ± 0.22 sec −1 , respectively. After a median of 2.4 years (interquartile range, 1.5–4.1 years), 12 patients (19%) presented with clinical events (heart failure in 11 patients, ventricular tachycardia in one patient). In Cox models, RV GS had the strongest association with clinical events (hazard ratio [HR] per 1%, 1.35; 95% confidence interval [CI], 1.14–1.58; P −1 , 1.06; 95% CI, 1.02–1.11; P = .006), GSRe (HR per −0.01 sec −1 , 1.04; 95% CI, 1.00–1.07; P = .031), and fractional area change (HR per −1%, 1.08; 95% CI, 1.00–1.17; P = .047). Other measures of RV function were not significantly associated with risk for events. In receiver operating characteristic analysis, RV GS ≥ −10% optimally predicted future events (C = 0.83; 95% CI, 0.71–0.91; P Conclusions Reduced longitudinal GS of the systemic right ventricle is associated with increased risk for clinical events among patients with D-transposition of the great arteries and prior atrial switch.

The public health impact and the need to intervene upon the worsening heart failure (HF) epidemic are currently a matter of national interest. The greater than $39 billion annual cost of caring for the 5.8 million patients living with HF in the United States places a considerable burden on the health care system. In 2006, HF was a contributing factor in more than 250,000 deaths. HF is the primary cause of more than 1 million and a contributing cause for more than 3 million hospitalizations. Because of lack of uniform definition, defining advanced HF precisely and, in turn, specifically assessing its epidemiology are difficult. However, with availability of more therapeutic options available for patients with advanced HF, the need to precisely define this entity is becoming ever more important. In general, patients with advanced HF have an extremely high mortality and morbidity and poor health status and quality of life. With the aging of the population and the worsening risk factor profile at large, for example, diabetes mellitus and obesity, the current epidemiological trends in advanced HF will likely get worse. Newer medical and device therapies as well as regenerative techniques hold considerable promise for these patients in future.

Diuretics and vasodilators have been the cornerstone of heart failure (HF) therapy for decades. Although not shown to reduce mortality, diuretic and vasodilator therapy remain commonplace for treating acute decompensated HF, with diuretics being the mainstay of therapy for the removal of excess fluid in all patients with HF. This article discusses results of recent trials concerning diuretic or vasodilator therapy and HF, including the Diuretic Optimization Strategies Evaluation (DOSE) trial, the Placebo-Controlled Randomized Study of the Selective A1 Adenosine Receptor Antagonist Rolofylline for Patients Hospitalized With Acute Decompensated Heart Failure and Volume Overload to Assess Treatment Effect on Congestion and Renal Function (PROTECT), and the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST), as well as results from the Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND-HF) trial and the Preliminary Study of Relaxin in Acute Heart Failure (Pre-RELAX-AHF).

BACKGROUND: The impact of abnormal spirometric findings on risk for incident heart failure among older adults without clinically apparent lung disease is not well elucidated.METHODS: We evaluated the association of baseline lung function with incident heart failure, defined as first hospitalization for heart failure, in 2125 participants of the community-based Health, Aging, and Body Composition (Health ABC) Study (age, 73.6 +/- 2.9 years; 50.5% men; 62.3% white; 37.7% black) without prevalent lung disease or heart failure. Abnormal lung function was defined either as forced vital capacity (FVC) or forced expiratory volume in 1(st) second (FEV1) to FVC ratio below lower limit of normal. Percent predicted FVC and FEV1 also were assessed as continuous variables.RESULTS: During follow-up (median, 9.4 years), heart failure developed in 68 of 350 (19.4%) participants with abnormal baseline lung function, as compared with 172 of 1775 (9.7%) participants with normal lung function (hazard ratio [HR] 2.31; 95% confidence interval [CI], 1.74-3.07; P

Background Only a few studies have examined the relationship of plasma BNP levels and congenital heart disease (CHD) in neonates and these mainly concern preterm neonates with patent ductus arteriosus. We aimed to investigate the diagnostic role of plasma BNP in neonates admitted in the neonatal intensive care unit, (NICU), with signs of congenital heart disease (CHD). Methods Prospective assessment of plasma BNP levels in 75 consecutive neonates with suspected CHD (heart murmur, respiratory distress, or cyanosis), admitted in the NICU of our university hospital. The final diagnosis was done with echocardiography. Results Haemodynamically significant Left to Right shunts, (hsLtR), were found in 29 neonates, insignificant LtR shunts in 22, no heart disease in 15 and cyanotic heart disease in 9. BNP levels were significantly higher in neonates with hsLtR shunts vs. all other groups (logBNP 2.9±0.5pg/ml vs. 1.5±0.4pg/ml vs. 1.5±0.3pg/ml vs. 1.6±0.2pg/ml, p 132.5pg/ml had 93.1% sensitivity and 100% specificity for diagnosing hsLtR shunts (accuracy 99.6%). Conclusions Plasma BNP is a reliable test for diagnosing hsLtR shunts in the NICU. This will alert the neonatologist for ordering an echocardiographic examination, or if the latter is not available, for transferring the neonate to an appropriate tertiary centre with neonatal-paediatric cardiology facilities. Normal BNP levels imply the absence of a significant LtR shunt, but may not exclude cyanotic heart disease.

A shared understanding of medical conditions between patients and their health care providers may improve self-care and outcomes. In this study, the concordance between responses to a medical history self-report (MHSR) form and the corresponding provider documentation in electronic health records (EHRs) of 19 select co-morbidities and habits in 230 patients with heart failure were evaluated. Overall concordance was assessed using the κ statistic, and crude, positive, and negative agreement were determined for each condition. Concordance between MHSR and EHR varied widely for cardiovascular conditions (κ = 0.37 to 0.96), noncardiovascular conditions (κ = 0.06 to 1.00), and habits (κ = 0.26 to 0.69). Less than 80% crude agreement was seen for history of arrhythmias (72%), dyslipidemia (74%), and hypertension (79%) among cardiovascular conditions and lung disease (70%) and peripheral arterial disease (78%) for noncardiovascular conditions. Perfect agreement was observed for only 1 of the 19 conditions (human immunodeficiency virus status). Negative agreement >80% was more frequent than >80% positive agreement for a condition (15 of 19 [79%] vs 8 of 19 [42%], respectively, p = 0.02). Only 20% of patients had concordant MSHRs and EHRs for all 7 cardiovascular conditions; in 40% of patients, concordance was observed for ≤5 conditions. For noncardiovascular conditions, only 28% of MSHR-EHR pairs agreed for all 9 conditions; 37% agreed for ≤7 conditions. Cumulatively, 39% of the pairs matched for ≤15 of 19 conditions. In conclusion, there is significant variation in the perceptions of patients with heart failure compared to providers’ records of co-morbidities and habits. The root causes of this variation and its impact on outcomes need further study.

Background— The recently developed and internally validated Health ABC HF model uses 9 routinely available clinical variables to determine incident heart failure risk. In this study, we sought to externally validate the Health ABC HF model. Methods and Results— Observed 5-year incidence of heart failure, defined as first hospitalization for new-onset heart failure, was compared with 5-year risk estimates derived from the Health ABC HF model among participants without heart failure at baseline in the Cardiovascular Health Study. During follow-up, 400 of 5335 (7.5%) participants developed heart failure over 5 years versus 364 (6.8%) predicted by the Health ABC HF model (predicted-to-observed ratio, 0.90). Observed versus predicted 5-year heart failure probabilities were 3.2% versus 2.8%, 9.0% versus 7.0%, 15.9% versus 13.7%, and 24.6% versus 30.8% for the 20% 5-year risk categories, respectively. The Hosmer-Lemeshow χ 2 was 14.72 (degrees of freedom, 10; P =0.14), and the C index was 0.74 (95% CI, 0.72 to 0.76). Calibration and discrimination demonstrated adequate performance across sex and race overall; however, risk was underestimated in white men, especially in the 5% to 10% risk category. Model performance was optimal when participants with normal left ventricular function at baseline were assessed separately. Performance was consistent across age groups. Analyses with death as a competing risk yielded similar results. Conclusions— The Health ABC HF model adequately predicted 5-year heart failure risk in a large community-based study, providing support for the external validity of the model. This tool may be used to identify individuals to whom to target heart failure prevention efforts.

It is unclear whether measures of glycemic status beyond fasting glucose (FG) levels improve incident heart failure (HF) prediction in patients without history of diabetes mellitus (DM).The association of measures of glycemic status at baseline (including FG, oral glucose tolerance testing [OGTT], fasting insulin, hemoglobin A(1c) [HbA(1c)] levels, and homeostasis model assessment of insulin resistance [HOMA-IR] and insulin secretion [HOMA-B]) with incident HF, defined as hospitalization for new-onset HF, was evaluated in 2386 elderly participants without history of DM enrolled in the Health, Aging, and Body Composition Study (median age, 73 years; 47.6% men; 62.5% white, 37.5% black) using Cox models. After a median follow-up of 7.2 years, 185 (7.8%) participants developed HF. Incident HF rate was 10.7 cases per 1000 person-years with FG100mg/dL, 13.1 with FG 100-125 mg/dL, and 26.6 with FGor=126 mg/dL (P=.002; P=.003 for trend). In adjusted models (for body mass index, age, history of coronary artery disease and smoking, left ventricular hypertrophy, systolic blood pressure and heart rate [HR], and creatinine and albumin levels), FG was the strongest predictor of incident HF (adjusted HR per 10mg/dL, 1.10; 95% CI, 1.02-1.18; P=.009); the addition of OGTT, fasting insulin, HbA(1c), HOMA-IR, or HOMA-B did not improve HF prediction. Results were similar across race and gender. When only HF with left ventricular ejection fraction (LVEF)or=40% was considered (n=69), FG showed a strong association in adjusted models (HR per 10mg/dL, 1.15; 95% CI, 1.03-1.29; P=.01). In comparison, when only HF with LVEF40%, was considered (n=71), the association was weaker (HR per 10mg/dL, 1.05; 95% CI; 0.94-1.18; P=.41).Fasting glucose is a strong predictor of HF risk in elderly without history of DM. Other glycemic measures provide no incremental prediction information.