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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<0.001) and those excluded (hazard ratio, 1.27; 95% CI=1.04, 1.55; p=0.016) had elevated mortality. In adjusted models, LDCW performance variables were associated mainly with mortality. Only 20-meter walking speed and resting heart rate retained prognostic value for HF. Longitudinal changes in LDCW did not predict subsequent incident HF or mortality.Conclusions: Completing an LDCW is strongly associated with lower 10-year mortality and HF risk in older adults. Therefore, walking capacity may serve as an early risk marker. [ABSTRACT FROM AUTHOR]

Background: How serum albumin levels are associated with risk for heart failure (HF) in the elderly is unclear.Methods: We evaluated 2,907 participants without HF (age 73.6 +/- 2.9 years, 48.0% male, 58.7% white) from the community-based Health ABC Study. The association between baseline albumin and incident HF was assessed with standard and competing risks proportional hazards models controlling for HF predictors, inflammatory markers, and incident coronary events.Results: During a median follow-up of 9.4 years, 342 (11.8%) participants developed HF. Albumin was a time-dependent predictor of HF, with significance retained for up to 6 years (baseline hazard ratio [HR] per -1 g/L 1.14, 95% CI 1.06-1.22, P < .001; annual rate of HR decline 2.1%, 95% CI 0.8%-3.3%, P = .001). This association persisted in models controlling for HF predictors, inflammatory markers, and incident coronary events (baseline HR per -1 g/L 1.13, 95% CI 1.05-1.22, P = .001; annual rate of HR decline 1.8%, 95% CI 0.5%-3.0%, P = .008) and when mortality was accounted for in adjusted competing risks models (baseline HR per -1 g/L 1.13, 95% CI 1.05-1.21, P = .001; annual rate of HR decline 1.9%, 95% CI 0.7%-3.1%, P = .002). The association of albumin with HF risk was similar in men (HR per -1 g/L 1.13, 95% CI 1.05-1.23, P = .002) and women (HR per -1 g/L 1.12, 95% CI 1.04-1.22, P = .005) and in whites and blacks (HR per -1 g/L 1.13, 95% CI 1.04-1.22, P< .01 for both races) in adjusted models.Conclusions: Low serum albumin levels are associated with increased risk for HF in the elderly in a time-dependent manner independent of inflammation and incident coronary events. [ABSTRACT FROM AUTHOR]

Submarine carbonate escarpments, documented in numerous sites around the world, consist of thick exposures of Mesozoic shallow water carbonate sequences – primarily limestones and dolomites – with reliefs of >1 km and slope gradients of >70°. Whilst most research efforts have focused on the processes that shaped carbonate escarpments into complex and extreme terrains, little attention has been paid to the geomorphology of shelves upslope of carbonate escarpments. In this study we investigate high resolution geophysical, sedimentological and visual data acquired from the eastern Malta Plateau, central Mediterranean Sea, to demonstrate that the outer shelf of a carbonate escarpment is directly influenced by escarpment-forming processes. We document forty eight erosional scars, six long channels and numerous smaller-scale channels, three elongate mounds, and an elongate ridge across the eastern Malta Plateau. By analysing their morphology, seismic character, and sedimentological properties, we infer that the seafloor of the eastern Malta Plateau has been modified by three key processes: (i) Mass movements – in the form of translational slides, spreading and debris flows – that mobilised stratified Plio-Pleistocene hemipelagic mud along the shelf break and that were likely triggered by seismicity and loss of support due to canyon erosion across the upper Malta Escarpment; (ii) NNW-SSE trending sinistral strike-slip deformation in Cenozoic carbonates – resulting from the development of a mega-hinge fault system along the Malta Escarpment since the Late Mesozoic, and SE-NW directed horizontal shortening since the Late Miocene – which gave rise to NW-SE oriented extensional grabens and a NNW-SSE horst; (iii) Flow of bottom currents perpendicular and parallel to the Malta Escarpment, associated with either Modified Atlantic Water flows during sea level lowstands and/or Levantine Intermediate Water flows at present, which was responsible for sediment erosion and deposition in the form of channels and contouritic drifts. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

In contrast to chronic heart failure (HF), the use of echocardiography in acute HF (AHF) is less well defined, both in clinical practice and in clinical trials. Current guidelines recommend the utility of echocardiography as an adjunct diagnostic tool in the clinical setting of new-onset or decompensated HF. However, despite its unique advantages as the only practical imaging modality in AHF, echocardiography poses unique challenges in this setting. Data from early-phase clinical studies and trials provide evidence that echocardiographic end points can be clinically meaningful surrogate end points as a means to track response to treatment in AHF; however, the optimal timing and selection of echocardiographic measures is under active investigation. In addition, despite a number of studies indicating that certain echocardiographic measures of cardiac function are predictive of post-discharge prognosis, the role of echocardiography as a tool for patient classification and risk determination in AHF is less well defined. Importantly, it is unclear whether echocardiography can be used to phenotype and select AHF patients for interventions. In this article, we (1) appraise the current evidence for use of echocardiographic measures in AHF, (2) identify knowledge gaps regarding optimal use of echocardiography in AHF, and (3) assess the evidence for echocardiography as a prognosis determination and risk stratification tool in AHF. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background Inotropes are widely used in hospitalized systolic heart failure (HF) patients, especially those with low systolic blood pressure (SBP) or cardiac index. In addition, inotropes are considered to be harmful in nonischemic HF. Methods and Results We examined the association of in-hospital inotrope use with (1) major events (death, ventricular assist device, or heart transplant) and (2) study days alive and out of hospital during the first 6 months in the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness, which excluded patients with immediate need for inotropic therapy. Predefined subgroups of interest were baseline SBP <100 versus ≥100 mm Hg, cardiac index <1.8 vs ≥1.8 L min-1 m-2, and ischemic versus nonischemic HF etiology. Inotropes were frequently used in both the <100 mm Hg (88/165 [53.3%]) and the ≥100 mm Hg (106/262 [40.5%]) SBP subgroups and were associated with higher risk for major events in both subgroups (adjusted hazard ratio [HR] 2.85, 95% confidence interval [CI] 1.59-5.12 [P < .001]; and HR 1.86, 95% CI 1.02-3.37 [P = .042]; respectively). Risk with inotropes was more pronounced among those with cardiac index ≥1.8 L min-1 m-2 (n = 114; HR 4.65, 95% CI 1.98-10.9; P < .001) vs <1.8 L min-1 m-2 (n = 82; HR 1.48, 95% CI 0.61-3.58; P = .39). Event rates were higher with inotropes in both ischemic (n = 215; HR 2.64, 95% CI 1.49-4.68; P = .001) and nonischemic (n = 216; HR 2.19, 95% CI 1.18-4.07; P = .012) patients. Across all subgroups, patients who received inotropes spent fewer study days alive and out of hospital. Conclusions In the absence of cardiogenic shock or end-organ hypoperfusion, inotrope use during hospitalization for HF was associated with unfavorable 6-month outcomes, regardless of admission SBP, cardiac index, or HF etiology. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to assess the association between frailty and risk for heart failure (HF) in older adults. Background: Frailty is common in the elderly and is associated with adverse health outcomes. Impact of frailty on HF risk is not known. Methods: We assessed the association between frailty, using the Health ABC Short Physical Performance Battery (HABC Battery) and the Gill index, and incident HF in 2825 participants aged 70 to 79 years. Results: Mean age of participants was 74 ± 3 years; 48% were men and 59% were white. During a median follow up of 11.4 (7.1-11.7) years, 466 participants developed HF. Compared to non-frail participants, moderate (HR 1.36, 95% CI 1.08-1.71) and severe frailty (HR 1.88, 95% CI 1.02-3.47) by Gill index was associated with a higher risk for HF. HABC Battery score was linearly associated with HF risk after adjusting for the Health ABC HF Model (HR 1.24, 95% CI 1.13-1.36 per SD decrease in score) and remained significant when controlled for death as a competing risk (HR 1.30; 95% CI 1.00-1.55). Results were comparable across age, sex, and race, and in sub-groups based on diabetes mellitus or cardiovascular disease at baseline. Addition of HABC Battery scores to the Health ABC HF Risk Model improved discrimination (change in C-index, 0.014; 95% CI 0.018-0.010) and appropriately reclassified 13.4% (net-reclassification-improvement 0.073, 95% CI 0.021-0.125; P = .006) of participants (8.3% who developed HF and 5.1% who did not). Conclusions: Frailty is independently associated with risk of HF in older adults. [Copyright &y& Elsevier]

Abstract: The existence of a slope equilibrium profile has been widely used to account for erosional and depositional processes on submarine slopes and turbidite systems. Profiles out-of-equilibrium are commonly observed in actively deforming areas where channels seem to be deflected or diverted by seafloor structures. In this study the concept of the submarine equilibrium profile is tested in an area of extensive surface faulting to examine whether channels adopt an equilibrium-type profile through time. The study area is on the slope of the Nile Delta, which is disrupted by a number of surface-rupturing normal faults. Prior to fault linkage, several submarine channels flowed down the slope and either utilised relay ramps or flowed through fault scarps of the fault array. Where a relay ramp had been utilised, post fault linkage, the channels of the area either avulsed or converged into one major channel in response to a change in the deformed slope profile to a more concave shape. The thalweg of the post fault linkage channel and two slope profiles either side of it are measured in the area of the fault array, to understand how the channel evolved in response to the active faulting. When fault displacement is relatively small the combination of channel erosion and aggradation results in a channel thalweg profile near-equilibrium with predictable modifications of channel dimensions (depth and width) even if sediment supply was infrequent and episodic. It is concluded that turbidite channels can conform to the concept of equilibrium and submarine base level if it is the most energy efficient route for submarine gravity flows downslope. The most energy efficient route will be one where flows bypass the slope without eroding or depositing and move in a direct downslope course towards base level. [Copyright &y& Elsevier]

Background: Although there is evidence linking smoking and heart failure (HF), the association between lifetime smoking exposure and HF in older adults and the strength of this association among current and past smokers is not well known. Methods: We examined the association between smoking status, pack-years of exposure, and incident HF risk in 2,125 participants of the Health, Aging, and Body Composition Study (age 73.6 ± 2.9 years, 69.7% women, 54.2% whites) using proportional hazard models. Results: At inception, 54.8% of participants were nonsmokers, 34.8% were past smokers, and 10.4% were current smokers. During follow-up (median 9.4 years), HF incidence was 11.4 per 1,000 person-years in nonsmokers, 15.2 in past smokers (hazard ratio [HR] vs nonsmokers 1.33, 95% CI 1.01-1.76, P = .045), and 21.9 in current smokers (HR 1.93, 95% CI 1.30-2.84, P = .001). After adjusting for HF risk factors, incident coronary events, and competing risk for death, a dose-effect association between pack-years of exposure and HF risk was observed (HR 1.09, 95% CI 1.05-1.14, P < .001 per 10 pack-years). Heart failure risk was not modulated by pack-years of exposure in current smokers. In past smokers, HR for HF was 1.05 (95% CI 0.64-1.72) for 1 to 11 pack-years, 1.23 (95% CI 0.82-1.83) for 12 to 35 pack-years, and 1.64 (95% CI 1.11-2.42) for >35 pack-years of exposure in fully adjusted models (P < .001 for trend) compared with nonsmokers. Conclusions: In older adults, both current and past cigarette smoking increase HF risk. In current smokers, this risk is high irrespective of pack-years of exposure, whereas in past smokers, there was a dose-effect association. [Copyright &y& Elsevier]

Abstract: 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 (HF) research have been used to provide pathophysiologic 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 HF. 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 HF 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 patients with HF. We use this framework to identify the challenges of biomarker adoption for risk prediction, disease management, and treatment selection for HF and suggest considerations for future research. [Copyright &y& Elsevier]

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

Abstract: Advances in modern echocardiography for quantification of cardiac structure and function have not been translated in clinical trial or practice applications to date. Imaging endpoints are especially well-suited for early trials with investigational therapies for heart failure as most drugs and devices approved for heart failure have shown favorable effects on cardiac structure and function also. Echocardiography is versatile and can be performed in most clinical settings. The modest interobserver and test-retest reproducibility of specific structural and functional parameters with conventional echocardiography can be improved on by using contemporary modalities, including 3-dimensional (3D) echocardiography for assessment of volumes and ejection fraction and speckle tracking for detailed functional assessment of the ventricles with mechanics-based parameters (strain and strain rate). The appropriate imaging endpoints (global vs. regional, systolic vs. diastolic) should be tailored to the specific research question and the mode of action of the therapy under investigation. The newer echocardiographic modalities, namely 3D echocardiography and speckle tracking, are more demanding in terms of equipment and personnel and therefore are better suited for implementation in experienced research centers with central interpretation. However, these modalities provide the best opportunity currently available to demonstrate treatment effects on the myocardium with investigational therapies and provide mechanistic insights for future directions. [Copyright &y& Elsevier]

Abstract: 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. [Copyright &y& Elsevier]

Abstract: Patients with heart failure (HF) are hospitalized over a million times annually in the United States. Hospitalization marks a fundamental change in the natural history of HF, leading to frequent subsequent rehospitalizations and a significantly higher mortality compared with nonhospitalized patients. Three-fourths of all HF hospitalizations are due to exacerbation of symptoms in patients with known HF. One-half of hospitalized HF patients experience readmission within 6 months. Preventing HF hospitalization and rehospitalization is important to improve patient outcomes and curb health care costs. To implement cost-effective strategies to contain the HF hospitalization epidemic, optimal schemes to identify high-risk individuals are needed. In this review, we describe the risk factors that have been associated with hospitalization risk in HF and the various multimarker risk prediction schemes developed to predict HF rehospitalization. We comment on areas that represent gaps in our knowledge or difficulties in interpretation of the current literature, representing opportunities for future research. We also discuss issues with using HF readmission rate as a quality indicator. [ABSTRACT FROM AUTHOR]

Objectives: The purpose of this study was to evaluate the association between inflammation and heart failure (HF) risk in older adults. Background: Inflammation is associated with HF risk factors and also directly affects myocardial function. Methods: The association of baseline serum concentrations of interleukin (IL)-6, tumor necrosis factor-α, and C-reactive protein (CRP) with incident HF was assessed with Cox models among 2,610 older persons without prevalent HF enrolled in the Health ABC (Health, Aging, and Body Composition) study (age 73.6 ± 2.9 years; 48.3% men; 59.6% white). Results: During follow-up (median 9.4 years), HF developed in 311 (11.9%) participants. In models controlling for clinical characteristics, ankle-arm index, and incident coronary heart disease, doubling of IL-6, tumor necrosis factor-α, and CRP concentrations was associated with 29% (95% confidence interval: 13% to 47%; p < 0.001), 46% (95% confidence interval: 17% to 84%; p = 0.001), and 9% (95% confidence interval: −1% to 24%; p = 0.087) increase in HF risk, respectively. In models including all 3 markers, IL-6, and tumor necrosis factor-α, but not CRP, remained significant. These associations were similar across sex and race and persisted in models accounting for death as a competing event. Post-HF ejection fraction was available in 239 (76.8%) cases; inflammatory markers had stronger association with HF with preserved ejection fraction. Repeat IL-6 and CRP determinations at 1-year follow-up did not provide incremental information. Addition of IL-6 to the clinical Health ABC HF model improved model discrimination (C index from 0.717 to 0.734; p = 0.001) and fit (decreased Bayes information criterion by 17.8; p < 0.001). Conclusions: Inflammatory markers are associated with HF risk among older adults and may improve HF risk stratification. [Copyright &y& Elsevier]

Abstract: The northwest African margin has been affected by numerous large-scale landslides during the late Quaternary. This study focuses on a recent collapse of the Sahara Slide headwall and characterises the resulting flow deposit. Core and seismic data from the base of the upper headwall reveal the presence of blocky slide debris, comprising heavily deformed hemipelagic slope sediments. The blocky slide debris spilled over a lower headwall ∼60 km downslope and formed a thick transparent debris flow unit. Cores recovered 200–250 km farther downslope contain a surficial turbidite that is interpreted to be linked to the headwall collapse event based on timing and composition. One core located approximately 200 km from the headwall scar (C13) contains debrite encased in turbidite. The debrite comprises sheared and contorted hemipelagic mudstone clasts similar as those seen in the vicinity of the Sahara Slide headwall, and lacks matrix. This debrite pinches out laterally within 25 km of C13, whereas the accompanying turbidite can be correlated across 700 km of the northwest African margin. The linked turbidite–debrite bed is interpreted to have formed through recent failure of the steep Sahara Slide headwall that either 1) generated both a debris flow and a turbidity current almost simultaneously, or 2) generated a debris flow which with entrainment of water and progressive dilution led to formation of an accompanying turbidity current. [Copyright &y& Elsevier]

Abstract: Background: 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). Methods and Results: The association of measures of glycemic status at baseline (including FG, oral glucose tolerance testing [OGTT], fasting insulin, hemoglobin A1c [HbA1c] 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 FG <100mg/dL, 13.1 with FG 100–125mg/dL, and 26.6 with FG ≥126mg/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, HbA1c, 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) ≤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 LVEF >40%, was considered (n=71), the association was weaker (HR per 10mg/dL, 1.05; 95% CI; 0.94–1.18; P =.41). Conclusions: Fasting glucose is a strong predictor of HF risk in elderly without history of DM. Other glycemic measures provide no incremental prediction information. [Copyright &y& Elsevier]

Abstract: Background: Incremental value of echocardiography over clinical parameters for outcome prediction in advanced heart failure (HF) is not well established. Methods and Results: We evaluated 223 patients with advanced HF receiving optimal therapy (91.9% angiotensin-converting enzyme inhibitor/angiotensin receptor blocker, 92.8% β-blockers, 71.8% biventricular pacemaker, and/or defibrillator use). The Seattle Heart Failure Model (SHFM) was used as the reference clinical risk prediction scheme. The incremental value of echocardiographic parameters for event prediction (death or urgent heart transplantation) was measured by the improvement in fit and discrimination achieved by addition of standard echocardiographic parameters to the SHFM. After a median follow-up of 2.4 years, there were 38 (17.0%) events (35 deaths; 3 urgent transplants). The SHFM had likelihood ratio (LR) χ2 32.0 and C statistic 0.756 for event prediction. Left ventricular end-systolic volume, stroke volume, and severe tricuspid regurgitation were independent echocardiographic predictors of events. The addition of these parameters to SHFM improved LR χ2 to 72.0 and C statistic to 0.866 (P < .001 and P =.019, respectively). Reclassifying the SHFM-predicted risk with use of the echocardiography-added model resulted in improved prognostic separation. Conclusions: Addition of standard echocardiographic variables to the SHFM results in significant improvement in risk prediction for patients with advanced HF. [Copyright &y& Elsevier]

Background: Impaired renal function portends poor heart failure (HF) outcomes. The Seattle Heart Failure Score (SHFS), a multimarker risk assessment tool, however does not incorporate renal function. In this study, we assessed the incremental value of renal function over the SHFS in patients with advanced HF on contemporary optimal treatment. Methods: Blood urea nitrogen (BUN), serum creatinine (sCr), BUN/sCr ratio, and estimated glomerular filtration rate were assessed in survival models with SHFS as the base model among 443 patients with HF (52 ± 12 years, male 68.5%, white 52.4%, ejection fraction 0.18 ± 0.08). Incremental value of renal function was assessed by changes in the likelihood ratio χ2 and the area under the receiver operating characteristic curves for 1-, 2-, and 3-year event prediction. Results: During a median follow-up of 21 months, 108 (24.5%) of 443 patients had an event (death [n = 92], urgent transplantation [n = 13], or ventricular assist device implantation [n = 3]). All renal parameters individually were associated with outcome (BUN, P < .001; sCr, P < .001; BUN/sCr ratio, P = .006; and estimated glomerular filtration rate, P = .006); however, only BUN was an independent predictor of events in multivariable analyses. Addition of BUN improved the predictive ability of SHFS (Δlikelihood ratio χ2 5.03, P = .025); however, the increase in the area under the receiver operating characteristic curve was marginal (year 1, 0.786 to 0.791; year 2, 0.732 to 0.741; year 3, 0.745 to 0.754; all P > .2). Conclusion: Among the various renal function parameters, BUN had the strongest association with outcomes in patients with advanced HF. However, the incremental value of renal function over the SHFS for risk determination was marginal. [Copyright &y& Elsevier]

Objectives: The aim of this study was to validate the Seattle Heart Failure Model (SHFM) in patients with advanced heart failure (HF). Background: The SHFM was developed primarily from clinical trial databases and extrapolated the benefit of interventions from published data. Methods: We evaluated the discrimination and calibration of SHFM in 445 advanced HF patients (age 52 ± 12 years, 68.5% male, 52.4% white, ejection fraction 18 ± 8%) referred for cardiac transplantation. The primary end point was death (n = 92), urgent transplantation (n = 14), or left ventricular assist device (LVAD) implantation (n = 3); a secondary analysis was performed on mortality alone. Results: Patients were receiving optimal therapy (angiotensin-II modulation 92.8%, beta-blockers 91.5%, aldosterone antagonists 46.3%), and 71.0% had an implantable device (defibrillator 30.4%, biventricular pacemaker 3.4%, combined 37.3%). During a median follow-up of 21 months, 109 patients (24.5%) had an event. Although discrimination was adequate (c-statistic >0.7), the SHFM overall underestimated absolute risk (observed vs. predicted event rate: 11.0% vs. 9.2%, 21.0% vs. 16.6%, and 27.9% vs. 22.8% at 1, 2, and 3 years, respectively). Risk underprediction was more prominent in patients with an implantable device. The SHFM had different calibration properties in white versus black patients, leading to net underestimation of absolute risk in blacks. Race-specific recalibration improved the accuracy of predictions. When analysis was restricted to mortality, the SHFM exhibited better performance. Conclusions: In patients with advanced HF, the SHFM offers adequate discrimination, but absolute risk is underestimated, especially in blacks and in patients with devices. This is more prominent when including transplantation and LVAD implantation as an end point. [Copyright &y& Elsevier]

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. [Display omitted] • 58 human metalloproteins were identified as targets of SARS-CoV-2. • The most infected metalloproteins are Zn-binding proteins. • The most infected metalloproteins interact with SARS-CoV2 orf8 protein. • Shared genes among infected Zn-proteome and human disorders were found. • These molecular linkage might increase the risk of severe COVID-19. [ABSTRACT FROM AUTHOR]

Decisions regarding cardiac transplantation listing are difficult in patients with heart failure who have relatively discordant peak exercise oxygen consumption (Vo 2) and cardiac index (CI) values. One hundred five patients with heart failure who underwent cardiopulmonary exercise testing and right-sided cardiac catheterization for transplantation evaluation were studied. Patients were divided into 4 groups on the basis of peak Vo 2 and CI: group 1, Vo 2 ≥12 ml/min/kg, CI ≥1.8 L/min/m2 (n = 30); group 2, Vo 2 ≥12 ml/min/kg, CI <1.8, L/min/m2 (n = 27); group 3, Vo 2 <12 ml/min/kg, CI ≥1.8 L/min/m2 (n = 25); and group 4, Vo 2 <12 ml/min/kg, CI <1.8 L/min/m2 (n = 23). Groups were compared for event-free (death or ventricular assist device) survival. The overall CI was 1.9 ± 0.4 L/min/m2 and peak Vo 2 was 12.4 ± 2.8 ml/min/kg; values in the 4 groups were as follows: group 1, peak Vo 2 14.7 ± 2.1 ml/min/kg, CI 2.2 ± 0.3 L/min/m2; group 2, peak VO2 14.2 ± 1.3 ml/min/kg, CI 1.5 ± 0.2 L/min/m2; group 3, peak Vo 2 10.2 ± 1.3 ml/min/kg, CI 2.1 ± 0.3 L/min/m2; and group 4, peak Vo 2 9.7 ± 2.0 ml/min/kg, CI 1.6 ± 0.2 L/min/m2. After a median follow-up period of 3.7 years, 28 patients (26.0%) had events. Event-free survival was 96%, 95%, 96%, and 79% for 6 months (p = 0.04); 88%, 81%, 90%, and 73% for 12 months (p = 0.09); 88%, 73%, 85%, and 65% for 18 months (p = 0.11); and 83%, 73%, 79%, and 53% for 24 months (p = 0.06) for groups 1 to 4, respectively. Median survival was 5.1, 3.0, 3.9, and 2.6 years, respectively, in groups 1 to 4 (p = 0.052). In conclusion, almost half the patients had relatively discordant peak Vo 2 and CI measurements. Patients with lower peak Vo 2 values but relatively preserved CI values had survival comparable to post-transplantation survival, whereas those with low CI but preserved Vo 2 had a lower survival rate. These results suggest that the former group may be safely monitored on medical therapy, whereas the latter may benefit from early listing. [Copyright &y& Elsevier]

Background Efficient conduct of clinical trials is essential for the timely generation of critical medical knowledge. Methods We systematically assessed size, duration, enrollment rates, and geographic distribution of randomized cardiovascular trials published between 2001 and 2012 in the 8 highest-impact journals in general medicine and cardiology. Results Of the 1,224 trials, 27.0% were conducted in North America, 36.5% in Western Europe, and 7.7% in other countries, and 28.8% were multiregional. Trials enrolled a median of 452 patients (interquartile range 167-1,530) in 20 sites (2-76). Median duration was 2.1 (1.3-3.3) years, with an estimated enrollment rate of 1.1 (0.5-3.5) patients/site per month. Between 2001-2003 and 2009-2012, the proportion of North American trials decreased from 34.5% to 25.7% ( P = .006), whereas that of multiregional trials (from 26.0% to 30.3%; P = .046) and trials conducted in other countries (from 4.6% to 10.3%; P = .012) increased. Over time, trials involved more patients (from 400 to 500 [median]; P = .032) and sites (from 20 to 22; P = .049), multiregional trials involved more countries (from 12 to 18; P = .031), and enrollment rate declined from 1.2 to 0.9 patients/site per month ( P = .017). The proportion of trials meeting their primary end point (“positive”) decreased from 69% to 57% ( P < .001). Trials with higher enrollment rates were more likely to be positive (odds ratio 1.20 per doubling, 95% CI 1.12-1.29), as were industry-sponsored compared with government-sponsored trials (odds ratio 2.62, 95% CI 1.67-4.12). Conclusions From 2001 to 2012, cardiovascular clinical trials have become larger, more global, and less likely to meet their primary end point. Enrollment rates have declined, requiring more sites and regions. [ABSTRACT FROM AUTHOR]