Ischemic cardiomyopathy: epidemiology, pathophysiology, outcomes, and therapeutic options.

Ischemic cardiomyopathy (ICM) is the most prevalent cause of heart failure (HF) in developed countries, with significant morbidity and mortality, despite constant improvements in the management of coronary artery disease. Current literature on this topic remains fragmented. Therefore, this review aimed to summarize the most recent data on ICM, focusing on its definition, epidemiology, outcomes, and therapeutic options. The most widely accepted definition is represented by a left ventricular dysfunction in the presence of significant coronary artery disease. The prevalence of ICM is largely influenced by age and sex, with older individuals and males being more affected. Its pathophysiology is characterized by plaque buildup, thrombus formation, hypoperfusion, ischemic cell death, and left ventricular remodeling. Despite improvements in therapy, ICM still represents a public health burden, with a 1-year mortality rate of 16% and a 5-year mortality rate of approximately 40% in the USA and Europe. Therefore, optimization of cardiovascular function, prevention of progressive remodeling, reduction of HF symptoms, and improved survival are the main goals of treatment. Therapeutic options for ICM include lifestyle changes, optimal medical therapy, revascularization, device therapy, mechanical circulatory support, and cardiac transplantation. Personalized management strategies and tailored patient care are needed to improve the outcomes of patients with ICM.

Endotoxemia Correlates with Kidney Function and Length of Stay in Critically Ill Patients.

INTRODUCTION: Endotoxin is a key driver of sepsis, which frequently causes acute kidney injury (AKI). However, endotoxins may also be found in non-bacteremic critically ill patients, likely from intestinal translocation. Preclinical models show that endotoxins can directly injure the kidneys, and in COVID-19 patients, endotoxemia correlated with AKI. We sought to determine correlations between endotoxemia and kidney and hospital outcomes in a broad group of critically ill patients. METHODS: In this single-center, serial prospective study, 124 predominantly Caucasian adult patients were recruited within 48 h of admission to Stony Brook University Hospital Intensive Care Unit (ICU). Demographics, vital signs, laboratory data, and outcomes were collected. Circulating endotoxin was measured on days 1, 4, and 8 using the endotoxin activity assay (EAA). The association of EAA with outcomes was examined with EAA: (1) categorized as <0.6, ≥0.6, and nonresponders (NRs); and (2) used as a continuous variable. RESULTS: Patients with EAA ≥0.6 had a higher prevalence of proteinuria, and lower arterial oxygen saturation (SaO2) to fraction of inspired oxygen (FiO2) (SaO2/FiO2) ratio versus patients with EAA <0.6. EAA levels positively correlated with serum creatinine (sCr) levels on day 1. Patients whose EAA level stayed ≥0.6 had a slower decline in sCr compared to those whose EAA started at ≥0.6 and subsequently declined. Patients with AKI stage 1 and EAA ≥0.6 on day 1 showed slower decline in sCr compared to patients with stage 1 AKI and EAA <0.6. EAA ≥0.6 and NR patients had longer hospital stay and delayed ICU discharge versus EAA <0.6. CONCLUSIONS: High EAA levels correlated with worse kidney function and outcomes. Patients whose EAA levels fell, and those with AKI stage I and day 1 EAA <0.6 recovered more quickly compared to those with EAA ≥0.6, suggesting that removal of circulating endotoxins may be beneficial in critically ill patients.

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

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

Contemporary Data on the Status and Medical Management of Acute Heart Failure.

PURPOSE OF REVIEW: Acute heart failure (AHF) is among the leading causes for unplanned hospital admission. Despite advancements in the management of chronic heart failure, the prognosis of AHF remains poor with high in-hospital mortality and increased rates of unfavorable post-discharge outcomes. With this review, we aim to summarize current data on AHF epidemiology, focus on the different patient profiles and classifications, and discuss management, including novel therapeutic options in this area. RECENT FINDINGS: There is significant heterogeneity among patients admitted for AHF in their baseline characteristics, heart failure (HF) aetiology and precipitating factors leading to decompensation. A novel classification scheme based on four distinct clinical scenarios has been included in the most recent ESC guidelines, in an effort to better risk stratify patients and guide treatment. Intravenous diuretics, vasodilators, and inotropes remain the cornerstone of management in the acute phase, and expansion of use of mechanical circulatory support has been noted in recent years. Meanwhile, many treatments that have proved their value in chronic heart failure demonstrate promising results in the setting of AHF and research in this field is currently ongoing. Acute heart failure remains a major health challenge with high in-hospital mortality and unfavorable post-discharge outcomes. Admission for acute HF represents a window of opportunity for patients to initiate appropriate treatment as soon as possible after stabilization. Future studies are needed to elucidate which patients will benefit the most by available therapies and define the optimal timing for treatment implementation.

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

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

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

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

High-dose methylprednisolone in nonintubated patients with severe COVID-19 pneumonia.

BACKGROUND: Recent trials with dexamethasone and hydrocortisone have demonstrated benefit in patients with coronavirus disease 2019 (COVID-19). Data on methylprednisolone are limited. METHODS: Retrospective cohort of consecutive adults with severe COVID-19 pneumonia on high-flow oxygen (FiO2  ≥ 50%) admitted to an academic centre in New York, from 1 March to 15 April 2020. We used inverse probability of treatment weights to estimate the effect of methylprednisolone on clinical outcomes and intensive care resource utilization. RESULTS: Of 447 patients, 153 (34.2%) received methylprednisolone and 294 (65.8%) received no corticosteroids. At 28 days, 102 patients (22.8%) had died and 115 (25.7%) received mechanical ventilation. In weighted analyses, risk for death or mechanical ventilation was 37% lower with methylprednisolone (hazard ratio 0.63; 95% CI 0.47-0.86; P = .003), driven by less frequent mechanical ventilation (subhazard ratio 0.56; 95% CI 0.40-0.79; P = .001); mortality did not differ between groups. The methylprednisolone group had 2.8 more ventilator-free days (95% CI 0.5-5.1; P = .017) and 2.6 more intensive care-free days (95% CI 0.2-4.9; P = .033) during the first 28 days. Complication rates were not higher with methylprednisolone. CONCLUSIONS: In nonintubated patients with severe COVID-19 pneumonia, methylprednisolone was associated with reduced need for mechanical ventilation and less-intensive care resource utilization without excess complications.

Streptococcus oralis MitraClip endocarditis following a dental procedure: a case report.

BACKGROUND: Transcatheter edge-to-edge mitral valve repair using the MitraClip device is increasingly used for high surgical risk patients with severe mitral regurgitation (MR). Previous guidelines for infective endocarditis prophylaxis prior to dental procedures focused on high-risk patients, but without explicit recommendation for MitraClip recipients. We believe this could be the first reported case to identify Streptococcus oralis as the causative organism. CASE PRESENTATION: An 87-year-old male with severe MR treated with two MitraClip devices three months prior to index admission, presented with worsening malaise and intermittent chills on a background of multiple comorbid conditions. The patient had dental work a month prior to presentation, including a root canal procedure, without antibiotic prophylaxis. Vitals were significant for fever and hypotension. On physical examination, there was a holosystolic murmur at the apex radiating to the axilla, bilateral pitting edema in the lower extremities, and elevated jugular venous pulsation. A transthoracic echocardiogram showed severe MR with a possible echodensity on the mitral valve, prompting a transesophageal echocardiogram, which demonstrated a pedunculated, mobile mass on the posterior leaflet of the mitral valve. Five blood cultures grew gram positive cocci in pairs and chains, later identified as Streptococcus oralis, with minimum inhibitory concentration to penicillin 0.06 mg/L. Initial empiric antibiotics were switched to ceftriaxone 2 gr daily and subsequent blood cultures remained negative. However, the patient developed pulmonary edema and worsening hemodynamic instability requiring vasopressors. As surgical risk for re-operation was considered prohibitive, the decision was made to continue medical management and comfort-directed care. The patient died a week later. CONCLUSIONS: Despite low incidence, infective endocarditis should be included in the differential among MitraClip recipients. The explicit inclusion of this growing patient population in the group requiring prophylaxis prior to dental procedures in the 2020 ACC/AHA valvular heart disease guidelines is an important step forward.

Association Between Atrial Fibrillation and Cognitive Impairment in Individuals With Prior Stroke: A Meta-Analysis and Meta-Regression Analysis.

Background and Purpose- Atrial fibrillation (AF) is the most common chronic arrhythmia. Dementia and cognitive impairment (CI) are major burdens to public health. The prevalence of all 3 entities is projected to increase due to population aging. Previous reports have linked AF with a higher risk of CI and dementia in patients without prior stroke. Stroke is known to increase the risk for dementia and CI. It is unclear if AF in patients with history of stroke can further increase the risk for dementia or CI. Our purpose was to evaluate the impact of AF on risk for dementia or CI among patients with history of stroke. Methods- Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines were followed. Pubmed, Scopus, and Cochrane central were searched. The outcomes of interest were dementia, CI, and the composite end point of dementia or CI. A random-effect model meta-analysis was performed. Meta-regression analysis was also performed. Publication bias was assessed with the Egger test and with funnel plots. Results- Fourteen studies and 14 360 patients (1363 with AF) were included in the meta-analysis. In the meta-analysis of adjusted odds ratio, AF was associated with increased risk of CI (odds ratio, 1.60 [95% CI, 1.20-2.14]), dementia (odds ratio, 3.11 [95% CI, 2.05-4.73]), and the composite end point of CI or dementia (odds ratio, 2.26 [95% CI, 1.61-3.19]). The heterogeneity for the composite end point of dementia or CI was moderate (adjusted analysis). The heterogeneity for the analysis of the end point of CI only was substantial in the unadjusted analysis and moderate in the adjusted analysis. The heterogeneity for the end point of dementia only was moderate in the unadjusted analysis and zero in the adjusted analysis. Conclusions- Our results indicate that an association between AF and CI or dementia is patients with prior strokes is possible given the persistent positive associations we noticed in the unadjusted and adjusted analyses. The heterogeneity levels limit the certainty of our findings.

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

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

Antihyperglycemic Therapies With Expansions of US Food and Drug Administration Indications to Reduce Cardiovascular Events: Prescribing Patterns Within an Academic Medical Center.

Sodium-glucose cotransport protein-2 inhibitors (SGLT2is) and glucagon-like peptide-1 receptor agonists (GLP-1RAs) have been shown to reduce cardiovascular events in high-risk patients with type 2 diabetes mellitus (T2DM). We examined real-world use of these agents at a US academic medical center in the state of Mississippi. Prescriptions, provider specialty, and insurance status of users of SGLT2is and GLP-1RAs in patients with T2DM, and T2DM and cardiovascular disease (CVD) seen from 1st January 2013 to 30th June 2019 were obtained by electronic health records review. We identified 21,173 patients with T2DM and CVD. Overall, 306 (1.4%) and 349 (1.6%) patients received a SGLT2i and GLP-1RA, respectively. After the US Food and Drug Administration (FDA) expanded empagliflozin and liraglutide indications, a mean difference of 19.2 and 12.7 greater quarterly new prescriptions was noted, respectively, whereas no such rise in canagliflozin was observed. Primary care physicians accounted for 53.4% SGLT2i prescriptions, endocrinology for 30.3%, and cardiology for 6.0%. Primary care physicians accounted for 45.1% GLP-1RA prescriptions, endocrinology for 45.0%, and cardiology for 1.4%. Prescription patterns did not largely differ by patient insurance status. In conclusion, prescription of evidence-based therapies to improve CVD outcomes in high-risk patients with T2DM remains very low after several years of evidence generation. Low uptake was evident across insurance types. Modest increases in use were observed after regulatory expansions in labeling; however, cardiologists rarely engaged in prescription, underscoring the need for widespread implementation strategies across health care systems.

Diagnosis and Prevention of Hypertensive Heart Failure.

Elevated blood pressure (BP) has a strong and continuous association with Stage B and C heart failure (HF) and carries the highest attributable risk for HF. Intensive treatment of hypertension is crucial, as progression from hypertension (Stage A HF) to left ventricular hypertrophy (LVH) or other structural damage (Stage B HF) is common despite therapy. Echo cardiography is the modality of choice to detect Stage B HF. Ideally, Stage B HF should be prevented. However, regression of established LVH and other structural damage is feasible and improves prognosis. Despite differences among antihypertensive agents, control of BP remains the most important goal.

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

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

Atrial fibrillation and cognitive function in patients with heart failure: a systematic review and meta-analysis.

Cognitive impairment and dementia are established complications of heart failure (HF) in adult patients and impair medication adherence and self-care. Atrial fibrillation (AF) is suggested to play an independent role in the cognitive decline in patients with HF. The objective of this systematic review was to assess the effect of AF on cognitive function in these patients. Medline (PubMed), Scopus, and the CENTRAL databases were queried from their inception up to April 30, 2016. The search included primary research articles evaluating the effect of AF on cognition in HF patients. There were five eligible studies, including a total of 1670 patients with HF; of these, 449 (26.9%) had AF. Different AF types were studied, including persistent, paroxysmal, or permanent. Four cognitive tests were used to assess cognitive function (Mini-Mental State Examination, Short Portable Mental Status Questionnaire, Modified Mini-Mental Examination, and Montreal cognitive assessment tool). Using the inverse variance method and a random effects model, we observed that presence of AF was significantly associated with increased risk of cognitive impairment in HF patients (odds ratio [OR], 1.94; 95% confidence interval [CI], 1.30-2.87), although with significant heterogeneity (I 2  = 39%). This heterogeneity can be attributed to the different populations and types of AF studied as well as to varying cognitive assessment methods. Concomitant AF may exacerbate cognitive dysfunction in HF patients. However, data are sparse and heterogeneous. Well-designed, prospective studies are needed to (a) establish a causative link and (b) identify the underlying mechanism in order to design appropriate interventions to attenuate risk of cognitive impairment in patients with HF.

Defining Advanced Heart Failure: A Systematic Review of Criteria Used in Clinical Trials.

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.

Echocardiography in Acute Heart Failure: Current Perspectives.

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.

Trends in Heart Failure Clinical Trials From 2001-2012.

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.

Trends in characteristics of cardiovascular clinical trials 2001-2012.

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.

Inotrope use and outcomes among patients hospitalized for heart failure: impact of systolic blood pressure, cardiac index, and etiology.

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.

High-sensitivity C-reactive protein in acute heart failure: insights from the ASCEND-HF trial.

BACKGROUND: Inflammation is associated with progression of chronic heart failure (HF). Few data exist on high-sensitivity C-reactive protein (hsCRP) levels and their importance in acute HF. METHODS AND RESULTS: In this biomarker substudy of the ASCEND-HF trial, we measured hsCRP levels at admission (n = 794), 48-72 hours (n = 677), and 30 days (n = 581) and evaluated their association with outcomes. Levels of hsCRP were considerably elevated at admission (median 12.6 mg/L, interquartile range [IQR] 5.23-30.5) and 48-72 hours (median 11.0 mg/L, IQR 4.87-29.9) and declined only at 30 days (median 4.7 mg/L, IQR 1.83-13.1). Admission hsCRP was not associated with dyspnea improvement at 6 hours (74.1%) and 24 hours (86.2%), in-hospital death or worsening HF (n = 37; 4.7%), 30-day mortality or HF readmission (death: n = 25 [3.2%]; combined death and HF readmission: n = 95 [12.0%]), or 180-day mortality (n = 96; 12.1%). Hospital stay (median 5 days, IQR 3-7) was longer among patients with higher admission hsCRP levels (0.57 days per log2-hsCRP in adjusted models; 95% confidence interval [CI] 0.33-0.81; P < .001). Levels of hsCRP at 48-72 hours did not predict 30-day mortality or HF readmission and were only marginally associated with 180-day mortality. However, higher hsCRP at 30 days among survivors was associated with higher 180-day mortality in models including admission hsCRP (adjusted hazard ratio [HR] per log2-hsCRP: 1.23; 95% CI 1.04-1.45; P = .016). Patients with an hsCRP increase at day 30, defined as >10% increase over baseline value, had higher 180-day mortality risk compared with those with unchanged or decreased 30-day hsCRP (HR 2.29, 95% CI 1.16-4.52; P = .017). CONCLUSIONS: Levels of hsCRP are elevated among patients with acute HF. Increasing levels at 30 days after discharge are associated with higher 180-day mortality.