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Congestion is the main reason for hospitalization in patients with acute decompensated heart failure and is an important target for therapy. However, achieving complete decongestion can be challenging. Furthermore, residual congestion before discharge from hospital is associated with a high risk of early rehospitalization and death. An improved understanding of the pathophysiology of congestion is of great importance in finding better and more personalized therapies. In this Review, we describe the two different forms of congestion — intravascular congestion and tissue congestion — and hypothesize that differentiating between and specifically treating these two different forms of congestion could improve the outcomes of patients with acute decompensated heart failure. Although the majority of these patients have a combination of both intravascular and tissue congestion, one phenotype can dominate. Each of these two forms of congestion has a different pathophysiology and requires a different diagnostic approach. We provide an overview of novel and established biomarkers, imaging modalities and mechanical techniques for identifying each type of congestion. Treatment with loop diuretics, the current cornerstone of decongestive treatment, reduces circulating blood volume and thereby reduces intravascular congestion. However, the osmolality of the circulating blood decreases with the use of loop diuretics, which might result in less immediate translocation of fluid from the tissues (lungs, abdomen and periphery) to the circulation when the plasma refill rate is exceeded. By contrast, aquaretic drugs (such as vasopressin antagonists) predominantly cause water excretion, which increases the osmolality of the circulating blood, potentially improving translocation of fluid from the tissues to the circulation and thereby relieving tissue congestion.Congestion is the main reason for hospitalization in patients with acute decompensated heart failure and is an important target for therapy. In this Review, Boorsma and colleagues distinguish between intravascular congestion and tissue congestion, and hypothesize that specifically treating these two different forms of congestion could improve patient outcomes.

In a trial involving 10,003 patients with suspected coronary artery disease, clinical outcomes at 2 years were not improved with an initial strategy of CT angiography, as compared with functional testing (exercise ECG, nuclear stress testing, or stress echocardiography). New-onset, stable chest pain is a common clinical problem that results in approximately 4 million stress tests annually in the United States in ambulatory patients without diagnosed heart disease. 1 Despite advances in cardiac testing, there is scant information on health-related outcomes and little consensus about which noninvasive test is preferable. 2 – 4 As a result, current patterns of care have been questioned, including the testing of very-low-risk populations 5 and the catheterization of patients who do not have obstructive coronary artery disease (CAD). 6 – 8 The development of coronary computed tomographic angiography (CTA) and its application in this context has the potential to . . .

•The bioavailability of furosemide 80 mg/mL SC injection is equivalent to that of furosemide 80 mg IV.•Diuresis, natriuresis, and kaliuresis are similar with furosemide 80 mg/mL SC injection and furosemide 80 mg IV.•Furosemide 80 mg/mL SC injection was generally well tolerated. Furoscix (furosemide injection) 80 mg/10 mL is a pH neutral formulation administered subcutaneously (SC) over 5 hours to treat edema in adults with chronic HF or chronic kidney disease. Furosemide 80 mg/mL is a novel concentrated formulation administered as a single 1.0-mL SC injection that could improve convenience for patients. This randomized, open-label, phase 1 study assessed the pharmacokinetics, bioavailability, pharmacodynamics, and safety of furosemide 80 mg/mL SC versus furosemide 80 mg administered intravenously (IV). Healthy volunteers were randomized 1:1 to furosemide 80 mg/mL SC or furosemide 80 mg IV (two 40-mg boluses, 2 hours apart), and after a 3-day washout, received the opposite treatment. Plasma furosemide pharmacokinetics, urine output, and urinary sodium and potassium excretion were measured through 12 hours post-dose. Bioavailability (the primary endpoint) was assessed as the least-squares mean ratio (LSMR) of area under the curve (AUC) from time 0−last (AUClast) and 0−infinity (AUCinf) between furosemide SC and furosemide IV. Plasma furosemide pharmacokinetics were assessed noncompartmentally. Pharmacodynamics were assessed using a repeated measures, mixed model analysis. Safety was assessed through end of study. Twenty-one participants were randomized (furosemide SC/IV, n = 10; furosemide IV/SC, n = 11). The furosemide SC/IV LSMR (90% confidence interval [CI]) AUClast was 106.1% (102.7%, 109.6%), and LSMR (90% CI) AUCinf was 107.3% (103.9%, 110.8%). Furosemide 80 mg/mL SC had bioavailability equivalent to furosemide 80 mg IV, as the CIs fell within 80.0%–125.0%. Mean (SD) Cmax was 4532.9 (1497.7) ng/mL with furosemide 80 mg/mL SC and 10,087.6 (2804.7) ng/mL with furosemide IV. The therapeutic effects of furosemide 80 mg/mL SC on diuresis, natriuresis, and kaliuresis occurred within 1 hour of treatment and were consistent with those of furosemide IV at all time points. There was no significant difference between furosemide 80 mg/mL SC versus furosemide IV in total urine output or urinary sodium or potassium excretion at 0–6 hours, 0–8 hours, or 0–12 hours. Adverse events (AEs) occurred in 14 (66.7%) participants (furosemide SC, n = 11 [52.4%]; furosemide IV, n = 7 [35.0%]) and were mild or moderate. Ten (47.6%) participants had injection site AEs, all of which were treatment-related, mild, non-serious, and resolved. Injection site pain scores graded on a Likert 11-point scale remained low (mean, <0.4; median, 0) at all time points, were similar between groups, and decreased over time. Furosemide 80 mg/mL SC injection was generally well tolerated and had bioavailability, diuresis, natriuresis, and kaliuresis consistent with those of furosemide IV.

Suspected coronary artery disease (CAD) is one of the most common, potentially life-threatening diagnostic problems clinicians encounter. However, no large outcome-based randomized trials have been performed to guide the selection of diagnostic strategies for these patients. The PROMISE study is a prospective, randomized trial comparing the effectiveness of 2 initial diagnostic strategies in patients with symptoms suspicious for CAD. Patients are randomized to either (1) functional testing (exercise electrocardiogram, stress nuclear imaging, or stress echocardiogram) or (2) anatomical testing with ≥64-slice multidetector coronary computed tomographic angiography. Tests are interpreted locally in real time by subspecialty certified physicians, and all subsequent care decisions are made by the clinical care team. Sites are provided results of central core laboratory quality and completeness assessment. All subjects are followed up for ≥1 year. The primary end point is the time to occurrence of the composite of death, myocardial infarction, major procedural complications (stroke, major bleeding, anaphylaxis, and renal failure), or hospitalization for unstable angina. More than 10,000 symptomatic subjects were randomized in 3.2 years at 193 US and Canadian cardiology, radiology, primary care, urgent care, and anesthesiology sites. Multispecialty community practice enrollment into a large pragmatic trial of diagnostic testing strategies is both feasible and efficient. The PROMISE trial will compare the clinical effectiveness of an initial strategy of functional testing against an initial strategy of anatomical testing in symptomatic patients with suspected CAD. Quality of life, resource use, cost-effectiveness, and radiation exposure will be assessed.

Preparticipation screening of athletes with 12-lead electrocardiography has been promoted for the detection of asymptomatic cardiovascular disease, particularly hypertrophic cardiomyopathy (HC). Although false-positive electrocardiographic (ECG) results for HC are well recognized in athlete screening, expected false-negative rates are unknown. The aim of this study was to characterize the rate of false-negative ECG findings in a cohort of young asymptomatic patients with phenotypically expressed HC, defined by cardiovascular magnetic resonance, using the 2010 European Society of Cardiology recommended ECG criteria for the identification of suspected heart disease in trained athletes. Cardiac magnetic resonance studies and 12-lead electrocardiography were performed in 114 consecutive asymptomatic patients with HC aged ≤35 years (mean age 22 ± 8 years; 77% male patients). Electrocardiograms were analyzed to distinguish pathologic ECG patterns from alterations considered nonpathologic and physiologic consequences of athletic training. Among the 114 patients with HC, 103 (90%) demonstrated ≥1 pathologic ECG abnormality, while the remaining 11 patients (10%) had normal or nonpathologic ECG patterns and therefore defined a subgroup in whom ECG screening would not be expected to raise suspicion of heart disease (i.e., false-negative results). In this false-negative ECG results group, maximal left ventricular wall thickness was 17 ± 2 mm (range 15 to 21), compared to patients with pathologic ECG patterns, in whom maximal left ventricular wall thickness was 22 ± 5 mm (p = 0.003). In conclusion, a substantial minority of young asymptomatic patients with HC with phenotypically expressed left ventricular hypertrophy have nonpathologic ECG findings on the basis of the 2010 European Society of Cardiology guidelines. In principle, this high false-negative rate of 10% represents an important limitation in applying 12-lead electrocardiography to large, apparently healthy athletic populations for the detection of HC.

While infarct size in patients with ST-segment elevation myocardial infarction (STEMI) has been generally associated with long-term prognosis, whether a therapeutic effect on infarct size has a corresponding therapeutic effect on long-term outcomes is unknown. Using combined patient-level data from 10 randomized trials of primary percutaneous coronary intervention (PCI) for STEMI, we created multivariable Cox proportional hazard models for one-year heart failure hospitalization and all-cause mortality, which included clinical features and a variable representing treatment effect on infarct size. The trials included 2679 participants; infarct size was measured at a median 4 days post infarction. Mean infarct size among the control groups ranged from 16% to 35% of the left ventricle, and from 12% to 36% among treatment groups. There was a significant relationship between treatment effect on infarct size and treatment effect on 1-year heart failure hospitalization (HR 0.85, 95% CI 0.77-0.93, P=.0006), but not on one-year mortality (HR 0.97, 95% CI 0.89-1.06). The treatment effect between infarct size and heart failure hospitalization was stable in sensitivity analyses adjusting for time from STEMI onset to infarct size assessment, and when considering heart failure as the main outcome and death as a competing risk. We conclude that early treatment-induced effects on infarct size are related in direction and magnitude to treatment effects on heart failure hospitalizations. This finding enables consideration of using infarct size as a valid surrogate outcome measure in assessing new STEMI treatments.

[...]many surgical candidates cannot (or will not) choose to travel to select centers for myectomy. [...]although myectomy is considered the gold standard treatment for most severely symptomatic patients with HC and outflow obstruction by expert consensus panels,2,3 a referral vacuum has nevertheless been created by the relative paucity of experienced surgeons prepared to perform this operation.

In 1998, the Journal published one of the early studies evaluating the sensitivity and specificity of coronary computed tomographic angiography (CTA), as compared with invasive coronary angiography, for the detection of obstructive coronary artery disease. 1 Subsequent studies have established that CTA has excellent sensitivity (95 to 99%) and high specificity (64 to 83%) for the detection of coronary stenoses of 50% or greater. 2 An analysis from the Prospective Multicenter Imaging Study for the Evaluation of Chest Pain (PROMISE) showed that CTA predicted subsequent cardiovascular events at least as well as, and perhaps better than, functional testing (C-statistic, 0.72 vs. 0.64; . . .

Aims Clinical studies of vagal nerve stimulation (VNS) for heart failure with reduced ejection fraction have had mixed results to date. We sought to compare VNS delivery and associated changes in symptoms and function in autonomic regulation therapy via left or right cervical vagus nerve stimulation in patients with chronic heart failure (ANTHEM‐HF), increase of vagal tone in heart failure (INOVATE‐HF), and neural cardiac therapy for heart failure (NECTAR‐HF) for hypothesis generation. Methods and results Descriptive statistics were used to analyse data from the public domain for differences in proportions using Pearson's chi‐square test, differences in mean values using Student's unpaired t‐test, and differences in changes of mean values using two‐sample t‐tests. Guideline‐directed medical therapy recommendations were similar across studies. Fewer patients were in New York Heart Association 3, and baseline heart rate (HR) was higher in ANTHEM‐HF. In INOVATE‐HF, VNS was aimed at peripheral neural targets, using closed‐loop delivery that required synchronization of VNS to R‐wave sensing by an intracardiac lead. Pulse frequency was low (1–2 Hz) because of a timing schedule allowing ≤3 pulses of VNS following at most 25% of detected R waves. NECTAR‐HF and ANTHEM‐HF used open‐loop VNS delivery (i.e. independent of any external signal) aimed at both central and peripheral targets. In NECTAR‐HF, VNS delivery at 20 Hz caused off‐target effects that limited VNS up‐titration in a majority of patients. In ANTHEM‐HF, VNS delivery at 10 Hz allowed up‐titration until changes in HR dynamics were confirmed. Six months after VNS titration, significant improvements in both HR and HR variability occurred only in ANTHEM‐HF. When ANTHEM‐HF and NECTAR‐HF were compared, greater improvements from baseline were observed in ANTHEM‐HF in standard deviation in normal‐to‐normal R‐R intervals (94 ± 26 to 111 ± 50 vs. 146 ± 48 to 130 ± 52 ms; P < 0.001), left ventricular ejection fraction (32 ± 7 to 37 ± 0.4 vs. 31 ± 6 to 33 ± 6; P < 0.05), and Minnesota Living with Heart Failure mean score (40 ± 14 to 21 ± 10 vs. 44 ± 22 to 36 ± 21; P < 0.002). When compared with INOVATE‐HF, greater improvement in 6‐min walk distance was observed in ANTHEM‐HF (287 ± 66 to 346 ± 78 vs. 304 ± 111 to 334 ± 111 m; P < 0.04). Conclusions In this post‐hoc analysis, differences in patient demographics were seen and may have caused the differential responses in symptoms and function observed in association with VNS. Major differences in technology platforms, neural targets, VNS delivery, and HR and HR variability responses could have also potentially played a very important role. Further study is underway in a randomized controlled trial with these considerations in mind.

Although early cardiac computed tomographic angiography (CCTA) might improve the management of emergency department (ED) patients with acute chest pain, it could also result in increased testing, costs, and radiation exposure. ROMICAT II was a randomized comparative effectiveness trial enrolling patients 40 to 74 years old without known coronary artery disease who presented to the ED with chest pain but without ischemic electrocardiographic (ECG) changes or elevated initial troponin and who required further risk stratification. Overall, 1000 patients at 9 sites within the United States were randomized to either CCTA as the first diagnostic test following serial biomarkers or to standard of care, which included no testing or functional testing such as exercise ECG, stress radionuclide imaging, or stress echocardiography. Test results were provided to ED physicians, yet patient management was not driven by a study protocol in either arm. Data were collected on diagnostic testing, cardiac events, and cost of medical care for the index hospitalization and during the following 28 days. The primary end point was length of hospital stay. Secondary end points were cumulative radiation exposure, resource utilization, and costs of competing strategies. Tertiary end points were institutional, physician, and patient characteristics associated with primary and secondary outcomes. Rate of missed acute coronary syndrome within 28 days was the safety end point. The ROMICAT II will provide rigorous data on whether CCTA is more efficient than standard of care in the management of patients with acute chest pain at intermediate risk for acute coronary syndrome.