Framework to Classify Reverse Cardiac Remodeling With Mechanical Circulatory Support: The Utah-Inova Stages.

BACKGROUND: Variable definitions and an incomplete understanding of the gradient of reverse cardiac remodeling following continuous flow left ventricular assist device (LVAD) implantation has limited the field of myocardial plasticity. We evaluated the continuum of LV remodeling by serial echocardiographic imaging to define 3 stages of reverse cardiac remodeling following LVAD. METHODS: The study enrolled consecutive LVAD patients across 4 study sites. A blinded echocardiographer evaluated the degree of structural (LV internal dimension at end-diastole [LVIDd]) and functional (LV ejection fraction [LVEF]) change after LVAD. Patients experiencing an improvement in LVEF ≥40% and LVIDd ≤6.0 cm were termed responders, absolute change in LVEF of ≥5% and LVEF <40% were termed partial responders, and the remaining patients with no significant improvement in LVEF were termed nonresponders. RESULTS: Among 358 LVAD patients, 34 (10%) were responders, 112 (31%) partial responders, and the remaining 212 (59%) were nonresponders. The use of guideline-directed medical therapy for heart failure was higher in partial responders and responders. Structural changes (LVIDd) followed a different pattern with significant improvements even in patients who had minimal LVEF improvement. With mechanical unloading, the median reduction in LVIDd was -0.6 cm (interquartile range [IQR], -1.1 to -0.1 cm; nonresponders), -1.1 cm (IQR, -1.8 to -0.4 cm; partial responders), and -1.9 cm (IQR, -2.9 to -1.1 cm; responders). Similarly, the median change in LVEF was -2% (IQR, -6% to 1%), 9% (IQR, 6%-14%), and 27% (IQR, 23%-33%), respectively. CONCLUSIONS: Reverse cardiac remodeling associated with durable LVAD support is not an all-or-none phenomenon and manifests in a continuous spectrum. Defining 3 stages across this continuum can inform clinical management, facilitate the field of myocardial plasticity, and improve the design of future investigations.

In-hospital and long-term mortality for acute heart failure: analysis at the time of admission to the emergency department.

AIMS: Acute heart failure (AHF) leads to a drastic increase in mortality and rehospitalization. The aim of the study was to identify prognostic variables in a real-life population of AHF patients admitted to the emergency department with acute shortness of breath. METHODS AND RESULTS: We evaluated potential predictors of mortality in 728 consecutive patients admitted to the emergency department with AHF. Possible predictors of all-cause and cardiovascular (CV) mortality were investigated by Cox and Fine and Gray models at multivariable analysis. Among the 728 patients, 256 died during the entire follow-up, 142 of these due to CV cause. The 1 year mortality rate was 20%, with the highest risk of death during the index hospitalization (with 8% estimate in-hospital mortality at 30 days). A higher risk of events during the index hospitalization was more evident for the CV deaths, for which we found a cumulative 1 year incidence of 12% with a cumulative incidence in the first 30 days of hospitalization of about 5%. At multivariable analysis, age (P < 0.001), New York Heart Association (NYHA) class IV vs. I-II-III (P = 0.001), systolic blood pressure (P < 0.001), non-cardiac co-morbidities (≥3 vs. 0, P = 0.05), oxygen saturation (P = 0.03), serum creatinine (P < 0.001), and left ventricular ejection fraction (LVEF) (40-49% vs. <40%, P = 0.004; ≥50% vs. <40%, P = 0.003) were independent predictors of all-cause mortality during the entire follow-up. Age (P = 0.03), systolic blood pressure (P = 0.01), oxygen saturation (P = 0.03), serum creatinine (P = 0.02), and LVEF (40-49% vs. <40%, P = 0.03; ≥50% vs. <40%, P = 0.004) were independent predictors of CV mortality during the entire follow-up. NYHA class IV vs. I-II-III (P < 0.001), serum creatinine (P = 0.01), and LVEF (40-49% vs. <40%, P = 0.02; ≥50% vs. <40%, P < 0.001) remained independent predictors for in-hospital death, while only serum creatinine (P = 0.04), LVEF (40-49% vs. <40%: 0.32, P = 0.04; ≥50% vs. <40%, P < 0.001), and NYHA class vs. I-II-III (P = 0.02) remained predictors for in-hospital CV mortality. CONCLUSIONS: In this real-life cohort of patients with AHF, the results showed a similar mortality rate comparing with other analysis and with the most important registries. Age, NYHA class IV, systolic blood pressure, creatinine levels, sodium levels, and ejection fraction were independent predictors of 1 year mortality, while LVEF <40% was the only predictor of both all-cause mortality and CV mortality.

Publication Rates of Heart Failure Clinical Trials Remain Low.

BACKGROUND: Under-reporting of clinical trial results inhibits dissemination of knowledge, limits understanding of therapeutic interventions, and may ultimately harm patients. OBJECTIVES: This study examined the rates and predictors of heart failure clinical trial publication and how they have changed over time. METHODS: This study assessed cross-sectional analysis of all heart failure clinical trials registered on ClinicalTrials.gov with at least 2 years follow-up after trial completion. The content area was chosen for the robust clinical trial activity in the field. The primary outcome was manuscript publication with multivariable proportional hazards adjustment to identify associations with publication. RESULTS: Of the 1,429 included studies, 806 (56%) were published as manuscripts, 623 were unpublished, and 97 (7%) reported results without manuscript publication. Of the total, 1,243 were completed after 2007, when the mean 1-year publication rate for interventional trials rose from 12.7% to 19.6% (p = 0.049), which was possibly associated with changes in government regulation. However, there was no further sustained improvement over time, and there was no multivariable association between later completion dates and reporting or publication of results. Funding from the National Institutes of Health and use of clinical (death, hospitalization, myocardial infarction, changes in functional classification) rather than nonclinical primary endpoints were associated with earlier publication. Whether the results were consistent with the primary study hypothesis was not associated with likelihood of publication. CONCLUSIONS: The rates of heart failure clinical trial publication or reporting of results remain unacceptably low. Additional efforts by all stakeholders, including investigators, sponsors, regulators, societies, editors, and journals are needed to improve data dissemination.

Endpoints in Heart Failure Drug Development: History and Future.

Heart failure (HF) patients experience a high burden of symptoms and functional limitations, and morbidity and mortality remain high despite successful therapies. The majority of HF drugs in the United States are approved for reducing hospitalization and mortality, while only a few have indications for improving quality of life, physical function, or symptoms. Patient-reported outcomes that directly measure patient's perception of health status (symptoms, physical function, or quality of life) are potentially approvable endpoints in drug development. This paper summarizes the history of endpoints used for HF drug approvals in the United States and reviews endpoints that measure symptoms, physical function, or quality of life in HF patients.

Sex differences in nocturnal growth hormone and prolactin secretion in healthy older adults: relationships with sleep EEG variables.

STUDY OBJECTIVES: To examine sex differences in nocturnal growth hormone and prolactin release in older adults. DESIGN: Sleep was polygraphically recorded for 2 consecutive nights, and blood was sampled at frequent intervals during the last 24 hours. SETTING: The University of Chicago Clinical Research Center. PARTICIPANTS: Two groups of healthy nonobese older subjects: 10 men (59 +/- 2 years, mean +/- SEM), and 10 postmenopausal women (63 +/- 2 years). INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: A spectral analysis of the electroencephalogram was performed in the delta and alpha bands. When delta activity was normalized for the activity in rapid eye movement sleep, women had lower delta activity than men. Growth hormone secretion was estimated by deconvolution. The prolactin profile was quantified by a best-fit curve. In both sexes, growth hormone was released both before and after sleep onset. In men, there was no relationship between presleep growth hormone release and subsequent sleep quality and postsleep growth hormone release correlated with delta activity. In women, presleep growth hormone release appeared to inhibit both postsleep growth hormone release and sleep consolidation. Prolactin release was related to rapid eye movement sleep and was lower in men than in women. Women with poor sleep maintenance had a lower prolactin acrophase. CONCLUSIONS: Major sex differences in the nocturnal profiles of growth hormone and prolactin and their relationship to sleep electroencephalogram variables are present in healthy older adults. Our analyses suggest that lower sleep-onset release of growth hormone in women as compared with men could be related to lower levels of delta activity. Improvements in the homeostatic control of sleep could have hormonal benefits in older adults.

Sex differences in delta and alpha EEG activities in healthy older adults.

STUDY OBJECTIVES: To examine sex effects on sleep stages and electroencephalogram (EEG) spectral power in older adults. DESIGN: Sleep was polygraphically recorded for 2 consecutive nights, and blood was sampled during the last 24 hours. SETTING: The University of Chicago Clinical Research Center. PARTICIPANTS: Two groups of healthy nonobese older subjects: 10 men (59 +/- 2 years), and 10 postmenopausal women (63 +/- 2 years). INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: A spectral analysis of the EEG was performed in the delta and alpha bands. There were no sex differences in sleep stages. Blood sampling resulted in reductions of total sleep time, sleep maintenance, slow-wave sleep, and absolute delta activity that were all larger in women than in men. In absolute values, delta and alpha activities in non-rapid eye movement (NREM) and rapid eye movement (REM) sleep were higher in women than in men, but, for delta activity, the sex differences were larger in REM than in NREM sleep. In women, but not in men, absolute delta activity in REM was decreased during blood sampling and was strongly correlated with absolute delta activity in NREM. Delta activity in REM did not dissipate across the night in either group. When normalized for the activity in REM sleep, the sex difference in delta activity in NREM sleep was reversed, with lower activity in women. CONCLUSIONS: Sex differences in sleep EEG variables are present in older adults. When normalized, delta activity in older women is lower than in older men, which may be more consistent with sex differences in subjective complaints, in fragility of sleep in the presence of environmental disturbances, and in the relationship to growth-hormone release.

Reciprocal interactions between the GH axis and sleep.

For more than 30 years, growth hormone (GH) has been observed to be preferentially secreted during deep, slow-wave sleep (SWS). However, the mechanisms that underlie this robust relationship that links anabolic processes in the body with behavioral rest and decreased cerebral metabolism remain to be elucidated. Current evidence indicates that GH secretion during the beginning of sleep appears to be primarily regulated by GH-releasing hormone (GHRH) stimulation occurring during a period of relative somatostatin withdrawal, which also is associated with elevated levels of circulating ghrelin. Apparently, two populations of GHRH neurons need to be simultaneously active to stimulate, in a coordinated fashion, SWS and pituitary GH release. Pharmacological interventions that are capable of increasing the duration and/or the intensity of SWS such as oral administration of gamma-hydroxybutyrate (GHB), also increase the rate of GH release. Because the normal negative feedback exerted by GH on central GHRH is inoperative in patients with GH deficiency, it is possible that the decreased energy levels and fatigue often reported by GH-deficient adults partly reflect an alteration in sleep-wake regulation. Preliminary data from a sleep study of adults with GH deficiency using wrist actigraphy for 6 nights at home and polysomnography in the laboratory indeed show decreased total sleep time and increased sleep fragmentation in GH-deficient patients as compared with normal controls.