Association is not causation: treatment effects cannot be estimated from observational data in heart failure

Aims: Treatment ‘effects’ are often inferred from non-randomized and observational studies. These studies have inherent biases and limitations, which may make therapeutic inferences based on their results unreliable. We compared the conflicting findings of these studies to those of prospective randomized controlled trials (RCTs) in relation to pharmacological treatments for heart failure (HF). Methods and results: We searched Medline and Embase to identify studies of the association between non-randomized drug therapy and all-cause mortality in patients with HF until 31 December 2017. The treatments of interest were: angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, mineralocorticoid receptor antagonists (MRAs), statins, and digoxin. We compared the findings of these observational studies with those of relevant RCTs. We identified 92 publications, reporting 94 non-randomized studies, describing 158 estimates of the ‘effect’ of the six treatments of interest on all-cause mortality, i.e. some studies examined more than one treatment and/or HF phenotype. These six treatments had been tested in 25 RCTs. For example, two pivotal RCTs showed that MRAs reduced mortality in patients with HF with reduced ejection fraction. However, only one of 12 non-randomized studies found that MRAs were of benefit, with 10 finding a neutral effect, and one a harmful effect. Conclusion: This comprehensive comparison of studies of non-randomized data with the findings of RCTs in HF shows that it is not possible to make reliable therapeutic inferences from observational associations. While trials undoubtedly leave gaps in evidence and enrol selected participants, they clearly remain the best guide to the treatment of patients

The year in cardiology: heart failure. The year in cardiology 2019.

No abstract available

Redefining heart failure phenotypes based on ejection fraction

No abstract available

Talking to patients with heart failure about end of life

No abstract available

Tricyclic pyrone compounds prevent aggregation and reverse cellular phenotypes caused by expression of mutant huntingtin protein in striatal neurons

<p>Abstract</p> <p>Background</p> <p>Huntington's disease (HD) is a progressive neurodegenerative disorder caused by a CAG repeat expansion mutation in the coding region of a novel gene. The mechanism of HD is unknown. Most data suggest that polyglutamine-mediated aggregation associated with expression of mutant huntingtin protein (mhtt) contributes to the pathology. However, recent studies have identified early cellular dysfunctions that preclude aggregate formation. Suppression of aggregation is accepted as one of the markers of successful therapeutic approaches. Previously, we demonstrated that tricyclic pyrone (TP) compounds efficiently inhibited formation of amyloid-β (Aβ) aggregates in cell and mouse models representing Alzheimer's Disease (AD). In the present study, we aimed to determine whether TP compounds could prevent aggregation and restore early cellular defects in primary embryonic striatal neurons from animal model representing HD.</p> <p>Results</p> <p>TP compounds effectively inhibit aggregation caused by mhtt in neurons and glial cells. Treatment with TP compounds also alleviated cholesterol accumulation and restored clathrin-independent endocytosis in HD neurons.</p> <p>Conclusion</p> <p>We have found that TP compounds not only blocked mhtt-induced aggregation, but also alleviated early cellular dysfunctions that preclude aggregate formation. Our data suggest TP molecules may be used as lead compounds for prevention or treatment of multiple neurodegenerative diseases including HD and AD.</p

The binding of ethidium bromide to chromatin : model for carcinogen interactions

Five forms of chromatin, which represent the in vivo folded forms of nucleic acid, were isolated and used as the binding substrate for model intercalating compound, ethidium bromide. For all forms of chromatin, the affinity, location and structural effects of binding were examined. On the level of the nucleosome, the binding of ethidium caused a step-wise dissociation of nucleoprotein complex resulting in the initial release of one copy each of H2A and H25 before complete dissociation to free DNA. Dissociation was induced by the intercalation mode of ethidium binding, and was not due to electrostatic interactions or alternate binding modes. The binding of ethidium resulted in no major particle unfolding event prior to step-wise dissociation. Initial ethidium binding to the core particle occurred only at the end 25 by of the core particle DNA, and occurred with very low affinity. Ethidium binding to the 11 nm fiber comprising polynucleosomes, free from H1 and non-histone chromosomal proteins, was characterized by high affinity, very similar to free DNA. The initial binding events were localized within the linker DNA in preference to the folded nucleosomal DNA. In contrast, ethidium binding to the long chromatin form containing H1, the extended 30 nm fiber, displayed a 10-fold lower affinity than either free DNA or the 11 nm fiber. More extensive folding of the 30 nm fiber to its condensed form, induced by the addition of monocations, resulted in a 30-fold decrease in binding affinity of ethidium relative to free DNA. In conclusion, the structure of the chromatin has a large effect on the binding of intercalating compounds. Generally, intercalation into DNA does occur, but the placement of dye molecules appears to be governed by the accessibility of the DNA at the expense of bound histone proteins. The in vitro data were used to construct a model for the interaction of mutagens and carcinogens in vivo and to gain structural information about the native nucleoprotein complexes

Palliative care needs in patients hospitalized with heart failure (PCHF) study: rationale and design

Abstract Aims The primary aim of this study is to provide data to inform the design of a randomized controlled clinical trial (RCT) of a palliative care (PC) intervention in heart failure (HF). We will identify an appropriate study population with a high prevalence of PC needs defined using quantifiable measures. We will also identify which components a specific and targeted PC intervention in HF should include and attempt to define the most relevant trial outcomes. Methods An unselected, prospective, near-consecutive, cohort of patients admitted to hospital with acute decompensated HF will be enrolled over a 2-year period. All potential participants will be screened using B-type natriuretic peptide and echocardiography, and all those enrolled will be extensively characterized in terms of their HF status, comorbidity, and PC needs. Quantitative assessment of PC needs will include evaluation of general and disease-specific quality of life, mood, symptom burden, caregiver burden, and end of life care. Inpatient assessments will be performed and after discharge outpatient assessments will be carried out every 4 months for up to 2.5 years. Participants will be followed up for a minimum of 1 year for hospital admissions, and place and cause of death. Methods for identifying patients with HF with PC needs will be evaluated, and estimates of healthcare utilisation performed. Conclusion By assessing the prevalence of these needs, describing how these needs change over time, and evaluating how best PC needs can be identified, we will provide the foundation for designing an RCT of a PC intervention in HF