Three drug classes (mineralocorticoid receptor antagonists MRAs, angiotensin receptor–neprilysin inhibitors ARNIs, and sodium/glucose cotransporter 2 SGLT2 inhibitors) reduce mortality in patients ...with heart failure with reduced ejection fraction (HFrEF) beyond conventional therapy consisting of angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) and β blockers. Each class was previously studied with different background therapies and the expected treatment benefits with their combined use are not known. Here, we used data from three previously reported randomised controlled trials to estimate lifetime gains in event-free survival and overall survival with comprehensive therapy versus conventional therapy in patients with chronic HFrEF.
In this cross-trial analysis, we estimated treatment effects of comprehensive disease-modifying pharmacological therapy (ARNI, β blocker, MRA, and SGLT2 inhibitor) versus conventional therapy (ACE inhibitor or ARB and β blocker) in patients with chronic HFrEF by making indirect comparisons of three pivotal trials, EMPHASIS-HF (n=2737), PARADIGM-HF (n=8399), and DAPA-HF (n=4744). Our primary endpoint was a composite of cardiovascular death or first hospital admission for heart failure; we also assessed these endpoints individually and assessed all-cause mortality. Assuming these relative treatment effects are consistent over time, we then projected incremental long-term gains in event-free survival and overall survival with comprehensive disease-modifying therapy in the control group of the EMPHASIS-HF trial (ACE inhibitor or ARB and β blocker).
The hazard ratio (HR) for the imputed aggregate treatment effects of comprehensive disease-modifying therapy versus conventional therapy on the primary endpoint of cardiovascular death or hospital admission for heart failure was 0·38 (95% CI 0·30–0·47). HRs were also favourable for cardiovascular death alone (HR 0·50 95% CI 0·37–0·67), hospital admission for heart failure alone (0·32 0·24–0·43), and all-cause mortality (0·53 0·40–0·70). Treatment with comprehensive disease-modifying pharmacological therapy was estimated to afford 2·7 additional years (for an 80-year-old) to 8·3 additional years (for a 55-year-old) free from cardiovascular death or first hospital admission for heart failure and 1·4 additional years (for an 80-year-old) to 6·3 additional years (for a 55-year-old) of survival compared with conventional therapy.
Among patients with HFrEF, the anticipated aggregate treatment effects of early comprehensive disease-modifying pharmacological therapy are substantial and support the combination use of an ARNI, β blocker, MRA, and SGLT2 inhibitor as a new therapeutic standard.
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Myocardial interstitial fibrosis is associated with cardiovascular disease and adverse prognosis. Here, to investigate the biological pathways that underlie fibrosis in the human heart, we developed ...a machine learning model to measure native myocardial T1 time, a marker of myocardial fibrosis, in 41,505 UK Biobank participants who underwent cardiac magnetic resonance imaging. Greater T1 time was associated with diabetes mellitus, renal disease, aortic stenosis, cardiomyopathy, heart failure, atrial fibrillation, conduction disease and rheumatoid arthritis. Genome-wide association analysis identified 11 independent loci associated with T1 time. The identified loci implicated genes involved in glucose transport (SLC2A12), iron homeostasis (HFE, TMPRSS6), tissue repair (ADAMTSL1, VEGFC), oxidative stress (SOD2), cardiac hypertrophy (MYH7B) and calcium signaling (CAMK2D). Using a transforming growth factor β1-mediated cardiac fibroblast activation assay, we found that 9 of the 11 loci consisted of genes that exhibited temporal changes in expression or open chromatin conformation supporting their biological relevance to myofibroblast cell state acquisition. By harnessing machine learning to perform large-scale quantification of myocardial interstitial fibrosis using cardiac imaging, we validate associations between cardiac fibrosis and disease, and identify new biologically relevant pathways underlying fibrosis.
Congenital heart diseases often involve maldevelopment of the evolutionarily recent right heart chamber. To gain insight into right heart structure and function, we fine-tuned deep learning models to ...recognize the right atrium, right ventricle and pulmonary artery, measuring right heart structures in 40,000 individuals from the UK Biobank with magnetic resonance imaging. Genome-wide association studies identified 130 distinct loci associated with at least one right heart measurement, of which 72 were not associated with left heart structures. Loci were found near genes previously linked with congenital heart disease, including NKX2-5, TBX5/TBX3, WNT9B and GATA4. A genome-wide polygenic predictor of right ventricular ejection fraction was associated with incident dilated cardiomyopathy (hazard ratio, 1.33 per standard deviation; P = 7.1 × 10
) and remained significant after accounting for a left ventricular polygenic score. Harnessing deep learning to perform large-scale cardiac phenotyping, our results yield insights into the genetic determinants of right heart structure and function.
Current accounts suggest that self-referential thought serves a pivotal function in the human ability to simulate the future during mind-wandering. Using experience sampling, this hypothesis was ...tested in two studies that explored the extent to which self-reflection impacts both retrospection and prospection during mind-wandering. Study 1 demonstrated that a brief period of self-reflection yielded a prospective bias during mind-wandering such that participants’ engaged more frequently in spontaneous future than past thought. In Study 2, individual differences in the strength of self-referential thought — as indexed by the memorial advantage for self rather than other-encoded items — was shown to vary with future thinking during mind-wandering. Together these results confirm that self-reflection is a core component of future thinking during mind-wandering and provide novel evidence that a key function of the autobiographical memory system may be to mentally simulate events in the future.
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