Should a Statin be Given to All Hypertensive Patients?

PURPOSE OF REVIEW: To review the milestone trials and recent literature supporting statin therapy for prevention of atherosclerotic cardiovascular disease (ASCVD) and to provide rationale for more generalized use of statin therapy among patients treated for hypertension. RECENT FINDINGS: Hypertension is a leading modifiable risk factor for ASCVD worldwide. Randomized controlled trial evidence supports initiation of antihypertensive medication for stage 2 hypertension regardless of ASCVD risk. The HOPE-3 trial tested statin therapy in intermediate-risk individuals (defined as an annual risk of major cardiovascular events of approximately 1%) for primary prevention of ASCVD and reported significant reductions in cardiovascular events in all statin treatment arms, with the greatest benefit observed in patients in the highest tertile of systolic blood pressure. Based on the current data, patients with stage 2 hypertension with an indication for antihypertensive therapy may benefit from the addition of statin therapy in the primary prevention setting. Patients with hypertension have an elevated risk for ASCVD that appears to be modifiable beyond implementation of antihypertensive therapy. The addition of statin therapy in patients treated with antihypertensive therapy may further help to lower risk of future cardiovascular events.

Autophagic signaling promotes systems-wide remodeling in skeletal muscle upon oncometabolic stress by D2-HG.

OBJECTIVES: Cachexia is a metabolic disorder and comorbidity with cancer and heart failure. The syndrome impacts more than thirty million people worldwide, accounting for 20% of all cancer deaths. In acute myeloid leukemia, somatic mutations of the metabolic enzyme isocitrate dehydrogenase 1 and 2 cause the production of the oncometabolite D2-hydroxyglutarate (D2-HG). Increased production of D2-HG is associated with heart and skeletal muscle atrophy, but the mechanistic links between metabolic and proteomic remodeling remain poorly understood. Therefore, we assessed how oncometabolic stress by D2-HG activates autophagy and drives skeletal muscle loss. METHODS: We quantified genomic, metabolomic, and proteomic changes in cultured skeletal muscle cells and mouse models of IDH-mutant leukemia using RNA sequencing, mass spectrometry, and computational modeling. RESULTS: D2-HG impairs NADH redox homeostasis in myotubes. Increased NAD+ levels drive activation of nuclear deacetylase Sirt1, which causes deacetylation and activation of LC3, a key regulator of autophagy. Using LC3 mutants, we confirm that deacetylation of LC3 by Sirt1 shifts its distribution from the nucleus into the cytosol, where it can undergo lipidation at pre-autophagic membranes. Sirt1 silencing or p300 overexpression attenuated autophagy activation in myotubes. In vivo, we identified increased muscle atrophy and reduced grip strength in response to D2-HG in male vs. female mice. In male mice, glycolytic intermediates accumulated, and protein expression of oxidative phosphorylation machinery was reduced. In contrast, female animals upregulated the same proteins, attenuating the phenotype in vivo. Network modeling and machine learning algorithms allowed us to identify candidate proteins essential for regulating oncometabolic adaptation in mouse skeletal muscle. CONCLUSIONS: Our multi-omics approach exposes new metabolic vulnerabilities in response to D2-HG in skeletal muscle and provides a conceptual framework for identifying therapeutic targets in cachexia.