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Production of trimethylamine-N-oxide (TMAO), a biomarker of CVD risk, is dependent on intestinal microbiota, but little is known of dietary conditions promoting changes in gut microbial communities. Resistant starches (RS) alter the human microbiota. We sought to determine whether diets varying in RS and carbohydrate (CHO) content affect plasma TMAO levels. We also assessed postprandial glucose and insulin responses and plasma lipid changes to diets high and low in RS. In a cross-over trial, fifty-two men and women consumed a 2-week baseline diet (41 percentage of energy (%E) CHO, 40 % fat, 19 % protein), followed by 2-week high- and low-RS diets separated by 2-week washouts. RS diets were assigned at random within the context of higher (51–53 %E) v. lower CHO (39–40 %E) intake. Measurements were obtained in the fasting state and, for glucose and insulin, during a meal test matching the composition of the assigned diet. With lower CHO intake, plasma TMAO, carnitine, betaine and γ-butyrobetaine concentrations were higher after the high- v. low-RS diet (P<0·01 each). These metabolites were not differentially affected by high v. low RS when CHO intake was high. Although the high-RS meal reduced postprandial insulin and glucose responses when CHO intake was low (P<0·01 each), RS did not affect fasting lipids, lipoproteins, glucose or insulin irrespective of dietary CHO content. In conclusion, a lower-CHO diet high in RS was associated with higher plasma TMAO levels. These findings, together with the absence of change in fasting lipids, suggest that short-term high-RS diets do not improve markers of cardiometabolic health.

The leading cause of death in the world, cardiovascular disease (CVD), remains a formidable condition for researchers, clinicians and patients alike. CVD comprises a broad collection of diseases spanning the heart, the vasculature and the blood that runs through and interconnects them. Limitations in CVD therapeutic and diagnostic landscapes have generated excitement for advances in nanomedicine, a field focused on improving patient outcomes through transformative therapies, imaging agents and ex vivo diagnostics. CVD nanomedicines are fundamentally shaped by their intended clinical application, including (1) cardiac or heart-related biomaterials, which can be functionally (for example, mechanically, immunologically, electrically) improved by incorporating nanomaterials; (2) the vasculature, involving systemically injected nanotherapeutics and imaging nanodiagnostics, nano-enabled biomaterials or tissue-nanoengineered solutions; and (3) improving the sensitivity and/or specificity of ex vivo diagnostic devices for patient samples. While immunotherapy has developed into a key pillar of oncology in the past dozen years, CVD immunotherapy and immunoimaging are recently emergent and likely to factor substantially in CVD management in the coming decade. The nanomaterials in CVD-related clinical trials and many promising preclinical strategies indicate that nanomedicine is on the cusp of greatly impacting patients with CVD. Here we review these recent advances, highlighting key clinical opportunities in the rapidly emerging field of CVD nanomedicine. Smith and Edelman discuss recent advances in cardiovascular and blood nanomedicine and highlight key clinical applications and opportunities.

Ketone bodies, the main one being β-hydroxybutyrate, have emerged as important regulators of the cardiovascular system. In healthy individuals, as well as in individuals with heart failure or post-myocardial infarction, ketones provide a supplemental energy source for both the heart and the vasculature. In the failing heart, this additional energy may contribute to improved cardiac performance, whereas increasing ketone oxidation in vascular smooth muscle and endothelial cells enhances cell proliferation and prevents blood vessel rarefication. Ketones also have important actions in signaling pathways, posttranslational modification pathways and gene transcription; many of which modify cell proliferation, inflammation, oxidative stress, endothelial function and cardiac remodeling. Attempts to therapeutically increase ketone delivery to the cardiovascular system are numerous and have shown mixed results in terms of effectiveness. Here we review the bioenergetic and signaling effects of ketones on the cardiovascular system, and we discuss how ketones can potentially be used to treat cardiovascular diseases. Lopaschuk and Dyck review the bioenergetic and signaling effects of ketones on the cardiovascular system and discuss the potential application of ketones for treating cardiovascular diseases.

The gut, microflora-dependent metabolite trimethylamine-N-oxide (TMAO) has emerged as a dietary-associated risk factor for incident cardiovascular events. Chronic obstructive pulmonary disease (COPD) is a prevalent disease worldwide with a high associated risk for cardiovascular disease and death due to an infectious cause. To study whether TMAO is predictive for adverse clinical outcomes in patients with exacerbated COPD. A total of 189 patients with COPD exacerbation were prospectively followed for a median of 6.1 y. TMAO plasma levels at the time of emergency department admission were measured by liquid chromatography coupled with tandem mass spectrometry. Cox and linear regression models were used to investigate associations of TMAO with all-cause mortality and different comorbidities. All-cause mortality was 55.6% after 6 y. The deceased patients showed significantly higher median admission TMAO (μmol/L) levels compared with survivors (3.9 [interquartile range: 2.3–7.1] versus 2.9 [interquartile range: 1.8–4.7]; P = 0.01), which resulted in an unadjusted hazard ratio of 1.8 ([95% confidence interval: 1.2–3.0], P = 0.01). This association was no longer significant after multivariate adjustment. Median TMAO levels were similar in nonpneumonic and pneumonic COPD exacerbation. Higher age, higher body mass index, diabetes mellitus, and chronic kidney disease were predictors for increased plasma TMAO levels in linear regression analysis. Increased circulating TMAO levels per se were associated with long-term all-cause mortality in patients with COPD independent of type of exacerbation. However, this association was largely explained by comorbidities and age. Whether TMAO levels can additionally be influenced by nutritional interventions should be addressed in future studies. •The gut, microflora-dependent metabolite trimethylamine-N-oxide (TMAO) is associated with mortality in patients with chronic obstructive pulmonary disease.•The prognostic value of TMAO was independent of type of exacerbation.•Comorbidities and age had a strong influence on TMAO levels.•Whether nutritional interventions influence TMAO warrants further investigation.

Platelets have emerged as key inflammatory cells implicated in the pathology of sepsis, but their contributions to rapid clinical deterioration and dysregulated inflammation have not been defined. Here, we show that the incidence of thrombocytopathy and inflammatory cytokine release was significantly increased in patients with severe sepsis. Platelet proteomic analysis revealed significant upregulation of gasdermin D (GSDMD). Using platelet-specific Gsdmd -deficient mice, we demonstrated a requirement for GSDMD in triggering platelet pyroptosis in cecal ligation and puncture (CLP)-induced sepsis. GSDMD-dependent platelet pyroptosis was induced by high levels of S100A8/A9 targeting toll-like receptor 4 (TLR4). Pyroptotic platelet-derived oxidized mitochondrial DNA (ox-mtDNA) potentially promoted neutrophil extracellular trap (NET) formation, which contributed to platelet pyroptosis by releasing S100A8/A9, forming a positive feedback loop that led to the excessive release of inflammatory cytokines. Both pharmacological inhibition using Paquinimod and genetic ablation of the S100A8/A9–TLR4 signaling axis improved survival in mice with CLP-induced sepsis by suppressing platelet pyroptosis. Su, Chen et al. show that sepsis-derived S100A8/A9 induces GSDMD-dependent platelet pyroptosis via the TLR4/ROS/NLRP3/caspase 1 pathway, leading to the release of ox-mtDNA contributing to neutrophil extracellular traps (NET) formation. NET in turn release S100A8/A9 and accelerate platelet pyroptosis, forming a positive feedback loop, thereby amplifying the production of proinflammatory cytokines. GSDMD deficiency in platelets or pharmacological inhibition of S100A9 using Paquinimod can break this detrimental feedback loop, thus ameliorating excessive NET-mediated inflammation in mouse models of severe sepsis.

Super-precise gene-editing approach switches off a gene in the liver that regulates ‘bad’ cholesterol. Super-precise gene-editing approach switches off a gene in the liver that regulates ‘bad’ cholesterol. Credit: Steve Gschmeissner/Science Photo Library Coloured SEM of cholesterol crystals (red) within a lipid droplet in a human liver.

Can cycles of dieting increase your risk of heart attack? In mice, an alternating high-fat and low-fat diet promotes plaque build-up in arteries by modulating the body’s innate immune responses. Cycling between a high-fat and low-fat diet exacerbates atherosclerosis.