Trained immunity, also known as innate immune memory, is a persistent hyper-responsive functional state of innate immune cells. Accumulating evidence implicates trained immunity as an underlying mechanism of chronic inflammation in atherosclerotic cardiovascular disease. In this context, trained immunity is induced by endogenous atherosclerosis-promoting factors, such as modified lipoproteins or hyperglycaemia, causing broad metabolic and epigenetic reprogramming of the myeloid cell compartment. In addition to traditional cardiovascular risk factors, lifestyle factors, including unhealthy diets, sedentary lifestyle, sleep deprivation and psychosocial stress, as well as inflammatory comorbidities, have been shown to activate trained immunity-like mechanisms in bone marrow haematopoietic stem cells. In this Review, we discuss the molecular and cellular mechanisms of trained immunity, its systemic regulation through haematopoietic progenitor cells in the bone marrow, and the activation of these mechanisms by cardiovascular disease risk factors. We also highlight other trained immunity features that are relevant for atherosclerotic cardiovascular disease, including the diverse cell types that show memory characteristics and transgenerational inheritance of trained immunity traits. Finally, we propose potential strategies for the therapeutic modulation of trained immunity to manage atherosclerotic cardiovascular disease.

Cardiovascular diseases (CVDs) are the leading causes of morbidity and mortality in individuals with type 2 diabetes mellitus (T2DM). Secular changes in CVD outcomes have occurred over the past few decades, mainly due to a decline in the incidence of ischaemic heart disease. The onset of T2DM at a young age (<40 years), leading to a greater number of life-years lost, has also become increasingly common. Researchers are now looking beyond established risk factors in patients with T2DM towards the role of ectopic fat and, potentially, haemodynamic abnormalities in mediating important outcomes (such as heart failure). T2DM confers a wide spectrum of risk and is not necessarily a CVD risk equivalent, indicating the importance of risk assessment strategies (such as global risk scoring, consideration of risk-enhancing factors and assessment of subclinical atherosclerosis) to inform treatment. Data from epidemiological studies and clinical trials demonstrate that successful control of multiple risk factors can reduce the risk of CVD events by ≥50%; however, only ≤20% of patients achieve targets for risk factor reduction (plasma lipid levels, blood pressure, glycaemic control, body weight and non-smoking status). Improvements in composite risk factor control with lifestyle management (including a greater emphasis on weight loss interventions) and evidence-based generic and novel pharmacological therapies are therefore needed when the risk of CVD is high.

The prevalence of obesity has reached pandemic proportions, and now approximately 25% of adults in Westernized countries have obesity. Recognized as a major health concern, obesity is associated with multiple comorbidities, particularly cardiometabolic disorders. In this Review, we present obesity as an evolutionarily novel condition, summarize the epidemiological evidence on its detrimental cardiometabolic consequences and discuss the major mechanisms involved in the association between obesity and the risk of cardiometabolic diseases. We also examine the role of potential moderators of this association, with evidence for and against the so-called 'metabolically healthy obesity phenotype', the 'fatness but fitness' paradox or the 'obesity paradox'. Although maintenance of optimal cardiometabolic status should be a primary goal in individuals with obesity, losing body weight and, particularly, excess visceral adiposity seems to be necessary to minimize the risk of cardiometabolic diseases.

Obstructive sleep apnoea (OSA), characterized by recurrent periods of upper airway obstruction and intermittent hypoxaemia, is prevalent in patients with cardiovascular disease (CVD), and is therefore important to consider in the prevention and management of CVD. Observational studies indicate that OSA is a risk factor for incident hypertension, poorly controlled blood pressure, stroke, myocardial infarction, heart failure, cardiac arrhythmias, sudden cardiac death and all-cause death. However, clinical trials have not provided consistent evidence that treatment with continuous positive airway pressure (CPAP) improves cardiovascular outcomes. These overall null findings might be explained by limitations in trial design and low levels of adherence to CPAP. Studies have also been limited by the failure to consider OSA as a heterogeneous disorder that consists of multiple subtypes resulting from variable contributions from anatomical, physiological, inflammatory and obesity-related risk factors, and resulting in different physiological disturbances. Novel markers of sleep apnoea-associated hypoxic burden and cardiac autonomic response have emerged as predictors of OSA-related susceptibility to adverse health outcomes and treatment response. In this Review, we summarize our understanding of the shared risk factors and causal links between OSA and CVD and emerging knowledge on the heterogeneity of OSA. We discuss the varied mechanistic pathways that result in CVD that also vary across subgroups of OSA, as well as the potential role of new biomarkers for CVD risk stratification.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce heart failure events by direct action on the failing heart that is independent of changes in renal tubular function. In the failing heart, nutrient transport into cardiomyocytes is increased, but nutrient utilization is impaired, leading to deficient ATP production and the cytosolic accumulation of deleterious glucose and lipid by-products. These by-products trigger downregulation of cytoprotective nutrient-deprivation pathways, thereby promoting cellular stress and undermining cellular survival. SGLT2 inhibitors restore cellular homeostasis through three complementary mechanisms: they might bind directly to nutrient-deprivation and nutrient-surplus sensors to promote their cytoprotective actions; they can increase the synthesis of ATP by promoting mitochondrial health (mediated by increasing autophagic flux) and potentially by alleviating the cytosolic deficiency in ferrous iron; and they might directly inhibit glucose transporter type 1, thereby diminishing the cytosolic accumulation of toxic metabolic by-products and promoting the oxidation of long-chain fatty acids. The increase in autophagic flux mediated by SGLT2 inhibitors also promotes the clearance of harmful glucose and lipid by-products and the disposal of dysfunctional mitochondria, allowing for mitochondrial renewal through mitochondrial biogenesis. This Review describes the orchestrated interplay between nutrient transport and metabolism and nutrient-deprivation and nutrient-surplus signalling, to explain how SGLT2 inhibitors reverse the profound nutrient, metabolic and cellular abnormalities observed in heart failure, thereby restoring the myocardium to a healthy molecular and cellular phenotype.

In the version of this article initially published, Julie Boussuge-Roze's surname was misspelled as Boussge-Roze. The error has been corrected in the HTML and PDF versions of the article.