Faculty Bibliography

Dyslipidemia, and specifically elevated low-density lipoprotein (LDL) cholesterol, is one of the most important cardiovascular risk factors. Statins are considered first line therapy for the primary and secondary prevention of cardiovascular disease. However, statins may not be adequate treatment for elevated circulating LDL levels and are ineffective in certain familial hypercholesterolemias. The discovery of proprotein convertase subtilisin/kexin type 9 (PCSK9), a regulatory protein that affects LDL receptors, offers a new alternative for these patients. Moreover, gain-of-function PCSK9 mutations were discovered to be the root cause of familial autosomal dominant hypercholesterolemia. Inhibition of PSCK9 reduces plasma LDL levels, even in patients for whom statins are ineffective or not tolerated. Alirocumab and evolocumab, human monoclonal antibodies that inhibit PCSK9, have been approved to lower LDL levels. While there are drawbacks to these treatments, including adverse events, administration by subcutaneous injection, and high cost, these drugs are indicated for the treatment of atherosclerotic cardiovascular disease and familial hypercholesterolemia as adjunct to diet and maximally tolerated statin therapy. PCSK9 inhibitors may work synergistically with statins to lower LDL. Novel approaches to PCSK9 inhibition are currently in development with the aim of providing safe and effective treatment options to decrease cardiovascular event burden, ideally at lower cost and with oral bioavailability.

Cardiovascular disease associated with obesity and autoimmunity is the leading cause of death in these populations and significant residual risk remains despite current treatment approaches. Obesity, type 1 diabetes mellitus (T1DM), rheumatoid arthritis (RA), and systemic lupus erythematosus (SLE) are linked to chronic inflammation, and subjects with these disorders have characteristic shifts in their gut microbiome composition. Recent data suggest that alterations in gut microbial and metabolic composition may be responsible, in part, for induction of chronic inflammation, thus promoting cardiovascular disease. Common microbiome changes observed in obesity, T1DM, RA, and SLE include a decrease in the ratio of bacteria, such as Gram-positive Firmicutes to Gram-negative Bacteroidetes, as well as an overabundance or depletion of certain species, including Prevotella copri. The consequent effects of these shifts include alterations in the metabolic composition of the gut, hyper-activation of toll-like receptor 4 (TLR-4), upregulation of inflammatory pathways, e.g. c-Jun N-terminal kinase and nuclear factor-kappa B (NFκB), increased intestinal permeability, increased C-reactive protein, and increased levels of trimethylamine N-oxide (TMAO). Differential microbiome compositions may also explain sex differences observed in autoimmunity, where a male gut microbiome promotes anti-inflammatory processes as compared to a female pro-inflammatory gut microbiome. Intervention at the level of the microbiota appears to attenuate symptoms in these inflammatory syndromes with probiotic treatment, such as Lactobacilli, playing a uniquely beneficial role in restoring intestinal health, decreasing inflammation, and reducing cardiovascular disease. This review will discuss obesity, T1DM, RA, and SLE in the context of how each unique microbiome profile contributes to elevated cardiovascular risk.