Beyond LDL-C: unravelling the residual atherosclerotic cardiovascular disease risk landscape-focus on hypertriglyceridaemia.

Aims: Historically, atherosclerotic cardiovascular disease (ASCVD) risk profile mitigation has had a predominant focus on low density lipoprotein cholesterol (LDL-C). In this narrative review we explore the residual ASCVD risk profile beyond LDL-C with a focus on hypertriglyceridaemia, recent clinical trials of therapeutics targeting hypertriglyceridaemia and novel modalities addressing other residual ASCVD risk factors. Findings: Hypertriglyceridaemia remains a significant ASCVD risk despite low LDL-C in statin or proprotein convertase subtilisin/kexin type 9 inhibitor-treated patients. Large population-based observational studies have consistently demonstrated an association between hypertriglyceridaemia with ASCVD. This relationship is complicated by the co-existence of low high-density lipoprotein cholesterol. Despite significantly improving atherogenic dyslipidaemia, the most recent clinical trial outcome has cast doubt on the utility of pharmacologically lowering triglyceride concentrations using fibrates. On the other hand, purified eicosapentaenoic acid (EPA), but not in combination with docosahexaenoic acid (DHA), has produced favourable ASCVD outcomes. The outcome of these trials suggests alternate pathways involved in ASCVD risk modulation. Several other pharmacotherapies have been proposed to address other ASCVD risk factors targeting inflammation, thrombotic and metabolic factors. Implications: Hypertriglyceridaemia poses a significant residual ASCVD risk in patients already on LDL-C lowering therapy. Results from pharmacologically lowering triglyceride are conflicting. The role of fibrates and combination of EPA and DHA is under question but there is now convincing evidence of ASCVD risk reduction with pure EPA in a subgroup of patients with hypertriglyceridaemia. Clinical guidelines should be updated in line with recent clinical trials evidence. Novel agents targeting non-conventional ASCVD risks need further evaluation.

Genetic imputation of kidney transcriptome, proteome and multi-omics illuminates new blood pressure and hypertension targets.

Genetic mechanisms of blood pressure (BP) regulation remain poorly defined. Using kidney-specific epigenomic annotations and 3D genome information we generated and validated gene expression prediction models for the purpose of transcriptome-wide association studies in 700 human kidneys. We identified 889 kidney genes associated with BP of which 399 were prioritised as contributors to BP regulation. Imputation of kidney proteome and microRNAome uncovered 97 renal proteins and 11 miRNAs associated with BP. Integration with plasma proteomics and metabolomics illuminated circulating levels of myo-inositol, 4-guanidinobutanoate and angiotensinogen as downstream effectors of several kidney BP genes (SLC5A11, AGMAT, AGT, respectively). We showed that genetically determined reduction in renal expression may mimic the effects of rare loss-of-function variants on kidney mRNA/protein and lead to an increase in BP (e.g., ENPEP). We demonstrated a strong correlation (r = 0.81) in expression of protein-coding genes between cells harvested from urine and the kidney highlighting a diagnostic potential of urinary cell transcriptomics. We uncovered adenylyl cyclase activators as a repurposing opportunity for hypertension and illustrated examples of BP-elevating effects of anticancer drugs (e.g. tubulin polymerisation inhibitors). Collectively, our studies provide new biological insights into genetic regulation of BP with potential to drive clinical translation in hypertension.