Bankstown Hospital - Grand Rounds - Further Reading

Welcome to the Grand Rounds Further Reading List, Cardiology edition, brought to you by the Clinical Library, on Level 4, next to the Auditorium.

This library guide is to help support you in your professional development. Please give us feedback so we can improve this list in the future.

If you have any questions, please contact the Clinical Library on 9722 8250 or email SWSLHD-BankstownLibrary@health.nsw.gov.au or visit us Monday to Fridays, 8.30am - 5.00pm. (closed Wednesday afternoons from 1.00pm to 5.00pm)

"Canary in a coal mine: lipoprotein(a) and other biomarkers of cardiovascular risk"

Atar, D., et al. (2021). "New cardiovascular prevention guidelines: How to optimally manage dyslipidaemia and cardiovascular risk in 2021 in patients needing secondary prevention?" Atherosclerosis 319: 51-61:  

https://www.sciencedirect.com/science/article/pii/S0021915020315872 FULL TEXT AT LINK

                Elevated low-density lipoprotein cholesterol (LDL-C) is a principally modifiable cause of atherosclerotic cardiovascular disease; accordingly, recent European and US multisociety dyslipidaemia guidelines emphasise the importance of lowering LDL-C to reduce cardiovascular risk. This review provides perspectives on established and emerging agents that reduce LDL-C to help providers synthesize the abundance of new evidence related to prevention of cardiovascular disease. We provide hypothetical cases of patients with different cardiovascular risk factors and medical histories to illustrate application of current lipid-lowering guidelines in various clinical settings. As a core focus of preventive therapy, both European and US lipid management guidelines emphasise the importance of identifying patients at very high cardiovascular risk and treating to achieve LDL-C levels as low as possible, with European guidelines setting a goal of <1.4 mmol/L (<55 mg/dL) in patients with very high-risk cardiovascular disease. The proprotein convertase subtilisin/kexin type 9 inhibitors are now included in the guidelines and may fulfil an important unmet need for very high-risk patients who are not able to achieve LDL-C goals with conventional agents. The recently approved bempedoic acid and other promising agents under development will add to the armamentarium of lipid-lowering drugs available for clinicians to help patients meet their treatment goals.

Duarte Lau, F. and R. P. Giugliano (2022). "Lipoprotein(a) and its Significance in Cardiovascular Disease: A Review." JAMA Cardiology 7(7): 760-769: https://doi.org/10.1001/jamacardio.2022.0987  REQUEST ARTICLE FROM LIBRARY

                Lipoprotein(a) (Lp[a]) is a low-density lipoprotein (LDL) cholesterol–like particle bound to apolipoprotein(a). This novel marker of cardiovascular disease acts through induction of vascular inflammation, atherogenesis, calcification, and thrombosis. While an absolute risk threshold remains to be universally accepted, an estimated 20% to 25% of the global population have Lp(a) levels of 50 mg/dL or higher, a level noted by the European Atherosclerosis Society to confer increased cardiovascular risk.Compelling evidence from pathophysiological, observational, and genetic studies suggest a potentially causal association between high Lp(a) levels, atherosclerotic cardiovascular disease, and calcific aortic valve stenosis. Additional evidence has demonstrated that elevated Lp(a) levels are associated with a residual cardiovascular risk despite traditional risk factor optimization, including LDL cholesterol reduction. These findings have led to the formulation of the Lp(a) hypothesis, namely that Lp(a) lowering leads to cardiovascular risk reduction, intensifying the search for Lp(a)-reducing therapies. The ineffectiveness of lifestyle modification, statins, and ezetimibe to lower Lp(a); the modest Lp(a) reduction with proprotein convertase subtilisin/kexin type 9 inhibitors; the adverse effect profile and unclear cardiovascular benefit of pharmacotherapies such as niacin and mipomersen; and the impracticality of regular lipoprotein apheresis represent major challenges to currently available therapies. Nevertheless, emerging nucleic acid–based therapies, such as the antisense oligonucleotide pelacarsen and the small interfering RNA olpasiran, are generating interest because of their potent Lp(a)-lowering effects. Assessment of new-onset diabetes in patients achieving very low Lp(a) levels will be important in future trials.Epidemiologic and genetic studies suggest a potentially causal association between elevated Lp(a) levels, atherosclerotic cardiovascular disease, and aortic valve stenosis. Emerging nucleic acid–based therapies have potent Lp(a)-lowering effects and appear safe; phase 3 trials will establish whether they improve cardiovascular outcomes.

Lacaze, P., et al. (2022). "Aspirin for Primary Prevention of Cardiovascular Events in Relation to Lipoprotein(a) Genotypes." Journal of the American College of Cardiology 80(14): 1287-1298: https://www.jacc.org/doi/abs/10.1016/j.jacc.2022.07.027 PDF AT LINK

Abstract: Background: The role of aspirin in reducing lipoprotein(a)-mediated atherothrombotic events in primary prevention is not established. Objectives: This study sought to assess whether low-dose aspirin benefits individuals with elevated plasma lipoprotein(a)-associated genotypes in the setting of primary prevention. Methods: The study analyzed 12,815 genotyped individuals ≥70 years of age of European ancestry and without prior cardiovascular disease events enrolled in the ASPREE (ASPirin in Reducing Events in the Elderly) randomized controlled trial of 100 mg/d aspirin. We defined lipoprotein(a)-associated genotypes using rs3798220-C carrier status and quintiles of a lipoprotein(a) genomic risk score (LPA-GRS). We tested for interaction between genotypes and aspirin allocation in Cox proportional hazards models for incidence of major adverse cardiovascular events (MACE) and clinically significant bleeding. We also examined associations in the aspirin and placebo arms of the trial separately. Results: During a median 4.7 years (IQR: 3.6-5.7 years) of follow-up, 435 MACE occurred, with an interaction observed between rs3798220-C and aspirin allocation (P = 0.049). rs3798220-C carrier status was associated with increased MACE risk in the placebo group (HR: 1.90; 95% CI: 1.11-3.24) but not in the aspirin group (HR: 0.54; 95% CI: 0.17-1.70). High LPA-GRS (vs low) was associated with increased MACE risk in the placebo group (HR: 1.70; 95% CI: 1.14-2.55), with risk attenuated in the aspirin group (HR: 1.41; 95% CI: 0.90-2.23), but the interaction was not statistically significant. In all participants, aspirin reduced MACE by 1.7 events per 1,000 person-years and increased clinically significant bleeding by 1.7 events per 1,000 person-years. However, in the rs3798220-C and high LPA-GRS subgroups, aspirin reduced MACE by 11.4 and 3.3 events per 1,000 person-years respectively, without significantly increased bleeding risk. Conclusions: Aspirin may benefit older individuals.

Parthymos, I., et al. (2021). "Lipoprotein (a) as a treatment target for cardiovascular disease prevention and related therapeutic strategies: a critical overview." European Journal of Preventive Cardiology 29(5): 739-755: https://doi.org/10.1093/eurjpc/zwab052 PDF AT LINK

                Advances in several fields of cardiovascular (CV) medicine have produced new treatments (e.g. to treat dyslipidaemia) that have proven efficacy in terms of reducing deaths and providing a better quality of life. However, the burden of CV disease (CVD) remains high. Thus, there is a need to search for new treatment targets. Lipoprotein (a) [Lp(a)] has emerged as a potential novel target since there is evidence that it contributes to CVD events. In this narrative review, we present the current evidence of the potential causal relationship between Lp(a) and CVD and discuss the likely magnitude of Lp(a) lowering required to produce a clinical benefit. We also consider current and investigational treatments targeting Lp(a), along with the potential cost of these interventions.

Ruscica, M., et al. (2021). "Lipoprotein(a): Knowns, unknowns and uncertainties." Pharmacological Research 173: 105812: https://www.sciencedirect.com/science/article/pii/S1043661821003960 FULL TEXT AT LINK

                Over the last 10 years, there have been advances on several aspects of lipoprotein(a) which are reviewed in the present article. Since the standard immunoassays for measuring lipoprotein(a) are not fully apo(a) isoform-insensitive, the application of an LC-MS/MS method for assaying molar concentrations of lipoprotein(a) has been advocated. Genome wide association, epidemiological, and clinical studies have established high lipoprotein(a) as a causal risk factor for atherosclerotic cardiovascular diseases (ASCVD). However, the relative importance of molar concentration, apo(a) isoform size or variants within the LPA gene is still controversial. Lipoprotein(a)-raising single nucleotide polymorphisms has not been shown to add on value in predicting ASCVD beyond lipoprotein(a) concentrations. Although hyperlipoproteinemia(a) represents an important confounder in the diagnosis of familial hypercholesterolemia (FH), it enhances the risk of ASCVD in these patients. Thus, identification of new cases of hyperlipoproteinemia(a) during cascade testing can increase the identification of high-risk individuals. However, it remains unclear whether FH itself increases lipoprotein(a). The ASCVD risk associated with lipoprotein(a) seems to follow a linear gradient across the distribution, regardless of racial subgroups and other risk factors. The inverse association with the risk of developing type 2 diabetes needs consideration as effective lipoprotein(a) lowering therapies are progressing towards the market. Considering that Mendelian randomization analyses have identified the degree of lipoprotein(a)-lowering that is required to achieve ASCVD benefit, the findings of the ongoing outcome trial with pelacarsen will clarify whether dramatically lowering lipoprotein(a) levels can reduce the risk of ASCVD.

Swerdlow, D. I., et al. (2021). "Treatment and prevention of lipoprotein(a)-mediated cardiovascular disease: the emerging potential of RNA interference therapeutics." Cardiovascular Research 118(5): 1218-1231: https://doi.org/10.1093/cvr/cvab100 PDF AT LINK

                Lipid- and lipoprotein-modifying therapies have expanded substantially in the last 25 years, resulting in reduction in the incidence of major adverse cardiovascular events. However, no specific lipoprotein(a) [Lp(a)]-targeting therapy has yet been shown to reduce cardiovascular disease risk. Many epidemiological and genetic studies have demonstrated that Lp(a) is an important genetically determined causal risk factor for coronary heart disease, aortic valve disease, stroke, heart failure, and peripheral vascular disease. Accordingly, the need for specific Lp(a)-lowering therapy has become a major public health priority. Approximately 20% of the global population (1.4 billion people) have elevated levels of Lp(a) associated with higher cardiovascular risk, though the threshold for determining ‘high risk’ is debated. Traditional lifestyle approaches to cardiovascular risk reduction are ineffective at lowering Lp(a). To address a lifelong risk factor unmodifiable by non-pharmacological means, Lp(a)-lowering therapy needs to be safe, highly effective, and tolerable for a patient population who will likely require several decades of treatment. N-acetylgalactosamine-conjugated gene silencing therapeutics, such as small interfering RNA (siRNA) and antisense oligonucleotide targeting LPA, are ideally suited for this application, offering a highly tissue- and target transcript-specific approach with the potential for safe and durable Lp(a) lowering with as few as three or four doses per year. In this review, we evaluate the causal role of Lp(a) across the cardiovascular disease spectrum, examine the role of established lipid-modifying therapies in lowering Lp(a), and focus on the anticipated role for siRNA therapeutics in treating and preventing Lp(a)-related disease.

• Therapeutic Guidelines: Cardiovascular
• Chest Pain Evaluation
• CVD Calculator