Stephen J. Nicholls's research while affiliated with Royal Victorian Eye and Ear Hospital and other places
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Publications (935)
Cardiovascular disease is the leading cause of non-cancer related mortality and morbidity among people living with or cured from cancer. Immune checkpoint inhibitors (ICIs) are systemic anti-cancer therapies that have revolutionised the treatment of numerous cancers, even achieving durable long-term responses among patients with metastatic disease....
Increasing evidence has implicated lipoprotein(a) [Lp(a)] in the causality of atherosclerosis and calcific aortic stenosis. This has stimulated immense interest in developing novel approaches to integrating Lp(a) into the setting of cardiovascular prevention. Current guidelines advocate universal measurement of Lp(a) levels, with the potential to i...
Obesity has become a pandemic in the Asia-Pacific region, with an alarming rate of increase in the prevalence of obesity. The impact of obesity and its associated comorbidities goes beyond the healthcare system, posing a substantial burden not only on the individual, but also on the society and the economy. In this review, we focus on the latest si...
Importance
Optimal health care delivery, both now and in the future, requires a continuous loop of knowledge generation, dissemination, and uptake on how best to provide care, not just determining what interventions work but also how best to ensure they are provided to those who need them. The randomized clinical trial (RCT) is the most rigorous in...
Lipoprotein(a) (Lp(a)), an independent, causal cardiovascular risk factor, is a lipoprotein particle that is formed by the interaction of a low-density lipoprotein (LDL) particle and apolipoprotein(a) (apo(a))1,2. Apo(a) first binds to lysine residues of apolipoprotein B-100 (apoB-100) on LDL through the Kringle IV (KIV) 7 and 8 domains, before a d...
Background
Primary prevention programs utilising traditional risk scores fail to identify all individuals who suffer acute cardiovascular events. We aimed to model the impact and cost effectiveness of incorporating a Polygenic risk scores (PRS) into the cardiovascular disease CVD primary prevention program in Australia, using a whole-of-system mode...
Importance
Lipoprotein(a) is a causal risk factor for atherosclerotic cardiovascular disease (ASCVD) and calcific aortic stenosis, with no pharmacological treatments approved by regulatory authorities.
Objectives
To assess the safety and tolerability of zerlasiran, a short interfering RNA targeting hepatic synthesis of apolipoprotein(a), and effec...
Importance
Severe hypertriglyceridemia (sHTG) confers increased risk of atherosclerotic cardiovascular disease (ASCVD), nonalcoholic steatohepatitis, and acute pancreatitis. Despite available treatments, persistent ASCVD and acute pancreatitis-associated morbidity from sHTG remains.
Objective
To determine the tolerability, efficacy, and dose of pl...
Background and aims
Randomized clinical trials have demonstrated the ability of glucagon-like peptide-1 analogues (GLP-1RAs) to reduce atherosclerotic cardiovascular disease events in patients with type 2 diabetes (T2D). How GLP-1RAs modulate diabetic atherosclerosis remains to be determined yet.
Methods
The OPTIMAL study was a prospective randomi...
Citation: Wong, N.K.P.; Solly, E.L.; Le, R.; Nankivell, V.A.; Mulangala, J.; Psaltis, P.J.; Nicholls, S.J.; Ng, M.K.C.; Bursill, C.A.; Tan, J.T.M. TRIM2 Selectively Regulates Inflammation-Driven Pathological Angiogenesis without Affecting Physiological Hypoxia-Mediated Angiogenesis. Int. J. Mol. Sci. 2024, 25, 3343. https://doi. These authors contr...
Background
Rilonacept, a once‐weekly interleukin‐1 alpha and beta cytokine trap, reduced pericarditis recurrence in the phase 3 study, RHAPSODY (Rilonacept Inhibition of Interleukin‐1 Alpha and Beta for Recurrent Pericarditis: A Pivotal Symptomatology and Outcomes Study). The RHAPSODY long‐term extension further explored recurrent pericarditis natu...
Atherosclerotic coronary artery disease (CAD) is the causal pathological process driving most major adverse cardiovascular events (MACE) worldwide. The complex development of atherosclerosis manifests as intimal plaque which occurs in the presence or absence of traditional risk factors. There are numerous effective medications for modifying CAD but...
Hypercholesterolaemia is one of the most common conditions treated by clinicians in Australia. Low-density lipoprotein cholesterol (LDL-C) plays a causal role in the development and progression of atherosclerosis and cardiovascular disease.
Every 1 mmol/L reduction in LDL-C concentration is associated with a 21 to 25% reduction in the relative risk...
Angiogenesis is a critical physiological response to ischemia but becomes pathological when dysregulated and driven excessively by inflammation. We recently identified a novel angiogenic role for tripartite-motif-containing protein 2 (TRIM2) whereby lentiviral shRNA-mediated TRIM2 knockdown impaired endothelial angiogenic functions in vitro. This s...
Background
Ischaemic stroke and coronary artery disease share risk factors and stroke survivors experience a high rate of cardiac events. Recent work suggests a high burden of asymptomatic coronary artery disease (CAD) in ischaemic stroke survivors. Thus, we performed this systematic review and meta-analysis to A) estimate the prevalence of CAD in...
Background
Echocardiographic quantification of mitral regurgitation (MR) remains challenging, requiring dedicated image acquisition, and is limited by potential error from geometric assumptions of annular dimensions. Volume is a product of area and flow and assuming proportional mitral/aortic areas, an increased mitral-inflow volume compared to LV/...
Background
Metabolic syndrome is characterized as the co-occurrence of interrelated cardiovascular risk factors, including insulin resistance, hyperinsulinemia, abdominal obesity, dyslipidemia and hypertension. Once weekly tirzepatide is approved in the US and EU for the treatment of type 2 diabetes (T2D) and obesity. In the SURPASS clinical trial...
Bempedoic acid is a novel therapeutic agent that is designed to reduce levels of low-density lipoprotein cholesterol (LDL-C). The purpose of this review is to provide the background for development of bempedoic acid, findings from clinical trials and to discuss clinical implications.
Bempedoic acid inhibits ATP citrate lyase within the liver and re...
Importance
The ATP citrate lyase (ACL) inhibitor, bempedoic acid, reduces low-density lipoprotein cholesterol (LDL-C) level and major adverse cardiovascular events (MACE) by 13% in patients at high cardiovascular risk with intolerance of statin and high-intensity statin medications. The effects of bempedoic acid on total cardiovascular events remai...
The cardiovascular benefits of omega‐3 polyunsaturated fatty acids (O3FA) remain a point of confusion in clinical medicine. Recently two large, randomised trials were published with discordant findings regarding the overall benefits of omega‐3 supplementation, resulting in unnecessary confusion and therapeutic nihilism. Epidemiological studies clea...
Introduction:
Plasma lipidomics has emerged as a powerful tool in cardiovascular drug discovery by providing insights into disease mechanisms, identifying potential biomarkers for diagnosis and prognosis, and discovering novel targets for drug development. Widespread application of plasma lipidomics is hampered by technological limitations and sta...
Importance
Epidemiological and genetic data have implicated lipoprotein(a) as a potentially modifiable risk factor for atherosclerotic disease and aortic stenosis, but there are no approved pharmacological treatments.
Objectives
To assess the safety, tolerability, pharmacokinetics, and effects of lepodisiran on lipoprotein(a) concentrations after...
Background
Identifying and targeting established modifiable risk factors such as hyperlipidaemia, blood pressure, smoking, and diabetes have led to a successful reduction in poor outcomes from coronary artery disease (CAD) at the population-level. However, up to one-in-four patients who present with ST elevation myocardial infarction do so in the a...
Background
Seasonal influenza immunisation reduces cardiovascular events by 30% in those with atherosclerotic cardiovascular disease (ASCVD) and up to 50% in those with recent acute coronary syndrome. However, uptake in high-risk patients remains poor. Clinician recommendation has been shown to increase adoption of influenza immunisation in the gen...
Background
Seasonal influenza immunisation reduces the risk of cardiovascular events. Patients with established cardiovascular disease (CVD) derive a greater benefit than those without yet up to 50% globally do not take up the immunisation.
Purpose
To describe the understanding and perceptions of seasonal influenza immuni2ation among patients CVD....
Background
Prompt revascularisation is central to achieving optimal outcomes for patients presenting with ST-segment elevation myocardial infarction (STEMI). To enable this, health systems have traditionally focused on the ‘door-to-balloon’ (DTB) component of total ischaemic time, while comparatively less attention has been given to symptom ‘onset-...
Background
Immune checkpoint inhibitors (ICI) are cancer therapies that have improved the prognoses of over 20 different tumour types (1). However, ICIs have been increasingly recognised to associate with major atherosclerotic cardiovascular events (MACE) in cancer survivorship (2).
Purpose
This study aimed to determine the incidence and predictor...
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Background
Lipoprotein(a) [Lp(a)] is a lipoprotein particle consisting of a low-density lipoprotein (LDL) particle and apolipoprotein(a) [apo(a)]. Lp(a) is a causal risk factor for cardiovascular disease. The formation of Lp(a) requires an initial interaction of apo(a) Kringle IV Domains 7 and 8 (KIV7, KIV8) with apoB-100 on LDL, followed by format...
The VALID BP project was initiated to increase the availability of validated blood pressure measuring devices (BPMDs). The goal is to eliminate non validated BPMDs and minimise over- and underdiagnosis of hypertension caused by inaccurate readings. This study was undertaken to assess the potential return on investment in the VALID BP project. The F...
Introduction: Among contemporary statin-treated patients, residual inflammatory risk assessed by high-sensitivity C-reactive protein (hsCRP) is a stronger predictor of future cardiovascular (CV) events and all-cause mortality than residual cholesterol risk assessed by low density lipoprotein cholesterol (LDLC). Whether these relationships are prese...
Background: Angiopoietin-like protein 3 (ANGPTL3) regulates lipoprotein metabolism by inhibiting lipoprotein and endothelial lipases. ANGPTL3 loss-of-function carriers have decreased circulating triglycerides (TGs), LDL-C, and HDL-C, and a lower risk of atherosclerotic cardiovascular disease (ASCVD). ARO-ANG3 is an investigational RNAi therapeutic...
Background: Obicetrapib is a selective CETP inhibitor that has been shown to reduce LDL-C, non-HDL-C, lipoprotein particles, and apolipoproteins when used as monotherapy, and in combination with ezetimibe, on background high-intensity statins. Previous studies of obicetrapib were conducted in predominantly Caucasian participants. There is a lack of...
Background
The risk of atherosclerotic cardiovascular disease (ASCVD) increases sharply with age. Some older individuals, however, remain unaffected despite high predicted risk. These individuals may carry cardioprotective genetic variants that contribute to resilience. Our aim was to assess whether asymptomatic older individuals without prevalent...
Background: Among patients treated with statin therapy to guideline-recommended cholesterol levels, residual inflammatory risk assessed by high-sensitivity C-reactive protein (hsCRP) is at least as strong a predictor of future cardiovascular events as is residual risk assessed by low-density lipoprotein cholesterol (LDLC). Whether these relationshi...
Background Familial hypercholesterolaemia (FH) is a genetic condition that is a preventable cause of premature car-diovascular morbidity and mortality. High-level evidence and clinical practice guidelines support preventative care for people with FH. However, it is estimated that less than 10% of people at risk of FH have been detected using any ap...
Disclosure: A. Lincoff: Advisory Board Member; Self; Novo Nordisk, Eli Lilly & Company. Consulting Fee; Self; GlaxoSmithKline, Medtronic, Ardelyx, Akebia, Endologix, Provention Bio. Grant Recipient; Self; Abbvie, Novartis Pharmaceuticals, Esperion, AstraZeneca, CSL Behring. Stock Owner; Self; Cadrenal. K. Ray: Consulting Fee; Self; Amgen Inc, Sanof...
Purpose of review
The aim of this study was to review the impact of combination lipid lowering with statins and proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors on coronary atherosclerosis using serial intravascular imaging.
Recent findings
Early studies using intravascular ultrasound established the ability of increasingly intensi...
Objective:
To evaluate the benefits of a pop-up health screening for cardiovascular risk factors (CVRF) in the Gippsland region, and to assess the acceptability of the screening and to determine whether such a process results in attendance at a general practitioner (GP).
Participants:
Overall, 454 participants over the age of 18 who were residen...
To evaluate if Indigenous Australians have higher coronary inflammation demonstrated non-invasively using pericoronary adipose tissue attenuation on coronary computed tomography angiography (CCTA). We retrospectively obtained a cohort 54 Indigenous patients age- and sex-matched to 54 non-Indigenous controls (age: 46.5 ± 13.1 years; male: n = 66) un...
Abstract
Reducing the incidence and prevalence of standard modifiable cardiovascular risk factors (SMuRFs) is critical to tackling the global burden of coronary artery disease (CAD). However, a substantial number of individuals develop coronary atherosclerosis despite no SMuRFs. SMuRFless patients presenting with myocardial infarction have been obs...
Importance:
Lipoprotein(a) (Lp[a]) is associated with atherosclerotic disease and aortic stenosis. Lp(a) forms by bonding between apolipoprotein(a) (apo[a]) and apo B100. Muvalaplin is an orally administered small molecule that inhibits Lp(a) formation by blocking the apo(a)-apo B100 interaction while avoiding interaction with a homologous protein...
Background
A lack of geographic and racial diversity in clinical trial populations may arise from a disproportionate focus on the United States and Europe for trial leadership and conduct. Inadequate diversity may compromise the external validity to the Asia-Pacific (APAC) region, where 60% of global cardiometabolic disease exists.
Objectives
This...
Significant advances have been made in artificial intelligence technology in recent years. Many health care applications have been investigated to assist clinicians and the technology is close to being integrated into routine clinical practice. The high prevalence of cardiac disease in Australia places overwhelming demands on the existing health ca...
Inflammation has been considered to promote atheroma instability. Coronary computed tomography angiography (CCTA) visualizes pericoronary adipose tissue (PCAT) attenuation, which reflects coronary artery inflammation. While PCAT attenuation has been reported to predict future coronary events, plaque phenotypes exhibiting high PCAT attenuation remai...
Calcified atheroma has been viewed conventionally as stable lesion which less likely increases no-reflow phenomenon. Given that lipidic materials triggers the formation of calcification, lipidic materials could exist within calcified lesion, which may cause no-reflow phenomenon after PCI. The REASSURE-NIRS registry (NCT04864171) employed near-infra...
Importance:
The effects of bempedoic acid on cardiovascular outcomes in statin-intolerant patients without a prior cardiovascular event (primary prevention) have not been fully described.
Objective:
To determine the effects of bempedoic acid on cardiovascular outcomes in primary prevention patients.
Design, setting, and participants:
This mask...
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Advantages of tailoring lipid lowering therapy with biomarkers versus imaging.
Background:
Identifying and targeting established modifiable risk factors has been a successful strategy for reducing the burden of coronary artery disease (CAD) at the population-level. However, up to one-in-four patients who present with ST elevation myocardial infarction do so in the absence of such risk factors. Polygenic risk scores (PRS) hav...
Background:
Obicetrapib, a selective cholesteryl ester transfer protein (CETP) inhibitor, reduces low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), lipoprotein particles, and apolipoproteins, when added to high-intensity statin in patients with dyslipidemia.
Objective:
To evaluate the safety and l...
Cancer and cardiovascular disease (CVD) commonly coexist, with increasing evidence that long-term cancer survivors are more likely to die from CVD than the general population. Effective management of CVD and its risk factors requires identification of patients at increased risk who may benefit from early intervention and their appropriate monitorin...
Background: Understanding the trajectories of metabolic risk factors for acute myocardial infarction (AMI) is necessary for healthcare policymaking. We estimated future projections of the incidence of metabolic diseases in a multi-ethnic population with AMI.
Methods: The incidence and mortality contributed by metabolic risk factors in the populati...
Aims
In this protocol-predefined sub-study of the RHAPSODY trial, the primary aim was to assess whether pericardial late gadolinium enhancement (LGE) was associated with time to pericarditis recurrence.
Methods and Results
RHAPSODY was a Phase 3 double-blind, placebo-controlled, randomized-withdrawal trial which demonstrated the efficacy of rilona...
Background:
Intravascular imaging has shown better response of coronary atheroma to statin-mediated lowering of low-density lipoprotein cholesterol in women. However, its detailed mechanism remains to be determined yet. Modifiability of coronary atheroma under lipid-lowering therapies is partly driven by lipidic plaque component. Given a smaller p...
Immune checkpoint inhibitors (ICI) are cancer therapies that have been associated with increased risk of atherosclerotic cardiovascular disease (ASCVD). Blood pressure (BP) measurements are routinely performed during day oncology center visits for administration of ICI therapy but are often not assessed temporally to screen and monitor hypertension...
Introduction:
There is abundant evidence that elevated lipoprotein(a) [LP(a)] associates with cardiovascular risk. Most lipid modifying therapies don't reduce Lp(a), but new technologies are emerging that act upstream, such as antisense oligonucleotides (ASO) and small interfering RNAs (siRNAs) that inhibit the translation of mRNA for proteins spe...
Introduction:
The world is undergoing a demographic transition to an older population. Preventive healthcare has reduced the burden of chronic illness at younger ages but there is limited evidence that these advances can improve health at older ages. Statins are one class of drug with the potential to prevent or delay the onset of several causes o...
Background:
Immune checkpoint inhibitors (ICI) have revolutionized the treatment of numerous cancers but are associated with increased risk of myocardial infarction. The prevalence of traditional cardiovascular risk factors (CVRF) in patients treated with ICIs is unknown. This study sought to describe the frequency of reporting of CVRFs among land...
Background:
Survival during the early period following myocardial infarction (MI) has significantly improved although there are limited data on cardiovascular recurrence during this period.
Methods:
We identified all emergency hospitalisations for MI from November 1, 2011 to October 31, 2016 in Western Australia from a linked hospitalisation/mor...
Given the limited accuracy of clinically used risk scores such as the Systematic COronary Risk Evaluation 2 system and the Second Manifestations of ARTerial disease 2 risk scores, novel risk algorithms determining an individual's susceptibility of future incident or recurrent atherosclerotic cardiovascular disease (ASCVD) risk are urgently needed....
Citations
... There are currently three ongoing phase III trials with obicetrapib [66][67][68], one of which is on CVD outcomes. The BROADWAY, with over 2500 patients with established ASCVD who require additional LDL-C-lowering [67,72]; the BROOKLYN trial with 354 participants across ten countries in North America, Europe, and Africa investigating Heterozygous Familial Hypercholesterolemia [66,72]; and the PREVAIL, which is targeting the enrollment of 9000 participants for the assessment of cardiovascular outcomes [68]. PREVAIL explores the potential of obicetrapib to reduce MACEs incidence (cardiovascular death, non-fatal MI, non-fatal stroke, and non-elective coronary revascularization) in patients with a history of ASCVD with poor LDL-C control regardless of statin therapy. ...
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... Other RNA targeting therapeutics being investigated to lower Lp(a) levels include zerlasiran and lepodisiran. Although both have been shown to reduce serum Lp(a) levels by up to 99% and 97%, respectively, their role in improving ASCVD outcomes has yet to be studied [98,99]. There are not currently any data regarding the use of RNA-based therapies in patients with both elevated Lp(a) levels and PAD. ...
... The SHASTA-2 randomized clinical trial presented by Gaudet et al. investigated the efficacy of plozasiran, a small interfering RNA targeting apolipoprotein C-III (apoC-III), in patients with severe hypertriglyceridemia [8]. The study enrolled 229 patients with triglyceride (TG) levels exceeding 500 mg/dl (5.6 mmol/l). ...
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... One approach to improve HDL functionality is the infusion of apolipoprotein A1 (apoA1) [18]. The AEGIS-II study by Gibson et al. [19] analyzed the effect of apoA1 infusion (CSL112; four weekly infusions of 6 g) versus placebo in 18,219 patients with acute myocardial infarction (AMI), multivessel coronary artery disease, and additional cardiovascular risk factors. CSL112 was administered within 5 days after the first medical contact for the AMI. ...
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... Conversely, comparable results were reported among both sexes in patients receiving bempedoic acid along with low-dose or no statin [161]. Most importantly though, bempedoic acid reduced LDL-C levels and cardiovascular risk similarly in women and men in the cardiovascular endpoint trial Clear Outcomes [162]. ...
... Angiopoietin-like protein type 3 (ANGTL3) plays a crucial role in the metabolism of triglyceride-rich lipoproteins [31,32]. A drug targeting ANGPTL3 currently used in clinical practice is evinacumab (a monoclonal antibody against ANGPTL3) [30,31]. ...
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... Whilst a number of societal statements or summaries have been published outlining gaps in evidence and roadmaps for research in specific areas of basic / translational, clinical or social research [105][106][107][108] , few have provided a broad overview of the gaps in evidence in cardio-oncology. To this end, we summarized the afore-identified gaps in evidence in Table 1 and Fig. 1 . ...
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... Bempedoic acid was superior to the placebo to reduce coronary revascularization by 19% (HR = 0.81; 95%CI, 0.72-0.92) [7] and also reduced the total number of cardiovascular events [134]. A recent subanalysis showed that in the on-treatment Per Protocol Set (PPS) analysis, LDL-C reduction was 0.71 mmol/L, with an HR for major vascular events of 0.80 (95%CI 0.71-0.89). ...
... Early-stage clinical trials indicated that siRNA is safe, well tolerated, and effective, both in patients with and without familial hypercholesterolemia [72]. The ARCHES-2 (Study of ARO-ANG3 in Adults with Mixed Dyslipidemia) phase II b study demonstrated that ARO-ANG3 significantly decreased ANGPTL3 expression and atherogenic triglyceride-rich lipoproteins, LDL-C and total apoB, in patients with mixed dyslipidemia [73]. The Gateway (Study of ARO-ANG3 in Participants with Homozygous Familial Hypercholesterolemia) trial (NCT05217667) is an ongoing phase II study, assessing the efficacy and safety of ARO-ANG3 among patients with homozygous familial hypercholesterolemia. Currently, two other siRNAs target the ANGPTL3 gene. ...
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... Therefore, developing novel biomarkers more sensitive to ACS is necessary for a more prompt and precise diagnosis of ACS. 2 of 12 Metabolomics is an omics approach that enables the simultaneous identification and quantification of hundreds of metabolites in biological samples. This technology has recently been applied to discover biomarkers for cardiovascular disease [8,9]. It involves systematically analyzing the comprehensive metabolites of biological samples, such as biofluids, cells, tissues, or organs, to elucidate their profile features. ...
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