Publications by authors named "Gerald F Watts"

517 Publications

New Insights Into the Regulation of Lipoprotein Metabolism by PCSK9: Lessons From Stable Isotope Tracer Studies in Human Subjects.

Front Physiol 2021 10;12:603910. Epub 2021 Feb 10.

School of Medicine, Faculty of Health and Medical Sciences, University of Western Australia, Perth, WA, Australia.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a convertase enzyme mostly produced by the liver. It is a key regulator of LDL metabolism because of its ability to enhance degradation of the LDL receptor. PCSK9 also regulates the metabolism of lipoprotein(a) [Lp(a)] and triglyceride-rich lipoproteins (TRLs). Its key role in modulating atherosclerotic cardiovascular disease (ASCVD) is supported by genetic studies and clinical outcome trials. Kinetic studies provide mechanistic insight into the role of PCSK9 in regulating the physiology and pathophysiology of plasma lipids and lipoproteins. Kinetic data have demonstrated that plasma PCSK9 concentration is inversely associated with the clearance of LDL in men. Gain-of-function mutations of PCSK9 markedly increase plasma LDL-cholesterol concentrations due to impaired LDL-apoB catabolism. Conversely, PCSK9 deficiency results in low LDL-cholesterol associated with enhanced LDL-apoB clearance. Inhibition of PCSK9 with monoclonal antibodies (such as evolocumab or alirocumab) lowers plasma LDL-cholesterol and apoB levels chiefly by upregulating the catabolism of LDL particles in healthy individuals. As monotherapy, PCSK9 inhibitor reduced Lp(a) concentrations by decreasing the production rate. However, as combination therapy, it reduced the plasma concentration of Lp(a) by increasing the fractional catabolism of Lp(a) particles. In statin-treated patients with high Lp(a), PCSK9 inhibition lowers plasma Lp(a) concentrations by accelerating the catabolism of Lp(a) particles. The effect of PCSK9 inhibition on TRL metabolism has been studied in healthy individuals and in patients with type 2 diabetes. These findings suggest that PCSK9 appears to play a less important role in TRL than LDL metabolism. Kinetic studies of PCSK9 inhibition therapy on lipoprotein metabolism in diverse high risk patient populations (such as familial hypercholesterolemia) and new therapeutic combination also merit further investigation.
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http://dx.doi.org/10.3389/fphys.2021.603910DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7902499PMC
February 2021

Hypercholesterolemia and cardiovascular disease: Focus on high cardiovascular risk patients.

Atheroscler Suppl 2020 Dec;42:e30-e34

Hacettepe University, Ankara, Turkey.

The widespread use of statins has largely improved the treatment of hypercholesterolemia, but many patients still fail to achieve the LDL-C targets recommended by guidelines. Furthermore, some patients continue to present a very high cardiovascular (CV) risk or even an extreme risk despite being well treated, mainly due to the presence of co-morbidities such as diabetes or peripheral artery disease, which significantly increase their global CV risk. For these very high CV risk patients, the most recent European guidelines have reviewed the LDL-C goals and recommend an LDL-C reduction of at least 50% and a goal of <55 mg/dL or even <40 mg/dL. Recent clinical trials have shown that patient stratification based on the presence or absence of atherothrombotic risk factors may represent a valuable tool to identify patients at extremely high CV risk who may benefit more from an aggressive LDL-C-lowering approach. In these patients it may be appropriate to aim for the lowest LDL-C level, independently of recommended goals, with all the available pharmacological approaches.
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http://dx.doi.org/10.1016/j.atherosclerosissup.2021.01.006DOI Listing
December 2020

The Yin and Yang of High-density Lipoprotein and Atherosclerotic Cardiovascular Disease: Focusing on Functionality and Cholesterol Efflux to Reframe the HDL Hypothesis.

Curr Med Chem 2021 Feb 8. Epub 2021 Feb 8.

School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, . Iran.

The inverse relationship between low plasma high-density lipoprotein cholesterol (HDL-C) concentrations and increased risk of Atherosclerotic Cardiovascular Disease (ASCVD) is well-known. However, plasma HDL-C concentrations are highly variable in subjects with ASCVD. In clinical outcome trials, pharmacotherapies that increase HDL-C concentrations are not associated with a reduction in ASCVD events. A causal relationship between HDL-C and ASCVD has also been questioned by Mendelian randomization studies and genome-wide association studies of genetic variants associated with plasma HDL-C concentrations. The U-shaped association between plasma HDL-C concentrations and mortality observed in several epidemiological studies implicates both low and very high plasma HDL-C concentrations in the etiology of ASCVD and non-ASCVD mortality. These data do not collectively support a causal association between HDL-C and ASCVD risk. Therefore, the hypothesis concerning the association between HDL and ASCVD has shifted from focus on plasma concentrations to the concept of functionality, in particular cellular cholesterol efflux and HDL holoparticle transport. In this review, we focus on these new concepts and provide a new framework for understanding and testing the role of HDL in ASCVD.
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http://dx.doi.org/10.2174/0929867328666210208182326DOI Listing
February 2021

Exploring the association between stroke and acute myocardial infarction and statins adherence following a medicines co-payment increase.

Res Social Adm Pharm 2021 Jan 28. Epub 2021 Jan 28.

Centre of Health Services Research, School of Population and Global Health, The University of Western Australia, Perth, Western Australia, Australia.

Objectives: Patient contributions (co-payments) for one months' supply of a publicly-subsidised medicine in Australia were increased by 21% in January 2005 (US$2.73-$3.31 for social security recipients and $17.05-$20.58 for others). This study investigates the relationship between patients' use of statin medication and hospitalisation for acute coronary syndrome and stroke, following this large increase in co-payments.

Methods: We designed a retrospective cohort study of all patients in Western Australia who were dispensed statin medication between 2004 and 05. Data for the cohort was obtained from State and Federal linked databases. We divided the cohort into those who discontinued, reduced or continued statin therapy in the first six months after the co-payment increase. The primary outcome was two-year hospitalisation for acute coronary syndrome or stroke-related event. Analysis was conducted using Fine and Gray competing risk methods, with death as the competing risk.

Results: There were 207,066 patients using statins prior to the co-payment increase. Following the increase, 12.5% of patients reduced their use of statin medication, 3.3% of patients discontinued therapy, and 84.2% continued therapy. There were 4343 acute coronary syndrome and stroke-related hospitalisations in the two-year follow-up period. Multivariate analysis demonstrated that discontinuing statins increased the risk of hospitalisation for acute coronary syndrome or stroke-related events by 18% (95%CI = 0.1%-40%) compared to continuing therapy. Subgroup analysis showed that men aged <70 years were at increased risk of 54-63% after discontinuing statins compared to those continuing, but that women and older men were not.

Conclusion: Discontinuing statin medication after a large increase patient cost contribution was associated with higher rates of acute coronary syndrome and stroke-related hospitalisation in men under 70 years. The findings highlight the importance of continued adherence to prescribed statin medication, and that discontinuing therapy for non-clinical reasons (such as cost) can possibly have negative consequences particularly for younger men.
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http://dx.doi.org/10.1016/j.sapharm.2021.01.011DOI Listing
January 2021

Bempedoic Acid in the Treatment of Patients with Dyslipidemias and Statin Intolerance.

Cardiovasc Drugs Ther 2021 Jan 27. Epub 2021 Jan 27.

School of Medicine, Faculty of Health and Medical Sciences, University of Western Australia, Perth, Western Australia, Australia.

An elevated plasma low-density lipoprotein cholesterol (LDL-C) level is a well-established atherosclerotic cardiovascular disease (ACSVD) risk factor. Randomized studies with statins (alone or in combination with other lipid-lowering drugs) have demonstrated their clinical efficacy in lowering LDL-C. Several classes of new, non-statin agents have been successfully studied and used (e.g., ezetimibe and inhibitors of proprotein convertase subtilisin/kexin type 9 [i-PSCK9]). However, many high ACSVD risk patients remain at a high residual cardiovascular risk, with at least 10% being statin intolerant. Bempedoic acid (ETC-1002) is a new inhibitor of cholesterol synthesis that targets ATP citrate lyase (ACL). Importantly, ETC-1002 is only converted into an active form in the liver and is free of muscle side effects.Area Covered: Mechanism of action of ETC-1002, clinical pharmacology, completed clinical studies with bempedoic acid, lipid-lowering efficacy/safety issues, and recent meta-analyses of trials with ETC-1002.Expert Opinion: ETC-1002 has been extensively studied in phase I-III clinical studies in over 4000 individuals from different patient populations (statin intolerance, familial hypercholesterolemia, and high ACSVD risk patients), ETC-1002 has been demonstrated to have moderate cholesterol-lowering efficacy and a good safety profile at a dose of 180 mg/day as a monotherapy and in combination with statins and ezetimibe. The ongoing study CLEAR Outcomes, with composite cardiovascular endpoints, will elucidate the role of bempedoic acid in the management of high ACSVD risk and statin-intolerant patients with hypercholesterolemia. Long-term safety data on bempedoic acid are needed to fully establish this agent in evidence-informed guidelines for managing of patients with dyslipidemias.
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http://dx.doi.org/10.1007/s10557-020-07139-xDOI Listing
January 2021

LDL-cholesterol lowering and clinical outcomes in hypercholesterolemic subjects with and without a familial hypercholesterolemia phenotype: Analysis from the secondary prevention 4S trial.

Atherosclerosis 2021 Jan 12;320:1-9. Epub 2021 Jan 12.

Imperial Centre for Cardiovascular Disease Prevention, Department of Primary Care and Public Health, School of Public Health, Imperial College London, London, United Kingdom.

Background And Aims: Trial evidence for the benefits of cholesterol-lowering is limited for familial hypercholesterolemia (FH) patients, since they have not been the focus of large outcome trials. We assess statin use in coronary artery disease (CAD) subjects with low-density lipoprotein cholesterol (LDL-C) ≥4.9 mmol/L with or without an FH phenotype.

Methods: The 4S trial randomized hypercholesterolemic CAD patients to simvastatin or placebo. We first stratified participants into baseline LDL-C <4.9 and ≥ 4.9 mmol/L; next, based on the DLCN criteria for FH, the latter group was stratified into four subgroups by presence of none, one or both of "premature CAD" and "family history of CAD". Participants having both are defined as having an FH phenotype.

Results: 2267 and 2164 participants had LDL-C <4.9 and ≥ 4.9 mmol/L, respectively. Mortality endpoints and major coronary events (MCE) were significantly reduced with simvastatin versus placebo in both groups over 5.4 years, but the latter derived greater absolute risk reductions (ARR) (4.1-4.3% for mortality endpoints, versus 2.5-2.8%). LDL-C reductions were similar among the 4 subgroups with levels ≥4.9 mmol/L. Participants with FH phenotype (n = 152) appeared to derive greater relative benefits with simvastatin than the other three subgroups (all-cause death: 84% relative risk reduction, p = 0.046; MCE: 55% reduction, p = 0.0297); statistical interaction was non-significant. Participants with FH phenotype derived greater ARR than any other group with simvastatin versus placebo (all-cause mortality: 6.6% ARR; MCE 13.2%; versus 3.8% and 8.3%, respectively, among participants with LDL-C ≥4.9 mmol/L but without features suggestive of FH).

Conclusions: The FH phenotype appeared to be associated with greater clinical benefits from a given magnitude of LDL-C reduction as compared to individuals without FH phenotype.
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http://dx.doi.org/10.1016/j.atherosclerosis.2021.01.003DOI Listing
January 2021

Editorial: Dyslipidaemia and cardiometabolic health: springboard for an emerging medical specialty?

Authors:
Gerald F Watts

Curr Opin Endocrinol Diabetes Obes 2021 04;28(2):83-84

School of Medicine, University of Western Australia.

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http://dx.doi.org/10.1097/MED.0000000000000622DOI Listing
April 2021

Validity and reliability of an adapted questionnaire measuring knowledge, awareness and practice regarding familial hypercholesterolaemia among primary care physicians in Malaysia.

BMC Cardiovasc Disord 2021 Jan 19;21(1):39. Epub 2021 Jan 19.

Institute of Pathology, Laboratory and Forensic Medicine (I-PPerForM), Universiti Teknologi MARA (UiTM), Sungai Buloh Campus, Jalan Hospital, 47000, Sungai Buloh, Selangor, Malaysia.

Background: Primary care physicians (PCP) play an important role in detecting Familial Hypercholesterolaemia (FH) early. However, knowledge, awareness and practice (KAP) regarding FH among Malaysian PCP are not well established, and there was no validated tool to assess their FH KAP. Thus, the aim of this study was to adapt an FH KAP questionnaire and determine its validity and reliability among Malaysian PCP.

Methods: This cross-sectional validation study involved Malaysian PCP with ≥ 1-year work experience in the primary care settings. In Phase 1, the original 19-item FH KAP questionnaire underwent content validation and adaptation by 7 experts. The questionnaire was then converted into an online survey instrument and was face validated by 10 PCP. In Phase 2, the adapted questionnaire was disseminated through e-mail to 1500 PCP. Data were collected on their KAP, demography, qualification and work experience. The construct validity was tested using known-groups validation method. The hypothesis was PCP holding postgraduate qualification (PCP-PG-Qual) would have better FH KAP compared with PCP without postgraduate qualification (PCP-noPG-Qual). Internal consistency reliability was calculated using Kuder Richardson formula-20 (KR-20) and test-retest reliability was tested on 26 PCP using kappa statistics.

Results: During content validation and adaptation, 10 items remained unchanged, 8 items were modified, 1 item was moved to demography and 7 items were added. The adapted questionnaire consisted of 25 items (11 knowledge, 5 awareness and 9 practice items). A total of 130 out of 1500 PCP (response rate: 8.7%) completed the questionnaire. The mean percentage knowledge score was found to be significantly higher in PCP-PG-Qual compared with PCP-noPG-Qual (53.5, SD ± 13.9 vs. 35.9, SD ± 11.79), t(128) = 6.90, p < 0.001. The median percentage awareness score was found to be significantly higher in PCP-PG-Qual compared with PCP-noPG-Qual (15.4, IqR ± 23.08 vs. 7.7, IqR ± 15.38), p = 0.030. The mean percentage practice score was significantly higher in PCP-PG-Qual compared with PCP-noPG-Qual (69.2, SD ± 17.62 vs. 54.4, SD ± 19.28), t(128) = 3.79, p < 0.001. KR-20 value was 0.79 (moderate reliability) and average Kappa was 0.796 (substantial agreement).

Conclusion: This study has proven that the 25-item adapted FH KAP questionnaire is valid and reliable. It can be used to measure and establish FH KAP among PCP in Malaysia.
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http://dx.doi.org/10.1186/s12872-020-01845-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7814747PMC
January 2021

Cost-Effectiveness of Coronary Artery Calcium Scoring in People With a Family History of Coronary Disease.

JACC Cardiovasc Imaging 2021 Jan 7. Epub 2021 Jan 7.

Baker Heart and Diabetes Research Institute, Melbourne, Australia; Monash University, Melbourne, Australia. Electronic address:

Background: The use of coronary artery calcium scoring (CAC) to guide primary prevention statin therapy in those with a family history of premature coronary artery disease (FHCAD) is inconsistently recommended in guidelines, and usually not reimbursed by insurance. We assessed the cost-effectiveness of CAC compared with traditional risk factor-based prediction alone in those with an FHCAD.

Methods: A microsimulation model was constructed in TreeAge Healthcare Pro using data from 1,083 participants in the CAUGHT-CAD (Coronary Artery Calcium Score: Use to Guide Management of HerediTary Coronary Artery Disease) trial. Outcomes assessed were quality-adjusted life years (QALYs): cost-effectiveness was assessed over a 15-year time horizon from the perspective of the US health care sector using real-world statin prescribing, accounting for the effect of knowledge of subclinical disease on adherence to guideline-directed therapies. Costs were assessed in 2020 USD, with discounting undertaken at 3%.

Results: Statins were indicated in 45% of the cohort using the CAC strategy and 27% using American College of Cardiology/American Heart Association (2019) treatment strategies. Compared with applying a statin treatment threshold of 7.5%, the CAC strategy was more costly ($145) and more effective (0.0097 QALY) with an incremental cost-effective ratio (ICER) of $15,014/QALY. CAC ICER was driven by CAC acquisition and statin prescription cost and improved with certain patient subgroups: male, age >60 years, and 10-year risk pooled cohort equation risk ≥7.5%. CAC scanning of low-risk patients (10-year risk <5%) or those 40 to 50 years of age was not cost-effective.

Conclusion: Systematic CAC screening and treatment of those with FHCAD and subclinical disease was more cost-effective than management using statin treatment thresholds, in the US health care system.
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http://dx.doi.org/10.1016/j.jcmg.2020.11.008DOI Listing
January 2021

Evaluation of Transthoracic Echocardiography in the Assessment of Atherosclerosis of the Left Main Coronary Artery: Comparison with Optical Frequency Domain Imaging (a Pilot Study).

J Clin Med 2021 Jan 12;10(2). Epub 2021 Jan 12.

Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, 20133 Milan, Italy.

Background: Risk stratification using non-invasive imaging of the coronary vessels is emerging as an optimal standard of care for patients with dyslipidemias. Of particular interest is the evaluation of the left main coronary artery (LMCA), where calcium deposition appears to be a predictor of cardiovascular events.

Methods: In coronary patients, we evaluated wall thickness and internal diameter of the LMCA examined by transthoracic echocardiography (TTE) and compared these with findings obtained by optical frequency domain imaging (OFDI), this latter also used to evaluate calcium deposition.

Results: A significant positive correlation between TTE and OFDI for the anterior wall thickness (r = 0.41, = 0.043) and internal diameter (r = 0.36, = 0.048) of the LMCA was detected. Echocardiographic wall measurements were higher in patients with fibro-calcific plaques. The receiver operating characteristic (ROC) curve showed that an anterior wall thickness of LMCA ≥ 1.4 mm was predictive of fibro-calcific plaque (area under the curve = 0.815 and = 0.006), sensitivity and specificity being 76.9% and 80%, respectively (Youden's Index = 0.56).

Conclusions: Measurement of anterior wall thickness of the LMCA by TTE and OFDI appears to be closely correlated and may predict the presence of coronary calcification.
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http://dx.doi.org/10.3390/jcm10020256DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7827741PMC
January 2021

Lipoprotein(a), LDL-cholesterol, and hypertension: predictors of the need for aortic valve replacement in familial hypercholesterolaemia.

Eur Heart J 2021 Jan 12. Epub 2021 Jan 12.

Fundación Hipercolesterolemia Familiar, Madrid, Spain.

Aims: Familial hypercholesterolaemia (FH) and elevated lipoprotein(a) [Lp(a)] are inherited disorders associated with premature atherosclerotic cardiovascular disease (ASCVD). Aortic valve stenosis (AVS) is the most prevalent valvular heart disease and low-density lipoprotein cholesterol (LDL-C) and Lp(a) may be involved in its pathobiology. We investigated the frequency and predictors of severe AVS requiring aortic valve replacement (AVR) in molecularly defined patients with FH.

Methods And Results: SAFEHEART is a long-term prospective cohort study of a population with FH and non-affected relatives (NAR). We analysed the frequency and predictors of the need for AVR due to AVS in this cohort. Five thousand and twenty-two subjects were enrolled (3712 with FH; 1310 NAR). Fifty patients with FH (1.48%) and 3 NAR (0.27%) required AVR [odds ratio 5.71; 95% confidence interval (CI): 1.78-18.4; P = 0.003] after a mean follow-up of 7.48 (3.75) years. The incidence of AVR was significantly higher in patients with FH (log-rank 5.93; P = 0.015). Cox regression analysis demonstrated an association between FH and AVR (hazard ratio: 3.89; 95% CI: 1.20-12.63; P = 0.024), with older age, previous ASCVD, hypertension, increased LDL-CLp(a)-years, and elevated Lp(a) being independently predictive of an event.

Conclusion: The need for AVR due to AVS is significantly increased in FH patients, particularly in those who are older and have previous ASCVD, hypertension, increased LDL-CLp(a)-years and elevated Lp(a). Reduction in LDL-C and Lp(a) together with control of hypertension could retard the progression of AVS in FH, but this needs testing in clinical trials.ClinicalTrials.gov number NCT02693548.
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http://dx.doi.org/10.1093/eurheartj/ehaa1066DOI Listing
January 2021

Hypertriglyceridemia and Alzheimer Disease: Opening the Mind to New Therapeutic Opportunities.

Clin Chem 2021 Jan;67(1):6-8

Curtin Health Innovation Research Institute, Curtin University, Perth, Western Australia, Australia.

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http://dx.doi.org/10.1093/clinchem/hvaa294DOI Listing
January 2021

Novel behavioural approaches and implementation science for mitigating genetic risk of cardiovascular disease due to elevated lipoprotein(a).

Curr Opin Endocrinol Diabetes Obes 2021 04;28(2):174-180

Faculty of Health and Medical Sciences, School of Medicine, University of Western Australia, Perth.

Purpose Of Review: Elevated lipoprotein(a) [Lp(a)] is a genetic trait that indicates higher risk of atherosclerotic cardiovascular disease (ASCVD). We review novel strategies to mitigate behavioural risk-factors in this genetic condition.

Recent Findings: Pharmacological and biological interventions are available for lowering Lp(a). However, the acceptability and feasibility of these approaches are questionable due to cost and lack of clinical evidence for their efficacy. A number of low-cost, minimal patient contact interventions are available for modifying behavioural risk-factors that are associated with increased risk of ASCVD familial hypercholesterolaemia and diabetes. These include lifestyle interventions designed to improve diet and physical activity. These interventions may be particularly important among individuals with elevated Lp(a) to manage their higher risk of diabetes and ASCVD. The following article outlines recent research that has examined such low-cost, minimal patient contact interventions.

Summary: The current research indicated that such interventions, which are grounded in psychological theory, can assist individuals to improve their diet and physical activity. These findings have implications for developing and implementing similar interventions for individuals with elevated Lp(a), so as to assist in reducing behavioural risk-factors associated with ASCVD.
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http://dx.doi.org/10.1097/MED.0000000000000609DOI Listing
April 2021

Gender difference in lipoprotein(a) concentration as a predictor of coronary revascularization in patients with known coronary artery disease.

Biochim Biophys Acta Mol Cell Biol Lipids 2021 Mar 15;1866(3):158869. Epub 2020 Dec 15.

U.O. Lipoapheresis and Center for Inherited Dyslipidaemias, Fondazione Toscana Gabriele Monasterio, Pisa, Italy. Electronic address:

Background And Aims: Whether there is a gender difference in the impact of elevated plasma Lp(a) levels on recurrent coronary events remains unclear. We, therefore, evaluated the association between Lp(a) levels and the occurrence of major adverse coronary events in a large series of coronary patients (32% women).

Methods: This single-center prospective cohort study investigated 3034 consecutive patients admitted to the Coronary Care Unit with a diagnosis of coronary ischemia. According to the inclusion criteria, 2374 patients completed the follow-up (mean of 2 years). The end-points were non-fatal myocardial infarction (MI), revascularization and coronary deaths.

Results: Elevated Lp(a) levels were significantly associated with rate of revascularization, but not with non-fatal MI and cardiac death. According to Lp(a) stratification (≤30 mg/dl, >30-50 mg/dl and ≥50 mg/dl), there was a significant rise of revascularization events in the whole sample of participants, with a trend in hazard ratio (HR) of 1.23 (95% CI 1.04-1.46) and a 6% rise for every 10 mg/dl increment in Lp(a) levels. This effect was mainly driven by women (HR 2.04, 95%CI 1.33-3.12) who showed a 14% incremental risk for every 10 mg/dl rise in Lp(a) levels.

Conclusions: In patients with coronary artery disease, elevated plasma Lp(a) levels were found to be a potentially useful predictor of the need for coronary revascularizations, especially in women.
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http://dx.doi.org/10.1016/j.bbalip.2020.158869DOI Listing
March 2021

Integrated Guidance for Enhancing the Care of Familial Hypercholesterolaemia in Australia.

Heart Lung Circ 2021 Mar 9;30(3):324-349. Epub 2020 Dec 9.

School of Medicine, Faculty of Health and Medical Sciences, University of Western Australia, Perth, WA, Australia.

Familial hypercholesterolaemia (FH) is a dominant and highly penetrant monogenic disorder present from birth that markedly elevates plasma low-density lipoprotein (LDL)-cholesterol concentration and, if untreated, leads to premature atherosclerosis and coronary artery disease (CAD). There are approximately 100,000 people with FH in Australia. However, an overwhelming majority of those affected remain undetected and inadequately treated, consistent with FH being a leading challenge for public health genomics. To further address the unmet need, we provide an updated guidance, presented as a series of systematically collated recommendations, on the care of patients and families with FH. These recommendations have been informed by an exponential growth in published works and new evidence over the last 5 years and are compatible with a contemporary global call to action on FH. Recommendations are given on the detection, diagnosis, assessment and management of FH in adults and children. Recommendations are also made on genetic testing and risk notification of biological relatives who should undergo cascade testing for FH. Guidance on management is based on the concepts of risk re-stratification, adherence to heart healthy lifestyles, treatment of non-cholesterol risk factors, and safe and appropriate use of LDL-cholesterol lowering therapies, including statins, ezetimibe, proprotein convertase subtilisin/kexin type 9 inhibitors and lipoprotein apheresis. Broad recommendations are also provided for the organisation and development of health care services. Recommendations on best practice need to be underpinned by good clinical judgment and shared decision making with patients and families. Models of care for FH need to be adapted to local and regional health care needs and available resources. A comprehensive and realistic implementation strategy, informed by further research, including assessments of cost-benefit, will be required to ensure that this new guidance benefits all Australian families with or at risk of FH.
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http://dx.doi.org/10.1016/j.hlc.2020.09.943DOI Listing
March 2021

Best practice for treating dyslipidaemia in patients with diabetes based on current international guidelines.

Curr Opin Endocrinol Diabetes Obes 2021 Apr;28(2):104-113

Departments of Internal Medicine and Cardiology, Royal Perth Hospital.

Purpose Of Review: Dyslipidaemia is a major modifiable risk factor for atherosclerotic cardiovascular disease (ASCVD) in type 2 diabetes. We provide an in-context overview of recent trials of lipid-lowering pharmacotherapies and of recommendations from international guidelines for managing dyslipidaemia in patients with diabetes.

Recent Findings: Clinical trials have demonstrated that patients with diabetes derive greater benefits from ezetimibe and proprotein convertase subtilisin-kexin type 9 inhibitors owing to the higher absolute ASCVD risk compared with patients without diabetes. Pure eicosapentaenoic acid ethyl ester therapy should be considered in high risk patients with diabetes and hypertriglyceridaemia who have well controlled low-density lipoprotein cholesterol on statin therapy. International guidelines from USA, Canada and Europe have been updated to support a more intensive approach to treating dyslipidaemia in diabetes.

Summary: Dyslipidaemia should be identified and treated intensively as part of overall diabetes management to reduce ASCVD risk. Although lifestyle modifications and statin therapy remain the cornerstone of management, add-on therapies should be strongly considered depending on the absolute risk of ASCVD and the degree of dyslipidaemia.
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http://dx.doi.org/10.1097/MED.0000000000000594DOI Listing
April 2021

F-Sodium Fluoride Positron Emission Tomography Activity Predicts the Development of New Coronary Artery Calcifications.

Arterioscler Thromb Vasc Biol 2021 01 3;41(1):534-541. Epub 2020 Dec 3.

School of Medicine (J.W.B., R.J.F., S.C.L., A.R., J.R.L., G.F.W., C.J.S.), University of Western Australia, Perth.

Objective: The coronary calcium score (CCS) predicts cardiovascular disease risk in individuals with diabetes, and rate of progression of CCS is an additional and incremental marker of risk. F-sodium fluoride positron emission tomography (F-NaF PET) detects early and active calcifications within the vasculature. We aimed to ascertain the relationship between F-NaF PET activity and CCS progression in patients with diabetes. Approach and Results: We identified individuals between 50 and 80 years with diabetes and no history of clinical coronary artery disease. Those with a CCS ≥10 were invited to undergo F-NaF PET scanning and then repeat CCS >2 years later. F-NaF PET and CCS analysis were performed on a per-coronary and a per-patient level. We compared the proportion of CCS progressors in F-NaF PET-positive versus F-NaF PET-negative coronary arteries. Forty-one participants with 163 coronary arteries underwent follow-up CCS 2.8±0.5 years later. F-NaF PET-positive coronary arteries (n=52) were more likely to be CCS progressors, compared with negative coronary arteries (n=111; 86.5% versus 52.3%, <0.001). Adjusting for baseline CCS, F-NaF PET-positive disease was an independent predictor of subsequent CCS progression (odds ratio, 2.92 [95% CI, 1.32-6.45], =0.008). All subjects (100%, 15/15) with ≥2 F-NaF-positive coronary arteries progressed in CCS.

Conclusions: In subjects with diabetes, F-NaF PET positivity at baseline, independently predicted the progression of calcifications within the coronary arteries 2.8 years later. These findings suggest F-NaF PET may be a promising technique for earlier identification of patients at higher risk of cardiovascular events.
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http://dx.doi.org/10.1161/ATVBAHA.120.315364DOI Listing
January 2021

Familial hypercholesterolaemia and cascade testing in general practice: Lessons from COVID-19.

Aust J Gen Pract 2020 Dec;49(12):859-860

MD, FRACGP, MRCGP, Professor and Director, General Practice and Primary Health Care Research, School of Medicine, The University of Notre Dame, WA; General Practitioner, Mosman Park Medical Centre, WA.

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http://dx.doi.org/10.31128/AJGP-07-20-5517DOI Listing
December 2020

Lipoprotein (a) and diabetes mellitus: causes and consequences.

Curr Opin Endocrinol Diabetes Obes 2021 Apr;28(2):181-187

School of Medicine, University of Western Australia.

Purpose Of Review: This review provides an update on the role of lipoprotein (a) [Lp(a)] in diabetes, including its impact as a risk factor as well as its contribution to the development of cardiovascular disease.

Recent Findings: Although a specific role for Lp(a) has not yet been conclusively established, it appears to have an inverse association with risk of diabetes. Several population-based studies have demonstrated associations between low levels of Lp(a) and increased risk of type 2 diabetes, but Mendelian randomization studies do not consistently support causality. Conversely, in patients with type 2 diabetes, elevated Lp(a) levels are associated with an increased risk of cardiovascular events.

Summary: Although Lp(a) contributes to the development of cardiovascular disease in patients with diabetes, few trials have investigated the benefits of reducing Lp(a) within this patient population. Furthermore, guidelines do not specifically address the risk associated with elevated Lp(a) levels. Despite this, Lp(a) should be measured in patients with diabetes and considered when evaluating their overall risk burden.
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http://dx.doi.org/10.1097/MED.0000000000000597DOI Listing
April 2021

Lipoprotein(a) in Patients With Type 2 Diabetes and Premature Coronary Artery Disease in the Coronary Care Unit.

Heart Lung Circ 2020 Nov 12. Epub 2020 Nov 12.

Medical School, The University of Western Australia, Perth, WA, Australia; Departments of Internal Medicine and Cardiology, Royal Perth Hospital, Perth, WA, Australia; Department of Clinical Biochemistry, PathWest Laboratory Medicine WA, Royal Perth and Fiona Stanley Hospitals, Perth, WA, Australia; Department of Biochemistry, Clinipath Pathology, Perth, WA, Australia.

Introduction: Lipoprotein(a) [Lp(a)] and diabetes are independently associated with premature coronary artery disease (pCAD). However, there is an inverse relationship between Lp(a) concentration and type 2 diabetes (T2D) risk. We examine whether Lp(a) distribution in patients with pCAD differs between those with or without T2D, and whether elevated Lp(a) is associated with pCAD in patients with T2D.

Methods: Lp(a) concentration was measured in consecutive acute coronary syndrome (ACS) patients in two coronary care units (study one: ACS with or without diabetes, study two: ACS and diabetes). Elevated Lp(a) mass concentration was defined as ≥0.5 g/L and pCAD where CAD was diagnosed age <60 years. The association between elevated Lp(a) and pCAD was assessed using logistic regression.

Results: Of 449 patients, 233 (51.9%) had pCAD and 278 (61.9%) had T2D. In patients with pCAD, those with T2D had a significantly lower median Lp(a) concentration (0.13 g/L versus 0.27 g/L, p=0.004). In patients with T2D, elevated Lp(a) was significantly associated with pCAD (OR 2.419, 95% CI 1.513-3.867, p<0.001). After adjusting for gender, smoking, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides, elevated Lp(a) remained significantly associated with pCAD (OR 2.895, 95% CI 1.427-5.876, p=0.003) in patients with T2D.

Conclusions: In coronary care patients with pCAD, patients with T2D had lower Lp(a) concentrations than those without T2D. Despite this, elevated Lp(a) remained predictive of pCAD in patients with T2D. Measurement of Lp(a) should be considered in younger adults with T2D to identify who may benefit from earlier preventative therapies to reduce pCAD burden.
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http://dx.doi.org/10.1016/j.hlc.2020.09.932DOI Listing
November 2020

Pharmacokinetics and pharmacodynamics of HTD1801 (berberine ursodeoxycholate, BUDCA) in patients with hyperlipidemia.

Lipids Health Dis 2020 Nov 12;19(1):239. Epub 2020 Nov 12.

HighTide Therapeutics, Rockville, MD, USA.

Background: Reduction in elevated serum cholesterol concentrations is important in the management of individuals at risk of atherosclerotic cardiovascular disease (ASCVD), such as myocardial infarction and thrombotic stroke. Although HMGCoA reductase inhibitors ("statins") are frequently used for this purpose, a significant proportion of patients remain at increased residual risk of ASCVD as they do not adequately address some of the associated co-morbidities such as diabetes and fatty liver disease.

Methods: A double-blind, randomized, placebo-controlled, dose ranging study was carried out that compared three doses of berberine ursodeoxycholate (BUDCA) to placebo in a cohort of subjects with a history of hypercholesterolemia and serum LDL cholesterol levels above 2.59 mmol/L (> 99.9 mg/dL). BUDCA was administered in two divided doses each day for 28 days. The primary endpoints of the study were safety and tolerability of this new compound, as well as its effect in lowering serum lipid and lipoprotein concentrations.

Results: A total of 50 subjects were enrolled into three dose cohorts in this study. BUDCA was generally well tolerated, even at doses of 2000 mg per day (the highest dose group); there were no significant adverse effects reported and this highest dose was associated with significant reductions in LDL cholesterol. By day 28 and with the highest dose of BUDCA, there were significant reductions in the serum concentrations of total cholesterol by 8.2% (P = 0.0004) and LDL cholesterol by 10.4% (P = 0.0006), but no significant changes in triglyceride and HDL cholesterol concentrations.

Conclusions: BUDCA is a new single molecular entity that has a significant but modest effect in safely lowering serum LDL-cholesterol concentrations in individuals with a history of hypercholesterolemia. It has a potential use for treating hypercholesterolemia in individuals who cannot take statins, and possibly as adjunctive to other agents, such as ezetimibe or bempedoic acid.

Trial Registration: The study was registered on Clinicaltrials.gov ( NCT03381287 ).
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http://dx.doi.org/10.1186/s12944-020-01406-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7661247PMC
November 2020

Increased risk of 2-year death in patients who discontinued their use of statins.

J Health Serv Res Policy 2020 Nov 8:1355819620965610. Epub 2020 Nov 8.

Chair in Public Health, Centre for Health Services Research, School of Population and Global Health, the University of Western Australia, Australia.

Objective: This study examined the association between statin usage (discontinued, reduced or continued) and two-year death following a 21% increase in the Pharmaceutical Benefits Scheme (PBS) consumer co-payment in Western Australia.

Methods: A retrospective observational study in Western Australia using linked administrative Commonwealth PBS data and State hospital inpatient and death data (n = 207,066) was undertaken. We explored the two-year all-cause and ischemic heart disease(IHD)/stroke-specific-death in individuals who discontinued, reduced or continued statin medication following the January 2005 PBS co-payment increase, overall, by beneficiary status (general population vs. social security recipients) and by a history of admission for ischemic heart disease or stroke. Non-cardiovascular (CVD)-related death was also considered.

Results: In the first six months of 2005, 3.3% discontinued, 12.5% reduced and 84.2% continued statin therapy. We found those who discontinued statins were also likely to discontinue at least two other medicines compared to those who continued therapy. There were 4,607 all-cause deaths. For IHD/stroke-specific death, there were 1,317. For all non-CVD-related death, there were 2,808 deaths during the 2-year follow-up period. Cox regression models, adjusted for demographic and clinical characteristics, showed a 39%-61% increase in the risk of all-cause death for individuals who reduced or discontinued statin medication compared to those who continued their statin medication (Discontinued: Adj HR = 1.61, 95% CI 1.40-1.85; Reduced: Adj HR = 1.39, 95% CI 1.28-1.51). For IHD/stroke-specific death, there was an increased risk of death by 28-76% (Discontinued: Adj sHR = 1.76, 95% CI 1.37-2.27; Reduced: Adj sHR = 1.28, 95% CI 1.10-1.49), and for non-CVD-related death, there was an increased risk of death by 44-57% (Discontinued: Adj sHR = 1.57, 95% CI 1.31-1.88; Reduced: Adj sHR = 1.44, 95% CI 1.30-1.60), for individuals who discontinued or reduced their statin medication compared to those who continued.

Conclusions: Patients who discontinued their statin therapy had a significantly increased risk of IHD and stroke death. Health professionals should be aware that large co-payment changes may be associated with patients discontinuing or reducing medicines to their health detriment. Factors that lead to such changes in patient medication-taking behaviour need to be considered and addressed at the clinical and policy levels.
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http://dx.doi.org/10.1177/1355819620965610DOI Listing
November 2020

Practical Guidance for Food Consumption to Prevent Cardiovascular Disease.

Heart Lung Circ 2021 Feb 3;30(2):163-179. Epub 2020 Nov 3.

Medical School, University of Western Australia, Perth, WA, Australia.

This dietary guidance, informed by best contemporary evidence, aims to assist medical practitioners and allied health professionals in advising patients for the primary and secondary prevention of cardiovascular disease (CVD). While differing in some details from other current guidelines, the core messages accord with those published in 2019 by the American College of Cardiology/American Heart Association and the European Society of Cardiology/European Atherosclerosis Society; the National Lipid Association in 2014 and the NH&MRC Australian Dietary Guidelines in 2013. These were assessed through the Appraisal of Guidelines for Research and Evaluation (AGREE II) and the levels of evidence and classes of a recommendation developed using the GRADE system. Recommendations with high levels of evidence include increased consumption of plant based foods comprising mainly complex, fibre enriched carbohydrates (wholegrains, fruits and vegetables) while limiting intake of refined starches; partial replacement of saturated fats with monounsaturated or polyunsaturated fats and oils; reduced salt intake; achievement and maintenance of healthy weight; and low-to-moderate consumption of alcohol. Additional guidance but with moderate levels of evidence includes increased consumption of fish (and fish oils where indicated); reduction in sugar-sweetened beverages and added sugars; avoidance of butter and cream especially in those at increased CVD risk but encouragement of yoghurt; allow moderate consumption of lean meat but limit intake of processed meats; and limit cholesterol-rich foods such as eggs and crustaceans for those at increased CVD risk. Guidance has been formulated qualitatively on food categories of commonly eaten foods while avoiding prescriptive quantitative measures that are less readily translatable. This approach accords with current guidelines such as the American College of Cardiology/American Heart Association 2019 guidelines and is understandable and readily implemented.
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http://dx.doi.org/10.1016/j.hlc.2020.08.022DOI Listing
February 2021

Under-Reporting of Family History of Premature Coronary Artery Disease in Patients Discharged From Coronary Care: Implications for the Detection of Familial Hypercholesterolaemia.

Heart Lung Circ 2021 Feb 26;30(2):e48-e49. Epub 2020 Oct 26.

School of Medicine, Faculty of Health and Medical Sciences, University of Western Australia, Perth, WA, Australia; Lipid Disorders Clinic, Cardiometabolic Services, Department of Cardiology, Royal Perth Hospital, Perth, WA, Australia. Electronic address:

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http://dx.doi.org/10.1016/j.hlc.2020.09.930DOI Listing
February 2021

The lipid profile in children prior to isotretinoin therapy: an opportunity to detect familial hypercholesterolaemia.

Pathology 2021 Feb 6;53(2):288-290. Epub 2020 Oct 6.

School of Medicine, University of Western Australia, Perth, WA, Australia; Lipid Disorders Clinic, Cardiometabolic Service, Department of Cardiology, Royal Perth Hospital, Perth, WA, Australia; Department of Clinical Biochemistry, PathWest Laboratory Medicine WA, Royal Perth Hospital and Fiona Stanley Hospital Network, Perth, WA, Australia; Department of Clinical Biochemistry, Clinipath, Osborne Park, WA, Australia. Electronic address:

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http://dx.doi.org/10.1016/j.pathol.2020.07.007DOI Listing
February 2021

Advances, gaps and opportunities in the detection of familial hypercholesterolemia: overview of current and future screening and detection methods.

Curr Opin Lipidol 2020 12;31(6):347-355

School of Medicine, Faculty of Health and Medical Sciences, University of Western Australia, Crawley.

Purpose Of Review: Studies reaffirm that familial hypercholesterolemia is more prevalent than initially considered, with a population frequency of approximately one in 300. The majority of patients remains unidentified. This warrants critical evaluation of existing screening methods and exploration of novel methods of detection.

Recent Findings: New public policy recommendations on the detection of familial hypercholesterolemia have been made by a global community of experts and advocates. Phenotypic tools for diagnosing index cases remain inaccurate. Genetic testing is the gold standard for familial hypercholesterolemia and a new international position statement has been published. Correction of LDL cholesterol (LDL-C) for the cholesterol content of lipoprotein(a) [Lp(a)] may increase the precision of the phenotypic diagnosis of familial hypercholesterolemia. Cascade cotesting for familial hypercholesterolemia and elevated Lp(a) levels provides a new opportunity to stratify risk in families. Digital technology and machine learning methods, coupled with clinical alert and decision support systems, lead the way in more efficient approaches for detecting and managing index cases. Universal screening of children, combined with child-parent cascade testing, appears to be the most effective method for underpinning a population strategy for maximizing the detection of familial hypercholesterolemia.

Summary: Detection of familial hypercholesterolemia can be enhanced by optimizing current diagnostic algorithms, probing electronic health records with novel information technologies and integrating universal screening of children with cascade testing of parents and other relatives.
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http://dx.doi.org/10.1097/MOL.0000000000000714DOI Listing
December 2020

High-coverage plasma lipidomics reveals novel sex-specific lipidomic fingerprints of age and BMI: Evidence from two large population cohort studies.

PLoS Biol 2020 09 28;18(9):e3000870. Epub 2020 Sep 28.

Baker Heart and Diabetes Institute, Melbourne, Australia.

Obesity and related metabolic diseases show clear sex-related differences. The growing burden of these diseases calls for better understanding of the age- and sex-related metabolic consequences. High-throughput lipidomic analyses of population-based cohorts offer an opportunity to identify disease-risk-associated biomarkers and to improve our understanding of lipid metabolism and biology at a population level. Here, we comprehensively examined the relationship between lipid classes/subclasses and molecular species with age, sex, and body mass index (BMI). Furthermore, we evaluated sex specificity in the association of the plasma lipidome with age and BMI. Some 747 targeted lipid measures, representing 706 molecular lipid species across 36 classes/subclasses, were measured using a high-performance liquid chromatography coupled mass spectrometer on a total of 10,339 participants from the Australian Diabetes, Obesity and Lifestyle Study (AusDiab), with 563 lipid species being validated externally on 4,207 participants of the Busselton Health Study (BHS). Heat maps were constructed to visualise the relative differences in lipidomic profile between men and women. Multivariable linear regression analyses, including sex-interaction terms, were performed to assess the associations of lipid species with cardiometabolic phenotypes. Associations with age and sex were found for 472 (66.9%) and 583 (82.6%) lipid species, respectively. We further demonstrated that age-associated lipidomic fingerprints differed by sex. Specific classes of ether-phospholipids and lysophospholipids (calculated as the sum composition of the species within the class) were inversely associated with age in men only. In analyses with women alone, higher triacylglycerol and lower lysoalkylphosphatidylcholine species were observed among postmenopausal women compared with premenopausal women. We also identified sex-specific associations of lipid species with obesity. Lysophospholipids were negatively associated with BMI in both sexes (with a larger effect size in men), whilst acylcarnitine species showed opposing associations based on sex (positive association in women and negative association in men). Finally, by utilising specific lipid ratios as a proxy for enzymatic activity, we identified stearoyl CoA desaturase (SCD-1), fatty acid desaturase 3 (FADS3), and plasmanylethanolamine Δ1-desaturase activities, as well as the sphingolipid metabolic pathway, as constituent perturbations of cardiometabolic phenotypes. Our analyses elucidate the effect of age and sex on lipid metabolism by offering a comprehensive view of the lipidomic profiles associated with common cardiometabolic risk factors. These findings have implications for age- and sex-dependent lipid metabolism in health and disease and suggest the need for sex stratification during lipid biomarker discovery, establishing biological reference intervals for assessment of disease risk.
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http://dx.doi.org/10.1371/journal.pbio.3000870DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7544135PMC
September 2020

Commentary: Statins, COVID-19, and coronary artery disease: killing two birds with one stone.

Metabolism 2020 12 23;113:154375. Epub 2020 Sep 23.

Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran. Electronic address:

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http://dx.doi.org/10.1016/j.metabol.2020.154375DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7511211PMC
December 2020

The economic impact of familial hypercholesterolemia on productivity.

J Clin Lipidol 2020 Nov - Dec;14(6):799-806.e3. Epub 2020 Aug 17.

School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia.

Background: Familial hypercholesterolemia (FH) is a common inherited cause for premature coronary artery disease that increases suffering and disability in affected people. However, the extent to which FH impacts work productivity at a population level is unclear.

Objective: We aimed to quantify the burden of heterozygous FH (HeFH) in terms of productivity-adjusted life years (PALYs) lost to HeFH in Australia.

Methods: A life-table model was constructed to quantify years of life and PALYs lived by Australians with HeFH (prevalence 1 in 300) and of working age (aged 20-69 years). Follow-up was simulated until age 70 years. The model was then resimulated, but assuming the cohort did not have HeFH. Increased cardiovascular mortality and reduction in productivity attributable to HeFH were sourced from published data. Differences in total years of life, quality-adjusted life years, and PALYs lived by the "HeFH cohort" and the same cohort without HeFH ("non-HeFH cohort") reflected the quality-adjusted life years and PALYs lost due to HeFH. All future costs and outcomes were discounted by 5% annually.

Results: In 2017, an estimated 51,587 people of working age in Australia (0.33%) had HeFH. Over their working lifetime, we predicted that 2950 excess cardiovascular deaths occurred in the current Australian population of working age individuals with HeFH, resulting in a loss of 24,727 years of life. In terms of productivity, HeFH led to the loss of 24,954 PALYs over the working lifetime. Based on gross domestic product (GDP) per full-time equivalent worker, this equated to a total of AUD 5.23 billion in lost GDP over the working lifetime, with an average of AUD 101,366 lost per person. A relative reduction of 20% in cardiovascular deaths (as can be achieved with adequate cholesterol control) would lead to 1113 PALYs and AUD 233 million in GDP saved in the HeFH cohort.

Conclusion: The impact of HeFH on work productivity is significant. Screening and prevention strategies tailored early in life are likely to exert not only a positive impact on health but also the economy.
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http://dx.doi.org/10.1016/j.jacl.2020.08.004DOI Listing
August 2020