Australian and New Zealand Living Guideline cholesterol-lowering therapy for people with chronic kidney disease (CARI Guidelines): Reducing the evidence-practice gap.

AIM: People with chronic kidney disease experience high rates of cardiovascular disease. Cholesterol-lowering therapy is a mainstay in the management but there is uncertainty in the treatment effects on patient-important outcomes, such as fatigue and rhabdomyolysis. Here, we summarise the updated CARI Australian and New Zealand Living Guidelines on cholesterol-lowering therapy in chronic kidney disease. METHODS: We updated a Cochrane review and monitored newly published studies weekly to inform guideline development according to international standards. The Working Group included expertise from nephrology, cardiology, Indigenous Health, guideline development and people with lived experience of chronic kidney disease. RESULTS: The guideline recommends people with chronic kidney disease (eGFR ≥15 mL/min/1.73 m2) and an absolute cardiovascular risk of 10% or higher should receive statin therapy (with or without ezetimibe) to reduce the risk of cardiovascular events and death (strong recommendation, moderate certainty evidence). The guidelines also recommends a lower absolute cardiovascular risk threshold (≥5%) for Aboriginal and Torres Strait Islander Peoples and Maori with chronic kidney disease to receive statin therapy (with or without ezetimibe) (strong recommendation, low certainty evidence). The evidence was actively surveyed from 2020-2023 and updated as required. No changes to guideline recommendations were made, with no new data on the balance and benefits of harms. CONCLUSIONS: The development of living guidelines was feasible and provided the opportunity to update recommendations to improve clinical decision-making in real-time. Living guidelines provide the opportunity to transform chronic kidney disease guidelines.

Prognostic utility of serum NT-proBNP (fragments 1-76aa and 13-71aa) and galectin-3 in predicting death and re-hospitalisation due to cardiovascular events in patients with heart failure.

Patients with heart failure (HF) are at a higher risk of rehospitalisation. In this study, we investigated the prognostic utility of galectin-3 (Gal-3) and NT-proBNP fragments (1-76aa and 13-71aa) as biomarkers to predict outcomes for patients with HF. We collected blood samples from patients with HF (n = 101). Gal-3 and NT-proBNP fragments (1-76aa and 13-71aa) concentrations were measured by immunoassay. Survival analysis and Cox proportional regression models were used to determine the prognostic utility of Gal-3 and NT-proBNP fragments. In patients with increased baseline levels of NT-proBNP1-76 the time to primary endpoint (cardiovascular death or re-hospitalisation) was significantly shorter (p = 0.0058), but not in patient with increased baseline levels of Gal-3 or NTproBNP13-71. Patients with increased levels of NT-proBNP13-71aa at 1 month showed reduced time to the primary endpoint (p = 0.0123). Our findings demonstrated that Gal-3 and NT-proBNP can be used as prognostic biomarkers to stratify patients with HF.

The 10 essential questions regarding lipoprotein(a).

PURPOSE OF REVIEW: Lp(a) is one of the most atherogenic lipoproteins, and significant progress has been made to understand its pathophysiology over the last 20 years. There are now selective therapies in late-stage clinical trials to lower Lp(a). Yet there are many outstanding questions about Lp(a). This review outlines 10 of the most burning questions and tries to answer some of them. RECENT FINDINGS: Antisense oligonucleotide (ASO) treatment is currently the most advanced therapy to lower plasma Lp(a) by 60-80%. There are, however, also two small molecule medications in early stage of development with similar efficacy. SUMMARY: This review aims to answer important preclinical and clinical questions about the metabolism and physiological role of Lp(a) and also outlines possible therapeutic approaches with nutraceuticals, currently available lipid-lowering therapies and new medications. In addition, ways are illustrated to use Lp(a) as a marker to better predict cardiovascular risk.

Omega-3 fatty acids and cardiovascular prevention: is the jury still out?

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 clearly show high intake of fish and measured O3FA (mainly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)) in tissues are inversely associated with cardiovascular events and total mortality. These fatty acids are 'essential' and depend almost entirely on intake with very little production from within the body. The efficacy of supplementation depends on background tissue levels, in contradistinction to drug therapy. Insufficient dosing of omega-3 supplementation using less than 1 g/day and lack of titration to target by failing to measure O3FA levels in the blood may explain these conflicting trial outcomes. We review the current evidence regarding O3FA supplementation and cardiovascular outcomes, describe possible reasons for the discrepant results in the literature including recent controversial data around the mineral oil comparator used in REDUCE-IT and discuss the potential use of the omega-3 index to guide management and optimise supplementation in those at greatest risk.

Barriers to and Facilitators of Implementing Guidelines for Detecting Familial Hypercholesterolaemia in Australia.

BACKGROUND: Familial hypercholesterolaemia (FH) is a genetic condition that is a preventable cause of premature cardiovascular 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 approach across Australian health settings. The aim of this study was to identify the implementation barriers to and facilitators of the detection of FH in Australia. METHODS: Four, 2-hour virtual focus groups were facilitated by implementation scientists and a clinicians as part of the 2021 Australasian FH Summit. Template analysis was used to identify themes. RESULTS: There were 28 workshop attendees across four groups (n=6-8 each), yielding 13 barriers and 10 facilitators across three themes: (1) patient related, (2) provider related, and (3) system related. A "lack of care pathways" and "upskilling clinicians in identifying and diagnosing FH" were the most interconnected barriers and facilitators for the detection of FH. CONCLUSIONS: The relationships between barriers and facilitators across the patient, provider, and system themes indicates that a comprehensive implementation strategy is needed to address these different levels. Future research is underway to develop a model for implementing the Australian FH guidelines into practice.

Australian Atherosclerosis Society Position Statement on Lipoprotein(a): Clinical and Implementation Recommendations.

This position statement provides guidance to cardiologists and related specialists on the management of adult patients with elevated lipoprotein(a) [Lp(a)]. Elevated Lp(a) is an independent and causal risk factor for atherosclerotic cardiovascular disease (ASCVD) and calcific aortic valve disease (CAVD). While circulating Lp(a) levels are largely determined by ancestry, they are also influenced by ethnicity, hormones, renal function, and acute inflammatory events, such that measurement should be done after accounting for these factors. Further, circulating Lp(a) concentrations should be estimated using an apo(a)-isoform independent assay that employs appropriate calibrators and reports the results in molar units (nmol/L). Selective screening strategies of high-risk patients are recommended, but universal screening of the population is currently not advised. Testing for elevated Lp(a) is recommended in all patients with premature ASCVD and those considered to be at intermediate-to-high risk of ASCVD. Elevated Lp(a) should be employed to assess and stratify risk and to enable a decision on initiation or intensification of preventative treatments, such as cholesterol lowering therapy. In adult patients with elevated Lp(a) at intermediate-to-high risk of ASCVD, absolute risk should be reduced by addressing all modifiable behavioural, lifestyle, psychosocial and clinical risk factors, including maximising cholesterol-lowering with statin and ezetimibe and, where appropriate, PCSK9 inhibitors. Apheresis should be considered in patients with progressive ASCVD. New ribonucleic acid (RNA)-based therapies which directly lower Lp(a) are undergoing clinical trials.

Corrigendum to Synopsis of an integrated guidance for enhancing the care of familial hypercholesterolaemia: An Australian perspective [American Journal of Preventive Cardiology 6 (2021) 100151].

[This corrects the article DOI: 10.1016/j.ajpc.2021.100151.].

Lp(a) and the Risk for Cardiovascular Disease: Focus on the Lp(a) Paradox in Diabetes Mellitus.

Lipoprotein(a) (Lp(a)) is one of the strongest causal risk factors of atherosclerotic disease. It is rich in cholesteryl ester and composed of apolipoprotein B and apo(a). Plasma Lp(a) levels are determined by apo(a) transcriptional activity driven by a direct repeat (DR) response element in the apo(a) promoter under the control of (HNF)4α Farnesoid-X receptor (FXR) ligands play a key role in the downregulation of APOA expression. In vitro studies on the catabolism of Lp(a) have revealed that Lp(a) binds to several specific lipoprotein receptors; however, their in vivo role remains elusive. There are more than 1000 publications on the role of diabetes mellitus (DM) in Lp(a) metabolism; however, the data is often inconsistent and confusing. In patients suffering from Type-I diabetes mellitus (T1DM), provided they are metabolically well-controlled, Lp(a) plasma concentrations are directly comparable to healthy individuals. In contrast, there exists a paradox in T2DM patients, as many of these patients have reduced Lp(a) levels; however, they are still at an increased cardiovascular risk. The Lp(a) lowering mechanism observed in T2DM patients is most probably caused by mutations in the mature-onset diabetes of the young (MODY) gene and possibly other polymorphisms in key transcription factors of the apolipoprotein (a) gene (APOA).

Management of Fetal Supraventricular Tachycardia: Case Series from a Tertiary Perinatal Cardiac Center.

BACKGROUND: Fetal supraventricular tachycardia is a relatively uncommon cardiac rhythm abnormality which is often associated with adverse perinatal outcomes if untreated. Although there are several treatment modalities and protocols in use globally, there is no consensus as to the most effective antiarrhythmic to manage this condition. AIM: This study aimed to evaluate perinatal outcomes following prenatal maternal therapy for fetal supraventricular tachycardia. MATERIALS AND METHODS: This was a 20-year retrospective cohort study. Institutional records were reviewed for antenatal therapy choice and maternal and fetal outcomes. RESULTS: Sixty-nine cases met diagnostic criteria for fetal SVT, of which 56 (81%) received maternal antiarrhythmic therapy. Digoxin was the most common, but least effective, first-line therapy in 28 patients, achieving successful rate reversion in 35.7%. Thirty-one patients (55%) required second-line therapy, and this was most successful with digoxin and flecainide polytherapy achieving rate reversion in 17 of 18 cases (94.5%) at a median of 3 days (1.5-7). Hydrops was present in 23 (33%) cases at initial presentation, 16 of which achieved rate reversion. There was minimal difference in treatment efficacy comparing single- or multiple-agent treatment in the setting of hydrops (50% vs. 42.8%). Side effects occurred in 14/56 treated patients (25%) but were severe in only 8 (14.3%) women, most commonly with digoxin and flecainide polytherapy (6 of 8 cases). There were 3 (4%) fetal deaths amongst the study cohort. CONCLUSIONS: Digoxin and flecainide polytherapy were well tolerated and successfully achieved rhythm and rate control in fetuses with prenatally diagnosed supraventricular tachycardia. The presence of hydrops was a poor prognostic feature.

Synopsis of an integrated guidance for enhancing the care of familial hypercholesterolaemia: an Australian perspective.

INTRODUCTION: Familial hypercholesterolaemia (FH) is a common, heritable and preventable cause of premature coronary artery disease, with significant potential for positive impact on public health and healthcare savings. New clinical practice recommendations are presented in an abridged guidance to assist practitioners in enhancing the care of all patients with FH. MAIN RECOMMENDATIONS: Core recommendations are made on the detection, diagnosis, assessment and management of adults, children and adolescents with FH. There is a key role for general practitioners (GPs) working in collaboration with specialists with expertise in lipidology. Advice is given on genetic and cholesterol testing and risk notification of biological relatives undergoing cascade testing for FH; all healthcare professionals should develop skills in genomic medicine. Management is under-pinned by the precepts of risk stratification, adherence to healthy lifestyles, treatment of non-cholesterol risk factors, and appropriate use of low-density lipoprotein (LDL)-cholesterol lowering therapies, including statins, ezetimibe and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. Recommendations on service design are provided in the full guidance. POTENTIAL IMPACT ON CARE OF FH: These recommendations need to be utilised using judicious clinical judgement and shared decision making with patients and families. Models of care need to be adapted to both local and regional needs and resources. In Australia new government funded schemes for genetic testing and use of PCSK9 inhibitors, as well as the National Health Genomics Policy Framework, will enable adoption of these recommendations. A broad implementation science strategy is, however, required to ensure that the guidance translates into benefit for all families with FH.

Essentials of a new clinical practice guidance on familial hypercholesterolaemia for physicians.

Familial hypercholesterolaemia (FH) is a common, heritable and preventable cause of premature coronary artery disease. New clinical practice recommendations are presented to assist practitioners in enhancing the care of all patients with FH. Core recommendations are made on the detection, diagnosis, assessment and management of adults, children and adolescents with FH. Management is under-pinned by the precepts of risk stratification, adherence to healthy lifestyles, treatment of non-cholesterol risk factors and appropriate use of low-density lipoprotein (LDL)-cholesterol-lowering therapies including statins, ezetimibe and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. The recommendations need to be utilised using judicious clinical judgement and shared decision-making with patients and families. New government-funded schemes for genetic testing and use of PCSK9 inhibitors, as well as the National Health Genomics Policy Framework, will enable adoption of the recommendations. However, a comprehensive implementation science and practice strategy is required to ensure that the guidance translates into benefit for all families with FH.

Asian Pacific Society of Cardiology Consensus Recommendations on Dyslipidaemia.

The prevalence of dyslipidaemia has been increasing in the Asia-Pacific region and this is attributed to dietary changes and decreasing physical activity. While there has been substantial progress in dyslipidaemia therapy, its management in the region is hindered by limitations in awareness, adherence and healthcare costs. The Asian Pacific Society of Cardiology (APSC) developed these consensus recommendations to address the need for a unified approach to managing dyslipidaemia. These recommendations are intended to guide general cardiologists and internists in the assessment and treatment of dyslipidaemia and are hoped to pave the way for improving screening, early diagnosis and treatment. The APSC expert panel reviewed and appraised the evidence using the Grading of Recommendations Assessment, Development, and Evaluation system. Consensus recommendations were developed, which were then put to an online vote. The resulting consensus recommendations tackle contemporary issues in the management of dyslipidaemia, familial hypercholesterolaemia and lipoprotein(a) in the Asia-Pacific region.

Gaps in the Care of Familial Hypercholesterolaemia in Australia: First Report From the National Registry.

BACKGROUND: Familial hypercholesterolaemia (FH) is under-diagnosed and under-treated worldwide, including Australia. National registries play a key role in identifying patients with FH, understanding gaps in care and advancing the science of FH to improve care for these patients. METHODS: The FH Australasia Network has established a national web-based registry to raise awareness of the condition, facilitate service planning and inform best practice and care services in Australia. We conducted a cross-sectional analysis of 1,528 FH adults enrolled in the registry from 28 lipid clinics. RESULTS: The mean age at enrolment was 53.4±15.1 years, 50.5% were male and 54.3% had undergone FH genetic testing, of which 61.8% had a pathogenic FH-causing gene variant. Only 14.0% of the cohort were family members identified through cascade testing. Coronary artery disease (CAD) was reported in 28.0% of patients (age of onset 49.0±10.5 years) and 64.9% had at least one modifiable cardiovascular risk factor. The mean untreated LDL-cholesterol was 7.4±2.5 mmol/L. 80.8% of patients were on lipid-lowering therapy with a mean treated LDL-cholesterol of 3.3±1.7 mmol/L. Among patients receiving lipid-lowering therapies, 25.6% achieved an LDL-cholesterol target of <2.5 mmol/L without CAD or <1.8 mmol/L with CAD. CONCLUSION: Patients in the national FH registry are detected later in life, have a high burden of CAD and risk factors, and do not achieve guideline-recommended LDL-cholesterol targets. Genetic and cascade testing are under-utilised. These deficiencies in care need to be addressed as a public health priority.

Integrated Guidance for Enhancing the Care of Familial Hypercholesterolaemia in 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.

Familial Hypercholesterolaemia in 2020: A Leading Tier 1 Genomic Application.

Familial hypercholesterolaemia (FH) is caused by a major genetic defect in the low-density lipoprotein (LDL) clearance pathway. Characterised by LDL-cholesterol elevation from birth, FH confers a significant risk for premature coronary artery disease (CAD) if overlooked and untreated. With risk exposure beginning at birth, early detection and intervention is crucial for the prevention of CAD. Lowering LDL-cholesterol with lifestyle and statin therapy can reduce the risk of CAD. However, most individuals with FH will not reach guideline recommended LDL-cholesterol targets. FH has an estimated prevalence of approximately 1:250 in the community. Multiple strategies are required for screening, diagnosing and treating FH. Recent publications on FH provide new data for developing models of care, including new therapies. This review provides an overview of FH and outlines some recent advances in the care of FH for the prevention of CAD in affected families. The future care of FH in Australia should be developed within the context of the National Health Genomics Policy Framework.

The potential prognostic utility of salivary galectin-3 concentrations in heart failure.

BACKGROUND: Patients with HF are at a higher risk of rehospitalisation and, as such, significant costs to our healthcare system. A non-invasive method to collect body fluids and measure Gal-3 could improve the current management of HF. In this study, we investigated the potential prognostic utility of salivary Galectin-3 (Gal-3) in patients with heart failure (HF). METHODS: We collected saliva samples from patients with HF (n = 105) either at hospital discharge or during routine clinical visits. Gal-3 concentrations in saliva samples were measured by ELISA. The Kaplan-Meier survival curve analysis and Cox proportional regression model were used to determine the potential prognostic utility of salivary Gal-3 concentrations. RESULTS: The primary end point was either cardiovascular death or hospitalisation. Salivary Gal-3 concentrations were significantly higher (p < 0.05) in patients with HF who subsequently experienced the primary endpoint compared to those who did not. HF patients with salivary Gal-3 concentrations > 172.58 ng/mL had a significantly (p < 0.05) higher cumulative risk of the primary endpoint compared to those with lower salivary Gal-3 concentrations. In patients with HF, salivary Gal-3 concentration was a predictor of the primary endpoint even after adjusting for other covariates. CONCLUSIONS: In our pilot study, HF patients with salivary Gal-3 concentrations of > 172.58 ng/mL demonstrated a higher cumulative risk of the primary outcome compared to those with lower Gal-3 levels, even after adjusting for other variables. Confirming our findings in a larger multi-centre clinical trial in the future would enable salivary Gal-3 measurements to form part of routine management for patients with HF.

Correction to: The potential prognostic utility of salivary galectin-3 concentrations in heart failure.

The original version of this article unfortunately contained a mistake.

Molecular, Population, and Clinical Aspects of Lipoprotein(a): A Bridge Too Far?

There is now significant evidence to support an independent causal role for lipoprotein(a) (Lp(a)) as a risk factor for atherosclerotic cardiovascular disease. Plasma Lp(a) concentrations are predominantly determined by genetic factors. However, research into Lp(a) has been hampered by incomplete understanding of its metabolism and proatherogeneic properties and by a lack of suitable animal models. Furthermore, a lack of standardized assays to measure Lp(a) and no universal consensus on optimal plasma levels remain significant obstacles. In addition, there are currently no approved specific therapies that target and lower elevated plasma Lp(a), although there are recent but limited clinical outcome data suggesting benefits of such reduction. Despite this, international guidelines now recognize elevated Lp(a) as a risk enhancing factor for risk reclassification. This review summarises the current literature on Lp(a), including its discovery and recognition as an atherosclerotic cardiovascular disease risk factor, attempts to standardise analytical measurement, interpopulation studies, and emerging therapies for lowering elevated Lp(a) levels.

Salivary Protein Panel to Diagnose Systolic Heart Failure.

Screening for systolic heart failure (SHF) has been problematic. Heart failure management guidelines suggest screening for structural heart disease and SHF prevention strategies should be a top priority. We developed a multi-protein biomarker panel using saliva as a diagnostic medium to discriminate SHF patients and healthy controls. We collected saliva samples from healthy controls (n = 88) and from SHF patients (n = 100). We developed enzyme linked immunosorbent assays to quantify three specific proteins/peptide (Kallikrein-1, Protein S100-A7, and Cathelicidin antimicrobial peptide) in saliva samples. The analytical and clinical performances and predictive value of the proteins were evaluated. The analytical performances of the immunoassays were all within acceptable analytical ranges. The multi-protein panel was able to significantly (p < 0.001) discriminate saliva samples collected from patients with SHF from controls. The multi-protein panel demonstrated good performance with an overall diagnostic accuracy of 81.6% (sensitivity of 79.2% and specificity of 85.7%) when distinguishing SHF patients from healthy individuals. In conclusion, we have developed immunoassays to measure the salivary concentrations of three proteins combined as a panel to accurately distinguish SHF patients from healthy controls. While this requires confirmation in larger cohorts, our findings suggest that this three-protein panel has the potential to be used as a biomarker for early detection of SHF.

The Effect of Tai Chi on Quality of Life in Centrally Obese Adults with Depression.

Objectives: The aim of this pilot study was to assess the effects of a t'ai chi program on health-related quality of life (HR-QOL) in centrally obese adults with depression. Methods: Two hundred thirteen participants were randomly allocated to either a t'ai chi intervention group (n = 106) or a usual medical care control group (n = 107). The t'ai chi group involved 3 × 1.5 h supervised and group-based training sessions per week for 24 weeks. Indicators of HR-QOL were assessed by questionnaire at baseline, 12 weeks, and 24 weeks. Results: There were significant improvements in favor of the t'ai chi group for the SF-36 subscales of physical functioning (p < 0.01), role physical (p < 0.01), and role emotional (p < 0.01) at 12 and 24 weeks. Scores for bodily pain were improved in the control group at 12 weeks (p < 0.01) and 24 weeks (p < 0.05), but not in the t'ai chi group. There was also a significant improvement in favor of the control group in general health (p < 0.05) at 12 weeks, but not at 24 weeks. A further analysis showed clinically significant changes in favor of the t'ai chi group in physical functioning (p < 0.05 or p = 0.05), role physical (p < 0.05), and role emotional (p < 0.05), and in favor of the control group in bodily pain (p < 0.05) at 12 and 24 weeks. Conclusions: The findings show that t'ai chi exercise improved indicators of HR-QOL including physical functioning, role physical, and role emotional in centrally obese adults with depression.