Reducing the Clinical and Public Health Burden of Familial Hypercholesterolemia: A Global Call to Action.

Importance: Familial hypercholesterolemia (FH) is an underdiagnosed and undertreated genetic disorder that leads to premature morbidity and mortality due to atherosclerotic cardiovascular disease. Familial hypercholesterolemia affects 1 in 200 to 250 people around the world of every race and ethnicity. The lack of general awareness of FH among the public and medical community has resulted in only 10% of the FH population being diagnosed and adequately treated. The World Health Organization recognized FH as a public health priority in 1998 during a consultation meeting in Geneva, Switzerland. The World Health Organization report highlighted 11 recommendations to address FH worldwide, from diagnosis and treatment to family screening and education. Research since the 1998 report has increased understanding and awareness of FH, particularly in specialty areas, such as cardiology and lipidology. However, in the past 20 years, there has been little progress in implementing the 11 recommendations to prevent premature atherosclerotic cardiovascular disease in an entire generation of families with FH. Observations: In 2018, the Familial Hypercholesterolemia Foundation and the World Heart Federation convened the international FH community to update the 11 recommendations. Two meetings were held: one at the 2018 FH Foundation Global Summit and the other during the 2018 World Congress of Cardiology and Cardiovascular Health. Each meeting served as a platform for the FH community to examine the original recommendations, assess the gaps, and provide commentary on the revised recommendations. The Global Call to Action on Familial Hypercholesterolemia thus represents individuals with FH, advocacy leaders, scientific experts, policy makers, and the original authors of the 1998 World Health Organization report. Attendees from 40 countries brought perspectives on FH from low-, middle-, and high-income regions. Tables listing country-specific government support for FH care, existing country-specific and international FH scientific statements and guidelines, country-specific and international FH registries, and known FH advocacy organizations around the world were created. Conclusions and Relevance: By adopting the 9 updated public policy recommendations created for this document, covering awareness; advocacy; screening, testing, and diagnosis; treatment; family-based care; registries; research; and cost and value, individual countries have the opportunity to prevent atherosclerotic heart disease in their citizens carrying a gene associated with FH and, likely, all those with severe hypercholesterolemia as well.

The sensitivity of 38 heart rate variability measures to the addition of artifact in human and artificial 24-hr cardiac recordings.

BACKGROUND: Artifact is common in cardiac RR interval data derived from 24-hr recordings and has a significant impact on heart rate variability (HRV) measures. However, the relative impact of progressively added artifact on a large group of commonly used HRV measures has not been assessed. This study compared the relative sensitivity of 38 commonly used HRV measures to artifact to determine which measures show the most change with increasing increments of artifact. A secondary aim was to ascertain whether short-term and long-term HRV measures, as groups, share similarities in their sensitivity to artifact. METHODS: Up to 10% of artifact was added to 20 artificial RR (ARR) files and 20 human cardiac recordings, which had been assessed for artifact by a cardiac technician. The added artifact simulated deletion of RR intervals and insertion of individual short RR intervals. Thirty-eight HRV measures were calculated for each file. Regression analysis was used to rank the HRV measures according to their sensitivity to artifact as determined by the magnitude of slope. RESULTS: RMSSD, SDANN, SDNN, RR triangular index and TINN, normalized power and relative power linear measures, and most nonlinear methods examined are most robust to artifact. CONCLUSION: Short-term time domain HRV measures are more sensitive to added artifact than long-term measures. Absolute power frequency domain measures across all frequency bands are more sensitive than normalized and relative frequency domain measures. Most nonlinear HRV measures assessed were relatively robust to added artifact, with Poincare plot SD1 being most sensitive.

Design of the Familial Hypercholesterolaemia Australasia Network Registry: Creating Opportunities for Greater International Collaboration.

Familial Hypercholesterolemia (FH) is the most common and serious monogenic disorder of lipoprotein metabolism that leads to premature coronary heart disease. There are over 65,000 people estimated to have FH in Australia, but many remain undiagnosed. Patients with FH are often under-treated, but with early detection, cascade family testing and adequate treatment, patient outcomes can improve. Patient registries are key tools for providing new information on FH and enhancing care worldwide. The development and design of the FH Australasia Network Registry is a crucial component in the comprehensive model of care for FH, which aims to provide a standardized, high-quality and cost-effective system of care that is likely to have the highest impact on patient outcomes. Informed by stakeholder engagement, the FH Australasia Network Registry was collaboratively developed by government, patient and clinical networks and research groups. The open-source, web-based Rare Disease Registry Framework was the architecture chosen for this registry owing to its open-source standards, modular design, interoperability, scalability and security features; all these are key components required to meet the ever changing clinical demands across regions. This paper provides a high level blueprint for other countries and jurisdictions to help inform and map out the critical features of an FH registry to meet their particular health system needs.

Triglyceride-lowering therapies reduce cardiovascular disease event risk in subjects with hypertriglyceridemia.

BACKGROUND: Cardiovascular outcomes trials of fibrates, niacin, or omega-3 fatty acids alone, or added to a statin, have not consistently demonstrated reduced risk, but larger, statistically significant clinical benefits have been reported in subgroups with elevated triglycerides (TG) and/or elevated TG plus low high-density lipoprotein cholesterol (HDL-C). OBJECTIVE: To perform a meta-analysis of the effects of therapies targeting TG and TG-rich lipoprotein cholesterol on cardiovascular disease event risk in subjects with elevated TG or elevated TG paired with low HDL-C. METHODS: Publications were identified using PubMed, the Cochrane Central Register of Controlled Trials, clinicaltrials.gov, the World Health Organization International Clinical Trials Registry Platform, and Internet Stroke Center. Random-effects meta-analysis models were used to generate summary relative risk estimates and 95% confidence intervals. Heterogeneity was assessed by χ(2) and I(2) statistics, and the impact of each trial was assessed in one study-removed sensitivity analyses. RESULTS: Six trials of fibrates, 2 of niacin, 1 of fibrate + niacin, and 1 of omega-3 eicosapentaenoic acid ethyl esters were identified. For the prespecified primary cardiovascular disease or coronary heart disease end point used in each trial, the summary relative risk estimate (95% confidence interval) for subjects with elevated TG was 0.82 (0.73-0.91), p-heterogeneity = 0.13, I(2) = 36.2, and for subjects with elevated TG and low-HDL-C, it was 0.71 (0.63-0.81), p-heterogeneity = 0.52, I(2) = 0.0. There was no evidence of publication bias, and the results remained statistically significant when each individual trial was removed. CONCLUSION: Drugs that substantially, but not exclusively, lower TG and TG-rich lipoprotein cholesterol may have cardiovascular benefits in individuals with elevated TG, particularly if accompanied by low HDL-C.

A preprocessing tool for removing artifact from cardiac RR interval recordings using three-dimensional spatial distribution mapping.

Artifact is common in cardiac RR interval data that is recorded for heart rate variability (HRV) analysis. A novel algorithm for artifact detection and interpolation in RR interval data is described. It is based on spatial distribution mapping of RR interval magnitude and relationships to adjacent values in three dimensions. The characteristics of normal physiological RR intervals and artifact intervals were established using 24-h recordings from 20 technician-assessed human cardiac recordings. The algorithm was incorporated into a preprocessing tool and validated using 30 artificial RR (ARR) interval data files, to which known quantities of artifact (0.5%, 1%, 2%, 3%, 5%, 7%, 10%) were added. The impact of preprocessing ARR files with 1% added artifact was also assessed using 10 time domain and frequency domain HRV metrics. The preprocessing tool was also used to preprocess 69 24-h human cardiac recordings. The tool was able to remove artifact from technician-assessed human cardiac recordings (sensitivity 0.84, SD = 0.09, specificity of 1.00, SD = 0.01) and artificial data files. The removal of artifact had a low impact on time domain and frequency domain HRV metrics (ranging from 0% to 2.5% change in values). This novel preprocessing tool can be used with human 24-h cardiac recordings to remove artifact while minimally affecting physiological data and therefore having a low impact on HRV measures of that data.

Lipid-modifying therapy in the elderly.

Cardiovascular disease (CVD) mortality and morbidity increases with increasing age, largely as a result of increased lifetime exposure as well as increased prevalence of CVD risk factors. Hospitalization for CVD increases by a factor of over 18× for those aged 85+ years versus those aged <30 years. In spite of this, life expectancy continues to increase, and in Australia for people reaching the age of 65 years, it is now 84 years in men and 87 years in women. The number of people for whom lipid management is potentially indicated therefore increases with aging. This is especially the case for secondary prevention and for people aged 65-75 years for whom there is also evidence of benefit from primary prevention. Many people in this age group are not treated with lipid-lowering drugs, however. Even those with CVD may be suboptimally treated, with one study showing treatment rates to fall from ~60% in those aged <50 years to <15% for those aged 85+ years. Treatment of the most elderly patient groups remains controversial partly from the lack of randomized trial intervention data and partly from the potential for adverse effects of lipid therapy. There are many complex issues involved in the decision to introduce effective lipid-lowering therapy and, unfortunately, in many instances there is not adequate data to make evidence-based decisions regarding management. This review summarizes the current state of knowledge of the management of lipid disorders in the elderly and proposes guidelines for management.

Clinical features and genetic analysis of three patients with severe hypertriglyceridaemia.

Hypertriglyceridaemia is a common biochemical abnormality that can be due to primary causes or, more commonly, secondary causes. Moderate hypertriglyceridaemia is a risk factor for cardiovascular disease and can develop into severe hypertriglyceridaemia which is a risk factor for acute pancreatitis. Familial chylomicronaemia is a rare autosomal recessive disorder, usually diagnosed in childhood and is characterized by marked hypertriglyceridaemia and biochemical deficiency of lipoprotein lipase (LPL), apolipoprotein (apo) C-II, homozygous (or compound heterozygous) gene mutations in LPL or more rarely, APOC2. Recently, loss-of-function mutations in the APOA5 gene have been reported in patients with severe hypertriglyceridaemia in whom LPL or APOC2 mutations were not found. We describe the clinical features and genetic analysis of three patients with severe hypertriglyceridaemia including novel mutations LPL c.464T>C (p.Leu155Pro) and APOA5 c.823C>T (p.Gln275*).

Use of fibrates in clinical practice: Queensland Lipid Group consensus recommendations.

BACKGROUND: Fibrates have been prescribed for decades as 'broad-spectrum' lipid modifying agents that can improve plasma levels of triglycerides, high-density lipoprotein cholesterol, and triglyceride-rich lipoproteins, including very low- and intermediate-density lipoproteins. Fibrates are variably effective in lowering low-density cholesterol levels. Available fibrates include gemfibrozil, fenofibrate, bezafibrate, etiofibrate and ciprofobrate; only fenofibrate and gemfibrozil are available in Australia. METHODS: Members of the Queensland Lipid Group provided consensus grades of recommendations for the clinical use of fibrates based on PubMed searches, product information, and personal clinical experience. RESULTS: Fibrates are well tolerated, and the combination of fenofibrate with statins appears to be safer than gemfibrozil, particularly with regard to adverse effects on muscle. Evidence has been provided recently for the efficacy of fenofibrate in reducing microvascular complications in diabetic patients, including progression of retinopathy, progression of microalbuminuria and nephropathy, development of sensory neuropathy, and leg amputation. Macrovascular benefits appear to be confined to those with reduced high-density lipoprotein cholesterol and/or increased triglyceride levels, and the relationship of microvascular benefits of fenofibrate to baseline lipid levels is variable and requires further assessment. CONCLUSIONS: Indications for fibrate therapy may be extended in the future to include protection from both macro- and micro-vascular disease, particularly in diabetic patients and patients with residual dyslipidaemia in spite of statin therapy. We provide recommendations on the use of fibrates in clinical practice to highlight these potential indications.

A new model of care for familial hypercholesterolaemia: what is the role of cardiology?

Familial hypercholesterolaemia (FH) is a co-dominantly inherited disorder that causes marked elevation in plasma cholesterol and premature coronary heart disease. There are at least 45,000 people with FH in Australia and New Zealand, but most remain undiagnosed and undertreated. To bridge this gap in coronary prevention the FH Australasia Network has developed a model of care for FH. We present the executive summary, with a commentary contrasting the recommendations with other international guidelines and highlighting the role of the cardiologist.

Mind and heart: heart rate variability in major depressive disorder and coronary heart disease - a review and recommendations.

OBJECTIVE: There is a reciprocal association between major depressive disorder (MDD) and coronary heart disease (CHD). These conditions are linked by a causal network of mechanisms. This causal network should be quantitatively studied and it is hypothesised that the investigation of vagal function represents a promising starting point. Heart rate variability (HRV) has been used to investigate cardiac vagal control in the context of MDD and CHD. This review aims to examine the relationship of HRV to both MDD and CHD in the context of vagal function and to make recommendations for clinical practice and research. METHODS: The search terms 'heart rate variability', 'depression' and 'heart disease' were entered into an electronic multiple database search engine. Abstracts were screened for their relevance and articles were individually selected and collated. RESULTS: Decreased HRV is found in both MDD and CHD. Both diseases are theorized to disrupt autonomic control feedback loops on the heart and are linked to vagal function. Existing theories link vagal function to both mood and emotion as well as cardiac function. However, several factors can potentially confound HRV measures and would thus impact on a complete understanding of vagal mechanisms in the link between MDD and CHD. CONCLUSIONS: The quantitative investigation of vagal function using HRV represents a reasonable starting point in the study of the relationship between MDD and CHD. Many psychotropic and cardiac medications have effects on HRV, which may have clinical importance. Future studies of HRV in MDD and CHD should consider antidepressant medication, as well as anxiety, as potential confounders.

A model of care for familial hypercholesterolaemia: key role for clinical biochemistry.

Familial hypercholesterolaemia (FH) is a dominantly inherited disorder present from birth that causes marked elevation in plasma low-density lipoprotein (LDL) cholesterol concentrations and premature coronary heart disease. There are at least 45,000 people with FH in Australia and New Zealand, but most remain unrecognised and those diagnosed remain inadequately treated. To bridge this gap in coronary prevention the FH Australasia Network has developed a model of care for FH. An executive summary of the model of care is presented, with a commentary on its recommendations and the key role of the clinical biochemistry laboratory.

Familial hypercholesterolaemia: a model of care for Australasia.

Familial hypercholesterolaemia (FH) is a dominantly inherited disorder present from birth that causes marked elevation in plasma cholesterol and premature coronary heart disease. There are at least 45,000 people with FH in Australia and New Zealand, but the vast majority remains undetected and those diagnosed with the condition are inadequately treated. To bridge this major gap in coronary prevention the FH Australasia Network (Australian Atherosclerosis Society) has developed a consensus model of care (MoC) for FH. The MoC is based on clinical experience, expert opinion, published evidence and consultations with a wide spectrum of stakeholders, and has been developed for use primarily by specialist centres intending starting a clinical service for FH. This MoC aims to provide a standardised, high-quality and cost-effective system of care that is likely to have the highest impact on patient outcomes. The MoC for FH is presented as a series of recommendations and algorithms focusing on the standards required for the detection, diagnosis, assessment and management of FH in adults and children. The process involved in cascade screening and risk notification, the backbone for detecting new cases of FH, is detailed. Guidance on treatment is based on risk stratifying patients, management of non-cholesterol risk factors, safe and effective use of statins, and a rational approach to follow-up of patients. Clinical and laboratory recommendations are given for genetic testing. An integrative system for providing best clinical care is described. This MoC for FH is not prescriptive and needs to be complemented by good clinical judgment and adjusted for local needs and resources. After initial implementation, the MoC will require critical evaluation, development and appropriate modification.

A topographical map of the causal network of mechanisms underlying the relationship between major depressive disorder and coronary heart disease.

OBJECTIVE: Major depressive disorder (MDD) and coronary heart disease (CHD) are both clinically important public health problems. Depression is linked with a higher incidence of ischaemic cardiac events and MDD is more prevalent in patients with CHD. No single comprehensive model has yet described the causal mechanisms linking MDD to CHD. Several key mechanisms have been put forward, comprising behavioural mechanisms, genetic mechanisms, dysregulation of immune mechanisms, coagulation abnormalities and vascular endothelial dysfunction, polyunsaturated omega-3 free fatty acid deficiency, and autonomic mechanisms. It has been suggested that these mechanisms form a network, which links MDD and CHD. The aim of this review is to examine the causal mechanisms underlying the relationship between MDD and CHD, with the aim of constructing a topological map of the causal network which describes the relationship between MDD and CHD. METHODS: The search term 'depression and heart disease' was entered into an electronic multiple database search engine. Abstracts were screened for relevance and individually selected articles were collated. RESULTS: This review introduces the first topological map of the causal network which describes the relationship between MDD and CHD. CONCLUSIONS: Viewing the causal pathways as an interdependent network presents a new paradigm in this field and provides fertile ground for further research. The causal network can be studied using the methodology of systems biology, which is briefly introduced. Future research should focus on the creation of a more comprehensive topological map of the causal network and the quantification of the activity between each node of the causal network.

Combination therapy of statin and ezetimibe for the treatment of familial hypercholesterolemia.

High-dose potent statin therapy in combination with ezetimibe is now standard practice for the treatment of adult patients with heterozygous familial hypercholesterolemia (heFH), as the result of numerous studies in patients with primary hypercholesterolemia or heFH. These studies have shown the combination to be both effective and safe in the short to medium term. Recently, short-term ezetimibe therapy has also been shown to be effective and safe in combination with statin therapy for children and adolescents with heFH. Effective statin-ezetimibe combination therapy is capable of achieving near-normal lipid profiles in heFH patients, with expected improvement in risk for cardiovascular disease (CVD) and improved life expectancy resulting predominantly from reduction in levels of low-density lipoprotein cholesterol. There are few data to support a pleiotropic action of ezetimibe with regard to CVD benefit, unlike therapy with statins. No serious and unexpected clinical adverse effects of combination statin-ezetimibe therapy have emerged till date, although data are limited in children and adolescents, for whom longer-term studies are required. Recent data suggesting possible proatherogenic effects of ezetimibe require confirmation. One large long-term randomized controlled clinical outcomes trial is in progress in non-FH patients to determine the efficacy and safety of ezetimibe therapy; it is unlikely that such a trial will ever be performed in patients with FH.

Managing residual risk in patients receiving statin therapy.

Until the results of several statin trials are available, it is recommended that the current indications and usage of ezetimibe be continued.

At sea with SEAS: the first clinical endpoint trial for ezetimibe, treatment of patients with mild to moderate aortic stenosis, ends with mixed results and more controversy.

SEAS (Simvastatin and Ezetimibe in Aortic Stenosis) hypothesised that aggressive lipid lowering with simvastatin/ezetimibe reduced cardiovascular disease (CVD) risk and the need for aortic valve replacement (AVR) in patients with asymptomatic aortic stenosis (AS). The study enrolled from 173 centres in seven European countries 1873 elderly non-diabetics with mild to moderate AS (mean aortic-valve area 1.28+/-0.47 cm(2)), who had no indication for lipid-lowering therapy. Patients were randomised to treatment with either simvastatin/ezetimibe 40/10mg daily or matching placebo after a four-week diet/placebo run-in period. Compared with placebo, LDL cholesterol was reduced by 61% (2.0 mmol/l). There was no difference in the primary endpoint (a combination of AVR, CV death, non-fatal MI, congestive heart failure from AS progression, coronary revascularisation, hospitalised unstable angina and non-haemorrhagic stroke). Compared with placebo, CVD events were reduced by 4.4% from 20.1% to 15.7% in the simvastatin/ezetimibe group (p=0.02). Cancer incidence and cancer deaths were more frequent in the simvastatin/ezetimibe group (9.9% vs. 7.0%, p=0.03 and 4.1% vs. 2.5%, p=0.05, respectively). These differences were not related to any form of cancer and did not increase with increased duration of therapy.