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.

An age-matched computed tomography angiographic study of coronary atherosclerotic plaques in patients with familial hypercholesterolaemia.

BACKGROUND AND AIMS: Familial hypercholesterolaemia (FH) is characterised by a high, but variable risk of premature coronary artery disease (CAD). Cardiac computed tomography angiography (CCTA) can be employed to assess subclinical coronary atherosclerosis. We investigated the features and distribution of coronary artery plaques in asymptomatic patients with and without genetically confirmed heterozygous FH. METHODS: We undertook an aged-matched case-control study of asymptomatic phenotypic FH patients with (cases, M+) and without (controls, M-) an FH-causing mutation. Coronary atherosclerosis was assessed by CCTA and calcium scoring. Coronary segments were evaluated for global and vessel-level coronary plaques and degree of stenosis. RESULTS: We studied 104 cases and 104 controls (mean age 49.9 ± 10.4 years), who had a similar spectrum of non-cardiovascular risk factors. Pre-treatment plasma LDL-cholesterol was higher in the M+ than M- group (7.8 ± 2.1 vs 6.2 ± 1.2 mmol/L, p<0.001). There was a greater proportion of patients with mixed and calcified plaque, as well as a higher coronary artery calcium score and segment stenosis score (all p<0.05), in the M+ compared with the M- group. M+ patients also had a significantly higher frequency of coronary artery calcium in the left main and anterior descending and right coronary arteries (all p<0.05), but not in the left circumflex. CONCLUSIONS: Among patients with phenotypic FH, those with a genetically confirmed diagnosis had a higher frequency and severity of coronary atherosclerotic plaques, and specifically more advanced calcified plaques.

Cerebral embolism and carotid-hyoid impingement syndrome.

Embolic stroke of undetermined source (ESUS) is not uncommon in young patients. Here, we describe two cases of stroke from an unusual aetiology; cerebral embolization from carotid artery injury presumed secondary to hyoid bone impingement. Both patients demonstrated angiographic evidence of hyoid bone impingement. Following resection of the greater cornu of the hyoid bone, neither patient had further strokes.

Parent-child genetic testing for familial hypercholesterolaemia in an Australian context.

AIM: The aim of this study was to evaluate the clinical outcome of parent-child testing for familial hypercholesterolaemia (FH) employing genetic testing and the likely additional cost of treating each child. METHODS: Parent-child testing for gene variants causative of FH was carried out according to Australian guidelines. The number of new cases detected, the low-density lipoprotein (LDL)-cholesterol that best predicted a mutation and the proportional reduction in LDL-cholesterol following statin treatment was evaluated. Treatment costs were calculated as the cost per mmol/L reduction in LDL-cholesterol. RESULTS: A total of 126 adult patients, known to have a pathogenic mutation causative of FH, and their children were studied. From 244 children identified, 148 (60.7%) were genetically screened; 84 children were identified as mutative positive (M+) and 64 as mutative negative. Six of the M+ children were already on statin treatment; 40 were subsequently treated with low-dose statins, with LDL-cholesterol falling significantly by 38% (P < 0.001). The estimated cost per mmol/L reduction of LDL-cholesterol of a child receiving statins from ages 10 to 18 years is AU$1361, which can potentially be cost-effective. An LDL-cholesterol threshold of 3.5 mmol/L had a sensitivity of 92.8% and specificity of 96.6% for the detection of a mutation. CONCLUSION: Genetic testing of children of affected parents with FH is an effective means of detecting new cases of FH. Cascade testing can enable early statin therapy with significant reductions in LDL-cholesterol concentration.

A Comparative Analysis of Phenotypic Predictors of Mutations in Familial Hypercholesterolemia.

Context: The gold standard for diagnosing familial hypercholesterolemia (FH) is identification of a causative pathogenic mutation. However, genetic testing is expensive and not widely available. Objective: To compare the validity of the Dutch Lipid Clinic Network (DLCN), Simon Broome (SB), Make Early Diagnosis to Prevent Early Deaths (MEDPED), and American Heart Association (AHA) criteria in predicting an FH-causing mutation. Design, Setting, and Patients: An adult cohort of unrelated patients referred to a lipid clinic for genetic testing. Main Outcome Measures: Odds ratio (OR), area under the curve (AUC), sensitivity, and specificity. Results: A pathogenic FH-causing mutation was detected in 30% of 885 patients tested. Elevated low-density lipoprotein (LDL) cholesterol and personal or family history of tendon xanthomata were independent predictors of a mutation (OR range 5.3 to 16.1, P < 0.001). Prediction of a mutation for the DLCN and SB definite and MEDPED criteria (ORs 9.4, 11.7, and 10.5, respectively) was higher than with the AHA criteria (OR 4.67). The balance of sensitivity and specificity was in decreasing order DLCN definite (Youden Index 0.487), MEDPED (0.457), SB definite (0.274), and AHA criteria (0.253), AUC being significantly higher with DLCN definite and MEDPED than other criteria (P < 0.05). Pretreatment LDL cholesterol and tendon xanthomata had the highest AUC in predicting a mutation. Conclusions: The DLCN, SB, and MEDPED criteria are valid predictors of an FH-causing mutation in patients referred to a lipid clinic, but concordance between these phenotypic criteria is only moderate. Use of pretreatment LDL cholesterol and tendon xanthomata alone may be particularly useful for deciding who should be genetically tested for FH.

A rare suspected case of chronic nodular granulomatous herpes simplex encephalitis in an adult.

Herpes simplex encephalitis is the most common sporadic viral encephalitis in the western world, HSV-1 (herpes simplex virus) being the mostly commonly implicated serotype. The disease is usually monophasic, although patients may relapse weeks, months or years after initial infection. This chronic granulomatous inflammatory process is almost exclusively described in children and rarely forms discrete enhancing parenchymal nodules. We present the clinical and radiological features of an unusual case of chronic nodular granulomatous herpes encephalitis with enhancing "mass-like" nodules in an adult. To the author's knowledge, this is the first reported case of macroscopic "mass-like" nodular granuloma formation in an adult.

Quality of Acute Care and Long-Term Quality of Life and Survival: The Australian Stroke Clinical Registry.

BACKGROUND AND PURPOSE: Uncertainty exists over whether quality improvement strategies translate into better health-related quality of life (HRQoL) and survival after acute stroke. We aimed to determine the association of best practice recommended interventions and outcomes after stroke. METHODS: Data are from the Australian Stroke Clinical Registry during 2010 to 2014. Multivariable regression was used to determine associations between 3 interventions: received acute stroke unit (ASU) care and in various combinations with prescribed antihypertensive medication at discharge, provision of a discharge care plan, and outcomes of survival and HRQoL (EuroQoL 5-dimensional questionnaire visual analogue scale) at 180 days, by stroke type. An assessment was also made of outcomes related to the number of processes patients received. RESULTS: There were 17 585 stroke admissions (median age 77 years, 47% female; 81% managed in ASUs; 80% ischemic stroke) from 42 hospitals (77% metropolitan) assessed. Cumulative benefits on outcomes related to the number of care processes received by patients. ASU care was associated with a reduced likelihood of death (hazard ratio, 0.49; 95% confidence interval, 0.43-0.56) and better HRQoL (coefficient, 21.34; 95% confidence interval, 15.50-27.18) within 180 days. For those discharged from hospital, receiving ASU+antihypertensive medication provided greater 180-day survival (hazard ratio, 0.45; 95% confidence interval, 0.38-0.52) compared with ASU care alone (hazard ratio, 0.64; 95% confidence interval, 0.54-0.76). HRQoL gains were greatest for patients with intracerebral hemorrhage who received care bundles involving discharge processes (range of increase, 11%-19%). CONCLUSIONS: Patients with stroke who receive best practice recommended hospital care have improved long-term survival and HRQoL.

Frequency of familial hypercholesterolemia in patients with early-onset coronary artery disease admitted to a coronary care unit.

BACKGROUND: Familial hypercholesterolemia (FH) is the most common dominantly inherited cause of premature coronary artery disease (CAD). However, the diagnosis of FH in patients who have premature CAD in hospital settings is under-recognized, this also represents a missed opportunity for screening their close family members and implementing primary prevention. OBJECTIVE: To investigate the point prevalence of FH in a coronary care unit (CCU) among patients with early-onset CAD. METHODS: The prevalence of FH, based on modified phenotypic Dutch Lipid Clinic Network Criteria, and the spectrum of associated CAD risk factors, were investigated in a CCU setting. Data were collected on 175 coronary care patients with onset of CAD at age <60 years. RESULTS: The prevalence of probable/definite FH was 14.3% (95% confidence interval, 9.0%-19.5%); 46.3% of the patients gave a family history of premature CAD and 20.6% had an untreated low-density lipoprotein cholesterol >5.0 mmol/L. Diabetes, hypertension, obesity, and smoking were common and equally prevalent in patients with and without FH. CONCLUSIONS: FH is relatively frequent among patients with a history of early-onset CAD in the CCU. Every effort should be made to detect FH in these patients and to initiate cascade testing of available family members to prevent the development of CAD in those who may be unaware that they also have the condition.

Elevated lipoprotein(a), hypertension and renal insufficiency as predictors of coronary artery disease in patients with genetically confirmed heterozygous familial hypercholesterolemia.

BACKGROUND: Familial hypercholesterolemia (FH) is characterized by elevated LDL-cholesterol and increased risk of premature coronary artery disease (CAD). Lipoprotein(a) [Lp(a)] increases CAD in FH, although the independence of this association relative to other CAD risk factors remains unclear. In this study, we examined the association between Lp(a) and other cardiovascular risk factors and prevalent CAD in patients with FH. METHODS: A cross-sectional study of 390 patients with genetically confirmed FH were studied. Clinical and biochemical parameters of FH patients with and without CAD were compared. RESULTS: FH patients with CAD were older and more often male and had a higher prevalence of hypertension, smoking, diabetes, obesity, reduced eGFR, and elevated plasma Lp(a) and pre-treatment LDL-cholesterol and triglyceride (or low HDL-cholesterol) than FH patients without CAD (P<0.05 for all). In univariate analyses, age, male gender, smoking, hypertension, reduced eGFR, diabetes, obesity, plasma creatinine, Lp(a) and pretreatment LDL-cholesterol, triglycerides and HDL-cholesterol levels were significant predictors of CAD in the FH patients (P<0.05 for all). Elevated LDL-cholesterol, raised Lp(a), hypertension and reduced eGFR remained significant independent predictors of CAD (P<0.05 for all) in FH after adjusting for other modifiable risk factors. CONCLUSIONS: Elevated Lp(a), hypertension and renal insufficiency are independent risk factors beyond elevated pretreatment LDL-cholesterol which predict CAD in patients with FH. In spite of the cross-sectional design of our study, we propose the need for identifying and managing these abnormalities to reduce excess CAD risk in FH patients. However, this proposal remains to be formally tested in a prospective study.

Effectiveness of genetic cascade screening for familial hypercholesterolaemia using a centrally co-ordinated clinical service: an Australian experience.

BACKGROUND: Familial hypercholesterolaemia (FH) is a co-dominantly inherited disorder of low-density lipoprotein (LDL) catabolism, causing elevated LDL-cholesterol and premature coronary artery disease (CAD). Several guidelines recommend genetic cascade screening relatives of probands (index cases) with genetically proven FH, but experience in a clinical service setting is limited. METHODS: Relatives from 100 index cases with genetically confirmed FH underwent genetic and lipid testing via a centralised screening program in Western Australia. The program's effectiveness was evaluated as the number of newly diagnosed relatives with FH per index case and the proportional reduction in LDL-cholesterol after treatment. RESULTS: Of 366 relatives tested for FH, 188 (51.4%) were found to have a pathogenic mutation. On average, 2 cases were detected per index case. Affected relatives were younger and less likely to have physical stigmata of FH and premature CAD than index cases (p < 0.001). Of the new cases, 12.8% had hypertension, 2.7% had diabetes and 16.0% were smokers; 48.4% were already on statin therapy and these were older (p < 0.001) and had more vascular risk factors and CAD (p < 0.01) than those not on therapy. Significant reductions in LDL-cholesterol (-24.3%, p < 0.001) were achieved overall, with previously untreated new cases of FH attaining a maximal average reduction of 42.5% in LDL-cholesterol after drug therapy. Over 90% of subjects were satisfied with screening and care. CONCLUSION: Genetic cascade screening co-ordinated by a centralised service is an effective and acceptable strategy for detecting FH in an Australian setting. A significant proportion of new cases exhibit other CAD risk factors and are already on statins, but have not received a prior diagnosis of FH.

Statin myopathy: the fly in the ointment for the prevention of cardiovascular disease in the 21st century?

INTRODUCTION: Cardiovascular disease (CVD) remains the leading cause of death in industrialized nations. Despite clear evidence of CVD risk reduction with HMG-CoA reductase inhibitors (statins), the side effects of these medications, particularly myopathy, limit their effectiveness. Studies into the mechanisms, aetiology and management of statin myopathy are limited by lack of an internationally agreed clinical definition and tools for assessing outcomes. Currently there is a paucity of evidence to guide the management of patients affected by statin myopathy; with the exception of dose reduction, there is little evidence that other strategies can improve statin tolerance, and even less evidence to suggest these alternate dosing strategies reduce cardiovascular risk. AREAS COVERED: This review will cover current definitions, clinical presentations, risk factors, pathogenesis and management. PubMed was searched (English language, to 2014) for key articles pertaining to statin myopathy. This review then briefly describes our experience of managing this condition in a tertiary lipid disorders clinic, in the setting of limited guiding evidence. EXPERT OPINION: Knowledge gaps in the field of statin myopathy are identified and future research directions are suggested. We urge the need for international attention to address this important, but largely neglected clinical problem, that if unresolved will remain an impediment to the effective prevention and treatment of CVD.

Familial hypercholesterolaemia in primary care: knowledge and practices among general practitioners in Western Australia.

AIM: To determine general practitioners' (GPs') knowledge and practice regarding familial hypercholesterolaemia (FH) in Western Australia. METHOD: A structured questionnaire was anonymously completed by GPs. Information was sought on awareness and knowledge of FH including, diagnosis, inheritance, prevalence, cardiovascular risk, management practices and opinions on FH screening. RESULTS: 191 GPs completed the survey, 62% were familiar with FH, 80% correctly defined FH and 68% identified the typical lipid profile, but only 33% were aware of national guidelines. There were knowledge deficits in prevalence, inheritance, and clinical features of FH, with correct responses in 27%, 45% and 38%, respectively. Most (84%) GPs considered themselves the most effective health professionals to detect FH, with 90% preferring laboratory interpretative commenting to highlight individuals at risk of FH. GPs identified appropriate cholesterol lowering drugs as mono (95%) or combination therapies (74%). CONCLUSION: The majority of GPs considered they were the most effective health practitioners for managing FH and preferred laboratory reports to alert them of possible FH. Although GPs knowledge of cholesterol lowering therapies was good, their awareness of national guidelines, hereditability, prevalence and diagnostic features of FH was suboptimal. Implementing a community model of care for FH requires more extensive GP education.

Intravenous minocycline in acute stroke: a randomized, controlled pilot study and meta-analysis.

BACKGROUND AND PURPOSE: Minocycline, in animal models and 2 small randomized controlled human trials, is a promising neuroprotective agent in acute stroke. We analyzed the efficacy and safety of intravenous minocycline in acute ischemic and hemorrhagic stroke. METHODS: A multicenter prospective randomized open-label blinded end point evaluation pilot study of minocycline 100 mg administered intravenously, commenced within 24 hours of onset of stroke, and continued 12 hourly for a total of 5 doses, versus no minocycline. All participants received routine stroke care. Primary end point was survival free of handicap (modified Rankin Scale, ≤2) at day 90. RESULTS: Ninety-five participants were randomized; 47 to minocycline and 48 to no minocycline. In the intention-to-treat population, 29 of 47 (65.9%) allocated minocycline survived free of handicap compared with 33 of 48 (70.2%) allocated no minocycline (rate ratio, 0.94; 95% confidence interval, 0.71-1.25 and odds ratio, 0.73; 95% CI, 0.31-1.71). A meta-analysis of the 3 human trials suggests minocycline may increase the odds of handicap-free survival by 3-fold (odds ratio, 2.99; 95% CI, 1.74-5.16) but there was substantial heterogeneity among the trials. CONCLUSIONS: In this pilot study of a small sample of acute stroke patients, intravenous minocycline was safe but not efficacious. The study was not powered to identify reliably or exclude a modest but clinically important treatment effect of minocycline. Larger trials would improve the precision of the estimates of any treatment effect of minocycline. CLINICAL TRIAL REGISTRATION URL: http://www.anzctr.org.au. Unique identifier: ACTRN12612000237886.

Reducing haemorrhagic transformation after thrombolysis for stroke: a strategy utilising minocycline.

Haemorrhagic transformation (HT) of recently ischaemic brain is a feared complication of thrombolytic therapy that may be caused or compounded by ischaemia-induced activation of matrix metalloproteinases (MMPs). The tetracycline antibiotic minocycline inhibits matrix MMPs and reduces macroscopic HT in rodents with stroke treated with tissue plasminogen activator (tPA). The West Australian Intravenous Minocycline and TPA Stroke Study (WAIMATSS) aims to determine the safety and efficacy of adding minocycline to tPA in acute ischaemic stroke. The WAIMATSS is a multicentre, prospective, and randomised pilot study of intravenous minocycline, 200 mg 12 hourly for 5 doses, compared with standard care, in patients with ischaemic stroke treated with intravenous tPA. The primary endpoint is HT diagnosed by brain CT and MRI. Secondary endpoints include clinical outcome measures. Some illustrative cases from the early recruitment phase of this study will be presented, and future perspectives will be discussed.

Genetic analysis of familial hypercholesterolaemia in Western Australia.

OBJECTIVE: To determine the spectrum of mutations associated with familial hypercholesterolaemia (FH) and their detection rate in the FH Western Australia (FHWA) Program. METHODS: Mutation testing of the LDLR gene, plus select regions in APOB and PCSK9, was performed in the first 343 patients considered to be phenotypic index cases of FH and classified on the basis of the Dutch Lipid Clinic Network Criteria (DLCNC) score as "possible", "probable", or "definite" FH. RESULTS: Overall, 86 different pathogenic (or likely pathogenic) mutations were identified in 129 patients, including four compound heterozygotes manifesting a more severe clinical phenotype. Fourteen of these mutations were novel and twelve (9.6%) were large deletions/duplications of the LDLR. The most common mutations were the familial defective apoB-100 mutation APOB p.Arg3527Gln (7.2%) and an LDLR intron 3 splice site mutation c.313 + 1G > A (4.8%). While 70% of 'definite' FH patients were found to carry a mutation, only 29% of 'probable' and 11% of 'possible' FH patients were mutation-positive. CONCLUSION: This information provides a useful DNA database on which to base ongoing cascade screening for FH and future research into the genetic aetiology of FH in Western Australia. These findings suggest genetic testing should be prioritised to those with high DLCNC scores and offers a cost-effective family screening method from FH index cases, leading to detection of other previously undiagnosed and younger family members, enabling early instigation of intervention and preventative measures for premature coronary heart disease.

Late-onset carbamoyl phosphate synthetase 1 deficiency in an adult cured by liver transplantation.

Urea cycle disorders (UCDs) are rare causes of hyperammonemic encephalopathy in adults. Most UCDs present in childhood and, if unrecognized, are rapidly fatal. Affected individuals who survive to adulthood may remain undiagnosed because of clinicians' unawareness of the condition or atypical presentations. We describe the case of a 49-year-old man who initially presented with a stroke and developed hyperammonemic encephalopathy over a period of 8 months. A diagnosis of carbamoyl phosphate synthetase type 1 deficiency was made, and the patient was referred for liver transplantation. One year after liver transplantation, the patient had normal plasma ammonia concentrations and had returned to work.

Detection of familial hypercholesterolaemia: a major treatment gap in preventative cardiology.

Familial hypercholesterolaemia (FH) is a common genetic disorder that untreated has an almost one hundredfold risk of coronary artery disease (CAD). In an audit of 334 patients with premature CAD admitted to a Department of Cardiology, only 60% of medical records had sufficient clinical information for identifying FH. Of those with sufficient information recorded, 54% of patients had possible to definite FH on recognised clinical criteria. Amongst those with FH, only 38% were on statin therapy and only 22% were treated to National Heart Foundation targets. Detection and treatment of FH represents a major gap in coronary prevention.