Cardiovascular diseases

An otherwise healthy 28-year-old man had a cardiac arrest after a day of motocross racing. He had consumed excessive amounts of a caffeinated “energy drink” throughout the day. We postulate that a combination of excessive ingestion of caffeine- and taurine-containing energy drinks and strenuous physical activity can produce myocardial ischaemia by inducing coronary vasospasm. Clinical recordA 28-year-old male amateur motocross rider was admitted to Port Macquarie Base Hospital in August 2007 after having an out-of-hospital cardiac arrest. He had collapsed shortly after participating in a motocross race. An off-duty paramedic and nurse had been on hand, and effective cardiopulmonary resuscitation was commenced promptly. Paramedics arrived after about 20 minutes of resuscitation. The patient’s initial cardiac rhythm was recorded as ventricular fibrillation (Box 1). He was restored to sinus rhythm after receiving two 150 J biphasic direct-current shocks. Adrenaline 1 mg and atropine 1 mg were both given as adjuvants. He was intubated by paramedics and transported to hospital. Later, the patient recalled feeling well earlier in the day, until after his second race, when he developed dull constant retrosternal chest pain. He described this as being mild in intensity, with no radiation or associated symptoms. It settled within 30 minutes of sitting down to rest. He went on to participate in (and win) one more race that afternoon. He collapsed at about 3 pm, approximately 20 minutes after the last race. There had been no symptoms immediately preceding the collapse that he could recall. The patient had been well in the week preceding these events. He denied having any previous episodes of chest pain or syncope. He had a large breakfast on the morning of the motocross race and had remained adequately hydrated throughout the day. Further, he had consumed 7–8 cans of a caffeinated “energy drink” between 8 am and his collapse 7 hours later. He was otherwise fit and well and taking no regular medication. There was no family history of premature coronary disease, sudden cardiac death or unexplained syncope. He was a smoker with a six pack-year history of smoking. He denied alcohol misuse or illicit drug use. On arrival at hospital, the patient was intubated and sedated. He was haemodynamically stable, and physical examination was unremarkable. An initial electrocardiograph (ECG) showed sinus rhythm and elevated anteroseptal ST segments with reciprocal inferior ST depression. Chest x-ray showed a normal cardiac silhouette and no signs of pulmonary venous congestion. Computed tomography scans of the chest and brain were unremarkable, specifically excluding aortic dissection. Abnormal findings from laboratory tests included an elevated level of troponin I (0.24 mmol/L; reference range [RR], < 0.05 mmol/L) and a lowered potassium level (3.0 mmol/L; RR, 3.6–5.4 mmol/L). Results of a urinary screen for drugs of misuse, including amphetamines and cocaine, were negative. Screening for anabolic steroids was not performed. The provisional diagnosis was of anteroseptal ST elevation myocardial infarction. The patient was given thrombolysis with 50 mg of tenecteplase and commenced on an infusion of intravenous heparin. He was given loading doses of 300 mg of both aspirin and clopidogrel, and 25 mg of metoprolol, all by nasogastric tube. Hypokalaemia was corrected via intravenous infusion. The patient was transferred to a tertiary referral centre for cardiac catheterisation. On arrival there, an ECG showed evolving ischaemic changes across the anterolateral leads (Box 2). A troponin I peak level of 12.2 mmol/L was measured; his potassium level had normalised at 4.0 mmol/L. Echocardiography showed mild left ventricular enlargement and low-normal systolic function with a hypokinetic anteroseptal segment. Coronary angiography, performed on the same day, gave normal results. No attempts were made during angiography to induce vasospasm. The patient was cooled for 24 hours and extubated without difficulty. He was discharged after 6 days. At discharge, he was taking atenolol 50 mg, aspirin 100 mg, spironolactone 25 mg and perindopril 2.5 mg. On follow-up 2 months later, the patient reported that he had remained well and symptom-free. Echocardiography showed preserved global left ventricular function with a limited residual area of akinesis of the anteroseptal wall. He continued taking aspirin, perindopril and atenolol (reduced to 25 mg). He was advised not to compete in motocross races for 6 months, after which a stress echocardiogram was performed; this was negative for exercise-induced ischaemia. DiscussionWe postulate a possible role of excessive consumption of caffeinated energy drinks in triggering the life-threatening cardiac events described in this case. Although sudden cardiac death is an uncommon occurrence in people under the age of 40 years, when it does happen it is most often associated with the presence of structural heart disease, most frequently premature coronary atherosclerosis. Other common associations are hypertrophic obstructive cardiomyopathy and myocarditis.1,2 However, autopsy review studies have found that some 10%–12% of subjects in this age group have no obvious cardiac abnormalities on postmortem examination.1,2 Of identified causes in this group, many are familial sudden cardiac deaths or disorders of conduction, such as Wolff–Parkinson–White syndrome.3 Our patient had electrocardiographic and echocardiographic features indicative of transmural ischaemia localised to the anterior territory. This is suggestive of a regional rather than a global process, and suggests an ischaemic event rather than a primary arrhythmia. However, the angiogram did not show any significant coronary lesions. Although non-stenotic atherosclerotic plaques may rupture or denude and cause infarction through the formation of superimposed thrombi, which may have then been dissolved by the administration of thrombolytics, we believe that — considering this man’s relative youth — there is a distinct possibility that the underlying abnormality was coronary vasospasm. An arrhythmia, possibly triggered by the ingestion of stimulants in the presence of hypokalaemia and physical exertion, was a differential diagnosis. However, this would not account for the regional abnormality seen. The cause of this patient’s hypokalaemia is unclear, but may have been related to electrolyte losses from excessive sweating during exertion. This effect may have been exacerbated by the diuretic effect of caffeine. The role of illicit stimulants, especially cocaine, in causing coronary vasospasm in young people is well established.4 However, this patient denied cocaine use and returned a negative result on his drug test, making this an unlikely cause. The energy drink consumed by our patient contains 80 mg of caffeine (equivalent to one cup of espresso) per can. He drank seven or eight cans within 7 hours — up to 640 mg of caffeine in total. The drink also contains high doses of taurine (an amino acid) and glucuronolactone (a glucose metabolite), neither of which are considered to have significant toxicity, although there is a paucity of data.5,6 Caffeine is a naturally occurring xanthine derivative related to theophylline; it has a number of potential pharmacological actions on the cardiovascular system. Its primary mechanism of action is thought to be through competitive inhibition of adenosine receptors.7 It also induces catecholamine release, and causes a rise in intracellular calcium in myocytes through release of calcium from the sarcoplasmic reticulum, leading variably to smooth muscle contraction and relaxation.8-10 The role of caffeine in triggering arrhythmia is well established.8 There have been a number of case reports on hospitalisations or deaths due to caffeine toxicity, although the mechanism usually seems to be tachyarrhythmia and involves far higher doses than in this case.11,12 The median lethal dose in rats is 200–400 mg/kg.13 A 1997 case report described a young woman who suffered a myocardial infarction due to caffeine toxicity; however, this involved an oral dose of 20 g.14 In-vitro studies have shown that taurine has an inotropic effect on cardiac muscle similar to that of caffeine, and potentiates caffeine-induced muscle contracture. Few taurine toxicity studies have been performed, and there are insufficient data to suggest what an unsafe level of taurine consumption might be, if any.9,14 Both taurine and caffeine have been shown in vitro to have physiological effects on intracellular calcium concentration within vascular smooth muscle, and they could conceivably induce coronary vasospasm. In-vivo studies have demonstrated a capacity for caffeine to decrease myocardial blood flow during exercise.15 We postulate that, in physiologically predisposed individuals, a combination of excessive ingestion of caffeine- and taurine-containing energy drinks and strenuous physical activity can induce myocardial ischaemia by coronary vasospasm, with potentially fatal results. Caffeine has been removed from the list of prohibited substances in sport but remains on a monitoring program run by the World Anti-Doping Agency.16 Anecdotal reports suggest that the many caffeinated energy drinks now on the market are widely used by amateur and professional athletes to enhance their performance. We are concerned that a combination of exercise and the caffeine contained in these drinks may have the potential to trigger serious cardiovascular events. We accept that this is a single case, which does not and cannot establish causality. However, in the context of concerns reported in the media in recent years relating to similar events overseas, and in the presence of a plausible pharmacological mechanism, we believe that the potential dangers of these caffeinated energy drinks should be highlighted, and monitoring for future adverse events should be conducted. 1 Patient’s initial cardiac rhythm, showing ventricular fibrillation 2 Patient’s electrocardiograph on arrival at tertiary referral centre, showing evolving ischaemic changes across the anterolateral leads

Adam J Berger MB BS, BSc(Med) · Kevin Alford MB BS, FRACP, DDU

Best-practice guidelines mandate a full postmortem examination in these deaths to identify genetic causes and allow potentially life-saving interventions in the victim’s relatives The sudden and unexpected death of an apparently fit, healthy young person has a devastating effect on the family and community. If there is no adequate explanation for the death, the desperate sadness is usually compounded by frustration and fear that another family member may be struck. Yet, there is no uniform process in place in Australia and New Zealand to obtain a proper medical history of the victim, or to examine and investigate the victim’s family. Such a process could provide clues to the diagnosis and also identify previously undiagnosed genetic diseases. The lack of a consistent definition for sudden unexpected death in young people means there are few prevalence data. The best studies of incidence and causes of sudden natural death in 1–40-year-olds have been conducted by two forensic pathology centres in New South Wales.1,2 These suggest an annual incidence of around 20 per million — about 400 deaths per year in Australia. A striking feature was that the postmortem examination identified no specific cause of death in a third. This suggests an arrhythmic death caused by an underlying cardiac channelopathy, such as long-QT syndrome, Brugada syndrome or catecholaminergic polymorphic ventricular tachycardia.3 Clinical and genetic studies have confirmed the presence of these conditions in the Australian and New Zealand populations.4 They are the consequence of inherited dysfunction of cardiac cell channels (for potassium, sodium and calcium), which are involved in generating the cardiac action potential. The mode of death is ventricular tachycardia or fibrillation. The results of the two NSW pathology studies1,2 were surprising, as previous studies on sudden death in young athletes found that the most prominent causes were the structural heart diseases, hypertrophic cardiomyopathy (HCM) and arrhythmogenic right ventricular cardiomyopathy (ARVC). Cardiac channelopathies, HCM and ARVC are all familial, with over 90% of cases inherited in an autosomal dominant fashion, meaning that 50% of first-degree relatives are potentially at risk. There is now good evidence that people with these conditions can benefit from interventions such as β-blockade and cardioverter defibrillators,5 so that identification of affected family members is potentially life-saving. Cardiological and genetic investigation of the relatives of young victims of sudden death can reveal an inherited heart disease in 40% of cases.6,7 To achieve this outcome, there is a need for a coordinated multidisciplinary team approach to the postmortem investigation of sudden deaths, including expert pathology, cardiology, clinical and molecular genetic assessment.8 The TRAGADY (Trans-Tasman Response Against Sudden Death in the Young) initiative was established in 2005, and comprises a group of over 50 highly motivated Australian and New Zealand health professionals, scientists and patient advocates who share the aim of reducing sudden death in the young caused by inherited heart diseases. The group has formulated a mission statement9 and, recognising the inconsistencies in postmortem practice across Australia and New Zealand, its first aim was to create a best-practice guideline for the postmortem investigation of sudden unexpected death in the young. This guideline has now been completed and formally approved by the Royal College of Pathologists of Australasia, and is available on the College website.10 A key message for the general practitioner is that a skilled postmortem examination is imperative after such deaths. There may be pressure from the family to avoid an autopsy, but ascribing such deaths to “heart attack”, for example, when there was some previous chest pain, misses the opportunity to make a proper diagnosis and potentially save the lives of other family members. Similarly, arrhythmic syndromes such as long-QT syndrome have been falsely diagnosed as epilepsy, and the death of any young person with epilepsy should be investigated in detail. Many families have suffered several sudden deaths because of a failure to investigate completely, as described on support group websites, such as that of the Australian Sudden Arrhythmia Death Syndromes Foundation (http://www.sads.org.au). Key points of the TRAGADY best-practice guidelines are summarised in the Box. Key points of best-practice guidelines on postmortem investigation of sudden death of a young person* A full postmortem examination should be completed in all cases of sudden unexpected death in young people (0–40 years). The investigation, ideally led by a pathologist, involves a team approach, including as a minimum: A person designated to liaise with the family; Specialist cardiology involvement with the family when non-cardiac causes are excluded; and Laboratories with molecular genetics, toxicology and metabolic expertise. A detailed antecedent clinical history must be obtained. A detailed and relevant family history must be obtained. Liaison with the family should be established early and be ongoing until a cause of death is ascertained. Skilled macroscopic and microscopic examination of the organs is required, particularly of the heart (especially right ventricular muscle), and the brain. This may require some specimens to be examined by other specialists. Adequate histological material must be obtained for review or, if necessary, referral. Tissue or blood suitable for DNA extraction must be obtained (paraffin-embedded tissue blocks are not suitable). * Devised by TRAGADY (Trans-Tasman Response Against Sudden Death in the Young) and endorsed by the Royal College of Pathologists of Australasia.

Jon R Skinner MD · Johan A Duflou MMed, FRCPA · Christopher Semsarian PhD, FRACP, FCSANZ

Combined with appropriate lifestyle modification and statin therapy, raising HDL levels may be an important strategy to reduce cardiovascular risk In the past two decades, we have made significant advances in the management of cardiovascular disease (CVD), with a dramatic reduction in cardiovascular events occurring in parallel with the widespread use of statins to lower low-density lipoprotein (LDL) cholesterol levels. Nevertheless, despite intensive use of statin therapy, a significant patient cohort remains at high risk of cardiovascular events, paving the way for new strategies to reduce their residual cardiovascular risk. One attractive target for such strategies is high-density lipoprotein (HDL) cholesterol. There is strong epidemiological evidence demonstrating the inverse relationship between the incidence of cardiovascular events in normal populations and serum HDL levels. Based on data from the Framingham Heart Study, the risk of myocardial infarction increases about 25% per 0.13 mmol/L decrement in serum HDL below median values.1 HDL levels are also predictive of coronary events in patients with known CVD across a range of LDL levels, as demonstrated in the Treating to New Targets trial, in which nearly 10 000 patients with established CVD were treated with statins.2 HDL levels were inversely predictive of time to first major cardiovascular event across the spectrum of LDL levels, including patients with treated LDL levels below 1.8 mmol/L, highlighting the predictive value of HDL levels independent of LDL levels. The atheroprotective effects of HDL have been attributed to its ability to mediate “reverse cholesterol transport”, where cholesterol in peripheral tissues is transferred via plasma to the liver for either recycling or excretion. More recently, the antioxidant and anti-inflammatory properties of HDL have been explored. In particular, intravenous preparations of HDL have been shown to dramatically reduce acute vascular inflammation in animal models, improve endothelial function (an important surrogate of cardiovascular risk), and promote atheroma regression and stabilisation in human studies.3 Moreover, because of the heterogeneity of human HDL, an appreciation of function as well as absolute concentration is becoming increasingly important. For example, HDL from subjects with diabetes has been shown to be less effective in its cholesterol-effluxing and anti-inflammatory capacity.4 Lifestyle modifications in the form of regular exercise, smoking cessation, weight loss and moderate alcohol consumption have each been shown to individually raise HDL levels by 5%–10%.5 Although statins are currently the cornerstone of lipid-modifying therapy, they raise HDL levels by only 5%–10%.6 On the other hand, fibrates have been shown to raise HDL levels by 10%–15%.7 Fibrates regulate HDL metabolism as ligands and activators of the nuclear transcription factor peroxisome proliferator-activated receptor-α.8 The benefits of using fibrates to raise HDL levels have been suggested by a number of randomised trials. For example, the Veterans Affairs High-Density Lipoprotein Intervention Trial (VA-HIT) included 2531 patients with CVD, with an LDL level ≤ 3.6 mmol/L, HDL level ≤ 1.0 mmol/L, and triglycerides ≤ 3.4 mmol/L; patients were randomly assigned to receive treatment with gemfibrozil or placebo. At 5 years, the combined primary endpoint of cardiac death and non-fatal myocardial infarction occurred less often in the gemfibrozil-treated group, and the reduction in this endpoint correlated strongly with both serum HDL levels and degree of weight loss, but was independent of changes in LDL cholesterol or triglycerides concentration.7,9 Nicotinic acid is another effective HDL-raising drug, with an ability to raise levels by up to 30%. The HDL-Atherosclerosis Treatment Study (HATS) reported the effects of combined therapy with a statin and niacin on 160 patients with CVD, with an HDL level < 0.9 mmol/L and LDL level < 3.75 mmol/L.10 Compared with placebo, patients receiving simvastatin plus niacin were significantly less likely to experience a cardiovascular event. Furthermore, the magnitude of the reduction of clinical events with drug therapy was greater than that observed in studies of statins alone, suggesting that raising HDL levels provides additional protection beyond that attributable to simply lowering LDL levels.10 The side-effect profile remains problematic with this drug class, though development of extended-release preparations may overcome these issues. Most recently, a novel class of HDL-raising medications, the cholesteryl ester transfer protein (CETP) inhibitors, which prevent the transfer of cholesteryl ester from HDL to triglyceride-rich lipoproteins in exchange for triglyceride, have been tested in large clinical trials. In particular, the CETP inhibitor torcetrapib was evaluated in the multicentre randomised Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events (ILLUMINATE) trial, which compared torcetrapib with placebo in more than 15 000 patients receiving atorvastatin.11 A significant increase in HDL levels (72%) and an additional decline in LDL levels (25%) below baseline after 12 months of torcetrapib therapy were seen. However, the trial was prematurely terminated due to a significant increase in cardiovascular events in the treatment arm; an “off target” effect on the aldosterone receptor leading to blood pressure elevations was postulated as a potential mechanism for this.11 Despite the setback experienced with torcetrapib, further studies are underway to develop more target-specific CETP inhibitors. Intravenous reconstituted HDL preparations and apolipoprotein A-I mimetic compounds are also in development. In the future, these compounds may be used to regress atheroma or suppress the arterial inflammation that is the hallmark of the acute coronary syndromes. Thus, raising HDL levels, in combination with optimising LDL cholesterol levels, blood pressure and glycaemic control, as well as appropriate lifestyle modification, represent important strategies for reducing residual cardiovascular risk. Such measures should see further improvements in clinical outcomes for patients with CVD.

Sanjay Patel MB BS, FRACP

Objective: To examine short- and medium-term outcomes of percutaneous coronary interventions (PCIs), with a focus on comparing drug-eluting stents (DESs) with bare-metal stents (BMSs).Design, setting and participants: Retrospective analysis of data from the Melbourne Interventional Group (MIG) registry, a large multicentre Australian registry. The study cohort consisted of 6364 consecutive patients undergoing 7167 PCIs between April 2004 and August 2007.Main outcome measures: Clinical events including death, myocardial infarction (MI), target lesion revascularisation (TLR), target vessel revascularisation (TVR) and major adverse cardiac events (MACE) (a composite of death, MI and TVR), at 30 days and at 12 months.Results: The cohort was predominantly male (74%), with a mean age of 64.7 years (SD, 12.0 years). DESs were used in 3482 (51.4%) of PCIs. In the overall cohort, rates of clinical events were low at 30 days: mortality (1.9%), MI (2.4%), TLR (2.0%), TVR (2.4%) and MACE (5.7%). At 12 months, event rates were: mortality (5.2%), MI (6.0%), TLR (5.8%), TVR (8.2%) and MACE (16.2%). Patients receiving DESs had similar mortality rates to those receiving BMSs (4.0% v 6.0%; P = 0.62 [propensity score-adjusted]); late thrombosis rates were also similar in the two groups (0.8% v 1.1%; P = 0.38). The proportion of patients receiving DESs fell significantly over time, from 54.9% in the first 24 months to 44.7% in the last 15 months of the study period (P < 0.01). Independent predictors of 12-month mortality included diabetes, renal failure, ST-segment-elevation MI and cardiogenic shock.Conclusion: Our clinical event rates were comparable with international registry outcomes. Rates of mortality and stent thrombosis were no higher in patients with DESs than those with BMSs. Although DESs were used in about half the procedures (preferentially for higher-risk lesions), recent trends suggest their use is in decline.

Andrew E Ajani MD, FRACP, FJFICM · Christopher M Reid BA, MSc, PhD · Stephen J Duffy FRACP, MRCP, PhD · Nick Andrianopoulos MB BS, MBiostat · Jeffrey Lefkovits MB BS, FRACP · Alexander Black MB BS, FRACP · Gishel New FRACP, FACC, PhD · Robert Lew MB BS, FRACP, PhD · James A Shaw MB BS, FRACP, PhD · Bryan P Yan MB BS, FRACP · Ronen Gurvitch MB BS · Ali Al-Fiadh MB BS · Angela L Brennan RN, CCRN · David J Clark MB BS, FRACP

To the Editor: The oculocardiac reflex is a potentially life-threatening phenomenon requiring prompt recognition and management. It is defined as a 20% or greater reduction in heart rate and/or the presence of arrhythmias during stimulation of the orbital contents.1 It is most commonly encountered in the context of paediatric squint surgery. We report its occurrence in a young healthy adult man after a traumatic facial injury. While being transported to hospital by ambulance, he had intermittent bradycardia, with a heart rate as low as 38 beats/min, and was administered a 1 g dose of intravenous atropine. His medical and ocular histories were unremarkable, and he had no history of unexplained syncope. In the emergency department, his heart rate remained low (40 beats/min) and his blood pressure was 122/52 mmHg. There was diffuse periorbital lid swelling and bony tenderness along the inferolateral orbital margin. He had restricted upgaze of his left eye; during this manoeuvre, his heart rate dropped to 20 beats/min and he developed hypotension, with a blood pressure of 92/48 mmHg. He was given three intravenous 500 μg boluses of atropine to improve his haemodynamic condition. An electrocardiogram showed sinus bradycardia, and subsequent recordings showed intermittent Mobitz II second-degree atrioventricular block. A computed tomography scan of the left orbit showed a moderately displaced fracture of the orbital floor involving the maxillary bone, with entrapment of orbital fat and the inferior rectus muscle (Box). Given the presence of the oculocardiac reflex with haemodynamic compromise, the fracture was immediately repaired surgically. Postoperatively, the patient’s blood pressure was 134/90 mmHg and his heart rate was 86 beats/min, with normal sinus rhythm. He recovered full eye movement, and no further oculocardiac reflex was recorded. He remained well 1 year after discharge. The oculocardiac reflex was first described by Aschner as a slowing of the radial pulse when pressure was applied to the eye.2 It is a rare but recognised occurrence among young healthy adults with orbital fractures. Clinical manifestations of the reflex may include bradycardia, hypotension, nausea, vomiting and syncope.3 The reflex is acknowledged as an important indication for immediate surgical repair of the orbit.4 In addition to reducing morbidity from the reflex, urgent repair is beneficial as it releases incarcerated soft tissue, leading to a more favourable outcome with less likelihood of squint.5 Cardiac decompensation due to traumatic facial injuries should alert clinicians to the possibility of the oculocardiac reflex and the need for urgent surgical intervention. Computed tomography scans of the patient’s left orbit Sagittal (A) and coronal (B) computed tomography scans showing left orbital floor fracture with entrapment of the inferior rectus muscle (arrows).

Vivek B Pandya · R Max Conway · Richard Conway

To the Editor: Streptococcus suis is an emerging zoonosis in humans and a common pathogen in Australian pigs.1 However, only two cases of human infection have previously been reported in Australia.2,3 We recently treated two Australian piggery workers, from the same town in New South Wales, for S. suis endocarditis. The first patient, a previously healthy 46-year-old woman, presented in October 2006 with a 3-month history of fatigue, anorexia, night sweats and weight loss of 20 kg. Her job involved hands-on work at a piggery. She was afebrile, with blood pressure of 145/50 mmHg, bilateral clubbing, splenomegaly, and a long diastolic murmur without evidence of heart failure. Transthoracic echocardiography confirmed severe aortic regurgitation associated with a vegetation. Blood cultures grew S. suis. The patient was treated with benzylpenicillin (1.8 g, 4-hourly for 6 weeks) and gentamicin (60 mg, 8-hourly for 2 weeks). Severity of aortic regurgitation necessitated aortic valve replacement. The second patient, a 58-year-old man, presented in January 2008 with headache, fever (38.7°C), neck stiffness and confusion. He had been unwell for 1 month with fevers, sweating, fatigue and weight loss of 6 kg. His job involved transporting pigs from local piggeries, including the one at which the first patient worked, to an abattoir, and involved direct contact with pigs. On admission, he was treated with ceftriaxone (2 g) and benzylpenicillin (2.4 g). Cerebrospinal fluid (CSF) examination showed leukocytosis (10 300 × 106/L; reference range, < 5 × 106/L) with 95% polymorphs. Scanty gram-positive cocci were visible, but there was no growth on culture of the CSF. Blood cultures grew S. suis. Transthoracic echocardiography revealed an aortic valve vegetation with trivial regurgitation. The patient was then treated with benzylpenicillin (1.8 g, 4-hourly for 4 weeks) and gentamicin (80 mg, 8-hourly for 2 weeks), and made a full recovery. Both cases were investigated by the NSW Department of Health, including assessment of workplace practices, staff education and rates of porcine infection at the piggeries and abattoir at which the patients had worked, but no significant factors for infection were identified. Since the first reported human infection with S. suis in Denmark in 1968,4 more than 400 cases have been reported, including an outbreak in China in 2005 that affected 215 people.5 The most common manifestations are meningitis (affecting 72.5% of patients) and bacteraemia (24.2%); endocarditis is relatively uncommon (1.1%).5 In a series of 16 cases of S. suis endocarditis, the mean period between onset of symptoms and diagnosis was 23 days, and seven patients required valve replacement.6 Similarly, our patients had subacute presentations: severe aortic regurgitation and secondary meningitis. In Australia, it is likely that there have been other S. suis infections in humans that have gone unrecognised because of mild presentations, difficulties with laboratory diagnosis, and empirical treatment of unrecognised infection. While it is unlikely that S. suis is a common zoonosis in Australia, these cases show that it is an occupational hazard in Australian piggeries, with potential public health, animal health and medicolegal implications.

Karina J Kennedy · Assad A Jadeer · Chong W Ong · Sanjaya N Senanayake · Peter J Collignon

A decade of research has led to more precise guidelines for a complex health problem It has long been considered that all patients with heart conditions that predispose to infective endocarditis should receive antibiotic prophylaxis when undergoing procedures that can lead to bacteraemia with organisms known to cause endocarditis. However, the evidence for such action is surprisingly poor.1 It is based on isolated case reports of endocarditis following dental or other procedures, and on theoretical considerations, rather than the results of randomised controlled trials. The American Heart Association (AHA) has published guidelines for endocarditis prophylaxis since 1955. In Australia, all editions of the Antibiotic guidelines (now Therapeutic guidelines: antibiotic, version 132) have also included recommendations for antibiotic prophylaxis against endocarditis. Of necessity, these guidelines have been complex, as three major variables were considered — the lifetime risk of endocarditis due to the underlying heart condition, the likelihood and nature of bacteraemia following the procedure, and the risk of adverse effects from antibiotic therapy.2 The lifetime risk associated with the cardiac condition was divided into three risk categories (high, medium and low), and the likelihood of bacteraemia from a procedure was similarly divided into risk categories. Thus, prophylaxis has been firmly recommended for patients with an underlying heart condition who are at high risk of endocarditis and are undergoing a procedure that has a high risk of leading to significant bacteraemia. Conversely, it has not been recommended for patients with conditions who are at low risk of endocarditis and are undergoing procedures with a low risk of leading to significant bacteraemia. Prophylaxis has been “possibly” and “probably” recommended for various intermediate-risk combinations. Over the past 10 years, thinking has changed for three main reasons. First, there is now strong evidence that bacteraemia with endocarditis-causing organisms frequently occurs following everyday activities, such as tooth brushing.3-6 Second, it has been recognised that very few cases of endocarditis can reasonably be attributed to a preceding procedure and are more likely to have resulted from everyday activities. Third, it has been realised that we should be more concerned about patients who are likely to have a poor outcome if they develop endocarditis than those who are at high risk of developing endocarditis at all.1 In the context of this change in thinking, organisations around the world (including the AHA) have published new guidelines for endocarditis prophylaxis that differ considerably from the previous versions.1,7,8 In Australasia, at the request of the Heart Foundation (formerly, the National Heart Foundation of Australia) and The Cardiac Society of Australia and New Zealand, Therapeutic Guidelines Limited convened an expert group to reconsider its guidelines. This expert group updated the Australian guidelines largely along the lines of the new AHA guidelines, continuing a trend to reduce the categories of patients for whom prophylaxis is recommended, while still specifying procedures for which it is required. In summary, the changes are: The list of heart conditions for which endocarditis prophylaxis is recommended is much shorter and is largely limited to conditions in which foreign material is implanted in the heart. In this setting, endocarditis is very difficult to eradicate, so an adverse outcome is more likely. Of note, the list does not include rheumatic valvular heart disease in non-Indigenous patients or mitral valve prolapse. The list of dental and respiratory procedures for which endocarditis prophylaxis should be given is more precise. For some dental procedures, the guidelines emphasise that the need for prophylaxis relates more to the circumstances of the procedure and the patient’s periodontal condition than to the procedure itself. The list of gastrointestinal and genitourinary procedures is similarly precise, and includes procedures that also have a requirement for surgical antibiotic prophylaxis, or which are being carried out in the presence of a related infection. The only significant difference between the new Australian guidelines and the AHA guidelines is that rheumatic valvular heart disease in Indigenous Australians has been retained in the list of cardiac conditions for which prophylaxis should be given. Experienced clinicians have the strong impression that the outcome of endocarditis in Indigenous Australians is poorer than in non-Indigenous Australians, possibly in part because of delays in diagnosis and therapy. Studies are currently being undertaken to determine whether this clinical impression is correct, but until the results are available, it was thought wise to retain this indication. These new guidelines might cause confusion at first, particularly when patients who previously received prophylaxis are advised that it is no longer necessary. To help ease this confusion, the new guidelines state that it is reasonable to give prophylaxis to patients who have previously received it and would prefer to be given it again. The new Australian guidelines are available free of charge on the Therapeutic Guidelines website (http://www.tg.com.au) and in its electronic publications (eTG complete and miniTG). The print versions of Therapeutic guidelines: antibiotic and Therapeutic guidelines: oral and dental will be updated as the new editions are published. We recommend these guidelines to Australian practitioners and trust they will find them useful and decide to follow them.

Robert F W Moulds BMedSc, PhD, FRACP · Melanie S Jeyasingham BPharm, MPS

Trials measuring major cardiovascular events as an endpoint are the best evidence to determine if an intervention such as ezetimibe conveys benefit At an American College of Cardiology meeting in Chicago earlier this year, the long-awaited results of the Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression (ENHANCE) trial were finally presented, with simultaneous publication in the New England Journal of Medicine.1 ENHANCE was a double-blind, randomised controlled trial comparing 80 mg of simvastatin plus placebo daily with 80 mg of simvastatin plus 10 mg of ezetimibe daily in patients with familial hypercholesterolaemia. The primary trial endpoint was change in mean carotid and femoral intima-media thickness (IMT) over a 24-month period (Box). Although the trial finished in mid 2006, the results were not forthcoming from the United States sponsors (Merck and Schering-Plough) until a US Congressional Committee required the companies to reveal them, which they did in the form of a press release earlier this year.2,3 In the combined-therapy group, the benefit expected from a 17% lower level of low-density lipoprotein cholesterol (LDL-C) due to ezetimibe was not realised — mean IMT did not differ between the two groups. There was progression in mean carotid IMT (CIMT) in both groups (P = 0.02 for simvastatin-only group and P < 0.01 for combined-therapy group). Regression occurred in 44.4% of the simvastatin-only group and 45.3% of the combined-therapy group. New lesions (> 1.3 mm CIMT) occurred in 2.8% of the simvastatin-only group and 4.7% of the combined-therapy group (P = 0.20). Various possible explanations for these unexpected results were given by the study authors.1 The first was that ezetimibe is not protective for the vasculature, in spite of its significant lowering of LDL-C levels; the second was that the methodology used to measure IMT was insufficient to detect small changes in response to the therapy; and the third was that the population with familial hypercholesterolaemia had virtually normal baseline IMT due to their previous extensive treatment with statins, which may have rendered their arteries relatively unresponsive to further LDL-C reduction. The first explanation is unlikely because ezetimibe has shown no previous evidence of vascular toxicity, and a recent study in which statin–ezetimibe therapy was used as part of an aggressive management algorithm showed regression of CIMT (although this was not a randomised trial of ezetimibe use).4 The second explanation is also unlikely, although ENHANCE did not employ electrocardiogram gating of images to control for image variability during the cardiac cycle, and used single-frame technology rather than cine-loop technology to improve image quality.2 The third explanation seems the most likely, for several reasons. Previous studies of CIMT have shown either lack of progression (ie, stabilisation) or regression with lipid-modifying therapy, primarily related to changes in LDL-C levels.5 Unlike ENHANCE, these studies involved patients with increased baseline CIMT and had inclusion criteria for CIMT. Data also presented at the American College of Cardiology meeting, but yet to be published, showed that statin-naïve patients had no significant change in CIMT with either therapy.2 Baseline CIMT in this group was also near-normal — an unusual finding for true familial hypercholesterolaemia patients. However, no data were presented to confirm the presence of LDL receptor mutations. If this explanation is correct, perhaps ENHANCE could never have shown a positive result, because most patients had been treated with statins for decades before enrolment in the trial. Evidence for this theory comes from the Atorvastatin versus Simvastatin on Atherosclerosis Progression (ASAP) extension study, in which patients in the earlier ASAP trial were continued on 80 mg of atorvastatin daily for a further 2 years.6 Patients in the original atorvastatin group (in whom there had been regression of 0.031 mm) showed no further change in CIMT, while those originally in the simvastatin 40 mg group (in whom there had been progression of 0.036 mm) showed significant regression.6 The results of the ENHANCE trial are important because ezetimibe accounts for a significant proportion of lipid-lowering medication prescriptions around the world (3% in Canada, similar to use in Australia; and 15% in the US).7 Ezetimibe was approved for marketing in the US about 5 years ago, based on its efficacy in lowering LDL-C levels rather than efficacy in reducing major adverse cardiovascular events or improving surrogate endpoints such as CIMT. This situation is the opposite for newer drugs such as torcetrapib, which, in spite of increasing high-density lipoprotein cholesterol levels by more than 50%, was withdrawn from the market because of negative results in trials investigating its effects on CIMT and major adverse cardiovascular events.8,9 So, where do we go from here? The first caveat is not to abandon the modern cholesterol hypothesis (“the lower the LDL-C, the better”) after one negative trial. Only trials measuring major adverse cardiovascular events as an endpoint can definitively answer the question of whether a given intervention conveys benefit, regardless of changes in surrogate markers like CIMT or plaque size. We must therefore await the results of a clinical endpoint trial with ezetimibe, which adds a further 15%–20% reduction in LDL-C levels to that achieved by statin therapy, and which should reduce major adverse cardiovascular events by a similar percentage. IMPROVE-IT is a trial comparing cardiovascular death, major coronary events and stroke in 18 000 patients with recent acute coronary syndromes treated with 40 mg of simvastatin either alone or in combination with 10 mg of ezetimibe.2 It is due to be reported in 2012. Until then, it seems prudent to continue clinical practice on the basis that the cholesterol hypothesis is alive and well, and to continue using ezetimibe in statin-intolerant patients and those taking maximum-tolerated doses of statins who have not yet achieved LDL-C target levels.10 Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression (ENHANCE) study1 720 patients with familial hypercholesterolaemia Baseline: low-density lipoprotein (LDL) cholesterol, 8.2 mmol/L; high-density lipoprotein (HDL) cholesterol, 1.2 mmol/L Compared simvastatin 80 mg + placebo daily with simvastatin 80 mg + ezetimibe 10 mg daily Primary endpoint was mean intima-media thickness (IMT) of carotid and femoral arteries with B-mode ultrasonography End of study: mean LDL cholesterol 16.5% lower in ezetimibe group (P < 0.01); no difference in HDL cholesterol No difference between treatment groups in carotid IMT after 2 years (P = 0.29): + 0.0058 mm in simvastatin–placebo group + 0.011 mm in simvastatin–ezetimibe group Side-effect and safety profiles similar in both groups

Ian R Hamilton-Craig MB BS, PhD, FRACP

Objective: To determine how well the current Pharmaceutical Benefits Scheme (PBS) eligibility criteria for subsidy of lipid-lowering drugs compare with current national guidelines for determining the population at high risk of developing cardiovascular disease (CVD).Design and participants: Analyses of the population-based, cross-sectional Australian Diabetes, Obesity and Lifestyle (AusDiab) study, conducted in 1999–2000. The 1991 Framingham risk prediction equation was used to compute 5-year risk of developing first-time CVD in 8286 participants aged 30–74 years with neither CVD nor diabetes. Based on the National Heart Foundation of Australia and Cardiac Society of Australia and New Zealand guidelines, people with either 5-year CVD risk ≥ 15% or with 5-year CVD risk of 10%–< 15% and the metabolic syndrome were defined as having estimated high absolute CVD risk.Main outcome measures: 5-year CVD risk; estimated population with high CVD risk.Results: Among participants without prevalent CVD or diabetes, 7.9% of men and 1.5% of women had a 5-year CVD risk ≥ 15%. Of the estimated residential Australian population in 2000 aged 30–74 years without CVD or diabetes, 717 000 people were considered to be at high absolute CVD risk. Among the high-risk AusDiab participants without CVD or diabetes, only 16.9% of men and 15.4% of women were being treated with lipid-lowering drugs. Of the 9.6% of participants free of CVD and diabetes who were untreated but eligible for subsidy under PBS criteria, only 27.4% had an estimated high absolute CVD risk.Conclusion: Strategies for CVD prevention using lipid-lowering medications can be improved by adoption of the absolute-risk approach.

Lei Chen MD, MMed · Sophie L Rogers MEpi · Stephen Colagiuri MD, FRACP · Dominique A Cadilhac MPubHlth, PhD · Timothy H Mathew MB BS, FRACP · Andrew N Boyden BM BS(Hons), MPH, FRACGP · Anna Peeters BSc(Hons), PhD · Dianna J Magliano MPH, PhD · Jonathan E Shaw MD, MRCP, FRACP · Paul Z Zimmet MD, PhD, FRACP · Andrew M Tonkin MB BS, MD, FRACP

Earlier this year, two industry-sponsored advertising campaigns for cholesterol awareness that target the general public were launched in Australia. These campaigns aimed to alert the public to the risks associated with having high cholesterol and encouraged cholesterol testing for wider groups than those specified by the National Heart Foundation. General practitioners should be aware of the potential for the two campaigns to confuse the general public as to who should be tested, and where. The campaign sponsors (Unilever Australasia and Pfizer) each have the potential to benefit by increased market share for their products, and increased profits. These disease awareness campaigns are examples of what is increasingly being termed “condition branding” by pharmaceutical marketing experts.

Danika V Hall BA, MEd · Megan D Cobcroft · John W Ketelbey

Robert Cutforth, a pioneer of cardiac services in Tasmania and an important contributor to the field of cardiology in Australia as a whole, died on 25 March 2008. Born in England on 19 August 1921, Robert graduated from St Thomas’ Hospital Medical School, London, in 1944 and became a House Physician at St Thomas’ before volunteering for the army and serving in India in 1945. In 1948, he resumed postgraduate training in cardiology at King’s College Hospital, London, where he became a medical tutor in 1954. Working with Dr Sam Oram, he published a highly quoted article on the electrocardiogram in pulmonary embolism.1 In 1960, Robert emigrated to Australia with his wife Grace to take a position as the Physician in North West Tasmania. Two years later, he was appointed Medical Director of the National Heart Foundation and Cardiologist at the Royal Hobart Hospital (RHH). For 30 years, he played a major role in crafting cardiac services in Tasmania. He was a pioneer in many ways — the first to perform cardiac catheterisation and angiography in Tasmania, and an innovator in cardiac rehabilitation. In the late 1960s and early 1970s, his unit at the RHH was highly sought after by aspiring physicians, and he was a tremendous mentor to young physicians going into medical research. In the mid 1970s, he established echocardiography services in Tasmania and worked at the RHH until 1979, when he opened a private practice and continued as a Visiting Medical Officer at the Hospital until he had a major heart attack in 1989. His experience as a cardiac patient led him to write a book for patients, Heart attack: what’s it really like?, which helped many patients recover from their own cardiac events. Robert was a superb clinician and a master of the stethoscope, a stickler for process and a great teacher, influencing the lives of many medical graduates from the University of Tasmania. He was a true Renaissance man, with wide interests in literature, politics, music and boat-building. Conversations on a broad range of topics often commenced around the daily ritual of morning tea in his office at the National Heart Foundation and continued during the hours spent researching or catheterising clinical patients. He had a great sense of humour and terrific communication skills with his patients, who benefited greatly from his expertise. One of Robert’s favourite sayings when you had got something correct was “Well done, that man!”. In terms of cardiology in Tasmania, we can only say “Well done, Robert Cutforth!”

Peter M Brooks · Michael G Loughhead

Percutaneous coronary intervention (PCI) is increasingly used in the management of acute coronary syndromes and refractory angina, and technical advances such as drug-eluting stents (DES) and potent antithrombotic therapies (such as clopidogrel and glycoprotein IIb/IIIa inhibitors) have been heralded as improving long-term outcomes. Offsetting these advances has been: considerable concern about the safety of DES in regard to late stent thrombosis and antithrombotic drug-induced bleeding; the rising use of PCI and DES in clinical situations where evidence of efficacy is lacking; preferential use of PCI in low-risk populations; and limited cost-effectiveness data comparing PCI with other treatments. There are few contemporary data in Australia on the efficacy, safety and costs of PCI — as used in everyday clinical practice — that matches clinical outcomes with baseline patient characteristics, indications for intervention, coronary anatomy, procedural technique, co-interventions and site of care. A national registry that prospectively collects standardised data on processes and outcomes of PCI is warranted. This would ensure safe and appropriate evidence-based use of limited resources in an era of expanding use of PCI in clinical circumstances not tested in randomised trials.

Ian A Scott FRACP, MHA, MEd

Stent thrombosis is an infrequent but severe complication after coronary stent implantation. Dual antiplatelet therapy has markedly reduced the occurrence of this potentially catastrophic event. The optimal duration of clopidogrel therapy in patients with drug-eluting stents is unknown. We describe a case of stent thrombosis 9 days after discontinuation of clopidogrel therapy, more than 3 years after placement of drug-eluting stents. (MJA 2008; 189: 229-230) Clinical record A 60-year-old man presented to his local community hospital with chest pain. He had had a percutaneous coronary intervention more than 3 years previously, when drug-eluting TAXUS stents (Boston Scientific Corporation, Natick, Mass, USA) were implanted in his left anterior descending coronary artery (LAD) and right coronary artery (RCA). Overlapping stents were placed in the LAD, measuring 2.5 × 16 mm and 2.5 × 8 mm, inflated to 1620.8 kPa. He had been taking aspirin and clopidogrel as dual antiplatelet therapy since that time. His past medical history included well controlled hypertension. At the time of presentation, he was haemodynamically stable, with normal resting electrocardiograms and normal troponin levels. As intermittent chest pain persisted despite medical management, he was transferred to an interventional centre for further investigations. Coronary angiography showed mild irregularities of his LAD with widely patent stents in both the LAD (Figure, A) and RCA, with normal left ventricular function. There was no evidence of in-stent restenosis or disease adjacent to the stents. The next day, the patient developed abdominal pain associated with liver function test abnormalities indicative of cholestasis. Ultrasound of his abdomen showed multiple gall stones. It was thought likely that his chest pain was the result of his subdiaphragmatic disease. His clopidogrel therapy was stopped in anticipation of surgery, and he underwent a successful laparoscopic cholecystectomy. Five days later, he was discharged and clopidogrel therapy was not reinitiated. The patient re-presented to his local hospital 4 days after discharge, with central chest pain. His electrocardiogram showed ST-segment elevation in the anterior leads, and reciprocal ST-segment depression in the inferior leads. In view of his recent surgery, he was not deemed a candidate for thrombolytic therapy, and was urgently transferred to our hospital. An angiogram showed thrombus within the stent in his LAD (1190 days after it was implanted), with slow antegrade filling of the distal vessel (thrombolysis in myocardial infarction [TIMI] grade 1 flow; Figure, B). His right coronary and circumflex arteries were normal, and a left ventriculogram showed severe hypokinesis of his apical wall. The clot was partially removed using a 6-French Export Aspiration Catheter (Medtronic Inc, Minneapolis, Minn, USA), and the artery was further dilated within the stent. No further stents were implanted. A small residual filling defect was noted after balloon angioplasty (Figure, C). Intravenous therapy with the glycoprotein IIb/IIIa inhibitor abciximab was initiated, and a loading dose of clopidogrel given. The period after percutaneous transluminal coronary angioplasty was uneventful, and the patient was subsequently discharged in a stable condition. A: Arrow indicates patent stents in the left anterior descending coronary artery. B: Arrow indicates thrombus within the stent in the left anterior descending coronary artery. C: Arrow points to a small residual filling defect after balloon angioplasty. DiscussionDrug-eluting stents (DES) have been shown to be more effective than bare-metal stents (BMS) in reducing angiographic restenosis, by limiting intimal hyperplasia. This reduces the need for subsequent revascularisation procedures.1-3 However, there is growing concern that delayed endothelisation and incomplete neointimal healing might lead to adverse cardiac outcomes and death as a result of late or very late stent thrombosis.4,5 Mortality rates have ranged from 16% in a recent published registry from Spain documenting definite angiographic thrombus6 to as high as 45% in another series including both definite and probable thrombosis.7 Stent thrombosis is an uncommon but life-threatening complication of stent implantation.7,8 Stent thrombosis may be classified according to the time since implantation:9 acute stent thrombosis occurs within 24 hours of the procedure; subacute stent thrombosis between 1 and 30 days after implantation; late stent thrombosis between 1 month and 1 year after implantation; and very late stent thrombosis more than 1 year after the procedure. The cumulative incidence of stent thrombosis with DES at 9–12 months has ranged from 0.5% to 1.5%, which is comparable to stent thrombosis with BMS,10,11 with an incidence as high as 0.6% per year thereafter.12 Recent clinical trials and registries have raised concern over increased rates of very late stent thrombosis with DES.10,13,14 The cessation of dual antiplatelet therapy has been implicated as a pathophysiological factor in late and very late stent thrombosis.7,11,15 Incomplete endothelisation of the metal struts because of the antiproliferative properties of the drug has also been implicated.7,12,15 Mechanical factors involved in stent thrombosis have included malapposition of the stent to the vessel wall when originally implanted, and late malapposition because of retraction of the vessel wall during vessel remodelling.11,12 Whether this is related to the drug, polymer, or stent platform itself is unknown.12 The optimal duration of dual antiplatelet therapy after DES placement is still unknown. Current guidelines recommend clopidogrel therapy for at least a month and ideally up to a year with BMS, and for at least a year for patients treated with DES after hospitalisation for an acute coronary syndrome.16 However, reports of very late cardiac events among patients with DES, particularly in relation to stent thrombosis and cessation of clopidogrel therapy, have cast doubt on these recommendations.10,17,18 A recent observational study comparing DES with BMS suggested that clinical events related to late stent thrombosis in patients with DES after the discontinuation of clopidogrel therapy might limit the benefit of DES.10 Though there have been similar case reports,17,18 ours is a unique example of an angiographically proven very late stent thrombosis, 3 years after placement of DES. During angiography 9 days prior to the event, no abnormality was noted within the previously implanted DES, nor at the stent edges before the cessation of clopidogrel therapy. Nine days after stopping therapy with this drug, filling defects were seen (Figure, B). This case highlights the concerns about the duration of clopidogrel therapy following implantation of DES. It also raises the question of whether life-long clopidogrel therapy may be warranted in some patients.

Rohit Barthwal MB BS, FRACP · Brian A Herman MD, PhD, FACC

Objective: To determine the incidence of venous thromboembolism (VTE), comprising deep vein thrombosis (DVT) and pulmonary embolism (PE), in a well defined urban community broadly representative of the Australian population in terms of age, sex and ethnic distribution.Design, setting and participants: A prospective, community-based study conducted over a 13-month period from 1 October 2003 to 31 October 2004. People in a population of 151 923 permanent residents of north-eastern metropolitan Perth, Western Australia, who developed VTE during the study period were identified prospectively and retrospectively through multiple overlapping sources.Main outcome measure: Number of cases of symptomatic, objectively verified DVT and PE.Results: 137 patients had 140 VTE events (87 DVT and 53 PE). The crude annual incidence per 1000 residents was 0.83 (95% CI, 0.69–0.97) for VTE, 0.52 (95% CI, 0.41–0.63) for DVT, and 0.31 (95% CI, 0.22–0.40) for PE. The annual incidence per 1000 residents after age adjustment to the World Health Organization World Standard Population was 0.57 (95% CI, 0.47–0.67) for VTE, 0.35 (95% CI, 0.26–0.44) for DVT, and 0.21 (95% CI, 0.14–0.28) for PE.Conclusion: If the crude annual incidence of VTE in this area of metropolitan Perth is externally valid, then VTE affects about 17 000 Australians annually. Future studies of trends in VTE incidence will be needed to measure the effectiveness of VTE prevention strategies.

Wai Khoon Ho FRACP, FRCPA · Graeme J Hankey MD, FRACP · John W Eikelboom FRACP, FRCPA

To the Editor: We report significant sinus bradycardia in a patient presenting with an acute coronary syndrome shortly after beginning bupropion therapy to assist with smoking cessation. A 53-year-old man was attended by paramedics for typical ischaemic chest pain. He had sinus bradycardia (45 beats/min) and hypotension (blood pressure, 85/60 mmHg), and was found to have a serum troponin I concentration of 1.2 μg/L, but no diagnostic electrocardiographic changes. He was admitted to our hospital with an acute coronary syndrome. He reported his medications at the time of admission as including metoprolol 50 mg twice daily (for hypertension) and paroxetine 20 mg daily (for depression). The patient was given multiple doses of intravenous atropine (total, 1.2 mg) and adrenalin (total, 2 mg). After an adrenalin infusion was begun, he developed ventricular tachycardia (170 beats/min), but his cardiac rhythm spontaneously returned to sinus bradycardia. Two days after admission, two coronary stents were successfully deployed in a critically stenosed right coronary artery. Bradycardia (45–50 beats/min) persisted. The following day, it was discovered that 3 weeks previously, the patient’s general practitioner had prescribed bupropion 150 mg twice daily to assist with smoking cessation, which he had been taking up until the day of admission. Bradycardia continued until hospital discharge. One month after discharge, he was in sinus rhythm (60 beats/min) and was clinically well. Bupropion is a selective noradrenalin, dopamine and serotonin reuptake inhibitor. The mechanism by which it enhances the ability of patients to abstain from smoking is unknown.1 Bupropion inhibits the activity of the cytochrome P450 2D6 isoenzyme, which metabolises metoprolol.2 Concurrent use of bupropion and metoprolol can increase serum metoprolol levels, and clinically significant bradycardia has been reported.3 Further, paroxetine, a selective serotonin reuptake inhibitor (SSRI), is a potent cytochrome P450 2D6 inhibitor, which would have further increased serum metoprolol levels. Bradycardia associated with metoprolol and paroxetine dual therapy has been described.5 Additionally, there is the potential for serotonin syndrome to develop in a patient administered multiple SSRIs. In our patient, the administration of bupropion and paroxetine could have potentially led to serotonin syndrome.6 Our patient’s pharmacological profile was complex, with potential adverse pharmacodynamic effects. The most likely precipitant of the patient’s bradycardia was his acute coronary syndrome, although bupropion may have contributed. The case highlights the potential for significant drug interactions when new drug therapies are initiated. Bupropion and metoprolol (and other drugs metabolised by the cytochrome P450 2D6 isoenzyme pathway) should be co-administered with caution. The importance of common pathways of drug metabolism should be recognised to avoid potential adverse events, particularly when multiple medications are used.

Jacqueline Landau · Andrew E Ajani

Aim: To determine the feasibility of performing a large clinical trial of the use of aspirin for the primary prevention of cardiovascular disease in older participants — the ASPirin in Reducing Events in the Elderly (ASPREE) trial.Design and participants: A randomised double-blind placebo-controlled pilot trial of 100 mg of enteric-coated aspirin tablets daily, in men and women aged 70 years and over who did not have overt cardiovascular disease, and who were followed for 12 months. Participants were identified from the computer databases of general practitioners who were co-investigators in a previous trial.Setting: The Melbourne metropolitan area between March 2003 and June 2005.Main outcome measures: The level of response to participation by GPs; the level of response from potential trial participants; the screening-to-randomisation rate to ensure the recruitment target could be achieved; and the retention of participants in the trial after 12 months.Results: Forty-two GPs (23% of 180 mailed) expressed interest in participating in the pilot trial. Nineteen became co-investigators, of whom six were not required to meet recruitment targets. Letters were sent to 2614 patients, of whom 243 were screened and 209 (86%) were randomly allocated to receive aspirin or placebo. At 12 months,192 (92%) returned for follow-up, and 153 of these (80%) were still taking trial medication. There was a significant reduction in mean haemoglobin level in those taking aspirin.Conclusions: The recruitment strategy for ASPREE, based on methods developed for the conduct of a previous large-scale trial conducted in general practice, was successfully redeployed in this pilot study, with improved efficiency resulting from computerised database searching, telephone pre-screening, a simpler run-in phase and participant familiarity with the trial drug. We conclude that conducting ASPREE in Australian general practice with 18 000 participants is feasible.Trial registration: International Standard Randomised Controlled Trial Number Register ISRCTN83772183.

Mark R Nelson FRACGP, PhD, FAFPHM · Christopher M Reid BA, MSc, PhD · David Ames MD, FRCPsych, FRANZCP · Lawrence J Beilin MD, FRACP, FRCP · Geoffrey A Donnan MD, FRACP · Peter Gibbs MB BS, FRACP · Colin I Johnston MB BS, FRACP · Henry Krum FRACP, PhD · Elsdon Storey DPhil, FRACP · Andrew Tonkin MB BS, FRACP · Rory Wolfe BSc, PhD · Robyn Woods BSc(Hons), PhD · John J McNeil PhD, FRACP

To the Editor: We believe that Tang and Nordin1 misunderstood the findings of our recent study of calcium supplementation.2 We disagree with their claim that the increase in the number of women with self- or family-reported myocardial infarction, stroke or sudden death became non-significant after adjustment for covariables. They correctly noted that the increased number of women experiencing the composite endpoint of cardiovascular events (after adjudication of events and inclusion of unreported events from hospital records) was not statistically significant. However, the increased event rate for this composite endpoint with calcium was statistically significant (rate ratio, 1.43; 95% CI, 1.01–2.04; P = 0.043). Thus, in our study, the number of women needed to treat with calcium for 5 years to cause one cardiovascular event was 29, and the corresponding number to prevent one fracture was 50.2 Tang and Nordin then meta-analysed data from five studies of calcium and vitamin D supplementation to conclude that calcium supplementation does not increase mortality.1 We disagree. For one of the studies, they classified a subgroup of participants who received annual vitamin D but no calcium supplements as having received “calcium supplementation”.3 Further, for the RECORD (Randomised Evaluation of Calcium Or vitamin D) study, they compared the number of deaths between people receiving and not receiving vitamin D (16.5% v 17.4%) rather than between those receiving and not receiving calcium (17.7% v 16.2%).4 The trend for increased deaths with calcium supplementation in RECORD was greater when analysis was restricted to those treated with calcium monotherapy (18.5%) and placebo (16.3%). As our study was of calcium monotherapy, the results of Tang and Nordin’s meta-analysis are of questionable relevance to our findings. In addition, ours was a 5-year study, and the differences in vascular events between the groups only emerged after 2 years.2 Only one study in Tang and Nordin’s meta-analysis had an average follow-up duration of more than 25 months.4 Further, there is evidence from other studies of trends towards vascular events occurring more frequently in people who take calcium monotherapy.2,5,6 In three out of four studies that reported mortality, there were trends towards increased death rates in people receiving calcium.2,4-6 As we concluded,2 these data are not definitive, but flag cardiac health as an area of concern in relation to calcium use. Finally, we did not suggest that calcium supplementation should not be given to older women. However, in view of the evidence that any fracture risk reduction with calcium is small (< 10%),7,8 and the suggestions that calcium supplementation might increase the risk of hip fractures9-11 and vascular events, it seems reasonable and timely to reassess the role of calcium supplementation.

Mark J Bolland · Andrew B Grey · Ian R Reid

In reply: In Table 5 of Bolland and colleagues’ study, the P value after allowing for covariables was 0.08,1 which is not significant. This was without including smoking, which would undoubtedly have reduced the significance further as there were more smokers in the calcium group. Based on Bolland and colleagues’ suggestion, we reanalysed the data by removing the group receiving vitamin D but no calcium supplements in the NoNOF (Nottingham Neck of Femur) study,2 and using data for those treated with calcium monotherapy (18.5%) compared to placebo (16.3%) in the RECORD (Randomised Evaluation of Calcium Or vitamin D) study.3 The reanalysis still failed to show any evidence of an increase in mortality (relative risk, 1.05; 95% CI, 0.88–1.26; P = 0.56).

Benjamin M P Tang · B E Christopher Nordin

To decrease overall mortality, we need to focus on maximising appropriate medical therapies Increasing attention is being given to assessing and improving the quality of care of patients presenting with acute coronary syndromes (ACS).1,2 In this issue of the Journal, Chew and colleagues report on the use and survival impact of early invasive management (coronary angiography and revascularisation) in 3393 patients with ACS enrolled in the Australian prospective ACACIA (Acute Coronary Syndrome Prospective Audit) registry.3 They used propensity-adjusted regression modelling to quantify effects of invasive care independently of other confounders such as patient characteristics, contraindications to invasive care and use of pharmacological treatments. While rates of invasive care appeared near to optimal (90%) in patients with ST-segment-elevation myocardial infarction (STEMI), rates were purported to be less optimal in those with non-STEMI (71%) and unstable angina (45%). The study is unique in showing a 47% reduction in all-cause death at 1 year as a result of early invasive care, a finding used to argue for a greater use of this approach across the spectrum of ACS. The magnitude of this treatment effect is at odds with systematic reviews of randomised trials which report that survival benefits are restricted to patients with STEMI undergoing primary angioplasty, with relative risk reduction of death (compared with thrombolysis) no more than 32%.4 Such patients represented just over a fifth of the patients evaluated in ACACIA. In contrast, contemporary trials of routine invasive care versus medical therapy in patients with non-ST-segment elevation ACS (NSTEACS), who comprised three-quarters of the cohort, show no conclusive mortality benefit, although reinfarction and anginal burden are significantly reduced.5 Separate analyses for patients with STEMI versus those with NSTEACS were not reported, which brings into question the validity of implying that greater use of an invasive strategy among all patients with ACS would translate into proportionately more survival benefit. The authors argue that their cohort included many high-risk patients who tend to be excluded from trials, and among whom they infer a survival benefit was achieved. Several issues warrant consideration. Can observational studies validly show treatment benefits not seen in randomised trials? How replicable are these effects? If such an effect is real, would the number of lives saved from optimising invasive care exceed that achieved from optimising other forms of care, thus serving as a quality improvement priority? If so, what might be the most effective optimisation strategies? Even the best observational design can be biased by prognostically important baseline differences among patients, often because of unobserved or unreported treatment selection biases. Chew et al did their best to minimise such bias by estimating the likelihood (or propensity) of patients to receive invasive care on the basis of patient characteristics ascertained before such treatment was given. The association between invasive care and 12-month mortality was then assessed with regression modelling that adjusted for variables known or thought highly likely to influence mortality, including medical therapies such as statins and angiotensin-converting enzyme (ACE) inhibitors — although antiplatelet agents and β-blockers were notably absent. This association was then further adjusted after inserting the propensity score as a continuous variable. Unfortunately, methodological concerns persist for several reasons. First, the literature is replete with high-profile examples of well performed observational studies (eg, hormone replacement therapy and cardiovascular mortality, β-carotene and cancer prevention) suggesting favourable treatment effects that were later dismissed or reversed in large, pragmatic randomised trials. Second, different observational studies, which have included analytical methods other than propensity scoring, give very different results. An American study showed that early coronary angiography for acute myocardial infarction (AMI) was associated with a 50% reduction in mortality at 7 years using propensity analysis (designed to control for overt bias), but this fell to a 16% decrease when instrumental variable analysis was used (designed to control for hidden bias as well).6 A propensity-adjusted analysis of French patients with STEMI presenting to interventional versus non-interventional hospitals (the former highly correlated with higher rates of invasive care) revealed only a 24% decrease in mortality at 1 year.7 Third, the most appropriate design for observational studies remains unclear, with some arguing propensity scoring is no better than traditional multivariate regression adjustment.8 Fourth, as propensity analysis cannot adjust for unmeasured characteristics, sensitivity analyses are recommended to gauge effects of potential confounders which, for invasive care in ACS, may include patients’ socioeconomic status.9 Finally, trials of invasive care may actually overestimate treatment effects achievable in routine practice given the expertise, logistical support and rapid institution required for the optimal results available in high-volume research centres. With regard to prioritising efforts at improving quality of care, the use of early invasive care in patients with STEMI in the study by Chew et al was in accordance with trials and guidelines. In contrast, within the total cohort, there was considerable underuse of key drugs at discharge and at 12 months, respectively: β-blockers, 68% and 57%; aspirin, 87% and 74%; statins, 82% and 72%; ACE inhibitors or angiotensin receptor antagonists, 67% and 64%. This underuse was most pronounced in patients not receiving invasive care and, by association, not admitted to a metropolitan centre. Of all AMI-related deaths that are prevented by therapeutic interventions, both acutely and as secondary prevention, medical treatments account for 80% of these (35% acutely, 45% secondarily) compared with only 6% for early invasive management.10 If all indicated drugs are prescribed to eligible patients, risk-adjusted mortality at 6 months is reduced by 90% compared with patients who receive none of these drugs.11 Routine use of more costly invasive care is not associated with population survival benefit beyond that seen with optimal medical management.12 Thus, if decreasing overall mortality is the aim, a focus on maximising administration of appropriate medical therapies across all hospitals should take precedence over extending invasive care to all or most patients with ACS, especially as there are low-cost interventions that can increase rates of prescribing at discharge up to 90%.13 This is not to say the delivery of timely invasive intervention, particularly to patients presenting to non-interventional hospitals, is unimportant given its mortality benefit in STEMI4 and morbidity reduction in high-risk NSTEACS.5 There are actionable strategies for improving region-wide access to intervention14 and reducing door-to-balloon times15 for patients with acute STEMI, and these deserve consideration in Australian settings. Risk stratification methods for identifying patients with NSTEACS who are most in need of referral to interventional centres16 require universal implementation. More globally, quality improvement strategies — comprising use of opinion leaders and educational outreach, guideline-based decision support tools, regular audit and feedback, and clinical process redesign — have been validated in the management of patients with ACS,17 and innovative, multidisciplinary programs that integrate multiple strategies need to be maintained. What is critical is the continuance of well designed prospective registries like ACACIA, which provide standardised and representative data that allow us to monitor the quality of care and the effects of whatever actions we may take towards improving it.

Ian A Scott FRACP, MHA, MEd

Long (or short) QT syndrome is life-threatening, not as rare as once thought, and treatable if diagnosed “The fault dear Brutus is not in our stars, but in ourselves”. Through the lens of molecular medicine we are now beginning to see those faults more clearly. We can now increasingly understand why some apparently healthy children and young adults die without warning. The long-QT syndrome is foremost among responsible causes, and is known to be the consequence of mutations in genes encoding ion channel function.1 Originally an esoteric condition of great rarity, its prevalence is now estimated as one in 2000.2 Life depends on the continuous sequence of depolarisation and repolarisation in our heart cells. The QT interval is the time from the onset of depolarisation (the q wave) to the end of repolarisation (completion of the T wave) and is best measured over several R-R intervals in leads II or V5. It is not a value physicians ordinarily pay much attention to when they read an electrocardiogram (ECG; Box). Nor is it always easy to measure. Exactly where the T wave merges with the isoelectric baseline is subject to individual interpretation and hence error.3 It also varies with heart rate, requiring normalisation for comparison, and is longer in women than men. But it is important. The long-QT syndrome is essentially an autosomal dominant condition in which sudden death is commonly linked to situations of increased adrenergic activity, such as exercise and emotion, but also occurs at rest and during sleep.4 Seizures are common and easily lead to misdiagnosis. Although mutations in at least 10 genes have been found, long-QT syndromes 1 (LQT1), 2 (LQT2) and 3 (LQT3) constitute 95% of genotyped cases. LQT1 and LQT2 involve decreased function and hence diminished current flow in the slow and fast repolarising potassium currents, IKs and IKr, respectively, while LQT3 involves an increase in slow sodium current during the plateau phase of the action potential. The net effect is prolongation of the action potential and, most importantly, an increased dispersion of recovery times in different myocardial cells. This increased dispersion allows re-entry to occur with potentially fatal ventricular tachycardia and fibrillation, which manifests clinically as fainting and sudden death. LQT1 is the most common type, and events are typically triggered by exercise, including swimming, and emotion.5 The child found unconscious at the bottom of the swimming pool may well have LQT1.6 Events may occur with exercise or at rest in LQT2 and also, characteristically, with loud noises such as being awakened by a telephone call.7 LQT3 has been linked to death during sleep or inactivity, with a lower likelihood of events, but increased mortality. What are the implications for physicans and general practitioners? Fainting is common, most often vasovagally mediated, and benign. How do we decide otherwise? The key is to be mindful of possible long-QT syndrome when checking the history; fainting or a seizure during exercise, or when upset or angry, and premature death (including drownings or accidents) in family members should ring alarm bells and trigger detailed exploration of the family history, close scrutiny of ECGs and appropriate referral. In such settings, a corrected QT (QTc) interval > 0.45 seconds in males and > 0.47 seconds in females makes the diagnosis virtually certain. With diagnosis comes the dual responsibility of triaging individual patient risk and screening the wider family. The most important factor determining individual risk is the length of the QT interval — long intervals (QTc ≥ 0.5 seconds) equal high risk.8 Knowledge of the genotype is also predictive. β-Blockers are generally first-line treatment, although in genotyped individuals, evidence is lacking for a protective action in LQT3. Modifying risk by avoidance of competitive sport and QT-prolonging drugs (see http://www.qtdrugs.org) is important. Implantable defibrillators are appropriate in high-risk patients, but decisions about prophylactic implantation in intermediate-risk patients must balance the reduction in probability of sudden death against the not inconsiderable morbidity of life-long device therapy in young people. As well as personal history and ECG, family screening should include genetic testing if it is available. When a functionally important mutation is uncovered, testing of family members will disclose up to a third of individuals whose QT intervals are normal, and yet who carry the mutation.9 However, a genotypic diagnosis is possible in only two-thirds of clinically certain cases. Continuing research may diminish this gap. The establishment of registries, such as presently exist in New Zealand (http://www.cidg.org), facilitates surveillance of widely dispersed families and aids ongoing research. While the risks of QT prolongation are now well established, attention has recently been drawn to excessively short QT intervals. In a small number of families identified to date, a QTc interval of < 340 milliseconds has been also associated with a family history of sudden death.10 The first two syndromes described (short-QT syndromes 1 and 2), show a gain of channel function for IKr and IKs, the mirror opposite of the corresponding LQT2 and LQT1 with loss of function in those same channels. Although five short-QT syndromes have been recognised already, it nonetheless seems unlikely that they will rival the long-QT syndrome in prevalence. In conclusion, cardiac repolarisation is a complex interplay of ionic currents precariously maintaining stability. Dramatic progress has been made over the past 50 years in recognising, deciphering and predicting the clinical risk of the long-QT syndrome. Yet this knowledge counts for little if we fail to identify and protect at-risk individuals. Perhaps you will take a closer look at the QT interval in your next patient presenting with “just” another fainting attack. Electrocardiogram showing a markedly prolonged QT interval. The long ST segment is suggestive of long-QT syndrome 3.

Warren M Smith MB BS, FRACP

Objective: To describe the impact of invasive management on 12-month survival among patients with suspected acute coronary syndrome (ACS) in Australia.Design and setting: Prospective nationwide multicentre registry.Patients: Patients presenting to 24 metropolitan and 15 non-metropolitan hospitals with ST-segment-elevation myocardial infarction (STEMI), and high-risk and intermediate-risk non-ST-segment-elevation ACS (NSTEACS) between 1 November 2005 and 31 July 2007.Main outcome measures: Death, myocardial infarction (MI) or recurrent MI, revascularisation and stroke at 12 months.Results: Among 3402 patients originally enrolled, vital status at 12 months was available for 3393 (99.7%). Patients from non-metropolitan areas (810) constituted 23.9% of patients. Early invasive management was more commonly undertaken among patients with STEMI (STEMI, 89.7% v non-STEMI, 70.8% v unstable angina, 44.8% v stable angina, 35.8%; P < 0.001). Factors most associated with receiving invasive management included admission with suspected STEMI or high-risk NSTEACS, being male and the hospital having an onsite cardiac surgical service. Overall mortality by 12 months among patients with STEMI, non-STEMI, unstable angina and stable angina was 8.0%, 10.5%, 3.3%, and 3.7% (P < 0.001), respectively. After adjusting for a propensity model predicting early invasive management and other known confounders, early invasive management was associated with a 12-month mortality hazard ratio of 0.53 (95% CI, 0.34–0.84, P = 0.007).Conclusions: A substantial burden of late morbidity and mortality persists among patients with ACS within contemporary Australian clinical practice. Under-use of invasive management may be associated with an excess in 12-month mortality, suggesting the need for more use of invasive management among these patients.

on behalf of the ACACIA investigators

Objective: To determine the causes of death in Australians with type 1 diabetes mellitus who died aged 40 years or younger.Design and setting: Retrospective review of autopsy reports at the Department of Forensic Medicine, Sydney, New South Wales, 1 January 1994 – 31 December 2006.Main outcome measure: Causes of mortality in people with type 1 diabetes aged ≤ 40 years.Results: Of the 26 682 autopsy reports, 1914 were for individuals with diabetes (type 1, 400; type 2, 1514). Cardiovascular disease accounted for 51% of deaths (169/333) in people with type 1 diabetes aged > 40 years, versus 13% among those aged ≤ 40 years (9/67; P = 0.001). Acute complications of diabetes (27%; 18/67), unnatural deaths (28%; 19/67), and sudden unexpected deaths (22%; 15/67) were the predominant causes of death in young individuals with diabetes. Sudden unexpected death was more common in those with type 1 diabetes compared with a sex-matched control population in the same age range (22% v 5%; χ2 P < 0.001). Of the sudden unexpected deaths, 10 people were found dead in an undisturbed bed with no cause of death found at autopsy (“dead-in-bed” syndrome; mean age [SD], 30.2 [9.4] years; males : females = 4 :1).Conclusions: In deceased young people with type 1 diabetes examined by the Coroner, acute diabetic complications, unnatural causes, and sudden unexpected deaths were the predominant causes of death. The relatively high frequency of sudden unexpected deaths, such as dead-in-bed syndrome, requires further investigation.

Emily Tu BSc · Stephen M Twigg PhD, FRACP · Johan Duflou FRCPA · Christopher Semsarian PhD, FRACP

Objective: To investigate rates and predictors of cardiac rehabilitation (CR) attendance after coronary artery bypass graft surgery (CABGS) at Royal Melbourne Hospital (RMH), Victoria, where current best practice referral and recruitment strategies have been adopted.Design, setting and participants: Prospective cohort study of 184 patients who underwent CABGS at RMH between July 2001 and April 2004. Patients completed questionnaires pre-operatively, and 170 patients (92%) had their CR attendance tracked after referral to CR either at RMH or elsewhere.Main outcome measures: Rates of CR attendance among RMH patients referred to CR either at RMH or elsewhere; sociodemographic, medical, cognitive, psychosocial and geographical predictors of CR non-attendance.Results: The CR attendance rate was 72%. Patients referred to CR at RMH were more than four times more likely to attend than patients referred elsewhere (odds ratio [OR], 4.36; P = 0.024). Travel time significantly predicted CR attendance (OR, 0.86; P = 0.039).Conclusions: CR attendance rates were found to be higher than previously reported for CABGS patients, suggesting that best practice referral and recruitment procedures minimise common barriers to CR attendance.

Rosemary O Higgins GradDipBehavHealthCare, BBSc · Barbara M Murphy PhD · Alan J Goble MD, FRCP, FRACP · Michael R Le Grande BSc(Hons), MPH · Peter C Elliott PhD · Marian U C Worcester PhD

Objective: To identify the health and mental health information needs of people with coronary heart disease (CHD), with and without comorbid depression.Design and setting: A qualitative study conducted in Melbourne in 2006, using thematic analysis of semi-structured interviews on the types of health information that patients with CHD considered useful to assist with the management of their illness. Structured clinical interviews were used to assess current and prior depressive episodes in these patients.Participants: 14 general practice patients (eight with current or prior history of major depression) who had experienced myocardial infarction, coronary artery bypass graft surgery, angioplasty or angina (confirmed via testing).Results: Four themes relating to information on how patients could manage their cardiovascular health and improve their psychosocial wellbeing emerged: psychosocial; physical activity; medical; and information for family. The most prominent information needs included identification and management of risk-related physical symptoms, and psychosocial information, most notably to enhance patients’ social support. Patients considered this information important for alleviating health anxiety and negative affect.Conclusion: This small patient sample endorsed the need for health and mental health information on a range of psychosocial and physical health topics. Participants desired specific types of information to assist with the self-management of their health and to assuage their health concerns.

Ciaran Pier PhD, BA(Hons)(Psych) · Kerrie A Shandley MPsych(Health), GradDip(Psych), BSc · Julie L Fisher PhD, MBusInfoSys, GradDipComputersInEducation · Frada Burstein MSc(ApplMath), PhD · Mark R Nelson PhD, FRACGP · Leon Piterman MMed, MEdSt, FRACGP

Takotsubo cardiomyopathy is an increasingly recognised syndrome characterised by transient apical left ventricular dysfunction in the absence of significant coronary artery disease. We describe a case of Takotsubo cardiomyopathy complicated by Dressler’s syndrome. To our knowledge, these two conditions have not previously been reported in combination. Clinical recordA 75-year-old woman presented with acute onset of discomfort in the chest, left scapula, neck and arm after being informed of the unexpected death of her son, and 2 days after undergoing an uncomplicated laparoscopic cholecystectomy. Her medical history included Graves’ disease and a hysterectomy. She had no modifiable risk factors for coronary artery disease. Examination revealed a heart rate of 90 beats per minute and a blood pressure of 120/80 mmHg, with no evidence of acute pulmonary oedema. At presentation, an electrocardiogram demonstrated 1–2 mm ST elevation in leads V1–V6, I and aVL (Box 1). The patient was immediately transferred to the cardiac catheter laboratory, where angiography revealed angiographically normal coronary arteries but extensive anteroapical and inferoapical ballooning consistent with Takotsubo cardiomyopathy.1-9 Peak creatinine kinase and troponin I levels were 245 μg/L (reference range [RR], < 200 μg/L) and 6.62 μg/L (RR, < 0.1 μg/L), respectively. The patient’s in-hospital course was complicated by heart failure, necessitating treatment with intravenous diuretics. The patient also developed pleuritic-type chest pain, but computed tomographic pulmonary angiography (CTPA) excluded pulmonary embolism. The patient was discharged 3 days after admission on a medication schedule of metoprolol 25 mg twice a day, and perindopril 2.5 mg, frusemide 40 mg and aspirin 150 mg once a day. A follow-up echocardiogram 6 weeks later showed normal left ventricular function and size, with a calculated ejection fraction of 72%. A trivial pericardial effusion measuring less than 0.2 cm was noted. All cardiac medications were ceased at that point. About a week after the follow-up echocardiogram, the patient presented again with severe pleuritic chest pain that was relieved by sitting forward. The pain was associated with low-grade fever, shortness of breath and a dry cough. She did not report any other symptoms suggestive of an upper respiratory tract infection. Examination revealed signs of a pericardial friction rub and bilateral pleural effusions but no evidence of cardiac tamponade. In view of the recent cholecystectomy, the patient underwent repeat CTPA, which excluded a pulmonary embolus but revealed a moderate pericardial effusion measuring up to 2.1 cm laterally and small bilateral pleural effusions (Box 2). An echocardiogram confirmed the pericardial effusion but showed no evidence of cardiac tamponade. Inflammatory markers were markedly elevated, with a C-reactive protein level of 290 mg/L (RR, < 12 mg/L) and an erythrocyte sedimentation rate of 103 mm/h (RR, < 21 mm/h). The patient had low-grade anaemia (haemoglobin level, 96 g/L; RR, 115–165 g/L), but this improved to 116 g/L without treatment. Her white cell count was elevated at 16 × 109/L (RR, 4–11 × 109/L), with predominant neutrophilia, and her platelet count was significantly elevated at 800 × 109/L (RR, 150–400 × 109/L). Renal function, urinalysis, autoimmune markers and a repeat troponin I measurement were normal. These findings were consistent with a diagnosis of Dressler’s syndrome. Treatment with ibuprofen 400 mg three times daily resulted in a rapid reduction in pain and levels of inflammatory markers. Inflammatory marker levels normalised within 3 months. DiscussionTakotsubo cardiomyopathy was first described in Japan in 1991. It is characterised by transient apical left ventricular ballooning in the absence of significant coronary artery disease.1 Our patient’s initial presentation was consistent with a diagnosis of Takotsubo cardiomyopathy. The pathogenesis of this condition is not well understood but is postulated to be caused by coronary artery vasospasm in association with intense emotional or physical stress, leading to apical myocardial stunning.2-4 As a result there is often minimal myocardial necrosis, as reflected by the minor cardiac enzyme rise in this case.5 Left ventricular function usually returns to normal within 1–4 weeks, as seen in our patient.6-8 The role of catecholamines in the pathogenesis of Takotsubo cardiomyopathy has been documented in numerous studies.9-12 Dressler’s syndrome was first described by Dressler in 1956.13 It is characterised by a late-presentation pericarditis, presenting weeks to months after a myocardial infarction. Six weeks after the diagnosis of Takotsubo cardiomyopathy, our patient displayed typical features of Dressler’s syndrome: pleuritic chest pain, pericardial friction rub with associated effusion, fever, leukocytosis, pleural effusions and elevated levels of inflammatory markers.13 The pathogenesis of Dressler’s syndrome is thought to be immune-mediated, as evidenced by late onset of the syndrome. The putative pathogenetic sequence begins with myocardial injury that releases cardiac antigens and stimulates antibody formation. The immune complexes that are generated then deposit onto the pericardium, pleura and lungs, eliciting an inflammatory response.14-16 Earlier studies quoted the incidence of Dressler’s syndrome to be as high as 3.3%–4.8% after myocardial infarction,17-18 but more recent estimates have been significantly lower, possibly as a result of reperfusion strategies that limit the size of the infarct and the release of cardiac antigens that stimulate an immune response.19 Our patient presented with Takotsubo cardiomyopathy and developed Dressler’s syndrome 6 weeks later. To our knowledge, Dressler’s syndrome following Takotsubo cardiomyopathy has not been previously described in the literature. This may be because the extent of biochemical myocardial damage demonstrated is often small in Takotsubo cardiomyopathy, whereas Dressler’s syndrome is often associated with significant myocardial necrosis. For this reason, the diagnosis of Dressler’s syndrome in our patient was unexpected and the mechanism is unclear. 1 Electrocardiogram showing 1–2 mm ST elevation in leads V1–V6, I and aVL ST elevation was noted anterolaterally, with reciprocal changes inferiorly. 2 Pericardial effusion seen on computed tomographic pulmonary angiography The pericardial effusion (white arrow) measured up to 2.1 cm laterally. A small pleural effusion (black arrow) is also visible.

Edmund J Lee MB BS(Hons) · Randall Hendriks MB BS, FRACP, FCSANZ · Alan P Whelan MB BS, MRCP, FRACP