Cardiovascular diseases

Ian Hamilton-Craig Chairman, MEDPED-FH Australia, North Adelaide Heart Centre, 80 Brougham Place, North Adelaide SA 5006. IhcATsahc.com.au To the Editor: In their editorial, Burnett and colleagues correctly emphasise the importance and cost-effectiveness of cascade family screening in the early diagnosis of familial hypercholesterolaemia (FH) among relatives of known cases. They point out that Australia does not have “a national program for detecting the vast majority of patients with FH in our community . . .”.1 Such an approach has been advocated since the 1980s by the international MEDPED-FH project, initiated in Utah to raise public and professional awareness of the need to detect and treat FH at an early age (MEDPED-FH stands for Make Early Diagnosis to Prevent Early Deaths in Familial Hypercholesterolaemia).2 Since then, the project has spread to over 30 countries, including Australia, and has over 25 000 patients with FH registered worldwide.3 In Australia, the MEDPED-FH program has registered about 700 patients with FH, about 2% of the estimated 33 000 patients overall.4 This proportion is similar to registrations in many other countries (including the US). Only the Netherlands, Denmark and Finland, where government-financed screening programs are in place, have higher proportions of registrations, with 10%–50% of patients with FH registered with MEDPED-FH. Also, in these countries, DNA detection of low-density lipoprotein cholesterol receptor gene mutations is used routinely for the diagnosis of FH. At present in Australia, nurse practitioners are performing FH cascade screening in collaboration with MEDPED-FH physicians in each capital city, supported by Pfizer Australia. Further work on FH is being carried out by Associate Professor David Sullivan and colleagues in Sydney, supported by the Western and Central Sydney Area Health Services. In addition, the Cardiac Society of Australia and New Zealand has established a working party to investigate cardiac genetic disorders, including FH, and is involved in further education among cardiologists regarding screening, diagnosis and treatment of FH. But these efforts are not enough. I support Burnett and colleagues in recommending the establishment of a nationwide screening program for FH, and also recommend that DNA diagnosis be incorporated as an essential component. There is a definite cost benefit of early detection and treatment with statins of patients with FH.

Ian Hamilton-Craig

John R Burnett,* David Ravine,† Frank M van Bockxmeer,‡ Gerald F Watts§ * Medical Biochemist, Department of Core Clinical Pathology and Biochemistry [corresponding author]; † Medical Geneticist, Medical Genetics Unit; ‡ Director, Cardiovascular Genetics Laboratory; § Physician, Department of Internal Medicine, Royal Perth Hospital, GPO Box X2213, Perth, WA 6847. john.burnettAThealth.wa.gov.au In reply: The international MEDPED-FH project has made a major contribution towards introducing family-based cascade screening into the Australian health care system. Although these achievements are important, we agree with Hamilton-Craig’s view that they are dwarfed by the magnitude of what now has to be done to deliver to all at-risk relatives the health gains that can be achieved by a proactive program of population screening. The risk of familial hypercholesterolaemia (FH) for a first-degree relative of an affected index case is 250 times greater than the risk for a member of the general population. The relative cost-efficiency of family-based cascade genetic screening is high, compared with population-wide screening for a dominantly inherited disorder.1,2 We disagree with Hamilton-Craig that DNA diagnosis is an essential component of an effective screening program. Among FH-affected families, biochemical testing has a sensitivity of 95%, and a specificity of 96%.3 The additional diagnostic gain from DNA testing in the context of screening relatives at 50% prior risk is marginal, although of use in determining with certainty whether or not a relative has inherited the family-specific trait. FH offers a paradigm of best clinical practice for improving health care outcomes for a widening range of “monogenic” disorders with complications that can be avoided or reduced by focused health care provision. The time has come when physicians, cardiologists, paediatricians, biochemists, geneticists, public health physicians, general practitioners and those administering the funding of health care delivery in Australia come together and formulate the changes necessary to allow cascade genetic screening for FH to become part of routine health care.

John R Burnett · David Ravine · Frank M van Bockxmeer · Gerald F Watts

Six patients being evaluated for phaeochromocytoma had misleading investigative findings: all initially had raised urinary catecholamine levels, and five had adrenal masses on imaging studies. Adrenalectomy in these five patients revealed only one pathologically confirmed phaeochromocytoma. Tricyclic antidepressant use produced misleading elevations in urinary catecholamine levels in three patients. 24-hour urine studies should be performed at least twice, after eliminating confounding factors (stressors, medications). Clinical recordThe details of six patients treated in the period April 1999 – October 2003 by members of the Section of Endocrine Surgery of the Royal Australasian College of Surgeons are outlined in Box 1. In all patients, clinical suspicion of phaeochromocytoma was raised by the presence of hypertension, paroxysmal symptoms, or both. Twenty-four-hour urinary catecholamine levels were found to be elevated, although in Patients 1–5 these abnormalities were confined to one or two analytes only. In all except Patient 2, adrenal lesions were discovered on imaging, with large haemorrhagic masses detected in patients with an acute presentation (Patients 5 and 6). Patients with abnormalities on computed tomography (CT) underwent surgery. In Patients 1, 3, and 4, the excised tissues were found to be pathologically normal or to show mild enlargement (benign). In Patients 5 and 6, blood clot and necrotic tissue comprised the bulk of the specimens (Box 2), with a phaeochromocytoma discovered in the latter patient. Of note, Patients 1–3 were receiving tricyclic antidepressants for non-standard uses that did not include the treatment of major depression. DiscussionFalse positive biochemical test results for phaeochromocytoma are common and present particular problems because of the low prevalence of the disease. The reported incidence of phaeochromocytoma is 2–8 per million people annually, accounting for less than 0.2% of all patients with hypertension.1 Despite the fact that phaeochromocytoma is a rare cause of hypertension, the diagnosis merits consideration in a potentially large group of patients for two reasons. Firstly, although the disease is frequently fatal if unrecognised, surgical removal is highly effective, achieving cure in greater than 90% of cases.2 Secondly, because no array of clinical indicators has proven to reliably include or exclude phaeochromocytoma,3 physicians must maintain a high level of suspicion and consider biochemical testing in patients at risk. The pretest probability for phaeochromocytoma is close to 0.5% (1 in 200 patients tested) in the presence of hypertension and suggestive symptoms.4 Assuming a specificity of 85% for biochemical testing, 30 false positive results are generated for every one patient with phaeochromocytoma identified.5 Fortunately, most false positive tests can be unmasked with careful additional investigation and/or the elimination of factors known to confound biochemical tests for levels of catecholamines and their metabolites. The misleading elevations in urinary noradrenaline levels in Patients 1–3 can be ascribed to their taking tricyclic antidepressants. Medications and conditions that may result in raised levels of plasma and/or urine catecholamines and their metabolites, and result in false positive test results for phaeochromocytoma, are listed in Box 3. Among these drugs, tricyclic antidepressants and phenoxybenzamine have been the most frequently implicated, together accounting for more than 40% of medication-associated false positive results in a recent large study.6 In Patients 3 and 4, false positive biochemical findings led to the identification of small (1.5 cm) adrenal masses on CT scanning, both of which were found, on histopathological examination, to be benign. Clinically unapparent adrenal masses (“incidentalomas”) are found in 2.1% of subjects at autopsy and in 1%–4% of abdominal imaging studies. Most of these masses are benign, hormonally inactive tumours that do not require surgical management.7 Phaeochromocytomas presenting with acute haemorrhage at presentation have been reported previously,8,9 with haemorrhagic tumours often losing characteristic imaging appearances and functional markers. Tumour necrosis may initially result in massive catecholamine release, followed by failure to demonstrate excess catecholamine levels, as was seen in Patient 6. Mildly elevated urinary catecholamine levels may also be seen as a consequence of hyperadrenergia from an acute stress response at the time of haemorrhage into a non-phaeochromocytoma lesion, as occurred in Patient 5. Role of biochemical testingAlthough measurement of plasma free metanephrine levels has been recently advocated by some groups, 24-hour urinary catecholamine levels and total metanephrine level have consistently proven to be the most specific tests available for the diagnosis of phaeochromocytoma.5,10 Elevations in the level of one or more of these analytes (above the 95% reference range designated as the upper limit of normal by laboratories) are common in patients with paroxysmal symptoms or poorly controlled hypertension not due to phaeochromocytoma. Thus, we recommend that higher cut-off values, roughly two times the upper limit of normal for most laboratories, be used to identify patients suitable for further workup. Repeat biochemical testing 6 weeks after stopping drugs likely to confound the results is ideal, and tests performed during major physical or psychological stress should be interpreted with extreme caution (if performed at all). It is important to note that alterations in plasma catecholamine levels may be caused not only by medications, but also by the underlying diseases being treated (eg, major depression in the case of tricyclic antidepressants or severe heart disease in the case of β-blockers).11-13 All patients should undergo at least two 24-hour urine collections for measuring levels of catecholamines and their metabolites. Clonidine suppression testing — the measurement of plasma free normetanephrine before and after the oral administration of 0.3 mg clonidine — is highly sensitive and specific, and may be a useful adjunct in patients with more than one prior set of equivocal tests.6 Role of imagingWhether imaging studies (both anatomical and functional) play a role in diagnosing phaeochromocytoma, as opposed to only localising tumours already diagnosed biochemically, remains controversial. In the patients described above, 131I‑metaiodobenzylguanidine scanning yielded true negative results in Patients 1–3, consistent with its known high specificity.4 However, current evidence suggests that, when appropriate biochemical tests are used, little discriminatory value is to be gained from imaging,14 and our experience illustrates how incidental radiographic findings may lead to unnecessary surgery. 1 Summary of the clinical records of six patients investigated for phaeochromocytoma Patient age/sex Presentation Blood pressure (mmHg) Medications 24-h Urinary catecholamine levels (nmol/d or μmol/d)* Radiological investigation† Surgical findings/ Clinical course Pathology Patient 1 49/M Weight loss (5 kg in 3 months), paroxysmal anxiety attacks, drenching sweats, chronic right flank pain 124/80 Clomipramine, 50 mg/day (anxiety) Adrenaline, 91/84 Noradrenaline, 860/1224 CT: 3 x 6-cm mass abutting upper pole of right kidney MIBG: negative Lobulated upper pole of kidney due to right renal artery branch running within posterior cleft Normal adrenal tissue Patient 2 41/M Migraines, chronic back pain, worsening hypertension, palpitations 145/85 Amitriptyline, 150 mg/day (migraine prophylaxis); amlodipine, 5 mg/day; ramipril, 5 mg/day; indapamide, 2.5 mg/day Adrenaline, 7/12 Noradrenaline, 485/1295 CT: No abnormalities MIBG: No abnormalities Normal findings on repeat urine studies after stopping amitriptyline — Patient 3 64/M Metastatic prostate cancer, poorly controlled hypertension 180/95 Imipramine, 100 mg/day (neuropathic pain); nifedipine, 180 mg/day; ramipril, 5 mg/day; chlorothiazide, 1000 mg/day Adrenaline, 115/99 Noradrenaline, 1070/1130 VMA, 33/38 CT: 1.5-cm left adrenal mass MIBG: negative Small left adrenal mass, macroscopically consistent with an adenoma Benign adrenal adenoma Patient 4 76/F Chronic hypertension, 15-month history of paroxysmal nausea and vomiting 144/80 Captopril, 25 mg/day Adrenaline, 65/129 Noradrenaline, 371/451 Dopamine, 1.55/2.02 CT: 1.5-cm left adrenal mass Smooth lesion palpable within left adrenal gland Enlarged adrenal gland (10.2 g; reference, 4 g) with thickened cortex but normal medulla Patient 5 75/M Sudden onset of intense back and left loin pain, chronic hypertension, weight loss (22 kg in 6 months), atrial fibrillation, diabetes, polymyalgia rheumatica 150/90 Warfarin, 5 mg/day; captopril, 25 mg/day; digoxin, 0.25 mg/day; isosorbide mononitrate, 60 mg/day; verapamil, 240 mg/day; prednisone, 5 mg/day; metformin, 2 g/day; rosiglitazone, 4 mg/day; thyroxine, 0.125 mg/day Adrenaline, 250 Noradrenaline, 720 Metanephrine, 1.68 Normetanephrine, 2.49 CT: 12-cm heterogeneous left adrenal mass (Box 2) Large blood clot with associated desmoplastic reaction occupying most of left adrenal gland Myelolipoma with haemorrhagic fat necrosis Patient 6 58/M Acute abdominal pain and hypertension, otherwise healthy 210/95 — Adrenaline, 2426/51 Noradrenaline, 18 370/464 Metanephrine, 13.3/0.8 Normetanephrine, 35.5/3.6 CT: 5-cm haemorrhagic left adrenal mass MRI (2 weeks after presentation): subacute haemorrhage into area without any distinct adrenal mass 12-cm dumbbell-shaped mass 3-cm phaeochromo-cytoma, large organising blood clot and necrotic tissue * Values separated by a forward slash represent separate collections, with abnormal values in bold. Reference ranges: adrenaline, < 100 nmol/d; noradrenaline, < 680 nmol/d; metanephrine, < 2.1 μmol/d; normetanephrine, < 5.6 μmol/d; VMA (vanillylmandelic acid), < 40 nmol/d; dopamine, < 3.0 μmol/d. †CT = computed tomography; MIBG = 131I-metaiodobenzylguanidine scanning; MRI = magnetic resonance imaging. 2 Computed tomography image of the haemorrhagic left adrenal mass in Patient 5 3 Medications and conditions that may cause false positive results of biochemical tests for phaeochromocytoma Medication or condition Test(s) confounded Tricyclic antidepressants Urinary catecholamines and metanephrines, plasma free metanephrines Clozapine Urinary catecholamines and metanephrines Phenoxybenzamine Plasma free metanephrines Calcium channel blockers Plasma noradrenaline, urinary noradrenaline, urinary adrenaline β-adrenergic blockers Urinary catecholamines and metanephrines, plasma free metanephrines (minor effect) α1-adrenergic blockers Urinary noradrenaline Sympathomimetics Urinary catecholamines and metanephrines, plasma free metanephrines Buspirone Urinary metanephrines Major physical or psychological stress* Urinary catecholamines and metanephrines, plasma free metanephrines * Hypoglycaemia, hypoxia, hypovolaemia, stroke, surgery, myocardial infarction, heart failure, severe pain, depression, panic disorder, sleep apnoea.

Jane L Harding MB BS · Michael W Yeh MD · Leigh W Delbridge MD, FRACS · Stan B Sidhu MB BS, FRACS · Bruce G Robinson MD, FRACP

An 81-year-old woman was fitted with a single-chamber pacemaker for atrial fibrillation and symptomatic bradycardia (Microny SR 2425T, Pacesetter, Sylmar, Calif, USA; silicone lead 1402 T, Siemens, Sylmar, Calif, USA). Seven years later, she presented with fatigue and presyncope of 1 week’s duration. She had also noticed contractions of the pectoral muscles on the left side of the chest. An electrocardiogram (Box 1) showed evidence of ventricular undersensing and non-capture, and a chest x-ray (Box 2) revealed complete fracture of the pacemaker lead. The pacemaker was replaced, and a new lead implanted using the cephalic vein cutdown approach. The patient’s medical record indicated that, 8 months previously, when she developed a cough, a chest x-ray had been performed by her physician. At around the same time, a routine check of the function of her pacemaker indicated that it was functioning normally. Re-examination of the x-ray revealed signs of lead erosion (Box 3) which had gone unnoticed. Thus, despite significant damage to the lead, pacemaker function may be unaffected. Friction of the lead, most often against the clavicle and the first rib (known as subclavian crush) can damage the lead. The incidence of fracture of pacemaker leads is about 1.0%–2.5% and increases with the age of the lead.1 A way of avoiding this complication is to introduce the lead into the axillary or cephalic vein rather than via subclavian vein puncture.2,3 Routine chest x-rays should be performed to monitor the condition of pacemaker leads, especially where they cross the clavicle. We recommend an annual chest x-ray for pacemaker-dependent patients. This may identify lead damage that may not be apparent during a standard pacemaker check, and thus, potentially, avoid syncope or sudden death. 1 Electrocardiogram on admission showing pacing spikes with evidence of ventricular undersensing and non-capture 2 Chest x-ray on admission showing complete section of the pacemaker lead at the level of the clavicle 3 Chest x-ray performed 8 months before admission, showing evidence of lead damage that went unnoticed

Stephane L Noble MD · Haran Burri MD · Henri Sunthorn MD

We still have no national program for detecting this potentially lethal disorder In 1985, Brown and Goldstein were awarded the Nobel Prize in Physiology and Medicine for unravelling the regulation of cholesterol metabolism in man. A key feature of their work was the elucidation of the molecular mechanism for autosomal dominant familial hypercholesterolaemia (FH), a potentially lethal disorder caused by defective endocytosis of low-density lipoprotein (LDL) cholesterol by its receptor (LDLR).1 This, in turn, led to the development of “statin” drugs, which potently lower plasma LDL cholesterol and reduce coronary heart disease (CHD) mortality. But, 20 years later, what have we achieved in detecting and treating FH? FH is characterised by lifelong marked hypercholesterolaemia (LDL cholesterol > 5 mmol/L) that leads to tissue cholesterol deposition — in such forms as tendinous xanthomata (particularly involving the Achilles), corneal arcus and palpebral xanthomas — and greatly increased risk of fatal CHD.2 Unfortunately, most people with FH are at present undiagnosed or only diagnosed after their first coronary event. We estimate that, of the roughly 40 000 cases of FH in Australia, about 20% are diagnosed and less than 10% are being adequately treated. Atherosclerosis in FH begins in early childhood. Children with FH are known to have endothelial dysfunction (the earliest phase of atherosclerosis) and increased carotid intima media thickness (CIMT), both surrogate markers of cardiovascular disease.3,4 Carotid atherosclerosis in FH rapidly progresses during childhood, at a rate proportional to plasma LDL cholesterol levels.4 FH typically involves mutations in the LDLR gene, with homozygotes having a more severe phenotype that heterozygotes. To date, about 1000 mutations have been identified in the LDLR gene (www.ucl.ac.uk/fh), most being unique, which makes the search for an unknown mutation challenging and expensive. Although heterozygous FH affects about 1 in 500 people overall,2 it occurs much more frequently in some populations such as Afrikaners, Christian Lebanese and French Canadians2 because of “founder” effects that occur when a few members of a population migrate and start a new colony. FH can be caused by mutations in genes other than LDLR. A mutation in the apolipoprotein B gene (APOB) may result in a clinical and biochemical picture that is indistinguishable from classic FH, although cholesterol levels are generally not as elevated and tendon xanthomas are less common.5 An autosomal recessive form of FH has also been described.6 The clinical picture of this condition is similar to that of homozygous FH, although it is generally less severe and more variable, with greater responsiveness to therapy. Except in “founder” populations, homozygosity for any of these conditions is exceedingly rare (about 1/1 000 000 people), and, without special intervention, such as LDL aphaeresis and liver transplantation, is typically lethal at an early age. Early statin treatment in children with FH improves endothelial function.3 A recent 2-year randomised controlled trial of pravastatin treatment (40 mg daily) in 214 children aged 8–18 years with FH showed regression of carotid atherosclerosis with no adverse effects on growth, sexual maturation, hormone concentrations, or serum liver and muscle enzyme levels.7 Despite this, the long-term safety and efficacy of statin use in children with FH is yet to be established. The Atorvastatin versus Simvastatin on Atherosclerosis Progression trial compared the effect of “aggressive” lipid-lowering treatment in FH with “conventional” lipid-lowering therapy.8 Over 2 years, LDL cholesterol lowering by high-dose atorvastatin resulted in regression of CIMT, whereas reduction with conventional-dose simvastatin did not. Moreover, the change in CIMT was proportional to the reduction in LDL cholesterol. These results support the concept that intensive lowering of LDL cholesterol levels in patients with CHD is beneficial. Although heterozygous FH patients are responsive to statins, additional treatment in combination with statins (for example, statin plus cholestyramine) is often required to achieve the desired LDL-cholesterol-lowering target.9 Moreover, combination therapy often permits use of a lower statin dose, which can benefit patients in whom adverse effects have occurred. Ezetimibe, a new drug that specifically inhibits intestinal cholesterol absorption alone, can reduce plasma LDL cholesterol concentrations by about 18%. Used in combination with a statin, it can achieve a further 25% reduction in LDL cholesterol levels over statin alone, by reducing both cholesterol supply to the liver and cholesterol biosynthesis.10 The long-term effects of ezetimibe on FH cardiovascular morbidity and mortality are unknown. The most cost-effective strategy for finding subjects with FH is to screen close relatives of patients already diagnosed with FH. Screening involves measurement of plasma LDL cholesterol, combined with either a clinical examination and family history or molecular genetic testing.11 Children born to an affected parent have a one in two risk of inheriting FH, and should be screened, at least biochemically, after the age of 2–3 years, when a cholesterol-lowering diet can be safely implemented.12 It is important to appreciate that a normal lipid profile does not rule out heterozygosity for an FH-causing mutation, particularly in early childhood.13 International experience shows that a family screening program must incorporate ethically acceptable protocols for approaching and interacting with relatives, follow-up communication with family members and their health care practitioners, as well as access to genetic counselling services, if required. Despite all these advances, it remains a tragedy that after 20 years of burgeoning knowledge about FH and the parallel development of powerful cholesterol-lowering drugs, Australia does not have a national program for detecting the vast majority of patients with FH in our community, let alone diminishing their risk of CHD.

John R Burnett MD, PhD, FRCPA · David Ravine DM, FRACP, FRCPA · Frank M van Bockxmeer BSc(Hons), PhD · Gerald F Watts DSc, MD, FRACP

Scott Kinlay Director, Vascular Medicine and Endovascular Therapy, Veterans Affairs Medical Center and Brigham and Women’s Hospital, 75 Francis Street, Boston, MA 02115, USA. skinlayATpartners.org To the Editor: Wang and Hoy1 deserve much credit for highlighting yet again the poor state of health of Indigenous Australians. However, their conclusion that the Framingham equation underestimated risk and that better prediction equations are needed may miss the point. The Framingham equations work well in other populations if the aim is to rank groups of individuals into higher or lower risk categories. Box 4 in the article by Wang and Hoy shows that they do this pretty well across increasing age groups. Framingham equations fall down when they are used to estimate absolute risk in populations whose coronary heart disease (CHD) rates are different from those in the Framingham study. Some years ago, we showed that adjusting the Framingham risk estimates in line with the overall incidence of CHD in the population modestly improved their performance.2 This is all very nice, but is better risk estimation the solution? We don’t estimate risk in other high-risk groups (eg, patients with CHD), because all are at high risk and all need risk factor reduction. A brief look at the risk factor profile in Box 2 of Wang and Hoy’s article reveals an alarming picture of uncontrolled CHD risk factors in a relatively young population (average age, 33–36 years). Cigarette smoking, dyslipidaemia, diabetes and overweight prevail. Perhaps, rather than concentrating on quantifying the exact risk in such a high-risk population, we should look at the reasons for the high rates of risk factors. What motivates some Indigenous people to smoke more, be more overweight and have a higher incidence of dyslipidaemia and diabetes than other Australians?3,4 Do they feel disenfranchised when governments infer they are “dirty” by tying financial aid to face-washing?5 Do they have attractive employment opportunities? Do they have enough sense of control over their lives to reduce their need to indulge in cigarettes and other short-term pleasures? Are there adequate supplies of healthy foods that they like? These factors may differ, as some rural Abori-ginal communities have much lower rates of smoking, overweight and diabetes6 than others. Exploring these issues will aid preventive methods aimed at the whole community. In the meantime, I would suggest that the Framingham equation does rank members of this community — into modest, high, and very high risk (the average 45–54-year-old has a 20% risk of a CHD event over 10 years1). This may help guide the medical treatment of risk factors and the pursuit of the medical model of prevention while social changes dictated by Aboriginal communities take effect.

Scott Kinlay

In reply: We agree with Kinlay that it is important to prevent risk factors at the population level (a population strategy). However, there is also a need to properly identify high-risk individuals who require immediate medical intervention (a high-risk strategy) and to understand the full spectrum of factors that determine such risk. The primary focus of our study was to assess whether the widely used Framingham risk functions were applicable to Aboriginal people in remote communities. Our data show that the Framingham functions significantly underestimated the risk of coronary heart disease (CHD). 1 The high CHD risk in Aboriginal people cannot be fully explained by traditional risk factors. Some major risk factors such as abnormal total cholesterol level and obesity in the study population are actually not as prevalent as those in the general Australian population. 2 Evaluation of traditional risk factors and identification of novel factors in this population are useful for the development of intervention strat-egies. Novel factors such as infection, inflammation, albuminuria and low birthweight have been suggested as predictors of CHD risk in this population. 3,4 Kinlay suggests that Framingham functions should be used to predict CHD risk in Aboriginal people. We disagree. Guidelines for the management of Aboriginal people need to recognise the serious underestimation of risk that the Framingham formulas provide. We agree that some high-risk groups, such as patients with established CHD, do not need additional risk estimates. With our current knowledge, however, we can not say whether the whole Aboriginal community should be treated as a very high-risk population.

Zhiqiang Wang · Wendy E Hoy

Dx/Rx: valvular heart disease. Dennis A Tighe, Theo E Meyer, Gerard P Aurigemma. Boston: Jones and Bartlett, 2005 (xi + 175pp). ISBN 0 7637 2385 1 This well presented pocket manual is part of the Dx/Rx Cardiology series. Written by clinicians from the Division of Cardiovascular Medicine at the University of Massachusetts Medical School, USA, it succeeds in providing, to quote the editor, “a clinical, concise and practical resource…” with which to approach cardiac valve disorders. Their aetiology, pathophysiology, natural history, clinical presentation and physical examination are discussed, followed by the diagnostic evaluation required and the suggested therapy — whether medical, interventional or surgical. The text is presented in a bullet-point format, aided by tables and figures throughout. Pertinent references are provided at the end of each chapter. Unfortunately, however, there are no illustrations of the various valvular abnormalities, which would have been helpful. The manual is more relevant to an adult population, although providing a considerable amount of information on congenital abnormalities of the valves. Aortic and mitral valve disease is reviewed in great detail with particular attention given to acquired valvular disease, especially rheumatic fever. Attention is also given to the less common disorders affecting the tricuspid and pulmonary valves. There is an excellent chapter on prosthetic valves, describing the types used, their specific clinical findings and the details of their assessment and follow-up requirements. Details of anticoagulation for mechanical valves are provided, including a special reference to difficulties associated with pregnancy. Homografts and autografts are briefly described. Infective endocarditis is referred to, where appropriate, throughout the text. Although aimed at postgraduate students, the manual may be a helpful resource for the busy clinician, whether general physician or family practitioner, as well as the practising cardiologist, for whom there is detailed information available related to less commonly used investigations, such as Doppler echocardiography to determine valve orifice size. While one could take issue with specific comments or details provided, I do think this well written manual achieves its goal. It may prove invaluable in the consulting room and may also become a welcome guide for interns, residents and registrars working in busy hospital settings. Within its small size, it contains a considerable amount of up-to-date information, clearly and concisely presented. Samuel MenahemCardiologist Monash Medical Centre and Royal Children’s Hospital, Melbourne, VIC

Samuel Menahem

Dx/Rx: heart failure. Theo E Meyer, Dennis A Tighe. Boston: Jones and Bartlett, 2005 (ix + 100pp). ISBN 0 7637 2309 6 This 100-page monograph on the diagnosis and management of heart failure, authored by two clinicians from the University of Massachusetts Medical School, USA, strikes a very good balance between the theoretical and practical aspects of this condition. An extremely well written, compact manual, it covers all aspects of heart failure in five sections. An introduction that deals with definition, classification, risk factors, prevalence and prognosis is followed by sections on the pathophysiology, clinical presentation, assessment and management of heart failure. Throughout the book, excellent tables and diagrams complement the text. I found the section about assessment very informative and thought the part on management contained useful practical information about the roles of different pharmacological and non-pharmacological agents used in the treatment of heart failure. Important results from various health failure trials are incorporated in a practical fashion, although in a book of this small size they cannot be presented or discussed in detail. I would highly recommend this book to all doctors who deal with patients who have heart failure, and am looking forward to reading other books in the Dx/Rx Cardiology series. Jitendra K VohraCardiologist Royal Melbourne Hospital, Melbourne, VIC

Jitendra K Vohra

Demands for efficiency should not be met at the expense of equity Despite countless reports over decades about the health disadvantages of Indigenous Australians, attention has only recently been turned to remedying disparities in the provision and quality of health care. A report in this issue of the Journal by Coory and Walsh about access to coronary procedures (page 507)1 adds to a growing body of evidence that Indigenous Australians do not receive the same level of care as other Australians.2-4 How might clinicians be contributing inadvertently to this “treatment gap”? And how can they remedy it? The responsibility for reducing ethnic disparities rests primarily with the health care system and its providers. Clinical decisions are based on imperfect information. To each clinical encounter, doctors bring prior beliefs about the likely nature of the condition. These beliefs differ according to the patient’s age, sex, socioeconomic status and ethnicity. They influence diagnosis, investigations and treatment. With identical descriptions of pain, a doctor is more likely to diagnose cardiac ischaemia in an elderly, sedentary, obese man than in a young, active woman of normal weight. Such stereotyping is helpful — and, indeed, promotes efficient practice — when it is based on epidemiology, statistical likelihood and best evidence. However, when incorrect, inappropriate and often implicit beliefs about the behaviour or health of a particular group are applied to individuals, stereotyping can be harmful. Uncertainty increases with patients who speak a different language or belong to a different cultural group. This, in turn, can lead to unhelpful, even harmful stereotyping. The experience of an Aboriginal politician who recently underwent emergency surgery demonstrates this. “I have had problems with my stomach and my abdomen for years. They were saying it was a problem with my kidneys and now that I have had this surgery on my bowels, they have found out that my kidneys are perfect,” she said. “So when I have gone to doctors complaining about illness over many years, I suppose they have taken my genetic heritage as a Tiwi Islander and thought it was renal.”5 Delays in diagnosis and treatment caused by such stereotyping might be partly responsible for Indigenous Australians’ poorer health outcomes. In the United States, concerns about the quality of health care received by racial and ethnic minorities compared with white Americans prompted Congress to request an investigation by the Institute of Medicine (IOM). Their landmark report, Unequal treatment: confronting racial and ethnic disparities in health care, found convincing evidence that racial and ethnic disparities exist across a wide range of conditions and health services and are associated with poorer outcomes.6 The report made several recommendations relevant to Australia, including cross-cultural training, use of interpreter services, and training more health care providers from ethnic and racial minority backgrounds.6 However, this might not suffice. Doctors who treat black Americans are less likely than those who treat white Americans to be “board certified” (ie, fully qualified) specialists. They are also more likely to report difficulty in arranging access to consultants, diagnostic imaging, and non-emergency hospital admission.7 In other words, doctors who treat black patients have less power, fewer resources, and possibly less training than doctors who treat whites. Is this also true in Australia? The IOM report defined disparities as racial or ethnic differences in the quality of health care not due to clinical need, patient preference or appropriateness of intervention.6 In Australia, these three factors have repeatedly been suggested as reasons for the treatment gap. Coory and Walsh suggest that the prevalence and severity of comorbidities may have a major impact on lower rates of coronary procedures and make providers question the appropriateness of such interventions.1 They note that selection favours lower-risk patients. However, even after controlling for the presence of comorbidities, Indigenous Australians still had significantly fewer interventions. With respect to patient preference, some commentators have suggested that, because Aboriginal people treated for chronic kidney disease fare poorly, they prefer not to be treated,8 but this hypothesis is contradicted by growing community activism to secure dialysis services in remote areas.9,10 A crucial issue is the increasing conflict between “efficiency” and equity. With increasing demands on health services, doctors attempt to maximise efficient use of scarce resources. Based on the mantra of “evidence-based medicine”, doctors perform more selective procedures and strive for lower rates of complications. A recent editorial suggested that people who cannot stop smoking should be excluded from a range of therapeutic interventions because of their higher risk of postoperative complications.11 Similar exclusions could also be applied to other groups, such as obese people. While this approach might increase “efficiency”, applying such standard criteria would greatly reduce Indigenous Australians’ access to beneficial interventions. Perhaps a higher complication rate is acceptable in the overall context of Indigenous Australians’ relative need for health care. Recovery from postoperative complications might be preferable to death without surgery. The responsibility for reducing ethnic disparities rests primarily with the health care system and its providers. System-level changes are clearly required, such as adequate funding for primary care, an adequate Indigenous health workforce, and improvements in the interface between primary care and specialist services.1,6,12 Clinicians have a central role to play in advocating for such changes. Because patients should be part of the solution, the IOM report recommends the development of appropriate education for patients in areas such as when and how to access health care, and how to participate effectively in clinical decision-making.6 However, most patients, in particular Indigenous Australian patients, are relatively powerless compared with doctors and “the system”. In Australia, the political debate about Indigenous health and development is framed in terms of “mutual obligation”. If we clinicians and researchers are to fulfil our obligation, we must first understand how we might inadvertently be contributing to the problem and then take steps to bridge the treatment gap.

Joan Cunningham ScD · Alan Cass PhD, FRACP · Peter C Arnold BSc, MB BCh, BA

Objective: To compare rates of percutaneous coronary interventions (PCI) and bypass surgery after acute myocardial infarction (AMI) in Indigenous and non-Indigenous patients.Design: Cohort study of public-sector patients who were followed up for 1 year using administrative hospital data.Participants and setting: We followed up 14 683 public-sector patients admitted to Queensland hospitals for AMI between 1998 and 2002. Of these, 558 (3.8%) identified as Indigenous.Outcome measures: Rates of PCI and bypass surgery, adjusted for differences between the Indigenous and non-Indigenous cohorts according to age, sex, socioeconomic status, remote residence, hospital characteristics, and comorbidities.Results: The adjusted rate for PCI during the index admission was significantly lower by 39% (rate ratio [RR], 0.61; 95% CI, 0.38–0.98) among Indigenous versus non-Indigenous patients with AMI; the adjusted rate for subsequent PCI was significantly lower by 28% (RR, 0.72; 95% CI, 0.54–0.96). Adjusted rates for bypass surgery were similar in the two cohorts. For any coronary procedure (ie, PCI or bypass surgery), the adjusted rate was significantly lower by 22% (RR, 0.78; 95% CI, 0.64–0.94) among Indigenous patients with AMI. Diabetes, chronic renal failure, pneumonia, and chronic rheumatic fever were at least twice as common among Indigenous patients with AMI as in the rest of the cohort, and chronic bronchitis and emphysema and heart failure were at least 60% more common. If a patient had at least one comorbidity, then their probability of having a coronary procedure was reduced by 40%.Conclusions: There are likely to be several reasons for the lower rates of coronary procedures among Indigenous patients, but their high rates of comorbidities and the association of comorbidities with lower procedure rates was an important finding. As investment in primary care can reduce the prevalence and severity of comorbidities, we suggest that adequate primary health care is a prerequisite for effective specialist care.

Michael D Coory PhD, FAFPHM · Warren F Walsh FRACP, FACC

Patients with acute coronary syndromes represent a clinically diverse group and their care remains heterogeneous. These patients account for a significant burden of morbidity and mortality in Australia. Optimal patient outcomes depend on rapid diagnosis, accurate risk stratification and the effective implementation of proven therapies, as advocated by clinical guidelines. The challenge is in effectively applying evidence in clinical practice. Objectivity and standardised quantification of clinical practice are essential in understanding the evidence–practice gap. Observational registries are key to understanding the link between evidence-based medicine, clinical practice and patient outcome. Data elements for monitoring clinical management of patients with acute coronary syndromes have been adapted from internationally accepted definitions and incorporated into the National Health Data Dictionary, the national standard for health data definitions in Australia. Widespread use of these data elements will assist in the local development of “quality-of-care” initiatives and performance indicators, facilitate collaboration in cardiovascular outcomes research, and aid in the development of electronic data collection methods.

Derek P B Chew MB BS, MPH, FRACP · Roger M Allan MB BS, FRACP Chair · Constantine N Aroney MD, FRACP · Noella J Sheerin RN, BAppSc (HMvt)

They reduce rates of restenosis but not mortality or infarction — so are they worth it? The development of drug-eluting coronary stents has proven to be a quantum advance in interventional cardiology, rivalling the impact of stenting itself. Drug-eluting coronary stents deliver effective local concentrations of antiproliferative drugs (thus avoiding systemic toxicities), without substantially modifying the technique of percutaneous coronary intervention (PCI). Two of the drugs used are sirolimus and paclitaxel. Sirolimus is an inhibitor of the G1-phase of the cell cycle, while paclitaxel inhibits microtubule formation, both of which are necessary for cell division. Thus, they inhibit the natural healing mechanisms — endothelial cell migration and extracellular matrix formation — that produce intimal hyperplasia, resulting in restenosis. Randomised clinical trials of patients with stents that elute these agents have demonstrated reduced angiographic restenosis rates when compared with patients with bare-metal stents.1,2 These individual trials are supported by a recent meta-analysis of 11 randomised clinical trials involving 5103 patients; this showed that, in patients with drug-eluting stents (compared with those receiving bare-metal stents), there was a significant reduction in the proportion of patients requiring target lesion revascularisation (Box).3 Thus, within the context of randomised trials, and when all other things are equal, drug-eluting stents are clearly superior in preventing restenosis, which is the most significant late morbidity associated with coronary intervention. But, not all things are equal — these stents come at an approximately threefold increase in economic cost. As a consequence of this cost differential, the benefits of this new technology need to be considered critically. While the meta-analysis confirmed that drug-eluting stents decrease rates of restenosis and target lesion revascularisation,3 there was no evidence that they reduced deaths and myocardial infarction rates. However, given the nature of the innovation, this would not be expected. Furthermore, from the patient’s perspective, the impact of drug-eluting stents on the more relevant endpoint of “any” coronary revascularisation (as opposed to “target lesion” revascularisation) has not been highlighted and will be eroded by the development of de novo disease in other areas of the coronary vasculature.6 Among cardiologists and patients, this technology has been embraced with substantial enthusiasm. Drug-eluting stents are now being implanted in patients in subgroups and with lesion types beyond those evaluated by randomised trials.7 Some clinicians have also proposed that multi-vessel PCI using drug-eluting stents provides a comparable alternative to coronary artery bypass grafting.8 This preference is best illustrated by the disparate rates of drug-eluting stent implantation in the private and public sectors, estimated at > 75% and < 25%, respectively, reflecting the difference in who is paying for this technology. Several issues make it difficult to compare the cost-effectiveness of the two types of stents. First, without a benefit in terms of mortality, assessment of cost-effectiveness by cost-per-life-year saved is precluded. To circumvent this issue, a published cost-effectiveness analysis from the SIRIUS trial of sirolimus-eluting stents in elective PCI used quality-adjusted life-year (QALY) data drawn from a trial of bare-metal stenting for reperfusion therapy after myocardial infarction.4 Whether these QALY data are applicable to the patients in the SIRIUS trial, and to Australian patients, is uncertain. Given the potential lack of generalisability of clinical trial data to clinical practice, the use of QALY data from patients treated within a different clinical context may lead to a cost-effectiveness extrapolation not relevant to our local context. The time has come for the Australian cardiology community to develop national systems that routinely assess the long-term clinical outcomes of all patients undergoing PCI and coronary artery bypass grafting. Such data should yield several benefits. First, actual local data on effectiveness are essential for locally relevant cost-effectiveness estimates. Second, data on specific patient and lesion subsets inadequately studied in randomised trials will allow us to apply this innovation to patients most likely to benefit from it.9 Such data are vital to the rational development of practice guidelines and reimbursement strategies for optimal patient outcomes and health care expenditure. Third, as with any emerging therapy or technology, routine evaluation of long-term safety remains a priority; this has been highlighted by the recent report of very late stent thrombosis associated with drug-eluting stents.10 Routine systems of evaluation would provide an effective infrastructure for surveillance of unexpected adverse events occurring after a new technology has been approved, and would be less reliant on physicians for recognition and reporting. Problems relating to the costs of data collection and the difficulties of risk adjustment remain to be solved before nationwide registries can be implemented. However, the clinical and economic consequences of inappropriate application of this and other technologies would exceed these costs, potentially by orders of magnitude. The resource burden associated with assessing implementation of a new technology should not be used as an argument against its conduct, but rather should encourage the incorporation of this activity into routine clinical practice and funding. It has been argued that, with time, the cost of drug-eluting stents will fall, clinical experience will grow, and the application of this technology to clinical practice will be optimised.11 Over the past 10 years, the cost of bare-metal stents has declined by approximately 60%. Yet, interventional practice remains heterogeneous, and outcomes remain uncertain. Registries designed to assess practice, outcomes and cost will offer essential objective data to inform rational choices — until the time when all things become equal. Summary of evidence related to drug-eluting stents A Bayesian meta-analysis* of 11 randomised controlled trials comparing drug-eluting stents with bare-metal stenting3 showed the former had: — No effect on mortality rates (odds ratio, 1.11; 95% credible interval*, 0.61–2.06)3 — No effect on rates of myocardial infarction (odds ratio, 0.92; 95% credible interval*, 0.66–1.25)3 — Substantially lower rates of target lesion revascularisation (odds ratio, 0.26; 95% credible interval*, 0.14–0.45)3 — Fewer major adverse cardiac events when death, myocardial infarction, and target vessel revascularisation are combined (odds ratio, 0.42; 95% credible interval*, 0.32–0.53)3 In a randomised comparison of sirolimus-eluting versus bare-metal stents in elective percutaneous coronary intervention, the incremental cost-effectiveness ratio was estimated to be US$27 540 per quality-adjusted life-year gained.4 This reflects the money that needs to be spent to gain a benefit of one quality-adjusted life-year with this technology. Up to 50% of patients undergoing percutaneous coronary intervention have characteristics that would have led to their exclusion from clinical trials of drug-eluting stents in the US Dynamic Registry, a comprehensive angioplasty registry sponsored by the National Heart, Lung and Blood Institute.5 * In a Bayesian meta-analysis, “credible interval” corresponds to confidence interval.

Derek PB Chew MB BS, MPH, FRACP

Objective: To identify variation in the rates of use of key evidence-based therapies and in clinical outcomes among patients hospitalised with acute coronary syndromes (ACS).Design: Retrospective analysis of data on care processes and clinical outcomes of representative patient samples recorded by the Queensland Health Cardiac Collaborative registry.Setting: 18 public hospitals (3 tertiary, 15 non-tertiary) in Queensland, August 2001 to December 2003.Study population: 2156 patients who died or were discharged after troponin-positive ACS.Main outcome measures: Comparison of proportions of highly eligible patients receiving indicated care and in-hospital mortality between subgroups categorised by age, sex, comorbidities (diabetes, renal failure, chronic obstructive pulmonary disease and mental disorder), type of admitting hospital (tertiary or non-tertiary), and cardiologist involvement (transfer or non-transfer to cardiology unit).Results: Patients aged ≥ 65 years were less likely than younger patients to receive heparin (79% v 87%), β-blockers (79% v 87%), lipid-lowering agents (78% v 87%), coronary angiography (51% v 66%), and referral to cardiac rehabilitation (17% v 33%). Patients with diabetes were less likely than others to receive coronary angiography (50% v 63%), while those with moderate to severe renal failure were less likely to receive thrombolysis (52% v 84%), heparin (71% v 83%), β-blockers (69% v 84%), lipid-lowering agents (61% v 84%), in-hospital cardiac counselling (46% v 64%) and referral to cardiac rehabilitation (9% v 25%). Patients admitted to tertiary hospitals were more likely than those admitted to non-tertiary hospitals to receive coronary angiography (85% v 55%) and referral to cardiac rehabilitation (36% v 21%). Risk-adjusted mortality was highest in patients with moderate to severe renal failure (15% v 3%) and older patients (6% v 2%).Conclusions: Variations exist in the provision of indicated care to patients with ACS according to age, diabetic status, renal function and type of admitting hospital. Excess mortality in elderly patients and in those with advanced renal disease may be partially attributable to failure to use key therapies.

Ian A Scott FRACP, MHA, MEd · Mark A Jones BSc(Hons) · Andy B Duke · Irene C Darwin BSpThy, GradCertManagement · Kathy H Harvey GradCertManagement

Objectives: To determine population-based rates and outcomes of hypertensive disorders in pregnancy.Design: Cross-sectional study using linked population databases.Setting and participants: All women, and their babies, discharged from hospital following birth in New South Wales, between 1 January 2000 and 31 December 2002.Main outcome measures: Rates of hypertensive disorders in pregnancy, maternal and infant morbidity and mortality, and level of hospital care for the birth admission.Results: 250 173 women and their 255 931 infants were included in the study. Overall, 24 517 women (9.8%) had a hypertensive disorder in pregnancy, including 1411 (0.6%) with chronic hypertension, 10 379 (4.2%) with pre-eclampsia, 731 (0.3%) with chronic hypertension with superimposed pre-eclampsia, and 10 864 (4.3%) with gestational hypertension. Women with, and infants exposed to, hypertension were more likely to suffer death or major morbidity than those without hypertension. Infants of mothers with hypertension were more likely to be to born preterm and small for gestational age. Just over half the women with major morbidity or mortality delivered in hospitals with a high level of medical care. In contrast, most infants with major morbidity or mortality were delivered in hospitals with neonatal intensive care units.Conclusions: Hypertension is a common complication of pregnancy, and adverse outcomes are increased among hypertensive women and their babies. Clinicians appear to be better at identifying and seeking an appropriate level of care for pregnancies where the infant is at risk of a poor outcome than when the mother is at risk. More specific antenatal indicators of poor maternal outcome would help guide the referral of hypertensive women to higher levels of care.

Christine L Roberts MB BS, DrPH · Jane B Ford BA(Hons), PhD · David J Henderson-Smart FRACP, PhD · Charles S Algert BSc, MPH · Jonathan M Morris FRANZCOG, PhD

A 58-year-old man of British descent presented in 2003 with chest pain, facial flushing and elevated jugular venous pressure but no leg oedema. He had been exposed to tuberculosis in childhood, had a strongly positive tuberculin test and had been followed up in the tuberculosis surveillance program with regular chest x-rays, but had never been diagnosed with tuberculosis. Chest x-ray on presentation showed calcified plaques and masses in the pericardium and mediastinum (Box 1). Computed tomography revealed extensive calcification of the pericardium (Box 2). Coronary angiography showed 70% stenosis in the left anterior descending artery. Cardiac catheterisation showed equalisation of diastolic pressures in all four chambers, with a positive square root sign (pattern of ventricular diastolic pressure characteristic of constrictive pericarditis). Pericardiectomy with left internal mammary bypass graft to the left anterior descending artery was performed. Severe constrictive pericarditis with a thick (up to 4 mm) layer of calcium plaque was found. Two large cystic masses within a thick calcified shell were present in the posterolateral aspect of the right side of the heart and the left posterior atrioventricular groove. Both contained creamy caseous material, which was drained (Box 3). Histopathological examination was consistent with chronic calcific pericarditis with no granuloma. Microbiological examination and culture did not show any organisms. The patient was treated with a 6-month regimen for Mycobacterium tuberculosis based on his known previous exposure to tuberculosis, strongly positive tuberculin test, and the operative and pathological findings. Corticosteroid therapy, which is sometimes recommended in the treatment of tuberculosis,1,2 was not considered as the patient did not have effusive pericarditis or active tuberculosis. At 12-month follow-up, he was fully active, without angina or shortness of breath. In Australia, the annual incidence of tuberculosis is 5–6 cases per 100 000.3,4 Tuberculous pericarditis is seen in 1%–2% of all cases of pulmonary tuberculosis.5 Extensive tuberculous pericarditis is rare in Anglo–Celtic populations. 1 Chest x-ray showing calcified mass along the diaphragmatic surface of heart (A) and calcified pericardium (B). 2 Pre-operative computed tomography scan showing large calcified masses (5 cm × 4 cm) in the left posterior atrioventricular groove (A) and right atrioventricular groove posterior to the tricuspid annulus (B), with calcification throughout. 3 Intraoperative photograph showing the opened large cystic mass posterior to the right atrioventricular groove, with caseous contents (arrow).

Shiromani Goyal M Ch · Kang-Teng Lim MB BS · Cheng-Hon Yap MB BS · Elizabeth W Ryan FRACP · Morteza Mohajeri FRACS

Alexandra A Bennett,* Jo-anne E Brien,† Peter S Macdonald‡ * PhD Candidate, † Professor of Clinical Pharmacy, University of Sydney, Sydney, NSW (address for correspondence: Therapeutics Centre, St Vincent's Hospital, Darlinghurst, NSW 2010); ‡ Associate Professor of Medicine, and Cardiologist, St Vincent's Hospital, Sydney, NSW. sashabATpharm.usyd.edu.au To the Editor: We wish to add our perspective to the article by Phillips et al. 1 Needs identified by GPs included education about the effectiveness and target dosing of angiotensin-converting enzyme (ACE) inhibitors and β-blockers, and improved communication. We wish to highlight the potential roles hospital and community pharmacists have in supporting GPs caring for patients with heart failure. It is expected that by 2010 there will be at least 25 patients with heart failure per GP and 100 per community pharmacy in Australia. A recent review of 100 patients with heart failure discharged from St Vincent’s Hospital (SVH) in New South Wales showed they were taking an average of 9.5 regular medications, two-thirds of which were cardiac medications. 2 Their average age was 70.5 years. They had an average of 7.3 diagnoses, including ischaemic heart disease, atrial fibrillation and osteoarthritis. They were commonly taking amiodarone, warfarin and digoxin. Six per cent of patients had taken cyclooxygenase-2 (COX-2) inhibitors before they were admitted to hospital. 2 While rates of ACE inhibitor (or angiotensin-II-receptor antagonist) and β-blocker use at discharge were high in patients with systolic dysfunction (84% and 65%, respectively), only a minority of patients were taking target doses (27% and 15%, respectively). This highlights the need for good communication between healthcare providers. Discharge letters are often illegible and do not necessarily prioritise issues or detail future management, such as stating whose responsibility it is to up-titrate the dose of ACE inhibitor or β-blocker. Electronic entry of medical information, including e-prescribing (currently being trialled in some hospitals), may assist. Some patients have typed medication cards from a pharmacist on discharge. However, this is not routine practice. Ideally, all patients should receive such cards with supporting information. Copies of this information should be provided for the GP and pharmacist. Such a system would support Australian Pharmaceutical Advisory Council guidelines for continuity of care. Since 2002, a pharmacist has consulted with patients in the SVH Heart Failure Clinic regarding medication and lifestyle issues. Problems identified are referred to the treating cardiologist. A pilot study of this service showed high patient satisfaction (T Hargraves, Pharmacist, St Vincent’s Hospital, personal communication). Such a service could also be provided by community pharmacists, perhaps linked to home medicines review. A pharmacist is also employed by the community multidisciplinary heart failure service based at SVH. These positions support patients and their carers as well as healthcare providers, including GPs, community and hospital pharmacists and nurses. Evidence for such roles for pharmacists is supported by US and UK data. 3 We propose that designs for future models of care for patients with heart failure should incorporate pharmacists.

Alexandra A Bennett · Jo-anne E Brien · Peter S Macdonald

Congenital heart disease is often regarded as a chance occurrence affecting only a small number of children. In fact, it affects nearly 1 in 100 newborn infants1,2 and is the leading non-infectious cause of death in this age group. A third of those affected will need surgical or catheter-based intervention in the first year of life. In 2002, congenital heart disease accounted for 224 deaths in Australian children.2 In the United States there are more than 35 000 new cases each year and over 1 million survivors of congenital heart disease in the community.3 Studies of gene expression in animal models have provided a window into how the human heart is constructed . . . Diagnosis and treatment of congenital heart disease has improved dramatically over the past 15 years. The mortality rate for surgical repair of some common conditions, such as tetralogy of Fallot, is currently less than 3%,4 and innovative catheter-based therapies, including closure of certain septal defects, have been developed. Preservation of ventricular function, avoidance of repeat surgery and freedom from arrhythmias are the next goals to be achieved. The first question affected families usually ask is: “What is the risk of having an affected offspring or another affected sibling?”. Population studies suggest that the risk is relatively small (2%, or double the background risk). The reason the risk is relatively modest may be that most congenital heart disease is the result of multiple gene defects and/or an interaction between single or multiple defective genes and the fetal environment. As the genotype and experience of each individual is unique, the occurrence of congenital heart disease in most individuals will not be in the context of a strong familial trait. However, there are many rare examples of families in which congenital heart disease is strongly inherited, and apparently caused by single-gene defects. Even in these families, cardiologic phenotypes can vary enormously, presumably because of the effects of modifier genes and/or influences other than genetic. Such families, if large enough, can be studied using classical genetic techniques (such as linkage analysis), but so far only a small number of clinical cases can be matched to a specific mutation. Thus, family genetic studies are currently not indicated for isolated, non-syndromal cases of congenital heart disease. With the advent of high-throughput genetic screening technology and improved cost benefit, indications for screening may be extended in the future. Recently, cardiac developmental and molecular biologists and geneticists have started to unravel the molecular circuitry underpinning heart formation. Significant progress has come about partly because we can now dissect the morphological and genetic basis of human congenital heart disease in animal models from zebra fish to mice. Aspects of cardiac development are, in fact, highly conserved through evolution, and many of the regulators that transform embryonic mesoderm to myocardium are similar across species. One example is the cardiac regulatory gene NKX2.5, which was first isolated because of its similarity to a gene present in the fruit fly, a laboratory model for genetic studies. The developmental approach has defined a number of key cardiac regulatory genes subsequently found by conventional linkage studies to underpin familial congenital heart disease.5 Mutations in NKX2.5 itself cause atrial septal defect and conduction abnormalities, while TBX5 mutations underpin heart and hand malformations of the Holt–Oram syndrome, and mutations in GATA4 cause atrial septal defect and more complex congenital heart disease. In clear cases of familial inheritance, genetic screening for mutations in these genes may be beneficial. Studies of gene expression in animal models have provided a window into how the human heart is constructed, and recent insights have led to a revision of traditional concepts of how cardiac chambers and valves develop. The heart begins as a rudimentary vascular tube,6 which, cardiologists are taught, is composed of anatomical segments that develop into chambers. Yet mapping of the cardiac precursor cell populations in the embryo has revealed a more complex picture. Gene expression patterns now show us that chambers arise from discrete zones, not segments, and that non-chamber myocardium gives rise to the central conduction system.7,8 Another significant advance is the discovery of a second distinct pool of cardiac precursor cells in the embryo that migrate into the forming heart tube from the region of the developing pharyngeal arches. These cells, the so-called “secondary heart field”, contribute importantly to the right ventricle, outflow tracts and atria.9 Characterisation of the secondary heart field has unified genetic, developmental and clinical observations in congenital heart disease. Abnormal development and/or deployment of the secondary heart field cells causes underdevelopment and malpositioning of the outflow tracts over the ventricles. This occurs in velocardiofacial syndrome (VCFS, incorporating DiGeorge syndrome), which is caused by microdeletions in chromosome 22q11.10 The TBX1 transcription factor gene is expressed in the secondary heart field and is deleted in VCFS. Its loss in mice has been causally related to abnormalities of the outflow tract that can arise in VCFS. One such abnormality is tetralogy of Fallot, in which unequal partitioning of the rudimentary outflow vessel produces a large aorta and a right ventricular outflow tract obstruction, with subsequent complications. Malalignment of the outflow vessels over the interventricular septum causes a large ventricular septal defect. Although fewer than a third of cases of tetralogy of Fallot are associated with the 22q11 microdeletion, single-gene mutations may prove to be a significant cause. In the case of interrupted aortic arch type B and truncus arteriosus, however, more than 50% of cases are associated with the 22q11 microdeletion. Recent developments in genome-wide screening technology have the power to detect microdeletions in individual patients on an unprecedented scale. This may revolutionise the detection of congenital heart disease genes. Pathological circumstances also provide deep insights into development. In the fetus, even simple primary structural disease (eg, a pulmonary valve that fails to develop) can cause complex secondary disorders as a result of disturbed blood-flow patterns. In heart development, function (flow) dictates form, and loss of normal blood-flow patterns can contribute to underdevelopment of chambers. In these circumstances, it is often difficult to predict from primary lesions the extent to which abnormal development and remodelling will occur as the fetus grows — this is one of the challenges of fetal echocardiography. Now, surgical correction during fetal life, long taboo, is being explored experimentally for valve correction,11 as this would allow more time for normal ventricular development. While only a small proportion of congenital heart lesions currently have identifiable gene markers, the number is growing rapidly. The next decade of research into congenital heart disease will see an exciting convergence of the disciplines of developmental biology, genetics and paediatric cardiology, and, we hope, will not only go further towards answering the question “Why did this happen to us?”, but also provide more secure grounds for genetic counselling and intervention.

David S Winlaw MB BS, MD, FRACS · Gary F Sholler MB BS, FRACP · Richard P Harvey PhD

Objective: To determine the extent to which the Framingham function predicts the risk of coronary heart disease (CHD) in Aboriginal people.Design and setting: Cohort study in an Aboriginal community in the Northern Territory.Participants: 687 Aboriginal people aged 20–74 years were followed up from a baseline examination in 1992–1995 through to 31 December 2003.Main outcome measure: First CHD events were identified through hospital and death records during the follow-up period.Methods: An original Framingham function was used to predict CHD risk according to the duration of follow-up and the values of traditional risk factors, which included age, sex, total cholesterol level, high-density lipoprotein (HDL) cholesterol level, blood pressure, the presence of diabetes, and smoking status. The predicted CHD incidence using the Framingham function was 4.4 per 1000 person-years, while the observed incidence was 11.0 (95% CI, 8.7–13.9) per 1000 person-years. The observed number of CHD events (68) was 2.5 times the number predicted (27) using the Framingham function. The observed incidence was about four and three times the predicted incidence for age groups < 35 and 35–44 years, respectively, and about twice the predicted incidence for those over 45 years of age. The Framingham function was a particularly unreliable predictor for women, especially younger women, in whom the observed CHD rate was 30 times the predicted rate.Conclusions: The Framingham function substantially underestimates the actual risk of CHD observed in Aboriginal people in a remote community, especially for women and younger adults. This implies that traditional risk factors have different degrees of impact and/or that other factors are contributing to risk. A population-specific risk function is needed.

Zhiqiang Wang PhD, MSc, MB · Wendy E Hoy MB BS, BScMed, FRACP

Given fundamental differences in the recommendations in guidelines from major national and international committees, we cannot rely on them unquestioningly. Different antihypertensive agents are known to have differing effects according to age and race. Exchanging (rather than following guideline recommendations of adding to) an ineffective first-line antihypertensive drug can result in control of hypertension with monotherapy. Conclusions about a preferable first-line antihypertensive agent are limited by trial protocols with varying drug doses and questionable drug combinations. Guidelines are often based on meta-analyses of drugs of a particular class, which could ignore important differences between drugs within a class. Trials of 3–5 years cannot determine the long-term effects of drugs which patients often take for decades.

Roger E Peverill PhD, FRACP

We report two elderly women who presented with hypertensive crisis and acute pulmonary oedema, which responded poorly to antihypertensive therapy. The patients were later diagnosed as having hepatitis C virus-related cryoglobulinaemia. Acute pulmonary oedema is a well-known complication of severe hypertension,1 but, to our knowledge, has never been reported in association with mixed cryoglobulinaemia. We report two patients with severe hypertension who presented with pulmonary oedema which was not controlled until cryoglobulinaemia was diagnosed and treated with plasmapheresis and methylprednisolone. Clinical recordsPatient 1Presentation: A 66-year-old woman presented to our emergency department in late February (winter) with severe dyspnoea of 2 hours’ duration. She had a 10-year history of hypertension, and had had a stroke 3 months before, but had recovered. Over the previous month, her blood pressure had been over 210/120 mmHg, and she had intermittent dyspnoea, orthopnoea and leg oedema. On examination, she was orthopnoeic, with blood pressure of 218/124 mmHg, regular pulse of 126 bpm, and respiratory rate of 36 breaths per minute. She had engorged jugular veins, bilateral chest crackles, hyperpigmentation of the legs and marked bipedal pitting oedema. A chest radiograph showed diffuse haziness over both lungs. Electrocardiography (ECG) showed inverted T waves in leads V4 to V6. Oxygen saturation was 77% while breathing 100% O2 (reference range [RR], 95%–100%). Initial management: The patient was intubated and mechanically ventilated. Her central venous pressure was 13 cmH2O (RR, 3–11 cmH2O), and pulmonary wedge pressure was 19 mmHg (RR, 6–12mmHg). She was treated with intravenous glyceryl trinitrate and diuretics, but over the next 48 hours her blood pressure fluctuated between 300/130 mmHg and 200/90 mmHg, and pulmonary oedema persisted. After 2 days, the patient was extubated. Over the next 24 hours, she developed massive bilateral pleural effusions and numerous petechiae over the legs. Echocardiography revealed a normal left ventricular (LV) ejection fraction (72%) and diastolic dysfunction. Radionuclide angiography confirmed these findings. Laboratory tests showed hypoalbuminaemia, proteinuria (daily protein loss, 9.3 g), haematuria with granular casts, impaired renal function, anaemia and thrombocytopenia (Box 1). Nephrotic syndrome was diagnosed. Further tests revealed a decreased serum concentration of complement components C3 and particularly C4, and markedly raised concentration of rheumatoid factor. However, tests were negative for antinuclear (ANA), anti-double-strand-DNA (anti-ds-DNA), antiglomerulo-basement-membrane and antineutrophil-cytoplasmic antibodies. A cryoglobulin test was positive (Box 2). Immunofixation electrophoresis of the cryoprecipitates showed monoclonal IgM/kappa and polyclonal IgG. A test for hepatitis C virus antibodies (anti-HCV) was then performed and was positive. Diagnosis: On Day 27 of admission, the patient was diagnosed with type II mixed cryoglobulinaemia associated with HCV infection. At that time, her blood pressure was still fluctuating between 230/130 mmHg and 180/100 mmHg, and pulmonary oedema and massive pleural effusions persisted, despite vigorous antihypertensive therapy with frusemide, intravenous glyceryl trinitrate, an α-adrenergic blocker and angiotensin-converting enzyme inhibitors. Repeated thoracocentesis was required to release massive effusions (initially transudative, but later haemorrhagic). Renal biopsy revealed diffuse glomerulonephritis with crescent formation. Management: Plasmapheresis was started on Day 27, along with pulse therapy of intravenous methylprednisolone (500 mg daily for 3 days). After five courses of plasmapheresis in 12 days, the hypertension and pulmonary oedema were controlled. The patient was discharged from hospital on Day 57 of admission. At discharge, serum creatinine level was 141 μmol/L (reference range [RR], 53–106 μmol/L), and she was taking prednisolone (25 mg), diltiazem (180 mg), spironolactone (75 mg) and doxazosin (8 mg) per day. Patient 2Presentation: In February, 2 years after Patient 1, a 77-year-old woman presented to our emergency department with a 1-day history of severe dyspnoea and orthopnoea. She had had hypertension for 3 years. On several occasions during the previous month, her blood pressure had risen to 200/120 mmHg. On examination, she was stuporous, with blood pressure of 200/110 mmHg, regular pulse of 112 bpm, and respiratory rate of 36 breaths per minute. She had engorged jugular veins, bilateral chest crackles, hepatomegaly, ascites and bipedal oedema. A chest radiograph showed bilateral diffuse haziness, and ECG showed a generalised low QRS complex. Blood gas analysis showed pH, 7.43 (RR, 7.35–7.45); Paco2, 3.9 kPa (RR, 4.7–5.3 kPa) and Pao2, 11.2 kPa (RR, 12.7–13.3 kPa) while breathing oxygen through a mask. Initial management: The patient was intubated and mechanically ventilated. Central venous pressure was 12 cmH2O. Echocardiography revealed concentric LV hypertrophy, normal LV ejection fraction, but impaired LV diastolic function. Blood pressure fell to 170–200/90–100 mmHg in 2 days, after diuretic and nitroprusside therapy, but pulmonary oedema and respiratory failure did not decrease, even after haemodialysis. She had massive ascites, bilateral pleural effusions, hypoalbuminaemia, proteinuria (daily protein loss, 3.5 g), haematuria, poor renal function, anaemia and thrombocytopenia (Box 1). Nephrotic syndrome was diagnosed. Levels of both C3 and C4 were markedly low. ANA and anti-ds-DNA antibodies were negative, but rheumatoid-factor titre was markedly high. Cryoglobulin tests on Days 14 and 16 of admission were positive. Immunofixation electrophoresis of serum cryoprecipitates showed polyclonal IgG. HCV tests were negative for anti-HCV antibody but positive for serum HCV RNA. Diagnosis: The diagnosis of type III mixed cryoglobulinaemia associated with HCV infection was thus established on Day 16 of admission. At that time, the patient was still being mechanically ventilated and needed repeated thoracocentesis (effusions were initially yellow, but later became haemorrhagic). Computed tomography of the head showed multiple ischaemic infarcts. Management: Plasmapheresis and methylprednisolone pulse therapy (1 g intravenously daily for 3 days) were started on Day 17 of admission. The patient was extubated the next day and discharged from hospital 2 weeks later, after two courses of plasmapheresis. Serum creatinine level at discharge was 291.5 μmol/L. DiscussionHypertensive crisis with rapid-onset pulmonary oedema has been associated with coronary artery disease,2 renal artery stenosis3,4 and phaeochromocytoma,5 but a search of English-language articles in PubMed revealed no previous reports of an association with mixed cryoglobulinaemia. The latter is characterised by the presence of cold-precipitable cryoglobulins in serum. Underlying diseases include autoimmune and infectious diseases, especially hepatitis C.6-9 “Mixed” indicates that the cryoglobulins in these patients contain either monoclonal plus polyclonal immunoglobulins (type II cryoglobulinaemia), or polyclonal immunoglobulins (type III cryoglobulinaemia).7 In hepatitis C, cryoglobulins usually contain anti-HCV antibody, HCV RNA and IgM rheumatoid factor (ie, anti-IgG autoantibody).9 Cryoglobulins often trigger the formation of immune complexes, leading to immune-complex-type vasculitis, and produce cutaneous, vasomotor, renal and neurological symptoms.7-9 In our patients, factors precipitating the acute pulmonary oedema included hypertensive crisis, renal insufficiency and probably coronary insufficiency. The hypertensive crisis and pulmonary oedema had abrupt onset, progressed rapidly to respiratory failure, were accompanied by nephrotic syndrome, and responded poorly to antihypertensive and diuretic therapy. Our patients had had moderate hypertension for 3–10 years before their blood pressure suddenly rose markedly 2 to 3 months before the development of pulmonary oedema. Hypertension has been found in 37% of patients with cryoglobulinaemia.6 When the underlying disease of cryoglobulinaemia (eg, hepatitis C) flares up, levels of cryoglobulins (which contain HCV-RNA) increase, resulting in higher levels of circulating immune complexes, acute vasculitis and raised blood viscosity. These factors all precipitate the abrupt rise in blood pressure and pulmonary oedema, and explain the failure of conventional antihypertensive agents. Treating cryoglobulinaemia in our patients decreased renal vasculitis and ischaemia, fluid overload, and ultimately hypertension and pulmonary oedema. Coronary vasculitis, found at autopsy in 22% of patients with mixed cryoglobulinaemia,6 could contribute to pulmonary oedema. However, both our patients had a normal LV ejection fraction, suggesting that neither had significant coronary vasculitis. In both patients, acute pulmonary oedema developed in winter. Whether cold weather worsens hypertension by precipitating more cryoglobulins and increasing viscosity awaits further observation. In our patients, the initial features that led to the suspicion of vasculitis were petechiae, proteinuria and haematuria. Further testing revealed decreased complement levels (especially C4). These and other manifestations, including oedema, ascites, recurrent pleural effusions, cerebral infarction and glomerulonephritis, were caused by circulating cold-precipitable immune complexes and resulting vasculitis.6-9 Chronic HCV infection stimulates B-cell clones to proliferate and produce cryoprecipitable IgM antibody with rheumatoid-factor activity10 — an important laboratory index of HCV-related mixed cryoglobulinaemia. However, Patient 2 was negative for anti-HCV antibody, possibly because the sensitivity of the anti-HCV immunoassay, although high, is still suboptimal,11 or because the anti-HCV antibodies were concentrated in cryoprecipitates, and therefore not detectable by the serum assay.7 In both patients, the refractory hypertension and pulmonary oedema responded to plasmapheresis and methylprednisolone therapy. Conventional treatment of mixed cryoglobulinaemia aims to reduce circulating immune complexes through immunosuppression and plasmapheresis.8 Although immunosuppressive therapy alone could ameliorate vasculitis,12 plasmapheresis has shown hypotensive effect in immune-complex nephritis, including mixed cryoglobulinaemia.13 It also reduces plasma viscosity and improves perfusion of the affected organs,14 thus helping in patients with hypertension, encephalopathy or severe renal impairment. Neither patient had a history of blood transfusion, surgery, intravenous drug use or tattooing. They probably acquired HCV infection through non-sterile injections or acupuncture in local clinics, the most common source of HCV infection in Taiwan.15,16 With the increasing prevalence of hepatitis C,17 knowledge of its extrahepatic manifestations is important. Our two patients illustrate the association with mixed cryoglobulinaemia presenting with hypertensive crisis and acute pulmonary oedema. 1 Blood test results before diagnosis of cryoglobulinaemia Test Patient 1 Patient 2 Reference range Serum albumin (g/L) 24 24 32–45 Serum urea nitrogen (mmol/L) 13.9 36.8 2.9–8.2 Serum creatinine (μmol/L) 230 412 53–106 Haemoglobin (g/L) 59 98 120–160 Platelet count (× 109/L) 105 69 150–450 Complement 3 (g/L) 0.62 0.30 0.79–1.19 Complement 4 (g/L) 0.02 0.07 0.17–0.37 Rheumatoid factor 1:10 240 > 1:20 480 < 1:40 2 Cryoglobulin test Cryoglobulin particles float in the serum and precipitate at the bottom of the test tube at 4°C. The particles dissolve on rewarming of serum to body temperature.

Li-Na Lee MD, PhD · Shyh-Chyi Lo MD · Fu-Chi Lin BS · Hon-Ping Lau MD · Jih-Shuin Jerng MD · Pan-Chyr Yang MD, PhD

Is there something wrong with the way CPR is presently practised? “That doctor — he should be sacked!” An elderly gentleman was talking about me, and he was doing it on the local television news! My crime was to make the observation in a letter to the MJA that “. . . regular involvement in cardiopulmonary resuscitation (CPR) makes me wish the technique had never been introduced.”1 I had waved a red rag in front of bulls. To disparage CPR creates fury in those who, professionally or otherwise, see it as the reason for their existence. My wife had warned me that I would be painted as the bad guy, and, when this happened, my daughter asked cheerfully, “Is Daddy going to be like Pauline Hanson?”. My first inkling of the coming storm was on the Monday the Journal appeared. A Perth radio personality wanted to interview me. I was not told that, immediately before me, he would be interviewing the head of St John’s Ambulance in Western Australia. “Doctors Give CPR Shock Treatment” was the headline in The Australian. A flurry of phone calls from journalists followed. The local paper picked up the story, and over the next few days a local general practitioner, the local ambulance chief, a surf-lifesaving identity and an editorial in the paper all attacked my purported position. I had several conversations with the medical superintendent of the hospital where I was working: I was free to express an opinion in the MJA, and I was not being reprimanded — as some in the media wished. But, he indicated that he was going to publicly distance the hospital from my remarks, and reaffirm hospital policy — to commence CPR in an emergency whenever a person has stopped breathing or has no pulse. (I am grateful to this medical superintendent, who expended time and effort publicly defending the hospital, and defending me for opinions which — like those expressed here — are mine alone, and not those of the hospital.) The local television station made the topic their main story, and repeatedly replayed the clip of the elderly gentleman who had survived two cardiac arrests and wanted me sacked. The story finished with the words, “Dr Mackay declined to be interviewed”. I did not know I had been invited. Someone had received and declined the invitation for me! An advanced healthcare directive Should I have my cardiac arrest while going about my duties in the emergency department — immediate defibrillation please! And maybe a whiff of oxygen. (If I don’t survive, I will be quite surprised.2) Should I arrest in the hospital dining room, forgo the mouth- to-mouth (I am squeamish about these things). I may (grudgingly) accept some chest compression, until the defibrillator arrives. But if you have not got me back after three shocks — call off the circus. Go back and finish your lunch. If I arrest in the street, you will do what you will. But I won’t be happy. I doubt you will be able to get a defibrillator to me quickly enough. If I arrest at home, I know it will be very difficult for you to do nothing. But it will be 15 minutes before the ambulance arrives. And to end up brain damaged on a ventilator is something I do not want. (But if you are clever enough to call the ambulance so that I arrest after it arrives, by all means use the defibrillator.) When I am in a bed in a hospital ward “old and grey and full of sleep”, do not use your hands to commit violence upon me — use them to comfort me. I became a member of a hospital cardiac arrest team in 1973. Formally or informally, I have been part of such teams ever since. Two things I have learnt from this: there are things I do to patients that I do not want done to me; and, an advanced healthcare directive can never be found when you want one — so I hope I will be forgiven for placing mine here (Box). I would have attended at least a couple of hundred cardiac arrests. My guess is that, sadly, only a dozen or so of these people survived to leave hospital. (A meta-analysis of 39 studies involving 33 124 out-of-hospital cardiac arrests has shown a survival rate of 6.4%.3) Some of the survivors I remember well. While one middle-aged man was telling me about his chest pain, I noticed the cardiac rhythm on the monitor change to ventricular fibrillation. I charged the defibrillator as he continued to talk. I waited until he lost consciousness and then shocked him. In seconds, he was asking me what happened. Such episodes are not unusual in emergency departments (or in the back of ambulances). Of the vast majority who have not survived, I have a clear memory of only a few. I was visiting a patient at his home. He was telling me about his “gallbladder pain” when he had a cardiac arrest. His wife phoned an ambulance while I began resuscitation. When the ambulance arrived, his wife and I had a pink patient with small pupils. At that time ambulances did not carry defibrillators. By the time we arrived at the hospital, which was only a hundred yards away, the patient was blue, his pupils were fixed and dilated, and he could not be revived. It is difficult to maintain effective and continuous external cardiac massage while loading and unloading an ambulance, and while the ambulance is in motion. An editorial in the MJA in 2003 bemoaned the fact that “cardiac arrest is more successfully treated in Chicago or Heathrow airport, on an American Airlines or Qantas jet, or in a Boston post office, than in the vestibules, corridors or general wards of Australia’s premier hospitals”.4 A review of 28 cardiac arrests occurring at the Melbourne Cricket Ground (MCG) revealed a quite extraordinary survival rate of 71%,5 compared with a 3% survival rate from out-of-hospital resuscitation reported, at about the same time, in metropolitan Melbourne as a whole.6 Each minute from the onset of ventricular fibrillation to the use of a defibrillator results in a 10% reduction in survival.7,8 Thus, there is every reason to encourage anything that can shorten the time between the onset of cardiac arrest and defibrillation.9 But there is a big difference between the population of the MCG and that of a general hospital ward. The former has been able to get to the MCG, whereas the latter may be unable to get to the bathroom. Patients in a general medical ward may have failing hearts, lungs, kidneys and brains; they may be dying of cancer, they may be failing to respond to treatment for severe infection, or they may be otherwise very unwell. Most MJA readers will be familiar with the following scene, which takes place regularly in hospital wards. The curtains are barely closed around the bed of an elderly woman; two people are taking it in turns to rhythmically compress her chest; three doctors are attacking her oedematous limbs with needles, unsuccessfully attempting to insert them into veins; a fourth is poking around her groin trying to cannulate her femoral vein; and a fifth has a laryngoscope in her throat. But on this occasion, I notice something rather unusual (though I have seen it before). As I ventilate her lungs through the endotracheal tube, her eyes are wide open, her pupils are small, she blinks, she seems to be looking straight at me. Someone remarks, “She has a dying heart”. Eventually, we allow the rest of her to follow. In the past, nurses used experience and common sense when deciding not to use CPR in most patients when they died. Now, they are expected to start CPR on anyone who collapses and does not have a “not-for-resuscitation” order. This order is supposed to be discussed with the patient. This exceptionally difficult task may fall to the most inexperienced doctor on the ward. The results of CPR in this ward population are likely to be poor, even if immediate defibrillation is available (which it is not10). If cardiac arrest in a general medical ward is to be treated, could management be limited to prompt defibrillation, oxygen by bag and mask, and little else? The management of out-of-hospital cardiac arrest seems particularly prone to controversy. During the 1990s, ambulances regularly arrived at emergency departments carrying patients on whom cardiac massage was being performed. Subsequent discussion with relatives revealed that many of these patients had not had a witnessed cardiac arrest. They had been found dead. It was treating these patients that made me wish that the technique of CPR had never been introduced. In the five years since I wrote those words (and while the notes for this piece were gathering dust), it has become accepted that “. . . survival for the victim of cardiac arrest not resuscitated by a determined trial of advanced cardiac life support at the scene is negligible and not improved by further emergency department efforts”.11 Ambulance officers now have authority to cease resuscitation at the scene when it has clearly failed. This has reduced the incidence of futile resuscitation being performed in ambulances, which then has to be continued for a respectable period of time in the emergency department. But it may not prevent futile resuscitation efforts being performed in patients’ living rooms. An 85-year-old woman may phone “triple 0” after finding her husband collapsed on the floor. She may be advised to commence CPR. Sometimes, mightn’t it be quite reasonable for her to disregard this advice, and, when the ambulance arrives, to ask the paramedics to let her husband remain undisturbed? One hundred and five paramedics, emergency nurses, and emergency physicians who regularly took part in CPR were asked at what point they would like CPR stopped if they were the patient.12 Ten per cent did not wish to have CPR started at all; and only 3% wished to complete a full CPR protocol based on standard American Heart Association guidelines. Does not this suggest that there might be something wrong with the way CPR is presently practised? I was explaining to an elderly woman that her dying brother would be unlikely to last the hour. I asked if she wished to be with him when he died. Her husband turned to her and said, “ No. You don’t want to be there when they put the paddles on.” The assumptions behind this remark startled me. Should cardiopulmonary resuscitation be a futile deathbed ritual — a secular last right? There are many ways to die. To die without fuss, here one minute gone the next — that is the best.

Michael J Mackay MB ChB, MHA, FACRRM

An 80-year-old woman with a history of hypertension presented to the emergency department with a 3-hour history of dyspnoea and precordial discomfort. Serum concentrations of troponin T, creatine kinase and creatine kinase MB isoenzyme were normal. An electrocardiogram (Box 1) showed changes consistent with myocardial ischaemia. When the patient developed haemodynamic instability, cardiac catheterisation was performed (Box 2). The patient’s condition improved after an intra-aortic balloon pump (a catheter-mounted balloon positioned in the descending aorta and timed to inflate during diastole) was placed for the management of cardiogenic shock. An echocardiogram 3 weeks later showed normal left ventricular size and function. The patient had acute transient apical ballooning with normal coronary arteries (“Takotsubo” cardiomyopathy). First described in 1990,1 the presentation is similar to that of acute transmural myocardial ischaemia, with chest symptoms and electrocardiographic changes ranging from ST-segment elevation to T-wave inversion without ST shifts.2,3 Postulated triggering factors for transient apical ballooning have included onset or exacerbation of systemic disorders (eg, cerebrovascular accident, asthma, acute abdomen) and extreme emotional distress.2 Women are 6–12 times more likely to be affected than men.2-4 The in-hospital mortality rate is less than 1%,2 and there is usually complete functional recovery of the left ventricle within 2 weeks.3,4 The 2-year recurrence rate is less than 3%.2 The optimal therapy for this condition is unknown. 1 Electrocardiogram, showing delayed R-wave progression and inverted T waves in the anterolateral leads 2 Images from cardiac catheterisation A. End-diastolic left ventriculogram. B. End-systolic left ventriculogram, showing akinesia/dyskinesia of the apical and mid portions of the left ventricle and hyperdynamic motion at the base. The left ventricular ejection fraction was 30%, with elevated left ventricular end-diastolic pressure of 35 mmHg. C. Normal end-systolic left ventriculogram (from a different patient). D. Left coronary angiogram, showing a normal left anterior descending artery.

Constantin B Marcu MD · Kristen M Andresen MD · Thomas J Donohue MD, FACC

Hypothermia is now standard care for some types of cardiac arrest Out-of-hospital cardiac arrest is a leading cause of unexpected death in the developed world, occurring in about 1 in 1500 adults each year.1 Successful recovery from out-of-hospital cardiac arrest depends on the rapid activation of the “chain of survival”: an immediate call to the ambulance service, bystander delivery of external cardiac massage and expired-air breathing, defibrillation and the provision of advanced life support by paramedics.2 Unfortunately, survival with good neurological outcome at hospital discharge is rare after out-of-hospital cardiac arrest. Studies in Perth and Melbourne show that less than 5% of these patients survive to hospital discharge.3,4 As the average response time of ambulances in most Australian cities is between 7 and 12 minutes, considerable neurological injury occurs during this prolonged period of cardiac arrest, even with bystander cardiopulmonary resuscitation. While paramedics may restore spontaneous circulation and transport some patients alive to an emergency department, most remain comatose because of the severe anoxic brain injury.4 To improve outcome, considerable emphasis has been placed on shortening the time between cardiac arrest and defibrillation. As decreasing ambulance response times towards 5 minutes would be prohibitively expensive, alternative approaches to earlier defibrillation have been proposed. These include fire-fighters co-responding with ambulance services to patients with suspected cardiac arrest,5 or installation of automatic defibrillators in public places.6 On the other hand, recent data from Canada have cast doubt on the effectiveness of paramedic advanced life-support programs, which did not improve survival rates when introduced.7 What therapies are available after arrival at the hospital? In most cases, no immediate cardiology intervention is required, and treatment has therefore been largely supportive until the neurological outcome could be determined. Common intensive care practice has been to defer neurological assessment for at least 3 days, to allow more accurate clinical assessment.8 Recently, an “old” therapy for anoxic brain injury — therapeutic hypothermia — has been re-introduced into clinical practice. In this issue of the Journal, Williamson and colleagues (page 500) describe the use of this therapy in a patient who was comatose after near-drowning.9 The use of mild therapeutic hypothermia after cardiac arrest was first described in the 1950s, but later abandoned without being formally tested in clinical trials.10 Interest in hypothermia was revived in the early 1990s when animal studies and preliminary clinical studies suggested benefit. Subsequently, two prospective, randomised, controlled clinical trials have been conducted.11,12 In a recent Australian trial, patients who remained comatose after resuscitation from out-of-hospital cardiac arrest were treated with either 12 hours of therapeutic hypothermia (33°C) or standard care.11 At hospital discharge, 49% of those treated with hypothermia were discharged home or to rehabilitation, compared with 24% of those treated with standard care. In a European study, 55% of patients treated with hypothermia (33°C for 24 hours) had a favourable outcome at 6 months, compared with 39% of those treated with standard care.12 Subsequently, the International Liaison Committee on Resuscitation (which includes the Australian Resuscitation Council) endorsed the use of therapeutic hypothermia for patients with anoxic brain injury after out-of-hospital cardiac arrest, particularly when the initial cardiac rhythm is ventricular fibrillation (Box).13 Therefore, this treatment should now be regarded as a standard of care for this condition. However, a number of issues require further consideration if therapeutic hypothermia is to be applied more widely. Firstly, uncertainty remains about the effectiveness of this therapy in patients with out-of-hospital cardiac arrest due to causes other than ventricular fibrillation. Patients with asystolic out-of-hospital cardiac arrest have a dismal prognosis,14 as do those with coma after near-drowning, hanging, or other causes of asphyxia. Clinical data on the effects of therapeutic hypothermia in these groups are lacking. The role that therapeutic hypothermia played in the recovery of the patient reported by Williamson and colleagues is uncertain. Secondly, a protocol needs to be established in the emergency department for the rapid induction of hypothermia in patients who are unconscious after out-of-hospital cardiac arrest. In most hospitals, this will require consensus to be reached between emergency physicians, intensive care physicians and cardiologists on the indications for the provision of this treatment. Finally, there are technical issues to be considered in the rapid induction of hypothermia. In previous studies, hypothermia was induced through surface cooling with ice packs and/or refrigerated air blankets.11,12 This approach is slow and logistically difficult in busy emergency departments. Other technologies for the rapid induction of hypothermia are therefore under investigation.10 Currently, we are exploring the use of a rapid intravenous infusion of large-volume (30 mL/kg), ice-cold crystalloid fluid to induce hypothermia. Preliminary data suggest that this is relatively simple, effective, inexpensive and not associated with pulmonary complications.15 As there is often a delay between resuscitation and emergency department initiation of hypothermia, cooling in the ambulance would be ideal. In a study supported by the National Heart Foundation, paramedics in Melbourne are now infusing large-volume (2000 mL), ice-cold crystalloid fluid, together with a muscle relaxant, immediately after out-of-hospital cardiac arrest to induce hypothermia as soon as possible after resuscitation. If this is confirmed as feasible, further studies are planned which will examine the use of therapeutic hypothermia after asystolic and asphyxial cardiac arrest. Recommendations on therapeutic hypothermia from the International Liaison Committee on Resuscitation In October 2002, the Advanced Life Support Task Force of the International Liaison Committee on Resuscitation recommended: Unconscious adult patients with spontaneous circulation after out-of-hospital cardiac arrest should be cooled to 32°C–34°C for 12–24 hours when the initial rhythm was ventricular fibrillation. Such cooling may also be beneficial for other rhythms or in-hospital cardiac arrest. Preliminary data from clinical trials of perinatal asphyxia indicate that induced hypothermia is feasible and safe, but data on long-term neurological morbidity are not yet available. Until additional paediatric data become available, clinicians should tailor therapy for individual patients based on their assessment of the risks and benefits of hypothermia.

Stephen A Bernard MD, FACEM, FJFICM

A 74-year-old woman presented to hospital with dyspnoea of sudden onset. She was in cardiogenic shock, with blood pressure of 90/50 mmHg, and pulse rate of 115 bpm. The electrocardiogram (ECG) was difficult to interpret because of severe, persistent and inexplicable artefacts (Box 1A). Chest x-ray showed acute pulmonary oedema thought secondary to left ventricular failure. Echocardiography showed a left ventricular ejection fraction of 40% and anterior akinesia. Coronary angiography confirmed a proximal occlusion of the left anterior descending coronary artery, which was successfully treated by direct angioplasty and stenting. Review of the patient’s previous medical records revealed, on a thoracoabdominal image derived from computed tomography data, a foreign body in the central abdominal region (Box 2). Questioning of the patient after the angioplasty revealed that this was an electrostimulator (Itrel II, Medtronic, Minneapolis, USA) implanted a few years earlier as part of a dynamic graciloplasty to treat faecal incontinence. An ECG performed 12 hours after the angioplasty with the device deactivated (by the patient’s control programmer) produced an ECG tracing free of artefacts (Box 1B). Persistent and inexplicable ECG artefacts should raise the suspicion of interference from a device generating high frequency electrical impulses. Such devices may include minute ventilation rate-responsive pacemakers1 and central or transcutaneous neurostimulators (eg, deep brain neurostimulators used in Parkinson’s disease,2 and spinal neurostimulators used in chronic back pain3). Occasionally, when the vector of impulses is perpendicular to an ECG lead, the tracing from that lead may be free of artefacts (eg,Box 1A, lead I). Intrathoracic devices are usually discovered on physical examination or standard chest x-ray, but devices in other parts of the body may not be obvious. In dynamic graciloplasty to treat anal incontinence, the gracilis muscle is transposed around the anal canal and electronically stimulated by a device placed in a subcutaneous pocket in the abdominal wall.4 In our case, this device led to ECG artefacts potentially interfering with the ability to diagnose the acute myocardial infarction. Implanted electrostimulation devices are being used increasingly in medicine and should be considered as a possible source of ECG artefacts, especially by frontline clinicians confronted daily with such life-threatening conditions as acute coronary syndromes. Electrocardiograms in a patient with an electrostimulation device A. On presentation, showing artefacts. B. After temporary deactivation of the device. 2 Thoracoabdominal image calculated from computed tomography data, showing the device (arrow)

Robert F Bonvini MD · Edoardo Camenzind MD