New directions for warm-up angina?

Transcription

1 European Heart Journal (2014) 35, doi: /eurheartj/ehu390 New directions for warm-up angina? Researchers at National Institute for Health Research Biomedical Research Centre at Guy s and St Thomas Hospital, London, examine new ideas for helping patients with coronary heart disease to warm up and exercise without adverse effects For nearly 250 years it has been known that, in patients with angina pectoris, a period of exercise inducing chest pain makes it easier to exercise later without pain. The first known observations were made by British physician Dr William Heberden (who gave his name to Heberden s nodes in rheumatic joint diseases). As cardiac rehabilitation for coronary artery disease has become commonplace, it has become a pressing question to make use of the phenomenon of what is now called warm-up angina or warm-up ischaemia, but the road to clear-cut advice is paved with obstacles. Patients who have recently suffered a myocardial infarction are naturally wary of inducing chest pain, whilst their physicians are caught between a rock and a hard place. Recommend too much exercise and they risk adverse events, yet recommend too little and they are perhaps not offering the optimal rehabilitation package. In an attempt to cast light on the counter-intuitive findings first noted by Heberden, a team at King s College, London, UK, led by Professors Michael S. Marber and Simon R. Redwood, has been studying the physiology and haemodynamics of the processes involved. The research unit is based at Guy s and St Thomas Hospital, London, and its National Institute for Health Research (NIHR) Biomedical Research Centre. One of their experimental set-ups involves an exercise bicycle placed on a table in the catheterization laboratory. Cath lab bicycle in action (credit Dr James Clark) Cath lab bicycle recordings (credit Dr James Clark) Their long-term goals are to elucidate the mechanisms of warm-up angina and thereby to identify the points at which pharmacological intervention might be able to achieve the same benefits at less risk than intense exercise. Such a treatment would be directed at reducing occurrence of angina-induced malignant ventricular arrhythmia and LV dysfunction, and thereby perhaps sudden death. Current AHA guidelines recommend moderately intense exercise (40 60% of VO 2 max) that at no time crosses a threshold set at a heart rate of 10 bpm less than that at which angina or ST depression of 1 mm occurs. 1 Evidence for the safety of endurance exercise in patients with angina, following a period of warm up (5 10 min), was published 6 years ago in EHJ by Noël et al. 2 In a study of 22 patients exercising to the point of myocardial ischaemia, Noël et al. showed that, with appropriate ECG monitoring, there was no evidence of arrhythmia, troponin-related myocardial damage, or left-ventricular dysfunction. Yet such a short-term relatively small study did not provide evidence of benefits over a less-intense exercise regimen based on the above AHA guidelines, as Professor Marber et al. have pointed out: Unfortunately, despite heroic efforts, the predicted benefits of prolonged ischaemia were not apparent. Recently, one of the King s College team, Dr Rupert Williams, reviewed the field. He said: I believe that there is benefit to be gained from high-intensity cardiac rehabilitation, given the cardio-protective effects seen from exercising to ischaemia in warm-up angina studies, though the objective proof is not yet there. A recent study showed high-intensity cardiac rehabilitation is as safe as moderateintensity cardiac rehabilitation, although it was underpowered. 3 He points out that warm-up angina is strictly defined in terms of findings at a second period of exercise of either reduced ischemia (in terms of ST depression) or a higher ischaemic threshold (defined as an increased rate pressure product [HR x SBP] for a certain ST depression, usually 1 mm). The period between the two exercise efforts is important, and should be about 15 min and no longer than 60 min. Some of the key research on warm-up ischaemia has been carried out by Dr Peter Bogaty at the Quebec Heart Institute, Ste-Foy, Quebec, Canada. He and his team tried to induce warm-up angina without exercising to ischaemia, but failed to observe the effect unless exercise was taken to this point, as evidenced by ST depression. Short-term exercise capacity was increased by exercising below the ischaemic threshold, but true warm-up in terms of reduced ischaemia was observed only when the threshold was reached. By carrying out extremely accurate haemodynamic measurements, the King s College group are hoping to elucidate some aspects of warm-up angina. The exercise bicycle on the Cath lab table, for example, is being used to study patients receiving an angioplasty. During the procedure, before the coronary artery stenosis is Published on behalf of the European Society of Cardiology. All rights reserved. & The Author For permissions please journals.permissions@oup.com.

2 3078 CardioPulse treated, the patient undergoes two periods of exercise with a wire placed beyond the stenosis to monitor pressure and flow. Dr Williams said that during the second period, coronary blood flow increases and microvascular resistance decreases, despite a reduction in perfusion pressure. Also, the augmentation index a measure of wave reflection and arterial stiffness decreases on second exercise, which indicates a relative reduction in afterload. There is, therefore, still great uncertainty about the mechanism of warm-up angina. One possibility is that it is a direct effect of dilatation of muscular conduit arteries during the first exercise period, especially the femoral and brachial arteries, thereby reducing the augmentation index on second exercise. Much interest has also been expressed in the apparent similarities between warm-up angina and ischaemic preconditioning, in which non-lethal ischaemia is associated with reduced infarct size in a subsequent myocardial infarction. However, the mechanisms seem to be different. At a molecular level, one possible mechanism, according to Dr Williams, is opening of potassium channels in myocyte mitochondria and the King s College group is hoping to test this idea with appropriate agonists, using cardiac MRI as a marker of perfusion. Outlining advice he gives to his patients, he said: I always tell them to warm up before exercise, especially if going out in cold weather which may place additional strain on their heart. People were scared of intense exercise in the past, but I believe it potentially offers cardioprotective effects, provided the build-up to intense exercise is slow and guided by the cardiac rehabilitation team. Most importantly I would like to emphasise the benefits of exercise and cardiac rehabilitation, which is currently an under-prescribed asset. Conflict of interest: none declared. References References are available as Supplementary material at European Heart Journal online. Refining electrocardiography interpretation criteria in elite athletes: redefining the limits of normal Better criteria for identifying athletes at risk of sudden cardiac death are discussed Sudden cardiac death (SCD) is the leading cause of non-traumatic mortality in young (,35 years old) athletes. A vast majority of cases are due to a diverse spectrum of inherited and congenital cardiac conditions that are readily detectable through a combination of history, examination, and 12-lead electrocardiography (ECG). Sudden death is usually the first manifestation in up to 80% of athletes and therefore some form of screening is necessary to identify those at risk. Consequently, an increasing number of sporting bodies and scientific organizations, including the European Society of Cardiology (ESC), recommends pre-participation cardiovascular evaluation of athletes using ECG prior to clearance to compete. 1 One study has demonstrated that ECG-based screening may indeed save lives. 2 A major reservation to ECG screening is the generation of falsepositive results, which arise from the overlap between physiological manifestations of the athlete s heart and pathological cardiac conditions. To facilitate the distinction between physiological and pathological ECG patterns, the ESC produced guidelines for interpretation of an athlete s ECG in However, these have consistently been associated with an unacceptably high false-positive rate of between 10 and 20%. 3 Furthermore, the ESC recommendations are derived entirely from non-elite Caucasian (white) athletes 4 and fail to account for ECG patterns in the most highly trained athletes or the influence of ethnicity on the athlete s heart, particularly with respect to athletes of African/Afro-Caribbean ethnicity (black athletes). Black athletes form an increasing population of sportsmen competing at the highest levels in Western countries. Data now unequivocally demonstrate that black athletes exhibit significantly greater electrical and structural adaptations in response to exercise compared with white athletes, 5 8 placing them at higher risk of falsepositive results and potential false disqualification from sport. Previous research from our group has demonstrated that up to 25% of black athletes exhibit T-wave inversions. Majority of these is confined to the anterior leads V1 V4 5 7 and do not represent significant pathology. 6 The recently published Seattle Criteria 9 has aided the interpretation of an athlete s ECG, in part by recognition of anterior T-wave inversion as a normal pattern in black athletes. However, as with the ESC recommendations, these criteria are largely consensus based. Our experience of screening several thousand elite athletes over almost 2 decades led us to suspect that in exercising individuals, several additional ECG patterns that are considered abnormal by current recommendations may simply be markers of cardiac enlargement or represent normal variants when found in isolation in an otherwise healthy athlete (Figure 1, orange circle). Specifically, these patterns include voltage criteria for left and right atrial

3 CardioPulse 3079 Figure 1 Refined ECG criteria for screening athletes. Taken from Sheikh et al. 12 enlargement, right-ventricular hypertrophy, and left- and right-axis deviation; together, these constitute over 60% of all abnormalities. Two studies published by our group in 2012 confirmed our suspicions: although comprising a high burden of positive ECGs in elite athletes, no evidence was found to support these five patterns to signify serious cardiac disease. 10,11 Our observations led us to devise a set of refined ECG screening criteria (Figure 1) whereby the above-mentioned ECG patterns, including anterior T-wave inversion in black athletes, were regarded as normal finings if observed in isolation in an otherwise asymptomatic athlete with no relevant family history or examination findings. On the basis of our own experience and in conjunction with the Bethesda guidelines, we also increased the cut-off for an abnormal corrected QT interval (QTc) to 470 ms in male and 480 ms in female athletes. In the current study, the impact of our refined criteria on the falsepositive ECG rate was assessed in a large cohort of black (n ¼ 1208) and white (n ¼ 4297) athletes undergoing pre-participation screening with history, examination, and 12-lead ECG between 2000 and The ECGs of all athletes were re-evaluated using the refined criteria, ESC recommendations, and Seattle Criteria, to determine the number of positive results requiring athletes to undergo further investigations. All three ECG criteria were also applied to a cohort of 103 young, asymptomatic athletes with HCM to determine the number of individuals in which suspicion of the condition was correctly raised by each criterion. The ESC recommendations resulted in a staggering 40.4% of black athletes exhibiting an abnormal ECG requiring further investigation prior to being given clearance to compete. Importantly, almost one in five white athletes (16.2%) also tested positive on the basis of the ESC recommendations. The Seattle criteria reduced the number of positive ECGs to 18.4% in black athletes and 7.1% in white athletes. However, the refined criteria further reduced abnormal ECGs to 11.5% in black athletes and 5.3% in white athletes. Significantly, all three criteria identified 98.1% of athletes with HCM. Overall, the study detected 40 athletes with pathology. Of these individuals, 25 were diagnosed with only minor congenital or valvular abnormalities. The remaining 15 were diagnosed with serious pathology, defined as a condition implicated as a recognized cause of exercise-related SCD. All 15 cases were identified by a combination of history and 12-lead ECG, with 14 (93.3%) identified on the basis of ECG alone. During the screening period, a significant proportion of athletes (n ¼ 3087) were required to undergo echocardiography as a standard part of their club s screening policy, regardless of history, examination, or ECG findings. This cohort was used to determine the sensitivity and specificity of the screening process using each of the three ECG screening criteria. The refined criteria improved specificity in black athletes from 40.3% using the ESC recommendations to 84.2%, and in white athletes from 73.8% using the ESC recommendations to 94.1%. Importantly, sensitivity for detecting all cardiac conditions, including HCM, remained 70% in black and 60% in white athletes, regardless of the criterion employed. Exclusion of minor pathology from our calculations resulted in a dramatic improvement in sensitivity to 100% in both black and white athletes without a compromise in specificity. The results of this study have furthered our understanding of benign vs. abnormal ECG patterns in athletes, and will have a significant impact on reducing the burden of false-positive results during pre-participation screening whilst maintaining sensitivity for serious cardiac conditions. Indeed, the ECG correctly identified 93.3% of serious cardiac pathology that may otherwise have not been detected. Further work should focus on reproducing our results in other centres screening large cohorts of elite athletes, and on further improving ECG specificity in black athletes, a significant proportion of whom continue to exhibit positive ECG results.

4 3080 CardioPulse References References are available as Supplementary material at European Heart Journal online. Performance enhancing agents and the heart * Professor Josef Niebauer, Salzburg, Austria, presented the latest evidence at EuroPRevent 2014 Doping isthe use of drugsthat appearon the World Anti-Doping Agency s List of Prohibited Substances. Even though the use of performanceenhancing drugs and the application of, for example, novel materials for sporting equipment is done for the same reason, i.e. to gain an edge over others, it is rightly banned and considered unethical because it exposes athletes to health risks and in the end may take their lives. Leisure time athletes and competitive athletes use performanceenhancing drugs, hoping to gain an edge over their competitors. More often than not athletes are aware of the potential hazards, and use such drugs to reach a goal they feel they are unable to reach without illegal substances. By taking this short-cut, they accept that this may expose them to severe and possibly deadly health risks. Protagonists of the legalized use of currently prohibited substances will have to understand that health risks cannot be fully controlled and that athletes will always be exposed to an unjustifiable risk which may not only be associated with increased morbidity but eventually reduced life expectancy. Doping is a phenomenon not limited to elite sport, but it is actually more common in leisure time athletes. It has been reported that up to 20% of members of fitness clubs and up to 60% of those who train to increase muscle mass take performance enhancing substances. Substances that induce cardiovascular complications and may thus be first noticed by a cardiologist include among others anabolic substances, peptide hormones, and stimulants. Anabolic steroids are most commonly used to increase muscle mass, but they also result in concentric left-ventricular hypertrophy without a concomitant increase in left-ventricular diameter, which can be documented by echocardiography. Since the rate of apoptosis is increased, myocardial fibrosis and necrosis may accidentally be found in myocardial biopsies or cardiac magnetic tomographic imaging performed for other reasons. During routine medical screening, arterial hypertension or dyslipidaemia, i.e. elevated levels of LDL and homocysteine as well as diminished levels of HDL, may be detected and might lead to the suspicion of anabolic steroid use, especially in muscular athletes. Combined with the reported endothelial dysfunction, the risk of atherosclerosis is increased and has been well documented in users of anabolic steroids. Furthermore, diastolic and systolic dysfunction may be picked up during echocardiography. Unfortunately, anabolic drug use remains undetected in the vast majority of these athletes and this may first become apparent when end organ damage, e.g. myocardial or cerebrovascular events, occurs as a result of increased platelet activity, reduced fibrinolytic activity, and subsequent thromboembolic events. Peptide hormones such as erythropoietin (Epo), insulin-like growth factor 1 (IGF-1), human growth factor (hgh), and human chorionic gonadotropin (hcg) are also widely used and may induce myocardial hypertrophy, interstitial myocardial fibrosis, arrhythmias, heart failure, and diabetes mellitus. Epo is still popular among endurance athletes, because it increases haemoglobin mass. Risks of elevated haematocrit, increased blood viscosity, and resulting thromboembolic events as myocardial infarction or stroke are well known even among athletes and coaches, but are neglected in order to take a reputed short-cut to success. Last but not the least, stimulating substances like amphetamines or its derivatives ephedrine or cathine are widely used, despite the fact that they induce tachycardias and arrhythmias which have led to sudden cardiac death. Unfortunately, the use of performance-enhancing drugs is rather common in both leisure time and also competitive athletes. Since many of these substances lead to cardiovascular and cerebrovascular manifestations, cardiologists have the privilege to be among the first to take a note of it. By bringing these life-threatening effects to the attention of the athlete, end-organ damage can be prevented and lives can possibly be saved. *Source: Wild&Team/SALK; free for use.

5 CardioPulse 3081 Sudden cardiac death in young competitive athletes Dr Michael Papadakis explains the essentials of cardiovascular screening in first-degree relatives The sudden death of a young athlete from a cardiac disorder is particularly emotive and is often associated with considerable media coverage, drawing attention to the athletic prowess of the individual and the number of life years lost. The majority of sudden cardiac deaths (SCDs) in the young are secondary to previously quiescent, inherited cardiac diseases that can potentially be detected during life, galvanizing discussions relating to primary and secondary prevention of similar catastrophes. The proposed preventative strategies focus primarily on averting further deaths in the context of competitive sport by cardiovascular evaluation of athletes and the use of automated external defibrillators in athletic venues. Pre-participation screening of young athletes with a 12-lead ECG remains a contentious issue. Despite data from the Italian national screening programme in athletes reporting a reduction in SCD with screening, there are concerns relating to false-positive tests, which may result in unnecessary investigations or erroneous disqualification. However, recent studies in large cohorts of young athletic individuals have resulted in refinement of the ECG criteria considered to denote an abnormal result, with a considerable improvement in the ECG specificity. 1 Prompt defibrillation (within 5 min) has been associated with survival rates in excess of 60% in athletes. A comprehensive medical action plan that is rehearsed on a regular basis is essential to ensure the best possible outcome in the context of mass gathering events in sports arenas. The SCD of a young individual is the beginning of a long and arduous road for the grieving family. With media interest focused on the tragic death, the family remains at the fringes of evolving events, and the medical community often overlooks the fact that close relatives are at potential risk of the same fate. The inherited nature of most conditions predisposing to SCDin theyoung highlightsthe importance of performing comprehensive post-mortem evaluation of the index case as well as offering cardiovascular screening to all first-degree relatives. After consent, a blood sample and splenic tissue should be retained from the deceased to enable genetic testing (molecular autopsy), which may prove invaluable for cascade familial screening. Examination of the heart by an experienced cardiac pathologist is crucial to ensure accurate interpretation of the autopsy findings, as false conclusions may misguide familial evaluation or offer false reassurance to surviving relatives and dissuade physicians from initiating familial screening. The interpretation of the results is a complex task as many disorders are rare or exhibit subtle findings at autopsy. In addition, uncertainty may exist regarding the causal relationship between the pathological findings and the sudden death. 2 A recent study demonstrated a disparity in 40% of cases as to the potential cause of death when comparing cardiac pathologist vs. general pathologist reports. 3 Familial evaluation should encompass a comprehensive cardiological assessment of all first-degree relatives. Investigations are guided by clinical suspicion based on data collected on the deceased, including pre-morbid history, circumstances of death, and autopsy findings. It is imperative to emphasize that, in a significant proportion of SCDs, an obvious cause of death cannot be identified, despite detailed histopathological and toxicological evaluation. Such deaths are classified as sudden arrhythmic death syndrome (SADS). Up to 50% of families with an SADS death demonstrate evidence of an ion-channel disorder following clinical assessment. Most importantly, 25% of SADS relatives are diagnosed with a previously unsuspected inherited cardiac condition, underscoring the need to refer such families for thorough specialist assessment. 2 Interventions ranging from advice for simple lifestyle modification to the implantation of a prophylactic ICD can reduce the risk of further fatalities. References References are available as Supplementary material at European Heart Journal online. Fit teenagers are less likely to have myocardial infarctions in later life A large Swedish study discusses the association of fitness during teenage years and myocardial infarction later in life Researchers in Sweden have found an association between a person s fitness as a teenager and their risk of myocardial infarction (MI) in later life. In a study of nearly men, they found that the more aerobically fit men were in late

6 3082 CardioPulse adolescence, the less likely they were to have an MI 30 or 40 years later. The study, published in the European Heart Journal, 1 found that the relationship between aerobic fitness and MI occurred regardless of the men s body mass index (BMI) when they were teenagers. However, fit but overweight or obese men had a significantly higher risk of a MI than unfit, lean men. Professor Peter Nordström, of Umeå University, Umeå, Sweden, who led the research, said: Our findings suggest that high aerobic fitness in late adolescence may reduce the risk of MI later in life. However, being very fit does not appear to fully compensate for being overweight or obese. Our study suggests that it s more important not to be overweight or obese than to be fit, but that it s even better to be both fit and of normal weight. Prof Nordström and his colleagues analysed data from Swedish men who underwent medical examinations at the age of 18 when they were conscripted into the Swedish armed forces between 1969 and Aerobic fitness was measured by a cycle test where the resistance was gradually increased until they were too exhausted to continue. The researchers found that every 15% increase in aerobic fitness was linked to an 18% reduced risk of MI 30 years later, after adjusting for various confounding factors including socioeconomic background and BMI. The results also suggested that regular cardiovascular training in late adolescence was independently associated with an 35% reduced risk of an early MI in later life. There were 7575 MIs in men during the total follow-up time where aerobic fitness was measured, which means the cumulative incidence was about 1222 per men, explained Prof Nordström. There were men (43.7%) who were normal weight or lean, and who had an aerobic fitness that was better than the average. Among these lean, fit men there were 2176 MIs, resulting in a cumulative incidence of about 803 MIs per men. Thus, the cumulative incidence of MIs was reduced by about 35% in this group. However, he warned that the study showed only that there was an association between fitness and a reduction in myocardial infarction, and it could not show that being aerobically fit caused the reduced risk of myocardial infarction. The relationship between aerobic fitness and heart disease is complex and may well be influenced by confounding factors that were not investigated in this study. For instance, some people may have a genetic predisposition to both high physical fitness and a low risk of heart disease. In a recent study of twins, we found that 78% of the variation in aerobic fitness at the time of conscription is related to genetic factors. At the time of the men s conscription they had a full medical examination, which included checking blood pressure, weight, height and muscle strength, as well as aerobic fitness. During the cycle test for aerobic fitness, the resistance was gradually increased at the rate of 25 Watts/min 2 until the men were too exhausted to continue. The final work rate (maximum watts) was used for the analysis. The average work rate for the men was 250 Watts. The men were followed for an average of 34 years (ranging from 5 to 41 years) until the date of an MI, death, or 1 January 2011, whichever came first. To investigate the link between aerobic fitness and risk of a later MI, the men s results were divided into five groups. Compared with men in the highest fifth for aerobic fitness, men in the lowest fifth had 2.1-fold increased risk of an MI during the followup period, after adjusting for BMI, age, place, and year of conscription. To investigate the joint effect of BMI and fitness with respect to risk of MIs, BMI were divided into four groups that matched the World Health Organization s BMI definitions: underweight/lean (BMI,18.5 kg/m 2 ), normal weight (BMI between 18.5 and 25 kg/m 2 ), overweight (BMI between 25 and 30 kg/m 2 ) and obese (BMI.30 kg/m 2 ). In all four BMI groups, the risk of a later MI was increased significantly when comparing the least fit with the fit. However, the fittest obese men had nearly double (71%) the risk of an MI than did the most unfit, but lean men, and more than four-fold increased risk compared with the fittest lean men. A similar pattern was seen for overweight men when compared with normal weight men. There are some limitationsto the research. These include the fact that the men s BMI, fitness, and blood pressure was only measured at the time of conscription so it is not known if and how these factors might have changed in later years; the research was carried out in young menandmaynotapplytowomenortheelderly;andtheeffectof smoking could be evaluated only in a sub-group of men. Prof Nordström said: As far as we know, this is the first study to investigate the links between an objective measure of physical fitness in teenagers and risk of MI in the general population. Further studies are needed to investigate the clinical relevance of these findings, but given the strong association that we have found, the low cost and easy accessibility of cardiovascular training, and the role of heart disease as a major cause of illness and death worldwide, these results are important with respect to public health. Note: One watt ¼ one joule per second. Andros Tofield Reference 1. Högström G, Nordström A, Nordström P. High aerobic fitness in late adolescence is associated with a reduced risk of MI later in life: a nationwide cohort study in men. Eur Heart J 2014;35: CardioPulse contact: Andros Tofield, Managing Editor. docandros@bluewin.ch