Clin Auton Res (2004) 14 (Suppl 1) : I/25���I/36 DOI 10.1007/s10286-004-1005-1 C. T. Paul Krediet Arthur A. M. Wilde Wouter Wieling John R. Halliwill Exercise related syncope, when it���s not the heart Introduction The occurrence of a syncopal or pre-syncopal episode in association with physical exercise or exertion is alarm- ing to both patient and care provider as it is sometimes a prodromal sign of such tragic events as sudden cardiac death during physical exercise. Syncope during exercise may be the first indication of a dangerous underlying cardiovascular condition. Thus, the diagnostic workup of patients presenting with exercise-related syncope must include assessment of the risk for acute cardiac death (Table 1). Many reviews on risk stratification for sudden cardiac death in subjects with exercise-related syncope have been published [4, 41, 63, 72], and we will only address the subject briefly. In the young ( 35 years of age), congenital car- diomyopathies are the most common cause of sudden cardiac death during physical exertion [2,4,8,41,63,65]. Hypertrophic cardiomyopathy (HCM) is the most im- portant cause and has been studied in particular in young athletes [63,65].The myofibrillar disarray associ- ated with this genetic disorder contributes to the devel- opment of fatal ventricular arrhythmias. In some Mediterranean countries arrhythmogenic right ventric- ular dysplasia (ARVD) is an important cause [2, 4]. In children, congenital aortic stenosis is a well-known cause of syncope and sudden death during exercise [41]. Among athletes severe aortic stenosis is however un- common, as the resulting hemodynamic abnormalities prevent such patients from achieving excellence in sports. In addition, due to the risks associated with aor- tic stenosis, these patients are excluded from competi- tive sports upon diagnosis [41].A rare cause of syncope with exertion in the young are congenital coronary artery abnormalities [65]. In the absence of structural heart disease, exercise- related symptoms in the young may be due to primary arrhythmia syndromes including long QT syndrome (LQTS) and catecholamine-induced polymorphic ven- tricular tachycardia or fibrillation (CPVT) [9, 72, 108]. Both syndromes typically affect youngsters.In these dis- orders,the family history most often reveals sudden car- diac death at young ages. In addition, a history of syn- CAR 1005 C. T. P. Krediet, MSc �� W.Wieling, MD, PhD Dept. of Internal Medicine Academic Medical Center University of Amsterdam Amsterdam, The Netherlands A.A. M.Wilde, MD, PhD Dept. of Cardiology Academic Medical Center University of Amsterdam Amsterdam, The Netherlands Dr. J. R Halliwill, PhD ( ) Dept. of Human Physiology 1240 University of Oregon Eugene (OR) 97403-1240, USA Tel.: +1-541/346-5425 Fax: +1-541/346-2841 E-Mail: halliwil@uoregon.edu ��� Abstract Syncope or pre-syn- cope in association with physical exercise may be the first indication of a dangerous underlying cardio- vascular condition. Thus, the diag- nostic workup of patients present- ing with exercise-related syncope must include assessment of the risk for acute cardiac death.When po- tentially lethal conditions have been ruled out, several hypotensive syndromes that are associated with exercise should be considered. This review aims to give a concise overview of several forms of exer- cise-related functional hypotensive syndromes causing syncope, in- cluding the physiology of post-ex- ercise hypotension. The focus is on underlying mechanisms, clinical considerations, and outlining treat- ment strategies for these syn- dromes. ��� Key words syncope �� exertion �� exercise �� differential diagnosis �� sports

I/26 cope after diving is strongly suggestive for type 1 LQTS [9, 108]. By definition the ECG is crucial in detecting a long QT syndrome. Exercise testing is a mandatory di- agnostic tool for both CPVT and type 1 LQTS [9, 108]. In the older patient who presents with exercise-re- lated syncope, common causes include valvular disease (e. g., aortic valve stenosis), ischemic heart disease, and arrhythmias secondary to established cardiac disease [9, 96]. ECG,exercise testing and echocardiography are indi- cated in every patient presenting with exercise induced syncope. These diagnostic tests cover all potentially lethal structural and electrophysiological pathologies listed above. When these potentially lethal conditions have been ruled out by means of appropriate testing, several hypotensive syndromes that are associated with exercise should be considered. This review discusses several forms of exercise related functional hypotensive syndromes that can produce syncope during or after ex- ercise (Table 2) including the physiology of post-exer- cise hypotension. The focus is on underlying mecha- nisms, clinical considerations, and outlining treatment strategies for these syndromes. ��� Epidemiology Very little is known about the prevalence of isolated ex- ercise-related syncope in the normal population, or any sub- or hospital population. To date, exercise-related syncope has not been explicitly characterized in any ma- jor epidemiological studies on syncope [29,69,73,89].In the 1950���s Dermskian and Lamb found two episodes of exercise-related syncope out of 113 syncopal attacks re- ported in 82 healthy young adult males ( 2%) [18].An- other exercise-related episode was reported out of 61 cases of syncope ( 1%) [59]. At the Academic Medical Center of the University of Amsterdam, analysis of 517 consecutive patients referred for the evaluation of unex- plained loss of consciousness showed a 1% prevalence (5/517) for exercise-related syncope [Wieling, unpub- lished data]. Thus, the prevalence seems to be low. As only one in 20,000 athletes (0.005%) has a condi- tion that might predispose them to serious cardiac prob- lems resulting in syncope [64], assuming that the vast majority of exercise-related syncope has a benign na- ture seems justified. However, in light of the conse- quences of a misdiagnosis, it must be recognized that the limited epidemiological evidence does not obviate the need for careful diagnostic evaluation of the indi- vidual patient. ��� Exercise related syncope: during or after? The most important question the physician should ask a patient with exercise-related syncope, is ���did you lose consciousness during exercise or after you stopped?��� The latter makes structural heart disease a far less likely underlying cause. Unfortunately, the literature on exer- cise-related syncope often fails to assess this important issue of timing. Syncope during exercise ��� Exercise hypotension in autonomic failure syndromes Hypotension during exercise in patients with chronic failure of the autonomic nervous system (e. g., Pure Au- tonomic Failure, Shy-Drager syndrome, Parkinson���s dis- Table 1 Potentially lethal causes of syncope associated with exercise Cardiac Arrhythmias Bradyarrhythmias Sick sinus syndrome Atrioventricular block Pacemaker malfunction Tachyarrhythmias Ventricular tachycardia Secondary to Hypertrophic cardiomyopathy Arrhythmogenic right ventricular dysplasia Long QT-syndrome Inherited Drug induced Electrolyte derangement Supraventricular tachycardia Obstruction to flow Obstruction to left ventricular outflow Aortic stenosis Hypertrophic cardiomyopathy Mitral stenosis Left atrial myxoma Obstruction to pulmonary outflow Pulmonary stenosis Pulmonary embolism Tetralogy of Fallot Pulmonary hypertension Right atrial myxoma Pump failure Congenital coronary artery abnormalities Myocardial infarction Aortic dissection Anomalous coronary artery (Adapted from [4] data derived from [51, 62]) Table 2 Functional hypotensive syndromes causing syncope associated with ex- ercise, with typical age-range and sex distribution Autonomic failure 50 years (males females) Symptomatic post-exercise hypotension all ages (males = females) Neurally mediated Neurally mediated during exercise 20 years (females males) Neurally mediated post-exercise all ages (males = females) Carotid sinus syndrome 50 years (males = females)