exercise in weight management


Published on

Published in: Health & Medicine
  • Be the first to comment

  • Be the first to like this

No Downloads
Total views
On SlideShare
From Embeds
Number of Embeds
Embeds 0
No embeds

No notes for slide

exercise in weight management

  1. 1. EXERCISE IN SECONDARY PREVENTION ANDCARDIAC REHABILITATION 0733-8651/01 $15.00 + .OO EXERCISE IN WEIGHT MANAGEMENT OF OBESITY Paul Poirier, MD, FRCP(C), and Jean-Pierre Despres, PhD Obesity has become an important burden 1960." In the United States and in Europe,for the health system of industrialized coun- the incidence of being overweight and obesetries and must be regarded as a serious public have reached epidemic proportions.2,61 Fur-health issue in our time. Obesity is associated thermore, in the past decade, the percentagewith reduced life expectancy,38 and it is now of overweight and obese individuals in thewell recognized that increased body fat is United States and in some countries in Eu-associated with heart disease, stroke, hyper- rope has increased to over 50% of adults agedtension, dyslipidemia, type 2 diabetes melli- 20 years or older.61* Childhood obesity is lo4tus, gallbladder disease, osteoarthritis, sleep also an alarming problem, and opportunitiesapnea and respiratory problems and numer- for physical activity have been lost in theous cancers (endometrial, breast, prostate and ~011th.~ Obesity in the youth may, in part,colon)?, The American Heart Association have been created by structural changes thathas stated that obesity is a major modifiable have reduced the ability to make healthyrisk factor for heart disease.40, This article choices (ie, it is unsafe for children to playreviews basic regulatory aspects of human outside). As many clinicians have often ob-adipose tissue metabolism with implications served, weight reduction is difficult tofor the cardiologist in terms of exercise pre- achieve and even more difficult to maintain.scription and the role of exercise and aerobic The reduced-obesity state is a self-perpetuat-physical training in the management of obe- ing condition, wherein homeostatic mecha-sity. nisms attempt to restrain further weight loss.4l Obesity is a very complex chronic dis-EPIDEMIOLOGY order that results from the interaction of ge- notypic versus environmental factors2,l9 and The incidence of obesity in the United involves multifaceted interactions among nu-States has increased progressively since merous potential determinants (humoral, neural, metabolic, psychological etc). Of great Support has been provided by grants from The Qu6bec consequence, the relative risk of diabetes in-Heart Institute and Le Fond de Recherche en Sant6 du creases by approximately 25% for each addi-Qu6bec (PP), the Canadian Institutes for Health Research tional unit of body mass index (BMI) over 22(J-PD), the Natural Sciences and Engineering ResearchCouncil (J-PD), the Canadian Diabetes Association (J- kg/m2,23and the practice of regular physicalPD), and the Heart and Stroke Foundation of Canada activities has been associated with the pre-(J-PD). vention of diabetes&, and decreased mortal- 78From the Department of Pharmacy, Laval University School of Pharmacy (PI); and the Departments of Human Nutrition 0-PD) and Research 0-PD), Institut de Cardiologie et de Pneumologie, Laval Hospital, Sainte-Foy, Que- bec, CanadaCARDIOLOGY CLINICS ~~VOLUME 19 NUMBER 3 AUGUST 2001 459
  2. 2. 460 POIRIER & DESP&Sity in obese individuals and those with type able metabolic h e t e r ~ g e n e i t y . ~ ~ - ~ ~ Thus, the2 diabetes.62, Likewise, insulin resistance is 111 challenge for the health care professional andfrequently associated with obesity, and it the cardiologist is to identify the overweight/should always be kept in mind that insulin- obese individuals "at high risk" of cardiovas-resistant individuals are at increased risk of cular disease (CVD).84 this regard, abun- Inheart disease. It was recently reported in three dant literature published over the last 20European cohorts (>17,000 men) followed for years has emphasized that abdominal obesityover 20 years that nondiabetic men with was more important than excess fatness as ahigher blood glucose had a significantly correlate of the complications that had beenhigher risk of death from cardiovascular and in the past considered as the consequence ofcoronary heart disease.14 Therefore, asymp- obesity per se.20, 59, 90 It has been shown that 26,tomatic glucose intolerance should no longer waist circumference is positively correlatedbe considered a benign metabolic condition, with abdominal fat content and that it is theand features associated with the insulin resis- most practical anthropometric measurementtance syndrome should be taken seriously by for assessing a patients abdominal fat con-the medical community. Indeed, data from tent.86 has been recently suggested that two Itthe Quebec Cardiovascular Study have sug- simple clinical variables, waist circumferencegested that hyperinsulinemia resulting from (290 cm) and fasting plasma triglyceride con-insulin resistance might be an independent centrations (22.0 mmol/L), might be usefulrisk factor for coronary artery disease.%This as screening tools to unmask men character-observation further stresses the importance ized by an atherogenic profile characteristicof exercise and aerobic physical training as of the insulin-resistance syndrome.@ Box 1effective interventions to increase insulin sen- shows some of the atherogenic profile fea-siti~ity.35, 87,93,102 tures associated with abdominal obesity. Obesity is age-dependent, with most sub-jects increasing their fat stores when they be-come older. Aging is associated with a decline ADIPOSE TISSUE METABOLISM ANDin physical activity that contributes to de- CARDIAC ADAPTATION IN OBESITYcreased exercise tolerance, decreased leanbody mass, and increased fat mass, with alter- Numerous enzyme pathways and hor-ations in glucose and lipoprotein metabolism. mones are implicated in adipose tissue me-Therefore, while aging, our population is be- tabolism.= Lipoprotein lipase (LPL) is synthe- coming obese. This trend has important pub- sized in adipose tissue and, by hydrolysing lic health implications, and proper nonphar- circulating triglyceride-rich lipoproteins, is macologic management of obesity and important in the provision of fatty acids for associated comorbidities is mandatory to de- their uptake and storage as triglycerides crease the burden of obesity on the health system. Unfortunately, data from the 1998 Be- havioral Risk Factor Surveillance System (BRFSS) indicate that two thirds of over- weight persons trying to lose weight reported Box 1. Abnormalities Associated with "At Risk" using physical activity as a strategy for Obesity (Insulin Resistance weight loss, but only one fifth reported being Syndrome) active at the recommended levels.4,79 t Triglycerides 1 HDL cholesterolDEFINITION t Apolipoprotein B levels t Proportion of small, dense LDL Overweight is defined as a body mass in- t Ratio of cholesteroVHDL cholesteroldex (BMI; weight in kilograms divided by the t Insulinsquare of height in meters) of 25 kg/m2 to t Glucose intolerance t Fibrinogen29.9 kg/m2 and obesity as a BMI 230 kg/m2.2 1 Factor VII activityAll overweight and obese adults aged >18 t Factor Vlllc activityyears with a BMI 225 kg/m2 are considered t TPA antigenat risk for developing cardiovascular comor- t PAL1 antigen and activitybidities.@However, it is important to empha- t C-reactive proteinsize that obesity is characterized by a remark-
  3. 3. EXERCISE IN WEIGHT MANAGEMENT OF OBESITY 461(TG).39 Insulin increases adipose tissue LPL.83 concomitant increase in lean body mass inThere are site differences in the regulation of these individuals. Higher cardiac output fromlipolysis in vitro and in vivo in normal- increased stroke volume and expanded intra- Inweight subjects.63 normal-weight men, adi- vascular volume are features of the higherpose tissue LPL activity is higher in the ab- metabolic demands generated by 0besity.5~~ 74dominal wall than in the gluteal/femoral In obesity, left ventricular filling pressure andregion1; in women, the opposite has been volume increase, shifting left ventricular func-reported.ll. 1 5 t a 9 This may be of clinical impor- tion to the left on the Frank-Starling curve. Atance because these site differences are more decrease in central blood volume accompan-marked in women than in men, and might ies weight reduction and, when present, reliefexplain why women have more fat in periph- of edema and dyspnea accompanies this im-eral sites than men. The most important lipo- p r ~ v e m e n t . ~Of, importance, because of the 56 ~lytic hormones in men are the catechol- need to move excess body weight, at anyamines, and their lipolytic effect is dependent given level of activity, the cardiac workloadupon the balance between a and p adrenergic is greater for obese subjects than for nonobesestimulation. The hormonal regulation of lipol- individuals.ysis, in particular the action of catechol-amines, is impaired in obesity, and in vivostudies have shown blunted catecholamineinduced lipolysis in obese subjects." Thus, ADIPOSE TISSUE METABOLISM ANDresistance to the lipolytic effect of catechol- EXERCISEamines and a greater antilipolytic effect ofinsulin are found in subjects with peripheral Whereas a-adrenergic mechanisms regulateas compared to abdominal obesity.24How- lipolysis at rest, P-adrenergic activity controlsever, in obese womenm,114 and fasting the lipolytic rate during exercise.1° Free fattyadipose tissue LPL activities have not been acid (FFA) availability is maximal at 25% toshown to be different between the abdominal 40% of Vozmax, and shifts in energy substratewall and gluteal regions, and the regulation mobilization and utilization occur as exerciseof the enzyme by insulin114and exercisem is intensity increases, particularly at intensitiesalso similar. This is due to increased 01-2 adre- above 70% to 80% of V ~ ~ m a Therefore,x.~~noceptor function and decreased P-adreno- above a certain degree of intensity, the muscleceptor expression in the gluteal/femoral fat preferentially operates on glycogen stored incells.63, 91 These results are in contrast to 71, situ. However, aerobic physical exercise in-what has been reported in normal-weight in- volves respiratory and circulatory systems asdividuals, in whom adipose tissue LPL differs well as the enzymatic machinery adaptationsbetween fat depots. Therefore, the alterations that facilitate the muscle to work more effec-in lipolysis associated with obesity favor tively. When adaptation to endurance exerciseweight maintenance. has taken place, the muscle is characterized The p-adrenoceptors that mediate vasodila- by more oxidative enzyme activity and istation in adipose tissue are mainly the pl- now better equipped to work at low intensitytype, whereas in skeletal muscle, the pz-sub- for long duration and to use FFA as the maintype is mainly responsible for vasodilatation. substrate. There are also changes occurring atAlthough there are differences between blood the site of lipid mobilization in adipose tissueflow in adipose tissue and other organs, the depending on the physical training fitnessincrement in blood flow with increasing adi- status." These include a more sensitive mech-posity is not proportional to the increment in anism for activation of hepatic sensitive lipaseadipose tissue mass.66Increases in total body (HSL)? and in untrained individuals, an in-fat result in higher total blood flow secondary crease in the lipolytic response of adiposeto the enlarged vascular bed, but in line with tissue to catecholamines after exercise both inthis, it is important to keep in mind that the ~ i t r o98, log, and in vivo.al Lipolysis is any- ~~adipose tissue is less vascularized than lean thing but rate limiting during exercise, and istissue with increasing obesity. Accordingly, probably in excess of that required.92 Even ifthe increase in systemic blood flow seen in p-blockade reduces the release of FFA fromobesity74cannot solely be explained by in- adipocytes, this reduction in energy supplycreased requirements due to adipose tissue to the exercising muscle is probably not clini-perfusion, but most probably occurs by the cally re1e~ant.l"~
  4. 4. 462 POIRIER & DESPRl%COMMON RISK FACTORS patients with high blood pressure are over-ASSOCIATED WITH OBESITY weight, and hypertension is about six times more frequent in obese than in leanDyslipidemia Moreover, weight gain in young people is an important risk factor for subsequent develop- As we have alluded to previously, some ment of hypertension.84Weight reduction isvery obese individuals may nevertheless one of the rare antihypertensive strategiesshow a fairly normal metabolic risk factor that decreases blood pressure in normoten-profile, whereas others may present all the sive as well as hypertensive persons.2, Asfeatures of an atherogenic and diabetogenic little as a 10% reduction in body weight canmetabolic p r ~ f i l e ~ ~ (see Box 1). Indeed, 64 - ~ ~ , decrease blood pressure among obese hyper-there is remarkable metabolic heterogeneity tensive patients.18ra It has also been suggestedamong obese subjects, and the presence of that an exaggerated blood pressure responsevisceral obesity generally worsens the meta- to exercise may be a better predictor of tar-bolic portrait. Accumulation of visceral fat get organ damage than resting blood pres-has been associated with type 2 diabetes mel- sure.47, Again, it has been reported that 50litus, hypertension, and coronary artery dis- weight loss could decrease blood pressureease.65For instance, disturbances in lipopro- and heart rate measured both at rest and attein metabolism, coagulation systems, plasma all exercise intensities.16 Interestingly, it hasinsulin-glucose homeostasis and an elevated been shown that weight reduction inducedblood pressure have all been reported in sub- by a modest exercise prescription and by ajects with visceral obesity=, =, 48, 67, 97, 97 (see hypocaloric diet could decrease left ventricu-Box 1). The dyslipidemic profile commonly lar mass, which is a well-recognized CVD riskassociated with abdominal obesity has been factor, regardless of blood pressure in obeseshown to include high TG, low HDL choles- subjects."terol and elevated apolipoprotein B concen-trations as well as an increased proportion ofsmall, dense LDL. All these features of anatherogenic dyslipidemic profile can be im- INFLUENCE OF PHYSICAL ACTIVITYproved by the incorporation of regular exer- ON ADIPOSE TISSUE METABOLISMcise in daily life activitie~.,~, 33 Fat loss 28,through dieting and/or exercise produces There is an inverse relationship betweencomparable and favorable changes in HDL the amount of daily physical activity andcholesterol and its subfractions HDL, and body weight. Exercise requires energy, andHDL, as well as in TG.43, Furthermore, the two main sources of fuel for muscle con-long-term aerobic exercise training could traction are carbohydrates (CHO) and lipid.even normalize the metabolic risk profile of The major source of lipid energy for muscleobese subjects despite the fact that subjects is the TG stored in adipose tissue, but avail-were still classified as "obese" at the end of able as FFA. Exercise is one of the most potentthe prograrn.O0 In addition, the improvement physiological stimuli for lipolysis; it is higherin the plasma lipid profile observed with the during exercise in trained subjects than thatuse of aerobic exercise in patients with type 2 reported during critical illness57 even after ordiabetes is also probably mediated mainly 84 hours of tarv vat ion.^^ In obesity, the ex-through body fat lO9 Of interest, exercise panded adipose tissue mass provides abun-seems to confer no additional benefit to dant lipid substrates to meet the needs ofweight loss when hemostatic factors are con- increased energy expenditure associated with~idered.~~ exercise. For instance, an 80-kg man with 25% body fat (20 kg) has stored in adipose tissue approximately 180,000 calories. Thus, only 1Hypertension kg of adipose tissue TG would be sufficient to provide energy for several marathons. Nu- Although it is well accepted that hyperten- merous factors associated with obesity, thatsion is a major CVD risk factor, an elevated is, gender, body fat mass, adipose tissue distri-blood pressure is an underrecognized and bution, and number and size of adipose cells,therefore an undertreated condition. It is im- contribute to the eventual response to exerciseportant to keep in mind that obesity and training. For instance, in response to a 20-hypertension often coexist; the majority of week exercise training program, Tremblay et
  5. 5. EXERCISE IN WEIGHT MANAGEMENT OF OBESITY 463a199reported that men, matched for body fat kJ (500 kcal)/d. Although aerobic exercisemass, with a high fat cell size, lost six times alone produces a modest weight reduction,more body fat mass (loss of 4.4 kg) than men generally 2% to 3%, increased physical activ-with small adipose cells (loss of 0.7 kg). Of ity is extremely important in sustaining thenote, women in this study with either high or weight-reduced state.36, lol An intervention 73,low fat cell size did not lose body fat. There- combining behavior therapy, a low-caloriefore, it seems that there might be a certain diet, and increased physical activity is proba-morphology (size + number of cells + distri- bly the most successful management ap-bution) that may explain, at least to a certain proach for weight loss and weight mainte-extent, the susceptibility to lose weight in nance. In overweight/obese patients whoresponse to an exercise p r ~ g r a mDuring ex- .~ have reached the proper ”readiness” state,ercise, the lipolytic rate has been shown to be this approach should be emphasized and sus-higher in abdominal subcutaneous than in tained for a few months before consideringgluteal/femoral subcutaneous adipose tissue, other strategies such as pharmacotherapy.especially in women,’O whereas there is no Weight loss programs that result in a slowgender difference at rest. Women also exhibit but steady weight reduction, eg, 1 pound toless lipolysis during exercise than 32 2 pounds per week, may be more effectiveand this phenomenon may help explain why long-term than those that result in rapidmen decrease body fat more efficiently with weight losses.1o5 Indeed, behavioral strategiesphysical training than do women.30, Another 99 reinforcing changes in diet and physical activ-important clinical issue that should be kept ity can produce weight loss in the range ofin mind is that when exercise is considered 10% over a period of 6 months in obesein the management of obesity, the weight loss adult^.^ Unfortunately, long-term follow-upmay be accompanied by an increase in appe- results of patients undergoing behavior ther-tite. Careful attention should be given to this apy show a return to baseline weight for theadaptation that may compromise weight majority of subjects in the absence of contin-10ss.37 ued behavior intervention.80, lo7These nega- lo6, tive results reinforce the importance of incor- porating daily exercise in the lifestyle ofEXERCISE PRESCRIPTION overweight/obese patients. Because of the presence of high left ventricular filling pres- The minimal objectives of a weight loss and sure and, as in type 2 diabetes, left ventricularmanagement program are: to prevent further diastolic dysfunction, the usually recom-weight gain, to reduce body weight, and to mended exercise prescription may be inap-permanently maintain a lower body weight. propriate for the obese i n d i v i d ~ a l sObesity .~~Regular physical activity is a well-recognized is associated with persistence of elevated car-tool for long-term weight maintenance be- diac filling pressures during exercise? l3 andcause it contributes to increased energy ex- the average left ventricular filling pressurependiture through a caloric deficit (although rises with exercise similarly (about 20 mmgenerally small) contributing to weight loss.1o2 Hg) after weight loss. Of interest, reducedAlthough epidemiologic studies have sug- ventricular compliance characterized by leftgested that weight cycling could be associ- ventricular diastolic dysfunction during exer-ated with an elevated risk of death from cise does not always regress with weightCVD,17,53 there is little evidence to support 10ss.5.13the view that weight cycling could be related An important issue is whether one needs toto an increased prevalence/risk of coronary focus on exercise intensity in order to achieveartery disease.77Patients should have their metabolic improvements and reduce the riskBMI and levels of abdominal fat measured of coronary heart disease in obese individu-with goals of weight reduction established to als. Concomitant with diet therapy, low-inten-favorably impact health outcomes, including sity training of 30% to 50% bo2max of longthe risk of a first or recurrent CVD event.loO, duration (90 minutes to 240 minutes) and112 Simply stated, weight reduction depends high frequency has been proposed for losingupon energy intake compared to energy ex- body fat. This recommendation is based onpenditure. Approximately 1 pound per week the premise that the dominant fuel for energycan be lost with no change in physical activity during the first 20 minutes of exercise is gly-if caloric intake can be reduced by only 2100 cogen; exercising more than 30 minutes will
  6. 6. 464 POIRIER & DESPRESincrease the usage of fat Of note, as (Borg scale) seem to predict the degree ofobese people have a lower mechanical effi- effort of walking.70In the clinical setting, itciency (defined by the relation between oxy- is most of the time impractical to measuregen uptake and external work), the most ap- Vo,max before giving advice on physical ac-propriate approach to prescribe exercise is to tivity. Nevertheless, measuring heart rate afterbase work intensity on the oxygen cost rela- a 4- to 6-minute walk may be a simpler waytive to Vo2max.46 This notion has clinical im- to judge the relative cost of walking. Heartportance, since subjects with obesity usually rate exceeding 100 beats per minute duringget standard recommendations to lose weight walking is generally associated with an exer-by decreasing food intake and increasing cise intensity of about 50% Vo,max (Fig. 1).physical activities. For instance, normal- Obese individuals who enjoy walking andweight subjects use about 35% Vo,max when who can tolerate this form of physical activitywalking at a self-selected, comfortable pace., without too many unpleasant side effectsThis activity is generally considered a conve- should certainly continue to do so. In general,nient and mild form of training. It is accessi- however, recommendations should focus onble to everyone and carries a low risk of training regimens, not generating pain overinjuries, which are increased in obesity be- time, otherwise compliance will obviously because of the burden of extra weight on the impaired. It is also important to keep in mindjoints. Joint considerations should, however, that various aerobic training modalitiesnot limit physical activity, since exercise com- (walking, cycling, swimming) may have a dif-bined with diet leads to improvement in pain, ferent impact on weight loss. Notably, swim-disability, performance and gait in obese ming protocols have generated rather disap-older adults with knee osteoarthritis." pointing results regarding weight However, individuals often find the exer- Health care professionals should also empha-cise prescription difficult to follow, since they size that heart rate should be properly as-get extremely tired while walking at the pace sessed at the wrist level, because the carotidrecommended by the clinician. Vozmax and pulsation may be difficult to find in obeseheart rate during brisk walking is higher in patients. It is also very important to informobese than in normal-weight i n d i v i d ~ a l s . ~ ~ patients about the results to be expected theThus, even walking may represent a difficult from the recommended exercise regimen inexercise modality for obese individuals, since order to avoid unrealistic expectations onthey can use as much as 56% Vo,max (some weight loss. Body weight normalizationusing between 64% to 98% Vo,max) to meet should obviously not be the target, but ratherthe demand of such an activity compared to some weight loss associated with improve-only about 35% in normal-weight subjects. ments in the risk factor profile. As an exam-Therefore, long and brisk walks should not ple, a working model of an algorithm for thebe regarded as low-intensity forms of trainingfor obese people in general. Since the averagework load during a day causes fatigue if it 100exceeds 30% to 40% Vozmax,2 it seems natu-ral that walking for exercise may be too de-manding for many obese patients. In addi- 80tion, walking outdoors can be demandingbecause of uneven or slippery surfaces, and ii Eheavy outdoor clothes during the autumn ON *>and winter seasons add to body weight. sMoreover, severe obesity may impair the abil-ity to properly walk, especially when the obe-sity is of the gynoid form. Gluteal fat in-creases the friction on clothing and skin,making it even more unpleasant to walk. This 80 90 100 110 120 130 140 150 common problem is often neglected in clinical Heart rate (beatslminute)practice. Increasing obesity and age, abnor-mal gait pattern, degenerative pain, friction Figure 1. Simple regression between percentage of of clothes and skin problems may increase Vo2max and heart rate during walking in obese women. r = 0.63; P < .0001. (Adapted from Mattsson E, Larsson the relative oxygen cost. Clinical assessment UE, Rossner S: Is walking for exercise too exhausting formay be difficult, because neither BMI, walk- obese women? Int J Obes Relat Metab Disord 21:380- ing speed rate, perceived exertion nor pain 386, 1997; with permission.)
  7. 7. EXERCISE IN WEIGHT MANAGEMENT OF OBESITY 465detection and management of the high-risk cutaneous abdominal and gluteal/ femoralobese individuals is suggested in Figure 2. adipose tissue regions.7j Thus, a reduction of body weight to a level that would still be considered as overweight is accompanied byReduced-0bese Individuals a decreased basal rate of lipolysis but by an improved catecholamine-stimulated lipolysis A better understanding of adipose tissue in vitros Insulin sensitivity is also increasedmetabolism in weight-reduced obese subjects after weight reduction under isocaloric main-is important because of the high recidivism. tenance of the reduced-obese state.l13,115 Al-Weight loss by hypocaloric diet decreases li- though most of the in vivo action of insulinpolysis and fat oxidation, adaptations that is accounted for by its effect on the skeletalmay predispose individuals to weight re- the ability of increased insulin sensi-gaining. The blunted utilization of fat as fuel tivity to predict weight regain in reduced-during a 60-minute bout of exercise at 50% obese is partly explained by theVo,max contributes to a positive fat balance effects of insulin on adipose tissue. Suggestedand possibly weight gain in formerly obese risk factors for body weight regain include:individuals.ssHowever, studies of adipose tis-sue function in vitro have shown that the Increased insulin sensitivityaddition of exercise training to a hypocaloric Low resting metabolic rate for a given bodydiet counteracts the decline in lipolytic re- size and compositionsponsiveness, fat oxidation and resting meta- Low ratio of fat to carbohydrate oxidationbolic rate in weight-reduced postmenopausal (ie, high respiratory quotient)women.76, Moreover, the lipolytic adapta- 88 Low levels of physical activitytions are of the same magnitude between sub- Caloric intake Risk factor risk factor according Further assessment of the risk profile BMI > 25 kg/m2 Low risk 1 High risk I I . profile management with emphasis on the Figure 2. Working model for an algorithm allowing effective and simple identification by health professionals of the high-risk form of overweightness and obesity among individuals asymptomatic for coronary artery disease (CAD). BMI = Body mass index; TG = triglycerides.
  8. 8. 466 POIRIER & DESP&SSUMMARY agement program that was designed for obese children.",95 Obesity is a chronic metabolic disorder as- Thirty to 45 minutes of physical activity ofsociated with CVD and increased morbidity moderate intensity, performed 3 to 5 days aand mortality. When the BMI is 2 30 kg/m*, week, should be encouraged. All adultsmortality rates from all causes, and especially should set a long-term goal to accumulate atCVD, are increased by 50% to 100%. There is least 30 minutes or more of moderate-inten-strong evidence that weight loss in over- sity physical activity on most, and preferablyweight and obese individuals improves risk all days.79Public health interventions pro-factors for diabetes and CVD. Additional evi- moting walking are likely to be the mostdence indicates that weight loss and the asso- successful. Indeed, walking is unique be-ciated diuresis reduce blood pressure in both cause of its safety, accessibility, and popular-overweight hypertensive and nonhyperten- ity. It is noteworthy that there is a clear dis-sive individuals, reduce serum TG levels, in- sociation between the adaptation of cardiore-crease high-density lipoprotein cholesterol spiratory fitness and the improvements in thelevels, and may produce some reduction in metabolic risk profile that can be induced bylow-density lipoprotein cholesterol concentra- endurance training programs. It appears thattions. Of interest, even if weight loss is mini- as long as the increase in energy expendituremal, obese individuals showing a good level is sufficient, low-intensity endurance exerciseof cardiorespiratory fitness are at reduced risk is likely to generate beneficial metabolic ef-for cardiovascular mortality than lean but fects that would be essentially similar topoorly fit subjects.62Insulin and catechola- those produced by high-intensity exercise.mines have pronounced metabolic effects on The clinician should therefore focus on thehuman adipose tissue metabolism. Insulin improvement of the metabolic profile ratherstimulates LPL and inhibits HSL; the opposite than on weight loss alone. Realistic goalsis true for catecholamines. There is regional should be set between the clinician and thevariation in adipocyte TG turnover favoring patient, with a weight loss of approximatelylipid mobilization in the visceral fat depots of 0.5 to 1pound per week. It should be keptand lipid storage in the peripheral subcutane- in mind that since it generally takes years toous sites. The hormonal regulation of adipo- become overweight or obese, a weight losscyte TG turnover is altered in obesity and pattern of 0.5 or 1 pound per week will re-is most marked in central obesity. There is quire time and perseverance to reach the pro-resistance to insulin stimulation of LPL; how- posed target. However, the use of physicalever, LPL activity in fasted obese subjects is activity as a method to lose weight seemsincreased and remains so following weight inversely related to patients age and BMIreduction. Catechol- and directly related to the level of education?amine-induced lipolysis is enhanced in vis- Thus, public health interventions helpingceral fat but decreased in subcutaneous fat. these groups to become physically active re-Numerous adaptive responses take place main a challenge61and further emphasize thewith physical training. These adaptations re- importance of the one-on-one interaction be-sult in a more efficient system for oxygen tween the clinician/health care professionaltransfer to muscle, which is now able to better with the obese individual "at risk" of CVD.utilize the unlimited lipid stores instead of This notion is critical, as it has been shownthe limited carbohydrate reserves available. that less than half of obese adults have re-In addition, the reduced adipose tissue mass ported being advised to lose weight underrepresents an important mechanical advan- the guidance of health care professionals.",tage, allowing better long-term work. Genderdifferences have been reported in the adapta-tion of adipose tissue metabolism to aerobicexercise training. Physical training helps Referencescounteract the permissive and affluent envi-ronment that predisposes reduced-obese sub- 1. The sixth report of the Joint National Committee onjects to regain weight. An exercise program prevention, detection, evaluation, and treatment of high blood pressure. Arch Intern Med 1572413-using weight resistance modalities may also 2446, 1997be included safely, and it improved program 2. Clinical Guidelines on the Identification, Evaluation,retention in a multidisciplinary weight man- and Treatment of Overweight and Obesity in
  9. 9. EXERCISE IN WEIGHT MANAGEMENT OF OBESITY 467 Adults-The Evidence Report. National Institutes of 22. Cigolini M, Targher G, Bergamo A1 et al: Visceral fat Health. Obes Res Suppl2:51S-209S, 1998 accumulation and its relation to plasma hemostatic 3. Executive summary of the clinical guidelines on the factors in healthy men. Arterioscler Thromb Vasc identification, evaluation, and treatment of over- Biol 16368-374,1996 weight and obesity in adults. Arch Intern Med 23. Colditz GA, Willett WC, Rotnitzky A et a1 Weight 15818551867,1998 gain as a risk factor for clinical diabetes mellitus in 4. Prevalence of leisure-time physical activity among women. Ann Intem Med 122481486,1995 overweight adults-United States, 1998. MMWR 24. Coppack SW, Jensen MD, Miles JM: In vivo regula- 49:32&330,2000 tion of lipolysis in humans. J Lipid Res 35:177-193, 5. Alexander JK, Peterson KL: Cardiovascular effects 1994 of weight reduction. Circulation 45:31&318, 1972 25. DeFronzo RA, Jacot E, Jequier E et al: The effect of 6. Andersen RE: The spread of the childhood obesity insulin on the disposal of intravenous glucose. Re- epidemic. CMAJ 163:1461-1462, 2000 sults from indirect calorimetry and hepatic and fem- 7. Anderson B, Xu XF, Rebuffe-Scrive M et al: The oral venous catheterization. Diabetes 3O:lOOO-1007, effects of exercise, training on body composition 1981 and metabolism in men and women. Int J Obes 26. DesprCs JP: Abdominal obesity and the risk of coro- 15:7.!%81, 1991 nary artery disease. Can J Cardiol8561-562, 1992 8. Amer P: Control of lipolysis and its relevance to 27. Despres JP: Dyslipidaemia and obesity. Baillieres development of obesity in man. Diabetes Metab Rev Clin Endocrinol Metab 8:629-660, 1994 4507-515, 1988 28. DesprCs JP: Visceral obesity, insulin resistance, and 9. Amer P: Impact of exercise on adipose tissue metab- dyslipidemia: contribution of endurance exercise olism in humans. Int J Obes Relat Metab Disord 19 training to the treatment of the plurimetabolic syn- Suppl4:S18-S21,1995 drome. Exerc Sport Sci Rev 25:271-300,199710. Amer P, Kriegholm E, Engfeldt P et a1 Adrenergic 29. DesprCs JP: The insulin resistance-dyslipidemic syn- regulation of lipolysis in situ at rest and during drome of visceral obesity: effect on patients’ risk. exercise. J Clin Invest 85:893-898, 1990 Obes Res 6 Suppl 1:8%17S, 199811. Arner P, Lithell H, Wahrenberg H et al: Expression of lipoprotein lipase in different human subcutane- 30. DesprCs JP, Bouchard C: Effects of aerobic training and heredity on body fatness and adipocyte lipoly- ous adipose tissue regions. J Lipid Res 32423-429, 1991 sis in humans. J Obes Weight Regul3:219-235,198412. Astrand PO, Rodahl KTextbook of work physiol- 31. DesprCs JP, Bouchard C, Savard R et al: Effects of ogy. Physiological bases of exercise. New York, exercise-training and detraining on fat cell lipolysis McGraw-Hill, 1986, pp 1-756 in men and women. Eur J Appl Physiol 53:25-30,13. Backman L, Freyschuss U, Hallberg D et al: Revers- 1984 ibility of cardiovascular changes in extreme obesity. 32. Despres JP, Bouchard C, Savard R et a1 The effect of Effects of weight reduction through jejunoileostomy. a 20-week endurance training program on adipose- Acta Med Scand 205:367-373,1979 tissue morphology and lipolysis in men and women.14. Balkau B, Shipley M, Jarrett RJ et al: High blood Metabolism 33:235239, 1984 glucose concentration is a risk factor for mortality 33. DesprCs JP, Lamarche B: Low-intensity endurance in middle-aged nondiabetic men. 20-year follow-up exercise training, plasma lipoproteins and the risk of in the Whitehall Study, the Paris Prospective Study, coronary heart disease. J Intern Med 236:7-22,1994 and the Helsinki Policemen Study. Diabetes Care 34. DesprCs JP, Lamarche 8, Mauriege P et a1 Hyperin- 21:360-367, 1998 sulinemia as an independent risk factor for ischemic15 Belfiore F, Borzi V Napoli E et al: Enzymes related , heart disease. N Engl J Med 334:952-957, 1996 to lipogenesis in the adipose tissue of obese subjects. 35. DesprCs JP,Pouliot MC, Moojani S et al: Loss of Metabolism 25:483-493, 1976 abdominal fat and metabolic response to exercise16 Ben-Dov I, Grossman E, Stein A et al: Marked training in obese women. Am J Physiol 261:E159- weight reduction lowers resting and exercise blood E167, 1991 pressure in morbidly obese subjects. Am J Hyper- 36. Doucet E, Imbeault P, fdmeras N et a1 Physical tens 13:251-255,2000 activity and low-fat diet: is it enough to maintain17 Blair SN, Shaten J, Brownell K et a1 Body weight weight stability in the reduced-obese individual fol- change, all-cause mortality and cause-specific mor- lowing weight loss by drug therapy and energy tality in the Multiple Risk Intervention Trial. Ann restriction? Obes Res 4323-333,1999 Intem Med 119:749-757, 1993 37. Doucet E, Imbeault P, St-Pierre S et al: Appetite after18. Blumenthal JA, Shenvood A, Gullette ECD et a1 weight loss by energy restriction and a low-fat diet- Exercise and weight loss reduce blood pressure in exercise follow-up. Int J Obes 2490&914,2000 men and women with mild hypertension. Effects on 38. Drenick EJ, Bale GS, Seltzer F et al: Excessive mor- cardiovascular, metabolic, and hemodynamic func- tality and causes of death in morbidly obese men. tioning. Arch Intern Med 1603947-1958,2000 JAMA 243:443-445, 198019. Bouchard C, DesprCs JP, Mauriege P: Genetic and 39. Eckel RH: Lipoprotein lipase. A multifunctional en- nongenetic determinants of regional fat distribution. zyme relevant to common metabolic diseases. N Endocr Rev 14:72-93, 1993 Engl J Med 320:1060-1068, 198920. Beumann B, Tremblay A Effects of exercise training 40. Eckel R : Obesity and heart disease: a statement H on abdominal obesity and related metabolic compli- for healthcare professionals from the Nutrition cations. Sports Med 21:191-212,1996 Committee, American Heart Association. Circula-21. Calle EE, Thun MJ, Petrelli JM et al: Body-mass tion 96:3248-3250,1997 index and mortality in a prospective cohort of US. 41. Eckel, R. H. Insulin resistance: an adaptation for adults. N Engl J Med 341:1097-1105, 1999 weight maintenance. Lancet 340, 1452-1453,2000.
  10. 10. 468 POWER & DESPRkS42. Eckel RH, Krauss RM: American Heart Association 61. Lappalainen R, Tuomisto MT, Giachetti I et al: Re- call to action: obesity as a major risk factor for cent body-weight changes and weight loss practices coronary heart disease. AHA Nutrition Committee. in the European Union. Public Health Nutrition Circulation 972099-2100, 1998 2:13!%141,200043. Eckel RH, Yost TJ: HDL subfractions and adipose 62. Lee CD, Blair SN, Jackson AS: Cardiorespiratory tissue metabolism in the reduced-obese state. Am J fitness, body composition, and all-cause and cardio- Physiol256E740-E746, 1989 vascular disease mortality in men. Am J Clin Nutr44. Epstein L, Coleman K, Myers M Exercise in treating 69:373-380, 1999 obesity in children and adolescents. Med Sci Sports 63. Leibel RL, Edens NK, Fried SK Physiologic basis Exerc 29:428-435, 1996 for the control of body fat distribution in humans.45. Eriksson KF, Lindgarde F: Prevention of type 2 Annu Rev Nutr 9417443,1989 (non-insulin-dependent) diabetes mellitus by diet 64. Lemieux I, Pascot A, Couillard C et al: Hypertriglyc- and physical exercise. The 6-year Malmo feasibility eridemic waist: A marker of the atherogenic meta- study. Diabetologia 34:891-898, 1991 bolic triad (hyperinsulinemia; hyperapolipoprotein46. Farrell PA, Gustafson AB, Kalkhoff RK: Assessment B; small, dense LDL) in Men? Circulation 102:179- of methods for assigning treadmill exercise work- 184,2000 loads for lean and obese women. Int J Obes 9:49- 65. Lemieux S, DesprCs JP: Metabolic complications of 58, 1985 visceral obesity: contribution to the aetiology of type47. Filipovsky J, Ducimetiere P, Safar ME: Progostic sig- 2 diabetes and implications for prevention and treat- nificance of exercise blood pressure and heart rate ment. Diabetes Metab. 20:375-393, 1994 in middle-aged men. Hypertension 20333-339,1992 66. Lesser GT, Deutsch S: Measurement of adipose tis-48. Folsom AR, Qamhieh HT, Wing RR et al: Impact of sue blood flow and perfusion in man by uptake of weight loss on plasminogen activator inhibitor (PAI- 85Kr. J Appl Physiol23:621-630, 1967 l), factor VII, and other hemostatic factors in moder- ately overweight adults. Arterioscler Thromb 67. Licata G, Scaglione R, Avellone G et a1 Hemostatic 13:162-169, 1993 function in young subjects with central obesity: rela-49. Galuska DA, Will JC, Serdula MK Are health care tionship with left ventricular function. Metabolism professionals advising obese patients to lose weight? 44~1417-1421, 1995 JAMA 28215761578, 1999 68. MacMahon SW, Wilcken DE, Macdonald GJ: The50. Gottdiener JS, Brown J, Zoltick J et a1 Left ventricu- effect of weight reduction on left ventricular mass. lar hypertrophy in men with normal blood pressure: A randomized controlled trial in young, overweight relation to exaggerated blood pressure response to hypertensive patients. N Engl J Med 314334-339, exercise. AM Intern. Med 112:161-166, 1990 198651. Grubbs L: The critical role of exercise in weight 69. Marin P Oden 8, Bjomtorp P Assimilation and , : control. Nurse Practitioner 18:20-29, 1993 mobilization of triglycerides in subcutaneous ab-52. Gwinup G: Weight loss without dietary restriction: dominal and femoral adipose tissue in vivo in men: efficacy of different forms of aerobic exercise. Am J effects of androgens. J Clin Endocrinol Metab Sports Med 15:275-279, 1987 80239-243, 199553. Hamm P, Shekelle RB, Stamler J: Large fluctuations 70. Mattsson E, Larsson UE, Rossner S: Is walking for in body weight during young adulthood and 25- exercise too exhausting for obese women? Int J Obes year risk of coronary death in men. Am J Epidemiol Relat Metab Disord 21:380-386, 1997 129~312-318,1989 71. MauriPge P, DesprCs JP, Prud’homme D et al: Re-54. Himeno E, Nishino K, Nakashima Y et a1 Weight gional variation in adipose tissue lipolysis in lean reduction regresses left ventricular mass regardless and obese men. J Lipid Res 32:1625-1633, 1991 of blood pressure level in obese subjects. Am Heart 72. MauriPge P, Prud’homme D, Marcotte M et a1 Re- J 131:313-319, 1996 gional differences in adipose tissue metabolism be-55. Kaltman AJ, Goldring RM: Role of circulatory con- tween sedentary and endurance-tained women. Am gestion in the cardiorespiratory failure of obesity. J Physiol273:E497-E506, 1997 Am J Med 60645-653,1976 73. McGuire MT, Wing RR, Klem ML et a1 Behavioral56. Karason K, Lindroos AK, Stenlof K et al: Relief of strategies of individuals who have maintained long- cardiorespiratory symptoms and increased physical term weight losses. Obes Res 43334-341, 1999 activity after surgically induced weight loss. Results 74. Messerli FH, Nunez BD, Ventura HO et al: Over- from the Swedish Obese Subjects Study. Arch Intem weight and sudden death. Increased ventricular ec- Med 160:1797-1802,2000 topy in cardiopathy of obesity. Arch Intem Med57. Klein S, Peters EJ, Shangraw RE et al: Lipolytic 1471725-1728, 1987 response to metabolic stress in critically ill patients. 75. Messier SP, Loeser RF, Mitchell MN et al: Exercise Crit Care Med 19:776-779, 1991 and weight loss in obese older adults with knee58. Klein S, Wolfe RR: Carbohydrate restriction regu- osteoarthritis: a preliminary study. J Am Geriatr SOC lates the adaptive response to fasting. Am J Physiol 48:1062-1072, 2000 262E631-E636,1992 76. Nicklas BJ, Rogus EM, Goldberg AP: Exercise blunts59. Kohrt WM, Kirwan JP, Staten MA et al: Insulin declines in lipolysis and fat oxidation after dietary- resistance in aging is related to abdominal obesity. induced weight loss in obese older women. Am J Diabetes 42:273-281, 1993 Physiol273:E149-E155, 199760. Lamarche B, DesprCs JP, Moorjani S et al: Evidence 77. Olson MB, Kelsey SF, Bittner V et al: Weight cycling for a role of insulin in the regulation of abdominal and high-density lipoprotein cholesterol in women: adipose tissue lipoprotein lipase response to exercise Evidence of an adverse effect. A report from the training in obese women. Int J Obes Relat Metab NHLBI-sponsored WISE study. J Am Coll Cardiol Disord 17255-261, 1993 36:1565-1571,2000
  11. 11. EXERCISE IN WEIGHT MANAGEMENT OF OBESITY 46978. Pan XR, Li GW, Hu YH et al: Effects of diet and in men. A randomized, controlled trial. Ann Intem exercise in preventing NIDDM in people with im- Med 133:92-103,2000 paired glucose tolerance. The Da Qing IGT and Dia- 94. Savard R, Despres JP, Marcotte M et al: Acute effects betes Study. Diabetes Care 20537-544, 1997 of endurance exercise on human adipose tissue me-79. Pate RR, Pratt M, Blair SN et al: Physical activity tabolism. Metabolism 36:480-485, 1987 and public health. A recommendation from the Cen- 95. Sothem MS, Loftin JM, Udall JN et al: Safety, feasi- ters for Disease Control and Prevention and the bility, and efficacy of a resistance training program American College of Sports Medicine. JAMA in preadolescent obese children. Am J Med Sci 273:402407, 1995 319:370-375, 200080. Perri MG, Nezu AM, Patti ET et al: Effect of lenght 96. Stamler R, Stamler J, Riedlinger WF et al: Weight of treatment on weight loss. J Consult Clin Psychol and blood pressure. Findings in hypertension 57:450-452, 1989 screening of 1 million Americans. JAMA 240:1607-81. Phillips SM, Green HJ, Tarnopolsky MA et a1 Effects 1610, 1978 of training duration on substrate turnover and oxi- 97. Svendsen OL, Hassager C, Christiansen C et al: dation during exercise. J Appl Physiol 81:2182- Plasminogen activator inhibitor-1, tissue-type plas- 2191, 1996 minogen activator, and fibrinogen: Effect of dieting82. Poirier P, Catellier C, Tremblay A et al: Role of body with or without exercise in overweight postmeno- fat loss in the exercise-induced improvement of the pausal women. Arterioscler Thromb Vasc Biol plasma lipid profile in non-insulin-dependent diabe- 16~381-385,1996 tes mellitus. Metabolism 453383-1387, 1996 98. Toode K, Viru A, Eller A Lipolytic actions of hor-83. Poirier P, Eckel RH: Adipose tissue metabolism and mones on adipocytes in exercise-trained organisms. obesity. In Claude Bouchard (ed): Physical activity Jpn J Physiol43:253-258, 1993 and obesity. Champaign, IL, Human Kinetics, 2000, 99. Tremblay A, Despres JP, Leblanc C et al: Sex dimor- pp 181-200 phism in fat loss in response to exercise-training. J84. Poirier P, Eckel RH: The heart and obesity. In Fuster Obes Weight Regul3:193-203, 1984 V Alexander RW, King S et a1 (eds): Hurst’s The , 100. Tremblay A, Desprks JP, Maheux J et a1 Normaliza- Heart, ed. 10. New York, McGraw-Hill Companies, tion of the metabolic profile in obese women by 2000, pp 2289-2303 exercise and a low fat diet. Med Sci Sports Exerc85. Poirier P, Gameau C, Bogaty P et a1 Impact of left 23:1326-1331, 1991 ventricular diastolic dysfunction on maximal tread- 101. Tremblay A, Doucet E, Imbeault P et al: Metabolic mill performance in normotensive subjects with fitness in active reduced-obese individuals. Obes well-controlled type 2 diabetes mellitus. Am J Res 6:556-563, 1999 Cardiol 85:473-477,2000 102. Tremblay A, Nadeau A, Desprks JP et al: Long-term86. Pouliot MC, Desprks JP, Lemieux S et al: Waist cir- exercise training with constant energy intake. 2: Ef- cumference and abdominal sagittal diameter: best fect on glucose metabolism and resting energy ex- simple anthropometric indexes of abdominal vis- penditure. Int J Obes 147584,1990 ceral adipose tissue accumulation and related car- 103. van Baak MA, Mooij JM, Wijnen JA: Effect of in- diovascular risk in men and women. Am J Cardiol creased plasma non-esterified fatty acid concentra- 73460468, 1994 tions on endurance performance during beta-adre-87. Pratley RE, Hagberg JM, Dengel DR et al: Aerobic noceptor blockade. Int J Sports Med 142-8, 1993 exercise training-induced reductions in abdominal 104. Vanltallie TB: Prevalence of obesity. Endocrinol fat and glucose-stimulated insulin responses in mid- Metab Clin North Am 252387-905, 1996 dle-aged and older men. J Am Geriatr SOC 481055- 105. Wadden TA, Foster GD, Letizia KA: One-year be- 1061,2000 havioral treatment of obesity; comparison of moder-88. Ranneries C, Bulow J, Buemann B et al: Fat metabo- ate and severe caloric restriction and the effects of lism in formerly obese women. Am J Physiol weight maintenance therapy. J Consult Clin Psychol 274E155-E161,1998 62165171,199489. Rebuffe-Scrive M, Enk L, Crona N et al: Fat cell 106. Wadden TA, Stemberg JA, Letizia KA et al: Treat- metabolism in different regions in women. Effect of ment of obesity by very low calorie diet, behavior menstrual cycle, pregnancy, and lactation. J Clin therapy, and their combination: a five-year perspec- Invest 75:1973-1976, 1985 tive. Int J Obes 13:3946, 198990. Reeder BA, Senthilselvan A, Despres JP et al: The 107. Wadden TA, Stunkard AJ: Controlled trial of very association of cardiovascular disease risk factors low calorie diet, behavior therapy, and their combi- with abdominal obesity in Canada. Canadian Heart nation in the treatment of obesity. J Consult Clin Health Surveys Research Group. CMAJ 157 Suppl Psychol 54482488,1986 1:539-545,1997 108. Wahrenberg H, Engfeldt P, Bolinder J et al: Acute91. Reynisdottir S, Wahrenberg H, Carlstrom K et al: adaptation in adrenergic control of lipolysis during Catecholamine resistance in fat cells of women with physical exercise in humans. Am J Physiol 1987 upper-body obesity due to decreased expression of 253:E383-E390,1987 beta 2-adrenoceptors. Diabetologia 37:428-435, 109. Walker KZ, Piers LS, Putt RS et al: Effects of regular 1994 walking on cardiovascular risk factors and body92. Romijn JA, Coyle EF, Sidossis LS et al: Regulation composition in normoglycemic women and women of endogenous fat and carbohydrate metabolism in with type 2 diabetes. Diabetes Care 22555561,1999 relation to exercise intensity and duration. Am J 110. Wee CC, McCarthy EP, Davis RB et al: Physician Physiol265E380-E391,1993 counseling about exercise. JAMA 282:1583-1588,93. Ross R, Dagnone D, Jones PJH et al: Reduction in 1999 obesity and related comorbid conditions after diet- 111. Wei M, Gibbons LW, Kampert JB et al: Low cardiore- induced weight loss or exercise-induced weight loss spiratory fitness and physical inactivity as pre-
  12. 12. 470 POIRIER & DESPaS dictors of mortality in men with type 2 diabetes. way for resumption of the obese state. J Clin Endo- Ann Intern Med 132605411,2000 crinol Metab 67259-264,1988112. Wood PD, Stefanick ML, Dreon DM et al: Changes 114. Yost TJ, Eckel RH: Regional similarities in the meta- in plasma lipids and lipoproteins in overweight men bolic regulation of adipose tissue lipoprotein lipase. during weight loss through dieting as compared Metabolism 41:33-36, 1992 with exercise. N Engl J Med 319:1173-1179, 1988 115. Yost TJ, Jensen DR, Eckel R :Weight regain follow- H113. Yost TJ, Eckel RH:Fat calories may be preferentially ing sustained weight reduction is predicted by rela- stored in reduced-obese women: a permissive path- tive insulin sensitivity. Obes Res 3:583-587,1995 Address reprint requests to Paul Poirier, MD, FRCPC Laval University School of Pharmacy Institut de Cardiologie et de Pneumologie Laval Hospital 2725 Chemin Sainte-Foy Sainte-Foy, Qukbec, Canada G1V 4G5