serious cardiovascular side effects of large doses of anabolic steroids … · 2017-04-12 ·...

European Heart Journal (1996) 17, 1576-1583

Serious cardiovascular side effects of large doses ofanabolic steroids in weight lifters

M. S. Nieminen*, M. P. Ramo*, M. Viitasalo*, P. Heikkilaf, J. Karjalainen*,M. Mantysaarii and J. Heikkila*

* Department of Medicine, Helsinki University Central Hospital, Finland; ^Department of Pathology,Helsinki University Central Hospital, Finland; \Central Military Hospital, Helsinki, Finland

Pathological cardiovascular manifestations are reported infour male patients, who had taken massive amounts ofanabolic steroids while undergoing many years of strengthtraining. One patient was referred because of ventricularfibrillation during exercise, one because of clinically mani-fest heart failure, and one because of arterial thrombus inhis lower left leg. The fourth patient was persuaded toattend for a check-up because of a long history of massiveuse of anabolic steroids. All four patients had cardiachypertrophy. Two of the patients had symptoms and signsof heart failure, and one of these two had a massivethrombosis in both right and left ventricles of his heart.After cessation of the use of anabolic steroids in the otherpatient with heart failure, left ventricular wall thickness

reduced quickly from 12 to 10-5 mm, and fractional short-ening increased from 14% to 27%. Endomyocardial biopsyrevealed increased fibrosis in the myocardium in two of thethree cases. HDL-cholesterol was 0-58mmol.l~' and0-35 mmol . 1 ~ ' in the two patients still using multipleanabolic steroids at the time of investigation. The cardio-vascular findings described in the present paper shouldwarn all physicians and athletes about the possible seriousacute and long-term side effects of the massive use ofanabolic steroids.(Eur Heart J 1996; 17: 1576-1583)

Key Words: Anabolic steroids, congestive heart failure,left ventricular hypertrophy, life threatening arrhythmia.

Introduction

Anabolic steroids stimulate cellular protein synthesis byandrogen receptors, and promote growth in all organsthat have the ability to grow1'1 similar to androgens'21.Their therapeutic use involves replacement therapy inhypogonadal males; they improve nitrogen balance incatabolic states, and stimulate erythropoiesis in thetreatment of bone marrow failures'31. Anabolic steroidshave been used by athletes to improve physicalperformance141.

Experimental studies have demonstrated thatprolonged treatment with anabolic steroids leads toincreased peripheral vascular resistance and dose-dependent cardiac hypertrophy together with depressedcontractility of the heart'5'6'. In myocardial cell cultures,testosterone cypionate causes a significant release oflactate dehydrogenase indicating cellular injury17'.

In weight lifters, anabolic steroids increaseventricular wall thickness, end-diastolic volume and left

Revision submitted 15 January 1996, and accepted 15 February1996.

Correspondence: Markku S. Nieminen, Cardiovascular Laboratory,Division of Cardiology, Department of Medicine, HelsinkiUniversity Central Hospital, FIN-00290 Helsinki, Finland.

ventricular mass, and isovolumetric relaxation time isprolonged significantly*81. Autopsy findings in a 28-year-old weight lifter who had taken anabolic steroids incombination with a protein-rich diet containing 2-3 gcholesterol daily demonstrated coronary atherosclerosisand interstitial fibrosis in the myocardium and endo-cardium191. In several reports, the use of anabolicsteroids has also been linked to arterial occlusion'10"1.They are potentially atherogenic through their action onthe lipid metabolism'121.

In the present paper we report four youngmen who had all used high doses of anabolic steroidsfor many years in combination with weight trainingand exhibited serious pathological cardiac manifesta-tions.

Methodological aspects

It is often difficult to find competitive athletes forcardiovascular investigations who admit that they havetaken anabolic steroids. The amount and use of steroidsis a delicate matter. However, it was possible to obtain adetailed history of anabolic steroid use in three of thepatients and the fourth admitted extensive use of thesedrugs.

0195-668X/96/101576 + 08 S18.00/0 © 1996 The European Society of Cardiology

Serious cardiovascular side effects by anabolic steroids 1577

Table 1 The dosages and duration of use of the anabolic steroids during the last yearprior to admission

Agent

Methandienone (po)Mesterelone (po)Oxymetholone (po)Stanatsolol (po)Methyltestosterone (po)Oxandrolone (po)Fluoxymesterone (po)Tamoxifen (po)Clenbuterol (po)Bromoknptin (po)Testosterone-undecanoate (po)Stanatsol (im)Testosterone (im)Testosterone-proprionate (im)Human corion gonadotropine (im)Growth hormone (sc)Insuhn (sc)

Patient

mg/IU

7501050

110870625250830348

400 ug**45

2000675

2375825

13 750IU89 IU19 IU

1

months

812

0-73

0-821722

5 days44263

4 days

Patient

mg/IU

762

69010

210

3001575 u g "

3318566

1700750

1300 IU120 IU

2

months

7

2-51 day

10 days

11-5

0-567153

Patient 3

mg i

1200

5004500

months

12

1212

po = by mouth (per ora); im = by intramuscular injections, sc = by subcutaneous route; ** = dosagesuncertain.

Routine echocardiography was performed in allof the patients, and because of left ventricular systolicand diastolic dysfunction, an endomyocardial biopsywas taken in three of the four. In the fourth patient,biopsy was contraindicated because of a ventricularthrombus. Maximal bicycle exercise testing was per-formed in three cases, and three of the patients had24-h ECG recordings. Coronary angiography, thalliumscintigraphy and programmed electrophysiologicalstimulation were performed, depending on clinicalindications. The events leading to referral and patienthistories are described individually.

Patients

Patient 1, uncomplicated, with leftventricular hypertrophy

A 33-year-old male, a close friend of patient 2, wasreferred for cardiac examination because of a longhistory of anabolic steroid use. He had been weighttraining for many years and had taken short periods ofanabolic steroids since 1985. The present use of anabolicsteroids began in December 1991 and during the years1992-1993 he took steroids and other hormones accord-ing to the list shown in Table 1. Echocardiographyshowed increased left ventricular wall thickening andventricular dilatation (Table 2). Endomyocardial biopsyrevealed diffuse and spotty fibrosis of the heart, endo-cardial thickening and diffuse oedema. Blood pressurewas 118/65 mmHg, pulse rate 51 beats . min~', and theECG was considered normal. No pathological findingswere found subsequent to the 24-h ambulatory ECG

recording. Maximal working capacity on bicycle exercisetesting was 300 W and no electrocardiographic abnor-malities were present. The amount of high densitylipoprotein in serum was significantly reduced (Table 3).

Patient 2, ventricular tachycardia duringexercise

A 29-year-old male, who had been weight training foryears, had taken anabolic steroids during several periodsover the past 8 years. The present prolonged use ofsteroids began in 1989 (Table 1). In March 1993 he waspreparing for a body-building competition by reducinghis weight (11 kg in 17 days) and using massive doses ofclenbuterol. At a routine exercise test at 250 W worklevel, a monomorphic ventricular tachycardia of230 beats. min ~ ' started from a preceding sinus rate of142 beats . min ~ ' (Fig. la). Exercise was stopped. After1 min of rest, the rhythm degenerated into a polymor-phic ventricular tachycardia, finally resembling ventricu-lar fibrillation and causing unconsciousness (Fig. lb).After cardioversion with 300 J and a few slow wide QRScomplexes, the same monomorphic ventricular tachy-cardia started again, returning spontaneously to sinusrhythm in 20 s.

On arrival at hospital, the patient was insinus rhythm. His blood pressure was 130/90 mmHg;serum sodium and potassium concentrations were141 mmol. 1 ~ ' and 4-3 mmol. 1 ~ ', respectively. Bloodhaemoglobin concentration was 155 g . 1 ~ ' and leuco-cyte count was normal. Blood glucose and lipid data areshown in the Table 3. There were no signs of myocardialischaemia or injury in the resting ECG. In the high

Eur Heart J, Vol. 17, October 1996

1578 M. S. Nieminen et al.

Table 2 Echocardiographic data of the patients

FSLVEDDLVESDLADRVDIVSTPWTE/ALVMi*

Patient 1March

33553726301414

1-4155

Patient 2

March

30604235341414

221

August

33543640341312

165

March

14796835201212

1-5318

Patient 3

July

196452311412121 2

225

December

27634626141111

1-7178

Patient 4May

13%78 mm68 mm51 mm74 mm11 mm15 mm

228 g m " 2

FS = fractional shortening; LAD = left atrial diameter; RVD = right ventricular diameter;IVST = interventricular septal thickness; PWT = posterior wall thickness; E/A = mitral flow Epoint/A point flow velocity index, LVMi = LVM/body surface area; 'Calculated by cubic formula.

Table 3 Blood lipid profile and glucose data of the patients

Parameter Patient 1 Patient 2 Patient 3* Patient 4*

Total cholesterolTGHDLB-glucose

3-50-70-35—

3-22-480-583-2

4-31 281084-3

2-9mmol I " 1

0-77mmol.r'0-54mmol . l " '7-4 mmol . 1 ~ '

*about 1 month after stopping using anabolic steroids.**about 1 week after stopping using testerone.

(a) (b)

Figure 1 (a) The start of ventricular tachycardia during exercise testing in patient 2. (b) Polymorphic ventriculartachycardia and ventricular fibrillation in patient 2 1 min later and cardioversion resulting in sinus rhythm 20 s later.

resolution ECG, the filtered QRS duration was 126 ms,but no abnormal late potential was present. Echo-cardiography showed a dilated left ventricle and markedthickening of the left ventricular walls (Table 2). Frac-tional shortening was 30%. Angiography showed open

epicardial coronary arteries, but coronary flow wasslow. The small side branches of these arteries werebarely visible. Left ventricular cineangiography revealeddilatation of the left ventricle with a 40% ejectionfraction. Inferior and antero-apical walls were



Figure 2 Histology of endomyocardial biopsy frompatient 2. Fibrous tissue has increased between the myo-cytes (arrows). A moderate amount of lipid droplets is alsoseen (*) .

Figure 4 Histology of an endomyocardial biopsy 6months later from patient 2, who had stopped usinganabolic steroids. Some fibrous strands are seen betweenthe myocytes, but no lipid is detectable.

hypokinetic. Cardiac output was 8 6 1 . min '. Themean pulmonary artery pressure was 20 mmHg.

Programmed electrophysiological stimulationwas performed. No ventricular tachycardia was induc-ible with or without isoprenaline infusion. A dual atrio-ventricular node was detected and during isoprenalineinfusion atrioventricular nodal re-entrant tachycardiawith a cycle length of 420 ms was induced. The anti-myosin map was considered normal. One month laterduring a bicycle exercise test of up to 300 W, there wereno signs of ischaemia on the ECG. The 24-h ambulatoryECG recording showed no spontaneous arrhythmia.

The patient had no symptoms of angina. Endomyo-cardial biopsy revealed focal fibrosis of the left ventricleand fat degeneration, (Figs 2 and 3). No signs ofgranulocyte infiltrations were seen.

Five months later, after the cessation of the useof anabolic steroids, echocardiography showed thatthe fractional shortening was 33%, left ventriculardimensions were normalized and hypertrophy of the leftventricular walls had reduced slightly (Fig. 4). No ven-tricular tachycardia attacks were observed duringfollow-up, possibly because of cessation of the use ofclenbuterol and anabolic steroids.

Figure 3 Ultrastructure of myocardial cells from patient 2. Thesarcoplasmic space is extended, and Z-bans are regular. Somedroplets of lipofuscin pigment (L) are situated in the perinuclearspace. Mitochondria (M) are numerous, and there is a slightvariation in mitochondria! size and space.



Patient 3, congestive heart failure

The patient was a 31-year-old male body-builder, whohad taken anabolic steroids for 2 years (1986-1988) toincrease muscle mass. From the beginning of 1991 untilthe day of examination, after a pause of 2-5 years, hestarted to take them again every week in approximatelythe doses described in Table 1. He was referred to theemergency department in October 1993 because of con-gestive heart failure. On admittance, the ECG showedleft ventricular hypertrophy, the pulse rate was70 beats. min ~ ' and blood pressure 120/70 mm Hg.Echocardiography (Table 2) revealed left ventricularhypertrophy and dilatation. Left ventricular fractionalshortening was 14%. After heart failure had been estab-lished, right-sided catheterization was performed. Themean right atrial pressure was 4 mmHg, mean pul-monary artery pressure 21 mmHg, and pulmonarywedge pressure 11 mmHg. Cardiac output was6 1 1 . min ~ ', which was partly related to the high heartrate (89 min), and stroke volume was low (69 ml) inrelation to left ventricular size.

Thallium scintigraphy demonstrated spotty,regular defects representing scar formation of theanterior and posterior walls of the left ventricular myo-cardium. Thallium washout was decreased indicatingdiffuse myopathy of the heart. During the ambulatoryECG performed in hospital, there were short periods ofWenckebach type AV-conduction disorders. Endomyo-cardial biopsy revealed some hypertrophy, variationin the size of the nuclei, but no fibrosis. Electronmicroscopy of endomyocardial biopsy samples showedsome thickening of the Z-lines between the myocytesand the clusters of mitochondria of various sizes.

During the bicycle exercise test, T-wave inver-sions in leads V3-V6 became positive. The maximalworking capacity was 150 W. Three successive ventricu-lar beats were also recorded. Four months later, afterthe cessation of the use of the anabolic steroids, leftventricular hypertrophy was reduced and the fractionalshortening of the left ventricle had increased from 14%up to 27%. The thickness of the interventricular septumand posterior wall had decreased by 1-2 mm (Table 2).The patient had started to lift weights again, but did notsuffer from dyspnoea during exercise. Five months later,fractional shortening had increased up to 27%. Bothsystolic and diastolic dimensions had normalized(Table 2).

Patient 4, thrombus in both ventricles

A 27-year-old male had been lifting weights atchampionship level for many years and used anabolicsteroids in massive doses, mainly testosterone. He haddiscontinued competing, but was still lifting weights andcoaching other weight lifters. Unfortunately we were notsuccessful in receiving the amounts and names of thesteroids he used. He admitted, however, that he mainlyused testosterone in very high doses and that he felt that

it was the only way to gain strength. In 1989 he wasdiagnosed as suffering from cardiac dilatation of un-known aetiology. Two years later, he was put on thefollowing medication: digitalis 0-25 mg . day" ' , ACE-inhibitor 25 mg x 2/day and furosemide 40 mg2 + 2+ .day"1 . The patient was referred to the emer-gency department with an arterial thrombus in his leftleg. An embolectomy was performed.

Echocardiography revealed a large lobular intra-ventricular thrombus in both right ( 4 x 4 cm) and left(5-5 x 2-4 cm) ventricles of his heart (Fig. 5). Dilatationof the left ventricle and hypertrophy of the posterior andinterventricular septum were confirmed (Table 2). Theright ventricular thrombus partly occluded the outflowtract of the right ventricle. His blood pressure was125/70 mmHg. The ECG showed sinus rhythm and rightbundle branch block. His total cholesterol level was low(Table 3). All tested components of his fibrinolyticcascade were normal. No right side invasive catheteriz-ations were performed because of a risk of furtherembolization. Pulmonary perfusion maps were normal.He was unwilling to undergo further evaluation, such ascoronary angiography and was lost for follow-up.

Discussion

Main findings

The side effects of anabolic steroids have been under-estimated in order to legitimize their use in sport, and itis well known that non-competitive and even competi-tive weight lifters abuse anabolic steroids in the hope ofimproving performance.

This paper presents four subjects with seriousclinical problems, all of whom took anabolic steroids inmassive doses for many years while weight training. Allfour patients exhibited abnormal cardiac hypertrophy.Diffuse myocardial fibrosis could be shown in two of thethree cases in whom biopsies were taken. Two of thesepatients had signs of heart failure (patients 3 and 4), andimpairment of coronary flow (patient 2) or perfusion(patient 3) was shown in two. In addition, two differ-ent potentially lethal side effects, malignant ventriculararrhythmia and massive intracardial thrombosis (Fig. 5),were verified.

Heart failure and hypertrophy

Overt cardiac hypertrophy with increased wall thicken-ing and left ventricular enlargement was present in allpatients on the echocardiogram. Wall thicknesses wereincreased comparable to that found in aortic stenosispatients, and two of the patients suffered from conges-tive heart failure. In all four patients, the ventriculardimensions were enlarged, and in three fractional short-ening was reduced. Previous echocardiographic studieshave associated excessive use of anabolic steroids with



Figure 5 Echocardiographic two-chamber view of patient 4 with abiventricular intracavity thrombosis. Both right and left ventricles areenlarged and left ventricular walls are thickened.

cardiac hypertrophy and diastolic dysfunction of theheart'8'. The E/A ratio was only slightly reduced in twoof our subjects (Table 2).

After cessation of the abuse of anabolic steroids,two of the patients demonstrated improved left ventricu-lar function. However, the follow-up period was notlong enough to see if the pathological changes andperformance of the heart would recover completely. Thepatients began to use anabolic steroids again, despite thewarnings given by the medical staff.

Experimental studies demonstrated that pro-longed treatment with anabolic steroids leads to cardiachypertrophy and increased peripheral vascular resist-ance151. In rats, prolonged high dose treatment anabolicsteroids induce dose-dependent cardiac hypertrophy anddepressed contractility161.

It has also been shown that the myocardialhypertrophy induced by anabolic steroids is .reversible,but that the reduced compliance of the left ventricle andthe decreased inotropic capacity of the myocardium isirreversible'61. Testosterone cypionate has been shown tosignificantly increase the beating activity and in myocar-dial cell cultures to induce release of lactate dehydro-genase indicating cellular injury171. When combined withtraining, some cells have even been observed to demon-strate necrotic signs, mitochondriolysis, myofibrinolysisand intracellular oedema'13'. In the right ventricularwall, anabolic steroids, together with exercise trainingalso increase the activity of lysosymal hydrolyticenzymes and collagen concentration'14'151.

Autopsy findings in the 28-year-old weight lifterwho had taken anabolic steroids in combination with aprotein-rich diet containing 2-3 g cholesterol daily dem-onstrated interstitial fibrosis of the myocardium andendocardium'91.

It has recently been shown in hypertensiveanimals, that aldosterone increases fibrinogenesis and

causes a reduction in the compliance of the myocardium.This can be prevented by spironolactone116-171. Syntheticsteroids are known to interact with other steroid recep-tors like aldosterone1181. The increased fibrosis of thehypertrophied myocardium observed after long-term useof anabolic steroids may be mediated by aldosterone-like effects.

Endomyocardial biopsy was performed on theright ventricular side. In general, the sample changeswere related to hypertrophy, with variations in nuclearsize and in the size of the myocytes. Increased interstitialfibrosis was observed in two of the biopsied patients. Inone of two patients, variation in the thickness of thez-bands was seen in the electron microscopic analysis.These observed changes were more remarkable if thebiopsies were performed in the left ventricle.

Androgens decrease elastic and increase fibrousproteins in arterial vascular tissue1'91, and in weightlifters they have been reported to increase systolic anddiastolic blood pressures'23241. All patients describedhere were, however, normotensive. Physical training isnot known to lead to myocardial fibrosis, but ratherto improve the pumping performance of the heart.Decreased perfusion as a result of microvascularchanges or atherogenicity may have induced the fibrosisin these cases.

Atherogenesis

Anabolic steroids are also potentially atherogenicthrough their actions on lipid metabolism. They havebeen shown to decrease blood HDL levels and increaseLDL levels significantly1121. Lyndberg reported diffusecoronary atherosclerosis following the autopsy of ayoung body-builder who had used anabolic steroids'9'.The narrow coronary arteries observed in the third



patient may be an indication of enhanced, diffuse cor-onary sclerosis, which could have been elucidated byintravascular ultrasound.

Thrombogenesis

Our fourth patient presented with intraventricularthrombus on both the right and left side of his heart. Inseveral earlier reports, the use of anabolic steroids hasalso been linked with arterial occlusion, but no directevidence of connecting this outcome with the use ofandrogens has been reported' 10>in. Possible mechanismsfor an increased risk of arterial thrombosis due toanabolic steroids included increased levels of severalprocoagulant factors, decreased fibrinolytic activity, in-creased platelet aggregation'19', decreased synthesis ofprostacyclin'20' and increased endothelin release aftervascular injury12'1. On the other hand, androgens havebeen shown to increase heparin cofactor II, Hagemanfactor, protein C and both free and total protein Sconcentrations'19-22'. In our patient, the specific mech-anism for increased thrombogenesis was not investigatedas he was rapidly anticoagulated.

Arrhythmias

There are no reports available concerning the possiblearrhythmogenic effects of anabolic steroids. One of ourpatients experienced a potentially lethal ventriculararrhythmia on exercise testing at submaximal worklevels. No signs of myocardial ischaemia or electrolyteimbalance could be found. The absence of late potentialsand inducible ventricular tachycardia indicates theabsence of an arrhythmogenic substrate. The dual atrio-ventricular node and electrophysiologically inducedatrioventricular nodal re-entrant tachycardia did notplay a role in the genesis of the clinical ventriculararrhythmia. Ambulatory ECG recording showed nocontinuous spontaneous arrhythmia. The lack of knownfactors predisposing to ventricular tachycardia andfibrillation indicates that the combination of the useof anabolic steroids, fasting, use of massive doses ofclenbuterol, and physical exercise may predispose toserious ventricular arrhythmias. The behaviour of theventricular tachycardia observed in our patient indicatesincreased automaticity as the possible electrophysio-logical mechanism of the arrhythmia.

Conclusion

As the number of athletes who have taken massive dosesof anabolic steroids for long periods is possibly increas-ing, the findings of the present report are of mostconcern and should warn all physicians and athletes ofthe serious risks involved in the continuous use of largedoses of anabolic steroids.

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