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C O L L E G E O F C A R D I O L O G Y F OU N D A T I O N . T H I S I S A N O P E N A C C E S S A R T I C L E U N D E R

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CASE REPORT

CLINICAL CASE

A Rare Case of Lead-InducedCardiomyopathy

Shruti Hegde, MD,a Michael Maysky,a Abbas Zaidi, MDb

ABSTRACT

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A 42-year-old man, painter by profession, presented with symptoms of heart failure. His work up was unrevealing except

for elevated blood lead levels (BLL). He was started on guideline-directed medical therapy and was referred to occu-

pational therapy. No improvement in his ejection fraction was noted until his BLL decreased. (Level of Difficulty:

Intermediate.) (J Am Coll Cardiol Case Rep 2020;-:-–-) © 2020 The Authors. Published by Elsevier on behalf

of the American College of Cardiology Foundation. This is an open access article under the CC BY-NC-ND license

(http://creativecommons.org/licenses/by-nc-nd/4.0/).

PRESENTATION

A 39-year-old male presented to the authors’ emer-gency room with complaints of shortness of breath onexertion and pedal edema for 1 month. His vital signswere significant for a heart rate of 105 beats/min,blood pressure of 150/95 mm Hg; he was afebrile, andhis oxygen saturation was 94% on room air. Physicalexamination was notable for elevated jugular venouspressure, 2þ pitting pedal edema, and bibasilarcrackles on respiratory examination, and S3 was heardon cardiac auscultation.

EARNING OBJECTIVES

To recognize chronic lead exposure as one ofthe causes of cardiomyopathy andmyocarditis.To understand that, with early diagnosis andmanagement, there can be a potentialimprovement in ejection fraction.To understand the spectrum of cardiovascu-lar effects of chronic lead exposure.

N 2666-0849

m the aDivision of Cardiology, St.Elizabeth’s Medical Center, Tufts Sch

epartment of Internal Medicine, St. Elizabeth’s Medical Center, Tufts Sch

rs have reported that they have no relationships relevant to the contents o

itor.

e authors attest they are in compliance with human studies committees

tutions and Food and Drug Administration guidelines, including patient co

JACC: Case Reports author instructions page.

nuscript received March 3, 2020; revised manuscript received April 29, 2

MEDICAL HISTORY. His medical history was signifi-cant for resistant hypertension, which was diagnosedat 35 years of age. He initially required 4 differentantihypertensive agents for optimal control of hisblood pressure. With lifestyle changes and weightloss, his therapy was reduced to hydrochlorothiazideand metoprolol succinate. He had undergone com-plete workup for secondary hypertension at the timeof diagnosis and was negative. The patient was apainter by profession, was never a smoker, and usedalcohol occasionally but not illicit drugs. His familyhistory was significant for diabetes in his mother. Atransthoracic echocardiogram performed at the timeof diagnosis of his hypertension showed normal leftventricular ejection fraction (LVEF).

INVESTIGATIONS. Electrocardiography revealed si-nus tachycardia with left ventricular hypertrophy andsecondary ST-T changes. A chest radiograph revealedan enlarged cardiac silhouette and pulmonary vascularcongestion. Complete blood count and basic metabolicprofile were within normal limits, as was his N-termi-nal pro–B-type natriuretic peptide concentration, and

https://doi.org/10.1016/j.jaccas.2020.05.047

ool of Medicine, Brighton, Massachussetts; and the

ool of Medicine, Brighton, Massachussetts. The au-

f this paper to disclose. Ashwin Ravichandran, Guest

and animal welfare regulations of the authors’ in-

nsent where appropriate. For more information, visit

020, accepted May 26, 2020.

ABBR EV I A T I ON S

AND ACRONYMS

BLL = blood lead level

CMR = cardiac magnetic

resonance

EMB = endomyocardial biopsy

LV = left ventricle

LVEF = left ventricular ejection

fraction

LVH = left ventricular

hypertrophy

PET = positron emission

tomography

RV = right ventricle

RVEF = right ventricular

ejection fraction

TTE = transthoracic

echocardiogram

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his troponin T peaked at 0.2 ng/ml (normalis <0.03 ng/ml). A transthoracic echocardio-gram showed an LVEF of 23%, a mild LV dila-tion, a severe left ventricular hypertrophy(LVH) (139 g/m2; normal 50 to 102 g/m2), amarkedly reduced right ventricular (RV)function, a mild to moderate central mitralregurgitation, and global hypokinesis.

DIFFERENTIAL DIAGNOSIS AND WORK-UP.

He underwent cardiac catheterization, whichshowed no angiographically apparentepicardial coronary artery disease andelevated filling pressures with normal cardiacoutput and index. He had had no viral syn-dromes in the preceding 6 months, and hetested negative for Trypanosoma cruzi infec-tion, HIV, and Lyme disease. His serum andurine protein electrophoreses were normal,

as were his serum iron and ferritin levels. He had nohistory of cocaine or other illicit drug use. He drank 2to 4 beers/week. He underwent cardiac magneticresonance (CMR), which revealed diffuse enlarge-ment of all cardiac chambers, with focal areas ofsubepicardial abnormal delayed enhancementconsistent with myocarditis. Diffuse moderate hypo-kinesis of the left ventricle without the focal area ofdyskinesis. Small pericardial effusion and depressedleft and right ventricular functions were observed.

TREATMENT AND FOLLOW-UP. He underwent inpa-tient intravenous diuresis and was discharged onguideline-directed medical therapy for heart failure.During his outpatient follow-up visit, careful scrutinyof his history reveled significant occupational expo-sure to lead. He had started working as a painter atthe age of 25 and had been exposed to lead in paints.He reported that he had not used protective facemask during work. His blood lead level (BLL) waselevated at 41 mg/dl (normal is 0 to 4.9 mg/dl). He wasreferred to occupational therapy, where it was rec-ommended he change his profession, which he did.The standard recommendation for lead chelation is80 mg/dl or above, hence, he did not receive anytreatment with chelating agents. A decision was madeto monitor his BLLs, and if it did not decrease as ex-pected, he would be started on chelation. His BLLsdecreased quickly to 15 mg/dl. The echocardiogramwas repeated 2 months later which showed improve-ment in EF to 52%, mild LVH (111 g/m2), and normal RVdimensions and function (Videos 1, 2, 3, and 4).

He continued to do well for the next 2 years. Heremained compliant with his medications andoutpatient follow-up examinations. Thereafter, hepresented with congestive heart failure symptoms to

his primary care physician again. During his visit, headmitted to going back to his painting profession buthas not been wearing masks. Repeat TTE showed adecline in LVEF to 31% and an increase in LV mass(141 g/m2), and his BLLs had increased to 38.7 mg/dl.He refused to switch jobs, hence, he was extensivelycounseled on wearing protective gear during work.His BLLs decreased slowly but steadily. TTE wasrepeated 6 months later, which showed improvementin EF to 46% and regression of LV mass index to 124 g/m2 (Videos 1 and 2).

DISCUSSION

Lead is a common environmental toxin absorbed intothe human body through the respiratory system,gastrointestinal tract, and skin. Chronic lead expo-sure is well known to affect a variety of organ sys-tems. However, little is known about its effect on thecardiovascular system. More recently, the effect ofchronic lead exposure has been implicated in resis-tant hypertension. The exact mechanism is still un-clear, but it is believed to be related to oxidativestress, nitric oxide dysregulation, and alteration inthe renin-angiotensin-aldosterone system (1). Popu-lation studies in the United States conducted by Na-tional Health and Nutrition Survey has found a directrelationship between lead exposure and elevatedblood pressure (2). This patient initially came tomedical attention years before the diagnosis of leadtoxicity with resistant hypertension, which was likelysecondary to his chronic lead exposure. Lead intoxi-cation has also been associated with an increasedincidence of coronary artery disease, stroke, periph-eral arterial disease, and an increase in non-high-density lipoprotein cholesterol. Potential mecha-nisms of these agents remains to be studied (3).

The effect of lead exposure on myocardial struc-ture and function has yet to be determined. Smallcase-controlled and observational studies have re-ported a decline in LVEF and global longitudinalstrain in people chronically exposed to lead (4,5). Asimilar observation was made in this patient, as well(Figures 1 and 2). He had no other causes for his LVdysfunction other than elevated BLLs. His LVEF wasat the lowest when his BLLs were at their peaks. Asthe BLL decreased, his LVEF, and his LV massregressed. When he started painting again, his BLLsincreased, LVEF dropped, and LV mass increased.This temporal association strongly suggested thepossibility of direct lead toxicity as the cause of adrop in his cardiac contractility. The exact associationbetween LVEF and lead is unknown. Animal experi-ments have indicated that the cardiotoxic effects of

FIGURE 1 Relationship of BLL With LVEF, GLS, and LV Mass

(A) End diastolic global longitudinal strain (GLS) (%) and time-to-peak longitudinal strain (ms) at blood lead level (BLL) of 41 mg/dl. (B) End-diastolic GLS and time-to-

peak longitudinal strain at BLL of 17 mg/dl. LVEF ¼ left ventricular ejection fraction.

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lead are likely related to its interference withcalcium-dependent cellular processes (6). There isalso a suggestion that depressed myocardialcontractility may be due to impaired phosphorylationof the myocardial contractile proteins (7). Thesefindings have yet to be confirmed. Finally, BLL is re-ported to significantly affect LV mass, LV end-diastolic dimension, and relative wall thickness. In astudy conducted in Poland, Kasperczyk et al. (4)which compared a group of individuals exposed tolead factories with a control group of administrativeworkers, who were not exposed to lead found that theLV end-diastolic dimension was 6% higher and an 11%increase in left ventricular mass index was observedin the group with lead exposure (4). That study didnot eliminate the confounding factor of blood pres-sure. A study by Schwartz (8) in 1991 showed a similarfinding after controlling for blood pressure. The pre-sent patient had evidence of concentric LVH with LV

mass index of 140 g/m2, an LV end-diastolic dimen-sion of 59 cm, and a relative wall thickness of 0.44.Because hypertension is an independent risk factorfor LVH, it became a confounder in interpreting thesedata in the present patient.

His initial presentation was consistent withmyocarditis with elevated troponin levels, depressedRV and LVEF, and CMR results suggestive of myocar-ditis with marked thinning of the myocardium. Thispatient had a complete workup for myocarditis, shortof endomyocardial biopsy (EMB). CMR is the imagingmode of choice for the workup of myocarditis.Fluorodeoxyglucose-labeled positron emission to-mography is a good alternative when cardiac CMRcannot be performed. Despite its limited sensitivityand specificity, EMB remains the gold standard for thediagnosis of myocarditis. However, given the rarity oflead cardiomyopathy, there are no defined guidelinesor findings to diagnose myocarditis caused by lead by

FIGURE 2 End Diastolic GLS and Time-to-Peak Longitudinal Strain

(A) End-diastolic GLS (%) and time-to-peak longitudinal strain (ms) at BLL of 39 mg/dl. (B) End-diastolic GLS and time-to-peak longitudinal strain BLL of 30 mg/dl.

Abbreviations as in Figure 1.

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EMB definitively. Histopathological examinations ofheart specimens of rats intoxicated with lead showeddegenerative changes in myocardial fibers, loss ofmuscle structure, and focal fibrosis (11). However, theexact mechanism of myocardial damage by lead islargely unknown. Some of the postulated mechanismsinclude a direct irritant effect on the myocardium, in-hibition of cardiometabolic enzymes, and selectivedisturbance of coronary circulation. None of theabove-mentioned hypotheses has been proven (9,10).

Myocarditis due to lead toxicity is a rare condition.It is a very challenging to diagnose because the pos-sibility of coincidental viral myocarditis cannot beruled out. Nevertheless, the diagnosis of lead car-diomyopathy was more likely in this patient with noviral prodromes in preceding months, and the tem-poral association of his BLL with his LV function andLV mass. In a review of the medical literature, 3 othercases of myocarditis due to chronic lead exposure inadults (11–13) were found. To the best of these

authors’ knowledge, this case is the fourth reportedcase of lead myocarditis and second reported case inan adult male.

CONCLUSIONS

The development of cardiomyopathy due to chroniclead exposure is most likely secondary to its directtoxic effect on the myocardium. More experimentalstudies are required to establish the cardiotoxicmechanisms of lead. Meanwhile, cardiovascular illeffects of chronic lead exposure should be brought tothe awareness of our health care providers for earlydiagnosis and management of these patients.

ADDRESS FOR CORRESPONDENCE: Dr. Shruti Hegde,Cardiovascular Division, Saint Elizabeth’s MedicalCenter, 736 Cambridge Street, Brighton, Massachu-setts 02135. E-mail: Shruti.Hegde15@gmail.com.

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RE F E RENCE S

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2. Harlan WR, Landis JR, Schmouder RL,Goldstein NG, Harlan LCJ. Blood lead and bloodpressure. Relationship in the adolescent and adultUS population. JAMA 1985;253:530–4.

3. Navas-Acien A, Guallar E, Silbergeld EK,Rothenberg SJ. Lead exposure and cardiovasculardisease—a systematic review. Environ Health Per-spect 2007;115:3–11.

4. Kasperczyk S, Przywara-Chowaniec B,Kasperczyk A, et al. Function of heart muscle inpeople chronically exposed to lead. Ann AgricEnviron Med 2005;12:207–10.

5. Yang W-Y, Zhang Z-Y, Thijs L, et al. Left ven-tricular structure and function in relation to envi-ronmental exposure to lead and cadmium. J AmHeart Assoc 2017;6:1–5.

6. Kopp SJ, Barany M, Erlanger M, Perry EF,Perry HM. The influence of chronic low-levelcadmium and/or lead feeding on myocardialcontractility related to phosphorylation of cardiacmyofibrillar proteins. Toxicol Appl Pharmacol1980;54:48–56.

7. Prentice RC, Kopp SJ. Cardiotoxicity of lead atvarious perfusate calcium concentrations: func-tional and metabolic responses of the perfusedrat heart. Toxicol Appl Pharmacol 1985;81:491–501.

8. Schwartz J. Lead, blood pressure, and cardio-vascular disease in men and women. EnvironHealth Perspect 1991;91:71–5.

9. Kosmider S, Petelenz T. Zmiany elek-trokardiograficzne u starszych osob z przewlekymzawodowym zatruciem olowiem. Pol Arch Med1962;32:437–40.

10. Sroczyfiski J. Zmiany elektrokardiograficzne wprzewleklej doswiadczalnej olowicy u kr6lik6w.Postepy Hig Med 1961;15:353–9.

11. Haubrich R. On the work of Richard Haubrich:Communication of a case of cardiac wall aneurysmafter acute lead poisoning. Klin Wochenschr 1948;26:473–4.

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KEY WORDS cardiomyopathy, globallongitudinal strain, lead toxicity, myocarditis

APPENDIX For supplemental videos,please see the online version of this paper.