Electronic ISSN 2287-0237

VOLUME

ADVANCED CORONARY ATHEROSCLEROSIS AND FATAL MYOCARDIAL INFARCTION IN MILD DYSLIPIDEMIC, LOW RISK YOUNG MAN: A CASE REPORT WITH LITERATURE REVIEWED

FEBRUARY 2019 - VOL.15 | CASE REPORT

A cute myocardial infarction (AMI) at young age, below 45 years, israre and little known in clinical practice. Most victims are male andshare common conventional coronary risk factors including cigarettesmoking, a family history of premature coronary artery disease (CAD),dyslipidemia, hypertension, diabetes mellitus and being overweight orobese.1-5 We reported a fatal AMI from advanced atherosclerosis in arelatively young man who had none of the aforementioned risk factors exceptdyslipidemia which was well controlled. Thus, all systemic risk scoreidentified him as a low risk candidate for developing future cardiovasculardisease and precluded primary prevention.

A 43-year old man, regular tennis player, had been well, with aphysically active life style for decades. In 2010, at the age of 39 years, hewas diagnosed with hypercholesterolemia, with a total cholesterol of 260mg/ dl. With dietary control, regular exercise i.e. swimming every day,jogging on weekend and simvastatin 10 mg/day, his lipid was well undercontrol, see Table 1. At the same time, he was diagnosed with a herniateddisc (L4-5 level) and spinal canal stenosis so surgery was recommended.He used to smoke cigarettes, for a year, and stopped seventeen yearsearlier. Preoperative physical examination was unremarkable; body massindex (BMI) was 25, BP was 110/70 mmHg and pulse rate was 76 beats perminute. Chest film was normal. Screening ECG showed regular sinus rhythm,normal QTc and had Q wave in lead III, see Figure 1. The total cholesterolwas 164 mg/dl, triglyceride was 50 mg/dl. His father drank alcohol and haddied during sleep in his mid 30’s. His brother and one uncle also haddyslipidemia (no details available) but none of them had known cardiovasculardiseases.

In Jan 2011, microdiscectomy and foraminostomy were uneventfullyperformed and allowed him to play tennis for two hours a day instead ofswimming. Serial blood test showed fasting glucose of 91 mg/dl, totalcholesterol of 177 mg/dl, triglyceride of 47 mg/dl, HDL-cholesterol of 78 mg/dl and LDL cholesterol of 96 mg/dl. In 2013, after havingdeveloped his own business, he exercised less, gained 6 kgand felt dyspnea on exertion. Cardiac check-up was scheduledbut he did not come. From 10/2013-11/2014, he had ten OPDvisits for pain of knee and back and took etoricoxib 90 mgdaily. Two weeks prior to the event, he had chest discomfortbut was still able to play two sets of tennis regularly. InDecember 2014, after having finished the first set, he felt dizzyand suddenly collapsed on the court. Resuscitation wasperformed by bystanders and later by paramedics but theyfailed to restore spontaneous circulation so he expired in the field.

An autopsy study was performed the next day. Nopathological cause of death was found in any other organexcept the heart. Cardiac weight was above average,6 425 gm,and the organ was covered by epicardial adipose tissue (EAT),mostly over anterior and some around apico- basal part of theleft ventricle (see Figure 2A&B). The pericardium and allvalves were normal. New and old myocardial infarction areaswere noted in postero-septum and posterior wall, as evidentby fibrosis intervening with hemorrhagic infarction, see Figure 5.Under light microscope, most myocytes were hypertrophicand had changed edematous, especially at cardiac rim.Evidence of contraction band necrosis was documented, seeFigure 5A. All three epicardial coronary arteries were occupiedby advanced calcified atheromatous plaque. The left anteriordescending artery (LAD) lumen was narrowed, ranging from50% to over 90% stenosis, see Figure 3A&B. The mid LADartery embedded, 10 mm, under myocardium for 20 mm inlength, but was free from atherosclerotic disease, see Figure3C. The circumflex (Cx) artery had calcified eccentric plaquecausing 80% luminal stenosis, see Figure 4A. The rightcoronary artery (RCA) had 50-80% luminal stenosis, seeFigure 4B.

Table 1: Summary of all available lipid profiles, exercise and mediCcoartoionanl fvrieowm 2010-2014

Figure 1: Pre-operative ECG in 2011 showed sinus rhythm with significant Q wave in lead III.Relative tall T wave was noted in V2 and V3. The QTc was within normal range.

 

Figure 2: The heart weight was above normal range, 425 gm. It was covered by the thick yellowish epicardialadipose tissue (EAT, black arrow), mostly over anterior (A), apico-basal parts of the left ventricle (B).

 

Figure 3: The lumen of the proximal left anterior descending artery (LAD) was occupied by atherosclerotic plaque(white arrow, A) causing over 90% luminal stenosis, as shown in histological section B. The mid LAD embedded, 10mm deep into myocardium (bridging or tunneled) for 20 mm length, and was free from atherosclerotic lesion (arrow, C).The epicardial adipose tissue (EAT) overlying the proximal LAD was obviously thickened, see Figure A & C.

 

Figure 4: Cross section profile of the circumflex artery showed severe eccentric atheroma causing 80%luminal stenosis (A). The right coronary artery had concentric plaque with 50-80% luminal stenosis alongits course (B).

 

Figure 5: A dark red, cross striation (black arrow, A) of myocytes, (contraction band necrosis) was noted. Area offibrotic scar (dashed black arrow) of previous myocardial infarction was shown in B.

The cause of death

AMI occurred at a young age, below 45 years old, whichis quite rare and accounts for only 5.7-7% of total AMIcases.1-5 In general, the etiologies of young AMI cases couldbe classified in four groups: 7,8 1) atheromatous coronary arterydisease (CAD); 2) non-atheromatous CAD i.e. vasculitis,coronary dissection, myocardial bridging; 3) hyper-coagulablestates ; and 4) AMI related to substance misuse. Historyprovided by his wife confirmed that he never used cocaine orany other substance and had no hyper-coagulable conditions.There was no evidence of vasculitis or spontaneous coronarydissection on examination. The presence of advancedatheromatous CAD in all coronary arteries (Figure 3A&B and4A), the scar and the contraction band necrosis located inpostero-septum of the left ventricle (Figure 5A&B) indicatedthat the cause of death was AMI on top of an old myocardialscar. Both ischemic myocardium and the scar could serve asan arrhythmogenic substrate for ventricular arrhythmia andled to sudden cardiac death.9

COX-2 inhibitor and adverse cardiovascular effect

In addition, our case often took the selective non-steroidalanti-inflammatory drug, etoricoxib 90 mg/day to treat kneeand back pain for five consecutive years, Table 1. It is knownthat COX-2 inhibitors predominantly suppress the formationof prostaglandin I2, the cardiac-protective cyclooxygenaseproduct in endothelium. It inhibits platelet aggregation,provides vasodilatation, and prevents the proliferation ofvascular smooth-muscle cells in vitro.10,11 Although thecardiovascular safety of selective cyclooxygenase-2 (COX-2)drugs had previously been reported but the data remainedcontroversial and conflicting.12,13 A recent meta-analysis of 31trials involving 116,429 patients, followed up with more than115,000 patient years, supported the excessive cardiovascularrisk of COX-2 inhibitor.14 Studied patients were allocated tonaproxen, ibuprofen, diclofenac, celecoxib, etoricoxib,rofecoxib, lumiracoxib, or placebo. Compared with placebo,Etoricoxib (rate ratio, RR, 4.07, 95% CI 1.23 to 15.7) anddiclofenac (RR 3.98, CI 1.48 to 12.7) were associated with thehighest risk of cardiovascular death. Rofecoxib was associatedwith the highest risk of myocardial infarction (RR 2.12, 95%CI 1.26 to 3.56), followed by lumiracoxib (RR 2.00, 95% CI0.71 to 6.21). Ibuprofen was associated with the highest riskof stroke (RR 3.36, 95% CI 1.00 to 11.6), followed by diclofenac(RR 2.86, 95% CI 1.09 to 8.36).14 In fact, two AMI Thaicases had been previously reported by our group and one ineach case had taken celecoxib and etoricoxib a few days beforehaving events.15 Although we still could not prove how muchetoricoxib contributed to AMI in this case, it has beenrecommended not to use COX2 inhibitors in knowncardiovascular disease patients.16,17 Only in case of need itshould be used within a short period and a low dose aspirinshould be added to reduce thromboxane A2 production.17

Role of myocardial bridging in sudden death

In the autopsy study, the tunneled mid LAD artery,so-called myocardial bridging (MB), was also noted, Figure3C. The prevalence of MB varied widely in the literature, from0.5-12% by angiography,18,19 to 26% by CT coronaryangiogram,20 and up to 58% in some autopsy studies.21 MBhad been considered a benign anatomical variant since the longterm prognosis was excellent. Krammer and colleague22reported the excellent five-year survival rate, 97.5%, in 81 MBcases. In the 11 ± 3 year study of 28 cases of isolated MB inthe LAD artery, the survival rate was very high, 98%, and thefew deaths that occurred in this report were not relevant toMB.23 However, acute myocardial infarction,24-26 ventricularseptal rupture,27 paroxysmal AV block,28 ventriculartachycardia during exercise29 or even sudden death30 had beenreported in MB cases. Recently, Hostiuc S et al.,31 performeda meta-analysis of 21 MB studies and found that MB wasassociated with major adverse cardiac events, OR = 1.52 (95%CI: 1.01–2.30), and myocardial ischemia, OR = 3.00 (95% CI:1.02–8.82), but not with acute myocardial infarction,cardiovascular death, ischemia (identified using imaging techniques), or positive exercise stress testing. In summary,MB could have significant cardiovascular consequences(MACE, myocardial ischemia) in three ways; 1) by directsystolic compression of the tunneled artery causes delayedrelaxation and reduces blood supply,32-34 2) by induced atherosclerosisof the proximal segment prior to the MB,35-37 as foundin this case, and 3) enhanced vasospasm.38 In other autopsystudies, the length (20-30 mm) and the depth of MB (2-3mm)were considered pathologic anatomy for sudden death.8 In ourcase, the length and the depth of MB segment were 20 mmand 10 mm respectively, so it could easily produce myocardialischemia during exertion and contributed to sudden cardiacdeath.

Current risk predictor failed to predict this case

In the autopsy study, the tunneled mid LAD artery,so-called myocardial bridging (MB), was also noted, Figure3C. The prevalence of MB varied widely in the literature, from0.5-12% by angiography,18,19 to 26% by CT coronaryangiogram,20 and up to 58% in some autopsy studies.21 MBhad been considered a benign anatomical variant since the longterm prognosis was excellent. Krammer and colleague22reported the excellent five-year survival rate, 97.5%, in 81 MBcases. In the 11 ± 3 year study of 28 cases of isolated MB inthe LAD artery, the survival rate was very high, 98%, and thefew deaths that occurred in this report were not relevant toMB.23 However, acute myocardial infarction,24-26 ventricularseptal rupture,27 paroxysmal AV block,28 ventriculartachycardia during exercise29 or even sudden death30 had beenreported in MB cases. Recently, Hostiuc S et al.,31 performeda meta-analysis of 21 MB studies and found that MB wasassociated with major adverse cardiac events, OR = 1.52 (95%CI: 1.01–2.30), and myocardial ischemia, OR = 3.00 (95% CI:1.02–8.82), but not with acute myocardial infarction,cardiovascular death, ischemia (identified using imaging techniques), or positive exercise stress testing. In summary,MB could have significant cardiovascular consequences(MACE, myocardial ischemia) in three ways; 1) by directsystolic compression of the tunneled artery causes delayedrelaxation and reduces blood supply,32-34 2) by induced atherosclerosisof the proximal segment prior to the MB,35-37 as foundin this case, and 3) enhanced vasospasm.38 In other autopsystudies, the length (20-30 mm) and the depth of MB (2-3mm)were considered pathologic anatomy for sudden death.8 In ourcase, the length and the depth of MB segment were 20 mmand 10 mm respectively, so it could easily produce myocardialischemia during exertion and contributed to sudden cardiacdeath.

AMI with no conventional coronary risk factors

All of these risk calculators required conventional riskfactors include gender, age, current smoker, blood pressure,serum lipid for calculation so they failed to predict thecardiovascular death in this reported case. It is known that15-40% of population could have CAD or AMI with no majorrisk factors. Knot and colleagues analyzed 122,458 CADcases that had been enrolled in 14 international randomizedtrials and found that 15.4% of women and 19.4% of men stillhad CAD without having the four major conventional risk factors,i.e. cigarette smoking, diabetes mellitus, hyperlipidemia andhypertension.45 In Southern China (Hakka) population, Zhanget al.,46 studied coronary risk factors of the first AMI 1,382cases. The authors found that 31.1% and 40.6% of non-elderlymen and women had AMI with normal LDL, HDL andtriglyceride levels. This led to the next question: how couldadvanced atherosclerotic CAD develop in these patients?

EAT, a new risk predictor

From other autopsied studies, the average heart weight ofThai men, age ranging from 35-45 years, varied from 265 ± 8gm to 302 ± 7 gm.6 In our case, the heart weight was up to 425gm.The thick epicardial adipose tissue (EAT) was found andpossibly contributed to an excess weight. The inflammatoryrole of EAT had been addressed in 2003 by Mazurek andcolleagues.47 By studying the inflammatory markers of EATvs subcutaneous fat in 42 CAD patients before undergoingcoronary bypass surgery, they found that the EAT exhibitedsignificantly higher levels of chemokine, MCP-1 and otherinflammatory cytokines: IL-1 , IL-6, IL-6sR, and TNF, thansubcutaneous fat did. Subsequent clinical studies supportedthis observation. In 2005, Meenakshi K and colleague48measured epicardial fat thickness by echocardiogram in 110patients who underwent coronary angiography. They foundthat epicardial fat is independently and linearly associated withCAD severity. Recently, Hwang et al.,49 performed a serialCoronary Computerized Tomogram of coronary artery (CTA)in 122 asymptomatic cases who had no CAD at baseline study.After the mean follow up of 65.4 months, EAT and diabetesmellitus independently predicted the development of newnon-calcified plaque with the odd ratio of 4.29 and 9.0respectively. All of these studies supported the paracrine effectof EAT by creating local inflammation, from outside to insidethe coronary artery, and contributed to atheromatous plaqueformation.47-50 Without studying the inflammatory marker ofEAT, we could only ask the question but could not confirmthis hypothesis in this reported case.

We report a sudden death after exercise of a relativelyyoung man who had no other conventional coronary riskfactors except for treated dyslipidemia. Thus, all riskcalculators failed to predict this fatal event. With no othermajor risk factors, his advanced atherosclerosis and fatal eventcould have resulted from various factors. The thick EAT, whichhad been previously shown to be the site of the inflammatorymarker, was found and possibly induced CAD development.The presence of MB of the mid LAD, 10 mm depth and 20mm long (also known as pathologic anatomy), could reducecoronary flow during exertion leading to ischemia. Thechronic use of COX-2 inhibitor could precipitate vascularthrombosis and an ischemic event. In retrospect, the inferiorQ wave on ECG and the calcium score, if it had been done,might have been a better predictor of risk in our case. Thiscase reminds us that prediction of sudden death in young AMIpatient remains one of a challenging issues. We should keepsearching for unidentified risk factors to find the better waysto predict and prevent these catastrophic events.