a b s t r a c t

Background: Myocardial infarction constitutes a significant cause of morbidity and mortality. Its pathophysiology varies according to age; atherosclerosis is the most common cause in older patients while thrombosis or Plaque rupture is behind premature MI. Objective: To compare the outcome differences between young (age <= 45 years) and older adults (age N 45 years) presenting with STEMI.

Method: This was a retrospective cohort study of patients presenting with STEMI to the Emergency Department of a tertiary care center, between 2008 and 2018.Cases were patients age <= 45 and controls were the older pop- ulation. Descriptive and bivariate analyses were conducted followed by Logistic regression to identify the out- comes.

Results: 107 cases were matched with 214 controls. Majority of patients were males (93% of cases and controls). Younger patients were more likely to be smokers (80% vs. 57%, p b 0.001) and with a family history of MI (56% vs. 37%, p = 0.002). Diabetes, hypertension, dyslipidemia and a previous history of MI were more common among controls, 37%, 60%, 43% and 42% respectively versus 10%, 24%, 36% and 25% in the younger population. Younger patients had a higher prevalence of single-vessel disease compared to older patients (73% vs. 50%, p = 0.001). LAD was the most commonly blocked vessel in both groups (71% vs. 64% respectively). Ejection fraction was within normal range in the majority of controls and cases (63% vs. 56% respectively and 57% vs. 60% respectively). Conclusion: Premature MI predominantly affects males and the associated risk factors are smoking and family his- tory of MI. It’s characterized by single-vessel disease as compared to older patients.

(C) 2019

Introduction

Myocardial infarction (MI¹) is a significant cause of morbidity and mortality in developed countries [1]. According to the American Heart Association (AHA), 16.5 million individuals, above the age of 20, have coronary heart disease. Furthermore, in the United States, 732,000 pa- tients presenting annually to the emergency department, are diagnosed with acute myocardial infarction (AMI) [2]. The sudden and sustained thrombotic occlusion of a coronary artery has been considered as the etiology of an MI [3]. It manifests with diverse clinical presentations ranging from mild discomfort to sudden cardiac death. The most com- mon presenting symptoms are chest pain, with or without radiation to the jaw, shoulder or arm, dyspnea or shortness of breath, diaphoresis, syncope or Epigastric pain.

* Corresponding author.

E-mail address: [email protected] (R.B. Chebel).

Although there is a lack of a universal consensus regarding the cutoff age for premature MI, most of the literature considers the age of 45 years as a reference. It constitutes approximately 6-10% of all MIs in the United States [4]. The pathophysiology of MI in young patients is different. A review by Alkhiary in 2011, suggested that premature MI is mostly the result of acute events, i.e., thrombosis or plaque rup- ture, rather than slowly progressing processes like atherosclerosis [5]. Premature MI was more likely associated with hypercoagulability, non-atherosclerotic coronary artery disease, and less likely with athero- sclerosis when compared to older patients [6]. Non-atherosclerotic cor- onary artery disease encompasses Coronary vasospasm, cocaine abuse, carbon monoxide poisoning, autoimmune vasculitis and viral myocardi- tis [7].

One of the main prognostic indicators for adverse outcome and mor- tality post MI is left ventricular ejection fraction (LVEF²) [8]. The “Auto- nomic Tone and Reflexes After Myocardial Infarction (ATRAMI)” study

¹ Myocardial infarction. ² Left ventricular ejection fraction.

https://doi.org/10.1016/j.ajem.2019.05.023

0735-6757/(C) 2019

showed that the Relative risks of cardiac death in patients with LVEF b35% and between 35 and 50% were 7.3 and 2.5 respectively, when compared to patients with LVEF N50% [9]. The LVEF post MI is an inde- pendent predictor of death and has an important prognostic value. Be- sides, the extent of left ventricular dysfunction following myocardial infarction was related to patient’s age. One of the studies done by Plakht et al. in 2015 found that the prevalence of severe left ventricular dys- function on echocardiography done at the time of presentation, is higher in patients above 65 years when compared to younger patients b65 years (15.1% vs. 7.3%, respectively) [10].

Given the variability in the studied endpoints in the aforementioned investigations and the fact that age-related outcome differences exist in patients presenting with ST- elevation myocardial infarction (STEMI), the purpose of this study is to compare the outcomes of young adults (age <=45 years) with premature myocardial infarction with older adults (age N45 years) presenting with a myocardial infarction.

Methodology

Study design

This is a retrospective, cohort study which was conducted in a single-centered academic emergency department (ED) of a large ter- tiary care center. The study was approved by the hospital’s institutional review board (IRB, BIO-2018-0410). Patients, who presented to the ED in the period ranging from January 2008 till August 2018, had their medical records extracted from the hospital’s electronic health record system. All clinical information, including laboratory and Imaging results, comorbidities and resuscitation parameters were retrieved from the scanned charts. To note, several meetings were held between the principal investigators and research fellows to standardize the data col- lection process.

Study population

Qualified data users from the Decision Support unit filtered patient’s ED encounters via the hospital’s EHR using specific keywords and ICD-9 coding (International Statistical Classification of Diseases, Ninth Revi- sion and Related Health Problems). At our hospital, the medical records department specifies an ICD-9 code after examining all the diagnoses made since patient’s admission to the hospital including the diagnosis made by the ED physician. The ICD-9 diagnoses that were used: myocar- dial infarction and STEMI. The Study group included all patients, be- tween the age of 18 and 45 years, presenting to the Emergency Department with an ST-elevation myocardial infarction and having an echocardiography report prior to discharge and during follow up after up to 1 year from the time of presentation. On the other hand, the Control group included all patients fulfilling the inclusion criteria and above 45 years of age. Patients b18 years old and those missing an echocardiography prior to discharge or during the first year from the time of presentation were excluded from the study. Coronary artery dis- ease (CAD) was defined as N75% luminal occlusion of any major coro- nary artery.

Outcomes

The primary outcome was the difference in ejection fraction prior to discharge between the two groups. Secondary outcomes included dif- ferences in ejection fraction 1 year from the presentation, differences in patient demographics, time of presentation, onset of symptoms, mode of arrival, Door-to-balloon time, number of stents placed, surgical intervention (CABG³), mortality, lengths of stay, and anatomic location of the culprit artery.

³ Coronary artery bypass graft surgery.

Data collection

The following information were retrieved: demographic data (age, gender, social history, past medical history, past history of MI, family history of MI), ejection fraction prior to discharge and after up to 1 year from the time of presentation, morbidity, mortality, lengths of stay, Door-to-Balloon time, number of stents placed, surgical interven- tion (CABG), time of presentation, onset of symptoms, mode of arrival and spatial localization of the infarct. Morbidity was assessed by the presence of angina, dyspnea, heart failure, stroke, recurrent MI, death within 1 year from discharge [11].

Data analyses

All statistical analyses were conducted using Stata MP version 13.0 (College Station, TX: StataCorp LP). Frequency and percentages were used to describe categorical variables, while mean and standard devia- tion were used for continuous ones. Association with premature MI was determined using Pearson’s Chi-Square test and Fisher’s Exact test for categorical variables, while the Wilcoxon Mann-Whitney rank-sum test was used for continuous ones. Furthermore, forward stepwise mul- tivariate logistic regression was used to determine the predictors of pre- mature MI. The model included variables of statistical significance at the bivariate level and variables of clinical significance. A significance level of 0.05 was taken.

Results

A total number of 2884 were diagnosed with STEMI during the study period, 175 of whom were <=45 years old. Among the latter, 68 were ex- cluded leaving 107 eligible patients constituting the study group. Pa- tients were excluded due to no echocardiography (N = 35), no scanned charts (N = 12) and no STEMI (N = 21). The study group was matched with 214 controls in a ratio of 1:2. Controls were patients presenting with a STEMI but were N45 years old. Controls were ran- domly selected from the total number of MI patients N45 years, in a way to match by gender and date of presentation with the study group (see Diagram 1). A total of 321 patients were included in the study. Of the 107 study cases, 93% were males and 7% were females; similar Gender distribution applies to the control group due to the matching.

Younger patients were found to have less hypertension (24.3% ver- sus 60.28%, p b 0.001), less diabetes (10.28 versus 36.92%, p b 0.001) than the controls. There were more smokers in the younger cohort (80.61% versus 57.22%, p = 0.001). A family history of MI was signifi- cantly more likely to be present in younger patients compared to older patients (56% versus. 37%, p = 0.002); however, older patients were more likely to have a history of myocardial infarction than youn- ger ones (42% versus 25%, p = 0.004). These results are summarized in Table 1.

Ejection fraction at discharge was similar in both groups with the most common findings on echocardiogram being a normal EF (63% vs. 56% respectively cases versus controls). Similarly, ejection fraction after 1 year follow up was normal in both groups (57% vs. 60% respec- tively). However, the control group had a higher number of severely de- pressed ejection fraction (7.87%versus 1.82%) at 1 year follow-up but this finding was not statistically significant. These results are summa- rized in Table 2.

Regardless of age, the majority of patients presented at night (59.79% and 48.81%), and drove themselves (98.26% versus 94.52%) to the Emergency Department. The average duration of onset of symptoms was similar in both cohorts (15.19 +- 31.51 min in controls and 13.89 +- 23.67 min in cases). There were no statistically significant differences in the hospital lengths of stay between both cohorts. These results are summarized in Table 2.

Diagram 1. Flow chart.

There was no difference in morbidity or mortality between older and younger patients (59.81% versus. 54.72%, p = 0.384 and 0.93% versus.

1.87%, p = 0.477 respectively).

Table 1

Patient’s characteristics.

Variable	Controls (N = 214) N (%)		Cases (N = 107) N (%)	p-Value
Gender	Female	14 (6.54)	7 (6.54)	0.744
Smoking status	Smoker	103 (57.22)	79 (80.61)	0.000
alcohol consumption	Yes	28 (18.42)	21 (27.27)	0.123
Hypertension	Yes	129 (60.28)	26 (24.30)	0.000
Hyperlipidemia	Yes	92 (42.99)	39 (36.45)	0.261
Diabetes	Yes	79 (36.92)	11 (10.28)	0.000
Family history of MI	Yes	71 (37.17)	55 (56.12)	0.002
Previous history of MI	Yes	89 (41.59)	27 (25.23)	0.004
Other risk factors	Yes	2 (0.93)	7 (6.54)	0.007
Time of day of presentationa	Night	116 (59.79)	41 (48.81)	0.090
Time during week of	Weekend	57 (26.64)	30 (28.04)	0.790
presentationb Mode of arrivalc	Driving	169 (98.26)	69 (94.52)	0.201
Duration of onset of symptoms	Mean +-	15.19 +-	13.89 +-	0.632
	SD	31.51	23.67
Door-to-balloon time	N90 min	8 (10.67)	1 (2.50)	0.120

^a Time of day refers to day versus night.

^b Time during week refers to weekday versus weekend.

^c Mode of arrival = driving versus EMS.

Furthermore, younger patients had a higher number of single-vessel disease in contrast to older patients (73% vs. 50%, p = 0.001). The mean average of coronary vessels involved in the study group is significantly lower than in the control group (1.36 vs. 1.71, p <=0.001). Analysis of cor- onary angiogram results showed that left anterior descending artery (LAD⁴) was the most commonly involved blocked vessel in both groups (71.5% versus 63.55%, p = 0.147), followed by the right coronary artery (RCA⁵), left circumflex artery (LCx⁶) and lastly posterior descending ar- tery (PDA⁷). These results are further explained in Table 2. Furthermore, in both cohorts, the majority of patients undergoing percutaneous cor- onary intervention (PCI), had 1 stent placed (46.26% in the control ver- sus 58.88% in the cases), followed by N2 stents. 51 control patients had 0 stent placed, none of which were due to vasospasm as compared to 17 patients of the cases, of which 4 were due to vasospasm. Finally, there was a similar number of patients who underwent CABG in both groups (5.61% versus 5.61%, p-value = 1.000). These results are summarized in Table 2.

Tables 3 and 4 show the results of the stepwise multivariate regres- sion. Variables included in the model, based on clinical and/or statistical significance at the bivariate level, were smoking status, hypertension, hyperlipidemia, diabetes, family history of MI, number of impacted

⁴ left anterior descending artery.

⁵ Right coronary artery.

⁶ Left circumflex artery.

⁷ Posterior descending artery.

Table 2

Descriptive outcomes of the control and study groups.

Variable Controls

(N = 214) N (%)

Morbidity	Yes	128	58 (54.72)	0.384
		(59.81)
Mortality during hospital	Yes	2 (0.93)	2 (1.87)	0.477
stay Number of blocked vessels	1	107	74 (72.55)	0.001
		(50.00)
	2	61 (28.50)	19 (18.63)
	3	46 (21.50)	9 (8.82)
Average of blocked vessels		1.71	1.36	0.0001
Blocked vessel (specified)	RCA	108	41 (38.32)	0.040
		(50.47)
	LCx	105	27 (25.23)	0.000
		(49.07)
	LAD	153	68 (63.55)	0.147
		(71.50)
	PDA	0 (0.00)	3 (2.80)	0.036
Surgical intervention	Yes	12 (5.61)	6 (5.61)	1.000
(CABG)
Ejection fraction at	Severe (b30)	14 (6.54)	6 (5.61)	0.533
discharge	Moderate	31 (14.49)	18 (16.82)
	(30-39)

Cases

(N = 107) N (%)

p-Value

more likely to have a normal versus severe EF at discharge when com- pared to controls (95% CI:[0.10-1.63]).

Discussion

The results of our study show that there were no significant differ- ences between younger and older patients when we examined ejection fraction at discharge. Older patients were found to have worse ejection fraction at one year after presentation; however this was not statisti- cally significant, possibly due to our study sample size. We speculate that similarity in ejection fractions between younger and older patients following myocardial infarction may still be clinically significant. This is based on the fact that younger patients are expected to live longer with an abnormal ejection fraction, which may affect their lifestyle and in- crease their chances of future morbidities. Further studies looking at the long term outcomes of premature myocardial infarction are needed. A study by Chua et al. looked at outcomes of patients undergoing PCI for a STEMI and found that Short-term outcomes, such as the risk of re- infarction, heart failure or mortality, were progressively higher with in- creasing age [12]. The pathophysiology of MI varies according to age.

Pineda et al. in 2008 enrolled a total of 400 patients with STEMI. His

study showed that younger patients (age b 45 years) had less initial mor-

Mild (40-49)	34 (15.89)	23 (21.50)	bidity, lower prevalence of multi-vessel disease (1.4 vs. 1.7) and higher
Normal (>=50)	135	60 (56.07)	prevalence of average Cardiovascular risk factors (2.1 vs. 1.8), mainly

Ejection fraction after 1

(63.08)

Severe (b30) 7 (7.87) 1 (1.82) 0.366

male gender, smoking habit, family history, and hyperlipidemia com- pared to older patients (age N 45 years) [13]. However, hypertension

year

Moderate

(30-39)

15 (16.85) 13 (23.64)

and diabetes prevalence were higher in older patients N45 years [13].

Mild (40-49) 16 (17.98) 8 (14.55)

Normal (>=50) 51 (57.30) 33 (60.00)

Number of stents placed 0 51 (23.83) 17 (15.89) 0.085

1 99 (46.26) 63 (58.88)

>=2 64 (29.91) 27 (25.23)

Length of stay Mean +- SD 4.34 +- 4.39 +- 4.91 0.268

3.37

vessels, number of stents placed, length of stay (days), and ejection frac- tion (%) at discharge. In our sample, we found that smokers and patients with family history of MI were significantly more likely to have prema- ture MI (OR = 2.40, 95% CI:[1.18-4.85], OR = 2.13, 95% CI:[1.15-3.96],

respectively). On the other hand, hypertensives and diabetics were sig- nificantly less likely to have premature MI (OR = 0.31, 95% CI: [0.15-0.61], and OR = 0.21, 95% CI:[0.08-0.50], respectively). As for the number of impacted vessels, cases were significantly less likely to have either two or three impacted vessels as opposed to one (OR = 0.40, 95% CI:[0.17-0.92], OR = 0.24, 95% CI:[0.08-0.71], respectively).

In contrast, cases were 1.17 times as likely to have one stent placed as opposed to none (95% CI:[0.42-3.23]), and 2.48 times as likely to have two or more stents placed as opposed to none (95% CI:[0.85-7.23]), though these results were not significant. We found no association be- tween premature MI and length of stay in days (OR = 1.00, 95% CI: [0.91-1.11]). Finally, we found next to no association between the ejec- tion fraction and premature MI. Patients with premature MI were 1.04 times as likely to have moderate versus severe EF (95% CI: [0.22-4.88]), and 0.91 time as likely to have mild versus severe EF (95% CI:[0.20-4.15]) when compared to controls. Furthermore, though not significant, we found that premature MI patients were 0.4 times

Table 3

Multivariate logistic regression of predictors of premature MI.

Variable	Adjusted OR	95% CI	p-Value
Smoking status	2.40	[1.18, 4.85]	0.015
Hypertension	0.31	[0.15, 0.61]	0.001
Hyperlipidemia	1.60	[0.81, 3.13]	0.175
Diabetes	0.21	[0.08, 0.50]	0.001
Family history of MI	2.13	[1.15, 3.96]	0.016

In the present study, smokers and patients with a family history of MI were significantly more likely to have premature MI. Furthermore, smoking was found to be the most prevalent risk factor in premature MI. Several studies proposed a greater blood thrombogenicity in youn- ger patients with smoking being the major factor associated with coro- nary thrombotic disease [4,14,15]. Similarly to Pineda et al., hypertensives and diabetics were significantly less likely to have MI at a younger age. Another study by Chua et al. looked at STEMI outcomes according to age and concluded that younger patients, at presentation to the Emergency department with MI, had a higher incidence of hyper- tension and diabetes [12]. On the other hand, a study by Han et al., con- cluded that cardiac risk factors are important predictors of acute coronary syndromes in patients b40 years, but have no clinical value in older patients [16].

Any coronary artery can be occluded by myocardial infarction. How- ever, several studies aimed at looking at the spatial distribution of MI by identifying the portion of the coronary tree that is involved. A study by Chua et al. in 2014 showed that the most common artery to be involved in MI, irrespective to gender, was the LAD, followed by the RCA and LCx. Furthermore, this study concluded that there is no significant difference in the spatial distribution of MI with age [12]. Other studies suggested that spatial localization of MI is age-dependent and that it has a prog- nostic value. For instance, in 2014, Kyto et al. enrolled 25,538 patients to study whether anterior STEMI were age and gender dependent. The results of this study showed that anterior STEMIs, due to LAD, were age-related, where they increased from 50% in patients b50 years of age, up to 66% in patients above 60 years of age [17]. In our study, the LAD was the most commonly occluded artery regardless of age.

Our results also show that patients older than 45 years are more prone to have multi-vessel disease at presentation compared to patients with age b45 years. The average of coronary vessels involved in the study group is significantly lower than in the control group. Indeed, in- farction occurring in 2 and 3 coronary arteries as compared to 1 coro- nary artery was less likely to occur in premature MI. This is in agreement with a study conducted by Pineda et al., where the number of vessels affected was lower in cases compared to controls (1.4 vs. 1.7; p = 0.013) [13]. It is important to note the similarity in the outcome findings between the study by Pineda et al., and our study, despite the differences between the Middle Eastern and European populations.

Table 4

Multivariate logistic regression of outcome profile of premature MI.

Variable		Adjusted OR	95% CI	p-Value
Number of vessels	1	Ref	–	–
	2	0.40	[0.17, 0.92]	0.031
	3	0.24	[0.08, 0.71]	0.010
Number of stents placed	0	Ref	–	–
	1	1.17	[0.42, 3.23]	0.759
	>=2	2.48	[0.85, 7.23]	0.096
Length of stay		1.00	[0.91, 1.11]	0.955
Ejection fraction at discharge	Severe (<=30)	Ref	–	–
	Moderate (30-39)	1.04	[0.22, 4.88]	0.963
	Mild (40-49)	0.91	[0.20, 4.15]	0.906
	Normal (>=50)	0.40	[0.10, 1.63]	0.199

Interventional therapy of MI, by means of percutaneous coronary in- tervention, showed that placement of 1 and 2 or more stents as com- pared to no stent was more likely to be present in younger patients but with no significant difference. Similarly, one study conducted by Chua et al., found that the number of stents placed was higher in pa- tients aged b65 years of age compared to older patients but also with no significant difference (0.8 vs. 0.68 respectively) [12]. Despite the higher number of blocked vessels in older patients, the predominance of interventional therapy in those who are younger may be attributed to the differences in risk factors and pathophysiology of myocardial in- farction between younger and older patients. Future studies should in- vestigate the nature of the relationship between premature myocardial infarction and the number of stents.

The absence of stent placement in patients from both groups, even when STEMI was induced by occlusive vessel diseases and not vaso- spasm, is due to the presence of multi-vessel disease among those pa- tients, who were planned for CABG afterward.

It is important to note that, there were no significant differences be- tween cases and controls regarding surgical treatment where 6% of both groups underwent CABG.

Every et al. studied the length of stay in hospital as a variable and they concluded that older age and increased comorbid conditions con- ferred a more extended hospital stay [18]. The study concluded that for every 10 year increase in patient’s age, the length of hospital stay in- creases by 0.6 days. In our study, it was interesting to note that the lengths of stays were similar between groups. It is important to note that the Every study was done 25 years ago. The discrepancy in Lengths of stays between the two studies is most likely due to the evolving med- ical care that STEMI patients received in the last 20 years [19].

Finally, in a study done by Plakht et al. in 2015 on 2763 patients with MI, the 10 year survival was assessed in young (b65 years) and old (N65 years) patients. The results showed a remarkably higher mortality rates in the elderly group, as compared to the younger group (70% ver- sus 19%). Furthermore, the same study showed that there is a linear cor- relation between age and mortality; every 1-year increase in age was correlated with OR of 1.08 for mortality [10]. Similarly, another study by Marcus et al. showed an increase mortality post myocardial infarc- tion from 7% in patients b50 years old to N15% in patients N50 years old [20]. In our study, there was no difference in mortality during hospi- tal stay between both groups, which might be explained by the fact that we only assessed in-hospital mortality.

Limitations

Chart review retrospective cohort study has its own inherent limita- tions and the principal investigators were aware of this issue. As such, to decrease biases, several meetings were conducted between the princi- pal investigators and data collectors to standardize the process of data collection, entry and cleaning. The decreased mortality seen in both groups could be due to multiple reasons. Firstly, the study stems from a referral tertiary center emergency department that has advanced

post cardiac catheterization care available, which could limit the gener- alizability of the results to the whole STEMI population. Secondly, the rapid door to balloon could also lead to decreased morality.

Regarding the data analysis process, both groups were found to be unmatched leading to difficulty in comparing them and extracting meaningful conclusions from them. In an effort to correct for this and to minimize confounding variables, a bivariate analysis was applied and significantly different characteristics, including clinically meaning- ful elements, between groups were controlled for via the multivariate analysis respectively. Therefore, our results should be interpreted with care.

Conclusion

In conclusion, premature myocardial infarction is an underestimated entity present among populations. It predominantly affects males and the associated risk factors are smoking and family history of MI with smoking being the major contributor to the thrombogenic state. Its pathophysiology is characterized by single-vessel disease as compared to older patients.

Declaration of Competing Interest

All authors of this study declare no conflict of interest.

Funding

This research did not receive any specific grant from funding agen- cies in the public, commercial, or not-for-profit sectors.

Disclosures

None

Acknowledgement

None.

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