Young South Asians With ST-Elevation Myocardial Infarction (STEMI) – Outcomes, Clinical and Angiographic Proles.

Background: Why STEMI in young South Asians (SAs) has more adverse outcomes compared to elder population is underexplored. We conducted this study to learn about common risk factors, disease patterns and prognostic factors in this population. Methods: It was an observational study from 2013-2019 done at the Aga Khan University Hospital, Karachi, Pakistan, a tertiary care hospital. Patients aged <45 years who presented with their rst episode of ST elevated Myocardial Infarction (STEMI) and who underwent Primay PCI were included. Patients with previous MI or revascularization were excluded. Details of risk factors, lesion complexity and outcomes were noted. Main outcome measures were: Results: Of a total of 1207 patients, only 165 patients (13%) were <45 years old. Common risk factors included male gender 90.3%, n=149, obesity in 48.3%, n=69, history of tobacco in 45%, n=74 and positive family history in 48.4%, n=80. LAD was the culprit in 77.0%, n=127 with Single vessel disease (SVCAD) in 68%, n=112. Primary outcome of 30 day All-cause mortality was seen in 3.6%, n=6 patients. Secondary outcomes: (i) Composite of Shock/CPR/VT/Vb was seen in 12%, n=20 associated to initial SBP <110 mmhg (OR 4.1, 95% CI 1.2-13.4) or heart failure (OR 3.5, 95% CI 1.0-12.6). (ii) Ejection fraction <35% was seen in 29%. n=48 associated to anterior infarction (OR 5.0, 95% CI 1.8-13.5 ), Time to hospital (TTH) >4 hours (OR 2.6, 95% CI 1.0-6.7) and heart failure (OR 5.1, 95% CI 1.7-15.4). (iii) Delayed discharge >5 days was seen in 27.3%, n=45 associated to TTH >4 hours (OR 3.8, 95% CI 1.3-11.2), the Composite of Shock/CPR/VT/VF (OR 6.4, 95% CI 1.9-21.6) and HTN (OR 2.1, 95% CI 1.0-5.2). Conclusion: Young SAs with STEMI are usually obese, tobacco-users with positive family history. LAD is the most common culprit vessel. Anterior STEMI, delayed presentation, initial SBP, and heart failure may help stratify these patients. heart failure


Introduction
Ischemic Heart disease (IHD) is the commonest cause of deaths globally. In 2016, Cardiovascular diseases (CVD) constituted 31% of all global deaths with 85% due to heart attack and stroke combined. However, deaths due to CVDs occur primarily in Low-and middle-income countries (LMIC). 1 In 2013, nearly 40% of all deaths in South Asia occurred due to CVDs where there were 125.7 deaths for every 100,000 individuals. 2 This can be attributed to delayed identi cation and treatment of risk factors, insu cient health facilities and poverty. 1 Whereas there is vast data for IHD in the elder, data focusing on the clinical features, risk factors and outcomes in young patients is lacking.
Most studies have used an age of 40 to 45 years to de ne "young" patients with coronary artery disease (CAD) as they have less traditional risk factors, have Single vessel disease (SVCAD) and a favorable prognosis. 3 South Asian (SA) ethnicity is itself a risk factor for Premature Coronary Artery Disease (PMCAD) with adverse outcomes. 4 Whereas mortality from CAD has improved in elder patients who are treated for risk factors, the incidence of death in young patients is static likely due to a high burden of unidenti ed and unaddressed risk factors and increasing prevalence of diabetes mellitus (T2DM), obesity, and hypertension (HTN) in developed countries. 5 As CAD prevention guidelines primarily address the traditional risk factors, they underestimate risks particular to the young population resulting in a static death incidence.
Mean age of onset of CAD in SAs is much younger (53 years) compared to European gures of 63. 6 This correlates with the mean age of 52.2 years for patients presenting with acute coronary syndromes (ACS) in Pakistan. 7 MI at a young age can have serious effects on one's mental health, working capability, and socioeconomic status and it can effect multiple dependents. As the data is scarce, in-depth research into this will help in designing better preventive measures and impact outcomes. We, therefore, designed this study to describe the risk factor pro le in patients ≤ 45 years of age with acute MI who require urgent coronary intervention. Additionally, we will also comment on the anatomy of the coronary lesions and outcomes in this young patient population.

Methods
We conducted an observational study from January 2013 to December 2019 at the Aga Khan University Hospital (AKUH), Karachi, Pakistan. All patients were admitted with the rst presentation of STEMI, aged 18 to 45 years and who underwent emergent Coronary Angiography (CAG) with/without Percutaneous Coronary Intervention (PCI). Data were extracted using Health Information Management System (HIMS) using the ICD diagnosis code 140.0-140.6. Patients with history of MI, revascularization or stroke or who were dialysis-dependent were excluded. Ethical exemption from ethical review committee at AKUH was obtained. Information was collected for risk factors, outcomes, and coronary anatomy on pre-designed data collection form.

Risk factors for CAD
Data for risk factors including obesity, T2DM, HTN, smoking, family history of Prematue Coronary Artery Disease (FHx-PMCAD) and lipid pro le was collected. Those with an HbA1c between 5.7-6.4% were classi ed as pre-diabetic and those with a known history or HbA1c values >6.5% were grouped as diabetics. 8 FHx-PMCAD was deemed positive if a parent, sibling, or a rst-degree relative had CAD (<55 years for males and <65 years for females) or there was a history of sudden cardiac death (SCD). 9 HTN was de ned as SBP >140/90 mmHg or patients with a known history of HTN or taking antihypertensive medicines. 10 Tobacco use was counted as positive if the patient was a former or current smoker or used chewable tobacco. 11 Obesity was de ned as per the Asian cut-off value of a BMI of >27.5 kg/m 2 . 12 LDL-C levels >150 mg/dl and LDL-C/HDL-C ratio >2.7 were considered elevated on presentation with ACS as they correlate well with increased risk of stent thrombosis, target lesion revascularization, and MACE. 13,14 Coronary angiography (CAG) Patients undergoing CAG that included at least one expert interventional cardiologist were included. At our center, eyeballing method is used to estimate the percentage, morphology, and length of the coronary lesion. Coronary vessels with stenosis >50% were counted as signi cant and counted as diseased. Any stenosis <50% was classi ed as non-obstructive. 15 Diseased vessels were classi ed as one vessel disease (SVCAD), two-vessel disease (2VCAD), or three vessel disease (3VCAD). Each vessel was subclassi ed as either a proximal segment or mid to distal segment based on the origin of major branches, An isolated diseased major branch ( rst diagonal or obtuse marginal) deemed necessary to revascularize was counted as branch vessel disease and classi ed along with the proximal segments of the vessels i.e. proximal LAD and proximal LCx respectively.

Outcomes
Data were collected to look for the primary outcome of All-cause mortality within 30 days after STEMI or related to the immediate consequences of STEMI, whether in-hospital or in a subsequent hospital visit.
Data was also collected for variables such as Cardiogenic shock (CS), Cardio-pulmonary resuscitation (CPR), Ventricular Tachycardia (VT) or Ventricular Fibrillation (VF), need for temporary pacing, invasive ventilation, and Ejection fraction (LVEF) on a transthoracic echocardiogram (TTE). CS was de ned as the presence of systolic blood pressure (SBP) <90mmHg for at least 30 minutes and/or need for one or more vasopressor agents to maintain SBP >90 mmHg in the absence of hypovolemia or sepsis along with a clinical presentation of ACS. 16 Secondary outcomes included patients with a (i) composite outcome of CS/CPR, VT, or VF, (ii) initial LVEF <35% on TTE, or (iii) delayed length of stay (LOS) up to 5 days or more.

Statistical analysis
Data analysis was performed by using SPSS version 22.0. Chicago. Continuous variables were calculated as mean ± (SD), and categorical variables were presented as counts and percentages. To evaluate the association between outcome variables and demographic and related factors, exploratory variables including an anterior infarction, SBP <110, Time to hospital (TTH) >4 hours on presentation to the emergency unit, pre-PCI brinolysis, gender, obesity, positive FHx-PMCAD, tobacco use, T2DM or history of HTN were used. A chi-square -test was used to compare categorical variables and a student t-test was used for continuous variables. Odds Ratios (OR) and their 95% con dence intervals (CI) were estimated using Logistic Regression. All p-values were two-sided and considered as statistically signi cant if < 0.05.

Results
Out of 1207 patients, 165 patients (13%) patients were <45 years old and ful lled the inclusion criteria. Out of these, 90.3% (n=149) patients were male and only 9.7% (n=16) patients were female. The mean age in this population was 39.5 years (SD 5.1).

Risk factors
Nearly half of the patients (n=69, 48.3%) were obese and had a BMI of (> 27.5 kg/m 2 ) and a signi cant proportion was overweight (38%). Data for BMI was missing for 22 patients. Similarly, nearly half of the patients had a positive FHx-PMCAD (n=80, 48.4%) or history of tobacco use (n=74, 45%). Baseline characteristics and risk factors in young STEMI patients (<45 years) are shown in Table 1.Of all these patients, 2.4% of patients (n=4) had chronic kidney disease but were non-dialysis dependent. Nearly 8.5% (n=14) patients received brinolysis before arriving at our center. Data for lipids were present only for a third of patients (n=49). Three patients presented in their early twenties and had a history of cocaine, hyperhomocysteinemia, and pheochromocytoma respectively.

Coronary Anatomy
Less than two-third patients (n=102, 62%) had anterior infarction of which a third (n=39) had extensive anterio-lateral STEMI. A third of patients (n=62, 37.2%) presented with inferoposterior or inferolateral infarction. A minority (1.8%, n=3) presented with lateral STEMI. More than two-third patients (n=112, 68%) had SVCAD followed by 2VCAD in 23% (n=38) and 3VCAD in a minority (n=13, 8%). Nearly three-fourths (n=127, 77%) had lesions in LAD. Right coronary artery (RCA) was the second most involved vessel in 37.3% (n=61) followed by Left Circum ex (LCx) in 23.6% (n=39) cases. Each proximal or distal segment was assigned a disease percentage out of the total number of patients i.e. 165. (Figure 1). Isolated branch vessel disease was present in only ve patients, that also in the OM1 requiring PCI. They were classi ed as 'proximal LCx.' Only six patients (3.6%) had Left Main (LM) or LM equivalent disease. Around 93% (n=154) patients received revascularization via PCI. The mean length of stents placed in proximal LAD was 25 (+8.4) mm with a mean diameter of 3.1 (+0.5) mm. Nearly 4.2% (n=7) patients underwent revascularization via emergent CABG. Only 3 patients underwent medical therapy either due to STEMI from a small branch that was non-signi cant or excess thrombus burden for which, the patient was put on oral anticoagulation.

Outcomes
A primary outcome of all-cause mortality was observed in nearly 3.6 % of the patients (n=6).
In the secondary outcomes, the composite of CS, CPR, VT, or VF was seen in 12% (n=20) whereas less than a third of patients (n=48, 29%) had LVEF <35%. Similarly, 27.3% patients (n=45) were discharged on or after the fth day of the indexed admission. Patients with history of HTN (OR 2.1, 95% CI 1.0-5.2) or T2DM (OR 2.5, 95% CI 1.0-6.7) were at borderline risk to have increased length of stay even after adjustment for other comorbids and gender ( Table 2). Patients with heart failure symptoms on presentation requiring diuresis were at a borderline risk for the composite outcome (OR 2.6, 95% CI 1.0-7.8) whereas those with initial SBP <110 mmhg were at a higher risk (OR 3.4, 95% CI 1.1-9.8) (Table 3). Similarly, patients with heart failure symptoms were also at risk for LVEF <35% (OR 5.1, 95% CI 1.7-15.4). Also Anterior location of STEMI was a risk factor for LVEF <35% (OR 5.0, CI 1.8-13.5). TTH > 4 hours imparted a borderline risk (OR 2.6. 95% CI 1.0-6.7) for LVEF <35% but was signi cantly associated to LOS >5 days (OR 3.8, 95% CI 1.3-11.2). Patients who had the composite outcomes of shock/CPR/VT or VF were at a higher risk of LOS >5 days (OR 6.4, 95% CI 1.9-21.6) but with a wide con dence interval after adjustment for other predictors. (Table 3) Only 4 patients were lost to follow-up. Two patients had stent thrombosis and presented within a week of PCI. A minority (7.9%, n=13) required invasive mechanical ventilation. Temporary pacing was required by 4.2% (n=7) of patients. None of our patients suffered from a periprocedural stroke.

Discussion
This was an observational study recruitng young STEMI patients. Majority were male, obese, tobacco users, and with positive FHx-PMCAD. Anterior STEMI was the commonest presentation with Proximal LAD involvement and SVCAD as the commonest pattern. Overall mortality was found to be 3.6%.
Studies show a prevalence of 1.2% of CAD in young patients however, prevalence in young SAs may vary from 5% to 10%. 6 SAs with IHD are more likely to have male gender, complex coronary disease, and anterior infarction. 17 The landmark study by Salim Yusuf conducted in 52 countries showed that risk factors responsible for PMCAD are smoking, HTN, T2DM and obesity. 18 The reason for higher obesity is the use of high cholesterol diet and lack of physical activity in addition to lack of facilites, sedentary lifestyle and lack of awareness about risk factors leading to a lack of health-seeking behavior at an early age. 19,20 Tobacco use, whether smoked or chewed is also quite prevalent in Asia with mean age of smoking initiation a little later than 20 years. 21 It signi cantly increases the risk of all-cause mortality in young adults and cessation can reduce risk. 22 Given the high burden of tobacco products in an LMIC, cost-effective and evidence-based interventions are critical to avoid future risk. 23 FHx-PMCAD as a risk factor can be attributed to genetic causes such as dysfunctional and lower levels of HDL-C, and higher Lipoprotein (a) concentrations. 18, 24 Further research regarding the inheritance patterns and ways to intervene is still required. Traditional risk factors like T2DM and HTN are less prevalent in young patients however, the INTERHEART study showed a higher prevalence of T2DM, increased waist-hip ratio, and increased ApoB100/ApoA-I ratio in young SAs comopared to other ethnicities. 18 This demands immediate screening and preventive measures at a much younger ages. High LDL-C/HDL-C ratio i.e. >2.7 has been associated with higher rates of target lesion revascularization (TLR), stent thrombosis (ST), and MACE in ACS patients receiving DES. Moreover, LDL-C levels as high as >150 mg/dl on presentation with ACS also predict microvascular injury. 13 In one study, as high as 50% of the patients presenting with ACS had a high LDL-C/HDL-C ratio >2.7. 14 In our study, nearly 80% of the patients had elevated LDL-C/HDL-C ratios.
The proximal segments of the coronary arteries form a bridging zone between elastic and muscular artery types such that these segments are more likely to develop foam cell lesions and lipid core plaque. 25 Foam cell lesions are already present in childhood and adolescent ages. 26 Also, a hemodynamic basis might be responsible for the development of atherosclerotic plaques in proximal segments. 27 At young ages, SVCAD with LAD involvement is the commonest pattern that can be explained partly by dynamic compression of the septal perforators with disturbed blood ow in the adjacent LAD segment favoring atherosclerosis. 27 Followed by LAD, the disease appears to cluster in the RCA and lastly the LCx. 28 This same pattern of disease was also determined by a few studies done in SAs in addition to the fact that SAs were more likely to have complex (Type B or C) disease. 29 International studies have shown a favorable prognosis in young patients with mortality rates as low as 1.6% at 30 days rising to 2.7% per year.In contrast, young SAs have higher in-hospital mortality, as high as 2.8% as do SA immigrants. 30 Although our study showed a 30 day mortality in only 3.6% (n=6), it was still higher compared to international data.This might be explained by higher risk factor clustering at young ages, lack of protective factors like exercise and healthy diet and lack of awareness about risk factors and symptoms for CAD in addition to a de ciency of appropriate health facilities. 31 CS and Sudden Cardiac Arrest (SCA) are known poor predictors after STEMI. Studies have quoted that nearly 5% of young STEMI patients present with cardiogenic shock and 1.7% and 0.3% of patients might present with VT and VF. 30,32 Risk factors such as elder age, ischemia time, anterior infarction or shock index can predict the occurrence of CS. 33 However, all these studies have included patients from all age groups and might not be a true representation of the young subgroup. Our study found that patients with initial SBP <110 mmHg and signs and symptoms of heart failure had borderline elevated risk for the composite outcome. Low admission SBP is known to be a predictor of short term mortality as well as CS.
Initial SBP between 130 to 140 mmHg correlate with the lowest event rates. 34 Also, signs and symptoms of heart failure predict the development of CS and other adverse outcomes and initial aggressive therapy might be preventive. 35 Patients with Severe LV dysfunction have increased risk of mortality. SCD-HeFT and MADIT-II trials showed mortality bene t of Implantable Cardioverter De brillator (ICD) in patients with an LVEF <35% around 90-days after revascularization for primary prevention. 36, 37 Elder age, increased TTH, proximal occlusion and multivessel stenosis are predictors of reduced LVEF in ACS patients and may also dictate mortality. TTH >5 hours is known to predict LV dysfunction regardless of the coronary vessel involved likely due to impaired microcirculation that causes extensive myocardial ischemia, injury and infarction along with a higher risk of cardiac complications. 38 Our study found the anterior location of infarction, TTH >4 hours, or heart failure symptoms requiring diuresis to be independently associated to EF<35% after adjustment of other factors.
Low-risk patients may be safely discharged early which is cost-effective and adds to the bene ts of PPCI. 39 Not much data is available focusing on predictors of delayed discharge in young patients, modi cation of which might be cost-effective. Patients with HTN are more likely to develop CS and hence may be at risk of increased LOS. 34 This can be due to greater endothelial injury in addition to the fact that HTN usually co-exists with other CV risk factors. 40 Similarly, patients with a TTH >4 hours or who develop CS/CPR/VT/VF maybe more likely to stay up to 5 days or more due to more myocardial damage. 38

Strength and Limitations
To the best of our knowledge, this is the rst study that has addressed the outcomes of young Pakistani patients with STEMI with a signi cant sample size. However, there are several limitations. This was a single-center observational study and the results may not be generalizable with some residual confounders including dietary patterns, medications and exercise status, effecting the clinical outcomes. Patients who died before receiving revascularization could not be included. Signi cant data on lipid pro les was missing which is why it was not included in the regression analysis. Also, this study lacks the long-term outcomes of this population due to a limited follow-up. Due to the fewer number, this study was limited in delineating predictors for mortality. In terms of secondary outcomes, this study was able to identify the relationship with some variables like TTH, anterior infarction, SBP<110 mmHg, and heart failure symptoms, however, larger studies with adequate sample size and power are further required to testify and expand on these impressions.

Conclusion
In conclusion, STEMI in young patients is not uncommon and SAs have increased mortality. Obesity, positive FHx-PMCAD, and tobacco use are common risk factors and SVCAD involving the LAD is the most common CAG nding. Various factors such as anterior infarction, delayed presentation, initial SBP, and heart failure symptoms may help stratify these patients.

Declarations
Ethics approval and consent to participate: Ethical exemption from Ethical Review Committee (ERC) at the Aga Khan University Hospital (AKUH) was obtained (ERC number 5438-Med-ERC-18) in accordance with declaration of Helsinki. The committee waived the need of informed consent for the study.
Consent for publication: Not applicable.
Availability of data and materials: The datasets used and/or analysed during the current study available from the corresponding author on reasonable request Competing interests: The authors declare that they have no competing interests.   Percentages of disease distribution at each segment*