SUMMARY

OBJECTIVE:

A decrease in the left ventricular ejection fraction (≤40%) in the setting of ST-segment elevation myocardial infarction is a significant predictor of mortality in the young ST-segment elevation myocardial infarction population. In this study, we aimed to investigate the predictors of left ventricular ejection fraction reduction and evaluate the long-term mortality rates in young ST-segment elevation myocardial infarction patients with or without decreased left ventricular ejection fraction.

METHODS:

We enrolled retrospectively 411 consecutive ST-segment elevation myocardial infarction patients aged 45 years or below who underwent primary percutaneous coronary intervention. Young ST-segment elevation myocardial infarction patients were divided into two groups according to their left ventricular ejection fraction (≤40%, n=72 and >40%, n=339), which were compared with each other.

RESULTS:

Statin use, white blood cell count, C-reactive protein, peak creatine kinase-MB, prolonged ischemia time, left anterior descending artery-related infarction, proximally/ostial located lesion, and no-reflow were independently associated with low left ventricular ejection fraction. Additionally, long-term mortality was considerably higher in the left ventricular ejection fraction ≤40% group than those in the left ventricular ejection fraction>40% group (18.1% versus 2.4%; p<0.001).

CONCLUSIONS:

In young ST-segment elevation myocardial infarction patients, lesion properties (left anterior descending lesion, proximally located lesion), no-reflow, and prolonged ischemia time appeared to be important determinants for the left ventricular ejection fraction decline, rather than coronary disease severity or demographic and hematological parameters. Statin use may be preventive in the development of left ventricular ejection fraction decline in young ST-segment elevation myocardial infarction patients.

KEYWORDS:
STEMI; Mortality; Adult; Percutaneous coronary intervention

INTRODUCTION

The incidence of ST-segment elevation myocardial infarction (STEMI) is 0.05–0.15% annually, and a significant number of STEMIs (5.5–11.6%) have been found at a young age (≤45 years)¹1. Ibanez B, James S, Agewall S, Antunes MJ, Bucciarelli-Ducci C, Bueno H, et al. 2017 ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: the task force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J. 2018;39(2):119-77. https://doi.org/10.1093/eurheartj/ehx393
https://doi.org/10.1093/eurheartj/ehx393... –³3. Chua SK, Hung HF, Shyu KG, Cheng JJ, Chiu CZ, Chang CM, et al. Acute ST-elevation myocardial infarction in young patients: 15 years of experience in a single center. Clin Cardiol. 2010;33(3):140-8. https://doi.org/10.1002/clc.20718
https://doi.org/10.1002/clc.20718... . Although in-hospital and long-term mortality rates are better in younger patients with myocardial infarction than in the older population, compared with the general male population, the risk of mortality is 2–4 times higher in men and even higher in women⁴4. Lisowska A, Makarewicz-Wujec M, Filipiak KJ. Risk factors, prognosis, and secondary prevention of myocardial infarction in young adults in Poland. Kardiol Pol. 2016;74(10):1148-53. https://doi.org/10.5603/KP.a2016.0098
https://doi.org/10.5603/KP.a2016.0098... ,⁵5. Nielsen S, Björck L, Berg J, Giang KW, Sandström TZ, Falk K, et al. Sex-specific trends in 4-year survival in 37 276 men and women with acute myocardial infarction before the age of 55 years in Sweden, 1987-2006: a register-based cohort study. BMJ Open.2014;4(5):e004598. https://doi.org/10.1136/bmjopen-2013-004598
https://doi.org/10.1136/bmjopen-2013-004... . To date, for different age groups or general STEMI patients, many parameters related to mortality have been introduced, including Killip class, advanced age, delay in treatment, coronary disease severity, renal failure, left ventricular ejection fraction (LVEF), post-percutaneous coronary intervention (PCI), thrombolysis in myocardial infarction (TIMI) flow, and noncompliance with pharmacological recommendations¹1. Ibanez B, James S, Agewall S, Antunes MJ, Bucciarelli-Ducci C, Bueno H, et al. 2017 ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: the task force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J. 2018;39(2):119-77. https://doi.org/10.1093/eurheartj/ehx393
https://doi.org/10.1093/eurheartj/ehx393... ,³3. Chua SK, Hung HF, Shyu KG, Cheng JJ, Chiu CZ, Chang CM, et al. Acute ST-elevation myocardial infarction in young patients: 15 years of experience in a single center. Clin Cardiol. 2010;33(3):140-8. https://doi.org/10.1002/clc.20718
https://doi.org/10.1002/clc.20718... ,⁶6. Bęćkowski M, Gierlotka M, Gąsior M, Poloński L, Zdrojewski T, Dąbrowski R, et al. Factors affecting early mortality and 1-year outcomes in young women with ST-segment-elevation myocardial infarction aged less than or equal to 45 years. Curr Probl Cardiol. 2021;46(3):100419. https://doi.org/10.1016/j.cpcardiol.2019.03.008
https://doi.org/10.1016/j.cpcardiol.2019... . In young patients, LVEF decrease (≤40%) in the course of STEMI is a strong predictor of mortality, consistent with the general STEMI population⁶6. Bęćkowski M, Gierlotka M, Gąsior M, Poloński L, Zdrojewski T, Dąbrowski R, et al. Factors affecting early mortality and 1-year outcomes in young women with ST-segment-elevation myocardial infarction aged less than or equal to 45 years. Curr Probl Cardiol. 2021;46(3):100419. https://doi.org/10.1016/j.cpcardiol.2019.03.008
https://doi.org/10.1016/j.cpcardiol.2019... . Aside from being a significant predictor of mortality, the reduced LVEF is also associated with reduced functional capacity and quality of life and with increased rehospitalization and the economic burden in surviving patients after myocardial infarction⁷7. Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JGF, Coats AJS, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC)Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J. 2016;37(27):2129-200. https://doi.org/10.1093/eurheartj/ehw128
https://doi.org/10.1093/eurheartj/ehw128... .

METHODS

Study population

This study was performed in accordance with the Principles of the Declaration of Helsinki and was approved by the Institutional Ethics Committee. We conducted this study by retrospectively enrolling consecutive 435 patients aged 45 years or below with STEMI who underwent pPCI between January 2012 and January 2017. Of these, 24 were excluded from the study because of previously known myocardial infarction and/or heart failure (n=16) and missing clinical and/or long-term follow-up data from hospital files (n=8). Thus, the final study consisted of 411 patients. Telephone interviews, hospital records, and the death registry database were the sources of long-term follow-up data. STEMI was defined according to the current guidelines¹1. Ibanez B, James S, Agewall S, Antunes MJ, Bucciarelli-Ducci C, Bueno H, et al. 2017 ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: the task force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J. 2018;39(2):119-77. https://doi.org/10.1093/eurheartj/ehx393
https://doi.org/10.1093/eurheartj/ehx393... .

Data collection

Patients’ medical history and data on baseline clinical and demographic characteristics were obtained from hospital records and patient files. These records indicated that blood biochemical parameters and a complete blood count had been obtained for all patients upon admission to the hospital. Blood samples were retested every 6 h for creatine kinase-myocardial band (CK-MB) and troponin T until peak levels were detected. LVEF obtained before discharge, which was assessed using a modified version of Simpson’s method, was considered in the study.

The digital angiograms (Dicom-viewer; MedCom GmbH, Darmstadt, Germany) of all patients who were treated with pPCI by experienced interventional cardiologists were analyzed quantitatively in terms of lesion and intervention characteristics. The coronary blood flow patterns before and after pPCI were evaluated based on TIMI flow grade, and epicardial no-reflow was defined as a TIMI flow grade <3 in the target vessel lesion. The thrombus burden was assessed according to the TIMI thrombus grading scale, as defined previously⁸8. Gibson CM, Cannon CP, Daley WL, Dodge Júnior JT, Alexander Júnior B, Marble SJ, McCabe CH, et al. TIMI frame count: a quantitative method of assessing coronary artery flow. Circulation. 1996;93(5):879-88. https://doi.org/10.1161/01.cir.93.5.879
https://doi.org/10.1161/01.cir.93.5.879... . The patients’ SYNergy between Percutaneous Coronary Intervention with TAXus and cardiac surgery (SYNTAX) score was calculated using the online SYNTAX score calculator (www.syntaxscore.org) to indicate the severity of coronary artery disease.

Statistical analysis

SPSS version 22.0 (SPSS, Inc., Chicago, IL, USA) was used for the statistical analysis. The Kolmogorov-Smirnov test was used to analyze the normality of the data. Continuous variables with normal distribution were expressed as mean±standard deviation and were compared using the independent t-test. Non-normal data were expressed as median (0.25–0.75 percentiles) values and compared using the Mann-Whitney U test. Fisher’s exact test or χ²2. Morillas P, Bertomeu V, Pabon P, Ancillo P, Bermejo J, Fernandez C, et al. Characteristics and outcome of acute myocardial infarction in young patients. The PRIAMHO II study. Cardiology. 2007;107(4):217-25. https://doi.org/10.1159/000095421
https://doi.org/10.1159/000095421... test was used to compare the categorical variables which were expressed as percentages. Multivariate logistic regression analyses were performed to identify the independent predictors of reduced LVEF, using the variables that showed a marginal association in the univariate analysis. Power analysis was performed with G*Power version 3.1.9.4 and the power values obtained in the post-hoc power analysis of the parameters found as predictors in the logistic regression analysis were between 0.684 and 0.988. The Kaplan-Meier survival curve analysis was used to demonstrate the event-free survival curves of the patients with LVEF ≤40% or >40%, and the log-rank test was used for comparison. A p-value of <0.05 indicated statistical significance.

RESULTS

The study population consisted of 411 young STEMI patients (mean age: 40±4 years; 8.5% female) who underwent pPCI. The average LVEF of the patients was 47.28±8.76. The patients were divided into two groups according to their LVEF values: the high (>40%) LVEF group (n=339, mean LVEF: 50.30±6.13) and the reduced (≤40%) LVEF group (n=72, mean LVEF: 33.07±3.92). The baseline characteristics of all the patients and those of the low and high LVEF groups are shown in Table 1. In patients in the low LVEF group, diabetes mellitus and dyslipidemia were more common. Patients in the low LVEF group had a higher prevalence of Killip class >1 (on admission), higher heart rate, and higher values of white blood cells (WBC), neutrophils, neutrophil-to-lymphocyte ratio (NLR), blood glucose, peak CK-MB, and C-reactive protein (CRP) than those in the high LVEF group. Furthermore, patients in the low LVEF group had lower levels of hemoglobin and estimated glomerular filtration rate than those in the high LVEF group. In comparing the properties of angiography and ischemia, patients in the low LVEF group had a longer total ischemia time and a higher SYNTAX score than those in the high LVEF group. Infarct-related artery (IRA) of the left anterior descending (LAD), proximal/ostial localization of the culprit lesion, no-reflow phenomenon, and high-grade thrombus burden were more frequent in the low LVEF group. The rate of long-term mortality was found to be considerably higher in the low LVEF group than in the high LVEF group (Table 1).

Multivariate regression analysis was performed to determine the independent predictors of reduced LVEF, using the parameters found to be associated with reduced LVEF in the univariate analysis. Statin use, WBC, CRP, peak CK-MB, total ischemia time, LAD as the IRA, proximal/ostial lesion for IRA, and no-reflow were found to be independently associated with low LVEF (Table 2).

During an average follow-up of 38±13 months, 21 (5.1%) deaths from all causes were reported. The rate of long-term mortality was significantly higher among patients in the low LVEF group than among those in the high LVEF group (n=13, 18.1% versus n=8, 2.4%; p<0.001). The Kaplan-Meier survival curve of long-term mortality is shown in Figure 1.

Figure 1.
Kaplan-Meier long-term survival curve of patients with low and high left ventricular ejection fraction.

DISCUSSION

In this study, we evaluated the predictors of reduced LVEF in patients with STEMI aged ≤45 years. The demographic features were not determined as predictors of decreased LVEF development, whereas statin use from the pharmacological history was found to be protective in the occurrence of decreased LVEF. While WBC and CRP were independent predictors of reduced LVEF, NLR, as an inflammatory parameter, was not a predictor of reduced LVEF. The most considerable findings of this study were that lesion localization, procedure characteristics (i.e., IRA, proximal/ostial lesion, and no-reflow), and prolonged ischemia time were the main causes of reduced LVEF.

The fact that LVEF is closely related to death and poor quality of life and that data about reduced LVEF predictors in young STEMIs are lacking has prompted us to investigate the predictors of LVEF decline in young STEMI patients. In our study, the demographic characteristics of the patients, including diabetes and hyperlipidemia, were not predictors of reduced LVEF. The reason that diabetes is not related to LVEF may be that many years are required to develop microvascular dysfunction and diabetic cardiomyopathy⁹9. Jia G, Hill MA, Sowers JR. Diabetic cardiomyopathy: an update of mechanisms contributing to this clinical entity. Circ Res. 2018;122(4):624-38. https://doi.org/10.1161/CIRCRESAHA.117.311586
https://doi.org/10.1161/CIRCRESAHA.117.3... . In parallel with previous randomized studies showing that statin use could reduce the risk of developing heart failure, in our study, the use of statin was a predictor of preventing the development of heart failure in young STEMI patients¹⁰10. Athyros VG, Papageorgiou AA, Mercouris BR, Athyrou VV, Symeonidis AN, Basayannis EO, et al. Treatment with atorvastatin to the National Cholesterol Educational Program goal versus ‘usual’ care in secondary coronary heart disease prevention. The GREek Atorvastatin and Coronary-heart-disease Evaluation (GREACE) study. Curr Med Res Opin. 2002;18(4):220-8. https://doi.org/10.1185/030079902125000787
https://doi.org/10.1185/0300799021250007... ,¹¹11. Kjekshus J, Pedersen TR, Olsson AG, Faergeman O, Pyörälä K. The effects of simvastatin on the incidence of heart failure in patients with coronary heart disease. J Card Fail. 1997;3(4):249-54. https://doi.org/10.1016/s1071-9164(97)90022-1
https://doi.org/10.1016/s1071-9164(97)90... .

Ischemic injury induces an inflammatory response, the intensity of which is an important predictor of ventricular remodeling. The CRP levels in STEMI patients have been shown to be closely associated with infarct size, reduced LVEF, and left ventricular volumes, aside from mortality¹²12. Orn S, Manhenke C, Ueland T, Damas JK, Mollnes TE, Edvardsen T, et al. C-reactive protein, infarct size, microvascular obstruction, and left-ventricular remodelling following acute myocardial infarction Eur Heart J. 2009;30(10):1180-6. https://doi.org/10.1093/eurheartj/ehp070
https://doi.org/10.1093/eurheartj/ehp070... . Similarly, NLR, as a recently identified inflammatory parameter, has been found to be a predictor of LVEF decline and mortality for unselected STEMI patients¹³13. Ghaffari S, Nadiri M, Pourafkari L, Sepehrvand N, Movasagpoor A, Rahmatvand N, et al. The predictive Value of Total Neutrophil Count and Neutrophil/Lymphocyte Ratio in Predicting In-hospital Mortality and Complications after STEMI. J Cardiovasc Thorac Res. 2014;6(1):35-41. https://doi.org/10.5681/jcvtr.2014.007
https://doi.org/10.5681/jcvtr.2014.007... . In our study, CRP was an independent predictor of reduced LVEF in young STEMI patients, which is consistent with the general STEMI cohort, but NLR was not.

Studies investigating the relationship between the infarct location/size and prognosis have shown that patients with a large infarct size (mostly confirmed by a high peak enzyme level) had a poor in-hospital and long-term prognosis and a reduced LVEF¹⁴14. Nienhuis MB, Ottervanger JP, Dambrink JH, Boer MJ, Hoorntje JC, Gosselink AT, et al. Comparative predictive value of infarct location, peak CK, and ejection fraction after primary PCI for ST elevation myocardial infarction. Coron Artery Dis. 2009;20(1):9-14. https://doi.org/10.1097/MCA.0b013e32831bd875
https://doi.org/10.1097/MCA.0b013e32831b... . Similarly, no-reflow has been found to be a strong determinant of infarct size and LVEF decrease¹⁵15. Ndrepepa G, Tiroch K, Fusaro M, Keta D, Seyfarth M, Byrne RA, et al. 5-year prognostic value of no-reflow phenomenon after percutaneous coronary intervention in patients with acute myocardial infarction. J Am Coll Cardiol. 2010;55(21):2383-9. https://doi.org/10.1016/j.jacc.2009.12.054
https://doi.org/10.1016/j.jacc.2009.12.0... . In our study, proximally located and LAD-related STEMIs and no-reflow were found to be predictors of reduced LVEF in young STEMI patients, consistently with the aforementioned studies. Moreover, CK-MB was higher in patients with lower LVEF and is a predictor of LVEF decline.

Delay in reperfusion therapy has been shown to be associated with both mortality and LVEF reduction¹⁶16. Kobayashi A, Misumida N, Aoi S, Steinberg E, Kearney K, Fox JT, et al. STEMI notification by EMS predicts shorter door-to-balloon time and smaller infarct size. Am J Emerg Med. 2016;34(8):1610-3. https://doi.org/10.1016/j.ajem.2016.06.022
https://doi.org/10.1016/j.ajem.2016.06.0... . In patients with delayed reperfusion, the LVEF decline is mostly attributed to increased infarct size. In the present study, prolonged total ischemia time was found to be an independent predictor of reduced LVEF in young STEMI patients, similar to the general STEMI population.

Previous studies evaluating mortality rates of young STEMI patients reported a mortality rate of 3–4%³3. Chua SK, Hung HF, Shyu KG, Cheng JJ, Chiu CZ, Chang CM, et al. Acute ST-elevation myocardial infarction in young patients: 15 years of experience in a single center. Clin Cardiol. 2010;33(3):140-8. https://doi.org/10.1002/clc.20718
https://doi.org/10.1002/clc.20718... ,¹⁷17. Khera S, Kolte D, Gupta T, Subramanian KS, Khanna N, Aronow WS, et al. Temporal Trends and Sex Differences in Revascularization and Outcomes of ST-Segment Elevation Myocardial Infarction in Younger Adults in the United States. J Am Coll Cardiol. 2015;66(18):1961-72. https://doi.org/10.1016/j.jacc.2015.08.865
https://doi.org/10.1016/j.jacc.2015.08.8... . We also found the long-term mortality rate (for 38±13 months) of patients with STEMI aged ≤45 years in the present study was 5.1%. LVEF was reduced to an average of 47.28%, and the rate of patients with reduced LVEF (≤40%) was 17.5% in the present study. This rate was consistent with the study investigating reduced LVEF following STEMI in a general STEMI cohort¹⁸18. Kaul P, Ezekowitz JA, Armstrong PW, Leung BK, Savu A, Welsh RC, et al. Incidence of heart failure and mortality after acute coronary syndromes. Am Heart J. 2013;165(3):379-85.e2. https://doi.org/10.1016/j.ahj.2012.12.005
https://doi.org/10.1016/j.ahj.2012.12.00... . In the present study, the rate of long-term mortality was considerably higher in the low LVEF group than in the high LVEF group (18.1 versus 2.4%) in young STEMI patients. This finding was consistent with a recent study in young STEMI women, which reported that every 5% increase in LVEF at discharge reduced the mortality rate by 60%⁶6. Bęćkowski M, Gierlotka M, Gąsior M, Poloński L, Zdrojewski T, Dąbrowski R, et al. Factors affecting early mortality and 1-year outcomes in young women with ST-segment-elevation myocardial infarction aged less than or equal to 45 years. Curr Probl Cardiol. 2021;46(3):100419. https://doi.org/10.1016/j.cpcardiol.2019.03.008
https://doi.org/10.1016/j.cpcardiol.2019... .

The possible clinical implication of our study is that revealing the factors associated with LVEF decline more precisely in young STEMI patients may substantially not only contribute to the development of new strategies in STEMI treatment and a reduction of the LVEF decline and its associated mortality rates for this specific patient group but also allow us to identify patients who are at higher risk of developing a reduced LVEF and, therefore, require closer clinical follow-up.

This study has some limitations. Although we determined the adequacy of our sample size by comparing it with similar studies in the literature and performing power analysis, our results should be validated in larger clinical trials. Although cardiac magnetic resonance imaging (CMRI) is the gold standard for assessing left ventricular function, CMRI could not be performed owing to the retrospective nature of the study and the high cost and limited availability of CMRI. LVEF measured before discharge was used in our study and no repeated measurements during the follow-up period were taken into account, as they were beyond the scope of the study. This study had a retrospective design and was based on a registry analysis. As the patients included in the study were young and had experienced their first myocardial infarction, the current reduced LVEF was attributed to their recent STEMI. That is, although there were no data, the presence of heart failure extending before STEMI could not be excluded.

CONCLUSIONS

In young STEMI patients, lesion localization (LAD lesion, proximally located lesion), no-reflow, and prolonged ischemia time seem to be important determinants of the LVEF decline, rather than coronary disease severity or demographic and hematological parameters. Moreover, statins should be used in dyslipidemic young patients to avoid procedural transactions that could cause no-reflow.

ACKNOWLEDGMENTS

This study protocol was approved by the Ethics Committee of the Kafkas University Medical Faculty. This study was conducted under the principles of the Declaration of Helsinki. Written informed consent was waived owing to the retrospective nature of the study.

REFERENCES

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