Risk Factors for Adverse One-year Prognosis in Patients With Low Left Ventricular Ejection Fraction After Myocardial Infarction and Chronic Cerebral Ischemia

Recent studies have reported the correlation between left ventricular dysfunction and asymptomatic carotid artery stenosis So, we aimed to determine the predictors of poor long-term survival in patients with left ventricular systolic dysfunction after and cerebral ischemia.


Conclusion
The presence of carotid atherosclerotic plaques and previous stroke affect the one-year prognosis in patients with myocardial infarction, complicated by heart failure and chronic cerebral ischemia.

Background
Coronary artery disease (CAD) and stroke being the most common cardiovascular diseases caused by atherosclerosis remain the leading causes of death worldwide [1,2]. Recent studies have provided evidence suggesting the presence of the association between coronary artery diseases and stroke risk factors due to the systemic nature of the atherosclerotic process [3,4]. The carotid intima-media thickness arteriopathy predicts the risk of new-onset coronary artery disease and its severity. A signi cant relationship between the presence of non-stenotic carotid atherosclerotic plaques and silent myocardial ischemia has been reported. The overall prevalence of CAD along with carotid artery stenosis is over 50% [5][6][7][8].
Half of the patients with acute coronary syndrome report carotid plaque ultrasonic heterogeneity suggesting their instability [9,10]. This fact con rms the existence of common underlying pathological mechanisms that contribute to the development of adverse cardiovascular and cerebral events.
The long-term prognosis after myocardial infarction (MI) is usually determined by many factors. Impaired left ventricular systolic function contributes greatly to poor survival [11]. Half of MI patients with left ventricular ejection fraction (LVEF) less than 40% die within 3 years. These patients have a 5-fold increased risk of sudden cardiac death than the general population [12][13][14]. Low LVEF in CAD patients is associated with both, multivessel coronary lesions and carotid stenosis [3]. Recent studies have reported the correlation between left ventricular dysfunction and asymptomatic carotid artery stenosis [9]. Besides, cerebral blood ow, especially in the presence of carotid stenosis, is largely determined by central hemodynamics with the cardiac output playing the key role. The presence of cerebral ischemia and its aggravation can further worsen the course of coronary artery disease, MI, and left ventricular failure [15,16]. There are frequent cases of MI in patients with strokes. Undoubtedly, it worsens the prognosis for this group of patients and necessitates the need for further studies to determine the new strategies for diagnosis and treatment [17]. Chronic cerebral ischemia (CCI) is now considered as an additional extracardiac factor contributing to a more severe course of acute and chronic CAD [18,19].
Our study is aimed at determining the predictors of an adverse one-year prognosis in patients with left ventricular systolic dysfunction and chronic cerebral ischemia after MI.
Methods 182 patients with left ventricular failure after Q-wave MI and CCI were recruited in a observational study. All patients suffered from left ventricular failure and chronic cerebral ischemia before the indexed event.
All patients with suspected MI were admitted to the hospital within 7.6 (5.3; 15.2) hours from the chest pain onset. Of them, 149 (81.9%) were men and 33 (18.1%) were women. The mean age of recruited patients was 60.4 (53; 69) years.
The inclusion criteria were as follows: Q-wave MI, left ventricular ejection fraction (LVEF) ≤ 40%, a positive history of chronic cerebral ischemia diagnosed before the onset of MI, Killip II-III. The exclusion criteria were as follows: non-Q-wave MI, persistent rhythm and conduction disturbances, Killip IV, valvular heart disease, severe diabetes, the refusal to sign written informed consent. MI was diagnosed based on (2012) [20].
The study was conducted following Good Clinical Practice and the principles of the World Association's Declaration of Helsinki "Ethical Principles for Medical Research Involving Human Subjects", 1975. The study protocol and informed consent were approved by the Local Ethics Committee. Written informed consent was obtained from each patient.
At admission, all patients underwent a standard clinical and instrumental examination. Left ventricular function was assessed with M-mode, B-mode, and Doppler echocardiography using including an assessment of the functional state of the LV according to ECHO-CG data in M-, B-and Doppler modes on an Acuson 128/XP10 ultrasound machine (USA). The measurements were performed according to the generally accepted protocol. All patients underwent selective coronary angiography (CAG) undertaken on Siemens Angioscop equipment (USA) and INNOVA 3100 (GE, USA). On days 2-3 after myocardial infarction, color ow duplex scanning of the brachiocephalic arteries and pulsed Doppler ultrasonography were performed on a Sonos-2500 ultrasound machine (Hewlett Packard). All patients underwent the MMSE test. Pre-existing chronic cerebral ischemia and the severity of encephalopathy before the onset of myocardial infarction were con rmed by an interventional neurologist based on the clinical examination, the MMSE scores (28-30 points: normal cognition; 24-27 points: pre-dementia; 20-23 points: mild dementia; 11-19 points: moderate dementia; 0-10 points -severe dementia) and echocardiography and ultrasonography ndings.
All patients included in the study received standard medical therapy: antiplatelet agents (after a loading dose of aspirin at a dose of 75-100 mg and clopidogrel 75 mg), enoxaparin, nitrovasodilators, betablockers, angiotensin-converting enzyme inhibitors (ACE inhibitors), or angiotensin receptor blockers (ARB), diuretics, mineralocorticoid receptor antagonists, statins, and individual calcium antagonists.
One year after MI, the following hard endpoints were collected: recurrent MI, progressive angina pectoris, need for revascularization, acute decompensated heart failure (HF), readmission to hospital, cerebrovascular events, deaths (cardiovascular mortality and overall mortality).
Statistical analysis was performed using the STATISTICA 8.0 and SPSS software packages. The Shapiro-Wilk test was used to test the normality of data. Continuous variables are presented as the median and interquartile range (Me (25; 75)). The Mann -Whitney U test was used to compare two groups where the variable of interest was continuous. The two-sided Fisher's exact test and Yates's chi-squared test were used to comparing the frequencies. Univariate and multivariate logistic regression was used to determine independent predictors of adverse outcomes. To assess each factor in predicting the event under study, the risk ratio (RR) and odds ratio (OR) were calculated with a 95% con dence interval (CI). Differences were considered statistically signi cant at p < 0.05.

Results
Clinical and demographic data of the study population are presented in Table 1. The vast majority of patients were men with pre-existing arterial hypertension, angina pectoris, and heart failure. Patients with anterior MI, multivessel coronary artery disease, and Killip II prevailed, 81.2% of patients underwent the revascularization of the infarct-related artery. Univariate regression reported that a history of stroke and carotid atherosclerotic plaques in the acute MI phase were the most signi cant individual risk factors associated with one-year mortality (Table 3). We then performed univariate regression to determine the most likely predictors of adverse outcomes associated with the development of cardiovascular events in patients who reached hard endpoints and those who did not (Table 4). The risk factors associated with the development of cardiovascular events within the follow-up included the presence of carotid atherosclerotic plaques con rmed during the hospitalization and a positive history of stroke. Percutaneous coronary intervention (PCI) of the infarct-related artery was associated with a favorable prognosis.

Discussion
Risk assessment of developing an adverse prognosis is crucial for understanding the medical and social signi cance of the disease and determining the intensity of subsequent treatment and secondary prevention. However, there are very few studies describing the effects of concomitant chronic cerebral ischemia on the prognosis after MI.
Systolic dysfunction developing after MI in patients with pre-existing carotid stenosis worsens chronic cerebral ischemia due to both, cardioembolic risk and hypoperfusion aggravation [18]. However, recent studies showed that the presence of signi cant brachiocephalic stenosis is not necessary in this case [21]. The presence of heart failure is known to contribute to the emergence or aggravation of autonomic, cognitive, and neuropsychological de cits due to a decrease in the thickness of the cerebral cortex, regardless of carotid stenosis [22]. A regional decrease in cerebral blood ow occurs in patients with heart failure. This decrease is particularly pronounced in those patients who have pre-existing cerebral ischemia [23]. However, there is no clear relationship of the presence and severity of carotid stenosis and with the clinical manifestations of cerebral ischemia in patients with heart failure [21][22][23]. No doubt, the interaction between the damaged myocardium and altered cerebral functions in chronic cerebral ischemia affects the prognosis. Non-stenotic cerebral atherosclerosis in its turn can further worsen the prognosis in patients after myocardial infarction due to the risk of cerebral atherothrombotic events [19].
We found that carotid intima-media thickening was the main manifestation of carotid artery arteriopathy. The prevalence of carotid atherosclerotic plaques was low. The one-year mortality rate was 6.2% in the study group. Complete myocardial revascularization and optimal drug therapy in most patients resulted in improved survival. Logistic regression analysis showed the high signi cance of cerebral atherosclerosis, in particular, the presence of carotid atherosclerotic plaque and prior stroke contributed greatly to one-year prognosis in patients with CCI after MI. The onset of acute coronary syndrome is accompanied by morphological changes in atherosclerotic plaques and other vascular areas. This argument is con rmed by the ultrasonography ndings reporting carotid plaque heterogeneity in the internal carotid arteries, their transition to an unstable state, "activation" in half of the patients several days after MI [14]. This transition from stable plaques to unstable plaques con rms the presence of common pathological mechanisms contributing to the development of adverse events. Our ndings suggest that cerebral vascular events were more signi cant for long-term prognosis than low LVEF in patients with chronic cerebral ischemia.
Our ndings are consistent with the results of the prospective CAFES-CAVE study suggesting the presence of a signi cant relationship between carotid atherosclerotic lesions and the incidence of cardiac complications [24]. Thus, the presence of even non-stenotic carotid atherosclerotic plaques signi cantly increased the risk of adverse cardiovascular events [24]. Thus, chronic cerebral perfusion can be considered as an additional extracardiac factor contributing to poor prognosis in patients with low LVEF after MI, including the risk of stroke. Large-scale studies showed that progressive impairment of left ventricular systolic function is associated with a 4-fold increase in the risk of stroke [25].

Conclusion
Page 10/13 The presence of carotid atherosclerotic plaques and previous stroke affect the long-term prognosis in patients with myocardial infarction, complicated by heart failure and chronic cerebral ischemia. Our ndings necessitate the development of target multidisciplinary approaches in secondary prevention and outpatient monitoring of patients with low left ventricular ejection fraction and concomitant chronic cerebral ischemia.

Not applicable
Availability of data and materials The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request

Competing interests
The Authors declare that there is no сompeting of interest.

Funding
The study was funded by the Ministry of Science and Higher Education (project No. 0546-2019-0003 "Atherosclerosis and Comorbidities. Diagnosis and risk management in a large Siberian industrial region").

Authors' contributions
Lebedeva N.B. developed the concept and design of the study, contributed to the analysis, interpretation and synthesis of the data obtained, approved the nal version of the article before submitting it for publication; Chesnokova L.Yu. made a signi cant contribution to the receipt of data, their analysis and interpretation, wrote the rst version of the article