Free-Radical Processes in Stroke Patients with Vascular Comorbidity

Acute oxygen and glucose defi ciency during brain ischemia leads to the inability of neurons producing a suffi cient amount of adenosine triphosphate (ATP) using an oxidative metabolism. Energy defi ciency leads to neuronal death via different mechanisms including oxidative stress. This study aimed to evaluate the changes and main characteristics of free-radical processes in patients with acute stroke and transient ischemic attacks (TIA) in the presence of vascular comorbidity. One hundred forty-one patients with stroke (male—72, mean age—65.4813.44 years) and with a history of cardiovascular diseases (CVD). Free-radical formation was assessed in plasma based on oxidative (chemiluminescence intensity index—basal [CIIb] and zymosan-stimulated [CIIs]) and lipid-peroxidation markers (antiperoxide plasma activity [APA] and malondialdehyde [MDA]). During the follow-up period (from 6 to 72 months) the incidence of recurrent cardiovascular events, outcomes, and survival were assessed using a telephone interview. All patients who survived were rehospitalized and underwent neurologic assessment. A high level of vascular comorbidity was demonstrated. The level of imbalance of free-radical processes correlated with an acute-stroke severity with a maximal intensity of lipid peroxidation in hemorrhagic stroke and the activation of oxidative stage of free-radical processes in ischemic stroke. There was a signifi cant decrease of APA in both types of stroke, whereas TIA was characterized by maintenance of high APA levels (p  0.05). In patients with an acute-stroke free-radical imbalance increased proportional to the level of a vascular comorbidity. The decrease of APA level and increase of MDA level, which refl ect signifi cant oxidative imbalance and more extensive vascular damage, correlate with inferior recovery during the inpatient period (r 5 0.357; p  0.05 и r 5 0.234; p  0.001 respectively). It was demonstrated that low MDA and high APA level in patients with acute stroke are the prognostic markers of a good functional recovery during inpatient treatment and decreased strokeassociated mortality during long-term follow-up. Citation: Silina EV, Orlova AS, Rumyantseva SA, Bolevich SB (2016) Free-Radical Processes in Stroke Patients with Vascular Comorbidity. Biol Med (Aligarh) 8: 344. doi:10.4172/0974-8369.1000344.


Introduction
Stroke is a disabling cerebrovascular disease with a mortality rate reaching up to 54% and disability rate of 50-80% [1,2]. Th e decrease of stroke morbidity and increase of treatment effi cacy is a priority task of practical health care [3].
Cerebral hypoxia and ischemia with the decrease of aerobic glycolysis resulting from the termination of a cerebral perfusion are the key pathologic processes in stroke [4]. Resulting energy-synthesis deterioration leads to imbalance of free-radical processes with the development of oxidative stress [5,6].
Vascular pathology, associated with atherosclerosis, arterial hypertension, and diabetes mellitus (DM) usually develops in multiple vessels of the organism simultaneously [7,8]. Th e presence of several cardiovascular conditions in one patient is referred as comorbidity (in Latin, Со means together, morbus means disease), which can adversely aff ect the course of acute stroke, associated outcomes, and prognosis [9].
Energy-synthesis imbalance in cells and tissues promotes a signifi cant change in free-radical processes, which are widely recognized as a key component of the development and maintenance of postischemic cerebral disorders and also of hypertension, DM, atrial fi brillation (AF) and coronary artery disease (CAD) [10][11][12].
At present, data on the changes and characteristics of free-radical processes in patients with acute stroke and transient ischemic attacks (TIA) with diff erent severity of vascular comorbidity are lacking.
Th e aim of this study was to evaluate the changes and main characteristics of free-radical processes in patients with acute stroke and transient ischemic attacks (TIA) in the presence of vascular comorbidity.
Stroke type was determined using computer/magnetic-resonance tomography (CT/MRT), clinical evaluation, and patient-history data.
Daily clinical monitoring was performed in all patients, including history and complaints assessment, blood pressure, pulse, respiratory rate, electrocardiogram and body temperature control, complete blood count, and blood chemistry. Neurologic evaluation was performed using NIH-NINDS scales; functional status and recovery were assessed according to modifi ed Renkin scale. Free-radical processes were assessed in serum at several time points on oxidative markers (indices of active oxygen-species formation in leukocytes-basal (ILCLIb) and zymosan-stimulated (ILCLIs) indices of leukocyte chemiluminescence intensity, and lipid peroxidation markers (index of antiperoxidation plasma activity [APA] and malondialdehyde [MDA]). Th e control group consisted of 33 healthy volunteers.
During the follow-up period (ranging from 6 months to 6 years) a telephone interview with 45 (31.9%) of 141 originally evaluated patients was performed. Survival, the incidence of recurrent cardiovascular accidents, and outcomes were assessed.

Abstract
Acute oxygen and glucose defi ciency during brain ischemia leads to the inability of neurons producing a suffi cient amount of adenosine triphosphate (ATP) using an oxidative metabolism. Energy defi ciency leads to neuronal death via different mechanisms including oxidative stress. This study aimed to evaluate the changes and main characteristics of free-radical processes in patients with acute stroke and transient ischemic attacks (TIA) in the presence of vascular comorbidity. One hundred forty-one patients with stroke (male-72, mean age-65.4813.44 years) and with a history of cardiovascular diseases (CVD). Free-radical formation was assessed in plasma based on oxidative (chemiluminescence intensity index-basal [CIIb] and zymosan-stimulated [CIIs]) and lipid-peroxidation markers (antiperoxide plasma activity [APA] and malondialdehyde [MDA]). During the follow-up period (from 6 to 72 months) the incidence of recurrent cardiovascular events, outcomes, and survival were assessed using a telephone interview. All patients who survived were rehospitalized and underwent neurologic assessment. A high level of vascular comorbidity was demonstrated. The level of imbalance of free-radical processes correlated with an acute-stroke severity with a maximal intensity of lipid peroxidation in hemorrhagic stroke and the activation of oxidative stage of free-radical processes in ischemic stroke. There was a signifi cant decrease of APA in both types of stroke, whereas TIA was characterized by maintenance of high APA levels (p  0.05). In patients with an acute-stroke free-radical imbalance increased proportional to the level of a vascular comorbidity. The decrease of APA level and increase of MDA level, which refl ect signifi cant oxidative imbalance and more extensive vascular damage, correlate with inferior recovery during the inpatient period (r 5 0.357; p  0.05 и r 5 0.234; p  0.001 respectively). It was demonstrated that low MDA and high APA level in patients with acute stroke are the prognostic markers of a good functional recovery during inpatient treatment and decreased strokeassociated mortality during long-term follow-up.

Results and Discussion
Vascular comorbidity level was assessed in all patients with acute stroke and TIA. Analysis revealed a high basal comorbidity level in the majority of patients (Table 1).
There was a significant free-radical imbalance in stroke and TIA patients on admission, including both oxidation and lipid-peroxidation markers. There were several differences between stroke types. It is important to note that TIA patients demonstrated significant differences only on oxidation markers compared to the normal group, with ILCLIb 1.73-fold lower than in the control group (р  0.05), 1.29-fold lower than in IS group (p  0.01), and 2.17-fold lower than in HS group (p  0.01). ILCLIs level in TIA patients was 1.52-fold higher compared to normal levels (p  0.05).
MDA and APA levels were intact in TIA patients on day 1 after admission. MDA level in IS patients was 1.37-fold higher (p  0.001); in HS patients-1.48-fold higher compared to TIA group (p  0.001) with no significant differences on MDA levels between IS and HS groups. APA level was 1.1-fold lower in IS group (р  0.05) and 1.19-fold lower in HS group compared to the control group (р  0.05) (Figure 1).
This suggests a preserved functioning of endogenous protective antioxidant system in patients with TIA, which prevents postischemic brain-tissue damage with temporary functional deterioration in TIA as a result of transient energy-production imbalance. The activation of endogenous antioxidant-protection system neutralizes metabolic disturbances, preventing the progression of postischemic apoptosis.
ILCLIb in patients with vascular comorbidity demonstrates a progressive decrease proportional to the increase in the number of cardiovascular conditions. In patients with three cardiovascular diseases (CVDs) ILCLIb was 1.20-fold lower; and in patients with four CVDs-1.75-fold lower (p  0.05) compared to stroke patients  (Figure 2).
A significant correlation of the number of diagnosed CVDs with ILCLIb levels (r 5 -0.249; p  0.01), MDA (r 5 0.240; p  0.01), and APA (r 5 -0.201; p  0.05) was observed. The decrease of APA and increase of MDA levels, characteristic to the progressive free-radical imbalance with the increase of the number of organs involved into pathologic cardiovascular process demonstrate a positive correlation with inferior recovery during inpatient treatment (r 5 0.357; р  0.05 and r 5 0.234; р  0.001, respectively).
Therefore an increase of free-radical imbalance was observed in patients with acute stroke and TIA, proportional to the level of vascular comorbidity.
The assessment of free-radical processes' characteristics in patients with comorbidity revealed that a decrease of APA on admission was associated with inferior functional outcome on Renkin scale. In patients with low APA, good functional outcome (Renkin 0) was observed in 26.2% cases; unfavorable functional outcome (Renkin 5), in 64.7% cases

Follow-up evaluation
During the 6 years of follow-up period after the initial stroke, 32.6% of patients died. The majority of patients died during the first year after discharge (nine of 15; 60%), which is 2.25-fold and 4.51-fold higher compared to the 2-3 and 4-6-year periods, respectively (р  0.05).
Survival rate in patients with one CVD was 2.8-fold higher; in patients with two and less than two CVDs-1.42-fold higher, compared    Table 2).
Markers of lipid peroxidation demonstrated the highest negative prognostic value both during the inpatient and follow-up periods (6 months to 6 years). An increase of lipid membrane-peroxidation marker (MDA) was associated with an unfavorable outcome during the inpatient period, whereas the depression of protective APA level on admission was associated with a negative prognosis in the long-term period (Figure 4).

Conclusion
It was demonstrated that low MDA (3.5 mMOL/L) and high APA (3 r.u.) levels in patients with acute stroke are prognostic markers of good functional recovery during inpatient treatment and decreased strokeassociated mortality during long-term follow-up. Marked free-radical imbalance in acute-stroke patients correlates with the level of vascular comorbidity and reflects the severity of oxidative stress and glycolysis disturbance, which may be considered a pathologic justification of longterm high-dose antioxidant therapy with energy-correction properties.
Severe cardiovascular comorbidity (combination of hypertension, CAD, PC, AF and DM), diagnosed in a majority of patients at the moment of stroke, substantiates the need for active multidisciplinary prevention strategies in the outpatient stage. Besides, severe cardiovascular comorbidity in acute stroke patients should be regarded as a significant prognostic factor for negative rehabilitation outcome.