Risk factors associated with ischemic heart disease occurence in acute ischemic stroke patients

Aims. At specific time periods following ischemic stroke (IS), acute coronary syndrome as ischemic heart disease (IHD) represents a higher risk of death than IS. Not all IS patients can undergo specific examination for IHD detection. The aim of this study was to assess exclusive risk factors (RFs) associated with IHD occurrence in IS patients. Knowledge of these RFs should help in stratifying IS patients for IHD detection. Materials and methods. This was a hospital-based, retrospective, single centre study. The sample consisted of 192 consecutive IS patients, divided into two subgroups – Subgroup 1 (54 patients without IHD; 55.6% males; 63.1 ± 11.8 years) and Subgroup 2 (138 patients with IHD; 39.1% males; 76.3 ± 9.6 years). The following factors were identified: age; sex; presence of arterial hypertension, atrial fibrillation, diabetes mellitus; plasma levels of total cholesterol, triglycerides, low-density cholesterol, high-density cholesterol; body mass index; presence of carotid plaques. Logistic regression analysis was used for statistical evaluation. Results. Of all identified risk factors only age (OR=1.109; 95% CI: 1.069 – 1.150, P=0.001) and the presence of arterial hypertension (OR=6.298; 95% CI: 2.215 – 17.905, P=0.003) were exclusively and significantly associated with the presence of IHD in IS patients. Conclusions. Age and arterial hypertension may be exclusive risk factors associated with IHD in IS patients.


INTRODUCTION
Ischemic stroke (IS) patients are mainly endangered by stroke recurrence in the first 2 years after the onset of IS (ref. 1 ).After this period, coronary death due to ischemic heart disease (IHD), is the main cause of the long-term mortality in IS patients, with an incidence of 1.5-5.4% p.a. (ref [2][3][4][5] ).Thus, a great deal of effort is devoted to IHD identification and its proper management [6][7][8] .It is not clear to date, why IHD is present only in some IS patients and not in others 9,10 .IHD and IS traditional risk factors have been well-studied and documented individually on large prospective cohorts [11][12][13][14][15] and there are new studies appearing.In the majority of cases, these risk factors are same for both entities.Atherosclerosis plays a crucial role both in the development of IHD and IS.Nevertheless, IS pathophysiology and etiology are far more complex and atherosclerosis represents just one of several causes.There are also differences in atherosclerosis itself and atherosclerosis may differ in intracranial and extracranial portions of the internal carotid artery 16,17 .
The aim of the present study was to identify the exclusive risk factors associated with IHD occurrence in IS patients.Identification of these risk factors and their proper management may lead to decrease in the occurrence of IHD in IS patients, and to the better long-term clinical outcome of IS patients.

MATERIALS AND METHODS
A retrospective, hospital based, single centre study was used.Discharge reports of 192 consecutive patients with documented IS admitted to the Department of Neurology, Hospital Liptovský Mikuláš, Slovakia, from December 2007 to January 2009 were systematically reviewed.
IS diagnosis was based on clinical findings and computed tomography (CT) results (presence of neurological deficit and corresponding acute ischemic area on CT or magnetic resonance imaging) according to the WHO criteria 18 and latest diagnostic progress 19 .Diagnosis of clinically manifest IHD was made by a senior internal medicine specialist based on the clinical (history of myocardial infarction) and electro-cardiographic (ECG) findings (ST segment changes, presence of Q wave) (ref 20 ).According to the IHD presence, IS patients were divided in two subgroups.
The following risk factors were identified: age; sex; presence of arterial hypertension (AH -either previously established diagnosis or repeated blood pressure values > 140/90 mm Hg after the period of acute stroke), atrial fibrillation on ECG, diabetes mellitus (either previously established diagnosis or fasting blood glucose ≥ 6.1 mmol/l); plasma levels of total cholesterol (mmol/l), triglycerides (mmol/l), low-density cholesterol (mmol/l), high-density cholesterol (mmol/l); body mass index (weight/height 2 ); presence of more than 50% carotid stenosis on ultrasound examination, smoking (more than 10 pack/years).Due to extensive missing data regarding smoking, smoking was excluded from statistical evaluation.
In order to control the confounding factors, multivariable logistic regression analysis (SAS Institute Inc., Cary, NC, USA) was used to identify the exclusive risk factors associated with IHD occurrence in IS patients.Odds ratios for the statistically significant risk factors with a confidence interval of 95% were calculated.

RESULTS
Based on the previously mentioned criteria, 192 consecutive IS patients were included in the study and divided into two subgroups.Fifty-four patients (55.6% males; 63.1 ± 11.8 years) had a negative IHD history (Subgroup 1), while the history of IHD was present in 138 patients (39.1% males; 76.3 ± 9.6 years) (Subgroup 2).All patients were Caucasians.Comparisons of the occurrence of the identified factors in the particular subgroups are shown in (Table 1).
Odds ratios for evaluation of independent association of particular risk factors and IHD occurrence were calculated using the logistic regression statistical model.Of all the observed risk factors included in the statistical model, only age (OR=1.109;95% CI: 1.069 -1.150, P=0.001) and the occurrence of AH (OR=6.298;95% CI: 2.215 -17.905,P=0.003) were significantly associated with the IHD presence in IS patients -see (Table 2).No other risk factors showed any significant relationship to IHD in IS patients and the odds ratios could not be established.
The association between the occurrence of IHD in IS patients in terms of age and the presence of AH is shown in (Fig. 1).Derived from this relation, a 60-year-old IS patient would have 10% probability of IHD presence in the case of AH absence.Theoretically, if the same patient was 9.3 years older and had AH, his chance of IHD would be 75%.This example illustrates, how strong the correlation between AH and IHD presence is.

DISCUSSION
Risk factors for atherosclerosis which plays a crucial role in the development of both IHD and IS, have already had been well-studied [11][12][13][14][15] .However, IHD and IS represent different nosological entities.The prognosis is poorer in patients with coincidental occurrence of these two diagnoses 9 .To date, one cannot clearly predict, whether an IS patient also suffers from IHD and or not.Knowledge of which risk factors are exclusively associated with IHD occurrence in IS patients, could help to identify the patients at higher risk.
In the presented study, a correlation between age and the AH occurrence was found.The strength of the association was quite strong in the case of AH (OR=6.298),but weaker in the case of age (OR=1.109).None of the remaining risk factors were associated with IHD occurrence.This finding may be explained by the etiological complexity of IS.Atherosclerosis plays a major role in IHD as well as IS development, but in IS stroke the situation is far more complex and other etiologies play a significant role too (e.g.cardio-embolism, small vessel disease, thrombophilia) [11][12][13][14][15] .
In the presented study, AH was shown to be the strongest risk factor for IHD occurrence in IS patients.AH was repeatedly reported to be a strong individual risk factor for both IHD and IS [11][12][13][14][15] .However, AH seems to be more strongly related to IHD than to IS.The etiological complexity of IS might be an explanation.
There are several etiological subtypes of IS (AH represents a risk factor in only some of them), while IHD is predominantly caused by atherosclerosis in which AH plays major role 12,21 .Schultz and Rothwell 22 showed in their meta-analysis of two population based stroke incidence studies involving more than 196000 patients, that vascular risk factors differ between the IS subtypes.In this meta-analysis, AH was surprisingly associated only with small vessel disease subtype of IS and not even with the atherosclerotic type.In this meta-analysis only the cardioembolic subtype of IS showed an association with atherosclerosis.In the Erlangen study 23 , AH even showed a  22,23 .Thus the relation between AH and ischemic stroke is much weaker, than it is in IHD.Age is another independent risk factor associated both with IS and IHD, when considered individually 24 .In the presented study, age was also shown to be an independent predictor of IHD occurrence in IS patients.However this correlation was rather weak.As the process of atherosclerosis develops over time, the incidence of IHD also increases with advanced age 25 .Thus, age is a logical risk factor for IHD presence in IS.
In previous studies [26][27][28][29] atrial fibrillation and carotid stenosis 30 showed positive correlation to IHD presence in IS patients.However study design and primary goals were different to this study.Moreover, this difference could be due to retrospective design and sample size of patients in the presented study.These factors also represent the main limitations of the study.
In the present study, the diagnosis of IHD was based upon clinical and ECG findings, as used in everyday clinical practice, not on the basis of radiological findings, such as coronarography, as used in previous studies [7][8][9][10] or laboratory findings as emerging studies suggest.Coronarography is a very sensitive and specific method for evaluation of degree of coronary stenosis.However it does not reveal anything about the clinical state of the patient since many stenoses are asymptomatic.Additionally, coronarography itself is associated with peri and postprocedural risks, radiation load and not all IS patients can undergo the examination.Thus for IHD identification in this study, clinical and ECG findings were used.The idea behind the whole study was to identify patients at risk for IHD presence in terms of risk factors, and those patients sent to coronarography, in order to confirm the suspicion.
Beside traditional risk factors, which were found in the present study, rarer risks such as thrombophilia, Wegener's granulomatosis and oral contraception intake have been described 31,32 .Risk factors for stroke also differ in young and older patients 33 .However, despite their great clinical impact, the incidence is low.Thus these rare risk factors were not found in this study.
The present study, despite its limitations, provides new insight into the role of risk factors in two major vascular diseases.Identification of risk factors exclusively associated with IHD in IS patients is an important goal for further studies.

CONCLUSIONS
Age and the presence of AH were identified as probable risk factors for IHD in IS patients in this study.However, further well-designed studies are needed to confirm these pilot results.

Fig. 1 .
Fig.1.Ischemic heart disease presence in ischemic stroke patients according to the age and the arterial hypertension occurrence.

Table 1 .
Characteristics of the study participants and occurrence of the observed risk factors.Plus-minus values are means ± standart deviation, CAD denotes coronary artery disease, BMI -body mass index, TG -triglicerides, LDL-CH -low density lipoproteins, HDL -high densitz lipoproteins, no -number

Table 2 .
Risk factors associated with the ischemic heart disease presence in ischemic stroke patients.