It was established that the carotid endarterectomy is the effective treatment to reduce the risk of subsequent stroke in symptomatic patients with carotid stenosis [6]. Moreover, the risk-benefit ratio prefers surgery for about 70% symptomatic stenosis. In correlation with symptomatic stenosis, it is the unusual behavior for the asymptomatic lesions [7]. Therefore, the stenosis degree stand-alone might not be sufficient to predict the risk of a stroke. Clearly, additional markers are required to characterize more precisely the patients who would benefit the most from a surgery.
The development of new diagnostic technologies is contributing to the transition to a multi-parameter systematic model that allows the formation of a personalized approach to the diagnosis and prevention of stroke.
The main criteria, evaluated in our study, were the degree of ICA stenosis, the morphological structure of the atherosclerotic plaque and the level of Lp-PLA2 concentration.
We propose to further study unique biomarker Lp-PLA2 – an enzyme produced by inflammatory cells and hydrolyzes oxidized phospholipids in LDL, which in connection with individual patient plague stability may lead to earlier detection of atherosclerosis progression / manifestation. Lipoprotein-associated phospholipase A2 is also known as platelet-activating factor acetylhydrolase (PAF-AH). In the blood it is mainly connected with low density lypoprotein (LDL, near 80%) and only less than 20% of this enzyme is associated with high density lypoprotein (HDL) [14].
The combination of three factors – stenosis, ulceration of the atherosclerotic plaque and the inflammatory process within it – is one of the leading mechanisms of embologenicity as well as the development of stroke [21, 22]. This mechanism is not taken into consideration by the classical approach to determining the indications for carotid endarterectomy where the main criterion is the degree of ICA stenosis (50% in symptomatic patients and 70% in asymptomatic patients).
Alongside with the degree of stenosis, plaque morphology can provide crucial information to predict the stroke risk. The recent ultrasound studies showed a higher risk of cerebrovascular events for hypo- or anechogenic plaques compared to echogenic ones [23].
Among symptomatic patients, unstable carotid plaques were found in 76.6% of cases, while stable plaques were detected in 23.4% of cases only. The difference was statistically significant (p < 0.0001).
Ultrasonographic assessment of tissue characteristics is performed according to the overall distribution of grey tones (overall brightness). There are anechogenic (dark) and hyperechogenic (bright) plaques [22].
To provide more objective description, there were developed more detailed classifications; however, an interobserver agreement was weak and there was observed a low correlation with the histopathological findings [24, 25].
Several classifications of plaque echogenicity have been reported in the literature. However, echogenicity on plaque character should be standardized against three reference structures: flowing blood for anechogenic, sternocleidomastoid muscle for isoechogenic, and the adjacent transverse apophysis of the cervical vertebrae for hyperechogenicity [26, 27].
Unstable carotid plaques are associated with increased risk of stroke not only in symptomatic but also in asymptomatic patients. A meta-analysis of eight prospective studies, with a total of 7,557 patients, observing patients with asymptomatic carotid stenosis found that patients with unstable, echolucent plaques had a 2.31-fold increased risk of stroke compared to patients with stable plaque based on ultrasound assessment [22, 28].
Although, according to the study ACST-1, carotid plaque echolucency assessment offered no predictive value for stroke risk [29].
In our research, 25% of patients with asymptomatic ICA stenosis had unstable atherosclerotic plaque.
Experimental studies have shown a key role of inflammation in destabilization and rupture of the atherosclerotic plaque [9, 11]. Specific vascular markers may serve as one of the criteria for assessing inflammation and destabilization of atherosclerotic plaque. In scientific journals, many articles on the comparison of different vascular markers were published [12, 13]. However, Lp-PLA2 is currently considered an independent biomarker for stroke, as well as coronary artery disease and peripheral arterial occlusive disease [15].
The JUPITER trial confirmed that patients with high Lp-PLA2 activity had more than twofold higher risk of developing cardiovascular events compared to those with low Lp-PLA2 activity [30].
Our study showed that patients with symptomatic stenosis of the internal carotid artery had significantly higher plasma levels of Lp-PLA2 compared to patients with asymptomatic stenosis.
When assessing the results, there was found a statistical significance between the increase in Lp-PLA2 concentration and the morphological structure of the atherosclerotic plaque.
Our results strongly confirm the role of Lp-PLA2 in the pathophysiology and clinical presentation of an unstable carotid plaque. Similar to our findings, some studies have reported the association of increased plasma levels of Lp-PLA2 in patients with unstable atherosclerotic plaque [31, 32].
The obtained results indicated the fact that in patients with soft atherosclerotic plaque, the level of Lp-PLA2 concentration was statistically higher compared to patients with hard atherosclerotic plaque. In addition, in patients with soft atherosclerotic plaque, the level of Lp-PLA2 increased to the level of Lp-PLA2 concentration observed in symptomatic patients.
Therefore, we can state that soft atherosclerotic plaque, as well as an increased concentration of Lp-PLA2, is a risk factor for developing stroke.
The innovative approach proposed, clinically verified individually detected formula for determining the risk of stroke development. It considers three main risk factors: the degree of ICA stenosis, atherosclerotic plaque structure and Lp-PLA2 concentration.
According to the results of our study, the consideration of several factors increases the accuracy of calculating the risk of stroke development for particular individuals, which is the basis for risk stratification algorithms.
The use of the proposed method for mathematical calculation of the risk index for stroke development using the formula “Stroke-Stop” may serve as an auxiliary criterion at the stage of determining and selecting treatment tactics for patients with ICA stenosis greater than 70%, and finally to apply predictive and prognostic patient-specific treatment of atherosclerosis supporting the shift from reactive medicine to predictive, preventive, and personalized medicine.
In addition, thus proposed formula accompanied and accomplished with lipid individual profile can be applied alternatively to typical post symptomatic treatment of atheroslerosis. HDL-associated Lp-PLA2 may substantially contribute to the HDL antiatherogenic activity, and could be additionally applicable for the prediction of the efficacy of prescribed medication. Correspondingly, our Stop-Stroke formula is recommended for implementation for personalized clinical application of therapies. It is anticipated that, ultimately, this change in diagnosis and therapy will help in the future design and development of new, more selective and effective therapies for each individual patient.