The association of ventricular tachycardia and endothelial dysfunction in the setting of acute myocardial infarction with ST elevation

Background

Ventricular tachycardia (VT) is characterized by wide QRS complexes of at least 3 consecutive ventricular beats and frequencies faster than or equal to 100 beats per minute. It is most common in men of middle age, and it is commonly caused by ischemic heart disease. Other causes include: other structural cardiac defects, medications, metabolic imbalance, inflammation (infectious/noninfectious), and genotype, but in about 10% of patients it is idiopathic. Pathophysiology and etiology of VT are not unique. The most common mechanism is the so-called reentry mechanism, in which the scarred myocardium is an electrically insufficient locus and pro-arrhythmogenic seat [1–4].

Acute myocardial infarction with ST elevation (STEMI) is the most severe form of the 3 clinical entities in acute coronary syndrome group: STEMI, unstable angina (UA), and myocardial infarction without ST elevation (NSTEMI) [5–8]. It is widely believed that coronary heart disease begins due to atherosclerosis, and that atherosclerosis is basically inflammation. Atherosclerotic arteries, before the development of constriction, show reduced vasodilatation ability, which is mediated by endothelial dysfunction (ED). ED represents inflammation and the loss of all protective features of the endothelium, which may be particularly important in the pathogenesis of STEMI. Atherosclerotic plaque causes narrowing of coronary arteries, and the properties and features on this plaque play a role in clinical coronary disease. ED is in turn a factor that determines whether the plaque will be unstable. During acute coronary syndrome (ACS), especially STEMI, significantly increased flow of cytokines and mediators of ED is registered.

Endothelial dysfunction (ED) is, simply put, the loss of endothelial protective factors – antiplatelet, anti-aggregation, and antiinflammatory – acting on the proliferation, migration, invasion, survival, and permeability of endothelial cells. ED is thus the common name for all those changes that cause damage to the wall of blood vessels. There is a very important role of ED at the microvascular level, in different organic systems in numerous acute infectious, but also noninfectious and chronic, diseases [9–18].

The objectives of our study were to investigate a possible association of individual markers of ED with VT that appeared as a result of STEMI, and to analyze possible differences in ED markers in patients with VT + STEMI in comparison to patients with STEMI only.

Material and Methods

SUBJECTS:

The study included a total of 90 subjects who were divided into 3 groups: 1) 30 patients with documented VT as a result of proven STEMI (VT + STEMI); 2) 30 patients who have had a myocardial infarction with ST segment elevation and no documented VT (STEMI); 3) a control group of 30 patients who did not have acute myocardial infarction or VT, but were under medical control due to hypertension or nonspecific stenocardia, but with no STEMI or STEMI+VT.

In this study, the term STEMI refers to patients within the first 48 h after onset of ischemia. VT refers to periprocedural VT and VT that occurred 6 h after PCI until 48 h of the beginning of ischemia. VT here does not include the reperfusion arrhythmias.

The study was approved by the Hospital “Sisters of Mercy” Ethics Committee’s and the Ethics Committee of the Medical Faculty in Zagreb. Croatian and international ethics norms were respected. By signing the informed consent, the subjects gave permission to perform all required tests, as well as the anonymous use of the results.

ASSESSMENT OF STUDY GROUPS:

Before the enrolment in the study, subjects had to meet a set of inclusion and exclusion criteria. Inclusion criteria were: 1) electrocardiographically (ECG) documented STEMI and VT in the first group of patients; 2) ECG-documented STEMI in patients in the second group; 3) urgent therapeutic percutaneous coronary intervention (PCI) and stent insertion into the coronary artery “culprit” lesion for the first 2 groups of patients; 4) negative results of treadmill testing among patients in the control group; 5) men and women below 76 years of age; 6) normal levels of serum potassium (K) and creatinine; 7) normal levels of magnesium (Mg) for the first group of patients; 8) metildigoxsin levels within therapeutic values for the patients of the first group, if the patient uses it; 9) fasting blood glucose levels 5.0–7.0 mmol/L (for the first 2 groups of patients, the first measured fasting plasma glucose in the Coronary Care Unit (CCU), and for patients in the control group it was a random fasting plasma glucose reading); 10) patients without or with well-controlled arterial hypertension (HA) in terms of measured values of pressure on both arms below or equal to 140/90 mmHg (for patients in the first 2 groups it was first measured blood pressure on arrival in the CCU, and for the control group of patients it was first measured blood pressure before the treadmill testing); 11) left ventricular ejection fraction (EFLV) ≥35% (in this study only due to ischemic or hypertensive cardiomyopathy); 12) for the first group of patients, they did not take treatment within 14 days before blood sampling or the appearance of VT, which has an adverse effect of QT interval prolongation (except for amiodarone, sotalol, and propafenone) and; 13) patients were included regardless of their smoking status. Exclusion criteria were: 1) diabetes; 2) congenital disorders such as arrhythmogenic right ventricular dysplasia, Brugada syndrome, long QT syndrome, or patients with idiopathic ventricular tachycardia or familial hypertrophic cardiomyopathy; 3) malignant and infectious diseases, as well as any other acute and/or chronic non-communicable diseases (e.g., renal insufficiency of any kind) other than atherosclerosis, hypertension, and hyperlipidemia.

ASSESSMENT OF OTHER RISK FACTORS:

From all patients, medical history was taken and physical examination was done by trained medical staff. In addition, the collection of blood samples and the assessment of cigarette smoking, blood biochemistry, body mass index (BMI), and blood pressure (systolic and diastolic) were performed. Smoking status was presented in units of “pack per year” and the number of years of smoking at a given number of cigarettes consumed per day. Known treated or untreated hypertension and hyperlipidemia were recorded as well.

LABORATORY TESTS:

From all patients, 5 mL of venous blood was taken for laboratory tests, and blood was tested in the hematology and biochemistry laboratories of the University Hospital “Sisters of Charity”, and ED markers were tested at the Department for Research, The University Hospital for Infectious Diseases “Dr. Fran Mihaljević”.

For all subjects, several blood tests were performed: total number of leukocytes (L), C-reactive protein (CRP), creatinine, potassium, fasting plasma glucose, cholesterol, triglycerides, low-density lipoprotein (LDL), and high-density lipoprotein (HDL). In patients with VT + STEMI and STEMI only, a few additional blood tests were performed at admission: the first measured value of troponin T (cTnT) and the maximal value of creatinine phosphokinase (CPK). In patients with VT+STEMI, serum level of magnesium (Mg) was determined. None of the patients involved used derivatives of digoxin; therefor, digoxin serum levels were not determined. None of the included patients had been using other anti-arrhythmics, besides low doses of nonselective beta-blockers, which used by some of our patients for treatment of hypertension.

Sera samples of all patients were tested for the soluble markers of endothelial dysfunction: 1) adhesion molecules – intracellular adhesive molecule-1 (sICAM-1) and vascular adhesive molecule-1 (sVCAM-1); 2) selectins – sP-selectin and sE-selectin; and 3) vascular endothelial growth factor (VEGF). ELISA was performed according to the manufacturer’s instructions (Quantikine TM, R & D Systems, Oxon, UK).

Forty-two serum samples from the first and second groups of patients were taken before primary PCI, or prior to the systemic and intracoronary application of heparin (which is proven to have a calming effect on ED markers). The remaining of 18 serum samples in this study were taken during the acute phase of STEMI, the first 24 h after performed PCI, and 6 h after coronary reperfusion.

STATISTICAL ANALYSIS:

Distributions of quantitative characteristics were tested for normality with the Kolmogorov-Smirnov test. To test the difference between the groups, nonparametric tests, Kruskal-Wallis, Mann-Whitney, and Fisher Exact tests were used. The possible correlation among tested variables was calculated by Spearman correlation coefficient.

Results

AGE AND SEX CHARACTERISTICS:

In total, this study included 77 (86%) males and 13 (14%) females. The same percentages of males (83%) and females (17%) were analyzed in the group of patients with STEMI and the control group. In the group of patients with STEMI+VT, the percentage of females was lower (10%), but the difference was not statistically significant (Fisher Exact test, χ2=0.57, p=0.353) (Table 1). Age structure analysis showed that STEMI or STEMI+VT in men occurred at the age of about 60 years, while women with STEMI or STEMI+VT were 10 years older (in their 70s). By contrast, in the control group (in which patients had hypertension or nonspecific stenocardia, but without STEMI, or STEMI+VT), women were slightly younger than men (Table 1).

RISK FACTORS:

Analyzing multiple parameters that represent risk factors for developing cardiovascular disease, we found statistically significant differences between the study groups in levels of several possible indicators: the levels of LDL (p<0.001) and triglycerides (p<0.001) were significantly higher in patients with STEMI or STEMI+VT in comparison to the control group. It was also clearly demonstrated that patients with STEMI or STEMI+VT smoked twice as much as subjects in the control group (p<0.001) (Table 2).

CPK AND TROPONIN T LEVELS:

Table 3 shows the results of maximum CPK values and the value of cardiac troponin T in patients with STEMI and STEMI+VT. No significant differences in these parameters were found between the 2 analyzed groups, although patients with STEMI had slightly higher levels of CPK. However, the maximum CPK value was in the VT+STEMI group.

CLINICAL AND OTHER LABORATORY PARAMETERS:

Table 4 shows differences between the groups in several clinical and laboratory parameters. There are significant differences in BMI between the control group and the STEMI group (Mann-Whitney test, p<0.001), as well as compared to STEMI+VT (Mann-Whitney test, p<0.001). Systolic blood pressure was significantly lower in patients with STEMI+VT compared to the control group (Mann-Whitney test, p=0.003), as well as in patients with STEMI only (Mann-Whitney test, p=0.040). Significantly lower diastolic blood pressure was observed in patients with STEMI+VT compared to the control group (Mann-Whitney test, p=0.038) and patients with STEMI only (Mann-Whitney test, p=0.037). Creatinine values were significantly higher in patients with STEMI+VT compared to the control group (Mann-Whitney test, p=0.004), while the number of leukocytes was significantly higher in the STEMI group (Mann-Whitney test, p<0.001), as well as in the group with STEMI+ VT (Mann-Whitney test, p <0.001), compared to the control group.

ECHOCARDIOGRAPHY:

One of the inclusion criteria was left ventricular ejection fraction (EFLV) ≥35% (in this study, only due to ischemic or hypertensive cardiomyopathy).

The lowest value of EFLV among the patients with STEMI+ peracute VT was 35%, and the median value was 42%.

The lowest value of EFLV among the patients with STEMI+ VT (non-peracute and non-reperfusion, starting from 6 hours post-PCI during the acute phase of STEMI) was 35%, and the median value was 53%.

The lowest value of EFLV among the patients with STEMI only was 45% and the median value was 50%.

VENTRICULAR TACHYCARDIA:

VT discussed here refers to periprocedural VT and VT that occurred 6 h after PCI until 48 h of the beginning of ischemia.

None of the patients used derivatives of digoxin; therefor, digoxin serum levels were not determined. None of the patients had previously used other anti-arrhythmics other than low-dose nonselective beta-blockers, which were used by some of our patients for treatment of hypertension.

There were 12 periprocedural VTs: 3 self-limited in a non-sustained form, 2 sustained that were then converted by amiodarone i.v., 1 hemodynamically unstable VT that was then converted by a direct current cardioversion during short-term general anesthesia, and 6 patients presented in cardiorespiratory arrest.

There were 18 postprocedural VTs: 10 in a self-limited non-sustained form and 8 in a sustained form (7 of those 8 were then treated with amiodarone, and 1 patient’s sinus rythm was restored by direct current cardioversion during short-term general anesthesia).

Altogether, 5 VTs later became ventricular fibrillation. The culprit lesion was in 16 cases in the left anterior descending (LAD) artery and 2 were in the left „main“ coronary artery.

MARKERS OF ENDOTHELIAL DYSFUNCTION:

Analyzing 6 markers of endothelial dysfunction, using the Kruskal-Wallis test, we found significant differences in the levels of 4 tested markers: sE-selectin (p=0.0107), sVCAM-1 (p=0.028), VEGF (p=0.099), and CRP (p=0.030) (Figure 1).

Looking at the selectins, we found that the serum levels of sE-selectin were significantly lower in patients with STEMI +VT than in the STEMI group (p=0.033) or the control group (p=0.005) (Figure 1A). The median levels of sP-selectin in the STEMI+VT group were also lower than in the other 2 groups, but without statistical significance (Figure 1B). Serum levels of sVCAM-1 were significantly higher in patients with STEMI compared to the control group (p=0.006), and some elevation was recorded in the STEMi+VT group (Figure 1C). However, there were no differences in the levels of sICAM-1 among all 3 groups (Figure 1D). A significant decrease of VEGF levels in sera of patients with STEMI only (p=0.025) were recorded in comparison to health controls (Figure 1E). The values of CRP (Figure 1F) were significantly higher in the control group (p=0.0297). Patients with VT were found to have higher CRP values than patients with STEMI, but no significant difference was observed.

Interestingly, a significant correlation (r=0.7046, p<0.001) between CRP and VCAM-1 in patients with STEMI+VT was found (data not shown).

Discussion

LIMITATIONS AND STRENGTHS OF THE STUDY:

We showed here for the first time the possible involvement of several different ED markers in the pathogenesis of STEMI+VT in comparison to patients with STEMI only or individuals with some other CVD like hypertension or non-specific stenocardia. It is clear that certain differences among ED markers could be found in patients with VT in comparison to other CVD patients. Future studies with higher numbers of patients should be undertaken to identify possible specific ED markers as predictors for VT development. Such markers may also be useful in VT prevention.

This study has several limitations. The number of patients was quite low and it is hard to expect that differences between individual ED markers will be clearly visible between all 3 tested groups, although some significant differences are detected. We believe that future studies with more patients with VT will show more precise differences in ED markers. Also, if highly sensitive ELISA tests were used, some more differences would be expected.

Conclusions

We indirectly may consider from our results that ED may have a certain role in the immunopathogenesis of VT in patients with STEMI, although its role in immunopathogenesis was not directly proven here. The role of sE-selectin and correlation of sVCAM-1 with CRP as possible ED predictive markers in patients with VT+STEMI should be further investigated in a larger cohort of patients.