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Lviv clinical bulletin 2016, 4(16): 8-14

https://doi.org/10.25040/lkv2016.04.008

The Peculiarities of the Endothelial Function, Blood Lipid Spectrum and Heart Rate Variability in Patients with Stable Angina, Depending on the Heart Rate Frequency

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Z. Bilous, О. Аbrahamovych

Danylo Halytsky Lviv National Medical University

Introduction. The ischemic heart disease (IHD) is one of the most significant social problems for already more than half of the century according to its prevalence, results and lethality. The ischemic heart disease has become the epidemic of the XX and XXI centuries. IHD is a heart muscle’s damage, which is caused by coronary circulation disorder when there is the inconsistency between oxygen supplement and methabolical needs in heart muscle. Stable angina (SA) is one of the IHD’s forms, which risk factor increases with age. In typical cases of SA the result of the fixed coronary obstruction is that the coronary circulation doesn’t supply the enough oxygen to the heart muscle compared with its needs. When these needs increase, the oxygen supplement becomes inadequate [9, 22].

The endothelium takes significant part in adaptation of the coronary circulation to the heart muscle’s needs in oxygen. It produces a lot of the vasoactive substances, such as the nitric oxide (NO), endothelin-1 (ET-1), prostacyclin, serotonine, thromboxane A2, von Willebrand factor (VWF) [2, 3, 9, 17, 18, 22]. The enough production of NO promotes vascular relaxation in normal conditions. The endothelium damage causes the disbalance between the endothelium-derived substances, which is called the endothelial dysfunction (ED). ED is a disbalance between the vasoconstrictors and vasodilatators. In this case more vasoconstrictors are produced, what leads to stenosis of atherosclerotic coronary vessels.

The loss of antiinflammatory, antioxidant and antithrombotic endothelial effects leads to perfusion’s disorder, hypoxia and increases ET-1 production. All this harmful factors (physical overloading, hypoxia, intoxication, inflammation, hemodynamical overloading and other) lead to vasoconstriction. ET-1 production’s damage is one of the earliest signs of coronary atherosclerosis. [2–4, 6, 9, 12, 13, 15, 17, 21–23, 26, 27].   

The von Willebrand factor (VWF) is one of the ED’s markers. The changes of the vWF’s concentration lead to hemostasis disorder. The more atherosclerotic vessels are present, the higher level of the vWF is supposed (according to researches). The vWF level correlates with the angina’s functional class without circadian changes of concentration [1, 7, 16, 19].

The biochemical markers display only some parts of the cascadic process. They are a result of the endothelial damage and show endothelial dysfunction. Endothelial dysfunction leads to monocytes clustrering in intima, disorders growth regulation of the vessel wall cells, changes the endothelial lipoprotein lipase’s activity and, as a result, disorder splitting of triglycerides, chylomicrons and very low-density lipoproteins, changes the lipoproteins ratio, increases the proatherogenic lipoproteins permeability and, that’s why atherogenesis is stimulated and the possibility of the atherosclerotic plaque’s destabilization and breaking increases [1, 5,  8, 14, 19, 20, 24].

The high connection between the sympathetic and parasympathetic parts of the vegetative nervous system (VNS) and the humoral influence provides coordination function and achievement of optimal results of adaptation to conditions of internal and external environment. The regulation system’s deviations precede the hemodynamic, methabolical and energetic disorders and are the early prognostic signs of the disease. Heart rate (HR) is one of the markers of the VNS’s state [10, 11, 25]. Increased HR mechanically damages the vessel wall and causes the ED. The vessel’s bloodstream is wave-shaped. Its type depends on the HR. The portions of blood, which move along the vessel wall with different speed, change the bloodstream type from laminar flow (normal) to turbulent.

The change of blood mechanical influence on endotheliocytes can lead to their functional state change, to ED. The intensity of the atherosclerotic damages is also associated with the HR value. High HR can impact on the hemostasis, lead to atherosclerotic plaque’s damage and breaking. The results of the experiment and the population researches show that HR is a determinant of atherosclerosis and its clinical manifestations.HR decreasing helps to provide significant antiischemic and antianginal effects in angina’s patients. In practice the HR normalization decreases quantity of angina attacks, improves the quality of life  [2, 3, 9, 12, 17, 21–23, 26, 27]. So, prolongation of researches and learning of the features of the endothelial function, blood lipid spectrum’s markers and heart rate variability (HRV) in patients with stable angina with different HR will have important theoretical and practical value.

The goal of the research. To find out the features of the endothelial function, blood lipid spectrum and heart rate variability in patients with stable angina depending on the heart rate frequency.

Matherials and methods of the research. The material’s research is done on the base of the cardiologic departure of the Clinical Municipal Communal Emergency Hospital and the Lviv Railway Clinical Hospital.

After getting the written consent on doing complex survey according to the principles of Declaration of Helsinki about human rights, Convention on Human Rights and Biomedicine of Council of Europe and the appropriate laws of Ukraine,  125 patients with stable angina [66 men (52.8 %), 59 women (47.2 %) in the age from 51 to 72 років, the average age – 59.87 ± 7.34 року], among them: 63 patients (50.4 %)  with SA of II functional class (FC) and 62 patients (49.6 %) with SA of III functional class (FC) were surveyed in randomized way. Control group, compared due to age and gender, included 34 almost healthy people. Diagnosis and treatment were executed according to the instruction of the Ministry of Health care of Ukraine № 436 (03.07.2006) about confirmation of providing of medical care in cardiologic speciality, recommendations of the European Society of Cardiology about diagnosis and treatment of stable angina (2006) and recommendations of The American College of Cardiology.

Patients were divided into 3 groups depending on the HR: 1st group – 62 patients with stable angina with HR > 80 beats per minute; 2nd group – 31 patients with stable angina with HR 60-80 beats per minute; 3rd group – 32 patients with stable angina with HR < 60 beats per minute; 4th group – control group.

The average HR of the patients of 1st, 2nd and 3rd groups was 89.9 ± 6.57 beats per minute, 70.26 ± 4.37 and 58.0 ± 1.12 beats per minute respectively. The average HR of the patients of control group was 70,7 ± 5,4 beats per minute (р1,4 < 0.05, р2,4 > 0.05, р3,4 < 0.05).

The ET-1 was detected in the blood whey by using the diagnostic sets (Biomedica) on the immunoferment analyzer. The VWF activity detection method is based on its ability to cause platelets aggregation when the Inductor of ristocitini is present. The blood lipid spectrum markers were researched on semiautomated analyzer Photometer 5010V5+ with using EliTechClinicalSystems agents: Total cholesterol (TC), high-density lipoproteins cholesterol (HDL cholesterol), low-density lipoproteins cholesterol (LDL cholesterol), triglycerides (TG), atherogenic coefficient (AC). The level of low-density lipoproteins cholesterol (LDL cholesterol) was calculated via the formula of W. Friedewald, atherogenic coefficient (AC) was calculated via the formula of A. M. Klimov.

Heart rate variability (HRV) was detected on the Polyspectrum-12 device (Neurosoft). The temporal (standard deviation of the NN-intervals (SDNN) – square root of scatter of this intervals; square root of medium squares of difference between adjacent NN-intervals (RMSSD); the proportion of the quantity of the intervals between adjacent NN, which are bigger than 50 ms, to the total quantity of the NN-intervals in the HRV record (pNN50) and spectral (the total spectrum’s power(TP), the very low frequency waves (VLF), the low frequency waves (LF), the high frequency waves (HF), LF/HF) HRV characteristics were analyzed.

The results of research were processed by the variational statistics method with using Statistica 6.0 and Microsoft Office Excel 2007 programs with the Student’s t-criterion. The minimal reliable value was р < 0.05. The connection analysis between samples was evaluated with using the correlation coefficient (r).

The results of the research and its discussion. The results of the ET-1 and vWF detection are present in the table 1.

Table 1

The concentration of the Endothelin 1 and von Willebrand factor in blood plasma in patients with stable angina depending on the heart rate (M ± m, р, r)

The ET-1 was detected higher in blood whey of the patients with stable angina. ET-1 was 5.85 ± 0.31 fmol/ml in the 1st group, 3.90 ± 0.25 fmol/ml in the 2nd group, 2.76 ± 0.27 fmol/ml in the 3rd group. The ET-1 level was higher in 1.5 times in the patients with stable angina with HR > 80 beats per minute than in patients with HR 60-80 beats per minute (р1,3 < 0.01), the ET-1 level in the 2nd group was higher in 1,4 times than ET-1 in the 3rd group (р2,3 < 0.01).

The VWF was higher in all groups of patients with stable angina: 186.3 ± 11.0 % in patients with HR > 80 beats per minute, in the 2nd group – 153.3 ± 9.1 %, in the 3rd group – 141.6 ± 9.9 %. The VWF in the 1st group was higher on 21.5 % than in the 2nd group (р1,2 < 0.05), on 31.6 % than in the 3rd group (р1,3 < 0.01), the difference between the second and third groups was 8.3 % (р2,3 > 0.05).

The reliable direct correlative connection is revealed between HR and the characteristics of endothelium function (VWF and ET-1) [for the 1st group – rET-1 = +0.722 (р < 0.001), rVWF = +0.724 (р < 0.001); for the 2nd group – rЕT-1 = +0.814 (р < 0.001), rVWF = +0.499 (р < 0.01); for the 3rd group– rЕT-1 = +0.366 (p < 0.05), rVWF = +0.330 (p > 0.05)] – the more ED is, the higher HR is.

This results show that all three groups of patients have increased ET-1 and VWF levels (the highest in the patients of the 1st group with HR > 80 beats per minute). This confirms the endothelial dysfunction presence in patients with stable angina.

The results of the blood lipid spectrum’s research are displayed in the table 2.

Таble 2

The blood lipid spectrum’s markers in patients with stable angina depending on the HR (M ± m, р, r)

The changes of the blood lipid spectrum’s markers are revealed in all groups of patients with stable angina. The TC was 5.80 ± 0.32 mmol/l in the 1st and 2nd groups. The TC was 5.70 ± 0.37 mmol/l in the 3rd group. The TC level was higher on 1.8 % in the 1st and 2nd groups than in the 3rd group (р1,2 > 0.05, р1,3 > 0.05, р2,3 > 0.05). The HDL cholesterol was 0.98 ± 0.09 and 1.00 ± 0.11 mmol/l in the 1st and 2nd groups respectively and 1.12 ± 0.08 mmol/l in the 3rd group. The difference between markers was 2.0 % the 1st and 2nd groups (р1,2 > 0.05), in 1st and 3rd groups – 14.2 % (р1,3 > 0.05), in 2nd and 3rd– 12,0 % (р2,3 > 0.05). The LDL cholesterol level was 4.27 ± 0.34 mmol/l in the 1st group, 4.12 ± 0.18 mmol/l in the 2nd group and 3.04 ± 0.20 mmol/l in the 3rd group. The LDL cholesterol level was higher on 3.6 % in the 1st group than in the 2nd group (р1,2 > 0.05) and on 40.5 % in the 1st group than in the 3rd group (р1,3 < 0.01). This marker was on 35.5 % higher in the 2nd group than in the 3rd group (р2,3 < 0.01). The TG level was 2.19 ± 0.08 mmol/l in the 1st group, 1.98 ± 0.06 mmol/l in the 2nd group, 1.90 ± 0.04 mmol/l in the 3rd group. The TG level was higher on 10.6 % in patients with HR > 80 beats per minute than in patients with HR 60-80 beats per minute and on 15.3 % higher compared with patients with HR < 60 beats per minute (р1,3 < 0.01). The TG level was higher on 4.2 % in the 2nd group than in the 3rd group (р2,3 > 0.05). The AC was 4.91 ± 0.08 і 4.80 ± 0.09 mmol/l in the 1st and 2nd groups respectively, 4.09 ± 0.12 mmol/l in the 3rd group. The AC was higher on 2.3 % in the 1st group than in the 2nd group (р1,2 > 0.05) and on 20.0 % higher compared with the 3rd group (р1,3 < 0.01). The AC was higher on 17.4 % in the 2nd group than in the 3rd group (р2,3 < 0.01).

The correlation coefficient between the HR and TC was: r1 = +0.164 (р1 > 0.05), r2 = +0.076 (р2 > 0.05), r3 = +0.112 (р3 > 0.05); for HDL cholesterol r1 = +0.072 (р1 > 0.05), r2 = +0.098 (р2 > 0.05), r3 = +0.207 (р3 > 0.05); for LDL cholesterol in the 1st group r = +0.637 (р < 0.01), in the 2nd and 3rd groups r = +0.479 (р < 0.01), r = +0.602 (р < 0.01) respectively; for TG in the 1st group r = +0.521 (р < 0.01), in the 2nd and 3rd groups r = +0.506 (р < 0.01), r = +0.46 (р < 0.01) respectively; AC in the 1st group r = +0.138 (р1 > 0.05), in the 2nd  group r = +0.053 (р2 > 0.05), in the 3rd group r = +0.188 (р3 > 0.05). The direct correlative connection is revealed between the HR, TC, HDL cholesterol and AC. But this connection is unreliable. The reliable direct correlative connection is revealed between the HR, LDL cholesterol and also TG.

In conclusion, proatherogenic changes of blood lipid spectrum’s markers are revealed in all groups of patients with stable angina, but the highest changes are revealed in the patients with HR > 80 beats per minutes. The reliable direct correlative connection is established between the HR, LDL cholesterol and TG, what shows the dependence between atherogenic markers of lipid flow and HR.

The HRV temporal characteristics are shown in the table 3.

Table 3

The heart rate variability (HRV) temporal characteristics in patients with stable angina depending on the HR (M ± m, р, r)

All groups of patients with stable angina have changes in HRV temporal characteristics. The SDNN level was 74.0 ± 7.2 ms in the 1st group, 91.0 ± 6.4 ms in the 2nd group, 96.0 ± 5.5 ms in the 3rd group. This marker was higher on 29.7 % in the patients with HR < 60 beats per minute than in the 1st group (р1,3 < 0.05) and on 5.5 % compared with the 2nd group (р2,3 > 0.05), but was higher on 23.0 % in the 2nd group compared with the 1st group (р1,2 > 0.05). This reveals significant decreasing of this marker in the group of patients with HR > 80 beats per minute.

The RMSSD was 10.60 ± 0.92 ms in the 1st group, 15.70 ± 1.30 ms in the 2nd group and 18.20 ± 3.20 ms in the 3rd group. The RMSSD of the 3rd group was on 71.7 % higher than RMSSD of the 1st group (р1,3 < 0.05) and on 15.9 % higher than RMSSD of the 2nd group (р2,3 > 0.05). This marker was on 48.1 % higher in the 2nd group compared with the 1st group (р1,2 < 0.01).

The pNN50 was 12.70 ± 0.60 % in the 1st group. The highest marker was revealed in the 3rd group (14.30 ± 0.07 %), what is on 12.6 % higher (р1,3 < 0.05) compared with the 1st group and on 6.7 % higher (р2,3 > 0.05) compared with the 2nd group (13.40 ± 0.70 %). The pNN50 was higher on 5.5 % in the 2nd group compared with the 3rd group (р1,2 > 0.05).

The correlation coefficient between HR and HRV temporal characteristics was: for SDNN r1 = -0.361 (р1 < 0.01), r2 = -0.332 (р2 < 0.05), r3 = -0.344 (р3 < 0.01), for RMSSD r1 = -0.438 (р1 < 0.01), r2 = -0.327 (р2 < 0.05), r3 = -0.305 (р3 < 0.05), for pNN50 r1 = -0.441 (р1 < 0.01), r2 = -0.194 (р2 > 0.05), r3 = -0.257 (р3 > 0.05). This reveals dependence between HR and HRV temporal characteristics.

Characteristic of HRV spectral markers is shown in the table 4.

Таble 4

The heart rate variability (HRV) spectral characteristics in patients with stable angina depending on the HR (M ± m, р, r)

All groups of patients have changes of HRV spectral characteristics. The ТР level was 1983.0 ± 52.5 ms2 in the 1st group, 2100.0 ± 81.7 and 2157.0 ± 67.1 ms2 in the 2nd and 3rd groups respectively. The ТР level was higher on 5.9 % in the 2nd group and on 8.8 % in the 3rd group compared with the 1st (р1,2 > 0.05, р1,3 < 0.05), ТР of the 3rd group was higher than TP of the 2nd group on 7.0 % (р2,3 > 0.05). The  VLF were 797.2 ± 18.1 ms2 in the 3rd group, 616.9 ± 19.4 ms2 in the 1st group, 783.3 ms2 in the 2nd group. The VLF of the 3rd group were higher on 29.2 % than in the 1st group (р1,3 < 0.01) and on 1.8 % higher compared with the 2nd group (р2,3 > 0.05). This marker was on 27.0 % higher in the 2nd group compared with the 1st group (р1,2 < 0.01). LF were 952.2 ± 19.5 ms2 in the 1st group, 877.8 ± 13.7 ms2 in the 2nd group, 873.9 ± 17.4 ms2 in the 3rd group. The LF of the 1st group was on 9.0 % higher compared with the 3rd group (р1,3 < 0.01) and on 8.5 % higher compared with the 2nd group (р1,2 < 0.01). The LF of the 2nd group were higher on 0.4 % compared with the 3rd group (р2,3 > 0.05). The HF were 413.9 ± 16.5 ms2 in the 1st group, 438.9 ± 12.2 ms2 in the 2nd group, 485.9 ± 14.2 ms2 in the 3rd group. The marker of the 3rd group was on 17.4 % higher compared with the 1st group (р1,3 < 0.01) and on 10.7 % higher compared with the 2nd group (р2,3 < 0.05), the marker of the 2nd group was on 6.0 % higher compared with the 1st group (р1,2 > 0.05). The highest LF/HF is revealed in the 1st group (2.30 ± 0.08). LF/HF of patients with normal and decreased HR is 2.00 ± 0.22 and 1.80 ± 0.24 respectively. This marker is on 15.0 % higher in the 1st group compared with the 2nd group and on 27.8 % higher compared with the 3rd group (р1,2 < 0.05, р1,3 < 0.01), LF/HF of the 2nd group is on 11.1 % higher compared with the 3rd group (р2,3 < 0.05).

The correlation coefficient between HR and HRV spectral characteristics is calculated and reliable connection between then is revealed [for ТР r1 = -0.438 (р1 < 0.01), r2 = -0.433 (р2 < 0.01), r3 = -0.459 (р3 < 0.01); for VLF r1 = 0.589 (р1 < 0.01), r2 = 0.328 (р2 < 0.05), r3 = 0.394 (р3 < 0.05); for LF r1 = 0.698 (р1 < 0.01), r2 = 0.607 (р2 < 0.01), r3 = 0.377 (р3 < 0.01); for HF r1 = 0.361 (р1 < 0.05), r2 = 0.385 (р2 < 0.05), r3 = 0.579 (р3 < 0.01); for LF/HF r1 = 0.455 (р1 < 0.01), r2 = -0.341 (р2 < 0.05), r3 = 0.307 (р3 < 0.05)] – the more vegetative dysfunction is, the higher HR is.

So, the preference of activity of sympathetic part of VNS in cardial work and the decreasing of average level of low, very low and high frequency waves are typical for all groups of patients. The patients with HR more than 80 beats per minute have HRV changes which show significant disruptions of vegetative homeostasis such as decreasing the total HRV, which is confirmed by temporal and spectral characteristics.

Conclusions. The patients with stable angina have features of endothelial function, blood lipid spectrum’s markers and heart rate variability depending on the heart rate frequency. The features include the most significant signs of endothelial disfunction, blood lipid spectrum’s deviation and disbalance of the vegetative nervous system with the preference of the sympathetic part in patients with heart rate more than 80 beats per minute. This can be used as the criterion for the difficulty of pathogenetic mechanisms evaluation.

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