PCSK9 Inhibitor causes a decrease in the level of oxidatively modified low-density lipoproteins in patients with coronary artery diseases.

AIM: We study the dynamics of oxidatively modified low-density lipoprotein (ox-LDL) content in blood plasma, as well as changes in the activity of key antioxidant enzymes such as Se-containing glutathione peroxidase (GSH-Px) Cu,Zn-superoxide dismutase (SOD) and catalase in erythrocytes of patients with coronary artery disease during treatment with PCSK9 inhibitor (ewolocumab). MATERIALS AND METHODS: The study included 9 men (59 ± 10 years) with coronary artery disease with atherosclerotic lesion at least one main coronary artery according to coronary angiography. Patients took standard therapy before taking the study, everyone took the maximum tolerated dose of statins. Since the target cholesterol levels of low-density lipoprotein cholesterol (LDL-C) were not achieved during the statin therapy, patients were prescribed lipid-lowering therapy with the inclusion of the inhibitor PCSK9-emocoucumab from Amgen 420 mg once a month. The content of lipid metabolism indices was determined by standard biochemical methods. The level of ox-LDL in the blood plasma was determined by the immunochemical method. The activity of antioxidant enzymes was determined in blood erythrocytes using biochemical techniques. RESULTS: Cholesterol-lowering drug of the new type - inhibitor protein convertase subtilisin/kexin type 9 (PCSK9) evolocumab (Amgen) not only effectively lowers the level of cholesterol in low density lipoprotein (LDL), but also significantly reduces the content of oxdatively modified LDL in blood plasma. Unlike statins, the inhibitor of PCSK9 does not cause a decrease in the activity of antioxidant enzymes of the blood. CONCLUSION: PCSK9 inhibitor has no effect on the parameters of oxidative stress.

Photoplethysmographic signal waveform index for detection of increased arterial stiffness.

The aim of this research was to assess the validity of the photoplethysmographic (PPG) waveform index PPGAI for the estimation of increased arterial stiffness. For this purpose, PPG signals were recorded from 24 healthy subjects and from 20 type II diabetes patients. The recorded PPG signals were processed with the analysis algorithm developed and the waveform index PPGAI similar to the augmentation index (AIx) was calculated. As a reference, the aortic AIx was assessed and normalized for a heart rate of 75 bpm (AIx@75) by a SphygmoCor device. A strong correlation (r = 0.85) between the PPGAI and the aortic AIx@75 and a positive correlation of both indices with age were found. Age corrections for the indices PPGAI and AIx@75 as regression models from the signals of healthy subjects were constructed. Both indices revealed a significant difference between the groups of diabetes patients and healthy controls. However, the PPGAI provided the best statistical discrimination for the group of subjects with increased arterial stiffness. The waveform index PPGAI based on the inexpensive PPG technology can be considered as a perspective measure of increased arterial stiffness estimation in clinical screenings.

Identification of the hemodynamic modulators and hemodynamic status in uncontrolled hypertensive patients.

Only 20-30% out of the treated hypertensive patients in Europe are achieving blood pressure (BP) control. Among other recognized factors, these poor results could be attributable to the fact that for many doctors it is very difficult to detect which is the predominant hemodynamic cause of the hypertension (hypervolemia, hyperinotropy or vasoconstriction). The aim of the study was to use non-invasive thoracic electrical bioimpedance (TEB) to evaluate hemodynamic modulators and subsequent hemodynamic status in uncontrolled hypertensive patients, receiving at least two antihypertensive drugs. A number of 134 uncontrolled hypertensive patients with essential hypertension were evaluated in nine European Hypertension Excellence centers by means of TEB (the HOTMAN(®) System). Baseline office systolic and diastolic BP averaged 156/92 mmHg. Hemodynamic measurements show that almost all patients (98.5%) presented at least one altered hemodynamic modulator: intravascular hypervolemia (96.4%) and/or hypoinotropy (42.5%) and/or vasoconstriction (49.3%). Eleven combinations of hemodynamic modulators were present in the study population, the most common being concomitant hypervolemia, hypoinotropy and vasoconstriction in 51(38%) patients. Six different hemodynamic states (pairs of mean arterial pressure and stroke index) were found. Data suggest that there is a strong relation between hypertension and abnormal hemodynamic modulators. This method might be helpful for treatment individualization of hypertensive patients.

Interrelation between malonyl dialdehyde-dependent modification and cholesterol content in low-density lipoproteins.

Epidemiological study of an independent representative sample of population revealed a strong positive correlation between the content of oxidized (MDA-modified) LDL and concentration of atherosclerosis biomarkers (total cholesterol and LDL cholesterol) in blood plasma from 348 probands. The correlation between these parameters was more significant in atherosclerotic patients, but was less pronounced in probands with diabetes mellitus. The correlation between the concentration of atherosclerosis markers and content of MDA was absent in probands with diabetes mellitus. These data attest to the presence of LDL-modifying agents differing from MDA (e.g., glyoxal and methylglyoxal) in the blood of diabetes mellitus patients. We conclude that the content of MDA-modified LDL can serve as an additional biomarker of atherosclerosis.

Lipid-altering efficacy of ezetimibe/simvastatin 10/20 mg compared with rosuvastatin 10 mg in high-risk hypercholesterolaemic patients inadequately controlled with prior statin monotherapy - The IN-CROSS study.

AIMS: To evaluate the efficacy of switching from a previous statin monotherapy to ezetimibe/simvastatin (EZE/SIMVA) 10/20 mg vs. rosuvastatin (ROSUVA) 10 mg. METHODS: In this randomised, double-blind study, 618 patients with documented hypercholesterolaemia [low-density lipoprotein cholesterol (LDL-C) > or = 2.59 and < or = 4.92 mmol/l] and with high cardiovascular risk who were taking a stable daily dose of one of several statin medications for > or = 6 weeks prior to the study randomisation visit entered a 6-week open-label stabilisation/screening period during which they continued to receive their prestudy statin dose. Following stratification by study site and statin dose/potency, patients were randomised to EZE/SIMVA 10/20 mg (n = 314) or ROSUVA 10 mg (n = 304) for 6 weeks. RESULTS: EZE/SIMVA produced greater reductions in LDL-C (-27.7% vs. -16.9%; p < or = 0.001), total cholesterol (-17.5% vs. -10.3%; p < or = 0.001), non-high-density lipoprotein cholesterol (HDL-C) (-23.4% vs. -14.0%; p < or = 0.001) and apolipoprotein B (-17.9% vs. -9.8%; p < or = 0.001) compared with ROSUVA, while both treatments were equally effective at increasing HDL-C (2.1% vs. 3.0%; p = 0.433). More patients achieved LDL-C levels < 2.59 mmol/l (73% vs. 56%), < 2.00 mmol/l (38% vs. 19%) and < 1.81 mmol/l (25% vs. 11%) with EZE/SIMVA than ROSUVA (p < or = 0.001). A borderline significantly greater reduction in triglycerides (p = 0.056) was observed for EZE/SIMVA (-11.0%) vs. ROSUVA (-5.3%). There were no between-group differences in the incidences of adverse events or liver transaminase and creatine kinase elevations. CONCLUSION: EZE/SIMVA 10/20 mg produced greater improvements in LDL-C, total cholesterol, non-HDL-C and apoB with a similar safety profile as for ROSUVA 10 mg.

Risk factors for coronary heart disease in 55- and 35-year-old men and women in Sweden and Estonia.

OBJECTIVE: To illustrate the geographical West-to-East division of coronary heart disease (CHD) by comparing a population from Sweden, that represents a Western country to a population from Estonia, that represents an Eastern country. Estonia has an approximately 2-4-fold higher CHD prevalence for 55-year-old women and men, respectively, than Sweden. DESIGN: Randomized screening of 35- and 55-year-old men and women in Sollentuna county, Sweden and Tartu county, Estonia. Eight hundred subjects, 100 from each cohort, were invited to participate in the study, 272 Swedes and 277 Estonians participated. SETTING: Preventive cardiology, administered by a primary health care centre at the Karolinska Hospital, Sweden and a cardiology centre at Tartu University Hospital, Estonia. MAIN OUTCOME MEASURES: The CHD risk factors (smoking, blood pressure, concentrations of lipoproteins, fibrinogen, and glucose) and certain environmental factors and attitudes related to CHD risk by questionnaires (fat-type and alcohol ingestion, self-assessed rating of CHD susceptibility). RESULTS: Of the 55-year-old men, 57% smoked in Estonia and 20% smoked in Sweden. Similar, although less pronounced differences showing higher smoking prevalence, were seen for 35-year-old Estonian men and women, whilst for 55-year-old women, less than 20% smoked in either country. Estonian 55-year-old women had lower HDL cholesterol and higher LDL cholesterol serum concentrations than Swedish 55-year-old women. Estonians reportedly ate food containing more saturated fats than Swedes, as indicated by the scale-score questionnaire. Estonians, relative to Swedes, rated their chance of developing CHD higher, and paradoxically, Estonians did to a much lesser degree believe that life style influences the risk of developing CHD. CONCLUSIONS: Elevated smoking prevalence is a striking difference between the Estonian and Swedish populations likely to explain the much higher CHD prevalence in Estonian men. The lower HDL cholesterol and higher LDL cholesterol in Estonian 55-year-old women may explain the higher CHD prevalence in Estonian women. Furthermore, the SWESTONIA CHD study (i.e. comparison between Sweden and Estonia) shows several environmental differences between the countries populations related to fat content in food, alcohol drinking patterns, and views on CHD risk and the importance of lifestyle intervention, that could contribute to the higher CHD prevalence in Estonia.

The renin-angiotensin system in essential hypertension: associations with cardiovascular risk.

The importance of the renin-angiotensin system (RAS) in blood pressure regulation is well established. High RAS activity has also been implicated in connection with elevated cardiovascular risk in patients with essential hypertension. Data from epidemiological studies have related high plasma renin levels in essential hypertensive patients to cardiovascular complications. However, whether renin itself is a risk factor of cardiovascular events or just acts as a marker for other risk factors still remains to be elucidated. Several possible mechanisms that could be responsible for the association between elevated RAS activity and cardiovascular risk are reviewed. The concept of high RAS activity being a cardiovascular risk factor is strongly supported by results from large clinical studies showing the beneficial effects of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers in congestive heart failure and hypertension. Knowing more about the exact mechanisms of the association between high RAS activity and cardiovascular complications would enable us to profile the treatment of high blood pressure more specifically to improve outcome in individuals or groups of patients.

Effect of ciprofibrate on platelet aggregation in patients with combined hyperlipidemia.

This study was designed to investigate the effect of ciprofibrate on platelet aggregation in patients with combined hyperlipidaemia. Platelet aggregation measurements in platelet-rich plasma were carried out in 30 patients using the Biola 230 LA platelet aggregation analyser before treatment, 4 weeks and 8 weeks after ciprofibrate (100 mg/day) therapy. A control group consisted of 37 healthy subjects. We found that spontaneous and 0.25 microM ADP-induced platelet aggregation were significantly decreased after 4-weeks of therapy, from 4.6 to 3.2% and from 11.3 to 7.6% , respectively. However, there was no difference 8 weeks after the treatment onset. Platelet aggregation induced by adrenaline was unchanged during the ciprofibrate therapy.

Platelet aggregation, sensitivity to prostaglandin E1 and thromboxane A2 release in recombinant hirudin- and heparin-anticoagulated blood.

Hirudin is the most potent known natural inhibitor of thrombin and is presently gaining popularity as an anticoagulant since recombinant forms have become available. The aim of the present study was to compare platelet aggregation, sensitivity to prostaglandin E1 and thromboxane A2 release in r-hirudinized and heparinized blood. Platelet aggregation was measured turbidimetrically using a dual channel aggregometer (Labor, Germany) in blood samples of healthy volunteers anticoagulated with r-hirudin W015 (Behring) and heparin (20 micrograms/ml blood each). Aggregation was induced by arachidonic acid (0.5, 1.0 and 2.0 mM) and adenosine diphosphate (1.0 microM). Prostaglandin E1 in concentrations 10, 20, 40 and 80 ng/ml was used. Plasma thromboxane B2 content was measured by gas chromatography/mass spectrometry. This study showed a significantly lower arachidonic acid induced platelet aggregation in r-hirudinized plasma. Three minutes after the aggregation induction by 0.5 mM arachidonic acid the plasma thromboxane B2 concentration was 23.0 ng/ml in blood anticoagulated with r-hirudin and 108.4 ng/ml in heparin-anticoagulated blood. The extent of the aggregation induced by adenosine diphosphate was nearly the same in hirudinized and heparinized plasma. Platelet sensitivity to prostaglandin E1 was significantly higher in r-hirudinized blood. Thus, platelet aggregation induced by arachidonic acid is significantly lower and sensitivity to prostaglandin E1 higher in r-hirudin-anticoagulated blood in comparison with heparin-anticoagulated blood.

Platelet Aggregation, Thromboxane A(2), Prostacyclin Generation and Platelet Sensitivity to Prostacyclin during the First Month after Myocardial Infarction.

This study was designed to investigate platelet aggregation, plasma thromboxane A, and prostacyclin concentration and platelet sensitivity to prostacyclin simultaneously during the first month after myocardial infarction (MI). Spontaneous platelet aggregation and aggregation responses to ADP and adrenaline were low on the day of admission, increased rapidly by the 7th day post-MI, remained elevated during the second week post-MI and reached the level of chronic coronary artery disease patients but not healthy persons at the end of the fourth week of illness. An increase in plasma thromboxane B, the spontaneous and stable breakdown product of thromboxane A, level and enhanced prostacyclin production, with a maximum on the third post-MI day, were observed. We also demonstrated a significant platelet resistance to prostacyclin in MI patients. Thrombocyte sensitivity to prostacyclin normalized by the end of the fourth post-MI week. These results indicate the need for therapy with platelet inhibitors in patients with MI.

Antiaggregative therapy with acetylsalicylic acid and diclofenac in patients with acute myocardial infarction.

A total of 109 male patients with acute transmural myocardial infarction (MI) were studied. 26 patients received a dose of acetylsalicylic acid (aspirin, ASA) 500 mg/d and 29 patients of 50 mg/d. 27 patients were given diclofenac (25 mg/d). 27 patients received no antiplatelet therapy. We observed thrombocyte hyperaggregation on the 1st MI day, a rapid increase in platelet activity by the 7th day and a considerable decrease in platelet aggregation during the 3rd and 4th weeks of illness in the group without antiaggregative treatment. The present study clearly demonstrated high antiaggregatory efficacy of ASA in dose of 50 mg/d which was significantly higher than that in daily dose of 500 mg ASA. Low-dose aspirin had fewer side-effects than aspirin 500 mg/d. However, although daily dose of 50 mg aspirin significantly inhibited platelet hyperaggregation on 7th day of MI, the hyperactivity of thrombocytes was not abolished. Diclofenac 25 mg daily had only a moderate antiaggregative efficacy in acute MI patients.

Antithrombotic effect and reperfusion by low molecular weight heparin in a canine model of coronary artery thrombosis.

The lability of an intracoronary thrombus, which is common in the case of unstable angina, indicates the presence of endogenous fibrinolysis. To prove our hypothesis that suppression of coagulation facilitates the thrombolytic process, low molecular weight heparin (LMWH) was given intravenously to dogs with intracoronary thrombi induced by copper coils. LMWH caused reperfusion in this model and suppressed the formation of intracoronary thrombi, thus supporting our hypothesis.