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Glucagon-like peptide 1 receptor agonists (GLP1-RA) and sodium-glucose cotransporter-2 inhibitors (SGLT2i) were individually proven to reduce major adverse cardiovascular events (MACE) in type 2 diabetes mellitus (T2DM) patients, but the relative magnitude of benefits from these two drug classes is debated. We aimed to review current available data on GLP1-RA and SGLT2i in T2DM patients and compare their efficacy and safety in this population.We systematically searched MEDLINE/PubMed, the Cochrane Library, Google Scholar, Embase, www.tctmd.com, www.clinicaltrials.gov, www.clinicaltrialresults.org, from inception to September 17, 2020 for randomized controlled trials (RCTs) comparing the effects of GLP1-RA vs SGLT2i vs optimal medical therapy (OMT) in adult T2DM patients. Three authors independently screened references and extracted data using a predefined data collection form. Outcomes were analyzed using an indirect comparison meta-analysis of aggregate study-level data. The primary combined efficacy outcome comprised cardiovascular death, nonfatal myocardial infarction (MI), or nonfatal stroke. Secondary efficacy outcomes included all-cause mortality, cardiovascular mortality, non-fatal MI, non-fatal stroke, heart failure hospitalizations (HFH), and worsening renal function (WRF).11 RCTs enrolling a total of 98572 patients were included; 56004 (57%) patients were derived from GLP1-RA RCTs and 42568 (43%) from SGLT2i RCTs. At a median follow-up of 3.0±1.3 years, compared with OMT, both GLP1-RA and SGLT2i similarly reduced the rate of the composite primary outcome (risk ratio [RR] 0.88; 95% confidence interval [95%CI] 0.83-0.93 and RR 0.88, 95%CI 0.82-0.95, respectively) with no difference between the drug classes (RR 1.00, 95%CI 0.92-1.10). Both classes similarly reduced MI rate, cardiovascular and all-cause mortality compared with OMT; stroke reduction was only observed with GLP1-RA with no difference in the indirect comparison with SGLT2i; conversely, only SGLT2i were effective in preventing HFH. Both GLP1-RA and SGLT2i were protective against WRF, with a major efficacy of SGLT2i in the indirect comparison.This meta-analysis report that GLP1-RA and SGLT2i reduced with a similar efficacy not only MACE as MI, but also cardiovascular mortality and all-cause mortality at a median 3 years follow-up. SGLT2i were more protective in HFH and WRF than GLP1RA. These new data highlight the efficacy of SGLT2i not only in HF and chronic kidney disease (CKD) but also in ischemic heart diseases (IHD), with a homogeneity among the class, whereas the results observed with GLP1-RA are heterogenous. These findings will help clinical's decisions to optimize therapeutic strategies for diabetic patients.

Atrial fibrillation (AF) is a leading risk factor of arterial thromboembolic events. Aim is to study the main arteries hemodynamics and kinetics in AF and to propose the functional classification of AF.We included 188 patients (80 as the control). We performed 24-hours ECG monitoring, blood lipids analysis, echocardiography, stress echocardiography, coronary angiography, renal arteries angiography, ultrasound Doppler of brachiocephalic arteries, abdominal aorta branches, renal arteries, lower extremities arteries, sphygmography. Patients were divided into 3 groups up to the duration of maximum pauses between ventricular complexes in AF: 1) with a pause1 second (64); 2) with a pause of ≥1, but2 seconds (62); 3) ≥ 2 seconds (62). We analyzed the thromboembolic events within 1 year.We observed the increase of linear blood flow velocity and volume flow in patients with AF during the spreading of the wave after a long pause between ventricles' contractions. The longer the pause between the ventricles' contractions, the more increase of arteries kinetics parameters is observed. The most frequent incidence of thromboembolic events within 1 year was in group 3.We propose a functional classification of AF: 1) AF with the pauses of less than 1 second; 2) more 1, but less than 2 seconds; 3) 2 or more seconds. The most unfavorable is AF with pauses of 2 seconds or more. We supplemented the CHA₂DS₂-VASc score with the new independent risk factor - type of AF - in accordance with the maximum duration of pauses between cardiac cycles.

Background. Premature ventricular contractions (PVCs) are not mentioned in the list of risk factors of stroke. Methods. In our investigation, we included 440 patients with PVCs more than 700 per 24 hours. In control group, there were 88 patients with PVCs less than 700 per 24 hours. Within instrumental methods we performed echocardiography (transthoracic or transesophageal), Doppler ultrasound of brachiocephalic arteries, 24-hours electrocardiography (ECG) monitoring, digital sphygmography of common carotid arteries (SG); computer tomography or magnetic resonance imaging of the brain. Laboratory tests were used to identify lipids level, hemoglobin A1c. The patients of the main group were divided into two subgroups up to the characteristics of the revealed PVCs. The 1st subgroup comprised 120 patients with PVCs whose ventricular systole occurred in the phase before the peak of transmitral blood flow in the cardiac cycle, regardless of the location of ectopic foci. In 320 patients with PVCs of the 2nd subgroup the systole of ventricular contraction occurred in the phase after the peak of transmitral blood flow in the cardiac cycle. We observed the patients during 1 year from the onset of the investigation and analyzed the appearance of stroke or transient ischemic attack (TIA). Results. In most instrumental and laboratory parameters subgroups 1, 2 and control group were identical. The most important differences were in hemodynamic and kinetic parameters in accordance to the quantity of PVCs per 24 hours (700 and more in the main subgroups 1,2) and the moment of the ventricular contraction appearance of the PVCs (before or after the transmitral blood flow peak in cardiac cycle). We revealed the following tendency: the earlier PVCs appeared in cardiac cycle the more an increase in hemodynamic and kinetic parameters was observed. All patients were on the common standard therapy. Despite of that, during 1 year from the beginning of the investigation we remarked the statistically significant different appearance of the stroke and TIA within the groups which was more frequent in the 1 subgroup. Conclusion. PVCs are an additional risk factor of stroke. The most dangerous type is when the ventricular contraction (PVC) appears before the transmitral blood flow peak in cardiac cycle. Increased hemodynamical parameters during the spread of the 1st post-extrasystolic wave cause an additional mechanical trauma of arterial intima and can be the key moment in atherosclerotic plaques non-stability with further defragmentation, embolism and onset of stroke. In patients with PVCs more than 700 per 24 hours the promising research can be using novel oral anticoagulants to prevent the cardiovascular events in the dosages as it is indicated in atrial fibrillation.

Objectives to determine the hemodynamic changes within arterial vessels in different variants of extrasystole, to analyze whether extrasystole is an additional risk factor for the development of atherosclerosis. Material and methods. The study included 286 patients (175 men and 111 women) with extrasystole of more than 3000 per day and 88 patients with extrasystole of less than 3000 per day as a control group. When selecting eligible patients for the study, we tried to minimize the impact of traditional risk factors of atherosclerosis. The presence of cardiocerebral complications in medical history was also considered. The examination methods used in the study are electrocardiography, phonocardiography, 24-hour electrocardiography monitoring, Doppler ultrasound of the brachiocephalic vessels, lower extremities arteries, renal arteries, transthoracic or transesophageal echocardiography. Stress echocardiography was performed if indicated; as well as renal artery angiography, coronary angiography, computed tomography of the brain with angioprogram. When performing a biochemical blood test, the lipid spectrum and hemostasiogram were necessarily determined. All patients underwent left ventricular apexcardiography, as well as sphygmography, recorded on arteries of elastic type (a. Carotis communis) and muscular-elastic type (a. Tibialis posterior). The clinical examinations were confirmed and modeled using the original "Device for modeling of intra-arterial circulation", developed by us (RF patent No. 202780 dated 05.03.2021). Results. We determined an increase in the main parameters of the heart biomechanics and the kinetics of the main arteries in the 1st post-extrasystolic wave in patients with various types of extrasystole with the following pattern: the earlier extrasystole had appeared in the cardiocycle, the greater was the increase in the parameters under observation. A universal concept of hydraulic shock and possible cases of its formation were described. Conclusion. Extrasystole is an additional risk factor for the onset and progression of atherosclerosis. Hydraulic shock during the passage of the 1st post-extrasystolic wave is a powerful traumatic factor for the walls of the arteries, which can lead to the formation of an atherosclerotic process.

im of our investigation is to evaluate the use of the device for modeling of intra-arterial circulation and substantiate the possibility of its use in experimental cardiology. Materials and methods. The principle part of the model is the cone-shaped narrowed glass cylinder 365 mm long with an inlet diameter of 20 mm, an outlet diameter of 16,5 mm. Two-way fitting with a rubber valve is screwed from the input side. Flexible silicone tubes are attached to both sides of the cylinder, with the other end attached to an electric water pump. The water pump is connected with 12 Volt battery. In one of the outer corners, we insert a needle for introducing dyes (clerical ink) and a silk thread through the fitting valve into the glass tube. We filled the closed circuit with an aqueous solution of glycerin, the viscosity of which was similar to the blood. The water pump provides continuous or intermittent circulation of the glycerin solution in a closed system. We observed the thread movements and turbulent flow colored by the ink during the spread of the pulse waves. Results. We simulated the pulse waves occurring in the regular heart rhythm, as well as arrhythmias. When simulating the extrasystoles, we observed a turbulent fluid flow during the spread of the 1st post-extrasystolic wave behind the installed diaphragm. With the spreading of the 1st post-extrasystolic wave, the pressure level inside the tube is increased in comparison with the regular rhythm. Conclusion. Device for modeling of intra-arterial circulation is simple and reliable in its construction. It imitates the intra-arterial processes in different hemodynamic situations, such as regular heart rhythm, arrhythmias, and atherosclerotic plaques. It can be used in the wide spectrum of experimental works in cardiology, vascular surgery, physiology, pathophysiology, biophysics.

To establish the relationship between AH and hemodynamically significant atherosclerotic stenosis of carotid bifurcation and study the effect of carotid endarterectomy (CEA) on the course of AH.In our investigation we included 320 patients: 243 (75,9%) men and 77 (24,1%), the mean age - 59,6 ± 8,2. All patients underwent CEA operation. Patients were divided into groups: I (320) - before CEA surgery and AH; II (320) - the same patients after CEA operation. All patients underwent laboratory tests, ECG, chest X-ray, ultrasound of the kidneys, thyroid gland, computer tomography (CT) of adrenal glands, of the brain, echocardiography, ultrasound or angiography of the renal arteries. Before and after the CEA, there were made Doppler ultrasound of brachiocephalic arteries, 24 hours blood pressure (BP) monitoring. Additional visits were made by 73 patients in 3, 6 and 12 months after the CEA.Most of the patients had significant decrease of BP in the postoperative period, which was observed in 257 (80,3%) patients on days 2-7, in 58 (18,1%) - did not change significantly, and only 5 (1,6%) had the increasing of BP. In 29 (39,7%) patients 1 year after CEA, there was no need to use antihypertensive therapy due for the normalization of BP after the surgery.It is necessary to highlight the cerebrovascular AH into a separate form of the secondary AH. The CEA has prominent, stable anti-hypertensive effect on these patients.

Objectives to study the mechanism of restenosis after the intra-arterial stenting using the original device for modeling of intra-arterial blood flow. Material and methods. To perform the experiment, we have created the original device simulating the intra-arterial blood flow. A glass tube of rotameter was the imitation of the arterial vessel. The closed system was filled with the liquid imitating blood, specifically the solution of glycerin the same viscosity as the human blood plasma. Using our original model of intra-artetial blood flow, we were able to study the intra-arterial hemodynamics under different conditions of cardiovascular system functioning, including arrhythmias. Results. In extrasystolic arrhythmia, during the spread of the first post-extrasystolic wave, we observed the intensive impact of pressure wave (the indicator was the silk thread) on the vessel walls with forming of reflected and standing waves. Putting the piezo crystal probe of pressure inside the tube, we verified our observations. The increase of pressure during the spread of the first post-extrasystolic wave in multiple measurements had a mean value of 160% in comparison with the pressure during the regular heart rhythm. Conclusion. The hydraulic shock appears during the spread of the first post-extrasystolic wave in the arterial vessel. Its effect on hemodynamics grows in case of the frequent extrasystoles and allorhythmia. The mechanical impact of hydraulic shock in extrasystoles can be the starting point of the restenosis onset and progressing in the intra-arterial stent.

Aim of our investigation is to study the relationship between the level of proprotein convertase subtilisin kexin type 9 (PCSK9) and atherosclerotic process of coronary and brachiocephalic arteries in patients with arterial hypertension (AH).Our investigation was performed in regional railway hospital. In our investigation we included 161 male train drivers who had AH with achieved target grades 1-2. All patients were performed laboratory tests including cholesterol, LDLC, triglycerides, glucose, hemostasiograms, PCSK9. Patients were divided into groups up to the PCSK9 level: in group 1 (n = 41) we included patients with PCSK9 level 108-250 ng/ml; group 2 (n = 37) 251 - 400 ng/ml; group 3 (n = 45) 420 - 560 ng/ml and group 4 (n = 38) 580 - 860 ng/ml. All patients were performed coronary angiography, ultrasound Doppler of brachiocephalic arteries, electrocardiography, transthoracic echocardiography.The groups of the patients were identical in age, body mass index, triglycerides, LDL-C, glucose, cholesterol levels. Also, there was no significant difference in the dependence of PCSK9 level on smoking status (χ2=3,1; p=0,3) and the presence of family history of AH (χ2=0,9; p=0,8). It was found that in the 1st group, patients with normal body mass index had normal carotid intima-media thickness ≤1 mm in most of the cases (34,1%). The severity of brachiocephalic and coronary arteries atherosclerosis was more advanced in the 4th group. The atherosclerotic plaques determine the cardiovascular risk in patients with AH.The level of PCSK9 in male patients is an additional cardiovascular risk factor independent from the traditional risk factors. The PCSK9 level is correlated with atherosclerotic severity process of brachiocephalic arteries (p=0,08; r=0,2). The concentration of PCSK9 in the blood serum more than 580 ng/ml in patients with AH determines more severe coronary arteries atherosclerosis. If more the level of PCSK9 than more cardiovascular risk (p=0,002).

Extrasystolic arrhythmia is not included in the list of risk factors of atherosclerosis. The aim of this investigation was to determine the relationship between atherosclerosis of main arteries and extrasystolic arrhythmia.We included 286 patients in our investigation. We performed 24-hours ECG monitoring, blood lipids analysis, transthoracic echocardiography, ultrasound Doppler of brachiocephalic arteries, abdominal aorta branches, lower extremities arteries, renal arteries. If prescribed we performed stress echocardiography, transesophageal echocardiography, coronary angiography, renal arteries angiography, pancerebral angiography. So, the investigation was made for the active revealing of atherosclerotic signs. The main parameters of heart biomechanics and main arteries kinetics we calculated using apexcardiography and sphygmography and included: speed, acceleration, power, work in each phase of the cardiocycle by apexcardiography, as well as in period of prevalence of inflow over outflow and in period of prevalence of outflow over inflow in sphygmography. All the patients were divided into two main groups according to the quantity of extrasystoles per 24 hours: 1 group - less than 3000, 2 group -3000 extrasystoles and more per 24 hours.We determined that the atherosclerotic process was more advanced and more often the group 2. The atherosclerosis was more severe in patients with extrasystoles before the mitral valve opening and in fast ventricles' filling phase in cardiocycle. The main parameters of heart biomechanics and main arteries kinetics (speed, acceleration, power, work) calculated by apexcardiography and sphygmography increased with the further tendency: if earlier extrasystole appears in cardiocycle, than more changes were observed. Analyzing the methods of physics for fluid movement - Newton equation for liquids and Reynold number - we demonstrated that in extrasystolic arrhythmia in first post-extrasystolic wave there are the conditions for the turbulent blood flow that can cause the onset and progressing of atherosclerotic process.Extrasystolic arrhythmia is an additional risk factor of main arteries atherosclerosis. Especially this thesis is fair for the extrasystoles that appear in cardiocycle before the mitral valve opening and in fast ventricles' filling phase.

Initially developed as glucose-lowering drugs, sodium-glucose co-transporter type 2 inhibitors (SGLT2i) have demonstrated to be effective agents for the risk reduction of cardiovascular (CV) events in patients with type 2 diabetes mellitus (T2DM). Subsequently, data has emerged showing a significant CV benefit in patients treated with SGLT2i regardless of diabetes status. Renal protection has been initially evaluated in CV randomized trials only as secondary endpoints; nonetheless, the positive results gained have rapidly led to the evaluation of nephroprotection as primary outcome in the CREDENCE trial. Different renal and vascular mechanisms can account for the CV and renal benefits enlightened in recent literature. As clinical guidelines rapidly evolve and the role of SGLT2i appears to become pivotal for CV, T2DM, and kidney disease management, in this review, we analyze the renal effects of SGLT2, the benefits derived from its inhibition, and how this may result in the multiple CV and renal benefits evidenced in recent clinical trials.

Introduction. Atherosclerosis is the main reason of cardiocerebral events, its mechanisms and reasons are still being studied. Hydraulic shock in arrhythmias has not been studied before. Aim. To perform the modeling of hydraulic shock as a risk factor of the main arteries in arrhythmias with original experimental model created by the authors. Materials and methods. We created the original experimental model, it was used to imitate hydraulic shock in arrhythmias. It imitated the real arterial vessel and it allowed to make intra-vessel circulation of liquid in the regular rhythm and in arrhythmias (extrasystole). Results. In extrasystolic arrhythmia imitation in the first post-extrasystolic contraction the speed of liquid flow was revealed to rise in mean value 158% in comparison with the regular rhythm. Conclusion. In extrasystolic arrhythmia during the spread of the wave of the first post-extrasystolic contraction, blood flow accelerates and reflected waves and standing waves form. These hemodynamic changes are characterized by the term hydraulic shock. The use of our original experimental model helps to make the wide range of investigations and studies connected with intra-arterial hemodynamics in different conditions of functioning of cardiovascular system.

Aims Although heart failure (HF) is one of the most common conditions affecting the heart, little attention has been placed on the role of arteries in contributing to the progression of this disease. We sought to determine the haemodynamic change of arteries in HF patients subdivided according to left ventricular ejection fraction. The major goal was to establish the active compensatory role of arteries in HF. Methods and results Using sphygmography, we systematically studied a cohort of 228 HF patients and 52 healthy controls. We focused on the common carotid as the main elastic artery and the posterior tibial as the main muscular artery (Figure 1). Moreover, we categorized the three HF groups, HFrEF, HFmrEF, HFpEF, into two subgroups (A and B) according to the presence or absence of HF signs at baseline. We discovered that all the parameters of measured arterial kinetics, i.e. work, power, acceleration, and speed, were significantly increased (P Conclusions We provide the first documentation of an active compensatory role of arteries during HF. Mechanistically, we explain these findings by a dual activity of large arteries accomplished via an active propulsive work and a concurrent haemodynamic suction. These underestimated arterial functions partially compensate for the heart dysfunction in HF, underlining a key interplay between the heart and the vessels. We propose a new paradigm that we define as ‘heart and vessels failure’ that explicitly focuses on both heart and vessels’ interaction during the progression of HF.

International audience; Despite major advances in cardiovascular research over the past decade, women with type 2 diabetes have a high risk of cardiovascular events. Several factors contribute to the poor prognosis for women, including higher levels of frailty and comorbidities, but their cardiovascular risk is underestimated and there is suboptimal implementation and uptitration of new evidence-based therapies, leading to high morbidity and mortality. Recent studies highlight the need for better management of diabetes in women that can be pursued and achieved in light of recent results from randomised controlled trials demonstrating evidence of the benefits of new therapeutic strategies in improving cardiovascular outcomes and quality of life of women covering the entire cardiovascular continuum. This review critically discusses the multiple benefits for women of new pharmacological treatments, such as glucagon-like peptide-1 receptor agonists, sodium–glucose cotransporter type 2 inhibitors (SGLT2i), proprotein convertase subtilisin/kexin type 9 inhibitors, inclisiran, icosapent ethyl and bempedoic acid in preventing cardiovascular events, and treatments, such as angiotensin receptor neprilysin inhibitors, SGLT2i, vericiguat and omecamtiv mecarbil, for preventing heart failure.

Background Although heart failure (HF) is one of the most common conditions affecting the heart, little attention has been placed on the role of arteries in contributing to the progression of this disease. Purpose We sought to determine the hemodynamic change of arteries in HF patients subdivided according to left ventricular ejection fraction. The major goal was to establish the active compensatory role of arteries in HF Methods Using sphygmography, we systematically studied a cohort of 228 HF patients and 52 healthy controls. We focused on the common carotid as the main elastic artery and the posterior tibial as the main muscular artery (Figure 1). Moreover, we categorized the three HF groups, HFrEF, HFmrEF, HFpEF, into two subgroups (A and B) according to the presence or absence of HF signs at baseline. Results We discovered that all the parameters of measured arterial kinetics, i.e., work, power, acceleration, and speed, were significantly increased (p Conclusions We provide the first documentation of an active compensatory role of arteries during HF. Mechanistically, we explain these findings by a dual activity of large arteries accomplished via an active propulsive work and a concurrent hemodynamic suction. These underestimated arterial functions partially compensate for the heart dysfunction in HF, underlining a key interplay between the heart and the vessels. We propose a new paradigm that we define as “heart and vessels failure” that explicitly focuses on both heart and vessels' interaction during the progression of HF. Funding Acknowledgement Type of funding sources: None. Figure 1. Sphygmograms of CCA and PTAFigure 2. Patients disposition & Results

Purpose of study Using an original device for modeling of intra-arterial blood circulation, to study the features of intravascular hemodynamics with a regular heart rhythm and with various rhythm disturbances. Material and methods We used an original device developed by us to simulate intra-arterial circulation (Document of invention No. RU 202780 U1). The main part of the device is a glass tube of a rotameter with a length of 365 mm, an inlet end with a diameter of 20 mm, an outlet end of 16.5 mm, which is a model of an arterial vessel. Flexible silicone tubes are attached to the rotameter on both sides, with free ends connected to an electric pump, with various modes of operation (imitation of pulse waves with regular rhythm, premature ventricular contractions (PVCs), atrial fibrillation (AF). An aqueous solution of glycerin was introduced into a closed system diluted with water corresponding to the viscosity of the blood. A 5 mm long silk thread was alternately installed inside the tube, an intravascular piezoelectric crystal pressure probe connected to an oscilloscope. Also it was injected inside the tube a dye - clerical ink. Results With electric pump, we simulated the spreading of the pulse wave in regular heart rate, PVCs and AF. We observed the effect of a pressure wave (deflection of a silk thread, the appearance of a turbulent flow when using a dye) on the walls of the rotameter, with the formation of standing, reflected waves during the PVCs and AF. The pressure probe registered an increase in pressure inside the tube during the spread of the 1st post-extrasystolic contraction wave up to 58%, the wave after a long pause of more than 2 seconds with AF by 44% compared to the regular rhythm. Conclusion A device for modeling of intra-arterial circulation allows a wide range of experimental work in cardiology, normal and pathological physiology, and biophysics. Funding Acknowledgement Type of funding sources: None.

Funding Acknowledgements Type of funding sources: None. Aim To determine the relationship between hemodynamic changes in extrasystolic arrhythmia and atherosclerosis of main arteries. Materials and methods We included 286 patients (175 men and 111 women). The investigation was made to reveal the signs of atherosclerosis. All patients were performed 24-hours ECG monitoring, blood lipid spectrum, TTE, TOE, ultrasound doppler of brachiocephalic arteries, abdominal aorta branches, lower extremities arteries, renal arteries. If prescribed - stress Echo, coronary angiography, renal arteries angiography, pancerebral angiography. All patients were made apexcardiography (ACG) and arterial vessels sphygmography (SG) of aa. carotis, ulnaris, radialis, femoralis, tibialis posterior. The main parameters included speed, acceleration, power, work in each phase of cardiocycle. In accordance with amount of extrasystoles per 24 hours all the patients were divided into 2 groups: 1 – less than 3000 (144 patients), 2 – 3000 and more (142). They were grouped due to the age (see table 1 on the picture). Groups were common in age, sex, comorbidities. Results In group 2 the development and severity of atherosclerosis was more in group 2 (see table 2 on the picture). We determined the hemodynamic main parameters increase in first post-extrasystolic contraction with the following tendency: if earlier extrasystole appeared in cardiocycle, than more changes were observed. Conclusion Extrasystoles are additional risk factors of atherosclerosis. Hemodynamic changes after the first post-extrasystolic contraction is the important mechanical trauma factor for the arterial vessels which can take part in atherosclerotic process. Weak places – carotid bifurcation, abdominal aorta bifurcation, large radius of aorta arch. We suppose that it’s necessary to treat the extrasystoles more than 3000 per 24 hours that appear early in cardiocycle (before the mitral valve opening and before the transmitral blood flow peak).

Funding Acknowledgements Type of funding sources: None. Within the main causes of the secondary arterial hypertensions the main roles play renal, endocrine and hemodynamic. In the list of reasons of the secondary hemodynamic arterial hypertension there’re no extrasystoles. Purpose. To determine the relationship between different types of extrasystoles and the the secondary hemodynamic arterial hypertension. Materials and methods. We observed 132 patients with supraventricular and ventricular extrasystoles. Extrasystoles were divided into groups due to the moment of their appearance in cardiocycle: 1. Extrasystoles before the mitral valve opening. 2,3. Exstrasystoles in phase of fast ventricules filling before and after the peak of transmitral blood flow. 4. Extrasystoles in slow ventricules filling phase. 5. Other extrasystoles (allorrhythmias and group extrasystoles). The reason for that dividing was the different contribution of each type into the hemodynamics and heart output. We analyzed the regular, extraordinary and first post-extrasystolic contractions. Intra-arterial blood flow was estimated by ultrasound-doppler. The moment of extrasystoles appearance was determined by echocardiography, electrocardiography and 24-hours ECG monitoring. The kinetics of vessel wall was calculated by sphygmograms and included speed, acceleration, power and work parameters. The BP measuring was made by Korotkov method that the moment of measuring was in the first post-extrasystolic wave on sphygmogram. We duplicated it after the normalization and calibration of carotid arteries sphygmograms. Results. The main importance to the hemodynamic changes has the moment of extrasystole appearance in cardio cycle and the ability of the first post-extrasystolic contraction to reestablish an adequate resulting blood flow. It is characterized by: stroke volume rising from 5 to 40%; systolic BP increase up to 30% (with formation of the secondary hemodynamic AH) compared with the systolic BP with normal heart rate; rising of arterial walls kinetic parameters (speed, acceleration, power, work); blood flow velocity rising; grown arterial wall deformation. The maximum of these parameters was in first post-extrasystolic contraction with extrasystoles before the mitral valve opening and extrasystoles before the transmitral peak blood outflow. The special hemodynamic situation appears when there’re allorrhythmias when, for example, in case of constant bigeminia, BP is increased in 50% of time, and in case of trigimenia – in 1/3 of time. Conclusion. We believe it’s necessary to include extrasystoles into the list of the reasons of the secondary hemodynamic arterial hypertension. The main features of this type of AH are: unstable BP rising, prevalence growth of systolic BP, direct relationship with extrasystoles’ appearance moment. The risen blood flow of first post-extrasystolic contraction can be the reason of additional arterial walls deformation and complications that may cause the any AH.

BACKGROUND: Although heart failure (HF) is one of the most common conditions affecting the heart, little attention has been placed on the role of arteries in contributing to the progression of this disease. We sought to determine the hemodynamic change of arteries in HF patients subdivided according to left ventricular ejection fraction. The major goal was to establish the active compensatory role of arteries in HF. METHODS: Using sphygmography, we systematically studied a cohort of 228 HF patients and 52 healthy controls. We focused on the common carotid as the main elastic artery and the posterior tibial as the main muscular artery. Moreover, we categorized the three HF groups, HFrEF, HFmrEF, HFpEF, into two subgroups (A and B) according to the presence or absence of HF signs at baseline. RESULTS: We discovered that all the parameters of measured arterial kinetics, i.e., work, power, acceleration, and speed, were significantly increased (P

Funding Acknowledgements Type of funding sources: None. Nowadays the term "heart-vessels failure" does not exist. Aim To study the kinetics and hemodynamics of arteries in the patients with heart failure with different ejection fraction. Materials and methods In our investigation we included 74 patients with heart failure with preserved ejection fraction more than 55% (44 were men and 30 women). Mediana age – 71,3 years old. In the control group we included 52 practically healthy people without cardiac and vessels pathologies. We divided patients into two groups (I and II) in accordance to the presence of clinical manifestations of heart failure in them. Group I - with clinical symptoms of heart failure (32), group II –without heart failure symptoms (42). We paid attention to the symptoms of heart failure, myocardial infarction, cardiomyopathies, valves defects, operations on heart in anamnesis. We performed 24-hours ECG monitoring, general blood analysis, biochemical blood analysis (lipids, electrolytes, urine, creatinine, bilirubin, potassium, glucose, NT-proBNP), transthoracic echocardiography, ultrasound doppler of brachiocephalic arteries, abdominal aorta branches, lower extremities arteries, renal arteries, chest radiography, ultrasound investigation of B-lines. If prescribed we performed stress echocardiography, transesophageal echocardiography, coronary angiography, renal arteries angiography, pancerebral angiography, magnet tomography of heart. All patients were registered sphygmography of main arteries: a.carotis communis, ulnaris, radialis, a.tibialis posterior. We analyzed the regular contractions in each type of arteries. The main parameters main arteries kinetics using sphygmography we calculated in automatic mode: speed, acceleration, power, work in period of prevalence of inflow over outflow and in period of prevalence of outflow over inflow. Results We analysed the main parameters of arteries kinetics and hemodynamics in each group of patients as well as in control group. We observed the effects: 1)In group II the parameters of arteries kinetics were higher than in group I. It indicates the active propulsive work of arteries in spreading the stroke volume of the heart. 2)In group I the parameters of arteries kinetics were lower than in control group. It indicates that propulsive function of the arteries is reduced in patients with heart failure. Conclusion Arterial vessels are active, full-fledged participant in cardiovascular system. Vessels make an active work in blood movement from the heart to the distal parts and tissues. The clinical manifestations of heart failure are determined not only the heart function but also the function of arteries that is needed to be examined. In patients with preserved ejection fraction we can observe the symptoms of heart failure, the function abilities of arteries are reduced. The term "heart-vessels failure" should be used and applied not only to the heart but also to the arteries function in their coupling with heart. Abstract Figure.

Background Extrasystolic arrhythmia is not included in the list of risk factors of atherosclerosis. The aim of investigation is to determine the relationship between atherosclerosis of main arteries and extrasystolic arrhythmia. Methods We included 286 patients in our investigation. We performed 24-hours ECG monitoring, blood lipids analysis, transthoracic echocardiography, ultrasound Doppler of brachiocephalic arteries, abdominal aorta branches, lower extremities arteries, renal arteries. If prescribed we performed stress echocardiography, transesophageal echocardiography, coronary angiography, renal arteries angiography, pancerebral angiography. So the investigation was made for the active revealing of atherosclerotic signs. The main parameters of heart biomechanics and main arteries kinetics we calculated using apexcardiography and sphygmography and included: speed, acceleration, power, work in each phase of the cardiocycle by apexcardiography, as well as in period of prevalence of inflow over outflow and in period of prevalence of outflow over inflow in sphygmography. All the patients were divided into two main groups according to the quantity of extrasystoles per 24 hours: 1 group - less than 3000, 2 group -3000 extrasystoles and more per 24 hours. Results We determined that the atherosclerotic process was more advanced and more often in the group 2. The atherosclerosis was more severe in patients with extrasystoles before the mitral valve opening and in fast ventricles' filling phase in cardiocycle. The main parameters of heart biomechanics and main arteries kinetics (speed, acceleration, power, work) calculated by apexcardiography and sphygmography increased with the further tendency: if earlier extrasystole appears in cardiocycle, than more changes were observed. Analyzing the methods of physics for fluid movement - Newton equation for liquids and Reynold number - we demonstrated that in extrasystolic arrhythmia in first post-extrasystolic wave there are the conditions for the turbulent blood flow that can cause the onset and progressing of atherosclerotic process. Conclusions Extrasystolic arrhythmia is an additional risk factor of main arteries atherosclerosis. Especially this thesis is fair for the extrasystoles that appear in cardiocycle before the mitral valve opening and in fast ventricles' filling phase.

Introduction: Advanced heart failure (AdvHF) in HCM was overlooked. Hypothesis: Based on a systematic revision, we described prevalence & outcomes of the main HCM phenotypes responsible for AdvHF, heart transplantation (HTx), LVAD implantation & HF-death. Methods: We classified the HCM profiles responsible for AdvHF in 1) End-stage HCM (ES-HCM) defined by an LVEF≤50%; 2) LVOTO despite optimal medical therapy (OMT) (Refractory HOCM); 3) Nonobstructive HCM with preserved EF (HNOCMpEF). The study screened 130 manuscripts in MEDLINE and EMBASE on AdvHF in HCM patients (pts) published from 2000 till January 2020, in adults. 8 manuscripts were eligible for the analysis. AdvHF was defined by the presence of severe NYHA symptoms (III & IV) because in all the manuscripts this definition was used. Mean follow-up = 7.6 years. Results: Figure 1: Prevalence of phenotypes responsible for AdvHF&HTx/LVAD implantation/HF-Death. Of 205 HCM pts, 119 (58%) underwent HTx, LVAD implantation, or died for HF. Figure 2: Outcome per each clinical phenotype. Conclusions: AdvHF in HCM has an ominous prognosis (58% of pts met HTx/LVAD implantation/HF-death) but with significant differences among the 3 phenotypes. HOCM has a very good outcome, indeed only few cases developed a Refractory HOCM & AdvHF & only 1 died for HF. 29.7% of AdvHF were caused by HNOCMpEF due to massive hypertrophy & restrictive physiology & only 16.4% of them died due to HF. ES-HCM represents the main cause of AdvHF in HCM & the major determinant for poor outcomes among all HCM pts (Only 1/3 of them were event-free). This reflects poor attention and portrays an unmet need for ES-HCM pts. Recently it was demonstrated that an extensive amount of myocardial fibrosis (MF) is the major determinant for ES-evolution. Taken together these findings show the importance of a strict follow-up for HCM pts to timely identify ES-HCM & early start HF OMT. Developing specific therapies to lower the burden of MF & stop adverse remodeling it's crucial.

Recreational drug use may cause coronary artery disease through several mechanisms. An increasing number of young patients with drug-related acute coronary syndrome have been reported over recent years. The present position statement reports the most recent epidemiological data on acute coronary syndrome in the setting of drug abuse, describes the main pathophysiological mechanisms underlying coronary artery disease and acute events in these patients, and provides practical recommendations on management and an overview of prognosis.

Type 2 diabetes mellitus (T2DM) portends high risk of atherosclerotic cardiovascular (CV) events and of CV mortality; moreover, this group of patients has a very high probability of developing heart failure (HF). In this review, we discuss new advances in pharmacological treatment both in CV prevention and in HF management with a special focus on T2DM patients. A large number of randomized clinical trials and meta-analyses provided strong evidence about therapeutic strategies acting on glucose metabolism, such as GLP-1 RA and SGLT2i and about lipid-lowering treatment, such as PCSK9i and icosapent ethyl. Moreover, SGLT2i demonstrated strong evidence of benefit particularly in HF management both in diabetic and non-diabetic patients. The pathophysiological bases of multiple mechanisms of benefit of this class of drug explain the unexpected and remarkable results demonstrated both by prevention trials and by trials dedicated only to HF (like DAPA-HF). These, new drugs in the CV therapeutic armamentarium are establishing a new comprehensive approach from prevention to therapy of HF, giving more emphasis on HF classification in four stages (A→D). New therapies, which are on the horizon, promise to further reduce CV mortality and morbidity in HF patients irrespective of diabetic status.

Background— Although noninvasively detected myocardial fibrosis (MF) has clinical implications in hypertrophic cardiomyopathy, the extent, type, and distribution of ventricular MF have never been extensively pathologically characterized. We assessed the overall amount, apex-to-base, circumferential, epicardial–endocardial distribution, pattern, and type of MF in 30 transplanted hearts of end-stage, hypertrophic cardiomyopathy. Methods and Results— Visual and morphometric histological analyses at basal, midventricular, and apical levels were performed. Overall MF ranged from 23.1% to 55.9% (mean=37.3±8.4%). Prevalent types of MF were as follows: replacement in 53.3%, interstitial-perimyocyte in 13.3%, and mixed in 33.3%. Considering left ventricular base-to-apex distribution, MF was 31.9%, 43%, and 46.2% at basal, midventricular, and apical level, respectively ( P Conclusions— In end-stage, hypertrophic cardiomyopathy patients undergoing transplantation, more than one-third of the left ventricular myocardium was replaced by fibrosis, mainly of replacement type. MF preferentially involved the left ventricular apex and the midwall. Inferior and anterior walls and septum were maximally involved, whereas inferolateral and right ventricular were usually spared. These observations reflect the complex pathophysiology of hypertrophic cardiomyopathy and may provide clues for the timely recognition of disease progression by imaging techniques capable of quantifying MF.

Tea phenolic acids and catechins containing gallic acid moieties are most abundant in green tea, and various medical benefits have been proposed from their consumption. In the following, the cytotoxicities of these major tea phenolics toward isolated rat hepatocytes have been ranked and the mechanisms of cytotoxicity evaluated. The order of cytotoxic effectiveness found was epigallocatechin-3-gallate>propyl gallate>epicatechin-3-gallate>gallic acid, epigallocatechin>epicatechin. Using gallic acid as a model tea phenolic and comparing it with the tea catechins and gallic acid-derivative food supplements, the major cytotoxic mechanism found with hepatocytes was mitochondrial membrane potential collapse and ROS formation. Epigallocatechin-3-gallate was also the most effective at collapsing the mitochondrial membrane potential and inducing ROS formation. Liver injury was also observed in vivo when these tea phenolics were administered ip to mice, as plasma alanine aminotransferase levels were significantly increased. In contrast, GSH conjugation, methylation, metabolism by NAD(P)H:quinone oxidoreductase 1, and formation of an iron complex were important in detoxifying the gallic acid. In addition, for the first time, the GSH conjugates of gallic acid and epigallocatechin-3-gallate have been identified using mass spectrometry. These results add insight into the cytotoxic and cytoprotective mechanisms of the simple tea phenolic acids and the more complex tea catechins.

Flavonoids, including isoflavones, are natural components in our diet and, with the burgeoning interest in alternative medicine, are increasingly being ingested by the general population. Plant phenolics, which form moieties on flavonoid rings, such as gallic acid, are also widely consumed. Several beneficial properties have been attributed to these dietary compounds, including antioxidant, anti-inflammatory, and anticarcinogenic effects. Flavonoid preparations are marketed as herbal medicines or dietary supplements for a variety of alleged nontoxic therapeutic effects. However, they have yet to pass controlled clinical trials for efficacy, and their potential for toxicity is an understudied field of research. This review summarizes the current knowledge regarding potential dietary flavonoid/phenolic-induced toxicity concerns, including their pro-oxidant activity, mitochondrial toxicity (potential apoptosis-inducing properties), and interactions with drug-metabolizing enzymes. Their chemopreventive activity in animal in vivo experiments may result from their ability to inhibit phase I and induce phase II carcinogen metabolizing enzymes that initiate carcinogenesis. They also inhibit the promotion stage of carcinogenesis by inhibiting oxygen radical-forming enzymes or enzymes that contribute to DNA synthesis or act as ATP mimics and inhibit protein kinases that contribute to proliferative signal transduction. Finally, they may prevent tumor development by inducing tumor cell apoptosis by inhibiting DNA topoisomerase II and p53 downregulation or by causing mitochondrial toxicity, which initiates mitochondrial apoptosis. While most flavonoids/phenolics are considered safe, flavonoid/phenolic therapy or chemopreventive use needs to be assessed as there have been reports of toxic flavonoid-drug interactions, liver failure, contact dermatitis, hemolytic anemia, and estrogenic-related concerns such as male reproductive health and breast cancer associated with dietary flavonoid/phenolic consumption or exposures.

The ability to reduce the peroxidase (myeloglobin/H2O2)-generated ABTS*+ [2,2'-azinobis-(3-ethylbenzthiazoline-6-sulfonic acid) radical cation] has been used to rank the antioxidant activity of various agents including dietary flavonoids and chalcones. Surprisingly, we found that in the presence of catalytic concentrations of the phenol B-ring containing flavonoids, apigenin, naringenin and the chalcone phloretin, the formation of the ABTS*+ was initially increased. The enhanced formation of the ABTS*+ was attributed to the peroxidase/H2O2 mediated generation of polyphenolic phenoxyl radicals that were able to co-oxidize ABTS. The relative ABTS*+ generating ability of these dietary polyphenolics correlated with their ability to co-oxidize NADH to the NAD* radical with the resultant generation of superoxide. This pro-oxidant activity was not observed for either luteolin or eriodyctiol, which are B-ring catecholic analogues of apigenin and naringenin, respectively, suggesting that these antioxidants are incapable of the transition metal-independent generation of reactive oxygen species. This pro-oxidant activity of the polyphenolics therefore needs to be taken into account when quantifying antioxidant activity.

Coenzyme Q (CoQ) is an essential component of the mitochondrial electron transport chain and serves as an electron donor and acceptor in mitochondrial energy-linked respiration. CoQ1 was shown to prevent ROS formation and cell death in complex 1 inhibited cells. Low concentrations of capsaicin like CoQ1 inhibited ROS formation but CoQ1 was more effective at restoring the mitochondrial membrane potential collapse caused by complex 1 inhibitors such as rotenone. At low concentrations, capsaicin acts as a CoQ mimic by protecting against rotenone induced ROS formation and mitochondrial membrane potential collapse. Lipid peroxidation in isolated rat hepatocytes induced by cumene hydroperoxide and chloroacetaldehyde was also prevented. At higher concentrations, capsaicin and CoQ1 became cytotoxic. Hep G2 cells were more susceptible than hepatocytes. The cytotoxic mechanism for both capsaicin and CoQ1 was shown to involve a collapse of the mitochondrial membrane potential, however, only capsaicin caused ROS formation. The capsaicin side chain was required for capsaicin induced cytotoxicity. The anticancer properties of CoQ1 and capsaicin should prove useful for inducing tumor cell apoptosis.

Many idiosyncratic non-steroidal anti-inflammatory drugs (NSAIDs) cause GI, liver and bone marrow toxicity in some patients which results in GI bleeding/ulceration/fulminant hepatic failure/hepatitis or agranulocytosis/aplastic anemia. The toxic mechanisms proposed have been reviewed. Evidence is presented showing that idiosyncratic NSAID drugs form prooxidant radicals when metabolised by peroxidases known to be present in these tissues. Thus GSH, NADH and/or ascorbate were cooxidised by catalytic amounts of NSAIDs and hydrogen peroxide in the presence of peroxidase. During GSH and NADH cooxidation, oxygen uptake and activation occurred. Furthermore the formation of NSAID oxidation products was prevented during the cooxidation indicating that the cooxidation involved redox cycling of the first formed NSAID radical product. The order of prooxidant catalytic effectiveness of fenamate and arylacetic acid NSAIDs was mefenamic acid>tolfenamic acid>flufenamic acid, meclofenamic acid or diclofenac. Diphenylamine, a common moiety to all of these NSAIDs was a more active prooxidant for NADH and ascorbate cooxidation than these NSAIDs which suggests that oxidation of the NSAID diphenylamine moiety to a cation and/or nitroxide radical was responsible for the NSAID prooxidant activity. The order of catalytic effectiveness found for sulfonamide derivatives was sulfaphenazole>sulfisoxazole≫dapsone>sulfanilic acid>procainamide>sulfamethoxazole>sulfadiazine>sulfadimethoxine whereas sulfanilamide, sulfapyridine or nimesulide had no prooxidant activity. Although indomethacin had little prooxidant activity, its major in vivo metabolite, N -deschlorobenzoyl indomethacin had significant prooxidant activity. Aminoantipyrine the major in vivo metabolite of aminopyrine or dipyrone was also more prooxidant than the parent drugs. It is hypothesized that the NSAID radicals and/or the resulting oxidative stress initiates the cytotoxic processes leading to idiosyncratic toxicity.

Quantitative structure activity relationship (QSAR) equations were obtained to describe the cytotoxicity of 22 polyphenols using toxicity (logLD50) representing the concentration for 50% cell survival in 2 h for isolated rat hepatocytes, log P representing octanol/water partitioning, and/or E(p/2) representing redox potential. One- and two-parameter equations were derived for the quantitative structure toxicity relationships (QSTR) for polyphenol induced hepatocyte cytotoxicity: e.g. log C(hepatocyte) (microM)=-0.65(-0.08)log P+4.12(-0.15) (n=19, r(2)=0.80, s=0.33, P1 x 10(-6)). One- and two-parameter QSAR equations were also derived to describe the inhibitory effects of 13 polyphenols on tumor cell growth when incubated with HeLa cells for 3 days: e.g. log C(tumor) (microM)=-0.34(+/-0.04)log P+2.40(+/-0.07) (n=11, r(2)=0.90, s=0.13, P1 x 10(-5)). These findings point to lipophilicity as a major characteristic determining polyphenol cytotoxicity. The E(p/2) also played a significant role in polyphenol cytotoxicity towards both cell types: e.g. log C(hepatocyte) (microM)=-0.60(+/-0.06)log P+2.01(+/-0.43)E(p/2) (V)+3.86(+/-0.12) (n=9, r(2)=0.96, s=0.15, P0.005). The involvement of log P and E(p/2) could be explained if polyphenol cytotoxicity involved the formation of radicals, which interacted with the mitochondrial inner membrane resulting in a disruption of the membrane potential.

The introduction includes a literature review of DNA reactive species and DNA adduct formation that results from aromatic amine N-oxidation catalyzed by hepatic cytochrome P450 vs. that catalyzed by nonhepatic peroxidases. Experimental evidence is then described for a novel oxidative stress mechanism involving prooxidant N-cation radical formation by both oxidases, which is proposed as a contributing mechanism for aromatic amine induced cytotoxicity and carcinogenesis. Aromatic amine N-cation radicals formed by peroxidases were found to cooxidize GSH or NADH and form reactive oxygen species. The latter could explain the reported DNA oxidative damage found in vivo following methylaminoazobenzene administration [Hirano et al. Analyses of Oxidative DNA Damage and Its Repair Activity in the Livers of 3'-Methyl-4-dimethylaminoazobenzene-Treated Rodents. Jpn. J. Cancer Res. 2000, 91, 681-685]. It was also found that the prooxidant activity of the aromatic amine increased as its redox potential, i.e., ease of oxidation decreased with o-anisidine and aminofluorene being the most effective at forming reactive oxygen species. This suggests that the rate-limiting step in the cooxidation is the rate of arylamine oxidation by the peroxidase. Incubation of hepatocytes with aromatic amines caused a decrease in the mitochondrial membrane potential before cytotoxicity ensued. The CYP1A2-induced hepatocytes isolated from 3-methylcholanthrene administered rats were much more susceptible to some arylamines and were protected by CYP1A2 inhibitors. Hepatocyte GSH was also depleted by all arylamines tested and extensive GSH oxidation occurred with o-anisidine and aminofluorene, which was prevented by CYP1A2 inhibitors. This suggests that in intact hepatocytes CYP1A2 may also catalyze a one-electron oxidation of some arylamines to form prooxidant cation radicals, which cooxidize GSH to form the reactive oxygen species.

Systemic amyloidosis still remains a challenging and probably underdiagnosed disease.1 The three most frequent types of systemic amyloidosis are (i) the acquired monoclonal immunoglobulin light chain amyloidosis (AL), characterised by clonal plasma cells in the bone marrow that produce the immunoglobulin lights chains of the fibrillary deposits; (ii) the hereditary, transthyretin (TTR)-related form (ATTR), which can be caused by 100 mutations of TTR, a transport protein synthesised mainly by the liver; and (iii) the wild-type (non-mutant) TTR-related amyloidosis called systemic ‘senile’ amyloidosis (SSA), which affects mainly the hearts of elderly men.1 ,2 Pozo et al 3 focus on the problem of LV remodelling and on the type of distribution of the ‘hypertrophy’ in patients with cardiac amyloidosis (CA). The concepts of ‘LV remodelling’ and ‘LV geometry’ have been elaborated in the last 20 years mainly related to coronary heart disease, hypertensive heart disease4 and valvular heart disease. Regarding hypertensive heart disease, a spectrum of LVH exists ranging from concentric LV hypertrophy (LVH), characterised by increased LV mass and increased ratio of the LV wall thickness to diastolic diameter (relative wall thickness, RWT), …

There is no nationally or internationally binding definition of the term "cytotoxic drug" although this term is used in a variety of regulations for pharmaceutical development and manufacturing of drugs as well as in regulations for protecting medical personnel from occupational exposure in pharmacy, hospital, and other healthcare settings. The term "cytotoxic drug" is frequently used as a synonym for any and all oncology or antineoplastic drugs. Pharmaceutical companies generate and receive requests for assessments of the potential hazards of drugs regularly - including cytotoxicity. This publication is intended to provide functional definitions that help to differentiate between generically-cytotoxic cancer drugs of significant risk to normal human tissues, and targeted cancer therapeutics that pose much lesser risks. Together with specific assessments, it provides comprehensible guidance on how to assess the relevant properties of cancer drugs, and how targeted therapeutics discriminate between cancer and normal cells. The position of several regulatory agencies in the long-term is clearly to regulate all drugs regardless of classification, according to scientific risk based data. Despite ongoing discussions on how to replace the term "cytotoxic drugs" in current regulations, it is expected that its use will continue for the near future.

Catalytic concentrations of apigenin (a flavone containing a phenol B ring) and naringin or naringenin (flavanones containing a phenol B ring) caused extensive GSH oxidation at a physiological pH in the presence of peroxidase. Only catalytic H2O2 concentrations were required, indicating a redox cycling mechanism that generated H2O2 was involved. Extensive oxygen uptake ensued, the extent of which was proportional to the extent of GSH oxidation to GSSG and was markedly increased by superoxide dismutase. These results suggest that prooxidant phenoxyl radicals formed by these flavonoids co-oxidized GSH to form thiyl radicals which activated oxygen. GSH also prevented the peroxidase-catalyzed oxidative destruction of these flavonoids which suggests that phenoxyl radicals initiated the oxidative destruction. This is the first time that a group of flavonoids have been identified as prooxidants independent of autoxidation reactions catalyzed by the transition metal ions Fe3+, Fe2+, Mn2+, and Cu2+.

A 54-year-old Caucasian woman was admitted to the emergency department of a peripheral hospital for palpitations. ECG showed a wide QRS complex tachycardia that resolved spontaneously (figure 1A). Clinical history was negative. At echocardiogram, hypokinesia and thinning of basal septum and mild pericardial effusion were the only abnormal findings (see online supplementary videos 1 and 2). Left ventricular (LV) ejection fraction (EF) was 55%. Coronary arteries were normal at coronary angiography. Chest x-ray was normal. At electrophysiological study ventricular tachycardia with the same morphology encountered at presentation was inducible. The patient …