Decrease In Stroke Volume Research Articles

Dynamics of hemodynamic parameters and tone of the autonomic nervous system in the rehabilitation of patients with neurocirculatory dystonia

Purpose: to substantiate, develop and evaluate the effectiveness of a physical therapy program for young women with hypertensive neurocirculatory dystonia at the outpatient stage. Material & Methods: under our supervision there were 28 women with a diagnosis of neurocirculatory dystonia of hypertonic type; they were randomly divided into two groups: main (14 patients) and control (14 patients); the average age of patients in the main group was 20,1±0,35 years, in the control group – 20,6±0,23 years. The course of physical therapy for patients of the main and control groups lasted for 5 months. The patients of the main group underwent rehabilitation measures according to the program of physical therapy, which included kinesiotherapy using therapeutic exercises based on dance aerobics in combination with regulated breathing exercises, taking into account the tone of the ANS and autogenic training, patients of the control group were engaged in the E.V. Doliger physical therapy program for patients with NCD. Results: the functional indicators of the cardiovascular and autonomic nervous system obtained during the primary study indicated the absence of economization of the work of the cardiovascular system, the presence of dysfunction of the autonomic nervous system in the direction of the predominance of the activity of the sympathetic department. After 5 months of using physical therapy programs, when re-examined, patients in both groups showed a decrease in heart rate and a decrease in blood pressure; stroke volume in the main group was within normal limits, in the control group, a decrease in stroke volume indicated a reduced myocardial contractility; the decrease in the minute volume of blood in the main group was due to a decrease in heart rate, in the control group – due to a decrease in heart rate and stroke volume. The value of the Kerdo index in the main group corresponded to the state of eutonia, in the control group – sympathicotonia. Conclusions: in the course of the study, we came to the conclusion that a physical therapy program was developed, which included kinesitherapy using therapeutic exercises based on dance aerobics in combination with regulated breathing exercises, taking into account the tone of the parasympathetic and sympathetic divisions of the autonomic nervous system and autogenic training, is effective and contributes to the normalization of hemodynamic parameters and the tone of the autonomic nervous system, which improves the quality of life of NCD patients. The conducted studies have confirmed the need for the use of physical therapy, including kinesitherapy using therapeutic exercises based on dance aerobics in combination with regulated breathing exercises, taking into account the tone of the ANS and autogenous training.

Prone restraint death: Possible role of the Valsalva maneuver.

There is an on-going debate about the safety of prone restraint and the exact role of the prone position in physical restraint death. Cardiac arrest in prone restraint death is essentially the end-result of a violent physical altercation wherein a combative individual suddenly loses consciousness while trying to counteract an opposing force. The direct correlations of increased static weight force with decreased inferior vena cava diameter, decreased cardiac output, and decreased stroke volume in prone restraint studies suggest that decreased venous return and decreased cardiac output could have a significant role to play in prone restraint death. Although the degree of changes observed in those studies might not be sufficient to cause cardiac arrest, they could predispose people who instinctively try to free themselves of the restraints to severe complications. The Valsalva maneuver, or forceful expiration against a closed airway, is frequently performed spontaneously in daily activities involving straining and resistance exercise, but has never been considered in restraint death. Pre-existing diminished venous return could increase the risk of major complications in individuals performing the Valsalva maneuver. A substantial decrease in venous return and cardiac output could increase the risk of cerebral hypoperfusion, loss of consciousness, hypoventilation, and sudden death. By increasing the risk of increased intra-abdominal pressure and its negative effect on venous return, high body mass index may be a significant risk factor in prone restraint death. The Valsalva maneuver may have different roles in prone restraint cardiac arrest and might be overlooked in prone restraint death.

Noninvasive Hemodynamic Evaluation Following TAVI for Severe Aortic Stenosis.

Background Various hemodynamic changes occur following transcatheter aortic valve implantation (TAVI) that may impact therapeutic decisions. NICaS is a noninvasive bioimpedance monitoring system aimed at hemodynamic assessment. We used the NICaS system in patients with severe aortic stenosis (AS) to evaluate short-term hemodynamic changes after TAVI. Methods and Results We performed hemodynamic analysis using NICaS on 97 patients with severe AS who underwent TAVI using either self-expandable (68%) or balloon-expandable (32%) valves. Patients were more often women (54%) and had multiple comorbidities including hypertension (83%), coronary artery disease (46%), and diabetes (37%). NICaS was performed at several time points-before TAVI, soon after TAVI, at hospital discharge, and during follow-up. Compared with baseline NICaS measurements, we observed a significant increase in systolic blood pressure and total peripheral resistance (systolic blood pressure 132±21 mm Hg at baseline versus 147±23 mm Hg after TAVI, P<0.001; total peripheral resistance 1751±512 versus 2084±762 dynes*s/cm5, respectively, P<0.001) concurrent with a decrease in cardiac output and stroke volume (cardiac output 4.2±1.5 versus 3.9±1.3 L/min, P=0.037; stroke volume 61.4±14.8 versus 56.2±15.9 mL, P=0.001) in the immediate post-TAVI period. At follow-up (median 59 days [interquartile range, 40.5-91]) these measurements returned to values that were not different from the baseline. A significant improvement in echocardiography-based left ventricular ejection fraction was observed from baseline to follow-up (55.6%±11.6% to 59.4%±9.4%, P<0.001). Conclusions Unique short-term adaptive hemodynamic changes were observed using NICaS in patients with AS soon after TAVI. Noninvasive hemodynamic evaluation immediately following TAVI may contribute to the understanding of complex hemodynamic changes and merits favorable consideration.

Rate-Adaptive Atrial Pacing for Heart Failure With Preserved Ejection Fraction

Reduced heart rate during exercise is common and associated with impaired aerobic capacity in heart failure with preserved ejection fraction (HFpEF), but it remains unknown if restoring exertional heart rate through atrial pacing would be beneficial. To determine if implanting and programming a pacemaker for rate-adaptive atrial pacing would improve exercise performance in patients with HFpEF and chronotropic incompetence. Single-center, double-blind, randomized, crossover trial testing the effects of rate-adaptive atrial pacing in patients with symptomatic HFpEF and chronotropic incompetence at a tertiary referral center (Mayo Clinic) in Rochester, Minnesota. Patients were recruited between 2014 and 2022 with 16-week follow-up (last date of follow-up, May 9, 2022). Cardiac output during exercise was measured by the acetylene rebreathe technique. A total of 32 patients were recruited; of these, 29 underwent pacemaker implantation and were randomized to atrial rate responsive pacing or no pacing first for 4 weeks, followed by a 4-week washout period and then crossover for an additional 4 weeks. The primary end point was oxygen consumption (V̇o2) at anaerobic threshold (V̇o2,AT); secondary end points were peak V̇o2, ventilatory efficiency (V̇e/V̇co2 slope), patient-reported health status by the Kansas City Cardiomyopathy Questionnaire Overall Summary Score (KCCQ-OSS), and N-terminal pro-brain natriuretic peptide (NT-proBNP) levels. Of the 29 patients randomized, the mean age was 66 years (SD, 9.7) and 13 (45%) were women. In the absence of pacing, peak V̇o2 and V̇o2 at anaerobic threshold (V̇o2,AT) were both correlated with peak exercise heart rate (r = 0.46-0.51, P < .02 for both). Pacing increased heart rate during low-level and peak exercise (16/min [95% CI, 10 to 23], P < .001; 14/min [95% CI, 7 to 21], P < .001), but there was no significant change in V̇o2,AT (pacing off, 10.4 [SD, 2.9] mL/kg/min; pacing on, 10.7 [SD, 2.6] mL/kg/min; absolute difference, 0.3 [95% CI, -0.5 to 1.0] mL/kg/min; P = .46), peak V̇o2, minute ventilation (V̇e)/carbon dioxide production (V̇co2) slope, KCCQ-OSS, or NT-proBNP level. Despite the increase in heart rate, atrial pacing had no significant effect on cardiac output with exercise, owing to a decrease in stroke volume (-24 mL [95% CI, -43 to -5 mL]; P = .02). Adverse events judged to be related to the pacemaker device were observed in 6 of 29 participants (21%). In patients with HFpEF and chronotropic incompetence, implantation of a pacemaker to enhance exercise heart rate did not result in an improvement in exercise capacity and was associated with increased adverse events. ClinicalTrials.gov Identifier: NCT02145351.

Correlation between frailty and cardiac structure and function in echocardiography in elderly patients with normal ejection fraction.

This study aims to accurately evaluate the cardiac structure and function of the frail population in elderlypatients with normal ejection fraction (EF) using the 3D volume quantification and speckle tracking of echocardiography, to explore the correlation between frailty and cardiac structure and function. A total of 350 elderly aged 65 and above in-patients, excluding those with congenital heart disease, cardiomyopathy, and severe valvular heart disease, were included in the study. Patients were divided into non-frail, pre-frail, and frail group. Echocardiography techniques including speckle tracking and 3D volume quantification, were used to analyze the cardiac structure and function of the study subjects. Comparative analysis was statistically significant if P < 0.05. The cardiac structure of the frail group was different compared with non-frail patients, the frail group demonstrated increased left ventricular myocardial mass index (LVMI), but decreased stroke volume. Cardiac function was also impaired in the frail group: reservoir strain and conduit strain of left atrium, strain of right ventricular (RV) free wall, strain of RV septum, 3D EF of RV, and global longitudinal strain of LV were significantly decreased. Frailty was significantly and independently associated with LV hypertrophy (OR 1.889; 95% CI 1.240,2.880; P = 0.003), LV diastolic dysfunction (OR 1.496; 95% CI 1.016,2.203; P = 0.041), left ventricular global longitudinal strain (LVGLS) reduction (OR 1.697; 95% CI 1.192, 2.416; P = 0.003), and reduced RV systolic function (OR 2.200; 95% CI 1.017, 4.759; P = 0.045). Frailty is closely associated with several heart structural and functional alterations, which not only manifested as LV hypertrophy and reduced LV systolic function, but also decreased LV diastolic function, RV systolic function, and left atrial systolic function. Frailty is an independent risk factor for LV hypertrophy, LV diastolic dysfunction, LVGLS reduction, and reduced RV systolic function. ChiCTR2000033419. Date of registration: May 31, 2020.

Effect of Work-to-Rest Cycles on Cardiovascular Strain and Maximal Oxygen Uptake during Heat Stress.

Cardiovascular drift-a progressive increase in heart rate (HR) and decrease in stroke volume (SV) during prolonged exercise-is exacerbated by heat stress and thermal strain, and often accompanied by a decrease in work capacity (indexed as maximal oxygen uptake [V.O2max]). To attenuate physiological strain during work in the heat, use of work:rest ratios is recommended by the National Institute for Occupational Safety and Health. The purpose of this study was to test the hypothesis that during moderate work in hot conditions, utilizing the recommended 45:15 min work:rest ratio would result in cardiovascular drift 'accumulating' over consecutive work:rest cycles and accompanying decrements in V.O2max. Eight people (5 women; (mean ± SD) age = 25 ± 5 y; body mass = 74.8 ± 11.6 kg; V.O2max = 42.9 ± 5.6 mL·kg-1·min-1) performed 120 min of simulated moderate work (201-300 kcal·h-1) in hot conditions (indoor wet-bulb globe temperature = 29.0 ± 0.6 °C). Participants completed two 45:15 min work:rest cycles. Cardiovascular drift was evaluated at 15 and 45 min of each work bout; V.O2max was measured after 120 min. On a separate day, V.O2max was measured after 15 min under identical conditions for comparison before and after cardiovascular drift occurred. HR increased 16.7% (18 ± 9 beats·min-1, p = 0.004) and SV decreased 16.9% (-12.3 ± 5.9 mL, p = 0.003) between 15 and 105 min, but V.O2max was unaffected after 120 min (p = 0.14). Core body temperature increased 0.5 ± 0.2 °C (p = 0.006) over 2 h. Recommended work:rest ratios preserved work capacity but did not prevent the accumulation of cardiovascular and thermal strain.

Соотношение ультразвуковых и электрокардиографических параметров внутрисердечной гемодинамики при физической нагрузке у человека

The purpose of this article was to study the mechanism of reduction in stroke volume after intense physical activity (the Astrand effect). Materials and methods. The research involved 23 apparently healthy male students of Syktyvkar State University named after Pitirim Sorokin (age: 19 ± 1 years, body weight: 75 ± 13 kg, height: 177 ± 7 cm, body mass index: 24 ± 4 kg/m2). The physical load consisted of the Stange test (voluntary inspiratory breath-holding) and the Martinet test (squats to failure) performed simultaneously. The parameters of intracardiac haemodynamics were assessed using electrocardiography and ultrasonography. Results. We established that at rest, about 80 cm3 of blood passes through the mitral valve and the aortic valve in a cardiac cycle lasting on average about 0.30 s. Under physical load, the total blood flow volume through the mitral valve is reduced by 8 %, while through the aortic valve, by 15 %. The decrease in stroke volume under physical load, accompanied by an increase in heart rate, is due to a reduction in the TP segment of the electrocardiogram (diastole). The free blood flow (during diastole) from the left atrium through the mitral valve stops and the forced flow (during systole) starts, coinciding in time with the PQ interval (left atrial systole) on the electrocardiogram. Changes in the subjects’ parameters associated with the flow dynamics through the mitral valve and further through the aortic valve, as well as the processes in the TP segment (diastole) indicate that it is the shortened diastole during exercise that serves as the main link in the mechanism of all subsequent rearrangements of intracardiac haemodynamics. This study contributes to the understanding of the mechanism of the Astrand effect. Moreover, it demonstrated the dependence of the diastolic function of the ventricles on the volume of free blood flow (during diastole) through the mitral valve during the contraction of the TP segment according to the electrocardiographic data.

ОСОБЕННОСТИ ПОКАЗАТЕЛЕЙ ЭХОКАРДИОГРАФИИ У ПАЦИЕНТОВ С КОМОРБИДНОСТЬЮ БРОНХИАЛЬНОЙ АСТМЫ И ГИПЕРТОНИЧЕСКОЙ БОЛЕЗНИ

Introduction. The presence of comorbidities in patients with bronchial asthma can increase the frequency of attacks, lead to more severe symptoms during exacerbations, and reduce the quality of life of patients. Aim. The purpose is the evaluation of morphological and functional changes in the heart of patients with a comorbidity of bronchial asthma with the hypertension disease. Material and methods. The study included 55 patients, 4 groups were formed. The main group included 19 people with a combination of bronchial asthma with the hypertension disease. Primary comparison group was 20 people with bronchial asthma. The second comparison group consisted of 16 people with hypertension. The control group consisted of 25 healthy people. Echocardiographic parameters were studied and compared with the clinical and functional picture of the disease. The analysis of the results was performed by using methods of descriptive statistics. The correlation analysis was performed with considering the Spearman’s rank correlation coefficient. Results and discussion. In the analysis of the heart morphological and functional characteristics of patients with bronchial asthma and hypertension disease in comparison with the control groups there was an increase in the left atrium dimension and volume, right ventricular wall thickness, right ventricular outflow tract at proximal, a decrease in stroke volume and end- systolic volume with negligible changes of the ejection fraction, a decrease in the thickness of the posterior wall of the left ventricle and the interventricular septum. Conclusion. This article distinguishes the characteristics of progression of the disease, as well as suggests mechanisms of pathogenetic interaction in comorbidity of hypertension disease and bronchial asthma by assessing the main parameters of echocardiography. This method is used for the earliest detection of structural and functional changes. In patients with bronchial asthma and hypertension was pronounced morphological changes in the right parts of the heart and functional changes in the pulmonary circulation in comparison in patients with isolated disease. However, because of decrease in diastolic pressure in left parts of the heart and redistribution blood volume on the right side of the heart in the left parts of the heart are less susceptible to remodeling.

ACETAMINOPHEN ATTENUATES PULMONARY VASCULAR RESISTANCE AND PULMONARY ARTERIAL PRESSURE AND INHIBITS CARDIOVASCULAR COLLAPSE IN A PORCINE MODEL OF ENDOTOXEMIA.

Acetaminophen (paracetamol) is often used in critically ill patients with fever and pain; however, little is known about the effects of acetaminophen on cardiovascular function during systemic inflammation. Here, we investigated the effect of acetaminophen on changes in the systemic and pulmonary circulation induced by endotoxin (0.5 μg/kg per hour) in anesthetized pigs. Endotoxin infusion led to a rapid increase in pulmonary artery pressure and pulmonary vascular resistance index. Acetaminophen delayed and attenuated this increase. Furthermore, acetaminophen reduced tachycardia and decreased stroke volume, accompanied by systemic inflammation, without affecting inflammatory parameters such as white blood cell count and TNF-α in blood. As a proof of concept, we injected a high dose of endotoxin (100 μg), which induced rapid cardiovascular collapse in pigs. Pigs treated with acetaminophen survived with no obvious hemodynamic instability during the 50-min observation period. In conclusion, acetaminophen attenuates the effects of endotoxin on pulmonary circulation in anesthetized pigs. This may play a role in severe systemic inflammation.

PS-B03-7: MAGNESIUM SULPHATE TREATMENT DURING HYPERTENSIVE PREGNANCY IMPROVES MATERNAL BUT NOT FETAL OUTCOMES IN RATS

Objective: There has been a recent rise in the incidence of cardiovascular disease amongst women of child-bearing age and hypertensive disorders in pregnancy, in particular pre-eclampsia. Though it is frequently diagnosed, therapeutic interventions are lacking. Magnesium sulphate (MgSO4) is known to induce a vasodilatory effect via increased NO production and improved endothelial function and is currently used to prevent the progression to eclampsia and seizures from pre-eclampsia in the clinic. Magnesium homeostasis is also crucial during a healthy pregnancy and hypomagnesemia has been linked to cardiovascular disease. We hypothesised that MgSO4 may be used as a preventative therapeutic during hypertensive pregnancies in a rodent model of super-imposed pre-eclampsia. Design and Methods: Spontaneously hypertensive stroke prone (SHRSP) female rats were time mated. On gestational day (GD) 10.5 0.9% saline (SHAM, n = 10) or 750ng/kg/min of ANGII (n = 17) were administered via mini pump. A subset of ANGII and SHAM animals received daily 1% w/v MgSO4 drinking water from GD0.5 (n = 4/group; SHAM/ANGII+MgSO4). Blood pressure, cardiac function, and uteroplacental blood flow were measured by tail-cuff plethysmography and Doppler ultrasound pre-pregnancy (PP) and at GD6.5, 12.5, and 18.5. Urine samples were collected by metabolic cage at PP, GD6.5, and GD18.5 for measurement of proteinuria. Fetal and placental measurements were collected at sacrifice. Results: ANGII shows features consistent with SPE in humans via decreased stroke volume and elevated blood pressure alongside decreased fetal and placental weights vs SHAM (****p &lt; 0.0001, **p &lt; 0.01, *p &lt; 0.05). Additionally, ANGII resulted in significantly altered fluid homeostasis and proteinuria vs SHAM (****p &lt; 0.0001, ***p &lt; 0.001, **p &lt; 0.01). ANGII+MgSO4 showed a decrease in blood pressure vs ANGII (**p &lt; 0.01). Treatment with MgSO4 had no significant effect on cardiac function, though there was a trend towards improvement in delta cardiac output. Neither ANGII nor additional MgSO4 altered indices of uteroplacental flow vs ANGII or SHAM. ANGII+MgSO4 exhibited a significant reduction in proteinuria vs ANGII (*p &lt; 0.05) as well as improvements in fluid homeostasis. Both fetal and placental weights were significantly reduced in ANGII+MgSO4 vs SHAM (**p &lt; 0.001) indicating a detrimental effect. Conclusions: These results suggest 1% w/v MgSO4 may be beneficial as a preventative therapeutic in pregnancies affected by super-imposed pre-eclampsia for maternal but not fetal outcomes. Further work is needed to elucidate the effects of MgSO4 in the context of hypertensive pregnancy.

Cardiovascular changes during phototherapy in newborns.

Phototherapy is the most effective non-invasive method of neonatal hyperbilirubinemia treatment. Application of this method can be associated with side effects including changes in the cardiovascular system. During phototherapy, the primary effects in the cardiovascular system include cutaneous vasodilation leading to skin hyperperfusion and subsequent redistribution of blood. The increased blood flow through the skin is associated with increased transepidermal water loss. Further effects include an increase in cerebral blood flow. Redistribution of blood to the cutaneous bed is compensated by hypoperfusion in the splanchnic area (mostly postprandial) and a significant reduction of the renal blood flow. Regarding closure/reopening of the ductus arteriosus, the results suggest that that phototherapy does not affect ductal patency. During phototherapy the cardiac output can be slightly reduced due to a decreased stroke volume, especially in preterm newborns. Systemic blood pressure is decreased and heart rate is elevated in both preterm and term newborns during phototherapy. The heart rate variability is slightly reduced. Symbolic dynamics analysis of the short-term HRV showed that during phototherapy the activity of the ANS regulating the heart rate is shifted towards the dominancy of the sympathetic activity. The responses in the cardiovascular system of premature/mature newborns without other pathology confirm a well physiologically functioning control of this system, even under specific conditions of phototherapy.

Effective Following: A Counterpart to Leadership

Effective Following: A Counterpart to Leadership

Морфофункціональні особливості серця в підлітків з ювенільним ідіопатичним артритом на тлі тривалого лікування

Juvenile idiopathic arthritis (JIA) is the term used for descriptions of a group of inflammatory diseases beginning before the age of 16 years. In the last 25-30 years many studies are devoted to the study of cardiovascular risk in adult patients with rheumatoid arthritis, since with the lengthening of the life expectancy of these patients, change in the structure of their mortality. Purpose - to establish the features of morphofunctional characteristics of the heart in adolescents with juvenile idiopathic arthritis on the background of a long (more one year) basic treatment. Materials and methods. Were examined 91 adolescents with polyarticular variant of JIA, of which - 70 girls and 21 boys aged 10 to 18 years old and the duration of the disease is about 80 months. All patients received methotrexate for more than 12 months, the dosing regimen was from 6.51 mg/m2 to 22.72 mg/m2 per week. The control group consisted 45 healthy peers, of which 29 girls and 16 boys. An ultrasound examination of the heart with determination of structural and functional parameters of the left (LV) and right ventricles (RV) of the heart was done for all patients. Results. In patients with a polyarticular JIA, LV functional parameters of the heart were within normal values, but compared with similar indicators of adolescents in the control group showed a decrease in of the end-diastolic size (EDS) and of the end-diastolic volume (EDV) of the LV, a decrease in emission fraction (EF) and stroke volume (SV) of the LV, but normal values of the minute blood volume (MVC) of the LV due to an increase in the heart rate. In patients with JIA, a significant increase in both systolic (the end-systolic size and the end-systolic volume) and diastolic (EDS, EDV) parameters of the RV, thickening of it’s myocardium (TM), increase in SV and the MVC, but decrease in EF. Conclusions. Development morphofunctional disorders of the left and especially the right ventricles of the heart in patients with JIA occurs with long periods of illness and the use of basic therapy, as well as with their delayed appointment and low doses of use. The study was carried out in accordance with the principles of the Declaration of Helsinki. Study Protocol adopted by the local ethics committee of the institution specified in the work. For holding studies obtained the informed consent of parents and children. No conflict of interests was declared by the authors.

Abstract 15376: Nrf2 Agonist Omaveloxolone Improves Cardiac Function in Mice With Friedreich's Ataxia

Introduction: Friedreich’s ataxia (FA) is an inherited, life-shortening, degenerative neuromuscular disorder affecting ~1 in every 50,000 people in the USA and Europe. Initial symptoms, typically seen in children and teenagers, include loss of balance and coordination, muscle weakness placing these patients in wheelchairs. Early death is common and most of FA patients die in their 30s or earlier from cardiac failure, caused by deficient frataxin (FXN) expression in the heart. Omaveloxolone (OMAV), a known Nrf-2 activator, has been recently proposed as the first treatment of the neurological symptoms of FA; however less is known about OMAV effects on cardiac function in FA. Aim: To test the hypothesis that OMAV improves cardiac function in a mouse model of FA via Nfr2 signaling pathway activation. Methods and Results: Cardiospecific FXN knockout (FXN Mck-Cre KO) mice were used as a model of severe cardiomyopathy which is characteristic for the late stage of FA. Animals of either sex were randomly split in vehicle and OMAV-treated groups. Treatment with 24 mg/kg OMAV started at 3 weeks of age and continued for 5 weeks. Cardiac function was examined in-vivo by echocardiography. We found that FXN cKO mice developed severe heart failure with 45% reduction in ejection fraction, increased left ventricular (LV) mass (+80%) and diameter (+308%), decreased stroke volume (-26%) and cardiac output (-38%, n=10) as compared to WT mice (n=12). Cardiac deficits were more pronounced in FA males compared to females. OMAV (n=14) significantly decreased LV mass (-24%), LV diameter (-28%), and partially recovered a decrease in ejection fraction (+40%), stroke volume (+22%) and cardiac output (+35%). Gene expression of NADP(H) quinoline oxidoreductase-1 (NQO1), superoxide dismutase 2 (SOD2), and glutathione S-transferase were decreased by 60-90% in FA and recovered by 60-90% by OMAV. Aconitase activity, used as a surrogate measure of frataxin's iron-sulfur biogenesis function, was decreased in FA by 49% and recovered 33% by OMAV. Conclusions: This is the first study to demonstrate sexual dimorphism in FA hearts and show that OMAV can improve cardiac function in FA mice with severe cardiomyopathy.

Abstract 15690: Bioactive Fumarate Improves Cardiac Function and Expands Lifespan in Friedreich's Ataxia

Introduction: Friedreich ataxia (FA) is a monogenic recessive ataxia caused by reduction of a single mitochondrial protein, frataxin (FXN). Although the name of FA refers to the neurodegenerative ataxia, the lethal event is cardiomyopathy, caused by deficient FXN expression in the heart. Previously, we identified that bioactive fumarates are protective in FA cell models. We have developed a novel monomethyl fumarate prodrug, IMF, which has much improved pharmacokinetic profile and compared its effect to the known fumarate prodrug dimethyl fumarate (DMF, Tecfidera). Aim: To test the hypothesis that novel bioactive fumarate improves cardiac function and survival via Nrf2 and HCA 2 signaling pathways activation. Methods and Results: Cardiospecific FXN knockout (FXN Mck-Cre KO) mice were used as a model of severe cardiomyopathy which is characteristic for the late stage of FA. Animals of either sex were randomly split in vehicle and fumarate-treated groups. Animals were treated by IMF or DMF at concentrations which release equimolar amount of monomethyl fumarate. Treatment started at 3 weeks of age and continued for 5 weeks in the cross-sectional study or until animal death in the survival study. Cardiac function was examined in-vivo by echocardiography. We found that FXN Mck-Cre KO mice developed severe heart failure with 45% reduction in ejection fraction, increased left ventricular (LV) mass (+80%) and diameter (+308%), decreased stroke volume (-26%) and cardiac output (-38%, n=10) as compared to WT mice (n=12). Cardiac deficits were more pronounced in FA males compared to females. Both DMF and IMF partially recovered cardiac deficits in FXN Mck-Cre KO mice but only IMF extended the lifespan in these mice by 13%. Expression of genes in Nrf2 (NQO1, SOD2, glutathione S-transferase) and HCA 2 (HCA 2 and Sirt1) signaling pathways were decreased in FXN Mck-Cre KO and restored to a different degree by DMF and IMF. Aconitase activity, used as a surrogate measure of frataxin's iron-sulfur biogenesis function, was decreased in FA by 49% and recovered 18% by IMF only. Conclusions: Novel fumarate prodrug IMF improved cardiac function and expanded the lifespan in FXN Mck-Cre KO mouse model of FA more effectively than DMF.

Modelling patient specific cardiopulmonary interactions

Mechanical ventilation is well known for having detrimental effects on the cardiovascular system, particularly when using high positive end-expiratory pressure. High positive end-expiratory pressure levels cause a decrease in stroke volume, which, under normal conditions, usually bring about a decrease in stressed blood volume. Stressed blood volume, defined as the total pressure generating volume of the cardiovascular system, has been shown to be a potential index of fluid responsiveness, making it a potentially important diagnostic tool. Generally, respiratory and haemodynamic care are provided independently of one another. However, that positive end-expiratory pressure alters both stroke volume and stressed blood volume suggests both the pulmonary and cardiovascular state should be conjointly optimised and used to guide positive end-expiratory pressure. However, the complex and patient-specific nature of cardiopulmonary interactions which occur during mechanical ventilation presents a challenge for accurate modelling of respiratory and cardiovascular interactions required to better optimise care. Previous models attempting to incorporate cardiopulmonary interactions have suffered from poor reliability at higher PEEP levels, largely due to an exaggerated effect of intrathoracic pressure on the cardiovascular system. A new parameter, alpha, is added to a previously validated cardiopulmonary model, to modulate the percentage of intrathoracic pressure applied to the vena cava and left ventricle. The new parameter aims to increase reliability under high PEEP conditions as well as provide a patient specific solution to modelling cardiopulmonary interactions. The results from the identified optimal alpha are compared to the original model to investigate how this new parameter may be used to create a more patient-specific cardiopulmonary model, which would be better suited for guidance of care in the ICU.

Effects of trunk posture on cardiovascular and autonomic nervous systems: A pilot study.

Objective: Although regular and moderate physical activity has been shown to improve the cardiovascular and autonomic nervous systems, little has been done to study the effects of postural changes in the movement on the heart and autonomic nervous system. To uncover changes in cardiac function and autonomic nerves induced by different underlying posture transitions and explore which trunk postures lead to chronic sympathetic activation. Therefore, this study investigated the effects of trunk posture on the cardiovascular and autonomic nervous systems. Methods: Twelve male subjects (age 24.7 ± 1.3) underwent this study. The non-invasive cardiac output NICOM monitoring equipment and the FIRSTBEAT system are used to dynamically monitor seven trunk postures in the sitting position simultaneously (neutral position, posterior extension, forward flexion, left lateral flexion, right lateral flexion, left rotation, right rotation). Each posture was maintained for 3min, and the interval between each movement was 3min to ensure that each index returned to the baseline level. Repeated analysis of variance test was used to compare and analyze the differences in human cardiac function, heart rate variability index, and respiratory rate under different postures. Results: Compared with the related indicators of cardiac output in a neutral trunk position: the cardiac index (CI) was significantly reduced in forwarding flexion and left rotation (3.48 ± 0.34 vs. 3.21 ± 0.50; 3.48 ± 0.34 vs. 3.21 ± 0.46, ΔL/(min/m2)) (p = 0.016, p = 0.013), cardiac output decreased significantly (6.49 ± 0.78 vs. 5.93 ± 0.90; 6.49 ± 0.78 vs. 6.00 ± 0.96, ΔL/min) (p = 0.006, p = 0.014), the stroke volume (stroke volume)decreased significantly (87.90 ± 15.10 vs. 81.04 ± 16.35; 87.90 ± 15.10 vs. 79.24 ± 16.83, Δml/beat) (p = 0.017, p = 0.0003); heart rate increased significantly in posterior extension (75.08 ± 10.43 vs. 78.42 ± 10.18, Δbeat/min) (p = 0.001); left rotation stroke volume index (SVI) decreased significantly (47.28 ± 7.97 vs. 46.14 ± 8.06, Δ ml/m2) (p = 0.0003); in the analysis of HRV-related indicators, compared with the neutral trunk position, the LF/HF of the posterior extension was significantly increased (1.90 ± 1.38 vs. 3.00 ± 1.17, p = 0.037), and the LF/HF of the forward flexion was significantly increased (1.90 ± 1.38 vs. 2.85 ± 1.41, p = 0.041), and the frequency-domain index LF/HF of right rotation was significantly increased (1.90 ± 1.38 vs. 4.06 ± 2.19, p = 0.008). There was no significant difference in respiratory rate (p > 0.05). Conclusion: A neutral trunk is the best resting position, and deviations from a neutral trunk position can affect the cardiovascular and autonomic nervous systems, resulting in decreased stroke volume, increased heart rate, and relative activation of sympathetic tone.

IL-1β is not critical to chronic heart dysfunction in mice with Chagas disease.

Long after Trypanosoma cruzi infection, 40% of individuals develop a progressive chronic chagasic cardiomyopathy (CCC), with systolic dysfunction and arrhythmias. Since we previously showed IL-1β mediates the development of systolic dysfunction and cardiac arrhythmias in diabetes mellitus and cardiorenal syndrome, and IL-1β remains elevated in Chagas disease patients, here we tested the role of IL-1β in CCC using a mouse model. Mice deficient in IL-1R expression (Il-1r-/- ) survived acute T. cruzi infection with greater parasitemia than controls but did not lose weight as wild-type (WT) did. At the chronic stage, WT presented prolonged ventricular repolarization intervals (QJ), while Il-1r-/- presented intervals like noninfected controls. Infected Il-1r-/- and WT did not differ in stroke volume (SV), the incidence of cardiac arrhythmias on electrocardiography (EKG), whole heart action potential duration (APD), or the incidence of triggered activity after S1-S2 protocol, which is a measure of susceptibility to cardiac arrhythmias. We also treated chronically infected WT mice with an IL-1R antagonist, anakinra. Treatment shortened the QJ interval but did not improve the SV or the incidence of cardiac arrhythmias on EKG. Anakinra failed to reduce triggered activity following the electrical extra-stimulation protocol. In conclusion, the absence of functional IL-1β/IL-1R signaling did not prevent or reverse the decrease of SV or the incidence of cardiac arrhythmias induced by chronic T. cruzi infection, implying this is not a critical mechanism in generating or maintaining CCC. Since similar cardiac abnormalities were previously credited to IL-1β signaling, ruling out this mechanism is important to discourage further attempts of IL-1β blockade as a therapeutical measure.

The electrocardiographic, hemodynamic, echocardiographic, and biochemical evaluation of treatment with edaravone on acute cardiac toxicity of aluminum phosphide

Aluminum phosphide (AlP) poisoning can be highly fatal due to its severe toxicity to the heart. Based on the evidence, edaravone (EDA) has protective effects on various pathological conditions of the heart. This research aimed to examine the potential protective effects of EDA on AlP-induced cardiotoxicity in rats. The rats were divided into six groups, including almond oil (control), normal saline, AlP (LD50), and AlP + EDA (20, 30, and 45 mg/kg). Thirty minutes following AlP poisoning, the electrocardiographic (ECG), blood pressure (BP), and heart rate (HR) parameters were examined for 180 min. The EDA was injected 60 min following the AlP poisoning intraperitoneally. Also, 24 h after poisoning, echocardiography was carried out to evaluate the ejection fraction (EF), stroke volume (SV), and cardiac output (CO). The biochemical and molecular parameters, such as the activities of the mitochondrial complexes, reactive oxygen species (ROS), apoptosis and necrosis, and troponin I and lactate levels, were also examined after 12 and 24 h in the heart tissue. According to the results, AlP-induced ECG abnormalities, decrease in blood pressure, heart rate, SV, EF%, and CO were significantly improved with EDA at doses of 30 and 45 mg/kg. Likewise, EDA significantly improved complex I and IV activity, apoptosis and necrosis, ROS, troponin I, and lactate levels following AlP-poisoning (p < 0.05). Also, the mean survival time was increased following EDA treatment, which can be attributed to the EDA’s protective effects against diverse underlying mechanisms of phosphine-induced cardiac toxicity. These findings suggest that EDA, by ameliorating heart function and modulating mitochondrial activity, might relieve AlP-induced cardiotoxicity. Nonetheless, additional investigations are required to examine any potential clinical advantages of EDA in this toxicity.

Unique cardiac remodeling in young adults born Small for Gestational Age with subsequent central obesity

Abstract Background Being born small-for-gestational age (SGA, 10 percent of all births) is associated with increased risk of cardiovascular mortality (1,2) in adulthood together with lower exercise tolerance (3), but mechanistic pathways are unclear. Central obesity is known to worsen cardiovascular outcomes, but it is uncertain how it affects the heart in adults born SGA. Purpose We aimed to assess whether central obesity makes young adults born SGA more susceptible to cardiac remodelling and dysfunction. Methods A perinatal cohort study including 80 young adults born SGA (birth weight below 10th centile) and 75 adults with normal birth weight (controls). Current waist-to-hip ratio was used as a surrogate of central obesity. Cardiac structure and function were assessed by cardiac magnetic resonance. Statistical shape analysis was used to study the regional geometric variability of the biventricular surfaces produced by central obesity and SGA, and synthetic surfaces representative of obese and non obese were generated for both SGA and controls. Results Figure 1 shows the superimposed representative surfaces of obese and non-obese according to our model, for controls (right column) and SGA (left column). Both SGA and waist-to-hip were highly associated to cardiac shape (F=3.94 p&amp;lt;0.001; F=5.18 p&amp;lt;0.001 respectively) with a statistically significant interaction (F=2.29, p=0.02), indicating a different cardiac remodelling due to obesity in SGA. While controls tend to increase left ventricular end-diastolic volumes, mass and stroke volume with increasing waist-to-hip ratio, young adults born SGA showed unique response with inability to increase cardiac dimensions or mass resulting in reduced stroke volume (both in absolute values and indexed by body surface area) and increased heart rate. Conclusions SGA young adults show unique cardiac adaptation to central obesity, which is associated with a decrease in stroke volume. Preventive strategies aiming to reduce cardiometabolic risk in SGA population may be warranted. Funding Acknowledgement Type of funding sources: Public grant(s) – EU funding. Main funding source(s): European Union Horizon 2020 Programme