Development of a Spinal Cord Injury Model Permissive to Study the Cardiovascular Effects of Rehabilitation Approaches Designed to Induce Neuroplasticity

As primary medical care for spinal cord injury (SCI) has improved over the last decades there are more individuals living with neurologically incomplete (vs. complete) cervical injuries. For these individuals, a number of promising therapies are being actively researched in pre-clinical settings that seek to strengthen the remaining spinal pathways with a view to improve motor function. To date, few, if any, of these interventions have been tested for their effectiveness to improve autonomic and cardiovascular (CV) function. As a first step to testing such therapies, we aimed to develop a model that has sufficient sparing of descending sympathetic pathways for these interventions to target yet induces robust CV impairment. Twenty-six Wistar rats were assigned to SCI (n = 13) or naïve (n = 13) groups. Animals were injured at the T3 spinal segment with 300 kdyn of force. Fourteen days post-SCI, left ventricular (LV) and arterial catheterization was performed to assess in vivo cardiac and hemodynamic function. Spinal cord lesion characteristics along with sparing in catecholaminergic and serotonergic projections were determined via immunohistochemistry. SCI produced a decrease in mean arterial pressure of 17 ± 3 mmHg (p < 0.001) and left ventricular contractility (end-systolic elastance) of 0.7 ± 0.1 mmHg/µL (p < 0.001). Our novel SCI model produced significant decreases in cardiac and hemodynamic function while preserving 33 ± 9% of white matter at the injury epicenter, which we believe makes it a useful pre-clinical model of SCI to study rehabilitation approaches designed to induce neuroplasticity.

Effect of moderate physical exercises on the relationship of variability of the heart rhythm with the level of blood pressure and hemodynamic functions in women with essential hypertension

Цель исследования - изучение взаимосвязи между вариабельностью сердечного ритма (ВСР) системой гемостаза и гемодинамическими функциями у женщин больных эссенциальной гипертензией (ГБ) в зависимости от методов применяемой терапии. Методика. Под наблюдением находились 72 женщины, страдающие гипертонической болезнью. Обследовано 2 группы пациенток: 1-я группа (ГБ-1) находилась на медикаментозной терапии, 2-я (ГБ-2) - наряду с медикаментозной терапией регулярно на протяжении 2-3 лет проходила не менее 3 полуторамесячных курсов кинезитерапии. Для изучения гемодинамики был использован датчик динамического рассеяния света (miniature Dynamic Light Scattering - mDLS) от Elfi-Tech (Rehovot, Israel), измеряющий сигналы, инициированные кожным кровотоком и использующий методику разложения сигнала на частотные компоненты, связанные с разными гемодинамическими источниками. Из пульсовой компоненты mDLS сигнала извлекалась информация о вариабельности RR интервалов, и рассчитывались индикаторы вариабельности сердечного ритма. Изучали показатели свёртывающей системы крови: активированное парциальное тромбопластиновое время - (АПТВ), протромбиновое время (ПТВ) с вычислением МНО, тромбиновое время (ТВ), концентрация фибриногена, факторов II (протромбин), IIa (тромбин), IX и Х [10]. Кроме перечисленных методов исследования определялся пространственный рост фибринового сгустка, осуществляемый с помощью прибора «Регистратор Тромбодинамики Т-2». Достоинством способа является его объективность и то, что программой предусмотрена фоторегистрация роста сгустка через 5, 15 и 30 мин. Результаты. Как в группе ГБ-1, так и ГБ-2 выявлены многочисленные корреляционные связи между различными показателями ВСР, системы гемостаза и гемодинамических Данные представленные в виде матрицы свидетельствуют о том, что сдвиги в системе гемостаза и гемодинамики у больных ГБ-1, обусловленные деятельностью сердца и осуществляемые при участии как симпатического, так и парасимпатического отделов АНС способствуют возникновению тромботических осложнений. В то же время у больных ГБ-2 ВСР практически не коррелирует с показателями системы гемостаза и в меньшей степени связана с гемодинамические функции, благодаря чему состояние гемостаза и гемодинамики приближается к показателям здоровых женщин. Между тем, выявленные взаимосвязи между системой гемостаза и гемодинамическими функциями как у больных ГБ-1, так и ГБ-2 направлены на предотвращение внутрисосудистого свёртывания крови. Заключение. Применение систематической умеренной физической нагрузки на протяжении 2 - 3 лет способствует нормализации взаимоотношений между ВСР, системой гемостаза и гемодинамическими функциями у больных ГБ и способствует более устойчивой нормализации кровяного давления. Aim. To study the relationship between heart rate variability (HRV), hemostasis, and hemodynamic functions in women with essential hypertension (EH), depending on the method of therapy. Methods. 72 women with hypertension were monitored. Two patient groups were evaluated: the first group (EH-1) had recceived only drug therapy and the second group (EH-2), in addition to drug therapy, had regularly participated in at least three 1.5 mos long courses of kinesitherapy over a 2-3 years period. To study hemodynamics, we used a miniature Dynamic Light Scattering (mDLS) sensor from Elfi-Tech (Rehovot, Israel), which measures signals initiated by skin blood flow and uses a technique for decomposing the signal into frequency components associated with different hemodynamic sources. Information on the variability of RR intervals was extracted from the pulse component of the mDLS signal, and parameters of heart rate variability were calculated. Indexes of the coagulation system were studied, including activated partial thromboplastin time (APTT), prothrombin time (PTT) with calculation of INR, thrombin time (TT), concentrations of fibrinogen and factors II (prothrombin), IIa (thrombin), IX, and X [10]. In addition, spatial fibrin clot growth was determined with a Thrombodynamics Registrator T-2 apparatus. The method benefits are its objectivity and a possibility of photorecording of the clot growth at 5, 15 and 30 min. Results. Both in the EH-1 and EH-2 groups, numerous correlations were detected between various parameters of HRV, the hemostatic system, and hemodynamic functions, as well as between the parameters of the hemostatic system and hemodynamic functions. The data are presented in the form of a matrix. The data indicate that shifts in the hemostatic and hemodynamic systems of EH-1 patients induced by cardiac activity and resulting from activities of both the sympathetic and parasympathetic sections of the autonomic nervous system (ANS) are aimed at enhancing the hemostatic properties of blood, and this contributes to thrombotic complications. At the same time, in EH-2 patients, HRV had practically no effect on the hemostatic system and to a lesser extent was related with the hemodynamic function. Due to this, the state of hemostasis and hemodynamics in EH-2 patients approaches the state found in healthy women. In addition, the relationship between the hemostatic system and hemodynamic function in both EH-1 and EH-2 patients are aimed at preventing intravascular coagulation. Conclusion. The use of systematic, moderate physical activity for 2 to 3 years helps hypertensive patients to normalize the relationship between HRV, the hemostatic system, and hemodynamic functions. This contributes to a more normal and stable blood pressure.

Kidney hemodynamic function in men and postmenopausal women with type 2 diabetes and preserved kidney function

Background Progression of kidney disease may differ between sexes in type 2 diabetes (T2D), with studies reporting slower decline in women. Glomerular hyperfiltration is a key factor driving kidney function decline. The current study aims to investigate the differences in kidney hemodynamic function between men and women with T2D. Methods A cross-sectional analysis of pooled data from three studies comparing kidney hemodynamic function between men and postmenopausal women with T2D without overt nephropathy. The outcome measures were GFR (inulin clearance), effective renal plasma flow (ERPF; para-aminohippurate clearance), filtration fraction (GFR/ERPF) and renal vascular resistance (RVR; mean arterial pressure/RBF). Glomerular hydraulic pressure (PGLO), afferent and efferent vascular resistance were estimated by Gomez-formulae. Sex differences were assessed with linear regression models adjusted for systolic blood pressure, glucose, use of renin-angiotensin-system blockers and body mass index. Results 101 men (age: 63[58-68] years; BMI 31.5±3.9 kg/m2; GFR 111±18 mL/min; HbA1c 7.4±0.7%) and 27 women (age: 66[62-69] years; BMI 30.9±4.5 kg/m2; GFR 97±11 mL/min; HbA1c 7.1±0.5%) were included. GFR was higher in men versus women (11.0 mL/min; [95%CI; 3.6;18.4]). Although statistically non-significant, PGLO trended higher in men (1.9 mmHg [95%CI; -0.1;4.0], while RVR (-0.012 mmHg/L/min [95%CI; -0.022;-0.002]) and afferent vascular resistance were lower (-361 dyne/sec/cm5 [95%CI;-801;78]). Conclusions In adults without overt nephropathy, GFR was higher in men compared to women. PGLO also trended to be higher in men. Both findings are possibly related to afferent vasodilation and suggest greater prevalence of hyperfiltration. This could contribute to accelerated GFR loss over time in men with T2D.

Aerobic Continuous and Interval Training under Hypoxia Enhances Endurance Exercise Performance with Hemodynamic and Autonomic Nervous System Function in Amateur Male Swimmers

Hypoxic training is often performed by competitive swimmers to enhance their performance in normoxia. However, the beneficial effects of aerobic continuous and interval training under hypoxia on hemodynamic function, autonomic nervous system (ANS) function, and endurance exercise performance remain controversial. Here we investigated whether six weeks of aerobic continuous and interval training under hypoxia can improve hematological parameters, hemodynamic function, ANS function, and endurance exercise performance versus normoxia in amateur male swimmers. Twenty amateur male swimmers were equally assigned to the hypoxic training group or normoxic training group and evaluated before and after six weeks of training. Aerobic continuous and interval training in the hypoxia showed a more significantly improved hemodynamic function (heart rate, −653.4 vs. −353.7 beats/30 min; oxygen uptake, −62.45 vs. −16.22 mL/kg/30 min; stroke volume index, 197.66 vs. 52.32 mL/30 min) during submaximal exercise, ANS function (root mean square of successive differences, 10.15 vs. 3.32 ms; total power, 0.72 vs. 0.20 ms2; low-frequency/high-frequency ratio, −0.173 vs. 0.054), and endurance exercise performance (maximal oxygen uptake, 5.57 vs. 2.26 mL/kg/min; 400-m time trial record, −20.41 vs. −7.91 s) than in the normoxia. These indicate that hypoxic training composed of aerobic continuous and interval exercise improves the endurance exercise performance of amateur male swimmers with better hemodynamic function and ANS function.

Hemodynamic Function of the Right Ventricular-Pulmonary Vascular-Left Atrial Unit: Normal Responses to Exercise in Healthy Adults

With each heartbeat, the right ventricle (RV) inputs blood into the pulmonary vascular (PV) compartment which conducts blood through the lungs at low pressure and concurrently fills the left atrium (LA) for output to the systemic circulation. This overall hemodynamic function of the integrated RV-PV-LA unit is determined by complex interactions between the components that vary over the cardiac cycle but are often assessed in terms of mean pressure and flow. Exercise challenges these hemodynamic interactions as cardiac filling increases, stroke volume augments, and cycle length decreases, with PV pressures ultimately increasing in association with cardiac output. Recent cardio-pulmonary exercise hemodynamic studies have enriched the available data from healthy adults, yielded insight into the underlying mechanisms which modify the PV pressure-flow relationship, and better delineated the normal limits of healthy responses to exercise. This review will examine hemodynamic function of the RV-PV-LA unit using the 2-element Windkessel model for the pulmonary circulation. It will focus on acute PV and LA responses that accommodate increased RV output during exercise, including PV recruitment and distension and LA reservoir expansion, and the integrated mean pressure-flow response to exercise in healthy adults. Finally, it will consider how these responses may be impacted by age-related remodeling and modified by sex-related cardio-pulmonary differences. Studying the determinants and recognizing the normal limits of PV pressure-flow relations during exercise will improve our understanding of cardio-pulmonary mechanisms that facilitate or limit exercise.

Abstract 17087: Mesenchymal Stem Cell-Derived Extracellular Vesicle Therapy Delivered in a Hydrogel Preserves Hemodynamic Function Following Myocardial Infarction

Introduction: Mesenchymal Stem Cell (MSC)-derived Extracellular Vesicles (EVs) are an emerging regenerative therapy for treatment of ischemic cardiomyopathy. In this study, we determine the efficacy of MSC-EV therapy in a shear-thinning hydrogel (STG) delivered via intramyocardial injection to the border zone of rat hearts following myocardial infarction (MI). Hypothesis: MSC EV-loaded STGs will preserve hemodynamic function and minimize ventricular scar formation in a rat model of acute MI. Methods: EVs were isolated from MSCs by PEG precipitation, and the EV proteome was characterized by MaxQuant 1.5.1.2 and Metacore analysis software. Varying concentrations of EVs were administered to rats following induction of acute MI by ligation of the left anterior descending artery. EVs were delivered in either sterile phosphate buffered saline (PBS) or STG for sustained EV release. Chronic injury was assessed at 4 weeks post-MI through transthoracic echocardiography, intraventricular pressure-volume loop displacement, and histology. Results: MSC EV proteomic analysis highlighted upregulation of VEGF angiogenic cascades and ILK-mediated proliferative pathways. The mean left ventricle ejection fraction (LVEF) for each treatment group at four weeks is displayed in Table 1. A 20 ug dose of MSC EVs in STG improved LVEF by 19.12% (p<0.05) compared to PBS, with a 90 ug dose of MSC EVs in STG increasing LVEF by 23.56% (p<0.01) (Fig. 1). Conclusions: Intramyocardial injection of MSC EVs in STG post-MI showed concentration dependent improvements in hemodynamics. These findings show that high doses of MSC EV in STG may have potential as a therapy for ischemic cardiomyopathy. Proteomic analysis revealed that angiogenesis, recruitment of cardiac progenitor cells, and immune modulation may be mechanistic drivers of MSC-EV therapy.