Reduced Stroke Volume Research Articles

Paradoxical increase in left atrial strains early after Covid-19 infection, a result of comprehensive recovery phase four-chamber strains study.

Cardiac consequences of Covid-19 infection have been mentioned in various studies as a serious risk factor for in-hospital mortality. However, the existence of residual cardiac dysfunction after the acute phase is seldom investigated especially in people without a history of specific medical disease.One hundred health care workers with positive reverse transcription-polymerase chain reaction test underwent comprehensive 2D and 3D echocardiography six to eight weeks after infection. Patients were classified into Mild, Moderate, and Severe groups based on their clinical characteristics of covid-19 infection, and all echocardiographic parameters were compared between the three groups. Left ventricular (LV) stroke volume index was reduced in all groups compared to normal ranges and was more prominent in the severe group (P-value < 0.05). 3D-derived LV global longitudinal strain (GLS) was significantly lower in the severe group in comparison to the mild group (- 19.3 ± 1 Vs. - 22.2 ± 2, P-value < 0.001) and correlated with highly sensitive CRP level at the acute phase. Left atrial (LA) strains, including LA peak strain, LA contraction strain, and LA reservoir strain, were considerably higher and LA volume index was significantly lower in the clinically severe covid patients. Analysis based on the extent of lung involvement showed significantly increased 3D-derived right ventricular volumes in patients who experienced severe pneumonia despite normalized strains. Conclusion: subclinical LV dysfunction as reduced stroke volume index and GLS exists in the early recovery phase of normal individuals with severe course of covid-19. LA function indicated by LA strains paradoxically increases in severe covid-19 infection in this phase.

Hypocapnia increases heart rate in patients with Postural Orthostatic Tachycardia Syndrome (POTS)

Background: Postural Orthostatic Tachycardia Syndrome (POTS) is characterized by chronic orthostatic intolerance and significantly impacts quality of life of patients. POTS predominantly affects women of child-bearing age with an estimated prevalence of up to 1%. POTS is defined by an excessive increase in heart rate (HR) of ≥30 bpm within 10 minutes of upright posture, in the absence of orthostatic hypotension. POTS is associated with chronic symptoms (≥6 months) including hyperventilation (HV) in the form of hyperpnea. HV reduces arterial CO 2 (hypocapnia) and worsens tachycardia in POTS. Whether it is hypocapnia that increases HR in these patients is unclear. Studies have not investigated the effects of CO 2 on HR due to the confounding effects of posture and ventilation. Objective: We aimed to determine if hypocapnia exacerbates tachycardia in POTS patients. Hypothesis: We hypothesize that hypocapnia will increase HR in POTS. Methods: We conducted a randomized crossover trial of hypocapnic HV vs. eucapnic HV in 13 female POTS patients (34±9 y). Participants completed the supine breathing protocol: 1) HV with resultant hypocapnia, and 2) HV (with end-tidal CO 2 (ETCO 2 ) clamped at baseline). Breath-by-breath respiratory (ventilation (V E ), tidal volume (V T ), ETCO 2 , end-tidal O 2 (ETO 2 )) and beat-to-beat hemodynamics (HR, stroke volume (SV), cardiac output (CO)) were measured. Data are reported as mean±SD. Paired t-tests were used to compare respiratory and hemodynamic parameters between hypocapnic HV vs. eucapnic HV. Results: During HV, ETCO 2 was significantly lower during hypocapnia vs. eucapnia (19.6±3.7 mmHg vs. 37.4±3.5 mmHg; p&lt;0.0001). ETO 2 was greater during hypocapnia vs eucapnia (117.4±4.7 mmHg vs. 114.6±3.1 mmHg; p&lt;0.001). There was no difference in V E (22.2±6.5 L/min vs. 22.0±5.1 L/min; p=0.8) or V T (1.4±0.4 L vs. 1.4±0.3 L; p=0.9) between hypocapnia and eucapnia. HR was significantly greater during hypocapnia vs. eucapnia (99±12 bpm vs 82±10 bpm; p&lt;0.001); SV was significantly lower during hypocapnia vs. eucapnia (66±14 mL vs. 74±13 mL; p=0.02); and there was no difference in CO between hypocapnia and eucapnia (6.4±1.3 L/min vs. 6.1±1.6 L/min; p=0.3). Conclusion: Independent of ventilation, hypocapnia increases HR in patients with POTS. Our findings suggests that hypocapnia causes a reduction in SV, perhaps due to increased blood pooling in the capacitance vessels leading to reduced venous return. This work was supported by Standing up to POTS. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

PO-01-126 SEXUAL DIMORPHISM AND CARDIAC ARRHYTHMIAS IN A MOUSE MODEL OF FRIEDREICH'S ATAXIA: WHAT DO WE KNOW?

Friedreich ataxia (FA) is a monogenic recessive disorder caused by the reduction of the mitochondrial protein, frataxin (FXN). Despite neurological deficits place patients with FA in the wheelchairs, most patients die from lethal cardiomyopathy in their 40s. FA patients develop progressive cardiac disease with characteristics similar to primary hypertrophic cardiomyopathy but with more progressive cardiac fibrosis, both diastolic and systolic dysfunction, and arrhythmias. However, the mechanisms leading to cardiomyopathy and arrhythmias in FA patients are poorly understood. To characterize electrical signal propagation and cardiac function in a mouse model which imitates the late-stage cardiomyopathy in FA patients. Cardiac-specific McK-Cre FXN knockout (FXN cKO) mice were used as a model of severe cardiomyopathy which is characteristic for the late-stage of FA. Due to premature death, animals of either sex at 8-weeks of age were used to assess cardiac function in-vivo by echocardiography and surface electrocardiogram (ECG). We found that FXN cKO mice developed idiosyncratic arrhythmias with varying time durations for beat-to-beat (RR) intervals and heart rate variability (HRV) parameters such as root mean squared successive differences (RMSSD, p<0.0358), revealing increased vagal activity. Mice presented extended P-wave (p<0.0113) and QTc intervals (>150 ms, p<0.0015), suggesting impaired atrial and left-ventricular function, resembling human patients. HRV frequency parameters showed increased low-frequency (0.023), high-frequency (p<0.264) and total (p<0.0326) power. Non-linear parameters showed varying short-term variation (SD1, p<0.019), increased long-term variation (SD2, p<0.0017) and ellipse area values (S, p<0.0074). Poincare plots of FXN cKO males included multiple clustering of RR and RR+1 identities while females generally sustained a single clustered ellipse (area, p<0.028). Similarly, QTc intervals were increased mostly in FXN cKO males. Contractile dysfunction was also more severe in FXN cKO males as evident by reduction in left ventricular fractional shortening, ejection fraction, stroke volume and cardiac output. Our study revealed sexual dimorphism and significant impairment in electrical and contractile function in FXN cKO males compared to females. A detailed characterization of impaired electrical signals in FA hearts will build a platform for drug testing to treat lethal cardiomyopathy in FA.

Differences in radiation-induced heart dysfunction in male versus female rats

Purpose Radiation therapy remains part of the standard of care for breast, lung, and esophageal cancers. While radiotherapy improves local control and survival, radiation-induced heart dysfunction is a common side effect of thoracic radiotherapy. Cardiovascular dysfunction can also result from non-therapeutic total body radiation exposures. Numerous studies have evaluated the relationship between radiation dose to the heart and cardiotoxicity, but relatively little is known about whether there are differences based on biological sex in radiation-induced heart dysfunction (RIHD). Materials and Methods We evaluated whether male and female inbred Dahl SS rats display differences in RIHD following delivery of 24 Gy in a single fraction to the whole heart using a 1.5 cm beam size (collimater). We also compared the 2.0 cm vs. 1.5 cm collimator in males. Pleural and pericardial effusions and normalized heart weights were measured, and echocardiograms were performed. Results Female SS rats displayed more severe RIHD relative to age-matched SS male rats. Normalized heart weight was significantly increased in females, but not in males. A total of 94% (15/16) of males and 55% (6/11) of females survived 5 months after completion of radiotherapy (p < .01). Among surviving rats, 100% of females and 14% of males developed moderate-to-severe pericardial effusions at 5 months. Females demonstrated increased pleural effusions, with the mean normalized pleural fluid volume for females and males being 56.6 mL/kg ± 12.1 and 10.96 mL/kg ± 6.4 in males (p = .001), respectively. Echocardiogram findings showed evidence of heart failure, which was more pronounced in females. Because age-matched female rats have smaller lungs, a higher percentage of the total lung was treated with radiation in females than males using the same beam size. After using a larger 2 cm beam in males which results in higher lung exposure, there was not a significant difference between males and females in terms of the development of moderate-to-severe pericardial effusions or pleural effusions. Treatment of males with a 2 cm beam resulted in comparable increases in LV mass and reductions in stroke volume to female rats treated with a 1.5 cm beam. Conclusion Together, these results illustrate that there are differences in radiation-induced cardiotoxicity between male and female SS rats and add to the data that lung radiation doses, in addition to other factors, may play an important role in cardiac dysfunction following heart radiation exposure. These factors may be important to factor into future mitigation studies of radiation-induced cardiotoxicity.

Dipeptidyl Amino-Peptidase 3 (DPP3) as an Early Marker of Severity in a Patient Population with Cardiogenic Shock.

Dipeptidyl amino-peptidase 3 (DPP3) is an aminopeptidase that is released into circulation upon cell death. DPP3 is involved in the degradation of angiotensins, enkephalines, and endomorphines. It has been shown that circulating DPP3 (cDPP3) plasma concentration increases in cardiogenic shock (CS) patients and correlates with high mortality risk. Cardiogenic shock is a life-threatening syndrome associated with organ hypoperfusion. One of the common causes of CS is acute myocardial infarction (AMI). This study aimed to investigate if cDPP3 levels are associated with CS severity and the need for ventilation in patients suffering from CS. Fifteen patients with CS were included in this study. Six patients were invasively ventilated. The values of cDPP3 were higher in ventilated patients than in non-ventilated patients at admission, 3 h, and 24 h after admission in the intensive care unit. Patients with pulmonary hypertension at admission also showed high cDPP3 values at all time points. Furthermore, high cDPP3 levels were associated with reduced stroke volume. Our results suggest that cDPP3 could predict CS progression and guide therapy escalation.

Repurposing the mucolytic agent ambroxol for treatment of sub-acute and chronic ischaemic stroke.

Ambroxol is a well-known mucolytic expectorant, which has gained much attention in amyotrophic lateral sclerosis, Parkinson's and Gaucher's disease. A specific focus has been placed on ambroxol's glucocerebrosidase-stimulating activity, on grounds that the point mutation of the gba1 gene, which codes for this enzyme, is a risk factor for developing Parkinson's disease. However, ambroxol has been attributed other characteristics, such as the potent inhibition of sodium channels, modification of calcium homeostasis, anti-inflammatory effects and modifications of oxygen radical scavengers. We hypothesized that ambroxol could have a direct impact on neuronal rescue if administered directly after ischaemic stroke induction. We longitudinally evaluated 53 rats using magnetic resonance imaging to examine stroke volume, oedema, white matter integrity, resting state functional MRI and behaviour for 1 month after ischemic stroke onset. For closer mechanistic insights, we evaluated tissue metabolomics of different brain regions in a subgroup of animals using ex vivo nuclear magnetic resonance spectroscopy. Ambroxol-treated animals presented reduced stroke volumes, reduced cytotoxic oedema, reduced white matter degeneration, reduced necrosis, improved behavioural outcomes and complex changes in functional brain connectivity. Nuclear magnetic resonance spectroscopy tissue metabolomic data at 24 h post-stroke proposes several metabolites that are capable of minimizing post-ischaemic damage and that presented prominent shifts during ambroxol treatment in comparison to controls. Taking everything together, we propose that ambroxol catalyzes recovery in energy metabolism, cellular homeostasis, membrane repair mechanisms and redox balance. One week of ambroxol administration following stroke onset reduced ischaemic stroke severity and improved functional outcome in the subacute phase followed by reduced necrosis in the chronic stroke phase.

Exaggerated postural sway improves orthostatic cardiovascular and cerebrovascular control.

Healthy individuals with poor cardiovascular control, but who do not experience syncope (fainting), adopt an innate strategy of increased leg movement in the form of postural sway that is thought to counter orthostatic (gravitational) stress on the cardiovascular system. However, the direct effect of sway on cardiovascular hemodynamics and cerebral perfusion is unknown. If sway produces meaningful cardiovascular responses, it could be exploited clinically to prevent an imminent faint. Twenty healthy adults were instrumented with cardiovascular (finger plethysmography, echocardiography, electrocardiogram) and cerebrovascular (transcranial Doppler) monitoring. Following supine rest, participants performed a baseline stand (BL) on a force platform, followed by three trials of exaggerated sway (anterior-posterior, AP; mediolateral, ML; square, SQ) in a randomized order. All exaggerated postural sway conditions improved systolic arterial pressure (SAP, p = 0.001) responses, while blunting orthostatic reductions in stroke volume (SV, p < 0.01) and cerebral blood flow (CBFv, p < 0.05) compared to BL. Markers of sympathetic activation (power of low-frequency oscillations in SAP, p < 0.001) and maximum transvalvular flow velocity (p < 0.001) were reduced during exaggerated sway conditions. Responses were dose-dependent, with improvements in SAP (p < 0.001), SV (p < 0.001) and CBFv (p = 0.009) all positively correlated with total sway path length. Coherence between postural movements and SAP (p < 0.001), SV (p < 0.001) and CBFv (p = 0.003) also improved during exaggerated sway. Exaggerated sway improves cardiovascular and cerebrovascular control and may supplement cardiovascular reflex responses to orthostatic stress. This movement provides a simple means to boost orthostatic cardiovascular control for individuals with syncope, or those with occupations that require prolonged motionless standing.

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.

Augmented Ouabain-Induced Vascular Response Reduces Cardiac Efficiency in Mice with Migraine-Associated Mutation in the Na+, K+-ATPase α2-Isoform

Heterozygous mice (α2+/G301R mice) for the migraine-associated mutation (G301R) in the Na+,K+-ATPase α2-isoform have decreased expression of cardiovascular α2-isoform. The α2+/G301R mice exhibit a pro-contractile vascular phenotype associated with decreased left ventricular ejection fraction. However, the integrated functional cardiovascular consequences of this phenotype remain to be addressed in vivo. We hypothesized that the vascular response to α2-isoform-specific inhibition of the Na+,K+-ATPase by ouabain is augmented in α2+/G301R mice leading to reduced cardiac efficiency. Thus, we aimed to assess the functional contribution of the α2-isoform to in vivo cardiovascular function of wild-type (WT) and α2+/G301R mice. Blood pressure, stroke volume, heart rate, total peripheral resistance, arterial dP/dt, and systolic time intervals were assessed in anesthetized WT and α2+/G301R mice. To address rate-dependent cardiac changes, cardiovascular variables were compared before and after intraperitoneal injection of ouabain (1.5 mg/kg) or vehicle during atrial pacing. The α2+/G301R mice showed an enhanced ouabain-induced increase in total peripheral resistance associated with reduced efficiency of systolic development compared to WT. When the hearts were paced, ouabain reduced stroke volume in α2+/G301R mice. In conclusion, the ouabain-induced vascular response was augmented in α2+/G301R mice with consequent suppression of cardiac function.

Dynamic MRI of the Mesenchymal Stem Cells Distribution during Intravenous Transplantation in a Rat Model of Ischemic Stroke.

Systemic transplantation of mesenchymal stem cells (MSCs) is a promising approach for the treatment of ischemia-associated disorders, including stroke. However, exact mechanisms underlying its beneficial effects are still debated. In this respect, studies of the transplanted cells distribution and homing are indispensable. We proposed an MRI protocol which allowed us to estimate the dynamic distribution of single superparamagnetic iron oxide labeled MSCs in live ischemic rat brain during intravenous transplantation after the transient middle cerebral artery occlusion. Additionally, we evaluated therapeutic efficacy of cell therapy in this rat stroke model. According to the dynamic MRI data, limited numbers of MSCs accumulated diffusely in the brain vessels starting at the 7th minute from the onset of infusion, reached its maximum by 29 min, and gradually eliminated from cerebral circulation during 24 h. Despite low numbers of cells entering brain blood flow and their short-term engraftment, MSCs transplantation induced long lasting improvement of the neurological deficit, but without acceleration of the stroke volume reduction compared to the control animals during 14 post-transplantation days. Taken together, these findings indicate that MSCs convey their positive action by triggering certain paracrine mechanisms or cell-cell interactions or invoking direct long-lasting effects on brain vessels.

The Impact of Standard Ablation Strategies for Atrial Fibrillation on Cardiovascular Performance in a Four-Chamber Heart Model

PurposeAtrial fibrillation is one of the most frequent cardiac arrhythmias in the industrialized world and ablation therapy is the method of choice for many patients. However, ablation scars alter the electrophysiological activation and the mechanical behavior of the affected atria. Different ablation strategies with the aim to terminate atrial fibrillation and prevent its recurrence exist but their impact on the performance of the heart is often neglected.MethodsIn this work, we present a simulation study analyzing five commonly used ablation scar patterns and their combinations in the left atrium regarding their impact on the pumping function of the heart using an electromechanical whole-heart model. We analyzed how the altered atrial activation and increased stiffness due to the ablation scars affect atrial as well as ventricular contraction and relaxation.ResultsWe found that systolic and diastolic function of the left atrium is impaired by ablation scars and that the reduction of atrial stroke volume of up to 11.43% depends linearly on the amount of inactivated tissue. Consequently, the end-diastolic volume of the left ventricle, and thus stroke volume, was reduced by up to 1.4 and 1.8%, respectively. During ventricular systole, left atrial pressure was increased by up to 20% due to changes in the atrial activation sequence and the stiffening of scar tissue.ConclusionThis study provides biomechanical evidence that atrial ablation has acute effects not only on atrial contraction but also on ventricular performance. Therefore, the position and extent of ablation scars is not only important for the termination of arrhythmias but is also determining long-term pumping efficiency. If confirmed in larger cohorts, these results have the potential to help tailoring ablation strategies towards minimal global cardiovascular impairment.

Association of central obesity with unique cardiac remodelling in young adults born small for gestational age.

Being born small for gestational age (SGA, 10% of all births) is associated with increased risk of cardiovascular mortality in adulthood together with lower exercise tolerance, 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. We aimed to assess whether central obesity makes young adults born SGA more susceptible to cardiac remodelling and dysfunction. A perinatal cohort from a tertiary university hospital in Spain of young adults (30-40 years) randomly selected, 80 born SGA (birth weight below 10th centile) and 75 with normal birth weight (controls) was recruited. We studied the associations between SGA and central obesity (measured via the hip-to-waist ratio and used as a continuous variable) and cardiac regional structure and function, assessed by cardiac magnetic resonance using statistical shape analysis. Both SGA and waist-to-hip were highly associated to cardiac shape (F = 3.94, P < 0.001; F = 5.18, P < 0.001 respectively) with a statistically significant interaction (F = 2.29, P = 0.02). 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 a unique response with inability to increase cardiac dimensions or mass resulting in reduced stroke volume and exercise capacity. SGA young adults show a unique cardiac adaptation to central obesity. These results support considering SGA as a risk factor that may benefit from preventive strategies to reduce cardiometabolic risk.

Continuous Positive Airway Pressure for the Treatment of Supine Hypertension and Orthostatic Hypotension in Autonomic Failure.

Supine hypertension affects most patients with orthostatic hypotension (OH) due to autonomic failure, but it is often untreated for fear of worsening OH. We hypothesized that increasing intrathoracic pressure with continuous positive airway pressure (CPAP) had a Valsalva-like blood-pressure-lowering effect that could be used to treat nocturnal supine hypertension in these patients, while reducing nocturnal pressure diuresis and improving daytime OH. In Protocol 1, we determined the acute hemodynamic effects of increasing levels of CPAP (0, 4, 8, 12, and 16 cm H2O, 3 minutes each) in 26 patients with autonomic failure and supine hypertension studied while awake and supine. In Protocol 2 (n=11), we compared the effects of overnight therapy with CPAP (8-12 cm H2O for 8 hours) versus placebo on nocturnal supine hypertension, nocturnal diuresis and daytime OH in a 2-night crossover study. In Protocol 1, acute CPAP (4-16 cm H2O) decreased systolic blood pressure in a dose-dependent manner (maximal drop 22±4 mmHg with CPAP 16) due to reductions in stroke volume (-16+3%) and cardiac output (-14±3%). Systemic vascular resistance and heart rate remained unchanged. In Protocol 2, overnight CPAP lowered nighttime systolic blood pressure (maximal change -23±5 versus placebo -1±7 mmHg; P=0.023) and was associated with lower nighttime diuresis (609±84 versus placebo 1004±160 mL; P=0.004) and improved morning orthostatic tolerance (AUC upright SBP 642±121 versus placebo 410±109 mmHg*min; P=0.014). CPAP is a novel nonpharmacologic approach to treat the supine hypertension of autonomic failure while improving nocturia and daytime OH. URL: https://www. gov; Unique identifier: NCT03312556.

PS-B04-3: SHORT-TERM LOW IODINE DIET EXACERBATES VASCULAR REACTIVITY WITHOUT ALTERING THYROID HORMONE PROFILES IN STROKE-PRONE SPONTANEOUSLY HYPERTENSIVE RATS

Objective: Iodine is an essential microelement required for thyroid hormone (TH) synthesis and regulation. Recent evidence links iodine to direct cardiovascular functional changes independent of TH. We aimed to determine the short-term effect of a low iodine diet on cardiovascular parameters in young Wistar Kyoto (WKY) and stroke-prone spontaneously hypertensive (SHRSP) rats. Design and method: 5-week-old WKY and SHRSP males and females (n = 5–7 per group) were assigned a normal (NID) or low iodine (LID) diet for 4 weeks. Iodine content was 1.2 mg/kg for NID and 0.211 mg/kg for LID. Tail cuff blood pressure (BP) and body weight were measured pre-diet and weekly. Transthoracic echocardiography, food intake, water consumption, and urine production were determined pre-diet and fortnightly. At sacrifice, thyroid tissue was weighed and snap-frozen for sodium iodide symporter (NIS) gene expression. Plasma was collected for thyroid-stimulating hormone (TSH), free triiodothyronine (fT3), and free thyroxine (fT4) measurement. Third-order mesenteric arteries were assessed for vascular function using wire myography. Results: Baseline TSH, fT3, and fT4 levels were not significantly different between strains. LID did not influence food intake, body weight, thyroid weight, left ventricular (LV) mass, relative wall thickness (RWT) or BP. TSH levels, but not fT3 or fT4, significantly increased by 63.3% in SHRSP males (p = 0.0002) and 74.5% in females fed LID (p = 0.018) but not in WKY when compared to strain, sex- and age-matched rats fed NID. NIS expression significantly increased by 3.27-fold in WKY males fed LID when compared to WKY males fed NID (p = 0.03) but not in SHRSP males. A similar trend in NIS expression was observed in WKY females fed LID. Water intake/urine output ratio significantly increased by 53.62% in SHRSP females fed LID compared to SHRSP females fed NID (p = 0.04). Trends towards reduced stroke volume (SV) and cardiac output (CO) were observed in males fed LID compared to those fed NID irrespective of strain. Vascular reactivity to U46619 in third-order mesenteric resistance arteries was significantly increased by 24.9% in SHRSP males fed LID compared to SHRSP males fed NID (p = 0.03). A similar trend was evident in SHRSP females fed LID when compared to SHRSP females fed NID. Conclusions: Our results demonstrate that short-term LID increases vascular reactivity in SHRSP male rats and is associated with altered expression of genes that encode iodine transport proteins yet independent of thyroid hormone levels.

The impact of pre-pregnant obesity on the maternal hemodynamics in early pregnancy

Maternal obesity is associated with a substantial risk of complications during pregnancy. Furthermore, it also impacts maternal cardiovascular adaptation, leading to cardiovascular disease later in life. This study aims to investigate the hemodynamic impact of obesity in the first trimester using USCOM® (Ultrasound Cardiac Output Monitor), a non-invasive and quantitative method. A prospective observational study of women with singleton pregnancy enrolled in prenatal care at a University of Miami clinic between January 2022 and July 2022. Pregnant women with a history of preexisting severe cardiorespiratory disease or congenital heart defect affecting cardiac function and taking Aspirin were excluded. Comprehensive cardiovascular parameters via USCOM® were obtained. Patients were divided into three subgroups: normal weight, overweight, and obesity according to pre-pregnancy BMI. Data were analyzed by one-way ANOVA with post hoc Bonferroni test for continuous parametric data, Kruskal-Wallis test for non-parametric data, and Pearson chi-square test for categorical data. P < .05 was considered statistically significant. Doppler waveforms for analysis were achieved for 48 women among 57 participants. Gestational age at inclusion, maternal age, ethnicity, race, blood pressure, history of preeclampsia, and preexisting chronic hypertension was not significantly different between groups. Maternal cardiovascular changes were identified in group 3. Compared to women with normal weight, obese women had significantly elevated Ejection Time Percentage (ET%) and Flow Time Corrected (FTc), and significantly reduced Stroke Volume Index(SVI), Cardiac Index(CI), and Inotropy Index(II). However, Stroke Volume (SV), Cardiac Output (CO), systemic vascular resistance (SVR), and Peak Velocity (PV) are not significantly different between groups. Our study shows that maternal hemodynamics is significantly altered in obese pregnant women from the first trimester and is characterized by high preload, low afterload, and reduced cardiac function.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

TILT TEST TOLERANCE AFTER TWO-WEEKS BED REST IN OLDER ADULTS IS NOT PROTECTED BY DAILY AEROBIC AND RESISTANCE EXERCISE

Abstract Bed rest is associated with increased risk of orthostatic intolerance on return to upright posture and, at least in young adults, regular exercise during bed rest is proposed as protective. 22 older adults (55-65 years, half women) participated in a randomized trial with 14-days of continuous 6-degree head-down bed rest. Half completed 60 min/day of aerobic and high-intensity interval cycling plus resistance exercises (Ex) while the other half were control (Con). A passive 80-degree head-up tilt (HUT) to a maximum of 15-min assessed orthostatic tolerance while cardio- and cerebrovascular responses were monitored to a pre-syncopal level of systolic blood pressure &amp;lt; 90 mmHg. In pre-bed rest baseline, all but 3 women (Ex) completed 15-min HUT. After 14-days bed rest, only 3 men (1 Ex) and 1 woman (Ex) completed 15-min with no differences in tolerance between men and women or Ex and Con. Vasovagal syncope presented in 5 participants (2 M-Con, 1 M-Ex, 1 F-Con, 1 F-Ex), most other non-finishers had progressive reduction in stroke volume without adequate vasoconstriction. Reductions in cerebral blood velocity measured during HUT by Doppler ultrasound revealed strong linear relationships to both end-tidal PCO2 and mean arterial pressure across all participants. These data indicate that neither older men nor older women were protected from orthostatic intolerance by 60-min per day exercise including high-intensity interval training. These data contrast with previous findings in younger adults in controlled trials of bed rest pointing to the need for greater understanding of mechanisms regulating blood pressure and brain blood flow.

Endothelial deletion of the cytochrome P450 reductase leads to cardiac remodelling.

The cytochrome P450 reductase (POR) transfers electrons to all microsomal cytochrome P450 enzymes (CYP450) thereby driving their activity. In the vascular system, the POR/CYP450 system has been linked to the production of epoxyeicosatrienoic acids (EETs) but also to the generation of reactive oxygen species. In cardiac myocytes (CMs), EETs have been shown to modulate the cardiac function and have cardioprotective effects. The functional importance of the endothelial POR/CYP450 system in the heart is unclear and was studied here using endothelial cell-specific, inducible knockout mice of POR (ecPOR-/-). RNA sequencing of murine cardiac cells revealed a cell type-specific expression of different CYP450 homologues. Cardiac endothelial cells mainly expressed members of the CYP2 family which produces EETs, and of the CYP4 family that generates omega fatty acids. Tamoxifen-induced endothelial deletion of POR in mice led to cardiac remodelling under basal conditions, as shown by an increase in heart weight to body weight ratio and an increased CM area as compared to control animals. Endothelial deletion of POR was associated with a significant increase in endothelial genes linked to protein synthesis with no changes in genes of the oxidative stress response. CM of ecPOR-/- mice exhibited attenuated expression of genes linked to mitochondrial function and an increase in genes related to cardiac myocyte contractility. In a model of pressure overload (transverse aortic constriction, TAC with O-rings), ecPOR-/- mice exhibited an accelerated reduction in cardiac output (CO) and stroke volume (SV) as compared to control mice. These results suggest that loss of endothelial POR along with a reduction in EETs leads to an increase in vascular stiffness and loss in cardioprotection, resulting in cardiac remodelling.

Abstract 12188: Acute Bi-Ventricular Dysfunction and Cardiogenic Shock Following Transcatheter Mitral Valve Repair

Background: For patients with functional mitral regurgitation (MR) who remain symptomatic despite GDMT, transcatheter mitral valve repair (TMVR) is emerging as a less-invasive alternatives and can improve symptoms and longevity. We describe a rare case of cardiogenic shock following TMVR. Case: 63-year-old male with PMHx of CAD with prior CABG, severe MR with EF of 40% developed progressive dyspnea and evaluated for TMVR with a Mitraclip device. TEE pre-deployment confirmed moderate to severe MR (Figure 1). Right heart catheterization revealed preserved cardiac index. Intraoperative TEE after deployment showed improved MR. Post-procedure, he developed respiratory distress and progressive hypotension requiring vasopressors and inotropes. TTE showed mild MR with severely reduced biventricular function (EF 10%). Cardiac catheterization showed a severely reduced CO/CI 3.1/1.42. Mechanical circulatory support was initiated with Impella CP due to persistent cardiogenic shock. By POD 3, he was off all inotropes and MCS was discontinued. His EF recovered to 45% during a 3- month visit. Decision Making: Causes of cardiogenic shock post mitral valve procedure include cardiac tamponade, acute mitral stenosis, intrathoracic hemorrhage and afterload mismatch. Afterload mismatch is due to reduction in left ventricular stroke volume when preload is not compensated for an acute increase in afterload. It is a known complication after mitral valve surgery; however it is rarely seen post TMVR. This patient likely experienced afterload mismatch after his mitral clipping procedure as evidenced by the acute, transient decline in LVEF (55% to 10%). Conclusion: Afterload mismatch is a rare phenomenon that can cause cardiogenic shock post percutaneous mitral repair procedures. It must be rapidly addressed with inotropic and/or mechanical support to prevent permanent end organ dysfunction and circulatory collapse. Prompt treatment allows for excellent recovery.

Nitrosylation of cardiac CaMKII at Cys290mediates mechanical afterload-induced increases in Ca2+ transient and Ca2+ sparks.

Cardiac mechanical afterload induces an intrinsic autoregulatory increase in myocyte Ca2+ dynamics and contractility to enhance contraction (known as the Anrep effect or slow force response). Our prior work has implicated both nitric oxide (NO) produced by NO synthase 1 (NOS1) and calcium/calmodulin-dependent protein kinase II (CaMKII) activity as required mediators of this form of mechano-chemo-transduction. To test whether a single S-nitrosylation site on CaMKIIδ (Cys290) mediates enhanced sarcoplasmic reticulum Ca2+ leak and afterload-induced increases in sarcoplasmic reticulum (SR) Ca2+ uptake and release, we created a novel CRISPR-based CaMKIIδ knock-in (KI) mouse with a Cys to Ala mutation at C290. These CaMKIIδ-C290A-KI mice exhibited normal cardiac morphometry and function, as well as basal myocyte Ca2+ transients (CaTs) and β-adrenergic responses. However, the NO donor S-nitrosoglutathione caused an acute increased Ca2+ spark frequency in wild-type (WT) myocytes that was absent in the CaMKIIδ-C290A-KI myocytes. Using our cell-in-gel system to exert multiaxial three-dimensional mechanical afterload on myocytes during contraction, we found that WT myocytes exhibited an afterload-induced increase in Ca2+ sparks and Ca2+ transient amplitude and rate of decline. These afterload-induced effects were prevented in both cardiac-specific CaMKIIδ knockout and point mutant CaMKIIδ-C290A-KI myocytes. We conclude that CaMKIIδ activation by S-nitrosylation at the C290site is essential in mediating the intrinsic afterload-induced enhancement of myocyte SR Ca2+ uptake, release and Ca2+ transient amplitude (the Anrep effect). The data also indicate that NOS1 activation is upstream of S-nitrosylation at C290 of CaMKII, and that this molecular mechano-chemo-transduction pathway is beneficial in allowing the heart to increase contractility to limit the reduction in stroke volume when aortic pressure (afterload) is elevated. KEY POINTS: A novel CRISPR-based CaMKIIδ knock-in mouse was created in which kinase activation by S-nitrosylation at Cys290 (C290A) is prevented. How afterload affects Ca2+ signalling was measured in cardiac myocytes that were embedded in a hydrogel that imposes a three-dimensional afterload. This mechanical afterload induced an increase in Ca2+ transient amplitude and decay in wild-type myocytes, but not in cardiac-specific CaMKIIδ knockout or C290A knock-in myocytes. The CaMKIIδ-C290 S-nitrosylation site is essential for the afterload-induced enhancement of Ca2+ transient amplitude and Ca2+ sparks.

Therapeutic Benefits of Adropin in Aged Mice After Transient Ischemic Stroke via Reduction of Blood-Brain Barrier Damage.

Adropin is a peptide encoded by the energy homeostasis-associated gene (Enho) that is highly expressed in the brain. Aging and stroke are associated with reduced adropin levels in the brain and plasma. We showed that treatment with synthetic adropin provides long-lasting neuroprotection in permanent ischemic stroke. However, it is unknown whether the protective effects of adropin are observed in aged animals following cerebral ischemia/reperfusion. We hypothesized that adropin provides neuroprotection in aged mice subjected to transient middle cerebral artery occlusion. Aged (18-24 months old) male mice were subjected to 30 minutes of middle cerebral artery occlusion followed by 48 hours or 14 days of reperfusion. Sensorimotor (weight grip test and open field) and cognitive tests (Y-maze and novel object recognition) were performed at defined time points. Infarct volume was quantified by 2,3,5-triphenyltetrazolium chloride staining at 48 hours or Cresyl violet staining at 14 days post-middle cerebral artery occlusion. Blood-brain barrier damage, tight junction proteins, and MMP-9 (matrix metalloproteinase-9) were assessed 48 hours after middle cerebral artery occlusion by ELISA and Western blots. Genetic deletion of Enho significantly increased infarct volume and worsened neurological function, whereas overexpression of adropin dramatically reduced stroke volume compared to wild-type controls. Postischemic treatment with synthetic adropin peptide given at the onset of reperfusion markedly reduced infarct volume, brain edema, and significantly improved locomotor function and muscular strength at 48 hours. Delayed adropin treatment (4 hours after the stroke onset) reduced body weight loss, infarct volume, and muscular strength dysfunction, and improved long-term cognitive function. Postischemic adropin treatment significantly reduced blood-brain barrier damage. This effect was associated with reduced MMP-9 and preservation of tight junction proteins by adropin treatment. These data unveil a promising neuroprotective role of adropin in the aged brain after transient ischemic stroke via reducing neurovascular damage. These findings suggest that poststroke adropin therapy is a potential strategy to minimize brain injury and improve functional recovery in ischemic stroke patients.