Cardiac Pump Function Research Articles

Reduced stroke volume by resting 2-dimensional echocardiography negatively affects survival in patients with abnormal ejection fraction

Abstract Background Abnormal (<50%) ejection fraction (EF) is a cornerstone of risk stratification and therapy, but also an imperfect proxy of left ventricular (LV) cardiac pump function, better assessed with stroke volume (SV). Aim To assess the value of SV in stratifying risk of patients with abnormal EF. Methods In a prospective, observational, multicenter study, we recruited 746 patients (age 66± 11 years, 536 males, 72%, 359 with previous myocardial infarction, 48%) with chronic coronary syndromes (CCS) and EF <50% referred for resting transthoracic echocardiography with technically successful 2-dimensional volumetric echocardiography in 17 accredited laboratories. We quantitatively assessed LV end-diastolic volume (EDV) and end-systolic volume (ESV) by Simpson’s biplane method. EF (EDV-ESV/EDV) and SV (EDV-ESV) were calculated from LV volumes. The outcome end-point was all-cause death. Results EF was 39±9%, SV 48±20 ml. There were 100 all-cause deaths during a median follow-up of 796 days (interquartile range 420-1286 days). Receiver-operating curve analysis identified SV≤31.4 ml/b as the best cut-off for predicting mortality. At multivariable analysis, after adjustment for age and prior myocardial infarction, EF <40% and SV ≤31.4 ml/b were significantly associated with decreased survival (HR 2.09, 95%, confidence intervals 1.09-4.01, p=0.024). The annual mortality was lowest (3.19%) in the group with mildly reduced (40-49%) EF and normal (>31.4 ml) SV, and highest (8.30%) in patients with both reduced EF and abnormal SV: see figure. Conclusion Patients with CCS and abnormal EF are a prognostically heterogeneous group, and the mortality rate is almost 3-times worse in patients with reduced EF and abnormal SV compared to patients with mildly reduced EF and normal SV. A simple resting volumetric two-dimensional echocardiography can offer an efficient risk stratification, beyond EF, with no extra imaging or analysis time.Figure

9246 Mineralocorticoid Receptor Regulation of the Molecular Clock in Cardiomyocytes Is Modulated by Time of Day

Abstract Disclosure: M. Kanki: None. S. Heanue: None. P.J. Fuller: None. T.J. Cole: None. C.D. Clyne: None. M.J. Young: None. The onset of cardiovascular disease events peaks in the early morning, which coincides with the diurnal surge in aldosterone and cortisol. Aldosterone-induced mineralocorticoid receptor (MR) activation in cardiomyocytes has established roles in cardiac pump function and electrophysiology and inappropriate MR activation promotes cardiovascular pathophysiology in experimental models of hypertension and heart failure and in the clinic. Recently, we identified a novel role for MR in regulating the circadian clock signalling network in cardiac cells and showed that time of day modulates MR activation in the heart. Whether time-of-day-dependent MR regulation of circadian clocks in cardiomyocytes modulates temporal expression of key functional pathways is unknown. Therefore, we sought to identify cardiac responsiveness to MR stimulation at lights on (7AM) versus lights off (7PM) in ≥8-week old male wildtype (WT) and cardiomyocyte-MR knockout (MyoMRKO) mice. RNA-seq analyses revealed that aldosterone (50 ug/kg) administered at 7PM but not at 7AM significantly enriched transcription of genes associated with 52 biological processes including “Circadian rhythm”, “Reg. of blood pressure”, “Ion transport” and “Reg. of the force of heart contraction” in WT hearts (p<0.05 versus 7PM vehicle-injected WT mice). These outcomes were absent in hearts isolated from MyoMRKO mice administered aldosterone at 7AM or 7PM. Analysis by RT-qPCR revealed that aldosterone versus vehicle administered at 7AM increased expression of circadian Period (Per) and Thyrotroph embryonic factor (Tef) genes in WT hearts, which was lost in MyoMRKO mice. Whole transcriptome analysis also detected significant enrichment in “Cell-cell signalling”, “Positive regulation of cell differentiation”, “Positive regulation of glucose metabolic process”, “Regulation of sodium ion transport”, and “Inflammatory response" processes between 7AM and 7PM in WT hearts, which was also lost in MyoMRKO mice. Our data show that MR transcription of genes associated with circadian rhythms and ion transport is temporally regulated, and demonstrates specificity for cardiomyocyte-MR regulation of circadian clocks. Taken together, we highlight that the role for cardiomyocyte-MR regulation of cardiac electrophysiology, heart rate variability, and metabolic processes is time-of-day-dependent. Understanding temporal coordination of MR activation in physiology and pathophysiology may inform new strategies for optimising MR-directed therapies in patients with heart disease. Presentation: 6/2/2024

7763 Mineralocorticoid Receptor Regulation of the Molecular Clock in Cardiomyocytes Is Modulated by Time of Day

Abstract Disclosure: M. Kanki: None. S. Heanue: None. P.J. Fuller: None. T.J. Cole: None. C.D. Clyne: None. M.J. Young: None. The onset of cardiovascular disease events peaks in the early morning, which coincides with the diurnal surge in aldosterone and cortisol. Aldosterone-induced mineralocorticoid receptor (MR) activation in cardiomyocytes has established roles in cardiac pump function and electrophysiology and inappropriate MR activation promotes cardiovascular pathophysiology in experimental models of hypertension and heart failure and in the clinic. Recently, we identified a novel role for MR in regulating the circadian clock signalling network in cardiac cells and showed that time of day modulates MR activation in the heart. Whether time-of-day-dependent MR regulation of circadian clocks in cardiomyocytes modulates temporal expression of key functional pathways is unknown. Therefore, we sought to identify cardiac responsiveness to MR stimulation at lights on (7AM) versus lights off (7PM) in ≥8-week old male wildtype (WT) and cardiomyocyte-MR knockout (MyoMRKO) mice. RNA-seq analyses revealed that aldosterone (50 ug/kg) administered at 7PM but not at 7AM significantly enriched transcription of genes associated with 52 biological processes including “Circadian rhythm”, “Reg. of blood pressure”, “Ion transport” and “Reg. of the force of heart contraction” in WT hearts (p<0.05 versus 7PM vehicle-injected WT mice). These outcomes were absent in hearts isolated from MyoMRKO mice administered aldosterone at 7AM or 7PM. Analysis by RT-qPCR revealed that aldosterone versus vehicle administered at 7AM increased expression of circadian Period (Per) and Thyrotroph embryonic factor (Tef) genes in WT hearts, which was lost in MyoMRKO mice. Whole transcriptome analysis also detected significant enrichment in “Cell-cell signalling”, “Positive regulation of cell differentiation”, “Positive regulation of glucose metabolic process”, “Regulation of sodium ion transport”, and “Inflammatory response" processes between 7AM and 7PM in WT hearts, which was also lost in MyoMRKO mice. Our data show that MR transcription of genes associated with circadian rhythms and ion transport is temporally regulated, and demonstrates specificity for cardiomyocyte-MR regulation of circadian clocks. Taken together, we highlight that the role for cardiomyocyte-MR regulation of cardiac electrophysiology, heart rate variability, and metabolic processes is time-of-day-dependent. Understanding temporal coordination of MR activation in physiology and pathophysiology may inform new strategies for optimising MR-directed therapies in patients with heart disease. Presentation: 6/2/2024

The Functional Significance of Cardiac Looping: Comparative Embryology, Anatomy, and Physiology of the Looped Design of Vertebrate Hearts.

The flow path of vertebrate hearts has a looped configuration characterized by curved (sigmoid) and twisted (chiral) components. The looped heart design is phylogenetically conserved among vertebrates and is thought to represent a significant determinant of cardiac pumping function. It evolves during the embryonic period of development by a process called "cardiac looping". During the past decades, remarkable progress has been made in the uncovering of genetic, molecular, and biophysical factors contributing to cardiac looping. Our present knowledge of the functional consequences of cardiac looping lags behind this impressive progress. This article provides an overview and discussion of the currently available information on looped heart design and its implications for the pumping function. It is emphasized that: (1) looping seems to improve the pumping efficiency of the valveless embryonic heart. (2) bilaterally asymmetric (chiral) looping plays a central role in determining the alignment and separation of the pulmonary and systemic flow paths in the multi-chambered heart of tetrapods. (3) chiral looping is not needed for efficient pumping of the two-chambered hearts of fish. (4) it is the sigmoid curving of the flow path that may improve the pumping efficiency of lower as well as higher vertebrate hearts.

Abstract Tu058: Reverse Remodeling with LVAD Therapy is Associated with Alternative Splicing of CAMK2D

Therapies for end-stage heart failure are lacking and the number of patients awaiting heart transplants far outweighs availability. Left ventricular assist devices (LVADs) take over cardiac pump function and are used as a bridge-to-transplant. Notably, some patients on LVADs experience recovery of cardiac function and reversal of pathological cardiac remodeling; however, the molecular mechanisms underlying these favorable outcomes are unknown. In this study, we studied 19 paired pre- and post-LVAD samples with 10 clinically categorized as responders and 9 as non-responders. Bulk mRNA sequencing identified 486 differentially expressed genes post-LVAD, including reduced pro-inflammatory gene expression and increased expression of genes involved in metal ion binding; however, just 23 total genes were differentially expressed between responders and non-responders. To determine whether LVAD differentially impacted the proteome in responders and non-responders, we next performed quantitative proteomics on post-LVAD samples. This analysis identified 154 differentially expressed proteins and revealed that factors involved in mRNA processing were higher expressed in LVAD responders. Re-analysis of our mRNA sequencing data for gene isoforms identified that alternative splicing of calcium and calmodulin-dependent protein kinase 2-delta ( CAMK2D ) was the most significantly impacted event with non-responders having increased inclusion of exon 14 (denoting the B isoform), which encodes a nuclear localization sequence. Notably, there was a strong negative correlation between exon 14 inclusion and ΔLVEF post-LVAD. We validated these findings using targeted exon-specific quantitative PCR, which confirmed that expression of CAMK2D B was higher both pre- and post-LVAD in non-responders, while responders had post-LVAD levels matching non-failing controls. We next investigated whether responders and non-responders differed at the phospho-proteome level via mass spectrometry and found three serines in CaMK2δ exon 14 were the only differentially abundant phosphosites and all increased in non-responders. Localization studies in vitro with adenoviruses expressing phospho-null or phospho-mimetic CaMK2D B constructs revealed that these phosphorylation events precluded nuclear localization. In conclusion, we identified differential alternative splicing and phosphorylation of CaMK2δ in LVAD responders, which may represent novel therapeutic targets for heart failure recovery.

Association of attenuated leptin signaling pathways with impaired cardiac function under prolonged high-altitude hypoxia

Cardiovascular function and adipose metabolism were markedly influenced under high altitudes. However, the interplay between adipokines and heart under hypoxia remains to be elucidated. We aim to explore alterations of adipokines and underlying mechanisms in regulating cardiac function under high altitudes. We investigated the cardiopulmonary function and five adipokines in Antarctic expeditioners at Kunlun Station (4,087 m) for 20 days and established rats exposed to hypobaric hypoxia (5,000 m), simulating Kunlun Station. Antarctic expeditioners exhibited elevated heart rate, blood pressure, systemic vascular resistance, and decreased cardiac pumping function. Plasma creatine phosphokinase-MB (CK-MB) and platelet-endothelial cell adhesion molecule-1 (sPecam-1) increased, and leptin, resistin, and lipocalin-2 decreased. Plasma leptin significantly correlated with altered cardiac function indicators. Additionally, hypoxic rats manifested impaired left ventricular systolic and diastolic function, elevated plasma CK-MB and sPecam-1, and decreased plasma leptin. Chronic hypoxia for 14 days led to increased myocyte hypertrophy, fibrosis, apoptosis, and mitochondrial dysfunction, coupled with reduced protein levels of leptin signaling pathways in myocardial tissues. Cardiac transcriptome analysis revealed leptin was associated with downregulated genes involved in rhythm, Na+/K+ transport, and cell skeleton. In conclusion, chronic hypoxia significantly reduced leptin signaling pathways in cardiac tissues along with significant pathological changes, thus highlighting the pivotal role of leptin in regulation of cardiac function under high altitudes.

The relationship between cardiac oxidative stress, inflammatory cytokine response, cardiac pump function, and prognosis post-myocardial infarction

This study delves into the potential connections between cardiac oxidative stress, inflammatory cytokine response, cardiac pump function, and prognosis in individuals following myocardial infarction. A total of 276 patients were categorized into two groups: the control group (n = 130) and the observation group (n = 146), based on the drug intervention strategies. The control group received standard drug treatment, while the observation group received early drug intervention targeting antioxidant and anti-inflammatory treatment in addition to standard treatment. Serum levels of inflammatory factors, including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-9 (IL-6), were assessed using enzyme-linked immuno sorbent assay (ELISA) kits. The Forkhead Box Protein A2 (FOX2) reagent was used to determine the overall oxidation level. Left Ventricular End-Diastolic Diameter (LVEDD), Left Ventricular Ejection Fraction (LVEF), and End-Systolic Diameter (ESD) were measured using Doppler ultrasound. The observation group exhibited significantly reduced serum levels of TNF-α, IL-1β, and IL-6 compared to the control group (P < 0.05). Moreover, the observation group exerted lower total oxidation levels, OSI, EDD, and ESD compared to the control group (P < 0.05), while the LVEF and TAS levels in the observation group were higher than those in the control group (P < 0.05). Remarkably, the observation group experienced a significant reduction in the incidences of reinfarction, heart failure, arrhythmia, and abnormal valve function compared to the control group (P < 0.05). Decreased cardiac pump function and a more unfavorable prognosis were associated with elevated levels of cardiac oxidative stress and inflammatory factors (P < 0.05). Timely intervention with appropriate medications have a crucial effect in decreasing inflammatory marker levels, mitigating oxidative pressure, and enhancing cardiac pumping capacity and overall prognosis.

Translating myosin-binding protein C and titin abnormalities to whole-heart function using a novel calcium-contraction coupling model

Mutations in cardiac myosin-binding protein C (cMyBP-C) or titin may respectively lead to hypertrophic (HCM) or dilated (DCM) cardiomyopathies. The mechanisms leading to these phenotypes remain unclear because of the challenge of translating cellular abnormalities to whole-heart and system function.We developed and validated a novel computer model of calcium-contraction coupling incorporating the role of cMyBP-C and titin based on the key assumptions: 1) tension in the thick filament promotes cross-bridge attachment mechanochemically, 2) with increasing titin tension, more myosin heads are unlocked for attachment, and 3) cMyBP-C suppresses cross-bridge attachment.Simulated stationary calcium-tension curves, isotonic and isometric contractions, and quick release agreed with experimental data. The model predicted that a loss of cMyBP-C function decreases the steepness of the calcium-tension curve, and that more compliant titin decreases the level of passive and active tension and its dependency on sarcomere length. Integrating this cellular model in the CircAdapt model of the human heart and circulation showed that a loss of cMyBP-C function resulted in HCM-like hemodynamics with higher left ventricular end-diastolic pressures and smaller volumes. More compliant titin led to higher diastolic pressures and ventricular dilation, suggesting DCM-like hemodynamics.The novel model of calcium-contraction coupling incorporates the role of cMyBP-C and titin. Its coupling to whole-heart mechanics translates changes in cellular calcium-contraction coupling to changes in cardiac pump and circulatory function and identifies potential mechanisms by which cMyBP-C and titin abnormalities may develop into HCM and DCM phenotypes. This modeling platform may help identify distinct mechanisms underlying clinical phenotypes in cardiac diseases.

Effects of hypoxic compound exercise to promote HIF-1α expression on cardiac pumping function, sleep activity behavior, and exercise capacity in Drosophila.

Alteration of HIF-1α expression levels under hypoxic conditions affects the sequence of its downstream target genes thereby producing different effects. In order to investigate whether the effect of hypoxic compound exercise (HE) on HIF-1α expression alters cardiac pumping function, myocardial structure, and exercise capacity, we developed a suitable model of hypoxic exercise using Drosophila, a model organism, and additionally investigated the effect of hypoxic compound exercise on nocturnal sleep and activity behavior. The results showed that hypoxic compound exercise at 6% oxygen concentration for five consecutive days, lasting 1 h per day, significantly improved the cardiac stress resistance of Drosophila. The hypoxic complex exercise promoted the whole-body HIF-1α expression in Drosophila, and improved the jumping ability, climbing ability, moving speed, and moving distance. The expression of HIF-1α in the heart was increased after hypoxic exercise, which made a closer arrangement of myofilaments, an increase in the diameter of cardiac tubules, and an increase in the pumping function of the heart. The hypoxic compound exercise improved the sleep quality of Drosophila by increasing its nocturnal sleep time, the number of deep sleeps, and decreasing its nocturnal awakenings and activities. Therefore, we conclude that hypoxic compound exercise promoted the expression of HIF-1α to enhance the exercise capacity and heart pumping function of Drosophila, and improved the quality of sleep.

Montelukast, an available and safe anti-asthmatic drug, prevents maladaptive remodelling and maintains cardiac functionality following myocardial infarction

Preclinical and clinical data indicate that the 5-lipoxygenase pathway becomes activated in cardiovascular diseases suggesting an important role of CysLTs in atherosclerosis and in its ischemic complications. This study aims to investigate the effects of montelukast, a CysLTR-1 antagonist, in a mouse model of myocardial infarction (MI). C57BL/6N female mice were subjected to coronary artery ligation and received montelukast (10 mg/kg/day, intraperitoneal) or vehicle. Montelukast exerted beneficial effects in the infarcted area, decreasing mRNA expression of inflammatory genes, such Il1β and Ccl2 (p < 0.05), at 48 h after MI, and reducing infarct size and preventing ischemic wall thinning (p < 0.05) at 4 weeks. Furthermore, montelukast counteracted maladaptive remodelling of whole heart. Indeed, montelukast reduced LV mass (p < 0.05) and remote wall thickening (p < 0.05), and improved cardiac pumping function, as evidenced by increased global ejection fraction (p < 0.01), and regional contractility in infarcted (p < 0.05) and in remote non-infarcted (p < 0.05) myocardium. Finally, montelukast prevented cardiomyocytes hypertrophy (p < 0.05) in remote myocardium, reducing the phosphorylation of GSK3β, a regulator of hypertrophic pathway (p < 0.05). Our data strongly demonstrate the ability of montelukast to contrast the MI-induced maladaptive conditions, thus sustaining cardiac contractility. The results provide evidences for montelukast “repurposing” in cardiovascular diseases and in particular in myocardial infarction.

The Relationship Between Resilience and Health-Related Quality of Life Among Heart Failure Patients in New York Heart Association Functional Classes II and III.

Heart failure is an intense, unpredictable, and stressful chronic disease caused by the decline in cardiac pumping function. The influence of heart failure affects patients not only in terms of physical capabilities but also in terms of their emotional and social dimensions, with patients in different functional classes experiencing different levels of effect. Although resilience and health-related quality of life have been studied in populations with heart failure, the scholarly understanding of different functional classes is limited. This study was designed to investigate the relationship between resilience and health-related quality of life among patients with heart failure in different physical functional classes in Taiwan. A cross-sectional design was applied to study patients with heart failure in northern Taiwan. Two structured questionnaires, including the Resilience Scale for Adults and the 12-item Short Form Health Survey, were used to assess resilience and health-related quality of life. New York Heart Association functional class was used to determine physical function status, and canonical correlation analysis was used to determine the weight of each resilience and quality-of-life domain for the different functional classes. The 100 participants had an average age of 65.52 years. Slightly over half (56%) were classified as Functional Class II. A group difference in health-related quality of life was observed. Personal strength (rs = .759) and social competence (rs = -.576) were found to influence the resilience and emotional role dimension of quality of life (rs = -.996) in the Functional Class II group. In addition, family cohesion (rs = -.922), dominant resilience, physical function (rs = .467), and bodily pain (rs = .465) were found to influence quality of life in the Functional Class III group. The efficacy of measures taken to increase resilience to heart failure varied in patients in different functional classes. Functional Class II individuals were better able to manage the disease using their personal strength, whereas Functional Class III individuals relied more heavily on family support and assistance for this effort. Furthermore, participant feelings about quality of life also varied by functional class, with physical function and bodily pain taking on significantly more importance for Functional Class III individuals.

The Role of Arterial Elasticity in Determining the Degree of Chronic Heart Failure in Myocardial Infarction.

Aim To study the left ventricular (LV) contractile and pumping function during the recovery phase following ligation of the anterior descending coronary artery (CA).Material and methods Cardiodynamic parameters were studied in Wistar rats 2-4 weeks after experimental myocardial infarction (MI). MI was induced by ligation of the anterior descending CA under zoletil anesthesia. LV catheterization was performed with a standard FTH-1912B-8018 PV catheter inserted into the LV through the right carotid artery.Results After the induction of MI, the mortality rate of animals was 50%. Survived animals developed significant LV dilatation and a decrease in ejection fraction (EF) by an average of 31%. However, major indexes of the pumping function, including minute volume, heart work, and maximum ejection velocity, were within a normal range whereas the maximum filling velocity was almost doubled. Approximately 50% of hearts with dilated LV had normal EF, delayed relaxation, and increased LV diastolic pressure, which qualified this group as a diastolic dysfunction group. The systolic dysfunction group with EF less than 50% of normal had similar values of myocardial contractility and relaxation but differed from the diastolic dysfunction group in more than 50% reduced maximum LV ejection velocity and 1.7 times increased elasticity of the arterial wall. A close inverse correlation was found between these values (r= -0.91).Conclusion The study results showed that, with a similar myocardial contractile function, the cardiac pumping function is determined by the elasticity of the aortic wall. Therefore, restriction of reactive fibrosis during MI is an important task of modern cardiology.

Delivery of SAV-siRNA via Exosomes from Adipose-Derived Stem Cells for the Treatment of Myocardial Infarction.

Myocardial infarction (MI) leads to cardiomyocyte death, poor cardiac remodeling, and heart failure, making it a major cause of mortality and morbidity. To restore cardiac pumping function, induction of cardiomyocyte regeneration has become a focus of academic interest. The Hippo pathway is known to regulate cardiomyocyte proliferation and heart size, and its inactivation allows adult cardiomyocytes to re-enter the cell cycle. In this study, we investigated whether exosomes from adipose-derived stem cells (ADSCs) could effectively transfer siRNA for the Hippo pathway regulator Salvador (SAV) into cardiomyocytes to induce cardiomyocyte regeneration in a mouse model of MI. Our results showed that exosomes loaded with SAV-siRNA effectively transferred siRNA into cardiomyocytes and induced cardiomyocyte re-entry into the cell cycle, while retaining the previously demonstrated therapeutic efficacy of ADSC-derived exosomes to improve post-infarction cardiac function through anti-fibrotic, pro-angiogenic, and other effects. Our findings suggest that siRNA delivery via ADSC-derived exosomes may be a promising approach for the treatment of MI.

Investigating the variability in pressure-volume relationships during hemorrhage and aortic occlusion.

The pressure-volume (P-V) relationships of the left ventricle are the classical benchmark for studying cardiac mechanics and pumping function. Perturbations in the P-V relationship (or P-V loop) can be informative and guide the management of heart failure, hypovolemia, and aortic occlusion. Traditionally, P-V loop analyses have been limited to a single-beat P-V loop or an average of consecutive P-V loops (e.g., 10 cardiac cycles). While there are several algorithms to obtain single-beat estimations of the end-systolic and end-diastolic pressure-volume relations (i.e., ESPVR and EDPVR, respectively), there remains a need to better evaluate the variations in P-V relationships longitudinally over time. This is particularly important when studying acute and transient hemodynamic and cardiac events, such as active hemorrhage or aortic occlusion. In this study, we aim to investigate the variability in P-V relationships during hemorrhagic shock and aortic occlusion, by leveraging on a previously published porcine hemorrhage model. Briefly, swine were instrumented with a P-V catheter in the left ventricle of the heart and underwent a 25% total blood volume hemorrhage over 30 min, followed by either Zone 1 complete aortic occlusion (i.e., REBOA), Zone 1 endovascular variable aortic control (EVAC), or no occlusion as a control, for 45 min. Preload-independent metrics of cardiac performance were obtained at predetermined time points by performing inferior vena cava occlusion during a ventilatory pause. Continuous P-V loop data and other hemodynamic flow and pressure measurements were collected in real-time using a multi-channel data acquisition system. We developed a custom algorithm to quantify the time-dependent variance in both load-dependent and independent cardiac parameters from each P-V loop. As expected, all pigs displayed a significant decrease in the end-systolic pressures and volumes (i.e., ESP, ESV) after hemorrhage. The variability in response to hemorrhage was consistent across all three groups. However, upon introduction of REBOA, we observed significantly high levels of variability in both load-dependent and independent cardiac metrics such as ESP, ESV, and the slope of ESPVR (Ees). For instance, pigs receiving REBOA experienced a 342% increase in ESP from hemorrhage, while pigs receiving EVAC experienced only a 188% increase. The level of variability within the EVAC group was consistently less than that of the REBOA group, which suggests that the EVAC group may be more supportive of maintaining healthier cardiac performance than complete occlusion with REBOA. In conclusion, we successfully developed a novel algorithm to reliably quantify the single-beat and longitudinal P-V relations during hemorrhage and aortic occlusion. As expected, hemorrhage resulted in smaller P-V loops, reflective of decreased preload and afterload conditions; however, the cardiac output and heart rate were preserved. The use of REBOA and EVAC for 44 min resulted in the restoration of baseline afterload and preload conditions, but often REBOA exceeded baseline pressure conditions to an alarming level. The level of variability in response to REBOA was significant and could be potentially associated to cardiac injury. By quantifying each P-V loop, we were able to capture the variability in all P-V loops, including those that were irregular in shape and believe that this can help us identify critical time points associated with declining cardiac performance during hemorrhage and REBOA use.

Multiscale computational modeling of the effects of 2'-deoxy-ATP on cardiac muscle calcium handling.

2'-Deoxy-ATP (dATP), a naturally occurring near analog of ATP, is a well-documented myosin activator that has been shown to increase contractile force, improve pump function, and enhance lusitropy in the heart. Calcium transients in cardiomyocytes with elevated levels of dATP show faster calcium decay compared with cardiomyocytes with basal levels of dATP, but the mechanisms behind this are unknown. Here, we design and utilize a multiscale computational modeling framework to test the hypothesis that dATP acts on the sarcoendoplasmic reticulum calcium-ATPase (SERCA) pump to accelerate calcium re-uptake into the sarcoplasmic reticulum during cardiac relaxation. Gaussian accelerated molecular dynamics simulations of human cardiac SERCA2A in the E1 apo, ATP-bound and dATP-bound states showed that dATP forms more stable contacts in the nucleotide binding pocket of SERCA and leads to increased closure of cytosolic domains. These structural changes ultimately lead to changes in calcium binding, which we assessed using Brownian dynamics simulations. We found that dATP increases calcium association rate constants to SERCA and that dATP binds to apo SERCA more rapidly than ATP. Using a compartmental ordinary differential equation model of human cardiomyocyte excitation-contraction coupling, we found that these increased association rate constants contributed to the accelerated rates of calcium transient decay observed experimentally. This study provides clear mechanistic evidence of enhancements in cardiac SERCA2A pump function due to interactions with dATP.

Phloretin ameliorates heart function after myocardial infarction via NLRP3/Caspase-1/IL-1β signaling

Objectives/AimsInflammation is crucial in structural and electrical remodeling after myocardial infarction (MI), affecting cardiac pump function and conduction pathways. Phloretin possesses an anti-inflammation role by inhibiting the NLRP3/Caspase-1/IL-1β pathway. However, the effects of Phloretin on cardiac contractile and electrical conduction function after MI remained unclear. Therefore, we aimed to investigate the potential role of Phloretin in a rat model of MI. MethodsRats were assigned into four groups: Sham, Sham+Phloretin, MI and MI+Phloretin, with ad libitum food and water. In the MI and MI+Phloretin groups, the left anterior descending coronary artery was occluded for 4 weeks, while the Sham and Sham+Phloretin groups received sham operation. The Sham+Phloretin group and the MI+Phloretin group received oral administration of Phloretin. In vitro, H9c2 cells were subjected to hypoxic conditions to simulate an MI model, with Phloretin for 24 h. Cardiac electrophysiological properties were assessed following MI, including the effective refractory period (ERP), action potential duration (APD)90 and ventricular fibrillation (VF) incidence. Echocardiography evaluated left ventricular ejection fraction (LVEF), left ventricular fraction shortening (LVFS), left ventricular internal diameter at end-diastole (LVIDd), left ventricular internal diameter at end-systole (LVIDs), left ventricular end-systolic volume (LVESV) and left ventricular end-diastolic volume (LVEDV) to assess cardiac function. Serum type B natriuretic peptide (BNP) level was applied to evaluate the degree of Heart failure (HF). The fibrosis area and severity were assessed by Masson staining and protein expression levels of collagen 3, collagen 1, TGF-β and α-SMA. Western blot analysis estimated the protein expression levels of NLRP3, Pro Caspase-1, Caspase-1, ASC, IL-18, IL-1β, pp38, p38, and Connexin43(Cx43) to elucidate the influence of inflammation on electrical remodeling after MI. ResultsOur findings demonstrate that Phloretin inhibits the NLRP3/Caspase-1/IL-1β pathway, leading to the upregulation of Cx43 by limiting p38 phosphorylation, which further decreases susceptibility to ventricular arrhythmias (VAs). Additionally, Phloretin attenuated fibrosis by inhibiting inflammation to prevent HF. In vitro experiments also provided strong evidence supporting the inhibitory effects of Phloretin on the NLRP3/Caspase-1/IL-1β pathway. ConclusionOur results suggest that Phloretin could suppress the NLRP3/Caspase-1/IL-1β pathway to reverse structural and electrical remodeling after MI to prevent the occurrence of VAs and HF.

Impaired cardiac pump function assessment with normalized cardiac power using cardiac magnetic resonance in patients with hypertrophic cardiomyopathy.

Cardiac power (CP; CP = 0.222 × cardiac output × mean blood pressure) output in patients with heart failure has been studied previously, but its importance in patients with hypertrophic cardiomyopathy (HCM) remains unclear. The present study aimed to explore the role of normalized CP (normalized CP = CP/ventricle mass) in assessing cardiac function in patients with HCM with normal ejection fraction using cardiac magnetic resonance (CMR). This cross-sectional study enrolled 99 patients with HCM who underwent CMR from December 2020 to January 2022 at Beijing Anzhen Hospital, and these patients were classified into heart failure or non-heart failure subgroups. Meanwhile, a control group comprising 65 gender- and age-matched healthy volunteers was also enrolled. The baseline clinical characteristics and cardiac functional parameters were compared between the patients with HCM and the controls, and multivariable linear regression analysis was performed to analyze the relationship between normalized CP and the relevant factors. Significantly higher CP (1.19 vs. 1.01 W; P=0.03) but lower normalized CP (0.73 vs. 1.12 W/100 g; P<0.001) were found in patients with HCM as compared with the controls. Multivariable analysis showed that HCM correlated well with normalized CP [β=-0.235; 95% confidence interval (CI): -0.341 to -0.129; P<0.001]. In the HCM group, there were 34 cases with heart failure and 65 with non-heart failure, and the patients with HCM with heart failure showed similar CP (1.14 vs. 1.24 W; P=0.06) but significantly lower normalized CP (0.54 vs. 0.78 W/100 g; P<0.001). The correlation analysis of normalized CP and functional parameters revealed that normalized CP was inversely correlated with left ventricle mass/body surface area (R=-0.509; 95% CI: -0.646 to -0.341; P<0.001) in patients with HCM. Normalized CP decreased significantly and was negatively correlated with ventricle mass, indicating impaired cardiac pump function in patients with HCM. Normalized CP might play a critical role in detecting and evaluating impaired cardiac pump function in patients with HCM with preserved ejection fraction.

Myocard Injury in COVID-19 Patients After Application Of Umbilical Cord Mesenchymal Stem Cell (UC-MSC) as Adjuvant Therapy in Persahabatan Hospital

Background: Myocardial injury was a frequent cardiovascular manifestation of COVID-19 and associated with high mortality. Cell-based approaches, primarily using mesenchymal stem cell (MSC) has demonstrated safety and possible efficacy as adjuvant therapy in COVID-19 patients. This study aims to evaluate myocardial injury in patients with moderate-severe and critically ill COVID-19 after the application of umbilical cord mesenchymal stem cell (UC-MSC) as adjuvant therapy in Persahabatan hospital. Method: This is a retrospective and prospective cohort study. A total of 28 subjects were allocated to 13 subjects in the control and 15 subjects in the experimental group. Subjects were given the standard treatment and UC-MSC or placebo. Myocardial injury is defined by an increase of troponin I &gt;26 pg/ml. The biomarkers of troponin I, NT-proBNP and CRP was examined periodically. Cardiac pump evaluated by EF and TAPSE from echocardiography examination before and after UC-MSC application. The evaluation of myocardial injury, biomarkers, cardiac pump and 15-day mortality were observed between the two groups. Results: The incidence of myocardial injury was 28,6% of total subjects. Subjects with worsening myocardial injury were higher in the control group (6 subjects) than the experimental group (4 subjects) although not statistically significant. The difference in biomarkers (troponin I, NT- pro-BNP and CRP), cardiac pump function (EF and TAPSE) and 15-day mortality between two groups were not statistically significant. There was a trend of decreasing troponin I, NT-proBNP and CRP in the experimental group. Conclusion: UC-MSC application can be an option as adjuvant therapy in improving myocardial injury of moderate-severe and critically ill COVID-19 patients.

Cell to whole organ global sensitivity analysis on a four-chamber heart electromechanics model using Gaussian processes emulators.

Cardiac pump function arises from a series of highly orchestrated events across multiple scales. Computational electromechanics can encode these events in physics-constrained models. However, the large number of parameters in these models has made the systematic study of the link between cellular, tissue, and organ scale parameters to whole heart physiology challenging. A patient-specific anatomical heart model, or digital twin, was created. Cellular ionic dynamics and contraction were simulated with the Courtemanche-Land and the ToR-ORd-Land models for the atria and the ventricles, respectively. Whole heart contraction was coupled with the circulatory system, simulated with CircAdapt, while accounting for the effect of the pericardium on cardiac motion. The four-chamber electromechanics framework resulted in 117 parameters of interest. The model was broken into five hierarchical sub-models: tissue electrophysiology, ToR-ORd-Land model, Courtemanche-Land model, passive mechanics and CircAdapt. For each sub-model, we trained Gaussian processes emulators (GPEs) that were then used to perform a global sensitivity analysis (GSA) to retain parameters explaining 90% of the total sensitivity for subsequent analysis. We identified 45 out of 117 parameters that were important for whole heart function. We performed a GSA over these 45 parameters and identified the systemic and pulmonary peripheral resistance as being critical parameters for a wide range of volumetric and hemodynamic cardiac indexes across all four chambers. We have shown that GPEs provide a robust method for mapping between cellular properties and clinical measurements. This could be applied to identify parameters that can be calibrated in patient-specific models or digital twins, and to link cellular function to clinical indexes.

Comparison of novel ventricular pacing strategies using an electro-mechanical simulation platform.

Focus of pacemaker therapy is shifting from right ventricular (RV) apex pacing (RVAP) and biventricular pacing (BiVP) to conduction system pacing. Direct comparison between the different pacing modalities and their consequences to cardiac pump function is difficult, due to the practical implications and confounding variables. Computational modelling and simulation provide the opportunity to compare electrical, mechanical, and haemodynamic consequences in the same virtual heart. Using the same single cardiac geometry, electrical activation maps following the different pacing strategies were calculated using an Eikonal model on a three-dimensional geometry, which were then used as input for a lumped mechanical and haemodynamic model (CircAdapt). We then compared simulated strain, regional myocardial work, and haemodynamic function for each pacing strategy. Selective His-bundle pacing (HBP) best replicated physiological electrical activation and led to the most homogeneous mechanical behaviour. Selective left bundle branch (LBB) pacing led to good left ventricular (LV) function but significantly increased RV load. RV activation times were reduced in non-selective LBB pacing (nsLBBP), reducing RV load but increasing heterogeneity in LV contraction. LV septal pacing led to a slower LV and more heterogeneous LV activation than nsLBBP, while RV activation was similar. BiVP led to a synchronous LV-RV, but resulted in a heterogeneous contraction. RVAP led to the slowest and most heterogeneous contraction. Haemodynamic differences were small compared to differences in local wall behaviour. Using a computational modelling framework, we investigated the mechanical and haemodynamic outcome of the prevailing pacing strategies in hearts with normal electrical and mechanical function. For this class of patients, nsLBBP was the best compromise between LV and RV function if HBP is not possible.