End-systolic Pressure-volume Relationship Research Articles

Correlation of Noninvasive Cardiac MRI Measures of Left Ventricular Myocardial Function and Invasive Pressure-Volume Parameters in a Porcine Ischemia-Reperfusion Model.

Purpose To assess the correlation between noninvasive cardiac MRI-derived parameters with pressure-volume (PV) loop data and evaluate changes in left ventricular function after myocardial infarction (MI). Materials and Methods Sixteen adult female swine were induced with MI, with six swine used as controls and 10 receiving platelet-derived growth factor-AB (PDGF-AB). Load-independent measures of cardiac function, including slopes of end-systolic pressure-volume relationship (ESPVR) and preload recruitable stroke work (PRSW), were obtained on day 28 after MI. Cardiac MRI was performed on day 2 and day 28 after infarct. Global longitudinal strain (GLS) and global circumferential strain (GCS) were measured. Ventriculo-arterial coupling (VAC) was derived from PV loop and cardiac MRI data. Pearson correlation analysis was performed. Results GCS (r = 0.60, P = .01), left ventricular ejection fraction (LVEF) (r = 0.60, P = .01), and cardiac MRI-derived VAC (r = 0.61, P = .01) had a significant linear relationship with ESPVR. GCS (r = 0.75, P < .001) had the strongest significant linear relationship with PRSW, followed by LVEF (r = 0.67, P = .005) and cardiac MRI-derived VAC (r = 0.60, P = .01). GLS was not significantly correlated with ESPVR or PRSW. There was a linear correlation (r = 0.82, P < .001) between VAC derived from cardiac MRI and from PV loop data. GCS (-3.5% ± 2.3 vs 0.5% ± 1.4, P = .007) and cardiac MRI-derived VAC (-0.6 ± 0.6 vs 0.3 ± 0.3, P = .001) significantly improved in the animals treated with PDGF-AB 28 days after MI compared with controls. Conclusion Cardiac MRI-derived parameters of MI correlated with invasive PV measures, with GCS showing the strongest correlation. Cardiac MRI-derived measures also demonstrated utility in assessing therapeutic benefit using PDGF-AB. Keywords: Cardiac MRI, Myocardial Infarction, Pressure Volume Loop, Strain Imaging, Ventriculo-arterial Coupling Supplemental material is available for this article. © RSNA, 2024.

Hemodynamic effects of treatment with the ketone body 3-hydroxybutyrate in cardiogenic shock - a randomized, controlled, assessor-blinded porcine trial

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): Novo Nordisk Foundation Independent Research Fund DK. Background Cardiogenic shock (CS) is a life-threatening disease with limited evidence-based treatment options. Treatment with the ketone body 3-hydroxybutyrate (3-OHB) induces favorable hemodynamic effects in patients with heart failure and CS. It increases cardiac output (CO) and left ventricular (LV) ejection fraction (LVEF) while reducing cardiac filling pressures. Yet, whether treatment with 3-OHB demonstrates beneficial hemodynamic effects during acute ischemic LV stunning in CS must be fully elucidated. This study aimed to examine the acute hemodynamic effects and underlying cardiovascular mechanisms of 3-OHB infusion in the acute phase of LV stunning in a porcine model of ischemic CS. Methods Sixteen 60-kg-pigs were included in a randomised, controlled, assessor-blinded crossover study. CS was achieved by repeated, slow injections of microspheres into the left main coronary artery. CS was defined as ≥30% reduction in CO and/or mixed venous saturation (SVO2). Upon the onset of CS, following a one-hour no-touch period, the pigs received an infusion with 3-OHB and isoosmolar, isovolumic saline (control) for two hours each in random order. Infusion periods were separated by a one-hour washout period. CO (primary endpoint), SVO2, and pulmonary pressures were measured by right heart catheterization. A pressure-volume admittance catheter was placed in the LV to measure LVEF, contractility (the slope of end systolic pressure-volume relationship, denoded as Ees), afterload (arterial elastance, Ea, and end-systolic pressure, ESP), preload (end-diastolic volume, EDV), and work-related parameters. Results CS was successfully achieved in all randomized animals. CO decreased by 36% from 4.5±1.0 L/min to 2.9±0.5 L/min (p&amp;lt;0.001) and SVO2 decreased by 31% from 55.0±8.1% to 37.7±5.8% (p&amp;lt;0.001). During 3-OHB infusion, CO increased by 0.9 L/min (95% CI: 0.4 to 1.3 L/min) compared with the control infusion. In parallel, Ees increased by 0.22 mmHg/mL (95% CI: 0.08 to 0.37 mmHg/mL), LVEF improved by 7 percentage points (95%CI: 1 to 13 percentage points) and cardiac efficiency increased by 6 percentage points (95%CI: 1 to 11 percentage points). Systemic vascular resistance was decreased by 479 dyn*cm5 (95% CI: 736 to 221 dyn*cm5); Ea and ESP remained similar. Heart rate was increased during 3-OHB infusion by 21 bpm (95% CI: 11 to 32 bpm) while no significant change was observed in stroke volume (p=0.6). Conclusion Treatment with 3-OHB improved CO, LVEF, and cardiac efficiency in CS. The increase was mediated through increased ventricular contractility and decreased peripheral resistance accompanied by increased heart rate.CO, Ees and cardiac efficiencyEndpoint parameters during 3-OHB

Microtubules distinctly contribute to the performance of the healthy and pressure-overloaded RV

Introduction: Microtubules (MT) are a key contributor to cardiomyocyte contractility and mechanics. Recently, our group reported that acute depolymerization of MT reduces viscosity and elasticity and alters anisotropy of healthy and pressure-overloaded right ventricular (RV) tissues. While RV free wall viscosity and elasticity are distinctly upregulated with chronic pressure overload, how organ function is affected by viscoelastic contribution of the MT remains unknown. Our aim was to investigate the role of MT polymerization in RV function from its effect on RV tissue viscoelasticity. We hypothesized that the MT differentially contributes to healthy and pressure-overloaded RV function. Methods: All procedures and methods were approved by Colorado State University IACUC. Pulmonary hypertension (PH) was induced in 6-week-old male rats via 3-week monocrotaline treatment. Healthy age- and sex-matched rats served as control. Pressure-volume (PV) relationships were obtained by RV catheterization before and after intramyocardial injections of 0.3mM colchicine (COL) to acutely depolymerize the MT network and reduce tissue viscoelasticity. Functional impacts were evaluated by monitoring changes in RV end-systolic pressure (ESP), cardiac output (CO), stroke volume (SV), ejection fraction (EF), dP/dt max and min, cardiac effciency (CE), and the end-systolic pressure-volume relation (ESPVR). Results: As expected, monocrotaline treatment induced marked PH and RV contractile dysfunction, indicated by a significant elevation of RV ESP with reduced CO and ESPVR. In the healthy RV, COL treatment led to marked reductions in all functional parameters, indicating that the MT network is critical to maintain RV performance and contractile function in the healthy heart. In the pressure-overloaded RV, COL treatment similarly reduced SV, CO, EF, and dP/dt max and min, but increased CE and ESPVR, indicating that MT depolymerization improved mechanical effciency and contractility. To rule out effects caused by bolus injections alone, we administered a similar quantity of saline and observed no effects on the PV parameters in healthy RV. Discussion: Our study is the first to investigate the acute effect of MT depolymerization on RV function in healthy and diseased states. We found distinct contributions of MT to the contractile function and mechanical effciency of healthy and pressure-overloaded RVs. These findings reveal a critical influence of tissue viscoelasticity on RV physiology and dysfunction, emphasizing the importance of considering myocardial viscoelastic behavior in future studies investigating cardiac remodeling and heart failure pathophysiology. This work is partially supported by the National Science Foundation (NSF) grant 2244994. This is the full abstract presented at the American Physiology Summit 2024 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.

Restoring Cardiac Health: Abstinence Leads to Recovery from Alcohol-Induced Cardiomyopathy

Chronic drinking can lead to alcohol-induced cardiomyopathy (ACM), a disease currently without a cure. Using a mouse model of ACM, we observed significant cardiac dysfunction after 30 days. Our study’s goal was to investigate the potential restoration of cardiac function following a period of abstinence. Our hypothesis is that abstinence can lead to an observable recovery in overall cardiac function. C57BL/6J mice were given the Lieber-DeCarli liquid diet with 5% ethanol for 30 days, with two ethanol binges on days 10 and 30 (5 g/kg). After the 30-day ethanol exposure, the mice were transitioned to an ethanol-free diet for an additional 30 days. Left ventricular catheterization and echocardiography were conducted at the 30- and 60-day timepoints. 30 days of ethanol consumption led to significant decreases in both systolic and diastolic function. However, following a period of alcohol abstinence, there was a marked improvement. Specifically, the 30-day ethanol mice exhibited increases in stroke work and dP/dt max after 30 days of abstinence; stroke work increased from 1119 ± 89 mmHg*μL to 2032 ± 139 mmHg*μL (p &lt; 0.0001), and dP/dt max increased from 8054 ± 664 mmHg/s to 11967 ± 449 mmHg/s (p &lt; 0.001). Diastolic function also improved; dP/dt min from -7711 ± 561 mmHg/s to -10202 ± 594 (p &lt; 0.01). We also found a significant increase in load-independent cardiac contractility, i.e. the slope of end systolic pressure volume relation: 6.89 ± 0.6 mmHg/μL to 10.59 ± 1.57 mmHg/μL (p &lt; 0.05). In conclusion, abstinence after chronic ethanol exposure can lead to a restoration of cardiac function in C57BL/6J mice. This model parallels limited clinical data on abstinence and will allow us to study the underlying mechanisms responsible for the restoration of function. R21AA029747 (JG, CB), F30AA030472 (JE). This is the full abstract presented at the American Physiology Summit 2024 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.

Daunorubicin Treatment Impairs Cardiac Function in The Ts65Dn Mouse Model Of Down Syndrome

Anthracycline treatment for leukemia is effective but has toxic side effects on the cardiovascular system. Few studies regarding the impact of anthracyclines on the heart in individuals with Down syndrome have been addressed although they are at a higher risk of developing leukemia. It is unknown if established mechanisms apply to individuals with Down syndrome. We hypothesize that anthracycline cardiotoxicity will lead to the enhanced impairment of cardiac function and initiate pronounced vascular dysfunction in a mouse model of Down syndrome. We used the Ts65Dn mouse model of Down syndrome to investigate the impact of daunorubicin chemotherapy on survival, arterial stiffness and left ventricular function. Four-month-old Ts65Dn (n=12) and wild-type control Ts65Dn (WT, n=8) mice were treated with 2mg/kg of daunorubicin or saline. Following treatment, left ventricular catheterization was performed to assess cardiac function. Serum cardiac troponin levels were evaluated using ELISA. Histological analysis was conducted on the heart and aorta of mice to assess the accumulation of elastin and collagen. We found decreased end-diastolic pressure (p=0.016) and ejection fraction (p=0.029) in Ts65Dn daunorubicin-treated mice compared to WT control. However, contractility (end-systolic pressure-volume relationship, p=0.221) and diastolic stiffness coeffcient (end-diastolic pressure-volume relationship, p=0.418) remained unchanged. Ts65Dn mice had a higher cardiac troponin concentration (p=0.02). Histological assessment showed no significant difference in collagen (p=0.841) and elastin (p=0.768) content. Daunorubicin negatively impacted end-diastolic pressure and ejection fraction of the Ts65Dn mouse model of Down syndrome. We demonstrated that we could recapitulate the findings of anthracycline cardiotoxicity in Ts65Dn mice indicating this is a good model to investigate toxicity. Continued work with this model will better elucidate the mechanisms underlying anthracycline cardiotoxicity in Down syndrome. This shows the need for constant screening after anthracycline treatment which will improve the survival of this population. NIH R21 HD099573. This is the full abstract presented at the American Physiology Summit 2024 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.

Myocardial ischemia-reperfusion injury released cellular fibronectin containing domain A (CFN-EDA): A destructive positive loop amplifying arterial thrombosis formation and exacerbating myocardial reperfusion injury

Previous research has identified intravascular platelet thrombi in regions affected by myocardial ischemia-reperfusion (MI/R) injury and neighbouring areas. However, the occurrence of arterial thrombosis in the context of MI/R injury remains unexplored.This study utilizes intravital microscopy to investigate carotid artery thrombosis during MI/R injury in rats, establishing a connection with the presence of prothrombotic cellular fibronectin containing extra domain A (CFN-EDA) protein. Additionally, the study examines samples from patients with coronary artery disease (CAD) both before and after coronary artery bypass grafting (CABG).Levels of CFN-EDA significantly increase following MI with further elevation observed following reperfusion of the ischemic myocardium. Thrombotic events, such as thrombus formation and growth, show a significant increase, while the time to complete cessation of blood flow in the carotid artery significantly decreases following MI/R injury induced by ferric chloride. The acute infusion of purified CFN-EDA protein accelerates in-vivo thrombotic events in healthy rats and significantly enhances in-vitro adenosine diphosphate and collagen-induced platelet aggregation. Treatment with anti-CFN-EDA antibodies protected the rat against MI/R injury and significantly improved cardiac function as evidenced by increased end-systolic pressure-volume relationship slope and preload recruitable stroke work compared to control. Similarly, in a human study, plasma CFN-EDA levels were notably elevated in CAD patients undergoing CABG. Post-surgery, these levels continued to rise over time, alongside cardiac injury biomarkers such as cardiac troponin and B-type natriuretic peptide.The study highlights that increased CFN-EDA due to CAD or MI initiates a destructive positive feedback loop by amplifying arterial thrombus formation, potentially exacerbating MI/R injury.

The additive prognostic value of end-systolic pressure-volume relation by stress CMR in patients with known or suspected coronary artery disease.

The difference between rest and peak stress end-systolic pressure-volume relation (ΔESPVR) is an afterload-independent index of left ventricular (LV) contractility. We assessed the independent prognostic value of ΔESPVR index by dipyridamole stress-cardiovascular magnetic resonance (CMR) in patients with known/suspected coronary artery disease (CAD). We considered 196 consecutive patients (62.74 ± 10.66years, 49 females). Wall motion and perfusion abnormalities at rest and peak stress were analysed. Replacement myocardial fibrosis was detected by late gadolinium enhancement(LGE) technique. The ESPVR was evaluated at rest and peak stress from raw measurement of systolic arterial pressure and end-systolic volume by biplane Simpson's method. A reduced ΔESPVR index (≤ 0.02mmHg/mL/m2) was found in 88(44.9%) patients and it was associated with a lower LV ejection fraction(EF) and with a higher frequency of abnormal stress CMR and myocardial fibrosis. During a mean follow-up of 53.17 ± 28.21months, 50(25.5%) cardiac events were recorded: 5 cardiac deaths, 17 revascularizations, one myocardial infarction, 23 hospitalisations for heart failure or unstable angina, and 4 ventricular arrhythmias. According to Cox regression analysis, diabetes, family history, LVEF, abnormal stress CMR, myocardial fibrosis, and reduced ΔESPVR were significant univariate prognosticators. In the multivariate analysis the independent predictors were ΔESPVR index ≤ 0.02mmHg/mL/m2 (hazard ratio-HR = 2.58, P = 0.007), myocardial fibrosis (HR = 2.13, P = 0.036), and diabetes (HR = 2.33, P = 0.012). ΔESPVR index by stress-CMR was independently associated with cardiac outcomes in patients with known/suspected CAD, in addition to replacement myocardial fibrosis and diabetes. Thus, the assessment of ΔESPVR index may be included into the standard stress-CMR exam to further stratify the patients.

Intrinsic mechanisms of right ventricular autoregulation

To elucidate the adaptation of the right ventricle to acute and intermittently sustained afterload elevation, targeted preload reductions and afterload increases were implemented in a porcine model involving 12 pigs. Preload reduction was achieved via balloon occlusion of the inferior vena cava before, immediately and 5 min after acute afterload elevation induced by pulmonary artery occlusion or thromboxane A2 analog (U46619) infusion. Ventricular response was monitored by registration of pressure–volume (PV) loops using a conductance catheter. The end-systolic pressure–volume relationship (ESPVR) during pure preload reduction was adequately described by linear regression (mean and SEM slope of ESPVR (Ees) 0.414 ± 0.064 mmHg/ml), reflecting the classical Frank-Starling mechanism (FSM). The ESPVR during acute afterload elevation exhibited a biphasic trajectory with significantly distinct slopes (mean and SEM Ees bilin1: 1.256 ± 0.066 mmHg ml; Ees bilin2: 0.733 ± 0.063 mmHg ml, p < 0.001). The higher slope during the first phase in the absence of ventricular dilation could be explained by a reduced amount of shortening deactivation (SDA). The changes in PV-loops during the second phase were similar to those observed with a preload intervention. The persistent increase in afterload resulted in an increase in the slopes of ESPVR and preload recruitable stroke work (PRSW) with a slight decrease in filling state, indicating a relevant Anrep effect. This effect became more pronounced after 5 min or TXA infusion. This study demonstrates, for the first time, the relevance of intrinsic mechanisms of cardiac autoregulation in the right ventricle during the adaptation to load. The SDA, FSM, and Anrep effect could be differentiated and occurred successively, potentially with some overlap. Notably, the Anrep effect serves to prevent ventricular dilation.

10 Pre-clinical studies of sotagliflozin in hypertrophic cardiomyopathy

OBJECTIVES/GOALS: Study the regulatory role of sodium glucose co-transporter 1 (SGLT1) in cardiomyocytes and the therapeutic potential of sotagliflozin in hypertrophic cardiomyopathy (HCM) by (a) quantifying SGLT1 expression in HCM and (b) examining the impact of sotagliflozin on cardiac mechanics. METHODS/STUDY POPULATION: * Use Western Blot in cardiac tissue from HCM and non-HCM patients and pre-existing RNA seq and proteomics datasets to quantify SGLT1 levels in HCM. Hypothesis: SGLT1 is upregulated in HCM * Determine how SGLT1/2 inhibition by sotagliflozin will affect cardiac mechanics using living myocardial slice (LMS) preparations. A vibratome creates 200um-thick slices from (a) failing HCM heart explants, (b) septal myectomy samples from HCM patients, and (c) nonfailing rejected donor hearts. LMS are mounted on a force transducer and work-loops are stimulated under varying pre- and after-loads. Collecting baseline and post-drug work loops allows each slice to function as its own control. Hypothesis: sotagliflozin will improve diastolic mechanics by reducing stiffness in the end-diastolic pressure-volume relationship RESULTS/ANTICIPATED RESULTS: * Preliminary results from RNA seq data indicate that SLC5A1 mRNA (encoding gene for SGLT1) is significantly decreased in HCM. No proteomics study examined thus far has detected SLC5A1, indicating that overall SGLT1 levels in cardiac tissue are quite low. We will examine SGLT1 levels in our own HCM and non-HCM tissue samples with both mass-spectrometry and Western Blot. * We analyze six slices from each heart and expect 15 donor hearts and 15 HCM hearts/myectomy samples. We visualize the work loop by plotting stress/strain. Stress/strain at mitral valve closure represents exponential end diastolic pressure-volume relationship; Stress/strain at aortic valve closure represents linear end systolic pressure volume relationship. A two-sample paired t-test will compare change in stiffness and elastance. DISCUSSION/SIGNIFICANCE: This project contributes to a growing body of research surrounding the currently unknown cardioprotective mechanism of SGLT 1/2 inhibitors, furthers the technique of using living myocardial slices to study cardiac mechanics, and supports a trial examining sotagliflozin in HCM, for which disease modifying therapy remains a prevailing unmet need.

Evaluation of vascular aging on measures of cardiac function and mechanical efficiency: insights from in-silico modeling.

This study evaluated the hypothesis that vascular aging (VA) reduces ventricular contractile function and mechanical efficiency (ME) using the left ventricular pressure-volume (PV) construct. A previously published in-silico computational model (CM) was modified to evaluate the hypothesis in two phases. In phase I, the CM included five settings of aortic compliance (CA) from normal to stiff, studied at a heart rate of 80 bpm, and phase II included the normal to stiff CA settings evaluated at 60, 100, and 140 bpm. The PV construct provided steady-state and transient data through a simulated vena caval occlusion (VCO). The steady-state data included left ventricular volumes (EDV and ESV), stroke work (SW), and VCO provided the PV area (PVA) data in addition to the three measures of contractile state (CS): end-systolic pressure-volume relationship (ESPVR), dP/dtmax-EDV and preload recruitable stroke work (PRSW). Finally, ME was calculated with the SW/PVA parameter. In phase I, EDV and ESV increased, as did SW and PVA. The impact on the CS parameters demonstrated a small decrease in ESPVR, no change in dP/dtmax-EDV, and a large increase in PRSW. ME decreased from 71.5 to 60.8%, respectively. In phase II, at the normal and stiff CA settings, across the heart rates studied, EDV and ESV decreased, ESPVR and dP/dtmax-EDV increased and PRSW decreased. ME decreased from 76.4 to 62.6% at the normal CA and 65.8 to 53.2% at the stiff CA. The CM generated new insights regarding how the VA process impacts the contractile state of the myocardium and ME.

Exploring the Connection Between Relaxed Myosin States and the Anrep Effect.

The Anrep effect is an adaptive response that increases left ventricular contractility following an acute rise in afterload. Although the mechanistic origin remains undefined, recent findings suggest a two-phase activation of resting myosin for contraction, involving strain-sensitive and posttranslational phases. We propose that this mobilization represents a transition among the relaxed states of myosin-specifically, from the super-relaxed (SRX) to the disordered-relaxed (DRX)-with DRX myosin ready to participate in force generation. This hypothesis offers a unified explanation that connects myosin's SRX-DRX equilibrium and the Anrep effect as parts of a singular phenomenon. We underscore the significance of this equilibrium in modulating contractility, primarily studied in the context of hypertrophic cardiomyopathy, the most common inherited cardiomyopathy associated with diastolic dysfunction, hypercontractility, and left ventricular hypertrophy. As we posit that the cellular basis of the Anrep effect relies on a two-phased transition of myosin from the SRX to the contraction-ready DRX configuration, any dysregulation in this equilibrium may result in the pathological manifestation of the Anrep phenomenon. For instance, in hypertrophic cardiomyopathy, hypercontractility is linked to a considerable shift of myosin to the DRX state, implying a persistent activation of the Anrep effect. These valuable insights call for additional research to uncover a clinical Anrep fingerprint in pathological states. Here, we demonstrate through noninvasive echocardiographic pressure-volume measurements that this fingerprint is evident in 12 patients with hypertrophic obstructive cardiomyopathy before septal myocardial ablation. This unique signature is characterized by enhanced contractility, indicated by a leftward shift and steepening of the end-systolic pressure-volume relationship, and a prolonged systolic ejection time adjusted for heart rate, which reverses post-procedure. The clinical application of this concept has potential implications beyond hypertrophic cardiomyopathy, extending to other genetic cardiomyopathies and even noncongenital heart diseases with complex etiologies across a broad spectrum of left ventricular ejection fractions.

PD-L1 and AKT Overexpressing Adipose-Derived Mesenchymal Stem Cells Enhance Myocardial Protection by Upregulating CD25+ T Cells in Acute Myocardial Infarction Rat Model.

This study explores the synergistic impact of Programmed Death Ligand 1 (PD-L1) and Protein Kinase B (Akt) overexpression in adipose-derived mesenchymal stem cells (AdMSCs) for ameliorating cardiac dysfunction after myocardial infarction (MI). Post-MI adult Wistar rats were allocated into four groups: sham, MI, ADMSC treatment, and ADMSCs overexpressed with PD-L1 and Akt (AdMSC-PDL1-Akt) treatment. MI was induced via left anterior descending coronary artery ligation, followed by intramyocardial AdMSC injections. Over four weeks, cardiac functionality and structural integrity were assessed using pressure-volume analysis, infarct size measurement, and immunohistochemistry. AdMSC-PDL1-Akt exhibited enhanced resistance to reactive oxygen species (ROS) in vitro and ameliorated MI-induced contractile dysfunction in vivo by improving the end-systolic pressure-volume relationship and preload-recruitable stroke work, together with attenuating infarct size. Molecular analyses revealed substantial mitigation in caspase3 and nuclear factor-κB upregulation in MI hearts within the AdMSC-PDL1-Akt group. Mechanistically, AdMSC-PDL1-Akt fostered the differentiation of normal T cells into CD25+ regulatory T cells in vitro, aligning with in vivo upregulation of CD25 in AdMSC-PDL1-Akt-treated rats. Collectively, PD-L1 and Akt overexpression in AdMSCs bolsters resistance to ROS-mediated apoptosis in vitro and enhances myocardial protective efficacy against MI-induced dysfunction, potentially via T-cell modulation, underscoring a promising therapeutic strategy for myocardial ischemic injuries.

Exploring the mechanisms responsible for afterload mismatch in severe aortic stenosis

Abstract Introduction Afterload mismatch (AM) is defined as a reduced ejection fraction (EF) in the setting of severe aortic stenosis (AS) (aortic valve area (AVA) of &amp;lt; 1cm2), but with transaortic pressure gradients in the severe range. The pathomechanism underlying the impaired EF remains unclear, especially with regards to the impact of ventricular hypertrophy and fibrosis, the role of afterload, and the integrity of the intrinsic contractile myocardial strength in AM. This knowledge gap unmasks a lack of understanding into the natural disease progression in AS. Purpose To characterise the morphological and functional contractile mechanics that distinguishes patients with reduced EF from patients with preserved EF in the setting of AS with high transvalvular gradients. Methods A prospective comparative analysis was performed on 21 sequential cases of patients with severe AS, 9 with AM (AVA &amp;lt; 1.0cm2; MG &amp;gt; 40mmHg; EF &amp;lt; 50%) and 12 with normal flow high gradient (NFHG) AS (AVA &amp;lt; 1.0cm2; MG &amp;gt; 40mmHg; EF &amp;gt; 50%). Patients with concomitant valve lesions or previously diagnosed myocardial infarction, were excluded. Myocardial morphology, function and tissue characteristics were evaluated using a) transthoracic echocardiography, b) cardiac magnetic resonance imaging, and c) an invasive hemodynamic study with pressure-volume loop derived data. Results Intrinsic load independent contractile muscle function parameters were similar between AM and NFHG AS (p-value non-significant for cardiac index, dP/dT(max), preload recruitable stroke work slope, end systolic pressure volume relationship slope and Starling contractile index slope). Afterload indices as assessed by peak systolic wall stress and valvuloarterial impedance were significantly higher in AM cases compared to NFHG AS (32.5 vs 19.9 N/cm2; p &amp;lt; 0.01 and 4.8 vs 3.4mmHg/ml; P = 0.05). This was driven by disproportionally higher degrees of valvular stenosis in the AM group (valve area 0.46 vs 0.78cm2; p &amp;lt; 0.01). The AM group expressed a more advanced disease phenotype with more symptoms (NYHA 3.3 vs 2.3; p=0.02), more pulmonary hypertension (50 vs 30mmHg; p=0.04), and more extensive myocardial fibrosis (24% vs 13% of left ventricular mass; p=0.03) (see Figure 1). Neither more severe LVH nor higher degrees of fibrosis in the AM group, was associated with a demonstrable impairment in the intrinsic contractile muscle function. Conclusion Our data suggest that the central problem in AM is related to an excessively increased afterload, primarily driven by more severe valvular stenosis, with preserved intrinsic left ventricular contractile function. AM is characterised by more severe myocardial fibrosis, as a marker of a more advanced disease phenotype, but this did not translate into worse intrinsic contractile muscle function. The known time dependence of progressive valvular stenosis and myocardial fibrosis would suggest that AM is an intermediate phase between NFHG AS and so-called low flow low gradient severe AS.A more advanced phenotype

Concurrent left ventricular pressure-loading improves right ventricular function, remodeling, and molecular signaling in response to pulmonary artery banding

Abstract Background Studies have established the significance of right ventricle (RV) function in individuals with many congenital heart diseases, however the impact of pressure overload (PO) on the RV, concomitant with changes in LV pressure, has yet to be fully understood. We have previously demonstrated that pulmonary artery banding (PAB) with simultaneous LVPO improved systolic function in both ventricles and reduced myocyte hypertrophy and collagen content compared to PAB alone1. These findings suggested that increasing LV afterload attenuated maladaptive RV remodeling and molecular signaling. Purpose We investigated whether the degree of LV afterload beneficially impacts RV function, remodeling, and molecular signaling pathways. Methods We established a model of double-banding (DB) in male Sprague-Dawley rats (n = 17) where the PA and transverse aorta were constricted with 16-gauge and 14-gauge needles, respectively. At 6-weeks post-surgery, Doppler-echocardiography was used to measure the flow velocity across the aortic constriction to divide the DB rats into moderate (DBMOD) and mild (DBMILD) groups. PAB-only (n=9) and Sham (n=9) groups were used as controls. All animals underwent echocardiography and cardiac catheterization 6-weeks post-surgery to assess RV/LV structure and hemodynamic function. Heart tissue was collected for Picrosirius red (PSR) staining to assess RV collagen content. Immunoblotting and RT-qPCR were used to quantify protein and transcripts of fibrosis and mechanotransduction pathways. Results Echocardiography identified increases in RV end-diastolic and end-systolic areas alongside a decrease in tricuspid annular plane systolic excursion (TAPSE) in PAB rats compared to shams. These changes were abrogated in DBMOD rats and to a lesser extent in DBMILD rats (p&amp;lt;0.001). Hemodynamic analyses identified significantly increased dP/dtmax/min, and end-systolic pressure-volume relationship in the PAB group, each of which returned to near-Sham levels in the DBMOD group (p&amp;lt;0.0001). PSR-staining revealed a significant decrease of RV fibrosis in the DBMOD group compared to PAB rats (p&amp;lt;0.05). Immunoblotting in RV tissue revealed increases in myocardin-related transcription factor A, and YAP/TAZ in PAB rats; protein expression returned to near-sham levels in the DBMOD group (p&amp;lt;0.05) with an intermediate expression in the DBMILD group (p&amp;lt;0.05). RT-qPCR of RV tissue revealed significantly increased collagen 1&amp;3, TGFβ1, and CTGF transcripts which returned to baseline in the DBMOD group (p&amp;lt;0.05). Conclusion Our results indicate that the degree of LV pressure provides a beneficial impact on RV function, remodeling, and both Hippo and profibrotic signaling during RV PO. Our study demonstrates the importance of ventricular interdependence from a physiological and molecular level and suggests that modulating LV pressures during diseases that impact the RV (such as pulmonary hypertension) offer a potentially attractive therapeutic route.

Left and right ventricular hemodynamic response after transcatheter mitral valve replacement

Abstract Background Transcatheter mitral valve replacement (TMVR) represents a novel treatment option for patients with relevant mitral regurgitation (MR), who are ineligible for surgical treatment. Although complete and predictable elimination of MR is achieved in most patients undergoing TMVR, little is known about left and right ventricular hemodynamic changes after TMVR. Purpose With this study, we sought to investigate left ventricular (LV) remodeling and right ventricular (RV) function in patients undergoing TMVR using data derived from non-invasive, echocardiography-based pressure volume loops. Methods A total of 49 consecutive patients with MR 3+ or 4+ undergoing TMVR with one of four dedicated devices were included in a prospective single-center TMVR registry between 05/2016 until 08/2022. For this study, only patients with technical success and available echocardiographic data at baseline and discharge were included. The end-diastolic and end-systolic pressure-volume relationships (EDPVR and ESPVR) were estimated non-invasively using single-beat echocardiographic measurements. VPed20 was calculated as a parameter describing the end-diastolic volume (EDV) at an end-diastolic pressure (EDP) of 20 mmHg. Ees, the slope describing the ESPVR, was calculated as surrogate parameter for LV contractility. Pulmonary artery systolic pressure (PASP), tricuspid annular plane systolic excursion (TAPSE) and RV-pulmonary artery (PA) coupling were assessed as parameters reflecting RV function. Results A total of 26 patients (77.0 years [IQR 73.9-80.1], N=17 [65.4%] male) with successful TMVR were included (secondary MR [N=21, 80.8%]; median LV ejection fraction 37.0% [IQR 30.7-50.7]). Overall, a significant decrease in VPed20 was observed following TMVR indicating a leftward shift of the EDPVR (165.3±75.8mL vs. 134.0±65.9mL, p&amp;lt;0.001, Figure 1). In addition, Ees increased from 1.4±0.9 at baseline to 2.5±2.4 at discharge (p=0.0071) indicating an increaseed intrinsic LV contractility, while LV ejection fraction remained unchanged, but forward ejection fraction improved significantly (38.9±21.9% vs. 53.4±29.8%, p&amp;lt;0.001) (Figure 1). After the procedure we observed an increased left-ventricular end-diastolic pressure (LVEDP) (22.6±4.0mmHg vs. 26.1±5.1mmHg, p=0.012). However, PASP significantly decreased (50.5±16.5mmHg vs. 35.7±10.8mmHg, p&amp;lt;0.001). While TAPSE (18.1±5.5mm vs. 15.5±5.8mm, p=0.015) was also decreased at discharge, RV-PA coupling remained stable (0.4±0.2mm/mmHg vs. 0.5±0.2mmHg, p=0.19). Conclusions Non-invasive assessment of pressure volume loops before and after TMVR demonstrate an early LV reverse remodelling effect and improved systolic LV contractility, while RV performance was preserved. These results indicate the potential impact of complete MR elimination after TMVR on LV and RV function. Long-term data are needed to assess the prognostic impact of MR elimination and LV reverse remodelling following TMVR.Figure 1

Non-invasive pressure-volume loops from cardiovascular magnetic resonance predict cardiovascular mortality in heart failure with reduced ejection fraction

Abstract Background Heart failure with reduced ejection fraction (HFrEF) is characterized by impaired ventricular energetics secondary to ventricular remodeling. Left ventricular pressure-volume (PV) loop analysis (Figure 1) can now be performed noninvasively using cardiovascular magnetic resonance (CMR) imaging, enabling study of cardiac thermodynamic efficiency without the risk and cost associated with invasive measurements (1–3). Here we investigated whether noninvasive PV loops from CMR can predict cardiovascular death in HFrEF patients. Methods We analyzed 135 datasets (age 60±12 years, 79% male) from HFrEF patients (LVEF≤40%) who underwent clinical CMR examination at our center between 2004-2013. Pressure-volume loop parameters were computed from manually segmented CMR data and same-day brachial blood pressure (Segment 4.0 R11026, Medviso, Lund, Sweden). The primary endpoint was cardiovascular mortality extracted from national registries with a 5-year follow-up. Parameters of interest were selected from univariate Cox regression, and associations with clinical outcome evaluated using multivariate Cox regression. Survival was visualized using Kaplan-Meier analysis. Statistical analysis was performed in R 4.0.3 (R Core Team). Results A total of 19 deaths from cardiovascular causes occurred during follow-up. Univariate Cox regression found stroke work (SW, joule), ventricular efficiency (VE, %), external power (J/s), contractility (mmHg/ml), and energy per ejected volume (mJ/ml) computed from PV loops associated with the primary endpoint alongside age, LVEF, and NT-proBNP level. In multivariate Cox regression adjusted for age, ventricular efficiency remained significant (HR 0.86, p&amp;lt;0.001), while EF did not (p = 0.077). Event-free survival is shown in Figure 2. Conclusion Ventricular efficiency derived from non-invasive pressure-volume loop analysis from standard CMR scans, may outperform LV EF as a predictor of cardiovascular mortality in HFrEF. Figures: Figure 1. Example of left ventricular pressure-volume (PV) loop. The area enclosed by the loop is the stroke work (SW). The area bounded by the PV loop and the end-systolic pressure-volume relationship (ESPVR) is the potential energy (PE). Ventricular efficiency (VE) is calculated as SW/(PE+SW). Figure 2. Kaplan-Meier plots of survival by tertiles of stroke work and ventricular efficiency.Figure 1Figure 2

Increased cardiac output and left ventricular contractility in pigs paced with vs. without restored respiratory sinus arrhythmia - proof of principle of a newly developed pacing device

Abstract Background Heart rate variability (HRV) correlates with the severity and mortality of heart failure. Respiratory sinus arrhythmia (RSA) is defined by the dynamic increase and decrease in heart rate between breaths. Restoration of RSA might be beneficial in patients with heart failure and/or patients in need of permanent pacing. Purpose The aim of this translational, proof-of-principle study was to investigate the effect of pacing with or without RSA using a newly designed pacing device on the left ventricular contractility and cardiac output. Methods The project was initiated with the aim of designing a new pacing device capable of restoring RSA in paced hearts with the help of lung inflation sensors. Neuronal networks were designed to reconstruct the human brain using ultra-low energy-consuming technology. The lung inflation sensor fed the detected inspiration data back to the pacing device, which paced the heart via pacing leads (DDD) in the right atrium and ventricle. In total, 5 intubated but spontaneously breathing landrace pigs were paced without RSA (fixed-rate pacing) and with restored RSA. Stroke volume and cardiac output were measured by echocardiography (diameter of left ventricular outflow tract and velocity time integral measured by pulsed wave doppler averaged over three heart beats). Preload-independent cardiac contractility was measured via a pressure-volume loop catheter in the left ventricle during occlusion of the inferior vena cava. Fig. 1 indicates the setup of the trial. The trials were conducted according to the relevant rules (NIH Publication no. 85-23 revised 1985) and in accordance with national law. Results Echocardiography (n=5) showed a mean left ventricular outflow tract diameter of 21 ± 0.1 mm. The mean intrinsic heart rate was 87 ± 14 bpm, and the mean paced heart rate was 104 ± 5 bpm in the pigs (65 ± 3 kg). The main outcomes are displayed in Fig. 2: The left ventricular stroke volume increased by 11ml (+21%, p=0.036) with 100% RSA compared to pacing without RSA, while cardiac output increased by 1.14 l/min (+21%, p=0.037). The pressure volume area is proportional to the total myocardial oxygen consumption and decreased by 6234 mmHg*ml (-39%, p=0.004). Cardiac efficiency represents the relative amount of blood being pumped consuming one unit energy and increased by 0.163 (+72%, p=0.033). End-systolic pressure volume relationship demonstrated a non-significant increase by 0.183 mmHg/ml (+45%, p=0.25). Parameters of diastolic function (Tau) did not differ between the groups. Conclusion Restoration of RSA by our newly developed pacing device significantly improved the cardiac contractility/output in our proof-of-principle large animal translational model. Chronic trials will be required to definitively confirm the positive effects of RSA on cardiac remodeling.Fig. 1: Set-up of the animal trials.Fig. 2: Main results (mean/std error)

Long-acting CRF2 peptide agonist improves cardiac function in a rat heart failure model

Abstract Introduction Corticotropin-releasing factor receptor type 2 (CRF2) is a G protein-coupled receptor largely expressed in the cardiorenal system. Upon CRF2 activation, endogenous ligands such as urocortin-2 (UCN-2) or urocortin-3 (UCN-3) have been reported to increase cardiac function, decrease vascular resistance and improve natriuresis and diuresis in heart failure (HF) patients and in various experimental heart failure settings. However UCN-2 or -3 suffer from a very short half-life which markedly limit further clinical investigations in HF patients. For this purpose, a very long acting CRF2 peptide agonist has been developed. Objectives The aim of this study is to determine the acute effect on cardiac hemodynamic of a long acting CRF2 peptide agonist, COR-1167, in a rat model of chronic heart failure. Methods In 10-week-old Wistar rats, a total occlusion of the left anterior descending coronary artery was performed to induce myocardial infarction. Twelve weeks after myocardial infarction, rats had developed heart failure and received COR-1167 at the dose of 0.3 µg/kg or 1 µg/kg, or placebo, administered SC. Left ventricular dimensions and function were then assessed by echocardiography and left ventricular pressure-volume analysis. Results Three months after left coronary artery ligation rats displayed the classical features of heart failure as illustrated by an increase in left ventricular diastolic diameter and reduced ejection fraction, and decreases in LV end-systolic pressure, dP/dtmax and LV end-systolic pressure volume relationship. Major LV diastolic dysfunction developed, as shown by the increases in LV end-diastolic pressure, and LV end-diastolic pressure volume relationship and the decrease in dP/dtmin. Echocardiography and left ventricular pressure-volume analysis showed that COR-1167 at 0.3 and 1 µg/kg SC improved in a dose-dependent manner cardiac contractility and relaxation as assessed by LVESPVR and LVEDPVR, respectively. In addition, stroke volume and cardiac output were significantly ameliorated by COR-1167 at 1.0 µg/kg SC, with no change in heart rate. Conclusion Single acute administration of COR-1167 improved cardiac function in a rat model of heart failure with reduced ejection fraction. Altogether these results confirm that CRF2 agonism is an attractive therapeutic target for the treatment of heart failure.

Abstract 14766: Acute Impact of Transapical Ventricular Reshaping Device on Dilated Left Ventricle With Functional Mitral Regurgitation in Swine Model

Introduction: Functional mitral regurgitation (FMR) after myocardial infarction (MI) exacerbates morbidity and mortality. Correcting FMR plays a critical role in mitigating or reversing ventricular remodeling in MI patients with FMR. However, the COAPT trial demonstrated that FMR correction yields favorable results in smaller left ventricles (LVs) but not in severely dilated LVs. In this study, we evaluated the efficacy of a transapical device in MI swine model with FMR, which can perform papillary muscle approximation (PMA) and simultaneous reduction of LV volume. Methods: Yorkshire pig (n=15) were used in this study. MI was induced by percutaneous occlusion of the left circumflex artery, which caused LV dilatation and FMR by 3 months. The device was implanted through the LV apex to achieve PMA and LV reshaping until FMR was eliminated (Figure A). The immediate effects of the device implantation on the mitral valve and the LV were assessed using echocardiography and pressure-volume loops. Results: The device implantation decreased inter-papillary muscle distance from 24.5±3.8mm to 16.7±3.8mm (p&lt;0.0001), and significantly reduced FMR. Coaptation length significantly increased from 3.4±0.7mm to 5.5±1.2mm (p&lt;0.0001). End-diastolic volume decreased from 153±48ml to 117±33ml, a 23.5% reduction (p=0.0004). The end-systolic pressure-volume relationship and preload adjusted dP/dt max significantly increased after the device implant, indicating an improvement of LV contractility. There were no differences observed in Tau and end-diastolic pressure-volume relationship, depicting minimal acute impact on diastolic ventricular function after device implantation (Figure B and C). Conclusions: This transapical reshaping device effectively corrects FMR in very enlarged LVs, but also reduces systolic chamber wall stress by reducing the LV volume. An acute improvement in LV systolic function was observed, potentially indicating a therapeutic effect.

An in silico study of the effects of left ventricular assist device on right ventricular function and inter-ventricular interaction.

Left ventricular assist device (LVAD) is associated with a high incidence of right ventricular (RV) failure, which is hypothesized to be caused by the occurring inter-ventricular interactions when the LV is unloaded. Factors contributing to these interactions are unknown. We used computer modeling to investigate the impact of the HeartMate 3 LVAD on RV functions. The model was first calibrated against pressure-volume (PV) loops associated with a heart failure (HF) patient and validated against measurements of inter-ventricular interactions in animal experiments. The model was then applied to investigate the effects of LVAD on (1) RV chamber contractility indexed by derived from its end-systolic PV relationship, and (2) RV diastolic function indexed by derived from its end-diastolic PV relationship. We also investigated how septal wall thickness and regional contractility affect the impact of LVAD on RV function. The impact of LVAD on RV chamber contractility is small at a pump speed lower than 4k rpm. At a higher pump speed between 4k and 9k rpm, however, RV chamber contractility is reduced (by ~3% at 6k rpm and ~10% at 9k rpm). The reduction of RV chamber contractility is greater with a thinner septal wall or with a lower myocardial contractility at the LV free wall, septum, or RV free wall. RV chamber contractility is reduced at a pump speed higher than 4k rpm, and this reduction is greater with a thinner septal wall or lower regional myocardial contractility. Findings here may have clinical implications in identifying LVAD patients who may suffer from RV failure.