End-diastolic Pressure-volume Relationship Research Articles

Benefit of combination therapy with dapagliflozin and eplerenone on cardiac function and fibrosis in rats with non-diabetic chronic kidney disease

Patients with chronic kidney disease (CKD) are at a high risk of cardiovascular (CV) complications. In these patients, sodium-glucose cotransporter-2 inhibitors (SGLT2i) have been shown to reduce CV events. Mineralocorticoid receptor antagonists (MRAs) exert similar benefits in diabetic CKD, though their effects in non-diabetic CKD remain unclear. This study aimed to evaluated whether the combination of Dapagliflozin (DAPA) and Eplerenone (EPLE) would have positive effects on cardiorenal functions in a non-diabetic CKD model. CKD was induced in rats via 5/6 nephrectomy, followed by treatment with DAPA (5 mg/kg/day PO), EPLE (100 mg/kg/day PO) or the combination for 3 months following CKD induction. Cardiorenal functions were assessed after the treatment period. All treated groups showed reduced kidney fibrosis though plasma creatinine and urea levels remained unchanged. Compared to untreated CKD, EPLE or DAPA/EPLE reduced left ventricle (LV) end-diastolic pressure and LV end-diastolic pressure volume relationship, whereas DAPA alone did not achieve significant reductions. Compared to untreated CKD, EPLE and DAPA/EPLE improved cardiac perfusion but DAPA alone did not. Cardiac fibrosis in CKD was blunted by either DAPA or EPLE alone, with the combination showing an additive effect. In conclusion, co-treatment with DAPA and EPLE enhances diastolic function, cardiac perfusion and reduces myocardial fibrosis in non-diabetic CKD rats.

MMP-8 causes leftward shift in end-diastolic pressure-volume relationship and may explain the development of diastolic dysfunction in septic cardiomyopathy.

Septic cardiomyopathy (SCM) with diastolic dysfunction carries a poor prognosis, and the mechanisms underlying the development of diastolic dysfunction remain unclear. Matrix metalloproteinase-8 (MMP-8) is released from neutrophils and degrades collagen I. MMP-8 levels correlate with SCM severity. We scrutinized, for the first time, the direct impact of MMP-8 on cardiac systolic and diastolic functions. Isolated rat hearts were perfused with Krebs-Henseleit solution in a Langendorff setup with computer-controlled filling pressures of both ventricles in an isovolumetric regime. The end-diastolic pressure (EDP) varied periodically between 3 and 20 mmHg. After baseline recordings, MMP-8 (100 µg/mL) was added to the perfusion. Short-axis views of both ventricles were continuously acquired by echocardiography. MMP-8 perfusion resulted in a progressive decline in peak systolic pressures (Psys) in both ventricles, but without significant changes in their end-systolic pressure-area relationships (ESPARs). Counterintuitively, conspicuous leftward shifts of the end-diastolic pressure-area relationships (EDPARs) were observed in both ventricles. The left ventricle (LV) end-diastolic area (EDA) decreased by 32.8 ± 5.7% (P = 0.008) at an EDP of 10.5 ± 0.4 mmHg, when LV Psys dropped by 20%. The decline of Psys was primarily due to the decrease in EDA, and restoring the baseline EDA by increasing EDP recovered 81.33 ± 5.87% of the pressure drop. Collagen I generates tensile (eccentric) stress, and its degradation by MMP-8 causes end-diastolic pressure-volume relationship (EDPVR) leftward shift, resulting in diastolic and systolic dysfunctions. The diastolic dysfunction explains the clinically observed fluid unresponsiveness, whereas the decrease in end-diastolic volume (EDV) diminishes the systolic functions. MMP-8 can explain the development of SCM with diastolic dysfunction.NEW & NOTEWORTHY MMP-8, released from activated neutrophils and macrophages, is markedly elevated in sepsis, correlating with sepsis severity and mortality. MMP-8 targets collagen I of the cardiac ECM and induces diastolic dysfunction with fluid unresponsiveness, associated with decreased EDV, reduced sarcomere length, and diminished systolic function. Unlike other MMPs that predominantly cleave collagen-III and contribute to cardiac dilatation, thereby increasing sarcomere length, MMP-8 leads to a leftward shift in the EDPVR, resulting in diastolic and systolic dysfunctions.

Abstract P377: Short-Chain Fatty Acids Improve Cardiac Function in a Hypertensive Rat Model of Heart Failure

Hypertension-induced ventricular remodeling contributes significantly to the progression of heart failure (HF). The global increase in HF prevalence results in heightened cardiovascular morbidity and mortality, yet treatment options remain limited. The gut microbiota ferments indigestible dietary fibers, producing essential metabolites such as short-chain fatty acids (SCFAs), amino acids metabolites. We hypothesize that direct oral administration of SCFAs modulates mucosal immune cells, thereby ameliorating the heart failure with preserved ejection fraction (HFpEF) phenotype in the double-transgenic rat (dTGR) model. Four-week-old male rats, double-transgenic for human renin and angiotensinogen (dTGRs), were utilized. These dTGR rats exhibit classical symptoms of HFpEF, including hypertension, inflammation, and fibrosis in the heart and kidneys. The rats were randomized into five experimental groups: healthy non-transgenic vehicle-treated controls (wild type), vehicle-treated dTGR, and dTGR treated with either acetate, propionate, or butyrate. Following a 3-week treatment period, comprehensive phenotyping was conducted, including echocardiography, Millar-tip catheterization, gene expression analysis, and histological examination. SCFA administration improves diastolic function, as evidenced by alterations in the end-diastolic pressure-volume relationship measured via Millar-tip catheter. Notably, butyrate treatment had the most pronounced effect on alleviating diastolic dysfunction and reducing blood pressure. Additionally, gene expressions such as atrial natriuretic peptide, connective tissue growth factor, and myosin heavy chain alpha and beta showed improvement in SCFA-treated dTGR HFpEF rats compared to vehicle-treated counterparts. Furthermore, SCFA treatment ameliorated cardiac inflammation. Our data suggest that SCFAs, particularly butyric acid, enhance hypertensive diastolic dysfunction and cardiac gene expression in dTGR rats, underscoring their therapeutic potential in HF.

Randomized Crossover Trial of 2-Week Ketone Ester Treatment in Patients With Type 2 Diabetes and Heart Failure With Preserved Ejection Fraction.

Heart failure with preserved ejection fraction (HFpEF) is a major cause of morbidity and mortality in patients with type 2 diabetes (T2DM). Acute increases in circulating levels of ketone body 3-hydroxybutyrate have beneficial acute hemodynamic effects in patients without T2DM with chronic heart failure with reduced ejection fraction. However, the cardiovascular effects of prolonged oral ketone ester (KE) treatment in patients with T2DM and HFpEF remain unknown. A total of 24 patients with T2DM and HFpEF completed a 6-week randomized, double-blind crossover study. All patients received 2 weeks of KE treatment (25 g D-ß-hydroxybutyrate-(R)-1,3-butanediol × 4 daily) and isocaloric and isovolumic placebo, separated by a 2-week washout period. At the end of each treatment period, patients underwent right heart catheterization, echocardiography, and blood samples at trough levels of intervention, and then during a 4-hour resting period after a single dose. A subsequent second dose was administered, followed by an exercise test. The primary end point was cardiac output during the 4-hour rest period. During the 4-hour resting period, circulating 3-hydroxybutyrate levels were 10-fold higher after KE treatment (1010±56 µmol/L; P<0.001) compared with placebo (91±55 µmol/L). Compared with placebo, KE treatment increased cardiac output by 0.2 L/min (95% CI, 0.1 to 0.3) during the 4-hour period and decreased pulmonary capillary wedge pressure at rest by 1 mm Hg (95% CI, -2 to 0) and at peak exercise by 5 mm Hg (95% CI, -9 to -1). KE treatment decreased the pressure-flow relationship (∆ pulmonary capillary wedge pressure/∆ cardiac output) significantly during exercise (P<0.001) and increased stroke volume by 10 mL (95% CI, 0 to 20) at peak exercise. KE right-shifted the left ventricular end-diastolic pressure-volume relationship, suggestive of reduced left ventricular stiffness and improved compliance. Favorable hemodynamic responses of KE treatment were also observed in patients treated with sodium-glucose transporter-2 inhibitors and glucagon-like peptide-1 analogs. In patients with T2DM and HFpEF, a 2-week oral KE treatment increased cardiac output and reduced cardiac filling pressures and ventricular stiffness. At peak exercise, KE treatment markedly decreased pulmonary capillary wedge pressure and improved pressure-flow relationship. Modulation of circulating ketone levels is a potential new treatment modality for patients with T2DM and HFpEF. URL: https://www.clinicaltrials.gov; Unique Identifier: NCT05236335.

Abstract Mo100: Predictive Accuracy of Rightward Extrapolation of the Left Ventricular End-Diastolic Pressure-Volume Relationship in Healthy Swine

Objective: Myocardial stiffness is a primary determinant of left ventricular (LV) diastolic function and can be quantitatively described by the end-diastolic pressure-volume relationship (EDPVR). The EDPVR is traditionally derived by measuring LV end-diastolic pressure (EDP) and volume (EDV) during transient reductions in venous return (preload). However, the accuracy of this approach in predicting changes in LVEDP in response to a rise in LVEDV via rightward extrapolation has not been directly studied. Accordingly, we sought to assess the predictive accuracy of preload reduction-derived EDPVRs in estimating LV diastolic stiffness (ΔLVEDP/ΔLVEDV) in healthy swine. Methods: LVEDP and LVEDV were measured in swine (n=6) at rest and during transient inferior vena cava (IVC) occlusion (reduced preload), transient aortic occlusion (increased afterload), and intravenous phenylephrine (PE; 0.5 mg/kg/hr; increased afterload and preload). Pressure-volume data collected during IVC occlusion were used to generate the EDPVR, the accuracy of which was determined via comparison to measurements of ΔLVEDP/ΔLVEDV during aortic occlusion and PE. Results: The LV diastolic stiffness coefficient was greater when derived via aortic occlusion vs. IVC occlusion (0.057±0.013 vs. 0.022±0.004; p=0.03). As a result, IVC occlusion-derived EDPVRs underestimated the rise in LVEDP during aortic occlusion (7.6±2.2 vs. 13.5±2.1 mmHg; p=0.08). Similarly, ΔLVEDP/ΔLVEDV in response to aortic occlusion (0.96±0.28 mmHg/mL) tended to be higher than that predicted from the IVC occlusion-derived EDPVR (0.44±0.09 mmHg/mL; p=0.12). Compared with aortic occlusion, PE elicited a greater rise in LVEDV (31.5±5.4 vs.18.6±4.2 mL; p=0.08) and LVEDP (20.8±1.3 vs. 13.5±2.1 mmHg; p=0.01) but ΔLVEDP/ΔLVEDV was comparable between each condition (0.78±0.16 mmHg/mL vs. 0.96±0.28 mmHg/mL; p=0.60). However, ΔLVEDP/ΔLVEDV derived from PE tended to be higher than that from IVC occlusion (0.78±0.16 mmHg/mL vs. 0.44±0.09 mmHg/mL; p=0.10). Conclusions: Rightward extrapolation of the EDPVR derived via IVC occlusion underestimates the rise in LVEDP when LVEDV is increased in the normal heart. This was observed with increased afterload as well as when afterload and preload were simultaneously increased via PE. These findings reinforce the importance of assessing the hemodynamic response to increased LV loading directly, rather than extrapolating from EDPVRs created via transient preload reduction.

Abstract Mo113: An Ovary-Intact Postmenopausal HFpEF Animal Model.

Background: The incidence of HFpEF in women significantly escalates following the age of menopause. This trend cannot solely be attributed to chronological aging, as evidenced by the more gradual increase in prevalence among men with HFpEF. This pattern suggests that menopause is a provocative event for HFpEF. However, the underlying mechanisms remain elusive and challenging to investigate in human subjects; moreover, the attempt to create HFpEF in ovariectomized (OVX) mice was unsuccessful. We aim to create an animal model of postmenopausal HFpEF that resembles the characteristics of HFpEF in women with natural menopause. Methods: We use the 4-vinyl cyclohexene dioxide (VCD) to induce “ovary-intact” menopause, combined with the 2hit regimen (HFpEF inducing regimen elicited by high-fat diet and nitric oxide synthase inhibitor) to model postmenopausal HFpEF. VCD gradually causes ovarian failure, providing the perimenopausal transition and preserving residual ovarian stroma, mimicking natural menopause. The HFpEF phenotypes were studied at the in vivo LV by pressure-volume (PV) analysis and at the single cell level by intact cell force measurement. Results: The Female-VCD-2hit model demonstrates diastolic dysfunction at both the LV and the cellular levels. At the LV level, the increase in the end-diastolic pressure-volume relation (EDPVR) stiffness coefficient and LV end-diastolic pressure (LVEDP) indicates a heightened stiffness of the LV chamber and an elevation in LV filling pressure, an HFpEF-like condition. At the cardiomyocyte level, the female-VCD-2hit model exhibits an increase in cellular diastolic stiffness, suggesting that the observed LV diastolic stiffness is derived from the stiffness of the cardiomyocytes. We compared the female-VCD-2hit mice with the OVX mice subjected to the 2hit regimen. The 2hit-OVX model showed a milder form of diastolic dysfunction, observed as a smaller increase in LV diastolic stiffness (EDPVR) and normal LV filling pressure (LVEDP). Conclusions: Female mice, either premenopausal or ovariectomized, are more resistant to the development of HFpEF, unlike their ovary-intact menopausal (VCD-treated) counterparts, which exhibit a vulnerability to HFpEF, making the VCD-2hit model a suitable model to study postmenopausal HFpEF. The LV diastolic dysfunction observed in the 2hit model is attributed to mechanical dysfunction at the cardiomyocyte level.

Racial Differences of Cardiac Structure and Function in Heart Failure With Preserved Ejection Fraction

Potential race differences in cardiac structure and function among patients with heart failure with preserved ejection fraction (HFpEF) are not well-understood, but may have pathophysiological and treatment implications. In this study, patients with HFpEF who self-identified as Asian (n = 360), White (n = 787), and Black (n = 171) from 3 institutions underwent comprehensive transthoracic echocardiography to evaluate for potential differences. The Asian HFpEF group was oldest and the Black HFpEF group was youngest (75 ± 12 years vs 73 ± 13 years vs 62 ± 12 years; P < .0001). Women constituted the lowest proportion of patients with HFpEF among Asian individuals, but were the largest among Black patients (49% vs 56% vs 73%; P < .0001). Body mass index and obesity prevalence were highest in Black patients with HFpEF and were lowest in Asian patients. Black individuals with HFpEF had greater left ventricular (LV) wall thickening and concentricity, smaller LV chamber size, leftward-shifted LV end-diastolic pressure-volume relationship, indicating greater LV stiffening, smallest left atrial volumes, and the most right ventricular dilatation. Asian individuals with HFpEF had greater LV and left atrial dilation, more rightward shifted LV end-diastolic pressure-volume relationship, and the highest arterial stiffness. In summary, we show that patients with HFpEF of Asian, Black, and White race display key differences in clinical, anthropometric, and cardiac structure-function indices, indicating that consideration of race-related differences might important to individualize treatment strategies in HFpEF.

Personalized evaluation of the passive myocardium in ischemic cardiomyopathy via computational modeling using Bayesian optimization.

Biomechanics-based patient-specific modeling is a promising approach that has proved invaluable for its clinical potential to assess the adversities caused by ischemic heart disease (IHD). In the present study, we propose a framework to find the passive material properties of the myocardium and the unloaded shape of cardiac ventricles simultaneously in patients diagnosed with ischemic cardiomyopathy (ICM). This was achieved by minimizing the difference between the simulated andthe target end-diastolic pressure-volume relationships (EDPVRs) using black-box Bayesian optimization, based on the finite element analysis (FEA). End-diastolic (ED) biventricular geometry and the location of the ischemia were determined from cardiac magnetic resonance (CMR) imaging. We employed our pipeline to model the cardiac ventricles of three patients aged between 57 and 66years, with and without the inclusion of valves. An excellent agreement between the simulated and thetarget EDPVRs has been reached. Our results revealed that the incorporation of valvular springs typically leads to lower hyperelastic parameters for both healthy and ischemic myocardium, as well as a higher fiber Green strain in the viable regions compared to models without valvular stiffness. Furthermore, the addition of valve-related effects did not result in significant changes in myofiber stress after optimization. We concluded that more accurate results could be obtained when cardiac valves were considered in modeling ventricles. The present novel and practical methodology paves the way for developing digital twins of ischemic cardiac ventricles, providing a non-invasive assessment for designing optimal personalized therapies in precision medicine.

Nonsteroidal Mineralocorticoid Receptor Antagonist Finerenone Improves Diastolic Dysfunction in Preclinical Nondiabetic Chronic Kidney Disease.

The mineralocorticoid receptor plays a significant role in the development of chronic kidney disease (CKD) and associated cardiovascular complications. Classic steroidal mineralocorticoid receptor antagonists are a therapeutic option, but their use in the clinic is limited due to the associated risk of hyperkalemia in patients with CKD. Finerenone is a nonsteroidal mineralocorticoid receptor antagonist that has been recently investigated in 2 large phase III clinical trials (FIDELIO-DKD [Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease] and FIGARO-DKD [Finerenone in Reducing Cardiovascular Mortality and Morbidity in Diabetic Kidney Disease]), showing reductions in kidney and cardiovascular outcomes. We tested whether finerenone improves renal and cardiac function in a preclinical nondiabetic CKD model. Twelve weeks after 5/6 nephrectomy, the rats showed classic signs of CKD characterized by a reduced glomerular filtration rate and increased kidney weight, associated with left ventricular (LV) diastolic dysfunction and decreased LV perfusion. These changes were associated with increased cardiac fibrosis and reduced endothelial nitric oxide synthase activating phosphorylation (ser 1177). Treatment with finerenone prevented LV diastolic dysfunction and increased LV tissue perfusion associated with a reduction in cardiac fibrosis and increased endothelial nitric oxide synthase phosphorylation. Curative treatment with finerenone improves nondiabetic CKD-related LV diastolic function associated with a reduction in cardiac fibrosis and increased cardiac phosphorylated endothelial nitric oxide synthase independently from changes in kidney function. Short-term finerenone treatment decreased LV end-diastolic pressure volume relationship and increased phosphorylated endothelial nitric oxide synthase and nitric oxide synthase activity. We showed that the nonsteroidal mineralocorticoid receptor antagonist finerenone reduces renal hypertrophy and albuminuria, attenuates cardiac diastolic dysfunction and cardiac fibrosis, and improves cardiac perfusion in a preclinical nondiabetic CKD model.

Kbtbd13R408C-knockin mouse model reveals impaired relaxation kinetics as novel pathomechanism for NEM6 cardiomyopathy

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): VENI-Nederlandse organisatie voor Wetenschappelijk Onderzoek (NWO) We identified a novel cardiomyopathy gene: KBTBD13 encoding kelch repeat and BTB (POZ) domain containing 13. The Dutch founder variant KBTBD13R408C not only affects skeletal muscle function resulting in nemaline myopathy type 6 (NEM6), but also affects the heart. In the Dutch NEM6 cohort, various cardiac abnormalities were observed, including systolic dysfunction, diastolic dysfunction, atrial fibrillation, ventricular tachycardia and three patients died of sudden cardiac death. The majority of NEM6 patients harbors the Dutch founder variant, c.1222C&amp;gt;T, p.Arg408Cys (KBTBD13R408C). To provide insight in the mechanism underlying cardiac dysfunction in NEM6, here we assessed cardiac structure and function in Kbtbd13R408C-knockin mice, which closely recapitulate the well characterized skeletal muscle phenotype, i.e. impaired relaxation kinetics and mitochondrial dysfunction. Pressure-volume loop analyses showed that the end-diastolic pressure-volume relation was steeper in Kbtbd13R408C-knockin mice, indicating diastolic dysfunction. Histological evaluation of cardiac structure revealed no increase in fibrosis in Kbtbd13R408C-knockin mice. Also, no alterations in titin isoform composition or myosin heavy chain composition were observed that could account for the increased diastolic stiffness. Next, we studied the contraction and relaxation kinetics in wild type (WT) and Kbtbd13R408C-knockin mice at the intact single cardiomyocyte level by a high-throughput contractility set-up. Our data showed a prolonged relaxation time in Kbtbd13R408C-knockin mice compared to WT mice, indicating impaired relaxation kinetics. No differences in the magnitude of contraction (percentage of shortening) was found between cardiomyocytes of Kbtbd13R408C-knockin and WT mice. In parallel, calcium-handling was assessed by calcium indicator Fura-2AM. These studies reveal that calcium-release is not affected, but calcium-reuptake is slower in Kbtbd13R408C-knockin mice, which might contribute to the impaired relaxation kinetics. Current studies focus on how KBTBD13R408C affects calcium-reuptake kinetics and sarcomere kinetics in NEM6 cardiomyocytes. Hence, our studies provide the first insights in the pathomechanism underlying cardiac dysfunction in NEM6.

NON-INVASIVE ASSESSMENT OF HEMODYNAMIC FORCES AND PRESSURE-VOLUME RELATION ANALYSIS IN TWIN PREGNANCY

Objective: This aim of the study was to prospectively investigate pattern of intraventricular Hemo-Dynamic Forces (HDF) associated with Left Ventricular (LV) function and remodeling in women with uncomplicated twin pregnancy. Design and method: Prospective, cohort study. Transthoracic echocardiography was performed on 35 women (aged 35.9±4.7 years) during gestation (&lt;14 w, T1; 14–27 w, T2; &gt;28 w, T3), and 6–7 months after delivery (T0). LV HDF were computed from echocardiography long axis data sets using a novel technique based on endocardial boundary tracking, both in apex-base (A-B) and latero-septal (L-S) directions. HDF distribution was evaluated by L-S over A-B HDF ratio (L-S/A-B HDF ratio). Results: At T1, L-S/A-B HDF ratio was higher than in T0 (p&lt;0.05) indicating HDF misalignment. At T2, a slight impairment of cardiac function was then recorded with a reduction of Global Longitudinal Strain (GLS) and left ventricular End-Systolic Elastance (Ees) at pressure-volume relationship analysis versus T1 (both p&lt;0.05). Finally, at T3, when HDF misalignment and LV contractility reduction (GLS and Ees) were all restored, a rightward shift of the End Diastolic Pressure-Volume Relationship (EDPVR) with an increase of ventricular capacitance were documented. Conclusions: In twin pregnancy, HDF misalignment in the first trimester precedes the slight temporary decrease in left ventricular systolic function in the second trimester; at the third trimester a rightward shift of the EDPVR was associated with a realignment of HDF and normalization of ventricular contractility indexes. These coordinated changes that occur in the maternal heart during twin pregnancy suggests the role of HDF in cardiac remodelling.

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.

Comparative analysis of ventricular stiffness across species.

Investigating ventricular diastolic properties is crucial for understanding the physiological cardiac functions in organisms and unraveling the pathological mechanisms of cardiovascular disorders. Ventricular stiffness, a fundamental parameter that defines ventricular diastolic functions in chordates, is typically analyzed using the end-diastolic pressure-volume relationship (EDPVR). However, comparing ventricular stiffness accurately across chambers of varying maximum volume capacities has been a long-standing challenge. As one of the solutions to this problem, we propose calculating a relative ventricular stiffness index by applying an exponential approximation formula to the EDPVR plot data of the relationship between ventricular pressure and values of normalized ventricular volume by the ventricular weight. This article reviews the potential, utility, and limitations of using normalized EDPVR analysis in recent studies. Herein, we measured and ranked ventricular stiffness in differently sized and shaped chambers using exvivo ventricular pressure-volume analysis data from four animals: Wistar rats, red-eared slider turtles, masu salmon, and cherry salmon. Furthermore, we have discussed the mechanical effects of intracellular and extracellular viscoelastic components, Titin (Connectin) filaments, collagens, physiological sarcomere length, and other factors that govern ventricular stiffness. Our review provides insights into the comparison of ventricular stiffness in different-sized ventricles between heterologous and homologous species, including non-model organisms.

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.

Impact of Interventricular Interaction on Ventricular Function: Insights From Right Ventricular Pressure-Volume Analysis

BackgroundInterventricular interactions may be responsible for the decline in ventricular performance observed in various disease states that primarily affect the contralateral ventricle. ObjectivesThis study sought to quantify the impact of such interactions on right ventricular (RV) size and function using clinically stable individuals with left ventricular assist devices (LVADs) as a model for assessing RV hemodynamics while LV loading conditions were acutely manipulated by changing device speed during hemodynamic optimization studies (ie, ramp tests). MethodsThe investigators recorded RV pressure-volume loops with a conductance catheter at various speeds during ramp tests in 20 clinically stable HeartMate3 recipients. ResultsWith faster LVAD speeds and greater LV unloading, indexed RV end-diastolic volume increased (72.28 ± 15.07 mL at low speed vs 75.95 ± 16.90 at high speed; P = 0.04) whereas indexed end-systolic volumes remained neutral. This resulted in larger RV stroke volumes and shallower end-diastolic pressure-volume relationships. Concurrently, RV end-systolic pressure decreased (31.58 ± 9.75 mL at low speed vs 29.58 ± 9.41 mL at high speed; P = 0.02), but contractility, as measured by end-systolic elastance, did not change significantly. The reduction in RV end-systolic pressure was associated with a reduction in effective arterial elastance from 0.65 ± 0.43 mm Hg/mL at low speed to 0.54 ± 0.33 mm Hg/mL at high speed (P = 0.02). ConclusionsInterventricular interactions resulted in improved RV compliance, diminished afterload, and did not reduce RV contractility. These data challenge the prevailing view that interventricular interactions compromise RV function, which has important implications for the understanding of RV-LV interactions in various disease states, including post-LVAD RV dysfunction.

Which Diastolic Pressure Should Be Used to Assess Diastolic Function?

Although high left ventricular filling pressures [left ventricular (LV) end-diastolic pressure or pulmonary capillary wedge pressure (PCWP)] are widely taken as surrogates for LV diastolic dysfunction, the actual distending pressure that governs LV diastolic stretch is transmural pressure difference (∆PTM). Clinically, preferring ∆PTM over PCWP may improve diagnostic and therapeutic decision-making. We aimed to compare the clinical implications of diastolic function characterization based on PCWP or ∆PTM. We retrospectively screened our hospital database for adult patients with a clinical diagnosis of heart failure who underwent right heart catheterization. Echocardiographic diastolic dysfunction was graded according to the current guidelines. LV end-diastolic properties were assessed with construction of complete end-diastolic pressure-volume relationship (EDPVR) curves using the single-beat method. Survival status was checked via the electronic national health-care system. A total of 693 cases were identified in our database; the final study population comprised 621 cases. ∆PTM-based, but not PCWP-based, EDPVR diastolic stiffness constants were significantly predictive of advanced diastolic dysfunction. PCWP-based diastolic stiffness constants were not able to predict 5-year mortality, whereas ∆PTM-based EDPVR stiffness constants and volumes all turned out to have significant predictive power for 5-year mortality. Left ventricular diastolic function assessment can be improved using ∆PTM instead of PCWP. As ∆PTM ultimately linked to right-sided functions, this approach emphasizes the limitations of taking LV diastolic function as an isolated phenomenon and underlines the need for a complete hemodynamic assessment involving the right heart in therapeutic and prognostic decision-making processes.

Left ventricular remodeling in twin pregnancy, noninvasively assessed using hemodynamic forces and pressure-volume relation analysis: prospective, cohort study.

This study was designed to prospectively investigate the pattern of intraventricular hemodynamic forces (HDFs) associated with left ventricular (LV) function and remodeling in women with uncomplicated twin pregnancy. Transthoracic echocardiography was performed on 35 women (aged 35.9 ± 4.7-yr old) during gestation (T1, <14 wk; T2, 14-27 wk; T3, >28 wk) and 6-7 mo after delivery (T0). LV HDFs were computed from echocardiography long-axis data sets using a novel technique based on endocardial boundary tracking, both in apex-base (A-B) and latero-septal (L-S) directions. HDF distribution was evaluated by L-S over A-B HDF ratio (L-S:A-B HDF ratio). At T1, L-S:A-B HDF ratio was higher than in T0 (P < 0.05) indicating HDF misalignment. At T2, a slight impairment of cardiac function was then recorded with a reduction of global longitudinal strain (GLS) and left ventricular end-systolic elastance (Ees) at pressure-volume relationship analysis versus T1 (both P < 0.05). Finally, at T3, when HDF misalignment and LV contractility reduction (GLS and Ees) were all restored, a rightward shift of the end-diastolic pressure-volume relationship (EDPVR) with an increase of ventricular capacitance was documented. In twin pregnancy, HDF misalignment in the first trimester precedes the slight temporary decrease in left ventricular systolic function in the second trimester; at the third trimester, a rightward shift of the EDPVR was associated with a realignment of HDF and normalization of ventricular contractility indexes. These coordinated changes that occur in the maternal heart during twin pregnancy suggest the role of HDFs in cardiac remodeling.NEW & NOTEWORTHY These changes indicate that 1) the misalignment of hemodynamic forces (HDFs) precedes a mild reduction in systolic function in twin pregnancy and 2) the positive left ventricular (LV) response to hemodynamic stress is mainly due to an improved diastolic function with enhanced LV cavity compliance.

Diabetes and chronic kidney disease synergistically contribute to left ventricular diastolic dysfunction and coronary microvascular disease in swine

Abstract Background Chronic kidney disease (CKD) and diabetes (DM) are common causes of cardiovascular disease (CVD), and contribute to the development of left ventricular diastolic dysfunction (LVDD) and coronary microvascular dysfunction (CMD). Purpose To investigate if CKD and DM contribute synergistically to the development of CMD and LVDD by increasing myocardial interstitial fibrosis in a swine model. Methods CKD was induced by renal microembolization at 10-12 weeks of age in 8 wild type (WT) and 6 DM (INSC94Y) swine, while 6 WT and 5 DM swine served as control. LVDD was assessed using pressure volume loops and coronary flow reserve (CFR) was measured by intracoronary infusion of adenosine in the left anterior descending coronary artery. Afterwards, myocardium and kidney tissues were histologically examined for interstitial fibrosis. Results DM was confirmed by increased blood glucose values in the DM and DMCKD (figure 1-A). Renal embolization resulted in renal fibrosis in the WTCKD and DMCKD (figure 1-B), which was accompanied by a trend towards proteinuria, i.e., elevated protein/creatinine ratios (figure 1-C). LVDD was evidenced by an increase in the slope of the end-diastolic pressure volume relationship (EDPVR) in WTCKD, DM and DMCKD as compared to WT, with the largest increase in DMCKD (figure 1-D). WTCKD and DMCKD animals showed higher interstitial fibrosis levels in the LV (figure 1-E). CFR tended to be decreased in WTCKD, DM and DMCKD swine compared to WT (figure 1-F). Conclusions Renal embolization resulted in proteinuria and renal fibrosis, particularly in DM animals. DM and CKD also caused myocardial interstitial fibrosis, which impaired left ventricular diastolic function. The effects tended to be larger in DMCKD as compared to DM or WTCKD. Moreover, CFR tended to be decreased, suggestive of CMD, with the largest effect in DMCKD. In conclusion, DM and CKD contributed synergistically to LVDD and CMD.

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.