Increase In Left Ventricular End-diastolic Pressure Research Articles

Analysis of the significance of echocardiographic signs of right ventricular dysfunction for predicting the outcome of heart failure with reduced left ventricular ejection fraction

Objective: to determine the ultrasound signs of right heart dysfunction, which increase the prognostic value of the recommended parameters of left ventricular (LV) dysfunction in patients with heart failure with reduced ejection fraction (HFrEF).Materials and methods. The prospective study included 79 patients with HFrEF LV with clinical manifestations of chronic heart failure functional class III according to the New York Heart Association (HF NYHA Class III) in 52 patients (65.8%) and HF NYHA Class IV in 27 (34.1%). The primary end point was death during a follow-up period of up to 3 years while waiting for heart transplantation.Results. Overall mortality was 33 patients (41.7%), 17 (21.5%) during the 1st year of follow-up. Regression analysis revealed the following independent ultrasound predictors of poor prognosis: LV ejection fraction on 3D-echocardiography (3DE LVEF), p = 0.014; global longitudinal strain of the LV (GLS LV), p = 0.010, and of the interventricular septum basal segment (IVSLS BS), p = 0.012; mean longitudinal strain of the basal segment of the right ventricle free wall (FWLS BS RV), p = 0.003. Changes in the configuration and dilatation of the LV cavity, an increase in LV end-diastolic pressure, impaired contractility, and strain of the LV myocardium can affect the function of the right ventricle (RV) through the common interventricular septum (IVS). Dilatation of the RV due to an increase in the end diastolic area (RV EDA) of more than 30 cm2 (p = 0.012) and end systolic area (RV ESA) of more than 25 cm2 (p = 0.001), an increase in the volume of the right atrium (3DE AKI) of more than 100 ml (p = 0.036), and a decrease in the % inspiratory collapse of the inferior vena cava (% IVC) less than 30% (p = 0.005) demonstrated a prognostic significance in the observed patients. A decrease in the deformation properties of the pancreas due to the longitudinal component and impaired strain of the basal segment makes a greater contribution to RV dysfunction (FWLS BS, % < -15% (p < 0.001)).Conclusions. RV dysfunction in patients with HFrEF is an unfavorable prognostic factor, independently associated with existing LV dysfunction. The most significant ultrasound sign for surveillance prediction of patients with LV HFrEF and RV dysfunction are indicators of ventricular myocardial deformation. Remodeling of the right chambers and dysfunction of the RV is a trigger for the separation of the RV and pulmonary artery, which ultimately leads to adverse outcomes.

Intact DNA Repair in Differentiated Cardiomyocytes Is Essential for Maintaining Cardiac Function in Response to Pressure Overload in Mice

Introduction: DNA in every cell is continuously damaged and DNA repair mechanisms are essential for protection against DNA damage-induced aging-related diseases. For example, deficient repair of endogenously generated DNA damage in mice with cardiomyocyte-restricted inactivation of Xpg, is associated with progressive heart failure (de Boer et al. Aging Cell 2023). Here we tested the hypothesis that unrepaired DNA damage in differentiated cardiomyocytes increases cardiac vulnerability in response to hemodynamic overload. Methods: At 8 weeks of age, αMHC-Xpgc/- and control (Ctrl) mice were subjected to pressure overload by mild transverse aortic constriction (TAC). Eight weeks after TAC, left ventricular (LV) function was assessed using echocardiography and hemodynamic measurements, followed by histological and molecular analyses. Results: Cardiomyocyte-restricted inactivation of Xpg resulted in systolic as well as diastolic LV dysfunction. TAC-induced LV hypertrophy was similar in both groups (Ctrl 38%; αMHC-Xpgc/- 34%). In Ctrl mice, LV hypertrophy was accompanied by minimal LV dilation and only modest changes in systolic and diastolic LV function. Conversely, TAC in αMHC-Xpgc/- produced severe LV dilation and dysfunction and resulted in overt backward failure, demonstrated by marked increases in LV end-diastolic pressure, left atrial weight and lung fluid weight. These changes were accompanied by further increases in the expression levels of the hypertrophic marker genes atrial natriuretic peptide and beta-myosin heavy chain. Moreover, lectin staining revealed a decrease in capillary density and TUNEL staining revealed further elevated levels of myocardial apoptosis in αMHC-Xpgc/--TAC mice as compared to Ctrl-TAC mice. In addition, a significant increase of myocardial collagen content was observed in αMHC-Xpgc/--TAC but not in Ctrl-TAC mice. Conclusion: Cardiomyocyte-restricted loss of DNA repair protein Xpg increases cardiac vulnerability to develop heart failure in response to pressure-overload. These findings underscore the importance of genomic stability for maintenance of cardiac function, not only under basal conditions, but also during increased cardiac loading conditions. Supported by the Dutch Heart Foundation [Grants 2017B018-ARENA-PRIME; 2021B008-RECONNEXT]. 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.

Cardiovascular dysfunction induced by combined exposure to nicotine inhalation and high-fat diet.

Smoking and high-fat diet (HFD) consumption are two modifiable risk factors for cardiovascular (CV) diseases, and individuals who are overweight or obese due to unhealthy diet are more likely to use tobacco products. In this study, we aim to investigate the combined effects of nicotine (the addictive component of all tobacco products) and HFD on CV health, which are poorly understood. C57BL/6N male mice were placed on either HFD (60 kcal% fat) or regular diet (22 kcal% fat) and exposed to air or nicotine vapor for 10-12 wk. CV function was monitored by echocardiography and radiotelemetry, with left ventricular (LV) catheterization and aortic ring vasoreactivity assays performed at end point. Mice on HFD exhibited increased heart rate and impaired parasympathetic tone, whereas nicotine exposure increased sympathetic vascular tone as evidenced by increased blood pressure (BP) response to ganglionic blockade. Although neither nicotine nor HFD alone or in combination significantly altered BP, nicotine exposure disrupted circadian BP regulation with reduced BP dipping. LV catheterization revealed that combined exposure to nicotine and HFD led to LV diastolic dysfunction with increased LV end-diastolic pressure (LVEDP). Moreover, combined exposure resulted in increased inhibitory phosphorylation of endothelial nitric oxide synthase and greater impairment of endothelium-dependent vasodilation. Finally, a small cohort of C57BL/6N females with combined exposure exhibited similar increases in LVEDP, indicating that both sexes are susceptible to the combined effect of nicotine and HFD. In summary, combined exposure to nicotine and HFD leads to greater CV harm, including both additive and new-onset CV dysfunction.NEW & NOTEWORTHY Nicotine product usage and high-fat diet consumption are two modifiable risk factors for cardiovascular diseases. Here, we demonstrate that in mice, combined exposure to inhaled nicotine and high-fat diet results in unique cardiovascular consequences compared with either treatment alone, including left ventricular diastolic dysfunction, dysregulation of blood pressure, autonomic dysfunction, and greater impairment of endothelium-dependent vasorelaxation. These findings indicate that individuals who consume both nicotine products and high-fat diet have distinctive cardiovascular risks.

Left atrial strain as a predictor of left ventricular filling pressures in coronary artery disease with preserved ejection fraction: a comprehensive study with left ventricular end-diastolic and pre-atrial contraction pressures.

Assessing left ventricular (LV) filling pressure (LVFP) is challenging in patients with coronary artery disease (CAD) and preserved LV ejection fraction (LVEF). We aimed to correlate left atrial strain (LAS) with two invasive complementary parameters of LVFP and compared its accuracy to other echocardiographic data to predict high LVFP.This cross-sectional, single-center study enrolled 81 outpatients with LVEF > 50% and significant CAD from a database. Near-simultaneous echocardiography and invasive measurements of both LV end-diastolic pressure (LVEDP) and LV pre-atrial contraction (pre-A) pressure were performed in each patient, based on the definition of LVEDP > 16 mmHg and LV pre-A > 12 mmHg as high LVFP.A moderate to strong correlation was observed between LAS reservoir (LASr), contractile strain, and LVEDP (r: 0.67 and 0.62, respectively; p < 0.001); the same was true for LV pre-A (r: 0.65 and 0.63, respectively; p < 0.001). LASr displayed good diagnostic performance to identify elevated LVFP, which was higher when compared to traditional parameters. Median value of LASr was higher for an isolated increase of LVEDP than for simultaneously high LV pre-A. The cutoff found to predict high LVFP was lower for LV pre-A than that one for LVEDP. In the current study, LASr did not provide an additional contribution to the 2016 diastolic function algorithm.LAS is a valuable tool for predicting LVFP in patients with CAD and preserved LVEF. The choice of LVEDP or LV pre-A as the representative marker of LVFP leads to different cutoffs to predict high pressures. The best strategy for adding this tool to a multiparametric algorithm requires further investigation.

Coronary artery disease is associated with impaired atrial function regardless of left ventricular filling pressure

BackgroundLeft atrial (LA) strain is impaired in left ventricular (LV) diastolic dysfunction, associated with increased LV end diastolic pressure (LVEDP). In patients with preserved LV ejection fraction (LVEF), coronary artery disease (CAD) is known to impair LV diastolic function. The relationship of LVEDP with CAD and impact on LA strain is not well studied. Methods and resultsPatients with LVEF >50% (n = 37, age 61 ± 7 years) underwent coronary angiography, high-fidelity LV pressure measurements and cardiac magnetic resonance imaging. LA volumes, LA emptying fraction (LAEF), LA reservoir strain (LARS) and LA long-axis shortening (LALAS) were measured. By coronary angiography, patients were assigned into 3 groups: severe-CAD (n = 19, with obstruction of major coronary arteries >70% and/or history of coronary revascularization), mild-to-moderate-CAD (n = 10, obstruction of major coronary arteries 30–60%), and no-CAD (n = 8, obstruction of major coronary arteries and branches <30%). Overall, LVEF was 65 ± 8% and LVEDP was 14.4 ± 5.6 mmHg. Clinical characteristics, LVEDP and LV function measurements were similar in 3 groups. Severe-CAD group had lower LAEF, LALAS and LARS than those in no-CAD group (P < 0.05 all). In regression analysis, LARS and LALAS were associated with CAD severity and treatment with Nitrates, whereas LAEF and LAEFactive were associated with CAD severity, treatment with Nitrates and LA minimum volume (P < 0.05 all). LAEFpassive was associated with LVED volume (P < 0.05). ConclusionsLA functional impairment may be affected by coexistent CAD severity, medications, in particular, Nitrates, and loading conditions, which should be considered when assessing LA function and LA-LV interaction. Our findings inspire exploration in a larger cohort.

The impact of aortic valve regurgitation on the combination therapy of VA-ECMO and Imeplla support in severe cardiogenic shock: a simulation study

Background: The utilization of a combination of veno-arterial extracorporeal membrane oxygenation (VA-ECMO) and Impella, ECPELLA, has become widespread among patients with cardiogenic shock. The utilization of VA-ECMO in the presence of aortic regurgitation (AR) can result in significant left ventricular (LV) distention. Additionally, the implantation of Impella via the aortic valve frequently induces AR clinically. We established a simulation model and evaluated the impact of AR on hemodynamics under ECPELLA. Furthermore, assuming that the reverse flow of AR is strongly determined by aortic pressure (AP) level, we simulated a scenario where AP was further decreased. Methods: We employed Simulink® (Mathworks, Inc.). The systemic and pulmonary circulations were modeled using a 5-element resistance-capacitance network. Four cardiac chambers were represented by time-varying elastance. We compared the aortic regurgitant flow (Far), total systemic flow (Ftotal), and LV pressure-volume relationship under various severities of AR and varying Impella (0-3.7 L/min) and VA-ECMO (0-5 L/min) flows. AR grades were adjusted by the regurgitant resistance and classified as mild, moderate, and severe, mimicking a clinical scenario. Results: Without AR, ECMO significantly increased Ftotal and raised LV end-diastolic pressure (LVEDP). Impella increased Ftotal and decreased LVEDP. The concomitant presence of AR exacerbated the increase of LVEDP by ECMO and the reduction of LVEDP by Impella. Under ECPELLA support (VA-ECMO: 3 L/min) with mild AR, the increase of Impella support (1 to 3.5 L) increased Ftotal and Far, while decreasing LVEDP, indicating the prevention of AR-induced LV distention. Additionally, the presence of mild AR prevented the Impella-induced left ventricular suction that is commonly observed under ECPELLA support with high-flow VA-ECMO. In the case of moderate AR, while the hemodynamic trends were similar to those observed under mild AR, Impella was unable to prevent the increment of LVEDP to a critical level (&lt; 20 mmHg). However, by decreasing AP through reducing resistance (e.g. vasodilators), both Far and LVEDP were dramatically reduced and Ftotal was increased under ECPELLA support. Conclusion: The concomitant presence of AR in ECPELLA condition increased LV load, while prevented LV suction. The use of vasodilator in ECPELLA with AR could attenuate AR, increase systemic perfusion, and reduce LV load. The optimal control of Impella and VA-ECMO flows and AP can maximize the hemodynamic and LV unloading impacts of ECPELLA. no funding This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Longitudinal characterization of clinically relevant haemodynamics in conscious Ossabaw pigs with HFpEF

Abstract Background The constantly growing population of patients suffering from heart failure with preserved ejection fraction (HFpEF) is one of the largest unmet needs in cardiovascular medicine and translational animal models are important for identification and profiling of novel therapeutic approaches. Large animal models have shown that chronic cardiac pressure overload by aortic banding (AoB), when combined with a Western diet leads to left ventricular hypertrophy, diastolic dysfunction and metabolic syndrome in the Ossabaw pig, reflecting important features of human HFpEF characteristics. However, the requirement of invasive diagnostics under anaesthesia often limits the ability to monitor disease development continuously and compromises the results. Therefore, current disease models lack the temporal progression of clinically relevant HFpEF parameters like the left ventricular end diastolic pressure (LVEDP) and time constant of left ventricular relaxation (Tau). Purpose We aim to non-invasively investigate disease progression in Ossabaw pigs exhibiting a cardiometabolic HFpEF phenotype. The longitudinal assessment of LVEDP, Tau and heart rate (HR) should identify a time window to test novel therapeutics. Methods Naive, female Ossabaw pigs were instrumented with telemetric devices followed by AoB to induce chronic cardiac pressure overload. The wound healing and acclimatization period was followed by the start of a Western diet feeding regime to mimic components of the metabolic syndrome. Disease progression was characterized over 9 months by monthly telemetric recordings of LVEDP, Tau and HR and compared to a control (Ctrl) measurement in healthy animals. All animal studies followed the `Principles of laboratory animal care'. Results Compared to Ctrl the LVEDP is significantly elevated already 1 month (+8.90±0.4 mmHg) after AoB and further increases over time until 8 months (+18.80±0.4 mmHg) post AoB. Significant elevations in Tau are evident 4 months (+1.61±0.4 ms) post AoB. After 1 month the HR is significantly elevated (+13.90±0.7 bpm) but tends to normalize between 5 to 7 months post AoB. After AoB a maximal relative increase in LVEDP (+5.12±0.4 mmHg), Tau (+5.04±0.4 ms) and HR (+16.90±0.7 bpm) can be observed after 8 months. Conclusions We present long term haemodynamic changes over time in a translational in vivo model for HFpEF in Ossabaw pigs with high temporal resolution. For the first time elevations in key parameters allow to set a time point where HFpEF characteristics are evident, and a drug testing regime could be started. The opportunity to non-invasively and longitudinally follow on LVEDP, Tau and HR will be a clear benefit in the development of novel treatment options for HFpEF. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Bayer AG, Wuppertal

Impairment of left ventricular diastolic function and exercise capacity after yoyo dieting in female mice with or without ovariectomy-induced post-menopausal condition

Follow-up studies show that weight gain in women proportionally increases the risk of coronary heart disease and that weight cycling is associated with adverse cardiometabolic markers. Moreover, women after menopause are prone to weight gain. To work out a protocol responsible for weight fluctuation and to measure the cardiac functional consequences after a final weight loss, in mice having undergone or not an ovariectomy (OVX). Five-month-old female underwent OVX or not. Starting 5 days after surgery, mice were subjected to Yoyo dieting with successive periods (I, II, III) of a biphasic alternation of a high fat diet (HFD) (4-week constant phase of HFD60%) followed by standard diet (SD) (phase of 4, 6, 10 weeks for period I, II, III, respectively). Non-OVX control (CTL) mice were maintained on SD. At the end of the last SD phase, the global metabolism was evaluated by an insulin tolerance test and echo-MRI, the blood pressure was measured by plethysmography, the exercise capacity was evaluated on treadmill, then the left ventricular (LV) function was assessed by ultrasound and invasive hemodynamics. Body weight in Yoyo and OVX-Yoyo mice was higher to that of CTL mice at the end of period III. Moreover, the first phase of HFD resulted in a higher weight gain in OVX-yoyo mice, which kept bigger than Yoyo mice until the end of the protocol, however without difference in body composition. There was decreased insulin sensitivity in both Yoyo and Yoyo-OVX mice compared to CTL. There was no difference in blood pressure nor in LV fractional shortening between groups. Invasive hemodynamics showed no difference in LV-end diastolic pressure (LVEDP) but an increased LV end-diastolic pressure volume relation (LVEDPVR) in OVX-Yoyo mice, indicating decreased compliance. LV weight was increased in Yoyo mice only. Treadmill stress test showed decreased running duration for OVX-Yoyo mice only ( Fig. 1 ). In female mice subjected to the same Yoyo diet protocol, those in post-menopausal condition after OVX show an increased risk of developing heart failure with preserved ejection fraction and reduced exercise capacity.

Ubiquitin Carboxyl-Terminal Hydrolase L1 of Cardiomyocytes Promotes Macroautophagy and Proteostasis and Protects Against Post-myocardial Infarction Cardiac Remodeling and Heart Failure.

Ubiquitin carboxyl-terminal hydrolase L1 (UCHL1) is a deubiquitinase known to play essential roles in the nervous tissue. Myocardial upregulation of UCHL1 was observed in human dilated cardiomyopathy and several animal models of heart disease, but the (patho)physiological significance of UCHL1 in cardiomyocytes remains undefined. Hence, we conducted this study to fill this critical gap. We produced cardiomyocyte-restricted Uchl1 knockout (CKO) by coupling the Uchl1-floxed allele with transgenic Myh6-Cre in C57B/6J inbred mice. Mice transgenic for Myh6-Cre were used as controls (CTL). Myocardial Uchl1 proteins were markedly reduced in CKO mice but they did not display discernible abnormal phenotype. Ten-week old CTL or CKO mice were subjected to left anterior descending artery ligation (myocardial infarction, MI) or sham surgery (Sham) and characterized at 7- and 28-day after surgery. Compared with Sham mice, significant increases in myocardial UCHL1 proteins were detected in CTL MI but not in CKO MI mice. MI-induced left ventricular (LV) chamber dilation, reduction of ejection fraction (EF) and fractional shortening (FS), and LV anterior wall thinning detected by echocardiography were comparable between the CTL MI and CKO MI groups 7-day post-MI. However, by 28-day post-MI, MI-induced LV chamber dilatation, EF and FS reduction, increases of myocardial ubiquitin conjugates, and increases in the heart weight to body weight ratio and the ventricular weight to body weight ratio were significantly more pronounced in CKO MI than CTL MI mice. As further revealed by LV pressure-volume relationship analyses, CKO MI mice but not CTL MI mice displayed significant decreases in stroke volume, cardiac output, and the maximum rates of LV pressure rising or declining and of LV volume declining, as well as significant increases in LV end-diastolic pressure and Tau, compared with their respective Sham controls. LC3-II flux assays reveal that autophagic flux is decreased in CKO mouse myocardium as well as in cultured Uchl1-deficient cardiomyocytes. In conclusion, UCHL1 of cardiomyocytes is dispensable for development but promotes macroautophagy in cardiomyocytes. Upregulation of UCHL1 in post-MI hearts occurs primarily in the cardiomyocytes and protects against post-MI cardiac remodeling and malfunction likely through supporting autophagic flux and proteostasis during a stress condition.

A Preclinical Rat Model of Heart Failure With Preserved Ejection Fraction With Multiple Comorbidities.

Heart failure with preserved ejection fraction (HFpEF) is a common complex clinical syndrome for which there are currently few evidence-based therapies. As patients with HFpEF very often present with comorbidities comprising the metabolic syndrome, we hypothesized, that metabolic syndrome could lead over time to the development of diastolic dysfunction and HFpEF. Obesity-prone rats were exposed to high-fat diet and compared to obesity-resistant rats fed with standard chow. Phenotyping of metabolic syndrome, associated with echocardiographic and cardiac hemodynamic measurements, was performed after 4 and 12 months. Blood and myocardial tissue sampling were performed for pathobiological evaluation. High-fat diet in obesity-prone rats elicited metabolic syndrome, characterized by increased body and abdominal fat weights, glucose intolerance and hyperlipidemia, as well as increased left ventricular (LV) systolic pressure (after 12 months). This was associated with LV diastolic dysfunction (assessed by increased LV end-diastolic pressure) and pulmonary hypertension (assessed by increased right ventricular systolic pressure). Echocardiography revealed significant concentric LV hypertrophy, while LV ejection fraction was preserved. LV remodeling was associated with cardiomyocyte hypertrophy, as well as myocardial and perivascular fibrosis. Circulating levels of soluble ST2 (the interleukin-1 receptor-like) markedly increased in rats with HFpEF, while plasma NT-proBNP levels decreased. RNA-sequencing analysis identified clusters of genes implicated in fatty acid metabolism and calcium-dependent contraction as upregulated pathways in the myocardium of rats with HFpEF. High-fat diet during 12 months in obesity-prone rats led to the development of a relevant preclinical model of HFpEF with multiple comorbidities, suitable for investigating novel therapeutic interventions.

Unmasking of Exercise-Induced Diastolic Dysfunction in Symptomatic Post Coronary Angiogram Patients with Normal Coronaries

Background Diastolic dysfunction is the cause in nearly half of cases of heart failure, the hemodynamic equivalent of which is elevated cardiac filling pressures. However, owing to its ubiquity, it is often diagnosed as an incidental finding, but an association with symptoms is not established in many of the patients. Most patients with hypertension or left ventricular (LV) hypertrophy have evidence of impaired diastolic function as a finding on Doppler echocardiography, but do not have any symptoms of heart failure at rest. However, these patients do have symptoms related to diastolic dysfunction only during exercise. In this study, we have contemplated to assess invasively, left ventricular filling pressures in patients with unexplained shortness of breath with normal systolic and diastolic function on echocardiography, on exercise and compare the level of rise in patients with established diastolic dysfunction. Methods This is an observational prospective study, done over a span of 3 months, wherein patients with typical symptoms such as chest pain and shortness of breath, after ruling out systemic causes, and were subjected to coronary angiogram. If no coronary lesion identified, patients were subjected to invasive cardiac catheterization during coronary angiogram. Patients were divided into two groups, one without diastolic dysfunction and the other with established diastolic dysfunction. Simultaneous left ventricular end diastolic pressures (LVEDP) were measured at rest and after 3-minute manual handgrip exercise and readings were noted. Results The mean age of the population (n = 30) was 55.8 ± 7.538 and 20 were males. The mean value of LVEDP in patients with no diastolic dysfunction at resting was 4.4 ± 3.169 and after exercise was 8.40 ± 4.169. The mean value of LVEDP in patients with established diastolic dysfunction at resting was 5.30 ± 3.948 and after exercise was 8.75 ± 4.506. Paired t-test among two groups revealed a significant p-value of 0.001 after exercise among both groups, suggesting a significant increase in LVEDP in patients with exercise. Unpaired t-test comparing both groups revealed that the elevation of LVEDP in no diastolic dysfunction group was comparable with patients with diastolic dysfunction (p = 0.432). Conclusion The increase in LVEDP with exercise is a well-established fact in patients with diastolic dysfunction. Our study adds to the fact that patients with unexplained shortness of breath can have raised LVEDP after exercise, thereby unmasking the underlying diastolic dysfunction. Our study stresses the importance of inclusion of exercise as a provocative test for the assessment of diastolic function, either invasively or non-invasively, in patients presenting with exertional dyspnea.

Loss of apical suction assessed by noninvasive pressure differences and twist in acute heart failure: a novel method using vector flow mapping

Abstract Background Early diastolic intraventricular pressure difference (IVPD) reflects left ventricular (LV) apical suction, and IVPD is closely related to cardiac function, especially LV twist. Vector Flow Mapping (VFM) allows visualization of regional pressure distribution and noninvasive quantification of IVPD. The purpose of the present study was to investigate if and how IVPDs are related to LV twist in a model of acute heart failure (HF). Methods In 15 open-chest dogs, HF was induced by intracoronary injection of microspheres. The HF model was classified into two groups based on the LV end-diastolic pressure (LVEDP) (group1: LVEDP&amp;lt;18 mmHg (n=10), group2: LVEDP≥18 mmHg (n=8)). Color Doppler images from apical long-axis views were acquired at baseline and during HF. From these images, pressure differences (ΔP) were calculated along the LV inflow tract throughout the cardiac cycle. For the purpose of this study, the differences between apex and base during isovolumic relaxation time (ΔPIRT) and rapid early inflow period (ΔPE) were used for analyses. Furthermore, apical and basal short axis high frame rate 2D images were acquired, and peak rotation and peak twist were analyzed. Results LVEDP was 7±9, 14±2, 21±3 mmHg for baseline, group1 HF, and group2 HF, respectively. Pressure differences (both ΔPIRT and ΔPE) were visibly changed by the increase of LVEDP (Figure), and the magnitude of ΔPIRT, ΔPE and peak twist decreased significantly with the severity of heart failure. There were significant relationships between pressure differences (ΔPIRT and ΔPE) and dP/dtmin, tau, EF and peak twist (Table). In multivariate analyses, tau and peak twist were independent predictors for ΔPIRT and peak twist was independent predictor for ΔPE. Conclusion VFM analysis is feasible to noninvasively assess the IVPDs in acute heart failure. The IVPDs are closely related to the twisting motion of the LV, and reflect loss of apical suction during severe HF. Funding Acknowledgement Type of funding sources: None. VFM images of pressure differencesCorrelations of pressure differences

Ventricular arrhythmia susceptibility in a new porcine model of heart failure (HF) with reduced ejection fraction

Abstract Introduction Sudden death secondary to ventricular arrhythmias is common in HF patients, with no effective treatment available outside of implantable cardiac defibrillators. While animal models are essential for the discovery of anti-arrhythmic drugs, no reliable large animal HF models with associated ventricular arrhythmias have been described so far. Objectives We aimed at evaluating ventricular remodeling and arrhythmia susceptibility in an HF pig model with reduced ejection fraction (EF) following myocardial infarction (MI). Methods MI was induced in 53 male Göttingen minipigs (12–15 months, 20–25 kg) by coronary embolization in mid-left anterior descending and mid-left circumflex coronary arteries using endovascular coils. Seven other pigs underwent sham operation and were used as control. Two weeks after surgery, cardiac function was assessed by echocardiography, and animals were included based on EF&amp;lt;50% (n=15/53), assigned either to 12 weeks of vehicle (n=9) or perindopril (n=6, 1 mg/kg/d, per os) group. At the end of the study, their left ventricular (LV) electrical remodeling was studied by echocardiography/electrocardiography and a programmed-electrical stimulation protocol was performed to evaluate the susceptibility to develop ventricular arrhythmias. Results At the end of the study, animals in the vehicle group had a significant LV remodeling associated with a reduced EF (p&amp;lt;0.05 vs. sham, see table). This remodeling was associated with cardio-pulmonary congestion, significant increases in LV end-diastolic pressure, left atrial volume, and lung mass (all p&amp;lt;0.05 vs. sham, see table), fully prevented by perindopril treatment. They had also an electrical remodeling as evidenced by an increase in PR, QRS, and QTc intervals, as well as LV effective refractory period (+18%, 14%, 33%, and 13%, respectively, p&amp;lt;0.05, compared to sham animals). Electrical changes were mitigated by perindopril treatment (p=NS vs. sham). LV mechanical dispersion measured with speckle-tracking echocardiography was significantly increased in vehicle group (58±5 vs. 22±1 ms in sham group, respectively) as well as in perindopril group. Programmed-electrical stimulations induced in 6/8 vehicle animals either non-sustained (n=3) or sustained (n=2) ventricular tachycardia, or ventricular fibrillation (n=1). In sham group only 1/7 animal had a ventricular fibrillation. No inducible ventricular arrhythmia was observed in animals treated with Perindopril. Conclusion In this new pig model of congestive HF with reduced EF, LV remodeling was associated with electrical remodeling and susceptibility to develop arrhythmias. Chronic angiotensin-converting enzyme inhibitor treatment prevented congestion, mitigated electrical remodeling, and suppressed arrhythmia susceptibility. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Servier Research Institute - CardioVascular &amp; Metabolic Diseases Center for Therapeutic Innovation Table 1

Clinical value and role of microRNA-29c-3p in sepsis-induced inflammation and cardiac dysfunction

BackgroundThe goal of this study was to investigate the diagnostic value of miR-29c-3p in sepsis and its role in sepsis-induced inflammatory response and cardiac dysfunction.MethodsSerum level of miR-29c-3p was detected by qRT-PCR. The ROC curve was used to evaluate the diagnostic value of miR-29c-3p for Sepsis. The cecal ligation and puncture method (CLP) was used to establish a rat sepsis model. To assess cardiac function, left ventricular systolic pressure (LVSP), left ventricular end diastolic pressure (LVEDP) and maximum rate of rise/fall of left ventricle pressure (± dp/dtmax) in different experimental groups were detected, and the serum cardiac troponin I (cTnI), creative kinase isoenzyme MB (CK-MB) were measured by ELISA. Meanwhile, TNF-α, IL-1β, and IL-6 were detected by ELISA to assess the level of inflammatory response in animals.ResultsmiR-29c-3p level was upregulated in sepsis patients. ROC curve revealed that miR-29c-3p had the ability to distinguish sepsis patients from healthy controls. Cardiac dysfunction and inflammation were observed in sepsis rat, which were characterized by the decrease of LVSP and + dp/dtmax, the increase of LVEDP, − dp/dtmax, cTnI, CK-MB, TNF-α, IL-1β, IL-6. All effects were reversed by the injection of miR-29c-3p antagomir. Logistics regression analysis manifested miR-29c-3p is an independent factor in the occurrence of cardiac dysfunction in sepsis patients.ConclusionsmiR-29c-3p has potential as a biomarker for the diagnosis of sepsis, and inhibition of miR-29c-3p expression in animal models reduced sepsis-induced cardiac dysfunction and inflammatory response.

Assisting the Heart to Assist the Lungs: LVAD Support in Restrictive Physiology and Pulmonary Hypertension

<h3>Introduction</h3> Pulmonary hypertension (PH) is a risk factor for mortality after heart transplantation (HTx). We present a case of treatment of post-capillary PH in a small pediatric patient with restrictive physiology using continuous flow ventricular assist device (VAD) support to achieve candidacy for HTx. <h3>Case Report</h3> A 4.5 year old female (0.57m²) with a history of acute myeloid leukemia and anthracycline chemotherapy in infancy developed mildly depressed left ventricular (LV) function at 2 years of age. Hemodynamic catheterization (cath) showed pre- and post-capillary PH secondary to LV diastolic dysfunction and restrictive physiology (Table). She was cautiously initiated on PDE5 inhibitor therapy (sildenafil) while maintaining LV reverse remodeling therapies. Her heart failure (HF) symptoms and biventricular systolic function worsened over the subsequent 2 years. Subsequent caths showed increasing PVRi, which was responsive to 100% FiO2 and inhaled nitric oxide (iNO), but also accompanied by increase in LV end-diastolic pressures (LVEDP). She was transitioned to endothelin receptor antagonist therapy (bosentan), but continued to worsen clinically, requiring initiation of milrinone. Due to her underlying restrictive physiology leading to worsening PH and severely depressed right ventricular (RV) function, a HeartWare HVAD (cannulation LV to Aorta) was implanted to allow aggressive optimization of PH therapies with simultaneous LV decompression. This enabled up-titration of bosentan as well as re-addition of sildenafil. After PH therapies including VAD implantation, PVRi decreased from a high of 10.7 WU.m2 to 4.7 WU.m2, and marked decline of LVEDP from 22 mmHg pre-VAD to 5 mmHg. She underwent HTx 6 months after VAD implantation, and was discharged home 12 days post-HTx on sildenafil. <h3>Summary</h3> VAD support in tandem with optimal PH therapies is a feasible strategy to treat post-capillary PH, optimize pulmonary vasculature to reduce RV dysfunction, and enable a successful bridge to HTx.

Sustained Improvement in Diastolic Reserve Following Percutaneous Pericardiotomy in a Porcine Model of Heart Failure With Preserved Ejection Fraction.

Heart failure with preserved ejection fraction is increasing in prevalence, but few effective treatments are available. Elevated left ventricular (LV) diastolic filling pressures represent a key therapeutic target. Pericardial restraint contributes to elevated LV end-diastolic pressure, and acute studies have shown that pericardiotomy attenuates the rise in LV end-diastolic pressure with volume loading. However, whether these acute effects are sustained chronically remains unknown. Minimally invasive pericardiotomy was performed percutaneously using a novel device in a porcine model of heart failure with preserved ejection fraction. Hemodynamics were assessed at baseline and following volume loading with pericardium intact, acutely following pericardiotomy, and then again chronically after 4 weeks. Cardiac structure was assessed by magnetic resonance imaging. The increase in LV end-diastolic pressure with volume loading was mitigated by 41% (95% CI, 27%-45%, P<0.0001; ΔLV end-diastolic pressure reduced from +9±3 mm Hg to +5±3 mm Hg, P=0.0003, 95% CI, -2.2 to -5.5). The effect was sustained at 4 weeks (+5±2 mm Hg, P=0.28 versus acute). There was no statistically significant effect of pericardiotomy on ventricular remodeling compared with age-matched controls. None of the animals developed hemodynamic or pathological indicators of pericardial constriction or frank systolic dysfunction. The acute hemodynamic benefits of pericardiotomy are sustained for at least 4 weeks in a swine model of heart failure with preserved ejection fraction, without excessive chamber remodeling, pericarditis, or clinically significant systolic dysfunction. These data support trials evaluating minimally invasive pericardiotomy as a novel treatment for heart failure with preserved ejection fraction in humans.

Diagnostic usefulness of passive leg raising test for detection of heart failure with preserved ejection fraction compared to cycle ergometer exercise (invasive hemodynamic study)

Abstract Background Invasive diastolic stress test using cycle ergometer is gold standard for diagnosis of heart failure with preserved ejection fraction (HFpEF) by demonstrating elevation of left ventricular end diastolic pressure (LVEDP) during exercise. It is well known that passive leg raising increases preload and augments LVEDP in HFpEF patients. However correlation between passive leg raising induced increase of LVEDP and cycle ergometer exercise induced increase of LVEDP is not well established. Therefore we investigated whether passive leg raising test could substitute cycle exercise test for diagnosis of HFpEF. Method Forty-five patients with unexplained dyspnea and ejection fraction &amp;gt;50% underwent invasive exercise test. After measuring baseline LVEDP in supine position using pigtail catheter through radial artery approach, LVEDP during passive leg raising was evaluated. Then exercise LVEDP was measured after 3 minutes of 20 watt supine cycle ergometer exercise. Patients with normal resting LVEDP &amp;lt;16mmHg were enrolled. Patients with cycle ergometer exercise LVEDP &amp;gt;26mmHg were classified as HFpEF and exercise LVEDP &amp;lt;26mmHg were defined as noncardiac dyspnea. Results Among 45 patients with unexplained dyspnea with preserved EF, 30 patients with ergometer exercise LVEDP &amp;gt;26mmHg were grouped as HFpEF and 15 patients with exercise LVEDP &amp;lt;26mmHg grouped as noncardiac dyspnea (NCD). Resting LVEDP was higher in HFpEF than NCD (14±2mmHg vs 11±3mmHg, P=0.01) but there was substantial overlap (figure 1) showing poor differentiation power of resting LVEDP. Passive leg raising increased LVEDP in both HFpEF and NCD but this was more marked in HFpEF group than in NCD group with minimal overlap (24±4mmHg vs 17±2mmHg, P&amp;lt;0.001) (figure 2). Passive leg raising LVEDP was well correlated with cycle ergometer exercise LVEDP (R2=0.60, P&amp;lt;0.01). The best cutoff value for passive leg raising LVEDP to detect HFpEF was 20mmHg (sensitivity, 0.87; specificity, 1.00), giving an area under the curve of 0.93 (95% confidence interval, 0.80 to 0.99). Positive predictive value of passive leg raising LVEDP &amp;gt;20mmHg for diagnosis of HFpEF was 96% and negative predictive value was 77%. Conclusion Passive leg raising induced augmentation of left ventricular end diastolic pressure (LVEDP) was well correlated with cycle exercise induced elevation of LVEDP in HFpEF patients. Passive leg raising test may be used for detecting HFpEF with good accuracy in substitution for cycle ergometer exercise test. Funding Acknowledgement Type of funding source: None

1963-P: Short- and Long-Term Empagliflozin Treatment Improves Cardiac Function in Rats with Chronic Heart Failure

Introduction: The SGLT2 inhibitor empagliflozin (EMPA) exerts beneficial cardiovascular effects in type-2 diabetes, but whether this occurs in chronic heart failure (CHF) is unknown. Thus we investigated, using a rat model whether EMPA exhibits protective effect in chronic heart failure (CHF). Methods: Rats with CHF were treated with EMPA (30 mg/kg PO for 7 days starting 83 days after coronary artery ligation or 90 days starting 7 days after coronary artery ligation) to assess effects on left ventricular (LV) function and hemodynamics (echocardiography, LV catheterization). Results: After 90 days untreated CHF rats presented LV systolic and diastolic dysfunction, illustrated by the decreases in LV end-systolic pressure (LV ESP) and in LV end-systolic pressure volume-relation (LV ESPVR) as well as the increases in LV end-diastolic pressure (LV EDP) and LV end-diastolic pressure volume-relation (LV EDPVR). Seven- and ninety-day EMPA treatment improved systolic and diastolic LV function, illustrated by the increases in LV ESP and in LV ESPVR as well as the reductions in LV EDP and in LV EDPVR. Conclusion: Short- and long-term EMPA treatment prevents LV dysfunction in rats with CHF. These results suggest that EMPA may exert protective effects in humans with CHF. Disclosure M. Soulié: None. Y. Stephan: None. L. Nicol: None. J. Henry: None. V. Richard: None. M. Pieper: Employee; Self; Boehringer Ingelheim Pharmaceuticals, Inc. P. Mulder: Research Support; Self; Bayer Healthcare Pharmaceuticals Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Poxel SA. Funding Boehringer Ingelheim

Inhibition of microRNA-146a attenuated heart failure in myocardial infarction rats.

The aim of the present study was to determine the roles of microRNA (miR)-146a on myocardial infarction (MI)-induced heart failure and cardiac remodeling. Experiments were carried out in Sprague-Dawley rats treated with ligation of left coronary artery to induce heart failure, and in primary neonatal rat cardiac fibroblasts (CFs) and cardiomyocytes treated with angiotensin (Ang) II. Four weeks after MI, rats were injected with miR-146a antagomiR or agomiR via tail vein. After 2 weeks of injection, the rats were killed. In MI rats, left ventricle (LV) ejection fraction and fractional shortening were reduced, and LV volumes in diastole and systole were increased, which were reversed by miR-146a antagomiR, and further exacerbated after miR-146a agomiR treatment. Administration of miR-146a antagomiR improved the decreases of LV ±dp/dtmax and LV systolic pressure (LVSP), and the increase in LV end-diastolic pressure (LVEDP) of MI rats, but miR-146a agomiR deteriorated the LV ±dp/dtmax, LVSP and LVEDP. The increases in the levels of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), collagen I and collagen III in the heart, and ST2 and norepinephrine in the serum of MI rats were inhibited by miR-146a antagomiR, but aggravated after miR-146a agomiR treatment. The increases of collagen I and collagen III levels induced by Ang II in CFs, and the increases of ANP and BNP levels induced by Ang II in cardiomyocytes were inhibited by miR-146a antagomiR, but aggravated by miR-146a agomiR. These results demonstrated that inhibition of miR-146a improved cardiac dysfunction and cardiac remodeling in heart failure rats.

Concomitant systolic and diastolic alterations during chronic hypertension in pig

The mechanical and cellular relationships between systole and diastole during left ventricular (LV) dysfunction remain to be established. LV contraction-relaxation coupling was examined during LV hypertrophy induced by chronic hypertension. Chronically instrumented pigs received angiotensin II infusion for4weeks to induce chronic hypertension (133 ± 7 mmHg vs 98 ± 5 mmHg for mean arterial pressure at Day 28 vs 0, respectively) and LV hypertrophy. LV function was investigated with the instrumentation and echocardiography for LV twist-untwist assessment before and after dobutamine infusion. The cellular mechanisms were investigated by exploring the intracellular Ca2+ handling. At Day 28, pigs exhibited LV hypertrophy with LV diastolic dysfunction (impaired LV isovolumic relaxation, increased LV end-diastolic pressure, decreased and delayed LV untwisting rate) and LV systolic dysfunction (impaired LV isovolumic contraction and twist) although LV ejection fraction was preserved. Isolated cardiomyocytes exhibited altered shortening and lengthening. Interestingly, contraction-relaxation coupling remained preserved both in vivo and in vitro during LV hypertrophy. LV systolic and diastolic dysfunctions were associated to post-translational remodeling and dysfunction of the type 2 cardiac ryanodine receptor/Ca2+ release channel (RyR2), i.e., PKA hyperphosphorylation of RyR2, depletion of calstabin 2 (FKBP12.6), RyR2 leak and hypersensitivity of RyR2 to cytosolic Ca2+ during both contraction and relaxation phases. In conclusion, LV contraction-relaxation coupling remained preserved during chronic hypertension despite LV systolic and diastolic dysfunctions. This implies that LV diastolic dysfunction is accompanied by LV systolic dysfunction. At the cellular level, this is linked to sarcoplasmic reticulum Ca2+ leak through PKA-mediated RyR2 hyperphosphorylation and depletion of its stabilizing partner.