Left Ventricular End-diastolic Volume Research Articles

A Novel Model of Venovenous Extracorporeal Membrane Oxygenation in Rats with Femoral Cannulation and Insights into Hemodynamic Changes.

The application of venovenous (VV) extracorporeal membrane oxygenation (ECMO) has gained wide acceptance for the treatment of acute severe respiratory failure. Since no rat model of VV ECMO therapy with femoral drainage has yet been described, although this cannulation strategy is commonly used in humans, this study aimed to establish such a model. Twenty male Lewis rats were randomly assigned to receive a sham procedure or VV ECMO therapy. After the inhalative induction of anesthesia, animals were intubated and the vascular accesses were placed surgically. While venous drainage was achieved through a modified multi-orifice 18 G cannula that was placed in the inferior vena cava through the femoral vein over a guide wire with an ultra-flexible tip, the venous return was realized via a shortened 20 G cannula into the jugular vein. Hemodynamic data were obtained from a tail artery and left ventricular pressure-volume catheter. Repetitive blood gas analyses were carried out, and systemic inflammation was measured using an enzyme-linked immunosorbent assay. While animals in the ECMO group showed adequate oxygenation and decarboxylation, there was no evidence of recirculation. VV ECMO therapy increased stroke volume (SV), cardiac output (CO), and left ventricular end-diastolic volume (LVEDV). ECMO-induced inflammation was reflected in increased levels of tumor necrosis factor alpha. However, no differences in interleukins 6 and 10 were seen. This study describes a frequently used cannulation strategy in humans for a rat model of VV ECMO. Despite successful oxygenation and decarboxylation, the oxygenated blood may reduce pulmonary vascular resistance and lead to an increased LVEDV, which is associated with increased SV and CO. This model allows us to answer research questions about topics such as intestinal microcirculation in further studies.

Detection of Subclinical Cardiac Dysfunction in Patients With Sickle Cell Disease Using Speckle-Tracking Echocardiography

Sickle cell disease (SCD) is characterized by chronic anemia and recurrent ischemia-reperfusion episodes, which can lead to high-output heart failure. The impact of SCD on cardiac structure and function remains underinvestigated. We conducted a single-institution retrospective analysis of clinical and echocardiographic data from patients with hemoglobin SS SCD (SCD-SS) between January 2016 and June 2022. Patients with known heart failure, left ventricular (LV) ejection fraction <50%, moderate or severe valvular heart disease, congenital heart disease, established coronary artery disease, diabetes mellitus, hypertension, or coexistent lung disease were excluded. Compared with healthy controls (n = 28), patients with SCD-SS (n = 66) had a significantly higher left atrial (LA) volume index (35.7 vs 23.9 ml/m², p <0.001) and average E/e' (7.4 vs 6.5, p = 0.003) but lower average e' (12.3 vs 13.6 cm/s, p = 0.047) and LA reservoir strain (32.9% vs 42.4%, p <0.001). Patients with SCD-SS had higher LV end-diastolic (132.5 vs 104.1 ml, p <0.001) and LV end-systolic volumes (51.0 vs 43.8 ml, p = 0.017) with reduced LV global longitudinal strain (17.6% vs 20.0%, p <0.001). In addition, patients with SCD-SS showed reduced right ventricular (RV) global longitudinal strain (19.7% vs 22.8%, p <0.001) in the setting of normal RV tricuspid annular plane systolic excursion. Maximal systolic tricuspid regurgitation velocity (231 vs 202 cm/s, p <0.001) and right atrial area (16.6 vs 12.8 cm², p <0.001) were statistically greater in SCD-SS. Hemoglobin and hematocrit negatively correlated with LA volume index, average E/e', LV end-diastolic and LV end-systolic volumes. In conclusion, patients with SCD-SS had notable differences in cardiac chamber size and impaired LV, RV, and LA strain compared with healthy controls. Further investigations are needed to assess the impact of these variables on SCD clinical course and prognosis.

Effectiveness of Vericiguat on right ventricle to pulmonary artery uncoupling associated with heart failure with reduced ejection fraction

BackgroundsA soluble guanylyl cyclase stimulator vericiguat has been shown to reduce cardiovascular mortality or hospitalization for heart failure in patients with worsening heart failure in the VICTORIA study. However, little is known about the effects of vericiguat on biventricular structure and function. Methods and resultsA retrospective analysis of 63 consecutive patients with heart failure with reduced ejection fraction (HFrEF) who were treated with vericiguat was performed. Clinical data and echocardiographic parameters were compared between baseline and follow-up after the initiation of vericiguat. The median follow-up duration was 266 days. Treatment with vericiguat significantly reduced the plasma BNP levels (log-transformed) compared to baseline (2.46 ± 0.51 vs. 2.14 ± 0.58, p < 0.0001). Left ventricular end-diastolic volume index and left ventricular end-systolic volume index were significantly reduced (LVEDVI, 113.5 ± 46.3 vs. 103.6 ± 51.0, p = 0.0056; LVESVI, 82.0 ± 41.9 vs. 72.8 ± 44.7, p = 0.0077; respectively). The tricuspid annular plane systolic excursion to pulmonary artery systolic pressure (TAPSE/PASP) ratio, an indicator of right ventricle-pulmonary artery (RV-PA) coupling, increased significantly after the treatment (0.56 ± 0.29 vs. 0.92 ± 1.09, p < 0.0001). Univariate and multivariate analyses showed that the treatment effects of vericiguat on BNP levels, LV reverse remodeling, and RV-PA coupling were not correlated with the achievement of the quadruple therapy with beta-blockers, renin-angiotensin system inhibitors, mineralocorticoid inhibitors, and sodium-glucose cotransporter-2 inhibitors, nor with worsening heart failure (WHF). ConclusionTreatment with vericiguat improved adverse LV remodeling and RV-PA uncoupling in HFrEF patients. These effects were independent of WHF and achieving the quadruple therapy. Patients with HFrEF may benefit from early initiation of vericiguat to prevent biventricular adverse remodeling.

Sex difference in mitral valve prolapse regurgitant volume is resolved by normalization of regurgitant volume to left ventricular end-diastolic volume

Women with primary mitral insufficiency have a smaller regurgitant volume at the same regurgitant fraction than men. We hypothesized that normalizing regurgitant volume with left ventricular end-diastolic volume or allometric scaling would eliminate the difference in regurgitant volume between women and men. The study cohort consisted of 101 patients with mitral valve prolapse undergoing cardiac MRI. Descriptive statistics and linear regression were performed to assess differences between sexes. Of the 101 patients, 46 (46%) were women. Women had a significantly smaller left and right ventricular end-diastolic volume, end-systolic volume, and stroke volume. While there was no difference in regurgitant fraction between women and men (34 ± 13% vs. 35 ± 14%; p = 0.71), women had a significantly smaller regurgitant volume (36 ± 18 ml vs. 49 ± 26 ml; p = 0.005). The slope-intercept relationship between regurgitant fraction and regurgitant volume revealed unique slopes and y-intercept values for men and women (p-value < 0.0001). Normalizing regurgitant volume to left ventricular end-diastolic volume (RVol/LVEDV), body surface area1.5 (RVol/BSA1.5) and height2.7 (RVol/height2.7) all had essentially identical slope-intercept relationships with regurgitant fraction for men and women, but RVol/LVEDV had the smallest effect size. In mitral insufficiency secondary to mitral valve prolapse women have a significantly smaller regurgitant volume than men despite no difference in regurgitant fraction. The significant difference in regurgitant volume between women and men is secondary to women having a smaller left ventricular end-diastolic volume.

The cardiovascular exercise response in children with overweight or obesity measured by cardiovascular magnetic resonance imaging.

Overweight and obesity are among the main causes of cardiovascular diseases. Exercise testing can aid in the early detection of subtle cardiac dysfunction not present in rest. We hypothesized that the cardiovascular response to exercise is impaired among children with overweight or obesity, characterized by the inability of the cardiovascular system to adapt to exercise by increasing cardiac volumes and blood pressure. We performed a cardiovascular stress test to investigate whether the cardiovascular exercise response is altered in children with overweight and obesity, as compared to children with a normal weight. A subgroup of the Generation R population-based prospective cohort study, consisting of 41 children with overweight or obesity and 166 children with a normal weight with a mean age of 16 years, performed an isometric exercise. Continuous heart rate and blood pressure were measured during rest, exercise and recovery. Cardiovascular magnetic resonance (CMR) measurements were performed during rest and exercise. Higher BMI was associated with a higher resting systolic and diastolic blood pressure (difference: 0.24 SDS (95% CI 0.10, 0.37) and 0.20 SDS (95% CI 0.06, 0.33)) and lower systolic and diastolic blood pressure increases from rest to peak exercise (-0.11 SDS (95% CI -0.20, -0.03) and -0.07 SDS (95% CI -0.07, -0.01)). BMI was also associated with a slower decrease in systolic and diastolic blood pressure during recovery (p values < 0.05). Higher childhood BMI was associated with lower BSA corrected left ventricular mass, end-diastolic volume and stroke volume (p values < 0.05). There were no associations of childhood BMI with the cardiac response to exercise measured by heart rate and CMR measurements. Childhood BMI is, across the full range, associated with a blunted blood pressure response to static exercise but there were no differences in cardiac response to exercise. Our findings suggest that adiposity may especially affect the vascular exercise reaction without affecting cardiac response.

Echocardiographic assessment of left ventricular volumes: a comparison of different methods in athletes.

Cardiac magnetic resonance imaging (cMRI) is considered the gold standard for the assessment of left ventricular (LV) systolic function. However, discrepancies have been reported in the literature between LV volumes assessed by transthoracic echocardiography (TTE) and cMRI. The objective of this study was to analyze the differences in LV volumes between different echocardiographic techniques and cMRI. In 64 male athletes (21.1 ± 4.9years), LV volumes were measured by TTE using the following methods: Doppler echocardiography, anatomical M-Mode, biplane/triplane planimetry and 3D volumetry. In addition, LV end-diastolic (LVEDV), end-systolic (LVESV), and stroke volumes (LVSV) were assessed in 11 athletes by both TTE and cMRI. There was no significant difference between LVEDV and LVESV determined by biplane/triplane planimetry and 3D volumetry. LVEDV and LVESV measured by M-Mode were significantly lower compared to 3D volumetry. LVSV determined by Doppler with 3D planimetry of LV outflow tract was significantly higher than 2D planimetry and 3D volumetry, whereas none of the planimetric or volumetric methods for determining LVSV differed significantly. There were no significant differences for LVEDV, LVESV, LVSV and LVEF between cMRI and TTE determined by biplane planimetry in the subgroup of 11 athletes. The choice of echocardiographic method used has an impact on LVSV in athletes, so the LVSV should always be checked for plausibility. The same echocardiographic method should be used to assess LVSV at follow-ups to ensure good comparability. The data suggest that biplane LV planimetry by TTE is not inferior to cMRI.

Apelin-13 administration allows for norepinephrine sparing in a rat model of cecal ligation and puncture-induced septic shock

BackgroundInfusion of exogenous catecholamines (i.e., norepinephrine [NE] and dobutamine) is a recommended treatment for septic shock with myocardial dysfunction. However, sustained catecholamine infusion is linked to cardiac toxicity and impaired responsiveness. Several pre-clinical and clinical studies have investigated the use of alternative vasopressors in the treatment of septic shock, with limited benefits and generally no effect on mortality. Apelin-13 (APL-13) is an endogenous positive inotrope and vasoactive peptide and has been demonstrated cardioprotective with vasomodulator and sparing life effects in animal models of septic shock. A primary objective of this study was to evaluate the NE-sparing effect of APL-13 infusion in an experimental sepsis-induced hypotension.MethodsFor this goal, sepsis was induced by cecal ligation and puncture (CLP) in male rats and the arterial blood pressure (BP) monitored continuously via a carotid catheter. Monitoring, fluid resuscitation and experimental treatments were performed on conscious animals. Based on pilot assays, normal saline fluid resuscitation (2.5 mL/Kg/h) was initiated 3 h post-CLP and maintained up to the endpoint. Thus, titrated doses of NE, with or without fixed-doses of APL-13 or the apelin receptor antagonist F13A co-infusion were started when 20% decrease of systolic BP (SBP) from baseline was achieved, to restore SBP values ≥ 115 ± 1.5 mmHg (baseline average ± SEM).ResultsA reduction in mean NE dose was observed with APL-13 but not F13A co-infusion at pre-determined treatment time of 4.5 ± 0.5 h (17.37 ± 1.74 µg/Kg/h [APL-13] vs. 25.64 ± 2.61 µg/Kg/h [Control NE] vs. 28.60 ± 4.79 µg/Kg/min [F13A], P = 0.0491). A 60% decrease in NE infusion rate over time was observed with APL-13 co-infusion, (p = 0.008 vs NE alone), while F13A co-infusion increased the NE infusion rate over time by 218% (p = 0.003 vs NE + APL-13). Associated improvements in cardiac function are likely mediated by (i) enhanced left ventricular end-diastolic volume (0.18 ± 0.02 mL [Control NE] vs. 0.30 ± 0.03 mL [APL-13], P = 0.0051), stroke volume (0.11 ± 0.01 mL [Control NE] vs. 0.21 ± 0.01 mL [APL-13], P < 0.001) and cardiac output (67.57 ± 8.63 mL/min [Control NE] vs. 112.20 ± 8.53 mL/min [APL-13], P = 0.0036), and (ii) a reduced effective arterial elastance (920.6 ± 81.4 mmHg/mL/min [Control NE] vs. 497.633.44 mmHg/mL/min. [APL-13], P = 0.0002). APL-13 administration was also associated with a decrease in lactate levels compared to animals only receiving NE (7.08 ± 0.40 [Control NE] vs. 4.78 ± 0.60 [APL-13], P < 0.01).ConclusionAPL-13 exhibits NE-sparing benefits in the treatment of sepsis-induced shock, potentially reducing deleterious effects of prolonged exogenous catecholamine administration.

Combination therapy of acupuncture and herbal medicine for heart failure: A systematic review and meta-analysis.

Heart failure (HF) is characterized by functional or structural dysfunction of the heart, resulting in impaired blood ejection or ventricular filling. Conventional Western Medicine (CWM) remains the mainstay of treatment for HF; however, the occurrence of adverse events (AEs) necessitates the exploration of alternative treatments. Herbal medicine and acupuncture are adjunctive therapies for HF and have shown potential for improving heart function. This systematic review and meta-analysis aimed to assess the effectiveness and safety of acupuncture and herbal medicine in treating HF. PubMed, Embase, Cochrane Central Register of Controlled Trials, China National Knowledge Infrastructure, Citation Information by National Institute of Informatics, KoreaMed, Research Information Sharing Service, and DBpia were searched for randomized controlled trials (RCTs) evaluating the effects of acupuncture and herbal medicine along with CWM as adjunctive treatments for HF, published from inception to May 31, 2024. Treatment effectiveness was determined by evaluating the left ventricular ejection fraction as the primary metric, along with the measurement of the total effective rate, brain natriuretic peptide level, N-terminal prohormone of brain natriuretic peptide level, left ventricular end-diastolic volume, and left ventricular end-systolic volume; the administration of the Minnesota Living with Heart Failure Questionnaire; and the conduct of a 6-minute walk test. Treatment safety was evaluated based on the incidence of AEs. The methodological quality of all included RCTs was assessed using the Cochrane risk of bias tool. A meta-analysis was performed using Review Manager, version 5.4.1. Of the 133 publications identified, 8 RCTs met the inclusion criteria. The meta-analysis showed significant improvements in left ventricular ejection fraction, brain natriuretic peptide levels, N-terminal prohormone of brain natriuretic peptide levels, left ventricular end-systolic volume, left ventricular end-diastolic volume, and 6-minute walk test results. Additionally, significant differences were observed in the total effective rate and Minnesota Living with Heart Failure Questionnaire responses. No significant medication-related AEs occurred in the intervention group. Conversely, 7 control patients developed well-known AEs associated with CWM. Acupuncture combined with herbal medicine and CWM is more effective than CWM alone, indicating a safe treatment approach. Consequently, the proactive administration of acupuncture alongside herbal medicine to patients with HF can be undertaken without concerns regarding AEs.

Abstract We073: CLEC4E Signaling in Myocardial Ischemia-Reperfusion Injury

Background: The innate immune receptor CLEC4E (C-type lectin domain family 4 member E) in cardiac resident cells and circulating leukocytes contributes to ischemic myocardial damage and adverse LV remodeling following ischemia reperfusion injury (I/R). Mice with loss of CLEC4E gene function show reduced cardiac injury and better LV remodeling but the mechanisms of this cardioprotection remain unknown. Aims: We investigated whether Clec4e gene function in cardiac resident cells vs infiltrating immune cells mediates cardioprotection during myocardial ischemia-reperfusion injury. Methods: We generated chimeric mice by IV infusion of 5 x 10 6 bone marrow cells originating from C57Bl6/J CLEC4E -/- and C57Bl6/J wild-type (WT) donor mice in 8w-old lethally irradiated (9.5 Gy) WT (n=36) and CLEC4E -/- (n=50) receptor mice, respectively. After 4 w, mice were subjected to ischemia reperfusion injury (I/R) by 60 min LAD occlusion. Troponin levels (TnI) were measured at 90 min post I/R and 7T-magnetic resonance imaging with late gadolinium enhancement (LGE) for infarct size evaluation was performed at 24 h and 28 d post I/R. Mice were euthanized at 28 days for immunohistochemistry and analysis of BM chimerism. Results: Immunohistochemistry for CLEC4E expression on bone marrow smears confirmed successful BM chimerism. At 24h post I/R, TnI levels and LGE-assessed infarct size on MRI were not significantly different between groups (42.1 vs 48.4 ng/ml, and 25.2% vs 31.5% of LVmass in CLEC4E -/- &amp; WT BM versus in WT &amp; CLEC4E -/- BM, respectively) suggesting similar myocardial damage . After 28 d, LV end-diastolic volumes (43µL vs 55µL), and end-systolic volumes (13µL vs 25µL) were significantly smaller in CLEC4E -/- &amp; WT BM than in WT &amp; CLEC4E -/- BM mice (P&lt;0.05 for both), resulting in better preserved global LV function (LVEF 62% vs 47%, P&lt;0.05) . Infarct size, semiquantitatively assessed using planimetry on Sirius red stains, was smaller in CLEC4E -/- &amp; WT BM than in WT &amp; CLEC4E -/- BM (6.9% vs 19.8%, P&lt;0.01). Conclusion: CLEC4E gene deletion in cardiac resident cells, but not in infiltrating hematopoietic immune cells is associated with better functional and structural remodelling after myocardial I/R. Inhibition of CLEC4E signaling via blocking antibodies or small molecule inhibitors in cardiac myocytes might be a promising cardioprotective strategy.

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.

Pediatric reference values for myocardial contraction fraction and global function index of the left ventricle: A cardiovascular magnetic resonance study

BackgroundCardiovascular magnetic resonance (CMR) derived global function index (GFI) and myocardial contraction fraction (MCF) were identified as useful imaging markers to assess left ventricular (LV) cardiac performance and can provide prognostic information for several cardiac diseases. As pediatric reference values are lacking, the aim of this retrospective study was to establish these values. Methods154 CMR examinations of healthy children and adolescents (4–18 years) were included. LV end-diastolic, end-systolic and stroke volumes, ejection fraction (LVEF) and myocardial mass were measured using short axis stacks. Results were used to calculate LVGFI and LVMCF. Statistically, the Lambda-Mu-Sigma (LMS)-method was applied to create percentile curves and tables. ResultsThe mean age (standard deviation) of the subjects was 13.8 (2.8) years, 102 were male (66%). Mean LVGFI was 46.3 (6.0)% and mean LVMCF was 110.6 (19.9) %. Both, LVGFI and LVMCF decreased significantly with age (LVGFI: r = −0.30, p < 0.001; LVMCF: −0.30, p < 0.001). There was no statistical difference between girls and boys (p all >0.05). Strong correlations between LVGFI and LVMCF (r = 0.78, p < 0.001) as well as between LVGFI and LVEF (r = 0.80, p < 0.001) were documented whereas the correlation of LVMCF and LVEF was weaker (r = 0.32, p < 0.001). Univariable and multivariable regression analysis demonstrated that LVGFI was strongly associated with age whereas LVMCF was associated with weight. Percentile curves and tables were created accordingly. ConclusionWe provide pediatric CMR reference values for the new cardiac functional markers LVGFI and LVMCF. These may improve the interpretation of clinical CMR studies and can be used for future research studies.

Abstract Tu101: Measuring Fibrosis Progression in Duchenne Cardiomyopathy Using Cardiac Magnetic Resonance in mice

Introduction: Transthoracic echocardiogram (TTE) is currently the gold standard for measuring cardiac function in mouse models of cardiomyopathy, however, it has its limitations. Challenges include poor acoustic windows, lower reproducibility, larger margin of error, and inability to accurately detect fibrosis. The detection of fibrosis is critical for assessing the severity of cardiac involvement and monitoring disease progression in Duchenne muscular dystrophy (DMD). Cardiac magnetic resonance imaging (CMR) can be used to more accurately measure cardiac function, chamber volumes, and tissue characterization to monitor the progression of fibrosis, including with parametric T1 mapping and late gadolinium enhancement (LGE). In this study, we have used a dystrophic mouse model (D2. mdx ) on the DBA/2J genetic background as a preclinical model of DMD. Hypothesis: We hypothesize that CMR can detect worsening cardiac function and signs of fibrosis in the left ventricle of D2. mdx mice compared to wildtype (DBA) controls. Methods: In a study group of 12 age-matched male mice (8 mdx, 4 DBA), CMR was performed with contrast to determine cardiac function and fibrotic developments in the heart. Results: D2. mdx mice displayed a higher left ventricular end-diastolic volume compared to DBA mice (32.8 ± 3.6 µL vs 27.4 ± 1.5 µL, p &lt; 0.05). Global longitudinal strain was decreased in D2. mdx compared to DBA mice (-11.0 ± 3.5% vs -18.2 ± 2.2%, p &lt; 0.05). Native T1 mapping (Fig 1A) showed significantly higher mean T1 times in D2. mdx mice compared to DBA controls (Fig 1B). LGE in the myocardium of the left ventricle was noted in 6 of 8 of the D2. mdx mice (Fig 1C), but not in DBA mice. Logistic regression modeling showed strong predictive value detecting LGE with increasing native T1 times (Fig 1D). Conclusion: CMR can detect tissue changes in D2. mdx myocardium representing fibrotic changes. Native T1 may be useful in longitudinal studies of antifibrotic therapies in these models.

Abstract We104: A New Small-Molecule ErbB4 Agonist Attenuates Adverse Ventricular Remodeling After Myocardial Infarction In a Sex-Specific Manner

Background: The beneficial effects of the neuregulin/ErbB pathway on the diseased heart have been well-established. The cardioprotective aspects of neuregulin are largely attributable to the activation of the ErbB4 receptor. We recently developed a small-molecule selective ErbB4 agonist, which reduced collagen production in fibroblasts and prevented oxidative-stress induced cardiomyocyte death in vitro . Hypothesis: We hypothesized that the ErbB4 agonist (referred to as compound, Cpd), would attenuate left ventricular remodeling, reduce interstitial cardiac fibrosis and preserve cardiac function in a murine model of myocardial infarction (MI). Since there is a potential interaction between the ErbB4 receptor and the estrogen receptor, we further hypothesized these effects would be sex-dependent. Methods: Mice were divided by sex and then further divided into three experimental groups: a sham group, an MI group receiving Cpd (MI/Cpd), and a control MI group receiving vehicle only (MI/Veh). Mice started treatment with either Cpd (2mg/kg/d) or its vehicle through subcutaneous osmotic minipumps seven days after MI. Cardiac ultrasound was performed weekly until mice were sacrificed after four weeks of treatment. Hearts were excised and stained with Masson’s trichrome to assess interstitial cardiac fibrosis in myocardium remote from the infarction scar. Results: In females (n=25), Cpd significantly decreased left ventricular end-diastolic volume compared to vehicle (Fig.1A, 80±23 µl vs.108±29µl, p=0.045) and induced a slightly increased left ventricular ejection fraction (Fig.2A, 32±12% vs. 22±9%, p=0.086). In addition, Cpd significantly reduced reactive interstitial fibrosis (fibrotic area, Fig.3A, 1.4±1.0% vs. vehicle: 3.8±3.1%, p=0.036) in females. In males (n=30), Cpd had no significant effects on either of the parameters mentioned above (Fig.1B, 2B, 3B). Conclusion: Treatment with the novel small-molecule ErbB4 agonist attenuates left ventricular dilation and reactive interstitial fibrosis after MI in female mice, but not in males. These data support the premise that small molecule-induced ErbB4 activation is a potential new therapy for heart failure, especially in female patients. The mechanisms underlying the sex-dependent effects warrant further exploration.

Self-Reported Sodium Intake and Sodium Vulnerability in Heart Failure With Preserved Ejection Fraction

ObjectiveTo determine the pathophysiologic and prognostic meaning of patient self-reported sodium intake in heart failure (HF) with preserved ejection fraction (HFpEF). MethodsThis cohort analysis used data from the Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist (TOPCAT) trial of patients enrolled in the Americas. Tertiles of baseline self-reported sodium intake were used to assess the relationship between self-reported sodium intake and clinical presentation/outcome and interactions with treatment effect of spironolactone. ResultsSelf-reported sodium intake of 1748 patients with HFpEF included in TOPCAT were divided according to tertiles of sodium intake (47% low, 35% moderate, and 18% high sodium intake). After covariate adjustment, lower self-reported sodium intake was associated with higher risk of HF hospital admission (P=.009). Patients with lower sodium intake had higher E-wave velocity, left ventricular end diastolic volume, and estimated plasma volume (P<.001). Lower sodium intake was associated with a larger treatment effect of spironolactone on HF hospitalizations (hazard ratio, 0.69; 95% CI, 0.53 to 0.91) vs the highest tertile (hazard ratio, 1.37; 95% CI, 0.79 to 2.38; interaction P=.030). In addition, linear mixed models indicated larger reductions in blood pressure, dyspnea, and edema (all interaction P<.001) in patients with lower sodium intake receiving spironolactone. ConclusionLow self-reported sodium level in HFpEF is associated with higher risk of HF hospital admissions and may indicate a sodium-vulnerable state; patients should not be falsely reassured that they are in a lower risk category despite greater adherence to medical recommendations.

Efficacy of early administration of sacubitril/valsartan after coronary artery revascularization in patients with acute myocardial infarction complicated by moderate-to-severe mitral regurgitation: a randomized controlled trial.

Effects of angiotensin receptor/neprilysin inhibitors (ARNI) on ventricular remodeling in patients with heart failure, especially heart failure with reduced ejection fraction (HFrEF), are better than those of angiotensin-converting enzyme inhibitors (ACEI). Acute myocardial infarction (AMI) complicated by mitral regurgitation exacerbates ventricular remodeling and increases the risk of heart failure. There is limited evidence on the effects of early administration of ARNI in patients with AMI complicated by mitral regurgitation. The aim of this trial was to examine the effectiveness and the safety of early administration of sacubitril/valsartan after coronary artery revascularization in patients with AMI complicated by moderate-to-severe mitral regurgitation. This was a randomized, single-blind, parallel-group, controlled trial. From June 2021 to June 2022, we enrolled 142 consecutive patients with AMI complicated by moderate-to-severe mitral regurgitation and followed them for 12months. The patients received standard treatment for AMI and were randomly assigned to receive ARNI or benazepril. The primary efficacy end points were the differences in mitral regurgitant jet area (MRJA), mitral regurgitant volume (MRV), concentration of n-terminal pro-brain natriuretic peptide (NT-proBNP), left ventricular ejection fraction (LVEF), and left ventricular end-diastolic volume and end-systolic volume (LVEDV and LVESV) between groups and within groups at baseline, 1, 3, 6, and 12months. Secondary end points included the rates of heart failure hospitalization, all-cause mortality, refractory angina, malignant arrhythmias, recurrent myocardial infarction, and stroke. Safety end points included the rates of hyperkalemia, renal dysfunction, hypotension, angioedema, and cough. The ARNI group had significantly lower NT-proBNP levels than the benazepril group at 1month and later (P < 0.001). MRJA and MRV significantly improved in the ARNI group compared with the benazepril group at 12months (MRJA: - 3.21 ± 2.18 cm2 vs. - 1.83 ± 2.81 cm2, P < 0.05; MRV: - 27.22 ± 15.22mL vs. - 13.67 ± 21.02mL, P < 0.001). The ARNI group also showed significant reductions in LVEDV and LVESV (P < 0.05) and improvement in LVEF (P < 0.05). Secondary end point analysis showed a significantly higher rate of heart failure hospitalization in the benazepril group compared with the ARNI group (HR = 2.03, 95% CI 1.12-3.68, P = 0.021). Safety end point analysis showed a higher rate of hypotension in the ARNI group (P < 0.05). Early use of sacubitril/valsartan after coronary artery revascularization in patients with AMI complicated by moderate-to-severe mitral regurgitation can significantly reduce mitral regurgitation, improve ventricular remodeling, and decrease heart failure hospitalization. Nevertheless, caution is needed to avoid hypotension. Chinese Clinical Trial Registry (ChiCTR2100054255) registered on December 11, 2021.

Large Right Atrial Size on Cardiac MRI is Associated with Post-operative Right Ventricular Dysfunction After the Cone Operation for Ebstein Anomaly.

The cone operation has revolutionized care for patients with Ebstein anomaly; however, acute post-operative right ventricular dysfunction (RVD) is common in this patient population. A single-center, retrospective review of 28 patients with Ebstein anomaly who underwent cardiac MRI (CMR) prior to cone reconstruction of the tricuspid valve was conducted. Measurements of atrial and ventricular size/function were assessed. Post-operative RVD was defined as the presence of moderate or severe systolic dysfunction on discharge echo. A two-tail t test was employed to compare the two groups. The average age at operation was 21.4years (range 1.6-57.8) and 14 (50%) had RVD at discharge. Patients with post-operative RVD had significantly larger pre-operative right atrial (RA) maximum volume (p = 0.016) and RA minimum volume (p = 0.030). Patients with RVD had smaller pre-operative left atrial (LA) minimum volume (p = 0.012). Larger pre-operative right ventricular (RV) end-systolic volume (p = 0.046), lower RV ejection fraction (0.029), and smaller left ventricular (LV) end-diastolic volume (p = 0.049) were significantly associated with post-operative RVD. Post-operative RVD was associated with longer milrinone duration (p = 0.009) and higher maximum milrinone dose (p = 0.005) but was not associated with intensive care or hospital length of stay (p = 0.19 and 0.67, respectively). Increased RA and RV dilation and decreased LA and LV volumes are associated with the development of post-operative RVD following cone operation for Ebstein anomaly. Post-operative RVD affects milrinone dose and duration but is not associated with increased length of stay.

Left and right atrioventricular coupling index in patients with beta-thalassemia major.

The aim of this cross-sectional study was to investigate the relationship of left atrioventricular coupling index (LACI) and right atrioventricular coupling index (RACI) with demographics, clinical data, cardiovascular magnetic resonance findings, and cardiac complications (heart failure, arrhythmias, and pulmonary hypertension) in a cohort of patients with beta-thalassemia major (β-TM). We evaluated 292 β-TM patients (151 females, 36.72 ± 11.76years) consecutively enrolled in the Extension-Myocardial Iron Overload in Thalassemia (E-MIOT) project. Moreover, we assessed 32 sex- and age-matched healthy controls (12 females, mean age 40.78 ± 14.35years). LACI was determined by calculating the ratio of the left atrium end-diastolic volume to the left ventricle end-diastolic volume, while RACI was defined by calculating the ratio of the right atrium end-diastolic volume to the right ventricle end-diastolic volume. Compared to healthy control, β-TM demonstrated increased LACI (22.99 ± 13.58% vs. 16.05 ± 5.28%; p < 0.0001) and RACI (27.84 ± 10.30% vs. 17.06 ± 5.03%; p < 0.0001). Aging, diabetes, splenectomy, and the presence of late gadolinium enhancement (LGE) showed a significant positive association with both LACI and RACI. In stepwise regression analysis, the presence of LGE was found to be an independent predictor of both impaired LACI and RACI (β coefficient = 0.244, p < 0.0001 and β coefficient = 0.218, p = 0.003; respectively). LACI and RACI were not correlated with myocardial iron overload. Patients with cardiac complications had significantly higher LACI and RACI than patients without cardiac complications. In patients with β-TM, LACI and RACI were significantly associated with the presence of LV LGE. In addition, patients with cardiac complications had impaired LACI and RACI.

Long-Term Prognostic Impact of Three-Dimensional Speckle-Tracking Echocardiography-Derived Left Ventricular Global Longitudinal Strain in Healthy Adults-Insights from the MAGYAR-Healthy Study.

Three-dimensional (3D) speckle-tracking echocardiography (STE) combines the advantages of STE and volumetric 3D echocardiography, which shows the left ventricle (LV) in 3D during the cardiac cycle and is also suitable for accurate strain measurements in addition to volumetric assessments using the same virtual 3D LV cast. The present study aimed to confirm the prognostic impact of 3DSTE-derived LV global longitudinal strain (GLS) in healthy adults during a 12-year follow-up period. The current study comprised 124 healthy individuals with a mean age of 31.0 ± 11.7 years (64 males) at the time of complete two-dimensional Doppler echocardiography (2DE) and 3DSTE. During a mean follow-up of 8.01 ± 4.12 years, 10 healthy individuals suffered cardiovascular events, including 2 cardiac deaths. Using ROC analysis, 3DSTE-derived LV-GLS ≥ 14.77% was found to be a significant predictor for cardiovascular event-free survival (sensitivity 70%, specificity 71%, area under the curve 76%, p = 0.007). Using 2DE, higher LV end-diastolic and end-systolic volumes, a larger LV end-systolic diameter and a lower LV ejection fraction could be detected in subjects with LV-GLS < 14.77% as compared to cases with LV-GLS ≥ 14.77%. Subjects with events had thicker interventricular septa, a larger LV mass and lower 3DSTE-derived LV-GLS and a higher ratio of cases had LV-GLS < 14.77%. From subjects with LV-GLS < 14.77%, seven individuals (18%) had events. Multivariate regression analysis identified age and LV-GLS as independent predictors of event-free survival. 3DSTE-derived LV-GLS is a strong independent predictor of cardiovascular survival in healthy adults.

Left ventricular volume and maximal functional capacity in heart failure with preserved ejection fraction: Size matters.

Emerging evidence suggests that smaller left ventricular volumes may identify subjects with lower cardiorespiratory fitness. Whether left ventricular size predicts functional capacity in patients with heart failure with preserved ejection fraction (HFpEF) is unclear. This study aimed to explore the association between indexed left ventricular end-diastolic volume (iLVEDV) and maximal functional capacity, assessed by peak oxygen consumption (peakVO2), in stable outpatients with HFpEF. We prospectively analysed data from 133 consecutive stable outpatients who underwent cardiopulmonary exercise testing and echocardiography on the same day. Data were validated in a cohort of HFpEF patients from San Paolo Hospital, Milan, Italy. A multivariable linear regression assessed the association between iLVEDV and peakVO2. The mean age was 73.2 ± 10.5 years, and 75 (56.4%) were women. The median iLVEDV, indexed left ventricular end-systolic volume, and left ventricular ejection fraction were 46 ml/m2 (30-56), 15 ml/m2 (11-19), and 66% (60-74%), respectively. The median peakVO2 and percentage of predicted peakVO2 were 11 ml/kg/min (9-13) and 64.1% (53-74.4), respectively. Adjusted linear regression analysis showed that smaller iLVEDV was associated with lower peakVO2 (p = 0.0001). In the validation cohort, adjusted linear regression analysis showed a consistent pattern: a smaller iLVEDV was associated with a higher likelihood of reduced peakVO2 (p = 0.004). In stable outpatients with HFpEF, a smaller iLVEDV was associated with a lower maximal functional capacity. These findings suggest a need for further studies to understand the pathophysiological mechanisms underlying these observations and to explore targeted treatment strategies for this patient subgroup.

Left ventricular dysfunction in pulmonary arterial hypertension is attributed to underfilling rather than intrinsic myocardial disease: a CMR 2D phase contrast study

The pathophysiology underlying impaired LV function in PAH remains unclear, with some studies implicating intrinsic myocardial dysfunction and others pointing to LV underfilling. Evaluation of pulmonary vein area (PVA) and flow may offer novel, mechanistic insight by distinguishing elevated LV filling pressure common in myocardial dysfunction from LV underfilling. This study aimed to elucidate LV filling physiology in PAH by assessing PVA and flow using cardiac magnetic resonance (CMR) and compare pulmonary vein flow in PAH with HFrEF as a model representing elevated filling pressures, in addition to healthy controls. Patients with PAH or heart failure with reduced ejection fraction (HFrEF) referred for CMR were retrospectively reviewed, and healthy controls were included as reference. Pulmonary vein S, D and A-wave were compared between groups. Associations between pulmonary vein area (PVA) by CMR and echocardiographic indices of LV filling pressure were evaluated. Nineteen patients with PAH, 25 with HFrEF and 24 controls were included. Both PAH and HFrEF had lower ejection fraction and S-wave velocity than controls. PAH displayed smaller LV end-diastolic volumes than controls, while HFrEF demonstrated larger PVA and higher A-wave reversal. PVA was associated with mitral E/e′ ratio (r2 = 0.10; p = 0.03), e′ velocity (r2 = 0.23; p = 0.001) and left atrial volume (r2 = 0.07; p = 0.005). Among PAH, PVA was not associated with LV-GLS. A PVA cut-off of 2.3cm2 displayed 87% sensitivity and 72% specificity to differentiate HFrEF and PAH (AUC = 0.82). PAH displayed lower pulmonary vein S-wave velocity, smaller LV volume and reduced function compared with controls. Reduced LV function in PAH may be owing to underfilling rather than intrinsic myocardial disease. PVA demonstrates promise as a novel, non-invasive imaging marker to assess LV filling status.