Ventricular Isovolumic Relaxation Research Articles

Hypoxia-Induced Myocardial Hypertrophy Companies with Apoptosis Enhancement and p38-MAPK Pathway Activation.

Li, Xiaoxu, Zhijun Pu, Gang Xu, Yidong Yang, Yu Cui, Xiaoying Zhou, Chenyuan Wang, Zhifeng Zhong, Simin Zhou, Jun Yin, Fabo Shan, Chengzhong Yang, Li Jiao, Dewei Chen, and Jian Huang. Hypoxia-induced myocardial hypertrophy companies with apoptosis enhancement and p38-MAPK pathway activation. High Alt Med Biol. 25:186-196, 2024. Background: Right ventricular function and remodeling are closely associated with symptom severity and patient survival in hypoxic pulmonary hypertension. However, the detailed molecular mechanisms underlying hypoxia-induced myocardial hypertrophy remain unclear. Methods: In Sprague-Dawley rats, hemodynamics were assessed under both normoxia and hypobaric hypoxia at intervals of 7 (H7), 14 (H14), and 28 (H28) days. Morphological changes in myocardial tissue were examined using hematoxylin and eosin (HE) staining, while myocardial hypertrophy was evaluated with wheat germ agglutinin (WGA) staining. Apoptosis was determined through TUNEL assays. To further understand the mechanism of myocardial hypertrophy, RNA sequencing was conducted, with findings validated via Western blot analysis. Results: The study demonstrated increased hypoxic pulmonary hypertension and improved right ventricular diastolic and systolic function in the rat models. Significant elevations in pulmonary arterial systolic pressure (PASP), mean pulmonary arterial pressure (mPAP), right ventricular mean pressure (RVMP), and the absolute value of +dp/dtmax were observed in the H14 and H28 groups compared with controls. In addition, right ventricular systolic pressure (RVSP), -dp/dtmax, and the mean dp/dt during isovolumetric relaxation period were notably higher in the H28 group. Heart rate increased in the H14 group, whereas the time constant of right ventricular isovolumic relaxation (tau) was reduced in both H14 and H28 groups. Both the right heart hypertrophy index and the heart weight/body weight ratio (HW/BW) were elevated in the H14 and H28 groups. Myocardial cell cross-sectional area also increased, as shown by HE and WGA staining. Western blot results revealed upregulated HIF-1α levels and enhanced HIF-2α expression in the H7 group. In addition, phosphorylation of p38 and c-fos was augmented in the H28 group. The H28 group showed elevated levels of Cytochrome C (Cyto C), whereas the H14 and H28 groups exhibited increased levels of Cleaved Caspase-3 and the Bax/Bcl-2 ratio. TUNEL analysis revealed a rise in apoptosis with the extension of hypoxia duration in the right ventricle. Conclusions: The study established a link between apoptosis and p38-MAPK pathway activation in hypoxia-induced myocardial hypertrophy, suggesting their significant roles in this pathological process.

105 Burning Heart - An Animal Model of Chronic Heart Failure Following Severe Burn Injury

Abstract Introduction Our clinical research unveiled chronic heart failure with preserved ejection fraction (HFpEF) as a long-term sequel in survivors of severe pediatric burn injury due to a yet unknown molecular pathomechanism. Applying a standardized rat model, we systematically determined the pathophysiological impact of burn injury on long-term cardiac performance to uncover systemic and molecular pathomechanisms that may cause post-burn HFpEF development. Methods Male adolescent SD-rats were subjected to a 60 % total body surface area (TBSA) full-thickness burn- or sham-trauma and subsequently characterized after burn-injury by serial transthoracic echocardiography, bulk myocardial next-generation sequencing and proteomics as well as RT-PCR, immuno-blotting (IB), histology and plasma proteomics for cardiac performance and molecular alterations, respectively, at 3, 7, 30 and 90days. Results In comparison to the sham-group (SG), animals from the burn-group (BG) recapitulated typical post-burn clinical traits, such as significant loss in body weight (BG 27 % less than SG at 30d, p< 0.05) or skeletal muscle wasting (27 % less at 30d, p< 0.05) in accord with elevated molecular atrophy markers. We show post-burn cardiac muscle wasting (BG 22 % less at 30d, p< 0.05) and persistent markers of cardiac dysfunction in accord with significant histological cardiomyocyte hypotrophy (BG -8 % at 30d, p< 0.05) and significantly diminished left ventricular (LV) global longitudinal strain and isovolumic relaxation time in BGs, while LV-EF remained unchanged. Weighted gene network correlation analysis from bulk myocardial NGS and clinical traits related activation of immunological and pro-fibrotic pathways in post-burn injury hearts to cardiac dysfunction in BGs. Subsequent RT-PCR and histology confirmed significant myocardial accumulation of cardio-depressive damage associated molecular patterns (i.e., S100A8 and A9) and infiltration by granulocytes and monocytes as well as significant LV fibrosis. Serial plasma proteomic analysis indicated elevated plasma levels of S100A8 and A9 and other heart failure markers that mirrored similar changes in human post-burn plasma samples. Conclusions Here we report the development of HFpEF as a novel systemic consequence of severe burn injury in a rodent model, which warrants further mechanistic and translational studies. Cardiac inflammation and fibrosis are known to negatively impact cardiac performance and may be mechanistic key findings that will guide further therapeutic studies and subsequent validation of post-burn heart failure biomarkers Applicability of Research to Practice This model is part of a translational and interdisciplinary experimental and clinical effort to inform pathophysiology and mechanistics of long-term heart failure in burn patients. Echocardiographic data and parameters from this model are currently being used to evaluate adult survivors of severe burn injury for signs of HFpEF.

Left ventricular isovolumetric relaxation time is a potentially new marker of short-term and long-term prognosis in patients with acute heart failure’s decompensation and mid-range ejection fraction

Purpose: to assess the role of left ventricular (LV) isovolumic relaxation time (IVRT) as a predictor of adverse outcome in acute decompensated heart failure (ADHF) against the background of intermediate ejection fraction (EF) of the left ventricle.Materials and methods. The study included 121 patients aged 37 to 85 years (mean age 67.2±2.5 years) with ADHF against the background of LV ЕF; 78 — male, 43 are fermale. In all patients, the time between the end of blood flow in the outflow tract and the beginning of blood flow in the inflow tract was determined, i.e., LV IVRT. According to this parameter, the whole group was divided into 3 samples: with an average LV IVRT (70–100 ms — 54 patients), increased (more than 100 ms — 15 patients) — or reduced LV IVRT (less than 70 ms — 52 patients).Results. The mean LV IVRT in group 1 was 87.5±6.4 ms, in group 2–106.4±9.7 ms, in group 3–55.3±4.1 ms. Hospital mortality (HM) in the entire sample was 5.3%, long-term (24 months) (LM) — 39.6%. The obtained results were subjected to correlation analysis: HM was characterized by a connection with LV IVRT (r= –0.295, p<0.05), but the dependence was inversely proportional. For LM, the correlation coefficient with LV IVRT was 0.519, p><0.05, which is typical for an average connection strength. Conclusions: 1. The value of IVRT in patients with midrange LV EF correlated negatively with the levels of both in-hospital and long-term mortality: low numbers of IVRT statistically significantly predicted an increase in mortality from all causes, while a decrease in mortality was observed at high values of IVRT. 2. In patients who are hospitalized for ADHF against the background of mid-range LV EF, it is advisable to determine the LV IVRT to assess the immediate and long-term prognosis of the disease. Keywords: heart failure, acute decompensation, time of isovolumetric relaxation of the left ventricle, prognosis> ˂ 0.05), but the dependence was inversely proportional. For LM, the correlation coefficient with LV IVRT was 0.519, p ˂ 0.05, which is typical for an average connection strength.Conclusions: 1. The value of IVRT in patients with midrange LV EF correlated negatively with the levels of both in-hospital and long-term mortality: low numbers of IVRT statistically significantly predicted an increase in mortality from all causes, while a decrease in mortality was observed at high values of IVRT. 2. In patients who are hospitalized for ADHF against the background of mid-range LV EF, it is advisable to determine the LV IVRT to assess the immediate and long-term prognosis of the disease.

Noninvasive assessment of myocardial work during left ventricular isovolumic relaxation in patients with diastolic dysfunction

BackgroundThis study aims to investigate the value of myocardial work (MW) parameters during the isovolumic relaxation (IVR) period in patients with left ventricular diastolic dysfunction (LVDD).MethodsThis study prospectively recruited 448 patients with risks for LVDD and 95 healthy subjects. An additional 42 patients with invasive measurements of left ventricular (LV) diastolic function were prospectively included. The MW parameters during IVR were noninvasively measured using EchoPAC.ResultsThe total myocardial work during IVR (MWIVR), myocardial constructive work during IVR (MCWIVR), myocardial wasted work during IVR (MWWIVR), and myocardial work efficiency during IVR (MWEIVR) of these patients were 122.5 ± 60.1 mmHg%, 85.7 ± 47.8 mmHg%, 36.7 ± 30.6 mmHg%, and 69.4 ± 17.8%, respectively. The MW during IVR was significantly different between patients and healthy subjects. For patients, MWEIVR and MCWIVR were significantly correlated with the LV E/e’ ratio and left atrial volume index, MWEIVR exhibited a significant correlation with the maximal rate of decrease in LV pressure (dp/dt per min) and tau, and the MWEIVR corrected by IVRT also exhibited a significant correlation with tau.ConclusionsMW during IVR significantly changes in patients with risks for LVDD, and is correlated to LV conventional diastolic indices, including dp/dt min and tau. Noninvasive MW during IVR may be a promising tool to evaluate the LV diastolic function.

6 EVALUATION OF ECHOCARDIOGRAPHIC PARAMETERS IN PATIENTS WITH MICROVASCULAR DYSFUNCTION: A PROSPECTIVE STUDY.

Abstract Background The prevalence of microvascular angina is underestimated in the general population because it is often difficult to detect. Microvascular dysfunction is defined by parameters of reduced coronary flow reserve (CFR <2) without epicardial stenosis and/or increased index of microvascular resistance (IMR> 25). Purpose The aim of this study was to evaluate the echocardiographic parameters in patients with symptoms of myocardial ischemia without evident coronary epicardial obstruction. Primary endpoint was to analyze the global longitudinal strain of the left ventricle and the left atria strain in patients with microvascular angina. Secondary endpoint was to analyze echocardiographic parameters to evaluate the diastolic function of the left ventricle, the prevalence of cardiovascular risk factors and the blood tests values. Methods Between 1st February 2019 and 1st May 2022, subjects with angina and not functionally significant epicardial stenosis (Resting Full-cycle Ratio > 0.91, Fractional flow reserve >0.80), underwent assessment of microvascular function and were divided into 2 cohorts. All patients had sinus rhythm, preserved left ventricular ejection fraction (LVEF> 55%), no severe left ventricular hypertrophy (interventricular septum <13 mm) or structural heart disease. For each patient we analyzed the left ventricular global longitudinal strain in the three apical views (4 chamber, 2 chamber and 3 chamber) and the left atria strain, PALS (peak atrial longitudinal strain) and PACS (peak atrial contraction strain), in two apical views (4 chamber and 2 chamber). We also measured the diastolic function indices (E/e’, isovolumic relaxation time, deceleration time), the left atrial area and pulmonary artery systolic pressure (PASP) evaluated on echocardiography. Results A total of 132 patients were enrolled. Of those, 47 had evidence of microvascular dysfunction and 85 had normal CFR/IMR. Primary Endpoint: patients with microvascular dysfunction had reduced values of left ventricular global longitudinal strain and reduced values of left atrial strain compared to controls (p<0,001). Secondary Endpoint: a higher prevalence of diabetic and obese women was associated with microvascular dysfunction. However, there were no significant differences in age, prevalence of hypertension, dyslipidemia, smoking and dysthyroidism. Numerically higher values of NTproB-type Natriuretic Peptide (NTproBNP) and C-reactive protein were seen in patients with microvascular dysfunction, while there were no significant differences in hemoglobin, white bold cells, platelets, cholesterol, creatinine and troponin values. Left ventricular isovolumic relaxation time, left atrium area, and pulmonary artery systolic pressure as well as E/e' values were significantly increased in patients with microvascular dysfunction. Furthermore, there was a significant reduction in deceleration time values. Conclusion Patient with microvascular dysfunction are frequently diabetic and obese women. Echocardiographic parameters show left ventricular diastolic dysfunction and possibly subsequent left atrial remodeling. Furthermore, the analysis of the global longitudinal strain of the left ventricle could reveal alterations in cardiac contractile mechanics that are difficult to identify with conventional echocardiography. NTproBNP values were not significantly higher, demonstrating that patients with microvascular dysfunction have an early diastolic dysfunction that is not clinically evident.

Predictive Value of Combined Plasma D-Dimer, SCUBE1, and Right Ventricular Tei Index for the Prognosis of Elderly Patients with Acute Pulmonary Thromboembolism.

Acute pulmonary thromboembolism (APTE) has become a non-negligible clinical concern due to its high mortality and complex symptoms. Early diagnosis and prognostic assessment of APTE are of great significance for the long-term benefits of patients, especially elderly patients. Elderly patients with pulmonary embolism (n = 250) who presented to our hospital from January 2018 to July 2021 were recruited into this study. In addition, 50 healthy elderly people with no history of allergies were selected as the control group. An enzyme-linked immunosorbent assay (ELISA) method was used to determine concentrations of D-dimer and signal peptide-CUB-EGF domain-containing protein-1 (SCUBE1) in their plasma. Right ventricular volume contraction time (ICT), ejection time (ET), and isovolumic relaxation time (IRT) were determined by Doppler ultrasound. Right ventricular Tei index was calculated as (ICT + IRT)/ET. High plasma D-dimer, plasma SCUBE1, and right ventricular Tei index are risk factors for poor prognosis in APTE patients after treatment. Plasma D-dimer, plasma SCUBE1, and right ventricular Tei index have predictive value for poor prognosis in APTE patients. Their combined detection (0.256*DD +0.04*SCUBE1 + 10.188*Tei) can improve the sensitivity and specificity of prediction. There is a predictive value of combined plasma D-dimer, SCUBE1, and right ventricular Tei index for the prognosis of elderly patients with APTE.

Assessment of left ventricular diastolic function in children with HIV/AIDS attending a tertiary health Facility in Enugu, Nigeria: a Doppler echocardiographic study

ObjectiveTo determine the prevalence and factors associated with left ventricular diastolic dysfunction in children with HIV/AIDS.MethodEchocardiographic studies were carried out in 90 children/adolescents aged 18 months to 14 years.with HIV/AIDS and a healthy control group of 90 age and gender matched.Results47.8% of the HIV/AIDS patients (subjects) had LVDD. This was more pronounced in the AIDS group (100%). The E/A ratio was 1.9 ± 0.56 in the HIV group, 2.09 ± 0.04 in the AIDS group, and 1.20 ± 0.39 in the control group (p = 0.04). The mean Left ventricular isovolumic relaxation time (IVRT) was 79.4 ± 20.12 in the HIV group, 110.4 ± 10.12 in the AIDS group and 89.22 ± 25.76 in the control group. (p = 0.04). Deceleration time (DT) was also lower in HIV carrier group compared to AIDS group, p = 0.02. A restrictive filling pattern was the most described; with 27 (36.5%) in the HIV group, 16 (100.0%) in the AIDS group and 2 (2.2%) in the control group. (p = 0.02). The impaired relaxation pattern, 3 (4.0%) seen in the HIV group only. Positive correlation exists between body surface area (BSA) and LVDD. Body surface area and younger age were the significant predictors (BSA: r = 0.425, p = 0.038 in HIV and r = 0.827, p = 0.042) of LVDD in the AIDS group.ConclusionThis study showed a high prevalence of LVDD in Nigerian children with HIV and AIDS. This justifies inclusion of echocardiographic studies in the policy care of children with HIV/AIDS in sub-Sahara Africa region.

Echocardiographic diagnosis of heart failure with preserved ejection fraction in elderly patients with hypertension

Objectives. The aim of this study is to evaluate the diagnostic performance of echocardiography for the diagnosis of heart failure with preserved ejection fraction (HFpEF) in the elderly and to validate the Heart Failure Association diagnostic algorithm (HFA-PEFF). Design. A case–control study was conducted in patients with hypertension with or without HFpEF who were matched for age (n = 33; 78.4 ± 5.3 years) and sex. Participants underwent echocardiography including assessment of left atrial (LA) volume index (LAVI), early mitral filling to early diastolic mitral annulus velocity ratio (E/e′), LA reservoir strain (LASr), tissue Doppler LA contraction (a′), right ventricular isovolumic relaxation time (RVIVRT), and a 6-minute walk test (6-MWT). The filling pressure algorithm from the European association of cardiovascular imaging (EACVI) 2021 was applied. The HFA-PEFF score was also applied, using echocardiography parameters and the value of NT pro-BNP, without considering symptomatic status. Results. Echocardiographic parameters identified patients with HFpEF with an area under the curve (AUC) >0.9 for E/e′, RVIVRT, LASr, a′, and the ratio of LAVI/a′. LASr correlated with 6-MWT (r = 0.59, p = .0003). The EACVI algorithm classified all controls with normal filling pressure and 94% of patients with HFpEF with increased filling pressure. When the HFA-PEFF diagnostic algorithm was validated, a high score (≥5 points) had 100% sensitivity for HFpEF, while 88% of controls had intermediate scores (2–4 points). Conclusion. The EACVI filling pressure algorithm, RVIVRT, LASr, and the ratio LAVI/a′ were accurate for diagnosing HFpEF in elderly patients with hypertension. The HFA-PEFF score had high sensitivity but limited ability to exclude HFpEF.

Dysregulated ACE/Ang II/Ang1-7 signaling provokes cardiovascular and inflammatory sequelae of endotoxemia in weaning preeclamptic rats

Weaning preeclamptic (PE) rats exhibit exaggerated endotoxic signs of hypotension and cardiac autonomic neuropathy. Considering the role of renin-angiotensin system (RAS) in maternal programming during PE, we investigated the hypothesis that gestational modulation of offensive (Angiotensin II, Ang II) and defensive (Ang 1–7) components of RAS alleviates cardiovascular hyperresponsiveness of weaning PE mothers to postpartum endotoxemia. PE was induced by treating pregnant rats with the nitric oxide synthase inhibitor L-NAME (50 mg/kg/day) for 7 consecutive days starting from gestational day 14. The PE-associated elevations in gestational systolic blood pressure and proteinuria were reduced after gestational treatment with Ang 1–7 (Ang II-derived vasodilator), losartan (AT1 receptor antagonist), pioglitazone (RAS modulator), or combined losartan/pioglitazone, with the latter therapy being the most effective. In weaning PE rats, the potentiated falls in mean arterial pressure and spectral index of cardiac sympathovagal balance (low frequency/high frequency ratio) caused by i.v. Lipopolysaccharides (LPS, 5 mg/kg) were attenuated by all therapies. Pioglitazone and Ang 1–7 were more effective in reversing increases and decreases in left ventricular contractility and isovolumic relaxation time constant, respectively, seen in endotoxic PE mothers. Immunohistochemically, cardiac Toll-like receptor 4 (TLR-4) expression was increased in endotoxic PE rats, and this effect was abrogated by Ang 1–7 or losartan/pioglitazone. The same treatments blunted the increased cardiac angiotensin converting enzyme (ACE) expression whereas ACE2 expression was altered by none of the intervening therapies. Overall, the mitigation of Ang II/ACE imbalances alleviates the sensitized cardiovascular and inflammatory actions of endotoxemia in weaning PE mothers.

Chronic heart failure as a sequel of severe burn injury: first insight into a novel pathological heart-skin axis

Abstract Research question Our clinical research unveiled chronic heart failure with preserved ejection fraction (HFpEF) as a long-term sequel in survivors of severe pediatric burn injury due to a yet unknown molecular pathomechanism (1). Applying a standardized scald injury rat model, which is widely used in burn research, we systematically determined the pathophysiological impact of burn injury on cardiac performance to uncover systemic and molecular pathomechanisms that may cause post-burn injury HFpEF development. Methods Male adolescent SD-rats were subjected to a 60% total body surface area (TBSA) full-thickness burn- or sham-trauma and subsequently characterized by serial transthoracic echocardiography, bulk myocardial next-generation sequencing and proteomics as well as RT-PCR, immuno-blotting (IB), histology and plasma proteomics for cardiac performance and molecular alterations, for up to 90 days (3, 7, 30 and 90d). Results In comparison to the sham-group (SG, n=10), animals from the burn-group (BG, n=10; survival rate 100%) recapitulated typical post-burn clinical traits, such as significant loss in body weight (BG 27% less than SG at 30d, p<0.05) or skeletal muscle wasting (i.e., 27% less at 30d, p<0.05) in accord with elevated molecular atrophy markers throughout the observation period. Our focus on the heart revealed for the first-time post-burn cardiac muscle wasting (BG 22% less at 30d, p<0.05) and persistent markers of cardiac dysfunction in accord with significant histological cardiomyocyte hypotrophy (BG −8% at 30d, p<0.05) and significantly diminished left ventricular (LV) global longitudinal strain and isovolumic relaxation time in BGs, while LV-EF remained unchanged. Subsequent IB analysis uncovered diminished protein synthesis activity and diminished mTOR pathway activity in BG hearts. Weighted gene network correlation analysis i.e., from bulk myocardial NGS and clinical traits related activation of immunological and pro-fibrotic pathways in post-burn injury hearts to cardiac dysfunction in BGs. Subsequent RT-PCR and histology confirmed significant myocardial accumulation of cardio-depressive damage associated molecular patterns (i.e., S100A8 and A9) and infiltration by granulocytes (myeloperoxidase+) and monocytes (CD 68+) as well as significant LV fibrosis. Serial plasma proteomic analysis indicated elevated plasma levels i.e., of S100A8 and A9 and other heart failure markers that mirrored similar changes in human post-burn injury plasma samples. Conclusion Here we report for the first time the development of HFpEF as a novel systemic consequence of severe burn injury in a rodent model, which prepares the ground for further mechanistic and translational studies. The initial observation of cardiac inflammation and fibrosis, which are known to negatively impact cardiac performance, may be mechanistic key findings that will guide further therapeutic studies and subsequent validation of post-burn heart failure biomarkers. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): Rolf-Schwiete Stiftung

Prolonged Asynchronous Left Ventricular Isovolumic Relaxation Constant in Ascending Compared to Descending Thoracic Aortic Stenosis for Chronic Early Left Ventricular Afterload and Late Left Ventricular Afterload Increase.

Background: In arterial hypertension, left ventricular relaxation is affected early on in relation to a chronic difference in peak left ventricular afterload with early development of HF. Objective: in ascending compares to descending thoracic aortic stenosis, resulting in chronic late and early LV afterload increase, to assess the left ventricular isovolumic relaxation pressure decay constant through regression analysis, a parameter of left ventricular relaxation on the 4th and 8th week period from invasive left ventricular pressure measurements. Methods: fourteen pigs underwent posterolateral thoracotomy for ascending aortic stenosis, resulting in chronic early left ventricular afterload increase (EL = 6], or descending thoracic aortic stenosis creating chronic late systolic left ventricular load (LL = 8]. Exponential regression with nonzero asymptote for τ assessment, with linear and nonlinear regression were performed on isovolumic relaxation pressure decay from the left ventricular invasive pressure measurements on 4th and 8th week. Two-way repeated measurement ANOVA, post-hoc Tukey test and linear regression were performed for statistical analysis. Results presented are mean ± SEM or median (quartiles], with significance is at p < 0.05. Results: The ascending aortic stenosis associated with prolonged biexponential asynchronous τ, compared to the descending thoracic aorta stenosis, resulted in data that were different at the 8th week in presence of respirations (interaction p < 0.05]. Monoexponential and linear τ were not different in either respiration being preserved or suspended transitionally and in preload reduction. Preload sensitive response of τ was found in ascending compared to descending thoracic aortic banding that reduced in EL and in LL it increased with load reduction (p < 0.05]. These results indicated that τ is not different in and between LV afterloading conditions in a chronic setting, although it indicates that myocardial ischemia is present and that it is greater in ascending aortic banding, compared to descending thoracic aorta banding at the 8th week. Conclusion: In different sequence of the left ventricular afterload, ventricular relaxation is affected early on, having in EL compared to LL prolonged biexponential asynchronous left ventricular relaxation constant, thus indicating the development left ventricular myocardial ischemia and different elastic recoil in an invasive left ventricular hemodynamic assessment.

Correlation between serum miR-122 and myocardial damage and ventricular function in patients with essential hypertension.

BackgroundMyocardial damage and decreased ventricular function are risk factors leading to a bad prognosis in patients with essential hypertension (EH). MicroRNAs play important roles in myocardial function impairment in patients with hypertension. The purpose of our research was to investigate the correlation between serum miR-122 and myocardial damage and ventricular functions in EH patients.MethodsThe clinic data of EH patients (group A, n=60) and healthy individuals (group B, n=60) from December 2016 to December 2019 in our hospital were collected and analyzed. Serum miR-122, myocardial damage markers [B-type brain natriuretic peptide (BNP), homocysteine (Hcy), cardiac troponin T (cTnT) and creatine kinase MB isoenzyme (CK-MB)] and cardiac function indicators [ejection fraction (EF), left ventricular septal thickness (IVST), left ventricular isovolumic relaxation time (IVRT), left ventricular end-diastolic diameter (LVEDD), left ventricular posterior wall thickness (LVPWT), and left ventricular end-systolic diameter (LVESD)] were assessed in both groups. The correlation between serum miR-122 and myocardial damage markers and ventricular function indicators was analyzed.Results(I) The mean serum miR-122 concentration in group A and group B was 6.86±1.23 and 3.36±1.87 µmol/L, respectively. The serum miR-122 concentration in group A was evidently increased compared with that in group B. (II) The levels of BNP, Hcy, cTnT, and CK-MB in the peripheral blood in group A were evidently increased compared with those in group B (P<0.05). (III) EF and IVRT were evidently decreased in group A compared with that in group B (P<0.05). (IV) Serum miR-122 concentration was positively correlated with the myocardial damage markers BNP, Hcy, cTnT and CK-MB, and serum miR-122 concentration was negatively correlated with the ventricular function indicators EF and IVRT but not significantly correlated with other ventricular function indicators (IVST, LVEDD, LVPWT and LVESD).ConclusionsThe serum miR-122 concentration in EH patients was higher than that in healthy individuals, and miR-122 concentration was positively correlated with myocardial damage markers. Serum miR-122 level was negatively correlated with the ventricular function indicators EF and IVRT but was not significantly correlated with other ventricular function indicators (IVST, LVEDD, LVPWT, and LVESD).

Nifedipine disturbs fetal cardiac function during hypoxemia in a chronic sheep model at near term gestation

Nifedipine is a widely used drug in pregnancies complicated by maternal hypertensive disorders that can be associated with placental insufficiency and fetal hypoxemia. The evidence regarding fetal myocardial responses to nifedipine in hypoxemia is limited. We hypothesized that nifedipine would not impair fetal sheep cardiac function under hypoxemic environment. In particular, we investigated the effects of nifedipine on fetal ventricular functional parameters and cardiac output. A total of 21 chronically instrumented fetal sheep at 122 to 134 gestational days (term, 145 days) were included in this study. Fetal cardiac function was evaluated by measuring global longitudinal strain, indices describing ventricular systolic and diastolic function, and cardiac outputs using two-dimensional speckle tracking and tissue and spectral pulsed-wave Doppler echocardiography. Fetal carotid artery blood pressure and blood gas values were invasively monitored. After baseline data collection, fetal hypoxemia was induced by maternal hyperoxygenation. After hypoxemia phase data collection, 9 fetuses received nifedipine infusion, and 12 fetuses received saline infusion. Data were collected 30 and 120 minutes after the infusion was started. After 120 minutes of data collection, maternal and fetal oxygenation were normalized, and normoxemia phase data were collected, while infusion was continued. Hypoxemia decreased fetal carotid artery mean arterial pressure from 40 (8) mm Hg to 35 (8) mm Hg (P<.007), and left ventricular global longitudinal strain showed less deformation than at baseline (P=.001). Under hypoxemia, nifedipine caused a reduction in right ventricular global longitudinal strain (P<.05), a decrease in right ventricular isovolumic relaxation velocity and its deceleration (P<.01) indicating diastolic dysfunction, and a drop in right ventricular cardiac output (P<.05). Nifedipine did not alter fetal left ventricular functional parameters or cardiac output. When normoxemia was restored, fetal right ventricular functional parameters and cardiac output returned to baseline level. In hypoxemic fetus, nifedipine impaired right ventricular function and reduced its cardiac output. The detrimental effects of nifedipine on fetal right ventricular function were abolished, when normoxemia was restored. Our findings suggest that in a hypoxemic environment nifedipine triggers detrimental effects on fetal right ventricular function.

Assessment of left ventricular dysfunction of sarcomere mutation carriers in hypertrophic cardiomyopathy by three-dimensional speckle tracking imaging combined with conventional echocardiography

Objective To explore the value of three-dimensional speckle tracking imaging (3D-STI) and conventional echocardiography in evaluating left ventricular function characteristics of sarcomere mutation carriers in hypertrophic cardiomyopathy. Methods Totally 91 subjects with sarcomere mutations in family HCM but without left ventricular hypertrophy (G+ /P- group), and 100 normal family members with gender and age matched as the control group (G-/P- group) were enrolled from the center of hypertrophic cardiomyopathy of Xijing Hospital affiliated to the Air Force Military Medical University from February 2013 to April 2017. They all received the comprehensive evaluation of 3D-STI and conventional echocardiography. The ultrasonic paramaters between the two groups were compared. And the diagnostic performance of these paramaters with sarcomere mutations was evaluated. Results Compared with the G-/P- group, the G+ /P-group had larger left atrial diameter (LAD), longer left ventricular isovolumic relaxation time (IVRT), reduced mitral annular systolic velocity (e′), elevated E/e′ ratio, as well as impaired left ventricular global longitudinal and radial strain(GLS and GRS) (P<0.05). Moreover, the GLS≤19.9%(AUC 0.861, sensitivity 61.4%, specificity 98.5%) and IVRT≥75.5 ms(AUC 0.762, sensitivity 61.4%, specificity 72.6%) showed the best diagnostic performance with sarcomere mutations (P<0.05). Conclusions In HCM family members, the sarcomere mutations carriers without left ventricular hypertrophy exhibit impaired left ventricular diastolic function, reduced longitudinal and radial systolic function.Moreover, the GLS and IVRT show the best diagnostic performance for those with sarcomere mutations. Key words: Three-dimensional speckle tracking imaging; Hypertrophic cardiomyopathy; Sarcomere mutation carriers; Ventricular function, left

Relationship between left ventricular isovolumic relaxation flow patterns and mitral inflow patterns studied by using vector flow mapping

The purpose of this study was to investigate the relationship between isovolumic relaxation flow (IRF) patterns in left ventricle (LV) and mitral inflow patterns. Color Doppler loops were acquired for vector flow mapping in apical long-axis view in 57 patients with coronary artery disease, 31 patients with dilated cardiomyopathy, and 58 healthy controls. IRF patterns were classified into three categories: pattern A, apically directed flow; pattern B, bidirectional flow with small scattered vortices; and pattern C, a large vortex. All normals and patients with normal LV filling (n = 10) showed pattern A. Patients with impaired relaxation consisted of 31 (66%) patients having pattern A, 11 (23%) having pattern B, and 5 (11%) having pattern C. Patients with pseudonormal filling included 4 (31%) patients having pattern A, 7 (54%) having pattern B, and 2 (15%) having pattern C. In patients with restrictive filling, 14 (78%) showed pattern C, 4 (22%) showed pattern B, and no patient showed pattern A. IRF patterns were associated with LV filling patterns (χ2 = 52.026, p < 0.001). There are significant relationships between LV filling and IRF patterns. IRF patterns may provide an index for evaluation of LV diastolic function.

Left Ventricular Relaxation Half-Time as a Predictor of Cardiac Events in Idiopathic Dilated Cardiomyopathy and Hypertrophic Cardiomyopathy With Left Ventricular Systolic and/or Diastolic Dysfunction

Diastolic dysfunction preceding systolic dysfunction is considered an important interaction in cardiomyopathy with poor prognosis. The aim of this study was to compare left ventricular (LV) isovolumic relaxation with the other parameters as a potential prognostic marker for patients with idiopathic dilated cardiomyopathy (IDC) and hypertrophic cardiomyopathy (HC). A total of 145 patients with IDC and 116 with HC were evaluated for hemodynamic parameters; LV pressure was directly measured by a micromanometer catheter, and relaxation half-time (T1/2) was used to determine LV isovolumic relaxation. The median follow-up period was 4.7 years. The mean ages of the patients with IDC and HC were 52.0 ± 12.0 and 57.1 ± 12.4 years, respectively. Each patient group was further divided into 2 groups based on the median value of T1/2: (1) <41.0 ms (D-L group) and ≥41.0 ms (D-H group) (2) <38.5 ms (H-L group) and ≥38.5 ms (H-H group). Kaplan-Meier analysis showed a significantly higher probability of cardiac events in the D-H group than in the D-L group (p = 0.001) and in the H-H group than in the H-L group (p = 0.028). Further, Cox proportional hazard regression analysis revealed that T1/2 was an independent predictor of cardiac events for patients with IDC (hazard ratio 1.109; p = 0.007) and HC (hazard ratio 1.062; p = 0.041). In conclusion, regardless of the type of cardiomyopathy, T1/2 as a measure of LV isovolumic relaxation function was found to be associated with the occurrence of cardiac events.

The Relationship Between Heart Rate and Left Ventricular Isovolumic Relaxation During Normoxia and Hypoxia-Asphyxia in Newborn Piglets.

Background: Many asphyxiated neonates have cardiac complications including arrhythmia and contractile dysfunction. Little is known about the relationship between heart rate (HR) and diastolic function in asphyxiated neonates. We aimed to study the relationship between HR and left ventricular (LV) isovolumic relaxation (IVR) in neonates with asphyxia using a swine model.Methods: Term newborn piglets were anesthetized and acutely instrumented with the placement of Millar® catheter in the left ventricle. Hemodynamic parameters including HR, cardiac output, stroke volume, dP/dtmax and dP/dtmin, and IVR time constant (Tau) were continuously measured and recorded. Sixteen piglets were exposed to 50-minute normocapnic hypoxia followed by asphyxia (mean of 3.2 min) by clamping of the endotracheal tube. Sham-operated piglets (n = 11) had no hypoxia nor asphyxia. The relationship between HR and other hemodynamic parameters were analyzed using Pearson Product Moment correlation test.Results: Asphyxiated piglets had cardiogenic shock and metabolic acidosis (vs. sham-operated piglets). There were significant correlations between HR and diastolic function as shown by Tau at baseline (sham-operated: r = -0.68, p = 0.02; asphyxia: r = -0.55, p = 0.03) and during normoxia (53 min) of sham-operated piglets (r = -0.69, p = 0.02). HR and Tau was not correlated during hypoxia-asphyxia (HA) (r = -0.01, p = 0.97). Cardiac output was tightly correlated with stroke volume (p < 0.001) but not HR throughout the experimental period in both groups. There was no significant correlation between HR and other hemodynamic parameters during the experimental period in both groups.Conclusion: We observed an uncoupling between HR and IVR Tau of the neonatal heart during HA, which deserves further studies of the relationship between HR and LV diastolic function.

Abstract 004: Novel Serum Metabolites Associate With Diastolic Function: Evidence From the Bogalusa Heart Study

Introduction: Diastolic dysfunction is one key causal factor for heart failure with preserved ejection fraction (HFpEF). We conducted a metabolome-wide association study to identify novel diastolic function-related metabolites in relatively young and healthy adults. Hypothesis: We hypothesized that serum metabolites could predict diastolic function and thus potentially serve as biomarkers for subclinical disease. Methods: The study cohort consisted of 1,038 participants of the Bogalusa Heart Study (34.9% black, 57.3% females, aged 33.6-57.5 years). Diastolic function was assessed via 2D and tissue doppler echocardiography, and included peak early filling velocity (E), peak velocity caused by atrial contraction (A), medial mitral annular velocity (e’), left ventricular isovolumic relaxation time (IVRT), as well as deceleration time (DT). Untargeted metabolomic analysis of fasting serum samples was conducted. Multivariable-adjusted linear regression models were employed to assess the relationship of metabolites with echocardiographic measures of diastolic function. Results: Following quality control, 1202 metabolites were tested for association with E/A ratio, E/e’ ratio, IVRT, and DT. After Bonferroni correction, 9 novel metabolites, derived from amino acid, cofactor, energy, lipid, and nucleotide pathways, were significantly associated with diastolic function in blacks with nominal significance and consistent effect direction in whites (Table). Of these significant metabolites, 2 and 6 metabolites were associated with the E/A ratio and E/e’ ratio, respectively. No significant associations of metabolites with IVRT or DT were found. Fatty acid metabolism was the biological sub-pathway most represented in significant diastolic function-metabolite associations. Conclusion: The current study identified novel metabolites associated with diastolic function, suggesting that the serum metabolome, and its underlying biological pathways, may be implicated in HFpEF pathogenesis.

3384 Serum Metabolites from the Trimethylamine Pathway Associate with Left Ventricular Diastolic Function: The Bogalusa Heart Study

OBJECTIVES/SPECIFIC AIMS: This population-based study aims to assess the individual and collective relationship between TMA-associated metabolites and echocardiographic parameters of left ventricular diastolic function. METHODS/STUDY POPULATION: The study cohort consisted of 1,039 adult participants of the Bogalusa Heart Study (35.13% black, 57.94% female, aged 33.60 to 57.47 years). Left ventricular diastolic function was assessed via two dimensional and tissue Doppler echocardiography. Echocardiographic parameters of diastolic function included peak early (E, cm/s) and late transmitral flow velocities (A, cm/s), septal mitral annular velocity (e’, cm/s), left ventricular isovolumic relaxation time (IVRT, ms), and peak early diastolic transmitral flow velocity deceleration time (DT, ms). Metabolomic analysis of fasting serum samples was conducted via ultrahigh performance liquid chromatography-tandem mass spectroscopy. Six metabolites in the TMA pathway, carnitine, choline, TMAO, betaine, ergothioneine, dimethylglycine, and two composite variables, the betaine/choline ratio as well as the weighted sum of the six TMA-associated metabolites (TMA score), were selected a priori and tested for association with echocardiographic parameters of diastolic function. Raw metabolite values were divided by their respective standard deviation to create an exposure variable for each individual metabolite. The betaine/choline ratio was calculated utilizing the raw value of each metabolite. The z-score method was used to transform the six metabolites to the same scale and these values were used to calculate the TMA score. Multivariable-adjusted linear regression models were employed to assess the relationship of TMA-associated metabolites with echocardiographic measures of diastolic function. Covariates adjusted for included sex, age, race, education, alcohol drinking, cigarette smoking, heart rate, systolic blood pressure, glomerular filtrate rate, body mass index, low density lipoprotein cholesterol, high density lipoprotein cholesterol, hemoglobin A1c, serum triglycerides, as well as blood pressure-, lipid-, and glucose-lowering medications. RESULTS/ANTICIPATED RESULTS: After stringent Bonferroni correction for multiple testing, four TMA-associated metabolites as well the TMA score were significantly associated with diastolic function. TMAO was inversely associated with IVRT (ß = −0.002 (0.00); p-value = 2.00E-03). Betaine (ß = 0.40 (0.08); p-value = 2.10E-07), carnitine (ß = 0.30 (0.07); p-value = 7.80E-05), dimethylglycine (ß = 0.27 (0.07); p-value = 3.00E-04), and the TMA score (ß = 0.10 (0.02); p-value = 3.40E-05), were positively associated with the septal E/e’ ratio. No significant associations were observed between metabolites or metabolite composite scores from the TMA pathway and the E/A ratio or DT. DISCUSSION/SIGNIFICANCE OF IMPACT: This is the first population-based study to assess the role of TMA-associated metabolites in left ventricular diastolic function. Betaine, carnitine, dimethylglycine, and a metabolite score combining serum metabolites from the TMA pathway were positively associated with the septal E/e’ ratio, suggesting that a higher concentration of TMA-associated metabolites correlates with impaired diastolic function. These results suggest that both individual and grouped metabolites from the TMA pathway may serve as early biomarkers for pre-clinical diastolic dysfunction, an important causal factor for HFpEF. Future longitudinal, multi-omic studies incorporating microbiome, metabolomic and dietary analyses are needed to characterize the risk of ventricular diastolic function and HFpEF in the setting of exposure to TMA-associated metabolites.

Suppression of angiotensin II-induced pathological changes in heart and kidney by the caveolin-1 scaffolding domain peptide.

Dysregulation of the renin-angiotensin system leads to systemic hypertension and maladaptive fibrosis in various organs. We showed recently that myocardial fibrosis and the loss of cardiac function in mice with transverse aortic constriction (TAC) could be averted by treatment with the caveolin-1 scaffolding domain (CSD) peptide. Here, we used angiotensin II (AngII) infusion (2.1 mg/kg/day for 2 wk) in mice as a second model to confirm and extend our observations on the beneficial effects of CSD on heart and kidney disease. AngII caused cardiac hypertrophy (increased heart weight to body weight ratio (HW/BW) and cardiomyocyte cross-sectional area); fibrosis in heart and kidney (increased levels of collagen I and heat shock protein-47 (HSP47)); and vascular leakage (increased levels of IgG in heart and kidney). Echocardiograms of AngII-infused mice showed increased left ventricular posterior wall thickness (pWTh) and isovolumic relaxation time (IVRT), and decreased ejection fraction (EF), stroke volume (SV), and cardiac output (CO). CSD treatment (i.p. injections, 50 μg/mouse/day) of AngII-infused mice significantly suppressed all of these pathological changes in fibrosis, hypertrophy, vascular leakage, and ventricular function. AngII infusion increased β1 and β3 integrin levels and activated Pyk2 in both heart and kidney. These changes were also suppressed by CSD. Finally, bone marrow cell (BMC) isolated from AngII-infused mice showed hyper-migration toward SDF1. When AngII-infused mice were treated with CSD, BMC migration was reduced to the basal level observed in cells from control mice. Importantly, CSD did not affect the AngII-induced increase in blood pressure (BP), indicating that the beneficial effects of CSD were not mediated via normalization of BP. These results strongly indicate that CSD suppresses AngII-induced pathological changes in mice, suggesting that CSD can be developed as a treatment for patients with hypertension and pressure overload-induced heart failure.