Ventricular Isovolumic Relaxation Time Research Articles

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.

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

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).

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

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.

Heterogeneity of patients with arterial hypertension and heart failure with preserved left ventricular ejection fraction according to the clinical and structural-functional profile of the heart and arteries depending on the available diagnostic criteria o

The aim — to determine the frequency of different combinations of criteria of heart failure (HF) with preserved ventricular ejection fraction (EF), established by the European Society of Cardiology (ESC) in 2016, in symptomatic patients with arterial hypertension (AH) in clinical practice and to assess their relationship to the clinical profile and the structural and functional state of the heart and arteries.Materials and methods. The study included 103 patients aged 43 to 85 years, with symptoms and signs of HF, AH and LVEF ³ 50 %, which had signs of diastolic dysfunction (DD) according to Doppler EchoCG data. The level of N­terminal fragment of the brain natriuretic peptide (NT­proBNP) was assessed by an enzyme immunoassay. The pulse wave velocity (carotid­femoral) (PWVcf) was assessed using applanation tonometry. Using ECG, the back wall thickness (BWT) of the left ventricle (LV) and interventricular septal thickness (IST), end­diastolic index (EDI) and end­systolic index (ESI) of the LV, left ventricular myocardial index (LVMI), left atrium volume index (LAVI) and left ventricular ejection fraction (LVEF). Early (E) and late diastolic left ventricular filling velocity (A), E/A ratio, diastolic speed of septal and lateral motion of fibrous mitral valve ring, the mean value e¢, the relation Е/e¢, tricuspidal regurgitation velocity (TRV), the deceleration time of early diastolic filling (DT) and left ventricular isovolumic relaxation time (IVRT), and systolic pulmonary artery pressure (SPAP) — with the use of Doppler EchoCG were evaluated. Patients with ratio E/e¢ 9 — 13 at rest underwent diastolic stress test.Results and discussion. According to the ESC algorithm, HF was absent in 11 (10.6 %) patients (group 1); 28 (30.4 %) patients had structural criteria and no functional criteria (group 2); 64 (69.5 %) patients had three structural and functional criteria of HF according to ESC algorithm (group 3). High left ventricular filling pressure (LVFP) was found in all 35 (54.6 %) patients of group 3 without atrial fibrillation (AF) and in 7 (26.9 %) patients of group 3. Normal left ventricular filling pressure was found in all patients of group 1 and 7 (26.9 %) patients of group 2. Left ventricular filling pressure could not be identified in 4 (36.3 %) patients of group 1 and 12 (46.1 %) patients of group 2 (all p < 0.01). AF was present in 29 (45.3 %) patients of group 3 and in 2 patients (7.1 %) of group 2 (p < 0.01). Increase in SPAP was noted in 52 (81.2 %) patients of group 3 and 4 (14.2 %) patients of group 2 (p < 0.01). The dilatation of the right ventricle (RV) was more pronounced in group 3 than in groups 2 and 1 (p < 0.01 and p < 0.05). Patients of groups 1 and 2 were comparable according to PWVcf, patients of group 3 had higher values of this indicator than those of groups 2 and 1 (all p < 0.01). E/e¢ while exercise stress was more than 13 in 78.5 % patients of group 2 and in 18.2 % of group 1 (p < 0.01). Groups 2 and 3 had high levels of NT­proBNP — 438.4 ± 97.2 and 1057.3 ± 157.0 pg/ml, accordingly, in group 1 its level was 199.7 ± 17.2 pg/ml (all p < 0.01).Conclusions. In 70 % of patients with hypertension and clinical signs of HF, both structural and functional criteria of diagnosis of HF with preserved LV EF were defined according to the recommendations of the ESC (2016), which was associated with an increase in LV feeling pressure, AF — in 45 %, pulmonary hypertension — in 52 (81.2 %), with right ventricle dilatation — in 81 % and 27 % increase in PWVcf in compared with age and sex matched patients with AH without HF. AH patients with only two structural criteria of heart failure with a preserved LVEF in the absence of functional criteria (30 % of cases) differ from patients with AH without HF in terms of the level of NT­proBNP, an increase in E/e’ while exercise (85 % of cases) and comparable severity of clinical signs of heart failure.

Longer Ischemic Time is Associated with Increased Ventricular Stiffness as Measured by Pressure-Volume Loop Analysis in Pediatric Heart Transplant Recipients.

The purpose of this study was to investigate the associations between clinical factors and cardiac function as measured by pressure-volume loops (PVLs) in a pediatric heart transplant cohort. Patients (age<20years) who underwent heart transplantation presenting for a clinically indicated catheterization were enrolled. PVLs were recorded using microconductance catheters (CD Leycom®, Zoetermeer, Netherlands). Demographic data, serum B-type natriuretic peptide (BNP), time from transplant, ischemic time, presence of transplant coronary artery disease, donor-specific antibodies, and history of rejection were recorded at the time of catheterization. PVL data included contractility indices: end-systolic elastance and preload recruitable stroke work; ventricular-arterial coupling index; ventricular stiffness constant, Beta; and isovolumic relaxation time constant, tau. Associations between PVL measures and clinical data were investigated using non-parametric statistical tests. A total of 18 patients were enrolled. Median age was 8.7years (IQR 5-14years). There were ten males and eight females. Six patients had a history of rejection and ten had positive donor-specific antibodies. There was no transplant coronary artery disease. Median BNP was 100pg/mL (IQR 46-140). Time from transplant to PVL obtained during catheterization procedure was 4.1years (IQR 1.7-7.8year). No single clinical characteristic was statistically significant when correlated with PVL data. However, longer ischemic time was associated with worse Beta (r=0.49, p=0.05). Our study found that longer ischemic times are associated with increased left ventricular stiffness. No other single clinical variable is associated with cardiac dysfunction as determined by PVL analysis.

Myocardial structure and function and predictors of recurrent atrial fibrillation in hypertensive patients after electrical cardioversion

Objective. To determine predictors of atrial fibrillation (AF) recurrence in patients with persistent AF and arterial hypertension (HTN) after sinus rhythm (SR) restoration by electrical cardioversion (ECV) using data on the dynamics of structural and functional changes in the heart during prolonged preventive antiarrhythmic therapy (AART). Design and methods. The study involved 127 patients with HTN and non-valvular form of persistent AF who underwent ECV leading to the restoration of sinus rhythm. All patients underwent Holter monitoring (HM) and echocardiography, and were randomized into groups for certain anti-arrhythmic drug (propafenone, sotalol, amiodarone). Results and conclusions. There is a strong negative correlation between the duration of sinus rhythm after ECV with the prolonged antiarrhythmic therapy and the value of anteroposterior size of the left atrium referred to the body surface area. There was no change in the structural parameters of the left heart one year after ECV when SR was maintained in patients receiving AART (propafenone, sotalol, amiodarone). Amiodarone is more effective for the prevention of AF recurrence after ECV than sotalol or propafenone; and is associated with a decrease in left ventricular isovolumic relaxation time and deceleration time of mitral flow.

Endothelial function, regulation of angiogenesis and embryonic central hemodynamics in ART-conceived pregnancies

This study was undertaken to compare the concentrations of pro- and anti-angiogenic growth factors, nitric oxide (NO) stable metabolites in maternal serum and embryonic left ventricular (LV) isovolumic relaxation time (IRT, ms) during the first trimester in two groups of women: with pregnancy conceived by assisted reproductive technologies (ART, n = 39) and normally conceived (control group, n = 68) pregnancy. The concentration of vasoconstrictor endothelin 1 was 45.5 times more in ART than in control group. On the contrary, the concentrations of NO stable metabolites in ART were 1.9 times less than in control women. The assessment of angiogenic suppressors in ART women demonstrates the decrease in s-endoglin concentration was 1.6 times and in soluble receptor to vascular endothelial growth factor concentration was 2.0 times in comparison with control group. There was a significant increase in LV IRT in ART embryos in comparison to control ones. These data suggest significant changes in pro- anti-angiogenic factors balance and increase in vascular impedance in ART-conceived embryos.

Right ventricular diastolic function assessment by Tissue Doppler in mitral stenosis – Correlation with functional capacity

IntroductionEchocardiography forms the cornerstone in the assessment and management of patients with mitral stenosis. We studied right ventricular diastolic function utilizing, Tissue Doppler imaging (TDI) and correlated it with symptom status in patients with moderate to severe mitral stenosis. Methods51 patients with moderate to severe mitral stenosis were classified into asymptomatic (Group I, NYHA class I) and symptomatic (Group II, NYHA class II–III) group. They underwent standard two dimensional echocardiographic assessment with special stress on right ventricular diastolic function using tissue Doppler imaging. Results were based on comparison of patients who were symptomatic and had right ventricular diastolic dysfunction as compared to those who were asymptomatic with similar mitral valve area. Tei index was also calculated in both these groups and compared. The results were analysed by appropriate statistical tests for correlations. ResultsAmong the right ventricular parameters isovolumic relaxation time (IVRT) in (asymptomatic) group I was lower as compared to (symptomatic) group II, (p < 0.05). Symptomatic group had a lower right ventricular E′/A′ as compared to asymptomatic group, (p < 0.001). Confidence interval plot showed minimal overlap suggestive of strong correlation. The mean Tei index value was higher in symptomatic group but did not achieve statistical significance (p > 0.05). ConclusionPatients with moderate to severe mitral stenosis who had symptoms, also had statistically significant right ventricular diastolic dysfunction in our study, compared to their asymptomatic counterparts. Thus routine assessment of right ventricular diastolic function in patients with mitral stenosis is recommended as it precedes symptomatic worsening.

Ultrasound markers of genetic pathology and early hemodynamic changes in human embryo

First trimester nuchal translucency (NT) and ductus venosus reverse blood flow (DVRBF) are used as ultrasound markers (UM) to determine the risk of fetal aneuploidy, heart defects and subsequent maternal preeclampsia. One pathophysiological explanation for these UM, encompassing both normal and pathological outcomes, is the development of transient heart failure due to increased vascular resistance (afterload). Left ventricular isovolumic relaxation time (LV IRT) was demonstrated as sensitive index of afterload increase in the second and third trimester fetus. The objective of study was to determine LV IRT in normally developing embryos and embryos with early UM of chromosomal and cardiac abnormalities and to test the hypothesis of embryonic hypertension as a cause of transient heart failure. An ultrasound study in 122 normally developing and 27 human embryos with increased NT (>3 mm) and DVRBF at gestational ages 11-14 weeks was perfomed. Mean LV IRT (41 +/- 3 ms) was 36.6 percent longer in embryos with UM as compared to the normal subset (30 +/- 2 ms) (p < 0.001).

Usefulness of right ventricular isovolumic relaxation time in predicting systolic pulmonary artery pressure

Objective Assessment of usefulness of right ventricular isovolumic relaxation time measured by Tissular Doppler imaging in predicting systolic pulmonary artery pressure. Methods 30 patients, 10 males and 20 females were included in the study. The mean age was (43.7 ± 14.96) years and SPAP was (52.77 ± 23.19) mmHg. 6 patients were hypertensive, 8 patients were diabetic, Referral diagnoses were valvular heart disease (n = 8), cardiomyopathy (n = 3) and coronary artery disease (n = 19) at Bab Al-She‘reya University Hospital – Al-Azhar University – Cairo – Egypt, from April 2009 to November 2009. Patients were classified according to systolic pulmonary artery pressure (SPAP) measured invasively through right heart catheterization into two groups: Group I – Patient with systolic pulmonary artery pressure less Than 40 mmHg and this group include 10 patients (normal group). Group II – Patient with systolic pulmonary artery pressure equal or more than 40 mmHg and this group include 20 patients (pulmonary hypertensive group) . All the patients had been subjected to the following: Informed consent, Brief history taking, Transthoracic echo-Doppler study with standerd views to calculate ESPAP and Tissue Doppler Imaging (TDI) taking the following parameters: – Right ventricular isovolumic relaxation time (r IVRT’) &peak systolic tricuspid annular excertion(S)’. Results An analyzable Doppler tricuspid diastolic signal could not be obtained in 2 patients. all of them were in the group of patients without PAH, which means that TR was not recordable in 20% of patients in this group. All patients of the PAH group had an analyzable tricuspid regurgitant jet, there were extremely significant statistical positive correlation between SPAP measured invasively through right heart catheterization and r IVRT’ measured by tissue Doppler imaging. (P value 0.0001, r = 0.80).this correlation improved maximally when patients with elevated RAP(above 8 mmhg) and patients with right ventricular dysfunction(S′ 11.5 Cm/S) are excluded (P value 0.0001, r = 0.91). Receiver-operating characteristics (ROC) curve for predicting a SPAP of 40 mmHg or higher showed That rIVRT’ > 38 ms predicts pulmonary hypertension with 100% sensitivity, 90%specificity, while a rIVRT’ 38 ms excluded pulmonary hypertension with 100% negative predictive value. Conclusions Although there is extremely positive correlation between SPAP measured invasively through right heart catheterization and that estimated from peak tricuspid regurge velocity there are difficulties in assessment of TR specially in obese and COPD patients. rIVRT’ appears to be helpful in evaluating SPAP, a normal rIVRT’ 38 ms can exclude PAH with a high negative predictive value. A prolonged rIVRT’ is indicative of PAH but cannot affirm it by itself.