Prolonged Isovolumetric Relaxation Time Research Articles

Abstract Tu039: Intestinal atrophy contributes to low-grade inflammation, cardiac dysfunction and metabolic syndrome-like phenotype in a model of heart failure with preserved ejection fraction.

Introduction: Heart failure with preserved ejection fraction (HFpEF) comprises half of all HF cases and lacks effective treatment. HFpEF is now seen as a systemic syndrome often linked to comorbidities like hypertension, obesity, and diabetes. These conditions are commonly associated with unhealthy diets rich in fats but lacking in fiber. We explored the effects of a 3-week exposure to excess mineralocorticoids, salt, and high fat diet (HFD) deficient in fiber. We hypothesize that these challenges lead to intestinal atrophy, contributing to low-grade inflammation that promotes the progression of heart failure and metabolic disease. Methods: We used a mix of 1% saline in drinking water and subcutaneous implantation of controlled-release DOCA pellets (0.83 mg/day) alongside a high-fat diet (60% fat) in 8-week-old female and male C57BL6/J mice. Control mice received a standard chow diet and regular water. Results: The challenge resulted in significant reductions in colon mass, colon length, crypt length, and mucus layer thickness compared to the control group. Additionally, elevated levels of C-reactive protein and IL-6 were detected in the plasma. These changes were accompanied by alterations in diastolic function, including decreased peak myocardial relaxation velocity (e'), elevated E/e' ratio, increased E/A ratio, and prolonged isovolumetric relaxation time (IVRT), while the ejection fraction (EF) remained unchanged. Contractility parameters, such as peak myocardial contraction velocity (s'), declined in challenged mice, along with diminished stroke volume (SV). We also found increased organ weight in the liver, spleen, and lungs indicative of organ congestion. Furthermore, signs of metabolic syndrome were identified, including increased body weight, increased adiposity characterized by gonadal and subcutaneous fat accumulation, and dysglycemia (see Data Table). Conclusions: Our data suggests that in this model, heart failure triggers intestinal hypoperfusion, resulting in intestinal atrophy and compromising the integrity of the intestinal lining. Additionally, a diet rich in fat and lacking in fiber alters the gut environment by diminishing mucus production and promoting a closer interaction between the microbiome and host cells. This compromised mucus layer and intestinal barrier facilitates bacterial wall products to move into the circulation, resulting in a pro-inflammatory state that subsequently affects both cardiac function and metabolism.

Serial tissue Doppler imaging in the evaluation of bronchopulmonary dysplasia-associated pulmonary hypertension among extremely preterm infants: a prospective observational study.

To evaluate serial tissue Doppler cardiac imaging (TDI) in the evolution of bronchopulmonary dysplasia-associated pulmonary hypertension (BPD-PH) among extremely preterm infants. Prospective observational study. Single-center, tertiary-level neonatal intensive care unit. Infant born <28 weeks gestation. Utility of TDI in the early diagnosis and prediction of BPD-PH and optimal timing for screening of BPD-PH. A total of 79 infants were included. Of them, 17 (23%) had BPD-PH. The mean gestational age was 25.9 ± 1.1 weeks, and mean birth weight was 830 ± 174 g. The BPD-PH group had a high incidence of hemodynamically significant patent ductus arteriosus (83% vs. 56%, p < 0.018), longer oxygen days (96.16 ± 68.09 vs. 59.35 ± 52.1, p < 0.008), and prolonged hospital stay (133.8 ± 45.9 vs. 106.5 ± 37.9 days, p < 0.005). The left ventricular eccentricity index (0.99 ± 0.1 vs. 1.1 ± 0.7, p < 0.01) and the ratio of acceleration time to right ventricular ejection time showed a statistically significant trend from 33 weeks (0.24 ± 0.05 vs. 0.28 ± 0.05, p < 0.05). At 33 weeks, the BPD-PH group showed prolonged isovolumetric contraction time (27.84 ± 5.5 vs. 22.77 ± 4, p < 0.001), prolonged isovolumetric relaxation time (40.3 ± 7.1 vs. 34.9 ± 5.3, p < 0.003), and abnormal myocardial performance index (0.39 ± 0.05 vs. 0.32 ± 0.03, p < 0.001). These differences persisted at 36 weeks after conceptional gestational age. TDI parameters are sensitive in the early evolution of BPD-PH. Diagnostic accuracy can be increased by combining the TDI parameters with conventional echocardiographic parameters. BPD-PH can be recognizable as early as 33-34 weeks of gestation.

The evaluation of fetal interventricular septum with M-mode and spectral tissue Doppler imaging in gestational diabetes mellitus: a case-control study.

To demonstrate possible functional changes in the frequently affected fetal interventricular septum (IVS) with spectral tissue Doppler imaging (TDI) and M-mode imaging to compare gestational diabetes mellitus (GDM) and control groups. A total of 63 pregnant women with GDM, 30 on diet (A1 GDM) and 33 on treated with insulin (A2 GDM), and 63 healthy pregnant women randomly selected and matched to the case group in the control group were included. The GDM fetuses had significantly thickened IVS, increased early diastole (E'), atrial contraction (A'), systole (S'), higher myocardial performance index (MPI'), prolonged isovolumetric relaxation time (IVRT'), shortened ejection time (ET'), and decreased septal annular plane systolic excursion (SAPSE) than the controls. The A2 GDM group fetuses had significantly thickened IVS, increased S' and shortened ET' than the A1 GDM group. In the GDM group, we found a significantly positive low correlation between glycated hemoglobin levels and maternal serum fasting glucose and one-hour postprandial glucose with fetal IVS thickness. We demonstrated a significantly negative low correlation between maternal serum one-hour postprandial glucose, glycated hemoglobin levels, and gestational weight gain with fetal IVS ET'. Fetal IVS diastolic and systolic functions were altered in the GDM group compared to controls, and systolic functions were altered in A2 GDM compared to A1 GDM. This may alert clinicians to possible cardiovascular diseases in the postnatal life, and early preventive strategies and long-term lifestyle changes may provide protection in fetuses with GDM.

Smoothelin-like 1 knockout mice display sex-dependent alterations in blood flow and cardiac function.

Smoothelin-like 1 (SMTNL1) modulates the contractile performance of smooth muscle and thus has a key role in vascular homeostasis. Elevated vascular tone, recognized as a contributor to the development of progressive cardiac dysfunction, was previously found with SMTNL1 deletion. In this study, we assessed cardiac morphology and function of male and female, wild-type (Smtnl1+/+) and global SMTNL1 knockout (Smtnl1-/-) mice at 10 weeks of age. Gross dissection revealed distinct cardiac morphology only in males; Smtnl1-/- hearts were significantly smaller than Smtnl1+/+, but the left ventricle (LV) proportion of heart mass was greater. Male Smtnl1-/- mice also displayed increased ejection fraction and fractional shortening, as well as elevated aortic and pulmonary flow velocities. The impact of cardiac stress with pressure overload by transverse aortic constriction (TAC) was examined in male mice. With TAC banding, systolic function was preserved, but the LV filling pressure was selectively elevated due to relaxation impairment. Smtnl1-/- mice displayed higher early/passive filling velocity of LV/early mitral annulus velocity ratio (E/E' ratio) and myocardial performance index along with a prolonged isovolumetric relaxation time. Taken together, the findings support a novel, sex-dimorphic role for SMTNL1 in modulating cardiac structure and function of mice.

The Variation in the Diastolic Period with Interventricular Septal Displacement and Its Relation to the Right Ventricular Function in Pulmonary Hypertension: A Preliminary Cardiac Magnetic Resonance Study.

Background: Pulmonary hypertension (PH) is known to alter the biventricular shape and temporal phases of the cardiac cycle. The presence of interventricular septal (IVS) displacement has been associated with the severity of PH. There has been limited cardiac magnetic resonance (CMR) data regarding the temporal parameters of the cardiac cycle in PH. This study aimed to quantify the temporal changes in the cardiac cycle derived from CMR in PH patients with and without IVS displacement and sought to understand the mechanism of cardiac dysfunction in the cardiac cycle. Methods: Patients with PH who had CMR and right heart catheterization (RHC) examinations were included retrospectively. Patients were divided into an IVS non-displacement (IVSND) group and an IVS displacement (IVSD) group according to IVS morphology, as observed on short-axis cine CMR images. Additionally, age-matched healthy volunteers were included as the health control (HC). Temporal parameters, IVS displacement, ventricular volume and functional parameters were obtained by CMR, and pulmonary hemodynamics were obtained by RHC. The risk stratification of the PH patients was also graded according to the guidelines. Results: A total of 70 subjects were included, consisting of 33 IVSD patients, 15 IVSND patients, and 22 HC patients. In the IVSND group, only the right ventricle ejection fraction (RVEF) was decreased in the ventricular function, and no temporal change in the cardiac cycle was found. A prolonged isovolumetric relaxation time (IRT) and shortened filling time (FT) in both ventricles, along with biventricular dysfunction, were detected in the IVSD group (p < 0.001). The IRT of the right ventricle (IRTRV) and FT of the right ventricle (FTRV) in the PH patients were associated with pulmonary vascular resistance, right cardiac index, and IVS curvature, and the IRTRV was also associated with the RVEF in a multivariate regression analysis. A total of 90% of the PH patients in the IVSD group were stratified into intermediate- and high-risk categories, and they showed a prolonged IRTRV and a shortened FTRV. The IRTRV was also the predictor of the major cardiovascular events. Conclusions: The temporal changes in the cardiac cycle were related to IVS displacement and mainly impacted the diastolic period of the two ventricles in the PH patients. The IRT and FT changes may provide useful pathophysiological information on the progression of PH.

Abstract 9852: Targeting Mek/Erk Signaling in the Treatment of Mitral Valve Prolapse

Introduction: Mitral valve prolapse (MVP) is one of the most common forms of cardiac valve disease, affecting 1 in 40 humans and ~70% of small breed dogs. There are no effective nonsurgical treatments for MVP and therapeutic efforts have been hindered due to an incomplete understanding of its fundamental causes. Recent studies by our group have described the genetic basis for non-syndromic MVP and have provided new insights into molecular processes that underlie the disease. We have used this genetic information to identify druggable targets that can provide a non-surgical option for humans. In particular, we have identified the MEK/ERK pathway as the major disease initiating pathway and prolonged hyperactivation of MEK/ERK drives disease progression and severity. Hypothesis: Pharmacological blockade of MEK/ERK activities will sufficiently arrest the disease pathway and maintain the valves in a sub-clinical condition. Methods and Results: The FDA-approved MEK1 inhibitor Trametinib was administered to Dzip1 S24R/+ mice; a disease model that phenocopies human MVP. Preliminary results suggest safety concerns in mice associated with chronic administration of Trametinib (1 mg/kg/day). Animals demonstrated signs of cardiotoxicity on echocardiography, including left atrial enlargement; a reduction in E/A wave intensity; left ventricular wall movement abnormalities; prolonged isovolumetric relaxation time, and a reduced ejection fraction. As such, our lab has focused our efforts on identifying novel MEK1 inhibitors with a favorable safety profile. Utilizing a machine learning based workflow, we have identified highly selective MEK1 inhibitors with retained activity (&lt;100nM IC50 values); high gastrointestinal absorption (&gt;85%); favorable predicted LD50 values (&gt;1,000 mg/kg), and devoid of major cytochrome interactions. Conclusions: MEK1 may serve as a druggable target in the treatment of mitral valve prolapse; however, currently available MEK inhibitors demonstrate limiting toxicities. Future studies will involve in vivo administration of our novel compounds to Dzip1 S24R/+ mice. We envision results from this study will help guide the development of systemic or targeted therapies for the use in human patients with mitral valve prolapse.

Left myocardial performance index in monochorionic diamniotic twin pairs complicated by selective fetal growth restriction with abnormal umbilical artery Doppler

To evaluate left myocardial performance index (MPI) and its time intervals in monochorionic diamniotic (MCDA) twin pairs complicated by selective fetal growth restriction (sFGR) with abnormal (persistent -type II- or intermittent -type III- absent or reversed end-diastolic flow) umbilical artery Doppler. Retrospective study including 16 MCDA twin pairs with sFGR type II, 26 MCDA twin pairs with sFGR type III and 42 gestational age-matched uncomplicated MCDA twin pairs in a single tertiary center. Left isovolumetric contraction time (ICT), ejection time (ET), and isovolumetric relaxation time (IRT) were measured and MPI calculated by conventional Doppler at diagnosis of sFGR. In sFGR type II, the smaller twin had shorter ET and prolonged IRT and MPI, while the larger twin showed prolonged ICT and MPI as compared to uncomplicated MCDA twins. In sFGR type III, the smaller twin had shorter ICT and ET, while the larger twin showed prolonged ICT, IRT, and MPI in comparison to controls. A differential pattern of MPI time intervals could be observed in MCDA twins with sFGR type II and III. All twins had echocardiographic signs of pressure/volume overload, except the smaller twin type III with shorter systolic times probably reflecting reduced volume load.

Isovolumetric Relaxation Time (IVRT): An Effective Tool in Management of Subclinical Hypothyroidism

Hypothyroidism is a common condition in which thyroid gland doesn't produce sufficient thyroid hormone. Normal range of TSH is 0.4 to 4 mIU/L. Patients with TSH between 5 and 10 mIU/L, with normal T4 are diagnosed to have subclinical hypothyroidism. Decision to treat, particularly the subclinical hypothyroidism is tailored to individual patients. In our study, isovolumetric relaxation time (IVRT) was used to detect the diastolic function of cardia in hypothyroid patient, with the help of 2D echocardiogram. Normal duration of IVRT is 54 to 65μs and in hypothyroidism it is expected to increase. To assess, whether IVRT is an effective tool in the management of subclinical hypothyroidism. 50 patients attending otorhinolaryngology OPD with TSH level of 5 to 10 mIU/L were selected for the study. All these were sent for 2D echocardiogram, for the measurement of IVRT. These 50 patients were divided into 2 groups. Group A-patients with TSH level 5 to 10 mIU/L and normal IVRT. Group B-patients with TSH level 5 to 10 mIU/L and prolonged IVRT. Patients in Group A were not given thyroxine, and after 3months, they were reviewed with TSH level and IVRT duration. Patients in Group B were started with thyroxine, and after 3months, they were reviewed with TSH level and IVRT duration. The basal and 3months follow up values of TSH and IVRT was analysed on both the groups. The p value of group A was not significant, but p value group B was significant. IVRT as a measuring tool in sub clinical hypothyroidism will definitely bring a major change in the concepts of treatment.

Early myocardial changes in normotensive children of hypertensive parents: a tissue Doppler study.

The aim of this study was to examine early left ventricular systolic and diastolic changes using tissue Doppler imaging (TDI) in normotensive children of hypertensive parents (NCHP), a risk group for cardiovascular diseases. Ninety-two children characterized as NCHP (age range: 6-18 years) and 90 age-, gender-, height-, weight-, and body mass index-matched children characterized as normotensive children of normotensive parents (NCNP) were included in the study. Left ventricular diastolic parameters were assessed using transmitral flow pulse wave Doppler echocardiography and mitral septal and lateral annular TDI. Left ventricular systolic and diastolic function was evaluated globally using the TDI-derived myocardial performance index (MPI'). Mean systolic, diastolic, and average blood pressure values were found to be higher in the NCHP group than in the NCNP group. Echocardiographic parameters in the NCHP group showed statistically significant differences, including increased interventricular septum end-diastolic wall thickness (p = 0.039), left ventricular end-diastolic posterior wall thickness (p = 0.011), relative wall thickness (p = 0.013), and transmitral flow A velocity (p = 0.003); parameters determined by TDI included a prolonged isovolumetric relaxation time (p < 0.001) and isovolumetric contraction time (p = 0.002), shortened ejection time (p = 0.001), and increased MPI' (p < 0.001) in the NCHP group. Early alterations in myocardial function, indicated by increased MPI' values, had a positive correlation with systolic blood pressure and myocardial thickness. Conversely, they were negatively correlated with the ejection fraction and E/A ratio, which decreases with diastolic dysfunction. The MPI' is considered a repeatable, non-invasive, and low-cost assessment method that can surpass conventional methods in the detection of early left ventricular systolic and diastolic functional changes in the subclinical period of hypertension in children with familial risk.

Assessment of Cardiac Function in Fetuses of Gestational Diabetic Mothers During the Second Trimester.

Fetuses of diabetic mothers may have structural or functional cardiac abnormalities which increase morbidity and mortality. Isolated functional abnormalities have been identified in the third trimester. The aim of the present study was to assess fetal cardiac function (systolic, diastolic, and global myocardial performance) in the second trimester in mothers with gestational diabetes, and also to relate cardiac function with glycemic control. Mothers with gestational diabetes mellitus referred for fetal cardiac evaluation in the second trimester (between 19 and 24 weeks) from March 2015 to February 2016 were enrolled as case subjects in this study. Non-diabetic mothers who had a fetal echocardiogram done between 19 and 24 weeks for other indications were enrolled as controls. Functional cardiac variables showed a statistically significant difference in isovolumetric relaxation and contraction times and the myocardial performance index and mitral E/A ratios in the gestational diabetic group (p = 0.003). Mitral annular plane systolic excursion was significantly less in the diabetic group (p = 0.01). The only functional cardiac variable found abnormal in mothers with poor glycemic control was the prolonged isovolumetric relaxation time. Functional cardiac abnormalities can be detected in the second trimester in fetuses of gestational diabetic mothers and timely intervention can improve postnatal outcomes.

Abstract 266: Is the Col4a3 -/- Alport Mouse a Novel Model for Heart Failure With Preserved Ejection Fraction?

Heart failure with preserved ejection fraction (HFpEF) accounts for more than 50% of all HF cases. HFpEF patients manifest normal or mildly reduced left ventricle (LV) ejection fraction (LVEF), LV hypertrophy, diastolic dysfunction, myocardial stiffness, cardiac fibrosis, hypertension, nephropathy and sudden death. There is no appropriate animal model for HFpEF. The Alport Col4a3 -/- mouse, a model of nephropathy, hypertension and early death, develops a cardiovascular pathology that is yet to be well characterized. We elected to analyze the cardiovascular pathology of the Alport mouse and investigate any commonalities with HFpEF. Male Alport and wild type (WT) littermates of mixed background at 2 months of age were subjected to echocardiographic and 2D speckle tracking analyses and heart tissues were used for histopathological examinations (N=6 mice per group). Circulating Galectin-3, a marker of HFpEF, was measured by Elisa in plasma samples. Data are shown as mean±SEM. Normalized heart weight increased in Alport relative to WT mice - p&lt;0.01, indicative of cardiac hypertrophy. Consistently, echocardiography showed interventricular septum (IVS) thickening -p&lt;0.05. Reduced stroke volume p&lt;0.01, and impaired global longitudinal and circumferential strain (GLS and GCS) indicated systolic dysfunction in Alport mice. No significant reduction in LVEF was observed. Alport mice developed diastolic dysfunction evidenced by a prolonged Isovolumetric relaxation time -P&lt;0.05, and a reduced E/A, a marker of LV relaxation and stiffness -p&lt;0.01. Elevated LV filling pressure and pulmonary artery wedge pressure were demonstrated by an increase in E/E’ - p&lt;0.01. Galectin-3 increased in Alport relative to WT plasma (P&lt;0.01). Alport hearts had more Fibronectin protein - P&lt;0.05 and increased number of fibroblasts with “activated” phenotype as demonstrated by increased mass of rough endoplasmic reticulum in EM cross sections. Our study suggests that the cardiovascular pathologies of the Alport mouse are similar to HFpEF, specifically preserved ejection fraction, diastolic dysfunction, hypertension, early death and cardiac stiffness and fibrosis. Further study of this multi-factorial pathology may render the Alport mouse as a useful novel model for HFpEF.

Abstract 85: Interactions Between Cardiac Myosin Binding Protein C and Actin Contribute to the Regulation of Cardiac Contraction

Cardiac myosin binding protein C (cMyBP-C) is a regulatory muscle protein that is essential for proper cardiac contraction, and mutations in cMyBP-C are commonly associated with hypertrophic cardiomyopathy. cMyBP-C not only interacts with myosin, but with actin as well. In vitro studies have demonstrated that multiple functions of cMyBP-C could readily be explained by an interaction between cMyBP-C and actin, but the in vivo significance of cMyBP-C binding to either myosin or actin is not well understood. Here we created transgenic mice with a single point mutation (L348P) in a key binding domain of cMyBP-C that enhances the binding affinity of cMyBP-C for actin in vitro (Bezold et al , JBC 2013) to gain insights into the relevance of cMyBP-C binding to actin in working hearts. Echocardiograms from 3 month old male L348P-Tg mice (N=23) and non-transgenic (nTg, N=17) controls were used to assess systolic and diastolic function. Results showed significantly prolonged isovolumetric relaxation time (L348P-Tg: 18.5±0.6 vs nTg: 10.2±0.3 ms) and slower movement of the mitral valve annulus (E’: -17.2±1.5 vs -32.2±1.6 and A’: -9.1±1.7 vs -17.6±1.0 mm/s, p&lt;0.05), accompanied by slower inflow of blood into the left ventricle (reduced E and A, prolonged mitral valve deceleration time). Pressure-volume measurements showed significantly reduced rates of pressure decay in L348P-Tg mice (Tau Glantz: 39.1±2.6 vs 12.7±0.9 ms) and an increased end-diastolic pressure volume relationship (0.13±0.02 vs 0.07±0.01). We challenged mice with acute beta-adrenergic stimulation (isoprenaline injection) to determine whether the L348P mutation affected contractile reserve. Isoprenaline had little effect on diastolic parameters, but revealed systolic dysfunction in L348P-Tg mice as evident from a blunted increase in contraction (e.g. fractional shortening after isoprenaline: 38.5±1.3 vs 44.2±1.7%). Taken together our results show for the first time that interactions between cMyBP-C and actin are relevant for functioning of the whole heart. Increasing the cMyBP-C-actin interaction by the L348P mutation caused increased stiffness of the left ventricle, slowed relaxation and diastolic dysfunction. Results also suggested that the L348P mutation reduces contractile reserve.

Assessment of Myocardial Function in Children before and after Autologous Peripheral Blood Stem Cell Transplantation.

Increased interest is focused on the long-term adverse effects of bone marrow transplantation. Subclinical cardiac involvement appears common in adults, but only a few reports have examined pediatric patients. A prospective case-control study of 19 children with normal cardiac function undergoing autologous hematopoietic stem cell transplantation (HSCT) was performed. Tissue Doppler imaging (TDI) and echocardiographic measurements were obtained according to the guidelines of the American Society of Echocardiography before and 3 months after HSCT. Lateral mitral annulus before HSCT showed significant reduced mitral systolic annular velocity (P < 0.0001), early diastolic annular velocity (P < 0.0001), late diastolic annular velocity (P = 0.02) and prolonged isovolumetric relaxation time (IRT) (P < 0.0001) compared with control. Significant reduced mitral systolic annular velocity (P < 0.0001), early diastolic annular velocity (P = 0.0005) and Em/Am ratio (P = 0.004), with higher late diastolic annular velocity (P = 0.02) and prolonged isovolumetric contraction time (ICT) (P = 0.003) and IRT (P = 0.002) after HSCT, were observed. Investigation of lateral tricuspid annulus showed nearly similar results as the lateral mitral annulus. LV and RV Tei indices were higher before HSCT compared with control and remained high after HSCT. TDI detected subtle abnormalities in systolic and diastolic functions before and after HSCT, which suggests that a conditioning regimen may affect cardiac function.

Identification of a definite diabetic cardiomyopathy in type 2 diabetes by comprehensive echocardiographic evaluation: A cross‐sectional comparison with non‐diabetic weight‐matched controls

Subclinical left ventricular (LV) dysfunction is prevalent in type 2 diabetes (T2DM). As obesity has been proposed as one causal factor in the disease process, this could bias the reported prevalences. We wanted to characterize echocardiographic LV dysfunction in obese T2DM subjects as compared to non-diabetic obese controls. One hundred patients with T2DM without clinical signs of heart failure (29% females, mean ± SD age 58.4 ± 10.5 years, body mass index (BMI) 30.1 ± 5.5 kg/m(2), blood pressure (BP) 141 ± 18/83 ± 9 mmHg) and 100 non-diabetic controls (29% females) matched for age (58.6 ± 10.5 years), BMI (29.8 ± 4.0 kg/m(2) and systolic BP (140 ± 14 mmHg) underwent echocardiography and color tissue Doppler imaging (TDI). Diastolic function was evaluated with conventional Doppler recordings and early (e') and late (a') myocardial velocities. The ratio between early transmitral filling (E) and the corresponding myocardial tissue velocity (e') served as an index of LV filling pressure. T2DM patients had more concentric hypertrophy with a relative wall thickness of 0.42 ± 0.07 vs controls 0.38 ± 0.07, P < 0.001. The T2DM group had signs of diastolic dysfunction with lower E/A ratio (0.91 ± 0.27 vs. 1.12 ± 0.38, P < 0.001), deceleration time (195 ± 49 vs 242 ± 72 ms, P < 0.001), e' (5.7 ± 2.0 vs. 6.6 ± 1.8 cm/s, P = 0.001), and a' (6.5 ± 2.0 vs. 7.6 ± 1.5 cm/s, P < 0.001) compared to the controls, and higher E/e' (13.3 ± 4.7 vs. 11.1 ± 3.5, P < 0.001). Thus, there were indications of pseudo normalization and increased filling pressure in the T2DM group, whereas the controls had evidence for relaxation abnormalities without elevated filling pressure. Compared to a non-diabetic obese group, more advanced subclinical impairment of diastolic function was seen in T2DM.

Clinical Asthma Phenotypes: Is There an Impact on Myocardial Performance?

Asthma is a systemic disease, which affects various body systems. We aimed to assess the impact of clinical asthma phenotypes on myocardial performance in asthmatic children using tissue Doppler imaging (TDI). We enrolled 58 children with moderate persistent asthma and 62 age- and sex-matched healthy controls. Asthmatic children were classified according to clinical asthma phenotypes into shortness of breath group (n = 26) and wheezy group (n = 32). Pulmonary function tests, and conventional and TDI echocardiography were performed. TDI echocardiography assessment of the studied groups showed that asthmatic children as a group had significant left and right ventricular dysfunction when compared with healthy controls. Children in the shortness of breath group had a significant diastolic dysfunction of both ventricles in the form of lower tricuspid and mitral annular early myocardial diastolic velocity (Em), early to late myocardial diastolic velocity (Em/Am) ratio, and prolonged isovolumetric relaxation time when compared with wheezy group (P < 0.001). In the shortness of breath group, TDI-derived myocardial performance index (MPI) of both ventricles was significantly higher when compared with wheezy group (P < 0.001) reflecting global myocardial dysfunction. Conventional echocardiography of both ventricles showed RV diastolic dysfunction in the form of a significantly lower tricuspid E/A ratio in the shortness of breath group when compared with wheezy group. Clinical asthma phenotypes have an impact on myocardial function especially those presented with shortness of breath. Thus, measurement of MPI by TDI can detect subclinical changes in the cardiac performance in asthmatic children.

Impaired relaxation is the main manifestation in transgenic mice expressing a restrictive cardiomyopathy mutation, R193H, in cardiac TnI

Transgenic mice were generated to express a restrictive cardiomyopathy (RCM) human cardiac troponin I (cTnI) R192H mutation in the heart (cTnI(193His) mice). The objective of this study was to assess cardiac function during the development of diastolic dysfunction and to gain insight into the pathophysiological impact of the RCM cTnI mutation. Cardiac function and pathophysiological changes were monitored in cTnI193His mice and wild-type littermates for a period of 12 mo. It progressed gradually from abnormal relaxation to diastolic dysfunction characterized with high-resolution echocardiography by a reversed E-to-A ratio, increased deceleration time, and prolonged isovolumetric relaxation time. At the age of 12 mo, cardiac output in cTnI(193His) mice was significantly declined, and some transgenic mice showed congestive heart failure. The negative impact of cTnI193His on ventricular contraction and relaxation was further demonstrated in isolated mouse working heart preparations. The main morphological change in cTnI193His myocytes was shortened cell length. Dobutamine stimulation increased heart rate in cTnI193His mice but did not improve CO. The cTnI193His mice had a phenotype similar to that in human RCM patients carrying the cTnI mutation characterized morphologically by enlarged atria and restricted ventricles and functionally by diastolic dysfunction and diastolic heart failure. The results demonstrate a critical role of the COOH-terminal domain of cTnI in the diastolic function of cardiac muscle.

Myocardial Dysfunction Late After Low-Dose Anthracycline Treatment in Asymptomatic Pediatric Patients

The occurrence of chronic anthracycline cardiotoxicity leading to heart failure and even death is a major concern in the treatment of childhood malignancies. Currently, most treatment protocols use reduced anthracycline doses compared with historical exposure. The long-term effect of these reduced doses on myocardial function has not been well studied. We examined 56 asymptomatic patients. They all had been treated with anthracyclines at a cumulative dose less than 300 mg/m2 5.2 (range: 2.0-15.2) years before the current evaluation. In all patients, standard two-dimensional, Doppler echocardiographic measurements, end-systolic wall stress calculation, and color Doppler myocardial imaging data were obtained. From the color Doppler myocardial imaging data, peak systolic myocardial velocities, peak systolic strain rate, and peak systolic strain [symbol: see text] were computed. The myocardial acceleration during isovolumetric contraction was measured at the basal left ventricular (LV) lateral and right ventricular free wall. Data were compared with 32 age-matched normal controls. In asymptomatic patients previously exposed to low-dose anthracycline treatment, several changes in cardiac function were noted: 1. LV diastolic function was abnormal with a prolonged isovolumetric relaxation time and abnormal pulmonary venous flow patterns. 2. End-systolic wall stress was increased. 3. LV annular motion was reduced. 4. Systolic myocardial deformation was reduced with a significant decrease in both radial and longitudinal peak systolic strain rate and [symbol: see text]. Changes in systolic and diastolic function are noted in asymptomatic patients with normal ejection fraction late after low-dose anthracycline treatment. This confirms that subclinical LV dysfunction is present in patients after low-dose anthracycline treatment during childhood. The long-term significance of these findings warrants further follow-up.

Diastolic dysfunction without left ventricular hypertrophy is an early finding in children with hypertrophic cardiomyopathy–causing mutations in the β-myosin heavy chain, α-tropomyosin, and myosin-binding protein C genes

We investigated the presence of left ventricular hypertrophy (LVH) and features of diastolic dysfunction in genotype-confirmed children from families with hypertrophic cardiomyopathy (HCM) and healthy control children. In subjects with HCM-causing mutations, LVH usually does not evolve until adolescence. Diastolic dysfunction has not been systematically evaluated in children carrying HCM-causing mutations. All children (aged 1.5-16.7 years) from 14 HCM families with identified disease-causing mutations (the Arg719Trp mutation in the beta-myosin heavy chain gene [MYH7], the Asp175Asn mutation in the alpha-tropomyosin gene [TPM1], the Gln1061X mutation in the myosin-binding protein C gene [MYBPC3], and the IVS5-2A-->C mutation in the MYBPC3 gene) and 53 matched control children were examined with electrocardiography and 2- and 3-dimensional echocardiography (2DE and 3DE). Natriuretic peptides were measured in children from HCM families and 67 control children. Of 53 children from HCM families, 27 (51%) had a disease-causing mutation (G+). G+ children had slightly thicker septum on 2DE compared with the control children (P = .004), but only 3 (11%) of 27 G+ children exceeded the 95th percentile values of the body surface area-adjusted maximal LV thickness of healthy children (the major echocardiographic criterion for HCM). However, prolonged isovolumetric relaxation time, increased left atrial volume on 3DE, or increased levels of NT-proANP, all features suggestive of diastolic dysfunction, were found in 14 (52%) of 27 G+ children. In children with HCM-causing mutations, signs of diastolic dysfunction are found in about half of the cases, as LVH is present only in small percentage of these children.

Echocardiographic assessment of left ventricular morphology and function in patients with Emery–Dreifuss muscular dystrophy

Background Emery–Dreifuss muscular dystrophy (EDMD) characterized by musculoskeletal abnormalities is often associated with atrioventricular conduction disturbances. Although some EDMD patients were reported to develop dilated cardiomyopathy, there are limited data on their left ventricular (LV) performance. Methods Therefore, we echocardiographically assessed 27 men (23 cases aged 26.4±6.8 years with X-linked, and four cases aged 22.2±8.6 years with autosomal dominant (AD)) EDMD. Control group included 16 male healthy controls aged 24.8±6.0 (18–37) years. Results Although LV end diastolic dimension was similar in EDMD and controls (4.9±0.6 and 4.99±1.1 cm, ns), dilated left ventricle was found in three X-linked EDMD subjects. LV ejection fraction was significantly reduced in EDMD (62.3±1% vs. 71.2±2%, p=0.01) and was below 50% in six (22.2%) X-linked EDMD patients. Doppler analysis disclosed prolonged isovolumetric relaxation time of the left ventricle in the studied group. This finding may indicate impaired LV relaxation. Conclusion A significant subgroup of X-linked EDMD patients shows pronounced abnormalities of left ventricular function. This warrants cardiologic follow up of EDMD patients.

Systolic time intervals in haemodialysis patients with normal ejection fraction: an echocardiographic study

SUMMARY: In this controlled study, systolic time intervals (STI) and diastolic functions were investigated in haemodialysis patients (HDp) with ejection fraction (EF) within normal limits. Echocardiographic findings in 86 HDp (M:F, 47:39, mean age 36 ± 13 years) and 51 healthy controls (M:F, 22:29, mean age 37±10 years) were compared for STI parameters (projection period (PEP), left ventricular ejection time (LVET) and STI index (PEP/LVET)) and diastolic dysfunction (isovolumetric relaxation time (IVRT) and E/A ratio and deceleration time). the pre‐ejection period (114±21 vs 94±4 msec, P &lt; 0.001) and STI index (0.41 ±0.11 vs 0.34 ±0.02, P &lt; 0.001) were higher in the HDp compared with controls. Increased STI index and prolonged PEP in HDp were independent of left ventricular (LV) hypertrophy and hypertension. Diastolic dysfunction was present in 61% of the patients. the IVRT were also found to be longer in HDp compared with controls (97±16 vs 75±16 msec, P &lt; 0.001), independent of the presence of LV hypertrophy or hypertension. Diastolic dysfunction indicated by IVRT &gt;100 msec and latent systolic dysfunction (STI index &gt;0.4) were randomly distributed, with nearly half (48%) of the patients with prolonged IVRT having an STI index within the normal limits and the other half of the patients with deteriorated STI index having a normal IVRT. the combined systolic and diastolic dysfunction was observed in 30% of the patients. It was concluded that STI indexes deteriorate before an overt systolic dysfunction (normal EF), and that systolic and/or diastolic dysfunction of the myocardium may appear singly or simultaneously because of a common pathogenetic mechanism of myocardial fibrosis.