Abstract 280: Deficiency of FKBP12 in the Heart Leads to Impaired Contractility and Pregnancy Induced Cardiomyopathy

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Joshua Oakes ◽  
Susan Hamilton

FK506 Binding Proteins (FKBPs) are a family of cis-trans prolyl isomerases that bind rapamycin and FK506. FKBP12 and 12.6 interact with ryanodine receptors (RyR), homotetrameric transmembrane ion channels that regulate Ca2+ release from the sarcoplasmic reticulum (SR). FKBP12 interacts with RyR1 in skeletal muscle and FKBP12.6 interacts with RyR2 in cardiac muscle to regulate the Ca2+ leak properties of these channels. Recently it has been suggested that FKBP12 also plays a role in regulating RyR2 activity. Using mice with a cardiac specific deficiency in FKBP12, we analyzed the role of FKBP12 in cardiac function. We found that both male and female mice with a α-MyHC Cre/Lox mediated deficiency in FKBP12 in the heart (FKBP12 KD) developed a mild dilated cardiomyopathy, with enlarged left ventricular diameter both during systole and diastole, decreased ejection fraction and decreased fractional shortening. To elucidate the mechanism for these effects we assessed Ca2+ sparks in isolated cardiomyocytes. We found an increase in both Ca2+ spark frequency and spark amplitude in FKBP12 cardiac deficient mice without a change in spark duration. Despite a mild phenotype in adult mice, we found that approximately 25% of all pregnancies (26/106) in the FKBP12 deficient mice resulted in the mothers dying following the birth. Autopsies show that these cardiac specific FKBP12 deficient mice had increased heart weight and significantly dilated ventricles compared to female Cre mice. Our data suggest that a cardiac specific deficiency in FKBP12 leads to the development of pregnancy induced cardiomyopathy. Echocardiography on FKBP12 deficient mice one day after giving birth found that there was no significant difference in ejection fraction or fractional shortening compared to α-MyHC Cre control mice. FKBP12 deficient females, however, had larger hearts and 50% (2/4) displayed heart failure and died. In conclusion, we show that FKBP12 does indeed alter Ca2+ handling in the heart and that a loss of FKBP12 leads to the development of pregnancy induced cardiomyopathies in females.

1991 ◽  
Vol 30 (05) ◽  
pp. 183-188
Author(s):  
A. Aydrner ◽  
A. Oto ◽  
E. Oram ◽  
O. Gedik ◽  
C. F. Bekdik ◽  
...  

Left ventricular function including regional wall motion (RWM) was evaluated by 99mTc first-pass and equilibrium gated blood pool ventriculography and glycohemoglobin (HbA1c) blood levels determined by a quantitative column technique in 25 young patients with insulin-dependent diabetes mellitus without clinical evidence of heart disease, and in healthy controls matched for age and sex. Phase analysis revealed abnormal RWM in 19 of 21 diabetic patients. The mean left ventricular global ejection fraction, the mean regional ejection fraction and the mean 1/3 filling fraction were lower and the time to peak ejection, the time to peak filling and the time to peak ejection /cardiac cycle were longer in diabetics than in controls. We found high HbA1c levels in all diabetics. There was no significant difference between patients with and without retinopathy and with and without peripheral neuropathy in terms of left ventricular function and HbA1c levels.


2017 ◽  
Vol 2 (2) ◽  
pp. 69-74
Author(s):  
Mohammad Aminullah ◽  
Fahmida Akter Rima ◽  
Asraful Hoque ◽  
Mokhlesur Rahman Sazal ◽  
Prodip Biswas ◽  
...  

Background: Cardiac remodeling is important issue after surgical closure of ventricular septal defect.Objective: The purpose of the present study was to evaluate cardiac remodeling by echocardiography by measuring the ejection fraction, fractional shortening, left ventricular internal diameter during diastole (LVIDd) and left ventricular internal diameter during systole (LVIDs) after surgical closure of ventricular septal defect in different age group. Methodology: This prospective cohort studies was conducted in the Department of Cardiac Surgery at National Institute of Cardiovascular Disease (NICVD), Dhaka. Patient with surgical closure of VSD were enrolled into this study purposively and were divided into 3 groups according to the age. In group A (n=10), patients were within the age group of 2.0 to 6.0 years; age of group B (n=8) patients were 6.1-18.0 years and the group C (n=6) aged range was 18.1-42.0 years. Echocardiographic variables such as ejection fraction, fractional shortening, LVIDd, LVIDs were taken preoperatively and at 1st and 3rd month of postoperative values. Result: A total number of 24 patients was recruited for this study. The mean ages of all groups were 12.60±12.09. After 1 month ejection fraction were decreased by 5.97%, 6.71% and 5.66% in group A, group B and group C respectively. After 3 months ejection fraction were increased by 6.13%, 5.13% and 5.14% in group A, group B and group C respectively. After 1 month fractional shortening were decreased by 13.55%, 9.30% and 9.09% in group A, group B and group C respectively. After 3 months fractional shortening were increased by 7.23%, 7.35% and 4.55% in group A, group B and group C respectively. After 1 month LVIDd were increased by 1.97%, 1.91% and 1.32% in group A, group B and group C respectively. After 3 months LVIDd were decreased by 10.84%, 9.89% and 7.34% in group A, group B and group C respectively. After 1 month LVIDs were increased by 2.19%, 2.86% and 1.98% in group A, group B and group C respectively. After 3 months LVIDs were decreased by 11.68%, 10.97% and 8.87% in group A, group B and group C respectively.Conclusion: Cardiac remodeling occurred after surgical closure of ventricular septal defect and remodeling were more significant in younger age group. Journal of National Institute of Neurosciences Bangladesh, 2016;2(2):69-74


2013 ◽  
Vol 2013 ◽  
pp. 1-5 ◽  
Author(s):  
Hamid Raieszadeh ◽  
Vahid Noaman ◽  
Mehrdad Yadegari

270 Ross broiler chickens of twenty days old were housed in 18-floor pens in a completely randomized design with six treatment groups and three replicate groups and fifteen chicks per each pen. The treatment groups (1–6) consisted of 0, 10, 20, 30, 50, and 70 ppm of nanocide in drinking water, respectively. At 26 days of age, 3 chickens were selected randomly for echocardiography using a 7.5 MHz linear probe, and the left ventricular internal diameter at the end of diastole (LVIDd), left ventricular internal diameter at the end of systole (LVIDs), left ventricular fractional shortening (LVFS), ejection fraction (EF), stroke volume (SV), interventricular septum thickness at the end of systole (IVSTs), and interventricular septum thickness at the end of diastole (IVSTd) were evaluated. LVIDd and LVIDs in group six were of higher rate than other groups and showed statistically significant differences with groups two, three, and four (P<0.05). LVFS, percentage of EF, and IVSTd were minimum in group six and had significant difference with other groups (P<0.05). The results of this study showed that prescription of high dosage of nanocide leads to cardiovascular problems with decrease in myocardial contractility and increase in the internal diameter of left ventricle.


Author(s):  
Akshar Jaglan ◽  
Sarah Roemer ◽  
Ana Cristina Perez Moreno ◽  
Bijoy K Khandheria

Abstract Aims Myocardial work (MW) is a novel parameter that can be used in a clinical setting to assess left ventricular (LV) pressures and deformation. We sought to distinguish patterns of global MW index in hypertensive vs. non-hypertensive patients and to look at differences between categories of hypertension. Methods and results Sixty-five hypertensive patients (mean age 65 ± 13 years; 30 male) and 15 controls (mean age 38 ± 12 years; 7 male) underwent transthoracic echocardiography at rest. Hypertensive patients were subdivided into Stage 1 (n = 32) and Stage 2 (n = 33) hypertension based on 2017 American College of Cardiology guidelines. Exclusion criteria were suboptimal image quality for myocardial deformation analysis, reduced ejection fraction, valvular heart disease, intracardiac shunt, and arrhythmia. Global work index (GWI), global constructive work (GCW), global wasted work (GWW), and global work efficiency were estimated from LV pressure–strain loops utilizing proprietary software from speckle-tracking echocardiography. LV systolic and diastolic pressures were estimated using non-invasive brachial artery cuff pressure. Global longitudinal strain and LV ejection fraction were preserved between the groups with no statistically significant difference, whereas there was a statically significant difference between the control and two hypertension groups in GWI (P = 0.01), GCW (P &lt; 0.001), and GWW (P &lt; 0.001). Conclusion Non-invasive MW analysis allows better understanding of LV response under conditions of increased afterload. MW is an advanced assessment of LV systolic function in hypertension patients, giving a closer look at the relationship between LV pressure and contractility in settings of increased load dependency than LV ejection fraction and global longitudinal strain.


2021 ◽  
Vol 2114 (1) ◽  
pp. 012006
Author(s):  
M K Mohammed ◽  
S I Essa

Abstract Ischemic heart disease is a major causes of heart failure. Heart failure patients have predominantly left ventricular dysfunction (systolic or diastolic dysfunction, or both). Acute heart failure is most commonly caused by reduced myocardial contractility, and increased LV stiffness. We performed echocardiography and gated SPECT with Tc99m MIBI within 263 patients and 166 normal individuals. Left ventricular end systolic volume (LVESV), left ventricular end diastolic volume (LVEDV), and left ventricular ejection fraction (LVEF) were measured. For all degrees of ischemia, there was a significant difference between ejection fraction values measured by SPECT and echocardiography, and there were no significant differences among end systolic volume and end diastolic volume value calculated by two methods for all cases. The mean value for EDV (ECHO)/EDV (SPECT) was 1.07 ± 0.31 for degree (1, 2); in the degree 3 the mean value was 1.02 ± 0.08, and 1.005 ± 0.07 for degree 4. The mean value for ESV (ECHO)/ESV (SPECT) was 1.08 ± 0.34 for degree (1, 2); while 1.03 ± 0.12, 1.021 ± 0.128 for degree 3 and 4 respectively. This study was showed a good relation between left ventricular size and ejection fraction measured by SPECT with Tc99m, and echocardiography.


2019 ◽  
Vol 57 (215) ◽  
Author(s):  
Raj Kumar Thapa ◽  
Kanchan K.C ◽  
Rishi Khatri ◽  
Devendra Khatri ◽  
Rajeeb Kumar Deo ◽  
...  

Introduction: Cardiomyopathies are diseases of heart muscle that may originate from genetic defects, cardiac myocyte injury or infiltration of myocardial tissues. Dilated cardiomyopathy is the most common phenotype and is often a final common pathway of numerous cardiac insults. Mostly it remains unknown in the absence of echocardiography, histopathology and genetic evaluation. Though common it is underdiagnosed with not much of data available in our setup.Methods: This study was analytical cross-sectional study of hospital data on Echocardiographic findings in 65 patients of DCM visiting cardiology unit for Echocardiographic evaluation from 1st of February to 31st July 2018 for the period of six months in Shree Birendra Hospital, a tertiary care military hospital at Chhauni, Kathmandu. Pediatric age group patients and those who refused to give consent were excluded. Data obtained were entered in Microsoft Excel 2010 and analyzed by IBM SPSS 21.Results: Among 65 patients enrolled 40 (61%) were male and 25 (39%) female with male to female ratio of 1.6:1. Elderly people (61-75 years) with an average age of 65 were commonly involved and they presented mostly with congestive heart failure, 32 (49%). Echocardiographic evaluation showed 36 (55%) with mildly dilated Left Ventricle (5.6-6.0cm). Majority had reduced Left ventricular systolic function with an average Ejection fraction (EF) of 39.6%. No significant difference between male and female with the average EF% (P=0.990) and there was no significant relation between age and average EF% (P=0.091).Conclusions: Dilated Cardiomyopathy is the commonest cardiomyopathy phenotype mostly presenting with congestive heart failure. It is often underdiagnosed in our part of the world, however echocardiography will easily detect the condition. Keywords: dilated cardiomyopathy; echocardiography; ejection fraction; left ventricle.


2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Marion Hofmann Bowman ◽  
Brandon Gardner ◽  
Judy Earley ◽  
Debra L Rateri ◽  
Alan Daugherty ◽  
...  

Background: Serum S100A12 and fibroblast growth factor (FGF) 23 are biomarkers for cardiovascular mortality in patients with chronic kidney disease (CKD) and are associated with left ventricular hypertrophy (LVH). FGF23 is induced in cultured cardiac fibroblasts in response to cytokines including IL-6, TNF-a, LPS and S100/calgranulins. Moreover, hBAC-S100 transgenic mice with CKD had increased FGF23 in valvular interstitial cells and exhibited LVH. The present study was designed to examine cardiac FGF23 expression in other murine models of LVH in the absence of CKD. Methods: Hearts from five groups of male mice were studied: (i) C57BL6/J with transgenic expression a bacterial artificial chromosome of the human S100/calgranulins (S1008/9 and S100A12, hBAC-S100), (ii) wild type littermates, (iii) LDLR-/- infused with saline (29 days, 0.9%), (iv) LDLR-/- infused with angiotensin (Ang) II (29 days, 1000 ng/kg/min), and (v) fibroblast specific depletion of angiotensin II type 1a receptor (AT1aR) (S100A4-Cre x AT1aR-/- x LDLR-/-) infused with AngII. Results: hBAC-S100, but not wild type littermate mice, developed significant LVH at 10 months by heart weight/body weight (5.9 ±1.1 mg/g vs. 4.2 ±0.8, p<0.04), decreased E/A ratio, and increased LVPW thickness, and associated with increased expression of FGF23 mRNA and protein in cardiac tissue lysates (2-4 fold increase). Similarly, Ang II induced significant LVH compared to saline infused LDLR-/- mice (6.1±1.3 vs. 3.6 ±0.9 mg/g, p<0.01), and associated with increased mRNA for hypertrophic genes (ANP, BNP, b-MHC, CTGF and Col1a1). However, there was no significant difference in FGF23 mRNA and protein between Ang II and saline infused mice. Cardiac hypertrophy was attenuated in AngII-infused mice with deficiency of AT1aR (S100A4-Cre+/-xAT1aRxLDLR-/-). In vitro, Ang II (100nM) did not induce FGF23 in valvular interstitial fibroblasts or myocytes. Summary: Transgenic expression of S100/calgranulins is sufficient to induce LVH in aged mice with normal renal function, and this is associated with FGF23 expression in cardiac interstitial fibroblasts. Future studies are needed to determine whether cardiac FGF23 promotes LVH in a paracrine manner. However, FGF23 does not play a role in Ang II-induced LVH.


Author(s):  
Parisa Gholami ◽  
Shoutzu Lin ◽  
Paul Heidenreich

Background: BNP testing is now common though it is not clear if the test results are used to improve patient care. A high BNP may be an indicator that the left ventricular ejection fraction (LVEF) is low (<40%) such that the patient will benefit from life-prolonging therapy. Objective: To determine how often clinicians obtained a measure of LVEF (echocardiography, nuclear) following a high BNP value when the left ventricular ejection fraction (LVEF) was not known to be low (<40%). Methods and Results: We reviewed the medical records of 296 consecutive patients (inpatient or outpatient) with a BNP values of at least 200 pg/ml at a single medical center (tertiary hospital with 8 community clinics). A prior diagnosis of heart failure was made in 65%, while 42% had diabetes, 79% had hypertension, 59% had ischemic heart disease and 31% had chronic lung disease. The mean age was 73 ± 12 years, 75% were white, 10% black, 15% other and the mean BNP was 810 ± 814 pg/ml. The LVEF was known to be < 40% in 84 patients (28%, mean BNP value of 1094 ± 969 pg/ml). Of the remaining 212 patients without a known low LVEF, 161 (76%) had a prior LVEF >=40% ( mean BNP value of 673 ± 635 pg/ml), and 51 (24%) had no prior LVEF documented (mean BNP 775 ± 926 pg/ml). Following the high BNP, a measure of LVEF was obtained (including outside studies documented by the primary care provider) within 6 months in only 53% (113 of 212) of those with an LVEF not known to be low. Of those with a follow-up echocardiogram, the LVEF was <40% in 18/113 (16%) and >=40% in 95/113 (84%). There was no significant difference in mean initial BNP values between those with a follow-up LVEF <40% (872 ± 940pg/ml), >=40% (704 ± 737 pg/ml), or not done (661 ± 649 pg/ml, p=0.5). Conclusions: Follow-up measures of LVEF did not occur in almost 50% of patients with a high BNP where the information may have led to institution of life-prolonging therapy. Of those that did have a follow-up study a new diagnosis of depressesd LVEF was noted in 16%. Screening of existing BNP and LVEF data and may be an efficient strategy to identify patients that may benefit from life-prolonging therapy for heart failure.


2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Toshinori Aoyagi ◽  
Takashi Matsui

The risk of heart failure following myocardial infarction is higher in diabetic patients than nondiabetic patients. The mammalian target of rapamycin (mTOR), a key downstream molecule of insulin-phosphoinositide 3-kinase (PI3K)-Akt signaling pathway, plays an important role in cardioprotection. However, the role of cardiac mTOR in ischemic injury in metabolic syndrome has not been well defined. To address this question, we studied the effect of overexpressing cardiac mTOR on cardiac function following ischemia/reperfusion (I/R) in mice with high-fat diet (HFD)-induced obesity. In this study, we used transgenic mice with cardiac-specific overexpression of mTOR (mTOR-Tg) as reported previously. mTOR-Tg and WT mice at 6 weeks old were fed HFD (60% fat by calories) ad libitum for 14 weeks. Control mTOR-Tg and WT mice were fed a normal chow diet (NCD). At 14 weeks after HFD, glucose and insulin tolerance tests demonstrated that HFD generated glucose intolerance and insulin resistance in both mTOR-Tg (n=20) and WT (n=24) mice. Body weight (BW) and heart weight (HW) were significantly higher in HFD mice than SCD mice (p<0.001 for BW in both strains; p<0.001 and p<0.01 for HW/tibia length, WT and mTOR-Tg, respectively) but there was no difference in BW or HW between HFD-mTOR-Tg and HFD-WT mice. Hearts from all four groups were subjected to global I/R (20 min ischemia, 40 min reperfusion) in the ex vivo Langendorff perfusion model. Baseline left ventricular developed pressure (LVDP) was higher in HFD mice than NCD mice in both strains [185.8 ± 10.7 vs. 143.6 ± 5.0 mmHg, HFD-WT (n=11) vs. NCD-WT (n=10) mice, p<0.01; 178.6 ± 10.1 vs. 135.0 ± 6.3, HFD-mTOR-Tg (n=8) vs. NCD-mTOR-Tg (n=11) mice, p<0.01]. Functional recovery after I/R was significantly lower in HFD-WT mice than NCD-WT mice (percent recovery of LVDP, 15.3 ± 5.4 vs. 44.6 ± 6.3 %, HFD-WT vs. NCD-WT mice, p<0.01). Intriguingly, there was no significant difference in LVDP recovery between HFD-mTOR-Tg and NCD-mTOR-Tg mice (36.5±10.8 vs. 58.8±6.0 %, HFD-mTOR-Tg vs. NCD-mTOR-Tg mice, n.s.). These findings suggest that cardiac mTOR is sufficient to substantially limit the metabolic syndrome-induced cardiac dysfunction following I/R in a mouse model of obesity with glucose intolerance and insulin resistance.


Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Stephanie Wu ◽  
Marie Lauzon ◽  
Jenna Maughan ◽  
Leslee J Shaw ◽  
Sheryl F Kelsey ◽  
...  

Background: Relatively high left ventricular ejection fraction (EF) (>65%) in women was recently associated with higher all-cause mortality over 6 years follow-up in the CONFIRM study. We sought to evaluate high EF and major adverse cardiovascular events (MACE) in the Women’s Ischemia Syndrome Evaluation (WISE) study. Methods: The WISE original cohort (enrolled 1996-2000) is a multicenter prospective study of women with suspected ischemic heart disease undergoing clinically indicated invasive coronary angiography. We investigated the relationship between high (>65%) and normal (55-65%) EF and MACE, defined as all-cause death, nonfatal myocardial infarction (MI), stroke and heart failure (HF) hospitalization using Kaplan Meier (KM) and regression analyses. Results: A total of 653 women were included (298 high and 355 normal EF). Mean age was 58±11 years and mean EF was 68±7%. There was no significant difference in MACE by EF group over a 10-year follow-up period (log rank p=0.54, Figure ). When patients were stratified by the presence of obstructive CAD, MACE rates remained similar between high and normal EF. High EF was not associated with stroke or HF but had a lower MI risk (log rank p=0.03, Table ). EF was not associated with MACE in a multivariable regression model. Conclusions: Among women presenting with evidence of ischemia, there was no significant difference in MACE between high and normal EF groups. High EF was associated with a lower risk of myocardial infarction as an individual component of MACE.


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