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Pubblicazioni recenti - cardiac hypertrophy
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Identification of inhibitors of the RGS homology domain of GRK2 by docking-based virtual screening.
Life Sci2019 Sep;():116872. doi: S0024-3205(19)30799-4.
Echeverría Emiliana, Rueda Ana Julia Velez, Cabrera Maia, Juritz Ezequiel, Burghi Valeria, Fabián Lucas, Davio Carlos, Menna Pablo Lorenzano, Fernández Natalia Cristina,
Abstract
AIMS:
G protein-coupled receptor (GPCR) kinases (GRKs) are mainly involved in the desensitization of GPCRs. Among them, GRK2 has been described to be upregulated in many pathological conditions and its crucial role in cardiac hypertrophy, hypertension, and heart failure promoted the search for pharmacological inhibitors of its activity. There have been several reports of potent and selective inhibitors of GRK2, most of them directed to the kinase domain of the protein. However, the homologous to the regulator of G protein signaling (RH) domain of GRK2 has also been shown to regulate GPCRs signaling. Herein, we searched for potential inhibitors of receptor desensitization mediated by RH domain of GRK2.
MATERIALS AND METHODS:
We performed a docking-based virtual screening utilizing the crystal structure of GRK2 to search for potential inhibitors of the interaction between GRK2 and G?q protein. To evaluate the biological activity of compounds we measured, calcium response of histamine H1 receptor (H1R) using Fura-2AM dye and H1R internalization by saturation binding experiments in A549 cells. GRK2(45-178)GFP translocation was determined in HeLa cells through confocal fluorescence imaging.
KEY FINDINGS:
We identified inhibitors of GRK2 able to reduce the RH mediated desensitization of the histamine H1 receptor and GRK2 translocation to plasma membrane. Also candidates presented adequate lipophilia and cytotoxicity profile.
SIGNIFICANCE:
We obtained compounds with the ability of reducing RH mediated actions of GRK2 that can be useful as a starting point in the development of novel drug candidates aimed to treat pathologies were GRK2 plays a key role.
Copyright © 2019. Published by Elsevier Inc.
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Automated and Interpretable Patient ECG Profiles for Disease Detection, Tracking, and Discovery.
Circ Cardiovasc Qual Outcomes2019 Sep;12(9):e005289. doi: 10.1161/CIRCOUTCOMES.118.005289.
Tison Geoffrey H, Zhang Jeffrey, Delling Francesca N, Deo Rahul C,
Abstract
BACKGROUND:
The ECG remains the most widely used diagnostic test for characterization of cardiac structure and electrical activity. We hypothesized that parallel advances in computing power, machine learning algorithms, and availability of large-scale data could substantially expand the clinical inferences derived from the ECG while at the same time preserving interpretability for medical decision-making.
METHODS AND RESULTS:
We identified 36?186 ECGs from the University of California, San Francisco database that would enable training of models for estimation of cardiac structure or function or detection of disease. We segmented the ECG into standard component waveforms and intervals using a novel combination of convolutional neural networks and hidden Markov models and evaluated this segmentation by comparing resulting electrical intervals against 141?864 measurements produced during the clinical workflow. We then built a patient-level ECG profile, a 725-element feature vector and used this profile to train and interpret machine learning models for examples of cardiac structure (left ventricular mass, left atrial volume, and mitral annulus e-prime) and disease (pulmonary arterial hypertension, hypertrophic cardiomyopathy, cardiac amyloid, and mitral valve prolapse). ECG measurements derived from the convolutional neural network-hidden Markov model segmentation agreed with clinical estimates, with median absolute deviations as a fraction of observed value of 0.6% for heart rate and 4% for QT interval. Models trained using patient-level ECG profiles enabled surprising quantitative estimates of left ventricular mass and mitral annulus e' velocity (median absolute deviation of 16% and 19%, respectively) with good discrimination for left ventricular hypertrophy and diastolic dysfunction as binary traits. Model performance using our approach for disease detection demonstrated areas under the receiver operating characteristic curve of 0.94 for pulmonary arterial hypertension, 0.91 for hypertrophic cardiomyopathy, 0.86 for cardiac amyloid, and 0.77 for mitral valve prolapse.
CONCLUSIONS:
Modern machine learning methods can extend the 12-lead ECG to quantitative applications well beyond its current uses while preserving the transparency that is so fundamental to clinical care.
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Pulmonary Artery to Left Atrium Fistula Presenting As Cardiomegaly in the Fetus: The Utility of Prenatal and Postnatal Three-Dimensional Imaging.
Circ Cardiovasc Imaging2019 Aug;12(8):e009336. doi: 10.1161/CIRCIMAGING.119.009336.
Kehr Jascha, Stirling John W, Bagnall Carol, Long Audrey, Artrip John H, Gentles Thomas L,
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Change in Physical Activity and Cardiac Structure over 10 Years: The Multi-Ethnic Study of Atherosclerosis.
Med Sci Sports Exerc2019 Oct;51(10):2033-2040. doi: 10.1249/MSS.0000000000002027.
Florido Roberta, Zhao D I, Ndumele Chiadi E, Bluemke David A, Heckbert Susan R, Allison Matthew A, Ambale-Venkatesh Bharath, Liu Chia-Ying, Lima Joao, Michos Erin D,
Abstract
INTRODUCTION:
Physical activity (PA) is inversely associated with risk of heart failure and cardiovascular disease (CVD), whereas increased left ventricular (LV) mass and mass to volume (m:v) ratio are unfavorable CVD risk factors. We assessed whether changes in leisure time PA were associated with longitudinal changes in cardiac structure in a community-based population.
METHODS:
We included 2779 Multi-Ethnic Study of Atherosclerosis participants, free of baseline CVD, who had available data on PA and cardiac magnetic resonance imaging at examinations 1 (2000-2002) and 5 (2010-2012). Physical activity was measured by a Typical Week PA Survey and converted to MET-minutes per week of moderate+vigorous activity. We used linear mixed effect models to estimate the associations of baseline and change in PA with baseline and change in cardiac structure, adjusting for CVD risk factors and body size.
RESULTS:
At baseline, the mean age was 59 yr, 53% were women, and 58% of nonwhite race/ethnicity. During average 10-yr follow-up, and after accounting for baseline PA levels, the highest quintiles of PA increase were significantly associated with increases in LV mass (2.3 g; 95% confidence interval [CI], 0.4-4.2), LV end-diastolic volume (4.7 mL; 95% CI, 2.4-7.0), and stroke volume (3.3 mL; 95% CI, 1.6-5.1), but lower M:V ratio (-2.9; 95% CI, -5.0 to -0.8) compared with the lowest quintiles. Increasing exercise PA was associated with increases in LV diameter and reductions in M:V ratio, whereas occupational PA was associated with increases in m:v ratio. Increasing PA over 10 yr was also associated with greater risk of eccentric dilated LV hypertrophy at examination 5.
CONCLUSIONS:
After accounting for baseline PA, greater positive changes in leisure-time PA levels were associated with a more eccentric-type of LV remodeling pattern over 10 yr. The clinical implications of such findings remain to be determined.
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HMGB1 enhances mechanical stress-induced cardiomyocyte hypertrophy in vitro via the RAGE/ERK1/2 signaling pathway.
Int J Mol Med2019 Jul;():. doi: 10.3892/ijmm.2019.4276.
Zhang Lei, Yang Xue, Jiang Guoliang, Yu Ying, Wu Jian, Su Yangang, Sun Aijun, Zou Yunzeng, Jiang Hong, Ge Junbo,
Abstract
Pressure overload?induced cardiac hypertrophy is associated with a complex spectrum of pathophysiological mechanisms, including the inflammation response. High mobility group box?1 (HMGB1), a pro?inflammatory cytokine, is not only increased in myocardium under pressure overload, but also exacerbates pressure overload?induced cardiac hypertrophy and dysfunction; however, the underlying mechanisms have remained elusive. In the present study, cultured cardiomyocytes were stimulated by mechanical stress and/or HMGB1 for various durations to examine the role of HMGB1 in cardiomyocyte hypertrophy, and to detect the expression of receptor for advanced glycation end products (RAGE), toll?like receptor 4 (TLR?4) and the activation status of mitogen?activated protein kinases (MAPKs) and Janus kinase 2 (JAK2)/STAT3. The results indicated that HMGB1 aggravated mechanical stress?induced cardiomyocyte hypertrophy. Furthermore, mechanical stress and HMGB1 stimulation activated extracellular signal?regulated kinase 1/2 (ERK1/2), P38 and JAK2/STAT3 signaling in cardiomyocytes, but an additive effect of the combined stimuli was only observed on the activation of ERK1/2. In addition, mechanical stress caused a prompt upregulation of the expression of RAGE and TLR?4 in cardiomyocytes, while the activation of ERK1/2 by HMGB1 was inhibited by blockage of RAGE, but not by blockage of TLR?4. In summary, the present results indicated that extracellular HMGB1 enhanced mechanical stress?induced cardiomyocyte hypertrophy in vitro, at least partially via the RAGE/ERK1/2 signaling pathway.
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Dysregulation of the Renin-Angiotensin System and Cardiometabolic Status in Mice Fed a Long-Term High-Fat Diet.
Med Sci Monit2019 Sep;25():6605-6614. doi: 10.12659/MSM.914877.
Jin Nana, Wang Yu, Liu Lin, Xue Feng, Jiang Tingbo, Xu Mingzhu,
Abstract
BACKGROUND This study aimed to investigate the renin-angiotensin system (RAS) and cardiometabolic status in mice fed a long-term high-fat diet (HFD). MATERIAL AND METHODS C57BL/6J mice were randomly assigned to the control group on a normal diet (ND) (n=15) and the HFD group (n=15). Serum biomarkers were measured, including total cholesterol (TC), triglyceride (TG), insulin, glycated hemoglobin (HbA1c), brain natriuretic peptide (BNP), renin, angiotensin-converting enzyme (ACE), angiotensin II (Ang-II), Ang-II type 1 receptor (AT?R), and aldosterone. Cardiac histology was measured by the cross-sectional area (CSA) of cardiomyocytes and collagen deposition. Levels of myocardial intercalated disc (ICD) proteins and mRNA were analyzed by Western blot and real-time quantitative polymerase chain reaction (RT-qPCR), respectively. The localization of ICD proteins was evaluated by immunohistochemistry (IHC). RESULTS Compared with ND, HFD resulted in increased blood glucose, body weight, TC, TG, HbA1c, insulin, and BNP and levels of serum ACE, Ang-II, aldosterone, AT?R, cardiomyocyte CSA, and interstitial collagen in the myocardium compared. Also, HFD significantly down-regulated connexin-43, and upregulated ß-catenin, N-cadherin, and plakoglobin in the hearts of HFD mice compared with ND mice. However, the deposition of ICD proteins was not changed in the hearts of HFD mice compared with ND mice. CONCLUSIONS Long-term HFD in mice resulted in left ventricular hypertrophy, interstitial fibrosis, dysregulation of RAS, and abnormal expression of ICD proteins compared with ND mice, but did not affect the distribution of cardiomyocyte ICD proteins. Long-term HFD resulted in cardiac remodeling and altered expression of ICD proteins through RAS activation.
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Superiority of Out-of-Office Blood Pressure for Predicting Hypertensive Heart Disease in Non-Hispanic Black Adults.
Hypertension2019 Sep;():HYPERTENSIONAHA11913542. doi: 10.1161/HYPERTENSIONAHA.119.13542.
Rader Florian, Franklin Stanley S, Mirocha James, Vongpatanasin Wanpen, Haley Robert W, Victor Ronald G,
Abstract
Black Americans suffer disproportionately from hypertension and hypertensive heart disease. Out-of-office blood pressure (BP) is more predictive for cardiovascular complications than clinic BP; however, the relative abilities of clinic and out-of-office BP to predict left ventricular hypertrophy in black and white adults have not been established. Thus, we aimed to compare associations of out-of-office and clinic BP measurement with left ventricular hypertrophy by cardiac magnetic resonance imaging among non-Hispanic black and white adults. In this cross-sectional study, 1262 black and 927 white participants of the Dallas Heart Study ages 30 to 64 years underwent assessment of standardized clinic and out-of-office (research staff-obtained) BP and left ventricular mass index. In multivariable-adjusted analyses of treated and untreated participants, out-of-office BP was a stronger determinant of left ventricular hypertrophy than clinic BP (odds ratio per 10 mm Hg, 1.48; 95% CI, 1.34-1.64 for out-of-office systolic BP and 1.15 [1.04-1.28] for clinic systolic BP; 1.71 [1.43-2.05] for out-of-office diastolic BP, and 1.03 [0.86-1.24] for clinic diastolic BP). Non-Hispanic black race/ethnicity, treatment status, and lower left ventricular ejection fraction were also independent determinants of hypertrophy. Among treated Blacks, the differential association between out-of-office and clinic BP with hypertrophy was more pronounced than in treated white or untreated participants. In conclusion, protocol-driven supervised out-of-office BP monitoring provides important information that cannot be gleaned from clinic BP assessment alone. Our results underscore the importance of hypertension management programs outside the medical office to prevent hypertensive heart disease, especially in high-risk black adults. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00344903.
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Cardiac manifestations and prognostic implications of hereditary transthyretin amyloidosis associated with transthyretin Ala97Ser.
J Formos Med Assoc2019 Sep;():. doi: S0929-6646(19)30489-9.
Lai Hsing-Jung, Huang Kuan-Chih, Liang Yun-Chieh, Chien Kuo-Liong, Lee Ming-Jen, Hsieh Sung-Tsang, Chao Chi-Chao, Yang Chih-Chao,
Abstract
BACKGROUND:
The cardiac manifestations of late-onset hereditary transthyretin amyloidosis with p.A97S variant have not been extensively studied, and the prognostic factors remain unclear.
METHODS:
The clinical profile, echocardiography, and ECG of patients diagnosed with ATTR p.A97S polyneuropathy between 2000 and 2016 were retrospectively collected. 67 patients with ATTR p.A97S were collected.
RESULTS:
A total of 82% of patients met the criteria for left ventricular (LV) hypertrophy. Reduced global longitudinal strain (GLS) was noted in 42.1% of patients, and 14% of patients had a relative apical sparing pattern. A low voltage pattern in the ECG was observed in 31.3% of patients, while 64.2% presented with a pseudoinfarction pattern. End-systolic LV inner dimension (HR: 2.25 (95% CI: 1.01-5.01), p = 0.048), reduced GLS (HR: 5.26 (1.08-25.0), p = 0.039), relative apical longitudinal strain (RALS>1, HR: 8.57 (1.69-43.3), p = 0.009), increased E/A ratio (HR: 6.51 (1.17-36.4), p = 0.033), and increased QRS duration (HR: 1.02 (1.00-1.04), p = 0.05) were correlated with reduced survival in univariate analysis. Multivariate analysis revealed reduced RALS was significantly correlated with reduced survival (HR: 13.00 (1.81-93.45), p = 0.011).
CONCLUSION:
Our findings reveal that ATTR p.A97S is a cardiomyopathy as well as a polyneuropathic syndrome. Routine use of more contemporary echocardiographic techniques are recommended to identify cardiac amyloidosis and provide prognostic information.
Copyright © 2019 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.
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Angiotensin II type 2 receptor mediates high fat diet-induced cardiomyocyte hypertrophy and hypercholesterolemia.
Mol Cell Endocrinol2019 Sep;():110576. doi: S0303-7207(19)30278-3.
Lima Vanessa M, Lino Caroline A, Senger Nathalia, de Oliveira Silva Tábatha, Fonseca Renata I B, Bader Michael, Santos Robson A S, Júnior Jose Donato, Barreto-Chaves Maria Luiza M, Diniz Gabriela P,
Abstract
Obesity is the major risk factor for several cardiovascular and metabolic disorders. Previous studies reported that deletion of Angiotensin II type 2 receptor (AT2R) protects against metabolic dysfunctions induced by high fat (HF) diet. However, the role of AT2R in obesity-induced cardiac hypertrophy remains unclear. Male AT2R knockout (AT2RKO) and wild type (AT2RWT) mice were fed with control or HF diet for 10 weeks. HF diet increased cardiac expression of AT2R in obese mice. Deletion of AT2R did not affect body weight gain, glucose intolerance and fat mass gain induced by HF feeding. However, loss of AT2R prevented HF diet-induced hypercholesterolemia and cardiac remodeling. Mechanistically, we found that pharmacological inhibition or knockdown of AT2R prevented leptin-induced cardiomyocyte hypertrophy in vitro. Collectively, our results suggest that AT2R is involved in obesity-induced cardiac hypertrophy.
Copyright © 2019. Published by Elsevier B.V.
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From embryogenesis to adulthood: Critical role for GATA factors in heart development and function.
IUBMB Life2019 Sep;():. doi: 10.1002/iub.2163.
Whitcomb Jamieson, Gharibeh Lara, Nemer Mona,
Abstract
Cardiac development is governed by a complex network of transcription factors (TFs) that regulate cell fates in a spatiotemporal manner. Among these, the GATA family of zinc finger TFs plays prominent roles in regulating the development of the myocardium, endocardium, and outflow tract. This family comprises six members three of which, GATA4, 5, and 6, are predominantly expressed in cardiac cells where they activate specific downstream gene targets via interactions with one another and with other TFs and signaling molecules. Their critical function in heart formation is evidenced by the phenotypes of animal models lacking these factors and by the broad spectrum of human congenital heart diseases associated with mutations in their genes. Similarly, in the postnatal heart, these proteins play significant and nonredundant roles in cardiac function, regulating adaptive stress responses including cardiomyocyte hypertrophy and survival, as well as endothelial homeostasis and angiogenesis. As such, decreased expression of either GATA4, 5, or 6 results in impaired cardiovascular homeostasis and increased risk of premature and serious cardiovascular events such as hypertension, arrhythmia, aortopathy, and heart failure. Although a great deal of progress has been made in understanding GATA-dependent regulatory processes in the heart, the molecular mechanisms underlying the specificity of GATA factors and their upstream regulation remain incompletely understood. The knowledge and tools developed since their discovery 25?years ago should accelerate progress toward further elucidation of their mechanisms of action in health and disease. This in turn will greatly improve diagnosis and care for the millions of individuals affected by congenital and acquired cardiac disease worldwide.
© 2019 International Union of Biochemistry and Molecular Biology.
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Founder effect of Fabry disease due to p.F113L mutation: Clinical profile of a late-onset phenotype.
Mol Genet Metab2019 Jul;():. doi: S1096-7192(19)30400-7.
Azevedo Olga, Gal Andreas, Faria Rui, Gaspar Paulo, Miltenberger-Miltenyi Gabriel, Gago Miguel F, Dias Fátima, Martins Alice, Rodrigues Jorge, Reimão Pedro, Pereira Olga, Simões Sónia, Lopes Emilia, Guimarães Maria José, Sousa Nuno, Cunha Damião,
Abstract
BACKGROUND:
Knowledge on clinical profiles of late-onset phenotypes of Fabry disease (FD) is essential to better define their natural history. Our study aims to demonstrate a founder effect of FD due to the GLA gene mutation c.337T>C (p.F113L) in the Portuguese region of Guimarães; and to characterize the clinical profile of this late-onset phenotype in a large cohort of genetically related adult patients, living in the same region.
METHODS AND RESULTS:
FD screening was performed in 150 adult patients with hypertrophic cardiomyopathy (HCM) and found 25 Fabry patients (16.6%). The p.F113L mutation was found in 21 of them, leading to a genealogy study and haplotype analysis of the p.F113L patients. Genealogy research revealed a 12-generation family tree with a common ancestor to p.F113L patients, suggesting a founder effect that was supported by haplotype findings. Pedigree analysis was performed and 120 consecutive p.F113L patients underwent a predefined diagnostic evaluation of FD multiorgan involvement. This late-onset phenotype was characterized by common and/or potentially severe cardiac manifestations (left ventricular hypertrophy 40.8%, atrial fibrillation 5%, non-sustained ventricular tachycardia 12.5%, atrioventricular block 18.3%, bifascicular block 13.4%). Extracardiac manifestations included albuminuria>30?mg/24?h 36.1%, chronic kidney disease?G3 7.6%, brain white matter lesions 54.4%, stroke 3.3%, sensorineural deafness 44.5%, cornea verticillata 13.9%. Plasma lyso-GB3 was undetectable in females, regardless of clinical manifestations.
CONCLUSION:
A founder effect of FD due to p.F113L mutation was documented by genealogy and genetics in a Portuguese region. In this late-onset phenotype, although cardiac manifestations carry the highest prognostic impact, extracardiac involvement is common.
Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.
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Differentiation between Fabry disease and hypertrophic cardiomyopathy with cardiac T1 mapping.
Diagn Interv Imaging2019 Sep;():. doi: S2211-5684(19)30201-3.
Deborde E, Dubourg B, Bejar S, Brehin A-C, Normant S, Michelin P, Dacher J-N,
Abstract
PURPOSE:
To evaluate the potential of non-contrast myocardial T1 mapping on cardiovascular magnetic resonance examination (CMR) in differentiating patients with Fabry disease (FD) from those with hypertrophic cardiomyopathy (HCM) and healthy control subjects.
MATERIALS AND METHODS:
Seventeen patients with FD (8 men, 9 women; mean age, 48 ±18 [SD] years; [range: 19-73 years]; 53% with left ventricular hypertrophy [LVH]) were matched with 36 patients with hypertrophic cardiomyopathy (HCM) (22 men, 14 women; mean age, 57±16 [SD] years; [range: 22-85 years]) and 70 healthy control subjects (34 men, 36 women; mean age, 38 ±15 [SD] years; [range: 18-65 years]). Cardiac T1 mapping was performed using the modified Look-Locker inversion (MOLLI®) sequence on a 1.5-T magnet. T1 values were calculated, on midventricular section, for septal left ventricular segments (S8-S9) and all mid-ventricular ones (global T1 values; S7-S12). Statistical analysis included unpaired Mann-Whitney test, receiver operating characteristic curve and likelihood ratios.
RESULTS:
Septal native T1 values were significantly decreased in patients with FD (889±61 [SD] ms; range: 784-980ms) compared to those with HCM (995±48 [SD] ms; range: 935-1125ms) (P<0.001) and versus healthy controls (965±29 [SD] ms; range: 910-1028ms) (P<0.001). Global native T1 values were also significantly decreased in patients with FD (891±49 [SD] ms; range 794-970ms) compared to those with HCM (995±34 [SD] ms; range: 952-1086ms) (P<0.001) and versus healthy controls (966±27 [SD] ms; range: 920-1042ms) (P<0.001). A septal left ventricular native T1 cutoff value of 940ms could distinguish FD from HCM with 88% sensitivity (95% CI: 73-100%) and 92% specificity (95% CI: 83-100%). Positive likelihood ratio was 11, negative likelihood ratio was 0.12. Compared to controls, the same threshold could distinguish FD with 88% sensitivity (95% CI: 73-100%) and 86% specificity (95% CI: 78-94%). Positive likelihood ratio was 6.3, negative likelihood ratio was 0.14. T1 value was abnormal in 4 of 8 (50%) of FD patients who did not have LVH.
CONCLUSION:
Native T1 values are significantly lower in patients with FD by comparison with those with HCM and healthy volunteers.
Copyright © 2019 Société française de radiologie. Published by Elsevier Masson SAS. All rights reserved.
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Carbonic anhydrase II/sodium-proton exchanger 1 metabolon complex in cardiomyopathy of ob type 2 diabetic mice.
J Mol Cell Cardiol2019 Sep;():. doi: S0022-2828(18)31255-0.
de Giusti Carolina Jaquenod, Blanco Paula G, Lamas Paula A, Velasquez Fernanda Carrizo, Lofeudo Juan M, Portiansky Enrique L, Alvarez Bernardo V,
Abstract
Heart failure is the leading cause of death among diabetic people. Cellular and molecular entities leading to diabetic cardiomyopathy are, however, poorly understood. Coupling of cardiac carbonic anhydrase II (CAII) and Na/H exchanger 1 (NHE1) to form a transport metabolon was analyzed in obese type 2 diabetic mice (ob) and control heterozygous littermates (ob). Echocardiography showed elevated systolic interventricular septum thickness and systolic posterior wall thickness in ob mice at 9 and 16?weeks. ob mice showed increased left ventricular (LV) weight/tibia length ratio and increased cardiomyocyte cross sectional area as compared to controls, indicating cardiac hypertrophy. Immunoblot analysis showed increased CAII expression in LV samples of obvs. ob mice, and augmented Ser phosphorylation on NHE1 in ob hearts. Reciprocal co-immunoprecipitation analysis showed strong association of CAII and NHE1 in LV samples of ob mice. NHE1-dependent rate of intracellular pH (pH) normalization after transient acid loading of isolated cardiomyocytes was higher in ob mice vs. ob. NHE transport activity was also augmented in cultured H9C2 rat cardiomyoblasts treated with high glucose/high palmitate, and it was normalized after CA inhibition. We conclude that the NHE1/CAII metabolon complex is exacerbated in diabetic cardiomyopathy of ob mice, which may lead to perturbation of pH and [Na] and [Ca] handling in these diseased hearts.
Copyright © 2018. Published by Elsevier Ltd.
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Noonan syndrome associated with anomalous left coronary artery from the pulmonary artery in a patient with the rare RAF1 mutation: A case report and review of literature.
Ann Pediatr Cardiol;12(3):298-301. doi: 10.4103/apc.APC_144_18.
Garcia Richard U, Safa Raya, Evans Chelsea, Alessio Dominic, Delius Ralph, Shehata Bahig,
Abstract
We present the case of a 7-week-old male infant diagnosed with anomalous left coronary artery from the pulmonary artery (ALCAPA) who underwent repair by left coronary artery reimplantation, followed by an eventful postoperative period including need for venous arterial extracorporeal membrane oxygenation and mitral valve replacement due to mitral calcification and severe insufficiency. He also required heart transplant due to severe rapidly progressive biventricular hypertrophy. The pathology examination of the explanted heart showed massive cardiomegaly. Subsequently, the infant's cardiomyopathy panel was positive for RAF1 mutation, consistent with diagnosis of a rare form of Noonan syndrome. To our knowledge, this autosomal dominant condition in association with ALCAPA has not been previously reported in the literature.
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Association Between High-Sensitivity Cardiac Troponin T and Echocardiographic Parameters in Chronic Kidney Disease: Results From the KNOW-CKD Cohort Study.
J Am Heart Assoc2019 Sep;8(18):e013357. doi: 10.1161/JAHA.119.013357.
Kang Eunjeong, Ryu Hyunjin, Kim Jayoun, Lee Joongyub, Lee Kyu-Beck, Chae Dong-Wan, Sung Su Ah, Kim Soo Wan, Ahn Curie, Oh Kook-Hwan,
Abstract
Background It is unclear whether high-sensitivity troponin T (hs-TnT) is associated with subclinical cardiac changes in chronic kidney disease (CKD). We evaluated the relationship between hs-TnT and left ventricular structure and function in a CKD population, according to estimated glomerular filtration rate. Methods and Results We analyzed 2017 patients with CKD stages 1 to 5 (predialysis) in the KNOW-CKD (Korean Cohort Study for Outcome in Patients With Chronic Kidney Disease) cohort. The predictor was hs-TnT level measured at baseline, and the outcomes were left ventricular hypertrophy (LVH) and systolic and diastolic dysfunction shown by echocardiography at baseline and after 4 years. Participants were categorized into quartiles according to hs-TnT levels. The associations between quartiles of hs-TnT and outcomes were assessed using multivariable logistic regression analysis with confounders including demographics, medical history, and laboratory findings. A receiver operating characteristic curve was used to assess the diagnostic power of hs-TnT for the outcomes as a continuous variable. For subgroup analysis, patients were stratified based on an estimated glomerular filtration rate of 60 mL/min per 1.73 m. Elevated hs-TnT was associated with LVH and diastolic dysfunction at baseline in an adjusted model but was not associated with systolic dysfunction. These associations remained significant for both estimated glomerular filtration rate subgroups. Receiver operating characteristic curve analysis showed that hs-TnT as a continuous variable exhibited fair significance for detection of LVH (area under the curve: 0.689) and diastolic dysfunction (area under the curve: 0.744). Multivariable analysis showed that higher hs-TnT levels at baseline were related to development of LVH but not diastolic dysfunction (n=864). Conclusions In CKD patients, hs-TnT is strongly associated with alterations of left ventricular structure and diastolic dysfunction for both estimated glomerular filtration rate strata. Baseline hs-TnT levels are predictive of new LVH on follow-up.
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Mechanics insights of curcumin in myocardial ischemia: Where are we standing?
Eur J Med Chem2019 Aug;183():111658. doi: S0223-5234(19)30802-5.
Ahmed Salman, Khan Haroon, Mirzaei Hamed,
Abstract
Cardiovascular disorders are known as one of the main health problems which are associated with mortality worldwide. Myocardial ischemia (MI) is improper blood supply to myocardium which leads from serious complications to life-threatening problems like AMI, atherosclerosis, hypertension, cardiac-hypertrophy as well as diabetic associated complications as diabetic atherosclerosis/cardiomyopathy/hypertension. Despite several efforts, the current therapeutic platforms are not related with significant results. Hence, it seems, developing novel therapies are required. In this regard, increasing evidences indicated, curcumin (CRC) acts as cardioprotective agent. Given that CRC and its analogs exert their cardioprotective effects via affecting on a variety of cardiovascular diseases-related mechanisms (i.e., Inflammation, and oxidative stress). Herein, for first time, we have highlighted the protective impacts of CRC against MI. This review might be a steppingstone for further investigation into the clinical implications of the CRC against MI. Furthermore, it pulls in light of a legitimate concern for scientific community, seeking novel techniques and characteristic dynamic biopharmaceuticals for use against myocardial ischemia.
Copyright © 2019 Elsevier Masson SAS. All rights reserved.
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Clinical and ECG variables to predict the outcome of genetic testing in hypertrophic cardiomyopathy.
Eur J Med Genet2019 Sep;():103754. doi: S1769-7212(18)30833-4.
Robyns Tomas, Breckpot Jeroen, Nuyens Dieter, Vandenberk Bert, Corveleyn Anniek, Kuiperi Cuno, Van Aelst Lucas, Van Cleemput Johan, Willems Rik,
Abstract
Knowledge on the influence of specific genotypes on the phenotypic expression of hypertrophic cardiomyopathy (HCM) is emerging. The objective of this study was to evaluate the genotype-phenotype relation in HCM patients and to construct a score to predict the genetic yield based to improve counseling. Unrelated HCM patients who underwent genetic testing were included in the analysis. Multivariate logistic regression was performed to identify variables that predict a positive genetic test. A weighted score was constructed based on the odds ratios. In total, 378 HCM patients were included of whom 141 carried a mutation (global yield 37%), 181 were mutation negative and 56 only carried a variant of unknown significance. We identified age at diagnosis <45 years, familial HCM, familial sudden death, arrhythmic syncope, maximal wall thickness ?20?mm, asymmetrical hypertrophy and the absence of negative T waves in the lateral ECG leads as significant predictors of a positive genetic test. When we included these values in a risk score we found very high correlation between the score and the observed genetic yield (Pearson r?=?0.98). MYBPC3 mutation carriers more frequently suffered sudden cardiac death compared to troponin complex mutations carriers (p?=?0.01) and a similar trend was observed compared to MYH7 mutation carriers (p?=?0.08) and mutation negative patients (p?=?0.11). To conclude, a simple score system based on clinical variables can predict the genetic yield in HCM index patients, aiding in counseling HCM patients. MYBPC3 mutation carriers had a worse outcome regarding sudden cardiac death.
Copyright © 2019. Published by Elsevier Masson SAS.
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Cardiac function modulation depends on the A-kinase anchoring protein complex.
J Cell Mol Med2019 Sep;():. doi: 10.1111/jcmm.14659.
Zhu Yan-Rong, Jiang Xiao-Xin, Zheng Yaguo, Xiong Jing, Wei Dongping, Zhang Dai-Min,
Abstract
The A-kinase anchoring proteins (AKAPs) are a group of structurally diverse proteins identified in various species and tissues. These proteins are able to anchor protein kinase and other signalling proteins to regulate cardiac function. Acting as a scaffold protein, AKAPs ensure specificity in signal transduction by enzymes close to their appropriate effectors and substrates. Over the decades, more than 70 different AKAPs have been discovered. Accumulative evidence indicates that AKAPs play crucial roles in the functional regulation of cardiac diseases, including cardiac hypertrophy, myofibre contractility dysfunction and arrhythmias. By anchoring different partner proteins (PKA, PKC, PKD and LTCCs), AKAPs take part in different regulatory pathways to function as regulators in the heart, and a damaged structure can influence the activities of these complexes. In this review, we highlight recent advances in AKAP-associated protein complexes, focusing on local signalling events that are perturbed in cardiac diseases and their roles in interacting with ion channels and their regulatory molecules. These new findings suggest that AKAPs might have potential therapeutic value in patients with cardiac diseases, particularly malignant rhythm.
© 2019 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.
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Chronic Pressure Overload Results in Deficiency of Mitochondrial Membrane Transporter ABCB7 Which Contributes to Iron Overload, Mitochondrial Dysfunction, Metabolic Shift and Worsens Cardiac Function.
Sci Rep2019 Sep;9(1):13170. doi: 10.1038/s41598-019-49666-0.
Kumar Vikas, A Aneesh Kumar, Sanawar Rahul, Jaleel Abdul, Santhosh Kumar T R, Kartha C C,
Abstract
We examined the hitherto unexplored role of mitochondrial transporters and iron metabolism in advancing metabolic and mitochondrial dysfunction in the heart during long term pressure overload. We also investigated the link between mitochondrial dysfunction and fluctuation in mitochondrial transporters associated with pressure overload cardiac hypertrophy. Left ventricular hypertrophy (LVH) was induced in 3-month-old male Wistar rats by constriction of the aorta using titanium clips. After sacrifice at the end of 6 and 15 months after constriction, tissues from the left ventricle (LV) from all animals were collected for histology, biochemical studies, proteomic and metabolic profiling, and gene and protein expression studies. LV tissues from rats with LVH had a significant decrease in the expression of ABCB7 and mitochondrial oxidative phosphorylation (mt-OXPHOS) enzymes, an increased level of lipid metabolites, decrease in the level of intermediate metabolites of pentose phosphate pathway and elevated levels of cytoplasmic and mitochondrial iron, reactive oxygen species (ROS) and autophagy-related proteins. Knockdown of ABCB7 in H9C2 cells and stimulation with angiotensin II resulted in increased ROS levels, ferritin, and transferrin receptor expression and iron overload in both mitochondria and cytoplasm. A decrease in mRNA and protein levels of mt-OXPHOS specific enzymes, mt-dynamics and autophagy clearance and activation of IGF-1 signaling were also seen in these cells. ABCB7 overexpression rescued all these changes. ABCB7 was found to interact with mitochondrial complexes IV and V. We conclude that in chronic pressure overload, ABCB7 deficiency results in iron overload and mitochondrial dysfunction, contributing to heart failure.
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Left Ventricular Noncompaction: Cause or Consequence of Myocardial Disease? A Case Report and Literature Review.
Cardiology2019 Sep;():1-5. doi: 10.1159/000500904.
Loria Valentina, Colizzi Christian, Vaccarella Marcello, Franceschi Francesco, Aspromonte Nadia,
Abstract
A 57-year-old woman presented to the Emergency Department with symptoms of worsening heart failure (HF). She had a past medical history of breast cancer treated with surgery and chemotherapy with anthracyclines and no family history of cardiomyopathy (CMP). In the last year, she received a diagnosis of HF with normal coronary arteries, during hospitalization for acute onset of dyspnea and was treated with medical therapy. After several months, few days before admission to our hospital, an echocardiography (ECHO) showed features of left ventricular noncompaction (LVNC), not described in previous ECHO and further confirmed by cardiac magnetic resonance. This case highlights the current uncertainties regarding the pathogenesis of LVNC and the clinical challenge of cardiologists facing LVNC morphology to decide if they are observing a genetic CMP, a phenotype overlapping with dilated or hypertrophic CMP, or a variant of the left ventricular (LV) wall anatomy. No consensus exists among scientific communities regarding diagnostic criteria of LVNC and in most cases; the key element in the diagnostic decision is not the LVNC by itself, but the associated LV dilation and/or dysfunction, hypertrophy, arrhythmias, and embolic events.
© 2019 S. Karger AG, Basel.
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