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Pubblicazioni recenti - cardiac hypertrophy
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Epoxyeicosatrienoic acid prevents maladaptive remodeling in pressure overload by targeting calcineurin/NFAT and Smad-7.
Exp Cell Res2019 Nov;():111716. doi: S0014-4827(19)30595-6.
Li Xuguang, Chu Guang, Zhu Feng, Zheng Zhifeng, Wang Xiang, Zhang Guobing, Wang Fang,
Abstract
BACKGROUND:
Emerging evidence demonstrates that epoxyeicosatrienoic acids (EETs) as important active eicosanoids that regulate cardiovascular homeostasis, but the mechanisms underlying its favorable anti-hypertrophic benefits in overpressure model remain obscure.
METHODS AND RESULTS:
Four weeks after transverse aortic constriction (TAC), TAC mice developed maladaptive cardiac hypertrophy and consequent cardiac failure. Conversely, a cardiotropic adeno-associated viral vector (AAV9) encoding CYP2J2 prevented transverse aortic constriction-induced cardiac hypertrophy with preserved ejection fraction. EET also conferred protection against phenylephrine-induced hypertrophy in H9c2 cardiomyoblasts. Further investigations indicate CYP2J2/EET exerts protection against cardiac hypertrophy through opposing the increase of intracellular Ca level and Ca-mediated calcineurin/NFATc3 signaling. Meanwhile, extended myocardial fibrosis in TAC mice was also effectively abolished with the administration of AAV9-2J2. Intriguingly, TAC mice display activated TGF-?/Samd-3 signaling with decreased Smad-7 expression, whereas AAV9-2J2 attenuated the phosphorylation of Smad-3 without altering TGF-? expression, whilst preservation of Smad-7. Subsequently, the differentiation of cardiac fibroblasts into myofibroblasts in the presence of TGF-?1 stimulation was significantly disrupted with EET treatment, accompanied by declined Smad-3 activation and collagen production, whereas inhibition of Smad-7 with SiRNA Smad-7 substantially abrogated these effects of EET on cardiac fibroblasts.
CONCLUSIONS:
EET has synergistic actions on cardiomyocytes and cardiac fibroblasts, preventing cardiac hypertrophy through inhibition of Ca-mediated calcineurin/NFATc3 signaling cascades, and ameliorating myocardial fibrosis dependent on Smad-7. This work further extends the potential mechanisms of EET, providing a novel therapeutic approach for the treatment of pathological remodeling and heart failure.
Copyright © 2019. Published by Elsevier Inc.
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Predicting sudden cardiac death in a general population using an electrocardiographic risk score.
Heart2019 Nov;():. doi: heartjnl-2019-315437.
Holkeri Arttu, Eranti Antti, Haukilahti M Anette E, Kerola Tuomas, Kenttä Tuomas V, Tikkanen Jani T, Anttonen Olli, Noponen Kai, Seppänen Tapio, Rissanen Harri, Heliövaara Markku, Knekt Paul, Junttila M Juhani, Huikuri Heikki V, Aro Aapo L,
Abstract
OBJECTIVE:
We investigated whether combining several ECG abnormalities would identify general population subjects with a high sudden cardiac death (SCD) risk.
METHODS:
In a sample of 6830 participants (mean age 51.2±13.9 years; 45.5% male) in the Mini-Finland Health Survey, a general population cohort representative of the Finnish adults aged ?30 years conducted in 1978-1980, we examined their ECGs, following subjects for 24.3±10.4 years. We analysed the association between individual ECG abnormalities and 10-year SCD risk and developed a risk score using five ECG abnormalities independently associated with SCD risk: heart rate >80?beats per minute, PR duration >220?ms, QRS duration >110?ms, left ventricular hypertrophy and T-wave inversion. We validated the score using an external general population cohort of 10?617 subjects (mean age 44.0±8.5 years; 52.7% male).
RESULTS:
No ECG abnormalities were present in 4563 subjects (66.8%), while 96 subjects (1.4%) had ?3?ECG abnormalities. After adjusting for clinical factors, the SCD risk increased progressively with each additional ECG abnormality. Subjects with ?3?ECG abnormalities had an HR of 10.23 (95% CI 5.29 to 19.80) for SCD compared with those without abnormalities. The risk score similarly predicted SCD risk in the validation cohort, in which subjects with ?3?ECG abnormalities had HR 10.82 (95% CI 3.23 to 36.25) for SCD compared with those without abnormalities.
CONCLUSION:
The ECG risk score successfully identified general population subjects with a high SCD risk. Combining ECG risk markers may improve the risk stratification for SCD.
© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.
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Lung Ultrasound-Guided Dry Weight Assessment and Echocardiographic Measures in Hypertensive Hemodialysis Patients: A Randomized Controlled Study.
Am J Kidney Dis2019 Nov;():. doi: S0272-6386(19)31005-4.
Loutradis Charalampos, Papadopoulos Christodoulos E, Sachpekidis Vassilios, Ekart Robert, Krunic Barbara, Karpetas Antonios, Bikos Athanasios, Tsouchnikas Ioannis, Mitsopoulos Efstathios, Papagianni Aikaterini, Zoccali Carmine, Sarafidis Pantelis,
Abstract
RATIONALE & OBJECTIVE:
Left ventricular (LV) hypertrophy and dysfunction are associated with adverse outcomes in hemodialysis patients. Hypertension and hypervolemia play important roles in these cardiac abnormalities. We report on the prespecified secondary outcome, echocardiographic indexes of LV function, from a previously reported study of the effect of lung ultrasound (US)-guided dry weight reduction on systolic blood pressure.
STUDY DESIGN:
Single-blind randomized trial.
SETTINGS & PARTICIPANTS:
71 clinically euvolemic hypertensive hemodialysis patients in Greece and Slovenia.
INTERVENTION:
The active intervention group's (n=35) volume removal was guided by the total number of lung US B-lines observed every week before a midweek dialysis session. The usual-care group (n=36) was treated using standard-of-care processes that did not include acquisition of US data.
OUTCOMES:
2-dimensional and tissue Doppler echocardiographic indexes at baseline and study end (8 weeks) that evaluated left and right heart chamber sizes, as well as systolic and diastolic function.
RESULTS:
Overall, 19 (54%) patients in the active intervention and 5 (14%) in the usual-care group had ultrafiltration intensification (P<0.001) during follow-up; changes in US B-lines (-5.3±12.5 vs+2.2±7.6; P<0.001) and dry weight (-0.71±1.39 vs+0.51±0.98kg; P<0.001) significantly differed between the active and usual-care groups. Inferior vena cava diameter decreased in the active compared with the usual-care group (-0.43±4.00 vs 0.71±4.82cm; P=0.03) at study end. Left (LA) and right (RA) atrial dimensions decreased more in the active group (LA surface, -1.09±4.61 vs 0.93±3.06cm; P=0.03; RA surface -1.56±6.17 vs 0.47±2.31; P=0.02). LA volume index nominally decreased more in the active group (-2.43±13.14 vs 2.95±9.42mL/m), though this was of borderline statistical significance (P=0.05). Reductions in LV end-diastolic diameter and volume were marginally greater in the active group. The change in LV filling pressures was significantly different in the active compared with the usual-care group (early transmitral diastolic velocities ratio [E/e'], -0.38±3.14 vs 1.36±3.54; P=0.03; E wave deceleration time, 35.43±85.25 vs-18.44±50.69; P=0.002]. Systolic function indexes were unchanged in both groups. In multivariable analysis, US B-line reduction was associated with a reduction in the E/e' LV ratio (OR, 4.542; 95% CI, 1.266-16.292; P=0.02).
LIMITATIONS:
Exploratory study; small sample size.
CONCLUSIONS:
A US-guided strategy for dry weight reduction is associated with decreased cardiac chamber dimensions and LV filling pressure, but no difference in systolic performance compared with usual care in hypertensive hemodialysis patients.
FUNDING:
European Renal Association-European Dialysis and Transplant Association.
TRIAL REGISTRATION:
Registered at ClinicalTrials.gov with study number NCT03058874.
Copyright © 2019 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.
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PPAR-? agonist, pioglitazone, reduced oxidative and endoplasmic reticulum stress associated with L-NAME-induced hypertension in rats.
Life Sci2019 Nov;():117047. doi: S0024-3205(19)30974-9.
Soliman Eman, Behairy Shereen F, El-Maraghy Nabila N, Elshazly Shimaa M,
Abstract
Peroxisome proliferator-activated receptor ? (PPAR-?) agonist, pioglitazone, is used clinically to improve the glycemic state in patients with type-2 diabetes mellitus. Independent of its blood glucose-lowering properties, pioglitazone ameliorates different cardiovascular disorders. The aim of the present study was to investigate the effect of pioglitazone on cardiovascular complications of N-nitro-L-arginine methyl ester (L-NAME)-induced hypertension and to determine the role of oxidative and endoplasmic reticulum (ER) stress in its activity. Nitric oxide (NO) deficiency induced by chronic L-NAME administration was associated with high blood pressure (BP) and cardiac hypertrophy. L-NAME induced oxidative stress as indicated by reduced glutathione (GSH) levels, superoxide dismutase (SOD) and catalase activities as well as increased malondialdehyde (MDA) levels. Furthermore, L-NAME increased the expression of ER stress markers, activating transcription factor-4 (ATF-4) and C/EPB?-homologous protein-10 (CHOP-10) in both heart and aorta of hypertensive rats. Activation of PPAR-? by pioglitazone reduced BP, restored the blunted NO levels, increased endothelial NO synthase (eNOS) expression, and restored the antioxidant status of L-NAME-induced hypertensive rats. Moreover, the antihypertensive activity of pioglitazone was associated with a reduction in ER stress and this effect was PPAR-? dependent. Interestingly, the effect of ER stress inhibitor, 4-phenylbutyric acid (4-PBA) and antioxidant, N-acetylcysteine (NAC), on BP, NO availability, oxidative stress and ER stress mimics the activity of pioglitazone. Taken together, our data suggests that PPAR-? is a potential target to inhibit vascular complications and cardiac damage associated with NO-deficient HTN and puts more emphasis on the importance of ER stress in regulating PPAR-? activity.
Copyright © 2019 Elsevier Inc. All rights reserved.
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Assessment of cardiac risk in chronic asymptomatic alcoholics using blood pressure and electrocardiogram, and the relation with duration of drinking.
J Basic Clin Physiol Pharmacol2019 Nov;():. doi: 10.1515/jbcpp-2019-0205.
Iyer Shruti, Omprakash Abirami,
Abstract
Background The Global Status Report 2017 reveals that 11% of Indians indulge in binge drinking. Chronic alcohol intake may lead to cardiac problems and hypertension. The aim of this study was to evaluate cardiovascular risk among asymptomatic chronic alcoholics. Methods A total of 80 asymptomatic chronic alcoholics of South Indian origin, from the psychiatry ward of Sri Ramachandra Institute of Higher Education and Research, India were diagnosed with alcohol dependence syndrome(ADS). Group I includes alcoholics for 10 years or less and group II includes alcoholics for more than 10 years. Alcohol consumption was measured using the DSM IV criteria. Blood pressure (BP) and electrocardiographic (ECG) data were measured on admission and 2 weeks later. The paired t-test compared a significant outcome of the two sets of data at p ? 0.05 level of significance. Results Forty percent of the patients were found to be hypertensive and only 2.5% were found to be pre-hypertensive on admission. The mean age of the hypertensives was 46.9 and nonhypertensives was 42.1 The difference in the BP evaluated after 2 weeks was staggering - systolic BP had a mean fall of 6.1 mm Hg (p < 0.001) and diastolic BP 2.25 mm Hg (p = 0.001). The electrocardiogram results showed significant changes like left ventricular hypertrophy, abnormal T waves, and QT prolongation. Conclusions Chronic alcoholism is a major criterion for heart abnormalities such as elevated BP and left ventricular enlargement, and our study supports this as we see that alcohol consumption for more than 10 years shows significant deterioration. Further clinical observations and long-term prospective studies are needed to confirm these observations.
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CRISPR-Mediated Activation of Endogenous Gene Expression in the Postnatal Heart.
Circ Res2019 Nov;():. doi: 10.1161/CIRCRESAHA.118.314522.
Schoger Eric, Carroll Kelli J, Iyer Lavanya M, McAnally John, Tan Wei, Liu Ning, Noack Claudia, Shomroni Orr, Salinas Gabriela, Gross Julia, Herzog Nicole, Doroudgar Shirin, Bassel-Duby Rhonda, Zimmermann Wolfram Hubertus, Zelarayan Laura C,
Abstract
Genome editing by CRISPR/Cas9 is evolving rapidly. Recently, second generation CRISPR/Cas9 activation systems based on nuclease inactive "dead" (d)Cas9 fused to transcriptional transactivation domains were developed for directing specific guide (g)RNAs to regulatory regions of any gene of interest, to enhance transcription. The application of dCas9 to activate cardiomyocyte transcription in targeted genomic loci in vivo has not been demonstrated so far. We aimed to develop a mouse model for cardiomyocyte-specific, CRISPR-mediated transcriptional modulation, and to demonstrate its versatility by targeting and loci (two well-characterized genes implicated in cardiac hypertrophy and homeostasis) for enhanced transcription. A mouse model expressing dCas9 with the VPR transcriptional transactivation domains under the control of the myosin heavy chain () 6 promotor was generated. These mice innocuously expressed dCas9 exclusively in cardiomyocytes. For initial proof-of-concept, we selected , which when overexpressed, led to hypertrophy and heart failure, and , which is lowly expressed in the neonatal heart. The most effective gRNAs were first identified in fibroblast (C3H/10T1/2) and myoblast (C2C12) cell lines. Using an improved triple gRNA expression system (TRISPR), up to three different gRNAs were transduced simultaneously to identify optimal conditions for transcriptional activation. For in vivo delivery of the validated gRNA combinations, we employed systemic administration via adeno-associated virus serotype (AAV) 9. Upon gRNA delivery targeting expression, we recapitulated the anticipated cardiac hypertrophy phenotype. Using gRNA targeting Klf15, we could enhance its transcription significantly, although is physiologically silenced at that time point. We further confirmed specific and robust dCas9VPR on-target effects. The developed mouse model permits enhancement of gene expression by utilizing endogenous regulatory genomic elements. Proof-of-concept in two independent genomic loci suggests versatile applications in controlling transcription in cardiomyocytes of the postnatal heart.
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Pharmacological blockage of ICAM-1 improves angiotensin II-induced cardiac remodeling by inhibiting adhesion of LFA-1 monocytes.
Am J Physiol Heart Circ Physiol2019 Nov;():. doi: 10.1152/ajpheart.00566.2019.
Lin Qiu-Yue, Lang Ping-Ping, Zhang Yun-Long, Yang Xiaolei, Xia Yunlong, Bai Jie, Li Hui-Hua,
Abstract
Intercellular adhesion molecule-1 (ICAM-1) is a member of an immunoglobulin-like superfamily of adhesion molecules that mediate leukocyte adhesion to vascular endothelium and are involved in several cardiovascular diseases, including ischemia/reperfusion injury, myocardial infarction and atherosclerosis. However, the role of ICAM-1 in angiotensin II (Ang II)-induced cardiac remodeling in mice remains unclear. Wild-type (WT) mice were administered an IgG control or ICAM-1 neutralizing antibody (1 and 2 mg/mouse, respectively) and Ang II (1000 ng/kg/min) for up to 14 days. Cardiac contractile function and structure were detected by echocardiography. Hypertrophy, fibrosis and inflammation were assessed by histological examination. The infiltration of LFA-1 monocytes/macrophages was assessed by immunostaining. The mRNA expression of genes was evaluated by quantitative RT-PCR analysis. Protein levels were tested by immunoblotting. We found that ICAM-1 expression in Ang II-infused hearts, and ICAM-1 levels in serum from human patients with heart failure (HF), were significantly increased. Moreover, Ang II infusion markedly enhanced Ang II-induced hypertension, caused cardiac contractile dysfunction and promoted cardiac hypertrophy, fibrosis, and LFA-1 macrophage infiltration. Conversely, blockage of ICAM-1 with a neutralizing antibody dose-dependently attenuated these effects. Moreover, our data further demonstrated that blocking ICAM-1 inhibited Ang II-induced LFA-1 macrophage adhesion to endothelial cells and migration. In conclusion, these results provide novel evidence that blocking ICAM-1 exerts a protective effect in Ang II-induced cardiac remodeling at least in part through the modulation of adhesion and infiltration of LFA-1 macrophages in the heart. Inhibition of ICAM-1 may represent a new therapeutic approach for hypertrophic heart diseases.
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Targeted molecular genetic testing in young sudden cardiac death victims from Western Denmark.
Int J Legal Med2019 Nov;():. doi: 10.1007/s00414-019-02179-x.
Larsen Maiken Kudahl, Christiansen Sofie Lindgren, Hertz Christin Løth, Frank-Hansen Rune, Jensen Henrik Kjærulf, Banner Jytte, Morling Niels,
Abstract
Sudden unexpected death in the young continues to be an important unsolved challenge. A significant proportion of the deaths are suspected to be caused by inherited cardiac diseases and are referred to as sudden cardiac deaths (SCD). We performed targeted molecular testing of 70 deceased individuals under 40 years of age that after forensic autopsy were suspected to have died of SCD. The individuals were previously genetically investigated using smaller numbers of genes associated with specific cardiac diseases. In our previous studies, seven (10%) individuals had pathogenic or likely pathogenic variants according to the 2015 ACMG guidelines. In order to investigate the value of expanding the panel to 100 genes associated with cardiac diseases, we histopathologically re-examined the 70 suspected SCD cases and grouped them according to phenotypes into suspected cardiomyopathy (the cardiomyopathy group), left ventricular hypertrophy (the hypertrophy group) and structural normal hearts (the SUD group). DNA was captured with the Haloplex target enrichment system and sequenced using an Illumina MiSeq. We found that 11 (16%) individuals harboured pathogenic or likely pathogenic variants. In the cardiomyopathy, hypertrophy and SUD groups, 22%, 6% and 17% of the individuals, respectively, harboured pathogenic or likely pathogenic variants. Our findings show that testing of a broad panel of genes associated with cardiac diseases identify potential pathogenic variants of cardiac diseases in a significant proportion of SCD cases, and this may have important implications in family screening to prevent future deaths.
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Role of inflammation, oxidative stress, and autonomic nervous system activation during the development of right and left cardiac remodeling in experimental pulmonary arterial hypertension.
Mol Cell Biochem2019 Nov;():. doi: 10.1007/s11010-019-03652-2.
Zimmer A, Teixeira R B, Bonetto J H P, Bahr A C, Türck P, de Castro A L, Campos-Carraro C, Visioli F, Fernandes-Piedras T R, Casali K R, Scassola C M C, Baldo G, Araujo A S, Singal P, Belló-Klein A,
Abstract
This study investigated the impact of experimental pulmonary arterial hypertension (PAH) progression by evaluating morphometric and functional parameters, oxidative stress, autonomic nervous system (ANS) activation, and inflammation in the right (RV) and left (LV) ventricles. Male rats were first divided into two groups: monocrotaline (MCT) and control. The MCT group received a single MCT injection (60 mg/kg, intraperitoneal), while control received saline. The MCT and control groups were further divided into four cohorts based on how long they were observed: 1, 2, 3, and 4 weeks. Animals were submitted to echocardiographic and hemodynamic analysis. RV and LV were used for morphometric, biochemical, and histological measurements. Autonomic modulation was evaluated by cardiac spectral analysis, considering two components: low frequency (LF) and high frequency (HF). Lung and liver weight was used for morphometric analysis. MCT induced 100% mortality at 4 weeks. In the RV, disease progression led to mild inflammation and enhanced reactive oxygen species (ROS) in week 1, followed by moderate inflammation, ROS production, and hypertrophy in week 2. By week 3, there was moderate inflammation, oxidative stress, and ANS imbalance, with development of right heart dysfunction. LV biochemical changes and inflammation were observed at week 3. The initial changes appeared to be related to inflammation and ROS, and the later ones to inflammation, oxidative stress, and ANS imbalance in MCT animals. This study reinforces the severity of the disease in the RV, the late effects in the LV, and the role of ANS imbalance in the development of heart dysfunction.
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A Case of Anomalous Origin of the Right Coronary Artery from the Left Sinus of Valsalva with a Malignant Course.
Cureus2019 Sep;11(9):e5794. doi: 10.7759/cureus.5794.
Gupta Amol, Kumar Vinod, Gupta Ravi, Samarany Samir,
Abstract
Congenital heart disease in adults, including congenital anomalies of the coronary arteries, can be asymptomatic and diagnosed incidentally, but they can also be a cause of sudden cardiac death. The recent guidelines on the management of adults with congenital heart disease from the American Heart Association (AHA) and the American College of Cardiologists (ACC) identify that an anomalous coronary artery origin can lead to myocardial ischemia, arrhythmias, or sudden cardiac death. When the course of the coronary artery runs between the aorta and pulmonary trunk, it is described as having a "malignant course." Emergency surgical correction is required to restore the normal anatomy of the aberrant coronary artery. This report is of a 57-year-old man with a history of hypertension who had a normal electrocardiogram (ECG). A nuclear exercise stress test showed a resting and exercise ejection fraction (EF) of 56% with transient ischemic dilatation (TID) of the left ventricle. Coronary artery computed tomography angiography (CTA) identified an anomalous right coronary artery (AORCA) originating from the left sinus of Valsalva and coursing between the aorta and pulmonary trunk. TID on nuclear imaging is usually associated with left ventricular hypertrophy, microvascular disease, or multivessel macrovascular disease and has not been previously described in AORCA.
Copyright © 2019, Gupta et al.
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Cardiomyocyte-Specific STIM1 (Stromal Interaction Molecule 1) Depletion in the Adult Heart Promotes the Development of Arrhythmogenic Discordant Alternans.
Circ Arrhythm Electrophysiol2019 Nov;12(11):e007382. doi: 10.1161/CIRCEP.119.007382.
Cacheux Marine, Strauss Benjamin, Raad Nour, Ilkan Zeki, Hu Jun, Benard Ludovic, Feske Stefan, Hulot Jean-Sebastien, Akar Fadi G,
Abstract
BACKGROUND:
STIM1 (stromal interaction molecule 1) is a calcium (Ca) sensor that regulates cardiac hypertrophy by triggering store-operated Ca entry. Because STIM1 binding to phospholamban increases sarcoplasmic reticulum Ca load independent of store-operated Ca entry, we hypothesized that it controls electrophysiological function and arrhythmias in the adult heart.
METHODS:
Inducible myocyte-restricted STIM1-KD (STIM1 knockdown) was achieved in adult mice using an ?MHC (?-myosin heavy chain)-MerCreMer system. Mechanical and electrophysiological properties were examined using echocardiography in vivo and optical action potential (AP) mapping ex vivo in tamoxifen-induced STIM1-Cre (STIM1-KD) and littermate controls for STIM1 (referred to as STIM1-Ctl) and for Cre without STIM deletion (referred to as Cre-Ctl).
RESULTS:
STIM1-KD mice (N=23) exhibited poor survival compared with STIM1-Ctl (N=22) and Cre-Ctl (N=11) with >50% mortality after only 8-days of cardiomyocyte-restricted STIM1-KD. STIM1-KD but not STIM1-Ctl or Cre-Ctl hearts exhibited a proclivity for arrhythmic behavior, ranging from frequent ectopy to pacing-induced ventricular tachycardia/ventricular fibrillation (VT/VF). Examination of the electrophysiological substrate revealed decreased conduction velocity and increased AP duration (APD) heterogeneity in STIM1-KD. These features, however, were comparable in VT/VF(+) and VT/VF(-) hearts. We also uncovered a marked increase in the magnitude of APD alternans during rapid pacing, and the emergence of a spatially discordant alternans profile in STIM1-KD hearts. Unlike conduction velocity slowing and APD heterogeneity, the magnitude of APD alternans was greater (by 80%, <0.05) in VT/VF(+) versus VT/VF(-) STIM1-KD hearts. Detailed phase mapping during the initial beats of VT/VF identified one or more rotors that were localized along the nodal line separating out-of-phase alternans regions.
CONCLUSIONS:
In an adult murine model with inducible and myocyte-specific STIM1 depletion, we demonstrate for the first time the regulation of spatially discordant alternans by STIM1. Early mortality in STIM1-KD mice is likely related to enhanced susceptibility to VT/VF secondary to discordant APD alternans.
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Neuronal ceroid lipofuscinosis with cardiac involvement.
Cesk Patol2019 ;55(3):176-181.
Silvia Iannaccone Farka?ová, Peter Vasov?ák, Dorota Sopková, Mária Pisar?íková, Marián ?vajdler, Lucia Fröhlichová, Lucia Mistríková, Daniel Farka?,
Abstract
Neuronal ceroid lipofuscinoses (NCLs) are a group of inherited neurodegenerative disorders with clinical presentation predominantly in the childhood. The NCLs represent lysosomal storage disorders characterized by the accumulation of autofluorescent lipopigment storage material. The most common clinical features include development failure, psychomotor regression, seizures, and progressive loss of vision. We present a case of neuronal ceroid lipofuscinosis with cardiac involvement diagnosed post-mortem in a 9,5-year-old boy, whose clinical symptomatology comprised partial epilepsy, psychomotor decline and sinus bradycardia. In contrast to ventricular hypertrophy, being more frequently associated with NCLs, we discovered cardiac atrophy. Histologic examination of the heart revealed not only the lipofuscinosis affecting cardiac conducting cells and cardiomyocytes, but also basophilic degeneration of myocardium.
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Association of thoracic spine deformity and cardiovascular disease in a mouse model for Marfan syndrome.
PLoS One2019 ;14(11):e0224581. doi: 10.1371/journal.pone.0224581.
de Souza Rodrigo Barbosa, Farinha-Arcieri Luis Ernesto, Catroxo Marcia Helena Braga, Martins Ana Maria Cristina Rebelo Pinto da Fonseca, Tedesco Roberto Carlos, Alonso Luis Garcia, Koh Ivan Hong Jun, Pereira Lygia V,
Abstract
AIMS:
Cardiovascular manifestations are a major cause of mortality in Marfan syndrome (MFS). Animal models that mimic the syndrome and its clinical variability are instrumental for understanding the genesis and risk factors for cardiovascular disease in MFS. This study used morphological and ultrastructural analysis to the understanding of the development of cardiovascular phenotypes of the the mg?loxPneo model for MFS.
METHODS AND RESULTS:
We studied 6-month-old female mice of the 129/Sv background, 6 wild type (WT) and 24 heterozygous animals from the mg?loxPneo model. Descending thoracic aortic aneurysm and/or dissection (dTAAD) were identified in 75% of the MFS animals, defining two subgroups: MFS with (MFS+) and without (MFS-) dTAAD. Both subgroups showed increased fragmentation of elastic fibers, predominance of type I collagen surrounding the elastic fiber and fragmentation of interlaminar fibers when compared to WT. However, only MFS animals with spine tortuosity developed aortic aneurysm/dissection. The aorta of MFS+ animals were more tortuous compared to those of MFS- and WT mice, possibly causing perturbations of the luminal blood flow. This was evidenced by the detection of diminished aorta-blood flow in MFS+. Accordingly, only MFS+ animals presented a process of concentric cardiac hypertrophy and a significantly decreased ratio of left and right ventricle lumen area.
CONCLUSIONS:
We show that mg?loxPneo model mimics the vascular disease observed in MFS patients. Furthermore, the study indicates role of thoracic spine deformity in the development of aorta diseases. We suggest that degradation of support structures of the aortic wall; deficiency in the sustenance of the thoracic vertebrae; and their compression over the adjacent aorta resulting in disturbed blood flow is a triad of factors involved in the genesis of dissection/aneurysm of thoracic aorta.
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Comparison of chest radiographic findings between severe fever with thrombocytopenia syndrome and scrub typhus: Single center observational cross-sectional study in South Korea.
Medicine (Baltimore)2019 Nov;98(46):e17701. doi: 10.1097/MD.0000000000017701.
Yun Ji Hyun, Hwang Hye Jeon, Jung Jiwon, Kim Min Jae, Chong Yong Pil, Lee Sang-Oh, Choi Sang-Ho, Kim Yang Soo, Woo Jun Hee, Kim Mi Young, Kim Sung-Han,
Abstract
Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease caused by SFTS virus (SFTSV) which involves multiple organ systems, including lungs. However, there is limited data on lung involvement of SFTS. Therefore, the present study investigated the chest radiographic findings of SFTS, including computed tomography (CT), and compared these with those of scrub typhus, which is the most common tick-borne illness in South Korea and share risk factors and occur in similar settings.Medical records of patients with confirmed SFTS and scrub typhus in a tertiary hospital in Seoul (South Korea), between January 2014 and June 2018, were reviewed. Initial chest radiography and CT were reviewed by 2 experienced radiologists.A total of 39 patients with SFTS and 101 patients with scrub typhus were analyzed. All patients except 3 patients with scrub typhus in both groups received chest radiography. Cardiomegaly (90%) and patchy consolidation with ground glass opacity (GGO) pattern (31%) were more common in SFTS group than scrub typhus group (20%, P?
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Transthyretin Cardiac Amyloidosis as Diagnosed by 99mTc-PYP Scanning in Patients with Acute Heart Failure and Preserved Ejection Fraction.
Crit Pathw Cardiol2019 Dec;18(4):195-199. doi: 10.1097/HPC.0000000000000183.
Lo Presti Saberio, Horvath Sofia A, Mihos Christos G, Rajadhyaksha Chetan, McCloskey Veronica, Santana Orlando,
Abstract
Transthyretin amyloid deposition is present in 17% of autopsies of patients with heart failure and a preserved ejection fraction (HFpEF). Technetium-pyrophosphate scintigraphy (Tc-PYP) is sensitive and specific to diagnose cardiac transthyretin amyloid deposition (ATTR). The prevalence of ATTR by Tc-PYP was evaluated along with echocardiographic parameters in patients with HFpEF. One-hundred consecutive patients with HFpEF, who had Tc-PYP, were retrospectively evaluated. Echocardiographic variables were analyzed to compare patients with positive versus negative ATTR infiltration. Myocardial ATTR was present in 19% of patients. Individuals with ATTR were older with a mean age of 82?±?7 versus 75?±?13 years (P = 0.03), had increased left ventricular hypertrophy with the interventricular septum measuring 1.6 (IQR, 1.4-2.0) versus 1.4 (IQR, 1.3-1.6) cm (P = 0.002), had a greater mean left ventricular mass index of 160?±?50?g/m versus 131?±?44?g/m (P = 0.01), and a reduced global longitudinal strain measuring -11% (IQR, -9 to -12) versus -12% (IQR, -10 to -16), P = 0.04. The prevalence of ATTR myocardial deposition demonstrated by Tc-PYP in patients with HFpEF is comparable to that of autopsy studies. It is more common in older patients, with increased left ventricular hypertrophy and reduced global longitudinal strain.
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Effect of endostatin overexpression on angiotensin II-induced cardiac hypertrophy in rats.
Chin Med J (Engl)2019 Nov;():. doi: 10.1097/CM9.0000000000000513.
Dai You-Jin, Gong Jue-Xiao, Bian Rong,
Abstract
BACKGROUND:
Endostatin, a biologically active fragment of collagen XVIII, has been observed in patients with ischemic heart disease. The aim of the present study was to investigate whether endostatin overexpression could attenuate cardiac hypertrophy by inhibiting the cyclic adenosine monophosphate-protein kinase A (cAMP-PKA) signaling pathway.
METHODS:
This study was examined in vivo in rats and in vitro in primary neonatal rat cardiomyocytes treated with angiotensin (Ang) II to model cardiac hypertrophy. Twenty-four male Sprague-Dawley rats were randomized into adenovirus (Ad)-green fluorescent protein, Ang II, Ad-endostatin, and Ang II + Ad-endostatin groups (n?=?6 in each group). Four weeks later, all the rats were weighed and sacrificed after transthoracic echocardiography. Cardiac function was evaluated by transthoracic echocardiography, cardiomyocyte size was evaluated by hematoxylin-eosin staining. Levels of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) were evaluated by quantitative reverse-transcription polymerase chain reaction or Western blotting, PKA level was evaluated by Western blotting, and cAMP level was evaluated by enzyme-linked immunosorbent assay. Statistical significance among multiple groups was evaluated by one-way analysis of variance.
RESULTS:
Endostatin overexpression reduced the increases in left ventricle (LV) mass (P?=?0.0063), LV mass/body weight (BW) (P?=?0.0013), interventricular septal thickness (IVS) in diastole (P?=?0.0013), IVS in systole (P?=?0.0056), left ventricular posterior wall thickness (LVPW) in diastole (P?=?0.0291), LVPW in systole (P?=?0.0080), heart weight (HW) (P?=?0.0138), HW/BW (P?=?0.0001), and HW/tibial length (P?=?0.0372) in Ang II-treated rats. In addition, endostatin overexpression reduced cardiomyocyte cross-sectional area expansion, and reduced the levels of ANP and BNP in Ang II-treated rats (P?=?0.0251 and 0.0477 for messenger RNA [mRNA]), and primary neonatal rat cardiomyocytes (P?=?0.0188 and P?=?0.0024 for mRNA; P?=?0.0023 and 0.0013 for protein, respectively). Additionally, endostatin overexpression reduced the increase of cAMP (P?=?0.0054) and PKA (P?=?0.0328) levels in cardiomyocytes treated with Ang II. Treatment with cAMP reversed the effects of endostatin overexpression on ANP (P?=?0.0263) and BNP (P?=?0.0322) levels in cardiomyocytes induced by Ang II.
CONCLUSION:
Endostatin overexpression could alleviate cardiac hypertrophy by inhibiting the cAMP-PKA signaling pathway.
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Alpha-calcitonin gene-related peptide prevents pressure-overload induced heart failure: role of apoptosis and oxidative stress.
Physiol Rep2019 Nov;7(21):e14269. doi: 10.14814/phy2.14269.
Kumar Ambrish, Supowit Scott, Potts Jay D, DiPette Donald J,
Abstract
Alpha-calcitonin gene-related peptide (?-CGRP) is a 37-amino acid neuropeptide that plays an important protective role in modulating cardiovascular diseases. Deletion of the ?-CGRP gene increases the vulnerability of the heart to pressure-induced heart failure and the administration of a modified ?-CGRP agonist decreases this vulnerability. Systemic administration of ?-CGRP decreases blood pressure in normotensive and hypertensive animals and humans. Here we examined the protective effect of long-term administration of native ?-CGRP against pressure-overload heart failure and the likely mechanism(s) of its action. Transverse aortic constriction (TAC) was performed to induce pressure-overload heart failure in mice. We found that TAC significantly decreased left ventricular (LV) fractional shortening, ejection fraction, and ?-CGRP content, and increased hypertrophy, dilation, and fibrosis compared to sham mice. Administration of ?-CGRP-filled mini-osmotic pumps (4 mg/kg bwt/day) in TAC mice preserved cardiac function and LV ?-CGRP levels, and reduced LV hypertrophy, dilation, and fibrosis to levels comparable to sham mice. Additionally, TAC pressure-overload significantly increased LV apoptosis and oxidative stress compared to the sham mice but these increases were prevented by ?-CGRP administration. ?-CGRP administration in TAC animals decreased LV AMPK phosphorylation levels and the expression of sirt1, both of which are regulatory markers of oxidative stress and energy metabolism. These results demonstrate that native ?-CGRP is protective against pressure-overload induced heart failure. The mechanism of this cardio-protection is likely through the prevention of apoptosis and oxidative stress, possibly mediated by sirt1 and AMPK. Thus, ?-CGRP is a potential therapeutic agent in preventing the progression to heart failure, and the cardio-protective action of ?-CGRP is likely the result of a direct cellular effect; however, a partial vasodilatory blood pressure-dependent mechanism of ?-CGRP cannot be excluded.
© 2019 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.
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mTOR pathway in human cardiac hypertrophy caused by LEOPARD syndrome: a different role compared with animal models?
Orphanet J Rare Dis2019 Nov;14(1):252. doi: 10.1186/s13023-019-1204-4.
Cui Hao, Song Lei, Zhu Changsheng, Zhang Ce, Tang Bing, Wang Shengwei, Wu Guixin, Zou Yubao, Huang Xiaohong, Hui Rutai, Wang Shuiyun, Wang Jizheng,
Abstract
BACKGROUND:
Animal studies suggested that blocking the activation of the mammalian target of rapamycin (mTOR) pathway might be effective to treat cardiac hypertrophy in LEOPARD syndrome (LS) caused by PTPN11 mutations.
RESULTS:
In the present study, mTOR pathway activity was examined in human myocardial samples from two patients with LS, four patients with hypertrophic cardiomyopathy (HCM), and four normal controls. The two patients with LS had p.Y279C and p.T468?M mutations of the PTPN11 gene, respectively. Although PTPN11 mutation showed initially positive regulation on phosphoinositide 3-kinase, overall the mTOR complex 1 pathway showed widely attenuated activity in LS. This included mildly hypophosphorylated mTOR and ribosomal protein S6 kinase and significantly hypophosphorylated Akt and ribosomal protein S6, which is similar to HCM. Akt is a basal molecule of the mTOR complex 2 pathway. Akt was less affected and showed hyperactivity in LS compared with HCM and normal controls. Additionally, MAPK/ERK kinase and ERK1/2 were significantly more phosphorylated in both HCM and LS than normal controls.
CONCLUSIONS:
In LS, the mTOR signaling pathway shows similar activity to HCM and is attenuated compared with normal controls. Thus, caution should be applied when using rapamycin to treat heart hypertrophy in LS.
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Novel PRKAG2 Variant Manifesting with a Cardiac Arrest in a Child.
Pediatr Cardiol2019 Nov;():. doi: 10.1007/s00246-019-02245-6.
Spentzou Georgia, McGowan Ruth, Hares Dominic, McLeod Karen,
Abstract
We describe the case of a novel PRKAG2 mutation that manifested with a ventricular fibrillation cardiac arrest in a child. The previously healthy 13-year old boy, was subsequently diagnosed with Wolff-White-Parkinson syndrome, mild left ventricular hypertrophy and atrial fibrillation. His father had also been diagnosed in the past with Wolff-White-Parkinson syndrome and developed left ventricular hypertrophy. A novel heterozygous likely pathogenic variant, c.911C>G, p.Ala304Gly was identified in the father and his son, which is absent from population databases. PRKAG2 gene variants have previously been shown to cause a familial syndrome of ventricular hypertrophy, ventricular pre-excitation, supraventricular tachycardia, and conduction abnormalities. However, to the best of our knowledge, this is the first description of this rare syndrome manifesting with a more severe phenotype in a second generation relative within the same family.
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Clinical characteristics and prognosis of Chinese patients with hereditary transthyretin amyloid cardiomyopathy.
Orphanet J Rare Dis2019 Nov;14(1):251. doi: 10.1186/s13023-019-1235-x.
He Shan, Tian Zhuang, Guan Hongzhi, Li Jian, Fang Quan, Zhang Shuyang,
Abstract
BACKGROUND:
Hereditary transthyretin amyloid cardiomyopathy (ATTR-CM) is an increasingly recognized progressive cardiomyopathy with heterogenous clinical manifestations that lead to its misdiagnosis and poor prognosis. This study was performed to describe the clinical characteristics and natural history of Chinese patients to improve clinical awareness of this condition.
METHODS:
In this study, we retrospectively investigated 23 patients with a confirmed diagnosis of hereditary ATTR-CM in Peking Union Medical College hospital from From January 1, 2000 to December 31, 2018.
RESULTS:
In all, 16 patients (69.6%) were males, the median age at disease onset was 45 (33,55) years old. The median duration from symptom onset to diagnosis was 30 (18,46) months. Phenotypes were classified as exclusively cardiac (n?=?1, 4.3%) and mixed type (n?=?22, 95.6%). The common mutations were Gly47Arg (7 patients [30.4%]) and Val30Ala (3 patients [13%]). Ventricular hypertrophy was observed in 23 (100%) patients, the mean thickness of the ventricular septum was 16.1?±?3.9?mm, the mean thickness of the left ventricular posterior wall was 15.1?±?2.8?mm. The mean left ventricle ejection fraction (LVEF) was 57.3?±?11.9% and only 5 patients (21.7%) had LVEF
CONCLUSIONS:
The clinical characteristics of ATTR are heterogeneous: men are more likely to be affected and onset symptoms are not obvious in the heart and mainly include peripheral neuropathy and autonomic neuropathy; however, LV hypertrophy, especially a thick ventricular septum and posterior wall with preserved LVEF, are often detected on echocardiography. Abnormal ECG manifestations are common. The prognosis is poor, and patients with EF >?50% have better survival. Clinicians should be more aware of the complex clinical profile of ATTR amyloidosis to avoid misdiagnosis in practice.
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