scholarly journals LAMP2 Cardiomyopathy: Consequences of Impaired Autophagy in the Heart

2021 ◽  
Author(s):  
Ronny Alcalai ◽  
Michael Arad ◽  
Hiroko Wakimoto ◽  
Dor Yadin ◽  
Joshua Gorham ◽  
...  
Keyword(s):  
Cardiac Electrophysiology ◽  
Morphological Changes ◽  
Systolic Function ◽  
Left Ventricular ◽  
Danon Disease ◽  
Conduction Disturbances ◽  
Expression Of Genes ◽  
Genes Encoding ◽  
Increased Sensitivity ◽  
Protein Components

Background Human mutations in the X‐linked lysosome‐associated membrane protein‐2 ( LAMP2 ) gene can cause a multisystem Danon disease or a primary cardiomyopathy characterized by massive hypertrophy, conduction system abnormalities, and malignant ventricular arrhythmias. We introduced an in‐frame LAMP2 gene exon 6 deletion mutation (denoted L2 Δ6 ) causing human cardiomyopathy, into mouse LAMP2 gene, to elucidate its consequences on cardiomyocyte biology. This mutation results in in‐frame deletion of 41 amino acids, compatible with presence of some defective LAMP2 protein. Methods and Results Left ventricular tissues from L2 Δ6 and wild‐type mice had equivalent amounts of LAMP2 RNA, but a significantly lower level of LAMP2 protein. By 20 weeks of age male mutant mice developed left ventricular hypertrophy which was followed by left ventricular dilatation and reduced systolic function. Cardiac electrophysiology and isolated cardiomyocyte studies demonstrated ventricular arrhythmia, conduction disturbances, abnormal calcium transients and increased sensitivity to catecholamines. Myocardial fibrosis was strikingly increased in 40‐week‐old L2 Δ6 mice, recapitulating findings of human LAMP2 cardiomyopathy. Immunofluorescence and transmission electron microscopy identified mislocalization of lysosomes and accumulation of autophagosomes between sarcomeres, causing profound morphological changes disrupting the cellular ultrastructure. Transcription profile and protein expression analyses of L2 Δ6 hearts showed significantly increased expression of genes encoding activators and protein components of autophagy, hypertrophy, and apoptosis. Conclusions We suggest that impaired autophagy results in cardiac hypertrophy and profound transcriptional reactions that impacted metabolism, calcium homeostasis, and cell survival. These responses define the molecular pathways that underlie the pathology and aberrant electrophysiology in cardiomyopathy of Danon disease.

scholarly journals Age-dependent changes in electrophysiology and calcium handling – implications for pediatric cardiac research

2019 ◽  
Author(s):  
Luther M. Swift ◽  
Morgan Burke ◽  
Devon Guerrelli ◽  
Manelle Ramadan ◽  
Marissa Reilly ◽  
...  
Keyword(s):  
Postnatal Development ◽  
Cardiac Electrophysiology ◽  
Calcium Handling ◽  
Cell Coupling ◽  
Altered Expression ◽  
Expression Of Genes ◽  
Age Dependent ◽  
Genes Encoding ◽  
Cardiac Maturation

ABSTRACTRationaleThe heart continues to develop and mature after birth and into adolescence. Accordingly, cardiac maturation is likely to include a progressive refinement in both organ morphology and function during the postnatal period. Yet, age-dependent changes in cardiac electrophysiology and calcium handling have not yet been fully characterized.ObjectiveThe objective of this study, was to examine the relationship between cardiac maturation, electrophysiology, and calcium handling throughout postnatal development in a rat model.MethodsPostnatal rat cardiac maturation was determined by measuring the expression of genes involved in cell-cell coupling, electrophysiology, and calcium handling. In vivo electrocardiograms were recorded from neonatal, juvenile, and adult animals. Simultaneous dual optical mapping of transmembrane voltage and calcium transients was performed on isolated, Langendorff-perfused rat hearts (postnatal day 0–3, 4-7, 8-14, adult).ResultsYounger, immature hearts displayed slowed electrical conduction, prolonged action potential duration and increased ventricular refractoriness. Slowed calcium handling in the immature heart increased the propensity for calcium transient alternans which corresponded to alterations in the expression of genes encoding calcium handling proteins. Developmental changes in cardiac electrophysiology were associated with the altered expression of genes encoding potassium channels and intercalated disc proteins.ConclusionUsing an intact whole heart model, this study highlights chronological changes in cardiac electrophysiology and calcium handling throughout postnatal development. Results of this study can serve as a comprehensive baseline for future studies focused on pediatric cardiac research, safety assessment and/or preclinical testing using rodent models.

scholarly journals Epicardial Adipose Tissue as a New Target of Therapeutic Interventions

2020 ◽  
Vol 16 (4) ◽  
pp. 585-589
Author(s):  
M. A. Druzhilov ◽  
T. Y. Kuznetsova
Keyword(s):  
Coronary Heart Disease ◽  
Adipose Tissue ◽  
Epicardial Adipose Tissue ◽  
Systolic Function ◽  
Dynamic Assessment ◽  
Therapeutic Interventions ◽  
Supraventricular Arrhythmias ◽  
Expression Of Genes ◽  
Genes Encoding ◽  
Modifiable Factor

There is evidence of a correlation between epicardial adipose tissue and the presence and severity of coronary heart disease, the development of hypertrophy, impaired diastolic and systolic function of the left ventricle, enlargement, fibrosis and electrophysiological remodeling of the atria, the occurrence and severity of supraventricular arrhythmias. There is also a lot of evidence of the influence of both non-drug methods and drugs on the severity and functional activity of epicardial adipose tissue, which can be considered as a potentially modifiable factor of cardiovascular risk, the various therapeutic interventions target and a criterion for their effectiveness. Its unique characteristics suggest the advisability of pharmacological strategies aimed at regulating the expression of genes encoding the secretion of adipocytokines and adipocyte function, and a dynamic assessment of the severity of epicardial fat during therapy can be a tool to evaluate its effectiveness in various cardiovascular diseases.

Genetics of cardiomyopathies: hypertrophic cardiomyopathy

ESC CardioMed ◽  
2018 ◽  
pp. 688-691
Author(s):  
Philippe Charron ◽  
Carole Maupain
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Troponin T ◽  
Friedreich Ataxia ◽  
Pathogenic Mutation ◽  
Left Ventricular ◽  
Danon Disease ◽  
Genetic Causes ◽  
Sarcomeric Protein ◽  
Genes Encoding ◽  
Ventricular Wall Thickness

Hypertrophic cardiomyopathy is characterized by the presence of increased left ventricular wall thickness that is not solely explained by abnormal loading conditions (such as hypertension or valvular disease). Hypertrophic cardiomyopathy is a genetic disease, usually with an autosomal dominant inheritance. About 35–60% of patients with hypertrophic cardiomyopathy carry a pathogenic mutation in sarcomeric protein genes. Most mutations are observed in genes encoding beta-myosin heavy chain (MYH7), cardiac myosin binding protein C (MYBPC3), or cardiac troponin T (TNNT2). Non-sarcomeric genetic causes exist, especially in children (Pompe disease, Noonan syndrome, or Friedreich ataxia). In adults, non-sarcomeric genetic causes include metabolic storage diseases such as Danon disease (LAMP2 gene), Fabry disease (GLA gene), left ventricular hypertrophy associated with Wolff–Parkinson–White syndrome (PRKAG2 gene), familial amyloidosis (TTR gene), and mitochondrial cardiomyopathies.

Abstract 292: Maternal Transfer of Anti-Cardiac Myosin Antibody Induces Dilated Cardiomyopathy and Underdevelopment of Aortic Arch in Newborn Rats

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Giv Heidari-Bateni ◽  
Lisa Goessling ◽  
Anoop Brar ◽  
Madeleine Cunningham ◽  
Pirooz Eghtesady
Keyword(s):  
Dilated Cardiomyopathy ◽  
Aortic Arch ◽  
Morphological Changes ◽  
Systolic Function ◽  
Left Ventricular Systolic Function ◽  
Left Ventricular ◽  
Control Group ◽  
Cardiac Myosin ◽  
Echocardiographic Study ◽  
Aorta Diameter

Introduction: Anti-cardiac myosin (CM) antibodies are induced following certain infectious diseases. We evaluated for the first time the effect of maternally-transferred anti-CM antibody on the newborn heart in a rat model. Methods: Female Lewis rats were immunized with 1 µg of emulsified CM and boosters (0.5 µg) were administered every 2 weeks, followed by mating; control rats (n=3) were injected with saline. After birth, pups were continually housed with dams. Echocardiography was performed on pups on day 20. Pups were sacrificed on day 21 and hearts were fixed, sectioned, and analyzed for morphological changes. Trichrome staining was performed to detect fibrotic changes. Results: All the pups in CM group (n=22) showed anti-CM antibody titers of more than 12800. Echocardiographic study revealed that 45.4% (10/22) of pups in the CM group had evidence of decreased left ventricular systolic function. The affected pups had both thinner anterior and inferior left ventricle walls compared with pups in control group (3.43±0.33 vs. 3.82±0.24, p=0.017 and 3.71±0.32 vs. 4.18±0.31, p=0.009 respectively). There were also evidence of underdevelopment of thoracic aorta and aortic arch (3.1±0.16 vs. 3.3±0.16 for ascending aorta diameter, p=0.002 and 2.6±0.14 vs. 2.8±0.25 for descending aorta diameter, p=0.008). Morphological changes consistent with dilated cardiomyopathy (image) and fibrosis were detected. Conclusion: Maternal anti-CM antibodies can cross the placenta and affect the development of the newborn heart; the resulting phenotype is one of dilated cardiomyopathy with associated hypoplasia of vascular structures perhaps secondary to reduced flow.

scholarly journals New-onset left bundle branch block after transcatheter aortic valve replacement is associated with adverse long-term clinical outcomes in intermediate-risk patients: an analysis from the PARTNER II trial

2019 ◽  
Vol 40 (27) ◽  
pp. 2218-2227 ◽  
Author(s):  
Tamim M Nazif ◽  
Shmuel Chen ◽  
Isaac George ◽  
Jose M Dizon ◽  
Rebecca T Hahn ◽  
...  
Keyword(s):  
Clinical Outcomes ◽  
Systolic Function ◽  
Multivariable Analysis ◽  
Left Ventricular Systolic Function ◽  
Left Ventricular ◽  
Intermediate Risk ◽  
Conduction Disturbances ◽  
Transcatheter Aortic Valve ◽  
Risk Patients ◽  
New Onset

Abstract Aims Transcatheter aortic valve replacement (TAVR) is now an established therapy for intermediate-risk surgical candidates with symptomatic, severe aortic stenosis. The clinical impact of new-onset left bundle branch block (LBBB) after TAVR remains controversial and has not been studied in intermediate-risk patients. We therefore sought to analyse outcomes associated with new LBBB in a large cohort of intermediate-risk patients treated with TAVR. Methods and results A total of 2043 patients underwent TAVR in the PARTNER II trial and S3 intermediate-risk registry and survived to hospital discharge. Patients were excluded from the current analysis due to baseline conduction disturbances, pre-existing permanent pacemaker (PPM), and new PPM during the index hospitalization. Clinical outcomes at 2 years were compared between patients with and without persistent, new-onset LBBB at hospital discharge, and multivariable analysis was performed to identify predictors of mortality. Among 1179 intermediate-risk patients, new-onset LBBB at discharge occurred in 179 patients (15.2%). Patients with new LBBB were similar to those without except for more frequent diabetes and more frequent treatment with SAPIEN 3 vs. SAPIEN XT. At 2 years, new LBBB was associated with increased rates of all-cause mortality (19.3% vs. 10.8%, P = 0.002), cardiovascular mortality (16.2% vs. 6.5%, P < 0.001), rehospitalization, and new PPM implantation. By multivariable analysis, new LBBB remained an independent predictor of 2-year all-cause [hazard ratio (HR) 1.98, 95% confidence interval (95% CI) 1.33, 2.96; P < 0.001] and cardiovascular (HR 2.66 95% CI 1.67, 4.24; P < 0.001) mortality. New LBBB was also associated with worse left ventricular systolic function at 1 and 2-year follow-up. Conclusions In a large cohort of intermediate-risk patients from the PARTNER II trial and registry, persistent, new-onset LBBB occurred in 15.2% of patients without baseline conduction disturbances or pacemaker. New LBBB was associated with adverse clinical outcomes at 2 years, including all-cause and cardiovascular mortality, rehospitalization, new pacemaker implantation, and worsened left ventricular systolic function. Clinical Trial Registration ClinicalTrials.gov #NCT01314313 and NCT03222128.

scholarly journals Transient Ischemic Attack and Ischemic Stroke in Danon Disease with Formation of Left Ventricular Apical Thrombus despite Normal Systolic Function

2017 ◽  
Vol 2017 ◽  
pp. 1-5
Author(s):  
Takeshi Tsuda ◽  
Amanda J. Shillingford ◽  
Jane Vetter ◽  
Vinay Kandula ◽  
Badal Jain ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Transient Ischemic Attack ◽  
Systolic Function ◽  
Wide Spectrum ◽  
Left Ventricular ◽  
Female Adolescent ◽  
Neurological Deficits ◽  
Danon Disease ◽  
Normal Systolic Function ◽  
Ischemic Attack

Danon disease is a rare X-linked dominant skeletal and cardiac muscle disorder presenting with hypertrophic cardiomyopathy, Wolf-Parkinson-White syndrome, skeletal myopathy, and mild intellectual disability. Early morbidity and mortality due to heart failure or sudden death are known in Danon disease, more in males than in females. Here, we present a 17-year-old female adolescent with Danon disease and severe concentric hypertrophy with normal left ventricular (LV) systolic function, who has been complaining of intermittent headache and weakness for about 3 years, initially diagnosed with hemiplegic migraine. Subsequently, her neurological manifestation progressed to transient ischemic attack (TIA) and eventually to ischemic stroke confirmed by CT scan with 1-day history of expressive aphasia followed by persistent left side weakness and numbness. Detailed echocardiogram for the first time revealed a small LV apical thrombus with unchanged severe biventricular hypertrophy and normal systolic function. This unexpected LV apical thrombus may be associated with a wide spectrum of neurological deficits ranging from TIA to ischemic stroke in Danon disease. Possibility of cerebral ischemic events should be suspected in Danon disease when presenting with neurological deficits even with normal systolic function. Careful assessment for LV apical thrombus is warranted in such cases.

scholarly journals Heme Competition Triggers an Increase in the Pathogenic Potential of Porphyromonas gingivalis in Porphyromonas gingivalis-Candida albicans Mixed Biofilm

2020 ◽  
Vol 11 ◽  
Author(s):  
Yanyang Guo ◽  
Yu Wang ◽  
Yijin Wang ◽  
Yabing Jin ◽  
Chen Wang
Keyword(s):  
Candida Albicans ◽  
Porphyromonas Gingivalis ◽  
Morphological Changes ◽  
Single Species ◽  
Healthy Human ◽  
Pathogenic Potential ◽  
Expression Of Genes ◽  
Gene Level ◽  
Genes Encoding ◽  
Laser Confocal Microscope

As one of the main pathogens of periodontitis, Porphyromonas gingivalis often forms mixed biofilms with other bacteria or fungi under the gingiva, such as Candida albicans. Heme is an important iron source for P. gingivalis and C. albicans that supports their growth in the host. From the perspective of heme competition, this study aims to clarify that the competition for heme enhances the pathogenic potential of P. gingivalis during the interaction between P. gingivalis and C. albicans. Porphyromonas gingivalis single-species biofilm and P. gingivalis-C. albicans dual-species biofilm were established in a low- and high-heme environment. The results showed that the vitality of P. gingivalis was increased in the dual-species biofilm under the condition of low heme, and the same trend was observed under a laser confocal microscope. Furthermore, the morphological changes in P. gingivalis were observed by electron microscope, and the resistance of P. gingivalis in dual-species biofilm was stronger against the killing effect of healthy human serum and antibiotics. The ability of P. gingivalis to agglutinate erythrocyte was also enhanced in dual-species biofilm. These changes disappeared when heme was sufficient, which confirmed that heme competition was the cause of thepathogenicy change in P. gingivalis. Gene level analysis showed that P. gingivalis was in a superior position in the competition relationship by increasing the expression of heme utilization-related genes, such as HmuY, HmuR, HusA, and Tlr. In addition, the expression of genes encoding gingipains (Kgp, RgpA/B) was also significantly increased. They not only participate in the process of utilizing heme, but also are important components of the virulence factors of P. gingivalis. In conclusion, our results indicated that the pathogenic potential of P. gingivalis was enhanced by C. albicans through heme competition, which ultimately promoted the occurrence and development of periodontitis and, therefore, C. albicans subgingival colonization should be considered as a factor in assessing the risk of periodontitis.

scholarly journals Genes Encoding ACE2, TMPRSS2 and Related Proteins Mediating SARS-CoV-2 Viral Entry are Upregulated with Age in Human Cardiomyocytes

2020 ◽  
Author(s):  
Emma L. Robinson ◽  
Kanar Alkass ◽  
Olaf Bergmann ◽  
Janet J. Maguire ◽  
H. Llewelyn Roderick ◽  
...  
Keyword(s):  
Viral Entry ◽  
Enzyme Inhibitors ◽  
Cardiovascular Complications ◽  
Left Ventricular ◽  
Older Individuals ◽  
Human Cardiomyocytes ◽  
Expression Of Genes ◽  
Genes Encoding ◽  
Approved Drugs ◽  
Related Proteins

AbstractAge is an independent risk factor for adverse outcome in patients following COVID-19 infection. We hypothesised that differential expression of genes encoding proteins proposed to be required for entry of SARS-Cov-2 in aged compared to younger cardiomyocytes might contribute to the susceptibility of older individuals to COVID-19-associated cardiovascular complications.We generated strand-specific RNA-sequencing libraries from RNA isolated from flow-sorted cardiomyocyte nuclei from left ventricular tissue. RNASeq data were compared between five young (19-25yr) and five older (63-78yr) Caucasian males who had not been on medication or exhibited evidence of cardiovascular disease post-mortem.Expression of relevant genes encoding ACE2, TMPRSS2, TMPRS11D, TMPRS11E, FURIN, CTSL, CTSB and B0AT1/SLC6A19 were upregulated in aged cardiomyocytes and the combined relative cardiomyocyte expression of these genes correlated positively with age. Genes encoding proteins in the RAAS and interferon/interleukin pathways were also upregulated such as ACE, AGTR1, MAS1 and IL6R.Our results highlight SARS-CoV-2 related genes that have higher expression in aged compared with young adult cardiomyocytes. These data may inform studies using selective enzyme inhibitors/antagonists, available as experimental compounds or clinically approved drugs e.g. remdesivir that has recently been rapidly accepted for compassionate use, to further understand the contribution of these pathways in human cardiomyocytes to disease outcome in COVID-19 patients.

scholarly journals Sports Activity and Arrhythmic Risk in Cardiomyopathies and Channelopathies: A Critical Review of European Guidelines on Sports Cardiology in Patients with Cardiovascular Diseases

Medicina ◽  
2021 ◽  
Vol 57 (4) ◽  
pp. 308
Author(s):  
Giovanni Volpato ◽  
Umberto Falanga ◽  
Laura Cipolletta ◽  
Manuel Antonio Conti ◽  
Gino Grifoni ◽  
...  
Keyword(s):  
Cardiovascular Diseases ◽  
Cardiac Electrophysiology ◽  
Systolic Function ◽  
Electrophysiological Study ◽  
Arrhythmogenic Right Ventricular Cardiomyopathy ◽  
Left Ventricular ◽  
Sports Cardiology ◽  
Sports Activity ◽  
European Guidelines ◽  
Prediction And Prevention

The prediction and prevention of sudden cardiac death is the philosopher’s stone of clinical cardiac electrophysiology. Sports can act as triggers of fatal arrhythmias and therefore it is essential to promptly frame the athlete at risk and to carefully evaluate the suitability for both competitive and recreational sports activity. A history of syncope or palpitations, the presence of premature ventricular complexes or more complex arrhythmias, a reduced left ventricular systolic function, or the presence of known or familiar heart disease should prompt a thorough evaluation with second level examinations. In this regard, cardiac magnetic resonance and electrophysiological study play important roles in the diagnostic work-up. The role of genetics is increasing both in cardiomyopathies and in channelopathies, and a careful evaluation must be focused on genotype positive/phenotype negative subjects. In addition to being a trigger for fatal arrhythmias in certain cardiomyopathies, sports also play a role in the progression of the disease itself, especially in the case arrhythmogenic right ventricular cardiomyopathy. In this paper, we review the latest European guidelines on sport cardiology in patients with cardiovascular diseases, focusing on arrhythmic risk stratification and the management of cardiomyopathies and channelopathies.

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