Pubblicazioni recenti - dilated cardiomyopathy
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FAM210A Regulates Mitochondrial Translation and Maintains Cardiac Mitochondrial Homeostasis.
bioRxiv2023 May;():. doi: 2023.05.20.541585.
Wu Jiangbin, Subbaiah Kadiam C Venkata, Hedaya Omar, Chen Si, Munger Joshua, Tang Wai Hong Wilson, Yan Chen, Yao Peng,
Abstract
AIMS:
Mitochondria play a vital role in cellular metabolism and energetics and support normal cardiac function. Disrupted mitochondrial function and homeostasis cause a variety of heart diseases. Fam210a (family with sequence similarity 210 member A), a novel mitochondrial gene, is identified as a hub gene in mouse cardiac remodeling by multi-omics studies. Human FAM210A mutations are associated with sarcopenia. However, the physiological role and molecular function of FAM210A remain elusive in the heart. We aim to determine the biological role and molecular mechanism of FAM210A in regulating mitochondrial function and cardiac health .
METHODS AND RESULTS:
Tamoxifen-induced -driven conditional knockout of in the mouse cardiomyocytes induced progressive dilated cardiomyopathy and heart failure, ultimately causing mortality. Fam210a deficient cardiomyocytes exhibit severe mitochondrial morphological disruption and functional decline accompanied by myofilament disarray at the late stage of cardiomyopathy. Furthermore, we observed increased mitochondrial reactive oxygen species production, disturbed mitochondrial membrane potential, and reduced respiratory activity in cardiomyocytes at the early stage before contractile dysfunction and heart failure. Multi-omics analyses indicate that FAM210A deficiency persistently activates integrated stress response (ISR), resulting in transcriptomic, translatomic, proteomic, and metabolomic reprogramming, ultimately leading to pathogenic progression of heart failure. Mechanistically, mitochondrial polysome profiling analysis shows that FAM210A loss of function compromises mitochondrial mRNA translation and leads to reduced mitochondrial encoded proteins, followed by disrupted proteostasis. We observed decreased FAM210A protein expression in human ischemic heart failure and mouse myocardial infarction tissue samples. To further corroborate FAM210A function in the heart, AAV9-mediated overexpression of FAM210A promotes mitochondrial-encoded protein expression, improves cardiac mitochondrial function, and partially rescues murine hearts from cardiac remodeling and damage in ischemia-induced heart failure.
CONCLUSION:
These results suggest that FAM210A is a mitochondrial translation regulator to maintain mitochondrial homeostasis and normal cardiomyocyte contractile function. This study also offers a new therapeutic target for treating ischemic heart disease.
TRANSLATIONAL PERSPECTIVE:
Mitochondrial homeostasis is critical for maintaining healthy cardiac function. Disruption of mitochondrial function causes severe cardiomyopathy and heart failure. In the present study, we show that FAM210A is a mitochondrial translation regulator required for maintaining cardiac mitochondrial homeostasis . Cardiomyocyte-specific FAM210A deficiency leads to mitochondrial dysfunction and spontaneous cardiomyopathy. Moreover, our results indicate that FAM210A is downregulated in human and mouse ischemic heart failure samples and overexpression of FAM210A protects hearts from myocardial infarction induced heart failure, suggesting that FAM210A mediated mitochondrial translation regulatory pathway can be a potential therapeutic target for ischemic heart disease.
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Dilated cardiomyopathy variant R14del increases phospholamban pentamer stability, blunting dynamic regulation of cardiac calcium handling.
bioRxiv2023 May;():. doi: 2023.05.26.542463.
Cleary Sean R, Teng Allen C T, Kongmeneck Audrey Deyawe, Fang Xuan, Phillips Taylor A, Cho Ellen E, Kekenes-Huskey Peter, Gramolini Anthony O, Robia Seth L,
Abstract
The sarco(endo)plasmic reticulum Ca ATPase (SERCA) is a membrane transporter that creates and maintains intracellular Ca stores. In the heart, SERCA is regulated by an inhibitory interaction with the monomeric form of the transmembrane micropeptide phospholamban (PLB). PLB also forms avid homo-pentamers, and dynamic exchange of PLB between pentamers and the regulatory complex with SERCA is an important determinant of cardiac responsiveness to exercise. Here, we investigated two naturally occurring pathogenic mutations of PLB, a cysteine substitution of arginine 9 (R9C) and an in-frame deletion of arginine 14 (R14del). Both mutations are associated with dilated cardiomyopathy. We previously showed that the R9C mutation causes disulfide crosslinking and hyperstabilization of pentamers. While the pathogenic mechanism of R14del is unclear, we hypothesized that this mutation may also alter PLB homo-oligomerization and disrupt the PLB-SERCA regulatory interaction. SDS-PAGE revealed a significantly increased pentamer:monomer ratio for R14del-PLB when compared to WT-PLB. In addition, we quantified homo-oligomerization and SERCA-binding in live cells using fluorescence resonance energy transfer (FRET) microscopy. R14del-PLB showed an increased affinity for homo-oligomerization and decreased binding affinity for SERCA compared to WT, suggesting that, like R9C, the R14del mutation stabilizes PLB in its pentameric form, decreasing its ability to regulate SERCA. Moreover, the R14del mutation reduces the rate of PLB unbinding from the pentamer after a transient Ca elevation, limiting the rate of re-binding to SERCA. A computational model predicted that hyperstabilization of PLB pentamers by R14del impairs the ability of cardiac Ca handling to respond to changing heart rates between rest and exercise. We postulate that impaired responsiveness to physiological stress contributes to arrhythmogenesis in human carriers of the R14del mutation.
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Native T1 high region and left ventricular ejection fraction recovery in patients with dilated cardiomyopathy.
Int J Cardiovasc Imaging2023 Jun;():. doi: 10.1007/s10554-023-02888-w.
Yazaki Mayu, Nabeta Takeru, Takigami Yu, Eda Yuko, Maemura Kenji, Oki Takumi, Fujita Teppei, Iida Yuichiro, Ikeda Yuki, Ishii Shunsuke, Inoue Yusuke, Ako Junya,
Abstract
Native T1 mapping is used to assess myocardial tissue characteristics without gadolinium contrast agents. The focal T1 high-intensity region can indicate myocardial alterations. This study aimed to identify the association between the native T1 mapping including the native T1 high region and left ventricular ejection fraction (LVEF) recovery in patients with dilated cardiomyopathy (DCM). Patients with newly diagnosed DCM (LVEF of 45%) who underwent cardiac magnetic resonance imaging with native T1 mapping were included in the analysis. Native T1 high region was defined as a signal intensity of >?5 SD in the remote myocardium. Recovered EF was defined as a follow-up LVEF of ??45% and an LVEF increase of ??10% after 2 years from baseline. Seventy-one patients met the inclusion criteria for this study. Forty-four patients (61.9%) achieved recovered EF. Logistic regression analysis showed that the native T1 value (OR: 0.98; 95% CI: 0.96-0.99; P?=?0.014) and the native T1 high region (OR: 0.17; 95% CI: 0.05-0.55; P?=?0.002), but not late gadolinium enhancement, were independent predictors of recovered EF. Compared with native T1 value alone, combined native T1 high region and native T1 value improved the area under the curve from 0.703 to 0.788 for predicting recovered EF. Myocardial damage, which was quantified using native T1 mapping and the native T1 high region were independently associated with recovered EF in patients with newly diagnosed DCM.
© 2023. The Author(s).
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A Kaposi's sarcoma-associated herpes virus-encoded microRNA contributes to dilated cardiomyopathy.
Signal Transduct Target Ther2023 Jun;8(1):226. doi: 10.1038/s41392-023-01434-3.
Zhao Yanru, Li Huaping, Du Hengzhi, Yin Zhongwei, He Mengying, Fan Jiahui, Nie Xiang, Sun Yang, Hou Huiying, Dai Beibei, Zhang Xudong, Cai Yuanyuan, Jin Kunying, Ding Nan, Wen Zheng, Chang Jiang, Chen Chen, Wang Dao Wen,
Abstract
Dilated cardiomyopathy (DCM) is the leading cause of heart transplantation. By microRNA (miRNA) array, a Kaposi's sarcoma-associated herpes virus (KSHV)-encoded miRNA, kshv-miR-K12-1-5p, was detected in patients with DCM. The KSHV DNA load and kshv-miR-K12-1-5p level in plasma from 696 patients with DCM were measured and these patients were followed-up. Increased KSHV seropositivity and quantitative titers were found in the patients with DCM compared with the non-DCM group (22.0% versus 9.1%, p?0.05; 168 versus 14 copies/mL plasma, p?0.05). The risk of the individual end point of death from cardiovascular causes or heart transplantation was increased among DCM patients with the KSHV DNA seropositivity during follow-up (adjusted hazard ratio 1.38, 95% confidence interval 1.01-1.90; p?0.05). In heart tissues, the KSHV DNA load was also increased in the heart from patients with DCM in comparison with healthy donors (1016 versus 29 copies/10 cells, p?0.05). The KSHV and kshv-miR-K12-1-5p in DCM hearts were detected using immunofluorescence and fluorescence staining in situ hybridization. KSHV itself was exclusively detectable in CD31-positive endothelium, while kshv-miR-K12-1-5p could be detected in both endothelium and cardiomyocytes. Moreover, kshv-miR-K12-1-5p released by KSHV-infected cardiac endothelium could disrupt the type I interferon signaling pathway in cardiomyocytes. Two models of kshv-miR-K12-1-5p overexpression (agomiR and recombinant adeno-associated virus) were used to explore the roles of KSHV-encoded miRNA in vivo. The kshv-miR-K12-1-5p aggravated known cardiotropic viruses-induced cardiac dysfunction and inflammatory infiltration. In conclusion, KSHV infection was a risk factor for DCM, providing developmental insights of DCM involving virus and its miRNA ( https://clinicaltrials.gov . Unique identifier: NCT03461107).
© 2023. The Author(s).
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Treatment Strategies for Cardiomyopathy in Children: A Scientific Statement From the American Heart Association.
Circulation2023 Jun;():. doi: 10.1161/CIR.0000000000001151.
Bogle Carmel, Colan Steven D, Miyamoto Shelley D, Choudhry Swati, Baez-Hernandez Nathanya, Brickler Molly M, Feingold Brian, Lal Ashwin K, Lee Teresa M, Canter Charles E, Lipshultz Steven E, ,
Abstract
This scientific statement from the American Heart Association focuses on treatment strategies and modalities for cardiomyopathy (heart muscle disease) in children and serves as a companion scientific statement for the recent statement on the classification and diagnosis of cardiomyopathy in children. We propose that the foundation of treatment of pediatric cardiomyopathies is based on these principles applied as personalized therapy for children with cardiomyopathy: (1) identification of the specific cardiac pathophysiology; (2) determination of the root cause of the cardiomyopathy so that, if applicable, cause-specific treatment can occur (precision medicine); and (3) application of therapies based on the associated clinical milieu of the patient. These clinical milieus include patients at risk for developing cardiomyopathy (cardiomyopathy phenotype negative), asymptomatic patients with cardiomyopathy (phenotype positive), patients with symptomatic cardiomyopathy, and patients with end-stage cardiomyopathy. This scientific statement focuses primarily on the most frequent phenotypes, dilated and hypertrophic, that occur in children. Other less frequent cardiomyopathies, including left ventricular noncompaction, restrictive cardiomyopathy, and arrhythmogenic cardiomyopathy, are discussed in less detail. Suggestions are based on previous clinical and investigational experience, extrapolating therapies for cardiomyopathies in adults to children and noting the problems and challenges that have arisen in this experience. These likely underscore the increasingly apparent differences in pathogenesis and even pathophysiology in childhood cardiomyopathies compared with adult disease. These differences will likely affect the utility of some adult therapy strategies. Therefore, special emphasis has been placed on cause-specific therapies in children for prevention and attenuation of their cardiomyopathy in addition to symptomatic treatments. Current investigational strategies and treatments not in wide clinical practice, including future direction for investigational management strategies, trial designs, and collaborative networks, are also discussed because they have the potential to further refine and improve the health and outcomes of children with cardiomyopathy in the future.
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Single coronary artery presenting dilated cardiomyopathy and hyperlipidemia with the and gene mutation: A case report and review of the literature.
Front Cardiovasc Med2023 ;10():1113886. doi: 1113886.
Hu Xiaoxia, Kong Jing, Niu Tingting, Chen Liang, Yang Jingjing,
Abstract
We present a 55-year-old man with chest tightness and dyspnoea after activity lasting for 2 months who was diagnosed with single coronary artery (SCA) and presented with dilated cardiomyopathy (DCM) with the c.1858C?>?T mutation in the gene. The computed tomography coronary angiogram (CTCA) showed congenital absence of the right coronary artery (RCA), and the right heart was nourished by the left coronary artery branch with no apparent stenosis. Transthoracic echocardiography (TTE) revealed enlargement of the left heart and cardiomyopathy. Cardiac magnetic resonance imaging (CMR) revealed DCM. Genetic testing showed that the c.1858C?>?T variant of the gene could lead to Brugada syndrome and DCM. SCA is a rare congenital anomaly of the coronary anatomy, and this case reported as SCA accompanied by DCM is even rarer. We present a rare case of a 55-year-old man with DCM with the c.1858C?>?T (p. Arg620Cys)/c.1008G?>?A (p.(Pro336=) variant of the gene, congenital absence of RCA, and c.990_993delAACA (p. Asp332Valfs*5) variant of the gene. To our knowledge, this is the first report of DCM combined with the gene mutation in SCA after searching the PubMed, CNKI and Wanfang databases.
© 2023 Hu, Kong, Niu, Chen and Yang.
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Midterm Outcome of Hybrid Transcatheter and Minimally Invasive Left Ventricular Reconstruction for the Treatment of Ischemic Heart Failure.
Struct Heart2022 Oct;6(5):100081. doi: 100081.
Hegeman Romy R M J J, Swaans Martin J, Van Kuijk Jan-Peter, Klein Patrick,
Abstract
BACKGROUND:
Left ventricular (LV) remodeling after anterior myocardial infarction (AMI) can cause a pathological increase in LV volume, reduction in LV ejection fraction (EF), and symptomatic heart failure (HF). This study evaluates the midterm results of a hybrid transcatheter and minimally invasive surgical technique to reconstruct the negatively remodeled LV by myocardial scar plication and exclusion with microanchoring technology.
METHODS:
Retrospective single-center analysis of patients who underwent hybrid LV reconstruction (LVR) with the Revivent TransCatheter System. Patients were accepted for the procedure when they presented with symptomatic HF (New York Heart Association class ? II, EF
RESULTS:
Between October 2016 and November 2021, 30 consecutive patients were operated. Procedural success was 100%. Comparing echocardiographic data preoperatively and directly postoperatively, LVEF increased from 33 ± 8% to 44 ± 10% (
CONCLUSIONS:
Hybrid LVR for symptomatic HF after AMI is safe and results in significant improvement in EF, reduction in LV volumes, and sustained improvement in symptoms.
© 2022 The Author(s).
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Risk factors of sudden cardiac death in Egyptian patients younger than 40 years.
Egypt Heart J2023 Jun;75(1):45. doi: 45.
Ali Ahmed Nabil, Abdeltawab Hend Ali, Eldamanhoury Hayam, Aboulmaaty Mervat,
Abstract
BACKGROUND:
Sudden cardiac death in young people is a major problem. The causes are well known; however, they may not be discovered before the episode of sudden death. A challenge for the future is identifying patients at risk before an episode of sudden cardiac death. Development of preventive and educational programs is required to identify sudden cardiac death/sudden cardiac arrest (SCD/SCA) risk factors, causes and characteristics. We aimed to study the characteristics of SCD/SCA in a cohort of young Egyptian population. Our retrospective cohort study included 246 patients of SCD/SCA who were collected from 5000 records of arrhythmia patients from January 2010 till January 2020. The records of the specialized arrhythmia clinic were reviewed to collect the families of SCD/SCA. All patients and/or their first-degree relatives were subjected to thorough history taking and clinical evaluation and investigations. Comparisons were done regarding age group and presence of positive family history of SCD.
RESULTS:
Males constituted 56.9% of the study population. Mean age was 26.6?±?12.73 years. Positive family history was present in 202 (82.1%) cases. Sixty-one percent of the cases had history of syncopal attacks. SCD/SCA during non-exertion or sleep occurred in 50.4% of cases. Hypertrophic cardiomyopathy was the most common cause of SCD/SCA (20.3%), followed by dilated cardiomyopathy (19.1%), long QT Syndrome (11.4%), complete heart block (8.5%), and Brugada syndrome (6.8%). In the older age group of 18-40 years, hypertrophic cardiomyopathy was responsible for SCD in 44 patients (25.3%) versus 6 patients (8.3%) in younger age group (p-value: 0.003). DCM was also dominant in older age group (42 patients; 24.1%) versus 5 patients (6.9%) in younger age group. Hypertrophic cardiomyopathy was more prevalent in positive family history group (46 patients; 22.8%) versus 4 patients (9.1%) in negative family history group (p-value: 0.041).
CONCLUSION:
Family history of SCD was the most common risk factor of SCD. The most common cause of SCD in young Egyptian patients below 40 years was hypertrophic cardiomyopathy, followed by dilated cardiomyopathy. Both diseases were more common in the age group between 18 and 40 years. Hypertrophic cardiomyopathy was more common in patients with positive family history of SCD/SCA.
© 2023. The Author(s).
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Non-sustained Ventricular Tachycardia as a Presentation of Arrhythmogenic Right Ventricular Cardiomyopathy.
Cureus2023 May;15(5):e38620. doi: e38620.
Amin Adina, Bailey Nadian, Warren Amanda, Reddy Bharath,
Abstract
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a rare disorder with familial (autosomal dominant) predisposition and can be challenging to diagnose. Non-sustained ventricular tachycardia (NSVT) is a relatively uncommon and short-lived arrhythmia when seen in the general, healthy population. NSVT with a left bundle branch block morphology is usually idiopathic but may also be seen in ARVC. It can also be associated with poorer prognosis and increased mortality. Repetitive monomorphic ventricular ectopic beats may suggest ARVC, but could also be idiopathic. Timely diagnosis is vital due to the unpredictability and progressive nature of ARVC. We present a case of a 40-year-old Caucasian female with heart palpitations and NSVT found on an outpatient Holter monitor, and later found to have clinical and radiological features consistent with ARVC.
Copyright © 2023, Amin et al.
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Transcatheter Tricuspid Valve Replacement With a Dedicated Device in a Patient With 2 Endocardial Leads.
JACC Case Rep2023 Jun;15():101848. doi: 101848.
Estevez-Loureiro Rodrigo, Barreiro-Pérez Manuel, Piñon Miguel, González Rocío, Dobarro David, Modine Thomas, Cheung Anson, Baz-Alonso Jose A, Caneiro-Queija Berenice, Íñiguez-Romo Andrés,
Abstract
A 79-year-old woman with a history of dilated cardiomyopathy who required a permanent peacemaker, recently upgraded to implantable cardioverter-defibrillator cardiac resynchronization therapy, was admitted for right heart failure. On echocardiography, torrential tricuspid regurgitation was noted, with 2 leads across the valve. After multidisciplinary evaluation, a dedicated transcatheter valve replacement was successfully implanted. ().
© 2023 The Authors.
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Editorial: Case reports in thrombosis: 2022.
Front Cardiovasc Med -
Implantable cardioverter defibrillator for primary prevention in patients with non-ischemic cardiomyopathy in the era of novel therapeutic agents- meta-analysis.
Front Cardiovasc Med2023 ;10():1192101. doi: 1192101.
Kolben Yotam, Hirsh Raccah Bruria, Koev Ivelin, Luria David, Amir Offer, Biton Yitschak,
Abstract
BACKGROUND:
Evidence regarding the mortality benefit of implantable cardioverter defibrillator (ICD) non-ischemic dilated cardiomyopathy (NIDCM) is inconsistent. The most recent randomized study, the DANISH trial, did not find improved outcomes with ICD. However, based on previous studies and meta-analyses, current guidelines still highly recommend ICD implantation in NIDCM patients. The introduction of novel medications for heart failure improved the clinical outcome dramatically. We aimed in this study to evaluate the effect of Angiotensin Receptor-Neprilysin Inhibitors (ARNi) and sodium-glucose transport protein 2 inhibitors (SGLT2i) on the mortality benefit of ICD in NIDCM.
METHODS:
We used a previous metanalysis algorithm and added an updated comprehensive literature search in PubMed for randomized control trials that examined the mortality benefit of ICD in NIDCM vs. optimal medical treatment. The primary outcome included death from any cause. We did a meta-regression analysis to search for a single independent factor affecting mortality. Using previous data, we evaluated the theoretical effect of ICD implementation on patients treated with SGLT2 inhibitors and ARNi.
RESULTS:
No new articles were added to the results of the previous meta-analysis. 2,622 patients with NIDCM from 5 cohort studies published between 2002 and 2016 were included in the analysis. 50% of them underwent ICD implantation for primary prevention of sudden cardiac death, and 50% did not. ICD was associated with a significantly decreased risk for death from any cause compared to control (OR?=?0.79, 95%CI: 0.66-0.95, ?=?0.01, ?=?0%). The theoretical addition of ARNi and the SGLT2 inhibitor dapagliflozin did not change the significant mortality effect of ICD (OR?=?0.82, 95%CI: 0.7-0.9, ?=?0.001, ?=?0%) and (OR?=?0.82, 95%CI: 0.7-0.9, ?=?0.001, ?=?0%). A meta-regression revealed no association between death from any cause and left bundle branch block (LBBB), use of amiodarone, use of angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers, year initiated enrollment, and the year ended enrollment (?=?0.0).
CONCLUSION:
In patients with NIDCM, the addition of ARNi and SGLT2i did not affect the mortality advantages of ICD for primary prevention.
PROSPERO REGISTRY NUMBER:
https://www.crd.york.ac.uk/prospero/, identifier: CRD42023403210.
© 2023 Kolben, Hirsh Raccah, Koev, Luria, Amir and Biton.
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Diagnostic yield and predictive value on left ventricular remodelling of genetic testing in dilated cardiomyopathy.
ESC Heart Fail2023 Jun;():. doi: 10.1002/ehf2.14395.
Bertero Edoardo, Fracasso Giulia, Eustachi Virginia, Coviello Domenico, Cecconi Massimiliano, Giovinazzo Stefano, Toma Matteo, Merlo Marco, Sinagra Gianfranco, Porto Italo, Ameri Pietro, Canepa Marco,
Abstract
AIMS:
We assessed the diagnostic yield of genetic testing and the relationship of left ventricular (LV) reverse remodelling (LVRR) with the presence of DNA pathogenic (P) or likely pathogenic (LP) variants in patients with dilated cardiomyopathy (DCM).
METHODS AND RESULTS:
From 680 outpatients followed at the Heart Failure Outpatient Clinic of our institution, we selected subjects with a diagnosis of DCM as defined by LV ejection fraction (LVEF) ?40% and LV dilatation not explained by coronary artery disease or other causes. All patients were offered genetic investigation of 42 disease-associated DCM genes with next-generation sequencing. Seventy patients fulfilled the definition of DCM and 66 underwent genetic investigation. We identified 18 P/LP variants in 16 patients, with a diagnostic yield of 24%. The most common variants were truncating TTN variants (n = 7), followed by LMNA (n = 3), cytoskeleton Z-disc (n = 3), ion channel (n = 2), motor sarcomeric (n = 2), and desmosomal (n = 1) genes. After a median follow-up of 53 months (inter-quartile range 20-111), patients without P/LP variants exhibited higher systolic and diastolic blood pressure, lower plasma brain natriuretic peptide levels, and a larger extent of LVRR, as reflected by the increase in LVEF (+14% vs. +1%, P = 0.0008) and decrease in indexed LV end-diastolic diameter (-6.5 vs. -2 mm/m , P = 0.03) compared with patients with P/LP variants.
CONCLUSIONS:
Our results confirm the high diagnostic yield of genetic testing in selected DCM patients and suggest that identification of P/LP variants in DCM portends poorer LVRR in response to guideline-directed medical therapy.
© 2023 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.
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Cardiac sympathetic activity and relationship to cardiac events and left ventricular reverse remodeling in patients with non-ischemic dilated cardiomyopathy.
Ann Nucl Med2023 Jun;():. doi: 10.1007/s12149-023-01838-9.
Mizutani Takashi, Morimoto Ryota, Isobe Satoshi, Ito Ryota, Araki Takashi, Kimura Yuki, Kazama Shingo, Oishi Hideo, Kuwayama Tasuku, Hiraiwa Hiroaki, Kondo Toru, Okumura Takahiro, Murohara Toyoaki,
Abstract
BACKGROUND:
Delayed heart-to-mediastinum ratio (HMR) has been associated with catecholamine levels and contractile reserve in dilated cardiomyopathy (DCM); however, there is scant evidence regarding the association between cardiac sympathetic activity and left ventricular reverse remodeling (LV-RR). We calculated the I-metaiodobenzylguanidine (I-mIBG) HMR and washout rate (WR) in patients with DCM and investigated their associations with LV-RR.
METHODS:
From April 2003 to January 2020, in 120 patients with DCM who underwent I-mIBG scintigraphy. 66 patients undergoing follow-up echo and taking a beta-blocker from baseline were examined the relationship between I-mIBG and LV-RR. After that, this prognostic value for composite cardiac events was evaluated in the entire 120 patients.
RESULTS:
In LV-RR analysis, patients were 50.4?±?12.2 years, with a mean left ventricular ejection fraction of 28.6%. Of 66 patients, 28 (42.4%) achieved LV-RR. Multiple logistic regression analysis of LV-RR revealed that not delayed HMR but the WR (cutoff value: 13.5%) was an independent predictor of LV-RR (odds ratio 6.514, p?=?0.002). In the analysis for composite cardiac events, even though WR itself does not have the prognostic capacity, Kaplan-Meier survival curves divided by the cutoff value (delayed HMR?=?2.0, WR?=?13.5) showed that delayed HMR and WR values enabled the stratification of high-risk patients (log-rank p?0.001).
CONCLUSIONS:
The I-mIBG WR was associated with the prevalence of LV-RR in patients taking 100% of beta-blockers and 98.5% of renin-angiotensin system inhibitors. Reflecting the contractile reserve, the combined assessment of the delayed HMR and WR could be used to further precisely stratify the patients with DCM.
© 2023. The Author(s) under exclusive licence to The Japanese Society of Nuclear Medicine.
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Left Bundle Branch Block-Induced Cardiomyopathy.
Turk Kardiyol Dern Ars2023 Jun;51(4):274-282. doi: 10.5543/tkda.2023.06737.
Murat Selda, Çavu?o?lu Yüksel,
Abstract
Left bundle branch block-induced cardiomyopathy is an increasingly recognized type of dilated cardiomyopathy identi?ed in a minority but not negligible proportion of patients with newly diagnosed heart failure. However, it has not yet been included among the possible etiologies of dilated cardiomyopathies or among the unclassi?ed cardiomyopathies. Although a few sets of diagnostic criteria have been proposed, currently there is a lack of universal consensus regarding diagnostic criteria. Some speci?c clinical features and electrocardiography, echocardiography, and cardiac magnetic resonance imaging ?ndings are recommended to help physicians in the diagnosis of left bundle branch block-induced cardiomyopathy. In this review, prevalence, pathophysiological mechanisms, diagnostic criteria, diagnostic modalities, and speci?c features of left bundle branch block-induced cardiomyopathy have been addressed with attention to the di?erential diagnosis of other dilated cardiomyopathies.
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Cardiomyopathy-associated variants alter the structure and function of the ?-actinin-2 actin-binding domain.
Biochem Biophys Res Commun2023 May;670():12-18. doi: 10.1016/j.bbrc.2023.05.050.
Atang Alexandra E, Rebbeck Robyn T, Thomas David D, Avery Adam W,
Abstract
Hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), and restrictive cardiomyopathy (RCM) are characterized by thickening, thinning, or stiffening, respectively, of the ventricular myocardium, resulting in diastolic or systolic dysfunction that can lead to heart failure and sudden cardiac death. Recently, variants in the ACTN2 gene, encoding the protein ?-actinin-2, have been reported in HCM, DCM, and RCM patients. However, functional data supporting the pathogenicity of these variants is limited, and potential mechanisms by which these variants cause disease are largely unexplored. Currently, NIH ClinVar lists 34 ACTN2 missense variants, identified in cardiomyopathy patients, which we predict are likely to disrupt actin binding, based on their localization to specific substructures in the ?-actinin-2 actin binding domain (ABD). We investigated the molecular consequences of three ABD localized, HCM-associated variants: A119T, M228T and T247 M. Using circular dichroism, we demonstrate that the mutant ABD proteins can attain a well-folded state. However, thermal denaturation studies show that all three mutations are destabilizing, suggesting a structural disruption. Importantly, A119T decreased actin binding, and M228T and T247M cause increased actin binding. We suggest that altered actin binding underlies pathogenesis for cardiomyopathy mutations localizing to the ABD of ?-actinin-2.
Copyright © 2023 Elsevier Inc. All rights reserved.
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Prognostic role of circulating LTBP-2 in patients with dilated cardiomyopathy: a novel biomarker reflecting extracellular matrix LTBP-2 accumulation.
Can J Cardiol2023 Jun;():. doi: S0828-282X(23)00445-2.
Nishiura Kazuto, Yokokawa Tetsuro, Misaka Tomofumi, Ichimura Shohei, Tomita Yusuke, Miura Shunsuke, Shimizu Takeshi, Sato Takamasa, Kaneshiro Takashi, Oikawa Masayoshi, Kobayashi Atsushi, Yoshihisa Akiomi, Takeishi Yasuchika,
Abstract
INTRODUCTION:
Dilated cardiomyopathy (DCM) is a life-threatening disease related to heart failure. Extracellular matrix proteins have an important role in the pathogenesis of DCM. Latent transforming growth factor beta-binding protein 2 (LTBP-2), a type of extracellular matrix protein, has not been investigated in DCM.
METHODS:
Firstly, we compared plasma LTBP-2 levels in 131 DCM patients who underwent endomyocardial biopsy and 44 controls who were matched for age and sex and had no cardiac abnormalities. Next, we performed immunohistochemistry for LTBP-2 on endomyocardial biopsy specimens and followed the DCM patients for ventricular assist device (VAD) implantation, cardiac death, and all-cause death.
RESULTS:
DCM patients had elevated plasma LTBP-2 levels compared to controls (P
CONCLUSIONS:
Circulating LTBP-2 can serve as a biomarker to predict adverse outcomes, reflecting extracellular matrix LTBP-2 accumulation in the myocardium in DCM.
Copyright © 2023. Published by Elsevier Inc.
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Only one beer can be mortal: a case report of two sisters with cardiac arrest due to a homozygous mutation in PPA2 gene.
Eur J Pediatr2023 Jun;():. doi: 10.1007/s00431-023-05034-9.
Manzanilla-Romero Héctor Hugo, Schermer Elisabeth, Mayr Agnes, Rudnik-Schöneborn Sabine,
Abstract
We report the long way to the correct diagnosis in two teenage sisters who developed a cardiac arrest after consuming minimal amounts of alcohol. The older girl dramatically survived two cardiac arrests at the age of 14 and 15 years. She underwent an extensive examination that revealed isolated cardiac abnormalities including fibrosis, dilated cardiomyopathy and inflammation. The younger girl also had a cardiac arrest at the age of 15 and died suddenly after consuming 1-2 beers, 3 years after her sister´s first incident. Autopsy of the heart revealed acute myocarditis without structural alterations. Multigene panel analysis (not including PPA2) showed SCN5A and CACNA1D variants in both sisters and their healthy mother. Six years later duo exome allowed the diagnosis of an autosomal recessive PPA2-related mitochondriopathy. We discuss the molecular results and clinical picture of our patients compared to other PPA2-related cases. We highlight the diagnostic contribution of multigene panels and exome analysis. The genetic diagnosis is important for medical care and for everyday life, specifically because alcohol intake can result in cardiac arrest and should be strictly avoided. Conclusion: Duo exome sequencing clarified the diagnosis of PPA2-related mitochondriopathy in two sisters with isolated cardiac features and sudden cardiac arrest triggered by minimal amounts of alcohol. What is Known: ? Multigene-Panel or exome analysis is a valuable tool to identify genetic causes of hereditary cardiac arrhythmias. ? Variants of unknown significance can lead to misinterpretation. PPA2-related mitochondriopathy is a very rare autosomal recessive condition that is normally fatal in infancy. What is New: ? Duo exome analysis in two teeenage sisters with cardiac arrest revealed a homozygous mild PPA2 mutation as the underlying pathology restricted to the heart muscle.
© 2023. The Author(s).
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Integrated bioinformatics analysis for identifying key genes and pathways in female and male patients with dilated cardiomyopathy.
Sci Rep2023 Jun;13(1):8977. doi: 8977.
Zhang Min, Wang Xinzhou, Chen Wenbo, Liu Wei, Xin Jile, Yang Debao, Zhang Zhongyuan, Zheng Xiaoke,
Abstract
Dilated cardiomyopathy (DCM) is a common cause of heart failure, and males are more likely to suffer from DCM than females. This research aimed at exploring possible DCM-associated genes and their latent regulatory effects in female and male patients. WGCNA analysis found that in the yellow module, 341 and 367 key DEGs were identified in females and males, respectively. A total of 22 hub genes in females and 17 hub genes in males were identified from the PPI networks of the key DEGs based on Metascape database. And twelve and eight potential TFs of the key DEGs were also identified in females and males, respectively. Eight miRNAs of 15 key DEGs were screened in both females and males, which may be differentially expressed in females and males. Dual-luciferase reporter assay demonstrated that miR-21-5P could directly target the key gene MATN2. Furthermore, Sex differences in KEGG pathways were identified. Both KOBAS and GSEA analysis identified 19 significantly enriched pathways related to immune response in both females and males, and the TGF-? signaling pathway was exclusively identified in males. Network pharmacology analysis revealed that seven key DEGs were potential targets for the treatment of DCM, of which the OLR1 gene was only identified in males, the expression levels of the seven genes were verified by RT-PCR. The above results could offer a novel understanding of sex differences in key genes and pathways in DCM progression.
© 2023. The Author(s).
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The important role of miR-770 as a novel potential diagnostic and therapeutic target for human cancer and other diseases.
Pathol Res Pract2023 May;248():154586. doi: 10.1016/j.prp.2023.154586.
Khalilian Sheyda, Hosseini Imani Seyedeh Zahra, Hosseini Sayedeh Azimeh, Ghafouri-Fard Soudeh,
Abstract
MicroRNA-770 (miR-770) is an RNA gene, located on chromosome 14q32.2. It has important effects on the pathobiology of cancers and other human diseases. It is known to be a tumor suppressor in breast cancer, ovarian cancer, gastric cancer, non-small cell lung cancer, prostate cancer, and glioblastoma. In colorectal adenocarcinoma and oral squamous cell carcinoma, miR-770 is regarded as an oncogenic miRNA. In several disorders, miR-770 dysregulation has been recognized as a potential biomarker for disease diagnosis and prognosis. Dysregulation of miR-770 has also been demonstrated in non-malignant human disorders, including Alzheimer's disease, dilated cardiomyopathy, diabetic nephropathy, Hirschsprung's disease, osteoarthritis, silicosis, and type 2 diabetes mellitus. In the current review, we have obtained the miR-770 target genes, ontology, and related pathways. We have also provided a comprehensive review of miR-770 in both malignant and non-malignant disorders and explained its possible therapeutic implications.
Copyright © 2023 Elsevier GmbH. All rights reserved.
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