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1.
Artigo em Inglês | MEDLINE | ID: mdl-33151750

RESUMO

Background - The X-linked Danon disease (DD) manifests by severe cardiomyopathy, myopathy, and neuropsychiatric problems. We designed this registry to generate a comprehensive picture of clinical presentations and outcome of patients with Danon disease (DD) in cardiomyopathy centers throughout Europe. Methods - Clinical and genetic data were collected in 16 cardiology centers from 8 European countries. Results - The cohort comprised 30 male and 27 female patients. The age at diagnosis was birth to 42 yr. in males and 2-65 in females. Cardiac involvement was observed in 96%. Extracardiac manifestations were prominent in males but not in females. Left ventricular (LV) hypertrophy was reported in 73% of male and 74% of female patients. LV systolic dysfunction was reported in 40% of males (who had LVEF 34±11%) and 59% of females (LVEF 28±13%). The risk of arrhythmia and heart failure (HF) were comparable among genders. The age of first HF hospitalization was lower in males (18 ± 6 vs. 28 ±17 yr., p<0.003). HF was the leading cause of death (10/17, 59%), and LV systolic dysfunction predicted an adverse outcome. Eight males and 8 females (28%) underwent heart transplantation or received a left ventricular assist device (LVAD). Our cohort suggests better prognosis of female compared to male heart transplant recipients. Conclusions - DD presents earlier in males than females and runs a malignant course in both genders, due to cardiac complications. Cardiomyopathy features: heart failure and arrhythmia, are similar among the genders. Clinical diagnosis and management is extremely challenging in females due to phenotypic diversity and absence of extracardiac manifestations.

2.
J Muscle Res Cell Motil ; 41(2-3): 251-258, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32902830

RESUMO

Homozygous calsequestrin 2 (CASQ2) point mutations leads to catecholaminergic polymorphic ventricular tachycardia: a common pathogenetic feature appears to be the drastic reduction of mutant CASQ2 in spite of normal transcription. Comparative biochemical analysis of R33Q and D307H knock in mutant mice identifies different pathogenetic mechanisms for CASQ2 degradation and different molecular adaptive mechanisms. In particular, each CASQ2 point mutation evokes specific adaptive cellular and molecular processes in each of the four adaptive pathways investigated. Thus, similar clinical phenotypes and identical cellular mechanism for cardiac arrhythmia might imply different molecular adaptive mechanisms.

3.
Am J Med Sci ; 360(4): 392-401, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32631573

RESUMO

BACKGROUND: The impact of sex on mortality in patients with acute heart failure (AHF) is unresolved. We aimed to investigate the impact of sex on both short- and long-term mortality outcomes after hospitalization for AHF. METHODS: We analyzed data of 2,328 patients with AHF who were enrolled in the multicenter national survey in Israel between March and April 2003 and followed up until December 2014. RESULTS: Women comprised 45% of the study population. In comparison with men, women were older, had higher rates of heart failure with preserved ejection fraction as well as hypertensive heart disease and had a lower rate of coronary artery disease (all P < 0.001). Survival analysis showed that at 1 year the rate of all-cause mortality was 31% among women compared to 28% among men (P = 0.19). At 10-year follow-up mortality rates were significantly higher among women compared to men (87% vs. 83%, P = 0.048). However, this sex association disappeared once multivariable analysis was carried out, (hazard ratio [HR] = 0.93; CI = 0.79-1.09, P = 0.36). Renal dysfunction, older age and severe heart failure were consistent independent predictors of mortality among men and women. Hyponatremia was a prognostic predictor only among men, whereas digoxin use predicted mortality only among women. CONCLUSIONS: There are important differences in the clinical characteristics between women and men hospitalized with AHF. There were no significant differences in both short- and long-term mortality following multivariable analysis. Although, most independent predictors of mortality were consistent among both sexes, few sex-based differences in prognostic predictors were identified.


Assuntos
Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/mortalidade , Mortalidade Hospitalar/tendências , Caracteres Sexuais , Idoso , Feminino , Insuficiência Cardíaca/etiologia , Hospitalização/estatística & dados numéricos , Humanos , Hiponatremia/etiologia , Hiponatremia/mortalidade , Israel/epidemiologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Fatores de Risco , Fatores Sexuais , Inquéritos e Questionários , Análise de Sobrevida
4.
J Am Coll Cardiol ; 76(2): 186-197, 2020 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-32646569

RESUMO

BACKGROUND: PRKAG2 gene variants cause a syndrome characterized by cardiomyopathy, conduction disease, and ventricular pre-excitation. Only a small number of cases have been reported to date, and the natural history of the disease is poorly understood. OBJECTIVES: The aim of this study was to describe phenotype and natural history of PRKAG2 variants in a large multicenter European cohort. METHODS: Clinical, electrocardiographic, and echocardiographic data from 90 subjects with PRKAG2 variants (53% men; median age 33 years; interquartile range [IQR]: 15 to 50 years) recruited from 27 centers were retrospectively studied. RESULTS: At first evaluation, 93% of patients were in New York Heart Association functional class I or II. Maximum left ventricular wall thickness was 18 ± 8 mm, and left ventricular ejection fraction was 61 ± 12%. Left ventricular hypertrophy (LVH) was present in 60 subjects (67%) at baseline. Thirty patients (33%) had ventricular pre-excitation or had undergone accessory pathway ablation; 17 (19%) had pacemakers (median age at implantation 36 years; IQR: 27 to 46 years), and 16 (18%) had atrial fibrillation (median age 43 years; IQR: 31 to 54 years). After a median follow-up period of 6 years (IQR: 2.3 to 13.9 years), 71% of subjects had LVH, 29% had AF, 21% required de novo pacemakers (median age at implantation 37 years; IQR: 29 to 48 years), 14% required admission for heart failure, 8% experienced sudden cardiac death or equivalent, 4% required heart transplantation, and 13% died. CONCLUSIONS: PRKAG2 syndrome is a progressive cardiomyopathy characterized by high rates of atrial fibrillation, conduction disease, advanced heart failure, and life-threatening arrhythmias. Classical features of pre-excitation and severe LVH are not uniformly present, and diagnosis should be considered in patients with LVH who develop atrial fibrillation or require permanent pacemakers at a young age.

5.
Int J Cardiol ; 317: 133-138, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32532510

RESUMO

BACKGROUND: Filamin C is a cytoskeletal protein expressed in cardiac cells. Nonsense variations in the filamin C gene (FLNC) were associated with dilated and arrhythmogenic cardiomyopathies. METHODS AND RESULTS: We identified an intronic variation in FLNC gene (c.3791-1G > C) in three unrelated Ashkenazi Jewish families with variable expression of arrhythmia and cardiomyopathy. cDNA was prepared from a mutation carrier's cultured skin fibroblasts. Quantitative PCR demonstrated a reduction in total FLNC transcript, and no other FLNC splice variants were found. Single-nucleotide polymorphism (SNP) analysis revealed heterozygous variations in the genomic DNA that were not expressed in the messenger RNA. Immunohistochemical analysis of cardiac sections detected a normal distribution of filamin C protein in the heart ventricles. CONCLUSION: The transcript that included the FLNC variant was degraded. Haploinsufficiency in filamin C underlies arrhythmogenic cardiomyopathy with variable symptoms.

6.
Clin Transplant ; 34(7): e13887, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32367594

RESUMO

OBJECTIVE: Heart transplantation (HT) is uniquely associated with the potential impact of thyroid hormone therapy at three intersecting levels-donor, operation, and recipient. We aimed to study the effect of thyroid hormone therapy of the donor on primary graft dysfunction (PGD). METHODS: A retrospective cohort study was conducted on 209 HT recipients assessed from 1997 to 2018; for 33 of the recipients, the donors had received T4 (DT4 group), and for 176, the donors had not (NoDT4 group). The primary endpoint was PGD defined according to the International Society for Heart and Lung consensus statement. RESULTS: Both the incidence (58% vs 35%, P = .022) and the severity of PGD (42% vs 25% moderate/severe, P = .007) were significantly higher in the DT4 recipients. Multivariable analysis showed donor T4 therapy to be independently associated with a ~3.5-fold increased risk for PGD (OR = 3.44, 95% CI 1.26-9.86). These results remained consistent after propensity score analysis. CONCLUSIONS: Donor thyroid hormone therapy is independently associated with an increased risk of PGD. Hypothesizing a "withdrawal effect" as the cause, we suggest that administration of thyroid hormone to the recipient at time of reperfusion could counter this negative effect. Prospective studies are needed to validate this hypothesis-generating study.

7.
Prostaglandins Other Lipid Mediat ; 150: 106454, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32413571

RESUMO

The global epidemic of cardiovascular disease continues unabated and remains the leading cause of death both in the US and worldwide. We hereby summarize the available therapies for diabetes and cardiovascular disease in diabetics. Clearly, the current approaches to diabetic heart disease often target the manifestations and certain mediators but not the specific pathways leading to myocardial injury, remodeling and dysfunction. Better understanding of the molecular events determining the evolution of diabetic cardiomyopathy will provide insight into the development of specific and targeted therapies. Recent studies largely increased our understanding of the role of enhanced inflammatory response, ROS production, as well as the contribution of Cyp-P450-epoxygenase-derived epoxyeicosatrienoic acid (EET), Peroxisome Proliferator-Activated Receptor Gamma Coactivator-1α (PGC-1α), Heme Oxygenase (HO)-1 and 20-HETE in pathophysiology and therapy of cardiovascular disease. PGC-1α increases production of the HO-1 which has a major role in protecting the heart against oxidative stress, microcirculation and mitochondrial dysfunction. This review describes the potential drugs and their downstream targets, PGC-1α and HO-1, as major loci for developing therapeutic approaches beside diet and lifestyle modification for the treatment and prevention of heart disease associated with obesity and diabetes.

8.
Am J Cardiol ; 125(11): 1694-1699, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32278464

RESUMO

Data are scarce regarding sex differences among patients with acute myocarditis (AM). Our aim was to define the sex differences in clinical characteristics as well as in-hospital outcomes in a cohort of consecutive patients hospitalized due to AM. We analyzed data of 322 consecutive patients from January 2005 to December 2017 who were hospitalized with the diagnosis of AM. Eighty-four percent (N = 272) of the patients were males. When compared to females, male patients were younger (36 ± 14 vs 45 ± 17 years, p <0.001), more likely to present with ST segment elevation (75% vs 44%. p <0.001) as well as PR depression upon ECG, and have higher admission troponin levels (7.6 ± 11 vs 2.3 ± 4 µg/L, p <0.001). Moreover, males were more likely to have late gadolinium enhancement upon cardiac magnetic resonance. While male patients were more likely to have ventricular arrhythmias during hospitalization (7% vs 0%, p = 0.05), there were no differences in the incidence of in-hospital mortality or the need for escalation therapy during hospitalization between both groups. There were no episodes of mortality upon all patients among a follow-up of 1 year. In conclusion, male patients, which constitute the majority of patients admitted with AM were younger, more likely to present with ST elevation, had higher troponin levels at admission, and had a higher rate of ventricular arrhythmias compared to females. There were no differences in post-discharge mortality rates between males and females.


Assuntos
Arritmias Cardíacas/epidemiologia , Mortalidade Hospitalar , Miocardite/epidemiologia , Doença Aguda , Corticosteroides/uso terapêutico , Antagonistas Adrenérgicos beta/uso terapêutico , Adulto , Distribuição por Idade , Antagonistas de Receptores de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Anti-Inflamatórios não Esteroides/uso terapêutico , Aspirina/uso terapêutico , Colchicina/uso terapêutico , Diuréticos/uso terapêutico , Ecocardiografia , Eletrocardiografia , Feminino , Humanos , Israel/epidemiologia , Tempo de Internação , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Miocardite/diagnóstico por imagem , Miocardite/tratamento farmacológico , Miocardite/fisiopatologia , Fatores Sexuais , Volume Sistólico , Troponina/sangue , Moduladores de Tubulina/uso terapêutico , Adulto Jovem
9.
Antioxid Redox Signal ; 32(17): 1273-1290, 2020 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-32027164

RESUMO

Significance: From studies of diabetic animal models, the downregulation of peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α)-heme oxygenase 1 (HO-1) axis appears to be a crucial event in the development of obesity and diabetic cardiomyopathy (DCM). In this review, we discuss the role of metabolic and biochemical stressors in the rodent and human pathophysiology of DCM. A crucial contributor for many cardiac pathologies is excessive production of reactive oxygen species (ROS) pathologies, which lead to extensive cellular damage by impairing mitochondrial function and directly oxidizing DNA, proteins, and lipid membranes. We discuss the role of ROS production and inflammatory pathways with multiple contributing and confounding factors leading to DCM. Recent Advances: The relevant biochemical pathways that are critical to a therapeutic approach to treat DCM, specifically caloric restriction and its relation to the PGC-1α-HO-1 axis in the attenuation of DCM, are elucidated. Critical Issues: The increased prevalence of diabetes mellitus type 2, a major contributor to unique cardiomyopathy characterized by cardiomyocyte hypertrophy with no effective clinical treatment. This review highlights the role of mitochondrial dysfunction in the development of DCM and potential oxidative targets to attenuate oxidative stress and attenuate DCM. Future Directions: Targeting the PGC-1α-HO-1 axis is a promising approach to ameliorate DCM through improvement in mitochondrial function and antioxidant defenses. A pharmacological inducer to activate PGC-1α and HO-1 described in this review may be a promising therapeutic approach in the clinical setting.

10.
Am J Cardiol ; 124(4): 554-559, 2019 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-31221464

RESUMO

Minimal attention has been paid to understanding the implications of the chronicity of heart failure (HF) diagnosis on prognosis of hospitalized patients with acute HF (AHF). We aimed to assess the differences in outcomes between hospitalized patients with AHF that are new-onset (de-novo) AHF and acutely decompensated chronic HF (ADCHF). We analyzed data of 2,328 patients with AHF, who were enrolled in the HF survey in Israel. Patients were classified into de-novo AHF and ADCHF. A total of 721 (31%) patients were classified as de-novo AHF and 1,607 (69%) patients were classified as ADCHF. Patients with de-novo AHF were more likely to be younger, with fewer co-morbidities represented by lower Charlson index, and less likely to have past myocardial infarction as well as coronary revascularization. At 30 days mortality rates were similar in both groups (9% vs 8% in de-novo AHF and ADCHF, respectively). Survival analysis showed that at 1 and 10 years the all-cause mortality rates were significantly higher in patients with ADCHF (33% vs 22% and 90% vs 72%, 1 and 10 years, log-rank p < 0.001, respectively). Consistently, multivariable analysis showed that patients with ADCHF had an independently 58% and 48%, higher mortality risk at 1 and 10 years, respectively, (1-year hazard ratio = 1.58; 95% confidence interval 1.05 to 2.38, p = 0.03; 10-year hazard ratio = 1.48; 95% confidence interval = 1.23 to 2.77; p < 0.001). In conclusion, previous history of HF is an independent predictor of 1-year and 10-year mortality after hospitalization for AHF. Distinction between de-novo AHF and ADCHF may improve our understanding and risk stratification of patients with AHF.


Assuntos
Insuficiência Cardíaca/mortalidade , Medição de Risco/métodos , Doença Aguda , Fatores Etários , Idoso , Doença Crônica , Comorbidade , Feminino , Hospitalização , Humanos , Israel/epidemiologia , Masculino , Prognóstico , Sistema de Registros , Fatores de Risco
11.
J Cardiol ; 74(5): 466-472, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31235420

RESUMO

BACKGROUND: While physical rehabilitation has been shown to be beneficial and safe for patients suffering from heart failure, data on rehabilitation for hypertrophic cardiomyopathy (HCM) patients are limited. METHODS: Forty-five HCM patients participated in an exercise rehabilitation program. Exercise capacity was measured in metabolic equivalent of task (METs) units and functional status was defined according to the New York Heart Association (NYHA). Self-reported measurements addressed the quality of life and daily life function. RESULTS: Of the 45 participants, 32 completed at least 3 months of rehabilitation and had data from two sequential exercise tests. A significant increase in exercise capacity (from mean 5.3 to 6.7 METs, p=0.01), was achieved at higher peak heart rates. Eighteen patients (56%) who showed improvement in exercise capacity did not differ in their NYHA class, clinical, electrocardiographic, or echo-Doppler parameters compared to those who did not improve. The benefit from training was associated with a lower exercise capacity at baseline and was most pronounced in those capable of less than 6.8 METs (p=0.008). No significant arrhythmias or adverse events were recorded in HCM patients during participation. In ∼40% of participants, training improved the subjective perception of functional capacity and quality of life; only 4 patients (9%) discontinued their participation due to discomfort during or following training. The improvement in exercise capacity was comparable between HCM and a reference group of dilated cardiomyopathy patients. CONCLUSIONS: Exercise rehabilitation appears to be applicable and safe in HCM. It mainly benefits patients suffering from significant functional limitation. Larger prospective studies are needed to validate these findings and better characterize patients expected to benefit from these programs.

13.
Int J Mol Sci ; 20(10)2019 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-31100876

RESUMO

Type 2 diabetes mellitus (DM2) leads to cardiomyopathy characterized by cardiomyocyte hypertrophy, followed by mitochondrial dysfunction and interstitial fibrosis, all of which are exacerbated by angiotensin II (AT). SIRT1 and its transcriptional coactivator target PGC-1α (peroxisome proliferator-activated receptor-γ coactivator), and heme oxygenase-1 (HO-1) modulates mitochondrial biogenesis and antioxidant protection. We have previously shown the beneficial effect of caloric restriction (CR) on diabetic cardiomyopathy through intracellular signaling pathways involving the SIRT1-PGC-1α axis. In the current study, we examined the role of HO-1 in diabetic cardiomyopathy in mice subjected to CR. METHODS: Cardiomyopathy was induced in obese diabetic (db/db) mice by AT infusion. Mice were either fed ad libitum or subjected to CR. In an in vitro study, the reactive oxygen species (ROS) level was determined in cardiomyocytes exposed to different glucose levels (7.5-33 mM). We examined the effects of Sn(tin)-mesoporphyrin (SnMP), which is an inhibitor of HO activity, the HO-1 inducer cobalt protoporphyrin (CoPP), and the SIRT1 inhibitor (EX-527) on diabetic cardiomyopathy. RESULTS: Diabetic mice had low levels of HO-1 and elevated levels of the oxidative marker malondialdehyde (MDA). CR attenuated left ventricular hypertrophy (LVH), increased HO-1 levels, and decreased MDA levels. SnMP abolished the protective effects of CR and caused pronounced LVH and cardiac metabolic dysfunction represented by suppressed levels of adiponectin, SIRT1, PPARγ, PGC-1α, and increased MDA. High glucose (33 mM) increased ROS in cultured cardiomyocytes, while SnMP reduced SIRT1, PGC-1α levels, and HO activity. Similarly, SIRT1 inhibition led to a reduction in PGC-1α and HO-1 levels. CoPP increased HO-1 protein levels and activity, SIRT1, and PGC-1α levels, and decreased ROS production, suggesting a positive feedback between SIRT1 and HO-1. CONCLUSION: These results establish a link between SIRT1, PGC-1α, and HO-1 signaling that leads to the attenuation of ROS production and diabetic cardiomyopathy. CoPP mimicked the beneficial effect of CR, while SnMP increased oxidative stress, aggravating cardiac hypertrophy. The data suggest that increasing HO-1 levels constitutes a novel therapeutic approach to protect the diabetic heart. Brief Summary: CR attenuates cardiomyopathy, and increases HO-1, SIRT activity, and PGC-1α protein levels in diabetic mice. High glucose reduces adiponectin, SIRT1, PGC1-1α, and HO-1 levels in cardiomyocytes, resulting in oxidative stress. The pharmacological activation of HO-1 activity mimics the effect of CR, while SnMP increased oxidative stress and cardiac hypertrophy. These data suggest the critical role of HO-1 in protecting the diabetic heart.


Assuntos
Restrição Calórica/métodos , Cardiomiopatias Diabéticas/tratamento farmacológico , Cardiomiopatias Diabéticas/metabolismo , Heme Oxigenase-1/metabolismo , Heme Oxigenase-1/uso terapêutico , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Angiotensina II/metabolismo , Animais , Glicemia , Carbazóis/farmacologia , Cardiomegalia/metabolismo , Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2/complicações , Masculino , Malondialdeído/sangue , Mesoporfirinas/uso terapêutico , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/metabolismo , Estresse Oxidativo/efeitos dos fármacos , PPAR gama/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Protoporfirinas/metabolismo , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sirtuína 1/antagonistas & inibidores , Sirtuína 1/metabolismo
14.
Eur J Heart Fail ; 21(5): 553-576, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30989768

RESUMO

Cardiomyopathies are a heterogeneous group of heart muscle diseases and an important cause of heart failure (HF). Current knowledge on incidence, pathophysiology and natural history of HF in cardiomyopathies is limited, and distinct features of their therapeutic responses have not been systematically addressed. Therefore, this position paper focuses on epidemiology, pathophysiology, natural history and latest developments in treatment of HF in patients with dilated (DCM), hypertrophic (HCM) and restrictive (RCM) cardiomyopathies. In DCM, HF with reduced ejection fraction (HFrEF) has high incidence and prevalence and represents the most frequent cause of death, despite improvements in treatment. In addition, advanced HF in DCM is one of the leading indications for heart transplantation. In HCM, HF with preserved ejection (HFpEF) affects most patients with obstructive, and ∼10% of patients with non-obstructive HCM. A timely treatment is important, since development of advanced HF, although rare in HCM, portends a poor prognosis. In RCM, HFpEF is common, while HFrEF occurs later and more frequently in amyloidosis or iron overload/haemochromatosis. Irrespective of RCM aetiology, HF is a harbinger of a poor outcome. Recent advances in our understanding of the mechanisms underlying the development of HF in cardiomyopathies have significant implications for therapeutic decision-making. In addition, new aetiology-specific treatment options (e.g. enzyme replacement therapy, transthyretin stabilizers, immunoadsorption, immunotherapy, etc.) have shown a potential to improve outcomes. Still, causative therapies of many cardiomyopathies are lacking, highlighting the need for the development of effective strategies to prevent and treat HF in cardiomyopathies.

15.
J Cell Mol Med ; 23(3): 2125-2135, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30618214

RESUMO

Duchenne muscular dystrophy (DMD) is an X-linked progressive muscle degenerative disease, caused by mutations in the dystrophin gene and resulting in death because of respiratory or cardiac failure. To investigate the cardiac cellular manifestation of DMD, we generated induced pluripotent stem cells (iPSCs) and iPSC-derived cardiomyocytes (iPSC-CMs) from two DMD patients: a male and female manifesting heterozygous carrier. Dystrophin mRNA and protein expression were analysed by qRT-PCR, RNAseq, Western blot and immunofluorescence staining. For comprehensive electrophysiological analysis, current and voltage clamp were used to record transmembrane action potentials and ion currents, respectively. Microelectrode array was used to record extracellular electrograms. X-inactive specific transcript (XIST) and dystrophin expression analyses revealed that female iPSCs underwent X chromosome reactivation (XCR) or erosion of X chromosome inactivation, which was maintained in female iPSC-CMs displaying mixed X chromosome expression of wild type (WT) and mutated alleles. Both DMD female and male iPSC-CMs presented low spontaneous firing rate, arrhythmias and prolonged action potential duration. DMD female iPSC-CMs displayed increased beat rate variability (BRV). DMD male iPSC-CMs manifested decreased If density, and DMD female and male iPSC-CMs showed increased ICa,L density. Our findings demonstrate cellular mechanisms underlying electrophysiological abnormalities and cardiac arrhythmias in DMD.

16.
Eur Heart J ; 40(21): 1671-1677, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-30358878

RESUMO

AIMS: Diabetes mellitus (DM) aggravates the clinical features of ischaemic and hypertensive heart diseases and worsens the prognosis of heart failure patients. Hypertrophic cardiomyopathy (HCM) and diabetes coexist fairly frequently in elderly patients but the impact of DM on the clinical phenotype of HCM is yet unknown. We sought to describe if predominant features of heart failure in DM patients exist independently in HCM. METHODS AND RESULTS: We reviewed clinical characteristics of 937 patients, age ≥40, diagnosed with HCM, from two tertiary medical centres in Spain and Israel. A propensity score matched cohort of 294 patients was also analysed. Our cohort comprised 102 HCM patients with diabetes (8.7%). Patients with DM were older at diagnosis {median 56 [interquartile range (IQR) 47-67] vs. 53 (IQR 43-63), P = 0.02} and had a higher prevalence of comorbidities. Hypertrophic cardiomyopathy patients with DM had a higher prevalence of diastolic dysfunction, pulmonary hypertension, significant mitral regurgitation, and pacemaker implantation. Hypertrophic cardiomyopathy patients with DM had a higher New York Heart Association (NYHA) class (P < 0.001) and lower exercise capacity [7.0 METS (IQR 5.0-10.0) vs. 9.0 METS (IQR 6.6-11.0), P = 0.002]. These findings were independent of age, gender, country of origin, hypertension, and coronary artery disease. Patients with diabetes had a significantly higher 15-year mortality (22% vs. 15%, P = 0.03), with no differences in sudden cardiac death, appropriate implanted cardioverter-defibrillator therapy, or heart transplantation. CONCLUSION: Hypertrophic cardiomyopathy patients with diabetes are older and have a higher cardiovascular risk profile. They have a lower functional capacity and more heart failure symptoms due to diastolic dysfunction.

17.
Mol Genet Metab ; 126(3): 224-235, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30413388

RESUMO

BACKGROUND: Heterozygous females with Fabry disease have a wide range of clinical phenotypes depending on the nature of their mutation and their X-chromosome inactivation pattern; it is therefore important to examine outcomes of enzyme replacement therapy (ERT) in the female patient population specifically. This paper presents the findings of a systematic literature review of treatment outcomes with ERT in adult female patients. METHODS: A comprehensive systematic literature review was conducted through January 2017 to retrieve published papers with original data on ERT in the treatment of Fabry disease. The review included all original articles that presented ERT outcomes data on patients with Fabry disease, irrespective of the study type. RESULTS: Clinical evidence for the efficacy of ERT in female patients was available from 67 publications including six clinical trial publications, and indicates significant reductions in plasma and urine globotriaosylceramide (GL-3) accumulation (in female patients with elevated pre-treatment levels) and improvements in cardiac parameters and quality of life (QoL). To date, data are insufficient to conclude on the effects of ERT on the nervous system, gastrointestinal manifestations, and pain in female patients with Fabry disease. CONCLUSIONS: This review of available literature data demonstrates that ERT in adult female patients with Fabry disease has a beneficial effect on GL-3 levels and cardiac outcomes. The current evidence also suggests that ERT may improve QoL in this patient population, though further studies are needed to examine these results.


Assuntos
Terapia de Reposição de Enzimas , Doença de Fabry/terapia , Ensaios Clínicos como Assunto , Feminino , Trato Gastrointestinal , Humanos , Isoenzimas/uso terapêutico , Sistema Nervoso , Estudos Observacionais como Assunto , Dor , Qualidade de Vida , Proteínas Recombinantes/uso terapêutico , Resultado do Tratamento , Triexosilceramidas/sangue , Triexosilceramidas/urina , alfa-Galactosidase/uso terapêutico
19.
Exp Cell Res ; 373(1-2): 112-118, 2018 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-30359575

RESUMO

Type 2 diabetes mellitus (DM2) follows impaired glucose tolerance in obesity and is frequently associated with hypertension, causing adverse myocardial remodelling and leading to heart failure. The DNA bound protein PARP (poly ADP ribose) polymerase catalyses a post translational modification (polymerization of negatively charged ADP-ribose chains) of nuclear proteins. PARP-1 activation is NAD+ dependent and takes part in DNA repair and in chromatin remodelling and has a function in transcriptional regulation, intracellular trafficking and energy metabolism. PARP-1 is activated in diabetic cardiomyopathy. We hypothesized that PARP-1 inhibition in diabetic mice may protect cardiomyocytes from inflammation and ROS production. METHODS: Obese Leptin resistant (db/db) mice suffering from DM2, were treated with angiotensin II (AT) for 4 weeks to enhance the development of cardiomyopathy. Mice were concomitantly treated with the PARP-1 inhibitor INO1001. Neonatal cardiomyocytes exposed to high levels of glucose (33 mM) with or without AT were treated with INO1001. or with SIRT inhibitor (EX-527) in the presence of INO1001 were tested in-vitro. RESULTS: The in-vivo tests show that hearts from AT treated DM2 mice exhibited cardiac hypertrophy, fibrosis and an increase in the inflammatory marker TNFα. DM2 mice had an increased oxidative stress, concomitant with elevated PARP-1 activity and reduced Sirtuin-1 (SIRT1) expression. PARP-1 inhibition led to increased SIRT1 and Peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC-1α) levels, attenuating oxidative stress, inflammation and fibrosis. In-vitro experiments demonstrated that inhibition of PARP-1 in cardiomyocytes exposed to high levels of glucose and AT led to a significant reduction in ROS (P < 0.01), which was abolished in the presence of the SIRT1 inhibitor together with increased protein expression of SIRT1 and PGC-1α. CONCLUSION: PARP1 inhibitor INO1001 attenuated cardiomyopathic features in diabetic mice through the activation of SIRT1 and its downstream antioxidant defence mechanisms. The results of this study suggest a pivotal role of PARP-1 inhibition in treating diabetic and AT-induced cardiomyopathy.


Assuntos
Cardiomiopatias Diabéticas/tratamento farmacológico , Inibidores Enzimáticos/uso terapêutico , Indóis/uso terapêutico , Poli(ADP-Ribose) Polimerase-1/antagonistas & inibidores , Animais , Células Cultivadas , Cardiomiopatias Diabéticas/enzimologia , Cardiomiopatias Diabéticas/patologia , Glucose/toxicidade , Coração/efeitos dos fármacos , Hipertensão/tratamento farmacológico , Inflamação/tratamento farmacológico , Masculino , Camundongos , Miocárdio/patologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/enzimologia , Tamanho do Órgão/efeitos dos fármacos , Estresse Oxidativo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Ratos Sprague-Dawley , Sirtuína 1/metabolismo
20.
PLoS One ; 13(10): e0205719, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30332462

RESUMO

AIMS: Dilated cardiomyopathy (DCM), a myocardial disorder that can result in progressive heart failure and arrhythmias, is defined by ventricular chamber enlargement and dilatation, and systolic dysfunction. Despite extensive research, the pathological mechanisms of DCM are unclear mainly due to numerous mutations in different gene families resulting in the same outcome-decreased ventricular function. Titin (TTN)-a giant protein, expressed in cardiac and skeletal muscles, is an important part of the sarcomere, and thus TTN mutations are the most common cause of adult DCM. To decipher the basis for the cardiac pathology in titin-mutated patients, we investigated the hypothesis that induced Pluripotent Stem Cell (iPSC)-derived cardiomyocytes (iPSC-CM) generated from patients, recapitulate the disease phenotype. The hypothesis was tested by 3 Aims: (1) Investigate key features of the excitation-contraction-coupling machinery; (2) Investigate the responsiveness to positive inotropic interventions; (3) Investigate the proteome profile of the AuP cardiomyocytes using mass-spectrometry (MS). METHODS AND RESULTS: iPSC were generated from the patients' skin fibroblasts. The major findings were: (1) Sarcomeric organization analysis in mutated iPSC-CM showed defects in assembly and maintenance of sarcomeric structure. (2) Mutated iPSC-CM exhibited diminished inotropic and lusitropic responses to ß-adrenergic stimulation with isoproterenol, increased [Ca2+]out and angiotensin-II. Additionally, mutated iPSC-CM displayed prolonged recovery in response to caffeine. These findings may result from defective or lack of interactions of the sarcomeric components with titin through its kinase domain which is absent in the mutated cells. CONCLUSIONS: These findings show that the mutated cardiomyocytes from DCM patients recapitulate abnormalities of the inherited cardiomyopathies, expressed as blunted inotropic response.


Assuntos
Cardiomiopatia Dilatada/genética , Diferenciação Celular/genética , Conectina/genética , Contração Miocárdica/genética , Miócitos Cardíacos/patologia , Adulto , Idoso , Cardiomiopatia Dilatada/patologia , Acoplamento Excitação-Contração/genética , Humanos , Células-Tronco Pluripotentes Induzidas/fisiologia , Isoproterenol/farmacologia , Masculino , Mutação , Contração Miocárdica/efeitos dos fármacos , Miócitos Cardíacos/fisiologia , Proteoma
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