RESUMO
The prevalence of heart failure is on the rise and imposes a major health threat, in part, due to the rapidly increased prevalence of overweight and obesity. To this point, epidemiological, clinical, and experimental evidence supports the existence of a unique disease entity termed "obesity cardiomyopathy," which develops independent of hypertension, coronary heart disease, and other heart diseases. Our contemporary review evaluates the evidence for this pathological condition, examines putative responsible mechanisms, and discusses therapeutic options for this disorder. Clinical findings have consolidated the presence of left ventricular dysfunction in obesity. Experimental investigations have uncovered pathophysiological changes in myocardial structure and function in genetically predisposed and diet-induced obesity. Indeed, contemporary evidence consolidates a wide array of cellular and molecular mechanisms underlying the etiology of obesity cardiomyopathy including adipose tissue dysfunction, systemic inflammation, metabolic disturbances (insulin resistance, abnormal glucose transport, spillover of free fatty acids, lipotoxicity, and amino acid derangement), altered intracellular especially mitochondrial Ca2+ homeostasis, oxidative stress, autophagy/mitophagy defect, myocardial fibrosis, dampened coronary flow reserve, coronary microvascular disease (microangiopathy), and endothelial impairment. Given the important role of obesity in the increased risk of heart failure, especially that with preserved systolic function and the recent rises in COVID-19-associated cardiovascular mortality, this review should provide compelling evidence for the presence of obesity cardiomyopathy, independent of various comorbid conditions, underlying mechanisms, and offer new insights into potential therapeutic approaches (pharmacological and lifestyle modification) for the clinical management of obesity cardiomyopathy.
Assuntos
Cardiomiopatias/etiologia , Cardiomiopatias/patologia , Obesidade/complicações , COVID-19/complicações , COVID-19/mortalidade , Cardiomiopatias/mortalidade , Humanos , Obesidade/etiologia , Obesidade/genética , SARS-CoV-2RESUMO
BACKGROUND: Transthyretin amyloidosis, also called ATTR amyloidosis, is associated with accumulation of ATTR amyloid deposits in the heart and commonly manifests as progressive cardiomyopathy. Patisiran, an RNA interference therapeutic agent, inhibits the production of hepatic transthyretin. METHODS: In this phase 3, double-blind, randomized trial, we assigned patients with hereditary, also known as variant, or wild-type ATTR cardiac amyloidosis, in a 1:1 ratio, to receive patisiran (0.3 mg per kilogram of body weight) or placebo once every 3 weeks for 12 months. A hierarchical procedure was used to test the primary and three secondary end points. The primary end point was the change from baseline in the distance covered on the 6-minute walk test at 12 months. The first secondary end point was the change from baseline to month 12 in the Kansas City Cardiomyopathy Questionnaire-Overall Summary (KCCQ-OS) score (with higher scores indicating better health status). The second secondary end point was a composite of death from any cause, cardiovascular events, and change from baseline in the 6-minute walk test distance over 12 months. The third secondary end point was a composite of death from any cause, hospitalizations for any cause, and urgent heart failure visits over 12 months. RESULTS: A total of 360 patients were randomly assigned to receive patisiran (181 patients) or placebo (179 patients). At month 12, the decline in the 6-minute walk distance was lower in the patisiran group than in the placebo group (Hodges-Lehmann estimate of median difference, 14.69 m; 95% confidence interval [CI], 0.69 to 28.69; P = 0.02); the KCCQ-OS score increased in the patisiran group and declined in the placebo group (least-squares mean difference, 3.7 points; 95% CI, 0.2 to 7.2; P = 0.04). Significant benefits were not observed for the second secondary end point. Infusion-related reactions, arthralgia, and muscle spasms occurred more often among patients in the patisiran group than among those in the placebo group. CONCLUSIONS: In this trial, administration of patisiran over a period of 12 months resulted in preserved functional capacity in patients with ATTR cardiac amyloidosis. (Funded by Alnylam Pharmaceuticals; APOLLO-B ClinicalTrials.gov number, NCT03997383.).
Assuntos
Amiloidose , Cardiomiopatias , Pré-Albumina , RNA Interferente Pequeno , Humanos , Cardiomiopatias/tratamento farmacológico , Cardiomiopatias/etiologia , Cardiomiopatias/genética , Cardiomiopatias/metabolismo , Pré-Albumina/genética , Pré-Albumina/metabolismo , RNA Interferente Pequeno/uso terapêutico , Amiloidose Familiar/complicações , Amiloidose Familiar/tratamento farmacológico , Amiloidose Familiar/genética , Fígado/metabolismo , Método Duplo-Cego , Amiloidose/complicações , Amiloidose/tratamento farmacológico , Amiloidose/genéticaRESUMO
BACKGROUND: Transthyretin amyloid (ATTR) cardiomyopathy is a progressive and fatal disease caused by misfolded transthyretin. Despite advances in slowing disease progression, there is no available treatment that depletes ATTR from the heart for the amelioration of cardiac dysfunction. NI006 is a recombinant human anti-ATTR antibody that was developed for the removal of ATTR by phagocytic immune cells. METHODS: In this phase 1, double-blind trial, we randomly assigned (in a 2:1 ratio) 40 patients with wild-type or variant ATTR cardiomyopathy and chronic heart failure to receive intravenous infusions of either NI006 or placebo every 4 weeks for 4 months. Patients were sequentially enrolled in six cohorts that received ascending doses (ranging from 0.3 to 60 mg per kilogram of body weight). After four infusions, patients were enrolled in an open-label extension phase in which they received eight infusions of NI006 with stepwise increases in the dose. The safety and pharmacokinetic profiles of NI006 were assessed, and cardiac imaging studies were performed. RESULTS: The use of NI006 was associated with no apparent drug-related serious adverse events. The pharmacokinetic profile of NI006 was consistent with that of an IgG antibody, and no antidrug antibodies were detected. At doses of at least 10 mg per kilogram, cardiac tracer uptake on scintigraphy and extracellular volume on cardiac magnetic resonance imaging, both of which are imaging-based surrogate markers of cardiac amyloid load, appeared to be reduced over a period of 12 months. The median N-terminal pro-B-type natriuretic peptide and troponin T levels also seemed to be reduced. CONCLUSIONS: In this phase 1 trial of the recombinant human antibody NI006 for the treatment of patients with ATTR cardiomyopathy and heart failure, the use of NI006 was associated with no apparent drug-related serious adverse events. (Funded by Neurimmune; NI006-101 ClinicalTrials.gov number, NCT04360434.).
Assuntos
Neuropatias Amiloides Familiares , Anticorpos , Cardiomiopatias , Insuficiência Cardíaca , Proteínas Recombinantes , Humanos , Neuropatias Amiloides Familiares/diagnóstico por imagem , Neuropatias Amiloides Familiares/tratamento farmacológico , Neuropatias Amiloides Familiares/complicações , Anticorpos/administração & dosagem , Anticorpos/efeitos adversos , Anticorpos/farmacologia , Anticorpos/uso terapêutico , Cardiomiopatias/diagnóstico por imagem , Cardiomiopatias/tratamento farmacológico , Cardiomiopatias/etiologia , Insuficiência Cardíaca/diagnóstico por imagem , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/etiologia , Imageamento por Ressonância Magnética , Pré-Albumina , Método Duplo-Cego , Doença Crônica , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/farmacocinética , Proteínas Recombinantes/uso terapêutico , Infusões IntravenosasRESUMO
ABSTRACT: Serial cardiovascular magnetic resonance evaluation of children and young adults with SCD who underwent hematopoietic cell transplantation showed mean ECV, representing diffuse myocardial fibrosis, decreased 3.4% from baseline to 12 months posttransplantation. This trial was registered at www.clinicaltrials.gov as #NCT04362293.
Assuntos
Anemia Falciforme , Fibrose , Transplante de Células-Tronco Hematopoéticas , Humanos , Anemia Falciforme/terapia , Anemia Falciforme/patologia , Anemia Falciforme/complicações , Masculino , Feminino , Adolescente , Criança , Adulto Jovem , Cardiomiopatias/etiologia , Cardiomiopatias/terapia , Cardiomiopatias/patologia , Adulto , Miocárdio/patologia , Imageamento por Ressonância Magnética , Pré-EscolarRESUMO
BACKGROUND: Viral infections can cause acute respiratory distress syndrome (ARDS), systemic inflammation, and secondary cardiovascular complications. Lung macrophage subsets change during ARDS, but the role of heart macrophages in cardiac injury during viral ARDS remains unknown. Here we investigate how immune signals typical for viral ARDS affect cardiac macrophage subsets, cardiovascular health, and systemic inflammation. METHODS: We assessed cardiac macrophage subsets using immunofluorescence histology of autopsy specimens from 21 patients with COVID-19 with SARS-CoV-2-associated ARDS and 33 patients who died from other causes. In mice, we compared cardiac immune cell dynamics after SARS-CoV-2 infection with ARDS induced by intratracheal instillation of Toll-like receptor ligands and an ACE2 (angiotensin-converting enzyme 2) inhibitor. RESULTS: In humans, SARS-CoV-2 increased total cardiac macrophage counts and led to a higher proportion of CCR2+ (C-C chemokine receptor type 2 positive) macrophages. In mice, SARS-CoV-2 and virus-free lung injury triggered profound remodeling of cardiac resident macrophages, recapitulating the clinical expansion of CCR2+ macrophages. Treating mice exposed to virus-like ARDS with a tumor necrosis factor α-neutralizing antibody reduced cardiac monocytes and inflammatory MHCIIlo CCR2+ macrophages while also preserving cardiac function. Virus-like ARDS elevated mortality in mice with pre-existing heart failure. CONCLUSIONS: Our data suggest that viral ARDS promotes cardiac inflammation by expanding the CCR2+ macrophage subset, and the associated cardiac phenotypes in mice can be elicited by activating the host immune system even without viral presence in the heart.
Assuntos
COVID-19 , Cardiomiopatias , Síndrome do Desconforto Respiratório , SARS-CoV-2 , COVID-19/imunologia , COVID-19/complicações , COVID-19/patologia , Animais , Humanos , Síndrome do Desconforto Respiratório/imunologia , Síndrome do Desconforto Respiratório/etiologia , Síndrome do Desconforto Respiratório/patologia , Síndrome do Desconforto Respiratório/virologia , Camundongos , Masculino , Feminino , Cardiomiopatias/imunologia , Cardiomiopatias/etiologia , Cardiomiopatias/patologia , Cardiomiopatias/virologia , Macrófagos/imunologia , Macrófagos/patologia , Macrófagos/metabolismo , Inflamação/patologia , Pessoa de Meia-Idade , Miocárdio/patologia , Miocárdio/imunologia , Camundongos Endogâmicos C57BL , IdosoRESUMO
Chronic kidney disease is associated with an increased risk for the development and progression of cardiovascular disorders including hypertension, dyslipidemia, and coronary artery disease. Chronic kidney disease may also affect the myocardium through complex systemic changes, resulting in structural remodeling such as hypertrophy and fibrosis, as well as impairments in both diastolic and systolic function. These cardiac changes in the setting of chronic kidney disease define a specific cardiomyopathic phenotype known as uremic cardiomyopathy. Cardiac function is tightly linked to its metabolism, and research over the past 3 decades has revealed significant metabolic remodeling in the myocardium during the development of heart failure. Because the concept of uremic cardiomyopathy has only been recognized in recent years, there are limited data on metabolism in the uremic heart. Nonetheless, recent findings suggest overlapping mechanisms with heart failure. This work reviews key features of metabolic remodeling in the failing heart in the general population and extends this to patients with chronic kidney disease. The knowledge of similarities and differences in cardiac metabolism between heart failure and uremic cardiomyopathy may help identify new targets for mechanistic and therapeutic research on uremic cardiomyopathy.
Assuntos
Cardiomiopatias , Doenças Cardiovasculares , Insuficiência Cardíaca , Insuficiência Renal Crônica , Humanos , Cardiomiopatias/etiologia , Insuficiência Cardíaca/metabolismo , Miocárdio/metabolismo , Insuficiência Renal Crônica/complicações , Doenças Cardiovasculares/metabolismoRESUMO
BACKGROUND: Sepsis-induced cardiomyopathy (SIC) is a cardiac dysfunction caused by sepsis, with mitochondrial dysfunction being a critical contributor. Pyruvate dehydrogenase kinase 4 (PDK4) is a kinase of pyruvate dehydrogenase with multifaceted actions in mitochondrial metabolism. However, its role in SIC remains unknown. METHODS: Serum PDK4 levels were measured and analyzed in 27 children with SIC, 30 children with sepsis, and 29 healthy children. In addition, for mice exhibiting SIC, the effects of PDK4 knockdown or inhibition on the function and structure of the myocardium and mitochondria were assessed. RESULTS: The findings from the analysis of children with SIC revealed that PDK4 was significantly elevated and correlated with disease severity and organ injury. Nonsurvivors displayed higher serum PDK4 levels than survivors. Furthermore, mice with SIC benefited from PDK4 knockdown or inhibition, showing improved myocardial contractile function, reduced myocardial injury, and decreased mitochondrial structural injury and dysfunction. In addition, inhibition of PDK4 decreased the inhibitory phosphorylation of PDHE1α (pyruvate dehydrogenase complex E1 subunit α) and improved abnormal pyruvate metabolism and mitochondrial dysfunction. CONCLUSIONS: PDK4 is a potential biomarker for the diagnosis and prognosis of SIC. In experimental SIC, PDK4 promoted mitochondrial dysfunction with increased phosphorylation of PDHE1α and abnormal pyruvate metabolism.
Assuntos
Cardiomiopatias , Doenças Mitocondriais , Proteínas Quinases , Sepse , Animais , Criança , Humanos , Camundongos , Cardiomiopatias/etiologia , Cardiomiopatias/metabolismo , Mitocôndrias/metabolismo , Doenças Mitocondriais/metabolismo , Miocárdio/metabolismo , Proteínas Quinases/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Piruvato Desidrogenase Quinase de Transferência de Acetil/metabolismo , Piruvatos/metabolismo , Sepse/complicações , Sepse/metabolismoRESUMO
Ongoing cardiomyocyte injury is a major mechanism in the progression of heart failure, particularly in dystrophic hearts. Due to the poor regenerative capacity of the adult heart, cardiomyocyte death results in the permanent loss of functional myocardium. Understanding the factors contributing to myocyte injury is essential for the development of effective heart failure therapies. As a model of persistent cardiac injury, we examined mice lacking ß-sarcoglycan (ß-SG), a key component of the dystrophin glycoprotein complex (DGC). The loss of the sarcoglycan complex markedly compromises sarcolemmal integrity in this ß-SG-/- model. Our studies aim to characterize the mechanisms underlying dramatic sex differences in susceptibility to cardiac injury in ß-SG-/- mice. Male ß-SG-/- hearts display significantly greater myocardial injury and death following isoproterenol-induced cardiac stress than female ß-SG-/- hearts. This protection of females was independent of ovarian hormones. Male ß-SG-/- hearts displayed increased susceptibility to exogenous oxidative stress and were significantly protected by angiotensin II type 1 receptor (AT1R) antagonism. Increasing general antioxidative defenses or increasing the levels of S-nitrosylation both provided protection to the hearts of ß-SG-/- male mice. Here we demonstrate that increased susceptibility to oxidative damage leads to an AT1R-mediated amplification of workload-induced myocardial injury in male ß-SG-/- mice. Improving oxidative defenses, specifically by increasing S-nitrosylation, provided protection to the male ß-SG-/- heart from workload-induced injury. These studies describe a unique susceptibility of the male heart to injury and may contribute to the sex differences in other forms of cardiac injury.
Assuntos
Antioxidantes , Cardiomiopatias , Miocárdio , Estresse Oxidativo , Sarcoglicanas , Animais , Masculino , Sarcoglicanas/metabolismo , Sarcoglicanas/genética , Feminino , Cardiomiopatias/metabolismo , Cardiomiopatias/genética , Cardiomiopatias/patologia , Cardiomiopatias/etiologia , Camundongos , Antioxidantes/metabolismo , Miocárdio/metabolismo , Miocárdio/patologia , Camundongos Knockout , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Suscetibilidade a Doenças , Isoproterenol , Receptor Tipo 1 de Angiotensina/metabolismo , Receptor Tipo 1 de Angiotensina/genéticaRESUMO
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.
Assuntos
Cardiomiopatias , Cardiomiopatia Restritiva , Cardiopatias , Humanos , American Heart Association , Cardiomiopatias/diagnóstico , Cardiomiopatias/terapia , Cardiomiopatias/etiologia , Cardiopatias/complicações , Fenótipo , CriançaRESUMO
BACKGROUND: The complex genetics underlying human cardiac disease is evidenced by its heterogenous manifestation, multigenic basis, and sporadic occurrence. These features have hampered disease modeling and mechanistic understanding. Here, we show that 2 structural cardiac diseases, left ventricular noncompaction (LVNC) and bicuspid aortic valve, can be caused by a set of inherited heterozygous gene mutations affecting the NOTCH ligand regulator MIB1 (MINDBOMB1) and cosegregating genes. METHODS: We used CRISPR-Cas9 gene editing to generate mice harboring a nonsense or a missense MIB1 mutation that are both found in LVNC families. We also generated mice separately carrying these MIB1 mutations plus 5 additional cosegregating variants in the ASXL3, APCDD1, TMX3, CEP192, and BCL7A genes identified in these LVNC families by whole exome sequencing. Histological, developmental, and functional analyses of these mouse models were carried out by echocardiography and cardiac magnetic resonance imaging, together with gene expression profiling by RNA sequencing of both selected engineered mouse models and human induced pluripotent stem cell-derived cardiomyocytes. Potential biochemical interactions were assayed in vitro by coimmunoprecipitation and Western blot. RESULTS: Mice homozygous for the MIB1 nonsense mutation did not survive, and the mutation caused LVNC only in heteroallelic combination with a conditional allele inactivated in the myocardium. The heterozygous MIB1 missense allele leads to bicuspid aortic valve in a NOTCH-sensitized genetic background. These data suggest that development of LVNC is influenced by genetic modifiers present in affected families, whereas valve defects are highly sensitive to NOTCH haploinsufficiency. Whole exome sequencing of LVNC families revealed single-nucleotide gene variants of ASXL3, APCDD1, TMX3, CEP192, and BCL7A cosegregating with the MIB1 mutations and LVNC. In experiments with mice harboring the orthologous variants on the corresponding Mib1 backgrounds, triple heterozygous Mib1 Apcdd1 Asxl3 mice showed LVNC, whereas quadruple heterozygous Mib1 Cep192 Tmx3;Bcl7a mice developed bicuspid aortic valve and other valve-associated defects. Biochemical analysis suggested interactions between CEP192, BCL7A, and NOTCH. Gene expression profiling of mutant mouse hearts and human induced pluripotent stem cell-derived cardiomyocytes revealed increased cardiomyocyte proliferation and defective morphological and metabolic maturation. CONCLUSIONS: These findings reveal a shared genetic substrate underlying LVNC and bicuspid aortic valve in which MIB1-NOTCH variants plays a crucial role in heterozygous combination with cosegregating genetic modifiers.
Assuntos
Doença da Válvula Aórtica Bicúspide , Cardiomiopatias , Cardiopatias Congênitas , Células-Tronco Pluripotentes Induzidas , Humanos , Animais , Camundongos , Cardiopatias Congênitas/complicações , Cardiomiopatias/etiologia , Miócitos Cardíacos , Valva Aórtica/diagnóstico por imagem , Fatores de Transcrição , Proteínas Cromossômicas não HistonaRESUMO
Duchenne muscular dystrophy (DMD) is a fatal X-linked genetic disorder affecting approximately 1 in 5000 male births worldwide. DMD is caused by mutations in the dystrophin gene. Dystrophin is essential for maintaining muscle cell membrane integrity and stability by linking the cytoskeleton to the extracellular matrix, which protects myofibers from contraction-induced damage. Loss of dystrophin leads to mechanically induced skeletal and cardiac muscle damage. Although the disease is not evident in DMD patients at birth, muscular dystrophy rapidly progresses and results in respiratory and cardiac muscle failure as early as the teenage years. Premature death in DMD patients is due to cardiac arrhythmias and left ventricular dysfunction. Currently, there is no effective treatment for DMD-related cardiac failure. Recently, we have shown that a Food and Drug Administration-approved small molecule, sunitinib, a multi-targeted tyrosine kinase inhibitor can mitigate skeletal muscle disease through an increase in myogenic capacity, cell membrane integrity, and improvement of skeletal muscle function via regulation of STAT3-related signaling pathway. Chronic activation of STAT3 has been shown to promote cardiac hypertrophy and failure. In this study, we examined the effects of long-term sunitinib treatment on cardiac pathology and function. Our results showed sunitinib treatment reduced STAT3 phosphorylation in the heart muscle of mdx mice, improved cardiac electrical function, increased cardiac output and stroke volume, decreased ventricular hypertrophy, reduced cardiomyocytes membrane damage, fibrotic tissue deposition and slightly decreased cardiac inflammation. Together, our studies support the idea that sunitinib could serve as a novel treatment to slow cardiomyopathy progression in DMD. One Sentence Summary In this study, we determined if sunitinib, a Food and Drug Administration-approved drug, could reduce the pathology and improve cardiac function in an animal model for DMD.
Assuntos
Cardiomiopatias , Distrofia Muscular de Duchenne , Animais , Cardiomiopatias/etiologia , Cardiomiopatias/genética , Modelos Animais de Doenças , Distrofina/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos mdx , Músculo Esquelético/metabolismo , Distrofia Muscular de Duchenne/tratamento farmacológico , Distrofia Muscular de Duchenne/genética , Distrofia Muscular de Duchenne/metabolismo , Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , Fosforilação , Sunitinibe/farmacologia , Sunitinibe/uso terapêuticoRESUMO
Among 301 newly diagnosed patients with acute myeloid leukaemia receiving venetoclax and a hypomethylating agent, 23 (7.6%) experienced major cardiac complications: 15 cardiomyopathy, 5 non-ST elevation myocardial infarction and/or 7 pericarditis/effusions. Four patients had more than one cardiac complication. Baseline characteristics included median age ± interquartile range; 73 ± 5 years; 87% males; 96% with cardiovascular risk factors; and 90% with preserved baseline ejection fraction. In multivariate analysis, males were more likely (p = 0.02) and DNMT3A-mutated cases less likely (p < 0.01) to be affected. Treatment-emergent cardiac events were associated with a trend towards lower composite remission rates (43% vs. 62%; p = 0.09) and shorter survival (median 7.7 vs. 13.2 months; p < 0.01). These observations were retrospectively retrieved and warrant further prospective examination.
Assuntos
Cardiomiopatias , Leucemia Mieloide Aguda , Sulfonamidas , Masculino , Humanos , Feminino , Estudos Retrospectivos , Resultado do Tratamento , Compostos Bicíclicos Heterocíclicos com Pontes/efeitos adversos , Cardiomiopatias/etiologia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversosRESUMO
BACKGROUND: The incidence of sudden cardiac death and sudden death caused by arrhythmia, as determined by autopsy, in persons with human immunodeficiency virus (HIV) infection has not been clearly established. METHODS: Between February 1, 2011, and September 16, 2016, we prospectively identified all new deaths due to out-of-hospital cardiac arrest among persons 18 to 90 years of age, with or without known HIV infection, for comprehensive autopsy and toxicologic and histologic testing. We compared the rates of sudden cardiac death and sudden death caused by arrhythmia between groups. RESULTS: Of 109 deaths from out-of-hospital cardiac arrest among 610 unexpected deaths in HIV-positive persons, 48 met World Health Organization criteria for presumed sudden cardiac death; of those, fewer than half (22) had an arrhythmic cause. A total of 505 presumed sudden cardiac deaths occurred between February 1, 2011, and March 1, 2014, in persons without known HIV infection. Observed incidence rates of presumed sudden cardiac death were 53.3 deaths per 100,000 person-years among persons with known HIV infection and 23.7 deaths per 100,000 person-years among persons without known HIV infection (incidence rate ratio, 2.25; 95% confidence interval [CI], 1.37 to 3.70). Observed incidence rates of sudden death caused by arrhythmia were 25.0 and 13.3 deaths per 100,000 person-years, respectively (incidence rate ratio, 1.87; 95% CI, 0.93 to 3.78). Among all presumed sudden cardiac deaths, death due to occult drug overdose was more common in persons with known HIV infection than in persons without known HIV infection (34% vs. 13%). Persons who were HIV-positive had higher histologic levels of interstitial myocardial fibrosis than persons without known HIV infection. CONCLUSIONS: In this postmortem study, the rates of presumed sudden cardiac death and myocardial fibrosis were higher among HIV-positive persons than among those without known HIV infection. One third of apparent sudden cardiac deaths in HIV-positive persons were due to occult drug overdose. (Supported by the National Heart, Lung, and Blood Institute.).
Assuntos
Cardiomiopatias/etiologia , Morte Súbita Cardíaca/etiologia , Soropositividade para HIV/complicações , Miocárdio/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Autopsia , Causas de Morte , Overdose de Drogas/complicações , Overdose de Drogas/mortalidade , Fibrose , Infecções por HIV/complicações , Humanos , Pessoa de Meia-Idade , Parada Cardíaca Extra-Hospitalar/etiologia , Estudos Prospectivos , Adulto JovemRESUMO
Cardiac hypertrophy is a common feature in several cardiomyopathies. We previously reported that loss of ADAM15 (disintegrin and metalloproteinase 15) worsened cardiac hypertrophy and dilated cardiomyopathy following cardiac pressure overload. Here, we investigated the impact of ADAM15 loss in female mice following cardiac pressure overload induced by transverse aortic constriction (TAC). Female Adam15-/- mice developed the same degree of cardiac hypertrophy, dilation, and dysfunction as the parallel female wild-type (WT) mice at 6 wk post-TAC. To determine if this is due to the protective effects of estrogen, which could mask the negative impact of Adam15 loss, WT and Adam15-/- mice underwent ovariectomy (OVx) 2 wk before TAC. Cardiac structure and function analyses were performed at 6 wk post-TAC. OVx similarly impacted females of both genotypes post-TAC. Calcineurin (Cn) activity was increased post-OVx-TAC, and more in Adam15-/- mice; however, this increase was not reflected in the total-to-phospho-NFAT levels. Integrin-α7 expression, which was upstream of Cn activation in male Adam15-/- -TAC mice, remained unchanged in female mice. However, activation of the mitogen-activated protein kinases (ERK, JNK, P38) was greater in Adam15-/--OVx-TAC than in WT-OVx-TAC mice. In addition, ADAM15 protein levels were significantly increased post-TAC in male but not in female WT mice. Myocardial fibrosis was comparable in non-OVx WT-TAC and Adam15-/- -TAC mice. OVx increased the perivascular fibrosis more in Adam15-/- compared with WT mice post-TAC. Our data demonstrate that loss of ovarian hormones did not fully replicate the male phenotype in the female Adam15-/- mice post-TAC. As ADAM15 levels were increased in males but not in females post-TAC, it is plausible that ADAM15 does not play a prominent role in post-TAC events in female mice. Our findings highlight the significance of factors other than sex hormones in mediating cardiomyopathies in females, which require a more thorough understanding.NEW & NOTEWORTHY Loss of ADAM15 in female mice, unlike the male mice, does not worsen the cardiomyopathy following cardiac pressure overload. Ovariectomy does not worsen the post-TAC cardiomyopathy in female Adam15-/- mice compared with female WT mice. Lack of deleterious impact of Adam15 deficiency in female mice is not because of the protective effects of ovarian hormones but could be due to a less prominent role of ADAM15 in cardiac response to post-TAC remodeling in female mice.
Assuntos
Proteínas ADAM , Proteínas de Membrana , Camundongos Knockout , Ovariectomia , Animais , Feminino , Proteínas ADAM/genética , Proteínas ADAM/metabolismo , Proteínas ADAM/deficiência , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Calcineurina/metabolismo , Calcineurina/genética , Modelos Animais de Doenças , Camundongos , Remodelação Ventricular , Fatores de Transcrição NFATC/metabolismo , Fatores de Transcrição NFATC/genética , Miocárdio/metabolismo , Miocárdio/patologia , Fibrose , Cardiomiopatias/fisiopatologia , Cardiomiopatias/metabolismo , Cardiomiopatias/genética , Cardiomiopatias/etiologia , Cardiomiopatias/patologia , Fatores Sexuais , Transdução de Sinais , Função Ventricular Esquerda , Hipertrofia Ventricular Esquerda/fisiopatologia , Hipertrofia Ventricular Esquerda/metabolismo , Hipertrofia Ventricular Esquerda/genética , Hipertrofia Ventricular Esquerda/patologia , Hipertrofia Ventricular Esquerda/etiologiaRESUMO
Myocardial dysfunction is a prevalent complication of sepsis (septic cardiomyopathy) with a high mortality rate and limited therapeutic options. Naringenin, a natural flavonoid compound with anti-inflammatory and antioxidant properties, holds promise as a potential treatment for sepsis-induced myocardial dysfunction. This study investigated the pharmacological effects of naringenin on septic cardiomyopathy. In vivo and in vitro experiments demonstrated that naringenin improved cardiomyocyte damage. Network pharmacology and database analysis revealed that HIF-1α is a key target protein of naringenin. Elevated expression of HIF-1α was observed in damaged cardiomyocytes, and the HIF-1α inhibitor effectively protected against LPS-induced cardiomyocyte damage. Molecular docking studies confirmed the direct binding between naringenin and HIF-1α protein. Importantly, our findings demonstrated that naringenin did not provide additional attenuation of cardiomyocyte injury on the biases of HIF-1α inhibitor treatment. In conclusion, this study proves that naringenin protects against septic cardiomyopathy through HIF-1α signaling. Naringenin is a promising therapeutic candidate for treating septic cardiomyopathy.
Assuntos
Cardiomiopatias , Flavanonas , Sepse , Animais , Camundongos , Cardiomiopatias/tratamento farmacológico , Cardiomiopatias/etiologia , Cardiomiopatias/prevenção & controle , Lipopolissacarídeos/farmacologia , Simulação de Acoplamento Molecular , Miócitos Cardíacos/metabolismo , Sepse/complicações , Sepse/tratamento farmacológico , Sepse/metabolismo , Subunidade alfa do Fator 1 Induzível por HipóxiaRESUMO
Fatty acid oxidation disorders (FAODs) are a family of rare, genetic disorders that affect any part of the fatty acid oxidation pathway. Patients present with severe phenotypes, such as hypoketotic hypoglycemia, cardiomyopathy, and rhabdomyolysis, and currently manage these symptoms by the avoidance of fasting and maintaining a low-fat, high-carbohydrate diet. Because knowledge about FAODs is limited due to the small number of patients, rodent models have been crucial in learning more about these disorders, particularly in studying the molecular mechanisms involved in different phenotypes and in evaluating treatments for patients. The purpose of this review is to present the different FAOD mouse models and highlight the benefits and limitations of using these models. Specifically, we discuss the phenotypes of the available FAOD mouse models, the potential molecular causes of prominent FAOD phenotypes that have been studied using FAOD mouse models, and how FAOD mouse models have been used to evaluate treatments for patients.
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Modelos Animais de Doenças , Ácidos Graxos , Erros Inatos do Metabolismo Lipídico , Oxirredução , Animais , Camundongos , Ácidos Graxos/metabolismo , Humanos , Erros Inatos do Metabolismo Lipídico/genética , Erros Inatos do Metabolismo Lipídico/metabolismo , Erros Inatos do Metabolismo Lipídico/patologia , Fenótipo , Cardiomiopatias/metabolismo , Cardiomiopatias/genética , Cardiomiopatias/patologia , Cardiomiopatias/etiologiaRESUMO
PURPOSE OF REVIEW: Cardiomyopathy in chronic kidney disease (CKD) is a complex condition with multiple triggers and poor prognosis. This review provides an overview of recent advances in CKD-associated cardiomyopathy, with a focus on pathophysiology, newly discovered biomarkers and potential therapeutic targets. RECENT FINDINGS: CKD is associated with a specific pattern of myocardial hypertrophy and fibrosis, resulting in diastolic and systolic dysfunction, and often triggered by nonatherosclerotic processes. Novel biomarkers, including amino-terminal type III procollagen peptide (PIIINP), carboxy-terminal type I procollagen peptide (PICP), FGF23, marinobufagenin, and several miRNAs, show promise for early detection and risk stratification. Treatment options for CKD-associated cardiomyopathy are limited. Sodium glucose cotransporter-2 inhibitors have been shown to reduce left ventricle hypertrophy and improve ejection fraction in individuals with diabetes and mild CKD, and are currently under investigation for more advanced stages of CKD. In hemodialysis patients calcimimetic etelcalcetide resulted in a significant reduction in left ventricular mass. SUMMARY: CKD-associated cardiomyopathy is a common and severe complication in CKD. The identification of novel biomarkers may lead to future therapeutic targets. Randomized clinical trials in individuals with more advanced CKD would be well posed to expand treatment options for this debilitating condition.
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Cardiomiopatias , Insuficiência Renal Crônica , Humanos , Peptídeos , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/terapia , Hipertrofia Ventricular Esquerda/etiologia , Cardiomiopatias/tratamento farmacológico , Cardiomiopatias/etiologia , BiomarcadoresRESUMO
OBJECTIVE: Myocardial fibrosis occurs in the early subclinical stage of cardiac involvement in idiopathic inflammatory myopathies (IIMs). Soluble suppression of tumorigenicity 2 (sST2) is known to have an immunomodulatory impact during autoimmune disease development. The current study investigated the diagnostic value of sST2 for myocardial fibrosis during early stage of cardiac involvement in IIM. METHODS: A total of 44 IIM patients with normal heart function and 32 age- and gender-matched healthy controls (HCs) were enrolled. Serum sST2 levels were measured by ELISA and cardiac magnetic resonance (CMR) parameters for myocardial fibrosis [native T1, extracellular volume (ECV), late-gadolinium enhancement (LGE)] and oedema (T2 values) were analysed. RESULTS: IIM patients had significantly higher sST2 levels than HCs [67.5 ng/ml (s.d. 30.4)] vs 14.4 (5.5), P < 0.001] and levels correlated positively with diffuse myocardial fibrosis parameters, native T1 (r = 0.531, P = 0.000), ECV (r = 0.371, P = 0.013) and focal myocardial fibrosis index and LGE (r = 0.339, P = 0.024) by Spearman's correlation analysis. sST2 was an independent predictive factor for diffuse and focal myocardial fibrosis after adjustment for age, gender, BMI and ESR. Risk increased ≈15.4% for diffuse [odds ratio (OR) 1.154 (95% CI 1.021, 1.305), P = 0.022] and 3.8% for focal [OR 1.038 (95% CI 1.006, 1.072), P = 0.020] myocardial fibrosis per unit increase of sST2. Cut-off values for diagnosing diffuse and focal myocardial fibrosis were sST2 ≥51.3 ng/ml [area under the curve (AUC) = 0.942, sensitivity = 85.7%, specificity = 98.9%, P < 0.001] and 53.3 ng/ml (AUC = 0.753, sensitivity = 87.5%, specificity = 58.3%, P < 0.01), respectively. CONCLUSION: sST2 showed a marked elevation during the subclinical stage of cardiac involvement in IIM and has potential as a biomarker for predicting diffuse and focal myocardial fibrosis in IIM.
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Cardiomiopatias , Miosite , Humanos , Meios de Contraste , Gadolínio , Cardiomiopatias/diagnóstico por imagem , Cardiomiopatias/etiologia , FibroseRESUMO
INTRODUCTION: Despite advancements in implantable cardioverter-defibrillator (ICD) technology, sudden cardiac death (SCD) remains a persistent public health concern. Chagas disease (ChD), prevalent in Brazil, is associated with increased ventricular tachycardia (VT) and ventricular fibrillation (VF) events and SCD compared to other cardiomyopathies. METHODS: This retrospective observational study included patients who received ICDs between October 2007 and December 2018. The study aims to assess whether mortality and VT/VF events decreased in patients who received ICDs during different time periods (2007-2010, 2011-2014, and 2015-2018). Additionally, it seeks to compare the prognosis of ChD patients with non-ChD patients. Time periods were chosen based on the establishment of the Arrhythmia Service in 2011. The primary outcome was overall mortality, assessed across the entire sample and the three periods. Secondary outcomes included VT/VF events and the combined outcome of death or VT/VF. RESULTS: Of the 885 patients included, 31% had ChD. Among them, 28% died, 14% had VT/VF events, and 37% experienced death and/or VT/VF. Analysis revealed that period 3 (2015-2018) was associated with better death-free survival (p = .007). ChD was the only variable associated with a higher rate of VT/VF events (p < .001) and the combined outcome (p = .009). CONCLUSION: Mortality and combined outcome rates decreased gradually for ICD patients during the periods 2011-2014 and 2015-2018 compared to the initial period (2007-2010). ChD was associated with higher VT/VF events in ICD patients, only in the first two periods.
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Cardiomiopatias , Desfibriladores Implantáveis , Taquicardia Ventricular , Humanos , Cardiomiopatias/etiologia , Morte Súbita Cardíaca/epidemiologia , Morte Súbita Cardíaca/prevenção & controle , Morte Súbita Cardíaca/etiologia , Desfibriladores Implantáveis/efeitos adversos , América Latina , Taquicardia Ventricular/diagnóstico , Taquicardia Ventricular/terapia , Taquicardia Ventricular/etiologia , Fibrilação Ventricular/diagnóstico , Fibrilação Ventricular/terapia , Fibrilação Ventricular/etiologia , Estudos RetrospectivosRESUMO
INTRODUCTION: Right ventricular (RV) pacing sometimes causes left ventricular (LV) systolic dysfunction, also known as pacing-induced cardiomyopathy (PICM). However, the association between specifically paced QRS morphology and PICM development has not been elucidated. This study aimed to investigate the association between paced QRS mimicking a complete left bundle branch block (CLBBB) and PICM development. METHODS: We retrospectively screened 2009 patients who underwent pacemaker implantation from 2010 to 2020 in seven institutions. Patients who received pacemakers for an advanced atrioventricular block or bradycardia with atrial fibrillation, baseline LV ejection fraction (LVEF) ≥ 50%, and echocardiogram recorded at least 6 months postimplantation were included. The paced QRS recorded immediately after implantation was analyzed. A CLBBB-like paced QRS was defined as meeting the CLBBB criteria of the American Heart Association/American College of Cardiology Foundation/Heart Rhythm Society in 2009. PICM was defined as a ≥10% LVEF decrease, resulting in an LVEF of <50%. RESULTS: Among the 270 patients analyzed, PICM was observed in 38. Baseline LVEF was lower in patients with PICM, and CLBBB-like paced QRS was frequently observed in PICM. Multivariate analysis revealed that low baseline LVEF (odds ratio [OR]: 0.93 per 1% increase, 95% confidence interval [CI]: 0.89-0.98, p = 0.006) and CLBBB-like paced QRS (OR: 2.69, 95% CI: 1.25-5.76, p = 0.011) were significantly associated with PICM development. CONCLUSION: CLBBB-like paced QRS may be a novel risk factor for PICM. RV pacing, which causes CLBBB-like QRS morphology, may need to be avoided, and patients with CLBBB-like paced QRS should be followed-up carefully.