RESUMO
Arrhythmogenic cardiomyopathy (ACM) is an umbrella term encompassing a wide variety of overlapping hereditary and nonhereditary disorders that can result in malignant ventricular arrhythmias and sudden cardiac death. Cardiac MRI plays a critical role in accurate diagnosis of various ACM entities and is increasingly showing promise in risk stratification that can further guide management particularly in decisions regarding use of implantable cardioverter defibrillator. Genotyping plays an important role in cascade testing but challenges remain due to incomplete penetrance and wide phenotypic variability of ACM as well as the presence of gene-elusive cases.
Assuntos
Cardiomiopatias , Desfibriladores Implantáveis , Humanos , Coração , Imageamento por Ressonância Magnética , Morte Súbita Cardíaca/etiologia , Morte Súbita Cardíaca/prevenção & controle , Cardiomiopatias/diagnóstico por imagemRESUMO
It is well accepted that hypertension may lead to the development of heart failure (HF). However, little is known about the development of hypotension that may contribute to the onset of hereditary cardiomyopathy (HCM), thus promoting heart failure and early death. The purpose of this study is to verify whether a decrease in blood pressure takes place during different phases of HCM (asymptomatic, necrosis, hypertrophy, and heart failure). Using the well-known animal model, the UM-X7.1 hamster strain of HCM (HCMH), our results showed the absence of a change in mean arterial pressure (MAP) during the asymptomatic phase preceding the development of necrosis in HCMHs when compared to age-matched normal hamster (NH). However, there was a progressive decrease in MAP that reached its lowest level during the heart failure phase. The MAP during the development of the necrosis phase of HCM was accompanied by a significant increase in the level of the sodium-hydrogen exchanger, NHE1. Treatments with the potent NHE1 inhibitor, EMD 87580 (rimeporide), did not affect MAP of NH. However, treatments with EMD 87580 during the three phases of the development of HCM significantly reversed the hypotension associated with HCM.Our results showed that the development of HCM is associated with hypotension. These results suggest that a decrease in blood pressure could be a biomarker signal for HCM leading to HF and early death. Since the blockade of NHE1 significantly but partially prevented the reduction in MAP, this suggests that other mechanisms can contribute to the development of hypotension in HCM.
Assuntos
Cardiomiopatias , Cardiomiopatia Hipertrófica , Insuficiência Cardíaca , Hipotensão , Animais , Cardiomiopatias/etiologia , Cricetinae , Necrose/complicações , Trocadores de Sódio-HidrogênioRESUMO
Hereditary cardiac disease accounts for a large proportion of sudden cardiac death (SCD) in young adults. Hereditary cardiac disease can be divided into hereditary structural heart disease and channelopathies. Hereditary structural heart disease mainly includes hereditary cardiomyopathy, which results in arhythmia, heart failure and SCD. The autopsy and histopathological examinations of SCD caused by channelopathies lack characteristic morphological manifestations. Therefore, how to determine the cause of death in the process of examination has become one of the urgent problems to be solved in forensic identification. Based on the review of recent domestic and foreign research results on channelopathies and hereditary cardiomyopathy, this paper systematically reviews the pathogenesis and molecular genetics of channelopathies and hereditary cardiomyopathy, and discusses the application of postmortem genetic testing in forensic identification, to provide reference for forensic pathology research and identification of SCD.
Assuntos
Canalopatias , Cardiopatias , Autopsia/métodos , Canalopatias/complicações , Canalopatias/genética , Morte Súbita Cardíaca/etiologia , Morte Súbita Cardíaca/patologia , Testes Genéticos , Cardiopatias/complicações , Cardiopatias/diagnóstico , Cardiopatias/genética , Humanos , Adulto JovemRESUMO
Heart failure (HF) is a syndrome encompassing several important etiologies that lead to the imbalance between oxygen demand and supply. Despite the usage of guideline-directed medical therapy for HF has shown better outcomes, novel therapeutic strategies are desirable, especially for patients with preserved or mildly reduced left ventricular ejection fraction. In this regard, understanding the molecular basis for cardiomyopathies is expected to fill in the knowledge gap and generate new therapies to improve prognosis for HF. This review discusses an evolutionary mechanism designed to regulate cardiac contraction and relaxation through the most often genetically determined cardiomyopathies associated with HF. In addition, both the myosin inhibitor and myosin activator are promising new treatments for cardiomyopathies. A comprehensive review from genetic mutations to the molecular basis of direct sarcomere modulators will help shed light on future studies for a better characterization of HF etiologies and potential therapeutic targets.
Assuntos
Benzilaminas/uso terapêutico , Miosinas Cardíacas/genética , Insuficiência Cardíaca/tratamento farmacológico , Terapia de Alvo Molecular , Uracila/análogos & derivados , Ureia/análogos & derivados , Benzilaminas/farmacologia , Miosinas Cardíacas/antagonistas & inibidores , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/patologia , Humanos , Miócitos Cardíacos/patologia , Uracila/farmacologia , Uracila/uso terapêutico , Ureia/farmacologia , Ureia/uso terapêuticoRESUMO
During the development of heart failure in humans and animal models, an increase in reactive oxygen species (ROS) levels was observed. However, there is no information whether this increase of ROS is associated with an increase in the density of specific isoforms of NADPH oxidases (NOXs) 1-5. The objective of this study was to verify whether the densities of NOXs 1-5 change during the development of heart failure. Using the well-known model of cardiomyopathic hamsters, the UM-X 7.1 line, a model that strongly resembles the pathology observed in humans from a morphological and functional point of view, our studies showed that, as in humans, NOXs 1-5 are present in both normal and UM-X7.1 hamster hearts. Even though the densities of NOXs 2 and 5 were unchanged, the levels of both NOXs 1 and 4 significantly decreased in UM-X7.1 hamster hearts during heart failure. These changes were accompanied with a significant increase in NOX3 level. These results suggest that, during heart failure, NOX3 plays a vital role in compensating the decrease of NOXs 1 and 4. This increase in NOX3 may also be responsible, at least in part, for the reported increase in ROS levels in heart failure.
Assuntos
Cardiomiopatias/complicações , Cardiomiopatias/genética , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/enzimologia , NADPH Oxidases/metabolismo , Animais , CricetinaeRESUMO
PURPOSE OF REVIEW: Genetic testing has become an important element in the care of patients with inherited cardiac conditions (ICCs). The purpose of this review is to provide clinicians with insights into the utility of genetic testing as well as challenges associated with interpreting results. RECENT FINDINGS: Genetic testing may be indicated for individuals who are affected with or who have family histories of various ICCs. Various testing options are available and determining the most appropriate test for any given clinical scenario is key when interpreting results. Newly published guidelines as well as various publicly accessible tools are available to clinicians to help with interpretation of genetic findings; however the subjectivity with respect to variant classification can make accurate assessment challenging. Genetic information can provide highly useful and relevant information for patients, their family members, and their healthcare providers. Given the potential ramifications of variant misclassification, expertise in both clinical phenotyping and molecular genetics is imperative in order to provide accurate diagnosis, management recommendations, and family risk assessment for this patient population.
Assuntos
Testes Genéticos/métodos , Cardiopatias/diagnóstico , Cardiopatias/genética , Humanos , Guias de Prática Clínica como Assunto , Medição de RiscoRESUMO
Background Hereditary cardiomyopathies are commonly occurring myocardial conditions affecting heart structure and function with a genetic or familial association, but the etiology is often unknown. Cardiomyopathies are linked to significant mortality, requiring robust risk stratification with genetic testing and early diagnosis. Hypothesis We hypothesized that health care disparities exist in genetic testing for hereditary cardiomyopathies within clinical practice and research studies. Methods In a narrative fashion, we conducted a literature search with online databases such as PubMed/MEDLINE, Google Scholar, EMBASE, and Science Direct on papers related to hereditary cardiomyopathies. A comprehensive analysis of findings from articles in English on disparities in diagnostics and treatment was grouped into four categories. Results Racial and ethnic disparities in research study enrollment and health care delivery favor White populations and higher socioeconomic status, resulting in differences in the development and implementation of effective genetic screening. Such disparities have shown to be detrimental, as minorities often suffer from disease progression to heart failure and sudden cardiac death. Barriers related to clinical genetic testing included insurance-related issues and health illiteracy. The underrepresentation of minority populations extends to research methodologies, as testing in ethnic minorities resulted in a significantly lower detection rate and diagnostic yield, as well as a higher likelihood of misclassification of variants. Conclusions Prioritizing minority-based participatory research programs and screening protocols can address systemic disparities. Diversifying research studies can improve risk stratification strategies and impact clinical practice.
RESUMO
Recently, we reported that during the hypertrophic phase (230 days old) of hereditary cardiomyopathy of the hamster (HCMH), short-term treatment (20 days) with 250 mg/kg/day of taurine prevents the development of hypertrophy in males but not in females. However, the mortality rate in non-treated animals was higher in females than in males. To verify whether the sex-dependency effect of taurine is due to the difference in the disease's progression, we treated the 230-day-old animals for a longer time period of 122 days. Our results showed that long-term treatment with low and high concentrations of taurine significantly prevents cardiac hypertrophy and early death in HCMH males (p < 0.0001 and p < 0.05, respectively) and females (p < 0.01 and p < 0.0001, respectively). Our results demonstrate that the reported sex dependency of short-term treatments with taurine is due to a higher degree of heart remodeling in females when compared to males and not to sex dependency. In addition, sex-dependency studies should consider the differences between the male and female progression of the disease. Thus, long-term taurine therapies are recommended to prevent remodeling and early death in hereditary cardiomyopathy.
Assuntos
Cardiomiopatias , Mortalidade Prematura , Feminino , Masculino , Animais , Cricetinae , Cardiomiopatias/prevenção & controle , Coração , Taurina/farmacologia , Taurina/uso terapêutico , Cardiomegalia/tratamento farmacológico , Cardiomegalia/prevenção & controleRESUMO
Background: Desmin is an intermediate filament protein that plays a critical role in the stabilization of the sarcomeres and cell contacts in the cardiac intercalated disk. Mutated DES gene can cause hereditary cardiomyopathy with heterogeneous phenotypes, while the underlying molecular mechanisms requires further investigation. Methods: We described a Chinese family present with cardiomyopathy and sudden cardiac death (SCD). Whole-exome sequencing (WES) and bioinformatics strategies were employed to explore the genetic entity of this family. Results: An unknown heterozygote missense variant (c.1300G > A; p. E434K) of DES gene was identified. The mutation cosegregates in this family. The mutation was predicted as pathogenic and was absent in our 200 healthy controls. Conclusion: We identified a novel DES mutation (p. E434K) in a Chinese family with cardiomyopathy and SCD. Our study not only provided a new case for the study of the relationship between DES mutations and hereditary cardiomyopathy but also broadened the spectrum of DES mutations.
RESUMO
Premature death due to heart failure is a major health problem. Taurine is a non-essential amino acid that has received much attention. However, although many studies have been carried out on the beneficial effects of taurine in cardiac pathophysiology, no studies have investigated the effect of taurine treatment on the development of hereditary cardiomyopathy (HCM) associated with hypertrophy, heart failure, and early death. This study aims to verify whether short-term treatment (20 days) with taurine in tap water prevents the development of hypertrophy and premature death in hereditary cardiomyopathy of the hamster (HCMH) of the line UM-X7.1 and if its effect is sex-dependent. Our results show that treatment for 20 days with taurine (250 mg/kg/day or 25 mg/animal/day) during the development of the hypertrophic phase (220 days old) significantly decreased (p < 0.01) the heart weight to body weight ratio in male HCMHs without affecting the female. During the 20 days (220−240 days old), there were nearly 40% premature deaths in non-treated males HCMHs and 50% in female HCMHs. Treatment for 20 days wholly and significantly prevented early death in both males and females HCMHs. Our results demonstrate that short-term treatment with taurine prevents the development of cardiac hypertrophy associated with HCM in a sex-dependent manner; however, it prevents early death in a sex-independent fashion. Our results suggest that taurine supplementation could be used to treat HCM.
Assuntos
Cardiomiopatias , Cardiomiopatia Hipertrófica , Insuficiência Cardíaca , Animais , Cardiomegalia/tratamento farmacológico , Cardiomegalia/prevenção & controle , Cardiomiopatia Hipertrófica/metabolismo , Cricetinae , Feminino , Masculino , Taurina/farmacologia , Taurina/uso terapêuticoRESUMO
BACKGROUND: Cardiac complications in Fabry disease are frequent and dominated by a high frequency of left ventricular hypertrophy; therefore, cardiologists may have an essential role in screening for this disease. Providing cardiologists with targeted information on Fabry disease would be valuable and could reduce both diagnostic and therapeutic delays. The aim of this study was to evaluate the efficiency of such strategy for Fabry screening. METHODS: We conducted a before-after control-impact study by comparing observations made before and after targeted information on Fabry disease among cardiologists. The information on Fabry disease consisted of (1) an educational booklet, (2) oral information and (3) screening kits. The programme was evaluated at the end of a 12-month study period. RESULTS: Forty-two cardiologists participated to this study. None of them had conducted screening test and new diagnostic for Fabry disease in the 3 years prior the information. After the information, screening with dried blood spots was performed in 55 patients (ranged 18-77 years, men: 39) with cardiac monitoring for supposed sarcomeric hypertrophic cardiomyopathy (n=41) or unexplained left ventricular hypertrophy (n=14) from January 2015 to January 2016. Two new cases of Fabry disease were diagnosed (3.4%) in two men (ages 58 and 51 years). The information was deemed relevant in both content and structure and was deemed useful for everyday practice. CONCLUSION: Cardiologists valued the targeted information on Fabry disease. This information had a direct clinical impact by allowing the diagnosis of two new families with Fabry disease.