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Formin homology 2 domain-containing 3 (FHOD3) gene has emerged as one of the main non-sarcomeric genes associated with hypertrophic cardiomyopathy (HCM), but no cases of biallelic variants associated with disease have been described to date. From 2014 until 2021, FHOD3 was evaluated in our center by next-generation sequencing in 22 806 consecutive unrelated probands. The p.Arg637Gln variant in FHOD3 was enriched in our HCM cohort (284 of 9668 probands; 2.94%) compared with internal controls (64 of 11 480; 0.59%) and gnomAD controls (373 of 64 409; 0.58%), with ORs of 5.40 (95% CI: 4.11 to 7.09) and 5.19 (95% CI: 4.44 to 6.07). The variant affects a highly conserved residue localised in a supercoiled alpha helix considered a clustering site for HCM variants, and in heterozygosis can act as a predisposing factor (intermediate-effect variant) for HCM, with an estimated penetrance of around 1%. Additionally, seven homozygous carriers of p.Arg637Gln in FHOD3 were identified. All but one (unaffected) showed an early presentation and a severe HCM phenotype. All this information suggest that p.Arg637Gln variant in FHOD3 is a low-penetrant variant, with an intermediate effect, that contributes to the development of HCM in simple heterozygosis, being associated with a more severe phenotype in homozygous carriers.
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Cardiomiopatia Hipertrófica , Humanos , Cardiomiopatia Hipertrófica/genética , Fenótipo , Homozigoto , Penetrância , Heterozigoto , Forminas/genéticaRESUMO
Uterine leiomyomas (ULs) are the most common benign tumors in women of reproductive age. Despite the high prevalence, tumor pathology remains unclear, which hampers the development of safe and effective treatments. Epigenetic mechanisms appear to be involved in UL development, particularly via DNA methylation that regulates gene expression. We aimed to determine the relationship between DNA methylation and gene expression in UL compared with adjacent myometrium (MM) to identify molecular mechanisms involved in UL formation that are under epigenetic control. Our results showed a different DNA methylation profile between UL and MM, leading to hypermethylation of UL, and a different global transcriptome profile. Integration of DNA methylation and whole-transcriptome RNA-sequencing data identified 93 genes regulated by methylation, with 22 hypomethylated/upregulated and 71 hypermethylated/downregulated. Functional enrichment analysis showed dysregulated biological processes and molecular functions involved in metabolism and cell physiology, response to extracellular signals, invasion, and proliferation, as well as pathways related to uterine biology and cancer. Cellular components such as cell membranes, vesicles, extracellular matrix, and cell junctions were dysregulated in UL. In addition, we found hypomethylation/upregulation of oncogenes (PRL, ATP8B4, CEMIP, ZPMS2-AS1, RIMS2, TFAP2C) and hypermethylation/downregulation of tumor suppressor genes (EFEMP1, FBLN2, ARHGAP10, HTATIP2), which are related to proliferation, invasion, altered metabolism, deposition of extracellular matrix, and Wnt/ß-catenin pathway dysregulation. This confirms that key processes of UL development are under DNA methylation control. Finally, inhibition of DNA methyltransferases by 5-aza-2'-deoxycitidine increased the expression of hypermethylated/downregulated genes in UL cells in vitro. In conclusion, gene regulation by DNA methylation is implicated in UL pathogenesis, and reversion of this methylation could offer a therapeutic option for UL. © 2022 The Pathological Society of Great Britain and Ireland.
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Leiomioma , Neoplasias Uterinas , Acetiltransferases/genética , Acetiltransferases/metabolismo , Proliferação de Células/genética , Metilação de DNA , Epigenoma , Matriz Extracelular/patologia , Proteínas da Matriz Extracelular/metabolismo , Feminino , Humanos , Leiomioma/genética , Leiomioma/metabolismo , Leiomioma/patologia , Fatores de Transcrição/genética , Transcriptoma , Neoplasias Uterinas/genética , Neoplasias Uterinas/metabolismo , Neoplasias Uterinas/patologiaRESUMO
Fabry disease is a rare X-linked inherited lysosomal storage disorder caused by the absence or reduction of alfa-galactosidase A activity in lysosomes, resulting in accumulation of glycosphingolipids in various tissues. The main organ affected is the heart, which frequently manifests as left ventricular hypertrophy and can ultimately lead to cardiac fibrosis, heart failure, valve disease, cardiac conduction abnormalities and sudden cardiac death. Today we know that myocyte damage starts before these signs and symptoms are detectable on routine studies, during the designated pre-clinical phase of Fabry disease. The initiation of specific therapy for Fabry disease during the early stages of the disease has a great impact on the prognosis of these patients avoiding progression to irreversible fibrosis and preventing cardiovascular complications. Cardiac imaging has become an essential tool in the management of Fabry disease as it can help physicians suspect the disorder, diagnose patients in the early stages and improve outcomes. The recent development of novel imaging techniques makes necessary an update on the subject. This review discusses the role of multimodal imaging in the diagnosis, staging, patient selection for treatment and prognosis of Fabry disease and discusses recent advances in imaging techniques that provide new insights into the pathogenesis of the disorder and the possibility of novel treatment targets.
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AIMS: To compare the clinical and epidemiological characteristics and the evolution of infective endocarditis in adults aged under 65 years, 65-79 years, and 80 years or older. METHODS: An observational retrospective cohort study in patients with infective endocarditis was performed in a public hospital in Spain from January 2013 to December 2017. RESULTS: Seventy-two patients were treated: 26 (36.1%) were under 65 years old, 28 (38.9%) were 65-79 years old, and 18 (25%) were aged 80 or older. Prosthetic valve endocarditis was less common in patients aged 65-79 years (3.6%) than in younger (23.1%; p = 0.047) or older (38.9%; p = 0.004) patients. In contrast, degenerative heart disease was more prevalent in the 65-79 year age group [64.3% compared to 15.4% (p < 0.001) in the youngest group, and 33.3% (p = 0.04) in the oldest]. Surgical interventions were similar in patients aged 65-79 (50%) and under 65 years (42.3%), but less common in people over 80 years (16.7%; p = 0.022). CONCLUSIONS: The characteristics of infective endocarditis are different in patients aged 65-79 years and in those over 80 years.
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Endocardite/epidemiologia , Distribuição por Idade , Idoso , Idoso de 80 Anos ou mais , Ecocardiografia , Humanos , Pessoa de Meia-Idade , Estudos Retrospectivos , Espanha/epidemiologiaRESUMO
PURPOSE: Despite the benefits of a loop ileostomy after total mesorectal excision (TME), it carries a significant associated morbidity. A "virtual ileostomy" (VI) has been proposed to avoid ileostomies in low-risk patients, which could then be converted into a real ileostomy (RI) in the event of anastomotic leak (AL). The aim of the present study is to evaluate safety and efficacy of VI associated with early endoscopy in patients undergoing rectal surgery with anastomosis to detect subclinical AL prior to the onset of clinical symptoms for sepsis. METHODS: This is a single-center, retrospective study of a consecutive series of patients undergoing elective or emergent colorectal surgery with low or ultralow colorectal or ileorectal anastomosis between September 2015 and September 2016. RESULTS: We included 44 consecutive, unselected patients. Eight patients (18.2%) required conversion into RI and one required terminal colostomy because of AL, of whom 44.4% were asymptomatic and AL was detected with early endoscopy. Fashioning of RI was not associated with further morbidity. All patients with AL converted into RI (n = 8/9) (88.9%), had adequate healed anastomosis, and later underwent stoma closure with no complications. A stoma was avoided in 79.6% of VI. Endoscopy was associated with 55% sensitivity and 100% specificity, with a global accuracy of 88%. CONCLUSIONS: The combination of VI with early postoperative endoscopy could avoid unnecessary ileostomies in patients with low or ultralow anastomoses and reveal AL before the onset of symptoms, thus reducing associated morbidity.
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Neoplasias Colorretais/cirurgia , Endoscopia Gastrointestinal , Ileostomia/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Anastomose Cirúrgica , Fístula Anastomótica/cirurgia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Estudos RetrospectivosRESUMO
AIMS: Physical activity (PA) is an important target for improving clinical outcomes in heart failure (HF) patients. Nonetheless, assessing the daily PA profile in this population is a challenging task, traditionally performed using self-report questionnaires such as the International PA Questionnaire Short Form (IPAQ-SF). This study aimed to evaluate the concurrent validity of the IPAQ-SF and accelerometer-assessed PA using six published cut-points in patients with HF and reduced or mildly reduced ejection fraction. METHODS AND RESULTS: The concordance between the IPAQ-SF and a hip-worn accelerometer regarding daily time spent performing moderate to vigorous PA in bouts of at least 10 min was assessed in 53 participants for seven consecutive days using six different cut-points (Barnett, Dibben, Mark, Sanders, Troiano, and Vaha-Ypya). Spearman's correlation and Bland-Altman plots were used to evaluate concurrent validity between methods. Regressions were used to study the association between patient variables, wear protocol (waking hour or 24 h), and absolute bias. The kappa index was used to evaluate the concordance between IPAQ-SF and accelerometry for classifying patients as active or non-active. All analyses were re-run using non-bouted metrics to investigate the effect of bouted versus non-bouted analysis. The IPAQ-SF and accelerometry showed low to negligible correlation (ρ = 0.12 to 0.37), depending on the cut-point used. The regression analysis showed that the absolute bias was higher in participants following the waking-hour protocol at all cut-points except Dibben's (P ≤ 0.007). The concordance between the two methods to classify patients as active and non-active was low when using Mark (κ = 0.23) and Barnett (κ = 0.34) cut-points and poor for the remaining cut-points (κ = 0.03 to 0.18). The results of the sensitivity analysis showed negligible to low correlation using non-bouted metrics (ρ = 0.27 to 0.33). CONCLUSIONS: Moderate to vigorous PA measures using IPAQ-SF and accelerometers are not equivalent, and we do not encourage researchers to use IPAQ-SF alone when assessing PA in HF patients. Moreover, applying personalized collection and processing criteria is important when assessing PA in HF patients. We recommend following the 24 h protocol and selecting cut-points calibrated in patients with cardiovascular diseases. Finally, it is necessary to develop a new tailored questionnaire that considers walking intensity and is adjusted to the current World Health Organisation recommendations, which use non-bouted metrics.
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Exercício Físico , Insuficiência Cardíaca , Humanos , Inquéritos e Questionários , Autorrelato , Acelerometria , Insuficiência Cardíaca/diagnósticoRESUMO
BACKGROUND: Disease penetrance in genotype-positive (G+) relatives of families with dilated cardiomyopathy (DCM) and the characteristics associated with DCM onset in these individuals are unknown. OBJECTIVES: This study sought to determine the penetrance of new DCM diagnosis in G+ relatives and to identify factors associated with DCM development. METHODS: The authors evaluated 779 G+ patients (age 35.8 ± 17.3 years; 459 [59%] females; 367 [47%] with variants in TTN) without DCM followed at 25 Spanish centers. RESULTS: After a median follow-up of 37.1 months (Q1-Q3: 16.3-63.8 months), 85 individuals (10.9%) developed DCM (incidence rate of 2.9 per 100 person-years; 95% CI: 2.3-3.5 per 100 person-years). DCM penetrance and age at DCM onset was different according to underlying gene group (log-rank P = 0.015 and P <0.01, respectively). In a multivariable model excluding CMR parameters, independent predictors of DCM development were: older age (HR per 1-year increase: 1.02; 95% CI: 1.0-1.04), an abnormal electrocardiogram (HR: 2.13; 95% CI: 1.38-3.29); presence of variants in motor sarcomeric genes (HR: 1.92; 95% CI: 1.05-3.50); lower left ventricular ejection fraction (HR per 1% increase: 0.86; 95% CI: 0.82-0.90) and larger left ventricular end-diastolic diameter (HR per 1-mm increase: 1.10; 95% CI: 1.06-1.13). Multivariable analysis in individuals with cardiac magnetic resonance and late gadolinium enhancement assessment (n = 360, 45%) identified late gadolinium enhancement as an additional independent predictor of DCM development (HR: 2.52; 95% CI: 1.43-4.45). CONCLUSIONS: Following a first negative screening, approximately 11% of G+ relatives developed DCM during a median follow-up of 3 years. Older age, an abnormal electrocardiogram, lower left ventricular ejection fraction, increased left ventricular end-diastolic diameter, motor sarcomeric genetic variants, and late gadolinium enhancement are associated with a higher risk of developing DCM.
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Cardiomiopatia Dilatada , Genótipo , Penetrância , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem , Cardiomiopatia Dilatada/genética , Cardiomiopatia Dilatada/fisiopatologia , Conectina/genética , Eletrocardiografia , Seguimentos , Espanha/epidemiologia , Estudos RetrospectivosRESUMO
BACKGROUND: Exercise-based cardiac rehabilitation (CR) is considered an effective treatment for enhancing endothelial function in patients with heart failure (HF). However, recent studies have been published and the optimal "dose" of exercise required to increase the benefits of exercise-based CR programmes on endothelial function is still unknown. OBJECTIVES: (a) To estimate the effect of exercise-based CR on endothelial function, assessed by flow-mediated dilation (FMD), in patients with HF; (b) to determine whether high-intensity interval training (HIIT) is better than moderate-intensity training (MIT) for improving FMD; and (c) to investigate the influence of exercise modality (i.e. resistance exercise vs. aerobic exercise and combined exercise vs. aerobic exercise) on the improvement of endothelial function. METHODS: Electronic searches were carried out in PubMed, Embase, and Scopus up to February 2022. Random-effects models of between-group mean differences were estimated. Heterogeneity analyses were performed by means of the chi-square test and I2 index. Subgroup analyses and meta-regressions were used to test the influence of potential moderator variables on the effect of exercise. RESULTS: We found a FMD increase of 3.09% (95% confidence interval [CI] = 2.01, 4.17) in favour of aerobic-based CR programmes compared with control groups in patients with HF and reduced ejection fraction (HFrEF). However, the results of included studies were inconsistent (p < .001; I2 = 95.2%). Higher FMD improvement was found in studies which were randomised, reported radial FMD, or performed higher number of training sessions a week. Moreover, HIIT enhanced FMD to a greater extent than MIT (2.35% [95% CI = 0.49, 4.22]) in patients with HFrEF. Insufficient data prevented pooled analyses for the effect of exercise in patients with HF and preserved ejection fraction and the influence of exercise modality on the improvement of endothelial function. CONCLUSION: Aerobic-based CR is a non-pharmacological treatment for enhancing endothelial function in patients with HFrEF. However, higher training frequency and HIIT induce greater adaptation of endothelial function in these patients, which should betaken into consideration when designing exercise-based CR programmes. Trial registration The protocol was prospectively registered on the PROSPERO database (CRD42022304687).
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The verification phase (VP) has been proposed as an alternative to the traditional criteria used for the determination of the maximum oxygen uptake (VO2 max) in several populations. Nonetheless, its validity in patients with heart failure with reduced ejection fraction (HFrEF) remains unclear. Therefore, the aim of this study was to analyse whether the VP is a safe and suitable method to determine the VO2 max in patients with HFrEF. Adult male and female patients with HFrEF performed a ramp-incremental phase (IP), followed by a submaximal constant VP (i.e., 95% of the maximal workload during the IP) on a cycle ergometer. A 5-min active recovery period (i.e., 10 W) was performed between the two exercise phases. Group (i.e., median values) and individual comparisons were performed. VO2 max was confirmed when there was a difference of ≤ 3% in peak oxygen uptake (VO2 peak) values between the two exercise phases. Twenty-one patients (13 males) were finally included. There were no adverse events during the VP. Group comparisons showed no differences in the absolute and relative VO2 peak values between both exercise phases (p = 0.557 and p = 0.400, respectively). The results did not change when only male or female patients were included. In contrast, individual comparisons showed that the VO2 max was confirmed in 11 patients (52.4%) and not confirmed in 10 (47.6%). The submaximal VP is a safe and suitable method for the determination of the VO2 max in patients with HFrEF. In addition, an individual approach should be used because group comparisons could mask individual differences.
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Insuficiência Cardíaca , Adulto , Humanos , Masculino , Feminino , Volume Sistólico , Consumo de Oxigênio , Oxigênio , Exercício Físico , Teste de Esforço/métodosRESUMO
Background: Exercise-based cardiac rehabilitation (CR) programs are used for improving prognosis and quality of life in patients with cardiovascular disease (CVD). Nonetheless, adherence to these programs is low, and exercise-based CR programs based on virtual reality (i.e., exergaming) have been proposed as an alternative to conventional CR programs. However, whether exergaming programs are superior to conventional CR programs in patients with CVD is not known. Objective: This systematic review with meta-analysis was conducted to explore whether exergaming enhances exercise capacity, quality of life, mental health, motivation, and exercise adherence to a greater extent than conventional CR programs in patients with CVD. Method: Electronic searches were carried out in PubMed, Embase, Web of Science, and Cumulative Index to Nursing and Allied Health Literature databases up to June 2021. Meta-analyses were performed using robust variance estimation with small-sample corrections. The effect sizes were calculated as the mean differences (MD) or standardized mean differences (SMD) as appropriate. The SMD magnitude was classified as trivial (<0.20), small (0.20−0.49), medium (0.50−0.79), or large (≥0.80). Heterogeneity was interpreted based on the I2 statistics as low (25%), moderate (50%), or high (75%). Results: Pooled analyses showed no differences between exergaming and conventional CR programs for enhancing exercise capacity (i.e., distance covered in the six-minute walk test) (MD+ = 14.07 m (95% confidence interval (CI) −38.18 to 66.32 m); p = 0.426) and mental health (SMD+ = 0.17 (95% CI −0.36 to 0.70); p = 0.358). The results showed a small, statistically nonsignificant improvement in quality of life in favor of exergaming (SMD+ = 0.22 (95% CI = −0.37 to 0.81); p = 0.294). Moderate heterogeneity was found for exercise capacity (I2 = 53.7%), while no heterogeneity was found for quality of life (I2 = 3.3%) and mental health (I2 = 0.0%). Conclusions: Exergaming seems not to be superior to conventional CR programs for improving exercise capacity, quality of life, or mental health in patients with CVD.
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Reabilitação Cardíaca , Doenças Cardiovasculares , Reabilitação Cardíaca/métodos , Doenças Cardiovasculares/etiologia , Terapia por Exercício , Jogos Eletrônicos de Movimento , Humanos , Qualidade de VidaRESUMO
AIMS: Dilated cardiomyopathy (DCM) associated with dystrophin gene (DMD) mutations in individuals with mild or absent skeletal myopathy is often indistinguishable from other DCM forms. We sought to describe the phenotype and prognosis of DMD associated DCM in DMD mutation carriers without severe skeletal myopathy. METHODS AND RESULTS: At 26 European centres, we retrospectively collected clinical characteristics and outcomes of 223 DMD mutation carriers (83% male, 33 ± 15 years). A total of 112 individuals (52%) had DCM at first evaluation [n = 85; left ventricular ejection fraction (LVEF) 34 ± 11.2%] or developed DCM (n = 27; LVEF 41.3 ± 7.5%) after a median follow-up of 96 months (interquartile range 5-311 months). DCM penetrance was 45% in carriers older than 40 years. DCM appeared earlier in males and was independent of the type of mutation, presence of skeletal myopathy, or elevated serum creatine kinase levels. Major adverse cardiac events (MACE) occurred in 22% individuals with DCM, 18% developed end-stage heart failure and 9% sudden cardiac death or equivalent. Skeletal myopathy was not associated with survival free of MACE in patients with DCM. Decreased LVEF and increased left ventricular end-diastolic diameter at baseline were associated with MACE. Individuals without DCM had favourable prognosis without MACE or death during follow-up. CONCLUSIONS: DMD-associated DCM without severe skeletal myopathy is characterized by incomplete penetrance but high risk of MACE, including progression to end-stage heart failure and ventricular arrhythmias. DCM onset is the major determinant of prognosis with similar survival regardless of the presence of skeletal myopathy.
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Cardiomiopatia Dilatada , Insuficiência Cardíaca , Doenças Musculares , Adolescente , Adulto , Cardiomiopatia Dilatada/epidemiologia , Cardiomiopatia Dilatada/genética , Distrofina/genética , Feminino , Insuficiência Cardíaca/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Estudos Retrospectivos , Volume Sistólico , Função Ventricular Esquerda , Adulto JovemRESUMO
INTRODUCTION AND OBJECTIVES: According to sudden cardiac death guidelines, an implantable cardioverter-defibrillator (ICD) should be considered in patients with LMNA-related dilated cardiomyopathy (DCM) and ≥ 2 risk factors: male sex, left ventricular ejection fraction (LVEF) <45%, nonsustained ventricular tachycardia (NSVT), and nonmissense genetic variants. In this study we aimed to describe the clinical characteristics of carriers of LMNA genetic variants among individuals from a Spanish cardiac-laminopathies cohort (REDLAMINA registry) and to assess previously reported risk criteria. METHODS: The relationship between risk factors and cardiovascular events was evaluated in a cohort of 140 carriers (age ≥ 16 years) of pathogenic LMNA variants (54 probands, 86 relatives). We considered: a) major arrhythmic events (MAE) if there was appropriate ICD discharge or sudden cardiac death; b) heart failure death if there was heart transplant or death due to heart failure. RESULTS: We identified 11 novel and 21 previously reported LMNA-related DCM variants. LVEF <45% (P=.001) and NSVT (P <.001) were related to MAE, but not sex or type of genetic variant. The only factor independently related to heart failure death was LVEF <45% (P <.001). CONCLUSIONS: In the REDLAMINA registry cohort, the only predictors independently associated with MAE were NSVT and LVEF <45%. Therefore, female carriers of missense variants with either NSVT or LVEF <45% should not be considered a low-risk group. It is important to individualize risk stratification in carriers of LMNA missense variants, because not all have the same prognosis.
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Laminopatias , Adolescente , Morte Súbita Cardíaca/epidemiologia , Morte Súbita Cardíaca/etiologia , Desfibriladores Implantáveis , Feminino , Humanos , Masculino , Sistema de Registros , Fatores de Risco , Volume Sistólico , Taquicardia Ventricular , Função Ventricular EsquerdaRESUMO
INTRODUCTION AND OBJECTIVES: Danon disease (DD) is caused by mutations in the LAMP2 gene. It is considered a multisystemic disease characterized by hypertrophic cardiomyopathy with pre-excitation and extreme hypertrophy, intellectual disability, myopathy, childhood presentation, and worse prognosis in men. There are scarce data on the clinical characteristics and prognosis of DD. METHODS: We analyzed the clinical records of patients with DD from 10 Spanish hospitals. RESULTS: Twenty-seven patients were included (mean age, 31 ± 19 years; 78% women). Male patients showed a high prevalence of extracardiac manifestations: myopathy (80%), learning disorders (83%), and visual alterations (60%), which were uncommon findings in women (5%, 0%, and 27%, respectively). Although hypertrophic cardiomyopathy was the most common form of heart disease (61%), the mean maximum wall thickness was 15 ± 7 mm and dilated cardiomyopathy was present in 12 patients (10 women). Pre-excitation was found in only 11 patients (49%). Age at presentation was older than 20 years in 16 patients (65%). After a median follow-up of 4 years (interquartile range, 2-9), 4 men (67%) and 9 women (43%) died or required a transplant. Cardiac disease and adverse events occurred later in women (37 ± 9 vs 23 ± 16 and 36 ± 20 vs 20 ± 11 years, respectively). CONCLUSIONS: The clinical characteristics of DD differ substantially from traditional descriptions: age at presentation of DD is older, the disease is not multisystemic in women, and pre-excitation is infrequent.
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Cardiomiopatia Hipertrófica/etiologia , Doença de Depósito de Glicogênio Tipo IIb/diagnóstico , Sistema de Registros , Síndrome de Wolff-Parkinson-White/etiologia , Adolescente , Adulto , Cardiomiopatia Hipertrófica/diagnóstico , Cardiomiopatia Hipertrófica/epidemiologia , Eletrocardiografia , Feminino , Doença de Depósito de Glicogênio Tipo IIb/complicações , Doença de Depósito de Glicogênio Tipo IIb/genética , Humanos , Incidência , Proteína 2 de Membrana Associada ao Lisossomo/genética , Proteína 2 de Membrana Associada ao Lisossomo/metabolismo , Masculino , Mutação , Fenótipo , Prognóstico , Estudos Retrospectivos , Espanha/epidemiologia , Síndrome de Wolff-Parkinson-White/diagnóstico , Síndrome de Wolff-Parkinson-White/epidemiologia , Adulto JovemRESUMO
BACKGROUND: The genetic cause of hypertrophic cardiomyopathy remains unexplained in a substantial proportion of cases. Formin homology 2 domain containing 3 (FHOD3) may have a role in the pathogenesis of cardiac hypertrophy but has not been implicated in hypertrophic cardiomyopathy. OBJECTIVES: This study sought to investigate the relation between FHOD3 mutations and the development of hypertrophic cardiomyopathy. METHODS: FHOD3 was sequenced by massive parallel sequencing in 3,189 hypertrophic cardiomyopathy unrelated probands and 2,777 patients with no evidence of cardiomyopathy (disease control subjects). The authors evaluated protein-altering candidate variants in FHOD3 for cosegregation, clinical characteristics, and outcomes. RESULTS: The authors identified 94 candidate variants in 132 probands. The variants' frequencies were significantly higher in patients with hypertrophic cardiomyopathy (74 of 3,189 [2.32%]) than in disease control subjects (18 of 2,777 [0.65%]; p < 0.001) or in the gnomAD database (1,049 of 138,606 [0.76%]; p < 0.001). FHOD3 mutations cosegregated with hypertrophic cardiomyopathy in 17 families, with a combined logarithm of the odds score of 7.92, indicative of very strong segregation. One-half of the disease-causing variants were clustered in a small conserved coiled-coil domain (amino acids 622 to 655); odds ratio for hypertrophic cardiomyopathy was 21.8 versus disease control subjects (95% confidence interval: 1.3 to 37.9; p < 0.001) and 14.1 against gnomAD (95% confidence interval: 6.9 to 28.7; p < 0.001). Hypertrophic cardiomyopathy patients carrying (likely) pathogenic mutations in FHOD3 (n = 70) were diagnosed after age 30 years (mean 46.1 ± 18.7 years), and two-thirds (66%) were males. Of the patients, 82% had asymmetric septal hypertrophy (mean 18.8 ± 5 mm); left ventricular ejection fraction <50% was present in 14% and hypertrabeculation in 16%. Events were rare before age 30 years, with an annual cardiovascular death incidence of 1% during follow-up. CONCLUSIONS: FHOD3 is a novel disease gene in hypertrophic cardiomyopathy, accounting for approximately 1% to 2% of cases. The phenotype and the rate of cardiovascular events are similar to those reported in unselected cohorts. The FHOD3 gene should be routinely included in hypertrophic cardiomyopathy genetic testing panels.
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Cardiomiopatia Hipertrófica/diagnóstico , Cardiomiopatia Hipertrófica/genética , Variação Genética/genética , Proteínas dos Microfilamentos/genética , Mutação/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Estudos de Coortes , Feminino , Seguimentos , Forminas , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Adulto JovemRESUMO
OBJECTIVE: To evaluate potential variations in the plasma metabolomic profile of endometriosis patients as a consequence of pathophysiologic alterations associated with this disorder. DESIGN: Prospective study. For each subject, a plasma sample was collected after overnight fasting and before surgery. SETTING: University medical center. PATIENT(S): The clinical cohort included 50 endometriosis patients, diagnosed at early (n = 6) and advanced (n = 44) stages of the disease, and 23 healthy women. All volunteers underwent diagnostic laparoscopy to visually confirm the presence or absence of endometriotic lesions. INTERVENTION(S): Metabolomic profiling of plasma samples based on 1H-nuclear magnetic resonance (NMR) spectroscopy in combination with statistical approaches. MAIN OUTCOME MEASURE(S): Comparative identification of metabolites present in plasma from endometriosis patients and healthy women. RESULT(S): The plasma metabolomic profile of endometriosis patients was characterized by increased concentration of valine, fucose, choline-containing metabolites, lysine/arginine, and lipoproteins and decreased concentration of creatinine compared with healthy women. Metabolic alterations identified in the plasma metabolomic profile of endometriosis patients correlate with pathophysiologic events previously described in the progression of this disease. CONCLUSION(S): The results highlight the potential of 1H-NMR-based metabolomics to characterize metabolic alterations associated with endometriosis in plasma samples. This information could be useful to get a better understanding of the molecular mechanisms involved in the pathogenesis of endometriosis, thus facilitating the noninvasive diagnosis of this pathology at early stages.
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Endometriose/sangue , Endometriose/fisiopatologia , Metabolômica/métodos , Espectroscopia de Prótons por Ressonância Magnética , Centros Médicos Acadêmicos , Adulto , Biomarcadores/sangue , Estudos de Casos e Controles , Endometriose/diagnóstico , Feminino , Humanos , Estudos ProspectivosRESUMO
OBJECTIVE: To investigate whether urine metabolomic profile can be used to identify biomarkers associated to endometriosis. DESIGN: Prospective study. For each subject, a urine sample was collected after overnight fasting and before surgery. SETTING: University medical center. PATIENT(S): The clinical cohort included 45 endometriosis patients, diagnosed at early (n = 6) and advanced (n = 39) stages of the disease, and 36 healthy women. All women underwent diagnostic laparoscopy to visually confirm the presence or absence of endometriotic lesions. INTERVENTION(S): Metabolomic profiling of urine samples based on (1)H-nuclear magnetic resonance (NMR) spectroscopy in combination with statistical approaches. MAIN OUTCOME MEASURE(S): Comparative identification of metabolites present in urine from endometriosis patients and healthy women. RESULT(S): The urine metabolomic profile of endometriosis patients exhibited higher concentrations of N(1)-methyl-4-pyridone-5-carboxamide, guanidinosuccinate, creatinine, taurine, valine, and 2-hydroxyisovalerate and decreased concentrations of lysine compared with healthy women. Most of these metabolites are involved in inflammation and oxidative stress processes. These pathophysiologic events had been previously described to be present in ectopic endometrial proliferation foci. CONCLUSION(S): Overall, the results demonstrate the potential of (1)H-NMR-based metabolomics, a rapid and noninvasive approach, to identify metabolic changes associated to endometriosis in urine samples. This information could be useful to get a better understanding of the pathogenesis of endometriosis, thus providing support to the noninvasive diagnosis of this pathology.
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Endometriose/urina , Metabolômica/métodos , Espectroscopia de Prótons por Ressonância Magnética , Adulto , Biomarcadores/urina , Estudos de Casos e Controles , Endometriose/diagnóstico , Feminino , Hospitais Universitários , Humanos , Laparoscopia , Análise Multivariada , Valor Preditivo dos Testes , Estudos Prospectivos , UrináliseRESUMO
INTRODUCTION: The causes of cardiac tamponade vary and it has been suggested that underlying causes should be sought in all cases. The purpose of this study was to determine the causes of cardiac tamponade in our environment, distinguishing between specific and idiopathic causes, and analyzing the proportion and causes in the subgroup of patients with relapsing tamponade. PATIENTS AND METHOD: We retrospectively studied all patients who underwent therapeutic pericardiocentesis between 1985 and 2001. The clinical and radiographic features and macroscopic characteristics of the pericardial fluid were analyzed. The final diagnosis in each patient was based on the clinical history, follow-up, pericardial fluid cytology, and pericardial biopsy, if available. RESULTS: Ninety-six patients were included (52 men/44 women), mean age 56.1 16.1 years. The cause of pericardial effusion was neoplasm in 50 patients (52.1%), 14 idiopathic pericarditis (14.6%), 12 renal failure (12.5%), 7 iatrogenic cases (7.3%), 4 mechanical tamponades (4.2%), 2 tuberculosis (2.1%), and 7 other causes (7.3%). Thirty-five patients had relapsing tamponade; only 2 of them had idiopathic pericarditis (5.7%). We found no significant differences in age, development time, extracted volume or fluid features between tamponade of specific or idiopathic origin. CONCLUSIONS: Most of the cardiac tamponades in our series had a specific cause. This made it necessary to identify a specific underlying cause in each case, especially in relapsing effusions. However, we did not find any variable suggestive of the cause of the disease.
Assuntos
Tamponamento Cardíaco/diagnóstico , Tamponamento Cardíaco/etiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Tamponamento Cardíaco/terapia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Derrame Pericárdico/patologia , Pericardiocentese , Pericárdio/patologia , Estudos RetrospectivosRESUMO
INTRODUCTION AND OBJECTIVES: Atrial fibrillation is an arrhythmia with high morbidity and mortality. Restoring sinus rhythm is one of the principle objectives in its management. The present study aimed to assess the efficacy of scheduled cardioversion on atrial fibrillation by comparing two different therapeutic approaches: electrical vs. pharmacological cardioversion. PATIENTS AND METHOD: Two hundred thirty patients with atrial fibrillation of more than 48 hours duration and requiring sinus rhythm restoration were included. One hundred forty-four patients underwent external electrical cardioversion and 86 patients received quinidine. We analyzed the rate of success, duration of hospital stay, complications and clinical and echocardiographic variable that might predict success. RESULTS: Sinus rhythm was restored in 181 of 230 patients (79%). The rate of success was 77% (111/144 patients) in the electrical group and 81% (70 of 86 patients) in the pharmacological group (ns). In 13 pharmacological group patients for whom the first attempt failed attempt, a second attempt with electrical cardioversion was made and was successful in 8 patients (61%). No embolic complication was recorded and only two electrical disturbances were seen. Only atrial fibrillation lasting less than 8 weeks was associated with a higher success rate (p < 0.01). CONCLUSIONS: Scheduled cardioversion in atrial fibrillation is an effective technique with a high success rate and a very low rate of complication. Electrical cardioversion and pharmacological cardioversion with quinidine are similarly effective, although the latter involves a longer hospital stay.
Assuntos
Fibrilação Atrial/terapia , Cardioversão Elétrica/métodos , Fibrilação Atrial/tratamento farmacológico , Terapia por Estimulação Elétrica , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos ProspectivosRESUMO
OBJECTIVE: To report the exceptional condition of retroperitoneal ectopic pregnancy after intrauterine insemination. DESIGN: Case report. SETTING: University hospital. PATIENT(S): A 37-year-old woman, gravida 2, para 1, presented to the emergency department 1 month after intrauterine insemination complaining of lower abdominal pain. INTERVENTION(S): A transvaginal ultrasound assessment revealed a complex mass containing a gestational sac with vitelline vesicle behind the left ovary. At laparoscopy, a nodular lesion was seen next to the left uterosacral ligament, suggesting the presence of an ectopic pregnancy in the retroperitoneal space. MAIN OUTCOME MEASURE(S): The unusual location of an ectopic pregnancy such as in the retroperitoneum should be examined in patients with clinical findings that suggest ectopic pregnancy if both the uterus and adnexa are normal during laparoscopic exploration. RESULT(S): The patient's retroperitoneal pregnancy was treated with a wide laparoscopic excision. To allow the removal of all trophoblastic tissue, a 3×2×2 cm hemorrhagic mass containing the ectopic pregnancy was removed from the retroperitoneal space. Retroperitoneal ectopic pregnancy was confirmed by the pathology diagnosis. CONCLUSION(S): Retroperitoneal pregnancy after assisted reproductive techniques is an exceptional condition that must be considered in patients with clinical findings that suggest ectopic pregnancy if both the uterus and adnexa are normal during laparoscopic exploration.