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BACKGROUND: Although extracorporeal life support (ECLS) can provide emergency systemic perfusion for acute fulminant myocarditis (AFM), the mortality rate remains extremely high, especially in those undergoing extracorporeal cardiopulmonary resuscitation (ECPR). Temporary ventricular assist device (VAD) can provide a more physiological blood flow direction and better subsequent organ perfusion than ECLS. We investigated temporary VAD efficacy in ECPR-revived AFM patients. METHODS: During January 2012-May 2019, we retrospectively recruited 22 AFM patients with hemodynamic collapse and ECPR; 11 underwent ECLS only and 11 underwent additional VAD support after ECLS. Systemic perfusion was compared via laboratory biochemistry at post-ECPR days 2 (D2) and 4 (D4). Consciousness and cardiac function were assessed through the Glasgow Coma Scale (GCS) and echocardiography, respectively. All major complications and causes of mortality were recorded; 30-day survival was analyzed and risk factors were predicted. RESULTS: The VAD group had significantly better hemodynamic improvement; more inotropes being tapered at D2 and D4; better data representative of systemic perfusion, including albumin, pH, bicarbonate, and lactate levels at D4; and better 30-day survival (72.7% vs. 27.2%, p = 0.033). The causes of mortality included central failure, multiple organ failure, and bacteremia with sepsis. The risk factors included lethal dysrhythmia before ECLS, GCS <5 at D2, and elevated cardiac enzymes at D4. CONCLUSION: For AFM patients, temporary VAD could provide better systemic perfusion and organ preservation than ECLS. VAD had better survival, including improved recovery and successful transplantation. Hence, temporary VAD should be considered if ECLS cannot revive the sustained cardiogenic shock.
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Reanimação Cardiopulmonar , Coração Auxiliar , Miocardite , Albuminas , Bicarbonatos , Humanos , Lactatos , Miocardite/terapia , Estudos Retrospectivos , Resultado do TratamentoRESUMO
This study addressed the hypothesis that cardiac Sirtuin 1 (Sirt1) deficiency alters cardiomyocyte Ca2+ and Na+ regulation, leading to cardiac dysfunction and arrhythmogenesis. We used mice with cardiac-specific Sirt1 knockout (Sirt1-/- ). Sirt1flox/flox mice were served as control. Sirt1-/- mice showed impaired cardiac ejection fraction with increased ventricular spontaneous activity and burst firing compared with those in control mice. The arrhythmic events were suppressed by KN93 and ranolazine. Reduction in Ca2+ transient amplitudes and sarcoplasmic reticulum (SR) Ca2+ stores, and increased SR Ca2+ leak were shown in the Sirt1-/- mice. Electrophysiological measurements were performed using patch-clamp method. While L-type Ca2+ current (ICa, L ) was smaller in Sirt1-/- myocytes, reverse-mode Na+ /Ca2+ exchanger (NCX) current was larger compared with those in control myocytes. Late Na+ current (INa, L ) was enhanced in the Sirt1-/- mice, alongside with elevated cytosolic Na+ level. Increased cytosolic and mitochondrial reactive oxygen species (ROS) were shown in Sirt1-/- mice. Sirt1-/- cardiomyocytes showed down-regulation of L-type Ca2+ channel α1c subunit (Cav1.2) and sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2a (SERCA2a), but up-regulation of Ca2+ /calmodulin-dependent protein kinase II and NCX. In conclusions, these findings suggest that deficiency of Sirt1 impairs the regulation of intracellular Ca2+ and Na+ in cardiomyocytes, thereby provoking cardiac dysfunction and arrhythmogenesis.
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Cálcio/metabolismo , Ventrículos do Coração/citologia , Miócitos Cardíacos/metabolismo , Sirtuína 1/deficiência , Sódio/metabolismo , Potenciais de Ação , Animais , Canais de Cálcio Tipo L/metabolismo , Citosol/metabolismo , Eletrocardiografia , Espaço Intracelular/metabolismo , Ativação do Canal Iônico , Camundongos Endogâmicos C57BL , Camundongos Knockout , Estresse Oxidativo , Retículo Sarcoplasmático/metabolismo , Sirtuína 1/metabolismo , Trocador de Sódio e Cálcio/metabolismoRESUMO
Sepsis, an inflammatory response to infection provoked by lipopolysaccharide (LPS), is associated with high mortality, as well as ischemic stroke and new-onset atrial arrhythmia. Severe bacterial infections causing sepsis always result in profound physiological changes, including fever, hypotension, arrhythmia, necrosis of tissue, systemic multi-organ dysfunction and finally death. LPS challenge-induced inflammatory responses during sepsis may increase the likelihood of the arrhythmogenesis. Lemnalol is known to possess potent anti-inflammatory effects. This study examined whether Lemnalol (0.1 µM) could modulate the electrophysiological characteristics and calcium homeostasis of atrial myocytes under the influence of LPS (1µg/mL). Under challenge with LPS, Lemnalol-treated LA myocytes, had a longer AP duration at 20%, 50% and 90% repolarization of the amplitude, compared to the LPS-treated cells. LPS-challenged LA myocytes showed increased late sodium current, Na+-Ca2+ exchanger current, transient outward current, rapid component of delayed rectifier potassium current, tumor necrosis factor-α, NF-κB and increased phosphorylation of ryanodine receptor (RyR), but a lower L-type Ca2+ current than the control LA myocytes. Exposure to Lemnalol reversed the LPS-induced effects. The LPS-treated and control groups of LA myocytes, with or without the existence of Lemnalol. showed no apparent alterations in the sodium current amplitude or Cav1.2 expression. The expression of sarcoendoplasmic reticulum calcium transport ATPase (SERCA2) was reduced by LPS treatment, while Lemnalol ameliorated the LPS-induced alterations. The phosphorylation of RyR was enhanced by LPS treatment, while Lemnalol attenuated the LPS-induced alterations. In conclusion, Lemnalol modulates LPS-induced alterations of LA calcium homeostasis and blocks the NF-κB pathways, which may contribute to the attenuation of LPS-induced arrhythmogenesis.
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Cálcio/metabolismo , Fenômenos Eletrofisiológicos/efeitos dos fármacos , Homeostase/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Sesquiterpenos/farmacologia , Animais , Citocinas/metabolismo , Átrios do Coração/efeitos dos fármacos , Insuficiência Cardíaca/tratamento farmacológico , Inflamação , Lipopolissacarídeos/farmacologia , Masculino , Modelos Animais , NF-kappa B/metabolismo , Técnicas de Patch-Clamp , Coelhos , Sepse/tratamento farmacológicoRESUMO
BACKGROUND AND AIMS: During coronary artery bypass graft (CABG) surgery, the residual hemostasis procedures, from weaning cardiopulmonary bypass to closing sternotomy, are always completed by residents and supervised by attending surgeons. We want to evaluate the teaching effectiveness for residents under the supervision of attending surgeons with different levels of seniority. MATERIALS AND METHODS: Between January 1st 2001 and December 31st 2010, 2279 consecutive CABG surgeries were performed in our medical center. In total, 83 patients underwent a reexploration for postoperative bleeding. All causes of bleeding were identified and recorded. Competent attending surgeons were defined as having >3 years' experience and young attending surgeons with â¦3 years' experience. We compared the reexploration rate and aimed to identify the common sources of bleeding by the two groups. We also assessed the impact of attending experience on the outcomes and major complications after reexploration. RESULTS: There were 36 surgical bleeding and 17 non-surgical bleeding in the young group and 16 surgical bleeding and 14 non-surgical bleeding in the competent group. The young group experienced more mediastinal drainage before a reexploration and a longer time interval to a reexploration. However, both are without statistical significance. Furthermore, the young group has a significant longer hospital stay. The most common intra-pericardium surgical bleeding included two-stage cannulation, side branch of the left internal mammary artery (LIMA), and side branch of vein grafts. The most common extra-pericardium surgical bleeding included a puncture hole by sternal wires, LIMA bed, and fragile sternum. CONCLUSION: Young attending surgeons indeed had both higher incidence of reexploration and surgical bleeding after a CABG. However, the supervisor experience only impacted hospital stay, not major complications or mortality after a reexploration. This might imply the competent attending surgeons provide higher teaching effectiveness for the hemostasis procedure after CABG.
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Ponte de Artéria Coronária/efeitos adversos , Ponte de Artéria Coronária/educação , Internato e Residência , Hemorragia Pós-Operatória/epidemiologia , Reoperação/estatística & dados numéricos , Idoso , Perda Sanguínea Cirúrgica/estatística & dados numéricos , Competência Clínica , Ponte de Artéria Coronária/mortalidade , Procedimentos Cirúrgicos Eletivos , Feminino , Humanos , Tempo de Internação , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Indicadores de Qualidade em Assistência à Saúde , Medição de Risco , Taiwan/epidemiologiaRESUMO
Sensing the size of individual molecules in an ensemble has proven to be a powerful tool to investigate biomolecular interactions and association-dissociation processes. In biologically relevant solution environments, molecular size is often sensed by translational or rotational diffusivity. The rotational diffusivity is more sensitive to the size and conformation of the molecules as it is inversely proportional to the cube of the hydrodynamic radius, as opposed to the inverse linear dependence of the translational diffusion coefficient. Single-molecule rotational diffusivity has been measured with time-resolved fluorescence anisotropy decay, but the ability to sense different sizes has been restricted by the limited number of photons available or has required surface attachment to observe each molecule longer, and the attachment may be perturbative. To address these limitations, we show how to measure and monitor single-molecule rotational diffusivity by combining the solution-phase Anti-Brownian ELectrokinetic (ABEL) trap and maximum likelihood analysis of time-resolved fluorescence anisotropy based on the information inherent in each detected photon. We demonstrate this approach by resolving a mixture of single- and double-stranded fluorescently labeled DNA molecules at equilibrium, freely rotating in a native solution environment. The rotational diffusivity, fluorescence brightness and lifetime, and initial and steady-state anisotropy are simultaneously determined for each trapped single DNA molecule. The time resolution and precision of this method are analyzed using statistical signal analysis and simulations. We present key parameters that define the usefulness of a particular fluorescent label for extracting molecular size information from single-molecule rotational diffusivity measurements.
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This study addressed the hypothesis that long-term deficiency of ovarian hormones after ovariectomy (OVx) alters cellular Ca2+-handling mechanisms in the heart, resulting in the formation of a proarrhythmic substrate. It also tested whether estrogen supplementation to OVx animals reverses any alterations to cardiac Ca2+ handling and rescues proarrhythmic behavior. OVx or sham operations were performed on female guinea pigs using appropriate anesthetic and analgesic regimes. Pellets containing 17ß-estradiol (1 mg, 60-day release) were placed subcutaneously in selected OVx animals (OVx + E). Cardiac myocytes were enzymatically isolated, and electrophysiological measurements were conducted with a switch-clamp system. In fluo-4-loaded cells, Ca2+ transients were 20% larger, and fractional sarcoplasmic reticulum (SR) Ca2+ release was 7% greater in the OVx group compared with the sham group. Peak L-type Ca2+ current was 16% larger in OVx myocytes with channel inactivation shifting to more positive membrane potentials, creating a larger "window" current. SR Ca2+ stores were 22% greater in the OVx group, and these cells showed a higher frequency of Ca2+ sparks and waves and shorter wave-free intervals. OVx myocytes showed higher frequencies of early afterdepolarizations, and a greater percentage of these cells showed delayed afterdepolarizations after exposure to isoprenaline compared with sham myocytes. The altered Ca2+ regulation occurring in the OVx group was not observed in the OVx + E group. These findings suggest that long-term deprivation of ovarian hormones in guinea pigs lead to changes in myocyte Ca2+-handling mechanisms that are considered proarrhythmogenic. 17ß-Estradiol replacement prevented these adverse effects.NEW & NOTEWORTHY Ovariectomized guinea pig cardiomyocytes have higher frequencies of Ca2+ waves, and isoprenaline-challenged cells display more early afterdepolarizations, delayed afterdepolarizations, and extra beats compared with sham myocytes. These alterations to Ca2+ regulation were not observed in myocytes from ovariectomized guinea pigs supplemented with 17ß-estradiol, suggesting that ovarian hormone deficiency modifies cardiac Ca2+ regulation, potentially creating proarrhythmic substrates.
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Sinalização do Cálcio , Cálcio/metabolismo , Miócitos Cardíacos/metabolismo , Ovariectomia , Potenciais de Ação , Agonistas Adrenérgicos beta/farmacologia , Animais , Arritmias Cardíacas/etiologia , Arritmias Cardíacas/metabolismo , Arritmias Cardíacas/fisiopatologia , Canais de Cálcio Tipo L/genética , Canais de Cálcio Tipo L/metabolismo , Sinalização do Cálcio/efeitos dos fármacos , Implantes de Medicamento , Estradiol/administração & dosagem , Terapia de Reposição de Estrogênios , Acoplamento Excitação-Contração , Feminino , Cobaias , Isoproterenol/farmacologia , Miócitos Cardíacos/efeitos dos fármacos , Retículo Sarcoplasmático/metabolismo , Fatores de TempoRESUMO
Patients with hypertrophic cardiomyopathy, particularly young adults, can die from arrhythmia, but the mechanism underlying abnormal rhythm formation remains unknown. C57Bl6 × CBA/Ca mice carrying a cardiac actin ( ACTC) E99K (Glu99Lys) mutation reproduce many aspects of human hypertrophic cardiomyopathy, including increased myofilament Ca2+ sensitivity and sudden death in a proportion (up to 40%) of young (28-40 day old) animals. We studied the hearts of transgenic (TG; ACTC E99K) mice and their non-TG (NTG) littermates when they were in their vulnerable period (28-40 days old) and when they were adult (8-12 wk old). Ventricular myocytes were isolated from the hearts of TG and NTG mice at these two time points. We also examined the hearts of mice that died suddenly (SCD). SCD animals had approximately four times more collagen compared with age-matched NTG mice, yet myocyte cell size was normal. Young TG mice had double the collagen content of NTG mice. Contraction and Ca2+ transients were greater in cells from young TG mice compared with their NTG littermates but not in cells from adult mice (TG or NTG). Cells from young TG mice had a greater propensity for Ca2+ waves than NTG littermates, and, despite similar sarcoplasmic reticulum Ca2+ content, a proportion of these cells had larger Ca2+ spark mass. We found that the probability of SCD in young TG mice was increased when the mutation was expressed in animals with a CBA/Ca2+ background and almost eliminated in mice bred on a C57Bl6 background. The latter TG mice had normal cellular Ca2+ homeostasis. NEW & NOTEWORTHY Mice with the actin Glu99Lys hypertrophic cardiomyopathy mutation ( ACTC E99K) are prone to sudden cardiac death around 40 days, associated with increased Ca2+ transients, spark mass, and fibrosis. However, adult survivors have normal Ca2+ transients and spark density accompanied by hypertrophy. Penetrance of the sudden cardiac death phenotype depends on the genetic background of the mouse. Listen to this article's corresponding podcast at http://ajpheart.podbean.com/e/calcium-regulation-in-e99k-mouse-heart/ .
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Sinalização do Cálcio , Cardiomiopatia Hipertrófica/metabolismo , Morte Súbita Cardíaca , Patrimônio Genético , Actinas/genética , Fatores Etários , Animais , Cardiomiopatia Hipertrófica/genética , Células Cultivadas , Colágeno/metabolismo , Coração/crescimento & desenvolvimento , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Mutação de Sentido Incorreto , Contração Miocárdica , Miócitos Cardíacos/metabolismoRESUMO
Lipopolysaccharide (LPS) triggers an inflammatory response, causing impairment of cardiomyocyte Ca2+ and Na + regulation. This study aimed to determine whether piscidin-1 (PCD-1), an antimicrobial peptide, improves intracellular Ca2+ and Na + regulation in LPS-challenged atrial cardiomyocytes. Rabbit atrial cardiomyocytes were enzymatically isolated from the left atria. Patch-clamp ionic current recording, intracellular Ca2+ monitoring using Fluo-3, and detection of cytosolic reactive oxygen species production were conducted in control, LPS-challenged, and LPS + PCD-1-treated atrial cardiomyocytes. LPS-challenged cardiomyocytes showed shortened durations of action potential at their 50% and 90% repolarizations, which was reversed by PCD-1 treatment. LPS-challenged cardiomyocytes showed decreased L-type Ca2+ channel currents and larger Na+/Ca2+ exchange currents compared to controls. While LPS did not affect the sodium current, an enhanced late sodium current with increased cytosolic Na+ levels was observed in LPS-challenged cardiomyocytes. These LPS-induced alterations in the ionic current were ameliorated by PCD-1 treatment. LPS-challenged cardiomyocytes displayed lowered Ca2+ transient amplitudes and decreased Ca2+ stores and greater Ca2+ leakage in the sarcoplasmic reticulum compared to the control. Exposure to PCD-1 attenuated LPS-induced alterations in Ca2+ regulation. The elevated reactive oxygen species levels observed in LPS-challenged myocytes were suppressed after PCD-1 treatment. The protein levels of NF-κB and IL-6 increased following LPS treatment. Decreased sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2a protein levels were observed in LPS-challenged cardiomyocytes. PCD-1 modulates LPS-induced alterations in inflammatory and Ca2+ regulatory protein levels. Our results suggest that PCD-1 modulates LPS-induced alterations in intracellular Ca2+ and Na + homeostasis, reactive oxygen species production, and the NF-κB inflammatory pathway in atrial cardiomyocytes.
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Cálcio , Átrios do Coração , Lipopolissacarídeos , Miócitos Cardíacos , Estresse Oxidativo , Espécies Reativas de Oxigênio , Sódio , Animais , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Lipopolissacarídeos/farmacologia , Coelhos , Cálcio/metabolismo , Sódio/metabolismo , Átrios do Coração/efeitos dos fármacos , Átrios do Coração/metabolismo , Átrios do Coração/citologia , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Peptídeos Catiônicos Antimicrobianos/farmacologia , Peptídeos Catiônicos Antimicrobianos/metabolismo , Masculino , Potenciais de Ação/efeitos dos fármacos , Retículo Sarcoplasmático/metabolismo , Retículo Sarcoplasmático/efeitos dos fármacosRESUMO
BACKGROUND: Second-generation antipsychotics increase the risk of atrial fibrillation. This study explores whether the atypical antipsychotic ziprasidone triggers inflammasome signaling, leading to atrial arrhythmia. METHODS: Electromechanical and pharmacological assessments were conducted on the rabbit left atria (LA). The patch-clamp technique was used to measure ionic channel currents in single cardiomyocytes. Detection of cytosolic reactive oxygen species production was performed in atrial cardiomyocytes. RESULTS: The duration of action potentials at 50 % and 90 % repolarization was dose-dependently shortened in ziprasidone-treated LA. Diastolic tension in LA increased after ziprasidone treatment. Ziprasidone-treated LA showed rapid atrial pacing (RAP) triggered activity. PI3K inhibitor, Akt inhibitor and mTOR inhibitor abolished the triggered activity elicited by ziprasidone in LA. The NLRP3 inhibitor MCC950 suppressed the ziprasidone-induced post-RAP-triggered activity. MCC950 treatment reduced the reverse-mode Na+/Ca2+ exchanger current in ziprasidone-treated myocytes. Cytosolic reactive oxygen species production decreased in ziprasidone-treated atrial myocytes after MCC950 treatment. Protein levels of inflammasomes and proinflammatory cytokines, including NLRP3, caspase-1, IL-1ß, IL-18, and IL-6 were observed to be upregulated in myocytes treated with ziprasidone. CONCLUSIONS: Our findings suggest ziprasidone induces atrial arrhythmia, potentially through upregulation of the NLRP3 inflammasome and enhancement of reactive oxygen species production via the PI3K/Akt/mTOR pathway.
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Fibrilação Atrial , Inflamassomos , Miócitos Cardíacos , Piperazinas , Proteínas Proto-Oncogênicas c-akt , Espécies Reativas de Oxigênio , Transdução de Sinais , Serina-Treonina Quinases TOR , Animais , Fibrilação Atrial/induzido quimicamente , Fibrilação Atrial/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Inflamassomos/metabolismo , Inflamassomos/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Coelhos , Espécies Reativas de Oxigênio/metabolismo , Piperazinas/farmacologia , Masculino , Fosfatidilinositol 3-Quinases/metabolismo , Tiazóis/farmacologia , Átrios do Coração/efeitos dos fármacos , Átrios do Coração/metabolismo , Potenciais de Ação/efeitos dos fármacos , Antipsicóticos/farmacologiaRESUMO
The shortage of organ donors remains a major problem for transplantation worldwide. Potential donors after brain death may become hemodynamically unstable, despite maximal medical management, which ultimately leads to failure of organ procurement. We reviewed the medical records of five brain-dead potential donors who presented with hemodynamic instability despite maximal medical management that were supported by extracorporeal circulation membrane oxygenation (ECMO). The outcomes of heart recipients were reviewed. The five donors under extracorporeal support finished a declaration of brain death without cardiac arrest. Donor organs, including three hearts, nine kidneys, and four livers, were harvested from the five donors under ECMO support. All three heart recipients recovered uneventfully after one yr of follow-up. Our experience indicates that potential donors may experience central-failure-related hemodynamic instability after brain death, despite maximal medical support, which leads to a fatal result. Beyond medical management, prompt and early extracorporeal support for salvaging brain-dead potential donors from cardiac death seems to be a practical strategy to increase the donor pool and preserve donor organs.
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Morte Encefálica , Oxigenação por Membrana Extracorpórea , Doadores de Tecidos/provisão & distribuição , Obtenção de Tecidos e Órgãos , Adulto , Feminino , Transplante de Coração , Hemodinâmica , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Adulto JovemRESUMO
Aneurysm of the left atrial appendage is extremely rare, and afflicted patients most commonly present with atrial tachyarrhythmia or thromboembolism. For these patients, resection of the aneurysm is the recommended and preferred therapy. We present the case of a 57-year-old woman who was found incidentally to have a large aneurysm of the left atrial appendage presenting as atrial fibrillation. After surgical intervention with resection of the aneurysm and a Cox maze III procedure, the patient recovered and was discharged in sinus rhythm.
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Apêndice Atrial/patologia , Fibrilação Atrial/patologia , Aneurisma Cardíaco/patologia , Átrios do Coração/patologia , Dor Abdominal , Apêndice Atrial/diagnóstico por imagem , Apêndice Atrial/cirurgia , Fibrilação Atrial/diagnóstico por imagem , Fibrilação Atrial/cirurgia , Feminino , Aneurisma Cardíaco/diagnóstico por imagem , Aneurisma Cardíaco/cirurgia , Átrios do Coração/cirurgia , Humanos , Pessoa de Meia-Idade , Radiografia , TaiwanRESUMO
BACKGROUND: Atypical antipsychotics increase the risk of atrial arrhythmias and sudden cardiac death. This study investigated whether ziprasidone, a second-generation antipsychotic, affected intracellular Ca2+ and Na+ regulation and oxidative stress, providing proarrhythmogenic substrates in atriums. METHODS: Electromechanical analyses of rabbit atrial tissues were conducted. Intracellular Ca2+ monitoring using Fluo-3, the patch-clamp method for ionic current recordings, and a fluorescence study for the detection of reactive oxygen species and intracellular Na+ levels were conducted in enzymatically dissociated atrial myocytes. RESULTS: Ziprasidone-treated atriums showed sustained triggered activities after rapid pacing, which were inhibited by KN-93 and ranolazine. A reduced peak L-type Ca2+ channel current and enhanced late Na+ current were observed in ziprasidone-treated atrial myocytes, together with an increased cytosolic Na+ level. KN-93 suppressed the enhanced late Na+ current in ziprasidone-treated atrial myocytes. Atrial myocytes treated with ziprasidone showed reduced Ca2+ transient amplitudes and sarcoplasmic reticulum (SR) Ca2+ stores, and increased SR Ca2+ leakage. Cytosolic and mitochondrial reactive oxygen species production was increased in atrial myocytes treated with ziprasidone. TNF-α and NLRP3 were upregulated in ziprasidone-treated myocytes, and the level of phosphorylated calcium/calmodulin-dependent protein kinase II protein was increased. CONCLUSIONS: Our results suggest that ziprasidone increases the occurrence of atrial triggered activity and causes intracellular Ca2+ and Na+ dysregulation, which may result from enhanced oxidative stress and activation of the TNF-α/NLRP3 inflammasome pathway in ziprasidone-treated myocytes.
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OBJECTIVE: Abdominal adiposity is strongly associated with diabetic and cardiovascular comorbidities. The long noncoding RNA HOTAIR (HOX Transcript Antisense Intergenic RNA) is an important epigenetic regulator with fat depot-specific expression. Its functional roles and epigenetic regulation in abdominal adipogenesis remain uncertain. METHODS: We collected different fat depots from healthy, severely obese, and uraemic subjects to measure fat-depot specific gene expression and quantify regional adiposity via dual-energy X-ray absorptiometry (DXA). HOTAIR was overexpressed to evaluate its functional roles. Reduced representation bisulfite sequencing (RRBS), RNA-sequencing, real-time qPCR and RNA/chromatin immunoprecipitation were performed to analyse HOTAIR-mediated epigenetic regulation. RESULTS: A negative correlation between adipose tissue HOTAIR expression (arm or abdominal subcutaneous fat depots) and regional adiposity under the status of severe obesity or uraemia was observed. HOTAIR overexpression using human immortalized abdominal preadipocytes further revealed its anti-adipogenic effects. Integrative analysis of genome-wide DNA methylation by reduced representation bisulfite sequencing (RRBS) and gene expression was performed. Overall, the differentially methylated genes were functionally enriched for nervous system development, suggesting that HOTAIR may be epigenetically associated with cell lineage commitment. We specifically found that HOTAIR-mediated genes showed strong changes in both DNA methylation and gene expression during abdominal adipogenesis. We observed that two HOTAIR-repressed genes, SLITRK4 and PITPNC1, present an obesity-driven fat-depot specific expression pattern that is positively correlated with the central body fat distribution. CONCLUSIONS: Our study indicated that HOTAIR is a key regulator of abdominal adipogenesis via intricate DNA methylation and is likely to be associated with the transcriptional regulation of genes involved in nervous system development and lipid metabolism, such as SLITRK4 and PITPNC1.
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Adipogenia , Metilação de DNA , Adipogenia/genética , Tecido Adiposo/metabolismo , Metilação de DNA/genética , Epigênese Genética/genética , Humanos , Proteínas de Membrana/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Obesidade/genética , Obesidade/metabolismo , RNA Longo não CodificanteRESUMO
BACKGROUND: Lipotoxicity causes endoplasmic reticulum (ER) stress, leading to cell apoptosis. Sirtuin 1 (Sirt1) regulates gene transcription and cellular metabolism. In this study, we investigated the role of Sirt1 in palmitate-induced ER stress. METHODS: Both H9c2 myoblasts and heart-specific Sirt1 knockout mice fed a palmitate-enriched high-fat diet were used. RESULTS: The high-fat diet induced C/EBP homologous protein (CHOP) and activating transcription factor 4 (ATF4) expression in both Sirt1 knockout mice and controls. The Sirt1 knockout mice showed higher CHOP and ATF4 expression compared to those in the control. Palmitic acid (PA) induced ATF4 and CHOP expression in H9c2 cells. PA-treated H9c2 cells showed decreased cytosolic NAD+/NADH alongside reduced Sirt1's activity. The H9c2 cells showed increased ATF4 and CHOP expression when transfected with plasmid encoding dominant negative mutant Sirt1. Sirt1 activator SRT1720 did not affect CHOP and ATF4 expression. Although SRT1720 enhanced the nuclear translocation of ATF4, the extent of the binding of ATF4 to the CHOP promoter did not increase in PA treated-H9c2 cells. CONCLUSION: PA-induced ER stress is mediated through the upregulation of ATF4 and CHOP. Cytosolic NAD+ concentration is diminished by PA-induced ER stress, leading to decreased Sirt1 activity. The Sirt1 activator SRT1720 promotes the nuclear translocation of ATF4 in PA-treated H9c2 cells.
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Bacteriophage TaidaOne was isolated from soil collected in Taipei, Taiwan, using the host Streptomyces griseus. It is a siphovirus with a 56,183-bp genome that contains 86 protein-coding genes. Based on gene content similarity, it was assigned to actinobacteriophage subcluster BI1, within which only TaidaOne and GirlPower genomes contain an acetyltransferase homolog gene.
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Background: The extracorporeal life support (ECLS) and temporary bilateral ventricular assist device (t-BiVAD) are commonly applied in patients with cardiogenic shock. Prolonged cardiopulmonary resuscitation (CPR) has poor prognosis. Herein, we report our findings on a combined ECLS and t-BiVAD approach to salvage cardiogenic-shock patients with CPR for more than one hour. Methods: Fifty-nine patients with prolonged CPR and rescued by ECLS and subsequent t-BiVAD were retrospectively collected between January 2015 and December 2019. Primary diagnoses included ischemic, dilated cardiomyopathy, acute myocardial infarction, post-cardiotomy syndrome, and fulminant myocarditis. The mean LVEF was 16.9% ± 6.56% before t-BiVAD. The median ECLS-to-VAD interval is 26 h. Results: A total of 26 patients (44%) survived to weaning, including 13 (22%) bridged to recovery, and 13 (22%) bridged to transplantation. Survivors to discharge demonstrated better systemic perfusion and hemodynamics than non-survivors. The CentriMag-related complications included bleeding (n = 22, 37.2%), thromboembolism (n = 5, 8.4%), and infection (n = 4, 6.7%). The risk factors of mortality included Glasgow Coma Scale (Motor + Eye) ≤ 5, and lactate ≥ 8 mmol/L at POD-1, persistent ventricular rhythm or asystole, and total bilirubin ≥ 6 mg/dL at POD-3. Mortality factors included septic shock (n = 11, 18.6%), central failure (n = 10, 16.9%), and multiple organ failure (n = 12, 20.3%). Conclusions: Combined ECLS and t-BiVAD could be a salvage treatment for patients with severe cardiogenic shock, especially for those already having prolonged CPR. This combination can correct organ malperfusion and allow sufficient time to bridge patients to recovery and heart transplantation, especially in Asia, where donation rates are low, as well as intracorporeal VAD or total artificial heart being seldom available.
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BACKGROUND: Phosphodiesterase inhibitors can be used to enhance second messenger signaling to regulate intracellular Ca2+ cycling. This study investigated whether ITI-214, a selective phosphodiesterase-1 inhibitor, modulates intracellular Ca2+ regulation, resulting in a positive inotropic effect in sirtuin 1 (Sirt1)-deficient cardiomyocytes. METHODS: Mice with cardiac-specific Sirt1 knockout (Sirt1-/-) were used, with Sirt1flox/flox mice serving as controls. Electromechanical analyses of ventricular tissues were conducted, and we monitored intracellular Ca2+ using Fluo-3 as well as reactive oxygen species production in isolated cardiomyocytes. RESULTS: Sirt1-/- ventricles showed prolonged action potential duration at 90% repolarization and increased contractile force after treatment with ITI-214. The rates and sustained durations of burst firing in ventricles were higher and longer, respectively, in Sirt1-/- ventricles than in controls. ITI-214 treatment decreased the rates and shortened the durations of burst firing in Sirt1-/- mice. Sirt1-/- cardiomyocytes showed reduced Ca2+ transient amplitudes and sarcoplasmic reticulum (SR) Ca2+ stores compared to those in control cardiac myocytes, which was reversed after ITI-214 treatment. SR Ca2+ leakage was larger in Sirt1-/- cardiac myocytes than in control myocytes. ITI-214 reduced SR Ca2+ leakage in Sirt1-/- cardiac myocytes. Increased levels of reactive oxygen species in Sirt1-/- cardiomyocytes compared to those in controls were reduced after ITI-214 treatment. Levels of Ca2+ regulatory proteins, including ryanodine receptor 2, phospholamban, and sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2a were not affected by ITI-214 administration. CONCLUSIONS: Our results suggest that ITI-214 improves intracellular Ca2+ regulation, which in turn exerts inotropic effects and suppresses arrhythmic events in Sirt1-deficient ventricular myocytes.
Assuntos
Arritmias Cardíacas/tratamento farmacológico , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Miócitos Cardíacos/efeitos dos fármacos , Inibidores de Fosfodiesterase/farmacologia , Sirtuína 1/deficiência , Potenciais de Ação/efeitos dos fármacos , Animais , Arritmias Cardíacas/genética , Arritmias Cardíacas/patologia , Cálcio/metabolismo , Sinalização do Cálcio/efeitos dos fármacos , Modelos Animais de Doenças , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Humanos , Masculino , Camundongos , Camundongos Knockout , Miócitos Cardíacos/patologia , Inibidores de Fosfodiesterase/uso terapêutico , Espécies Reativas de Oxigênio/metabolismo , Sirtuína 1/genéticaRESUMO
Contradictory findings of estrogen supplementation in cardiac disease highlight the need to investigate the involvement of estrogen in the progression of heart failure in an animal model that lacks traditional comorbidities. Heart failure was induced by aortic constriction (AC) in female guinea pigs. Selected AC animals were ovariectomized (ACOV), and a group of these received 17ß-estradiol supplementation (ACOV+E). One hundred-fifty days post-AC surgery, left-ventricular myocytes were isolated, and their electrophysiology and Ca2+ and Na+ regulation were examined. Long-term absence of ovarian hormones exacerbates the decline in cardiac function during the progression to heart failure. Estrogen supplementation reverses these aggravating effects.
RESUMO
A 28-year-old man who had a history of type 1 diabetes mellitus with poor medication compliance was referred to the emergency department of our institute with suspected diabetic ketoacidosis. The patient developed sudden cardiac arrest following continuous insulin administration. Laboratory data revealed severe hypokalaemia. Cardiopulmonary resuscitation was performed immediately for 63 minutes. Although his spontaneous circulation resumed, the haemodynamics remained unstable. Peripheral extracorporeal membrane oxygenation was therefore employed for mechanical circulatory support. Echocardiography under these conditions revealed generalised hypokinesia of the bilateral ventricles. The left ventricular ejection fraction was only 10-15%. The chest film revealed bilateral pulmonary congestion. The patient developed multiple organ dysfunction, including acute kidney injury, liver congestion and persistent pulmonary oedema, although the hypokalaemia resolved. A temporary bilateral ventricular assist device (Bi-VAD) was used for superior systemic perfusion and unloading of the bilateral ventricles after 16 hours of extracorporeal membrane oxygenation support. After the start of maintenance using the Bi-VAD, extracorporeal membrane oxygenation was discontinued and the inotropic agents were tapered down immediately. Subsequently, the haemodynamics stabilised. All the visceral organs were well perfused with Bi-VAD support. Subsequent echocardiography demonstrated recovery from the myocardial stunning, with the left ventricular ejection fraction returning to 50-60%. The Bi-VAD was gradually weaned and successfully removed 12 days after implantation. The patient had an uneventful recovery and was discharged without organ injury. Over one year of follow up in our out-patient clinic, adequate cardiac function and improved diabetes control were found.
Assuntos
Glicemia/efeitos dos fármacos , Diabetes Mellitus Tipo 1/tratamento farmacológico , Oxigenação por Membrana Extracorpórea , Parada Cardíaca/terapia , Coração Auxiliar , Hiperpotassemia/induzido quimicamente , Hipoglicemiantes/efeitos adversos , Insulina/efeitos adversos , Adulto , Biomarcadores/sangue , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/diagnóstico , Parada Cardíaca/induzido quimicamente , Parada Cardíaca/diagnóstico , Parada Cardíaca/fisiopatologia , Humanos , Hiperpotassemia/sangue , Hiperpotassemia/diagnóstico , Hipoglicemiantes/administração & dosagem , Insulina/administração & dosagem , Masculino , Recuperação de Função Fisiológica , Resultado do Tratamento , Função Ventricular EsquerdaRESUMO
Posttransplantation lymphoproliferative disorder (PTLD) is a serious complication of organ transplantation, with an incidence of 0.8% to 20% in heart transplant (HTx) recipients, and standard treatment may be too toxic in some cases. Rituximab is an anti-CD20 monoclonal antibody that has demonstrated efficacy in patients with various lymphoid malignancies and has been demonstrated effective in combination with chemotherapy regimens such as CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone). Cardiotoxicity with CHOP remains a major concern for treating HTx recipients with PTLD, however. We present a case of an HTx recipient with sick sinus syndrome and PTLD who was successfully treated with rituximab alone, avoiding the cardiotoxicity of CHOP. The cardiotoxicity induced by CHOP should be kept in mind in HTx recipients with PTLD, especially when there is an existing heart problem in such recipients. Monotherapy with rituximab can be considered a safe choice.