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PURPOSE OF REVIEW: The goal of this review is to describe the current evidence available for remote monitoring devices available for patients with chronic heart failure, and also detail practical clinical recommendations for implementing these tools in daily clinical practice. RECENT FINDINGS: Several devices ranging from sophisticated multiparametric algorithms in defibrillators, implantable pulmonary artery pressure sensors, and wearable devices to measure thoracic impedance can be utilized as important adjunctive tools to reduce the risk of heart failure hospitalization in patients with chronic heart failure. Pulmonary artery pressure sensors provide the most granular data regarding hemodynamic status, while alerts from wearable devices for thoracic impedance and defibrillator-based algorithms increase the likelihood of worsening clinical status while also having high negative predictive value when values are within normal range. SUMMARY: Multiple device-based monitoring strategies are available to reduce longitudinal risk in patients with chronic heart failure. Further studies are needed to best understand a practical pathway to integrate multiple signals of data for early clinical decompensation risk predictionVideo abstract: http://links.lww.com/HCO/A95.
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Desfibriladores Implantáveis , Insuficiência Cardíaca , Humanos , Doença Crônica , Valor Preditivo dos Testes , Insuficiência Cardíaca/terapia , AlgoritmosRESUMO
BACKGROUND: Hydrogen sulfide (H2S) exerts mitochondria-specific actions that include the preservation of oxidative phosphorylation, biogenesis, and ATP synthesis, while inhibiting cell death. 3-MST (3-mercaptopyruvate sulfurtransferase) is a mitochondrial H2S-producing enzyme whose functions in the cardiovascular disease are not fully understood. In the current study, we investigated the effects of global 3-MST deficiency in the setting of pressure overload-induced heart failure. METHODS: Human myocardial samples obtained from patients with heart failure undergoing cardiac surgeries were probed for 3-MST protein expression. 3-MST knockout mice and C57BL/6J wild-type mice were subjected to transverse aortic constriction to induce pressure overload heart failure with reduced ejection fraction. Cardiac structure and function, vascular reactivity, exercise performance, mitochondrial respiration, and ATP synthesis efficiency were assessed. In addition, untargeted metabolomics were utilized to identify key pathways altered by 3-MST deficiency. RESULTS: Myocardial 3-MST was significantly reduced in patients with heart failure compared with nonfailing controls. 3-MST KO mice exhibited increased accumulation of branched-chain amino acids in the myocardium, which was associated with reduced mitochondrial respiration and ATP synthesis, exacerbated cardiac and vascular dysfunction, and worsened exercise performance following transverse aortic constriction. Restoring myocardial branched-chain amino acid catabolism with 3,6-dichlorobenzo1[b]thiophene-2-carboxylic acid (BT2) and administration of a potent H2S donor JK-1 ameliorates the detrimental effects of 3-MST deficiency in heart failure with reduced ejection fraction. CONCLUSIONS: Our data suggest that 3-MST derived mitochondrial H2S may play a regulatory role in branched-chain amino acid catabolism and mediate critical cardiovascular protection in heart failure.
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Insuficiência Cardíaca , Sulfeto de Hidrogênio , Disfunção Ventricular Esquerda , Trifosfato de Adenosina/metabolismo , Aminoácidos de Cadeia Ramificada/metabolismo , Animais , Insuficiência Cardíaca/metabolismo , Humanos , Sulfeto de Hidrogênio/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo , Miocárdio/metabolismo , Disfunção Ventricular Esquerda/metabolismoRESUMO
BACKGROUND: We studied longitudinal levels of angiotensin-II type 1 receptor antibody (AT1R-Ab) and their effects on adverse events (death, treated rejection and cardiac allograft vasculopathy) in patients who were bridged to heart transplant using a continuous flow left ventricular assist device (LVAD). METHODS AND RESULTS: Sera of 77 patients bridged to heart transplant (from 2009 to 2017) were tested for AT1R-Ab and CRP before and after LVAD. Elevated AT1R-Ab was defined as >10.0 U/mL. The median follow-up after transplant was 3.6 years (interquartile range, 2.2-5.6 years). After LVAD, AT1R-Ab levels increased from baseline and remained elevated until transplant. Freedom from adverse events at 5 years was lower in those with elevated AT1R-Ab levels at time of transplant. In an adjusted, multivariable Cox analysis, an AT1R-Ab level of >10 U/mL was associated with developing the primary end point (adjusted hazard ratio 3.4, 95% confidence interval 1.2-9.2, Pâ¯=â¯.017). Although C-reactive protein levels were high before and after LVAD placement, C-reactive protein did not correlate with AT1R-Ab. CONCLUSIONS: In LVAD patients bridged to heart transplant, an increased AT1R-Ab level at time of transplant was associated with poor outcomes after heart transplant. Post-LVAD AT1R-Ab elevations were not correlated with serum markers of systemic inflammation. Larger studies are needed to examine the pathologic role of AT1R-Ab in heart transplant.
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Insuficiência Cardíaca , Transplante de Coração , Coração Auxiliar , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/terapia , Transplante de Coração/efeitos adversos , Coração Auxiliar/efeitos adversos , Humanos , Morbidade , Estudos Retrospectivos , Resultado do TratamentoRESUMO
PURPOSE: Phosphodiesterase-5 (PDE5) inhibitors were shown to exert powerful protection in various animal models of cardiomyopathy. Tadalafil is a long-acting and highly specific PDE5 inhibitor, which makes it the most attractive in its class for long-term management of patients with heart failure. We studied the effects of tadalafil in attenuating ischemic cardiomyopathy in mice. METHODS AND RESULTS: Adult male mice underwent myocardial infarction (MI) by permanent left coronary artery ligation and were treated daily with tadalafil (1 mg/kg; ip) or volume-matched 10% DMSO for 4 weeks. Twenty four hours after coronary ligation, infarct size, measured by TTC staining, was reduced from 70.1 ± 3.1% in DMSO-treated group to 49.3 ± 2.6% with tadalafil (P < 0.05). Similarly, tadalafil treatment yielded a smaller fibrotic area (8.8 ± 2.8% of LV), assessed by Masson's trichrome staining, as compared to DMSO group (21.9 ± 3.9%, P < 0.05). Apoptosis, measured by TUNEL assay, also declined with tadalafil (2.1 ± 0.2%) as compared to DMSO (6.7 ± 0.4%, P < 0.05) at 28 days post MI. Tadalafil also attenuated the increase in cardiac hypertrophy and pulmonary edema following infarction. These parameters reflect diminished left ventricular (LV) adverse remodeling and preserved fractional shortening with tadalafil at 7 and 28 days post infarction. CONCLUSIONS: Tadalafil attenuates ischemic cardiomyopathy in mice and preserves LV function.
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Carbolinas/farmacologia , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/prevenção & controle , Animais , Apoptose/efeitos dos fármacos , Cardiomegalia/dietoterapia , Cardiomegalia/tratamento farmacológico , Cardiomiopatias/tratamento farmacológico , Vasos Coronários/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos ICR , Infarto do Miocárdio/tratamento farmacológico , Inibidores de Fosfodiesterase/farmacologia , Edema Pulmonar/tratamento farmacológico , Tadalafila , Disfunção Ventricular Esquerda/tratamento farmacológico , Função Ventricular Esquerda/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacosRESUMO
Cinaciguat (BAY 58-2667) is a novel nitric oxide (NO)-independent activator of soluble guanylate cyclase (sGC), which induces cGMP-generation and vasodilation in diseased vessels. We tested the hypothesis that cinaciguat might trigger protection against ischemia/reperfusion (I/R) in the heart and adult cardiomyocytes through cGMP/protein kinase G (PKG)-dependent generation of hydrogen sulfide (H(2)S). Adult New Zealand White rabbits were pretreated with 1 or 10 µg/kg cinaciguat (iv) or 10% DMSO (vehicle) 15 min before I/R or with 10 µg/kg cinaciguat (iv) at reperfusion. Additionally, adult male ICR mice were treated with either cinaciguat (10 µg/kg ip) or vehicle 30 min before I/R or at the onset of reperfusion (10 µg/kg iv). The PKG inhibitor KT5283 (KT; 1 mg/kg ip) or dl-propargylglycine (PAG; 50 mg/kg ip) the inhibitor of the H(2)S-producing enzyme cystathionine-γ-lyase (CSE) were given 10 and 30 min before cinaciguat. Cardiac function and infarct size were assessed by echocardiography and tetrazolium staining, respectively. Primary adult mouse cardiomyocytes were isolated and treated with cinaciguat before simulated ischemia/reoxygenation. Cinaciguat caused 63 and 41% reduction of infarct size when given before I/R and at reperfusion in rabbits, respectively. In mice, cinaciguat pretreatment caused a more robust 80% reduction in infarct size vs. 63% reduction when given at reperfusion and preserved cardiac function following I/R, which were blocked by KT and PAG. Cinaciguat also caused an increase in myocardial PKG activity and CSE expression. In cardiomyocytes, cinaciguat (50 nM) reduced necrosis and apoptosis and increased H(2)S levels, which was abrogated by KT. Cinaciguat is a novel molecule to induce H(2)S generation and a powerful protection against I/R injury in heart.
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Benzoatos/farmacologia , Ativadores de Enzimas/farmacologia , Guanilato Ciclase/metabolismo , Sulfeto de Hidrogênio/metabolismo , Infarto do Miocárdio/prevenção & controle , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Miócitos Cardíacos/efeitos dos fármacos , Receptores Citoplasmáticos e Nucleares/metabolismo , Animais , Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , GMP Cíclico/metabolismo , Proteínas Quinases Dependentes de GMP Cíclico/antagonistas & inibidores , Proteínas Quinases Dependentes de GMP Cíclico/metabolismo , Cistationina gama-Liase/antagonistas & inibidores , Cistationina gama-Liase/genética , Cistationina gama-Liase/metabolismo , Modelos Animais de Doenças , Ativação Enzimática , Inibidores Enzimáticos/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos ICR , Infarto do Miocárdio/diagnóstico por imagem , Infarto do Miocárdio/enzimologia , Infarto do Miocárdio/fisiopatologia , Traumatismo por Reperfusão Miocárdica/diagnóstico por imagem , Traumatismo por Reperfusão Miocárdica/enzimologia , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Miócitos Cardíacos/enzimologia , Miócitos Cardíacos/patologia , Necrose , RNA Mensageiro/metabolismo , Coelhos , Guanilil Ciclase Solúvel , Ultrassonografia , Regulação para Cima , Função Ventricular Esquerda/efeitos dos fármacosRESUMO
INTRODUCTION: We examined the impact and time course of de novo human leukocyte antigen (HLA) allosensitization following left ventricular assist device (LVAD) implantation. METHODS AND RESULTS: Forty patients had a calculated panel reactive antibody (cPRA) prior to LVAD surgery between January 2014 and December 2018. Of these patients, we retrospectively studied 33 patients who had pre-LVAD cPRA <10%. De novo allosensitization was defined as cPRA ≥10% within 3 months following LVAD surgery, and "persistent allosensitization" was defined as cPRA ≥10% at time of heart transplant or death. One-third (11/33) of our cohort developed de novo allosensitization within 3-months post-LVAD. Median duration of follow-up during LVAD support was 588 days (IQR 337-1071 days), or approximately 19 months. In an adjusted, multivariable analysis, female sex remained associated with de novo allosensitization (adjusted odds ratio [95%CI]: 11 (1.4-85), P = 0.026). De novo allosensitization was subsequently associated with persistent allosensitization (P = 0.024). Both axial-flow and centrifugal-flow LVADs had similar rates of allosensitization. Compared to those with no allosensitization, patients with de novo allosensitization did not appear to have inferior post-transplant outcomes of death or treated rejection. CONCLUSION: In our single-center experience, one-third of patients developed de novo allosensitization which did not appear to associate with inferior post-transplant outcomes. Female sex was associated with de novo allosensitization.
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Transplante de Coração , Coração Auxiliar , Anticorpos , Feminino , Antígenos HLA , Antígenos de Histocompatibilidade Classe I , Antígenos de Histocompatibilidade Classe II , Humanos , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Chronic inhibition of phosphodiesterase-5 with sildenafil immediately after permanent occlusion of the left anterior descending coronary artery was shown to limit ischemic heart failure (HF) in mice. To mimic a more clinical scenario, we postulated that treatment with sildenafil beginning at 3 days post-myocardial infarction (MI) would also reduce HF progression through the inhibition of the RhoA/Rho-kinase pathway. Adult male ICR mice with fractional shortening < 25% at day 3 following permanent left anterior descending coronary artery ligation were continuously treated with either saline (volume matched, ip, 2 times/day) or sildenafil (21 mg/kg, ip, 2 times/day) for 25 days. Echocardiography showed fractional shortening preservation and less left ventricular end-diastolic dilatation with sildenafil treatment compared with saline treatment at 7 and 28 days post-MI (P < 0.05). Both fibrosis and apoptosis, determined by Masson's trichrome and terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling (TUNEL), respectively, were attenuated in the sildenafil-treated mice (P < 0.05 vs. saline). Western blot analysis showed enchanced Bcl-2-to-Bax ratio with sildenafil treatment (P < 0.05 vs. saline). Activity assay showed sildenafil-mediated PKG activation 1 day after treatment (P < 0.05 vs. sham and saline). PKG activation was associated with sildenafil-mediated inhibition of Rho kinase (P < 0.05) compared with saline treatment, whereas PKG inhibition with KT-5823 abolished this inhibitory effect of sildenafil. In conclusion, for the first time, our findings show that chronic sildenafil treatment, initiated at 3 days post-MI, attenuates left ventricular dysfunction independent of its infarct-sparing effect, and this cardioprotection involves the inhibition of the RhoA/Rho-kinase pathway. Sildenafil may be a promising therapeutic tool for advanced HF in patients.
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Insuficiência Cardíaca/prevenção & controle , Insuficiência Cardíaca/fisiopatologia , Inibidores da Fosfodiesterase 5/uso terapêutico , Piperazinas/uso terapêutico , Transdução de Sinais/fisiologia , Sulfonas/uso terapêutico , Quinases Associadas a rho/antagonistas & inibidores , Proteína rhoA de Ligação ao GTP/antagonistas & inibidores , Animais , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Cardiomegalia/fisiopatologia , Proteínas Quinases Dependentes de GMP Cíclico/fisiologia , Insuficiência Cardíaca/patologia , Hemodinâmica/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos ICR , Modelos Animais , Inibidores da Fosfodiesterase 5/farmacologia , Piperazinas/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Purinas/farmacologia , Purinas/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Citrato de Sildenafila , Sulfonas/farmacologia , Disfunção Ventricular Esquerda/fisiopatologia , Proteína X Associada a bcl-2/metabolismo , Quinases Associadas a rho/fisiologia , Proteína rhoA de Ligação ao GTP/fisiologiaRESUMO
INTRODUCTION: Guidelines derived from patients in clinical trials indicate that emergency department patients with likely myocardial infarction (MI) who have new left bundle-branch block (LBBB) should undergo rapid reperfusion therapy. Whether this pertains to lower risk emergency department patients with LBBB is unclear. METHODS: A total of 401 consecutive patients with LBBB undergoing an MI rule-out protocol were included. Left bundle-branch blocks were classified as chronic; new; or, if no prior electrocardiogram (ECG) was available, as presumably new. Left bundle-branch blocks were considered concordant if there was ≥1 mm concordant ST elevation or depression. Rates of MI, peak MB values in MI patients, and 30-day mortality were compared across groups. RESULTS: A majority of patients (64%) had new (37%) or presumably new LBBB (27%). A total of 116 patients (29%) had MI, with no significant difference in prevalence or size of MI among the 3 ECG groups. Myocardial infarction was diagnosed in 86% of patients with concordant ECG changes versus 27% of patients without concordant ECG changes (P < .01). Peak MB was >5× normal in 50% who had concordant ST changes compared to none of those who did not. Concordant ST changes were the most important predictor of MI (odds ratio 17, 95% CI 3.4-81, P < .001) and an independent predictor of mortality (odds ratio 4.3, 95% CI 1.3-15, P < .001); new or presumably new LBBB was neither. CONCLUSIONS: Most patients with possible MI with new or presumably new LBBB do not have MI. Concordant ECG changes were an important predictor of MI and death. Current guidelines regarding early reperfusion therapy for patients with LBBB should be reconsidered.
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Bloqueio de Ramo/complicações , Bloqueio de Ramo/diagnóstico , Infarto do Miocárdio/complicações , Infarto do Miocárdio/diagnóstico , Idoso , Idoso de 80 Anos ou mais , Bloqueio de Ramo/terapia , Doença Crônica , Eletrocardiografia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/terapia , Resultado do TratamentoRESUMO
RATIONALE: Most patients with pulmonary arterial hypertension (PAH) die from right heart failure. Beta-adrenergic receptor blockade reduces mortality by about 30% in patients with left-sided systolic heart failure, but is not used in PAH. OBJECTIVES: To assess the effect of the adrenergic receptor blocker carvedilol on the pulmonary circulation and right heart in experimental pulmonary hypertension in rats. METHODS: Angioproliferative pulmonary hypertension was induced in rats by combined exposure to the vascular endothelial growth factor-receptor antagonist SU5416 and hypoxia. Carvedilol treatment was started after establishment of pulmonary hypertension and right heart dysfunction. MEASUREMENTS AND MAIN RESULTS: Compared with vehicle-treated animals, treatment with carvedilol resulted in increased exercise endurance; improved right ventricular (RV) function (increased tricuspid annular plane systolic excursion and decreased RV dilatation); and an increased cardiac output. The morphology of the pulmonary vessels and the RV afterload were not affected by carvedilol. Carvedilol treatment was associated with enhancement of RV fetal gene reactivation, increased protein kinase G (PKG) activity, and a reduction in capillary rarefaction and fibrosis. Metoprolol had similar but less pronounced effects in the SU5416 and hypoxia model. Cardioprotective effects were noted of both carvedilol and metoprolol in the monocrotaline model. In the case of carvedilol, but not metoprolol, part of these effects resulted from a prevention of monocrotaline-induced lung remodeling. CONCLUSIONS: Adrenergic receptor blockade reverses RV remodeling and improves RV function in experimental pulmonary hypertension. Beta-adrenergic receptor blockers are not recommended in humans with PAH before their safety and efficacy are assessed in well-designed clinical trials.
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Antagonistas Adrenérgicos/farmacologia , Carbazóis/farmacologia , Hipertensão Pulmonar/tratamento farmacológico , Propanolaminas/farmacologia , Disfunção Ventricular Direita/tratamento farmacológico , Remodelação Ventricular/efeitos dos fármacos , Animais , Carvedilol , Modelos Animais de Doenças , Hipertensão Pulmonar/induzido quimicamente , Indóis/administração & dosagem , Masculino , Circulação Pulmonar/efeitos dos fármacos , Pirróis/administração & dosagem , Ratos , Ratos Sprague-Dawley , Fator A de Crescimento do Endotélio Vascular/administração & dosagem , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Disfunção Ventricular Direita/induzido quimicamenteRESUMO
Patients on left ventricular assist device (LVAD) support may be susceptible to severe disease and complications from coronavirus disease-19 (COVID-19). The purpose of this study was to describe the clinical course of COVID-19 in LVAD patients. A retrospective review was performed at our center; 28 LVAD patients who developed COVID-19 between March 2020 and March 2021, and six patients with a prior COVID-19 infection who underwent LVAD implantation, were identified and examined. Of the 28 patients, nine (32%) died during the study period, five (18%) during their index hospitalization for COVID-19. Two patients (7%) presented with suspected pump thrombosis. In a nonadjusted binary regression logistic analysis, admission to the intensive care unit (unadjusted odds ratio, 7.6 [CI, 1.2-48], P = 0.03), and the need for mechanical ventilation (unadjusted odds ratio 14 [CI, 1.3-159], P = 0.03) were associated with mortality. The six patients who previously had COVID-19 and subsequently received a LVAD were on intra-aortic balloon pump and inotropic support at time of surgery. All six experienced a complicated and prolonged postoperative course. Three patients (50%) suffered from ischemic stroke, and there was one (17%) 30 day mortality. We observed an increased risk of morbidity and mortality in LVAD patients with COVID-19.
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COVID-19 , Insuficiência Cardíaca , Coração Auxiliar , Insuficiência Cardíaca/cirurgia , Coração Auxiliar/efeitos adversos , Humanos , Estudos Retrospectivos , SARS-CoV-2 , Resultado do TratamentoRESUMO
Accurate device optimization of the Syncardia temporary total artificial heart is difficult while waiting for heart transplantation. In this challenging clinical cohort, using an implantable hemodynamic monitor (CardioMEMS HF system) can assist in volume and hemodynamic assessments. (Level of Difficulty: Advanced.).
RESUMO
BACKGROUND: Tadalafil is a novel long-acting inhibitor of phosphodiesterase-5. Because cGMP-dependent protein kinase (PKG) signaling plays a key role in cardioprotection, we hypothesized that PKG activation with tadalafil would limit myocardial ischemia/reperfusion (I/R) injury and dysfunction. Additionally, we contemplated that cardioprotection with tadalafil is mediated by hydrogen sulfide (H(2)S) signaling in a PKG-dependent fashion. METHODS AND RESULTS: After baseline transthoracic echocardiography (TTE), adult ICR mice were injected i.p. with vehicle (10% DMSO) or tadalafil (1 mg/kg) with or without KT5823 (KT, PKG blocker, 1 mg/kg) or dl-propargylglycine (PAG, Cystathionine-gamma-lyase [CSE, H(2)S-producing enzyme] blocker; 50 mg/kg) 1 hour before coronary artery ligation for 30 minutes and reperfusion for 24 hours, whereas C57BL wild-type and CSE-knockout mice were treated with either vehicle or tadalafil. After reperfusion, TTE was performed and hearts were collected for infarct size (IS) measurement using TTC staining. Survival was increased with tadalafil (95%) compared with control (65%, P<0.05). Infarct size was reduced with tadalafil (13.2+/-1.7%) compared to vehicle (40.6+/-2.5%; P<0.05). KT and PAG abolished tadalafil-induced protection (IS: 39.2+/-1% and 51.2+/-2.4%, respectively) similar to genetic deletion of CSE (47.2+/-5.1%). Moreover, tadalafil preserved fractional shortening (FS: 31+/-1.5%) compared to control (FS: 22+/-4.8%, P<0.05). Baseline FS was 44+/-1.7%. KT and PAG abrogated the preservation of LV function with tadalafil by decline in FS to 17+/-1% and 23+/-3%, respectively. Compared to vehicle, myocardial H(2)S production was significantly increased with tadalafil and was abolished with KT. CONCLUSIONS: PKG activation with tadalafil limits myocardial infarction and preserves LV function through H(2)S signaling.
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Carbolinas/farmacologia , Proteínas Quinases Dependentes de GMP Cíclico/fisiologia , Sulfeto de Hidrogênio/metabolismo , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Inibidores da Fosfodiesterase 5 , Inibidores de Fosfodiesterase/farmacologia , Animais , Cistationina beta-Sintase/fisiologia , Feminino , Hemodinâmica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos ICR , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/patologia , Traumatismo por Reperfusão Miocárdica/mortalidade , Tadalafila , Remodelação VentricularRESUMO
BACKGROUND: Interleukin-1 (IL-1) is an inflammatory cytokine that responds as an acute phase reactant during acute myocardial infarction. Conflicting data describe the role of anti-IL-1 interventions to reduce cardiac remodeling after AMI. IL-1 Trap is a modified recombinant fusion protein that binds circulating IL-1. Our study evaluated the effects of murine IL-1 Trap on cardiac remodeling after AMI resulting from permanent surgical coronary artery ligation. METHODS: Mice received treatment with intraperitoneal injection of murine IL-1 Trap (1 mg/kg [n = 5], 5 mg/kg [n = 5], or 30 mg/kg [n = 5]) or NaCl 0.9% (saline; n = 10) every 48 hours after surgery. Transthoracic echocardiography was performed at baseline and 7 days after surgery. Inhibition of IL-1 signaling was determined by measurement of IL-6 plasma levels (enzyme-linked immunosorbent assay) after IL-1b injection. Apoptosis (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling) was measured in murine heart samples and in a primary culture of murine cardiomyocytes. RESULTS: Mice treated with 5 mg/kg or 30 mg/kg IL-1 Trap had more favorable cardiac remodeling and echocardiographic assessment of infarct size at 7 days compared with saline (P < 0.05 for each comparison). Treatment with IL-1 Trap also reduced apoptosis and IL-6 levels compared with saline treatment. CONCLUSIONS: IL-1 Trap ameliorates cardiac remodeling and reduces cardiomyocyte apoptosis after experimental acute myocardial infarction in the mouse.
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Modelos Animais de Doenças , Interleucina-1beta/administração & dosagem , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/metabolismo , Proteínas Recombinantes de Fusão/administração & dosagem , Proteínas Recombinantes de Fusão/uso terapêutico , Remodelação Ventricular/fisiologia , Animais , Morte Celular/fisiologia , Células Cultivadas , Interleucina-1beta/fisiologia , Interleucina-6/antagonistas & inibidores , Masculino , Camundongos , Camundongos Endogâmicos ICR , Infarto do Miocárdio/patologia , Miócitos Cardíacos/fisiologia , Transdução de Sinais/fisiologiaRESUMO
AIMS: Hydrogen sulfide (H2S) protects against ischemic and inflammatory injury following myocardial ischemia via induction of microRNA (miR)-21. We sought to determine whether H2S attenuates ischemic heart failure with reduced ejection fraction (HFrEF) and interrogate the role of cofilin-2, a target of miR-21, in this protective process. METHODS AND RESULTS: Adult male mice underwent myocardial infarction (MI) by coronary artery ligation after baseline echocardiography. Following MI, mice were treated with Na2S (100 µg/kg/day; intraperitoneal [IP]) or saline up to 28 days. End-diastolic pressure, measured by Millar catheter, was significantly increased (P < .05 vs sham) at 3 days post-MI in the saline group, which was attenuated with Na2S. Left ventricular (LV) fractional shortening decreased significantly at 28 days post-MI in the saline group but was preserved with Na2S and LV infarct scar size was smaller in Na2S group as compared to control. Apoptotic signaling, measured by Bcl-2/Bax ratio, was significantly increased in the saline group but was mitigated with Na2S. Survival rate was 2-fold higher in Na2S group compared to saline control (P < .05). Proteomic analysis and Matrix-Assisted Laser Desorption/Ionization-Time of Flight (TOF)/TOF tandem mass spectrometry identified significant changes in proapoptotic cofilin-2 expression, a specific target of miR-21, between saline- and sodium sulfide -treated mice at 28 days post-MI. Western blot analysis confirmed a significant increase in cofilin-2 after MI, which was suppressed with Na2S treatment. Chronic Na2S treatment also attenuated inflammasome formation and activation leading to reduction of maladaptive signaling. CONCLUSION: Na2S treatment after MI preserves LV function and improves survival through attenuation of inflammasome-mediated adverse remodeling. We propose H2S donors as promising therapeutic tools for ischemic HFrEF.
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Cofilina 2/metabolismo , Insuficiência Cardíaca/prevenção & controle , Sulfeto de Hidrogênio/farmacologia , Infarto do Miocárdio/tratamento farmacológico , Miocárdio/metabolismo , Sulfetos/farmacologia , Animais , Apoptose/efeitos dos fármacos , Modelos Animais de Doenças , Regulação para Baixo , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/patologia , Insuficiência Cardíaca/fisiopatologia , Inflamassomos/metabolismo , Masculino , Camundongos Endogâmicos C57BL , MicroRNAs/genética , MicroRNAs/metabolismo , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Infarto do Miocárdio/fisiopatologia , Miocárdio/patologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Função Ventricular Esquerda/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacosRESUMO
As health systems worldwide grapple with the coronavirus disease-2019 (COVID-19) pandemic, patients with durable LVAD support represent a unique population at risk for the disease. This paper outlines the case of such a patient who developed COVID-19 complicated by a "cytokine storm" with severe acute respiratory distress syndrome and myocardial injury and describes the challenges that arose during management.
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There is a desperate search to discover effective therapies against coronavirus disease-2019 (COVID-19). Patients with human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) comprise a unique population whose clinical course may provide insights into the effects of antiretroviral therapy on COVID-19. We describe the case of a patient with HIV/AIDS on left ventricular assist device support who was hospitalized and recovered from COVID-19. (Level of Difficulty: Intermediate.).
RESUMO
BACKGROUND: Sacubitril/valsartan (SAC/VAL) is approved by the U.S. Food and Drug Administration for heart failure with reduced ejection fraction (HFrEF). OBJECTIVES: This study investigated the effects of SAC/VAL on acute myocardial infarction (MI) and cardiac remodeling in a translational rabbit model of MI. METHODS: New Zealand White rabbits were sedated and underwent conscious MI (45-min ischemia) by balloon inflation (previously implanted surgically) followed by 72 h (acute protocol) or 10 weeks (chronic protocols) of reperfusion. "Infarct-sparing" protocol: SAC/VAL, VAL, or placebo were randomly allocated and administered at reperfusion. "HFrEF-treatment" protocol: rabbits were randomized, and treatment commenced after echocardiography-confirmed left ventricular ejection fraction (LVEF) ≤40%. "HFrEF-prevention" protocol: treatment started at reperfusion and continued daily throughout the study. RESULTS: Compared with placebo, SAC/VAL and VAL significantly reduced infarct size (TTC staining) and plasma troponin levels; however, only SAC/VAL preserved LVEF at 72 h post-MI. In the HFrEF-treatment protocol, LVEF improvement was observed with SAC/VAL compared with both placebo and VAL starting 2 weeks post-treatment, a benefit that persisted throughout study duration. In the HFrEF-prevention protocol, SAC/VAL and VAL attenuated the decline in LVEF post-MI, although SAC/VAL offered better functional protection. The functional improvement observed in both treatment protocols was paralleled by significant reduction in left ventricular (LV) scar size (Picrosirius red staining) in the SAC/VAL groups. CONCLUSIONS: Reperfusion therapy with SAC/VAL or VAL offers robust acute infarct-sparing benefits; however, SAC/VAL treatment offered superior short-term and long-term benefits in preventing MI-induced LV dysfunction compared with VAL. SAC/VAL also significantly attenuated LV scar size following MI compared with placebo, whereas VAL did not reach statistical significance in scar reduction.