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Heart failure (HF) is a heterogeneous condition that can be categorized according to the left ventricular ejection fraction (EF) into HF with reduced (HFrEF) or preserved (HFpEF) EF. Although HFrEF and HFpEF share some common clinical manifestations, the mechanisms underlying each phenotype are often found to be distinct. Identifying shared and divergent pathophysiological features might expand our insights on HF pathophysiology and assist the search for therapies for each HF subtype. In this study, we evaluated and contrasted two new murine models of non-ischaemic HFrEF and cardiometabolic HFpEF in terms of myocardial structure, left ventricular function, gene expression, cardiomyocyte calcium handling, mitochondrial polarization and protein acetylation in a head-to-head fashion. We found that in conditions of similar haemodynamic stress, the HFrEF myocardium underwent a more pronounced hypertrophic and fibrotic remodelling, whereas inflammation was greater in the HFpEF myocardium. We observed opposing features on calcium release, which was diminished in the HFrEF cardiomyocyte but enhanced in the HFpEF cardiomyocyte. Mitochondria were less polarized in both HFrEF and HFpEF cardiomyocytes, reflecting similarly impaired metabolic capacity. Hyperacetylation of cardiac proteins was observed in both models, but it was more accentuated in the HFpEF heart. Despite shared features, unique triggering mechanisms (neurohormonal overactivation in HFrEF vs. inflammation in HFpEF) appear to determine the distinct phenotypes of HF. The findings of the present research stress the need for further exploration of the differential mechanisms underlying each HF subtype, because they might require specific therapeutic interventions. KEY POINTS: The mechanisms underlying heart failure with either reduced (HFrEF) or preserved (HFpEF) ejection fraction are often found to be different. Previous studies comparing pathophysiological traits between HFrEF and HFpEF have been conducted on animals of different ages and strains. The present research contrasted two age-matched mouse models of non-ischaemic HFrEF and cardiometabolic HFpEF to uncover divergent and shared features. We found that upon similar haemodynamic stress, the HFrEF heart experienced a more pronounced hypertrophic and fibrotic remodelling, whereas inflammation appeared to be greater in the HFpEF myocardium. Calcium release was diminished in the HFrEF cardiomyocyte and enhanced in the HFpEF cardiomyocyte. Mitochondria were comparably less polarized in both HFrEF and HFpEF myocytes. Hyperacetylation of proteins was common to both models, but stronger in the HFpEF heart. Casting light on common and distinguishing features might ease the quest for phenotype-specific therapies for heart failure patients.
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BACKGROUND: Inflammation affecting the heart and surrounding tissues is a clinical condition recently reported following COVID-19 mRNA vaccination. Assessing trends of these events related to immunization will improve vaccine safety surveillance and best practices for forthcoming vaccine campaigns. However, the causality is unknown, and the mechanisms associated with cardiac myocarditis are not understood. CASE PRESENTATION: After the first dose, we reported an mRNA vaccine-induced perimyocarditis in a young patient with a history of recurrent myocardial inflammation episodes and progressive loss of cardiac performance. We tested this possible inflammatory cytokine-mediated cardiotoxicity after vaccination in the acute phase (ten days), and we found a significant elevation of MCP-1, IL-18, and IL-8 inflammatory mediators. Still, these cytokines decreased considerably at the recovery phase (42 days later). We used the cardiomyoblasts cell line to test the effect of serum on cell viability, observing that serum from the acute phase reduced the cell viability to 75%. We did not detect this toxicity in cells when we tested serum from the patient in the recovery phase. We also tested serum-induced hypertrophy, a phenomenon in myocarditis and heart failure. We found that acute phase-serum has hypertrophy effects, increasing 25% of the treated cardiac cells' surface and significantly increasing B-type natriuretic peptide. However, we did not observe the hypertrophic effect in the recovery phase or sera from healthy controls. CONCLUSION: Our results opened the possibility of the inflammatory cytokines or serum soluble mediators as key factors for vaccine-associated myocarditis. In this regard, identifying anti-inflammatory molecules that reduce inflammatory cytokines could help avoid vaccine-induced myocardial inflammation.
Assuntos
COVID-19 , Miocardite , Humanos , Miocardite/etiologia , Vacinas contra COVID-19/efeitos adversos , COVID-19/prevenção & controle , Hipertrofia , Inflamação , Citocinas , Vacinas de mRNARESUMO
Cardiovascular diseases (CVDs) are the result of complex pathophysiological processes in the tissues comprising the heart and blood vessels. Inflammation is the main culprit for the development of cardiovascular dysfunction, and it may be traced to cellular stress events including apoptosis, oxidative and shear stress, and cellular and humoral immune responses, all of which impair the system's structure and function. An intracellular chaperone, heat shock protein 60 (HSP60) is an intriguing example of a protein that may both be an ally and a foe for cardiovascular homeostasis; on one hand providing protection against cellular injury, and on the other triggering damaging responses through innate and adaptive immunity. In this review we will discuss the functions of HSP60 and its effects on cells and the immune system regulation, only to later address its implications in the development and progression of CVD. Lastly, we summarize the outcome of various studies targeting HSP60 as a potential therapeutic strategy for cardiovascular and other diseases.
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Doenças Cardiovasculares , Sistema Cardiovascular , Apoptose , Chaperonina 60 , Humanos , Sistema ImunitárioRESUMO
Myocarditis is generally a mild and self-limited consequence of systemic infection of cardiotropic viruses. However, patients can develop a temporary or permanent impairment of cardiac function including acute cardiomyopathy with hemodynamic compromise or severe arrhythmias. In this setting, specific causes of inflammation are associated with variable risks of death and transplantation. Recent translational studies suggest that treatments tailored to specific causes of myocarditis may impact clinical outcomes when added to guideline-directed medical care. This review summarizes recent advances in translational research that influence the utility of endomyocardial biopsy for the management of inflammatory cardiomyopathies. Emerging therapies for myocarditis based on these mechanistic hypotheses are entering clinical trials and may add to the benefits of established heart failure treatment.
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Cardiomiopatias/terapia , Insuficiência Cardíaca/terapia , Miocardite/terapia , Animais , Cardiomiopatias/diagnóstico , Cardiomiopatias/etiologia , Cardiomiopatias/fisiopatologia , Progressão da Doença , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/fisiopatologia , Humanos , Miocardite/diagnóstico , Miocardite/etiologia , Miocardite/fisiopatologia , Recuperação de Função Fisiológica , Fatores de Risco , Resultado do TratamentoRESUMO
PURPOSE: The risks and benefits of remote corticosteroid weaning in heart transplant recipients more than 2 years post-transplant are unknown. We compared outcomes in patients undergoing early and remote steroid weaning after heart transplantation. METHODS: We performed a retrospective study (range 09, 1991-04, 2017). Primary outcomes included short-term and long-term mortality, allograft dysfunction, and burden of rejection. Secondary outcomes included impact on hemoglobin A1c, lipid panel, bone scan T-score, and body mass index. RESULTS: 63 patients underwent corticosteroid weaning between 2012 and 2017. Outcomes of patients weaned early (n = 34; median time from transplant = 1.1 years) were compared with those weaned late (n = 29; median time from transplant = 4.4 years). 52 (82.5%) patients were successfully weaned off corticosteroids. No statistically significant difference in outcomes was found between the early and late weaning groups (p = .20). There were no differences in allograft function (p-value = .16), incidence of rejection (p = .46), or mortality (p = .15). Improvement in metabolic profile was seen in both groups but was not statistically significant. CONCLUSIONS: In heart transplant recipients, remote vs early weaning of corticosteroids is not associated with significant differences in graft function or the incidence of rejection after 1-year follow-up. Moreover, there were no significant differences in survival up to 3 years between the two groups.
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Rejeição de Enxerto , Transplante de Coração , Corticosteroides/uso terapêutico , Rejeição de Enxerto/tratamento farmacológico , Rejeição de Enxerto/etiologia , Rejeição de Enxerto/prevenção & controle , Humanos , Estudos Retrospectivos , DesmameRESUMO
PURPOSE OF REVIEW: In heart failure, whether it is associated with reduced or preserved ejection fraction, the immune system is activated and contributes to heart remodeling and impaired function. RECENT FINDINGS: Studies indicate that cells of the immune system not only play a role in the pathology but are also critical regulators of heart function. Knowledge about the role of the immune system driving heart failure will lead to the development of new targets to this system, particularly in those patients that, despite the apparent wellness, relapse and worsen. In this review, we will address the diverse mechanisms that trigger inflammation and their impact on heart failure progression.
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Insuficiência Cardíaca , Insuficiência Cardíaca/etiologia , Humanos , Inflamação , Volume SistólicoRESUMO
BACKGROUND/AIMS: Cyclophilin D (CypD) mediates the mitochondrial permeability transition pore (mPTP) opening that contributes to mitochondrial dysfunction. CypD is regulated by its acetylation/deacetylation state that depends on Sirtuin-3 (SIRT3) mitochondrial deacetylase. Since obesity and metabolic syndrome decrease SIRT3 activity and expression, we tested the hypothesis that CypD hyperacetylation promotes mitochondrial dysfunction under this pathophysiological state, which is associated with ventricular dysfunction and heart failure. METHODS: Myocardial tissue samples from patients with left ventricular heart failure, with either obesity or normal weight, were processed for the expression of SIRT3 and acetylation profile by Western Blot (WB). In addition, a rat model of obesity and metabolic syndrome induced by 30% (w/v) of sucrose was conducted. The WB analysis was used to determine the levels of mitochondrial expression of SIRT3, Adenine Nucleotide Translocator (ANT), CypD and the acetylation profile, as well as immunoprecipitation to establish the acetylation levels of CypD. Mitochondrial function was assessed by oxygen consumption analysis and maximum Ca2+ retention capacity. Oxidative stress was assessed by aconitase activity, protein carbonyl and thiol groups content. RESULTS: SIRT3 expression in the biopsies of the failing human hearts showed a 46% decrease in the expression levels of obese patients in comparison to the non-obese patients (p=0.0219). Remarkably, body mass index was associated with protein acetylation (0.627; p = 0.035), suggesting that the acetylation profiles of the failing hearts of obese patients are partly mediated by a reduction in SIRT3, which is also associated with higher BNP levels, indicating a more severe ventricular dysfunction (-0.636; p = 0.043). Accordingly, obese rats demonstrated a SIRT3 mitochondrial expression decrease of 22% concomitantly with a hyperacetylated mitochondrial profile, including CypD. Cardiac mitochondria from obese animals were 2.5-fold more prone to mPTP opening than the controls. CONCLUSION: Our results indicate that obesity reduces SIRT3 expression and that CypD hyperacetylation increases mPTP opening, suggesting that the activation of SIRT3 might be a potential target to decrease ventricular dysfunction and slow the progression of heart failure.
Assuntos
Mitocôndrias Cardíacas/metabolismo , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , Obesidade/metabolismo , Sirtuína 3/metabolismo , Acetilação , Adulto , Idoso , Animais , Índice de Massa Corporal , Cálcio/metabolismo , Peptidil-Prolil Isomerase F , Ciclofilinas/metabolismo , Feminino , Insuficiência Cardíaca/metabolismo , Humanos , Imunoprecipitação , Técnicas In Vitro , Masculino , Síndrome Metabólica/metabolismo , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Translocases Mitocondriais de ADP e ATP/metabolismo , Poro de Transição de Permeabilidade Mitocondrial , Consumo de Oxigênio/fisiologia , Ratos , Ratos WistarRESUMO
Heart failure (HF) is a cardiovascular syndrome characterized by maladaptive changes with an underlying inflammatory mediated pathogenesis. Nevertheless, current therapy is aimed at the heart workload and neurohormonal axis; thus, prognosis remains poor. To continue improving treatment, we rely on murine models for a better understanding of HF pathophysiology. Among them, pressure overload HF (PO-HF) animal models are a common strategy. Development of PO-HF is characterized by monocyte infiltration, which orchestrates a cascade of events leading to sustained inflammation and maladaptive changes. Here, we divide the PO-HF model progression into four phases and describe the inflammatory, structural, and gene expression profiles. This division is relevant due to its similarities with clinical hypertensive heart disease progression to HF. Evidence shows improvement in hemodynamic and other local parameters by altering the inflammatory response in a specific immune response at a specific point of time. Thus, it is relevant to focus on the time-dependent immune response interaction in order to provide more effective therapy. This review summarizes the pathogenesis of PO-HF murine models, highlighting the inflammatory events in a time frame view. By this approach, we expect to provide researchers with a better understanding of the intertwining time-dependent events that occur in PO-HF.
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Linfócitos B/imunologia , Insuficiência Cardíaca/imunologia , Hipertensão/imunologia , Monócitos/imunologia , Linfócitos T/imunologia , Angiotensina II/administração & dosagem , Angiotensina II/efeitos adversos , Animais , Aorta/imunologia , Aorta/patologia , Linfócitos B/patologia , Cardiomegalia/imunologia , Cardiomegalia/patologia , Movimento Celular , Constrição Patológica/imunologia , Constrição Patológica/patologia , Citocinas/biossíntese , Citocinas/imunologia , Modelos Animais de Doenças , Fibrose Endomiocárdica/imunologia , Fibrose Endomiocárdica/patologia , Insuficiência Cardíaca/induzido quimicamente , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/patologia , Humanos , Hipertensão/complicações , Hipertensão/patologia , Camundongos , Monócitos/patologia , Linfócitos T/patologia , Fatores de Tempo , Disfunção Ventricular Esquerda/imunologia , Disfunção Ventricular Esquerda/patologiaRESUMO
Recent evidence has shown that nanoparticles that have been used to improve or create new functional properties for common products may pose potential risks to human health. Silicon dioxide (SiO2) has emerged as a promising therapy vector for the heart. However, its potential toxicity and mechanisms of damage remain poorly understood. This study provides the first exploration of SiO2-induced toxicity in cultured cardiomyocytes exposed to 7- or 670-nm SiO2 particles. We evaluated the mechanism of cell death in isolated adult cardiomyocytes exposed to 24-h incubation. The SiO2 cell membrane association and internalization were analyzed. SiO2 showed a dose-dependent cytotoxic effect with a half-maximal inhibitory concentration for the 7 nm (99.5 ± 12.4 µg/ml) and 670 nm (>1,500 µg/ml) particles, which indicates size-dependent toxicity. We evaluated cardiomyocyte shortening and intracellular Ca2+ handling, which showed impaired contractility and intracellular Ca2+ transient amplitude during ß-adrenergic stimulation in SiO2 treatment. The time to 50% Ca2+ decay increased 39%, and the Ca2+ spark frequency and amplitude decreased by 35 and 21%, respectively, which suggest a reduction in sarcoplasmic reticulum Ca2+-ATPase (SERCA) activity. Moreover, SiO2 treatment depolarized the mitochondrial membrane potential and decreased ATP production by 55%. Notable glutathione depletion and H2O2 generation were also observed. These data indicate that SiO2 increases oxidative stress, which leads to mitochondrial dysfunction and low energy status; these underlie reduced SERCA activity, shortened Ca2+ release, and reduced cell shortening. This mechanism of SiO2 cardiotoxicity potentially plays an important role in the pathophysiology mechanism of heart failure, arrhythmias, and sudden death.NEW & NOTEWORTHY Silica particles are used as novel nanotechnology-based vehicles for diagnostics and therapeutics for the heart. However, their potential hazardous effects remain unknown. Here, the cardiotoxicity of silica nanoparticles in rat myocytes has been described for the first time, showing an impairment of mitochondrial function that interfered directly with Ca2+ handling.
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Cálcio/metabolismo , Cardiotoxicidade/metabolismo , Metabolismo Energético/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Nanopartículas/toxicidade , Dióxido de Silício/toxicidade , Trifosfato de Adenosina/metabolismo , Animais , Membrana Celular/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Glutationa/metabolismo , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias Cardíacas/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Ratos , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismoRESUMO
Mitochondrial dysfunction has been implicated as a cause of energy deprivation in heart failure (HF). Herein, we tested individual and combined effects of two pathogenic factors of nonischemic HF, inhibition of nitric oxide synthesis [with l-N(G)-nitroarginine methyl ester (l-NAME)] and hypertension [with angiotensin II (AngII)], on myocardial mitochondrial function, oxidative stress, and metabolic gene expression. l-NAME and AngII were administered individually and in combination to mice for 5 wk. Although all treatments increased blood pressure and reduced cardiac contractile function, the l-NAME + AngII group was associated with the most severe HF, as characterized by edema, hypertrophy, oxidative stress, increased expression of Nppa and Nppb, and decreased expression of Atp2a2 and Camk2b. l-NAME + AngII-treated mice exhibited robust deterioration of cardiac mitochondrial function, as observed by reduced respiratory control ratios in subsarcolemmal mitochondria and reduced state 3 levels in interfibrillar mitochondria for complex I but not for complex II substrates. Cardiac myofibrils showed reduced ADP-supported and oligomycin-inhibited oxygen consumption. Mitochondrial functional impairment was accompanied by reduced mitochondrial DNA content and activities of pyruvate dehydrogenase and complex I but increased H2O2 production and tissue protein carbonyls in hearts from AngII and l-NAME + AngII groups. Microarray analyses revealed the majority of the gene changes attributed to the l-NAME + AngII group. Pathway analyses indicated significant changes in metabolic pathways, such as oxidative phosphorylation, mitochondrial function, cardiac hypertrophy, and fatty acid metabolism in l-NAME + AngII hearts. We conclude that l-NAME + AngII is associated with impaired mitochondrial respiratory function and increased oxidative stress compared with either l-NAME or AngII alone, resulting in nonischemic HF.
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Angiotensina II/farmacologia , Inibidores Enzimáticos/farmacologia , Insuficiência Cardíaca/etiologia , Mitocôndrias Cardíacas/efeitos dos fármacos , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Vasoconstritores/farmacologia , Animais , Fator Natriurético Atrial , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/efeitos dos fármacos , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/genética , Cardiomegalia , DNA Mitocondrial/efeitos dos fármacos , DNA Mitocondrial/metabolismo , Complexo I de Transporte de Elétrons/efeitos dos fármacos , Complexo I de Transporte de Elétrons/metabolismo , Complexo II de Transporte de Elétrons/efeitos dos fármacos , Complexo II de Transporte de Elétrons/metabolismo , Expressão Gênica/efeitos dos fármacos , Coração/efeitos dos fármacos , Peróxido de Hidrogênio/metabolismo , Camundongos , Mitocôndrias Cardíacas/metabolismo , Miocárdio/metabolismo , Miocárdio/patologia , Peptídeo Natriurético Encefálico/efeitos dos fármacos , Peptídeo Natriurético Encefálico/genética , Peptídeo Natriurético Tipo C/efeitos dos fármacos , Peptídeo Natriurético Tipo C/genética , Precursores de Proteínas/efeitos dos fármacos , Precursores de Proteínas/genética , Complexo Piruvato Desidrogenase/efeitos dos fármacos , Complexo Piruvato Desidrogenase/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/efeitos dos fármacos , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/genéticaRESUMO
BACKGROUND: Thrombotic events in patients with continuous flow left ventricular assist devices (CF-LVADs) are associated with significant morbidity and mortality. The objective of this study was to delineate the frequency, clinical characteristics, and outcomes of patients with hypercoagulable states who undergo CF-LVAD implantation. METHODS: We performed a retrospective review of 168 consecutive patients who underwent CF-LVAD implantation between 2010 and 2013. Chart and laboratory data were reviewed for the presence of a hereditary and/or acquired hypercoagulable state. Adverse outcomes were defined as death, confirmed pump thrombosis, aortic root clot, stroke, deep vein thrombosis, and pulmonary embolism. Fisher's exact test and Kaplan-Meier estimate were used to analyze frequency of adverse outcomes and event free survival, respectively. RESULTS: A hypercoagulable state was identified in 20 patients (11.9%). There were 18 patients with acquired, 1 with a congenital, and 1 with both congenital and acquired hypercoagulable states. The median follow-up was 429 days and 475 days in patients with and without hypercoagulable states, respectively. During the study period, 15% (3/20) of the patients with a hypercoagulable state had a diagnosis of deep vein thrombosis vs 3% (4/148) of the patients without a hypercoagulable state (P = .030). Only patients with a hypercoagulable state had a subarachnoid hemorrhage (3/20 vs 0/148; P < .01). The event-free survival was lower in the patients with hypercoagulable states (P = .005). CONCLUSION: Hypercoagulable states are not uncommon in patients with CF-LVADs and may be associated with increased morbidity. Prospective studies are needed to more accurately identify the incidence, prevalence, and significance of hypercoagulable states in patients being considered for CF-LVAD.
Assuntos
Insuficiência Cardíaca/cirurgia , Coração Auxiliar/efeitos adversos , Trombofilia/etiologia , Trombose/etiologia , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Trombofilia/congênito , Trombofilia/diagnósticoRESUMO
OBJECTIVES: Right ventricular failure is the primary reason for mortality in pulmonary hypertension (PH), but little is understood about the energetics of the failing right myocardium. Our aim was to examine mitochondrial function and proteomic signatures in paired remodeled right (RM-RV) and non-remodeled left (NRM-LV) ventricular tissue samples procured during heart-lung transplantation. METHODS AND RESULTS: Contractile dysfunction in RM-RV and preserved contractile function in NRM-LV were determined clinically and by echocardiography. Mitochondria were isolated from fresh paired RV and LV wall specimens of explanted hearts. Respiratory states in response to 4 substrates and an uncoupler were analyzed. Proteomic analysis on the mitochondrial isolates was performed with the use of liquid chromatography-mass spectrometry. The RM-RV mitochondria exhibited higher succinate state 4 levels with lower respiratory control ratio (RCR) compared with state 4 levels for pyruvate-malate (PM) and glutamate-malate (GM). RM-RV mitochondria also exhibited lower state 3 for palmitoyl-carnitine (PC) and state 4 for all complex I substrates compared with NRM-LV. The mean RCR were greater in RM-RVs than in NRM-LVs for PM and GM, which is consistent with tight coupling (low state 4 rates, higher RCRs); however, low RM-RV state 3 rates suggest concurrent substrate-dependent impairment in respiratory capacity. Mitochondrial proteomics revealed greater levels of mitochondrial ADP-ATP translocase and proteins of ATP synthesis, mitochondrial pyruvate and short branched chain acyl-CoA metabolism in RM-RV. CONCLUSIONS: The mitochondrial respiration and proteomics in RM-RV are different from NRM-LV. These results have important implications in expanding our understanding of RV metabolism and future management of RV failure.
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Insuficiência Cardíaca/fisiopatologia , Ventrículos do Coração/fisiopatologia , Hipertensão Pulmonar/complicações , Mitocôndrias Cardíacas/metabolismo , Disfunção Ventricular Direita/fisiopatologia , Remodelação Ventricular , Adolescente , Idoso , Ecocardiografia , Complexo I de Transporte de Elétrons/metabolismo , Feminino , Insuficiência Cardíaca/etiologia , Humanos , Pessoa de Meia-Idade , Mitocôndrias Cardíacas/enzimologia , Translocases Mitocondriais de ADP e ATP/metabolismo , Proteômica , Disfunção Ventricular Direita/etiologiaRESUMO
BACKGROUND: The length of hospital stay (LOS) is important in patients admitted for acute heart failure (AHF) because it prolongs an unpleasant experience for the patients and adds substantially to health care costs. METHODS AND RESULTS: We examined the association between LOS and baseline characteristics, 10-day post-discharge HF readmission, and 90-day post-discharge mortality in 1347 patients with AHF enrolled in the VERITAS program. Longer LOS was associated with greater HF severity and disease burden at baseline; however, most of the variability of LOS could not be explained by these factors. LOS was associated with a higher HF risk of both HF readmission (odds ratio for 1-day increase: 1.08; 95% confidence interval [CI] 1.01-1.16; P = .019) and 90-day mortality (hazard ratio for 1-day increase: 1.05; 95% CI 1.02-1.07; P < .001), although these associations are partially explained by concurrent end-organ damage and worsening heart failure during the first days of admission. CONCLUSIONS: In patients who have been admitted for AHF, longer length of hospital stay is associated with a higher rate of short-term mortality. CLINICAL TRIAL REGISTRATION: VERITAS-1 and -2: Clinicaltrials.gov identifiers NCT00525707 and NCT00524433.
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Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/mortalidade , Mortalidade Hospitalar , Tempo de Internação , Piridinas/uso terapêutico , Tetrazóis/uso terapêutico , Doença Aguda , Idoso , Análise de Variância , Método Duplo-Cego , Feminino , Insuficiência Cardíaca/diagnóstico por imagem , Hospitalização/estatística & dados numéricos , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Alta do Paciente/estatística & dados numéricos , Readmissão do Paciente , Prognóstico , Modelos de Riscos Proporcionais , Análise de Sobrevida , Fatores de Tempo , Resultado do TratamentoRESUMO
Stress-induced cardiomyopathy, triggered by acute catecholamine discharge, is a syndrome characterized by transient, apical ballooning linked to acute heart failure and ventricular arrhythmias. Rats receiving an acute isoproterenol (ISO) overdose (OV) suffer cardiac apex ischemia-reperfusion damage and arrhythmia, and then undergo cardiac remodeling and dysfunction. Nevertheless, the subcellular mechanisms underlying cardiac dysfunction after acute damage subsides are not thoroughly understood. To address this question, Wistar rats received a single ISO injection (67 mg/kg). We found in vivo moderate systolic and diastolic dysfunction at 2 wk post-ISO-OV; however, systolic dysfunction recovered after 4 wk, while diastolic dysfunction worsened. At 2 wk post-ISO-OV, cardiac function was assessed ex vivo, while mitochondrial oxidative metabolism and stress were assessed in vitro, and Ca(2+) handling in ventricular myocytes. These were complemented with sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA), phospholamban (PLB), and RyR2 expression studies. Ex vivo, basal mechanical performance index (MPI) and oxygen consumption rate (MVO2) were unchanged. Nevertheless, upon increase of metabolic demand, by ß-adrenergic stimulation (1-100 nM ISO), the MPI versus MVO2 relation decreased and shifted to the right, suggesting MPI and mitochondrial energy production uncoupling. Mitochondria showed decreased oxidative metabolism, membrane fragility, and enhanced oxidative stress. Myocytes presented systolic and diastolic Ca(2+) mishandling, and blunted response to ISO (100 nM), and all these without apparent changes in SERCA, PLB, or RyR2 expression. We suggest that post-ISO-OV mitochondrial dysfunction may underlie decreased cardiac contractility, mainly by depletion of ATP needed for myofilaments and Ca(2+) transport by SERCA, while exacerbated oxidative stress may enhance diastolic RyR2 activity.
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Sinalização do Cálcio , Cardiomiopatias/metabolismo , Traumatismo por Reperfusão Miocárdica/metabolismo , Estresse Oxidativo , Agonistas Adrenérgicos/toxicidade , Animais , Proteínas de Ligação ao Cálcio/genética , Proteínas de Ligação ao Cálcio/metabolismo , Cardiomiopatias/etiologia , Cardiomiopatias/fisiopatologia , Células Cultivadas , Ventrículos do Coração/citologia , Ventrículos do Coração/metabolismo , Ventrículos do Coração/fisiopatologia , Isoproterenol/toxicidade , Camundongos , Mitocôndrias Cardíacas/metabolismo , Contração Miocárdica , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Consumo de Oxigênio , Ratos , Ratos Wistar , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/genética , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismoRESUMO
BACKGROUND: Common adverse events in patients supported with Continuous-flow left ventricular assist devices (CF-LVAD) include infections and cerebrovascular accidents (CVA). Some studies have suggested a possible association between blood stream infection (BSI) and CVA. METHODS AND RESULTS: Medical records of patients who received Heartmate II (HMII) CF-LVADs in 2008-2012 at a single center were reviewed. CVA was categorized as either hemorrhagic (HCVA) or ischemic (ICVA). BSI was divided into persistent (pBSI) and nonpersistent (non-pBSI). pBSI was defined as BSI with the same organism on repeated blood culture >72 hours from initial blood culture despite antibiotics. Univariate and multivariate analyses were performed to determine predictors. A total of 149 patients had HMII implanted; 76% were male, and the overall mean age was 55.4 ± 13 years. There were a total of 19 (13%) patients who had CVA (7 HCVA and 12 ICVA) at a median of 295 days (range 5-1,096 days) after implantation. There were a total of 28 (19%) patients with pBSI and 17 (11%) patients with non-pBSI. Patients with pBSI had a trend toward greater BMI (31 kg/m(2) vs 27 kg/m(2); P = .09), and longer duration of support (1,019 d vs 371 d; P < .001) compared with those with non-pBSI. Persistent BSI was associated with an increased risk of mortality and with all-cause CVA on multivariate analysis (odds ratio [OR] 5.97; P = .003) as well as persistent Pseudomonas aeruginosa infection (OR 4.54; P = .048). CONCLUSIONS: Persistent BSI is not uncommon in patients supported by CF-LVAD and is highly associated with all-cause CVA and increased all-cause mortality.
Assuntos
Bacteriemia/diagnóstico , Contaminação de Equipamentos , Coração Auxiliar/efeitos adversos , Complicações Pós-Operatórias/diagnóstico , Pseudomonas aeruginosa/isolamento & purificação , Acidente Vascular Cerebral/diagnóstico , Adulto , Idoso , Bacteriemia/mortalidade , Feminino , Coração Auxiliar/microbiologia , Humanos , Masculino , Pessoa de Meia-Idade , Mortalidade/tendências , Complicações Pós-Operatórias/microbiologia , Complicações Pós-Operatórias/mortalidade , Estudos Retrospectivos , Fatores de Risco , Acidente Vascular Cerebral/microbiologia , Acidente Vascular Cerebral/mortalidadeRESUMO
BACKGROUND: Acute heart failure (HF) is common in the elderly, but the association of age with clinical outcomes and prognostic factors has not been examined thoroughly. METHODS AND RESULTS: We analyzed the clinical and laboratory characteristics and the outcomes of 1,347 patients with acute HF enrolled in the VERITAS trial. Subjects were subdivided based on their median age of 72 years. Older patients had a higher prevalence of comorbidities and a higher prevalence of hypertension and atrial fibrillation. During a mean follow-up of 149 ± 61 days, 432 patients (32.1%) reached the composite end point of death, in-hospital worsening HF, or HF rehospitalization by 30 days, and 135 patients (10.4%) died by 90 days, with a worse outcome in elderly patients in both cases. At multivariable analysis, different variables were related with each of these outcomes in elderly compared with younger patients. Regarding deaths at 90 days, plasma urea nitrogen and hemoglobin levels were predictive only in the younger patients, whereas respiratory rate and albumin levels were associated with mortality only in the older patients. CONCLUSIONS: Elderly patients with acute HF have different clinical characteristics and poorer outcomes. Prognostic variables differ in elderly compared with younger patients.
Assuntos
Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/mortalidade , Doença Aguda , Idoso , Idoso de 80 Anos ou mais , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/mortalidade , Fibrilação Atrial/terapia , Método Duplo-Cego , Feminino , Insuficiência Cardíaca/terapia , Hospitalização/tendências , Humanos , Hipertensão/diagnóstico , Hipertensão/mortalidade , Hipertensão/terapia , Masculino , Pessoa de Meia-Idade , Mortalidade/tendências , Prognóstico , Resultado do TratamentoRESUMO
RATIONALE: CD34+ transplantation in dilated cardiomyopathy was associated with short-term improvement in left ventricular ejection fraction and exercise tolerance. OBJECTIVE: We investigated long-term effects of intracoronary CD34+ cell transplantation in dilated cardiomyopathy and the relationship between intramyocardial cell homing and clinical response. METHODS AND RESULTS: Of 110 dilated cardiomyopathy patients, 55 were randomized to receive CD34+ stem cell transplantation (SC group) and 55 received no cell therapy (controls). In the SC group, CD34+ cells were mobilized by granulocyte colony-stimulating factor and collected via apheresis. Patients underwent myocardial scintigraphy and cells were injected in the artery supplying segments with the greatest perfusion defect. At baseline, 2 groups did not differ in age, sex, left ventricular ejection fraction, or N-terminal B-type natriuretic peptide levels. At 5 years, stem cell therapy was associated with increased left ventricular ejection fraction (from 24.3 ± 6.5% to 30.0 ± 5.1%; P=0.02), increased 6-minute walk distance (from 344 ± 90 m to 477 ± 130 m; P<0.001), and decreased N-terminal B-type natriuretic peptide (from 2322 ± 1234 pg/mL to 1011 ± 893 pg/mL; P<0.01). Left ventricular ejection fraction improvement was more significant in patients with higher myocardial homing of injected cells. During follow-up, 27 (25%) patients died and 9 (8%) underwent heart transplantation. Of the 27 deaths, 13 were attributed to pump failure and 14 were attributed to sudden cardiac death. Total mortality was lower in the SC group (14%) than in controls (35%; P=0.01). The same was true of pump failure (5% vs. 18%; P=0.03), but not of sudden cardiac death (9% vs. 16%; P=0.39). CONCLUSIONS: Intracoronary stem cell transplantation may be associated with improved ventricular function, exercise tolerance, and long-term survival in patients with dilated cardiomyopathy. Higher intramyocardial homing is associated with better stem cell therapy response.
Assuntos
Antígenos CD34/metabolismo , Cardiomiopatia Dilatada/cirurgia , Miocárdio/patologia , Transplante de Células-Tronco , Células-Tronco/imunologia , Função Ventricular Esquerda , Biomarcadores/metabolismo , California , Cardiomiopatia Dilatada/sangue , Cardiomiopatia Dilatada/diagnóstico , Cardiomiopatia Dilatada/imunologia , Cardiomiopatia Dilatada/mortalidade , Cardiomiopatia Dilatada/patologia , Cardiomiopatia Dilatada/fisiopatologia , Causas de Morte , Movimento Celular , Rastreamento de Células , Distribuição de Qui-Quadrado , Circulação Coronária , Ecocardiografia , Teste de Esforço , Tolerância ao Exercício , Feminino , Seguimentos , Humanos , Injeções Intra-Arteriais , Interleucina-6/sangue , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Imagem de Perfusão do Miocárdio , Miocárdio/imunologia , Peptídeo Natriurético Encefálico/sangue , Fragmentos de Peptídeos/sangue , Modelos de Riscos Proporcionais , Recuperação de Função Fisiológica , Eslovênia , Transplante de Células-Tronco/efeitos adversos , Transplante de Células-Tronco/mortalidade , Volume Sistólico , Texas , Fatores de Tempo , Resultado do Tratamento , Fator de Necrose Tumoral alfa/sangueRESUMO
AIMS: Various reports have raised the possibility of humoral immune responses as contributors for the progression of heart failure. Previous studies, however, have focused on the analysis of serum and documented circulating antibodies against a variety of cardiac proteins. However, there is little evidence on whether anti-cardiac antibodies are deposited in end-stage failing myocardium. Our objective was to determine whether or not there was evidence of deposition of anti-cardiac antibodies and/or activated complement components in end-stage failing human myocardium. METHODS AND RESULTS: Myocardial samples were obtained from 100 end-stage heart failure patients and 40 donor control biopsies. Sections were cut and stained using standard fluorescent immunohistochemistry techniques with anti-human immunoglobulin G (IgG), IgG3, and C3c. Gel electrophoresis and protein identification by mass spectrometry were used to confirm the presence of IgG and its antigen. Immunoglobulin G was localized to the sarcolemma in 71% of patients, 48% of those being positive for the subtype IgG3. The proportion of patients with ischaemic heart disease that was positive for IgG was 65% and among those with non-ischaemic aetiologies was 76%. In a subgroup analysis, the presence of IgG and its subunits were confirmed by mass spectrometry and adenosine triphosphate synthase ß subunit identified as an antigen. Complement was activated in 31% of all patients. The presence of IgG, IgG3, and C3c was directly correlated with the length of disease (r = 0.451, P = 0.006). CONCLUSION: Evidence of anti-cardiac antibodies and complement activation was found in a large number of patients with end-stage cardiomyopathy regardless of the aetiology. Adenosine triphosphate synthase appears to be a new prominent antigenic stimulus; but more interestingly, the simultaneous co-existence of activated complement components suggests that this humoral mechanism may participate in disease progression.
Assuntos
Anticorpos/metabolismo , Insuficiência Cardíaca/imunologia , Miocárdio/imunologia , Adenosina Trifosfatases/imunologia , Antígenos/metabolismo , Estudos de Casos e Controles , Progressão da Doença , Feminino , Humanos , Imunidade Humoral/imunologia , Imunoglobulina G/metabolismo , Masculino , Pessoa de Meia-IdadeRESUMO
In heart failure mitochondrial dysfunction is thought to be responsible for energy depletion and contractile dysfunction. The difficulties in procuring fresh left ventricular (LV) myocardium from humans for assessment of mitochondrial function have resulted in the reliance on surrogate markers of mitochondrial function and limited our understanding of cardiac energetics. We isolated mitochondria from fresh LV wall tissue of patients with heart failure and reduced systolic function undergoing heart transplant or left ventricular assist device placement, and compared their function to mitochondria isolated from the non-failing LV (NFLV) wall tissue with normal systolic function from patients with pulmonary hypertension undergoing heart-lung transplant. We performed detailed mitochondrial functional analyses using 4 substrates: glutamate-malate (GM), pyruvate-malate (PM) palmitoyl carnitine-malate (PC) and succinate. NFLV mitochondria showed preserved respiratory control ratios and electron chain integrity with only few differences for the 4 substrates. In contrast, HF mitochondria had greater respiration with GM, PM and PC substrates and higher electron chain capacity for PM than for PC. Surprisingly, HF mitochondria had greater respiratory control ratios and lower ADP-independent state 4 rates than NFLV mitochondria for GM, PM and PC substrates demonstrating that HF mitochondria are capable of coupled respiration ex vivo. Gene expression studies revealed decreased expression of key genes in pathways for oxidation of both fatty acids and glucose. Our results suggest that mitochondria from the failing LV myocardium are capable of tightly coupled respiration when isolated and supplied with ample substrates. Thus energy starvation in the failing heart may be the result of dysregulation of metabolic pathways, impaired substrate supply or reduced mitochondrial number but not the result of reduced mitochondrial electron transport capacity.
Assuntos
Insuficiência Cardíaca/metabolismo , Mitocôndrias Cardíacas/metabolismo , Adulto , Antígenos CD36/genética , Antígenos CD36/metabolismo , Estudos de Casos e Controles , Respiração Celular , Complexo I de Transporte de Elétrons/metabolismo , Complexo II de Transporte de Elétrons/metabolismo , Feminino , Insuficiência Cardíaca/patologia , Ventrículos do Coração/metabolismo , Ventrículos do Coração/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Oxirredução , Oxigênio/metabolismo , Transcriptoma , Adulto JovemRESUMO
BACKGROUND: In an open-label blinded study, we compared intracoronary and transendocardial CD34(+) cell transplantation in patients with nonischemic dilated cardiomyopathy. METHODS AND RESULTS: Of the 40 patients with dilated cardiomyopathy, 20 were randomized to receive intracoronary injection and 20 received transendocardial CD34(+) cell delivery. In both groups, CD34(+) cells were mobilized by filgrastim, collected via apheresis, and labeled with technetium-99m radioisotope for single-photon emission computed tomographic imaging. In the intracoronary group, cells were injected intracoronarily in the artery supplying segments of greater perfusion defect on myocardial perfusion scintigraphy. In the transendocardial group, electroanatomic mapping was used to identify viable but dysfunctional myocardium, and transendocardial cell injections were performed. Nuclear single-photon emission computed tomographic imaging for quantification of myocardial retention was performed 18 hours thereafter. At baseline, groups did not differ in age, sex, left ventricular ejection fraction, or N-terminal pro-brain natriuretic peptide levels. The number of CD34(+) cells was also comparable (105 ± 31 × 10(6) in the transendocardial group versus 103 ± 27 × 10(6) in the intracoronary group, P=0.62). At 18 hours after procedure, myocardial retention was higher in the transendocardial group (19.2 ± 4.8%) than in the intracoronary group (4.4 ± 1.2%, P<0.01). At 6 months, left ventricular ejection fraction improved more in the transendocardial group (+8.1 ± 4.3%) than in the intracoronary group (+4.2 ± 2.3%, P=0.03). The same pattern was observed for the 6-minute walk test distance (+125 ± 33 m in the transendocardial group versus +86 ± 13 m in the intracoronary group, P=0.03) and N-terminal pro-brain natriuretic peptide (-628 ± 211 versus -315 ± 133 pg/mL, P=0.04). CONCLUSIONS: In patients with dilated cardiomyopathy, transendocardial CD34(+) cell transplantation is associated with higher myocardial retention rates and greater improvement in ventricular function, N-terminal pro-brain natriuretic peptide, and exercise capacity compared with intracoronary route. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01350310.