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2.
Mayo Clin Proc ; 94(7): 1199-1209, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31272568

RESUMO

OBJECTIVE: To characterize the obese heart failure with preserved ejection fraction (HFpEF) phenotype in a multicenter cohort. PATIENTS AND METHODS: This was a secondary analysis of the randomized clinical trial RELAX (Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Heart Failure with Preserved Ejection Fraction) performed between October 1, 2008, and February 1, 2012. Patients with HFpEF were classified by body mass index (BMI) as obese (BMI≥35 kg/m2) and nonobese (BMI<30 kg/m2) for comparison. RESULTS: Obese patients with HFpEF (n=81) were younger (median age, 64 [interquartile range (IQR), 67-79] years vs 73 [IQR, 56-70] years; P<.001) but had greater peripheral edema (31% [25] vs 9% [6]; P<.001), more orthopnea (76% [56] vs 53% [35]; P=.005), worse New York Heart Association class (P=.006), and more impaired quality of life (P<.001) as compared with nonobese patients with HFpEF (n=70). Despite more severe signs and symptoms, obese patients with HFpEF had lower N-terminal pro B-type natriuretic peptide level (median, 481 [IQR, 176-1183] pg/mL vs 825 [IQR, 380-1679] pg/mL [to convert to pmol/L, multiply by 0.118]; P=.007) and lower left atrial volume index (median, 38 [IQR, 31-47] mL/m2 vs 54 [IQR, 41-63] mL/m2; P<.001). Serum C-reactive protein (median, 5.0 [IQR, 2.4-9.9] mg/dL vs 2.7 [IQR, 1.6-5.4] mg/dL [to convert to mg/L, multiply by 10-3]; P<.001) and uric acid (median, 7.8 [IQR, 6.1-8.7] mg/dL vs 6.8 [IQR, 5.5-8.3] mg/dL; P=.03) levels were higher in obese HFpEF, indicating greater systemic inflammation, than in nonobese HFpEF. Peak oxygen consumption was impaired in obese HFpEF (median, 11.1 [IQR, 9.6-14.4] mL/kg per minute vs 13.1 [IQR, 11.3-14.7] mL/kg per minute; P=.008), as was submaximal exercise capacity (6-minute walk distance, 272 [IQR, 200-332] m vs 355 [IQR, 290-415] m; P<.0001). CONCLUSION: Obese HFpEF is associated with decreased quality of life, worse symptoms of heart failure, greater systemic inflammation, worse exercise capacity, and higher metabolic cost of exertion as compared with nonobese HFpEF. Further study is required to understand the pathophysiology and potential distinct treatments for patients with the obese phenotype of HFpEF. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00763867.

3.
JCI Insight ; 52019 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-31162139

RESUMO

Whereas prior studies have demonstrated an important immunomodulatory role for the neuronal cholinergic system in the heart, the role of the non-neuronal cholinergic system is not well understood. To address the immunomodulatory role of the non-neuronal cholinergic system in the heart we used a previously validated diphtheria toxin (DT)-induced cardiomyocyte ablation model (Rosa26-DTMlc2v-Cre mice). DT-injected Rosa26-DTMlc2v-Cre mice were treated with diluent or Pyridostigmine Bromide (PYR), a reversible cholinesterase inhibitor. PYR treatment resulted in increased survival and decreased numbers of MHC-IIlowCCR2+ macrophages in DT-injected Rosa26-DTMlc2v-Cre mice compared to diluent treated Rosa26-DTMlc2v-Cre mice. Importantly, the expression of CCL2/7 mRNA and protein was reduced in the hearts of PYR-treated mice. Backcrossing Rosa26-DTMlc2v-Cre mice with a transgenic mouse line (Chat-ChR2) that constitutively overexpresses the vesicular acetylcholine transporter (VAChT) resulted in decreased expression of Ccl2/7 mRNA and decreased numbers of CD68+ cells in DT-injured Rosa26-DTMlc2v-Cre/Chat-ChR2 mouse hearts, consistent with the pharmacologic studies with PYR. In vitro studies with cultures of LPS-stimulated peritoneal macrophages revealed a concentration-dependent reduction in CCL2 secretion following stimulation with ACh, nicotine and muscarine. Viewed together, these findings reveal a previously unappreciated immunomodulatory role for the non-neuronal cholinergic system in regulating homeostatic responses in the heart following tissue injury.

4.
JACC Heart Fail ; 7(7): 602-611, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31078480

RESUMO

OBJECTIVES: This study sought to explore clinical characteristics and outcomes in women and men with ambulatory advanced heart failure (HF). BACKGROUND: Women have been underrepresented in studies of advanced HF and have an increased mortality on the transplant waiting list and early after mechanical circulatory support (MCS). An increased understanding of the differential burden of HF between women and men is required to inform the use of mechanical circulatory support in ambulatory advanced HF patients. METHODS: REVIVAL (Registry Evaluation for Vital Information on Ventricular Assist Devices in Ambulatory Life) is a prospective, observational study of 400 outpatients with chronic systolic HF, New York Heart Association functional class II to IV, and 1 additional high-risk feature. Clinical characteristics, quality of life, and functional capacity were compared between women and men, as was a primary composite endpoint of death, durable MCS, or urgent heart transplantation at 1 year. RESULTS: REVIVAL enrolled 99 women (25% of the cohort) who had similar age, ejection fraction, INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support) profiles, medication use, and willingness to consider MCS as the men enrolled; however, women reported significantly greater limitations in quality of life with respect to physical limitation, reduced 6-min walk distance, and more frequent symptoms of depression. Nevertheless, 1-year combined risk of death, durable MCS, or urgent transplantation did not differ between women and men (24% vs. 22%; p = 0.94). CONCLUSIONS: This study represents the largest report to date of women with ambulatory advanced HF receiving contemporary therapies. Systematic elicitation of patient-reported outcome measures uncovered an added burden of HF in women and may be an appropriate target of augmented support and intervention.

5.
Eur Heart J ; 40(26): 2155-2163, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-30957868

RESUMO

Randomized clinical trials initially used heart failure (HF) patients with low left ventricular ejection fraction (LVEF) to select study populations with high risk to enhance statistical power. However, this use of LVEF in clinical trials has led to oversimplification of the scientific view of a complex syndrome. Descriptive terms such as 'HFrEF' (HF with reduced LVEF), 'HFpEF' (HF with preserved LVEF), and more recently 'HFmrEF' (HF with mid-range LVEF), assigned on arbitrary LVEF cut-off points, have gradually arisen as separate diseases, implying distinct pathophysiologies. In this article, based on pathophysiological reasoning, we challenge the paradigm of classifying HF according to LVEF. Instead, we propose that HF is a heterogeneous syndrome in which disease progression is associated with a dynamic evolution of functional and structural changes leading to unique disease trajectories creating a spectrum of phenotypes with overlapping and distinct characteristics. Moreover, we argue that by recognizing the spectral nature of the disease a novel stratification will arise from new technologies and scientific insights that will shape the design of future trials based on deeper understanding beyond the LVEF construct alone.

6.
J Clin Invest ; 129(6): 2293-2304, 2019 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-30830879

RESUMO

Non-apoptotic forms of cell death can trigger sterile inflammation through the release of danger-associated molecular patterns, which are recognized by innate immune receptors. However, despite years of investigation the mechanisms which initiate inflammatory responses after heart transplantation remain elusive. Here, we demonstrate that ferrostatin-1 (Fer-1), a specific inhibitor of ferroptosis, decreases the level of pro-ferroptotic hydroperoxy-arachidonoyl-phosphatidylethanolamine, reduces cardiomyocyte cell death and blocks neutrophil recruitment following heart transplantation. Inhibition of necroptosis had no effect on neutrophil trafficking in cardiac grafts. We extend these observations to a model of coronary artery ligation-induced myocardial ischemia reperfusion injury where inhibition of ferroptosis resulted in reduced infarct size, improved left ventricular systolic function, and reduced left ventricular remodeling. Using intravital imaging of cardiac transplants, we uncover that ferroptosis orchestrates neutrophil recruitment to injured myocardium by promoting adhesion of neutrophils to coronary vascular endothelial cells through a TLR4/TRIF/type I IFN signaling pathway. Thus, we have discovered that inflammatory responses after cardiac transplantation are initiated through ferroptotic cell death and TLR4/Trif-dependent signaling in graft endothelial cells. These findings provide a platform for the development of therapeutic strategies for heart transplant recipients and patients, who are vulnerable to ischemia reperfusion injury following restoration of coronary blood flow.

7.
ESC Heart Fail ; 6(2): 297-307, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30816013

RESUMO

AIMS: There is debate on whether the beneficial effect of implantable cardioverter-defibrillators (ICDs) is attenuated in patients with non-ischaemic cardiomyopathy (NICM). We assess whether any ICD benefit differs between patients with NICM and those with ischaemic cardiomyopathy (ICM), using data from the Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction (WARCEF) trial. METHODS AND RESULTS: We performed a post hoc analysis using WARCEF (N = 2293; ICM, n = 991 vs. NICM, n = 1302), where participants received optimal medical treatment. We developed stratified propensity scores for having an ICD at baseline using 41 demographic and clinical variables and created 1:2 propensity-matched cohorts separately for ICM patients with ICD (N = 223 with ICD; N = 446 matched) and NICM patients (N = 195 with ICD; N = 390 matched). We constructed a Cox proportional hazards model to assess the effect of ICD status on mortality for patients with ICM and those with NICM and tested the interaction between ICD status and aetiology of heart failure. During mean follow-up of 3.5 ± 1.8 years, 527 patients died. The presence of ICD was associated with a lower risk of all-cause death among those with ICM (hazard ratio: 0.640; 95% confidence interval: 0.448 to 0.915; P = 0.015) but not among those with NICM (hazard ratio: 0.984; 95% confidence interval: 0.641 to 1.509; P = 0.941). There was weak evidence of interaction between ICD status and the aetiology of heart failure (P = 0.131). CONCLUSIONS: The presence of ICD is associated with a survival benefit in patients with ICM but not in those with NICM.


Assuntos
Aspirina/uso terapêutico , Cardiomiopatias/terapia , Desfibriladores Implantáveis , Insuficiência Cardíaca/mortalidade , Pontuação de Propensão , Função Ventricular Esquerda/fisiologia , Varfarina/uso terapêutico , Idoso , Anticoagulantes/uso terapêutico , Cardiomiopatias/complicações , Cardiomiopatias/diagnóstico , Causas de Morte/tendências , Ecocardiografia , Feminino , Seguimentos , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/terapia , Ventrículos do Coração/diagnóstico por imagem , Ventrículos do Coração/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Inibidores da Agregação de Plaquetas/uso terapêutico , Ventriculografia com Radionuclídeos , Estudos Retrospectivos , Fatores de Risco , Volume Sistólico , Taxa de Sobrevida/tendências , Estados Unidos/epidemiologia
8.
Eur J Clin Invest ; : e13092, 2019 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-30801690

RESUMO

BACKGROUND: A high pulse pressure (PP) is associated with adverse cardiovascular (CV) outcomes; however, this relationship may be reversed in patients with heart failure with reduced ejection fraction (HFREF). METHODS: Patients from the WARCEF trial with left ventricular ejection fraction ≤35% were included. PP was divided into tertiles: ≤42, 42-54 and >54 mm Hg. Age and ejection fraction adjusted Kaplan-Meier curves were generated to evaluate the relationship between PP and outcomes [mortality, CV mortality, stroke and HF hospitalizations (HFH)]. Cox proportional hazards models were created incorporating PP as a continuous variable. The interaction of PP with New York Heart Association (NYHA) functional class was examined. Linear and restricted cubic splines were used to study nonlinear association between PP and outcomes. RESULTS: We included 2,299 patients with a mean(±SD) follow-up of 3.5 ± 1.8 years. The lowest tertile of PP (≤42 mm Hg) was associated with significantly higher CV mortality and HFH. Cox proportional hazards models showed a reduction in CV death and HFH with higher PP, with adjusted hazard ratios (HR) of 0.91 (P = 0.02) and 0.93 (P = 0.04) per 10 mm Hg increase in PP. This relationship was more pronounced in subjects with NYHA functional class III-IV. Spline analysis showed that the association between PP and CV mortality and HFH was only seen at PP values lower than 40 mm Hg. CONCLUSIONS: In patients with advanced HFREF, a low PP (<40 mm Hg) portends a worse prognosis, whereas a high PP (>50 mm Hg) predicts a relatively favourable prognosis.

11.
JAMA ; 320(17): 1764-1773, 2018 11 06.
Artigo em Inglês | MEDLINE | ID: mdl-30398602

RESUMO

Importance: There are few effective treatments for heart failure with preserved ejection fraction (HFpEF). Short-term administration of inorganic nitrite or nitrate preparations has been shown to enhance nitric oxide signaling, which may improve aerobic capacity in HFpEF. Objective: To determine the effect of 4 weeks' administration of inhaled, nebulized inorganic nitrite on exercise capacity in HFpEF. Design, Setting, and Participants: Multicenter, double-blind, placebo-controlled, 2-treatment, crossover trial of 105 patients with HFpEF. Participants were enrolled from July 22, 2016, to September 12, 2017, at 17 US sites, with final date of follow-up of January 2, 2018. Interventions: Inorganic nitrite or placebo administered via micronebulizer device. During each 6-week phase of the crossover study, participants received no study drug for 2 weeks (baseline/washout) followed by study drug (nitrite or placebo) at 46 mg 3 times a day for 1 week followed by 80 mg 3 times a day for 3 weeks. Main Outcomes and Measures: The primary end point was peak oxygen consumption (mL/kg/min). Secondary end points included daily activity levels assessed by accelerometry, health status as assessed by the Kansas City Cardiomyopathy Questionnaire (score range, 0-100, with higher scores reflecting better quality of life), functional class, cardiac filling pressures assessed by echocardiography, N-terminal fragment of the prohormone brain natriuretic peptide levels, other exercise indices, adverse events, and tolerability. Outcomes were assessed after treatment for 4 weeks. Results: Among 105 patients who were randomized (median age, 68 years; 56% women), 98 (93%) completed the trial. During the nitrite phase, there was no significant difference in mean peak oxygen consumption as compared with the placebo phase (13.5 vs 13.7 mL/kg/min; difference, -0.20 [95% CI, -0.56 to 0.16]; P = .27). There were no significant between-treatment phase differences in daily activity levels (5497 vs 5503 accelerometry units; difference, -15 [95% CI, -264 to 234]; P = .91), Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (62.6 vs 61.9; difference, 1.1 [95% CI, -1.4 to 3.5]; P = .39), functional class (2.5 vs 2.5; difference, 0.1 [95% CI, -0.1 to 0.2]; P = .43), echocardiographic E/e' ratio (16.4 vs 16.6; difference, 0.1 [95% CI, -1.2 to 1.3]; P = .93), or N-terminal fragment of the prohormone brain natriuretic peptide levels (520 vs 533 pg/mL; difference, 11 [95% CI, -53 to 75]; P = .74). Worsening heart failure occurred in 3 participants (2.9%) during the nitrite phase and 8 (7.6%) during the placebo phase. Conclusions and Relevance: Among patients with HFpEF, administration of inhaled inorganic nitrite for 4 weeks, compared with placebo, did not result in significant improvement in exercise capacity. Trial Registration: ClinicalTrials.gov Identifier: NCT02742129.


Assuntos
Tolerância ao Exercício/efeitos dos fármacos , Insuficiência Cardíaca/tratamento farmacológico , Nitritos/uso terapêutico , Administração por Inalação , Idoso , Estudos Cross-Over , Método Duplo-Cego , Teste de Esforço , Tolerância ao Exercício/fisiologia , Feminino , Insuficiência Cardíaca/fisiopatologia , Humanos , Compostos Inorgânicos/farmacologia , Compostos Inorgânicos/uso terapêutico , Masculino , Pessoa de Meia-Idade , Nitritos/efeitos adversos , Nitritos/farmacologia , Consumo de Oxigênio , Volume Sistólico , Falha de Tratamento
14.
JACC Basic Transl Sci ; 3(2): 330-331, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30062218
16.
Am J Cardiol ; 122(5): 821-827, 2018 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-30037426

RESUMO

Previous studies in patients with atrial fibrillation showed that a history of heart failure (HF) could negatively impact anticoagulation quality, as measured by the average time in therapeutic range (TTR). Whether additional markers of HF severity are associated with TTR has not been investigated thoroughly. We aimed to examine the potential role of HF severity in the quality of warfarin control in patients with HF with reduced ejection fraction. Data from the Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction Trial were used to investigate the association between TTR and HF severity. Multivariable logistic regression models were used to examine the association of markers of HF severity, including New York Heart Association (NYHA) class, Minnesota Living with HF (MLWHF) score, and frequency of HF hospitalization, with TTR ≥70% (high TTR). We included 1,067 participants (high TTR, N = 413; low TTR, N = 654) in the analysis. In unadjusted analysis, patients with a high TTR were older and less likely to have had strokes or receive other antiplatelet agents. Those patients also had lower NYHA class, better MLWHF scores, greater 6-minute walk distance, and lower frequency of HF hospitalizations. Multivariable analysis showed that NYHA class III and/or IV (Odds ratio [OR] 0.68 [95% confidence intervals [CIs] 0.49 to 0.94]), each 10-point increase in MLWHF score (i.e., worse health-related quality of life) (OR 0.92 [0.86 to 0.99]), and higher number of HF hospitalization per year (OR0.45 [0.30 to 0.67]) were associated with decreased likelihood of having high TTR. In HF patients with systolic dysfunction, NYHA class III and/or IV, poor health-related quality of life, and a higher rate of HF hospitalization were independently associated with suboptimal quality of warfarin anticoagulation control. These results affirm the need to assess the new approaches, such as direct oral anticoagulants, to prevent thromboembolism in this patient population.

17.
ESC Heart Fail ; 5(5): 800-808, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30015405

RESUMO

AIMS: Left atrium (LA) dilation is associated with adverse cardiovascular (CV) outcomes. Blood stasis, thrombus formation and atrial fibrillation may occur, especially in heart failure (HF) patients. It is not known whether preventive antithrombotic treatment may decrease the incidence of CV events in HF patients with LA enlargement. We investigated the relationship between LA enlargement and CV outcomes in HF patients and the effect of different antithrombotic treatments. METHODS AND RESULTS: Two-dimensional echocardiography with LA volume index (LAVi) measurement was performed in 1148 patients with systolic HF from the Warfarin versus Aspirin in Reduced Ejection Fraction (WARCEF) trial. Patients were randomized to warfarin or aspirin and followed for 3.4 ± 1.7 years. While the primary aim of the trial was a composite of ischaemic stroke, death, and intracerebral haemorrhage, the present report focuses on the individual CV events, whose incidence was compared across different LAVi and treatment subgroups. After adjustment for demographics and clinical covariates, moderate or severe LA enlargement was significantly associated with total death (hazard ratio 1.6 and 2.7, respectively), CV death (HR 1.7 and 3.3), and HF hospitalization (HR 2.3 and 2.6) but not myocardial infarction (HR 1.0 and 1.4) or ischaemic stroke (1.1 and 1.5). The increased risk was observed in both patients treated with warfarin or aspirin. In warfarin-treated patients, a time in therapeutic range >60% was associated with lower event rates, and an interaction between LAVi and time in therapeutic range was observed for death (P = 0.034). CONCLUSIONS: In patients with systolic HF, moderate or severe LA enlargement is associated with death and HF hospitalization despite treatment with antithrombotic medications. The possibility that achieving a more consistent therapeutic level of anticoagulation may decrease the risk of death requires further investigation.

18.
JCI Insight ; 3(11)2018 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-29875326

RESUMO

Despite the long-standing recognition that the immune response to acute myocardial injury contributes to adverse left ventricular (LV) remodeling, it has not been possible to effectively target this clinically. Using 2 different in vivo models of acute myocardial injury, we show that pirfenidone confers beneficial effects in the murine heart through an unexpected mechanism that depends on cardiac B lymphocytes. Naive hearts contained a large population of CD19+CD11b-CD23-CD21-IgD+IgMlo lymphocytes, and 2 smaller populations of CD19+CD11b+ B1a and B1b cells. In response to tissue injury, there was an increase in neutrophils, monocytes, macrophages, as well as an increase in CD19+ CD11b- B lymphocytes. Treatment with pirfenidone had no effect on the number of neutrophils, monocytes, or macrophages, but decreased CD19+CD11b- lymphocytes. B cell depletion abrogated the beneficial effects of pirfenidone. In vitro studies demonstrated that stimulation with lipopolysaccharide and extracts from necrotic cells activated CD19+ lymphocytes through a TIRAP-dependent pathway. Treatment with pirfenidone attenuated this activation of B cells. These findings reveal a previously unappreciated complexity of myocardial B lymphocytes within the inflammatory infiltrate triggered by cardiac injury and suggest that pirfenidone exerts beneficial effects in the heart through a unique mechanism that involves modulation of cardiac B lymphocytes.

19.
JACC Heart Fail ; 6(10): 874-883, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29754812

RESUMO

OBJECTIVES: This study sought to confirm a subgroup analysis of the prior FIX-HF-5 (Evaluate Safety and Efficacy of the OPTIMIZER System in Subjects With Moderate-to-Severe Heart Failure) study showing that cardiac contractility modulation (CCM) improved exercise tolerance (ET) and quality of life in patients with ejection fractions between 25% and 45%. BACKGROUND: CCM therapy for New York Heart Association (NYHA) functional class III and IV heart failure (HF) patients consists of nonexcitatory electrical signals delivered to the heart during the absolute refractory period. METHODS: A total of 160 patients with NYHA functional class III or IV symptoms, QRS duration <130 ms, and ejection fraction ≥25% and ≤45% were randomized to continued medical therapy (control, n = 86) or CCM (treatment, n = 74, unblinded) for 24 weeks. Peak Vo2 (primary endpoint), Minnesota Living With Heart Failure questionnaire, NYHA functional class, and 6-min hall walk were measured at baseline and at 12 and 24 weeks. Bayesian repeated measures linear modeling was used for the primary endpoint analysis with 30% borrowing from the FIX-HF-5 subgroup. Safety was assessed by the percentage of patients free of device-related adverse events with a pre-specified lower bound of 70%. RESULTS: The difference in peak Vo2 between groups was 0.84 (95% Bayesian credible interval: 0.123 to 1.552) ml O2/kg/min, satisfying the primary endpoint. Minnesota Living With Heart Failure questionnaire (p < 0.001), NYHA functional class (p < 0.001), and 6-min hall walk (p = 0.02) were all better in the treatment versus control group. There were 7 device-related events, yielding a lower bound of 80% of patients free of events, satisfying the primary safety endpoint. The composite of cardiovascular death and HF hospitalizations was reduced from 10.8% to 2.9% (p = 0.048). CONCLUSIONS: CCM is safe, improves exercise tolerance and quality of life in the specified group of HF patients, and leads to fewer HF hospitalizations. (Evaluate Safety and Efficacy of the OPTIMIZER System in Subjects With Moderate-to-Severe Heart Failure; NCT01381172).

20.
Circ Heart Fail ; 11(5): e004351, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29716898

RESUMO

BACKGROUND: To better understand reverse left ventricular (LV) remodeling, we developed a murine model wherein mice develop LV remodeling after transverse aortic constriction (TAC) and a small apical myocardial infarct (MI) and undergo reverse LV remodeling after removal of the aortic band. METHODS AND RESULTS: Mice studied were subjected to sham (n=6) surgery or TAC+MI (n=12). Two weeks post-TAC+MI, 1 group underwent debanding (referred to as heart failure debanding [HF-DB] mice; n=6), whereas the aortic band remained in a second group (heart failure [HF] group; n=6). LV remodeling was evaluated by 2D echocardiography at 1 day, 2 weeks and 6 weeks post-TAC+MI. The hearts were analyzed by transcriptional profiling at 4 and 6 weeks and histologically at 6 weeks. Debanding normalized LV volumes, LV mass, and cardiac myocyte hypertrophy at 6 weeks in HF-DB mice, with no difference in myofibrillar collagen in the HF and HF-DB mice. LV ejection fraction and radial strain improved after debanding; however, both remained decreased in the HF-DB mice relative to sham and were not different from HF mice at 6 weeks. Hemodynamic unloading in the HF-DB mice was accompanied by a 35% normalization of the HF genes at 2 weeks and 80% of the HF genes at 4 weeks. CONCLUSIONS: Hemodynamic unloading of a pathophysiologically relevant mouse model of HF results in normalization of LV structure, incomplete recovery of LV function, and incomplete reversal of the HF transcriptional program. The HF-DB mouse model may provide novel insights into mechanisms of reverse LV remodeling.

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