Pablo Maria Alberto Pomerantzeff

Transfusion requirements after cardiac surgery: the TRACS randomized controlled trial.

CONTEXT Perioperative red blood cell transfusion is commonly used to address anemia, an independent risk factor for morbidity and mortality after cardiac operations; however, evidence regarding optimal blood transfusion practice in patients undergoing cardiac surgery is lacking. OBJECTIVE To define whether a restrictive perioperative red blood cell transfusion strategy is as safe as a liberal strategy in patients undergoing elective cardiac surgery. DESIGN, SETTING, AND PATIENTS The Transfusion Requirements After Cardiac Surgery (TRACS) study, a prospective, randomized, controlled clinical noninferiority trial conducted between February 2009 and February 2010 in an intensive care unit at a university hospital cardiac surgery referral center in Brazil. Consecutive adult patients (n = 502) who underwent cardiac surgery with cardiopulmonary bypass were eligible; analysis was by intention-to-treat. INTERVENTION Patients were randomly assigned to a liberal strategy of blood transfusion (to maintain a hematocrit ≥30%) or to a restrictive strategy (hematocrit ≥24%). MAIN OUTCOME MEASURE Composite end point of 30-day all-cause mortality and severe morbidity (cardiogenic shock, acute respiratory distress syndrome, or acute renal injury requiring dialysis or hemofiltration) occurring during the hospital stay. The noninferiority margin was predefined at -8% (ie, 8% minimal clinically important increase in occurrence of the composite end point). RESULTS Hemoglobin concentrations were maintained at a mean of 10.5 g/dL (95% confidence interval [CI], 10.4-10.6) in the liberal-strategy group and 9.1 g/dL (95% CI, 9.0-9.2) in the restrictive-strategy group (P < .001). A total of 198 of 253 patients (78%) in the liberal-strategy group and 118 of 249 (47%) in the restrictive-strategy group received a blood transfusion (P < .001). Occurrence of the primary end point was similar between groups (10% liberal vs 11% restrictive; between-group difference, 1% [95% CI, -6% to 4%]; P = .85). Independent of transfusion strategy, the number of transfused red blood cell units was an independent risk factor for clinical complications or death at 30 days (hazard ratio for each additional unit transfused, 1.2 [95% CI, 1.1-1.4]; P = .002). CONCLUSION Among patients undergoing cardiac surgery, the use of a restrictive perioperative transfusion strategy compared with a more liberal strategy resulted in noninferior rates of the combined outcome of 30-day all-cause mortality and severe morbidity. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01021631.

Prognostic Significance of Myocardial Fibrosis Quantification by Histopathology and Magnetic Resonance Imaging in Patients With Severe Aortic Valve Disease

OBJECTIVES We sought to determine whether the quantitative assessment of myocardial fibrosis (MF), either by histopathology or by contrast-enhanced magnetic resonance imaging (ce-MRI), could help predict long-term survival after aortic valve replacement. BACKGROUND Severe aortic valve disease is characterized by progressive accumulation of interstitial MF. METHODS Fifty-four patients scheduled to undergo aortic valve replacement were examined by ce-MRI. Delayed-enhanced images were used for the quantitative assessment of MF. In addition, interstitial MF was quantified by histological analysis of myocardial samples obtained during open-heart surgery and stained with picrosirius red. The ce-MRI study was repeated 27+/-22 months after surgery to assess left ventricular functional improvement, and all patients were followed for 52+/-17 months to evaluate long-term survival. RESULTS There was a good correlation between the amount of MF measured by histopathology and by ce-MRI (r=0.69, p<0.001). In addition, the amount of MF demonstrated a significant inverse correlation with the degree of left ventricular functional improvement after surgery (r=-0.42, p=0.04 for histopathology; r=-0.47, p=0.02 for ce-MRI). Kaplan-Meier analyses revealed that higher degrees of MF accumulation were associated with worse long-term survival (chi-square=6.32, p=0.01 for histopathology; chi-square=5.85, p=0.02 for ce-MRI). On multivariate Cox regression analyses, patient age and the amount of MF were found to be independent predictors of all-cause mortality. CONCLUSIONS The amount of MF, either by histopathology or by ce-MRI, is associated with the degree of left ventricular functional improvement and all-cause mortality late after aortic valve replacement in patients with severe aortic valve disease.

Rheumatic Heart Disease: Proinflammatory Cytokines Play a Role in the Progression and Maintenance of Valvular Lesions

Heart lesions of rheumatic heart disease (RHD) patients contain T-cell clones that recognize heart proteins and streptococcal M peptides. To functionally characterize heart-infiltrating T lymphocytes, we evaluated their cytokine profile, both directly in situ and in T-cell lines derived from the heart (HIL). Interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha, interleukin (IL)-4, and IL-10 expressions were characterized in 20 heart tissue infiltrates from 14 RHD patients by immunohistochemistry. IFN-gamma-, TNF-alpha-, and IL-10-positive cells were consistently predominant, whereas IL-4 was scarce in the valves. In agreement with these data, the in vitro experiments, in which 13 HILs derived from heart samples of eight patients were stimulated with M5 protein and the immunodominant M5 (81-96) peptide, IL-4 was detected in HIL derived from the atrium (three of six) but not from the valve (zero of seven). IFN-gamma and IL-10 production were detected in culture supernatants in 11 of 13 and 6 of 12 HILs, respectively. The predominant IFN-gamma and TNF-alpha expression in the heart suggests that Th1-type cytokines could mediate RHD. Unlike in reversible myocardium inflammation, the significantly lower IL-4 expression in the valvular tissue (P = 0.02) may contribute to the progression of the RHD leading to permanent valvular damage (relative risk, 4.3; odds ratio, 15.8). The lack of IL-4 in vitro production by valve-derived HIL also emphasizes the more severe tissue destruction in valves observed in RHD.

Oxidant Generation Predominates Around Calcifying Foci and Enhances Progression of Aortic Valve Calcification

Objective—We hypothesized that reactive oxygen species (ROS) contribute to progression of aortic valve (AV) calcification/stenosis. Methods and Results—We investigated ROS production and effects of antioxidants tempol and lipoic acid (LA) in calcification progression in rabbits given 0.5% cholesterol diet +104 IU/d Vit.D2 for 12 weeks. Superoxide and H2O2 microfluorotopography and 3-nitrotyrosine immunoreactivity showed increased signals not only in macrophages but preferentially around calcifying foci, in cells expressing osteoblast/osteoclast, but not macrophage markers. Such cells also showed increased expression of NAD(P)H oxidase subunits Nox2, p22phox, and protein disulfide isomerase. Nox4, but not Nox1 mRNA, was increased. Tempol augmented whereas LA decreased H2O2 signals. Importantly, AV calcification, assessed by echocardiography and histomorphometry, decreased 43% to 70% with LA, but increased with tempol (P≤0.05). Tempol further enhanced apoptosis and Nox4 expression. In human sclerotic or stenotic AV, we found analogous increases in ROS production and NAD(P)H oxidase expression around calcifying foci. An in vitro vascular smooth muscle cell (VSMC) calcification model also exhibited increased, catalase-inhibitable, calcium deposit with tempol, but not with LA. Conclusions—Our data provide evidence that ROS, particularly hydrogen peroxide, potentiate AV calcification progression. However, tempol exhibited a paradoxical effect, exacerbating AV/vascular calcification, likely because of its induced increase in peroxide generation.

Mimicry in Recognition of Cardiac Myosin Peptides by Heart-Intralesional T Cell Clones from Rheumatic Heart Disease

Molecular mimicry between Streptococcus pyogenes Ags and human proteins has been considered as a mechanism leading to autoimmune reactions in rheumatic fever and rheumatic heart disease (RHD). Cardiac myosin has been shown as a putative autoantigen recognized by autoantibodies of rheumatic fever patients. We assessed the human heart-intralesional T cell response against human light meromyosin (LMM) and streptococcal M5 peptides and mitral-valve-derived proteins by proliferation assay. Cytokines induced by LMM peptides were also evaluated. The frequency of intralesional T cell clones that recognized LMM peptides was 63.2%. Thirty-four percent of T cell clones presented cross-reactivity with different patterns: 1) myosin and valve-derived proteins; 2) myosin and streptococcal M5 peptides; and 3) myosin, valve-derived proteins and M5 peptides. In addition, several LMM peptides were recognized simultaneously showing a multiple reactivity pattern of heart-infiltrating T cells. Inflammatory cytokines (IFN-γ and TNF-α) were predominantly produced by heart-infiltrating T cells upon stimulation with LMM peptides. The alignment of LMM and streptococcal M5 peptides showed frequent homology among conserved amino acid substitutions. This is the first study showing the cellular response by human heart-infiltrating T cells against cardiac myosin epitopes in RHD patients. The high percentage of reactivity against cardiac myosin strengthens its role as one of the major autoantigens involved in rheumatic heart lesions. T cell reactivity toward myosin epitopes in RHD patients may also trigger the broad recognition of valvular proteins with structural or functional similarities.

T-Cell Reactivity against Streptococcal Antigens in the Periphery Mirrors Reactivity of Heart-Infiltrating T Lymphocytes in Rheumatic Heart Disease Patients

ABSTRACT T-cell molecular mimicry between streptococcal and heart proteins has been proposed as the triggering factor leading to autoimmunity in rheumatic heart disease (RHD). We searched for immunodominant T-cell M5 epitopes among RHD patients with defined clinical outcomes and compared the T-cell reactivities of peripheral blood and intralesional T cells from patients with severe RHD. The role of HLA class II molecules in the presentation of M5 peptides was also evaluated. We studied the T-cell reactivity against M5 peptides and heart proteins on peripheral blood mononuclear cells (PBMC) from 74 RHD patients grouped according to the severity of disease, along with intralesional and peripheral T-cell clones from RHD patients. Peptides encompassing residues 1 to 25, 81 to 103, 125 to 139, and 163 to 177 were more frequently recognized by PBMC from RHD patients than by those from controls. The M5 peptide encompassing residues 81 to 96 [M5(81–96) peptide] was most frequently recognized by PBMC from HLA-DR7+DR53+ patients with severe RHD, and 46.9% (15 of 32) and 43% (3 of 7) of heart-infiltrating and PBMC-derived peptide-reactive T-cell clones, respectively, recognized the M5(81–103) region. Heart proteins were recognized more frequently by PBMC from patients with severe RHD than by those from patients with mild RHD. The similar pattern of T-cell reactivity found with both peripheral blood and heart-infiltrating T cells is consistent with the migration of M-protein-sensitized T cells to the heart tissue. Conversely, the presence of heart-reactive T cells in the PBMC of patients with severe RHD also suggests a spillover of sensitized T cells from the heart lesion.

Ten-year clinical laboratory follow-up after application of a symptom-based therapeutic strategy to patients with severe chronic aortic regurgitation of predominant rheumatic etiology.

OBJECTIVES This study was designed to assess the feasibility and the long-term results of a symptom-based strategy of aortic valve replacement in a Brazilian population with predominant rheumatic etiology. BACKGROUND Optimal criteria for valve replacement in aortic regurgitation (AR) are still not entirely clear. The appearance of symptoms is an indication for surgery, but may be associated with myocardial damage. Although cardiac imaging data have provided a safer guide for such decisions, the use of symptom-based surgical indication has not been validated and might conceivably be better in populations with predominant rheumatic etiology and younger age. METHODS Echocardiography and rest-exercise radionuclide ventriculography were performed in 75 patients with severe AR, age 28 +/- 9 years, over a period of 10 +/- 0.69 years. Thirty-seven patients developed symptoms and underwent aortic valve replacement surgery within six months. Thirty-eight patients remained asymptomatic and were managed medically. RESULTS Survival was 100% in asymptomatic patients and 82% in symptomatic. Surgical treatment caused marked ventricular remodeling, with ventricular diameter involution and an improvement of rest-exercise ejection fraction percent variation. Multivariate analysis showed that the probability of developing symptoms within 10 years was 58% for a patient with a left ventricular end-diastolic diameter > or =70 mm and 76% for a patient with left ventricular end-systolic (LVESD) > or =50 mm. Logistic regression identified LVESD and age as the most predictive and specific, but not sensitive, indicators of symptom development. CONCLUSIONS Application of a standardized therapeutic strategy to patients with severe AR and predominant rheumatic etiology resulted in 90.6% survival after 10 years of follow-up.

Influence of the maze procedure on the treatment of rheumatic atrial fibrillation – evaluation of rhythm control and clinical outcome in a comparative study

OBJECTIVE The aim of this study was to evaluate the influence of the maze procedure on the treatment of rheumatic atrial fibrillation in patients with mitral valve disease. METHODS Fifty-five patients (mean age 51 years; 47 females) with rheumatic mitral valve disease and associated atrial fibrillation in New York Heart Association functional class III or IV, preoperatively, were operated upon. Thirty-five had double dysfunction, 19 had stenosis, and one had mitral regurgitation. None had other associated heart diseases or previous operations. The patients were divided into two groups: GI, 20 patients were treated for mitral valve disease with associated maze procedure; GII, 35 patients were treated for mitral valve disease without the maze procedure. The preoperative echocardiogram showed a left atrial diameter in GI of 5.35 mm and in GII of 5.57 mm (P=0.779). The groups were considered clinically similar (P=0.759). Cardiopulmonary bypass was used in all patients. The mitral valve was replaced with a biological prosthesis in 24 patients and repaired in 31 patients. RESULTS Three hospital deaths occurred, one in GI, two in GII. After cardiopulmonary bypass, 37.1% of patients in GII remained in atrial fibrillation. All patients in GI recovered regular rhythm (P<0.0001). In the ICU, atrial fibrillation was detected in 80% of patients in GII and maintained in 76.4% in a mean follow-up period of 38.5 months. In GI, atrial fibrillation occurred in 20% of patients in the ICU and maintained in 5.3% in 41 months of mean follow-up (P=0.0001). None of the patients in GI and 20.6% of patients in GII had a thromboembolic episode 1-63 months after the operation (P=0.041). Four late deaths occurred (two in each group), two being due to progression of valvular disease, one after an episode of pulmonary infection and one with no cardiac cause. CONCLUSION The maze procedure is effective in treating atrial fibrillation in patients with rheumatic mitral valve disease. The results are sustained in the mid-term follow-up period, preventing postoperative thromboembolic episodes, and with acceptable morbidity and mortality.

PDIA3, HSPA5 and vimentin, proteins identified by 2-DE in the valvular tissue, are the target antigens of peripheral and heart infiltrating T cells from chronic rheumatic heart disease patients.

Rheumatic fever (RF) is a post-infectious autoimmune disease due to sequel of group A streptococcus (GAS) pharyngitis. Rheumatic heart disease (RHD), the major manifestation of RF, is characterized by inflammation of heart valves and myocardium. Molecular mimicry between GAS antigens and host proteins has been shown at B and T cell level. However the identification of the autoantigens recognized by B and T cells within the inflammatory microenvironment of heart tissue in patients with RHD is still incompletely elucidated. In the present study, we used two-dimensional gel electrophoresis (2-DE) and mass spectrometry to identify valvular tissue proteins target of T cells from chronic RHD patients. We could identify three proteins recognized by heart infiltrating and peripheral T cells as protein disulfide isomerase ER-60 precursor (PDIA3), 78kD glucose-regulated protein precursor (HSPA5) and vimentin, with coverage of 45%, 43 and 34%, respectively. These proteins were recognized in a proliferation assay by peripheral and heart infiltrating T cells from RHD patients suggesting that they may be involved in the autoimmune reactions that leads to valve damage. We also observed that several other proteins isolated by 2-DE but not identified by mass spectrometry were also recognized by T cells. The identified cardiac proteins are likely relevant antigens involved in T cell-mediated autoimmune responses in RF/RHD that may contribute to the development of RHD.

Effect of Perioperative Goal-Directed Hemodynamic Resuscitation Therapy on Outcomes Following Cardiac Surgery: A Randomized Clinical Trial and Systematic Review.

Objectives:To evaluate the effects of goal-directed therapy on outcomes in high-risk patients undergoing cardiac surgery. Design:A prospective randomized controlled trial and an updated metaanalysis of randomized trials published from inception up to May 1, 2015. Setting:Surgical ICU within a tertiary referral university-affiliated teaching hospital. Patients:One hundred twenty-six high-risk patients undergoing coronary artery bypass surgery or valve repair. Interventions:Patients were randomized to a cardiac output–guided hemodynamic therapy algorithm (goal-directed therapy group, n = 62) or to usual care (n = 64). In the goal-directed therapy arm, a cardiac index of greater than 3 L/min/m2 was targeted with IV fluids, inotropes, and RBC transfusion starting from cardiopulmonary bypass and ending 8 hours after arrival to the ICU. Measurements and Main Results:The primary outcome was a composite endpoint of 30-day mortality and major postoperative complications. Patients from the goal-directed therapy group received a greater median (interquartile range) volume of IV fluids than the usual care group (1,000 [625–1,500] vs 500 [500–1,000] mL; p < 0.001], with no differences in the administration of either inotropes or RBC transfusions. The primary outcome was reduced in the goal-directed therapy group (27.4% vs 45.3%; p = 0.037). The goal-directed therapy group had a lower occurrence rate of infection (12.9% vs 29.7%; p = 0.002) and low cardiac output syndrome (6.5% vs 26.6%; p = 0.002). We also observed lower ICU cumulative dosage of dobutamine (12 vs 19 mg/kg; p = 0.003) and a shorter ICU (3 [3–4] vs 5 [4–7] d; p < 0.001) and hospital length of stay (9 [8–16] vs 12 [9–22] d; p = 0.049) in the goal-directed therapy compared with the usual care group. There were no differences in 30-day mortality rates (4.8% vs 9.4%, respectively; p = 0.492). The metaanalysis identified six trials and showed that, when compared with standard treatment, goal-directed therapy reduced the overall rate of complications (goal-directed therapy, 47/410 [11%] vs usual care, 92/415 [22%]; odds ratio, 0.40 [95% CI, 0.26–0.63]; p < 0.0001) and decreased the hospital length of stay (mean difference, –5.44 d; 95% CI, –9.28 to –1.60; p = 0.006) with no difference in postoperative mortality: 9 of 410 (2.2%) versus 15 of 415 (3.6%), odds ratio, 0.61 (95% CI, 0.26–1.47), and p = 0.27. Conclusions:Goal-directed therapy using fluids, inotropes, and blood transfusion reduced 30-day major complications in high-risk patients undergoing cardiac surgery.