Luis Eduardo Paim Rohde

Targeted deletion of matrix metalloproteinase-9 attenuates left ventricular enlargement and collagen accumulation after experimental myocardial infarction

Matrix metalloproteinase-9 (MMP-9) is prominently overexpressed after myocardial infarction (MI). We tested the hypothesis that mice with targeted deletion of MMP9 have less left ventricular (LV) dilation after experimental MI than do sibling wild-type (WT) mice. Animals that survived ligation of the left coronary artery underwent echocardiographic studies after MI; all analyses were performed without knowledge of mouse genotype. By day 8, MMP9 knockout (KO) mice had significantly smaller increases in end-diastolic and end-systolic ventricular dimensions at both midpapillary and apical levels, compared with infarcted WT mice; these differences persisted at 15 days after MI. MMP-9 KO mice had less collagen accumulation in the infarcted area than did WT mice, and they showed enhanced expression of MMP-2, MMP-13, and TIMP-1 and a reduced number of macrophages. We conclude that targeted deletion of the MMP9 gene attenuates LV dilation after experimental MI in mice. The decrease in collagen accumulation and the enhanced expression of other MMPs suggest that MMP-9 plays a prominent role in extracellular matrix remodeling after MI.

Matrix Metalloproteinase Inhibition Attenuates Early Left Ventricular Enlargement After Experimental Myocardial Infarction in Mice

BACKGROUND Extracellular matrix synthesis and degradation contribute to the morphological changes that occur after myocardial infarction (MI). METHODS AND RESULTS We tested the hypothesis that inhibition of matrix metalloproteinases (MMPs) attenuates left ventricular remodeling in experimental MI. Seventy-one male FVB mice that survived ligation of the left anterior coronary artery were randomized to a broad-spectrum MMP inhibitor (CP-471,474) or placebo by gavage. Echocardiographic studies were performed before randomization (within 24 hours of surgery) and 4 days later and included short-axis imaging at the midpapillary and apical levels. Infarction as defined by wall motion abnormality was achieved in 79% of the procedures (n=56), and mortality rate during the 4-day protocol was 23% (9 of 36 on treatment vs 7 of 35 on placebo; P=NS). Baseline end-diastolic and end-systolic dimensions and areas were similar (P=NS) between treated and placebo groups. At follow-up, infarcted mice allocated to MMP inhibitor had significantly smaller increases in end-systolic and end-diastolic dimensions and areas at both midpapillary and apical levels compared with infarcted mice allocated to placebo (all P<0.05). In addition, infarcted animals that received MMP inhibitor had no change in fractional shortening (-3+/-13%), whereas animals that received placebo had a decrease in fractional shortening (-12+/-12%) (P<0.05). In an analysis stratified by baseline end-diastolic area, the effects of MMP inhibition on the changes in end-systolic area and end-diastolic area were most prominent in animals that had more initial left ventricular dilatation (both P<0.05). CONCLUSIONS -Administration of an MMP inhibitor attenuates early left ventricular dilation after experimental MI in mice. Further studies in genetically altered mice and other models will improve understanding of the role of MMPs in left ventricular remodeling.

Impact of Age on Perioperative Complications and Length of Stay in Patients Undergoing Noncardiac Surgery

As the U.S. population ages, major surgical procedures are being performed in elderly patients with increasing frequency (1), but few data are available to guide preoperative risk stratification. Several studies have described correlates of cardiac morbidity and mortality in patients undergoing noncardiac surgery (2-8), but the number of elderly patients in most series has been small. Furthermore, few data are available on noncardiac complications, the overall complication rate, and length of stay. We describe the influence of age on perioperative complication and mortality rates in a large cohort of patients undergoing noncardiac surgery. As discussed elsewhere, age was not an independent correlate of major cardiac complications in this cohort (7). This analysis tests the hypothesis that advanced age is a correlate of the overall rate of complications, after adjustment for functional status. Methods Patients All patients 50 years of age or older who underwent major nonemergent noncardiac procedures at Brigham and Womens Hospital, Boston, Massachusetts, from 18 July 1989 to 28 February 1994 were eligible for the study. Major noncardiac procedures were defined as those with an expected length of stay of 2 or more days. Procedures were electively scheduled or were performed nonemergently during inpatient admissions. Eligibility criteria included the ability to speak English and adequate cognitive function to give informed consent. The enrollment and clinical data collection protocols were approved by the institutional review board of Brigham and Womens Hospital. The full study protocol included preoperative interviews by clinical study personnel (physicians or research nurses). Of the 4315 patients who provided informed consent to participate, 621 (14.4%) did not provide consent before surgery for the serial interview portion of the study, which included interviews 1 and 6 months after surgery. Patients who were not interviewed before surgery were not excluded on the basis of age or clinical status, but solely according to the availability of study personnel. Data Collection The data collection protocol is described elsewhere (7, 9, 10). In brief, patients who provided informed consent to the full study protocol underwent preoperative evaluation by clinical investigators (physicians or research nurses) using a structured data form. These evaluations included detailed medical histories, physical examinations, and laboratory tests. For patients who did not undergo this evaluation because they could not be approached or because they declined participation in the interview portion of the study, we obtained clinical data from the structured evaluation by the anesthesiologist found in the medical record. This data source was also used to obtain American Society of Anesthesiologists classification for all patients. Hence, prospectively recorded clinical data were available for all patients. Consenting patients agreed to postoperative sampling of creatine kinase and, if total creatine kinase levels were elevated, measurement of creatine kinaseMB immediately after surgery, at 8 p.m. on the evening of surgery, and on the next two mornings. In all other enrolled patients, creatine kinaseMB was measured according to the physicians orders. Among all participants, the mean (SD) number of cardiac enzyme samples obtained was 4.0 2.2. Electrocardiography was performed in the recovery room and on the first, third, and fifth postoperative days if the patient remained hospitalized. The Charlson Comorbidity Index, a weighted comorbidity score based on the number and the severity of 16 selected medical diseases, was used to quantify the burden of medical comorbid conditions (11). The mean number of other common comorbid conditions in this population was calculated for all patients. Preoperative functional status was assessed in 3890 patients by performing structured interviews using the Specific Activity Scale, an ordinally scaled, four-class instrument based on metabolic expenditure in various personal care, housework, occupational, and recreational activities (12, 13). This group included 196 patients who consented to preoperative interviews but did not consent to the full study protocol, including long-term follow-up. Classification of Outcomes The occurrence of major cardiac events postoperatively was classified by a single reviewer who was blinded to preoperative clinical data and who evaluated only postoperative clinical information, including cardiac enzyme measurements, electrocardiograms, and clinical events. Myocardial infarction was diagnosed on the basis of creatine kinaseMB levels and electrocardiographic findings (10). Major cardiac complications were unstable angina (postoperative typical chest pain associated with ischemic electrocardiographic changes), myocardial infarction, cardiogenic pulmonary edema, documented ventricular tachycardia, ventricular fibrillation or primary cardiac arrest, and sustained complete heart block requiring pacemaker. Major noncardiac events were pulmonary embolism documented by autopsy, angiography, or a high-probability ventilationperfusion scan; respiratory failure requiring intubation for more than 2 days or reintubation; noncardiogenic pulmonary edema; lobar pneumonia confirmed by chest radiography and requiring antibiotic therapy; acute renal failure requiring dialysis; or cerebrovascular accident with new neurologic deficit. In-hospital mortality was also recorded, and the combined end point of major cardiac or noncardiac complications or death was used in these analyses. Statistical Analysis To evaluate the impact of age on postoperative complications, we performed analyses in which age was considered as a continuous variable and as four categories (50 to 59 years, 60 to 69 years, 70 to 79 years, and 80 years). Because age was not linearly associated with the risk for outcomes, categorized age variables are used throughout this report. Univariate correlations between clinical characteristics and age category were analyzed by using the chi-square test and the Fisher exact test for categorical variables and a t-test or Wilcoxon test for continuous variables. Because several clinical and laboratory variables are associated with age and because it is difficult to exclude the association of age with the event of interest, we included all relevant clinical variables in the multivariate analysis. Logistic regression analysis was used to determine the independent association of age with postoperative complications while controlling for the presence of comorbid conditions, sex, ethnicity, functional status as measured by Specific Activity Scale class, type of procedure, and preoperative laboratory data. Patients for whom data on selected variables were missing were excluded from the model. Clinically relevant variables from the regression model were analyzed for potential interactions, and potentially significant interaction terms were considered in the regression models. A two-sided P value less than 0.05 was considered statistically significant in all analyses. Linear regression models were used to estimate the independent variation in length of stay attributable to age, controlling for sex, ethnicity, preoperative clinical characteristics, American Society of Anesthesiologists classification, type of procedure, postoperative events, and in-hospital mortality. The logarithmic transformation of length of stay was used because of the non-normal distribution of this variable. The percentage change in the geometric mean of length of stay in the final model was used to estimate the numbers of adjusted hospital days attributable to age groups. All analyses were performed by using SAS statistical software for Windows, version 6.12 (SAS Institute, Inc., Cary, North Carolina). Role of the Funding Source The funding source had no role in data collection and analysis or in subsequent decisions about publication of manuscripts. Results Patients The study sample constituted 4315 patients who had a mean age of 67 9 years; 2096 patients (48%) were male and 3903 (90%) were white. Twenty-four percent (1015 patients) were younger than 59 years, 38% (1646 patients) were 60 to 69 years of age, 31% (1341 patients) were 70 to 79 years of age, and 7% (313 patients) were older than 80 years of age. These patients undergoing elective surgery had a low prevalence of comorbid conditions, and 3187 (74%) patients had Charlson Comorbidity Index scores of 0 through 2. The types of procedures performed were orthopedic (35%), intrathoracic (12%), abdominal (12%), abdominal aortic aneurysm (5%), other vascular (17%), and other general surgical procedures (33%). In the oldest age group, significantly fewer patients were male and nonwhite compared with the younger age groups (Table 1). The number of comorbid conditions and the average Charlson Comorbidity Index scores increased with increasing age. The distribution of Specific Activity Scale class and American Society of Anesthesiology class was also significantly worse in the older age groups; a greater proportion of patients 70 to 79 years of age and 80 years of age was classified as class 3 or 4. As expected, the type of surgical procedure performed varied among age groups. Higher percentages of older patients underwent orthopedic procedures, aortic aneurysm repair, and other vascular surgeries (Table 1). Table 1. Patient Characteristics Perioperative Complications Major or fatal perioperative complications occurred in 44 (4.3%) patients younger than 59 years of age, 93 (5.7%) patients 60 to 69 years of age, 129 (9.6%) patients 70 to 79 years of age, and 39 (12.5%) patients 80 years of age or older (P<0.001) (Figure). Age was significantly associated with a higher risk for cardiogenic pulmonary edema, myocardial infarction, ventricular arrhythmias, bacterial pneumonia, respiratory failure requiring intubation, and in-hospital mortality. All other major complications e

Survey of C-Reactive Protein and Cardiovascular Risk Factors in Apparently Healthy Men

Several prospective studies have demonstrated a direct association between C-reactive protein (CRP) levels and the risks of developing cardiovascular disease. Few studies, however, have explored the interrelations between CRP levels and other risk factors for cardiovascular disease. We evaluated the relation of CRP with several cardiovascular risk factors in a cross-sectional survey of 1,172 apparently healthy men. There were significant positive associations between CRP levels and age, number of cigarettes smoked per day, body mass index, systolic and diastolic blood pressure, total cholesterol, triglycerides, lipoprotein(a), apolipoprotein B, tissue-type plasminogen activator antigen, D-dimers, total homocysteine, and fibrinogen (all p values <0.05). Significant inverse associations were observed for exercise frequency, high-density lipoprotein cholesterol, and apolipoprotein A-I and A-II (all p values <0.02). In multivariate analysis, age, smoking status, and serum levels of tissue-type plasminogen activator antigen, fibrinogen, lipoprotein(a), and total homocysteine were independent correlates of CRP levels. Finally, in an analysis controlled either for all the independent correlates or for several usual risk factors, we observed progressive increases in levels of CRP with increasing prevalence of risk factors (p for trend <0.001 for independent correlates and <0.01 for usual risk factors). In conclusion, in a large cohort of apparently healthy men, CRP levels were associated with several cardiovascular risk factors. These data are compatible with the hypothesis that CRP levels may be a marker for preclinical cardiovascular disease.

Circulating Cell Adhesion Molecules Are Correlated With Ultrasound-Based Assessment of Carotid Atherosclerosis

Although cellular adhesion molecules (CAMs) are hypothesized to play an important role in atherogenesis, the relationship between CAMs and systemic atherosclerosis is uncertain. Among 92 outpatients (48 men; mean+/-SD age, 65+/-9 years), we evaluated the association of soluble vascular CAM-1 (sVCAM-1) and intercellular adhesion molecule-1 (sICAM-1) with carotid intimal-medial thickness (IMT), an index of early atherosclerosis. All subjects underwent a 2-dimensional ultrasound examination of both carotid arteries at the distal common carotid arteries and bifurcation. sVCAM-1 and sICAM-1 levels measured by enzyme-linked immunosorbent assay were significantly correlated with mean IMT of the common carotid artery (r=0.34 and r=0.30, respectively; P<0.01) and carotid bifurcation (r=0.31 and r=0.26, respectively; P<0.05), whereas sVCAM-1 was also positively associated with maximal carotid IMT (r=0.35, P<0.01). Adjustment for age attenuated the association between sVCAM-1 and common (r=0.16, P=0.13) and bifurcation (r=0.18, P=0.07) carotid IMT but had minimal effect on the associations between sICAM-1 and carotid measurements (r=0.32, P<0.01; r=0.23, P<0.05; for common and bifurcation IMT, respectively). Age-adjusted sICAM-1 levels increased in a stepwise fashion across common carotid IMT tertiles (253+/-27 versus 275+/-24 versus 384+/-26 pg/mL for the lowest, intermediate, and highest IMT tertiles, respectively; P<0.01). A similar trend was also found between sVCAM-1 levels and common carotid IMT tertiles (625+/-60 versus 650+/-53 versus 714+/-58 pg/mL; P<0.15). These associations were minimally affected in analyses adjusting for hypertension, diabetes, smoking, low and high density lipoprotein cholesterol, lipoprotein(a), and homocysteine, or in a subgroup analysis limited to those with no prior history of atherothrombotic disease. These data demonstrate a positive association between serum CAMs with carotid IMT and further support the hypothesis that systemic inflammation may have a role in atherosclerotic lesion development.

Cross-Sectional Study of Soluble Intercellular Adhesion Molecule-1 and Cardiovascular Risk Factors in Apparently Healthy Men

An elevated plasma concentration of the soluble intercellular adhesion molecule-1 (sICAM-1) is associated with increased risk for future coronary events. However, data exploring the interrelations of sICAM-1 with known cardiovascular risk factors are sparse. We determined sICAM-1 levels in 948 middle-aged men with no prior history of cardiovascular disease. sICAM-1 levels increased with age (P<0.001) and were significantly associated with smoking (P<0.001), hypertension (P<0.05), and frequent alcohol consumption (P=0.006). Positive correlations were observed between sICAM-1 and triglycerides (r=0.15; P<0.001), fibrinogen (r=0.21; P<0.001), tissue-type plasminogen activator antigen (r=0.17; P<0.001), and total homocysteine (r=0.09; P=0.02); whereas a negative correlation was observed for high density lipoprotein cholesterol (r=-0.15; P<0. 001). Overall, plasma concentrations of sICAM-1 increased with increasing prevalence of usual cardiovascular risk factors; mean plasma concentrations were 231, 236, 245, 257, and 312 ng/mL for those subjects with 0, 1, 2, 3, and >4 risk factors, respectively (P<0.01 for trend). In multivariate analysis, age, smoking status, diabetes, systolic blood pressure, positive family history of coronary disease, and serum levels of total homocysteine and fibrinogen were all independently associated with sICAM-1 levels (all P</=0.05). sICAM-1 levels are associated with several established cardiovascular risk factors. Further studies will be needed to evaluate whether these associations reflect the role of sICAM-1 as a marker of preclinical atherosclerosis, and whether such interrelations might have a causal basis.

Usefulness of transthoracic echocardiography as a tool for risk stratification of patients undergoing major noncardiac surgery.

Transthoracic echocardiography (TTE) is frequently ordered before noncardiac surgery, although its ability to predict perioperative cardiac complications is uncertain. To evaluate the incremental information provided by TTE after consideration of clinical data for prediction of cardiac complications after noncardiac surgery, 570 patients who underwent TTE before major noncardiac surgery at a university hospital were studied. Preoperative clinical data and clinical outcomes were collected prospectively according to a structured protocol. TTE data included left ventricular (LV) function, hypertrophy indexes, and Doppler-derived measurements. In univariate analyses, preoperative systolic dysfunction was associated with postoperative myocardial infarction (odds ratio [OR] 2.8, 95% confidence interval [CI] 1.1 to 7.0), cardiogenic pulmonary edema (OR 3.2, 95% CI 1.4 to 7.0), and major cardiac complications (OR 2.4, 95% Cl 1.3 to 4.5). Moderate to severe LV hypertrophy, moderate to severe mitral regurgitation, and increased aortic valve gradient were also associated with major cardiac events (OR 2.3, 95% CI 1.2 to 4.6; OR 2.2, 95% CI 1.1 to 4.3; OR 2.1, 95% CI 1.0 to 4.5, respectively). In logistic regression analysis, models with echocardiographic variables predicted major cardiac complications significantly better than those that included only clinical variables (c statistic 0.73 vs 0.68; p <0.05). Echocardiographic data added significant information for patients at increased risk for cardiac complications by clinical criteria, but not in otherwise low-risk patients. In conclusion, preoperative TTE before noncardiac surgery can provide independent information about the risk of postoperative cardiac complications in selected patients.

I Latin American Guidelines for the assessment and management of decompensated heart failure

Edimar Alcides Bocchi, Fabio Vilas-Boas, Sergio Perrone, Angel G Caamano, Nadine Clausell, Maria da Consolacao VMoreira, Jorge Thierer, Hugo Omar Grancelli, Carlos Vicente Serrano Junior, Denilson Albuquerque, Dirceu Almeida,Fernando Bacal, Luis Felipe Moreira, Adonay Mendonza, Antonio Magana, Arturo Tejeda, Daniel Chafes, Efraim Gomez,Erick Bogantes, Estela Azeka, Evandro Tinoco Mesquita, Francisco Jose Farias B Reis, Hector Mora, Humberto Vilacorta,Jesus Sanches, Joao David de Souza Neto, Jose Luis Vuksovic, Juan Paes Moreno, Julio Aspe y Rosas, Lidia ZytynskiMoura, Luis Antonio de Almeida Campos, Luis Eduardo Rohde, Marcos Parioma Javier, Martin Garrido Garduno, MucioTavares, Pablo Castro Galvez, Raul Spinoza, Reynaldo Castro de Miranda, Ricardo Mourilhe Rocha, Roberto Paganini,Rodolfo Castano Guerra, Salvador Rassi, Sofia Lagudis, Solange Bordignon, Solon Navarette, Waldo Fernandes, AntonioCarlos Pereira Barretto, Victor Issa, Jorge Ilha Guimaraes.

Targeted deletion of caspase-1 reduces early mortality and left ventricular dilatation following myocardial infarction.

Objective. - Mice with targeted deletion of caspase-1 (interleukin-1beta (IL-1beta)-converting enzyme) lack the active forms of IL-1beta and IL-18, two cytokines implicated in maladaptive ventricular remodeling following cardiac injury. We, therefore, investigated the extent of ventricular dilation in caspase-1-knockout (KO) mice. Methods and results. - Transthoracic echocardiography was performed at days 1, 4, and 9 following left anterior descending artery ligation in caspase-1-KO and wild-type (WT) control animals, including M-mode and short-axis imaging at both mid-papillary and apical levels. Although initial post-operative mortality was lower in KO than in WT animals (21.4% WT, 12.0% KO, P < 0.001), there was no difference in mortality between 24 h and 9 d (P = n.s.). Caspase-1 KOs exhibited significantly less mid-papillary ventricular dilatation at days 4 and 9 compared to day 1 post-myocardial infarction (MI) (P < 0.05). Caspase-1 KOs also had a marked (50%) reduction in the level of matrix metalloproteinase 3 (MMP-3), although no significant changes occurred in other MMPs or in tissue inhibitors of metalloproteinase 1 levels by immunoblot analysis. Although IL-beta plasma levels were not detectable, both IL-18 levels and the rate of apoptosis in remodeling, non-infarcted muscle were significantly higher in WT compared to caspase-1-KO animals.Conclusion. - Mice lacking caspase-1 exhibited both improved peri-infarct survival and a decreased rate of ventricular dilatation, possibly due in part to a decrease in MMP-3 activity, IL-18 production, and a reduction in the rate of apoptosis after experimental MI.

Plasma Concentrations of Interleukin-6 and Abdominal Aortic Diameter Among Subjects Without Aortic Dilatation

Previous studies suggest that cytokine-induced tissue inflammation may participate in the pathogenesis of abdominal aortic aneurysms. Serum inflammatory markers may reflect arterial inflammation in asymptomatic phases of the aneurysmal disease. We studied 120 outpatients (62 men; age, 65+/-9 years) by ultrasound evaluation of the abdominal aorta to evaluate the association of circulating levels of interleukin-6 (IL-6) with abdominal aortic diameter in subjects with normal aortic size. Aortic diameter was measured at the infrarenal level and indexed for body surface area. Seven patients with abdominal aortic dilatation (indexed aortic diameter, >1.3 cm/m2) were also identified. Plasma concentrations of IL-6, serum amyloid A (SAA), C-reactive protein (CRP), total homocysteine, and lipids were measured. Among the 113 subjects without aortic dilatation, indexed aortic diameter was positively associated with serum levels of IL-6 (P<0.01), SAA (P<0.01), and total homocysteine (P=0.01). IL-6 levels increased in a stepwise fashion among dichotomized groups of aortic size (low and high aortic diameters) and peaked in patients with aortic dilatation (2.3+/-1.2 versus 2. 7+/-0.9 versus 3.2+/-0.9 pg/mL, respectively; P for trend=0.039). None of the serum lipid measurements correlated with abdominal aortic diameter. Although CRP levels were associated with SAA levels (r=0.60; P<0.001), associations between CRP and aortic diameter were nonsignificant. In multivariate analysis, levels of IL-6 (P=0.02), SAA (P=0.001), and total homocysteine (P<0.001) were independent correlates of indexed aortic diameter. In conclusion, circulating levels of IL-6, SAA, and total homocysteine may reflect processes involved in the early phases of abdominal aortic aneurysm formation, before dilation of the abdominal aorta is established. These data support a role for chronic inflammation in the progression of asymptomatic aortic disease.