Combining experimental and mathematical modeling to reveal mechanisms of macrophage-dependent left ventricular remodeling.

BACKGROUND: Progressive remodeling of the left ventricle (LV) following myocardial infarction (MI) can lead to congestive heart failure, but the underlying initiation factors remain poorly defined. The objective of this study, accordingly, was to determine the key factors and elucidate the regulatory mechanisms of LV remodeling using integrated computational and experimental approaches. RESULTS: By examining the extracellular matrix (ECM) gene expression and plasma analyte levels in C57/BL6J mice LV post-MI and ECM gene responses to transforming growth factor (TGF-ß1) in cultured cardiac fibroblasts, we found that key factors in LV remodeling included macrophages, fibroblasts, transforming growth factor-ß1, matrix metalloproteinase-9 (MMP-9), and specific collagen subtypes. We established a mathematical model to study LV remodeling post-MI by quantifying the dynamic balance between ECM construction and destruction. The mathematical model incorporated the key factors and demonstrated that TGF-ß1 stimuli and MMP-9 interventions with different strengths and intervention times lead to different LV remodeling outcomes. The predictions of the mathematical model fell within the range of experimental measurements for these interventions, providing validation for the model. CONCLUSIONS: In conclusion, our results demonstrated that the balance between ECM synthesis and degradation, controlled by interactions of specific key factors, determines the LV remodeling outcomes. Our mathematical model, based on the balance between ECM construction and destruction, provides a useful tool for studying the regulatory mechanisms and for predicting LV remodeling outcomes.

Relation of concentric remodeling to adverse outcomes in patients with stable coronary artery disease (from the Heart and Soul Study).

Concentric remodeling (CR) is defined as increased left ventricular (LV) wall thickness with normal total LV mass. When encountered in populations with hypertension or patients undergoing aortic valve replacement, some studies have shown that CR predicts cardiovascular (CV) events and stroke. To expand our understanding of the prognostic implications of this common echocardiographic finding, we examined the association of CR and adverse CV events in ambulatory patients with coronary artery disease (CAD). We tested the hypothesis that finding CR on echocardiogram in ambulatory CAD independently predicts heart failure hospitalizations and CV death. Transthoracic echocardiograms were recorded in 973 participants from the Heart and Soul Study. Participants were divided into 4 groups: normal, CR, concentric LV hypertrophy, and eccentric LV hypertrophy. CV events were determined by 2 independent adjudicators and these were analyzed by Cox proportional hazards models. After mean 4.9 ± 1.5 years of follow-up, adverse outcomes occurred more frequently in those with concentric and eccentric LV hypertrophy but not in those with CR. After multivariate adjustment, concentric and eccentric LV hypertrophies were associated with increased risk of death and heart failure hospitalization, whereas CR was not. In conclusion, our hypothesis was not supported because CR was not associated with adverse CV events in our cohort of patients with stable CAD.

Aesthetic outcomes in breast conservation therapy.

BACKGROUND: Since the National Surgical Adjuvant Breast and Bowel Project B06 (NSABP-B06) trial demonstrated equivalent survival outcomes between patients with breast cancer undergoing modified radical mastectomy versus lumpectomy and radiation, an increasing number of patients are seeking breast conservation therapy. Traditionally, only patients who have undergone total mastectomy have been referred for reconstruction. OBJECTIVE: The purpose of the study was to determine the number of dissatisfied patients treated with breast conservation therapy who have suboptimal cosmesis and should be referred for reconstruction. METHODS: After obtaining approval from the Institutional Review Board and patient consent, patients identified as more than 1 year posttreatment from breast conservation therapy (1999-2004) were interviewed and photographed. Data were gathered by use of a questionnaire that included patient aesthetic score, patient satisfaction, and change in body image. Photographs were shown to a surgical oncologist, a general surgeon, and a plastic surgeon for a physician aesthetic score. RESULTS: Thirteen of 46 patients (28.3%) were dissatisfied with their cosmetic result. Women who were dissatisfied with their cosmetic result were more likely to have a negative change in their body image when compared with patients who were satisfied with their cosmetic result (46.2 % vs 6.1%, P = .02). Additionally, dissatisfied patients were more likely to rate their cosmetic result as poor (15.4 % vs 0%, P = .007) and were more likely to consider reconstruction (46.2% vs 9.1%, P = .01) when compared with satisfied patients. Risk factors to predict dissatisfaction in our patient population included age younger than 52 years and the resection of tumor from the upper inner quadrant. CONCLUSIONS: Twenty-eight percent of patients in this study were dissatisfied with their cosmetic result. Furthermore, a large portion of these patients would consider reconstruction if it were offered. Although this study only identified a few broad risk factors for suboptimal cosmetic outcome, it confirms our hypothesis that many patients who have undergone breast conservation therapy should be referred for plastic surgery consultation.

Peripheral thermal injury causes early blood-brain barrier dysfunction and matrix metalloproteinase expression in rat.

High mortality incidence after serious systemic thermal injury is believed to be linked to significant increases in cerebral permeability, ultimately leading to irreversible blood-brain barrier (BBB) breakdown. The aim of this study was to investigate whether disruption of microvascular integrity in a rat thermal injury model is associated with early matrix metalloproteinase (MMP) expression. A total of 35 Sprague-Dawley rats were studied in thermal injury and control groups, each group containing two subgroups, one for brain edema and Evans blue analysis and another for MMP mRNA analysis. Thermally injured animals were anesthetized and submerged vertically in 85 degrees C water to the neck for 6 seconds producing a third degree burn affecting 70% of the total body surface area. BBB integrity was determined by measuring amount of Evans blue after 7 hours of injury with a spectrophotometer. Brain edema was detected by calculating water content. Brain mRNA levels were determined with real-time PCR 3 and 7 hours post-injury. Brain water content was significantly increased after peripheral injury at hour 7. Evans blue leakage was also significantly increased at the same time, suggesting an impaired BBB function after injury. Expressions of MMP-2 and MMP-9 mRNA in brain were increased as early as 3 hours after injury and remained at hour 7. Our study demonstrated a significant increase in cerebral permeability that occurs after serious systemic thermal injury. The underlying mechanisms could be related to early expression of MMPs.

Peripheral thermal injury causes blood-brain barrier dysfunction and matrix metalloproteinase (MMP) expression in rat.

Mortality after serious systemic thermal injury may be linked to significant increases in cerebral vascular permeability and edema due to blood-brain barrier (BBB) breakdown. This BBB disruption is thought to be mediated by a family of proteolytic enzymes known as matrix metalloproteinases (MMPs). The gelatinases, MMP-2 and MMP-9, digest the endothelial basal lamina of the BBB, which is essential for maintaining BBB integrity. The current study investigated whether disruption of microvascular integrity in a rat thermal injury model is associated with gelatinase expression and activity. Seventy-two adult Sprague-Dawley rats were anesthetized and submerged horizontally, in the supine position, in 100 degrees C (37 degrees C for controls) water for 6 s producing a third-degree burn affecting 60-70% of the total body surface area. Brain edema was detected by calculating water content. Real time PCR, Western blot, and zymography were used to quantify MMP mRNA, protein, and enzyme activity levels. Each group was quantified at 3, 7, 24, and 72 h post thermal injury. Brain water content was significantly increased 7 through 72 h after burn. Expression of brain MMP-9 mRNA was significantly increased as early as 3 h after thermal injury compared to controls, remained at 7 h (p<0.01), and returned to control levels by 24 h. MMP-9 protein levels and enzyme activity began to increase at 7 h and reached significant levels between 7 and 24 h after thermal injury. While MMP-9 protein levels continued to increase significantly through 72 h, enzyme activity returned to control level. The increase in MMP-9 expression and activity, associated with increased BBB permeability following thermal injury, indicates that MMP-9 may contribute to observed cerebral edema in peripheral thermal injury.

Early inflammatory response in rat brain after peripheral thermal injury.

Previous studies have shown that the cerebral complications associated with skin burn victims are correlated with brain damage. The aim of this study was to determine whether systemic thermal injury induces inflammatory responses in the brain. Sprague Dawley rats (n=28) were studied in thermal injury and control groups. Animals from the thermal injury (n=14) and control (n=14) group were anesthetized and submerged to the neck vertically in 85 degrees C water for 6 s producing a third degree burn affecting 60-70% of the animal body surface area. The controls were submerged in 37 degrees C water for 6 s. Early expression of tumor necrosis factor-alpha (TNF-alpha), interleukin 1-beta (IL-1beta), and intracellular cell adhesion molecules (ICAM-1) protein levels in serum were determined at 3 (n=7) and 7 h (n=7) by enzyme-linked immunoabsorbent assay (ELISA). mRNA of TNF-alpha, IL-1beta, and ICAM-1 in the brain was measured at the same time points with a real-time reverse transcriptase-polymerase chain reaction (RT-PCR). An equal animal number was used for controls. Systemic inflammatory responses were demonstrated by dramatic up-regulations (5-50 fold) of TNF-alpha, IL-1beta, and ICAM-1 protein level in serum at 7 h after the thermal injury. However, as early as 3 h after peripheral thermal injury, a significant increase (3-15 fold) in mRNA expression of TNF-alpha, IL-1beta and ICAM-1 was observed in brain homogenates, with increased levels remaining at 7 h after injury. This study demonstrated an early inflammatory response in the brain after severe peripheral thermal injury. The cerebral inflammatory reaction was associated with expression of systemic cytokines and an adhesion molecule.