Showing papers by "Francis G. Spinale published in 2016"

Crossing Into the Next Frontier of Cardiac Extracellular Matrix Research.

Abstract: The extracellular matrix (ECM) is a complex and dynamic entity that drives the formation and development of the cardiovascular system, determines critical aspects of cardiovascular performance, and plays key roles in the initiation and progression of abnormal cardiovascular function with aging and disease Microscopic studies in the late 1700s identified fibrous structures surrounding cells, which led scientists to conclude that the ECM was primarily a foundational unit to provide support1 Unfortunately, this historic view that the ECM is a static scaffold is still to this day held by many who are not in the field Using molecular, cell based, and dynamic imaging systems, however, experts now recognize that the ECM is an ever-changing component that responds to normal and abnormal molecular and biophysical cues and, in turn, drives changes in overall cardiovascular structure and function The ECM contains structural and nonstructural proteins, interacts dynamically with unique and differentiating cell types, serves as a reservoir and processing site for signaling molecules, and forms communication corridors for both protein and genetic information Thus, the ECM is a diverse entity that presents a novel and exciting research frontier that could yield improvements in diagnostics, prognostics, therapeutics, and prevention of cardiovascular disease A recent Pubmed search (accessed August 23, 2016) using the terms ECM and cardiovascular, cardiac, or vascular revealed that this field has been growing annually since the 1990s (Figure) Driving forces for the increased interest in ECM research include the recognition of biological and pathophysiological importance, improvements in biochemical, cellular, and molecular techniques by which to study this complex unit, and advances in the capacity at microscopic and macroscopic levels to provide greater insight into the dynamically changing ECM Using combinatorial approaches, ECM research can be explored at greater depths than previously possible This editorial forms a coalescence of discussions by …

Basigin Promotes Cardiac Fibrosis and Failure in Response to Chronic Pressure Overload in Mice

Abstract: Objective—Basigin (Bsg) is a transmembrane glycoprotein that activates matrix metalloproteinases and promotes inflammation. However, the role of Bsg in the pathogenesis of cardiac hypertrophy and failure remains to be elucidated. We examined the role of Bsg in cardiac hypertrophy and failure in mice and humans. Approach and Results—We performed transverse aortic constriction in Bsg+/– and in wild-type mice. Bsg+/– mice showed significantly less heart and lung weight and cardiac interstitial fibrosis compared with littermate controls after transverse aortic constriction. Both matrix metalloproteinase activities and oxidative stress in loaded left ventricle were significantly less in Bsg+/– mice compared with controls. Echocardiography showed that Bsg+/– mice showed less hypertrophy, less left ventricular dilatation, and preserved left ventricular fractional shortening compared with littermate controls after transverse aortic constriction. Consistently, Bsg+/– mice showed a significantly improved long-term ...

Sonomicrometry-Based Analysis of Post-Myocardial Infarction Regional Mechanics

Abstract: Following myocardial infarction (MI), detrimental changes to the geometry, composition, and mechanical properties of the left ventricle (LV) are initiated in a process generally termed adverse post-MI remodeling. Cumulatively, these changes lead to a loss of LV function and are deterministic factors in the progression to heart failure. Proposed therapeutic strategies to target aberrant LV mechanics post-MI have shown potential to stabilize LV functional indices throughout the remodeling process. The in vivo quantification of LV mechanics, particularly within the MI region, is therefore essential to the continued development and evaluation of strategies to interrupt the post-MI remodeling process. The present study utilizes a porcine MI model and in vivo sonomicrometry to characterize MI region stiffness at 14 days post-MI. Obtained results demonstrate a significant dependence of mechanical properties on location and direction within the MI region, as well as cardiac phase. While approaches for comprehensive characterization of LV mechanics post-MI still need to be improved and standardized, our findings provide insight into the issues and complexities that must be considered within the MI region itself.

Improving Delivery of a Biomaterial Payload in Myocardial Infarction

Abstract: Survival after an acute coronary syndrome has greatly improved because of advances in thrombolytic therapy, stabilization of the culprit lesion such as with coronary stents, and the use of pharmacological approaches to prevent recurrent thrombotic and arrhythmic events. Despite these approaches, however, myocardial injury culminating in myocardial infarction (MI) continues to be an all too common sequela. The MI region is a highly heterogeneous structure that contains several cell types, such as residual cardiac myocytes, inflammatory cells of different lineages, proliferating and transdifferentiating fibroblasts, and extracellular matrix proteins and signaling molecules. Although canonical thought was that the MI region was a rather static, fibrotic structure, it is now clear that this is a dynamic and ever-evolving entity with changes in geometry, biophysical properties, and cellular/extracellular composition. The time course and extent of these post-MI processes have been generically termed post-MI remodeling and is recognized as a milestone event for the initiation and progression to left ventricular (LV) dilation and dysfunction. One ubiquitous feature of post-MI remodeling is a progressive thinning and dyskinesia of the MI region, which is because of the summation of several factors: a loss of cardiac myocytes and thus functional myocardium, continuous turnover and instability of the extracellular matrix, and significant shifts in stress–strain patterns within this region throughout the cardiac cycle. Specifically, significant heterogeneity arises in the stress–strain patterns both within and surrounding the MI region and in turn can contribute to a feed-forward process of continuous activation of bioactive molecules and extracellular matrix instability. These biomechanical changes result in continued MI thinning and recruitment of border zone myocardium into the MI region, which is defined as MI expansion. As the MI expansion process continues in an inexorable fashion, the degree of heterogeneity in stress–strain relations are exacerbated, bulging of the MI region becomes evident by …