Myeloperoxidase and Plasminogen Activator Inhibitor 1 Play a Central Role in Ventricular Remodeling after Myocardial Infarction

Left ventricular (LV) remodeling after myocardial infarction (MI) results in LV dilation, a major cause of congestive heart failure and sudden cardiac death. Ischemic injury and the ensuing inflammatory response participate in LV remodeling, leading to myocardial rupture and LV dilation. Myeloperoxidase (MPO), which accumulates in the infarct zone, is released from neutrophils and monocytes leading to the formation of reactive chlorinating species capable of oxidizing proteins and altering biological function. We studied acute myocardial infarction (AMI) in a chronic coronary artery ligation model in MPO null mice (MPO−/−). MPO−/− demonstrated decreased leukocyte infiltration, significant reduction in LV dilation, and marked preservation of LV function. The mechanism appears to be due to decreased oxidative inactivation of plasminogen activator inhibitor 1 (PAI-1) in the MPO−/−, leading to decreased tissue plasmin activity. MPO and PAI-1 are shown to have a critical role in the LV response immediately after MI, as demonstrated by markedly delayed myocardial rupture in the MPO−/− and accelerated rupture in the PAI-1−/−. These data offer a mechanistic link between inflammation and LV remodeling by demonstrating a heretofore unrecognized role for MPO and PAI-1 in orchestrating the myocardial response to AMI

950-95 Enhanced Detection of Endocardial Motion by Spatiotemporal Fourier Filtration of 2-D Echocardiographic Acoustic Quantification Images

Automated detection of endocardial borders by 2-D echocardiography can be useful for the assessment of regional wall motion. Although Acoustic Quantification (AQ) currently provides on-line endocardial edge detection, the presence of high frequency noise in AQ images limits its utility for this purpose. We propose that spatiotemporal Fourierfiltration (FF) of AQ images may improve signal-to-noise ratio and enhance accuracy of analysis of endocardial motion.MethodsWe stored digitally the 2-D AQ echocardiographic images obtained from the parasternal short axis view in 10 study subjects. These were processed using a stepwise computer algorithm that included smoothing using FF with spatial and temporal cutoff of 10 and 5 harmonics, respectively. We tested the accuracy of the FF against the raw AQ images by 1) comparing the vertical axis diameters of the raw AQ and FF images with the measurements obtained from digitized M-Mode tracings, and 2) counting the number of LV internal diameter reversals during each cardiac cycle along the vertical and horizontal axis. Five successive frames of endocardial borders from a loop of raw AQ and after FF are superimposed below.Results1) The correlation between M-mode and raw AQ was 0.86, vs. 0.95 between M-mode and FF (p<0.001). 2) The number of reversals per cycle was 13±3.5 for AQ vS. 3.1±3 for FF (p<0.001).ConclusionBy eliminating high frequency noise from the echocardiographic AQ images, spatiotemporal Fourier filtration provides a more accurate representation of the endocardial edge motion

The “Swirling” Pattern of Atrial Spontaneous Echo Contrast can be Characterized by Integrated Backscatter Using Fourier Analysis

Atrial spontaneous echo contrast (smoke) refers to dynamic smoke-like echos that has both increased intensity and a distinctive “swirling” pattern. We have previously shown that smoke can be measured by integrated backscatter (IBS) intensity, and now hypothesize that the swirling pattern could be characterized by frequency spectrum analysis of IBS sequences by Fast Fourier Transformation (FFT).MethodsWe acquired IBS sequences during TEE in 25 pts. who had been qualitatively assessed independently for smoke severity. We analyzed IBS intensity of the LA smoke region, as well as reference intensity sequences from the left ventricular cavity (LV) and the interatrial septum (lAS), for 60 consecutive frames at 30Hz under optimal imaging gains. We calculated FFT centroid frequencies to characterize the shape and distribution of the frequency pattern for all acquired IBS sequences.ResultsMild and severe LA smoke IBS sequences were characterized by low dominant frequency with high amplitude variability, whereas the no smoke, LV, and lAS sequences were characterized by high frequency with low amplitude variability, consistent with random interframe noise. The mean FFT centroid frequency for atrial smoke sequences (6.2±2.7) was significantly lower than the centroid frequency for no-smoke sequences (11.9±4.1; P<0.001). Total IBS variance (integral of all non-zero components) was significantly associated with the qualitative grade of atrial smoke (p<0.003).Conclusions1) Analysis of IBS FFT spectra shows that atrial smoke is a unique echocardiographic phenomenon, clearly distinguishable from either artifact or tissue; 2) IBS intensity analysis and IBS FFT frequency analysis each provide an objective quantitative measure of smoke which may serve to assess thrombogenic potential and embolic risk in patients with spontaneous echo contrast

Cardiac Overexpression of Myotrophin Triggers Myocardial Hypertrophy and Heart Failure in Transgenic Mice

Cardiac hypertrophy and heart failure remain leading causes of death in the United States. Many studies have suggested that, under stress, myocardium releases factors triggering protein synthesis and stimulating myocyte growth. We identified and cloned myotrophin, a 12-kDa protein from hypertrophied human and rat hearts. Myotrophin (whose gene is localized on human chromosome 7q33) stimulates myocyte growth and participates in cellular interaction that initiates cardiac hypertrophy in vitro. In this report, we present data on the pathophysiological significance of myotrophin in vivo, showing the effects of overexpression of cardio-specific myotrophin in transgenic mice in which cardiac hypertrophy occurred by 4 weeks of age and progressed to heart failure by 9-12 months. This hypertrophy was associated with increased expression of proto-oncogenes, hypertrophy marker genes, growth factors, and cytokines, with symptoms that mimicked those of human cardiomyopathy, functionally and morphologically. This model provided a unique opportunity to analyze gene clusters that are differentially up-regulated during initiation of hypertrophy versus transition of hypertrophy to heart failure. Importantly, changes in gene expression observed during initiation of hypertrophy were significantly different from those seen during its transition to heart failure. Our data show that overexpression of myotrophin results in initiation of cardiac hypertrophy that progresses to heart failure, similar to changes in human heart failure. Knowledge of the changes that take place as a result of overexpression of myotrophin at both the cellular and molecular levels will suggest novel strategies for treatment to prevent hypertrophy and its progression to heart failure