Adjacent Noninfarcted Myocardium Research Articles

Targeted delivery of antibody conjugated liposomal drug carriers to rat myocardial infarction

Immunoliposome (IL) targeting to areas of inflammation after an acute myocardial infarction (MI) could provide the means by which pro-angiogenic compounds can be selectively targeted to the infarcted region. The adhesion of model drug carriers and ILs coated with an antibody to P-selectin was quantified in a rat model of MI following left coronary artery ligation. Anti-P-selectin coated model drug carriers showed a 140% and 180% increase in adhesion in the border zone of the MI 1 and 4 h post-MI, respectively. Radiolabeled anti-P-selectin ILs injected immediately post-MI and allowed to circulate 24 h showed an 83% increase in targeting to infarcted myocardium when compared to adjacent non-infarcted myocardium. Radiolabeled anti-P-selectin ILs injected 4 h post-MI and allowed to circulate for 24 h showed a 92% increase in accumulation in infarcted myocardium when compared to adjacent non-infarcted myocardium. Targeting to upregulated adhesion molecules on the endothelium provides a promising strategy for selectively delivering compounds to the infarct region of the myocardium using our liposomal-based drug delivery vehicle.

The Angiotensin II Type 2 Receptor and Improved Adjacent Region Function Post-MI

Angiotensin II type 2 receptor (AT2-R) overexpression in the mouse heart preserves left ventricular (LV) size and global LV function during post-MI remodeling. We hypothesized that CMR tagging would localize regional improvements in myocardial function during post-MI remodeling in AT2-R cardiac overexpressed transgenic mice (TG), which could explain the preservation of global LV function post-MI. Six male wild-type (WT) C57BL/6 mice and 10 TG mice were studied by CMR at baseline (day 0) and days 1, 7, and 28 post-MI. MI was induced by 1 hour occlusion of the LAD followed by reperfusion. On day 1 post-MI, gadolinium-DTPA was injected to assess infarct size. LV size and function was assessed by cine CMR. Mean % circumferential shortening (%CS) was calculated within infarcted, adjacent, and remote regions at each time point in WT and TG mice. Quantitative interstitial collagen and mean myocyte cross-sectional area was measured postmortem at day 28 post-MI. LV end-systolic volume was lower and ejection fraction higher at baseline in the TG group and these differences were maintained post-MI. Within infarcted and remote zones, although %CS was higher in TG mice at day 0, there was no difference by day 28 between groups. Within adjacent regions, while there was no difference at day 0 or 1 in TG vs. WT, %CS was significantly higher in TG mice by day 7, and these changes persisted out to day 28 post-MI. Regional interstitial collagen and myocyte size were similar between groups. Thus, myocardial tagging can detect regional differences in contractile function post-MI in TG mice, and AT2-R overexpression is associated with improved contractile function in adjacent noninfarcted myocardium.

Altered Excitation–Contraction Coupling in Myocytes from Remodeled Myocardium after Chronic Myocardial Infarction

Following myocardial infarction (MI), the left ventricle undergoes progressive dilatation and eccentric hypertrophy, i.eremodeling, which is greater in the adjacent than the remote region. The cellular mechanisms underlying these regional differences were studied. One (n=5) and 8 weeks (n=8) after anteroapical MI in sheep, cardiac myocytes were isolated from the adjacent and remote regions. At 8 weeks after MI, myocyte function in the remote region was not different from values either in sham controls (n=3) or animals 1 week after MI. At 8 weeks after MI, myocyte contractile function (% contraction) was decreased, P<0.01, in the adjacent region (6.4±0.4%), as compared with the remote region (8.8±0.5%) and was associated with decreased amplitude of Ca2+transients (adjacent, 0.69±0.09 v remote, 1.08±0.20, P<0.05) and L-type Ca2+current density (adjacent, 3.6±0.2 v remote, 4.8±0.2 pA/pF, P<0.05). Relaxation was also impaired significantly in myocytes from the adjacent region, associated with decreased protein levels of SERCA2a. The myocytes were hypertrophied more in the adjacent region than the remote region. Furthermore, focal areas of central myofibrillar lysis and increased glycogen deposition were observed in the adjacent region. These results indicate that impaired excitation–contraction coupling underlies dysfunction of myocytes from the adjacent non-infarcted myocardium after chronic MI, even in the absence of heart failure. Hypertrophy is implicated as the mechanism, since these changes were noted at 8 weeks, but not at 1 week after MI.

Differences in time course of myocardial mRNA expression in non-infarcted myocardium after myocardial infarction.

In non-infarcted myocardium after myocardial infarction, the change of cardiac phenotypic modulation of contractile protein, extracellular matrix and intracellular Ca2+ transport protein, such as sarcoplasmic reticulum Ca2+(SR-Ca2+)-ATPase, Na+-Ca2+ exchanger, have a important role during cardiac remodeling. However, the time course in this gene expression in the adjacent and remote left ventricular, or right ventricular myocardium after myocardial infarction has not been well examined. The purpose of this study was to examine the left ventricular function and regional cardiac gene expression after myocardial infarction. Myocardial infarction was produced in Wistar rats by the ligation of the left anterior descending coronary artery. After 3 weeks, 2 months and 4 months from myocardial infarction, we performed Doppler echocardiography and measured the systolic and diastolic function. Then, we analyzed the contractile protein, extracellular matrix and intracellular Ca2+ transport protein mRNAs of cardiac tissues in the adjacent and the remote noninfarcted myocardium, and right ventricular myocardium by Northern blot hybridization. Fractional shortening of infarcted heart progressively decreased. Peak early diastolic filling wave (E wave) velocity increased, and the deceleration rate of the E wave velocity was more rapid in myocardial infarction areas. Atrial filling wave (A wave) velocity decreased, resulting in a marked increase in the ratio of E wave to A wave velocity. Expression of myocardial alpha-skeletal actin, beta-MHC and ANP mRNA, or collagen I and III mRNA were higher at 3 weeks after myocardial infarction. SR Ca2+-ATPase mRNA in the adjacent non-infarcted myocardium was decreased at 2 months, and that in remote myocardium was decreased at 4 months after infarction. Na+-Ca2+ exchanger mRNA levels were increased at 3 weeks, but was decreased at 2 months in the adjacent non-infarcted myocardium and at 4 months in the remote myocardium. These findings suggest that the compensation for myocardial infarction by myocardial gene expression in non-infarcted myocardium may occur at an early phase after myocardial infarction, and myocardial dysfunction may begin from adjacent to remote non-infarcted myocardium during progressive cardiac remodeling.

Assessment of cardiac function and gene expression at an early phase after myocardial infarction.

The purpose of this study was to examine left ventricular function and cardiac gene expressions at an acute phase after myocardial infarction (MI). MI was induced in rats by ligation of the left coronary artery. Two days after MI, we performed Doppler-echocardiography and measured the systolic and diastolic function. We then analyzed the contractile protein and extracellular matrix mRNAs of cardiac tissues in the infarcted region, including the adjacent noninfarcted myocardium (the adjacent noninfarcted myocardium) and the remote noninfarcted myocardium, by Northern blot hybridization. Fractional shortening decreased significantly to 28%. Peak early diastolic filling wave (E wave) velocity increased in MI rats (MI; 90 +/- 3 cm/s versus the control; 71 +/- 2 cm/s, p < 0.05), and the deceleration rate of the E wave velocity was more rapid in MI rats (MI; 22.0 +/- 2.6 m/s2 versus the control; 16.5 +/- 2.0 m/s2, p < 0.01). Atrial filling wave (A wave) velocity decreased, resulting in a marked increase in the ratio of E wave to A wave velocity (MI; 3.1 +/- 0.3 versus the control; 2.1 +/- 0.2, p < 0.01). In the adjacent noninfarcted myocardium, mRNA levels for alpha-skeletal actin, atrial natriuretic polypeptide (ANP), transforming growth factor-beta 1(TGF-beta 1), fibronectin, and collagen types I and III increased significantly. In the remote noninfarcted myocardium, mRNA levels for alpha-skeletal actin, ANP, and collagen types I and III increased, while mRNA levels for beta-myosin heavy chain, TGF-beta 1 and fibronectin did not change. We observed left ventricular dysfunction and different gene expression between adjacent noninfarcted myocardium and in the remote noninfarcted myocardium two days after MI. These findings suggest that cardiac gene expression after MI may be a compensation reaction for cardiac dysfunction induced by myocardial damage.

Functional implications of myocardial scar structure.

During healing after myocardial infarction, scar collagen content and stiffness do not correlate. We studied regional mechanics and both area fraction and orientation of large collagen fibers 3 wk after coronary ligation in the pig. During passive inflation of isolated, arrested hearts, the scar tissue demonstrated significantly less circumferential strain but similar longitudinal and radial deformation in comparison with noninfarcted regions of the same hearts. The observed selective resistance to circumferential deformation was consistent with the finding that most of the large collagen fibers in the scar were oriented within 30 degrees of the local circumferential axis. Furthermore, data from a previous study indicate that during ventricular systole these scars resist circumferential stretching, whereas they deform similarly to noninfarcted myocardium in the longitudinal and radial directions. We conclude that large collagen fiber structure is an important determinant of scar mechanical properties and that scar anisotropy allows the scar to resist circumferential stretching while deforming compatibly with adjacent noninfarcted myocardium in the longitudinal and radial directions.

Differences in Expression of Sarcoplasmic Reticulum Ca2+-ATPase and Na+–Ca2+Exchanger Genes Between Adjacent and Remote Noninfarcted Myocardium After Myocardial Infarction

Although cardiac failure can develop over time after myocardial infarction, the mechanism responsible for this is still unknown. The change of intracellular Ca2+transport protein, such as sarcoplasmic reticulum (SR) Ca2+-ATPase (SR-Ca2+), Na+–Ca2+exchanger (Na+–Ca2+), or cardiac phenotypic modulation of contractile protein in noninfarcted myocardium may have a important role. However, the time course in gene expression of sarcoplasmic reticulum (SR) Ca2+-ATPase (SR-Ca2+), Na+–Ca2+exchanger (Na+–Ca2+), and contractile protein in the adjacent and remote noninfarcted myocardium after myocardial infarction has not been examined. At 1, 3 weeks and 3 months after myocardial infarction, hemodynamics were measured and mRNA of the left ventricle was analyzed. Left ventricular end-diastolic volume and weight increased both with time. Ascites became apparent at 3 months after infarction. SR-Ca2+mRNA levels in the adjacent noninfarcted myocardium were 0.7- (P<0.01), 0.9- (n.s.), and 0.7-fold (P<0.01) of control, and Na+–Ca2+mRNA levels were 2.1- (P<0.01), 1.4- (P<0.01), and 0.8-fold (P<0.01) of control, at 1, 3 weeks and 3 months after infarction, respectively.β-Myosin heavy chain (MHC) mRNA was increased to 2.1- (P<0.01), 1.5- (P<0.01), and 1.4-fold (P<0.01), andα-skeletal actin was increased to 2.4- (P<0.01), 3.8- (P<0.01), and 1.6-fold (P<0.01) control levels, at 1 week, 3 weeks and 3 months, respectively. In contrast,α-MHC mRNA level was decreased at 1 week and 3 months after infarction.α-cardiac actin mRNA level did not change over time after infarction. In the remote non-infarcted myocardium,β-MHC,α-skeletal actin, and Na+–Ca2+mRNA levels were increased, but SR-Ca2+,α-MHC, andα-cardiac actin mRNA did not change after infarction. These findings suggest that: (1) intracellular Ca2+handling system after myocardial infarction may be different between adjacent and remote non-infarcted myocardium; and that (2) both decreased gene expression of SR Ca2+-ATPase and Na+–Ca2+exchanger in the adjacent non-infarcted myocardium may progress cardiac dysfunction.

725-6 Persistent Intramyocardial Segmental Dysfunction After Anterior Infarction Treated with Reperfusion and ACE Inhibition

We have previously demonstrated intramyocardial segmental dysfunction throughout the LV in the first week after anterior myocardial infarction We used magnetic resonance tagging (MRI) to determine the evolution in regional intramyocardial function and LV mass index (LVMI), end-diastolic and end-systolic volumes (EDV, ESV), and ejection fraction (EF) during the first 8 weeks after anterior MI in patients treated with reperfusion and ACE inhibitors (ACEI). We studied 10 normals (7 male, 3 female, ages 43 ± 14) and 8 patients (7 male, age 52 ± 16) after first anterior MI with peak CK 2871 ± 2244 with MRI at day 6 ± 2 (week 1) and day 58 ± 10 (week 8) post-MI. All patients had isolated LAD disease and were reperfused with tPA (n = 1), PTCA (n = 3), or both (n = 4). All were treated with ACEI and 5 with β-blockers at both time points. Breath-hold, segmented k-space, TurboFlash, tagged images with the subject prone on an elliptical spine coil were obtained throughout systole with 7 mm thick short axis slices (n = 11 ± 2) spanning the LV from apex to base. Global parameters did not change over the 8 week period (mean ± S.D.):Empty CellWeek 1Week 8pLVMI (g/m2)114 ± 22118 ± 9NSEDV (ml)87 ± 27108 ± 24NSESV (ml)55 ± 1864 ± 29NSEF (%)36 ± 1142 ± 16NS Percent intramyocardial circumferential end-systolic segment shortening (%S) was measured at 3 transmural locations in each of the 4 regions on each LV short axis slice. Mean %S ± SO was compared by long axis locationEmpty CellNormalsPts. (Week 1)Pts. (Week 8)Apex (%)23.0 ± 2.96.3 ± 6.3*10.0 ± 3*,#Mid-ventricle (%)20.5 ± 2.68.6 ± 4.4*11.3 ± 4.3*Base (%)17.0 ± 4.911.3 ± 3.7*13.5 ± 3.2†*p &lt; 0.02 vs. normals#p &lt; 0.02 vs. 1 week†p = 0.07 vs. normals p &lt; 0.02 vs. normals p &lt; 0.02 vs. 1 week p = 0.07 vs. normals Significant improvement is limited to the apex, which includes infarcted and adjacent noninfarcted myocardium. while reperfusion and ACE inhibition blunt remodeling after anterior infarction, intramyocardial segmental function remains depressed throughout the left ventricle.

746-3 Impaired Wall Thickening of Adjacent Non-Infarcted Myocardium is Associated with Regional Myocyte Hypertrophy and Dysfunction During Post-Infarct Remodeling

Wall thickening (WT) is impaired in non-infarcted regions adjacent to Myocardial Infarction (MI) and is thought to be caused by mechanical overload and geometric chamber distortion. The contribution of abnormalities intrinsic to the myocyte to impaired WT during remodeling has not been examined. To correlate local WT in vivo with myocyte morphology and function during LV remodeling, magnetic resonance imaging (MRI) was performed 2 weeks after MI (left coronary artery ligation) by obtaining EKG-gated spin-echo shortaxis images (1.5 Tesla, 3 inch coil). Myocytes were isolated from 14 rats with MI and 4 shams. Local WT in regions adjacent (A) and remote (R) to the infarct scar visible by MRI was correlated with cell morphology and function, studied in myocytes isolated from A and R. MI size measured by planimetry ranged from 5% to 30% (mean 18.7%) of the outer LV area. Regional differences in local WT were present in MI hearts: average %WT in A was lower than in R (27.8 ± 6.14 (sem) vs 54.0 ± 10.17: p &lt; 0.01). In rats with large MI (MI &gt; 20%, n = 7). cells were longer than in sham (p &lt; 0.05: n = 175) both in R(143.1 ± 1.76 vs 120.9 ± 2.40 μm) and in A (150.3 ± 1.89 vs 122.6 ± 2.02 μm) while no changes were evidenced in cell width. Cells from A were longer than those from R(p &lt; 0.05). A positive correlation between MI size and cell length was found (for A: r = 0.8, slope 0.07). Electrically-stimulated cell contraction (see figure, %ES: cell shortening / diastolic length: values aTe mean ± sem), was impaired in A with respect to sham (**: p &lt; 0.05) and to R (*: p = 0.06). Thus, during post-MI remodeling, dysfunction in A non-infarcted regions is associated with greater myocyte elongation and dysfunction than in R. In conclusion, local myocyte dysfunction contributes to WT impairment in adjacent regions after MI.

Large animal model of left ventricular aneurysm

In 28 Dorsett sheep, ligation of the distal homonymous (equivalent to human left anterior descending) and second diagonal coronary arteries produced a constant transmural infarct of 22.9% ± 2.5% (mean ± standard deviation) of the left ventricular mass. Serial left ventriculograms showed that within four hours the infarct segment expands, wall thickness decreases, and aceurysmal dilalation occurs and progresses over the next 60 days in all sheep. Epicardial ventricular point references indicated that adjacent noninfarcted myocardium participates in the formation of the aneurysm. Anatomy of the coronary vasculature was studied in 22 excised sheep hearts. In sheep, coronary arterial anatomy is remarkably constant. The left coronary artery provides all of the blood supply to the left ventricle and septum and only a small rim of both the anterior and posterior right ventricles. Crdiac veins from the left ventricle drain into the coronary sinus, which also receives the left azygos vein. Right ventricular veins drain separately. The essentially separate coronary circulations to the two ventricles, the paucity of coronary collateral circulation, and the consistent evolution of left ventricular infants into aneurysms are important advantages of the ovine model for both metabolic and ventricular maechanical studies of acute myocardial infarction and left ventricular aneurysm.

Assessment of left ventricular wall thickness in healed myocardial infarction by magnetic resonance imaging

The ability of magnetic resonance imaging (MRI) to detect and localize healed myocardial infarction (MI) was assessed. Seventeen consecutive patients with healed MI assessed by biplane contrast ventriculography underwent MRI using oblique imaging planes. Seven normal subjects underwent MRI as controls. In each patient, ventriculography identified regional wall motion abnormalities. MRI, performed with a 0.15-Tesla resistive magnet and oblique imaging planes relating to the left ventricle, detected zones of regional wall thinning conforming to the wall motion abnormalities localized by ventriculography in 16 patients. In these patients, adjacent areas of intact myocardium were identified in areas shown by ventriculography to be normal. The left ventricular wall thickness at the site of MI was significantly less than adjacent noninfarcted myocardium (p less than 0.001) and normal hearts (p less than 10(-6)). The ratio of the thickness of the infarct to adjacent normal wall averaged 0.40 (range 0.22 to 0.62). MRI could differentiate healed MI from adjacent noninfarcted myocardium and normal hearts.