OBJECTIVES The purpose was to examine the cardioprotective effects of recombinant P-selectin glycoprotein ligand-immunoglobulin (rPSGL-Ig) in ischemia-reperfusion injury by real-time myocardial contrast echocardiography (MCE). BACKGROUND P-selectin mediates leukocyte recruitment into areas of inflammation. METHODS Sixteen pigs underwent 45 min of left anterior descending coronary artery occlusion followed by reperfusion and received rPSGL-Ig or vehicle. To assess changes in myocardial perfusion (A ), MCE was performed. RESULTS After 120 min of reperfusion, A in the risk area was higher (0.84 0.15 dB/s vs. 0.28 0.1 dB/s, p 0.0001), and the infarct size was lower (30.3 12% vs. 57 14%, p 0.002) in the rPSGL-Ig group compared with the vehicle group. CONCLUSIONS Recombinant PSGL-Ig improved postischemic reflow accurately detected by real-time MCE. (J Am Coll Cardiol 2004;44:887–91) © 2004 by the American College of Cardiology Foundation

OBJECTIVES:We investigated whether cardiac computed tomography (CCT) can determine intraventricular dyssynchrony in comparison to real-time three-dimensional echocardiography (RT3DE) in patients who are considered for cardiac resynchronisation therapy (CRT).METHODS:35 patients considered for CRT were examined. Left ventricular (LV) dyssynchrony was quantified by calculating the standard deviation index (SDI) of 17 myocardial LV segments by RT3DE and ECG-gated contrast-enhanced 64-slice dual-source CCT. For both analyses the same software algorithm (4D LV-Analysis) was used.RESULTS:Close correlations were observed for end-systolic volume, end-diastolic volume and LV ejection fraction between the two techniques (r = 0.94, r = 0.92 and r = 0.95, respectively, P < 0.001 for all). For the global dyssynchrony index SDI, a high correlation was found between RT3DE and CCT (r = 0.84, P < 0.001), which further increased after exclusion of segments with poor image quality by echocardiography (r = 0.90, P < 0.001). The required time for quantitative analysis was significantly shorter (162 ± 22 s vs. 608 ± 112 s per patient, P < 0.001) and reproducibility was significantly higher for CCT compared with RT3DE (interobserver variability of 4.5 ± 3.1% vs. 7.9 ± 6.1%, P < 0.05).CONCLUSION:Quantitative assessment of LV dyssynchrony is feasible by CCT. Owing to its higher reproducibility and faster analysis time compared with RT3DE, this technique may represent a valuable alternative for dyssynchrony assessment.KEY POINTS:• Quantitative assessment of left ventricular dyssynchrony is feasible by cardiac computed tomography (CCT). • This technique has been compared with real-time three-dimensional echocardiography (RT3DE). • Reproducibility is significantly higher for CCT compared with RT3DE. • Time spent for analysis is significantly shorter for CCT. • Computed tomography may represent a valuable alternative to ultrasound for dyssynchrony assessment.

A 21-year-old male German patient, was referred to our intensive care unit from a peripheral hospital with severe septic illness and fever. The echocardiographic investigation revealed a massive pericardial thickening of at least 20 mm mainly located posterolateral and inferior, without typical pericardial effusion. An inspiratory diastolic septal shift to the left, as well as pathological respiratory PW-Doppler profiles of mitral and tricuspid inflow velocities could clearly been detected in the examination. The patient describes at the interview in our intensive care unit, that he has previously been well, without any symptoms of cardiac failure or joint pain. We diagnosed an adult onset Still's disease (AOSD). Thus, prednisone pulse-therapy was initiated with 250 mg and reduced stepwise in the following days. All the symptoms improved dramatically within a few days. The documented pericardial thickening showed a significant reduction to approximately 6 mm already after 4 days of therapy AOSD should not be forgotten in the differential diagnosis of pericardial disease due to its potentially life threatening complications. Usually, echocardiography reveals typical pericardial effusion. In this case the patient presented with an impressing, atypical thickening of the pericardium in the posterolateral region, hardly ever seen in AOSD.

Cardiac myocyte growth is under differential control of mammalian target of rapamycin (mTOR) and glycogen‐synthase‐kinase‐3β (GSK3β). Whereas active GSK3β negatively regulates growth and down‐regulates cellular protein synthesis, activation of the mTOR pathway promotes protein expression and cell growth. Here we report that depletion of mTOR via siRNA mediated knockdown causes marked down‐regulation of GSK3β protein in cardiac myocytes. As a result, GSK3β target protein β‐catenin becomes stabilized and translocates into the nucleus. Moreover, mTOR knockdown leads to increase in cardiac myocyte surface area and produces an up‐regulation of the fetal gene program. Our findings suggest a new type of convergence of mTOR and GSK3β activities, indicating that GSK3β‐dependent stabilization of β‐catenin in cardiac myocytes is influenced by mTOR.

The evolutionary conserved Wnt signaling pathway regulates cardiogenesis. However, members of the Wnt pathway are also expressed in the adult heart. Although Wnt-signaling is quiescent under normal conditions, we noticed activation on pathological stress of the heart, such as chronic afterload increase. To examine the role of Wnt signaling on the postnatal heart, we modified the expression and function of the Wnt regulator dishevelled 1 (Dvl-1) both in transgenic mice with cardiac-specific overexpression of Dvl-1 (Dvl-1-Tg) and in cultured cardiac myocytes. Dvl-1-Tg mice (3 months) had severe cardiac hypertrophy (heart weight:body weight ratio: 5.2±0.3 mg/g wild-type [WT] versus 6.4±0.7 mg/g Dvl-1-Tg; P <0.01), an increase in cardiomyocyte size (86% increase in Dvl-1-Tg compared with WT; P <0.01) and marked raise of atrial natriuretic factor expression (12-fold increase versus WT; P <0.01). Hypertrophy was associated with left ventricular dilatation in Dvl-1-Tg and a reduction of ejection fraction (4.4±0.1 mm versus 5.5±0.2 mm, 80±2% and 43±4% in WT versus Dvl-1-Tg, respectively; P <0.01). Transgenic animals died prematurely before 6 months of age. Both canonical as well as noncanonical Wnt signaling branches were activated in the Dvl-1-Tg animals. Small interfering RNA–mediated depletion of Dvl-1 was used to further characterize the role of Dvl-1 in cardiac myocytes. Whereas baseline parameters were unaltered, β-adrenergic hypertrophic response was abrogated in Dvl-1 knockdown cardiac myocytes, indicating a mandatory role in β-adrenergic stimulation. Therefore, activation of Wnt signaling is sufficient and critical for the induction of myocardial hypertrophy and cardiomyopathy.

A 78‐year‐old male patient was referred cardiovascular risk evaluation before elective resection of a bronchial carcinoma. A myocardial infarction with a subsequent coronary artery bypass revascularization and a mitral prosthetic valve surgery were known. Left lateral decubitus (LLD) was permanently avoided because of significant trepopnea since several years. No signs of heart failure were found in the physical examination. A mitral valve prosthesis presented normal characteristics at examination. Left ventricular dimensions and function were normal. A severe tricuspid regurgitation could be documented during examination in the LLD, with changing characteristics in dorsal decubitus, when it could be graded as moderate. Trepopnea associated with severe paroxysmal tricuspid regurgitation was never described before in the literature. Sympathetic/parasympathetic modulation of papillary muscles of the tricuspid valve can be proposed as a probable cause of this dynamic valvular dysfunction. (Echocardiography 2010;27:E77‐E79)

Introduction: A prerequisite of hypertrophic response of the myocardium is an increase in protein synthesis. A central regulator of translation initiation is eIF2B, the Guanine Nucleotide Exchange ...

INTRODUCTION:Congenital abnormalities of the mitral valve are considered to be very rare cardiac anomalies. In particular, more severe malformations, such as the complete absence of either aortic (anterior) or mural (posterior) mitral leaflet, are usually considered to be incompatible with life. Ebstein-like malformation of the mitral valve is an extremely rare form of mitral valve deformity hitherto unreported in an asymptomatic adult patient.MATERIALS AND METHODS:The detection of such a malformation prompted us to perform a prospective analysis of 26,484 consecutive comprehensive 2D-echocardiographic examinations, conducted at our tertiary care university hospital between April 2007 and July 2008, with regard to the presence of malformations of the mitral valvular apparatus.RESULTS:In total, we found three cases of hypoplastic or even absent functional mural valve leaflets. All were diagnosed in adult patients who attended our outpatient department and were surprisingly asymptomatic regarding this finding. From our patient cohort, we calculate an actual prevalence of asymptomatic hypoplasia of the mitral valve of 1:8,800.CONCLUSIONS:Our findings broaden the spectrum of known mitral valve pathologies. The comparatively high prevalence of this malformation in our preselected patient cohort might indicate that this particular malformation has so far been under-diagnosed. In the context of this observation, both embryological development of the atrioventricular (AV) valves and recent functional insights into mitral valve physiology gained by mitral valve reconstructive surgery are discussed.

Intravenous delivery of mesenchymal stem cells (MSCs) preserves myocardial function after infarction. This dose-escalating study was performed to examine pathologic remodeling and scar formation in a pig model of permanent coronary occlusion without restoration of reperfusion. MSCs labeled with fluorescent dye 48 h or saline (negative control, n = 8) were given intravenously 48 h post proximal left anterior descending artery occlusion. Animals received either autologous or allogeneic MSCs in doses from 1 x 10(3) up to 1 x 10(6) per kg bodyweight from an unrelated donor pig. Infarct size and myocardial function were assessed after 1 month. Morphologic analysis revealed that labeled autologous MSCs migrated in the peri-infarct region resulting in smaller infarct size (19 +/- 7% vs. 32 +/- 7%, p < 0.008) and higher fractional area shortening (33 +/- 7% vs. 21 +/- 3%, p < 0.001). Similarly, allogeneic MSCs had dose-dependent beneficial effects on cardiac function, statistically significant at 1 x 10(5) and 1 x 10(6) cells per kg bodyweight. Autologous as well as allogeneic MSCs specifically "home" to the heart after systemic delivery, leading to limited myocardial infarct size and improved functional outcome, even without coronary reperfusion. Therefore, intravenously administration of MSCs is an attractive minimal-invasive approach for cardiac tissue repair.

Objectives. Intravenous delivery of mesenchymal stem cells (MSCs) is an attractive approach for regeneration of infarcted myocardium. However, its efficacy is not well-defined in large animals. Methods. Pigs (n =8) received intravenously autologous, allogeneic porcine or human MSCs (1106 per kg bodyweight) labeled with fluorescent dye 48 hours post proximal LAD occlusion. Infarct size, histology and myocardial function were assessed 4 weeks later. Results. Labeled MSCs migrated in the peri-infarct region resulting in improved myocardial function. Infarct size was larger in the control group (327%) compared to autologous (197%, p =0.008), allogeneic (244%, p =0.01) and human MSCs (265%, p =0.03). Fractional area shortening significantly increased after 4 weeks in pigs receiving autologous MSCs (347%, p =0.001), allogeneic MSCs (282%, p =0.004) and human MSCs (245%, p =0.027), but was lower in the control group (233%, n.s.). However, substantial callus formation and a non-malignant cardiac tumor containing mesenchymal tissue was observed in one animal treated with human MSCs. Conclusions. Intravenously administered MSCs prevent pathologic remodeling and scar formation but bare potential risks from inflammatory-related products.

Background: Inhibition of β-adrenergic signaling plays a key role in treatment of heart failure. GSα (excitatory subunit of Gα-protein) is essential for β-adrenergic signal transduction. Transgenic...

OBJECTIVES:Intravenous delivery of mesenchymal stem cell (MSC) is a noninvasive approach for myocardial tissue repair. We aimed to test this strategy in a pig model of myocardial infarction and to examine the usefulness of new echocardiographic applications to monitor cardioprotective effects of stem cell therapy.METHODS:Pigs (n = 8) received autologous or allogeneic MSCs (1 x 10(6)/kg body weight) labeled with fluorescent dye 48 hours after proximal left anterior descending coronary artery occlusion. Infarct size, myocardial function, and perfusion (A x beta) were assessed by myocardial contrast echocardiography and standard histologic methods after 1 month.RESULTS:Morphologic analysis revealed that labeled MSCs migrated in the peri-infarct region resulting in smaller infarct size by myocardial contrast echocardiography (control vs autologous and allogeneic MSC: 38 +/- 10% vs 25 +/- 5% and 28 +/- 6%, P < .01), higher fractional area shortening (23 +/- 3% vs 34.0 +/- 7% and 28 +/- 2%, P < .01), higher cardiac synchrony (167 +/- 36 vs 68 +/- 17 and 85 +/- 26 milliseconds, P < .003), and improved microvascular flow A x beta in the ischemic border zone (0.18 +/- 0.2 vs 0.56 +/- 0.3 and 0.49 +/- 0.2, P < .03).CONCLUSIONS:Systemic delivery of autologous and allogeneic MSCs preserves myocardial viability even in large animals and is, therefore, an attractive approach for tissue repair. Myocardial contrast echocardiography is useful to evaluate microvascular perfusion, which was enhanced by MSCs.

Systemic delivery of bone marrow-derived mesenchymal stem cells (MSCs) is a noninvasive approach for myocardial repair. We aimed to test this strategy in a pig model of myocardial infarction. Pigs (n = 8) received autologous MSCs (1 x 10(6)/kg body weight) labeled with fluorescent dye 48 h post proximal left anterior descending artery (LAD) occlusion. Hemodyamics, infarct size, and myocardial function were assessed at baseline and after 1 month. Morphologic analysis revealed that labeled MSCs migrated in the peri-infarct region, resulting in smaller infarct size (32 +/- 7 vs. 19 +/- 7%, p = 0.01), higher fractional area shortening (23 +/- 3 vs. 34.0 +/- 7%, p = 0.001), lower left ventricular end diastolic pressure (18.7 +/- 5 vs. 10.2 +/- 4 mmHg, p = 0.02) and higher +dp/dt (4,570 +/- 540 vs. 6,742 +/- 700 mmHg/s, p = 0.03) during inotropic stimulation. Systemic intravenous delivery of MSCs to pigs limits myocardial infarct size and is an attractive approach for tissue repair.

Background: Real-time myocardial contrast echocardiography (MCE) is increasingly used to assess myocardial perfusion. However, objective methods for evaluating MCE are not yet widely available. We sought to validate the ability of Fourier analysis applied to MCE to assess serial changes in microvascular perfusion during coronary occlusion and reperfusion. Methods: Six pigs underwent 45 min of left anterior descending coronary artery (LAD) occlusion followed by 120 min of reperfusion. Real time MCE was performed at baseline, during coronary occlusion, and at 5, 30, 60 and 120 min of reperfusion. Signal intensities from replenishment curves were fitted to an exponential function to obtain plateau SI (A) and the rate of SI rise (b). MCE images were mathematically transformed using a first-harmonic Fourier algorithm displaying the sequence of myocardial intensity changes as phase angles in parametric images. The phase angle difference (PD) of posterior vs. anterior region was calculated as an index of myocardial opacification heterogeneity and compared to MCE index of myocardial blood flow A×b. Results: After initial hyperemia, a progressive reduction in flow was observed during reperfusion. During LAD occlusion signal intensities were significantly reduced in anterior regions (A×b= 0.02 ± 0.01) compared to baseline (1.2 ± 0.34, p < 0.01) defining risk areas and approached higher levels postrecanalization (A×b= 1.48 ± 0.6) but gradually decreased during 120 min of reperfusion (A= 0.51 ± 0.3, p < 0.01). Similarly, profiles of phase angles in LAD perfusion territorities were consistently modified during reperfusion. The mean PD at baseline was 18°± 15°. PD decreased during coronary occlusion to −108°± 38°, increased to 29°± 19° postrecanalization but decreased to −61°± 35° after 120 min of reperfusion. PD significantly correlated with A(r= 0.8, p < 0.0001) and b(r= 0.73, p < 0.0001). Conclusions: The progressive reduction in post-ischemic microvascular perfusion was accurately detected by real-time MCE. Fourier phase imaging is feasible to quantify dynamics of myocardial opacification in a simple and objective format and is a promising approach for the interpretation of contrast echocardiograms.