Sung-A Chang

Differential Effect of Intracoronary Infusion of Mobilized Peripheral Blood Stem Cells by Granulocyte Colony–Stimulating Factor on Left Ventricular Function and Remodeling in Patients With Acute Myocardial Infarction Versus Old Myocardial Infarction The MAGIC Cell-3-DES Randomized, Controlled Trial

Background— The efficacy of intracoronary infusion of granulocyte colony-stimulating factor (G-CSF) mobilized peripheral blood stem cells (PBSCs) has not been compared between patients with acute (AMI) versus old myocardial infarction (OMI). In addition, the potential risk of restenosis associated with G-CSF–based stem cell therapy has not been evaluated in the setting of drug eluting stent (DES) implantation. Methods and Results— We randomly allocated 96 patients with myocardial infarction who underwent coronary revascularization with DES for the culprit lesion into 4 groups. Eighty-two patients completed 6-month follow-up; AMI cell infusion (n=25), AMI control (n=25), OMI cell infusion (n=16), and OMI control group (n=16). In cell infusion groups, PBSCs were mobilized by G-CSF for 3 days and delivered to infarcted myocardium via intracoronary infusion. The AMI cell infusion group showed a significant additive improvement in left ventricular ejection fraction (LVEF) and remodeling compared with controls (change of LVEF: +5.1±9.1% versus −0.2±8.6%, P<0.05; change of end-systolic volume: −5.4±17.0 mL versus 6.5±21.9 mL, P<0.05). In OMI patients, however, there was no significant change of LVEF and ventricular remodeling in spite of significant improvement of coronary flow reserve after cell infusion. G-CSF–based cell therapy did not aggravate neointimal growth with DES implantation. Conclusions— Intracoronary infusion of mobilized PBSCs with G-CSF improves LVEF and remodeling in patients with AMI but is less definite in patients with OMI. G-CSF–based stem cell therapy with DES implantation is both feasible and safe, eliminating any potential for restenosis.

Usefulness of 64-slice multidetector computed tomography as an initial diagnostic approach in patients with acute chest pain.

BACKGROUND Recently, multidetector computed tomography (MDCT) has been proposed as an accurate diagnostic tool to evaluate for coronary artery disease. However, the role of MDCT as part of the initial diagnostic for evaluating acute chest pain is less well established. METHODS We prospectively enrolled patients presenting with acute chest pain to the emergency department (ED) and risk stratified them based on the pretest probability for an acute coronary syndrome (ACS): (1) very low, (2) low, (3) intermediate, (4) high, and (5) very high or definite. After exclusion of very low and very high risk patients, 268 patients were randomized to either immediate 64-slice cardiac MDCT or a conventional diagnostic strategy. Number of admissions, ED and hospital length of stay (LOS), and major adverse cardiac events over 30 days of follow-up were compared between the strategies based on the pretest probability for ACS. RESULTS The number of patients ultimately diagnosed with an ACS did not differ between the 2 strategies. Emergency department LOS and total admissions were not different between strategies. Patients in the MDCT-based strategy had a decreased hospital LOS (P = .049) and fewer admissions deemed unnecessary (P = .007). Reductions in unnecessary admissions were more prominent in intermediate-risk patients (P = .015). None of the patients discharged from the ED in the MDCT-based strategy experienced major adverse cardiac events at follow-up. CONCLUSION Use of an MDCT-based strategy in the ED as part of the initial diagnostic approach for patients presenting with acute chest pain is safe and efficiently reduces avoidable admissions in patients with an intermediate pretest probability for ACS.

Impact of Myocardial Infarct Proteins and Oscillating Pressure on the Differentiation of Mesenchymal Stem Cells : Effect of Acute Myocardial Infarction on Stem Cell Differentiation

Stem cell transplantation in acute myocardial infarction (AMI) has emerged as a promising therapeutic option. We evaluated the impact of AMI on mesenchymal stem cell (MSC) differentiation into cardiomyocyte lineage. Cord blood‐derived human MSCs were exposed to in vitro conditions simulating in vivo environments of the beating heart with acute ischemia, as follows: (a) myocardial proteins or serum obtained from sham‐operated rats, and (b) myocardial proteins or serum from AMI rats, with or without application of oscillating pressure. Expression of cardiac‐specific markers on MSCs was greatly induced by the infarcted myocardial proteins, compared with the normal proteins. It was also induced by application of oscillating pressure to MSCs. Treatment of MSCs with infarcted myocardial proteins and oscillating pressure greatly augmented expression of cardiac‐specific genes. Such expression was blocked by inhibitor of transforming growth factor β1 (TGF‐β1) or bone morphogenetic protein‐2 (BMP‐2). In vitro cellular and electrophysiologic experiments showed that these differentiated MSCs expressing cardiomyocyte‐specific markers were able to make a coupling with cardiomyocytes but not to selfbeat. The pathophysiologic significance of in vitro results was confirmed using the rat AMI model. The protein amount of TGF‐β1 and BMP‐2 in myocardium of AMI was significantly higher than that in normal myocardium. When MSCs were transplanted to the heart and analyzed 8 weeks later, they expressed cardiomyocyte‐specific markers, leading to improved cardiac function. These in vitro and in vivo results suggest that infarct‐related biological and physical factors in AMI induce commitment of MSCs to cardiomyocyte‐like cells through TGF‐β/BMP‐2 pathways.

Impact of Loading Condition on the 2D Speckle Tracking–Derived Left Ventricular Dyssynchrony Index in Nonischemic Dilated Cardiomyopathy

Background—The effects of left ventricular (LV) loading conditions on LV dyssynchrony have not been elucidated. We modified LV loading conditions to reveal their effects on echocardiography-derived LV dyssynchrony index (LVdys) in patients with documented nonischemic dilated cardiomyopathy. Methods and Results—Thirty-seven patients were consecutively enrolled. After baseline measurements, pneumatic compression of the lower extremities (Pcom) was used to increase LV afterload. Subsequently, sublingual nitroglycerin (SL-NG) was administered to modify preload. Conventional echocardiographic parameters, LVdys (by speckle-tracking radial strain analysis) and LV end-systolic wall stress (LV-ESWS), were calculated under each condition. LVdys-6 (defined as the maximal difference in time-to-peak radial strain between 6 myocardial segments) and LV-ESWS increased under Pcom (for LVdys-6, 159±117 at baseline versus 239±140 ms under Pcom, P<0.05; for LV-ESWS, 191±63 versus 228±80 g/m2, P<0.05) After SL-NG application, both parameters decreased significantly (for LVdys-6, 239±140 under Pcom versus 147±103 ms after SL-NG, P<0.05; for LV-ESWS, 228±80 under Pcom versus 189±67 g/m2 after SL-NG, P<0.05). When the presence of LV dyssynchrony was defined as the absolute difference in time-to-peak radial strain between the anteroseptal and posterior segments (LVdys-2), the results were unchanged. Using 130 ms as a cutoff value, the proportion of patients with LV dyssynchrony changed significantly (29.7% at baseline, 45.9% under Pcom, and 35.1% after SL-NG). When the presence of LV dyssynchrony was defined as standard deviation of the time to peak radial strain for 6 segments (LVdys-SD), the results were same. LVdys and LV-ESWS showed a modest but significant association with each other (r=0.47, P<0.001 for LVdys-6; r=0.41, P<0.001 for LVdys-2; r=0.46, P<0.001 for LVdys-SD). Conclusions—To the best of our knowledge, the present study provides the first evidence of a significant association between LVdys and LV loading status, reflective of a dynamic nature of LVdys. Accordingly, LV loading conditions should be taken into account when echocardiographic LVdys is used for clinical decision-making of selecting candidates for cardiac resynchronization therapy or when it is used as a surrogate marker of prognosis.

Left ventricular twist mechanics in patients with apical hypertrophic cardiomyopathy: assessment with 2D speckle tracking echocardiography

Objective: Left ventricular (LV) apical rotation significantly contributes to LV twist, which has been reported to have a vital role in maintaining LV systolic and diastolic function. Apical hypertrophic cardiomyopathy (ApHCM) is a unique disease with pathological LV hypertrophy at the apex. We aimed (1) to evaluate LV twist mechanics in ApHCM and (2) to demonstrate the influence of predominantly local, pathological involvement of the apical myocardium on LV twist mechanics. Methods: 21 patients diagnosed with ApHCM were consecutively enrolled and compared with normal controls. After a standard echocardiographic examination, we scanned parasternal basal and apical short-axis planes to quantify LV rotations and LV twist using the speckle tracking technique. For better understanding of LV twist mechanics in ApHCM, LV radial and biplanar strains and LV twist-volume curve were also evaluated. Results: Compared with the normal controls, apical rotation was markedly decreased in ApHCM patients (p<0.001), but the decreases in basal rotation were not significant. As a consequence, LV twist was significantly lower in ApHCM patients (p = 0.007). Apical radial (p = 0.01) and biplanar (p<0.001) strains in ApHCM were also significantly decreased. Compared to normal controls, LV twist-volume and twist-radial displacement curves clearly showed a decrement in the slope of the linear systolic phase and a loss of an inflection point separating the early from late untwisting phase in ApHCM patients. Conclusion: LV twist in ApHCM was significantly decreased due to a reduction in apical rotation, suggesting that regional myocardial changes in ApHCM can modify the global LV twist mechanics. Given the close interconnection between LV systolic and diastolic function, impairment of LV twist may lead to the loss of early diastolic suction and finally generate diastolic dysfunction in ApHCM.

Velocity Vector Imaging in the Measurement of Left Ventricular Twist Mechanics: Head-to-Head One Way Comparison Between Speckle Tracking Echocardiography and Velocity Vector Imaging

BACKGROUND Velocity vector imaging (VVI) is based on myocardial feature tracking, which incorporates speckle and endocardial border tracking and allows myocardial strains, strain rates, and velocities to be quantified. However, the accuracies of VVI-derived left ventricular rotation-associated values have not been validated, and the aim of this study was thus to perform a head-to-head comparison of twist-related values determined by VVI and speckle-tracking echocardiography (STE). METHODS Thirty-five patients with a wide spectrum of cardiac pathologies and 19 healthy subjects (a total of 54 subjects) were enrolled. Apical and basal short-axis images were obtained using GE Vivid 7 scanners at frame rates of 80 to 100 frames/s. Left ventricular rotation-related parameters were first obtained using EchoPAC version 7.0.1. For comparison purposes, the same basal and apical short-axis images were converted into uncompressed Digital Imaging and Communications in Medicine format and subsequently analyzed using Syngo version 3.0, which uses a VVI tracking algorithm. RESULTS Basal and apical peak rotation and peak twist determined using STE and VVI were well correlated (r = 0.80, P < .001, r = 0.87, P < .001, and r = 0.90, P < .001, respectively). With regard to rotation velocities, peak rotation and derotation velocities were moderately correlated at the basal (r = 0.70, P < .001, and r = 0.72, P < .001, respectively) and apical (r = 0.66, P < .001, and r = 0.51, P < .001, respectively) levels. Furthermore, twist and untwist velocities were moderately correlated between the two methods. However, the timings of peak rotation and derotation velocities and twist and untwist velocities were only weakly correlated at the basal and apical levels. CONCLUSIONS VVI is a feasible modality for assessing twist-related parameters. Although VVI agreed well with STE for most of the rotation-related parameters, poor concordance was found between the two methods for a few parameters. It is hypothesized that this discrepancy originates from the different tracking algorithms used. The findings indicate that caution should be exercised when interpreting or comparing twist-related parameters obtained using different echocardiographic devices with proprietary image analyzers.

Effect of Rosuvastatin on Cardiac Remodeling, Function, and Progression to Heart Failure in Hypertensive Heart With Established Left Ventricular Hypertrophy

Hypertensive patients with left ventricular hypertrophy (LVH) are the most common high-risk group to develop heart failure with preserved ejection fraction. Recent reports have noted the favorable effect of statins on LVH. We evaluated the effect of rosuvastatin on cardiac remodeling, function, and progression to heart failure in a hypertensive rat model with established LVH. Dahl salt-sensitive rats were fed a high-salt diet until 13 weeks of age. After LVH was confirmed by echocardiography, rats were randomly assigned to control and statin treatment (n=18 each group). The statin-treated group was treated with rosuvastatin until 21 weeks of ages. Serial echocardiography, blood pressure monitoring, and miniaturized conductance catheter hemodynamic monitoring were performed at 21 weeks. Echocardiographic parameters were not significantly different between the groups. On hemodynamic monitoring, systolic performance parameters were similar between the groups, whereas end diastolic pressure-volume relationships were lower in the statin-treated group (0.014±0.008 versus 0.008±0.004 mm Hg/μL, P<0.05), suggesting improvement in myocardial stiffness. Pathological analysis showed attenuation of perivascular and interstitial fibrosis in the statin-treated group (P<0.02). Rosuvastatin therapy did not alleviate LVH in hypertensive rats with established LVH, but it attenuated myocardial fibrosis and LV stiffness. It seems that rosuvastatin has limited therapeutic value when used to prevent progression from LVH to heart failure in hypertensive hearts.

Restoration of left ventricular synchronous contraction after acute myocardial infarction by stem cell therapy: new insights into the therapeutic implication of stem cell therapy for acute myocardial infarction.

Objective: To evaluate the effects of stem cell therapy on restoration of the left ventricular (LV) synchronous contraction in patients with acute myocardial infarction (AMI). Methods: 40 patients with AMI who underwent successful coronary revascularisation were randomly allocated to the cell infusion or the control group. Evaluations were performed with echocardiographic tissue synchronisation imaging to determine LV dyssynchrony and with cardiac magnetic resonance imaging to estimate LV ejection fraction (LVEF) at baseline and at 6 months. To quantify the severity of systolic LV dyssynchrony, the standard deviations of time to peak systolic velocity of the 12 LV segments (Ts-SD) were calculated. Results: At 6 months, greater improvements of Ts-SD (ΔTs-SD: −45.0 (40.2) vs 5.0 (39.9) ms, p<0.001) and LVEF (ΔLVEF: 6.8% (9.1%) vs −0.2% (6.9%), p = 0.015) relative to the corresponding baseline values were observed in the cell infusion group than in the control group. By multivariate analysis, ΔTs-SD and baseline LVEF emerged as the independent determinants of LVEF improvement and cell infusion, and baseline Ts-SD as the determinant of ΔTs-SD improvement. Maximal exercise capacity measured by symptom-limited treadmill testing correlated well with Ts-SD but not with LVEF at 6 months of follow-up. Conclusion: Stem cell therapy had a favourable effect on the restoration of LV synchronous contraction in patients with AMI.

Comprehensive evaluation of coronary arteries by multidetector-row cardiac computed tomography according to the glucose level of asymptomatic individuals.

BACKGROUND Early detection of atherosclerosis in individuals with diabetes is important because of high cardiovascular mortality in this population. We performed multidetector-row computed tomography (MDCT) in asymptomatic individuals to investigate the status of coronary artery stenosis and plaque characteristics depending on the glucose level. METHODS AND RESULTS The plaque burden (number of diseased coronary segments), severity of stenosis, plaques characteristics, and coronary artery calcium score (CACS) were assessed by MDCT in 1043 asymptomatic individuals. Anthropometric parameters and metabolic profiles were also acquired. Twenty-one percents of subjects had plaques and 5% had significant stenosis. Mean (+/-S.D.) CACS of study population was 17+/-81. Subjects with impaired fasting glucose (IFG, n=215, 21%) or diabetes (n=112, 11%) had a greater plaque burden, more coronary stenosis (>50% of diameter stenosis) and higher CACS than normal subjects (all, p<0.01). Noncalcified and mixed plaques were observed more in subjects with diabetes (19%) and IFG (11%) than normal (7%). After adjustment for confounding factors, higher fasting glucose was strongly associated with significant coronary stenosis and a greater plaque burden. CONCLUSIONS More significant coronary stenosis and multivessel involvement, higher CACS, and greater plaque burden were observed in subjects with IFG or diabetes by MDCT, even they are asymptomatic. Proactive screening, irrespective of the imaging modalities used, in asymptomatic subjects with prediabetes and diabetes is helpful to identify those who have a higher cardiovascular morbidity and mortality. Further studies will guide us with respect to which imaging modality is more appropriate.

Role of pericardium in the maintenance of left ventricular twist

Background The role of pericardium in left ventricular (LV) twist has not been directly investigated. We sought to determine the role of pericardium in maintenance of LV twist function in an animal experiment, before and after pericardial opening. Methods 13 mongrel dogs were initially operated on, but two dogs were excluded from the final analyses owing to poor speckle tracking. Intraoperative echocardiography for conventional and speckle tracking measurements was performed at baseline with intact pericardium, and after pericardial opening. Using the speckle tracking technique, LV twist and strains were obtained before and after pericardial opening in 11 animals and additionally after pericardial repair in five animals. Results LV twist was significantly decreased after pericardial opening (10.1° (5.1°) to 7.4° (6.4°), p=0.001). LV twist and untwist rate were also decreased (115.0° (99.6°)/s to 66.7° (42.5°)/s for twist rate, −127.6° (74.3°)/s to −84.2° (734°)/s for untwist rate, p=0.015 and 0.009, respectively). LV stroke volume and ejection fraction were similar irrespective of pericardial opening, but radial strain measured at the mid ventricular level was significantly increased (31.7% (17.4%) to 32.3% (24.0%), p=0.02) after pericardial opening without changes in circumferential and longitudinal strains. LV twist degree was restored after pericardial repair. Conclusion The pericardium is an important structure for maintaining LV twist. Given no significant impact of the presence or absence of pericardium on LV systolic performance, an increase in LV radial strain serves as a compensatory mechanism to preserve LV systolic function despite a decrease in LV twist in the absence of pericardium.