Mao-Yuan M. Su

Diffusion Tensor Magnetic Resonance Imaging Mapping the Fiber Architecture Remodeling in Human Myocardium After Infarction Correlation With Viability and Wall Motion

Background— Diffusion tensor magnetic resonance imaging (DT-MRI) provides a means for nondestructive characterization of myocardial architecture. We used DT-MRI to investigate changes in direction-dependent water diffusivity to reflect alterations in tissue integrity (trace apparent diffusion coefficients [ADCs] and fractional anisotropy [FA]), as well as indicators of remodeling of fiber helix angles, in patients after myocardial infarction. Methods and Results— Thirty-seven patients (35 men, 2 women; median age, 59) after acute myocardial infarction (median interval from onset, 26 days) were enrolled. DT-MRI was performed at the midventricular level to measure trace ADC, FA, and helix angles of myofibers. Helix angles were grouped into left-handed helical fibers, circumferential fibers, and right-handed helical fibers. Measurements were correlated with viability and regional wall motion assessed by contrast-delay-enhancement and cine MRI, respectively. The infarct zone showed significantly increased trace ADC and decreased FA than the remote zone. The percentage of left-handed helical fibers increased from the remote zone (mean±SD, 13.3±5.8%) to the adjacent zone (19.2±9.7%) and infarct zone (25.8±18.4%) (MANOVA, P=0.004). The percentage of right-handed helical fibers decreased from the remote zone (35.0±9.0%) to the adjacent zone (25.5±11.5%) and infarct zone (15.9±9.2%) (P<0.001). Multiple linear regression showed that the percentage of left-handed helical fibers of the infarct zone was the strongest correlate of infarct size and predictor of ejection fraction. Conclusions— In vivo DT-MRI of postinfarct myocardium revealed a significant increase in trace ADC and a decrease in FA, indicating altered tissue integrity. The redistribution of fiber architecture correlated with infarct size and left ventricular function. This technique may help us understand structural correlates of functional remodeling after infarction.

Sequential Changes of Myocardial Microstructure in Patients Postmyocardial Infarction by Diffusion-Tensor Cardiac Mr Correlation with Left Ventricular Structure and Function

Background—We used diffusion-tensor cardiac MR to investigate myocardial microstructure changes, including tissue integrity (mean diffusivity [MD], fractional anisotropy) and fiber architecture (helix angles) in patients with recent myocardial infarction (MI). This study aimed to investigate the sequential changes of myocardial microstructure and its relationships with changes of macrostructure and function of the left ventricle post-MI. Methods and Results—Seventeen patients (age, 55.1±11.5 years; all men) participated in the follow-up study. Diffusion-tensor cardiac MR, cine gradient echo for left ventricle function, and late gadolinium enhancement for viability were measured from recent to chronic MI (median interval, 191 days). When compared with the remote zone, the infarct-adjacent zone showed overall increase of MD (2-way MANOVA, F1,16=36.3; P<0.001), decrease of fractional anisotropy (F1,16=5.8; P=0.029), and decrease of mean helix angles (F1,16=62.0; P<0.001). From recent to chronic MI, there was overall sequential decrease of MD (F1,16=22.6; P<0.001) and increase of fractional anisotropy (F1,16=7.8; P=0.013). Multiple linear regression showed that the improvement of wall thickening in the infarct-adjacent zone correlated with sequential decrease of MD in the infarct-adjacent zone (r=−0.70; P=0.002) and increase of mean helix angles (ie, more right-handed helical myofiber reorientation, predominantly subendocardial location) in the remote zone (r=0.60; P=0.011). Likewise, wall thickening in the remote zone correlated with MD in the remote zone (r=−0.72; P=0.001) and mean helix angles in the infarct-adjacent zone (r=0.72; P=0.001). Conclusion—Diffusion-tensor cardiac MR suggests that sequential zonal improvement of tissue integrity and fiber architecture remodeling both associate with sequential recovery of zonal wall thickening of the left ventricle from recent to chronic MI.

CMR-Verified Diffuse Myocardial Fibrosis Is Associated With Diastolic Dysfunction in HFpEF

OBJECTIVES The purpose of this study was to investigate diffuse myocardial fibrosis in patients with systolic heart failure (SHF) and in patients with heart failure with preserved ejection fraction (HFpEF) and the association with diastolic dysfunction of the left ventricle (LV). BACKGROUND Increased diffuse myocardial fibrosis may impair LV diastolic function. However, no study has verified the association between the degree of diffuse myocardial fibrosis and the severity of impaired diastolic function in SHF and HFpEF. METHODS Forty patients with SHF, 62 patients with HFpEF, and 22 patients without HF underwent cardiac magnetic resonance (CMR), including T1 mapping and cine CMR on a 3-T system. Extracellular volume fraction (ECV), a measure of diffuse myocardial fibrosis, was quantified from T1 mapping. Systolic and diastolic functions of the LV were assessed by cine CMR. The ECV values and LV functional indexes were compared among the 3 groups. Associations between ECV and LV diastolic function were also investigated. RESULTS Compared with patients without HF, significantly higher ECV was found in patients with SHF (31.2% [interquartile range (IQR): 29.0% to 34.1%] vs. 27.9% [IQR: 26.2% to 29.4%], p < 0.001) and HFpEF (28.9% [IQR: 27.8% to 31.3%] vs. 27.9% [IQR: 26.2% to 29.4%], p = 0.006). Peak filling rate, a diastolic functional index assessed by cine CMR, was significantly decreased in patients with SHF (1.00 s(-1) [IQR: 0.79 to 1.49 s(-1)] vs. 3.86 s(-1) [IQR: 3.34 to 4.48 s(-1)], p < 0.001) and HFpEF (2.89 s(-1) [IQR: 2.13 to 3.50 s(-1)] vs. 3.86 s(-1) [IQR: 3.34 to 4.48 s(-1)], p < 0.001). Myocardial ECV was significantly correlated with peak filling rate in the HFpEF group (r = -0.385, p = 0.002), but no correlation was found in the SHF and non-HF groups (r = 0.030, p = 0.856 and r = -0.238, p = 0.285, respectively). CONCLUSIONS In patients with HF, only those with HFpEF show a significant correlation between increased diffuse myocardial fibrosis and impaired diastolic function. Diffuse myocardial fibrosis plays a unique role in the pathogenesis of HFpEF.

Effect of Cardiac Rehabilitation on Myocardial Perfusion Reserve in Postinfarction Patients

Cardiac rehabilitation is believed to increase myocardial perfusion reserve (MPR), but this has not been adequately studied because of poor delineation of infarcted myocardium in previous studies. The purpose of this study was to determine the effect of cardiac rehabilitation on MPR in the remote and infarcted myocardium with contrast-enhanced magnetic resonance imaging; 39 postinfarction patients were recruited for this study and randomly assigned to a training group (n = 20) or a nontraining group (n = 19). Those in the training group participated in a 3-month rehabilitation training program at an exercise intensity of 55% to 70% of peak oxygen uptake (VO2); those in the nontraining group continued their usual lifestyle. Nineteen age-, weight-, and height-matched subjects without cardiovascular risk factors were selected as healthy controls. After myocardial infarction, a reduction in perfusion reserve was seen not only in the infarcted myocardium, but also in the remote myocardium. In the training group, exercise capacity increased by 15% (p <0.01), to the same level as in healthy controls. The post-training MPR increased in both remote (30%, p <0.01) and infarcted myocardium (25%, p <0.05) and reached the same level as in healthy controls. The change in exercise capacity correlated with the change in MPR in the remote myocardium (r = 0.55, p <0.001 for peak VO2). In the nontraining group, exercise capacity and MPR were unchanged. In conclusion, cardiac rehabilitation improves perfusion reserve in both infarcted and remote myocardium, with a parallel increase in exercise capacity.

Effect of cardiac rehabilitation on angiogenic cytokines in postinfarction patients

Objective: To determine whether cardiac rehabilitation influences plasma levels of angiogenic cytokines and their correlation with myocardial blood flow (MBF). Design: Randomised controlled study. Setting: Tertiary cardiac centre. Patients: 39 postinfarction patients randomised to either a 3-month training group (n = 20) or a non-training group (n = 19), and 19 normal controls. Interventions: Cardiac rehabilitation. Main outcome measures: MBF by cardiac magnetic resonance imaging, and plasma levels of stem cell factor (SCF), stromal-derived factor-1 (SDF-1), and vascular endothelial growth factor (VEGF) measured at enrolment and at 3 months after randomisation. Results: At baseline, when compared with the healthy subjects, postinfarction patients had a lower MBF in the infarcted myocardium during dipyridamole-induced stress (1.65 (0.58) vs 2.77 (0.78) ml/min/g, p<0.001) but higher plasma levels of VEGF (3.65 (0.75) vs 2.77 (0.59) pg/ml, p<0.001 expressed as the natural logarithm) and SDF-1 (2113 (345) vs 1869 (309) pg/ml, p = 0.009). Only SDF-1 was inversely associated with stress MBF in both remote (r = −0.39, p = 0.03) and infarcted myocardium (r = −0.62, p<0.001). After 3 months, the training group’s stress MBF had increased by 33% in the remote (p<0.001) and 28% in infarcted myocardium (p = 0.02), while VEGF decreased by 9% (p = 0.01), and SDF-1 decreased by 11% (p = 0.02). The change in SDF-1 was inversely correlated with the change in stress MBF in both remote (r = −0.40, p = 0.01) and infarcted myocardium (r = −0.50, p = 0.001). In the non-training group, MBF and cytokines were unchanged. Conclusion: Cardiac rehabilitation improves stress MBF in postinfarction patients, with an inverse decrease in circulating angiogenic cytokines.

First-Pass Myocardial Perfusion Cardiovascular Magnetic Resonance at 3 Tesla

PURPOSE To test the feasibility of first-pass contrast-enhanced myocardial perfusion imaging at 3 Tesla and to evaluate the change in perfusion index between normal, remote and ischemic myocardium, we obtained perfusion index from healthy subjects and patients with coronary artery stenosis. MATERIALS AND METHODS First-pass contrast-enhanced perfusion imaging was performed on 12 patients and 32 age-matched healthy subjects in both rest and dipyridamole-induced stress states. After bolus injection of contrast agent, Gd-DTPA with dose of 0.025 mmol/kg body weight and injection time of 1.5 s, three short-axis images from apex to base of the left ventricle (LV) were acquired for 80 cardiac cycles using saturation recovery turbo FLASH sequence. The maximal upslope (Upslope) was derived from the signal-time curves of the LV cavity and myocardium to measure myocardial perfusion. Within 72 hours after cardiovascular magnetic resonance examination, patients received coronary angiography, and the results were correlated with cardiovascular magnetic resonance results. RESULTS Using our protocol of contrast agent administration, sufficient perfusion contrast was obtained without susceptibility-induced signal drop-out at the interface between LV cavity and the myocardium. In healthy volunteers, Upslope showed no dependence on myocardial segments or coronary territories. Upslope increased significantly from rest to stress in normal myocardium (0.09 +/- 0.03 vs. 0.16 +/- 0.05, p < 0.001) and remote myocardium (0.09 +/- 0.03 vs. 0.13 +/- 0.03, p < 0.001), whereas in ischemic myocardium the change was insignificant (0.11 +/- 0.03 vs. 0.10 +/- 0.04, p = ns). This resulted in significant difference in the ratio of Upslope at stress to that at rest, representing myocardial perfusion reserve, between ischemic and non-ischemic myocardium (0.96 +/- 0.41 vs. 1.71 +/- 0.42, p < 0.001 for ischemic vs. normal myocardium; 0.96 +/- 0.41 vs. 1.59 +/- 0.40, p < 0.001 for ischemic vs. remote myocardium). CONCLUSIONS First-pass gadolinium-enhanced myocardial perfusion imaging at 3 Tesla is feasible. The Upslope ratio can differentiate ischemic from non-ischemic myocardium.

Circulating biomarkers of collagen type I metabolism mark the right ventricular fibrosis and adverse markers of clinical outcome in adults with repaired tetralogy of Fallot

BACKGROUND Right ventricular (RV) fibrosis is common in patients with repaired tetralogy of Fallot (rTOF). Although accumulating evidence indicates the role of circulating biomarkers of collagen metabolism in left ventricular fibrosis, rTOF data are lacking. This study examined the expression profile and clinical relevance of circulating biomarkers of collagen type I metabolism in rTOF patients. METHODS Serum biomarkers of collagen type I synthesis (carboxy-terminal propeptide of procollagen type I, PICP), degradation (carboxy-terminal telopeptide of collagen type I, CITP), and enzymes regulating collagen degradation (matrix metalloproteinases, and type I tissue inhibitor, TIMP-1) were measured in 70 rTOF and 91 control adults. All patients had complete clinical data and received cardiovascular magnetic resonance scans with late gadolinium enhancement (LGE). RESULTS Compared to the controls, rTOF patients had higher PICP levels (p<0.001), PICP:CITP ratios (p<0.001), and TIMP-1 concentrations (p<0.001). Increasing PICP levels correlated with higher RV LGE scores (r=0.427, p<0.001), lower VO2max (r=-0.428, p=0.002), and larger RV volumes. Furthermore, stepwise multivariate linear regression analysis identified RV end-diastolic volume index >150mL/m(2) (β=40.52, p=0.016), RV LGE score (β=3.94, p=0.008), and age (β=-1.77, p=0.011) as independent correlates of circulating PICP levels. CONCLUSIONS Patients with rTOF exhibited a profibrotic state with excessive collagen type I synthesis and dysregulated degradation. Elevated circulating PICP levels might reflect RV fibrosis, and link to adverse markers of clinical outcome.

CXCR4 antagonist TG-0054 mobilizes mesenchymal stem cells, attenuates inflammation, and preserves cardiac systolic function in a porcine model of myocardial infarction

Interaction between chemokine stromal cell-derived factor 1 and the CXC chemokine receptor 4 (CXCR4) governs the sequestration and mobilization of bone marrow stem cells. We investigated the therapeutic potential of TG-0054, a novel CXCR4 antagonist, in attenuating cardiac dysfunction after myocardial infarction (MI). In miniature pigs (minipigs), TG-0054 mobilized CD34+CXCR4+, CD133+CXCR4+, and CD271+CXCR4+ cells into peripheral circulation. After isolation and expansion, TG-0054-mobilized CD271+ cells were proved to be mesenchymal stem cells (designated CD271-MSCs) since they had trilineage differentiation potential, surface markers of MSCs, and immunosuppressive effects on allogeneic lymphocyte proliferation. MI was induced in 22 minipigs using balloon occlusion of the left anterior descending coronary artery, followed by intravenous injections of 2.85 mg/kg of TG-0054 or saline at 3 days and 7 days post-MI. Serial MRI analyses revealed that TG-0054 treatment prevented left ventricular (LV) dysfunction at 12 weeks after MI (change of LV ejection fraction from baseline, −1.0 ± 6.2% in the TG-0054 group versus −7.9 ± 5.8% in the controls). The preserved cardiac function was accompanied by a significant decrease in the myocardial expression of TNF-α, IL-1β, and IL-6 at 7 days post-MI. Moreover, the plasma levels of TNF-α, IL-1β, and IL-6 were persistently suppressed by the TG-0054 treatment. Infusion of TG-0054-mobilized CD271-MSCs reduced both myocardial and plasma cytokine levels in a pattern, which is temporally correlated with TG-0054 treatment. This study demonstrated that TG-0054 improves the impaired LV contractility following MI, at least in part, by mobilizing MSCs to attenuate the postinfarction inflammation. This insight may facilitate exploring novel stem cell-based therapy for treating post-MI heart failure.

Contrast-enhanced MRI index of diffuse myocardial fibrosis is increased in primary aldosteronism.

To assess the degree of myocardial fibrosis in patients with primary aldosteronism (PA).

Conductive channels identified with contrast-enhanced MR imaging predict ventricular tachycardia in systolic heart failure.

OBJECTIVES This study evaluated whether the conductive channel (CC) identified by late gadolinium enhanced-cardiac magnetic resonance (LGE-CMR) is associated with ventricular tachycardia (VT) in patients with systolic heart failure (HF). BACKGROUND One recent study demonstrated that the CC formed by heterogeneous tissue within the core scar could be detected by LGE-CMR and that the CC is responsible for clinical VT. We hypothesized that the CC could help identify HF patients at risk for VT. METHODS A total of 63 patients from a CMR database with left ventricular ejection fraction (LVEF) below 50% and with hyperenhancement on LGE-CMR were included. The cine and LGE images were analyzed to derive the LV function and scar characteristics, and to identify the CC. The outcomes, including VT, ventricular fibrillation (VF), and total mortality, were obtained by reviewing medical records. RESULTS After a median 1,379 (interquartile range: 271 to 1,896) days of follow-up, 8 patients had VT/VF attacks and 14 patients died. Among the CMR-measured parameters, only the probability of identifying the CC by LGE-CMR was higher in patients with VT/VF than those without VT/VF (75.0% vs. 16.4%, p < 0.001). The probability of identifying the CC was also higher in the total mortality group than the survival group (50.0% vs. 16.3%, p = 0.004). The other LGE-CMR variables were not significantly different between the 2 groups. A univariate Cox regression model showed that CC identification was positively associated with VT/VF attacks (hazard ratio [HR]: 27.032, 95% confidence interval [CI]: 3.291 to 222.054, p = 0.002) and excess total mortality (HR: 4.766, 95% CI: 1.643 to 13.824, p = 0.004). The LVEF was inversely associated with VT/VF attacks (HR: 0.119, 95% CI: 0.015 to 0.977, p = 0.048) and excess total mortality (HR: 0.491, 95% CI: 0.261 to 0.925, p = 0.028) during follow-up. CONCLUSIONS We demonstrated that CC identification using LGE-CMR can help identify HF patients at risk for VT/VF.