OBJECTIVES: The purpose of this study was to test the hypothesis, with noninvasive multimodality imaging, that allogeneic mesenchymal stem cells (MSCs) produce and/or stimulate active cardiac regeneration in vivo after myocardial infarction (MI).

BACKGROUND: Although intramyocardial injection of allogeneic MSCs improves global cardiac function after MI, the mechanism(s) underlying this phenomenon are incompletely understood.

METHODS: We employed magnetic resonance imaging (MRI) and multi-detector computed tomography (MDCT) imaging in MSC-treated pigs (n = 10) and control subjects (n = 12) serially for a 2-month period after anterior MI. A sub-endocardial rim of tissue, demonstrated with MDCT, was assessed for regional contraction with MRI tagging. Rim thickness was also measured on gross pathological specimens, to confirm the findings of the MDCT imaging, and the size of cardiomyocytes was measured in the sub-endocardial rim and the non-infarct zone.

RESULTS: Multi-detector computed tomography demonstrated increasing thickness of sub-endocardial viable myocardium in the infarct zone in MSC-treated animals (1.0 ± 0.2 mm to 2.0 ± 0.3 mm, 1 and 8 weeks after MI, respectively, p = 0.028, n = 4) and a corresponding reduction in infarct scar (5.1 ± 0.5 mm to 3.6 ± 0.2 mm, p = 0.044). No changes occurred in control subjects (n = 4). Tagging MRI demonstrated time-dependent recovery of active contractility paralleling new tissue appearance. This rim was composed of morphologically normal cardiomyocytes, which were smaller in MSC-treated versus control subjects (11.6 ± 0.2 µm vs. 12.6 ± 0.2 µm, p < 0.05).

CONCLUSIONS: With serially obtained MRI and MDCT, we demonstrate in vivo reappearance of myocardial tissue in the MI zone accompanied by time-dependent restoration of contractile function. These data are consistent with a regenerative process, highlight the value of noninvasive multimodality imaging to assess the structural and functional basis for myocardial regenerative strategies, and have potential clinical applications.

Journal of the American College of Cardiology, 2006. 48(10): p. 2116-2124.

10.1016/j.jacc.2006.06.073.

http://content.onlinejacc.org/cgi/content/full/48/10/2116

Aims: We sought to determine whether intra-aortic balloon pump (IABP) counterpulsation improves the recovery of left ventricular (LV) systolic function after reperfused acute myocardial infarction (AMI).

Methods and results: Fourteen dogs underwent 90‐min coronary artery occlusion followed by reperfusion. Seven animals were randomized to IABP counterpulsation immediately after reperfusion. Tagged, cine, and contrast-enhanced magnetic resonance imaging were used for regional and global LV functional assessment and MI characterization, respectively. Image acquisition was performed at 1 h, 6 h, and 24 h after reperfusion, during which the IABP device was paused.
Animals randomized to IABP demonstrated an earlier improvement of LV ejection fraction when compared with controls (25±3 vs. 25±2% at 1 h, P=0.91; 36±3 vs. 26±2% at 6 h, P=0.015; and 38±3 vs. 35±1% at 24 h, P=0.34). Regional functional analyses revealed the same behaviour among non-infarcted risk regions, i.e., earlier circumferential systolic strain improvement in the IABP group than in controls (−5.4±0.4 vs. −5.3±0.5% at 1 h, P=0.86; −12.1±1.0 vs. −6.0±0.4% at 6 h, P<0.001; and −13.9±1.1% vs. −12.8±0.6% at 24 h, P=0.40). Importantly, however, the degree of LV functional recovery 24 h after reperfusion was similar whether IABP counterpulsation was used or not.

Conclusion: IABP counterpulsation accelerates but does not significantly improve the recovery of LV systolic function after reperfused AMI.

European Heart Journal, 2005. 26(12): p. 1235-1241.

10.1093/eurheartj/ehi137.

http://eurheartj.oxfordjournals.org/content/26/12/1235.full

Aims: This study was designed to characterise both the systolic and diastolic mechanical properties of regions with different degrees of myocardial ischaemic injury after reperfused acute myocardial infarction (AMI).

Methods and Results: Fourteen dogs underwent 90-min coronary artery occlusion followed by reperfusion. Image acquisition was performed 24 h after reperfusion using three techniques: tagged, first-pass perfusion and delayed-enhancement magnetic resonance imaging (MRI). Systolic circumferential strain and both systolic and diastolic strain rates were calculated in 30 segments/animal. Transmural AMI segments displayed reduced systolic contractility when compared to subendocardial AMI segments (systolic strain=–2.5±0.5% versus –6.0±0.9%, P<0.01 and systolic strain rate=–0.11±0.12 versus –0.82±0.16 s–1, P<0.01), and both exhibited significant systolic and diastolic dysfunction compared to remote. Moreover, AMI segments presenting with microvascular obstruction ("no-reflow") displayed further compromise of systolic and diastolic regional function (P<0.05 for both). Importantly, risk region segments only exhibited diastolic impairment (diastolic strain rate=1.62±0.14 versus 2.99±0.13 s–1, P<0.001), but not systolic dysfunction compared to remote 24 h after reperfusion.

Conclusion: Reversibly injured regions can demonstrate persistent diastolic dysfunction despite complete systolic functional recovery after reperfused AMI. Moreover, the presence of no-reflow entails profound systolic and diastolic dysfunction. Finally, tagged magnetic resonance imaging (MRI) strain rate analysis provides detailed mechanical characterisation of regions with different degrees of myocardial ischaemic injury.

European Heart Journal, 2004. 25(16): p. 1419-1427.

10.1016/j.ehj.2004.06.024.

http://eurheartj.oxfordjournals.org/content/25/16/1419.full

Background: In compensated aortic stenosis (AS), cardiac performance measured at the ventricular chamber is typically supranormal, whereas measurements at the myocardium are often impaired. We investigated intramyocardial mechanics after aortic valve replacement (AVR) and the effects relative to the presence or absence of coronary artery disease (CAD+ or CAD–), respectively.

Methods and Results: Twenty-nine patients (46 to 91years, 10 female) with late but not decompensated AS underwent cardiovascular MRI before AVR (PRE), with follow-up at 6±1 (EARLY) and 13±2 months (LATE) to determine radiofrequency tissue-tagged left ventricle (LV) transmural circumferential strain, torsion, structure, and function. At the myocardial level, concentric LV hypertrophy regressed 18% LATE (93±22 versus 77±17g/m2; P<0.0001), whereas at the LV chamber level, ejection fraction was supranormal PRE, 67±6% (ranging as high as 83%) decreasing to 59±6% LATE (P<0.05), representing not dysfunction but a return to more normal LV physiology. Between the CAD+ and CAD– groups, intramyocardial strain was similar PRE (19±10 versus 20±10) but different LATE, with dichotomization specifically related to the CAD state. In the CAD– patients, strain increased to 23±10% (+20%), whereas in CAD+ patients it fell to 16±11% (–26%), representing a nearly 50% decline after AVR (P<0.05). This was particularly evident at the apex, where CAD– strain LATE improved 17%, whereas for CAD+ it decreased 2.5-fold. Transmural strain and myocardial torsion followed a similar pattern, critically dependent on CAD. AVR impacted LV geometry and mitral apparatus, resulting in decreased mitral regurgitation, negating the double valve consideration.

Conclusions: In AS patients after AVR, reverse remodeling of the supranormal systolic function parallels improvement in cardiovascular MRI-derived regression of LV hypertrophy and LV intramyocardial strain. However, discordant effects are evident after AVR, driven by CAD status, suggesting that the typical AVR benefits are experienced disproportionately by those without CAD and not by those obliged to undergo concomitant coronary artery bypass grafting/AVR.

Circulation, 2005. 112(9_suppl): p. I-429-436.

10.1161/CIRCULATIONAHA.104.525501.

http://circ.ahajournals.org/cgi/content/abstract/circulationaha;112/9_suppl/I-429

Purpose: To retrospectively evaluate with dynamic magnetic resonance (MR) imaging the changes in global and regional left ventricular (LV) function after surgical ventricular restoration (SVR) performed in chronic ischemic heart disease patients with large nonaneurysmal or aneurysmal postmyocardial infarction zones.

Materials and Methods: The study was performed with institutional review board approval, and a waiver of individual informed consent was obtained. The study was HIPAA compliant. Patients (83 men, 22 women; mean age, 61 years ± 9 [standard deviation]) were evaluated with MR imaging before and after SVR as follows: pre-SVR examination (n = 105; 25 days ± 39 before SVR; median, 7 days; range, 1–189 days), early post-SVR examination (n = 95, 7 days ± 3 after SVR), and late post-SVR (n = 35, 313 days ± 158 after SVR). Cine MR imaging allowed calculation of ejection fraction and rate-corrected velocity of circumferential fiber shortening (VcfC) for global LV functional evaluation, whereas tagged MR imaging (spatial modulation of magnetization with harmonic phase analysis) permitted assessment of regional circumferential strain (EC) with coronary distribution. VcfC and EC were computed at both LV base- and mid-LV short-axis levels remote from the site of anteroapical SVR.

Results: Prior to SVR, LV dilatation and diminished global and regional LV function were observed. At early post-SVR examination, VcfC had improved significantly but EC showed a worsening trend overall, although only EC of the right coronary artery at the mid-LV level worsened significantly. At late post-SVR examination, VcfC values were improved when compared with pre-SVR values, although EC showed no statistically significant improvement. When compared with that at early post-SVR examination, however, EC showed significant improvement in two segments: left anterior descending artery and right coronary artery at mid-LV level.

Conclusion: Although volume-based indexes of global LV function improve significantly after SVR, regional LV function did not improve significantly; there was evidence of continued LV remodeling after SVR.

Radiology, 2006. 241(3): p. 710-717.

10.1148/radiol.2413051440.

http://radiology.rsna.org/content/241/3/710.full

Two-dimensional (2-D) strain (ε2-D) on the basis of speckle tracking is a new technique for strain measurement. This study sought to validate ε2-D and tissue velocity imaging (TVI)–based strain (εTVI) with tagged harmonic-phase (HARP) magnetic resonance imaging (MRI). Thirty patients (mean age 62 ± 11 years) with known or suspected ischemic heart disease were evaluated. Wall motion (wall motion score index 1.55 ± 0.46) was assessed by an expert observer. Three apical images were obtained for longitudinal strain (16 segments) and 3 short-axis images for radial and circumferential strain (18 segments). Radial εTVI was obtained in the posterior wall. HARP MRI was used to measure principal strain, expressed as maximal length change in each direction. Values for ε2-D, εTVI, and HARP MRI were comparable for all 3 strain directions and were reduced in dysfunctional segments. The mean difference and correlation between longitudinal ε2-D and HARP MRI (2.1 ± 5.5%, r = 0.51, p <0.001) were similar to those between longitudinal εTVI and HARP MRI (1.1 ± 6.7%, r = 0.40, p <0.001). The mean difference and correlation were more favorable between radial ε2-D and HARP MRI (0.4 ± 10.2%, r = 0.60, p <0.001) than between radial εTVI and HARP MRI (3.4 ± 10.5%, r = 0.47, p <0.001). For circumferential strain, the mean difference and correlation between ε2-D and HARP MRI were 0.7 ± 5.4% and r = 0.51 (p <0.001), respectively.
In conclusion, the modest correlations of echocardiographic and HARP MRI strain reflect the technical challenges of the 2 techniques. Nonetheless, ε2-D provides a reliable tool to quantify regional function, with radial measurements being more accurate and feasible than with TVI. Unlike εTVI, ε2-D provides circumferential measurements.

The American Journal of Cardiology, 2006. 97(11): p. 1661-1666.

10.1016/j.amjcard.2005.12.063.

http://www.ajconline.org/article/S0002-9149(06)00381-X/abstract

Current patient selection criteria for Cardiac Resynchronization Therapy (CRT), an efficacious treatment for heart failure, include no measure of disconjugate cardiac contractility other than prolonged QRS on electrocardiogram. Using cardiac magnetic resonance imaging, we examined the roles of cardiac asymmetry, asynchrony, and circumferential strain in DCC with the principal aim of generating a robust numerical index for use in future trials of CRT. Standard cardiac magnetic resonance imaging was done on a GE 1.5 Tesla Signa LX MRI clinical scanner (GE Healthcare, Milwaukee, WI, USA) and analyzed by MASS Analysis (MEDIS, Leiden, The Netherlands). The methods were evaluated in eleven patients with advanced heart failure due to ischemic and non-ischemic cardiomyopathy, who did not qualify under current criteria for CRT, five CRT candidates pre-op and eleven normal subjects. Using t-test and standardized differences (SD = sd/diff, Power (N) = number of patients to reach p < .05) we determined efficacy. Indices of asymmetry and asynchrony (Ism and Isn, respectively) could be measured with accuracy and provided excellent statistical power when used as surrogate markers to delineate heart failure and CRT patients from control subjects. Asymmetry and asynchrony in heart contraction are both critical components of dilated cardiomyopathy that can be improved by CRT. Magnetic resonance asynchrony is efficacious in screening patients and should now be compared with recently published echocardiography data to improve outcome for this costly but valuable therapy.

Journal of Cardiovascular Magnetic Resonance, 2005. 7(5): p. 827 - 834.

10.1080/10976640500287992

http://informahealthcare.com/doi/abs/10.1080/10976640500287992?journalCode=lcmr

OBJECTIVES: This study sought to determine whether increased carotid intima-media thickness (IMT) is related to reduced regional myocardial function in participants of the Multi-Ethnic Study of Atherosclerosis (MESA).

BACKGROUND: Carotid artery IMT is an established index of subclinical atherosclerosis, and tagged magnetic resonance imaging (MRI) can detect incipient alterations of segmental function that precede overt myocardial failure.

METHODS: The MESA study is a prospective observational study including four ethnic groups free from clinical cardiovascular disease. Peak midwall systolic circumferential strain (ECC) and regional strain rates were calculated by harmonic phase from tagged MRI data of 500 participants. Systolic ECC and diastolic strain rate were regressed on IMT of the common carotid artery defined by ultrasound, with adjustments for body mass index, blood pressure, cholesterol, diabetes, smoking, left ventricular hypertrophy, C-reactive protein, age, and gender.

RESULTS: The mean participant age was 66 ± 10 years (mean ± SD). Among the 58 participants, 4% were male and the interquartile (25th to 75th percentile) range for IMT was 0.25 mm. Multiple linear regression analyses showed that increased IMT was related to reduced systolic regional function (less shortening ECC) in all myocardial regions (p < 0.05), except in the inferior wall. The analyses also showed that greater IMT was associated with a lower diastolic strain rate (diastolic reduced function) in all regions (p < 0.01), except in the anterior wall.

CONCLUSIONS: Greater carotid IMT is associated with alterations of myocardial strain parameters reflecting reduced systolic and diastolic myocardial function. These observations indicate a relationship between subclinical atherosclerosis and incipient myocardial dysfunction in a population free of clinical heart disease.

Journal of the American College of Cardiology, 2006. 47(12): p. 2420-2428.

10.1016/j.jacc.2005.12.075.

http://content.onlinejacc.org/cgi/content/full/47/12/2420

Purpose: To prospectively determine whether mechanical behavior of left ventricular wall segments that contain different degrees of scar tissue and are located at different distances from the interface between infarcted and noninfarcted myocardial tissue can help predict inducibility of monomorphic ventricular tachycardia (VT) in patients with ischemic cardiomyopathy.

Materials and Methods: This HIPAA-compliant study was institutional review board approved; written informed consent was obtained from all patients. Forty-six patients (36 men, 10 women; mean age ± standard deviation, 61.6 years ± 11.9) with prior myocardial infarction (MI) and left ventricular dysfunction were referred for defibrillator implantation and underwent an electrophysiologic examination and tagged contrast-enhanced magnetic resonance (MR) imaging. Peak circumferential shortening strain (Ecc) and time to peak Ecc were measured in 12 segments from short-axis sections. Remote, adjacent, and border zones were defined according to increasing proximity to the MI. Patients in whom monomorphic VT could be induced (ie, inducible patients) were considered positive for inducibility. Relationships between inducibility of monomorphic VT, peak Ecc, and time to peak Ecc were analyzed with one-way analysis of variance and Bonferroni test.

Results: Inducible patients had more infarcted and border zone sectors and a shorter time to peak Ecc than did noninducible patients in the border zone and adjacent and infarcted regions (P < .001). Peak Ecc in the border zone of inducible patients (−11.42% ± 0.46 [standard error]) was greater than that in noninducible patients (−10.18% ± 0.38; P < .05). Ratio of Ecc in border zone and in remote regions was greater (P < .05) in inducible patients than in noninducible patients (1.31 ± 0.27 vs 0.64 ± 0.13, respectively).

Conclusion: Enhanced border zone function defined as greater Ecc and earlier time to peak Ecc showed positive correlation to VT inducibility in patients with prior MI and left ventricular dysfunction.

Radiology, 2007. 245(3): p. 712-719.

10.1148/radiol.2452061615.

http://radiology.rsna.org/content/245/3/712.abstract

Background: Left ventricular (LV) torsion is due to oppositely directed apical and basal rotation and has been proposed as a sensitive marker of LV function. In the present study, we introduce and validate speckle tracking echocardiography (STE) as a method for assessment of LV rotation and torsion.

Methods and Results: Apical and basal rotation by STE was measured from short-axis images by automatic frame-to-frame tracking of gray-scale speckle patterns. Rotation was calculated as the average angular displacement of 9 regions relative to the center of a best-fit circle through the same regions. As reference methods we used sonomicrometry in anesthetized dogs during baseline, dobutamine infusion, and apical ischemia, and magnetic resonance imaging (MRI) tagging in healthy humans. In dogs, the mean peak apical rotation was –3.7±1.2° (±SD) and –4.1±1.2°, and basal rotation was 1.9±1.5° and 2.0±1.2° by sonomicrometry and STE, respectively. Rotations by both methods increased (P<0.001) during dobutamine infusion. Apical rotation by both methods decreased during left anterior descending coronary artery occlusion (P<0.007), whereas basal rotation was unchanged. In healthy humans, apical rotation was –11.6±3.8° and –10.9±3.3°, and basal rotation was 4.8±1.7° and 4.6±1.3° by MRI tagging and STE, respectively. Torsion measurement by STE showed good correlation and agreement with sonomicrometry (r=0.94, P<0.001) and MRI (r=0.85, P<0.001).

Conclusions: The present study demonstrates that regional LV rotation and torsion can be measured accurately by STE, suggesting a new echocardiographic approach for quantification of LV systolic function.

Circulation, 2005. 112(20): p. 3149-3156.

10.1161/CIRCULATIONAHA.104.531558.

http://circ.ahajournals.org/cgi/content/short/112/20/3149