Myocardial scar as arrhythmia risk in patients with hypertrophic cardiomyopathy.

PURPOSE OF REVIEW: To provide an overview of the potential use of contrast-enhanced MRI as tool for further risk stratification in patients with hypertrophic cardiomyopathy (HCM). RECENT FINDINGS: The presence of scar measured by contrast-enhanced MRI has been shown to predict poor prognosis in several models of cardiomyopathy, including ischemic and nonischemic dilated cardiomyopathy. Current strategy to identify HCM patients who are at increased risk for sudden cardiac death is still not ideal. Recent data suggest that the presence of scar measured by contrast-enhanced MRI is a predictor of arrhythmias and poor prognosis in patients with HCM. SUMMARY: MRI is a potential technique to help identify HCM patients who are at risk for sudden cardiac death.

Characterization of peri-infarct zone heterogeneity by contrast-enhanced multidetector computed tomography: a comparison with magnetic resonance imaging.

OBJECTIVES: This study examined whether multidetector computed tomography (MDCT) improves the ability to define peri-infarct zone (PIZ) heterogeneity relative to magnetic resonance imaging (MRI). BACKGROUND: The PIZ as characterized by delayed contrast-enhancement (DE)-MRI identifies patients susceptible to ventricular arrhythmias and predicts outcome after myocardial infarction (MI). METHODS: Fifteen mini-pigs underwent coronary artery occlusion followed by reperfusion. Both MDCT and MRI were performed on the same day approximately 6 months after MI induction, followed by animal euthanization and ex vivo MRI (n = 5). Signal density threshold algorithms were applied to MRI and MDCT datasets reconstructed at various slice thicknesses (1 to 8 mm) to define the PIZ and to quantify partial volume effects. RESULTS: The DE-MDCT reconstructed at 8-mm slice thickness showed excellent correlation of infarct size with post-mortem pathology (r2 = 0.97; p < 0.0001) and MRI (r2 = 0.92; p < 0.0001). The DE-MDCT and -MRI were able to detect a PIZ in all animals, which correlates to a mixture of viable and nonviable myocytes at the PIZ by histology. The ex vivo DE-MRI PIZ volume decreased with slice thickness from 0.9 +/- 0.2 ml at 8 mm to 0.2 +/- 0.1 ml at 1 mm (p = 0.01). The PIZ volume/mass by DE-MDCT increased with decreasing slice thickness because of declining partial volume averaging in the PIZ, but was susceptible to increased image noise. CONCLUSIONS: A DE-MDCT provides a more detailed assessment of the PIZ in chronic MI and is less susceptible to partial volume effects than MRI. This increased resolution best reflects the extent of tissue mixture by histopathology and has the potential to further enhance the ability to define the substrate of malignant arrhythmia in ischemic heart disease noninvasively.

Early improvement in cardiac tissue perfusion due to mesenchymal stem cells.

The underlying mechanism(s) of improved left ventricular function (LV) due to mesenchymal stem cell (MSC) administration after myocardial infarction (MI) remains highly controversial. Myocardial regeneration and neovascularization, which leads to increased tissue perfusion, are proposed mechanisms. Here we demonstrate that delivery of MSCs 3 days after MI increased tissue perfusion in a manner that preceded improved LV function in a porcine model. MI was induced in pigs by 60-min occlusion of the left anterior descending coronary artery, followed by reperfusion. Pigs were assigned to receive intramyocardial injection of allogeneic MSCs (200 million, approximately 15 injections) (n = 10), placebo (n = 6), or no intervention (n = 8). Resting myocardial blood flow (MBF) was serially assessed by first-pass perfusion magnetic resonance imaging (MRI) over an 8-wk period. Over the first week, resting MBF in the infarct area of MSC-treated pigs increased compared with placebo-injected and untreated animals [0.17 +/- 0.03, 0.09 +/- 0.01, and 0.08 +/- 0.01, respectively, signal intensity ratio of MI to left ventricular blood pool (LVBP); P < 0.01 vs. placebo, P < 0.01 vs. nontreated]. In contrast, the signal intensity ratios of the three groups were indistinguishable at weeks 4 and 8. However, MSC-treated animals showed larger, more mature vessels and less apoptosis in the infarct zones and improved regional and global LV function at week 8. Together these findings suggest that an early increase in tissue perfusion precedes improvements in LV function and a reduction in apoptosis in MSC-treated hearts. Cardiac MRI-based measures of blood flow may be a useful tool to predict a successful myocardial regenerative process after MSC treatment.

The adult Göttingen minipig as a model for chronic heart failure after myocardial infarction: focus on cardiovascular imaging and regenerative therapies.

Porcine models have become increasingly popular in cardiovascular research. The standard farm pig rapidly increases in body weight and size, potentially confounding serial measurements of cardiac function and morphology. We developed an adult porcine model that does not show physiologic increases in heart mass during the study period and is suitable for long-term study. We compared adult minipigs with the commonly used adolescent Yorkshire swine. Myocardial infarction was induced in adult Göttingen minipigs and adolescent Yorkshire swine by occlusion of the left anterior descending coronary artery followed by reperfusion. At 8 wk after infarction, the left ventricular ejection fraction was 34.1 +/- 2.3% in minipigs and 30.7 +/- 2.0% in Yorkshire swine. The left ventricular end-diastolic mass in Yorkshire pigs assessed by magnetic resonance imaging increased 17 +/- 5 g, from 42.6 +/- 4.3 g at week 1 after infarction to 52.8 +/- 6.6 g at week 8, whereas it remained unchanged in minipigs. Cardiac anatomy and physiology in adult minipigs were evaluated invasively by angiography and noninvasively by Multidetector Computed Tomography and by Magnetic Resonance Imaging at 1.5 T and 3 T prior to myocardial infarction and during folow-up. This porcine heart failure model is reproducible, mimics the pathophysiology in patients who have experienced myocardial infarction, and is suitable for imaging studies. New heart failure therapies and devices can be tested preclinically in this adult animal model of chronic heart failure.

Chronic allopurinol administration ameliorates maladaptive alterations in Ca2+ cycling proteins and beta-adrenergic hyporesponsiveness in heart failure.

Xanthine oxidase (XO) activity contributes to both abnormal excitation-contraction (EC) coupling and cardiac remodeling in heart failure (HF). beta-Adrenergic hyporesponsiveness and abnormalities in Ca(2+) cycling proteins are mechanistically linked features of the HF phenotype. Accordingly, we hypothesized that XO influences beta-adrenergic responsiveness and expression of genes whose products participate in deranged EC coupling. We measured inotropic (dP/dt(max)), lusitropic (tau), and vascular (elastance; E(a)) responses to beta-adrenergic (beta-AR) stimulation with dobutamine in conscious dogs administered allopurinol (100 mg po daily) or placebo during a 4-wk induction of pacing HF. With HF induction, the decreases in both baseline and dobutamine-stimulated inotropic responses were offset by allopurinol. Additionally, allopurinol converted a vasoconstrictor effect to dobutamine to a vasodilator response and enhanced both lusitropic and preload reducing effects. To assess molecular correlates for this phenotype, we measured myocardial sarcoplasmic reticulum Ca(2+)-ATPase 2a (SERCA), phospholamban (PLB), phosphorylated PLB (P-PLB), and Na(+)/Ca(2+) transporter (NCX) gene expression and protein. Although SERCA mRNA and protein concentrations did not change with HF, both PLB and NCX were upregulated (P < 0.05). Additionally, P-PLB and protein kinase A activity were greatly reduced. Allopurinol ameliorated all of these molecular alterations and preserved the PLB-to-SERCA ratio. Preventing maladaptive alterations of Ca(2+) cycling proteins represents a novel mechanism for XO inhibition-mediated preservation of cardiac function in HF, raising the possibility that anti-oxidant therapies for HF may ameliorate transcriptional changes associated with adverse cardiac remodeling and beta-adrenergic hyporesponsiveness.

Multimodality noninvasive imaging demonstrates in vivo cardiac regeneration after mesenchymal stem cell therapy.

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 mum vs. 12.6 +/- 0.2 mum, 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.

Contrast-enhanced multidetector computed tomography viability imaging after myocardial infarction: characterization of myocyte death, microvascular obstruction, and chronic scar.

BACKGROUND: The ability to distinguish dysfunctional but viable myocardium from nonviable tissue has important prognostic implications after myocardial infarction. The purpose of this study was to validate the accuracy of contrast-enhanced multidetector computed tomography (MDCT) for quantifying myocardial necrosis, microvascular obstruction, and chronic scar after occlusion/reperfusion myocardial infarction. METHODS AND RESULTS: Ten dogs and 7 pigs underwent balloon occlusion of the left anterior descending coronary artery (LAD) followed by reperfusion. Contrast-enhanced (Visipaque, 150 mL, 325 mg/mL) MDCT (0.5 mm x 32 slice) was performed before occlusion and 90 minutes (canine) or 8 weeks (porcine) after reperfusion. MDCT images were analyzed to define infarct size/extent and microvascular obstruction and compared with postmortem myocardial staining (triphenyltetrazolium chloride) and microsphere blood flow measurements. Acute and chronic infarcts by MDCT were characterized by hyperenhancement, whereas regions of microvascular obstruction were characterized by hypoenhancement. MDCT infarct volume compared well with triphenyltetrazolium chloride staining (acute infarcts 21.1+/-7.2% versus 20.4+/-7.4%, mean difference 0.7%; chronic infarcts 4.15+/-1.93% versus 4.92+/-2.06%, mean difference -0.76%) and accurately reflected morphology and the transmural extent of injury in all animals. Peak hyperenhancement of infarcted regions occurred approximately 5 minutes after contrast injection. MDCT-derived regions of microvascular obstruction were also identified accurately in acute studies and correlated with reduced flow regions as measured by microsphere blood flow. CONCLUSIONS: The spatial extent of acute and healed myocardial infarction can be determined and quantified accurately with contrast-enhanced MDCT. This feature, combined with existing high-resolution MDCT coronary angiography, may have important implications for the comprehensive assessment of cardiovascular disease.

Cardiac repair with intramyocardial injection of allogeneic mesenchymal stem cells after myocardial infarction.

Although clinical trials of autologous whole bone marrow for cardiac repair demonstrate promising results, many practical and mechanistic issues regarding this therapy remain highly controversial. Here, we report the results of a randomized study of bone-marrow-derived mesenchymal stem cells, administered to pigs, which offer several new insights regarding cellular cardiomyoplasty. First, cells were safely injected by using a percutaneous-injection catheter 3 d after myocardial infarction. Second, cellular transplantation resulted in long-term engraftment, profound reduction in scar formation, and near-normalization of cardiac function. Third, transplanted cells were pre-prepared from an allogeneic donor and were not rejected, a major practical advance for widespread application of this therapy. Together, these findings demonstrate that the direct injection of cellular grafts into damaged myocardium is safe and effective in the perii-nfarct period. The direct delivery of cells to necrotic myocardium offers a valuable alternative to intracoronary cell injections, and the use of allogeneic mesenchymal stem cells provides a valuable strategy for cardiac regenerative therapy that avoids the need for preparing autologous cells from the recipient.

Xanthine oxidase inhibition ameliorates cardiovascular dysfunction in dogs with pacing-induced heart failure.

We hypothesized that chronic xanthine oxidase inhibition (XOI) would have favorable effects on both ventricular and vascular performance in evolving heart failure (HF), thereby preserving ventricular-vascular coupling. In HF, XOI reduces oxidative stress and improves both vascular and myocardial function. Dogs were randomized to receive either allopurinol (100 mg/day p.o.) or placebo following surgical instrumentation for chronic measurement of left-ventricular pressure and dimension and during induction of HF by rapid pacing. In the placebo group (n = 8), HF was characterized by increased LV end-diastolic pressure (LVEDP, 10.2 +/- 5.5 and 29.8 +/- 3.9 mmHg, before and after HF, respectively, P < 0.05), end-diastolic dimension (LVEDD, from 29.5 +/- 3.2 to 34.3 +/- 3.2 mm, P < 0.001), and afterload (arterial elastance, Ea, from 17.9 +/- 1.2 to 42.6 +/- 7.9 mmHg/mm, P < 0.05), and reduced contractility (End-systolic ventricular elastance, Ees, from 10.8 +/- 1.3 to 5.6 +/- 2.3 mmHg/mm, P < 0.05). Thus, ventricular-vascular coupling (Ees/Ea ratio) fell 57.6+/-9% (0.61 +/- 0.1 to 0.16 +/- 0.1, P < 0.05). Allopurinol (n = 9) profoundly attenuated both the Ea increase (from 22.3 +/- 3 to 25.6 +/- 4.6 mmHg/mm, P = NS) and the fall in Ees (from 11.8+/-1.1 to 11.7+/-1, P = NS), thereby preserving the Ees/Ea ratio (from 0.58 +/- 0.1 to 0.56 +/- 0.1, P < 0.001 vs. placebo). Allopurinol did not affect the increase in preload (LVEDP and LVEDD). XO cardiac mRNA and protein were similarly upregulated approximately fourfold in both groups. Allopurinol ameliorates increases in afterload and reductions in myocardial contractility during evolving HF, thereby preserving ventricular-vascular coupling. These results demonstrate a unique and potent hemodynamic profile of XOI, thereby providing further rationale for developing XOIs as a novel HF therapy.

The effect of intra-aortic balloon counterpulsation on left ventricular functional recovery early after acute myocardial infarction: a randomized experimental magnetic resonance imaging study.

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.

Accurate and objective infarct sizing by contrast-enhanced magnetic resonance imaging in a canine myocardial infarction model.

OBJECTIVES: To identify an accurate and reproducible method to define myocardial infarct (MI) size, we conducted a study in a closed-chest canine model of acute myocardial infarction, in which MI size was measured using different thresholding techniques and by imaging at different delay times after contrast administration. BACKGROUND: The MI size by contrast-enhanced magnetic resonance imaging (CE-MRI) is directly related to long-term prognosis. However, previous measurements were done using nonuniform methods and tended to overestimate nonviable areas. METHODS: Thirteen animals underwent 90 min of coronary artery occlusion, followed by reperfusion. The CE-MRI data were acquired within 24 h after reperfusion and compared with triphenyltetrazolium chloride pathology. In the first nine animals, images were obtained approximately 15 min after gadolinium diethylene triamine penta-acetic acid (Gd-DTPA) using an inversion-recovery gradient-echo pulse sequence. To identify the most accurate method, MI size by CE-MRI was measured visually and by semi-automatic thresholding techniques, using different criteria. In four additional animals, images were acquired every 6 min until 30 min after Gd-DTPA. RESULTS: Postmortem MI size was 13.5 +/- 2.6% of left ventricular volume. Semi-automatic techniques, using full-width at half-maximum (FWHM) criterion, correlated best with postmortem data (r(2) = 0.94, p < 0.001; results confirmed by Bland-Altman plots). Using FWHM, there was no difference in MI size between different delay times after contrast (15.2 +/- 2.9% to 14.5 +/- 4.2% at 6 and 30 min, respectively; p = NS). CONCLUSIONS: When an objective technique is used to define MI size by CE-MRI, accurate infarct size measurements can be obtained from images obtained up to 30 min after contrast administration.

Persistent diastolic dysfunction despite complete systolic functional recovery after reperfused acute myocardial infarction demonstrated by tagged magnetic resonance imaging.

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.

Late systolic onset of regional LV relaxation demonstrated in three-dimensional space by MRI tissue tagging.

Left ventricular (LV) relaxation entails myocardial deformation that induces LV filling. Yet, the precise mechanisms of the earliest changes in tissue properties that characterize myocardial relaxation remain incompletely understood. Ten healthy volunteers (seven males), 25-43 yr, underwent tagged and cine MRI with high temporal resolution (25-35 ms). Normal strains including radial (E(rr)), circumferential (E(cc)), and longitudinal (E(ll)) strains, shear strains including E(cl) (circumferential-longitudinal), E(cr) (circumferential-radial), and E(rl) (radial-longitudinal), and principal strains (E(1), E(2), and E(3)) were calculated using a displacement field-fitting method. Temporal changes in angular strains indicative of shear and torsion release and normal strains were studied during late systole and early relaxation. The onset of individual relaxation strains was heterogeneous relative to LV filling. Shear strains (E(cr), E(rl), and E(cl)) and radial thinning were first to develop. Times of onset of E(cr), E(rl), E(cl), and E(rr) occurred 108, 93, 67, and 73 ms before aortic valve closure, respectively. E(ll), E(cc), and LV volume change commenced significantly later after the onset of diastolic shear strains and radial thinning. The onset of E(cc), E(ll), and LV volume change was noted 38 ms before aortic valve closure (P < or = 0.05 relative to the onset of shear strains and E(rr)). Myocardial relaxation is characterized by a three-dimensional unfolding deformation that includes release of torsion, shear, and radial thinning beginning before aortic valve closure. This unfolding pattern precedes longitudinal and circumferential elongation and may facilitate early diastolic filling.

Reduction of "no-reflow" phenomenon by intra-aortic balloon counterpulsation in a randomized magnetic resonance imaging experimental study.

OBJECTIVES: Intra-aortic balloon counterpulsation (IABC) can improve post-myocardial infarction (MI) outcomes, but the mechanisms of such effect remain unclear. We hypothesized that IABC augmentation reduces the extent of microvascular obstruction after acute infarction. BACKGROUND: Microvascular obstruction or "no-reflow" (MO) has been shown to negatively influence left ventricular (LV) remodeling after myocardial infarction (MI). METHODS: Seventeen dogs underwent 90 min of coronary artery occlusion followed by reperfusion. Animals were then randomized to either IABC (n = 9) or control (n = 8); IABC augmentation was performed for 24 h after MI. Microvascular obstruction and infarct size by first-pass and delayed contrast-enhanced magnetic resonance imaging (MRI) were measured at 1 and 24 h after reperfusion and compared with postmortem infarct size and MO by microspheres. RESULTS: Microvascular obstruction by MRI, expressed as percent LV mass, decreased significantly in IABC (4.9 +/- 2.2% to 3.6 +/- 1.5%) and increased in controls (3.4 +/- 0.5% to 4.9 +/- 1.1% from 1 to 24 h, respectively; p < 0.001). Similar results were found for MO defined by microspheres. In the control group, MO increased significantly, during 24 h of study (from 8.8 +/- 1.7% to 43.2 +/- 11.1% of infarcted myocardium; p < 0.05), whereas not important change was observed in the IABC group (from 21.3 +/- 7.1% to 25.8 +/- 14.7%; p < 0.05 vs. control at 24 h). Infarct size, measured by MRI, increased in both groups (13.2 +/- 1.8 to 15.5 +/- 2.1 from 1 to 24 h, respectively; p < 0.05). CONCLUSIONS: Intra-aortic balloon counterpulsation augmentation performed after reperfusion improves myocardial perfusion at the tissue level, and reduces the extent of no-reflow caused by microvascular obstruction.

In vivo magnetic resonance imaging of mesenchymal stem cells in myocardial infarction.

BACKGROUND: We investigated the potential of magnetic resonance imaging (MRI) to track magnetically labeled mesenchymal stem cells (MR-MSCs) in a swine myocardial infarction (MI) model. METHODS AND RESULTS: Adult farm pigs (n=5) were subjected to closed-chest experimental MI. MR-MSCs (2.8 to 16x107 cells) were injected intramyocardially under x-ray fluoroscopy. MRIs were obtained on a 1.5T MR scanner to demonstrate the location of the MR-MSCs and were correlated with histology. Contrast-enhanced MRI demonstrated successful injection in the infarct and serial MSC tracking was demonstrated in two animals. CONCLUSIONS: MRI tracking of MSCs is feasible and represents a preferred method for studying the engraftment of MSCs in MI.