Background

Patients with human immunodeficiency virus (HIV) infection are at increased risk of accelerated coronary artery disease (CAD) and cardiovascular events. Stress echocardiography (SE) is routinely used for risk stratification and prognosis of patients with known or suspected CAD. The prognostic value of SE in this high-risk group is unknown. The purpose of this study was to evaluate the prognostic value of SE in HIV-infected patients with known or suspected CAD.

Methods and Results

We evaluated 311 patients (age, 52±9 years; 74% men; left ventricular ejection fraction, 54±12%) with history of HIV, undergoing SE (56% dobutamine). Left ventricular wall motion was evaluated on a 16-segment model, 5-point scale. An abnormal SE was defined by a fixed (infarction), biphasic, or new (ischemia) wall motion abnormality on stress. Follow-up for cardiac death and myocardial infarction was obtained. Seventy-nine (26%) patients had an abnormal SE. After 2.9±1.9 years, 17 confirmed myocardial infarction and 14 cardiac deaths occurred. SE risk-stratified patients into normal versus abnormal subgroups (event rate, 0.6% per year versus 11.8% per year; P<0.0001). Both abnormal SE (hazard ratio, 28.2; 95% confidence interval, 6.2 to 128.0; P<0.0001) and the presence of any ischemia on SE (hazard ratio, 3.4; 95% confidence interval, 1.3 to 8.6; P=0.009) were independent predictors of cardiac events. On a forward conditional Cox proportional hazards regression model, SE provided incremental prognostic value over clinical, stress ECG, and resting echocardiographic variables (global χ2 increased from 17.8 to 24.5 to 65 to 109, P<0.05 across all groups).

Conclusions

SE can effectively risk-stratify and prognosticate patients with HIV. The presence of ischemia and scar during SE provides independent and incremental prognostic value over traditional variables. A normal SE response portends a benign prognosis even in this high-risk subset.

Background

There is a well-recognized need for a new generation of single photon emission computed tomography (SPECT) perfusion tracers with improved myocardial extraction over a wide flow range. Radiotracers that target complex I of the mitochondrial electron transport chain have been proposed as a new class of myocardial perfusion imaging agents. 7-(Z)-[125I]iodorotenone (125I-ZIROT) has demonstrated superior myocardial extraction and retention characteristics in rats and in isolated perfused rabbit hearts. We sought to fully characterize the biodistribution and myocardial extraction versus flow relationship of 123I-ZIROT in an intact large-animal model.

Methods and Results

The 123I-ZIROT was administered during adenosine A2A agonist-induced hyperemia in 5 anesthetized dogs with critical left anterior descending (LAD) stenoses. When left circumflex (LCx) flow was maximal, 123I-ZIROT and microspheres were coinjected and the dogs were euthanized 5 minutes later. 123I-ZIROT biodistribution was evaluated in 2 additional dogs by in vivo planar imaging. At 123I-ZIROT injection, transmural LAD flow was unchanged from baseline (mean±SEM, 0.90±0.22 versus 0.87±0.11 mL/[min · g]; P=0.92), whereas LCx zone flow increased significantly (mean±SEM, 3.25±0.51 versus 1.00±0.17 mL/[min · g]; P<0.05). Myocardial 123I-ZIROT extraction tracked regional myocardial flow better than either thallium-201 or 99mTc-sestamibi from previous studies using a similar model. Furthermore, the 123I-ZIROT LAD/LCx activity ratios by ex vivo imaging or well counting (mean±SEM, 0.42±0.08 and 0.45±0.1, respectively) only slightly underestimated the LAD/LCx microsphere flow ratio (0.32±0.09).

Conclusions

The ability of 123I-ZIROT to more linearly track blood flow over a wide range makes it a promising new SPECT myocardial perfusion imaging agent with potential for improved coronary artery disease detection and better quantitative estimation of the severity of flow impairment.

Background

Systemic-pulmonary collateral (SPC) flow occurs commonly in single ventricle patients after superior cavo-pulmonary connection, with unclear clinical significance. We sought to evaluate the association between SPC flow and acute post-Fontan clinical outcomes using a novel method of quantifying SPC flow by cardiac magnetic resonance (CMR).

Methods and Results

All patients who had SPC flow quantified by CMR prior to Fontan were retrospectively reviewed to assess for acute clinical outcomes after Fontan completion. Forty-four subjects were included who had Fontan completion between May, 2008 and September, 2010. SPC flow prior to Fontan measured 1.5 ± 0.9 L/min/m2, accounting for 31 ± 11% of total aortic flow and 44 ± 15% of total pulmonary venous flow. There was a significant linear association between natural log-transformed duration of hospitalization and SPC flow as a proportion of total aortic (rho=0.31, p=0.04) and total pulmonary venous flow (rho=0.29, p=0.05). After adjustment for Fontan type and presence of a fenestration, absolute SPC flow was significantly associated with hospital duration ≥ 7 days (OR=9.2, p=0.02) and chest tube duration ≥ 10 days (OR=22.7, p=0.009). Similar associations exist for SPC flow as a percentage of total aortic (OR=1.09, p=0.048 for hospitalization ≥ 7 days; OR=1.24, p=0.007 for chest tube duration ≥ 10 days) and total pulmonary venous flow (OR=1.07, p=0.048 for hospitalization ≥ 7 days; OR=1.18, p=0.006 for chest tube duration ≥ 10 days).

Conclusions

Increasing SPC flow before Fontan, as measured by CMR, is associated with increased duration of hospitalization and chest tube following Fontan completion.

Background

We quantified absolute myocardial blood flow (MBF) using a spin labeling magnetic resonance imaging (SL-MRI) method after transplantation of endothelial cells (ECs) into the infarcted heart. Our aims were to study the temporal changes in MBF in response to EC transplantation, and to compare regional MBF with contractile function (wall motion) and microvascular density.

Methods and Results

We first validated the SL-MRI method with the standard microsphere technique in normal rats. We then induced myocardial infarction (MI) in athymic rats and injected 5-million ECs (human umbilical vein endothelial cells) suspended in Matrigel or Matrigel alone (vehicle) along the border of the blanched infarcted area. At 2-weeks post-MI, MBF averaged over the entire slice (p = 0.038) and in the infarcted region (p = 0.0086) was significantly higher in EC vs. vehicle group; the greater MBF was accompanied by an increase of microvasculature density in the infarcted region (p = 0.0105 vs. vehicle). At 4-weeks post-MI, MBF in the remote region was significantly elevated in EC-treated hearts (p = 0.0277); this was accompanied by increased wall motion in this region assessed by circumferential strains. Intraclass correlation coefficients and Bland-Altman plot revealed a good reproducibility of the SL-MRI method.

Conclusions

Myocardial blood flow in free-breathing rats measured by SL-MRI is validated by the standard color microsphere technique. SL-MRI allows quantification of temporal changes of regional MBF in response to EC treatment. The proof-of-principle study indicates that MBF is a unique and sensitive index to evaluate EC-mediated therapy for the infarcted heart.

Background

An increase in left ventricular mass (LVM) is associated with mortality and cardiovascular morbidity in patients with end-stage renal disease.

Methods and Results

The Frequent Hemodialysis Network (FHN) Daily Trial randomized 245 patients to 12 months of 6 times per week daily in-center hemodialysis or conventional hemodialysis; the FHN Nocturnal Trial randomized 87 patients to 12 months of 6 times per week nocturnal hemodialysis or conventional hemodialysis. The main cardiac secondary outcome was change in LVM. In each trial, we examined whether several pre-defined baseline demographic or clinical factors, as well as change in volume removal, blood pressure or solute clearance influenced the effect of frequent hemodialysis on LVM. In the Daily Trial, frequent hemodialysis resulted in a significant reduction in LVM (13.1(95% CI 5.0 to 21.3) g, p=0.002), LVM index (6.9 (2.4 to 11.3) g/m2, p=0.003) and percent change in geometric mean of LVM (7.0 (1.0 to 12.6)%, p =0.02). Similar trends were noted in the Nocturnal Trial but did not reach statistical significance. In the Daily Trial, a more pronounced effect of frequent hemodialysis on LVM was evident among patients with left ventricular hypertrophy at baseline. Changes in LVM were associated with changes in blood pressure (conventional hemodialysis: R=0.28, P=0.01, daily hemodialysis: R=0.54, P<0.001) and were not significantly associated with changes in other parameters.

Conclusions

Frequent in-center hemodialysis reduces LVM. The benefit of frequent hemodialysis on LVM may be mediated by salutary effects on blood pressure.

Background

Annually, ~80,000 Americans receive guideline-based primary prevention implantable cardioverter defibrillators (ICDs), but appropriate firing rates are low. Current selection criteria for ICDs rely on LVEF, which lacks sensitivity and specificity. Because scar-related, myocardial tissue heterogeneity is a substrate for life-threatening arrhythmias, we hypothesized that cardiac magnetic resonance (CMR) identification of myocardial heterogeneity improves risk stratification through: (1) its association with adverse cardiac events independent of clinical factors and biomarker levels; and (2) its ability to identify particularly high- and low-risk subgroups.

Methods and Results

In 235 ischemic and nonischemic patients with LVEF≤35%, undergoing clinically-indicated primary prevention ICD, gadolinium-enhanced CMR was prospectively performed to quantify the amount of heterogeneous myocardial tissue (gray zone-GZ) and dense core scar. Serum high sensitivity C-reactive protein (hsCRP) and other biomarkers were assayed. The primary endpoint was appropriate ICD shock for ventricular tachycardia/fibrillation or cardiac death, which occurred in 45 patients (19%) at 3.6 year median follow-up. On univariable analysis, only diuretics, hsCRP, GZ and core were associated with outcome. After multivariable adjustment, GZ and hsCRP remained independently associated with outcome (p<0.001). Patients in the lowest tertile for both GZ and hsCRP (n=42) were at particularly low risk (0.7%/year event rate) while those in the highest tertile for both GZ and hsCRP (n=32) had an event rate of 16.1%/year, p<0.001.

Conclusions

In a cohort of primary prevention ICD candidates, combining a myocardial heterogeneity index with an inflammatory biomarker identified a subgroup with a very low risk of adverse cardiac events, including ventricular arrhythmias. This novel approach warrants further investigation to confirm its value as a clinical risk stratification tool.

Clinical Trial Registration

URL: http://www.clinicaltrials.gov. Unique identifier: NCT00181233.

Background

X-ray magnetic resonance fusion (XMRF) allows for use of 3D data during cardiac catheterization. However, to date, technical requirements have limited the use of this modality in clinical practice. We report on a new internal-marker XMRF method that we have developed and describe how we used XMRF during cardiac catheterization in congenital heart disease.

Methods and Results

XMRF was performed in a phantom and in 23 patients presenting for cardiac catheterization who also needed cardiac MRI for clinical reasons. The registration process was performed in <5 minutes per patient, with minimal radiation (0.004 to 0.024 mSv) and without contrast. Registration error was calculated in a phantom and in 8 patients using the maximum distance between angiographic and 3D model boundaries. In the phantom, the measured error in the anteroposterior projection had a mean of 1.15 mm (standard deviation, 0.73). The measured error in patients had a median of 2.15 mm (interquartile range, 1.65 to 2.56 mm). Internal markers included bones, airway, image artifact, calcifications, and the heart and vessel borders. The MRI data were used for road mapping in 17 of 23 (74%) cases and camera angle selection in 11 of 23 (48%) cases.

Conclusions

Internal marker–based registration can be performed quickly, with minimal radiation, without the need for contrast, and with clinically acceptable accuracy using commercially available software. We have also demonstrated several potential uses for XMRF in routine clinical practice. This modality has the potential to reduce radiation exposure and improve catheterization outcomes.

Background

T2-weighted cardiac magnetic resonance (CMR) is useful in diagnosing acute inflammatory myocardial diseases such as myocarditis and tako-tsubo cardiomyopathy (TTCM). We hypothesized that quantitative T2 mapping could better delineate myocardial involvement in these disorders vs. T2-weighted imaging.

Methods and Results

Thirty patients with suspected myocarditis or TTCM referred for CMR who met established diagnostic criteria underwent myocardial T2 mapping. T2 values were averaged in involved and remote myocardial segments, both defined by a reviewer blinded to T2 data. In myocarditis, T2 was 65.2±3.2ms in the involved myocardium vs. 53.5±2.1 in remote myocardium (p<0.001). In TTCM, T2 was 65.6±4.0ms in the involved myocardium vs. 53.6±2.7ms in remote segments (p<0.001). T2 values were similar across remote myocardial segments in patients and all myocardial segments in controls (p>0.05 for all). T2 maps provided diagnostic data even in patients with difficulty breath-holding. A T2 cutoff of 59ms identified areas of myocardial involvement with sensitivity and specificity of 94% and 97%, respectively. T2 mapping revealed regions of abnormal T2 beyond those identified by wall motion abnormalities or LGE-positivity. Conventional T2-weighted short tau inversion recovery (T2W-STIR) images were uninterpretable in 7 patients due to artifact and unremarkable in 2 who had elevated T2 values. T2-prepared steady state free precession (T2p-SSFP) images showed areas of signal hyperintensity in only17/30 patients.

Conclusions

Quantitative T2 mapping reliably identifies myocardial involvement in patients with myocarditis and TTCM. T2 mapping delineated greater extent of myocardial disease in both conditions compared to that identified by wall motion abnormalities, T2W-STIR, T2p-SSFP or LGE. Quantitative T2 mapping warrants consideration as a robust technique to identify myocardial injury in patients with acute myocarditis or TTCM.

Background

Among intermediate to high-risk patients with chest pain, we have shown that a cardiac magnetic resonance (CMR) stress-test strategy implemented in an observation unit (OU) reduces 1-year healthcare costs compared to inpatient care. In this study, we compare two OU strategies to determine among lower-risk patients if a mandatory CMR stress test strategy was more effective than a physicians’ ability to select a stress test modality.

Methods and Results

Upon ED arrival and referral to the OU for management of low to intermediate-risk chest pain, 120 individuals were randomized to receive an a) CMR stress imaging test (n=60), or b) a provider selected stress test (n=60: stress echo [62%], CMR (32%), cardiac catheterization (3%), nuclear (2%), and coronary CT [2%]). No differences were detected in length of stay (median CMR = 24.2 hours vs 23.8 hours, p=0.75), catheterization without revascularization (CMR=0% vs 3%), appropriateness of admission decisions (CMR 87% vs 93%, p=0.36), or 30-day ACS (both 3%). Median cost was higher among those randomized to the CMR mandated group ($2005 vs $1686, p<0.001).

Conclusions

In patients with lower-risk chest pain receiving ED-directed OU care, the ability of a physician to select a cardiac stress imaging modality (including echocardiography, CMR, or radionuclide testing) was more cost effective than a pathway that mandates a CMR stress test. Contrary to prior observations in individuals with intermediate to high-risk chest pain, in those with lower risk chest pain, these results highlight the importance of physician-related choices during ACS diagnostic protocols.

Clinical Trial Registration

URL: http://www.clinicaltrials.gov. Unique identifier: NCT00869245.

Background

Mesenchymal stem cells (MSCs) can differentiate into endothelial cells in vivo. However, it is unknown if the differentiated MSCs persist in vivo and if this potential persistence contributes to functional improvement following experimental myocardial infarction (EMI).

Methods and Results

We generated a lentivector encoding two distinct reporter genes, one driven by a constitutive murine stem cell virus promoter and the other, by an endothelial specific Tie-2 promoter. The endothelial specificity of the lentivector was validated by its expression in endothelial cells, but not in human MSCs (hMSCs). The lentivirus-transduced hMSCs were injected into peri-infarct areas of the hearts of severe combined immune-deficient mice. Persistence of injected cells was tracked by bioluminescence imaging (BLI) and verified by immunohistochemical staining (IHS). The BLI signal from the endothelial-specific reporter revealed that hMSCs differentiated into endothelial cells 48 hours following injection. However, both the constitutive and the endothelial-specific BLI signals disappeared by day 50. Nonetheless, the improvement in left ventricle ejection fraction with hMSC therapy persisted for up to 6 months. IHS showed that hMSC-derived endothelial cells integrated into endogenous CD31+ vessels. Furthermore, hMSC-transplanted hearts had more CD31+ vessels and a lesser degree of cardiac fibrosis compared to the controls at 6 months.

Conclusions

hMSCs differentiated into endothelial cells and integrated into blood vessels after EMI. The differentiated hMSCs only lasted for up to 50 days in vivo, but improvement in cardiac function persisted for up to 6 months. Increased angiogenesis and decreased fibrosis were associated with cardiac functional improvement following hMSC transplantation.

Background

Main pulmonary artery diameter (mPA) and ratio of mPA to ascending aorta diameter (ratio PA) derived from chest CT are commonly reported in clinical practice. We determined the age and sex-specific distribution and normal reference values for mPA and ratio PA by CT in an asymptomatic community-based population.

Methods and Results

In 3171 men and women (mean age 51 ± 10 years, 51% men) from the Framingham Heart Study, a non-contrast ECG gated eight-slice cardiac multi-detector CT was performed. We measured the mPA and transverse axial diameter of the ascending aorta at the level of the bifurcation of the right pulmonary artery and calculated the ratio PA. We defined the healthy referent cohort (n=706) as those without obesity, hypertension, current and past smokers, chronic obstructive pulmonary disease, history of pulmonary embolism, diabetics, cardiovascular disease, and heart valvular surgery. The mean mPA diameter in the overall cohort was 25.1 ± 2.8mm and mean ratio PA was 0.77 ± 0.09. The sex-specific 90th percentile cutoff value for mPA diameter was 28.9 mm in men and 26.9 mm in women and was associated with increase risk for self-reported dyspnea (adjusted odds ratio 1.31, p=0.02). The 90th percentile cutoff value for ratio PA of the healthy referent group was 0.91, similar between gender, but decreased with increasing age (range 0.82 to 0.94), though not associated with dyspnea.

Conclusions

For simplicity, we established 29 mm in men and 27 mm in women as sex-specific normative reference values for mPA and 0.9 for ratio PA.

Background

Current techniques to image cell death in the myocardium are largely non-specific. Here we report the use of a novel DNA-binding gadolinium chelate (Gd-TO) to specifically detect the exposed DNA in acutely necrotic (ruptured) cells in vivo.

Methods and Results

In vivo MRI was performed in 20 mice with myocardial infarction (MI). The mice were injected with Gd-TO or Gd-DTPA at varying time points post-MI. MRI was performed 2 hours after probe injection, to avoid nonspecific signal from the late gadolinium enhancement effect. Cell rupture (Gd-TO uptake) was present within 2 hours of infarction, but peaked 9–18 hours after the onset of injury. A significant increase in the longitudinal relaxation rate (R1) in the infarct was seen in mice injected with Gd-TO within 48 hours of MI, but not in those injected more than 72 hours post MI (R1 = 1.24 ± 0.08 and 0.92 ± 0.03 s−1, respectively, p < 0.001). Gd-DTPA, unlike Gd-TO, washed completely out of acute infarcts within 2 hours of injection (p < 0.001). The binding of Gd-TO to exposed DNA in acute infarcts was confirmed with fluorescence microscopy.

Conclusions

Gd-TO specifically binds to acutely necrotic cells and can be used to image the mechanism and chronicity of cell death in injured myocardium. Cell rupture in acute MI begins early but peaks many hours after the onset of injury. The ruptured cells are efficiently cleared by the immune system and are no longer present in the myocardium 72 hours after injury.

Background

The safety and clinical utility of magnetic resonance imaging at 1.5T in patients with cardiac implantable devices such as pacemakers (PM) and implantable cardioverter defibrillators (ICD) have been reported. This study aims to evaluate the extent of artifacts on cardiac magnetic resonance (CMR) in patients with PM and ICD (PM/ICD).

Methods and Results

A total of 71 CMR studies were performed with an established safety protocol in patients with pre-pectoral PM/ICD. The artifact area around the PM/ICD generator was measured in all short axis (SA), horizontal (HLA) and vertical long axis (VLA) SSFP cine planes. The location and extent of artifacts were also assessed in all SA (20 sectors/plane), HLA, and VLA (6 sectors/plane) late gadolinium enhanced CMR (LGE-CMR) planes. The artifact area on cine CMR was significantly larger with ICD versus PM generators in each plane (P<0.001, respectively). In patients with left-sided ICD or biventricular ICD systems, the percentages of sectors with any artifacts on LGE-CMR were 53.7%, 48.0% and 49.2% in SA, HLA and VLA planes, respectively. Meanwhile, patients with left-sided PM or right-sided PM/ICD had fewer artifacts. Anterior and apical regions were severely affected by artifact due to left-sided PM/ICD generators.

Conclusions

In contrast to patients with right-sided PM/ICD and left-sided PM, the anterior and apical left ventricle can be affected by susceptibility artifacts in patients with left-sided ICD. Artifact reduction methodologies will be necessary to improve the performance of CMR in patients with left sided ICD systems.

Background

In HCM, myocardial abnormalities are commonly heterogeneous. Two patterns of LGE have been reported: a bright “confluent” and an intermediate intensity abnormality termed “diffuse,” each representing different degrees of myocardial scarring. We used MRI to study the relation between intramural cardiac function and the extent of fibrosis in HCM. The aim of this study was to determine whether excess collagen or myocardial scarring, as determined by late gadolinium enhancement (LGE) MRI, are the primary mechanisms leading to heterogeneous regional contractile function in patients with hypertrophic cardiomyopathy (HCM).

Methods and Results

Intramural left ventricular (LV) strain, transmural LV function, and regions of myocardial fibrosis/scarring were imaged in 22 patients with HCM using displacement encoding with stimulated echoes (DENSE), cine MRI and LGE. DENSE systolic strain maps were qualitatively and quantitatively compared with LGE images. Intramural systolic strain by DENSE was significantly depressed within areas of confluent and diffuse LGE but also in the core of the most hypertrophic non-enhanced segment (all p<0.001 vs. non-hypertrophied segments). DENSE demonstrated an unexpected inner rim of largely preserved contractile function and a non-contracting outer wall within hypertrophic segments in 91% of patients.

Conclusions

LGE predicted some but not all of the heterogeneity of intramural contractile abnormalities. This indicates that myocardial scarring or excess interstitial collagen deposition does not fully explain the observed contractile heterogeneity in HCM. Thus, myofibril disarray or other non-fibrotic processes affect systolic function in a large number of patients with HCM.

Background

Delayed gadolinium (Gd) enhancement MRI (DEMRI) identifies non-viable myocardium, but is non-specific and may overestimate nonviable territory. Manganese (Mn2+)-enhanced MRI (MEMRI) denotes specific Mn2+ uptake into viable cardiomyocytes. We performed a dual-contrast myocardial assessment in a porcine ischemia-reperfusion (IR) model to test the hypothesis that combined DEMRI and MEMRI will identify viable infarct border zone (BZ) myocardium in vivo.

Methods and Results

Sixty-minute LAD ischemia-reperfusion injury (IR) was induced in 13 adult swine. Twenty-one days post-IR, 3T cardiac MRI was performed. MEMRI was obtained after injection (0.7 cc/kg) of Mn2+ contrast agent (EVP1001-1, Eagle Vision Pharmaceutical Corp.). DEMRI was then acquired after 0.2mmol/kg Gd injection. Left ventricular (LV) mass, infarct, and function were analyzed. Subtraction of MEMRI defect from DEMRI signal identified injured border zone myocardium. Explanted hearts were analyzed by 2,3,5-triphenyltetrazolium chloride (TTC) stain and tissue electron microscopy (TEM) to compare infarct, BZ, and remote myocardium. Average LV ejection fraction was reduced (30±7%). MEMRI and DEMRI infarct volumes correlated with TTC (MEMRI: r=0.78; DEMRI: r=0.75; p<0.004). MEMRI infarct volume percentage was significantly lower than DEMRI (14±4%* vs. 23±4%; *p<0.05). BZ MEMRI SNR was intermediate to remote and core infarct SNR (7.5±2.8* vs. 13.2±3.4 and 2.9±1.6; *p<0.0001), and DEMRI BZ SNR tended to be intermediate to remote and core infarct (8.4±5.4 vs. 3.3±0.6 and 14.3±6.6; p>0.05). TEM analysis exhibited preserved cell structure in BZ cardiomyocytes despite transmural DEMRI enhancement.

Conclusions

Dual-contrast MEMRI-DEMRI detects BZ viability within DEMRI infarct zones. This approach may identify injured, at-risk myocardium in ischemic cardiomyopathy.

Background

In select patient populations, Doppler echocardiographic indices may be used to estimate left sided filling pressures. It is not known, however, whether changes in these indices track changes in left-sided filling pressures within individual healthy subjects or patients with heart failure with preserved ejection fraction (HFpEF). This knowledge is important as it would support, or refute, the serial use of these indices to estimate changes in filling pressures associated with the titration of medical therapy in patients with heart failure.

Methods and Results

Forty seven volunteers were enrolled: 11 highly screened elderly outpatients with a clear diagnosis of HFpEF, 24 healthy elderly subjects and 12 healthy young subjects. Each patient underwent right heart catheterization with simultaneous transthoracic echo. Pulmonary capillary wedge pressure (PCWP) and key echo indices (E/e’ & E/Vp) were measured at two baselines and during four preload altering maneuvers: lower body negative pressure (LBNP) -15 mmHg; LBNP -30 mmHg; rapid saline infusion of 10-15 ml/kg; and rapid saline infusion of 20-30 ml/kg. A random coefficient mixed model regression of PCWP vs. E/e’ and PCWP vs. E/Vp was performed for: 1) a composite of all data points; 2) a composite of all data points within each of the three groups. Linear regression analysis was performed for individual subjects. With this protocol, PCWP was manipulated from 0.8 to 28.8 mmHg. For E/e’, the composite random effects mixed model regression was PCWP = 0.58×E/e’+7.02 (p<0.001) confirming the weak but significant relationship between these two variables. Individual subject linear regression slopes (range: -6.76 to 11.03) and r2 (0.00 to 0.94) were highly variable and often very different than those derived for the composite and group regressions. For E/Vp, the composite random coefficient mixed model regression was PCWP = 1.95×E/Vp +7.48 (p=0.005); once again, individual subject linear regression slopes (range: -16.42 to 25.39) and r2 (range: 0.02 to 0.94) were highly variable and often very different than those derived for the composite and group regressions.

Conclusions

Within individual subjects the non-invasive indices E/e’ and E/Vp do not reliably track changes in left-sided filling pressures as these pressures vary, precluding the use of these techniques in research studies with healthy volunteers or the titration of medical therapy in patients with HFpEF.

Background

Accurate quantification of mitral regurgitation (MR) is important for patient treatment and prognosis. Three-dimensional echocardiography allows for the direct measure of the regurgitant orifice area (ROA) by 3D-guided planimetry of the vena contracta area (VCA). We aimed to (1) establish 3D VCA ranges and cutoff values for MR grading, using the American Society of Echocardiography–recommended 2D integrative method as a reference, and (2) compare 2D and 3D methods of ROA to establish a common calibration for MR grading.

Methods and Results

Eighty-three patients with at least mild MR underwent 2D and 3D echocardiography. Direct planimetry of VCA was performed by 3D echocardiography. Two-dimensional quantification of MR included 2D ROA by proximal isovelocity surface area (PISA) method, vena contracta width, and ratio of jet area to left atrial area. There were significant differences in 3D VCA among patients with different MR grades. As assessed by receiver operating characteristic analysis, 3D VCA at a best cutoff value of 0.41 cm2 yielded 97% of sensitivity and 82% of specificity to differentiate moderate from severe MR. There was significant difference between 2D ROA and 3D VCA in patients with functional MR, resulting in an underestimation of ROA by 2D PISA method by 27% as compared with 3D VCA. Multivariable regression analysis showed functional MR as etiology was the only predictor of underestimation of ROA by the 2D PISA method.

Conclusions

Three-dimensional VCA provides a single, directly visualized, and reliable measurement of ROA, which classifies MR severity comparable to current clinical practice using the American Society of Echocardiography–recommended 2D integrative method. The 3D VCA method improves accuracy of MR grading compared with the 2D PISA method by eliminating geometric and flow assumptions, allowing for uniform clinical grading cutoffs and ranges that apply regardless of etiology and orifice shape.

Background

Carnitine acetyltransferase (CAT) catalyses the reversible conversion of acetyl-CoA into acetylcarnitine. The aim of this study was to use the metabolic tracer hyperpolarised [2-13C]pyruvate with magnetic resonance spectroscopy (MRS) to determine if CAT facilitates carbohydrate oxidation in the heart.

Methods and Results

Ex vivo, following hyperpolarised [2-13C]pyruvate infusion, the [1-13C]acetylcarnitine MR resonance was saturated with a radiofrequency pulse and the effect of this saturation on [1-13C]citrate and [5-13C]glutamate was observed. In vivo, [2-13C]pyruvate was infused into three groups of fed male Wistar rats; (a) controls, (b) rats in which dichloroacetate enhanced PDH flux and (c) rats in which dobutamine elevated cardiac workload. In the perfused heart, [1-13C]acetylcarnitine saturation reduced the [1-13C]citrate and [5-13C]glutamate resonances by 63% and 51%, indicating rapid exchange between pyruvate-derived acetyl-CoA and the acetylcarnitine pool. In vivo, dichloroacetate increased the rate of [1-13C]acetylcarnitine production by 35% and increased the overall acetylcarnitine pool size by 33%. Dobutamine decreased the rate of [1-13C]acetylcarnitine production by 37% and decreased the acetylcarnitine pool size by 40%.

Conclusions

Hyperpolarised 13C MRS has revealed that acetylcarnitine provides a route of disposal for excess acetyl-CoA, and also a means to replenish acetyl-CoA when cardiac workload is increased. Cycling of acetyl-CoA through acetylcarnitine appears key to matching instantaneous acetyl-CoA supply with metabolic demand, thereby helping to balance myocardial substrate supply and contractile function.

Background

Using a resolution 1000 fold higher than prior studies, we studied 1) the degree to which late gadolinium enhancement (LGE) cardiac magnetic resonance (CMR) tracks fibrosis from chronic myocardial infarction (MI); and 2) the relationship between intermediate signal intensity and partial volume averaging at distinct “smooth” infarct borders versus disorganized mixtures of fibrosis and viable cardiomyocytes.

Methods and Results

Sprague Dawley rats underwent MI by coronary ligation. Two months later rats were euthanized 10 minutes after administration of 0.3 mmol/kg intravenous gadolinium. LGE images ex vivo at 7 Tesla with a 3D gradient echo sequence with 50x50x50 micron voxels were compared with histologic sections (Masson’s trichrome). Planimetered histologic and LGE regions of fibrosis correlated well (y = 1.01x – 0.01; R2=0.96; p<0.001). In addition, LGE images routinely detected clefts of viable cardiomyocytes 2–4 cells thick that separated bands of fibrous tissue. While LGE clearly detected disorganized mixtures of fibrosis and viable cardiomyocytes characterized by intermediate signal intensity voxels, the percentage of apparent intermediate signal intensity myocardium increased significantly (p<0.01) when image resolution was degraded to resemble clinical resolution consistent with significant partial volume averaging.

Conclusions

These data provide important validation of LGE at nearly the cellular level for detection of fibrosis after MI. While LGE can detect heterogeneous patches of fibrosis and viable cardiomyocytes as patches of intermediate signal intensity, the percentage of intermediate signal intensity voxels is resolution dependent. Thus, at clinical resolutions, distinguishing the peri-infarct border zone from partial volume averaging with LGE is challenging.

Background

Matrix metalloproteinases (MMPs) are known to modulate left ventricular (LV) remodeling after a myocardial infarction (MI). However, the temporal and spatial variation of MMP activation and their relationship to mechanical dysfunction post MI remains undefined.

Methods and Results

MI was surgically induced in pigs (n=23) and cine MR and dual isotope hybrid SPECT/CT imaging obtained using thallium-201 (201Tl) and a technetium-99m labeled MMP targeted tracer (99mTc-RP805) at 1, 2 and 4 weeks post MI along with controls (n=5). Regional myocardial strain was computed from MR images and related to MMP zymography and ex vivo myocardial 99mTc-RP805 retention. MMP activation as assessed by in vivo and ex vivo 99mTc-RP805 imaging/retention studies was increased nearly 5-fold within the infarct region at 1 week post-MI and remained elevated up to 1 month post-MI. The post-MI change in LV end-diastolic volumes was correlated with MMP activity (y=31.34e0.48x, p=0.04). MMP activity was increased within the border and remote regions early post-MI, but declined over 1 month. There was a high concordance between regional 99mTc-RP805 uptake and ex vivo MMP-2 activity.

Conclusions

A novel, multimodality non-invasive hybrid SPECT/CT imaging approach was validated and applied for in vivo evaluation of MMP activation in combination with cine MR analysis of LV deformation. Increased 99mTc-RP805 retention was seen throughout the heart early post-MI and was not purely a reciprocal of 201Tl perfusion. 99mTc-RP805 SPECT/CT imaging may provide unique information regarding regional myocardial MMP activation and predict late post-MI LV remodeling.

Background

The clinical significance of magnetic resonance imaged (MRI) plaque characteristics in the superficial femoral artery (SFA) is not well established. We studied associations of the ankle brachial index (ABI) and leg symptoms with MRI-measured plaque area and percent lumen area in the SFA in participants with and without lower extremity peripheral arterial disease (PAD).

Methods and Results

Four hundred twenty-seven participants (393 with PAD) underwent plaque imaging of the first 30 millimeters of the SFA. Twelve 2.5 millimeter cross-sectional images of the SFA were obtained. Outcomes were normalized plaque area, adjusted for artery size (0–1 scale, 1=greatest plaque), and lumen area, expressed as a percent of the total artery area. Adjusting for age, sex, race, smoking, statins, cholesterol, and other covariates, lower ABI values were associated with higher normalized mean plaque area (ABI < 0.50:0.79; ABI 0.50 to 0.69:0.73; ABI 0.70 to 0.89:0.65; ABI 0.90 to 0.99:0.62; ABI 1.00 to 1.09:0.48; ABI 1.10–1.30:0.47 (P trend <0.001)) and smaller mean percent lumen area (P trend<0.001). Compared to PAD participants with intermittent claudication, asymptomatic PAD participants had lower normalized mean plaque area (0.72 vs. 0.65, p=0.005) and larger mean percent lumen area (0.30 vs. 0.36, p=0.01), adjusting for the ABI and other confounders.

Conclusions

Lower ABI values are associated with greater MRI-measured plaque burden and smaller lumen area in the first 30 millimeters of the SFA. Compared to PAD participants with claudication, asymptomatic PAD participants have smaller plaque area and larger lumen area in the SFA.