Methods and Results— We included 7348 consecutive patients (mean age, 64±13 years; 51% men) referred for SPECT-MPI between March 2002 and October 2006. Renal function was estimated using the estimated glomerular filtration rate formula. Patients were followed up for the incidence of all-cause mortality. Patients with decreased glomerular filtration rate were more often older, with higher prevalence of conventional risk factors (P<0.001). After a median follow-up of 2.6 years (25th to 75th percentiles, 1.5 to 3.7), 693 (9.4%) patients died. The risk of death increased with worsening kidney function. At each stage of impaired renal function, patients with abnormal SPECT-MPI had increased hazard of adverse events (P<0.0001). Using Cox proportional hazards analysis, the magnitude of total perfusion deficit and ischemia on MPI were associated with worse outcome after adjusting for confounding variables including glomerular filtration rate and ejection fraction.

Conclusions— SPECT-MPI adds modest incremental prognostic information to identify patients at higher relative risk of death across a wide spectrum of renal function.

Methods and Results— Two hundred four eligible subjects from 252 consecutive subjects undergoing late postgadolinium myocardial enhancement (LGE) cardiac magnetic resonance and Doppler echocardiography were investigated. Subjects with normal diastolic function exhibited no or minimal fibrosis (median LGE score, 0; interquartile range, 0 to 0). In contrast, the majority of patients with cardiomyopathy (regardless of underlying cause) had abnormal diastolic function indices and substantial fibrosis (median LGE score, 3; interquartile range, 0 to 6.25). Prevalence of LGE positivity by diastolic filling pattern was 13% in normal, 48% in impaired relaxation, 78% in pseudonormal, and 87% in restrictive filling (P<0.0001). Similarly, LGE score was significantly higher in patients with deceleration time <150 ms (P<0.012), and it progressively increased with increasing left ventricular filling pressure estimated by tissue Doppler imaging–derived E/E' (P<0.0001). After multivariate analysis, LGE remained significantly correlated with degree of diastolic dysfunction (P=0.0001).

Conclusions— Severity of myocardial fibrosis by LGE significantly correlates with the degree of diastolic dysfunction in a broad range of cardiac conditions. Noninvasive assessment of myocardial fibrosis may provide valuable insights into the pathophysiology of left ventricular diastolic function and therapeutic response.

Methods and Results— We examined the effect of CRT on 34 patients with functional MR before and after CRT (209±81 days). MR regurgitant volume, closing forces on MV (derived from Doppler transmitral pressure gradients), including dP/dt and a factor (closing pressure ratio) expressing how long the peak closing gradient is maintained over systole (closing pressure ratio=velocity time integral/MR peak velocityxmitral regurgitation time), and dyssynchrony by tissue Doppler were measured. End-diastolic volume, end-systolic volume, mitral valve annular area (MAA) and contraction (percent change in MAA from end-diastole to midsystole), leaflet closing area (leaflet area during valve closure), and tenting volume (volume under leaflets to annular plane) were measured by 3D echocardiography. After CRT, end-diastolic volume (253±111 versus 221±110 mL, P<0.001) and end-systolic volume (206±97 versus 167±91 mL, P<0.001) decreased and ejection fraction (19±6 versus 27±9%, P<0.001) increased. MR regurgitant volume decreased from 35±17 to 23±14 mL (P<0.001), MAA from 11.6±3.5 to 10.5±3.1 cm² (P<0.001), leaflet closing area from 15.4±5 to 13.7±3.8 cm² (P<0.001), and tenting volume from 5.7±2.6 to 4.6±2.2 mL (P<0.001). Peak velocity (and therefore transmitral closing pressure) was more sustained throughout systole, as reflected by the increase in the closing pressure ratio (0.77±0.1 versus 0.84±0.1 before CRT versus after CRT, P=0.01); dP/dt also improved after CRT. There was no change in dyssynchrony or MAA contraction.

Conclusions— Reduction in MR after CRT is associated with favorable changes in MV geometry and closing forces on the MV. It does so by favorably affecting the force balance acting on the MV in 2 ways: reducing tethering through reversal of LV remodeling and increasing the systolic duration of peak transmitral closing pressures.

Methods and Results— In each of 10 anesthetized sheep, sonomicrometry crystals were implanted on the endocardium and epicardium at the LV basal, mid, and apical anterior and lateral walls. LV 3D-STI data sets were obtained from the apical approach at a frame rate of approximately 30 frames/s. Segmental longitudinal (LS), radial (RS), and circumferential strain (CS) measurements by 3D-STI were compared with those by sonomicrometry at baseline and during pharmacological stress tests (dobutamine and propranolol infusion) and acute myocardial ischemia induced by coronary artery occlusion. Data were available from 136 LS, 108 CS, and 175 RS measurements. Good correlations were observed between strain measurements by 3D-STI and those by sonomicrometry (LS: r=0.89, P<0.001; RS: r=0.84, P<0.001; CS: r=0.90, P<0.001). In each segmental study, significant correlations of the 3 strain components were observed (LS: r=0.65 to 0.68, P<0.001; RS: r=0.59 to 0.70, P<0.001; CS: r=0.71 to 0.78, P<0.001).

Conclusions— The newly developed 3D-STI technique can estimate LV regional circumferential, longitudinal, and radial strain components with reasonable correlation to sonomicrometry data. This methodology could be applied clinically to assess alteration of myocardial function by accurately measuring strain in basal, mid, and apical LV segments, even during pharmacological and ischemic interventions. Therefore, 3D-STI appears to be a reliable tool to assess LV regional wall function.

Methods and Results— Mice with transient coronary ligation were injected intravenously at the onset of reperfusion with AnxCLIO-Cy5.5 (n=7) or the control probe Inact_CLIO-Cy5.5 (n=6). T2*-weighted MR images (9.4 T) were acquired within 4 to 6 hours of reperfusion. The contrast-to-noise ratio between injured and uninjured myocardium was measured. The mice were then injected with Gd-DTPA-NBD, and delayed-enhancement imaging was performed within 10 to 30 minutes. Uptake of AnxCLIO-Cy5.5 was most prominent in the midmyocardium and was significantly greater than that of Inact_CLIO-Cy5.5 (contrast-to-noise ratio, 8.82±1.5 versus 3.78±1.1; P<0.05). Only 21±3% of the myocardium with accumulation of AnxCLIO-Cy5.5 showed delayed-enhancement of Gd-DTPA-NBD. Wall thickening was significantly reduced in segments with delayed enhancement and/or transmural accumulation of AnxCLIO-Cy5.5 (P<0.001). Fluorescence microscopy of AnxCLIO-Cy5.5 and immunohistochemistry of Gd-DTPA-NBD confirmed the presence of large numbers of apoptotic but potentially viable cardiomyocytes (AnxCLIO-Cy5.5 positive, Gd-DTPA-NBD negative) in the midmyocardium.

Conclusions— A novel technique to image cardiomyocyte apoptosis and necrosis in vivo within 4 to 6 hours of injury is presented and reveals large areas of apoptotic but viable myocardium in the midmyocardium. Strategies to salvage the numerous apoptotic but potentially viable cardiomyocytes in the midmyocardium in acute ischemia should be investigated.

Methods and Results— Female mice with overexpression of Gaq were studied. Two weeks postpartum, these mice develop a cardiomyopathy characterized by low levels of CM apoptosis and minimal myocardial necrosis or inflammation. The mice were injected with the annexin-labeled nanoparticle (AnxCLIO-Cy5.5) or a control probe (CLIO-Cy5.5) and imaged in vivo at 9.4 T. Uptake of AnxCLIO-Cy5.5 occurred in isolated clusters, frequently in the subendocardium. Myocardial T2* was significantly lower (7.6±1.5 versus 16.8±2.7 ms, P<0.05) in the mice injected with AnxCLIO-Cy5.5 versus CLIO-Cy5.5, consistent with the uptake of AnxCLIO-Cy5.5 by apoptotic CMs. A strong correlation (r²=0.86, P<0.05) was seen between in vivo T2* (AnxCLIO-Cy5.5 uptake) and myocardial caspase-3 activity.

Conclusions— The ability of molecular MRI to image sparsely expressed targets in the myocardium is demonstrated in this study. Moreover, a novel platform for high-resolution and specific imaging of CM apoptosis in heart failure is established. In addition to providing novel insights into the pathogenesis of CM apoptosis, the developed platform could facilitate the development of novel antiapoptotic therapies in heart failure.

Methods and Results— A total of 101 patients with normal LV systolic function underwent CMR and echocardiography (echo) within 7 days. LV-METRIC generated LV filling profiles via automated segmentation of contiguous short-axis images (204±39 images, 2:04±0:53 minutes). Diastolic function by CMR was assessed via early:atrial filling ratios, peak diastolic filling rate, time to peak filling rate, and a novel index—diastolic volume recovery (DVR), calculated as percent diastole required for recovery of 80% stroke volume. Using an echo standard, patients with versus without diastolic dysfunction had lower early:atrial filling ratios, longer time to peak filling rate, lower stroke volume–adjusted peak diastolic filling rate, and greater DVR (all P<0.05). Prevalence of abnormal CMR filling indices increased in relation to clinical symptoms classified by New York Heart Association functional class (P=0.04) or dyspnea (P=0.006). Among all parameters tested, DVR yielded optimal performance versus echo (area under the curve: 0.87±0.04, P<0.001). Using a 90% specificity cutoff, DVR yielded 74% sensitivity for diastolic dysfunction. In multivariate analysis, DVR (odds ratio, 1.82; 95% CI, 1.13 to 2.57; P=0.02) was independently associated with echo-evidenced diastolic dysfunction after controlling for age, hypertension, and LV mass (²=73.4, P<0.001).

Conclusions— Automated CMR segmentation can provide LV filling profiles that may offer insight into diastolic dysfunction. Patients with diastolic dysfunction have prolonged diastolic filling intervals, which are associated with echo-evidenced diastolic dysfunction independent of clinical and imaging variables.

Methods and Results— Positron emission tomography (PET) imaging was used to quantitatively assess myocardial glucose uptake (MGU) in 6 adult subjects with the PRKAG2 cardiac syndrome and 6 healthy, matched control subjects using the glucose analogue ¹⁸F-Fluoro-2-deoxyglucose (FDG). Studies were performed under a euglycemic hyperinsulinemic clamp to ensure stable blood glucose levels. Rubidium-82 perfusion scans were performed to ensure that myocardial differences in myocardial glucose uptake were not the result of significant myocardial scar. In adult patients with phenotypic expression of disease, the median myocardial glucose uptake of the left ventricle was 0.18 µmol/min/g (interquartile range, 0.14, 0.24), compared with 0.40 µmol/min/g (interquartile range, 0.30 to 0.45) in the control group (P=0.01). The median blood glucose during FDG-PET imaging was 4.72 mmol/L (interquartile range, 4.32 to 4.97) in the PRKAG2 group and 4.38 mmol/L (interquartile range, 3.90, 4.79) in the control group (P=NS). The significant decrease observed in myocardial glucose uptake in affected patients occurred in the absence of significant myocardial scar.

Conclusions— The PRKAG2 cardiac syndrome is associated with a reduction of glucose uptake in adult patients affected with this genetic condition. In this pilot study, ¹⁸F-FDG-PET imaging is a useful tool to assess alterations in myocardial glucose transport in this inherited metabolic disease and provide insight into the biochemical pathophysiology of the diseased state.

Methods and Results— This study consisted of a dose-escalating, single-blinded phase and a placebo-controlled, double-blinded phase conducted in healthy, young adults with documented mild, intermittent, asthma. In the single-blinded phase, 3 sequential cohorts of 8 subjects received intravenous binodenoson (0.5, 1.0, and 1.5 µg/kg). In the double-blinded phase, commenced after medical review of results from the single-blinded phase, subjects were randomly assigned 2:1 to either binodenoson 1.5 µg/kg (n=41) or placebo (n=22). The primary end point was clinically significant bronchoconstriction, defined as a decrease in forced expiratory volume in 1 second of ≥20% from the preinjection measure. Secondary safety end points were changes from preinjection measure in forced expiratory volume in 1 second, forced vital capacity, and forced expiratory flow during the middle 50% of the forced vital capacity; vital signs; pulse oximetry; and adverse events. Binodenoson caused no clinically significant bronchoconstriction or alterations in pulmonary function parameters and transiently increased heart rate and systolic blood pressure. The most common treatment-emergent adverse events were tachycardia, dizziness, and flushing.

Conclusions— Binodenoson was safe, well tolerated, and caused no clinically significant bronchoconstriction or pulmonary responses in a small population of healthy subjects with mild, intermittent asthma.