Person:

Ruskin, Jeremy

Background: The study of myofiber reorganization in the remote zone after myocardial infarction has been performed in 2D. Microstructural reorganization in remodeled hearts, however, can only be fully appreciated by considering myofibers as continuous 3D entities. The aim of this study was therefore to develop a technique for quantitative 3D diffusion CMR tractography of the heart, and to apply this method to quantify fiber architecture in the remote zone of remodeled hearts. Methods: Diffusion Tensor CMR of normal human, sheep, and rat hearts, as well as infarcted sheep hearts was performed ex vivo. Fiber tracts were generated with a fourth-order Runge-Kutta integration technique and classified statistically by the median, mean, maximum, or minimum helix angle (HA) along the tract. An index of tract coherence was derived from the relationship between these HA statistics. Histological validation was performed using phase-contrast microscopy. Results: In normal hearts, the subendocardial and subepicardial myofibers had a positive and negative HA, respectively, forming a symmetric distribution around the midmyocardium. However, in the remote zone of the infarcted hearts, a significant positive shift in HA was observed. The ratio between negative and positive HA variance was reduced from 0.96 ± 0.16 in normal hearts to 0.22 ± 0.08 in the remote zone of the remodeled hearts (p<0.05). This was confirmed histologically by the reduction of HA in the subepicardium from −52.03° ± 2.94° in normal hearts to −37.48° ± 4.05° in the remote zone of the remodeled hearts (p < 0.05). Conclusions: A significant reorganization of the 3D fiber continuum is observed in the remote zone of remodeled hearts. The positive (rightward) shift in HA in the remote zone is greatest in the subepicardium, but involves all layers of the myocardium. Tractography-based quantification, performed here for the first time in remodeled hearts, may provide a framework for assessing regional changes in the left ventricle following infarction.

A cardiac-tailored framework for 3D Diffusion Tensor MRI tractography is developed and used to characterize myofiber architecture in normal and remodeled myocardium. We show that myofibers in the subepicardium of the remote infarct zone become less oblique (more circumferential) as the heart dilates and remodels. This fiber realignment may play an important role in the loss of contractile function in the remote zone over time.

Background: Patients undergoing cardiac resynchronization therapy (CRT) are at high risk for ventricular arrhythmias and risk stratification in this population remains poor. Methods and Results: This study followed 269 patients (LVEF < 35%, QRS > 120ms, NYHA III/IV) undergoing CRT with defibrillator (CRT-D) for 553±464 days after CRT-D implantation to assess for independent predictors of appropriate device therapy for ventricular arrhythmias (VAs). Baseline medication use, medical comorbidities, and echocardiographic parameters were considered. The 4-year incidence of appropriate device therapy was 36%. A Cox proportional hazard model identified left ventricular end systolic diameter (LVESD) > 61mm as an independent predictor in the entire population (HR 2.66, p = 0.001). Those with LVESD > 61mm had a 51% 3-year incidence of VA compared to a 26% incidence among those with a less dilated ventricle (p = 0.001). Among patients with LVESD ≤61mm, multivariate predictors of appropriate therapy were absence of beta-blocker therapy (HR 6.34, p<0.001, LVEF < 20% (HR 4.22, p <0.001), and history of sustained VA (2.97, p = 0.013). Early (<180d after implant) shock therapy was found to be a robust predictor of heart failure hospitalization (HR 3.41, p < 0.004) and mortality (HR 5.16 p < 0.001.) Conclusions: Among CRT-D patients, LVESD > 61mm is powerful predictor of ventricular arrhythmias and further risk stratification of those with less dilated ventricles can be achieved based on assessment of EF, history of sustained VA, and absence of beta-blocker therapy.

Background: Late gadolinium enhancement (LGE) is the current standard for myocardial scar delineation. In this study, we introduce the tractographic propagation angle (PA), a metric of myofiber curvature (degrees/unit distance) derived from diffusion tensor imaging (DTI), and compare its use to LGE and invasive scar assessment by endocardial voltage mapping. Methods and Results: DTI was performed on 7 healthy human volunteers, 5 patients with myocardial infarction, 6 normal mice, and 7 mice with myocardial infarction. LGE to delineate the infarct and border zones was performed with a 2‐dimensional inversion recovery gradient‐echo sequence. Ex vivo DTI was performed on 5 normal human and 5 normal sheep hearts. Endocardial electroanatomic mapping and subsequent ex vivo DTI was performed on 5 infarcted sheep hearts. PA in the normal human hearts varied smoothly and was generally <4. The mean PA in the infarct zone was significantly elevated (10.34±1.02 versus 4.05±0.45, P<0.05). Regions with a PA ≤4 consistently had a bipolar voltage ≥1.5 mV, whereas those with PA values between 4 and 10 had voltages between 0.5 and 1.5 mV. A PA threshold >4 was the most accurate DTI‐derived measure of infarct size and demonstrated the greatest correlation with LGE (r=0.95). Conclusions: We found a strong correlation between infarct size by PA and LGE in both mice and humans. There was also an inverse relationship between PA values and endocardial voltage. The use of PA may enable myocardial scar delineation and characterization of arrhythmogenic substrate without the need for exogenous contrast agents.

Background: Mitochondrial membrane potential (ΔΨm) arises from normal function of the electron transport chain. Maintenance of ΔΨm within a narrow range is essential for mitochondrial function. Methods for in vivo measurement of ΔΨm do not exist. We use 18F-labeled tetraphenylphosphonium (18F-TPP+) to measure and map the total membrane potential, ΔΨT, as the sum of ΔΨm and cellular (ΔΨc) electrical potentials. Methods: Eight pigs, five controls and three with a scar-like injury, were studied. Pigs were studied with a dynamic PET scanning protocol to measure 18F-TPP+ volume of distribution, VT. Fractional extracellular space (fECS) was measured in 3 pigs. We derived equations expressing ΔΨT as a function of VT and the volume-fractions of mitochondria and fECS. Seventeen segment polar maps and parametric images of ΔΨT were calculated in millivolts (mV). Results: In controls, mean segmental ΔΨT = -129.4±1.4 mV (SEM). In pigs with segmental tissue injury, ΔΨT was clearly separated from control segments but variable, in the range -100 to 0 mV. The quality of ΔΨT maps was excellent, with low noise and good resolution. Measurements of ΔΨT in the left ventricle of pigs agree with previous in in-vitro measurements. Conclusions: We have analyzed the factors affecting the uptake of voltage sensing tracers and developed a minimally invasive method for mapping ΔΨT in left ventricular myocardium of pigs. ΔΨT is computed in absolute units, allowing for visual and statistical comparison of individual values with normative data. These studies demonstrate the first in vivo application of quantitative mapping of total tissue membrane potential, ΔΨT.