Evidence of structural remodeling in the dyssynchronous failing heart.

Ventricular remodeling of both geometry and fiber structure is a prominent feature of several cardiac pathologies. Advances in MRI and analytical methods now make it possible to measure changes of cardiac geometry, fiber, and sheet orientation at high spatial resolution. In this report, we use diffusion tensor imaging to measure the geometry, fiber, and sheet architecture of eight normal and five dyssynchronous failing canine hearts, which were explanted and fixed in an unloaded state. We apply novel computational methods to identify statistically significant changes of cardiac anatomic structure in the failing and control heart populations. The results demonstrate significant regional differences in geometric remodeling in the dyssynchronous failing heart versus control. Ventricular chamber dilatation and reduction in wall thickness in septal and some posterior and anterior regions are observed. Primary fiber orientation showed no significant change. However, this result coupled with the local wall thinning in the septum implies an altered transmural fiber gradient. Further, we observe that orientation of laminar sheets become more vertical in the early-activated septum, with no significant change of sheet orientation in the late-activated lateral wall. Measured changes in both fiber gradient and sheet structure will affect both the heterogeneity of passive myocardial properties as well as electrical activation of the ventricles.

Cardiac dyssynchrony analysis using circumferential versus longitudinal strain: implications for assessing cardiac resynchronization.

BACKGROUND: QRS duration is commonly used to select heart failure patients for cardiac resynchronization therapy (CRT). However, not all patients respond to CRT, and recent data suggest that direct assessments of mechanical dyssynchrony may better predict chronic response. Echo-Doppler methods are being used increasingly, but these principally rely on longitudinal motion (epsilonll). It is unknown whether this analysis yields qualitative and/or quantitative results similar to those based on motion in the predominant muscle-fiber orientation (circumferential; epsiloncc). METHODS AND RESULTS: Both epsilonll and epsiloncc strains were calculated throughout the left ventricle from 3D MR-tagged images for the full cardiac cycle in dogs with cardiac failure and a left bundle conduction delay. Dyssynchrony was assessed from both temporal and regional strain variance analysis. CRT implemented by either biventricular (BiV) or left ventricular-only (LV) pacing enhanced systolic function similarly and correlated with improved dyssynchrony based on epsiloncc-based metrics. In contrast, longitudinal-based analyses revealed significant resynchronization with BiV but not LV for the overall cycle and correlated poorly with global functional benefit. Furthermore, unlike circumferential analysis, epsilonll-based indexes indicated resynchronization in diastole but much less in systole and had a lower dynamic range and higher intrasubject variance. CONCLUSIONS: Dyssynchrony assessed by longitudinal motion is less sensitive to dyssynchrony, follows different time courses than those from circumferential motion, and may manifest CRT benefit during specific cardiac phases depending on pacing mode. These results highlight potential limitations to epsilonll-based analyses and support further efforts to develop noninvasive synchrony measures based on circumferential deformation.

Regional alterations in protein expression in the dyssynchronous failing heart.

BACKGROUND: Left ventricular (LV) mechanical dyssynchrony induces regional heterogeneity of mechanical load and is an independent predictor of mortality and sudden death in heart failure (HF) patients. We tested whether dyssynchrony also induces localized disparities in the expression of proteins involved with mechanical stress, function, and arrhythmia susceptibility. METHODS AND RESULTS: Eleven dogs underwent tachycardia-induced HF pacing, either from the right atrium or high right ventricular free wall. Whereas global LV dysfunction was similar between groups, LV contractile coordination assessed by tagged MRI was markedly dyssynchronous with right ventricular pacing but synchronous with right atrial pacing. In dyssynchronous failing hearts, the lateral LV endocardium displayed a 2-fold increase in phosphorylated erk mitogen-activated protein kinase expression (with no change in phospho-p38 or phospho-jnk), a 30% decline in sarcoplasmic reticulum Ca2+-ATPase, an 80% reduction in phospholamban, and a 60% reduction in the gap junction protein connexin43, relative to neighboring myocardial segments. In contrast, hearts from both right atrial-paced HF dogs and an additional 4 noninstrumented control animals showed minimal regional variability in protein expression. CONCLUSIONS: LV dyssynchrony in failing hearts generates myocardial protein dysregulation concentrated in the late-activated, high-stress lateral endocardium. Such molecular polarization within the LV creates transmural and transchamber expression gradients of calcium handling and gap junction proteins that may worsen chamber function and arrhythmia susceptibility.

Systolic improvement and mechanical resynchronization does not require electrical synchrony in the dilated failing heart with left bundle-branch block.

BACKGROUND: Biventricular (BiV) and left ventricular (LV) pacing similarly augment systolic function in left bundle-branch block (LBBB)-failing hearts despite different electrical activation. We tested whether electrical synchrony is required to achieve mechanical synchronization and functional benefit from pacing. METHODS AND RESULTS: Epicardial mapping, tagged MRI, and hemodynamics were obtained in dogs with LBBB-failing hearts during right atrial, LV, and BiV stimulation. BiV and LV both significantly improved chamber hemodynamics (eg, 25% increase in dP/dt(max) and aortic pulse pressure) compared with atrial pacing-LBBB, and this improvement correlated with mechanical resynchronization. Electrical dispersion, however, decreased 13% with BiV but increased 23% with LV pacing (P<0.01). CONCLUSION: Improved mechanical synchrony and function do not require electrical synchrony. Mechanical coordination plays the dominant role in global systolic improvement with either pacing approach.

A US Food and Drug Administration perspective on cardiac resynchronization and ventricular assist device trials.

Cardiac resynchronization therapy and ventricular assist devices are two of the many US Food and Drug Administration-regulated medical device technologies that are intended for patients with heart failure. Cardiac resynchronization therapy devices have been shown to significantly improve the quality and potentially the duration of life for patients with moderate-to-severe congestive heart failure and electrical dyssynchrony. Likewise, ventricular assist devices have benefited patients with end-stage heart failure through both bridge-to-transplant and destination therapy. The pivotal trials that supported the first approvals for these devices, as well as subsequent trials, were shaped by unique technologic and patient-related concerns. The US Food and Drug Administration has worked to understand these evolving concerns and the role each should play in the design of trials intended to demonstrate the safety and effectiveness of these critical devices.

Cardiac resynchronization devices: the Food and Drug Administration's regulatory considerations.

Cardiac resynchronization therapy (CRT) devices have been studied clinically since 1998, and have been on the U.S. market since the Food and Drug Administration (FDA) approval of the first product in 2001. Since that time, the FDA has approved many different models from three different manufacturers, representing the first and second generations of these products. All of these products have undergone the FDA pre-market approval process, which examines the safety and effectiveness of the devices for their intended use. Over the last several years, the FDA has adapted recommendations for CRT clinical trials based on an evolving understanding of what these devices can achieve. This paper will outline the dynamic nature of the FDA's approval process for CRT devices and briefly review the clinical trial designs for the first generation devices.

Electromechanical mapping with MRI tagging and epicardial sock electrodes.

Methods currently exist for the precise measurement of local three-dimensional myocardial motion noninvasivly with magnetic resonace imaging tagging. From these motion estimates, strain images representing the local deformation of the myocardium can be formed to show local myocardial contraction. These images clearly show the sequence of mechanical events during the activation and relaxation of the heart, making them ideal to visualize abnormalities caused by asynchronous electrical activation or ischemia. Coupled with the near simultaneous mapping of electrical depolarization with a sock electrode array, we can investigate the relationship between electical activity and mechanical function on a local level in the in vivo heart. Registered fiber angle maps can be also be obtained in the same heart with diffusion magnetic resonance imaging to assist in the construction of the electromechanical model of the whole heart.

Torsion of the left ventricle during pacing with MRI tagging.

The effects of different pacing protocols on left ventricular (LV) torsion were evaluated over the full cardiac cycle. A systolic and diastolic series of magnetic resonance imaging (MRI) scans were combined and used to calculate the torsion of the LV in a canine model. The asynchronous activation resulting from ventricular pacing interferes with the temporal evolution of LV torsion. The torsion of the left ventricle was investigated under three different protocols: 1) right atrial pacing, 2) right ventricular pacing, and 3) simultaneous pacing from the right ventricular apex and LV base. The temporal evolution of torsion was determined from tagged MRI and evaluated over the cardiac cycle. The peak rotation for the atrially paced hearts was 11.1 degrees (+/- 3.5 degrees) compared to 6.1 degrees (+/- 1.7 degrees) and 6.1 degrees (+/- 0.7 degree) for those hearts paced from the right ventricle and from both ventricles, respectively. While biventricular pacing increases the synchrony of contraction, it significantly alters the pattern of LV torsion. From these experiments we have shown that measuring torsion is an extremely sensitive indicator of the existence of ectopic excitation.

Effects of single- and biventricular pacing on temporal and spatial dynamics of ventricular contraction.

Resynchronization is frequently used for the treatment of heart failure, but the mechanism for improvement is not entirely clear. In the present study, the temporal synchrony and spatiotemporal distribution of left ventricular (LV) contraction was investigated in eight dogs during right atrial (RA), right ventricular apex (RVa), and biventricular (BiV) pacing using tagged magnetic resonance imaging. Mechanical activation (MA; the onset of circumferential shortening) was calculated from the images throughout the left ventricle for each pacing protocol. MA width (time for 20-90% of the left ventricle to contract) was significantly shorter during RA (43.6 +/- 17.1 ms) than BiV and RVa pacing (67.4 +/- 15.2 and 77.6 +/- 16.4 ms, respectively). The activation delay vector (net delay in MA from one side of the left ventricle to the other) was significantly shorter during RA (18.9 +/- 8.1 ms) and BiV (34.2 +/- 18.3 ms) than during RVa (73.8 +/- 16.3 ms) pacing. Rate of LV pressure increase was significantly lower during RVa than RA pacing (1,070 +/- 370 vs. 1,560 +/- 300 mmHg/s) with intermediate values for BiV pacing (1,310 +/- 220 mmHg/s). BiV pacing has a greater impact on correcting the spatial distribution of LV contraction than on improving the temporal synchronization of contraction. Spatiotemporal distribution of contraction may be an important determinant of ventricular function.

Timing of depolarization and contraction in the paced canine left ventricle: model and experiment.

INTRODUCTION: For efficient pump function, contraction of the heart should be as synchronous as possible. Ventricular pacing induces asynchrony of depolarization and contraction. The degree of asynchrony depends on the position of the pacing electrode. The aim of this study was to extend an existing numerical model of electromechanics in the left ventricle (LV) to the application of ventricular pacing. With the model, the relation between pacing site and patterns of depolarization and contraction was investigated. METHODS AND RESULTS: The LV was approximated by a thick-walled ellipsoid with a realistic myofiber orientation. Propagation of the depolarization wave was described by the eikonal-diffusion equation, in which five parameters play a role: myocardial and subendocardial velocity of wave propagation along the myofiber cm and ce; myocardial and subendocardial anisotropy am and ae; and parameter k, describing the influence of wave curvature on wave velocity. Parameters cm, ae, and k were taken from literature. Parameters am and ce were estimated by fitting the model to experimental data, obtained by pacing the canine left ventricular free wall (LVFW). The best fit was found with cm = 0.75 m/s, ce = 1.3 m/s, am = 2.5, ae = 1.5, and k = 2.1 x 10(-4) m2/s. With these parameter settings, for right ventricular apex (RVA) pacing, the depolarization times were realistically simulated as also shown by the wavefronts and the time needed to activate the LVFW. The moment of depolarization was used to initiate myofiber contraction in a model of LV mechanics. For both pacing situations, mid-wall circumferential strains and onset of myofiber shortening were obtained. CONCLUSION: With a relatively simple model setup, simulated depolarization timing patterns agreed with measurements for pacing at the LVFW and RVA in an LV. Myocardial cross-fiber wave velocity is estimated to be 0.40 times the velocity along the myofiber direction (0.75 m/s). Subendocardial wave velocity is about 1.7 times faster than in the rest of the myocardium, but about 3 times slower than as found in Purkinje fibers. Furthermore, model and experiment agreed in the following respects. (1) Ventricular pacing decreased both systolic pressure and ejection fraction relative to natural sinus rhythm. (2) In early depolarized regions, early shortening was observed in the isovolumic contraction phase; in late depolarized regions, myofibers were stretched in this phase. Maps showing timing of onset of shortening were similar to previously measured maps in which wave velocity of contraction appeared similar to that of depolarization.

Endocardial versus epicardial electrical synchrony during LV free-wall pacing.

Cardiac resynchronization therapy has been most typically achieved by biventricular stimulation. However, left ventricular (LV) free-wall pacing appears equally effective in acute and chronic clinical studies. Recent data suggest electrical synchrony measured epicardially is not required to yield effective mechanical synchronization, whereas endocardial mapping data suggest synchrony (fusion with intrinsic conduction) is important. To better understand this disparity, we simultaneously mapped both endocardial and epicardial electrical activation during LV free-wall pacing at varying atrioventricular delays (AV delay 0-150 ms) in six normal dogs with the use of a 64-electrode LV endocardial basket and a 128-electrode epicardial sock. The transition from dyssynchronous LV-paced activation to synchronous RA-paced activation was studied by constructing activation time maps for both endo- and epicardial surfaces as a function of increasing AV delay. The AV delay at the transition from dyssynchronous to synchronous activation was defined as the transition delay (AVt). AVt was variable among experiments, in the range of 44-93 ms on the epicardium and 47-105 ms on the endocardium. Differences in endo- and epicardial AVt were smaller (-17 to +12 ms) and not significant on average (-5.0 +/- 5.2 ms). In no instance was the transition to synchrony complete on one surface without substantial concurrent transition on the other surface. We conclude that both epicardial and endocardial synchrony due to fusion of native with ventricular stimulation occur nearly concurrently. Assessment of electrical epicardial delay, as often used clinically during cardiac resynchronization therapy lead placement, should provide adequate assessment of stimulation delay for inner wall layers as well.

Novel technique for cardiac electromechanical mapping with magnetic resonance imaging tagging and an epicardial electrode sock.

Near-simultaneous measurements of electrical and mechanical activation over the entire ventricular surface are now possible using magnetic resonance imaging tagging and a multielectrode epicardial sock. This new electromechanical mapping technique is demonstrated in the ventricularly paced canine heart. A 128-electrode epicardial sock and pacing electrodes were placed on the hearts of four anesthetized dogs. In the magnetic resonance scanner, tagged cine images (8-15 ms/frame) and sock electrode recordings (1000 Hz) were acquired under right-ventricular pacing and temporally referenced to the pacing stimulus. Electrical recordings were obtained during intermittent breaks in image acquisition, so that both data sets represented the same physiologic state. Since the electrodes were not visible in the images, electrode recordings and cine images were spatially registered with Gd-DTPA markers attached to the sock. Circumferential strain was calculated at locations corresponding to electrodes. For each electrode location, electrical and mechanical activation times were calculated and relationships between the two activation patterns were demonstrated. This method holds promise for improving understanding of the relationships between the patterns of electrical activation and contraction in the heart.