Search

Role of Ischemia and Scar in CRT Patients with CAD Introduction Cardiac resynchronization therapy (CRT) recipients with ischemic cardiomyopathy (ICM) have scar segments that may limit ventricular resynchronization and clinical response. The impact of myocardial viability at the left ventricular (LV) pacing site on CRT response is poorly elucidated. Methods and Results A retrospective cohort of 160 ICM patients with single photon emission computed tomography-myocardial perfusion imaging before device implantation were included. Coronary venous angiography and chest radiographs helped classify segmental location of LV lead (LVL). The primary outcome was a composite of heart failure (HF) hospitalization and mortality at 3 years, and secondary outcome was change in systolic function at 6 months. The patients were divided into groups based on the myocardial substrate at the site of LVL: LVL on or adjacent to (1) normal myocardium (LVL-N, n = 64), (2) segmental scar (LVL-S, n = 62), and (3) scar and ischemia (LVL-SI, n = 34). Upon follow-up, 75 (47%) patients reached primary endpoint with a higher incidence noted in LVL-S (60%), and LVL-SI (53%), compared to 31% in LVL-N (P = 0.004). Kaplan Meier method demonstrated poor event free survival for primary outcome in LVL-S (P = 0.002), and LVL-SI (P = 0.03). In Cox proportional hazard model, LVL-S (HR: 2.26, P = 0.004), and LVL-SI (1.9, P = 0.047) were independent predictors of primary outcome. Conclusion In CRT recipients with ICM, scar and reversible ischemia in or adjacent to LV pacing site were independent predictors of HF hospitalization and death.

ObjectivesThe aim of this study was to determine whether left ventricular (LV) midwall fibrosis, detected by midwall hyperenhancement (MWHE) on late gadolinium enhancement cardiovascular magnetic resonance (CMR) imaging, predicts mortality and morbidity in patients with dilated cardiomyopathy (DCM) undergoing cardiac resynchronization therapy (CRT).BackgroundMidwall fibrosis predicts mortality and morbidity in patients with DCM.MethodsPatients with DCM with (+) or without (−) MWHE (n = 20 and n = 77, respectively) as well as 161 patients with ischemic cardiomyopathy (ICM) undergoing CRT (n = 258) were followed up for a maximum of 8.7 years.ResultsAmong patients with DCM, +MWHE predicted cardiovascular mortality (hazard ratio [HR]: 18.6; 95% confidence intervals [CI]: 3.51 to 98.5; p = 0.0008), total mortality or hospitalization for major adverse cardiovascular events (HR: 7.57; 95% CI: 2.71 to 21.2; p < 0.0001), and cardiovascular mortality or heart failure hospitalizations (HR: 9.56; 95% CI: 2.72 to 33.6; p = 0.0004), independent of New York Heart Association class, QRS duration, atrial fibrillation, LV volumes, LV ejection fraction, and a CMR-derived measure of dyssynchrony. Among patients with DCM and ICM, the risk of cardiovascular mortality for DCM +MWHE (adjusted HR: 18.5; 95% CI: 3.93 to 87.3; p = 0.0002) was similar to that for ICM (adjusted HR: 21.0; 95% CI: 5.06 to 87.2; p < 0.0001). Both DCM +MWHE and ICM were predictors of pump failure death as well as sudden cardiac death. LV reverse remodeling was observed in DCM −MWHE and in ICM but not in DCM +MWHE.ConclusionsMidwall fibrosis is an independent predictor of mortality and morbidity in patients with DCM undergoing CRT. The outcome of DCM with midwall fibrosis is similar to that of ICM. This relationship is mediated by both pump failure and sudden cardiac death.

Recently, attention has been focused on comparing left ventricular (LV) endocardial (ENDO) with epicardial (EPI) pacing for cardiac resynchronization therapy. However, the effects of ENDO and EPI lead placement at multiple sites have not been studied in failing hearts. We hypothesized that differences in the improvement of ventricular function due to ENDO vs. EPI pacing in dyssynchronous (DYSS) heart failure may depend on the position of the LV lead in relation to the original activation pattern. In six nonfailing and six failing dogs, electrical DYSS was created by atrioventricular sequential pacing of the right ventricular apex. ENDO was compared with EPI biventricular pacing at five LV sites. In failing hearts, increases in the maximum rate of LV pressure change (dP/d t; r = 0.64), ejection fraction ( r = 0.49), and minimum dP/d t ( r = 0.51), relative to DYSS, were positively correlated ( P < 0.01) with activation time at the LV pacing site during ENDO but not EPI pacing. ENDO pacing at sites with longer activation delays led to greater improvements in hemodynamic parameters and was associated with an overall reduction in electrical DYSS compared with EPI pacing ( P < 0.05). These findings were qualitatively similar for nonfailing hearts. Improvement in hemodynamic function increased with activation time at the LV pacing site during ENDO but not EPI pacing. At the anterolateral wall, end-systolic transmural function was greater with local ENDO compared with EPI pacing. ENDO pacing and intrinsic activation delay may have important implications for management of DYSS heart failure.

Background: Both anatomic interlead separation and left ventricle lead electrical delay (LVLED) have been associated with outcomes following cardiac resynchronization therapy (CRT). However, the relationship between interlead distance and electrical delay in predicting CRT outcomes has not been defined. Methods: We studied 61 consecutive patients undergoing CRT for standard clinical indications. All patients underwent intraprocedural measurement of LVLED. Interlead distances in the horizontal (HD), vertical (VD), and direct (DD) dimensions were measured from postprocedure chest radiographs (CXR). Remodeling indices [percent change in left ventricle (LV) ejection fraction, end-diastolic, end-systolic dimensions] were assessed by transthoracic echocardiogram. Results: There was a positive correlation between corrected LVLED and HD on lateral CXR (r = 0.361, P = 0.004) and a negative correlation between LVLED and VD on posteroanterior (PA) CXR (r =−0.281, P = 0.028). To account for this inverse relationship, we developed a composite anatomic distance (defined as: lateral HD—PA VD), which correlated most closely with LVLED (r = 0.404, P = 0.001). Follow-up was available for 48 patients. At a mean of 4.1 ± 3.2 months, patients with optimal values for both corrected LVLED (≥75%) and composite anatomic distance (≥15 cm) demonstrated greater reverse LV remodeling than patients with either one or neither of these optimized values. Conclusions: We identified a significant correlation between LV–right ventricular interlead distance and LVLED; additionally, both parameters act synergistically in predicting LV anatomic reverse remodeling. Efforts to optimize both interlead distance and electrical delay may improve CRT outcomes. (PACE 2010; 575–582)

To study the impact of biventricular pacing (BiV) and scar size on left ventricular (LV) regional and global function using a detailed finite element model of three-dimensional electromechanics in the failing canine heart.Cardiac resynchronization therapy (CRT) clinical trials have demonstrated that up to 30% of patients may be classified as non-responders. The presence of a scar appears to contribute to those that do not respond to CRT. A recent study in patients with myocardial scar showed that LV dyssynchrony was the sole independent predictor of reverse remodeling, and not scar location or size.Two activation sequences were simulated: left bundle branch block (LBBB) and acute simultaneous BiV (with leads in the left and right ventricle) in hearts with chronic scars of various sizes. The dependence of regional function (mean fiber ejection strain, variance of fiber isovolumic strain and fraction of tissue stretched during ejection) and global function (left ventricular dP/dt(max), ejection fraction, stroke work) on scar size and pacing protocol was tested.Global function and regional function averaged over the whole LV during LBBB and BiV decreased as a function of scar size. In the non-scarred regions, however, regional function was largely independent of scar size for a fixed pacing site.The model results suggest that uniformity of mechanical contraction in non-scarred regions in the failing heart during biventricular pacing is independent of scar size for a fixed pacing site.

Introduction:We tested the feasibility of a new technique of direct left ventricular endocardial lead placement across the aortic valve in a chronic (six month) pig model. The potential for aortic valve damage, systemic embolization, and pacing lead maturation and function within the left ventricle are unknown. Methods:Ten minipigs were successfully implanted with a transaortic left ventricular lead (Medtronic CapSureFix®, Minneapolis, MN, USA) placed in the left ventricular apex via the carotid artery. Each pig received either a polyurethane (n = 5) or silicone (n = 5) lead. Post implant each pig received clopidogrel and aspirin for seven days. After six months all surviving pigs underwent thorough necropsy. Results:Each pig had adequate sensing (12.1 ± 4 mV) and pacing thresholds (0.79 ± 0.2 @ 0.5 V) at implant. Postoperatively two pigs died of a respiratory illness. One pig died postoperatively due to sepsis. At the six-month follow-up, all surviving pigs (n = 7) were in a healthy state. Of the pigs without dislodgement (n = 5) there was adequate sensing, but a rise in pacing thresholds. Echocardiography revealed a normal ejection fraction and only trace to mild aortic insufficiency in all pigs. Of the seven surviving pigs there were no thromboembolic events noted. One silicone lead was noted to have thrombosis along the lead screw and shaft. Conclusion:Direct transaortic placement of a left ventricular lead is feasible. After six months, there was no significant aortic regurgitation and no evidence of thromboembolism despite no anticoagulation. Lead function was acceptable and only one silicone lead (and no polyurethane lead) was noted to have significant thrombosis.

Electrical dyssynchrony leads to prestretch in late-activated regions and alters the sequence of mechanical contraction, although prestretch and its mechanisms are not well defined in the failing heart. We hypothesized that in heart failure, fiber prestretch magnitude increases with the amount of early-activated tissue and results in increased end-systolic strains, possibly due to length-dependent muscle properties. In five failing dog hearts with scars, three-dimensional strains were measured at the anterolateral left ventricle (LV). Prestretch magnitude was varied via ventricular pacing at increasing distances from the measurement site and was found to increase with activation time at various wall depths. At the subepicardium, prestretch magnitude positively correlated with the amount of early-activated tissue. At the subendocardium, local end-systolic strains (fiber shortening, radial wall thickening) increased proportionally to prestretch magnitude, resulting in greater mean strain values in late-activated compared with early-activated tissue. Increased fiber strains at end systole were accompanied by increases in preejection fiber strain, shortening duration, and the onset of fiber relengthening, which were all positively correlated with local activation time. In a dog-specific computational failing heart model, removal of length and velocity dependence on active fiber stress generation, both separately and together, alter the correlations between local electrical activation time and timing of fiber strains but do not primarily account for these relationships.

Although scar has been associated with poor outcome after CRT, the impact of coronary artery disease (CAD) severity or ischemia on CRT response remains uncertain. A prospective cohort of CRT patients with ischemic cardiomyopathy was evaluated for ischemia and scar with nuclear perfusion imaging.

Background— Heart failure (HF) in combination with mechanical dyssynchrony is associated with a high mortality rate. To quantify contractile dysfunction in patients with HF, investigators have proposed several indices of mechanical dyssynchrony, including percentile range of time to peak shortening (WTpeak), circumferential uniformity ratio estimate (CURE), and internal stretch fraction (ISF). The goal of this study was to compare the sensitivity of these indices to 4 major abnormalities responsible for cardiac dysfunction in dyssynchronous HF: dilation, negative inotropy, negative lusitropy, and dyssynchronous activation. Methods and Results— All combinations of these 4 major abnormalities were included in 3D computational models of ventricular electromechanics. Compared with a nonfailing heart model, ventricles were dilated, inotropy was reduced, twitch duration was prolonged, and activation sequence was changed from normal to left bundle branch block. In the nonfailing heart, CURE, ISF, and WTpeak were 0.97±0.004, 0.010±0.002, and 78±1 milliseconds, respectively. With dilation alone, CURE decreased 2.0±0.07%, ISF increased 58±47%, and WTpeak increased 31±3%. With dyssynchronous activation alone, CURE decreased 15±0.6%, ISF increased 14-fold (±3), and WTpeak increased 121±4%. With the combination of dilation and dyssynchronous activation, CURE decreased 23±0.8%, ISF increased 20-fold (±5), and WTpeak increased 147±5%. Conclusions— Dilation and left bundle branch block combined synergistically decreased regional cardiac function. CURE and ISF were sensitive to this combination, but WTpeak was not. CURE and ISF also reflected the relative nonuniform distribution of regional work better than WTpeak. These findings might explain why CURE and ISF are better predictors of reverse remodeling in cardiac resynchronization therapy.

Cardiac dyssynchrony often accompanies patients with heart failure (HF) and can lead to an increase in mortality rate. Cardiac resynchronization therapy (CRT) has been shown to provide substantial benefits to the HF population with ventricular dyssynchrony; however, there still exists a group of patients who do not respond to this treatment. In order to better understand patient response to CRT, it is necessary to quantitatively characterize both electrical and mechanical dyssynchrony. The quantification of mechanical dyssynchrony via characterization of contraction strain field inhomogeneity is the focus of this modeling investigation. Raw data from a 3D finite element (FE) model were received from Roy Kerckhoffs et al. and analyzed in MATLAB. The FE model consisted of canine left and right ventricles coupled to a closed circulation with the effects of the pericardium acting as a pressure on the epicardial surface. For each of three simulations (normal synchronous, SYNC, right ventricular apical pacing, RVA, and left ventricular free wall pacing, LVFW) the Gauss point locations and values were used to generate lookup tables (LUTs) with each entry representing a location in the heart. In essence, we employed piecewise cubic interpolation to generate a fine point cloud (LUTs) from a course point cloud (Gauss points). Strain was calculated in the fiber direction and was then displayed in multiple ways to better characterize strain inhomogeneity. By plotting average strain and standard deviation over time, the point of maximum contraction and the point of maximal inhomogeneity were found for each simulation. Strain values were organized into seven strain bins to show operative strain ranges and extent of inhomogeneity throughout the heart wall. In order to visualize strain propagation, magnitude, and inhomogeneity over time, we created 2D area maps displaying strain over the entire cardiac cycle. To visualize spatial strain distribution at the time point of maximum inhomogeneity, a 3D point cloud was created for each simulation, and a CURE index was calculated. We found that both the RVA and LFVW simulations took longer to reach maximum contraction than the SYNC simulation, while also exhibiting larger disparities in strain values during contraction. Strain in the hoop direction was also analyzed and was found to be similar to the fiber strain results. It was found that our method of analyzing contraction strain pattern yielded more detailed spacial and temporal information about fiber strain in the heart over the cardiac cycle than the more conventional CURE index method. We also observed that our method of strain binning aids in visualization of the strain fields, and in particular, the separation of the mass points into separate images associated with each strain bin allows the strain pattern to be explicitly compartmentalized.

In recent years, cardiac resynchronization therapy (CRT) has become an effective and popular approach to the treatment of heart failure with a conduction disturbance, but it is unclear why 30% of patients do not respond. With improvements in computer power, diagnostic and therapeutic medical technologies, it is increasingly feasible to apply patient-specific modeling to guide and predict the response to CRT. In this chapter we discuss strategies as to how computational modeling of CRT could be used to try to predict the outcome of this therapy patient-specifically.

Here we describe new computational models of cardiac electromechanics starting from the cellular scale and building to the tissue, organ and system scales. We summarize application to human genetic diseases (LQT1 and LQT3) and to modeling of congestive heart failure.

Cardiac resynchronization therapy (CRT) is a promising therapy for heart failure patients with a conduction disturbance, such as left bundle branch block. The aim of CRT is to resynchronize contraction between and within ventricles. However, about 30% of patients do not respond to this therapy. Therefore, a better understanding is needed for the relation between electrical and mechanical activation. In this paper, we focus on to what extent animal experiments and mathematical models can help in order to understand the pathophysiology of asynchrony to further improve CRT.

Insights into intracellular calcium regulation and contractile state can be accomplished by changing pacing rate. Steady-state increases in heart rate (HR) (force-frequency relationship, FFR), and introduction of extrasystoles (ES) (force-interval relationship, FIR) have been used to investigate this relationship. This study focused on the recirculation fraction (RF) and potentiation ratio (PR), obtained from the recovery of the FFR and FIR. These parameters may provide insight on intracellular Ca(2+) regulation. Left ventricular (LV) pressures and HR were assessed in anesthetized canines (n = 7). Intrinsic data were collected prior to and following HR increases to 150, 180, and 200 bpm, as well as following delivery of an ES at 280 ms. The RF was calculated as the slope of dP/dt(max(n + 1)) vs. dP/dt(max(n)), where n = beat number. The PR was calculated by normalizing dP/dt(max) from the first beat following the ES (or the last paced beat) to the steady-state dP/dt(max). The RF due to an ES was not significantly different than that from a HR of 200 bpm. The PR from an ES was not significantly different than from a HR of 150 bpm. The impact of an ES delivered at an interval of 280 ms produces a PR similar to that from a HR of 150 bpm; yet, it recovers similarly to the termination of pacing at 200 bpm, eliciting a similar RF value. The method of measuring RF by an ES versus an increased HR may provide a safer and more feasible approach to collecting diagnostic information.

Clinical trials evaluating cardiac resynchronization therapy (CRT) have demonstrated that 30% of patients with heart failure and wide QRS do not respond to CRT (especially patients with myocardial infarcts). We have developed 3D numerical models of failing hearts, with and without chronic infarcts in different regions of the left ventricle. The hearts were coupled to a closed circulation, and the model included effects of the pericardium. The hearts were either paced at the right ventricular apex (RVA) or left ventricular free wall (LVFW). In normal and failing hearts, LV pump function was moderately better for LVFW pacing. In the normal heart model, heterogeneity of ejection strain was similar for RVA and LVFW pacing. However, in the failing heart model, LVFW pacing was associated with 44% less heterogeneity of ejection strain. This may be an important factor in the remodeling process associated with pacing.

Despite recent advances in techniques of reperfusion for acute myocardial ischemia, myocardial salvage remains suboptimal. β-Blockers have been shown to limit infarct size during acute ischemia, but their negative inotropic properties have limited their use. Cardiopulmonary bypass is an attractive technique for cardiac resuscitation because it can stabilize a hemodynamically compromised patient and potentially reduce myocardial oxygen consumption. In an attempt to maximize myocardial salvage in the setting of acute ischemia, the combination of esmolol, an ultrashort-acting β-blocker, with percutaneous cardiopulmonary bypass was evaluated. Four groups of instrumented dogs underwent 2 hours of myocardial ischemia induced by occlusion of the proximal left anterior descending coronary artery, followed by 1 hour of reperfusion. Throughout the period of ischemia and reperfusion, esmolol plus percutaneous cardiopulmonary bypass was compared with esmolol alone, percutaneous cardiopulmonary bypass alone, and control conditions. After the reperfusion period, the extent of infarction of the left ventricle at risk was determined. Four animals had intractable arrhythmias: one in the esmolol plus bypass group, one in the esmolol group, and two in the control group. The extent of infarction of the left ventricle at risk was significantly reduced in the esmolol plus bypass group (30%) compared with bypass alone (52%), with esmolol alone (54%), and with the control groups (59%; p < 0.05). We conclude that in this experimental model the combination of esmolol with bypass improves myocardial salvage after ischemia and reperfusion. (J THORAC CARDIOVASC SURG 1996;111:1085-91)

Ectopic ventricular pacing leads to regional myocardial prestretch. In-vivo studies suggest that the timing of prestretch determines the effect on pump function and can lead to regional wall remodeling. Here we measure the direct effects of prestretch timing on the magnitude of tension development in isolated cardiac muscle. Prestretch strongly affected tension development but primarily during a brief interval of the twitch. The effects of prestretch were simulated using excised murine right ventricular papillary muscles. A high-speed computer-controlled motor was used to impose precisely timed stretches, while a force transducer measured force output and strain was monitored using a CCD camera and topical markers. The timing of the stretches greatly influenced tension production. A critical stretch timing interval was observed to begin 25 ms after stimulation and extending until 100 ms after stimulation, where stretches occurring in this interval exhibited statistically significant increases in peak tension of as much as 500%. Muscle shortening occurring in the critical interval (from stretches initiated prior to stimulation) showed the opposite effect of stretching in the interval, with peak tension inhibited significantly by as much as 40%. A simple model showed that the varying impact of stretch timing could not be explained by time-varying elastance alone. Therefore, a more detailed and mechanistic myofilament model that included cooperative activation (Campbell et al 2010) was refined to include length dependence and strain-dependent cross-bridge kinetics. By comparing model results and experimental measurements, the strain history dependent mechanisms of these observations was evaluated. These evaluations have led us to the conclusion that even prestretches performed at slow physiologic velocities cause alterations in twitch kinetics that cannot be explained by time varying elastance.