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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)

The excitation-contraction coupling properties of cardiac myocytes isolated from different regions of the mammalian left ventricular wall have been shown to vary considerably, with uncertain effects on ventricular function. We embedded a cell-level excitation-contraction coupling model with region-dependent parameters within a simple finite element model of left ventricular geometry to study effects of electromechanical heterogeneity on local myocardial mechanics and global haemodynamics. This model was compared with one in which heterogeneous myocyte parameters were assigned randomly throughout the mesh while preserving the total amount of each cell subtype. The two models displayed nearly identical transmural patterns of fibre and cross-fibre strains at end-systole, but showed clear differences in fibre strains at earlier points during systole. Haemodynamic function, including peak left ventricular pressure, maximal rate of left ventricular pressure development and stroke volume, were essentially identical in the two models. These results suggest that in the intact ventricle heterogeneously distributed myocyte subtypes primarily impact local deformation of the myocardium, and that these effects are greatest during early systole.

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.

Advances in computer power, novel diagnostic and therapeutic medical technologies, and an increasing knowledge of pathophysiology from gene to organ systems make it increasingly feasible to apply multiscale patient-specific modeling based on proven disease mechanisms. Such models may guide and predict the response to therapy in many areas of medicine. This is an exciting and relatively new approach, for which efficient methods and computational tools are of the utmost importance. Investigators have designed patient-specific models in almost all areas of human physiology. Not only will these models be useful in clinical settings to predict and optimize the outcome from surgery and non-interventional therapy, but they will also provide pathophysiologic insights from the cellular level to the organ system level. Models, therefore, will provide insight as to why specific interventions succeed or fail.

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.

Introduction Pacing site is known to influence the contractile state of the ventricle. Non-physiologic pacing sites such as the right ventricular apex (RVA) or left ventricular freewall (LVFW) have been shown to decrease the contractile state of normal myocardium, due to abnormal electrical propagation. The impact of pacing at these sites may alter mechanical restitution (MR), a fundamental cardiac property involving the electro-mechanical regulation of contraction. This, in turn, may affect cardiac function. The present study was conducted to determine if pacing site alters the time constant of MR: τ. Methods and results Anesthetized canines (n = 6) were acutely paced at four sites: right atrium (RA), RVA, right ventricular septum (RVS), and LVFW. MR data was captured by the S1–S2 pacing protocol and used to create MR curves, generating a restitution time constant, τ, at each site. No significant difference in τ was found between pacing sites. A linear regression analysis of MR curves revealed that there was no significant difference in slope between pacing sites. Conclusion Although pacing site has been found to influence the contractile state of the ventricle, this is the first known study to demonstrate no change in τ in an in vivo preparation. This suggests that alteration of electro-mechanical coupling described by MR is not sufficiently robust to provide insight into pacing site and cardiac function in healthy hearts.

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.

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.

Introduction: It is known that as stimulation frequency is increased in a healthy heart, a corresponding increase in LV contractile function (dP/dtmax) is observed, i.e., force–frequency relationship. The impact of this relationship on systolic and diastolic mechanical restitution in an ejecting, in vivo preparation has yet to be explored. Understanding this relationship may lead to further insight on the cellular processes that govern the contraction and relaxation of the heart, in addition to providing a safer, more feasible clinical diagnostic tool. Methods and Results: Anesthetized canines (n = 8) were paced from the RA at rates of 130, 150, and 180 bpm. At each rate, extrasystoles were delivered at varying intervals. The LV dP/dtmax and dP/dtmin associated with the extrasystolic beat were expressed as a percentage of steady-state levels and plotted as a function of the extrasystolic interval to obtain mechanical restitution curves. The systolic restitution time constant length decreased significantly with all increases in heart rate, P < 0.05. In the diastolic case, significant decreases in restitution time constants were seen when heart rate was increased from 130 bpm to 180 bpm, and from 150 bpm to 180 bpm, P < 0.05. Conclusion: This study was the first to quantify the finding that the time constant of restitution significantly and consistently decreased with a consistent increase in heart rate. The identification of such behavior may be employed to develop stimulation protocols and chronic diagnostic tools to more safely and sensitively identify and optimize the clinical status of patients receiving pacing therapy.

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.

Using an optical fiber whose transmission loss depends in a linear way on temperature, a thermometric system can be designed that will allow direct measurement of the temperature averaged along the length of the fiber. This paper describes such a system used to test the feasibility of using rare earth-doped fibers in practical distributed measurements of average temperature.© (1992) COPYRIGHT SPIE--The International Society for Optical Engineering. Downloading of the abstract is permitted for personal use only.

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)