An Approach to the Stepwise Management of Severe Mitral Regurgitation with Optimal Cardiac Pacemaker Function

Right ventricular apical pacing may cause or worsen mitral regurgitation (MR). Potential mechanisms for this adverse sequelae include intraventricular dyssynchrony, altered papillary muscle function, pacing-induced cardiomyopathy with left ventricular dilation, and annular dilation. In contrast, biventricular (BiV) pacing may improve MR presumably by opposing the negative effects. Whether or not left ventricular lead location is important in treating mitral regurgitation in patients with pacemakers is unknown.We report a case of severe MR and left ventricular (LV) systolic failure in a patient with right ventricular pacing. Multiple potential etiologies for the worsening valve function were noted, and a stepwise iterative optimizing scheme that included basal lateral LV pacing improved mitral valve function and ameliorated heart failure symptoms.     

Biventricular pacing in the early postoperative period after cardiac surgery

Cardiac resynchronization therapy is not commonly used in the early postoperative period in patients undergoing cardiac surgery who have left ventricular (LV) dysfunction and a history of heart failure. We performed a prospective randomized clinical trial to compare atrial synchronous right ventricular (DDD RV) and biventricular (DDD BIV) pacing within 72 hours after cardiac surgery in patients with an EF ≤35 %, a QRS interval longer than 120 msec and who had LV dyssynchrony detected by real-time three-dimensional echocardiography (RT3DE). Epicardial pacing was provided by a modified Medtronic INSYNC III pacemaker. An LV epicardial pacing lead was implanted on the latest activated segment of the LV based on RT3DE. The study included 18 patients with ischemic heart disease, with or without valvular heart disease (14 men, 4 women, average age 71 years). Patients undergoing DDD BIV pacing had a statistically significant greater CO and CI (CO 6.7±1.8 l/min, CI 3.4±0.7 l/min/m(2)) than patients undergoing DDD RV pacing (CO 5.5±1.4 l/min, CI 2.8±0.7 l/min/m(2)), p<0.001. DDD BIV pacing in the early postoperative period after cardiac surgery corrects LV dyssynchrony and has better hemodynamic results than DDD RV pacing.     

Exhaustion of the Frank-Starling mechanism in conscious dogs with heart failure induced by chronic coronary microembolization

The role of the Frank-Starling mechanism in the regulation of cardiac systolic function in the ischemic failing heart was examined in conscious dogs. Left ventricular (LV) dimension, pressure and systolic function were assessed using surgically implanted instrumentations and non-invasive echocardiogram. Heart failure was induced by daily intra-coronary injections of microspheres for 3-4 weeks via implanted coronary catheters. Chronic coronary embolization resulted in a progressive dilation of the left ventricle (12+/-3%), increase in LV end-diastolic pressure (118+/-19%), depression of LV dP/dt(max) (-19+/-4%), fractional shortening (-36+/-7%), and cardiac work (-60+/-9%), and development of heart failure, while the LV contractile response to dobutamine was depressed. A brief inferior vena caval occlusion in dogs with heart failure decreased LV preload to match the levels attained in their control state and caused a further reduction of LV dP/dt(max), fractional shortening, stroke work and cardiac work. Moreover, in response to acute volume loading, the change in the LV end-diastolic dimension-pressure (DeltaLVEDD-DeltaLVEDP) curve in the failing heart became steeper and shifted significantly to the left, while the increases in LV stroke work and cardiac work were blunted. Thus, our results suggest that the Frank-Starling mechanism is exhausted in heart failure and unable to further respond to increasing volume while it plays an important compensatory role in adaptation to LV dysfunction in heart failure.     

Effect of acute high-intensity interval exercise on postexercise biventricular function in mild heart failure

We studied the acute effect of high-intensity interval exercise on biventricular function using cardiac magnetic resonance imaging in nine patients [age: 49 ± 16 yr; left ventricular (LV) ejection fraction (EF): 35.8 ± 7.2%] with nonischemic mild heart failure (HF). We hypothesized that a significant impairment in the immediate postexercise end-systolic volume (ESV) and end-diastolic volume (EDV) would contribute to a reduction in EF. We found that immediately following acute high-intensity interval exercise, LV ESV decreased by 6% and LV systolic annular velocity increased by 21% (both P < 0.05). Thirty minutes following exercise (+30 min), there was an absolute increase in LV EF of 2.4% (P < 0.05). Measures of preload, left atrial volume and LV EDV, were reduced immediately following exercise. Similar responses were observed for right ventricular volumes. Early filling velocity, filling rate, and diastolic annular velocity remained unchanged, while LV untwisting rate increased 24% immediately following exercise (P < 0.05) and remained 18% above baseline at +30 min (P < 0.05). The major novel findings of this investigation are 1) that acute high-intensity interval exercise decreases the immediate postexercise LV ESV and increases LV EF at +30 min in patients with mild HF, and this is associated with a reduction in LV afterload and maintenance of contractility, and 2) that despite a reduction in left atrial volume and LV EDV immediately postexercise, diastolic function is preserved and may be modulated by enhanced LV peak untwisting rate. Acute high-intensity interval exercise does not impair postexercise biventricular function in patients with nonischemic mild HF.     

Biventricular mechanical asynchrony predicts hemodynamic effect of uni- and biventricular pacing

We tested whether biventricular resynchronization explains contractile function changes with univentricular and biventricular pacing in heart failure patients with varying magnitudes of baseline biventricular asynchrony. Thirty patients (New York Hospital Association class > or = III, QRS duration > or =120 ms) were tested. Contractile function was measured by left ventricular maximum first derivative of pressure over time (dP/dtmax). Biventricular mechanical asynchrony was quantified by the normalized pressure-pressure (NPP) loop area formed by the cross-plot of right and left intraventricular pressure curves from each cardiac cycle. Any ventricular pacing increased dP/dtmax if it decreased baseline NPP loop area and almost always worsened dP/dtmax and asynchrony when baseline NPP loop area <0.3. The quantitative relationship between dP/dtmax and NPP loop area change depended on ventricular pacing site and timing relative to intrinsic activation. For similar NPP loop decreases, dP/dtmax increased 16% more with left and biventricular pacing compared with right ventricular pacing. In conclusion, right, left, or biventricular pacing can improve contractile function only in patients having sufficient baseline biventricular asynchrony. However, biventricular resynchronization is only one of the improvement mechanisms.     

Hemodynamics-driven mathematical model of first and second heart sound generation

We propose a novel, two-degree of freedom mathematical model of mechanical vibrations of the heart that generates heart sounds in CircAdapt, a complete real-time model of the cardiovascular system. Heart sounds during rest, exercise, biventricular (BiVHF), left ventricular (LVHF) and right ventricular heart failure (RVHF) were simulated to examine model functionality in various conditions. Simulated and experimental heart sound components showed both qualitative and quantitative agreements in terms of heart sound morphology, frequency, and timing. Rate of left ventricular pressure (LV dp/dt_max) and first heart sound (S1) amplitude were proportional with exercise level. The relation of the second heart sound (S2) amplitude with exercise level was less significant. BiVHF resulted in amplitude reduction of S1. LVHF resulted in reverse splitting of S2 and an amplitude reduction of only the left-sided heart sound components, whereas RVHF resulted in a prolonged splitting of S2 and only a mild amplitude reduction of the right-sided heart sound components. In conclusion, our hemodynamics-driven mathematical model provides fast and realistic simulations of heart sounds under various conditions and may be helpful to find new indicators for diagnosis and prognosis of cardiac diseases.New & noteworthyTo the best of our knowledge, this is the first hemodynamic-based heart sound generation model embedded in a complete real-time computational model of the cardiovascular system. Simulated heart sounds are similar to experimental and clinical measurements, both quantitatively and qualitatively. Our model can be used to investigate the relationships between heart sound acoustic features and hemodynamic factors/anatomical parameters.     

Adverse effects of atrioventricular synchronous right ventricular pacing on left ventricular sympathetic activity, efficiency, and hemodynamic status

Right ventricular (RV) pacing is now recognized to play a role in the development of heart failure in patients with and without underlying left ventricular (LV) dysfunction. We used the cardiac norepinephrine spillover method to test the hypothesis that RV pacing is associated with cardiac sympathetic activation. We studied 8 patients with normal LV function using temporary right atrial and ventricular pacing wires. All measurements were carried out during a fixed atrial pacing rate. The radiotracer norepinephrine spillover technique was employed to measure total body and cardiac sympathetic activity while changes in LV performance were evaluated with a high-fidelity manometer catheter. Atrioventricular synchronous RV pacing, compared with atrial pacing alone, was associated with a 65% increase in cardiac norepinephrine spillover, an increase in LV end-diastolic pressure, and a reduction in myocardial efficiency. These responses may play a role in the development of heart failure and poor outcomes that are associated with chronic RV pacing.     

Impact of physiological variables and genetic background on myocardial frequency-resistivity relations in the intact beating murine heart

Conductance measurements for generation of an instantaneous left ventricular (LV) volume signal in the mouse are limited, because the volume signal is a combination of blood and LV muscle, and only the blood signal is desired. We have developed a conductance system that operates at two simultaneous frequencies to identify and remove the myocardial contribution to the instantaneous volume signal. This system is based on the observation that myocardial resistivity varies with frequency, whereas blood resistivity does not. For calculation of LV blood volume with the dual-frequency conductance system in mice, in vivo murine myocardial resistivity was measured and combined with an analytic approach. The goals of the present study were to identify and minimize the sources of error in the measurement of myocardial resistivity to enhance the accuracy of the dual-frequency conductance system. We extended these findings to a gene-altered mouse model to determine the impact of measured myocardial resistivity on the calculation of LV pressure-volume relations. We examined the impact of temperature, timing of the measurement during the cardiac cycle, breeding strain, anisotropy, and intrameasurement and interanimal variability on the measurement of intact murine myocardial resistivity. Applying this knowledge to diabetic and nondiabetic 11- and 20- to 24-wk-old mice, we demonstrated differences in myocardial resistivity at low frequencies, enhancement of LV systolic function at 11 wk and LV dilation at 20-24 wk, and histological and electron-microscopic studies demonstrating greater glycogen deposition in the diabetic mice. This study demonstrated the accurate technique of measuring myocardial resistivity and its impact on the determination of LV pressure-volume relations in gene-altered mice.     

NADH Fluorescence Imaging of Isolated Biventricular Working Rabbit Hearts

Since its inception by Langendorff¹, the isolated perfused heart remains a prominent tool for studying cardiac physiology². However, it is not well-suited for studies of cardiac metabolism, which require the heart to perform work within the context of physiologic preload and afterload pressures. Neely introduced modifications to the Langendorff technique to establish appropriate left ventricular (LV) preload and afterload pressures³. The model is known as the isolated LV working heart model and has been used extensively to study LV performance and metabolism^4-6. This model, however, does not provide a properly loaded right ventricle (RV). Demmy et al. first reported a biventricular model as a modification of the LV working heart model^{7, 8}. They found that stroke volume, cardiac output, and pressure development improved in hearts converted from working LV mode to biventricular working mode⁸. A properly loaded RV also diminishes abnormal pressure gradients across the septum to improve septal function. Biventricular working hearts have been shown to maintain aortic output, pulmonary flow, mean aortic pressure, heart rate, and myocardial ATP levels for up to 3 hours⁸.When studying the metabolic effects of myocardial injury, such as ischemia, it is often necessary to identify the location of the affected tissue. This can be done by imaging the fluorescence of NADH (the reduced form of nicotinamide adenine dinucleotide)^9-11, a coenzyme found in large quantities in the mitochondria. NADH fluorescence (fNADH) displays a near linearly inverse relationship with local oxygen concentration¹² and provides a measure of mitochondrial redox state¹³. fNADH imaging during hypoxic and ischemic conditions has been used as a dye-free method to identify hypoxic regions^{14, 15} and to monitor the progression of hypoxic conditions over time¹⁰.The objective of the method is to monitor the mitochondrial redox state of biventricular working hearts during protocols that alter the rate of myocyte metabolism or induce hypoxia or create a combination of the two. Hearts from New Zealand white rabbits were connected to a biventricular working heart system (Hugo Sachs Elektronik) and perfused with modified Krebs-Henseleit solution¹⁶ at 37 °C. Aortic, LV, pulmonary artery, and left & right atrial pressures were recorded. Electrical activity was measured using a monophasic action potential electrode. To image fNADH, light from a mercury lamp was filtered (350±25 nm) and used to illuminate the epicardium. Emitted light was filtered (460±20 nm) and imaged using a CCD camera. Changes in the epicardial fNADH of biventricular working hearts during different pacing rates are presented. The combination of the heart model and fNADH imaging provides a new and valuable experimental tool for studying acute cardiac pathologies within the context of realistic physiological conditions.     

Video-Assisted Implantation of a Left Ventricular Lead and Intrathoracic Tunneling to a Right-Sided CRT-D Device

We describe two cases in which a biventricular implantable cardioverter defibrillator for cardiac resynchronization therapy had to be placed on the right side due to unsuitability of the left subclavian vein. Endocardial implantation of a left ventricular lead through the coronary sinus was previously attempted but was unsuccessful. Implantation of the epicardial left ventricular pacing lead was performed through video-assisted thoracic surgery on the left side. The connector end of the left ventricular pacing lead was tunnelized through the anterior mediastinum into the right pleural space. The right-sided pocket was then opened. A tunnel was created from the pocket to the thoracic wall, and the pleural space was entered over the second rib. The lead was retrieved from the right pleural space and connected with the Cardiac resynchronization therapy-device (CRT-D). Both procedures and postoperative periods were uneventful. Intrathoracic left-to-right tunneling of an epicardial left ventricular lead by video-assisted thoracic surgery is feasible and safe. It provides an alternative to subcutaneous tunneling.     

Myostatin is elevated in congenital heart disease and after mechanical unloading

Background

Myostatin is a negative regulator of skeletal muscle mass whose activity is upregulated in adult heart failure (HF); however, its role in congenital heart disease (CHD) is unknown.

Methods

We studied myostatin and IGF-1 expression via Western blot in cardiac tissue at varying degrees of myocardial dysfunction and after biventricular support in CHD by collecting myocardial biopsies from four patient cohorts: A) adult subjects with no known cardiopulmonary disease (left ventricle, LV), (Adult Normal), (n = 5); B) pediatric subjects undergoing congenital cardiac surgery with normal RV size and function (right ventricular outflow tract, RVOT), (n = 3); C) pediatric subjects with worsening but hemodynamically stable LV failure [LV and right ventricle (LV, RV,)] with biopsy collected at the time of orthotopic heart transplant (OHT), (n = 7); and D) pediatric subjects with decompensated bi-ventricular failure on BiVAD support with biopsy collected at OHT (LV, RV, BiVAD), (n = 3).

Results

The duration of HF was longest in OHT patients compared to BIVAD. The duration of BiVAD support was 4.3±1.9 days. Myostatin expression was significantly increased in LV-OHT compared to RV-OHT and RVOT, and was increased more than double in decompensated biventricular HF (BiVAD) compared to both OHT and RVOT. An increased myostatin/IGF-1 ratio was associated with ventricular dysfunction.

Conclusions

Myostatin expression in increased in CHD, and the myostatin/IGF-1 ratio increases as ventricular function deteriorates. Future investigation is necessary to determine if restoration of the physiologic myostatin/IGF-1 ratio has therapeutic potential in HF.     

Left ventricular dysfunction due to right ventricular stimulation: is biventricular upgrade really necessary?

Left ventricular (LV) dysfunction can occur due to chronic right ventricular apical pacing. Upgrading of the pacemaker to biventricular pacing is an option to reverse LV dysfunction but reprogramming of the atrioventricular (AV) timing can also be favourable. In this case report we describe the effect of AV-time reprogramming in a patient with LV function deterioration that emerged two years after implantation of a dual chamber system for sick sinus syndrome. Echocardiographc studies demonstrated a tremendous improvement in LV function during two years follow-up whereas the percentage of right ventricular pacing diminished dramatically. Careful analysis of the cause of LV deterioration can avoid unnecessary upgrading to biventricular pacing. (Neth Heart J 2010;18:604–5.)     

Training-specific changes in cardiac structure and function: a prospective and longitudinal assessment of competitive athletes.

This prospective, longitudinal study examined the effects of participation in team-based exercise training on cardiac structure and function. Competitive endurance athletes (EA, n = 40) and strength athletes (SA, n = 24) were studied with echocardiography at baseline and after 90 days of team training. Left ventricular (LV) mass increased by 11% in EA (116 +/- 18 vs. 130 +/- 19 g/m(2); P < 0.001) and by 12% in SA (115 +/- 14 vs. 132 +/- 11 g/m(2); P < 0.001; P value for the compared Delta = NS). EA experienced LV dilation (end-diastolic volume: 66.6 +/- 10.0 vs. 74.7 +/- 9.8 ml/m(2), Delta = 8.0 +/- 4.2 ml/m(2); P < 0.001), enhanced diastolic function (lateral E': 10.9 +/- 0.8 vs. 12.4 +/- 0.9 cm/s, P < 0.001), and biatrial enlargement, while SA experience LV hypertrophy (posterior wall: 4.5 +/- 0.5 vs. 5.2 +/- 0.5 mm/m(2), P < 0.001) and diminished diastolic function (E' basal lateral LV: 11.6 +/- 1.3 vs. 10.2 +/- 1.4 cm/s, P < 0.001). Further, EA experienced right ventricular (RV) dilation (end-diastolic area: 1,460 +/- 220 vs. 1,650 +/- 200 mm/m(2), P < 0.001) coupled with enhanced systolic and diastolic function (E' basal RV: 10.3 +/- 1.5 vs. 11.4 +/- 1.7 cm/s, P < 0.001), while SA had no change in RV parameters. We conclude that participation in 90 days of competitive athletics produces significant training-specific changes in cardiac structure and function. EA develop biventricular dilation with enhanced diastolic function, while SA develop isolated, concentric left ventricular hypertrophy with diminished diastolic relaxation.     

Contributions of hemodynamic monitoring to the treatment of chronic congestive heart failure.

Optimal therapy for congestive cardiac failure requires identification of correctable factors that aggravate it as well as an understanding of its etiology. Increased sympathetic nervous system activity, reduced renal blood flow, and cardiac hypertrophy and dilation are the main compensatory processes that occur in response to cardiac failure. Although they may be of initial benefit in supporting a reduced stroke volume, they may ultimately prove self-defeating. New drugs for the treatment of severe congestive heart failure include dopamine, which has a selective nonadrenergic dilator effect on the renal vascular bed, and dobutamine, which has potent inotropic effects, lowers the left ventricular filling pressure and does not increase the heart rate or the systemic vascular resistance. By reducing both the resistance to left ventricular ejection and the venous return to the right heart, vasodilators result in improved peripheral perfusion and reduced pulmonary congestion. Optimal therapy for refractory cardiac failure can be rationally determined by characterizing the hemodynamic profile through measurement of the mean arterial pressure, the left ventricular filling pressure, the cardiac output and the systemic vascular resistance. The specific therapy can then be effectively and safely delivered by a careful analysis of the dose-response relation as identified by hemodynamic monitoring.     

Continuous monitoring of right ventricular volume changes using a conductance catheter in the rabbit.

To assess the reliability of conductance (G) catheter for evaluating right ventricular (RV) volume changes, a miniature (3.5F) six-electrode catheter was developed and tested in 11 New Zealand rabbit hearts. In five animals the heart was excised; in six it was left in the thorax. RV conductance was recorded while the RV was filled with blood in 0.25-ml steps at different left ventricular (LV) volumes. Linear correlation of measured conductance vs. reference volumes was computed. RV conductance was highly correlated with reference volume [correlation coefficient (r) ranging from 0.991 to 0.999]. Slope of regression lines was not significantly affected by LV volume variations in 1-ml steps or by acute conductance changes of structures surrounding the heart, whereas the intercept was affected only by the 0- to 1-ml LV volume change. In four rabbits, RV conductance changes during a cardiac cycle [stroke volume- (SV) G] were compared in vivo with electromagnetic flow probe-derived estimates of SV (SVem) as stroke volume was varied by graded inferior vena caval occlusion. SV-G correlated well with SVem (r ranging from 0.92 to 0.96). This correlation persisted after the thorax was filled with saline; however, significant differences were found in individual slopes (P < 0.001). These results show that the conductance catheter has a potential to reliably monitor in vivo relative RV volume changes in small-animal hearts.     

Load-insensitive measurements from an isolated perfused biventricular working rat heart

To determine whether a rat heart model can provide load-insensitive measurements of cardiac function, a recently developed biventricular perfused preparation was tested. Using 29 Sprague-Dawley rat hearts perfused with modified Krebs-Henseleit buffer, ventricles functioned simultaneously with adjustable independent preload (venous reservoirs) and afterload (compliance chambers). Ultrasonic crystal pairs provided continuous left (LV) and right ventricular (RV) short-axis dimensions. LV and RV pressure-length loops (loop area = work) were generated from paired intraventricular pressure and short-axis dimensions. Load-insensitive measurements were obtained from the slopes (elastance) and x-intercepts (L₀) of regression lines generated from the end-systolic coordinates of these pressure-length loops over ranges of RV and LV preloads. Measurements were made after 15 min of stable function and after 20 min of warm (37°C) ischemia. During perturbations in LV afterload, there were linear changes in dP/dt, but loop work remained relatively unchanged. RV dP/dt and work varied little with physiologic ranges of afterload. Increased RV afterload had little effect on LV function. Ischemia affected LV function more than RV function using these measurements. Elastance, however, increased after ischemia with diastolic creep (increased L₀) for both ventricles. Load-insensitive and other sophisticated hemodynamic measurements are possible with this new preparation.     

Effects of glossopharyngeal insufflation on cardiac function: an echocardiographic study in elite breath-hold divers.

Glossopharyngeal insufflation (GI), a technique used by breath-hold divers to increase lung volume and augment diving depth and duration, is associated with untoward hemodynamic consequences. To study the cardiac effects of GI, we performed transthoracic echocardiography, using the subcostal window, in five elite breath-hold divers at rest and during GI. During GI, heart rate increased in all divers (mean of 53 beats/min to a mean of 100 beats/min), and blood pressure fell dramatically (mean systolic, 112 to 52 mmHg; mean diastolic, 75 mmHg to nondetectable). GI induced a 46% decrease in mean left ventricular end-diastolic area, 70% decrease in left ventricular end-diastolic volume, 49% increase in mean right ventricular end-diastolic area, and 160% increase in mean right ventricular end-diastolic volume. GI also induced biventricular systolic dysfunction; left ventricular ejection fraction decreased from 0.60 to a mean of 0.30 (P = 0.012); right ventricular ejection fraction, from 0.75 to a mean of 0.39 (P < 0.001). Wall motion of both ventricles became significantly abnormal during GI; the most prominent left ventricular abnormalities involved hypokinesis or dyskinesis of the interventricular septum, while right ventricular wall motion abnormalities involved all visible segments. In two divers, the inferior vena cava dilated with the appearance of spontaneous contrast during GI, signaling increased right atrial pressure and central venous stasis. Hypotension during GI is associated with acute biventricular systolic dysfunction. The echocardiographic pattern of right ventricular systolic dysfunction is consistent with acute pressure overload, whereas concurrent left ventricular systolic dysfunction is likely due to ventricular interdependence.     

Hemodynamic effects of cardiac cycle-specific increases in intrathoracic pressure

Changes in intrathoracic pressure (ITP) can influence cardiac performance by affecting ventricular loading conditions. Because both systemic venous return and factors determining left ventricular (LV) ejection may vary over the cardiac cycle, phasic increases in ITP may differentially affect preload or afterload if delivered at specific points within the cardiac cycle. We studied the hemodynamic effects of cardiac cycle-specific increases in ITP (pulses) delivered by a high-frequency jet ventilator in an acute closed-chested canine model (n = 11), using electromagnetic flow probes to measure biventricular stroke volume. Measurements were taken during a control condition after the induction of acute ventricular failure (AVF) by propranolol hydrochloride and volume infusion. ITP was independently varied without changing lung volume by the inflation of thoracoabdominal binders. Although synchronous pulses had minimal hemodynamic effects in unbound controls, binding pulses timed to occur in early diastole resulted in decreases in LV filling pressure and left ventricular stroke volume (SVlv) (P less than 0.05). In the AVF condition, pulses increased LV performance, evidenced by increases in SVlv (P less than 0.01), despite decreases in LV filling pressure (P less than 0.05). This effect is maximized by binding and by timing the pulses to occur in systole. We conclude that cardiac cycle-specific increases in ITP can significantly affect cardiac performance. These effects appear to be related to the ability of such timed pulses to selectively affect LV preload and afterload.     

Improvement in pump function with endocardial biventricular pacing increases with activation time at the left ventricular pacing site in failing canine hearts

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/dt; r = 0.64), ejection fraction (r = 0.49), and minimum dP/dt (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.