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Background: Autonomic dysfunction, characterized by sympathetic activation and vagal withdrawal, contributes to the progression of heart failure (HF). Although the therapeutic benefits of sympathetic inhibition with beta-blockers in HF are clear, the role of increased vagal tone in this setting has been less studied. We have investigated the impact of enhancing vagal tone (achieved through chronic cervical vagus nerve stimulation, [VNS]) on HF development in a canine high-rate ventricular pacing model., Methods and Results: Fifteen dogs were randomized into control (n=7) and VNS (n=8) groups. All dogs underwent 8 weeks of high-rate ventricular pacing (at 220 bpm for the first 4 weeks to develop HF and another 4 weeks at 180 bpm to maintain HF). Concomitant VNS, at an intensity reducing sinus rate approximately 20 bpm, was delivered together with the ventricular pacing in the VNS group. At 4 and 8 weeks of ventricular pacing, both left ventricular end-diastolic and -systolic volumes were lower and left ventricular ejection fraction was higher in the VNS group than in the control group. Heart rate variability and baroreflex sensitivity improved in the VNS dogs. Rises in plasma norepinephrine, angiotensin II, and C-reactive protein levels, ordinarily expected in this model, were markedly attenuated with VNS treatment., Conclusions: Chronic VNS improves cardiac autonomic control and significantly attenuates HF development in the canine high-rate ventricular pacing model. The therapeutic benefit of VNS is associated with pronounced anti-inflammatory effects. VNS is a novel and potentially useful therapy for treating HF.

Aims: We sought to determine the association between myocardial scarring, gender, and survival in patients with significant coronary artery disease (CAD) and severe systolic left ventricular (LV) dysfunction using delayed hyper-enhancement cardiac magnetic resonance imaging (DHE-CMR)., Methods and Results: We studied 339 patients (24% women, mean age 65 +/- 11 years) referred for assessment of myocardial viability by DHE-CMR. Scar was defined as myocardium with an intensity >2 SD above viable myocardium. Left ventricular scar (defined as a percentage of total LV myocardium), LV volumes, risk factors, cardiac transplantation (CTx), and all-cause mortality were recorded. There were 84 deaths and five CTx over 3.7 +/- 1.6 years (median 4 years, interquartile range 2.6-4.9 years). Left ventricular ejection fraction (LVEF) in men was only slightly different from women (23% +/- 9 vs. 25% +/- 10, P = 0.05), whereas mean scar % was similar in both groups (32 +/- 21 vs. 29 +/- 20, P = 0.3). On univariable survival analysis, age [hazard ratio, HR, 1.03 (1.01-1.05), P = 0.002], female gender [HR 2.02 (1.31-3.12), P = 0.001], and scar % [HR 1.01 (1.003-1.02), P = 0.009] predicted outcomes; and also on multivariable analysis (chi(2) 32, P < 0.0001). Women with scar % greater than the median had more events, compared with men with or without a high scar burden (log-rank P < 0.001)., Conclusion: In patients with CAD and severely reduced LVEF, women have worse outcomes than men, irrespective of myocardial scar burden.

Two-dimensional (2-D) speckle tracking echocardiography (STE) accurately quantifies circumferential strain (S(circ)) and radial strain (S(rad)) in humans and in large and small animals. This study was performed to assess sensitivity of S(circ) and S(rad) to left ventricular (LV) dysfunction in mouse models. We performed 2-D and M-mode echocardiography 1) in 6 mice during superficial and profound isoflurane anesthesia, 2) serially in 12 mice to monitor the development of heart failure induced by transverse aortic constriction (TAC) and in 8 corresponding control mice, and 3) in 26 mice with varying degrees of TAC-induced heart failure and 12 corresponding control mice immediately before euthanasia. Fractional shortening (FS) and LV mass were measured from standard M-mode tracings, whereas S(circ) and S(rad) were derived by STE. Percent fibrosis and myocyte diameters were assessed from whole heart cross-sectional specimens stained by Masson trichrome. Profound isoflurane anesthesia decreased S(circ) (P = 0.027) but not S(rad) (P > 0.05). Mice subjected to TAC showed an immediate and sustained decrease in FS (P = 0.035), S(circ) (P = 0.016), and S(rad) (P = 0.012). S(circ) showed better correlation with FS (r = 0.56 and P < 0.0001) and LV mass (r = 0.42 and P = 0.0003) than S(rad) (r = 0.54 and P < 0.0001 for FS and r = 0.37 and P = 0.014 for LV mass, respectively). Percent fibrosis correlated better with S(circ) (r = 0.46 and P = 0.004) than with S(rad) (r = -0.32 and P = 0.05), whereas myocyte diameter showed similar correlation with both strains (r = 0.45 and r = -0.44, respectively, and P = 0.006 for both). STE correctly identifies LV dysfunction and histological changes in mice and can be used for the serial assessment of cardiac remodeling in murine models.

Aims: To assess the impact of left ventricular (LV) volume/mass ratio on diastolic function parameters in subjects with dilated cardiomyopathy (DCM) or hypertrophic cardiomyopathy (HCM) and healthy controls., Methods and Results: We performed echocardiography in 44 healthy controls, 35 HCM subjects, 29 DCM subjects with narrow QRS complex (DCM-n), and 27 DCM subjects with wide QRS complex (DCM-w). Mitral annulus velocity (E(a)) and transmitral E-wave velocity were used to estimate time constant of isovolumic pressure decay (tau). LV flow propagation velocity (V(p)) and early intraventricular pressure gradient (IVPG) were derived from colour M-mode of LV inflow. We calculated LV twist and peak untwisting rate (UntwR) by speckle tracking. Mean LV volume/mass ratio was 0.34 +/- 0.09 mL/g in healthy controls, 0.15 +/- 0.06 mL/g in HCM, 0.6 +/- 0.2 mL/g in DCM-n, and 0.8 +/- 0.3 mL/g in DCM-w patients (P < 0.001 for all groups). Resting LV ejection fractions were 63 +/- 7, 64 +/- 8, 31 +/- 8, and 26 +/- 8%, respectively (P < 0.01 vs. controls for DCM groups). In a multivariate analysis, LV volume/mass ratio remained a strong independent predictor of V(p) (P < 0.001), IVPG (P = 0.009), and UntwR (P < 0.001) but not for E(a) (P = 0.25)., Conclusion: LV volume/mass ratio had influences on diastolic function parameters independent of intrinsic diastolic function and filling pressures. It should be considered when assessing patients suspected of LV diastolic dysfunction.

Aims: Although multislice computed tomography (MSCT) detects obstructive coronary artery disease (CAD) with high diagnostic accuracy, there is a paucity of long-term prognostic data. We sought to assess the incremental prognostic value of 64-slice CT in patients with suspected but no documented CAD., Methods and Results: Coronary MSCT was performed on 227 individuals (61% men, mean age 54 +/- 12 years, 63% with intermediate pre-test probability) without documented CAD, referred for coronary evaluation. Coronary artery disease by MSCT was categorized as follows: none or mild CAD (<50%, n = 172), > or =50% in one vessel (n = 23), two vessels [or in the proximal left anterior descending (LAD), n = 12], and three vessels (or in two vessels including the proximal LAD or left main, n = 20). Baseline risk factors, length of follow-up, and major adverse cardiac events (MACE), including cardiac death, myocardial infarction (MI), and coronary revascularization were recorded. Over a mean follow-up of 2.3 +/- 0.8 years, there were 18 MACE [including four hard events (one cardiac death and three MIs)]. Also, patients with one or more vessel obstructive CAD had increased hard events compared with those with less than one-vessel disease (log-rank statistic P-value 0.01). One or more vessel obstructive CAD was a significant predictor of MACE on univariable and multivariable Cox proportional survival analysis [hazard ratios 29.1 (6.7-126.6) and 9.82 (3.58-27.01), respectively, both P < 0.0001]. In 172 patients, with no or mild CAD, there was 99% freedom from MACE during follow-up., Conclusion: Multislice computed tomography-classified extent of CAD provides incremental prognostic information in patients with suspected but no documented CAD.

Objectives: The objective of the study was to determine whether the extent of left ventricular scar, measured with delayed hyperenhancement cardiac magnetic resonance (DHE-CMR), predicts survival in patients with ischemic cardiomyopathy (ICM) and severely reduced left ventricular ejection fraction (LVEF)., Background: Patients with ICM and reduced LVEF have poor survival. Such patients have a high myocardial scar burden. CMR is highly accurate in delineation of myocardial scar., Methods: We studied 349 patients (76% men) with severe ICM (>or=70% disease in >or=1 epicardial coronary, and mean LVEF of 24%) that underwent DHE-CMR (Siemens 1.5-T scanner, Erlangen, Germany), between 2003 and 2006. Scar (quantified as percentage of myocardium) was defined on DHE-MR images as an intensity >2 standard deviations above the viable myocardium. Transmurality score was semiquantitatively recorded in a 17-segment model as: 0 = no scar, 1 = 1% to 25% scar, 2 = 26% to 50%, 3 = 51% to 75%, and 4 = >75%. The LVEF, demographic data, risk factors, need for cardiac transplantation (CTx), and all-cause mortality were recorded., Results: The mean age and follow-up were 65 +/- 11 years and 2.6 +/- 1.2 years (median 2.4 years [1.1, 3.5]), respectively. There were 56 events (51 deaths and 5 CTx). Mean scar percentage and transmurality score were higher in patients with events versus those without (39 +/- 22 vs. 30 +/- 20, p = 0.003, and 9.7 +/- 5 vs. 7.8 +/- 5, p = 0.004). On Cox proportional hazard survival analysis, quantified scar was greater than the median (30% of total myocardium), and female gender predicted events (relative risk 1.75 [95% Confidence Interval: 1.02 to 3.03] and relative risk 1.83 [95% Confidence Interval: 1.06 to 3.16], respectively, both p = 0.03)., Conclusions: In patients with ICM and severely reduced LVEF, a greater extent of myocardial scar, delineated by DHE-CMR is associated with increased mortality or the need for cardiac transplantation, potentially aiding further risk-stratification.

Background: In heart failure patients with left ventricular dyssynchrony, contractility in delayed segments does not fully contribute to end-systolic function. We quantified this reserve of contraction related to mechanical dyssynchrony to predict response to cardiac resynchronization therapy by the strain delay index, which was defined as the sum of the difference between peak and end-systolic strain across 16 segments., Methods and Results: In 100 heart failure patients (ejection fraction=26+/-9%, QRS=154+/-29 ms, 94% in New York Heart Association class III), we studied left ventricular dyssynchrony before cardiac resynchronization therapy by the strain delay index using longitudinal strain by 2D speckle tracking and by the SD of time to peak myocardial velocity in 12 segments. The optimal cutoff value of the strain delay index to predict response to cardiac resynchronization therapy was determined in a retrospective group (n=65) and then confirmed in a validation group (n=35). Left ventricular end-systolic volume reduction at 3 months >15% (responder) occurred in 64 of 100 patients. In the retrospective group, the strain delay index but not the SD of time to peak myocardial velocity was greater in responders (n=42/65) than nonresponders (35+/-8% versus 19+/-7%, P<0.0001), and the optimal cutoff value to identify response to cardiac resynchronization therapy was 25%. In the validation group, strain delay index > or =25% identified 82% (18/22) of responders and 92% (12/13) of nonresponders. Among the entire population (n=100), strain delay index correlated with reverse remodeling in both the ischemic (r=-0.68, P<0.0001) and nonischemic (r=-0.68, P<0.0001) population., Conclusions: Use of the strain delay index with longitudinal strain by speckle tracking has a strong predictive value for predicting response to cardiac resynchronization therapy in both ischemic and nonischemic patients.

Nuclear factor-kappaB (NF-kappaB) is a ubiquitous transcription factor that regulates various kinds of genes including inflammatory molecules, macrophage infiltration factors, cell adhesion molecules, and so forth, in various disease processes including cardiac hypertrophy and heart failure. Previously, we have demonstrated that activation of NF-kappaB was required in myotrophin-induced cardiac hypertrophy, in spontaneously hypertensive rats, and in dilated cardiomyopathy human hearts. Moreover, our recent study using the myotrophin-overexpressed transgenic mouse (Myo-Tg) model showed that short hairpin RNA-mediated knockdown of NF-kappaB significantly attenuated cardiac mass associated with improved cardiac function. Although it has been shown that NF-kappaB is substantially involved in cardiovascular remodeling, it is not clear whether the continuous blockade of NF-kappaB is effective in cardiovascular remodeling. To address this question, we took a genetic approach using IkappaB alpha triple mutant mice (3M) bred with Myo-Tg mice (a progressive hypertrophy/heart failure model). The double transgenic mice (Myo-3M) displayed an attenuated cardiac hypertrophy (9.8+/-0.62 versus 5.4+/-0.34, p<0.001) and improved cardiac function associated with significant inhibition of the NF-kappaB signaling cascade, hypertrophy marker gene expression, and inflammatory and macrophage gene expression at 24 weeks of age compared to Myo-Tg mice. NF-kappaB-targeted gene array profiling displayed several important genes that were significantly downregulated in Myo-3M mice compared to Myo-Tg mice. Furthermore, Myo-3M did not show any changes of apoptotic gene expression, indicating that significant inhibition of NF-kappaB activation reduces further proinflammatory reactions without affecting susceptibility to apoptosis. Therefore, development of therapeutic strategies targeting NF-kappaB may provide an effective approach to prevent adverse cardiac pathophysiological consequences.

Framingham risk score is an office-based tool used for long-term coronary heart disease risk stratification. Most acute coronary events occur in association with proximal nonobstructive atherosclerotic plaque. Multislice computed tomography detects both obstructive coronary artery disease (CAD) and proximal atherosclerotic plaque with high accuracy. The association of Framingham risk score with obstructive CAD and proximal atherosclerotic plaque was tested. Coronary multislice computed tomography was performed in 295 patients (61% men, mean age 54 +/- 13 years) without documented CAD referred for evaluation of cardiac symptoms. Framingham risk score was computed and patients were stratified according to 10-year risk (n = 213 [72%] low, n = 74 [25%] intermediate, and n = 8 [3%] high). Obstructive CAD was defined as > or =50% stenosis in > or =1 epicardial coronary artery. Proximal atherosclerotic plaque was defined as calcified or noncalcified plaque in the left main or proximal left anterior descending artery. In the low- and intermediate-Framingham risk score groups, there was a high frequency of proximal atherosclerotic plaque (44% and 75%) and obstructive CAD (16% and 34%), although both findings were more prevalent in the high-Framingham risk score group (63% for atherosclerotic plaque, 88% for obstructive CAD), respectively. Proximal atherosclerotic plaque was noncalcified in approximately 13 of patients. In women (n = 114) and younger (<55 years) patients (n = 148), most (93% and 91%, respectively) had a low Framingham risk score. There were 48 women and 51 younger patients with proximal atherosclerotic plaque, of whom only 40% (in each group) were on statin therapy. In conclusion, of patients with a low and intermediate Framingham risk score, a significant proportion had proximal atherosclerotic plaque or obstructive CAD.

Activation of the nuclear factor (NF)-kappaB signaling pathway may be associated with the development of cardiac hypertrophy and its transition to heart failure (HF). The transgenic Myo-Tg mouse develops hypertrophy and HF as a result of overexpression of myotrophin in the heart associated with an elevated level of NF-kappaB activity. Using this mouse model and an NF-kappaB-targeted gene array, we first determined the components of NF-kappaB signaling cascade and the NF-kappaB-linked genes that are expressed during the progression to cardiac hypertrophy and HF. Second, we explored the effects of inhibition of NF-kappaB signaling events by using a gene knockdown approach: RNA interference through delivery of a short hairpin RNA against NF-kappaB p65 using a lentiviral vector (L-sh-p65). When the short hairpin RNA was delivered directly into the hearts of 10-week-old Myo-Tg mice, there was a significant regression of cardiac hypertrophy, associated with a significant reduction in NF-kappaB activation and atrial natriuretic factor expression. Our data suggest, for the first time, that inhibition of NF-kappaB using direct gene delivery of sh-p65 RNA results in regression of cardiac hypertrophy. These data validate NF-kappaB as a therapeutic target to prevent hypertrophy/HF.

Left ventricular (LV) untwisting starts early during the isovolumic relaxation phase and proceeds throughout the early filling phase, releasing elastic energy stored by the preceding systolic deformation. Data relating untwisting, relaxation, and intraventricular pressure gradients (IVPG), which represent another manifestation of elastic recoil, are sparse. To understand the interaction between LV mechanics and inflow during early diastole, Doppler tissue images (DTI), catheter-derived pressures (apical and basal LV, left atrial, and aortic), and LV volume data were obtained at baseline, during varying pacing modes, and during dobutamine and esmolol infusion in seven closed-chest anesthetized dogs. LV torsion and torsional rate profiles were analyzed from DTI data sets (apical and basal short-axis images) with high temporal resolution (6.5 +/- 0.7 ms). Repeated-measures regression models showed moderately strong correlation of peak LV twisting with peak LV untwisting rate (r = 0.74), as well as correlations of peak LV untwisting rate with the time constant of LV pressure decay (tau, r = -0.66) and IVPG (r = 0.76, P < 0.0001 for all). In a multivariate analysis, peak LV untwisting rate was an independent predictor of tau and IVPG (P < 0.0001, for both). The start of LV untwisting coincided with the beginning of relaxation and preceded suction-aided filling resulting from elastic recoil. Untwisting rate may be a useful marker of diastolic function or even serve as a therapeutic target for improving diastolic function.

Background: Patients referred for radiofrequency pulmonary vein antral isolation undergo contrast-enhanced multidetector computed tomography (MDCT) to assess pulmonary vein and left atrial anatomy as well as transesophageal echocardiography (TEE) to detect intraatrial thrombus. We sought to determine the accuracy of MDCT to qualitatively and quantitatively detect severe spontaneous echo contrast (SEC) or thrombus by TEE in the left atrial appendage (LAA)., Methods: Two hundred twenty-three consecutive MDCT and TEE studies performed within 7 days of each other were retrospectively identified. The LAA was evaluated by MDCT for filling defects and by TEE for thrombus or SEC. Severe SEC or thrombus on TEE was considered positive. In patients with preserved ejection fraction, the Hounsfield unit (HU) density of a 1-cm2 region of interest was measured in the LAA and ascending aorta (AA) of the same slice to calculate an LAA/AA HU ratio., Results: Visually identified filling defects in LAA by MDCT correspond to severe SEC and thrombus with a sensitivity, specificity, positive predictive value, and negative predictive value of 93%, 85%, 31%, and 99%, respectively. Multidetector CT missed severe SEC detected by TEE in one examination; all thrombi, however, were correctly identified. There is a significant inverse association between mean LAA/AA HU ratios with increasing grades of SEC or thrombus (P < .001). Using an LAA/AA HU ratio cutoff of 0.25, the positive predictive value and specificity increased to 75% and 96%, respectively, while preserving a high negative predictive value (96%)., Conclusions: Multidetector CT can qualitatively and quantitatively identify and distinguish severe LAA SEC/thrombus from lesser grades of SEC.

Stem cell transplantation at the time of acute myocardial infarction (AMI) improves cardiac function. Whether the improved cardiac function results from regeneration of cardiac myocytes, modulation of remodeling, or preservation of injured tissue through paracrine mechanisms is actively debated. Because no specific stem cell population has been shown to be optimal, we investigated whether the benefit of stem cell transplantation could be attributed to a trophic effect on injured myocardium. Mesenchymal stem cells secrete SDF-1 and the interaction of SDF-1 with its receptor, CXCR4, increases survival of progenitor cells. Therefore, we compared the effects of MSC and MSC engineered to overexpress SDF-1 on cardiac function after AMI. Tail vein infusion of syngeneic MSC and MSC:SDF-1 1 day after AMI in the Lewis rat led to improved cardiac function by echocardiography by 70.7% and 238.8%, respectively, compared with saline controls 5 wk later. The beneficial effects of MSC and MSC:SDF-1 transplantation were mediated primarily through preservation, not regeneration of cardiac myocytes within the infarct zone. The direct effect of SDF-1 on cardiac myocytes was due to the observation that, between 24 and 48 h after AMI, SDF-1-expressing MSC increased cardiac myocyte survival, vascular density (18.2+/-4.0 vs. 7.6+/-2.3 vessels/mm2, P<0.01; SDF-1:MSC vs. MSC), and cardiac myosin-positive area (MSC: 49.5%; mSC:SDF-1: 162.1%) within the infarct zone. There was no evidence of cardiac regeneration by the infused MSC or endogenous cardiac stem cells based on lack of evidence for cardiac myocytes being derived from replicating cells. These results indicate that stem cell transplantation may have significant beneficial effects on injured organ function independent of tissue regeneration and identify SDF-1:CXCR4 binding as a novel target for myocardial preservation.

Objective: We performed this study to validate the single-beat estimation of end-systolic elastance (E(es)) in an animal model of chronic mitral regurgitation (MR) and to use E(es) to predict postoperative left ventricular (LV) systolic function with the noninvasively derived single-beat E(es) (E(es-s)) in patients with MR., Methods: Eight sheep with MR were studied under 4 different loading conditions. E(es) was measured as the slope of the end-systolic pressure-volume relationship with a conductance catheter during inferior vena cava occlusion. E(es-s) was calculated using a bilinearly approximated time-varying elastance curve. We also studied 105 patients with MR who had undergone mitral valve repair. All measurements in these patients were performed before surgery and repeated at about 1 week after surgery., Results: In the animals in a total of 23 different stages, E(es-s) showed a good correlation and agreement with invasively determined E(es) (y = 0.84 x + 0.38; r = 0.8; P < .01, mean difference = 0.1 +/- 0.6 mm Hg/mL). In the clinical study, preoperative E(es-s) (r = 0.77; P < .001) and end-systolic volume index correlated well with postoperative ejection fraction (r = -0.69; P < .001). Multivariate analyses revealed that only E(es-s) was an independent predictor of postoperative LV function. Preoperative E(es-s) less than or equal to 1.0 mm Hg/mL was most predictive for identifying patients with LV dysfunction after surgery (sensitivity 87%; specificity 76%)., Conclusions: LV end-systolic elastance can be estimated noninvasively and is useful to detect latent LV dysfunction in patients with MR before surgery.

Healthy aging results in changes in Doppler measures of diastolic function. It is unclear whether these alterations are a specific manifestation of the aging process or reflect a cardiac adaptation to a more sedentary lifestyle. It was hypothesized that healthy, but sedentary, aging would result in slowing of diastolic filling and myocardial relaxation, whereas lifelong endurance training would prevent such changes. Doppler data were measured in young subjects and sedentary and fit seniors across a broad range of loading conditions. Thirteen sedentary healthy (70+/-4 years) and 12 fit Masters athlete (68+/-3 years) seniors were recruited. Twelve young healthy (32+/-9 years) subjects were used for comparison. Pulmonary capillary wedge pressure and Doppler variables were measured at the 6 loading conditions of baseline (twice), -15 and -30 mm Hg lower body negative pressure, and 2 levels of saline solution infusion. Doppler variables consisted of early and late mitral inflow velocity (E/A) ratio, isovolumetric relaxation time (IVRT), tissue Doppler velocities (TDI Emean), and propagation velocity of mitral inflow. Aging resulted in a decrease in E/A ratio (p<0.001), TDI Emean (p<0.001), and propagation velocity of mitral inflow (p<0.001) and an increase in IVRT (p=0.001). Lifelong endurance training did not completely prevent the changes in E/A ratio (p=0.212), IVRT (p=0.546), or propagation velocity of mitral inflow (p=1.00). Fit seniors were able to achieve E/A ratios of 1.0 during baseline and saline solution infusion. TDI Emean was higher in fit versus sedentary seniors at baseline (p=0.012) and during maximal lower body negative pressure (p=0.036), but not during saline solution infusion (p=0.493). In conclusion, age-associated abnormalities in Doppler measures of myocardial filling and relaxation are only partially minimized by lifelong endurance training and therefore may be more specific to the aging process than secondary to years of deconditioning.

Recent loss-of-function studies highlight the importance of the transcription factor GATA4 in the myocardial response to injury in the adult heart. However, the potential effects of gain-in-function of GATA4 overexpression, and transcription factors in general, is hindered by the fact that transcription factors are neither secreted nor taken up by cells. Chimeric proteins incorporating motifs of cell-penetrating proteins are secreted from cells and internalized by surrounding cells. We engineered a chimeric protein consisting of GATA4 and the cell-penetrating protein VP22. Cardiac fibroblasts stably transfected with the GATA4:VP22, GFP:VP22, or green fluorescent protein (GFP) constructs were transplanted into Lewis rats 1 month after left anterior descending ligation. GATA4:VP22 expression in the border zone was associated with increased cardiac myosin expression and cardiac myocyte size (30 mum versus 19 mum, P<0.01). Compared with the GFP:VP22 control group, 6 weeks after cardiac fibroblast transplantation (10 weeks after myocardial infarction), animals that received GATA4:VP22-expressing cardiac fibroblasts demonstrated increased cardiac function and less negative remodeling. These data demonstrate a novel strategy for transcription factor delivery to injured myocardium and indicate that the delivery of GATA4 locally to the infarct border zone induces multiple local effects in the border zone cardiac myocytes resulting in beneficial ventricular remodeling and improved global left ventricular function.

Clinical studies suggest increased arrhythmia risk associated with cell therapy for myocardial infarction (MI); however, the underlying mechanisms are poorly understood. We hypothesize that the degree of electrical viability in the infarct and border zone associated with skeletal myoblast (SKMB) or mesenchymal stem cell (MSC) therapy will determine arrhythmia vulnerability in the whole heart. Within 24 h of LAD ligation in rats, 2 million intramyocardially injected SKMB (n=6), intravenously infused MSC (n=7), or saline (n=7) was administered. One month after MI, cardiac function was determined and novel optical mapping techniques were used to assess electrical viability and arrhythmia inducibility. Shortening fraction was greater in rats receiving SKMB (17.8%+/-5.3%, p=0.05) or MSC (17.6%+/-3.0%, p<0.01) compared to MI alone (10.1%+/-2.2%). Arrhythmia inducibility score was significantly greater in SKMB (2.8+/-0.2) compared to MI (1.4+/-0.5, p=0.05). Inducibility score for MSC (0.6+/-0.4) was significantly lower than SKMB (p=0.01) and tended to be lower than MI. Optical mapping revealed that MSC therapy preserved electrical viability and impulse propagation in the border zone, but SKMB did not. In addition, injected SKMBs were localized to discrete cell clusters where connexin expression was absent. In contrast, infused MSCs engrafted in a more homogeneous pattern and expressed connexin proteins. Even though both MSC and SKMB therapy improved cardiac function following MI in rat, SKMB therapy significantly increased arrhythmia inducibility while MSC therapy tended to lower inducibility. In addition, only MSC therapy was associated with enhanced electrical viability, diffuse engraftment, and connexin expression, which may explain the differences in arrhythmia inducibility.

Cell-based gene therapy to alter the myocardial tissue microenvironment has been shown to improve mechanical cardiac function, but little is known regarding its effects on arrhythmogenic risk. Clinical studies with skeletal myoblasts (SKMBs) have suggested a potential increase in arrhythmogenic risk. Therefore, we studied the functional mechanical and electrical effects of transient reestablishment of stem cell homing via transplantation of stromal-cell derived factor-1 (SDF-1)-expressing SKMBs. Eight weeks after anterior myocardial infarction, rats received in five divided doses into the periinfarct zone 1 million SKMBs transfected with AdSDF-1 (n=15) or AdGFP (n=8). Echocardiography was used to quantify changes in cardiac function, and optical mapping was used to determine the arrhythmogenic risk. Eight weeks after cell therapy, we observed a 54% (p=0.004) increase in shortening fraction in AdSDF-1:SKMB-treated rats, but only an 18.8% increase (p=not significant) with GFP:SKMB. SDF-1-treated hearts exhibited an increase in vascular density compared with control SKMBs (34.9+/-7.1 vs. 20.7+/-5.6 vessels/mm2; p<0.01). Optical mapping performed 8 weeks after cell therapy revealed that all animals that received SKMBs regardless of viral transfection had inducible ventricular tachycardia (VT) whereas only 50% of saline-treated animals had inducible VT (p<0.05). Transient reestablishment of stem cell homing via transplantation of modified SKMBs is sufficient to improve cardiac function. However, despite improved mechanical function, the risk of ventricular tachycardia increased. We propose that future studies on functional effects of cell-based gene therapies should address both mechanical and electrical consequences.

We aimed to clarify the myocardial adaptation to short-term high-intensity exercise among trained athletes. We screened 17 participants in the 2004 World Indoor Rowing Championships before and after a 2000-m sprint. Echocardiography included standard measurements and tissue Doppler-derived strain (epsilon), strain rate, and 2-dimensionally derived speckle-tracking imaging for left ventricular (LV) torsion. LV volumes and ejection fraction were unchanged after exercise. There was a reduction in early and an increase in late diastolic filling velocities and a decrease in the flow propagation velocity. Annular systolic velocities, slope of the systolic acceleration, septal and lateral epsilon, and speckle tracking-derived torsion were increased. The increased LV torsion was a result of increased basal and apical rotation. Right ventricular apical epsilon decreased. In conclusion, maximal intensity short-duration exercise was associated with attenuation of LV diastolic function, augmentation of LV systolic function, and a reduction in apical right ventricular contractility.

Background: Left ventricular aneurysm (LVA) may affect diastolic intraventricular blood flow. Color M-mode (CMM) Doppler flow propagation patterns are abnormal in the presence of apical aneurysms. The aim of this study was to validate the accuracy of CMM echocardiography for assessing the existence and size of LVA and to determine the intraventricular pressure gradient in LVA., Methods: CMM of the transmitral inflow in early diastole was obtained from the apical 4-chamber view in 19 sheep. The presence of the break point where the velocity decreased abruptly in the mitral inflow (point D) was determined and the distance between the apex and point D was measured. The intraventricular pressure difference between the base and the apex was measured by a catheter while it was calculated using CMM with the Euler equation., Results: The presence of the break point D showed 84% sensitivity and 100% specificity for determining the existence of an LVA. Distance between the apex and point D correlated well with scar size. Catheter- and CMM-derived intraventricular pressure difference correlated and agreed well (y = 1.0 x -0.2, r = 0.94)., Conclusions: The point of abrupt decrease in propagation velocity of the CMM recording indicated the presence and size of LVA. Intraventricular pressure gradients were determined noninvasively by CMM echocardiography with reasonable accuracy.

Objective: To compare head to head the indices of left ventricular contractile reserve assessed by high-dose dobutamine in the five-year prognosis of patients with idiopathic dilated cardiomyopathy., Design and Setting: Prospective study in a tertiary care centre., Patients: 63 consecutive patients with idiopathic dilated cardiomyopathy., Interventions: High-dose dobutamine stress echocardiography was performed in progressive stages lasting 5 min each. Wall motion score index, ejection fraction, cardiac power output and end systolic pressure to volume ratio were evaluated as indices of left ventricular contractility., Main Outcome Measure: Five-year cardiac mortality., Results: During the follow up of 59 patients, 27 (45.8%) died of cardiac causes. According to Kaplan-Meier and receiver operating characteristic analyses all indices of contractile reserve differentiated patients with respect to cardiac death. Wall motion score index achieved the best separation (log rank 21.75, p < 0.0001, area under the curve 0.84), followed by change in ejection fraction (log rank 11.25, p = 0.0008, area under the curve 0.79), end systolic pressure to volume ratio (log rank 14.32, p = 0.0002, area under the curve 0.75) and cardiac power output (log rank 9.84, p = 0.0017, area under the curve 0.71). Cox's regression model identified wall motion score index as the only independent predictor of cardiac death., Conclusions: These data show that all examined indices of left ventricular contractile reserve are predictive of five-year prognosis, but change in wall motion score index may have the greatest prognostic potential.

The optimal pacing site in cardiac resynchronization therapy (CRT) remains controversial. Tissue synchronization imaging is a novel echocardiographic technique that color-codes for areas of maximal delay in myocardial velocities. This study aimed to identify whether the left ventricular (LV) pacing lead position in CRT should be guided by a patient's area of maximal mechanical delay. Fifty-four patients with advanced heart failure were assessed echocardiographically before and 6 months after CRT. Response was analyzed according to the relation between the LV lead position and the area of maximal delay to peak velocity by tissue synchronization imaging in the first half of the ejection phase: group 1 (n = 22) had lead placement corresponding to the segment of maximal delay; group 2 (n = 13) had lead placement 1 segment adjacent; and group 3 (n = 19) had lead placement remote from this site. Evidence of LV reverse remodeling and improved systolic function was documented in group 1 (mean percentage decrease in end-systolic volume 23%) more than in group 2 (mean decrease 15%), and more than in group 3 (mean increase 8.9%, p <0.0001 compared with groups 1 and 2). In group 1, 16 of 22 patients had reverse remodeling (>15% decrease in end-systolic volume); reverse remodeling was seen in 7 of 13 patients in group 2 and 1 of 19 in group 3. The placing of the lead position proximal to the site of maximal delay by tissue synchronization imaging was correlated with reverse remodeling (r = 0.449, p = 001). Of 7 patients with delay confined to the septum and anterior wall only, none had evidence of reverse remodeling after CRT. In conclusion, pacing at the site of maximal mechanical delay was associated with reverse remodeling. Individually tailored LV lead positioning should be considered before CRT.

Late myocardial infarction (MI) is associated with ventricular arrhythmias and sudden cardiac death. The exact mechanistic relationship between abnormal cellular electrophysiology, conduction abnormalities, and arrhythmogenesis associated with late MI is not completely understood. We report a novel, rapid dye superfusion technique to enable whole heart, high-resolution optical mapping of late MI. Optical mapping of action potentials was performed in normal rats and rats with anterior MI 7 days after left anterior descending artery ligation. Hearts from normal rats exhibited normal action potentials and impulse conduction. With the use of programmed stimulation to assess arrhythmia inducibility, 29% of hearts with late MI had inducible sustained ventricular tachycardia, compared with 0% in normal rats. A causal relationship between the site of infarction, abnormal action potential conduction (i.e., block and slow conduction), and arrhythmogenesis was observed. Optical mapping techniques can be used to measure high-resolution action potentials in a whole heart model of late MI. This experimental model reproduces many of the electrophysiological characteristics (i.e., conduction slowing, block, and ventricular tachycardia) associated with MI in patients. Importantly, the results of this study can enhance our ability to understand the interplay between cellular heterogeneity, conduction abnormalities, and arrhythmogenesis associated with MI.

Background: Although the continuity equation remains the noninvasive standard, planimetry using transesophageal echocardiography is often used to assess valve area for patients with aortic stenosis (AS). Not uncommonly, however, anatomic valve area (AVAA) obtained by planimetry overestimates continuity-derived effective valve area (AVAE) in bicuspid AS., Methods: Transthoracic Doppler and transesophageal echocardiography were performed to obtain AVAE and AVAA in 31 patients with bicuspid AS (age 61 +/- 11 years) and 22 patients with degenerative tricuspid AS (age 71 +/- 13 years). Aortic root and left ventricular outflow tract dimensions and the directional angle of the stenotic jet were assessed in all patients. Using these data, a computational fluid dynamics model was constructed to test the effect of these variables in determining the relationship between AVAE and AVAA., Results: For patients with tricuspid AS, the correlation between AVAA (1.15 +/- 0.36 cm2) and AVAE (1.13 +/- 0.46 cm2) was excellent (r = 0.91, P < .001, Delta = 0.02 +/- 0.21 cm2). However, AVAA was significantly larger (1.19 +/- 0.35 cm2) than AVAE (0.89 +/- 0.29 cm2) in the bicuspid AS group (r = 0.71, P < .001, Delta = 0.29 +/- 0.25 cm2). Computer simulation demonstrated that the observed discrepancy related to jet eccentricity., Conclusion: For a given anatomic orifice, functional severity tends to be greater in bicuspid AS than in tricuspid AS. This appears to be primarily related to greater jet eccentricity and less pressure recovery.

In the recently published clinical study [Use of Nitroprusside in Left Ventricular Dysfunction and Obstructive Aortic Valve Disease (UNLOAD)], sodium nitroprusside (SNP) improved cardiac function in patients with severe aortic stenosis (AS) and left ventricular (LV) systolic dysfunction. We explored the possible mechanisms of these findings using a series of numerical simulations. A closed-loop lumped parameters model that consists of 24 differential equations relating pressure and flow throughout the circulation was used to analyze the effects of varying hemodynamic conditions in AS. Hemodynamic data from UNLOAD study subjects were used to construct the initial simulation. Systemic vascular resistance (SVR), heart rate, and aortic valve area were directly entered into the model while end-systolic and end-diastolic pressure-volume (P-V) relationships were adjusted using previously published data to match modeled and observed end-systolic and end-diastolic pressures and volumes. Initial simulation of SNP treatment by a reduction of SVR was not adequate. To obtain realistic model hemodynamics that reliably reproduce SNP treatment effects, we performed a series of simulations while simultaneously changing end-systolic elastance (E(es)), end-systolic volume at zero pressure (V(0)), and diastolic P-V shift. Our data indicate that either an E(es) increase or V(0) decrease is necessary to obtain realistic model hemodynamics. In five patients, we corroborated our findings by using the model to duplicate individual P-V loops obtained before and during SNP treatment. In conclusion, using a numerical model, we identified ventricular function parameters that are responsible for improved hemodynamics during SNP infusion in AS with LV dysfunction.

Coupled pacing (CP), a method for controlling ventricular rate during atrial fibrillation (AF), consists of a single electrical stimulation applied to the ventricles after each spontaneous activation. CP results in a mechanical contraction rate approximately one-half the rate during AF. Paired stimulation in which two electrical stimuli are delivered to the ventricles has also been proposed as a therapy for heart failure. Although paired stimulation enhances contractility, it greatly increases energy consumption. The primary hypothesis of the present study is that CP improves cardiac function during acute AF without a similar increase in energy consumption because of the reduced rate of ventricular contractions. In a canine model, CP was applied during four stages: sinus rhythm (SR), acute AF, cardiac dysfunction (CD), and AF in the presence of cardiac dysfunction. The rate of ventricular contraction decreased in all four stages as the result of CP. In addition, we determined the changes in external cardiac work, myocardial oxygen consumption, and myocardial efficiency in the each of four stages. CP partially reversed the effects of AF and CD on external cardiac work, whereas myocardial oxygen consumption increased only moderately. In all stages but SR, CP increased myocardial efficiency because of the marked increases in cardiac work compared with the moderate increases in total energy consumed. Thus this pacing therapy may be a viable therapy for patients with concurrent atrial fibrillation and heart failure.

Left ventricular (LV) diastolic function during atrial fibrillation (AF) remains poorly understood due to the complex interaction of factors and beat-to-beat variability. The purpose of the present study was to elucidate the physiological determinants of beat-to-beat changes in LV diastolic function during AF. The RR intervals preceding a given cardiac beat were measured from the right ventricular electrogram in 12 healthy open-chest mongrel dogs during AF. Doppler echocardiography and LV pressure and volume beat-to-beat analyses were performed. The LV filling time (FT) and early diastolic mitral inflow velocity-time integral (E(vti)) were measured using the pulsed Doppler method. The LV end-diastolic volume (EDV), peak systolic LV pressure (LVP), minimum value of the first derivative of LV pressure curve (dP/dt(min)), and the time constant of LV pressure decay (tau) were evaluated with the use of a conductance catheter for 100 consecutive cardiac cycles. Beat-to-beat analysis revealed a cascade of important causal relations. LV-FT showed a significant positive linear relationship with E(vti) (r = 0.87). Importantly, there was a significant positive linear relationship between the RR interval and LV-EDV in the same cardiac beat (r = 0.53). Consequently, there was a positive linear relationship between LV-EDV and subsequent peak systolic LVP (r = 0.82). Furthermore, there were significant positive linear and negative curvilinear relationships between peak systolic LVP and dP/dt(min) (r = 0.95) and tau (r = -0.85), respectively, in the same cardiac beat. In addition, there was a significant negative curvilinear relationship between dP/dt(min) and tau (r = -0.86). We have concluded that the determinants of LV diastolic function in individual beats during AF depend strongly on the peak systolic LVP. This suggests that the major benefit of slower ventricular rate appears related to lengthening of LV filling interval, promoting subsequent higher peak systolic LVP and greater LV relaxation.

Background: The distribution and magnitude of left ventricular hypertrophy are not uniform in patients with hypertrophic cardiomyopathy (HCM). Previous echocardiographic studies have focused on global left ventricular function. Recently, myocardial Doppler strain (epsilon) imaging, a newly developed technique, has allowed the quantification of regional myocardial motion. The aim of this study was to characterize regional left ventricular systolic function by myocardial Doppler epsilon imaging in patients with HCM., Methods: Included in this study were 31 patients with asymmetric septal hypertrophy and HCM, and 41 age-matched healthy patients. Regional longitudinal axial systolic epsilon was assessed at the basal, mid, and apical segments of the septal and lateral walls and compared between both groups., Results: Patients with HCM had reduced epsilon at the ventricular septum (-10.3 +/- 5.7%) compared with control patients (-19.4 +/- 3.3%, P <.001). In the HCM group, epsilon in the midseptum (-1.3 +/- 8.2%) was significantly less than at the basal (-12.2 +/- 8.7%, P <.01) and apical septum (-17.3 +/- 10.4%, P <.01), and was also less than at the midlateral wall (-9.4 +/- 5.3%, P <.05). There was a significant correlation between midseptal epsilon and intraventricular septum to posterior wall thickness ratio (r = 0.81, P <.001)., Conclusion: Midseptal longitudinal epsilon was markedly decreased, even reversed in patients with HCM (paradoxic longitudinal systolic expansion), which was directly related to the degree of septal hypertrophy. Myocardial Doppler epsilon imaging could offer a unique approach to quantify regional systolic dysfunction in these patients.

Background: The aim of our study was to quantitatively compare the changes and correlations between pulmonary venous flow variables and mean left atrial pressure (mLAP) under different loading conditions in animals with chronic mitral regurgitation (MR) and without MR., Methods: A total of 85 hemodynamic conditions were studied in 22 sheep, 12 without MR as control (NO-MR group) and 10 with MR (MR group). We obtained pulmonary venous flow systolic velocity (Sv) and diastolic velocity (Dv), Sv and Dv time integrals, their ratios (Sv/Dv and Sv/Dv time integral), mLAP, left ventricular end-diastolic pressure, and MR stroke volume. We also measured left atrial a, x, v, and y pressures and calculated the difference between v and y pressures., Results: Average MR stroke volume was 10.6 +/- 4.3 mL/beat. There were good correlations between Sv (r = -0.64 and r = -0.59, P <.01), Sv/Dv (r = -0.62 and r = -0.74, P <.01), and mLAP in the MR and NO-MR groups, respectively. Correlations were also observed between Dv time integral (r = 0.61 and r = 0.57, P <.01) and left ventricular end-diastolic pressure in the MR and NO-MR groups. In velocity variables, Sv (r = -0.79, P <.001) was the best predictor of mLAP in both groups. The sensitivity and specificity of Sv = 0 in predicting mLAP 15 mm Hg or greater were 86% and 85%, respectively., Conclusion: Pulmonary venous flow variables correlated well with mLAP under altered loading conditions in the MR and NO-MR groups. They may be applied clinically as substitutes for invasively acquired indexes of mLAP to assess left atrial and left ventricular functional status.