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Objectives Nitric oxide (NO) is a critical regulator of vascular tone and signal transduction in the cardiovascular system. NO is synthesized by three unique enzymes (nitric oxide synthases [NOS]): endothelial and neuronal NOS, both constitutively expressed, and inducible NOS (iNOS), which is induced by proinflammatory stimuli and subsequently produces a burst of NO. NO has been implicated as both an injurious and a beneficial mediator after cardiac arrest and resuscitation. A previous study in swine found that iNOS expression is absent in the myocardium prior to cardiac arrest and that it increases after 10 minutes of untreated ventricular fibrillation (VF), decreases somewhat during the early postresuscitation period, and then steadily increases up to 6 hours postresuscitation. Because this time course of iNOS expression mirrors that of postresuscitation myocardial dysfunction, this study was designed to test the hypothesis that selective inhibition of iNOS improves postresuscitation outcomes in swine. Methods Thirty-two domestic swine of either sex were randomly assigned to receive one of the following treatments 15 minutes after return of spontaneous circulation (ROSC): 1) NG-nitro-l-arginine methyl ester (l-NAME), a global NO inhibitor; 2) aminoguanidine (AG), a selective iNOS inhibitor; or 3) saline as control. After 10 minutes of untreated VF, swine received a standard resuscitation protocol. Twenty-four-hour survival, neurological status, left ventricular (LV) function, and hemodynamic measurements were obtained. Results Return of spontaneous circulation occurred in 28 of 32 animals (88%). Only successfully resuscitated animals were assigned to treatment groups and completed the study. There were no differences in survival or neurological outcomes between groups. There were also no differences in LV function or hemodynamic variables found between the control group and the AG group. Global inhibition of NOS with l-NAME post-ROSC increased aortic pressure and transiently decreased pulse pressure. Treatment with l-NAME also increased LV end diastolic pressure and decreased cardiac output within 30 minutes post-ROSC, which was sustained throughout the 4-hour measurements, compared to both the control and the AG groups. In addition, LV ejection fraction recovered to baseline measurements in both the control and AG groups, but failed to recover in the l-NAME group. Conclusions Global inhibition of NOS after cardiac arrest and resuscitation markedly worsens hemodynamic variables. Selective inhibition of iNOS after cardiac arrest and resuscitation does not prevent postresuscitation myocardial stunning. There were no significant differences in neurological outcome or survival between treatment groups.

Cardiovascular (CV) diseases are known to have a negative impact on the brain and neurocognition, and contribute to the development of vascular dementia and neurodegenerative diseases such as Alzheimer's disease (AD). Among CV diseases, congestive heart failure (CHF) after myocardial infarction (MI) is a condition where the ability of the left ventricle to eject blood to the circulation is impaired. As a consequence, CHF triggers inflammation and results in reduced cerebral blood flow which are considered among the risk factors for development of AD. However, biochemical alterations in the brain following MI and CHF remain unknown. To address this issue, we investigated microglia activation; levels of BACE1, the key rate-limiting enzyme involved in the pathogenesis of AD; and VEGF levels in the hippocampus and cortex following MI. We created MI by the ligation of the left anterior descending coronary artery in Sprague-Dawley male rats and collected brains either 3 days after MI (AMI) or 21 days after MI (CHF). We investigated microglia activation in AMI and CHF brains by immunohistochemistry and immunoblotting using macrophage/microglia marker Ionized calcium binding adaptor molecule 1 (Iba-1), and observed activated morphology of microglia in the cortex of rats in both AMI and CHF. We also showed the levels of BACE1 were increased in the cortex and hippocampus of CHF rats. To determine whether hypoxia occurs in the CHF brain, we assessed levels of VEGF in the hippocampus and cortex. Western blotting analysis showed up-regulation of VEGF in the hippocampus of CHF brains. These results suggest that neuroinflammation takes place secondary to myocardial infarction. In addition, CHF-induced hypoxia might play a role in the elevation of BACE1 and VEGF levels.

This study was designed to determine if a viable biodegradable three-dimensional fibroblast construct (3DFC) patch implanted on the left ventricle after myocardial infarction (MI) improves left ventricular (LV) function and blood flow. We ligated the left coronary artery of adult male Sprague-Dawley rats and implanted the 3DFC at the time of the infarct. Three weeks after MI, the 3DFC improved LV systolic function by increasing ( p < 0.05) ejection fraction (37 ± 3% to 62 ± 5%), increasing regional systolic displacement of the infarcted wall (0.04 ± 0.02 to 0.11 ± 0.03 cm), and shifting the passive LV diastolic pressure volume relationship toward the pressure axis. The 3FDC improved LV remodeling by decreasing ( p < 0.05) LV end-systolic and end-diastolic diameters with no change in LV systolic pressure. The 3DFC did not change LV end-diastolic pressure (LV EDP; 25 ± 2 vs. 23 ± 2 mmHg) but the addition of captopril (2mg/L drinking water) lowered ( p < 0.05) LV EDP to 12.9 ± 2.5 mmHg and shifted the pressure–volume relationship toward the pressure axis and decreased ( p < 0.05) the LV operating end-diastolic volume from 0.49 ± 0.02 to 0.34 ± 0.03 ml. The 3DFC increased myocardial blood flow to the infarcted anterior wall after MI over threefold ( p < 0.05). This biodegradable 3DFC patch improves LV function and myocardial blood flow 3 weeks after MI. This is a potentially new approach to cell-based therapy for heart failure after MI.

Angiotensin II receptor blockade (ARB) increases vasorelaxation in heart failure by enhancing endothelial nitric oxide (NO). To determine the effects of valsartan on NO-mediated peripheral vascular function after myocardial infarction (MI), we treated adult male Sprague-Dawley rats immediately after MI with valsartan for 3 weeks (sham, n = 10; MI, n = 11) and 6 weeks (sham, n = 6; MI, n = 8). At both time points, valsartan lowered (P < 0.05) left ventricular (LV) systolic pressure (103 +/- 4 and 107 +/- 4 vs. 93 +/- 3 and 85 +/- 4 mm Hg, respectively) and LV end-diastolic pressure (25 +/- 1 and 25 +/- 2 to 13 +/- 2 and 18 +/- 3 mm Hg, respectively). Valsartan lowered (P < 0.05) LV dP/dt only at 6 weeks (4676 +/- 168 and 4503 +/- 232 vs. 4539 +/- 281 and 3372 +/- 417 mm Hg/sec); valsartan shortened (P < 0.05) the time constant of LV relaxation or tau only at 3 weeks (24.2 +/- 1.8 and 26.5 +/- 2.3 vs. 20.1 +/- 0.7 and 23.8 +/- 1.4 msec). At 6 weeks, the vasorelaxation response to acetycholine in aortic rings was decreased (P < 0.05) with MI and improved at acetycholine doses (10, 10, and 10; P < 0.06) with valsartan. Endothelial nitric oxide synthase (eNOS) protein was undetectable in aortic tissue from valsartan treated rats or from aortic tissue incubated with valsartan (2.5, 25, and 50 mg/mL). These data suggest that valsartan improves cardiac function after MI by modulating LV remodeling, decreasing LV end-diastolic pressure, and enhancing both LV diastolic and endothelial function. These effects are mediated, in part, by NO but upregulation of eNOS may not be required for improved systemic endothelial function in heart failure.

Background— This study was designed to determine the effects of pretreatment with an angiotensin receptor blocker on left ventricular (LV) function and remodeling during acute myocardial infarction (MI). Methods and Results— Sprague-Dawley rats were pretreated with candesartan (10 mg · kg −1 · d −1 ) for 2 weeks and studied at 1, 3, and 6 minutes after MI. Compared with untreated rats, pretreatment with candesartan lowered ( P P P P =0.04) and 70% ( P =0.002), and constitutive microtubulin increased 260% ( P =0.0005) and 111% ( P =0.003). Candesartan had no effect on LV tissue endothelial nitric oxide synthase levels but attenuated the increase in constitutive microtubulin by 77% ( P =0.004) and 37% ( P Conclusions— Pretreatment with candesartan before an acute MI improves global LV function, prevents LV dilation, and blunts the increase in constitutive microtubulin, with minimal effects on LV hemodynamics, regional function, or tissue endothelial nitric oxide synthase. Thus, candesartan given before an MI attenuates LV remodeling and alters the cytoskeleton matrix of the left ventricle.

This study was designed to determine whether tissue engineering could be used to reduce ventricular remodeling in a rat model of non-transmural, non-ST-elevation myocardial infarction.We grafted an acellular 3-dimensional (3D) collagen type 1 scaffold (solid porous foam) onto infarcted myocardium in rats. Three weeks after grafting, the scaffold was integrated into the myocardium and retarded cardiac remodeling by reducing left ventricular (LV) dilation. The LV inner and outer diameters, measured at the equator at zero LV pressure, decreased (p0.05) from 11,040 +/- 212 to 9,144 +/- 135 microm, and 13,469 +/- 187 to 11,673 +/- 104 microm (N = 12), after scaffold transplantation onto infarcted myocardium. The scaffold also shifted the LV pressure-volume curve to the left toward control and induced neo-angiogenesis (700 +/- 25 vs 75 +/- 11 neo-vessels/cm2, N = 5, p0.05). These vessels (75 +/- 11%) ranged in diameter from 25 to 100 microm and connected to the native coronary vasculature. Systemic treatment with granulocyte-colony stimulating factor (G-CSF), 50 microg/kg/day for 5 days immediately after myocardial injury, increased (p0.05) neo-vascular density from 700 +/- 25 to 978 +/- 57 neo-vessels/cm2.A 3D collagen type 1 scaffold grafted onto an injured myocardium induced neo-vessel formation and reduced LV remodeling. Treatment with G-CSF further increased the number of vessels in the myocardium, possibly due to mobilization of bone marrow cells.

Summary Background For prolonged VF, perfusion of the myocardium by pre-shock chest compressions can improve myocardial readiness for successful defibrillation. Characteristics of the VF waveform correlate with the duration of VF when there is no structural heart disease. A "smart" automated external defibrillator (AED) could therefore analyze the VF waveform, determine if VF has been prolonged, and then direct rescuers to either deliver a shock first or chest compressions first. We hypothesized that ischemic heart failure might alter the waveform content of ventricular fibrillation compared with normal hearts, complicating the determination of VF duration. Methods Myocardial infarction was induced by ligating the proximal left coronary artery. Six weeks later, VF was then induced in 10 rats with myocardial infarction and heart failure (MI-CHF) and 9 control rats. Waveforms were analyzed for total signal amplitude, median frequency, dominant frequency and bandwidth (the frequency interval containing 50% of the total amplitude about the median frequency). Results All of these VF waveform characteristics were altered substantially in MI-CHF rats compared to normal controls. In particular, MI-CHF rats had decreased signal amplitude early in VF ( p =0.02), a broader bandwidth ( p =0.001) and different frequency characteristics over time ( p Conclusions VF waveforms vary over time in a typical manner among rats with and without ischemic heart failure. However, the time-course and waveform characteristics of ventricular fibrillation are altered in rats with myocardial infarctions and ischemic heart failure compared to normal controls. These findings have important implications regarding the use of waveform analyses to determine the duration of VF.

This review briefly highlights the major mechanisms of left ventricular (LV) remodeling following myocardial infarction in heart failure and presents novel strategies to limit infarct size and retard the progression of LV remodeling. This is important since interventions that have been shown to improve mortality in patients with heart failure such as angiotensin converting enzyme inhibitor and beta-blockers had a favorable impact on the LV remodeling process. Although several other animal models of heart failure are available, we chose the rat infarct model because of its accurate reflection of human pathophysiology. It is clear from this review that the understanding of the mechanisms responsible for the regression of ventricular remodeling is still unclear. Further investigations in this area will certainly lead to the development of new therapy for heart failure.

Background Interstitial fibrosis and fibrotic scar formation contribute to cardiac remodeling and loss of cardiac function in myocardial infarction (MI) and heart failure. Recent studies showed that histone deacetylase (HDAC) inhibitors retard fibrosis formation in acute MI settings. However, it is unknown whether HDAC inhibition can reverse cardiac fibrosis in ischemic heart failure. In addition, specific HDAC isoforms involved in cardiac fibrosis and myofibroblast activation are not well defined. Thus, the purpose of this study is to determine the effects of selective class I HDAC inhibition on cardiac fibroblasts activation and cardiac fibrosis in a congestive heart failure (CHF) model secondary to MI. Methods MI was created by left anterior descending (LAD) coronary artery occlusion. Class I HDACs were selectively inhibited via Mocetinostat in CD90+ fibroblasts isolated from atrial and ventricular heart tissue in vitro. In vivo, Class I HDACs were inhibited in 3 weeks post MI rats by injecting Mocetinostat for the duration of 3 weeks. Cardiac function and heart tissue were analyzed at 6 weeks post MI. Results In sham hearts, HDAC1 and HDAC2 displayed differential expression patterns where HDAC1 mainly expressed in cardiac fibroblast and HDAC2 in cardiomyocytes. On the other hand, we showed that HDAC1 and 2 were upregulated in CHF hearts, and were found to co-localize with CD90+ cardiac fibroblasts. In vivo treatment of CHF animals with Mocetinostat improved left ventricle end diastolic pressure and dp/dt max and decreased the total collagen amount. In vitro treatment of CD90+ cells with Mocetinostat reversed myofibroblast phenotype as indicated by a decrease in α-Smooth muscle actin (α-SMA), Collagen III, and Matrix metalloproteinase-2 (MMP2). Furthermore, Mocetinostat increased E-cadherin, induced β-catenin localization to the membrane, and reduced Akt/GSK3β signaling in atrial cardiac fibroblasts. In addition, Mocetinostat treatment of atrial CD90+ cells upregulated cleaved-Caspase3 and activated the p53/p21 axis. Conclusions Taken together, our results demonstrate upregulation of HDAC1 and 2 in CHF. In addition, HDAC inhibition reverses interstitial fibrosis in CHF. Possible anti-fibrotic actions of HDAC inhibition include reversal of myofibroblast activation and induction of cell cycle arrest/apoptosis.

Angiotensin II type 1 (AT1) receptor blockade attenuates myocardial fibrosis after myocardial infarction (MI). However, whether inhibition of fibrosis by AT1 receptor blockade influences myocardial stiffness and contractility is unknown. We measured left ventricular (LV) hemodynamics, papillary muscle function, and myocardial stiffness and fibrosis in rats randomized to losartan or placebo 1 day after MI and treated subsequently for 8 wk. Losartan decreased LV and right ventricular weights as well as mean aortic and LV systolic pressures in sham and MI rats. LV end-diastolic pressure increased after MI and was decreased with losartan. Maximal developed tension and peak rate of tension rise and decline were decreased in MI vs. sham rats. Interstitial fibrosis developed after MI and was prevented in losartan-treated MI rats. The development of abnormal myocardial stiffness after MI was prevented by losartan. After MI, AT1 receptor blockade prevents an abnormal increase in myocardial collagen content. This effect was associated with a normalization of passive myocardial stiffness.

— Adaptations of the aging left ventricle (LV) to hemodynamic overload are functionally and structurally distinct from those of the young organism. This study describes the influence of aging on LV hemodynamics and remodeling late after myocardial infarction (MI) in Fischer 344 Brown Norway rats. In sham rats at 23 mo, LV weight, myocyte cross-sectional area (CSA), and myocardial fibrosis were increased, whereas LV dP/d t, LV relaxation, and maximal LV systolic function declined with respect to younger rats (7, 12, and 18 mo of age). Isometric myocardial function was evaluated in papillary muscles of 12- and 23-mo-old sham rats. Myocardial systolic function was decreased in older rats. To determine how aging affects LV function and remodeling after MI, rats were infarcted at 7 and 18 mo of age and were studied 5 mo later. Infarct size was similar in each group. Right ventricular weight, LV end-diastolic pressure, and volume index were increased, whereas LV dP/d t, peak cardiac index, and peak developed LV pressure declined after MI. However, there were no significant differences between young and older rats in any variable of LV systolic function or remodeling after MI. Myocyte CSA increased in younger rats after MI but was unchanged in 23-mo-old rats. After MI, myocardial fibrosis was significantly increased from baseline only in younger rats. The negative interaction of aging and MI on myocyte hypertrophy and fibrosis was highly significant. The findings indicate that baseline LV and myocardial function decline with age. In the aging rat after MI, despite limited compensatory hypertrophy and more advanced baseline myocardial fibrosis, the long-term functional and structural adaptations to MI are similar to those of the mature adult heart.

Background Progenitor cells isolated from cardiac explant–derived cells improve cardiac function after myocardial infarction (MI). To fully realize the therapeutic potential of these cells, it is essential to develop a safe and efficient delivery method. Therefore, the objective of this study was to determine the efficacy of our newly developed approach to retrograde coronary vein (RCV) infusion of cardiac c-Kit + cells in a small-animal model of congestive heart failure (CHF). Methods Sprague-Dawley rats underwent experimental MI. After 21 days, cardiac explant–derived c-Kit + cells were delivered to both sham and CHF animals using RCV delivery. Vehicle-treated (serum-free medium) sham and CHF animals were used as controls. Cardiac function and heart tissues were evaluated 21 days post-transplantation. Results RCV-delivered cells were retained in infarcted hearts for at least 21 days after transplantation. At 21 days post-RCV infusion, the majority of transplanted c-Kit + /GFP + cells were localized in the left ventricle. Compared with vehicle-treated CHF animals, RCV-treated rats showed a significant improvement in cardiac function. Furthermore, RCV-treated rats exhibited an increase in capillary density, a decrease in total heart collagen, and a reduction in both infarct size and cardiomyocyte hypertrophy when compared with vehicle-treated CHF rats. Conclusions Our study showed that the RCV infusion approach is an efficient technique for targeted cell delivery to the infarcted myocardium. Cardiac c-Kit + cells, delivered using RCV infusion ameliorated progression of heart failure, improved cardiac function and retarded myocardial remodeling in heart failure rats.

Varying strategies are currently being evaluated to develop tissue-engineered constructs for the treatment of ischemic heart disease. This study examines an angiogenic and biodegradable cardiac construct seeded with neonatal cardiomyocytes for the treatment of chronic heart failure (CHF).We evaluated a neonatal cardiomyocyte (NCM)-seeded 3-dimensional fibroblast construct (3DFC) in vitro for the presence of functional gap junctions and the potential of the NCM-3DFC to restore left ventricular (LV) function in an in vivo rat model of CHF at 3 weeks after permanent left coronary artery ligation.The NCM-3DFC demonstrated extensive cell-to-cell connectivity after dye injection. At 5 days in culture, the patch contracted spontaneously in a rhythmic and directional fashion at 43 ± 3 beats/min, with a mean displacement of 1.3 ± 0.3 mm and contraction velocity of 0.8 ± 0.2 mm/sec. The seeded patch could be electrically paced at nearly physiologic rates (270 ± 30 beats/min) while maintaining coordinated, directional contractions. Three weeks after implantation, the NCM-3DFC improved LV function by increasing (p0.05) ejection fraction 26%, cardiac index 33%, dP/dt(+) 25%, dP/dt(-) 23%, and peak developed pressure 30%, while decreasing (p0.05) LV end diastolic pressure 38% and the time constant of relaxation (Tau) 16%. At 18 weeks after implantation, the NCM-3DFC improved LV function by increasing (p0.05) ejection fraction 54%, mean arterial pressure 20%, dP/dt(+) 16%, dP/dt(-) 34%, and peak developed pressure 39%.This study demonstrates that a multicellular, electromechanically organized cardiomyocyte scaffold, constructed in vitro by seeding NCM onto 3DFC, can improve LV function long-term when implanted in rats with CHF.

Myofibroblast activation after myocardial infarction (MI) is one of the major mechanisms of myocardial fibrosis and subsequent heart failure. Elucidating the mechanisms of myofibroblast activation will provide a strategy to treat heart failure. Histone Deacetylases (HDAC) were reported to regulate myofibroblast differentiation and extracellular matrix deposition in idiopathic pulmonary fibrosis. Furthermore, HDAC inhibitors were shown to retards myocardial remodeling and improve cardiac function after MI. Therefore, here we examined whether HDAC1/2 are up-regulated after MI, and identify which myocardial cell type is predominately expressing HDAC. MI was created in rats by ligation of the left coronary artery. First, we assessed expression of HDAC 1 and 2 following MI in heart sections. Both HDACs uniformly expressed in myocardium in right ventricular (LV) and left ventricular (LV) in sham hearts. On the other hand, we observed up-regulation of both HDAC1 and 2 in the infarcted LV following MI. In addition, HDAC1 and 2 were co-localized with fibroblast marker Vimentin in the infarcted area. Next, we performed western blot analysis to investigate protein levels of HDAC1 and HDAC2 in right ventricular (RV), septum (S) and LV (infarcted and remote area). We found up-regulation of HDAC1 and HDAC2 only in the infarcted area compared to sham rats. Altogether these results suggest HDAC1 and 2 play a role in fibrosis following MI.

This study examines a viable biodegradable three-dimensional fibroblast construct (3DFC) in a model of chronic heart failure. The viable fibroblasts, cultured on a vicryl mesh, secrete growth factors that stimulate angiogenesis.We ligated the left coronary artery of male Sprague-Dawley rats, implanted the 3DFC 3 weeks after myocardial infarction and obtained end point data 3 weeks later, that is, 6 weeks after myocardial infarction.Implanting the 3DFC increases (p0.05) myocardial blood flow twofold, microvessel formation (0.02±0.01 vs. 0.07±0.03 vessels/μm2), and ventricular wall thickness (0.53±0.02 to 1.02±0.17mm). The 3DFC shifts the passive pressure volume loop toward the pressure axis but does not alter left ventricular (LV) ejection fraction, systolic displacement, LV end-diastolic pressure/dimension, or LV cavity area. The 3DFC stimulates selected cytokine activation with a decrease in the proinflammatory cascade and increased total protein content stimulated by strained 3DFC in vitro.The 3DFC functions as a cell delivery device providing matrix support for resident cell survival and integration into the heart. The imbedded fibroblasts of the 3DFC release a complex blend of cardioactive cytokines promoting increases in microvessel density and anterior wall blood flow but does not improve ejection fraction or alter LV remodeling.

Cell-based therapy for myocardial infarction (MI) holds great promise; however, the ideal cell type and delivery system have not been established. Obstacles in the field are the massive cell death after direct injection and the small percentage of surviving cells differentiating into cardiomyocytes. To overcome these challenges we designed a novel study to deliver cardiac progenitor cells as a cell sheet.Cell sheets composed of rat or human cardiac progenitor cells (cardiospheres), and cardiac stromal cells were transplanted onto the infarcted myocardium after coronary artery ligation in rats. Three weeks later, transplanted cells survived, proliferated, and differentiated into cardiomyocytes (14.6 +/- 4.7%). Cell sheet transplantation suppressed cardiac wall thinning and increased capillary density (194 +/- 20 vs. 97 +/- 24 per mm(2), P0.05) compared with the untreated MI. Cell migration from the sheet was observed along the necrotic trails within the infarcted area. The migrated cells were located in the vicinity of stromal-derived factor (SDF-1) released from the injured myocardium, and about 20% of these cells expressed CXCR4, suggesting that the SDF-1/CXCR4 axis plays, at least, a role in cell migration. Transplantation of cell sheets resulted in a preservation of cardiac contractile function after MI, as was shown by a greater ejection fraction and lower left ventricular end diastolic pressure compared with untreated MI.The scaffold-free cardiosphere-derived cell sheet approach seeks to efficiently deliver cells and increase cell survival. These transplanted cells effectively rescue myocardium function after infarction by promoting not only neovascularization but also inducing a significant level of cardiomyogenesis.

Summary Aim Increases in serum cytokines have been reported after successful resuscitation from prolonged ventricular fibrillation (VF). Pro-inflammatory cytokines can stimulate inducible nitric oxide synthase (iNOS) to produce excessive levels of nitric oxide (NO). High levels of both myocardial inflammatory cytokines and nitric oxide levels can depress myocardial contractile function. We hypothesized that myocardial pro-inflammatory cytokines and iNOS activity would increase following successful resuscitation from prolonged ventricular fibrillation cardiac arrest, and that such increases would parallel the development of post-resuscitation myocardial dysfunction. Methods Ventricular fibrillation cardiac arrest was induced in seven domestic swine (25 ± 5 kg). After 10 min of untreated VF, the animals were defibrillated and resuscitated. Left ventricular (LV) systolic and diastolic function measurements, serum samples (arterial and coronary sinus) for IL-8 cytokine quantification, and LV myocardial biopsies were collected before, during, and after resuscitation. Quantification of myocardial endothelial (eNOS) and inducible (iNOS) nitric oxide synthase protein levels were determined using immunoblot analyses and protein localization was examined using immunohistochemistry. Results Post-resuscitation LV systolic and diastolic functions were depressed while increases in both coronary sinus IL-8 levels and myocardial iNOS activity were found. Compared to pre-arrest baseline, levels of iNOS protein increased during VF ( p ≤ 0.05) and continued to increase throughout the post-resuscitation study period of 6 h ( p ≤ 0.05). Conclusions Myocardial inflammatory cytokines and iNOS activity increase during and after prolonged cardiac arrest and successful resuscitation. These increases correspond to the well described decrease in LV function post-resuscitation.

Published guidelines recommend continuing β-adrenergic receptor blockade in patients undergoing stress testing. We evaluated the role of pharmacological versus exercise stress testing in achieving target heart rate (THR) among patients on β-adrenergic blockade. We compared data from 140 patients who underwent dobutamine stress echo (DSE) and 143 patients who underwent exercise treadmill testing (ETT). In both groups, β-adrenergic blocker was continued at the time of stress testing. Overall, patients undergoing DSE achieved THR more frequently than ETT. With β-adrenergic blockade, DSE patients met THR more frequently than ETT patients (p < 0.001). Without β-adrenergic blockade, there was no difference between either modality in achieving THR. In both DSE and ETT patients, absence of β-adrenergic blockade increased the odds of achieving THR [odds ratio (OR): 2.46, p = 0.042 and OR: 7.44, p < 0.001, respectively]. Atropine use with DSE increased the odds of achieving THR (OR: 3.76, p = 0.006). In conclusion, pharmacological stress testing appears to be superior to exercise stress testing in achieving THR among patients on β-adrenergic blockade.

The efficacy of amiodarone used in combination with a pacemaker cardioverter defibrillator (PCD) to decrease episodes of ventricular tachycardia and subsequent PCD shocks is not clear. We examined a retrospective registry of 82 patients with PCD implantation to define the efficacy of amiodarone treatment. We compared patients treated with amiodarone (for 24 consecutive months without interruption) versus no amiodarone. In patients treated with amiodarone there was a 3-fold increase (p = 0.02) in PCD shocks; in patients not on beta-blockers, amiodarone resulted in a 6-fold increase (p < 0.05) in PCD shocks. Patients with a left ventricular ejection fraction >30% on amiodarone and patients

We identified abnormalities in the vascular β-adrenergic receptor (β-AR) signaling pathway in heart failure after myocardial infarction (MI). To examine these abnormalities, we measured β-AR-mediated hemodynamics, vascular reactivity, and the vascular β-AR molecular signaling components in rats with heart failure after MI. Six weeks after MI, these rats had an increased left ventricular (LV) end-diastolic pressure, decreased LV systolic pressure, and decreased rate of LV pressure change (dP/d t). LV dP/d t responses to isoproterenol were shifted downward, although the responses for systemic vascular resistance were shifted upward in heart failure rats ( P < 0.05). Isoproterenol- and IBMX-induced vasorelaxations were blunted in heart failure rats ( P< 0.05) with no change in the forskolin-mediated vasorelaxation. These changes were associated with the following alterations in β-AR signaling ( P < 0.05): decreases in β-AR density (aorta: 58.7 ± 6.0 vs. 35.7 ± 1.9 fmol/mg membrane protein; carotid: 29.6 ± 5.6 vs. 18.0 ± 3.9 fmol/mg membrane protein, n = 5), increases in G protein-coupled receptor kinase activity levels (relative phosphorimage counts of 191 ± 39 vs. 259 ± 26 in the aorta and 115 ± 30 vs. 202 ± 7 in the carotid artery, n = 5), and decreases in cGMP and cAMP in the carotid artery (0.85 ± 0.10 vs. 0.31 ± 0.06 pmol/mg protein and 2.3 ± 0.3 vs. 1.2 ± 0.1 pmol/mg protein, n = 5) with no change in Gαsor Gαiin the aorta. Thus in heart failure there are abnormalities in the vascular β-AR system that are similar to those seen in the myocardium. This suggests a common neurohormonal mechanism and raises the possibility that treatment in heart failure focused on the myocardium may also affect the vasculature.

Background 'Stone heart' resulting from ischemic contracture of the myocardium, precludes successful resuscitation from ventricular fibrillation (VF). We hypothesized that mild hypothermia might slow the progression to stone heart. Methods Fourteen swine (27 ± 1 kg) were randomized to normothermia (group I; n = 6) or hypothermia groups (group II; n = 8). Mild hypothermia (34 ± 2°C) was induced with ice packs prior to VF induction. The LV and right ventricular (RV) cross-sectional areas were followed by cardiovascular magnetic resonance until the development of stone heart. A commercial 1.5T GE Signa NV-CV/i scanner was used. Complete anatomic coverage of the heart was acquired using a steady-state free precession (SSFP) pulse sequence gated at baseline prior to VF onset. Un-gated SSFP images were obtained serially after VF induction. The ventricular endocardium was manually traced and LV and RV volumes were calculated at each time point. Results In group I, the LV was dilated compared to baseline at 5 minutes after VF and this remained for 20 minutes. Stone heart, arbitrarily defined as LV volume Conclusions In this closed-chest swine model of prolonged untreated VF, hypothermia reduced the early LV dilatation and importantly, delayed the onset of stone heart thereby extending a known, morphologic limit of resuscitability.

Background Tissue engineering is a novel method to restore myocardial function in ischemic heart disease. One technique is to apply a biologically active graft onto the infarcted region (IR) of the left ventricle (LV). The effects of a fibroblast patch (3DFC) placement on the IR of the LV on systolic/diastolic function in a coronary artery ligation (CAL) model of heart failure were evaluated. Methods CAL to induce myocardial infarction (MI) is performed on Sprague-Dawley rats. The 3DFC patch is placed on the IR. Echos were done at 3 weeks. Hemodynamics was measured. LV regional systolic displacement (SD), LV ejection fraction (LVEF), LV fractional shortening (FS), and LV pressure/diameter relaxation curves were obtained. Results 3DFC patch placement improved (p Summary Implantation of a fibroblast mesh on the IR of the LV improved LV systolic function. The patch also prevented LV dilation and normalized LV diastolic function post MI. Our data illustrate the future potential of using a biologically active graft in the treatment of ischemic heart failure.

Background Left ventricular (LV) remodeling after myocardial infarction (MI) leads to heart failure (HF). While alterations in LV wall strain are seen in the infarcted regions (IR), it is unclear if this also affects the non-infarcted regions (NIR) of the LV. Additionally, while LV tissue eNOS and constituitive microtubulin (CM) are altered in chronic HF, it is unknown what happens to these biomarkers acutely. We evaluated changes in LV wall strain; myocardial eNOS and CM acutely post MI. Methods LV wall motion of Sprague Dawley rats (N = 10) was analyzed by echocardiography at several time points after MI. Hemodynamic measurements were obtained via a Millar catheter. Alterations in myocardial contraction (δ strain) are measured via M-mode echocardiography. CM and eNOS were determined via immunoblot techniques. Results Systolic blood pressure decreased (P ≤ 0.05) acutely post MI (127.1 ± 6.1 vs 101.7± 10.1 mmHg). LV end diastolic pressure increased (P≤0.05) acutely after MI (5.8 ± 0.5 vs. 19.9 ± 2.0 mmHg). These changes were accompanied by a decrease (P≤ 0.05) in LV dP/dt after MI (7106 ± 520 vs. 4671± 350, mmHg/sec). δ strain was decreased in the anterior IR immediately (0.15 ± 0.04 vs 0.1 ± 0.02 mm, P ≤ 0.01); similarly δ strain was also decreased in the posterior NIR starting at 1 minute (0.17 ± 0.02 vs 0.1 ± 0.02 mm, P ≤ 0.01). A decrease in eNOS was seen with both the IR and NIR of the LV (20.8± 3.8 intensity unit (IU)/50 μg of tissue vs 11.1 ± 3.3 IU/50 μg, P = 0.04) and (26.7 ± 4.8 vs 8.14 ± 1.6 IU/50 μg, P = 0.002), respectively after MI. Conversely, CM was increased in both IR and NIR of the LV (10.3 ± 2.4 IU/25 μg vs 26.2 ± 4.6 IU/25 μg, P = 0.0005) and (9.3 ± 1.8 vs 18.5 ± 3.7 IU/25 μg, P = 0.003), respectively. Conclusion Decreases in δ strain occurred in both IR and NIR of the LV acutely after MI. This is accompanied by alterations in eNOS and CM levels throughout the LV immediately after MI. Our data demonstrate that physical and biomarkers signaling LV remodeling occur immediately after MI, rather than over time.