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Background: Cardiac power output (CPO), derived from the product of cardiac output and mean aortic pressure, is an important yet underexploited parameter for hemodynamic monitoring of critically ill patients in the intensive-care unit (ICU). The conductance catheter-derived pressure-volume loop area reflects left ventricular stroke work (LV SW). Dividing LV SW by time, a measure of LV SW min - 1 is obtained sharing the same unit as CPO (W). We aimed to validate CPO as a marker of LV SW min - 1 under various inotropic states., Methods: We retrospectively analysed data obtained from experimental studies of the hemodynamic impact of mild hypothermia and hyperthermia on acute heart failure. Fifty-nine anaesthetized and mechanically ventilated closed-chest Landrace pigs (68 ± 1 kg) were instrumented with Swan-Ganz and LV pressure-volume catheters. Data were obtained at body temperatures of 33.0 °C, 38.0 °C and 40.5 °C; before and after: resuscitation, myocardial infarction, endotoxemia, sevoflurane-induced myocardial depression and beta-adrenergic stimulation. We plotted LVSW min - 1 against CPO by linear regression analysis, as well as against the following classical indices of LV function and work: LV ejection fraction (LV EF), rate-pressure product (RPP), triple product (TP), LV maximum pressure (LVP max ) and maximal rate of rise of LVP (LV dP/dt max )., Results: CPO showed the best correlation with LV SW min - 1 (r 2  = 0.89; p < 0.05) while LV EF did not correlate at all (r 2  = 0.01; p = 0.259). Further parameters correlated moderately with LV SW min - 1 (LVP max r 2  = 0.47, RPP r 2  = 0.67; and TP r 2  = 0.54). LV dP/dt max correlated worst with LV SW min - 1 (r 2  = 0.28)., Conclusion: CPO reflects external cardiac work over a wide range of inotropic states. These data further support the use of CPO to monitor inotropic interventions in the ICU.

Background: Xenon and isoflurane are known to have cardioprotective properties. We tested the hypothesis that these anesthetics positively influence myocardial remodeling 28 days after experimental perioperative myocardial infarction and compared their effects., Methods: A total of 60 male Sprague-Dawley rats were subjected to 60 min of coronary artery occlusion and 120 min of reperfusion. Prior to ischemia, the animals were randomized for the different narcotic regimes (0.6 vol% isoflurane, 70 vol% xenon, or intraperitoneal injection of s-ketamine). Acute injury was quantified by echocardiography and troponin I. After 4 weeks, left ventricular function was assessed by conductance catheter to quantify hemodynamic compromise. Cardiac remodeling was characterized by quantification of dilatation, hypertrophy, fibrosis, capillary density, apoptosis, and expression of fetal genes (α/β myosin heavy chains, α-skeletal actin, periostin, and sarco/endoplasmic reticulum Ca2+-ATPase)., Results: Whereas xenon and isoflurane impeded the acute effects of ischemia-reperfusion on hemodynamics and myocardial injury at a comparable level, differences were found after 4 weeks. Xenon in contrast to isoflurane or ketamine anesthetized animals demonstrated a lower remodeling index (0.7 ± 0.1 vs. 0.9 ± 0.3 and 1.0 ± 0.3g/ml), better ejection fraction (62 ± 9 vs. 49 ± 7 and 35 ± 6%), and reduced expression of β-myosin heavy chain and periostin. The effects on hypertrophy, fibrosis, capillary density, and apoptosis were comparable., Conclusions: Compared to isoflurane and s-ketamine, xenon limited progressive adverse cardiac remodeling and contractile dysfunction 28 days after perioperative myocardial infarction.

Background: Mild hypothermia (MH) decreases infarct size and mortality in experimental reperfused myocardial infarction, but may potentiate ischaemia-induced left ventricular (LV) diastolic dysfunction., Methods: In anaesthetized pigs (70 ± 2 kg), polystyrol microspheres (45 μm) were infused repeatedly into the left circumflex artery until cardiac power output decreased >40%. Then, pigs were assigned to normothermia (NT, 38.0°C, n=8) or MH (33.0°C, n=8, intravascular cooling) and followed for 6h (CME 6h). p<0.05 vs baseline, †p<0.05 vs NT., Results: In NT, cardiac output (CO) decreased from 6.2 ± 0.3 to 3.4 ± 0.2 l/min, and heart rate increased from 89 ± 4 to 101 ± 6 bpm. LV end-diastolic volume fell from 139 ± 8 to 64 ± 4 ml, while LV ejection fraction remained constant (49 ± 1 vs 53 ± 4%). The corresponding end-diastolic pressure-volume relationship was progressively shifted leftwards, reflecting severe LV diastolic dysfunction. In MH, CO fell to a similar degree. Spontaneous bradycardia compensated for slowed LV relaxation, and the leftward shift of the end-diastolic pressure-volume relationship was less pronounced during MH. MH increased systemic vascular resistance, such that mean aortic pressure remained higher in MH vs NT (69 ± 2† vs 54 ± 4 mm Hg). Mixed venous oxygen saturation at CME 6h was higher in MH than in NT (59 ± 4† vs 42 ± 2%) due to lowered systemic oxygen demand during cooling., Conclusion: We conclude that (i) an acute loss of end-diastolic LV compliance is a major component of acute cardiac pump failure during experimental myocardial infarction, and that (ii) MH does not potentiate this diastolic LV failure, but stabilizes haemodynamics and improves systemic oxygen supply/demand imbalance by reducing demand., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

We previously showed that human cardiomyocyte progenitor cells (hCMPCs) injected after myocardial infarction (MI) had differentiated into cardiomyocytes in vivo 3 months after MI. Here, we investigated the short-term (2 weeks) effects of hCMPCs on the infarcted mouse myocardium. MI was induced in immunocompromised (NOD/scid) mice, immediately followed by intramyocardial injection of hCMPCs labelled with enhanced green fluorescent protein (hCMPC group) or vehicle only (control group). Sham-operated mice served as reference. Cardiac performance was measured 2 and 14 days after MI by magnetic resonance imaging at 9.4 T. Left ventricular (LV) pressure-volume measurements were performed at day 15 followed by extensive immunohistological analysis. Animals injected with hCMPCs demonstrated a higher LV ejection fraction, lower LV end-systolic volume and smaller relaxation time constant than control animals 14 days after MI. hCMPCs engrafted in the infarcted myocardium, did not differentiate into cardiomyocytes, but increased vascular density and proliferation rate in the infarcted and border zone area of the hCMPC group. Injected hCMPCs engraft into murine infarcted myocardium where they improve LV systolic function and attenuate the ventricular remodelling process 2 weeks after MI. Since no cardiac differentiation of hCMPCs was evident after 2 weeks, the observed beneficial effects were most likely mediated by paracrine factors, targeting amongst others vascular homeostasis. These results demonstrate that hCMPCs can be applied to repair infarcted myocardium without the need to undergo differentiation into cardiomyocytes., (© 2011 The Authors Journal of Cellular and Molecular Medicine © 2011 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.)

Objectives: This study sought to examine whether exenatide is capable of reducing myocardial infarct size., Background: Exenatide is a glucagon-like peptide (GLP)-1 analogue with insulinotropic and insulinomimetic properties. Because insulin and GLP-1 have been described as reducing apoptosis, exenatide might confer cardioprotection after acute myocardial infarction (MI)., Methods: Pigs were randomized to exenatide or phosphate-buffered saline (PBS) treatment after 75 min of coronary artery ligation and subsequent reperfusion. Infarct size was assessed with Evans Blue (Sigma-Aldrich, St. Louis, Missouri) and triphenyltetrazolium chloride. Cardiac function was measured with epicardial ultrasound and conductance catheter-based pressure-volume loops. Western blotting, histology, and activity assays were performed to determine markers of apoptosis/survival and oxidative stress., Results: Exenatide reduced myocardial infarct size (32.7 +/- 6.4% vs. 53.6 +/- 3.9%; p = 0.031) and prevented deterioration of systolic and diastolic cardiac function (systolic wall thickening: 47.3 +/- 6.3% vs. 8.1 +/- 1.9%, p < 0.001; myocardial stiffness: 0.12 +/- 0.06 mm Hg/ml vs. 0.22 +/- 0.07 mm Hg/ml; p = 0.004). After exenatide treatment, myocardial phosphorylated Akt and Bcl-2 expression levels were higher compared with those after PBS treatment, and active caspase 3 expression was lower. In addition, fewer cells were terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling-positive. In addition, nuclear oxidative stress as assessed with an 8-hydroxydeoxyguanosine staining was reduced in the exenatide treatment arm, and superoxide dismutase activity and catalase activity were increased. Serum insulin levels increased after exenatide treatment, without affecting glucose levels., Conclusions: These data identify exenatide as a potentially effective compound to reduce infarct size in adjunction to reperfusion therapy in patients with acute MI.

Mesenchymal stem cells (MSCs) from healthy donors improve cardiac function in experimental acute myocardial infarction (AMI) models. However, little is known about the therapeutic capacity of human MSCs (hMSCs) from patients with ischemic heart disease (IHD). Therefore, the behavior of hMSCs from IHD patients in an immune-compromised mouse AMI model was studied. Enhanced green fluorescent protein-labeled hMSCs from IHD patients (hMSC group: 2 x 10(5) cells in 20 microl, n = 12) or vehicle only (medium group: n = 14) were injected into infarcted myocardium of NOD/scid mice. Sham-operated mice were used as the control (n = 10). Cardiac anatomy and function were serially assessed using 9.4-T magnetic resonance imaging (MRI); 2 wk after cell transplantation, immunohistological analysis was performed. At day 2, delayed-enhancement MRI showed no difference in myocardial infarction (MI) size between the hMSC and medium groups (33 +/- 2% vs. 36 +/- 2%; P = not significant). A comparable increase in left ventricular (LV) volume and decrease in ejection fraction (EF) was observed in both MI groups. However, at day 14, EF was higher in the hMSC than in the medium group (24 +/- 3% vs. 16 +/- 2%; P < 0.05). This was accompanied by increased vascularity and reduced thinning of the infarct scar. Engrafted hMSCs (4.1 +/- 0.3% of injected cells) expressed von Willebrand factor (16.9 +/- 2.7%) but no stringent cardiac or smooth muscle markers. hMSCs from patients with IHD engraft in infarcted mouse myocardium and preserve LV function 2 wk after AMI, potentially through an enhancement of scar vascularity and a reduction of wall thinning.

Background: Cyclooxygenase (COX)-2 expression in the heart increases after myocardial infarction (MI). In murine models of MI, COX-2 inhibition preserves left ventricular dimensions and function. We studied the effect of selective COX-2 inhibition on left ventricular remodeling and function after MI in a pig model., Methods and Results: Twenty-two pigs were assigned to COX-2 inhibition with a COX-2 inhibitor (COX-2i; celecoxib 400 mg twice daily; n=14) or a control group (n=8). MI was induced by left circumflex coronary artery ligation, and the animals were euthanized 6 weeks later. Cardiac dimensions and function were assessed with echocardiography and conductance catheters. Infarct size and collagen density were analyzed with triphenyltetrazolium chloride staining and picrosirius red staining, respectively. COX-2 inhibition increased mortality compared with controls (50% versus 0%, P=0.022), whereas infarct size was similar (13.1+/-0.7% versus 14.1+/-0.1%, P=0.536). The decrease in thickness of the infarcted myocardial wall was more pronounced in the COX-2i group (60.6+/-9.6% versus 36.2+/-5.7%, P=0.001). End-diastolic volume was higher in the COX-2i group (133.9+/-33.5 versus 91.1+/-24.0 mL; P=0.021), as was the end-systolic volume at 100 mm Hg (81.7+/-27.8 versus 56.3+/-21.1 mL; P=0.037), which indicates that systolic function was more severely impaired. Infarct collagen density was lower after COX-2i treatment (25.3+/-3.9 versus 56.1+/-23.8 gray value/mm2; P=0.005)., Conclusions: In pigs, COX-2 inhibition after MI is associated with increased mortality, enhanced left ventricular remodeling, and impaired systolic function, probably due to decreased infarct collagen fiber density.

The human heart has a limited capacity for self-repair because, unlike most other cells, cardiomyocytes do not regenerate. Therefore, if a substantial number of myocytes is lost after a myocardial infarction, the performance of the heart may become severely limited, leading to a condition of heart failure. Recently, cell transplantation has emerged as a potential therapy for patients with end-stage heart failure. Of the various cell types being investigated for this purpose, skeletal myoblasts are an attractive option, because they are readily available from muscle biopsies and, if autologous cells are used, immunosuppression is not required and ethical issues are avoided. Several studies have shown that the cells can survive and differentiate after transplantation, and promising clinical results have been reported. However, effects of this therapy on left ventricular function remain largely unknown. In the present study, we investigated the long-term hemodynamic effects of intramyocardial injection of autologous skeletal myoblasts in patients with ischemic heart failure. Our findings indicate hemodynamic improvement after follow-up for up to 1 year, which is especially promising in view of the expected decline in left ventricular function in these patients.

Objective: Surgical left ventricular restoration by means of endoventricular patch aneurysmectomy in patients with postinfarction aneurysm should result in acute improved left ventricular performance by decreasing mechanical dyssynchrony and increasing energy efficiency., Methods: Nine patients with left ventricular postinfarction aneurysm were studied intraoperatively before and after ventricular restoration with a conductance volume catheter to analyze pressure-volume relationships, energy efficiency, and mechanical dyssynchrony. The end-systolic elastance was used as a load-independent index of contractile state. Left ventricular energy efficiency was calculated from stroke work and total pressure-volume area. Segmental volume changes perpendicular to the long axis were used to calculate mechanical dyssynchrony. Statistical analysis was performed with the paired t test and least-squares linear regression., Results: Endoventricular patch aneurysmectomy reduced end-diastolic volume by 37% (P < .001), with unchanged stroke volume. Systolic function improved, as derived from increased +dP/dt(max), by 42% (P < .03), peak ejection rate by 28% (P < .02), and ejection fraction by 16% (P < .0002). Early diastolic function improved, as shown by reduction of -dP/dt(max) by 34% (P < .006) and shortened tau by 30% (P < .001). Left ventricular end-systolic elastance increased from 1.2 +/- 0.6 to 2.2 +/- 1 mm Hg/mL (P < .001). Left ventricular energy efficiency increased by 36% (P < .002). Left ventricular mechanical dyssynchrony decreased during systole by 33% (P < .001) and during diastole by 20% (P < .005)., Conclusions: Left ventricular restoration induced acute improvements in contractile state, energy efficiency, and relaxation, together with a decrease in left ventricular mechanical dyssynchrony.

Hearts of normotensive angiotensin II type 2 receptor (AT2)-deficient mice do not develop fibrosis after angiotensin II-induced chronic hypertension. Thus, the goal of our study was to clarify whether AT2 knockouts (KOs) are also characterized by altered left ventricular (LV) function and modified remodeling of the extracellular matrix (ECM) after induction of myocardial infarction (MI). MI was induced in 5-mo-old female AT2-deficient mice and controls by occlusion of the left coronary artery. Time-matched sham-operated animals served as controls. After 48 h, the first sets of mice were hemodynamically characterized using a pressure-tip catheter (n = 8/group). We also obtained pressure volume loops using a microconductance catheter in additional sets of animals 3 wk after induction of MI (n = 7/group). Finally, the collagen index was illustrated by Sirius red staining and quantified by digital analysis. Whereas the LV function of sham-operated animals did not differ between both genotypes, the collagen index was 44% lower in KO animals. Forty-eight hours and 3 wk post-MI, systolic and diastolic LV function were impaired in both AT2-deficient and wild-type (WT) animals to the same extent by approx 45%. No differences were found between the two genotypes with respect to LV hypertrophy and the fibrosis index in the infarcted and noninfarcted areas 3 wk post-MI. While AT2-KO mice had less cardiac collagen content under basal conditions, the receptor deficiency had no significant influence on LV function at the two investigated time points after induction of MI or on the remodeling of ECM at the latter time point. Thus, hypertension-induced fibrosis is probably triggered by other control mechanisms than fibrosis induced by MI.

Background: Hypercholesterolemia is a major risk factor for ischemic heart disease including acute myocardial infarction. However, long-term effects of hypercholesterolemia in a rodent myocardial ischemia-reperfusion injury model are unknown. Therefore, the effects of diet-induced hypercholesterolemia on cardiac function and remodeling were investigated up to eight weeks after myocardial ischemia-reperfusion (MI-R) injury which was induced in either normocholesterolemic (NC-MI) or hypercholesterolemic (HC-MI) APOE*3-Leiden mice. Methods: Left ventricular (LV) dimensions were serially assessed using parasternal long-axis echocardiography followed by LV pressure-volume measurements. Subsequently, infarct size and the inflammatory response were analyzed by histology and fluorescence-activated cell sorting (FACS) analysis. Results: Intrinsic LV function eight weeks after MI-R was significantly impaired in HC-MI compared to NC-MI mice as assessed by end-systolic pressure, dP/dtMAX, and -dP/dtMIN. Paradoxically, infarct size was significantly decreased in HC-MI compared to NC-MI mice, accompanied by an increased wall thickness. Hypercholesterolemia caused a pre-ischemic peripheral monocytosis, in particular of Ly-6Chi monocytes whereas accumulation of macrophages in the ischemic-reperfused myocardium of HC-MI mice was decreased. Conclusion: Diet-induced hypercholesterolemia caused impaired LV function eight weeks after MI-R injury despite a reduced post-ischemic infarct size. This was preceded by a pre-ischemic peripheral monocytosis, while there was a suppressed accumulation of inflammatory cells in the ischemic-reperfused myocardium after eight weeks. This experimental model using hypercholesterolemic APOE*3-Leiden mice exposed to MI-R seems suitable to study novel cardioprotective therapies in a more clinically relevant animal model. [ABSTRACT FROM AUTHOR]

Background: We investigated whether (1) monocrotaline(MCT)-induced right ventricular (RV) dilatation is associated with re-expression of myocardial tenascin-C (TNC), (2) elevated plasma TNC levels can be used as a marker of ventricular dilatation, and (3) MCT-induced RV dilatation is associated with alterations of other remodeling-related proteins. Methods: Rats were treated with MCT in low dose (30 mg/kg, MCT30, n=10) to induce compensated RV hypertrophy, in high dose (80 mg/kg, MCT80, n=11) to induce RV failure, and with saline as control (CONT, n=9). After 4 weeks, RV function was assessed. TNC gene expression, protein levels, and plasma levels were assayed. Myocardial gene expression of integrin subunit α6 and β1, and myocardial proMMP2 and proMMP9 levels were assessed. Results: TNC gene expression in the RV of MCT80 rats was significantly upregulated compared with RV of CONT (4-fold, p<0.001) and MCT30 rats (3-fold, p<0.01), whereas TNC gene expression was very low in LV and IVS of MCT80 rats, and absent in those of CONT and MCT30 rats. Myocardial TNC protein levels were only observed in MCT80 rats, and were higher in RV (0.62±0.64 ng/mg) than in LV (0.21±0.44 ng/mg) or IVS (0.21±0.09 ng/mg) (p<0.01, RV vs LV and IVS). Plasma levels of TNC were significantly elevated in MCT80 rats compared with CONT (p<0.05). RV volumes correlated positively with TNC plasma levels and RV ejection fraction correlated negatively with TNC plasma levels. MCT-induced RV failure was also associated with a significant downregulation of integrin α6 gene expression (by 48%, p<0.01). Conclusions: MCT-induced RV failure is associated with an upregulation of TNC gene expression, resulting in re-expression of myocardial TNC protein levels, and elevated TNC plasma levels. As RV ejection fraction correlated significantly with TNC plasma levels, TNC plasma levels may serve as a marker of ventricular failure. De-adhesive properties of TNC in combination with a downregulation of integrin α6 may have caused cardiomyocyte slippage, leading to adverse ventricular remodeling. Copyright © 2009 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]