End-systolic Pressure-volume Relationship Research Articles

Preclinical Evaluation of the Engineered Stem Cell Chemokine Stromal Cell–Derived Factor 1α Analog in a Translational Ovine Myocardial Infarction Model

After myocardial infarction, there is an inadequate blood supply to the myocardium, and the surrounding borderzone becomes hypocontractile. To develop a clinically translatable therapy, we hypothesized that in a preclinical ovine model of myocardial infarction, the modified endothelial progenitor stem cell chemokine, engineered stromal cell-derived factor 1α analog (ESA), would induce endothelial progenitor stem cell chemotaxis, limit adverse ventricular remodeling, and preserve borderzone contractility. Thirty-six adult male Dorset sheep underwent permanent ligation of the left anterior descending coronary artery, inducing an anteroapical infarction, and were randomized to borderzone injection of saline (n=18) or ESA (n=18). Ventricular function, geometry, and regional strain were assessed using cardiac MRI and pressure-volume catheter transduction. Bone marrow was harvested for in vitro analysis, and myocardial biopsies were taken for mRNA, protein, and immunohistochemical analysis. ESA induced greater chemotaxis of endothelial progenitor stem cells compared with saline (P<0.01) and was equivalent to recombinant stromal cell-derived factor 1α (P=0.27). Analysis of mRNA expression and protein levels in ESA-treated animals revealed reduced matrix metalloproteinase 2 in the borderzone (P<0.05), with elevated levels of tissue inhibitor of matrix metalloproteinase 1 and elastin in the infarct (P<0.05), whereas immunohistochemical analysis of borderzone myocardium showed increased capillary and arteriolar density in the ESA group (P<0.01). Animals in the ESA treatment group also had significant reductions in infarct size (P<0.01), increased maximal principle strain in the borderzone (P<0.01), and a steeper slope of the end-systolic pressure-volume relationship (P=0.01). The novel, biomolecularly designed peptide ESA induces chemotaxis of endothelial progenitor stem cells, stimulates neovasculogenesis, limits infarct expansion, and preserves contractility in an ovine model of myocardial infarction.

Dimensional reductions of a cardiac model for effective validation and calibration

Complex 3D beating heart models are now available, but their complexity makes calibration and validation very difficult tasks. We thus propose a systematic approach of deriving simplified reduced-dimensional models, in "0D"-typically, to represent a cardiac cavity, or several coupled cavities-and in "1D"-to model elongated structures such as muscle samples or myocytes. We apply this approach with an earlier-proposed 3D cardiac model designed to capture length-dependence effects in contraction, which we here complement by an additional modeling component devised to represent length-dependent relaxation. We then present experimental data produced with rat papillary muscle samples when varying preload and afterload conditions, and we achieve some detailed validations of the 1D model with these data, including for the length-dependence effects that are accurately captured. Finally, when running simulations of the 0D model pre-calibrated with the 1D model parameters, we obtain pressure-volume indicators of the left ventricle in good agreement with some important features of cardiac physiology, including the so-called Frank-Starling mechanism, the End-Systolic Pressure-Volume Relationship, as well as varying elastance properties. This integrated multi-dimensional modeling approach thus sheds new light on the relations between the phenomena observed at different scales and at the local versus organ levels.

Curcumin Treatment Protects Against Renal Ischemia and Reperfusion Injury–Induced Cardiac Dysfunction and Myocardial Injury

ObjectivesRenal ischemia and reperfusion (I/R) injury frequently leads to acute renal failure (ARF) and multiple-organ injury with a substantial morbidity rate. The primary cause of ARF-associated death is, however, cardiac failure instead of renal failure itself, and the pathogenesis of renal I/R-induced cardiac injury is still poorly understood. We evaluated the efficacy of curcumin pretreatment on cardioprotection. MethodsThirty Sprague-Dawley rats were evenly divided into 3 groups of sham-operated control, renal I/R injury, and a curcumin pretreatment group. Renal ischemia was conducted by bilateral occlusions of pedicles for 45 minutes, followed by 3 hours of reperfusion. The cardiac function was assessed by the left ventricular end-systolic-pressure-volume-relation (ESPVR), systolic pressure (SP), ejection fraction (EF), and stroke volume (SV). Myocardial injury was assessed based on creatine kinase muscle brain fraction (CK-MB) and Troponin I (cTnI), and kidney injury was assessed based on blood urea nitrogen (BUN) and creatinine. We also assessed the levels of tumor necrosis factor-α (TNF-α) and malondialdehyde (MDA) in the heart tissues. ResultsSV, EF, and SP reduced moderately during the ischemic phase with no major change in ESPVR. During reperfusion, SV, SP, and ESPVR initially increased, and then steadily decreased. Myocardial and kidney injury were marked by the increases in serum CK-MB and cTnI, and creatinine and BUN level. Curcumin pretreatment ameliorated ESPVR and attenuated injuries of both the heart and kidney resulting from I/R insult. ConclusionsCurcumin pretreatment improved cardiac contractility and attenuated myocardial and renal injury through reducing inflammatory response in the kidney and heart and oxidative stress in the myocardium.

Abstract 195: Cardioprotective and Anti-inflammatory Effects of Treatment With Adenocaine/mg2+ in a Porcine Model of Endotoxemia

Introduction: The combination of adenosine + lidocaine (adenocaine) and Mg2+ (ALM) has demonstrated cardioprotective properties in models of cardiac arrest and hemorrhagic shock, and anti-neutrophil effects in vitro. This study evaluates whether ALM also demonstrates cardioprotective and anti-inflammatory properties in an endotoxemic porcine model. Methods: Pigs (37-42kg) received lipopolysaccharide (LPS) at 1 μg/kg/h for 5 hours, and were randomized to: LPS (control) (n=8) or LPS + ALM (n=8). Pigs received a bolus of ALM at start of LPS infusion followed by 4 hours of infusion. Cardiac function was evaluated using pressure-volume loops, and inflammation was assessed by plasma TNF-α and leukocyte superoxide generation. Results: Infusion of ALM maintained mean arterial pressure (MAP) at a lower level during the 4 hour infusion period (ALM: 47 ± 1.6 mmHg vs. control: 80 ± 2.9 mmHg, p&lt;0.0001). After discontinuation of ALM, MAP immediately returned to and was maintained at baseline group values (ALM: 89 ± 5 mmHg vs. control: 86 ± 3 mmHg). The slope of the end-systolic pressure-volume relationship (ESPVR) was unchanged during the experiment in both groups. However, a rightward shift of the volume axis intercept (V0) in the control group indicated decreased contractility; this shift was not observed in the ALM group (control: -0.1 ± 12 ml vs. ALM: -32.5 ± 7.6 ml, p= 0.04). Preload recruitable stroke work (PRSW), an index of overall cardiac performance, decreased in the control group (baseline: 71 ± 4: end: 37 ± 4 mmHg · ml / ml), but was preserved in the ALM group (baseline: 72 ± 5; end: 62 ± 4 mmHg · ml / ml, p&lt;0.001 between groups). Diastolic function evaluated by dP/dtmin (ALM 2221 ± 170 vs. 1793 ± 89 mmHg/sec; p=0.04) and Tau (ALM 36 ± 1.2 vs. 44 ± 2.2 msec; p=0.007) was also significantly improved in the ALM group. Peak TNF-α levels were lower in the ALM group (ALM 7653 ± 1092 vs. 11989 ±1057 pg/ml; p=0.01). While neutrophil superoxide anion release increased by 19 ± 27 % in the control group, it decreased by 74 ± 8% in the ALM group (p=0.0006). Conclusions: In this porcine model of endotoxemia, ALM improved cardiac function and reduced the inflammatory response to LPS, thereby extending the beneficial effects of ALM as reported for cardiac surgery, hemorrhagic shock and cardiac arrest.

Abstract 344: Periodic Acceleration (pGz) Improves Left Ventricular Function and Remodeling in Rats After Myocardial Infarction

BACKGROUND: Heart Failure (HF) post MI remains a important cause of mortality and morbidity Whole body periodic acceleration (pGz) is the repetitive motion of the supine body in a sinusoidal head to foot direction achieved with a motorized platform. pGz induces pulsatile shear stress on the vascular endothelium. Pulsatile shear stress activates endothelial nitric oxide synthase (eNOS) to produce increased release of nitric oxide (eNO). pGz pre-and postconditioning can induce cardioprotective affects in an in-vivo rat model of myocardial infarction (MI) reducing mortality, arrhythmias and infarct size. The effects of pGz on myocardial function and remodeling after MI are unknown. Left ventricular (LV) pressure-volume (PV) relationships are an invasive but comprehensive method to assess myocardial function. OBJECTIVE: We investigated the effects of pGz on LV function and remodeling induced by chronic MI in rats. Methods: After MI, rats (SD-300gms) were randomized to receive pGz (MI-pGz) (n=5) Control (MI-C) (n=5) for 4 weeks and a separate sham surgery group (n=5). In vivo LV pressure-volume relationships were analyzed using a conductance catheter (Millar Instruments, Texas). LV fibrosis was analyzed using trichrome staining and digital microscopy. RESULTS: pGz after MI reduced left ventricular fibrosis by 40% [MI-C 36( 4 )% vs MI-pGz 21(2)% (p &lt; 0.01) as a % of the LV]. There were no differences in heart rate between groups. pGz significantly improved ejection fraction (EF), left ventricular end systolic pressure (LVESP), dP/dtmax, and both end systolic (ESPVR) and diastolic (EDPVR) pressure volume relations (Table). Data: X(SD) * p&lt; 0.01 (Sham vs. MI-C) and † p&lt; 0.01 (MI-C vs MI-pGz) Conclusions: In a rat model HF induced by chronic MI, pGz markedly improved LV function. These findings have implications for cardiac rehabilitation post MI.

Impact of Acute Changes of Left Ventricular Contractility on the Transvalvular Impedance: Validation Study by Pressure-Volume Loop Analysis in Healthy Pigs

BackgroundThe real-time and continuous assessment of left ventricular (LV) myocardial contractility through an implanted device is a clinically relevant goal. Transvalvular impedance (TVI) is an impedentiometric signal detected in the right cardiac chambers that changes during stroke volume fluctuations in patients. However, the relationship between TVI signals and LV contractility has not been proven. We investigated whether TVI signals predict changes of LV inotropic state during clinically relevant loading and inotropic conditions in swine normal heart.MethodsThe assessment of RVTVI signals was performed in anesthetized adult healthy anesthetized pigs (n = 6) instrumented for measurement of aortic and LV pressure, dP/dtmax and LV volumes. Myocardial contractility was assessed with the slope (Ees) of the LV end systolic pressure-volume relationship. Effective arterial elastance (Ea) and stroke work (SW) were determined from the LV pressure-volume loops. Pigs were studied at rest (baseline), after transient mechanical preload reduction and afterload increase, after 10-min of low dose dobutamine infusion (LDDS, 10 ug/kg/min, i.v), and esmolol administration (ESMO, bolus of 500 µg and continuous infusion of 100 µg·kg−1·min−1).ResultsWe detected a significant relationship between ESTVI and dP/dtmax during LDDS and ESMO administration. In addition, the fluctuations of ESTVI were significantly related to changes of the Ees during afterload increase, LDDS and ESMO infusion.ConclusionsESTVI signal detected in right cardiac chamber is significantly affected by acute changes in cardiac mechanical activity and is able to predict acute changes of LV inotropic state in normal heart.

Minimally invasive intraoperative estimation of left-ventricular end-systolic elastance with phenylephrine as loading intervention

Left-ventricular end-systolic elastance (Ees) is an index of cardiac contractility, but the invasive nature of its assessment has limited perioperative application. We explored the feasibility of a minimally invasive method of Ees estimation for perioperative assessment of cardiac function and evaluated the suitability of phenylephrine as a loading intervention. In 17 surgical patients, Ees was determined as the slope of the end-systolic pressure-volume relation, which was obtained from non-invasive or invasive continuous arterial pressure measurements and left-ventricular volume determinations using transoesophageal echocardiography (TOE). Ees was determined using as loading interventions preload reduction by inferior vena cava compression (IVCC) and afterload increase by phenylephrine administration. Median invasive Ees determined with phenylephrine estimated 1.05 (0.59-1.21) mm Hg ml(-1) and with IVCC 0.58 (0.31-1.13) mm Hg ml(-1). Bland-Altman analysis to evaluate the level of agreement between minimally invasive and invasive Ees estimation revealed a bias of -0.03 (0.12) mm Hg ml(-1) with limits of agreement from -0.27 to 0.21 mm Hg ml(-1) and the percentage error was 33%. Agreement between Ees obtained with phenylephrine and IVCC revealed a bias of 0.15 (0.69) mm Hg ml(-1) with limits of agreement from -1.21 to 1.51 mm Hg ml(-1) and a percentage error of 149%. It is feasible to determine Ees combining continuous non-invasive arterial pressure measurements and left-ventricular volume determinations with TOE. However, administration of phenylephrine cannot substitute IVCC as a loading intervention, indicating that estimation of Ees in the intraoperative setting remains a challenge.

Gene deletion of protein tyrosine phosphatase 1B limits cardiovascular dysfunction and mortality during endotoxinic shock

Sepsis-associated cardiovascular dysfunction is one of the main causes of mortality in critically ill patients. PTP1B is negative regulator of insulin signaling and endothelial Nitric Oxide (NO) production, two mechanisms likely involved in the pathogenesis of sepsis. We recently showed that gene deletion or pharmacological inhibition of PTP1B improves endothelial dysfunction and reduces the severity of heart failure. The aim of the present study was to assess the effect of PTP1B gene deletion on lipopolysaccharide (LPS)-induced cardiovascular dysfunction and mortality in mice. PTP1B-/- or wild-type (WT) mice received LPS (15mg/kg) or vehicle followed by subcutaneous saline resuscitation (30ml/kg). LPS significantly enhanced cardiac and arterial PTP1B mRNA expression. Compared with WT, PTP1B-/- mice displayed markedly reduced mortality (Survival 4 days after LPS: WT: 0%; PTP1B-/- 70%, p<0.01), associated with a higher locomotor activity. Evaluation of vascular function 8h after LPS in isolated mesenteric resistance arteries (arteriograph system) showed that PTP1B-/- LPS mice had improved contractile response to phenylephrine, and restored flow mediated, NO dependent-dilatation (% dilatation to 200μl/min: WT 6,3±3; PTP1B-/- 16,5±2, p<0.05) associated with significant increases in phosphorylation of Akt and eNOS, and reduced mRNA expression of VCAM-1, ICAM-1, COX-2, IL-1β, iNOS and Gp91phox (PCR). Evaluation of left ventricular (LV) function by echocardiography, and pressure-volume curves 8h after LPS revealed reduced cardiac dysfunction in PTP1B-/- mice as shown by an increased LV fractional shortening (WT 17,3±1; PTP1B-/- 24±1, p<0.05) and LV end systolic pressure-volume relation (WT 16±2; PTP1B-/- 20±2, p<0.05) together with reduced LV end diastolic pressure-volume relation (WT 4,7±1,7; PTP1B-/- 2.4±0.9 mmHg/RVU, p<0.05). Improved cardiac contractility was also observed ex-vivo in hearts isolated and perfused 8h after LPS (LV Developed Pressure: WT 25±5; PTP1B-/- 50±5 mmHg, p<0.05). Improved cardiac function was associated with significant decreases in myocardial markers of inflammation and oxidative stress (VCAM-1, ICAM-1, CD45, IL-1β, TNF-α and Gp91phox), reduced P38 and ERK1/2 phosphorylation and limited decrease of phospholamban phosphorylation (WT -42%; PTP1B-/- -22.8, p<0.05). Thus, we demonstrate for the first time that PTP1B gene deletion protects against lipopolysaccharide-induced cardiovascular dysfunction and mortality. These results suggest that PTP1B is an attractive target for the treatment of sepsis.

Abstract 062: Mitoubiquinone Decreases Reactive Oxygen Species Production and Improves Cardiac Efficiency in Chronic Volume Overload

Background: The hemodynamic stress of left ventricular (LV) volume overload (VO) produces LV dysfunction accompanied by mitochondrial and cytoskeletal disruption in cardiomyocytes. Because mitochondria are both a source and target of reactive oxygen species (ROS), we hypothesize myocyte damage and LV dysfunction are mediated by mitochondrially produced ROS and can be attenuated by the mitochondrially targeted antioxidant, mitoubiquinone (MitoQ). Methods: Aortocaval fistula (ACF) was induced for 8 weeks in adult rats ± MitoQ. Echocardiography and high-fidelity LV pressure catheter recordings were used to study the LV end-systolic pressure-volume relationship and cardiac efficiency. Isolated cardiomyocytes were loaded with Carboxy-H2DFFDA (CM-DCF) and tetramethylrhodamine (TMRM) to measure mitochondrial ROS production and membrane potential. Results: Isolated cardiomyocyte studies demonstrated increased ROS production and decreased mitochondrial membrane potential in VO animals, both of which were attenuated with MitoQ. Treatment with MitoQ demonstrated a strong trend toward improvement in LV contractility, as cardiac efficiency improved significantly in MitoQ-treated VO animals. Untreated VO animals exhibited mitochondrial swelling and myofibrillar disruption that was prevented by MitoQ. Conclusion: These studies suggest an early interplay between mitochondrial-derived ROS production and cardiac ultrastructure and function.

Combination of Real Time Three‐Dimensional Echocardiography with Diagnostic Catheterization to Derive Left Ventricular Pressure‐Volume Relations

The aim of this study was to investigate the left ventricular (LV) myocardial contractility index-Emax using transesophageal real time three-dimensional echocardiography (RT3DE) combined with catheterization. Transesophageal RT3DE (single beat, X7-2 × matrix, iE33, Philips) was used to obtain real time LV volumes in pigs. Volumes were integrated with LV pressures from conductance catheterization (CC) to create RT3DE pressure-volume relations. At the same time, CC was used for measuring conventional pressure-volume relations that served as reference. The slope Emax was determined from RT3DE and CC end-systolic pressure-volume relations. All measurements were made at rest and during dobutamine infusion. In six pigs, the mean ± SD (mmHg/mL) values were Emax-CC 1.86 ± 1.1 and Emax-RT3DE 1.78 ± 1.2 (P = 0.502) at baseline. On dobutamine, mean Emax-CC was 3.43 ± 1.5 and Emax-RT3DE 3.60 ± 1.23 (P = 0.171). Bland-Altman analysis showed good agreements between the RT3DE- and CC-derived Emax for measurements performed at baseline and on dobutamine. Emax can be determined from RT3DE integrated with catheterization-derived pressures. RT3DE is a promising method for enhancing clinical applicability of pressure-volume relations for assessment of myocardial contractility.

Exposure to diesel exhaust particulates induces cardiac dysfunction and remodeling

Chronic exposure to diesel exhaust particulates (DEP) increases the risk of cardiovascular disease in urban residents, predisposing them to the development of several cardiovascular stresses, including myocardial infarctions, arrhythmias, thrombosis, and heart failure. DEP contain a high level of polycyclic aromatic hydrocarbons, which activate the aryl hydrocarbon receptor (AHR). We hypothesize that exposure to DEP elicits ventricular remodeling through the activation of the AHR pathway, leading to ventricular dilation and dysfunction. Male Sprague-Dawley rats were exposed by nose-only nebulization to DEP (SRM 2975, 0.2 mg/ml) or vehicle for 20 min/day × 5 wk. DEP exposure resulted in eccentric left ventricular dilation (8% increased left ventricular internal diameter at diastole and 23% decreased left ventricular posterior wall thickness at diastole vs. vehicle), as shown by echocardiograph assessment. Histological analysis using Picrosirius red staining revealed that DEP reduced cardiac interstitial collagen (23% decrease vs. vehicle). Further assessment of cardiac function using a pressure-volume catheter indicated impaired diastolic function (85% increased end-diastolic pressure and 19% decreased Tau vs. vehicle) and contractility (57 and 48% decreased end-systolic pressure-volume relationship and maximum change in pressure over time vs. end-diastolic volume compared with vehicle, respectively) in the DEP-exposed animals. Exposure to DEP significantly increased cardiac expression of AHR (19% increase vs. vehicle). In addition, DEP significantly decreased the cardiac expression of hypoxia inducible factor-1α, the competitive pathway to the AHR, and vascular endothelial growth factor, a downstream mediator of hypoxia inducible factor-1α (26 and 47% decrease vs. vehicle, respectively). These findings indicate that exposure to DEP induced left ventricular dilation by loss of collagen through an AHR-dependent mechanism.

The effects of adenocaine (adenosine and lidocaine) on early post-resuscitation cardiac and neurological dysfunction in a porcine model of cardiac arrest

AimReturn of spontaneous circulation (ROSC) elicits ischaemia/reperfusion injury and myocardial dysfunction. The combination of adenosine and lidocaine (AL, adenocaine) has been shown to (1) inhibit neutrophil inflammatory activation and (2) improve left ventricular function after ischaemia. We hypothesized that resuscitation with adenocaine during early moments of cardiopulmonary resuscitation (CPR) attenuates leucocyte oxidant generation and myocardial dysfunction. MethodsPigs were randomized to: (1) sham (n=7), (2) cardiac arrest (CA; n=16), or 3) cardiac arrest+adenocaine (CA+AL; n=12). After 7min of electrically induced ventricular fibrillation, start of CPR was followed by infusion of saline (CA) or adenocaine (CA+AL) for 6min. Haemodynamics, cardiodynamics (pressure–volume loops) and leucocyte superoxide anion generation were assessed. Neurological function was evaluated after 24h by histology and neurological deficit score (0=normal; 500=brain dead). ResultsRate of ROSC was comparable between groups: CA group 11/16 and CA+AL group 7/12 p=0.57). Cardiac index transiently increased after ROSC in both groups. Left ventricular dysfunction demonstrated by a rightward shift of the intercept of end-systolic pressure–volume relations in CA was avoided in the CA+AL group. Leucocyte superoxide anion generation 2h after ROSC was significantly attenuated in the CA+AL group compared to the CA group. Neurological deficit scores [CA: median: 17.5(IQR:0–75) and CA+AL: 35(IQR:15–150)] and histopathological damage were comparable in both groups (p=0.37). ConclusionInfusion of adenocaine during early resuscitation from CA significantly improved early post-resuscitation cardiac function and attenuated leucocyte superoxide anion generation, without a change in post-ROSC neurological function. (IACUC protocol number 023-2009).

Ventricular-Arterial Coupling, Remodeling, and Prognosis in Chronic Heart Failure

The objective of this study was to compare the physiological determinants of ejection fraction (EF)-ventricular size, contractile function, and ventricular-arterial (VA) interaction-and their associations with clinical outcomes in chronic heart failure (HF). EF is a potent predictor of HF outcomes, but represents a complex summary measure that integrates several components including left ventricular size, contractile function, and VA coupling. The relative importance of each of these parameters in determining prognosis is unknown. In 466 participants with chronic systolic HF, we derived quantitative echocardiographic measures of EF: cardiac size (end-diastolic volume [EDV]); contractile function (the end-systolic pressure volume relationship slope [Eessb] and intercept [V0]); and VA coupling (arterial elastance [Ea]/Eessb). We determined the association between these parameters and the following adverse outcomes: 1) the combined endpoint of death, cardiac transplantation, or ventricular assist device (VAD) placement; and 2) cardiac hospitalization. Over a median follow-up of 3.4 years, there were 76 deaths, 52 transplantations, 14 VAD placements, and 684 cardiac hospitalizations. EF was independently associated with death, transplantation, and VAD placement (adjusted hazard ratio [HR]: 3.0; 95% confidence interval [CI]: 1.8 to 5.0 comparing third and first tertiles), as were EDV (HR: 2.6; 95% CI: 1.5 to 4.2); V0 (HR: 3.6; 95% CI: 2.1 to 6.1); and Ea/Eessb (HR: 2.1; 95% CI: 1.3 to 3.3). EDV, V0, and Ea/Eessb were also associated with risk of cardiac hospitalization. Eessb was not significantly associated with any adverse outcomes in adjusted analyses. Left ventricular size, V0, and VA coupling are associated with prognosis in systolic HF, but end-systolic elastance (Eessb) is not. Assessment of VA coupling via Ea/Eessb is an additional noninvasively derived metric that can be used to gauge prognosis in human HF.

Clinical applications of the areas under ESPVR.

It has long been observed that the use of the ejection fraction (EF) to assess the condition of the heart offers serious limitations (1). It is estimated that half of the patients presenting with symptoms of cardiomyopathies and heart failure (HF) have preserved EF defined as EF >50%. It was shown in (2) that the areas under the end-systolic pressure-volume relation (ESPVR) in the heart ventricles are sensitive indexes to reflect the state of the myocardium, a review of some clinical applications of indexes derived from the ESPVR can be found in (3). An objective of the study by Doyle et al. (4) is precisely to show that areas under the ESPVR, or bivariate combination of areas with another index, can be used as a prognostically useful tool for studying cases of women with suspected myocardial ischemia.

The incremental diagnostic value of coronary flow reserve and left ventricular elastance during high-dose dipyridamole stress echocardiography in patients with normal wall motion at rest

A “normal” dipyridamole stress echocardiogram by wall motion criteria identifies a subset of patients at low risk of experiencing hard events in the follow-up [1]. The sensitivity for identifying significant coronary artery disease (CAD) is suboptimal, and can be increased by adding coronary flow reserve (CFR) assessment by Doppler echocardiography [2] or myocardial contrast echo [3]. Another possible variable of incremental value over wall motion is the assessment of contractile reserve (CR) via the end-systolic pressure–volume relationship (PVR), which has been used with pacing [4], exercise [5] or dobutamine [6] — not yet with dipyridamole. We prospectively enrolled 111 patients (60men; age 68, SD 10 years) with normal baseline function who underwent dipyridamole (0.84 mg/ kg over 6 min) stress echocardiography with CFR evaluation of LAD by Doppler [7] and CR calculated as peak stress ESP (end-systolic pressure)/ ESV (end-systolic volume)− rest ESP/ESV [6]. All patients underwent quantitative coronary angiography performed independently of test results. Informed consent was obtained from each patient and the study protocol conforms to the ethical guidelines of the 1975 Declaration of Helsinki as reflected in a priori approval by the institution's human research committee. The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology. All continuous data are reported as mean values ± standard deviation (SD). Known normal vs abnormal cutoff values of variation with stress (i.e., positive ESP/ESV index changes; CFR N 2) were tested as predictor of obstructive coronary disease in patients without inducible ischemia. Receiver operator characteristic curve analysis was used to determine potentially useful threshold values of ΔESP/ ESV derived predictors for identification of coronary artery disease in negative stress echo. Contingency tables were constructed to assess the sensitivity and specificity of the method. SPSS 13.0 (SPSS, Inc., Chicago, IL, USA) was used for the analysis. Stress echocardiogramwas positive for ischemia in 23 patients (21%). One or more significant coronary stenoses (≥50% luminal narrowing) were present in 51 patients (46%). Regional wall motion abnormalities (WMA) showed a sensitivity of 45% (95% CI 31% to 60%), which rose to 88% (95% CI 76% to 96%) with the combination of CFR positivity (LAD flow reserve≤ 2.0) and CR (b0.36 mmHg/mL/m) criteria (Fig. 1). Contractile reserve was negative (−3.6 SD 3 mmHg/mL/m) in patients with positive stress. In the subset with negative stress, contractile reserve was +3.5 SD 3 mmHg/mL/m in the 42 negative patients without, vs−1.4 SD 3.6 mmHg/mL/m in the 28 negative patients with ≥50% coronary stenosis diagnosis. With a receiver operating characteristic analysis, a ΔESP/ESV index b0.36 mmHg/mL/m from baseline to peak stress was the best value to identify angiographic evidence of significant (≥50%) coronary stenosis patient population (area under curve 0.9, 95% CI 0.84 to 0.96; Younden index= 1.73). This criterion showed good sensitivity (86%, 95% CI 74% to 94%) and specificity (87%, 95% CI 75% to 94%) for ≥50% coronary stenosis diagnosis. Specificity was 100% (95% CI 94% to 100%) with WMA and fell to 83% (95% CI 71% to 92%) with the combination of CFR and CR criteria. At individual patient analysis, all patients with wall motion abnormalities showed CAD, with high prevalence of CFR and CR impairment. In patients without wall motion abnormalities, CAD was more frequent in the presence of a depressed CR and/or CFR. The likelihood of underlying CAD was higher when both were altered (Fig. 2).

Inotropic and lusitropic effects of calcitonin gene-related peptide in the heart

Previous studies have demonstrated positive-inotropic effects of calcitonin gene-related peptide (CGRP), but the mechanisms remain unclear. Therefore, two experiments were performed to determine the physiological correlates of the positive-inotropic effects of CGRP. Treatments designed to antagonize the effects of physiologically active CGRP₁₋₃₇ included posttreatment with CGRP₈₋₃₇ and pretreatment with LY-294002 (LY, an inhibitor of phosphatidylinositol 3-kinase), 17β-estradiol (E), and progesterone (P) were also used to modulate the effects of CGRP₁₋₃₇. Experiment 1 was in vitro studies on sarcomeres and cells of isolated adult rat cardiac myocytes. CGRP₁₋₃₇, alone and in combination with E and P, decreased sarcomere shortening velocities and increased shortening percentages, effects that were antagonized by CGRP₈₋₃₇, but not by LY. CGRP₁₋₃₇ increased resting intracellular calcium ion concentrations and Ca(2+) influxes, effects that were also antagonized by both CGRP₈₋₃₇ and LY. Experiment 2 was in vivo studies on left ventricular pressure-volume (PV) loops. CGRP₁₋₃₇ increased end-systolic pressure, ejection fraction, and velocities of contraction and relaxation while decreasing stroke volume, cardiac output, stroke work, PV area, and compliance. After partial occlusion of the vena cava, CGRP₁₋₃₇ increased the slope of the end-systolic PV relationship. CGRP₈₋₃₇ and LY attenuated most of the CGRP-induced changes. These findings suggest that CGRP-induced positive-inotropic effects may be increased by treatments with estradiol and progesterone and inhibited by LY. The physiological correlates of CGRP-induced positive inotropy observed in rat sarcomeres, cells, and intact hearts are likely to reveal novel mechanisms of heart failure in humans.

Adiponectin Restores Diabetic Heart Sensitivity to Ischemic Posctconditioning: Role of STAT3 Activation

Diabetic hearts are prone to ischemia reperfusion (IR) injury and not sensitivity to ischemic postconditioning (IPostC) cardioprotection, and the mechanism is unclear. Adiponectin (APN) confers cardioprotection in non‐diabetes by activating STAT3 (pSTAT3), a key protein in mediating IPostC protection. In diabetic heart, APN is decreased, together with reduced pSTAT3. We hypothesized APN may activate STAT3 in diabetic heart and restore its sensitivity to IPostC. Control (C) and Streptozotocin induced diabetic (D) rats were subjected to 30 min coronary artery ligation followed by 2 hours of reperfusion, without or with IPostC achieved by 3 episodes of 10s reperfusion and 10s re‐occlusion at the onset of reperfusion. Rat was injected with APN (1×109pfu) 7 days before inducing IR. Cardiac functions were assessed by pressure volume (PV) conductance system. Post‐ischemic myocardial infarct size was higher in D relative to C, together with significant reduction of cardiac pSTAT3 and reduction of end systolic PV relation,a reliable measure of ventricular systolic function, in D rats. All these changes in D were reverted by IPostC in the presence but not in the absence of APN (P&lt;0.05 vs. D+APN+IPostC vs. D or D+APN), and abolished by AG490 (which inhibits STAT3 activation). It is concluded that APN restores diabetic heart sensitivity to IPostC by activating STAT3.Supported by RGC/GRF (784011, 768211), NSFC (81270899)

Right Ventricular Support for Pulmonary Arterial Hypertension: An Acute Feasibility Study in Sheep

<h3>Purpose</h3> Mechanical support of the failing right ventricle (RV) can be a life-saving option in patients with pulmonary hypertension. Since the RV is very afterload dependent, this support can have unpredictable effects and is more likely to lead to RV dilatation. Therefore we wanted to assess the acute hemodynamic effects of RV support in different conditions of RV failure (RVF). <h3>Methods and Materials</h3> A Circulite^TM Synergy^TM micro-pump was inserted in adult sheep via a left thoracotomy. Blood was withdrawn from the right atrium to the pulmonary artery. Hemodynamic parameters were registered and pressure-volume loops were recorded at baseline and at 22000 RPM. To mimic different types of RVF, this procedure was performed in each animal 1) in control conditions (STANDARD), 2) after induction of pressure overload by banding the PA distal to the pump outflow (BANDING) and 3) after ligating the right coronary artery in these pressure overloaded sheep (BANDING + LIGATION). <h3>Results</h3> Changes in hemodynamics in the 3 different conditions are depicted in figure 1. Comparable to the other two conditions, in the ischemic and pressure overloaded RV, contractility (reflected by dP/dt_max, end systolic pressure volume relationship and preload recruitable stroke work) had a tendency to increase after starting the pump. <h3>Conclusions</h3> RV support in different types of RVF improves both systemic and pulmonary hemodynamics. Decreasing RV output and power, increasing total cardiac output and power and a stable central venous pressure reflect the successful unloading of the RV and good tolerance of this support. The pressure overloaded and ischemic failing RV improves since contractility remains preserved and since there is no increase in energetic need.

Pharmacologically Induced Hypothermia with WIN55,212-2 and Extracorporeal Life Support after Cardiac Arrest as a Preservation Strategy for Heart Transplantation

Purpose To investigate the hypothesis that induction of therapeutic hypothermia with cannabinoid receptor agonist WIN55,212-2 and extracorporeal life support (ECLS) after cardiac arrest is an effective heart preservation strategy. Methods and Materials Ventricular fibrillation (VF) was induced in male Wistar rats. After 10 min of untreated VF, venoarterial ECLS was instituted and rats were randomized to three groups of ten: normothermia, therapeutic hypothermia (32°C) and pharmacological hypothermia by WIN55,212 intravenous infusion (1 mg/kg/h). After 120 minutes heterotopic heart transplantation was performed in syngeneic donors using a working heart model. After 24 hours left ventricular (LV) systolic and diastolic functions were evaluated at different preloads using a conductance catheter. Results WIN55,212-2 led to a significantly better recovery of the slope of the LV end-systolic pressure volume relationship (Ees) and Preload recruitable stroke work (PRSW) than hypothermia and normothermia: as percent of baseline 87+12 vs 54+9 vs 39+11 and 88+11 vs 59+10 vs 33+8 respectively (p.01). LV stiffness expressed by end-diastolic pressure volume relationship (EDPVR) was significantly lower after WIN55,212-2 administration (p Conclusions Pharmacologically induced hypohermia with WIN55,212-2 during ECLS improve myocardial protection through activation of the pro-survival kinase Akt and ERK and could be an organ preservation strategy after cardiac arrest.

Catharanthine Dilates Small Mesenteric Arteries and Decreases Heart Rate and Cardiac Contractility by Inhibition of Voltage-Operated Calcium Channels on Vascular Smooth Muscle Cells and Cardiomyocytes

Catharanthine is a constituent of anticancer vinca alkaloids. Its cardiovascular effects have not been investigated. This study compares the in vivo hemodynamic as well as in vitro effects of catharanthine on isolated blood vessels, vascular smooth muscle cells (VSMCs), and cardiomyocytes. Intravenous administration of catharanthine (0.5-20 mg/kg) to anesthetized rats induced rapid, dose-dependent decreases in blood pressure (BP), heart rate (HR), left ventricular blood pressure, cardiac contractility (dP/dt(max)), and the slope of the end-systolic pressure-volume relationship (ESPVR) curve. Catharanthine evoked concentration-dependent decreases (I(max) >98%) in endothelium-independent tonic responses of aortic rings to phenylephrine (PE) and KCl (IC(50) = 28 µM for PE and IC(50) = 34 µM for KCl) and of third-order branches of the small mesenteric artery (MA) (IC(50) = 3 µM for PE and IC(50) = 6 µM for KCl). Catharanthine also increased the inner vessel wall diameter (IC(50) = 10 µM) and reduced intracellular free Ca(2+) levels (IC(50) = 16 µM) in PE-constricted MAs. Patch-clamp studies demonstrated that catharanthine inhibited voltage-operated L-type Ca(2+) channel (VOCC) currents in cardiomyocytes and VSMCs (IC(50) = 220 µM and IC(50) = 8 µM, respectively) of MA. Catharanthine lowers BP, HR, left ventricular systolic blood pressure, and dP/dt(max) and ESPVR likely via inhibition of VOCCs in both VSMCs and cardiomyocytes. Since smaller vessels such as the third-order branches of MAs are more sensitive to VOCC blockade than conduit vessels (aorta), the primary site of action of catharanthine for lowering mean arterial pressure appears to be the resistance vasculature, whereas blockade of cardiac VOCCs may contribute to the reduction in HR and cardiac contractility seen with this agent.