Left Ventricular End-systolic Pressure Research Articles

2363

OBJECTIVES/SPECIFIC AIMS: Our goal was to compare the ventriculo-arterial coupling and left ventricular mechanical work of patients with systolic and diastolic heart failure (SHF and DHF). METHODS/STUDY POPULATION: Patients with New York Heart Association Functional Class II-III HF symptoms were included. SHF was defined as left ventricular (LV) ejection fraction<50% and DHF as >50%. Analysis of the fingertip arterial blood pressure tracing captured with a finger plethysmography cuff according to device-specific algorithms provided brachial artery blood pressure and stroke volume. LV end-systolic volume was measured separately via transthoracic echocardiography. Arterial elastance (Ea), a measure of pulsatile and nonpulsatile LV afterload, was calculated as LV end-systolic pressure (ESP)/end-diastolic volume. End-systolic elastance (Ees), a measure of load-independent LV contractility, was calculated as LV ESP/end-systolic volume. Ventriculo-arterial coupling (VAC) ratio was defined as Ea/Ees. Stroke work (SWI) was calculated as stroke volume index×LV end-systolic pressure×0.0136 and potential energy index (PEI) as 1/2×(LV end-systolic volume×LV end-systolic pressure×0.0136). Total work index (TWI) was the sum of SWI+PEI. RESULTS/ANTICIPATED RESULTS: Patients with SHF (n=52) and DHF (n=29) were evaluated. Median (IQR) age was 57 (51–64) years. There were 48 (58%) and 59 (71%) patients were male and African American, respectively. Cardiac index was 2.8 (2.2–3.2) L/minute and 3.0 (2.8–3.3) L/minute in SHF and DHF, respectively (p=0.12). Self-reported activity levels (Duke Activity Status Index, p=0.48) and heart failure symptoms (Minnesota Living with Heart Failure Questionnaire, p=0.55) were not different between SHF and DHF. Ea was significantly lower in DHF compared with SHF patients [1.3 (1.2–1.6) vs. 1.7 (1.4–2.0) mmHg; p<0.001] whereas Ees was higher in DHF vs. SHF [2.8 (2.1–3.1) vs. 0.9 (0.7-1.3) mmHg; p<0.001). VAC was 1.8 (1.3–2.8) in SHF Versus 0.5 (0.4–0.7) in DHF (p<0.001). Compared with SHF, DHF patients had higher SWI [71 (57–83) vs. 48 (39–68) gm×m; p<0.001) and lower PEI [19 (12–26) vs. 44 (36–57) gm×m; p<0.001]. TWI did not differ between SHF and DHF (p=0.14). Work efficiency was higher in DHF than SHF [0.80 (0.74–0.84) vs. 0.53 (0.46–0.64); p<0.001]. DISCUSSION/SIGNIFICANCE OF IMPACT: The results underscore the differences in pathophysiology between SHF and DHF patients with similar symptom burden and exercise capacity. These results highlight the difference in myocardial energy utilization between SHF and DHF.

Efficacy of irbesartan combined with metoprolol in the treatment of patients with chronic congestive heart failure

Objective To observe the efficacy of irbesartan combined with metoprolol in the treatment of chronic congestive heart failure. Methods From April 2015 to April 2016, 60 patients with chronic congestive heart failure in Central Hospital of Zhuji were randomly divided into the observation group and the control group, 30 cases in each group.The two groups were given conventional treatment, the control group was treated with metoprolol, and the observation group was treated with irbesartan combined with metoprolol.The changes of left ventricular ejection fraction (LVEF), left ventricular end systolic diameter (LVESD), left ventricular end diastolic diameter (LVEDD), heart rate, systolic pressure and diastolic pressure before and after treatment in two groups were observed.And the clinical efficacy of the two groups was compared. Results After treatment, compared with the control group, the heart function index of the observation group changed obviously, LVEF increased (t=5.88, P<0.01), LVESD and LVEDD significantly decreased (t=7.19, 4.11, all P<0.01). The heart rate of the observation group was significantly slowed down (t=2.72, P<0.01), systolic blood pressure and diastolic blood pressure were also significantly reduced (t=2.93, 3.98, all P<0.01). The total effective rate of the observation group was 93.3%, which of the control group was 73.3%, the difference was statistically significant (χ2=4.32, P<0.05). Conclusion Irbesartan combined with metoprolol in the treatment of chronic congestive heart failure has significant clinical efficacy, is conducive to ease the clinical symptoms and improve heart function effectively. Key words: Heart failure, systolic; Irbesartan; Metoprolol

Doxorubicin upregulates CXCR4 via miR-200c/ZEB1-dependent mechanism in human cardiac mesenchymal progenitor cells

Doxorubicin (DOXO) treatment is limited by its cardiotoxicity, since it causes cardiac-progenitor-cell depletion. Although the cardioprotective role of the stromal cell-derived factor-1/C-X-C chemokine receptor type 4 (SDF1/CXCR4) axis is well established, its involvement during DOXO-induced cardiotoxicity has never been investigated. We showed that in a mouse model of DOXO-induced cardiomyopathy, CXCR4+ cells were increased in response to DOXO, mainly in human cardiac mesenchymal progenitor cells (CmPC), a subpopulation with regenerative potential. Our in vitro results showed a CXCR4 induction after 24 h of DOXO exposure in CmPC. SDF1 administration protected from DOXO-induced cell death and promoted CmPC migration. CXCR4 promoter analysis revealed zinc finger E-box binding homeobox 1 (ZEB1) binding sites. Upon DOXO treatment, ZEB1 binding decreased and RNA-polymerase-II increased, suggesting a DOXO-mediated transcriptional increase in CXCR4. Indeed, DOXO induced the upregulation of miR-200c, that directly targets ZEB1. SDF1 administration in DOXO-treated mice partially reverted the adverse remodeling, decreasing left ventricular (LV) end diastolic volume, LV ejection fraction and LV anterior wall thickness in diastole, recovering LV end systolic pressure and reducing±dP/dt. Moreover, in vivo administration of SDF1 partially reverted DOXO-induced miR-200c and p53 protein upregulation in mouse hearts. In addition, downmodulation of ZEB1 mRNA and protein by DOXO was significantly increased by SDF1. In keeping, p21 mRNA, that is induced by p53 and inhibited by ZEB1, is induced by DOXO treatment and is decreased by SDF1 administration. This study showed new players of the DOXO-induced cardiotoxicity, that can be exploited to ameliorate DOXO-associated cardiomyopathy.

Novel Rotational Speed Modulation System Used With Venoarterial Extracorporeal Membrane Oxygenation

Femoral venoarterial extracorporeal membrane oxygenation (VA-ECMO) is widely used to maintain blood flow in patients with cardiogenic shock. However, retrograde blood flow increases left ventricular (LV) afterload during femoral VA-ECMO. Additional support by means of an intraaortic balloon pump (IABP) alleviates LV afterload but is associated with significant adverse events. We previously developed a system for rotational speed modulation in synchrony with the native cardiac cycle, for use with implantable continuous-flow LV assist devices. Here, we aimed to evaluate whether our novel rotation speed modulation system can improve coronary artery flow and reduce LV during femoral VA-ECMO. VA-ECMO was installed by means of right atrial drainage and distal abdominal aortic perfusion in six adult goats. Cardiogenic shock was induced with β-adrenergic antagonist infusion. An IABP was placed in the descending aorta. LV stroke work, LV end-systolic pressure, and coronary arterial flow were evaluated. Data were collected under five conditions (modes): baseline, circuit-clamp (cardiogenic shock), continuous mode (constant rotational speed), counterpulse mode (increasing rotational speed during diastole), and continuous mode with IABP support. LV stroke work and LV end-systolic pressure tended to be lower in the counterpulse mode, indicating decreased LV work load and afterload in this mode. Furthermore, coronary arterial flow tended to be higher in the counterpulse mode. Our system enabled an increase in coronary arterial flow and a decrease in LV work load and afterload during VA-ECMO. The system offers the effects of VA-ECMO and an IABP in a single device.

Acute Hemodynamic Effects of Intra-aortic Balloon Counterpulsation Pumps in Advanced Heart Failure

BackgroundThe utility of intra-aortic balloon counterpulsation pumps (IABPs) in low cardiac output states is unknown and no studies have explored the impact of IABP therapy on ventricular workload in patients with advanced heart failure (HF). For these reasons, we explored the acute hemodynamic effects of IABP therapy in patients with advanced HF. MethodsWe prospectively studied 10 consecutive patients with stage D HF referred for IABP placement before left ventricular assist device (LVAD) surgery and compared with 5 control patients with preserved left ventricular (LV) ejection fraction (EF) who did not receive IABP therapy. Hemodynamics were recorded using LV conductance and pulmonary artery catheters. Cardiac index (CI)-responder and CI-nonresponder status was assigned a priori as being “equal to or above” or below the median of the IABP effect on CI, respectively, within 24 hours after IABP activation. ResultsCompared with controls, patients with advanced HF had lower LVEF, lower LV end-systolic pressure, lower LV stroke work, and higher LV end-diastolic pressures and volumes before IABP activation. IABP activation reduced LV stroke work primarily by reducing end-systolic pressure. IABP therapy increased CI by a median of 20% as well as increased diastolic pressure time index and the myocardial oxygen supply:demand ratio. Compared with CI-nonresponders, CI-responders had higher systemic vascular resistance, lower right heart filling pressures, and a trend toward lower left heart filling pressures with improved indices of right heart function. Compared with CI-nonresponders, the diastolic pressure time index was increased among CI-responders. ConclusionsIABP therapy may be effective at reducing LV stroke work, increasing CI, and favorably altering the myocardial oxygen supply:demand ratio in patients with advanced HF, especially among patients with low right heart filling pressures and high systemic vascular resistance.

Therapeutic effect of combined use of FGF1-loaded nano-liposomes and ultrasound-targeted microbubble destruction technique on treating rats with experimental diabetic cardiomyopathy

Objective: The therapeutic effect of acid fibroblast growth factor 1(FGF1) on rats with diabetic cardiomyopathy (DCM) was evaluated by using nano-liposomes combined with ultrasound-targeted microbubble destruction technique (UTMD). Methods: The FGF1-loaded nano-liposomes were prepared by water-in-water emulsion method combined with lyophilization technique.TypeⅠdiabetes model was induced by intraperitoneal injection of streptozotocin (STZ, 70 mg/kg) in 60 male SD rats.Sixteen weeks later, diabetic rats were randomly divided into: placebo group (saline treatment), FGF1 group, FGF1-loaded nano-liposomes group, and FGF1-loaded nano-liposomes plus UTMD group (n=15 each). After two weeks of intervention followed by 2 weeks intervention stop, all rats underwent cardiac catheterization, and the left ventricular end-systolic pressure (LVESP), left ventricular end-diastolic pressure (LVEDP) and the maximal increase/decrease rate of left ventricular pressure (LV±dp/dtmax) were measured.Then, the rats were sacrificed and myocardial tissue were obtained for Masson trichrome staining, TUNEL apoptotic staining and CD31 immunohistochemistry staining to quantify myocardial collagen fraction (CVF), cardiac myocyte apoptotic index and myocardial microvascular density (MVD). Results: (1)Scanning electron microscope results revealed good morphology and FGF1 encapsulation efficiency (84.3±2.8)% with high stability and dispensability of FGF1 loaded nano-liposomes.(2)The hemodynamic evaluation showed that LVESP, LV + dp/dt(max) and LV -dp/dt(max) were all significantly higher, while LVEDP was significantly lower in the FGF1-loaded nano-liposome+ UTMD group than in DCM group, FGF1 solution group, and FGF1 nano-liposome group(all P<0.05). (3)The Masson trichrome staining demonstrated that CVF was significantly higher in all DCM groups than in control group and was significantly lower in the FGF1-loaded nano-liposome+ UTMD group than in DCM group, FGF1 solution group, and FGF1 nano-liposome group (all P<0.05). (4)The CD31 immunohistochemical staining results showed that MVD was significantly lower in all DCM groups than in control group and was significantly higher in the FGF1-loaded nano-liposome+ UTMD group than in DCM group, FGF1 solution group, and FGF1 nano-liposome group (all P<0.05). (5)The TUNEL results showed that apoptotic index was significantly higher in all DCM groups than in control group and was significantly lower in the FGF1-loaded nano-liposome + UTMD group than in DCM group, FGF1 solution group, and FGF1 nano-liposome group (all P<0.05). Conclusion: FGF1 nano-liposomes combining with UTMD technique can significantly improve cardiac functions and attenuate myocardial CVF and apoptosis and enhance myocardial MVD in DCM rats.

Mouse Genome-Wide Association Study of Preclinical Group II Pulmonary Hypertension Identifies Epidermal Growth Factor Receptor.

Pulmonary hypertension (PH) is associated with features of obesity and metabolic syndrome that translate to the induction of PH by chronic high-fat diet (HFD) in some inbred mouse strains. We conducted a genome-wide association study (GWAS) to identify candidate genes associated with susceptibility to HFD-induced PH. Mice from 36 inbred and wild-derived strains were fed with regular diet or HFD for 20 weeks beginning at 6-12 weeks of age, after which right ventricular (RV) and left ventricular (LV) end-systolic pressure (ESP) and maximum pressure (MaxP) were measured by cardiac catheterization. We tested for association of RV MaxP and RV ESP and identified genomic regions enriched with nominal associations to both of these phenotypes. We excluded genomic regions if they were also associated with LV MaxP, LV ESP, or body weight. Genes within significant regions were scored based on the shortest-path betweenness centrality, a measure of network connectivity, of their human orthologs in a gene interaction network of human PH-related genes. WSB/EiJ, NON/ShiLtJ, and AKR/J mice had the largest increases in RV MaxP after high-fat feeding. Network-based scoring of GWAS candidates identified epidermal growth factor receptor (Egfr) as having the highest shortest-path betweenness centrality of GWAS candidates. Expression studies of lung homogenate showed that EGFR expression is increased in the AKR/J strain, which developed a significant increase in RV MaxP after high-fat feeding as compared with C57BL/6J, which did not. Our combined GWAS and network-based approach adds evidence for a role for Egfr in murine PH.

Distinct Effects of Left or Right Atrial Cannulation on Left Ventricular Hemodynamics in a Swine Model of Acute Myocardial Injury.

Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) and the TandemHeart left ventricular (LV) assist device are increasingly employed as mechanical circulatory support devices during acute LV injury. We examined the effects of right atrial to femoral artery (RA-FA; VA-ECMO) bypass versus left atrial to femoral artery (LA-FA; TandemHeart) bypass using a centrifugal pump (Cardiac Assist Inc, Pittsburgh, PA) on LV hemodynamics in a swine model of acute LV injury. In eight male swine, the RA-FA bypass group employed a 21 Fr inflow cannula in the right atrial (RA) and a 17 Fr FA outflow cannula. The LA-FA bypass group employed a 21 Fr inflow cannula in the LA and a 17 Fr FA outflow cannula. Both pump configurations were activated at 3,500 rotations per minute (RPMs) followed by balloon angioplasty-mediated occlusion of the left circumflex (LCx) artery. After 30 minutes of LCx occlusion, RPMs through the centrifugal pump were increased from 3,500, 5,500 then to a maximum at 7,500 RPMs. At 7,500 RPMs, RA-FA and LA-FA bypass generated 3.5 ± 0.1 and 3.6 ± 0.2 liters/minute (LPM) of flow, respectively. At maximum flow, RA unloading increased LV end-systolic pressure and estimated wall stress, whereas LA unloading reduced LV end-diastolic pressure, end-diastolic volume, and native stroke volume without changing estimated wall stress. Veno-arterial extracorporeal membrane oxygenation acutely increases mean arterial pressure (MAP) without unloading the LV, whereas the TandemHeart maintains MAP and unloads the LV. These findings indicate that RA versus LA cannulation for circulatory support have distinct acute hemodynamic effects on the LV.

Promising approach for the preclinical assessment of cardiac risks using left ventricular pressure-volume loop analyses in anesthetized monkeys

IntroductionLoad-independent cardiac parameters obtained from the ventricular pressure-volume relationship are recognized as gold standard indexes for evaluating cardiac inotropy. In this study, for better analyses of cardiac risks, load-independent pressure-volume loop parameters were assessed in addition to load-dependent inotropic, hemodynamic and electrocardiographic changes in isoflurane-anesthetized monkeys. MethodsThe animals were given milrinone (a PDE 3 inhibitor), metoprolol (a β-blocker), or dl-sotalol (a β+IKr blocker) intravenously over 10min at two dose levels including clinically relevant doses (n=5/drug). ResultsMilrinone and metoprolol produced positive and negative inotropy, respectively. These effects were detected as changes in the slope of the preload-recruitable stroke work, which is a load-independent inotropic parameter. However, dl-sotalol did not alter the slope of the preload-recruitable stroke work. That means dl-sotalol produced no inotropy, although it decreased load-dependent inotropic parameters, including maximal upstroke velocity of left ventricular pressure, attributable to decreased heart rate and blood pressure. Other typical pharmacological effects of the compounds tested were also detected. Both β-blockers produced PR prolongation, decreased left ventricular end-systolic pressure, increased left ventricular end-diastolic pressure, and increased maximal descending velocity of left ventricular pressure and time constant for isovolumic relaxation. dl-Sotalol also prolonged heart-rate-corrected QT interval. Milrinone induced reflex tachycardia, PR shortening, and decreased left ventricular end-diastolic pressure. DiscussionThe overall assessment by not only load-dependent inotropic parameters but also load-independent parameters obtained from the ventricular pressure-volume loop analysis using monkeys can provide further appropriate information for the assessment of drug-induced cardiac risks.

PROTECTIVE EFFECT OF Ailanthus excelsa ROXB IN MYOCARDIAL INFARCTION POST MESENCHYMAL STEM CELL TRANSPLANTATION: STUDY IN CHRONIC ISCHEMIC RAT MODEL.

Background:Thia study evaluates the effects of Ailanthus excelsa Roxb methanolic extract (AER-ME) in rats induced with Myocardial Infarction (MI) followed by transplantation of MSCs.Material and Methods:Rats were induced with MI by ligation technique of left coronary artery. The sham-operated the control and AER-ME treated group of rats received transplantation of PKH-26 and marked MSCs followed by normal saline and AER-ME treatment (200mg/kg/day of AER-ME extract) respectively for 30 days. Parameters such as cardiac function, inflammation, oxidative stress, apoptosis and differentiation of MSCs (angiogenesis) were evaluated. Histological studies of infracted myocardium reveled anti-inflammatory activity of AER-ME treatment.Result and Discussion:Oxidative stress parameters revealed decrease in levels of malondialdehyde (MDA) and increase in superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSHpx) activity significantly indicating antioxidant activity of the extract. There was a reduction in cell death rate of treated rats due to the decrease in apoptotic index with prolongation of MI when compared to both control and sham-operated groups. The expression of Fas protein was parallel to apoptotic index. The vascular density increased significantly in extract treated group. The treatment showed improved cardiac activity with decreased left ventricular end diastolic (LVEDP) and arterial pressure while the left ventricular end systolic pressure (LVEP) and dp/dtmax increased significantly when compared to both control and sham-operated groups respectively showing the protective effect of the extract as necessitated by the transplantation of MSCs. The study marked the protective outcomes of AER-ME treatment for MSCs in microenvironment of infracted myocardium by improving their viability and increasing differentiation into cardiomyocytes.

Cardioprotection induced by hypoxic preconditioning and ischemic preconditioning in in vivo hearts of dogs: using double CPB circuits

Objective To evaluate the cardioprotection induced by ischemic preconditioning(IPC)and hypoxic preconditioning(HPC)which were carried out by using the double cardiopulmonary bypass(CPB) circuits in in vivo hearts of dogs. Methods Eighteen healthy male dogs, weighing 17.5-24.5 kg, aged 13-24 months, were divided into 3 groups (n=6 each) using a random number table: myocardial ischemia-reperfusion group (group I/R), IPC group and HPC group.The double CPB circuits were established as follows: systemic and coronary circulation, and independent systemic and coronary circulation was carried out.In group IPC, the aorta was clamped, and the coronary circulation pump was suspended for 5 min followed by 5 min opening, repeating for 3 cycles.In group HPC, the aorta was clamped, the coronary circulation was started, and pure nitrogen was insufflated for 5 min followed by 5 min of oxygen insufflation, repeating for 3 cycles.CPB was performed for 1 h starting from the time point immediately after IPC or HPC.Before splitting of sternum (T1), after establishment of double CPB circuits (T2), at the end of preconditioning (T3), and at 60 and 120 min after restoration of spontaneous heart beat (T4, 5), heat rate, mean arterial pressure, central venous pressure, left ventricular end-systolic pressure, left ventricular end-diastolic pressure and the maximum rate of increase/decrease of left ventricular pressure were recorded.Blood samples were collected from the right internal jugular vein at T1 and T4, 5 for determination of serum cardiac troponin I concentrations.The animals were sacrificed after determination of the parameter or after blood sampling at T5, myocardial specimens were obtained for examination of the ultrastructure and for detection of apoptosis in cardiomyocytes, and apoptosis index was calculated.Before aortic clamping, immediately after aortic unclamping and at 30 min after aortic unclamping, myocardial specimens were obtained for determination of ATP contents in cardiomyocytes. Results Compared with I/R group, left ventricular end-systolic pressure was significantly increased, and the serum cardiac troponin I concentrations were significantly decreased at T4, 5, the myocardial ATP contents were significantly increased immediately after aortic unclamping and at 30 min after aortic unclamping, apoptosis index was significantly decreased (P<0.05 or 0.01), and the pathological changes were significantly attenuated in IPC and HPC groups.Compared with group IPC, the myocardial ATP contents were significantly increased(P<0.05), and the pathological changes were attenuated in group HPC. Conclusion Both HPC and IPC can exert cardioprotection when carried out by using the double CPB circuits, and HPC provides better cardioprotection than IPC in in vivo hearts of dogs. Key words: Ischemic preconditioning, myocardial; Anoxia; Myocardial reperfusion injury

Simulated microgravity increases myocardial susceptibility to ischemia-reperfusion injury via a deficiency of AMP-activated protein kinase.

Gravitation is an important factor in maintaining cardiac contractility. Our study investigated whether simulated microgravity increases myocardial susceptibility to ischemia-reperfusion (IR) injury. Using the Langendorff-perfused heart model with 300 beats/min pacing, 4-week tail suspension (SUS) and control (CON) male Sprague-Dawley rats (n = 10 rats/group) were subjected to 60 min of left anterior descending coronary artery (LAD) occlusion followed by 120 min of reperfusion. Left ventricular end-systolic pressure (LVESP), left ventricular end-diastolic pressure (LVEDP), creatine kinase (CK) and lactate dehydrogenase (LDH) activity, and infarct size were assessed. Data demonstrated that there were significantly increased LVEDP, CK, LDH, and infarct size in SUS compared with CON (P < 0.05), accompanied by decreased LVESP (P < 0.05). Furthermore, TUNEL-positive cardiomyocytes were higher in SUS than that in CON (P < 0.01), and AMP-activated protein kinase (AMPK) phosphorylation and Bcl-2/Bax in SUS were less compared with CON (P < 0.05). Similarly, isolated hearts pre-treated with A-769662 exhibited better recovery of cardiac function, increased AMPK phosphorylation, and reduced necrosis and apoptosis. Furthermore, AMPKα protein showed a significant suppression in 4-week hindlimb unweighting rats. These results suggest that AMPK deficiency increases myocardial susceptibility to IR injury in rats subjected to simulated microgravity.

The Effects of High Frequency Oscillatory Ventilation (HFOV) with Volume Guarantee (VG) on Left Ventricular Function, Systemic and Regional Oxygenation, and Ventilation When Compared to HFOV and Conventional Mechanical Ventilation (CMV) in A Newborn Piglet Model of Respiratory Distress Syndrome (RDS)

Abstract BACKGROUND: RDS due to surfactant deficiency is commonly seen in preterm infants. These infants often require ventilatory support such as CMV and HFOV. HFOV with VG (HFOV+VG) is an alternative mode that delivers a set tidal volume. There is limited data on either HFOV mode regarding the effects on left ventricular (LV) function, systemic and regional oxygenation, and ventilation. OBJECTIVES: We primarily compared the effects of CMV with VG, HFOV, and HFOV+VG on cardiac index (CI). Secondary parameters included heart rate (HR), mean arterial pressure (MAP), LV ejection fraction (EF), stroke volume (SV), dP/dt max, LV end-systolic volume and pressure (ESV, ESP), end-diastolic volume and pressure (EDV, EDP), and measures of oxygenation and ventilation. Oxygenation parameters included cerebral and renal near-infrared spectroscopy (NIRS), partial pressure of arterial oxygen (PaO2), and carotid artery flow index (CAFI). Ventilation parameters included partial pressure of arterial carbon dioxide (PaCO2) and minute ventilation (MV). DESIGN/METHODS: Piglets (1.4-2.4 kg; 1-3 days old) were acutely anesthetized and instrumented with the placement of a right femoral arterial catheter for blood gas analysis, NIRS probes (Invos®), Transonic® flow probe on right common carotid artery, and Millar® catheter in the LV. Warm saline lung lavage was performed to achieve an AaDO2 of 300-450 mmHg to simulate moderate to severe RDS. Piglets were then block-randomized to CMV, HFOV or HFOV+VG for 4 hours using a Fabian HFO ventilator (Acutronic Medical Systems AG, Switzerland)(n=8 per group). Sham-operated piglets without RDS were monitored for the same duration under CMV (n=6). Two-way repeated measures ANOVA was used to analyze the data between modes or time points. RESULTS: Piglets developed moderately severe RDS with comparable AaDO2 and Paw along with stable hemodynamic parameters. Both HFOV and HFOV+VG groups had similar PaCO2 whereas the CMV group had elevated PaCO2 when compared to that of the Sham (p&amp;lt;0.01). Switching to HFOV resulted in a higher MV than its baseline. HFOV+VG but not HFOV or CMV groups had lower regional oxygenation and CAFI than its respective normoxic baseline (all p&amp;lt;0.01). HFOV and HFOV+VG had higher CI, EF, and SV than CMV at 4 hours of recovery (p&amp;lt;0.05) with similar HR, MAP, dP/dt max, ESV, ESP, EDV and EDP. CONCLUSION: In our piglet model of RDS, HFOV shows benefits to LV function and ventilation when compared to CMV. HFOV+VG does not show benefits compared to HFOV.

Oxymatrine protects against sepsis-induced myocardial injury via inhibition of the TNF-α/p38-MAPK/caspase-3 signaling pathway.

Oxymatrine (OMT), which is a quinolizidine alkaloid extracted from the traditional Chinese herb Sophoraflavescens Aiton, is often used to treat various inflammatory diseases. The present study aimed to investigate the protective effects of OMT against septic shock‑induced myocardial injury in rats, and to determine the underlying mechanisms. In the present study, cecal ligation and puncture (CLP) was applied to generate a rat model of sepsis. The rats were randomly divided into six groups (n=8/group): Sham operation (CON) group, OMT control group, CLP model group, and CLP+OMT (high dose, 52mg/kg; medium dose, 26mg/kg; low dose, 13mg/kg) groups. Cardiac function and histological alterations were analyzed by light microscopy and electron microscopy. Myocardial cell apoptosis was detected by terminal deoxynucleotidyl transferase dUTP nick end labeling assay. The mRNA and protein expression levels were examined by reverse transcription-polymerase chain reaction and western blotting, respectively. Furthermore, the levels of tumor necrosis factor (TNF)‑α in the myocardial tissue were determined by radioimmunoassay. The results demonstrated that OMT exhibited anti‑inflammatory properties, improved myocardial contractility and compliance, and significantly decreased pathological injury to rat myocardial ultrastructure. In addition, OMT significantly decreased heart rate and left ventricular end diastolic pressure, and increased mean arterial pressure, left intraventricular pressure change rate, and left ventricular end systolic pressure in rats following septic shock. Treatment with OMT attenuated the mRNA expression of lipopolysaccharide binding protein, cluster of differentiation14, nuclear factor (NF)‑κB (p65), TNF‑α, p38‑mitogen‑activated protein kinase (MAPK) and caspase‑3, and decreased the protein expression of NF‑κB (p65), phosphorylated (p)NF‑κB inhibitor‑α, p‑p38‑MAPK caspase‑3 and TNF‑α in septic myocardial tissue. The present study concluded that OMT may offer substantial therapeutic potential for the treatment of septic shock‑induced myocardial injury by inhibiting the TNF-α/p38-MAPK/caspase-3 signaling pathway.

Cardioprotective effects of diminazene aceturate in pressure-overloaded rat hearts

AimsAngiotensin-converting enzyme 2 (ACE2) is a key modulator of the renin-angiotensin system. Recent studies have shown that diminazene aceturate (DIZE) acts as an ACE2 activator. The aim of this study was to evaluate the cardiac effects of chronic treatment with DIZE in pressure-overloaded rats. Main methodsMale Wistar rats were divided into 4 groups: (1) sham; (2) aortic banded rats (AB); (3) AB+DIZE (1mg/kg, gavage); and (4) AB+DIZE+A-779 (120μg/day, osmotic mini-pumps). Cardiac hypertrophy was evaluated by ventricular mass index and myocyte cross-sectional area. mRNA expression of atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP) and transforming growth factor beta 1 (TGF-β) was quantified by RT-PCR. Cardiac function was assessed according to the Langendorff technique. The ACE2 and Mas protein expression was examined by western blot analysis. Key findingsDIZE treatment prevented the cardiomyocyte hypertrophy promoted by AB and A-779 inhibited this effect. Also, DIZE induced the expression of ANP and BNP mRNA in cardiac tissue from AB rats and attenuated the impairment in left ventricular end-systolic pressure and left ventricular developed pressure, +dP/dt and −dP/dt caused by AB. These effects were blocked by A-779. Moreover, DIZE prevented the increase in the expression of TGF-β mRNA in AB hearts, but it did not change the ACE2 and Mas protein expression. SignificanceThese results showed that DIZE was efficient in preventing the cardiomyocyte hypertrophy and attenuated the left ventricular contractile impairment induced by pressure overload. However, further studies are necessary to confirm whether these effects were due to ACE2 activation.

Dietary Phenolic Acids of Macrotyloma uniflorum (Horse Gram) Protect the Rat Heart Against Isoproterenol-Induced Myocardial Infarction.

The present study investigates the cardioprotective activity of the Macrotyloma uniflorum seed extract (MUSE) and its phenolic acids (p-coumaric acid and ferulic acid) in isoproterenol (ISO)-induced myocardial infarction in rats. The previously mentioned phenolic acids were isolated and quantified from MUSE by HPLC. Pretreatment of gemfibrozil (reference standard), MUSE (250 and 500 mg/kg) and the phenolic acids for 30 days to rats treated with ISO (85 mg/kg) on the last 2 days resulted in a significant attenuation of the ISO-elevated levels of serum marker enzymes (aspartate aminotransferase, lactate dehydrogenase and creatine phosphokinase MB), total cholesterol, triglycerides, uric acid, C-reactive protein and malondialdehyde and a restoration of the levels of the ISO-depleted marker enzymes, reduced glutathione and the antioxidant enzymes-superoxide dismutase, catalase, glutathione peroxidase and glutathione reductase in heart. Restoration of the ISO-altered electrocardiogram pattern and haemodynamic parameters (left ventricular end diastolic pressure, heart rate, systolic, diastolic and mean arterial pressure) was also brought about by treatment with MUSE and the phenolic acids. It may be concluded that MUSE treatment to ISO-challenged rats exhibits a significant cardioprotective effect probably because of the potent antioxidant activity of its phenolic acids that salvage the myocardium from the deleterious effects of ISO. Copyright © 2016 John Wiley & Sons, Ltd.

Spontaneous Hypertension in Nonhuman Primate African Green Monkeys Is Associated with Left Ventricular Hypertrophy Without Significant Cardiac or Aortic Fibrosis

The African Green Monkey (AGM; Chlorocebus aethiops sabeus) develops hypertension in approximately 35% of individuals. It is likely that this hypertension is associated with elevated sympathetic nerve activity since hypertensive (HT) AGMs have significantly elevated heart rates compared to normotensive (NT) animals. Thus, hypertension in the AGM may exhibit elevated total peripheral resistance and increased cardiac after load that would lead to elevated left ventricular end systolic pressure. We hypothesize that in AGMs, chronic spontaneous hypertension elicits significant left ventricular hypertrophy (LVH), and increased myocardial and/or aortic collagen deposition compared with NT AGMs. Sedated AGMs were characterized as either HT (SBP≥140mmHg) or NT (SBP&lt;120mmHg) using forearm plethysmography (ketamine HCl, 15 mg/kg i.m.). Cardiac and aortic tissues were obtained immediately following euthanasia (Na+ pentobarbital overdose; 150 mg/kg i.v.). Cardiac and aortic tissues were fixed with paraformaldehyde (5%) and stored in ethanol (70%) or rapidly frozen and stored at −20 °C in isopentane. Fixed ventricular and aortic cross sections were cut (5 μm), mounted and stained with hematoxylin and eosin. Randomly selected colony HT AGMs had increased left ventricular myocardial cell area compared with NT animals (1658± 515 μm2, n=6, HT vs. 791± 210 μm2, n=7, NT; p&lt;0.01). Ventricular and aortic fibrosis was assessed using picosirius red stain which selectively identifies collagen deposition in tissue. Average area of collagen was greater in HT compared to NT AGMs (55.27 ± 2.33%, n=9 NT vs. 66.12 ± 4.22%, n=6 HT; p&lt;0.05). No difference was measured in average area of collagen per left ventricular myocardial tissue area between HT and NT AGMs (12.22 ± 0.80%, n=10 NT vs. 14.17 ± 3.29%, n=9 HT; p=0.84). Next, total tissue collagen was measured by quantifying tissue hydroxyproline from frozen aorta and left ventricular myocardium. Collagen content between HT and NT AGMs were not different in aorta (745.64 ± 44.49 μg/ml, n=11 HT vs. 668.39 ± 31.06 μg/ml, n=11 NT, p=0.17) or in left ventricular myocardium (194.02 ± 8.61 μg/ml, n=11 HT vs. 201.70 ± 18.89 μg/ml, n=10 NT, p=0.71). These results demonstrate that chronic elevation of blood pressure in AGM is associated with LVH. Despite this LVH in hypertensive AGM, collagen biosynthesis and deposition within aorta and left ventricular myocardium is similar to NT control animals. We conclude that AGMs with chronic elevation of arterial pressure develop LVH likely from increased after load arising from increased total peripheral resistance. This LVH however, must develop in response to factors other than increased deposition of intercellular collagen. Ongoing experiments in HT AGMs will assess the deposition of other intercellular connective proteins in both left ventricle and aorta as well as the presence of pro‐inflammatory cytokines known to contribute to LVH in other experimental models of hypertension.Support or Funding InformationSupported by American Physiological Society, National Science Foundation Integrative Organismal Systems Award No. IOS‐ 1238831, and Biomedical Science Research Group, L.L.C.

Early Improvements in Blood Lipid Profile and Vascular Alterations after Gastric Bypass Surgery Prior to Dramatic Weight Loss

With 6.6% of adults in the U.S. classified as morbidly obese, excess bodyweight is now the sixth most significant risk factor contributing to the overall burden of disease, emerging as one of the most serious public health concerns in the 21st century. Bariatric surgery has been shown to eliminate comorbid conditions associated with obesity. The aim of this study is to evaluate the effect of weight reduction following laparoscopic Roux‐en Y gastric bypass (RYGB) on remodeling and improvements in arterial function, in addition to immediate reversal of metabolic deviations as weight is lost.Patients that meet protocol inclusion criteria are invited to join the study during their 1 week pre‐operative clinical appointment. At this time patients are consented and instructed to lie supine for 10 minutes of quite relaxation. Patients then begin a sequence of non‐invasive examinations starting with a 12‐lead electrocardiogram, followed by an echocardiogram, carotid artery ultrasound, radial applanation tonometry, and endothelial function analysis using EndoPAT technology. Upon completion of the non‐invasive procedures a fasting blood sample is taken for analysis.Preliminary findings show that RYGB results in significant body weight reduction (pre: 131.8 ±5.6 to post: 125 ±5.2 kg) in morbidly obese subjects, along with reductions in BMI (pre: 45.2 ±2.3 to post: 42.9 ± 2.2) and waist circumference (pre: 122.1 ±5.0 to post: 111.9 ± 3.2 cm) at the 1‐week time point. Decrease in body size and weight was aided by a reduction in low‐density lipoprotein (pre: 127 ±6.2 to post: 113 ±4.5 mg/dL), as well as suggested decreases in glucose levels. Such changes can be associated with an improvement of the lipid and glucose metabolism. However, these results appear before subjects have lost a substantial amount of weight (one week post‐operative), suggesting that noteworthy cardiovascular improvements post‐RYGB are achieved prior to the hypothesized weight‐related change. In addition, a number of improvements to the cardiovascular system were also marked at the 1‐week time point. Estimated left ventricular end systolic pressure and direct measure of left ventricular end systolic volume (pre: 66 ±4 to post: 55 ±3 mmHg) declined post‐GBS with an array of additional markers supporting alterations in central systolic blood pressure and myocardial oxygen demand. The data suggests that vascular changes are happening in the early stages of recovery, prior to dramatic weight loss, thus suggesting vascular modifications are a result of an alternate surgical benefit.

C-Type Natriuretic Peptide Improves Left Ventricular Functional Performance at Rest and Restores Normal Exercise Responses after Heart Failure.

In heart failure (HF), the impaired left ventricular (LV) arterial coupling and diastolic dysfunction present at rest are exacerbated during exercise. C-type natriuretic peptide (CNP) is elevated in HF; however, its functional effects are unclear. We tested the hypotheses that CNP with vasodilating, natriuretic, and positive inotropic and lusitropic actions may prevent this abnormal exercise response after HF. We determined the effects of CNP (2 μg/kg plus 0.4 μg/kg per minute, i.v., 20 minutes) on plasma levels of cGMP before and after HF and assessed LV dynamics during exercise in 10 chronically instrumented dogs with pacing-induced HF. Compared with the levels before HF, CNP infusion caused significantly greater increases in cGMP levels after HF. After HF, at rest, CNP administration significantly reduced LV end-systolic pressure (PES), arterial elastance (EA), and end-diastolic pressure. The peak mitral flow (dV/dtmax) was also increased owing to decreased minimum LVP (LVPmin) and the time constant of LV relaxation (τ) (P < 0.05). In addition, LV contractility (EES) was increased. The LV-arterial coupling (EES/EA) was improved. The beneficial effects persisted during exercise. Compared with exercise in HF preparation, treatment with CNP caused significantly less important increases in PES but significantly decreased τ (34.2 vs. 42.6 ms) and minimum left ventricular pressure with further augmented dV/dtmax Both EES, EES/EA (0.87 vs. 0.32) were increased. LV mechanical efficiency improved from 0.38 to 0.57 (P < 0.05). After HF, exogenous CNP produces arterial vasodilatation and augments LV contraction, relaxation, diastolic filling, and LV arterial coupling, thus improving LV performance at rest and restoring normal exercise responses after HF.

Cardiac and arterial elastance and myocardial wall stress in children with pectus excavatum.

Pectus excavatum (PE) is one of the most common skeletal deformities of childhood. The study was undertaken to assess cardiac functions in children with PE. Echocardiography was performed on 32 children with PE and 40 age-matched healthy controls. The following parameters were monitored: meridional left ventricular (LV) wall stress (WSM), arterial elastance (Ea), LV elastance at end-systole derived by single beat (Ees(sb)), LV circumferential end-systolic wall stress (ESWSc), midwall shortening fraction (SFmid), predicted midwall fiber shortening for a measured fiber stress (midwall VCFc), myocardial fiber stress (MFS), LV end-systolic dimension (LVES), LV end-diastolic dimension (LVED) and end-systolic blood pressure (Pes), LV wall thickness at end-systole (hes). To assess the severity of PE, Haller index (HI) was calculated by computed tomography of the thorax. SFmid, ESWSc, midwall VCFc and MFS were lower in PE children than in controls. The degree to which the parameters SFmid, ESWSc, midwall VCFc and MFS were altered in PE children was 14.9, 27.5, 20.3 and 20.3%, respectively. The minimum HI value of children with PE was 2.00, the maximum value was 4.93 and the arithmetic mean was 2.62 ± 0.56. Of the 32 children, 14 (43.75%) demonstrated mild deformity, 15 (46.88%) showed moderate and only 3 (9.37%) had severe deformity. In children with PE, there was no statistically significant correlation between the cardiac data (ESWSc, midwall VCFc, MFS, Ea, Ees(sb), LVES, LVED, Pes, hes) and HI. We found ESWSc, MFS, midwall VCFc and SFmid to be lower in children with PE than in controls. We concluded that the myocardial contractility and afterload is affected in children with PE.