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Right ventricular (RV) fibrosis is associated with RV dysfunction in a variety of RV pressure-loading conditions in which RV mechanical stress is increased, but the underlying mechanisms driving RV fibrosis are incompletely understood. In pulmonary and cardiovascular diseases characterized by elevated mechanical stress and transforming growth factor-β1 signaling, myocardin-related transcription factor A (MRTF-A) is a mechanosensitive protein critical to driving myofibroblast transition and fibrosis. In this study, we investigated whether MRTF-A inhibition improves RV profibrotic remodeling and function in response to a pulmonary artery banding (PAB) model of RV pressure loading. Rats were assigned into either sham or PAB groups. MRTF-A inhibitor CCG-1423 was administered daily at 0.75 mg/kg in a subset of PAB animals. Echocardiography and pressure–volume hemodynamics were obtained at a terminal experiment 6 weeks later. RV myocardial samples were analyzed for fibrosis, cardiomyocyte hypertrophy, and profibrotic signaling. MRTF-A inhibition slightly reduced systolic dysfunction in PAB rats reflected by increased lateral tricuspid annulus peak systolic velocity, whereas diastolic function parameters were not significantly improved. RV remodeling was attenuated in PAB rats with MRTF-A inhibition, displaying reduced fibrosis. This was accompanied with a reduction in PAB-induced upregulation of Yes-associated protein (YAP) and its paralog transcriptional coactivator with PDZ-binding motif (TAZ). We also confirmed, using a second-generation MRTF-A inhibitor CCG-203971, that MRTF-A is critical in driving RV fibroblast expression of TAZ and markers of myofibroblast transition in response to transforming growth factor-β1 stress and RhoA activation. These studies identify RhoA, MRTF-A, and YAP/TAZ as interconnected regulators of profibrotic signaling in RV pressure loading and as potential targets to improve RV profibrotic remodeling. [ABSTRACT FROM AUTHOR]

Anemia and renal failure are independent risk factors for perioperative stroke, prompting us to assess the combined impact of acute hemodilutional anemia and bilateral nephrectomy (2Nx) on microvascular brain P o 2 (PBr o 2) in a rat model. Changes in PBr o 2 (phosphorescence quenching) and cardiac output (CO, echocardiography) were measured in different groups of anesthetized Sprague-Dawley rats (1.5% isoflurane, n = 5–8/group) randomized to Sham 2Nx or 2Nx and subsequently exposed to acute hemodilutional anemia (50% estimated blood volume exchange with 6% hydroxyethyl starch) or time-based controls (no hemodilution). Outcomes were assessed by ANOVA with significance assigned at P < 0.05. At baseline, 2Nx rats demonstrated reduced CO (49.9 ± 9.4 vs. 66.3 ± 19.3 mL/min; P = 0.014) and PBr o 2 (21.1 ± 2.9 vs. 32.4 ± 3.1 mmHg; P < 0.001) relative to Sham 2Nx rats. Following hemodilution, 2Nx rats demonstrated a further decrease in PBr o 2 (15.0 ± 6.3 mmHg, P = 0.022). Hemodiluted 2Nx rats did not demonstrate a comparable increase in CO after hemodilution compared with Sham 2Nx (74.8 ± 22.4 vs. 108.9 ± 18.8 mL/min, P = 0.003) that likely contributed to the observed reduction in PBr o 2. This impaired CO response was associated with reduced fractional shortening (33 ± 9 vs. 51 ± 5%) and increased left ventricular end-systolic volume (156 ± 51 vs. 72 ± 15 µL, P < 0.001) suggestive of systolic dysfunction. By contrast, hemodiluted Sham 2Nx animals demonstrated a robust increase in CO and preserved PBr o 2. These data support the hypothesis that the kidney plays a central role in maintaining cerebral perfusion and initiating the adaptive increase in CO required to optimize PBr o 2 during acute anemia. NEW & NOTEWORTHY: This study has demonstrated that bilateral nephrectomy acutely impaired cardiac output (CO) and microvascular brain P o 2 (PBr o 2), at baseline. Following acute hemodilution, nephrectomy prevented the adaptive increase in CO associated with acute hemodilution leading to a further reduction in PBr o 2, accentuating the degree of cerebral tissue hypoxia. These data support a role for the kidney in maintaining PBr o 2 and initiating the increase in CO that optimized brain perfusion during acute anemia. [ABSTRACT FROM AUTHOR]

S100A1 is a small [Ca.sup.2+]-binding protein expressed in the myocardium and blood vessels that is down-regulated in the diseased heart and plays a role in the regulation of cardiac muscle [Ca.sup.2+] homeostasis and contractility. To understand its physiological role under basal conditions and after myocardial infarction (MI), we used a mouse strain with targeted deletion of the S100A1 gene [S100A1 knockout (KO) mice]. We compared 49 wild-type (WT) and 56 S100A1 KO mice (6-8 wk old) over 28 days after MI with sham-operated controls. We also examined the effect of S100A1 deficiency on vascular function of isolated blood vessels. S100A1 KO mice demonstrated worse survival compared with WT mice (21% vs. 69%, respectively, P < 0.001). Hemodynamic evaluation revealed a higher mean arterial pressure (MAP) in sham-operated KO animals compared with WT animals (99 [+ or -] 4 vs. 77 [+ or -] 3 mmHg, respectively, P < 0.001) that persisted in both groups after MI (86 [+ or -] 2 vs. 66 [+ or -] 4 mmHg, respectively, P < 0.001). Sham-operated male S100A1 KO mice had higher MAP than female KO mice (122 [+ or -] 5 vs. 93 [+ or -] 3 mmHg, respectively P < 0.05) and reduced survival after MI (4% vs. 27%, respectively, P < 0.05). In isolated aortas and mesenteric arteries, ACh-evoked vasodilatation in KO mice was significantly reduced compared with WT mice (P < 0.05). Nitric oxide production was reduced in endothelial cells isolated from KO mice. Thus, absence of S100A1 results in acute functional impairment and high mortality after MI associated with a gender-specific hypertensive phenotype. S100A1 appears to play a role in the endothelium-dependent regulation of blood pressure. [Ca.sup.+]-binding protein; vascular tone; heart failure; hypertrophy; knockout

Angiotensin receptor blockers (ARBs) reduce adverse left ventricular (LV) remodeling and improve LV function and survival when started postmyocardial infarction (MI). ARBs also reduce ventricular arrhythmias during ischemia-reperfusion injury when started pre-MI. No information exists regarding their efficacy and safety when started pre-MI and continued peri- and post-MI. We evaluated whether the ARB losartan improves the outcome when started pre-MI and continued peri- and post-MI. Male Wistar rats (n = 502) were treated for 7 days pre-MI with losartan at a high dose (30 mg x [kg.sup.-1] x [day.sup.-1]), progressively increasing dose (3 mg x [kg.sup.-1] x [day.sup.-1] increased to 10 mg x [kg.sup.-1] x [day.sup.-1] 10 days and 30 mg x [kg.sup.-1] x [day.sup.-1] 20 days post-MI), or no treatment. Ambulatory systolic blood pressure and Holter monitoring were performed for 24 h post-MI. Echocardiography was done 30 days post-MI, and LV remodeling, cardiac hemodynamics, and fetal gene expression were assessed 38 days post-MI. High-dose losartan reduced 24-h post-MI survival compared with the progressive dose and control (21.9% vs. 36.6% and 38.1%, P = 0.033 and P = 0.009, respectively). This was associated with greater hypotension in the high dose and no change in ventricular arrhythmias in all groups. In 24-h post-MI survivors, the progressive dose group had reduced mortality from 24 h to 38 days (8.5% vs. 28.6% for control vs. 38.9% for high dose, P = 0.032 and P = 0.01, respectively). Survivors of both losartan groups demonstrated improved LV remodeling, cardiac hemodynamics, preserved GLUT-4, and reduced cardiac fetal gene expression. Pretreatment with ARBs does not reduce 24-h post-MI ventricular arrhythmias or survival, and high doses increase mortality by causing excessive hypotension. In 24-h post-MI survivors, progressively increasing doses of losartan have multiple beneficial effects, including improved survival. angiotensin II receptor blockers; heart failure; infarction; remodeling; hypotension

We showed previously that the vasopeptidase inhibitor (VPI) omapatrilat improves peri-myocardial infarction (MI) survival, but the mechanisms involved and whether these effects are sustained remained to be determined, and are the subject of this study. Rats (n = 272) received omapatrilat (20 mg* [kg.sup.-1]*[day.sup.-1]) starting 7 days before MI and continued peri- and post-MI, or no treatment (control). One group of rats had continuous ambulatory ECG and blood pressure recordings started 6 h before MI and continued until 24 h after MI, when survival was evaluated, and the rats were killed, and MI size was evaluated. A second group had left ventricular (LV) remodeling evaluated by echocardiography at 30 days and, at 38 days, had cardiac hemodynamics and morphology done and survival evaluated. Survival 24 h after MI (n = 255) improved with omapatrilat (60% vs. 46% for control; P = 0.0378). Over the next 37 days, there was no further improvement with omapatrilat but the early benefit was sustained. Omapatrilat reduced MI size 24 h after MI (36 [+ or -] 2 vs. 42 [+ or -] 2 [mm.sup.2] for controls; P = 0.034). Omapatrilat reduced ventricular arrhythmia score 1-12 h after MI. Omapatrilat decreased blood pressure, but not during the first 24 h after MI. Omapatrilat reduced LV diastolic and systolic dimensions and LV and right ventricular weights compared with control large MI, indicating a decrease in reactive hypertrophy. Improvement in cardiac remodeling was accompanied by improved cardiac hemodynamics. Thus this study indicates that pre-, peri-, and post-MI treatment with the VPI omapatrilat is beneficial in survival, ventricular arrhythmias, LV remodeling, and cardiac function. vasopeptidase inhibitor

Sensing changes in blood oxygen content (CaO2) is an important physiological role of the kidney; however, the mechanism(s) by which the kidneys sense and respond to changes in CaO2 are incompletely understood. Accurate measurements of kidney tissue oxygen tension (PktO2) may increase our understanding of renal oxygen-sensing mechanisms and could inform decisions regarding the optimal fluid for intravascular volume resuscitation to maintain renal perfusion. In some clinical settings, starch solution may be nephrotoxic, possibly due to inadequacy of tissue oxygen delivery. We hypothesized that hemodilution with starch colloid solutions would reduce PktO2 to a more severe degree than other diluents. Anesthetized Sprague-Dawley rats (n = 77) were randomized to undergo hemodilution with either colloid (6% hydroxyethyl starch or 5% albumin), crystalloid (0.9% saline), or a sham procedure (control) (n = 13–18 rats/group). Data were analyzed by ANOVA with significance assigned at P < 0.05. After hemodilution, mean arterial pressure (MAP) decreased marginally in all groups, while hemoglobin (Hb) and CaO2 decreased in proportion to the degree of hemodilution. Cardiac output was maintained in all groups after hemodilution. PktO2 decreased in proportion to the reduction in Hb in all treatment groups. At comparably reduced Hb, and maintained arterial oxygen values, hemodilution with starch resulted in larger decreases in PktO2 relative to animals hemodiluted with albumin or saline (P < 0.008). Renal medullary erythropoietin (EPO) mRNA levels increased more prominently, relative to other hypoxia-regulated molecules (GLUT-1, GAPDH, and VEGF). Our data demonstrate that the kidney acts as a biosensor of reduced CaO2 following hemodilution and that PktO2 may provide a quantitative signal for renal cellular responsiveness to acute anemia. Evidence of a more severe reduction in PktO2 following hemodilution with starch colloid solution suggests that tissue hypoxia may contribute to starch induced renal toxicity. [ABSTRACT FROM AUTHOR]

Background: Low hemoglobin concentration (Hb) and low mean arterial blood pressure (MAP) impact outcomes in critically ill patients. We utilized an experimental model of 'normotensive' vs. 'hypotensive' acute hemodilutional anemia to test whether optimal tissue perfusion is dependent on both Hb and MAP during acute blood loss and fluid resuscitation, and to assess the value of direct measurements of the partial pressure of oxygen in tissue (PO). Methods: Twenty-nine anesthetized rats underwent 40% isovolemic hemodilution (1:1) (or sham-hemodilution control, n = 4) with either hydroxyethyl starch (HES) ( n = 14, normotensive anemia) or saline ( n = 11, hypotensive anemia) to reach a target Hb value near 70 g/L. The partial pressure of oxygen in the brain and skeletal muscle tissue (PO) were measured by phosphorescence quenching of oxygen using G4 Oxyphor. Mean arterial pressure (MAP), heart rate, temperature, arterial and venous co-oximetry, blood gases, and lactate were assessed at baseline and for 60 min after hemodilution. Cardiac output (CO) was measured at baseline and immediately after hemodilution. Data were analyzed by repeated measures two-way ANOVA. Results: Following 'normotensive' hemodilution with HES, Hb was reduced to 66 ± 6 g/L, CO increased ( p < 0.05), and MAP was maintained. These conditions resulted in a reduction in brain PO (22.1 ± 5.6 mmHg to 17.5 ± 4.4 mmHg, p < 0.05), unchanged muscle PO, and an increase in venous oxygen extraction. Following 'hypotensive' hemodilution with saline, Hb was reduced to 79 ± 5 g/L and both CO and MAP were decreased ( P < 0.05). These conditions resulted in a more severe reduction in brain PO (23.2 ± 8.2 to 10.7 ± 3.6 mmHg ( p < 0.05), a reduction in muscle PO (44.5 ± 11.0 to 19.9 ± 12.4 mmHg, p < 0.05), a further increase in venous oxygen extraction, and a threefold increase in systemic lactate levels ( p < 0.05). Conclusions: Acute normotensive anemia (HES hemodilution) was associated with a subtle decrease in brain tissue PO without clear evidence of global tissue hypoperfusion. By contrast, acute hypotensive anemia (saline hemodilution) resulted in a profound decrease in both brain and muscle tissue PO and evidence of inadequate global perfusion (lactic acidosis). These data emphasize the importance of maintaining CO and MAP to ensure adequacy of vital organ oxygen delivery during acute anemia. Improved methods of assessing PO may provide an earlier warning signal of vital organ hypoperfusion. [ABSTRACT FROM AUTHOR]

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Although the influence of the adrenergic system has been studied in the presence of heart failure, controver-sies still exist. Since cyclooxygenase derivatives appear to modulate coronary and cardiac adaptation in the failing heart, we hypothesized that cyclooxygenase derivatives may participate in the altered adrenergic responses in this situation. Isolated hearts from cardiomyopathic (UM-X7.1 subline) and normal hamsters, aged >240 days, were utilized. Coronary and cardiac response to α[sub1]-, β[sub1]-, and β[sub2]-adrenergic stimulations was observed before and after pretreatment with indomethacin, a cyclooxygenase inhibitor. Reduction of coronary flow elicited by α[sub1]-adrenergic stimulation was unchanged in the presence of heart failure, while β[sub1]- and β[sub2]-induced vasodilatations were reduced. Inotropic response to α[sub1] and β[sub1] stimulations were also reduced in failing hearts, while β[sub2]-adrenergic action was unchanged. Pretreatment with indomethacin exacerbated coronary flow reduction observed with α[sub1] stimulation in failing hearts only. Β[sub2]-induced coronary vasodilatation and inotropic response to α[sub1]and &beta[sub2] stimulations were impaired similarly in the presence of indomethacin in normal and failing hearts. The results suggest a complex interaction between adrenergic and cyclooxygenase activation. [ABSTRACT FROM AUTHOR]

Introduction: Coronary reperfusion by coronary artery bypass graft (CABG) surgery is the standard approach to the management of acute ischemic syndromes. However, on-pump CABG often induces a systemic inflammatory response leading to myocardial injury and apoptosis. Hypothesis: The molecular pattern recognition receptor toll-like receptor (TLR)-4 is upregulated in key injuries to the heart, including ischemia/reperfusion injury, and may regulate the inflammatory response by recognition of the alarmin S100B, a member of the calcium binding S100 family of proteins. Methods: We examined the expression of TLR-4, the inflammatory cytokines tumor necrosis factor (TNF)-α and interleukin (IL)-1β, and indices of apoptosis in atrial tissue taken before aortic occlusion and after reperfusion from 59 CABG patients consisting of 15 women and 44 men with a mean±S.E. age of 66.57±1.78 and 64.02±1.25 yrs respectively. Results: Atrial TLR-4 (mRNA and protein) increased 2-2.5 fold post CABG. S100B, TNF-α, IL-1β, and markers of atrial apoptosis, caspase-3 activity, BAX/BCL2 ratio, and TUNEL positive myocyte nuclei all increased 1.5-5.0 fold post CABG. Positive correlations were observed between atrial TLR-4 and TNF-α mRNAs (r=0.605, p<0.001), TLR-4 and S100B mRNAs (r=0.585, p<0.001) and TLR4 and pro-apoptotic BAX mRNAs (r=0.326, p=0.012). To identify the functional importance of TLR-4 in myocardial injury, 12 week old TLR-4 knockdown (KD) mice underwent coronary artery ligation to produce myocardial infarction (MI). We compared 19 wild-type (WT), 29 TLR-4 mice over 35 days following MI with sham-operated controls. Of those, 11/19 WT-, and 5/29 TLR-4 KD -infarcted and 0/28 sham-operated mice died during the observation period. Among survivors, echocardiography, hemodynamic studies, and postmortem examination indicated that the WT and TLR-4KD-infarcted mice mounted left ventricular (LV) peri-infarct inflammatory (WT 1098±129 vs. TLR-4, 148±45 TNF-α pg/mL protein p<0.001) and apoptotic (WT. 0.45±0.03 vs. TLR-4 0.17±0.01 % TUNEL positive nuclei, p<0.05) responses augmented in WT mice. The LV end-diastolic pressure was reduced in TLR-4KD mice (9.1±1.2 vs. 14.5±1.7 mmHg, p<0.05). In the MI WT group, LV peri-infarct and plasma S100B increased approximately 4-5 fold vs. TLR4. Immunoprecipitation and imunoflurescence showed an association of S100B and TLR4 in LV peri-infarct of WT AMI mice. Conclusions: S100B/TLR-4 signaling may constitute a novel target in the treatment of ischemic heart failure [ABSTRACT FROM AUTHOR]