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Aldosterone in vascular and metabolic dysfunction.
Luther JM
(2016) Curr Opin Nephrol Hypertens 25: 16-21
MeSH Terms: Adipocytes, Aldosterone, Animals, Blood Glucose, Blood Pressure, Coronary Circulation, Diabetic Nephropathies, Humans, Mineralocorticoid Receptor Antagonists, Muscle, Smooth, Vascular, Receptors, Mineralocorticoid, Vascular Endothelial Growth Factor Receptor-1
Show Abstract · Added November 30, 2015
PURPOSE OF REVIEW - This review will highlight recent developments in mineralocorticoid receptor research which impact aldosterone-associated vascular and cardiometabolic dysfunction.
RECENT FINDINGS - The mineralocorticoid receptor is also expressed in vascular smooth muscle and vascular endothelium, and contributes to vascular function and remodeling. Adipocyte-derived leptin stimulates aldosterone secretion, which may explain the observed link between obesity and hyperaldosteronism. Adipocyte mineralocorticoid receptor overexpression produces systemic changes consistent with metabolic syndrome. Ongoing studies with novel nonsteroidal mineralocorticoid receptor antagonists may provide a novel treatment for diabetic nephropathy and heart failure in patients with chronic kidney disease, with reduced risk of hyperkalemia.
SUMMARY - Ongoing research continues to demonstrate novel roles of the vascular and adipocyte mineralocorticoid receptor function, which may explain the beneficial metabolic and vascular benefits of mineralocorticoid receptor antagonists.
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12 MeSH Terms
Impairment of subendocardial perfusion reserve and oxidative metabolism in nonischemic dilated cardiomyopathy.
Bell SP, Adkisson DW, Ooi H, Sawyer DB, Lawson MA, Kronenberg MW
(2013) J Card Fail 19: 802-10
MeSH Terms: Adult, Cardiomyopathy, Dilated, Coronary Circulation, Female, Humans, Male, Middle Aged, Myocardial Perfusion Imaging, Oxygen Consumption, Prospective Studies, Retrospective Studies
Show Abstract · Added March 5, 2014
BACKGROUND - Cardiac magnetic resonance (CMR) and [(11)C]acetate positron emission tomography (PET) were used to assess the hypothesis that patients with nonischemic dilated cardiomyopathy (NIDCM) have decreased subendocardial perfusion reserve and impaired oxidative metabolism, consistent with the concept of "energy starvation" in heart failure (HF).
METHODS AND RESULTS - CMR myocardial perfusion was evaluated in 13 NIDCM patients and 15 control subjects with coronary risk factors and normal myocardial perfusion. The NIDCM patients underwent [(11)C]acetate PET. The myocardial perfusion index (MPI) was calculated as the normalized rate of myocardial signal augmentation following gadolinium contrast injection. Hyperemic transmural, subendocardial, and subepicardial MPI were reduced in NIDCM compared with control subjects [0.13 vs 0.18 (P < .001), 0.13 vs 0.17 (P < .001), and 0.13 vs 0.17 (P = .008), respectively]. The subendocardial perfusion reserve was 1.59 ± 0.21 vs 1.86 ± 0.32 for the subepicardium (P = .002), demonstrating reduced perfusion reserve. The myocardial oxidative metabolic rate (kmono) per unit demand (rate-pressure product) was reduced in proportion to perfusion reserve (P = .02) CONCLUSIONS: Impaired subendocardial perfusion reserve in NIDCM confirmed results previously attained only in animal models. Impaired perfusion and impaired oxidative metabolism are consistent with subendocardial energy starvation in HF.
Published by Elsevier Inc.
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11 MeSH Terms
Visualizing regional myocardial blood flow in the mouse.
Krueger MA, Huke SS, Glenny RW
(2013) Circ Res 112: e88-97
MeSH Terms: Animals, Blood Flow Velocity, Computer Simulation, Coronary Artery Disease, Coronary Circulation, Coronary Vessels, Disease Models, Animal, Endocardium, Fluorescent Dyes, Image Interpretation, Computer-Assisted, Ligation, Mice, Microspheres, Models, Statistical, Myocardial Perfusion Imaging, Numerical Analysis, Computer-Assisted, Optical Imaging, Pericardium, Regional Blood Flow, Time Factors
Show Abstract · Added May 27, 2014
RATIONALE - The spatial distribution of blood flow in the hearts of genetically modified mice is a phenotype of interest because derangements in blood flow may precede detectable changes in organ function. However, quantifying the regional distribution of blood flow within organs of mice is challenging because of the small organ volume and the high resolution required to observe spatial differences in flow. Traditional microsphere methods in which the numbers of microspheres per region are indirectly estimated from radioactive counts or extracted fluorescence have been limited to larger organs for 2 reasons; to ensure statistical confidence in the measured flow per region and to be able to physically dissect the organ to acquire spatial information.
OBJECTIVE - To develop methods to quantify and statistically compare the spatial distribution of blood flow within organs of mice.
METHODS AND RESULTS - We developed and validated statistical methods to compare blood flow between regions and with the same regions over time using 15-µm fluorescent microspheres. We then tested this approach by injecting fluorescent microspheres into isolated perfused mice hearts, determining the spatial location of every microsphere in the hearts, and then visualizing regional flow patterns. We demonstrated application of these statistical and visualizing methods in a coronary artery ligation model in mice.
CONCLUSIONS - These new methods provide tools to investigate the spatial and temporal changes in blood flow within organs of mice at a much higher spatial resolution than currently available by other methods.
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20 MeSH Terms
Effect of transendocardial delivery of autologous bone marrow mononuclear cells on functional capacity, left ventricular function, and perfusion in chronic heart failure: the FOCUS-CCTRN trial.
Perin EC, Willerson JT, Pepine CJ, Henry TD, Ellis SG, Zhao DX, Silva GV, Lai D, Thomas JD, Kronenberg MW, Martin AD, Anderson RD, Traverse JH, Penn MS, Anwaruddin S, Hatzopoulos AK, Gee AP, Taylor DA, Cogle CR, Smith D, Westbrook L, Chen J, Handberg E, Olson RE, Geither C, Bowman S, Francescon J, Baraniuk S, Piller LB, Simpson LM, Loghin C, Aguilar D, Richman S, Zierold C, Bettencourt J, Sayre SL, Vojvodic RW, Skarlatos SI, Gordon DJ, Ebert RF, Kwak M, Moyé LA, Simari RD, Cardiovascular Cell Therapy Research Network (CCTRN)
(2012) JAMA 307: 1717-26
MeSH Terms: Angina Pectoris, Bone Marrow Transplantation, Coronary Artery Disease, Coronary Circulation, Double-Blind Method, Female, Heart Failure, Humans, Injections, Male, Middle Aged, Myocardial Ischemia, Oxygen Consumption, Tomography, Emission-Computed, Single-Photon, Transplantation, Autologous, Treatment Outcome, Ventricular Dysfunction, Left
Show Abstract · Added November 13, 2012
CONTEXT - Previous studies using autologous bone marrow mononuclear cells (BMCs) in patients with ischemic cardiomyopathy have demonstrated safety and suggested efficacy.
OBJECTIVE - To determine if administration of BMCs through transendocardial injections improves myocardial perfusion, reduces left ventricular end-systolic volume (LVESV), or enhances maximal oxygen consumption in patients with coronary artery disease or LV dysfunction, and limiting heart failure or angina.
DESIGN, SETTING, AND PATIENTS - A phase 2 randomized double-blind, placebo-controlled trial of symptomatic patients (New York Heart Association classification II-III or Canadian Cardiovascular Society classification II-IV) with a left ventricular ejection fraction of 45% or less, a perfusion defect by single-photon emission tomography (SPECT), and coronary artery disease not amenable to revascularization who were receiving maximal medical therapy at 5 National Heart, Lung, and Blood Institute-sponsored Cardiovascular Cell Therapy Research Network (CCTRN) sites between April 29, 2009, and April 18, 2011.
INTERVENTION - Bone marrow aspiration (isolation of BMCs using a standardized automated system performed locally) and transendocardial injection of 100 million BMCs or placebo (ratio of 2 for BMC group to 1 for placebo group).
MAIN OUTCOME MEASURES - Co-primary end points assessed at 6 months: changes in LVESV assessed by echocardiography, maximal oxygen consumption, and reversibility on SPECT. Phenotypic and functional analyses of the cell product were performed by the CCTRN biorepository core laboratory.
RESULTS - Of 153 patients who provided consent, a total of 92 (82 men; average age: 63 years) were randomized (n = 61 in BMC group and n = 31 in placebo group). Changes in LVESV index (-0.9 mL/m(2) [95% CI, -6.1 to 4.3]; P = .73), maximal oxygen consumption (1.0 [95% CI, -0.42 to 2.34]; P = .17), and reversible defect (-1.2 [95% CI, -12.50 to 10.12]; P = .84) were not statistically significant. There were no differences found in any of the secondary outcomes, including percent myocardial defect, total defect size, fixed defect size, regional wall motion, and clinical improvement.
CONCLUSION - Among patients with chronic ischemic heart failure, transendocardial injection of autologous BMCs compared with placebo did not improve LVESV, maximal oxygen consumption, or reversibility on SPECT.
TRIAL REGISTRATION - clinicaltrials.gov Identifier: NCT00824005.
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17 MeSH Terms
Pericardial fat and myocardial perfusion in asymptomatic adults from the Multi-Ethnic Study of Atherosclerosis.
Brinkley TE, Jerosch-Herold M, Folsom AR, Carr JJ, Hundley WG, Allison MA, Bluemke DA, Burke GL, Szklo M, Ding J
(2011) PLoS One 6: e28410
MeSH Terms: Adipose Tissue, Adult, Aged, Aged, 80 and over, Atherosclerosis, Coronary Circulation, Female, Hemodynamics, Humans, Male, Middle Aged, Multivariate Analysis, Myocardium, Perfusion, Pericardium
Show Abstract · Added February 15, 2014
BACKGROUND - Pericardial fat has adverse effects on the surrounding vasculature. Previous studies suggest that pericardial fat may contribute to myocardial ischemia in symptomatic individuals. However, it is unknown if pericardial fat has similar effects in asymptomatic individuals.
METHODS - We determined the association between pericardial fat and myocardial blood flow (MBF) in 214 adults with no prior history of cardiovascular disease from the Minnesota field center of the Multi-Ethnic Study of Atherosclerosis (43% female, 56% Caucasian, 44% Hispanic). Pericardial fat volume was measured by computed tomography. MBF was measured by MRI at rest and during adenosine-induced hyperemia. Myocardial perfusion reserve (PR) was calculated as the ratio of hyperemic to resting MBF.
RESULTS - Gender-stratified analyses revealed significant differences between men and women including less pericardial fat (71.9±31.3 vs. 105.2±57.5 cm(3), p<0.0001) and higher resting MBF (1.12±0.23 vs. 0.93±0.19 ml/min/g, p<0.0001), hyperemic MBF (3.49±0.76 vs. 2.65±0.72 ml/min/g, p<0.0001), and PR (3.19±0.78 vs. 2.93±0.89, p = 0.03) in women. Correlations between pericardial fat and clinical and hemodynamic variables were stronger in women. In women only (p = 0.01 for gender interaction) higher pericardial fat was associated with higher resting MBF (p = 0.008). However, this association was attenuated after accounting for body mass index or rate-pressure product. There were no significant associations between pericardial fat and hyperemic MBF or PR after multivariate adjustment in either gender. In logistic regression analyses there was also no association between impaired coronary vasoreactivity, defined as having a PR <2.5, and pericardial fat in men (OR, 1.18; 95% CI, 0.82-1.70) or women (OR, 1.11; 95% CI, 0.68-1.82).
CONCLUSIONS - Our data fail to support an independent association between pericardial fat and myocardial perfusion in adults without symptomatic cardiovascular disease. Nevertheless, these findings highlight potentially important differences between asymptomatic and symptomatic individuals with respect to the underlying subclinical disease burden.
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15 MeSH Terms
Comparison of physiological motion filters for in vivo cardiac ARFI.
Giannantonio DM, Dumont DM, Trahey GE, Byram BC
(2011) Ultrason Imaging 33: 89-108
MeSH Terms: Acoustics, Animals, Coronary Circulation, Dogs, Elasticity Imaging Techniques, Image Interpretation, Computer-Assisted, Least-Squares Analysis, Myocardial Contraction, Signal Processing, Computer-Assisted
Show Abstract · Added May 29, 2014
Acoustic radiation force impulse (ARFI) imaging is being utilized to investigate mechanical properties ofcardiac tissue. The underlying physiological motion, however, presents a major challenge. This paper aims to investigate the effectiveness of various physiological motion filters using in vivo canine data with a simulated ARFI push pulse. Ideally, the motion filter will exactly model the physiological motion and, when subtracted from the total displacement, leave only the simulated ARFI displacement profile. We investigated three temporal quadratic motion filters: (1)interpolation, (2) extrapolation and (3) a weighted technique. Additionally, the various motion filters were compared when using 1-D versus 2-D autocorrelation methods to estimate motion. It was found that 2D-autocorrelation always produced better physiological motion estimates regardless of the type of filter used. The extrapolation filter gives the most accurate estimate of the physiological motion at times immediately after the ARFI push (0.1 ms) while a close-time interpolation filter using displacement estimates at times before full tissue recovery gives the most accurate estimates at later times after the ARFI push (0.7 ms). While improvements to the motion filter during atrial systole and the onset of ventricular systole are needed, the weighted, close-time interpolation and extrapolation motion filters all offer promising results for estimating cardiac physiological motion more accurately, while allowing faster ARFI frame rates than previous motion filters. This study demonstrates the ability to eliminate physiological motion in a clinically-feasible manner, opening the door for more extensive clinical experimentation.
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9 MeSH Terms
Regional increase of extracellular potassium leads to electrical instability and reentry occurrence through the spatial heterogeneity of APD restitution.
Sidorov VY, Uzelac I, Wikswo JP
(2011) Am J Physiol Heart Circ Physiol 301: H209-20
MeSH Terms: Action Potentials, Anesthetics, Local, Animals, Arrhythmias, Cardiac, Cardiac Pacing, Artificial, Coronary Circulation, Coronary Vessels, Data Interpretation, Statistical, Electric Stimulation, Electrophysiological Phenomena, Extracellular Space, Female, Fluorescent Dyes, Heart Conduction System, Heart Rate, In Vitro Techniques, Kinetics, Male, Myocardial Ischemia, Myocardium, Potassium, Rabbits
Show Abstract · Added May 29, 2014
The heterogeneities of electrophysiological properties of cardiac tissue are the main factors that control both arrhythmia induction and maintenance. Although the local increase of extracellular potassium ([K(+)](o)) due to coronary occlusion is a well-established metabolic response to acute ischemia, the role of local [K(+)](o) heterogeneity in phase 1a arrhythmias has yet to be determined. In this work, we created local [K(+)](o) heterogeneity and investigated its role in fast pacing response and arrhythmia induction. The left marginal vein of a Langendorff-perfused rabbit heart was cannulated and perfused separately with solutions containing 4, 6, 8, 10, and 12 mM of K(+). The fluorescence dye was utilized to map the voltage distribution. We tested stimulation rates, starting from 400 ms down to 120 ms, with steps of 5-50 ms. We found that local [K(+)](o) heterogeneity causes action potential (AP) alternans, 2:1 conduction block, and wave breaks. The effect of [K(+)](o) heterogeneity on electrical stability and vulnerability to arrhythmia induction was largest during regional perfusion with 10 mM of K(+). We detected three concurrent dynamics: normally propagating activation when excitation waves spread over tissue perfused with normal K(+), alternating 2:2 rhythm near the border of [K(+)](o) heterogeneity, and 2:1 aperiodicity when propagation was within the high [K(+)](o) area. [K(+)](o) elevation changed the AP duration (APD) restitution and shifted the restitution curve toward longer diastolic intervals and shorter APD. We conclude that spatial heterogeneity of the APD restitution, created with regional elevation of [K(+)](o), can lead to AP instability, 2:1 block, and reentry induction.
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22 MeSH Terms
Vascular endothelial growth factor blockade promotes the transition from compensatory cardiac hypertrophy to failure in response to pressure overload.
Izumiya Y, Shiojima I, Sato K, Sawyer DB, Colucci WS, Walsh K
(2006) Hypertension 47: 887-93
MeSH Terms: Adaptation, Physiological, Animals, Aorta, Capillaries, Cardiac Output, Low, Cardiomegaly, Collagen, Constriction, Coronary Circulation, Echocardiography, Fibrosis, Gene Transfer Techniques, Hypertension, Immunoglobulin Fc Fragments, Male, Mice, Mice, Inbred C57BL, Myocardial Contraction, Myocardium, Up-Regulation, Vascular Endothelial Growth Factor A, Vascular Endothelial Growth Factor Receptor-2, Ventricular Remodeling
Show Abstract · Added March 5, 2014
Cardiac hypertrophy is associated with upregulation of vascular endothelial growth factor (VEGF) in the myocardium. Here, we evaluated the effects of a decoy VEGF receptor on heart morphology and function to a murine model of pressure overload hypertrophy. Mice were administered adenoviral vector encoding a decoy VEGF receptor (Ad-Flk), and their hearts were subjected to pressure overload by transverse aortic constriction (TAC). Treatment with Ad-Flk led to a net reduction in capillary density in hearts subjected to TAC. Ad-Flk also led to a reduction in TAC-induced cardiac hypertrophy and promoted left ventricle dilatation and a loss in contractile function. Treatment with Ad-Flk markedly increased myocardial fibrosis and collagen gene upregulation. In contrast, Ad-Flk had no effect on any of these parameters in sham-treated mice. Administration of a VEGF trap reagent diminished pressure overload cardiac hypertrophy and promoted the progression to heart failure but had no effect on sham-treated animals. These findings suggest that VEGF is required to maintain myocardial capillary density and that reductions in the vascular bed are associated with the transition from compensatory hypertrophy to failure.
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23 MeSH Terms
Simultaneous measurement of arterial input function and tumor pharmacokinetics in mice by dynamic contrast enhanced imaging: effects of transcytolemmal water exchange.
Zhou R, Pickup S, Yankeelov TE, Springer CS, Glickson JD
(2004) Magn Reson Med 52: 248-57
MeSH Terms: Animals, Body Water, Contrast Media, Coronary Circulation, Magnetic Resonance Imaging, Mice, Mice, Inbred C3H, Neoplasms, Experimental
Show Abstract · Added November 13, 2013
A noninvasive technique for simultaneous measurement of the arterial input function (AIF) for gadodiamide (Omniscan) and its uptake in tumor was demonstrated in mice. Implantation of a tumor at a suitable location enabled its visualization in a cardiac short axis image. Sets of gated, low-resolution saturation recovery images were acquired from each of five tumor-bearing mice following intravenous administration of a bolus of contrast agent (CA). The AIF was extracted from the signal intensity changes in left ventricular blood using literature values of the CA relaxivity and a precontrast T1 map. The time-dependent 1H2O relaxation rate constant (R1 = 1/T1) in the tumor was modeled using the BOLus Enhanced Relaxation Overview (BOLERO) method in two modes regarding the equilibrium transcytolemmal water exchange system: 1) constraining it exclusively to the fast exchange limit (FXL) (the conventional assumption), and 2) allowing its transient departure from FXL and access to the fast exchange regime (FXR), thus designated FXL/FXR. The FXL/FXR analysis yielded better fittings than the FXL-constrained analysis for data from the tumor rims, whereas the results based on the two modes were indistinguishable for data from the tumor cores. For the tumor rims, the values of Ktrans (the rate constant for CA transfer from the vasculature to the interstitium) and ve (volume fraction of the tissue extracellular and extravascular space) returned from FXL/FXR analysis are consistently greater than those from the FXL-constrained analysis by a factor of 1.5 or more corresponding to a CA dose of 0.05 mmole/kg.
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8 MeSH Terms
Na(+)/H(+) exchange inhibition prevents endothelial dysfunction after I/R injury.
Gumina RJ, Moore J, Schelling P, Beier N, Gross GJ
(2001) Am J Physiol Heart Circ Physiol 281: H1260-6
MeSH Terms: Acetylcholine, Animals, Coronary Circulation, Coronary Vessels, Dogs, Endothelium, Vascular, Guanidines, Heart Ventricles, Hemodynamics, Ischemic Preconditioning, Myocardial, Myocardial Infarction, Myocardial Ischemia, Myocardial Reperfusion, Organ Size, Reperfusion Injury, Sodium-Hydrogen Exchangers, Sulfones
Show Abstract · Added February 21, 2015
Whereas inhibition of the Na(+)/H(+) exchanger (NHE) has been demonstrated to reduce myocardial infarct size in response to ischemia-reperfusion injury, the ability of NHE inhibition to preserve endothelial cell function has not been examined. This study examined whether NHE inhibition could preserve endothelial cell function after 90 min of regional ischemia and 180 min of reperfusion and compared this inhibition with ischemic preconditioning (IPC). In a canine model either IPC, produced by one 5-min coronary artery occlusion (1 x 5'), or the specific NHE-1 inhibitor eniporide (EMD-96785, 3.0 mg/kg) was administered 15 min before a 90-min coronary artery occlusion followed by 3 h of reperfusion. Infarct size (IS) was determined by 2,3,5-triphenyl tetrazolium chloride staining and expressed as a percentage of the area-at-risk (IS/AAR). Endothelial cell function was assessed by measurement of coronary blood flow in response to intracoronary acetylcholine infusion at the end of reperfusion. Whereas neither control nor IPC-treated animals exhibited a significant reduction in IS/AAR or preservation of endothelial cell function, animals treated with the NHE inhibitor eniporide showed a marked reduction in IS/AAR and a significantly preserved endothelial cell function (P < 0.05). Thus NHE-1 inhibition is more efficacious than IPC at reducing IS/AAR and at preserving endothelial cell function in dogs.
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17 MeSH Terms