scholarly journals Circulating levels of cytochromecafter resuscitation from cardiac arrest: a marker of mitochondrial injury and predictor of survival

2007 ◽  
Vol 292 (2) ◽  
pp. H767-H775 ◽  
Author(s):  
Jeejabai Radhakrishnan ◽  
Sufen Wang ◽  
Iyad M. Ayoub ◽  
Julieta D. Kolarova ◽  
Rita F. Levine ◽  
...  
Keyword(s):  
Cardiac Arrest ◽  
Cytochrome C ◽  
Left Ventricular ◽  
Whole Body ◽  
Stroke Work ◽  
Western Immunoblotting ◽  
Mitochondrial Injury ◽  
Ventricular Tissue ◽  
Apoptotic Pathways

Ca2+overload and reactive oxygen species can injure mitochondria during ischemia and reperfusion. We hypothesized that mitochondrial injury occurs during cardiac resuscitation, causing release of cytochrome c to the cytosol and bloodstream while activating apoptotic pathways. Plasma cytochrome c was measured using reverse-phase HPLC and Western immunoblotting in rats subjected to 4 or 8 min of untreated ventricular fibrillation and 8 min of closed-chest resuscitation followed by 240 min of postresuscitation hemodynamic observation. A sham group served as control. Plasma cytochrome c rose progressively to levels 10-fold higher than in sham rats 240 min after resuscitation ( P < 0.01), despite reversal of whole body ischemia (decreases in arterial lactate). Cytochrome c levels were inversely correlated with left ventricular stroke work ( r = −0.40, P = 0.02). Western immunoblotting of left ventricular tissue demonstrated increased levels of 17-kDa cleaved caspase-3 fragments in the cytosol. Plasma cytochrome c was then serially measured in 12 resuscitated rats until the rat died or cytochrome c returned to baseline. In three survivors, cytochrome c rose slightly to ≤2 μg/ml and returned to baseline within 96 h. In nine nonsurvivors, cytochrome c rose progressively to significantly higher maximal levels [4.6 (SD 2.0) vs. 1.6 (SD 0.3) μg/ml, P = 0.029] and at faster rates [0.7 (SD 0.5) vs. 0.1 (SD 0.1) μg·ml−1·h−1, P = 0.046] than in survivors. Plasma cytochrome c may represent a novel in vivo marker of mitochondrial injury after resuscitation from cardiac arrest that relates inversely with survival outcome.

Cardiac dysfunction in mice lacking cytochrome-c oxidase subunit VIaH

2002 ◽  
Vol 282 (2) ◽  
pp. H726-H733 ◽  
Author(s):  
Nina B. Radford ◽  
Bang Wan ◽  
Angela Richman ◽  
Lidia S. Szczepaniak ◽  
Jia-Ling Li ◽  
...  
Keyword(s):  
Cytochrome C ◽  
Cytochrome C Oxidase ◽  
Cardiac Dysfunction ◽  
Mechanical Performance ◽  
Left Ventricular ◽  
Mutant Mice ◽  
Stroke Work ◽  
Wild Type ◽  
Oxidase Subunit ◽  
End Diastolic Volume

Cytochrome -c oxidase subunit VIaH (COXVIaH) has been implicated in the modulation of COX activity. A gene-targeting strategy was undertaken to generate mice that lacked COXVIaH to determine its role in regulation of oxidative energy production and mechanical performance in cardiac muscle. Total COX activity was decreased in hearts from mutant mice, which appears to be a consequence of altered assembly of the holoenzyme COX. However, total myocardial ATP was not significantly different in wild-type and mutant mice. Myocardial performance was examined using the isolated working heart preparation. As left atrial filling pressure increased, hearts from mutant mice were unable to generate equivalent stroke work compared with hearts from wild-type mice. Direct measurement of left ventricular end-diastolic volume using magnetic resonance imaging revealed that cardiac dysfunction was a consequence of impaired ventricular filling or diastolic dysfunction. These findings suggest that a genetic deficiency of COXVIaH has a measurable impact on myocardial diastolic performance despite the presence of normal cellular ATP levels.

scholarly journals Smaller organ mass with greater age, except for heart

2009 ◽  
Vol 106 (6) ◽  
pp. 1780-1784 ◽  
Author(s):  
Qing He ◽  
Stanley Heshka ◽  
Jeanine Albu ◽  
Lawrence Boxt ◽  
Norman Krasnow ◽  
...  
Keyword(s):  
African Americans ◽  
The Elderly ◽  
Left Ventricular ◽  
Fat Free Mass ◽  
Whole Body ◽  
Organ Mass ◽  
Total Body ◽  
Age Range ◽  
Negative Relationships

Autopsy/cadaver data indicate that many organs and tissues are smaller in the elderly compared with young adults; however, in vivo data are lacking. The aim of this study was to determine whether the mass of specific high-metabolic-rate organs is different with increasing age, using MRI. Seventy-five healthy women (41 African-Americans and 34 Caucasians, age range 19–88 yr) and 36 men (8 African-Americans and 28 Caucasians, age range 19–84 yr) were studied. MRI-derived in vivo measures of brain, heart, kidneys, liver, and spleen were acquired. Left ventricular mass (LVM) was measured by either echocardiography or cardiac gated MRI. Total body fat mass and fat-free mass (FFM) were measured with a whole body dual-energy X-ray absorptiometry (DXA) scanner. Multiple regression analysis was used to investigate the association between the organ mass and age after adjustment for weight and height (or DXA measures of FFM), race, sex, and interactions among these variable. No statistically significant interaction was found among age, sex, and race in any regression model. Significant negative relationships between organ mass and age were found for brain ( P < 0.0001), kidneys ( P = 0.01), liver ( P = 0.001), and spleen ( P < 0.0001). A positive relationship between LVM and age was found after adjustment for FFM ( P = 0.037). These findings demonstrate that age has a significant effect on brain, kidneys, liver, spleen, and heart mass. The age effect was independent of race and sex.

Short-term exercise improves myocardial tolerance to in vivo ischemia-reperfusion in the rat

2001 ◽  
Vol 91 (5) ◽  
pp. 2205-2212 ◽  
Author(s):  
Haydar A. Demirel ◽  
Scott K. Powers ◽  
Murat A. Zergeroglu ◽  
R. Andrew Shanely ◽  
Karyn Hamilton ◽  
...  
Keyword(s):  
Heat Stress ◽  
Maximum Rate ◽  
Treadmill Exercise ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Antioxidant Defenses ◽  
Whole Body ◽  
Sprague Dawley ◽  
Short Term

These experiments examined the independent effects of short-term exercise and heat stress on myocardial responses during in vivo ischemia-reperfusion (I/R). Female Sprague-Dawley rats (4 mo old) were randomly assigned to one of four experimental groups: 1) control, 2) 3 consecutive days of treadmill exercise [60 min/day at 60–70% maximal O2 uptake (V˙o 2 max)], 3) 5 consecutive days of treadmill exercise (60 min/day at 60–70%V˙o 2 max), and 4) whole body heat stress (15 min at 42°C). Twenty-four hours after heat stress or exercise, animals were anesthetized and mechanically ventilated, and the chest was opened by thoracotomy. Coronary occlusion was maintained for 30-min followed by a 30-min period of reperfusion. Compared with control, both heat-stressed animals and exercised animals (3 and 5 days) maintained higher ( P < 0.05) left ventricular developed pressure (LVDP), maximum rate of left venticular pressure development (+dP/d t), and maximum rate of left ventricular pressure decline (−dP/d t) at all measurement periods during both ischemia and reperfusion. No differences existed between heat-stressed and exercise groups in LVDP, +dP/d t, and −dP/d t at any time during ischemia or reperfusion. Both heat stress and exercise resulted in an increase ( P < 0.05) in the relative levels of left ventricular heat shock protein 72 (HSP72). Furthermore, exercise (3 and 5 days) increased ( P < 0.05) myocardial glutathione levels and manganese superoxide dismutase activity. These data indicate that 3–5 consecutive days of exercise improves myocardial contractile performance during in vivo I/R and that this exercise-induced myocardial protection is associated with an increase in both myocardial HSP72 and cardiac antioxidant defenses.

scholarly journals Tirilazad mesylate (U-74006F) inhibits effects of endotoxin in dogs

1995 ◽  
Vol 268 (5) ◽  
pp. H1847-H1855 ◽  
Author(s):  
H. Zhang ◽  
H. Spapen ◽  
P. Manikis ◽  
P. Rogiers ◽  
G. Metz ◽  
...  
Keyword(s):  
Endotoxic Shock ◽  
Left Ventricular ◽  
Oxygen Extraction ◽  
Volume Index ◽  
Whole Body ◽  
Control Group ◽  
Stroke Work ◽  
Critical Oxygen ◽  
Group 3 ◽  
Group 2

The present study explored the effects of a potent antioxidant, the 21-aminosteroid U-74006F, on the systemic and regional hemodynamics and the oxygen extraction capabilities during endotoxic shock. Twenty-four anesthetized dogs were randomized into three groups. Group 1 (n = 8) served as control. Group 2 (n = 8) and group 3 (n = 8) received 2 mg/kg iv of Escherichia coli endotoxin, followed 30 min later by saline infusion. Group 3 was given U-74006F as an intravenous bolus of 80 micrograms/kg followed by an infusion of 10 micrograms.kg-1.min-1, and group 2 received an equivalent volume of vehicle. Tamponade was induced 30 min later to study the oxygen extraction capabilities of the animals. Compared with the endotoxin-alone group, the U-74006F-treated dogs maintained higher mean arterial pressure, cardiac index, stroke volume index, and left ventricular stroke work index and lower pulmonary vascular resistance. They also showed a higher fractional blood flow to mesenteric and renal beds. Endotoxin administration increased whole body critical oxygen delivery (DO2crit) from 7.7 +/- 2.4 to 12.0 +/- 1.9 ml.kg-1.min-1 (P < 0.05), but U-74006F decreased DO2crit to 7.8 +/- 2.0 ml.kg-1.min-1 (P < 0.05 vs. endotoxin alone). Endotoxin decreased critical oxygen extraction ratio (O2ERcrit) from 75.0 +/- 12.7 to 44.3 +/- 8.7% (P < 0.05), but U-74006F increased O2ERcrit to 64.1 +/- 11.2% (P < 0.05 vs. endotoxin alone). U-74006F also decreased endotoxin-induced elevation of mesenteric and renal DO2crit and markedly increased regional O2ERcrit. Systemic and regional blood lactate concentrations were lower in the U-74006F-treated animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Rat model of exercise-induced cardiac hypertrophy: hemodynamic characterization using left ventricular pressure-volume analysis

2013 ◽  
Vol 305 (1) ◽  
pp. H124-H134 ◽  
Author(s):  
Tamás Radovits ◽  
Attila Oláh ◽  
Árpád Lux ◽  
Balázs Tamás Németh ◽  
László Hidi ◽  
...  
Keyword(s):  
Exercise Training ◽  
Cardiac Hypertrophy ◽  
Rat Model ◽  
Left Ventricular ◽  
Heart Weight ◽  
Stroke Work ◽  
Functional Changes ◽  
Exercise Induced

Long-term exercise training is associated with characteristic structural and functional changes of the myocardium, termed athlete's heart. Several research groups investigated exercise training-induced left ventricular (LV) hypertrophy in animal models; however, only sporadic data exist about detailed hemodynamics. We aimed to provide functional characterization of exercise-induced cardiac hypertrophy in a rat model using the in vivo method of LV pressure-volume (P-V) analysis. After inducing LV hypertrophy by swim training, we assessed LV morphometry by echocardiography and performed LV P-V analysis using a pressure-conductance microcatheter to investigate in vivo cardiac function. Echocardiography showed LV hypertrophy (LV mass index: 2.41 ± 0.09 vs. 2.03 ± 0.08 g/kg, P < 0.01), which was confirmed by heart weight data and histomorphometry. Invasive hemodynamic measurements showed unaltered heart rate, arterial pressure, and LV end-diastolic volume along with decreased LV end-systolic volume, thus increased stroke volume and ejection fraction (73.7 ± 0.8 vs. 64.1 ± 1.5%, P < 0.01) in trained versus untrained control rats. The P-V loop-derived sensitive, load-independent contractility indexes, such as slope of end-systolic P-V relationship or preload recruitable stroke work (77.0 ± 6.8 vs. 54.3 ± 4.8 mmHg, P = 0.01) were found to be significantly increased. The observed improvement of ventriculoarterial coupling (0.37 ± 0.02 vs. 0.65 ± 0.08, P < 0.01), along with increased LV stroke work and mechanical efficiency, reflects improved mechanoenergetics of exercise-induced cardiac hypertrophy. Despite the significant hypertrophy, we observed unaltered LV stiffness (slope of end-diastolic P-V relationship: 0.043 ± 0.007 vs. 0.040 ± 0.006 mmHg/μl) and improved LV active relaxation (τ: 10.1 ± 0.6 vs. 11.9 ± 0.2 ms, P < 0.01). According to our knowledge, this is the first study that provides characterization of functional changes and hemodynamic relations in exercise-induced cardiac hypertrophy.

scholarly journals Activation of caspase-3 may not contribute to postresuscitation myocardial dysfunction

2009 ◽  
Vol 296 (4) ◽  
pp. H1164-H1174 ◽  
Author(s):  
Jeejabai Radhakrishnan ◽  
Iyad M. Ayoub ◽  
Raúl J. Gazmuri
Keyword(s):  
Cytochrome C ◽  
Dna Fragmentation ◽  
Rat Model ◽  
Caspase 3 ◽  
Myocardial Dysfunction ◽  
Left Ventricular ◽  
Stroke Work ◽  
Protective Effects ◽  
Apoptotic Pathway ◽  
Apoptosis Protein

We have previously reported that postresuscitation myocardial dysfunction is accompanied by the release of cytochrome c and caspase-3 activation. We now investigated the role of caspase-3 activation by examining whether such process prompts apoptotic DNA fragmentation, whether caspase-3 inhibition attenuates myocardial dysfunction, and whether myocardial protective effects of sodium-hydrogen exchanger isoform-1 (NHE-1) inhibition involve caspase-3 inhibition using a rat model of ventricular fibrillation (VF) of closed-chest resuscitation. Resuscitation after 4 or 8 min of untreated VF caused significant reductions in left ventricular stroke work index averaging 23% of sham control rats at 4 h postresuscitation. Left ventricular dysfunction was accompanied by increases in cytosolic cytochrome c, decreases in pro- and cleaved caspase-9 fragments, increases in 17-kDa caspase-3 fragments, and increases in caspase-3 activity indicating the activation of the mitochondrial apoptotic pathway but without evidence of apoptotic DNA fragmentation. In addition, levels of heat shock protein 70 were increased and levels of X-linked inhibitor of apoptosis protein and αβ-crystallin were preserved, all of which can exert antiapoptotic effects. In a separate series, the caspase-3 inhibitor z-Asp-Glu-Val-Asp chloromethyl ketone given before the induction of VF failed to prevent postresuscitation myocardial dysfunction despite reductions in caspase-3 activity (2.3 ± 0.5 vs. 1.3 ± 0.5 pmol fluorophore AFC released·mg protein−1·min−1; P < 0.03). Treatment with the NHE-1 inhibitor cariporide had no effect on caspase-3 activity. Accordingly, in this rat model of VF and severe postresuscitation myocardial dysfunction, activation of caspase-3 did not lead to DNA fragmentation or contribute to myocardial dysfunction. Concomitant activation of intrinsic antiapoptotic mechanisms could play a protective role downstream to caspase-3 activation.

Desflurane, Sevoflurane, and Isoflurane Affect Left Atrial Active and Passive Mechanical Properties and Impair Left Atrial–Left Ventricular Coupling In Vivo 

2001 ◽  
Vol 95 (3) ◽  
pp. 689-698 ◽  
Author(s):  
Meir Gare ◽  
David A. Schwabe ◽  
Douglas A. Hettrick ◽  
Judy R. Kersten ◽  
David C. Warltier ◽  
...  
Keyword(s):  
Left Atrial ◽  
Minimum Alveolar Concentration ◽  
Left Ventricular ◽  
Atrial Function ◽  
Left Atrial Function ◽  
Atrial Pressure ◽  
Left Atrial Pressure ◽  
Stroke Work ◽  
Ventricular Elastance

Background The effects of volatile anesthetics on left atrial function in vivo have not been described. The authors tested the hypothesis that desflurane, sevoflurane, and isoflurane alter left atrial mechanics evaluated with invasively derived pressure-volume relations. Methods Barbiturate-anesthetized dogs (n = 24) were instrumented for measurement of aortic, left atrial, and left ventricular pressures (micromanometers) and left atrial volume (orthogonal sonomicrometers). Left atrial contractility and chamber stiffness were assessed with end-systolic and end-reservoir pressure-volume relations, respectively, obtained from differentially loaded diagrams. Relaxation was determined from the slope of left atrial pressure decline after contraction. Stroke work and reservoir function were assessed by A and V loop areas, respectively. Left atrial-left ventricular coupling was determined by the ratio of left atrial contractility and left ventricular elastance. Dogs received 0.6, 0.9, and 1.2 minimum alveolar concentration desflurane, sevoflurane, or isoflurane in a random manner, and left atrial function was determined after 20-min equilibration at each dose. Results Desflurane, sevoflurane, and isoflurane decreased heart rate, mean arterial pressure, and maximal rate of increase of left ventricular pressure and increased left atrial end-diastolic, end-systolic, and maximum volumes. All three anesthetics caused dose-related reductions in left atrial contractility, relaxation, chamber stiffness, and stroke work. Administration of 0.6 and 0.9 minimum alveolar concentration desflurane, sevoflurane, and isoflurane increased V loop area. All three anesthetics decreased the ratio of stroke work to total left atrial pressure-volume diagram area, increased the ratio of conduit to reservoir volume, and reduced left atrial contractility-left ventricular elastance to equivalent degrees. Conclusions The results indicate that desflurane, sevoflurane, and isoflurane depress left atrial contractility, delay relaxation, reduce chamber stiffness, preserve reservoir and conduit function, and impair left atrial-left ventricular coupling in vivo.

In vivo murine left ventricular pressure-volume relations by miniaturized conductance micromanometry

1998 ◽  
Vol 274 (4) ◽  
pp. H1416-H1422 ◽  
Author(s):  
Dimitrios Georgakopoulos ◽  
Wayne A. Mitzner ◽  
Chen-Huan Chen ◽  
Barry J. Byrne ◽  
Huntly D. Millar ◽  
...  
Keyword(s):  
Left Ventricular Pressure ◽  
Left Ventricular ◽  
Genetically Engineered ◽  
Ventricular Pressure ◽  
Stroke Work ◽  
Time Varying ◽  
End Diastolic Volume ◽  
Novel Approach ◽  
Preload Reduction

The mouse is the species of choice for creating genetically engineered models of human disease. To study detailed systolic and diastolic left ventricular (LV) chamber mechanics in mice in vivo, we developed a miniaturized conductance-manometer system. α-Chloralose-urethan-anesthetized animals were instrumented with a two-electrode pressure-volume catheter advanced via the LV apex to the aortic root. Custom electronics provided time-varying conductances related to cavity volume. Baseline hemodynamics were similar to values in conscious animals: 634 ± 14 beats/min, 112 ± 4 mmHg, 5.3 ± 0.8 mmHg, and 11,777 ± 732 mmHg/s for heart rate, end-systolic and end-diastolic pressures, and maximum first derivative of ventricular pressure with respect to time (dP/d t max), respectively. Catheter stroke volume during preload reduction by inferior vena caval occlusion correlated with that by ultrasound aortic flow probe ( r 2 = 0.98). This maneuver yielded end-systolic elastances of 79 ± 21 mmHg/μl, preload-recruitable stroke work of 82 ± 5.6 mmHg, and slope of dP/d t max-end-diastolic volume relation of 699 ± 100 mmHg ⋅ s−1 ⋅ μl−1, and these relations varied predictably with acute inotropic interventions. The control normalized time-varying elastance curve was similar to human data, further supporting comparable chamber mechanics between species. This novel approach should greatly help assess cardiovascular function in the blood-perfused murine heart.

A load-independent in vivo model for evaluating therapeutic interventions in injured myocardium

1998 ◽  
Vol 275 (5) ◽  
pp. H1834-H1844 ◽  
Author(s):  
Cleveland W. Lewis ◽  
B. Zane Atkins ◽  
Kelley A. Hutcheson ◽  
Christian T. Gillen ◽  
Mary C. Reedy ◽  
...  
Keyword(s):  
Left Ventricular ◽  
Therapeutic Interventions ◽  
Segment Length ◽  
In Vivo Model ◽  
Myocardial Segment ◽  
Stroke Work ◽  
Injured Myocardium ◽  
Rabbit Myocardium ◽  
Models Of Injury

Although cardiomyocyte damage is normally irreversible, gene therapy and somatic cell transfer offer potential for improving function in damaged regions of the heart. However, in ischemic models of injury, variability in depth, size, and location of damage compromises statistical evaluation of in vivo function. We have adapted cryoablation to create a reproducible, posterior, transmural lesion within rabbit myocardium in which small changes in function are measurable in vivo. Before and at 2 and 6 wk postinjury, in vivo left ventricular intracavitary pressure and myocardial segment length were measured. Regional indexes of performance, segmental stroke work (SW), and percent systolic shortening (SS) were significantly decreased ( P < 0.001) postcryoinjury as was the slope ( M w) of the linear preload recruitable SW relationship between SW and end-diastolic segment length ( P = 0.0001). Decreased SW, SS, and M w correlated with wall thinning, loss of myocytes, presence of fibroblasts, and transmural scar formation. Reproducible changes in regional myocardial performance in vivo postcryoinjury suggest that this is a reasonable model for evaluating novel therapies for cardiovascular disease.

Cardiac performance in semi-isolated heart of the crab Carcinus maenas

1994 ◽  
Vol 266 (3) ◽  
pp. R781-R789
Author(s):  
J. L. Wilkens ◽  
B. R. McMahon
Keyword(s):  
Heart Rate ◽  
Cardiac Output ◽  
Isolated Heart ◽  
Carcinus Maenas ◽  
Ventricular Volume ◽  
Whole Body ◽  
Shore Crab ◽  
Stroke Work ◽  
Adaptive Responses

A semi-isolated, in situ heart preparation of the shore crab, Carcinus maenas, supported by its alary ligaments, pumps vigorously for hours at a mean heart rate of 49.7 beats/min and cardiac output of 30 ml.kg-1.min-1. These hearts show no adaptive responses to changes in pericardial sinus pressure, outflow resistance, or afterload. Direct perfusion-induced stretch of the heart wall causes increases in contractile force but minimal changes in heart rate. Stroke work and power are lower than comparable values for animals with myogenic hearts and closed circulatory systems. The values for heart rate and cardiac output are lower than in vivo values and may in part reflect the technique used as well as intrinsic performance of the heart without neural and neurohormonal inputs. Morphometrically the heart represents 0.2% of whole body weight, and the mean stroke volume of 0.35-0.45 ml/kg represents an ejection fraction of 27-34% of ventricular volume (1.4 ml/kg).

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