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PubMed2000

[Chronic ischemic left ventricular dysfunction: myocardial hibernation?].

Hibernating myocardium is a term which covers chronic ischaemic left ventricular dysfunction which is potentially reversible after revascularisation. Hibernating myocardium is classically associated with chronic hypoperfusion responsible for hypocontraction and cellular degeneration. This "classical" conception has been questioned as some workers emphasise that the reduction in coronary reserve responsible for repeated episodes of ischaemia and stunning could be the main causes of myocardial dysfunction. Position emission tomography (PET), and, most of all, myocardial scintigraphy and dobutamine echocardiography are the most commonly used techniques for detecting hibernating myocardium. Their sensitivity is good but the specificity and positive predictive value of dobutamine echocardiography seems to be better than the isotopic techniques. Structural abnormalities of hibernating myocardium and the delay, which is often long, between revascularisation and improvement, may explain some of the discordances between these techniques. Irrespective of the term used, hibernation or chronic ischaemic left ventricular dysfunction with myocardial viability, the reported data is in favour of coronary revascularisation with improved long-term quality of life and reduced mortality in patients with positive viability tests.

Cardiotonic Agents↗
PubMedDate not supplied

Hibernating myocardium: is there evidence for chronic flow reduction?

Myocardial hibernation is defined as a state of chronically reduced contractility in response to a reduction in blood supply and the ability to recover function after revascularization. There is controversy about the chronicity of a reduction in myocardial perfusion for induction of the adaptive mechanisms of hibernation. A search was conducted of the clinical literature for evidence showing that myocardial perfusion is chronically reduced in hibernating myocardium. Ninety-three clinical studies in patients with dysfunctional but viable myocardium (hibernating myocardium) and revascularization were reviewed. Contractile function, as assessed by ventriculography, radionuclide ventriculography, or echocardiography, was measured before revascularization in 91 studies (97.8%). Viability was assessed before revascularization using nuclear imaging--particularly 18-fluorodeoxyglucose positron emission tomography (PET) or (201)thallium-201 single-photon emission tomography (SPECT)--or pharmacologic stress echocardiography in 66 studies (71%). Myocardial perfusion measurements using (99m)Tc sestamibi SPECT, (13)N-ammonia, or (15-)O-water in PET, were obtained before revascularization in 68 studies (73.1%). There were no studies that measured myocardial perfusion more than once before revascularization. After revascularization, contractile function was assessed in 85 studies (91.4%), viability in 19 studies (20.4%), and myocardial perfusion in 28 studies (30.1%). Multiple measurements of perfusion, viability, and contractile function were performed after revascularization in two (2.2%), two (2.2 %), and ten (10.8%) studies, respectively. There was a lack of evidence in the clinical literature for chronic reduction in myocardial perfusion in patients with hibernating myocardium, because multiple measurements of perfusion have not been systematically performed at different time points with respect to revascularization.

Coronary Circulation↗
PubMed2002

Myocardial hibernation.

Patients with chronic coronary artery disease frequently have contractile dysfunction that recovers upon reperfusion. The concept of myocardial hibernation views the observed reduction in contractile function not as the result of an ongoing energetic deficit, but as an adaptive down-regulation that serves to maintain myocardial integrity and viability. In the experiment, perfusion-contraction matching during the initial hours of ischemia, recovery of energy and substrate metabolism during ongoing ischemia, the potential for recruitment of inotropic reserve, lack of necrosis, and therefore recovery of function upon reperfusion are established features of hibernation. Apart from reduced calcium responsiveness, the underlying mechanisms are still unclear. In patients, the importance of reduced baseline blood flow vs that of superimposed repetitive stunning is somewhat controversial; however, in most studies blood flow is reduced, and the myocardium must be ischemic often enough to have persistent dysfunction. Morphologically, hibernating myocardium displays features of dedifferentiation, with loss of cardiomyocytes and myofibrils, and of degeneration, with increased interstitial fibrosis. Patients with hibernating myocardium must be identified and undergo revascularization. With a better understanding of the underlying mechanisms of hibernation, these adaptive responses to ischemia can potentially be recruited and reinforced pharmacologically to delay impending myocardial infarction.

Coronary Vessels↗
PubMed2000

[The digestive apparatus during hibernation: morphological and functional changes].

During hibernation feeding is suspended and the digestive apparatus is in a condition of functional rest. This paper is a review of data published in the period from 1966 to 1999 on the structure/function relationship in the digestive apparatus of hibernating animals. The available information is partial, due to differences in methodology and species used; however, it is apparent from the data that the digestive apparatus undergoes an important rearrangement during hibernation, inclusive of mass loss and reduced/arrested mitotic activity, in the presence of a generally preserved morphology of the organs. All changes are reversible upon arousal. Recent findings show that, during hibernation, protein expression may be enhanced in the intestine as well as transport activities in the mucosa. Therefore, the hibernation condition is finely regulated, representing a potentially useful model for studies aimed at improving organ preservation procedures (e.g. for transplantation).

English Abstract↗
PubMed1993

Hibernating and stunned myocardium.

The term "hibernating" myocardium has been introduced to indicate the presence of regional asynergy due to persistent hypoperfusion, which can be reversed after revascularization. The mechanisms underlying the prolonged functional adaptation of myocardial cells to hypoperfusion are still not clear, although preliminary experimental data indicate that a reduced availability of intracellular Ca++ may play an important role. The identification of hibernating myocardium may have therapeutic implications, since it has been demonstrated that the revascularization of hibernating myocardial territories may lead to regional and global improvement of systolic left ventricular function. The noninvasive identification of hibernating myocardium can be accomplished by positron emission tomography, which demonstrates the presence of preserved metabolic activity in hibernating myocardial territories. However, exercise 201thallium scintigraphy, using the reinjection technique, with a quantitative regional analysis of 201thallium uptake, has also been reported to provide information comparable to that obtained by positron emission tomography. "Stunning" of the myocardium indicates a condition of transient impaired regional systolic function, following an episode of ischemia. The mechanisms determining the slow recovery of function after ischemia are still not completely understood. Experimental data suggest in this case a reduced Ca++ affinity of the myofibrils and a reduced maximal calcium-activated force.

Animals↗
PubMed1985

Activation of osteoclasts and the repopulation of bone surfaces following hibernation in the bat, Myotis lucifugus.

In previous studies of the adult bat, Myotis lucifugus, bone loss that occurred during the hibernating period was attributed to osteocytic osteolysis, rather than osteoclastic activity. We have used histochemistry and light and electron microscopy to determine the functional state of the skeleton during the hibernating period. We find that during hibernation the marrow cavity of the long bones is filled with lipid deposits interspersed with vascular sinusoids containing mononuclear cells and red blood cells. The lipid deposits are found within fat cells and at extracellular sites. Hematopoietic cells are absent, osteoclasts are absent, and the bone surfaces are covered with quiescent bone-lining cells. Osteocytes retain their structural integrity and maintain canalicular systems with the bone lining cells and with other osteocytes. During the arousal period, osteoclasts reappear on the bone surface, followed in time by increased numbers of osteoblast-like cells. Perivascular cells undergo structural hypertrophy. Many mononuclear cells are now found in extravascular sites. The lipid content in the marrow is gradually reduced and replaced by hematopoietic cells. Each of these events occurs in a repeatable sequence that is related to the state of hibernation of Myotis lucifugus.

Animals↗
PubMed1986

Pineal melatonin: circadian rhythm and variations during the hibernation cycle in the ground squirrel, Spermophilus lateralis.

Variations in pineal melatonin content throughout a 24-hour period and during different phases of the hibernation bout cycle were studied in the golden-mantled ground squirrel (Spermophilus lateralis). In addition to pineal melatonin, the circadian variation in the activities of pineal N-acetyltransferase (NAT) and hydroxyindole-O-methyltransferase (HIOMT) were also investigated in summer animals maintained at 22 +/- 2 degrees C, on a light:dark (L:D) schedule of 12:12 hr for 1 month (lights on at 08.00 hr). Pineal glands were collected from six animals in each group at 1200, 1600, 2000, 2400, 0200, 0400, and 0800 hr. Changes in pineal melatonin content during the hibernation bout cycle were investigated in ground squirrels housed at 4 +/- .05 degrees C in relative darkness (1.9-3.4 lux; 10:14 LD). Pineal glands were obtained between 12:00 and 18:00 hr from 30 animals during one of three phases of the cycle (deep hibernation, euthermic interbout, and entrance into hibernation). Pineal melatonin was also measured for comparison in six winter euthermic animals that were housed at 22 +/- 2 degrees C, on a L:D schedule of 10:14 hr. Melatonin was measured in individual pineal glands by radioimmunoassay. The daily melatonin rhythm in S. lateralis was characterized by a marked increase in pineal melatonin during the dark phase, in which peak nighttime values were nearly 20-fold greater than daytime basal levels. The daily rhythm for NAT activity paralleled the changes in melatonin, showing a peak activity at 0200 hr that was 45 times greater than mean daytime values.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylserotonin O-Methyltransferase↗
PubMed1990

Endocrine correlates of hibernation-independent gonadal recrudescence and the limited late-winter breeding season in woodchucks, Marmota monax.

Woodchucks (Marmota monax) normally experience gonadal recrudescence towards the end of a 4-5 month hibernation, emerge in late winter, immediately breed in a short 3-week breeding season, and have regressed gonads before the next hibernation. Our studies of wild and captive animals show that fertile females give birth to single litters after a 32-day gestation and their breeding season is terminated by a reactivation of the corpora lutea of pregnancy for 1-3 months immediately postpartum. In nonbred females the breeding season is likewise terminated by spontaneous luteinization of the ovaries for 1-3 months shortly after the vernal equinox. Tests regress and testosterone declines during and after the breeding season. Circannual reproductive cycles persist in the absence of hibernation and are shortened to 9-10 months after 3-5 years of a 12L:12D photoperiod. Unique aspects of this species that merit endocrine investigation include descent/retraction of testes, transient luteolysis at parturition, superactivation of postpartum corpora lutea, regulation of the pituitary-gonadal axis by an annual endogenous metabolic cycle entrained to the annual change in photoperiod, and the hormonal basis of hibernation.

Animal Husbandry↗
PubMed2000

Enzymes of adenylate metabolism and their role in hibernation of the white-tailed prairie dog, Cynomys leucurus.

AMP deaminase (AMPD) and adenylate kinase (AK) were purified from skeletal muscle of the white-tailed prairie dog, Cynomus leucurus, and enzyme properties were assayed at temperatures characteristic of euthermia (37 degrees C) and hibernation (5 degrees C) to analyze their role in adenylate metabolism during hibernation. Total adenylates decreased in muscle of torpid individuals from 6.97 +/- 0. 31 to 4.66 +/- 0.58 micromol/g of wet weight due to a significant drop in ATP but ADP, AMP, IMP, and energy charge were unchanged. The affinity of prairie dog AMPD for AMP was not affected by temperature and did not differ from that of rabbit muscle AMPD, used for comparison. However, both prairie dog and rabbit AMPD showed much stronger inhibition by ions and GTP at 5 degrees C, versus 37 degrees C, and inhibition by inorganic phosphate, NH(4)Cl, and (NH(4))(2)SO(4) was much stronger at 5 degrees C for the prairie dog enzyme. Furthermore, ATP and ADP, which activated AMPD at 37 degrees C, were strong inhibitors of prairie dog AMPD at 5 degrees C, with I(50) values of 1 and 14 microM, respectively. ATP also inhibited rabbit AMPD at 5 degrees C (I(50) = 103 microM). Strong inhibition of AMPD at 5 degrees C by several effectors suggests that enzyme function is specifically suppressed in muscle of hibernating animals. By contrast, AK showed properties that would maintain or even enhance its function at low temperature. K(m) values for substrates (ATP, ADP, AMP) decreased with decreasing temperature, the change in K(m) ATP paralleling the decrease in muscle ATP concentration. AK inhibition by ions was also reduced at 5 degrees C. The data suggest that adenylate degradation via AMPD is blocked during hibernation but that AK maintains its function in stabilizing energy charge.

AMP Deaminase↗
PubMed2001

Fine structural modifications of liver, pancreas and brown adipose tissue mitochondria from hibernating, arousing and euthermic dormice.

An ultrastructural and morphometric study was performed on mitochondria of euthermic, hibernating and arousing hazel dormice (Muscardinus avellanarius), in order to investigate possible modifications during the seasonal cycle. Hepatocytes, pancreatic acinar cells and brown adipocytes were considered. Our results demonstrated that: (1) the general morphology of mitochondria of all cell types shows slight modifications during the seasonal cycle; (2) mitochondrial size and inner membrane length significantly increase from euthermia to hibernation and decrease upon arousal in all cell types; (3) mitochondrial matrix granules drastically increase in number during hibernation and decrease upon arousal in hepatocytes and pancreatic acinar cells, whereas they do not change in brown adipocytes. These structural modifications are probably related to the changes in cellular energy needs during the euthermia-hibernation-arousal cycle.

Adipose Tissue, Brown↗
PubMed1995

Modulation of synaptic transmission at low temperatures by hibernation-related changes in ionic microenvironment in hippocampal slices of golden hamsters.

In hamsters, the entrance into hibernation is associated with a respiratory acidosis and elevation of the blood plasma concentrations of potassium, calcium, and magnesium. To investigate the effects of presumed hibernation-related ionic changes in the brain interstitium on neuronal function, the transmission properties of hippocampal slices prepared from golden hamsters were studied at low temperatures in vitro. Slices were investigated at 15-20 degrees C in artificial cerebrospinal fluid (ACSF) of variable composition (K+, 3-5 mM; Ca2+, 2-4 mM; Mg2+, 2-4 mM; pH 7.0-7.7). Population action potentials (population spikes, PS) of CA1 pyramidal cells were continuously evoked with 100-microseconds stimulus pulses delivered to the Schaffer collaterals/commissural fibers in intervals of 30 s. The PS amplitude was measured as a function of extracellular ion concentrations at given temperatures or as a function of temperature at a given ACSF composition. Elevation of [K+]o, [Mg2+]o, or [H+]o all reduced the PS amplitude at low temperatures, whereas elevation of [Ca2+]o increased the PS amplitude. In conclusion, changes in the ionic microenvironment occurring during entrance into hibernation presumably result in depression of synaptic transmission at low temperatures in the hamster hippocampus. The modulatory effect of ionic changes may be an important factor supporting a general depression of the brain during entrance into hibernation.

Animals↗
PubMed1998

Hibernation induces expression of moesin in intestinal epithelial cells.

Identification of proteins that are differentially expressed in mammals that hibernate can provide insight into mechanisms that preserve cellular function at low temperatures. A candidate protein was identified in intestinal brush border membranes of 13-lined ground squirrels. Intestinal brush border membrane proteins were separated using SDS-PAGE and gels were stained with Coomassie blue. We observed a approximately 75-kDa band that was specifically increased in brush border membranes isolated from torpid squirrels compared with summer active squirrels. The 75-kDa band was cut from one-dimensional gels and sequenced. A 17 amino acid sequence was identified of which amino acids 2-17 matched exactly a portion of moesin, a membrane-cytoskeletal linking protein and member of the ERM (ezrin/radixin/moesin) family. The sequence results were confirmed using anti-moesin antibodies that detected strong bands at approximately 75 kDa on Western blots of brush border membranes in torpid squirrels (Tb approximately 7 degreesC) and only faint signals in summer squirrels (Tb approximately 37 degrees C) or aroused hibernators (Tb approximately 37 degrees C). In contrast, signals obtained using anti-ezrin antibodies were uniformly strong in all squirrels, regardless of activity state. Intestinal brush borders of mice and rats expressed ezrin but not moesin. These results provide evidence for the physiological induction of an ERM protein in intestinal epithelial cells of torpid hibernators and support the idea that hibernation involves differential expression of gene products that may facilitate viability of cells at low temperatures.

Animals↗
PubMed1998

Thyroid hormone concentrations in black bears (Ursus americanus): hibernation and pregnancy effects.

Previous studies on thyroid hormones in hibernating bears have used very few sampling periods, so that the time course of any change is poorly understood. In this study, plasma sampled from pregnant and nonpregnant black bears before and during hibernation (16 samples each at 10-day intervals) was assayed by radioimmunoassay for concentrations of thyroxine (T4) and triiodothyronine (T3). Only free T4 showed a difference (P = 0.019) between females that produced cubs and those that did not, but this appeared to be due to higher preimplantation values. Free T3, total T3, and free T4 varied (P = 0.001, 0.038, 0.002, respectively) among sampling periods: during December, bears had depressed concentrations. These lowered concentrations were maintained during hibernation for the free hormones. Our data confirm previous work showing that food restriction and/or physiological preparation for hibernation is coincident with depressed plasma concentrations of thyroid hormones. Hormonal changes associated with pregnancy were minor.

Analysis of Variance↗
PubMed1994

Search for rhythmicity during hibernation in the European hamster.

Temporal patterns of hibernation were studied by continuous monitoring of body temperature by radiotelemetry over 6 months in European hamsters, Cricetus cricetus, at constant temperature and photoperiod. Entrances into hibernation occurred mostly at the end of the night (0000-0800 hours), while arousals were randomly distributed between day and night. This is at variance with a control of bout duration by a clock with a period of 24 h. Consequently, the timing of entrances implies a phase-resetting of the circadian clock on each arousal. Persistence of circadian rhythmicity with a period different from 24 h during deep hibernation was investigated examining whether the durations of torpor bouts were integer multiples of a constant period. A non-parametric version of the classical contingency test of periodicity was developed for this purpose. Periods ranging from 21 to 29 h were tested. Nine animals out of ten showed at least one significant period in this range (P < 0.01), either below 24 h (21.8 +/- 0.5 h, n = 4) or above (27.3 +/- 0.5 h, n = 7). However, we have found a theoretical model of bout durations for which the contingency test of periodicity sometimes gives false significant results. This indicates that the power of the test is weak. With this reservation our results suggest that a circadian oscillator controls the duration of a bout of hibernation, which would occur after an integer, but variable and possibly temperature-dependent number of cycles.

Animals↗
PubMed1988

Photoperiodic regulation of body mass, food intake, hibernation, and reproduction in intact and castrated male European hamsters, Cricetus cricetus.

A group of sexually active male European hamsters were raised either in short-photoperiod conditions (SP; LD 8:16) or in long-photoperiod conditions (LP; LD 16:8) from their capture at the end of the hibernation period. Another group of hamsters was castrated in April and gonadectomized animals were maintained in SP and cold (7 degrees C) or in a succession of SP and LP plus cold. Another group, castrated in May or in September and raised in LP conditions, was transferred in September to SP conditions and cold. 1. Normal hamsters raised in continuous SP or LP apparently did not show signs of rhythmic behavior, except possibly in gonadal activity. 2. Body weight increased continuously, plasma testosterone levels oscillated between 1.5 and 2.5 ng/ml, and animals raised in SP and in cold did not enter hibernation. 3. Similar results were also found in castrated animals kept in SP conditions and cold. 4. The sequence LP-SP induced a decrease in food intake and body weight and a decrease in plasma testosterone levels and triggered entry into hibernation in both intact and castrated animals. 5. After 6 months continuously in SP and with exposure to cold spontaneous recrudescence in food intake and body weight occurred and hibernation ended in both intact and castrated animals. 6. In normal animals a spontaneous increase in plasma testosterone levels was observed. 7. In both normal and gonadectomized animals the phase of refractoriness could be broken by exposure to LP conditions. 8. The critical photoperiod lies between 15 and 15.5 h. These results demonstrate that the European hamster is a photoperiodic species.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Time-course of blood acid-base state during arousal from hibernation in the European hamster.

1. Arterial blood was sampled at 15 min-intervals in European hamsters Cricetus cricetus fitted with indwelling catheters, from deep hibernation to full arousal. Temperature-corrected pH and PCO2, respectively pH* and P*CO2, were directly measured at 37 degrees C. 2. Deep hibernation corresponded to a respiratory acidosis: pH* = 7.01 +/- 0.01 (mean +/- SE), P*CO2 = 160 +/- 4 Torr (n = 9 animals). 3. Three periods could be distinguished in the arousal: (i) a period of hyperventilation (28 +/- 5 min), in which P*CO2 was reduced to 79 +/- 4 Torr, while cheek pouch temperature increased only by 0.9 +/- 0.2 degrees C; (ii) a period of metabolic acidification by lactate accumulation (84 +/- 6 min), corresponding to the period of peak thermogenesis; (iii) a progressive return to euthermic conditions (104 +/- 10 min), by simultaneous respiratory and metabolic alkalinization. 4. Over 60% of the blood CO2 stores accumulated at the beginning of the hibernation bout were released by hyperventilation during the first period, prior to the full development of thermogenesis. This is in agreement with the hypothesis of an inhibitory role of the respiratory acidosis in hibernation.

Acid-Base Equilibrium↗
PubMed1985

Intracellular pH in hibernation and respiratory acidosis in the European hamster.

Intracellular pH was determined (DMO method) in European hamsters, in the spontaneously-occurring respiratory acidosis of hibernation, in hypercapnia due to breathing 12% CO2 in air in euthermy in spring, and in euthermicnormocapnic controls. From euthermy to hibernation, the temperature coefficient of pH was lowest in blood plasma and brain, intermediate in striated muscles (thigh muscles and diaphragm), and highest in heart and liver (Fig. 1). Correspondingly, the estimated dissociation ratio of the protein imidazole buffer groups, alpha Im, decreased markedly in plasma and brain, denoting an acid titration, but varied little in liver and heart. Striated muscles were intermediate (Fig. 2). Like in other mammals, intracellular responses to short-term euthermic respiratory acidosis were characterized by a partial metabolic compensation in the brain and a small metabolic acidification in striated muscles. In hibernation, a powerful metabolic compensation took place in liver and heart, nearly restoring alpha Im, but none occurred in brain (Figs. 3 to 5). The existence of an intracellular acidosis in brain and striated muscles during hibernation is in keeping with an inhibitory role of acidosis, whereas the homeostasis of intracellular alpha Im in liver and heart would subserve the eurythermal functioning of metabolic regulations in these organs, like in most organs of ectotherms.

Acidosis, Respiratory↗
PubMed1996

Dense granular bodies: a novel nucleoplasmic structure in hibernating dormice.

Dense granular bodies (DGB) are particular structural constituents observed in cell nuclei of different tissues-liver, pancreas, brown adipose tissue, adrenal cortex-of hibernating dormice. They appear as strongly electron-dense clusters of closely packed granules, with thin fibrils spreading out at their periphery. DGB always occur in the nucleoplasm, sometimes making contact with other nuclear structural constituents typical of the hibernating state, such as coiled bodies, amorphous bodies and nucleoplasmic fibrils. DGB are present only during deep hibernation and rapidly disappear upon arousal from hibernation. Cytochemical and immunocytochemical analyses showed that DGB contain ribonucleoproteins and several nucleoplasmic RNA processing factors, suggesting that DGB can represent accumulation sites of splicing factors which are provided to splicing sites when normal metabolic activity is rapidly restored during arousal.

Adrenal Glands↗