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PubMed2002

Rate dependence of [Na+]i and contractility in nonfailing and failing human myocardium.

BACKGROUND: In the failing human heart, altered Ca2+ homeostasis causes contractile dysfunction. Because Ca2+ and Na+ homeostasis are intimately linked through the Na+/Ca2+ exchanger, we compared the regulation of [Na+]i in nonfailing (NF) and failing human myocardium. METHODS AND RESULTS: [Na+]i was measured in SBFI-loaded muscle strips. At slow pacing rates (0.25 Hz, 37 degrees C), isometric force was similar in NF (n=6) and failing (n=12) myocardium (6.4+/-1.2 versus 7.2+/-1.9 mN/mm2), but [Na+]i and diastolic force were greater in failing (22.1+/-2.6 mmol/L and 15.6+/-3.2 mN/mm2) than in NF (15.9+/-3.1 mmol/L and 3.50+/-0.55 mN/mm2; P<0.05) myocardium. In NF hearts, increasing stimulation rates resulted in a parallel increase in force and [Na+]i without changes in diastolic tension. At 2.0 Hz, force increased to 136+/-17% of the basal value (P<0.05), and [Na+]i to 20.5+/-4.2 mmol/L (P<0.05). In contrast, in failing myocardium, force declined to 45+/-3%, whereas [Na+]i increased to 27.4+/-3.2 mmol/L (both P<0.05), in association with significant elevations in diastolic tension. [Na+]i was higher in failing than in NF myocardium at every stimulation rate. [Na+]i predicted in myocytes from Na+ (pipette)-contraction relations was 8.0 mmol/L in NF (n=9) and 12.1 mmol/L in failing (n=57; P<0.05) myocardium at 0.25 Hz. Reverse-mode Na+/Ca2+ exchange induced significant Ca2+ influx in failing but not NF myocytes, compatible with higher [Na+]i in failing myocytes. CONCLUSIONS: Na+i homeostasis is altered in failing human myocardium. At slow heart rates, the higher [Na+]i in failing myocardium appears to enhance Ca2+ influx through Na+/Ca2+ exchange and maintain sarcoplasmic reticulum Ca(2+) load and force development. At faster rates, failing myocytes with high [Na+]i cannot further increase sarcoplasmic reticulum Ca2+ load and are prone to diastolic Ca2+ overload.

Benzofurans↗
PubMed1993

Reduced content of connexin43 gap junctions in ventricular myocardium from hypertrophied and ischemic human hearts.

BACKGROUND: Gap junctions are a determinant of myocardial conduction. Disturbances of gap-junctional content may account for abnormalities of impulse propagation, contributing to the arrhythmic tendency and mechanical inefficiency of ischemic and hypertrophied myocardium. The aim of this study was to characterize gap junction organization in normal human ventricular myocardium and to establish whether abnormalities exist in myocardium of chronically ischemic and hypertrophied hearts. METHODS AND RESULTS: Cardiac gap-junctional connexin43 antibodies and confocal microscopy were used in a quantitative immunohistochemical study of surgical myocardial samples to explore the structural basis of electromechanical ventricular dysfunction in chronic ischemic and hypertrophic heart diseases. Normal adult human left ventricular myocardium had a gap-junctional surface area of 0.0051 micron2/micron3 myocyte volume; gap junctions were confined to intercalated disks, of which there was a mean of 11.6 per cell. The right ventricle showed similar gap junction surface area. Left ventricular myocardium from ischemic hearts (distant from any fibrotic scarring), despite normal numbers of intercalated disks per cell, had a reduced gap junction surface area (0.0027 micron2/micron3; P = .02), as did hypertrophied myocardium (0.0031 micron2/micron3; P = .05). The cardiac myocytes in the pathological tissues were larger than normal, and estimated gap-junctional content per cell was reduced in ischemic ventricle (P = .02) compared with normal. CONCLUSIONS: Gap junctions in normal adult human working ventricular myocardium occupy an area of 0.0051 micron2/micron3 myocyte volume. This surface area is reduced in ventricular myocardium from hearts subject to chronic hypertrophy and ischemia, despite a normal number of intercellular abutments, and this alteration may contribute to abnormal impulse propagation in these hearts.

Adult↗
PubMed1995

31P nuclear magnetic resonance spectroscopic imaging of regions of remodeled myocardium in the infarcted rat heart.

BACKGROUND: The clinical course of a patient with a myocardial infarction (MI) depends largely on the ability of the noninfarcted region to remodel and compensate for the loss of the infarcted region. Previous studies have shown that the remaining viable myocardium remodels morphologically, functionally, and biochemically. The purpose of this study was to define the regional distribution of the biochemical remodeling that occurs after MI in rat hearts by use of a technique that could be applied noninvasively to human subjects. METHODS AND RESULTS: Infarcts of the left ventricular apex and anterolateral wall were induced by occluding a coronary artery. Eight to 10 weeks after infarction, one-dimensional chemical shift imaging (CSI) was used to obtain 31P nuclear magnetic resonance (NMR) spectra of eight 2.5-mm-thick cross-sectional slices along the long axis (from base to apex) of isolated buffer-perfused rat hearts. Regional ATP and phosphocreatine (PCr) contents were compared in remodeled versus normal (sham) myocardium. Spin-echo 1H MR images identified the mass of each slice, allowing calculations of metabolite amount per unit myocardium in each slice. 1H MR images identify the hypertrophy of remodeled myocardium but do not discriminate between scar and viable tissue. In contrast, 31P CSI does distinguish viable tissue. Compared with shams, there was less 31P signal in the slices distal to the occlusion containing mainly scar tissue and increased signal intensity in slices proximal to the occlusion because of myocyte hypertrophy. The ATP signal intensity changed in direct proportion to the viable tissue mass in the slice, suggesting that the amount of ATP per unit mass in viable remodeled myocardium is the same as that of the shams. In contrast, the amount of PCr per unit mass in remodeled myocardium decreased. This decrease is uniform across the slices, correlates with infarct size, and parallels a similar decrease in tissue creatine content. CONCLUSIONS: 31P CSI of post-MI hearts shows that (1) PCr decreases uniformly (ie, independent of the distance from the scar) in the noninfarcted remodeled myocardium, and its amount inversely correlates with infarct size; and (2) the ATP signal provides a profile of viable myocardium and is a biochemical marker of morphological remodeling and hypertrophy that has occurred in noninfarcted regions. Thus, 31P CSI provides both a marker that tissue injury has occurred (decreased PCr) and a marker of the extent of remodeling in response to injury (ATP distribution) in a single set of noninvasive measurements.

Adenosine Triphosphate↗
PubMed2002

Dissociation of regional adaptations to ischemia and global myolysis in an accelerated Swine model of chronic hibernating myocardium.

We tested the hypothesis that an acute critical limitation in coronary flow reserve could rapidly recapitulate the physiological, molecular, and morphological phenotype of hibernating myocardium. Chronically instrumented swine were subjected to a partial occlusion to produce acute stunning, followed by reperfusion through a critical stenosis. Stenosis severity was adjusted serially so that hyperemic flow was severely reduced yet always higher than the preocclusion resting level. After 24 hours, resting left anterior descending coronary artery (LAD) wall thickening had decreased from 36.3+/-4.0% to 25.5+/-3.7% (P<0.05), whereas resting flow had remained normal (67+/-6 versus 67+/-8 mL/min, respectively). Although peak hyperemic flow exceeded the prestenotic value, resting flow (45+/-10 mL/min) and LAD wall thickening (17.0+/-5.0%) progressively decreased after 2 weeks, when physiological features of hibernating myocardium had developed. Regional reductions in sarcoplasmic reticulum proteins were present in hibernating myocardium but absent in stunned myocardium evaluated after 24 hours. Histological analysis showed an increase in connective tissue along with myolysis (myofibrillar loss per myocyte >10%) and increased glycogen typical of hibernating myocardium in the LAD region (33+/-3% of myocytes from animals with hibernating myocardium versus 15+/-4% of myocytes from sham-instrumented animals, P<0.05). Surprisingly, the frequency of myolysis was similar in normally perfused remote regions from animals with hibernating myocardium (32+/-7%). We conclude that the regional physiological and molecular characteristics of hibernating myocardium develop rapidly after a critical limitation in flow reserve. In contrast, the global nature of myolysis and increased glycogen content dissociate them from the intrinsic adaptations to ischemia. These may be related to chronic elevations in preload but appear unlikely to contribute to chronic contractile dysfunction.

Adaptation, Physiological↗
PubMed1996

Inhomogeneous disappearance of myofilament-related cytoskeletal proteins in stunned myocardium of guinea pig.

The decrease in Ca2+ responsiveness of myofilaments in stunned myocardium implies that there may be structural changes in proteins composing the contractile machinery. To elucidate the lesion in stunned myocardium, isolated guinea pig hearts were subjected to global ischemia at 37 degrees C and reperfused. SDS-PAGE revealed that the contents of desmin, alpha-actinin, and spectrin decreased in the myofibrillar fraction isolated from hearts reperfused after 60-minute ischemia compared with nonischemic control hearts. To examine the change of cytoskeletal proteins in stunned myocardium, immunohistochemical studies with antibodies against these proteins were performed after 15 minutes of ischemia. In stunned myocardium, the staining was largely intact, but there were some lesions where desmin was not stained and alpha-actinin and spectrin were only weakly identified. The percentage of normally stained areas in the myocardium (percent stained area), quantified by image processing, was significantly lower in stunned myocardium (79.6 +/- 3.6%, mean +/- SEM) than in nonischemic control myocardium (96.5 +/- 0.7%). Percent recovery of developed pressure significantly correlated with percent stained area (r = .82, P < .001). In hearts subjected to 15-minute ischemia but not reperfused, or in hearts reperfused with Ca(2+)-free solution after 15-minute ischemia, staining by the antibodies remained intact, suggesting that the change of the cytoskeletal proteins is mediated by Ca2+ overload during reperfusion. In hearts treated with the protease inhibitor leupeptin (50 mumol/L) or calpain inhibitor I (100 mumol/L), both developed pressure and staining were well preserved. These results indicate that contractile dysfunction in stunned myocardium has a strong correlation with the disappearance of cytoskeletal proteins that may be mediated by a Ca(2+)-dependent intracellular protease activated during reperfusion. The disruption of cytoskeletal proteins is a possible mechanism for stunning, although it may be a secondary effect of protease activation.

Actin Cytoskeleton↗
PubMed1996

Apoptosis in ischemic and reperfused rat myocardium.

Apoptosis has been observed previously in hearts subjected to either continuous ischemia or ischemia followed by reperfusion. The purpose of this study was to compare the timing and extent of apoptosis in both continuously ischemic and reperfused myocardium. We show that rats subjected to continuous coronary artery occlusion display characteristic signs of apoptosis solely in the ischemic myocardium after only 2.25 hours of ischemia, as illustrated by positive in situ end labeling (ISEL) of apoptotic cardiomyocyte nuclei in tissue sections and/or the presence of DNA "ladders" in agarose gels. In contrast, reperfusion after a 45-minute occlusion accelerated the process, with apoptosis becoming evident solely in the reperfused myocardium after only 1 hour of reperfusion. ISEL and DNA ladder intensity increased with duration of ischemia or reperfusion. The volume of myocardium in which ISEL was observed was smaller in the reperfused hearts, and the ISEL-stained nuclei represented 23% and 33% of the total nuclei in the reperfused and permanently occluded myocardium, respectively. Therefore, the data suggest that reperfusion lowers the extent of apoptosis in ischemic myocardium but, paradoxically, accelerates the residual apoptosis, possibly because of reperfusion injury. A large accumulation of neutrophils was observed in both the permanently occluded and reperfused myocardium, suggesting that the inflammatory response may have contributed to apoptosis in both settings. This study therefore confirms that both ischemic and reperfused rat myocardium can undergo apoptotic cell death. However, the data suggest that although reperfusion lowers the number of myocytes undergoing apoptosis, it accelerates apoptosis in the nonsalvageable cells.

Animals↗
PubMed1999

Ca2+ handling and sarcoplasmic reticulum Ca2+ content in isolated failing and nonfailing human myocardium.

Disturbed sarcoplasmic reticulum (SR) Ca2+ content may underlie the altered force-frequency and postrest contractile behavior in failing human myocardium. We used rapid cooling contractures (RCCs) to assess SR Ca2+ content in ventricular muscle strips isolated from nonfailing and end-stage failing human hearts. With an increase in rest intervals (1 to 240 s; 37 degrees C), nonfailing human myocardium (n=7) exhibited a parallel increase in postrest twitch force (at 240 s by 121+/-44%; P<0.05) and RCC amplitude (by 69+/-53%; P<0.05). In contrast, in failing myocardium (n=30), postrest twitch force decreased at long rest intervals and RCC amplitude declined monotonically with rest (by 25+/-9% and 53+/-9%, respectively; P<0.05). With an increase in stimulation frequencies (0.25 to 3 Hz), twitch force increased continuously in nonfailing human myocardium (n=7) by 71+/-17% (at 3 Hz; P<0.05) and RCC amplitude increased in parallel by 247+/-55% (P<0.05). In contrast, in failing myocardium (n=26), twitch force declined by 29+/-7% (P<0. 05) and RCC amplitude increased only slightly by 36+/-14% (P<0.05). Paired RCCs were evoked to investigate the relative contribution of SR Ca2+ uptake and Na+/Ca2+ exchange to cytosolic Ca2+ removal during relaxation. SR Ca2+ uptake (relative to the Na+/Ca2+ exchange) increased significantly in nonfailing but not in failing human myocardium as stimulation rates increased. We conclude that the negative force-frequency relation in failing human myocardium is due to an inability of SR Ca2+ content to increase sufficiently at high frequencies and thus cannot overcome the frequency-dependent refractoriness of SR Ca2+ release. The rest-dependent decay in twitch force in failing myocardium is due to rest-dependent decline in SR Ca2+ content. These alterations could be secondary to depressed SR Ca2+-ATPase combined with enhanced cytosolic Ca2+ extrusion via Na+/Ca2+ exchange.

Adult↗
PubMed1999

Basic fibroblast growth factor increases regional myocardial blood flow and salvages myocardium in the infarct border zone in a rabbit model of acute myocardial infarction.

Basic fibroblast growth factor (bFGF) has been shown by some to promote angiogenesis and myocardial salvage in experimentally induced acute myocardial infarction. Although these findings have spurred much clinical interest, they are not universally observed, and the true efficacy of bFGF remains unclear. The authors used a rabbit model of acute myocardial infarction to further elucidate the effects of bFGF on acutely infarcted myocardium containing few collaterals. Myocardial infarction was evoked by ligation of the left coronary artery. Prior to ligation, either 100 microg of bFGF (bFGF group; n = 15) or physiological saline (control group; n = 22) was injected into the myocardium supplied by the ligated artery. With use of nonradioactive colored microspheres, regional blood flow (Qm) was measured before, immediately after, and 4 weeks after coronary artery ligation. Infarct and border zone sizes were measured in cross-sectional slices of the resected hearts, and the amount of viable myocardium (myocardium score) and the extent of fibrosis were histologically determined in each area. Four weeks after ligation, Qm values in the infarcted area did not significantly differ between the bFGF and control groups (0.54 +/- 0.36 vs 0.48 +/- 0.30 mL/min/g); in the border zone, Qm tended to be higher in the bFGF group (3.39 +/- 2.68 vs 1.47 +/- 0.80 mL/min/g), but the difference was not significant; finally in the noninfarcted area, Qm was significantly (p < 0.05) higher in the bFGF group (6.06 +/- 3.85 vs 2.09 +/- 0.82 mL/min/g). There was no significant difference in the amount of viable myocardium or the extent of fibrosis in the infarcted areas of the two groups. In the border zone, however, the amount of viable myocardium was significantly (p < 0.005) larger in the bFGF group (61.8 +/- 8.5% vs 35.8 +/- 20.3% of the visual field). Likewise, as graded on a scale from 0 to 5, the extent of fibrosis was significantly (p < 0.005) less in the bFGF group (2.1 +/- 0.5 vs 3.3 +/- 0.8). In conclusion, injection of bFGF into acutely infarcted myocardium increased blood flow to the noninfarcted area and salvaged the myocardium in the border zone.

Animals↗
PubMed2004

[Alterations of adrenomedullin and its receptor system in calcified myocardium and aorta of rats].

OBJECTIVE: To explore the production of ADM, changes and significance of adrenomedullin (ADM) mRNA and ADM receptor system-calcitonin receptor-like receptor (CRLR) and receptor activity modifying proteins (RAMPs) mRNA in calcified myocardium and aorta of rats. METHODS: Contents of ADM in plasma, myocardium and vessel were measured by radioimmunoassay (RIA). The amount of ADM, CRLR and RAMPs mRNA was determined by semi-quantitative RT-PCR. RESULTS: The contents of calcium in calcified myocardium and aorta were increased by 342% and 606% (all P<0.01), respectively, and alkaline phosphatase activities in calcified myocardium and vessel were increased by 66.5% and 82.7% (all P<0.01), respectively, compared with the control. Contents of ADM in plasma, myocardium and aorta were increased by 58 % (P<0.01), 14.3%(P<0.01) and 27.8%(P<0.05). Furthermore, it was found that the levels of ADM, CRLR and RAMP2 mRNA in calcified myocardium were elevated by 90.6% 157.5% and 119.6%(all P<0.01), respectively, but RAMP3 mRNA was decreased by 14.1 %(P<0.01). The levels of ADM, CRLR, RAMP2 and RAMP3 mRNA in calcified aorta were elevated by 37.7%(P<0.01), 41.4%(P<0.01),60.1%(P<0.05) and 13%(P<0.01) respectively, compared with the control. The elevated levels of CRLR, RAMP2 or RAMP3 mRNA were positively correlated with up regulations of ADM mRNA in calcified myocardium and aorta. CONCLUSION: Calcified myocardium and aorta may generate an increased amount of ADM, different alterations of gene expressions of ADM and its receptor system. These RESULTS suggest that ADM and its receptor system might participate in the regulation of calcification in heart and vessel.

Adrenomedullin↗
PubMed2006

[Changes in substance P in myocardium and dorsal root ganglion following coronary artery occlusion in rats].

OBJECTIVE: To observe the changes in substance P in myocardium and dorsal root ganglion (DRG) following ligation of the left anterior descending branch of coronary artery. The substance P is commonly considered released mainly from afferent nerve fibers under noxious stimulation and could induce neurogenic inflammation in peripheral tissue. METHODS: Twenty-four adult male Sprague-Dawley rats, weighing 270-300 g, were randomly divided into four groups: sham-operated group, coronary artery occlusion (CAO) 1 hour group, CAO 3 hours group and CAO 6 hours group, and 6 animals were in each group. The left anterior descending branch of coronary artery was occluded to establish the acute myocardial ischemia model except in the sham-operated group. The myocardium in ischemic and non-ischemic (the contralateral side of ischemic myocardium) region and DRG were harvested as scheduled and processed for immunohistochemistry and for substance P mRNA semi-quantitative examination using reverse transcription-polymerase chain reaction (RT-PCR) technique. RESULTS: (1) substance P and substance P mRNA levels in myocardium of ischemic areas and myocardium of non-ischemic areas were significantly elevated after CAO compared with sham-operated group (all P<0.05), and they were highest in rats of CAO 3 hours group (all P<0.05). In the myocardium of non-ischemic areas, substance P and substance P mRNA levels were lower than those in myocardium of ischemic areas in CAO groups (all P<0.05). (2) substance P mRNA levels in DRG were significantly elevated after CAO compared with sham-operated group (all P<0.05), and were highest in rats of CAO 3 hours group (both P<0.05). CONCLUSION: CAO could evoke an increase in substance P in entire myocardium and substance P mRNA expression in DRG in rats, and the results might imply that neurogenic mechanism participates in the pathophysiological changes following myocardial ischemia.

Animals↗
PubMed1991

[Down-regulation and hibernating myocardium].

Some homeothermic animals can survive adverse conditions by hibernation, i.e., by reducing their body temperature in accordance with ambient temperature, thus reducing metabolism and vital functions. Six years ago, the term hibernation was introduced to describe a particular state of the myocardium. Although the meaning is different from that used in zoology and, thus, is misleading, it is used increasingly to describe a condition induced by moderate reduction in coronary flow. Some evidence in the literature suggests that the myocardium can actively reduce its mechanical function as a consequence of reduced coronary flow in order to prevent ischemia-induced injury. It is conceivable that the hibernating myocardium is the result of such a down-regulation of function. The hibernating myocardium can be characterized by decreased function in the hypoperfused area, which still exhibits active metabolism and remains viable. This is in contrast to "stunned" myocardium, which represents dysfunction during postischemic reperfusion, i.e., with coronary blood flow being close to normal. In analogy to hibernation in its original meaning, down-regulation and hibernating myocardium are considered to represent a protective mechanism, because such myocardium can quickly regain its initial function after restoration of physiologic blood flow. Because hibernating myocardium is salvageable, it has to be distinguished from other dysfunctional tissue that has lost its function due to ischemic damage, so that appropriate clinical interventions can succeed in restoring normal coronary blood flow.

Adaptation, Physiological↗
PubMed1984

Distribution of cytosolic and mitochondrial aspartate aminotransferase in normal, ischemic, and necrotic myocardium. An immunohistochemical study.

We utilized immunoperoxidase methods to study the distribution of both cytosolic or soluble(s) and mitochondrial (m) aspartate aminotransferase (AspAT) in normal, ischemic, and necrotic myocardium. Human myocardium was obtained from autopsy (n = 9) and surgery (n = 6). Cardiac tissue from 26 dogs with experimental myocardial infarction induced by closed-chest balloon occlusion and four dogs with myocardial ischemia without necrosis induced by a 50% reduction in left main coronary artery flow for 3 hours were studied. Duration of occlusion was 45 minutes (n = 1), 3 hours (n = 11), 5 to 6 hours (n = 10), or 15 to 24 hours (n = 4). Highly purified m- and s-AspAT and specific antibodies were prepared in our laboratory. In all cases, control experiments were performed. Microscopically normal human and dog myocardium uniformly stained for m- and s-AspAT. Necrotic myocardium from patients with infarcts showed markedly reduced immunostaining. In those dogs with myocardial necrosis, all dogs with coronary occlusion of 5 to 24 hours, and eight of 11 dogs with 3-hour occlusions, immunostaining was significantly reduced for both s- and m-AspAT in regions confirmed to be necrotic by triphenyl tetrazolium chloride and hematoxylin and eosin staining. Myocardial necrosis was confirmed in the 3-hour infarcts by electron microscopy. In the four dogs with a 50% reduction in left main flow for 3 hours, and one dog with a 45-minute coronary occlusion, ischemia was demonstrated by glycogen loss in period acid-Schiff-stained sections but there was no evidence of necrosis by electron microscopy or triphenyl tetrazolium chloride staining and there was no loss of immunostaining evident for s- or m-AspAT. Thus, s- and m-AspAT were visualized in normal and ischemic myocardium with decreased staining in necrotic tissue using immunoperoxidase techniques. Loss of both s- and m-AspAT can be demonstrated in human myocardium and in experimental canine myocardium as early as 3 hours after coronary occlusion and appears to be specific for irreversible myocardial injury. No depletion of isoenzyme can be detected by immunohistochemical techniques in tissue that is ischemic but not necrotic. Furthermore, by these immunoperoxidase techniques, loss of s- and m-AspAT from necrotic myocardium appears to be simultaneous.

Animals↗
PubMed1998

Length dependence of calcium- and force-transients in normal and failing human myocardium.

UNLABELLED: Two questions were analysed: (1) Is the Frank-Starling mechanism operative in failing human myocardium? (2) Are length-dependent changes in force accompanied by length-dependent changes in intracellular calcium transients in human myocardium? METHODS: (I) in electrically stimulated left-ventricular trabeculae [normal donor heart (NDH), n = 8; end stage dilated cardiomyopathy (DCM), n = 11], isometric force development was analysed as a function of muscle length (37 degrees C, oxygenated Krebs-Henseleit solution, supramaximal electrical stimulation, frequency: 1 Hz). (II) Myocardium from the same patients were loaded with the fluorescent dye FURA-2/AM for simultaneous measurements of intracellular calcium transient (ICT) and force development at different muscle lengths. Muscle length, resting force, developed force and intracellular Calcium ("ratio method") were monitored continuously. RESULTS: (I) developed force increased up to an optimum as a function of muscle length in NDH- and DCM-myocardium. The slope of this increase was flatter in DCM-myocardium (P < 0.01). (II) In NDH- and DCM-myocardium, diastolic and systolic calcium increased significantly with muscle length. With decreasing muscle lengths the ICT became broader, the diastolic decay was retarded and the peak of the ICT was flatter. At Lmax the calcium amplitude was 23% smaller in DCM than in NDH (P < 0.04). CONCLUSION: there is a clear length dependence of active force in DCM-myocardium. The length dependence of force development is associated with length-dependent modulations of the ICT. The flatter slope of the length-force curve in DCM may be partly explained by altered intracellular calcium handling in failing myocardium.

Calcium↗
PubMed1994

Responses of blood flow, oxygen consumption, and contractile function to inotropic stimulation in stunned canine myocardium.

To examine the effects of inotropic stimulation on regional myocardial blood flow (MBF), oxidative metabolism, and contractile function in stunned myocardium, nine closed-chest dogs were studied 2 hours postreperfusion after a 25 minute occlusion of the left anterior descending coronary artery (LAD). MBF was determined with microspheres, and regional myocardial oxygen consumption (MVO2) was estimated from the rate constant k1 of the rapid clearance phase of [1-11C] acetate time activity curves, recorded with dynamic positron emission tomography. Myocardium at risk was determined from [13N] ammonia images obtained during occlusion. Wall motion, assessed by two-dimensional echocardiography, was impaired in postischemic myocardium in all dogs 2 hours after reperfusion. Dobutamine infusion increased the rate pressure product by 70% +/- 31% and significantly improved contractile function in the postischemic region in all dogs. In remote myocardium, MVO2 increased from 5.7 +/- 1.2 to 8.6 +/- 1.6 mumol/gm/min, and blood flow from 0.87 +/- 0.16 to 1.52 +/- 0.42 ml/gm/min in response to dobutamine. In reperfused myocardium, MVO2 increased from 3.1 +/- 0.7 to 7.4 +/- 1.5 mumol/gm/min, and blood flow from 0.51 +/- 0.12 to 1.2 +/- 0.4 ml/gm/min. Oxygen extraction increased significantly in reperfused myocardium relative to remote myocardium consistent with a flow-limited response to dobutamine stimulation. The improvement in contractile function failed to correlate significantly with relative increases in MBF or MVO2, suggesting that mechanical function is not as tightly coupled as MBF and MVO2 in postischemic myocardium during inotropic stimulation.

Analysis of Variance↗
PubMed1994

Usefulness of transesophageal atrial pacing combined with two-dimensional echocardiography (echo-pacing) in predicting the presence and site of residual jeopardized myocardium after uncomplicated acute myocardial infarction.

The usefulness of transesophageal atrial pacing combined with 2-dimensional echocardiography (echo-pacing) in predicting the presence and site of jeopardized myocardium, defined as areas of myocardium perfused by a vessel with a stenosis > or = 75% or by a collateral circulation if the supplying vessel was occluded, was evaluated in 31 patients with uncomplicated acute myocardial infarction who underwent coronary angiography. All 5 patients without jeopardized myocardium had a negative test, whereas 24 of 26 with jeopardized muscle had a positive test (sensitivity 92%; specificity 100%). To identify the site of jeopardized myocardium, tests that were positive for development of new asynergies were analyzed further, distinguishing those positive in the infarct or remote zone. Seven of 8 patients with new asynergies in the remote zone had areas of jeopardized myocardium outside the territory of distribution of the infarct-related vessel, whereas only 2 of 12 with new asynergies in the infarct zone had areas of jeopardized myocardium outside that territory (p < 0.01), correctly predicting the site of jeopardized myocardium in 17 of 20 cases. In conclusion, echo-pacing is useful for detecting the presence and site of jeopardized myocardium after an acute myocardial infarction.

Adult↗
PubMed2006

Adaptation of nonrevascularized human hibernating and chronically stunned myocardium to long-term chronic myocardial ischemia.

It is unknown whether human chronically ischemic dysfunctional myocardium degenerates over time or adapts to chronic ischemia. We studied whether perfusion, metabolism, and contractile function and reserve can be preserved in nonrevascularized human chronically stunned and hibernating myocardium. We studied 16 event-free, medically treated patients with ejection fractions of 31 +/- 2% and chronically stunned or hibernating myocardium in 56 +/- 5% of the left ventricle on technetium-99m sestamibi single-photon emission computed tomography/fluorine-18 fluorodeoxyglucose (FDG) positron emission tomography. Patients underwent repeat single-photon emission computed tomography, positron emission tomography, and tissue Doppler echocardiography at rest and during stress at follow-up after 25 +/- 4 months, and we investigated whether measurements of myocardial viability remained stable over time. Patients were stable with respect to New York Heart Association class and global left ventricular function (30 +/- 2%, p = 0.81). Wall motion score was unaltered in hibernating myocardium and chronically stunned regions, and a contractile reserve by tissue Doppler stress echocardiography was preserved. Overall, 74% of hibernating myocardium and chronically stunned regions retained their initial perfusion/metabolism pattern at follow-up. In hibernating myocardium, initial and follow-up sestamibi uptakes (53 +/- 1% and 53 +/- 2%, p = 0.85) and FDG uptakes (76 +/- 1% and 74 +/- 1%, p = 0.21) did not differ. In chronically stunned regions, sestamibi uptake displayed a minor decrease at follow-up (70 +/- 1% vs 67 +/- 1%, p <0.01) and FDG uptake remained constant (68 +/- 2% and 67 +/- 1%, p = 0.21). In conclusion, myocardial perfusion, FDG uptake, and contractile function in nonrevascularized chronically stunned and hibernating myocardium adapt to chronic ischemia in patients who are free of events. In chronically stunned regions, adaptation may be less complete than in hibernating myocardium.

Adaptation, Physiological↗
PubMed2006

Dosage-dependent transcriptional regulation by the calcineurin/NFAT signaling in developing myocardium transition.

Thin spongy myocardium is critical at early embryonic stage [before embryonic day (E) 13.5 in mice] to allow diffusion of oxygen and nutrients to the developing cardiomyocytes. However, establishment of compact myocardium at later stage ( approximately E16.5) during development is necessary to prepare for the increase in demand for blood circulation. Elucidating molecular targets of the spongy-compact myocardium transition between E13.5 and E16.5 in heart development is thus important. Previous studies demonstrated that multiple transcription factors and signaling pathways are involved in the regulation and function of the myocardium in heart development. Disruption of certain transcription factors or critical components of signaling pathways frequently causes structural malformation in heart and persistence of "thin spongy myocardium". We have recently demonstrated activation of the calcineurin/NFAT signaling pathway at E14.5 in developing myocardium. Constitutive inhibition of the calcineurin/NFAT signaling pathway caused embryonic lethality. Molecular targets downstream of the calcineurin/NFAT signaling pathway, however, remains elusive. Here, we report transcription targets, independently and dependently, regulated by the calcineurin/NFAT signaling during the E13.5-E16.5 myocardium transition. We have uncovered that expression of one-third of the induced genes during myocardium transition is calcineurin/NFAT-dependent. Among these calcineurin/NFAT-dependent transcription targets, there is a dosage-dependent regulation. Molecular studies indicate that formation of distinct NFAT:DNA complex, in part, accounts for the dosage-dependent regulation. Thus, in addition to temporal and spatial regulation, dosage-dependent threshold requirement provides another mechanism to modulate transcription response mediated by the calcineurin/NFAT signaling during heart development.

Animals↗
PubMed2002

Variability of contractile reserve in hibernating myocardium: dependence on the method of inotropic stimulation.

OBJECTIVE: Contractile reserve during graded beta-adrenergic stimulation identifies viability in patients with left ventricular dysfunction. Nevertheless, contractile reserve is frequently absent in viable, chronically dysfunctional myocardium with reduced resting flow (hibernating myocardium). The goal of this study was to evaluate the mechanisms responsible for limited contractile reserve in hibernating myocardium. METHODS: Pigs were chronically instrumented with a left anterior descending coronary artery (LAD) stenosis to produce hibernating myocardium; and regional flow, function and hemodynamics were assessed during graded beta-adrenergic stimulation (epinephrine). RESULTS: The chronic LAD stenosis produced a critical reduction in coronary flow reserve with regional reductions in resting subendocardial flow (0.69+/-0.05 vs. 1.03+/-0.11 ml/min/g in shams, P<0.05) and wall thickening (2.0+/-0.4 vs. 4.3+/-0.4 mm in shams, P<0.05), consistent with hibernating myocardium. In sham controls, LAD flow and function increased during graded, steady-state increases in epinephrine. Nevertheless, despite similar external determinants of demand in animals with hibernating myocardium, neither subendocardial flow (peak response: 0.66+/-0.14 and peak dose: 0.58+/-0.13 ml/min/g, respectively) nor wall thickening (3.0+/-0.5 and 2.5+/-0.6 mm, respectively) increased during graded epinephrine infusion. However, during a transient epinephrine infusion to the maximum dose used in the graded protocol, flow remained unchanged (0.80+/-0.06 to 0.85+/-0.08 ml/min/g) but wall thickening improved (2.3+/-0.4 to 4.1+/-0.6 mm, P<0.05). CONCLUSIONS: These data indicate that variability in contractile reserve in hibernating myocardium is at least partly related to the protocol used for beta-adrenergic stimulation. The blunted steady-state responses to beta-adrenergic stimulation raise the possibility that, like moderate supply-induced ischemia, an exquisite matching between flow and function develops during moderate demand-induced ischemia. This prevents metabolic deterioration in hibernating myocardium but limits contractile function during increases in the external determinants of myocardial metabolism.

Adrenergic beta-Agonists↗