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PubMed2000

Differences in time course of myocardial mRNA expression in non-infarcted myocardium after myocardial infarction.

In non-infarcted myocardium after myocardial infarction, the change of cardiac phenotypic modulation of contractile protein, extracellular matrix and intracellular Ca2+ transport protein, such as sarcoplasmic reticulum Ca2+(SR-Ca2+)-ATPase, Na+-Ca2+ exchanger, have a important role during cardiac remodeling. However, the time course in this gene expression in the adjacent and remote left ventricular, or right ventricular myocardium after myocardial infarction has not been well examined. The purpose of this study was to examine the left ventricular function and regional cardiac gene expression after myocardial infarction. Myocardial infarction was produced in Wistar rats by the ligation of the left anterior descending coronary artery. After 3 weeks, 2 months and 4 months from myocardial infarction, we performed Doppler echocardiography and measured the systolic and diastolic function. Then, we analyzed the contractile protein, extracellular matrix and intracellular Ca2+ transport protein mRNAs of cardiac tissues in the adjacent and the remote noninfarcted myocardium, and right ventricular myocardium by Northern blot hybridization. Fractional shortening of infarcted heart progressively decreased. Peak early diastolic filling wave (E wave) velocity increased, and the deceleration rate of the E wave velocity was more rapid in myocardial infarction areas. Atrial filling wave (A wave) velocity decreased, resulting in a marked increase in the ratio of E wave to A wave velocity. Expression of myocardial alpha-skeletal actin, beta-MHC and ANP mRNA, or collagen I and III mRNA were higher at 3 weeks after myocardial infarction. SR Ca2+-ATPase mRNA in the adjacent non-infarcted myocardium was decreased at 2 months, and that in remote myocardium was decreased at 4 months after infarction. Na+-Ca2+ exchanger mRNA levels were increased at 3 weeks, but was decreased at 2 months in the adjacent non-infarcted myocardium and at 4 months in the remote myocardium. These findings suggest that the compensation for myocardial infarction by myocardial gene expression in non-infarcted myocardium may occur at an early phase after myocardial infarction, and myocardial dysfunction may begin from adjacent to remote non-infarcted myocardium during progressive cardiac remodeling.

Animals↗
PubMed1987

Substrate use in ischemic and reperfused canine myocardium: quantitative considerations.

The patterns of use of substrate in reperfused myocardium are not yet well elucidated, and their delineation is essential for adequate interpretation of results of analyses performed after positron emission tomography with labeled substrates to differentiate normal from abnormal heart muscle. Accordingly, in open-chest, anesthetized dogs we measured glucose and fatty acid utilization in normal, ischemic, and reperfused myocardium and assessed the contributions of metabolism of each substrate to overall oxidative metabolism. Intracoronary [3H]glucose and [14C]palmitate were administered in five control dogs, eight dogs subjected to 1 h of coronary occlusion, and nine dogs subjected to reperfusion after 1 h of ischemia. Regional coronary venous blood samples were assayed sequentially. In reperfused myocardium, utilization of glucose (463 +/- 88 nmol X g-1 X min-1) was 103% greater than that in ischemic and 273% greater than in normal myocardium (P less than 0.05 for each). Utilization of fatty acid during reperfusion (55 +/- 10 nmol X g-1 X min-1), although greater than that in ischemic myocardium, was significantly less than that in normal myocardium (48% of control, P less than 0.05) despite restoration of flow to 80% of control values. Although glucose constituted 70% of the substrate oxidized in ischemic myocardium, its contribution to overall oxidative metabolism in reperfused myocardium was only 25%. In contrast, despite diminished net uptake of fatty acid, oxidation of fatty acid accounted for 63% of total oxygen consumption in reperfused myocardium. These studies indicate that canine myocardium reperfused after 1 h of ischemia exhibits enhanced uptake of glucose and impaired utilization of palmitate.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Energetics of isometric force development in control and volume-overload human myocardium. Comparison with animal species.

Alteration in crossbridge behavior and myocardial performance have been associated with myosin isoenzyme composition in animal models of myocardial hypertrophy or atrophy. In the hypertrophied human heart, myocardial performance is altered without significant changes in myosin isoenzymes. To better understand this discrepancy, isometric heat and force measurements were carried out in 1) control and volume-overload human myocardium, 2) control, pressure-overload, and hyperthyroid rabbit myocardium, and 3) control and hypothyroid rat myocardium. In control human myocardium, peak isometric twitch tension was 44.0 +/- 11.7 mN/mm2, and maximum rate of tension rise was 69.2 +/- 21.0 mN/sec.mm2. In volume-overload human myocardium, peak twitch tension and maximum rate of tension rise were reduced by 55% (p less than 0.05) and 65% (p less than 0.05), respectively. The average force-time integral of the individual crossbridge cycle, calculated by myothermal techniques, was increased by 85% (p less than 0.005) in volume-overload human myocardium. In control and hormonally altered myocardium, both across and within species (control human, control rat, control rabbit, hypothyroid rat, and hyperthyroid rabbit), there was a close relation between the crossbridge force-time integral and the percentage of V3-type myosin isoenzyme in the myocardium. However, hemodynamically altered (volume-overload human and pressure-overload rabbit) myocardium did not follow this relation. Across and within species, there were significant correlations between maximum rate of tension rise and average tension-dependent heat rate (r = 0.97, p less than 0.001) and between maximum rate of tension fall and average tension-independent heat rate (r = 0.82; p less than 0.025). Furthermore, there were close inverse relations between these heat rates and the crossbridge force-time integral. In addition, there was an inverse relation between tension-independent heat and the crossbridge force-time integral. Across and within species total myocardial energy turnover was significantly correlated with the crossbridge force-time integral (relative total heat, r = -0.84, p less than 0.02; relative total-activity related heat, r = -0.88, p less than 0.01). The present findings indicate that 1) factors separate from myosin isoenzymes account for the altered crossbridge cycle in volume-overload human and pressure-overload rabbit myocardium, 2) changes in excitation-contraction coupling processes accompany changes in the crossbridge cycle within and across species, and 3) the force-time integral of the crossbridge cycle is a major determinant of total myocardial energy turnover.

Animals↗
PubMed1999

Metabolism of radioiodinated fatty acid analogs in ischemic and hypoxic canine myocardium.

UNLABELLED: Myocardial metabolism of 17-[123I]-iodoheptadecanoic acid (IHDA), 15-(p-[131I]-iodophenyl)pentadecanoic acid (pIPPA) and 15-(p-[125I]-iodophenyl)-3,3-dimethylpentadecanoic acid (DMIPP) was assessed during ischemia and hypoxia. The simultaneous investigation allowed us to evaluate differences in metabolic handling of these three fatty acids. METHODS: In 17 open-chest dogs, the left ascending coronary artery was cannulated and extracorporeal bypass (ECB) perfused. In 3 dogs, ECB flow was kept normal, and these control experiments showed that kinetics of the radioiodinated fatty acids were not affected by the ECB technique itself. In 9 dogs, ECB flow was reduced to one third (ischemia), and in 5 dogs, the ECB area was perfused with venous blood and was kept at control values (hypoxia). After simultaneous intravenous injection of IHDA, pIPPA and DMIPP, seven paired biopsy specimens from the native and ECB-perfused myocardium were taken over an assay period of 35 min. Total activity and the distribution in the aqueous phase and lipid fractions were determined, and time-activity curves were constructed. RESULTS: In ischemic (Is) but not in hypoxic (Hy) myocardium, peak total activity of IHDA, pIPPA and DMIPP decreased significantly versus normal (N) myocardium (IHDA: N = 700 +/- 267 versus Is = 335 +/- 158 dpm/mg/mCi; pIPPA: N = 988 +/- 318 versus Is = 438 +/- 180 dpm/mg/mCi; DMIPP: N = 352 +/- 146 versus Is = 179 +/- 82 dpm/mg/mCi; all P values < 0.001). The relative decrease was similar for IHDA, pIPPA or DMIPP. Half-time values of total activity were prolonged for IHDA and pIPPA but were shortened for DMIPP in ischemic and hypoxic myocardium (IHDA: N = 22, Is = 44 and Hy = 50 min; pIPPA: N = 24, Is = 95 and Hy = 169 min; DMIPP: N = 528, Is = 409 and Hy = 115 min). The aqueous phase activity for IHDA, pIPPA and DMIPP decreased significantly versus normal myocardium in both ischemic (IHDA: N = 71% +/- 9% versus Is = 36% +/- 9%, P < 0.001; pIPPA: N = 62% +/- 10% versus Is = 25% +/- 8%, P < 0.001; DMIPP: N = 26% +/- 11% versus Is = 18% +/- 3%, P < 0.05) and hypoxic (IHDA: N = 76% +/- 8% versus Hy = 62% +/- 8%, P < 0.05; pIPPA: N = 66% +/- 8% versus Hy = 46% +/- 10%, P < 0.05; DMIPP: N = 32% +/- 6% versus Hy = 24% +/- 4%, P < 0.05) myocardium. The relative decrease was significantly highest for pIPPA and lowest for DMIPP. Incorporation into triacylglycerols increased significantly for IHDA, pIPPA and DMIPP in both ischemic and hypoxic myocardium. In normal myocardium, DMIPP was already mainly incorporated into triacylglycerols. Activity of IHDA and pIPPA in acylcarnitine increased significantly in ischemic and hypoxic myocardium. CONCLUSION: Kinetics of the radioiodinated fatty acid analogs in myocardium are altered during oxygen deprivation in a similar fashion as documented in literature for natural fatty acids. However, the changes were different between IHDA, pIPPA and DMIPP, suggesting different metabolic handling and thus reflecting different aspects of myocardial fatty acid metabolism.

Animals↗
PubMed2003

Comparison of microsphere-equivalent blood flow (15O-water PET) and relative perfusion (99mTc-tetrofosmin SPECT) in myocardium showing metabolism-perfusion mismatch.

UNLABELLED: Myocardial perfusion imaging with (99m)Tc-tetrofosmin is based on the assumption of a linear correlation between myocardial blood flow (MBF) and tracer uptake. However, it is known that (99m)Tc-tetrofosmin uptake is directly related to energy-dependent transport processes, such as Na(+)/H(+) ion channel activity, as well as cellular and mitochondrial membrane potentials. Therefore, cellular alterations that affect these energy-dependent transport processes ought to influence (99m)Tc-tetrofosmin uptake independently of blood flow. Because metabolism ((18)F-FDG)-perfusion ((99m)Tc-tetrofosmin) mismatch myocardium (MPMM) reflects impaired but viable myocardium showing cellular alterations, MPMM was chosen to quantify the blood flow-independent effect of cellular alterations on (99m)Tc-tetrofosmin uptake. Therefore, we compared microsphere-equivalent MBF (MBF_micr; (15)O-water PET) and (99m)Tc-tetrofosmin uptake in MPMM and in "normal" myocardium. METHODS: Forty-two patients with severe coronary artery disease, referred for myocardial viability diagnostics, were examined using (18)F-FDG PET and (99m)Tc-tetrofosmin perfusion SPECT. Relative (18)F-FDG and (99m)Tc-tetrofosmin uptake values were calculated using 18 segments per patient. Normal myocardium and MPMM myocardium were classified using a previously validated (99m)Tc-tetrofosmin SPECT/(18)F-FDG PET score. In addition, (15)O-water PET was performed to assess kinetic-modeled MBF (MBF_kin), the water-perfusable tissue fraction (PTF), and the resulting MBF_micr (MBF_kin x PTF), which is comparable to tracer uptake values. (99m)Tc-tetrofosmin uptake and MBF_micr values were calculated for all normal and MPMM segments and averaged within their respective classifications. RESULTS: Mean relative (99m)Tc-tetrofosmin uptake was 86% +/- 1% in normal myocardium and 56% +/- 1% in MPMM, showing a significant difference (P < 0.001), as was expected from the classification. Contrary to these findings, mean MBF_micr in MPMM myocardium was 0.60 +/- 0.03 mL x min(-1) x mL(-1), which did not significantly differ from normal myocardium (0.64 +/- 0.01 mL x min(-1) x mL(-1)). All values are given as mean +/- SEM. CONCLUSION: Differences between reduced (99m)Tc-tetrofosmin uptake and the unchanged MBF_micr in MPMM myocardium suggest that the pathophysiologic basis of MPMM is not a blood flow reduction but cellular alterations that affect uptake and retention of (99m)Tc-tetrofosmin independently of blood flow. Therefore, it seems that perfusion deficits in MPMM myocardium are greatly overestimated by (99m)Tc-tetrofosmin and that it tends to give false-positive findings.

Adult↗
PubMed2005

Regional 11C-hydroxyephedrine retention in hibernating myocardium: chronic inhomogeneity of sympathetic innervation in the absence of infarction.

UNLABELLED: We have previously shown that ex vivo counting of (131)I-metaiodobenzylguanidine can identify regional reductions in sympathetic norepinephrine uptake in pigs with hibernating myocardium. However, nonneuronal uptake limited relative differences between regions and would preclude accurate assessment with conventional imaging. We therefore hypothesized that the superior specificity of the positron-emitting isotope (11)C-hydroxyephedrine (HED) would facilitate the imaging of regional differences, and we designed this study to determine whether altered uptake of norepinephrine by sympathetic nerves in viable, dysfunctional myocardium can be imaged in vivo and to determine the temporal progression and stability of sympathetic dysinnervation in hibernating myocardium. METHODS: Pigs (n = 15) were chronically instrumented with a 1.5-mm stenosis of the left anterior descending coronary artery, a procedure that we have previously shown to produce viable chronically dysfunctional myocardium with reduced resting flow, or hibernating myocardium, after 3 mo. Physiologic studies and HED PET were performed 1-5 mo later with the animals in the closed-chest sedated state. One animal with a myocardial infarct was analyzed separately. RESULTS: After 3 mo, anterior hypokinesis developed (wall thickening, 32% +/- 4% vs. 60% +/- 4%, P < 0.001), with reductions in resting flow (subendocardial flow, 0.81 +/- 0.11 vs. 1.20 +/- 0.18 mL/min/g, P < 0.05) and a critical reduction in subendocardial flow reserve (subendocardial adenosine flow, 0.53 +/- 0.20 vs. 3.96 +/- 0.43 mL/min/g, P < 0.001). Extensive defects in HED uptake were found for hibernating myocardium, with regional retention approximately 50% lower than that in normally perfused remote myocardium (0.035 +/- 0.002 vs. 0.066 +/- 0.002 min(-1), P < 0.001). Relative HED uptake (left anterior descending coronary artery/remote) was lower in chronically instrumented animals than in control animals (n = 4, P < 0.001) and animals studied 1 mo after instrumentation (n = 2, P < 0.05). The regional reduction in sympathetic nerve function was persistent and unaltered for at least 2 mo after the development of hibernating myocardium. CONCLUSION: Hibernating myocardium is associated with persistent reductions in regional uptake of norepinephrine by sympathetic nerves. The inhomogeneity in sympathetic innervation in viable dysfunctional myocardium is similar to that occurring after myocardial infarction and may contribute to arrhythmic death in patients with ischemic cardiomyopathy.

Animals↗
PubMed1997

Effect of milrinone and atrial pacing on stunned myocardium.

OBJECTIVE: Most mammalian cardiac muscles show a positive force-frequency relation, which is turned into a negative relation in failing hearts. Stunned myocardium shows similar defects as failing myocardium, it has a functional reserve recruitable by positive inotropic interventions, and possibly shows a disturbed response to increased heart rate. The present experiments compare in vivo the response of stunned and intact myocardium to atrial pacing before and during inotropic stimulation by milrinone. METHODS: In anaesthetised (piritramide) open chest pigs, heart rate, left ventricular and aortic pressure, left descending (LAD) and circumflex (LCX) coronary artery and aortic blood flow, myocardial systolic shortening in the LAD and LCX area were monitored, and myocardial power was calculated. The LAD region was subjected to ischaemia and reperfused. Heart rate was raised by right atrial pacing after 90 min reperfusion before and during i.v. milrinone (105 microg/kg bolus + 8 microg/kg per min infusion). The ischaemic/reperfused area was sliced post mortem and stained by triphenyl tetrazolium chloride to exclude myocardial infarction. Data from ten experiments are presented. RESULTS: After 90 min LAD reperfusion, LAD blood flow and power were 110 and 36% of preischaemic control, respectively, indicating myocardial stunning. The power of the intact area was not changed (102% of control). Pacing from 87 to 164 per min increased the power of the intact area (+96%), the power of the stunned myocardium decreased (-64%). Milrinone increased the power of the stunned region to 72% of the pre-stunning level and the power of the intact area by +51%. Pacing from 111 to 164 per min during milrinone increased the power of the intact myocardium to the same level as before milrinone, the power of the stunned region did not change. CONCLUSIONS: Stunned myocardium responds pathologically to atrial pacing with a negative staircase in contrast to the positive staircase of intact myocardium. Inotropic stimulation by the phosphodiesterase inhibitor milrinone recruited the functional reserve of stunned myocardium. Milrinone did not restore a positive staircase in stunned myocardium, but power was maintained during atrial pacing. The pathological staircase of stunned myocardium may arise from an impaired availability of cyclic AMP, but the data do not exclude defects in calcium handling, a dysfunction of the sarcoplasmic reticulum, or an impaired Ca-sensitivity of the myofilaments.

Animals↗
PubMed2004

The effect of tropomyosin on force and elementary steps of the cross-bridge cycle in reconstituted bovine myocardium.

The role of tropomyosin (Tm) in the elementary steps of the cross-bridge cycle in bovine myocardium was investigated. The thin filament was selectively removed using gelsolin (thin filament severing protein), and the actin filament was reconstituted from G-actin. Tm was further reconstituted without troponin (Tn), and the kinetic constants of the elementary steps of the cross-bridge cycle were deduced using sinusoidal analysis at pCa </= 4.66, pH 7.00, and 25 degrees C. The association constant of MgATP to cross-bridges (K(1)) after reconstitution of Tm was 20.7 +/- 2.3 mm(-1), which was about 2 x the control (untreated) myocardium (9.1 +/- 1.3 mm(-1)). Following reconstitution of Tm, the equilibrium constant of the cross-bridge detachment step (K(2)), the phosphate (P(i)) association constant (K(5)) and the equilibrium constant of the force-generation step (K(4)), which significantly changed in the actin filament-reconstituted myocardium, recovered to those of the control myocardium. Active tension after reconstitution of Tm was 0.69 x the control myocardium, a value between the control (1.00 x) and the actin filament-reconstituted myocardium (0.59 x). Tm-reconstituted myocardium was further reconstituted with Tn, and the effect of MgATP on the rate constants (K(1), K(2)) was studied. Following reconstitution with Tn, the myocardium regained the Ca(2+)-sensitivity and the active tension became 0.83 x the control myocardium. In addition, K(1) recovered to the value of the control myocardium with Tn reconstitution. These results indicate that both Tm and Tn enhance the force generated by each cross-bridge, and that Tm is primarily responsible for the change in the kinetic constants of the elementary steps of the cross-bridge cycle.

Actin Cytoskeleton↗
PubMed2005

Blunted functional responses to pre- and postjunctional sympathetic stimulation in hibernating myocardium.

Regional reductions in norepinephrine-tracer uptake are found in pigs with hibernating myocardium. Clinical studies would suggest that this is evidence for denervation; however, the functional responses to sympathetic stimulation have not been evaluated, and our previous studies with beta-adrenergic stimulation have not suggested denervation hypersensitivity. Therefore, pigs were chronically instrumented to produce hibernating myocardium characterized by chronic regional dysfunction and histological viability. Open-chest studies were performed to determine changes in regional function in response to both pre- and postjunctional stimulation. Regional segment shortening was reduced at rest in hibernating myocardium compared with controls (13 +/- 3% vs. 27 +/- 3%, P = 0.004). During stellate ganglion stimulation, regional function increased in both groups of animals (P = 0.008 vs. baseline), but the increase in hibernating myocardium was blunted compared with controls (Delta%, 3 +/- 2% vs. 8 +/- 3%, P = 0.04). Similar results occurred with intracoronary tyramine (10 mug/kg). Functional improvement during intravenous epinephrine infusion (0.35 mug.kg(-1).min(-1)) was also blunted in hibernating myocardium compared with controls (Delta%, 7 +/- 1% vs. 15 +/- 2%, P = 0.04). Even when the improvement in function was expressed relative to the reduced baseline, there was no evidence for catecholamine-mediated hypersensitivity in hibernating myocardium. We therefore conclude that functional responses to both pre- and postjunctional sympathetic stimulation are blunted in pigs with hibernating myocardium. In contrast to previous studies of infarcted, denervated, and acutely stunned myocardium, there is no catecholamine-induced hypersensitivity in hibernating myocardium. These data suggest a downregulation in functional responses to stimulation that would protect hibernating myocardium from demand-induced ischemia at the expense of contractile reserve during sympathetic stimulation.

Animals↗
PubMed1991

Chronic ischaemic ('hibernating') and postischaemic ('stunned') dysfunctional but viable myocardium.

Myocardial stunning might be defined as a transient postischaemic contractile abnormality seen after reperfusion has been achieved. The benefits of reperfusion therapy might be delayed, but will occur within hours to days after reperfusion. Consequently, the stunned myocardium is viable, but its full recovery might be delayed for a few weeks. While multiple pathophysiological mechanisms are reported to be responsible for the stunning phenomenon, a partial failure of calcium cycling seems to be the cause of the electromechanical uncoupling demonstrated in the stunned myocardium. No pharmacological or other means were used to detect myocardial viability in the stunned myocardium since it is, by definition, a viable myocardium. The 'hibernating' myocardium differs from the stunned myocardium in that it is a viable (partially or completely), chronically underperfused myocardium with an impaired metabolism and function which is slowly reversible when adequate blood flow is restored. This condition represents an 'extreme defence mechanism' in response to profound and chronic ischaemia; however, it does not occur in all patients with chronic myocardial ischaemia. In some circumstances the myocardium might undergo ischaemic necrosis instead of hibernation, with irreversible structural and functional damage. The mechanism leading to one or other response to chronic ischaemia is unclear and might depend on the degree and duration of myocardial ischaemia and histopathological response. Thus, the detection of hibernated myocardium is highly significant because it constitutes a potentially salvageable myocardium. The gold standard for the clinical detection of these conditions is positron emission tomography (PET), but it is uncertain what role echocardiography and pharmacological tests could play in this field.

Coronary Disease↗
PubMed1994

[Postinfarction hibernating myocardium].

The detection of hibernating myocardium after infarction is important because it justifies the discussion concerning the revascularisation of infarcted zones irrigated by occluded or severely stenosed vessels, but with an adequate collateral circulation to allow hibernation. The detection of hibernating myocardium is particularly important in patients without the classical indications for revascularisation, such as residual spontaneous ischaemia or ischaemia provoked by exercise or pharmacological stress testing. All techniques currently in use tend to overestimate the size of the necrosed, fibrous scar, compared with the amount of viable myocardium. Improved regional myocardial function after revascularisation is the most convincing proof of hibernating myocardium but it can only be obtained retrospectively. The detection of a reserve of contractility in the necrosed territory by an inotropic stimulus is well adapted to the demonstration of stunned myocardium but this method has not been proved in hibernating myocardium. Thallium scintigraphy is certainly useful in the prospective diagnosis of hibernating myocardium but the protocol of examination should be adapted to this specific problem. There is little available data concerning the evaluation of hibernating myocardium by positron emission tomography: the technical advantages of this method in assessing myocardial viability should enable a more accurate evaluation of post-infarction hibernating myocardium. Adequate revascularisation of necrosed territories depends on a deeper understanding and more precise prospective assessment of postinfarction hibernating myocardium.

Humans↗
PubMed1994

Characterization of hibernating and stunned myocardium.

Both the hibernating and the stunned myocardium are characterized by reversible contractile dysfunction. In hibernating myocardium ischemia is still ongoing, whereas in stunned myocardium blood flow is fully or almost fully restored. Both the hibernating and the stunned myocardium retain an inotropic reserve. In hibernating myocardium the increase in contractile function is at the expense of metabolic recovery whereas in stunned myocardium no metabolic deterioration occurs during inotropic stimulation. Therefore, inotropic stimulation in combination with metabolic imaging may help not only to identify viable, dysfunction myocardium but also to distinguish hibernating and stunned myocardium. The only causal therapy of hibernating myocardium is to restore blood flow to the hypoperfused tissue. Myocardial stunning per se requires no therapy at all, since by definition blood flow is normal and contractile function will recover spontaneously. If, however, myocardial stunning involves large parts of the left ventricle and thus impairs global left ventricular function, the extent of myocardial stunning can be reduced by inotropic stimulation, without inducing further damage to the myocardium. In the experimental setting, antioxidant agents, calcium antagonists and ACE inhibitors attenuate stunning, most effectively when administered before ischemia.

Adenosine Triphosphate↗
PubMed1996

Hibernating myocardium: a review.

Within a few seconds after a sudden reduction of coronary blood flow regional contractile dysfunction ensues. The mechanisms responsible for the rapid reduction in contractile function during acute myocardial ischemia remain unclear, but may involve a rise in inorganic phosphate. When severe ischemia, such as resulting from a sudden and complete coronary artery occlusion, is prolonged for more than 20-40 min, myocardial infarction develops, and there is irreversible loss of contractile function. When myocardial ischemia is less severe but nevertheless prolonged, the myocardium is dysfunctional but can remain viable. In such ischemic and dysfunctional myocardium, contractile function is reduced in proportion to the reduction in regional myocardial blood flow; i.e. a state of "perfusion-contraction matching" exists. The metabolic status of such myocardium improves over the first few hours, as myocardial lactate production is attenuated and creatine phosphate, after an initial reduction, returns towards control values. Ischemic myocardium, characterized by perfusion-contraction matching, metabolic recovery and lack of necrosis, has been termed "short-term hibernating myocardium". Short-term hibernating myocardium can respond to an inotropic stimulation with increased contractile function, however, at the expense of a renewed worsening of the metabolic status. This situation of an increased regional contractile function at the expense of metabolic recovery during inotropic stimulation can be used to identify short-term hibernating myocardium. When inotropic stimulation is prolonged, the development of short-term hibernation is impaired and myocardial infarction develops. The mechanisms responsible for the development of short-term myocardial hibernation remain unclear at present; a significant involvement of adenosine and of activation of ATP-dependent potassium channels has been excluded. Whereas short-term hibernation is well characterized in animal experiments, the existence of hibernation over weeks or months (long-term hibernation) can only be inferred from clinical studies. Hibernation, as defined by Rahimtoola, is a state of chronic contractile dysfunction which is fully reversible upon reperfusion. Clinical syndromes consistent with the existence of myocardial hibernation include unstable and stable angina, acute myocardial infarction and left ventricular dysfunction and/or congestive heart failure. In long-term hibernating myocardium morphological alterations occur; the myofibrils are reduced in number and disorganized and myocardial glycogen content as well as the extracellular collagen network are increased. Thus, despite the fact that the myocardium remains viable during persistent ischemia and contractile dysfunction is reversible upon reperfusion, there are severe morphological alterations. Understandably, full functional recovery following reperfusion might therefore require weeks or even months.

Animals↗
PubMed1998

Increased amounts of collagenase and gelatinase in porcine myocardium following ischemia and reperfusion.

We studied the presence of collagen degrading enzymes (matrix metalloproteinases, MMPs) in porcine myocardium following ischemia and late reperfusion. In nine pigs, left anterior descending coronary artery was occluded for 6 h followed by reperfusion for 3 h. Six pigs without coronary occlusion served as controls. After the reperfusion period, transmural biopsies from the anterior (ischemic zone) and posterior wall (non-ischemic myocardium) in the left ventricle were obtained and extracted. Heparin-Sepharose isolated components in extracts were analysed for collagenase (triple-helical collagen degradation) and gelatinase activity (zymography). Immunohistochemistry using anti-human (MMP-1, MMP-2, MMP-9, and fibronectin) antibodies was performed on additional biopsies. Collagenase (MMP-1) and gelatinases (MMP-2, MMP-9) could be demonstrated in the extracts of non-ischemic myocardium from ischemic/reperfused as well as control pigs and MMP-1 and MMP-9 activity was found to be increased in ischemic/reperfused myocardium compared with non-ischemic myocardium. In ischemic/reperfused myocardium from live pigs investigated, myocyte necrosis could be confirmed by fibronectin immunoreaction in myocytes and MMP-1 and MMP-9 immunoreactions were increased. MMP-9 was present in cells likely to be infiltrating leukocytes in a patchy distribution throughout the ischemic myocardium. Quite coincident with MMP-9 positive cells, MMP-1 immunoreaction appeared in necrotic myocytes, in addition to reactions observed in vessel walls, endo- and epicardium, and extracellular matrix in non-ischemic myocardium. Thus, the results showed increased amounts of collagenase (MMP-1) and gelatinase (MMP-9) in ischemic/ reperfused myocardium, indicating the appearance of increased amounts of collagen degrading enzymes very early following ischemia and late reperfusion.

Animals↗
PubMedDate not supplied

Production and metabolism of ceramide in normal and ischemic-reperfused myocardium of rats.

Ceramide has been shown to be a key signaling molecule involved in the apoptotic effect of tumor necrosis factor alpha (TNF-alpha) and other cytokines. Given the importance of cytokines such as TNF-alpha in myocardial ischemia-reperfusion injury, we hypothesize that ceramide is increased during ischemia or reperfusion, and that the activity of enzymes responsible for its production or breakdown should be increased and/or decreased, respectively. Therefore, in the present study, we characterized the enzymatic activities responsible for ceramide production and metabolism in the myocardium of rats, and determined the contribution of these enzymes to altered ceramide levels during myocardial ischemia and reperfusion. The basal ceramide concentration in the myocardium of rats was 34.0 pmol/mg tissue. As determined by the conversion of 14C-sphingomyelin into ceramide and 14C-choline phosphate, both neutral (N-) and acidic (A-) SMase were detected in the myocardium, with a conversion rate of 0.09 +/- 0.008 and 0.32 +/- 0.05 nmol/min per mg protein, respectively. The activity of A-SMase (78 % of total cellular activity) was significantly higher in microsomes than in cytosol, while the activity of N-SMase was similar in both fractions. Ceramidase, a ceramide-metabolizing enzyme, was also detected in the myocardium of rats. It metabolized ceramide into sphingosine at a rate of 9.94 +/- 0.42 pmol/min per mg protein. In anesthetized rats, 30 min of ischemia had no apparent effect on ceramide concentrations in the myocardium, while 30 min of ischemia followed by 3 h of reperfusion resulted in a significant increase in ceramide by 48 %. The activities of both N- and A-SMase were reduced by 44 % and 32 %, respectively, in the myocardium subjected to ischemia followed by reperfusion, but unaltered in the ischemic myocardium. It was also found that myocardial ischemia followed by reperfusion produced a marked inhibition of ceramidase (by 29 %). These results demonstrate that the myocardium of rats expresses N- and A-SMase and ceramidase, which contribute to the production and metabolism of ceramide, respectively. Tissue ceramide concentrations increased in reperfused myocardium. These increases in ceramide were not associated with enhanced SMase activity, but rather with reduced ceramidase activity.

Animals↗
PubMed1985

Quantification of myocardium at risk in unstable angina: comparison of patients with and without previous infarction.

We studied two subgroups of patients with unstable angina pectoris: 35 without (Group A) and 73 with (Group B) previous myocardial infarction. The severity of coronary artery disease was assessed by means of a previously described scoring system. This scoring system was used to calculate the proportion of left ventricular myocardium fed by significantly (greater than 75% luminal area reduction) stenosed coronary arteries (called percent myocardium threatened). To estimate the amount of myocardium lost by previous infarction we used a four-point wall motion score for each of seven left ventricular wall segments: a value of 2 was given to normokinetic segments, 1 for hypokinetic segments, 0 for akinetic and -1 for dyskinetic segments. The deficit in wall motion score was used to estimate the amount of myocardium infarcted. This was then subtracted from the proportion of myocardium threatened to yield the proportion of myocardium still in jeopardy. We found a different extent and severity of coronary artery disease between the two subgroups. In the group without previous infarction, the numbers of patients with one-, two- and three-vessel disease were 15, 9, and 11, respectively (or 43, 26, and 31%). In those with a previous infarction, the respective numbers were 11, 23, and 39 (or 15, 31.5, and 53.5%). This difference is statistically significant (P less than 0.01). The mean number of stenotic arteries was 1.9 +/- 0.9 in the patients without previous infarction and 2.4 +/- 0.7 in those with an infarction (P less than 0.05). Using the above-mentioned scoring system the score was 3.2 +/- 1.4 in patients without previous infarction and 4.0 +/- 1.6 in those with previous infarction (P less than 0.05). The percent myocardium threatened was 53.6 +/- 24.1 vs. 68.7 +/- 24.7 (P less than 0.01). Wall motion score was 13.8 +/- 0.6 in Group A and 10.6 +/- 3.1 in Group B (P less than 0.01), which gives values for the proportion of myocardium infarcted of 1.6 +/- 4.2 and 24.2 +/- 22.0%, respectively. The percentage still in jeopardy (after subtracting that infarcted from that threatened) was 51.8 +/- 22.7 in those without and 44.2 +/- 31.1 in those with a previous infarction: this difference is not statistically significant. We conclude that patients with unstable angina pectoris who have sustained a previous myocardial infarction have more severe coronary artery disease than similar patients without previous infarction. The amount of left ventricular myocardium still in jeopardy of becoming infarcted is, however, the same.

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PubMed2004

Ultrastructural evidence of increased tolerance of hibernating myocardium to cardioplegic ischemia-reperfusion injury.

OBJECTIVES: The goal of this study was to investigate the effects of ischemia-reperfusion on myocardial ultrastructure in patients with and without hibernating myocardium. BACKGROUND: It is generally accepted that chronically dysfunctional, hibernating myocardium may remain nonetheless viable for a long time. It has been postulated that hibernating myocytes may survive, despite being subtended by a severe coronary artery stenosis, as they might be less susceptible to ischemic insults. However, whether hibernating myocardium is indeed more resistant to ischemia has never been investigated. METHODS: Myocardial biopsies were taken before cardiac arrest and after reperfusion from the anterior wall of the left ventricle in patients undergoing coronary artery bypass surgery, divided according to presence (n = 7) or absence (n = 7) of hibernating myocardium. Ultrastructural changes were studied by electron microscopy. Because ischemia-reperfusion injury is related to oxidative stress, we also evaluated coronary sinus concentration of the antioxidants alpha-tocopherol, beta-carotene, and ubiquinol, and of lipid peroxidation products pre-ischemia and after reperfusion. RESULTS: Both groups were similar with respect to length of ischemia and changes in the various indexes of oxidative stress. In normally contracting myocardium, ischemia/reperfusion induced moderate overall ultrastructural changes, and marked alterations at the mitochondrial level. In contrast, post-reperfusion biopsies of hibernating myocardium displayed only minor overall ultrastructural changes, and scored significantly better on mitochondrial damage. CONCLUSIONS: Despite similar severity of ischemia/reperfusion, hibernating myocardium showed significantly less ultrastructural evidence of cell injury compared with normally contracting myocardium. These data indicate that human hibernating myocardium is intrinsically more resistant to ischemia/reperfusion injury.

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PubMed2001

Ischemically compromised myocardium displays different time-courses of functional recovery: correlation with morphological alterations?

OBJECTIVE: It has been demonstrated that positron emission tomography (PET) predicts the functional recovery of viable but ischemically compromised myocardium. Reversible contractile dysfunction after revascularization has been reported for 'hibernating myocardium' and stunned myocardium, however, there are little data concerning the time-course and the extent of improvement of the two different pathophysiological conditions. METHODS: Twenty-nine patients with advanced coronary artery disease and severely reduced left ventricular function (EF 18--35%) who were referred for isolated coronary artery bypass grafting underwent preoperative PET viability assessment and were functionally assessed by two-dimensional echocardiography preoperatively at 11 days, 14 weeks, and more than 12 months after surgical revascularization. Intraoperative biopsies were taken from dysfunctional areas defined by PET as segments of normal perfusion and normal metabolism (stunned myocardium) and from areas with a 'mismatch' between perfusion and metabolism (hibernating myocardium). The degree of morphological alterations was evaluated by electron microscopy. RESULTS: In 70% of the 240 dysfunctional segments, 'stunned myocardium' was present whereas 'hibernating myocardium' could be detected in only 24% (P < 0.01). Hibernating myocardium was associated with more severe preoperative wall motion abnormalities and incomplete postoperative recovery. After 1 year, 31% of 'stunned' segments vs. only 18% of 'hibernating' segments showed complete functional restoration (P < 0.05). This incomplete improvement was associated with more severe morphological alterations including depletion of sarcomeres, accumulation of glycogen, loss of sarcoplasmatic reticulum, and cellular sequestration. CONCLUSIONS: These data indicate that in patients with severe ischemic left ventricular dysfunction 'stunned myocardium' is more prevalent than 'hibernation'. Functional normalization is more frequent in 'stunned' segments, whereas areas of 'hibernation' showed more severe tissue injury and protracted recovery. Different degrees of myocardial injury coexist in most patients, which determines the time-course and the extent of improvement after revascularization.

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