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PubMed1999

Profound apoptosis-mediated regional myocyte loss and compensatory hypertrophy in pigs with hibernating myocardium.

BACKGROUND: Myocyte apoptosis is seen in ischemic heart disease, but whether it can occur after reversible ischemia or independent of necrosis and replacement fibrosis is unknown. METHODS AND RESULTS: Pigs were instrumented with a stenosis of the left anterior descending coronary artery to chronically reduce coronary flow reserve over a period of 3 months. At this time, there was viable dysfunctional myocardium having the physiological features of hibernating myocardium. Resting subendocardial perfusion was reduced to 0.65+/-0.08 (mean+/-SEM) mL. min(-1). g(-1) in hibernating myocardium of instrumented pigs compared with 0.98+/-0.14 mL. min(-1). g(-1) in myocardium of sham-operated pigs (P<0.05). There was a critical limitation in subendocardial flow during vasodilation to 0.78+/-0.20 mL. min(-1). g(-1) in instrumented pigs versus 3. 24+/-0.50 mL. min(-1). g(-1) in sham-operated pigs (P<0.001). Histology revealed a regional reduction in myocyte nuclear density to 995+/-100 nuclei/mm(2) in hibernating myocardium from the instrumented group versus 1534+/-65 nuclei/mm(2) in myocardium from the sham-operated group (P<0.05), regional myocyte hypertrophy (myocyte volume per nucleus, 14 183+/-2594 in the instrumented group versus 9130+/-1301 microm(3) in the sham group; P<0.05), and minimal increases in connective tissue (5.8+/-0.9% in the instrumented group versus 3.0+/-0.2% in the sham group, P<0.05). Necrosis was not identified, but apoptosis was increased from 30+/-9 myocytes per 10(6) myocyte nuclei in myocardium from the sham group to 220+/-77 myocytes per 10(6) myocyte nuclei in hibernating myocardium (P<0.05). CONCLUSIONS: These findings indicate that reversible ischemia in an area of chronically reduced coronary flow reserve induces regional myocyte loss via an apoptotic mechanism. This may contribute to the progression of chronic coronary disease to heart failure and explain the lack of complete functional recovery after revascularization in hibernating myocardium.

Animals↗
PubMed2001

Viable myocardium in reperfused acute myocardial infarction: rest and stress first-pass mr imaging.

Feasibility of identifying viable myocardium in rest and stress magnetic resonance imaging (MRI) was evaluated using 3 hr occlusion and 30 min reperfusion model of left anterior descending (LAD) coronary artery in 12 felines. At rest MRI, viable myocardium confirmed by 2,3,5-triphenyl tetrazolium chloride (TTC)-staining showed rapid signal intensity (SI) rise followed by gradual decline not significantly different from normal myocardium that the two hyperperfused regions were distinguishable only from the hypoperfused nonviable myocardium. At stress MRI, hyperemia induced perfusion change was most pronounced in normal myocardium with earlier and greater peak enhancement followed by brisk 'washout' phase while minimally augmented enhancement in viable myocardium was still in 'washin' phase. From these findings, it was concluded that viable myocardium is identified in rest and stress MRI as redistributing hypo- perfusion compared to persistent hyper-perfusion of the normal myocardium and the persistent hypo-perfusion of the nonviable myocardium.

Animals↗
PubMedDate not supplied

[Experimental-theoretical study of the force-interval relationship in the developing chicken myocardium].

The force-interval relationship was studied on myocardium preparations from chick embryos and hatched chickens. It is shown that the force-interval relationships of myocardium change during ontogenesis. A negative staircase (a decrease in the isometric force with increasing stimulation rate) in the chick embryo myocardium and a positive steady-state relationship in hatched stage myocardium were revealed. Changes in the force after switching from one stimulation frequency to another, the effects of poststimulation potentiation, as well as responses to the introduction of pauses and extrasystols at a constant stimulation rate were recorded. All the effects observed in the transient processes in preparations from hatched stage myocardium were more pronounced than in embryo myocardium. Our previous mathematical model of calcium recirculation in cardiomyocytes was adapted for simulating the main features of force-interval relationships in embryonal and relatively developed myocardium. The main source of regulatory calcium in the model of hatched stage myocardium is sarcoplasmic reticulum. In the model of embryo myocardium, it was postulated, based on data available in literature, that the main regulator of contractile response of the muscle is calcium that enters cardiomyocytes from extracellular medium. To describe force-interval relationships, by this model, the decreasing dependence of the entry of extracellular calcium on the intervals between stimuli was introduced.

Animals↗
PubMed2002

The role of SR Ca(2+)-content in blunted inotropic responsiveness of failing human myocardium.

The effects of inotropic agents are blunted in end-stage failing human myocardium. This has been related to a number of subcellular alterations including desensitization of the beta -adrenergic system. However, it is unknown whether alterations in SR Ca(2+)-handling contribute to blunted inotropic responsiveness of failing myocardium. We tested the hypothesis that the reduced effectiveness of Ca(2+)-dependent inotropic interventions results from the inability of the SR to sufficiently increase its Ca(2+)-content in failing human myocardium. Experiments were performed in ventricular muscle preparations from a total of four non-failing and 18 end-stage failing hearts. Isometric twitch force and SR Ca(2+)-content (using rapid cooling contractures; RCCs) were assessed under basal experimental conditions (1 Hz, 37 degrees C, [Ca(2+)](o) 2.5 mmol/l), and at increasing [Ca(2+)](o) (1.25-15 mmol/l), increasing concentrations of the beta -adrenergic agonist isoproterenol (ISO; 0.01-10 micromol/l), or the glycolytic substrate pyruvate (5-15 mmol/l). In addition, paired RCCs were evoked in a subset of experiments to investigate the relative contribution of SR Ca(2+)-uptake v Na(+)/Ca(2+)-exchange to cytosolic Ca(2+)-elimination. In non-failing human myocardium, Ca(2+), ISO, and pyruvate exerted significant positive inotropic effects (increase in twitch force by maximally 396%, 437%, and 82%, respectively). The inotropic effects were associated with increasing RCCs (by 147%, 193%, and 51%, respectively). In failing myocardium, the inotropic effects of Ca(2+) and ISO were significantly less pronounced (with maximal increases in twitch force by 226% and 138%, respectively), associated with blunted effects on RCCs (increase by 33% and 79%, respectively). In contrast, the inotropic effect of pyruvate was unchanged in failing myocardium (increase by 66%), while the corresponding RCCs increased only by 30%. We conclude that the inotropic effects of Ca(2+), ISO, and pyruvate are associated with a significant increase in SR Ca(2+)-content in non-failing human myocardium. In end-stage failing myocardium, the reduced inotropic response to Ca(2+) and ISO is associated with the inability of the SR to appropriately increase its Ca(2+)-content, possibly related to decreased SR Ca(2+)-ATPase and increased Na(+)/Ca(2+)-exchanger expression. In contrast, the maintained inotropic response to pyruvate despite reduced SR Ca(2+)-loading points to additional subcellular effects such as enhanced myofilament Ca(2+)-responsiveness.

Calcium↗
PubMed1991

Calcium handling in myocardium from amphibian, avian, and mammalian species: the search for two components.

Steps involved in excitation-contraction coupling in mammalian myocardium have been derived using a relatively limited number of animal species. However, the use of animal models for investigations into excitation-contraction coupling in normal and disease states has encompassed a wide range of animal species. We addressed the question as to whether excitation-contraction coupling as currently understood applies to intracellular calcium handling in myocardium from multiple mammalian species, amphibian, and avian myocardium. The bioluminescent calcium indicator aequorin was used to record intracellular calcium transients in both ventricular and atrial tissue. We report that in all mammalian and avian species studied the calcium transient recorded in both ventricular and atrial myocardium is monophasic and reflects calcium release and re-uptake by the sarcoplasmic reticulum. In contrast, the Ca2+ transient recorded from salamander myocardium is prolonged relative to mammalian and avian myocardium, and appears to reflect in part trans-sarcolemmal calcium entry. Only in diseased myocardium derived from human and swine myocardium was a second component detected in the calcium transient. These data indicate that sarcoplasmic reticulum calcium handling is pivotal in excitation-contraction coupling for multiple species with differing physiologies. Also, in disease states, intracellular calcium handling is often affected with resultant alterations in the time-course and/or configuration of the calcium transient.

Aequorin↗
PubMed1980

Digoxin concentration in right atrial myocardium, skeletal muscle and serum in man: influence of atrial rhythm.

Serum, right atrial myocardium and skeletal muscle collected from 32 adult patients undergoing open heart surgery were analyzed for digoxin by radioimmunoassay. Preoperatively 20 patients were in sinus rhythm, but not in patients with atrial fibrillation, there was a highly significant correlation between digoxin concentration in serum and right atrial myocardium, in skeletal muscle and right atrial myocardium, and in serum and skeletal muscle. The means and variances of the ratios right atrial myocardium/serum and right atrial myocardium skeletal muscle were significantly higher in patients with atrial fibrillation than in those with sinus rhythm. This, plus the lack of difference in ratios skeletal muscle serum between these groups of patients, indicate increased right atrial digoxin binding in atrial fibrillation in man. This conclusion is further supported by the finding of similar or higher digoxin concentration in right atrial myocardium than in left ventricular myocardium in atrial fibrillation (6 patients), and a lower digoxin concentration in right atrial myocardium than in left ventricular myocardium in sinus rhythm (3 patients).

Adult↗
PubMed2001

(31)P-MR Spectroscopy for the evaluation of energy metabolism in intact residual myocardium after acute myocardial infarction in humans.

OBJECTIVE: Experimental studies have demonstrated that acute myocardial infarction (MI) alters energy metabolism even in non-infarcted adjacent tissue. In patients with subacute MI, the influence of the regional ischemic insult on energy metabolism of intact septal myocardium was analyzed using 31P-Magnetic resonance spectroscopy (MRS). PATIENTS AND METHODS: In eight patients with wall motion abnormalities in the anterior wall 31P-spectra were obtained from non-infarcted adjacent septal myocardium, as well as infarcted anterior myocardium (voxel size 25 ccm each) 29+/-8 days after MI using a 3D-CSI technique. Additionally, cardiac function was analyzed using breath-hold cine MRI. MRI was repeated 6 months after revascularization to assess viability of infarcted segments. Eight age-matched healthy volunteers served as control group. RESULTS: According to follow-up MRI 4/8 patients showed regional wall motion recovery. Here, PCr/ATP-ratios were not significantly reduced in intact septal myocardium as well as infarcted anterior myocardium compared to healthy volunteers (1.28+/-0.10 and 1.14+/-0.09 vs. 1.45+/-0.29). No recovery of regional function was detected in 4/8 patients with-therefore-non-viable anterior myocardium. PCr/ATP-ratios were significantly reduced in intact and infarcted myocardium compared with healthy volunteers as well as to patients with wall motion recovery (0.77+/-0.17 and 0.49+/-0.23; P<0.05). DISCUSSION: These preliminary results indicate that energy metabolism is reduced in patients with persisting wall motion abnormalities after myocardial infarction and revascularization in ischemically injured as well as in adjacent non-injured myocardium.

Aged↗
PubMed1999

Calcium-sensitivity of the SR calcium release channel in failing and nonfailing human myocardium.

BACKGROUND: Altered Ca2+ metabolism of the sarcoplasmic reticulum results in changes of the contractile behavior in failing human myocardium. The ryanodine-sensitive Ca2+ release channel of the sarcoplasmic reticulum plays a key role in the intracellular Ca2+ handling in cardiac myocytes. Recently, we showed that the density of 3H-ryanodine binding sites which correspond to the SR Ca2+ release channel in human myocardial homogenates is unchanged in failing human myocardium. However, the sensitivity of the channel towards Ca2+, which acts as the trigger signal of channel activation and thereby initiates contraction, has not yet been investigated in failing and nonfailing myocardium. METHODS: Homogenates (100 micrograms protein) from hearts with dilated (DCM, n = 10) or ischemic (ICM, n = 9) cardiomyopathy were incubated with a saturating concentration of 3H-ryanodine (12 nM) in the presence of different Ca2+ concentrations ranging from 1 nM to 10 mM. For comparison, myocardium of 8 nonfailing hearts which could not be transplanted for technical reasons was investigated. Non-specific binding was determined in the presence of a high concentration (10 microM) of unlabeled ryanodine. RESULTS: 3H-ryanodine binding to the Ca2+ release channel showed a bell-shaped pattern with an increase in specific binding at submicromolar Ca2+ concentrations and a decrease at higher Ca2+ concentrations than 0.5 mM, whereas nonspecific binding was not influenced by different Ca2+ concentrations. In nonfailing myocardium, maximal 3H-ryanodine binding (Bmax) was 85.2 +/- 3.1 fmol/mg protein and half-maximal binding was reached at a free Ca2+ concentration of 0.25 (0.22-0.30) microM (EC50). Neither EC50 values nor maximal specific 3H-ryanodine binding differed between nonfailing and failing myocardium of both etiologies. EC50 values were 0.24 (0.23-0.26) microM (DCM, n = 10) or 0.28 (0.25-0.31) microM (ICM, n = 9), respectively. Caffeine (2 mM) and the ATP-analogon AMP-PCP (1 mM) led to a shift towards lower Ca2+ concentrations consistent with an activation of the channel by these compounds, whereas Mg2+ (0.7 mM) shifted the Ca(2+)-dependence of 3H-ryanodine binding towards higher Ca2+ concentrations indicating inhibition of channel opening. After activation of the Ca2+ release channel by caffeine or AMP-PCP as well as after the inhibition with Mg2+ EC50 values were the same in failing and nonfailing myocardium. CONCLUSION: Caffeine and AMP-PCP sensitize, whereas Mg2+ desensitizes the myocardial Ca2+ release channel to Ca2+. The determination of Ca(2+)-dependent 3H-ryanodine binding to the human myocardial Ca2+ release channel is a useful tool to investigate its open probability. Furthermore, the Ca(2+)-sensitivity and the pharmacological behavior of the human SR Ca2+ release channel are similar in failing and nonfailing myocardium.

Calcium↗
PubMedDate not supplied

Targeting of Lin-Sca+ hematopoietic stem cells with bispecific antibodies to injured myocardium.

Bispecific antibodies (BiAbs) are being used to target T cells or other immune cells to antigen-specific tumor targets. Anti-CD3 activated T cells (ATC) armed with anti-CD3 x anti-HER2 BiAb (HER2Bi) have been used to target Her2/neu + breast and prostate carcinoma cells. We adapted BiAb technology to target stem cells to injured myocardium. Since myocardial infarctions can lead to cardiac death and disability, rapid repair and rejuvenation of damaged myocardium is critically needed. Effective homing of stem cells and transdifferentiation of the stem cells into functional elements of the myocardium is needed for repair of damaged myocardium. We use a BiAb that binds c-kit on murine stem cells and VCAM-1 adhesion molecules up-regulated on injured myocardial cells. To test for specific binding and homing in a mouse, we produced anti-c-kit x anti-VCAM-1 to target purified Lin-Sca+ murine stem cells to the injured myocardium. Mice with infarcts created by ligation of the left anterior descending artery (LAD) were directly injected with armed stem cells or injected via the internal jugular vein (IJ) with FACS sorted Lin-Sca+ stem cells from bone marrow after fluorescent dye labeling. There were increased numbers of armed Lin-Sca+ cells retained in infracted myocardium after direct injection of armed Lin-Sca+ cells and increased numbers of Lin-Sca+ cells that were found in injured myocardium after IJ injection. These results suggest that stem cells retargeted with BiAb can be directly injected and retained by injured myocardium or targeted to injured myocardial tissues for tissue regeneration.

Animals↗
PubMed2003

Disproportionate enhancement of myocardial contractility by the xanthine oxidase inhibitor oxypurinol in failing rat myocardium.

OBJECTIVE: Xanthine oxidase (XO) inhibitors enhance myofilament Ca(2+) responsiveness of normal rat myocardium. We examined whether this inotropic action is preserved or magnified in failing rat myocardium and whether the magnitude of this effect correlates with tissue xanthine-oxidoreductase (XOR) activity. METHODS: Hearts of 18-20 month-old SHHF (spontaneous hypertensive/heart failure) rats with end-stage heart failure, as well as of normal control rats, were perfused with the XO inhibitor oxypurinol. Afterwards, [Ca(2+)](i) and tension were measured simultaneously in fura-2-loaded intact isolated right ventricular trabeculae. XOR activity was determined fluorometrically in myocardial homogenates. RESULTS: In failing myocardium, 100 microM oxypurinol significantly increased systolic twitch tension (by 87 and 92% at 1.0 and 1.5 mM extracellular [Ca(2+)], respectively), without altering [Ca(2+)](i) transient amplitude. Oxypurinol did not alter the midpoint or cooperativity of the steady-state tension-[Ca(2+)](i) relationship, but significantly enhanced maximum Ca(2+)-activated tension by 75% in failing myocardium. Oxypurinol also exerted a positive inotropic effect in failing myocardium, which was, however, of significantly smaller relative magnitude. Failing rat myocardium exhibited higher XOR activity than nonfailing myocardium, and this activity was largely suppressed in oxypurinol-treated preparations. CONCLUSIONS: The magnitude of functional improvement with XOR inhibitors depends on the initial level of XOR activity. Specifically, the inotropic actions of oxypurinol are more pronounced in failing rat myocardium, a tissue that exhibits enhanced XOR activity. Our findings rationalize how XO inhibitors boost cardiac contractility and improve mechanoenergetic coupling, and why the effects might be relatively 'selective' for heart failure.

Animals↗
PubMed2000

Glucose metabolism in reperfused myocardium measured by [2-18F] 2-fluorodeoxyglucose and PET.

OBJECTIVE: [2-18F] 2-fluorodeoxyglucose (FDG) is widely used to trace glucose metabolism for cardiac imaging with positron emission tomography. Because the transport and phosphorylation rates differ for glucose and FDG, a lumped constant (LC) is used to correct for these differences. The effects of ischemia and reperfusion on the LC in vivo are unknown. To determine the validity of FDG as a tracer of glucose metabolism in post-ischemic myocardium in vivo, the relationship between glucose uptake (GU) and FDG metabolic rate (FDG-MR) was assessed early post-reperfusion following a transient ischemic event. METHODS: FDG metabolic rate, measured with FDG and PET, was compared to invasive measurements of substrate metabolism in reperfused and global myocardium of dogs subjected to 25 min ischemia and 2 h reperfusion. RESULTS: The FDG metabolic rate was decreased 20 +/- 4% in reperfused relative to remote myocardium. Glucose oxidation and lactate uptake were also decreased in reperfused relative to global myocardium, by 26 +/- 6% and 60 +/- 8% respectively. Glucose uptake did not differ significantly between reperfused and global myocardium. A linear correlation between FDG metabolic rate and glucose uptake was found in both reperfused and remote myocardium. Estimates of the LC from the slopes of the regression lines were similar in reperfused and remote myocardium, 1.25 and 1.44 respectively, and did not differ significantly from the LC determined in control dogs, 1.1. CONCLUSIONS: We conclude that the FDG metabolic rate continues to correlate well with glucose metabolism in reperfused myocardium. While FDG metabolic rate was modestly decreased in the absence of a significant change in glucose uptake, large alterations in the LC are not found 2 h post-reperfusion in vivo.

Animals↗
PubMed1987

Selective perfusion of ischemic myocardium during coronary venous retroinjection: a study of the causative role of venoarterial and venoventricular pressure gradients.

Coronary venous retroinjection is often associated with preferential distribution of flow to ischemic myocardium. The purpose of this study was to define the mechanism of such retrodistribution of flow. In 24 anesthetized open chest dogs, Monastral blue dye (10 ml) was injected by way of a balloon catheter in the distal great cardiac vein as a marker for retrograde flow distribution. The injection rate (0.6 to 2.4 ml/s) was adjusted such that systolic pressure in the anterior interventricular vein ranged between 60 and 85 mm Hg. In 11 dogs with no ischemia and normal myocardial perfusion pressure (96 +/- 8 mm Hg), no myocardial staining occurred despite retrograde filling of epicardial veins. One minute after occlusion of the left anterior descending coronary artery, dye injections caused selective staining of the cyanotic area in 15 of 18 episodes, sparing the normal myocardium within the zone of retroperfused veins. In five dogs, with the arterial pressure less than 55 mm Hg, retroinjection resulted in homogeneous staining of all the myocardium drained by the retroperfused veins. Selective staining of the ischemic myocardium caused by retroinjection was associated with the following pressure gradients: during systole from the anterior interventricular vein to the occluded coronary artery, 31 to 58 mm Hg, and during diastole from the retroperfused veins to the left ventricular chamber, 9 to 28 mm Hg. There was no diastolic venoarterial gradient in the ischemic myocardium. In normal myocardium, retroinjection did not reverse the arteriovenous pressure gradient. In conclusion, retrograde flow is primarily directed to myocardium with low anterograde perfusion pressure. Selective retrograde penetration of acutely ischemic myocardium can thus be achieved by a mechanism consistent with the development of venoarterial and venoventricular pressure gradients.

Animals↗
PubMed2001

Characterization of beta(1)-selectivity, adrenoceptor-G(s)-protein interaction and inverse agonism of nebivolol in human myocardium.

Intrinsic activity and beta(1)-selectivity are important features of beta-blockers in the treatment of patients with coronary syndromes and heart failure. In human myocardium, intrinsic activity and beta(1)-selectivity of the novel beta-adrenoceptor antagonist nebivolol have not yet been determined. The study examines intrinsic activity, beta-adrenoceptor-G-protein coupling and beta(1)-selectivity of nebivolol and bisoprolol in human ventricular myocardium. Furthermore, intrinsic activity of both compounds is compared to the one of bucindolol, carvedilol and metoprolol in human atrial myocardium. Radioligand binding studies ([(125)I]-lodocyanopindolol) were performed on membrane preparations of human failing and nonfailing myocardium and on COS-7 cells transfected with human beta(1)- and beta(2)-adrenoceptors, respectively. Functional experiments were carried out on isolated muscle preparations of human left ventricular and right atrial myocardium from failing and nonfailing hearts. Radioligand binding studies reveal 3 - 4 fold beta(1)-selectivity for nebivolol and 16 - 20 fold beta(1)-selectivity for bisoprolol in human myocardium. In COS-7-cells, beta(1)-selectivity is 3 fold for nebivolol and 15 fold for bisoprolol. Neither the binding of nebivolol nor of bisoprolol is affected by the presence of guanylylimidodiphosphate (Gpp(NH)p). Nebivolol and bisoprolol exert similar inverse agonist activity in human ventricular as well as atrial myocardium. In atrial myocardium, inverse agonism of both compounds is higher compared to bucindolol, equal to carvedilol and lower compared to metoprolol. Favourable haemodynamic effects of nebivolol in humans are not due to beta(1)-selectivity or partial agonist activity of this agent. Other mechanisms, i.e. the production of nitric oxide, may thus be responsible for its unique haemodynamic profile.

Adrenergic beta-Agonists↗
PubMed2001

Myocardium extending from the left atrium onto the pulmonary veins: a comparison between subjects with and without atrial fibrillation.

Rapid discharges from the myocardium extendingfrom the left atrium onto the pulmonary vein (PV) have been shown to initiate AF, and AF may be eradicated by the catheter ablation within the PV. However, if there is any difference in the distribution patterns of the myocardial sleeve onto the PV between the subjects with and without AF is to be determined. Twenty-one autopsied hearts were examined. Eleven patients previously had AF before death and another 10 patients had normal sinus rhythm as confirmed from the medical records including ECGs before death. After exposing the heart, the distance to the peripheral end of the myocardium was measured from the PV-atrial junction in each PV. Then, the PVs were sectioned and stained and the distal end of myocardium and the distribution pattern were studied. The anteroposterior diameter of the left atrium was also measured. In 74 of 84 PVs, the myocardium extended beyond the PV-atrial junction. The myocardium was localized surrounding the vascular smooth muscle layerforming a myocardial sleeve. The peripheral end of the myocardial sleeve was irregular and the maximal and minimal distances were measured in each PV. The myocardium extended most distally in the superior PVs compared to the inferior ones and the maximal distance to the peripheral end was similar between the AF and non-AF subjects (8.4 +/- 2.8 vs 8.7 +/- 4.4 mm for the left superior and 6.5 +/- 3.5 vs 5.1 +/- 3.9 mm for the right superior PV, respectively). A significant difference was found in the maximal distance in the inferior PVs: 7.3 +/- 4.6 vs 3.3 +/- 2.8 mm for the left (P < 0.05) and 5.7 +/- 2.4 vs 1.7 +/- 1.9 mm for the right inferior PV (P < 0.001) in the subjects with and without AF, respectively. The diameter of left atrium was slightly dilated in AF patients but insignificantly (4.1 +/- 0.1 vs 3.6 +/- 0.1 cm, P > 0.07). The myocytes on the PV were less uniform and surrounded by more fibrosis in patients with AF compared to those without AF. In conclusion, the myocardium extended beyond the atrium-vein junction onto the PVs. The distribution patterns of the myocardium was almost similar between subjects with and without AF, but the histology suggested variable myocytes in size and fibrosis in patients with AF.

Aged↗
PubMed2002

Regional overexpression of insulin-like growth factor-I and transforming growth factor-beta1 in the myocardium of patients with hypertrophic obstructive cardiomyopathy.

OBJECTIVE: Hypertrophic obstructive cardiomyopathy has been proposed to be the result of gene mutations of contractile proteins. However, we have previously shown significant elevation of insulin-like growth factor-I (IGF-I) and transforming growth factor-beta1 (TGF-beta1) at the messenger RNA, protein, and receptor levels in patients with hypertrophic obstructive cardiomyopathy when compared with myocardium from patients without this disorder. We hypothesized that this growth factor overexpression is a regional phenomenon. To test this hypothesis, we compared levels of IGF-I and TGF-beta1 in hypertrophic and nonhypertrophic myocardium within the same group of patients with hypertrophic obstructive cardiomyopathy. METHODS: Two biopsy specimens were obtained from each patient undergoing septal myectomy for severely symptomatic hypertrophic obstructive cardiomyopathy, from hypertrophied septum and from nonhypertrophied myocardium (8 patients in total). Clinical data were prospectively recorded. Messenger RNA levels for growth factor were quantified by means of multiplex reverse transcriptase-polymerase chain reaction, expressed as a densitometric ratio of growth factor/glyceraldehyde-3-phosphate dehydrogenase. Protein levels were quantified by means of chemiluminescent slot blot analysis. Growth factor proteins were used to generate a standard curve. RESULTS: IGF-I messenger RNA and protein levels in hypertrophic myocardium were 2.6 and 2.9 times greater, respectively, than in nonhypertrophic myocardium of the same patients (both P <.01). TGF-beta 1 messenger RNA and protein levels in the hypertrophic myocardium were 2.5 and 2.8 times greater, respectively, than the levels in the nonhypertrophied myocardium (both P <.01). There was a significant correlation between the IGF-I protein ratio (hypertrophic/nonhypertrophic myocardium) and the inducible left ventricular outflow tract gradients measured at cardiac catheterization (r = 0.77, P =.025). CONCLUSIONS: Myocardial overexpression of IGF-I and TGF-beta1 is a regional phenomenon in patients with hypertrophic obstructive cardiomyopathy and is likely involved in the pathogenesis of the disorder.

Cardiomyopathy, Hypertrophic↗
PubMed1984

Distribution of LDH-1 in normal, ischemic, and necrotic myocardium. An immunoperoxidase study.

To study the distribution of lactate dehydrogenase (LDH-1) (H4) in normal, ischemic, and necrotic myocardium using the peroxidase-antiperoxidase technic, the authors studied formalin-fixed paraffin-embedded sections of human (n = 11) and canine (n = 28) myocardium. All normal control myocardium showed positive immunostaining for LDH-1 (H4). In infarcts 10 hours or more old, the histologically necrotic myocardium (by triphenyl tetrazolium chloride staining) (TTC) showed markedly diminished immunostaining. In 24-dogs ischemia was induced in a closed-chest model using a balloon-tipped catheter inflated in the left anterior descending coronary artery. In dogs with 3 hours or more of occlusion, myocardium that was necrotic by TTC staining, light and/or electron microscopy, showed diminished staining for LDH-1, while normal, control myocardium stained intensely. In four dogs, ischemia was induced by a controlled perfusion apparatus by which left main coronary flow was reduced by 50%. Ischemia without necrosis was documented by demonstration of glycogen loss with no light or electron microscopic evidence of necrosis. These ischemic fibers stained intensely for LDH-1, as did controls. Thus, by immunoperoxidase staining, LDH-1 can be demonstrated in normal human and canine myocardium. In experimental models of ischemia in dogs, tissue that was ischemic but not necrotic showed no diminished staining. LDH-1 loss can be detected in necrotic myocardium as early as 3 hours after coronary artery occlusion.

Animals↗
PubMed1993

Increased activity of the sarcoplasmic reticular calcium pump in porcine stunned myocardium.

OBJECTIVE: The aim was to determine whether changes in sarcoplasmic reticular Ca2+ transport activity and the degree of phosphorylation of phospholamban of "stunned" myocardium are involved in the reversible depression of contractile function. METHODS: In anaesthetised open chest swine, stunning was induced by subjecting the myocardium perfused by the left anterior descending coronary artery to two cycles of 10 min of occlusion and 30 min of reperfusion. Before and after stunning, systemic haemodynamic variables and regional myocardial function and perfusion were determined, while biopsies were taken for determination of the content of high energy phosphate compounds. Sarcoplasmic reticular function (ATP dependent Ca2+ transport and phosphorylation of phospholamban) of the stunned and control myocardium was determined at the end of the stunning protocol. RESULTS: In the stunned myocardium the segment length shortening decreased from 17.4(SD 4.0)% to 3.5(4.4)%, while perfusion was 38% less than at baseline. ATP and total adenine nucleotide levels of the stunned myocardium were about 35% lower than in the control myocardium, but the energy charge was normal as creatine phosphate levels had increased by 66% over the content determined at baseline. Ca2+ uptake by the sarcoplasmic reticulum isolated from the stunned region was 17% (p < 0.05) higher than Ca2+ uptake from the control region [1240(303) and 1450(280) nmol.min-1.mg-1 protein, respectively]. In the presence of exogenous cyclic AMP dependent protein kinase the amount of 32P incorporated into phospholamban was similar for both myocardial regions. CONCLUSIONS: In this model of stunned porcine myocardium, the phosphorylation state of phospholamban was unchanged, but Ca2+ uptake by the sarcoplasmic reticulum was slightly increased. The results indicate that a change in active Ca2+ transport by the sarcoplasmic reticulum is most likely not to be the principal cause of contractile dysfunction of stunned myocardium.

Adenosine Diphosphate↗
PubMed2001

PKA accelerates rate of force development in murine skinned myocardium expressing alpha- or beta-tropomyosin.

In myocardium, protein kinase A (PKA) is known to phosphorylate troponin I (TnI) and myosin-binding protein-C (MyBP-C). Here, we used skinned myocardial preparations from nontransgenic (NTG) mouse hearts expressing 100% alpha-tropomyosin (alpha-Tm) to examine the effects of phosphorylated TnI and MyBP-C on Ca2+ sensitivity of force and the rate constant of force redevelopment (k(tr)). Experiments were also done using transgenic (TG) myocardium expressing approximately 60% beta-Tm to test the idea that the alpha-Tm isoform is required to observe the mechanical effects of PKA phosphorylation. Compared with NTG myocardium, TG myocardium exhibited greater Ca2+ sensitivity of force and developed submaximal forces at faster rates. Treatment with PKA reduced Ca2+ sensitivity of force in NTG and TG myocardium, had no effect on maximum k(tr) in either NTG or TG myocardium, and increased the rates of submaximal force development in both kinds of myocardium. These results show that PKA-mediated phosphorylation of myofibrillar proteins significantly alters the static and dynamic mechanical properties of myocardium, and these effects occur regardless of the type of Tm expressed.

Animals↗