Cardiomyopathic Myocardium Research Articles

Myocardial extracellular volume fraction to differentiate healthy from cardiomyopathic myocardium using dual-source dual-energy CT

ObjectiveTo evaluate the feasibility of dual-energy CT (DECT)-based iodine quantification to estimate myocardial extracellular volume (ECV) fraction in patients with and without cardiomyopathy (CM), as well as to assess its ability to distinguish healthy myocardial tissue from cardiomyopathic, with the goal of defining a threshold ECV value for disease detection. MethodsTen subjects free of heart disease and 60 patients with CM (mean age 66.4 ± 9.4; 59 males and 11 females; 40 ischemic and 20 non-ischemic CM) underwent late iodine enhanced DECT imaging. Myocardial iodine maps were obtained using 3-material decomposition. ECV of the left ventricle was estimated from hematocrit levels and the iodine maps using the AHA 16-segment model. Receiver operating characteristic curve analysis was performed, with corresponding area under the curve, along with Youden's index assessment, to establish a threshold for CM detection. ResultsThe median ECV for healthy myocardium, non-ischemic CM, and ischemic CM were 25.4% (22.9–27.3), 38.3% (33.7–43.0), and 36.9% (32.4–41.1), respectively. Healthy myocardium showed significantly lower ECV values compared to ischemic and non-ischemic CM (p < 0.001). From Youden's index analysis, an ECV>29.5% would indicate the presence of CM in the myocardium (sensitivity = 90.3; specificity = 90.3); the AUC for this criterion was 0.950 (p < 0.001). ConclusionThe findings of this study resulted in a statistically significant distinction between healthy myocardium and CM ECVs. This led to the establishment of a promising threshold ECV value that could facilitate the differentiation between healthy and diseased myocardium, and highlights the potential of this DECT methodology to detect cardiomyopathic tissue.

Longitudinal observations of progressive cardiac dysfunction in a cardiomyopathic animal model by self-gated cine imaging based on 11.7-T magnetic resonance imaging

The purpose of this study was to longitudinally assess left ventricular function and wall thickness in a hamster model of cardiomyopathy using 11.7-T magnetic resonance imaging (MRI). MRI were performed for six cardiomyopathic J2N-k hamsters and six J2N-n hamsters at 5, 10, 15, and 20 weeks of age. Echocardiography was also performed at 20 weeks. The ejection fraction (EF) at 15 and 20 weeks of age in J2N-k hamsters showed a significant decrease compared with those in controls. Conversely, the end-systolic and end-diastolic volumes in cardiomyopathic hamsters showed a significant increase compared with those in controls. Moreover, the heart walls of J2N-k hamsters at 15 and 20 weeks were thicker than those of controls at end-systole; however, there were no significant differences at end-diastole. Optical microscopy with Masson’s trichrome staining depicted no fibrosis in the control myocardium, although it showed interstitial fibrosis in the 20-week-old J2N-k cardiomyopathic myocardium. There were no differences in EF and the wall thickness observed on MRI and those observed on echocardiography. These results indicate the presence of systolic dysfunction in cardiomyopathic hamsters. Self-gated cine imaging based on 11.7-T MRI can be used for serial measurements of cardiac function and wall thickness in a cardiomyopathic model.

Nitric oxide: the missing lusitrope in failing myocardium

During the last decade, the effects of nitric oxide (NO) on contractile function of failing myocardium elicited a lot of interest and research activity. Because of initial reports of NO acutely reducing the extent and velocity of shortening of isolated cardiomyocytes, especially following β-adrenergic stimulation, and because of increased activity of inducible nitric oxide synthase (NOS2) in human cardiomyopathic myocardium, numerous reports and reviews have persistently and erroneously identified NO as deleterious for contractile function of failing myocardium.1 Shortly after these initial reports, a rosier picture of NO's functional myocardial effects emerged, highlighting NO's ability to improve left ventricular (LV) diastolic function. In the normal human heart, intracoronary administration of NO donors instantaneously hastens onset of LV relaxation and increases LV diastolic distensibility.2 These effects appear to be especially favourable in patients with dilated cardiomyopathy as they lower LV filling pressures and increase LV preload reserve. The mechanisms involved in these favourable lusitropic effects of NO differ between exogenous NO and NO produced by some of the nitric oxide synthases (NOSs) because of compartimentalization of the NOSs within the cardiomyocyte. Protein kinase G (PKG)-induced troponin I phosphorylation results in myofilamentary desensitization and thereby mediates lusitropic effects of exogenous NO and of NO produced by endothelial nitric oxide synthase (NOS3),2 whereas sarcoplasmic reticular (SR) phospholamban phosphorylation and an increase in calcium sequestration by the SR accounts for lusitropic effects of NO produced by neuronal nitric oxide synthase (NOS1).3 Tang and co-workers from the Cleveland Clinic reappraised the importance of myocardial NO bioavailability for LV diastolic function in patients with ischaemic and non-ischaemic dilated cardiomyopathy.4 In this study, low myocardial NO bioavailability, evident from high plasma levels of monomethylarginine (MMA), asymmetric dimethylarginine (ADMA), and symmetric dimethylarginine (SDMA) were strongly related to diastolic LV dysfunction or to N-terminal … *Corresponding author. Tel: +31 20 4448110, Fax: +31 20 4448255, Email: wj.paulus{at}vumc.nl

Myocardial Ischemia Diagnosed by Dual-Energy Computed Tomography

For decades, dual-energy imaging has been used for tissue differentiation with several x-ray–based imaging modalities, exploiting the fact that the tissues in the human body show different absorption characteristics when penetrated with different x-ray spectra, spectra that are typically generated by different kV settings of the x-ray tube. Recently, dual-source computed tomography (CT) with 2 x-ray tubes and 2 detector arrays mounted in the same gantry has become available.1 After experience with earlier experimental prototypes, this dual-source CT for the first time enables the clinical acquisition of dual-energy CT studies simultaneously with a single scan. We used a dual-source CT scanner (Definition, Siemens, Forchheim, Germany) in dual-energy mode for performing coronary CT angiography in a 74-year–old woman with suspected coronary artery disease and prior abnormal nuclear rest/stress single-photon emission CT (SPECT). The CT scan was acquired with retrospective ECG-gating and the following scan parameters: 330-ms gantry rotation, pitch 0.2, and 32×2×0.6-mm …

Up-regulated inflammatory factors endothelin, NFκB, TNFα and iNOS involved in exaggerated cardiac arrhythmias in l-thyroxine-induced cardiomyopathy are suppressed by darusentan in rats

The exaggerated cardiac arrhythmias in cardiomyopathy induced by l-thyroxine treatment are related to ion channelopathies and to an abnormal endothelin (ET) pathway. It was hypothesized that an increased incidence of ventricular fibrillation (VF) could be mediated by inflammatory factors including the ET pathway, nuclear factor kappa B (NFκB), tumor necrosis factor-α (TNFα) and inducible nitric oxide synthase (iNOS). Abnormal expression of NFκB, TNFα, iNOS and enhanced VF are linked with the activated ET pathway and a significant reversion could be achieved by the selective endothelin A receptor antagonist darusentan. Cardiomyopathy in rats was produced by l-thyroxine treatment (0.3 mg kg − 1 d − 1 , sc) for 10 days. The mRNA expression of the ET pathway, NFκB, TNFα, iNOS and the activity of the redox system were assayed in association with the incidence of VF produced by coronary ligation/reperfusion. Darusentan was administered on days 6–10 of l-thyroxine treatment. The VF incidence, which was higher in the l-thyroxine cardiomyopathy group, was suppressed by darusentan. The mRNA levels of preproET-1, endothelin converting enzyme, endothelin receptor A (ET AR), endothelin receptor B (ET BR), NFκB, TNFα and iNOS in left ventricle were up-regulated in the cardiomyopathic heart. There was significant oxidative stress in this cardiomyopathy model. Darusentan suppressed the up-regulated mRNA levels of ET AR, ET BR, NFκB, TNFα, and iNOS. These results indicate that the high incidence of VF which is related to up-regulation of inflammatory factors in the cardiomyopathic myocardium is significantly suppressed by selective ET AR blockade.

Stem cell activation sustains hereditary hypertrophy in hamster cardiomyopathy

Recent studies have documented the presence of stem cells within the myocardium and their role in the repair of ischaemic injury. Nevertheless, the pathogenic role of stem cells in non-ischaemic myocardial diseases, as well as the factors potentially responsible for their activation, is still under debate. The present study demonstrates the presence of an increased number of c-kit positive, MDR-positive, and Sca-1-positive stem cells within the myocardium of hereditary delta-SG null hamsters, a spontaneously occurring model of hypertrophic cardiomyopathy. When hamsters are 80 days old, ie at the 'hypertrophic' stage of the disease, but without haemodynamic overload, these cells associate with a multitude of cells co-expressing c-kit, cMet, GATA4, or MEF-2, and proliferating myocytes co-expressing myosin heavy chain, telomerase, ki67 and cyclin B. Furthermore, at the same animal age, the number of myocardial cells co-expressing c-kit and Flk-1, and the number of capillary vessels, is also amplified. In order to identify factors potentially responsible for stem cell activation, the myocardial expression of HGF and cMet and HGF plasma levels were evaluated, demonstrating their increase in 80-day-old delta-SG null hamsters. To demonstrate the possible ability of HGF to induce stem cell differentiation, bone-marrow-derived mesenchymal stem cells were challenged with HGF at the same plasma concentration observed in vivo. HGF induced cMet phosphorylation, and caused loss of stem cell features and overexpression of MEF-2, TEF1, and MHC. Our results demonstrate that stem cell activation occurs within the cardiomyopathic myocardium, very likely to maintain an efficient cardiac architecture. In this context, elevated levels of HGF might play a role in induction of stem cell commitment to the cardiomyocyte lineage and in cardioprotection through its anti-apoptotic action. Consistently, when cytokine levels declined to physiological concentrations, as in 150-day-old cardiomyopathic animals, myocardial apoptosis prevailed, prejudicing cardiac function.

Intracellular signaling in cardiomyopathic hamster myocardium

Intracellular signaling in cardiomyopathic hamster myocardium

β-Adrenergic and endothelin receptor interaction in dilated human cardiomyopathic myocardium

Background: Although end-stage dilated cardiomyopathy (DCM) is characterized by defects in β-adrenergic receptor (β-AR) activity and increased endothelin-1 (ET-1), possible interactions between these 2 systems remain to be defined. Accordingly, the goal of this study was to determine the effects of ET receptor activation on β-AR signaling through measurement of cyclic adenosine monophosphate (cAMP) in normal and DCM myocardium. Methods and Results: Myocardial sarcolemmal preparations were prepared from normal human (n = 6), dilated cardiomyopathic (n = 10), and ischemic cardiomyopathic (ICM, n = 10) tissue. Basal cAMP production was measured in the presence of ET-1 alone (10−6 to 0−9 mol/L) as well as after (−)isoproterenol (10−6 to 10−2 mol/L) or forskolin (0.05 to 30.0 μmol/L) stimulation. β-AR and ET receptor profiles were determined by radiolabeled ligand assays. ET-1 inhibited basal cAMP production in all preparations in a concentration-dependent manner. However, β-AR-stimulated cAMP production by either isoproterenol or forskolin was not significantly affected by ET-1. β-AR receptor density was reduced, and a selective reduction of the ETB receptor occurred in both forms of DCM. Conclusions: Under basal conditions, ET receptor stimulation reduced cAMP levels, which may influence contractility, particularly with DCM.

Heart Cell Transplantation Improves Heart Function in Dilated Cardiomyopathic Hamsters

Background —Little is known about the effect of heart cell transplantation into the dilated cardiomyopathic myocardium. This study was designed to evaluate the effect of heart cell transplantation into dilated cardiomyopathic hamsters. Methods and Results —Ventricular heart cells were isolated from 4-week-old BIO 53.58 hamsters and cultured for 2 weeks before transplantation. The cells were labeled with bromodeoxyuridine (BrdU) before transplantation for identification. Adult hamsters (17 weeks old) were used as recipients. Heart cells (4×10 6 cells) or culture medium was transplanted into the left ventricular free wall (transplantation and control groups, respectively, n=12 each). Sham-operated hamsters (n=12) underwent the surgery but not the transplantation. Cyclosporine A was administered subcutaneously to all hamsters daily after the operation. Four weeks after the transplantation, heart function was evaluated with the use of a Langendorff preparation. Histology showed severe focal myocardial necrosis in all groups. BrdU-stained tissue was found at the cell transplantation sites. The transplanted hearts had greater ( P &lt;0.001) developed pressures at all balloon volumes and improved dP/dt (transplantation 915±253 versus control 453±120 and sham 530±187 mm Hg/s, P &lt;0.001, balloon volume of 15 μL). No differences in ventricular function were found between control and sham-operated hamsters. Conclusions —The transplanted ventricular heart cells formed cardiac-like tissue in cardiomyopathic myocardium and improved its contractile function.

Heart cell transplantation improves heart function in dilated cardiomyopathic hamsters.

Little is known about the effect of heart cell transplantation into the dilated cardiomyopathic myocardium. This study was designed to evaluate the effect of heart cell transplantation into dilated cardiomyopathic hamsters. Ventricular heart cells were isolated from 4-week-old BIO 53. 58 hamsters and cultured for 2 weeks before transplantation. The cells were labeled with bromodeoxyuridine (BrdU) before transplantation for identification. Adult hamsters (17 weeks old) were used as recipients. Heart cells (4 x 10(6) cells) or culture medium was transplanted into the left ventricular free wall (transplantation and control groups, respectively, n=12 each). Sham-operated hamsters (n=12) underwent the surgery but not the transplantation. Cyclosporine A was administered subcutaneously to all hamsters daily after the operation. Four weeks after the transplantation, heart function was evaluated with the use of a Langendorff preparation. Histology showed severe focal myocardial necrosis in all groups. BrdU-stained tissue was found at the cell transplantation sites. The transplanted hearts had greater (P:<0. 001) developed pressures at all balloon volumes and improved dP/dt (transplantation 915+/-253 versus control 453+/-120 and sham 530+/-187 mm Hg/s, P:<0.001, balloon volume of 15 microL). No differences in ventricular function were found between control and sham-operated hamsters. The transplanted ventricular heart cells formed cardiac-like tissue in cardiomyopathic myocardium and improved its contractile function.

Fractionated electrograms in dilated cardiomyopathy: Origin and relation to abnormal conduction

We sought to investigate the origin of the fractionated electrogram and its relations to abnormal conduction in cardiomyopathic myocardium. Patients with dilated cardiomyopathy have a high incidence of ventricular tachycardias. Electrograms recorded in these patients are often fractionated. High resolution mapping (200-microM interelectrode distance) of the electrical activity was carried out in 11 superfused papillary muscles and 6 trabeculae from 7 patients who underwent heart transplantation because of dilated cardiomyopathy. Similar measurements were taken in four papillary muscles from dog hearts in which electrical barriers had been artificially made. Ten human preparations were studied histologically. All preparations revealed sites with fractionated electrograms. In three human preparations, activation patterns showed a discernible line of activation block running parallel to the fiber direction. Fractionated electrograms were recorded at sites contiguous to the line of block. In five preparations, fractionated electrograms were recorded at sites where lines of block were not identified. In these preparations, electrical barriers consisted of short stretches of fibrous tissue. In the remaining nine preparations, fractionated electrograms were recorded, both from sites contiguous to distinct obstacles and sites without evidence of a barrier. Our observations showed that fractionated electrograms recorded in myocardium damaged by cardiomyopathy were due to both distinct, long strands and short stretches of fibrous tissue. Delayed conduction was caused by curvation of activation around the distinct lines of block and by the wavy course of activation between the short barriers. The latter reflects extreme nonuniform anisotropy.

Tension-frequency relationships in normal and cardiomyopathic dog and hamster myocardium

The objective of this study was to evaluate the tension-frequency relationship in normal and cardiomyopathic myocardium from one species with a negative or biphasic relationship, the hamster, and one with a positive relationship, the dog. Left ventricular papillary muscles from 100-day-old normal Syrian and cardiomyopathic (CHF-147) hamsters and right ventricular papillary muscles or trabeculae from normal mongrel dogs and dog with pacing-induced heart failure were used for the study. Stimulation frequency was varied from 1 to 90/min and isometric contractions recorded at each frequency prior to and after the addition of phenylephrine 10 microM. A tension-frequency relationship at varying extracellular calcium concentrations (1.25, 2.5 and 5.0 mM) was also constructed in normal hamster myocardium. Ryanodine 1.2 microM was added to a bath with normal hamster muscles and a force-frequency relationship constructed prior to and after adding phenylephrine 10 microM. A calcium dose-response curve in normal and cardiomyopathic dog myocardium was also constructed. Normal and cardiomyopathic hamster myocardium had a biphasic tension-frequency relationship with the increase in tension during the second phase being greater in normal v cardiomyopathic hamster myocardium (0.66 +/- 0.19 v 0.12 +/- 0.03 g/mm2, P < 0.05). The initial decrease in tension in response to increasing stimulation frequency was markedly attenuated in normal hamster myocardium by increasing extracellular calcium concentration. Developed tension was eliminated at lower stimulation rates by ryanodine such that when developed tension did occur, it increased with increasing stimulation rates. The addition of phenylephrine to hamster myocardium modified the tension-frequency relationship of both normal and cardiomyopathic dog myocardium and their response to phenylephrine were similar. In each case, tension increased progressively with increasing stimulation rate. Although the absolute increase in tension caused by increasing extracellular calcium was less in cardiomyopathic dog myocardium, the percent increase in tension and shortening was greater. We conclude that the tension-frequency relationship of normal and cardiomyopathic hamster myocardium are biphasic, with the initial negative phase being the result of limitations of sarcoplasmic reticulum calcium handling. Phenylephrine modifies this relationship to a uniphasic positive one, likely by its effects on both the sarcolemma and the sarcoplasmic reticulum. Also, the tension-frequency relationship of normal and cardiomyopathic dog myocardium are similar and unmodified by phenylephrine.

Pathological changes of myocardial cytoskeleton in cardiomyopathic hamster.

Immunocytochemical investigation was performed on the cytoskeletal proteins in cardiac tissue of the cardiomyopathic hamster. Male cardiomyopathic UM-X7.1 hamsters at 180 days of age (n = 8) and age- and sex-matched normal BIO-RB hamsters (n = 8) were used in this study. Immunofluorescence microscopy using monoclonal antibodies against desmin, alpha-actinin, titin, and vincullin was employed. The heart weight to body weight ratio was significantly increased in the heart of cardiomyopathic hamster compared with that of normal hamster. In cardiomyopathic hamster, the left ventricular cavity was markedly dilated. Light microscopically, hypertrophy and atrophy of myocytes and myocardial fibrosis were prominently observed in cardiomyopathic myocardium. Immunocytochemically, desmin, alpha-actinin and titin showed the cross striations along the myofibers in normal myocardium. In contrast, in cardiomyopathic myocardium, desmin was irregularly distributed in myocytes and the amount of desmin was increased. Loss of cross striations of alpha-actinin and titin were frequently observed. Immunofluorescence against vinculin was not significantly altered. We conclude that the alterations of cytoskeletal proteins in myocardial cells may relate to decreased myocardial function in cardiomyopathic hamster failing heart.

Age related changes in contractility and 1 adrenergic responsiveness of myocardium from normal hamsters and hamsters with hereditary cardiomyopathy

The aim was to evaluate age related changes in myocardial contractility and alpha 1 adrenergic responsiveness in myocardium from normal and cardiomyopathic hamsters. 50 male cardiomyopathic hamsters (CHF 147) and 45 golden Syrian hamsters were killed at 30, 50, 100, 200, or 300 days of age. Left ventricular papillary muscles were isolated and mounted in an isolated bath and isometric, isotonic, and unloaded contractions were recorded during a phenylephrine dose-response curve. The effects of increasing stimulation rate from 6 to 45 x min-1 and of increasing temperature from 29 degrees C to 35 degrees C before and after the addition of phenylephrine were verified in 100 day old hamsters. At 30 days of age, tension generation and shortening indices were similar in both strains. Thereafter, contractility increased in normal hamsters, to reach a peak at 50 d which was maintained until 300 d, when a slight decrease occurred. In cardiomyopathic hamsters, contractility increased more slowly, such that by 50 d tension was lower than in normals, at 15.8(SEM 1.9) v 26.5(2.2) mN.mm-2 (p < 0.01). This decrease persisted until 200 d, when it normalised and then decreased again by 300 d. The response of normal and cardiomyopathic muscles to phenylephrine was similar at 30 days of age. Thereafter, the response of cardiomyopathic muscles decreased more than in normals. This decrease was accompanied by a rightward shift in the dose-response curve. Increasing stimulation rate had no effect under basal conditions; however, once phenylephrine was added it caused tension to increase in cardiomyopathic muscles instead of decreasing, thereby rendering the relative effects of phenylephrine at 45 stimuli.min-1 similar in both groups. Force generating and shortening indices in normal and cardiomyopathic hamster myocardium are similarly immature at 30 days of age. Normal myocardium reaches its full potential by 50 d, but cardiomyopathic myocardium does not reach it until 200 d, and it decreases thereafter. A decrease in alpha 1 adrenergic responsiveness in cardiomyopathic myocardium at lower stimulation rates can be reversed by increasing the stimulation rate.

Alteration of collagen phenotypes in ischemic cardiomyopathy.

Ischemic cardiomyopathy refers to a significant impairment of left ventricular function, a condition resulting from atherosclerotic coronary artery disease. The left ventricular ejection fraction is usually 35% or less, and electron microscopy shows an increased deposition of collagen in the space between the capillaries and the myocytes. The present study shows the alteration in collagen concentration and phenotypes in ischemic cardiomyopathy, and the effect captopril treatment has on these parameters. In patients with ischemic cardiomyopathy, collagen concentration estimated from hydroxyproline increased from 7.96 +/- 1.24 mg/g to 13.9 +/- 1.30 mg/g, P less than 0.05. Ischemic cardiomyopathic patients given captopril therapy had a significantly lower collagen concentration of 10.03 +/- 1.46 mg/g, P less than 0.05. The collagen type I:III ratio decreased from 1.93 +/- 0.52 to 1.23 +/- 0.27 in patients with ischemic cardiomyopathy. Of these patients, those receiving captopril had a collagen type I:III ratio of 1.49 +/- 0.38, which did not differ significantly from the ratio of individuals with normal myocardium. There was no significant difference in type I collagen concentration in the myocardium of normal individuals, patients with ischemic cardiomyopathy, and patients with ischemic cardiomyopathy receiving captopril therapy. The type III collagen concentration increased significantly from 2.56 +/- 0.21 mg/g in normal myocardium to 6.10 +/- 0.58 mg/g in ischemic cardiomyopathic myocardium. Patients receiving captopril had a myocardial collagen type III concentration of 4.87 +/- 0.64 mg/g, which was significantly lower than that found in patients with ischemic cardiomyopathy. An increased deposition of type III collagen may be partly responsible for altering the compliance of the myocardium, resulting in dilatation of the heart and possibly leading to eventual heart failure.

Effect of antireceptor antibodies in dilated cardiomyopathy on the cycling of cardiac beta receptors

A substantial proportion of patients with dilated cardiomyopathy have circulating autoantibodies directed againts the cardiac β-adrenoceptor. These antireceptor antibodies inhibit both ligand binding to membrane β-receptors and isoproterenol-sensitive adenylate cyclase. The functional consequences of antibody-receptor interactions were further studied by examining their influence on β-adrenoceptor cycling. Sera from eight patients with cardiomyopathy induced a loss of β-receptors from the surface of cardiac myocytes consistent with internalization. This loss was inhibited by concanavalin A, suggesting that receptor sequestration preceded internalization but was unaffected by the cytoskeleton inhibitors colchicine and cytochalasin. In cell-free preparations, serum-induced desensitization of β-receptors was prevented by heparin but not the inhibitor of protein kinase A; this is consistent with a requirement for receptor phosphorylation by the β-receptor kinase. In contrast to isoproterenol-mediated endocytosis, β-receptors internalized under the influence of cardiomyopathic sera do not recycle to the plasma membrane. These results indicate that antireceptor antibodies in human dilated cardiomyopathy induce downregulation by interfering at several steps in the cycling of β-receptors. These effects would dontribute to the reported decline in β-receptor responsiveness in cardiomyopathic myocardium.

Beta-adrenergic receptor number and adenylate cyclase function in denervated transplanted and cardiomyopathic human hearts.

To test the hypothesis that there is up-regulation of beta-adrenergic receptor density or supersensitivity of beta-adrenergic receptor-stimulated adenylate cyclase in the denervated transplanted human heart, we studied myocardium from transplanted, normal, and failing hearts. Myocardium was obtained from 10 patients 9 +/- 3 months after cardiac transplantation, from 10 patients without cardiac disease, and from eight patients with symptomatic congestive heart failure due to idiopathic cardiomyopathy. beta-Adrenergic receptor density in transplanted myocardium (15 +/- 3 fmol/mg protein, 1.20 +/- 0.14 fmol/mg DNA) was not different from that in normal myocardium (22 +/- 3 fmol/mg protein, 1.46 +/- 0.13 fmol/mg DNA; p = NS for both). In myocardium from cardiomyopathic hearts, beta-adrenergic receptor density was markedly reduced (8 +/- 2 fmol/mg protein, 0.84 +/- 0.13 fmol/mg DNA; p less than 0.05 and p less than 0.01 vs. normal myocardium, respectively). Likewise, the response of adenylate cyclase to isoproterenol in transplanted myocardium was not significantly different from that in normal myocardium, but the response was markedly depressed in cardiomyopathic myocardium. Although forskolin-stimulated adenylate cyclase activity was similar in all three groups, guanine nucleotide-stimulated adenylate cyclase activity was markedly reduced in transplanted myocardium (20 +/- 17 vs. 78 +/- 13 pmol/mg/min for normal myocardium, p less than 0.01) and to a lesser degree in cardiomyopathic myocardium (39 +/- 14 pmol/mg/min, p less than 0.03 vs. normal myocardium). Thus, there is no evidence of beta-adrenergic receptor up-regulation or supersensitivity in denervated transplanted human myocardium.(ABSTRACT TRUNCATED AT 250 WORDS)

Ultrastructural localization of calcium in the myocardium of cardiomyopathic Syrian hamsters

Cardiomyopathy of the Syrian hamster is characterized by myocardial calcium overload and focal myocardial necrosis. The cause of the myocardial calcium overload is not yet fully understood. In this study, the ultrastructural localization of calcium was determined in normal hamster hearts and in non-necrotic and necrotic myocardium of cardiomyopathic hamsters (strain BIO 82.62). In many cells from the non-necrotic myocardium of the cardiomyopathic hamsters the calcium deposits, visible as 20 nm particles, were confined to the inner leaflet of the plasma membrane, the T-tubules and the intercalated disks. This corresponds to the calcium distribution found in normal hamsters and other mammalian species. A number of morphologically normal cells, however, displayed an increased amount of calcium precipitate in the mitochondria as well as at the sarcolemma indicating that, in the cardiomyopathic hamster, focal calcium overload is detectable cytochemically in cells which otherwise do not show gross abnormalities. In cells showing morphological signs of myolytic degeneration a marked redistribution of calcium precipitate took place. Sarcolemma became devoid of calcium deposits whereas an enormous amount of clustered precipitate occurred in largely swollen mitochondria. These data are in support of a relationship between impaired ion homeostasis and degeneration events in cardiomyopathy. Furthermore, there appears to be a clear parallelism in calcium redistribution between hypoxic and cardiomyopathic myocardium.

Histological and electron microscopic stereological study of the myocardium of newborn genetically cardiomyopathic hamsters

It has been suggested from qualitative ultrastructural studies that the ventricular myocardium of genetically cardiomyopathic Syrian hamsters is developmentally retarded at birth, possessing an abundance of lighter-staining cells with poorly organized myofibrils (so-called “cardiomyoblasts”). We performed a histological, SEM, and TEM analysis on hearts from randomly bred, normal, and inbred (strain UM-X7.1) cardiomyopathic newborns. Myocardial water content was determined from wet and dry weights. Myocardial tissue organization and cellular makeup was analyzed from low-magnification electron micrographs. The cytoplasmic content of myofibrils and mitochondria was determined for left ventricular myocytes in outer (subepicardial), middle, and inner (subendocardial) zones by an electron microscopic stereological point-counting analysis. About 25% of the CM hearts displayed ventricular abnormalities, most being thin-walled and a few thick-walled. CM hearts also had a lower water content, and contained as few lighter-staining “clear” cells (probably dividing myocytes) as did the normal myocardium. In tissue organization and cellular makeup the CM myocardium seemed normal. Within statistical limits, myocytes from all three zones of the cardiomyopathic myocardium certainly did not contain less myofibrils and mitochondria, but did not clearly contain more than normal. These findings show that, from its ultrastructure at least, the ventricular myocardium of this highly reliable genetically cardiomyopathic strain is certainly not retarded developmentally, and argue against any connection between developmental retardation and the predilection of a myocardium for cardiomyopathy.

The electrophysiological and contractile responses of hypertrophic cardiomyopathic myocardium.

The electrophysiological and contractile responses of hypertrophic cardiomyopathic myocardium.