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PubMed1992

Cardiac morphology after conditions of microgravity during COSMOS 2044.

Light- and electron-microscopic studies were performed on cardiac muscle from rats flown on COS-MOS 2044 and from four control groups. Average cross-sectional area of myofibers was measured by video analysis of the light-microscopic images of papillary and ventricular muscle samples from all animals. This cross-sectional area was significantly decreased in flight rats (P = 0.03) compared with synchronous controls. Additional findings at the electron-microscopic level consistent with this atrophy were obtained by stereological analysis and optical diffraction analysis of papillary muscle samples. Slightly higher mitochondrial volume density values and mitochondria-to-myofibril ratios as well as normal A-band spacings (d1,0) and Z-band spacings of myofibrils were observed in the tail-suspension and flight groups. General morphological features similar to those in ventricular samples from the previous COSMOS 1887 flight were observed.

Animals↗
PubMed1994

Diaphragm injury and myofibrillar structure induced by resistive loading.

The purpose of this study was to determine whether ventilatory failure is associated with muscle fiber damage and myofibrillar protein alterations. Ventilatory failure was induced by tightening a polyvinyl band around the trachea of hamsters (TB; n = 14) for 6 days, which resulted in severe respiratory acidosis (PCO2: 97.9 +/- 29.6 vs. 51.6 +/- 19.6 Torr; pH: 7.16 vs. 7.35), hypoxemia (PO2: 42.8 +/- 16.8 vs. 65.9 +/- 25.8 Torr), and increased pulmonary resistance (1.89 +/- 1.61 vs. 0.29 +/- 0.27 cmH2O.ml-1 x min; P < 0.05). The point-counting technique of hematoxylin- and eosin-stained cross sections showed a higher area fraction of abnormal muscle and inflammatory cells in the costal [0.133 +/- (SE) 0.33 vs. 0.040 +/- 0.010] and crural regions (0.069 +/- 0.020 vs. 0.012 +/- 0.003) of the diaphragm in TB hamsters than in control hamsters. Electron micrographs revealed sarcomeric disruption and Z band streaming in the diaphragm of TB hamsters. Myofibrillar changes of the diaphragm associated with ventilatory failure were quantitative (i.e., a lower yield of purified myofibrils) but not qualitative (similar sodium dodecyl sulfate-polyacrylamide gel electrophoresis protein profiles); however, sulfhydryl group reactivities were reduced (P < 0.05). Proteolysis of purified myofibrils from the diaphragm digested with calpain showed faster degradation rates for tropomyosin and alpha-actinin but not for all proteins for the TB animals. Ventilatory failure induced by resistive loading was associated with diaphragm injury; some of this injury was linked to changes in myofibrillar complexes, specifically their susceptibility to calpain-mediated degradation.

Actinin↗
PubMed1978

Microfibrils in the myotendon junctions.

Myotendon junctions in the rectus abdominis muscles of bull frogs were examined by the fixation combination of tannic acid and glutaraldehyde using electron microscopy. The features observed on myotendon junctions were the following: (1) There were many deep invaginations of muscle cell membrane at the end of the muscle fibers. Terminal thin filaments of myofibrils were attached to the electron-dense layer lining under the muscle cell membrane on the lateral walls of invaginations. (2) The basement membrane covering the muscle cell membrane was thicker in the invaginations than on the other sites of muscle fibers. (3) Collagen fibers in the invaginations gradually tapered off toward the bottom of the invaginations. But it was not seen that the collagen fibers were attached to both the basement membrane and cell membrane of muscle cells. (4) On the observations using the tannic acid-glutaraldehyde fixation, it was clearly seen that the microfibrils extend from the outer leaflets of the cell membrane to the collagen fibers in invaginations via the basement membrane. It was concluded that the myofibrils might be fastened to the collagen fibers of the tendon by the intermediates of the microfibrils.

Animals↗
PubMed1975

Fine structural changes in embryonic chick heart ventricle induced by lead poisoning.

The embryonic chick heart ventricle of day 11 was studied electron microscopically to learn the structural changes that develop in lead poisoning. The chick embryos were administered with 0.015 mg/egg of lead acetate at day 2. The most pronounced changes observed in the ventricle were: malformed mitochondria, disorganized, short and scanty myofibrils and abundance of swollen vacuoles. The ultrastructure of the ventricle from the control chick embryos was normal. The most frequent change noted in the ventricular tissue was an alteration in the myofibrils. This study indicates that electron microscopic changes can be induced in the embryonic chick heart ventricle by lead poisoning.

Animals↗
PubMed1979

Quantitative analysis of morphological changes in skeletal muscle of the rat after hormone administration.

Thyroxine and cortisone acetate administration of rats of 4--7 days of age is not only accompanied by the induction of the muscle-specific enzyme, creatine kinase, but the hormones also induce morphological changes in the gastrocnemius during this period. Administration of thyroxine to these rats causes a splitting of myofibrils as shown by stereological measurements on electron micrographs. This splitting of myofibrils was not observed upon cortisone acetate administration and when both hormones were given simultaneously. It is suggested that cortisone acetate counteracts the effect of thyroxine. Both thyroxine and cortisone acetate increase the volume percentage taken by the mitochondria at 7 days of age. The effect of the simultaneous injection of both hormones is equal to the sum of the separate effects of these hormones. These changes in volume percentage of the mitochondria were compared with changes in a mitochondrial marker enzyme, i.e. citrate synthase. The difference between the morphological measurements and citrate synthase activity is due to a change in the specific activity of citrate synthase in the mitochondria.

Animals↗
PubMed1994

Myofibrillar Ca2+ sensitization predominantly enhances function and mechanical efficiency of stunned myocardium.

BACKGROUND: Myocardial stunning is characterized not only by a decreased regional postischemic function but also by a relatively high oxygen consumption (ie, decreased mechanical efficiency). Several lines of evidence suggest that the underlying mechanism may involve a decreased sensitivity of the myofibrils to calcium, but in vivo evidence is lacking. We therefore evaluated this hypothesis in vivo using EMD 60263, a calcium-sensitizing agent, which is devoid of any phosphodiesterase-inhibiting properties. METHODS AND RESULTS: We first established the effect of two consecutive doses of EMD 60263 (0.75 and 1.5 mg/kg i.v., n = 7), administered at 15-minute intervals, on segment length shortening (SLS), external work index (EW; the area inside the left ventricular pressure-segment length loop), myocardial oxygen consumption (MVO2), and mechanical efficiency (EW/MVO2) in anesthetized pigs with normal myocardium. After the highest dose of EMD 60263, SLS in the distribution area of the left anterior descending coronary artery (LADCA) increased from 13 +/- 1% at baseline to 17 +/- 1% (P < .05). However, EW, MVO2, and EW/MVO2 were not significantly affected (123 +/- 10%, 98 +/- 9%, and 85 +/- 13% of baseline, respectively). In 14 other anesthetized pigs, myocardial stunning was induced by two sequences of 10 minutes of LADCA occlusion and 30 minutes of myocardial reperfusion. After induction of stunning, the two doses of EMD 60263 (n = 7) or saline (3 and 6 mL, n = 7) were infused. In the distribution area of the LADCA, the stunning protocol caused decreases in SLS from 16 +/- 1% to 8 +/- 1% (P < .05) and in EW to 49 +/- 5% of baseline (P < .05), whereas MVO2 was only minimally affected (P > .05). Consequently, mechanical efficiency decreased to 59 +/- 8% of baseline (P < .05). Saline infusion did not affect any of these regional myocardial variables, but after administration of EMD 60263 SLS recovered dose-dependently to 15 +/- 2% after the highest dose of the drug. EW and mechanical efficiency also recovered dose-dependently to 89 +/- 4% (P < .05 versus stunning) and to 88 +/- 7% (NS versus baseline) of baseline, respectively. In the not-stunned segment, SLS increased from 15 +/- 2% (at baseline) to 18 +/- 2% (after the highest dose), and EW per beat was not changed significantly. An adrenergic mode of action of EMD 60263 was excluded by blocking the alpha- and beta-adrenergic receptors with phentolamine and propranolol, respectively, 15 minutes before administration of EMD 60263 (ie, 15 minutes into the second reperfusion period) in five additional experiments. In these experiments the EMD 60263-induced increases in SLS and EW were not attenuated. Because EMD 60263 decreased heart rate from 106 +/- 4 to 76 +/- 3 beats per minute (P < .05) in the animals with stunned myocardium, we performed five experiments with the specific negative chronotropic compound zatebradine (UL-FS 49, 0.1 to 0.5 mg/kg) to rule out bradycardia as a factor contributing to the effects of EMD 60263. These zatebradine doses lowered heart rate from 116 +/- 5 to 55 +/- 1 beats per minute (P < .05) but had no effect on SLS of stunned and not-stunned myocardium. CONCLUSIONS: Calcium sensitization affects function and mechanical efficiency of stunned myocardium more profoundly than of not-stunned myocardium, lending support to the hypothesis that Ca2+ desensitization of the myofibrils is involved in myocardial stunning.

Animals↗
PubMed2004

Developmentally regulated switching of titin size alters myofibrillar stiffness in the perinatal heart.

Before birth, the compliance of the heart is limited predominantly by extracardiac constraint. Reduction of this constraint at birth requires that myocardial compliance be determined mainly by the heart's own constituents. Because titin is a principal contributor to ventricular passive tension (PT), we studied the expression and mechanics of cardiac-titin isoforms during perinatal rat heart development. Gel electrophoresis and immunoblotting revealed a single, 3.7-MDa, N2BA isoform present 6 days before birth and an additional, also previously unknown, N2BA isoform of 3.5 to 3.6 MDa expressed in the near-term fetus. These large isoforms rapidly disappear after birth and are replaced by a small N2B isoform (3.0 MDa) predominating in 1-week-old and adult rats. In addition, neonatal pig hearts showed large N2BA-titin isoforms distinct from those present in the adult porcine myocardium. By quantitative reverse transcriptase-polymerase chain reaction, developmentally expressed titin-mRNA species were detected in rat heart. Titin-based PT was much lower (approximately 15 times) in fetal than adult rat cardiomyocytes, and measured PT levels were readily predictable with a model of worm-like chain titin elasticity. Immunofluorescence microscopy showed the extensibility of the differentially spliced molecular spring regions of fetal/neonatal titin isoforms in isolated rat cardiomyofibrils. Whereas the titin-isoform shift by 700 kDa ensures high passive stiffness of the postnatal cardiac myofibrils, the expression of specific fetal/neonatal cardiac-titin isoforms may also have important functions for contractile properties, myofibril assembly or turnover, and myocardial signaling during perinatal heart development.

Alternative Splicing↗
PubMed1984

Atrophy reversal and cardiocyte redifferentiation in reloaded cat myocardium.

We have recently described rapid cardiac atrophy in response to decreased load. The present study was designed to determine whether this atrophy is solely a degenerative response of damaged myocardium or is, instead, an adaptive response of viable myocardium. A discrete portion of cat myocardium was unloaded by severing the chordae tendinae of a single right ventricular papillary muscle. One week later, the muscle was reloaded by attachment of its apex to the ventricular free wall. This allowed the load to be removed and restored without altering the blood supply, innervation, or frequency of contraction of the tissue. In myocardium unloaded for 1 week, the cardiocyte cross-sectional area and the volume densities of mitochondria and myofibrils decreased significantly. Large areas of cytoplasm were devoid of organelles, and the few remaining myofilaments were oriented in a variety of directions rather than longitudinally within the cell. Upon reloading for 1 week, the cardiocyte cross-sectional area, volume density of mitochondria, and ultrastructural organization all returned to normal. The volume density of the myofibrils increased toward control, and they reoriented with respect to the long axis of the cardiocyte. The contractile function of the papillary muscles, which was depressed as early as 1 day after unloading and almost absent at times later than 3 days after unloading, returned to normal after 2 weeks of reloading. This study demonstrates that adult mammalian myocardium responds to unloading with a marked loss of cellular differentiation, organization, and function which is fully reversible with reloading. This plasticity in response to load may well be the basic mechanism responsible for the development and maintenance of normal cardiac structure and function.

Aging↗
PubMed1987

Developmental changes in the ultrastructure and sarcomere shortening of the isolated rabbit ventricular myocyte.

Sarcomere shortening and ultrastructure of intact isolated myocytes from ventricles of three-week-old and adult rabbits were examined. Cells were fixed and embedded, and after measuring their sarcomere shortening in response to electrical stimulation, they were examined in serial thin sections by electron microscopy. This structure-function analysis showed that adult cells were significantly larger, had longer rest sarcomere lengths, greater amount and velocity of sarcomere shortening, greater velocity of reextension, and shorter contraction duration than immature cells. In immature myocytes, a thin outer shell of myofibrils enveloped a central mass of mitochondria and nuclei, but in adult cells, the cytoskeleton divided the cell into compartments with the mitochondria arranged around and interspersed among the myofibrils. The different arrangement of the organelles and the cytoskeleton at the two ages may account for the shorter rest sarcomere length in the young myocytes and may confer differing internal loads that contribute to their smaller amount and velocity of sarcomere shortening. The corbular and longitudinal sarcoplasmic reticulum were less demarcated in immature than in adult cells. Myocytes from both ages showed postextrasystolic potentiation, suggesting that the sarcoplasmic reticulum modulates calcium at both ages. Restitution of contractility between contractions, obtained by measuring sarcomere shortening of interpolated extrasystoles, was faster in immature than in adult cells and may reflect the structural differences in the sarcoplasmic reticulum. The developmental differentiation in the sarcoplasmic reticulum suggests that changes in compartmentalization of calcium and in the distribution of putative calcium-release sites contribute to the increased contractility of adult myocytes.

Animals↗
PubMed1988

Changes in myofibrillar content and Mg-ATPase activity in ventricular tissues from patients with heart failure caused by coronary artery disease, cardiomyopathy, or mitral valve insufficiency.

Force development and shortening by cardiac muscle occur as a result of the interaction between actin and myosin within the myofibrillar lattice. This interaction is dependent upon intracellular ionized calcium and is controlled by the troponin-tropomyosin regulatory proteins situated along the actin filament. In this study, we compared the myofibrillar content and myofibrillar Mg-ATPase activity of normal human ventricular muscle with that of ventricular muscle from patients in end-stage failure caused by coronary artery disease or cardiomyopathy and ventricular muscle from patients with heart failure due to mitral valve insufficiency. The results show that the amount of myofibrillar protein (mg/g wet wt ventricle) in hearts in end-stage failure (coronary artery disease and cardiomyopathy) is significantly lower compared with normal hearts and hearts in failure due to mitral valve insufficiency. However, the Mg-ATPase activity of myofibrils from hearts in both end-stage failure and failure due to mitral valve insufficiency is significantly lower compared with myofibrils from normal hearts. The data suggest that the reduction in the amount of myofibrillar protein in ventricular tissue is a pivotal event that may be responsible for the progression of heart disease to the point of end-stage failure.

Ca(2+) Mg(2+)-ATPase↗
PubMed1991

Morphological characterization of cardiomyocytes isolated from a transplantable cardiac tumor derived from transgenic mouse atria (AT-1 cells).

We have developed a transplantable tumor lineage derived from transgenic mouse atrial cardiomyocytes that express the SV40 large T oncogene and have named these cardiomyocytes AT-1 cells. In this study, the transplantable tumors, freshly isolated tumor cardiomyocytes, and cultured tumor cardiomyocytes were examined using phase-contrast microscopy, autoradiography, and electron microscopy. The vast majority of the subcutaneous tumor cells, greater than 90% of the cellular mass of the tumor, exhibited sarcomeric banding. Ultrastructural characteristics typical of in vivo atrial cardiac muscle cells, including well-organized myofibrils, gap junctions, and atrial-specific cytoplasmic granules, were observed in in situ and in freshly isolated AT-1 cells. Those cells that did not contain some form of organized myofibrils were primarily vascular elements, such as endothelial cells. Labeling with [3H]thymidine indicated that greater than 90% of cultured AT-1 cells were synthesizing DNA; furthermore, many cells could be seen undergoing cell division. Electron microscopy revealed that the cultured AT-1 cardiomyocytes contained all of the above-described characteristics, including a well-developed transverse tubular system.

Animals↗
PubMed1993

Contractile activity modulates actin synthesis and turnover in cultured neonatal rat heart cells.

In this study, the role that active tension development plays in the formation and maintenance of cardiac myocyte myofibrillar structure and cellular shape was investigated. By use of the calcium channel blocker verapamil, spontaneous contractile activity of neonatal rat heart myocytes was inhibited for 24 to 96 hours. Confocal microscopy of rhodamine phalloidin-stained cells revealed that, within 24 hours of contractile arrest, actin filaments of myofibrils were no longer aligned with one another at their I bands and Z lines. Cellular shape was also affected, with the cells developing a less stellate appearance while remaining attached to the substrate as well as to one another. By 48 hours, actin fibrils were largely absent from these cells. The disappearance of actin was confirmed by measurements of actin synthesis and accumulation rates and by pulse-chase biosynthetic labeling experiments. It was revealed that, although actin synthesis was significantly reduced in arrested myocytes, the rapid disappearance of total cellular actin was largely due to increased rates of actin degradation. Contractile arrest produced by L-type calcium channel blockade with verapamil (or other calcium channel blockers) accelerated actin degradation to a greater extent than K+ depolarization. Chloroquine partially suppressed the accelerated rate of actin degradation, indicating that lysosomal proteolysis may be involved in actin degradative processing. Protein kinase C activation also partially inhibited the accelerated rate of actin degradation but did not restore actin filaments in arrested myocytes. The reformation of actin fibrils and their reassembly into striated myofibrils occurred when contractile activity was restored by removal of verapamil from the culture medium. The period of time required for myocytes to reassemble actin filaments and to regain their elongated morphology was proportional to the period of time that the cells were inhibited from contracting. Data are presented to indicate that active tension development by neonatal cardiac myocytes in culture is critical to the maintenance of filamentous actin structure via mechanisms involving actin assembly, disassembly, and degradation.

Actins↗
PubMed1997

Expression of a mutant (Arg92Gln) human cardiac troponin T, known to cause hypertrophic cardiomyopathy, impairs adult cardiac myocyte contractility.

The mechanism(s) by which mutations in sarcomeric proteins cause hypertrophic cardiomyopathy (HCM) remains unknown. A leading hypothesis proposes that mutant sarcomeric proteins impair cardiac myocyte contractility, providing an impetus for compensatory hypertrophy. To test this hypothesis, we determined the impact of expression of a mutant (Arg92Gln) human cardiac troponin T (cTnT), known to cause HCM in humans, on adult cardiac myocyte contractility. A full-length human cTnT cDNA was cloned, and the Arg92Gln mutation was induced. Recombinant adenoviruses Ad5/CMV/cTnT-N and Ad5/CMV/cTnT-Arg92Gln were generated through homologous recombination. Adult feline cardiac myocytes were infected with recombinant adenoviruses or a control viral vector (Ad5 delta E1) at a multiplicity of infection of 100. Expression levels of the full-length normal and mutant cTnT proteins were equal on Western blots. Expression of the exogenous cTnT proteins in cardiac myocytes was also shown by immunocytochemistry and immunofluorescence, and their incorporation into myofibrils was confirmed by Western blotting on myofibrillar extracts. Electron microscopy showed intact sarcomere structure in rod-shaped cardiac myocytes in all groups. Cell fractional shortening and the peak velocity of shortening were not significantly different among the groups 24 hours after transduction. However, 48 hours after transduction, both fractional shortening and the peak velocity of shortening were significantly reduced (24% [P < .001] and 26% [P < .001], respectively) in cardiac myocytes in the Ad5/CMV/cTnT-Arg92Gln compared with the Ad5/CMV/cTnT-N groups. The magnitude of the reductions was greater at 72 hours after transduction (45% and 39%, respectively; P < .001). Our results indicated that expression of the mutant (Arg92Gln) cTnT, known to cause HCM in humans, impaired intact adult cardiac myocyte contractility. Our data also show that both normal and mutant cTnT were incorporated into myofibrils. These results provide a potential mechanism by which mutations in sarcomeric proteins cause HCM.

Adult↗
PubMed1999

Subcellular creatine kinase alterations. Implications in heart failure.

We have tested the hypothesis that decreased functioning of creatine kinase (CK) at sites of energy production and utilization may contribute to alterations in energy fluxes and calcium homeostasis in congestive heart failure (CHF). Heart failure was induced by aortic banding in 3-week-old rats. Myofilaments, sarcoplasmic reticulum (SR), mitochondrial functions, and CK compartmentation were studied in situ using selective membrane permeabilization of left ventricular fibers with detergents (saponin for mitochondria and SR and Triton X-100 for myofibrils). Seven months after surgery, animals were in CHF. A decrease in total CK activity could be accounted for by a 4-fold decrease in activity and content (Western blots) of mitochondrial CK and a 30% decrease in M isoform of CK (MM-CK) activity. In myofibrils, maximal force, crossbridge kinetics, and alpha-myosin heavy-chain expression decreased, whereas calcium sensitivity of tension development remained unaltered. Myofibrillar CK efficacy was unchanged. Calcium uptake capacities of SR were estimated from the surface of caffeine-induced tension transient (SCa) after loading with different substrates. In CHF, SCa decreased by 23%, and phosphocreatine was 2 times less efficient in enhancing calcium uptake. Oxidative capacities of the failing myocardium measured as oxygen consumption per gram of fiber dry weight decreased by 28%. Moreover, the control of respiration by creatine, ADP, and AMP was severely impaired. Our observations provide evidence that alterations in CK compartmentation may contribute to alterations of energy fluxes and calcium homeostasis in CHF.

Animals↗
PubMed2001

Ras reduces L-type calcium channel current in cardiac myocytes. Corrective effects of L-channels and SERCA2 on [Ca(2+)](i) regulation and cell morphology.

Heart failure is associated with dysregulation of intracellular calcium ([Ca(2+)](i)), reduction in myofibrils, and increased activation of Ras, a regulator of signal-transduction pathways. To evaluate the potential effects of Ras on [Ca(2+)](i), we expressed constitutively active Ras (Ha-Ras(V12)) in cardiac myocytes and monitored [Ca(2+)](i) via fluorescence and electrophysiological techniques. Ha-Ras(V12) reduced the magnitude of the contractile calcium transients. Unexpectedly, however, calcium loading of the sarcoplasmic reticulum was increased, suggesting that Ha-Ras(V12) introduces a defect in excitation-calcium release coupling. Consistent with this idea, L-channel calcium currents were reduced by Ha-Ras(V12), which also downregulated the activity of the L-channel gene promoter. Coexpression of L-channels and SERCA2 largely corrected Ha-Ras(V12)-induced dysregulation of [Ca(2+)](i). Furthermore, whereas Ha-Ras(V12) downregulated myofibrils, this effect was blocked by coexpression of L-channels. These results suggest that Ras downregulates L-channel expression, which may play a pathophysiological role in cardiac disease.

Animals↗
PubMed2001

Phosphorylation of troponin I by protein kinase A accelerates relaxation and crossbridge cycle kinetics in mouse ventricular muscle.

Phosphorylation of cardiac myofibrils by cAMP-dependent protein kinase (PKA) can increase the intrinsic rate of myofibrillar relaxation, which may contribute to the shortening of the cardiac twitch during beta-adrenoceptor stimulation. However, it is not known whether the acceleration of myofibrillar relaxation is due to phosphorylation of troponin I (TnI) or of myosin binding protein-C (MyBP-C). To distinguish between these possibilities, we used transgenic mice that overexpress the nonphosphorylatable, slow skeletal isoform of TnI in the myocardium and do not express the normal, phosphorylatable cardiac TNI: The intrinsic rate of relaxation of myofibrils from wild-type and transgenic mice was measured using flash photolysis of diazo-2 to rapidly decrease the [Ca(2+)] within skinned muscles from the mouse ventricles. Incubation with PKA nearly doubled the intrinsic rate of myofibrillar relaxation in muscles from wild-type mice (relaxation half-time fell from approximately 150 to approximately 90 ms at 22 degrees C) but had no effect on the relaxation rate of muscles from the transgenic mice. In parallel studies with intact muscles, we assessed crossbridge kinetics indirectly by determining f(min) (the frequency for minimum dynamic stiffness) during tetanic contractions. Stimulation of beta-adrenoceptors with isoproterenol increased f(min) from 1.9 to 3.1 Hz in muscles from wild-type mice but had no effect on f(min) in muscles from transgenic mice. We conclude that the acceleration of myofibrillar relaxation rate by PKA is due to phosphorylation of TnI, rather than MyBP-C, and that this may be due, at least in part, to faster crossbridge cycle kinetics.

Adrenergic beta-Agonists↗
PubMed2006

Subcellular remodeling as a viable target for the treatment of congestive heart failure.

It is now well known that congestive heart failure (CHF) is invariably associated with cardiac hypertrophy, and changes in the shape and size of cardiomyocytes (cardiac remodeling) are considered to explain cardiac dysfunction in CHF. However, the mechanisms responsible for the transition of cardiac hypertrophy to heart failure are poorly understood. Several lines of evidence both from various experimental models of CHF and from patients with different types of CHF have indicated that the functions of different subcellular organelles such as extracellular matrix, sarcolemma, sarcoplasmic reticulum, myofibrils, mitochondria, and nucleus are defective. Subcellular abnormalities for protein contents, gene expression, and enzyme activities in the failing heart become evident as a consequence of prolonged hormonal imbalance, metabolic derangements, and cation maldistribution. In particular, the occurrence of oxidative stress, development of intracellular Ca2+ overload, activation of proteases and phospholipases, and alterations in cardiac gene expression result in changes in the biochemical composition, molecular structure, and function of different subcellular organelles (subcellular remodeling). Not only does subcellular remodeling appear to be intimately involved in the transition of cardiac hypertrophy to heart failure, the mismatching of the function of different subcellular organelles leads to the development of cardiac dysfunction. Although blockade of the renin-angiotensin system, sympathetic nervous system, and various other hormonal actions have been reported to produce beneficial effects on cardiac remodeling and heart dysfunction in CHF, the actions of various cardiac drugs on subcellular remodeling have not been examined extensively. Some recent studies have indicated that both the angiotensin-converting enzyme inhibitors and angiotensin receptor antagonists attenuate changes in sarcolemma, sarcoplasmic reticulum, and myofibril enzyme activities, protein contents, and gene expression, and partly improve cardiac function in the failing hearts. It is suggested that subcellular remodeling is an excellent target for the development of improved drug therapy for CHF. Furthermore, extensive studies should investigate the effects of different agents individually or in combination on reverse subcellular remodeling, cardiac remodeling, and cardiac dysfunction in various experimental models of CHF.

Animals↗
PubMed2006

High glucose alters cardiomyocyte contacts and inhibits myofibrillar formation.

CONTEXT: The frequency of diabetes-related heart failure along with the prevalence of diabetes is increasing. Diabetic cardiomyopathy is considered to be a distinct disease in the absence of discernible coronary artery and other defined heart disease. Previously we have shown that glucose and palmitic acid induce degeneration of myofibrils and modulate apoptosis in cultivated cardiomyocytes. OBJECTIVE: Here we studied the mechanisms of diabetic cardiomyopathy in more detail. RESULTS: Streptozotocin-induced diabetes led to a significant increase in cardiac cell apoptosis. Furthermore, cardiomyocyte contacts were reduced. In vitro, prolonged exposure of cultured adult cardiomyocytes to high glucose concentrations drastically reduced myofibrillar formation. In particular, sarcomeric myosin heavy chains and cardiac alpha-actin were reduced, whereas the nonsarcomeric smooth muscle alpha-actin remained unaffected. The deleterious effects of glucose on myofibril formation were prevented by antioxidative regimens. CONCLUSIONS: Thus, a diabetic milieu leads to multiple structural alterations of the heart including apoptosis, loss of intercellular contacts, and malformation of contractile structures.

Animals↗