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J Schaper

Publications and source records attributed to J Schaper.

At least 37 records · Page 2Linked to original sources
PubMed2001

Primary B-cell lymphoma of bone in children.

UNLABELLED: Primary lymphoma of bone (PLB) is a rare entity of extranodal non-Hodgkin lymphoma (NHL). We report on two children with PLB focussing on diagnostic evaluation and treatment strategy. Clinical and radiographic presentation in both children suggested a primary bone tumour such as Ewing sarcoma. A 13-year-old girl showed osteolytic tumours in the right 7th rib and right iliac crest. Additional skeletal lesions were found by whole-body positron emission tomography. A 6-year-old boy presented with an isolated, osteolytic lesion of the left distal femur. In both patients staging procedures excluded any organ involvement besides the skeletal tumours. Tumour biopsy and immunohistological studies revealed lymphoblastic non-Hodgkin lymphoma of B-cell lineage in both children. They received a polychemotherapy for B-cell lymphoma according to the NHL-BFM 95 protocol and are in complete remission with a follow up of 24 and 18 months respectively. CONCLUSION: Isolated, primary lymphoma of bone in children may clinically and radiographically impose as primary bone tumour. Multiple therapeutic strategies have been applied in the treatment of this malignancy, however, treatment modalities are not well focussed on immunological patterns in the case of primary lymphoma of bone. Staging techniques should include immunophenotyping to initiate specific cell lineage treatment.

Adolescent↗
PubMed2001

Occurrence and distribution of atrial natriuretic peptide-containing cells in the left ventricle of hypertensive rats. Effect of antihypertensive treatment.

In the ventricles of adult mammalian hearts, production of atrial natriuretic peptide (ANP) is negligible, restricted to the impulse-conducting cells, the papillary muscles, and a minority of subendocardial myocytes. ANP expression is reinduced in the ventricles of pressure-overloaded and failing hearts and is frequently used as a marker for myocyte hypertrophy. Using an immunohistochemical approach, we have characterized the size distribution of ANP-containing myocytes in the left ventricle of the spontaneously hypertensive rat (SHR) before and after chronic antihypertensive therapy and compared the results to age-matched normotensive Wistar rats (WR). Our findings show that in SHR the frequency of cells presenting ANP granularity is positively correlated with myocyte size (r=0.746, P<0.02). The highest proportion of ANP-positive myocytes (55-57%) was measured among cells of diameters 30-34 microm. In any corresponding cell size, the proportion of ANP-presenting myocytes was five- to tenfold higher in SHR than in the normotensive WR. We studied the effects of the antihypertensive drugs captopril, hydralazine, and nifedipine and found that, regardless of their effect on blood pressure or hypertrophy, all three eliminated ANP immunoproducts from the majority of the left ventricular myocytes and reduced the level of ANP mRNA, captopril being the most effective. The positive correlation between myocyte size and ANP expression was not maintained in the hearts of drug-treated SHR. Myocytes on the border of fibrotic areas or in regions of ANP presentation within the normal heart resisted the suppressive effect of the antihypertensive therapy, indicating that blood pressure or hypertrophy are not the sole correlates for ANP expression.

Animals↗
PubMed2001

Activation of the cardiac renin-angiotensin system and increased myocardial collagen expression in human aortic valve disease.

OBJECTIVES: We sought to determine whether the cardiac renin-angiotensin system (RAS) is activated in human aortic valve disease depending on left ventricular function, and we analyzed the concomitant regulation of the extracellular matrix components. BACKGROUND: In animal models with pressure or volume load, activation of the cardiac RAS increases fibrosis. In human aortic valve disease, the ventricular collagen protein content is increased, but only scarce data on the activation state of the cardiac RAS and its effects on collagen and fibronectin messenger ribonucleic acid (mRNA) are available. METHODS: In left ventricular biopsies from patients with aortic valve stenosis (AS) and aortic valve regurgitation and from control subjects, we quantitated mRNAs for angiotensin-converting enzyme (ACE), chymase, transforming growth factor-beta1 (TGF-beta1), collagen I, collagen III and fibronectin by reverse-transcription polymerase chain reaction. Proteins were localized by immunohistochemistry; ACE activity was determined by high performance liquid chromatography; and TGF-beta protein by quantitative enzyme immunoassay. RESULTS: Protein, ACE and TGF-beta1 mRNA were significantly increased in patients with AS and AR (1.5- to 2.1-fold) and correlated with each other. The increase occurred also in patients with normal systolic function. Collagen I and III and fibronectin mRNAs were both upregulated about twofold in patients with AS and AR. In AS, collagen and fibronectin mRNA expression levels were positively correlated with left ventricular end-diastolic pressure and inversely with left ventricular ejection fraction (LVEF). CONCLUSIONS: In human hearts, pressure and volume overload increases cardiac ACE and TGF-beta1 in the early stages. This activation of the cardiac RAS may contribute to the observed increase in collagen I and III and fibronectin mRNA expression. The increase in extracellular matrix already exists in patients with a normal LVEF, and it increases with functional impairment.

Aged↗
PubMed2001

Autosomal dominant distal myopathy: further evidence of a chromosome 14 locus.

In 1995 Laing et al. (Am J Hum Genet 56(1995)422) described a single family with nine members affected by an autosomal dominant infantile onset distal myopathy. This family generated a LOD score of 2.6 for a locus on chromosome 14. We describe two families with an infantile onset distal myopathy: a new family with four affected members and the family previously described by Scoppetta et al. (Acta Neurol Scand 92(1955)122) in both of which haplotype segregation was compatible with linkage to the same chromosome 14 locus, generating LOD scores of 0.9 at a penetrance of 100% for the markers D14S283 and D14S64 (theta=0) in both families. The loci for autosomal recessive hereditary inclusion body myopathy and Nonaka myopathy on chromosome 9 and for autosomal dominant distal myopathy of Markesberry-Griggs and Udd on chromosome 2q31-33 were excluded by linkage analysis. The disease followed a uniform course with selective wasting of the anterior tibial muscles, starting in infancy and recognizable by a characteristic clinical sign of the 'hanging big toe'. This was followed by slow progression, with involvement of the finger and wrist extensor muscles in the third decade and proximal limb muscles in the fourth decade. Interestingly, we also found evidence of an accompanying mild peripheral neuropathy in the oldest individual with hypomyelination of numerous large myelinated fibres. In addition, this patient's muscle biopsy also showed autophagic vacuoles and numerous intranuclear tubulo-filamentous inclusions of 15-20 nm diameter. Given that all three families with infantile onset distal myopathy are compatible with linkage to the same locus on chromosome 14, this study supports evidence for, and enlarges the clinical and neuropathological spectrum of the distal myopathy on chromosome 14.

Adolescent↗
PubMed2001

[Quality assessment using AGIR: results and experience].

PURPOSE: To evaluate whether a new software from the working group for interventional radiology (AGIR) is an appropriate tool for quality assurance in interventional radiology, and presentation of results acquired within the quality improvement process in 1999. PATIENTS AND METHODS: AGIR-defined parameters such as patient data, risk profile, given interventions as well as complications were registered by a recently developed software. Based on monthly data analyses, possible complications were identified and discussed in morbidity and mortality conferences. RESULTS: 1014 interventions were performed in our institution in 1999. According to criteria established by AGIR, the complication rate was 2.7%. In addition and according to SCVIR criteria, complications were distinguished quantitatively in five classes and semiquantitatively in minor and major groups. The result was a minor complication rate of 1.8%, and a major rate of 0.9%. There were no cases of death associated with the intervention. Further strategies were developed in order to reduce the complication rate. CONCLUSION: Extensive quality assurance methods can be integrated in daily routine work. These methods lead to an intensive transparency of treatment results, and allow the implementation of continuous quality improvements. The development of the software is a first step in establishing a nation-wide quality assurance system. Nevertheless, modification and additional definition of the AGIR predefined parameters are required, for example, to avoid unnecessary procedures.

Adolescent↗
PubMed2000

Genotypic and phenotypic spectrum in tricho-rhino-phalangeal syndrome types I and III.

Tricho-rhino-phalangeal syndrome (TRPS) is characterized by craniofacial and skeletal abnormalities. Three subtypes have been described: TRPS I, caused by mutations in the TRPS1 gene on chromosome 8; TRPS II, a microdeletion syndrome affecting the TRPS1 and EXT1 genes; and TRPS III, a form with severe brachydactyly, due to short metacarpals, and severe short stature, but without exostoses. To investigate whether TRPS III is caused by TRPS1 mutations and to establish a genotype-phenotype correlation in TRPS, we performed extensive mutation analysis and evaluated the height and degree of brachydactyly in patients with TRPS I or TRPS III. We found 35 different mutations in 44 of 51 unrelated patients. The detection rate (86%) indicates that TRPS1 is the major locus for TRPS I and TRPS III. We did not find any mutation in the parents of sporadic patients or in apparently healthy relatives of familial patients, indicating complete penetrance of TRPS1 mutations. Evaluation of skeletal abnormalities of patients with TRPS1 mutations revealed a wide clinical spectrum. The phenotype was variable in unrelated, age- and sex-matched patients with identical mutations, as well as in families. Four of the five missense mutations alter the GATA DNA-binding zinc finger, and six of the seven unrelated patients with these mutations may be classified as having TRPS III. Our data indicate that TRPS III is at the severe end of the TRPS spectrum and that it is most often caused by a specific class of mutations in the TRPS1 gene.

Adolescent↗
PubMed2000

Syndrome of gingival hypertrophy, hirsutism, mental retardation and brachymetacarpia in two sisters: specific entity or variant of a described condition?

Two sisters born to consanguineous Lebanese parents had mental retardation and epilepsy, brachymetacarpalia, hirsutism, bulbous soft nose, thick floppy ears with abnormal configuration and gingival hypertrophy. One girl presented additionally with tetralogy of Fallot and the other with congenital hypothyroidism and bilateral ureteral stenosis. These manifestations resemble the syndrome of hypertrichosis-gingival fibromatosis-mental retardation and seizures of Anavi et al. [1989: Dev Med Child Neurol 31:538-542] but our two girls additionally have brachymetacarpia. The inheritance seems to be autosomal recessive. These two sisters may represent a hitherto undescribed syndrome. We discuss the findings in our patients in relation to the literature.

Abnormalities, Multiple↗
PubMed2000

Interaction of hCLIM1, an enigma family protein, with alpha-actinin 2.

Enigma proteins are proteins that possess a PDZ domain at the amino terminal and one to three LIM domains at the carboxyl terminal. They are cytoplasmic proteins that are involved with the cytoskeleton and signal transduction pathway. By virtue of the two protein interacting domains, they are capable of protein-protein interactions. Here we report a study on a human Enigma protein hCLIM1, in particular. Our study describes the interaction of the human 36 kDa carboxyl terminal LIM domain protein (hCLIM1), the human homologue of CLP36 in rat, with alpha-actinin 2, the skeletal muscle isoform of alpha-actinin. hCLIM1 protein was shown to interact with alpha-actinin 2 by yeast two-hybrid screening and immunochemical analyses. Yeast two-hybrid analyses also demonstrated that the LIM domain of hCLIM1 binds to the EF-hand region of alpha-actinin 2, defining a new mode of LIM domain interactions. Immunofluorescent study demonstrates that hCLIM1 colocalizes with alpha-actinin at the Z-disks in human myocardium. Taken together, our experimental results suggest that hCLIM1is a novel cytoskeletal protein and may act as an adapter that brings other proteins to the cytoskeleton.

Actinin↗
PubMed2000

Increased expression of cytoskeletal, linkage, and extracellular proteins in failing human myocardium.

Experimental studies have shown that in hypertrophy and heart failure, accumulation of microtubules occurs that impedes sarcomere motion and contributes to decreased ventricular compliance. We tested the hypothesis that these changes are present in the failing human heart and that an entire complex of structural components, including cytoskeletal, linkage, and extracellular proteins, are involved in causing functional deterioration. In explanted human hearts failing because of dilated cardiomyopathy (ejection fraction </=20%), expression of alpha- and beta-tubulin, desmin, vinculin, fibronectin, and vimentin was determined by Northern and Western blot analysis and compared with normal myocardium from explants not used for transplantation. The mRNA for alpha- and beta-tubulin was increased to 2.4-fold (P<0.01) and 1.25-fold (NS), respectively; for desmin, 1.2-fold (P<0.05); for fibronectin, 5-fold (P<0.001); and for vimentin, 1.7-fold (P<0.05). Protein levels for alpha-tubulin increased 2.6-fold (P<0.02); for beta-tubulin, 1.2-fold (P<0.005); for desmin, 2.1-fold (P<0.001); for vinculin, 1.2-fold (P<0.005); for fibronectin, 2.9-fold (P<0.001); and for vimentin, 1.5-fold (P<0. 005). Confocal microscopy showed augmentation and disorganization of all proteins studied. In combination with the loss of myofilaments and sarcomeric skeleton previously reported, these changes suggest cardiomyocyte remodeling. Increased fibronectin and elevated interstitial cellularity (vimentin labeling) indicate progressive fibrosis. The present results suggest a causative role of cytoskeletal abnormalities and myofilament loss for intrinsic contractile and diastolic dysfunction in failing hearts.

Adult↗
PubMed2000

The role of the cytoskeleton in heart failure.

The cytoskeleton of cardiac myocytes consists of actin, the intermediate filament desmin and of alpha- and beta-tubulin that form the microtubules by polymerization. Vinculin, talin, dystrophin and spectrin represent a separate group of membrane-associated proteins. In numerous experimental studies, the role of cytoskeletal alterations especially of microtubules and desmin, in cardiac hypertrophy and failure (CHF) has been described. Microtubules were found to be accumulated thereby posing an increased load on myocytes which impedes sarcomere motion and promotes cardiac dysfunction. Other groups were unable to confirm microtubular densification. The possibility exists that these changes are species, load and chamber dependent. Recently, damage of the dystrophin molecule and MLP (muscle LIM protein) were identified as possible causes of CHF. Our own studies in human hearts with chronic CHF due to dilated cardiomyopathy (DCM) showed that a morphological basis of reduced contractile function exists: the cytoskeletal and membrane-associated proteins are disorganized and increased in amount confirming experimental reports. In contrast, the contractile myofilaments and the proteins of the sarcomeric skeleton including titin, alpha-actinin, and myomesin are significantly decreased. These changes can be assumed to occur in stages and are here presented as a testable hypothesis: (1) The early and reversible stage as present in animal experiments is characterized by accumulation of cytoskeletal proteins to counteract an increased strain without loss of contractile material. (2) Further accumulation of microtubules and desmin to compensate for the increasing loss of myofilaments and titin represents the late clinical and irreversible state. We suggest, based on a structural basis for heart failure, an integrative view which closes the gap between changes within cardiac myocytes and the involvement of the extracellular matrix, including the development of fibrosis. These factors contribute significantly to structural ventricular remodeling and dilatation finally resulting in reduced cardiac function.

Animals↗
PubMed2000

Apoptosis is initiated by myocardial ischemia and executed during reperfusion.

Ischemia/reperfusion leading to myocyte cell death has been reported as either necrotic or apoptotic or a combination of both. The importance of necrosis is well established but the role of apoptosis and the time of initiation are still unknown. Normothermic global ischemia of either 45 or 90 min duration followed by 6 h of reperfusion were induced in isolated canine hearts. After 45 min of ischemia, left ventricular function and adenine nucleotide (AN) content had recovered during reperfusion indicating reversible injury. DNA fragmentation determined by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) was absent as was the 85 kDa fragment of poly-(ADP-ribose) polymerase (PARP). After 90 min of ischemia, electron microscopy indicated necrotic cell death in 90% of myocytes. Recovery of function and AN content during reperfusion was minimal. At the end of ischemia, caspase-3 was activated in 30% of all myocytes and PARP 85 kDa fragments were present by Western blot, indicating initiation of the apoptotic cascade. Lamin-B(1)labeling was significantly reduced from 90% in myocytes in control and ischemia to 30% in early reperfusion. Completion of apoptosis seen by TUNEL was evident in late reperfusion (7.6% of myocytes and 8.3% of non-myocytes). Experiments with 6 h ischemia without reperfusion showed absence of DNA fragmentation. We conclude that apoptotic cell death is initiated by ischemia but that reperfusion is needed for completion of the apoptotic cascade. Furthermore, it is concluded that cell death in acute global ischemia followed by reperfusion occurs predominantly by necrosis and that apoptosis is of minor importance in this pathophysiological situation.

Adenine Nucleotides↗
PubMed2000

Unresolved issues regarding the role of apoptosis in the pathogenesis of ischemic injury and heart failure.

UNLABELLED: Apoptosis is "suicidal" programmed cell death followed by necrosis, i.e. cellular degradation. This review presents a critical evaluation of the methods used for detection of apoptosis and on data regarding the role of apoptosis in ischemia and heart failure. METHODS: DNA laddering by electrophoresis and the TUNEL method in histology for the final stage of apoptosis, Annexin V labeling, evidence of caspase activation, cleavage of substrates, measurements of mitochondrial pro-apoptotic and anti-apoptotic factors (Bcl-2, Bax and others) and determination of the mitochondrial transitional pore potential. Much work has been carried out regarding the mechanism and the importance of apoptosis in ischemia and heart failure but many issues still remain unsolved: (1)Time needed for completion of apoptosis from stimulus to DNA fragmentation? (2)Importance of mitochondrial pathway considering the fact that cardiomyocytes contain the highest volume density of mitochondria of all mammalian cells (25% in humans, 37% in mice)? (3)Means of removal of dead cells, disconnection at the intercalated disc from neighbouring myocytes, time frame of this process? (4)Reversibility of apoptosis? (5)Differences between physiological (postnatal differentiation of the conduction system) v pathological apoptotic cell death? (6)Why do cells, under ischemic conditions, die by either apoptosis or oncosis? (7)Is apoptosis an epiphenomenon or a true cause of heart failure? (8)Quantification of the rate of apoptosis in different pathophysiological situations? Clarification of these unresolved issues will then allow an estimation of the importance of apoptosis in cardiac pathophysiology and, if necessary because the role of apoptosis has been established, the development of new therapeutic concepts.

Animals↗
PubMed2000

Altered balance between extracellular proteolysis and antiproteolysis is associated with adaptive coronary arteriogenesis.

To study the role of extracellular proteolysis and antiproteolysis during adaptive arteriogenesis (collateral vessel growth) we took 58 collaterals at various developmental stages from 14 dogs with chronic occlusion of the left circumflex coronary artery (LCx) by ameroid constrictor. Immunofluorescence and quantitative immunofluorescence with antibodies against alpha-smooth muscle actin, desmin, matrix metalloproteinases 2 (MMP-2), MMP-9, tissue inhibitor of metalloproteinases 1 (TIMP-1) and 2 (TIMP-2), urokinase-type plasminogen activator (u-PA) and its inhibitor-1 (PAI-1) were studied with confocal microscopy. Additionally, SDS-PAGE zymography was employed. We found that in normal coronary arteries, MMP-2, MMP-9 and PAI-1 were present in all layers of the wall in small amounts. TIMP-1 was found only in smooth muscle cells. In contrast, in growing collaterals, MMP-2 and MMP-9 were 3.4-fold and 4.1-fold higher in the neointima than in the media respectively. TIMP-1 was 4.4-fold higher in the media over the growing neointima. Zymography showed MMP-2 and MMP-9 activated. PAI-1 was increased, especially in the growing neointima where it was 1.4-fold higher. In mature collaterals, MMP-2 and MMP-9 were downregulated in the neointima, 1.4-fold and 1.3-fold higher over the media. TIMP-1 was 1.4-fold increased in the neointima but PAI-1 was downregulated. Desmin and alpha-smooth muscle actin were significantly increased in the neointima compared to growing vessels. U-PA was moderately increased in growing vessels. TIMP-2 was not detectable in collaterals. We conclude that expression of MMP-2 and 9, TIMP-1 and PAI-1 showed a spatial and temporal pattern which is closely associated with the development of collateral vessels. The shift of the balance between proteolysis and antiproteolysis is regulated not only by MMPs and TIMP-1, but also by the PA-PAI system.

Adaptation, Physiological↗
PubMed2000

[Diagnostic imaging in viral encephalitis].

The diagnostic procedure in viral encephalitis is based on the synopsis of clinical signs and symptoms, serological data, CSF analysis and diagnostic imaging findings. This article summarizes the findings of those viral encephalitides most frequently encountered in Western Europe. MRI is more sensitive than CT for the detection of inflammatory brain lesions due to the higher contrast resolution. The pattern of parenchymal damage is highly specific in only some viral encephalitides (e.g., the frequently hemorrhagic lesions of structures of the limbic system in herpes simplex virus type I encephalitis; the symmetric and confluent lesions of the frontal white matter of progressive diffuse leukoencephalopathy in AIDS). In the majority of viral encephalitides MRI demonstrates the location and extension of parenchymal damage. The specific diagnosis in terms of the causative agent is based on serological studies.

Brain↗
PubMed2000

Ultrastructure and molecular histology of rabbit hind-limb collateral artery growth (arteriogenesis).

Previous studies in the canine heart had shown that the growth of collateral arteries occurs via proliferative enlargement of pre-existing arteriolar connections (arteriogenesis). In the present study, we investigated the ultrastructure and molecular histology of growing and remodeling collateral arteries that develop after femoral artery occlusion in rabbits as a function of time from 2 h to 240 days after occlusion. Pre-existent arteriolar collaterals had a diameter of about 50 microm. They consisted of one to two layers of smooth muscle cells (SMCs) and were morphologically indistinguishable from normal arterioles. The stages of arteriogenesis consisted of arteriolar thinning, followed by transformation of SMCs from the contractile- into the proliferative- and synthetic phenotype. Endothelial cells (ECs) and SMCs proliferated, and SMCs migrated and formed a neo-intima. Intercellular adhesion molecule (ICAM-1) and vascular cell adhesion molecule (VCAM-1) showed early upregulation in ECs, which was accompanied by accumulation of blood-derived macrophages. Mitosis of ECs and SMCs started about 24 h after occlusion, whereas adhesion molecule expression and monocyte adhesion occurred as early as 12 h after occlusion, suggesting a role of monocytes in vascular cell proliferation. Treatment of rabbits with the pro-inflammatory cytokine MCP-1 increased monocyte adhesion and accelerated vascular remodeling. In vitro shear-stress experiments in cultured ECs revealed an increased phosphorylation of the focal contacts after 30 min and induction of ICAM-1 and VCAM-1 expression between 2 h and 6 h after shear onset, suggesting that shear stress may be the initiating event. We conclude that the process of arteriogenesis, which leads to the positive remodeling of an arteriole into an artery up to 12 times its original size, can be modified by modulators of inflammation.

Animals↗
PubMed2000

A self-perpetuating vicious cycle of tissue damage in human hibernating myocardium.

Recently, we proposed the hypothesis that a vicious cycle exists in human hibernating myocardium (HM) between the progression of myocyte degeneration and the development of fibrosis. We now investigated the pathomechanism of this cycle in more detail and established a correlation between the severity of the morphological changes and the degree of postoperative functional recovery of HM. HM was diagnosed by dobutamine echocardiography, thallium-201 scintigraphy and radionuclide ventriculography. Functional recovery was present at 3 months after coronary bypass surgery but remained unchanged at 15 months. Forty patients were subdivided into 2 groups: A with complete and B with incomplete recovery. Biopsies taken during surgery and studied by electron microscopy, immunocytochemistry, rt-PCR, and morphometry revealed myocyte degeneration and inflammatory and fibrinogenic changes in a widened interstitial space. We report here for the first time an upregulation of TGF-beta1 evident by a 5-fold increase of fibroblasts and macrophages exhibiting a TGF-beta1 content 3-fold larger than in control, and a > 3-fold increase in TGF-beta1 mRNAby rt-PCR. The number of angiotensin converting enzyme (ACE) containing structures was increased (n/mrm2: control-11.4, A-17.6, B-19.2, control vs. A and B, p < 0.05). Fibrosis was more severe in group B than A or control (%: C-10.1; A-21.2; B-40.6; p < 0.05). Capillary density was significantly reduced (n/mm2: C-1152; A-782; B-579, p < 0.05) and intercapillary distance was widened (microm: C-29.5, A-36.1, B-43.3, p < 0.05). The number of CD 3 (n/mm2: C-5.0; A-9.6; B-9.4, ns) and CD 68 positive cells (n/mm2: C-37.2; A-80.7; B-55.0, C vs. A p < 0.05) was elevated in HM as compared to control indicating an inflammatory reaction. Cut-off points for functional recovery are fibrosis > 32%, capillary density < 660/mm2 and intercapillary distance > 39.0 microm. In HM a self-perpetuating vicious cycle of tissue alterations leads to progressive replacement fibrosis and continuous intracellular degeneration which should be interrupted by early revascularization.

Adult↗
PubMed2000

The cytoskeleton and related proteins in the human failing heart.

In addition to functional alterations, heart failure has a structural basis as well. This concerns all components of the cardiac myocytes as well as the extracellular space. Proteins of the cardiomyocyte can be subdivided in 5 different categories: 1) Contractile proteins including myosin, actin, tropomyosin and the troponins. 2) Sarcomeric skeleton: titin, myosin binding protein C, alpha-actinin, myomesin, and M-protein. 3) True 'cytoskeletal' proteins: tubulin, desmin and actin. 4) Membrane-associated proteins: dystrophin, spectrin, talin, vinculin, ankyrin and others. 5) Proteins of the intercalated disc: desmosomes consisting of desmoplakin, desmocollin, desmoglein and desmin; adherens junctions with N-cadherin, the catenins and vinculin, and gap junctions with connexin. Failing myocardium obtained from patients undergoing cardiac transplantation exhibits ultrastuctural degeneration and an altered nucleus/cytoplasm relationship. The contractile proteins and those of the sarcomeric skeleton, especially titin, are downregulated, the cytoskeletal proteins desmin and tubulin and membrane-associated proteins such as vinculin and dystrophin are upregulated and those of the intercalated disc are irregularly arranged. Elevation of cytoskeletal proteins correlates well with diastolic and contractile dysfunction in these patients. The enlarged interstitial space contains fibrosis, i.e. accumulations of fibroblasts and extracellular matrix components, in addition to macrophages and microvascular elements. Loss of the contractile machinery and related proteins such as titin and alpha-actinin may be the first and decisive event initiating an adaptive increase in cytoskeleton and membrane associated components. Fibrosis may be stimulated by subcellular degeneration. The hypothesis is put forward that all proteins of the different myocardial compartments contribute to the deterioration of cardiac function in heart failure.

Cardiomyopathy, Dilated↗