Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cardiomyopathies are responsible for a high proportion of cases of congestive heart failure and sudden death, as well as for the need for transplantation. Understanding of the causes of these disorders has been sought in earnest over the past decade. We hypothesized that DCM is a disease of the cytoskeleton/sarcolemma, which affects the sarcomere. Evaluation of the sarcolemma in DCM and other forms of systolic heart failure demonstrates membrane disruption; and, secondarily, the extracellular matrix architecture is also affected. Disruption of the links from the sarcolemma to ECM at the dystrophin C-terminus and those to the sarcomere and nucleus via N-terminal dystrophin interactions could lead to a "domino effect" disruption of systolic function and development of arrhythmias. We also have suggested that dystrophin mutations play a role in idiopathic DCM in males. The T-cap/MLP/alpha-actinin/titin complex appears to stabilize Z-disc function via mechanical stretch sensing. Loss of elasticity results in the primary defect in the endogenous cardiac muscle stretch sensor machinery. The over-stretching of individual myocytes leads to activation of cell death pathways, at a time when stretch-regulated survival cues are diminished due to defective stretch sensing, leading to progression of heart failure. Genetic DCM and the acquired disorder viral myocarditis have the same clinical features including heart failure, arrhythmias, and conduction block, and also similar mechanisms of disease based on the proteins targeted. In dilated cardiomyopathy, the process of progressive ventricular dilation and changes of the shape of the ventricle to a more spherical shape, associated with changes in ventricular function and/or hypertrophy, occurs without known initiating disturbance. In those cases in which resolution of cardiac dysfunction does not occur, chronic DCM results. It has been unclear what the underlying etiology of this long-term sequela could be, but viral persistence and autoimmunity have been widely speculated.
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PMID:Inflammatory cardiomyopathy: there is a specific matrix destruction in the course of the disease. 1632 65

Titin is a giant protein that constitutes the third myofilament of the sarcomere. Single titin molecules anchor in the Z-disk and extend all the way to the M-line region of the sarcomere. Successive titin molecules are arranged head-to-head and tail-to-tail, providing a continuous filament along the full length of the myofibril. The majority of titin's I-band region is extensible and functions as a molecular spring that when extended develops passive force. We will discuss mechanisms for adjusting titin-based force, including alternative splicing and posttranslational modifications. Multiple biological functions can be assigned to different regions of the titin molecule. In addition to titin's role in determining passive muscle stiffness, recent evidence suggests a role in protein metabolism, compartmentalization of metabolic enzymes, binding of chaperones, and positioning of the membrane systems of the T-tubules and sarcoplasmic reticulum. We will also discuss titin-based force adjustments that occur in various muscle diseases and several disease-causing titin mutations that have been discovered. We will focus on the role of titin in heart failure patients that was recently investigated in patients with end-stage heart failure due to non-ischemic dilated cardiomyopathy. In end-stage failing hearts, compliant titin isoforms comprise a greater percentage of titin and changes in titin isoform expression in heart failure patients with DCM significantly impact diastolic filling by lowering myocardial stiffness.
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PMID:Titin: physiological function and role in cardiomyopathy and failure. 1641 44

The heart very often becomes a victim of endocrine abnormalities such as thyroid hormone imbalance and insulin deficiency, which are manifested in a broad spectrum of cardiac dysfunction from mildly compromised function to severe heart failure. These functional changes in the heart are largely independent of alterations in the coronary arteries and instead reside at the level of cardiomyocytes. The status of cardiac function reflects the net of underlying subcellular modifications induced by an increase or decrease in thyroid hormone and insulin plasma levels. Changes in the contractile and regulatory proteins constitute molecular and structural alterations in myofibrillar assembly, called myofibrillar remodeling. These alterations may be adaptive or maladaptive with respect to the functional and metabolic demands on the heart as a consequence of the altered endocrine status in the body. There is a substantial body of information to indicate alterations in myofibrillar proteins including actin, myosin, tropomyosin, troponin, titin, desmin, and myosin-binding protein C in conditions such as hyperthyroidism, hypothyroidism, and diabetes. The present article is focussed on discussion how myofibrillar proteins are altered in response to thyroid hormone imbalance and lack of insulin or its responsiveness, and how their structural and functional changes explain the contractile defects in the heart.
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PMID:Molecular defects in cardiac myofibrillar proteins due to thyroid hormone imbalance and diabetes. 1646 7

Heart failure of different etiologies is due to changes in cardiac structure and function. During normal diastolic filling, the passive stretch of the ventricular myocardium is modulated by titin, a giant elastic protein that acts as a molecular spring and leads to the recapitulation of single cell mechanics at global ventricular level. The mechanics of a dilated failing heart are at least partially determined by variations in the passive filling properties of the myocardium that impair contraction. Current volume reduction surgery is based on Laplace's law and obtained by rigid means that may impair diastolic function. We postulate that inserting one or more elastic elements at different levels of a failing ventricle (the mitral annulus, equator and apex) could improve cardiac performance. We describe our invention for the first time by presenting the results of two animal experiments.
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PMID:The Titan can help titin: from micro to macro myocardial elasticity. 1664 78

Titin is a giant protein that is in charge of the assembly and passive mechanical properties of the sarcomere. Cardiac titin contains a unique N2B region, which has been proposed to modulate elasticity of the titin filament and to be important for hypertrophy signaling and the ischemic stress response through its binding proteins FHL2 and alphaB-crystallin, respectively. To study the role of the titin N2B region in systole and diastole of the heart, we generated a knockout (KO) mouse deleting only the N2B exon 49 and leaving the remainder of the titin gene intact. The resulting mice survived to adulthood and were fertile. Although KO hearts were small, they produced normal ejection volumes because of an increased ejection fraction. FHL2 protein levels were significantly reduced in the KO mice, a finding consistent with the reduced size of KO hearts. Ultrastructural analysis revealed an increased extension of the remaining spring elements of titin (tandem Ig segments and the PEVK region), which, together with the reduced sarcomere length and increased passive tension derived from skinned cardiomyocyte experiments, translates to diastolic dysfunction as documented by echocardiography. We conclude from our work that the titin N2B region is dispensable for cardiac development and systolic properties but is important to integrate trophic and elastic functions of the heart. The N2B-KO mouse is the first titin-based model of diastolic dysfunction and, considering the high prevalence of diastolic heart failure, it could provide future mechanistic insights into the disease process.
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PMID:Targeted deletion of titin N2B region leads to diastolic dysfunction and cardiac atrophy. 1736 Jun 64

Mechanical stress signals transmitted through the heart walls during hemodynamic loading are sensed by the myocytes, which respond with changes in contractile performance and gene expression. External forces play an important role in physiological heart development and hypertrophy, but disruption of the well-balanced stress-sensing machinery causes mechanical dysregulation, cardiac remodelling, and heart failure. Nodal points of mechanosensing in the cardiomyocytes may reside in the Z-disk, I-band, and M-band regions of the sarcomeres. Longitudinal linkage of these regions is provided by the titin filament, and several 'hot spots' along this giant protein, in complex with some of its >20 ligands, may be pivotal to the myofibrillar stress or stretch response. This review outlines the known interaction partners of titin, highlights the putative stress/stretch-sensor complexes at titin's NH(2) and COOH termini and their role in myopathies, and summarizes the known disease-associated mutations in those titin regions. Another focus is the elastic I-band titin section, which interacts with a diverse number of proteins and whose main function is as a determinant of diastolic distensibility and passive stiffness. The discussion centers on recent insights into the plasticity, mechanical role, and regulation of the elastic titin springs during cardiac development and in human heart disease. Titin and titin-based protein complexes are now recognized as integral parts of the mechanosensitive protein network and as critical components in cardiomyocyte stress/stretch signalling.
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PMID:Sense and stretchability: the role of titin and titin-associated proteins in myocardial stress-sensing and mechanical dysfunction. 1747 30

The molecular and cellular mechanisms that cause cumulative dose-dependent anthracycline-cardiotoxicity remain controversial and incompletely understood. Studies examining the effects of anthracyclines in cardiac myocytes inA vitro have demonstrated several forms of cellular injury. Cell death in response to anthracyclines can be observed by one of several mechanisms including apoptosis and necrosis. Cell death by apoptosis can be inhibited by dexrazoxane, the iron chelator that is known to prevent clinical development of heart failure at high cumulative anthracycline exposure. Together with clinical evidence for myocyte death after anthracycline exposure, in the form of elevations in serum troponin, make myocyte cell death a probable mechanism for anthracycline-induced cardiac injury. Other mechanisms of myocyte injury include the development of cellular \'sarcopenia\' characterized by disruption of normal sarcomere structure. Anthracyclines suppress expression of several cardiac transcription factors, and this may play a role in the development of myocyte death as well as sarcopenia. Degradation of the giant myofilament protein titin may represent an important proximal step that leads to accelerated myofilament degradation. Titin is an entropic spring element in the sarcomere that regulates length-dependent calcium sensitivity. Thus titin degradation may lead to impaired diastolic as well as systolic dysfunction, as well as potentiate the effect of suppression of transcription of sarcomere proteins. An interesting interaction has been noted clinically between anthracyclines and newer cancer therapies that target the erbB2 receptor tyrosine kinase. Studies of erbB2 function in viro suggest that signaling through erbB2 by the growth factor neuregulin may regulate cardiac myocyte sarcomere turnover, as well as myocyte-myocyte/myocyte-matrix force coupling. A combination of further in vitro studies, with more careful monitoring of cardiac function after exposure to these cancer therapies, may help to understand to what extent these mechanisms are at work during clinical exposure of the heart to these important pharmaceuticals.
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PMID:Molecular and cellular mechanisms of anthracycline cardiotoxicity. 1765 15

Dilated cardiomyopathy (DCM) is a disease of the myocardium, which causes heart failure and premature death. It has been described in humans and several domestic animals. In the Newfoundland dog, DCM is an autosomal dominant disease with late onset and reduced penetrance. We analyzed 15 candidate genes for their involvement in DCM in the Newfoundland dog. Polymorphic microsatellite markers and single Nucleotide Polymorphisms were genotyped in 4 families of Newfoundland dogs segregating dilated cardiomyopathy for the genes encoding alpha-cardiac actin (ACTC), caveolin (CAVI), cysteine-rich protein 3 (CSRP3), LIM-domain binding factor 3 (LDB3), desmin (DES), lamin A/C (LMNA), myosin heavy polypeptide 7 (MYH7), delta-sarcoglycan (SGCD), troponin I (TNNTI3), troponin T (TNNT2), alpha-tropomyosin (TPMI), titin (TTN) and vinculin (VCL). A Logarithm of the odds (LOD) score of less than -2.0 in 2-point linkage analysis indicated exclusion of all but 2 genes, encoding CSRP3 and DES. A (LOD) score between -1.5 and -2.0 for CSRP3 and DES makes these genes unlikely causes of DCM in this dog breed. For the phospholamban (PLN) and titin cap (TTN) genes, a direct mutation screening approach was used. DNA sequence analysis of all exons showed no evidence that these genes are involved in DCM in the Newfoundland dog.
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PMID:Evaluation of 15 candidate genes for dilated cardiomyopathy in the Newfoundland dog. 1799 75

Heart failure with normal ejection fraction occurs in elderly patients with hypertensive heart disease. We hypothesized that, in such patients, mineralocorticoid receptor activation accelerates the types of ventricular and vascular remodeling and dysfunction believed important in the transition to heart failure. We tested this hypothesis by administering deoxycorticosterone acetate (DOCA) without salt loading or nephrectomy to elderly dogs with experimental hypertension. Elderly dogs were made hypertensive by renal wrapping. After 5 weeks, dogs were randomly assigned to DOCA (1 mg/kg per day IM; old hypertensive [OH]+DOCA; n=11) or not (OH; n=11) for 3 weeks. At week 8, conscious echocardiography and hemodynamic assessment under anesthesia were performed. DOCA resulted in further increases in conscious blood pressure (P<0.05) without increases in cardiac output or diastolic volume. In the conscious state, effective arterial elastance (P<0.05) and systemic vascular resistance (P=0.06) were increased, and systemic arterial compliance (P<0.05) was decreased in OH+DOCA animals. After anesthesia, instrumentation, and autonomic blockade, blood pressure was lower, whereas left ventricular (LV) systolic elastance, LV diastolic stiffness, and ex vivo myofiber diastolic stiffness were increased in OH+DOCA animals. LV collagen was increased in OH+DOCA animals (P<0.05 for all), but LV mass, LV brain natriuretic peptide, and titin isoform profiles were not. Neither aortic stiffness nor aortic structure was altered in OH+DOCA animals. These findings suggest that age and hypertensive heart disease enhance sensitivity to exogenous mineralocorticoid administration and that mineralocorticoid receptor activation could contribute to the transition to heart failure in elderly persons by promoting increases in LV diastolic and systolic stiffness.
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PMID:Mineralocorticoid signaling in transition to heart failure with normal ejection fraction. 1808 43

Titins, giant sarcomere proteins with major mechanical/signaling functions, are expressed in 2 main isoform classes in the mammalian heart: N2B (3000 kDa) and N2BA (>3200 kDa). A dramatic isoform switch occurs during cardiac development, from fetal N2BA titin (3700 kDa) expressed before birth to a mix of smaller N2BA/N2B isoforms found postnatally; adult rat hearts almost exclusively have N2B titin. The isoform switch, which can be reversed in chronic human heart failure, alters myocardial distensibility and mechanosignaling. Here we determined factors regulating this switch using, as a model system, primary cardiomyocyte cultures prepared from embryonic rats. In standard culture, the mean N2B percentage initially was 14% and increased by approximately 60% within 1 week, resembling the in vivo switching. The titin isoform transition was independent of endothelin-1-induced myocyte hypertrophy and was not altered by pacing, contractile arrest, or cell stretch; however, it was modestly impaired by decreasing substrate rigidity and strongly dependent on serum components. Angiotensin II significantly promoted the transition. The mean N2B proportion in 1-week-old cultures dropped 20% to 25% in hormone-reduced medium, but addition of 3,5,3'-triiodo-l-thyronine (T3) nearly restored the proportion to that found in standard culture. This T3 effect was not prevented by bisphenol A, a specific inhibitor of the classic genomic pathway of T3 action. In contrast, the titin switch could be stalled by the phosphatidylinositol 3-kinase inhibitor LY294002, which decreased the proportion of N2B mRNA transcripts within hours and suppressed a rapid T3-induced increase in Akt phosphorylation. Also, angiotensin II, but not endothelin-1 or cell stretch, enhanced Akt phosphorylation. Thus, although matrix stiffness modulates developmental titin isoform transitions, these transitions are mainly regulated through phosphatidylinositol 3-kinase/Akt-dependent signaling triggered particularly by T3 via a rapid action pathway.
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PMID:Thyroid hormone regulates developmental titin isoform transitions via the phosphatidylinositol-3-kinase/ AKT pathway. 1809 19


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