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)

Idiopathic dilated cardiomyopathy (IDCM) is the main cause of cardiac transplantation in young adults in the 20-40 years age group in the Western world. Recent evidence supports a possible role for autoimmune pathogenesis in IDCM and it has been suggested that T cells could mediate the disease. Cardiac myosin is one of the putative autoantigens recognized by antibodies from patients with IDCM, but T cell responses to cardiac myosin have not previously been assessed. Proliferation to cardiac myosin by peripheral blood mononuclear cells (PBMC) from patients, their relatives and controls was assessed in a lymphoproliferation assay specifically designed to measure low frequency T cell precursor responses. The study group consisted of 23 patients with IDCM and 29 relatives. The control groups consisted of 10 patients with heart failure secondary to ischaemic heart disease (IHD) and 22 healthy laboratory controls. A response to myosin was observed in 16.7% of the subjects studied. However, these responses were all of low precursor frequency and no dose response for antigen-specific proliferation could be observed. More importantly, there was no correlation between myosin-specific T cell responses and IDCM, as only one IDCM patient and four IDCM relatives (three out of the four with left ventricular enlargement (LVE)) were among the 14 subjects whose PBMC exhibited a proliferative response. However, proliferation of PBMC to purified protein derivative of Mycobacterium bovis (PPD) was significantly suppressed in IDCM patients when compared with the laboratory control group (P<0.05). PPD response data suggested that the PPD suppression correlated with disease progression. The results of our present study indicate an absence, or lack, of cardiac myosin-specific peripheral blood T cells in IDCM patients, along with the possibility of underlying impaired cell mediated immunity, reflected in the suppressed responses to PPD. Future studies looking at T cell immune mechanisms in IDCM should concentrate on the analysis of T cells from the heart itself, or look at other potential cardiac antigens from normal and diseased heart tissue.
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PMID:Lack of T cell response to cardiac myosin and a reduced response to PPD in patients with idiopathic dilated cardiomyopathy. 918 83

We sought to characterize the effects of the nonselective Ca2+ channel antagonist, verapamil, and the vascular-selective Ca2+ channel antagonist, felodipine, on obese, hypertensive, heart failure-prone, female SHHF/Mcc-fa(cp) rats. Rats were treated for < or = 2 months with verapamil (57 mg/kg/day) or felodipine (24 mg/kg/day). Blood pressures were determined at monthly intervals by the tail-cuff method. Heart weights and myosin isoforms were measured at the end of treatment. Direct cardiac effects of verapamil and felodipine were examined in electrically field stimulated, fura-2/AM-loaded cardiomyocytes. Both Ca2+ channel antagonists reduced systolic blood pressures. Verapamil, but not felodipine, increased heart weights and decreased expression of the myosin V1 isoform. In older animals, 75% of those treated with verapamil developed end-stage congestive heart failure. Age-matched control and felodipine-treated rats remained healthy. In isolated cardiomyocytes, 10(-9) M verapamil significantly reduced Ca2+ transient amplitudes but 10(-9) M felodipine did not. Both Ca2+ channel antagonists reduced blood pressures in obese, hypertensive, female SHHF rats. Verapamil, but not felodipine, produced heart failure in a large number of these animals. Differences between the in vivo effects of the two Ca2+ channel antagonists may be related to the differing effects on sarcolemmal Ca2+ influx.
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PMID:Verapamil accelerates the transition to heart failure in obese, hypertensive, female SHHF/Mcc-fa(cp) rats. 923 52

Alterations in troponin T (TnT) isoforms have been reported in severe human and experimental heart failure (HF), and may play a role in the depressed myofibrillar ATPase activity observed in this condition. It is unclear whether these alterations reflect very severe hemodynamic derangement or are a component of mild hypertrophic stress. Therefore, we studied the expression of TnT isoforms (SDS-PAGE, Western blots), myosin isoforms, myofibrillar ATPase activity, and left ventricular (LV) mechanoenergetics (rbc perfused, isovolumically contracting isolated heart) in a rabbit model of mild hypertrophy (LVH) due to gradual hypertension caused by 12 weeks of cellophane wrap of the kidneys (n=12). LV/body weight ratio increased by 28% in LVH compared to shams (P<0.001); no animals had evidence of HF. In LVH, the percentage of TnT2 was modestly but significantly increased compared to shams [6.2+/-1.9 (+/-S.D. ) v 3.7+/-1.0%, P<0.05], mainly as a consequence of a parallel decrease in TnT4 (P=0.07). Sham hearts ranged from 75-100% V3 isomyosin, whereas all LVH hearts had 100% of the V3 form. There were no significant differences in myofibrillar ATPase activity or mechanical variables, including contraction and relaxation rates. The slope of the VO2-pressure-volume-area relation (a measure of the energy conversion efficiency of the contractile machinery) was also unchanged. We conclude that in the rabbit, shifts in TnT isoforms toward a more "fetal" pattern occur during mild LVH and, therefore, are likely to be a general feature of the response to hemodynamic stress, rather than a phenomenon confined to end-stage disease. These modest shifts are not associated with major alterations in LV myofibrillar ATPase activity or mechanoenergetics.
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PMID:Altered expression of troponin T isoforms in mild left ventricular hypertrophy in the rabbit. 929 58

The multiple mechanisms that bring about the decompensation of the hypertrophic remodeled myocardium are synergistic and not fully understood. Our current hypothesis is that the increased stress on the ventricle is initially offset by compensatory myocardial hypertrophy. In many instances, however, progressive ventricular dilatation and heart failure occur as a result of maladaptive hypertrophy (abnormal myosin-actin production), programmed cell death (apoptosis) and/or changes in the interstitial vasculature and collagen composition. The molecular and genetic background to these processes includes changes in myocardial gene expression, activation of the local tissue renin-angiotensin and other neurohormonal systems, increased matrix metalloproteinase activity (including collagenase), and expression of certain components of the immune system, such as TNF-alpha. Future research will hopefully provide better methods for limiting the remodeling-ventricular dilatation process by novel pharmacotherapies, gene therapy and, possibly, surgical therapy, and determine the impact of such interventions on survival.
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PMID:Ventricular remodeling: from bedside to molecule. 933 Jul 35

Around 85% of embryos homozygous for the splotch (Sp2H) allele (Sp2H/Sp2H), a Pax3 mutation, develop persistent truncus arteriosus (PTA), a defect related to the cardiac neural crest. These embryos die by 14.5 days post coitum. In an investigation of the cause of lethality in these embryos, we used digital video imaging microscopy to examine beating embryonic hearts in situ at 13.5 dpc. The hearts of Sp2H/Sp2H embryos with PTA clearly showed poor function when compared with normal litter mates. Contractile force was examined in detergent-skinned ventricular muscle strips from Sp2H/Sp2H embryos at ages 12.5 and 13.5 dpc. There was no significant difference in the maximum force or in myosin content between Sp2H/Sp2H and control groups, indicating no significant dysfunction of the contractile apparatus in hearts from Sp2H/Sp2H embryos. Ca2+ transients were examined in enzymatically-dissociated ventricular myocytes and were significantly reduced in defective hearts, indicating that reduced cardiac function in Sp2H/Sp2H embryos with PTA was due to impaired excitation-contraction (EC) coupling. Ca2+ currents were examined using the perforated patch clamp technique. The magnitude of the Ca2+ current was found to be reduced by approximately 3.2-fold in Sp2H/Sp2H hearts with PTA compared to normal. Since the sarcoplasmic reticulum is sparse or absent in the embryonic heart, the impaired EC coupling was due to the reduction in Ca2+ current. These observations suggest that neural crest abnormalities result in a defect in EC coupling, causing depressed myocardial function and death in utero from cardiac failure. Interestingly, Sp2H/Sp2H hearts without PTA had normal EC coupling. These results indicated that impaired EC coupling was secondary to the Pax3 mutation. The findings in this report indicate an important role for the neural crest in the development of normal myocardial function, and represent the first demonstration of impaired excitation-contraction coupling in a genetically-defined embryonic mammalian model of a cardiac structural defect.
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PMID:Neural crest is involved in development of abnormal myocardial function. 934 62

Current information regarding the molecular and biochemical mechanisms of myocardial hypertrophy, as obtained from isolated cardiomyocytes and/or healthy animals with aortic banding, does not permit dissection of the hierarchical relationship among different steps and triggers of the pathogenic process in vivo. The aim of the present study was to depict the temporal relationship among myocardial structural and functional characteristics, the embryonic gene program, and transforming growth factor (TGF) beta 1 expression in euthyroid hereditary hypertrophic cardiomyopathic hamsters (CMPH). This investigation was performed using Western and Northern blot and in situ hybridization techniques. The results show that in CMPH, the severity of the hemodynamic overload is not related to any modification in structural myocardial characteristics (cardiac mass, cardiomyocyte dimensions, total RNA, and protein content), whereas an early activation of the embryonic gene program occurs in not yet overloaded 90-day-old CMPH (left ventricular end diastolic pressure < 15 mm Hg). In these animals, a 30% to 90% decrease in the alpha myosin heavy chain (alpha MHC) relative content was found in ventricles, whereas beta MHC increased 5-fold. In addition, the alpha skeletal actin expression was enhanced 2-fold versus age-matched controls. No modifications were observed in myosin function evaluated by in vitro motility assay, whereas the administration of L-thyroxine (100 micrograms/kg intraperitoneally daily) to CMPH was able to reinduce the ventricular expression of the alpha MHC isoform (5-fold increase). Conversely, no changes were found in alpha cardiac actin and myosin light chain 2 (MLC2) expression. A close temporal relationship occurred in CMPH ventricles between the re-expression of the embryonic gene program and a 3-fold enhancement of the expression of TGF beta 1. These results indicate that the CMPH provides a useful model for investigating the expression of embryonic genes in hypertrophic ventricles in the absence of mechanical and hormonal stimuli, and that TGF beta 1 is involved in regulating in vivo the "embryonic step" of myocardial hypertrophy. Furthermore, the study offers new insights into the pathophysiologic mechanisms leading to heart failure.
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PMID:Embryonic gene expression in nonoverloaded ventricles of hereditary hypertrophic cardiomyopathic hamsters. 938 92

We recently demonstrated dynamic alterations in protein turnover 3 days and 1 month after surgical induction of aortic regurgitation (AR). To characterize protein synthesis and degradation during the long-term plateau phase, we performed [3H]-leucine infusion 2.5 years after induction of AR in 10 New Zealand White rabbits and 12 sham-operated controls. Protein fractional synthesis rates were obtained by analyses of plasma and protein hydrolysates, growth rates from protein concentration and heart weight measurements, and degradation rates by subtraction of growth from synthesis rates. AR (regurgitant fraction 25 +/- 11%) caused a 57% increase in left ventricular (LV) weight in comparison with controls (7.4 +/- 1.7 vs. 4.7 +/- 0.6 g, p < 0.001) and no evidence of heart failure. Although concentrations of total cardiac protein, myosin heavy chain and actin were similar, the enlarged AR hearts had increased amounts of total cardiac protein (1,009 +/- 312 vs. 682 +/- 120 mg/LV, p < 0.05), myosin heavy chain (148 +/- 91 vs. 81 +/- 29 mg/LV, p < 0.05), and actin (73 +/- 42 vs. 44 +/- 16 mg/LV, p < 0.06). Individual protein fractional synthesis and degradation rates were closely balanced. However, myosin fractional synthesis rates were 152% (p < 0.01) greater than those of total cardiac protein in AR animals, while only 52% (p < 0.05) greater in controls (AR vs. controls, p = 0.05). Variations in actin turnover between AR and control animals did not attain statistical significance. Myosin and actin fractional synthesis rates correlated closely in AR rabbits (R = 0.81, p < 0.02), but not among controls (R = 0.41, NS). Thus, selective alterations in myofibrillar protein turnover contribute to the maintenance of increased myofibrillar protein content in the 'compensatory' LV hypertrophy of chronic AR.
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PMID:Protein turnover in compensated chronic aortic regurgitation. 939 5

Hypertrophic cardiomyopathy is a dominantly inherited disease of the heart. Heterogeneous sets of mutations responsible for this condition have been identified in seven genes coding for proteins involved in the contraction mechanism or in the control of contraction of the myocardium. Known mutations imply structural and functional changes in the following proteins: in ventricle specific beta-myosin heavy chain, in essential and regulatory myosin light chains, in troponin subunits T and I, in alpha-tropomyosin and in myosin binding protein-C. The gene of one additional genomic HCM-locus is not known. Since two thirds or more of all cases can be traced to one of the respective genes, HCM has been classified as a disease of the cardiac sarcomere. Heterogeneity does not only exist between genes, but also within genes. At least 84 different mutations have been identified to date. More than half of them have been detected in the beta-myosin heavy chain gene. Thus, mutations in this gene account for most of the cases of HCM. The extent of data about causes is in contrast to the lack of definite knowledge about pathogenic mechanisms. Since the disorder is in many cases mild with symptoms developing frequently not before the end of the second decade, myocardial dysfunctions can presumably not directly be traced to altered contractility, but rather to effects which accumulate with a long asymptomatic lag period and which gradually lead to hypertrophy, conduction problems and ultimately to cardiac failure. The disease may be considered as an indirect and secondary response to a mildly distorted contraction process. The rapid progress in the analysis of causes suggests that the study of genes will assume a role in the context of the clinical management of HCM, in particular regarding diagnosis, prognosis, counselling of patients and families and--possibly--therapy.
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PMID:[Genetic causes of hypertrophic cardiomyopathy]. 959 35

Cardiac hypertrophy is an adaptive response that normalizes wall stress and compensates for increased workload. It is accompanied by distinct qualitative and quantitative changes in the expression of protein isoforms concerning contractility, intracellular Ca(2+)-homeostasis and metabolism. Changes in the myosin subunit isoform expression improves contractility by an increase in force generation at a given Ca(2+)-concentration (increased Ca(2+)-sensitivity) and by improving the economy of the chemo-mechanical transduction process per amount of utilised ATP (increased duty ratio). In the human atrium this is achieved by partial replacement of the endogenous fast myosin by the ventricular slow-type heavy and light chains. In the hypertrophic human ventricle the slow-type beta-myosin heavy chains remain unchanged, but the ectopic expression of the atrial myosin essential light chain (ALC1) partially replaces the endogenous ventricular isoform (VLC1). The ventricular contractile apparatus with myosin containing ALC1 is characterised by faster cross-bridge kinetics, a higher Ca(2+)-sensitivity of force generation and an increased duty ratio. The mechanism for cross-bridge modulation relies on the extended Ala-Pro-rich N-terminus of the essential light chains of which the first eleven residues interact with the C-terminus of actin. A change in charge in this region between ALC1 and VLC1 explains their functional difference. The intracellular Ca(2+)-handling may be impaired in heart failure, resulting in either higher or lower cytosolic Ca(2+)-levels. Thus the state of the cardiomyocyte determines whether this hypertrophic adaptation remains beneficial or becomes detrimental during failure. Also discussed are the effects on contractility of long-term changes in isoform expression of other sarcomeric proteins. Positive and negative modulation of contractility by short-term phosphorylation reactions at multiple sites in the myosin regulatory light chain, troponin-I, troponin-T, alpha-tropomyosin and myosin binding protein-C are considered in detail.
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PMID:Modulation of contractility in human cardiac hypertrophy by myosin essential light chain isoforms. 961 95

Cardiomyocyte apoptosis or programmed cell death has been shown to occur in end-stage explanted failed human hearts and in dogs with chronic heart failure (HF). We tested the hypothesis that early long-term monotherapy with an angiotensin-converting enzyme (ACE) inhibitor attenuates cardiomyocyte apoptosis in dogs with moderate HF. Left ventricular (LV) dysfunction (ejection fraction 30-40%) was produced in dogs by multiple sequential intracoronary microembolizations. Dogs were randomized to 3 mo of therapy with enalapril (Ena, 10 mg twice daily, n = 7) or to no therapy at all (control, n = 7). After 3 mo of therapy, dogs were euthanized and the hearts removed. Presence of nuclear DNA fragmentation (nDNAf), a marker of apoptosis, was assessed in frozen LV sections using the immunohistochemical deoxynucleotidal transferase-mediated dUTP-digoxigenin nick-end labeling (TUNEL) method. Sections were also stained with ventricular anti-myosin antibody to identify cells of cardiocyte origin. From each dog, 80 fields (x40) were selected at random, 40 from LV regions bordering old infarcts and 40 from LV regions remote from any infarcts, for quantifying the number of cardiomyocyte nDNAf events per 1,000 cardiomyocytes. The average number of cardiomyocyte nDNAf events per 1,000 cardiomyocytes was significantly lower in Ena-treated dogs compared with controls (0.81 +/- 0.13 vs. 2.65 +/- 0.81, P < 0.029). This difference was due to a significantly lower incidence of cardiomyocyte nDNAf events in LV regions bordering scarred tissue (infarcts) in Ena-treated dogs compared with controls. We conclude that early long-term Ena therapy attenuates cardiomyocyte apoptosis in dogs with moderate HF. Attenuation of cardiomyocyte apoptosis may be one mechanism by which ACE inhibitors preserve global LV function in HF.
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PMID:Effects of ACE inhibition on cardiomyocyte apoptosis in dogs with heart failure. 968 52


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