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)

Heart disease is the leading cause of mortality and morbidity in the world. As such, biomarkers are needed for the diagnosis, prognosis, therapeutic monitoring and risk stratification of acute injury (acute myocardial infarction (AMI)) and chronic disease (heart failure). The procedure for biomarker development involves the discovery, validation, and translation into clinical practice of a panel of candidate proteins to monitor risk of heart disease. Two types of biomarkers are possible; heart-specific and cardiovascular pulmonary system monitoring markers. Here we review the use of MS in the process of cardiac biomarker discovery and validation by proteomic analysis of cardiac myocytes/tissue or serum/plasma. An example of the use of MS in biomarker discovery is given in which the albumin binding protein sub-proteome was examined using MALDI-TOF MS/MS. Additionally, an example of MS in protein validation is given using affinity surface enhanced laser desorption ionization (SELDI) to monitor the disease-induced post-translational modification and the ternary status of myocyte-originating protein, cardiac troponin I in serum.
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PMID:Heart disease, clinical proteomics and mass spectrometry. 1550 50

Mutations in the cardiac troponin I (CTnI) gene occur in approximately 5% of families with familial hypertrophic cardiomyopathy (FHC) and 20 mutations in this gene that cause FHC have now been described. The clinical manifestations of CTnI mutations that cause FHC are diverse, ranging from asymptomatic with high life expectancy to severe heart failure and sudden cardiac death. Most of these FHC mutations in CTnI result in cardiac hypertrophy unlike cardiac troponin T FHC mutations. All CTnI FHC mutations investigated in vitro affect the physiological function of CTnI, but other factors such as environmental or genetic factors (other genes that may affect the CTnI gene) are likely to be involved in influencing the severity of the phenotype produced by these mutations, since the distribution of hypertrophy among affected individuals varies within and between families. CTnI mutations mainly alter myocardial performance via changes in the Ca2+ -sensitivity of force development and in some cases alter the muscle relaxation kinetics due to haemodynamic or physical obstructions of blood flow from the left ventricle.
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PMID:Cellular and molecular aspects of familial hypertrophic cardiomyopathy caused by mutations in the cardiac troponin I gene. 1552 71

A cardiac troponin I (cTnI) gene knockout mouse model has been created and the phenotype of the cTnI null mice is an acute heart failure resulting from the deficiency of TnI and a diastolic dysfunction. Two isoforms of TnI (the fetal form ssTnI and the adult form cTnI) are mainly expressed in the heart under a developmentally regulated program. In our previous studies, we demonstrated that thyroid hormone could alter the time course of ssTnI gene expression in the heart. In the present study, we have successfully cultured neonatal cardiac myocytes from wild type and cTnI null mouse hearts. The ssTnI gene expression pattern has been investigated in these cells. By using Western blotting assays, a TnI isoform switching has been observed in the wild type cardiac myocytes. The pattern of TnI isoform switching is very similar to that of in vivo study we reported previously. In cTnI null cardiac myocytes cultured from day 1 to day 7, there is a continuous decline in ssTnI concentration in the cells. The time course of ssTnI decline in cTnI null cells is similar to that of wild type cardiac myocytes, suggesting that there is no significant compensation of ssTnI gene expression for the absence of the cTnI. This observation is different from what we found previously at a whole heart level. In addition, when thyroid hormone T3 (20 ng/ml) is added to cultured cTnI null cardiac myocytes, the decline of ssTnI concentration occurs earlier. This is inconsistent with our observations from previous in vivo studies. The data demonstrate that thyroid hormone can alter the time course of ssTnI gene expression in cultured cardiac myocytes and TnI gene regulation is also controlled by some unknown programmed events inside of cardiac myocytes.
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PMID:Thyroid hormone inhibits slow skeletal TnI expression in cardiac TnI-null myocardial cells. 1569 75

Protein kinase C (PKC)-induced phosphorylation of cardiac troponin I (cTnI) depresses the acto-myosin interaction and may be important during the progression of heart failure. Although both PKCbetaII and PKCepsilon can phosphorylate cTnI, only PKCbeta expression and activity are elevated in failing human myocardium during end-stage heart failure. Furthermore, although increased cTnI phosphorylation was observed in mice with cardiac-specific PKCbeta II overexpression, no differences were observed in cTnI phosphorylation status between wild type and cardiac-specific PKCepsilon overexpression mice. A potentially important downstream effector of PKCs is p90 ribosomal S6 kinase (p90RSK), which plays an important role in cell growth by activating several transcription factors as well as Na+/H+ exchanger. Since both Ser23 and Ser24 of cTnI are contained in putative consensus sequences of p90RSK phosphorylation sites, we hypothesized that p90RSK is downstream from PKCbeta II and can be a cTnI (Ser(23/24)) kinase. p90RSK, but not ERK1/2 activation, was increased in PKCbetaII overexpression mice but not in PKCepsilon overexpression mice. p90RSK could phosphorylate cTnI in vitro with high substrate affinity but not cardiac troponin T (cTnT). To confirm the role of p90RSK in cTnI phosphorylation in vivo, we generated adenovirus containing a dominant negative form of p90RSK (Ad-DN-p90RSK). We found that the inhibition of p90RSK prevented H2O2-mediated cTnI (Ser(23/24)) phosphorylation but not ERK1/2 and PKCalpha/betaII activation. Next, we generated cardiac-specific p90RSK transgenic mice and observed that cTnI (Ser(23/24)) phosphorylation was significantly increased. LY333,531, a specific PKCbeta inhibitor, inhibited both p90RSK and cTnI (Ser(23/24)) phosphorylation by H2O2. Taken together, our data support a new redox-sensitive mechanism regulating cTnI phosphorylation in cardiomyocytes.
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PMID:Role of p90 ribosomal S6 kinase (p90RSK) in reactive oxygen species and protein kinase C beta (PKC-beta)-mediated cardiac troponin I phosphorylation. 1584 May 86

Dilated cardiomyopathy (DCM) was identified histopathologically in a colony of owl monkeys (Aotus nancymae) over a 15-year period. We characterized the incidence of cardiac disease echocardiographically in the colony over a 14-month period. Of 77 monkeys, 21 had systolic myocardial failure, and postmortem examination confirmed the antemortem diagnosis of DCM in eight animals. Monkeys with a questionable diagnosis at the first examination demonstrated progression of disease with time. Left ventricular end-systolic cross-sectional area and left ventricular fractional area change were the indices that most reliably discriminated between normal and diseased animals. Serum cardiac troponin I concentrations were below detectable limits in normal and diseased monkeys. The apparent high prevalence of disease in this colony precluded establishment of reference intervals for Aotus nancymae. Our study provides the first comprehensive echocardiographic evaluation of owl monkeys with cardiomyopathy.
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PMID:Cardiomyopathy in captive owl monkeys (Aotus nancymae). 1588 79

Cardiac troponin T (cTnT) and cardiac troponin I (cTnI) are considered to be the most specific and sensitive biochemical markers of myocardial damage. Troponins have been studied in a wide range of clinical settings, including heart failure; however, there are few data on the role of regulatory proteins in the pathogenesis of heart failure, although a few interesting hypotheses have been proposed. A considerable body of evidence favours the view that alteration of the myocardial thin filament is the primary event leading to defective contractility of the failing myocardium, while the changes in Ca(2+) handling are a compensatory response. A better understanding of the role of regulatory proteins under different physiological and pathological conditions could lead to new therapeutic approaches in heart failure. Recently, calcium sensitisation has been proposed as a novel method by which cardiac performance may be enhanced via an increase in the affinity of troponin C for calcium but without affecting intracellular calcium concentration. To date, the only calcium sensitizer used in clinical practice is levosimendan.
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PMID:Myocardial regulatory proteins and heart failure. 1630 57

Because cardiomyocytes lose the ability to divide upon differentiation, myocardial failure is assumed to be generally irreversible. For terminal cardiac insufficiency, the potential for regenerative treatment by stem cells, especially embryonic stem (ES) cells, offers hope for the future. Recent studies showed that stem cells fuse spontaneously with cells remaining in damaged tissues, and restore tissue function. To imitate spontaneous fusion in vivo, we used polyethylene glycol (PEG) in vitro to fuse mouse ES cells and fetal cardiomyocytes and analyzed the cytochemical properties of the fused cells. Confocal laser scanning microscopy coupled with lipophilic dye labeling of the living cell membranes showed that there were fused cells of ES cells and cardiomyocytes after PEG treatment. By flow cytometry, the fusion efficiency between ES cells and cardiomyocytes was estimated to be about 45% of the total resulting cells. When green fluorescent protein (GFP)-expressing ES cells were fused with cardiomyocytes, the fused cells had immunoreactivity for GFP in their cytoplasm and cardiac troponin I in their myofibrils. Some of these cells also expressed proliferating cell nuclear antigen up to 11 days after fusion, the last time point examined. This study shows that PEG-induced fusions of mouse ES cells and cardiomyocytes have the cardiomyocyte phenotype and proliferation potential.
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PMID:Phenotype-specific cells with proliferative potential are produced by polyethylene glycol-induced fusion of mouse embryonic stem cells with fetal cardiomyocytes. 1640 81

We have previously reported a transgenic mouse that over-expresses constitutively active PKCepsilon in the myocardium and exhibits a steady progression to heart failure. Associated with the decline in function was an increased phosphorylation of sarcomeric proteins including cardiac troponin I (cTnI). To determine whether PKCepsilon phosphorylation of cTnI is sufficient to induce cardiac maladaptation, we have generated a double transgenic mouse (DbTG) that expresses constitutively active PKCepsilon and cTnI harboring non-phosphorylatable mutations in the putative PKC phosphorylation sites (S43A, S45A). We compared the hemodynamic and biochemical properties of the hearts from the DbTG mice to the non-transgenic and single transgenic lines at both 3 and 12 months of age. While no significant differences in LV function were noted in 3-month groups, the depression of function in the PKCepsilon mice was attenuated in the double transgenic mice at 12 months. The improvement in cardiac function was correlated with decreased beta-myosin heavy chain and ANF mRNA expression in the 12m DbTG mice. The extent of cTnI phosphorylation was determined using a novel one-dimensional, non-equilibrium isoelectric focusing technique. At 3 months the migration of cTnI phospho-species was different in the PKCepsilon mice and to a lesser degree in the DbTG compared to all other groups. At 12 months additional phospho-species were observed in both the PKCepsilon and DbTG samples, along with an overall shift in the distribution of phospho-species in all groups due to age. These results suggest that phosphorylation of cTnI by PKCepsilon is associated with contractile dysfunction and partial replacement of serines 43/45 improves cardiac performance. Therefore, we conclude that phosphorylation of cTnI at Ser 43 and 45 may contribute to the progression of failure.
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PMID:Partial replacement of cardiac troponin I with a non-phosphorylatable mutant at serines 43/45 attenuates the contractile dysfunction associated with PKCepsilon phosphorylation. 1651 95

We made quantitative measurements of phosphorylation in troponin isolated from 6 non-failing donor hearts and 6 explanted hearts with end-stage heart failure in SDS-PAGE gels using Pro-Q Diamond phosphoprotein stain. The troponin T phosphorylation level was the same in troponin from failing and non-failing heart (3.1 mol Pi/mol). However, troponin I phosphorylation was significantly lower in failing (0.37+/-0.18 mol Pi/mol) compared with non-failing heart troponin (2.25+/-0.36 mol Pi/mol). Levels of troponin I PKA-dependent phosphorylation, measured with a phosphoserine 23/24-specific antibody, were also significantly lower in failing heart troponin (0.19+/-0.06 mol Pi/mol) compared to non-failing troponin (1.14+/-0.09 mol Pi/mol). We calculate that there is phosphorylation in addition to serine 23/24 of 1.11+/-0.34 mol Pi/mol in non-failing reduced to 0.18+/-0.17 mol Pi/mol in failing heart troponin, attributed to phosphorylation on the PKC sites. To test for the functional role of troponin I phosphorylation, the native troponin I from either non-failing or failing heart troponin was exchanged for a recombinant (unphosphorylated) human cardiac troponin I. Thin filament Ca(2+)-regulatory function was studied with the quantitative in vitro motility assay: thin filaments containing the replaced troponin I resulted in a failing phenotype of a 17-26% reduced sliding speed and an increased Ca(2+)-sensitivity relative to non-failing troponin (EC(50) TnI-exchanged/non-failing=0.57, p<0.001). When exchanged with troponin I phosphorylated with PKA motility parameters reverted to a pattern indistinguishable from non-failing troponin (p=0.35-0.75). We suggest that changes in troponin function can account for the contractile abnormality in failing heart muscle and that the functional changes in troponin are due to reduced phosphorylation of troponin I at the PKA sites.
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PMID:Troponin phosphorylation and regulatory function in human heart muscle: dephosphorylation of Ser23/24 on troponin I could account for the contractile defect in end-stage heart failure. 1708 61

Translating research into clinical practice has been a challenge throughout medical history. From the present review, it should be clear that this is particularly the case for heart failure. As a consequence, public awareness of this disease has been disillusionedly low, despite its prognosis being worse than that of most cancers and many other chronic diseases. We explore how over the past 150 years since Ludwig and Marey concepts about the evaluation of cardiac performance in patients with heart failure have emerged. From this historical-physiologic perspective, we have seen how 3 increasingly reductionist approaches or schools of thought have evolved in parallel, that is, an input-output approach, a hemodynamic pump approach, and a muscular pump approach. Each one of these has provided complementary insights into the pathophysiology of heart failure and has resulted in measurements or derived indices, some of which still being in use in present-day cardiology. From the third, most reductionist muscular pump approach, we have learned that myocardial and ventricular relaxation properties as well as temporal and spatial nonuniformities have been largely overlooked in the 2 other, input-output and hemodynamic pump, approaches. A key message from the present review is that relaxation and nonuniformities can be fully understood only from within the time-space continuum of cardiac pumping. As cyclicity and rhythm are, in some way, the most basic aspects of cardiac function, considerations of time should dominate over any measurement of cardiac performance as a muscular pump. Any measurement that is blind for the arrow of cardiac time should therefore be interpreted with caution. We have seen how the escape from the time domain-as with the calculation of LV ejection fraction-fascinating though as it may be, has undoubtedly served to hinder a rational scientific debate on the recent, so-called systolic-diastolic heart failure controversy. Lacking appreciation of early relaxation abnormalities and inappropriate degrees of nonuniformities has, indeed, led to some unfortunate misunderstandings about the pathophysiologic time progression of heart failure, in particular, heart failure with compensated hemodynamic pump function (ie, with normal or preserved LV ejection fraction). We have seen that with the introduction of newer powerful diagnostic techniques, as, for example, TDI and MRI, to evaluate ventricular "muscular pump" function, this debate can now be held in a more serene physiologic context. These aspects will be elaborated further in subsequent chapter papers of this symposium. With ongoing stem and other cell-based therapies and future reductionistic insights into cardiac cellular performance, we foresee the emergence of a fourth simple-parallel school of thought viewing the heart as a network of communicating different cell types, that is, cardiomyocytes, endothelial cells, fibroblasts, neurons. In this postgenomic age with the introduction of the rapidly evolving discipline of in vivo molecular imaging techniques, we anticipate that novel measurements of cardiac performance in patients with heart failure will soon become available and complement biopsy and other already available cardiac cellular biomarkers (cardiac troponin I; creatine kinase-MB; myoglobin; BNP). Through the use of these novel biomarkers as a fourth diagnostic track in the evaluation of cardiac performance in patients with heart failure, we will soon be able to increasingly understand the behavior of the heart as a complex biologic system-in other words, how these "low-level" biologic functions and signal transduction pathways at a cellular level contribute to the above "high-level" or system-level approach of cardiac performance at the muscular, the hemodynamic, and the input-output pump system levels and, hopefully, how they could contribute to an early diagnosis of chronic heart failure, in patients.
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PMID:Cardiac dysfunction in heart failure: the cardiologist's love affair with time. 1708 77


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