Functional consequences of the deletion mutation deltaGlu160 in human cardiac troponin T.
(57/1406)
To explore the functional consequences of a deletion mutation of troponin T (DeltaGlu160) found in familial hypertrophic cardiomyopathy, the mutant human cardiac troponin T, and wild-type troponins T, I, and C were expressed in Escherichia coli and directly incorporated into isolated porcine cardiac myofibrils using our previously reported troponin exchange technique. The mutant troponin T showed a slightly reduced potency in replacing the endogenous troponin complex in myofibrils and did not affect the inhibitory action of troponin I but potentiated the neutralizing action of troponin C, suggesting that the deletion of a single amino acid, Glu-160, in the strong tropomyosin-binding region affects the tropomyosin binding affinity of the entire troponin T molecule and alters the interaction between troponin I and troponin C within ternary troponin complex in the thin filament. This mutation also increased the Ca(2+) sensitivity of the myofibrillar ATPase activity, as in the case of other mutations in troponin T with clinical phenotypes of poor prognosis similar to that of Glu160. These results provide strong evidence that the increased Ca(2+) sensitivity of cardiac myofilament is a typical functional consequence of the troponin T mutation associated with a malignant form of hypertrophic cardiomyopathy. (+info)
Effect of Arg145Gly mutation in human cardiac troponin I on the ATPase activity of cardiac myofibrils.
(58/1406)
In order to determine the functional consequences of the Arg145Gly mutation in troponin I found in familial hypertrophic cardiomyopathy, human cardiac troponin I and its mutant were expressed in Escherichia coli and purified, and then their effects on the ATPase activity of porcine cardiac myofibrillar preparations from which both troponins C and I had been depleted were examined. Both the wild-type and mutant troponin Is suppressed the ATPase activity of the troponin C.I-depleted myofibrils, but the maximum inhibition caused by mutant troponin I was weaker than that by wild-type troponin I. In the Ca(2)(+)-activation profile of the myofibrillar ATPase activity after reconstitution with both troponins I and C, the Ca(2)(+)-sensitivity with mutant troponin I was higher than that with wild-type troponin I, whereas the maximum level of the ATPase activity with mutant troponin I was lower than that with wild-type troponin I. These findings strongly suggest that the Arg145Gly mutation in human cardiac troponin I modulates the Ca(2)(+)-regulation of contraction by impairing the interaction of troponin I with both actin-tropomyosin and troponin C. (+info)
Myofibrillar disruption in hypocontractile myocardium showing perfusion-contraction matches and mismatches.
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Chronically instrumented dogs underwent 2- or 5-h regional reductions in coronary flow that were followed, respectively, by balanced reductions in myocardial contraction and O(2) consumption ("hibernation") and persistently reduced contraction despite normal myocardial O(2) consumption ("stunning"). Previously unidentified myofibrillar disruption developed during flow reduction in both experimental models and persisted throughout the duration of reperfusion (2-24 h). Aberrant perinuclear aggregates that resembled thick filaments and stained positively with a monoclonal myosin antibody were present in 34 +/- 3.8% (SE) and 68 +/- 5.9% of "hibernating" and "stunned" subendocardial myocytes in areas subjected to flow reduction and in 16 +/- 2.5% and 44 +/- 7.4% of subendocardial myocytes in remote areas of the same ventricles. Areas of myofibrillar disruption also showed glycogen accretion and unusual heterochromatin clumping adjacent to the inner nuclear envelope. The degrees of flow reduction employed were sufficient to reduce regional myofibrillar creatine kinase activity by 25-35%, but troponin I degradation was not evident. The observed changes may reflect an early, possibly reversible, phase of the myofibrillar loss characteristic of hypocontractile myocardium in patients undergoing revascularization. (+info)
Ingenuous interpretation of elevated blood levels of macromolecular markers of myocardial injury: a recipe for confusion.
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Several assumptions about elevations of macromolecular markers of myocardial injury in blood require critical consideration. The dichotomy of modest, persistent elevations of troponins I and T as prognostic factors in patients with unstable angina and absent elevations of isoenzymes of creatine kinase is presently unexplained. Factors influencing the appearance of macromolecular markers of myocardial injury in blood are considered, including the need to estimate baseline values, to consider elevations as deviations from baseline rather than simply points within a distribution of baseline values in normal subjects, to recognize operative biochemical and physiologic determinants of marker release from injured myocytes and washout and to take into account the influence of apoptosis. Elucidation and consideration of mechanisms underlying the appearance of specific macromolecular markers in blood appear likely to improve diagnosis and explain the prognostic power of the troponins in patients with unstable angina. Detection of proteolytic breakdown products of troponins in blood is likely to explain the modest, persistent elevations seen in some patients with unstable angina and their prognostic implications. (+info)
Clinical efficacy of three assays for cardiac troponin I for risk stratification in acute coronary syndromes: a Thrombolysis In Myocardial Infarction (TIMI) 11B Substudy.
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BACKGROUND: Significant analytic variability exists between the multiple assays for cardiac troponin I (cTnI) approved for clinical use. Until adequate cTnI standardization is possible, an evidence-based approach evaluating each assay at specific thresholds appears warranted. METHODS: We examined the efficacy of three cTnI assays for predicting death, myocardial infarction (MI), or the composite of death, MI, or urgent revascularization at 43 days among patients with non-ST-elevation acute coronary syndromes enrolled in the Thrombolysis In Myocardial Infarction (TIMI) 11B study. RESULTS: Six hundred eighty-one patients with serum samples obtained at baseline and/or 12-24 h had cTnI determined using all three assays. Baseline cTnI was > or = 0.1 microg/L for 368, 395, and 418 patients with the Bayer Immuno 1(TM), ACS:180, and Dimension RxL assays, respectively. Correlation coefficients for the RxL with the ACS:180 and Bayer Immuno 1 results were 0.89 (P = 0.0001) and 0.87 (P = 0.0001), with a coefficient of 0.92 (P = 0.0001) for the ACS:180 and Bayer Immuno 1 assays. Patients with cTnI > or = 0.1 microg/L were at increased risk fo death or MI by 43 days (relative risk, 2.2-3.0; P <0.0006), regardless of the assay used. This prognostic capacity persisted among those with creatine kinase MB isoenzyme concentrations within the reference interval. Moreover, cTnI was the strongest multivariate predictor of death, MI, or urgent revascularization with adjusted odds ratios of 2.1-2.9 (P <0. 0006). CONCLUSION: This study demonstrates the prognostic efficacy of three independently developed cTnI assays at a threshold of 0.1 microg/L for the prediction of adverse clinical outcomes among patients with non-ST-elevation acute coronary syndromes. (+info)
Propofol-associated rhabdomyolysis with cardiac involvement in adults: chemical and anatomic findings.
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Propofol, a central-acting sedative agent, has been implicated in the development of rhabdomyolysis in children. We describe two adults who developed rhabdomyolysis after receiving high rates of propofol infusion. Rhabdomyolysis of both skeletal and cardiac muscle was suggested in both patients by marked increases of creatine kinase (>170 000 U/L) and cardiac troponin I (11 and 46 microg/L in patients one and two, respectively). Creatine kinase and cardiac troponin I values were highly correlated in each patent (r = 0.786 and 0.988 in patients one and two, respectively). Autopsy of one patient confirmed the diagnosis of skeletal and cardiac rhabdomyolysis. (+info)
Serum cardiac troponin I and ST-segment elevation in patients with acute pericarditis.
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OBJECTIVE: ST-segment elevation in acute pericarditis is believed to be caused by superficial myocardial inflammation or epicardial injury. We used cardiac troponin I, a sensitive and specific marker of myocardial injury, to assess myocardial lesions in idiopathic acute pericarditis and its relationship to ST-segment elevation. PATIENTS AND METHODS: Sixty-nine consecutive patients (53 men, 48+/-17 years) with idiopathic acute pericarditis were included. We used an enzymoimmunoflurometric method to measure serum cardiac troponin I on admission (myocardial infarction threshold was 1.5 ng. ml(-1)). RESULTS: Cardiac troponin I was detectable in 34 patients (49%) and was beyond the 1.5 ng. ml(-1)threshold in 15 (22%). Coronary angiography performed in seven of these 15 patients was normal in all of them. ST-segment elevation was observed in 93% of the patients with cardiac troponin I >1.5 ng. ml(-1)vs 57% of those without (P<0.01). Sensitivity of ST-segment elevation to detect myocardial injury was 93% and specificity 43%. Patients with a cardiac troponin I increase higher than 1.5 ng. ml(-1)were more likely to have had a recent infection (66% vs 31%;P=0.01) and were younger (37+/-14 vs 52+/-16 years;P=0.002). There was no significant relationship with other parameters such as pericardial friction rub, fever, PR segment abnormalities, echocardiographic findings or C-reactive protein. CONCLUSION: In patients with idiopathic acute pericarditis, an increase in cardiac troponin I is frequently observed, especially in younger patients and those with a recent infection. Although ST-segment elevation does not reliably indicate myocardial injury, a significant cardiac troponin I increase is only seen in these patients. (+info)
cGMP-mediated phosphorylation of heat shock protein 20 may cause smooth muscle relaxation without myosin light chain dephosphorylation in swine carotid artery.
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Nitrovasodilators such as nitroglycerine, via production of nitric oxide and an increase in [cGMP], can induce arterial smooth muscle relaxation without proportional reduction in myosin light chain (MLC) phosphorylation or myoplasmic [Ca2+]. These findings suggest that regulatory systems, other than MLC phosphorylation and Ca2+, partially mediate nitroglycerine-induced relaxation. In swine carotid artery, we found that a membrane-permeant cGMP analogue induced relaxation without MLC dephosphorylation, suggesting that cGMP mediated the relaxation. Nitroglycerine-induced relaxation was associated with a reduction in O2 consumption, suggesting that the interaction between phosphorylated myosin and the thin filament was inhibited. Nitroglycerine-induced relaxation was associated with a 10-fold increase in the phosphorylation of a protein on Ser16. We identified this protein as heat shock protein 20 (HSP20), a member of a family of proteins known to bind to thin filaments. When homogenates of nitroglycerine-relaxed tissues were centrifuged at 6000 g, phosphorylated HSP20 preferentially sedimented in the pellet, suggesting that phosphorylation of HSP20 may increase its affinity for the thin filament. We noted that a domain of HSP20 is partially homologous to the 'minimum inhibitory sequence' of skeletal troponin I. The peptide HSP20110-121, which contains this domain, bound to actin-containing filaments only in the presence of tropomyosin, a characteristic of troponin I. High concentrations of HSP20110-121 abolished Ca2+-activated force in skinned swine carotid artery. HSP20110-121 also partially decreased actin-activated myosin S1 ATPase activity. These data suggest that cGMP-mediated phosphorylation of HSP20 on Ser16 may have a role in smooth muscle relaxation without MLC dephosphorylation. HSP20 contains an actin-binding sequence at amino acid residues 110-121 that inhibited force production in skinned carotid artery. We hypothesize that phosphorylation of HSP20 regulates force independent of MLC phosphorylation via binding of HSP20 to thin filaments and inhibition of cross-bridge cycling. (+info)