Dataset Information

Heart Failure-Related Hyperphosphorylation in the Cardiac Troponin I C Terminus Has Divergent Effects on Cardiac Function In Vivo.

ABSTRACT: In human heart failure, Ser199 (equivalent to Ser200 in mouse) of cTnI (cardiac troponin I) is significantly hyperphosphorylated, and in vitro studies suggest that it enhances myofilament calcium sensitivity and alters calpain-mediated cTnI proteolysis. However, how its hyperphosphorylation affects cardiac function in vivo remains unknown.To address the question, 2 transgenic mouse models were generated: a phospho-mimetic cTnIS200D and a phospho-silenced cTnIS200A, each driven by the cardiomyocyte-specific ?-myosin heavy chain promoter. Cardiac structure assessed by echocardiography and histology was normal in both transgenic models compared with littermate controls (n=5). Baseline in vivo hemodynamics and isolated muscle studies showed that cTnIS200D significantly prolonged relaxation and lowered left ventricular peak filling rate, whereas ejection fraction and force development were normal (n=5). However, with increased heart rate or ?-adrenergic stimulation, cTnIS200D mice had less enhanced ejection fraction or force development versus controls, whereas relaxation improved similarly to controls (n=5). By contrast, cTnIS200A was functionally normal both at baseline and under the physiological stresses. To test whether either mutation impacted cardiac response to ischemic stress, isolated hearts were subjected to ischemia/reperfusion. cTnIS200D were protected, recovering 88±8% of contractile function versus 35±15% in littermate controls and 28±8% in cTnIS200A (n=5). This was associated with less cTnI proteolysis in cTnIS200D hearts.Hyperphosphorylation of this serine in cTnI C terminus impacts heart function by depressing diastolic function at baseline and limiting systolic reserve under physiological stresses. However, paradoxically, it preserves heart function after ischemia/reperfusion injury, potentially by decreasing proteolysis of cTnI.

SUBMITTER: Li Y

PROVIDER: S-EPMC5612410 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Heart Failure-Related Hyperphosphorylation in the Cardiac Troponin I C Terminus Has Divergent Effects on Cardiac Function In Vivo.

Li Yuejin Y Zhu Guangshuo G Paolocci Nazareno N Zhang Pingbo P Takahashi Cyrus C Okumus Nazli N Heravi Amir A Keceli Gizem G Ramirez-Correa Genaro G Kass David A DA Murphy Anne M AM

Circulation. Heart failure 20170901 9

<h4>Background</h4>In human heart failure, Ser199 (equivalent to Ser200 in mouse) of cTnI (cardiac troponin I) is significantly hyperphosphorylated, and in vitro studies suggest that it enhances myofilament calcium sensitivity and alters calpain-mediated cTnI proteolysis. However, how its hyperphosphorylation affects cardiac function in vivo remains unknown.<h4>Methods and results</h4>To address the question, 2 transgenic mouse models were generated: a phospho-mimetic cTnIS200D and a phospho-sil ...[more]

PMID: 28899987

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Project description:In striated muscle, the protein troponin complex turns contraction on and off in a calcium-dependent manner. The calcium-sensing component of the complex is troponin C, which is expressed from the TNNC1 gene in both cardiac muscle and slow-twitch skeletal muscle (identical transcript in both tissues) and the TNNC2 gene in fast-twitch skeletal muscle. Cardiac troponin C (cTnC) is made up of two globular EF-hand domains connected by a flexible linker. The structural C-domain (cCTnC) contains two high affinity calcium-binding sites that are always occupied by Ca(2+) or Mg(2+) under physiologic conditions, stabilizing an open conformation that remains anchored to the rest of the troponin complex. In contrast, the regulatory N-domain (cNTnC) contains a single low affinity site that is largely unoccupied at resting calcium concentrations. During muscle activation, calcium binding to cNTnC favors an open conformation that binds to the switch region of troponin I, removing adjacent inhibitory regions of troponin I from actin and allowing muscle contraction to proceed. Regulation of the calcium binding affinity of cNTnC is physiologically important, because it directly impacts the calcium sensitivity of muscle contraction. Calcium sensitivity can be modified by drugs that stabilize the open form of cNTnC, post-translational modifications like phosphorylation of troponin I, or downstream thin filament protein interactions that impact the availability of the troponin I switch region. Recently, mutations in cTnC have been associated with hypertrophic or dilated cardiomyopathy. A detailed understanding of how calcium sensitivity is regulated through the troponin complex is necessary for explaining how mutations perturb its function to promote cardiomyopathy and how post-translational modifications in the thin filament affect heart function and heart failure. Troponin modulating drugs are being developed for the treatment of cardiomyopathies and heart failure.

Project description:AimsThis study aimed to evaluate the cumulative high-sensitivity cardiac troponin T (hs-cTNT) from admission to 12 months after discharge and its association with mortality after 12 months among patients with acute heart failure (HF).MethodsWe used data from the China Patient-Centered Evaluative Assessment of Cardiac Events Prospective Heart Failure Study (China PEACE 5p-HF Study), which enrolled patients hospitalized primarily for HF from 52 hospitals between 2016 and 2018. We included patients who survived within 12 months and had hs-cTNT data at admission (within 48 h of admission) and 1 and 12 months after discharge. To evaluate the long-term cumulative hs-cTNT, we calculated cumulative hs-cTNT levels and cumulative times of high hs-cTNT level. Patients were divided into groups according to the quartiles of cumulative hs-cTNT levels (Quartiles 1-4) and cumulative times of high hs-cTNT levels (0-3 times). Multivariable Cox models were constructed to examine the association of cumulative hs-cTNT with mortality during the follow-up period.ResultsWe included 1137 patients with a median age of 64 [interquartile range (IQR), 54-73] years; 406 (35.7%) were female. The median cumulative hs-cTNT level was 150 (IQR, 91-241) ng/L*month. Based on the cumulative times of high hs-cTNT levels, 404 (35.5%) patients were with zero time, 203 (17.9%) with one time, 174 (15.3%) with two times, and 356 (31.3%) with three times. During a median follow-up of 4.76 (IQR, 4.25-5.07) years, 303 (26.6%) all-cause deaths occurred. The increasing cumulative hs-cTNT level and cumulative times of high hs-cTNT level were independently associated with excess all-cause mortality. Compared with Quartile 1 group, Quartile 4 had the highest hazard ratio (HR) of all-cause mortality [4.14; 95% confidence interval (CI): 2.51-6.85], followed by Quartile 3 (HR: 3.35; 95% CI: 2.05-5.48) and Quartile 2 (HR: 2.47; 95% CI: 1.49-4.08) groups. Similarly, taking the patients with zero time of high hs-cTNT level as the reference, the HRs were 1.60 (95% CI: 1.05-2.45), 2.61 (95% CI: 1.76-3.87), and 2.86 (95% CI: 1.98-4.14) in patients who had one, two, and three times of high hs-cTNT level, respectively.ConclusionsElevated cumulative hs-cTNT from admission to 12 months after discharge was independently associated with mortality after 12 months among patients with acute HF. Repeated measurements of hs-cTNT after discharge may help monitor the cardiac damage and identify patients with high risk of death.

Project description:IMPORTANCE:High-sensitivity cardiac troponin T (hs-cTnT) is a biomarker of cardiovascular risk and could be approved in the United States for clinical use soon. However, data linking long-term temporal change in hs-cTnT to outcomes are limited, particularly in primary prevention settings. OBJECTIVE:To examine the association of 6-year change in hs-cTnT with incident coronary heart disease (CHD), heart failure (HF), and all-cause mortality. DESIGN, SETTING, AND PARTICIPANTS:This prospective observational cohort study, performed from January 1, 1990, to December 31, 2011, included 8838 participants with biracial representation from the Atherosclerosis Risk in Communities Study who were initially free of CHD and HF and who had hs-cTnT measured twice, 6 years apart. Data analysis was performed from October 28, 2014, to March 9, 2016. MAIN OUTCOME AND MEASURES:Risk factor and temporal hs-cTnT data were collected. Using Cox proportional hazards regression, we examined the association of hs-cTnT change with subsequent CHD, HF, and death during a maximum of 16 years. Improvement in discrimination was determined by the Harrell C statistic. RESULTS:Of the 8838 participants (mean age, 56 years; 5215 female [59.0%]; 1891 black [21.4%]) there were 1157 CHD events, 965 HF events, and 1813 deaths overall. Incident detectable hs-cTnT (baseline, <0.005 ng/mL; follow-up, ?0.005 ng/mL) was independently associated with subsequent CHD (hazard ratio [HR], 1.4; 95% CI, 1.2-1.6), HF (HR, 2.0; 95% CI, 1.6-2.4), and death (HR, 1.5; 95% CI, 1.3-1.7), relative to an hs-cTnT level less than 0.005 ng/mL at both visits. In addition, HRs as high as 4 for CHD and death and 8 for HF were recorded among individuals with the most marked hs-cTnT increases (eg, baseline, < 0.005 ng/mL; follow-up, ?0.014 ng/mL). Risk for subsequent outcomes was lower among those with relative hs-cTnT reductions greater than 50% from baseline. Furthermore, information on hs-cTnT change improved discrimination for HF and death when added to a model that included traditional risk factors, N-terminal pro-brain natriuretic peptide, and baseline hs-cTnT level. Among individuals with adjudicated HF hospitalizations, hs-cTnT change appeared to be similarly associated with HF with reduced and preserved ejection fraction. CONCLUSIONS AND RELEVANCE:Temporal increases in hs-cTnT, suggestive of progressive myocardial damage, are independently associated with incident CHD, death, and, above all, HF. Serial determination of hs-cTnT trajectory adds clinically relevant information to baseline testing and may be useful in prognostic assessments and the targeting of prevention strategies to high-risk individuals, especially among persons with stage A or B HF.

Dataset Information

Heart Failure-Related Hyperphosphorylation in the Cardiac Troponin I C Terminus Has Divergent Effects on Cardiac Function In Vivo.

Publications

Heart Failure-Related Hyperphosphorylation in the Cardiac Troponin I C Terminus Has Divergent Effects on Cardiac Function In Vivo.

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