scholarly journals Contractile protein phosphorylation predicts human heart disease phenotypes

2013 ◽  
Vol 304 (12) ◽  
pp. H1644-H1650 ◽  
Author(s):  
Lori A. Walker ◽  
David A. Fullerton ◽  
Peter M. Buttrick

Human heart failure has been associated with a low level of thin-filament protein phosphorylation and an increase in calcium sensitivity of contraction relative to both “control” human heart tissue and tissue from small animal models. However, diverse strategies of human tissue procurement and the reliance on tissue obtained from subjects with end-stage heart failure suggest this may be an incomplete characterization. Therefore, we evaluated cardiac left ventricular (LV) biopsy samples from patients with aortic stenosis undergoing valve replacement who presented either with LV hypertrophy and preserved systolic function (Hyp) or with LV dilation and reduced ejection fraction (Dil). In Hyp, total troponin I (TnI) phosphorylation was markedly increased and myosin light chain 2 (MLC2) phosphorylation was unchanged relative to a control group of patients with normal LV function. Conversely, in Dil, total TnI phosphorylation was significantly reduced compared with control subjects and MLC2 phosphorylation was increased. Site-specific analysis of TnI phosphorylation revealed phenotype-specific differences such that Hyp samples demonstrated significant increases in phosphorylation at serine 22/23 and Dil samples had significant decreases at serine 43. The ratio of phosphorylation at the two sites was biased toward serine 22/23 in Hyp and toward serine 43/45 in Dil. Western blot analysis showed that protein phosphatase-1 was reduced in Hyp and protein phosphatase-2 was reduced in Dil. These data suggest that posttranslational modifications of sarcomeric proteins, both singly and in combination, are stage specific. Defining these changes in progressive heart disease may provide important diagnostic and treatment information.

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Marcus Sandri ◽  
Stephan Gielen ◽  
Norman Mangner ◽  
Volker Adams ◽  
Sandra Erbs ◽  
...  

Background: The concept of ventricular-arterial coupling implies that LV-function is determined by the three factors left ventricular diastolic, left ventricular systolic and arterial elastance. We have previously documented an improvement in endothelial function and systolic LV-function in patients with chronic heart failure (CHF) after 6 months of exercise training (ET). It remains, however, unclear, how shorter ET periods may affect endothelial, systolic and diastolic ventricular function as echocardiographic parameters related to ventricular arterial coupling in patients with CHF. METHODS: In this ongoing study we randomised 43 patients with stable CHF (age 60.3 ± 2.9 years, EF 27.4 ± 1.7%, VO 2 max 14.7 ± 4.3ml/kg*min) to a training or a control group (C). Patients in the training group exercised 4 times daily at 70% of the individual heart rate reserve for 4 weeks under supervision. At baseline and after 4 weeks the E/A ratio and septal/lateral E’/A’ velocities were determined by echocardiography with tissue Doppler. Exercise capacity was measured by ergospirometry and flow-mediated dilatation (FMD) was assessed by high-resolution radial ultrasound. RESULTS: After only 4 weeks of ET oxygen uptake at peak exercise increased from 14.9 ± 3.3 to 18.1 ± 4.7 ml/min/kg, (p<0.01 vs. C) in training subjects. Left ventricular ejection fraction improved from 26.8 ± 4.6 to 33.1 ± 5.5% (p<0.05 vs. C) in patients of the training group while it remained unchanged in the control group. E/A-ratio mended from 0.63 ± 0.12 to 0.81 ± 0.22 (p<0.01 vs. C) in training patients. Septal E’ velocities increased from 5.5 ± 0.5 to 7.8 ± 1.4 cm/s in training patients (p<0.05 vs. C). FMD of the radial artery improved from 8.2 ± 2.1 to 15.2 ± 3.8% (p<0.01 vs. C) as a result of ET. CONCLUSIONS: Only 4 weeks of endurance training are highly effective with significantly improved FMD accompanied by an emended systolic and diastolic LV-function. We hypothesise that the improvement in LV-EF in training patients may be caused by a corrected ventricular-arterial coupling: ventricular diastolic relaxation and effective endothelial function are ameliorated resulting in an augmentation of stroke volume.


Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Mihály Ruppert ◽  
Christian Karime ◽  
Alex A Sayour ◽  
Attila Oláh ◽  
Dávid Nagy ◽  
...  

Introduction: Both sustained left ventricular (LV) pressure overload (PO) and volume overload (VO) induces LV remodeling and eventually development of heart failure (HF). Using rat models, the present study aimed to provide a detailed comparison of distinct aspects of LV function in PO- and VO-induced HF. Methods: PO and VO was induced by transverse aortic constriction (TAC, n=12) and aortocaval shunt (AV-shunt, n=12) creation respectively. Controls underwent corresponding sham operations (n=11). LV remodeling was characterized by echocardiography, histology, qRT PCR, and western blot. LV function was assessed by invasive pressure-volume (P-V) analysis. Results: Both sustained PO and VO resulted in the development of HF, as evidenced by increased LV BNP mRNA expression, pulmonary edema, and characteristic symptoms. While the extent of LV hypertrophy was comparable between the HF models, PO induced concentric while VO evoked eccentric LV remodeling. P-V analysis revealed impaired systolic function in both HF models. Accordingly, decreased ejection fraction and impaired ventriculo-arterial coupling (calculated as the ratio of arterial elastance/LV contractility [VAC]: 0.38±0.05 vs. 1.30±0.13, ShamTAC vs. TAC and 0.52±0.08 vs. 1.17±0.13, ShamAV-Shunt vs. AV-shunt; p<0.05) was detected in both HF models. However, in case of VO the severely reduced LV contractility (slope of end-systolic P-V relationship: 1.79±0.19 vs. 0.52±0.06, ShamAV-Shunt vs. AV-shunt, p<0.05 and 2.14±0.28 vs. 2.03±0.21, ShamTAC vs. TAC p>0.05) underpinned the contractility-afterload mismatch, while in case of PO the increased afterload (arterial elastance: 0.77±0.07 vs. 2.64±0.28, ShamTAC vs. TAC and 0.80±0.07 vs. 0.54±0.05, ShamAV-Shunt vs. AV-shunt; p<0.05) was the main determinant. Furthermore, prolongation of active relaxation occurred to a greater extent in case of PO. In addition, increased myocardial stiffness was only observed in PO-induced HF. Conclusion: Systolic function was reduced in both HF models. However, different factors underpinned the impaired VAC in case of VO (reduced LV contractility) and PO (increased arterial elastance). Furthermore, although diastolic function deteriorated in both models, it occurred to a greater extent in case of PO.


2001 ◽  
Vol 102 (1) ◽  
pp. 9-14 ◽  
Author(s):  
Suneel TALWAR ◽  
Iain B. SQUIRE ◽  
Russell J. O'BRIEN ◽  
Paul F. DOWNIE ◽  
Joan E. DAVIES ◽  
...  

The glycoprotein 130 (gp130) signalling pathway is important in the development of heart failure. Cardiotrophin-1 (CT-1), a cytokine acting via the gp130 pathway, is involved in the process of ventricular remodelling following acute myocardial infarction (AMI) in animals. The aims of the present study were to examine the profile of plasma CT-1 following AMI in humans, and its relationship with echocardiographic parameters of left ventricular (LV) systolic function. Serial measurements of plasma CT-1 levels were made in 60 patients at 14-48h, 49-72h, 73-120h and 121-192h following AMI and at a later clinic visit. LV function was assessed using a LV wall motion index (WMI) score on admission (WMI-1) and at the clinic visit (WMI-2). Compared with values in control subjects (29.5±3.6fmol/ml), the plasma CT-1 concentration was elevated in AMI patients at 14-48h (108.1±15.1fmol/ml), 49-72h (105.2±19.7fmol/ml), 73-120h (91.2±14.9fmol/ml) and 121-192h (118.8±22.6fmol/ml), and at the clinic visit (174.9±30.9 fmol/ml) (P < 0.0001). Levels were higher following anterior compared with inferior AMI. For patients with anterior AMI, CT-1 levels were higher at the clinic visit than at earlier times. WMI-1 correlated with CT-1 at all times prior to hospital discharge (P < 0.05). On best subsets analysis, the strongest correlate with WMI-1 was CT-1 level at 49-72h (R2 = 20%, P < 0.05). In conclusion, plasma levels of CT-1 are elevated soon after AMI in humans and rise further in the subsequent weeks in patients after anterior infarction. CT-1 measured soon after AMI is indicative of LV dysfunction, and this cytokine may have a role in the development of ventricular remodelling and heart failure after AMI.


2014 ◽  
Vol 307 (11) ◽  
pp. H1605-H1617 ◽  
Author(s):  
Kristin Wilson ◽  
Anuradha Guggilam ◽  
T. Aaron West ◽  
Xiaojin Zhang ◽  
Aaron J. Trask ◽  
...  

Aortocaval fistula (ACF)-induced volume overload (VO) heart failure (HF) results in progressive left ventricular (LV) dysfunction. Hemodynamic load reversal during pre-HF (4 wk post-ACF; REV) results in rapid structural but delayed functional recovery. This study investigated myocyte and myofilament function in ACF and REV and tested the hypothesis that a myofilament Ca2+ sensitizer would improve VO-induced myofilament dysfunction in ACF and REV. Following the initial sham or ACF surgery in male Sprague-Dawley rats (200–240 g) at week 0, REV surgery and experiments were performed at weeks 4 and 8, respectively. In ACF, decreased LV function is accompanied by impaired sarcomeric shortening and force generation and decreased Ca2+ sensitivity, whereas, in REV, impaired LV function is accompanied by decreased Ca2+ sensitivity. Intravenous levosimendan (Levo) elicited the best inotropic and lusitropic responses and was selected for chronic oral studies. Subsets of ACF and REV rats were given vehicle (water) or Levo (1 mg/kg) in drinking water from weeks 4–8. Levo improved systolic (% fractional shortening, end-systolic elastance, and preload-recruitable stroke work) and diastolic (τ, dP/d tmin) function in ACF and REV. Levo improved Ca2+ sensitivity without altering the amplitude and kinetics of the intracellular Ca2+ transient. In ACF-Levo, increased cMyBP-C Ser-273 and Ser-302 and cardiac troponin I Ser-23/24 phosphorylation correlated with improved diastolic relaxation, whereas, in REV-Levo, increased cMyBP-C Ser-273 phosphorylation and increased α-to-β-myosin heavy chain correlated with improved diastolic relaxation. We concluded that Levo improves LV function, and myofilament composition and regulatory protein phosphorylation likely play a key role in improving function.


2012 ◽  
Vol 2012 ◽  
pp. 1-6 ◽  
Author(s):  
Piercarlo Ballo ◽  
Irene Betti ◽  
Giuseppe Mangialavori ◽  
Leandro Chiodi ◽  
Gherardo Rapisardi ◽  
...  

Management of patients with peripartum cardiomyopathy (PPCM) is still a major clinical problem, as only half of them or slightly more show complete recovery of left ventricular (LV) function despite conventional evidence-based treatment for heart failure. Recent observations suggested that bromocriptine might favor recovery of LV systolic function in patients with PPCM. However, no evidence exists regarding its effect on LV diastolic dysfunction, which is commonly observed in these patients. Tissue Doppler (TD) is an echocardiographic technique that provides unique information on LV diastolic performance. We report the case of a 37-year-old white woman with heart failure (NYHA class II), moderate LV systolic dysfunction (ejection fraction 35%), and severe LV diastolic dysfunction secondary to PPCM, who showed no improvement after 2 weeks of treatment with ramipril, bisoprolol, and furosemide. At 6-week followup after addition of bromocriptine, despite persistence of LV systolic dysfunction, normalization of LV diastolic function was shown by TD, together with improvement in functional status (NYHA I). At 18-month followup, the improvement in LV diastolic function was maintained, and normalization of systolic function was observed. This paper might support the clinical utility of bromocriptine in patients with PPCM by suggesting a potential benefit on LV diastolic dysfunction.


Author(s):  
Mahmood H. Khan ◽  
Mirza Md. Nazrul Islam ◽  
Md. Shafiqul Islam ◽  
Kaisar Nasrullah Khan ◽  
Shamim Chowdhury ◽  
...  

Background: Coronary Heart Disease (CHD) is the most common category of the heart disease and is found to be the single most important cause that leads to premature death in the developed world. Recognizing a patient with ACS is important because the diagnosis triggers both triage and management. cTnI is 100% tissue-specific for the myocardium and it has shown itself as a very sensitive and specific marker for AMI. Ventricular function is the best predictor of death after an ACS. It serves as a marker of myocardial damage and provides information on systolic function as well as diagnosis and prognosis. The study aimed at investigating the impact of LVEF on elevated troponin-I level in patients with first attack of NSTEMI.Methods: This cross-sectional analytical study was conducted in the department of cardiology in Mymensingh Medical College Hospital from December, 2015 to November, 2016. Total 130 first attack of NSTEMI patients were included considering inclusion and exclusion criteria. The sample population was divided into two groups: Group-I: Patients with first attack of NSTEMI with LVEF: ≥55%. Group-II: Patients with first attack of NSTEMI with LVEF: <55%. Then LVEF and troponin-I levels were correlated using Pearson’s correlation coefficient test.Results: In this study mean troponin-I of group-I and group-II were 5.53±7.43 and 16.46±15.79ng/ml respectively. It was statistically significant (p<0.05). The mean LVEF value of groups were 65.31±10.30% and 40.17±4.62% respectively. It was statistically significant (p<0.05). The echocardiography showed that patients with high troponin-I level had low LVEF and patients with low troponin-I level had preserved LVEF. Analysis showed that patients with highest level of troponin-I had severe left ventricular systolic dysfunction (LVEF <35%) and vice versa-the patients with the lowest levels of troponin-I had preserved systolic function (LVEF ≥55%). In our study, it also showed that the levels of troponin-I had negative correlation with LVEF levels with medium strength of association (r= -0.5394, p=0.001). Our study also discovered that Troponin-I level ≥6.6ng/ml is a very sensitive and specific marker for LV systolic dysfunction.Conclusions: The study has enabled the research team to conclude that the higher is the Troponin-I level the lower is the LVEF level and thus more severe is the LV systolic dysfunction in first attack of NSTEMI patients.


2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 10519-10519
Author(s):  
Lisa M. Kopp ◽  
Mark L. Bernstein ◽  
Cindy L. Schwartz ◽  
David Ebb ◽  
Vivian L Franco ◽  
...  

10519 Background: Dexrazoxane is protective for lower-dose doxorubicin ( < 300 mg/m2) cardiotoxicity in childhood cancer, but the effect of dexrazoxane (DXRZ) administered with higher-dose (HD) doxorubicin (DOXO) is unknown. Methods: We evaluated patients from Children’s Oncology Group trials for localized (P9754) and metastatic (AOST0121) osteosarcoma (OS) who received HD DOXO (375-600 mg/m2) preceded by DXRZ (10:1 ratio), methotrexate, and cisplatin; some also received ifosfamide alone or ifosfamide/etoposide ± trastuzumab. Cardiotoxicity was identified by echocardiography and by serum N-terminal pro-brain natriuretic peptide (NT-proBNP) concentrations. Results: 81 DXRZ -treated OS patients ( age at enrollment = 13.7 years; range 3.8 - 23.7 years) had normal left ventricular (LV) systolic function as measured by LV fractional shortening and no heart failure. Female sex and longer follow-up since DOXO were associated with a significantly smaller LV dimension z-score normalized to BSA (μ = -1.20, 95%CI [-1.70, -0.70]). Similarly, in the one-third of patients treated > 81 days after minimal expected treatment (groups equally partitioned by time), significantly thinner LV posterior wall thickness for BSA (μ = -0.57, [-1.05, -0.09]) was found. Interventricular septal wall thickness (μ = -0.84, [-1.2, -0.48]) and LV mass (μ = -0.73, [-1.06, -0.40]) were significantly smaller for BSA than normal for both sexes. For females, these became significantly more abnormal with increasing length of follow-up. Females also showed progressive increases in NT-proBNP. Conclusions: DXRZ is cardioprotective for HD DOXO in terms of LV function and heart failure. Females had progressive abnormalities of LV structure, leading to smaller hearts for body size. This was associated with increasing cardiac stress, as measured by NT-proBNP. DXRZ protection was incomplete for HD DOXO effects on LV structure, resulting in higher LV stress and risk for late LV dysfunction. DXRZ should continue to be used in this population, including for females who exhibit more cardiotoxicity than males at specific cumulative DOXO doses.


Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Kazuhisa Nishimura ◽  
Hideki Okayama ◽  
Makoto Saito ◽  
Katsuji Inoue ◽  
Toyofumi Yoshii ◽  
...  

(Background) Left ventricular (LV) untwisting behavior is a novel index of LV diastolic function since it is a powerful determinant of LV diastolic suction. The LV of patients with hypertrophic cardiomyopathy (HCM) and hypertensive heart disease (HHD) has diastolic dysfunction despite normal systolic function. However, the role of untwisting behavior in HCM and HHD in the pathophysiology of diastolic dysfunction is unknown. The aim of this study was to investigate the difference of LV twisting behavior between patients with HCM and HHD. (Methods) Forty-four patients with HCM (mean age, 63+/−15 y, 34 males), 30 patients with HHD (mean age, 62+/−12 y, 20 males), and 20 age and sex-matched control subjects were evaluated. After a standard echocardiographic examination, LV twist and twisting velocity profiles from apical and basal short-axis images were analyzed using two-dimensional speckle tracking imaging. All temporal parameters were normalized by R-R intervals. (Results) LV diastolic and systolic dimensions, and ejection fraction were not significantly different among the groups. LV mass index and early diastolic mitral annular velocity were not significantly different between the HCM and HHD groups. The peak torsion in the HCM and HHD groups was significantly greater than that in the control group (Table ). The peak untwisting velocity in the HCM group was comparable to that in the control group. However, when the peak untwisting velocity was corrected by peak torsion, the value in the HCM group was significantly decreased compared with that in the HHD and control groups. The time to peak untwisting velocity from aortic valve closure in the HCM group was significantly longer than that in the HHD and control groups. (Conclusion) These results suggest that enhanced peak torsion in HCM might compensate for untwisting behavior, but this mechanism fails to fully compensate for untwisting behavior compared with HHD. Left ventricular twisting behavior


Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Tetsuari Onishi ◽  
Yasue Tsukishiro ◽  
Hiroya Kawai

Background: Both Left ventricular (LV) global longitudinal strain (GLS) and LV ejection fraction (LVEF) are useful parameters for assessment of LV function. The aim of this study is to confirm the prognostic value of them in patients with non-ischemic and ischemic heart disease. Methods: We studied 179 patients (DCM group: Age 61±15 years, 70 females, LVEF 33±9%) with non-ischemic dilated cardiomyopathy and heart failure symptom, and 97 patients (MI group: Age 66±13 years, 18 females, LVEF 45±7%) who were successfully treated with percutaneous coronary intervention for acute anteroseptal myocardial infarction. Echocardiography was used for LV GLS derived from 2D speckle-tracking method and LVEF with modified Simpson’s method. Outcome was assessed according to death and re-hospitalization with heart failure in the follow-up period. Results: 40 patients in DCM group and 10 patients in MI group experienced at least one event. In these 2 groups, significant differences in GLS and LVEF were found between patients with and without cardiac events (p<0.05). Kaplan-Meier analysis showed patients with worse GLS had an unfavorable outcome in both DCM and MI groups (p<0.05), but LVEF did not associated with outcome. Conclusion: LV GLS has the potential to predict the outcome with higher sensitivity than LVEF in patients with heart disease regardless of ischemic etiology.


2010 ◽  
Vol 6 (1) ◽  
pp. 21 ◽  
Author(s):  
Tarun Pandey ◽  
Kedar Jambhekar ◽  
◽  

Left ventricular (LV) diastolic dysfunction and diastolic heart failure (DHF) account for approximately 40–50% of all patients with congestive heart failure (CHF). Diastolic dysfunction can be evaluated directly by invasive cardiac catheterisation techniques or non-invasively by transthoracic echocardiography (TTE) or cardiac magnetic resonance (CMR) imaging. Due to its high spatial and temporal resolution, CMR is the accepted gold standard for evaluating ventricular systolic function. Using the cine-phase contrast technique, CMR can interrogate inflow through the mitral valve and pulmonary veins towards evaluation of diastolic dysfunction and has shown good correlation with TTE. Additionally, CMR can evaluate direct myocardial diastolic parameters that have no echo correlate, such as diastolic torsion rate. As CMR has the ability to characterise a range of diastolic impairments, it will likely become an important diagnostic test in the future, capable of comprehensive LV function evaluation. In this article, we focus on LV diastology, and review CMR methodology and parameters for the diagnosis of diastolic dysfunction.


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