Abstract 843: Restrictive Cardiomyopathy Linked cTnI Mutation (K178E) Causes Severe Heart Failure and Early Mortality

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Pierre-Yves Jean-Charles ◽  
Jianfeng Du ◽  
Yuejin Li ◽  
Nariman Gobara ◽  
Xupei Huang
Keyword(s):  
Heart Failure ◽  
Transgenic Mice ◽  
Diastolic Dysfunction ◽  
Troponin I ◽  
Severe Heart Failure ◽  
Restrictive Cardiomyopathy ◽  
Left Ventricular ◽  
Early Mortality ◽  
Cardiac Contraction ◽  
Actin Binding

Multiple mutations in cardiac troponin I (cTnI) have been linked to the development of restrictive cardiomyopathy (RCM) in human patients. Among them, K178E mutation has the worst clinical phenotype. K178E mutation may influence the inhibitory function through actin binding since previous studies have shown that amino acids number 173–181 bind to actin and increase the inhibitory effect of TnI. We modeled the mutation of lysine 178→glutamate (K178E) in human cTnI by cardiac specific expression of the mutated protein (cTnI 179Glu in mouse sequence) in transgenic mice. Multiple lines were generated with varying degrees of expression to establish a dose relationship. Increased resting tension in isolated cardiac myocytes and decreased myofibrillar compliance were the main manifestations in cellular function measurements. In vivo cardiac function measured by high-resolution ultrasonic imaging and Doppler echocardiography revealed a significant diastolic dysfunction characterized with decrease of left ventricular end diastolic dimension (LVEDD), decreased cardiac ejection fraction (EF) and left ventricular faction of shortening (FS) as well as a decreased cardiac output (CO). Doppler measurements showed a restrictive left ventricular filling pattern, i.e. reversed E/A ratio; decreased deceleration time (DT); decreased isovolumic relaxation time (IVRT). Enlarged left and right atria was a dramatic sign, which was observed in most of the transgenic mice, and was developed early and fast (at age of 2–3 weeks). Severely affected lines developed a pathology similar to that observed in human restrictive cardiomyopathy patients who carry the same mutation and with a high early mortality. Our data indicate the causality of this mutation for diastolic dysfunction and heart failure and provide a useful animal model for further understanding the thin filament structure-function relationships and the physiological function of triponin in cardiac contraction and relaxation. (Supported by NIH GM073621 and AHA0715116B) This research has received full or partial funding support from the American Heart Association, AHA Greater Southeast Affiliate (Alabama, Florida, Georgia, Louisiana, Mississippi, Puerto Rico & Tennessee).

scholarly journals Cardiac Troponin I C-Terminal Mutations (K178E and K179E) Cause Severe Heart Failure and Early Mortality in Transgenic Mice

2012 ◽  
Vol 102 (3) ◽  
pp. 560a ◽  
Author(s):  
Pierre-Yves Jean-Charles ◽  
Yuejin Li ◽  
Changlong Nan ◽  
Nariman Gobara ◽  
Xupei Huang
Keyword(s):  
Heart Failure ◽  
Transgenic Mice ◽  
Cardiac Troponin ◽  
Troponin I ◽  
Severe Heart Failure ◽  
Early Mortality ◽  
Cardiac Troponin I

scholarly journals Impaired relaxation is the main manifestation in transgenic mice expressing a restrictive cardiomyopathy mutation, R193H, in cardiac TnI

2008 ◽  
Vol 294 (6) ◽  
pp. H2604-H2613 ◽  
Author(s):  
Jianfeng Du ◽  
Jing Liu ◽  
Han-Zhong Feng ◽  
M. M. Hossain ◽  
Nariman Gobara ◽  
...  
Keyword(s):  
Heart Failure ◽  
Transgenic Mice ◽  
Cardiac Function ◽  
Diastolic Dysfunction ◽  
Troponin I ◽  
Negative Impact ◽  
Diastolic Heart Failure ◽  
Critical Role ◽  
Restrictive Cardiomyopathy ◽  
Contraction And Relaxation

Transgenic mice were generated to express a restrictive cardiomyopathy (RCM) human cardiac troponin I (cTnI) R192H mutation in the heart (cTnI193His mice). The objective of this study was to assess cardiac function during the development of diastolic dysfunction and to gain insight into the pathophysiological impact of the RCM cTnI mutation. Cardiac function and pathophysiological changes were monitored in cTnI193His mice and wild-type littermates for a period of 12 mo. It progressed gradually from abnormal relaxation to diastolic dysfunction characterized with high-resolution echocardiography by a reversed E-to-A ratio, increased deceleration time, and prolonged isovolumetric relaxation time. At the age of 12 mo, cardiac output in cTnI193His mice was significantly declined, and some transgenic mice showed congestive heart failure. The negative impact of cTnI193His on ventricular contraction and relaxation was further demonstrated in isolated mouse working heart preparations. The main morphological change in cTnI193His myocytes was shortened cell length. Dobutamine stimulation increased heart rate in cTnI193His mice but did not improve CO. The cTnI193His mice had a phenotype similar to that in human RCM patients carrying the cTnI mutation characterized morphologically by enlarged atria and restricted ventricles and functionally by diastolic dysfunction and diastolic heart failure. The results demonstrate a critical role of the COOH-terminal domain of cTnI in the diastolic function of cardiac muscle.

Incidence and severity of cardiotoxicity in metastatic renal cell carcinoma (RCC) patients treated with targeted therapies.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 4610-4610 ◽  
Author(s):  
Philip S Hall ◽  
Ronald Witteles ◽  
Sandy Srinivas ◽  
Lauren Christine Harshman
Keyword(s):  
Heart Failure ◽  
Targeted Therapies ◽  
Troponin I ◽  
Hypoxia Inducible Factor ◽  
Severe Heart Failure ◽  
Mtor Inhibitors ◽  
Left Ventricular ◽  
Close Monitoring ◽  
Cardiovascular Toxicity ◽  
Asymptomatic Patients

4610 Background: Almost all patients with advanced RCC are treated with therapies targeting the hypoxia inducible factor axis. The potential for these agents to cause cardiovascular (CV) toxicity has been increasingly recognized but the overall incidence and extent have not been well described. We sought to identify and characterize the incidence and severity of CV toxicity among RCC patients treated with targeted therapies. Methods: Between 2004 and 2011, all RCC patients treated with targeted therapies directed against the VEGF or mTOR axes were identified at our institution. The incidence of hypertension, left ventricular (LV) dysfunction, changes in serum markers of CV toxicity (e.g., troponin I, NT-proBNP) and heart failure were assessed and graded according to the Common Terminology Criteria for Adverse Events (CTCAE v.4.0). Results: Cardiovascular toxicity developed in 116 of 159 patients (73%). Excluding hypertension, 52 of 159 (33%) developed cardiovascular toxicity. Cardiac toxicity ranged from asymptomatic drops in LV ejection fraction (LVEF) to rises in NT-proBNP to severe heart failure. Asymptomatic cardiotoxicity as defined by decrease in LVEF or increase in NT-proBNP occurred in 43 patients (27%). Symptomatic heart failure (grade 2-3) and grade 3-4 decrease in LVEF each occurred in 4%. Sunitinib was the most frequently used and most common offending agent, with 66 of 101 sunitinib-treated patients (65%) developing a form of CV toxicity, or 32 of 101 (32%) excluding hypertension. However, it was notable that CV toxicity was observed in 68%, 66%, and 51% of patients treated with bevacizumab, sorafenib, and pazopanib as well. The mTOR inhibitors elicited significantly less CV toxicity, but sample sizes were small. Conclusions: Cardiovascular toxicity is an important adverse event related to targeted therapy administration. Close monitoring for the development of CV toxicity with the use of these agents should become standard of care as early detection of asymptomatic patients could preempt symptomatic toxicity and reduce treatment-related morbidity and mortality.

scholarly journals The association of high-sensitivity cardiac troponin I and T with echocardiographic stages of heart failure with preserved ejection fraction

2019 ◽  
Vol 56 (4) ◽  
pp. 431-441
Author(s):  
Julia Hoffmann ◽  
Michael Behnes ◽  
Uzair Ansari ◽  
Kathrin Weidner ◽  
Philip Kuche ◽  
...  
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Diastolic Dysfunction ◽  
Troponin I ◽  
High Sensitivity ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Preserved Ejection Fraction ◽  
Ventricular Ejection Fraction ◽  
Grade Iii

Background This study evaluates the associations between high-sensitivity troponin I and T (hs-TnI/hs-TnT) and the stages of heart failure with preserved ejection fraction (HFpEF)/diastolic dysfunction. Methods Blood samples for biomarker measurements (hs-TnI/hs-TnT/NT-proBNP) were collected within 24 h of routine echocardiographic examination. Patients with left ventricular ejection fraction <50%, right ventricular dysfunction and moderate-to-severe valvular heart disease were excluded. Graduation of diastolic dysfunction was determined according to current guidelines. Results A total of 70 patients were included. Hs-TnT concentrations increased significantly according to the progression of diastolic dysfunction ( P = 0.024). Hs-TnT was able to discriminate patients with diastolic dysfunction grade III (AUC = 0.737; P = 0.013), while NT-proBNP revealed a greater AUC (AUC 0.798; P = 0.002). Concentrations of hs-TnI increased only numerically according to the increasing stages of diastolic dysfunction ( P = 0.353). In multivariable logistic regression models, hs-TnT concentrations > 28 ng/L were associated with diastolic dysfunction grade III (OR = 4.7, P = 0.024), even after adjusting for NT-proBNP. Conclusion Increasing concentrations of hs-TnT may reflect the stages of diastolic dysfunction being assessed by echocardiography, whereas hs-TnI does not show any association with diastolic dysfunction.

scholarly journals Bromine inhalation mimics ischemia-reperfusion cardiomyocyte injury and calpain activation in rats

2019 ◽  
Vol 316 (1) ◽  
pp. H212-H223 ◽  
Author(s):  
Shama Ahmad ◽  
Juan Xavier Masjoan Juncos ◽  
Aftab Ahmad ◽  
Ahmed Zaky ◽  
Chih-Chang Wei ◽  
...  
Keyword(s):  
Diastolic Dysfunction ◽  
Troponin I ◽  
Ischemia Reperfusion ◽  
Cardiac Injury ◽  
Specific Inhibitor ◽  
Left Ventricular ◽  
Cardiac Contraction ◽  
Calpain Activity ◽  
Fatty Acid Binding ◽  
Cardiac Symptoms

Halogens are widely used, highly toxic chemicals that pose a potential threat to humans because of their abundance. Halogens such as bromine (Br2) cause severe pulmonary and systemic injuries; however, the mechanisms of their toxicity are largely unknown. Here, we demonstrated that Br2 and reactive brominated species produced in the lung and released in blood reach the heart and cause acute cardiac ultrastructural damage and dysfunction in rats. Br2-induced cardiac damage was demonstrated by acute (3–24 h) increases in circulating troponin I, heart-type fatty acid-binding protein, and NH2-terminal pro-brain natriuretic peptide. Transmission electron microscopy demonstrated acute (3–24 h) cardiac contraction band necrosis, disruption of z-disks, and mitochondrial swelling and disorganization. Echocardiography and hemodynamic analysis revealed left ventricular (LV) systolic and diastolic dysfunction at 7 days. Plasma and LV tissue had increased levels of brominated fatty acids. 2-Bromohexadecanal (Br-HDA) injected into the LV cavity of a normal rat caused acute LV enlargement with extensive disruption of the sarcomeric architecture and mitochondrial damage. There was extensive infiltration of neutrophils and increased myeloperoxidase levels in the hearts of Br2- or Br2 reactant-exposed rats. Increased bromination of sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) and increased phosphalamban after Br2 inhalation decreased cardiac SERCA activity by 70%. SERCA inactivation was accompanied by increased Ca2+-sensitive LV calpain activity. The calpain-specific inhibitor MDL28170 administered within 1 h after exposure significantly decreased calpain activity and acute mortality. Bromine inhalation and formation of reactive brominated species caused acute cardiac injury and myocardial damage that can lead to heart failure. NEW & NOTEWORTHY The present study defines left ventricular systolic and diastolic dysfunction due to cardiac injury after bromine (Br2) inhalation. A calpain-dependent mechanism was identified as a potential mediator of cardiac ultrastructure damage. This study not only highlights the importance of monitoring acute cardiac symptoms in victims of Br2 exposure but also defines calpains as a potential target to treat Br2-induced toxicity.

scholarly journals Predictor of Early Mortality for Severe Heart Failure Patients With Left Ventricular Assist Device Implantation

2012 ◽  
Vol 76 (7) ◽  
pp. 1631-1638 ◽  
Author(s):  
Daisuke Yoshioka ◽  
Taichi Sakaguchi ◽  
Shunsuke Saito ◽  
Shigeru Miyagawa ◽  
Hiroyuki Nishi ◽  
...  
Keyword(s):  
Heart Failure ◽  
Left Ventricular Assist Device ◽  
Severe Heart Failure ◽  
Left Ventricular ◽  
Early Mortality ◽  
Assist Device ◽  
Ventricular Assist ◽  
Heart Failure Patients ◽  
Device Implantation ◽  
Left Ventricular Assist

scholarly journals Acute Heart Failure in a Healthy Young Patient after Severe Carbon Monoxide Poisoning

2019 ◽  
Author(s):  
Christos E Lampropoulos ◽  
Evagelia Sklavou ◽  
Charalampos Anastogiannis ◽  
Vasiliki Papanikolaou ◽  
Dimitris Tsilivarakis ◽  
...  
Keyword(s):  
Heart Failure ◽  
Carbon Monoxide ◽  
Troponin I ◽  
Carbon Monoxide Poisoning ◽  
Severe Heart Failure ◽  
Left Ventricular ◽  
Co Poisoning ◽  
Jugular Veins ◽  
X Ray ◽  
Cellular Hypoxia

Introduction: Carbon monoxide (CO) poisoning may cause severe cellular hypoxia. Materials and methods: A 28-year-old male presented reduced levels of consciousness and dyspnoea after CO exposure. Clinical examination revealed tachypnoea, bilateral rales, dilated jugular veins and confusion. Troponin I, lactate and carboxyhaemoglobin levels were increased. Thoracic X-ray depicted pulmonary oedema and an echocardiogram, severe heart failure (HF; EF<25%). He was intubated due to clinical deterioration. Results: He remained intubated for 5 days with excellent improvement of left ventricular function (EF>55%). He was discharged 1 week later with full recovery. Discussion: Acute HF is a rare serious complication of CO poisoning, even in healthy young individuals.

523 Troponin I could stratify the patients with severe heart failure

2003 ◽  
Vol 2 (1) ◽  
pp. 108
Author(s):  
G DAN ◽  
A DAN ◽  
I DAHA ◽  
C STANESCU ◽  
V ILIE ◽  
...  
Keyword(s):  
Heart Failure ◽  
Troponin I ◽  
Severe Heart Failure

Cardiac mitofusin-1 is declined in non-responding patients with idiopathic dilated cardiomyopathy

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
Y Hsiao ◽  
I Shimizu ◽  
T Wakasugi ◽  
S Jiao ◽  
T Watanabe ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Heart Failure ◽  
Ventricular Myocytes ◽  
Severe Heart Failure ◽  
Left Ventricular ◽  
Neonatal Rat ◽  
Heart Failure Patients ◽  
Underlying Mechanisms ◽  
Neonatal Rat Ventricular Myocytes ◽  
Mitofusin 1

Abstract Background/Introduction Mitochondria are dynamic regulators of cellular metabolism and homeostasis. The dysfunction of mitochondria has long been considered a major contributor to aging and age-related diseases. The prognosis of severe heart failure is still unacceptably poor and it is urgent to establish new therapies for this critical condition. Some patients with heart failure do not respond to established multidisciplinary treatment and they are classified as “non-responders”. The outcome is especially poor for non-responders, and underlying mechanisms are largely unknown. Purpose Studies indicate mitochondrial dysfunction has causal roles for metabolic remodeling in the failing heart, but underlying mechanisms remain to be explored. This study tried to elucidate the role of Mitofusin-1 in a failing heart. Methods We examined twenty-two heart failure patients who underwent endomyocardial biopsy of intraventricular septum. Patients were classified as non-responders when their left-ventricular (LV) ejection fraction did not show more than 10% improvement at remote phase after biopsy. Fourteen patients were classified as responders, and eight as non-responders. Electron microscopy, quantitative PCR, and immunofluorescence studies were performed to explore the biological processes or molecules involved in failure to respond. In addition to studies with cardiac tissue specific knockout mice, we also conducted functional in-vitro studies with neonatal rat ventricular myocytes. Results Twenty-two patients with IDCM who underwent endomyocardial biopsy were enrolled in this study, including 14 responders and 8 non-responders. Transmission electron microscopy (EM) showed a significant reduction in mitochondrial size in cardiomyocytes of non-responders compared to responders. Quantitative PCR revealed that transcript of mitochondrial fusion protein, Mitofusin-1, was significantly reduced in non-responders. Studies with neonatal rat ventricular myocytes (NRVMs) indicated that the beta-1 adrenergic receptor-mediated signaling pathway negatively regulates Mitofusin-1 expression. Suppression of Mitofusin-1 resulted in a significant reduction in mitochondrial respiration of NRVMs. We generated left ventricular pressure overload model with thoracic aortic constriction (TAC) in cardiac specific Mitofusin-1 knockout model (c-Mfn1 KO). Systolic function was reduced in c-Mfn1 KO mice, and EM study showed an increase in dysfunctional mitochondria in the KO group subjected to TAC. Conclusions Mitofusin-1 becomes a biomarker for non-responders with heart failure. In addition, our results suggest that therapies targeting mitochondrial dynamics and homeostasis would become next generation therapy for severe heart failure patients. Funding Acknowledgement Type of funding source: None

Estimation of Left Ventricular Wall Stiffness by Analysis of Late Diastolic Pressure Components

2011 ◽  
Author(s):  
Casandra L. Niebel ◽  
Kelley C. Stewart ◽  
Takahiro Ohara ◽  
John J. Charonko ◽  
Pavlos P. Vlachos ◽  
...  
Keyword(s):  
Heart Failure ◽  
Left Ventricle ◽  
Diastolic Dysfunction ◽  
Diastolic Pressure ◽  
Left Ventricular Diastolic Dysfunction ◽  
Left Ventricular ◽  
Ventricular Wall ◽  
Ventricular Relaxation ◽  
Wall Stiffness ◽  
Ventricular Diastolic Dysfunction

Left ventricular diastolic dysfunction (LVDD) is any abnormality in the filling of the left ventricle and is conventionally evaluated by analysis of the relaxation driven phase, or early diastole. LVDD has been shown to be a precursor to heart failure and the diagnosis and treatment for diastolic failure is less understood than for systolic failure. Diastole consists of two filling waves, early and late and is primarily dependent on ventricular relaxation and wall stiffness.

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