Ignite Creation Date:
2024-05-06 @ 7:23 AM
Last Modification Date:
2024-10-26 @ 11:48 AM
Study NCT ID:
NCT02527330
Status:
COMPLETED
Last Update Posted:
2017-07-25
First Post:
2015-08-17
Brief Title:
Evaluation of Myocardial Iron Deposition in Patients of Heart Failure Using T2 MR Imaging
Sponsor:
Chang Gung Memorial Hospital
Organization:
Chang Gung Memorial Hospital
Study Overview
Official Title:
Evaluation of Myocardial Iron Deposition in Patients of Heart Failure Using T2 MR Imaging
Status:
COMPLETED
Status Verified Date:
2016-08
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
CHFIRONMR
Brief Summary:
Heart failure from myocardial iron deposition is a severe complication for patients with hematological disorders who need repeated blood transfusions Increased cardiac iron content impacts the contractility of cardiomyocytes and can also lead to myocarditis pericarditis and arrhythmias The severity of cardiac dysfunction depends on the amount of iron deposited in the myocardium
Cardiovascular magnetic resonance CMR imaging is used as noninvasive method to evaluate the amount of iron in the heart Myocardial T2 value has been shown to correlate well with biopsy-derived iron concentration in the heart and myocardial T2 values less than 20ms indicating elevated iron were found to be associated with LV dysfunction and improve in concert with LV function during recovery The majority of the recent studies about myocardial iron overload and the effect of iron chelation therapy were focused on patients with transfusion-dependent hematological disorder especially beta-thalassemia major
The objective of this 3-year project is to evaluate myocardial iron deposition in patients with heart failure induced by variable causes With myocardial T2 imaging the investigators will analyze the decreased signal intensity in the ventricular septum and quantitatively acquire the T2 value as marker for myocardial iron deposition The first year is a cross-sectional study The investigators aim to compare the severity of myocardial iron deposition of normal subjects and that of stable HF patients in recovery with normal or impaired ejection fraction EF Total 60 subjects will be enrolled with 20 subjects in each group In the 2nd and 3rd years the investigators plan a prospective longitudinal study of 40 subjects Enrolled patients will be evaluated with cardiac T2 imaging at three time points ie disease onset 6 months and one year after treatment and will be followed up until the end of this project 153-year follow up In total 120 MR scans will be performed in the 2nd and 3rd years The presence and severity of myocardial iron deposition will be correlated with the disease course patient biochemistry data and clinical outcome
Cardiovascular magnetic resonance CMR imaging is used as noninvasive method to evaluate the amount of iron in the heart Myocardial T2 value has been shown to correlate well with biopsy-derived iron concentration in the heart and myocardial T2 values less than 20ms indicating elevated iron were found to be associated with LV dysfunction and improve in concert with LV function during recovery The majority of the recent studies about myocardial iron overload and the effect of iron chelation therapy were focused on patients with transfusion-dependent hematological disorder especially beta-thalassemia major
The objective of this 3-year project is to evaluate myocardial iron deposition in patients with heart failure induced by variable causes With myocardial T2 imaging the investigators will analyze the decreased signal intensity in the ventricular septum and quantitatively acquire the T2 value as marker for myocardial iron deposition The first year is a cross-sectional study The investigators aim to compare the severity of myocardial iron deposition of normal subjects and that of stable HF patients in recovery with normal or impaired ejection fraction EF Total 60 subjects will be enrolled with 20 subjects in each group In the 2nd and 3rd years the investigators plan a prospective longitudinal study of 40 subjects Enrolled patients will be evaluated with cardiac T2 imaging at three time points ie disease onset 6 months and one year after treatment and will be followed up until the end of this project 153-year follow up In total 120 MR scans will be performed in the 2nd and 3rd years The presence and severity of myocardial iron deposition will be correlated with the disease course patient biochemistry data and clinical outcome
Detailed Description:
Introduction
Heart failure HF is a complex clinical syndrome resulting from any structural or functional cardiac disorder that impairs the ability of the ventricle to fill with or eject blood In Taiwan HF is a growing epidemic owing to the aging population and the increasing survival of patients presenting with acute myocardial infarction and various other heart diseases The reported 5- and 10-year mortality ranged from 14 and 482 in those with impaired LVEF versus 141 and 244 in those with pre- served LVEF respectively
The diagnosis of HF is based on symptoms typical of heart failure and signs typical of heart failure and an objective evidence structural or functional abnormality of the heart Asymptomatic structural or functional abnormalities of the heart myocardial remodeling are usually progressive disorders and are considered as precursors of symptomatic heart failure Therefore early diagnosis of the underlying etiology and cause should always be sought for guiding a suitable and preventive treatment
Myocardial iron deposition leads to progressive heart dysfunction and is thought to be a leading cause of death in transfusion-dependent anemia Endomyocardial biopsy which has been used to evaluate iron deposition in the heart is risky and has unacceptable sampling variability Non-invasive MR scanning is currently the imaging method shown to be reliable and accurate to assess myocardial iron loading The application of the MR transverse relaxation times T2 has been successfully demonstrated for quantitative assessment of the iron concentration in the heart
Purpose The objective of this project is to evaluate myocardial iron deposition in patients with heart failure HF Deposition of iron on the myocardium is expected to be found in patients with heart failure induced by other cause rather than transfusion-dependent hematological disorder In this longitudinal study we will attempt to analyze the presence and severity of myocardial iron deposition variation along the course and correlate with clinical outcome in patients with HF
Methods This is a 3-year project on human subjects focusing on myocardial iron deposition Direct myocardial iron measurement using endomyocardial biopsy is risky and has unacceptable sampling variability Therefore MR T2 imaging is chosen in this project due to non-invasiveness and T2 value quantitatively correlates with the severity of myocardial iron overload
The inclusion criteria for this study are 1 heart failure patients diagnosed in the Keelung Chang Gung Memorial Hospital 2 patients must be 20 and 70 years of age 3 patients must be willing to undergo standard treatment and follow up in the Heart Failure Center 4 patients must be able to give informed consent The exclusion criteria are 1 patients who are judged to be noncompliant to treatment or not accessible for follow up 2 patients with contraindications to MR scanning such as claustrophobia cardiac pacemaker metal implants or unable to cooperate for MRI study due to mental status 3 Severe renal function impairment glomerular filtration rate less than 30 mLmin173m2 4 pregnant or breast-feeding 5 history of open-heart surgery Medical records of eligible patients will be identified and centrally reviewed in the project joint meeting before enrollment to ensure the study quality
1 st year plan The first year is a cross-sectional study By using T2 imaging we aim to compare the severity of myocardial iron deposition of normal subjects and that of stable HF patients in recovery with normal or impaired ejection fraction EF Total 60 subjects will be enrolled with a group of treated HF patients with normal EF n20 a group of treated HF patients with impaired EF n20 and a control group n20 The control group consists of age and gender matched normal volunteers without previously documented cardiac disease In this part to compare the T2value of the HF patient group and the normal group two-sample t equality test will be considered and sample size can be chosen to achieve an 80 power for detecting a clinically meaningful difference at level of significance α005 The GPower 314 software 4 is utilized to compute required sample size for the first year study The two-independent-sample t-test with the effect size of 074 level of significance α005 and power of 08 requires a total sample of 60 participants 20 for each group The clinically meaningful effect size is set at 074 according to our small pilot studies
2 nd and 3rd years In the 2nd and 3rd years we plan a prospective longitudinal study of 40 subjects Enrolled patients will be evaluated with cardiac MR T2 imaging at three time points ie disease onset 6 months and one year after treatment and will be followed up until the end of this project 153-year follow up Therefore in total 120 MR scans will be performed in the 2nd and 3rd years The presence and severity of myocardial iron deposition will be correlated with the disease course patient biochemistry data and clinical outcome
MRI imaging and data analysis
Cardiac MRI will be performed in a 3-T MRI scanner with intravenous administration of gadolinium-based MR contrast medium for the HF subjects in order to identify any ischemia foucs and assess myocardial viability For all the test subjects EF will be calculated with Simpson disk summation method using short-axis cine steady-state free precession images of the left ventricle LV as previously reported 12 LV endocardial borders will be semi-automated traced on each short-axis image obtained in both end-diastole and end-systole to determine the ventricular cavity area for each slice The area of the tracing for each image slice will be multiplied by the slice interval slice thickness plus image gap to determine a volume for that slice The volumes of the slices will be summed to determine an LV volume LVEF can be determined by end-diastolic volume EDV and end-systolic volume ESV using the following equation
LVEF stroke volume EDV - ESV EDV 1
Iron in the myocardium was quantified by measuring T2 1R2 a MR relaxation parameter that has been shown to vary inversely with tissue iron concentration This technique has high reproducibility and inter-MRI scanner agreement MRI measurements will be performed using a 3-T clinical MRI scanner Skyra Siemens AG with a new pulse sequence Multi Echo GRE WIP 732 Siemens Myocardial T2 will be assessed with the use of a single breath-hold multiecho technique In brief a single 10-mm-thick short-axis mid-ventricular slice of the LV will be acquired at 8 echo times with standard shimming in a single breath-hold For analysis a full-thickness region of interest will be chosen in the interventricular septum The signal intensity of this region will be measured for each image with the use of in-house designed software CMRtools Cardiovascular Imaging Solutions London UK
Statistical analysis plan Descriptive statistics will be calculated for all characteristics of the study subjects For continuous data two-independent-sample t-test will be used to test the difference of T2 value between two groups and methods of analysis of variance ANOVA will be used to assess difference between 3 or more groups The non-parametric methods of Mann-Whitney U or Kruskal-Wallis H will be used to compare two or more groups for small sample size or continuous variables not following the normal distribution The Pearsons chi-square test will be used to evaluate the association between variables The Spearmans rho test will be used to correlate LVEF and T2 value measured by MRI
Expected problems and difficulties
One of the large hurdles to overcome is patient collection because this project involves clinical imaging and follow up For the close coordination of researchers in various departments and good operation of the patients we need an in-house research assistant to assure the workflow and data completeness
Because T2 at high field decreases substantially and its quantitation is vulnerable to increased B0 inhomogeneity it is especially challenging at 3T Therefore we will integrate a committed interdisciplinary team of radiologist and MR physicists to overcome these challenges
To solve the technical challenges accompanied with the high field strength 3 Tesla systems such as field inhomogenicity and susceptibility artifact Second-order shimming water peak line width 47 Hz has been proven in 3 Tesla MR system to be better than first-order 165 Hz and iterative shimming 18 Hz and will be applied in this project to improve the correction of air and tissue susceptibility differences
Use of instruments The MR T2 imaging study will be performed in a 3-Tesla Siemens Skyra MR system at Keelung Chang Gung Memorial Hospital There will be 60 scans in the 1st year and 120 scans in the 2nd and 3rd years In total 180 MR scans will be arranged over 3 years Given 45 working weeks per year on average there will be 13 scan per week Each cardiac MR study will require 2 scan slots about 2 hours plus post-processing time and will be charged as only one slot The scanner time occupancy is approved under the MRI regulation of Department of Radiology
Heart failure HF is a complex clinical syndrome resulting from any structural or functional cardiac disorder that impairs the ability of the ventricle to fill with or eject blood In Taiwan HF is a growing epidemic owing to the aging population and the increasing survival of patients presenting with acute myocardial infarction and various other heart diseases The reported 5- and 10-year mortality ranged from 14 and 482 in those with impaired LVEF versus 141 and 244 in those with pre- served LVEF respectively
The diagnosis of HF is based on symptoms typical of heart failure and signs typical of heart failure and an objective evidence structural or functional abnormality of the heart Asymptomatic structural or functional abnormalities of the heart myocardial remodeling are usually progressive disorders and are considered as precursors of symptomatic heart failure Therefore early diagnosis of the underlying etiology and cause should always be sought for guiding a suitable and preventive treatment
Myocardial iron deposition leads to progressive heart dysfunction and is thought to be a leading cause of death in transfusion-dependent anemia Endomyocardial biopsy which has been used to evaluate iron deposition in the heart is risky and has unacceptable sampling variability Non-invasive MR scanning is currently the imaging method shown to be reliable and accurate to assess myocardial iron loading The application of the MR transverse relaxation times T2 has been successfully demonstrated for quantitative assessment of the iron concentration in the heart
Purpose The objective of this project is to evaluate myocardial iron deposition in patients with heart failure HF Deposition of iron on the myocardium is expected to be found in patients with heart failure induced by other cause rather than transfusion-dependent hematological disorder In this longitudinal study we will attempt to analyze the presence and severity of myocardial iron deposition variation along the course and correlate with clinical outcome in patients with HF
Methods This is a 3-year project on human subjects focusing on myocardial iron deposition Direct myocardial iron measurement using endomyocardial biopsy is risky and has unacceptable sampling variability Therefore MR T2 imaging is chosen in this project due to non-invasiveness and T2 value quantitatively correlates with the severity of myocardial iron overload
The inclusion criteria for this study are 1 heart failure patients diagnosed in the Keelung Chang Gung Memorial Hospital 2 patients must be 20 and 70 years of age 3 patients must be willing to undergo standard treatment and follow up in the Heart Failure Center 4 patients must be able to give informed consent The exclusion criteria are 1 patients who are judged to be noncompliant to treatment or not accessible for follow up 2 patients with contraindications to MR scanning such as claustrophobia cardiac pacemaker metal implants or unable to cooperate for MRI study due to mental status 3 Severe renal function impairment glomerular filtration rate less than 30 mLmin173m2 4 pregnant or breast-feeding 5 history of open-heart surgery Medical records of eligible patients will be identified and centrally reviewed in the project joint meeting before enrollment to ensure the study quality
1 st year plan The first year is a cross-sectional study By using T2 imaging we aim to compare the severity of myocardial iron deposition of normal subjects and that of stable HF patients in recovery with normal or impaired ejection fraction EF Total 60 subjects will be enrolled with a group of treated HF patients with normal EF n20 a group of treated HF patients with impaired EF n20 and a control group n20 The control group consists of age and gender matched normal volunteers without previously documented cardiac disease In this part to compare the T2value of the HF patient group and the normal group two-sample t equality test will be considered and sample size can be chosen to achieve an 80 power for detecting a clinically meaningful difference at level of significance α005 The GPower 314 software 4 is utilized to compute required sample size for the first year study The two-independent-sample t-test with the effect size of 074 level of significance α005 and power of 08 requires a total sample of 60 participants 20 for each group The clinically meaningful effect size is set at 074 according to our small pilot studies
2 nd and 3rd years In the 2nd and 3rd years we plan a prospective longitudinal study of 40 subjects Enrolled patients will be evaluated with cardiac MR T2 imaging at three time points ie disease onset 6 months and one year after treatment and will be followed up until the end of this project 153-year follow up Therefore in total 120 MR scans will be performed in the 2nd and 3rd years The presence and severity of myocardial iron deposition will be correlated with the disease course patient biochemistry data and clinical outcome
MRI imaging and data analysis
Cardiac MRI will be performed in a 3-T MRI scanner with intravenous administration of gadolinium-based MR contrast medium for the HF subjects in order to identify any ischemia foucs and assess myocardial viability For all the test subjects EF will be calculated with Simpson disk summation method using short-axis cine steady-state free precession images of the left ventricle LV as previously reported 12 LV endocardial borders will be semi-automated traced on each short-axis image obtained in both end-diastole and end-systole to determine the ventricular cavity area for each slice The area of the tracing for each image slice will be multiplied by the slice interval slice thickness plus image gap to determine a volume for that slice The volumes of the slices will be summed to determine an LV volume LVEF can be determined by end-diastolic volume EDV and end-systolic volume ESV using the following equation
LVEF stroke volume EDV - ESV EDV 1
Iron in the myocardium was quantified by measuring T2 1R2 a MR relaxation parameter that has been shown to vary inversely with tissue iron concentration This technique has high reproducibility and inter-MRI scanner agreement MRI measurements will be performed using a 3-T clinical MRI scanner Skyra Siemens AG with a new pulse sequence Multi Echo GRE WIP 732 Siemens Myocardial T2 will be assessed with the use of a single breath-hold multiecho technique In brief a single 10-mm-thick short-axis mid-ventricular slice of the LV will be acquired at 8 echo times with standard shimming in a single breath-hold For analysis a full-thickness region of interest will be chosen in the interventricular septum The signal intensity of this region will be measured for each image with the use of in-house designed software CMRtools Cardiovascular Imaging Solutions London UK
Statistical analysis plan Descriptive statistics will be calculated for all characteristics of the study subjects For continuous data two-independent-sample t-test will be used to test the difference of T2 value between two groups and methods of analysis of variance ANOVA will be used to assess difference between 3 or more groups The non-parametric methods of Mann-Whitney U or Kruskal-Wallis H will be used to compare two or more groups for small sample size or continuous variables not following the normal distribution The Pearsons chi-square test will be used to evaluate the association between variables The Spearmans rho test will be used to correlate LVEF and T2 value measured by MRI
Expected problems and difficulties
One of the large hurdles to overcome is patient collection because this project involves clinical imaging and follow up For the close coordination of researchers in various departments and good operation of the patients we need an in-house research assistant to assure the workflow and data completeness
Because T2 at high field decreases substantially and its quantitation is vulnerable to increased B0 inhomogeneity it is especially challenging at 3T Therefore we will integrate a committed interdisciplinary team of radiologist and MR physicists to overcome these challenges
To solve the technical challenges accompanied with the high field strength 3 Tesla systems such as field inhomogenicity and susceptibility artifact Second-order shimming water peak line width 47 Hz has been proven in 3 Tesla MR system to be better than first-order 165 Hz and iterative shimming 18 Hz and will be applied in this project to improve the correction of air and tissue susceptibility differences
Use of instruments The MR T2 imaging study will be performed in a 3-Tesla Siemens Skyra MR system at Keelung Chang Gung Memorial Hospital There will be 60 scans in the 1st year and 120 scans in the 2nd and 3rd years In total 180 MR scans will be arranged over 3 years Given 45 working weeks per year on average there will be 13 scan per week Each cardiac MR study will require 2 scan slots about 2 hours plus post-processing time and will be charged as only one slot The scanner time occupancy is approved under the MRI regulation of Department of Radiology
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None