Ignite Creation Date:
2024-05-05 @ 5:30 PM
Last Modification Date:
2024-10-26 @ 9:32 AM
Study NCT ID:
NCT00461240
Status:
COMPLETED
Last Update Posted:
2012-07-26
First Post:
2007-04-16
Brief Title:
Cardiac and Skeletal Muscle Energy Metabolism in Abnormal Growth Hormone States
Sponsor:
Barts The London NHS Trust
Organization:
Barts The London NHS Trust
Study Overview
Official Title:
Cardiac and Skeletal Muscle Energy Metabolism in Abnormal Growth Hormone States
Status:
COMPLETED
Status Verified Date:
2012-07
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:
None
Brief Summary:
Growth hormone GH is important for growth in childhood but also has important effects on a number of tissues throughout life GH deficiency and GH excess acromegaly caused by a pituitary tumour are both cause serious abnormalities of metabolism and long-standing abnormal GH status causes abnormal heart function In both cases cardiovascular disease is a leading cause of early premature death In the current study we wish to investigate the energy status of the heart in patients with GH excess and deficiency and compare that with age-matched controls We will perform a blood test to study metabolic parameters We will perform measurements before treatment after normalisation of improvement of GH levels and 2 years after start of treatment
Objectives
1 Determine cardiac and skeletal muscle energy metabolism in patients with GH excess acromegaly or GH deficiency and detect changes after normalisation of GH and IGF-1 levels IGF-I is a hormone directly influenced by GH
2 To correlate muscle energy metabolism parameters to GH and IGF-1 status in the control subjects and in both patient groups
3 Determine the prevalence of coronary artery calcifications in patients with GH excess and GH deficiency and correlate this with their metabolic status
4 To correlate coronary artery calcifications to abdominal obesity Patients will be identified by Endocrinology physicians involved in the study in outpatients clinics or Endocrine wards and they will receive standard care for their disease Tests related to endocrine hormone abnormalities will be performed as usual clinical practice The study will involve three 3-hour visits to the Oxford Research Centre and two 1-hour visits to London Scanning Centre
The visits at the Oxford research centre will include Cardiac and skeletal investigations
Standard cardiac MRI will be used to measure right and left ventricular morphology and global function
31P Magnetic Resonance Spectroscopy MRS to monitor heart muscle energy levels by measuring intracellular PCr and ATP in heart muscle
Heart failure severity so called NYHA status will be determined from the 6 min walk test
Peak oxygen uptake will be estimated from a metabolic gas exchange analysis performed during maximal treadmill exercise testing
Skeletal muscle MR imaging and spectroscopy will be performed at rest and during exercise
Fasting blood test will be performed see details in protocol
Electrocardiogram ECG
Epworth Sleepiness Scale questionnaire and 5 point test for sleep apnoea The visits at the London Scanning Centre will include
Electron beam coronary CT EBCT to assess coronary disease The number of coronary disease lesions will be measured in several coronary arteries and values will add up to an overall score In addition a single picture will be taken at the level of the umbilicus belly button to measure fat tissue within the abdomen Patient selection Patients will be recruited at St Bartholomews Hospital Dr P Jenkins and Prof A Grossman Kings Hospital Dr S Aylwin and St Thomass Hospital Dr P Carroll in London Royal Free Hospital Prof P Boloux the John Radcliffe Hospital Oxford Prof J Wass Addenbrooks Hospital Cambridge Dr H Simpson Sheffield Dr J Newell-Price and Stroke-on-Trent Prof R Clayton from the Endocrine Wards and outpatient clinics This constitutes a large recruitment base We estimate that 45 new acromegaly patients and 60-80 new GHD patients per year will be screened Patients will be selected on the basis of clinical diagnosis of acromegaly or GH deficiency see details of these in the formal protocol
Patients will be managed according to the clinical protocols of the referring centre
The patients will have a report of their investigation results with their treating physicians
Control subjects will be selected from the general population via advertisements They will undergo all tests in the Oxford centre once
Expected value of results
These studies will increase our knowledge of the metabolic changes associated with GH excess and GH deficiency which can lead to increased cardiac morbidity and mortality in both cases Our studies will help to clarify the mechanism of abnormal cardiac function The study has been powered to have appropriate number of subjects within a two year period therefore we anticipate that it will last from start to finish 4 years
Objectives
1 Determine cardiac and skeletal muscle energy metabolism in patients with GH excess acromegaly or GH deficiency and detect changes after normalisation of GH and IGF-1 levels IGF-I is a hormone directly influenced by GH
2 To correlate muscle energy metabolism parameters to GH and IGF-1 status in the control subjects and in both patient groups
3 Determine the prevalence of coronary artery calcifications in patients with GH excess and GH deficiency and correlate this with their metabolic status
4 To correlate coronary artery calcifications to abdominal obesity Patients will be identified by Endocrinology physicians involved in the study in outpatients clinics or Endocrine wards and they will receive standard care for their disease Tests related to endocrine hormone abnormalities will be performed as usual clinical practice The study will involve three 3-hour visits to the Oxford Research Centre and two 1-hour visits to London Scanning Centre
The visits at the Oxford research centre will include Cardiac and skeletal investigations
Standard cardiac MRI will be used to measure right and left ventricular morphology and global function
31P Magnetic Resonance Spectroscopy MRS to monitor heart muscle energy levels by measuring intracellular PCr and ATP in heart muscle
Heart failure severity so called NYHA status will be determined from the 6 min walk test
Peak oxygen uptake will be estimated from a metabolic gas exchange analysis performed during maximal treadmill exercise testing
Skeletal muscle MR imaging and spectroscopy will be performed at rest and during exercise
Fasting blood test will be performed see details in protocol
Electrocardiogram ECG
Epworth Sleepiness Scale questionnaire and 5 point test for sleep apnoea The visits at the London Scanning Centre will include
Electron beam coronary CT EBCT to assess coronary disease The number of coronary disease lesions will be measured in several coronary arteries and values will add up to an overall score In addition a single picture will be taken at the level of the umbilicus belly button to measure fat tissue within the abdomen Patient selection Patients will be recruited at St Bartholomews Hospital Dr P Jenkins and Prof A Grossman Kings Hospital Dr S Aylwin and St Thomass Hospital Dr P Carroll in London Royal Free Hospital Prof P Boloux the John Radcliffe Hospital Oxford Prof J Wass Addenbrooks Hospital Cambridge Dr H Simpson Sheffield Dr J Newell-Price and Stroke-on-Trent Prof R Clayton from the Endocrine Wards and outpatient clinics This constitutes a large recruitment base We estimate that 45 new acromegaly patients and 60-80 new GHD patients per year will be screened Patients will be selected on the basis of clinical diagnosis of acromegaly or GH deficiency see details of these in the formal protocol
Patients will be managed according to the clinical protocols of the referring centre
The patients will have a report of their investigation results with their treating physicians
Control subjects will be selected from the general population via advertisements They will undergo all tests in the Oxford centre once
Expected value of results
These studies will increase our knowledge of the metabolic changes associated with GH excess and GH deficiency which can lead to increased cardiac morbidity and mortality in both cases Our studies will help to clarify the mechanism of abnormal cardiac function The study has been powered to have appropriate number of subjects within a two year period therefore we anticipate that it will last from start to finish 4 years
Detailed Description:
INTRODUCTION The effect of GH and IGF-I on the heart has been demonstrated in numerous experimental studies GH and IGF-I receptors are expressed in cardiac myocytes and IGF-I causes hypertrophy of cultured rat cardiomyocytes and delays cardiomyocyte apoptosis In addition GH and IGF-I have a direct effect on myocardial contractility increasing the intracellular calcium content and enhancing the calcium sensitivity of myofilaments in cardiomyocytes Clinical studies in patients with disorders of the GHIGF-1 axis confirm the significant relationship between GHIGF-I and the cardiovascular system Interestingly both GH excess and deficiency states are associated with abnormal cardiac function and with an attendant increased risk for cardiovascular morbidity and mortality in both Our contention is that the apparent paradox of the relationship may be due to changes in the energy state of the myocardium in GH excess acromegaly and deficiency GHD in hypopituitarism and the inability of cellular metabolism to change appropriately between the competing demands of oxidative stress and anabolic processes Data from the giant GH-overexpressing transgenic mouse demonstrate reduced creatinine phosphate-to-ATP ratio supporting an effect of GH on cardiac energy status
AMP-activated protein kinase AMPK is the energy sensor of the cell and has been shown to be an important regulator of cell metabolism including cardiac cells Dyck Lopaschuk 2002 AMPK is activated by rising AMPATP ratio and programs intracellular metabolism to conserve energy for oxidate metabolism and to suspend anabolic processes A substantial body of evidence testifies to the importance of AMPK and the associated regulation of myocardial energy status to cardiac function
Reduced activity of AMPK is a feature of inherited cardiomyopathies
Low energy status measured non-invasively is a predictor of death in dilated cardiomyopathy
Activation of AMPK reduces the injury in experimental models of ischaemia
Reduced cardiac energy reserve is a feature of type 2 diabetes mellitus T2DM and cardiovascular death accounts for over 80 of mortality in T2DM
Drugs which are known to activate AMPK improve mortality in type 2 diabetes such as metformin and glitazones Kahn et al 2005
Cannabinoids and ghrelin first identified by our group to increase cardiac AMPK levels have been shown to improve ischaemia-reperfusion injury Frascarelli et al 2003 Underdown et al 2005 Shibata et al 2005
Taking these experimental observations together it can be inferred that in diabetic cardiac muscle there is impaired activation of AMPK despite low energy levels and potentially a failure of the normal mechanism to favour oxidative metabolism and cytoprotective functions during ischaemia
In patients cardiac AMPK cannot be directly studied although in a related animal study we will assess the effect of GH excess and deficiency on the activation of AMPK cardiac intracellular energy status and myocardium function However using 31P Magnetic Resonance Spectroscopy MRS in vivo measurement of high energy phosphate molecules can be assessed non-invasively and these have been shown in other diseases to have important clinical consequences Specifically both phosphocreatine PCr and ATP can be determined and ADP levels derived from the phosphocreatineATP ratio Scheurmann-Freestone 2003 This approach has been recently used to demonstrate low ambient level of myocardial ADP in patients with T2DM In the current study we will investigate the energy status in patients with acromegaly and GHD before and after normalisation of their GH status We hypothesise that in untreated acromegaly the unrestrained drive of anabolism will be associated with a low energy status and particularly in inability to respond to exercise We propose that in GHD reduced anabolism will be associated with relatively high levels of energy but an impairment of muscle mass We further anticipate that the normalisation of hormone levels resulting from either medical or surgical therapy will result in improvement in energy-storing phosphate molecule ratios in the myocardium
Acromegaly - Cardiac function Acromegalic cardiomyopathy is the specific myocardial disease of acromegaly Clayton 2003 Sacca et al 2003 Colao et al 2004b Active acromegaly is associated with a 2- to 3-fold increase in mortality mainly from cardiovascular disease although with effective treatment the excess mortality can be reversed Sheppard 2005 In its early stages acromegalic cardiomyopathy is characterised by increased left ventricular mass with eccentric remodeling and normal diastolic function with a high cardiac output state with reduction of systemic vascular resistance Fazio et al 2000 In the next stage increased heart mass and diastolic dysfunction attributed to direct injury of the myocardium with GH hypersecretion occur in the absence of associated diseases like hypertension diabetes mellitus and thyroid dysfunction These abnormalities can progress to dilated cardiomyopathy and heart failure if acromegaly remains untreated for many years There are specific structural changes in the myocardium with increased myocyte size and interstitial fibrosis of both ventricles Left ventricular hypertrophy is common in 64 of newly diagnosed cases even in young patients with short duration of disease Colao et al 2003 Functionally the main consequence of these changes is impaired left ventricular diastolic function particularly when exercising such that exercise tolerance is reduced Colao et al 2002 Myocardial perfusion is impaired in patients with active acromegaly as assessed by single photon emission computed tomography SPECT thus representing an early stage of cardiac involvement in acromegaly that may be directly mediated by GH excess Herrmann et al 2003 Some of these structural and functional changes can be reversed by effective treatment to lower serum GH levels to less than 1-2 ngml glucose suppressed or random respectively and normalize IGF-I and long-term outcome and survival is improved Colao et al 2002 Jaffrain-Rea et al 2003 Diastolic function improves with treatment but the effect on exercise tolerance is more variable and more longitudinal data are required to assess the benefits
Acromegaly - Coronary atherosclerosis Although coronary disease has a prevalence of 3-40 in acromegalic patients there is considerable controversy whether this is directly related to GH excess According to a well-controlled study Otsuki et al 2001 in which intima thickness was measured the extent of atherosclerosis in the acromegalic patients was not higher than that in non-acromegalic subjects and considering their increased number of atherosclerotic risk factors such as lipid abnormalities diabetes increased homocystein lipoprotein a fibrinogen and platelet activator inhibitor 1 levels which are all strong predictors of coronary vascular disease GH might therefore be even protective Matta Caron 2003 In a recently described study with 79 acromegalic patients with 22 age-matched controls again no difference was observed in intima thickness Paisley et al 2006 Increased concentration of IGF-I - via its vasodilatotary effect mediated by nitric oxide - might be involved in the lack of susceptibility to atherosclerosis in some acromegalic patients There are no previously published studies using electron beam coronary CT in this group of patients
Acromegaly - Skeletal muscle It is recognised that skeletal muscle in acromegaly fatigues rapidly but this has not been adequately explained particularly in relation to the increase in muscle mass It has been suggested that this may result from associated metabolic derangements diabetes or thyroid abnormalities or a direct effect of GH excess on muscle Increase in muscle specific creatinine kinase levels have been detected in patients with active disease which improves with a reduction of serum GH McNab Khandwala 2005 Microscopic examination of skeletal muscle from acromegalic patients shows type 1 fibre hypertrophy Nagulesparen et al 1976
GHD - Cardiac function Patients with GH deficiency have an increased mortality due to cardiovascular disease Most studies show decreases in heart function such as reduced left ventricular mass and cardiac output and reduced left ventricular ejection fraction particularly during exercise in addition there is an increased incidence of coronary artery disease Colao et al 2004a Colao et al 2004b Svensson et al 2005 The mechanism of cardiac abnormalities in GHD is debated but most data support the hypothesis that GHD leads to reduced cardiac mass reduced contractility reduced pre-load and increased after-load all of which could lead to reduced stroke-volume and reduced cardiac output Colao et al 2004b Treatment with GH results in improvement in cardiac function and reduction of peripheral resistance due to direct anabolic actions of the myocardium but increased dimensions could also be secondary to an increased cardiac output and stroke volume as a result of increased contractility and increased pre-load In conclusion GHD is associated with cardiac dysfunction related to the degree and duration of GHD and GH replacement seems to enhance ventricular mass and cardiac function and to reverse diastolic abnormalities Juul 1996
GHD - Coronary sclerosis The evidence linking coronary sclerosis and GHD is robust although it is unclear whether this is a direct effect of GH deficiency on cardiac endothelium or an indirect effect of the increase in cardiovascular risk factors documented in patients with hypopituitarism and GH deficiency These include increased abdominal adiposity abnormal LDL and triglyceride levels high fibrinogen and plasminogen activator inhibitor activity increased markers of inflammation such as interleukin-6 and C-reactive protein and consequently increased intima-thickness Colao et al 2004a Colao et al 2004b In our studies we will use electron-beam CT EBCT as a non-invasive means of determining coronary artery disease which is a sensitive indicator of IHD This will allow us to control for changes in the onset andor recovery from ischaemia that might be due to macrovascular ischemia rather than reduced intracellular capacitance There are no previously published studies using electron beam coronary CT in these groups of patients
GHD - Skeletal muscle Adult growth hormone deficiency AGHD is associated with fatigue tiredness and isometric muscle strength is reduced to 76 After 6 months of GH therapy muscle mass increases 5 Bengtsson et al 1993 Juul 1996 Neuromuscular dysfunction is also observed abnormal electromyogram and interference pattern analysis which improves after initiating GH therapy Webb et al 2003 The reduced exercise capacity observed in GHD is multifactorial but reduced skeletal muscle mass has an important contribution to it Juul 1996
In summary existing evidence demonstrates that patients with both GH deficiency and GH excess have abnormal cardiac and skeletal muscle function although the nature of the cardiac abnormality differs In acromegaly there is hypertrophy and impaired contractility with dysfunction amplified during exercise In GHD risk factors for IHD cause premature occlusive coronary artery disease coupled with a poor anabolic stimulus and reduced muscle mass Skeletal muscle echoes these processes In transgenic mice overexpressing GH an acromegalic mouse the phosphocreatine -to-ATP ratio measured by MRS is significantly lower in GH overexpressing mice than controls suggesting impaired energy level in the myocardium Bollano et al 2000 We hypothesise that chronic growth hormone excess may lead to reduced energy level within the myocardium and that restoration of normal GH level will ameliorate this abnormality Our model would also predict that in GHD resting energy levels would be normal or even high and that the primary defect is a reduction in muscle mass due to reduced anabolic stimulus In patients with GH excess and GHD we will assess cardiac energy levels with MRS a non-invasive technique of assessing myocardial energy metabolism before and after treatment a technique that has been successfully used to establish abnormal heart energy levels in patients with diabetes and heart failure Scheuermann-Freestone et al 2003
Objectives
1 Determine cardiac at rest and skeletal muscle at rest peak exercise and recovery energy metabolism in patients with GH excess and detect changes after normalisation of GH and IGF-1 levels
2 Determine cardiac and skeletal muscle energy metabolism in patients with GH deficiency and detect changes after normalisation of IGF-1 levels
3 To correlate muscle energy metabolism parameters to GH and IGF-1 status in the control subjects and in both patient groups
4 Determine the prevalence of coronary artery calcifications in patients with GH excess and GH deficiency and correlate with their risk factors and other surrogate markers of CHD serum levels of high sensitivity CRP lipoprotein a homocysteine and insulin resistance HOMA analysis
5 Determine the anatomical distribution of the atheromatous plaques within the coronary arteries and the extent of isolated plaques compared to diffuse disease
Methods Cardiac and skeletal investigations
MRI at 15T Siemens Sonata will be used to measure right and left ventricular morphology and global function Sandstede et al 2005 ie left and right ventricular systolic and end-diastolic volumes and ejection fractions Tissue phase mapping will be used to measure radial and rotational tissue velocities for regional wall motion abnormalities and abnormal contractile patterns
31P MRS will be used as previously described Crilley et al 2000 Roest et al 2001 to monitor intracellular PCr and ATP in heart muscle Acquisition will be triggered using electrocardiographic gating Cardiac diastolic function will be measured using cine MRI volume-time curves and tissue phase mapping parameters
Heart failure severity NYHA status will be determined from the degree of dyspnoea 6 min walk test
Peak O2 uptake MVO2 will be estimated from a metabolic gas exchange analysis performed during maximal treadmill cardiopulmonary exercise testing
Skeletal muscle MR imaging and spectroscopy The protocol for the 31P MRS determination of calf muscle gastrocnemius and soleus metabolism at rest and during dynamic exercise is well established Scheuermann-Freestone et al 2003 A T1-weighted MR image will be used to determine the muscle cross-sectional area and 31P MRS of the gastrocnemius muscle will be performed at rest during and after exercise Each subject will lie in the 3T superconducting magnet with their calf overlying a 6 cm diameter surface coil The muscle will be exercised by plantar flexion of the right ankle lifting a weight of 10 lean body mass a distance of 7 cm at a rate of 30min After acquisition of four spectra each 125 min the weight will be incrementally increased by 2 of lean body mass every other minute The subject will exercise until stopping when fatigued and the muscle will then be studied during recovery On retesting after therapy exercise will continue again until the subject is stopped by fatigue treatment may lengthen this time Relative concentrations of Pi PCr and ATP will be measured from their signal intensities in the spectra as described previously Adamopoulos et al 1999 Butterworth et al 2000 Scheuermann-Freestone et al 2003
Electron beam coronary CT EBCT to assess coronary disease As calcium is deposited in the earliest stages of atheroma formation EBCT can detect sub-clinical coronary disease many years before it results in ischaemia The extent of coronary artery calcification reflects the overall impact of risk factors both known and unknown on the end organ the arterial wall and as such gives a superior predictive value over the Framingham risk assessment Thompson Partridge 2004 Pletcher et al 2004 EBCT scanning will be performed using a GE-IMATRON 300 scanner using a conventional protocol Calcium deposition within coronary arteries will be assessed by total volume and by the Agatson correction The number of plaques and calcium score will be measured in the left main artery left anterior descending left circumflex and right coronary artery in addition to an overall score
Other investigations will include Demographic and clinical data incl medication will be obtained for all patients and control subjects ECG Epworth Sleepiness Scale questionnaire and 5 point test for sleep apnoea blood samples will be taken after a 12 h fast after 30 min rest for glucose lactate free fatty acids ketone bodies insulin triglyceride cholesterol HDL LDL ANP BNP noradrenalin electrolytes creatinine creatinine kinase uric acid TNF-alpha leptin Hb and glycosylated Hb determinations Apoprotein AB High sensitivity C-reactive protein Lipoprotein a Homocysteine Insulin HOMA analysis biochemistry and liver function pregnancy test Endocrine investigations will include Glucose tolerance tests for acromegaly patient for GHD if necessary GH day-curve a mean of 5 estimations throughout the day serum IGF-I pituitary and peripheral hormones LH FSH cortisol TFT testoE2 PRL estimation of duration of the disease the presumed duration of acromegaly will be estimated by comparison of patients photographs taken over a 1-3-decade span and by interviews to date the onset of acral enlargement and other clinical symptoms Damjanovic et al 2002 Colao et al 2003 Patient selection Patients will be recruited at St Bartholomews Hospital Dr P Jenkins and Prof A Grossman Kings Hospital Dr S Aylwin and St Thomass Hospital Dr P Carroll in London Royal Free Hospital Prof P Boloux the John Radcliffe Hospital Oxford Prof J Wass Sheffield Dr J Newell-Price and Stroke-on-Trent Prof R Clayton from the Endocrine Wards and outpatient clinics This constitutes a large recruitment base We estimate that 45 new acromegaly patients and 60-80 new GHD patients per year will be screened Patients will be selected on the basis of the clinical diagnosis of acromegaly Acromegaly typical signs and symptoms and biochemical evidence GH 1μgl during OGTT IGF-I above age-related reference range GHD a structural hypothalamo-pituitary defect at least one other pituitary hormone deficiency AGHDA score 11 NICE criterion and evidence of severe biochemical GHD usually a peak GH response to an insulin or glucagon stress test of 3 μgl Patients will be managed according to the clinical protocols of the referring centre
Inclusion criteria for acromegaly
Clinical and biochemical diagnosis of acromegaly Thyroid and glucocorticoid replacement if necessary stable for at least 4 weeks before the study Gonadotrophin status will be recorded and whenever possible patients will be studied in the same status
Males and females aged 18-70 years willing to give informed consent
At least 6 months after the onset of symptoms of acromegaly and on stable medication for heart failure treatment if any for at least 4 weeks prior to inclusion into the study
Systolic blood pressure 180 mmHg diastolic blood pressure 110 mmHg
Exclusion criteria
Change in medication in the preceding 4 weeks
Patients on subcutaneous insulin therapy
Hyperthyroidism
Not being in sinus rhythm
Unstable angina pectoris and decompensated heart failure define as NYHA 3-4
Clinically significant valvular disease clinically significant chronic obstructive pulmonary disease
History of myocardial infarction or stroke within the last 6 months major cardiac surgery within the last 6 months
Significant history of drug- or alcohol abuse or unable to give informed consent
Any other significant surgical or medical condition which would considerably affect results in view of the identifying clinician
Typical contraindication for MR eg metal implants in delicate positions aneurysm clips shrapnel injuries pacemakers internal defibrillators and severe claustrophobia
Pregnancy
Inclusion criteria for GHD
Clinical and biochemical diagnosis of GHD All hormones replaced if clinically necessary except GH Thyroid and glucocorticoid replacement if necessary stable for at least 4 weeks before the study Gonadotrophin status will be recorded and whenever possible patients will be studied in the same status
Males and females aged 18-70 years willing to give informed consent
At least 6 months after the onset of symptoms of acromegaly and on stable medication for heart failure treatment if any for at least 4 weeks prior to inclusion into the study
Systolic blood pressure 180 mmHg diastolic blood pressure 110 mmHg
Exclusion criteria
Change in medication in the preceding 4 weeks
Previous history of acromegaly
Child-hood onset GHD
Patients on subcutaneous insulin therapy metformin probably an exclusion
Hyperthyroidism
Not being in sinus rhythm
Unstable angina pectoris and decompensated heart failure define as NYHA 3-4
Clinically significant valvular disease clinically significant chronic obstructive pulmonary disease
History of myocardial infarction or stroke within the last 6 months major cardiac surgery within the last 6 months
Significant history of drug- or alcohol abuse or unable to give informed consent
Any other significant surgical or medical condition which would considerably affect results in view of the identifying clinician
Typical contraindication for MR eg metal implants in delicate positions aneurysm clips shrapnel injuries pacemakers internal defibrillators and severe claustrophobia
Pregnancy
POST-TREATMENT ASSESSMENT Three months is estimated to be sufficient time to reach altered improved cardiac metabolism as assessed by MRS based on previous studies K Clarke manuscript submitted Therefore the first post-treatment assessment will be 3 months after biochemical cure
In acromegalic patients 3 months after documented biochemical remission IGF-1 levels reached upper limit of age-related normal range and day-curve for GH mean 25 mcgl or GH 1 mcgl during OGTT repeat MRI MRS and biochemical investigations If patient is not in biochemical remission by 24 months then repeat investigation at 24 months after the start of therapy will be performed as the final assessment
In GHD patients 3 months after recorded completed dose titration IGF-I values in the upper third of the age-related normal range repeat MRI MRS and biochemical investigations If patient has not completed GH dose titration by 24 months then repeat investigation at 24 months after the start of GH therapy anyway
24 months after start of therapy repeat EBCT There are data to suggest that for example changing lipid status can improve EBCT after 12 months of therapy Achenbach et al 2002 Age and sex matched control subjects will be recruited and studied according to the pre-treatment protocol Males and females aged 18 to 75 years willing to give informed consent will be selected without endocrine or coronary disease with further exclusion criteria as above
Power calculation
The primary endpoint will be a change in cardiac energetics as assessed by 31P magnetic resonance spectroscopy MRS expressed as PCrATP ratio Power calculations using data from our cardiac 31P MRS study Scheuermann-Freestone et al 2003 showed a highly significant reduction in cardiac PCrATP from 249 - 031 to 155 - 037 a difference of 094 In order to find a biologically significant difference between groups of one standard deviation SD with 90 power at P 005 we would need to include 21 subjects in each group For a paired study in which the effects of therapy were tested on the same patient we would need to include 11 patients in each group to find a significant difference between groups of 1 SD with 90 power at P 005 while for unpaired comparison with control subjects 15 patients are necessary To allow for patient drop-outs we will include a minimum of 30 subjects in the studies Secondary endpoints for all studies will include cardiac function MRI and skeletal muscle function and energetics MRI and MRS respectively
AMP-activated protein kinase AMPK is the energy sensor of the cell and has been shown to be an important regulator of cell metabolism including cardiac cells Dyck Lopaschuk 2002 AMPK is activated by rising AMPATP ratio and programs intracellular metabolism to conserve energy for oxidate metabolism and to suspend anabolic processes A substantial body of evidence testifies to the importance of AMPK and the associated regulation of myocardial energy status to cardiac function
Reduced activity of AMPK is a feature of inherited cardiomyopathies
Low energy status measured non-invasively is a predictor of death in dilated cardiomyopathy
Activation of AMPK reduces the injury in experimental models of ischaemia
Reduced cardiac energy reserve is a feature of type 2 diabetes mellitus T2DM and cardiovascular death accounts for over 80 of mortality in T2DM
Drugs which are known to activate AMPK improve mortality in type 2 diabetes such as metformin and glitazones Kahn et al 2005
Cannabinoids and ghrelin first identified by our group to increase cardiac AMPK levels have been shown to improve ischaemia-reperfusion injury Frascarelli et al 2003 Underdown et al 2005 Shibata et al 2005
Taking these experimental observations together it can be inferred that in diabetic cardiac muscle there is impaired activation of AMPK despite low energy levels and potentially a failure of the normal mechanism to favour oxidative metabolism and cytoprotective functions during ischaemia
In patients cardiac AMPK cannot be directly studied although in a related animal study we will assess the effect of GH excess and deficiency on the activation of AMPK cardiac intracellular energy status and myocardium function However using 31P Magnetic Resonance Spectroscopy MRS in vivo measurement of high energy phosphate molecules can be assessed non-invasively and these have been shown in other diseases to have important clinical consequences Specifically both phosphocreatine PCr and ATP can be determined and ADP levels derived from the phosphocreatineATP ratio Scheurmann-Freestone 2003 This approach has been recently used to demonstrate low ambient level of myocardial ADP in patients with T2DM In the current study we will investigate the energy status in patients with acromegaly and GHD before and after normalisation of their GH status We hypothesise that in untreated acromegaly the unrestrained drive of anabolism will be associated with a low energy status and particularly in inability to respond to exercise We propose that in GHD reduced anabolism will be associated with relatively high levels of energy but an impairment of muscle mass We further anticipate that the normalisation of hormone levels resulting from either medical or surgical therapy will result in improvement in energy-storing phosphate molecule ratios in the myocardium
Acromegaly - Cardiac function Acromegalic cardiomyopathy is the specific myocardial disease of acromegaly Clayton 2003 Sacca et al 2003 Colao et al 2004b Active acromegaly is associated with a 2- to 3-fold increase in mortality mainly from cardiovascular disease although with effective treatment the excess mortality can be reversed Sheppard 2005 In its early stages acromegalic cardiomyopathy is characterised by increased left ventricular mass with eccentric remodeling and normal diastolic function with a high cardiac output state with reduction of systemic vascular resistance Fazio et al 2000 In the next stage increased heart mass and diastolic dysfunction attributed to direct injury of the myocardium with GH hypersecretion occur in the absence of associated diseases like hypertension diabetes mellitus and thyroid dysfunction These abnormalities can progress to dilated cardiomyopathy and heart failure if acromegaly remains untreated for many years There are specific structural changes in the myocardium with increased myocyte size and interstitial fibrosis of both ventricles Left ventricular hypertrophy is common in 64 of newly diagnosed cases even in young patients with short duration of disease Colao et al 2003 Functionally the main consequence of these changes is impaired left ventricular diastolic function particularly when exercising such that exercise tolerance is reduced Colao et al 2002 Myocardial perfusion is impaired in patients with active acromegaly as assessed by single photon emission computed tomography SPECT thus representing an early stage of cardiac involvement in acromegaly that may be directly mediated by GH excess Herrmann et al 2003 Some of these structural and functional changes can be reversed by effective treatment to lower serum GH levels to less than 1-2 ngml glucose suppressed or random respectively and normalize IGF-I and long-term outcome and survival is improved Colao et al 2002 Jaffrain-Rea et al 2003 Diastolic function improves with treatment but the effect on exercise tolerance is more variable and more longitudinal data are required to assess the benefits
Acromegaly - Coronary atherosclerosis Although coronary disease has a prevalence of 3-40 in acromegalic patients there is considerable controversy whether this is directly related to GH excess According to a well-controlled study Otsuki et al 2001 in which intima thickness was measured the extent of atherosclerosis in the acromegalic patients was not higher than that in non-acromegalic subjects and considering their increased number of atherosclerotic risk factors such as lipid abnormalities diabetes increased homocystein lipoprotein a fibrinogen and platelet activator inhibitor 1 levels which are all strong predictors of coronary vascular disease GH might therefore be even protective Matta Caron 2003 In a recently described study with 79 acromegalic patients with 22 age-matched controls again no difference was observed in intima thickness Paisley et al 2006 Increased concentration of IGF-I - via its vasodilatotary effect mediated by nitric oxide - might be involved in the lack of susceptibility to atherosclerosis in some acromegalic patients There are no previously published studies using electron beam coronary CT in this group of patients
Acromegaly - Skeletal muscle It is recognised that skeletal muscle in acromegaly fatigues rapidly but this has not been adequately explained particularly in relation to the increase in muscle mass It has been suggested that this may result from associated metabolic derangements diabetes or thyroid abnormalities or a direct effect of GH excess on muscle Increase in muscle specific creatinine kinase levels have been detected in patients with active disease which improves with a reduction of serum GH McNab Khandwala 2005 Microscopic examination of skeletal muscle from acromegalic patients shows type 1 fibre hypertrophy Nagulesparen et al 1976
GHD - Cardiac function Patients with GH deficiency have an increased mortality due to cardiovascular disease Most studies show decreases in heart function such as reduced left ventricular mass and cardiac output and reduced left ventricular ejection fraction particularly during exercise in addition there is an increased incidence of coronary artery disease Colao et al 2004a Colao et al 2004b Svensson et al 2005 The mechanism of cardiac abnormalities in GHD is debated but most data support the hypothesis that GHD leads to reduced cardiac mass reduced contractility reduced pre-load and increased after-load all of which could lead to reduced stroke-volume and reduced cardiac output Colao et al 2004b Treatment with GH results in improvement in cardiac function and reduction of peripheral resistance due to direct anabolic actions of the myocardium but increased dimensions could also be secondary to an increased cardiac output and stroke volume as a result of increased contractility and increased pre-load In conclusion GHD is associated with cardiac dysfunction related to the degree and duration of GHD and GH replacement seems to enhance ventricular mass and cardiac function and to reverse diastolic abnormalities Juul 1996
GHD - Coronary sclerosis The evidence linking coronary sclerosis and GHD is robust although it is unclear whether this is a direct effect of GH deficiency on cardiac endothelium or an indirect effect of the increase in cardiovascular risk factors documented in patients with hypopituitarism and GH deficiency These include increased abdominal adiposity abnormal LDL and triglyceride levels high fibrinogen and plasminogen activator inhibitor activity increased markers of inflammation such as interleukin-6 and C-reactive protein and consequently increased intima-thickness Colao et al 2004a Colao et al 2004b In our studies we will use electron-beam CT EBCT as a non-invasive means of determining coronary artery disease which is a sensitive indicator of IHD This will allow us to control for changes in the onset andor recovery from ischaemia that might be due to macrovascular ischemia rather than reduced intracellular capacitance There are no previously published studies using electron beam coronary CT in these groups of patients
GHD - Skeletal muscle Adult growth hormone deficiency AGHD is associated with fatigue tiredness and isometric muscle strength is reduced to 76 After 6 months of GH therapy muscle mass increases 5 Bengtsson et al 1993 Juul 1996 Neuromuscular dysfunction is also observed abnormal electromyogram and interference pattern analysis which improves after initiating GH therapy Webb et al 2003 The reduced exercise capacity observed in GHD is multifactorial but reduced skeletal muscle mass has an important contribution to it Juul 1996
In summary existing evidence demonstrates that patients with both GH deficiency and GH excess have abnormal cardiac and skeletal muscle function although the nature of the cardiac abnormality differs In acromegaly there is hypertrophy and impaired contractility with dysfunction amplified during exercise In GHD risk factors for IHD cause premature occlusive coronary artery disease coupled with a poor anabolic stimulus and reduced muscle mass Skeletal muscle echoes these processes In transgenic mice overexpressing GH an acromegalic mouse the phosphocreatine -to-ATP ratio measured by MRS is significantly lower in GH overexpressing mice than controls suggesting impaired energy level in the myocardium Bollano et al 2000 We hypothesise that chronic growth hormone excess may lead to reduced energy level within the myocardium and that restoration of normal GH level will ameliorate this abnormality Our model would also predict that in GHD resting energy levels would be normal or even high and that the primary defect is a reduction in muscle mass due to reduced anabolic stimulus In patients with GH excess and GHD we will assess cardiac energy levels with MRS a non-invasive technique of assessing myocardial energy metabolism before and after treatment a technique that has been successfully used to establish abnormal heart energy levels in patients with diabetes and heart failure Scheuermann-Freestone et al 2003
Objectives
1 Determine cardiac at rest and skeletal muscle at rest peak exercise and recovery energy metabolism in patients with GH excess and detect changes after normalisation of GH and IGF-1 levels
2 Determine cardiac and skeletal muscle energy metabolism in patients with GH deficiency and detect changes after normalisation of IGF-1 levels
3 To correlate muscle energy metabolism parameters to GH and IGF-1 status in the control subjects and in both patient groups
4 Determine the prevalence of coronary artery calcifications in patients with GH excess and GH deficiency and correlate with their risk factors and other surrogate markers of CHD serum levels of high sensitivity CRP lipoprotein a homocysteine and insulin resistance HOMA analysis
5 Determine the anatomical distribution of the atheromatous plaques within the coronary arteries and the extent of isolated plaques compared to diffuse disease
Methods Cardiac and skeletal investigations
MRI at 15T Siemens Sonata will be used to measure right and left ventricular morphology and global function Sandstede et al 2005 ie left and right ventricular systolic and end-diastolic volumes and ejection fractions Tissue phase mapping will be used to measure radial and rotational tissue velocities for regional wall motion abnormalities and abnormal contractile patterns
31P MRS will be used as previously described Crilley et al 2000 Roest et al 2001 to monitor intracellular PCr and ATP in heart muscle Acquisition will be triggered using electrocardiographic gating Cardiac diastolic function will be measured using cine MRI volume-time curves and tissue phase mapping parameters
Heart failure severity NYHA status will be determined from the degree of dyspnoea 6 min walk test
Peak O2 uptake MVO2 will be estimated from a metabolic gas exchange analysis performed during maximal treadmill cardiopulmonary exercise testing
Skeletal muscle MR imaging and spectroscopy The protocol for the 31P MRS determination of calf muscle gastrocnemius and soleus metabolism at rest and during dynamic exercise is well established Scheuermann-Freestone et al 2003 A T1-weighted MR image will be used to determine the muscle cross-sectional area and 31P MRS of the gastrocnemius muscle will be performed at rest during and after exercise Each subject will lie in the 3T superconducting magnet with their calf overlying a 6 cm diameter surface coil The muscle will be exercised by plantar flexion of the right ankle lifting a weight of 10 lean body mass a distance of 7 cm at a rate of 30min After acquisition of four spectra each 125 min the weight will be incrementally increased by 2 of lean body mass every other minute The subject will exercise until stopping when fatigued and the muscle will then be studied during recovery On retesting after therapy exercise will continue again until the subject is stopped by fatigue treatment may lengthen this time Relative concentrations of Pi PCr and ATP will be measured from their signal intensities in the spectra as described previously Adamopoulos et al 1999 Butterworth et al 2000 Scheuermann-Freestone et al 2003
Electron beam coronary CT EBCT to assess coronary disease As calcium is deposited in the earliest stages of atheroma formation EBCT can detect sub-clinical coronary disease many years before it results in ischaemia The extent of coronary artery calcification reflects the overall impact of risk factors both known and unknown on the end organ the arterial wall and as such gives a superior predictive value over the Framingham risk assessment Thompson Partridge 2004 Pletcher et al 2004 EBCT scanning will be performed using a GE-IMATRON 300 scanner using a conventional protocol Calcium deposition within coronary arteries will be assessed by total volume and by the Agatson correction The number of plaques and calcium score will be measured in the left main artery left anterior descending left circumflex and right coronary artery in addition to an overall score
Other investigations will include Demographic and clinical data incl medication will be obtained for all patients and control subjects ECG Epworth Sleepiness Scale questionnaire and 5 point test for sleep apnoea blood samples will be taken after a 12 h fast after 30 min rest for glucose lactate free fatty acids ketone bodies insulin triglyceride cholesterol HDL LDL ANP BNP noradrenalin electrolytes creatinine creatinine kinase uric acid TNF-alpha leptin Hb and glycosylated Hb determinations Apoprotein AB High sensitivity C-reactive protein Lipoprotein a Homocysteine Insulin HOMA analysis biochemistry and liver function pregnancy test Endocrine investigations will include Glucose tolerance tests for acromegaly patient for GHD if necessary GH day-curve a mean of 5 estimations throughout the day serum IGF-I pituitary and peripheral hormones LH FSH cortisol TFT testoE2 PRL estimation of duration of the disease the presumed duration of acromegaly will be estimated by comparison of patients photographs taken over a 1-3-decade span and by interviews to date the onset of acral enlargement and other clinical symptoms Damjanovic et al 2002 Colao et al 2003 Patient selection Patients will be recruited at St Bartholomews Hospital Dr P Jenkins and Prof A Grossman Kings Hospital Dr S Aylwin and St Thomass Hospital Dr P Carroll in London Royal Free Hospital Prof P Boloux the John Radcliffe Hospital Oxford Prof J Wass Sheffield Dr J Newell-Price and Stroke-on-Trent Prof R Clayton from the Endocrine Wards and outpatient clinics This constitutes a large recruitment base We estimate that 45 new acromegaly patients and 60-80 new GHD patients per year will be screened Patients will be selected on the basis of the clinical diagnosis of acromegaly Acromegaly typical signs and symptoms and biochemical evidence GH 1μgl during OGTT IGF-I above age-related reference range GHD a structural hypothalamo-pituitary defect at least one other pituitary hormone deficiency AGHDA score 11 NICE criterion and evidence of severe biochemical GHD usually a peak GH response to an insulin or glucagon stress test of 3 μgl Patients will be managed according to the clinical protocols of the referring centre
Inclusion criteria for acromegaly
Clinical and biochemical diagnosis of acromegaly Thyroid and glucocorticoid replacement if necessary stable for at least 4 weeks before the study Gonadotrophin status will be recorded and whenever possible patients will be studied in the same status
Males and females aged 18-70 years willing to give informed consent
At least 6 months after the onset of symptoms of acromegaly and on stable medication for heart failure treatment if any for at least 4 weeks prior to inclusion into the study
Systolic blood pressure 180 mmHg diastolic blood pressure 110 mmHg
Exclusion criteria
Change in medication in the preceding 4 weeks
Patients on subcutaneous insulin therapy
Hyperthyroidism
Not being in sinus rhythm
Unstable angina pectoris and decompensated heart failure define as NYHA 3-4
Clinically significant valvular disease clinically significant chronic obstructive pulmonary disease
History of myocardial infarction or stroke within the last 6 months major cardiac surgery within the last 6 months
Significant history of drug- or alcohol abuse or unable to give informed consent
Any other significant surgical or medical condition which would considerably affect results in view of the identifying clinician
Typical contraindication for MR eg metal implants in delicate positions aneurysm clips shrapnel injuries pacemakers internal defibrillators and severe claustrophobia
Pregnancy
Inclusion criteria for GHD
Clinical and biochemical diagnosis of GHD All hormones replaced if clinically necessary except GH Thyroid and glucocorticoid replacement if necessary stable for at least 4 weeks before the study Gonadotrophin status will be recorded and whenever possible patients will be studied in the same status
Males and females aged 18-70 years willing to give informed consent
At least 6 months after the onset of symptoms of acromegaly and on stable medication for heart failure treatment if any for at least 4 weeks prior to inclusion into the study
Systolic blood pressure 180 mmHg diastolic blood pressure 110 mmHg
Exclusion criteria
Change in medication in the preceding 4 weeks
Previous history of acromegaly
Child-hood onset GHD
Patients on subcutaneous insulin therapy metformin probably an exclusion
Hyperthyroidism
Not being in sinus rhythm
Unstable angina pectoris and decompensated heart failure define as NYHA 3-4
Clinically significant valvular disease clinically significant chronic obstructive pulmonary disease
History of myocardial infarction or stroke within the last 6 months major cardiac surgery within the last 6 months
Significant history of drug- or alcohol abuse or unable to give informed consent
Any other significant surgical or medical condition which would considerably affect results in view of the identifying clinician
Typical contraindication for MR eg metal implants in delicate positions aneurysm clips shrapnel injuries pacemakers internal defibrillators and severe claustrophobia
Pregnancy
POST-TREATMENT ASSESSMENT Three months is estimated to be sufficient time to reach altered improved cardiac metabolism as assessed by MRS based on previous studies K Clarke manuscript submitted Therefore the first post-treatment assessment will be 3 months after biochemical cure
In acromegalic patients 3 months after documented biochemical remission IGF-1 levels reached upper limit of age-related normal range and day-curve for GH mean 25 mcgl or GH 1 mcgl during OGTT repeat MRI MRS and biochemical investigations If patient is not in biochemical remission by 24 months then repeat investigation at 24 months after the start of therapy will be performed as the final assessment
In GHD patients 3 months after recorded completed dose titration IGF-I values in the upper third of the age-related normal range repeat MRI MRS and biochemical investigations If patient has not completed GH dose titration by 24 months then repeat investigation at 24 months after the start of GH therapy anyway
24 months after start of therapy repeat EBCT There are data to suggest that for example changing lipid status can improve EBCT after 12 months of therapy Achenbach et al 2002 Age and sex matched control subjects will be recruited and studied according to the pre-treatment protocol Males and females aged 18 to 75 years willing to give informed consent will be selected without endocrine or coronary disease with further exclusion criteria as above
Power calculation
The primary endpoint will be a change in cardiac energetics as assessed by 31P magnetic resonance spectroscopy MRS expressed as PCrATP ratio Power calculations using data from our cardiac 31P MRS study Scheuermann-Freestone et al 2003 showed a highly significant reduction in cardiac PCrATP from 249 - 031 to 155 - 037 a difference of 094 In order to find a biologically significant difference between groups of one standard deviation SD with 90 power at P 005 we would need to include 21 subjects in each group For a paired study in which the effects of therapy were tested on the same patient we would need to include 11 patients in each group to find a significant difference between groups of 1 SD with 90 power at P 005 while for unpaired comparison with control subjects 15 patients are necessary To allow for patient drop-outs we will include a minimum of 30 subjects in the studies Secondary endpoints for all studies will include cardiac function MRI and skeletal muscle function and energetics MRI and MRS respectively
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
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Is a FDA Regulated Device?:
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Is an Unapproved Device?:
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Is a PPSD?:
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Is a US Export?:
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Is an FDA AA801 Violation?:
None