Cardiac and Skeletal Muscle Energy Metabolism in Abnormal Growth Hormone States
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 入组人数
- 25
- 试验地点
- 1
研究概览
简要总结
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
- 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)
- To correlate muscle energy metabolism parameters to GH and IGF-1 status in the control subjects and in both patient groups
- Determine the prevalence of coronary artery calcifications in patients with GH excess and GH deficiency and correlate this with their metabolic status
- 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. Bartholomew's Hospital (Dr P. Jenkins and Prof. A. Grossman), King's Hospital (Dr S. Aylwin) and St Thomas's 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.
详细描述
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 GH/IGF-1 axis confirm the significant relationship between GH/IGF-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 AMP/ATP 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 phosphocreatine:ATP 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.
研究设计
- 研究类型
- Observational
- 观察模型
- Case Control
- 时间视角
- Prospective
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
- •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.
排除标准
- •for acromegaly
- •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 (e.g. metal implants in delicate positions, aneurysm clips, shrapnel injuries, pacemakers, internal defibrillators and severe claustrophobia)
- •Pregnancy
- •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 (e.g. metal implants in delicate positions, aneurysm clips, shrapnel injuries, pacemakers, internal defibrillators and severe claustrophobia)
- •Pregnancy
研究者
Marta Korbonits
Professor
Barts & The London NHS Trust