Autonomic Cardiovascular Control After Heart Transplantation

Study Overview
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Brief Summary
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The purpose of this prospective study is to investigate denervation (ie. surgical cutting of autonomic nerves) and re-innervation (ie. growth of autonomic nerves) in heart transplant recipients. More specifically, we focus on: The physiological consequences of denervation, in particular its consequences for clinical symptoms, orthostatic tolerance (ie. the ability to stand upright) and exercise capacity. We hypothesize that denervation has negative consequences for all these factors. The pathological consequences of denervation and reinnervation, in particular its association to acute rejection and coronary artery disease (cardiac allograft vasculopathy, CAV). We hypothesize that reinnervation protects against acute rejection and development of CAV Donor and recipient factors associated with the reinnervation process. We hypothesize that characteristics of the surgical procedure (such as aorta cross-clamp time) as well as the rehabilitation process of the recipient (such as physical activity) impacts on the reinnervation process.

Detailed Description
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Heart transplantation is annually offered to more than 3500 patients worldwide. In Norway, the number is approximately 30/year, and all transplants are carried out at one single hospital (Oslo University Hospital, Rikshospitalet). Normally, the heart function is intimately controlled by the autonomic nervous system (ANS), but all nervous connections are lost during the surgical transplantation procedure, and the transplanted heart thus becomes denervated. In time, regrowth of nerves may cause partial reinnervation of the new heart. Some evidence suggests that reinnervation improves exercise capacity and reduces episodes of acute rejections and the development of cardiac allograft vasculopathy. The purpose of this study is further to investigate the changes over time with respect to all parts of the autonomic nervous system (the sympathetic, parasympathetic and sensoric part), and the associated physiological and pathological consequences. The study may provide knowledge which ultimately could help us improve health and quality of live for heart transplant recipients.

Official Title
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Autonomic Cardiovascular Control After Heart Transplantation

Conditions
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Heart Transplant Recipients

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria HTRs: Completed heart transplantation during the last 7-12 weeks Age > 16 years and < 70 years Exclusion criteria HTRs: Peri- or postoperative complications causing permanent dysfunction of the allograft (such as hyperacute rejection episodes, severe myocardial ischemia, etc.) Diabetes with HbA1C > 6,5 % and/or manifest diabetic complications Renal failure with plasma creatinine > 200 µmol/L ECG abnormalities (scattered ectopic beats ad minor conduction problems are allowed) Permanently bed-ridden Inclusion criteria healthy controls: - Age and gender matching the HTRs Exclusion criteria healthy controls: Another chronic disease (such as diabetes mellitus) Permanent use of pharmaceuticals (including hormone drugs) Pregnancy

Ages Eligible for Study
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Minimum Age: 17 Years
Maximum Age: 69 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Heart transplant recipients<br>Patients receiving orthotopic heart transplant in the enrollment period | |
| Healthy controls<br>Healthy control subjects, having the same age and sex distribution as the heart transplant recipients | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cardiac allograft vasculopathy | Indications of cardiac allograft vasculopathy (CAV), assessed by intravascular ultrasound (IVUS) during coronary catheterization. | 1 year | 
| Acute rejections | The frequency of acute rejections episodes and time to first rejection (combined time/event outcome), as assessed by analyses of heart biopsy specimens | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cardiac allograft vasculopathy | Cf. above | 3 years | 
| Acute rejections | Cf. above | 2 and 3 years | 
| Autonomic cardiovascular responses | Autonomic cardiovascular responses (such as changes in blood pressures, heart rate, cardiac output, total peripheral resistance and heart rate variability) during head-up tilt-test, valsalva maneuver and isometric exercise | 6 months, 1, 2 and 3 years | 
| Exercise capacity | Cardio-pulmonary responses to a standardized exercise tolerance test (treadmill), such as maximal oxygen consumption(maxVO2), heart rate increase, blood pressure increase, etc. | 1, 2 and 3 years | 
| Activity recordings | Number of steps/day during 7 consecutive days, assessed by an accelerometer | 6 months, 1, 2 and 3 years | 
| Hormonal levels | The levels of catecholamines, cortisol and other hormones influenced by autonomic nervous activity in blood, urine and saliva | 6 months, 1, 2 and 3 years | 
| General immune activity | The blood levels of cytokines and other markers of immune function, as well as whole blood gene expression. | 6 months, 1, 2 and 3 years | 
| Pain threshold | Assessment of pain sensitivity by means of an algometer. Anatomically well-defined trigger-points are subjected to increasing pressure; the patients alert at the point where the pressure is perceived to be painful | 6 months, 1, 2 and 3 years | 
| Clinical symptoms | Validated questionnaires assessing: symptoms of autonomic dysfunction, quality of life, pain, fatigue, anxiety, depression and sleep problems. | 6 months, 1, 2 and 3 years | 
| MetaIodoBenzylGuanidin-scan | The degree of sympathetic cardiac reinnervation as assessed by the scintigraphic method MetaIodoBenzylGuanidin-scan | 1 and 3 years | 
| Echocardiographic indices | Echocardiographic indices of cardiac function, such as as systolic and diastolic velocities of the ventricular myocardium based on Tissue Doppler Imaging | 1, 2 and 3 years | 
| Ambulant blood pressure recording | 24 hours ambulant blood pressure recordings | 1, 2 and 3 years | 
| Cardiac catheterization | Routine data from surveillance cardiac catheterization procedures, such as pressure recordings, angiograms and biopsy assessments | 1, 2 and 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Heart transplantation, Autonomic cardiovascular control, Acute rejection, Cardiac allograft vasculopathy