Autonomic Cardiovascular Control After Heart Transplantation (AccHeart)

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:

1. 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.
2. 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
3. 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.

Study Overview

• Status: Unknown
• Conditions: Heart Transplant Recipients

Detailed Description

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.

• Study Type: Observational
• Enrollment (Actual): 100

Contacts and Locations

Study Locations

• Norway
  • Oslo, Norway, N-0027
    • Dept. of Cardiology, Oslo University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 17 years to 69 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

This study is to enroll 50 Heart Transplant Recipients (HTRs) and 50 healthy control subjects.

HTRs are consecutively invited to participate. Baseline investigations are carried out 7-12 weeks after transplantation surgery. Follow-up investigations are scheduled to 6 months and 1, 2 and 3 years after transplantation

Healthy control subjects will be recruited to matcht the distribution of age and gender among HTRs. The will be examined at one time point only; thus, the healthy controls are not subjected to prospective follow-up.

Description

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

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Control
• Time Perspectives: Prospective

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
Heart transplant recipients; Patients receiving orthotopic heart transplant in the enrollment period
Healthy controls; Healthy control subjects, having the same age and sex distribution as the heart transplant recipients

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Oslo University Hospital
• Collaborators: South-Eastern Norway Regional Health Authority
• Investigators: Principal Investigator: Vegard B Wyller, MD,PhD, Oslo University Hospital

Publications and helpful links

General Publications

• Christensen AH, Nygaard S, Rolid K, Nytroen K, Gullestad L, Fiane A, Thaulow E, Dohlen G, Saul JP, Wyller VBB. Early Signs of Sinoatrial Reinnervation in the Transplanted Heart. Transplantation. 2021 Sep 1;105(9):2086-2096. doi: 10.1097/TP.0000000000003580.

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2013
• Primary Completion (Actual): March 1, 2016
• Study Completion (Anticipated): December 1, 2019

Study Registration Dates

• First Submitted: December 28, 2012
• First Submitted That Met QC Criteria: December 28, 2012
• First Posted (Estimate): January 3, 2013

Study Record Updates

• Last Update Posted (Actual): April 11, 2018
• Last Update Submitted That Met QC Criteria: April 10, 2018
• Last Verified: April 1, 2018

More Information

Terms related to this study

• Keywords: Cardiac allograft vasculopathy; Heart transplantation; Acute rejection; Autonomic cardiovascular control
• Other Study ID Numbers: 2012/1428