Myocardial function, oxygen consumption and efficiency assessment in the right ventricle of patients with idiophathic pulmonary hypertrophy using positron emission tomography.

The transition of right ventricular (RV) hypertrophy to the often-fatal right
heart failure in pulmonary hypertension (PH) is poorly understood. Based on
preclinical research with monocrotaline-injected PH rats, we have suggested
that cellular hypoxia is the probable cause of the transition to heart failure
(Des Tombe et al., 2002). A mismatch of oxygen supply and demand can develop
during hypertrophic growth, which can result in myocyte hypoxia, mitochondrial
dysfunction, ROS production, cytochrome C release, and ultimately right heart
failure (fig. 1 in protocol).
The current study. The development of hypoxia in the cell cores depends on
the oxygen demand. This is in turn dependent on the myocardial workload, and on
the cardiac efficiency: the ratio of the cardiac power (= cardiac output × mean
PAP) to the total amount of energy produced with cardiac oxygen consumption
(MVO2). The efficiency of both healthy LV and RV is ~20%. Decrease of the
cardiac efficiency is a sign of failure; and it is also an increased risk for
myocyte hypoxia. The MVO2 in the hypertrophic RV in PH is increased as a result
of an elevated myocardial workload. The MVO2 rises even more with RV failure,
partly due to increased oxidative stress, e.g. ROS production in the
cardiomyocytes. The MVO2 can be measured with PET with two methods: firstly,
11C-acetate tracer is directly cleared via the Krebs cycle . Its clearance rate
is an indirect measure for the MVO2. Secondly, with 15O-O2 gas tracer it is
possible to measure the total oxygen use during cardiac metabolism, in which a
small amount of oxygen is also used in other reactions, e.g. ROS production.
The difference between 11 C-acetate and 15O-O2 gas tracer can thus be used as a
measure of the oxidative stress, which would be a possible indication for RV
failure. A second mechanism which can be observed in the failing heart is a
shift to an increased glucose oxidation (473 kJ/mol O2), instead of oxidizing
free fatty acids (439 kJ/mol O2), which is the preferred energy substrate in
the healthy heart. Little is known about substrate alterations in the
hypertrophic and failing RV. The coronary perfusion can also influence the
cardiac oxygen supply. Our hypotheses are:
1. The RV efficiency is decreased as the RV function deteriorates in the
progression of PH; simultaneously the glucose uptake per gram tissue is
increased in the decompensated RV. In contrast, the (assumed) unaffected LV
would have a normal efficiency, while the glucose uptake per gram tissue is
less compared to the RV in PH.
2. The oxygen consumption measured with the 15O2 tracer is higher than that
measured with 11C-acetate, the difference relates to the severity of RV
failure. (assessment RV function explained on p. 9, paragraph 'Hemodynamic
Data')

The study investigates the role of the RV efficiency in the deterioration of RV
function to failure in PH (measured with stroke volume index as the parameter
of RV function); efficiency will be related to MVO2, alterations in substrate
metabolism and myocardial perfusion (reserve) of RV:
1. Measurement of the RV efficiency in patients with different stages of PH.
For calculation of the efficiency is it necessary to measure the MVO2 and the
cardiac power (obtained from CO × mPAP from right heart catheterisation).
2. Measurement of MVO2 with 11C-acetate and 15O-O2, relate the difference to RV
function.
3. Measurement of glucose uptake by the hypertrophic RV with 18FDG.
4. Measurement of the myocardial perfusion on exertion and in rest with
15O-H2O, from which the myocardial perfusion reserve (MPR, ratio of the
myocardial blood flow on exertion to that at rest) is calculated to relate with
the RV efficiency and function; the perfusion in rest will be related with MVO2
and glucose uptake (see also ch. 5.1, p. 13).
Correlation of the parameters between the RV en LV will be made.

PET scan research in order of inclusion, a single PET scan measurement
(performed in one or two days) as part of the
work-up protocol to evaluate the diseased in known iPH patients, under optimal
medicine therapy for PH.

- An extensive study protocol, which should be scanned preferably on one day.
The alternative scheme will also be offered to the patients, in which the scan
protocol - and thus the scan time and burden - is divided over two days. Any
participant can choose for the 'two-day' protocol if he/she finds the 'one-day'
protocol too extensive. Moreover, the choice for the 'one or two-day' scan will
also be based on the clinical condition of the patient. During the scanning the
patient must lie still. Mobilisation can be carried out during the two breaks
between the scans.
- Placement of one intravenous and one intra-arterial line in the arms; the
tracer injections are given through the iv-line, the blood samplings are drawn
via one of both lines. On the second day (of the two-day protocol), it is
strived to re-use the iv-entry of the first day, by the means of a 'waaknaald'
overnight.
- The total amount of blood sampling is 150ml during the entire protocol.
Patiens are excluded from this study if they have anemia. The patient will
receive extra oral fluid to compensate the blood drawn.
- Radiation dose is 9.05 mSv. This stays below the maximal radiation dose of 10
mSv, allowed to conduct biomedical research with ionized radiation on subjects,
according to the IRCP-guidelines.
- During a perfusion scan the patients perform a light exercise for 10 minutes
on the recumbent bike at 40% of their maximal workload previously acquired.