Exertional dyspnea in patients with suspected heart failure with preserved ejection fraction: are symptoms really caused by impaired left ventricular filling? * A prospective case-control study

The incidence of heart failure with preserved ejection fraction (HFPEF) has
increased over the last 15 years and accounts for almost half of the total
heart failure population. Dyspnea on exertion with corresponding exercise
intolerance is one of the key symptoms of heart failure. Despite the increasing
prevalence, the diagnosis of HFPEF is difficult and is based for a great part
on the exclusion of other causes of exertional dyspnea. A standardized
diagnostic work-up is lacking for these patients, due to ongoing uncertainty
about the pathophysiology of HFPEF and its symptoms. This may lead to a lot of
misdiagnosed patients with HFPEF. In addition, little progress has been made in
the treatment of HFPEF, which is also due to a lack of a proper
pathophysiologic basis. Additionally, misdiagnosed patients can be a reason for
therapy failure. Thus, there is great need for the characterization of the main
mechanisms in HFPEF and its symptoms to improve both diagnostic strategies and
treatment. There are clues that both backward and forward failure play a role
in the development of symptoms in HFPEF, but the relative contribution of each
is not fully understood. Moreover, the role of pulmonary hypertension (PH) as a
mechanism for dyspnea on exertion in HFPEF is currently emerging as an
additional or alternative cause, since exercise-induced PH is a common,
previously underappreciated cause of exertional dyspnea and seems to be an
early and mild form of PH. Therefore, the role of PH along with backward and
forward failure in HPFEP needs to be clarified. Susceptibility to High Altitude
Pulmonary Edema (HAPE), a frequently observed problem, has a possible
implication in the development of PH and complaints in HFPEF because it is
known to cause exercise induced elevation of pulmonary artery pressure at
normoxic conditions. Several mechanisms have been suggested in the pathogenesis
of exercise-induced abnormal pulmonary vascular response such as endothelial
dysfunction, myocardial dysfunction and sympathetic overactivity. It needs to
be determined whether and to what extent these underlying mechanisms of PH play
a role in the pathophysiology of HFPEF. The role of these factors is of utmost
importance because they would serve as the basis for potential therapeutic
targets in patients that are currently difficult to be treated. Because of the
persistent shortcomings of Doppler echocardiography for determining LV fillings
pressures, invasive investigations are still the only fully reliable way to
obtain LV filling pressures, especially during exercise. Moreover, the role of
finapres methodology for non-invasive determination of cardiac hemodynamics in
general and during exercise remains to be further evaluated.

The primary objective is to gain insight into the causative mechanisms of
exertional dyspnea in HFPEF. We hypothesize that exercise induced pulmonary
hypertension plays a significant role in the development of complaints.

The secondary objectives are: 1) to determine if any non-invasive techniques
are able to adequately replace invasive techniques for measurements of cardiac
and pulmonary hemodynamics and for examining HFPEF patients, 2) to determine
whether and to what extent suggested underlying mechanisms of PAH (i.e.
disturbances of pulmonary endothelial dysfunction, hypercoagulability connected
with endothelial injury, myocardial function, sympathetic tone) can be found in
HFPEF patients with exertional dyspnea compared to hypertensive controls and
pulmonary hypertension patients

Prospective case-controlled study with a 3:1 design.

Patiënten will undergo routine diagnostic work-up (standarad care) that
comprises physical examination, laboratory testing, ECG, echocardiography and
pulmonary function testing. For this study we perform some extra diagnostic
tests, namely Ergospirometry echocardiography and right sided heart
catheterization. A part of these tests would also be performed if patient would
not participate in this study. Which tests are performed purely for scientific
purpose differs for each group and is stated as follows:

Group 1: For an adequate clinical diagnostic work-up, all routine medical
examinations (ECG, echocardiography, pulmonary function test and laboratory
testing) performed in the present study are performed as part of the clinical
routine. When all other common causes of exertional dyspnea are excluded
according to the diagnostic algorithm, it is clinically indicated and generally
accepted to perform ergospirometry as the next step, mainly to objectify
complaints during exercise and to see whether a specific pulmonary or cardiac
limitation can be found. Therefore, the ergospirometry is clinically indicated
in this study-group, too. Right-sided heart catheterization and
echocardiography during exercise are not always performed in the clinical
work-up of these patients. However if no clinical explanation has been found
for patients exertional dyspnea more diagnostic test should be performed and
exercise-induced pulmonary hypertension should be evaluated. However this is
not yet routine clinical work-up. These tests can provide insight into the
cause of the patients* complaints and may have direct therapeutic consequences.
Therefore, patients in group 1 may benefit from participating in the present
study. Drawing of venous and arterial blood during rest and exercise will not
have direct consequences, but may be helpful for pathophysiologic
considerations.

Group 2: Patients enlisted to undergo right-sided heart catheterization for
suspected or confirmed primary pulmonary hypertension will be asked to
participate in group 3 of the study. The added burden due to participation in
this study is that they have to perform exercise during the right-sided heart
catheterization (routinely, exercise is only performed if pulmonary arterial
pressure are borderline increased) Additional investigations on behalf of the
study in these patients will be the drawing of venous and arterial blood
samples and the performance of a transthoracic echocardiography during exercise
testing. Other study-related investigations would also take place in these
patients for clinical reasons. Patients in group 3 have no direct benefit from
participating in this study

Here we will describe more detailed each diagnostic test:

Transthoracic echocardiography: Echocardiography will be performed using
standard equipment. Quantitative assessment of cardiac dimensions and left
ventricular systolic function will be performed in the 2D mode. Right
ventricular systolic function will be assessed using the tricuspid anterior
motion (TAM) and the systolic tissue Doppler velocity of the tricuspid annulus
(37). For diastolic measurements, inflow pattern of both ventricles will be
obtained using pw-Doppler echocardiography. Using Doppler tissue imaging, the
wall motion velocity patterns will be recorded in the apical 4-chamber view.
From the obtained patterns peak velocities during systole (Sm), early diastole
(Em), and late diastole (Am) will be calculated. Additionally, cw-recordings of
both outflow tracts and of tricuspid regurgitation will be obtained. Data of
the echocardiographic parameters will be stored on a digital data carrier and
interpreted after the examination by an experienced echocardiographer blinded
to the patient history and the invasively obtained measurements. The duration
of the test is 30 minutes.

Ergospirometry: Ergospriometry will be performed using standard equipment. This
test combines ergometry with spirometry and involves cycling under
electrocardiographic monitoring while breath tests are performed.
Ergospirometry will be performed on an ergometer using a three-step protocol.
Gas exchange will be assessed breath-by-breath using a commercially available
exercise system. The system will be calibrated before each test. O2 will be
analyzed by a rapidly responding zirconia fuel cell and CO2 by an infrared
analyzer. Flow measurements will be performed using a disposable
pneumotachograph. In resting position, an arterial punction will be performed
and 1.5 ml blood will be drawn. Patients will start cycling after reaching a
steady state of gas exchange for at least 1 min. In the first phase, patients
will cycle at 0,5 W/kg for 6 minutes. In the phase thereafter, resistance will
be increased to augment the workload by 0,15 W/kg body weight per minute untill
exhaustion. These two stages of workload were based on previous work. [63] The
peak work load will be determined and will serve to determine the workload
during central haemodynamics. Patient will have to perform a maximum effort.
The duration of the test is on average 45 minutes.

Central haemodynamics + ergometry: Assessment of main study parameters will be
performed using right heart catheterization. A Swan-Ganz catheter will be
inserted using the Seldinger-technique via puncture of the right cubital vein
(this access for group 2 patients mandatory) or right internal jugular vein,
respectively, under local anesthesia and advanced with the use of radioscopy.
Right atrial (RA) pressure will only be measured at rest and at the end of the
exercise test to make it unnecessary to manipulate the catheter during
exercise. Measurement of systemic arterial pressure will be performed using an
arterial catheter inserted under local anesthesia in the left radial or
brachial artery. During the test, arterial blood gas analysis will be performed
4 times by analysing 2ml of blood take from the arterial catheter. (no extra
arterial punction) Using a Swan-Ganz catheter the PAP and PWCP will be measured
. Blood is drawn using the Swan-Ganz catheter, 4 time 2ml blood will be used
for analysis. Cardiac output (Q) will be determined by measurement of oxygen
saturation in central venous and arterial blood with the use of the Fick
method. (Fick cardiac output = estimated oxygen consumption/ 10 (arteriovenous
oxygen difference); arteriovenous oxygen difference= (1.34) (Hb concentration)
(SaO2-SvO2)). Tranthoracic echocardiography will be performed. ECG and blood
pressure will be monitored continuously. Firstly, all above mentioned
measurements (hemodynamic measurements, blood gas analysis, echocardiography)
will be performed in the resting state. Then, ergometry during right-sided
heart catheterization will be performed on an ergometer with the patient in
recumbent position. Subjects will cycle at a rate of 0.5 Watt/kg during the low
workload phase and, thereafter, at 30% of maximum workload (determined at
ergospirometry), reflecting moderate exercise. All above mentioned measurements
will be performed again during these two phases of exercise. In case of early
fatigue, the final set of measurements will be done immediately prior to
exhaustion. All equipment used performing this test is also used in standard
medical care. The duration of the test is 90 minutes.

Laboratory measurements: Mixed venous and peripheral arterial blood samples
will be drawn from the tip of the Swan-Ganz catheter and from the arterial
catheter, respectively, at rest and during moderate exercise. In total 70ml
blood will be drawn during the central haemodynamics. Blood will be collected
into chilled tubes containing EDTA and aprotinin. Thereafter, plasma will be
separated immediately using a refrigerated centrifuge and stored at *80°C until
performance of the assay. All equipment used performing this test is used in
standard medical care.

Nexfin: A Nexfin monitor with hemodynamic module upgrade will be used for
non-invasive measurement of blood pressure, heart rate, cardiac output, stroke
volume, cardiac index, systemic vascular resistance and maximum first derivate
of the pressure (dP/dt). This monitor uses a single sensor fingercuff to
perform beat-to-beat measurements. This is a very user-friendly and
non-invasive tool. For an example, see the attached brochure in the appendix.

Heart rate variability: Ambulatory ECG recordings were analyzed using MARS
holter analysis system (GE Healthcare), which provides both spectral and
temporal heart rate variability measurements.
All equipment used performing this test is used in standard medical care.

All diagnostic tests performed in the present study are being used routinely in
clinical practice. Here we will discuss safety issues for the different
diagnostic modalities used.

Echocardiography: Echocardiography is a non-invasive diagnostic measure and is
not associated with any adverse reactions. It may cause some discomfort due to
the probe used, but this is usually very minor. This test is performed by a

Nexfin monitoring: Nexfin monitoring is a non-invasive diagnostic measure and
is not associated with any adverse reactions.

Arterial catheterization: Catheterization of the radial or brachial artery is a
routine procedure frequently practiced by anesthesists, in intensive care
medicine, and in the cardiac catheter laboratory. Minor side effects related to
this procedure are haematoma formation or bleeding at the puncture site which
can be counteracted by adequate compression after removal of the cannula. The
radial artery is the most common site for arterial cannulation. The most common
associated complication is temporary occlusion of the artery which generally
has no serious sequelae. Permanent occlusion of the radial artery requiring
invasive intervention or pseudoaneurysm formation, on the other hand, appear
very seldom with a mean incidence of 0.09% each reported from a series of
19'617 (ambulatory or permanent) cannulations [64]. To ensure blood circulation
of the hand in any case a normal Allen-Test showing adequate circulation
deriving from a patent ulnar artery will be a pre-requisite for performance of
the radial artery cannulation. As an alternative cannulation site the brachial
artery will be used. When applied for ambulatory purposes the brachial artery
access is also documented to have a low risk profile. In a study of 1000
patients in which the brachial artery was used for invasive monitoring in
ambulatory patients only one relevant complication was found (infected
haematoma arising from a pseudoaneurysm [65]). Another study that employed the
brachial artery for arterial blood sampling in 6185 patients also showed a
small number of complications (incidence 0.2%), mainly paresthesias [66]. Our
study group has performed approximately 4000 brachial and radial artery
punctures in the context of clinical investigations. Fortunately, no serious
side effects had to be observed so far.

Right heart catheterization: Right heart catheterisation using a Swan-Ganz
catheter is a routinely performed diagnostic procedure in patients suffering
from heart failure or in the evaluation of pulmonary hypertension. Also, the
influence of exercise on central haemodynamics is frequently assessed during
right heart catheterization. The catheter will be inserted into the right
cubital vein or right internal jugular vein. The side effect most frequently
observed with this procedure is bleeding or haematoma at the puncture side. The
risk of occurrence of a serious complication is very low. In literature, in
large series of right heart catheterizations using a Swan-Ganz catheter,
significant arrhythmias were observed in <0.3%. Life-threatening complications
occurred in <0.1% (ventricular arrhythmias, pulmonary arterial complications
[i.e. pulmonary artery embolus, rupture]) [67]. Pulmonary artery rupture, in
particular, is reported to occur at a rate of 0.031% [68]. Of note, this
complication was primarily seen in high risk patients. Among them are patients
suffering from pulmonary hypertension [69] and anticoagulated patients. As a
consequence, patients with primary pulmonary hypertension will only be included
in the study if they have a clinical indicated diagnostic and/or therapeutic
indication for performance of right heart catheterization. Patients under oral
anticoagulation will be excluded (see exclusion criteria). Considering these
safety precutions, the overall safety profile of right heart catheterization is
very good and in the range of standard exercise testing (see below).

(Spiro)ergometry: Exercise testing has an excellent overall safety record and
is a routine examination in clinical cardiology. Although ECG stress-test is
planned as part of this study, the indication for this examination may also be
appropriate for medical reasons in patients suffering from dyspnea as well as
in patients with arterial hypertension. In a non-selected population undergoing
a stress-test, the mortality is reported to be < 0.002% and morbidity < 0.01%
[70]. In patients with compensated congestive heart failure as well, exercise
testing has also been documented to be a safe procedure [71]. A spiroergometry
exhibits no additional risk to ergometry.

Combined right heart catheterization & ergometry: The combination of right
heart catheterization and simultaneous performance of an ergometry has been
reported to exhibit no additional risk to right heart catheterization at rest
[67]. The low risk of occurrence of a serious complication during exercise and
right heart catheterization can additionally be reduced by keeping the patient
closely under surveillance during the diagnostic procedure with monitoring of
the electrocardiogram, arterial blood pressure, and symptoms. During the test,
two physicians and at least one experienced study nurse will be present. The
right heart catheterization will be performed only by medical doctors who are
very experienced with right heart catheterization. This minimizes the risk of
the procedure even more. The catheter room is equipped with appropriate gear
for first aid procedure and resuscitation. Thus, in the very unlikely event of
occurrence of a serious complication, required measures can be initiated
immediately. If further medical treatment will be required due to such an
adverse event the patient will be hospitalized in the Maastricht University
Medical Centre.

Considering the time span and burden for the patient we can say that the
diagnostic tests will take 1,5 day of a patients time: 0,5 day on the 1st
test-day for the ergospirometry and echocardiography and 1 day (2nd test-day)
for the right sided heart catheterization. In between of the two test days
there will be a waiting period of at least two days with a maximum of 1 month.
In case of chance findings during the study protocol we will inform the patient
and take adequate measures concerning further diagnostics, treatment or
referral.