Echocardiographic Assessment of Pulmonary Transit Time Following Exercise
Phase: PHASE4
Conditions: Heart Failure, Diastolic
Sponsor: Vanderbilt University Medical Center

Protocol Version #: 2 
 
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Protocol Date:  April 2020 
 
 
 
 
 
 
 
 
Echocardiographic assessment of pulmonary 
transit time following exercise 
 
Ken Monahan, M.D. 
Vanderbilt Heart and Vascular Institute 
April 2020 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Protocol Version #: 2 
 
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Protocol Date:  April 2020 
Table of Contents: 
 
Study Schema 
1.0 
Background 
2.0 
Rationale and Specific Aims 
3.0 
Animal Studies and Previous Human Studies 
4.0 
Inclusion/Exclusion Criteria 
5.0 
Enrollment/Randomization 
6.0 
Study Procedures 
7.0 
Risks of Investigational Agents/Devices (side effects) 
8.0 
Reporting of Adverse Events or Unanticipated Problems involving Risk 
to Participants or Others 
9.0 
Study Withdrawal/Discontinuation 
10.0 Statistical Considerations 
11.0 Privacy/Confidentiality Issues 
12.0 Follow-up and Record Retention 
 

Protocol Version #: 2 
 
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Protocol Date:  April 2020 
1.0 
Background 
 
The prevalence of heart failure with preserved ejection fraction (HFpEF) is comparable 
to that of heart failure with reduced ejection fraction (HFrEF), carries a similarly grim 
prognosis [1], and there are no effective disease-modifying medical therapies [2-5].  A 
common and diagnostic characteristic of HFpEF is dyspnea in response to physiologic 
stress, such as exercise, that can correlate with increased left-sided filling pressure as 
measured by invasive hemodynamics [6-7].  While definitive, this modality is not 
practical to apply widely in clinical practice and remains challenging to pursue even for 
research studies that aim to evaluate underlying physiologic mechanisms and responses 
to treatment.  Therefore, a non-invasive approach to estimating left-sided filling 
pressure post-exercise would be helpful in this regard.  Standard tissue Doppler imaging 
on echocardiography (i.e. E/e’), which can be helpful at rest to estimate pulmonary 
arterial wedge pressure (PAWP) [8], may be less accurate due to fusion of E and A 
waves at the higher heart rates expected post-exercise. 
 
Prior work using echocardiographic contrast to derive pulmonary transit time (PTT) has 
suggested that a related metric, pulmonary blood volume (PBV), correlates with PAWP 
at rest [9-12; IRB #110362, #131075, #131355].  The current study proposes to 
measure PTT and PBV post-exercise.  Demonstration of technical plausibility of this 
approach would justify future studies to compare directly echocardiographically-derived 
PBV and invasive exercise hemodynamics post-exercise.  If PBV were shown to be a 
reasonable surrogate for PAWP with exercise, the capability to study the defining feature 
of HFpEF could be expanded to a non-invasive technique.  
 
2.0 
Rationale and Specific Aims 
 
While PTT in patients at rest has been successfully measured via contrast-
echocardiography, whether post-exercise data can be reliably obtained and analyzed is 
unclear.  Therefore, we propose to conduct a feasibility study to achieve the following 
aims: 
 
1. Record the flow of ultrasound contrast across the pulmonary circulation after a 
standardized exercise protocol 
2. Compare PTT and PBV pre- and post-exercise in the same cohort 
3. Compare the time from contrast administration to appearance in the right-heart 
pre- and post-exercise (i.e. vein-to-heart time) 
4. Compare PTT obtained by analysis of time-intensity curves to the PTT estimate 
obtained by visual assessment 
 
3.0 
Animal Studies and Previous Human Studies 
 
As above, prior studies have used essentially the same methodology to obtain PTT.  The 
main difference in the proposed study is the addition of post-exercise acquisition of PTT.  
Ultrasound contrast is commercially available and is widely used in Echocardiography 
Laboratories worldwide, including at VUMC. 
 
4.0 
Inclusion/Exclusion Criteria 

Protocol Version #: 2 
 
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Protocol Date:  April 2020 
 
To be eligible for enrollment, patients must meet all the following criteria: 
 
Inclusion Criteria: 
 
1. Age ≥ 18 years old  
2. Able to give informed consent 
 
To be eligible for enrollment, patients cannot meet any of the following criteria: 
 
Exclusion criteria: 
 
1. Known allergic reaction to Definity or Optison ultrasound contrast 
2. Pregnancy/Nursing – as assessed/disclosed by the participant 
3. Any faculty/staff whose performance will be directly and formally evaluated by 
the investigator or sub-investigators 
 
5.0 
Enrollment/Randomization 
 
As this study is limited in size and aims to evaluate PTT post-exercise, we will 
concentrate enrollment efforts towards a focused group of prospective participants with 
(self-reported) adequate exercise capacity.  Namely, the focus will be on individuals that 
attend conferences/meetings given by the Division of Cardiovascular Medicine who 
report engaging in relatively regular exercise (i.e. some form of aerobic exercise at least 
twice per month).  This group includes faculty, sonographers, administrators, support 
staff, and occasional guests from other departments (particularly for inter-disciplinary 
conferences).  Within this pool of potential candidates, there is sufficient demographic 
diversity to be permit inclusion of individuals across a range of age, gender, and 
ethnicity.  Cardiology fellows and NPs are not eligible to avoid the appearance of undue 
influence to participate. 
 
Invitations to participate in the study will be made to those in attendance at divisional 
conferences (i.e. Faculty Meeting, Echocardiography conference) and will not target 
specific individuals within the above groups.  Interested individuals will contact KSP, who 
will then help facilitate the study visit at the CRC. 
 
6.0 
Study Procedures 
 
All study procedures will take place over a single day during a single visit to the CRC.  
Participants will experience the following: 
 
1. Baseline demographics and anthropomorphic measurements.  Basic 
information on age, gender, and self-identified ethnicity will be collected along 
with height and weight. 
2. Pre-exercise echocardiographic evaluation.  This assessment will be 
performed by the CRC sonographer and will include heart rate, LVOT diameter, 
LVOT VTI, mitral valve inflow, mitral valve tissue Doppler imaging, IVC 
size/respirophasic changes in caliber, and a recording of the apical 4-chamber 

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view (the view in which contrast flow will be recorded) to ensure adequate 
visualization. 
3. Pre-exercise PTT measurement.  Following placement of a standard 
peripheral IV by a CRC nurse, ultrasound contrast will be administered and the 
pathway of the contrast from entry into the right-heart through appearance in 
the left-heart will be recorded in order to obtain the data necessary to measure 
PTT.  The interval between the beginning of the contrast injection and the 
appearance in the right-heart will be recorded.  The IV line will then be flushed 
with saline to remove any residual contrast.  After the acquisition of these data, 
the ‘FLASH’ feature of the ultrasound machine will be employed to rapidly 
remove the remaining contrast from the field of view such that there is minimal, 
if any, residual contrast when it is time for administration of contrast post-
exercise. 
4. Exercise protocol.  Participants will exercise on a treadmill (provided by the 
Metabolic Core) following a Standard Bruce Protocol until their heart rate reaches 
~ 2.5-times their baseline level or until they reach maximum effort.  Exercise 
capacity, blood pressure, and heart rate will be recorded at standard intervals 
throughout exercise.  If it proves to be more logistically favorable, an exercise 
bicycle (also supplied by the Metabolic Core) can be used rather than a treadmill.  
5. Post-exercise PTT measurement.  This administration of contrast will be 
similar to the pre-exercise PTT measurement and will occur as soon as an 
adequate echocardiographic image can be obtained following exercise.  Heart 
rate will also be recorded during this step.  Mitral valve inflow, mitral valve tissue 
Doppler imaging, and IVC size/respirophasic changes in caliber will be re-
assessed as well.   
6. Contingencies for additional contrast administration.  Should there be 
unforeseen technical issues with contrast administration or image acquisition at 
pre- or post-exercise, additional doses of contrast can be given as permitted by 
the remaining volume in the vial (typically, 1-2 mL of contrast are used per 
injection and a single vial yields 8-10 mL of contrast). 
 
7.0 
Risks 
 
The key study procedures that could incur risk include placement of a peripheral IV, 
administration of echocardiographic contrast, and treadmill/stationary bicycle exercise. 
 
The risks associated with peripheral IV placement include damage to the vein, 
inadvertent arterial puncture, infection, and infiltration into the underlying skin.  In 
general, and in this setting in particular (i.e. non-acutely ill individuals having an IV 
placed by an experienced nurse), complications of peripheral IV placement are rare. 
 
The safety record of Definity and Optison ultrasound contrast, the two agents approved 
for clinical use in the United States, is long-established and has been presented in prior 
protocols cited above.  In summary, studies reporting on hundreds of thousands of 
administered doses have shown extremely low adverse event rates. 
 
Specifically, with Definity, serious cardiopulmonary reactions (including fatalities) have 
occurred during or following administration; most serious reactions occur within 30 

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Protocol Date:  April 2020 
minutes of administration.  These include:  Cardiovascular: Flushing (1%) Central 
nervous system: Headache (2%) Gastrointestinal: Nausea (1%) Neuromuscular & 
skeletal: Back pain (1%) Renal: Renal pain (1%). 
 
Specifically, with Optison, serious cardiopulmonary reactions (some fatal) have occurred 
uncommonly during or within 30 minutes following administration. Serious anaphylactoid 
reaction. Cardiovascular: Flushing (4%), chest pain (1%) Central nervous system: 
Headache (5%), dizziness (3%), chills (≤1%), fatigue (≤1%), malaise (≤1%) 
Gastrointestinal: Nausea (≤4%), vomiting (≤4%), dysgeusia (2%) Local: Discomfort at 
injection site (1%) Neuromuscular & skeletal: Weakness (≤1%) Respiratory: Dyspnea 
(1%), flu-like symptoms (1%) Miscellaneous: Fever (≤1%). 
 
The risks associated with exercise on the treadmill (Standard Bruce Protocol) or exercise 
bicycle include mechanical injury (from loss of balance or equipment failure), 
muscle/joint pain, orthopedic injury, and unanticipated cardiac events (i.e. triggering of 
acute coronary syndrome or arrhythmias).  In the population targeted for this study, 
these risks are anticipated to be small. 
 
8.0 
Reporting of Adverse Events or Unanticipated Problems involving Risk 
to Participants or Others 
 
Adverse events determined to be related to the study will be reported to the VUMC IRB 
by either the PI or KSP as required by VHRPP policy III.L within 7 calendar days of the 
PI's knowledge of the problem. 
 
9.0 
Study Withdrawal/Discontinuation 
 
Patients who wish to be withdrawn from the study for any reason will notify the PI or 
other study personnel.  Patient data that have not been used or analyzed prior to this 
notification will be deleted from the REDCap database. 
 
10.0 Statistical Considerations 
 
As there are no current data on (or estimates of) the differences in PTT between rest 
and exercise, there is no formal power calculation to determine sample size.  We will 
aim for a cohort of 15 participants, realizing that there may be a ‘learning curve’ that 
could render data from the initial participants unable to be used in quantitative analyses.   
 
The primary analysis will consist of an intra-individual comparison of pre- and post-
exercise PTT and PBV.  As these will be paired observations that will likely not be 
normally distributed, the Wilcoxon matched-pairs signed rank test will be used for this 
evaluation.  Similar methodology will be used to analyze the vein-to-heart times pre- 
and post-exercise.  Bland-Altman analysis will be used to compare PTT obtained by two 
different techniques (intensity-time curves and visual assessment). 
 
11.0 Privacy/Confidentiality Issues 

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Protocol Date:  April 2020 
Participant privacy and confidentiality will be protected by the usual practices of the 
VUMC CRC.  The confidentiality of participant data will be protected by maintaining a 
single master list linking Study ID (from the REDCap database) with Medical Record 
Number, which will be stored in the REDCap file repository.  Any documents or 
electronic datasheets with identifying information will also be stored in the REDCap file 
repository.  Only the PI and key study personnel will have access to the REDCap 
database.  Given that the participants are likely to be colleagues of study personnel, 
study personnel will not access participants’ charts in the electronic medical record for 
the purposes of this study except to document participation and consent, as required 
(i.e. an ‘on-study’ note). 
12.0 Follow-up and Record Retention 
Data derived from this study will be kept in a REDCap database.  The data will be kept 
for a minimum of six years and, potentially, indefinitely, particularly if follow-up studies 
are pursued. 

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Protocol Date:  April 2020 
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