Pulmonary hypertension (PH) is an important prognostic indicator in patients with
chronic obstructive pulmonary disease (COPD); however, PH in these patients is typically
mild-to-moderate severity and invasive testing is not typically utilized.1 Though
echocardiography can be used to screen for PH, it has limited accuracy in measuring
pulmonary artery (PA) pressure and often hindered by window limitations in COPD patients.2
Cardiovascular magnetic resonance (CMR) does not have window limitations and can accurately
evaluate the right ventricular (RV) and PA function. Therefore, there is a growing
interest in the use of CMR for the diagnosis and management of PH, including patients
with lung diseases. Recently, we have validated a novel non-invasive CMR-derived parameter
that, similar to impedance, reflects pulsatile and resistive properties of the PA.3
This approach relies on the principle that compliant PA vessel walls cause changes
in the velocity profile as it travels through the PA over the cardiac cycle. The frequency-dependent
relationship between the input and output velocity profiles is described by a velocity
transfer function (VTF), which is the relationship between the frequency spectra of
input and output velocity.3 In suspected PH patients who underwent right heart catheterization,
we found that VTF correlates with invasive PA impedance and the mean high-frequency
modulus (MHFM) of VTF correlates with the pulmonary vascular resistance (PVR) and
RV remodeling.3 Moreover, MHFM >1 accurately predicted an increased PVR.3 We hypothesized
that elevated MHFM of VTF, reflecting increased PVR and pulmonary vascular disease,
would be associated with reduced exercise capacity measured by 6-mins walk distance
(6MWD) in a COPD cohort.
Materials And Methods
We prospectively recruited participants with COPD and mild-to-moderate airflow obstruction
based on Global Initiative for Chronic Obstructive Lung Disease (GOLD) spirometric
staging.4 Participants were excluded if they had known cardiac or pulmonary vascular
disease. This study was approved by the University of Alabama at Birmingham Institutional
Review Board and all participants gave written informed consent (IRB#110809004). Participants
completed clinical evaluation,4 post-bronchodilator spirometry with measurement of
percent predicted forced expiratory volume in 1-second (FEV1%),5 quantitative emphysema
as measured by chest computed tomography (CT),6 6-mins walk test,7 and CMR study.
The 6-mins walk test was performed as a part of clinical care, prior to the CMR, and
was conducted one time according to ATS standards7 on room air without stops for a
rest. All participants completed the 6-mins walk test. CMR was performed using a 1.5-T
magnetic resonance scanner (GE Signa, Milwaukee, Wisconsin) optimized for cardiac
applications. Phase-contrast CMR technique (ECG gated breath-hold fast gradient echo
(FGRE) sequence) was used for flow measurements in the right PA (RPA) (Figure 1A).
Typical parameters were as follows: field of view, 40 cm; scan matrix, 256x128; encoding
velocity, 150 cm/s; number of excitations, 1; flip angle, 15°; repetition/echo times,
7.8/3.2 ms; band width, ±31.25 kHz; 8 views per segment. Thirty-two phases were reconstructed.
Contours were drawn and mean velocity-time profiles over a cardiac cycle were computed
using CAAS MR Flow 1.2 (Pie Medical Imaging, the Netherlands) and exported to MATLAB
2015a for VTF and MHFM of VTF calculation as previously described (Figure 1B and C).3
Cine CMR (ECG gated breath-hold balanced steady-state fast processing (bSSFP) sequence)
was used for measurements of RV and left ventricular (LV) structure and function using
endocardial and epicardial contours manually traced on short-axis cine images acquired
near end-diastole and end-systole as previously described.3 CMR measurements were
blinded to the 6-mins walk test, clinical evaluation, spirometry, and CT measurements.
Participants were categorized into MHFM>1 and MHFM<1 groups. Clinical, cardiopulmonary
functional indices, LV and RV function was compared between MHFM groups using Mann–Whitney-U
test. The strength of association between MHFM of VTF and 6MWD was studied using Spearman’s
rank correlation coefficient (ρ). Linear regression models adjusted for FEV1% were
used to measure associations between 6MWD and elevated MHFM (MHFM >1). All analyses
were performed in SPSS v.23 and P<0.05 indicated statistical significance.
MHFM of VTF in COPD.
Notes: (A) Representative MAG and PC images from the proximal (red contour) and distal
(green contour) portions of the RPA. (B) Representative mean velocity profiles over
the cardiac cycle measured in the proximal (red trace) and distal (green trace) portions
of the RPA. (C) Representative examples of Fourier transform magnitudes and VTF in
subjects with high (>1) and low (<1) MHFM (average modulus for harmonics 5–7).
Abbreviations: MHFM, mean high-frequency modulus; VTF, velocity transfer function;
MAG, magnitude; PC, phase-contrast; RPA, right pulmonary artery.
The 21 patients recruited were 60±9 (mean ± standard deviation) years old, 62% male,
with an FEV1% of 61±27% and LV ejection fraction of 62±8%. Twelve participants had
MHFM<1 (median 0.85 [interquartile range (IQR) 0.75–0.90]) and nine participants had
MHFM>1 (1.23 [IQR 1.10–1.67]). In MHFM>1 group, RV ejection fraction (51% [IQR 47–64%]),
end diastolic volume index (50 [IQR 45–68] mL/m2), and stroke volume (33 [IQR 23–38]
mL/m2) were similar to that in MFHM<1 group (57% [IQR 54–61%] (P=0.70), 59 [IQR 56–67]
mL/m2 (P=0.25), and 34 [IQR 32–36] mL/m2 (P=0.76), respectively). LV ejection fraction,
LV volumes, and cardiac index were also similar between MHFM groups (P>0.1). The MHFM>1
group had a larger RV mass/volume ratio and RV/LV mass ratio (Figure 2A–C). There
were no between-group differences in LV mass index and LV mass to volume ratio (P>0.1).
Cardiac and pulmonary measurements in COPD with high (>1) and low (<1) MHFM of VTF.
Notes: High and low MHFM groups had different RVM/V (A), RVM/LVM (B); but did not
differ by RVMI (C), FEV1 PP (D), or emphysema (E). However, 6MWD was lower in the
high MHFM group (F).
Abbreviations: MHFM, mean high-frequency modulus; VTF, velocity transfer function;
RVM/V, right ventricular mass to volume ratio; RVM/LVM, ratio of right and left ventricular
mass; RVMI, right ventricular mass index; FEV1 PP, percent predicted forced expiratory
volume in 1-second; 6MWD, 6-mins walk distance.
MHFM>1 group had numerically worse clinical symptoms (though not reaching statistical
significance) assessed by modified Medical Research Council (mMRC) Dyspnea Scale (3
[IQR 2–3] vs. 2 [IQR 0–3] in MHFM<1 group, P=0.25) and severity of airflow limitation
by Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria for GOLD
stage (3 [IQR 2–3] vs 1.5 [IQR 0.5–3] in MHFM<1 group, P=0.28). FEV1% was not statistically
different in the MHFM>1 versus MHFM<1 group (P=0.26, Figure 2D). There were no between-group
differences in quantitative emphysema (Figure 2E). In the entire cohort, results of
the 6-mins walk test were markedly worse than expected for healthy population,7 with
6MWD of 337 [IQR 296–385] meters. There was a significant inverse correlation between
6MWD and MHFM of VTF (Spearman’s ρ= −0.56, P=0.009). The MHFM>1 group had shorter
6MWD (293 [IQR 268–329] meters vs. 361 [IQR 343–402] meters in MHFM<1 group, P=0.0012)
(Figure 2F). In a linear regression model adjusting for FEV1%, MHFM>1 accounted for
a −60.7±16.7 meter shorter 6MWD (P=0.002).
Data from our pilot study show that measuring the MHFM of VTF may have utility in
assessing pulmonary vascular disease in COPD. Our findings suggest that MHFM of VTF
>1 is associated with signs of RV remodeling as well as impaired exercise tolerance
as measured by 6MWD in COPD. These observed differences occurred in the absence of
differences in LV structure or function, percent of emphysema or FEV1%. Importantly,
we found that the association between MHFM>1 and reduced 6MWD was independent from
FEV1%, suggesting that it has additional value beyond lung function in identifying
impaired exercise function in COPD. Together, MHFM>1 and FEV1% accounted for 53.5%
of the variability in 6MWD. Our study was limited by the small sample size and the
lack of invasive hemodynamic assessments, though it mirrored usual clinical care of
these patients with COPD, since they usually do not undergo right-sided heart catheterization
due to the lack of therapeutic options specific for this population. Our findings
should be validated in larger COPD cohorts.
In this proof of concept study, we excluded patients with severe COPD as we were interested
in whether VTF could be used as a tool to identify the pulmonary vascular abnormalities
in the absence of severe parenchymal destruction and chronic hypoxia. The investigation
of VTF utility in more advanced lung disease is therefore needed. In our study, VTF
was measured only under resting conditions, yet the measurement of VTF with exercise
may provide additional diagnostic power, and thus should be evaluated in future studies.
Because we measured VTF in the RPA, any heterogeneity in vessel impedance and stiffness
in the pulmonary vasculature could be missed by this technique. Further research is
needed to utilize VTF in the main PA and left PA for assessment of heterogeneity in
In conclusion, measurement of the mean high-frequency modulus (MHFM) of the VTF, a
non-invasive marker of PVR, is associated with impairments in exercise capacity and
RV remodeling in a cohort of mild-to-moderate COPD. Therefore, VTF could be a valuable
tool for characterizing pulmonary vascular disease among COPD patients. However, further
research is required for accurate evaluation of the VTF application in COPD.