A cross-sectional comparison of invasive and noninvasive aortic pulse wave velocity measurement in patients with or at risk for heart failure with preserved ejection fraction

Introduction

Aortic pulse wave velocity (aPWV) is associated with atherosclerosis and adverse cardiovascular outcomes (1-5). Most recently, various studies have evaluated the prognostic significance of aPWV in patients with heart failure with preserved ejection fraction (HFpEF). HFpEF is predominantly seen in patients with no obstructive coronary disease with a relatively higher prevalence in women (6), and HFpEF is the leading adverse cardiovascular outcome among women with signs and symptoms of ischemia and no obstructive coronary artery disease (INOCA) often related to coronary microvascular dysfunction (CMD) (7,8). The factors leading to HFpEF are poorly understood as our targets for treatment and prevention among women (9). A recent study has shown increased aPWV to be associated with progression from CMD to symptomatic heart failure via. ventricular-arterial coupling (10).

By convention, aPWV is measured invasively during cardiac catheterization (cath-aPWV) or non-invasively via carotid-femoral applanation tonometry (cf-aPWV). However, aPWV is also increasingly measured by magnetic resonance imaging (MRI). Few studies have directly compared all three approaches. To facilitate investigation linking CMD with HFpEF, we compared MRI-measured aPWV with traditional invasive or noninvasive measurements of aPWV in a cross-sectional study design. We present this article in accordance with the STROBE reporting checklist (available at https://cdt.amegroups.com/article/view/10.21037/cdt-24-137/rc).

Methods

Study population

Participants (n=118) who underwent research comprehensive MRI were evaluated using a cross-sectional design study at Cedars-Sinai Medical Center in the Women’s Ischemia Syndrome Evaluation-HFpEF (NCT02582021, October 2015-Feb 2020). The WISE-HFpEF study aimed to understand the links between CMD and HFpEF among patients with no obstructive coronary artery disease. The cohort included (I) women with suspected INOCA, and (II) individuals with chronic HFpEF. INOCA participants were enrolled prior to clinically indicated invasive coronary function testing for the diagnosis of coronary vasomotor dysfunction. HFpEF participants were recruited from the outpatient setting if they met modified European Society of Cardiology criteria (11), i.e., symptoms of heart failure, left ventricular ejection fraction ≥45%, structural evidence of cardiovascular abnormalities (evidence of abnormal filling or relaxation, left atrial enlargement, or left ventricular hypertrophy documented by echocardiogram), and evidence of elevated left ventricular filling pressure (LVEDP) or pulmonary capillary wedge pressure at rest >15 mmHg and/or with exercise ≥25 mmHg, b-type natriuretic peptide >100 pg/mL, or current use of diuretic). Exclusion criteria were atrial fibrillation at the time of imaging, significant valvular heart disease, significant chronic pulmonary disease, a known history of hypertrophic or infiltrative cardiomyopathy, or constrictive pericarditis. Obstructive coronary artery disease was ruled out in HFpEF subjects using cardiac-computed tomographic angiography (12). None of the participants in this analysis had disease of the aorta (aortic aneurysm, aortic dissection, aortic replacement). For each aPWV procedure, all vasoactive medications were withdrawn and participants were caffeine-free and nicotine free for 24 h before testing. Heart rate and blood pressure were measured and recorded throughout the study.

The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by institutional review board at Cedars-Sinai Medical Center (No. Pro00037321) and informed consent was taken from all the patients. Majority of participants completed each of the aPWV measurements if time permitted. The WISE angiographic, vascular, and MRI core labs analyzed each aPWV measurement to ensure quality control, and only measurements deemed to meet quality control standards were included in this analysis.

aPWV measurement via invasive catheterization

During invasive angiography, a pigtail catheter was pulled back from the left ventricle (LV) to the ascending aorta above the aortic valve. The catheter was flushed, and a central aortic pressure wave was recorded along with the electrocardiogram (ECG) (at paper speed 100). The catheter was then pulled back 30 cm (flushed again), and a distal (peripheral) pressure wave was recorded at the same speed. aPWV was calculated as the change in distance divided by time difference between the foot of the peripheral pressure wave form and the central pressure wave form, expressed as aPWV (m/s) = 0.3 m/(Δ t). Additional details are provided in the Appendix 1.

aPWV measurement via carotid-femoral applanation tonometry

Tonometer-derived carotid-femoral pulse wave velocity was measured using SphygmoCor XCEL (AtCor Medical, Australia), according to standard protocols. In brief, this method uses uses arterial tonometers to record pressure waveforms sequentially at both sites, referencing them to an ECG. Details provided in the Appendix 1.

aPWV measurement via MRI

MRI was performed using a 3T scanner (Siemens Healthineers, Erlangen, Germany), with ECG-gating and a phased-array receiver coil (C.P. Body Array Flex; Siemens Healthineers). Details of the MRI protocol can be found in the Appendix 1. To assess MRI-aPWV, two separate through-plane phase-contrast images were acquired: (I) at the level of the ascending aorta, and (II) ~10 cm distal, along the descending aorta. The distance between the ascending and descending images was manually determined from a sagittal image of the aortic arch. All image analyses were performed using commercially available software (CVI42 version 5.6.8; Circle Cardiovascular Imaging Inc., Calgary, AB, Canada). The distance between ascending and the distal portion of descending aorta was measured between the precise locations where the through-plane phase-contrast images were collected using an oblique sagittal image through the thoracic aorta. The aortic transit time was calculated as the average time difference between the systolic upslope of the ascending and descending aortic flow curves. aPWV was calculated as the distance between the ascending and descending aorta, divided by the transit time between the two aortic locations (Figure 1).

Figure 1 MRI-aPWV. The left panel demonstrates a sagittal oblique (candy-cane) view of the aorta; two cross-section series are acquired in the proximal (yellow line) and distal (green line) aorta. In the through-plane phase contrast MRI images on the right, the yellow circles represent the contour of the AA and PDA cross-section, while the green circle represents the contour of the DDA cross-section. AA, ascending aorta; DA, descending aorta; DDA, distal descending aorta; MRI, magnetic resonance imaging; MRI-aPWV, aortic pulse wave velocity measurement via MRI; PDA, proximal descending aorta.

Statistical analysis

Variables were summarized using means and standard deviations or counts and percentages. Agreement between three measures of aPWV was assessed in two pair-wise comparisons using a Bland-Altman type comparison (13). The mean of two measurements was compared to the difference in the two measurements and plotted, along with a plot of the two measurements against each other. Pearson correlations between the measurements were also compared. A paired t-test was used to compare the difference between two measurements to assess bias. Spearman correlations were used between the three aPWV measures and various MRI measures and invasive coronary function measures due to non-normal distributions. The study sample size was based practical considerations. All hypothesis tests used a significance level of 0.05 and two-sided tests when relevant.

Results

Baseline characteristics of the study cohort are outlined in detail in Table 1. Inclusion of participants according to the PWV method: (I) MRI through-plane phase-contrast imaging at the ascending and distal descending aorta (MRI-aPWV) (n=78); (II) invasively via catheter pullback (cath-aPWV) (n=68); and (III) carotid-femoral applanation tonometry (cf-aPWV; SphygmoCor XCEL, Atcor Medical) (n=87) is depicted in Figure 2. The aPWV measurement was missing or excluded in a subset of participants (n=40, MRI-aPWV; n=50, cath-aPWV; n=31, cf-aPWV). The mean aPWV measured via MRI was 8.48±3.21 m/s (MRI-aPWV) (n=78), 7.51±2.79 m/s via invasive catheterization (cath-aPWV) (n=68), and 8.68±1.83 m/s via applanation tonometry (cf-aPWV) (n=87).

Figure 2 Inclusion of participants according to PWV method. MRI-aPWV, aortic pulse wave velocity measurement via magnetic resonance imaging; cath-aPWV, aortic pulse wave velocity measurement invasively via catheter pullback; cf-aPWV, aortic pulse wave velocity measurement via carotid-femoral applanation tonometry; PWV, pulse wave velocity.

Agreement between different measures of aPWV

The aPWV measured from three sources (MRI, invasive catheterization, and applanation tonometry) was studied using Bland-Altman plots. Of 118 participants, 48 had all of the three measurements, while 53 subjects had both invasive and MRI measurements. Agreement between two measurement sources with one plot of the measurements against each other and a Bland-Altman plot (13) of the difference vs. the mean of the two measurements is presented in Figures 3,4.

Figure 3 Agreement between MRI-aPWV and cath-aPWV. The left panel represents the plot of measurements against each other, in which the blue line is the line of perfect agreement where the two measurements are equal, and the red line is a linear regression estimate of the two variables. The right panel represents the Bland-Altman plot of the difference vs. the mean of the two measurements. The blue line at zero is the line of perfect agreement, where the difference is zero. The solid black line is the average of the differences observed, or the average bias. The dotted black lines show a confidence interval for the average bias. The dashed lines are the limits of agreement, which is the bias ±1.96 standard deviations of the difference. MRI-aPWV, aortic pulse wave velocity measurement via magnetic resonance imaging; cath-aPWV, aortic pulse wave velocity measurement invasively via catheter pullback.

Figure 4 Agreement between MRI-aPWV and cf-aPWV. The left panel represents the plot of measurements against each other, in which the blue line is the line of perfect agreement where the two measurements are equal, and the red line is a linear regression estimate of the two variables. The right panel represents the Bland-Altman plot of the difference vs. the mean of the two measurements. The blue line at zero is the line of perfect agreement, where the difference is zero. The solid black line is the average of the differences observed, or the average bias. The dotted black lines show a confidence interval for the average bias. The dashed lines are the limits of agreement, which is the bias ±1.96 standard deviations of the difference. MRI-aPWV, aortic pulse wave velocity measurement via magnetic resonance imaging; cf-aPWV, aortic pulse wave velocity measurement via carotid-femoral applanation tonometry.

MRI-aPWV vs. cath-aPWV

The Pearson correlation between the measures is estimated to be 0.52 [95% confidence interval (CI): 0.29–0.69, P<0.001]. The linear regression has an intercept at 3.52 and a slope of 0.46. The mean difference was −0.74 with a standard deviation (SD) of 2.78 (Figure 3).

MRI-aPWV vs. cf-aPWV

The Pearson correlation between the measurements was estimated to be r=0.74 (95% CI: 0.61–0.83, P<0.001). The regression intercept was 4.93 and the slope was 0.44. The mean difference was −0.18 with an SD of 2.14 (Figure 4).

Discussion

To our knowledge, this is the first study to compare MRI with traditional invasive and non-invasive measurements of aPWV. We found that MRI-aPWV strongly correlated with measurements made with applanation tonometry and showed a modest correlation with invasive measurements during cardiac catheterization.

aPWV is a marker of arterial stiffness and an independent predictor of coronary heart disease, stroke and cardiovascular mortality (1,4,5). Studies have shown that there is ventricular-arterial independence with increased stiffness, which causes LV strain and can lead to diastolic dysfunction (14,15). Our recent work demonstrates that HFpEF is associated with greater arterial stiffness and lower myocardial perfusion reserve, suggesting that arterial stiffness may contribute to the progression to HFpEF in INOCA patients (16). Thus, reliable methods for measuring aPWV have clinical implications for improving risk prediction. Invasive assessment of aPWV is limited to patients undergoing invasive angiography for other reasons. On the other hand, noninvasive measurement via applanation tonometry, which is easily applied without expensive noninvasive testing, is not without its flaws; it does not take into account the tortuosity of the aorta and can also lead to false assessments due to inaccurate femoral pulse measurements (17,18). Moreover, the viscoelastic property of the proximal aorta dampens the pulsatile flow after LV ejection which cannot be assessed by cf-aPWV due to its inability to assess velocity in the aortic arch (19). The distance measurement used in cf-aPWV is also not standardized and can cause errors of up to 30% for PWV measurement (20).

MRI provides additional detail by directly estimating central aortic stiffness in the proximal and distal aorta, with ability to sample at various points along the aorta (20). MRI-aPWV of the proximal ascending to distal descending aorta was previously shown to have good agreement with cath-aPWV in a small study of 18 patients (83% male) (21). Our study showed similar correlation between MRI-aPWV and cath-aPWV in a larger cohort consisting of women, thus this technique is now valid in both sexes. Our study also shows that MRI correlates well with tonometry measurement of aPWV velocity, a predictor of CVD events beyond conventional risk factors (5). Reliable MRI measurement of arterial stiffness using commercial software allows this method to enter clinical practice. Combining MRI-aPWV with MRI measures of ventricular remodeling, fibrosis, scar and perfusion may offer a single noninvasive modality for providing pathophysiology insights and treatment targets for treatment and prevention of HFpEF (9).

Limitations of our study include the generalizability of the results, as the measurements were performed in majority of women, middle-aged, and only in patients with no obstructive coronary artery disease. In addition, not all participants completed all three aPWV measurements, due to time restraints or quality of measurement. We found that MRI-aPWV only modestly correlated with conventional invasive measurements made during cardiac catheterization. This may be influenced by differences in sedation between visits (present during catheterization but not MRI) and/or length of time between measurements, as the invasive and noninvasive measurements were made on different days. Our study adds to the growing body of research using various MRI measurements to understand the mechanistic of HFpEF.

Conclusions

MRI measurement of aPWV showed good agreement with traditional invasive and noninvasive measurements in a predominantly female cohort with or at risk for HFpEF. Reliable measurement of arterial stiffness combined with cardiac MRI measures of ventricular remodeling, fibrosis, scar and perfusion may offer pathophysiology insights and treatment targets for treatment and prevention of HFpEF.

Acknowledgments

We would like to acknowledge Behzad Sharif, PhD, Bruce Samuels, MD, Babak Azarbal MD, Edward Gill, Denise Barajas, Taylor Heryford, Jenna Maughan, Rohan Paul, Gabriel Pazooky, Timothy Wynter, Sandy Young, and Warren Youseffian, for their contributions to this study.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://cdt.amegroups.com/article/view/10.21037/cdt-24-137/rc

Data Sharing Statement: Available at https://cdt.amegroups.com/article/view/10.21037/cdt-24-137/dss

Peer Review File: Available at https://cdt.amegroups.com/article/view/10.21037/cdt-24-137/prf

Funding: This work was supported by the National Heart, Lung, and Blood Institutes [Nos. K23 HL125941 (to J.W.), K23 HL127262 (to CS), R01 HL146158 (to N.B.M., M.D.N., J.W.), R01 HL153500 (to M.D.N., J.W.), U54 AG065141 (to N.B.M., M.D.N.)]; General Clinical Research Center grant MO1-RR00425 from the National Center for Research Resources; the Edythe L. Broad and the Constance Austin Women’s Heart Research Fellowships, Cedars-Sinai Medical Center, Los Angeles, CA; the Barbra Streisand Women’s Cardiovascular Research and Education Program, Cedars-Sinai Medical Center, Los Angeles, CA; The Society for Women’s Health Research, Washington, D.C.; the Linda Joy Pollin Women’s Heart Health Program; the Erika Glazer Women’s Heart Health Project; and the Adelson Family Foundation, Cedars-Sinai Medical Center, Los Angeles, CA.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://cdt.amegroups.com/article/view/10.21037/cdt-24-137/coif). D.S.B. has served as a consultant for GE Healthcare. C.N.B.M. serves as Board of Director for iRhythm, and reports consulting fees paid through CSMC from Abbott Diagnostics and Sanofi. J.W. has served on an advisory board for Abbott Vascular, fees paid to institution. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by institutional review board at Cedars-Sinai Medical Center (No. Pro00037321) and informed consent was taken from all the patients.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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