Non-invasive detection of coronary endothelial response to sequential handgrip exercise in coronary artery disease patients and healthy adults

Abstract

Objectives: Our objective is to test the hypothesis that coronary endothelial function (CorEndoFx) does not change with repeated isometric handgrip (IHG) stress in CAD patients or healthy subjects.

Background: Coronary responses to endothelial-dependent stressors are important measures of vascular risk that can change in response to environmental stimuli or pharmacologic interventions. The evaluation of the effect of an acute intervention on endothelial response is only valid if the measurement does not change significantly in the short term under normal conditions. Using 3.0 Tesla (T) MRI, we non-invasively compared two coronary artery endothelial function measurements separated by a ten minute interval in healthy subjects and patients with coronary artery disease (CAD).

Methods: Twenty healthy adult subjects and 12 CAD patients were studied on a commercial 3.0 T whole-body MR imaging system. Coronary cross-sectional area (CSA), peak diastolic coronary flow velocity (PDFV) and blood-flow were quantified before and during continuous IHG stress, an endothelial-dependent stressor. The IHG exercise with imaging was repeated after a 10 minute recovery period.

Results: In healthy adults, coronary artery CSA changes and blood-flow increases did not differ between the first and second stresses (mean % change ±SEM, first vs. second stress CSA: 14.8%±3.3% vs. 17.8%±3.6%, p = 0.24; PDFV: 27.5%±4.9% vs. 24.2%±4.5%, p = 0.54; blood-flow: 44.3%±8.3 vs. 44.8%±8.1, p = 0.84). The coronary vasoreactive responses in the CAD patients also did not differ between the first and second stresses (mean % change ±SEM, first stress vs. second stress: CSA: -6.4%±2.0% vs. -5.0%±2.4%, p = 0.22; PDFV: -4.0%±4.6% vs. -4.2%±5.3%, p = 0.83; blood-flow: -9.7%±5.1% vs. -8.7%±6.3%, p = 0.38).

Conclusion: MRI measures of CorEndoFx are unchanged during repeated isometric handgrip exercise tests in CAD patients and healthy adults. These findings demonstrate the repeatability of noninvasive 3T MRI assessment of CorEndoFx and support its use in future studies designed to determine the effects of acute interventions on coronary vasoreactivity.

Conflict of interest statement

Competing Interests: One of the authors (Michael Schär) is employed by a commercial company (Philips Healthcare). This affiliation does not alter the PLOS ONE policies on sharing data and materials, as detailed in the online guide for authors.

Figures

Figure 1. Diagram illustrating MRI study flow with measured parameters.

Hemodynamic parameters have been measured at all time-points (blood pressure and heart rate).

Figure 2. Typical anatomical and flow-velocity encoded coronary images using magnetic resonance imaging at rest and with sequential isometric handgrip stresses in a healthy subject.

In image (A), a scout scan obtained parallel to the RCA is shown together with the location for cross-sectional imaging (white line). (B) shows (white arrow) the region (corresponding to the cross-sectional location from A) that was selected for analysis at rest (B), during the first handgrip stress (C) and second handgrip stress (D). The white arrow in E shows a cross-section of the RCA that was selected for analysis of coronary flow velocity measures in the healthy volunteer. The signal intensity is proportional to flow velocity with a black signal indicating high velocity down through the imaging plane. In the view of the RCA (white arrow) at baseline (E) and during the first handgrip stress (F) and second handgrip stress (G) the change in luminal coronary signal intensity (increased blackness) indicates a proportional change in through-plane coronary flow velocity.

Figure 3. Typical anatomical and flow-velocity encoded coronary images using magnetic resonance imaging at rest and during sequential isometric handgrip stress in a CAD patient.

A scout scan obtained parallel to the left anterior descending (LAD) artery (A) is shown together with the location for cross-sectional imaging (white line). The corresponding cross-section of the LAD is shown at rest (B) and during the first (C), and second handgrip stress (D, white arrows) and indicates no significant change in coronary cross sectional area during each stress. The white arrow in E shows a velocity-encoded image of the same LAD cross section at rest, during the first handgrip (F) and second handgrip stress (G). In this case, because the direction of blood flow is being analyzed in the LAD, the change in luminal coronary signal intensity (degree of “whiteness”) indicates a proportional change in through-plane coronary flow velocity.

Figure 4. Rate pressure product (RPP, systolic blood pressure X heart rate) is shown at baseline and during isometric handgrip stress (first and second) in both healthy subjects (blue bars) and coronary artery disease patients (red bars).

* signifies p

Figure 5. Percent change in coronary endothelial vasoreactive parameters (area, velocity and flow) is shown during first and second isometric handgrip stress for both healthy subjects (blue bars) and CAD patients (red bars).

Error bars indicate standard error of the mean. In the healthy group, a normal coronary endothelial response is seen with an increase in coronary artery area, velocity and flow with stress, and no significant difference between stress 1 and stress 2 response. In the CAD group, there is an abnormal coronary endothelial response with no increase or decrease in the same three parameters with stress, and no significant difference in response between stress 1 and 2.

Figure 6. Bland-Altman plots for intra-observer and inter-observer variability.

Bland-Altman plots for intra-observer variability (A and C) and inter-observer variability (B and D) of coronary artery cross-sectional area (A and B) and peak diastolic flow velocity (C and D) measurements in CAD patients and healthy subjects. Solid lines above and below the mean represent ±2 standard deviations and the mean differences are shown. P-values are derived from Pitman’s test of differences.