The Influence of Right Atrial Pressure on Fractional Flow Reserve

To the Editor:

In 1977, it was proposed that the functional severity of a stenotic lesion could be assessed by its effect on maximal flow rather than on resting flow.¹ Distal coronary pressures (P_d) were measured before and after a stenosis was dilated.² However, the correlation of resting pressure gradients with outcome was disappointing and this technique was abandoned. About a decade later, fractional flow reserve (FFR) was defined as the maximal achievable flow in the artery in the presence of a stenosis divided by maximum flow expected in the same artery without that stenosis.³

The formula for pressure-derived FFR, ie, FFR = (P_d – P_ra)/(P_a – P_ra), where P_a is aortic pressure and P_ra is right atrial pressure, is often abbreviated as FFR ≈ P_d/P_a since P_ra is assumed to be 0 mm Hg. In the first trial of an FFR-guided strategy, percutaneous coronary intervention (PCI) was deferred in one of the groups, which then came to be known as the DEFER study, a threshold FFR of 0.75 for intervening on an intermediate lesion was established.⁴ In a small study based on this threshold, 14% of all lesions were misclassified as insignificant and the sensitivity of FFR decreased to 64% if P_ra was ignored and specificity declined if higher values of Pra were assumed.⁵ However, Pra was not measured in either the DEFER study or in the subsequent Fractional Flow Reserve versus Angiography for Guiding PCI in Patients with Multivessel Coronary Artery Disease (FAME) study, which evaluated a threshold FFR of 0.80.⁶ Thus, this mathematical analysis of the effect of P_ra on FFR was conducted to simulate scenarios where P_ra measurement may be necessary.

P_d and P_a values between 50 and 140 mm Hg and P_ra values of 0, 5, 10, and 15 mm Hg were cross-tabulated. The actual FFR was computed as (P_d – P_ra)/(P_a – P_ra) and the estimated FFR was computed as Pd/Pa. JMP 9.0 (SAS Institute Inc) was used for data analysis.

A total of 17,012 combinations of actual and estimated FFRs were calculated for various values of P_ra and stratified according to Pa (50 ≤ P_a <80; 80 ≤ P_a < 110; and 110 ≤ P_a ≤ 140; Figures 1A, 1B, and 1C). Using P_ra of 15 mm Hg as an upper limit, the cut-off FFRs for mean 50 ≤ P_a < 80 mm Hg is 0.850, 80 ≤ P_a < 110 mm Hg is 0.838, and 110 ≤ P_a ≤ 140 mm Hg is 0.827. If the estimated FFRs are higher than these cut-off values, there is no incremental value of measuring P_ra as the actual FFRs will not be ≤0.80 provided that P_ra does not exceed 15 mm Hg. Using a FFR threshold of ≤0.80 for PCI, 489 combinations (2.87%) would have resulted in inappropriately high estimated FFRs if P_ra was not considered.

The principal findings of this analysis are: (1) an estimated FFR of 0.80 or less does not necessitate P_ra measurement; and (2) the effect of P_ra on FFR is less in hypertensive patients.

Using an FFR of 0.80 or less as a threshold value may affect choice of treatment strategy depending on P_ra value. A prior study implied that P_ra needs to be measured even when FFR was between 0.70-0.80 (0.75 was used as the threshold value in that study).⁵ This analysis indicates that the usage of the P_d/P_a estimation can only over-estimate the actual FFR. With progressive decrease in P_a, the effect of the same P_ra on actual FFR increases since we are subtracting the same P_ra from a lower Pa and an even lower Pd. Pra values higher than 15 mm Hg are unusual in the absence of previously known severe cardiopulmonary disease and are less commonly encountered in general interventional cardiology practice and thus, these were not modeled. In addition, the validity and clinical utility of FFR in the presence of heart failure (which may be associated with higher P_ra values) remains untested.

Routine measurement of P_ra during PCI is not currently performed at most centers. In patients with typical anginal symptoms and an intermediate lesion with an FFR of >0.80, P_ra measurement and FFR re-calculation may be considered. In this context, the usage of an absolute threshold FFR value is becoming increasingly common. Although the FAME study evaluated 0.80 as a threshold value for an ischemia-inducing lesion, it was not designed to evaluate whether 0.79 or 0.81 would be better. An FFR of <0.75 is clearly ischemic and an FFR >0.80 is clearly non-ischemic, but a “grey zone” clearly exists between these values. In FAME, the threshold value was extended to 0.80 to ensure that all functionally “significant” lesions were treated. Some of the cases where P_ra measurement would have made a difference were accounted for by raising the threshold. In our analysis, only 2 scenarios (0.012%) remain where an estimated FFR of >0.80 corrects to <0.75 after P_ra measurement.

The 2011 ACCF/AHA/SCAI Guidelines for Percutaneous Coronary Intervention have defined coronary stenoses with an FFR of ≤0.80 as “significant.”⁷ It must be noted that this level of precision for using FFR to guide clinical decision-making is not supported by the literature at present and therefore, the addition of P_ra measurement may improve accuracy of FFR, but its effect on meaningful clinical outcomes in large populations needs to be tested.

References

1. Young DF, Cholvin NR, Kirkeeide RL, Roth AC. Hemodynamics of arterial stenoses at elevated flow rates. Circ Res. 1977;41(1):99-107.
2. Anderson HV, Roubin GS, Leimgruber PP, et al. Measurement of transstenotic pressure gradient during percutaneous transluminal coronary angioplasty. Circulation. 1986;73(6):1223-1230.
3. Pijls NHJ, van Son JA, Kirkeeide RL, de Bruyne B, Gould KL. Experimental basis of determining maximum coronary, myocardial, and collateral blood flow by pressure measurements for assessing functional stenosis severity before an after percutaneous transluminal coronary angioplasty. Circulation. 1993;87(4):1354-1367.
4. Bech GJ, De Bruyne B, Pijls NH, et al. Fractional flow reserve to determine the appropriateness of angioplasty in moderate coronary stenosis: a randomized trial. Circulation. 2001;103(24):2928-2934. 
5. Perera D, Biggart S, Postema P, et al. Right atrial pressure: can it be ignored when calculating fractional flow reserve and collateral flow index? J Am Coll Cardiol. 2004;44(10):2089-2091.
6. Tonino PA, De Bruyne B, Pijls NH, et al; FAME Study Investigators. Fractional flow reserve versus angiography for guiding percutaneous coronary intervention. N Engl J Med. 2009;360(3):213-224.
7. Levine GN, Bates ER, Blankenship JC, et al. 2011 ACCF/AHA/SCAI guideline for percutaneous coronary intervention: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. Circulation. 2011;124(23):E574-E651.

Gautam Kumar, MBBS, MRCP(UK), FACC
Emory University, Division of Cardiology, Atlanta VA Medical Center
1670 Clairmont Road (111C/D)
Decatur, GA 30033
Email: gautam.kumar@emory.edu

Disclosure: The authors report no financial relationships or conflicts of interest regarding the content herein.