Pressure-Based Physiological Testing Results Diverge Between LAD, LCx

Relying on iFR/FFR values from the LCx alone could mean many patients with left main disease miss out on revascularization.

Pressure-Based Physiological Testing Results Diverge Between LAD, LCx

For patients with isolated left main (LM) coronary artery disease, pressure-based physiological testing—whether by fractional flow reserve (FFR) or instantaneous wave-free ratio (iFR)—reveals different findings based on the territory in which the assessment is done, new data show.

FFR and iFR results are consistently lower when measured in the left anterior descending (LAD) versus the left circumflex (LCx) artery, researchers found, a discrepancy that they say could inadvertently lead to undertreatment of the LM. Interestingly, too, there were differences in flow even among patients without LM disease.

Lead author Ozan M. Demir, PhD, and senior author Divaka Perera, MD (both from King’s College London, England), pointed out to TCTMD that patients with LM disease were excluded from the large, randomized trials of physiological assessment, making it an area ripe for further study.

Historically, “the left main has just been thought of as a no-go zone for coronary physiology, because you know as soon as you see [the disease] on angiography, people have been referring patients for bypass surgery,” said Perera. “Although physiology is used quite extensively in downstream disease, the highest-risk group potentially [wasn’t] having it assessed.”

Even at centers that do perform physiological testing for LM disease, there can be confusion when results are inconsistent between the LAD and LCx, he added. Some patients with these ambiguous findings are then sent for revascularization, while others are not—all depending on where they’re being managed.

“Approximately a quarter of patients will have had their left main ignored if the circumflex values were used” to determine next steps, Perera noted.

The size of the discrepancy between the LAD and the LCx came as a surprise, said Demir. “The results were more striking than we [would have] thought, to be honest with you.”

Demir and Perera said the clinical implications of their data are clear: operators using physiological testing to decide whether to revascularize the left main should use results from the LAD—not the LCx—as their guide. “This gives real clarity about how you should assess a left main,” Perera stressed.

What these data reveal about the unknowns of physiology, though, “is a little bit more troubling and a little bit more disruptive to people,” he said, because it lends some uncertainty to the evidence base on assessment.

The results were more striking than we [would have] thought, to be honest with you. Ozan M. Demir

FFR pioneer William F. Fearon, MD (Stanford University, CA), who authored a forthcoming editorial on the paper, described the disparity between the LAD and LCx as “unexpected.”

“I think the basic laws of fluid dynamics wouldn’t have predicted these findings, and that’s what makes it sort of unusual,” he commented to TCTMD, adding that the results are “very novel.”

In practice, it certainly makes sense to prioritize assessing the LAD, “both because it supplies a lot more myocardium and also [because of] the findings of this study,” said Fearon. In cases where there are any doubts or there’s downstream disease, operators should also use intravascular imaging, he advised. “It’s such an important vessel. You want to try to make sure you get it right.”

José María de la Torre Hernández, MD, PhD (Hospital Universitario Marqués de Valdecilla, Santander, Spain), who commented on the results for TCTMD, noted that this isn’t the first time differences in FFR/iFR have been observed between the LAD and LCx, citing a 2022 paper he coauthored on the topic that hinted at the same mismatch.

That prior work explored the correlation, or lack thereof, between iFR and FFR. It also showed that testing led to fewer deferrals of revascularization when done in the LAD, “because with the [LCx] you miss some significant left main lesions,” said de la Torre Hernández.

The latest study, he said, features “an elegant design, because they selected patients with and without left main disease,” and it helpfully attempts to tease out the mechanism by looking at microvascular function. In short, de la Torre Hernández noted, “there is a higher flow rate and lower minimal resistance in the LAD. This explains the differences.”

De la Torre Hernández agreed with the researchers’ clinical message, though, like Fearon, he specified that in cases where there may potentially be other lesions downstream, operators should use “IVUS or OCT to see the plaque in the left main.”

Physiology by Territory

The researchers enrolled 80 patients (mean age 65 years; 56% male): 47 had isolated LM disease and 33 had an unobstructed LM coronary artery. They performed both FFR and iFR as well as Doppler assessment in 22 of the patients with isolated LM disease and all of those without LM disease.

With iFR and FFR, and with the distal coronary pressure to aortic pressure ratio (Pd/Pa), values were significantly higher in the LCx as compared to the LAD. This was true in both isolated LM disease and unobstructed LM coronary arteries (P < 0.0001 for all).

LM Coronary Artery: Flow and Pressure

 

LAD

LCx

Isolated LM Disease

    iFR

    FFR

    Pd/Pa

 

0.89 (0.76-0.92)

0.74 ± 0.11

0.91 (0.87-0.93)

 

0.94 (0.88-0.97)

0.81 ± 0.11

0.96 (0.92-0.98)

Unobstructed LM

    iFR

    FFR

    Pd/Pa

 

0.95 ± 0.04

0.91 ± 0.05

0.96 ± 0.03

 

0.99 ± 0.02

0.97 ± 0.03

0.99 ± 0.02


Pressure-wire pullback confirmed that the pressure drop was greater between the LM and LAD ostia than between the LM and LCx ostia. On the other hand, “the pressure gradient between the distal vessel and ostium was minimal and similar between the LAD and LCx, confirming the absence of functionally significant downstream disease,” the investigators report.

Fully 21% of patients considered FFR-negative in the LCx would be reclassified as having functionally significant disease if based on LAD values. Using iFR, 28% would be reclassified.

A possible explanation for the phenomenon, Demir et al suggest, could relate to microvascular resistance reserve (MRR), which was higher in the LAD than in the LCx in both patient cohorts. Mean values were 3.57 versus 2.50, respectively, in the presence of disease and 3.40 versus 2.47, respectively, in unobstructed LM (P < 0.0001). In the LAD, MRR was similar for both obstructed and unobstructed arteries, and the same was true in the LCx.

The fact that similar patterns were seen “in patients without epicardial or microvascular coronary artery disease [suggests] that these differences are intrinsic to the hemodynamics of coronary circulation rather than a consequence of LM coronary artery disease,” the researchers write.

Beyond the clinical applications, the data “also suggest the need for territory-specific thresholds for defining abnormal microvascular function or epicardial conductance,” they conclude.

Fearon noted that it’s possible the observed imbalance between the LAD and LCx isn’t as great as it seems. It’s unusual to find truly isolated LM, he said, and undetected disease in other locations might have influenced the results of iFR/FFR. Helpfully, the researchers “did very careful pullbacks of the pressure wire to try to look for [downstream disease], but the resolution isn’t as good as we’d like and it gets challenging to know whether you’re looking at a gradient that’s just from the left main or if there’s some contribution from the ostium or the LAD,” he explained.

Another possible contributor to the imbalance are hydrostatic forces on intracoronary pressure measurements that relate to differences in heights of the sensors, suggested Fearon, though he noted that Demir and colleagues did adjust for this factor but still found the LAD/LCx mismatch.

It’s such an important vessel. You want to try to make sure you get it right. William F. Fearon

Perera pointed out that results of physiological testing are not inherently incorrect for either the LCx or the LAD. “This isn’t about discordance between the two, because discordance assumes that you should be getting the same value,” he said.

“We have now understood and shown that, actually, even [when] through a diseased left main, you may be getting adequate flow down to your circumflex and therefore you have a normal FFR or iFR value [in the LCx]. But it doesn’t mean that the left main as a whole is benign,” said Perera.

The implications also may extend beyond the left main.

There could be nuances to measuring flow in other bifurcations as well, said Perera. “It’s not that the indices are wrong, [but instead that] you really have to think about what it’s telling you—it just tells you about the impact of the stenosis on that territory. You cannot use that information to then make inferences about what it means to another territory.”

Perera said the next step should be a larger, multicenter trial exploring whether different approaches to physiological testing in left main have the potential to alter outcomes. Fearon, too, called for additional research to confirm and better understand the underlying roots of the study results.

Caitlin E. Cox is News Editor of TCTMD and Associate Director, Editorial Content at the Cardiovascular Research Foundation. She produces the…

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Disclosures
  • Demir, Perera, and de la Torre Hernández report no relevant conflicts of interest.
  • Fearon reports research funding from Abbott, CathWorks, and Medtronic; consulting fees from Edwards Lifesciences and Shockwave; and minor stock options from Heartflow.

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