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Fractional flow reserve (FFR) values may be altered in patients who experience profound hypotension due to intravenous adenosine infusion, according to findings published online January 7, 2014, ahead of print in Circulation: Cardiovascular Interventions. According to the authors, FFR in such patients, who are frequently obese, may lead to overestimation of the need for revascularization.

After IV infusion of adenosine, investigators led by Javier Escaned, MD, PhD, of Hospital Clínico San Carlos (Madrid, Spain), measured FFR, coronary flow reserve, and the index of microcirculatory resistance in 93 arteries with intermediate stenosis (40%-70% by QCA) in 79 patients.

Adenosine produced a mean BP decrease of -12 ± 11 mm Hg, which corresponded to a mean change in aortic pressure from baseline to stable hyperemia of -13.6 ± 12%. Adenosine-induced hypotension was analyzed across tertiles of the percentage change in aortic pressure:

• Mild (> -6.7%)
• Moderate (-6.7% to -17.2%)
• Profound (< -17.2%)

Obesity Tied to Profound Hypotension

BMI was associated with change in aortic pressure (P = 0.037), with a trend toward greater BP declines in obese patients (BMI ≥ 30 kg/m²; P = 0.056). Compared with mild and moderate tertiles of change in aortic pressure, patients experiencing profound hypotension were more likely to be diabetic (P = 0.021) and obese (P = 0.009). However, only obesity was an independent predictor of profound hypotension (OR 3.95; 95% CI 1.48-10.54; P = 0.006). Adenosine dosage was not associated with BP response.

Neither QCA, baseline pressures, nor the hyperemic transtenotic pressure gradient was linked with the percentage change in aortic pressure. However, a trend was seen toward an association between FFR and percentage change in aortic pressure (P = 0.051), suggesting a relationship between the degree of adenosine-induced hypotension and hyperemic coronary hemodynamics. The link was stronger when stenoses assessed during profound hypotension were compared with those measured in patients with mild or moderate changes in aortic pressure. During the former, FFR values were lower (P = 0.021) and more likely to be below the ≤ 0.80 cutoff for revascularization (P = 0.008). Moreover, the decrease in aortic pressure observed during assessment of stenoses with a low FFR was greater than in those with a normal FFR (-17.1 ± 11.9% vs. -11.0 ± 11.6%; P = 0.014).

Microcirculatory Resistance, FFR Lower

In addition, an association was observed between coronary microcirculatory resistance and BP decline. Stenoses assessed during profound hypotensive responses had lower microvascular resistance values than those assessed during mild or moderate changes in aortic pressure (P = 0.001).  Coronary flow reserve was also associated with percentage change in aortic pressure (r = -0.246; P = 0.017).

Stenoses assessed during profound hypotensive responses had higher coronary flow reserve values than those assessed during mild and moderate declines in aortic pressure, although the difference did not reach statistical significance. However, the authors say, the observed increase in coronary flow reserve during profound hypotension may be clinically relevant because during that condition the prevalence of vessels with FFR ≤ 0.80 and coronary flow reserve greater than 2 was higher (P = 0.023).

Multivariate analysis identified the index of microcirculatory resistance (P < 0.001) as an independent predictor of FFR. When FFR values were plotted across tertiles of percentage change in aortic pressure, both FFR and microcirculatory resistance index values tended to be lower when measured during profound hypotension.

A profound hypotensive response in obese patients may be triggered by impaired sympathetic autonomic or adenosine receptor function, according to the authors. But regardless of the mechanism, “the potential contribution of this phenomenon to overestimation of coronary stenosis severity” is supported by the proportion of vessels with normal coronary flow despite an abnormal FFR, they write, adding that preserved coronary flow may justify refraining from intervention.

Variability in Adenosine Response Clear, Implications Not

“Physicians who do a lot of FFR have noticed a huge variation in adenosine response,” Allen Jeremias, MD, of Stony Brook University Medical Center (Stony Brook, NY), told TCTMD in a telephone interview. This paper is a formal assessment of that phenomenon as well as an attempt to identify the potential consequences, he observed.

“This topic is a bit confusing for everybody,” confessed Morton J. Kern, MD, of the University of California, Irvine (Irvine, CA), in a telephone interview with TCTMD. “But clinicians just have to appreciate that some patients are very sensitive to adenosine and may experience a marked drop in blood pressure.” In those individuals, microcirculatory resistance can change dramatically, leading to higher flow and a lower FFR, but the clinical implications remain unclear, he added.

The question of which is the more important determinant of ischemia—high coronary flow or low perfusion pressure—is controversial, Dr. Kern reported. Some research suggests that about 15% of patients have both, and “that’s kind of the unknown territory,” he said. “Clinical studies say a low FFR is associated with more events, but not everybody has events. And some would argue that if flow is substantial, it doesn’t matter what the pressure gradient is.”  

“When there is a discrepancy between flow and pressure, I think most physicians who deal with physiology would think that the flow results are more accurate, that coronary flow reserve trumps FFR,” Dr. Jeremias asserted. In fact, the literature suggests that patients with a coronary flow reserve greater than 2 have an excellent prognosis with medical management alone, he said.

Adenosine Alternative Desirable 

However, coronary flow reserve has fallen out of favor, in part because measurement with a Doppler wire is difficult and expensive, Drs. Kern and Jeremias agreed. Moreover, in most cases microcirculatory resistance is minimized by hyperemia, making pressure and flow almost equivalent, so pressure is a reasonable surrogate. But when microcirculatory resistance is low, flow can increase substantially, “and then even a mild stenosis could appear significant if you just measure FFR,” Dr. Jeremias explained.

Large clinical studies show that if patients are risk-stratified by FFR, outcomes are good, Dr. Jeremias acknowledged. “But if you look on an individual basis, there is a chance for misclassification,” he said, “and those chances are more than doubled with an [exaggerated] response to adenosine.” For that reason, “many investigators believe it might be worthwhile to revisit the concept of looking at flow,” he added.

Dr. Kern was less sanguine about reviving that strategy. But the uncertainty surrounding some FFR results is “one of the fundamental reasons you would like to have an alternative to adenosine,” he commented.

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