Basal Stenosis Resistance

Hyperemic and Basal Stenosis Resistance Versus FFR

Before looking at basal markers of lesion significance, we know that the hyperemic pressure gradient/flow ratio (HSR) and the hyperemic absolute pressure ratio (FFR) both measure translesional flow responses indicative of inducible ischemia. HSR normalizes the pressure gradient for flow (velocity) and is purportedly less impacted by the variability of the hyperemic flow response.³ In the authors’ 2002 report,² the HSR also had a higher AUC (0.90) than FFR (AUC 0.82) or CFVR (AUC 0.80), postulated to be due to a decreased sensitivity of HSR to variations in hyperemic flow, which might limit the accuracy of both FFR and CFVR. Fast forward 10 years, Van de Hoef et al¹ using the nearly the same data now show that BSR, although not as good as HSR, is at least as good as FFR for correlation to MPS. Why would BSR perform as well as FFR in this study?

In predicting ischemia, it is already agreed that HSR is better than BSR,^1,2 that is, hyperemia trumps basal data. By what mechanism could basal flow match hyperemic responses to detect ischemia? Although the authors offer no clear explanation, most of their discussion¹ involves questioning where FFR might fail such as FFR’s performance in patients with impaired microcirculation, diffuse coronary artery disease, or insufficient or variable adenosine responses. Little comment is made about the potential problems of BSR and flow velocity measurements or false-positive/negative MPS results in some patients.

For example, because microvascular function is a critical determinant of flow, it was postulated that FFR may not fully characterize the ischemic stenosis in the case of some microcirculatory pathologies.^3–5 Meuwissen et al⁴ showed that the degree of hyperemia (ie, a high CFVR), more than the pressure gradient (ie, loss of distal pressure), correlated better with MPS results. Does this same observation about flow hold for BSR? From Van de Hoef,¹ the positive and negative MPS studies had basal stenosis pressure gradients averaging approximately 13 and 5 mmHg with average peak flow velocity averaging 16±9 and 18±8 cm/s, respectively. Higher flow at rest regardless of the distal pressure² was associated with negative MPS, but the overlap of data makes it impossible for a single BSR value to predict the ischemic slope of the pressure/flow curve (Figure). Hyperemia in this data set still appears to be critical to make a definitive decision about stenosis significance.

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Figure.

Illustration of hypothetical zone of basal stenosis resistance (BSR) values and the association with pressure/flow curves of positive and negative myocardial perfusion scintigraphy (MPS). Although some BSR values may fall on the positive MPS slope, others close by will fall on the negative MPS slope. Prediction on which slope BSR resides is difficult. ΔP indicates pressure gradient (mm Hg); V, intracoronary flow velocity (cm/s). (Graphic suggested from Meuwissen et al.²)

However, unlike for BSR, the resting flow velocity is not a factor for FFR because resting pressure/flow (ie, resistance) is excluded in the FFR derivation. FFR predicts ischemia with >90% sensitivity and specificity.⁶ Recall that for Pijls et al,⁶ detection of ischemia required use of a rigorous 3-stress test standard in a Bayesian approach. One or more tests had to convert from positive to negative after percutaneous coronary intervention to be considered as a true ischemic result. Although the concordance or discordance of MPS results between CFVR and FFR may relate, in part, to severe microvascular dysfunction, it is puzzling that BSR (also with an unmeasured microvascular response) can predict a positive or negative MSP.

MPS and True Myocardial Ischemia

The use of MPS as the ischemia gold standard is a limitation to the validation of all lesion assessment indices. Of note, in their 2 studies^1,2 using the same MPS and nearly the same patients, HSR had different AUCs (0.90 and 0.81). Any noninvasive imaging modality posing as the gold standard becomes problematic because known false-positive/negative test rates become more pronounced in specific patient subsets such as those with multivessel or diffuse coronary artery disease, severe microvascular disease, left bundle branch block, and myocardiopathies. Although abnormal MPS is the result of relative maldistribution of flow between myocardial regions with and without hemodynamically significant coronary stenoses and is presumed to represent ischemia, the agreement between repeated adenosine-MPS studies was found to be poor at only 62%.⁷ The use of MPS is a significant impediment to accepting the premise that basal pressure/flow performs as well as hyperemic data.

Is Adenosine a Confounder to Lesion Assessment Accuracy?

Some operators attribute failure of maximal hyperemia with adenosine as the cause of FFR values not matching their clinical impression or MPS results. In some patients with severely impaired microvascular function or significant ischemia, there can be a paradoxical adenosine response.^5,8,9 In such circumstances, adenosine led to reduced coronary flow and hence the conclusion that hyperemia-based indices underestimated disease severity. Conceivably in this rare setting, the BSR would be equal to FFR.

Adenosine vasodilation interacts with dynamic myocardial contraction, which contributes to maintenance of normal intracoronary pressure.¹⁰ In most cases, adenosine minimizes not only the distal resistance, but unmasks the true pressure gradient across a stenosis. Does adenosine-induced ischemia alter contractile function and translesional pressure producing a suboptimal FFR? At this time we await studies to address this conjecture, recall that FFR remains highly reproducible across a wide array of changing hemodynamic conditions¹¹ and that FFR-guided outcomes are consistent across study populations with variable microvascular and myocardial contractile status. It is highly unlikely that adenosine, either in dose or action, can explain or support BSR’s performance relative to FFR.

Other Contenders for Adenosine-Free Lesion Assessment

Hyperemia (FFR, HSR) unmasks the ischemic potential of a stenosis, similar to that of exercise in patients with no symptoms at rest (BSR) who develop exertion-related ischemia because myocardial oxygen demand exceeds coronary supply. In the quest for adenosine-free lesion assessment tools, numerous pressure and flow indices have been tested and discarded (see the Table ). Recently, the instantaneous pressure ratio during the diastolic wave-free period was proposed as an alternative to FFR.¹² However, the strong instantaneous pressure ratio–FFR correlation was questioned due to excessive weighting of the Spearman coefficient toward insignificant and highly significant lesions and did not demonstrate reproducible results, especially for intermediate lesions.²⁰ Unfortunately, in comparing BSR and FFR,¹ we are not provided with the individual point correlations. All indices will show strong correlations for near normal lesions and for very severe lesions. In addition, a preliminary report showed that hyperemic instantaneous pressure ratio had a lower value than resting instantaneous pressure ratio, challenging the fundamental proposition that basal data can equal hyperemic data.²⁰ The debate about an adenosine-free index continues.

Although HSR bested and BSR equaled FFR against a MPS standard, neither stenosis resistance index is widely used nor investigated due to understandable technical problems with the availability of flow velocity guidewires and the challenges in obtaining reproducible Doppler signals. Compared with >15 years of clinical experience and validation of FFR by multiple groups across multiple patient subtypes, HSR and especially BSR have a long road ahead before they can be considered as real contenders to FFR.

Despite implications to the contrary,^1,12 for most accurate lesion assessment, hyperemia trumps resting values except perhaps under rare circumstances. Further explanation and validation of novel resting lesion assessment indices is required before anointing any contender king.