Martijn Meuwissen

Physiological Assessment of Coronary Artery Disease in the Cardiac Catheterization Laboratory A Scientific Statement From the American Heart Association Committee on Diagnostic and Interventional Cardiac Catheterization, Council on Clinical Cardiology

With advances in technology, the physiological assessment of coronary artery disease in patients in the catheterization laboratory has become increasingly important in both clinical and research applications, but this assessment has evolved without standard nomenclature or techniques of data acquisition and measurement. Some questions regarding the interpretation, application, and outcome related to the results also remain unanswered. Accordingly, this consensus statement was designed to provide the background and evidence about physiological measurements and to describe standard methods for data acquisition and interpretation. The most common uses and support data from numerous clinical studies for the physiological assessment of coronary artery disease in the cardiac catheterization laboratory are reviewed. The goal of this statement is to provide a logical approach to the use of coronary physiological measurements in the catheterization lab to assist both clinicians and investigators in improving patient care.

Single-Wire Pressure and Flow Velocity Measurement to Quantify Coronary Stenosis Hemodynamics and Effects of Percutaneous Interventions

Background—Lack of high-fidelity simultaneous measurements of pressure and flow velocity distal to a coronary artery stenosis has hampered the study of stenosis pressure drop–velocity (&Dgr;P-v) relationships in patients. Methods and Results—A novel 0.014-inch dual-sensor (pressure and Doppler velocity) guidewire was used in 15 coronary lesions to obtain per-beat averages of pressure drop and velocity after an intracoronary bolus of adenosine. &Dgr;P-v relations from resting to maximal hyperemic velocity were constructed before and after stepwise executed percutaneous coronary intervention (PCI). Before PCI, half of the &Dgr;P-v relations revealed the presence of a compliant stenosis, which was stabilized by angioplasty. Fractional flow reserve (FFR), coronary flow reserve (CFVR), and velocity-based indices of stenosis resistance (h-SRv) and microvascular resistance (h-MRv) at maximal hyperemia were compared. Stepwise PCI significantly lowered h-SRv, with an initial marked reduction in hyperemic pressure drop followed by further gains in velocity. A concomitant significant reduction of h-MRv accounted for half of the gain in velocity after PCI. The average magnitude of absolute incremental hemodynamic changes was highest for h-SRv (56.8±39.2%) compared with CFVR (35.3±34.5%, P <0.005) or FFR (19.5±25.2%, P <0.0001). Conclusions—&Dgr;P-v relations comprehensively visualize improvements in coronary hemodynamics after PCI. h-SRv is a powerful and sensitive descriptor of the functional gain achieved by PCI, combining information about both pressure gradient and velocity, which are oppositely affected by PCI. Simultaneous assessment of stenosis and microvascular resistance may provide a valuable tool for guidance of PCI.

Physiological Basis and Long-Term Clinical Outcome of Discordance Between Fractional Flow Reserve and Coronary Flow Velocity Reserve in Coronary Stenoses of Intermediate Severity

Background—Discordance between fractional flow reserve (FFR) and coronary flow velocity reserve (CFVR) may reflect important coronary pathophysiology but usually remains unnoticed in clinical practice. We evaluated the physiological basis and clinical outcome associated with FFR/CFVR discordance. Methods and Results—We studied 157 intermediate coronary stenoses in 157 patients, evaluated by FFR and CFVR between April 1997 and September 2006 in which revascularization was deferred. Long-term follow-up was performed to document the occurrence of major adverse cardiac events: cardiac death, myocardial infarction, or target vessel revascularization. Discordance between FFR and CFVR occurred in 31% and 37% of stenoses at the 0.75, and 0.80 FFR cut-off value, respectively, and was characterized by microvascular resistances during basal and hyperemic conditions. Follow-up duration amounted to 11.7 years (Q1–Q3, 9.9–13.3 years). Compared with concordant normal results of FFR and CFVR, a normal FFR with an abnormal CFVR was associated with significantly increased major adverse cardiac events rate throughout 10 years of follow-up, regardless of the FFR cut-off applied. In contrast, an abnormal FFR with a normal CFVR was associated with equivalent clinical outcome compared with concordant normal results: ⩽3 years when FFR <0.75 was depicted abnormal and throughout 10 years of follow-up when FFR ⩽0.80 was depicted abnormal. Conclusions—Discordance of CFVR with FFR originates from the involvement of the coronary microvasculature. Importantly, the risk for major adverse cardiac events associated with FFR/CFVR discordance is mainly attributable to stenoses where CFVR is abnormal. This emphasizes the requirement of intracoronary flow assessment in addition to coronary pressure for optimal risk stratification in stable coronary artery disease.

Hyperemic Stenosis Resistance Index for Evaluation of Functional Coronary Lesion Severity

Background—Both coronary blood flow velocity reserve (CFVR) and myocardial fractional flow reserve (FFR) are used to evaluate the hemodynamic severity of coronary lesions. However, discordant results between CFVR and FFR have been observed in 25% to 30% of intermediate coronary lesions. An index of stenosis resistance based on a combination of intracoronary pressure and flow velocity may improve the assessment of functional coronary lesion severity. Methods and Results—Single photon emission computed tomography (SPECT) was performed in 151 patients with angina to determine reversible perfusion defects within one-week before cardiac catheterization. Coronary pressure and flow velocity was measured distal to 181 single coronary lesions with a mean diameter stenosis of 56% (range: 32% to 85%). Maximum hyperemia was induced by 15 to 20 &mgr;g IC adenosine to determine CFVR, FFR, and the hyperemic stenosis resistance index (h-SRv), defined as the ratio of hyperemic stenosis pressure gradient (mean aorta pressure-mean distal pressure) and hyperemic average peak-flow velocity. Receiver-operating-characteristic curves of CFVR, FFR, and h-SRv were calculated to evaluate the predictive value for presence of reversible perfusion defects on SPECT with the use of the area under curve (AUC). The AUC was significantly higher for h-SRv (0.90±0.03) compared with those for CFVR (0.80±0.04;P =0.024) and FFR (0.82±0.03;P =0.018), respectively. Agreement with SPECT was particularly higher (73%) than for CFVR (49%, P =0.022) or FFR (51%, P =0.037) in the group of lesions showing discordant results between CFVR and FFR Conclusion—These results indicate that hyperemic stenosis resistance index is a more powerful predictor of reversible perfusion defects than CFVR or FFR.

Fractional flow reserve, absolute and relative coronary blood flow velocity reserve in relation to the results of technetium-99m sestamibi single-photon emission computed tomography in patients with two-vessel coronary artery disease.

OBJECTIVES We sought to perform a direct comparison between perfusion scintigraphic results and intracoronary-derived hemodynamic variables (fractional flow reserve [FFR]; absolute and relative coronary flow velocity reserve [CFVR and rCFVR, respectively]) in patients with two-vessel disease. BACKGROUND There is limited information on the diagnostic accuracy of intracoronary-derived variables (CFVR, FFR and rCFVR) in patients with multivessel disease. METHODS Dipyridamole technetium-99m sestamibi (MIBI) single-photon emission computed tomography (SPECT) was performed in 127 patients. The presence of reversible perfusion defects in the region of interest was determined. Within one week, angiography was performed; CFVR, rCFVR and FFR were determined in 161 coronary lesions after intracoronary administration of adenosine. The predictive value for the presence of reversible perfusion defects on MIBI SPECT of CFVR, rCFVR and FFR was evaluated by the area under the curve (AUC) of the receiver operating characteristics curves. RESULTS The mean percentage diameter stenosis was 57% (range 35% to 85%), as measured by quantitative coronary angiography. Using per-patient analysis, the AUCs for CFVR (0.70 +/- 0.052), rCFVR (0.72 +/- 0.051) and FFR (0.76 +/- 0.050) were not significantly different (p = NS). The percentages of agreement with the results of MIBI SPECT were 76%, 78% and 77% for CFVR, rCFVR and FFR, respectively. Per-lesion analysis, using all 161 measured lesions, yielded similar results. CONCLUSIONS The diagnostic accuracy of three intracoronary-derived hemodynamic variables, as compared with the results of perfusion scintigraphy, is similar in patients with two-vessel coronary artery disease. Cut-offvalues of 2.0 for CFVR, 0.65 for rCFVR and 0.75 for FFR can be used for clinical decision-making in this patient cohort. Discordant results were obtained in 23% of the cases that require prospective evaluation for appropriate patient management.

Usefulness of fractional flow reserve for risk stratification of patients with multivessel coronary artery disease and an intermediate stenosis

Intracoronary-derived, pressure-based fractional flow reserve (FFR) is important for clinical decision-making in patients with 1-vessel coronary artery disease (CAD). In the present study, we investigated the prognostic value of FFR in patients with intermediate stenoses and multivessel CAD. Therefore, we analyzed 107 patients with stable angina pectoris who underwent myocardial perfusion scintigraphy and showed no perfusion defects in the region of the intermediate lesion. At angiography, FFR was determined distal to the intermediate lesion. FFR was abnormal (i.e., <0.75) in 15 of 107 stenoses (14%). Angioplasty of the intermediate stenosis was deferred based on the absence of a perfusion defect. Patients were followed for 1 year to document major cardiac events related to the intermediate lesion. At 1-year follow-up, a total of 12 (11%: no deaths, 3 myocardial infarctions, 2 coronary bypass operations, 7 coronary angioplasties) events occurred in the entire group that were related to the intermediate lesion. The event rate was significantly higher when angioplasty was deferred despite FFR <0.75 compared with the group with FFR > or = 0.75 (4 of 15 [27%] vs 8 of 92 [9%]; p <0.041). The relative risk of FFR for predicting cardiac events (mainly revascularization procedures) was 3.1 (95% confidence interval 1.1 to 8.9; p <0.05). In conclusion, deferral of angioplasty of intermediate coronary narrowings is safe based on FFR > or = 0.75 in this patient cohort; this coincides with previous reports in patients with 1-vessel CAD. Furthermore, these results suggest that FFR is more useful than single-photon emission computed tomography for clinical decision-making and risk stratification in patients with multivessel CAD.

Influence of Percutaneous Coronary Intervention on Coronary Microvascular Resistance Index

Background—Coronary microvascular resistance during maximal hyperemia is generally assumed to be unaffected by percutaneous coronary interventions (PCIs). We assessed a velocity-based index of hyperemic microvascular resistance (h-MRv) by using prototypes of a novel, dual-sensor (Doppler velocity and pressure)–equipped guidewire before and after PCI to test this hypothesis. Methods and Results—Aortic pressure, flow velocity (h-v), and pressure (h-Pd) distal to 24 coronary lesions were measured simultaneously during maximal hyperemia induced by intracoronary adenosine. Measurements were obtained in the reference vessel before PCI and in the target vessel before and after PCI, stenting, and ultrasound-guided, upsized stenting. h-Pd increased from 57.9±17.0 to 85.5±15.6 mm Hg, and h-MRv (ie, h-Pd/h-v) decreased from 2.74±1.40 to 1.58±0.61 mm Hg · cm−1 · s after stenting (both P<0.001). The reduction in h-MRv accounted for 34% of the decrease in total coronary resistance achieved by PCI. h-MRv of the target vessel after PCI was lower than that of the corresponding reference vessel despite a higher h-Pd in the reference vessel (P<0.01). Post-PCI baseline MRv was correlated with baseline Pd before PCI (P<0.01). Conclusions—PCI-induced restoration of Pd resulted in a reduction of h-MRv in accordance with the pressure dependence of h-MRv. The decrease in h-MRv to a level below that of the corresponding reference vessel in the immediate post-PCI period and a lowered baseline MRv suggest microvascular remodeling induced by long-term exposure to a low-pressure environment.

Fractional flow reserve as a surrogate for inducible myocardial ischaemia

Documentation of inducible myocardial ischaemia, related to the coronary stenosis of interest, is of increasing importance in lesion selection for percutaneous coronary intervention (PCI). Fractional flow reserve (FFR) is an easily understood, routine diagnostic modality that has become part of daily clinical practice, and is used as a surrogate technique for noninvasive assessment of myocardial ischaemia. However, the application of a single, discrete, cut-off value for FFR-guided lesion selection for PCI, and its adoption in contemporary revascularization guidelines, has limited the requirement for a thorough understanding of the physiological basis of FFR. This limitation constitutes an obstacle for the adequate use and interpretation of this technique, and also for the understanding of new and future modalities of physiological functional intracoronary testing. In this Review, we revisit the fundamental elements of coronary physiology in the absence or presence of coronary artery disease. We provide insight into three essential characteristics of FFR as a diagnostic tool in contemporary clinical practice—the theoretical framework of FFR and its associated limitations; the characteristics and role of FFR as a surrogate for noninvasively assessed myocardial ischaemia; and the requirement and associated caveats of potent vasodilatory drugs to induce maximal vasodilatation of the coronary vascular bed.

Multiple Biomarkers at Admission Significantly Improve the Prediction of Mortality in Patients Undergoing Primary Percutaneous Coronary Intervention for Acute ST-Segment Elevation Myocardial Infarction

OBJECTIVES We investigated whether multiple biomarkers improve prognostication in ST-segment elevation myocardial infarction (STEMI) patients undergoing primary percutaneous coronary intervention. BACKGROUND Few data exist on the prognostic value of combined biomarkers. METHODS We used data from 1,034 STEMI patients undergoing primary percutaneous coronary intervention in a high-volume percutaneous coronary intervention center in the Netherlands and investigated whether combining N-terminal pro-brain natriuretic peptide, glucose, C-reactive protein, estimated glomerular filtration rate, and cardiac troponin T improved the prediction of mortality. A risk score was developed based on the strongest predicting biomarkers in multivariate Cox regression. The additional prognostic value of the strongest predicting biomarkers to the established prognostic factors (age, body weight, diabetes, hypertension, systolic blood pressure, heart rate, anterior myocardial infarction, and time to treatment) was assessed in multivariable Cox regression. RESULTS During follow-up (median, 901 days), 120 of the 1,034 patients died. In Cox regression, glucose, estimated glomerular filtration rate, and N-terminal pro-brain natriuretic peptide were the strongest predictors for mortality (p < 0.05, for all). A risk score incorporating these biomarkers identified a high-risk STEMI subgroup with a significantly higher mortality when compared with an intermediate- or low-risk subgroup (p < 0.001). Addition of the 3 biomarkers to established prognostic factors significantly improved prediction for mortality, as shown by the net reclassification improvement (0.481, p < 0.001) [corrected] and integrated discrimination improvement (0.0226, p = 0.03) [corrected]. CONCLUSIONS Our data suggest that addition of a multimarker to a model including established risk factors improves the prediction of mortality in STEMI patients undergoing primary percutaneous coronary intervention. Furthermore, the use of a simple risk score based on these biomarkers identifies a high-risk subgroup.

Effect of Multivessel Coronary Disease With or Without Concurrent Chronic Total Occlusion on One-Year Mortality in Patients Treated With Primary Percutaneous Coronary Intervention for Cardiogenic Shock

Despite early revascularization, mortality remains high in patients with ST-segment elevation myocardial infarction (STEMI) complicated by cardiogenic shock. It has been shown that the effect of multivessel disease (MVD) on mortality in patients with STEMI treated with primary percutaneous coronary intervention is mainly caused by the presence of chronic total occlusion (CTO) in a noninfarct-related coronary artery. Whether this association also exists in patients with STEMI with cardiogenic shock is unknown. In our institution, 292 consecutive patients with STEMI complicated by cardiogenic shock were admitted from 1997 to 2005 and treated with primary percutaneous coronary intervention. Patients were classified as having single vessel disease, MVD without CTO, and CTO. Cox regression analysis was used for multivariate analysis. The 1-year mortality rate of patients with single-vessel disease, MVD, and CTO was 31%, 47%, and 63%, respectively. After adjustment for possible confounders, MVD alone was not an independent predictor of 1-year mortality (hazard ratio 1.5, 95% confidence interval 0.98 to 2.3, p = 0.07). In contrast, CTO in a noninfarct-related artery was an independent predictor of 1-year mortality (hazard ratio 2.1, 95% confidence interval 1.5 to 3.1, p <0.01). In conclusion, the presence of CTO in a non-infarct-related artery was an independent predictor of 1-year mortality. In contrast, MVD alone lost its predictive significance after multivariate analysis.