Fractional flow reserve (FFR) determines the functional significance of epicardial stenoses assuming negligible venous pressure (P v ) and microvascular resistance. However, these assumptions may be invalid in end-stage liver disease (ESLD) because of fluctuating P v and vasodilation. Accordingly, all patients with ESLD who underwent right-sided cardiac catheterization and coronary angiography with FFR as part of their orthotopic liver transplantation evaluation between 2013 and 2018 were included in the present study. Resting mean distal coronary pressure (P d )/mean aortic pressure (P a ), FFR, and P v were measured. FFR accounting for P v (FFR − P v ) was defined as (P d − P v )/(P a − P v ). The hyperemic effect of adenosine was defined as resting P d /P a − FFR. The primary outcome was all-cause mortality at 1 year. In 42 patients with ESLD, 49 stenoses were interrogated by FFR (90% were <70% diameter stenosis). Overall, the median model for ESLD score was 16.5 (10.8 to 25.5), FFR was 0.87 (0.81 to 0.94), P v was 8 mm Hg (4 to 14), FFR-P v was 0.86 (0.80 to 0.94), and hyperemic effect of adenosine was 0.06 (0.02 to 0.08). FFR-P v led to the reclassification of 1 stenosis as functionally significant. There was no significant correlation between the median model for ESLD score and the hyperemic effect of adenosine ( R = 0.10). At 1 year, 13 patients had died (92% noncardiac in etiology), and patients with FFR ≤0.80 had significantly higher all-cause mortality (73% vs 17%, p = 0.001. In conclusion, in patients with ESLD who underwent orthotopic liver transplantation evaluation, P v has minimal impact on FFR, and the hyperemic effect of adenosine is preserved. Furthermore, even in patients with the predominantly angiographically-intermediate disease, FFR ≤0.80 was an independent predictor of all-cause mortality.
Previous studies of patients with end-stage liver disease (ESLD) have demonstrated worse clinical outcomes in those with concomitant coronary artery disease (CAD) and improvements in long-term mortality with revascularization previous to orthotopic liver transplantation (OLT). Fractional flow reserve (FFR) is a validated coronary pressure wire-based index that evaluates the functional significance of epicardial coronary stenoses and is commonly used to interrogate angiographically-intermediate disease. , The derivation of FFR assumes negligible central venous pressure (P v ) and microvascular coronary resistance. However, these assumptions may be invalid in ESLD because of pathophysiology characterized by dynamic P v s and marked vasodilation. To the best of our knowledge, FFR has not been previously studied in a dedicated ESLD population. In the present study, we aimed to assess the accuracy and prognostic impact of FFR in patients with ESLD who underwent OLT evaluation.
This single-center retrospective cohort study included all adult patients with ESLD at the University of California, Los Angeles (UCLA) who underwent right-sided cardiac catheterization (RHC) and coronary angiography with FFR between 2013 and 2018 as part of their OLT evaluation. Patients aged <18 years were excluded. The study protocol was approved by the UCLA Institutional Review Board.
Hemodynamic data measured during the index procedure included resting mean distal coronary pressure (P d )/mean aortic pressure (P a ), FFR, and central P v . Resting P d /P a was defined as the ratio of P d to P a . FFR was defined as the P d /P a at maximal hyperemia during administration of adenosine, and values ≤0.80 were considered functionally significant. P v was defined as the mean right atrial pressure. We defined an adjusted FFR accounting for P v (FFR-P v ) as (P d − P v )/(P a − P v ) and the hyperemic effect of adenosine as resting P d /P a − FFR. FFR-guided percutaneous coronary intervention (PCI) was defined as PCI of the interrogated stenosis during the index procedure or in a staged fashion (i.e., planned PCI within the following 60 days).
The primary outcome was all-cause mortality at 1 year. Secondary outcomes included nonperiprocedural myocardial infarction (MI), repeat revascularization, and the composite of all-cause mortality, MI, and repeat revascularization at 1 year (major adverse cardiovascular events [MACE]). MI was defined as an increase in troponin levels to >99th percentile of the upper reference limit in addition to either new ischemic electrocardiographic or echocardiographic changes. Repeat revascularization was defined as any subsequent PCI excluding staged PCI.
Data are expressed as frequency (percentages) or median (interquartile range). Independent samples t tests and chi-square tests (as appropriate) were used to test for differences between groups of continuous and categorical variables, respectively, and Spearman rank correlation coefficients were used to assess the correlation between continuous variables. Time-to-event data were analyzed using Kaplan-Meier curves and log-rank tests stratified by FFR ≤0.80. Cox proportional hazards regression models including FFR ≤0.80 and key demographic, cardiovascular, and ESLD-related factors were constructed to determine independent predictors of clinical outcomes (multivariable models included factors with p <0.10 in univariable analyses). These Cox regression data are presented as hazard ratios (HRs) with 95% confidence intervals (CIs). Statistical analyses were performed with SPSS Statistics, version 27.0 (SPSS Inc., Chicago, Illinois). A p value <0.05 was considered statistically significant.
A total of 42 patients underwent RHC and coronary angiography with FFR as part of their OLT evaluation at UCLA from 2013 to 2018. The median age was 62 years (57.5 to 66.6), 62% were men, and the median model for ESLD (MELD) score was 16.5 (10.8 to 25.5) ( Table 1 ). In the 42 patients with ESLD, 49 coronary stenoses were interrogated by FFR. Of these stenoses, 90% were angiographically mild or intermediate (<70% diameter stenosis on visual inspection) and 69% were located in the left main coronary artery (2%) or left anterior descending artery (67%). The median resting P d /P a was 0.94 (0.89 to 0.98) and the median FFR was 0.87 (0.81 to 0.94); these data indicated a median hyperemic effect of adenosine of 0.06 (0.02 to 0.08), which did not significantly correlate with MELD score ( R = 0.10). The median P v was 8 mm Hg (4 to 14), yielding a median FFR-P v of 0.86 (0.80 to 0.94). There was no significant difference between FFR-P v and FFR (p = 0.28). FFR-P v led to the reclassification of 1 stenosis from functionally nonsignificant to functionally significant. In the 12 patients with functionally significant stenoses, 11 underwent revascularization (10 PCI and 1 coronary artery bypass grafting), whereas 1 died before planned revascularization ( Table 2 ).
| N = 42 | |
|---|---|
| Age (years) | 62 (57.5 – 66.6) |
| Male | 26 (62%) |
| White | 15 (36%) |
| Black | 3 (7%) |
| Hispanic | 13 (31%) |
| Asian | 11 (26%) |
| Body mass index (kg/m 2 ) | 28.1 (24.5 – 34.5) |
| Hypertension | 30 (71%) |
| Hyperlipidemia | 14 (33%) |
| Diabetes mellitus | 30 (71%) |
| Chronic kidney disease | 18 (43%) |
| Cerebrovascular disease | 3 (7%) |
| Peripheral arterial disease | 0 (0%) |
| Prior heart failure | 0 (0%) |
| Prior myocardial infarction | 2 (5%) |
| Prior percutaneous coronary intervention | 5 (12%) |
| Left ventricular ejection fraction <50% | 1 (2%) |
| Tobacco Use (current or former) | 27 (64%) |
| Family history of coronary artery disease | 5 (12%) |
| Stress test | |
| Positive | 2 (5%) |
| Negative/equivocal | 27 (64%) |
| None | 13 (31%) |
| Model for End-Stage Liver Disease Score | 16.5 (10.8 – 25.5) |
| Cause of end-stage liver disease | |
| Alcohol | 5 (12%) |
| Hepatitis C virus | 16 (38%) |
| Multifactorial | 2 (5%) |
| Non-alcoholic steatohepatitis | 9 (21%) |
| Other | 10 (24%) |
| N = 49 | |
|---|---|
| Stenosis degree Iinterrogated | |
| Mild (0-39%) | 3 (6%) |
| Moderate (40-69%) | 41 (84%) |
| Severe (≥ 70%) | 5 (10%) |
| Stenosis location interrogated | |
| Left main | 1 (2%) |
| Left anterior descending | 33 (67%) |
| Left circumflex | 5 (10%) |
| Right coronary artery | 10 (21%) |
| P d /P a | 0.94 (0.89 – 0.98) |
| Fractional flow reserve | 0.87 (0.81 – 0.94) |
| ≤ 0.80 | 12 (25%) * |
| > 0.80 | 37 (75%) |
| P d /P a – FFR | 0.06 (0.02 – 0.08) |
| Venous pressure (mm Hg) | 8 (4 – 14) |
| Right ventricular systolic pressure (mm Hg) | 29.5 (22.5 – 36.8) |
| Right ventricular diastolic pressure (mm Hg) | 7.0 (4.0 – 10.8) |
| Pulmonary artery systolic pressure (mm Hg) | 28.0 (22.0 – 36.5) |
| Pulmonary artery diastolic pressure (mm Hg) | 14.5 (10.0 – 19.0) |
| Mean pulmonary artery pressure (mm Hg) | 20.0 (15.8 – 27.3) |
| Pulmonary capillary wedge pressure (mm Hg) | 13.0 (10.0 – 17.0) |
| Thermodilution cardiac output (L/min) | 6.7 (5.4 – 8.5) |
| Thermodilution cardiac index (L/min/m 2 ) | 3.5 (3.1 – 4.8) |
| FFR-P v | 0.9 (0.8 – 0.9) |
| ≤ 0.80 | 13 (27%) |
| > 0.80 | 36 (73%) |
| Reclassified as ≤ 0.80 per FFR-P v | 1 (3%) |
| FFR − FFR-P v | 0.01 (0.01 – 0.03) |
| Revascularization | |
| FFR ≤ 0.80 | 11/12 (91%) |
| Percutaneous coronary intervention | 10 (83%) |
| Coronary artery bypass graft | 1 (8%) |
| FFR > 0.80 | 1/37 (3%) |
| Percutaneous coronary intervention | 1 (3%) |
| Coronary artery bypass graft | 0 |
| Stent Type | |
| Bare mental stent | 10/11 (91%) |
| Drug eluting stent | 1/11 (9%) |
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