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Original Contribution
High Left Ventricular Mass Index Does Not Limit the Utility of Fractional Flow Reserve for the Physiologic Assessment of Lesion
November 2006
Myocardial fractional flow reserve (FFR) is an invasive index of the physiologic significance of a coronary stenosis. FFR is simply measured as the mean intracoronary pressure distal to a lesion divided by the mean aortic pressure during maximal hyperemia. An FFR value of 1–5 As there has been much debate regarding the possible effects of microvascular disease on the pressure measurements used to calculate FFR, this initial work was performed in patients with normal left ventricular mass (LVM) and no evidence of ventricular hypertrophy. It has been postulated that the presence of microvascular disease, as in diabetes, elevated left ventricular mass6 or acute myocardial infarction may limit maximal microvascular vasodilation and thus render FFR measurement less precise.2,7–9 Whether these theoretic concerns significantly limit the clinical value of FFR is not established.
Accordingly, the goal of the present study was to compare FFR measurements of stenotic arteries in patients with elevated LVM to FFR of angiographically-matched control vessels in patients with normal LVM. We hypothesized that clinical measurements of FFR for vessels matched by angiographic lesion severity and length will not be significantly different for patients with high versus normal LVM.
Materials and Methods
Patient population. The patient population was derived from 112 consecutive patients who had undergone coronary angiography, left ventriculography and FFR measurements between August 1999 and August 2002 at the University of Virginia. The study group consisted of patients with elevated left ventricular mass index (LVMI) calculated by contrast left ventriculography. Elevated LVMI was defined as > 100 g/m2 for women and > 130 g/m2 for men, in accordance with published data.10 The control group consisted of a cohort of patients with normal LVMI who had lesions that were angiographically matched to the study group with respect to minimal lumen diameter (MLD), percent diameter stenosis (%DS) and lesion length. The study group was compared to the matched control group with respect to clinical, angiographic and hemodynamic parameters.
Clinical data. Clinical data were retrospectively acquired from a point of care, prospectively entered University of Virginia cardiac catheterization laboratory database.
Quantitative angiography. A single observer (blinded to the clinical data) performed quantitative coronary angiography offline (DICOM, Heartlab, Inc., Westerly, Rhodes Island). Single frames demonstrating the most severe luminal narrowing without foreshortening were selected for analysis. The angiographic catheter diameter was used as a calibration standard. The luminal diameter proximal or just distal to the stenosis (reference lumen) was determined for all lesions. Lesion length was determined as the length of the diseased area. The %DS was calculated as the ratio of MLD to reference luminal diameter.
Ventriculography. Left ventriculography was performed in all patients and global LV ejection fraction was calculated from the right anterior oblique (RAO) projection at the time of diagnostic catheterization. For all patients, LVM was calculated using a modification of the Rackley method from contrast left ventriculography11 to account for regional variability in left ventricular wall thickness in patients with remodeled ventricles. Right and left anterior oblique still frames in diastole were used to measure left ventricular length and chamber area, from which the transverse diameter of the ellipse approximating the LV chamber was calculated. Left ventricular wall thickness was measured two-thirds of the distance from the aortic root to the apex in the anterior wall on the RAO projection and at the mid-posterior wall in the left anterior oblique (LAO) projection (Figure 1A). Four measurements were made in each projection which were averaged to calculate the mean left ventricular wall thickness. LVM was calculated using a modification of the equation described by Rackley,11 and outlined in Figure 1A. Although this method had been previously validated against autopsy data,12 we sought to confirm a correlation between our calculations and calculations of LVM derived from magnetic resonance imaging (MRI). Figure 1B demonstrates that LVM calculated by contrast left ventriculography correlated well with LVM measured by cardiac MRI in 24 patients (not included in this study) who had undergone both tests (r = 0.77, p Fractional flow reserve. Fractional flow reserve was calculated at the time of diagnostic angiography. A 0.014-inch pressure-monitoring wire (Radi Medical Systems, Upsulla, Sweden) was advanced to the tip of the guiding catheter and equalized to aortic pressure as measured through the guiding catheter. The pressure wire was then advanced distal to the lesion identified by angiography and a baseline gradient was identified as the mean pressure distal to the lesion (Pd) divided by mean aortic pressure (PAo). Intracoronary adenosine (30 µg for the right coronary artery and 40–60 µg for the left coronary artery) was then administered as a bolus through the guide and continuous measurements of distal intracoronary pressure and aortic pressures were recorded. The FFR was calculated as the ratio of Pd divided by PAo during maximal hyperemia. Postprocedure, the pressure wire and guiding catheter pressures were again checked with the wire at the tip of the catheter to assure absence of signal drift.
Statistical analysis. Values are given as mean ± standard deviations. Comparisons between the study and control groups were made using chi square test for discrete variables; Students’ t-test, using two-tailed testing of unequal variance for continuous variables; and Pearson’s R and Spearman’s rho were used for continuous correlations. A regression model was used to compare the slopes and intercepts of the correlation between %DS and FFR in patients with high and normal LVMI. A multivariate analysis was then performed to assess the influence of known anatomic determinants of FFR (MLD and lesion length) as well as LVMI on FFR calculations. A p-value Clinical variables. Table 1 summarizes the clinical characteristics of the patients in the study and control groups. There were no significant differences in prevalence of diabetes, hypertension, or dyslipidemia between the elevated LVMI and control patients. The mean LVMI in the study and control groups were 126 ± 21 g/m2 and 84 ± 21 g/m2, respectively.
Angiographic data. Table 2 displays the angiographic data for the two groups. The distributions of lesions within coronary arteries were similar in both groups. There were no significant differences in reference diameter (3.3 ± 0.5 mm versus 3.1 ± 0.7 mm; p = NS), lesion length (14.2 ± 7.0 mm versus 14.3 ± 7.0 mm; p = NS), MLD (1.3 ± 0.6 mm versus 1.3 ± 0.6 mm; p = NS), or %DS (61 ± 13% versus 62 ± 13%; p = NS), indicating well-matched angiographic features for the two groups. Global left ventricular ejection fraction was similar in the two groups (58 ± 8% versus 62 ± 7%; p = NS).
Hemodynamic data in high LVMI versus normal LVMI patients. Table 3 displays the hemodynamic data for the two groups. No significant differences were observed in baseline aortic pressure (98 ± 15 versus 97 ± 16 mmHg; p = NS) or FFR (0.79 ± 12 versus 0.78 ± 16; p = NS) between patients with elevated LVMI and angiographically matched controls with normal LVMI. Figures 2A and B compare individual percent diameter stenoses and fractional flow reserves between the two groups of patients.
Figures 3A and B, demonstrate that there is a significant correlation between %DS and FFR for both patients with elevated LVMI (r = -0.65, p r = -0.53, p i.e, %DS, MLD and lesion length. No difference was observed in the correlation between %DS and FFR in tertiles I, II and III (r = -0.60, -0.55 and -0.52, respectively).
Multivariate analysis. Of the variables tested (MLD, lesion length, LVMI) only MLD correlated with FFR (p p 1–5,13,14 FFR measurements 1–5,15 No data are available regarding the utility of FFR measurements in a large cohort of patients with increased LVMI.
The present study demonstrates that, for coronary lesions with matched angiographic characteristics, FFR of vessels in patients with elevated LVMI is similar to that of vessels in patients with normal LVMI. Furthermore, the correlation between %DS and FFR (and the slope and intercept of the correlation) is similar in patients with elevated and normal LVMI, and LVMI does not correlate with FFR in multivariate analysis.
Increased LVM is most commonly due to systemic hypertension. Increased myocardial fibrosis and left ventricular hypertrophy lead to a relative reduction in capillaries per gram of myocardium. In addition, there may be microvascular abnormalities resulting from chronically elevated coronary perfusion pressures as well as concomitant atherosclerosis.
Whether clinical FFR measurements of coronary stenoses are affected by the pathophysiology associated with increased LVM was unknown. The premise for pressure measurement reflecting coronary flow involves the assumption that coronary resistance is minimal and constant during maximal hyperemia induced by vasodilators. It has been postulated that the microvascular changes present in patients with elevated LVM might impair vasodilator response during pressure measurement and FFR calculation. Conversely, it has been argued that for a given diseased microvascular bed, as in patients with elevated LVM, while maximal vasodilation may not be as great as normal beds, myocardial resistance should nevertheless be minimal and constant for those circumstances, providing conditions for coronary pressure to be proportional to flow.9,16
The known determinants of FFR include anatomic measures of lesion severity and lesion length, as well as determinants of microvascular function such as diabetes mellitus, elevated LVMI and myocardial infarction. With angiographically well-matched lesions with respect to %DS and lesion length, and similar proportions of patients with diabetes, hypertension, myocardial infarction and dyslipidemia in the study and control groups, elevated LVM represents the main difference between the study and control patients. Multivariate analysis confirmed that only MLD, and not elevated LVMI, significantly affected FFR measurement.
While the pathophysiology of myocardial infarction is different from that of increased LVM in the absence of infarction, both conditions are common and affect the coronary microvasculature and resistance. Debryune et al16 have shown that FFR measurements are useful in vessels subtending remote infarction, and we have recently shown that FFR is no different in vessels subtending recently infarcted myocardium compared with that in matched noninfarct patients.17 Our current results would suggest that FFR may also have value in assessing lesion severity in patients with increased LVMI.
The prevalence of elevated LVM in our study was 22/112 (20%), similar to that documented in the Framingham Study18 (16% in men and 19% in women). Furthermore, LVM has become a useful clinical variable for the prediction of adverse cardiac events.19,20 Therefore, the applicability of FFR measurements for assessment of lesion severity in patients with elevated LVMI has substantial clinical significance.
Study limitations. The first limitation of this study is that FFR of vessels in patients with normal and elevated LVM were compared using matched quantitative coronary angiographic parameters and not intravascular ultrasound, which is considered the gold standard for defining plaque volumes. Nevertheless, in the absence of diffuse angiographic disease and with similar prevalence of conditions other than infarction that might alter microvascular resistance (diabetes, hypertension, dyslipidemia), the major determinants of FFR are lesion stenosis and lesion length, which were matched between groups.
The second limitation of this study is that we did not have independent physiologic corroboration of the hemodynamic effects of the lesions with either noninvasive imaging (nuclear scintigraphy, positron emission tomography or dobutamine echocardiography) or invasive assessment such as Doppler-derived coronary flow reserve assessment or hyperemic stenosis resistance index.21 However, the clinical variables were similar between the two groups. Furthermore, this study was designed to compare FFR of vessels in patients with elevated LVMI to FFR of vessels in patients with normal LVMI, a setting where FFR is already extensively validated as an invasive physiologic index of lesion severity.1–5
The final limitation of this study is that our LVM calculations were made by left ventriculography, which is not the usual method for making such determinations. Alternate methods such as cardiac MRI might more fully define eccentric LV hypertrophy. However, our calculations of LVM were based on measurements of LV wall thickness in two planes, and correlated well with MRI in 24 patients undergoing both tests.
Conclusions
The present study demonstrates that FFR of lesions in patients with elevated LVM is not significantly different from that of angiographically-matched lesions in patients with normal LVM. These findings suggest that elevated LVM does not limit the use of FFR as a physiologic index of lesion severity.
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