Impact of Myocardial Fibrosis in Patients With Symptomatic Severe Aortic Stenosis
Background— In this prospective follow-up study, the effect of myocardial fibrosis on myocardial performance in symptomatic severe aortic stenosis was investigated, and the impact of fibrosis on clinical outcome after aortic valve replacement (AVR) was estimated.
Methods and Results— Fifty-eight consecutive patients with isolated symptomatic severe aortic stenosis underwent extensive baseline characterization before AVR. Standard and tissue Doppler echocardiography and cardiac magnetic resonance imaging (late-enhancement imaging for replacement fibrosis) were performed at baseline and 9 months after AVR. Endomyocardial biopsies were obtained intraoperatively to determine the degree of myocardial fibrosis. Patients were analyzed according to the severity of interstitial fibrosis in cardiac biopsies (severe, n=21; mild, n=15; none, n=22). The extent of histologically determined cardiac fibrosis at baseline correlated closely with New York Heart Association functional class and markers of longitudinal systolic function (all P<0.001) but not global ejection fraction or aortic valve area. Nine months after AVR, the degree of late enhancement remained unchanged, implying that AVR failed to reduce the degree of replacement fibrosis. Patients with no fibrosis experienced a marked improvement in New York Heart Association class from 2.8±0.4 to 1.4±0.5 (P<0.001). Only parameters of longitudinal systolic function predicted this functional improvement. Four patients with severe fibrosis died during follow-up, but no patient from the other groups died.
Conclusions— Myocardial fibrosis is an important morphological substrate of postoperative clinical outcome in patients with severe aortic stenosis and was not reversible after AVR over the 9 months of follow-up examined in this study. Because markers of longitudinal systolic function appear to indicate sensitively both the severity of myocardial fibrosis and the clinical outcome, they may prove valuable for preoperative risk assessment in patients with aortic stenosis.
Received December 30, 2008; accepted June 5, 2009.
In patients with aortic stenosis, left ventricular (LV) hypertrophy compensates for pressure overload. LV hypertrophy in patients with aortic stenosis may be accompanied by interstitial myocardial fibrosis starting at the subendocardial layers1 and progressing toward replacement fibrosis.2 These alterations gradually affect LV systolic and diastolic function, thus contributing to the typical symptoms of dyspnea and angina pectoris.2–4
Clinical Perspective on p 584
European and American guidelines for the management of patients with valvular heart disease5,6 evaluate aortic stenosis severity and prognosis by aortic valve area, pressure gradient. and parameters of global LV systolic function (eg, ejection fraction). However, these indexes sometimes correlate poorly with patient symptoms and depend on stroke volume.7,8 Furthermore, ejection fraction may be related mainly to global radial function, which is reduced only in end-stage disease.9 Importantly, fibrotic changes induced by aortic stenosis start subendocardially1 and affect mainly longitudinal function, which is not well represented by ejection fraction. To date, it is unknown whether and how the remodeling of the LV toward fibrosis in patients with aortic stenosis is related to LV function and/or clinical outcome after aortic valve replacement (AVR).
Thus, the purposes of this clinical study on patients with symptomatic severe aortic stenosis were to invasively and noninvasively assess and compare the degree of myocardial fibrosis, to investigate the influence of myocardial fibrosis on global and regional myocardial function, and to estimate the impact of myocardial fibrosis on the clinical outcome after AVR. We hypothesized that fibrosis is a major predictor of late clinical outcome and that the preoperative assessment of longitudinal systolic function and late enhancement in cardiac magnetic resonance imaging (cMRI) may help in the prediction of later outcome of patients with aortic stenosis.
This clinical prospective study included consecutive patients with symptomatic severe aortic stenosis referred to the Würzburg University Hospital between March 2006 and February 2007 for left-sided heart catheterization and evaluation before AVR. Patients were eligible if they had isolated severe aortic stenosis defined as symptoms on exertion and an aortic valve area ≤1.0 cm2.5,6 Patients with previous myocardial infarction, significant coronary artery disease (degree of stenosis ≥50%), prior heart surgery, malignant cancer, or other valvular abnormalities greater than stage I were excluded.
Within 3 days after heart catheterization, all subjects were examined by echocardiography, including measurement of mitral ring displacement (assessment of longitudinal wall function), ejection fraction (assessment of global LV function), strain rate imaging (assessment of regional LV function), and cMRI (assessment of replacement fibrosis). In addition, venous blood was drawn for the measurement of biomarkers of fibrosis (Orion, Espoo, Finland) and routine laboratory parameters. Within the next 3 weeks, AVR was performed on all patients, and 2 endomyocardial biopsies were taken intraoperatively through the LV outflow tract from the endocardium of the basal LV septum (assessment of interstitial fibrosis). Ten days after AVR, echocardiography was repeated. Nine months after AVR, patients were invited to attend follow-up studies, including echocardiography and cMRI. The study conformed to the principles outlined in the Declaration of Helsinki, and informed consent was obtained from all patients before any investigation.
Selective coronary angiography was performed with 5F catheters via a right femoral artery approach (Cordis, Miami, Fla). Systolic and end-diastolic LV pressure recordings were made with fluid-filled pigtail catheters after retrograde passage of the aortic valve. After the pigtail catheter in the ascending aorta was pulled back, the peak systolic pressure gradient was calculated. Through the use of a venous approach, right heart catheterization was done with a Swan-Ganz catheter, and the wedge pressure was measured in the wedge position. Stroke volume was calculated with the thermodilution method.
Transthoracic echocardiography was performed with a VIVID7 3.5-MHz ultrasound scanner (GE Ultrasound, Horten, Norway). A standard echocardiographic study for the evaluation of left and right heart dimensions and valvular heart disease was done. Left atrial, LV end-diastolic, and end-systolic dimensions, as well as end-diastolic thickness of the posterior wall and septum, were measured from parasternal LV long-axis images. Ejection fraction was calculated from the biplane modified Simpson method, and meridional end-systolic wall stress was calculated as previously described.10 Aortic valve area was calculated by the continuity equation according to American Heart Association guidelines.5 Blood-pool pulsed Doppler of the mitral valve inflow was used to extract the ratio of early to late diastolic flow velocity (E/A) and the deceleration time. Early diastolic ring motion from the medial side (E′) was extracted by pulsed-wave tissue Doppler imaging, and the E/E′ ratio was calculated. Systolic mitral ring displacement was measured at the septal side with M-mode echocardiography from an apical 4-chamber view and served as a surrogate of the overall systolic longitudinal function of the septum.11 The reproducibility of this parameter was examined by triple (intraobserver) and double (interobserver) measurements of 10 different patients, yielding coefficients of variation of 5.5% and 6.3% for intraobserver and interobserver reproducibility, respectively.
Strain Rate Imaging
Real-time 2-dimensional color Doppler myocardial imaging data were recorded from the interventricular septum using a standard apical 4-chamber view to evaluate longitudinal function. To assess radial function of the posterior wall, parasternal long-axis views were used. Because this method is angle dependent, care was taken that the investigated myocardium and the ultrasound beam were aligned to nearly 0°. Data were analyzed with dedicated software (Echopac, GE Ultrasound).12 Strain rate curves were extracted for the basal septum (longitudinal function) and the basal posterior wall (radial function). Strain rate profiles were averaged over 3 consecutive cardiac cycles and integrated over time to derive natural strain profiles with end diastole as the reference point. From the averaged strain rate and strain data, systolic strain (which is related to regional stroke volume) and peak systolic strain rate (which is related to regional contractility) were calculated.11
Cine cMRI was carried out on all patients without contraindications (n=46). Short-axis views were applied to detect changes in tissue integrity in LV myocardium.13 To detect late enhancement, images were acquired 10 to 15 minutes after the injection of gadopentetate dimeglumine (Magnevist, Schering, Berlin, Germany; 0.2 mmol/kg body weight) by use of an inversion recovery sequence (field of view, 240×320 mm2; matrix, 165×256). All LV segments were evaluated for the presence of myocardial fibrosis according to the standardized nomenclature for imaging of the heart.14 In an initial clinical study, focal late enhancement could be observed in the hypertrophic myocardium of patients with aortic stenosis.15
Grading of Endomyocardial Biopsies and Patient Groups
Patients were divided into 3 groups based on the histological result of the biopsies taken during AVR. Percentage area of fibrosis was calculated and used as the index of the degree of fibrosis.16 The percentage area of fibrosis in the section was obtained by dividing the sum of the fibrotic areas of the section by that of the total tissue area as described by Tanaka et al.16 According to this fibrosis index, 22 patients were classified as having no fibrosis, 15 as having mild fibrosis, and 21 as having severe fibrosis.
Data are presented as mean (SD), median (25th to 75th percentile), or frequency (percent) as appropriate. Image analyses (echocardiography and cMRI) was performed blinded with respect to the evaluation of New York Heart Association (NYHA) functional class and to the amount of fibrosis assessed by myocardial biopsies. We used χ2 tests for linear trend or linear regression analyses to compute probability values for trend across the categories of fibrosis in Table 1. Because ≈25 variables were assessed, the level of statistical significance was set to 0.002 (Table 1). Variables with nonnormal distribution were log normalized before linear regression was performed. Correlations were computed through the use of Spearman correlation coefficient. Changes in hemodynamic variables from baseline to follow-up were tested by ANCOVA, with the difference as the dependent variable, group as the factor, and baseline variable as the covariate. Posthoc significance was tested with the Waller-Duncan t test, which uses the bayesian method to take into account unequal group sizes. ANOVA for repeated measurements was used to compute the probability values presented in Table 2. Determinants of improvement in NYHA functional class were sought through logistic regression, with change in NYHA class from baseline to follow-up as the response variable. Subjects who improved ≥1 functional class were coded as 1, ie, responders. Because 4 subjects died, these analyses refer to 54 subjects. A conventional value of P=0.05 was accepted to indicate statistical significance. Odds ratios with 95% confidence interval (CI) and the Wald statistic (ie, the ratio of the coefficient to its SE squared; the higher the Wald statistic, the more a variable contributes to the model) are reported. All tests were performed 2 sided. SPSS version 16.0.1 (SPSS Inc, Chicago, Ill) was used.
The authors had full access to and take full responsibility for the integrity of the data and the accuracy of the data analysis. All authors have read and agree to the manuscript as written.
In total, 110 patients were screened, and 58 patients were included in the final data set. The main reasons for noneligibility were previous myocardial infarction, significant coronary artery disease, and other valve abnormalities. The amount of fibrosis in the myocardial biopsies varied substantially, as exemplified in Figure 1. Baseline characteristics of patients are presented in Table 1, stratified according to the degree of fibrosis. Dyspnea was the major limitation, and NYHA functional class showed a positive graded relationship with degree of fibrosis (P<0.001 for trend). Further correlations were found for the EuroScore for aortic stenosis6 and levels of amino-terminal probrain natriuretic peptide (a marker for myocardial stress) and procollagen type III amino-terminal propeptide (a collagen III degradation product) (both P<0.001 for trend). In addition, brain natriuretic peptides and procollagen type III amino-terminal propeptide were highest in patients with severe fibrosis (Table 1).
Cardiac Function and Morphology
Table 1 shows that aortic valve area and surrogates of global systolic function as the ejection fraction were similar among the 3 groups. Inverse graded relationships with the degree of fibrosis were found for stroke volume, LV end-systolic pressure, mean and maximum aortic gradients (echocardiography), longitudinal strain and strain rate, and mitral ring displacement (Figure 2). Positive graded associations with degree of fibrosis were found for LV and left atrial diameters and E/E′. Mitral ring displacement was closely correlated with stroke volume and longitudinal strain rate (r=0.50 and r=0.61, both P<0.001).
Baseline cMRI was not feasible in 12 subjects because of claustrophobia (n=8) or implanted devices (n=4). Hence, cMRI was completed in 46 patients (no fibrosis, n=18; mild, n=12; severe, n=16). The distribution of late enhancement positive segments within the 3 groups is shown in Figure 3. Of the patients with severe fibrosis, 88% (n=14) had ≥2 positive segments. In contrast, 89% of the patients with no fibrosis (n=16) had no positive segment (ie, no late enhancement). The distribution of the late-enhancement–positive segments within the 17-segment model of the LV is shown in Figure 4. In general, the late-enhancement distribution within 1 segment was rather patchy. However, it was detected mainly at the subendocardial layer. Only 5 patients had 1 segment and 3 patients had 2 segments with a late-enhancement transmurality of >50% (all from the group with severe fibrosis). LV mass assessed by cMRI was comparable among the 3 groups (no fibrosis, 211±70 g; mild, 193±32 g; severe, 198±68 g; P=0.195). Mitral ring displacement, a parameter of longitudinal function, decreased gradually with increasing number of late-enhancement–positive segments in cMRI (P<0.001 for trend).
Forty patients received an aortic bioprosthesis, and 18 received a mechanical valve. Four patients, all with severe fibrosis, died during the follow-up period because of cardiac complications (3 died within the first 30 days). The relatively high mortality could be due to the facts that all patients were severely symptomatic and that many patients were in an advanced stage of the disease. Nine months after AVR, mean aortic valve area was normal in all patients (no fibrosis, 2.1±0.5 cm2; mild, 2.0±0.3 cm2; severe, 2.0±0.5 cm2). Ejection fraction increased in subjects with no fibrosis at baseline (8±5%; P<0.001), was unchanged in mild fibrosis (+2±5%; P=0.42), and showed a trend for reduction in severe fibrosis (−4±2%; P=0.050). End-diastolic thickness of the posterior wall was unchanged after 10 days but decreased in all 3 groups after 9 months (percent decrease: no fibrosis, −21.1%; mild fibrosis, −14.5%; severe fibrosis, −9.8%; all P<0.05). In parallel, the LV mass assessed by cMRI decreased significantly in all 3 groups 9 months after AVR (no fibrosis, −24.2%; mild fibrosis, −12.9%; severe fibrosis, −11.9%; all P<0.05).
The changes in radial and longitudinal strain and strain rate during follow-up are shown in Table 2. In patients with no or mild fibrosis, radial strain and strain rate increased as early as 10 days after valve replacement (for strain rate, +36% and +32%, respectively; P<0.001 and P=0.004). In contrast, an increase in longitudinal septal strain and strain rate became apparent only after 9 months and was confined to patients with no fibrosis (Table 2). There was no significant change in the late-enhancement–positive segments 9 months after AVR in all patient groups (Figure 3).
The changes in NYHA functional class 9 months after AVR are displayed in Figure 5. Patients with no fibrosis at baseline showed a marked improvement in NYHA functional class, from 2.8±0.4 to 1.4±0.5 (P=0.01). Some patients with mild fibrosis also showed a clinical improvement, although statistically only a trend was observed (P=0.16). Of note, none of the subjects with severe fibrosis improved except for 2 subjects who improved from NYHA class IV to III. In logistic regression analyses with fixed adjustment for age and sex and alternative adjustment for surrogates of fibrosis, mitral ring displacement (Wald, 11.1; odds ratio, 2.0 per 1 mm; 95% CI, 1.3 to 3.0; P<0.001), longitudinal strain rate (odds ratio, 1.7 per 0.1 second−1; 95% CI, 1.2 to 2.3; Wald, 10.2; P=0.001), or EuroScore above the median of 8.71 (odds ratio, 0.18; 95% CI, 0.04 to 0.85; Wald, 4.7; P<0.001) was independently predictive for the improvement in NYHA functional class after AVR. In particular, a mitral ring displacement of >7 mm had a very good diagnostic utility to predict improved NYHA class after AVR: positive predictive value, 0.97 (95% CI, 0.87 to 1.00); sensitivity, 0.82 (95% CI, 0.76 to 0.87); and specificity, 0.93 (95% CI, 0.84 to 0.98). In contrast, the ejection fraction and parameters of diastolic function were not predictive of better outcome after AVR.
This prospective clinical study provides evidence that myocardial replacement fibrosis is an important factor in symptomatic severe aortic stenosis: It is common, determines regional impairment of the LV in systole, is not reversible in the course of 9 months after AVR, and has a profound impact on the long-term outcome after AVR. Furthermore, it was demonstrated that the effect of regional myocardial fibrosis on cardiac function could be assessed by measuring the displacement of the septal mitral ring in echocardiography. Because mitral ring displacement predicted the degree of long-term functional improvement after AVR, it may serve as an adjunct in the preoperative management of this clinically challenging group of patients.
Myocardial Fibrosis in Aortic Stenosis
In the hypertrophic myocardium of patients with severe aortic stenosis, myocardial perfusion is decreased and systolic wall stress is increased. Both phenomena apply predominantly to the subendocardial layers, leading first to interstitial and later to replacement fibrosis during disease progression.1,17 We used endomyocardial biopsy, the current reference standard for the assessment of myocardial fibrosis, to rate the degree of fibrosis in our patients at baseline. In addition, replacement fibrosis was visualized noninvasively with late-enhancement imaging during cMRI. Interestingly, myocardial segments positive for late enhancement were mainly found at the LV base, where regional wall stress is highest as a result of the flat curvature of the LV.18 It is reasonable to assume that replacement of cardiac fibers by noncontractile fibrotic tissue should affect myocardial function. However, ejection fraction, as the reference standard for global LV function, was normal in most patients. Ejection fraction is determined mainly by radial myocardial function, which is not substantially affected by subendocardial abnormalities.9 Accordingly, radial function was rather preserved in our study, even in patients with severe fibrosis. It has previously been shown that ejection fraction will decrease at the very advanced phase of the disease, when both radial function and longitudinal function are compromised.2 Obviously, AVR should be performed before this stage of disease progression has been reached. In contrast, longitudinal function is affected mainly by subendocardial fibrosis. In line with this hypothesis, our measurements of regional function, ie, systolic strain and strain rate, revealed a marked reduction in patients with severe fibrosis. Accordingly, mitral ring displacement, the surrogate of overall longitudinal function of the septum, showed a graded relationship with the degree of myocardial fibrosis, with the lowest levels in the group with severe fibrosis. The present study suggests that modern imaging techniques allow us to judge fibrotic changes and use this information for preoperative risk stratification.
Fibrosis-related functional abnormalities also affect global hemodynamics.4 Stroke volume was reduced in patients with severe fibrosis, resulting in a lower mean transvalvular gradient (low-gradient aortic stenosis). This finding matches a recently published study demonstrating that patients with low-gradient aortic stenosis had a worse outcome after AVR.19 In addition, serum biomarkers for the degradation of collagen (procollagen type III amino-terminal propeptide) and for myocardial stress (NT-probrain natriuretic peptide) were highest in patients with severe fibrosis. The latter finding is in good accord with the Truly or Pseudo-Severe Aortic Stenosis (TOPAS) study, in which patients with lower values of natriuretic peptides had a better survival after AVR.20 Furthermore, patients with a higher degree of fibrosis were more symptomatic before AVR and had a worse long-term clinical outcome. Of note, all patients who died during follow-up in the present study were patients with severe fibrosis.
The clinical management of patients with aortic stenosis is based mainly on the assessment of valvular parameters, ejection fraction, and symptoms.5,6 Valvular parameters like aortic valve area and transvalvular gradient do not predict clinical outcome after AVR.19 Ejection fraction as a marker of global LV function is normal in most patients and therefore not helpful for long-term patient management. The findings of the present study support a preoperative diagnostic approach that emphasizes the primary structural abnormalities of the LV myocardium because they are altered much earlier along the disease continuum and appear to determine the long-term clinical outcome after AVR. In this context, myocardial fibrosis seems to be the critical abnormality that can be visualized directly by cMRI in most of these patients. Of further clinical interest is the observation that this type of fibrosis was irreversible in the postoperative period. Consistently, in patients with severe fibrosis, longitudinal function and NYHA functional class also were not improved after AVR.
With respect to the clinical assessment of the patient with severe aortic stenosis, mitral ring displacement emerged as a marker of structural abnormalities and a useful surrogate of myocardial fibrosis. Mitral ring displacement can be assessed conveniently and reliably in every patient with aortic stenosis with standard echocardiographic methods. A displacement of the mitral ring >7 mm had an excellent positive predictive value for functional improvement after AVR. However, because of the relatively small sample size, these data are preliminary, and the clinical utility of this promising marker (eg, in an improved preoperative diagnostic algorithm) needs to be investigated in future prospective studies.
The clinical outcome after AVR was assessed only by NYHA class. A 6-minute walking test would allow a more precise quantification of exercise capacity after AVR. This might also be the explanation why in the group of patients with severe fibrosis no improvement could be documented.
During disease progression, patients with aortic stenosis gradually develop myocardial fibrosis, typically located subendocardially at the basal segments of the LV. This type of fibrosis has a profound impact on the long-term clinical outcome but remains undetected by standard echocardiographic examination up to the terminal stage of the disease. The longitudinal displacement of the mitral ring can be measured reliably during standard echocardiography, captures the functional consequences of myocardial fibrosis, and predicts functional improvement after valve repair.
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Aortic valve stenosis remains a diagnostic and therapeutic challenge, particularly in the elderly. In patients with aortic stenosis, left ventricular hypertrophy compensates for pressure overload. Left ventricular hypertrophy may be accompanied by interstitial myocardial fibrosis starting at the subendocardial layers and progressing toward replacement fibrosis. Importantly, fibrosis also may have an impact on patient outcome after aortic valve replacement. In a clinical follow-up study, we assessed the degree of myocardial fibrosis and its influence on myocardial function and clinical outcome after aortic valve replacement in patients with symptomatic severe aortic stenosis. The findings support a preoperative diagnostic approach that focuses on the structural abnormalities of the left ventricular myocardium. In this context, myocardial replacement fibrosis seems to be the critical abnormality that can be visualized directly with late-enhancement cardiac magnetic resonance imaging in most of these patients. This type of fibrosis has a profound impact on the long-term clinical outcome but remains undetected by standard echocardiographic examination. However, the longitudinal displacement of the mitral ring can be measured reliably during standard echocardiography, captures the functional consequences of myocardial fibrosis, and predicts functional improvement after aortic valve replacement. Thus, the evaluation of mitral ring displacement also may prove valuable for routine preoperative risk assessment.
↵*The first 2 authors contributed equally to this work.
The online-only Data Supplement is available with this article at http://circ.ahajournals.org/cgi/content/full/CIRCULATIONAHA.108.847772/DC1.