Published online before print April 23, 2007, doi: 10.1161/CIRCULATIONAHA.106.657023
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(Circulation. 2007;115:2418-2425.)
© 2007 American Heart Association, Inc.
Imaging |
Evidence for Microvascular Dysfunction in Hypertrophic Cardiomyopathy
New Insights From Multiparametric Magnetic Resonance Imaging
From the Department of Cardiovascular Medicine and University of Oxford Centre for Clinical Magnetic Resonance Research, University of Oxford, Oxford, UK (S.E.P., L.E.H., M.D.R., J.M.F., J.B.S., S.N., H.W.); Advanced Imaging Research Center, Oregon Health & Science University, Portland, Ore (M.J.-H.); and Department of Public Health, University of Oxford, Oxford, UK (H.A.D.).
Correspondence to Steffen E. Petersen, MD, DPhil, University of Oxford Centre for Clinical Magnetic Resonance Research, Department of Cardiovascular Medicine, John Radcliffe Hospital, Oxford, OX3 9DU, UK. E-mail steffen.petersen{at}cardiov.ox.ac.uk
Received August 7, 2006; accepted March 2, 2007.
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Abstract |
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Background— Microvascular dysfunction in hypertrophic cardiomyopathy (HCM) may create an ischemic substrate conducive to sudden death, but it remains unknown whether the extent of hypertrophy is associated with proportionally poorer perfusion reserve. Comparisons between magnitude of hypertrophy, impairment of perfusion reserve, and extent of fibrosis may offer new insights for future clinical risk stratification in HCM but require multiparametric imaging with high spatial and temporal resolution.
Methods and Results— Degree of hypertrophy, myocardial blood flow at rest and during hyperemia (hMBF), and myocardial fibrosis were assessed with magnetic resonance imaging in 35 HCM patients (9 [26%] male/26 female) and 14 healthy controls (4 [29%] male/10 female), aged 18 to 78 years (mean±SD, 42±14 years) with the use of the American Heart Association left ventricular 16-segment model. Resting MBF was similar in HCM patients and controls. hMBF was lower in HCM patients (1.84±0.89 mL/min per gram) than in healthy controls (3.42±1.76 mL/min per gram, with a difference of –0.95±0.30 [SE] mL/min per gram; P<0.001) after adjustment for multiple variables, including end-diastolic segmental wall thickness (P<0.001). In HCM patients, hMBF decreased with increasing end-diastolic wall thickness (P<0.005) and preferentially in the endocardial layer. The frequency of endocardial hMBF falling below epicardial hMBF rose with wall thickness (P=0.045), as did the incidence of fibrosis (P<0.001).
Conclusions— In HCM the vasodilator response is reduced, particularly in the endocardium, and in proportion to the magnitude of hypertrophy. Microvascular dysfunction and subsequent ischemia may be important components of the risk attributable to HCM.
Key Words: cardiomyopathy • contrast media • fibrosis • magnetic resonance imaging • perfusion
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Introduction |
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Hypertrophic cardiomyopathy (HCM) is a disease entity characterized by the development of cardiac hypertrophy without an obvious extrinsic cause, such as pressure or volume overload, and is a disease of the sarcomere.1 Sudden cardiac death is a well-recognized feature of this disease, and HCM is the most common cause of sudden death in the younger population, particularly in young athletes.2 The risk of sudden cardiac death increases with multiple clinical risk factors, such as nonsustained ventricular tachycardia, syncope, exercise blood pressure response, family history of sudden death, and extreme left ventricular (LV) hypertrophy.3 In addition, marked LV outflow tract obstruction and coronary microvascular dysfunction have been found to be independent predictors of sudden death in HCM.4,5 Moon and colleagues6 demonstrated an association between the extent of myocardial fibrosis and progressive ventricular dilatation and markers of sudden death.
Clinical Perspective p 2425
Although adverse microvascular remodeling and coronary microvascular dysfunction, reflected by an inadequate increase in myocardial blood flow (MBF) in response to a coronary vasodilator, has been noted in HCM, it remains unknown whether the impairment of the hyperemic response is related to the degree of LV hypertrophy.5,7–12 Hypertrophy is an independent risk factor for sudden death in HCM, but the underlying mechanism is unclear; potentially sudden death could be associated with impaired myocardial perfusion or extent of myocardial fibrosis. Current risk factor stratification does not assess either of these parameters reliably.3
Cardiovascular magnetic resonance imaging (MRI) during the first pass of a contrast agent allows the evaluation of myocardial perfusion both at rest and during pharmacological stress. Cardiovascular MRI first-pass perfusion is an attractive novel methodology with which to explore the uncertainties regarding myocardial perfusion in HCM: First, it has been validated against the gold standard of microspheres13; second, it is characterized by superior spatial resolution compared with nuclear imaging methods (including positron emission tomography [PET]), permitting the assessment of transmural perfusion gradients; third, myocardial perfusion can be quantified in absolute terms in milliliters per minute per gram, which has the advantage of identifying abnormalities in perfusion that lead to spatially coherent reductions in both rest and stress perfusion, therefore potentially creating the misleading impression of a "normal" perfusion reserve; fourth, cardiovascular MRI first-pass perfusion data can be matched within given myocardial segments to other important parameters provided by cardiovascular MRI for risk stratification, such as wall thickness or extent of fibrosis, which cannot be provided by any other single imaging modality.14
In the present study we assessed the association of blood flow in relation to wall thickness and extent of fibrosis with the use of high-resolution quantitative cardiovascular MRI. Advancing knowledge and understanding of these pathophysiological interrelations may form an important initial step toward improved clinical risk assessment for sudden cardiac death in HCM.
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Methods |
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Ethics and Study Population
The study was approved by our institutional ethics committee, and informed written consent was obtained from each patient. All MRI data were analyzed in a blinded manner.
Thirty-five consecutive patients with HCM from the University of Oxford Cardiomyopathy Clinic (9 male/26 female; mean age, 44±15 years) and 14 healthy controls (4 male/10 female; mean age, 39±11 years) were enrolled into the study. The diagnosis of HCM was based on genetic confirmation of a pathogenic mutation, or when no genetic confirmation of HCM was available, it was based on the conventional criteria of LV hypertrophy not originating from other causes (
15 mm or 13 mm in documented familial disease) determined by echocardiography.15 Healthy volunteers had no history of cardiac disease, hypertension, and other cardiac risk factors and had a normal 12-lead ECG.
Subjects with contraindications for MRI were not enrolled. Typical contraindications for adenosine applied, including asthma and higher degree of heart block. All subjects undergoing adenosine administration had abstained from caffeine intake for at least 12 hours before the study. Table 1 highlights characteristics of HCM patients and healthy subjects.
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MRI Protocol
All cardiovascular MRI examinations were performed on a 1.5-T MRI system (Sonata; Siemens Medical Solutions, Erlangen, Germany). After scout imaging was performed, steady state free precession cine images were acquired in horizontal and vertical long-axis views, and short-axis views were obtained parallel to the atrioventricular groove and included the entire LV.16
A gadolinium-based contrast agent (gadodiamide [Omniscan]; Nycomed Amersham, Amersham, UK) was then administered intravenously as a bolus at a dose of 0.025 mmol/kg body wt (injection rate, 5 mL/s; concentration, 0.5 mmol/mL), followed by a saline flush of 13 mL at the same rate. Perfusion imaging was performed every heartbeat during the first pass of the contrast bolus with the use of a T1-weighted fast (spoiled) gradient echo sequence with saturation-recovery magnetization preparation, as described previously.14 Perfusion images were acquired in 3 short-axis sections at basal (between LV outflow tract and the papillary muscles), midventricular, and apical levels chosen according to recommended guidelines.17 To allow sufficient contrast washout, we performed stress perfusion imaging 10 minutes after the study at rest. Adenosine was used as the pharmacological vasodilator and was administered at a rate of 140 µg/kg per minute for at least 2 minutes before and during data acquisition. After stress perfusion imaging, we gave an additional dose of 0.1 mmol/kg gadodiamide to reach a total administered dose of 0.15 mmol/kg. The delayed enhancement images were acquired after an additional 10-minute delay with the use of an inversion-recovery prepared, segmented gradient echo sequence, as previously described (Figure 1).18,19
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Image Analysis
Both global LV function and segmental wall thickness were analyzed with the use of commercially available computer software by manual tracing of endocardial and epicardial contours (Argus and Syngo2002B; Siemens Medical Solutions, Erlangen, Germany). The following global parameters (normalized to the body surface area) were determined by planimetry of short-axis cine images: LV end-diastolic volume index (mL/m2), LV end-systolic volume index (mL/m2), LV stroke volume index (mL/m2), LV ejection fraction (%), and LV mass index (g/m2). End-diastolic wall thickness was determined in 6 basal, 6 midventricular, and 4 apical segments.17
For perfusion analysis, the endocardial and epicardial contours were traced manually with the use of the software MRI-MASS (Medis, Leiden, the Netherlands). Again, the myocardium was divided into 16 corresponding segments and was further subdivided into endocardial (inner 50% of transmural thickness) and epicardial (outer 50% of transmural thickness) layers. MBF was determined by model-independent deconvolution of signal intensity curves with an arterial input function measured in the LV blood pool,13 with explicit accounting for any delay in the arrival of the tracer (Figure 2).20 Details about the estimation of MBF are provided in the online-only Data Supplement.
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Delayed contrast-enhanced images were quantified with the use of computer-assisted planimetry with a 16-segment model identical to that described above. Hyperenhanced pixels were defined as those with signal intensities >2 SD above the mean signal intensity in remote myocardium in the same slice.21 The segmental extent of fibrosis was expressed as a percentage of hyperenhanced pixels within each segment [ie, segmental extent of fibrosis=100xhyperenhanced pixels/(hyperenhanced+nonhyperenhanced pixels)]. The incidence of fibrosis was a dichotomous parameter based on presence or absence of hyperenhancement within each segment.
Statistical Analysis
Values are expressed as mean±SD. Regression analysis with the use of linear mixed-effects models with a random intercept for subject was performed to take account of within-patient correlations of repeated measurements.22 The analysis was performed in the R statistical analysis environment (R, version 2.3.1; The R Foundation for Statistical Computing, Vienna, Austria, 2006; http://www.r- project.org/). Linear regression models were used to test for significant associations between resting or hyperemic blood flow and end-diastolic wall thickness as a measure of the magnitude of hypertrophy. The dependent variable was adjusted in the fixed-effects part of the linear mixed-effects model for differences in age, gender, rate-pressure product at rest (in the case of resting MBF), extent of contrast enhancement, and HCM diagnosis. For hyperemic MBF (hMBF) as the dependent variable, we additionally tested for the hypothesis that the presence of LV outflow tract gradient >30 mm Hg caused a significant decrease of MBF. hMBF was adjusted simultaneously for resting MBF instead of using a ratio of hyperemic blood flow divided by resting blood flow because the latter quantity has ill-defined statistical properties. Myocardial ischemia and the magnitude of hypertrophy were considered putative causes of fibrosis. Therefore, logistic regression model analysis was used to analyze the incidence of myocardial fibrosis and to determine whether its likelihood is associated with end-diastolic wall thickness and hMBF. The logistic regression model analysis with repeated measurements of fibrosis in each patient was performed with a general linear model with logit link and with mixed effects using linearization about the best linear unbiased predictors.23 The Student t test for unpaired data was used for comparison of baseline characteristics for continuous variables, and the 
2 test was used for categorical data (gender). Statistical significance was taken throughout at the 5% level (P<0.05).
The authors had full access to and take full responsibility for the integrity of the data. All authors have read and agree to the manuscript as written.
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Results |
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Study Population
Healthy controls and HCM patients differed only in LV mass index but not in age, gender, and other characteristics listed in Table 1. Overall, the HCM patient cohort was considered low risk according to clinical risk stratification and was mainly asymptomatic, with 68% in New York Heart Association class I (Table 2).3 In HCM patients, 475 of 560 segments (35x16 segments) were used for statistical analysis, with complete data in each of these segments for wall thickness, resting and stress perfusion, and delayed contrast enhancement. Incomplete data sets were mainly a result of gaps in perfusion data either because of insufficient data quality or because of acquisition of only 2 slices during adenosine infusion in patients with heart rates not allowing acquisition of a third slice. The contrast-to-noise ratio for all perfusion studies averaged 23:1±11:1 and was significantly higher during hyperemia (28:1±12:1) than during rest (18:1±7:1; P<0.001 for paired t test).
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In HCM patients, 142 of 475 myocardial segments (29.9%) had an end-diastolic wall thickness >12 mm (range for the 475 segments, 1 to 34.5 mm; mean±SD, 10.9±5.0 mm), and 72 of 475 myocardial segments (15.2%) showed delayed gadolinium contrast enhancement. The extent of delayed contrast enhancement in segments with any delayed contrast enhancement ranged from 10% to 100% (mean±SD, 58.8±27.4%). The incidence of fibrosis (P<0.001) was found to increase significantly across quartiles of end-diastolic wall thickness (Figure 3A). In the logistic regression model, with end-diastolic wall thickness treated as a continuous variable, the odds for presence of delayed contrast enhancement in HCM patients were 1.13:1 for each millimeter increase in end-diastolic wall thickness (P<0.001).
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In healthy controls, the end-diastolic wall thickness ranged from 3.5 to 11.9 mm (mean±SD, 7.3±1.8 mm).
A proportion of the 35 patients with HCM were on medications with potential confounding effects on MBF (Table 2): 15 took ß-blockers (43%), 2 were treated with calcium channel inhibitors of the verapamil/diltiazem type (6%), 4 were treated with disopyramide (12%), and 6 were on amiodarone (17%).
Five of 35 HCM patients (14.3%) had a resting LV outflow tract gradient >30 mm Hg on echocardiography. This parameter was documented as a dichotomous variable because of intraindividual variability of this parameter and on the basis of the proposed cutoff of 30 mm Hg in a prospective study demonstrating its prognostic value.4
Myocardial Perfusion Reserve
Resting MBF averaged 0.71±0.27 mL/min per gram in HCM patients and 0.85±0.30 mL/min per gram in controls. Resting MBF, adjusted for age (P=0.58), gender (P<0.001), and resting rate pressure product (P<0.001), was similar in HCM patients and controls but with a significant (P<0.001) difference of 0.21±0.06 mL/min per gram between female and male subjects.
Myocardial fibrosis was observed more frequently in a segment with poor hyperemic response. Figure 3B demonstrates the decreasing incidence of fibrosis with increasing hyperemic blood flow. The odds for fibrosis in a myocardial segment increased by 2.2:1 (P<0.01) for each 1 mL/min per gram decrease of hyperemic blood flow (P<0.01), with simultaneous adjustment for age (P=0.11) and gender (P=0.11).
The average of hMBF in HCM patients was 1.84±0.89 mL/min per gram in HCM patients and lower than the mean of 3.42±1.76 mL/min per gram in healthy controls (P<0.01 for t test of per-subject means of MBF between HCM patients and healthy controls). hMBF in myocardial segments remained significantly lower in HCM patients (by –0.95±0.30 [SE] mL/min per gram; P<0.001), with adjustment for age (P=0.13), gender (P=0.90), end-diastolic segmental wall thickness (–0.013±0.004 [SE] mL/min per gram per millimeter wall thickness; P<0.001), resting MBF (P<0.001), presence of LV outflow tract gradient >30 mm Hg (P=0.06), and extent of delayed contrast enhancement (P=0.95) in the linear mixed-effects model (Figure 4A). hMBF in the endocardial layer of myocardial segments was lower by –1.23±0.39 mL/min per gram in HCM patients than in normal volunteers (P=0.001), with simultaneous adjustment for age, gender, end-diastolic wall thickness (P<0.001), resting MBF (P<0.001), presence of LV outflow tract gradient >30 mm Hg, and extent of delayed contrast enhancement (P=0.64). The ratio of endocardial to epicardial hMBF averaged over all segments was 1.08:1 in healthy controls and 0.99:1 in HCM patients (P=0.07 for Wilcoxon rank sum test). Within the HCM patients, the incidence of a hyperemic endocardial hMBF lower than epicardial hMBF increased over quartiles of end-diastolic wall thickness (P=0.03; odds increased by 1.05:1 per millimeter increase of end-diastolic wall thickness), suggesting a preferential reduction of hMBF in the endocardial layer with increasing magnitude of hypertrophy (Figure 4C).
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Within the group of HCM patients, hMBF decreased by 0.011 mL/min per gram (SE 0.0035) for each millimeter increase of end-diastolic wall thickness (P<0.005), with simultaneous adjustment for age (P=0.27), gender difference (P=0.74), resting MBF (P<0.001), extent of contrast hyperenhancement (ie, fibrosis) (P=0.48), and presence of LV outflow tract gradient of >30 mm Hg (coefficient mean±SE, –0.86±0.33 mL/min per gram; P<0.02). Similarly, in the endocardial layer, hMBF decreased by 0.017 mL/min per gram (SE 0.003) for each millimeter increase of end-diastolic wall thickness. Figure 5 shows the transmural and endocardial layer averages of hMBF by quartiles of end-diastolic wall thickness. hMBF in the endocardial layer was modeled as a function of the transmural hMBF or epicardial hMBF and end-diastolic wall thickness (quartile) categories. The rate at which endocardial hMBF increases with transmural or epicardial hMBF was reduced significantly for the 2 highest end-diastolic wall thickness quartiles (P<0.05), with the most pronounced interaction effect in the highest end-diastolic wall thickness quartile.
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Discussion |
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In the present MRI study, we demonstrate in patients with HCM a reduced myocardial perfusion reserve as measured by hMBF, particularly in the endocardium, and in proportion to the magnitude of hypertrophy. It has been shown that the magnitude of hypertrophy is related directly to the risk of sudden death,24 but the pathophysiological mechanisms of sudden death remain largely unknown. It was observed previously that the vasodilator response is impaired in HCM in both hypertrophied and nonhypertrophied wall segments.10 The association of vasodilator response impairment and end-diastolic wall thickness observed in the present study indicates that ischemia is more prevalent and more severe in hypertrophied segments. The diagnosis of HCM was in itself associated with a significant reduction of hMBF with simultaneous multivariable adjustment, including end-diastolic wall thickness, LV outflow tract gradient >30 mm Hg, and extent of delayed contrast enhancement. This suggests that the vasodilator response in HCM patients is already impaired in segments without hypertrophy and decreases further with hypertrophy. Furthermore, our finding of decreased incidence of myocardial fibrosis with increasing hMBF may suggest a pathophysiological link between repetitive hypoperfusion during stress and development of myocardial fibrosis. The unique ability of cardiac MRI to match perfusion and myocardial fibrosis data in a single investigation thus provides novel insights into a potential mechanism for the development of myocardial fibrosis in HCM patients. It is tempting to speculate that hypoperfusion and/or the associated fibrosis may contribute to the increased risk of sudden cardiac death during or after strenuous physical exercise in these patients.
Myocardial perfusion and perfusion reserve have been shown to be of prognostic value in patients with HCM, and these parameters may become an integral part of clinical risk stratification.5 Elliott and colleagues3 introduced the concept of risk factor burden, including syncope and family history of sudden cardiac death, nonsustained ventricular tachycardia, abnormal blood pressure response, and marked LV hypertrophy (>30 mm). The use of MRI in the present study provided the important advantage of spatially matched, high-resolution measurements of LV hypertrophy, MBF, and myocardial fibrosis all made within 1 MRI study of <60 minutes in duration.25–27 We found reduced hMBF in HCM patients with and without hypertrophy. This is consistent with PET data demonstrating impaired microvascular function in both hypertrophied and nonhypertrophied myocardium in such patients,10 although the resolution of PET is suboptimal for assessing the magnitude of hypertrophy. In addition, myocardial fibrosis, a possibly important confounding factor, could also be assessed directly in the present MRI study with high spatial resolution. Although the results are reported here for a standardized American Heart Association segment model, the underlying measurements are made with resolution sufficient to investigate perfusion, viability, and function in the endocardial and epicardial layers and to show a higher predisposition of the endocardial layer to ischemia. An MRI study previously showed, in a selected cohort of patients with the Asp175Asn mutation of the 
-tropomyosin gene, an association between perfusion and LV hypertrophy by a semiquantitative approach rather than by an absolute quantification of MBF.28 Furthermore, myocardial fibrosis was not assessed in that previous MRI study, and a confounding of myocardial fibrosis with perfusion impairments could not be excluded. The present study clearly demonstrates a higher incidence of myocardial fibrosis with increasing wall thickness, in agreement with work by other groups,29–31 but the inverse relationship of LV hypertrophy and perfusion reserve still remains after adjustment for the extent of fibrosis. The identified association between LV hypertrophy and hMBF exists in both patients with and patients without outflow tract obstruction, suggesting that perfusion reserve as a risk factor does not simply reflect obstruction, an emerging risk stratification parameter with prognostic importance.4 These findings suggest that LV hypertrophy should be interpreted as a continuous risk parameter rather than a dichotomous one with an arbitrary threshold. Furthermore, myocardial perfusion may hold additional prognostic information over LV wall thickness measurements as part of clinical risk stratification, which may be particularly valuable in patients with mild LV hypertrophy and few clinical risk factors, as demonstrated in our low-risk HCM cohort.
MBF quantification by first-pass MRI has been validated in experimental work with the use of microspheres.13,32,33 In the present study we used a smaller dosage of Gd-DTPA contrast than in most previous studies to maintain a linear relation between signal and contrast concentration, an important assumption of the analysis. The majority of our flow data in both healthy volunteers and HCM patients at rest and during hyperemia are in agreement with previous studies using first-pass MRI and other modalities, such as PET.5,10,27 Slight deviations may be explained by differences in baseline characteristics, such as age, gender distribution, and blood pressure, because all of these substantially influence MBF.34 In agreement with data from Camici and colleagues,10 we confirmed that the MBF at rest in HCM was not different from that in healthy controls, and this finding was independent of wall thickness, myocardial fibrosis, and other potential confounders.
Recently, we demonstrated decreased MBF at rest in myocardial segments with significant amounts of delayed contrast enhancement in patients with ischemic heart disease.14 Similarly, in our HCM cohort we observed a significant association between hMBF and the extent of myocardial fibrosis as measured by delayed contrast enhancement.
We have demonstrated preferential reduction of endocardial hMBF with increasing wall thickness. With the use of the superior spatial resolution of MRI over PET, this now allows new insights into the transmural blood flow distribution. A PET study has shown improved endocardial to epicardial blood flow ratios in hypertrophied septal segments after verapamil treatment of HCM patients despite unchanged total MBF. Endocardial and epicardial flows could not be assessed in nonhypertrophied segments because of the spatial resolution limit of PET in that study of 
6 mm.11 Muehling and colleagues35 have demonstrated the feasibility of establishing a normal range of distribution of endocardial and epicardial MBF at rest and during administration of adenosine in myocardium of young healthy volunteers with normal wall thickness using first-pass MRI.
There may have been some selection bias in the present study. HCM patients with a high risk of sudden cardiac death and an internal cardioverter-defibrillator device were excluded from this study (MRI contraindication), as well as patients with higher-degree atrioventricular block (adenosine contraindication). Our patient cohort is thus predominantly at low risk of sudden cardiac death. This may be viewed as a strength of the study, suggesting a potential role for hMBF in the risk assessment of relatively lower-risk patients.
In conclusion, our present study shows that in HCM perfusion reserve is reduced, particularly in the endocardium, and in proportion to the magnitude of hypertrophy. Thus, microvascular dysfunction and ischemia may be important components of the risk attributable to hypertrophy in HCM, and future clinical risk assessment should include these parameters.
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Acknowledgments |
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Sources of Funding
This study was supported by grants from the German Academic Exchange Service (to Dr Petersen), the British Heart Foundation (to Dr Petersen, L. Hudsmith, Dr Selvanayagam, Dr Neubauer, and Dr Watkins) and the Wellcome Trust (to Drs Neubauer and Watkins). Dr Jerosch-Herold was supported by R01 HL65394 from the National Institutes of Health. Dr Neubauer received research support from Siemens Medical Solutions.
Disclosures
None.
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The online-only Data Supplement, consisting of an addendum with figures, is available with this article at http://circ.ahajournals.org/cgi/ content/full/CIRCULATIONAHA.106.657023/DC1.
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Circulation 2007 115: 2369.
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