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DOI: 10.1148/radiol.2402051038
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(Radiology 2006;240:380-388.)
© RSNA, 2006

Cardiac Imaging

Does Myocardial Fibrosis Hinder Contractile Function and Perfusion in Idiopathic Dilated Cardiomyopathy? PET and MR Imaging Study1

Paul Knaapen, MD, Marco J. W. Götte, MD, PhD, Walter J. Paulus, MD, PhD, Jaco J. M. Zwanenburg, MSc, Pieter A. Dijkmans, MD, Ronald Boellaard, PhD, J. Tim Marcus, PhD, Jos W. R. Twisk, PhD, Cees A. Visser, MD, PhD, Albert C. van Rossum, MD, PhD, Adriaan A. Lammertsma, PhD and Frans C. Visser, MD, PhD

1 From the Departments of Cardiology (P.K., M.J.W.G., P.A.D., C.A.V., A.C.v.R., F.C.V.), Physiology (W.J.P.), Physics and Medical Technology (J.J.M.Z., J.T.M.), Nuclear Medicine and PET Research (R.B., A.A.L.), and Clinical Epidemiology and Biostatistics (J.W.R.T.), VU University Medical Center, De Boelelaan 1117, Room 6D 120, 1081 HV Amsterdam, the Netherlands. Received June 22, 2005; revision requested August 23; revision received September 9; accepted September 23; final version accepted October 31. Address correspondence to P.K. (e-mail: p.knaapen{at}vumc.nl).


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 References
 
Purpose: To prospectively evaluate, by using positron emission tomography (PET) and magnetic resonance (MR) imaging, the interrelationships between regional myocardial fibrosis, perfusion, and contractile function in patients with idiopathic dilated cardiomyopathy (DCM).

Materials and Methods: The study protocol was approved by the hospital ethics committee, and all subjects gave written informed consent. Sixteen patients with idiopathic DCM (mean age, 54 years ± 11 [standard deviation]; nine men) and six healthy control subjects (mean age, 28 years ± 2; five men) were examined with PET and MR tissue tagging. Oxygen 15–labeled water and carbon monoxide were used as tracers at PET to assess myocardial blood flow (MBF) and the perfusable tissue index (PTI), which is inversely related to fibrosis. MBF was determined at rest and during pharmacologically induced hyperemia. Maximum circumferential shortening (Ecc) was determined with MR tissue tagging. Student t tests were performed for comparison of data sets, and linear regression was used to investigate the association between parameters.

Results: Mean global hyperemic MBF (2.23 mL/min/mL ± 0.73), Ecc (–10.5% ± 2.9), and PTI (0.95 ± 0.10) were lower in the patients with DCM than in the control subjects (4.33 mL/min/mL ± 0.85, –17.4% ± 0.6, and 1.09 ± 0.12, respectively; P < .05 for all). In the patients with DCM, regional PTI was related to Ecc (r = –0.21, P = .009) but not to resting or hyperemic MBF. Furthermore, regional Ecc was correlated to both resting (r = –0.28, P = .004) and hyperemic MBF (r = –0.29, P < .001). In addition, the ratio of left ventricular end-diastolic volume to mass, as a reflection of wall stress, was related to global hyperemic MBF (r = –0.52, P = .047) and to global Ecc (r = 0.69, P = .003).

Conclusion: In idiopathic DCM, the extent of myocardial fibrosis is related to the impairment in contractile function, whereas fibrosis and perfusion do not seem to be interrelated. The degree of impairment of hyperemic myocardial perfusion is related to contractility and end-diastolic wall stress.

© RSNA, 2006


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 References
 
Idiopathic dilated cardiomyopathy (DCM) is a primary cardiac disease characterized by depressed contractility and dilatation of the left and/or right ventricle in the presence of normal coronary arteries (1). In DCM, the interstitium is altered and collagen content is increased (1–9), leading to diastolic dysfunction (10). The effects of a stiff cardiac interstitium on systolic performance in this patient group, however, remain unclear because reported studies have yielded conflicting results (3,4,6–9). In particular, the difficulty of performing accurate quantification of fibrosis and contractile function has been a major limitation in these studies. Moreover, myocardial fibrosis and function are not always homogeneously distributed in patients with DCM (2,3,5,11,12). Assessment of these parameters on a regional level is, therefore, necessary for the exploration of a potential correlation.

Another hallmark of DCM is impairment of perfusion reserve, the severity of which is related to systolic dysfunction (13) and contractile reserve (14). In addition, impairment of perfusion reserve is an independent prognostic factor for adverse events (15). It has been hypothesized that, in addition to endothelial dysfunction (16) and high wall stress (13,14,17), increased collagen content may in part be responsible for these perfusion abnormalities (18–20). Data supporting this hypothesis, however, are missing.

Nowadays, improved imaging techniques offer the possibility of overcoming some of the aforementioned limitations. Positron emission tomography (PET) performed by using oxygen 15–labeled water (H215O) and carbon monoxide (C15O), enables noninvasive quantification of both myocardial perfusion (21,22) and fibrosis (23). The latter can be quantified through calculation of the perfusable tissue index (PTI), which enables differentiation between perfusable and nonperfusable tissue (22,23). Studies have demonstrated that a reduction in PTI can be used as an estimate of fibrosis in a chronic myocardial infarction model (24) and in patients with idiopathic DCM (25). The amount and timing of regional myocardial contraction can be measured accurately—thereby enabling quantification of contractile function—by using cardiovascular magnetic resonance (MR) tissue tagging (26,27).

Thus, the purpose of our study was to prospectively evaluate, by using PET and MR imaging, the interrelationships between regional myocardial fibrosis, perfusion, and contractile function in patients with idiopathic DCM.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 References
 
Patient and Control Populations
Sixteen consecutive patients with idiopathic DCM (New York Heart Association functional class, III or IV; left ventricular [LV] ejection fraction, <45%) and six healthy control subjects were examined at our institution with PET and MR imaging between September 2003 and November 2004. The patients with DCM ranged in age from 32 to 69 years (mean, 54 years ± 11), and the control subjects ranged in age from 25 to 30 years (mean, 28 years ± 2). The diagnosis of DCM was based on increased LV dimensions, a globally decreased contraction pattern as determined with echocardiography, and normal coronary arteries at angiography. None of the patients with DCM underwent myocardial biopsy. Patients were excluded when there was an absolute or relative contraindication to PET or MR imaging (eg, a pacemaker, claustrophobia, atrial fibrillation) or if there was evidence of uncontrolled systemic hypertension or any other systemic disease. Patients were clinically stable on medications that included angiotensin-converting enzyme inhibitors, diuretics, digoxin, and ß-blockers. All healthy control subjects underwent a physical examination, electrocardiography, laboratory testing, and echocardiography. None of the results from these examinations revealed any abnormalities. Characteristics of the study population and results of statistical comparisons are given in Table 1. All subjects gave written informed consent, and the protocol was approved by the medical ethics committee. The investigation conformed to the principles outlined in the Declaration of Helsinki.


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  		Table 1. Characteristics of Control Subjects and Patients with Idiopathic DCM

 
Imaging Protocols
PET scanning.—All examinations were performed in two-dimensional mode by using an ECAT EXACT HR+ scanner (Siemens/CTI, Knoxville, Tenn). Patients and subjects were constantly monitored with single-lead electrocardiography, and blood pressure was measured every 3 minutes. After a transmission scan, 1100 MBq of H215O dissolved in 5 mL of saline was injected intravenously in 2 seconds by using a pump; this was followed by a 40-mL saline flush at a rate of 4 mL/sec (bolus injection). A dynamic scan (ie, a scan with multiple frames) was performed that consisted of the acquisition of 40 frames with variable frame length for a total of 10 minutes (ie, 12 frames were acquired for 5 seconds each; 12 frames, for 10 seconds each; six frames, for 20 seconds each; and 10 frames, for 30 seconds each).

After the rest study, myocardial blood flow (MBF) was determined during hyperemia by infusing adenosine at a rate of 140 µg per kilogram of body weight per minute. In one patient with DCM, adenosine infusion during PET was terminated because of anxiety caused by palpitations. Data on hyperemic MBF in patients with DCM therefore consist of findings in 15 patients. Blood pool imaging was then performed. During a 2-minute period, the patient or subject inhaled at least 2000 MBq of C15O and a single frame (static scan) was acquired for 6 minutes, starting 1 minute after the end of inhalation to allow for equilibration in the blood pool. During the C15O scan, three venous blood samples were drawn intravenously and were counted in a sodium iodide well counter that was cross calibrated against the scanner.

Emission data were corrected for the physical decay of 15O, dead time, scatter, randoms, and photon attenuation. Reconstruction of the H215O emission scans was performed by using filtered back projection with a Hanning filter at 0.5 of the Nyquist frequency. Transmission and C15O scans were iteratively reconstructed by using ordered-subset expectation maximization, or OSEM (version 7.1.1; CTI, Knoxville, Tenn), with two iterations and 16 subsets. OSEM images underwent 5-mm full width at half maximum Gaussian postsmoothing to ensure resolution matching between images reconstructed with OSEM and those reconstructed with filtered back projection (resolution, approximately 7 mm).

MR imaging.—Electrocardiographically triggered MR imaging was performed with a 1.5-T system (Sonata; Siemens Medical Systems, Erlangen, Germany) and a phased-array body coil. Patients and subjects were imaged in the supine position. Conventional cine imaging was performed to enable assessment of LV volumes and ejection fraction (26,27). Steady-state free precession cine imaging with myocardial tagging, in conjunction with linearly increasing start-up angles, was applied to acquire tagged images with a high temporal resolution (14 msec) (Fig 1) (28). Five short-axis tagged images (tag-to-tag distance, 7 mm) with complementary spatial modulation of magnetization tagging for improved strain calculations were acquired from base to apex (yielding two basal and two midventricular sections and one apical section) by using the multiple expiration breath-hold technique to suppress the blurring effect of respiratory motion (29). In addition, delayed contrast material–enhanced images were acquired in the same view as that used at cine MR imaging by using a two-dimensional segmented inversion-recovery prepared gradient-echo sequence (repetition time msec/echo time msec/inversion time msec, 9.8/4.4/250–300; typical voxel size, 1.3 x 1.6 x 5 mm3) 15–20 minutes after intravenous administration of 0.2 mmol/kg gadopentetate dimeglumine.


Figure 1
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  		Figure 1: Example MR tagging images for patient with idiopathic DCM (top row) and healthy subject (bottom row). Tag lines become an intrinsic property of the myocardium for a brief period, and maximum circumferential shortening (Ecc) can be calculated from the extent of deformation of tag lines from the resting state to end systole (ES). Note that deformation of tag lines at end systole occurs more homogeneously and to a greater extent in the healthy subject.

 
Data Analysis
PET.—Anatomic tissue images were generated as described previously (25). Transaxial anatomic tissue fraction (ATF) images of the left ventricle were reoriented according to the anatomic axis of the heart, and sections were displayed as five short-axis sections (two basal and two midventricular sections and one apical section) that were identical to the anatomic images derived at MR imaging (Fig 2). The same resectioning parameters were applied to the dynamic H215O images. ROIs (size range, 3–20 mm3, depending on heart size) were defined manually at the basal and midventricular levels such that each section was divided into six equidistant sectors angled 60° apart starting from the posterior insertion of the right ventricular free wall into the LV myocardium. All regions were defined independently of the MR imaging data by a single observer (P.K., with 6 years of experience in cardiac PET). Corresponding ROIs from two sections (either basal or midventricular) were grouped in each patient to generate 12 (six basal and six midventricular) volumes of interest. The inferior volumes of interest were excluded from analysis because of anticipated perfusable tissue spillover effects from the liver (25); this resulted in a 10 segments per patient model. The apex was also excluded from analysis because of the difficulty of delineating apical myocardium from adjacent structures on the short-axis ATF images in the patient group.


Figure 2
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  		Figure 2a: PET-derived short-axis ATF images in (a) healthy volunteer and (b) patient with idiopathic DCM. Note marked dilatation of left ventricle in patient with DCM. ATF images were used to define regions of interest (ROIs) that were subsequently projected onto dynamic myocardial perfusion images obtained with H215O. The inferior wall was excluded from analysis because of spillover artifacts from the liver.

 

Figure 2
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  		Figure 2b: PET-derived short-axis ATF images in (a) healthy volunteer and (b) patient with idiopathic DCM. Note marked dilatation of left ventricle in patient with DCM. ATF images were used to define regions of interest (ROIs) that were subsequently projected onto dynamic myocardial perfusion images obtained with H215O. The inferior wall was excluded from analysis because of spillover artifacts from the liver.

 
Additional ROIs were defined in the left and right ventricular chambers. This set of ROIs was projected on the dynamic H215O images to generate image-derived input functions. Using the standard single tissue compartment model together with these input functions, we determined MBF (in milliliters per minute per milliliter of perfusable tissue) and perfusable tissue fraction (in milliliters per milliliter) for all myocardial tissue time-activity curves. Intrinsic corrections for spillover from both left and right ventricles were performed by using the method described by Hermansen et al (30). PTI was then obtained as the ratio of perfusable tissue fraction to ATF. Because resting MBF is related to the rate-pressure product, or RPP (ie, heart rate in beats per minute multiplied by systolic blood pressure in millimeters of mercury), corrected resting MBF, or MBFcorr, which was calculated as (MBF/RPP) · 10.000, was also determined. Regional differences in MR imaging and PET parameters were evaluated by grouping volumes of interest so that the heart was divided into three segments (anterior, lateral, and septal).

MR imaging.—All MR imaging postprocessing was performed by a single observer (M.J.W.G., with 10 years of experience in cardiac MR imaging). Global LV function parameters, including LVEDV, LV end-systolic volume, LV ejection fraction, and myocardial mass were derived from the cine images by using the MASS software package (MEDIS, Leiden, the Netherlands) The ratio of LVEDV to LV mass (LVM) was calculated and used as a measure of the extent of adaptive LV hypertrophy and thus a reflection of global end-diastolic wall stress (31).

The images acquired with complementary spatial modulation of magnetization were used to calculate circumferential strain curves by using the harmonic phase strain analysis method. Ecc, which indicates maximum regional myocardial contraction, was derived for each region from the strain curves (Fig 3).


Figure 3
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  		Figure 3: Circumferential strain curve from myocardial segment in healthy volunteer. Circumferential shortening is observed for approximately 600 msec after the R wave with a temporal resolution of 14 msec. After 400 msec, circumferential shortening has reached its maximum negative value (ie, maximum contraction).

 
Each myocardial segment was evaluated for the presence of hyperenhancement, which was defined as an area of signal enhancement greater than 5 standard deviations of the signal of nonenhanced myocardium.

Statistical Analysis
Data are expressed as means ± standard deviations. For comparison of two data sets, paired or unpaired Student t tests were performed where appropriate. Comparison of multiple data sets was performed by using analysis of variance, and specific differences were identified with a Student t test whose results were corrected for multiple comparisons with the Bonferroni inequality adjustment. Correlation coefficients were calculated to describe the associations between study variables. When correlation coefficients were estimated on a segmental level, all 10 segments per patient were used, with application of a correction for the interdependency of the segmental data within one patient. To this end, a linear mixed-effects model was used. Regional differences in MR imaging and PET parameters were evaluated by grouping volumes of interest so that the heart was divided into three segments (anterior, lateral, and septal). For graphic presentation, regional measurements were corrected for intersubject variation by dividing the values of each volume of interest by the respective mean value for that patient; this yielded normalized parameters. Differences with a P value of less than .05 were considered statistically significant. All analyses were performed by using SPSS, version 12 (SPSS, Chicago, Ill).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 ADVANCES IN KNOWLEDGE
 References
 
PET and MR Imaging Data
Rate-pressure product increased during the hyperemic PET studies for both control subjects (from 8020 beats per minute · mm Hg ± 1955 to 11 443 beats per minute · mm Hg ± 1308, P < .001) and patients with idiopathic DCM (from 8001 beats per minute · mm Hg ± 2007 to 9822 beats per minute · mm Hg ± 2163, P < .001). Neither control subjects nor patients with DCM demonstrated any delayed contrast enhancement.

Resting MBF did not differ between groups. Correcting MBF for the rate-pressure product (MBFcorr) did not alter the results (Table 2). Hyperemic MBF was significantly blunted in the patients with DCM (P < .001). Average PTI was decreased in patients with DCM (P = .014). Ecc was less negative in patients with DCM (P < .001), indicating reduced contractile function. The LVEDV/LVM ratio was significantly higher in patients with DCM (P = .004).


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  		Table 2. PET and MR Imaging Data for Control Subjects and Patients with DCM

 
Regarding the regional distribution of the PET and MR imaging parameters in the patients with DCM, there was a gradual increase in all parameters from the interventricular septum to the lateral wall (P < .05 [analysis of variance]); this was most significant for Ecc (Fig 4). In healthy volunteers, similar observations of Ecc were made, although regional differences were small. In healthy volunteers, resting and hyperemic perfusion and PTI were distributed homogeneously.


Figure 4
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  		Figure 4a: Bar graph shows normalized values for MBF, hyperemic MBF, PTI, and Ecc in septum (SEP) and anterior (ANT) and lateral (LAT) walls in control subjects and patients with idiopathic DCM. (a) In control subjects, only Ecc demonstrated a small but significant regional difference (* = P < .05 [analysis of variance]). (b) In patients with DCM, all parameters are distributed heterogeneously (* = P < .05 [analysis of variance]).

 

Figure 4
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  		Figure 4b: Bar graph shows normalized values for MBF, hyperemic MBF, PTI, and Ecc in septum (SEP) and anterior (ANT) and lateral (LAT) walls in control subjects and patients with idiopathic DCM. (a) In control subjects, only Ecc demonstrated a small but significant regional difference (* = P < .05 [analysis of variance]). (b) In patients with DCM, all parameters are distributed heterogeneously (* = P < .05 [analysis of variance]).

 
Correlations between Segmental PET and MR Imaging Parameters
In patients with DCM, Ecc correlated with MBFcorr, hyperemic MBF, and PTI (Table 3). When segments were divided into three subgroups, the mean Ecc decreased progressively in direct relation to MBFcorr, hyperemic MBF, and PTI (Fig 5) (P < .01 [analysis of variance]). PTI was not related to either resting or hyperemic MBF. None of these correlations were present for control subjects.


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  		Table 3. Correlations between Segmental PET and MR Imaging Data in Patients with DCM

 

Figure 5
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  		Figure 5a: Bar graphs show relationships between Ecc and (a) MBFcorr, (b) hyperemic MBF, and (c) PTI for patients with DCM. Results are based on all analyzed segments. (Ten segments were analyzed per patient; they were subsequently divided into subgroups for trend analysis.) For each PET parameter, Ecc decreased progressively for the three subgroups. P values were calculated with analysis of variance. Error bars = standard error of the mean.

 

Figure 5
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  		Figure 5b: Bar graphs show relationships between Ecc and (a) MBFcorr, (b) hyperemic MBF, and (c) PTI for patients with DCM. Results are based on all analyzed segments. (Ten segments were analyzed per patient; they were subsequently divided into subgroups for trend analysis.) For each PET parameter, Ecc decreased progressively for the three subgroups. P values were calculated with analysis of variance. Error bars = standard error of the mean.

 

Figure 5
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  		Figure 5c: Bar graphs show relationships between Ecc and (a) MBFcorr, (b) hyperemic MBF, and (c) PTI for patients with DCM. Results are based on all analyzed segments. (Ten segments were analyzed per patient; they were subsequently divided into subgroups for trend analysis.) For each PET parameter, Ecc decreased progressively for the three subgroups. P values were calculated with analysis of variance. Error bars = standard error of the mean.

 
Correlations between Extent of Adaptive LV Hypertrophy and Global PET and MR Imaging Parameters
The LVEDV/LVM ratio was positively related to global Ecc (r = 0.69, P = .003), and inversely related to hyperemic MBF (r = –0.52, P = .047) in patients with DCM, whereas no correlation was present for control subjects (Fig 6). There was no correlation between LVEDV/LVM ratio and global resting MBFcorr (r = –0.33, P = .80), or PTI (r = 0.16, P = .55) in patients with DCM or control subjects.


Figure 6
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  		Figure 6a: Scatterplots show correlations between LVEDV/LVM ratio and (a) Ecc and (b) hyperemic MBF for patients with DCM (bullet) and control subjects ({circ}). Linear regression was applied to the patient data only. No correlations were present for the control subjects.

 

Figure 6
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  		Figure 6b: Scatterplots show correlations between LVEDV/LVM ratio and (a) Ecc and (b) hyperemic MBF for patients with DCM (bullet) and control subjects ({circ}). Linear regression was applied to the patient data only. No correlations were present for the control subjects.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
ADVANCES IN KNOWLEDGE
 References
 
To the best of our knowledge, this is the first study to explore the interrelationships between myocardial fibrosis, contractile function, perfusion at rest, and hyperemic perfusion in patients with idiopathic DCM. The results indicate that myocardial fibrosis is related to contractile function, whereas fibrosis and resting or hyperemic perfusion do not seem to be interrelated. Furthermore, the degree of impairment of hyperemic myocardial perfusion and of systolic function were both related to end-diastolic wall stress.

Delayed Contrast-enhanced MR Imaging in Patients with DCM
None of the patients with idiopathic DCM demonstrated any delayed contrast enhancement, which excludes the possibility of a previous myocardial infarction (32). Apparently, the interstitial fibrosis that is irrefutably present in these patients (33) is not detected with delayed contrast-enhanced MR imaging. These results are in line with data from McCrohon et al (32), who demonstrated that in the majority of patients with DCM, delayed contrast enhancement is absent. The lack of a normal reference area, which is necessary to null the delayed contrast-enhanced signal, is responsible for the inability of late contrast-enhanced MR imaging to depict diffusely spread interstitial fibrosis in patients with DCM (32). Therefore, late contrast-enhanced MR imaging cannot be relied on to reveal the true presence or extent of interstitial fibrosis in such patients.

Fibrosis versus Contractile Function
Use of the PTI, because it enables differentiation between perfusable and nonperfusable tissue, can permit quantification of myocardial fibrosis after chronic myocardial infarction. This has been validated in both experimental (24) and clinical settings (34). More recently, it has been demonstrated that PTI could be used as a potential noninvasive marker of fibrosis in idiopathic DCM. However, no correlation could be established between LV ejection fraction and PTI (25). In fact, previous studies of the relation between fibrosis and systolic performance in DCM have yielded conflicting results (3,4,6–9). The lack of consistent results suggests that a one-to-one relationship between the extent of fibrosis and systolic function in DCM is unlikely. Moreover, the distribution pattern of collagen is not always homogeneous, necessitating a regional approach to investigate potential relationships (2,3,5). Myocardial dysfunction in DCM is generally considered to be caused by myocyte abnormality (eg, energy compromise, calcium handling dysfunction, alterations of sarcomeric protein) (35).

The relationship observed in the present study between PTI and Ecc in patients with idiopathic DCM could be consistent with the presence of a higher degree of interstitial fibrosis accompanying more severe myocyte dysfunction. Interstitial stiffening could, however, also exert a direct detrimental effect on myocyte contractile performance, because recent studies (36,37) on perfused rat papillary muscles have shown that reversible stiffening of the myocardial interstitial matrix appears to be accompanied by transient reductions in tension development. More studies are needed to explore a potential causal relation between fibrosis and function in this patient group.

Fibrosis versus Perfusion
It has been hypothesized that fibrosis might lead to perfusion abnormalities (18–20). Parodi and colleagues (20) examined the effects of fibrosis on resting perfusion in patients with ischemic or nonischemic heart failure undergoing heart transplantation. Neglia et al (19) investigated the relationship between fibrosis and perfusion reserve in patients with DCM. Neither group could demonstrate a clear link between the extent of fibrosis and perfusion abnormalities. The present study did not reveal such a correlation either.

Hyperemic Perfusion versus Contractile Function versus Wall Stress
Impairment of myocardial perfusion reserve is one of the hallmarks of DCM. Endothelial dysfunction (16) and high wall stress (13,14,17) are thought to be the main mechanisms for this phenomenon. Impairment in perfusion reserve is believed to induce intermittent periods of ischemia (repetitive stunning), which subsequently affect myocardial function. Signs of ischemia have been observed in patients with idiopathic DCM at PET (13) and dobutamine stress echocardiography (38). As heart failure progresses, remodeling occurs and diastolic wall stress increases (1), causing extravascular compression of the microvascular bed. In baseline conditions, myocardial perfusion is unaffected by these forces because the microvascular bed has the capability of compensating through vasodilation (20). During pharmacologically induced vasodilation, however, this mechanism is exhausted and compression of the microvascular bed occurs, leading to a reduction in hyperemic perfusion that is proportional to the level of wall stress (13,14,17).

The results of the present study support the presence of this mechanism in that a direct relationship between LVEDV/LVM ratio and hyperemic perfusion was found. Consequently, a vicious circle, in which the increased wall stress limits hyperemic perfusion and induces demand ischemia, may be created. These ischemic episodes can exacerbate systolic dysfunction and lead to a further increase in wall stress (13,38). Moreover, increased mechanical stress itself may lead to activation of intracellular signaling pathways that have direct detrimental effects on cardiomyocytes (eg, hampering hypertrophy, favoring apoptosis, and impairing calcium handling) (39); these effects further compromise contractile function.

Contractile Function versus Resting Perfusion
In general, DCM is not considered to be a regional myocardial disorder because the entire myocardium is affected. Nevertheless, heterogeneity in contractile function (11,12), oxygen consumption (11), wall stress (40), and perfusion (25) have been noted, although the mechanisms of the heterogeneity of these factors warrant further investigation. In the present study a correlation between regional resting myocardial perfusion and contractile function was found. This might be expected, because resting myocardial perfusion is closely coupled to oxygen consumption and thus to myocardial function through autoregulation of the microvascular bed in response to varying demand (41).

Clinical Implications
From a clinical point of view, the results of this study suggest that reduction of wall stress and regression of interstitial fibrosis are potential therapeutic goals in patients with idiopathic DCM. Some of the beneficial effects of pharmacologic agents that antagonize the neurohumoral pathway (eg, angiotensin-converting enzyme inhibitors, ß-blockers) are related to the reduction in loading conditions they exert. The reduction in wall stress may subsequently enhance hyperemic MBF and decrease episodes of ischemia. A similar mechanism has recently been observed during wall stress reduction by cardiac resynchronization therapy in patients with heart failure (42). Furthermore, angiotensin-converting enzyme inhibitors are known to induce regression of interstitial fibrosis in patients with hypertensive LV hypertrophy and are associated with recovery of systolic function (43). Regression of fibrosis in patients with idiopathic DCM that is mediated through angiotensin-converting enzyme inhibitors could result in similar recovery of myocardial function, although more studies are needed to test this hypothesis.

Study Limitations
We used PTI to assess interstitial fibrosis. Although it has been shown that PTI enables accurate identification of myocardial fibrosis after infarction (24,34), histologic comparisons in patients with DCM are currently lacking. Therefore, further studies on the use of PTI as a marker of fibrosis are needed. In addition, in the control subjects, due to the high spatial and temporal resolution of MR imaging, minute physiologic regional differences in contractile function were observed, as recently described (26,27). These differences could not be observed in the PET parameters, most likely due to the relatively limited resolution of PET. Finally, control subjects were not matched to the patients with respect to age or population size. The role of the control population in this study, however, was limited because the main goal was to establish relationships within the DCM population.

Conclusions
The results of our study indicate that in idiopathic DCM, the extent of myocardial fibrosis is related to contractile dysfunction, whereas fibrosis and perfusion do not seem to be interrelated. Furthermore, the degree of impairment of hyperemic myocardial perfusion is related to contractile function and end-diastolic wall stress. These results indicate that wall stress and not fibrosis limits hyperemic perfusion.


   ADVANCES IN KNOWLEDGE
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
References
 


   FOOTNOTES
 

Abbreviations: ATF = anatomic tissue fraction • DCM = dilated cardiomyopathy • Ecc = maximum circumferential shortening • LV = left ventricular • LVEDV = LV end-diastolic volume • LVM = LV mass • MBF = myocardial blood flow • PTI = perfusable tissue index • ROI = region of interest

Authors stated no financial relationship to disclose.

Author contributions: Guarantors of integrity of entire study, P.K., M.J.W.G., F.C.V.; study concepts/study design or data acquisition or data analysis/interpretation, all authors; manuscript drafting or manuscript revision for important intellectual content, all authors; approval of final version of submitted manuscript, all authors; literature research, P.K., M.J.W.G., R.B., F.C.V.; clinical studies, P.K., M.J.W.G., J.J.M.Z., P.A.D., J.T.M.; statistical analysis, P.K., M.J.W.G., R.B., J.T.M., J.W.R.T., F.C.V.; and manuscript editing, P.K., M.J.W.G., W.J.P., J.J.M.Z., R.B., J.T.M., J.W.R.T., C.A.V., A.C.v.R., A.A.L., F.C.V.


   References
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 References
 

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