Coronary atherosclerosis in end-stage idiopathic dilated cardiomyopathy: an innocent bystander?

Alessandra Repetto1, Barbara Dal Bello2, Michele Pasotti1, Manuela Agozzino2, Mario Viganò3, Catherine Klersy4, Luigi Tavazzi1 and Eloisa Arbustini2,*

1Department of Cardiology, IRCCS Policlinico San Matteo, Piazzale Golgi 2, 27100 Pavia, Italy
2Molecular Diagnostics, Cardiovascular and Transplant Pathology Laboratory, Transplant Research Area, IRCCS Policlinico San Matteo, Via Forlanini 16, 27100 Pavia, Italy
3Dubost Transplant Centre, University of Pavia, IRCCS Policlinico San Matteo, Piazzale Golgi 2, 27100 Pavia, Italy
4Clinical Epidemiology and Biometry Service, IRCCS Policlinico San Matteo, Piazzale Golgi 2, 27100 Pavia, Italy

Received 8 December 2004; revised 23 April 2005; accepted 28 April 2005; online publish-ahead-of-print 25 May 2005.

* Corresponding author. Tel: +39 0382 501206; fax: +39 0382 525866. E-mail address: e.arbustini{at}smatteo.pv.it


    Abstract
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgements
 References
 
Aims Coronary atherosclerosis is occasionally found in the hearts of patients diagnosed with idiopathic dilated cardiomyopathy (IDCM), who have undergone heart transplantation (HTx). This study investigates the pathology of coronary trees in IDCM patients and correlates the findings with risk factors for atherosclerosis.

Methods and results The coronary trees of hearts excised at transplantation from 55 IDCM patients [43 males, mean (±SD) age at diagnosis and HTx: 37.4±13.4 and 42.1±14.6 years, respectively] underwent systematic pathological investigation. The inclusion criteria were: interval between the last pre-HTx angiography and the HTx of <10 years and the absence of ischaemic events in between; the absence of ventricular scars at pathological study; optimal pre-HTx medical treatment, and no ventricular assist devices. The median time between the pre-HTx angiography and the HTx was 13 months (range: 1–93). Fifteen of the 55 patients (27%) had critical plaques in at least one of the 70 segments of the epicardial coronary tree. A multivariate statistical analysis showed that male sex, age, and dyslipidaemia were independent predictors of critical atherosclerosis.

Conclusion One-fourth of the patients with end-stage IDCM hearts excised at HTx (all with angiographically normal coronary arteries at first diagnosis) have bystander critical coronary atherosclerosis whose functional role (if any) deserves investigation.

Key Words: Idiopathic dilated cardiomyopathy (IDCM) • Heart transplantation (HTx) • Atherosclerosis • Risk factors


    Introduction
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgements
 References
 
The diagnosis of idiopathic dilated cardiomyopathy (IDCM) relies on the presence of left ventricular dysfunction and the demonstration of ‘angiographically’ normal coronary arteries on the basis of the WHO criteria.1 Briefly, the patients diagnosed with IDCM have no significant coronary artery disease (luminal narrowing ≥50%) at coronary angiography, no specific heart muscle disease or myocarditis at endomyocardial biopsy, and a reduced (<45%) left ventricular ejection fraction. The exclusion criteria for a diagnosis of IDCM are arterial hypertension (≥160/100 mmHg at repeated measurements), insulin-dependent diabetes mellitus (IDDM), valvular heart disease, coronary artery disease, congenital heart disease, thyroid dysfunction, anaemia, amyloidosis or sarcoidosis, hypertrophic cardiomyopathy, drugs and substances having cardiotoxic effects, and an alcohol consumption of ≥100 g per day.2

The current diagnostic criteria should guarantee a correct diagnosis, and once IDCM has been diagnosed, coronary angiography is not repeated. Angiographically, non-obstructive lesions may occasionally be found but, in such cases, the atherosclerotic disease is probably unrelated to the left ventricular dysfunction. However, obstructive coronary atherosclerosis has been pathologically identified in hearts excised at transplantation from patients diagnosed as having IDCM, in which case a misdiagnosis has been usually considered.35 Furthermore, a recent gadolinium-enhanced cardiovascular magnetic resonance study has shown that 13% of patients diagnosed as having IDCM on the basis of normal luminal appearances by coronary angiography may have an incorrect diagnosis because they show myocardial enhancement indistinguishable from the patients with coronary artery disease.6

The occurrence of epicardial coronary artery atherosclerosis in patients diagnosed as having IDCM raises two major questions concerning the potential contributory role of atherosclerosis to ventricular dysfunction and the definition of ‘IDCM’ in patients with the classical risk factors for coronary atherosclerosis. This latter point particularly needs clarification: severe dyslipidaemia in a smoker with ‘angiographically’ normal coronary arteries and left ventricular dysfunction does not interfere with the diagnosis of IDCM, which is the same as in patients without risk factors; but these risk factors assume a major role in ‘ischaemic cardiomyopathy’.7

IDCM hearts excised at transplantation constitute a unique set of pathological samples because risk factors for coronary atherosclerosis, such as hypertension and IDDM, are absent, but risk factors that do not interfere with the IDCM diagnostic criteria, such as borderline hypertension, non-IDDM, cigarette smoking, and dyslipidaemia, may be present. The aim of this study was to demonstrate that critical coronary atherosclerosis and risk factors may co-exist in IDCM and that, on the basis of the current diagnostic criteria, IDCM patients with atherosclerosis are classified in the same way as those without it. We, therefore, investigated the coronary artery trees of a consecutive series of IDCM hearts excised at transplantation from patients with a known time interval between the last pre-transplantation coronary angiography examination and the heart transplantation (HTx) and the correlated risk factors with the presence of critical coronary atherosclerosis.


    Methods
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgements
 References
 
Clinical series
The clinical series consisted of 55 patients (43 males and 12 females) who underwent HTx for IDCM diagnosed according to the WHO criteria.1 The inclusion criteria were: patients whose illness has been managed in our hospital from the first diagnosis to the HTx and whose family had clinical screening in our centre; time interval between the last pre-HTx angiography and the HTx of <10 years and the absence of ischaemic events in between; the absence of ventricular scars at pathological study; optimal pre-HTx medical treatment; no aortic valve homograph recovery at surgery; no cardiomyoplasty before HTx; and no ventricular assist devices implanted as a bridge to HTx.

Of the 372 patients who had undergone HTx in our hospital from 1993 to 2003, 155 were diagnosed with IDCM, both familial and sporadic, and underwent ortotopic HTx. Of these latter, 55 met the inclusion criteria and entered in the study. All data for the aforementioned patients are available.

Their mean (SD) age at diagnosis was 37.4 (13.4) years (range 14–60 years) and age at transplantation was 42.1 (14.6) years. The median interval between the last pre-HTx angiography and the HTx was 12.4 months (range 1–93). Coronary angiography had documented ‘angiographically’ normal coronary arteries [defined as absence of significant atherosclerotic luminal narrowing (>50%) in each of the three epicardial coronary arteries]8 in all the patients, all of whom had undergone pre-transplant endomyocardial biopsy. None of the patients had IDDM, and severe hypertension; smoking habits, non-IDDM, borderline hypertension, and dyslipidaemia were recorded (Table 1).


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Table 1 Clinical characteristics
 
The patients were classified as having familial or sporadic IDCM on the basis of evidence-based data from the serial non-invasive screening of first and second-degree relatives, the direct clinical management of more than one affected family member, and the clinical records documenting the cause of death in the case of deceased patients.9

Myocardium and coronary arteries
The pathological series consisted of the native hearts excised at transplantation from the 55 patients. As previously described,10,11 the major epicardial coronary arteries were dissected from formalin-fixed or unfixed hearts, including the left main coronary trunk, the left anterior descending artery (LAD), the left circumflex artery (LCx), the right coronary artery (RCA), and the posterior descending artery. LAD, LCx, and RCA were divided into proximal, middle, and distal portions, each of which was cut into segments 3–5 mm long. In 29 cases, we also dissected the first diagonal, obtuse marginal, and posterolateral branches. This approach provided approximately 70 3–5 mm long segments of the epicardial coronary arteries from each explanted heart. The coronary artery samples were decalcified, when necessary, routinely processed, cut, and then embedded in paraffin. Sections with a thickness of 5 µm were cut and stained with haematoxylin–eosin (H&E), Movat Pentachrome and immunostained with anti-CD68, anti-CD45RO, anti-CD34, and anti-CD20 antibodies,12 and examined using a Zeiss Axioplan microscope. The severity of luminal narrowing was evaluated by two independent operators (BDB and EA).

Full-circumference ventricular samples were transversely cut for histological examination of both the left and the right ventricles at basal, middle, and apical levels (n=16 blocks/heart). The myocardial samples were fixed, processed and stained using the same procedure as that used for the coronary arteries. The aim of this part of the study was to investigate the occurrence of acute and chronic myocardial ischaemic changes, coagulative necrosis, myocytolysis, contraction band necrosis, and fibrosis.

Definitions
Coronary atherosclerosis was defined by the structural characteristics of the plaques: the core was surrounded by either fibrous capsule or fibrous plaques, according to the previously reported classifications.1316 A cross-sectional area lumen reduction of 75% or more was considered significant. The coronary arteries were grouped into four categories: no atherosclerotic plaques (Group 0); non-stenosing plaques <50% (Group 1); mildly-moderately stenosing plaques ≥50 to <75% (Group 2); and critically stenosing plaques ≥75% (Group 3).

Cardiovascular risk factors: hypertension, defined as a systolic blood pressure of >140 and <160 mmHg and a diastolic blood pressure of >90 and <100 mmHg; cigarette smoking, with current smokers being defined as those reporting that they had smoked regularly during the 3 years preceding the IDCM diagnosis or had smoked regularly for at least 3 years but stopped during the previous year; type II diabetes, defined as hyperglycaemia requiring oral antidiabetic drugs; hypercholesterolaemia, defined as fasting total serum cholesterol levels of >220 mg/dL or the use of anti-hypercholesterolaemic medications; and hypertriglyceridaemia, defined as triglycerides concentration >165 mg/dL.

Statistical analysis
Descriptive statistics were computed as mean values and standard deviation (SD) for continuous variables [or median values and interquartile range (IQR) if skewed] and as absolute frequencies and per cent values for categorical variables. Logistic models were fitted to identify the predictors of coronary lesions of hemodynamic relevance (≥75%). The following potential risk factors were considered: age, gender, months between the last pre-HTx coronary angiography and the HTx, smoking habits, diabetes, hypertension, dyslipidaemia, and the number of risk factors (among the last four). Only the variables that were significant at the 10% level at univariate analysis (data not shown) were included in the final model. Multiple collinearity was checked, and two competitive models were fitted with the inclusion of the actual risk factors or the number of risk factors, together with age, gender, and time from angiography (two variables were considered to be collinear when their correlation coefficient R was >0.4). Odds ratios and their 95% confidence intervals (95% CI) were computed, as were the predicted probabilities of coronary lesion of haemodynamic relevance for selected scenarios. The goodness-of-fit of the model and the linearity of effect for continuous and ordinal variables were verified by including a quadratic term in the model. The model underwent bootstrap validation, with the calculation of the c statistic to evaluate discrimination and the shrinkage coefficient to evaluate calibration; in both cases, the closer the value to 1, the better. Finally, ordinal logistic regression was also fitted to the final model, with the dependent variable being codified as non-stenosing plaques, mildly-moderately stenosing plaques, and critically stenosing plaques. The assumption of proportional odds was tested, and the results were not different from those of the logistic models. Stata 8 (StataCorp, College Station, TX, USA) was used for computation. The Spearman correlation coefficient was used to investigate the association between study variables. A two-sided P-value of 0.05 was considered statistically significant.


    Results
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgements
 References
 
Clinical series
Twenty of the 55 patients (36.4%) had familial IDCM and 35 sporadic disease (63.6%) (Table 1). Of the 20 cases of familial IDCM, 12 were autosomal dominant [eight patients were carriers of LMNA gene defects: Ins ctgc at 2869 cDNA, Glu111Stop (two sibs), Lys97Glu (two sibs), Arg190Trp, Arg89Leu, delC165mRNA; one had a Cypher/ZASP gene mutation: Asp117Asn], one was matrilinear with heteroplasmic mitochondrial DNA mutation (tRNAThr A15902G), one had X-linked recessive disease with dystrophin gene defects (deletion exons 48–49), and six were from families with affected sib pairs. The forms with affected sib pairs and three autosomal dominant IDCMs have still not been genotyped.

At the time of coronary angiography, mean ejection fraction was 21±3%. Twenty-nine (53%) patients were in NYHA functional Class IV and 26 (47%) in NYHA functional Class III. No significant difference was observed in ejection fraction and NYHA functional class in the four groups (P=NS). No correlation was found between the interval coronary angiography-HTx (months) and the pathologic presence of atherosclerosis (r=0.26, P=NS).

Risk factors
Five patients had non-IDDM, 14 had dyslipidaemia (associated with non-IDDM in two cases), three had borderline arterial hypertension, and 23 had been prior smokers. None was a current smoker at the time of HTx (Table 1).

Atherosclerosis in the epicardial coronary tree
Prevalence and severity
Coronary atherosclerotic plaques were found in 36 of the 55 coronary artery trees (65.5%): 12 had mild, non-narrowing plaques (Group 1), nine had moderately stenosing plaques ≥50 to <75% (Group 2), and 15 had critical lesions in at least one segment of the three epicardial vessels (Group 3) (Figure 1). In these latter cases, plaques involved proximal (n=12), mid (n=13), and distal (n=5) segments of the coronary arteries. Intimal fibrous thickening was found in 12 of the remaining 20 patients. Eight coronary trees did not show any histopathological abnormalities. The luminal narrowing identified at pathology did not correspond to the angiographic patency in any of the cases in which critical plaques were pathologically observed (Figure 2).



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Figure 1 The pathological spectrum of coronary atherosclerosis in the four groups of patients with IDCM (Movat pentachrome). The four cartoons illustrate the drafts corresponding the above figures. The blue arrows highlight the effects of inverse remodelling on the tunica media. Group 0: the two figures show a very mild fibrous intimal thickening. Internal elastic lamina is focally discontinued; Group 1: the two figures show more pronounced fibrous intimal thickening and small atherosclerotic nuclei. Internal elastic lamina is discontinued in the upper figure and reduplicated in the lower one. The latter also shows medial thickening; Group 2: the two figures show prominent plaques mostly constituted of fibrous tissue. Internal elastic lamina is well preserved and only shows focal interruptions and reduplication. Inverse remodelling of the tunica media is absent; and Group 3: the two figures show severe eccentric atherosclerotic plaques with inverse remodelling. In both, the major plaque component is fibrous tissue. The tunica media is absent in more than half circumference of the upper vessel and in less than half circumference in the lower figure. The internal elastic lamina is still visible in half of the upper vessel and in majority of the circumference of the lower vessel.

 


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Figure 2 The coronary angiography of LAD of a 50-year-old male diagnosed by IDCM at the age of 45 (AC). The corresponding pathological feature of proximal LAD 35 months later when he underwent HTx is shown in figures (DG), showing, respectively, the morphology of the plaque with mild negative remodelling of the arterial wall, a small core, and vascular neogenesis (D); CD68 positive macrophages clustered around the core (E); integrity of CD34 positive endothelial cell layer (F); T-lymphocytes mostly clustered in the adventitia (G) [(D), Movat pentachrome; (EG), peroxidase antiperoxidase immunostain].

 
Gender
Coronary plaques were found in five of the 12 female patients (41.6%) (three >50 years old at transplantation), and in 31 of the 43 male patients (69.7%) (11>50 years old at transplantation).

Age
Coronary atherosclerosis was present in two patients aged <30, seven aged 31–40, 12 aged 41–50, 10 aged 51–60, and five aged >60.

Coronary atherosclerosis in familial IDCM
Of the 20 patients with familial IDCM, four (three males without risk factors and one female with non-IDDM) had mild-moderate atherosclerotic, non-critically narrowing plaques (Group 2) and seven (six males and one female) had critical lesions in at least one segment of the three epicardial vessels (Group 3). In the latter subgroup, one patient had hypertension, two had dyslipidaemia, one had non-IDDM plus dysplipidaemia, and one was a previous smoker. One patient from Group 1, one from Group 2, and one from Group 3 had LMNA gene mutations. In the genotyped patients with familial DCM, the qualitative features were similar to those seen in patients with atherosclerosis and sporadic IDCM.

Myocardial histopathology
None of the hearts had coagulative necrosis. All showed foci of myofibrillar loss, and contraction bands. The interstitium showed perimyocyte fibrosis involving the subendocardial layers and distributed in small non-contiguous microfoci of fibrosis (Figure 3).



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Figure 3 The panel illustrates the spectrum of interstitial fibrosis commonly found in IDCM [(A, B, and D), Movat pentachrome stain; (C), haematoxylin–eosin stain]. The figures show (A) mild but diffuse interstitial fibrosis; (B) focal distribution of the interstitial fibrosis (see upper left area); and (C and D) severe interstitial fibrosis surrounding single or groups of myocytes.

 
Plaque morphology
Coronary atherosclerotic plaques showed typical fibrofatty and fibrous histopathologic composition. Plaque ulcerations and thrombosis were absent. The cellular component was characterized by the presence of smooth muscle cells and fibroblasts, of inflammatory cells, mostly T-lymphocytes (CD3, CD45RO) and macrophages (CD68). CD34-positive endothelial cells lined the lumen of the coronary arteries and capillary vessels present in the plaques (Figure 3). No morphological difference was noted between the plaques observed in this series and the uncomplicated plaques commonly seen in patients with chronic CAD.

Predictors of haemodynamically relevant coronary lesions
At multivariate and ordinal logistic regression, gender, age at transplant, and dyslipidaemia or number of risk factors were independent predictors of the presence/degree of coronary lesions (Table 2). An increased risk was observed for the male sex, an older age, and the presence of dyslipidaemia, as well as for an increasing number of risk factors. According to model validation statistics, both models were comparable in their predictive ability, which was fairly good, although some overfitting was present (shrinkage coefficient <0.7 for model 1, see Table 2). The probabilities of coronary plaques of haemodynamic relevance are summarized in Table 3 for selected scenarios based on combinations of age, gender, and the presence of dyslipidaemia. The probability of pathologically critical atherosclerosis was highest for a 50-year-old male patient with dyslipidaemia and lowest for a 30-year-old female patient without dyslipidaemia.


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Table 2 Predictors of haemodynamic coronary lesions (logistic multivariate model)
 

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Table 3 Probabilities of critical plaques for selected scenarios, calculated according to logistic Model 1
 

    Discussion
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgements
 References
 
The results of this study show that 15 of 55 patients with IDCM (27%), and angiographically normal coronary arteries at the time of first diagnosis, had coronary atherosclerosis with critical luminal narrowing in at least one segment of the major epicardial arteries in the end stage of their disease. The atherosclerosis significantly associated with older age, male sex, and the risk factors for coronary artery disease, particularly dyslipidaemia.

Coronary atherosclerosis is a common disease; the prevalence of critical lesions in our series of IDCM is similar to that found in patients dying as a result of non-cardiac causes. One-third of the latter subjects in their sixties are pathologically proved to have CAD that is critical in at least one epicardial coronary artery.11 The presence of risk factors for CAD in IDCM cases and the correlation between CAD and age, sex, and risk factors confirm expected prevalence data, as well as the link between risk factors and atherosclerosis.1719 However, the same diagnosis of IDCM is formulated in an 18-year-old patient without risk factors and in a 60-year-old smoker and dyslipidaemic patient, once coronary arteries are found to be angiographically normal. This consideration suggests the need to subgroup patients by co-existing morbidities (such as risk factors for CAD) or combined pathological findings, to increase knowledge on factors potentially influencing IDCM evolution and to answer the question on whether coincident CAD or related risk factors influences IDCM.

The role of coronary atherosclerosis in left ventricular dysfunction is beyond the scope of this study that aimed at documenting the possible presence of significant coronary atherosclerosis in IDCM and its correlation with sex, age, and risk factors for CAD, which do not exclude the diagnosis of IDCM, such as dyslipidaemia. Our observation is not new because previous pathological studies have demonstrated severe atherosclerosis in IDCM hearts.35 The differences between this and previous studies include the serial coronary tree study, the analysis of risk factors, the correlation of the interval between the last angiography and the pathological study, and the documentation of CAD in patients with familial IDCM caused by genetic defects. Therefore, our data prove that the DCM was correctly defined as idiopathic and that the finding of CAD at HTx does not imply a wrong pre-HTx diagnosis but rather documents a bystanding comorbidity that could be either not present or not detectable at the time of the first diagnosis.

The angio-pathological mismatch found in our series may have been due to various factors. Coronary atherosclerosis is underestimated by coronary angiography,2026 which reflects the negative image of the luminal area but does not provide information concerning the integrity of the arterial wall, as well as the severity of the plaque, and the per cent of patent luminal area with respect to the overall cross-sectional area of the affected coronary segment. Both angiography and pathology investigate the lumen, but the latter also investigates the arterial wall, with eventual remodeling, and the plaque. Vice versa, the angiographic estimation of the severity of stenosis is the result of a comparison between the maximal upstream luminal patency vs. the maximal plaque-related narrowing. Furthermore, pathological evaluations are made on fixed coronary artery samples, which may contribute to overestimate lumen narrowing.27,28 In any case, although pathology may overestimate the extent of luminal narrowing, plaques found in Group 3 are severe. Other potential factors include the coronary artery dilation that accompanies left ventricular dilation2931 and the possible progression of atherosclerosis in the interval between angiography and HTx.32,33 If the latter contributor is true and CAD development could be considered a potential contributor in IDCM evolution, functional studies could investigate its role, especially in older male patients with risk factors that do not interfere with the diagnosis of IDCM, such as dyslipidaemia, borderline hypertension, NIDDM, and smoking. Perfusion imaging could explore segmental ischaemia; however, the risk of false positive could lead to further need of angiographies, which are unnecessary, on the basis of current knowledge, for treatment decisions but could help to elucidate the effects of CAD in IDCM evolution. In the clinical setting, when significant coronary atherosclerosis is angiographically found in hearts with left ventricular dysfunction, then, the latter is attributed to atherosclerosis. When significant atherosclerosis is not found in patients with left ventricular dysfunction, then there are two clinical scenarios: the one in which segmental left ventricular dysfunction may suggest a prior infarction with angiographically normal coronary arteries and the other in which diffuse left ventricular dysfunction coincides with the WHO diagnostic criteria of IDCM. In our series, the exclusion of hearts with post-infarction scars excludes the so-called infarction with normal coronary arteries.34 In the pathological setting, the identification of coronary atherosclerosis in IDCM does not per se modify the original diagnosis formulated on the basis of the WHO criteria; the patients with familial IDCM of Group 3 are the evidence. However, it is an intriguing datum in the complex evolution of IDCM in which coronary artery comorbidity is not usually considered.

Whether CAD plays a role in the evolution of the left ventricular dysfunction or is an innocent bystander deserves investigation. The high number of candidates for HTx, the small number of available hearts, the wide spectrum of in vivo studies that can be used to assess myocardial hibernation (PET, nuclear or echocardiography-based functional techniques),35 the potential use of revascularization procedures, and the treatment choices for dyslipidaemia are all good reasons for investing in research aimed at elucidating the role, if any, of coronary atherosclerosis in IDCM. Recent data obtained using gadolinium-enhanced cardiovascular magnetic resonance suggest that an incorrect diagnosis may occur in a relevant proportion of IDCM patients. McCrohon et al.6 found that coronary angiography as the arbiter for the presence of left ventricular dysfunction caused by coronary artery disease may have led to ‘an incorrect assignment of DCM as caused in 13% of their patients’. This is extremely relevant clinically, so far as the diagnosis of IDCM vs. CAD-related congestive heart failure has both treatment and familial implications.

In conclusion, our and previous pathological data,35 as well as recent cardiovascular magnetic resonance data,6 raise the questions of coronary co-morbidity in IDCM and, when critically narrowing the lumen, of its possible contribution to the evolution of the disease. Whether IDCM patients who develop coronary atherosclerotic comorbidity should be differentiated from those with truly normal coronary arteries and absence of risk factors warrant in vivo functional investigation.

Limits of the study
The limits of the study are:


    Acknowledgements
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgements
 References
 
This study was supported by research grants from ‘Ricerche Finalizzate e Correnti’ IRCCS Policlinico San Matteo of Pavia, Italy.


    References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgements
 References
 

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