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Cardiovascular Research 2002 55(1):97-103; doi:10.1016/S0008-6363(02)00331-0
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Copyright © 2002, European Society of Cardiology

Abnormalities in myocardial contractility, metabolism and perfusion reserve in non-stenotic coronary segments in heart failure patients

Ad F.M van den Heuvela,*, Jeroen J Baxb, Paul K Blanksmaa, Willem Vaalburgc, Harry J.G.M Crijnsd and Dirk J van Veldhuisena,1

aDepartment of Cardiology/Thoraxcenter, University Hospital Groningen, Hanzeplein 1, P.O. Box 30.001, 9700 RB Groningen, The Netherlands
bDepartment of Cardiology, Leiden University Medical Center, Leiden, The Netherlands
cPET Center, University Hospital Groningen, Groningen, The Netherlands
dDepartment of Cardiology, Maastricht University Medical Center, Maastricht, The Netherlands

a.f.m.van.den.heuvel{at}thorax.azg.nl

* Corresponding author. Tel.: +31-50-361-2355; fax: +31-50-361-4391

Received 2 October 2001; accepted 15 February 2002


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Objective: Myocardial blood flow (MBF) reserve is impaired in congestive heart failure (CHF), while fluorine-18-deoxyglucose (18FDG) uptake is relatively preserved. To determine whether this mismatch could be interpreted as ischemia, we performed dobutamine stress echocardiography (DSE). Methods: 12 males with coronary artery disease (CAD) and CHF were compared with 12 controls with similar CAD but normal left ventricular (LV) function. MBF in non-infarct-related artery areas was assessed using [13N]ammonia positron emission tomography (PET), at rest and after dipyridamole infusion and 18FDG uptake was determined. DSE was performed with doses up to 40 µg/kg per min. Results: In areas with non-stenotic arteries MBF reserve was more impaired in CHF patients (1.6±0.6 vs. 2.2±0.5; CHF versus normal LV, respectively, P<0.05). MBF reserve was related to LV ejection fraction (r = 0.6, P<0.05) and wall stress (r = –0.72, P<0.05). PET showed mismatch in 4±1% of the myocardium in normal LV, compared to 26±26% in CHF (P<0.05), coinciding with more ischemic wall motion abnormalities on DSE (21 vs. 4%; CHF versus normal LV, respectively, P<0.05). Conclusions: In CHF, mismatch was found in areas supplied by non-stenotic coronary arteries. Corresponding areas showed ischemic wall motions on DSE. These findings suggest that the condition of CHF may play a role in perpetuating myocardial failure by inducing myocardial ischemia. Follow-up studies to investigate the ischemia–CHF relationship in time would be needed.

KEYWORDS Heart failure; Ischemia; Regional blood flow; Cardiomyopathy; Energy metabolism


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
Studies in patients with idiopathic dilated cardiomyopathy reported a decreased myocardial blood flow (MBF) reserve (assessed by positron emission tomography, PET) [1–3]. This observation suggests that the condition of chronic heart failure (CHF) is associated with changes in MBF. Whether similar abnormalities are also present in CHF due to coronary artery disease (CAD) is unknown.

Dobutamine stress echo (DSE) is frequently used to identify ischemic myocardium [4]. PET imaging permits non-invasive quantification of MBF (reserve) and metabolism [5,6]. Sequential imaging with [13N]ammonia and 18FDG can demonstrate regions of ‘mismatch’, where reduced uptake of [13N]ammonia but preserved or increased uptake of 18FDG is indicative of ischemic myocardium [7].

The aim of the present study is to evaluate whether changes in MBF and metabolic parameters in patients with CHF and CAD are related to changes during DSE. If this could be shown, one might speculate that the condition of CHF as such could lead to myocardial ischemia, and as such they could further extend the previous findings in patients with idiopathic dilated cardiomyopathy [3,8].


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
2.1 Study population
Demographic and clinical characteristics of the study population are presented in Table 1. We studied 12 consecutive male patients with CAD and symptomatic CHF (LV ejection fraction <0.45), who took part in a viability study, and compared them with age-matched controls with similar coronary abnormalities and normal LV function (LV ejection fraction >0.50). Exclusion criteria included three vessel coronary artery disease, unstable angina pectoris, recent (<3 months) myocardial infarction, severe CHF and diabetes mellitus. All patients underwent PET and DSE to assess myocardial viability as part of a viability study protocol. In both groups we studied the MBF (reserve) and glucose uptake in the non-infarct related areas (IRA) supplied by stenotic (≥70%) coronary arteries and compared these with non-IRA areas supplied by angiographically normal vessels or vessels with a non-significant (<70%) stenosis. The DSE wall motion was analyzed in the same vascular territories. Informed written consent from each patient for every investigation and approval of the local hospital review board had been obtained.


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  		Table 1 Patients characteristics

 
2.2 PET imaging
All PET studies were performed as recently described in detail [2], after subjects had refrained from any medical therapy for five plasma half-lives as well as from caffeinated beverages for 24 h before the studies. MBF was studied, according to the methods of Schelbert et al. [6] and Bellina et al. [5] using [13N]ammonia as tracer. Subjects were positioned in a 951 Siemens (ECAT) positron camera (Siemens, Knoxville, TN, USA) which images 31 planes simultaneously over 10.8 cm. Measurements were repeated after dipyridamole infusion (0.56 mg/kg administered intravenously in 4 min). MBF reserve is defined as the ratio of MBF during dipyridamole and MBF at rest. Myocardial glucose uptake was measured with 18FDG as tracer as described previously by Choi et al. [9].

2.3 PET data analysis
From the PET data, dynamic parametric polar maps were constructed [10]. MBF data were corrected for partial volume effect and spillover. Data analysis of 18FDG uptake was performed with a PATLAK analysis. Calculation of the extent of mismatch areas was calculated from these data [10]. Thirteen regions were defined, depending on coronary anatomy: anterior (basal and apical) and antero-septal (basal and apical) were four segments considered to be perfused by the left anterior descending (LAD) coronary artery. Antero-lateral (basal and apical) were two segments considered to be perfused by the circumflex coronary artery (RCX). Postero-septal (basal and apical) were two segments considered to be perfused by the right coronary artery (RCA). The two postero-lateral (basal and apical) and two inferior (basal and apical) segments were considered to be perfused by the RCA or RCX, depending on coronary anatomy. The apex was considered as one segment perfused by either LAD or RCA.

2.4 Dobutamine stress echocardiography
DSE was performed using a standard protocol [4,11]. Dobutamine was infused at dosages of 5 and 10 µg/kg per min, for 3 min at each dose. Subsequently, three further steps from 20 to 40 µg/kg per min (3 min each) were added.

The interpretation of echocardiograms was performed by two experienced observers, blinded to the clinical, angiographic and PET results of the individual patients. The assessment was semiquantitative, and a 13-segment model was used [12], in which the four apical segments were taken as one segment. The wall motion, including wall thickening, of every segment was scored with a five-point scoring system, where 1=normal wall motion and thickening, 2=moderately hypokinetic, 3=severely hypokinetic (SH), 4=akinetic (AK) and 5=dyskinetic. Myocardial viability (i.e., presumed post-ischemic wall segments) was judged to be present in an AK or SH segment when wall motion improved during the infusion of low-dose dobutamine by at least one point of the scoring system. In the low-high dose dobutamine protocol four patterns are observed. (1) Biphasic response: improvement of wall motion during low dose (either 5 or 10 µg) followed by worsening of wall motion during high dose dobutamine. (2) Sustained improvement: improvement at either low or high dose dobutamine without deterioration of wall motion. (3) Worsening: deterioration of wall motion during either low or high dose dobutamine. (4) No change: absence of improvement or worsening during the entire test. Patterns 1 and 3 were considered indicative of viable but ischemically jeopardized myocardium. Patterns 2 and 4 were considered different grades of scar, ranging from subendocardial to transmural.

2.5 Measurement of LV wall stress
Global LV wall stress was measured with two-dimensional echocardiography, as previously described [13]. Normal systolic wall stress in our echo-lab is 106±11x103 dynes/cm2.

2.6 Coronary angiography
In both groups the vascular regions were divided into two subgroups: (1) no significant disease (<70% diameter stenosis); (2) significant disease (≥70% diameter stenosis). No patient had ≥95% stenosis or stenosis of the left main stem. Normal segments were considered to be (1) the region supplied by the vessel without significant angiographic stenosis in patients with two-vessel disease, and (2) the mean of the two regions supplied by vessels without significant angiographic disease in patients with single-vessel disease. The infarct areas were excluded from analysis.

2.7 Statistical analysis
Values were given as mean±S.D. Group differences of perfusion dynamics were given using a Wilcoxon two-sample test on the deltas from baseline and during dipyridamole. The data in the four groups (stenotic/nonstenotic, normal LV and LV dysfunction) where compared by a two-way ANOVA with a Bonferroni correction. The Spearman rank order correlation coefficient was used to investigate the associations between study parameters. To confirm that the data were normally distributed, the Shapiro–Wilk test was used. Differences with a P value <0.05 were considered statistically significant. Statistical analysis were performed with SAS statistical software, version 6.08. Myocardial blood flow was given in milliliters per minute per 100 g and glucose utilization in micromoles per minute per 100 g. A flow-metabolism (13NH3/18FDG) mismatch pattern was represented as percentage of total myocardium.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
3.1 Patient population
The study group consisted of 12 male patients with CAD and CHF (LV ejection fraction 0.34±0.08) and 12 controls with CAD (LV ejection fraction 0.56±0.12). The number of previous myocardial infarctions was higher in the group with CHF (Table 1).

3.2 PET findings
In stenotic (≥70%) artery areas (Table 2, right panel), MBF at rest was not decreased in patients with CHF as compared to patients with normal LV function. After dipyridamole, the increase in MBF was slightly more pronounced in patients with normal LV (172±27 ml/min per 100 g) than in those with CHF (164±22 ml/min per 100 g) (P = NS), also the MBF reserve was slightly different (P = NS). Further, areas of match and mismatch tended to be larger in patients with CHF compared to patients with normal LV, but due to the large S.D., only match was statistically significant.


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  		Table 2 PET measurements

 
In non-stenotic (<70%) coronary artery areas (Table 2, left panel), MBF was similar at rest in both groups (95±24 vs. 90±22 ml/min per 100 g, CHF versus normal LV, respectively). In contrast, after dipyridamole, the increase in MBF in patients with CHF was lower (155±26 ml/min per 100 g) than in patients with normal LV function (210±21 ml/min per 100 g, P<0.05 between groups), and MBF reserve was also different (1.6±0.6 in CHF versus 2.2±0.5 in patients with normal LV, P<0.05). In CHF patients, MBF reserve showed a significant positive relation with LV ejection fraction (r = 0.6, P<0.05) (Fig. 1), and a negative correlation with LV wall stress (r = –0.72, P<0.05) (Fig. 2). In patients with normal LV function, the correlation between LV wall stress and MBF reserve was also present (r = –0.54, P<0.05, Fig. 2), but there was no relation between LVEF and MBF reserve (Fig. 1) in these patients.


Figure 1
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  		Fig. 1 Myocardial blood flow (MBF) reserve in non-stenotic regions in patients with left ventricular (LV) dysfunction (black dots) and in patients with normal LV function (open triangles). In LV dysfunction MBF reserve was impaired and correlated with LV ejection fraction (r = 0.6, P<0.05).

 

Figure 2
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  		Fig. 2 Myocardial blood flow (MBF) reserve in non-stenotic regions in patients with left ventricular (LV) dysfunction (black dots) and in patients with normal LV function (open triangles). In LV dysfunction MBF reserve was impaired, but MBF reserve correlated with LV wall stress in both groups.

 
In the CHF group, mismatch was observed in 26±26% of the myocardium in the non-stenotic, non-infarct related areas, as compared to 4.0±1.3% in the normal LV group (P<0.05 between groups) (Table 2). Also match was more pronounced in the CHF group.

3.3 DSE findings
During DSE (Table 3), a total of 135 segments were evaluable in the patients with normal LV versus 97 segments in the CHF group. In the stenotic artery areas, DSE showed ischemia in 17% of the segments in the normal LV group (nine segments showed a biphasic response and two segments worsened) versus 18% of the segments in the CHF group (nine segments showed a biphasic response and two segments worsened) (P = NS between groups).


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  		Table 3 DSE measurements

 
In the non-stenotic regions, the total percentage of segments in the normal LV group showing ischemia was 4% (two segments showed a biphasic response and one segment worsened), as compared to 21% (six segments showed a biphasic response and two segments worsened) in the CHF group (P<0.05 between groups). In the CHF group, more improvement (non-transmural myocardial infarction) (15 segments; 15%) and irreversible wall motion abnormalities (transmural infarction) (17 segments; 17%) were observed. In the normal LV group these figures were six segments (5%) and three segments (2%), respectively.


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
4.1 Ischemia in CHF
It has long been known, that myocardial ischemia causes LV dysfunction and, ultimately, CHF, and reversal of this ischemia by either pharmacological or mechanical intervention (coronary angioplasty or bypass surgery) leads to improvement of LV function. The data of the present study suggest, that the reverse may also be true, i.e., the condition of CHF per se leads to ischemia. In CHF patients, the MBF reserve was impaired, and was related to the severity of CHF, as it correlated with the decrease in LV ejection fraction, and the increase in LV wall stress, both well-known indices of severity of CHF. In addition, mismatch patterns, which are indicators of myocardial ischemia during PET, were also more pronounced in patients with CHF, in areas supplied by non-stenotic coronary arteries. Together, these data comply with other, recent data from our institution, which showed that both hemodynamic and metabolic abnormalities, as assessed by PET, were present in patients with idiopathic dilated cardiomyopathy (who by definition had normal coronary arteries), which could be compatible with the concept of myocardial ischemia in these patients [2]. The novel aspect of the present study is, that we now show, that the above-described abnormalities coincide with ischemic responses during DSE, which are generally considered to represent ischemia. Therefore, the present data may support the notion that the condition of CHF per se leads to myocardial ischemia. This concept has been suggested before by Unverferth et al. [14], and these authors indicated that primarily subendocardial ischemia would play a role, for which they provided both metabolic/physiological and histological evidence.

4.2 Possible mechanisms of ischemia
The regulation of myocardial blood flow is a complex phenomenon which depends on coronary perfusion pressure, the presence of atherosclerotic narrowing [15], and/or vasomotor changes in epicardial conduit vessels [16] and neurohormonal activation, the function of coronary microcirculation and extravascular forces, such as intramyocardial pressure and wall stress [17]. Vatner et al. [18] showed that in dogs with left ventricular hypertrophy, the increased LV wall stress led to impairment of MBF reserve, and subsequently caused CHF. In patients with idiopathic dilated cardiomyopathy, endothelial function is impaired [19], as well as MBF reserve, which correlates with LV wall stress [2]. Coronary microvascular abnormalities as an early component of CHF, were also found in other clinical and experimental studies of CHF [16,20–22], and are influenced by the severity of CHF (increased sympathetic tone). In these regions, infusion of dobutamine results in contractile dysfunction [23]. It has been suggested, that by decreasing the microvascular ischemia in patients with dilated cardiomyopathy, LV function may improve [24].

MBF at rest in non-stenotic coronary arteries was not impaired in patients with CHF (compared to patients with normal LV), which agrees with previous work [1,2]. MBF reserve, however, was impaired proportional to the severity of LV dysfunction. In these regions, DSE showed ischemic contraction patterns. These areas may thus be called hibernating [25]. Hibernation is well-known to play a role in CHF [26], and as discussed above, may be (partly) reversed by treatment. If episodes of myocardial ischemia last longer, this may lead to hibernation and deterioration of LV function [27]. If this hibernation is present during extended periods of time, however, cellular degeneration (cardiomyocytes) may occur [28], and this may lead to apoptosis [29–31]. Watanabe et al. [32] recently also reported, that the myocardium of cardiomyopathic hamsters was hypoxic, which might contribute to the development of cardiomyopathy. In accordance with the present and previous work [2] are studies in patients with hypertrophic cardiomyopathy (and normal coronary arteries), which showed increased changes in coronary sinus pH during dipyridamole stress, which might also suggest myocardial ischemia [33]. However, the present study did not investigate whether there is evidence of anaerobic metabolism in mismatch regions, PET imaging with C11-acetate will be needed to address this issue.

In CHF, MBF reserve is reduced and mismatch was more common in myocardial territories in which epicardial coronary stenoses are unlikely to limit perfusion. A plausible explanation is increased extravascular forces (wall-stress, see Fig. 2). That these segments also demonstrate excess wall motion abnormalities during DSE speaks for ischemia induced as a consequence of the reduced MBF reserve which could be due either to mechanical or microvascular functional factors. An important therapeutic hypothesis arising from these findings is that reduction of wall stress would improve MBF reserve and thus cease the vicious circle of ischemia–CHF–ischemia.

Neurohormonal activation is enhanced in patients with CHF. When hibernating myocardium is stimulated with (endogenous or exogenous) catecholamines to cause positive inotropy, acute effects are perfusion-metabolism augmentation and contractile function improvement, but after long-term stimulation progressive cell loss occurs [25]. If myocardial ischemia is indeed present in CHF, this may be an additional explanation why positive inotropic agents have been shown ineffective. Also, one may speculate that induction of angiogenesis through gene therapy may be of potential value in CHF [34].

4.3 Limitations and further study
Given the small sample size of the present mechanistic study, conclusions based on these data, for example regarding underlying pathophysiology, should be drawn with caution. Further, it is not possible to exclude the presence of significant coronary disease in the non-stenotic areas, since we did not use intravascular ultrasound (IVUS) to quantify the degree of coronary artery stenosis.

The effect of concomitant medication is uncertain, although in a previous study we found no effect of ACE inhibition on myocardial imaging pattern [35].

Studies, specifically aimed to examine the relation between myocardial ischemia and CHF, and studies in which the effects of reducing ischemia in CHF is investigated, will be needed to further explore the reciprocal relation between CHF and ischemia.

Time for primary review 31 days.


   Notes
 
1 Dr. D.J. van Veldhuisen is an Established Investigator of the Netherlands Heart Foundation, Grant D97-017. Back


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 

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