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Ischemia and Left Ventricular Dysfunction: A Reciprocal Relation?

van Veldhuisen, Dirk J.; van den Heuvel, Ad F. M.; Blanksma, Paul K.*; Crijns, Harry J. G. M.

Journal of Cardiovascular Pharmacology: 1998 - Volume 32 - Issue - p S46-S51
Treatment of Heart Failure: Current Insights and New Treatment Options
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There is convincing evidence that (prolonged) episodes of myocardial ischemia lead to impairment of left ventricular (LV) function and ultimately to chronic congestive heart failure(CHF), but whether the opposite is also true has not been well established. We studied this issue in two groups of CHF patients with positron emission tomography (PET) by using [13N]ammonia (13NH3) as a tracer. In the first protocol we compared 12 patients with idiopathic dilated cardiomyopathy (who have normal coronary arteries) with 12 healthy controls. In the second protocol we studied a group of 24 patients with documented coronary artery disease (CAD). In this protocol, we compared patients with normal LV function to those with LV dysfunction and CHF. In patients with cardiomyopathy, myocardial blood flow at rest was normal but flow reserve (after dipyridamole infusion) was significantly impaired (1.7 ± 0.08) compared with normal subjects (2.7 ± 0.04; p <0.05). Furthermore, by examining [18F]fluorodeoxyglucose (18FDG) uptake, a perfusion-metabolism mismatch was observed in 24 ± 6% of the myocardium in patients with cardiomyopathy as opposed to 0% of normals (p <0.05). In patients with CAD, myocardial blood flow reserve (measured in non-stenotic arteries to non-infarcted area) was impaired in CHF patients (1.7 ± 0.06) compared to those with normal LV function (2.3 ± 0.05; p <0.05). In both groups of CHF patients, the impairment of blood flow reserve showed a significant correlation with the severity of CHF. In conclusion, myocardial blood flow reserve is impaired in patients with CHF in proportion to the degree of CHF. Metabolic studies with 18FDG further show that, in patients with idiopathic dilated cardiomyopathy and CHF, flow-metabolism mismatch is present in a substantial part of the myocardium, suggesting a pathogenetic role for ischemia.

Department of Cardiology/Thoraxcenter and *National PET Center, University Hospital Groningen, Groningen, The Netherlands

Address correspondence and reprint requests to Dr. D. J. van Veldhuisen at Department of Cardiology/Thoraxcenter, University Hospital Groningen, PO Box 30.001, 9700 RB Groningen, The Netherlands.

Coronary artery disease (CAD) has become the most important underlying etiology for the development of chronic congestive heart failure (CHF) in the Western world. In most of these patients, progressive CAD leads to one or more myocardial infarctions (MIs), causing left ventricular (LV) dysfunction. However, it has become increasingly clear that segmental (chronic) myocardial ischemia also plays a role in this respect because it may lead to additional ventricular dysfunction, often referred to as "myocardial hibernation" (1,2). These areas of noncontractile but viable myocardium are important because they may recover after revascularization, which may lead to improved cardiac performance and an increase in the LV ejection fraction(LVEF) (3). Assessment of reversibility of such areas is possible with several techniques, including both 201thallium and technetium-99m sestamibi single-photon emission tomography (SPECT), (dobutamine) stress echocardiography, and positron emission tomography (PET) (2,4), of which the latter is considered the gold standard. Therefore, there is convincing evidence that prolonged (episodes of) ischemia and also ischemia occurring early during coronary occlusion with angioplasty (5) lead to impairment of myocardial relaxation and contraction.

Whether the reverse is also true, i.e., whether LV dysfunction also leads to perfusion or flow impairment and ischemia, is much less well known. However, several changes take place in CHF that may cause or aggravate impairment of coronary blood flow and ischemia. First, endothelial function is impaired in several models of CHF and vascular disease (6,7), and also in patients with CHF resulting from idiopathic dilated cardiomyopathy (8). Second, several plasma neurohormones that cause vasoconstriction are increased in CHF, including norepinephrine, angiotensin II, and endothelin, and these neurohormones may also cause coronary vasoconstriction. Third, (compensatory) myocardial hypertrophy may occur in CHF, leading to impairment of subendocardial perfusion during episodes of stress, such as exercise (9).

To establish whether the condition of CHF may in itself lead to impairment of myocardial perfusion (and its response to vasodilatation), which in turn may lead to ischemia, we recently performed PET scanning in a group of patients with CHF resulting from idiopathic dilated cardiomyopathy(10) and in a group of patients with CHF resulting from CAD(11). Moreover, we related the observed changes in CHF patients to parameters that reflect the severity of CHF, such as LVEF and peak oxygen consumption(peak VO2).

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METHODS

Patients

Two separate protocols were conducted. In the first, we compared patients with proven idiopathic dilated cardiomyopathy with healthy controls, and in the second we examined patients with CHF due to coronary artery disease and (old) MI and compared them to patients with CAD of similar severity (percentage of lesions and vessels involved), but no CHF, and used them as controls. All CHF patients had undergone left and right heart cardiac catheterization to assess the degree of CAD and to optimize the hemodynamic status. A diagnosis of idiopathic dilated cardiomyopathy was made on the basis of clinical, laboratory, and echocardiographic findings. In addition, CAD was excluded and endomyocardial biopsy was performed in all patients to confirm the diagnosis. At baseline, the severity of CHF was assessed by scoring functional class according to the New York Heart Association (NYHA) classification and by measuring LVEF using radionuclide ventriculography. In patients with idiopathic dilated cardiomyopathy, peak VO2 was also determined.

Controls were carefully selected from our database of healthy volunteers, who did not have any relevant medical history, including systemic hypertension, diabetes mellitus, hypercholesterolemia, or any other systemic illness. All underwent a careful history and physical examination, as well as an ECG and laboratory analysis. Before the studies, subjects in both studies gave their written informed consent, and both protocols were approved by the Ethics Committee of our hospital.

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Positron emission tomography

Myocardial perfusion was studied with positron emission tomography (PET) according to the method of Schelbert et al. (12), using [13N]ammonia(13NH3) as a tracer, as previously described in detail from our institution(13,14). All studies were performed in the National PET Center at the University Hospital Groningen, using an ECAT Siemens 951/31 camera(Siemens CTI; Knoxville, TN, U.S.A.). After patients were positioned in the PET camera with the help of a rectilinear scan, a transmission scan was obtained to correct for tissue attenuation. Dynamic imaging was started at the time of 13NH3 injection (370 MBq) and was continued for 15 min (frames: 12 × 10 s, 1 × 2 min, 1 × 4 min, 1 × 7 min). A control study was made to examine myocardial blood flow at rest, followed after 20 min by a provocation study with dipyridamole, which was injected slowly over 4 min (at: 0.56 mg/kg body weight). Two minutes after that, a second injection of 13NH3 was administered and the myocardial blood flow during stress was obtained. With this method, the ratio of maximal flow to flow at rest was calculated: the (myocardial or coronary) flow reserve. In patients with CAD, we assessed myocardial blood flow at rest and after stress only in the non-infarcted regions, and a distinction was made between the stenotic (>70%) and non-stenotic (<70%) arteries.

To evaluate possible ischemia (15,16) in patients with idiopathic dilated cardiomyopathy, we also examined myocardial glucose uptake by use of [18F]fluorodeoxyglucose (18FDG), using glucose loading, as previously described (13). In short, 185 MBq of 18FDG was injected, after which the following frames were collected: 8 × 15 s, 4 × 30 s, 1 × 1 min, 1 × 5 min, 1 × 10 min, 1 × 15 min, 1 × 20 min). By comparing myocardial blood flow (as assessed above) with this 18FDG uptake, the relation between blood flow (or perfusion) and metabolism could be determined, resulting in a percentage "match" (or "mismatch"), in which a mismatch pattern has been shown to be associated with hibernating myocardium(15-17).

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Statistical analysis

All data are expressed as mean ± SEM. In both protocols, data from CHF patients were compared with controls with normal LV function using the Wilcoxon matched-pairs, signedranks test. A value of p <0.05 was considered statistically significant.

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RESULTS

Patients

A total of 48 subjects were evaluated in the two studies. In the first protocol, 12 patients with idiopathic dilated cardiomyopathy and CHF were examined and compared to 12 healthy volunteers(controls). The 12 cardiomyopathy patients were 32 ± 4 years old and eight of them were males. Control subjects were well matched with the cardiomyopathy patients and were 34 ± 3 years old; there were also eight males and four females. Of the 12 cardiomyopathy patients, seven were classified as being NYHA functional class II and five were classified as NYHA class III. Their mean LVEF was 0.38 ± 0.07, mean peak VO2 was 21.2 ± 2.0 ml/min/kg, and plasma norepinephrine was 616 ± 20 pg/ml.

In the second protocol, 24 other subjects were studied: 12 patients with CAD and CHF and 12 controls who had similar CAD but no CHF. Subjects in this protocol were usually older, but the two groups in this protocol were also well matched (Table 1).

TABLE 1

TABLE 1

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Myocardial blood flow, flow reserve (after dipyridamole), and 18FDG uptake

In the first protocol (10), there was no difference in myocardial blood flow at rest between healthy subjects (102 ± 6 ml/min/100 g) and patients with CHF and idiopathic dilated cardiomyopathy (100 ± 8 ml/min/100 g). In contrast, after dipyridamole infusion, peak myocardial flow was significantly lower in CHF/ cardiomyopathy patients (164 ± 14 ml/min/100 g) compared to healthy controls (280 ± 40 ml/min/100 g) (p <0.05) (Fig. 1). As a consequence, the ratio of blood flow at rest to blood flow after dipyridamole infusion (flow reserve) was also reduced in cardiomyopathy/CHF patients (1.7 ± 0.08 vs. 2.7 ± 0.04 in controls).

FIG. 1

FIG. 1

When 18FDG was used, perfusion(using 13NH3; myocardial blood flow) and metabolism (18FDG uptake) were well matched throughout the myocardium in healthy controls (0% mismatch). In contrast, in patients with idiopathic dilated cardiomyopathy, 24 ± 6% (range 0-61%) of the myocardium showed a mismatch (p <0.05 vs. controls).

In patients with CAD (second protocol) (11), myocardial blood flow in stenotic (>70%) arteries was normal at rest in both groups (no CHF and CHF), but myocardial flow reserve was significantly impaired in both groups(p = NS between CHF and no-CHF patients). In nonstenotic(<70%) coronary arteries, myocardial blood flow was similar at rest in both groups. After dipyridamole, blood flow significantly increased in no-CHF patients (albeit less than in healthy and younger volunteers in the first protocol), but this was markedly impaired in patients with CHF (Fig. 2). The ratio of myocardial blood flow at rest to that after dipyridamole infusion was therefore also markedly lower in patients with CAD and CHF (1.7 ± 0.06) compared to those with CAD and normal LV function and no CHF (2.3 ± 0.05; p <0.05).

FIG. 2

FIG. 2

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Relation between myocardial blood flow (reserve) and severity of CHF

In patients with idiopathic dilated cardiomyopathy, myocardial blood flow at rest was not significantly related to the severity of CHF, as assessed by both LVEF and peak VO2. In contrast, after stress (dipyridamole infusion), the myocardial blood flow reserve was significantly more impaired in patients with more advanced CHF compared to those with less advanced disease, and a significant correlation was observed between flow reserve on the one hand and LVEF (r = 0.6; p = 0.02) and peak VO2 (r = 0.5; p = 0.04) (Fig. 3) on the other. In patients with CHF and CAD, a similar relation was observed, because patients with the most advanced CHF (as reflected by the lowest LVEF) had the most impaired myocardial flow reserve after vasodilatation with dipyridamole (r = 0.6; p= 0.03 (Fig. 4).

FIG. 3

FIG. 3

FIG. 4

FIG. 4

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DISCUSSION

It is now well established that myocardial ischemia leads, at some point, to impairment of myocardial performance. However, there is also increasing evidence that the reverse is true and that LV dysfunction(and CHF) per se cause coronary perfusion abnormalities, myocardial ischemia, and myocardial hibernation, particularly after stress (such as pharmacologic interventions and exercise). In this article we have described two recent studies from our institution in which we examined myocardial flow and its reserve (and myocardial metabolism) in patients with CHF. The data show that, in patients with CHF, myocardial flow reserve is impaired and that this impairment is related to the severity of CHF. This holds true both for patients with CHF due to idiopathic dilated cardiomyopathy (who, by definition, have normal epicardial coronary arteries) and for patients with CAD, in whom we examined the non-infarcted, non-stenotic arteries. These data therefore strongly suggest that the condition of CHF in itself leads to an impairment of myocardial flow reserve. In addition to this, we also showed that, in patients with idiopathic dilated cardiomyopathy, a large part (mean 24%) of the myocardium showed a perfusion-metabolism mismatch, suggesting the presence of ischemia and/or hibernation. Because it has often been assumed that myocardial ischemia does not play a role in these patients, this latter finding is particularly interesting, and it confirms earlier findings with 201-thallium scintigraphy in patients with idiopathic dilated cardiomyopathy(18).

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Mechanisms for impaired myocardial flow reserve and ischemia in CHF

There are several potential explanations for the observed findings in patients with CHF, which have already been briefly discussed above. First, endothelial function is impaired in CHF, regardless of the underlying etiology, in patients both with and without concomitant vascular disease (19). Although the mechanism of this impairment is not completely understood, the balance between endothelium-derived relaxing and constricting factors may well play a role. In this respect, both the low-flow state and the production of oxygen-derived free radicals in CHF also appear to play a role, but their importance is thus not fully clear. A second important factor in CHF is the presence of markedly increased (vasoconstrictive) plasma neurohormones, such as (nor)-epinephrine, angiotensin II, endothelin, and arginine vasopressin. These neurohormones not only lead to (increased) coronary vasoconstriction but also have growth-promoting properties, leading to more structural vascular changes(20). A third potential explanation for the occurence of ischemia in CHF is the development of (compensatory) ventricular hypertrophy and elevated wall stress, which leads to an increased metabolic demand. Particularly in the endocardium, this may cause impairment of flow reserve and ischemia (9).

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Clinical implications

If ischemia plays a role in CHF, it is tempting to speculate that drugs that reduce ischemia can also be beneficial in CHF and that drugs that work in CHF would also favorably affect ischemia and ischemic events. With regard to the latter, angiotensin-converting enzyme (ACE) inhibitors may have a beneficial effect on myocardial ischemia (21), and recent data indicate that ACE inhibitors also reduce the incidence of ischemic events after myocardial infarction(22). The opposite may also be true for β-blockers, because these drugs are potent anti-ischemic agents and recent data with carvedilol support their use in CHF (23). Interestingly, in contrast to more conventional(selective) β-blockers which affected mortality primarily in patients with idiopathic dilated cardiomyopathy (24), carvedilol, which has ancillaryα-blocking properties (25), was also found to reduce mortality in patients with CAD disease and CHF. It can be speculated that this may be related to the α-blocking properties, which may be important in the setting of CHF and increased coronary vasomotor tone. To evaluate whether carvedilol reduces ischemia in patients with CHF and thereby improves LV function, several trials are now under way, including the CHRISTMAS Study in the United Kingdom, which uses nuclear scintigraphy, and a study in our own institution in which PET scanning is used.

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CONCLUSIONS

Myocardial ischemia leads to LV dysfunction (and CHF) but, given the findings of two presented studies in patients with CHF, the opposite may also be true, and a reciprocal relation can therefore be assumed. This may have important clinical implications and may affect drug treatment in patients with CHF.

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Section Description

Proceedings of a symposium held in Apeldoorn, The Netherlands May 31, 1997

Keywords:

Congestive heart failure; Idiopathic dilated cardiomyopathy; Ischemia; Left ventricular function; Metabolic studies

© Lippincott-Raven Publishers.