Window on Cardiology

Coronary Microvascular Dysfunction

Paolo G Camici, MD FESC FACC FAHA FRCP Medical Research Council Clinical Sciences Centre, Faculty of Medicine, Imperial College, London, UK http://www.csc.mrc.ac.uk

Address for Correspondence: Professor Paolo G. Camici, MRC Clinical Sciences Centre, Imperial College, Hammersmith Hospital, Du Cane Road, London W12 0NN, United Kingdom (E-mail and other contact info can be obtained from CWWJ's Editor-in-Chief).

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Coronary flow reserve (CFR), the ratio of MBF during near maximal coronary vasodilatation to basal MBF, is an integrated measure of flow through both the large epicardial coronary arteries and the microcirculation, and has been proposed as an indirect parameter to evaluate the function of the coronary circulation. An abnormal CFR can be due to narrowing of the epicardial coronary arteries or, in the absence of angiographically demonstrable atherosclerotic disease, may reflect dysfunction of the coronary microcirculation.

Studies in healthy human volunteers using positron emission tomography (PET) have established that the normal CFR in response to a standard intravenous dose of vasodilators (dipyridamole or adenosine) is approximately 3,5-4. In normal subjects resting MBF is higher in females and older subjects whilst hyperemic MBF starts to decline over 55 years of age. In older subjects, there is a signi?cant increase in resting MBF associated with an increase in systolic blood pressure which, combined with the reduction in hyperemic MBF, leads to a reduction of CFR (1).

Coronary Microvascular Dysfunction in Subjects with Risk Factors for CAD

Cigarette smoking. This is a well-established risk factor for cardiovascular disease, affecting both the coronary and the peripheral circulation. Endothelial dysfunction in brachial and coronary arteries has been demonstrated in long-term smokers and even in passive smokers (2-3). The findings of a recent PET study extend these observations and demonstrate that the noxious pro-oxidant effects of smoking extend beyond the epicardial arteries to the coronary microcirculation affecting the regulation of MBF (4). In smokers, adenosine-induced hyperemia was reduced by 17% and CFR by 21% compared with nonsmoking controls (p<0.05) (Figure 1).

Although the mechanisms of smoking-associated vascular damage are not fully established, several factors may be involved. Nicotine has been shown to produce structural damage in aortic endothelial cells of animals (5). The gas phase of cigarette smoke contains large amounts of free radicals and pro-oxidants lipophilic quinones (6), which can form the highly reactive hydroxyperoxide radical. These oxidants may increase the amount of oxidized low-density lipoprotein (LDL), which is markedly more effective than native LDL in impairing nitric oxide (NO) synthase. Short-term administration of the antioxidant vitamin C restored coronary microcirculatory responsiveness and normalized CFR in smokers (Figure 1) without any significant effect in nonsmoking controls, lending support to the hypothesis that the damaging effect of smoking is at least in part explained by an increased oxidative stress.

Figure 1. CFR is significantly lower in asymptomatic smokers than in healthy controls. This can be reversed by short-term infusion of high dose vitamin C.
(Reproduced from ref. (4) with permission).

Hypercholesterolemia. A reduction in CFR in asymptomatic hypercholesterolemic subjects with angiographically normal coronary arteries, as well as its reversibility with the use of cholesterol-lowering strategies, has been documented by means of PET (7). However, results from in vitro studies, suggest that endothelial dysfunction is due to reduced NO release or increased production of superoxide anion by oxidized LDL cholesterol, or both, rather than by an increase in total cholesterol (TC). In a recent study in a population which included asymptomatic subjects with normal or elevated TC (8), no difference in either rest and hyperemic MBF or CRF was found based on TC. When all subjects (i.e. with normal and abnormal TC) were considered, there was a weak correlation between CFR and high-density lipoprotein (HDL) cholesterol, but not between CFR and LDL cholesterol. However, when only the subjects with high TC were considered, CFR was inversely related to the LDL subfraction (-0.61, p<0.01). Similarly, previous studies, had demonstrated a significant inverse correlation between CFR and lipid subfractions, including LDL cholesterol (9). These in-vivo results are in agreement with the previous observations identifying the LDL subfraction as a cause of endothelial dysfunction, and extend these findings to the coronary microcirculation in humans. Furthermore, this provides pathophysiologic support for a clinical strategy (10) aimed at the treatment of the entire lipid profile rather than targeting TC reduction alone.

Diabetes mellitus. It is a well-known finding of the Framingham study that patients with diabetes have an increased risk for development of micro- and macro-angiopathy and cardiac disease (11). In addition, angina or silent ischemia appears to be frequent in diabetic patients who have been shown to have angiographically normal coronary arteries. Although much of the excess CAD risk can be accounted for by the presence of diabetes-associated coronary risk factors such as obesity, dyslipidemia, and hypertension, a significant proportion of it remains unexplained (12). A recent PET study (13) has found markedly impaired coronary microvascular function in response to adenosine (reflecting partly endothelium-independent vasodilation) and to cold pressor test (reflecting primarily endothelium-dependent vasodilation) in young subjects with uncomplicated diabetes. The findings were very similar in type 1 and type 2 diabetes, although patients with type 1 diabetes are insulin-deficient (rather than insulin-resistant, the latter being the hallmark of type 2 diabetes). This provides further support for a key role of hyperglycemia in the pathogenesis of vascular dysfunction in diabetes.

The Emerging Concept of "Coronary Microvascular Disease"

Until quite recently, many of the most important forms of cardiovascular disease were considered to involve primarily large vessels, particularly the conduit coronary arteries. However, recent advances have highlighted the crucial involvement of the microcirculation in many cardiovascular conditions. A new concept has emerged where "microvascular disease" is a well-defined condition that often precedes the development of full-blown diseases and may bear independent prognostic value.

Although direct visualization of the coronary microcirculation has been achieved in experimental animal preparations using intravital microscopy and stroboscopic epi-illumination of the heart (14-15), there is no technique which enables the direct visualization of the coronary microcirculation in man in vivo. The resistive vessels in the coronary circulation are not generally visible on angiography and are too small to be amenable to selective catheterization. Therefore, study of the human coronary microcirculation is indirect and relies on assessing parameters, which reflect its functional status, such as MBF and CFR. These are principally regulated by the coronary microcirculation and thus, in the absence of coronary stenoses, their measurement provides an index of microvascular function (16) .

Hypertrophic cardiomyopathy (HCM) is a genetically determined disease with a wide range of clinical manifestations and pathophysiological substrates (17). Symptoms and signs of myocardial ischemia are often found in patients with HCM despite angiographically normal coronary arteries. Myocardial ischemia can contribute to some of the lethal complications of HCM including ventricular arrhythmias, sudden death, progressive left ventricular remodeling and systolic dysfunction.

In the past decade, a number of PET studies (18-21) have demonstrated that in HCM patients the vasodilator response to dipyridamole, and hence CFR, are markedly impaired not only in the hypertrophied septum, but also in the least hypertrophied left ventricular free wall. In the absence of coronary stenoses, this finding is indicative of a diffuse microvascular dysfunction which is in line with the autoptic evidence of widespread remodeling of the intramural coronary arterioles (22). This inadequate hyperemic MBF response to demand in patients with HCM is clinically relevant in that it predisposes them to myocardial ischemia, which in turn, has been implicated in the pathogenesis of syncope, abnormal blood-pressure response to exercise, left ventricular systolic dysfunction, and sudden death. Several factors have been associated with an unfavorable outcome, but the identification of patients at risk for sudden death or progression to heart failure remains a formidable challenge (23-24). A recent PET study has documented that the severity of coronary microvascular dysfunction is an independent predictor of long-term clinical deterioration and death from cardiovascular causes in patients with HCM (25) (Figure 2).

Figure 2. Click the image to enlarge

Dilated Cardiomyopathy (DCM). Impaired MBF at rest and during hyperemia as well as impaired CFR have been demonstrated in patients with DCM (26-28). In a recent PET study coronary microcirculatory dysfunction has been documented in patients with DCM as compared to healthy controls (29). Interestingly, in contrast to healthy volunteers there was no correlation between PET findings of impaired coronary microcirculation and flow-mediated dilation of the brachial artery. This suggests that the assessment of endothelial function made in the peripheral circulation cannot be necessarily extrapolated to the coronary circulation. Impaired vasodilator capacity has been shown to be an independent predictor of subsequent cardiac events and is associated with an increased relative risk of death and further progression of heart failure (30).

Hypertensive Heart Disease. Abnormal CFR, despite angiographically normal coronary arteries, has been demonstrated in several studies in patients with essential hypertension (31-33). This observation has often been attributed to the effects of left ventricular hypertrophy secondary to hypertension. These include increased extravascular compressive forces with elevated systolic/diastolic wall stress and impaired relaxation and structural alterations such as myocyte hypertrophy, interstitial fibrosis and rarefaction of coronary microvasculature leading to reduced MBF. However, impairment of CFR in hypertensive patients is not necessarily related to the presence or degree of left ventricular hypertrophy (34). Impairment of CFR was found to be mainly caused by a reduction in the vasodilating capacity of the coronary resistance vessels rather than by effects linked to hypertrophy alone. This may be a consequence of vascular remodeling, such as media thickening, perivascular fibrosis or functional alterations linked to endothelial dysfunction.

A recent study has provided new insights into the complex interactions among hypertension, left ventricular hypertrophy and impaired CFR (35). The authors found a significantly impaired CFR in hypertensive patients compared to normotensive controls. The global impairment, however, was not directly linked to the presence or degree of left ventricular hypertrophy as assessed by echocardiography. In addition, the abnormality of hyperemic MBF was found to be regionally heterogeneous. In patients with heterogeneous regional MBF, the flow impairment affected only a few areas, whereas others seemed unaffected. By contrast, in patients with homogenous MBF, the whole myocardium displayed a reduced CFR, possibly indicating a more advanced stage of the disease. The presence of left ventricular hypertrophy represented an indicator for those hypertensive patients who showed a stress-induced heterogeneous MBF. It is possible that regionally impaired vasodilating response may predispose to abnormal patterns of myocardial electrical depolarization and repolarization or regional myocardial ischemia, or both, during high flow demand conditions. Such a substrate could represent a focus for inducing clinically relevant arrhythmias.

Aortic Stenosis (AS). Development of left ventricular hypertrophy in patients with AS is an adaptive response, which attempts to reduce wall stress in the left ventricle. Development of left ventricular hypertrophy also affects the coronary circulation, and patients with AS have a reduced CFR despite angiographically normal coronary arteries (36). This impairment of CFR is mainly due to a curtailment in maximal MBF (37). Hyperemia is hindered by a series of unfavorable hemodynamic changes including high left ventricular cavity pressure, low coronary perfusion pressure, and increased extra-vascular compressive forces that lead to increased minimal coronary resistance. In addition, characteristic pathological changes which contribute to impair microvascular function have been described in the hypertrophied ventricle of patients with AS. These consist of perimyocytic fibrosis (38) and reduction in the number of resistance vessels per unit weight.

A recent PET study has demonstrated that CFR was more severely impaired in the left ventricular subendocardium in patients with cardiac hypertrophy due to severe AS. Severity of impairment was related to aortic valve area, hemodynamic load imposed, and diastolic perfusion time, rather than to left ventricular mass (39). Furthermore, in a subsequent study, the same authors have demonstrated that changes in coronary microcirculatory function in patients with AS after aortic valve replacement are not directly dependent on regression of left ventricular mass (40).

Conclusion

It can be summarized that a new concept has emerged where "microvascular disease" is a well-defined condition that often precedes the development of full-blown diseases and may bear independent prognostic value. For further reading, a list of selected references can be found on the next couple of pages.

References

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Last updated: 1 September 2005Created
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