Number 45, 2009
Diabetes and cardiovascular disease

Reduction of coronary flow reserve in a patient with type 2 diabetes mellitus without epicardial coronary stenosis

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Maurizio Galderisi, Rosa Raia
Department of Clinical and Experimental Medicine, Federico II University, Naples, Italy
Correspondence: Dr Maurizio Galderisi, Laboratory of Echocardiography of Division of Cardioangiology with CCU, Department of Clinical and Experimental Medicine, Block 1, Federico II University Hospital, Via S. Pansini 5, 80131 Naples, Italy.
Tel: +39 (0)81 7462145; fax: +39 (0)81 5466152; e-mail: mgalderi@unina.it

Introduction
Functional and structural alterations of the coronary microcirculation are possible in patients who have type 2 diabetes mellitus but do not present coronary artery stenosis [1–3]. Although frequently associated with myocardial perfusion defects on single photon emission computed tomography (SPECT) [4], these alterations can remain silent for several years during the time course of the disease, or contribute to the development of myocardial ischemia and angina pectoris when myocardial oxygen demand is increased [5].
The function of the coronary microcirculation may be clinically evaluated by quantitation of the coronary flow reserve (CFR), which is the ratio between hyperemic and resting coronary flow. In the absence of significant stenosis of the epicardial coronary arteries, a reduction in CFR represents a reliable marker of coronary microvascular dysfunction [6]. Today, CFR may also be determined by non invasive transthoracic echocardiography (TTE), which enables the measurement of coronary flow velocities in the mid-distal left anterior descending artery [7,8]. TTE-derived CFR shows excellent agreement with CFR estimated by intracoronary Doppler flow wire [9], and is highly practicable and reproducible [7].
We present the case of a patient with asymptomatic type 2 diabetes mellitus, normal coronary angiography, and a SPECT-derived myocardial perfusion defect, in whom transthoracic Doppler-derived CFR was of additional value in achieving the correct diagnosis.

Case report
A 48-year-old woman affected by type 2 diabetes mellitus presented at the outpatient clinic of the Department of Clinical and Experimental Medicine of Federico II University Hospital. The diagnosis of diabetes mellitus was based on the American Diabetic Association guidelines [10]. Fasting blood glucose was 149 mg/dL and the glycated hemoglobin value (HbA_1c) 7.7%. The duration of the patient's type 2 diabetes mellitus was 10 years. No signs of retinopathy had been found by fundus oculi. The patient was referred to the Echocardiography Laboratory of our Department because of inducible myocardial ischemia detected on both effort electrocardiogram (ECG) and effort myocardial SPECT (Figure 1), and after the performance of a coronary angiography that revealed evidence of absence of significant epicardial coronary artery stenosis (Figure 2). At the time of the echocardiogram, the woman was receiving antihypertensive therapy with an angiotensin-converting enzyme inhibitor and a β-blocker; her blood pressure was 140/80 mm Hg.

Discussion
The case presented here demonstrates the usefulness of transthoracic Doppler-derived CFR in distinguishing coronary microvascular dysfunction from epicardial coronary artery stenosis in type 2 diabetes mellitus. Our patient, in fact, had signs of inducible ischemia on effort ECG and SPECT, but no angiographic evidence of epicardial coronary artery stenosis. On these grounds, coronary microvascular impairment was identified because the CFR was reduced, whereas regional wall motion was completely normal, after high-dose dipyridamole.
Diabetes mellitus induces functional and structural abnormalities of the coronary microvascular environment, which can play a part in the development of diabetic cardiomyopathy [14,15]. Coronary microvascular function may be evaluated non invasively by the assessment of TTE-derived CFR. Reduction in CFR corresponds to coronary microvessel damage when stenosis of the epicardial coronary arteries is excluded [6]. An impairment of CFR has been documented in both type 1 and type 2 diabetes mellitus. Several factors such as hyperglycemia, insulin resistance, endothelial dysfunction, and increased cardiac sympathetic activity [16–19] can be involved in this impairment. However, the impact of concomitant cardiovascular risk factors, particularly of increased blood pressure, should also be taken into account [15].
Left ventricular hypertrophy is an independent hallmark of cardiovascular risk in the general population [20]. It develops frequently in diabetic patients, independent of the effect of concomitant risk factors [21], but can also be induced by the often coexisting increased blood pressure [20]. Worthy of note, the presence of LVH is associated with left ventricular diastolic dysfunction [22]. In agreement with previously reported observations [15,23], the CFR in our patient with type 2 diabetes mellitus was reduced, mainly as a result of a blunted hyperemic response to dipyridamole. The reduction in CFR was combined with structural changes to the left ventricle, mainly concentric LVH and left ventricular diastolic dysfunction, whereas the metabolic picture (fasting blood glucose concentration, HbA_1c values) was near normal. This evidence is in agreement with the findings of previous studies indicating that impairment of the coronary microvessels in patients with type 2 diabetes mellitus and hypertension could be, at least in part, mediated by changes in left ventricular structure associated with LVH. Extravascular compressive forces and concomitant hypertrophy of the coronary microvascular walls might be mechanisms underlying the abnormalities of CFR observed in the diabetic and hypertensive heart [15].

Conclusion
The clinical case presented highlights the role of transthoracic Doppler-derived CFR in the diagnosis of isolated coronary microvascular dysfunction in type 2 diabetes mellitus, and illustrates that abnormalities of the coronary microvessels are associated more with myocardial structural changes than with metabolic status.

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