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Silent Ischemia as a Central Problem: Regional Brain Activation Compared in Silent and Painful Myocardial Ischemia

Stuart D. Rosen, MA, MRCP; Eraldo Paulesu, MD; Petros Nihoyannopoulos, MD; Dimitris Tousoulis, MD; Richard S.J. Frackowiak, MD, FRCP; Christopher D. Frith, PhD; Terry Jones, DSc; and Paolo G. Camici, MD
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From Hammersmith Hospital and the Institute of Neurology, London, United Kingdom, and Istituto Scientifico H San Raffaele, Universita degli Studi, Milano, Italy. Acknowledgments: The authors thank Mr. Andrew Blythe, MSc, DCR, and Ms. Andreana Williams, DCR, for assistance with positron emission tomography; Dr. Ignathios Ikonomides for assistance with echocardiography; and Professor Alberto Malliani, Universita di Milano, for helpful advice. Grant Support: In part by British Heart Foundation project grant PG/94/039. Requests for Reprints: Dr. S.D. Rosen, Cyclotron Unit, MRC Clinical Sciences Centre, Hammersmith Hospital, Du Cane Road, London W12 0NN, United Kingdom. Current Author Addresses: Drs. Rosen, Jones, and Camici: Cyclotron Unit, MRC Clinical Sciences Centre and Royal Postgraduate Medical School, Hammersmith Hospital, Du Cane Road, London W12 0NN, United Kingdom.

Copyright ©2004 by the American College of Physicians

Ann Intern Med. 1996;124(11):939-949. doi:10.7326/0003-4819-124-11-199606010-00001
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Objective: To test whether the silence of painless myocardial ischemia is caused by abnormal handling by the central nervous system of afferent messages from the heart.

Design: Nonrandomized study.

Setting: A tertiary referral center (postgraduate medical school).

Patients: 2 matched groups of nondiabetic patients with coronary artery disease. Group A consisted of nine patients with reproducible stress-induced angina; group B consisted of nine patients with reproducible stress-induced myocardial ischemia but no angina.

Interventions: Intravenous placebo infusion and low-dose (5 and 10 µg/kg per minute) and high-dose (20 to 35 µg/kg per minute) dobutamine infusions.

Measurements: Positron emission tomography was used to measure regional cerebral blood flow changes as an index of neuronal activation during painful and silent myocardial ischemia induced by intravenous dobutamine.

Results: Regional cerebral blood flow changes during myocardial ischemia were compared with those during baseline conditions and during placebo infusion. During myocardial ischemia, regional cerebral blood flow increased bilaterally in the thalami and prefrontal, basal frontal, and ventral cingulate cortices in patients in group A. Both thalami were activated in group B, but cortical activation was limited to the right frontal region. A formal comparison of groups A and B showed significant differences (P < 0.01) in activation of the basal frontal cortex, ventral cingulate cortex, and left temporal pole. In both groups, thalamic regional cerebral blood flow remained increased after the symptoms and signs of ischemia had ceased.

Conclusions: Bilateral activation of the thalamus can be shown in both angina and silent ischemia; thus, peripheral nerve dysfunction cannot completely explain silent ischemia. Frontal cortical activation appears to be necessary for the sensation of pain. Abnormal central processing of afferent pain messages from the heart may play a determining role in silent myocardial ischemia.


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Figure 2.
Time course of regional cerebral blood flow changes in selected regions of the brain.PPP

Changes in regional cerebral blood flow (rCBF) in the left thalamus, right Brodmann area (BA) 24, and left Brodmann area 10 over time. These areas show the difference in frontal activation between patients with silent ischemia and those with angina pectoris and the difference in the time course of activation between the frontal areas and the thalami. Thus, the regional cerebral blood flow changes in Brodmann area 24 and Brodmann area 10 during myocardial ischemia are significantly greater in patients with angina pectoris than in patients with silent ischemia. Although the regional cerebral blood flow increases in Brodmann area 24 and Brodmann area 10 entirely resolved by the baseline 3 scan, thalamic regional cerebral blood flow remained increased in both patient groups during the scan done after ischemia. ● equals patients with angina; □ equals patients with silent ischemia. * < 0.001, myocardial ischemia compared with baseline 1 and 2 (both groups); ** < 0.01, baseline 3 compared with baseline 2 (both groups); ** < 0.001, angina pectoris compared with silent ischemia.

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Figure 1.
Cerebral areas activated during angina pectoris and silent ischemia.Top.Middle.Bottom.

Averaged blood flow maps from all patients and all conditions normalized into a standard stereotactic space. These pictures can be used for anatomical localization of the activation foci, which are shown as statistical parametric maps in the same stereotactic anatomical space shown in the averaged blood flow maps. Results for the patients with silent ischemia. Results for the patients with angina pectoris. The magnitude of the Z scores is displayed for both patient groups according to the same linear color scale (threshold for significance, 3.7). AC-PC equals intercommissural plane. Distances are expressed in millimeters from the intercommissural plane.

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