Effect of epinephrine infusion on chest pain in syndrome X in the absence of signs of myocardial ischemia

doi:10.1016/0002-9149(95)80028-Q

The American Journal of Cardiology

Volume 75, Issue 4, 1 February 1995, Pages 241-245

https://doi.org/10.1016/0002-9149(95)80028-Q Get rights and content

Abstract

Eight female patients (aged 51 to 65 years) with New York Heart Association class II angina pectoris, normal coronary angiograms, normal hyperventilation, and abnormal exercise stress tests (chest pain and ST depression), and 5 sex- and age-matched controls participated in this study. Epinephrine was given intravenously to both patients and controls at 5-minute intervals in doses of 0.1, 0.2, 0.3, 0.4, and 0.6 nmol/kg/min. After rest (15 minutes), the α-adrenoceptor antagonist phentolamine or placebo was administered intravenously to patients in a double-blind, crossover study on 2 separate occasions in doses of 250 μg/min for 5 minutes and 500 μg/min for the next 10 minutes; the epinephrine infusion was repeated. Blood pressure, heart rate, and electrocardiogram were monitored continuously and pain was estimated on the Borg CR-10 scale. On a third occasion, chest pain was induced in patients using the same epinephrine protocol during echocardiographic monitoring. In the control group, all patients received the maximal epinephrine dose. No chest discomfort or pain developed. In the patient group, the maximal tolerable epinephrine dose (0.39 ± 0.19 nmol/kg/min) decreased diastolic pressure (−14 ± 9 mmHg, p <0.01) and increased heart rate (+24 ± 10 beats/min, p <0.01), not statistically different from the control group. Pulse pressure increased in the patient group (27 ± 17 mmHg, p <0.01) but not in the controls. Left ventricular ejection fraction at baseline was within reference limits (58% to 75%) and did not change during epinephrine infusion. Chest pain, which was not different in quality, intensity, or location from the patient's habitual angina-like pain, was induced in 7 of the 8 patients, 4 of whom endured only a moderate dose of epinephrine. No ST depressions were observed. After administration of phentolamine, chest pain developed to a degree similar to that with epinephrine alone. Chest pain is induced by epinephrine infusion in patients with syndrome X. Because no signs of ischemia occurred, a hypersensitive afferent cardiac nervous system may be an important cause of chest pain.

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Cited by (31)

Women, Cardiac Syndrome X, and Microvascular Heart Disease
2012, Canadian Journal of Cardiology
Citation Excerpt :
Thus, an important consideration in understanding the etiology of CSX is the possibility of abnormal visceral pain perception. More intriguing is the work of Eriksson et al.,33 who studied the effect of epinephrine infusion (using 3 different protocols) in 8 patients with CSX and found that, in most cases, patient's typical chest pain was reproduced in the absence of ST-segment changes and no evidence of left ventricular wall motion abnormality. As cited in Rosen and Camici,31 Eriksson et al.33 concluded that CSX might be “a sympathetic maintained pain of neurogenic origin due to dysregulation in the complex cardiac nervous system” (p. 133).
New data suggest that persistent chest pain, despite normal coronary angiography, is less benign than previously thought. It has long been recognized that cardiac syndrome X (CSX) is associated with significant suffering, disability, and health care costs, but the biggest shift in thinking comes in terms of long-term risk. It is now recognized that the prognosis is not benign and that a significant proportion of patients are at increased cardiovascular disease risk. Of major debate is the question of whether the mechanisms that explain this chest pain are cardiac vs noncardiac. The most current definition of CSX is the triad of angina, ischemia, and normal coronary arteries, which is associated with an increased cardiovascular risk. This paper provides a review of CSX, epidemiology of the problem, proposed explanatory mechanisms, and important next steps in research. Central to this review is the proposition that new insights into CSX will be fostered by both clinical and scientific collaboration between cardiovascular and pain scientists.
De récentes données suggèrent qu'une douleur thoracique, en dépit d'une coronarographie normale, est moins bénigne qu'on ne le croyait par le passé. Il a été longtemps reconnu que le syndrome X (SX) cardiaque était lié à une souffrance, une incapacité et des coûts de soins de santé importants, mais le plus grand changement dans la façon de penser a trait au risque à long terme. Il est maintenant reconnu que le pronostic n'est pas bénin et qu'une proportion significative de patients voit leur risque de maladie cardiovasculaire augmenté. La plus grande controverse est la question de savoir si les mécanismes qui expliquent cette douleur thoracique sont cardiaques ou non cardiaques. La définition la plus courante du SX cardiaque est la triade associant l'angine, l'ischémie et des artères coronaires normales, laquelle est liée à une augmentation du risque cardiovasculaire. Cet article passe en revue le SX cardiaque, l'épidémiologie du problème, les mécanismes explicatifs proposés et les prochaines étapes importantes de la recherche. Le point central de cette revue est la proposition de parrainage des nouvelles découvertes sur le SX cardiaque par la collaboration clinique et scientifique des chercheurs dans le domaine des maladies cardiovasculaires et de la douleur.
From Heart to Brain: The Genesis and Processing of Cardiac Pain
2012, Canadian Journal of Cardiology
Citation Excerpt :
The positive evidence in support of syndrome X being a neurophysiological rather than a cardiac ischemic disorder includes the demonstration of: A lower threshold for cardiac pain between syndrome X patients during pharmacological stress, whether with adenosine, epinephrine, or dobutamine infusion;76,83 The absence of relationships amongst myocardial blood flow (measured by PET), chest pain, and ECG changes;76 and
Angina pectoris is important because of its association with heart disease and risk of death. Historically after Heberden's account of angina in 1772, the association of pain with coronary artery disease quickly followed. Within a few years, Burns suggested an etiological role for ischemia. Subsequently, theories of differential myocardial stretch dominated thinking until Lewis' chemical hypothesis in 1932, in which the local release of chemical substances during ischemia was seen as the cause of pain.
This review considers how ischemia at the tissue level triggers activation of afferent nociceptive pain fibres. The afferent projections of sympathetic and vagal afferent fibres are described, with a number of methodologies cited (eg, injection of pseudorabies virus into the heart with mapping of the retrograde viral transport pathways; and elevation of neuronal c-fos synthesis in brain regions activated by capsaicin application to the heart). Our own functional neuroimaging studies of angina are also reviewed.
There are 2 intriguing features of angina. The first is the poor correlation between symptoms and extent of coronary disease. The spectrum ranges from entirely silent myocardial ischemia to that of a functional pain syndrome—the ‘sensitive heart’—of cardiac syndrome X. An even more difficult aspect is the wide variability in symptoms experienced by an individual patient.
A new paradigm is presented which, besides considering myocardial oxygen supply/demand imbalance, also draws insights from the broader field of pain research. Neuromodulation applies at multiple levels of the neuraxis—peripheral nerves, spinal cord, and brain—and it invites exploitation, whether pharmacological or electrical, for the benefit of the cardiac patient in pain.
L'angine de poitrine est importante en raison de son lien avec la maladie cardiaque et le risque de mortalité. Historiquement, après les travaux d'Heberden sur l'angine, en 1772, le lien entre la douleur et la maladie coronarienne a rapidement été reconnu. En quelques années, Burns suggérait un rôle étiologique à l'ischémie. Subséquemment, les théories d'étirement myocardique différentiel ont dominé jusqu'à l'hypothèse chimique de Lewis, en 1932, selon laquelle la libération locale de substances chimiques durant l'ischémie était considérée comme la raison de la douleur.
Cette revue examine comment l'ischémie au niveau tissulaire déclenche l'activation des fibres nociceptives afférentes. Les projections afférentes de fibres afférentes sympathiques et vagales sont décrites, avec un grand nombre de méthodologies citées (par exemple, l'injection du virus de la pseudorage dans le cœur avec cartographie des voies de transport viral rétrograde et l'augmentation de la synthèse neuronale de la protéine c-fos dans les régions du cerveau activées par l'application de capsaïcine au cœur). Nos propres études en imagerie neurologique fonctionnelle sur l'angine sont aussi revues.
Il y a 2 caractéristiques intrigantes de l'angine. La première est la mauvaise corrélation entre les symptômes et l'étendue de la maladie coronarienne. Le spectre s'étend de l'ischémie myocardique silencieuse à celui d'un syndrome de douleur fonctionnelle – le « cœur sensible » – du syndrome X cardiaque. Un aspect encore plus difficile est la grande variabilité dans les symptômes ressentis par chacun des patients. Un nouveau paradigme est présenté lequel, en plus de considérer le déséquilibre entre la demande et l'approvisionnement du myocarde en oxygène, nous donne aussi un aperçu du vaste domaine de la recherche sur la douleur. La neuromodulation applique à plusieurs niveaux de l'axe neural – nerfs périphériques, moelle épinière et cerveau – et elle invite à l'exploitation, tant pharmacologique qu'électrique, au bénéfice du patient cardiaque souffrant de douleur.
Asians differ from non-Hispanic Whites in experimental pain sensitivity
2011, European Journal of Pain
Citation Excerpt :
Contribution of sympathetic nervous system activation to pain states has long been implicated (Hord et al., 2003; Janicki, 2003). An important role for β-adrenergic receptors in mediating increased pain perception under these circumstances comes from: (1) animal and in vitro models showing that activation of the β-adrenergic receptors result in hyperalgesia (Ferreira, 1980; Khasar et al., 1999, 2003); (2) human studies showing that infusions of epinephrine result in anginal pain in the absence of ischemia (Eriksson et al., 2005); and (3) human studies showing that propranolol (a β-adrenergic receptor antagonist) is effective in reducing clinical pain in patients with TMD and fibromyalgia (Light et al., 2009). While the Asians in this study did not have greater HR levels at rest or in response to stress than the Whites, nonetheless, there was a robust relationship involving both resting and stress-induced HR levels and pain sensitivity in the Asians that was not evident in the Whites.
This study examined differences between Asians and non-Hispanic Whites (Whites) in pain sensitivity, and its relationship to mean arterial pressure (MAP) and heart rate (HR). In 30 Whites (50% female) and 30 Asians (50% female), experimental pain sensitivity was assessed with a hand cold pressor task, yielding measures of pain threshold, tolerance, intensity, and unpleasantness. Mean arterial pressure and HR measurements taken at rest and in response to speech stress were assessed. Perceived stress, anxiety, perfectionism, parental criticism, parental expectations and depressive symptoms were also measured. The results indicated that for the cold pain test, Asians demonstrated significantly lower pain threshold and tolerance levels than Whites. Although no ethnic differences were seen for MAP or HR responses to stress, for Whites higher stress MAP levels were correlated with reduced pain sensitivity, while for Asians higher baseline and stress HR levels were correlated with reduced pain sensitivity. Asians reported higher parental expectations and greater parental criticism than Whites. For Asians only, higher levels of perfectionism were related to more depressive symptoms, anxiety and perceived stress. These results indicate that Asian Americans are more sensitive to experimental pain than Whites and suggest ethnic differences in endogenous pain regulatory mechanisms (e.g. MAP and HR). The results may also have implications for understanding ethnic differences in clinical pain.
Cardiovascular responses in patients with acute allergic reactions treated with parenteral epinephrine
2005, American Journal of Emergency Medicine
The present study describes the cardiovascular responses to epinephrine (Epi) given into the arm, in adult patients with acute allergic reactions, and the differential responses to subcutaneous (SC) and intramuscular (IM) administration. Sixty-three adult patients were treated with Epi administered SC or IM after H₁ and H₂ receptor blockade. Heart rate and blood pressure (BP) were then measured for 20 minutes. Changes in heart rate and BP variables were analyzed. Pulse pressure and systolic BP showed increases with time. Diastolic BP also showed a modestly decreasing values over time. Heart rates did not change. Time-related changes between IM and SC Epi treatment were not observed. Sex influenced timed BP values and a significant sex by time effect was observed. In subset analysis, only male patients showed an overall time effect for BP variables, especially pulse pressure. In conclusion, adults with acute allergic syndromes treated with arm-injected Epi show a modest but definite increase in pulse pressure and systolic BP. This pattern is observed more in males. Heart rate and blood pressure differences between IM and SC arm-injected Epi treatments do not appear to be significant.
Physical training in syndrome X: Physical training counteracts deconditioning and pain in syndrome X
2000, Journal of the American College of Cardiology
OBJECTIVES
The aim of this study was to evaluate the effects of exercise training and body-awareness training in female patients with Syndrome X.
BACKGROUND
Patients with Syndrome X, defined as effort-induced angina pectoris, a positive exercise test and a normal coronary angiogram, suffer from a chronic pain disorder. We hypothesized that this disorder results in physical deconditioning with decreased exertional pain threshold.
METHODS
Twenty-six patients were randomly assigned to two training groups (A, B) and a control group (C). Group A (n = 8) started, after baseline measurements, with eight weeks of body-awareness training followed by eight weeks of exercise training on a bicycle ergometer three times a week for 30 min at an intensity of 50% of peak work rate. Group B (n = 8) performed only eight weeks of exercise training. Group C (n = 10) acted as controls without any intervention whatsoever. The effects on exercise performance, hormonal secretion, vascular function, adenosine sensitivity and quality of life were evaluated.
RESULTS
Body-awareness training did not change the pain response. The two training groups did not differ in effects of exercise training. Exercise capacity before training was below the gender- and age-matched reference range and improved by 34% with training to a level not different from the reference range. Onset of pain was delayed by 100% from 3 ± 2 to 6 ± 3 min (p < 0.05) while maximum pain did not change. Thus the pain-response-to-exercise curve was shifted to the right. Syndrome X patients showed a hypersensitivity to low-dose adenosine infusion compared to healthy age- and gender-matched controls (p < 0.0001) that did not change with exercise training. Endothelium-dependent blood flow increase was at baseline within reference range and tended to increase (p < 0.06) following training. In Group A the concentration of cortisol in urine decreased by 53% after body-awareness training (p < 0.05), and this change from baseline remained after physical exercise training (p < 0.05). A similar decrease occurred with only exercise training (Group B).
CONCLUSIONS
Physical deconditioning with lower exertional threshold for pain is a prominent feature in Syndrome X. Physical training in Syndrome X results in an increased exercise capacity with lesser anginal pain. We suggest physical training as an effective treatment in Syndrome X.
Atenolol versus amlodipine versus isosorbide-5-mononitrate on anginal symptoms in syndrome X
1999, American Journal of Cardiology

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^☆: This study was supported by funds granted by the Karolinska Institute.

^∗: Address for reprints: Christer Sylvén, MD, PhD, Department of Medicine, Huddinge University Hospital, S-141 86 Huddinge, Sweden.

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Effect of epinephrine infusion on chest pain in syndrome X in the absence of signs of myocardial ischemia☆

Abstract

Am J Cardiol

J Am Coll Cardiol

J Am Coll Cardiol

Am Heart J

J Am Coll Cardiol

J Am Coll Cardiol

Am J Cardiol

Pain

Am J Cardiol

The anginal syndrome with normal coronary arteriography

Trans Assoc Am Physicians

Chest pain with normal coronary angiograms

N Engl J Med

Reduced coronary dilatory capacity and ultrastructural changes in the myocardium in patients with angina pectoris but normal coronary arteriograms

Circulation

Four-year follow-up in patients with angina pectoris and normal coronary arteriograms (“syndrome X”)

Circulation

Is altered cardiac sensation responsible for chest pain in patients with normal coronary arteries?

Br Med J

Altered pattern of circadian neural control of heart rate period in syndrome X (abstr)

Eur Heart J