Cardiac Cardiac syndrome Xsyndrome X

BYBY

Ragab Abdelsalam Ragab Abdelsalam (MD)(MD)

Prof. of Cardiology Prof. of Cardiology

Patients with cardiac Patients with cardiac syndrome –X typically syndrome –X typically presents with :presents with :

1- predominantly1- predominantly effort induced effort induced angina angina

2- ST segment2- ST segment depression depression suggestive of myocardial suggestive of myocardial ischaemia during spontaneous ischaemia during spontaneous or provoked angina or provoked angina

3- normal3- normal coronary arteries at coronary arteries at angiography angiography

4-absence4-absence of spontaneous or of spontaneous or provoked epicardial coronary provoked epicardial coronary artery spasm artery spasm

5-absence5-absence of cardiac (for example, of cardiac (for example, hypertrophic or dilated hypertrophic or dilated cardiomyopathy) or systemic (for cardiomyopathy) or systemic (for example, hypertension, diabetes)example, hypertension, diabetes)

6- diseases6- diseases potentially associated potentially associated with microvascular dysfunction. with microvascular dysfunction.

PATHOGENETIC PATHOGENETIC MECHANISMSMECHANISMS

Syndrome X is characterised by Syndrome X is characterised by two major abnormalities:two major abnormalities:

1- coronary microvascular 1- coronary microvascular dysfunction; and dysfunction; and

2- abnormal cardiac2- abnormal cardiac pain pain sensitivity sensitivity

1- Microvascular dysfunction :1- Microvascular dysfunction :Since its first description it was Since its first description it was

suggested that, suggested that, in syndrome X,in syndrome X, angina is caused by myocardial angina is caused by myocardial ischaemia determined by a ischaemia determined by a dysfunction of small resistance dysfunction of small resistance coronary artery vessels (< 500 µm) coronary artery vessels (< 500 µm) not visible at coronary angiography, not visible at coronary angiography, a condition defined as a condition defined as ""microvascular anginamicrovascular angina

** There are ** There are 1- transient1- transient ST ST segment segment

depression and reversible depression and reversible perfusion defects on nuclear perfusion defects on nuclear imaging during anginal pain,imaging during anginal pain,

either :either :

> spontaneous > spontaneous

> or induced by exercise> or induced by exercise or pharmacological stressor pharmacological stress tests. tests.

2- Furthermore2- Furthermore, , metabolic metabolic evidence of stress induced evidence of stress induced myocardial ischaemia, including myocardial ischaemia, including transmyocardial lactate transmyocardial lactate production, coronary sinus production, coronary sinus oxygen desaturation, and pH oxygen desaturation, and pH reduction, as well as myocardial reduction, as well as myocardial high energy phosphate depletion high energy phosphate depletion on nuclear magnetic resonanceon nuclear magnetic resonance. .

3- There is impairment3- There is impairment of of both endothelium dependent both endothelium dependent (for example, in response to (for example, in response to pacing, acetylcholine) and pacing, acetylcholine) and endothelium independent (for endothelium independent (for example, in response to example, in response to dipyridamole, papaverine) dipyridamole, papaverine) coronary vasodilation, using coronary vasodilation, using different techniquesdifferent techniques

4- Furthermore4- Furthermore, , coronary coronary vasoconstrictor stimuli (for vasoconstrictor stimuli (for example, ergonovine, cold example, ergonovine, cold pressor test, hyperventilation, pressor test, hyperventilation, handgrip, and acetylcholine) handgrip, and acetylcholine) have been found to induce have been found to induce symptoms and/or signs of symptoms and/or signs of myocardial ischaemia in a myocardial ischaemia in a proportion of patientsproportion of patients. .

In contrastIn contrast, , other other studies failed to find studies failed to find evidence of either evidence of either microvascular microvascular dysfunction or metabolic dysfunction or metabolic abnormalities typical of abnormalities typical of myocardial ischaemia myocardial ischaemia during stress tests.during stress tests.

More importantlyMore importantly, , echocardiographic studies have echocardiographic studies have consistently failed to provide consistently failed to provide evidence of transient regional wall evidence of transient regional wall motion abnormalities during angina motion abnormalities during angina and transient ST segment and transient ST segment depression, thus questioning the depression, thus questioning the ischaemic, or even cardiac, origin of ischaemic, or even cardiac, origin of syndrome X.syndrome X.

THE PREVIOUS Figure THE PREVIOUS Figure Proposed pathophysiological Proposed pathophysiological

mechanism of syndrome X.mechanism of syndrome X.

> Coronary microvascular dysfunction> Coronary microvascular dysfunction might be limited to pre-arterioles, might be limited to pre-arterioles, (responsible for metabolic regulation (responsible for metabolic regulation of coronary blood flow), supplying of coronary blood flow), supplying small myocardial regions scattered small myocardial regions scattered throughout the myocardium. throughout the myocardium.

* An inappropriate * An inappropriate constrictionconstriction and/or impaired pre- and/or impaired pre-arteriolar dilation, in response to arteriolar dilation, in response to metabolic or pharmacological metabolic or pharmacological arteriolar dilatation, would cause arteriolar dilatation, would cause ischaemia in small myocardial ischaemia in small myocardial regions surrounded by areas with a regions surrounded by areas with a normal microvascular function, normal microvascular function, exhibiting normal, or even exhibiting normal, or even compensatory increased myocardial compensatory increased myocardial contractility, which would limit contractility, which would limit regional (and global) contractile regional (and global) contractile abnormalities. abnormalities.

* Adenosine:* Adenosine: > might by itself induce > might by itself induce

- chest pain- chest pain (because of its (because of its algogenic effect mediated by A1 algogenic effect mediated by A1 receptor stimulation on cardiac pain receptor stimulation on cardiac pain receptors), receptors),

- ischaemia-like- ischaemia-like ST changes ST changes (because of its electrophysiological (because of its electrophysiological effect mediated by A1 receptor effect mediated by A1 receptor stimulation on myocardial fibres),stimulation on myocardial fibres),

- even exacerbate- even exacerbate subendocardial subendocardial ischaemia through a steal mechanismischaemia through a steal mechanism

> A sustained compensatory> A sustained compensatory release of adenosine from myocardialrelease of adenosine from myocardial ischaemic regions might contribute to ischaemic regions might contribute to limit the degree of ischaemialimit the degree of ischaemia

>> Yet adenosineYet adenosine might by itself might by itself induce induce

- chest pain (because of- chest pain (because of its algogenic its algogenic effect mediated by A1 receptor effect mediated by A1 receptor stimulation onstimulation on cardiac pain receptors), cardiac pain receptors),

> ischaemia-like ST > ischaemia-like ST segmentsegment changes (because changes (because of its electrophysiological of its electrophysiological effect mediated by A1 effect mediated by A1 receptor stimulationreceptor stimulation on on myocardial fibres), myocardial fibres),

> and even exacerbate> and even exacerbate subendocardial ischaemiasubendocardial ischaemia through a steal mechanism. through a steal mechanism.

This pathophysiological This pathophysiological hypothesishypothesis is supported by is supported by studies with PET, whichstudies with PET, which have have shown increased heterogeneity shown increased heterogeneity of coronary blood flow amongof coronary blood flow among small myocardial regions, both small myocardial regions, both at rest and in response to at rest and in response to dipyridamoledipyridamole, , in syndrome X in syndrome X patients, as compared to patients, as compared to healthy controls healthy controls

** Oxidative Stress ** Oxidative Stress There might be a sustained There might be a sustained

increase of lipid increase of lipid hydroperoxides and hydroperoxides and conjugated dienesconjugated dienes

two markers of ischaemia–two markers of ischaemia–reperfusion oxidative stress—reperfusion oxidative stress—in the great cardiac vein in the great cardiac vein blood after atrial pacing blood after atrial pacing induced ST segment induced ST segment depression and angina. depression and angina.

** Indeed, oxidative ** Indeed, oxidative stressstress products are products are much more sensitive much more sensitive than conventional than conventional metabolic markers in metabolic markers in revealing ischaemia, revealing ischaemia,

Cardiac production of Cardiac production of oxidativeoxidative hydroperoxides hydroperoxides (ROOHs) (left panel) and (ROOHs) (left panel) and conjugated dienes (CD) (right conjugated dienes (CD) (right panel) after atrial pacing in panel) after atrial pacing in patients with syndrome X. patients with syndrome X.

The production of these The production of these oxidativeoxidative lipoperoxide lipoperoxide products during pacing, in the products during pacing, in the presence of ST segment presence of ST segment depression and angina, is depression and angina, is indicative of an ischaemia–indicative of an ischaemia–reperfusion damagereperfusion damage

The causes of microvascularThe causes of microvascular dysfunction in syndrome X have dysfunction in syndrome X have not yet been fully elucidated and not yet been fully elucidated and are likely to be multiple. are likely to be multiple. Structural abnormalities, mainly Structural abnormalities, mainly consisting of medial hypertrophy consisting of medial hypertrophy and/or fibrosis of arteriolar and/or fibrosis of arteriolar vessels, frequently associated vessels, frequently associated with systemic hypertension, with systemic hypertension, have been described in small have been described in small series of patients. series of patients.

** Endothelial Dysfunction:** Endothelial Dysfunction:

It isIt is suggested by a decreased suggested by a decreased coronary flow response to coronary flow response to acetylcholineacetylcholine, , atrial pacing, and atrial pacing, and other endothelium mediated other endothelium mediated vasodilator stimulivasodilator stimuli, , and and believed to be caused by believed to be caused by impaired nitric oxide (NO) impaired nitric oxide (NO) releaserelease and/or activity and/or activity

A) Decreased NO generation A) Decreased NO generation has beenhas been suggested by lower suggested by lower nitrate/nitrite systemic nitrate/nitrite systemic concentrations,9 although cGMP (the concentrations,9 although cGMP (the intracellular messenger for NO) intracellular messenger for NO) release in the coronary circulation release in the coronary circulation was not found to be decreased after was not found to be decreased after atrial pacing in a group of atrial pacing in a group of syndrome syndrome X patients.X patients.

b) Of note, an increased b) Of note, an increased synthesissynthesis of asymmetric of asymmetric dimethylarginine, which is known to dimethylarginine, which is known to reduce the bioavailability of L-reduce the bioavailability of L-arginine for NO synthesis in arginine for NO synthesis in endothelial cells, has recently been endothelial cells, has recently been suggested to contribute to impaired suggested to contribute to impaired NO activity in NO activity in syndrome X patientssyndrome X patients..

c) Several findings, c) Several findings, howeverhowever, suggest that endothelial , suggest that endothelial dysfunction might cause not only dysfunction might cause not only impaired vasodilation, but also impaired vasodilation, but also inappropriate vasoconstriction.inappropriate vasoconstriction.

> Indeed> Indeed, increased plasma , increased plasma concentrations of the powerful concentrations of the powerful vasoconstrictor endothelin-1 (ET-1) vasoconstrictor endothelin-1 (ET-1)

> Moreover> Moreover, ET-1 has been , ET-1 has been found to increase in the coronary found to increase in the coronary circulation of syndrome X patients in circulation of syndrome X patients in response to atrial pacingresponse to atrial pacing

** However,** However, there is there is impairment of coronaryimpairment of coronary microvascular dilation in microvascular dilation in response to adenosine, response to adenosine, dipyridamoledipyridamole, , and papaverine and papaverine —>>that is, to endothelium —>>that is, to endothelium independent independent

stimuli — >>> suggestingstimuli — >>> suggesting a a possible primary smooth possible primary smooth muscle cell abnormality muscle cell abnormality

** Enhanced sodium–hydrogen ** Enhanced sodium–hydrogen (Na+–H+)(Na+–H+) exchanger activity exchanger activity in cell membranes :in cell membranes :

> represents> represents

1- a potential1- a potential cause of cause of microvascular dysfunction as it microvascular dysfunction as it may induce cellular alkalinisation, may induce cellular alkalinisation, thus resulting in increased thus resulting in increased susceptibility of smooth muscle susceptibility of smooth muscle cells to constrictor stimuli in cells to constrictor stimuli in patients patients with CSX.. with CSX..

2- Furthermore,2- Furthermore, it might it might be involved in several other be involved in several other typical features of syndrome typical features of syndrome X, X, including: including:

> insulin resistance > insulin resistance > altered adrenergic > altered adrenergic activity, activity,

> also enhanced > also enhanced pain perceptionpain perception

** More recently, a role ** More recently, a role for intracellular rho-for intracellular rho-kinasekinase, ,

which maywhich may enhance enhance vasoconstriction in vascular vasoconstriction in vascular smooth muscle cells bysmooth muscle cells by facilitating calcium overload, facilitating calcium overload, has also been suggestedhas also been suggested

as pathogenic of CSX.as pathogenic of CSX.

** Finally, recent data ** Finally, recent data suggest that low grade suggest that low grade inflammation :inflammation :

ItIt mightmight also play a also play a pathogenetic role in the pathogenetic role in the microvascular dysfunctionmicrovascular dysfunction of of patients with patients with cardiac cardiac syndrome - X. syndrome - X.

> Increased inflammatory > Increased inflammatory markers markers

> High levels of C-reactive > High levels of C-reactive protien.protien.

2- Abnormal cardiac pain 2- Abnormal cardiac pain perceptionperception

Several studies have Several studies have consistently shown that consistently shown that patients with angina and patients with angina and normal coronary arteries normal coronary arteries exhibit enhanced pain exhibit enhanced pain perception. perception.

a) -The first hypothesisa) -The first hypothesis

> pain is> pain is elicited by elicited by low rate heart low rate heart stimulation, in the stimulation, in the absence of ST segment absence of ST segment depression, during depression, during ventricular pacing, but ventricular pacing, but not during atrial pacingnot during atrial pacing

b)-Cardiac syndrome X b)-Cardiac syndrome X might be a "cortical pain might be a "cortical pain syndrome",syndrome",

resulting in a resulting in a "top down"top down" " process which facilitates the process which facilitates the transmission to the pain area transmission to the pain area of the cortex of stimuli which of the cortex of stimuli which are usually blocked at are usually blocked at subcortical levelsubcortical level

c) Hyperreactivityc) Hyperreactivity of of cardiac pain receptors, abnormal cardiac pain receptors, abnormal transmissiontransmission and/or modulation and/or modulation of pain signal at subcortical of pain signal at subcortical level(s), orlevel(s), or a variable a variable combination of all these combination of all these abnormalities, might equallyabnormalities, might equally account for the abnormal account for the abnormal activation of specific cerebral activation of specific cerebral areas areas

** Regardless of its Regardless of its locationlocation,, most most syndrome X patients syndrome X patients exhibit pronounced exhibit pronounced functional abnormalities functional abnormalities of cardiac adrenergic of cardiac adrenergic nerve fibres nerve fibres

Hypothesis:Hypothesis: a) repeated episodesa) repeated episodes of myocardial of myocardial

ischaemia might induce functional ischaemia might induce functional alterations in cardiac afferent nerve alterations in cardiac afferent nerve endings, resulting in increased reactivity endings, resulting in increased reactivity to usually innocuous stimuli. to usually innocuous stimuli.

b) Inflammatoryb) Inflammatory or metabolic or metabolic abnormalities might also adversely affect abnormalities might also adversely affect cardiac afferent nerve fibrescardiac afferent nerve fibres. .

Notably, abnormal Notably, abnormal function of efferentfunction of efferent

cardiac adrenergic cardiac adrenergic fibres might fibres might adversely influence adversely influence microvascular microvascular function and function and coronary blood flow. coronary blood flow.

Radionuclide imagesRadionuclide images obtained three obtained three hours after the injection of 123I hours after the injection of 123I metaiodobenzylguanidine (MIBG) from a metaiodobenzylguanidine (MIBG) from a healthy subject (left panel) and from a healthy subject (left panel) and from a patient with syndrome X (right panel). patient with syndrome X (right panel).

     DIAGNOSISDIAGNOSIS

Imortant: Imortant: Non-cardiac causes of symptoms, Non-cardiac causes of symptoms,

such as musculoskeletal, such as musculoskeletal, psychiatric, and, particularly, psychiatric, and, particularly, gastrointestinal disorders must be gastrointestinal disorders must be excluded by appropriate diagnostic excluded by appropriate diagnostic investigations. investigations.

* Furthermore* Furthermore, , in patients with angina and in patients with angina and normal coronary arteries, an normal coronary arteries, an intracoronary (or intracoronary (or intravenous) ergonovine test intravenous) ergonovine test should be performed, in should be performed, in particular when angina particular when angina occurs predominantly at rest, occurs predominantly at rest, in order to exclude occlusive in order to exclude occlusive coronary artery spasm. coronary artery spasm.

* clinical features* clinical features do not do not allow differentiation allow differentiation between those who will be between those who will be found to have normal found to have normal coronary arteries from those coronary arteries from those who will be found to have who will be found to have obstructive stenoses at obstructive stenoses at coronary angiography. coronary angiography.

* some clinical features which * some clinical features which may suggest the presence of may suggest the presence of normal coronary arteries, normal coronary arteries, including including

1- a prolonged (> 10 minutes) duration 1- a prolonged (> 10 minutes) duration 2- a dull persistence after effort 2- a dull persistence after effort

interruption,interruption, 3- an inconstant or slow response to 3- an inconstant or slow response to

sublingual nitrates. sublingual nitrates. 4- those with angina and normal 4- those with angina and normal

coronary arteries are more frequently coronary arteries are more frequently women often in a post-menopausal state. women often in a post-menopausal state.

* Exercise test * Exercise test resultsresults : :

do not help identify patients with do not help identify patients with syndromesyndrome X; indeed ST segment X; indeed ST segment changes during exercise stress changes during exercise stress test aretest are similar in patients with similar in patients with syndrome X and in those with syndrome X and in those with anginaangina and critical epicardial and critical epicardial coronary stenoses. coronary stenoses.

** Furthermore, myocardial** Furthermore, myocardial scintigraphyscintigraphy shows typical shows typical reversible myocardial perfusion reversible myocardial perfusion defectsdefects in about a half of patients in about a half of patients with syndrome X. with syndrome X.

** Yet the induction** Yet the induction of severe of severe angina and ST segment changes angina and ST segment changes during stress testingduring stress testing in the in the absenceabsence of regional of regional and global left and global left ventricular contractile abnormalities ventricular contractile abnormalities at echocardiographyat echocardiography, , strongly strongly suggests a microvascular origin of suggests a microvascular origin of symptoms symptoms

* * Repeat exercise testingRepeat exercise testing after sublingual nitrates also may after sublingual nitrates also may help to identify patients with help to identify patients with microvascular dysfunction. microvascular dysfunction.

> Indeed,> Indeed, whereas short acting whereas short acting nitrate administration usually nitrate administration usually improves exercise test results in improves exercise test results in patients with epicardial coronary patients with epicardial coronary stenoses, it may not affect or may stenoses, it may not affect or may even worsen the results of exercise even worsen the results of exercise testing in testing in syndrome X syndrome X patients.patients.

These findingsThese findings are in are in keeping with the variable keeping with the variable response of chest pain to response of chest pain to sublingual nitrates and with sublingual nitrates and with the evidence that short the evidence that short acting nitrates may acting nitrates may paradoxically decrease paradoxically decrease coronary flow and ischaemic coronary flow and ischaemic threshold during atrial threshold during atrial pacing in these patientspacing in these patients. .

In contrastIn contrast to patients with to patients with obstructive coronary stenoses, who obstructive coronary stenoses, who present increased platelet aggregation present increased platelet aggregation in response to exercise, syndrome X in response to exercise, syndrome X patients exhibit a reduction of platelet patients exhibit a reduction of platelet aggregation after exercise, aggregation after exercise,

>> possibly>> possibly representing a protective representing a protective effect against stress induced vascular effect against stress induced vascular events.events.

>> Notably>> Notably, a lengthening of the , a lengthening of the aggregation time 10 seconds was aggregation time 10 seconds was detectable in patients with syndrome detectable in patients with syndrome X only. X only.

>> These>> These findings are probably findings are probably explained, at least in part, by explained, at least in part, by sustained compensatory release of sustained compensatory release of adenosine (known to inhibit platelet adenosine (known to inhibit platelet aggregation)aggregation)

* The assessment* The assessment of platelet of platelet aggregation before and after aggregation before and after exercise testing may also help to exercise testing may also help to identify syndrome X patientsidentify syndrome X patients

TREATMENTREATMENTT

As the As the prognosisprognosis is is excellentexcellent, the primary end , the primary end point in the treatment of point in the treatment of patients with angina and patients with angina and normal coronary arteries is normal coronary arteries is symptom control. symptom control.

Accordingly,Accordingly, interventions found to have interventions found to have beneficial effects on beneficial effects on symptoms should be preferred symptoms should be preferred to treatment tested only on to treatment tested only on non-clinical end points, non-clinical end points, including ischaemic ECG including ischaemic ECG changes or coronary flow changes or coronary flow response to vasoactive stimuli. response to vasoactive stimuli.

* Interventions proposed* Interventions proposed in these in these patients are directed at either improving patients are directed at either improving microvascular function or decreasing chest microvascular function or decreasing chest pain perception, in an attempt to pain perception, in an attempt to counteract the accepted counteract the accepted pathophysiological mechanisms of the pathophysiological mechanisms of the syndrome. syndrome.

* Unfortunately,* Unfortunately, most treatments most treatments have been evaluated in small numbers of have been evaluated in small numbers of patients and/or in uncontrolled trials, thus patients and/or in uncontrolled trials, thus making it difficult to establish their real making it difficult to establish their real degree of effectiveness. degree of effectiveness.

TraditionalTraditional anti-ischaemic anti-ischaemic drugs remain the first line drugs remain the first line approach to these patients. approach to these patients.

Yet theyYet they frequently fail to frequently fail to achieve a satisfactory achieve a satisfactory suppression of symptoms, suppression of symptoms, thus stimulating the search thus stimulating the search for alternative therapeutic for alternative therapeutic options. options.

Anti-ischaemic drugsAnti-ischaemic drugs ß Blockersß Blockers Some studiesSome studies have reported that ß have reported that ß

blockers improve symptoms, exercise test blockers improve symptoms, exercise test results, and ST segment depression on results, and ST segment depression on Holter monitoring in patients with typical Holter monitoring in patients with typical syndrome X.syndrome X.

In generalIn general, ß blocking agents should , ß blocking agents should constitute the first line drug treatment in constitute the first line drug treatment in these patients, particularly when there is these patients, particularly when there is evidence of increased adrenergic tone (for evidence of increased adrenergic tone (for example, high heart rate or decreased example, high heart rate or decreased heart rate variability during 24 hour Holter heart rate variability during 24 hour Holter monitoring, or rapid increase of heart rate monitoring, or rapid increase of heart rate and/or blood pressure during exerciseand/or blood pressure during exercise..

NitratesNitrates > Sublingual> Sublingual nitrates may be used to nitrates may be used to

treat chest pain attacks in syndrome X treat chest pain attacks in syndrome X patients. patients.

> However> However, in about 50% of cases their , in about 50% of cases their effectiveness is limited. Long effectiveness is limited. Long actingacting nitrates have only been assessed in our nitrates have only been assessed in our small trial, showing, on average, no small trial, showing, on average, no significant effect on symptoms. significant effect on symptoms.

Calcium antagonistsCalcium antagonists

Verapamil Verapamil was shown to improve was shown to improve exercise test results and symptoms, exercise test results and symptoms, but patients were selected according but patients were selected according to a previous favourable to a previous favourable symptomatic response to calcium symptomatic response to calcium antagonists.antagonists.

DiltiazemDiltiazem, but not propranolol, was , but not propranolol, was found to improve exercise test found to improve exercise test results in one study, but it failed to results in one study, but it failed to improve coronary flow in another improve coronary flow in another study. study.

Among dihydropyridineAmong dihydropyridine drugs, drugs, nifedipine was found to improve nifedipine was found to improve coronary blood flow and exercise test coronary blood flow and exercise test results, but its administration was results, but its administration was associated with worsening of associated with worsening of symptoms in some patients.symptoms in some patients.

Favourable effectsFavourable effects have been have been reported with nisoldipine, reported with nisoldipine,

Additional forms of treatmentAdditional forms of treatment

* Xanthine derivatives* Xanthine derivatives

Favourable effects on symptoms Favourable effects on symptoms and exercise test results have and exercise test results have been reported both with been reported both with theophylline and bamiphylline, theophylline and bamiphylline, although the latter seems to be although the latter seems to be better tolerated. better tolerated.

The beneficialThe beneficial effects of both effects of both compounds are probably caused compounds are probably caused by adenosine receptor blockade, by adenosine receptor blockade,

It may resultIt may result in both an anti- in both an anti-algogenic effect (due to the direct algogenic effect (due to the direct involvement of adenosine in involvement of adenosine in cardiac pain generation) cardiac pain generation)

It may resultIt may result in an anti- in an anti-ischaemic effect (owing to a more ischaemic effect (owing to a more favourable redistribution of favourable redistribution of coronary blood flow.coronary blood flow.

Imipramine :Imipramine : > Chronic visceral> Chronic visceral pain inhibitors pain inhibitors

> inhibits> inhibits pain transmission from pain transmission from visceral tissuesvisceral tissues and was found to and was found to reduce anginal episodes in patients reduce anginal episodes in patients with anginawith angina and normal coronary and normal coronary arteries in two studies. arteries in two studies.

> However> However, quality, quality of life was not of life was not significantly improved in another significantly improved in another study, becausestudy, because of unpleasant side of unpleasant side effects effects

OestrogensOestrogensAs notedAs noted above, above, epidemiological studies show epidemiological studies show that that syndrome Xsyndrome X patients patients are often post-menopausal are often post-menopausal women, thus suggesting that women, thus suggesting that oestrogen deficiency may oestrogen deficiency may have a pathogenic role. have a pathogenic role.

Notably,Notably, oestrogens cause oestrogens cause endothelial mediated coronary endothelial mediated coronary vasodilation.vasodilation.

In a randomisedIn a randomised, placebo , placebo controlled trial, 17ß oestradiol was controlled trial, 17ß oestradiol was found to determine a mild to found to determine a mild to moderate reduction of anginal moderate reduction of anginal episodes in post-menopausal episodes in post-menopausal women, although it failed to improve women, although it failed to improve exercise test results. exercise test results.

ACE inhibitorsACE inhibitors They haveThey have been proposed in been proposed in

the assumption that the the assumption that the renin–angiotensin system renin–angiotensin system might play a role in causing might play a role in causing microvascular dysfunction. microvascular dysfunction.

Although Although there are limited data there are limited data on these drugs, favourable on these drugs, favourable effects have been reported on effects have been reported on exercise test results, and on exercise test results, and on symptoms in small controlled symptoms in small controlled trials. trials.

AccordinglyAccordingly, in a recent study , in a recent study in patients with angina and in patients with angina and normal coronary arteries, normal coronary arteries, enalapril has been found to have enalapril has been found to have favourable effects on NO favourable effects on NO availability.availability.

StatinsStatinsVery recent data haveVery recent data have shown that shown that

use of statins may improve use of statins may improve angina symptoms and exercise angina symptoms and exercise tolerance in tolerance in syndrome Xsyndrome X patients, likely because of patients, likely because of improvement of endothelial improvement of endothelial vasodilator function mediated by vasodilator function mediated by reduction of oxidative stress.reduction of oxidative stress.

>Fatty acid>Fatty acid oxidation partial oxidation partial inhibitorsinhibitorsMyocardial cells utilise both fatty Myocardial cells utilise both fatty acids and glucose as fuel, but acids and glucose as fuel, but glucose oxidation is more efficient. glucose oxidation is more efficient.

> By switching> By switching cell metabolism cell metabolism toward glucose oxidation, these toward glucose oxidation, these drugs should allow more work for drugs should allow more work for the same amount of oxygen and the same amount of oxygen and delay the appearance of ischaemic delay the appearance of ischaemic suffering during stress conditions. suffering during stress conditions.

Trimetazidine,:Trimetazidine,: a fatty acida fatty acid oxidation partial oxidation partial

inhibitor, was found to have inhibitor, was found to have beneficial effects on exercise test beneficial effects on exercise test results in a small group of patients results in a small group of patients with syndrome X, but no effects were with syndrome X, but no effects were observed on symptoms and on observed on symptoms and on exercise test results in another exercise test results in another study. study.

Thus the clinicalThus the clinical utility of this drug utility of this drug is at least controversial. is at least controversial.

ET-1, Na+–H+ exchanger, ET-1, Na+–H+ exchanger, and rho-kinase inhibitors:and rho-kinase inhibitors:

> > The demonstrationThe demonstration that ET-1 that ET-1 and Na+–H+ exchanger may be and Na+–H+ exchanger may be involved in the pathogenesis of involved in the pathogenesis of syndrome X suggests that their syndrome X suggests that their specific antagonists specific antagonists (for example, (for example, bosentan and cariporide, bosentan and cariporide, respectively)respectively) are worth trying in are worth trying in randomised controlled trials. randomised controlled trials.

> Similarly,> Similarly, the recent the recent

observation that the observation that the rho-kinase rho-kinase inhibitorinhibitor (fasudil ) (fasudil ) may may prevent vasoconstriction induced by prevent vasoconstriction induced by acetylcholine in patients with acetylcholine in patients with microvascular angina suggests a microvascular angina suggests a possible use in these patients. possible use in these patients.

Electrical neuromodulationElectrical neuromodulation>> Spinal cord stimulationSpinal cord stimulation modulates pain transmission from themodulates pain transmission from the heart to the brain and might improve heart to the brain and might improve myocardial ischaemia throughmyocardial ischaemia through inhibition inhibition of sympathetic efferent nerves. of sympathetic efferent nerves.

> Spinal cord stimulation> Spinal cord stimulation has has been shown to improve exercise test been shown to improve exercise test results in one studyresults in one study in patients with in patients with typical syndrome X, and transcutaneous typical syndrome X, and transcutaneous electricalelectrical nerve stimulation has been nerve stimulation has been reported to improve coronary flowreported to improve coronary flow in in another study. another study.

> Furthermore> Furthermore, , spinal cord spinal cord stimulation was associated with a stimulation was associated with a notable improvementnotable improvement of symptoms of symptoms and quality of life in about 50% of a and quality of life in about 50% of a small groupsmall group of patients with of patients with syndrome X refractory to other forms syndrome X refractory to other forms of treatmentof treatment, , in the absence of major in the absence of major complications. complications.

** Thus,** Thus, this approach should this approach should be be considered in patients with angina considered in patients with angina refractory to multi-drugrefractory to multi-drug treatment treatment

Stepwise approachStepwise approach In patients withIn patients with angina and normal angina and normal

coronary arteries, the response to coronary arteries, the response to treatment is rather unpredictable. treatment is rather unpredictable.

TreatmentTreatment, therefore, is necessarily , therefore, is necessarily empiric and requires an optimal empiric and requires an optimal interaction between caring physician and interaction between caring physician and patient in an attempt to achieve optimal patient in an attempt to achieve optimal symptom control. symptom control.

1- a ß blocker1- a ß blocker as first line as first line treatment and then treatment and then addadd a a non-dihydropiridine (or even non-dihydropiridine (or even a dihydropiridine) calcium a dihydropiridine) calcium antagonist antagonist and/or a longand/or a long acting nitrate, as a second acting nitrate, as a second line of treatment.line of treatment.

2- When conventional2- When conventional anti-ischaemic treatment is not anti-ischaemic treatment is not satisfactory, usually add satisfactory, usually add bamiphyllinebamiphylline (600 mg twice a (600 mg twice a day). day).

>> An ACE inhibitor>> An ACE inhibitor, oestrogens , oestrogens (in post-menopausal women) (in post-menopausal women) and, according to recent data, a and, according to recent data, a statin can be tried at any time. statin can be tried at any time.

3- Occasionally,3- Occasionally, alpha- blockers alpha- blockers may also be tried, while a trial with may also be tried, while a trial with imipramine (25 mg/day) should be imipramine (25 mg/day) should be reserved for the most symptomatic reserved for the most symptomatic patients, in particular if signs of patients, in particular if signs of depression are apparent. depression are apparent.

4- In patients4- In patients who remain who remain severely symptomatic on multiple severely symptomatic on multiple drug treatment we tend now to drug treatment we tend now to resort to resort to spinal cord spinal cord stimulation. stimulation.

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