Cardiac syndrome X: Difference between revisions

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==Overview==
==Overview==
'''(Cardiac) syndrome X''' is [[Angina pectoris|angina]] associated with objective evidence of myocardial ischemia in the absence of epicardial  [[coronary artery disease]].  Syndrome X has been hypothesized to be a disorder of the coronary microvasculature rather than the large caliber epicardial coronary arteries.
'''Cardiac syndrome X''' is [[Angina pectoris|angina]] associated with objective evidence of myocardial ischemia in the absence of epicardial  [[coronary artery disease]].  Syndrome X has been hypothesized to be a disorder of the coronary microvasculature rather than the large caliber epicardial coronary arteries.


==Pathophysiology==
==Pathophysiology==
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* The underlying pathophysiology is most likely heterogenous. Multiple pathophysiologic mechanisms have been proposed with variable data to support them such as: ischemia, adenosine, dysautonomia, female pattern, hypersensitivity, panic disorders, and viral infections.
* The underlying pathophysiology is most likely heterogenous. Multiple pathophysiologic mechanisms have been proposed with variable data to support them such as: ischemia, adenosine, dysautonomia, female pattern, hypersensitivity, panic disorders, and viral infections.


===Ischemia is Present in Syndrome X===
====Ischemia is Present in Syndrome X====
* Researchers debate whether ischemia is present in patients with Syndrome X. There may be no wall motion abnormalities or coronary sinus lactate production during an episode of ischemic discomfort. This may be due to focal involvement of the myocardium.
* Researchers debate whether ischemia is present in patients with syndrome X. There may be no wall motion abnormalities or coronary sinus lactate production during an episode of ischemic discomfort. This may be due to focal involvement of the myocardium.
* When [[coronary sinus]] samples of more sensitive markers of ischemia reperfusion / oxidative stress are analyzed such as lipid hydroperoxides (ROOHs) and conjugated dienes (CDs) before and after pacing, there is an increase in ROOH and CD levels (from 4.83 +/- 1.18 micromol/l at baseline to 7.88 +/- 1.12 micromol/l and from 0.038 +/- 0.002 to 0.051 +/- 0.003 arbitrary units, respectively, P < 0.01).<ref name="pmid11087214">Buffon A, Rigattieri S, Santini SA, Ramazzotti V, Crea F, Giardina B et al. (2000) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=11087214 Myocardial ischemia-reperfusion damage after pacing-induced tachycardia in patients with cardiac syndrome X.] ''Am J Physiol Heart Circ Physiol'' 279 (6):H2627-33. PMID: [http://pubmed.gov/11087214 11087214]</ref>
* When [[coronary sinus]] samples of more sensitive markers of ischemia reperfusion/oxidative stress are analyzed such as lipid hydroperoxides (ROOHs) and conjugated dienes (CDs) before and after pacing, there is an increase in ROOH and CD levels (from 4.83 +/- 1.18 micromol/l at baseline to 7.88 +/- 1.12 micromol/l and from 0.038 +/- 0.002 to 0.051 +/- 0.003 arbitrary units, respectively, P < 0.01).<ref name="pmid11087214">Buffon A, Rigattieri S, Santini SA, Ramazzotti V, Crea F, Giardina B et al. (2000) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=11087214 Myocardial ischemia-reperfusion damage after pacing-induced tachycardia in patients with cardiac syndrome X.] ''Am J Physiol Heart Circ Physiol'' 279 (6):H2627-33. PMID: [http://pubmed.gov/11087214 11087214]</ref>
* In contrast,  ROOH and CD levels did not increase in control patients after pacing.
* In contrast,  ROOH and CD levels did not increase in control patients after pacing.


===Adenosine as a Cause of Chest Pain===
====Adenosine as a Cause of Chest Pain====
*Both, endogenous and exogenous adenosine can cause chest discomfort through stimulation of sensory nerves in the heart. <ref>http://www.nejm.org/doi/full/10.1056/NEJM200210243471717</ref><ref name="pmid7544544">{{cite journal| author=Huang MH, Sylvén C, Horackova M, Armour JA| title=Ventricular sensory neurons in canine dorsal root ganglia: effects of adenosine and substance P. | journal=Am J Physiol | year= 1995 | volume= 269 | issue= 2 Pt 2 | pages= R318-24 | pmid=7544544 | doi= | pmc= | url= }} </ref>
*Both, endogenous and exogenous adenosine can cause chest discomfort through stimulation of sensory nerves in the heart.<ref>http://www.nejm.org/doi/full/10.1056/NEJM200210243471717</ref><ref name="pmid7544544">{{cite journal| author=Huang MH, Sylvén C, Horackova M, Armour JA| title=Ventricular sensory neurons in canine dorsal root ganglia: effects of adenosine and substance P. | journal=Am J Physiol | year= 1995 | volume= 269 | issue= 2 Pt 2 | pages= R318-24 | pmid=7544544 | doi= | pmc= | url= }} </ref>
* Huang et al have demonstrated that both A1- and A2-adenosine receptors are present on the cardiac sensory nerve endings of [[dorsal root ganglion]] neurons. These sensory neurons are active in the absence of ischemia but become further activated during myocardial [[ischemia]].<ref name="pmid7544544">{{cite journal| author=Huang MH, Sylvén C, Horackova M, Armour JA| title=Ventricular sensory neurons in canine dorsal root ganglia: effects of adenosine and substance P. | journal=Am J Physiol | year= 1995 | volume= 269 | issue= 2 Pt 2 | pages= R318-24 | pmid=7544544 | doi= | pmc= | url= }} </ref>
* Huang et al have demonstrated that both A1- and A2-adenosine receptors are present on the cardiac sensory nerve endings of [[dorsal root ganglion]] neurons. These sensory neurons are active in the absence of ischemia but become further activated during myocardial [[ischemia]].<ref name="pmid7544544">{{cite journal| author=Huang MH, Sylvén C, Horackova M, Armour JA| title=Ventricular sensory neurons in canine dorsal root ganglia: effects of adenosine and substance P. | journal=Am J Physiol | year= 1995 | volume= 269 | issue= 2 Pt 2 | pages= R318-24 | pmid=7544544 | doi= | pmc= | url= }} </ref>
* In one study in which adenosine was administered by infusion, 95% of patients with Syndrome X experienced [[chest pain]] compared to only 40% of control patients (p<0.001).<ref name="pmid12075055">{{cite journal| author=Panting JR, Gatehouse PD, Yang GZ, Grothues F, Firmin DN, Collins P et al.| title=Abnormal subendocardial perfusion in cardiac syndrome X detected by cardiovascular magnetic resonance imaging. | journal=N Engl J Med | year= 2002 | volume= 346 | issue= 25 | pages= 1948-53 | pmid=12075055 | doi=10.1056/NEJMoa012369 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12075055  }} </ref>
* In one study in which adenosine was administered by infusion, 95% of patients with syndrome X experienced [[chest pain]] compared to only 40% of control patients (p<0.001).<ref name="pmid12075055">{{cite journal| author=Panting JR, Gatehouse PD, Yang GZ, Grothues F, Firmin DN, Collins P et al.| title=Abnormal subendocardial perfusion in cardiac syndrome X detected by cardiovascular magnetic resonance imaging. | journal=N Engl J Med | year= 2002 | volume= 346 | issue= 25 | pages= 1948-53 | pmid=12075055 | doi=10.1056/NEJMoa012369 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12075055  }} </ref>


===An Extension of Dysautonomias===
====An Extension of Dysautonomias====
* Syndrome X has been associated with [[dysautonomias]] and with a greater frequency of autonomic symptoms such as: <ref name="pmid3337115">{{cite journal| author=Katon W, Hall ML, Russo J, Cormier L, Hollifield M, Vitaliano PP et al.| title=Chest pain: relationship of psychiatric illness to coronary arteriographic results. | journal=Am J Med | year= 1988 | volume= 84 | issue= 1 | pages= 1-9 | pmid=3337115 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3337115  }} </ref>
Syndrome X has been associated with [[dysautonomias]] and with a greater frequency of autonomic symptoms such as:<ref name="pmid3337115">{{cite journal| author=Katon W, Hall ML, Russo J, Cormier L, Hollifield M, Vitaliano PP et al.| title=Chest pain: relationship of psychiatric illness to coronary arteriographic results. | journal=Am J Med | year= 1988 | volume= 84 | issue= 1 | pages= 1-9 | pmid=3337115 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3337115  }} </ref>
:* [[Tachycardia]] <ref name="pmid3337115">{{cite journal| author=Katon W, Hall ML, Russo J, Cormier L, Hollifield M, Vitaliano PP et al.| title=Chest pain: relationship of psychiatric illness to coronary arteriographic results. | journal=Am J Med | year= 1988 | volume= 84 | issue= 1 | pages= 1-9 | pmid=3337115 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3337115  }} </ref>
* [[Tachycardia]]<ref name="pmid3337115">{{cite journal| author=Katon W, Hall ML, Russo J, Cormier L, Hollifield M, Vitaliano PP et al.| title=Chest pain: relationship of psychiatric illness to coronary arteriographic results. | journal=Am J Med | year= 1988 | volume= 84 | issue= 1 | pages= 1-9 | pmid=3337115 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3337115  }} </ref>
:* [[Dyspnea]] <ref name="pmid3337115">{{cite journal| author=Katon W, Hall ML, Russo J, Cormier L, Hollifield M, Vitaliano PP et al.| title=Chest pain: relationship of psychiatric illness to coronary arteriographic results. | journal=Am J Med | year= 1988 | volume= 84 | issue= 1 | pages= 1-9 | pmid=3337115 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3337115  }} </ref>
* [[Dyspnea]]<ref name="pmid3337115">{{cite journal| author=Katon W, Hall ML, Russo J, Cormier L, Hollifield M, Vitaliano PP et al.| title=Chest pain: relationship of psychiatric illness to coronary arteriographic results. | journal=Am J Med | year= 1988 | volume= 84 | issue= 1 | pages= 1-9 | pmid=3337115 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3337115  }} </ref>
:* [[Dizziness]] <ref name="pmid3337115">{{cite journal| author=Katon W, Hall ML, Russo J, Cormier L, Hollifield M, Vitaliano PP et al.| title=Chest pain: relationship of psychiatric illness to coronary arteriographic results. | journal=Am J Med | year= 1988 | volume= 84 | issue= 1 | pages= 1-9 | pmid=3337115 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3337115  }} </ref>
* [[Dizziness]]<ref name="pmid3337115">{{cite journal| author=Katon W, Hall ML, Russo J, Cormier L, Hollifield M, Vitaliano PP et al.| title=Chest pain: relationship of psychiatric illness to coronary arteriographic results. | journal=Am J Med | year= 1988 | volume= 84 | issue= 1 | pages= 1-9 | pmid=3337115 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3337115  }} </ref>
:* [[Paresthesias]] <ref name="pmid3337115">{{cite journal| author=Katon W, Hall ML, Russo J, Cormier L, Hollifield M, Vitaliano PP et al.| title=Chest pain: relationship of psychiatric illness to coronary arteriographic results. | journal=Am J Med | year= 1988 | volume= 84 | issue= 1 | pages= 1-9 | pmid=3337115 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3337115  }} </ref>
* [[Paresthesias]]<ref name="pmid3337115">{{cite journal| author=Katon W, Hall ML, Russo J, Cormier L, Hollifield M, Vitaliano PP et al.| title=Chest pain: relationship of psychiatric illness to coronary arteriographic results. | journal=Am J Med | year= 1988 | volume= 84 | issue= 1 | pages= 1-9 | pmid=3337115 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3337115  }} </ref>
*It has, therefore, been hypothesized that Syndrome X may be an extension of abnormalities of the [[autonomic nervous system]].
It has, therefore, been hypothesized that syndrome X may be an extension of abnormalities of the [[autonomic nervous system]].


===Female Pattern of Atherosclerosis===
====Female Pattern of Atherosclerosis====
* Although coronary arteriogram may appear normal, diffuse atherosclerosis may still be present. This is termed a female pattern of atherosclerotic disease.
* Although coronary arteriogram may appear normal, diffuse atherosclerosis may still be present. This is termed a female pattern of atherosclerotic disease.


===Enhanced Pain Sensitivity===
====Enhanced Pain Sensitivity====
* Patients with normal coronary arteries and myocardial ischemia have a lower pain threshold and a lower tolerance to pain induced by adenosine <ref name="pmid1389759">{{cite journal| author=Lagerqvist B, Sylvén C, Waldenström A| title=Lower threshold for adenosine-induced chest pain in patients with angina and normal coronary angiograms. | journal=Br Heart J | year= 1992 | volume= 68 | issue= 3 | pages= 282-5 | pmid=1389759 | doi= | pmc=PMC1025071 | url= }} </ref>.
* Patients with normal coronary arteries and myocardial ischemia have a lower pain threshold and a lower tolerance to pain induced by adenosine.<ref name="pmid1389759">{{cite journal| author=Lagerqvist B, Sylvén C, Waldenström A| title=Lower threshold for adenosine-induced chest pain in patients with angina and normal coronary angiograms. | journal=Br Heart J | year= 1992 | volume= 68 | issue= 3 | pages= 282-5 | pmid=1389759 | doi= | pmc=PMC1025071 | url= }} </ref>


===Panic Disorder===
====Panic Disorder====
* Approximately one third of patients with [[angina pectoris]] and normal coronary arteries are diagnosed with [[panic disorder]] <ref name="pmid3565851">{{cite journal| author=Mukerji V, Beitman BD, Alpert MA, Lamberti JW, DeRosear L, Basha IM| title=Panic disorder: a frequent occurrence in patients with chest pain and normal coronary arteries. | journal=Angiology | year= 1987 | volume= 38 | issue= 3 | pages= 236-40 | pmid=3565851 | doi= | pmc= | url= }} </ref>.
* Approximately one third of patients with [[angina pectoris]] and normal coronary arteries are diagnosed with [[panic disorder]].<ref name="pmid3565851">{{cite journal| author=Mukerji V, Beitman BD, Alpert MA, Lamberti JW, DeRosear L, Basha IM| title=Panic disorder: a frequent occurrence in patients with chest pain and normal coronary arteries. | journal=Angiology | year= 1987 | volume= 38 | issue= 3 | pages= 236-40 | pmid=3565851 | doi= | pmc= | url= }} </ref>


===Viral Infection===
====Viral Infection====
* Viral infection of the coronary microvasculature may be related to the poor response to anti-ischemic drugs
* Viral infection of the coronary microvasculature may be related to the poor response to anti-ischemic drugs.
* Left ventricular endomyocardial biopsies were compared in patients with chronic stable angina versus patients with drug resistant Syndrome X.  Interstitial and replacement [[fibrosis]] were present in all patients with Syndrome X. Viral genomes were identified 69% of patients with CSX which included Epstein-Barr virus in four patients, adenovirus in three patients, human herpes virus (HHV) 6 in one patient, and Epstein-Barr adenovirus co-infection in one. Epstein-Barr and adenovirus were localised to both the cardiomyocytes as well as intramural vessels, while HHV-6 virus confined solely to the vessel wall.<ref name="pmid20889988">{{cite journal| author=Chimenti C, Sale P, Verardo R, Cicalini S, Petrosillo N, Russo MA et al.| title=High prevalence of intramural coronary infection in patients with drug-resistant cardiac syndrome X: comparison with chronic stable angina and normal controls. | journal=Heart | year= 2010 | volume= 96 | issue= 23 | pages= 1926-31 | pmid=20889988 | doi=10.1136/hrt.2010.196626 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20889988  }} </ref>
* Left ventricular endomyocardial biopsies were compared in patients with chronic stable angina versus patients with drug resistant syndrome X.  Interstitial and replacement [[fibrosis]] were present in all patients with syndrome X. Viral genomes were identified 69% of patients with CSX which included Epstein-Barr virus in four patients, adenovirus in three patients, human herpes virus (HHV) 6 in one patient, and Epstein-Barr adenovirus co-infection in one. Epstein-Barr and adenovirus were localised to both the cardiomyocytes as well as intramural vessels, while HHV-6 virus confined solely to the vessel wall.<ref name="pmid20889988">{{cite journal| author=Chimenti C, Sale P, Verardo R, Cicalini S, Petrosillo N, Russo MA et al.| title=High prevalence of intramural coronary infection in patients with drug-resistant cardiac syndrome X: comparison with chronic stable angina and normal controls. | journal=Heart | year= 2010 | volume= 96 | issue= 23 | pages= 1926-31 | pmid=20889988 | doi=10.1136/hrt.2010.196626 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20889988  }} </ref>


==Epidemiology and Demographics==
==Epidemiology and Demographics==
* Syndrome X occurs more often in women.
* Syndrome X occurs more often in women.
* 61.5% of women with Syndrome X are postmenopausal at the time of onset.<ref name="pmid7884081">{{cite journal| author=Kaski JC, Rosano GM, Collins P, Nihoyannopoulos P, Maseri A, Poole-Wilson PA| title=Cardiac syndrome X: clinical characteristics and left ventricular function. Long-term follow-up study. | journal=J Am Coll Cardiol | year= 1995 | volume= 25 | issue= 4 | pages= 807-14 | pmid=7884081 | doi=10.1016/0735-1097(94)00507-M | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7884081  }} </ref>
* 61.5% of women with syndrome X are postmenopausal at the time of onset.<ref name="pmid7884081">{{cite journal| author=Kaski JC, Rosano GM, Collins P, Nihoyannopoulos P, Maseri A, Poole-Wilson PA| title=Cardiac syndrome X: clinical characteristics and left ventricular function. Long-term follow-up study. | journal=J Am Coll Cardiol | year= 1995 | volume= 25 | issue= 4 | pages= 807-14 | pmid=7884081 | doi=10.1016/0735-1097(94)00507-M | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7884081  }} </ref>
* Some studies have found an increased risk of other vasospastic disorders in syndrome X patients, such as [[migraine]] and [[Raynaud's phenomenon]].
* Some studies have found an increased risk of other vasospastic disorders in syndrome X patients, such as [[migraine]] and [[Raynaud's phenomenon]].


==Natural History, Complications and Prognosis==
==Natural History, Complications and Prognosis==
* Syndrome X does not appear to be associated with an excess of major coronary events.
* Syndrome X does not appear to be associated with an excess of major coronary events.
* In a longitudinal study of 99 patients with Syndrome X followed for an average of 7 years (+/- 4 years deviation), left ventricular function was stable: fractional shortening at baseline was 35.4 +/- 4% vs. 35.6 +/- 3% at follow-up and [[congestive heart failure]] developed in only one patient. <ref name="pmid7884081">{{cite journal| author=Kaski JC, Rosano GM, Collins P, Nihoyannopoulos P, Maseri A, Poole-Wilson PA| title=Cardiac syndrome X: clinical characteristics and left ventricular function. Long-term follow-up study. | journal=J Am Coll Cardiol | year= 1995 | volume= 25 | issue= 4 | pages= 807-14 | pmid=7884081 | doi=10.1016/0735-1097(94)00507-M | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7884081  }} </ref> Symptomatic outcome varied across patients: where it did not change in about 65% of patients, improved in 10% of patients, and worsened in about a 25% of patients <ref name="pmid7884081">{{cite journal| author=Kaski JC, Rosano GM, Collins P, Nihoyannopoulos P, Maseri A, Poole-Wilson PA| title=Cardiac syndrome X: clinical characteristics and left ventricular function. Long-term follow-up study. | journal=J Am Coll Cardiol | year= 1995 | volume= 25 | issue= 4 | pages= 807-14 | pmid=7884081 | doi=10.1016/0735-1097(94)00507-M | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7884081  }} </ref>
* In a longitudinal study of 99 patients with syndrome X followed for an average of 7 years (+/- 4 years deviation), left ventricular function was stable: fractional shortening at baseline was 35.4 +/- 4% vs. 35.6 +/- 3% at follow-up and [[congestive heart failure]] developed in only one patient.<ref name="pmid7884081">{{cite journal| author=Kaski JC, Rosano GM, Collins P, Nihoyannopoulos P, Maseri A, Poole-Wilson PA| title=Cardiac syndrome X: clinical characteristics and left ventricular function. Long-term follow-up study. | journal=J Am Coll Cardiol | year= 1995 | volume= 25 | issue= 4 | pages= 807-14 | pmid=7884081 | doi=10.1016/0735-1097(94)00507-M | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7884081  }} </ref> Symptomatic outcome varied across patients: where it did not change in about 65% of patients, improved in 10% of patients, and worsened in about a 25% of patients.<ref name="pmid7884081">{{cite journal| author=Kaski JC, Rosano GM, Collins P, Nihoyannopoulos P, Maseri A, Poole-Wilson PA| title=Cardiac syndrome X: clinical characteristics and left ventricular function. Long-term follow-up study. | journal=J Am Coll Cardiol | year= 1995 | volume= 25 | issue= 4 | pages= 807-14 | pmid=7884081 | doi=10.1016/0735-1097(94)00507-M | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7884081  }} </ref>
* The absence of significant coronary artery disease on coronary angiography is associated with a good prognosis. Among 3,136 patients with normal angiograms, the seven year survival rate was 96%.<ref name="pmid3512658">{{cite journal| author=Kemp HG, Kronmal RA, Vlietstra RE, Frye RL| title=Seven year survival of patients with normal or near normal coronary arteriograms: a CASS registry study. | journal=J Am Coll Cardiol | year= 1986 | volume= 7 | issue= 3 | pages= 479-83 | pmid=3512658 | doi= | pmc= | url= }} </ref>
* The absence of significant coronary artery disease on coronary angiography is associated with a good prognosis. Among 3,136 patients with normal angiograms, the seven year survival rate was 96%.<ref name="pmid3512658">{{cite journal| author=Kemp HG, Kronmal RA, Vlietstra RE, Frye RL| title=Seven year survival of patients with normal or near normal coronary arteriograms: a CASS registry study. | journal=J Am Coll Cardiol | year= 1986 | volume= 7 | issue= 3 | pages= 479-83 | pmid=3512658 | doi= | pmc= | url= }} </ref>


==Risk Factors==
==Risk Factors==
* Female gender and [[left ventricular hypertrophy]] are associated with an excess risk of Syndrome X.
* Female gender and [[left ventricular hypertrophy]] are associated with an excess risk of syndrome X.
* The onset in women often occurs after [[menopause]].<ref name="pmid7884081">{{cite journal| author=Kaski JC, Rosano GM, Collins P, Nihoyannopoulos P, Maseri A, Poole-Wilson PA| title=Cardiac syndrome X: clinical characteristics and left ventricular function. Long-term follow-up study. | journal=J Am Coll Cardiol | year= 1995 | volume= 25 | issue= 4 | pages= 807-14 | pmid=7884081 | doi=10.1016/0735-1097(94)00507-M | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7884081  }} </ref>
* The onset in women often occurs after [[menopause]].<ref name="pmid7884081">{{cite journal| author=Kaski JC, Rosano GM, Collins P, Nihoyannopoulos P, Maseri A, Poole-Wilson PA| title=Cardiac syndrome X: clinical characteristics and left ventricular function. Long-term follow-up study. | journal=J Am Coll Cardiol | year= 1995 | volume= 25 | issue= 4 | pages= 807-14 | pmid=7884081 | doi=10.1016/0735-1097(94)00507-M | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7884081  }} </ref>
* Syndrome X and its accompanying microvascular dysfunction are not associated with traditional cardiovascular risk factors.<ref name="pmid21135582">{{cite journal| author=Sestito A, Lanza GA, Di Monaco A, Lamendola P, Careri G, Tarzia P et al.| title=Relation between cardiovascular risk factors and coronary microvascular dysfunction in cardiac syndrome X. | journal=J Cardiovasc Med (Hagerstown) | year= 2011 | volume= 12 | issue= 5 | pages= 322-7 | pmid=21135582 | doi=10.2459/JCM.0b013e3283406479 | pmc= | url= }} </ref>
* Syndrome X and its accompanying microvascular dysfunction are not associated with traditional cardiovascular risk factors.<ref name="pmid21135582">{{cite journal| author=Sestito A, Lanza GA, Di Monaco A, Lamendola P, Careri G, Tarzia P et al.| title=Relation between cardiovascular risk factors and coronary microvascular dysfunction in cardiac syndrome X. | journal=J Cardiovasc Med (Hagerstown) | year= 2011 | volume= 12 | issue= 5 | pages= 322-7 | pmid=21135582 | doi=10.2459/JCM.0b013e3283406479 | pmc= | url= }} </ref>
* Syndrome X has been associated with elevations of inflammatory markers such as: [[C reactive protein]] and soluble [[CD40 ligand]].<ref name="pmid20980002">{{cite journal| author=Dominguez-Rodriguez A, Abreu-Gonzalez P, Avanzas P, Gomez MA, Kaski JC| title=Elevated circulating soluble form of CD40 ligand in patients with cardiac syndrome X. | journal=Atherosclerosis | year= 2010 | volume= 213 | issue= 2 | pages= 637-41 | pmid=20980002 | doi=10.1016/j.atherosclerosis.2010.09.031 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20980002  }} </ref>
* Syndrome X has been associated with elevations of inflammatory markers such as: [[C reactive protein]] and soluble CD40 ligand.<ref name="pmid20980002">{{cite journal| author=Dominguez-Rodriguez A, Abreu-Gonzalez P, Avanzas P, Gomez MA, Kaski JC| title=Elevated circulating soluble form of CD40 ligand in patients with cardiac syndrome X. | journal=Atherosclerosis | year= 2010 | volume= 213 | issue= 2 | pages= 637-41 | pmid=20980002 | doi=10.1016/j.atherosclerosis.2010.09.031 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20980002  }} </ref>


==Other Conditions to Distinguish Syndrome X From==
==Other Conditions to Distinguish Syndrome X From==
* Syndrome X should be distinguished from [[Prinzmetal's angina]], a disorder which involves spasm of the main epicardial coronary arteries.
* Syndrome X should be distinguished from [[prinzmetal's angina]], a disorder which involves spasm of the main epicardial coronary arteries.
* Syndrome X involves dysfunction of the downstream microvasculature.
* Syndrome X involves dysfunction of the downstream microvasculature.
* Syndrome X must also be distinguished from [[esophageal spasm]].
* Syndrome X must also be distinguished from [[esophageal spasm]].


==Diagnosis==
==Diagnosis==
===Symptoms===
====Symptoms====
* In one study, all 99 patients with Syndrome X had exertional angina. 41 patients reported angina at rest.<ref name="pmid7884081">{{cite journal| author=Kaski JC, Rosano GM, Collins P, Nihoyannopoulos P, Maseri A, Poole-Wilson PA| title=Cardiac syndrome X: clinical characteristics and left ventricular function. Long-term follow-up study. | journal=J Am Coll Cardiol | year= 1995 | volume= 25 | issue= 4 | pages= 807-14 | pmid=7884081 | doi=10.1016/0735-1097(94)00507-M | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7884081  }} </ref>
* In one study, all 99 patients with syndrome X had exertional angina. 41 patients reported angina at rest.<ref name="pmid7884081">{{cite journal| author=Kaski JC, Rosano GM, Collins P, Nihoyannopoulos P, Maseri A, Poole-Wilson PA| title=Cardiac syndrome X: clinical characteristics and left ventricular function. Long-term follow-up study. | journal=J Am Coll Cardiol | year= 1995 | volume= 25 | issue= 4 | pages= 807-14 | pmid=7884081 | doi=10.1016/0735-1097(94)00507-M | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7884081  }} </ref>
* In patients with syndrome X, the anginal pain tends to last longer after cessation of exertion (> 10 minutes in 53% of patients<ref name="pmid7884081">{{cite journal| author=Kaski JC, Rosano GM, Collins P, Nihoyannopoulos P, Maseri A, Poole-Wilson PA| title=Cardiac syndrome X: clinical characteristics and left ventricular function. Long-term follow-up study. | journal=J Am Coll Cardiol | year= 1995 | volume= 25 | issue= 4 | pages= 807-14 | pmid=7884081 | doi=10.1016/0735-1097(94)00507-M | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7884081  }} </ref>) than is typical of patients with fixed obstructions of the epicardial arteries (pain generally lasts 2 to 5 minutes).
* In patients with syndrome X, the anginal pain tends to last longer after cessation of exertion (> 10 minutes in 53% of patients<ref name="pmid7884081">{{cite journal| author=Kaski JC, Rosano GM, Collins P, Nihoyannopoulos P, Maseri A, Poole-Wilson PA| title=Cardiac syndrome X: clinical characteristics and left ventricular function. Long-term follow-up study. | journal=J Am Coll Cardiol | year= 1995 | volume= 25 | issue= 4 | pages= 807-14 | pmid=7884081 | doi=10.1016/0735-1097(94)00507-M | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7884081  }} </ref>) than is typical of patients with fixed obstructions of the epicardial arteries (pain generally lasts 2 to 5 minutes).
* Sublingual nitroglycerine is often not as effective in the patient with Syndrome X as it is in the patient with obstructive epicardial disease, with only 42% of patients reporting relief.<ref name="pmid7884081">{{cite journal| author=Kaski JC, Rosano GM, Collins P, Nihoyannopoulos P, Maseri A, Poole-Wilson PA| title=Cardiac syndrome X: clinical characteristics and left ventricular function. Long-term follow-up study. | journal=J Am Coll Cardiol | year= 1995 | volume= 25 | issue= 4 | pages= 807-14 | pmid=7884081 | doi=10.1016/0735-1097(94)00507-M | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7884081  }} </ref>
* Sublingual nitroglycerine is often not as effective in the patient with syndrome X as it is in the patient with obstructive epicardial disease, with only 42% of patients reporting relief.<ref name="pmid7884081">{{cite journal| author=Kaski JC, Rosano GM, Collins P, Nihoyannopoulos P, Maseri A, Poole-Wilson PA| title=Cardiac syndrome X: clinical characteristics and left ventricular function. Long-term follow-up study. | journal=J Am Coll Cardiol | year= 1995 | volume= 25 | issue= 4 | pages= 807-14 | pmid=7884081 | doi=10.1016/0735-1097(94)00507-M | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7884081  }} </ref>


===Ambulatory Holter Monitoring===
====Ambulatory Holter Monitoring====
* Approximately two thirds of patients (64/99 in one study) may experience ST segment depression on ambulatory Holter monitoring.<ref name="pmid7884081">{{cite journal| author=Kaski JC, Rosano GM, Collins P, Nihoyannopoulos P, Maseri A, Poole-Wilson PA| title=Cardiac syndrome X: clinical characteristics and left ventricular function. Long-term follow-up study. | journal=J Am Coll Cardiol | year= 1995 | volume= 25 | issue= 4 | pages= 807-14 | pmid=7884081 | doi=10.1016/0735-1097(94)00507-M | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7884081  }} </ref>
* Approximately two thirds of patients (64/99 in one study) may experience ST segment depression on ambulatory Holter monitoring.<ref name="pmid7884081">{{cite journal| author=Kaski JC, Rosano GM, Collins P, Nihoyannopoulos P, Maseri A, Poole-Wilson PA| title=Cardiac syndrome X: clinical characteristics and left ventricular function. Long-term follow-up study. | journal=J Am Coll Cardiol | year= 1995 | volume= 25 | issue= 4 | pages= 807-14 | pmid=7884081 | doi=10.1016/0735-1097(94)00507-M | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7884081  }} </ref>


===Cardiac Magnetic Resonance Imaging (CMR)===
====Cardiac Magnetic Resonance Imaging (CMR)====
* While there is no difference between control patients and patients with Syndrome X in subepicardial perfusion, there is a greater relative magnitude of subendocardial hypoperfusion on CMR during adenosine infusion in patients with Syndrome X.  As a result, "the ratio of subendocardial to subepicardial myocardial-perfusion reserve index is significantly lower in patients with syndrome X". <ref name="pmid12075055">{{cite journal| author=Panting JR, Gatehouse PD, Yang GZ, Grothues F, Firmin DN, Collins P et al.| title=Abnormal subendocardial perfusion in cardiac syndrome X detected by cardiovascular magnetic resonance imaging. | journal=N Engl J Med | year= 2002 | volume= 346 | issue= 25 | pages= 1948-53 | pmid=12075055 | doi=10.1056/NEJMoa012369 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12075055  }} </ref>
* While there is no difference between control patients and patients with syndrome X in subepicardial perfusion, there is a greater relative magnitude of subendocardial hypoperfusion on CMR during adenosine infusion in patients with syndrome X.  As a result, the ratio of subendocardial to subepicardial myocardial-perfusion reserve index is significantly lower in patients with syndrome X.<ref name="pmid12075055">{{cite journal| author=Panting JR, Gatehouse PD, Yang GZ, Grothues F, Firmin DN, Collins P et al.| title=Abnormal subendocardial perfusion in cardiac syndrome X detected by cardiovascular magnetic resonance imaging. | journal=N Engl J Med | year= 2002 | volume= 346 | issue= 25 | pages= 1948-53 | pmid=12075055 | doi=10.1056/NEJMoa012369 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12075055  }} </ref>


===Diagnostic Studies and Criteria for Diagnosis===
====Diagnostic Studies and Criteria for Diagnosis====
* Syndrome X is often a diagnosis of exclusion. The diagnostic criteria are as follows:
* Syndrome X is often a diagnosis of exclusion. The diagnostic criteria are as follows:
:*There must be evidence of '''[[myocardial ischemia]]''':  Diagnostic studies include an exercise [[ECG]], [[stress scintigraphy]], or [[stress echocardiography]] in conjunction with anginal chest discomfort.
:*There must be evidence of [[myocardial ischemia]]:  Diagnostic studies include an exercise [[ECG]], [[stress scintigraphy]], or [[stress echocardiography]] in conjunction with anginal chest discomfort.
:* '''[[Angina pectoris|Angina]]''': Angina pectoris must be present. The angina pectoris associated with Syndrome X may last longer that the anginal discomfort associated with the fixed epicardial stenoses of atherosclerotic heart disease.
:* [[Angina pectoris|Angina]]: Angina pectoris must be present. The angina pectoris associated with syndrome X may last longer that the anginal discomfort associated with the fixed epicardial stenoses of atherosclerotic heart disease.
:* '''[[Coronary angiogram]]''': There is no narrowing of the epicardial arteries.  However, Syndrome X may be associated with a reduction in coronary [[vasodilator reserve]] presumably due to abnormalities in the [[coronary microcirculation]].  During stress, sampling of the [[coronary sinus]] may demonstrate the production of [[lactate]] by the [[myocardium]].  Intracoronary [[acetylcholine]] can be administered to evaluate endothelium-dependent [[coronary flow reserve]].
:* [[Coronary angiogram]]: There is no narrowing of the epicardial arteries.  However, syndrome X may be associated with a reduction in coronary [[vasodilator reserve]] presumably due to abnormalities in the [[coronary microcirculation]].  During stress, sampling of the [[coronary sinus]] may demonstrate the production of [[lactate]] by the [[myocardium]].  Intracoronary [[acetylcholine]] can be administered to evaluate endothelium-dependent coronary flow reserve.


===ESC Guidelines for investigation in patients with Syndrome X (DO NOT EDIT)<ref name="pmid16735367">{{cite journal| author=Fox K, Garcia MA, Ardissino D, Buszman P, Camici PG, Crea F et al.| title=Guidelines on the management of stable angina pectoris: executive summary: The Task Force on the Management of Stable Angina Pectoris of the European Society of Cardiology. | journal=Eur Heart J | year= 2006 | volume= 27 | issue= 11 | pages= 1341-81 | pmid=16735367 | doi=10.1093/eurheartj/ehl001 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16735367  }} </ref>===
==Treatment==
{{cquote|
The mainstay of treatment in patients with syndrome X are [[calcium channel blocker]]s, such as [[nifedipine]] and [[diltiazem]]. Other therapies include:
===[[European society of cardiology#Classes of Recommendations|Class I]]===
'''1.''' [[Chronic stable angina echocardiography|Resting echocardiogram]] in patients with [[Chronic stable angina definition|angina]] and normal or non-obstructed coronary arteries to assess for presence of [[LVH|ventricular hypertrophy]] and/or [[diastolic dysfunction]]. ''([[European society of cardiology#Level of Evidence|Level of Evidence: C]])''


===[[European society of cardiology#Classes of Recommendations|Class IIb]]===
*[[Nitrates]]: Sublingual nitroglycerine is often not as effective in the patient with syndrome X as it is in the patient with obstructive epicardial disease, with only 42% of patients reporting relief.<ref name="pmid7884081">{{cite journal| author=Kaski JC, Rosano GM, Collins P, Nihoyannopoulos P, Maseri A, Poole-Wilson PA| title=Cardiac syndrome X: clinical characteristics and left ventricular function. Long-term follow-up study. | journal=J Am Coll Cardiol | year= 1995 | volume= 25 | issue= 4 | pages= 807-14 | pmid=7884081 | doi=10.1016/0735-1097(94)00507-M | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7884081  }} </ref>
'''1.''' Intracoronary acetylcholine during coronary arteriography, if the arteriogram is visually normal, to assess endothelium-dependent coronary flow reserve, and exclude [[vasospasm]]. ''([[European society of cardiology#Level of Evidence|Level of Evidence: C]])''
*[[Beta blockers]]
*[[Aminophylline]]: Evidence exists to suggest this therapy may be effective via inhibition of adenosine receptors.
*[[Estrogen]]: Evidence exists to suggest this therapy  may be effective in women.
*[[Ranolazine]]: In a recent randomized, controlled trial of ranolzazine in women with syndrome X, ranolazine was found to be superior to placebo with respect to physical functioning (p = 0.046), angina stability (p = 0.008), and quality of life (p = 0.021). With respect to objective quantitative measure, ranolazine administration tended to be associated with higher (improved) CMR mid-ventricular MPRI (2.4 [2.0 minimum, 2.8 maximum] vs. 2.1 [1.7 minimum, 2.5 maximum], p = 0.074).  Women with a coronary flow reserve (CFR) ≤ 3.0 achieved significantly greater improvement in MPRI on ranolazine versus placebo (Δ in MPRI 0.48 vs. -0.82, p = 0.04).<ref name="pmid21565740">{{cite journal| author=Mehta PK, Goykhman P, Thomson LE, Shufelt C, Wei J, Yang Y et al.| title=Ranolazine improves angina in women with evidence of myocardial ischemia but no obstructive coronary artery disease. | journal=JACC Cardiovasc Imaging | year= 2011 | volume= 4 | issue= 5 | pages= 514-22 | pmid=21565740 | doi=10.1016/j.jcmg.2011.03.007 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21565740  }} </ref>
*[[Estrogen replacement therapy]]: [[ERT]] or selective ERT may reduce the frequency of [[chest pain]] in post menopausal women with syndrome X.<ref name="pmid20935411">{{cite journal| author=Chen YX, Luo NS, Lin YQ, Yuan WL, Xie SL, Nie RQ et al.| title=Selective estrogen receptor modulators promising for cardiac syndrome X. | journal=J Postgrad Med | year= 2010 | volume= 56 | issue= 4 | pages= 328-31 | pmid=20935411 | doi=10.4103/0022-3859.70936 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20935411  }} </ref>


'''2.''' Intracoronary ultrasound, coronary flow reserve, or FFR measurement to exclude missed obstructive lesions, if angiographic appearances are suggestive of a nonobstructive lesion rather than completely normal, and stress imaging techniques identify an extensive area of [[ischaemia]]. ''([[European society of cardiology#Level of Evidence|Level of Evidence: C]])''}}
==ESC Guidelines for Investigation in Patients with Syndrome X (DO NOT EDIT)<ref name="pmid16735367">{{cite journal| author=Fox K, Garcia MA, Ardissino D, Buszman P, Camici PG, Crea F et al.| title=Guidelines on the management of stable angina pectoris: executive summary: The Task Force on the Management of Stable Angina Pectoris of the European Society of Cardiology. | journal=Eur Heart J | year= 2006 | volume= 27 | issue= 11 | pages= 1341-81 | pmid=16735367 | doi=10.1093/eurheartj/ehl001 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16735367  }} </ref>==


==Treatment==
{|class="wikitable"
The mainstay of treatment in patients with Syndrome X are [[calcium channel blocker]]s, such as [[nifedipine]] and [[diltiazem]]. Other therapies include:
|-
| colspan="1" style="text-align:center; background:LightGreen"|[[European society of cardiology#Classes of Recommendations|Class I]]
 
|-
| bgcolor="LightGreen"|<nowiki>"</nowiki>'''1.''' [[Chronic stable angina echocardiography|Resting echocardiogram]] in patients with [[Chronic stable angina definition|angina]] and normal or non-obstructed coronary arteries to assess for presence of [[LVH|ventricular hypertrophy]] and/or [[diastolic dysfunction]]. ''([[European society of cardiology#Level of Evidence|Level of Evidence: C]])''<nowiki>"</nowiki>
|}
 
{|class="wikitable"
|-
| colspan="1" style="text-align:center; background:LemonChiffon"|[[European society of cardiology#Classes of Recommendations|Class IIb]]
 
|-
| bgcolor="LemonChiffon"|<nowiki>"</nowiki>'''1.''' Intracoronary acetylcholine during coronary arteriography, if the arteriogram is visually normal, to assess endothelium-dependent coronary flow reserve, and exclude [[vasospasm]]. ''([[European society of cardiology#Level of Evidence|Level of Evidence: C]])''<nowiki>"</nowiki>
|-
| bgcolor="LemonChiffon"|<nowiki>"</nowiki>'''2.''' Intracoronary ultrasound, coronary flow reserve, or FFR measurement to exclude missed obstructive lesions, if angiographic appearances are suggestive of a nonobstructive lesion rather than completely normal, and stress imaging techniques identify an extensive area of [[ischaemia]]. ''([[European society of cardiology#Level of Evidence|Level of Evidence: C]])''<nowiki>"</nowiki>
|}


*'''[[Nitrates]]''': Sublingual nitroglycerine is often not as effective in the patient with Syndrome X as it is in the patient with obstructive epicardial disease, with only 42% of patients reporting relief.<ref name="pmid7884081">{{cite journal| author=Kaski JC, Rosano GM, Collins P, Nihoyannopoulos P, Maseri A, Poole-Wilson PA| title=Cardiac syndrome X: clinical characteristics and left ventricular function. Long-term follow-up study. | journal=J Am Coll Cardiol | year= 1995 | volume= 25 | issue= 4 | pages= 807-14 | pmid=7884081 | doi=10.1016/0735-1097(94)00507-M | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7884081  }} </ref>
==ESC Guidelines for Pharmacological Therapy to Improve Symptoms in Patients with Syndrome X (DO NOT EDIT)<ref name="pmid16735367">{{cite journal| author=Fox K, Garcia MA, Ardissino D, Buszman P, Camici PG, Crea F et al.| title=Guidelines on the management of stable angina pectoris: executive summary: The Task Force on the Management of Stable Angina Pectoris of the European Society of Cardiology. | journal=Eur Heart J | year= 2006 | volume= 27 | issue= 11 | pages= 1341-81 | pmid=16735367 | doi=10.1093/eurheartj/ehl001 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16735367 }} </ref>==
*'''[[Beta blockers]]'''
*'''[[Aminophylline]]''': Evidence exists to suggest this therapy may be effective via inhibition of adenosine receptors.
*'''[[Estrogen]]''' Evidence exists to suggest this therapy  may be effective in women.
*'''[[Ranolazine]]''': In a recent randomized, controlled trial of ranolzazine in women with Syndrome X, ranolazine was found to be superior to placebo with respect to physical functioning (p = 0.046), angina stability (p = 0.008), and quality of life (p = 0.021). With respect to objective quantitative measure, ranolazine administration tended to be associated with higher (improved) CMR mid-ventricular MPRI (2.4 [2.0 minimum, 2.8 maximum] vs. 2.1 [1.7 minimum, 2.5 maximum], p = 0.074).  Women with a coronary flow reserve (CFR) ≤ 3.0 achieved significantly greater improvement in MPRI on ranolazine versus placebo (Δ in MPRI 0.48 vs. -0.82, p = 0.04).<ref name="pmid21565740">{{cite journal| author=Mehta PK, Goykhman P, Thomson LE, Shufelt C, Wei J, Yang Y et al.| title=Ranolazine improves angina in women with evidence of myocardial ischemia but no obstructive coronary artery disease. | journal=JACC Cardiovasc Imaging | year= 2011 | volume= 4 | issue= 5 | pages= 514-22 | pmid=21565740 | doi=10.1016/j.jcmg.2011.03.007 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21565740  }} </ref>
*[[Estrogen replacement therapy]]: [[ERT]] or selective ERT may reduce the frequency of [[chest pain]] in post menopausal women with Syndrome X.<ref name="pmid20935411">{{cite journal| author=Chen YX, Luo NS, Lin YQ, Yuan WL, Xie SL, Nie RQ et al.| title=Selective estrogen receptor modulators promising for cardiac syndrome X. | journal=J Postgrad Med | year= 2010 | volume= 56 | issue= 4 | pages= 328-31 | pmid=20935411 | doi=10.4103/0022-3859.70936 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20935411 }} </ref>


===ESC Guidelines for pharmacological therapy to improve symptoms in patients with Syndrome X (DO NOT EDIT) <ref name="pmid16735367">{{cite journal| author=Fox K, Garcia MA, Ardissino D, Buszman P, Camici PG, Crea F et al.| title=Guidelines on the management of stable angina pectoris: executive summary: The Task Force on the Management of Stable Angina Pectoris of the European Society of Cardiology. | journal=Eur Heart J | year= 2006 | volume= 27 | issue= 11 | pages= 1341-81 | pmid=16735367 | doi=10.1093/eurheartj/ehl001 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16735367  }} </ref>===
{|class="wikitable"
{{cquote|
|-
===[[European society of cardiology#Classes of Recommendations|Class I]]===
| colspan="1" style="text-align:center; background:LightGreen"|[[European society of cardiology#Classes of Recommendations|Class I]]
'''1.''' Therapy with [[Chronic stable angina treatment nitrates|nitrates]], [[Chronic stable angina treatment beta blockers|beta blockers]], and [[Chronic stable angina treatment calcium channel blockers|calcium channel blockers]] alone or in combination. ''([[European society of cardiology#Level of Evidence|Level of Evidence: B]])''


'''2.''' [[Chronic stable angina treatment anti-lipid agents|Statin therapy]] in patients with [[hyperlipidaemia]]. ''([[European society of cardiology#Level of Evidence|Level of Evidence: B]])''
|-
| bgcolor="LightGreen"|<nowiki>"</nowiki>'''1.''' Therapy with [[Chronic stable angina treatment nitrates|nitrates]], [[Chronic stable angina treatment beta blockers|beta blockers]], and [[Chronic stable angina treatment calcium channel blockers|calcium channel blockers]] alone or in combination. ''([[European society of cardiology#Level of Evidence|Level of Evidence: B]])''<nowiki>"</nowiki>
|-
| bgcolor="LightGreen"|<nowiki>"</nowiki>'''2.''' [[Chronic stable angina treatment anti-lipid agents|Statin therapy]] in patients with [[hyperlipidaemia]]. ''([[European society of cardiology#Level of Evidence|Level of Evidence: B]])''<nowiki>"</nowiki>
|-
| bgcolor="LightGreen"|<nowiki>"</nowiki>'''3.''' [[ACE inhibitors]] in patients with [[hypertension]]. ''([[European society of cardiology#Classes of Recommendations|Level of Evidence: C]])''<nowiki>"</nowiki>
|}


'''3.''' [[ACE inhibitors]] in patients with [[hypertension]]. ''([[European society of cardiology#Classes of Recommendations|Level of Evidence: C]])''
{|class="wikitable"
|-
| colspan="1" style="text-align:center; background:LemonChiffon"|[[European society of cardiology#Classes of Recommendations|Class IIa]]


===[[European society of cardiology#Classes of Recommendations|Class IIa]]===
|-
'''1.''' Trial of therapy with other anti-anginals including [[nicorandil]] and metabolic agents. ''([[European society of cardiology#Level of Evidence|Level of Evidence: C]])''
| bgcolor="LemonChiffon"|<nowiki>"</nowiki>'''1.''' Trial of therapy with other anti-anginals including [[nicorandil]] and metabolic agents. ''([[European society of cardiology#Level of Evidence|Level of Evidence: C]])''<nowiki>"</nowiki>
|}


===[[European society of cardiology#Classes of Recommendations|Class IIb]]===
{|class="wikitable"
'''1.''' [[Aminophylline]] for continued pain, despite [[European society of cardiology#Classes of Recommendations|Class I]] measures. ''([[European society of cardiology#Level of Evidence|Level of Evidence: C]])''
|-
| colspan="1" style="text-align:center; background:LemonChiffon"|[[European society of cardiology#Classes of Recommendations|Class IIb]]


'''2.''' Imipramine for continued pain, despite [[European society of cardiology#Classes of Recommendations|Class I]] measures. ''([[European society of cardiology#Level of Evidence|Level of Evidence: C]])''}}
|-
| bgcolor="LemonChiffon"|<nowiki>"</nowiki>'''1.''' [[Aminophylline]] for continued pain, despite [[European society of cardiology#Classes of Recommendations|Class I]] measures. ''([[European society of cardiology#Level of Evidence|Level of Evidence: C]])''<nowiki>"</nowiki>
|-
| bgcolor="LemonChiffon"|<nowiki>"</nowiki>'''2.''' Imipramine for continued pain, despite [[European society of cardiology#Classes of Recommendations|Class I]] measures. ''([[European society of cardiology#Level of Evidence|Level of Evidence: C]])''<nowiki>"</nowiki>
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==References==
==References==
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Latest revision as of 07:27, 15 March 2016

Chronic stable angina Microchapters

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Synonyms and key words: Microvascular angina

Overview

Cardiac syndrome X is angina associated with objective evidence of myocardial ischemia in the absence of epicardial coronary artery disease. Syndrome X has been hypothesized to be a disorder of the coronary microvasculature rather than the large caliber epicardial coronary arteries.

Pathophysiology

  • In a large percentage of patients, there is coronary microvascular dysfunction in which microvasculature cannot dilate to accommodate increased blood flow during exertion caused by an increased myocardial metabolic demand.
  • There does not appear to be a systemic abnormality in vasomotor function as brachial artery reactivity is normal.[1]
  • The underlying pathophysiology is most likely heterogenous. Multiple pathophysiologic mechanisms have been proposed with variable data to support them such as: ischemia, adenosine, dysautonomia, female pattern, hypersensitivity, panic disorders, and viral infections.

Ischemia is Present in Syndrome X

  • Researchers debate whether ischemia is present in patients with syndrome X. There may be no wall motion abnormalities or coronary sinus lactate production during an episode of ischemic discomfort. This may be due to focal involvement of the myocardium.
  • When coronary sinus samples of more sensitive markers of ischemia reperfusion/oxidative stress are analyzed such as lipid hydroperoxides (ROOHs) and conjugated dienes (CDs) before and after pacing, there is an increase in ROOH and CD levels (from 4.83 +/- 1.18 micromol/l at baseline to 7.88 +/- 1.12 micromol/l and from 0.038 +/- 0.002 to 0.051 +/- 0.003 arbitrary units, respectively, P < 0.01).[2]
  • In contrast, ROOH and CD levels did not increase in control patients after pacing.

Adenosine as a Cause of Chest Pain

  • Both, endogenous and exogenous adenosine can cause chest discomfort through stimulation of sensory nerves in the heart.[3][4]
  • Huang et al have demonstrated that both A1- and A2-adenosine receptors are present on the cardiac sensory nerve endings of dorsal root ganglion neurons. These sensory neurons are active in the absence of ischemia but become further activated during myocardial ischemia.[4]
  • In one study in which adenosine was administered by infusion, 95% of patients with syndrome X experienced chest pain compared to only 40% of control patients (p<0.001).[5]

An Extension of Dysautonomias

Syndrome X has been associated with dysautonomias and with a greater frequency of autonomic symptoms such as:[6]

It has, therefore, been hypothesized that syndrome X may be an extension of abnormalities of the autonomic nervous system.

Female Pattern of Atherosclerosis

  • Although coronary arteriogram may appear normal, diffuse atherosclerosis may still be present. This is termed a female pattern of atherosclerotic disease.

Enhanced Pain Sensitivity

  • Patients with normal coronary arteries and myocardial ischemia have a lower pain threshold and a lower tolerance to pain induced by adenosine.[7]

Panic Disorder

Viral Infection

  • Viral infection of the coronary microvasculature may be related to the poor response to anti-ischemic drugs.
  • Left ventricular endomyocardial biopsies were compared in patients with chronic stable angina versus patients with drug resistant syndrome X. Interstitial and replacement fibrosis were present in all patients with syndrome X. Viral genomes were identified 69% of patients with CSX which included Epstein-Barr virus in four patients, adenovirus in three patients, human herpes virus (HHV) 6 in one patient, and Epstein-Barr adenovirus co-infection in one. Epstein-Barr and adenovirus were localised to both the cardiomyocytes as well as intramural vessels, while HHV-6 virus confined solely to the vessel wall.[9]

Epidemiology and Demographics

  • Syndrome X occurs more often in women.
  • 61.5% of women with syndrome X are postmenopausal at the time of onset.[10]
  • Some studies have found an increased risk of other vasospastic disorders in syndrome X patients, such as migraine and Raynaud's phenomenon.

Natural History, Complications and Prognosis

  • Syndrome X does not appear to be associated with an excess of major coronary events.
  • In a longitudinal study of 99 patients with syndrome X followed for an average of 7 years (+/- 4 years deviation), left ventricular function was stable: fractional shortening at baseline was 35.4 +/- 4% vs. 35.6 +/- 3% at follow-up and congestive heart failure developed in only one patient.[10] Symptomatic outcome varied across patients: where it did not change in about 65% of patients, improved in 10% of patients, and worsened in about a 25% of patients.[10]
  • The absence of significant coronary artery disease on coronary angiography is associated with a good prognosis. Among 3,136 patients with normal angiograms, the seven year survival rate was 96%.[11]

Risk Factors

  • Female gender and left ventricular hypertrophy are associated with an excess risk of syndrome X.
  • The onset in women often occurs after menopause.[10]
  • Syndrome X and its accompanying microvascular dysfunction are not associated with traditional cardiovascular risk factors.[12]
  • Syndrome X has been associated with elevations of inflammatory markers such as: C reactive protein and soluble CD40 ligand.[13]

Other Conditions to Distinguish Syndrome X From

  • Syndrome X should be distinguished from prinzmetal's angina, a disorder which involves spasm of the main epicardial coronary arteries.
  • Syndrome X involves dysfunction of the downstream microvasculature.
  • Syndrome X must also be distinguished from esophageal spasm.

Diagnosis

Symptoms

  • In one study, all 99 patients with syndrome X had exertional angina. 41 patients reported angina at rest.[10]
  • In patients with syndrome X, the anginal pain tends to last longer after cessation of exertion (> 10 minutes in 53% of patients[10]) than is typical of patients with fixed obstructions of the epicardial arteries (pain generally lasts 2 to 5 minutes).
  • Sublingual nitroglycerine is often not as effective in the patient with syndrome X as it is in the patient with obstructive epicardial disease, with only 42% of patients reporting relief.[10]

Ambulatory Holter Monitoring

  • Approximately two thirds of patients (64/99 in one study) may experience ST segment depression on ambulatory Holter monitoring.[10]

Cardiac Magnetic Resonance Imaging (CMR)

  • While there is no difference between control patients and patients with syndrome X in subepicardial perfusion, there is a greater relative magnitude of subendocardial hypoperfusion on CMR during adenosine infusion in patients with syndrome X. As a result, the ratio of subendocardial to subepicardial myocardial-perfusion reserve index is significantly lower in patients with syndrome X.[5]

Diagnostic Studies and Criteria for Diagnosis

  • Syndrome X is often a diagnosis of exclusion. The diagnostic criteria are as follows:

Treatment

The mainstay of treatment in patients with syndrome X are calcium channel blockers, such as nifedipine and diltiazem. Other therapies include:

  • Nitrates: Sublingual nitroglycerine is often not as effective in the patient with syndrome X as it is in the patient with obstructive epicardial disease, with only 42% of patients reporting relief.[10]
  • Beta blockers
  • Aminophylline: Evidence exists to suggest this therapy may be effective via inhibition of adenosine receptors.
  • Estrogen: Evidence exists to suggest this therapy may be effective in women.
  • Ranolazine: In a recent randomized, controlled trial of ranolzazine in women with syndrome X, ranolazine was found to be superior to placebo with respect to physical functioning (p = 0.046), angina stability (p = 0.008), and quality of life (p = 0.021). With respect to objective quantitative measure, ranolazine administration tended to be associated with higher (improved) CMR mid-ventricular MPRI (2.4 [2.0 minimum, 2.8 maximum] vs. 2.1 [1.7 minimum, 2.5 maximum], p = 0.074). Women with a coronary flow reserve (CFR) ≤ 3.0 achieved significantly greater improvement in MPRI on ranolazine versus placebo (Δ in MPRI 0.48 vs. -0.82, p = 0.04).[14]
  • Estrogen replacement therapy: ERT or selective ERT may reduce the frequency of chest pain in post menopausal women with syndrome X.[15]

ESC Guidelines for Investigation in Patients with Syndrome X (DO NOT EDIT)[16]

Class I
"1. Resting echocardiogram in patients with angina and normal or non-obstructed coronary arteries to assess for presence of ventricular hypertrophy and/or diastolic dysfunction. (Level of Evidence: C)"
Class IIb
"1. Intracoronary acetylcholine during coronary arteriography, if the arteriogram is visually normal, to assess endothelium-dependent coronary flow reserve, and exclude vasospasm. (Level of Evidence: C)"
"2. Intracoronary ultrasound, coronary flow reserve, or FFR measurement to exclude missed obstructive lesions, if angiographic appearances are suggestive of a nonobstructive lesion rather than completely normal, and stress imaging techniques identify an extensive area of ischaemia. (Level of Evidence: C)"

ESC Guidelines for Pharmacological Therapy to Improve Symptoms in Patients with Syndrome X (DO NOT EDIT)[16]

Class I
"1. Therapy with nitrates, beta blockers, and calcium channel blockers alone or in combination. (Level of Evidence: B)"
"2. Statin therapy in patients with hyperlipidaemia. (Level of Evidence: B)"
"3. ACE inhibitors in patients with hypertension. (Level of Evidence: C)"
Class IIa
"1. Trial of therapy with other anti-anginals including nicorandil and metabolic agents. (Level of Evidence: C)"
Class IIb
"1. Aminophylline for continued pain, despite Class I measures. (Level of Evidence: C)"
"2. Imipramine for continued pain, despite Class I measures. (Level of Evidence: C)"

References

  1. ↑ Bøtker HE, Sonne HS, Sørensen KE (1996) Frequency of systemic microvascular dysfunction in syndrome X and in variant angina. Am J Cardiol 78 (2):182-6. PMID: 8712140
  2. ↑ Buffon A, Rigattieri S, Santini SA, Ramazzotti V, Crea F, Giardina B et al. (2000) Myocardial ischemia-reperfusion damage after pacing-induced tachycardia in patients with cardiac syndrome X. Am J Physiol Heart Circ Physiol 279 (6):H2627-33. PMID: 11087214
  3. ↑ http://www.nejm.org/doi/full/10.1056/NEJM200210243471717
  4. ↑ 4.0 4.1 Huang MH, Sylvén C, Horackova M, Armour JA (1995). "Ventricular sensory neurons in canine dorsal root ganglia: effects of adenosine and substance P.". Am J Physiol. 269 (2 Pt 2): R318–24. PMID 7544544.
  5. ↑ 5.0 5.1 Panting JR, Gatehouse PD, Yang GZ, Grothues F, Firmin DN, Collins P; et al. (2002). "Abnormal subendocardial perfusion in cardiac syndrome X detected by cardiovascular magnetic resonance imaging". N Engl J Med. 346 (25): 1948–53. doi:10.1056/NEJMoa012369. PMID 12075055.
  6. ↑ 6.0 6.1 6.2 6.3 6.4 Katon W, Hall ML, Russo J, Cormier L, Hollifield M, Vitaliano PP; et al. (1988). "Chest pain: relationship of psychiatric illness to coronary arteriographic results". Am J Med. 84 (1): 1–9. PMID 3337115.
  7. ↑ Lagerqvist B, Sylvén C, Waldenström A (1992). "Lower threshold for adenosine-induced chest pain in patients with angina and normal coronary angiograms". Br Heart J. 68 (3): 282–5. PMC 1025071. PMID 1389759.
  8. ↑ Mukerji V, Beitman BD, Alpert MA, Lamberti JW, DeRosear L, Basha IM (1987). "Panic disorder: a frequent occurrence in patients with chest pain and normal coronary arteries". Angiology. 38 (3): 236–40. PMID 3565851.
  9. ↑ Chimenti C, Sale P, Verardo R, Cicalini S, Petrosillo N, Russo MA; et al. (2010). "High prevalence of intramural coronary infection in patients with drug-resistant cardiac syndrome X: comparison with chronic stable angina and normal controls". Heart. 96 (23): 1926–31. doi:10.1136/hrt.2010.196626. PMID 20889988.
  10. ↑ 10.0 10.1 10.2 10.3 10.4 10.5 10.6 10.7 10.8 Kaski JC, Rosano GM, Collins P, Nihoyannopoulos P, Maseri A, Poole-Wilson PA (1995). "Cardiac syndrome X: clinical characteristics and left ventricular function. Long-term follow-up study". J Am Coll Cardiol. 25 (4): 807–14. doi:10.1016/0735-1097(94)00507-M. PMID 7884081.
  11. ↑ Kemp HG, Kronmal RA, Vlietstra RE, Frye RL (1986). "Seven year survival of patients with normal or near normal coronary arteriograms: a CASS registry study". J Am Coll Cardiol. 7 (3): 479–83. PMID 3512658.
  12. ↑ Sestito A, Lanza GA, Di Monaco A, Lamendola P, Careri G, Tarzia P; et al. (2011). "Relation between cardiovascular risk factors and coronary microvascular dysfunction in cardiac syndrome X.". J Cardiovasc Med (Hagerstown). 12 (5): 322–7. doi:10.2459/JCM.0b013e3283406479. PMID 21135582.
  13. ↑ Dominguez-Rodriguez A, Abreu-Gonzalez P, Avanzas P, Gomez MA, Kaski JC (2010). "Elevated circulating soluble form of CD40 ligand in patients with cardiac syndrome X." Atherosclerosis. 213 (2): 637–41. doi:10.1016/j.atherosclerosis.2010.09.031. PMID 20980002.
  14. ↑ Mehta PK, Goykhman P, Thomson LE, Shufelt C, Wei J, Yang Y; et al. (2011). "Ranolazine improves angina in women with evidence of myocardial ischemia but no obstructive coronary artery disease". JACC Cardiovasc Imaging. 4 (5): 514–22. doi:10.1016/j.jcmg.2011.03.007. PMID 21565740.
  15. ↑ Chen YX, Luo NS, Lin YQ, Yuan WL, Xie SL, Nie RQ; et al. (2010). "Selective estrogen receptor modulators promising for cardiac syndrome X." J Postgrad Med. 56 (4): 328–31. doi:10.4103/0022-3859.70936. PMID 20935411.
  16. ↑ 16.0 16.1 Fox K, Garcia MA, Ardissino D, Buszman P, Camici PG, Crea F; et al. (2006). "Guidelines on the management of stable angina pectoris: executive summary: The Task Force on the Management of Stable Angina Pectoris of the European Society of Cardiology". Eur Heart J. 27 (11): 1341–81. doi:10.1093/eurheartj/ehl001. PMID 16735367.

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