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| {{Chronic stable angina}} | | __NOTOC__ |
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| {{CMG}} | | {{CMG}} |
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| ''The terms '''Syndrome X''' or '''Metabolic syndrome X''' may also be referring to [[metabolic syndrome]].''
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| '''''Synonyms and key words:''''' Microvascular angina
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| ==Overview== | | ==Overview== |
| '''(Cardiac) syndrome X''' is [[Angina pectoris|angina]] (chest pain) associated with objective evidence of myocardial ischemia in the absence of epicardial [[coronary artery disease]]. The disorder has been hypothesized to be a disorder of the coronary microvasculature rather than the large caliber epicardial coronary arteries.
| | Syndrome X may refer to [[cardiac syndrome X]], [[metabolic syndrome]] and single X syndrome, where an individual has a single X chromosome, typically described as [[Turner syndrome]]. The otherwise unidentifiable rare disease afflicting [[Brooke Greenberg]] and only about half a dozen other people in the world. |
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| ==Pathophysiology==
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| In a large percentage of patients, there is microvascular dysfunction. Specifically, the microvasculature cannot dilate to accomadate increased blood flow during exertion to meet the needs of myocardial metabolism.
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| Most likely the underlying pathophysiology is heterogenous, and multiple pathophysiologic mechanisms have been proposed with variable data to support them:
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| ===Adenosine as a Cause of Chest Pain===
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| 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>. In one study in which adenosine was infused, 95% of patients with Syndrome X had [[chest pain]] whereas only 40% of control patients experienced [[chest pain]] (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>
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| ===An Extension of Dysautonomias===
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| Syndrome X has been associated with [[dysautonomias]] and with a greater frequency of autonomic symptoms such as [[tachycardia]], [[dyspnea]], [[dizziness]], and [[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.
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| ==="Female Pattern" of Atherosclerosis===
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| It has also been speculated that although the coronary arteriogram may appear normal, there may in fact be diffuse atherosclerosis present in what has been termed "a female pattern" of disease.
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| ===Enhanced Pain Sensitivity===
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| 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>.
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| ===Panic Disorder===
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| 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>.
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| ==Epidemiology and Demographics==
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| 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>. Some studies have found an increased risk of other vasospastic disorders in syndrome X patients, such as [[migraine]] and [[Raynaud's phenomenon]].
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| ==Natural history, complications, and prognosis==
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| Syndrome X does not appear to be associated with an excess of major coronary events. In a longitudinal study of 99 patients with Syndorme X over 7 +/- 4 years, 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>. Symptoms did not change in about tho thirds of patients, they improved in 10% of patients, and they were worse in about a quarter 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>
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| The absence of significant coronary artery disease on coronary angiography is associated with a good prognosis. Among 3,136 patients with normal angiograms, the 7 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>.
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| ==Risk Factors==
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| 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>.
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| ==Other Conditions to Distinguish Syndrome X From==
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| 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]].
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| ==Diagnosis==
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| ===Symptoms===
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| All 99 patients with Syndrome X in one study had exertional angina, and 41 of them had 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). 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>.
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| ===Ambulatory Holter Monitoring===
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| Approximately two thirds of patients (64/99 in one study) will 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>.
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| ===Cardiac Magnetic Resonance Imaging (CMR)===
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| 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>.
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| ===Diagnostic Studies and Criteria for Diagnosis===
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| Syndrome X is often a diagnosis of exclusion. The diagnostic criteria are as follows:
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| *There must be evidence of [[myocardial ischemia]]: Diagnostic studies include an exercise [[ECG]], [[stress scintigraphy]], or [[stress echocardiography]] in conjunction with anginal chest discomfort.
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| * [[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.
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| * Abnormal [[Cardiac stress test]]: ST changes are typically similar to those of [[coronary artery disease]] and opposite of those with [[Prinzmetal's angina]]. Myocardial perfusion imaging can be abnormal in 30% of patients.
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| * [[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]] demonstrates the production of [[lactate]] by the [[myocardium]]. Intracoronary [[acetylcholine]] can be administered to evaluate endothelium-dependent [[coronary flow reserve]].
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| ===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>===
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| {{cquote|
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| ===Class I===
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| '''1.''' [[Chronic stable angina echocardiography|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)''
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| ===Class IIb===
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| '''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)''
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| '''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)''}}
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| ==Treatment==
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| The mainstay of treatment in patients with Syndrome X are [[calcium channel blocker]]s, such as [[nifedipine]] and [[diltiazem]]. Other therapies include:
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| *[[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>.
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| *[[Beta blockers]]
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| *[[Aminophylline]] - may be effective via inhibition of adenosine receptors.
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| *[[Estrogen]] - may be effective in women.
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| ===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>===
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| {{cquote|
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| ===Class I===
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| '''1.''' Therapy with [[nitrates]], [[beta blockers]], and [[calcium channel blockers]] alone or in combination. ''(Level of Evidence: B)''
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| '''2.''' [[Statin]] therapy in patients with [[hyperlipidaemia]]. ''(Level of Evidence: B)''
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| '''3.''' [[ACE inhibitors]] in patients with [[hypertension]]. ''(Level of Evidence: C)''
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| ===Class IIa===
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| '''1.''' Trial of therapy with other anti-anginals including nicorandil and metabolic agents. ''(Level of Evidence: C)''
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| ===Class IIb===
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| '''1.''' [[Aminophylline]] for continued pain, despite Class I measures. ''(Level of Evidence: C)''
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| '''2.''' Imipramine for continued pain, despite Class I measures. ''(Level of Evidence: C)''}}
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| ==References== | | ==References== |
| {{reflist|2}} | | {{reflist|2}} |
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| ==Review Articles==
| | {{WH}} |
| *[http://heartdisease.about.com/cs/coronarydisease/a/CSX.htm Cardiac Syndrome X]
| | {{WS}} |
| *[http://www.texasheartinstitute.org/HIC/Topics/Cond/CardiacSyndromeX.cfm Texas Heart Institute]
| | [[Category:Disease]] |
| *[http://content.nejm.org/cgi/content/full/347/17/1377 New England Journal of Medicine Editorials]
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| {{Circulatory system pathology}} | |
| {{SIB}} | |
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| [[Category:Ailments of unknown etiology]] | |
| [[Category:Cardiology]] | | [[Category:Cardiology]] |
| [[Category:Disease state]]
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| [[Category:Ischemic heart disease]]
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| [[Category:Mature chapter]]
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