Syndrome X and Microvascular Coronary Dysfunction
2011; Lippincott Williams & Wilkins; Volume: 124; Issue: 13 Linguagem: Inglês
10.1161/circulationaha.110.974212
ISSN1524-4539
AutoresC. Noel Bairey Merz, Carl J. Pepine,
Tópico(s)Coronary Interventions and Diagnostics
ResumoHomeCirculationVol. 124, No. 13Syndrome X and Microvascular Coronary Dysfunction Free AccessCase ReportPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissionsDownload Articles + Supplements ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toSupplementary MaterialsFree AccessCase ReportPDF/EPUBSyndrome X and Microvascular Coronary Dysfunction C. Noel Bairey Merz, MD and Carl J. Pepine, MD C. Noel Bairey MerzC. Noel Bairey Merz From the Women's Heart Center, Cedars-Sinai Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA (C.N.M.B.), and the Division of Cardiovascular Medicine, University of Florida, Gainesville, FL (C.J.P.). and Carl J. PepineCarl J. Pepine From the Women's Heart Center, Cedars-Sinai Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA (C.N.M.B.), and the Division of Cardiovascular Medicine, University of Florida, Gainesville, FL (C.J.P.). Originally published27 Sep 2011https://doi.org/10.1161/CIRCULATIONAHA.110.974212Circulation. 2011;124:1477–1480Case presentation: A 44-year-old woman is referred for worsening chest pain since 2007, with abnormal stress testing in May 2008, followed by coronary angiography in June 2008. She had several prior hospitalizations to evaluate possible myocardial infarction, and 1 with an elevated troponin level in 2001. She has a history of breast cancer in 2007. She currently reports daily exertional substernal chest pain that radiates to her left arm and hand that is relieved with rest. She works as an undercover police officer, frequently has to chase suspects, and is concerned about being able to do her job. A review of cardiac risk factors is negative. She takes tamoxifen with vitamins, and her physical examination and resting ECG are normal. Review of the prior coronary angiography confirms absence of obstructive coronary artery disease and normal left ventricular function.To further evaluate the basis for her symptoms, she underwent coronary reactivity testing (CRT), which demonstrated a limited coronary flow reserve (CFR) to adenosine and coronary blood flow reserve (Figure 1) as well as coronary artery constriction with acetylcholine, indicative of endothelial dysfunction (Figure 2). Adenosine stress cardiac magnetic resonance imaging was consistent with microvascular coronary dysfunction (MCD; Figure 3).Download figureDownload PowerPointFigure 1. Intracoronary Doppler blood flow velocity waveforms in response to intracoronary adenosine and acetylcholine. Coronary flow reserve (CFR) is the ratio of average peak velocities before and after adenosine. Coronary blood flow (CBF) reserve is the ratio of average peak CBF before and after acetylcholine.Download figureDownload PowerPointFigure 2. Intracoronary acetylcholine (ACH) demonstrating constriction of the coronary arteries (arrow) and intracoronary nitroglycerin (NTG) coronary angiography demonstrating dilation.Download figureDownload PowerPointFigure 3. Adenosine stress perfusion base-ventricle cardiac magnetic resonance imaging (left) and rest perfusion base-ventricle cardiac magnetic resonance imaging (right). Arrows indicate areas of reduced myocardial perfusion, worsened during stress (left).MCD Is a High-Risk Subset of Cardiac Syndrome XManagement of patients with angina and evidence of myocardial ischemia on stress testing without obstructive coronary artery disease by angiography (previously referred to as cardiac syndrome X, or CSX) is a challenge. Patients with this syndrome may have persistent chest pain, evidence of angina, and ischemic-type ST-segment depression or noninvasive perfusion or wall-motion abnormality during stress testing. Common knowledge based on early reports suggested a benign prognosis; however, data from the National Heart, Lung, and Blood Institute (NHLBI)–Women's Ischemia Syndrome Evaluation (WISE) document that up to 50% of these patients may have MCD, which is associated with an adverse prognosis.1 On the basis of the WISE experience,1 the largest and most completely investigated cohort with midlife women and this syndrome, patients with MCD frequently have atherosclerosis on intravascular coronary ultrasound2 and face a 2.5% annual adverse cardiac event rate, which includes myocardial infarction, stroke, hospitalization for congestive heart failure, and sudden cardiac death.3,4 Thus, MCD appears to be a high-risk subgroup within CSX.In the absence of obstructive coronary artery disease, the small arteries and arterioles downstream from epicardial coronary arteries are the major sites of resistance to myocardial blood flow. The structure and function of these microvessels have a role in myocardial perfusion and its regional distribution within the myocardium and transmurally. Microvascular dysfunction may include the following, alone or in combination: (1) Altered resting vascular smooth muscle tone secondary to either endothelial or smooth muscle cell dysfunction; (2) altered responses to constrictor or dilator stimuli; (3) reduced number of arterioles and capillaries (eg, rarefaction); and (4) structural alterations that contribute to decreased lumen size, increased wall-to-lumen ratio, increased stiffness, and remodeling. Myocardial capillary rarefaction has been described in dilated cardiomyopathy5 and cardiac transplant vasculopathy6 and is present in noncardiac vessels in both hypertension7 and CSX.8 Recently, it has been shown that vascular smooth muscle cells have a profound influence on endothelial cell biology, which suggests a regulatory interaction not previously appreciated.9 Coronary microcirculation abnormalities are important prognostic determinants in acute and chronic coronary syndromes,10 as well as diabetes, hypertrophic cardiomyopathy, and transplant coronary vasculopathy,11 and in CSX from our studies in the WISE.4Invasive Diagnosis of MCDTherapeutic success hinges on diagnostic certainty. For risk stratification and planning an optimal management strategy, CRT with intracoronary infusions of adenosine, acetylcholine, and nitroglycerin to assess microvascular and macrovascular (epicardial) endothelial and nonendothelial function should be considered in subjects with signs and symptoms of ischemia when no obstructive coronary artery disease is found. With a standard adenosine-Doppler wire protocol, as is used for CFR measurement,12 quantitative and qualitative coronary angiography, and intracoronary acetylcholine and nitroglycerin,3 possible mechanistic pathways for MCD can be assessed.12 The benefit of this diagnostic testing probably outweighs the risk of diagnostic uncertainty and absence of risk reduction therapy.4 However, potentially serious complications such as coronary artery dissection can occur, so CRT should be performed only by experienced interventional cardiologists in appropriate at-risk subjects. It is also important to understand that CFR, the principal non–endothelium-dependent CRT measure, is influenced by myocardial oxygen demand. Therefore, measures of CFR must account for heart rate, blood pressure, and left ventricular filling pressure and contractility.13Our patient has evidence of endothelial dysfunction of her epicardial coronaries (eg, constriction to acetylcholine). This dysfunction likely extends to the microvasculature, and she also has evidence of arteriolar dysfunction (eg, low CFR with adenosine). Her epicardial coronary dilator response to exogenous nitroglycerin appears normal.Noninvasive Diagnosis of MCDAlthough evidence of abnormal myocardial perfusion secondary to abnormal CRT can be detected noninvasively by single-photon emission computed tomography, positron emission testing, and stress cardiac magnetic resonance imaging,1 the sensitivity and specificity of these measures remain incompletely characterized. The reference standard for diagnosis of MCD remains the invasive CRT. An ongoing NHLBI-sponsored WISE Ancillary Study is investigating the utility of cardiac magnetic resonance imaging for diagnosis and prognosis (risk assessment) of MCD in women.14 If preliminary reports14–16 are confirmed, cardiac magnetic resonance imaging will be the only method currently applicable for clinical use to evaluate the transmural distribution (eg, endocardial versus epicardial) of coronary blood flow.Treatment of CSX and MCDCurrent angina/CSX guidelines do not specifically address MCD.17,18 Treatment should focus on 2 main goals: (1) Antiatherosclerosis and antiischemia therapy to reduce adverse cardiac event risk and (2) relief of angina to improve quality of life. Because of the high prevalence of coronary atherosclerosis and adverse prognosis observed in these subjects, we also incorporate the National Cholesterol Education Program expert panel's guidelines (Adult Treatment Panel III)19 for therapeutic lifestyle change,20 low-dose aspirin, and statin therapy in these patients as coronary heart disease equivalents.Trial evidence supports use of β-blockers, angiotensin-converting enzyme inhibitors, nitrates, calcium antagonists, ranolazine, xanthine derivatives such as aminophylline, enhanced external counterpulsation, cognitive behavioral therapy, low-dose tricyclic antidepressants, and neurostimulation to improve angina symptoms, stress test parameters, and endothelial function (Table). Notably, the α-blocker doxazosin is not beneficial, and its association with increased stroke and heart failure risk in ALLHAT (the Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial) should exclude this agent even if the woman has hypertension. Low-dose hormone therapy1 does not appear to be effective, and l-arginine supplementation had an adverse effect in postmyocardial infarction patients, despite improving signs and symptoms in a CSX population. Diltiazem fails to improve CFR in these patients. However, β-blockers consistently demonstrate superiority over nitrates and calcium antagonists in randomized clinical trials. An exploratory WISE Ancillary Trial testing sildenafil in this patient group suggested improved CFR.Table. Treatment of Subjects With Angina, Evidence of Myocardial Ischemia, and No Obstructive Coronary Artery DiseaseMicrovascular coronary dysfunctionAbnormal endothelial function Angiotensin-converting enzyme inhibitors Statins l-Arginine supplementation Aerobic exercise Enhanced external counterpulsationAbnormal nonendothelial function β-blockers/α-β-blockers NitratesAntianginal/antiischemic Ranolazine Xanthine derivativesAbnormal smooth muscle function (Prinzmetal angina) Calcium antagonists NitratesAbnormal cardiac nociception Low-dose tricyclic medication Spinal cord stimulation Cognitive behavioral therapyReprinted from Mehta and Merz20 with permission.ConclusionsAmong subjects with CSX, defined as persistent chest symptoms that suggest angina, evidence of ischemia, and no obstructive coronary artery disease, MCD is highly prevalent and is associated with an adverse prognosis. CRT remains the reference standard for diagnosis; noninvasive testing for MCD is currently under investigation and appears promising. Therapeutic lifestyle change, low-dose aspirin, and lipid-lowering therapy are recommended because of the high prevalence of coronary atherosclerosis and elevated risk of adverse cardiovascular events. Limited trial evidence suggests that use of antiischemia and antianginal therapy, most consistently with β-blockers, may improve symptoms, stress test parameters, and endothelial and/or microvascular coronary function. Although large outcome trials are being planned in MCD subjects, sufficient but evolving data exist to incorporate specific recommendations for this population into existing angina and acute coronary syndrome guidelines. Key points for the clinician include recognition of ischemia and deployment of guideline-endorsed therapy for angina and reduction of cardiac risk factors.Case Follow-Up and DispositionThe patient was prescribed simvastatin 40 mg by mouth every day, aspirin 81 mg by mouth every day, carvedilol 6.25 mg by mouth twice daily, and sublingual nitroglycerin 0.4 mg as needed and before physical exertion. At 2-year follow-up, she reports decreased symptoms, has maintained her job, and has had no further hospitalizations for angina or suspected acute coronary syndrome.Sources of FundingThis work was supported by contracts from the NHLBI (Nos. N01-HV-68161, N01-HV-68162, N01-HV-68163, and N01-HV-68164); a General Clinical Research Centers grant (MO1-RR00425) from the National Center for Research Resources; and grants from the Gustavus and Louis Pfeiffer Research Foundation, Denville, NJ, the Women's Guild of Cedars-Sinai Medical Center, Los Angeles, CA, the Edythe L. Broad Women's Heart Research Fellowship, Cedars-Sinai Medical Center, Los Angeles, CA, and the Barbra Streisand Women's Cardiovascular Research and Education Program, Cedars-Sinai Medical Center, Los Angeles, CA. Dr Pepine is supported by NIH/NHLBI grants 5 U01 HL087366-04, 5 R01 HL091005-03, 5 R01 HL090957-03, and 2 U01 GM074492-06; NIH/AG (National Institute on Aging) grant 3 U01 AG022376-05A2S1; and NIH/National Center for Research Resources grant 5 UL1 RR029890-02.DisclosuresDr Bairey Merz has received research grants from the WISE (NIH/NHLBI5 R01 HL090957); honoraria from the WomenHeart Coalition, Los Robles Medical Center, Monterey Community Hospital, Pri-med, Los Angeles OB-GYN Society, and the North American Menopause Society; and consulting fees from the NHLBI. Dr Pepine has received research grants from WISE (NIH/NHLBIU01 HL6489 and NIH/NHLBI5 R01 HL090957).FootnotesCorrespondence to C. 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September 27, 2011Vol 124, Issue 13 Advertisement Article InformationMetrics © 2011 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.110.974212PMID: 21947935 Originally publishedSeptember 27, 2011 PDF download Advertisement SubjectsAtherosclerosisChronic Ischemic Heart DiseaseComputerized Tomography (CT)Congenital Heart DiseaseCoronary CirculationEndothelium/Vascular Type/Nitric OxideHypertensionImaging
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