Microvascular angina

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Microvascular angina

  1. 1. Cardiac Syndrome X Microvascular angina
  2. 2. Cardiac syndrome X Heart 2007;93:159–166 • Cardiac syndrome Xとは, 狭心痛や労作時のST低下を認めるが,  CAGでは正常で他に心疾患, 全身疾患(DM, HT等)を認めない病態. • 血管機能異常が原因と考えられており, 現在では冠血管のなかのMicrovascularの障害が原因とされ, Microvascular anginaという名前もついている. • 現在では他の全身疾患を認めない項目が無くなり, 『CAGで正常な狭心痛を来す疾患』という概念で語られていることも多い また, Microvascularの異常がない例もある.
  3. 3. • 現在のCSXの定義は以下の通り • 典型的な安定狭心症, 特に労作時に多い. • 心筋虚血や冠動脈の Microvascularの障害が検査で示唆. • • • Table 1 Proposed definition of cardiac syndrome X l Typical stable angina, exclusively or predominantly induced by effort l Findings compatible with myocardial ischaemia/coronary microvascular dysfunction on diagnostic investigation* l Normal (or near normalÀ) coronary arteries at angiography l Absence of any other specific cardiac disease (for example, variant angina, cardiomyopathy, valvular disease) *Including one or more of (1) diagnostic ST segment depression during spontaneous or stress-induced typical chest pain; (2) reversible perfusion defects on stress myocardial scintigraphy; (3) documentation of stressrelated coronary blood flow abnormalities by more advanced diagnostic techniques (for example, cardiac magnetic resonance (MR), positron emission tomography (PET) or Doppler ultrasound); (4) metabolic evidence of transient myocardial ischaemia (cardiac PET or MR, invasive assessment). ÀVascular wall irregularities or discrete very mild stenosis (,20%) in epicardial vessels at angiography. Heart 2007;93:159–166 mechanisms. This is not surprising, however, as up to 15–20% CAGで正常, 狭窄を認めない(20%未満の狭窄も含む) CAD also have no apparent risk of patients with obstructive factor. A further point of the proposed definition of CSX concerns patients with minor atherosclerotic lesions (that is, irregula他に同様の症状を来す心疾患を認めない mild stenosis of , 20%) in epicardial vessels at rities or very these by the (Variant angina, 心筋症, 弁膜症等) angiography. The inclusion ofcannotpatients is justified angina fact that these abnormalities be responsible for symptoms, that some degree of coronary atherosclerosis may also be found by intracoronary ultrasound imaging in a proportion of patients with classic CSX,3 and that their clinical outcome seems similar to that of patients with classic CSX. Finally, it should be stressed that coronary microvascular abnormalities may be involved in angina syndromes other than CSX, including angina after successful percutaneous coronary interventions, microvascular vasospastic203 January 26; 5(): -7 World J Cardiol angina and some cases of non-ST elevation acute coronary syndromes with normal VSA患者では, 冠動脈の内皮障害が認められるが, Microvascularは保たれており, VSAとCSXは異なる病態.
  4. 4. • 典型例は閉経後女性の狭心痛; CSXの70%が女性例. 40-50歳台が好発年齢. • 2776 primary CMVD according to the mode of presentation, i.e. either as an acute (unstable) or chronic (stable) angina. This may help in distinguishing pathogenic mechanisms and perhaps identifying patients with different clinical outcomes.25 The challenge, however, remains to identify aetiologicAugust and specific triggers Trends Cardiovasc Med. 2012 factors ; 22(6): 161–168 (Table 4). 虚血性心疾患疑いでCAGを行った患者の内, 男性例の8%, 女性例の41%がCAG正常であった報告もある. • Microvascular dysfunctionでは以下に分類される Table 2 Modified clinical classification of coronary microvascular dysfunction CMVD Definition Type 1 Primary, i.e. in the absence of structural heart disease Type 2 In the presence of cardiomyopathies (incl. LVH, HCM, DCM, amyloidosis) Type 3 In the presence of obstructive CAD (incl. ACS) Type 4 Type 5 After coronary interventions After cardiac transplantation ................................................................................ ................................................................................ Modifiers Duration Symptoms Therapy European Heart Journal (2012) 33, 2771–2781 Acute or chronic Asymptomatic or symptomatic None, minimal, moderate, or maximal level ACS, acute coronary syndrome; DCM, dilated cardiomyopathy; HCM, hypertrophic cardiomyopathy; LVH, left ventricular hypertrophy.
  5. 5. Microvascular障害の機序 Heart 2007;93:159–166 • 血管内皮 依存性, 非依存性の血管拡張能の障害が認められる • 糖尿病や高血圧等は血管内皮 依存性血管拡張の障害に強く関与. 他には耐糖能障害, 閉経後(エストロゲン欠乏), 軽度の炎症反応, 高脂血症も関与する. • 血管内皮の異常では拡張障害を生じるだけではなく, ET-1の過剰産生による血管収縮の亢進も合併する. CSXの患者群ではET-1の血中濃度が高いとの報告もある. • 交感神経系にも異常を来たし, MIBGシンチでは取り込みが低下する  → 心筋におけるノルアドレナリンの作用異常が示唆.
  6. 6. Cardiac syndrome X 163 • • • • Traditional CV risk factors Insulin resistance Low grade inflammation Oestrogen deficiency (women) • • • • Endothelial dysfunction Abnormal adrenergic function Hypertension Other CV risk factors? Abnormal NHE activity Smooth muscle cell dysfunction Impaired vasodilation Increased vasoconstriction Coronary microvascular dysfunction Figure 4 Scheme of the main pathogenetic mechanisms and functional abnormalities that may variably contribute to microvascular dysfunction in patients with cardiac syndrome X, according to data reported in the medical literature. CV, cardiovascular; NHE, Na+/H+ exchanger. variability of the pathophysiological mechanisms responsible for the syndrome. (1) the clinical observation that recurrent chest pain is usually the only kind of pain these patients have; (2) evidence that abnormal pain sensitivity is confined Heart 2007;93:159–166 to the heart32–34; and (3)
  7. 7. CSX患者では心臓の痛覚も亢進 Heart 2007;93:159–166 • CSX患者と健常人でカテーテルや薬剤刺激を行い, 狭心痛を誘発すると, • CSX患者で有意に 痛感受性が亢進しているとの結果がでている. 明らかな心筋虚血がなくとも血管収縮を来す薬剤で狭心痛を生じる. • 心臓以外の体表の痛覚も亢進している.
  8. 8. Heterogeneous causes Microvascular dysfunction Myocardial ischaemia Cardiac nerve dysfunction Unknown causes Efferent, sympathergic Afferent, nociceptive Cardiac MIBG defects Abnormal cardiac pain sensitivity Figure 5 Possible relations between microvascular dysfunction and cardiac nerve ending abnormalities in cardiac syndrome X (CSX). Microvascular dysfunction in patients with CSX may cause repeated episodic reduction of coronary blood flow, which may induce alterations in both efferent and afferent cardiac nerve fibres. The abnormal efferent adrenergic function can be indicated by the reduced uptake of meta-121iodobenzylguanidine (MIBG) by the heart, whereas abnormalities in afferent cardiac fibres may lead to increased generation and transmission of pain signals (increased cardiac pain perception). Abnormal activity of adrenergic fibres may, in turn, influence microvascular function. Pathological mechanisms different from microvascular dysfunction, however, may be responsible for primary cardiac nerve abnormalities, leading to the same clinical picture. Adapted from Lanza.36 casual independent occurrence of both abnormalities in the same patient. It should be stressed that in patients with CSX with increased cardiac pain sensitivity, stimuli other than • also cause angina cardiacOn the other hand, ischaemia may pain. increased cardiac nociception can also be the only cause of angina-like symptoms in some patients with chest pain and normal coronary arteries, such as the few patients who develop chest pain in relation to intermittent left bundle branch block. In these patients several stimuli, including the physiological cardiac release of adenosine during exercise, may cause chest pain. These patients can be identified by the failure to find any towards CSX. These, in particular, are a prolonged (. 15– 20 min) dull persistence of chest discomfort after resolution of typical chest pain induced by exercise and a lack of response, or a slow or incomplete response, to administration of shortacting nitrates to relieve pain, both features occurring in about 50% of patients.37 Among diagnostic stress tests, the careful analysis of abnormal exercise and stress scintigraphic results also does not usually help to identify patients with CSX. In contrast, the induction of typical, often severe angina during echocardiographic stress test (for example, Heart 2007;93:159–166 with dipyridamole or Microvascularの障害から心臓神経の異常を来たし, 痛覚過敏となる説がある.
  9. 9. 心筋虚血のアセスメント Heart 2007;93:159–166 • 労作時のST低下の検出が有用. 労作時以外にもAtrial pacing, 虚血誘発薬剤でも生じる. Holter心電図でもしばしば検出可能とされる. • ストレス心筋シンチでは可逆性の証明もでき, CSX患者の50~90%異常で陽性となる. • 同様にドブタミン負荷におけるGa造影心臓MRIでも 162 労作時の心筋虚血の検出が可能. Lanza Figure 2 Evidence of subendocardial septal perfusion defect (panel A, arrow) at peak dobutamine infusion (40 mg/kg/min) and its absence at rest (panel B) on gadolinium cardiac magnetic resonance in a patient with cardiac syndrome X. No abnormalities in left ventricular function were detectable.
  10. 10. Microvascularが保たれた前壁 塞のCAG, MRI, perfusion echo所見;  Microvascularによるmyocardial blushが認められ(D),  エコーでは中隔の心膜下の造影効果と25-50%の壁肥厚あり  Perfusion echoでは正常. European Heart Journal (2012) 33, 2771–2781
  11. 11. Figure 3 Illustration of two cases of anterior myocardial infarction with the restoration of blood flow in the left anterior descending artery (A – C, upper and lower panel). In the presence of microvascular integrity, the following can be seen: myocardial blush grade 3 (D, upper panel) a lack of oedema, homogeneous myocardial perfusion, subendocardial anteroseptal enhancement of 25– 50% wall thickness on magnetic resonance imaging (MRI, E – G, upper panel) and normal perfusion on myocardial contrast echocardiography (MCE, H, upper panel). On the contrary, in the setting of coronary microvascular impairment, myocardial blush is poor (D, lower panel) along with a large area of oedema, an anteroseptal perfusion defect and extensive delayed enhancement with microvascular obstruction on MRI (E – G, lower panel), and a large perfusion defect on MCE (H, lower panel). Modified from Porto et al.112 Used with the permission of Elsevier. Microvascularが破綻した前壁 塞のCAG, MRI, perfusion echo所見;  Microvascularによるmyocardial blushが消失(D)し, 浮腫を認める  中隔の造影障害とエコーでの還流障害が認められる. European Heart Journal (2012) 33, 2771–2781
  12. 12. Table 1 Modalities to assess coronary microvascular function Method Tracer Primary parameter Secondary parameter Microvascular distinction Endothelial Pros assessment Cons ............................................................................................................................................................................................................................................. PET101 Radioisotopes MBF (0.6–1.3 mL/min/g) MBF reserve (.2 –2.5) No No Validated and reproducibility Limited availability, radioactivity SPECT Radioisotopes Perfusion (no defect) (Perfusion reserve) No No Availability, low costs MBF only with dynamic upgrade, radioactivity MDCT102 Iodine contrast MBF (0.9–1.3 mL/min/g) MBF reserve (.2 –2.5) No No Availability Investigational, image quality, radiation MRI103 Gadolinium MBF (0.7–1.1 mL/min/g) MBF reserve (.2 –2.5) No No One-stop test, no radiation or radioactivity Investigational, technical limitations MCE104 Echo contrast Perfusion, MBF option (0.5–2.9 mL/min/g) MBF reserve option (.2–2.5) No No One-stop test, no radiation or radioactivity Volumetric modelling, image quality Doppler echo 105 Echo contrast Flow velocity (24–36 cm/s) Flow reserve (.2– 2.5) No No One-stop test, no radiation or radioactivity No MBF option, position and image dependent TFC8 Iodine contrast Contrast flow velocity (18–24) TFC reserve (.2 –2.5) Assumed if no epicardial dx No Ease of use, low cost No CBF option, subjectivity MBG4 Iodine contrast Contrast staining (Grade 3) None Assumed if no epicardial dx No Ease of use, low cost No CBF option, subjectivity ICD106 None Flow velocity (10–22 cm/s) (relative) flow velocity reserve Assumed if no epicardial dx Yes Direct measurement No CBF option, invasiveness ICD +QCA/ IVUS 107 Iodine contrast CBF (44–59 mL/min) CBF reserve (.2 –2.5) Yes Yes Complete assessment Costs, invasiveness TPS108 Saline IMF (15–22 U) None Yes Yes Complete assessment Costs, invasiveness PET, positron emission tomography; SPECT, single photo emission computed tomography; MDCT, multi-detector computed tomography; MRI, magnetic resonance imaging; MCE, myocardial contrast echocardiography; TFC, TIMI frame count; MBG, myocardial blush grade; ICD, intracoronary Doppler; QCA, quantitative coronary angiography; IVUS, intravascular ultrasound; TPS, temperature and pressure sensor; MBF, myocardial blood flow (mL/time/myocardial mass); CBF, coronary blood flow (mL/time unit). European Heart Journal (2012) 33, 2771–2781
  13. 13. CSXの予後 Heart 2007;93:159–166 • 長期予後を評価したStudyは未だ無く, そもそも診断自体が難しい. • 分かっている範囲では, ACSへ移行する可能性は非常に低く, 予後は良好と言われている.
  14. 14. CSXの治療 Heart 2007;93:159–166 • CSXではACSリスクの上昇は無いため, 治療の目的は症状の緩和にある. • β阻害薬, 非ジヒドロピリジン系のCa-ch阻害薬 (ベラパミル, ジルチアゼム)が1st choiceとなる. • ジヒドロピリジン系のCCB, 長期作用型硝酸薬は2nd lineとして追加.
  15. 15. ting. Obviously, the extent of underlying CAD plays an importprognostic role. This holds true also for the much-debated ity of PMI, and no study so far has evaluated the differential ognostic impact of PMI due to side-branch occlusion (type I or oximal type) or microcirculatory impairment (type II or distal e).45,46 For this reason, the prognostic implications of CMVD he setting of PCI remain uncertain. 診断∼治療まで ardiomyopathy patients with dilated cardiomyopathy, a severely (.60%) uced hyperaemic MBF response to dipyridamole increases the ative risk of death and heart failure development or progression times, independent of other factors such as the degree of LV function and the presence of overt heart failure.103 Likewise, abnormal CFR (,2) and lack of inotropic reserve in response dipyridamole were independent predictors of survival in ients with idiopathic DCM (adjusted harzard ratios 2.8 and respectively).104 Importantly, the prognostic merit of severe R impairment in heart failure is independent of CAD and the isemic burden and is evident in both ischaemic and nonhaemic cardiomyopathy.105 n hypertrophic obstructive cardiomyopathy, the MBF response dipyridamole potently predicts symptomatic progression to HA class III and IV and life-threatening ventricular arrhythmias uiring ICD placement and is an independent mortality predict106 Especially those patients with the lowest MBF response are mingly at the highest risk (adjusted hazard ratio 10 for cardiocular mortality and 20 for all cardiovascular events), which in becomes apparent not immediately but during long-term ow-up (i.e. 6 years). Interestingly, these patients also had a European Heart Journal (2012) 33, 2771–2781 Figure 5 Although the discussion of management strategies is beyond the scope of the present manuscript, this figure shows a flow chart outlining a suggested algorithm for the management of patients with chest pain despite angiographically normal coronary arteries, in whom the underlying mechanism is coronary microvascular dysfunction. ACS, acute coronary syndrome; CAD, coronary artery disease; CFR, coronary flow reserve; CV, cardiovascular; ETA, endothelin-type A receptor; IMR, index of microvascular resistance; IVUS, intravascular ultrasound; MBF, myocardial blood flow.

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