心肌微循环障碍评估方法的研究进展

近年来冠心病发病率和死亡率呈逐年上升趋势，随着经皮冠状动脉介入治疗的普及和冠脉慢血流现象的认识，心肌微循环障碍日益受到临床医生的关注。目前评估心肌微循环障碍的方法主要有冠状动脉血流储备分数、心肌声学造影、心肌磁共振成像及冠脉微循环阻力指数（IMR）,但上述方法各有一定的局限性，部分指标特异性及敏感性有待于询证医学的进一步验证，本文对心肌微循环障碍的评估方法及研究进展做一综述。     

心脏磁共振在冠状动脉微循环障碍评估中的应用进展

冠状动脉微循环障碍指冠状动脉微循环的结构或功能异常所导致的冠状动脉血流储备降低,其是未来发生不良心血管事件的强预测因子。冠脉微循环的结构、功能完整性对存活心肌的恢复和永久性损伤的防止具有重要的意义。心脏磁共振近来被认为是无创评估心肌微循环功能的金标准,其无辐射、无衰减,具有良好的空间分别率及动态追踪对比剂分布的特点,有很好的发展潜力。     

Effect of estradiol-drospirenone hormone treatment on myocardial perfusion reserve in postmenopausal women with angina pectoris

Recent randomized clinical studies failed to show cardiovascular protection with postmenopausal hormone therapy (HT), instead raising widespread concerns about possible increased cardiovascular risk. However, these studies primarily assessed the combination of conjugated equine estrogen and medroxyprogesterone acetate, which is suspected to abolish the beneficial effects of estrogen on the microcirculation. This preliminary study evaluated the effects of HT combining 17beta-estradiol (E2) with a new progestin, drospirenone, on myocardial perfusion reserve, a surrogate marker of coronary function. In this double-blind randomized study, 56 postmenopausal women with angina pectoris received oral E2 1 mg plus drospirenone 2 mg or placebo for 6 weeks. Myocardial perfusion reserve was measured using radioactive oxygen-labeled water and positron emission tomography before and after therapy. Myocardial perfusion reserve increased significantly in the E2-drospirenone group after 6 weeks versus placebo (p<0.0008). Mean myocardial perfusion reserve increased from 4.83 at baseline to 5.13 after 6 weeks in the E2-drospirenone group (n=27), but decreased from 4.84 to 4.13 in the placebo group (n=29). No significant side effects were observed with E2-drospirenone. A larger trial is needed to investigate whether myocardial perfusion improvements will be sustained and translate into a clinical benefit in postmenopausal women at risk of coronary heart disease. In conclusion, E2-drospirenone HT for 6 weeks has favorable effects on myocardial function in postmenopausal women with angina pectoris. These data suggest that drospirenone has the desired progestin actions on the endometrium, but does not abolish the beneficial effects of estradiol on cardiac microcirculation.     

Positron emission tomography to assess the haemodynamics of the coronary circulation.

Positron emission tomography (PET) allows the non-invasive measurement of absolute myocardial blood flow (ml/min/g of myocardium) in man. This has made possible the measurement of myocardial blood flow and the coronary vasodilator reserve (an index of the ability of the coronary microcirculation to dilate) in healthy volunteers to establish the normal values and ranges of these parameters. This technique allows the assessment of the functional significance of epicardial coronary stenoses as well as the investigation of the function of the coronary microcirculation in patients with and without coronary artery disease.     

Myocardial perfusion echocardiography and coronary microvascular dysfunction

Our understanding of coronary syndromes has evolved in the last two decades out of the obstructive atherosclerosis of epicardial coronary arteries paradigm to include anatomo-functional abnormalities of coronary microcirculation. No current diagnostic technique allows direct visualization of coronary microcirculation, but functional assessments of this circulation are possible. This represents a challenge in cardiology. Myocardial contrast echocardiography (MCE) was a breakthrough in echocardiography several years ago that claimed the capability to detect myocardial perfusion abnormalities and quantify coronary blood flow. Research demonstrated that the integration of quantitative MCE and fractional flow reserve improved the definition of ischemic burden and the relative contribution of collaterals in non-critical coronary stenosis. MCE identified no-reflow and low-flow within and around myocardial infarction, respectively, and predicted the potential functional recovery of stunned myocardium using appropriate interventions. MCE exhibited diagnostic performances that were comparable to positron emission tomography in microvascular reserve and microvascular dysfunction in angina patients. Overall, MCE improved echocardiographic evaluations of ischemic heart disease in daily clinical practice, but the approval of regulatory authorities is lacking.     

Coronary physiology revisited : practical insights from the cardiac catheterization laboratory

Various coronary physiological measurements can be made in the cardiac catheterization laboratory using sensor-tipped guidewires; they include the measurement of poststenotic absolute coronary flow reserve, the relative coronary flow reserve, and the pressure-derived fractional flow reserve of the myocardium. Ambiguity regarding abnormal microcirculation has been reduced or eliminated with measurements of relative coronary flow reserve and fractional flow reserve. The role of microvascular flow impairment can be separately determined with coronary flow velocity reserve measurements. In addition to lesion assessment before and after intervention, emerging applications of coronary physiology include the determination of physiological responses to new pharmacological agents, such as glycoprotein IIb/IIIa blockers, in patients with acute myocardial infarction. Measurements of coronary physiology in the catheterization laboratory provide objective data that complement angiography for clinical decision-making.     

Coronary autoregulation and optimal myocardial oxygen utilization

The complex relationship among myocardial contractility, preload, afterload, and coronary autoregulation was studied using both analytical and numerical methods. To study autoregulation and coronary reserve changes in response to changes in cardiac oxygen consumption and in arterial pressure generation, a new variable was introduced: myocardial resistance to oxygen flow ( ). This variable was defined as the ratio of the coronary driving pressure to left-ventricular oxygen uptake. High values for this variable indicate small consumption relative to the generated aortic pressure. Conditions which produce the highest obtainable value for are considered as optimal. An expression relating to ventricular hemodynamic variables was developed and studied using a mathematical model of the cardiovascular system. The model included a mechanism of local autoregulation based on the assumption that, in steady state, the amount of oxygen consumed equals the amount extracted from coronary blood. Heart rate, peripheral resistance, end-diastolic volume, and myocardial contractility were varied while the coronary circulation was adjusted to meet ventricular oxygen consumption at each state. The model predicts that, for each state of the circulation, there is an optimal level of cardiac contractility for which the coronary reserve is maximized.     

腺苷对心血管系统的作用及在评价冠心病中的应用

腺苷是一种较强的血管扩张剂 ,对心血管系统有多重作用。其与导管技术、核素心肌灌注显像、冠状动脉内超声或经胸超声等技术结合可用于冠状动脉血流储备研究、冠心病的诊断及评价存活心肌等。     

Left ventricular remodeling impairs coronary flow reserve in hypertensive patients

BACKGROUND : In arterial hypertension, changes in both left ventricular mass and geometry may occur. Concentric left ventricular remodeling (i.e. an increased wall thickness relative to end diastolic diameter) has been implicated as an independent cardiovascular risk factor in hypertensive patients. The influence of concentric remodeling on the coronary microcirculation is not known. OBJECTIVE : To investigate the impact of left ventricular geometry on coronary flow reserve in patients with arterial hypertension and angiographically normal coronary arteries. METHODS : Following exclusion of coronary artery disease by cardiac catheterization, coronary flow reserve (dipyridamole, 0.5 mg/kg body weight intravenously; argon gas-chromatographic method) was measured in 49 patients with arterial hypertension and in six age-matched controls. Hypertensive patients were grouped by echocardiographic findings according to left ventricular mass and relative left ventricular wall thickness (i.e. left ventricular posterior wall plus septal thickness divided by end diastolic diameter): seven patients had normal left ventricular mass and geometry, 19 had eccentric hypertrophy (i.e. normal relative wall thickness but increased mass), concentric remodeling (i.e. normal mass but increased relative wall thickness) was present in nine patients, and 14 patients had concentric hypertrophy. RESULTS : There was a marked reduction in coronary flow reserve in all hypertensive groups as compared with control values (4.2 +/- 0.5). Within the hypertensive subgroups, the coronary flow reserve was differentially reduced in the following rank order: concentric remodeling (2.0 +/- 0.7) approximately concentric hypertrophy (2.3 +/- 0.8) < eccentric hypertrophy (2.9 +/- 0.6) mu normal geometry (2.7 +/- 0.4). Multi-factorial regression analysis showed that the relative wall thickness but not left ventricular mass was independently linked to the coronary flow reserve. CONCLUSIONS : Concentric left ventricular remodeling is an independent predictor of the coronary flow reserve in hypertensive patients with chest pain and normal coronary angiogram. The impairment of the coronary microcirculation may contribute to the excess cardiovascular event rate associated with hypertensive concentric left ventricular remodeling.     

PET measurement of the coronary flow reserve and microcirculatory function

This review article discusses some of the potentially beneficial effects of calcium antagonists on the coronary microcirculation. These include their vasodilating action on coronary resistance vessels as well as their effects on extravascular resistance (i.e. intramyocardial pressure). Examples are presented of how the non-invasive measurement of myocardial blood flow and flow reserve by means of positron emission tomography (PET) can contribute to the understanding of the effects of drug treatment on the coronary microcirculation. The action of calcium antagonists on the coronary microcirculation can contribute to explain the efficacy of these drugs against ischemia and ischemia-reperfusion damage.     

Smoking habit and cardiovascular diseases

The relationship between smoking and ischemic heart disease was discussed, in terms of the smoking habit and the mechanisms of acute and chronic effects of smoking on the cardiovascular system as one of the coronary risk factors, with reference to exercise capacity and coronary flow reserve. The smoking habits of 1000 consecutive patients with ischemic heart disease, who were evaluated with coronary angiography, were analyzed. High percentages of smokers were observed in the younger generation. It was up to 86% in the 4th decade, though it was only 48% in the 8th decade. There was no large difference in other risk factors between smokers and non-smokers. The exercise capacity with and without smoking was evaluated with treadmill exercise test in 6 healthy volunteers. The exercise time was decreased with smoking, compared to without smoking, indicating a decrease in exercise capacity due to smoking. The elevated concentration of carbon monoxide in blood decreased the ability of oxygen transport. The increased lactic acid level in blood with smoking suggested anaerobic energy production acting as a part of the energy source. The smoking increased the myocardial oxygen consumption in relation to increase in heart rate and blood pressure. It decreased coronary flow reserve, shown by a peak to resting flow velocity ratio measured with the Doppler flow velocimeter. In coronary heart disease, therefore, the threshold of myocardial ischemia was decreased by smoking. The decrease in coronary flow reserve recovered with cessation of smoking for more than 2 days.     

Different effects of a high-cholesterol diet on ischemic cardiac dysfunction and remodeling induced by coronary stenosis and coronary occlusion

OBJECTIVES: The aim of the study was to assess whether and how the high-cholesterol diet (HCD)-related worsening of heart failure differs between coronary stenosis (CS)-induced myocardial ischemia and coronary occlusion-induced myocardial infarction (MI). BACKGROUND: An HCD, a risk factor for coronary artery disease, also worsens ischemic heart failure. Although accelerated coronary plaque formation may be a cause of this, other mechanism(s), such as its effects through the coronary microcirculation, remain to be clarified. METHODS: In rats fed a normal chow diet or HCD, CS or MI was created surgically, and we assessed left ventricular (LV) function by echocardiography and myocardial inflammation by histopathology. In the CS groups, CS severity by histopathology, myocardial perfusion by microspheres, myocardial protein kinase C (PKC) translocation by Western blotting, and myocardial endothelial nitric oxide (NO) function were also investigated by the in vitro myocardial oxygen consumption method. RESULTS: Coronary stenosis impaired myocardial endothelial NO function and reduced coronary flow reserve, evoking myocardial ischemia, as shown by PKC- activation, myocardial inflammation, fibrosis, cardiac dysfunction, and remodeling. By itself, HCD greatly augmented such CS-induced myocardial abnormalities without modulating the CS severity. Such detrimental effects of HCD were ameliorated by supplying a cofactor of endothelial NO synthase-tetrahydrobiopterin. In contrast, MI-induced heart failure was not aggravated by HCD. CONCLUSIONS: The CS-induced ischemic myocardium seems to be more susceptible to the pro-inflammatory effect of HCD than infarcted myocardium, leading to aggravation of LV dysfunction and remodeling via modification of the coronary circulation downstream of the epicardial CS site, partly through impairment of endothelial NO.     

Quantitative assessment of harmonic power Doppler myocardial perfusion imaging with intravenous Levovist in patients with myocardial infarction: comparison with myocardial viability evaluated by thallium-201 single-photon emission computed tomography and coronary flow reserve.

BACKGROUND: Intravenous myocardial contrast echocardiography with harmonic power Doppler imaging is a novel technique for assessing myocardial perfusion. AIMS: The aim of this study was to quantitatively assess myocardial perfusion by harmonic power Doppler imaging in patients with a previous myocardial infarction and compare myocardial contrast echocardiography results with myocardial viability evaluated by thallium-201 single-photon emission computed tomography ((201)Tl-SPECT) and the results of Doppler flow measurement of coronary flow velocity reserve. METHODS: Twenty-three patients with anterior myocardial infarction who were scheduled for adenosine stress (201)Tl-SPECT underwent myocardial contrast echocardiography with harmonic power Doppler imaging. Harmonic power Doppler imaging was performed at rest and during adenosine infusion (0.15 mg/kg/min) using an intravenous infusion of Levovist. The peak colour pixel intensity ratios of the risk area to the control area were used for quantitative analysis of myocardial perfusion by harmonic power Doppler imaging. Coronary blood flow velocity was measured using Doppler-tipped guidewire in the distal portion of left anterior descending artery and coronary flow velocity reserve was calculated. RESULTS: In patients with myocardial viability assessed by (201)Tl-SPECT, pixel intensity ratios both at rest and during hyperaemia were significantly higher compared with those in patients without myocardial viability (at rest: 0.62 +/- 0.28 vs 0.37 +/- 0.17, P=0.038, during hyperaemia 0.72 +/- 0.19 vs 0.40 +/- 0.18, P=0.003). Coronary flow velocity reserve was significantly different between two groups (2.35 +/- 0.43 vs 1.49 +/- 0.53, P <0.01). CONCLUSIONS: Quantitative assessment of microvascular integrity by harmonic power Doppler imaging corresponds to the evaluation of the microcirculation by coronary flow velocity reserve.     

Coronary reserve in Takayasu's arteritis: transesophageal echocardiographic analysis

BACKGROUND: The incidence of coronary arteries lesion in Takayasu's arteritis varies from 9% to 10% and is usually discovered at autopsy. Recent studies have demonstrated the value of echocardiography in noninvasive detection of significant coronary stenosis. AIM: The aim of our study was to evaluate coronary reserve in 15 patients with Takayasu's arteritis using contrast transesophageal echocardiography (Optison). METHODS: Transesophageal echocardiogram under basal conditions and in the hyperemic phase with dipyridamole challenge, myocardial perfusion studies and coronary angiography were performed on all patients. Seventy-three percent of them had histories of systemic hypertension, and the most frequent cardiovascular symptoms were shortness of breath (80%), headache (46%), angina (40%), and dizziness (33%). RESULTS: The transthoracic echocardiogram showed left ventricular systolic dysfunction in 6% and diastolic dysfunction in 53%. Aortic regurgitation was found in 67% of the patients, and 60% had mitral and/or tricuspid regurgitation. Coronary reserve was diminished in 3 patients with significant coronary lesions and in 2 patients with coronary dilation (33%). In the 3 patients with obstructive lesions and diminished coronary reserve, reversible perfusion defects were found with thallium-201 single-photon emission computed tomography. One patient with coronary dilation had normal perfusion, while the other demonstrated reversible and irreversible perfusion defects. One patient without coronary lesions and with normal coronary reserve had an irreversible fibrotic changes and the other reversible defects due to abnormal microcirculation. CONCLUSIONS: Transesophageal echocardiography is a feasible and promising technique for assessing coronary reserve in patients with Takayasu's arteritis.     

The coronary circulation and blood flow in left ventricular hypertrophy

Two distinct types of left ventricular hypertrophy (LVH) have been described: the so called "physiologic" hypertrophy, which is normally found in professional athletes, and "pathologic" LVH which is found in patients with inherited heart muscle disease such as hypertrophic cardiomyopathy (HCM) or patients with cardiac and systemic diseases characterized by pressure or volume overload. Patients with pathologic LVH have often symptoms and signs suggestive of myocardial ischemia despite normal coronary angiograms. Under these circumstances ischemia is due to coronary microvascular dysfunction (CMD). The abnormalities of the coronary microcirculation may be unrelated to the degree of LVH and cause a reduction in maximum myocardial blood flow which, in the absence of epicardial stenoses, is suggestive of CMD. There is no technique that enables direct visualization of coronary microcirculation in vivo in humans. Therefore, its assessment relies on the measurement of parameters which reflect its functional status, such as myocardial blood flow and coronary flow reserve which is an integrated measure of flow through both the large epicardial coronary arteries and the microcirculation. In this review article we discuss the pathophysiological mechanisms responsible for CMD in patients with primary and secondary LVH and how the recognition of this phenomenon is providing new important information on patient stratification and prognosis. Finally, we discuss how assessment of CMD may be used as a valuable surrogate marker to test the efficacy of old and new drugs. This article is part of a Special Issue entitled "Coronary Blood Flow".     

Técnicas de imagen híbridas en cardiopatía isquémica

Hybrid imaging for ischemic heart disease refers to the fusion of information from a single or usually from multiple cardiovascular imaging modalities enabling synergistic assessment of the presence, the extent, and the severity of coronary atherosclerotic disease along with the hemodynamic significance of lesions and/or with evaluation of the myocardial function. A combination of coronary computed tomography angiography with myocardial perfusion imaging, such as single-photon emission computed tomography and positron emission tomography, has been adopted in several centers and implemented in international coronary artery disease management guidelines. Interest has increased in novel hybrid methods including coronary computed tomography angiography-derived fractional flow reserve and computed tomography perfusion and these techniques hold promise for the imminent diagnostic and management approaches of patients with coronary artery disease. In this review, we discuss the currently available hybrid noninvasive imaging modalities used in clinical practice, research approaches, and exciting potential future technological developments.     

Myokardiale Mikroinfarkte

Atherosclerotic plaque rupture is the key event in the pathogenesis of acute coronary syndromes and it also occurs during coronary interventions. Atherosclerotic plaque rupture does not always result in complete thrombotic occlusion of the epicardial coronary artery with subsequent impending myocardial infarction, but may in milder forms result in the embolization of atherosclerotic and thrombotic debris into the coronary microcirculation. The consequences of coronary microembolization are arrhythmias, reduced coronary reserve, microinfarction, inflammation and oxidative modification of contractile proteins, contractile dysfunction, and perfusion-contraction mismatch. TNF-α has a bidirectional role in this context. TNF-α is responsible for the contractile dysfunction, but simultaneously induces protection against infarction after ischemia/reperfusion.     

Relationship between retinal arteriolar narrowing and myocardial perfusion: multi-ethnic study of atherosclerosis

Retinal arteriolar narrowing is a marker of chronic hypertension. Myocardial perfusion reflects microvascular processes in the heart. The relationship between these 2 measures has not been studied previously and is examined in 212 men and women aged 45 to 84 years and free of cardiovascular disease diagnoses. Retinal caliber was measured through fundus photography and presented as central retinal arteriolar and venular caliber equivalents. Myocardial blood flow was measured using MRI during rest and adenosine-induced hyperemia. Among subjects with no coronary artery calcification (n=98), smaller retinal arteriolar caliber was associated with lower hyperemic myocardial blood flow and perfusion reserve (calculated as the ratio of hyperemic:resting blood flow). Mean hyperemic blood flow (3.43, 3.28, 3.26, and 3.09 mL/min per gram; P(linear)=0.006) and mean perfusion reserve (3.52, 3.37, 3.19, and 3.10; P(linear)=0.01) progressively decreased across decreasing quartiles of retinal arteriolar caliber. These associations remained significant after adjusting for age, gender, and race/ethnicity but were no longer significant after additionally adjusting for other cardiovascular risk factors. In contrast, among subjects with coronary calcification (n=114), retinal arteriolar caliber was not associated with hyperemic myocardial blood flow (P(linear)=0.73) or perfusion reserve (P(linear)=0.79). There were no associations between retinal venular caliber and perfusion measurements. We conclude that narrower retinal arterioles were associated with lower hyperemic myocardial blood flow and perfusion reserve in asymptomatic adults with no coronary calcification, which is partially mediated by traditional cardiovascular risk factors. This finding suggests that retinal arteriolar narrowing may serve as a marker of coronary microvascular disease.     

Evaluation of myocardial blood flow reserve in patients with chronic congestive heart failure due to idiopathic dilated cardiomyopathy

This study demonstrates a significant impairment in coronary blood flow reserve in most patients with idiopathic dilated cardiomyopathy despite normal epicardial coronary arteries. This change may prevent appropriate increases in coronary blood flow and thus lead to myocardial ischemia and progression of disease. An association between decreased response to adenosine and acetylcholine supports previous observations indicating that adenosine-induced vasodilation of coronary microcirculation is dependent on endothelial nitric oxide production.     

Neutrophils as potential participants in acute myocardial ischemia: relevance to reperfusion

An interaction among leukocytes, platelets and endothelial cells is important in atherogenesis and in maintenance of blood flow and vascular tone. These complex cell-cell interactions are mediated by release of such metabolic substances as arachidonic acid metabolites, growth factors, oxygen free radicals and endothelium-derived relaxing factor. These substances participate in the regulation of blood flow in health and disease, and perturbation in the delicate equilibrium among various cellular elements may lead to evolution and propagation of myocardial ischemia. During reperfusion of ischemic myocardium, neutrophils together with platelets cause capillary plugging in the coronary microcirculation and exert detrimental effects on endothelial function resulting in the "no reflow" phenomenon, ventricular arrythmias, loss of coronary vascular reserve and, perhaps, extension of cellular injury. This review addresses the mechanisms of cell-cell interactions with special reference to myocardial ischemia and the potential for development of improved therapy to protect and preserve ischemic myocardium.