Perfusion-contraction Mismatch Research Articles

Establishment and Characterization of an Experimental Model of Coronary Thrombotic Microembolism in Rats

To establish a model of coronary thrombotic microembolism in rats, either automicrothrombotic particulates (CM group) or saline control (SHAM group) was injected into temporarily clamped aortas of male Sprague-Dawley rats. After automicrothrombotic particulate injection, serum c-troponin I and von Willebrand factor levels, the no-flow area as evaluated by Thioflavin S, myocardial leukocyte infiltration levels, myocardial expressions of tumor necrosis factor alpha and interleukin-6, the percentage of arterioles obstructed by thrombosis, and myocardial fibrosis were all significantly increased whereas cardiac function as evaluated by echocardiography and hemodynamic measurements were significantly reduced compared with the sham group. Thus, aortic automicrothrombotic particulate injection could induce coronary microembolism in rats, and this model could be of value in improving the understanding of pathophysiology of coronary microembolism.

Delivery of Glycoprotein IIb/IIIa Inhibitor Therapy for Percutaneous Coronary Intervention

A major goal of any antithrombotic regimen administered during percutaneous coronary intervention (PCI) is the preservation of coronary microvascular perfusion, which is critical for myocardial survival. In addition to macrovascular thrombosis, microembolization into the downstream coronary artery bed that occurs during spontaneous plaque rupture and PCI plays a prominent role in the development of microvascular dysfunction that leads to myocardial infarction. In addition to physical obstruction of the lumen by the embolus, vasoconstriction and edema due to inflammation also impair microvascular flow.1 These events likely occur more frequently during PCI performed in the setting of unstable coronary syndromes.2 With Doppler guidewire technology, it was estimated that an average of 25 embolic events occurred during primary PCI for ST-segment elevation myocardial infarction.3 Article see p 784 Platelet aggregates are important components of coronary microemboli, along with leukocytes, erythrocytes, platelet-leukocyte aggregates, cholesterol crystals, and hyalin. Platelets and leukocytes within microemboli play a particularly important role in the pathophysiological changes of blood flow by promoting in situ microvascular thrombosis, vasoconstriction, and inflammation. Interestingly, the composition of the embolized material is similar in the settings of spontaneous and catheter-induced plaque rupture.1 In animal models, distal microembolization of inert microspheres is associated with an immediate reduction in flow due to vessel occlusion, followed by enhanced blood flow due to the effects of adenosine released from the embolized myocardium into the adjacent noninvolved myocardium.4 Microembolization results in overall reduced flow reserve and the progressive loss of contractile function, which often reverses within weeks. The degree of myocardial contractile dysfunction is disproportionate to the degree of infarction and is the result of inflammation.5 However, in the clinical condition, a more complex pathophysiology exists due to the influence of multiple components of the emboli. Platelets aggregate when fibrinogen binds to the active …

Flow-function relationships in chronic left-ventricular ischemic dysfunction: Impact of the transmurality of infarction

We examined flow-function relationships in humans with chronic coronary artery disease (CAD) in relation to the transmural extent of necrosis, aiming to distinguish the various pathophysiologic conditions that cause chronic ischemic dysfunction, ie, chronic hibernation (perfusion-contraction match) from chronic stunning (perfusion-contraction mismatch). Twenty-two patients (18 men, 61 +/- 13 years) with CAD and chronic contractile dysfunction (ejection fraction, 26% +/- 13%) and 6 volunteers underwent tagged and gadolinium (Gd)-DTPA contrast-enhanced magnetic resonance imaging as well as (13)NH(3)-positron emission tomography. The relationship between regional circumferential shortening strain (ECC), transmural necrosis, and absolute transmural myocardial perfusion (MBF) was examined quantitatively in dysfunctional segments (<10% ECC). Noninfarcted (<25% transmurality), dysfunctional myocardium presented a perfusion-contraction mismatch, as indicated by a 72% reduction (to -5% +/- 4% shortening) of ECC, versus only a 12% (to 63 +/- 20 mL/min/100 g) reduction of transmural MBF. With increasing amounts of necrosis, reductions between perfusion versus contraction became increasingly matched, ie, dysfunctional segments with a greater than 75% transmural extent of necrosis had a 57% reduction of MBF (to 30 +/- 17 mL/min/100 g), for a similar severe reduction of 80% of ECC (to -3% +/- 3% shortening). Noninfarcted, dysfunctional human myocardium mostly presents with a perfusion-contraction mismatch, consistent with stunning. By contrast, dysfunctional myocardium presenting with a perfusion-contraction match is always associated with significant amounts of necrosis.

416 Optimal timing of microvascular damage assessment in the prediction of post-infarct LV dilatation. Insight into post-ischemic perfusion-contraction mismatch and in the definition of viability

416 Optimal timing of microvascular damage assessment in the prediction of post-infarct LV dilatation. Insight into post-ischemic perfusion-contraction mismatch and in the definition of viability

Viable Myocardium: How Much Is Enough?

Left ventricular systolic dysfunction is mainly a result of coronary artery disease (CAD). Decrease in myocardial contractility results as a response to a chronic hypoperfusion state that produces a change in cardiac myocyte metabolism, resulting in a perfusion-contraction mismatch in which function is sacrificed for survival. If revascularization is performed in a timely fashion, metabolism can be restored leading to recovery of function. Through the use of noninvasive imaging modalities, assessing myocardial viability can be easily performed and will aid in selecting those patients who will benefit from revascularization. Viable myocardium can be identified by nuclear modalities that have a high sensitivity but a lower specificity, such as thallium-201 single photon emission computed tomography and positron emission tomography (PET); or by the use of dobutamine stress echocardiogram (DSE), which has a decreased sensitivity but a better specificity. A modality that is increasingly being used with an overall good sensitivity and specificity is contrast-enhanced magnetic resonance imaging. The purpose of this review is to explore the amount of myocardial viability that is relevant to pursue revascularization, since as myocardial function improves there is a decrease in morbidity and mortality from heart failure and arrhythmias.

Glucocorticoid treatment prevents progressive myocardial dysfunction resulting from experimental coronary microembolization.

The frequency and importance of microembolization in patients with acute coronary syndromes and during coronary interventions have recently been appreciated. Experimental microembolization induces immediate ischemic dysfunction, which recovers within minutes. Subsequently, progressive contractile dysfunction develops over several hours and is not associated with reduced regional myocardial blood flow (perfusion-contraction mismatch) but rather with a local inflammatory reaction. We have now studied the effect of antiinflammatory glucocorticoid treatment on this progressive contractile dysfunction. Microembolization was induced by injecting microspheres (42-microm diameter) into the left circumflex coronary artery. Anesthetized dogs were followed up for 8 hours and received placebo (n=7) or methylprednisolone 30 mg/kg IV either 30 minutes before (n=7) or 30 minutes after (n=5) microembolization. In addition, chronically instrumented dogs received either placebo (n=4) or methylprednisolone (n=4) 30 minutes after microembolization and were followed up for 1 week. In acute placebo dogs, posterior systolic wall thickening was decreased from 20.0+/-2.1% (mean+/-SEM) at baseline to 5.8+/-0.6% at 8 hours after microembolization. Methylprednisolone prevented the progressive myocardial dysfunction. Increased leukocyte infiltration in the embolized myocardium was prevented only when methylprednisolone was given before microembolization. In chronic placebo dogs, progressive dysfunction recovered from 5.0+/-0.7% at 4 to 6 hours after microembolization back to baseline (19.1+/-1.6%) within 5 days. Again, methylprednisolone prevented the progressive myocardial dysfunction. Methylprednisolone, even when given after microembolization, prevents progressive contractile dysfunction.

Clinical utility of contrast echocardiography in the management of patients with acute myocardial infarction

The extensive use of myocardial contrast echocardiography (MCE) in patients with acute myocardial infarction has provided critical information regarding the perfusion-contraction mismatch that is observed in post-ischaemic dysfunctioning segments. ‘No-reflow’ phenomena, microvascular stunning, and the relation between microvascular integrity and inotropic reserve within the infarct zone represent areas in which NICE could provide useful information. Rapid technological progress has been made in echocardiographic imaging (harmonic and ultraharmonic imaging, real-time perfusion imaging), and new ultrasound contrast agents such as SonoVue (Bracco, Milan, Italy) have been introduced into the market. These have rendered non-invasive assessment of myocardial perfusion a clinical reality, and thus demonstrate the potential role of NICE in assessing myocardial salvage after reperfusion therapy and suggest that routine NICE use in a coronary care unit may be possible.

Reduced coronary and inotropic reserves with coronary microembolization.

Microembolized myocardium is characterized by perfusion-contraction mismatch with reduced contractile function and unchanged or even elevated blood flow. The present study investigated the consequences of microembolization on coronary and inotropic reserves. In eight anesthetized dogs, left circumflex coronary blood flow (CBF), regional blood flow (RBF), and posterior systolic wall thickening were measured. Repetitive injection of 42-microm microspheres into the left circumflex coronary artery decreased systolic wall thickening by 50% (17.2 +/- 2.4% vs. 8.0 +/- 1.4%; means +/- SD). Coronary reserve was determined by either intracoronary infusion of adenosine (n = 4) or the reactive hyperemia response following 15 s of coronary occlusion (n = 4); inotropic reserve was recruited by intracoronary infusion of dobutamine. The amount of injected microspheres was 158,000 +/- 48,000. CBF (45.5 +/- 16.5 vs. 47.8 +/- 14.4 ml/min) and RBF (1.15 +/- 0.18 vs. 1.33 +/- 0.39 ml x min(-1) x g(-1)) remained unchanged. Coronary reserve in response to intracoronary infusion of adenosine (410 +/- 94% vs. 290 +/- 77%; P < 0.05) and reactive hyperemia repayment (360 +/- 174% vs. 155 +/- 66%; P < 0.05) were blunted after microembolization. Inotropic reserve, i.e., the increment in systolic wall thickening with dobutamine, was decreased from 12.4 +/- 3.9% to 8.0 +/- 3.3% (P < 0.05). We conclude that coronary microembolization reduces coronary and inotropic reserves.

Balance and imbalance of regional myocardial contractile function and blood flow.

During normoperfusion, both contractile function and myocardial blood flow are heterogeneously distributed throughout the left ventricle. Midwall segment shortening is greater at the apex than at the base of the left ventricle, and it is greater in the anterior than in the posterior wall. Also, transmural heterogeneity of myocardial deformation exists, with greater segment shortening and wall thickening in inner than in outer myocardial layers. Myocardial blood flow is greater in inner than in outer myocardial layers. Apart from transmural heterogeneities, there are adjacent regions with largely different resting flow in the same heart. While an increase in myocardial contractile function will lead to a metabolically mediated increase in myocardial blood flow, an increase in regional coronary perfusion within or above the autoregulatory range does not, in turn, increase regional myocardial contractile function. During hypoperfusion induced by a proximal coronary stenosis, the reduction in subendocardial blood flow is more pronounced than that in subepicardial blood flow, and contractile function in the inner myocardial layers ceases more rapidly than that in outer myocardial layers. The reduced regional myocardial contractile function is closely matched to the reduced regional myocardial blood flow; however, such coupling between reduced flow and function is lost when ischemia is prolonged for several hours, i.e., function for a given flow is further reduced. Acute embolization of the coronary microcirculation induces a progressive loss of regional myocardial function at unchanged regional myocardial blood flow, i.e., perfusion-contraction mismatch. During reperfusion, regional myocardial contractile function remains depressed for a prolonged period of time, depending on the severity, duration and location of the preceding ischemic episode, while regional myocardial blood flow is restored.

Perfusion-contraction mismatch with coronary microvascular obstruction: role of inflammation.

A close relationship exists between regional myocardial blood flow (RMBF) and function during acute coronary inflow restriction (perfusion-contraction matching). However, the relationship of flow and function during coronary microvascular obstruction is unknown. In 12 anesthetized dogs, the left circumflex coronary artery was perfused from an extracorporeal circuit. After control measurements, 3,000 microspheres (42 micrometer diameter) per milliliter per minute inflow were injected to cause a microembolism (ME, n = 6). With unchanged systemic hemodynamics and RMBF, posterior systolic wall thickening (PWT) decreased from 19.8 +/- 1.9% SD at control to 13.3 +/- 4.0, 10.3 +/- 3.8, and 6.9 +/- 4.7% (P < 0.05 vs. control) at 1, 4, and 8 h, respectively. For comparison, inflow was progressively reduced to match PWT to that of the ME group at 1, 4, and 8 h (stenosis, STE, n = 6). RMBF in the STE group was reduced in proportion to PWT. Infarct size was not different among groups (6.5 +/- 4.5 vs. 3.4 +/- 3.2%). However, the number of leukocytes infiltrating the area at risk was significantly greater in the ME group than in the STE group. Coronary microembolization results in perfusion-contraction mismatch and is associated with an inflammatory response.

Myocardial perfusion and oxygen consumption in reperfused noninfarcted dysfunctional myocardium after unstable angina: Direct evidence for myocardial stunning in humans

OBJECTIVESTo positively establish the diagnosis of myocardial stunning in patients with unstable angina and persistent wall motion abnormalities after reperfusion by coronary angioplasty.BACKGROUNDAlthough myocardial stunning is thought to occur in several clinical conditions, definite proof of its existence in humans is still lacking, owing to the difficulty of measuring myocardial blood flow (MBF) in absolute terms.METHODSWe studied 14 patients with unstable angina due to proximal left anterior descending coronary artery disease who presented persistent anterior wall motion abnormalities despite revascularization of the culprit lesion by percutaneous coronary angioplasty (PTCA) and who did not have clinical evidence of necrosis. Dynamic positron emission tomography (PET) with [13N]-ammonia and [11C]-acetate was performed 48 h after PTCA to determine absolute MBF and oxygen consumption (MVO2). Regional wall thickening and regional cardiac work were determined using two-dimensional echocardiography. Improvement of segmental wall motion abnormalities was followed for a median of 4 months (1.5 to 14 months).RESULTSAs judged from the changes in segmental wall motion score, regional dysfunction was spontaneously reversible in 12/14 patients and improved from 2.2 ± 0.3 to 1.2 ± 0.3 at late follow-up (p < 0.001). With PET, [13N]-ammonia MBF was similar among dysfunctional and remote normally contracting segments (85 ± 29 vs. 99 ± 20 ml·min−1·100g−1, p = not significant [n.s.]), thus demonstrating a perfusion-contraction mismatch. Despite the reduced contractile function, dysfunctional myocardium presented near normal levels of MVO2(6.5 ± 4.2 vs. 8.0 ± 1.9 ml·min−1·100g−1, p = n.s.). Consequently, the regional myocardial efficiency (regional work divided by MVO2) of the dysfunctional myocardium was found to be markedly decreased as compared with normally contracting myocardium (6 ± 6% vs. 26 ± 6%, p < 0.001).CONCLUSIONSThis study demonstrates that human dysfunctional myocardium capable of spontaneously recovering contractile function after unstable angina endures a state of perfusion-contraction mismatch. These data for the first time provide unequivocal direct evidence for the existence of acute myocardial stunning in humans.

178 Perfusion contraction mismatch during reperfusion by contrast and two dimensional echocardiography in canine model of acute myocardial infarction

178 Perfusion contraction mismatch during reperfusion by contrast and two dimensional echocardiography in canine model of acute myocardial infarction

178 Perfusion contraction mismatch during reperfusion by contrast and two dimensional echocardiography in canine model of acute myocardial infarction

178 Perfusion contraction mismatch during reperfusion by contrast and two dimensional echocardiography in canine model of acute myocardial infarction

Coronary microembolization--its role in acute coronary syndromes and interventions.

The diagnosis coronary artery disease is classically based on patient's symptoms and morphology, as analyzed by angiography. The importance of risk factors for the development of coronary atherosclerosis and disturbance of coronary vasomotion is clearly established. However, microembolization of the coronary circulation has also to be taken into account. Microembolization may occur as a single or as multiple, repetitive events, and it may induce inflammatory responses. Spontaneous microembolization may occur, when the fibrous cap of an atheroma or fibroatheroma (Stary i.v. and Va) ruptures and the lipid pool with or without additional thrombus formation is washed out of the atheroma into the microcirculation. Such events with progressive thrombus formation are known as cyclic flow variations. Plaque rupture occurs more frequently than previously assumed, i.e. in 9% of patients without known heart disease suffering a traffic accident and in 22% of patients with hypertension and diabetes. Also, in patients dying from sudden death microembolization is frequently found. Patients with stable and unstable angina show not only signs of coronary plaque rupture and thrombus formation, but also microemboli and microinfarcts, the only difference between those with stable and unstable angina being the number of events. Appreciation of microembolization may help to better understand the pathogenesis of ischemic cardiomyopathy, diabetic cardiomyopathy and acute coronary syndromes, in particular in patients with normal coronary angiograms, but plaque rupture detected by intravascular ultrasound. Also, the benefit from glycoprotein IIb/IIIa receptor antagonist is better understood, when not only the prevention of thrombus formation in the epicardial atherosclerotic plaque, but also that of microemboli is taken into account. Microembolization also occurs during PTCA, inducing elevations of troponin T and I and elevations of the ST segment in the EKG. Elevated baseline coronary blood flow velocity, as a potential consequence of reactive hyperemia in myocardium surrounding areas of microembolization, is more frequent in patients with high frequency rotablation than in patients with stenting and in patients with PTCA. The hypothesis of iafrogenic microembolization during coronary interventions is now supported by the use of aspiration and filtration devices, where particles with a size of up to 700 microns have been retrieved. In the experiment, microembolization is characterized by perfusion-contraction mismatch, as the proportionate reduction of flow and function seen with an epicardial stenosis is lost and replaced by contractile dysfunction in the absence of reduced flow. The analysis of the coronary microcirculation, in addition to that of the morphology and function of epicardial coronary arteries, and in particular appreciation of the concept of microembolization will further improve the understanding of the pathophysiology and clinical symptoms of coronary artery disease.

The relation of contractile function to myocardial perfusion. Perfusion-contraction match and mismatch.

During normoperfusion, both myocardial blood flow and contractile function are heterogeneously distributed throughout the left ventricle. Midwall segment shortening is greater at the apex than at the base of the left ventricle, and greater in the anterior than in the posterior wall. Also, transmural heterogeneity of myocardial deformation exists, with greater segment shortening and wall thickening in inner than in outer myocardial layers. Myocardial blood flow is greater in inner than in outer myocardial layers. Apart from transmural heterogeneities, there are adjacent regions with largely different resting flow in the same heart. While an increase in myocardial contractile function will lead to a metabolically mediated increase in myocardial blood, an increase in regional coronary perfusion within or above the autoregulatory range does not increase regional myocardial contractile function. During hypoperfusion induced by a proximal coronary stenosis, the reduction in subendocardial blood flow is more pronounced than that in subepicardial blood flow, and contractile function in the inner myocardial layers ceases more rapidly than in the outer myocardial layers. The reduced regional myocardial contractile function is closely matched to the reduced regional myocardial blood flow; however, such a coupling between reduced flow and function is lost when ischemia is prolonged for several hours in that function for a given flow is further reduced. Also, acute embolization of the coronary microcirculation induces a progressive loss of regional myocardial function at an unchanged regional myocardial blood flow, i.e. perfusion-contraction mismatch. During reperfusion, regional myocardial contractile function remains depressed for a prolonged period of time, depending on the severity, duration and location of the preceding ischemic episode, while regional myocardial blood flow is restored to almost normal. Recovery of contractile function in the outer myocardial layers is faster than in the inner myocardial layers.

Chronic myocardial hibernation in humans. From bedside to bench.

Since the pioneering work of Tennant and Wiggers,1 it has been known that total ischemia leads to a prompt cessation of contraction and eventually results in the appearance of cell damage and irreversible myocardial necrosis. Accordingly, in the minds of many cardiologists, the discovery of an abnormal regional contraction in a patient with coronary artery disease has long been equated with the presence of irreversible myocardial necrosis. With the advent of recanalization therapy, however, evidence progressively accumulated that prolonged regional “ischemic” dysfunction did not always arise from irreversible tissue damage and, to some extent, could be reversed by restoration of blood flow.2 3 4 5 These observations have led to the speculation that chronically hypoperfused myocardium, which is often referred to as “hibernating,”2 3 4 5 6 could maintain viability by simply reducing its metabolic demand to match the decreased supply for as long as myocardial perfusion was inadequate. The chronic impairment of contractile function in this setting has been regarded as a protective mechanism by which the heart spontaneously downgrades its myocardial function, minimizes its energy requirements, and prevents the appearance of irreversible tissue damage.2 4 5 The concept of chronic hibernation thus consists of two parts: a unique clinical observation that bears important implications for the management of patients with chronic coronary artery disease2 3 4 5 6 and a pathophysiological hypothesis, yet to be demonstrated, implying that the chronic dysfunction is due to a chronic reduction of resting MBF.4 5 Other aspects that were not included in the original description, ie, the rapidity of mechanical recovery after successful revascularization7 and the response of dysfunctional myocardium to inotropic stimulation, are now also considered to be integral parts of this condition. The purpose of this discussion is to review some of the …

Inotropic stimulation by dobutamine increases left ventricular regional function at the expense of metabolism in hibernating myocardium

The mechanism by which dobutamine increases the contraction of chronically dysfunctional myocardium and its effects on metabolism are still unknown. The aim of this study was to assess regional myocardial metabolism at rest and during an intracoronary dobutamine infusion in patients with hibernating myocardium. Eleven asymptomatic patients with single proximal stenosis of the left anterior descending coronary artery and persistent left ventricular dysfunction at rest (undergoing percutaneous transluminal coronary angioplasty [PTCA]) were studied prospectively. Regional left ventricular function was assessed by two-dimensional (2D) echocardiography and regional perfusion by thallium-201 single-proton-emission computed tomography. Great cardiac vein and aortic blood samples were obtained for measurements of lactate and plasma free fatty acid (FFA) concentrations. Inotropic challenge, obtained by using intracoronary dobutamine infusion, increases regional left ventricular function. However, the arteriovenous AV lactate difference was 0.206 ± 0.070 mmol/L at rest, and it decreased to 0.018 ± 0.069 mmol/L ( p < 0.05 vs baseline) and 0.066 ± 0.068 mmol/L ( p < 0.05 vs baseline) at 4 and 10 minutes of dobutamine infusion, respectively. Thus the hibernating myocardium does not produce lactate at rest. However, when regional contraction is stimulated, dobutamine-induced inotropic challenge may cause a perfusion-contraction mismatch with an activation of anaerobic glycolysis.

811-2 Evidence that Myocardial Stunning Occurs in Humans Following Unstable Angina

Reversible postischemic dysfunction, or myocardial stunning, is a well defined experimental entity which is characterized by the presence of a perfusion-contraction mismatch, i.e. the persistence of segmental dysfunction despite complete restoration of nutritive perfusion. Reversible dysfunction occurs following ischemic syndromes such as non-Q wave infarction, unstable angina, cardio-pulmonary bypass. Definite demonstration that reversible dysfunction indeed represents myocardial stunning is lacking, owing to the difficulty of measuring myocardial blood flow (MBF) in absolute terms. Therefore, we measured regional wall motion (by 2D echo) and absolute MBF with 13 N-ammonia and positron emission tomography (PET) in 11 patients with unstable angina, Despite successful PTCA of the culprit lesion on the left anterior descending coronary artery, all patients showed persistent anterior. wall dysfunction at the time of the PET study (within 48 hours after PTCA). As judged from the changes in segmental wall motion (in 6 ± 2 abnormal segments, mean ± sd, out of 16 in each patient) from the time of PET study to 4–8 weeks later, regional dysfunction was entirely reversible in 9/11 patients. In these 9 patients, the segmental wall motion score improved from 2.4 ± 0.3 to 1.2 ± 0.1 at late follow-up. With PET, 13 N-ammonia MBF was within the normal range in 8/9 patients (95 ± 21 ml/min/l00 g, range 60124 ml/min/l 00 g), while it was decreased (33 ml/min/l00 g) in the remaining patient. On average, in the 9 patients, absolute MBF was similar among stunned and remote normally contracting myocardial segments (88 ± 28 vs 85 ± 25 ml/min/100 g, p = ns). Our data thus show perfusion-contraction mismatch, confirming that myocardial stunning can occur in humans following attacks of unstable angina.