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Obstructive disease of the epicardial coronary arteries is the main cause of angina. However, a number of patients with anginal symptoms have normal coronaries or non-obstructive coronary artery disease (CAD) despite electrocardiographic evidence of ischaemia during stress testing. In addition to limited microvascular vasodilator capacity, the coronary microcirculation of these patients is particularly sensitive to vasoconstrictor stimuli, in a condition known as microvascular angina. This review briefly summarizes the determinants and control of coronary blood flow (CBF) and myocardial perfusion. It subsequently analyses the mechanisms responsible for transient myocardial ischaemia: obstructive CAD, coronary spasm and coronary microvascular dysfunction in the absence of epicardial coronary lesions, and variable combinations of structural anomalies, impaired endothelium-dependent and/or -independent vasodilation, and enhanced perception of pain. Lastly, we exemplify mechanism of angina during tachycardia. Distal to a coronary stenosis, coronary dilator reserve is already recruited and can be nearly exhausted at rest distal to a severe stenosis. Increased heart rate reduces the duration of diastole and thus CBF when metabolic vasodilation is no longer able to increase CBF. The increase in myocardial oxygen consumption and resulting metabolic vasodilation in adjacent myocardium without stenotic coronary arteries further acts to divert blood flow away from the post-stenotic coronary vascular bed through collaterals., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)

Primary percutaneous coronary intervention is nowadays the preferred reperfusion strategy for patients with acute ST-segment-elevation myocardial infarction, aiming at restoring epicardial infarct-related artery patency and achieving microvascular reperfusion as early as possible, thus limiting the extent of irreversibly injured myocardium. Yet, in a sizeable proportion of patients, primary percutaneous coronary intervention does not achieve effective myocardial reperfusion due to the occurrence of coronary microvascular obstruction (MVO). The amount of infarcted myocardium, the so-called infarct size, has long been known to be an independent predictor for major adverse cardiovascular events and adverse left ventricular remodeling after myocardial infarction. Previous cardioprotection studies were mainly aimed at protecting cardiomyocytes and reducing infarct size. However, several clinical and preclinical studies have reported that the presence and extent of MVO represent another important independent predictor of adverse left ventricular remodeling, and recent evidences support the notion that MVO may be more predictive of major adverse cardiovascular events than infarct size itself. Although timely and complete reperfusion is the most effective way of limiting myocardial injury and subsequent ventricular remodeling, the translation of effective therapeutic strategies into improved clinical outcomes has been largely disappointing. Of importance, despite the presence of a large number of studies focused on infarct size, only few cardioprotection studies addressed MVO as a therapeutic target. In this review, we provide a detailed summary of MVO including underlying causes, diagnostic techniques, and current therapeutic approaches. Furthermore, we discuss the hypothesis that simultaneously addressing infarct size and MVO may help to translate cardioprotective strategies into improved clinical outcome following ST-segment-elevation myocardial infarction.

The coronary circulation is both culprit and victim of acute myocardial infarction. The rupture of an epicardial atherosclerotic plaque with superimposed thrombosis causes coronary occlusion, and this occlusion must be removed to induce reperfusion. However, ischaemia and reperfusion cause damage not only in cardiomyocytes but also in the coronary circulation, including microembolization of debris and release of soluble factors from the culprit lesion, impairment of endothelial integrity with subsequently increased permeability and oedema formation, platelet activation and leucocyte adherence, erythrocyte stasis, a shift from vasodilation to vasoconstriction, and ultimately structural damage to the capillaries with eventual no-reflow, microvascular obstruction (MVO), and intramyocardial haemorrhage (IMH). Therefore, the coronary circulation is a valid target for cardioprotection, beyond protection of the cardiomyocyte. Virtually all of the above deleterious endpoints have been demonstrated to be favourably influenced by one or the other mechanical or pharmacological cardioprotective intervention. However, no-reflow is still a serious complication of reperfused myocardial infarction and carries, independently from infarct size, an unfavourable prognosis. MVO and IMH can be diagnosed by modern imaging technologies, but still await an effective therapy. The current review provides an overview of strategies to protect the coronary circulation from acute myocardial ischaemia/reperfusion injury. This article is part of a Cardiovascular Research Spotlight Issue entitled 'Cardioprotection Beyond the Cardiomyocyte', and emerged as part of the discussions of the European Union (EU)-CARDIOPROTECTION Cooperation in Science and Technology (COST) Action, CA16225., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2018. For permissions, please email: journals.permissions@oup.com.)

This opinionated article reviews current concepts of myocardial ischemia. Specifically, the historical background is briefly presented. Then, the prevailing paradigm of myocardial oxygen-supply-demand imbalance is criticized since demand is a virtual parameter that cannot be measured and data on measurements of myocardial blood flow and contractile function rather support matching between flow and function. Finally, a concept of myocardial ischemia that focusses on the reduction of coronary blood flow to below 8-10 µl/g per beat with consequences for myocardial electrical, metabolic, contractile and morphological features is advocated.

Plaque erosion, fissuring or rupture occurs spontaneously or during coronary interventions. At some residual blood flow, the atherothrombotic debris is washed into the coronary microcirculation, causing physical obstruction, vasoconstriction, inflammation and ultimately microinfarction. Coronary microembolization also contributes to microvascular obstruction in reperfused acute myocardial infarction. Patients with microvascular obstruction after reperfused myocardial infarction have worse prognosis. Cardioprotective strategies to avoid acute coronary microembolization and rescue myocardium from microvascular obstruction have not yet been established in clinical practice. Subclinical coronary microembolization together with release of thrombogenic, vasoconstrictor and inflammatory substances from a culprit lesion can sensitize the coronary microcirculation and contribute to angina in the absence of major epicardial coronary obstruction. Repetitive coronary microembolization can induce progressive loss of functional cardiomyocytes and induce heart failure in the absence of overt myocardial infarction., (Copyright © 2017. Published by Elsevier B.V.)

Regional myocardial blood flow and contractile function in ischemic myocardium are well matched, and there is no evidence for an oxygen supply/demand imbalance. Thus, myocardial ischemia is lack of coronary blood flow with electric, functional, metabolic, and structural consequences for the myocardium. All therapeutic interventions must aim to improve blood flow to ischemic myocardium as much and as quickly as possible., (© 2016 American Heart Association, Inc.)

The atherosclerotic coronary vasculature is not only the culprit but also a victim of myocardial ischemia/reperfusion injury. Manifestations of such injury are increased vascular permeability and edema, endothelial dysfunction and impaired vasomotion, microembolization of atherothrombotic debris, stasis with intravascular cell aggregates, and finally, in its most severe form, capillary destruction with hemorrhage. In animal experiments, local and remote ischemic pre- and postconditioning not only reduce infarct size but also these manifestations of coronary vascular injury, as do drugs which recruit signal transduction steps of conditioning. Clinically, no-reflow is frequently seen after interventional reperfusion, and it carries an adverse prognosis. The translation of cardioprotective interventions to clinical practice has been difficult to date. Only 4 drugs (brain natriuretic peptide, exenatide, metoprolol, and esmolol) stand unchallenged to date in reducing infarct size in patients with reperfused acute myocardial infarction; unfortunately, for these drugs, no information on their impact on the ischemic/reperfused coronary circulation is available., (© 2016 American Heart Association, Inc.)

Aims: Myocardial injury reflected by a post-procedural increase of serum troponin I (TnI) occurs frequently during transcatheter aortic valve implantation (TAVI). It is potentially caused by intraprocedural hypotension, periprocedural coronary microembolisation and post-procedural (para)valvular leakages (PVLs). We invasively assessed coronary flow dynamics including coronary flow velocity reserve (CFVR), embolic high-intensity transient signals (HITS) as well as rapid pacing induced hypotension and post-procedural PVLs to determine their contribution to post-procedural TnI increases., Methods and Results: In 15 transfemoral TAVI patients, TnI was measured serially, and cardiac MRIs with late gadolinium enhancement (LGE) were performed pre- and post-interventionally. There were no significant correlations between coronary flow dynamics, CFVR and the area under the curve (AUC) of TnI over 72 hours. Despite the detection of HITS in all patients and during all procedural steps, there was also no correlation between the amount of HITS and the AUC of TnI. However, there were positive correlations between the duration of rapid pacing as well as the time of subsequent blood pressure recovery and the AUC of TnI. Both LGE and more than mild PVL were observed in a single case only., Conclusions: Myocardial injury after TAVI appears to be related more to hypoperfusion-induced ischaemia than to periprocedural microembolisation.

In remote ischemic conditioning (RIC), brief, reversible episodes of ischemia with reperfusion in one vascular bed, tissue, or organ confer a global protective phenotype and render remote tissues and organs resistant to ischemia/reperfusion injury. The peripheral stimulus can be chemical, mechanical, or electrical and involves activation of peripheral sensory nerves. The signal transfer to the heart or other organs is through neuronal and humoral communications. Protection can be transferred, even across species, with plasma-derived dialysate and involves nitric oxide, stromal derived factor-1α, microribonucleic acid-144, but also other, not yet identified factors. Intracardiac signal transduction involves: adenosine, bradykinin, cytokines, and chemokines, which activate specific receptors; intracellular kinases; and mitochondrial function. RIC by repeated brief inflation/deflation of a blood pressure cuff protects against endothelial dysfunction and myocardial injury in percutaneous coronary interventions, coronary artery bypass grafting, and reperfused acute myocardial infarction. RIC is safe and effective, noninvasive, easily feasible, and inexpensive., (Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Cardioprotection, i.e. the reduction in infarct size by pre-, post-, or remote conditioning, has originally been characterized in young and healthy experimental animals. Over the last two decades many signalling steps of cardioprotection have been identified, again in young and healthy animals. Although proof-of-concept studies unequivocally demonstrated the recruitment of all forms of cardioprotection in humans, the translation of cardioprotection to clinical routine has been poor. The apparent lack of translation has been attributed to poor design of clinical trials, but also to the neglect of confounders, such as age, sex, comorbidities, and comedications, in experimental studies. The present opinionated review focuses on the coronary circulation as a major determinant of cardioprotection. Coronary occlusion and the restoration of coronary blood flow are the causes of myocardial ischaemia and reperfusion injury from which protection is sought. On the other hand, brief cycles of coronary occlusion and reperfusion are also the stimulus for protection from myocardial ischaemia/reperfusion injury. The recruitment of collateral blood flow also contributes to protection from infarction. Finally, the coronary microcirculation is also a target of both injury by myocardial ischaemia/reperfusion and protection from it. Different manifestations of coronary artery disease, such as coronary stenosis or coronary microembolization, impact on both injury and protection.

A percutaneous coronary intervention (PCI) is a unique condition to study the effects of ischemia and reperfusion in patients with severe coronary atherosclerosis when coronary vasomotor function is compromised by loss of endothelial and autoregulatory vasodilation. We studied the effects of intracoronary non-selective α-, as well as selective α(1)- and α(2)-blockade in counteracting the observed vasoconstriction in patients with stable and unstable angina and in patients with acute myocardial infarction. Coronary vasoconstriction in our studies was a diffuse phenomenon and involved not only the culprit lesion but also vessels with angiographically not visible plaques. Post-PCI vasoconstriction was reflected by increased coronary vascular resistance and associated with decreased LV-function. α (1)-Blockade with urapidil dilated epicardial coronary arteries, improved coronary flow reserve and counteracted LV dysfunction. Non-selective α-blockade with phentolamine induced epicardial and microvascular dilation, while selective α(2)-blockade with yohimbine had only minor vasodilator and functional effects. Intracoronary α-blockade also attenuated the no-reflow phenomenon following primary PCI. This article is part of a Special Issue entitled "Coronary Blood Flow"., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Activation of coronary vascular α-adrenoceptors results in vasoconstriction which competes with metabolic vasodilation during sympathetic activation. Epicardial conduit vessel constriction is largely mediated by α(1)-adrenoceptors; the constriction of the resistive microcirculation largely by α(2)-adrenoceptors, but also by α(1)-adrenoceptors. There is no firm evidence that α-adrenergic coronary vasoconstriction exerts a beneficial effect on transmural blood flow distribution. In fact, α-blockade in anesthetized and conscious dogs improves blood flow to all transmural layers, during normoperfusion and hypoperfusion. Also, in patients with coronary artery disease, blockade of α(1)- and α(2)-adrenoceptors improves coronary blood flow, myocardial function and metabolism., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Coronary microembolization from the erosion or rupture of a vulnerable atherosclerotic plaque occurs spontaneously in acute coronary syndromes and iatrogenically during percutaneous coronary interventions. Typical consequences of coronary microembolization are microinfarcts with an inflammatory response, contractile dysfunction, and reduced coronary reserve. Apart from transient elevations of creatine kinase and troponin, microemboli can be visualized by intracoronary Doppler and the resulting microinfarcts by late-enhancement nuclear magnetic resonance. Statins, antiplatelet agents, and coronary vasodilators protect against microembolization and microinfarction when started before percutaneous coronary interventions. Distal protection devices can retrieve atherothrombotic debris and prevent its embolization into the microcirculation, but their effect on clinical outcome has been disappointing so far, except for saphenous vein bypass grafts. Devices for aspiration of thrombi and thrombus-derived vasoconstrictor, thrombogenic, and inflammatory substances, however, reduce thrombus burden, improve perfusion, and provide protection in patients with acute myocardial infarction.

Aims: Effects of the bradycardic agent ivabradine on regional blood flow, contractile function, and infarct size were studied in a pig model of myocardial ischaemia/reperfusion. Heart rate reduction by beta-blockade is associated with negative inotropism and unmasked alpha-adrenergic coronary vasoconstriction. Ivabradine is the only available bradycardic agent for clinical use., Methods and Results: Anaesthetized pigs were subjected to 90 min controlled left anterior descending coronary artery hypoperfusion and 120 min reperfusion. Regional blood flow was measured with microspheres, regional function with sonomicrometry, and infarct size with triphenyl tetrazolium chloride staining. Pigs received placebo or ivabradine (0.6 mg/kg i.v.) before or during ischaemia or before reperfusion, respectively. Pre-treatment with ivabradine reduced infarct size from 35 +/- 4 (SEM) to 19 +/- 4% of area at risk (AAR). Ivabradine 15-20 min after the onset of ischaemia increased regional myocardial blood flow from 2.12 +/- 0.31 to 3.55 +/- 0.56 microL/beat/g and systolic wall thickening from 6.7 +/- 1.0 to 16.3 +/- 3.0%; infarct size was reduced from 12 +/- 4 to 2 +/- 1% of AAR. Ivabradine 5 min before reperfusion still reduced infarct size from 36 +/- 4 to 21 +/- 5% of AAR. The benefit of ivabradine on flow and function was eliminated by atrial pacing, but part of the reduction of infarct size by ivabradine was not., Conclusion: Ivabradine's protection goes beyond heart rate reduction.

Starting out from a brief description of the determinants of coronary blood flow (perfusion, pressure, extravascular compression, autoregulation, metabolic regulation, endothelium-mediated regulation and neurohumoral regulation) the present review highlights the overwhelming importance of metabolic regulation such that coronary blood flow is increased at increased heart rate under physiological circumstances and the overwhelming importance of extravascular compression such that coronary blood flow is decreased at increased heart rate through reduction of diastolic duration in the presence of severe coronary stenoses. The review goes on to characterize the role of heart rate in the redistribution of regional myocardial blood flow between a normal coronary vascular tree with preserved autoregulation and a poststenotic vasculature with exhausted coronary reserve. When flow is normalized by heart rate, there is a consistent close relationship of regional myocardial blood flow and contractile function for each single cardiac cycle no matter whether or not there is a coronary stenosis and what the actual blood flow is. beta-Blockade improves both flow and function along this relationship. When the heart rate reduction associated with beta-blockade is prevented by pacing, alpha-adrenergic coronary vasoconstriction is unmasked and both flow and function are deteriorated. Selective heart rate reduction, however, improves both flow and function without any residual negative effect such as unmasked alpha-adrenergic coronary vasoconstriction or negative inotropic action.

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. This review summarizes the present experimental pathophysiology of coronary microembolization in animal models of acute coronary syndromes and highlights the main consequences of coronary microembolization--reduced coronary reserve, microinfarction, inflammation and oxidative modification of contractile proteins, contractile dysfunction and perfusion-contraction mismatch.Furthermore, the review presents the available clinical evidence for coronary microembolization in patients and compares the clinical observations with observations in the experimental model.

Transient episodes of angina preceding acute myocardial infarction may both, protect the myocardium by ischemic preconditioning or damage it when associated with coronary microembolization. We now studied the potential loss of ischemic preconditioning with coronary microembolization. Anesthetized pigs (group 1; n=8) were subjected to 90 min sustained low-flow ischemia. Group 2 (n=8) was subjected to coronary microembolization (i.e. microspheres; 42 microm slashed circle; 3000 per ml min-1 inflow) 35 min before sustained ischemia. In group 3, coronary microembolization was followed 10 min later by one cycle of ischemic preconditioning (10 min ischemia/15 min reperfusion) before subsequent sustained ischemia. Infarct size was determined after 2 h reperfusion by triphenyl tetrazolium chloride staining. Infarct size after sustained ischemia alone (group 1) was 19.4+/-3.4% of the area at risk (mean+/-S.E.M.). With coronary microembolization before sustained ischemia (group 2) infarct size was only slightly larger (23.6+/-4.6%, ns). In group 3 with microembolization followed by ischemic preconditioning, infarct size was reduced to 12.7+/-3.0% (P<0.05 vs. group 2). The relationships between infarct size and transmural blood flow in groups 1 and 3 were not different, giving the impression that ischemic preconditioning failed to protect microembolized myocardium. However, additional coronary microembolization shifted the relationship between infarct size and blood flow upwards to a larger infarct size at any given blood flow. Thus when comparing the relationship of group 3 to its true control (group 2), it was shifted downwards (P<0.05; analysis of covariance (ANCOVA)) indicating persistent protection of microembolized myocardium by ischemic preconditioning. Coronary microembolization induces additional infarction when superimposed on sustained ischemia but does not interfere with the endogenous protection by ischemic preconditioning.

Chronic coronary artery stenosis results in patchy necrosis in the dependent myocardium and impairs global and regional left ventricular (LV) function in rats in vivo. The aim of the present study was to compare regional myocardial blood flow (RMBF) and function (F) in poststenotic myocardium by using magnetic resonance imaging (MRI) and to compare MRI blood flow changes to histological alterations to assess whether RMBF in the viable poststenotic tissue remains normal. MRI was performed in 11 anesthetized Wistar rats with 2-wk stenosis of the left coronary artery. Postmortem, the extent of fibrotic tissue was quantified. Poststenotic RMBF was significantly reduced to 2.21 +/- 0.30 ml.g(-1).min(-1) compared with RMBF in the remote myocardium (4.05 +/- 0.50 ml.g(-1).min(-1)). A significant relationship between the poststenotic RMBF (%remote area) and the poststenotic F (%remote myocardium) was calculated (r = 0.61, P < 0.05). Assuming perfusion in scar tissue to be 32 +/- 5% of perfusion of remote myocardium, as measured in five additional rats, and that in remote myocardium to be 114 +/- 25% of that in normal myocardium, as assessed in five sham rats, the calculated perfusion in partially fibrotic tissue samples (35.7 +/- 5.2% of analyzed area) was 2.88 +/- 0.18 ml.g(-1).min(-1), whereas measured MRI perfusion was only 1.86 +/- 0.24 ml.g(-1).min(-1) (P < 0.05). These results indicate that resting perfusion in viable poststenotic myocardium is moderately reduced. Alterations in global and regional LV function are therefore secondary to both patchy fibrosis and reduced resting perfusion.

The pathophysiology of myocardial hibernation is characterized as a situation of reduced regional contractile function distal to a coronary artery stenosis that recovers after removal of the coronary stenosis. A subacute "downregulation" of contractile function in response to reduced regional myocardial blood flow exists, which normalizes regional energy and substrate metabolism but does not persist for more than 12-24 h. Chronic hibernation develops in response to one or more episodes of myocardial ischemia-reperfusion, possibly progressing from repetitive stunning with normal blood flow to hibernation with reduced blood flow. An upregulation of a protective gene program is seen in hibernating myocardium, putting it into the context of preconditioning. The morphology of hibernating myocardium is characterized by both adaptive and degenerative features.

Atherosclerotic plaque rupture is a key event in the pathogenesis of acute coronary syndromes and during coronary interventions. Atherosclerotic plaque rupture does not necessarily lead to thrombotic occlusion of a coronary artery and subsequent myocardial infarction. Milder forms may result in the embolization of atherosclerotic and/or thrombotic debris into the coronary microcirculation. The characteristic consequences of coronary microembolization are arrhythmias, microinfarcts, and a reduced coronary reserve. Experimental studies revealed that an inflammatory reaction is causally involved in the progressive contractile dysfunction following coronary microembolization. Thus, anti-inflammatory treatment appears as a promising strategy to protect patients from the consequences of coronary microembolization.

The renin-angiotensin system is activated during myocardial ischemia, and angiotensin II is locally formed in ischemic hearts. At least four angiotensin II receptor subtypes have been identified, the AT1- and the AT2-receptor being the most prominent in the cardiovascular system. AT1-receptor blockade--like inhibition of the angiotensin-converting-enzyme (ACE)--limits infarct size, improves functional recovery following myocardial ischemia and attenuates ventricular remodeling, post-myocardial infarction and the resulting development of heart failure. The potential mechanisms responsible for the cardioprotection by AT1-receptor blockade remain to be elucidated in detail, but appear to involve AT2-receptor activation and--like ACE-inhibitors--bradykinin and prostaglandins. Combined treatment with ACE-inhibitors and AT1-receptor blockers has the potential to further reduce infarct size and improve ventricular remodeling over each monotherapy alone.

Background: Coronary flow reserve (CFR) is not normalized shortly after coronary stenting. We hypothesized that alpha-adrenergic coronary vasoconstriction acts to limit CFR., Methods and Results: We assessed flow velocity by Doppler wires and cross-sectional area by angiography in 46 patients undergoing coronary culprit lesion stenting (81+/-4% stenosis). Hyperemia was induced by adenosine (24 micro g IC or 140 micro g/kg per minute IV) before and after stenting. Finally, either the alpha(1)-antagonist urapidil (10 mg IC) or the alpha(2)-antagonist yohimbine (3 mg IC) was randomly combined with adenosine. In 8 subjects with angiographically normal coronary arteries, CFR was increased from 3.21+/-0.30 to 3.74+/-0.43 by yohimbine and to 4.58+/-0.65 by urapidil, respectively (P=0.0001). Patients were divided according to the cutoff of CFR > or =3.0 (n=18) or <2.5 (n=28). Revascularization per se did not change CFR. However, 15 minutes after stenting, CFR decreased to 2.05+/-0.55 from CFR 3.64+/-0.58, whereas in patients with CFR 2.39+/-0.51, it remained unchanged. Yohimbine improved CFR to 3.26+/-0.42 and to 3.41+/-0.58 in patients with >3.0 and <2.05+/-0.55 baseline CFR, respectively. Urapidil improved CFR to 3.52+/-0.30 and 3.98+/-1.07, respectively., Conclusions: Urapidil and yohimbine attenuated the CFR impairment occurring after revascularization by increasing both the epicardial vasodilator effect of adenosine and the blood flow velocity, thus suggesting that the adrenergic system plays an important role in limiting the capacity of the coronary circulation to dilate.

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.

Coronary microembolization is a frequent complication of atherosclerotic plaque rupture in acute coronary syndromes and during coronary interventions. Experimental coronary microembolization results in progressive contractile dysfunction associated with a local inflammation. We studied the causal role of tumor necrosis factor-alpha (TNF-alpha) in the progressive contractile dysfunction resulting from coronary microembolization. Anesthetized dogs were subjected to either coronary microembolization with infusion of 3.000 microspheres (42 microm diameter) per ml coronary inflow into the left circumflex coronary artery (n=9), or to intracoronary infusion of recombinant human TNF-alpha without microembolization (n=4), or to treatment with anti-murine TNF-alpha sheep antibodies prior to microembolization (n=4). Posterior systolic wall thickening (PWT; sonomicrometry) decreased from 21.1+/-5.3% (s.d.) at baseline to 5.5+/-2.2% (P<0.05) at 8 h after microembolization. Infarct size (1.8+/-1.9%; TTC and histology) and the amount of apoptosis (<0.1%; TUNEL and DNA-laddering) were small. TNF-alpha at the protein level (WEHI cytolytic assay) was increased and localized to leukocytes (immunostaining), which were increased in number (quantitative histology). In situ hybridization for TNF-alpha mRNA identified viable cardiomyocytes surrounding the microinfarcts as the major source of TNF-alpha. Supporting the role of TNF-alpha, infusion of TNF-alpha without microembolization decreased PWT from 27.3+/-6.9% at baseline to 10.1+/-4.9% after 8 h (P<0.05); in contrast, in the presence of TNF-alpha antibodies, microembolization no longer reduced PWT (19.3+/-7.0% at baseline v 16.9+/-5.0% at 8 h). In conclusion, TNF-alpha is the mediator responsible for the profound contractile dysfunction following coronary microembolization., (Copyright 2002 Academic Press.)

Myocardial blood flow is spatially heterogeneous, reflecting nonuniform oxygen supply. Also, myocardial oxidative metabolism is spatially heterogeneous. The effects of acute ischemia and reperfusion on the relationship between local myocardial blood flow (LMF) and oxidative metabolism are still unknown. LMF was measured in isolated, blood-perfused rabbit hearts using colored microspheres and oxidation water labeled with 18O2 (H2(18)O). Three protocols were performed: 18O2-perfusion during normoxia (N; n=7), during early reperfusion (ER; 10 min, n=6), and late reperfusion (LR; 40 min, n=6) following 20 min no-flow ischemia. LMF and local H2(18)O residues were determined within defined myocardial samples (105+/-15 mg). For interindividual comparison, values were normalized to the mean of the individual experiment and expressed as percentages. LMF ranged from 18 to 193% (N), 12 to 250% (ER), and 11 to 180% (LR). The H2(18)O tissue residue ranged from 63 to 132% (N), 73 to 142% (ER) and 32 to 148% (LR). The correlation between LMF and local oxidative metabolism during N (r=0.77; n=56) was lost in the postischemic heart during ER and LR. LMF during N and ER were only weakly correlated (r=0.24; n=48), whereas LMF during N and LR correlated well (r=0.87; n=48). It is concluded that the heterogeneous LMF pattern at baseline is maintained in the stunned myocardium whereas that of local oxidative metabolism is not. Apart from the established mechanisms underlying myocardial stunning, a mismatch between local flow and oxidative metabolism might also contribute.

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.

The 894T allele of a G894T polymorphism in the endothelial nitric oxide synthase (eNOS) gene is associated with decreased eNOS activity, cleavage of the protein, and endothelial dysfunction. The present study evaluated the association with coronary blood flow (CBF) at rest and during adenosine (ADO)-induced hyperemia. CBF was determined by Doppler flow wire and angiography in 97 left anterior descending arteries of individuals without coronary artery disease. At rest, average peak velocity (APV) was lower and coronary vascular resistance (CVR) was higher in homozygous carriers of the 894T allele than in heterozygotes and individuals without the 894T allele. CBF tended to be lower in eNOS 894T allele carriers. During ADO-induced hyperemia (18 microg ic), APV, CVR, and CBF were not statistically different between the genotypes. The reduced APV at rest in conjunction with an increased CVR indicates a vasomotor dysfunction related to an increased microvascular resting tone in eNOS 894T allele carriers.

Background: Residual reduction of relative coronary flow velocity reserve (rCVR) after successful coronary intervention has been related to microvascular impairment. However, the incidence of cardiac enzyme elevation as a surrogate marker of an underlying embolic myocardial injury in these cases has not been studied., Methods and Results: A series of 55 consecutive patients with successful coronary stenting, periprocedural intracoronary Doppler analysis, and determination of creatine kinase (CK; upper limit of normal [ULN] for women 70 IU/L, for men 80 IU/L) and cardiac troponin T (cTnT; bedside test, threshold 0.1 ng/mL) before and 6, 12, and 24 hours after intervention were studied. Postprocedural rCVR was the only intracoronary Doppler parameter that independently correlated with cTnT (r=-0.498, P<0.001) and CK outcome (r=-0.406, P=0.002). Receiver operating characteristic analysis identified a postprocedural rCVR of 0.78 as the best discriminating value, with a sensitivity of 83.3% and 69.2% and a specificity of 79.1% and 76.2% for detection of cTnT and CK elevation, respectively. Stratified according to this cutoff value, the incidence of cTnT elevation was 52.6% in patients with (n=19) and 5.6% in patients without (n=36) a postprocedural rCVR <0.78 (P<0.001), associated with a CK elevation >1 times the ULN in 36.8% and 5.6% (P=0.005) of patients, respectively., Conclusions: Cardiac marker elevation can frequently be found after coronary procedures that are associated with a persistent reduction of rCVR, indicating procedural embolization of atherothrombotic debris with microvascular impairment and myocardial injury as a potential underlying mechanism.

It is unclear whether perfusion-contraction matching (PCM) is maintained during prolonged myocardial ischemia. In 27 anesthetized pigs, left anterior descending coronary arterial inflow was reduced to decrease an anterior work index (WI) at 5 min of hypoperfusion by 40% and then maintained at this level for 12 or 24 h. With 12 h of hypoperfusion, the myocardium remained viable in 6 of 7 pigs (with triphenyltetrazolium chloride; TTC) and with 24 h of hypoperfusion in 5 of 11 pigs (TTC, histology). The reduction in WI to 62 +/- 4 and 62 +/- 3% of baseline in the two groups was matched to the reduction of transmural blood flow (TBF; microspheres) at 5 min of hypoperfusion, averaging 59 +/- 4 and 60 +/- 2% of baseline. With prolonged hypoperfusion, WI decreased to 30 +/- 5% at 12 h and 18 +/- 3% at 24 h; TBF remained unchanged (53 +/- 4 and 54 +/- 4%). The added calcium concentration required for the half-maximal increase in WI increased from 121 +/- 25 microg/ml blood at baseline to 192 +/- 26 microg/ml blood at 12 h of hypoperfusion. Thus, with hypoperfusion for 24 h, PCM is progressively lost, and calcium responsiveness is reduced.

The present article describes the concept of perfusion-contraction matching originally proposed by Ross, goes on to critically discuss the available techniques to measure both regional myocardial blood flow and function in the experimental and clinical setting, and finally analyzes the available evidence for perfusion-contraction match and mismatch during normoperfusion and various scenarios of myocardial ischemia/reperfusion, including acute and subacute ischemia, coronary microembolization, stunning and hibernation.

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.

In mammalian hearts, local myocardial flow (LMF) varies between 20 and 200% of the mean. It is not clear whether oxidative metabolism has a similar degree of heterogeneity. Therefore, we investigated the relation between LMF and local oxidative metabolism in isolated rabbit hearts. Buffer oxygenation with (18)O(2) resulted in labeled myocardial oxidation water (H(2)(18)O). In four hearts, myocardial oxygen consumption (MVO(2)) was calculated from the H(2)(18)O production and compared with that calculated according to Fick. In eight additional hearts, LMF was measured using microspheres. Coronary venous H(2)(18)O kinetics and local H(2)(18)O residues were determined and analyzed by mathematical modeling. MVO(2) recovery from H(2)(18)O was >93% compared with that according to Fick. LMF ranged from 1.91 to 11.24 ml. min(-1). g(-1), and local H(2)(18)O residue ranged from 0.41 to 1.04 micromol/g. Both variables correlated (r = 0.62, n = 64, P < 0.001). Measurements in nine hearts were fitted by modeling using capillary permeability-surface area products (PS(c)) from 2 to 10 ml. min(-1). g(-1). With flow-proportional PS(c), a 3.33-fold difference in LMF was associated with a 6.45-fold difference in local MVO(2). Both LMF and local oxidative metabolism are spatially heterogeneous, and they correlate to one another.

Ischemic myocardium does not inevitably undergo necrosis but rather can survive through downregulation of contractile function, ie, "hibernate." To study the role of endogenous NO in this adaptation, 41 enflurane-anesthetized swine were subjected to 90 minutes of moderate left anterior descending coronary artery hypoperfusion and assigned to placebo (P), to 30 mg/kg N(G)-nitro-L-arginine (L-NNA) IV to inhibit NO synthase, or to aortic constriction (AO) to match the increased left ventricular pressure observed with L-NNA. During normoperfusion, a regional myocardial external work index (WI, mm Hg. mm, sonomicrometry and micromanometry) was reduced with L-NNA (from 326+/-27 [SEM] to 250+/-19, P<0.05) but increased with AO (from 321+/-16 to 363+/-19, P<0.05 versus L-NNA). At 10 minutes of ischemia, WI was lower with L-NNA (109+/-10, P<0.05) than P (180+/-22) and AO (170+/-11) and did not change further at 85 minutes of ischemia. Relationships between WI and transmural myocardial blood flow and oxygen consumption were shifted rightward by L-NNA versus P and AO at both 10 and 85 minutes of ischemia. The maximal increment in calcium-activated external work was not different during normoperfusion among groups but was decreased during ischemia with L-NNA. L-NNA transiently increased myocardial contractile calcium sensitivity along with systemic pressure but reduced it during ongoing ischemia. The free-energy change of ATP hydrolysis after an early ischemic decrease recovered toward baseline values in all groups, and necrosis was absent after 2 (triphenyltetrazolium chloride staining) or 8 (histology) hours of reperfusion. Thus, endogenous NO contributes to hibernation by reducing oxygen consumption and preserving calcium sensitivity and contractile function without an energy cost during ischemia.

The evaluation of regional myocardial blood flow (RMBF) during cardiac catheterization is of particular diagnostic interest. The purpose of this investigation was to validate x-ray densitometric parameters for the evaluation of RMBF. In five anesthetized dogs, arterial flow in the circumflex coronary artery was measured continuously with an electromagnetic flowmeter, and RMBF was determined by colored microspheres. Five different perfusion levels were created by mechanical obstruction of the coronary artery or by intravenous infusion of adenosine. At each steady-state perfusion level, digital subtraction coronary angiograms were obtained for densitometric analysis. Results documented a close correlation between the related time parameters 1/Mean Transit Time (1/MTT, r2 = 0.969), and 1/Rise Time (1/RT, r2 = 0.965) and RMBF over a wide range between 0.36 ml/(min x g) and 11.16 ml/(min x g). Maximum myocardial contrast density (Imax) also showed a good, but inverse correlation (r2 = 0.889) with RMBF and, therefore, did not reflect vascular volume. Contrast medium Appearance Time (AT) showed no correlation to RMBF (r2 = 0.017). Repeat densitometric measurements for different perfusion levels revealed a good reproducibility for MTT (accuracy: 0.001 s; precision: 0.447 s or 6.7 %) and RT (accuracy: 0.014 s; precision: 0.202 s or 10.4 %), while AT (accuracy: 0.072 s; precision: 0.420 s or 68.5%) and Imax (accuracy: 0.022 GL; precision: 1.197 GL or 44.5%) showed substantial variation. Myocardial perfusion reserve (MPR) calculated from RT (r2 = 0.90) or MTT (r2 = 0.94) showed better correlations to RMBF reserve than MPR calculated from AT (r2 = 0.04). In conclusion, only 1/MTT and 1/RT showed a good reproducibility and a close correlation to RMBF. Therefore, only these parameters can be recommended for calculations of RMBF and its reserve under clinical conditions.

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.

Background: Although adrenergic activation plays a major role in the initiation of experimental myocardial ischemia, the significance of alpha-adrenergic coronary constriction in humans has been questioned. The present study assessed the impact of selective alpha-adrenergic receptor activation in patients with normal or atherosclerotic coronary arteries., Methods and Results: In 39 patients, coronary blood flow (CBF, mL/min) was determined from combined angiography and Doppler measurements. In 8 patients with normal coronary arteries (group 1) and 9 with single coronary artery stenosis (group 2), doses of 1, 2.5, 5, and 10 mg IC of the alpha1-agonist methoxamine (M) were injected. Identical doses of the alpha2-agonist BHT933 (B) were injected in 8 patients with normal coronary arteries (group 3) and 8 with single stenosis (group 4). In 6 additional patients with single stenosis (group 5), aortocoronary sinus lactate differences were measured in response to M and B. CBF remained unchanged in group 1. In contrast, CBF was decreased dose-dependently in group 2, with a maximum at 10 mg M (39.0+/-9.4 versus 15.2+/-7.0). In groups 3 and 4, CBF was also decreased dose-dependently, with a maximum at 10 mg B (63.3+/-24.8 versus 49. 1+/-27.9 and 41.5+/-19.0 versus 12.7+/-8.0, respectively). In group 5, there was more net lactate production with B than with M (-0. 34+/-0.11 versus -0.04+/-0.09 mmol/L)., Conclusions: In normal coronary arteries, alpha1-adrenergic activation does not reduce CBF, whereas alpha2-adrenergic activation reduces CBF by microvascular constriction. Both alpha1- and alpha2-adrenergic epicardial and microvascular constriction are augmented by atherosclerosis and can induce myocardial ischemia.

Background: AMI reperfusion by thrombolysis does not improve TIMI flow and LV function. The role of infarct-related artery (IRA) stenosis and superimposed changes in coronary vasomotor tone in maintaining LV dysfunction must be elucidated., Methods and Results: Forty patients underwent diagnostic angiography 24 hours after thrombolysis. Seventy-two hours after thrombolysis, the culprit lesion was dilated with coronary stenting. During angioplasty, LV function was monitored by transesophageal echocardiography. Percent regional systolic thickening was quantitatively assessed before PTCA, soon after stenting, 15 minutes after stenting, and after phentolamine 12 microg/kg IC (n=10), the alpha1-blocker urapidil 600 microg/kg IV (n=10), or saline (n=10). Ten patients pretreated with beta-blockers received urapidil 10 mg IC. Coronary stenting significantly improved thickening in IRA-dependent and in non-IRA-dependent myocardium (from 27+/-15% to 38+/-16% and from 40+/-15% to 45+/-15%, respectively). Simultaneously, TIMI frame count decreased from 39+/-11 and 40+/-11 in the IRA and non-IRA, respectively, to 23+/-10 and 25+/-7 (P<0.05). Fifteen minutes after stenting, thickening worsened in both IRA- and non-IRA-dependent myocardium (to 19+/-14% and 28+/-14%, P<0.05), and TIMI frame count returned, in both the IRA and non-IRA, to the values obtained before stenting. Phentolamine and urapidil increased thickening to 36+/-17% and 41+/-14% in IRA and to 48+/-11% and 49+/-17% in non-IRA myocardium respectively, and TIMI frame count decreased to 16+/-6 and to 17+/-5, respectively. Changes were attenuated with beta-blocker pretreatment., Conclusions: Our finding that alpha-adrenergic blockade attenuates vasoconstriction and postischemic LV dysfunction supports the hypothesis of an important role of neural mechanisms in this phenomenon.

During normoperfusion, both myocardial blood flow and contractile function are heterogeneously distributed throughout the left ventricle, in that midwall segment shortening is higher 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 occurring in inner than in outer myocardial layers. A transmural heterogeneity of myocardial blood flow-with greater inner as compared to outer wall perfusion-exists which is not simply related to temporal fluctuations since the heterogeneous flow pattern is stable over at least a few minutes. 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 increase regional myocardial contractile function. During hypoperfusion, 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. 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.

Background: A threshold concept for ischemic preconditioning (IPc) has been proposed. It is unclear, however, whether IPc, above a certain threshold, is an all-or-nothing or a graded phenomenon., Methods and Results: In 71 enflurane-anesthetized swine, severe left anterior descending coronary artery hypoperfusion for 90 minutes followed by 2 hours of reperfusion resulted in an infarct size (IS, by triphenyltetrazolium chloride) of 16.7+/-3.4% (SEM) of the area at risk. IPc by 2 minutes of low-flow ischemia and 15 minutes of reperfusion before the 90-minute target ischemia did not reduce IS (21.9+/-7.0%). IS was decreased to 9.0+/-2.6% (P<0.05) by 3 minutes of IPc and reduced further to 1.9+/-0.9% (P<0.05) by 10 minutes of IPc. The interstitial adenosine concentration (microdialysis, high-performance liquid chromatography) was unchanged with 2 and 3 minutes of IPc but increased with 10 minutes of IPc (by 573+/-144%). The interstitial bradykinin concentration (microdialysis, radioimmunoassay) remained unchanged with 2 minutes of IPc but increased to a similar extent with 3 minutes (by 198+/-32%) and 10 minutes (by 224+/-30%) of IPc. The IS reduction by 3 minutes of IPc was abolished by blockade of the bradykinin B2 receptor with intracoronary HOE 140 (16.6+/-4.3%) but not with intracoronary infusion of adenosine deaminase (8.4+/-2.5%, P<0.05). HOE 140, however, did not affect the IS reduction (3.5+/- 1.1%, P<0.05) by 10 minutes of IPc. Combined infusion of HOE 140 and adenosine deaminase abolished the IS reduction by 10 minutes of IPc (15.4+/-6.7%)., Conclusions: IS reduction by IPc is a graded phenomenon. Whereas bradykinin is essential during preconditioning ischemia of shorter duration, adenosine is more important during preconditioning ischemia of longer duration.

During moderate prolonged myocardial ischemia, the myocardium is dysfuctional but can remain viable. In such ischemic and dysfunctional myocardium, contractile function is reduced in proportion to the reduction in regional myocardial blood flow, i.e., a state of "perfusion-contraction matching" exists. The metabolic status of such myocardium improves over the first few hours, as myocardial lactate production is attenuated and creatine phosphate, after an initial reduction, returns to control values. Ischemic myocardium, characterized by perfusion-contraction matching, metabolic recovery and lack of necrosis, has been termed "short-term hibernating myocardium". "Short-term hibernating" myocardium can respond to an inotropic stimulation with increased contractile function, however, at the expense of a renewed worsening of the metabolic status. A role for endogenous adenosine in the development of hibernation has been excluded, since neither contractile function, metabolic parameters, nor viability are altered by increased catabolism of endogenous adenosine by infusion of adenosine deaminase. Also activation of ATP-dependent potassium channels is not responsible for "short-term hibernation". "Short-term hibernating" myocardium has, however, reduced calcium responsiveness.

The present study characterizes the hemodynamic and neurohumoral responses to moderate treadmill exercise in conscious dogs with pacing-induced heart failure. Seven dogs were instrumented with a left ventricular micromanometer, ultrasonic crystals for the measurement of systolic wall thickening, left atrial and aortic catheters for the injection of colored microspheres and reference withdrawal, respectively, and ventricular pacing leads with a subcutaneous pacemaker. Dogs were run on a treadmill at a speed of 5 km/h. After control studies, heart failure was induced by rapid left ventricular pacing at 250 beats/min for (mean +/- SD) 23 +/- 6 days. In the control state, cardiac output was increased from 4.5 +/- 1.5 to 7.9 +/- 1.4 l/min (P < 0.05 vs. rest). With heart failure, cardiac output was decreased to 2.5 +/- 0.5 l/min at rest (P < 0.05 vs. control state) and was only 3.0 +/- 0.3 l/min during exercise (P < 0.05 vs. control state; not significant vs. rest). Myocardial and, more so, skeletal muscle blood flows at rest were reduced in heart failure; their increases with exercise were attenuated. An increase in renal blood flow during exercise in the control state was no longer seen in heart failure. Increases in plasma catecholamines and lactate during exercise were more pronounced in heart failure. In conclusion, in heart failure, the increase in cardiac output during exercise was largely attenuated. Increased catecholamine levels may have contributed to splanchnic vasoconstriction and preferential distribution of cardiac output into the working skeletal muscle.

X-ray densitometric evaluation of digital subtraction coronary arteriograms allows a qualitative and quantitative detection of contrast medium propagation through the epicardial coronary arteries, the capillary system and the coronary venous system. So-called "time-density-curves" (TDCs) can be generated following Lambert-Beer's law similar to indicator dilution curves by using contrast medium as the indicator. Several time and density parameters can be derived from these TDCs, which are related to local myocardial perfusion. Different animal validation studies have shown the applicability of this concept for in-vivo evaluation of coronary blood flow and myocardial perfusion. Nevertheless, absolute measurement of volumetric coronary blood flow or myocardial perfusion failed. Therefore, relative changes in coronary blood flow or myocardial perfusion in response to pharmacologically induced maximum hyperemia were measured and coronary or myocardial perfusion reserve was calculated as the ratio of hyperemic flow or perfusion divided by baseline values. Despite theoretical attractions for an application during routine cardiac catheterization, this densitometric approach did not get a wide acceptance. Primary reason for this limited use in specialized centers was the time consuming process of densitometric evaluation of the subtraction coronary arteriograms, which require digital cine angiography and necessitates enormous computer hard ware. This main limitation has been overcome since more powerful computer hard ware (processor speed, hard disk space, digitization boards) has become rapidly available during the last years at more moderate pricing and digital techniques today are state of the art in cardiac catheterization laboratories. In addition, soft ware program packages allowed an automatization of the digitization and densitometric evaluation process. These programs include ECG triggered cine image digitization with improved temporal resolution, semiautomatic definition of regions-of-interest including definition of reference regions-of-interest for the detection of background density changes and quality-controlled densitometric parameter analysis. This progress made an application during routine cardiac catheterization feasible. In animal validation studies this improved X-ray densitometric approach for evaluation of local myocardial perfusion was validated versus colour-coded microsphere techniques. The time parameter "rise time", defined as the time from the start of local contrast medium induced density change to its maximum revealed a close correlation (r2 = 0.965) to the results of the microsphere technique over a wide range of perfusion. We have applied this technique before and after coronary interventions such as balloon angioplasty and stenting. Results documented an improvement of poststenotic myocardial perfusion reserve immediately after coronary balloon angioplasty and an additional improvement after adjunct coronary stenting. Only after stenting but usually not after coronary balloon angioplasty alone poststenotic myocardial perfusion reserve gained the intraindividual reference level, measured in a perfusion bed supplied by an epicardial coronary artery without stenoses. These results documented the functional benefit of coronary stenting on poststenotic myocardial perfusion in addition to the well known morphologic benefit with the creation of a larger and more circular conduit.

It has been suggested that the myocardial perfusion can be qualitatively and quantitatively assessed by different ultrasound contrast techniques. It has been reported that the intracoronary or intraaortic administration of the ultrasound contrast agents can be used to visualize perfusion defects or to analyze the coronary flow reserve. The perfusion analysis after intracoronary injection of ultrasound contrast agents seems to be established, but there are a lot of open questions. A topographic (qualitative) perfusion analysis with visualization of perfusion defects and perfusion areas or analysis of collaterals has been demonstrated. A quantitative analysis of myocardial blood flow has been described but the existing studies are inconsistent. It is not known which parameters of the contrast wash-out curves should be used for perfusion analysis and if the Stewart-Hamilton curve analysis can be transferred to all ultrasound contrast agents as a model for quantitative myocardial blood flow assessment. The development of the transpulmonary contrast agents for echocardiographic evaluation of left ventricular cavity has the impact for myocardial perfusion imaging. The increase of myocardial intensity does not mean that a qualitative or quantitative perfusion analysis can be clinically used. In this field we have to differentiate between the possibilities of qualitative discrimination of perfusion defects and quantitative perfusion (myocardial blood flow) analysis. The different scanning conditions, the poor transthoracic ultrasound window and insufficient enhancement of the myocardial intensity make it problematic to quantify the myocardial perfusion. At the moment myocardial intensity will be increased after intravenous injection of transpulmonary contrast agents, but the value for perfusion analysis has not been shown. New ultrasound technologies such as second harmonic imaging, power-mode and raw data analysis have to show the clinical importance of these techniques for perfusion analysis in daily clinical routine. The open questions of the perfusion analysis by contrast echocardiography will be discussed in this review article.