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Zusammenfassung: Die Task Force „Chest-Pain-Unit“ (CPU) der Deutschen Gesellschaft für Kardiologie erarbeitete Richtlinien für Mindestvoraussetzungen, die erfüllt sein müssen, um als CPU zertifiziert zu werden. Wichtige Voraussetzungen sind unter anderem ein Herzkatheterlabor mit einer ständigen Verfügbarkeit (365 Tage/24 h), mindestens 4 Überwachungsplätze, eine 24-h-Anbindung an ein Notfalllabor sowie in Bezug auf die Bildgebung, die Möglichkeit zur Echokardiographie, CT und MRT (bei Verdacht auf Aortendissektion) und zur Abdomensonographie. Leitliniengerechte Behandlungspfade für den Patienten mit Brustschmerz und dem Verdacht auf ein akutes Koronarsyndrom (STEMI, NSTEMI und der instabilen AP) sollen vorliegen, um unnötige stationäre Behandlungen, aber auch den Patienten gefährdende Entlassungen zu vermeiden. Die Transferzeiten von der CPU in das Herzkatheterlabor sollen den Zeitraum von 15 min nicht überschreiten. Das betreuende Pflegepersonal und die Ärzte sollen durch ein spezielles Schulungsprogramm ausgebildet werden. Das ärztliche Personal sollte ausreichende Kenntnisse im Bereich der Echokardiographie und der internistischen Intensivmedizin besitzen. Die CPU muss von einem Kardiologen geleitet werden, und die CPU kann aus der Notfallversorgung nicht abgemeldet werden.

Gegenwärtige Studien konnten sowohl lineare als auch nicht-lineare Dynamik in der Variabilität der Herzfrequenz nachweisen. Der physiologische Ursprung hierfür ist bislang unbekannt. Die vorliegende Studie untersuchte den Einfluss der zerebralen Funktion auf die lineare und nicht-lineare Dynamik der Herzfrequenzvariabilität. Elektrokardiogramme von sieben hirntoten Organspendern und sieben gesunden Freiwilligen wurden analysiert. Die gesunden Freiwilligen erhielten Atropin zur Anpassung ihrer Herzfrequenz an die der Organspender. Verglichen mit gesunden Freiwilligen ohne Atropin war die lineare Dynamik der Herzfrequenzvariabilität, charakterisiert durch Zeit- und Frequenzparameter, nach Atropingabe signifikant reduziert. Noch ausgeprägter war dieser Unterschied im Vergleich zu den Organspendern. Atropin führte zu einem tendenziellen Anstieg der Komplexität und Nicht-Linearität der Herzfrequenzvariabilität der gesunden Probanden, gemessen als Korrelationsdimension D bzw. größter Lyapunov Exponent L (D=9,43±2,93 vs. 7,65±0,97 und L=0,525±0,099 vs. 0,504±0,047 bits·beat–1; n.s.), während diese Kennwerte bei den Organspendern signifikant (p<0,05) um 19,5±12,8% bzw. 15,0±11,7% abnahmen (D=6,16±0,98 und L=0,428±0,059 bits·beat–1). Ein Verlust der zerebralen Funktion reduziert also sowohl lineare als auch nicht-lineare Komponenten der Herzfrequenzvariabilität. Recent studies outlined linear and non-linear dynamics in heart rate variability; however, their physiological origin is still unknown. The present study investigated the impact of cerebral function on linear and non-linear dynamics in heart rate variability. Electrocardiograms from seven brain dead organ donors and seven healthy volunteers were analyzed. Atropine was used in healthy volunteers to adjust their heart rate to that of the donors. As compared to healthy volunteers without atropine, the linear dynamics of heart rate variability, determined by time and frequency domain analyses, were significantly reduced in healthy volunteers with atropine and, to an even greater extent, in donors. Atropine tended to increase the complexity and non-linearity of heart rate variability in healthy volunteers, as determined by the correlation dimension D and the largest Lyapunov exponent L, respectively (D=9.43±2.93 vs. 7.65±0.97 and L=0.525±0.099 vs. 0.504±0.047 bits·beat–1; both NS), while these indices were significantly reduced in donors by 19.5±12.8% and 15.0±11.7%, respectively (D=6.16±0.98 and L=0.428±0.059 bits·beat–1; both p<0.05 vs. volunteers). Thus, loss of cerebral function reduces both linear and non-linear components of heart rate variability.

Zusammenfassung: Gegenwärtige Studien konnten sowohl lineare als auch nicht-lineare Dynamik in der Variabilität der Herzfrequenz nachweisen. Der physiologische Ursprung hierfür ist bislang unbekannt. Die vorliegende Studie untersuchte den Einfluss der zerebralen Funktion auf die lineare und nicht-lineare Dynamik der Herzfrequenzvariabilität. Elektrokardiogramme von sieben hirntoten Organspendern und sieben gesunden Freiwilligen wurden analysiert. Die gesunden Freiwilligen erhielten Atropin zur Anpassung ihrer Herzfrequenz an die der Organspender. Verglichen mit gesunden Freiwilligen ohne Atropin war die lineare Dynamik der Herzfrequenzvariabilität, charakterisiert durch Zeit- und Frequenzparameter, nach Atropingabe signifikant reduziert. Noch ausgeprägter war dieser Unterschied im Vergleich zu den Organspendern. Atropin führte zu einem tendenziellen Anstieg der Komplexität und Nicht-Linearität der Herzfrequenzvariabilität der gesunden Probanden, gemessen als Korrelationsdimension D bzw. größter Lyapunov Exponent L (D=9,43±2,93 vs. 7,65±0,97 und L=0,525±0,099 vs. 0,504±0,047 bits·beat–1; n.s.), während diese Kennwerte bei den Organspendern signifikant (p<0,05) um 19,5±12,8% bzw. 15,0±11,7% abnahmen (D=6,16±0,98 und L=0,428±0,059 bits·beat–1). Ein Verlust der zerebralen Funktion reduziert also sowohl lineare als auch nicht-lineare Komponenten der Herzfrequenzvariabilität.

The concept of myocardial hibernation implies a downregulation of contractile function as an adaptation to a reduction in myocardial blood flow that serves to maintain myocardial integrity and viability during persistent ischemia. Unequivocal evidence for this concept exists in scenarios of myocardial ischemia that last for several hours; the recovery of energy and substrate metabolism, the potential for recruitment of inotropic reserve at the expense of metabolic recovery, and lack of necrosis are established criteria of short-term hibernation. Furthermore, experimental studies have demonstrated regional myocardial dysfunction at reduced resting blood flow that recovered upon reperfusion, which is consistent with chronic hibernation. In patients, the importance of reduced baseline blood flow vs. that of superimposed reetitive stunning is somewhat controversial; however, in most studies blood flow is reduced, and the myocardium must be ischemic often enough to have persistent dysfunction. Morphologically, hibernating myocardium displays features of dedifferentiation with loss of cardiomyocytes and myofibrils and of degeneration with increased interstitial fibrosis. The mechanisms of short-term hibernation, apart from reduced calcium responsiveness, are not clear at present. With the identification of the underlying mechanism(s) of hibernation, it can potentially be recruited and reinforced pharmacologically to delay impending myocardial infarction.

Abstract: The effect of AT1 receptor blockade on myocardial stunning is still somewhat ambiguous. In some prior studies, coronary occlusion was of too long duration such that the effects of infarction and stunning on the recovery of contractile function could not be distinguished. In others, blood pressure was decreased such that the improved wall excursion could be the consequence of reduced afterload and/or of attenuated stunning. The present study, therefore, investigated the effect of the AT1 receptor antagonist candesartan in a pure model of myocardial stunning with controlled systemic hemodynamics. Fourteen anesthetized open-chest dogs were subjected to 15 minutes occlusion of the left circumflex coronary artery (LCx) and 4 hours subsequent reperfusion. Systemic hemodynamics (micromanometer), regional myocardial blood flow (colored microspheres), and posterior wall thickening (PWT, sonomicrometry) were measured, and data were compared between 7 placebo controls (group 1) and 7 dogs receiving 1 mg/kg candesartan i.v. before LCx occlusion (group 2). Left ventricular peak pressure was kept constant by an intra-aortic balloon, and heart rate did not change throughout the protocol. Regional myocardial blood flow was not different between the groups under control conditions, increased in response to candesartan in group 2 (posterior subendocardial blood flow from 0.99 ± 0.18 to 1.57 ± 0.45; p < 0.05 vs. control conditions), but was not different during myocardial ischemia and at 4 hours of reperfusion between the groups. Under control conditions and during myocardial ischemia, PWT was also not different between the groups. At 4 hours of reperfusion, PWT was still depressed in group 1 (−1.5 ± 3.4 % vs. 17.7 ± 5.6 % during control conditions, p < 0.05), whereas PWT had recovered in group 2 (11.4 ± 3.7 % at 4 hours reperfusion vs. 18.3 ± 2.7 during control conditions, NS, p < 0.05 vs. group 1). In conclusion, pretreatment with the AT1 receptor antagonist candesartan improved the functional recovery of reperfused myocardium. This attenuation of myocardial stunning was not based on more favorable systemic hemodynamics or regional myocardial blood flow.

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 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.

Zusammenfassung: Die röntgendensitometrische Analyse von digitalen Subtraktionsangiokardiogrammen erlaubt eine qualitative und quantitative Erfassung des Kontrastmitteldurchstroms durch das epikardiale, das kapilläre und das koronarvenöse Gefäßsystem. Aus den so gewonnenen Dichte-Zeit-Kurven (Densogrammen) können Parameter berechnet werden, welche eine Beurteilung der lokalen Myokardperfusion erlauben. Diese sehr zeit- und rechenintensiven Vorgänge erlaubten bisher nur eine Anwendung in wenigen Zentren und waren praktisch nicht in das Routinevorgehen im Rahmen von Herzkatheteruntersuchungen zu integrieren. Erst durch Verbesserung der Computerhardware (Prozessorgeschwindigkeit, Festplattenspeicher, Digitalisierkarten), insbesondere jedoch durch eine softwaregesteuerte Automatisierung des EKG-getriggerten Bilddigitalisiervorgangs mit deutlich verbesserter zeitlicher Auflösung, durch semiautomatische Meßfensterpositionierung inklusive Referenzmeßfensterpositionierung zur Erfassung von Hintergrunddichteschwankungen und durch qualitätskontrollierte Parameteranalyse der Densogramme ist eine routinemäßige Anwendung im Rahmen von Herzkatheteruntersuchungen möglich geworden. Tierexperimentelle Untersuchungen stellten eine enge Beziehung zwischen dem so gewonnenen Parameter „Anstiegszeit” der Densogramme und der mittels farbkodierter Mikrosphärentechnik bestimmten lokalen Myokardperfusion dar. Klinische Anwendungen dieser Technik konnten zeigen, daß die poststenotische myokardiale Perfusionreserve, definiert als Quotient aus der Anstiegszeit vor und während pharmakologisch (Papaverin) induzierter Hyperämie, nach koronarer Ballonangioplastie und nach zusätzlicher Gefäßstützen-implantation verbessert wird, diese aber erst nach Gefäßstützenimplantation das intraindividuelle Referenzniveau, welches von einer nicht stenosierten Koronararterie versorgt wird, erreicht. Diese Ergebnisse verdeutlichen den zusätzlichen funktionellen Aspekt der koronaren Gefäßstützen-implantation auf die poststenotische Myokardperfusion zusätzlich zu dem morphologischen Aspekt der optimierten Gefäßlumenweitung.

Summary: 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 transfered 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 enhancemant 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.

Heart failure is characterized not only by systolic, but also by diastolic dysfunction. The present study tested whether or not diastolic dysfunction is associated with changes in tissue properties and collagen network structure. Heart failure was induced in seven chronically instrumented, conscious dogs by rapid left ventricular pacing (250 min−1). After 2–5 [mean: 4±1 (s.d.)] weeks pacing, heart failure was apparent from clinical symptoms (ascites, cachexia, edema, exercise intolerance) and hemodynamic parameters (significant increases of heart rate and left ventricular end-diastolic pressure and decreases of left ventricular maximal pressure, dP/dtmaxand systolic wall thickening). The left ventricle was dilated, as indicated by a decrease of end-diastolic wall thickness (6.3±2.0v7.2±2.1 mmP<0.05; sonomicrometry). The left ventricular end-diastolic pressure—strain relation (strain: relative change of end-diastolic wall thickness) was obtained during alterations of loading conditions by inferior caval vein and descending thoracic aortic occlusion. The slope of this relation increased from 85±20 to 428±188 in heart failure, indicating an increase of left ventricular stiffness. Collagen was stained with picrosirius red and analyzed using polarized light microscopy. In heart failure, the collagen volume fraction remained unchanged (1.9±1.2v2.3±1.3%; N.S.), while the nonuniformity of collagen orientation, as reflected by its standard deviation, was increased (11.1±1.8v6.1±0.4 oP<0.05). The nonuniformity of collagen fiber orientation correlated with left ventricular stiffness [r=0.75].

The renin-angiotensin system is activated during myocardial ischemia, and local angiotensin II formation occurs in ischemic hearts. At least two angiotensin II receptor subtypes, the AT1and AT2receptor, have been identified. The cardiovascular effects of angiotensin II have been largely attributed to activation of AT1receptors. In ventricular preparations from normal rat and pig hearts, the density of AT1receptors is higher than that of AT2receptors, whereas data on the AT receptor subtype density and its distribution in human hearts remain controversial. AT1receptor blockade increases coronary blood flow during ischemia in dogs and during reperfusion in rats. It also reduces the incidence of ischemia-related arrhythmias in rats and guinea pigs, limits infarct size in pigs, improves functional and metabolic recovery following myocardial ischemia, and attenuates ventricular remodelling post-myocardial infarction in rats. The potential mechanisms responsible for the cardioprotection by AT1receptor blockade remain to be elucidated in detail, but appear to involve AT2receptor activation and the subsequent action of bradykinin, prostaglandins, and/or nitric oxide. Patients under treatment with AT1receptor antagonists for indications such as hypertension and ventricular dilatation after myocardial infarction are likely to have improved prognosis when suffering an acute myocardial infarction.

Summary In clinical studies stress-induced myocardial ischemia in patients with coronary artery disease is used to evaluate the severity of this disease. The discussion on the importance of some parameters measured during this intervention is controversial, other parameters are difficult to obtain. On the basis of an experimental model of stress-induced myocardial ischemia, we tried to find an index that reflects best this cardiac state.

Controversies on acetylcholine-induced increases or decreases in coronary blood flow arise from obvious species differences, the role of endothelium in mediating vascular smooth muscle responses, and the marked negative chronotropic and inotropic effects of acetylcholine. In man, there appears to be a predominant dilation of intact epicardial coronary arteries and a constriction of artherosclerotic segments. However, at present there is no evidence for a vagal initiation of myocardial ischemia.

Summary Ultrasonic techniques for the measurement of ventricular dimensions are widely used in acute and chronic experiments. Implantation of ultrasonic crystals is associated with reversible and irreversible myocardial damage which might limit the interpretation of the obtained results, in particular during acute experiments. We therefore developed a sonomicrometric device which can be easily and quickly implanted, and thus reduces the reversible myocardial damage induced by prolonged surgical implantation.

Summary In 14 open-chest mongrel dogs, the effects of heart rate on hemodynamic severity of proximal coronary artery stenosis were studied. Stenosis was produced by a circumferential wire snare on left cirucmflex coronary artery. An intermediate stenosis was defined by reduction of peak reactive hyperemia response to 200% of control flow, a critical stenosis by prevention of any reactive hyperemia flow to a 15-s occlusion. Heart rate was increased stepwise from control to 160 and 200 beats/min by left atrial pacing. In intermediate stenosis, increased pacing rate reduced peripheral coronary pressure distal to the stenosis from 77±3 to 73±4 to 65±3 mm Hg (p<0.05) and increased stenosis resistance from 0.30±0.05 to 0.34±0.05 to 0.35±0.05 resistance units (p<0.05). In critical stenosis, increased heart rate changed peripheral coronary pressure from 45±5 to 49±5 to 48±5 mm Hg (p<0.01) and reduced stenotic resistance from 1.24±0.19 to 1.08±0.18 to 1.15±0.19 resistance units (p<0.005). A significant correlation between changes in stenotic resistance and peripheral coronary pressure was obtained (r=−0.71, p<0.001). In maximally dilated coronary arteries, a circumferential stenosis decreased circumflex artery flow to 50%. Increased pacing rate up to nearly 200 beats/min raised peripheral coronary pressure distal to the stenosis from 51±4 to 56±4 mm Hg (p<0.005) and changed stenotic resistance from 0.41±0.13 to 0.30±0.06 to 0.33±0.10 resistance units (p<0.05).

Summary In a series of experiments on 12 normotensives and 12 essential hypertensives the influence of traffic noise (81 dB) on autonomous functions after stress exposure was examined. The process of the stress reaction was started by visually presented arithmetic tasks under affecting noise. With normotensives and hypertensives this combination of stressors led to a significant increase of the systolic and diastolic blood pressure, heart rate, and muscle tone.

The present study tested (1) whether xamoterol recruits an inotropic reserve in reperfused myocardium and (2) whether acute inotropic stimulation by xamoterol has deleterious consequences on the long-term recovery of the reperfused myocardium. Sixteen anaesthetized, open-chest dogs were bilaterally vagotomized and heart rate kept constant by left atrial pacing. The distal left circumflex coronary artery was occluded for 15 min and then reperfused for 8 h. The coronary occlusion resulted in regional myocardial dyskinesia and myocardial function remained severely depressed after release of the occlusion. At 10 min reperfusion, 8 dogs received xamoterol (100 µg/kg i. v.), whereas the remaining 8 dogs served as controls and received saline. Xamoterol increased mean systolic wall thickening velocity (from 1.47 ± 2.34 (SD) mm/s at 10 min reperfusion to 7.13 ± 3.55 mm/s at 30 min reperfusion and 7.64 ± 2.48 mm/s at 1 h reperfusion, respectively, both P < 0.05). In the control group, only a slow recovery of mean systolic wall thickening velocity was observed (from 3.14 ± 3.30 mm/s to 2.96 ± 3.74 mm/s and 4.03 ± 3.00 mm/s at 10 min, 30 min, and 1 h reperfusion, respectively). At 8 h reperfusion, mean systolic wall thickening velocity was similar in both groups (7.97 ± 4.23 mm/s in the xamoterol-group and 6.87 ± 4.00 mm/s in the placebo-group). Histological examination revealed no difference in the extent of necrosis between the two groups after 8 h reperfusion. We conclude that (1) xamoterol recruits an inotropic reserve in reperfused myocardium, and (2) this recruitment of an inotropic reserve does not compromise functional recovery and structural integrity of the reperfused myocardium.

Positive inotropic substances which enhance the myocardial cAMP level or inhibit the Na+/K+-ATPase are known for their proarrhythmic side-effects. This study was performed to investigate the inotropic and arrhythmogenic action of the Na+-channel activator BDF 9148 (racemate) in comparison to its S-enantiomer BDF 9196, its congener DPI 201-106 (racemate), to norepinephrine, and to ouabain. In 30 open-chest dogs, the effects of these substances on the first derivative of left ventricular pressure (dP/dt, Millar-tip catheter) and anterior systolic wall thickening (AWT, sonomicrometry) were studied. Concomitantly, myocardial excitability, conduction times, and refractory period were assessed with a transmural, three-dimensional, 16-electrode array in the anterior wall. For the study of the Na+-channel activators, a- and ß-adrenergic and muscarinic receptors were blocked. A first set of measurements was performed during normoperfusion with administration of BDF 9148 (1 mg/kg, n=8), BDF 9196 (0.5 mg/kg, n=8), and DPI 201-106 (1 mg/kg, n=8), respectively. A second set of measurements was performed with administration of the threefold dosage of either substance. With a severe stenosis on the left anterior descending coronary artery, a final set of measurements was performed, again using the higher dosage of either substance. For the study of norepinephrine (0.5 µg/kg/min i.v., n=6) and ouabain (40 µg/kg i.v., n=4), measurements were performed during normoperfusion in additional animals.

The effect of selective a1-adrenoceptor blockade on regional myocardial blood flow and contractile function during exercise-induced myocardial ischemia was determined in nine dogs having chronic single vessel coronary stenosis (ameroid constrictor). Treadmill exercise performed after ß-adrenoceptor blockade (1.0 mg/kg i.v. propranolol), to block potential prejunctional effects recently recognized with a-blockade, elicited severe regional myocardial ischemia with a steady-state reduction of regional systolic wall thickening of the post-stenotic myocardium from a resting value of 21.8% to 7.0%. Blood flow to the ischemic subendocardium was reduced from 0.76 to 0.36 ml/min/g (microspheres). Prazosin (80 µg/kg i.v.) was administered during continued running, and angiotensin II was simultaneously infused to prevent the decrease in systemic arterial pressure caused by prazosin. During the subsequent steady state, with arterial pressure matched to the pre-prazosin level, regional subendocardial blood flow improved to 0.60 ml/min/g and systolic wall thickening in the post-stenotic region increased modestly to 10.2%. No changes in blood flow to the outer portion of the post-stenotic region or the remote control region were seen, and prazosin caused no effect on regional function in the control area, indicating effective blockade of prejunctional effects of prazosin (demonstrated in pilot studies). The finding that blockade of a1-adrenoceptors resulted in improved ischemic zone subendocardial blood flow and contractile function are consistent with a1-adrenoceptor-mediated reduction of blood flow to the ischemic subendocardium during exercise-induced ischemia in dogs with ß-blockade.

Ventricular arrhythmias are primarily responsible for sudden cardiac death early after the onset of acute myocardial ischemia. We designed an experimental model to simultaneously characterize regional myocardial function, myocardial blood flow, and electrophysiological parameters, and to determine predisposing factors for the development of early ventricular arrhythmias (EVA).

Summary The “Gregg phenomenon” implies that myocardial function and oxygen consumption ( ) increase when coronary perfusion is enhanced within or above the autoregulatory range. We have recently demonstrated that the “Gregg phenomenon” has no significance for regional myocardial function and in anesthetized swine in situ. There is, however, some evidence that the “Gregg phenomenon” may exist within stunned myocardium. To test whether coronary hyperperfusion increases regional myocardial function and in stunned myocardium, in six anesthetized swine the left anterior descending coronary artery (LAD) was cannulated and perfused at constant pressure (CAP) using an extracorporal circuit. The coronary vein which parallels the LAD was cannulated to allow measurement of regional and regional systolic wall thickening (WT%) of the anterior myocardium was assessed using sonomicrometry. Blood flow (CBF) to the LAD was increased by increasing CAP within the extracorporal circuit or by intracoronary adenosine infusion (150 μg/min). In normal myocardium, increasing CBF from 71.4 ± 19.7 (SD) to 156.7 ± 48.8 ml/min/100 g by increasing CAP from 100 ± 10 to 190 ± 10 mm Hg or increasing CBF from 75.1 ± 29.1 to 189.2 ± 45.8 ml/min/100 g by intracoronary adenosine infusion did not increase WT% (34.3 ± 12.2 % vs 32.1 ± 10.6 % and 32.3 ± 10.7 % vs 30.1 ± 13.2 %, respectively). was not changed during enhanced CAP (6.94 ± 1.05 vs 8.10 ± 1.08 ml/min/100 g) and during intracoronary adenosine infusion (6.67 ± 1.45 vs 7.30 ± 2.23 ml/min/100 g). Twenty min of hypoperfusion followed by 30 min of reperfusion depressed WT% by 47 % (p < 0.05). However, was only decreased by 23 % (NS). In the stunned myocardium, increasing CBF from 62.1 ± 36.4 to 157.1 ± 60.0 ml/min by increasing CAP was not associated with an increase in WT%. , however, increased from 5.14 ± 1.07 to 8.88 ± 1.83 ml/min/100 g (p < 0.05). Comparable results were achieved when CBF was increased from 60.3 ± 28.7 to 176.9 ± 48.5 ml/min by intracoronary adenosine infusion. WT% was unaffected, while increased from 4.69 ± 0.92 to 9.46 ± 3.39 ml/min/100 g (p < 0.05). Thus, increasing coronary perfusion within or above the autoregulatory range increases in stunned myocardium, but without a simultaneous increase in regional myocardial function.

Summary The prevailing paradigm of coronary physiology and pathophysiology is that a balance between blood flow (i.e., supply) and function (i.e., demand) exists under normal conditions and that an imbalance between supply and demand occurs during ischemia. However, this paradigm is derived largely from studies relating changes in total coronary inflow to global ventricular function. The present article examines the relationship between myocardial blood flow and function on a regional level and proposes that a change may be needed in the current paradigm of coronary pathophysiology. In normal myocardium, considerable heterogeneity of regional blood flow exists, indicating either similar heterogeneity of metabolic demand and function or questioning the precision of metabolic coupling between flow and function. After the onset of ischemia, a transient imbalance between the reduced blood flow and function may exist. However, myocardial function rapidly declines and during early steady-state ischemia regional myocardial blood flow and function are once again evenly matched. Such supply-demand balance may persist over prolonged periods of ischemia enabling the myocardium to remain viable through reduction of energy expenditure for contractile function, i.e., to “hibernate”. Whereas in “hibernating” ischemic myocardium, regional myocardial blood flow and function are both reduced but appropriately matched to one another, flow and function appear to be largely uncoupled in reperfused “stunned” myocardium. The clinical identification of viable but ischemic (hibernating) and postischemic (stunned) myocardium is of utmost importance in patients undergoing reperfusion procedures. A new paradigm of coronary and myocardial pathophysiology, encompassing a regional as well as a global view of perfusion and function, will have to include explanations for phenomena such as myocardial hibernation and myocardial stunning.

Summary The primary purpose of this study was to evaluate parameters used for the measurement of regional myocardial contractile function in the setting of left ventricular (LV) asynchrony. Secondarily, we tested whether the peak negative value of left ventricular dP/dt (-dP/dt) can be used to estimate global LV end-systole during asynchrony. In seven anesthetized (Isoflurane) swine the left anterior descending coronary artery was cannulated and perfused at constant blood flow rates. To produce LV asynchrony, dobutamine (D) was infused into the perfusion system. This was repcated later during coronary hypoperfusion (HYPO) sufficient to produce regional contractile dysfunction. The amount of LV wall thickening during systole (% WT, sonomicrometry) was calculated using either - dP/dt or the closure of the aortic valve (AO, electromagnctic flow probc) for estimating the timing of global LV end-systole. % WT was compared to other paramcters which are not dependent upon the timing of global LV end-systole, including the amplitude of the first harmonic of the Fourier transform (AMP) and regional myocardial work (WI) estimated from the left ventricular pressure-wall thickness relationship. A close correlation between global LV end-systole defined by the AO or - dP/dt existed during control. D or HYPO. During HYPO+D no such relationship was found (r=.22, NS), and % WT calculated using - dP/dt as an estimate of end-systole was underestimated when comparcd to % WT calculated by use of the AO to estimate end-systole (2.9±6.8% vs 6.3±6.6%, p<.05). % WT, AMP, and WI showed similar results during control, D and HYPO. However, D during HYPO increased the AMP from .59±.23 mm to .76±.32 mm and WI from 67±20 mm Hg*mm to 95±24 mm Hg*mm (p<.05), respectively. This increase in regional myocardial function, however, was not detected by % WT (10.5±6.4% vs 6.3±6.6%). Thus, during left ventricular asynchrony, the measurement of LV-dP/dt to estimate the timing of global LV end-systole is inappropriate and can lcad to inaccuracies in the measurement of regional contractile function. Parameters such as AMP or WI are advantageous since global LV end-systole docs not need to be accurately defined.

Summary Impaired excitation-contraction coupling has been suggested as the underlying mechanism of postischemic contractile dysfunction of reperfused myocardium in in-vitro studies. To test this hypothesis in situ, postextrasystolic potentiation (PESP) following an extrasystole with constant prematurity and three different postextrasystolic time intervals (compensated, regular, abbreviated) was analyzed in 12 anesthetized dogs. Changes in regional inotropic state were assessed by comparison of end-systolic wall thickness (sonomicrometry) during PESP to the respective pressure-matched values of an end-systolic pressure/wall-thickness relationship established during brief manual clamping of the aorta. Before ischemia, posterior end-systolic wall-thickness was increased by 0.19±0.35 (SD) mm during PESP with an abbreviated, by 0.36±0.42 mm with a regular, and by 0.60±0.42 mm with a compensated postextrasystolic interval. Bascline systolic wall thickening was decreased from 16.2±5.4% (before ischemia) to −3.0±3.4% at the end of 15 min left circumflex coronary occlusion, and to 2.8±7.5% at 10 min, 7.2±3.9% at 4 h, and 7.9±4.1% at 8 h reperfusion. Stepwise increases in regional inotropic state during PESP with increasing postextrasystolic intervals were not different in normal and reperfused myocardium. Thus, excitation-contraction coupling appears not to be impaired during inotropic stimulation of reperfused myocardium in situ.

Summary Contractile dysfunction of reversibly injured, reperfused myocardium can be enhanced by inotropic interventions. A decrease in the Ca-sensitivity of contractile proteins with slow recovery during reperfusion has been suggested as a potential mechanism underlying this postischemic dysfunction. We therefore tested the effects of the cardiotonic agent AR-L 57 (1 mg/kg i.v.) in six anesthetized, vagotomized dogs during constant atrial pacing at 192±6 beats/min. Before ischemia, AR-L 57 increased left ventricular pressure from 131±22 to 138±21 mm Hg and maximum dP/dt from 3,022±1,427 to 4,337±2,608 mm Hg/s. Mean systolic thickening velocity of the posterior myocardium was increased from 8.9±1.1 to 11.7±1.1 mm/s. After release of a 15 min LCX-occlusion which caused complete regional akinesia, baseline function in the posterior myocardium was severely depressed and only gradually returned towards control values over 8 h of reperfusion. AR-L 57 increased systolic thickening velocity at 10 min, 4 and 8 h reperfusion to a similar extent as before ischemia. With reference to a purported Ca-sensitizing mechanism underlying the positive inotropic action of AR-L 57, our data suggest no change in the Ca-sensitivity of reperfused myocardium.

Nach einer akuten Reduktion der Myokarddurchblutung stellt sich, wenn eine gewisse Restdurchblutung vorhanden ist, für einige Stunden ein neuer Zustand mit pari passureduzierter Durchblutung und Funktion ohne Entwicklung eines irreversiblen Schadens ein. Diese Situation anhaltender kontraktiler Dysfunktion in vitalem Myokard, die sich nach Reperfusion normalisiert, wird “short-term hibernation” genannt. Der metabolische Zustand des “short-term hibernating” Myokards verbessert sich über die ersten Stunden insofern die initial auftretende myokardiale Laktatproduktion mit der Zeit abgeschwächt ist und die Kreatinphosphatkonzentration nach einer kurzfristigen Reduktion bis auf die Ausgangswerte zurückkehrt. “Short-term hibernating” Myokard reagiert auf kurzfristige inotrope Stimulation durch Dobutamin mit einer gesteigerten kontraktilen Funktion. Diese Steigerung der kontraktilen Funktion während kurzdauernder inotroper Stimulation erfolgt jedoch auf Kosten der metabolischen Erholung. Der beschleunigte Abbau des während einer Ischämie vermehrt freigesetzten endogenen Adenosins durch intrakoronare Infusion von Adenosin-Deaminase verhindert die metabolische Erholung des “short-term hibernating” Myokards nicht, reduziert das Ausmaß der inotropen Reserve nicht und induziert keine Nekrosen. Damit ist das während Ischämie vermehrt freigesetzte endogene Adenosin nicht an der Entstehung des “short-term hibernating” Myokards beteiligt. Auch die Aktivierung ATP-abhängiger Kaliumkanäle ist nicht für die Entstehung des “short-term hibernation” verantwortlich. “Short-term hibernating” Myokard weist jedoch eine reduzierte Kalziumreagibilität auf. During moderate prolonged myocardial ischemia, the myocardium is dysfunctional 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.

1)Despite certain similarities between ischemic preconditioning and myocardial hibernation, these two cardioprotective phenomena are different in nature. 2) Intermittent reperfusion inbetween the preconditioning and the sustained ischemic period is not necessary for infarct size reduction by ischemic preconditioning.

Conclusion Since in the clinical setting stunning may coexist with persistently ischemic and infarcting myocardium, the ben fit el therapeutic interventions on the stunned myocardium must be weighed against potential deleterious effects on the ischemic myocardium.

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Adenosine has been reported to attenuate the positive inotropic effects of catecholamines in in vitro-heart preparations of rodents. These results were not confirmed in anesthetized dogs during intracoronary infusion of isoproterenol. However, these experiments did not study the effects of adenosine on the inotropic effects of endogenously released catecholamines. Therefore we performed cardiac sympathetic nerve stimulation (CSNS) in 5 anesthetized, vagotomized dogs. The left circumflex coronary artery was perfused at a constant pressure of 130±4 mmHg. The contractile function of the circumflex-perfused myocardium was analyzed by sonomicrometry. CSNS at 1, 2, 5, 10 and 20 Hz increased systolic segment shortening (SScx) in a frequency-dependent manner from 10.9±2.6 at control to 15.3±3.4 % at 20 Hz. During intracoronary infusion of adenosine (50 µg/ kg/min) CSNS still increased SSCXfrequency-dependently from 9.9±3.5 to 16.3±4.5 %. The lack of any adenosine-catecholamine antagonism in our experiments was not due to the sequence of procedures, nor to the marked flow increase induced by adenosine, since SSCXat rest was rather reduced with adenosine infusion and since during intracoronary infusion of papaverine and sodium-nitroprusside similar results were obtained. It seems that the observation of adenosine-catecholamine antagonism in rodents is a species dependent phenomenon. Supported by SFB 30 - Kardiologie, Düsseldorf

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