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From available results, the following schematic can be drawn: Reductions in perfusion pressure are not associated with impaired ventricular function as long as they take place within the autoregulatory range. Additional reductions in perfusion pressure that moderately diminish coronary blood flow will result in a particular ischemia with decreased but stable function: perfusion and contraction match, the myocardium hibernates. The process responsible for this new equilibrium could be termed down regulation of function. The trigger inducing hibernation is so far unknown. The strategy, however, is similar to that used by hibernating animals. Likewise, myocardial hibernation is a protective mechanism. As hibernators recover initial function after unfavourable periods are terminated, hibernating myocardium recovers after institution of physiologic perfusion. It is under debate, whether function quickly recovers or remains temporarily depressed. As hibernating animals might finally even die, if unfavourable periods last too long, myocardium might become irreversibly injured due to ischemia lasting too long. Additional reductions in perfusion pressure and oxygen supply below the hibernating range produce ischemia in the more classical sense, because oxygen supply and demand no longer match. Damage will become irreversible in case the situation persists longer than about 20 min. After onset of reperfusion, the myocardial function would remain depressed, however, for a considerable period: myocardial stunning. Considering the regional heterogeneities of myocardial blood flow, distinct differentiation between moderate and severe ischemia is difficult. Ischemia will induce more articulate damage in subendocardial than in subepicardial layers. Similarly, damage in the ischemic core will be more pronounced than in the border zone.(ABSTRACT TRUNCATED AT 250 WORDS)

A possible cause for the decreased function in postischemic reperfused (= stunned) myocardium could be a decrease in Ca++ sensitivity. To test this hypothesis, we used an agent with reportedly Ca++ sensitizing properties (EMD 57033) and performed experiments on a total of 17 isolated rabbit hearts that were perfused with an erythrocyte-containing medium in a modified Langendorff setting (hct = 30%; Ca++ = 2.0 meq/l). The hearts were divided into two groups. In one group (n = 9), the Ca++ sensitizer (30 microM) was administered to nonischemic myocardium, and in a second group (n = 8), the Ca++ sensitizer was administered after 30 min of reperfusion that followed a period of 20 min normothermic, no-flow ischemia. In the nonischemic group, addition of the agent, improved left ventricular (LV) function significantly. In the ischemic group, LV-function was depressed at 30 min reperfusion compared to control. Again, the agent improved LV-function significantly. The increase in systolic and diastolic function was comparable in both groups as well as the oxygen consumption that was significantly increased after administration of the agent. In both groups, the agent neither exhibited significant, positive chronotropic nor arrhythmogenic effects. We summarize that the novel Ca++ sensitizer acts as a potent positive inotropic agent in the isolated blood-perfused rabbit heart. Because of the agent's properties to ameliorate postischemic contractile dysfunction, this general strategy may be useful for treating poorly functioning reperfused myocardium.

Efficiency is defined as the ratio of the energy delivered by a system to the energy supplied to it. Depending on the particular question being addressed, there exist a plethora of definitions of efficiency in medical texts, thus hampering their comparison. If only the ventricular work seen by the arterial system is under investigation, pressure-volume work will serve as a useful numerator. If, on the other hand, external and internal work together, i.e. the total mechanical work, is of interest, the pressure-volume area might be employed. Total myocardial oxygen consumption (MVO2) will be a useful denominator in the case of aerobic energy production. The MVO2 for the unloaded contraction must be assessed if, as in other energy transfer systems, net efficiency is to be addressed. If even smaller steps in the chain of energy transfer are to be investigated MVO2 for the arrested heart must be assessed. With an appropriate therapy, hemodynamic determinants can be varied, to improve cardiac efficiency. Nonetheless, measurement of all variables necessary for the calculation of efficiency remains a challenge, in particular in the clinical setting. Separation of the direct effects of drugs on efficiency is even more difficult, since hemodynamic conditions can hardly be controlled throughout the observation period, and changes in efficiency might be secondary to changes in hemodynamics. Whether the heart by itself employs mechanisms to improve its efficiency is still a matter of discussion: there is evidence that when oxygen supply decreases, the heart can switch from one substrate to a less costly one, or possibly can improve efficiency through better use of oxygen. Moreover, the heart seems to "sense" an even more decreased oxygen supply and reduce function in response. Myocardial stunning could be regarded as a protective mechanism as well, with function remaining depressed and the oxygen supply being normal or close to normal. One may conclude from the decreased efficiency that the excess oxygen consumption is used up for repair processes. The improved efficiency found in hypertrophied hearts represents another adaptive process. The underlying mechanism is unclear: a shift towards isomyosin V3 or some undefined shift in metabolic pathway is discussed. It is also still a moot question towards which objective the efficiency of the heart is adjusted. It has been described that under physiologic conditions, the efficiency of both the left and the right ventricle ought to be maximized.(ABSTRACT TRUNCATED AT 400 WORDS)

Sudden increases in aortic pressure (AoP, mm Hg) are associated with increases in left ventricular (LV) function which persist even after diastolic volume has returned to its initial value (Anrep effect). Likewise, increases in coronary arterial pressure (CAP, mm Hg) are associated with improved LV function (gardenhouse effect). In situ, increases in AoP are paralleled by increases in both CAP and coronary blood flow, i.e., oxygen supply. We investigated the individual contributions of AoP and CAP increases on function (peak systolic pressure: LVPmax, mm Hg; dP/dtmax, mm Hg/s; end-diastolic pressure: LVPed, mm Hg) and end-diastolic geometry (inner diameter: IDed, mm; wall thickness: WTed, mm; sonomicrometry). CAP-induced increases in coronary flow were prevented by admixing dextran to the perfusate. The experiments were performed on isolated, saline-perfused, working rabbit hearts. Increasing CAP from 60 to 80 mm Hg (n = 11) resulted in improved function: LVPmax 89 +/- 3 vs. 94 +/- 3, dP/dtmax 1160 +/- 50 vs. 1250 +/- 50, LVPed 17 +/- 1 vs. 16 +/- 1 (mean +/- SEM). IDed decreased from 9.96 +/- 0.25 to 9.64 +/- 0.33 and WTed increased from 6.02 +/- 0.16 to 6.15 +/- 0.17. In a second series, AoP was increased from 60 to 80 (n = 9). Both LVPmax, dP/dtmax and LVPed increased (90 +/- 4 vs. 97 +/- 3, 1170 +/- 70 vs. 1270 +/- 90 and 18 +/- 1 vs. 19 +/- 1). IDed increased from 9.76 +/- 0.39 to 9.99 +/- 0.37 and WTed decreased from 6.08 +/- 0.22 to 5.86 +/- 0.25. After additionally increasing CAP to 80, function further improved (LVPmax: 101 +/- 3, dP/dtmax: 1310 +/- 80) while LVPed decreased (18 +/- 1). This time, IDed decreased to 9.71 +/- 0.36 and WTed increased to 6.03 +/- 0.26. Increases in CAP improve LV function via the gardenhose effect and likely do not depend on simultaneous increases in coronary flow or oxygen supply. On the other hand, increases in AoP alone improve systolic function via the Frank-Starling mechanism. Increases in both pressures together amplify this effect. Increases in CAP and in AoP have opposing effects on IDed and WTed. In conclusion, the homeometric Anrep effect--at least in part--can be viewed as synergistic action of the Frank-Starling mechanism and the gardenhose effect for this experimental model.

One central hypothesis of cardiovascular physiology has been a balance between myocardial blood flow and contractile function during natural conditions, i.e. supply and demand are matched. This hypothesis was derived from studies relating total coronary blood flow to global ventricular function. The present article examines the relationship between myocardial blood flow and function on a regional level. In normal myocardium, considerable heterogeneity of blood flow exists, indicating similar heterogeneity of metabolic demand and potentially also function. However, when the degree of metabolic coupling between flow and function is questioned, there is no evidence whether or not flow and function are matched on a regional level. One closely related hypothesis of cardiovascular pathology has been an imbalance or mismatch between supply and demand during ischemia. Because myocardial function rapidly declines during early ischemia, residual, regional myocardial blood flow and function may be once again matched on a lower level. Such low-level supply-demand balance may persist over prolonged periods of ischemia and permit the myocardium to remain viable, i.e. the myocardium can "hibernate." Analyzing myocardial blood flow and function on a regional level has generated new insight into strategies of adaptation to the adverse situation of reduced blood flow. Whereas in hibernating (ischemic) myocardium, regional myocardial blood flow and function are matched, flow and function appear to be unmatched in reperfused, dysfunctional, i.e. 'stunned' myocardium. "Stunned myocardium" appears once more as a result of a strategy of adaptation, as the preceding ischemia did not induce irreversible myocardial damage but preserved the ischemic myocardium viable, although functionally impaired.

The prolonged regional contractile failure of reperfused myocardium has usually been characterized in terms of systolic function, while only few reports on its diastolic function are available. None of these studies considered changes in the isovolumic diastole and the subsequent filling phase separately. Therefore, in the present study, the velocities of wall excursion during systole (Vsys), isovolumic diastole (Viso) and filling phase (Vfill) were determined in 12 anesthetized dogs. Additionally, post-ejection thickening (Pejt), a marker of left ventricular asynchrony, was determined. Measurements were performed under control conditions, during a 15 minute left circumflex (LCX) coronary artery occlusion (CAO) and at 10 minutes, 4 and 8 hours reperfusion. Heart rate, left ventricular pressure, and Vsys, Viso, Vfill, and Pejt of the anterior myocardium remained unchanged throughout the experiments. During CAO, systolic wall-thickening of the posterior wall was reversed to systolic wall-thinning. Upon reperfusion, Vsys started to recover (2.5 +/- 3.2 mm/s at 10 minutes) and gradually improved over 8 hours of reperfusion (4.6 +/- 3.2 mm/s at 4 hours, 6.4 +/- 1.5 mm/s at 8 hours). Viso became positive during CAO (9.4 +/- 7.1 mm/s vs. -5.6 +/- 3.9 mm/s under control conditions) and was unchanged at 10 minutes reperfusion (7.9 +/- 5.2 mm/s). After 4 hours and 8 hours of reperfusion, Viso recovered to 1.2 +/- 9.2 mm/s and -0.3 +/- 10.7 mm/s, respectively. Vfill also became positive during CAO (1.5 +/- 6.2 mm/s vs. -18 +/- 8.7 mm/s under control conditions). There was a quick recovery of Vfill (-9.4 +/- 7.5 mm/s) with the onset of reperfusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Some homeothermic animals can survive adverse conditions by hibernation, i.e., by reducing their body temperature in accordance with ambient temperature, thus reducing metabolism and vital functions. Six years ago, the term hibernation was introduced to describe a particular state of the myocardium. Although the meaning is different from that used in zoology and, thus, is misleading, it is used increasingly to describe a condition induced by moderate reduction in coronary flow. Some evidence in the literature suggests that the myocardium can actively reduce its mechanical function as a consequence of reduced coronary flow in order to prevent ischemia-induced injury. It is conceivable that the hibernating myocardium is the result of such a down-regulation of function. The hibernating myocardium can be characterized by decreased function in the hypoperfused area, which still exhibits active metabolism and remains viable. This is in contrast to "stunned" myocardium, which represents dysfunction during postischemic reperfusion, i.e., with coronary blood flow being close to normal. In analogy to hibernation in its original meaning, down-regulation and hibernating myocardium are considered to represent a protective mechanism, because such myocardium can quickly regain its initial function after restoration of physiologic blood flow. Because hibernating myocardium is salvageable, it has to be distinguished from other dysfunctional tissue that has lost its function due to ischemic damage, so that appropriate clinical interventions can succeed in restoring normal coronary blood flow.

Bradycardic agents could limit the consequences of myocardial ischemia via two mechanisms: by decreasing myocardial oxygen demand (MVO2) and by increasing diastolic coronary blood flow (CBF). We investigated whether the benzazepinone UL-FS 49 affects only sinus node cells or also smooth muscle and/or myocardial cells. To avoid confounding interactions with the periphery, we performed experiments on 11 isolated, blood-perfused canine hearts. Injection of UL-FS 49 (1 mg/kg i.c.) significantly reduced heart rate (HR) from 104 +/- 7 to 93 +/- 7 min-1 (mean +/- SEM) and increased stroke volume (n = 6: 9.8 +/- 1.1 vs. 13.2 +/- 1.6 ml), so that cardiac output remained unchanged (n = 6: 1.1 +/- 0.1 vs. 1.2 +/- 0.1 l/min). The contractile state, assessed by isovolumic peak systolic pressure, was unaltered by UL-FS 49 (n = 5: 72 +/- 6 vs. 72 +/- 6 mmHg). At a constant coronary arterial pressure (CAP) of 80 mmHg, mean CBF was slightly decreased (102 +/- 11 vs. 97 +/- 10 ml/[min.100 g]) by UL-FS 49, such that mean coronary resistance remained unchanged (0.9 +/- 0.1 vs 1.0 +/- 0.1 mmHg.min.100 g/ml). The slight decreases in arteriovenous oxygen content difference (n = 6: 6.6 +/- 0.7 vs. 6.5 +/- 0.7 ml/100 ml) and in CBF lead to a calculated, significant decrease in MVO2 (n = 6: 6.9 +/- 0.5 vs. 6.0 +/- 0.4 ml.100 g/min). In conclusion, UL-FS 49 at the dose used decreases MVO2 by reducing HR in isolated canine hearts. In the absence of negative inotropic and vasodilating effects, cardiac output is maintained via increased stroke volume, and CAP will likely be preserved in situ. Thus, this specific bradycardic agent could be useful in treating ischemic myocardial disease.

The effect of the alpha 2-adrenoceptor antagonist 4-fluoro-2-(imidazoline-2-ylamino)-isoindoline maleate (BDF 8933) on poststenotic end-diastolic distal coronary resistance and poststenotic myocardial function (sonomicrometry) was investigated under control conditions and during cardiac sympathetic nerve stimulation (CSNS = electrical stimulation of the left ventrolateral cervical cardiac nerve). In 7 vagotomized, open-chest dogs end-diastolic distal coronary resistance was determined. This variable was essentially unchanged after administration of the agent. In additional 6 dogs regional myocardial function was measured as systolic wall thickening (SWT). CSNS increased SWT of the posterior circumflex-perfused myocardium from 12.7 +/- 4.6% to 21.9 +/- 8.4% (p less than 0.05) under control conditions. With a severe stenosis on the left circumflex coronary artery, SWT was reduced to 5.4 +/- 4.0% and further decreased to 2.1 +/- 5.1% (p less than 0.05) during CSNS. After i.v. injection of 150 micrograms/kg BDF 8933, poststenotic myocardial function at rest was 4.2 +/- 4.2%, and 5.6 +/- 3.6% during CSNS. Regarding to the systemic effects BDF 8933 significantly increased peak left ventricular pressure in all 13 dogs. Thus, the new alpha 2-adrenoceptor antagonist BDF 8933 at the chosen dosage prevents sympathetically induced myocardial ischemia, but increases left ventricular afterload resistance.

We tested the afterload and contractile state dependency of three indexes of myocardial oxygen consumption (MVO2): total energy requirement (Et), pressure work index (PWI), and pressure-volume area (PVA). MVO2 was measured in seven isolated canine hearts at four or five different end-diastolic volumes at each of three settings of afterload resistance and with the hearts contracting isovolumically. In several hearts, contractility was also varied by dobutamine infusion. Measured MVO2 (MMVO2) was compared with values predicted (PMVO2) by each index. There was always a high degree of correlation between MMVO2 and PMVO2 for each of the indexes. However, there was a large degree of variability in the coefficients of the MMVO2-PMVO2 relation from one heart to another. We also observed a statistically significant influence of both afterload and contractile state on the predictive power of each of the indexes. Thus each index that we tested had shortcomings in being able to predict MVO2 accurately over a wide range of hemodynamic conditions.

In a first series, we tested whether the relative ischemia distal to a severe stenosis on the left circumflex coronary (CX) artery increases the activity of cardiac sympathetic (CS) nerves which, in turn, may result in a poststenotic vasoconstriction and an aggravation of ischemia. In 23 anesthetized, vagotomized dogs, an acute stenosis that reduced CX blood flow to 50% of control was produced and maintained for 20 min. The activity of postganglionic CS nerves increased by 23 +/- 4% within 20 min. In parallel, poststenotic coronary resistance increased from 0.48 +/- 0.03 (SEM) to 0.61 +/- 0.03 mm Hg.min.100 g/ml, resulting in a net lactate production after 15 min. The selective alpha 2-adrenoceptor antagonist rauwolscine (0.2 mg/kg i.v.; n = 6) and the calcium antagonist nifedipine (10 micrograms/kg i.v.; n = 6) prevented the progressive increase in poststenotic resistance and the net lactate production, but still permitted an increase in CS activity. Segmental anesthesia of CS nerves with epidural infiltration of procaine at segments C7-T6 (n = 6) prevented the sympathetic activation, the progressive increase in poststenotic resistance and the net lactate production. In six additional dogs with intact vagus nerves, CS activation and a concomitant increase in poststenotic resistance resulting in myocardial ischemia were also found. These data suggest a vicious cycle between poststenotic coronary vasoconstriction and CS activation, resulting in severe myocardial ischemia. In a second series, stimulation of high-threshold somatic afferents (= nociceptive stimulation: NCS) was used to cause reflex CS activation. The superficial peroneal nerve was electrically stimulated in 14 anesthetized, vagotomized dogs. With intact CX arteries, a 1 min stimulation resulted in a pronounced increase in CX blood flow and perfusion pressure. In contrast, NCS in the presence of a severe stenosis on the CX artery increased end-diastolic poststenotic coronary resistance by 96 +/- 15% due to a reflex activation of CS nerve fibers. This activation was markedly reduced after injection of fentanyl (27 micrograms/kg i.v.; n = 6). Injection of naloxone (60 micrograms/kg) restored the original effect. Systolic wall thickening (WT; sonomicrometry) in the CX artery-perfused myocardium was increased during NCS (10.9 +/- 3.9 (SD) vs. 13.6 +/- 5.0%) in additional five dogs with intact coronary arteries. In the presence of a stenosis on the CX artery, systolic WT was reduced to 7.0 +/- 2.5% and was further decreased to 4.6 +/- 2.3% during NCS. The additional deterioration of systolic regional function during NCS was prevented after i.v. injection of fentanyl, as was the increase in poststenotic coronary resistance.(ABSTRACT TRUNCATED AT 400 WORDS)

We predicted the shape of the end-systolic pressure-thickness relationship (ESPTR) by modeling the left ventricle as thick-walled sphere. To test the validity of the predicted relationships, we then measured the ESPTR over wide volume ranges in seven isolated blood-perfused canine hearts. Both simulation and experiments demonstrated that the ESPTR is curvilinear. However, within a physiological left ventricular systolic pressure range (80-150 mmHg), the ESPTR was described reasonably well by a straight line. Within that pressure range, changes in left ventricular contractile state, assessed by slope changes of the end-systolic pressure-volume relationship, were associated with almost parallel shifts in the ESPTR. In contrast, in a low pressure range (less than 80 mmHg), contractility changes were associated with slope changes of the ESPTR. We conclude that, in general, there are limitations in the application of ESPTR for assessing left ventricular contractility, but if the limitations are recognized and accounted for, then the ESPTR may be useful for assessing contractility changes in vivo.

Nisoldipine reportedly has little direct myocardial effect. However, because of interactions between the heart and vascular load, the effects on myocardial contractility and left ventricular oxygen consumption (LVO2) have not been established. The authors performed experiments on six isolated, blood-perfused canine left ventricles that were isovolumically contracting and paced at constant rate. Coronary arterial pressure (CAP) and coronary blood flow were measured for evaluation of coronary vascular resistance, and coronary arteriovenous oxygen difference was measured for determination of LVO2. Intracoronary injection of 1 and 10 micrograms of nisoldipine decreased coronary vascular resistance by 16.9 and 36.8% (CAP approximately 40 mm Hg), respectively, and by 21.5 and 47.7% (CAP approximately 80 mm Hg). At both doses, nisoldipine caused no decrease in peak systolic pressure as long as CAP was kept constant at 80 mm Hg. However, when CAP was decreased to 40 mm Hg, peak systolic pressure was significantly decreased even without nisoldipine. This impaired contractile state was associated with a decreased coronary blood flow and a slight decrease in LVO2, whereas 10 micrograms of nisoldipine at CAP approximately 80 mm Hg increased LVO2 significantly. Using the end-systolic pressure-volume relationship as an index of contractility, the authors found nisoldipine not to change the contractile state at CAP approximately 80 mm Hg. They conclude that nisoldipine decreases coronary vascular resistance over a wide range of CAP. It neither depresses the contractile state nor decreases LVO2 in the canine left ventricle. Nisoldipine might effectively counteract anginal attacks by dilating the coronary vessels without depressing myocardial contractility as found in this study on normal ventricle.

The acetylcholine-induced relaxation of isolated coronary arteries is reversed to contraction in the absence of endothelium. The importance of endothelium for the regulation of coronary blood flow remains unclear. We thus tested the effects of acetylcholine on epicardial arteries and on coronary resistance vessels in situ in 8 anesthetized dogs. The left circumflex coronary artery was perfused at constant pressure. Epicardial vasomotion was evaluated by sonomicrometry, the vasomotion of coronary resistance vessels by calculated end-diastolic resistance. Acetylcholine (1 microgram/kg/min i.c.) decreased epicardial resistance by 8.6 +/- 1.6% and end-diastolic resistance by 65.8 +/- 6.3%. The epicardial coronary segment was perfused with distilled water for 65 +/- 5 s to denude it of endothelium. After removal of epicardial endothelium, the decrease in end-diastolic resistance caused by acetylcholine was unchanged (59.6 +/- 1.2%); however, epicardial resistance was increased by 7.7 +/- 1.7%. Application of glyceryl trinitrate (5 micrograms/kg/min i.c.) induced a similar decrease of epicardial resistance before and after removal of endothelium:7.9 +/- 1.4 and 6.2 +/- 1.9%, respectively. We conclude that acetylcholine-induced dilation of epicardial coronary arteries is endothelium-dependent in vivo. However, the constriction of epicardial coronary arteries in the absence of endothelium is insufficient to reduce blood flow and to induce myocardial ischemia.

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. We therefore compared in eight anesthetized open-chest dogs control conditions with three other hemodynamic states with increasing imbalance between myocardial oxygen demand and oxygen supply: severe stenosis on circumflex coronary artery, 60 s cardiac sympathetic nerve stimulation (CSNS) with a severe stenosis on circumflex coronary artery, and 60 s complete occlusion of circumflex coronary artery. Using a one-way analysis of variance, we found two significantly changed parameters during the stress-induced ischemia: Regional lactate extraction was turned to production (32 +/- 4 vs. -4 +/- 1%) and the ratio of dP/dtmin to dP/dtmax was decreased (1.13 +/- 0.05 vs. 0.67 +/- 0.05; control vs. CSNS with a severe stenosis on circumflex coronary artery). We conclude that the ratio of dP/dtmin to dP/dtmax is an easily accessible, sensitive, and dynamic index for characterization of an stress-induced myocardial ischemia.