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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.

Myocardial blood flow exhibits considerable heterogeneity. Consequently, oxygen supply to the myocardium is also heterogeneous, as is myocardial metabolism. Many lines of evidence show a close correlation between local flow and local metabolism in the normoxic myocardium. So far, myocardial metabolism has predominantly been assessed indirectly by using labeled substrates. We used the (18)O isotope, permitting analytical separation of H2(18)O from the (18)O isotope, as well as quantification of regional oxidative metabolism by measuring the tissue residue of oxidation water in the rabbit myocardium. Correlation of local flow with oxidative metabolism was significant in the normoxic myocardium. This correlation was lost in the postischemic/reperfused myocardium. Apart from the established mechanisms underlying myocardial stunning, a mismatch between local flow and oxidative metabolism might thus also contribute to the postischemic dysfunction. In the normoxic myocardium, function should correlate with metabolism and blood flow. For technical reasons, function has not been assessed on a very local scale. Nevertheless, some considerations are presented on the heterogeneity of function as well as on the scale on which heterogeneity should be investigated to convey physiologically meaningful information on regulatory cardiac mechanisms.

Under physiologic circumstances, cardiac function determines myocardial oxygen consumption and consequently coronary perfusion. Surprisingly, in a reverse direction, improved coronary perfusion also increased myocardial oxygen consumption and contractile function. This experimental finding, now 40 years old, is termed the Gregg phenomenon. Some 10 years later, in experiments by Arnold and co-workers, an isolated increase in perfusion pressure improved ventricular function. In this context, the term 'gardenhose effect' was coined, implying a hydraulic explanation of the Gregg phenomenon. In the following, we attempt to distinguish the Gregg phenomenon from the gardenhose effect and to critically evaluate them.

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.

In the following, three newer concepts are brought together: myocardial hibernation, heterogeneity in myocardial blood flow and oxidative metabolism, and effects of hibernating animal serum on non-hibernators. Myocardial hibernation is viewed as a protective mechanism that helps to maintain myocardial integrity and viability by down-regulating contractile function as an adaptation to reduced blood flow. Myocardial flow is considerably heterogeneous. Consequently, oxygen supply to the myocardium is also heterogeneous. Many lines of evidence show a close correlation between regional flow and regional metabolism. In low-flow/low-metabolism areas, myocardial function must be reduced, since the myocardium would otherwise undergo necrosis. Thus, others and we hypothesize that function must be down-regulated to induce hibernation in low-flow areas. Because no regional histologic differences exist (the mitochondria are uniformly distributed within the myocardium), the pattern of heterogeneity seems to shift over time. Hence, we hypothesize that such very regional hibernation presents an evolutionary, protective mechanism, permitting subsequent myocardial areas to rest within the ceaselessly working heart. We also hypothesize that this mechanism ensures the down-regulation of function following myocardial ischemia in order to induce myocardial hibernation on a broader level. Surprisingly, a substance (opioid in nature) contained in hibernator serum both induced hibernation-like state in non-hibernators and suppressed myocardial oxygen consumption. Thus, we lastly hypothesize that myocardial hibernation is a remnant of the early stages of evolution and is closer to physiologic hibernation than traditionally viewed.

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.

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.

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.

Unlabelled: We conducted this study to determine the interaction of MCI-154, 6-[4-(4'-pyridylamino)phenyl]-4,5-dihydro-3(2H)-pyridazinone hydrochloride, a calcium sensitizer, and isoflurane on myocardial contractility as well as systemic and coronary hemodynamics in chronically instrumented dogs after pharmacological autonomic nervous system activity blockade. MCI-154 increased heart rate and left ventricular function with no change in rate pressure product, pressure work index, and coronary blood flow, with a decrease in coronary vascular resistance (CVR) in the conscious state. Isoflurane decreased heart rate and left ventricular function, with a decrease in rate pressure product and pressure work index. Isoflurane also decreased CVR, but not coronary blood flow. The cardiovascular actions of MCI-154 during isoflurane anesthesia were qualitatively similar to those observed in the conscious state. In contrast to the finding in the conscious state, MCI-154 reversed the decrease in cardiac output and preload recruitable stroke work caused by isoflurane, but these are not significantly different from the effects of isoflurane alone. These results indicate that MCI-154 increases myocardial contractility and decreases CVR without changing calculated myocardial oxygen consumption during both the conscious state and isoflurane anesthesia., Implications: MCI-154, a calcium sensitizer, restores the myocardial contractility depressed by isoflurane and enhances the coronary vasodilating effect of isoflurane in chronically instrumented dogs.

The aim of this study was to investigate the effect of coronary flow (CF) changes and inflammatory indices on myocardial microcirculation—assessed by myocardial contrast echocardiography (MCE)—and on left ventricular remodelling, in an experimental ischaemia–reperfusion model. In 15 pigs, weighing 30 ± 5 kg, ligation of the left anterior descending (LAD) coronary artery was performed, followed by reperfusion for 120 min. Peak, mean, duration and volume of systolic and diastolic components of CF distal to the LAD ligation were measured using a butterfly flowmeter and their ratio was calculated. The following two-dimensional echocardiography indices of LV geometry/function were measured from the apical four-chamber view: LV end-systolic (ESD) and end-diastolic (EDD) dimension long- (Ls, Ld) and short-axis (Ss, Sd) and their ratio (Ld/Sd, Ls/Ss, defined as the sphericity index). Interleukin (IL) 1 β, 6, 10 and tumour necrosis factor (TNF) were measured in samples obtained from the LV cavity and coronary sinus. A 0.5 ml/min injection slow bolus over 30 s of SonoVue was made into the left ventricle (LV) in order to assess myocardial perfusion by MCE. Standard apical four-chamber views were digitally acquired and stored for off-line analysis using the Echofit system. The peak intensity (Ac) of the microbubbles at the apex, distally to ligation, was normalised with respect to the peak intensity of the microbubbles in the LV cavity. All parameters were recorded at baseline, immediately after ligation and at 5, 15, 30, 60, 120 min during reperfusion. The percentage changes of CF indices, echocardiographic parameters, interleukins and Ac between baseline and reperfusion were calculated. Mean systolic CF, systolic volume, peak and mean diastolic flow (MDF) changes and epicardial mean CF, Ld/Sd, Ls/Ss changes and coronary sinus IL-6 (IL-6 cs) were inversely correlated with Ac changes during reperfusion. At 5 and 15 min of reperfusion (hyperaemic phase), the greatest median increase of mean diastolic (172% and 86%), and mean systolic CF (713% and 344%) and the greatest reduction of Ac (−41% at 5 min) compared to baseline ( P < 0.05) were observed. The maximum increase of IL-6 cs (40%) was detected at 120 min. ROC analysis showed that of all examined echocardiography indices an increase of mean diastolic CF > 22% was the best predictor of a >25% reduction of Ac with 76% sensitivity and 65% specificity (area 71%, CI 54%–85%, P = 0.02). In addition an >32% increase of IL-6 at 120 min of reperfusion predicted a >25% reduction of Ac with a 76% sensitivity and 65% specificity (area 71% CI 61%–97%, P = 0.01). Changes of mean diastolic CF and IL-6 cs are associated with alterations in myocardial microvascular integrity after ischaemia–reperfusion and may be used as a predictor of myocardial dysfunction. [ABSTRACT FROM AUTHOR]

The article focuses on the mechanical factors that contribute to the two-way interactions between cardiac muscle and coronary vasculature. It offers an introduction on the functional arrangement of cardiac muscle and vasculature and discusses the effect of the cardiac muscle on the coronary vasculature. It discusses the mechanisms of cross-talk and their relation to existing experimental data and the role of extracellular matrix in mechanical cross-talk.

In this review, the regional heterogeneity of the oxygen supply-consumption ratio within the heart is discussed. This is an important functional parameter because it determines whether regions within the heart are normoxic or dysoxic. Although the heterogeneity of the supply side of oxygen has been primarily described by flow heterogeneity, the diffusional component of oxygen supply should not be ignored, especially at high resolution (tissue regions ≪ 1 g). Such oxygen diffusion does not seem to take place from arterioles or venules within the heart, but seems to occur between capillaries, in contrast to data recently obtained from other tissues. Oxygen diffusion may even become the primary determinant of oxygen supply during obstructed flow conditions. Studies aimed at modelling regional blood flow and oxygen consumption have demonstrated marked regional heterogeneity of oxygen consumption matched by flow heterogeneity. Direct, non-invasive indicators of the balance between oxygen supply and consumption include NADH videofluorimetry (mitochondrial energy state) and microvascular PO2 measurement by the Pd-porphyrin phosphorescence technique. These indicators have shown a relatively homogeneous distribution during physiological conditions supporting the notion of regional matching of oxygen supply with oxygen consumption. NADH videofluorimetry, however, has demonstrated large increases in functional heterogeneity of this ratio in compromised hearts (ischemia, hypoxia, hypertrophy and endotoxemia) with specific areas, referred to as microcirculatory weak units, predisposed to showing the first signs of dysoxia. It has been suggested that these weak units show the largest relative reduction in flow (independent of absolute flow levels) during compromising conditions, with dysoxia initially developing at the venous end of the capillary. [ABSTRACT FROM PUBLISHER]

Objective: The low transmural pressure of the thin right ventricular (RV) wall may render it responsive to right coronary (RC) pressure-induced changes in systolic stiffness and account for the dependence of RV MVO2 on RC pressure (RCP). Methods: In eight dogs anesthetized with pentobarbital and fentanyl, RCP was lowered from the baseline to 30 mmHg in 10 mmHg steps by adjusting an occluder on the proximal RC. Myocardial segment length and isometric developed force were measured, and the slope of the force-length curve during ejection period (ΔF/ΔSL) was used as an index of systolic myocardial stiffness. MVO2 was calculated from RC flow and arteriovenous O2 difference. Results: As RCP was varied from 120 to 40 mmHg with positive lactate uptake, RC flow, maximum developed force (Fmax), ΔF, and MVO2 decreased linearly, whereas end-diastolic length, ΔSL, and other hemodynamic variables stayed constant. Thus, RV systolic stiffness fell linearly with RC pressure. When RCP was further lowered from 40 to 30 mmHg, Fmax and ΔF continued to fall, end-diastolic segment length and right atrial pressure increased significantly, ΔSL and RV dP/dtmax fell significantly, and ΔF/ΔSL reached its lowest value. RV systolic stiffness was 22% of previously reported left ventricular systolic stiffness for coronary perfusion pressure at 100 mmHg, and varied less steeply with coronary pressure. Conclusions: (1) Reductions in RV systolic stiffness preserve ΔSL as coronary pressure is reduced over a wide range. (2) The resulting increase in RV efficiency reduces oxygen demand as oxygen supply is reduced, so ischemia is avoided. (3) RV systolic stiffness is much less than left ventricular stiffness, consistent with their anatomical and functional differences. [ABSTRACT FROM PUBLISHER]