Effects of dobutamine on myocardial blood flow, contractile function, and bioenergetic responses distal to coronary stenosis: implications with regard to dobutamine stress testing

To determine the effects of dobutamine stimulation on myocardium distal to a coronary stenosis, transmural spatially localized phosphorus 31 nuclear magnetic resonance measurements of myocardial high-energy phosphate compounds (adenosine triphosphate and phosphocreatine), inorganic phosphate, and blood flow and systolic wall thickening were made in 8 open-chested dogs. Data were collected under (1) control conditions, (2) after the application of a moderate coronary stenosis, (3) during infusion of dobutamine with continuing stenosis, and (4) after the release of the stenosis with continuing dobutamine. Stenosis was associated with concordant reductions of subendocardial blood flow, wall thickening, and high-energy phosphate, and mild elevation of inorganic phosphate; subepicardial measurements were essentially unchanged. During dobutamine infusion, blood flow increased in all myocardial layers. Wall thickening returned to control values in the subendocardium and increased nonsignificantly in the subepicardium. Additional loss of high-energy phosphate occurred only in the subepicardium. The data suggest that improved contractile function associated with dobutamine infusion resulted from the inotropic effects of dobutamine and was made possible by the improved blood flow it produced. The data indicate that measurements of blood flow and contractile function do not reliably predict the transmural myocardial metabolic responses to inotropic perturbations in the hypoperfused heart. Taken together, the present findings yield insights with regard to the interpretation of diagnostic dobutamine stimulation testing with single photon emission tomography, radionuclide angiography, and echocardiography.     

Rapid genomic changes in newly synthesized amphiploids of Triticum and Aegilops. II. Changes in low-copy coding DNA sequences

Postischemic myocardium possesses considerable contractile and metabolic reserves, but their mobilization could result in increased cell death. We tested the hypothesis that beta-adrenergic stimulation of reperfused myocardium would increase segment work more than O2 consumption, thereby improving efficiency without increased cell death. In 16 open-chest anesthetized dogs, the left anterior descending coronary artery (LAD) was ligated for 2 h; during the reperfusion period, isoproterenol (ISO; 0.1 microg/kg/min, i.v.) was administered to nine of the animals. Regional myocardial segment length and force were measured in the anterior (LAD) and posterior circumflex coronary artery (CFX) regions of the left ventricular myocardium. Work was calculated as the integrated products of force and shortening for each region. Regional myocardial O2 consumption was obtained from LAD flow and arterial and local venous O2 saturations. Infarct size (tetrazolium) was measured in the treated and untreated hearts at the end of the experiment. In untreated hearts, the first derivative of left ventricular pressure, cardiac output, and external work were significantly depressed during reperfusion; ISO restored all values to preocclusion levels. Regional myocardial work in both LAD and CFX regions was significantly increased by ISO (from 564 +/- 207 to 1,635 +/- 543 g/mm/min in LAD, and from 753 +/- 90 to 1,426 +/- 245 g/mm/min in CFX). Efficiency (work/oxygen consumption) of the reperfused region was similarly increased. LAD flow was significantly increased by ISO, and O2 extraction was unchanged. Infarct size was 28.2 +/- 4.7% in untreated hearts and 29.0 +/- 3.5% in ISO hearts. Thus isoproterenol stimulation significantly improved both regional and global function without subsequent evidence of increased cell death.     

Myotrophic effects of muscle extracts obtained at different intervals after denervation

BACKGROUND: The assessment of return of function within dysfunctional myocardium after acute myocardial infarction (MI) using contractile reserve has been primarily qualitative. Magnetic resonance (MR) myocardial tagging is a novel noninvasive method that measures intramyocardial function. We hypothesized that MR tagging could be used to quantify the intramyocardial response to low-dose dobutamine and relate this response to return of function in patients after first MI. METHODS AND RESULTS: Twenty patients with a first reperfused MI (age, 53+/-12 years; 16 male; 11 inferior MIs) were studied. Patients underwent breath-hold MR-tagged short-axis imaging on day 4+/-2 after MI at baseline and during dobutamine infusion at 5 and 10 microg x kg(-1) x min(-1). At 8+/-1 weeks after MI, patients returned for a follow-up MR tagging study without dobutamine. Quantification of percent intramyocardial circumferential segment shortening (%S) was performed. Low-dose dobutamine MRI was well tolerated. Overall, mean %S was 15+/-11% at baseline (n=227 segments), increased to 16+/-10% at 5 microg x kg(-1) x min(-1) dobutamine (P=NS), 21+/-10% at peak (P<0.0001 versus baseline and 5 microg x kg(-1) x min(-1), and 18+/-10% at 8 weeks (P<0.004 versus baseline and peak). The increase in %S with peak dobutamine was greater in dysfunctional myocardium (103 segments, +9+/-10%) than in normal tissue (124 segments, +4+/-12%, P<0.0001). In dysfunctional regions, %S also increased from 6+/-7% at baseline to 14+/-10% at 8 weeks after MI (P<0.0001). In dysfunctional regions that responded normally to peak dobutamine (> or =5% increase in %S), the increase in %S from baseline to 8 weeks after MI (+9+/-9%) was greater than in those regions that did not respond normally (+5+/-9%, P<0.04). Midmyocardial and subepicardial response to dobutamine were predictive of functional recovery, but the subendocardial response was not. CONCLUSIONS: The response of intramyocardial function to low-dose dobutamine after reperfused MI can be quantified with MR tagging. Dysfunctional tissue after MI demonstrates a larger contractile response to dobutamine than normal myocardium. A normal increase in shortening elicited by dobutamine within dysfunctional midwall and subepicardium predicts greater functional recovery at 8 weeks after MI, but the response within the subendocardium is not predictive.     

Mechanism of coronary microvascular responses to metabolic stimulation

Previous studies from our laboratory have shown that coronary microvascular dilation to increased myocardial oxygen consumption (MVO2) is greater in vessels < 100 microns. The mechanism responsible for this response is uncertain. OBJECTIVES: We tested the hypothesis that microvascular dilation to increased MVO2 is mediated by nitric oxide (NO). Since NO release may occur in response to increased shear, we also tested the hypothesis that metabolic byproducts released in response to increase in MVO2 will stimulate opening of the ATP-sensitive potassium channel. METHODS: Changes in epicardial coronary microvascular diameters were measured in 9 dogs given NG-nitro-L-arginine (LNNA; 100 microM, topically), 7 dogs given glibenclamide (10 microM, topically) and 12 control (C) dogs during increases in metabolic demand using dobutamine (DOB, 10 micrograms/kg/min, i.v.) with rapid atrial pacing (PAC, 300 bpm). Diameters of arterioles were measured using intravital microscopy coupled to stroboscopic epi-illumination. RESULTS: During the protocol, MVO2 increased to a similar degree in both experimental groups (LNNA and glibenclamide). Baseline hemodynamics and coronary microvascular diameters were similar between the two experimental groups and their respective control groups. In the presence of LNNA, coronary arteriolar (< 100 microns) dilation (% change from baseline) was impaired during the protocol (DOB: vehicle 18 +/- 5, LNNA 2 +/- 2 [P < 0.05]; DOB + RAP: vehicle 40 +/- 11, LNNA 6 +/- 2% [P < 0.05]). In contrast, glibenclamide did not impair coronary microvascular responses to increased MVO2 despite increases in MVO2. CONCLUSION: This study indicates that coronary microvascular dilation in response to increased metabolic stimulation using dobutamine in conjunction with rapid pacing is mediated through a nitric-oxide-dependent mechanism and not ATP-sensitive potassium channels. These results may have important implications in pathological disease states where nitric oxide mechanisms are impaired, such as diabetes and hypertension.     

Chemical, physical, and sensory characteristics of mozzarella cheese fortified using protein-chelated iron or ferric chloride

OBJECTIVE: Short-term myocardial hibernation is characterized by an adaptation of contractile function to the reduced blood flow, the recovery of creatine phosphate content and lactate balance back towards normal, whereas ATP content remains reduced at a constant level. We examined the hypothesis that, despite the absence of ATP recovery, the short-term hibernating myocardium regains an energetic balance. METHODS: An enzymatic method was modified for the measurement of inorganic phosphate (Pi) in transmural myocardial drill biopsies (about 5 mg). In 12 anaesthetized swine, moderate ischemia was induced by reduction of coronary inflow into the cannulated left anterior descending coronary artery to decrease regional myocardial function (sonomicrometry) by 50%. RESULTS: The development of short-term hibernation was verified by the recovery of creatine phosphate content, the persistence of inotropic reserve in response to dobutamine and the absence of necrosis (triphenyl tetrazolium chloride). At 5-min ischemia, Pi was increased from 3.6 +/- 0.3 (SD) to 8.1 +/- 1.1 mumol/gwet wt (p < 0.05). The free energy of ATP hydrolysis (delta GATP) was decreased from -57.8 +/- 0.8 to -52.2 +/- 1.4 kJ/mol (p < 0.05). The relationships between function and Pi (r = -0.81) and delta GATP (r = -0.83), respectively, during control and at 5-min ischemia became invalid at 90-min ischemia, as myocardial blood flow and function remained reduced at a constant level, but Pi decreased back to 4.9 +/- 0.9 mumol/g (p < 0.05 vs. control and 5-min ischemia), and delta GATP fully recovered back to -57.2 +/- 1.3 kJ/mol (p < 0.05 vs. 5-min ischemia). CONCLUSIONS: In short-term hibernating myocardium, myocardial inorganic phosphate content recovers partially and the free energy change of ATP hydrolysis returns to control values. Contractile function remains reduced by mechanisms other than an energetic deficit.     

Effect of MCI-154, a cardiotonic agent, on regional contractile function and myocardial oxygen consumption in the presence and absence of coronary artery stenosis in dogs

The effects of MCI-154 (6-[4-(4'-pyridyl)aminophenyl]-4,5-dihydro-3(2H)- pyridazinone hydrochloride.3H2O), a cardiotonic agent with calcium sensitizing actions, on regional contractile function and myocardial oxygen consumption (MVO2) were studied in the dog hearts with and without partial occlusion of the left anterior descending coronary artery and compared with those of dobutamine. Segment shortening by sonomicrometry, regional myocardial blood flow by microspheres and the oxygen content of coronary venous blood drawn from the ischemic left anterior descending coronary artery area were simultaneously measured. The ischemic zone segment shortening and left ventricular (LV) dP/dtmax were decreased after partial occlusion. The infusion of MCI-154 starting 20 min after ischemia improved the depressed segment shortening and LV dP/dtmax without increasing the ischemic zone MVO2 and regional myocardial blood flow. In the nonischemic hearts, MCI-154 did not increase MVO2 and coronary blood flow despite the augmentation of myocardial contractility. MCI-154 decreased LV end-diastolic pressure and systemic blood pressure. On the other hand, dobutamine failed to increase the ischemic zone segment shortening, but the drug increased MVO2, coronary blood flow and LV dP/dtmax in both ischemic and nonischemic hearts. These results indicate that MCI-154 alleviates the ischemic contractile failure without increasing myocardial oxygen demand. Thus, MCI-154 may be useful in the management of heart failure with reduced coronary reserve.     

Frequency-dependence of myocardial energetics in failing human myocardium as quantified by a new method for the measurement of oxygen consumption in muscle strip preparations

Diastolic dysfunction at high heart rates may be associated with increased myocardial energy consumption. Frequency-dependent changes of isometric force and oxygen consumption (MVO2) were investigated in strip preparations from endstage failing human hearts exhibiting various degrees of diastolic dysfunction. MVO2 was determined by a new method which was validated. When stimulation rate was increased from 40 to 200 min-1 (n=7), developed force decreased from 16.5+/-4.3 to 7.9+/-2.9 mN/mm2 (P<0.01), diastolic force increased from 15.9+/-3.2 to 22.0+/-3.0 mN/mm2 (P<0.01), and total MVO2 increased from 2.6+/-0.6 to 4.7+/-0.9 ml/min/100 g (P<0.025). Resting MVO2 and resting force were 1.8+/-0.4 ml/min/100 g and 15.9+/-3.0 mN/mm2, respectively. After addition of 30 mm 2,3-butanedione monoxime (BDM) to inhibit crossbridges, resting MVO2 and resting force decreased by 46% (P<0.05) and 15% (P<0.01), respectively, indicating the presence of active force generation in unstimulated failing human myocardium. In each muscle preparation, there was a significant correlation between force-time integral (FTI) and total MVO2 (r=0.96+/-0.01). The strength of these correlations did not vary with the contribution of diastolic FTI to total FTI. The ratio of activity related MVO2 to developed FTI, an inverse index of the economy of contraction, increased depending on the rise of diastolic FTI at higher stimulation rates. In conclusion, in failing human myocardium, diastolic force development is occurring at the same energy expenditure as systolic force generation. Therefore, in muscle preparations with disturbed diastolic function economy of contraction decreases with higher stimulation rates, depending on the rise of diastolic force.     

EMD 53998 acts as Ca(2+)-sensitizer and phosphodiesterase III-inhibitor in human myocardium

The effect of EMD 53998 (EMD) (0.1-100 mumol/l), chemically a racemic thiadiazinone derivative, suggested to be a potent Ca(2+)-sensitizer, was studied in human failing and nonfailing left ventricular myocardium. For comparison, the effects of the pyridazinone derivative pimobendan (0.1-300 mumol/l), isoprenaline (Iso) (0.001-3 mumol/l) as well as CaCl2 (1.8-15 mmol/l Ca2+) were investigated. The positive inotropic responses were examined in electrically driven (1 Hz, 37 degrees C) human left ventricular papillary muscle strips from terminally failing hearts (NYHAIV, n = 24) and nonfailing donor hearts (NF, n = 9). The effect of EMD on the Ca(2+)-sensitivity of skinned fiber preparations from the very same human failing hearts were studied as well. EMD and pimobendan increased force of contraction (FOC) in a concentration-dependent manner. As judged from the EC50-values, EMD increased FOC more potently than pimobendan. EMD was significantly more effective than pimobendan to increase FOC in papillary muscle strips from NYHA IV (EMD: +2.5 +/- 0.1 mN; pimobendan: +0.8 +/- 0.2 mN) as well as from nonfailing hearts (EMD: +3.1 +/- 0.5 mN; pimobendan: +1.2 +/- 0.2 mN). Only in terminally failing myocardium, EMD increased FOC as effectively as Iso. After inotropic stimulation with EMD, pimobendan, or Iso, carbachol (1000 mumol/l) reduced FOC in left ventricular papillary muscle strips, indicating a cAMP-dependent mode of action. In skinned fiber experiments, EMD increased Ca(2+)-sensitivity significantly more (p < 0.01) than pimobendan. In conclusion: EMD increases FOC in human myocardium via sensitizing of the contractile proteins towards Ca2+ and by inhibition of phosphodiesterase III-isoenzymes. EMD is a potent calcium sensitizing agent in human myocardium. Thiadiazinone derivatives could be one step in the evolution to more potent and selective calcium-sensitizers.     

Breath-hold dobutamine magnetic resonance myocardial tagging: normal left ventricular response

Analysis of the changes in myocardial deformation produced by adrenergic stress has been limited by the imaging techniques used. We used rapid magnetic resonance imaging (MRI) myocardial tagging to map the dose-dependent response to incremental dobutamine in the normal human left ventricle. Thirteen volunteers underwent breath-hold tagged cine MRI during dobutamine infusion. Images were acquired throughout systole to a peak dose of 20 microg/kg/min. End-systolic percent circumferential shortening (%S) was measured at 3 transmural locations and 4 circumferential locations at 3 long-axis positions. Mean circumferential shortening velocity (CSV) was also calculated at each location and dose. Mean %S reached a maximum of 26 +/- 3% at 10 microg/kg/min compared with 21 +/- 4% at baseline (p <0.003). Peak %S was reached by 10 microg/kg/min before a significant increase in heart rate or blood pressure and was unchanged at higher doses. In contrast, CSV increased linearly with dobutamine dose from 4.4 +/- 0.9 mm/s at baseline to 9.8 +/- 1.4 mm/s at 20 microg/kg/min (p <0.0001). Breath-hold tagged dobutamine MRI is safe and effective in detecting regional and transmural changes in function during incremental dobutamine. CSV increased continuously across the dobutamine dose range. At low dose (< or =10 microg/kg/min) %S increased without any change in blood pressure or heart rate. Maintenance of peak %S beyond 10 microg/kg/min in the presence of decreasing systolic intervals resulted from a continued increase in CSV. Thus, CSV may be the preferred measure of contractile function during dobutamine stimulation in human myocardium.     

Assessment of hibernating myocardium by dobutamine stimulation in a canine model

OBJECTIVES: The purpose of this study was to 1) develop an animal model of hibernating myocardium, and 2) evaluate the ability of dobutamine stimulation to detect hibernating myocardium using both qualitative and quantitative assessment of regional myocardial function. BACKGROUND: Left ventricular dysfunction may be due to chronic ischemia with or without myocardial infarction and may improve after coronary blood flow is enhanced by revascularization procedures. This condition has been coined "hibernating myocardium" and variably defined in recent years. The results of recent clinical studies suggest that dobutamine echocardiography may be useful for detecting viable myocardium in patients with left ventricular dysfunction. METHODS: Twenty-one dogs underwent initial operation. Sonomicrometer crystals were implanted, and baseline measurements of segment shortening and wall thickening (by echocardiography) were made. A coronary artery was ligated; the chest was closed; and measurements were repeated. Dobutamine was incrementally infused with determination of wall thickening and segment shortening at baseline and on days 3 and 7 and weeks 2 and 4 after coronary artery occlusion. Finally, the chest was reopened; the ligated vessel was bypassed; and measurements were repeated. RESULTS: Of the 10 dogs that completed the entire protocol, 7 had varying degrees of nontransmural myocardial infarction (group 1), and 3 had complete transmural myocardial infarction (group 2). In group 1, baseline function was significantly impaired compared with preligation function but increased during dobutamine infusion. When reperfused after 4 weeks, both wall thickening and segment shortening increased significantly. In group 2, significant changes were not seen during the dobutamine studies or after reperfusion. Myocardial perfusion during dobutamine infusion increased in group 1 but did not change in group 2. CONCLUSIONS: We demonstrated improvement in chronically dysfunctional myocardium after restoration of previously interrupted myocardial blood flow in dogs after nontransmural myocardial infarction, thus validating a canine model of hibernating myocardium. As assessed by two independent methods, dobutamine infusion identified hibernating myocardium in an animal model.     

Experimental hypothermia: effects of core cooling and rewarming on hemodynamics, coronary blood flow, and myocardial metabolism in dogs

Conflicting results have been reported as to the extent that cardiovascular function can be reestablished after rewarming from hypothermia. We measured hemodynamic function, myocardial metabolism and tissue water content in dogs core-cooled to 25 degrees C and later rewarmed. At 25 degrees C left ventricular (LV) systolic pressure (LVSP) was 54% +/- 4%, maximum rate of LV pressure rise (LV dP/dtmax) 44% +/- 5%, aortic pressure (AOP) 50% +/- 6%, heart rate (HR) 40% +/- 0%, cardiac output (CO) 37% +/- 5%, myocardial blood flow (MBF) 34% +/- 5%, and myocardial oxygen consumption (MVO2) 8% +/- 1%, compared to precooling. Stroke volume (SV) and LV end-diastolic pressure (LVEDP) were unchanged. As normothermia (37 degrees C) was reestablished, the depression of cardiac function and myocardial metabolism remained the same as that at 25 degrees C: LVSP 71% +/- 6%, LV dP/dtmax 73% +/- 7%, SV 60% +/- 9%, AOP 70% +/- 6%, CO 57% +/- 9%, MBF 53% +/- 8%, and MVO2 44% +/- 8% HR, in contrast, recovered to precooling values. The arterial concentrations of glucose and free fatty acids (FFA) did not change significantly during the experimental period, whereas an increase in lactate of nonmyocardial origin appeared after rewarming. Increased myocardial contents of creatine phosphate and water were found during both hypothermia and rewarming. The present study demonstrates a persistent depression of cardiac function after hypothermia and rewarming in spite of adequate energy stores. Thus, a direct influence on myocardial contractile function by the cooling and rewarming process is suggested.     

Effects of hyperthermic stress on myocardial function during experimental coronary ischemia

We evaluated hyperthermic influences on ischemic hearts by comparing two groups of intact working swine hearts (n = 20) made globally ischemic. Heart muscle temperature was selectively increased from 37.5 +/- 0.3 degrees C to 39.7 +/- 0.3 degrees C in one group (n = 11) by warming the coronary perfusate. Ischemia in normothermic hearts significantly (P less than 0.05) decreased mechanical function (as reflected by increases in left ventricular end-diastolic pressure [LVEDP]), myocardial oxygen consumption (MVO2), glucose uptake, glycolytic flux, free fatty acid (FFA) uptake and oxidation, and tissue stores of high energy phosphates. Hearing in ischemic hearts further depressed mechanical function at similar reductions in coronary flow and MVO2. Glucose uptake was terminally increased over normothermic values (329 vs. 221 mumol/hr per g) as was glycolytic metabolism, FFA uptake (26 vs. 17 mumol/hr per g), and FFA oxidation (21 vs. 11 mumol/hr per g). However, these changes were not translated into increased energy stores of tissue creatine phosphate and ATP. Thus, in ischemic hearts, hyperthermia neither prevented the development of mechanical deterioration nor improved oxidative phosphorylation despite increases in metabolic substrate utilization. These data suggest that in experimental global ischemia heat is an added energy drain in already burdened myocardium.     

Diminished contractile reserve in patients with left ventricular hypertrophy and increased end-systolic stress during Dobutamine stress echocardiography

Left ventricular hypertrophy (LVH) is associated with decreased contractile response to inotropic stimulation in animal models, but this has not been documented in humans. To determine whether LVH is associated with decreased myocardial contractile reserve, we measured left ventricular mass, heart rate-corrected velocity of circumferential fiber shortening (Vcfc), end-systolic stress, and LV ejection fraction (LVEF) in patients with LVH and increased end-systolic stress (n = 6) and in patients without LVH (n = 7) who had a normal response to dobutamine stress echocardiography (increased LVEF and no wall motion abnormalities). The afterload-dependent indexes of left ventricular systolic performance were normal at baseline and showed significant increases at peak dobutamine dose (LVH group: Vcfc 0.91 +/- 0.11 to 1.76 +/- 0.59, p = 0.006; LVEF 49 +/- 5 to 65 +/- 6, p = 0.001; group without LVH: Vcfc 1.16 +/- 0.24 to 1.99 +/- 0.36, p = 0.001; LVEF 61 +/- 6 to 68 +/- 6, p = 0.05). The Vcfc/ end-systolic stress relation, a load-independent index of myocardial contractility, rose in a dose-dependent fashion in both groups, but the increment was significantly less for patients with LVH (p < 0.02), suggesting a blunted myocardial contractile reserve to inotropic stimulation. The change in heart rate-corrected velocity of circumferential fiber shortening per unit of change in end-systolic stress in each patient at each dobutamine dose showed a linear and inverse relationship. The increment in heart rate-corrected velocity of circumferential fiber shortening for a given reduction in end-systolic stress was larger in patients without LVH than in patients with LVH (p = 0.01). These results suggest that in patients with LVH and increased end-systolic stress, ventricular performance is maintained at the expense of limited myocardial contractile reserve, and that inotropic stimulation unmasks this abnormality, despite a normal response in LVEF and velocity of circumferential fiber shortening. This approach may identify patients with LVH at risk of developing systolic dysfunction and heart failure.     

Hibernating myocardium: a review

Within a few seconds after a sudden reduction of coronary blood flow regional contractile dysfunction ensues. The mechanisms responsible for the rapid reduction in contractile function during acute myocardial ischemia remain unclear, but may involve a rise in inorganic phosphate. When severe ischemia, such as resulting from a sudden and complete coronary artery occlusion, is prolonged for more than 20-40 min, myocardial infarction develops, and there is irreversible loss of contractile function. When myocardial ischemia is less severe but nevertheless prolonged, 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 towards 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. This situation of an increased regional contractile function at the expense of metabolic recovery during inotropic stimulation can be used to identify short-term hibernating myocardium. When inotropic stimulation is prolonged, the development of short-term hibernation is impaired and myocardial infarction develops. The mechanisms responsible for the development of short-term myocardial hibernation remain unclear at present; a significant involvement of adenosine and of activation of ATP-dependent potassium channels has been excluded. Whereas short-term hibernation is well characterized in animal experiments, the existence of hibernation over weeks or months (long-term hibernation) can only be inferred from clinical studies. Hibernation, as defined by Rahimtoola, is a state of chronic contractile dysfunction which is fully reversible upon reperfusion. Clinical syndromes consistent with the existence of myocardial hibernation include unstable and stable angina, acute myocardial infarction and left ventricular dysfunction and/or congestive heart failure. In long-term hibernating myocardium morphological alterations occur; the myofibrils are reduced in number and disorganized and myocardial glycogen content as well as the extracellular collagen network are increased. Thus, despite the fact that the myocardium remains viable during persistent ischemia and contractile dysfunction is reversible upon reperfusion, there are severe morphological alterations. Understandably, full functional recovery following reperfusion might therefore require weeks or even months.     

Nitroglycerin enhances the ability of dobutamine stress echocardiography to detect hibernating myocardium

BACKGROUND: A biphasic response of wall thickening with initial improvement and subsequent deterioration during dobutamine stress echocardiography (DSE) has been increasingly used for detection of hibernating myocardium. However, the improvement of wall thickening at low-dose DSE may be limited in hibernating myocardium by severe hypoperfusion. Nitroglycerin (NTG) improves myocardial perfusion, reduces oxygen demand, and may enhance low-dose dobutamine to improve wall thickening. METHODS AND RESULTS: A pig model of myocardial hibernation of 24 hours to 7 days was created through severe left anterior descending coronary artery stenosis with coronary flow reductions of approximately 40%, producing severe regional left ventricular dysfunction but no infarction in seven pigs. Myocardial infarction was produced in five pigs with occlusion of the artery. DSE was performed with incremental doses with and without an NTG infusion of 50 to 100 microg/min. In the hibernating group, NTG alone improved wall thickening in the hibernating region modestly from 11.4+/-7.2% at baseline to 19.1+/-7.0%. The improvement was associated with increased regional coronary flow from 0.46+/-0.12 to 0.55+/-0.13 mL x beat(-1) x 100 g myocardium(-1) (P<.05). There was an additive effect of NTG to low-dose (2.5 to 5 microg x kg(-1) x min(-1)) dobutamine on wall thickening in the hibernating region. The improvement of wall thickening of hibernating myocardium with NTG and dobutamine, from 23.7+/-11.1% to 31.1+/-8.9% (P<.001), was associated with an increase in regional coronary flow (P<.01). NTG did not prevent high doses of dobutamine from inducing deterioration of wall thickening in hibernating myocardium. In the infarcted group, no improvement in wall thickening was observed in infarcted regions during NTG infusion, dobutamine infusion, or the combination. CONCLUSIONS: NTG enhances the improvement of wall thickening at low-dose dobutamine and does not prevent high-dose dobutamine from inducing ischemia in hibernating myocardium. Thus, NTG augments the biphasic response of wall thickening and improves the accuracy of DSE for detecting viable myocardium.     

Acute encephalopathy and seizure rates in children under age two years in Oregon and Washington state

The use of small-volume injections of hypertonic saline solutions (HSS) in resuscitation from hemorrhagic shock is accompanied by well-maintained and pronounced increases in coronary blood flow (CBF) and by increases in myocardial contractility. The present study was performed in open-chest, anesthetized dogs to evaluate the contribution of direct coronary vasodilator and positive inotropic effects of HSS to these therapeutic responses. The left anterior descending coronary artery (LAD) was cannulated and perfused at constant pressure (100 mm Hg) with normal arterial blood. CBF in LAD was measured electromagnetically, and used to calculate myocardial oxygen consumption (MVO2) and coronary arterial plasma osmolality. Percent segmental shortening in LAD bed (% SS) was evaluated with ultrasonic crystals. Measurements were obtained during infusion into LAD of 2.5, 5.0, and 7.5% HSS at 2 ml/min. These HSS solutions yielded calculated plasma osmolalities of 329 +/- 3, 361 +/- 8, and 378 +/- 10 mOsm/kg, respectively. The increases in plasma osmolality by 2.5% HSS were in the therapeutic range, whereas those by 5.0 and 7.5% HSS were supertherapeutic. HSS caused initial peak increases in CBF (reflecting decreases in coronary vascular resistance), which waned rapidly to achieve modest steady-state increases within 2-3 min. The magnitude of the peak and steady-state increases in CBF by HSS correlated to osmolality. The 2.5% HSS had no effect on MVO2 and % SS, whereas the 5.0% and 7.5% HSS increased these variables in an osmolality-dependent manner. Conclusions: (1) intracoronary infusions of HSS caused modest steady-state coronary vasodilation, (2) Supertherapeutic elevations of plasma osmolality by HSS were required for direct positive inotropic effects, and (3) the present findings suggest that the direct cardiac actions of HSS contribute minimally to the increases in coronary blood flow and myocardial contractility that follow the use of these solutions for resuscitation from hemorrhagic shock.     

Myocardial perfusion and function in dogs with moderate coronary stenosis

MRI studies of first-pass contrast enhancement with polylysine-Gd-DTPA and myocardial tagging using spatial modulation of magnetization (SPAMM) were performed to assess the feasibility of a combined regional myocardial blood flow and 2D deformation exam. Instrumented closed-chest dogs were imaged at a baseline control state (Cntl) followed by two interventions: moderate coronary stenosis (St) achieved by partial occlusion of the left anterior descending (LAD) and moderate coronary stenosis with dobutamine loading (StD). Hypoperfusion of the anterior region (ANT) of the myocardium (LAD distribution) relative to the posterior wall (POS) based on the upslope of the signal intensity time curve from the contrast-enhanced MR images was demonstrated only with dobutamine loading (ANT:POS Cntl = 1.077 +/- 0.15 versus ANT:POS StD = 0.477 +/- 0.11, P < 0.03) and was confirmed with radiolabeled microspheres measurements (ANT:POS Cntl = 1.18 +/- 0.2 ml/min/g versus ANT:POS StD = 0.44 +/- 0.1 ml/min/g; P < 0.002). Significant changes in regional myocardial shortening were only seen in the StD state (P < 0.02); the anterior region showed impaired myocardial shortening with dobutamine loading (P = NS), whereas the nonaffected POS region showed a marked increase in shortening when compared with Cntl (Cntl = 0.964 +/- 0.02 versus StD = 0.884 +/- 0.03; P < 0.001). These results demonstrate that an integrated quantitative assessment of regional myocardial function and semiquantitative assessment of myocardial blood flow can be performed noninvasively with ultrafast MRI.     

Effects of critical coronary stenosis on global systolic left ventricular function quantified by pressure-volume relations during dobutamine stress in the canine heart

OBJECTIVES: In this study we quantified the effects of a critical coronary stenosis on global systolic function using pressure-volume relations at baseline and during incremental dobutamine stress. BACKGROUND: The effects of coronary stenosis have previously been analyzed mainly in terms of regional (dys)function. Global hemodynamics are generally considered normal until coronary flow is substantially reduced. However, pressure-volume analysis might reveal mechanisms not fully exposed by potentially load-dependent single-beat parameters. Moreover, no systematic analysis by pressure-volume relations of the effects of dobutamine over a wide dose range has previously been presented. METHODS: In 14 dogs left ventricular volume and pressure were measured by conductance and micromanometer catheters, and left circumflex coronary flow by Doppler probes. Measurements in control and with left circumflex stenosis were performed at baseline and at five levels of dobutamine (2.5 to 20 microg/kg/min). The end-systolic pressure-volume relation (ESPVR) dP/dtMAX vs. end-diastolic volume (dP/dtMAX - V(ED)) and the relation between stroke work and end-diastolic volume (preload recruitable stroke work [PRSW]) were derived from data obtained during gradual caval occlusion. RESULTS: In control, dobutamine gradually increased heart rate up to 20 microg/kg/min, the inotropic effect blunted at 15 microg/kg/min. With stenosis, the chronotropic effect was similar, however, contractile state was optimal at approximately 10 microg/kg/min and tended to go down at higher levels. At baseline, the positions of ESPVR and PRSW, but not of dP/dtMAX - V(ED), showed a significant decrease in function with stenosis. No differences between control and stenosis were present at 2.5 microg/kg/min; the differences were largest at 15 microg/kg/min. CONCLUSIONS: Pressure-volume relations and incremental dobutamine may be used to quantify the effects of critical coronary stenosis. The positions of these relations are more consistent and more useful indices than the slopes. The positions of the ESPVR and PRSW show a reduced systolic function at baseline, normalization at 2.5 microg/kg/min and a consistent significant difference between control and stenosis at dobutamine levels of 5 microg/kg/min and higher.     

Role of PKC in the effects of alpha1-adrenergic stimulation on Ca2+ transients, contraction and Ca2+ current in guinea-pig ventricular myocytes

The effects of alpha1-adrenoceptor stimulation on intracellular Ca2+ transients, contractility and L-type Ca2+ current (ICa,L) were studied in single cells isolated from ventricles of guinea-pig hearts. The aim of our study was to elucidate the mechanisms of the positive inotropic effect of alpha1-adrenergic stimulation by focussing on the role of protein kinase C (PKC). Phenylephrine, an alpha1-adrenergic agonist, at concentrations of 50-100 microM elicited a biphasic inotropic response: a transient negative inotropic response (22.9+/-6.0% of control) followed by a sustained positive inotropic response (61.0+/-8.4%, mean+/-SE, n=12). The Ca2+ transient decreased by 10.2+/-3.9% during the negative inotropic phase, while it increased by 67.7+/-10% (n=12) during the positive inotropic phase. These effects were inhibited by prazosin (1 microM), a alpha1-adrenergic antagonist. Phenylephrine increased the ICa,L by 60.8+/-21% (n=5) during the positive inotropic phase. To determine whether activation of PKC is responsible for the increases in Ca2+ transients, contractile amplitude and ICa,L during alpha1-adrenoceptor stimulation, we tested the effects of 4beta-phorbol 12-myristate 13-acetate (PMA), a PKC activator, and of bisindolylmaleimide I (GF109203X) and staurosporine, both of which are PKC inhibitors. PMA mimicked phenylephrine's effects on Ca2+ transients, contractile amplitude and ICa,L. PMA (100 nM) increased the Ca2+ transient, contractile amplitude and ICa,L by 131+/-17%, 137+/-25% (n=8), and 81.1+/-26% (n=5), respectively. Prior exposure to GF109203X (1 microM) or staurosporine (10 nM) prevented the phenylephrine-induced increases in Ca2+ transients, contractile amplitude and ICa,L. Our study suggests that during alpha1-adrenoceptor stimulation increase in ICa,L via PKC causes an increase in Ca2+ transients and thereby in the contractile force of the ventricular myocytes.     

Acadesine increases blood flow in the collateralized heart during exercise

Acadesine, an adenosine-regulating agent, has been shown to increase coronary flow and exert cardioprotective effects in acutely ischemic myocardium, but a beneficial effect on coronary collateral flow during exercise has not been demonstrated. We examined the effect of acadesine, 100 micromol/min, i.v., on myocardial blood flow during treadmill exercise in six normal dogs and seven dogs with moderately well-developed coronary collateral vessels. Collateral vessel growth was produced with 2-min intermittent occlusions of the left circumflex coronary artery followed by permanent occlusion. During resting conditions, myocardial blood flow in the collateral zone was not significantly less than in the normal zone, but during exercise, blood flow increased by only 79 +/- 21% (from 0.98 +/- 0.29 ml/min/g to 1.64 +/- 0.19 ml/min/g; p < 0.05) in the collateral zone as compared with 118 +/- 32% (from 1.09 +/- 0.28 ml/min/g to 2.14 +/- 0.2 ml/min/g; p < 0.01) in the normal zone. During exercise, acadesine further increased mean blood flow in the collateral-dependent region by 24 +/- 5% (to 2.04 +/- 0.26 ml/min/g; p < 0.05) with no change in the transmural distribution of perfusion. The increase in collateral zone blood flow in response to acadesine resulted from a decrease in both transcollateral resistance from 25.1 +/- 2.7 mm Hg/min/g/ml to 18.8 +/- 8 mm Hg/min/g/ml (p < 0.05) and small-vessel resistance in the collateral-dependent myocardium from 45.3 +/- 6.6 mm Hg/min/g/ml to 36.4 +/- 5.8 mm Hg/min/g/ml (p < 0.05). Acadesine also significantly increased normal-zone flow in the collateralized dogs (to 2.62 +/- 0.33 ml/min/g; p < 0.05). In contrast, acadesine had no effect on coronary blood flow in normal dogs. In dogs with moderately well-developed collateral vessels, acadesine increased blood flow in both the collateral-dependent and normal myocardial zones during exercise. In contrast, acadesine did not increase blood flow in normal dogs. These findings suggest that adenosine metabolism is altered not only in the collateral-dependent region but also in the normal region of hearts with a coronary artery occlusion.