An efficient optimization technique for recovering ventilation-perfusion distributions from inert gas data. Effects of random experimental error.

A variable metric optimization method of numerical analysis has been used to recover known distributions of intrapulmonary ventilation-perfusion ratios from inert gas data. Hypothetical lungs were simulated and corresponding inert gas retentions calculated. By using error-free retentions for seven gases and a 50-compartment model, it was possible to recover distributions containing up to three modes accurately and with greater efficiency than with other numerical methods. When random error of a magnitude consistent with present analytical techniques was introduced into retention data, the recovered distributions differed qualitatively from the original ones. This resulted from the ill-conditioned nature of the mathematical problem, which makes a recovered distribution extremely sensitive to small errors in retention. Thus, present levels of measurement error represent an important limitation in current techniques for deriving distributions from inert gas measurements.

Evaluation of venous bypass grafts from aorta to coronary artery by inert gas desaturation and direct flowmeter techniques.

Blood flow through aorta-to-coronary artery bypass grafts has been measured selectively in 16 patients at or within 6 wk after operation. Inert gas desaturation curves were obtained from coronary venous blood samples after a 7-15 min infusion of dissolved H(2) directly into the graft. Samples were analyzed chromatographically and curves resolved to 1-3% of initial H(2) concentrations. Average flow per unit volume (F/V) was 67+/-21 (sd) ml/min per 100 g. Semilogarithmic plots showed F/V to be distributed heterogeneously in every case. In nine studies at operation, H(2) measurements of average F/V were combined with electromagnetic measurements of total flow to estimate revascularized tissue mass. Electromagnetic flows ranged from 25 to 170 ml/min and averaged 69 ml/min. Tissue mass ranged from 46 to 155 g and averaged 88 g. We conclude that bypass grafts provide nutritive flow to significant amounts of myocardium at and shortly after operation. However, nutritive flow is not distributed evenly throughout the revascularized segment. The majority of the segment has a F/V within the accepted range of normal but there remain areas in which F/V is reduced significantly. The combination of inert gas and electromagnetic techniques allows a revascularized area to be characterized in terms of total flow, F/V, and tissue mass.

Measurement of cardiac output in man with a nonrecirculating indicator.

The present investigation was undertaken to evaluate the utility of constant-rate injection of a nonrecirculating indicator (H(2)) for the measurement of cardiac output in man. 42 patients were studied during cardiac catheterization and 8 during acute complications of arteriosclerotic heart disease, including acute myocardial infarction. Pulmonary (or systemic) arterial H(2) concentration was measured chromatographically from 2.0 ml blood samples drawn during constant-rate injection of dissolved H(2) into the systemic venous circulation (or left heart). The chromatograph was a thermal conductivity unit housed in a constant-temperature water bath to achieve an improved signal-to-noise ratio. Intrapulmonary H(2) elimination from mixed venous blood was measured directly in 14 patients and averaged 98 +/-1.5% (SD). Reproducibility of output measurements was evaluated using triplicate determinations obtained over 45-60 sec in 25 consecutive patients. Coefficients of variation (SD/Mean x 100) averaged 3.4 +/-2.0%, making it possible to evaluate relatively small changes in measured output with conventional statistical tests. Individual measurements could be repeated at 10-15 sec intervals. Comparisons of H(2) and direct Fick measurements were made in 14 patients; H(2) outputs averaged 106 +/-4% (SEM) of Fick outputs (P > 0.1). Comparisons of H(2) and dye dilution measurements were performed in an additional 24 patients. Seven had angiographically-negligible valvular regurgitation and dye outputs averaged 106 +/-3% of H(2) outputs (P > 0.1). 17 had moderate-to-severe regurigation and dye outputs averaged 91 +/-4% of H(2) outputs (P < 0.05), suggesting a small but systematic error due to undetected recirculation of dye. The H(2) technique appears advantageous for rapidly repeated determinations of output, for quantitation of small changes in output, and for situations in which recirculation of conventional indicators is a potentially significant problem.

Effects of heterogeneous myocardial perfusion on coronary venous H2 desaturation curves and calculations of coronary flow.

The present investigation was intended to evaluate myocardial inert gas desaturation curves for manifestations of heterogeneous coronary perfusion. The test gas was hydrogen (H(2)) and blood H(2) analyses were performed with a gas chromatograph capable of detecting small but prolonged venous-arterial H(2) differences produced by areas of reduced flow. Curves were initially obtained after 4-min left ventricular infusions of H(2)-saturated saline in six patients with arteriographically proven coronary artery disease, three patients with normal coronary arteries, and nine closed-chest dogs. The dogs were studied before and after embolic occlusion of a portion of the left coronary artery. Although the slopes of their semilogarithmically plotted venous desaturation curves varied with time before embolization, they showed more distinct deviations from single exponentials after embolization (after H(2) concentrations had fallen below 15% of their initial values). The human curves divided similarly, those from coronary artery patients deviating appreciably from single exponentials. A similar separation was also evident in studies of coronary venous-arterial H(2) differences after 20 min of breathing 2% H(2): data were obtained in four dogs before and after coronary embolization, and in three normal patients, and five patients with coronary artery disease. Additional data indicated that the findings were not the result of right atrial admixture in sampled coronary venous blood, although admixture occurred frequently when blood was sampled in the first 2 cm of the coronary sinus (as seen in the frontal projection). Finally, average coronary flows calculated from a given set of data varied significantly with different methods of calculation. Areas of below-average flow seemed likely to be overlooked when single rate constants of desaturation, relatively insensitive analytical techniques, or relatively short periods of saturation and (or) desaturation are employed.

Zero-flow pressures and pressure-flow relationships during single long diastoles in the canine coronary bed before and during maximum vasodilation. Limited influence of capacitive effects.

The proposal that diastolic coronary flow is regulated by an intramyocardial "back-pressure" that substantially exceeds coronary venous and ventricular diastolic pressures has been examined in an open-chest canine preparation in which instantaneous left circumflex pressure and flow could be followed to cessation of inflow during prolonged diastoles. Despite correlation coefficients consistently >0.90, pressure-flow data during individual diastoles were concave to the flow axis before and during pharmacologically induced maximum coronary vasodilation. Data were better fitted (P < 0.01) by second-order equations than by linear equations in >90% of cases. Second-order pressure-axis intercepts (P(f=0))(1) averaged 29+/-7 (SD) mm Hg before vasodilation and 15+/-2 mm Hg during vasodilation; left and right atrial pressures were always substantially lower (8+/-3 and 5+/-2 mm Hg before vasodilation and 8+/-2 and 4+/-1 mm Hg during dilation). Values of P(f=0) before vasodilation varied directly with levels of coronary inflow pressure. A modification of the experimental preparation in which diastolic circumflex pressure could be kept constant was used to evaluate the suggestion that P(f=0) measured during long diastoles are misleadingly high because of capacitive effects within the coronary circulation as inflow pressure decreases. Decreases in P(f=0) attributable to capacitive effects averaged only 5.9+/-3.0 mm Hg before vasodilation and were smaller during dilation. We conclude that P(f=0) is a quantitatively important determinant of coronary driving pressure and flow, resulting from both factors related to, and independent of, vasomotor tone. Adjustments of flow during changing physiological situations may involve significant changes in P(f=0) as well as in coronary resistance.

Limits of detection of regional differences in vasodilated flow in viable myocardium by first-pass magnetic resonance perfusion imaging.

BACKGROUND: Perfusion imaging techniques intended to identify regional limitations in coronary flow reserve in viable myocardium need to identify 2-fold differences in regional flow during coronary vasodilation consistently. This study evaluated the suitability of current first-pass magnetic resonance approaches for evaluating such differences, which are 1 to 2 orders of magnitude less than in myocardial infarction. METHODS AND RESULTS: Graded regional differences in vasodilated flow were produced in chronically instrumented dogs with either left circumflex (LCx) infusion of adenosine or partial LCx occlusion during global coronary vasodilation. First-pass myocardial signal intensity-time curves were obtained after right atrial injection of gadoteridol (0.025 mmol/kg) with an MRI inversion recovery true-FISP sequence. The area under the initial portion of the LCx curve was compared with that of a curve from a remote area of the ventricle. Relative LCx and remote flows were assessed simultaneously with microspheres. The ratio of LCx and remote MRI curve areas and the ratio of LCx and remote microsphere concentrations were highly correlated and linearly related over a 5-fold range of flow differences (y=0.96 x+/-0.07, P<0.0001, r(2)=0.87). The 95% confidence limits for individual MRI measurements were +/-35%. Regional differences of >/=2-fold were consistently apparent in unprocessed MR images. CONCLUSIONS: Clinically relevant regional reductions in vasodilated flow in viable myocardium can be detected with 95% confidence over the range of 1 to 5 times resting flow. This suggests that MRI can identify and quantify limitations in perfusion reserve that are expected to be produced by stenoses of >/=70%.

Relationship of MRI delayed contrast enhancement to irreversible injury, infarct age, and contractile function.

BACKGROUND: Contrast MRI enhancement patterns in several pathophysiologies resulting from ischemic myocardial injury are controversial or have not been investigated. We compared contrast enhancement in acute infarction (AI), after severe but reversible ischemic injury (RII), and in chronic infarction. METHODS AND RESULTS: In dogs, a large coronary artery was occluded to study AI and/or chronic infarction (n = 18), and a second coronary artery was chronically instrumented with a reversible hydraulic occluder and Doppler flowmeter to study RII (n = 8). At 3 days after surgery, cine MRI revealed reduced wall thickening in AI (5+/-6% versus 33+/-6% in normal, P<0.001). In RII, wall thickening before, during, and after inflation of the occluder for 15 minutes was 35+/-5%, 1+/-8%, and 21+/-10% and Doppler flow was 19.8+/-5.3, 0.2+/-0.5, and 56.3+/-17.7 (peak hyperemia) cm/s, respectively, confirming occlusion, transient ischemia, and reperfusion. Gd-DTPA-enhanced MR images acquired 30 minutes after contrast revealed hyperenhancement of AI (294+/-96% of normal, P<0.001) but not of RII (98+/-6% of normal, P = NS). Eight weeks later, the chronically infarcted region again hyperenhanced (253+/-54% of normal, n = 8, P<0.001). High-resolution (0.5 x 0.5 x 0.5 mm) ex vivo MRI demonstrated that the spatial extent of hyperenhancement was the same as the spatial extent of myocyte necrosis with and without reperfusion at 1 day (R = 0.99, P<0.001) and 3 days (R = 0.99, P<0.001) and collagenous scar at 8 weeks (R = 0.97, P<0.001). CONCLUSIONS: In the pathophysiologies investigated, contrast MRI distinguishes between reversible and irreversible ischemic injury independent of wall motion and infarct age.

Visualization of discrete microinfarction after percutaneous coronary intervention associated with mild creatine kinase-MB elevation.

BACKGROUND: Mild elevations in creatine kinase-MB (CK-MB) are common after successful percutaneous coronary interventions and are associated with future adverse cardiac events. The mechanism for CK-MB release remains unclear. A new contrast-enhanced MRI technique allows direct visualization of myonecrosis. METHODS AND RESULTS: Fourteen patients without prior infarction underwent cine and contrast-enhanced MRI after successful coronary stenting; 9 patients had procedure-related CK-MB elevation, and 5 did not (negative controls). The mean age of all patients was 61 years, 36% had diabetes, 43% had multivessel coronary artery disease, and all had a normal ejection fraction. Twelve patients (86%) received an intravenous glycoprotein IIb/IIIa inhibitor; none underwent atherectomy, and all had final TIMI 3 flow. Of the 9 patients with CK-MB elevation, 5 had a minor side branch occlusion during stenting, 2 had transient ECG changes, and none developed Q-waves. The median CK-MB was 21 ng/mL (range, 12 to 93 ng/mL), which is 2.3x the upper limit of normal. Contrast-enhanced MRI demonstrated discrete regions of hyperenhancement within the target vessel perfusion territory in all 9 patients. Only one developed a new wall motion abnormality. The median estimated mass of myonecrosis was 2.0 g (range, 0.7 to 12.2 g), or 1.5% of left ventricular mass (range, 0.4% to 6.0%). Hyperenhancement persisted in 5 of the 6 who underwent a repeat MRI at 3 to 12 months. No control patient had hyperenhancement. CONCLUSIONS: Contrast-enhanced MRI provides an anatomical correlate to biochemical evidence of procedure-related myocardial injury, despite the lack of ECG changes or wall motion abnormalities. Mild elevation of CK-MB after percutaneous coronary intervention is the result of discrete microinfarction.

Measurements of coronary blood flow and degree of stenosis: current clinical implications and continuing uncertainties.

Initial measurements of coronary blood flow in human beings were limited by methodologic inadequacies causing clinically important areas of reduced perfusion to be incompletely represented or overlooked. More recent measurements have provided insight into clinically relevant pathophysiology. There has been increasing appreciation of the need for values of flow to be related to concomitant myocardial oxygen demand, and of the importance of evaluating perfusion in relation to coronary vascular reserve. Regional flow measurement techniques have progressed significantly during the past decade and have provided better insight into perfusion deficits in ischemic heart disease. A greatly improved understanding of the relation between the arteriographic degree of stenosis and perfusion limitation also has developed. In reviewing studies addressing these points, the present article attempts to highlight their current clinical implications and address continuing uncertainties meriting further attention.

Dissociation of diastolic pressure-segment length and pressure-wall thickness relations during vasodilation in the conscious dog.

The effects of pharmacologic vasodilation and reductions in circumflex coronary artery pressure on the ventricular diastolic pressure-segment length and pressure-wall thickness relations were studied in nine conscious dogs equipped with an inflatable cuff on the proximal circumflex artery, a micromanometer in the left ventricle and four sets of piezoelectric crystals to measure wall thickness and endocardial segment length in the left circumflex and left anterior descending artery territories. Adenosine infusion into the circumflex coronary artery increased endocardial and transmural blood flow to that territory (measured by microspheres) by 436% and 487%, respectively (both p less than 0.05), and shifted the left circumflex artery territory pressure-wall thickness curve upward (p less than 0.05) without affecting the circumflex pressure-segment length, the left anterior descending artery territory pressure-segment length or pressure-wall thickness curves significantly; papaverine also shifted the circumflex region pressure-wall thickness curve upward (p less than 0.05). Both with and without vasodilation, moderate reductions in circumflex artery perfusion pressure did not affect the position of the ventricular pressure-wall thickness or the pressure-segment length curve (although during adenosine infusion endocardial blood flow decreased from 436% to approximately 100% of control values). More severe reductions in perfusion pressure (less than 45 mm Hg under control conditions and less than 30 mm Hg during adenosine infusion) decreased coronary blood flow below control values and caused a marked downward shift of the circumflex region pressure-segment length curve without affecting the position of the pressure-wall thickness curve.(ABSTRACT TRUNCATED AT 250 WORDS)

Endothelium-derived relaxing factor (nitric oxide) has a tonic vasodilating action on coronary collateral vessels.

OBJECTIVES: We sought to determine whether endothelium-derived relaxing factor (nitric oxide) exerts a tonic vasodilating effect on coronary collateral channels developed in response to myocardial ischemia. BACKGROUND: Although the coronary collateral circulation is known to react to several vasoactive agents, the role of endogenously produced nitric oxide is unclear. METHODS: Coronary collateral channels were induced in the left circumflex artery bed of 12 chronically instrumented dogs by either ameroid implantation or repeated occlusion of the left circumflex coronary artery. With the native circumflex artery occluded, aortic and circumflex pressures and microsphere flows were measured before and after systemic administration of NG-nitro-L-arginine methyl ester, an arginine analogue known to block the synthesis of nitric oxide. RESULTS: NG-nitro-L-arginine methyl ester increased mean aortic pressure from a mean +/- SEM of 92 +/- 4 to 114 +/- 4 mm Hg, whereas pressure in the occluded circumflex artery decreased from 61 +/- 4 to 55 +/- 4 mm Hg. The increase in aortic-circumflex pressure gradient (from 31 +/- 4 to 59 +/- 5 mm Hg) was accompanied by a decrease in flow in the circumflex bed (from 1.31 to +/- 0.14 to 1.09 +/- 0.15 ml/min per g), resulting in an increase in coronary collateral resistance averaging 173 +/- 37% (from 26 +/- 4 to 64 +/- 9 mm Hg/ml per min per g, p < 0.01). The increase in collateral resistance could be partially reversed by administration of L-arginine. CONCLUSIONS: We conclude that nitric oxide normally exerts a substantial tonic dilating effect in coronary collateral vessels. Disease-induced alterations in endothelial function may limit collateral perfusion importantly.

Reductions in coronary flow under resting conditions in collateral-dependent myocardium of patients with complete occlusion of the left anterior descending coronary artery.

Flow per unit weight in collateral-dependent myocardium was quantified selectively in seven patients with complete occlusion of the proximal left anterior descending artery and prominent distal collateralization from the right coronary artery by infusing dissolved hydrogen into the right coronary artery for 10 to 15 minutes and monitoring hydrogen desaturation in the great cardiac vein. Coronary flow per unit weight in all myocardium draining into the great cardiac vein was quantified simultaneously by having the patient breathe helium and by monitoring arterial and great cardiac vein helium desaturation. Flow per unit weight in collateral-dependent myocardium averaged 38 +/- 8 (standard deviation) ml/min per 100 g and was in each case below the 95% confidence limit for normal individuals with the same rate-pressure product. Flow per unit weight in all myocardium draining into the great cardiac vein was systematically higher (51 +/- 8 ml/min per 100 g); because arteries other than the anterior descending had no stenoses greater than 30% in diameter, these values presumably reflect mixtures of subnormally perfused collateralized myocardium and adjacent normally perfused tissue. The findings suggest that coronary flow per unit weight is not maintained at usual basal values in densely collaterlized myocardium that is entirely collateral-dependent. The reductions in flow are presumably associated with marked reductions in local arterial pressure and raise the possibility of a chronic reduction in local myocardial metabolic demand.

Proportionate reversible decreases in systolic function and myocardial oxygen consumption after modest reductions in coronary flow: hibernation versus stunning.

OBJECTIVES: This study sought to determine whether modest short-term reductions in coronary flow can produce subsequent proportionate reductions in myocardial function and O2 consumption compatible with myocardial hibernation. BACKGROUND: Acute studies indicate that myocardial energy utilization can be downregulated during moderate flow reduction. Whether this apparently beneficial adjustment persists into the reperfusion period is unsettled because most postischemic contractile dysfunction has been presumed to represent stunned or irreversibly injured myocardium. METHODS: Responses of regional myocardial function and O2 consumption were assessed in chronically instrumented dogs after approximately 50% reductions in flow for 2 h (n = 8) or repeated 2-min total coronary occlusions (n = 6). RESULTS: When unrestricted perfusion was restored after sustained partial occlusions, regional function and O2 consumption stabilized at proportionate, systematically decreased levels ([mean +/- SEM] 80 +/- 3.1% and 81 +/- 5.1% of control values, both p < 0.05) and then returned to control values within 24 h. Similar proportionate reductions occurred after as few as five cycles of brief total occlusion (79 +/- 5.1% and 83 +/- 1.6% of control values, both again p < 0.05); these persisted with additional occlusions and then returned to baseline values within 3 h. The absence of irreversible injury was documented histologically in both series. Sham animals (n = 5) showed no changes in regional function or O2 consumption throughout similar experimental periods. CONCLUSIONS: Moderate decreases in coronary flow or repeated brief coronary occlusions can be followed by proportionate reversible reductions in regional systolic function and O2 consumption compatible with the traditional definition of myocardial hibernation. These findings emphasize the complexity of myocardial responses to flow restriction and call attention to limitations in characterizing reversibly hypocontractile myocardium as simply hibernating or stunned.

Coronary vascular responsiveness to adenosine is impaired additively by blockade of nitric oxide synthesis and a sulfonylurea.

OBJECTIVES: We sought to define effects of glibenclamide, a sulfonylurea known to block ATP-dependent potassium (KATP) channels, and Nomega-nitro-L-arginine methyl ester (L-NAME), an L-arginine analog known to block nitric oxide (NO) synthesis, on coronary vascular responsiveness to adenosine. BACKGROUND: The role of adenosine in coronary flow regulation becomes increasingly important when KATP channel function or NO synthesis is impaired. Both variables are potentially altered in patients with coronary artery disease taking a sulfonylurea. METHODS: Dose-response curves relating coronary conductance to plasma adenosine concentration were obtained by using intracoronary infusions of adenosine (10 to 1,000 microg/min) in chronically instrumented dogs. RESULTS: ED50, the plasma concentration of adenosine needed to produce 50% of the maximal increase in conductance under baseline conditions, increased threefold after either 1 or 10 mg/kg of L-NAME. ED50 also increased in response to glibenclamide in a dose-related fashion (5.7-fold increase per 1 mg/kg body weight of glibenclamide). Effects of combined blockade of KATP channels and NO synthesis were additive, with increases in ED50 as high as 15-fold. Both L-NAME and glibenclamide increased systemic pressure and reduced coronary conductance, confirming the roles of NO and KATP channels in regulating coronary and systemic vascular tone under rest conditions as well as during stress. CONCLUSIONS: Coronary vascular responsiveness to adenosine is blunted in vivo by both L-NAME and glibenclamide. Effects of the sulfonylurea and blockade of NO synthesis are additive and can limit coronary vasodilation as well as other responses involving KATP channels and NO.

Contrast-enhanced magnetic resonance imaging of myocardium at risk: distinction between reversible and irreversible injury throughout infarct healing.

OBJECTIVES: We sought to determine the relationship of delayed hyperenhancement by contrast magnetic resonance imaging (MRI) to viable and nonviable myocardium within the region at risk throughout infarct healing. BACKGROUND: The relationship of delayed MRI contrast enhancement patterns to injured but viable myocardium within the ischemic bed at risk has not been established. METHODS: We compared in vivo and ex vivo MRI contrast enhancement to histopathologic tissue sections encompassing the entire left ventricle in dogs (n = 24) subjected to infarction with (n = 12) and without (n = 12) reperfusion at 4 h, 1 day, 3 days, 10 days, 4 weeks and 8 weeks. In vivo MR imaging was performed 30 min after contrast injection. RESULTS: The sizes and shapes of in vivo myocardial regions of elevated image intensity (828+/-132% of remote) were the same as those observed ex vivo (241 slices, r = 0.99, bias = 0.05+/-1.6% of left ventricle [LV]). Comparison of ex vivo MRI to triphenyltetrazolim chloride-stained sections demonstrated that the spatial extent of hyperenhancement was the same as the spatial extent ofinfarction at every stage of healing (510 slices, lowest r = 0.95, largest bias = 1.7+/-2.9% of LV). Conversely, hyperenhanced regions were smaller than the ischemic bed at risk defined by fluorescent microparticles at every stage of healing (239 slices, 35+/-24% of risk region, p<0.001). Image intensities of viable myocardium within the risk region were the same as those of remote, normal myocardium (102+/-9% of remote, p = NS). CONCLUSIONS: Delayed contrast enhancement by MRI distinguishes between viable and nonviable regions within the myocardium at risk throughout infarct healing.

Adjustments in regional coronary perfusion accompanying reductions in regional coronary arterial pressure.

Regional flow per unit weight has been found to be reduced under basal conditions in areas of human myocardium which are supplied by severely stenotic coronary arteries or are entirely collateral-dependent. Coronary arterial pressure within these areas is presumably reduced substantially in relation to systemic arterial pressure. In experimental animals it has recently been demonstrated that reductions in local coronary arterial pressure can result in reductions in regional myocardial flow (in all transmural layers) before vasodilator reserve is exhausted. Although the functional and metabolic accompaniments of regional flow reductions occurring in the face of vasodilator reserve remain incompletely defined, a reduction in regional metabolic demand is among the possibilities deserving consideration.

Measurement of heterogeneous myocardial blood flow.

Inert gas measurements of myocardial blood flow have been compared to simultaneous radioactive microsphere flow measurements. Average flow per unit weight agreed within 20% in 20 of 24 comparisons. With the inert gas technique flows up to 580 ml/min/100 g could be measured. Semilogarithmically plotted desaturation curves were distinctively curvilinear. It is concluded that the shape of the washout curve is a function of the underlying flow pattern.