Arterial and Venous Coronary Pressure-Flow Relations in Anesthetized Dogs

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1 238 Arterial and Venus Crnary Pressure-Flw Relatins in Anesthetized Dgs Evidence fr a Vascular Waterfall in Epicardial Crnary Veins Paul N. Uhlig, Rbert W. Baer, Gus J. Vlahakes, Frank L. Hartley, Luis M. Messina, and Julien I.E. Hffman Frm the Cardivascular Research Institute, and the Departments f Pediatrics and Physilgy, University f Califrnia, San Francisc, Califrnia Dwnladed frm by n September 17, 2018 SUMMARY. The crnary circulatin f anesthetized dgs was tested fr the presence f vascular waterfalls by manipulating crnary arterial and crnary venus pressures. The left main crnary artery and the crnary sinus were cannulated, and relatinships between crnary artery pressure, crnary sinus pressure, and crnary flw were studied. Experiments were cnducted during diastlic arrests, under steady state cnditins, in the absence f autregulatin. Relatins f crnary flw t crnary sinus pressure at cnstant crnary artery pressure were cnsistent with the presence f a vascular waterfall in the crnary sinus. When the great cardiac vein was cannulated, relatins f great vein flw t great vein pressure at cnstant crnary artery pressure were cnsistent with the presence f a vascular waterfall in the great vein, indicating that waterfall behavir can ccur in epicardial veins ther than the crnary sinus. In dgs n right heart bypass, with the crnary sinus and great vein uncannulated, the relatinship between right atrial pressure and crnary sinus pressure shwed a waterfall pattern, indicating that the waterfall is nt an artifact f venus cannulatin. In the right heart bypass experiments, venus waterfall behavir was seen in beating hearts as well as during diastlic arrests. We cnclude that a vascular waterfall is present in epicardial crnary veins which can significantly influence crnary bld flw. (Circ Res 55: , 1984) THE term vascular waterfall was used by Permutt et al. (1962) t describe the pressure-flw characteristics f cllapsible vessels subjected t external cmpressive frces. It is nw generally accepted that vascular waterfalls influence flw in the systemic venus system (Hlt, 1941) and in the pulmnary circulatin (Permutt et al., 1962; Lpez-Muniz et al., 1968). Recently, several investigatrs have suggested that vascular waterfalls als influence crnary flw. Despite increasing interest in the pssible existence f crnary vascular waterfalls, n unifrm hypthesis has emerged: the waterfall prpsed by Scharf et al. (1971) is lcated in the crnary venus system and influences the partitin f venus flw between crnary sinus and nncrnary sinus pathways; the waterfall as cnceived by Archie (1973) and Dwney and Kirk (1974, 1975) results frm systlic cmpressin f intramycardial veins and influences the transmural distributin f arterial flw; whereas the waterfall f Bellamy (1978) results frm diastlic tissue pressure acting in cncert with arterial smth muscle tne, regulates arterial flw, and may be influenced by venus pressure (Bellamy et al., 1980). If vascular waterfalls are present in a circulatin, characteristic relatinships between inflw pressure, utflw pressure, and flw shuld be present. These relatinships are well understd fr cllapsible vessels in general (Cnrad, 1969; Fry et al., 1980), and prvide the means by which waterfalls have been shwn t exist. The purpse f ur study was t test fr vascular waterfalls in the crnary circulatin by examining relatinships between crnary arterial pressure, crnary venus pressure, and crnary flw. T eliminate the effects f capacitance (Eng et al., 1982), changing smth muscle tne (Spaan, 1979), and systlic-diastlic interactins (Spaan et al., 1981), data were recrded during equilibrated lng diastlic arrests at cnstant inflw and utflw pressure, after autregulatin was ablished with chrmnar. The cnditins f ur study thus prevented recgnitin f waterfalls prduced by systle, r dependent entirely upn active smth muscle tne. The principal experiments were perfrmed n dgs in which the left main crnary artery and the crnary sinus r great cardiac vein were cannulated. Additinal experiments were perfrmed with dgs n right heart bypass in which the crnary sinus and great cardiac vein were uncannulated. T aid in interpreting ur results, an additinal experiment was perfrmed, using a mechanical Starling resistr.

2 Dwnladed frm by n September 17, 2018 Uhlig et al. /Crnary Venus Waterfall Theretical Mdel We cnsidered the crnary circulatin t be a series-parallel circuit, with an upstream segment representing the arterial and capillary beds, and a dwnstream segment f parallel pathways representing the venus bed. This mdel is supprted by anatmic studies shwing n arterivenus cmmunicatins except by way f the capillary bed, and extensive cmmunicatins between venus pathways (Barldi and Scmazzni, 1967). In additin, physilgical studies have shwn that venus flw can be shunted t alternate venus pathways if cnditins f a primary pathway are changed (Bartelstne et al., 1966; Scharf et al., 1971; Nakazawa et al., 1978). We cnsidered a vascular waterfall t be a classical Starling resistr interpsed at a chsen lcus within the circulatin. Flw was predicted by pressure gradients and resistance, and reversed flw in any segment was allwed, if nt blcked by a clsed waterfall (i.e., waterfall pressure greater than pressure in either directin at the waterfall lcus). Figure 1 illustrates pressure-flw relatins predicted frm the mdel fr experiments in which crnary sinus pressure is varied while crnary artery pressure is held cnstant. The venus circulatin is represented as parallel crnary sinus and cmbined nncrnary sinus pathways. The subpanels f the figure illustrate the theretical effects f the presence and lcatin f vascular waterfalls. Figure 1A illustrates the predicted relatins f crnary artery flw and crnary sinus flw t crnary sinus pressure with n waterfall in the circulatin. Flw int the arterial segment is determined by the difference between arterial pressure and a weighted mean utflw pressure fr the cmbined venus pathways, and by the ttal crnary CORONARY SINUS PRESSURE CORONARY SINUS PRESSURE FIGURE 1. Theretical relatins between flw and crnary sinus pressure at cnstant crnary artery pressure, based upn the presence and lcatin f vascular waterfalls. Panel A: n waterfall; panel B: upstream waterfall (arterial r capillary lcatin); panel C: venus waterfall (crnary sinus lcatin); panel D: upstream and venus waterfalls. 239 resistance. The partitin f venus flw between crnary sinus and nncrnary sinus pathways depends upn the relative resistances and utflw pressures f the pathways. Any change f crnary sinus pressure influences arterial flw by altering the mean back pressure t flw, and influences crnary sinus flw by altering ttal flw and the fractinal distributin f venus flw between crnary sinus and nncrnary sinus venus pathways. Figure IB illustrates the relatins with a waterfall in the segment upstream frm the cmmn rigin f the venus pathways. At a critical crnary sinus pressure, waterfall pressure becmes the back pressure t flw in the segment upstream frm the waterfall. At crnary sinus pressures less than this critical pressure, changes f crnary sinus pressure d nt influence arterial flw, but cntinue t influence crnary sinus flw by altering the fractinal distributin f venus flw. Figure 1C illustrates relatins with a waterfall in the crnary sinus pathway. At a critical crnary sinus pressure, waterfall pressure becmes the back pressure t flw in the crnary sinus pathway. At crnary sinus pressures less than this critical pressure, changes f crnary sinus pressure influence neither arterial flw, nr the fractinal distributin f venus flw. Figure ID illustrates the relatins with tw waterfalls, ne in the segment upstream frm the cmmn rigin f the venus pathways, and the secnd, with a lwer waterfall pressure, in the crnary sinus pathway. Tw critical crnary sinus pressures wuld be present. At crnary sinus pressures less than the lwer critical pressure, changes f crnary sinus pressure influence neither arterial flw nr the fractin f flw which drains thrugh the crnary sinus pathway. At crnary sinus pressures between the tw critical pressures, changes f crnary sinus pressure influence crnary sinus flw by altering the fractinal distributin f venus flw, but d nt influence arterial flw. The mdel des nt accunt fr reginal variatins in waterfall pressure which may exist acrss the heart wall during diastle (Baird and Adiseshiah, 1976). If such variatins exist at the waterfall lcus, a gradual transitin rather than a sharp inflectin at a critical pressure wuld be expected in the pressureflw relatins. The range f pressures in the transitin area wuld reflect the range f waterfall pressures. Methds Venus Cannulatin Experiments Experiments were perfrmed n nine mngrel dgs weighing kg. Anesthesia was induced with sdium thipental (25 mg/kg, i.v.) and was maintained by ventilatin with halthane ( %) and xygen (99.0 t 98.5%) frm an anesthesia machine (Dupac mdel 78 anesthesia apparatus; Flutec 3 vaprizer). After adequate

3 240 Circulatin Research/V/. 55, N. 2, August 1984 Dwnladed frm by n September 17, 2018 anesthesia was assured, pancurnium brmide (0.05 mg/ kg, i.v.) was given t prduce muscle relaxatin. Arterial P 2, Pc 2/ and ph were measured peridically, and the respiratr was adjusted and sdium bicarbnate administered as necessary t maintain nrmal acid-base balance. A thermstatically cntrlled heating blanket and an infrared lamp were used t keep cre temperature in the nrmal range. The heart was expsed thrugh a left thractmy with resectin f the fifth rib. The pericardium was pened widely, parallel t the phrenic nerve, and suspended t prvide supprt fr the heart. Electrdes cnnected t a pacemaker (Medtrnic 5880A) were sutured t the free wall f the right ventricle. Cmplete heart blck was prduced by injecting 40% frmalin int the atriventricular nde (Steiner and Kvalik, 1968), and the ventricle was paced. A specially frmed stainless steel perfusin cannula (inside diameter, 0.45 cm; length, 27.5 cm) was placed int the left main crnary artery via the left subclavian artery and secured with a suture tied arund the prximal prtin f the crnary artery. Oxygenated bld flwed int the cannula frm a pressurized reservir heated by a water bath. Bld was supplied t the reservir by rller pump frm the femral artery. The reservir was cnnected t a cmpressed air surce which culd be rapidly regulated. In eight f the nine dgs, the crnary sinus was cannulated with a special cannula cnstructed by attaching a 2-cm length f thin-walled aluminum tubing (.d., 0.6 cm; i.d., 0.46 cm), with a small flange at the tip (tip diameter, 0.8 cm), t a 15-cm segment f flexible Tygn plastic tubing (.d., 5 /i6 inch; i.d., Via inch). The cannula was passed thrugh a purse-string suture in the right atrial wall and secured within the crnary sinus with tw suture ligatures. The integrity f the cannula-crnary sinus junctin was determined at the end f each experiment by pening the crnary sinus and nting the lcatin f the sutures. In the ninth dg, the great cardiac vein was cannulated with a stainless steel cannula (.d., 0.35 cm) at the junctin f the great vein with the crnary sinus. In this dg, the crnary sinus was nt cannulated. The crnary sinus r great vein cannula was drained t a cllecting bttle which culd be raised r lwered t adjust utflw pressure. Frm this bttle, bld was returned by pump t the external jugular vein. Heparin (200 U/kg, i.v.) was given just befre cannulatin, and additinal dses were given every 45 minutes during the experiment. The vlume f the cmbined perfusin systems was apprximately 450 ml; the system was primed with heparinized Ringer's slutin. Venus utflw pressure was measured with ne r mre fluid-filled catheters. In sme dgs, crnary venus pressure was measured as depicted in the inset f Figure 3, by advancing ne r mre catheters upstream thrugh the venus cannula. In ther dgs, crnary venus pressure was measured with a Silastic pressure catheter placed directly int the crnary sinus thrugh its wall by a mdified Herd-Berger technique (Verrier et al., 1980), with the catheter end facing dwnstream. Orientatin f the pressure catheter did nt influence the results. The lcatin f utflw pressure measurement, hwever, significantly influenced the results, as will be described in Results. Crnary artery pressure was measured at the tip f the perfusin cannula with a fluid-filled catheter. Left ventricular pressure was measured with a slid state pressure transducer (Millar Instruments, 7 Fr.) intrduced thrugh a purse-string suture in the left atrial appendage. Artic pressure was measured in the ascending arta with a slid state pressure transducer (Millar Instruments, 7 Fr.) inserted via the femral artery. All fluid-filled catheters were cnnected t Statham P23Db pressure transducers. Zer pressure levels were assumed t be at mid-chest fr all pressure catheters; the crnary sinus catheters were apprximately 2 cm belw mid-right atrial level, and the great vein catheter was apprximately 2 cm abve midright atrial level. Crnary artery and crnary venus flws were measured with cannulating flw transducers (Hwell Instruments) in the perfusin circuits, cupled t electrmagnetic flwmeters (Narcmatic RT-500). Pressure and flw signals were recrded n an eight-channel plygraph (Beckman R612), and n FM magnetic tape. Tape recrded signals were simultaneusly digitized at 5- msec intervals (Hrwitz and Glantz, 1979; Hrtwitz, 1980), and analyzed by digital cmputer (PDP 11/70, Digital Equipment Crpratin). After cmpleting the surgical prcedure, chrmnar (10 mg/kg, i.v.) was given t ablish autregulatin; adequacy f the dse was cnfirmed by absence f reactive hyperemia after a 15-secnd cclusin f crnary flw. Additinal chrmnar (2 mg/kg, i.v.) was given if test cclusins later in the experiment revealed that reactive hyperemia had returned. Data were cllected during lng diastlic arrests induced by temprarily switching ff the ventricular pacemaker. The interval between the nset f the arrest and the first escape beat culd be prlnged by a blus injectin f lidcaine (1.5 mg/kg, i.v.), and this was dne as necessary t prvide arrests f adequate duratin. Between arrests, the heart was paced at a rate f apprximately 100 beats/min. At the nset f each arrest, crnary artery and crnary venus pressures were set t cnstant values. Data fr each pressure-flw pint were taken after cmplete equilibratin f pressures and flws, usually abut 6 secnds after the nset f arrest. Figure 2 shws data recrded during a typical arrest. Tw types f studies were cnducted. In the first type, during a series f arrests, crnary artery pressure was repeatedly set t the same value, whereas crnary sinus pressure r great vein pressure was set t a range f values. In mst dgs, several series f arrests were perfrmed, using a different cnstant crnary artery pressure fr each series. Plts f crnary artery inflw as a functin f crnary sinus r gteat vein pressure were TIME (Secnds) CORONARY ARTERY FLOW (ml/min) LV PRESSURE CORONARY ARTERY PRESSURE (mmhg) AORTIC PRESSURE CORONARY SINUS PRESSURE (mmhg) CORONARY SINUS FLOW (ml/min) 1000-j J :J FIGURE 2. Recrding f a representative diastlic arrest. Each pressure-flw relatin was cnstructed frm a series f such arrests.

4 Dwnladed frm by n September 17, 2018 Uhlig et a/./crnary Venus Waterfall cnstructed. Additinally, plts f crnary sinus utflw as a functin f crnary sinus pressure were cnstructed fr dgs in which the crnary sinus was cannulated and the junctin between the crnary sinus and the cannula was fund t be secure. Plts f great vein utflw as a functin f great vein pressure were cnstructed in the dg in which the great vein was cannulated. In the secnd type f study, perfrmed nly in dgs in which the crnary sinus was cannulated, crnary sinus pressure was repeatedly set t the same value during a series f arrests, whereas crnary artery pressure was set t a range f values. In each dg, several series f arrests were perfrmed, using a different, cnstant crnary sinus pressure fr each series. Plts f crnary artery flw as a functin f crnary artery pressure at the different crnary sinus pressures were cnstructed. Linear and quadratic regressins f crnary artery flw n crnary artery pressure fr each pressure-flw relatin were calculated. Pressure-axis intercepts were calculated using bth methds f regressin. Right Heart Bypass Experiments The relatinship between pressures in the right atrium and in the uncannulated crnary sinus was bserved in three dgs n right heart bypass. Each dg was anesthetized as described abve. The left chest and pericardium were pened, atriventricular blck was prduced, and the right ventricle was paced. The azygus vein was ligated, the superir and inferir venae cavae were cannulated with size 32 Fr. right-angle cannulas, and the pulmnary artery was cannulated thrugh the right ventricular utflw tract with a flexible perfusin cannula. A large cannula with multiple side hles was placed thrugh the right atrial appendage acrss the triscuspid valve int the right ventricle. This cannula was drained t a cllecting bttle; pressure in the right atrium and right ventricle culd be set t any desired level by adjusting the height f this bttle. Frm the cllecting bttle, bld was pumped t a cmmn venus bypass reservir which was heated by a water bath. The cmbined vlume f the bypass reservir, the cllecting bttle, and the assciated perfusin tubing was apprximately 700 ml; the system was primed with heparinized Ringer's slutin. In tw f the three dgs, the left main crnary artery was cannulated and perfused as in the venus cannulatin experiments; in these dgs, chrmnar (10 mg/kg, i.v.) was given t ablish reactive hyperemia. In the third dg the crnary artery was nt cannulated. Right atrial pressure was measured with a plyvinyl catheter (0.030 inch i.d.) inserted thrugh a purse-string suture in the right atrial wall several centimeters frm the rifice f the crnary sinus. Crnary sinus pressure was measured with the mdified Herd-Barger technique previusly described. The tip f the catheter rested apprximately 2 cm frm the crnary sinus rifice and faced dwnstream. Bth fluid-filled pressure catheters were cnnected t Statham P23Db pressure transducers calibrated frm a cmmn pressure surce. Artic pressure was measured with a slid state pressure transducer (Millar Instruments, 7 Fr.). In the tw dgs in which the crnary artery was cannulated, left ventricular pressure was measured with a similar slid-state pressure transducer. In the third dg, left ventricular pressure was nt measured. In all three dgs, with the heart beating, right atrial pressure was varied by slwly raising then lwering the reservir draining the right atrium and right ventricle. The 241 relatinship between right atrial and crnary sinus pressures was bserved. In ne f the tw dgs in which the crnary artery was cannulated, tw series f diastlic arrests were perfrmed. During each series f arrests, crnary artery pressure was repeatedly set t a cnstant value, whereas right atrial pressure was set t a range f values. Plts f crnary sinus pressure as a functin f right atrial pressure were cnstructed. In bth dgs in which the crnary artery was cannulated, the influence f left ventricular pressure r crnary sinus pressure at lw right atrial pressure was examined. With the heart beating, right atrial pressure was set t a minimum value by lwering the reservir draining the right atrium and right ventricle. Left ventricular functin was then depressed by intracrnary injectin f pentbarbital (0.025 mg/kg), resulting in an increase f diastlic and a decrease f systlic left ventricular pressure. After recvery, the descending thracic arta was partially cnstricted, resulting in an increase f bth diastlic and systlic left ventricular pressures. The effects f these interventins n crnary sinus pressure were bserved. Penrse Tubing Experiment Outflw pressures were measured simultaneusly at three lcatins within a mechanical Starling resistr, and the influence f the lcatin f utflw pressure measurement n relatins between flw and utflw pressure at cnstant inflw pressure was studied. A segment f Penrse tubing (Argyle, i.d. 5 /i6 inch) was munted n tw tubular plastic cannulas ( 3 /s inch.d., 5 /i6 inch i.d.) and adjusted s that, with the cannulas separated by 6 cm, the tubing was under n tensin. The tubing was nt enclsed; thus, atmspheric pressure acted as surrunding pressure. The Penrse segment was perfused frm a pressurized fluid reservir. The inflw tubing cntained a cannulating flw transducer (Hwell Instruments) cupled t an electrmagnetic flwmeter (Narcmatic RT-500). Inflw pressure was measured with a needle intrduced int the perfusin tubing several centimeters upstream frm the Penrse segment, cnnected t a Statham P23Db pressure transducer. A screw clamp was placed n the perfusin line between the Penrse segment and the site f inflw pressure measurement, and adjusted s that a perfusin pressure f 60 mm Hg prduced a flw f apprximately 500 ml/min. The Penrse segment was drained t a cllectin bttle pen t the air; the bttle culd be raised r lwered t vary utflw pressure. Ringer's slutin was used as the perfusate, and was returned t the perfusin reservir frm the cllectin bttle by rller pump. Needles were placed int the perfusin tubing just dwnstream frm the Penrse segment, and three plyvinyl pressure catheters (0.030 inch.d., inch i.d.) were advanced thrugh the needles int the utflw cannula and the Penrse segment. The first catheter was psitined s that its tip rested just within the rifice f the utflw cannula, the secnd catheter s that its tip was upstream frm the first catheter, 1.5 cm within the Penrse segment, and the third catheter s that its tip was upstream frm the secnd catheter, 3.0 cm within the Penrse segment (Fig. 7, inset). The three catheters were cnnected t Statham P23Db pressure transducers which were calibrated simultaneusly frm a cmmn pressure surce. While inflw pressure was held cnstant, utflw pressure was increased stepwise by raising the cllectin bttle

5 242 frm its initial psitin well belw the level f the Penrse segment. Flw and pressures were recrded with each increase in height f the cllectin bttle. This prcedure was repeated at five cnstant inflw pressures (14, 20, 40, 60, and 80 mm Hg). Plts f flw as a functin f utflw pressure were cnstructed fr each f the three sites f utflw pressure measurement within the Penrse segment and utflw cannula. Results Venus Cannulatin Experiments Of the eight dgs in which the crnary sinus was cannulated, venus pressure was measured nly at the rifice f the venus cannula in ne dg, nly within the crnary sinus in six dgs, and simultaneusly at bth lcatins in ne dg. In the dg in which the great vein was cannulated, pressure was measured simultaneusly at the rifice f the cannula and within the great vein. Unexpectedly, the lcatin f venus pressure measurement influenced the relatinships bserved between crnary flw and crnary venus pressure at cnstant crnary artery pressure. This is illustrated in Figure 3, frm the dg in which the crnary sinus was cannulated, Circulatin Research/V/. 55, N. 2, August 1984 and pressures were measured simultaneusly at the rifice f the cannula and within the crnary sinus. When pressure was measured at the rifice f the cannula (catheter A, inset, Fig. 3), the relatins f crnary artery flw and crnary sinus flw t cannula pressure shwed distinct plateaus. This is illustrated in panel A fr tw cnstant crnary artery pressures, 59.8 ± 1.1 (S.D.) mm Hg (upper left), and 37.6 ± 0.8 mm Hg (lwer left). At bth cnstant crnary artery pressures, belw a critical pressure f apprximately 12 mm Hg cannula pressure ceased t influence either crnary artery r crnary sinus flw. At higher cannula pressures, crnary artery flw and crnary sinus flw varied inversely with cannula pressure; fr a given increase in cannula pressure, there was a relatively greater decrease in crnary sinus flw as cmpared t crnary artery flw, thereby indicating a redistributin f flw away frm the crnary sinus. When pressure was measured actually within the crnary sinus (catheter B, inset, Fig. 3), plateaus were much less distinct. This is illustrated in panel B, fr the same tw cnstant crnary artery pressures illustrated in panel A. At bth cnstant crnary artery pressures, the range f crnary sinus 700 B Dwnladed frm by n September 17, 2018 " S O O OO i i *\ CORONARY SINUS CANNULA PRESSURE CORONARY SINUS PRESSURE (tnmhg) FIGURE 3. Influence f the lcatin f venus pressure measurement n relatins between crnary flw and crnary venus pressure at cnstant crnary artery pressure. Pressures were measured simultaneusly at the rifice f the venus cannula, and within the crnary sinus (inset). Panel A: crnary artery flw (pen circles) and crnary sinus flw (clsed circles) vs. cannula pressure (catheter A) fr tw cnstant crnary artery pressures (upper graph: 59.8 mm Hg; lwer graph: 37.6 mm Hg); panel B: the same flw data pltted against pressures measured within the crnary sinus (catheter B).

6 Dwnladed frm by n September 17, 2018 Uhlig et al. /Crnary Venus Waterfall pressures was much less than the range f cannula pressures, even thugh the data presented in panels A and B fr each cnstant crnary artery pressure were recrded simultaneusly. At the higher cnstant crnary artery pressure (upper right), n clear plateau was present in either the crnary artery r the crnary sinus pressure-flw relatins. At the lwer cnstant crnary artery pressure (lwer right), belw a critical pressure f apprximately 12 mm Hg, crnary sinus pressure ceased t influence either crnary artery flw r crnary sinus flw; hwever, the plateau was much shrter than that seen in the crrespnding relatin f panel A (lwer left). At higher crnary sinus pressures, crnary artery and crnary sinus flws decreased, and there was redistributin f flw away frm the crnary sinus pathway. The relatins in figure 3, panel A, are representative f the nine relatins f crnary flw t cannula pressure btained in these experiments. Distinct plateaus were present in the relatins f bth crnary artery flw and crnary venus flw t cannula pressure at all cnstant crnary artery pressures studied. Within each relatin, cannula pressure ceased t influence bth crnary artery and crnary venus flws at a cmmn critical pressure. The apprximate range f critical pressures was 5-15 mm Hg. The relatins in Figure 3, panel B, are representative f the 23 relatins f crnary flw t actual venus pressure btained in these experiments. Distinct plateaus were nt present in relatins btained at relatively high cnstant crnary artery pressures (50-60 mm Hg). Plateaus were present in sme relatins btained at lwer cnstant crnary artery pressures (30-40 mm Hg), but were relatively shrt. Within each relatin cntaining a plateau, crnary venus pressure ceased t influence bth crnary artery and crnary venus flws at a cmmn critical pressure. The apprximate range f critical pressures was 5-15 mm Hg. The relatinship between pressures at the tw sites f venus pressure measurement used in these experiments is illustrated in Figure 4, panels A and B. The data illustrated in figure 4, panel A, are frm the experiment presented in the upper half f Figure 3, in which the crnary sinus was cannulated. The data illustrated in Figure 4, panel B, are frm the experiment in which the great vein was cannulated. In bth sets f data, a critical cannula pressure is present, belw which upstream venus pressure is independent f cannula pressure; at higher cannula pressures, upstream pressure varies" directly with cannula pressure. Table 1 summarizes the results f experiments in which relatins between crnary artery flw and crnary artery pressure were determined at cnstant crnary sinus pressures. Analysis f variance was used t determine the significance f the imprvement in fit ffered by the quadratic regressin. 243 Althugh the quadratic regressin always reduced the residual sum f squares, this was significant fr nly five f the 11 relatins. Slpes f the pressureflw relatins at different crnary sinus pressures in each dg were tested fr change by analysis f cvariance. In nly ne dg was there a significant difference in slpe at different crnary sinus pressures. Pressure-axis intercepts calculated using either linear r quadratic regressins were greater than crnary sinus pressure by several mm Hg, at lw cnstant crnary sinus pressures. The intercepts were less than crnary sinus pressure when cnstant crnary sinus pressures were high. Figure 5 is representative f this grup f experiments, and illustrates pressure-flw relatins frm dg number three (Table 1), btained at three different cnstant crnary sinus pressures. Each pressure-flw relatin shws mild curvilinearity extending ver the entire range f crnary artery pressures studies. At lw, cnstant crnary sinus pressure, the pressure axis intercept f the pressure-flw relatin is greater than crnary sinus pressure by several mm Hg. At higher crnary sinus pressures, there is a rightward shift f the pressure-flw relatin alng the pressure axis; hwever, the magnitude f the shift is less than the magnitude f the change in crnary sinus pressure. Right Heart Bypass Experiments In all three dgs, with the heart beating, a characteristic relatinship was seen between right atrial pressure and crnary sinus pressure as right atrial pressure was varied. When right atrial pressure was set equal t atmspheric pressure, crnary sinus pressure was greater than right atrial pressure. Crnary sinus pressure was mre pulsatile than right atrial pressure, with a crnary sinus pulse pressure f apprximately 4-8 mm Hg. Bth right atrial and crnary sinus pressures varied with respiratin. As right atrial pressure was gradually increased, there was n change in crnary sinus pressure until a certain, critical right atrial pressure was reached which was apprximately 2-3 mm Hg belw the minimum crnary sinus pressure. As right atrial pressure was elevated abve the critical pressure, crnary sinus pressure increased with right atrial pressure. Bth right atrial and crnary sinus pressures became mre pulsatile at higher pressures because the right atrium and right ventricle were drained by a cmmn cannula. As right atrial pressure was lwered frm a maximum value, bth right atrial and crnary sinus pressures decreased tgether until the critical right atrial pressure was reached. Belw this pressure, further decreases in right atrial pressure resulted in decreased pulsatility f the right atrial pressure, but did nt change crnary sinus pressure. The critical right atrial pressure was fund t be apprximately 5 mm Hg in ne dg, apprximately 18 mm Hg in anther dg, and in the third dg apprximately 5 mm Hg at the

7 244 Circulatin Research/V/. 55, N. 2, August 1984 B C : CORONARY SINUS CANNULA PRESSURE (mmhg) < 1 I < -JO GREAT VEIN CANNULA PRESSURE RIGHT ATRIAL PRESSURE FIGURE 4. Relatinship f utflw pressures during diastlic arrests at cnstant crnary artery pressure. Panel A: crnary sinus pressure vs. cannula pressure frm the experiment illustrated in the upper panels f Figure 3. Panel B: great vein pressure vs. cannula pressure frm the experiment in which the great vein was cannulated. Panel C: crnary sinus pressure vs. right atrial pressure frm a right heart bypass experiment. Dwnladed frm by n September 17, 2018 beginning f the experiment and 15 mm Hg at the end f the experiment. The increase in critical pressure in the third dg cincided with vlume lading which increased left ventricular pressure frm apprximately 60/10 mm Hg t apprximately 60/20 mm Hg. The left ventricular pressure f the first dg was apprximately 65/5 mm Hg, and the left ventricular pressure f the secnd dg was nt recrded. The relatinship between crnary sinus pressure and right atrial pressure during diastlic arrests at cnstant crnary artery pressure is illustrated in Figure 4, panel C. Belw a critical right atrial pressure f apprximately 5 mm Hg, crnary sinus pressure is independent f right atrial pressure. Abve this critical pressure, crnary sinus and right atrial pressures are directly related. The mean left Dg 1 2 CS pressure (mean ± SD) 11.5 ± ± ± ± 0.4 TABLE l Crnary Artery Pressure-Flw Relatins at Cnstant Crnary Sinus (CS) Pressures Linear regressin Quadratic regressin N. f pints ventricular pressure during this series f diastlic arrests was 2.1 ± 2.1 mm Hg; crnary artery pressure was 38.7 ±1.6 mm Hg. The secnd series f arrests at a higher cnstant crnary artery pressure f apprximately 60 mm Hg shwed a similar pattern. In ne dg n right heart bypass, a perfusin line was inadvertently clamped, causing left ventricular pressure t becme unstable. During this perid, right atrial pressure was held cnstant at a pressure just greater than atmspheric pressure by the reservir draining the right atrium and right ventricle. Figure 6 illustrates that crnary sinus pressure varied with diastlic left ventricular pressure during this episde. This relatinship was reprduced in tw ther dgs by depressing left ventricular func- Pressureaxis intercept Slpe (ml/min per mm Hg) st 5.5 ' R 2 Pressureaxis intercept R 2 Significance* P<0.05 P < ± ± ± P < 0.05 P<t).OOl P < ± ± % ± ± * Significance f the imprvement in fit by quadratic regressin. fp<0.01.

8 Uhlig et al. /Crnary Venus Waterfall r Crnry S nus Pressure 200 > UJ I (sd 0.8) mmhg) 13.8 (sd 0.6) mm Hg) *30.0(sd 0.5) mm Hg) O* A O * O LV PRESSURE 0 60 RA PRESSURE CS PRESSURE Dwnladed frm by n September 17, 2018 IO!00-0 O.»A A l* * CORONARY ARTERY PRESSURE (mmhg) FIGURE 5. Crnary artery pressure-flw relatins at three cnstant crnary sinus pressures during equilibrated diastlic arrests. tin with an intracrnary injectin f pentbarbital. When left ventricular systlic and diastlic pressures were increased by partial cclusin f the thracic arta, the same assciatin f crnary sinus pressure and diastlic left ventricular pressure was seen. Penrse Tubing Experiment Relatins between flw and utflw pressure are cmpared in Figure 7 fr the three lcatins f utflw pressure measurement. In panel A, flw data are pltted against pressures in the utflw cannula. At all perfusin pressures, plateaus were present in the relatins belw a critical utflw pressure f apprximately 0 mm Hg. In panel B, flw data are pltted against pressures within the cllapsible tubing, just upstream frm the utflw cannula. At lw perfusin pressures, plateaus were clearly present belw a critical pressure f apprximately 0 mm Hg. At higher perfusin pressures, hwever, plateaus were less well defined. In panel C, flw data are pltted against pressures measured well within the cllapsible tubing. N plateaus were present in the relatins. Discussin The purpse f ur study was t test the crnary circulatin fr the presence f vascular waterfalls by manipulating crnary arterial and crnary venus pressure. In the venus cannulatin experiments, relatins f crnary flw t crnary venus pressure at cnstant crnary arterial pressure were fund t depend upn the lcatin f venus pressure measurement. When venus pressure was measured at the rifice f the venus cannula (Fig. 3, panel A) distinct plateaus were present, similar t the theretical pattern predicted fr a vascular waterfall in the crnary venus system (Fig. 1, panel C). When venus pressure was measured actually within the crnary sinus r great cardiac vein, hwever, the pattern f relatins was less easily 80 CS PRESSURE LVEDP FIGURE 6. Assciatin f diastlic left ventricular pressure with crnary sinus pressure at lw right atrial pressure. Panel A: serendipitus bservatin during perid f unstable left ventricular pressure in right heart bypass experiment. Panel B: crnary sinus pressure CO vs. diastlic left ventricular pressure 00 frm recrding in panel A. The relatinship is: Y = 4.8 ± 0.62X, with s YX = 1.94 and r = interpreted. Relatins perfrmed at relatively lw crnary artery pressures (Fig. 3, panel B, lwer right) ften had shrt plateaus suggesting the presence f a venus waterfall; yet relatins perfrmed at higher crnary artery pressures (Fig. 3, panel B, upper right) were withut plateaus, similar t the theretical pattern predicted fr n waterfall in the circulatin (Fig. 1, panel A). We believe that these results reflect the presence f a vascular waterfall in the dwnstream prtin f the crnary venus sytem that varies in extent f cllapse depending upn experimental cnditins. Pressure-flw relatins frm the rifice f the venus cannula detected the waterfall under all cnditins because the regin f venus cllapse was upstream frm the lcatin f pressure measurement. Pressure-flw relatins frm within the crnary sinus r great cardiac vein detected the waterfall at lw cnstant crnary arterial pressures, when the regin f venus cllapse extended far enugh upstream t incrprate the lcatin f pressure measurement, but did nt detect the waterfall at high cnstant crnary arterial pressures when the regin f venus cllapse was limited t a mre dwnstream prtin f the venus system. This interpretatin is supprted by the results f the Penrse tubing experiment. At high perfusin pressures, the regin f cllapse was cnfined t the B

9 Dwnladed frm by n September 17, mst dwnstream prtin f the Penrse segment, whereas at lwer perfusin pressures the regin f cllapse included prgressively mre f the Penrse segment. This behavir f the cllapsible segment f a Starling resistr is well knwn (Cnrad, 1969; Fry et al., 1980). As illustrated in Figure 7, pressureflw relatins using pressure data frm the rifice f the utflw cannula shwed plateaus at all per- CANNULA TUBING O OUTFLOW PRESSURE FIGURE 7. Influence f the lcatin f utflw pressure measurement n relatins f flw vs. utflw pressure at cnstant inflw pressure. Pressures were measured simultaneusly at three lcatins within a mechanical Starling resistr (inset). Panel A, flw vs. pressure measured at the rifice f the utflw cannula (catheter A) fr five cnstant inflw pressures (14, 20, 40, 60, 80 mm Hg). Panel B: the same flw data pltted against pressure measured 1.5 cm within the cllapsible segment (catheter B). Panel-C: the same flw data pltted against pressure measured 3.0 cm within the cllapsible segment (catheter O. Circulatin Research/Vl. 55, N. 2, August 1984 fusin pressures (panel A); relatins using pressure data frm the middle f the cllapsible segment shwed plateaus at lw perfusin pressure which disappeared at higher perfusin pressures (panel B); and relatins using pressure data frm the mst upstream prtin f the cllapsible segment shwed n plateaus at high r lw perfusin pressures (panel C). Pressure-flw relatins frm the rifice f the utflw cannula are identical t thse frm the rifice f the venus cannula; relatins frm the middle f the Penrse segment are identical t thse frm the crnary sinus r great vein. In these experiments, any change f venus pressure which prduced a change f crnary venus flw als prduced a change f crnary arterial flw. This finding argues against the presence f additinal waterfalls upstream frm the venus waterfall under the cnditins f ur study. It is pssible, hwever, that because f variability in ur data, the secnd break pint which wuld indicate an upstream waterfall (Fig. 1, relatin D) might nt have been recgnized. In additin, it is pssible that a waterfall in which venus pressure influences arterial pressure such as that hypthesized by Bellamy et al. (1980) culd be present and remain undetected by this type f experiment. T test fr the presence f an upstream waterfall, we perfrmed experiments similar t thse f Bellamy et al. in which crnary arterial pressure-flw relatins were cnstructed at several cnstant crnary sinus pressures. Like Bellamy et al., we fund that the pressure axis intercepts f arterial pressureflw relatins perfrmed at lw cnstant crnary sinus pressure were greater than crnary sinus pressure (Fig. 5; table 1). Hwever, whereas Bellamy et al. fund a large difference between intercept pressure and crnary sinus pressure, in ur experiments the difference was small. At higher cnstant crnary sinus pressures, the pressure-flw relatins were shifted t the right alng the pressure axis. The magnitude f the shift was less than the magnitude f the change f crnary sinus pressure; in all dgs the pressure axis intercept at high crnary sinus pressures was less than crnary sinus pressure. This is in cntrast t the results f the study f Bellamy et al., in which the pressure-axis intercept was fund t exceed crnary sinus pressure at all crnary sinus pressures studied. The bservatin that the pressure-axis intercept exceeded crnary sinus pressure when crnary sinus pressure was lw implies that a back pressure t flw greater than the measured crnary sinus pressure was present at sme pint in the circulatin under the cnditins f these experiments. Because the magnitude f the difference between crnary sinus pressure and the pressure axis intercept was quite small in ur studies, several alternative explanatins can be cnsidered. It is pssible that pressure, as measured in the dwnstream prtin f the crnary sinus, did nt accurately reflect venus

10 Dwnladed frm by n September 17, 2018 Uhlig et al./crnary Venus Waterfall waterfall pressure at lw flws. This phenmenn was seen in the Penrse tubing experiment (Fig. 7), in which at lwer perfusin pressures subatmspheric pressures were recrded within the dwnstream prtin f the cllapsible segment, even thugh waterfall pressure equal t atmspheric pressure was the effective back pressure t flw. Intercept pressure might therefre crrectly reflect venus waterfall pressure, yet appear t be several mm Hg higher than crnary sinus pressure. Because pressure was cntrlled nly in the cannulated prtin f the venus bed, pressure gradients must have existed within the venus system. This is evident frm the bservatin that at very high crnary sinus pressures, backflw int the crnary sinus ften ccurred. In the absence f an upstream waterfall, intercept pressure shuld equal a weighted mean utflw pressure f the venus pathways; thus the nn-crnary sinus pathways culd cause intercept pressure t exceed crnary sinus pressure when crnary sinus pressure was lw, and likewise culd explain the bservatin that intercept pressure fell belw crnary sinus pressure when crnary sinus pressure was elevated. Finally, it is pssible that an upstream waterfall with a waterfall pressure several mm Hg higher than venus waterfall pressure was present. The mst likely cause f the differences between ur studies and thse f Bellamy et al. is the way in which the pressure-flw relatins were cnstructed. Data fr each pressure-flw relatin in the experiments f Bellamy et al. were recrded in the left circumflex crnary artery during a single lng diastle during which crnary artery pressure was declining. Vasdilatin was prduced by temprarily ccluding the crnary artery prir t the arrest. In ur experiments, data fr each pressure-flw relatin were recrded in the left main crnary artery during a series f diastlic arrests after cmplete equilibratin f pressures and flws. Vasdilatin was prduced by ablishing autregulatin with chrmnar. Recently, we have shwn that the zerflw pressure-axis intercept in the left circumflex crnary artery is artifactually elevated by cllateral inflw frm ther branches f the left crnary artery (Messina et al., 1983). Furthermre, it has been suggested that effects f capacitance (Eng et al., 1982) and autregulatin f the crnary bed during cllectin f pressure-flw data (Spaan, 1979) may influence the results f pressure-flw studies perfrmed under nn-equilibrated cnditins. Althugh the significance f capacitance and autregulatin effects is cntrversial (Bellamy, 1979; Klcke et al., 1981), it is pssible that the pressure-axis intercepts in the study f Bellamy et al. verestimate back pressure t flw. At least tw ther studies have identified waterfall behavir in the crnary venus circulatin. In an islated, beating heart preparatin with the crnary sinus cannulated, Scharf et al. (1971) fund a critical 247 crnary sinus pressure f apprximately 12 mm Hg, belw which crnary sinus pressure did nt influence the partitin f crnary venus flw be- tween crnary sinus and nn-crnary sinus venus pathways. In a similar preparatin, Traystman (1971) fund a critical crnary sinus pressure in the range f 0-15 mm Hg, belw which crnary sinus pressure did nt influence either intramycardial bld vlume r crnary artery pressure at cnstant crnary flw. Bth Scharf et al. and Traystman measured crnary sinus pressure at the rifice f the cannula draining the crnary sinus. Althugh bth Scharf et al. and Traystman cncluded that a waterfall is present in the crnary venus system, they did nt mre cmpletely define its lcatin. It seems prbable that the waterfall recgnized by Scharf et al. and Traystman is the same waterfall we have identified in the great vein and crnary sinus. This hypthesis is strengthened by the similarity f critical pressures in the three studies, and by the fact that in the Traystman study intramycardial bld vlume did nt increase until the critical crnary sinus pressure was exceeded. The mechanism prducing the waterfall cannt be determined with certainty frm ur experiments. The right heart bypass experiments were undertaken t determine whether waterfall behavir bserved in the crnary sinus and great cardiac vein was an artifact f cannulatin. As illustrated in Figure 4, the relatinship between pressures in the right atrium and the uncannulated crnary sinus during diastlic arrests (panel C) was identical t relatinships between pressures in the venus cannula and the crnary sinus (panel A), and the venus cannula and the great vein (panel B) in the venus cannulatin experiments. This implies that the waterfall is nt an artifact f venus cannulatin. A serendipitus bservatin in the right heart bypass experiments was an apparent assciatin f crnary sinus pressure with diastlic left ventricular pressure, in the absence f a change f right atrial pressure, during an episde f acute left ventricular failure (Fig. 6). This relatinship was reprduced by intracrnary injectin f pentbarbital, and by partial cclusin f the thracic arta. This assciatin f venus waterfall pressure with the filling state f the left ventricle is cnsistent with a hypthesis that the venus waterfall is prduced by cmpressin f epicardial veins between the heart wall and surrunding tissues. Althugh the pericardium was pen in the right heart bypass and venus cannulatin experiments, the crnary sinus was dependent and thus cmpressed by the heart against the pericardial cradle. Hwever, waterfall behavir was als seen in the cannulated great cardiac vein n the expsed surface f the heart. Additinally, the waterfall behavir nted by Scharf et al. and by Traystman ccurred in islated, suspended hearts. Althugh the epicardial veins are surface vessels, they lie beneath the epicardium (visceral pericar-

11 248 Circulatin Research/Vl. 55, N. 2, August 1984 Dwnladed frm by n September 17, 2018 dium). It is pssible that the epicardium acts as a restraining influence, allwing subepicardial pressures t be transmitted t epicardial crnary veins. Baird and Adisehiah (1976) studied the effect f vlume lading n diastlic inrramycardial tissue pressure and fund that pressures in the subepicardium increased frm 11 mm Hg at left ventricular end-diastlic pressures f 0-4 mm Hg, t 24 mm Hg at left ventricular end-diastlic f greater than 20 mm Hg. These values fr subepicardial tissue pressure are similar t values f venus waterfall pressure in ur studies, and thse f Scharf et al. and Traystman. We cnclude that under apprpriate cnditins a vascular waterfall exists in the epicardial venus system which is capable f influencing arterial as well as venus crnary flw. Diastlic left ventricular pressure appears t be a determinant f venus waterfall pressure. Hwever, in ur experiments, we culd nt determine whether venus waterfall pressure was changed by left ventricular systlic pressure, diastlic pressure, r diastlic dimensins. Because waterfall pressure, rather than right atrial pressure, can be the back pressure t flw in large prtins f the crnary venus bed, the venus waterfall shuld be cnsidered when interpreting studies f flw and pressure acrss the crnary circulatin. If the venus waterfall perates in the intact circulatin, its influence n crnary flw shuld be small under nrmal cnditins. Hwever, when left ventricular diastlic pressure increases withut a cmparable increase in right atrial pressure, a cnditin ften seen in disease, the crnary venus waterfall may uncuple crnary venus pressure frm right atrial pressure, and thus substantially reduce the driving pressure fr crnary perfusin. We thank Jse Mrales and Judith Jester fr their utstanding technical assistance, Carl McWatters fr preparing the illustratins, Dr. Oluwle Adeb fr assistance in develping the right heart bypass prcedures, Hechst-Russel Labratries, Inc., fr a generus dnatin f chrmnar, and Kathy Strer and Ann Uhlig fr preparing the manuscript. This wrk was supprted by Prgram Prject Grant HL25847 frm the U.S. Public Health Service. Dr. Uhlig's present address is: Department f Surgery, Massachusetts General Hspital, Bstn, Massachusetts Address fr reprints: Julien I.E. Hffman. M.D., 1403 HSE, University f Califrnia, San Francisc, Califrnia Received July 26, 1982; revised manuscript received Nvember 9, 1983; accepted fr publicatin June 8, References Archie JP (1973) Determinants f reginal inrramycardial pressure. ] Surg Res 14: Baird RJ, Adiseshiah M (1976) The respnse f diastlic mycardial tissue pressure and reginal crnary bld flw t increased prelad frm bld, cllid, and crystallid. 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Circ Res 49: Steiner C, Kvalik ATW (1968) A simple technique fr prductin f chrnic cmplete heart blck in dgs. J Appl Physil 25: Traystman RJ (1971) The relatinships f pressure, flw, and vlume in the crnary vascular bed. Dctral thesis. The Jhns Hpkins University, Baltimre Verrier Ed, Edelist G, Cnsigny PM, Rbinsn S, Hffman JIE (1980) Greater crnary vascular reserve in dgs anesthetized with halthane. Anesthesilgy 53: INDEX TERMS: Starling resistr Pressure-flw relatins Pressure-axis intercept Left ventricular diastle pressure Right heart bypass