This Article Abstract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kohno, F. Articles by Sasayama, S. Search for Related Content PubMed PubMed Citation Articles by Kohno, F. Articles by Sasayama, S.

(Circulation. 1996;93:2080-2087.)
© 1996 American Heart Association, Inc.

Articles

Change in Aortic End-Systolic Pressure by Alterations in Loading Sequence and Its Relation to Left Ventricular Isovolumic Relaxation

Fujimasa Kohno, MD; Toshiaki Kumada, MD; Masashi Kambayashi, MD; Wataru Hayashida, MD; Noboru Ishikawa, MD; Shigetake Sasayama, MD

From the Third Division, Department of Internal Medicine, Faculty of Medicine, Kyoto University, Kyoto, Japan.

Correspondence to Toshiaki Kumada, MD, Third Division, Department of Internal Medicine, Faculty of Medicine, Kyoto University, 54 Kawara-cho shogoin, Sakyo-ku, Kyoto, 606, Japan.

	Abstract

Top Abstract Introduction Methods Results Discussion References

 
Background A brief, sustained constriction of the descending and the ascending aortas produces systolic loads at different times during ejection, and descending intervention prolongs left ventricular (LV) relaxation more than ascending intervention. Although alterations in the sequence of loading the ventricle have been suggested as a cause of such load-induced relaxation abnormalities, the relation of the loading system to relaxation has been unclear.

Methods and Results LV peak systolic pressure was elevated by approximately 40 mm Hg by constricting the descending and ascending aortas in seven anesthetized dogs. The descending intervention increased aortic end-systolic pressure (AoESP, 110.4±9.3 to 150.8±11.5 mm Hg; P<.05), reduced aortic flow (P<.05), and prolonged LV relaxation (time constant [T], 31.9±4.4 to 69.8±12.8 ms; P<.05). LV ejection time was reduced, but the systolic time interval was unchanged. In contrast, ascending intervention decreased AoESP (111.9±11.4 to 101.5±10.3 mm Hg; P<.05), reduced aortic flow (P<.05), and prolonged T (31.2±5.4 to 42.2±8.3 ms; P<.05), whereas ejection time and systolic time interval increased (both P<.01). Prolongation of T was significantly greater during descending intervention (P<.05) and was associated with an increase in AoESP during descending intervention but a decrease in AoESP during ascending intervention.

Conclusions Descending intervention induced greater prolongation of T than ascending intervention. Prolongation of T was closely related to an increase in AoESP in the descending intervention but a decrease in AoESP in the ascending intervention. These data suggest that not only the loading sequence but also the pressure level at the onset of isovolumic relaxation determines LV relaxation.

Key Words: hemodynamics • systole • pressure • aorta • ventricles

	Introduction

Top Abstract Introduction Methods Results Discussion References

 
The clinical importance of detecting impaired LV relaxation has been stressed by many investigators.^{1 2 3 4 5 6} Such impairment is mainly due to abnormality of inactivation or of loading conditions or nonuniform distribution of load and inactivation in space and in time.⁷ The effects of systolic load on relaxation remain controversial,^{8 9 10 11 12 13 14} probably because of differences in preparations and methodology. In addition, most of these studies paid little regard to the timing when load was imposed.

Recent experimental studies of the cardiac muscle by Brutsaert et al^{15 16} and Gillebert et al¹⁷ documented that load clamps early during isotonic shortening resulted in delayed onset of muscle relaxation. In contrast, load clamps late during isotonic shortening led to premature onset of relaxation and reduced the peak rate of tension fall.^{15 16 17} This property of cardiac muscle is called load-dependent relaxation.^{6 15 16} The dependency of onset of relaxation on the timing of systolic load has been observed not only in the isolated^{18 19} but also in the intact heart.^{11 12 13 14 20 21 22} However, studies of load effects on LV relaxation in the whole heart have yielded conflicting data.^{11 12 13 18 19 20 21 22 23 24} Of these studies, findings in the intact heart appear to be consistent, in which LV relaxation was less prolonged by loading early in systole than by loading late in systole.^{11 12 13 14 20 21 22} Such load-dependent relaxation is also manifested during brief, sustained constriction of the aorta, which can change the magnitude and the timing of systolic load.^{12 14 22} Constriction of the aorta may reduce total arterial compliance²⁵ and increase peak systolic pressure with the peak at various times during the ejection period.^{12 14 22} Therefore, mechanical constriction of the aorta may lead to a change in systolic load similar to a change in capacitance and resistance vessels.²⁶ However, little information is available regarding the relation of LV relaxation to capacitive and resistive characteristics of the loading system.²⁷ Since the interaction between the left ventricle and the arterial system determines waveforms of the ascending aortic pressure as well as those of LV pressure,^{23 25 26 27 28 29 30 31} the change in LV systolic pressure waveforms should be reflected in aortic systolic pressure waveforms, and analysis of the aortic pressure waveform may provide more direct information on the change in the loading system. Therefore, the present study attempted to examine how the aortic pressure waveform is altered by the descending and the ascending aortic constriction and how the change in the aortic pressure influences LV relaxation. The result showed that both interventions caused quite different responses in aortic systolic pressure waveforms and that aortic end-systolic pressure level significantly influenced LV relaxation.

	Methods

Top Abstract Introduction Methods Results Discussion References

 
Seven adult mongrel dogs weighing between 17 and 25 kg (mean, 20.1 kg) were anesthetized with sodium pentobarbital (25 mg/kg IV). Pentobarbital was then infused continuously at the rate of 4 mg/kg per hour during the study, and the dogs were ventilated with a Harvard respirator. A left thoracotomy was made at the fifth intercostal space. The pericardium was incised, and the heart was suspended in a pericardial cradle. An ultrasonic transit-time flowmeter (T201, Transonic Systems Inc) was placed around the proximal ascending aorta 3 to 5 cm distal to the aortic valve. A high-fidelity micromanometer (Konigsberg, P-7) and a polyethylene tube were inserted into the left ventricle from the left atrial appendage. The pressure of the ascending aorta was measured by a catheter-tipped micromanometer (Millar Instruments, 6F) through the left carotid artery. To calibrate pressures from both high-fidelity micromanometers, a Millar catheter placed at the ascending aorta was inserted into the left ventricle through the aortic valve, and LV pressures from both micromanometers were matched with the pressure obtained by a Statham PD23ID transducer connected to the fluid-filled lumen of a polyethylene tube. The zero reference of pressure was taken at the midventricular level. After pressure matching, the catheter was withdrawn from the left ventricle into the ascending aorta, and the catheter tip was positioned 1.5 to 2.0 cm distal to the aortic valve. To increase afterload, a constrictor was placed around the ascending and thoracic aortas, respectively; the former constrictor was placed just distal to the flowmeter and was used to constrict the ascending aorta. The latter was placed around the descending aorta approximately 5 cm distal to the aortic arch and was used to constrict the descending aorta. Therefore, the micromanometer for measuring ascending aortic pressure was positioned between the aortic valve and constrictor. For measurement of wall thickness, one pair of ultrasonic dimension gauges (5 MHz, 2-mm diameter) was positioned at the anterior base of the left ventricle (the basal one third of the LV long axis). A pair of dimension gauges was interfaced parallel to the surface at the endocardium and the pericardium.³²

LV end diastole was defined as the beginning of pressure rise after the atrial kick. Since the purpose of this study was to analyze the time course of the LV pressure fall during the isovolumic relaxation phase, which starts just after the aortic valve closure, ie, after the incisura, LV end systole was defined as the incisura of the aortic pressure curve. AoDP was measured at the beginning of the rise in aortic systolic pressure, and AoESP was taken at the aortic incisura. LV pressure corresponding to the time of AoESP was defined as the pressure at onset of LV isovolumic relaxation and expressed as Pes. Pes so obtained was always lower than AoESP (Table). Such a discrepancy between AoESP and Pes has been reported to result from a retrograde transmission of aortic pressure: Using high fidelity micromanometers, Noble²³ reported that LV pressure was higher than aortic pressure (positive pressure gradient) early in the ejection phase, but aortic pressure was higher than LV pressure (negative gradient) in the late systole, and the range of a negative gradient varied from 4.1 to 23.0 mm Hg among dogs. LV STI was defined as the duration from LV end diastole to AoESP, and LV ejection time as the duration from AoDP to AoESP. In addition, the duration from LV end diastole to LV PSP was measured and expressed as t-PSP; since the timing when PSP occurred varied in the control state among dogs and the purpose of measuring t-PSP was to compare the change in t-PSP during descending aortic constriction with that during ascending aortic constriction, t-PSP was measured at 40 mm Hg increments of PSP during both interventions. Stroke volume was calculated by integrating the phasic aortic flow curve.

View this table: [in this window] [in a new window]   Table 1. Hemodynamic Parameters (n=7)

Regional wall thickening was evaluated by the percent wall thickness change as follows: (1) the percent wall thickening from end diastole to end systole (%W_es)=100x(end-systolic wall thickness minus end-diastolic wall thickness)/end-diastolic wall thickness and (2) the percent wall thickness change from end diastole to PSP (%W_ps)=100x(wall thickness at PSP minus end-diastolic wall thickness)/end-diastolic wall thickness. In addition, the increase in the percent wall thickening from PSP to end systole was measured by the difference between %W_es and %W_ps and expressed as %.

The LV isovolumic relaxation period was defined as the interval between AoESP and the LV pressure corresponding to 5 mm Hg above the LV end-diastolic pressure. Time constant of LV pressure fall was calculated with a nonzero asymptote method during the isovolumic relaxation period.⁸

After the control recording, the descending aorta was constricted abruptly for less than 6 seconds to raise PSP, and the constrictor then was released completely. After hemodynamics recovered fully, the second control recording was made and the ascending aorta was constricted to increase PSP to the same level as in the descending aorta (Table). Recordings were made with respirations suspended at end expiration. Pressures, aortic phasic flows, and wall thickness were recorded on a chart by a multichannel recorder (EVR, Electronics for Medicine) and simultaneously on a magnetic tape by a data recorder (SR51, Teac) for subsequent data analysis. Parameters in the control state were averaged on 8 subsequent beats, and those during increase in afterload were taken at the level closest to the 40 mm Hg increment of PSP. Comparison of the parameters was made between the control state and 40 mm Hg increment of PSP and between constriction of the ascending and the descending aortas. In addition, beat-to-beat analysis of the relationship between T and PSP, between T and AoESP, and between T and Pes was performed during both interventions in each dog.

All data were expressed as mean±1 SD. Statistical analysis was performed by ANOVA, and P<.05 was considered significant. This study was approved by the Animal Care Committee of the School of Medicine, Kyoto University.

	Results

Top Abstract Introduction Methods Results Discussion References

 
Findings are summarized in the Table. Constriction of the descending and ascending aortas equally increased PSP by approximately 40 mm Hg above the control level.

Constriction of the Descending Aorta
Constriction of the descending aorta did not change the RR intervals. LV end-diastolic pressure rose significantly from 7.3±1.1 mm Hg at the control state to 10.6±2.3 mm Hg at 40 mm Hg increment of PSP (P<.05). Peak (+)dP/dt increased slightly (P<.05), but peak (-)dP/dt was unchanged. End-diastolic wall thickness decreased from 9.17±0.55 to 8.78±0.56 mm (P<.05). Percent wall thickening at end systole (%W_es) was significantly reduced from 18.3±3.0% to 13.7±3.5% (P<.05).

Pes increased from 87.9±13.6 (at the control) to 132.8±14.7 mm Hg (at 40 mm Hg increment), and this change was significant (P<.05). Similarly, AoESP increased significantly from 110.4±9.3 to 150.8±11.5 mm Hg (P<.05). Stroke volume decreased from 10.8±3.1 to 8.1±3.6 mL (P<.05).

STI was unchanged (from 205±26 to 204±25 ms; NS). Ejection time decreased significantly from 139±19 to 130±19 ms (P<.05; Table). During the descending aortic constriction, PSP occurred late in ejection in all dogs (Fig 1), and t-PSP was 173±29 ms at 40 mm Hg increment of PSP, which corresponded to approximately 76% of ejection time. T significantly increased from 31.9±4.4 to 69.8±12.8 ms (P<.05; Table).

View larger version (31K): [in this window] [in a new window]   Figure 1. Representative examples of changes in hemodynamics during descending and ascending aortic constrictions. From top to bottom; aortic flow (AoF), aortic pressure (AoP), LV pressure (LVP), LV dP/dt, and wall thickness (WT). Control indicates before interventions; P40, 40 mm Hg increment of LV peak systolic pressure. There were marked differences in LV and aortic pressure waveforms, negative dP/dt upstroke patterns, and flow signals between the descending and ascending aortic constrictions. Thick arrows indicate aortic end-systolic pressures. Note that negative dP/dt upstroke patterns (thin arrows) during ascending intervention showed a less convex-downward configuration than those during descending intervention. For details, see text.

Constriction of the Ascending Aorta
RR intervals decreased slightly (P<.05) with constriction of the aorta. End-diastolic pressure rose significantly from 7.4±1.3 to 10.6±2.6 mm Hg (P<.05). Peak (+)dP/dt was unchanged, but peak (-)dP/dt decreased slightly (P<.05). End-diastolic wall thickness decreased from 9.16±0.53 to 8.81±0.57 mm (P<.05). %W_es significantly decreased from 17.9±3.8% to 12.7±4.5% (P<.05).

In contrast to the descending aortic constriction, Pes and AoESP decreased significantly from 88.6±15.8 to 76.7±18.9 mm Hg (P<.05) and from 111.9±11.4 to 101.5±10.3 mm Hg, respectively (P<.05). Stroke volume decreased from 10.7±3.3 to 4.4±2.0 mL (P<.05).

STI was prolonged significantly from 205±25 to 224±29 ms (P<.05), associated with an increase in ejection time from 135±17 to 163±26 ms (P<.05). During ascending aortic constriction, PSP occurred in the mid ejection phase, and t-PSP was 145±23 ms, which corresponded to approximately 48% of ejection time. T increased slightly from 31.2±5.4 to 42.2±8.3 ms (P<.05).

Comparison Between Descending and Ascending Aortic Constriction
There was no significant difference in hemodynamic parameters in the control state between descending and ascending aorta interventions (Table).

On comparison of the descending intervention with the ascending intervention, there was no significant difference in RR intervals, peak (+)dP/dt, peak (-)dP/dt, and LV end-diastolic pressure. Pes, AoESP, and AoDP were significantly lower at the 40 mm Hg increment of PSP during ascending intervention (P<.05) because these parameters changed in the opposite direction of those during descending intervention (Table). Stroke volume was more reduced during ascending intervention than during descending intervention (P<.05). Of interest, in comparison to descending intervention, aortic flow during ascending intervention was more reduced from the early ejection phase and maintained at that low flow level throughout the second half of the ejection period despite PSP rising to the same level (Fig 1). There was no significant difference in the change in end-diastolic wall thickness and %W_es between the descending and ascending interventions. On the one hand, %W_ps was significantly greater during descending intervention than during ascending intervention (P<.05); thus the increment of percent wall thickening from PSP to end systole (%) was significantly greater during ascending intervention (P<.05). This indicates that the extent of fiber shortening from PSP to end systole was greater during ascending intervention.

STI and ejection time were more prolonged during ascending intervention than during descending intervention, and these changes were significant (P<.05). t-PSP was more significantly prolonged during descending intervention than during ascending intervention (P<.05; Table), since PSP occurred late in ejection during descending intervention but in mid ejection during ascending intervention (Fig 1).

Prolongation of T was significantly greater during descending intervention than during ascending intervention at the 40 mm Hg increment of PSP (P<.05; Table). Beat-to-beat analysis of the relation between T and PSP was performed during both interventions in all seven dogs. In five of seven dogs, T increased with an increase in PSP during the period in which PSP rose by 40 mm Hg, and the slope of this relation was less during ascending intervention than during descending intervention (Fig 2). This indicates that descending intervention impaired LV relaxation more than ascending intervention. However, when T was plotted against AoESP or Pes in these five dogs, T increased with an increase in AoESP during descending intervention, whereas T increased with a decrease in AoESP during ascending intervention (Fig 3). The value for T tended to be minimal during the control state for both interventions. In the remaining two dogs, PSP was elevated by 40 mm Hg during ascending intervention but T did not increase, indicating that an increase in PSP of more than 40 mm Hg was required to increase T (Fig 4). However, during the period in which PSP was increased by 40 mm Hg from the control level, AoESP (or Pes) changed slightly (a variation of approximately 8 mm Hg), and further increase in PSP caused a decrease in AoESP (or Pes), associated with an increase in T (Fig 4). The value for T was minimal during control state, again.

View larger version (14K): [in this window] [in a new window]   Figure 2. Relation of time constant (T) to LV peak systolic pressure (PSP). The slope of the relation was steeper in the descending aortic constriction than in the ascending aortic constriction, indicating that LV relaxation was more prolonged in descending aortic constriction at a given PSP level.

View larger version (12K): [in this window] [in a new window]   Figure 3. Relations of T to AoESP and to LV pressures at AoESP (Pes) (same dog as in Fig 2). Note that T increased with an increase in AoESP (top) and Pes (bottom) in the descending aortic constriction, whereas T decreases with a decrease in AoESP and Pes in the ascending constriction.

View larger version (14K): [in this window] [in a new window]   Figure 4. Relations of T to PSP and to AoESP. Note that during ascending aortic constriction, T did not increase until PSP increased by approximately 40 mm Hg from the control level (top plot) during which period AoESP varied only slightly (bottom plot). T increased with an increment of PSP beyond 40 mm Hg during ascending intervention (open triangles with arrows in the top plot). However, the relation of T to AoESP showed that the increase in T was related to the decrease in AoESP (open triangles with arrows in the bottom plot). Arrows indicate beats with a pressure increase above 40 mm Hg.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
In the present study, PSP rose to the same level during descending and ascending aortic constrictions. Descending intervention produced PSP in the late ejection phase and increased AoESP and AoDP but did not change STI. In contrast, the ascending intervention produced PSP in the mid ejection phase, decreased AoESP and AoDP, and increased STI. LV relaxation, T, was more prolonged during descending intervention than during ascending intervention, and the prolongation of T was closely related to the change in AoESP.

Changes in Aortic Pressure Waveforms During Descending and Ascending Aortic Constrictions
The aortic pressure pulse can be regarded as a summation of forward and backward waves.^{25 26 27 28 29 30 31} Forward waves run from the heart into the arterial system, whereas backward waves are caused by reflections of forward waves from many sites in the system.^{25 29} Descending aortic occlusion produces larger reflected waves and summation of the forward wave, with the reflected wave causing a secondary rise in late systolic pressure²⁵ leading to increased systolic pressure with a peak late in ejection.^{25 29} This explains late occurrence of PSP during descending aortic constriction in the present study. Increased late systolic load can interrupt myocardial shortening and cause a premature decrease in LV pressure,^{15 16 21 23} which leads to premature closure of the aortic valve. This, in combination with an increased PSP, accounts for the increase in AoESP observed in the present study. Increased AoESP and decreased runoff during descending aortic constriction caused the increase in AoDP. On one hand, it is reported that occurrence of reflection waves becomes earlier as the distance from the occlusion site to the ascending aorta becomes short.²⁵ We constricted the proximal aorta 5 cm distal to the aortic valve and placed a pressure sensor between the aortic valve and the constrictor. Therefore, the distance between the constrictor and the pressure sensor could be short enough to produce reflection waves in the mid ejection phase (Table). Of interest was that the ascending intervention significantly decreased AoESP and AoDP (Table). These changes were the opposite of those during descending intervention. The duration of aortic pressure fall from the PSP to the aortic incisura during ascending intervention was approximately twice that during descending intervention. Such a long duration of the late systolic pressure fall resulted in a decrease in AoESP, leading to lower AoDP.

Elzinga and Westerhof²⁶ reported that changes in peripheral resistance and aortic capacitance led to marked differences in the aortic pressure and flow waveforms. An increase in peripheral resistance increased PSP and AoDP, and PSP occurred late in ejection. The aortic flow decreased with a similar pattern to that before increase in resistance, and ejection time was abbreviated.²⁶ By contrast, a decrease in capacitance increased PSP slightly and decreased AoDP. The pattern of the decreased aortic flow signal was more pronounced, and PSP occurred earlier. AoESP was greatly reduced, and ejection time was prolonged.²⁶ The similarity between our result and theirs suggests that a brief, sustained constriction of the descending aorta can induce a response similar to that induced by an increase in peripheral resistance, whereas a brief, sustained constriction of the ascending aorta can result in a response similar to that induced by a decrease in capacitance.

The present results showed that ascending intervention caused greater decrease in aortic flow from the early ejection phase, and this low flow was maintained until the end of ejection (Fig 1). In contrast, reduction of the flow was more marked during the late ejection phase during descending intervention. This suggests that both interventions produced different loading sequences in the left ventricle and that load during ascending intervention was quite high from the early ejection phase, whereas load during descending intervention increased during late ejection. In fact, percent wall thickening from the beginning of contraction to PSP (%W_ps) increased to 82.5% of the total wall thickening (%W_es) during descending intervention, while %W_ps increased to 54.3% of %W_es during ascending intervention (Table). Thus, maximal loading effects appear to be manifested in the late ejection phase during descending intervention and in the early to mid ejection phase during ascending intervention. Contraction load, which is a load imposed early in ejection, prolongs onset of relaxation, while relaxation load, which is a load imposed late in ejection, induces premature onset of relaxation.^{15 16} Therefore, the present finding that STI was unchanged by descending intervention suggests that the effect of relaxation load on STI was modified by the effect of the contraction load. On one hand, STI was significantly prolonged during ascending intervention (Table), suggesting that predominantly the ventricular muscle responded to contraction load during ascending intervention. This finding was similar to the response in the isolated muscle or in a single load clamp.^{15 16}

Difference in LV Relaxation Between the Descending and Ascending Interventions and the Mechanism That Causes This Difference
The present study showed that LV relaxation (T) was more prolonged during descending aortic constriction than during ascending aortic constriction (Table). Such a response to afterload in the intact heart illustrates load-dependent relaxation of the cardiac muscle^{15 16 17} and is consistent with the findings obtained by other investigators.^{14 21 22} It has been suggested that prolongation of LV relaxation after late versus early pressure increases may be related to delayed cross-bridge inactivation and load dependence.^{15 16 21} When load is imposed late in ejection, the availability of calcium is reduced, which limits the formation of additional cross-bridges, and the resultant stress on individual cross-bridges increases, leading to a delay in cross-bridge inactivation. In contrast, when load is already established during the first half or the first two thirds of the contraction phase (ie, contraction load) and sufficient activating calcium is available, then additional cross-bridges can attach to readjust to the contraction load so that the resultant stress on the individual cross-bridge will not change. This may contribute to decreased impairment of relaxation during early systolic loading. Therefore, the ability of cross-bridge recruitment and the availability of calcium may determine the relaxation response to late or early systolic load.^{15 16 21} However, such a hypothesis cannot fully explain the present finding that despite the predominance of contraction load during ascending intervention, LV relaxation was prolonged in proportion to a decrease in AoESP or Pes (see Table and Figs 3 and 4). When fiber shortening ceased and the aortic valve closed at a lower LV pressure level, a large number of cross-bridges will have been detached (inactivation), so that the subsequent pressure fall is expected to be accelerated. Occurrence of PSP in the mid systolic period also may contribute to early detachment of cross-bridges.^{15 16 18 21} However, the present finding during ascending intervention was the opposite, which may result from a lower pressure level at the onset of isovolumic relaxation. Our hypothesis is that instantaneous pressure during the isovolumic relaxation phase, which is a total load on the ventricle, may act as a relaxation load. In the isotonic-isometric relaxation mode in which force decay started after completion of inactivation, the time course of force decay depended on total load.^{15 16} In addition, the ratio of the number of cross-bridges to total load could be the major determinant of isotonic relaxation of cardiac muscle.¹⁶ Were this the case, a lower ventricular pressure at the onset of isovolumic relaxation not only would increase this ratio but also decrease the relaxation load, both of which would reduce relaxation velocity. Such a hypothesis may be supported by the fact that during ascending intervention in two dogs, AoESP changed slightly despite the 40 mm Hg increment in PSP, during which period T did not increase. However, as PSP increased further beyond 40 mm Hg, AoESP decreased and T increased noticeably (Fig 4). This strongly suggests that the increase in T by our early to mid systolic load depends not on the increase in PSP but on the decrease in AoESP, that is, the pressure at onset of LV relaxation. The decrease in AoESP was the result of constriction of the ascending aorta, which can reduce the total arterial capacitance.²⁵ From this, it is speculated that alterations in the capacitive characteristics of the arterial system by constricting the ascending aorta produced early to mid systolic load, by which AoESP was reduced, leading to a change in the pressure level at onset of isovolumic relaxation. Probably, load at and after onset of isovolumic relaxation after end ejection plays an important role in decreasing the number of attached cross-bridges, and the lowering of the load level could unmask the dependency of muscle relaxation on inactivation.

Other mechanisms may involve dependency of T on AoESP during ascending aortic constriction. Ascending intervention reduced AoESP and AoDP, shortened RR intervals, and prolonged STI (Table). This decreases coronary driving pressure and duration of diastole, which may lead to subendocardial ischemia.³³ In addition, end-systolic dimension (expected by the decrease in %W_es) was increased despite the decrease in LV end-systolic pressure (Pes), suggesting a rightward shift of the end-systolic pressure-volume relation and thus a decrease in myocardial contractility. Although LV elastance may not have been maximal (Emax) at the end-systolic point during ascending intervention because Pes was greatly reduced, we cannot exclude the possibility that a brief ascending aortic constriction may have caused a transient subendocardial ischemia³³ leading to decrease in myocardial contractility and prolongation of relaxation. Further studies on this relationship are needed. Nonuniformity of wall motion in different regions may cause different relaxation responses to early and late loads.²² In fact, reduction in stroke volume was greater during ascending intervention despite the decrease in %W_es being similar in both interventions (Table). Therefore, it is possible that fiber shortening in other regions except for the region where we implanted dimension gauges may have been more decreased, although the effect of alterations in loading sequence on regional nonuniformity and relaxation remains controversial.^{21 22 24} Using the servo-controlled isolated heart, Hori et al³⁴ reported that early occurrence of end-ejection impaired relaxation. This differs from our finding in the ascending intervention that LV relaxation was progressively impaired as STI was prolonged (Fig 3). However, in their model of early end ejection (Fig 4 in Reference 34³⁴ ), ventricular ejection ceased in the mid contraction phase so that the subsequent systolic pressure did not fall but rather rose until PSP while the ventricle was kept isovolumic at end-systolic volume from end ejection to mitral valve opening.³⁴ These data indicate that the aortic valve closed at mid contraction, the timing of the valve closure that was abnormally early. Therefore, it is not surprising that the relation of the timing of end ejection (or STI) to relaxation differed between their isolated heart model and our intact heart model.

Limitations and Clinical Implications
Heart rate increased significantly during ascending aortic constriction and tended to decrease with descending constriction (Table). Although there was no significant difference in heart rate or peak (+)dP/dt between ascending and descending aortic constrictions, and although changes in T during both interventions were similar to those reported by other investigators,^{20 21 22} we cannot exclude the possibility that neurohumoral activation may have modified the results.¹¹ Second, LV relaxation (T) was prolonged by both interventions, but T tended to be shortest in the control state. This suggests that in the intact anesthetized dogs at rest, the left ventricle starts isovolumic relaxation at an optimal pressure level for force decline. However, it is unclear whether this finding can be applied to other conditions such as the conscious state or changes in the inotropic state. Further study is needed to clarify this. Finally, AoESP significantly decreased during the ascending intervention so that the isovolumic relaxation phase decreased. This may lead to miscalculating the value for T. However, the finding that prolongation of T was less during ascending intervention than during descending intervention was consistent with that reported by other investigators.^{14 22} In addition, the fact that the (-)dP/dt upstroke pattern was more convex-downward during descending intervention than during ascending intervention (see Fig 1) indicates greater prolongation of T^{4 5 32} during descending intervention than during ascending intervention. This suggests the reasonableness of T measurements. It should be considered that the time of AoESP does not always indicate onset of isovolumic relaxation: In mitral regurgitation, the end of fiber shortening may cause a relative delay in the time of aortic valve closure so that isovolumic relaxation starts after AoESP.¹⁶ On the other hand, the isovolumic relaxation phase may be absent in aortic regurgitation.¹⁶ Therefore, determining the onset of isovolumic relaxation by AoESP is limited in these diseases.

The present findings have important clinical implications. Peripheral resistance is known to increase in various cardiovascular diseases such as hypertensive, valvular, or ischemic heart disease or dilated cardiomyopathy. Increase in peripheral resistance imposes excess load late in systole, leads to late occurrence of PSP, and may impair LV relaxation, as seen during descending intervention. Hence, afterload reduction therapy is of clinical value in improving relaxation as well as ventricular pump function. Arteriosclerosis progresses with aging and decreases aortic compliance.³⁰ This may increase afterload but has little effect on or even decreases AoESP,²⁶ which may impair LV relaxation,²⁷ as seen during ascending intervention. Such a decrease in AoESP may reduce coronary blood flow because of the resultant lower perfusion pressure, which, coupled with impaired relaxation, may facilitate myocardial ischemia and finally lead to myocardial damage. Therefore, early detection of abnormalities in loading sequence could provide a useful guide for preventing further impairment of relaxation and subsequent ventricular filling.^{35 36}

	Selected Abbreviations and Acronyms

 

AoDP = aortic end-diastolic pressure AoESP = aortic end-systolic pressure LV = left ventricular Pes = LV pressure at aortic end-systolic pressure PSP = peak systolic pressure STI = systolic time interval T = time constant t-PSP = time interval from end-diastolic pressure to PSP

Received July 20, 1995; revision received October 30, 1995; accepted November 5, 1995.

	References

Top Abstract Introduction Methods Results Discussion References

 

1. McLaurin LP, Rollett EL, Grossman W. Impaired left ventricular relaxation during pacing-induced ischemia. Am J Cardiol. 1973;32:751-757. [Medline] [Order article via Infotrieve]
   
2. Chen W, Gibson D. Relation of isovolumic relaxation to left ventricular wall movement in man. Br Heart J. 1979;42:51-56. [Free Full Text]
   
3. Hirota Y. A clinical study of left ventricular relaxation. Circulation. 1980;62:756-763. [Abstract/Free Full Text]
   
4. Hayashida Y, Kumada T, Nohara R, Tanio H, Kambayashi M, Ishikawa N, Nakamura Y, Himura Y, Kawai C. Left ventricular regional wall stress in dilated cardiomyopathy. Circulation. 1990;82:2075-2083. [Abstract/Free Full Text]
   
5. Hayashida Y, Kumada T, Kohno F, Noda M, Ishikawa N, Kojima J, Himura Y, Kawai C. Left ventricular regional relaxation and its nonuniformity in hypertrophic nonobstructive cardiomyopathy. Circulation. 1991;84:1496-1504. [Abstract/Free Full Text]
   
6. Eichhorn EJ, Willard JE, Alvarez L, Kim AS, Glamann DB, Risser RC, Grayburn PA. Are contraction and relaxation coupled in patients with and without congestive heart failure? Circulation. 1992;85:2132-2139. [Abstract/Free Full Text]
   
7. Brutsaert DL, Rademakers FE. Triple control of relaxation: implications in cardiac disease. Circulation. 1983;69:190-196. [Free Full Text]
   
8. Raya TE, Gay RG, Lancaster L, Aguirre M, Moffet C, Goldman S. Serial changes in left ventricular relaxation and chamber stiffness after large myocardial infarction in rats. Circulation. 1988;77:1424-1431. [Abstract/Free Full Text]
   
9. Karliner JS, LeWinter F, Mahler R, Engler R, O'Rouke RAO. Pharmacologic and hemodynamic influences on the rate of isovolumic left ventricular relaxation in the normal conscious dog. J Clin Invest. 1977;60:511-521.
   
10. Frederiksen JW, Weiss JL, Weisfeldt ML. Time constant of isovolumic pressure fall: determinants in the working left ventricle. Am J Physiol. 1978;235:H701-H706.
    
11. Gaasch WH, Blaustein AS, Andrias CW, Donahue RP, Avitall B. Myocardial relaxation, II: hemodynamic determinants of rate of left ventricular isovolumic pressure decline. Am J Physiol. 1980;239:H1-H6.
    
12. Blaustein AS, Gaasch WH. Myocardial relaxation, VI: effects of ß-adrenergic tone and asynchrony on LV relaxation rate. Am J Physiol. 1983;244:H417-H422.
    
13. Gaasch WH, Blaustein AS, Bing OHL. Asynchronous (segmental early) relaxation of the left ventricle. J Am Coll Cardiol. 1985;5:891-897. [Abstract]
    
14. Hori M, Inoue M, Kitakaze M, Tsujioka K, Ishida Y, Fukunami M, Nakajima S, Kitabatake A, Abe H. Loading sequence is a major determinant of afterload-dependent relaxation in intact canine heart. Am J Physiol. 1985;249:H747-H754.
    
15. Brutsaert DL, De Clerck NM, Goethals MA, Housmans PR. Relaxation of ventricular cardiac muscle. J Physiol. 1978;283:469-480. [Abstract/Free Full Text]
    
16. Brutsaert D, Sys SU. Relaxation and diastole of the heart. Physiol Rev. 1989;69:1228-1315. [Abstract/Free Full Text]
    
17. Gillebert TC, Sys SU, Brutsaert DL. Influence of loading pattern on peak length-tension relation and on relaxation in cardiac muscle. J Am Coll Cardiol. 1989;13:483-490. [Abstract]
    
18. Ariel Y, Gaasch WH, Bogen DK, McMahon TA. Load-dependent relaxation with late systolic volume steps: servo-pump studies in the intact canine heart. Circulation. 1987;75:1287-1294. [Abstract/Free Full Text]
    
19. Zatko FJ, Martin P, Bahler RC. Time course of systolic loading is an important determinant of ventricular relaxation. Am J Physiol. 1987;252:H461-H466. [Abstract/Free Full Text]
    
20. Goethals MA, Kersschat IE, Claes VA, Hermans CF, Jageneau AH, Brutsaert DL. Influence of abrupt pressure increments on left ventricular relaxation. Am J Cardiol. 1980;45:392. Abstract.
    
21. Gillebert TC, Lew WY. Influence of systolic pressure profile on rate of left ventricular pressure fall. Am J Physiol. 1991;261:H805-H813. [Abstract/Free Full Text]
    
22. Yano M, Kohno M, Konishi M, Takahashi T, Seki K, Matsuzaki M. Influence of left ventricular regional nonuniformity on afterload-dependent relaxation in intact dogs. Am J Physiol. 1994;267:H148-H154. [Abstract/Free Full Text]
    
23. Noble MIM. The contribution of blood momentum to left ventricular ejection in the dog. Circ Res. 1968;23:663-670. [Abstract/Free Full Text]
    
24. Leite-Moreira AF, Gillebert TC. Nonuniform course of left ventricular pressure fall and its regulation by load and contractile state. Circulation. 1994;90:2481-2491. [Abstract/Free Full Text]
    
25. Van Den Bos GC, Westerhof N, Elzinga G, Sipkema P. Reflection in the systemic arterial system: effects of aortic and carotid occlusion. Cardiovasc Res. 1976;10:565-573. [Medline] [Order article via Infotrieve]
    
26. Elzinga G, Westerhof N. Pressure and flow generated by the left ventricle against different impedances. Circ Res. 1973;32:178-186. [Abstract/Free Full Text]
    
27. Maughan WL, Sunagawa K, Weisfeldt ML. Time constant of relaxation: influence of peripheral resistance, capacitance, and characteristic impedance. Circulation. 1982;66(suppl II):II-253. Abstract.
    
28. Laskey WK, Kussmaul WG. Arterial wave reflection in heart failure. Circulation. 1987;75:711-722. [Abstract/Free Full Text]
    
29. Murgo JP, Westerhof N, Giolma JP, Altobelli SA. Aortic input impedance in normal man: relationship to pressure waveforms. Circulation. 1980;62:105-116. [Free Full Text]
    
30. Latham RD, Westerhof N, Sipkema P, Rubal BJ, Peuderink P, Margo JP. Regional wave travel and reflections along the human aorta: a study with six simultaneous micromanometric pressures. Circ Res. 1985;72:1257-1269.
    
31. Nichols WW, Conti CR, Walker WE, Milnor WR. Input impedance of the systemic circulation in man. Circ Res. 1977;40:451-458. [Abstract/Free Full Text]
    
32. Kumada T, Karliner JS, Pouleur H, Gallagher KP, Shirato K, Ross J Jr. Effects of coronary occlusion on early ventricular diastolic events in conscious dogs. Am J Physiol. 1979;237:H542-H549.
    
33. Buckberg GD, Fixler DE, Archie JP, Hoffman JIE. Experimental subendocardial ischemia in dogs with normal coronary arteries. Circ Res. 1972;30:67-81. [Abstract/Free Full Text]
    
34. Hori M, Kitakaze M, Ishida Y, Fukunami M, Kitabatake A, Inoue M, Kamada T, Yue DT. Delayed end ejection increases isovolumic ventricular relaxation rate in isolated perfused canine hearts. Circ Res. 1991;68:300-308. [Abstract/Free Full Text]
    
35. Cheng C, Little WC. Enhanced load sensitivity of left ventricular relaxation and early diastolic filling in congestive heart failure. Circulation. 1993;88(suppl I):I-527. Abstract.
    
36. Asanoi H, Ishizaka S, Kameyama T, Ishise H, Sasayama S. Disparate inotropic and rusitropic responses to pimobendan in conscious dogs with tachycardia-induced heart failure. J Cardiovasc Pharmacol. 1994;23:268-274.[Medline] [Order article via Infotrieve]
    

This article has been cited by other articles:

				B. A. Borlaug, V. Melenovsky, M. M. Redfield, K. Kessler, H.-J. Chang, T. P. Abraham, and D. A. Kass Impact of Arterial Load and Loading Sequence on Left Ventricular Tissue Velocities in Humans J. Am. Coll. Cardiol., October 16, 2007; 50(16): 1570 - 1577. [Abstract] [Full Text] [PDF]

				D. Levy, S.-J. Hwang, A. Kayalar, E. J. Benjamin, R. S. Vasan, H. Parise, M. G. Larson, T. J. Wang, J. Selhub, P. F. Jacques, et al. Associations of Plasma Natriuretic Peptide, Adrenomedullin, and Homocysteine Levels With Alterations in Arterial Stiffness: The Framingham Heart Study Circulation, June 19, 2007; 115(24): 3079 - 3085. [Abstract] [Full Text] [PDF]

				P. Colin, B. Ghaleh, L. Hittinger, X. Monnet, M. Slama, J.-F. Giudicelli, and A. Berdeaux Differential effects of heart rate reduction and beta -blockade on left ventricular relaxation during exercise Am J Physiol Heart Circ Physiol, February 1, 2002; 282(2): H672 - H679. [Abstract] [Full Text] [PDF]

				J. L. Abramson, W. S. Weintraub, and V. Vaccarino Association Between Pulse Pressure and C-Reactive Protein Among Apparently Healthy US Adults Hypertension, February 1, 2002; 39(2): 197 - 202. [Abstract] [Full Text] [PDF]

				M. Yano, M. Kohno, S. Kobayashi, M. Obayashi, K. Seki, T. Ohkusa, T. Miura, T. Fujii, and M. Matsuzaki Influence of timing and magnitude of arterial wave reflection on left ventricular relaxation Am J Physiol Heart Circ Physiol, April 1, 2001; 280(4): H1846 - H1852. [Abstract] [Full Text] [PDF]

				R. J. Glynn, C. U. Chae, J. M. Guralnik, J. O. Taylor, and C. H. Hennekens Pulse Pressure and Mortality in Older People Arch Intern Med, October 9, 2000; 160(18): 2765 - 2772. [Abstract] [Full Text] [PDF]

				S. B. Solomon, S. D. Nikolic, R. W. M. Frater, and E. L. Yellin Contraction-relaxation coupling: determination of the onset of diastole Am J Physiol Heart Circ Physiol, July 1, 1999; 277(1): H23 - H27. [Abstract] [Full Text] [PDF]

				C. U. Chae, M. A. Pfeffer, R. J. Glynn, G. F. Mitchell, J. O. Taylor, and C. H. Hennekens Increased Pulse Pressure and Risk of Heart Failure in the Elderly JAMA, February 17, 1999; 281(7): 634 - 643. [Abstract] [Full Text] [PDF]

				D. J Penny, H. Chen, and J. J Smolich Increased aortic blood pressure contributes to potentiated dobutamine inotropic responses after systemic NO synthase inhibition in sheep Cardiovasc Res, November 1, 1998; 40(2): 282 - 289. [Abstract] [Full Text] [PDF]

				W. Hayashida, J. Donckier, H. Van Mechelen, A. A. Charlier, and H. Pouleur Load-sensitive diastolic relaxation in hypertrophied left ventricles Am J Physiol Heart Circ Physiol, February 1, 1998; 274(2): H609 - H615. [Abstract] [Full Text] [PDF]

				D. S. Berger, K. Vlasica, C. M. Quick, K. A. Robinson, and S. G. Shroff Ejection has both positive and negative effects on left ventricular isovolumic relaxation Am J Physiol Heart Circ Physiol, December 1, 1997; 273(6): H2696 - H2707. [Abstract] [Full Text] [PDF]

				T. C. Gillebert, A. F. Leite-Moreira, and S. G. De Hert Relaxation–Systolic Pressure Relation: A Load-Independent Assessment of Left Ventricular Contractility Circulation, February 4, 1997; 95(3): 745 - 752. [Abstract] [Full Text]

This Article Abstract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kohno, F. Articles by Sasayama, S. Search for Related Content PubMed