Heart Vessels (2003) 18:136–141 DOI 10.1007/s00380-003-0697-9
© Springer-Verlag 2003
ORIGINAL ARTICLE
Nobuyuki Ohte · Che-Ping Cheng · William C. Little
Tachycardia exacerbates abnormal left ventricular–arterial coupling in heart failure
Received: October 26, 2002 / Accepted: March 7, 2003
Abstract The purpose of this study was to assess the effect of heart rate on left ventricular (LV)–arterial coupling and LV mechanical efficiency before and after heart failure (CHF). The production of LV stroke work (SW) and mechanical efficiency depends on the coupling of the LV and arterial system. The response of LV–arterial coupling to tachycardia may be altered in heart failure. We compared the response of LV–arterial coupling to increased heart rate (HR) in six conscious, instrumented dogs before and after pacing-induced CHF. Coupling was quantified as EES/EA, where EES is the slope of end-systolic pressure (P)–volume (V) relation, and EA is arterial elastance. Mechanical efficiency was determined as the ratio of SW to a total P–V area (PVA). Before CHF, EES and EA increased similarly with increased heart rate to 180 min1. Thus, EES/EA remained unaltered (0.96 0.08 vs 0.94 0.35), and SW/PVA was unchanged (0.62 0.03 vs 0.59 0.06). Compared with the results prior to CHF and after CHF the resting EES was decreased, thus both EES/EA (0.58 0.09) and SW/PVA (0.48 0.06) were less (P 0.05) than baseline. After CHF, an increase in HR to 180 min1 increased EA but not EES, thus EES/EA fell to 0.44 0.06 (P 0.05) and SW/PVA fell to 0.41 0.05 (P 0.05). Under normal conditions, LV– arterial coupling remains optimal during increases in HR. After CHF, tachycardia exacerbates the suboptimal baseline LV–arterial coupling, reducing the efficiency of producing SW. Key words Conscious dog · Congestive heart failure · Force–frequency relation · Left ventricular–arterial coupling N. Ohte (*)1 · C.-P. Cheng · W.C. Little Cardiology Section, Wake Forest University School of Medicine, Winston-Salem, NC, USA Present address: 1 Department of Internal Medicine and Pathophysiology, Nagoya City University Graduate School of Medical Sciences, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan Tel. 81-52-853-8221; Fax 81-52-852-3796 e-mail:
[email protected]
Introduction The performance of the cardiovascular system depends on the interaction of its components. The left ventricle (LV) pumps the stroke volume (SV) into the arterial system that delivers the flow to the tissues. Thus, optimal cardiovascular function requires appropriate coupling of the LV and the arterial system. Functional analysis of this interaction requires that the LV and arterial system be described in similar terms.1 Sunagawa et al.2 and Burkhoff and Sagawa3 proposed that LV–arterial coupling could be analyzed in the pressure–volume (P–V) plane. The intersection of the LV end-systolic pressure (PES)–volume (VES) relation and the arterial PES–SV relation determines the SV. The slope of the PES–VES relation is the end-systolic elastance (EES) of the LV, whereas the slope of the arterial PES–SV relation represents the effective arterial end-systolic elastance (EA). If the ejection portion of the LV P–V loop is assumed to be flat and the end-diastolic pressure is negligible, this analysis predicts that stroke work (SW) should be maximized when EA equals EES.2,4,5 The efficiency of producing SW is predicted to decline as EES/EA is reduced. Despite the limitations of the required simplifying assumptions, these predictions are correct in conscious animals. Furthermore, at rest, the LV and arterial system operate close to this point that produces optimal SW.6 Furthermore, SW is within 95% of its maximum value when EES/EA is between 0.9 and 1.3. During exercise in normal animals, the EES/EA ratio remains in this range, indicating that the LV and arterial system are nearly optimally coupled to produce SW, both at rest and during exercise.6,7 We hypothesized that heart failure (CHF) should adversely alter LV–arterial coupling as EES is reduced and EA may be increased, thus reducing EES/EA to below 0.9 where SW rapidly declines with decreasing EES/EA. Normally, EES increases with higher heart rates,8 which would be expected to match the increase in EA. This manifestation of the force–frequency response is lost in CHF due to changes in sarcoplasmic reticular calcium handling.9,10 In addition,
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there is autonomic dysfunction and reduced adrenergic sensitivity in CHF.11,12 Thus, we hypothesized that tachycardia would further exacerbate the abnormal LV–arterial coupling in CHF, reducing both SW and LV efficiency. Accordingly, we undertook this study to test these hypotheses by evaluating the alteration of LV–arterial coupling in response to increasing heart rate before and after pacinginduced CHF.
Materials and methods Instrumentation Six healthy, adult, heart-worm-negative mongrel dogs (weight 25–36 kg) were instrumented under anesthesia after induction with xylazine (2 mg/kg i.m.) and sodium thiopental (6 mg/kg i.v.), and maintained with halothane (0.5%– 2.0%). Micromanometer pressure transducers (Konigsberg Instruments, Pasadena, CA, USA) and polyvinyl catheters (1.1 mm i.d.) for transducer calibration were inserted into the LV through an apical stab wound and into the left atrium from the left atrial appendage. Three pairs of ultrasonic crystals (5 MHz) were implanted in the endocardium of the LV to measure the anterior-to-posterior, septalto-lateral, and base-to-apex (long-axis) dimensions, using methods previously described from our laboratory.13 Hydraulic occluder cuffs were placed around the inferior and superior venae cavae. Pacing leads were attached to the right atrium and right ventricle and connected to programmable pacemakers (Model 8329, Medtronic, Minneapolis, MN, USA) implanted subcutaneously. All wires and tubing were exteriorized through the posterior neck. Data collection Studies were performed after full recovery from instrumentation (from 10 days to 2 weeks after surgery) with the dogs standing. The LV catheter was connected to a pressure transducer (Statham P23Db, Gould, Cleveland, OH, USA) calibrated with a mercury manometer. The signal from the micromanometer was adjusted to match that of the catheter. The analog signals were recorded on an eight-channel chart recorder (Astro-Med, West Warwick, RI, USA), digitized with an online analog-to-digital converter (Data Translation Devices, Marlboro, MA, USA) at 200 Hz. Experimental protocol Studies before CHF Steady-state data and data during transient caval occlusion were recorded at rest while the animals were standing. Three sets of variably-loaded pressure–volume loops were generated by caval occlusion. We analyzed the data recorded at control and at 3 min after each stage of increased heart rate by right atrial pacing. The heart rates of 140, 160,
and 180 min1 were adjusted using an external magnetic control unit. Atropine was not required to produce ventricular capture. Studies during the development of CHF After the completion of the baseline study, the right ventricular pacemaker rate was adjusted to 220–250 beats/min. Three times per week, the pacemaker rate was adjusted to below the spontaneous rate. The animal was allowed to equilibrate for 30 min and then data were collected. After each study, the pacing rate was returned to 220–250 min1. After pacing for 4–5 weeks, when the LV end-diastolic pressure (PED) during the nonpaced period had increased by more than 15 mmHg over the prepacing control level, the animals had begun to show clinical evidence of CHF (anorexia, mild ascites, and pulmonary congestion). Studies after the onset of CHF The pacemaker was turned off, and the animal was allowed to stabilize for at least 30 min. Steady-state data and data during transient caval occlusion were collected with the animal standing as in the protocol performed in dogs before CHF. Data processing and analysis The LV volume (VLV) was calculated as a modified general ellipsoid using the following formula: VLV ( p 6)DAP ◊ DSL ◊ DLA where DAP is the anterior to posterior LV diameter, DSL is the septal to lateral LV diameter, and DLA is the long-axis LV diameter. This method gives a consistent measure of VLV (r 0.97; standard estimated error (SEE) 2 ml) despite changes in LV loading conditions, configurations, and heart rate.13–15 To account for respiratory changes in intrathoracic pressure, steady-state measurements were averaged over the 12- to 15-s recording period that spanned multiple respiratory cycles. End-diastole was defined as the relative minimum of LV pressure occurring after the A wave. End-systole was defined as the upper left corner of the LV P–V loop. Stroke volume was calculated as VED minus VES. LV stroke work was also calculated by point-by-point integration of the LV P–V loop for each beat as described by Glower et al.16 The rate of LV relaxation was analyzed by determining the time constant of the isovolumic fall in LV pressure. LV pressure from the time of minimum dP/dt until mitral valve opening was fit to an exponential equation: P PA exp(t T ) PB where P is LV pressure, t is time, and PA, PB, and T are constants determined by data. Although the fall in isovolumic pressure is not exactly exponential, the time
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constant, derived from the exponential approximation, provides an index of the rate of LV relaxation. The effective arterial elastance, EA, was calculated as LV PES divided by SV. Only caval occlusions that produced a fall in LV PES of approximately 30 mmHg were analyzed. Premature beats and the subsequent beat were excluded from analysis. The LV PES–VES data during the fall in LV pressure, produced by each caval occlusion, were fit using the least squares method to: PES EES (VED V0 ) where EES is the slope of the linear PES–VES relation, representing the LV end-systolic elastance, and V0 is the intercept with the volume axis. The slope and volume–axis intercept for each condition was evaluated as the mean value of the two or three caval occlusions performed under each condition. We calculated the total pressure–volume area (PVA) as defined by Suga et al.17,18 The LV PES–VES relation obtained during caval occlusion was superimposed on the steadystate P–V loop that was averaged over a 12–15-s recording period. SW was calculated as above. The remaining PVA (potential work PVA) was calculated as potential work PVA PES ◊ (VES Vo ) 2 Total PVA was calculated as
PVA SW potential work PVA The energy conversion of PVA to SW (SW/PVA), i.e., mechanical efficiency, was calculated as the SW divided by the PVA.17,19 Postmortem evaluation At the conclusion of the studies, the animals were killed by lethal injections of sodium thiopental (100 mg/kg, i.v.), and
the heart was examined to confirm the proper position of the instrumentation. Statistical analysis All data are expressed as mean SD. LV function parameters before and during pacing were compared using repeated-measures analysis of variance with a Bonferroni adjustment. Those before and after CHF were compared using Student’s paired t-test. P values of less than 0.05 were considered significant.
Results Effects of tachycardia before CHF Steady-state measurements The effects of pacing-induced tachycardia in normal animals are summarized in Table 1. Increased heart rates produced significant (P 0.05) decreases in LV VES and LV VED. SV progressively decreased from 13.7 2.7 to 11.5 2.3*, 9.3 2.3*, and 8.3 2.5* ml, respectively (*P 0.05 vs control), while LV PES was relatively unchanged. Thus, EA was significantly increased from 7.6 2.0 to 9.2 2.4*, 11.7 3.2*, and 13.8 4.4* mm Hg/ml, respectively (*P 0.05 vs control). The time constant of LV relaxation (τ) was progressively reduced by the increased heart rates from 26.3 3.9 to 25.2 3.8*, 23.4 3.2*, and 22.0 3.6* ms, respectively (*P 0.05 vs control) (Table 1). Pressure–volume analysis The effect of increased heart rates on variably loaded P–V loops before CHF is shown in Fig. 1. Before CHF, increased heart rates produced significant increases in EES from 7.3 1.9 to 8.7 2.1*, 10.5 2.7*, and 12.0 2.7* mm Hg/ml, respectively (*P 0.05 vs control), that matched the in-
Table 1. Effects of heart rate increase in normal dogs Pacing rate
Heart rate (min1) LV end-systolic pressure (mmHg) LV end-systolic volume (ml) LV end-diastolic volume (ml) LV end-diastolic pressure (mmHg) Stroke volume (ml) Time constant τ (ms) EES (mmHg/ml) EA (mmHg) EES/EA SW (mmHg · ml) PVA (mmHg · ml) SW/PVA
Control
140 (min1)
160 (min1)
180 (min1)
123 13 100 5.2 27.8 7.9 41.4 10.5 11.2 2.8 13.7 2.7 26.3 3.9 7.3 1.9 7.6 2.0 0.96 0.08 1 347 220 2 196 396 0.62 0.03
141 0.5* 102 4.3 26.7 7.5* 38.2 9.8* 7.2 3.2* 11.5 2.3* 25.2 3.8* 8.7 2.1* 9.2 2.4* 0.94 0.09 1 053 197* 1 743 355* 0.61 0.03
159 1.0* 104 6.1 26.6 7.5* 36.0 9.8* 7.0 2.9* 9.3 2.3* 23.4 3.2* 10.5 2.7* 11.7 3.2* 0.92 0.19 918 192* 1 560 393* 0.59 0.04
181 1.3* 105 6.2 26.3 7.7* 34.6 10.2* 6.9 3.0* 8.3 2.5* 22.0 3.6* 12.0 2.7* 13.8 4.4* 0.94 0.35 822 242* 1 393 447* 0.59 0.06
LV, left ventricular; EA, effective arterial elastance; EES, slope of linear end-systolic pressure–volume relation; PVA, pressure volume area; SW, stroke work * P 0.05 vs control
139 Fig. 1. Variably loaded pressure– volume loops at increasing heart rates in the same animal before and after congestive heart failure (CHF). The solid line indicates the left ventricular (LV) endsystolic pressure–volume relation (ESPVR). Before CHF, in response to increased heart rate, the LV ESPVR shifts toward the left with an increase in slope (EES). The dotted line indicates the arterial pressure–volume relation, plotted with stroke volume indicated as the change from end-diastolic volume. The slope of this relation is EA. Both before and after CHF, EA increases with increasing heart rate. After CHF, there is little change in the ESPVR with increased heart rate
Table 2. Effects of heart rate increase after CHF Pacing rate
Heart rate (min1) LV end-systolic pressure (mmHg) LV end-systolic volume (ml) LV end-diastolic volume (ml) LV end-diastolic pressure (mmHg) Stroke volume (ml) Time constant τ (ms) EES (mmHg/ml) EA (mmHg/ml) EES/EA SW (mmHg µ ml) PVA (mmHg µ ml) SW/PVA
Control
140 (min1)
160 (min1)
180 (min1)
126 9.0 97.8 6.2 37.1 11.0 49.1 13.1 29.8 5.9 12.0 2.1 37.2 3.3 4.8 1.0 8.4 2.0 0.58 0.09 989 283 2 072 560 0.48 0.06
141 0.9* 98.1 5.4 36.7 11.5 47.0 13.3* 23.5 5.8* 10.3 1.8* 37.5 3.8 4.9 0.9 9.9 2.0* 0.50 0.04* 841 261 1 878 491 0.44 0.05*
159 2.8* 96.7 3.0 36.5 10.6 46.0 12.8* 23.2 5.5* 9.5 1.8* 36.6 2.1 4.9 0.9 10.5 2.5* 0.47 0.05* 776 251* 1 785 409 0.43 0.07*
181 2.3* 99.6 5.6 36.4 10.7 44.7 12.2* 22.8 5.9* 8.7 1.5* 35.6 1.8 5.2 1.1 11.8 2.4* 0.44 0.06* 665 153* 1 617 368 0.41 0.05*
* P 0.05 vs control
creases in EA. EES/EA was relatively unchanged by the increasing heart rate (Fig. 2) as shown in Table 1. SW/PVA was unaltered during pacing-induced tachycardia.
Effects of tachycardia after CHF
Effect of pacing-induced CHF
After CHF, the increased heart rates from control to 140, 160, and 180 min1 also produced significant decreases in LV VED. Thus, the SV was reduced from 12.0 2.1 to 10.3 1.8*, 9.5 1.8*, and 8.7 1.5* ml, respectively (*P 0.05 vs control), but did not affect the LV VES (Table 2). The reductions in SV with tachycardia were similar to those prior to CHF. Similarly, as prior to CHF, tachycardia did not alter LV PES. Similar to the effects prior to CHF, EA with tachycardia was significantly increased from 8.4 2.0 to 9.9 2.0*, 10.5 2.5*, and 11.8 2.4* mm Hg/ml, respectively (*P 0.05 vs control). After CHF, the time
After the development of CHF, the LV PED increased from 11.1 2.8 to 29.8 5.9 mmHg (*P 0.05). The LV VES and VED significantly increased, whereas SV was significantly decreased. The time constant τ increased (26.3 3.9 vs 37.2 3.3 ms, P 0.05) (Tables 1 and 2). The LV contractility was also significantly impaired as indicated by decreased EES (7.3 1.9 vs 4.8 1.0 mm Hg/ml, P 0.05). EA was increased (7.6 2.0 vs 8.4 2.0 mm Hg/ml, P 0.05) (Tables 1 and 2).
Steady-state data measurements
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Fig. 2. Under normal conditions, left ventricular end-systolic elastance (EES) and effective arterial elastance (EA) increase together with increasing heart rate. After CHF, EA is greater than EES at control and with increasing heart rates, EA increases while EES does not
constant τ of LV relaxation was not reduced by the increased heart rates (Table 2). The effect of increased heart rates on variably loaded P– V loops after CHF is shown in Fig. 1. After CHF, increased heart rate from control to 140, 160, and 180 min1 still significantly increased EA (Table 2). After CHF, EES/EA was lower than normal (0.58 0.09) at baseline and progressively decreased with increasing heart rates to 0.50 0.04*, 0.47 0.05*, and 0.44 0.06*, respectively (*P 0.05 vs control) (Table 2 and Fig. 2). The SW/PVA was significantly reduced from 0.48 0.06 to 0.44 0.05*, 0.43 0.07*, and 0.41 0.05*, respectively (*P 0.05 vs control) (Table 2).
Discussion Under normal conditions, the LV and arterial system is matched with EES/EA close to 1. This is near the center of the range of EES/EA (0.9–1.3) that results in near maximal production of SW. In this study, we observed that under normal conditions, EES/EA remains close to 1 during increases in heart rate as EES and EA increase together. We also observed that following the development of CHF, EES/EA decreased to 0.58 0.09 as EES fell and EA increased. During tachycardia in CHF, EA increased, but EES did not increase, resulting in a further decrease in EES/EA. Thus, the LV and arterial system are not optimally coupled at rest in CHF, and this adverse coupling is exacerbated during tachycardia. A positive force–frequency relation has been observed in most species, and frequency potentiation of contractile function is a major mechanism of the increase in myocardial performance during exercise.8,20,21 However, in the failing
heart, the frequency potentiation of contractile function is reduced or reversed.22,23 Pieske et al.10 has demonstrated that the lost force–frequency relation in CHF was due to an inability of sarcoplasmic reticulum Ca2 content to increase sufficiently at high frequencies. This appears to be due to reduced protein levels of sarcoplasmic reticulum Ca2-ATPase combined with enhanced cytosolic Ca2 extrusion via the Na/Ca2 exchanger in CHF.24 In this study, we verified a blunted force-frequency relation in conscious CHF dogs using the relatively load-independent index of LV contractile function, EES. In the conscious state, LV–arterial coupling is influenced not only by intrinsic factors, but also by neural adjustment of the cardiovascular system.25,26 When the LV and arterial system are intact, EA and EES respond to baroreflex activation to the same extent so as to keep the mean arterial pressure within the physiologic range, thus optimizing SW.25 However, when the responsiveness of either the ventricle or the arterial system is suppressed, as in cases of depressed cardiac contractility (blunted response in EES), the unaffected part of the cardiovascular system must bear the burden of responding to the body’s requirements (increase in EA), resulting in ventricular–arterial mismatch. βadrenergic amplification of the force–frequency effect on myocardial contractility is also impaired in the failing heart. In addition, CHF is accompanied by autonomic dysfunction, where cardiovascular regulation through baroreflexes might be attenuated.11,12 Increases in heart rate influence the arterial system. We quantitated this effect by calculating EA, the slope of the arterial PES–SV relation, as PES/SV. Because PES approximates the mean arterial pressure, EA is approximated by the peripheral vascular resistance times the heart rate.4,5 Thus, EA increases with increased heart rate, both under normal conditions and after CHF. The coupling of the LV and arterial system is an important determinant of LV efficiency. The sum of the SW and the area under the remaining portion of the PES–VES relation (termed PVA) is the mechanical determinant of myocardial oxygen demand. At a constant contractile state, myocardial oxygen consumption (MVO2) linearly increases with increases in PVA. The energy cost of the useful work of the LV (i.e., SW) is determined by both the ratio of SW to PVA and the relation of MVO2 to PVA.17 As the EES/EA ratio decreases, the ratio of SW to PVA also decreases.1,3,19 Thus, the ratio of SW/PVA is a measure of mechanical efficiency and is decreased as EES/EA decreases. As predicted, we found that mechanical efficiency is reduced after CHF and further impaired with increases in heart rate. This is consistent with the observation of Shinke et al.27 that in patients with heart failure, reductions in heart rate increase SW without increasing MVO2. However, we did not measure MVO2, so we cannot be certain of the effects of tachycardia on myocardial efficiency. The description of the arterial system by EA ignores the contribution of the higher-frequency components of arterial impedance to LV–arterial coupling. Under normal circumstances, these components of arterial impedance account for only about 10% of the energy loss; however, their
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importance may be increased with slower heart rates, increased vascular tone, or other conditions.28 Our results1 and the observations of Sunagawa et al.2,4,5 in isolated hearts suggest that, under most circumstances, considering the arterial system in terms of EA provides a framework for understanding LV–arterial coupling. Analysis of the dynamic coupling throughout the period of LV ejection or during marked alterations in pulsatile loading will require consideration of the higher-frequency components of arterial impedance. The adverse effect of increased heart rate on LV–arterial coupling in CHF with resulting impairment of SW and mechanical efficiency may contribute to impaired exercise tolerance in CHF. Blunting increases in heart rate during exercise and lowering resting heart rate may contribute to the beneficial effects of β-adrenergic blockage in CHF. Our study was performed with the animals standing since exercise occurs in this position. In addition, after CHF the animals frequently had respiratory distress when lying down. Our results might have been somewhat different if the animals had been studied in the supine position. In conclusion, we found that in dogs with pacing-induced CHF the abnormal LV–arterial coupling is exacerbated by tachycardia, leading to reduced LV mechanical efficiency. Acknowledgments This study was supported in part by grants from the NIH (HL45258, HL53541, and T32HL07868) and the American Heart Association (9640189N).
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