1
Left Bundle Branch Block Increases Left Ventricular
1
Diastolic Pressure during Tachycardia due to
2
Incomplete Relaxation
3 4 5
OS. Andersen1,3-5, MR. Krogh2,4, E. Boe1,5, P. Storsten1,4-5, JM. Aalen1,4-5, CK. Larsen1,4- 6
5, H. Skulstad1-5, HH. Odland3-5, OA. Smiseth1,3-4, EW. Remme1-4 7
8 9
1Institute for Surgical Research, 2Intervention Center, 3Department of Cardiology, 10
4Center for Cardiological Innovation, Oslo University Hospital, Rikshospitalet, Oslo, 11 Norway, and
12
5Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway 13
14
Address for correspondence 15
Espen Remme 16
Institute for Surgical Research 17
Oslo University Hospital, Rikshospitalet 18 Postboks 4950 Nydalen
19
0424 Oslo 20
Norway 21
Fax: +47 23071397 22
Phone: +47 23071413 23
25
26 Brief title:
27
Tachycardia induces diastolic dysfunction in LBBB 28
29
2 Abstract:
30 31
Background: We investigated whether tachycardia in left bundle branch block (LBBB) 32
decreases left ventricular (LV) diastolic distensibility and increases diastolic pressures 33
due to incomplete relaxation, and if cardiac resynchronization therapy (CRT) modifies 34
this response.
35
Methods: Thirteen canines were studied at baseline heart rate (120 bpm) and atrial 36
paced tachycardia (180 bpm) before and after induction of LBBB and during CRT. LV 37
and left atrial (LAP) pressures were measured by micromanometers and dimensions by 38
sonomicrometry. The time constant tau of exponential pressure decay and degree of 39
incomplete relaxation at mitral valve opening (MVO) and end diastole (ED) based on 40
extrapolation of the exponential decay were assessed. Changes in LV diastolic 41
distensibility were investigated using the LV transmural pressure-volume (PV) relation.
42
Results: LBBB caused prolongation of tau (p<0.03) and increased the degree of 43
incomplete relaxation during tachycardia at MVO (P<0.001) and ED (P=0.08) compared 44
to normal electrical activation. This was associated with decreased diastolic 45
distensibility seen as upward shift of the PV-relation at MVO by 18.4±7.0 vs. 12.0±5.0 46
mmHg, at ED by 9.8±2.3 vs. 4.7±2.3 mmHg and increased mean LAP to 11.4±2.7 vs.
47
8.5±2.6 mmHg, all P<0.006. CRT shifted the LV diastolic PV-relation downwards during 48
tachycardia, reducing LAP and LV diastolic pressures (P<0.03).
49
Conclusions: Tachycardia in LBBB reduced LV diastolic distensibility and increased LV 50
diastolic pressures due to incomplete relaxation, while CRT normalized these effects.
51
Clinical studies are needed to determine if a similar mechanism contributes to dyspnea 52
and exercise intolerance in LBBB and if effects of CRT are heart rate dependent.
53 54
3 Key words:
55
Left bundle branch block 56
Diastolic dysfunction 57
Cardiac resynchronization therapy 58
Dyssynchrony 59
Heart failure 60
61
New and noteworthy:
62
Compared to normal electrical conduction, tachycardia in left bundle branch block 63
resulted in incomplete relaxation during filling, particularly of the late activated left 64
ventricular lateral wall. This further resulted in reduced left ventricular diastolic 65
distensibility and elevated diastolic pressures and thus amplified the benefits of cardiac 66
resynchronization therapy in this setting.
67 68
4
BACKGROUND
69
In left bundle branch block (LBBB) dyssynchronous contractions slow left 70
ventricular (LV) pressure rise, which prolongs the isovolumic contraction phase (IVC).
71
Similarly, dyssynchronous relaxations slow LV pressure decay, prolonging the 72
isovolumic relaxation phase (IVR).2,6 The prolonged isovolumic phases shorten the time 73
available for diastolic filling.3,11,18 74
In the normal heart tachycardia shortens diastole and time for filling. In hearts with 75
LBBB, since there is shortened filling time at resting heart rate (HR), further shortening 76
of diastole during tachycardia may compromise LV filling as there may not be sufficient 77
time for complete LV relaxation. We hypothesized that tachycardia in LBBB would 78
reduce diastolic LV distensibility due to incomplete relaxation and elevate diastolic 79
pressures. Elevated LV filling pressure is clinically important as it may cause pulmonary 80
congestion, dyspnea, and reduced exercise tolerance. Furthermore, if the effect of LBBB 81
on diastolic function is heart rate dependent, it could imply enhanced effect of cardiac 82
resynchronization therapy (CRT) during tachycardia. We investigated the hypothesis in 83
an experimental model of LBBB, which allowed accurate measurement of LV relaxation, 84
diastolic pressures and shifts in the diastolic pressure-volume relation at different heart 85
rates and during CRT.
86 87
METHODS
88
Thirteen canines of either sex with body weight of 39 kg (range: 27-50 kg) were 89
initially anesthetized with a single dose of methadone (0.2 mg/kg) followed by propofol 90
(3-4 mg/kg) to desired effect and a bolus of fentanyl (2-3 μg/kg). Propofol (0.2-1 91
mg/kg/min) and fentanyl (5-40 /kg/hr) were used for continuous anesthesia. The 92
animals were artificially ventilated through a cuffed endotracheal tube on room air and 93
5 20 to 50 % O2. Response to anesthesia was regularly evaluated by tone and interdigital 94
reflex. The ECG was monitored from limb leads. Body temperature was monitored, and a 95
heating mattress was used to maintain normothermia. Volume status was controlled, 96
and fluid replaced. At the end of the experiment, the animal was euthanized by an 97
intracardial injection of pentobarbital. The National Animal Experimental Board 98
approved the study. The laboratory animals were supplied by Center for Comparative 99
Medicine, Oslo University Hospital, Rikshospitalet, Norway.
100 101
Instrumentation 102
A median sternotomy was performed exposing the heart. Eight 2-3 mm 103
sonomicrometric crystals (Sonometrics, London, Ontario, Canada) were implanted 104
subendocardially in the LV as illustrated in Figure 1. This enabled us to measure LV 105
volume17 and segment lengths (SL). The four crystals implanted at the equator of the LV 106
included intramyocardial electromyograms (EMG) to assess regional electrical 107
activation. Electrical activation was defined as onset of R in the EMG, with onset R 108
defined as the first spike that lead to a deflection of more than 20 % of maximal R-peak 109
amplitude.9 In LBBB there is substantial dyssynchronous electrical activation of these 4 110
EMGs. We defined end diastole (ED) as the average time between activation of the 111
second and third of these EMGs around the equator, indicating the time-point when 112
approximately half of the LV was activated. This time-point was used to extract all the 113
ED values of the different variables.
114
Micromanometers were used to measure pressures in the right ventricle (RV), LV 115
and left atrium. Fluid filled catheters in the right and left atrium served as absolute 116
pressure references to allow drift-adjustment of the micromanometers using the stable 117
pressure phase during the prolonged diastasis following an extra systole induced at the 118
6 end of each intervention. The combination of crystals and pressure catheters enabled 119
assessment of pressure-volume (PV) as well as pressure-segment length relations.
120
Pacemaker leads were attached epicardially on the middle third of the LV lateral wall, 121
endocardially on the basal septum in the RV outflow tract, and on the posterior wall of 122
the right atrium. Constrictors were placed around the inferior and superior vena cava.
123
This allowed controlled vascular constriction so that diastolic pressures could be 124
compared at overlapping volumes for assessment of decreased diastolic distensibility.
125
To monitor pericardial pressure (PcP), a flat, fluid containing balloon, calibrated as 126
previously described,22 was inserted under the pericardium over the LV lateral wall. The 127
pericardium was loosely resutured after the instrumentation.
128 129
Interventions 130
LBBB was induced by radiofrequency ablation as previously described.10 Before 131
and after induction of LBBB, atrial pacing was performed at HR 120 and 180 bpm. Heart 132
rates in dogs are higher than in humans13, but time parameters scales with body size4, 133
and consequently negative effects observed during tachycardia in dogs will occur at a 134
lower HR in humans. Measurements were obtained at intrinsic HR and both atrial paced 135
HRs, before and after induction of LBBB, and in LBBB also during CRT pacing. Intrinsic 136
heart rate was 101±8 bpm during normal electrical conduction and 111±9 bpm in LBBB.
137
There were no significant changes in diastolic pressures or PV-relations from intrinsic 138
HR to atrial pacing at HR 120 bpm, neither during normal electrical conduction nor in 139
LBBB (P=ns). Measurements during tachycardia, i.e. atrial pacing at HR 180 bpm, were 140
therefore compared with measurements during atrial pacing at HR 120 bpm. Caval 141
constrictions were performed in all settings enabling the assessment of PV and 142
7 pressure-segment length relations. Measurements were acquired with the ventilator 143
turned off to avoid respiratory artifacts.
144 145
Analyses 146
Diastolic pressures:
147
LV pressure at mitral valve opening (LVPMVO), LV end diastolic pressure (LVEDP), 148
and mean left atrial pressure (LAP) over the cardiac cycle were measured.
149
Pressure decay:
150
LV relaxation rate was assessed by calculating the time constant of LV isovolumic 151
pressure decay, tau.24 152
Duration of diastolic phases:
153
Isovolumic relaxation time (IVRT) was measured from minimum LV dP/dt to MVO 154
defined as first diastolic pressure crossover between LAP and LVP. The time-point for 155
end of filling was generally not identical to the ED time-point as defined from the EMGs 156
described above. Therefore, duration of filling was measured as time from MVO to 157
maximum volume near ED.
158
Estimation of incomplete relaxation:
159
It is commonly considered that relaxation is practically completed by a duration of 160
3.5•tau following end systole (ES).23 This is based on extrapolating the exponential LV 161
pressure decay during IVR = ES pressure • exp(-t/tau), where t is the time from end 162
systole. After a duration of t=3.5•tau, the exponential part of the equation is reduced to:
163
exp(-3.5) = 0.03 164
I.e. 3 % of relaxation remains relative to end systole. We estimated the degree of 165
incomplete relaxation at MVO and ED in a similar manner as:
166
exp(-(time from ES to MVO or ED)/tau) • 100 % 167
8 Global left ventricular diastolic pressure-volume relations:
168
Tachycardia-induced reduction of diastolic distensibility was investigated by 169
assessing the upward shift of the diastolic LV transmural PV relation when HR was 170
increased from 120 to 180 bpm. Transmural LV pressure was calculated as LVP–(0.67 171
PcP + 0.33 RVP).16 The shift was assessed at both the time of MVO and ED. Generally, the 172
ED volume will be different at different heart rates. Caval constrictions were performed 173
so that ED points occurred at lower pressure and volume for each heartbeat. This 174
resulted in some heartbeats having ED points at overlapping volumes for the 2 different 175
HRs as shown in Figure 2. The shift of the ED PV relation was then assessed as the 176
difference in pressure at the heartbeats with highest overlapping volumes (Figure 2).
177
Similarly, a shift in pressure at overlapping volumes at MVO was used to assess the shift 178
in the PV relation at MVO. In cases where volumes did not overlap, the shift was 179
assessed as the pressure difference for the beats with closest volumes (Figure 2).
180
With HR 180 bpm, pulsus alternans was observed in 7 cases, where a small PV loop 181
was preceded by a large PV loop.15 Although the PV loop area varies with pulsus 182
alternans, diastolic properties are in general not affected.15 This was verified in our data 183
where we had recordings from 2 animals both with and without pulsus alternans during 184
tachycardia. Tau and ED PV relation were identical. Furthermore, the response in tau 185
and ED PV relation to tachycardia were identical in animals with (n=3) and without 186
(n=6) pulsus alternans (p=0.9). However, in 3 cases the alternans made interpretation of 187
PV loops infeasible, and the corresponding PV relations were excluded from the analysis.
188
Diastolic pressure-segment length relations:
189
Regional diastolic pressure-segment length relation was assessed in the septum 190
and the LV lateral wall to investigate if there were regional differences in degree of 191
relaxation. A similar analysis as with global LV PV relation was performed for the septal 192
9 and LV lateral wall pressure-segment length relations using the two crystal-pairs in 193
these regions shown in Figure 1. Transmural pressure for the septal segment was 194
calculated as LVP – RVP, and LVP –PcP for the LV lateral wall segment.
195 196
Statistical analysis 197
Two animals were excluded due to total atrioventricular block. For the remaining 198
11 animals, we could not perform every measurement in each animal as described 199
above. This resulted in some differences of which animals were compared between 200
normal electrical conduction vs. LBBB and compared between LBBB vs. CRT. Hence, we 201
present separate paired t-tests for these two comparisons in Figure 3 as well as in Table 202
1 and 2 where the number of measurements compared (n) is declared. As a consequence 203
there are slight differences in some of the parameter values between the two tables and 204
in the text.
205
All values represent the mean of three consecutive heart cycles, except data 206
collected during transient caval constriction, where we used consecutive beats, and data 207
obtained with pulsus alternans, where we used 6 beats (3 small and 3 large PV loops).
208
Values are expressed as mean ± standard deviation (SD). Significance for mean 209
difference was assessed using paired t-test. P<0.05 was considered significant. Statistical 210
analyses were performed using SPSS version 23 (IBM Corp., Armonk, N.Y., USA).
211 212
RESULTS
213
Pacing tachycardia during normal electrical conduction 214
Tachycardia during normal electrical conduction resulted in minor, nonsignificant 215
changes in LVPMVO and mean LAP, and a reduction of LVEDP associated with a leftward 216
displacement of the PV-loop, i.e. reductions in EDV (P<0.01) and ESV (P=0.052) (Table 1, 217
10 Figure 3-5). Tachycardia trended to speed up the relaxation rate, seen as a reduction of 218
tau from 37±3 to 35±3 ms (P=0.10).
219
Incomplete relaxation at the start of filling was on average increased from 15±8 to 220
26±11 % (P<0.005) by tachycardia. Complete relaxation had been reached by ED at 221
baseline HR while incomplete relaxation was on average 6±2 % (P<0.001) during 222
tachycardia.
223
Tachycardia induced an upward shift of the PV relation of 7.4±3.9 (P<0.002) and 224
1.1±1.8 mmHg (P=0.09) at MVO and ED, respectively. At MVO, there were significant 225
upward shifts of the pressure-segment length relations both in the LV lateral wall and 226
septum: 7.8±3.1 and 6.3±3.2 mmHg, respectively (both P<0.01). At ED the upward shift 227
in the LV lateral wall was 1.5±1.3 mm Hg (P<0.04) whereas the upward shift in septum 228
was 1.0±1.1 mmHg (P=0.07). There was no significant difference between the shifts 229
observed in the LV lateral wall and septum neither at MVO (P=0.34) or at ED (P=0.54).
230
Pacing tachycardia in LBBB:
231
The diastolic pressures were significantly higher during tachycardia in LBBB 232
compared to normal electrical conduction (Figure 3) as reflected in substantial increases 233
in LVPMVO and mean LAP by 11.7±6.1 and 4.4±2.6 mmHg, respectively, both P<0.003, 234
whereas LVEDP was unchanged (Figure 3 and 4). The leftward displacement of the PV- 235
loop was absent (Table 1).
236
Relaxation rate was slowed at both heart rates (44±4 and 47±11 ms, respectively) 237
compared to normal electrical conduction (both P<0.02) (Figure 3).
238
Pacing tachycardia increased incomplete relaxation at MVO from 16±2 to 40±10 % 239
(P<0.001), and at ED from 1±1 to 12±6 % (P<0.008) (Figure 6). The incomplete 240
relaxation at MVO during tachycardia was significantly higher compared to normal 241
electrical conduction (P<0.001), while it was nonsignificantly higher at ED (P=0.08).
242
11 Pacing tachycardia caused an upward shift of the PV relation at MVO of 12.5±7.5 243
mmHg, significantly higher compared to the shift during normal electrical conduction 244
(P<0.03). At ED a less pronounced, but still significantly higher upward shift than during 245
normal electrical conduction, was seen (3.1±2.0 mmHg, P=0.02). In Figure 5 PV loops 246
before and after induction of LBBB, are presented.
247
Tachycardia caused a significantly larger upward shift of the pressure-segment 248
length relation at MVO in the late activated LV lateral wall compared to the earlier 249
activated septum (13.1±9.1 vs. 9.3±8.6 mmHg, P=0.04). At ED the upward shifts in the 250
two walls were smaller (2.5±1.5 vs. 0.9±3.0 mmHg, respectively, P=0.29). Figure 7 251
shows the typical segment length patterns in LBBB and the differences in segmental 252
pressure-segment length relations.
253
CRT pacing 254
Applying CRT pacing improved the diastolic function. Tau was shortened at both 255
heart rates (Figure 3). CRT did not significantly change mean LAP or LVPMVO at 120 bpm, 256
whereas a minor reduction in LVEDP by 1.0 ±1.0 mmHg (P<0.04) was seen. CRT reduced 257
all 3 pressures during tachycardia: mean LAP, LVPMVO, and LVEDP were reduced by 258
2.4±1.8, 7.0±3.9, and 2.6±2.3 mmHg, respectively (all P<0.03) (Figure 3 and 4).
259
Incomplete relaxation at MVO was nonsignificantly increased from 20±7 to 23±9 260
% (P=0.43) by tachycardia. Complete relaxation had been reached by ED at baseline HR 261
while incomplete relaxation was on average 10±7 % (P=0.02) during tachycardia. The 262
incomplete relaxation at MVO was significantly lower during tachycardia compared to 263
LBBB (P<0.001), while the difference was nonsignificant at ED (P=0.41).
264
Relative to baseline HR, tachycardia shifted the pressure-volume relation at MVO 265
upwards by 4.7±5.6 mmHg during CRT. This upward shift was significantly less than the 266
shift induced by tachycardia in LBBB (P=0.03). At ED the upward shift caused by 267
12 tachycardia was 2.7±1.7 mmHg with CRT pacing, which was of similar magnitude as in 268
LBBB (P=0.73). During tachycardia the PV relation at the time of MVO, was lowered by 269
7.3±2.5 mmHg (P<0.001) when CRT was turned on during LBBB, whereas at ED the 270
relation was nonsignificantly lowered by 1.9±3.2 mmHg (P=0.16). Applying CRT during 271
baseline HR, did not significantly shift these PV-relations which were lowered on 272
average less than 1 mmHg at both MVO and ED.
273 274
DISCUSSION
275
The present study shows that pacing tachycardia in LBBB resulted in filling 276
starting while a substantial fraction of relaxation remained, thereby causing decreased 277
diastolic distensibility and elevation of diastolic pressures. The decreased diastolic 278
distensibility was attributed to delayed relaxation in the late activated LV lateral wall as 279
demonstrated by diastolic pressure-segment length analysis. At low HR, LBBB had only 280
minor impact on diastolic pressures as there was sufficient time for complete relaxation.
281
Consequently, CRT had marginal effects on LV diastolic pressures at low HR, while CRT 282
reversed the elevated diastolic pressures during tachycardia, indicating that CRT has 283
augmented benefits in this setting.
284
Weiss et al.24 found a small decrease of tau with pacing-induced tachycardia in 285
dogs. In our data there was also a trend towards faster relaxation at high HR during 286
normal electrical conduction. Furthermore, there was a leftward displacement of the PV- 287
loop. Due to the rising slope of the ED PV relation with increasing volumes, a leftward 288
displacement of the PV-loop implies that for a lower ED volume, there is a reduction in 289
ED pressure. Hence, leftward displacement of the PV-loop and faster relaxation are both 290
factors that tend to reduce pressures during filling when HR increases. In LBBB both 291
these responses to increased HR were impaired.
292
13 In the healthy heart, there is an abundance of time for filling reflected by the 293
diastasis, effectively representing a reserve time capacity. As HR increases, diastole is 294
shortened more than systole. Due to both dyssynchronous activation and relaxation in 295
LBBB, the filling time was already shorter at low HR. However, this did not substantially 296
affect pressures during filling at low HR. At low HR, the slowed pressure decay 297
prolonged IVRT (Table 1), and by the time of MVO, the pressure had reached the same 298
level as during normal electrical conduction. In this sense, the reserve time capacity 299
from normal electrical conduction is spent on prolongation of the isovolumic phases in 300
LBBB. The price comes at high HR when duration of filling can no longer be much 301
shorter and filling must start despite substantial incomplete relaxation. During 302
tachycardia in LBBB this was seen by the significantly higher pressure at MVO. The 303
pressure-volume loop showed that pressure continued to fall during almost all of filling 304
(Figure 5) which is a distinct sign of ongoing relaxation.20 The upward shift of the 305
pressure-volume relation was higher at onset of filling than at ED. Consistent with these 306
upward shifts in the pressure-volume relation, the estimated incomplete relaxation at 307
MVO and ED showed that there was substantial incomplete relaxation at beginning of 308
filling (40 %) while the effect was lower at ED (12 %) during tachycardia in LBBB. The 309
smaller effect at ED can be expected due to the exponential decay of relaxation.
310
Interestingly, mean LAP as well as peak RVP (Table 1) were significantly increased 311
despite the relatively moderate effects observed at ED. As LAP is a determinant of 312
pulmonary congestion, it seems that what happens during early filling may have 313
clinically important effects, not only the ED state.
314
Our results share some resemblance to those of pacing-induced ischemia, with an 315
upward-shift of the diastolic limb of the PV-loop and elevated diastolic pressure.1,19 316
Causes of altered diastolic distensibility during pacing-induced ischemia have been 317
14 debated and include incomplete relaxation, altered diastolic tone, partial ischemic 318
contracture of myofibrils within the distribution of the stenotic or occluded coronary 319
artery, altered right ventricular loading, and influence of the pericardium.12 The upward 320
shift in the diastolic LV pressure-dimension relation was seen in the absence of the 321
pericardium and small changes in RVEDP21, so incomplete relaxation or impaired 322
diastolic calcium sequestration seems to be the most plausible explanation, though a 323
firm conclusion is yet to be drawn.12 In our model we measured RV and pericardial 324
pressures as well as regional segment lengths. Thus, we could correct for the external LV 325
pressures in both regional and global measures of distensibility allowing a better 326
pinpointing of the cause as delayed relaxation. Furthermore, the experiments were 327
performed in healthy dogs without known coronary stenosis or myocardial ischemia.
328
Thus, it seems unlikely that the effect on diastolic function during tachycardia was 329
caused by ischemia. However, if our findings were a result of myocardial underperfusion 330
and ischemia due to the shorter diastolic period, there should be a gradual prolongation 331
of tau as well as the upward shift in the diastolic pressure-volume relation from the first 332
beats after onset of pacing tachycardia to the later beats when such ischemia would take 333
effect. We did not see such a development. Thus, we believe the effect on diastolic 334
function during tachycardia is related to delayed relaxation in the late activated regions.
335
Interestingly, there seems to be a difference in the slope of the lower limb of the 336
pressure-volume loops in our study compared to previously published studies regarding 337
pacing induced ischemia. We observed a larger upward shift at MVO compared to at ED, 338
so filling started before relaxation had completed resulting in considerable ongoing 339
relaxation during filling and hence the downward slope of the limb with filling occurring 340
during falling pressure. In contrast published figures seem to show a more parallel 341
upward shift of the limb in pacing induced ischemia, i.e. both the early filling and late 342
15 filling phases are shifted approximately equally, both during tachycardia1 and in the 343
immediate post pacing period19. This raises the question if the more constant upward 344
shift is associated with increased resting calcium level rather than slowing of the 345
ongoing relaxation that is characterized by a more dynamic change in diastolic 346
distensibility with a downward sloped limb.
347
Decreased restoring forces may cause increased pressure during early filling. In 348
LBBB the normal leftward shift of the PV-loop in response to tachycardia was blunted 349
resulting in higher ESV, i.e. less restoring forces. However, we derived the pressure- 350
volume relation at MVO and compared the upward shift for beats with the same volume 351
at MVO, i.e. presumably same restoring forces. In these acute experiments, there were 352
most likely no changes in passive stiffness. Hence, it seems incomplete relaxation was 353
the main cause of this shift.
354
Increased HR in our study was accomplished by atrial pacing. While pacing- 355
induced tachycardia reduces stroke volume and maintains cardiac output19, physical 356
activity increases cardiac output by increasing both HR and stroke volume. Physical 357
activity may attenuate our findings as it increases sympathetic tone causing positive 358
lusitropy, which enhance filling. On the other hand, as stroke volume is increased, it puts 359
higher demand on diastolic function to fill a larger stroke volume. Hence, the effects 360
found in our study, may potentially be further amplified in situations with increased 361
demand for filling. Thus, further studies under actual physical activity are needed to 362
investigate how these effects will attenuate or amplify our findings. In this respect our 363
findings have similarities to results from dogs running on treadmills.7,8 In those studies 364
diastolic function was compared before and after tachycardia-induced chronic heart 365
failure. The normal response to activity was increased relaxation rate and lowering of 366
minimum LVP with unaltered LAP, generating a higher pressure gradient to 367
16 accommodate the increased demand for cardiac output. In contrast, in the failing heart 368
with global slowing of relaxation, minimum LVP did not decrease while LAP increased.
369 370
Clinical perspectives 371
Elevated LAP leads to increased pulmonary venous pressures, with the potential of 372
congestion and pulmonary edema. Thus, the mechanism demonstrated in this study 373
might cause dyspnea during exercise in LBBB patients. This raises questions regarding 374
medical treatment of these patients. As improved rate control might be beneficial, one 375
could imagine that these patients could benefit from beta-blockers or calcium channel 376
blockers to avoid tachycardia induced diastolic dysfunction.
377
As LBBB had minor effects on diastolic parameters at low HR in our model, CRT 378
had limited effect on diastolic function in this setting. However, CRT reversed the 379
impaired diastolic function present at high HR suggesting amplified effects of CRT in 380
situations with higher demand and HRs compared to at rest. Today’s guidelines 381
recommend CRT to patients with LBBB and LVEF <35 %. Our findings suggest that 382
evaluation of LV diastolic function, both at rest and during exercise, could be used as 383
part of the decision process to decide whether a patient with LBBB should receive CRT 384
treatment or not.
385 386
Limitations 387
Our study was performed in an acute experimental model where the animal was 388
under general anesthesia with open chest and a heavily instrumented heart. Thus, 389
recordings prior to induction of LBBB did not represent normal physiology. The 390
resulting strain values were lower than normal reference values. This may be due to 391
effects of anesthesia, supine open chest conditions, and misalignment as well as 392
17 myocardial damage when placing the crystals. However, each animal served as its own 393
control allowing comparison of the effects of interventions such as induction of LBBB, 394
increased HR and CRT. We applied a relatively strong anesthetic dose. This may have 395
impaired myocardial function over time from recordings during normal conduction to 396
the recordings obtained after induction of LBBB. However, subsequent CRT 397
measurements showed normalization of the response to tachycardia, suggesting the 398
observed effects in LBBB were not primarily a result of impaired myocardial function 399
but rather due to the dyssynchrony.
400
Heart rates in dogs are higher than in humans8 and the heart rates used in our dog 401
model is much higher than what is expected in LBBB patients. However, the allometric 402
scaling of time parameters with body size,4 will alter duration of IVC, IVR and tau, and 403
we suspect the same effects of increased HR may occur at a lower HR in humans with a 404
larger body size. Furthermore, patients with LBBB frequently have an underlying heart 405
disease that may aggravate diastolic dysfunction even more. As typically both heart 406
failure7,8 and LBBB are associated with impaired relaxation, the two in combination may 407
prolong tau more than any of the two alone and hence amplify the negative effects of 408
increased HR. Further studies are needed to test if our findings will be further amplified 409
in case of more aggravated systolic and diastolic dysfunction and to confirm if our 410
findings will be present also in humans.
411
Tachycardia was accomplished by atrial pacing in our model. The atrioventricular 412
interval was thus not changed with tachycardia, as it would with tachycardia during 413
physiologic conditions. A shorter atrioventricular delay would potentially have 414
increased the atrial contribution to filling and increased end diastolic volume. However, 415
this limitation was present both during normal electrical conduction and LBBB, thus 416
presumably it did not impact on our qualitative results between these two situations.
417
18 Furthermore, the major differences in pressures and incomplete relaxation were seen 418
during early filling prior to the potential impact of active atrial contribution.
419
The estimation of degree of incomplete relaxation during diastole was based on 420
the assumption that relaxation follows an exponential decay with the same time- 421
constant as the pressure during IVR. A relatively similar approach has been used 422
previously for calculating the so-called “residual” pressure during filling.5 Furthermore, 423
measured relaxation in isolated papillary muscles has been described using such an 424
exponential decay following the time of peak relaxation rate (equivalent to the time- 425
point of minimum LV dP/dt).14 However, the presented method for estimation of degree 426
of incomplete relaxation has not been validated, and the reported numbers should be 427
viewed with this in mind.
428
The sonomicrometric crystals were positioned subendocardially so there was 429
some tissue between the crystal and the endocardium. The cavity volume, calculated 430
from the diameters between the crystals17, will therefore be exaggerated, while stroke 431
volume should be accurately calculated assuming myocardial incompressibility. As a 432
consequence ejection fraction will be underestimated in our model.
433 434
Conclusions 435
Tachycardia in hearts with LBBB reduced diastolic LV distensibility and increased 436
LV diastolic pressures due to incomplete relaxation. Application of CRT pacing 437
normalized these effects. Clinical studies are needed to determine if a similar 438
mechanism contributes to dyspnea and exercise intolerance in LBBB and if effects of 439
CRT are heart rate dependent.
440 441 442
19 Funding Sources
443
OSA, MRK, PS, and CKL were funded by South-Eastern Norway Regional Health 444
Authority [Project Numbers 2014068, 2014076, 2014069, and 2015010 respectively], 445
EB and JA were funded by the Norwegian Health Association, EWR was funded by the 446
K.G. Jebsen Foundation.
447 448
Disclosures 449
None.
450 451
Contributions of each author:
452
All authors contributed to the writing of the article. OSA, MRK, EB, CK, PS, JA, HS, HHO, 453
and EWR participated in the experiments.
454 455 456
References:
457
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24 Figure legends:
554 555
Figure 1: Schematic illustration of the placement of the sonomicrometry crystals.
556 557
Figure 2: Pressure-volume loops from a representative animal.
558
Upper panel: By constriction of the caval veins, LV volume was gradually reduced 559
producing a series of pressure-volume loops.
560
Lower panel: High pressure gain version of the upper panel, zooming in on the diastolic 561
part. A distinct upward shift of the lower limb during tachycardia can be seen in LBBB.
562
The shift is most marked at the beginning of filling, resulting in almost all of filling 563
occurring during falling pressure indicating ongoing relaxation. Quantification of the 564
shifts was performed as illustrated in the LBBB-panel: as the difference in the pressure 565
at the maximum overlapping volumes, shown for ED in this example, or in cases when 566
there was no overlapping volumes: as the difference in pressure for the two loops with 567
the closest volumes, which is shown for mitral valve opening in this example.
568 569
Figure 3: Diastolic measurements during normal electrical conditions, left bundle 570
branch block (LBBB) and cardiac resynchronization therapy (CRT) at baseline heart rate 571
120 bpm and during tachycardia at 180 bpm. LV: left ventricular; MVO: mitral valve 572
opening; ED: end diastolic.
573 574
Figure 4: Diastolic left atrial and ventricular pressures. The left and middle panels show 575
pressures during normal electrical conduction and in LBBB for HR of 120 and 180 bpm, 576
respectively, whereas the right panel shows pressures in LBBB and CRT at HR 180 bpm.
577
At 120 bpm LV pressure at mitral valve opening, LV end diastolic pressure and LA 578
25 pressure were almost equal during normal electrical conduction and in LBBB, whereas 579
at 180 bpm these pressures were significantly higher in LBBB. CRT significantly reduced 580
LV pressure at mitral valve opening, LV end diastolic pressure, and mean LA pressure.
581 582
Figure 5: Pressure-volume loops from a representative animal. During normal electrical 583
conduction (left panel) tachycardia displaced the pressure-volume loop leftwards, while 584
this displacement was blunted in LBBB (right panel, Table 1). The LV operated on a 585
higher pressure during filling in LBBB during tachycardia with most pronounced 586
upward shift during beginning of filling. During tachycardia LV filling occurred mainly 587
during falling pressure, consistent with ongoing relaxation.20 588
589
Figure 6: Degree of incomplete relaxation relative to end systole. The figure shows the 590
principle for estimating the degree of incomplete relaxation at different time-points. In 591
the left panel, the presumed exponential decay of relaxation is plotted using the average 592
time constant tau = 47 ms from LBBB. The corresponding average values at mitral valve 593
opening (MVO) and end diastole (ED) for heart rates 120 and 180 bpm are indicated.
594
The red part of the curve shows that most of filling during tachycardia occurs while 595
there is still a high degree of incomplete relaxation. In the right panel, a schematic of 596
attached myosin-actin crossbridges at the different time-points are shown to illustrate 597
the ongoing relaxation.
598 599
Figure 7: Segment length traces and pressure-segment length loops during caval 600
constrictions in left bundle branch block from a representative animal.
601
Upper panel A: The septal segment is activated earlier than the lateral wall segment as 602
seen by the electromyograms (EMGs). The order of segmental relaxation was consistent 603
26 with the order of electrical activation as seen by lengthening starting prior to end
604
systole in the septum while the lateral wall segment continued shortening after end 605
systole.
606
Lower panel B: While the upward shift during tachycardia of the lower limb of the 607
lateral wall pressure-segment length relation is distinct, particularly during beginning of 608
filling, the shift is markedly smaller for the septal segment, which is more easily seen at 609
high pressure gain in the right sub-panels. The difference in peak pressure for the 2 610
segments is due to the difference in calculation of transmural segmental pressure as 611
defined in the text.
612 613 614
27 Table 1: Summary of measurements comparing normal electrical conduction and LBBB.
Mean (SD).
Measurement n Normal
electrical conduction
LBBB P-value (normal electrical conduction
vs. LBBB).
Tau, HR 120 bpm (ms) 9 38 (3) 47 (7) 0.001
Tau, HR 180 bpm (ms) 7 34 (4) 47 (11) 0.01
IVRT at HR 120 bpm (ms) 9 71 (13) 81 (11) 0.005
IVRT at HR 180 bpm (ms) 8 48 (13) 44 (11) ns
Duration of filling at HR 120 bpm (ms) 9 167 (25) 142 (24) 0.007 Duration of filling at HR 180 bpm (ms) 8 81 (18) 83 (13) ns
Peak LVP at HR 120 bpm (mmHg) 9 90 (18) 85 (15) ns
Peak LVP at HR 180 bpm (mmHg) 8 85 (18) 75 (16) 0.03
Stroke volume at HR 120 bpm (ml) 9 18 (5) 18 (5) ns
Stroke volume at HR 180 bpm (ml) 8 13 (3) 16 (6) ns
Cardiac output at HR 120 bpm (ml/min) 9 2164 (610) 2170 (594) ns Cardiac output at HR 180 bpm (ml/min) 8 2371 (604) 2813
(1112) ns
Delay EMG activation at HR 120 bpm
(ms) 9 4 (8) 49 (13) <0.001
Delay EMG activation at HR 180 bpm
(ms) 8 7 (9) 50 (11) <0.001
LV dP/dt max at HR 120 bpm (mmHg/s) 9 1138 (215) 944 (189) 0.002 LV dP/dt max at HR 180 bpm (mmHg/s) 8 1209 (253) 972 (199) 0.01 LV dP/dt min at HR 120 bpm (mmHg/s) 9 -1293 (470) -1061
(294) ns
LV dP/dt min at HR 180 bpm (mmHg/s) 8 -1345 (416) -968 (327) ns LV EDV at HR 120 bpm (ml) 9 104 (17) 111 (17) <0.001
LV EDV at HR 180 bpm (ml) 8 96 (16) 110 (12) 0.006
LV ESV at HR 120 bpm (ml) 9 86 (15) 93 (16) 0.001
LV ESV at HR 180 bpm (ml) 8 83 (15) 94 (12) 0.03
Septal wall strain at HR 120 (%) 7 -7.7 (3.5) -5.8 (2.4) 0.01 Septal wall strain at HR 180 (%) 6 -7.0 (4.3) -5.9 (2.2) 0.04 Lateral wall strain at HR 120 (%) 8 -8.3 (5.4) -11.3 (5.8) ns Lateral wall strain at HR 180 (%) 8 -6.9 (4.0) -10.4 (4.2) 0.02
Peak RVP at HR 120 bpm (mmHg) 9 25 (5) 25 (5) ns
Peak RVP at HR 180 bpm (mmHg) 8 24 (5) 28 (5) 0.02
Average RAP at HR 120 bpm (mmHg) 9 5.0 (1.5) 5.6 (2.9) ns Average RAP at HR 180 bpm (mmHg) 8 5.7 (2.4) 7.1 (4.5) ns IVRT: Isovolumic relaxation time; HR: heart rate. LV: left ventricular; LVP: LV pressure.
EMG: electromyogram; EDV: end diastolic volume; ESV: end systolic volume; RVP: right ventricular pressure; RAP: right atrial pressure.
615 616
28 Table 2: Summary of measurements comparing LBBB and CRT. Mean (SD).
Measurement n LBBB CRT P-value
(CRT vs.
LBBB).
Tau, HR 120 bpm (ms) 9 47 (7) 42 (7) 0.001
Tau, HR 180 bpm (ms) 8 44 (10) 39 (9) 0.02
IVRT at HR 120 bpm (ms) 9 81 (11) 71 (13) 0.02
IVRT at HR 180 bpm (ms) 9 44 (11) 59 (9) <0.001
Duration of filling at HR 120 bpm (ms) 9 142 (24) 168 (24) 0.02 Duration of filling at HR 180 bpm (ms) 9 83 (13) 77 (10) ns
Peak LVP at HR 120 bpm (mmHg) 9 85 (15) 86 (15) ns
Peak LVP at HR 180 bpm (mmHg) 8 84 (19) 90 (19) ns
Stroke volume at HR 120 bpm (ml) 8 18 (5) 16 (3) ns
Stroke volume at HR 180 bpm (ml) 8 17 (5) 14 (4) ns
Cardiac output at HR 120 bpm (ml/min) 8 2133 (624) 1958 (401) ns Cardiac output at HR 180 bpm (ml/min) 8 2961 (972) 2436 (671) ns Delay EMG activation at HR 120 bpm
(ms) 9 49 (13) 5 (25) <0.001
Delay EMG activation at HR 180 bpm
(ms) 9 50 (12) 9 (29) 0.001
LV dP/dt max at HR 120 bpm (mmHg/s) 9 944 (189) 1070 (235) 0.02 LV dP/dt max at HR 180 bpm (mmHg/s) 8 1116 (271) 1363 (313) 0.04 LV dP/dt min at HR 120 bpm (mmHg/s) 9 -1061
(294) -1324
(385) 0.03
LV dP/dt min at HR 180 bpm (mmHg/s) 8 -1115
(353) -1324
(385) ns
LV EDV at HR 120 bpm (ml) 8 110 (18) 105 (16) 0.006
LV EDV at HR 180 bpm (ml) 8 98 (28) 95 (29) ns
LV ESV at HR 120 bpm (ml) 8 93 (17) 89 (15) 0.005
LV ESV at HR 180 bpm (ml) 8 82 (27) 81 (28) ns
Septal wall strain at HR 120 (%) 7 -5.8 (2.4) -8.2 (4.8) ns Septal wall strain at HR 180 (%) 8 -6.2 (3.2) -8.7 (3.3) 0.03 Lateral wall strain at HR 120 (%) 8 -11.3 (5.8) -7.9 (5.4) 0.01 Lateral wall strain at HR 180 (%) 8 -10.0 (5.3) -5.5 (2.6) 0.02
Peak RVP at HR 120 bpm (mmHg) 9 25 (5) 26 (5) ns
Peak RVP at HR 180 bpm (mmHg) 8 27 (4) 26 (5) ns
Average RAP at HR 120 bpm (mmHg) 9 5.6 (2.9) 5.4 (2.8) ns Average RAP at HR 180 bpm (mmHg) 8 6.5 (2.8) 6.0 (2.2) ns
*Incomplete relaxation was lower in all 9 animals by an average of 0.6 (0.6) %. IVRT:
Isovolumic relaxation time; HR: heart rate. LV: left ventricular; LVP: LV pressure. EMG:
electromyogram; EDV: end diastolic volume; ESV: end systolic volume; RVP: Right ventricular pressure; RAP: Right atrial pressure.
617
