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Articles in PresS. Am J Physiol Heart Circ Physiol (July 26, 2013). doi:10.1152/ajpheart.00191.2013 Russell et al. 1 Assessment of wasted myocardial work – A novel method to quantify 2 energy loss due to un-coordinated left ventricular contractions 3 4 Russell et al, a novel method to quantify wasted myocardial work 5 6 Kristoffer Russell, MD; Morten Eriksen, MD, PhD.; Lars Aaberge, MD, PhD; Nils 7 Wilhelmsen; Helge Skulstad, MD, PhD; Ola Gjesdal, MD, PhD; Thor Edvardsen, MD, PhD; 8 Otto A. Smiseth, MD, PhD, FACC. 9 Institute for Surgical Research and Department of Cardiology, Rikshospitalet, Oslo 10 University Hospital, Norway. University of Oslo, Medical faculty 11 12 Address for correspondence: 13 Otto A. Smiseth 14 Department of Cardiology 15 Rikshospitalet Oslo university Hospital 16 N-0027 Oslo, Norway 17 Phone: +47 23070000/+47 23073271 18 Fax: +47 23073917 19 E-mail: [email protected] 20 Total Word Count: 4479 21 Key words: Heart failure, myocardial function, dyssynchrony, cardiac resynchronization 22 therapy 23 24 1 Copyright © 2013 by the American Physiological Society. Russell et al. 25 Background: 26 Left ventricular (LV) dyssynchrony reduces myocardial efficiency because work 27 performed by one segment is wasted by stretching other segments. We introduce a novel non- 28 invasive clinical method which quantifies wasted energy as the ratio between work consumed 29 during segmental lengthening (wasted work) divided by work during segmental shortening. 30 Methods: 31 The wasted work ratio (WWR) principle was studied in 6 anesthetized dogs with left 32 bundle branch block (LBBB), and in 28 patients with cardiomyopathy, including 12 with 33 LBBB and 10 with cardiac resynchronization therapy (CRT). Twenty healthy individuals 34 served as controls. Myocardial strain was measured by speckle tracking echocardiography 35 (STE), and left ventricular pressure (LVP) by micromanometer and a previously validated 36 non-invasive method. Segmental work was calculated by multiplying strain rate and LVP to 37 get instantaneous power, which was integrated to give work as a function of time. A global 38 WWR was also calculated. 39 Results: 40 In dogs WWR by estimated LVP and strain showed strong correlation (r =0.94) and 41 good agreement with WWR by LV micromanometer and myocardial segment length by 42 sonomicrometry. In patients, non-invasive WWR showed strong correlation (r =0.96) and 43 good agreement with WWR using LV micromanometer. In healthy controls global WWR 44 was 0.09±0.03, in patients with LBBB 0.36±0.16, and in cardiomyopathy patients without 45 LBBB 0.21±0.09. CRT reduced global WWR from 0.36±0.16 to 0.17±0.07, (p<0.001). 46 47 48 2 Russell et al. 49 50 Conclusions: Energy loss due to in-coordinated contractions can be quantified non-invasively as LV 51 wasted work ratio. This method may be applied to evaluate the mechanical impact of 52 dyssynchrony. 53 3 Russell et al. 54 Introduction 55 In a normal left ventricle (LV) all segments contract in a synchronized fashion and 56 myocardial energy is utilized effectively to eject blood out of the ventricle. In ventricles with 57 regional differences in contractility as in ischemia or delay in electrical conduction as in 58 LBBB, some segments are stretched in systole while others contract, resulting in a 59 dyssychronous contraction pattern. The result of this dyssynchrony is that a substantial 60 amount of LV work is “wasted” on stretching opposing segments and therefore does not 61 contribute effectively to LV ejection. There is currently no clinical method to quantify how 62 much work is wasted due to dyssynchrony. 63 Recently we introduced a non-invasive clinical method to quantify regional LV work 64 (9). This method measures regional work in terms of LV pressure-strain loop areas which are 65 constructed from a non-invasive LV pressure curve in combination with strain by STE. 66 Analogous to the principle that the area of the LV pressure-volume loop reflects stroke work 67 and global myocardial oxygen consumption (11; 12), it has been shown by Delhaas et al (1) 68 and by Russell et al (9) that the pressure-strain loop area may serve as an index of regional 69 myocardial work and metabolism when comparing segments within a given ventricle. In the 70 present paper we propose to use segmental LV pressure-strain data acquired by a non- 71 invasive approach to quantify how much work is wasted in ventricles with dyssynchronous 72 contractions. This energy loss is expressed as work consumed during segmental lengthening 73 (negative work) as the ratio of work during segmental shortening (positive work), and we 74 named this the wasted work ratio (WWR). 75 76 The main objective of the present study was to validate WWR and investigate changes in WWR to CRT in patients with heart failure and LBBB. 4 Russell et al. 77 First we investigated if LV WWR can be measured and quantified non-invasively. 78 Second, we studied if WWR can be measured by LV pressure-strain analysis in a dog model 79 using sonomicrometry as a refrence method for speckle tracking strain and in patients using 80 micromanometer as reference method for LV pressure. Finally, we investigated changes in 81 WWR to CRT in patients with heart failure and LBBB. Methods 82 83 Experimental study 84 Animal preparation 85 Six mongrel dogs of either sex and body weight 35 ± 1 kg were anesthetized, ventilated, 86 and surgically prepared as previously described (13), including induction of LBBB (n=6) by 87 radiofrequency ablation (2). The study was approved by the National Animal 88 Experimentation Board. The laboratory animals were supplied by Centre for Comparative 89 Medicine, Oslo University Hospital, Rikshospitalet, Norway. 90 Sonomicrometry 91 Segment lengths were measured by pairs of 2 mm wide sonomicrometry crystals 92 (Sonometrics Corp., London, Ontario, Canada) implanted subendocardially. Four 93 circumferential segments incorporating all LV walls were analyzed. Strain was calculated as 94 percent length deviation from the end-diastolic length. Data were sampled at 200 Hz. 95 Hemodynamic measurements 96 Aortic, left atrial and LV pressures (LVP) were measured by micromanometers (MPC- 97 500, Millar Instruments Inc, Houston, Tex). A fluid-filled catheter placed in the left atrium 98 served as an absolute pressure reference for the LV micromanometer. 5 Russell et al. 99 100 Echocardiography A Vivid 7 ultrasound scanner (GE Vingmed Ultrasound AS, Horten, Norway) was used 101 to record conventional 2-D grayscale images (frame rate 64±12 s-1) of the LV (at the level of 102 the papillary muscle) short-axis and apical 4 and 2 chamber views for STE. 103 104 105 106 Experimental protocol Measurements were performed before and after induction of LBBB. Data were recorded with the ventilator temporarily switched off. 107 108 Clinical study 109 Validation of non-invasive vs. invasively measured WWR 110 18 patients (mean age 66±8 years, 25% females) underwent LV catheterization, 111 including 11 with ischemic cardiomyopathy and 7 with non-ischemic dilated 112 cardiomyopathy. Twelve of these patients had LBBB (QRS 160±20 ms). Two of the patients 113 with LBBB had a CRT device allowing for measurements with CRT on and off. 114 Response in WWR to Cardiac Resynchronization Therapy 115 Ten additional patients with heart failure and NYHA II-IV and LBBB were included. 116 Coronary artery stenosis was ruled out by angiography prior to investigation. 117 Echocardiography was preformed prior to implantation of CRT device (n=10) and at follow 118 up 8±3 months later (n=9). To assess changes in wasted work after CRT we deliberately 119 included only responders in the patient population (>10% reduction in end systolic volume) 120 in order to demonstrate changes in work as a result of resynchronization treatment. 121 6 Russell et al. 122 123 WWR in healthy controls Twenty age and sex matched healthy individuals were recruited from the hospital staff. 124 All had normal clinical examination, ECG and echocardiography. 125 The study was approved by the Regional Committee for Medical Research Ethics. All 126 subjects gave written informed consent. 127 128 129 Hemodynamic and Echocardiographic measurements In all patients myocardial strain was measured by STE (Vivid 7) in apical long-axis, 2 130 and 4 chamber views (frame rate 65±6 s-1). Narrow sector 2-D imaging over the valves 131 (frame rate 87±22 s-1) was used to define opening and closure of the aortic and mitral valves. 132 In the invasive LV pressure group, LVP was measured by a micromanometer-tipped catheter 133 (Microtip, Millar Instruments) and a fluid-filled catheter connected to an external pressure 134 transducer served as absolute pressure reference. Pressure and strain data were recorded in a 135 synchronised fashion and stored for offline analysis. An average of 16±2 segments (from a 136 total of 18) were analyzed in each patient. 137 Data analysis 138 Estimation of LV pressure curve 139 The method for calculating the non-invasive LV pressure analogue has been described 140 in detail previously (9). In short, we utilized an empiric reference curve for the LV pressure 141 profile. This curve was obtained by pooling LVP data from a number of patients with 142 different pathologies, and for each patient the durations of IVC, LV ejection and IVR, 143 defined by echocardiography, were set to the same arbitrary value by stretching or 144 compressing the curves along the time axis. From this series of individual curves a common 145 average waveform was constructed. The profile of the averaged LV pressure waveform was 7 Russell et al. 146 used for predicting LVP in each specific subject by measuring the actual valvular timing for 147 the relevant cardiac cycle and adjusting the duration of time intervals of isovolumic 148 contraction (IVC), ejection and isovolumic relaxation (IVR) phases by stretching or 149 compressing the time axis of the averaged LV pressure curve to match the measured time 150 intervals. To scale the amplitude of the pressure curve peak arterial pressure was used in the 151 experimental study and arterial cuff pressure in patients and controls. Separate reference 152 curves were used for dogs and patients. 153 154 155 Calculation of segmental work Work for individual segments as a function of time throughout the cardiac cycle was 156 calculated from the strain recordings and from measured or estimated LV pressure from a 157 representative heart beat. This was done by obtaining the rate of segmental shortening (strain 158 rate) by differentiation of the strain curve and multiplying this with instantaneous LVP. This 159 resulted in a measure of instantaneous power, which was integrated over time to give work as 160 a function of time (Figure 1). Performing this calculation for the IVC, ejection and IVR 161 phases is mathematically the same as calculation of the area between the x-axis and the 162 corresponding segment of the strain – pressure loop, however keeping in mind that areas 163 under sections of the loop that represent elongation are counted as negative (further details 164 are presented in the appendix). Work was calculated from mvc until mvo. The reason for this 165 is that work losses can occur by stretching of segments in the isovolumic phases, especially in 166 hearts with a dysynchroneous contraction pattern. 167 168 8 Russell et al. 169 170 Analysis of segmental work Information was extracted from the segmental work curves over a time interval 171 spanning from mitral valve closure to mitral valve opening. The following variables were 172 calculated: 173 Wpos 174 175 Total positive work, sum of all work performed during shortening of the segment. By definition a positive number. Wneg Total negative work, sum of all work performed during elongation of the 176 segment. Although a negative number by definition, Wneg is presented as a 177 positive number to facilitate understanding of the relative differences between 178 negative and positive work. 179 180 181 182 183 184 Global WWR was calculated from the sum of work for all segments: WWRglobal = W W neg pos The net work contributing to systolic ejection for each segment was calculated as: Wnet = W pos − Wneg A Wasted Work Ratio for each segment was also calculated: Segmental Wasted Work Ratio = Wneg W pos 185 Figure 2 shows positive work (in black) and negative work (in red) during systole for a septal 186 and lateral wall segment before and during CRT in a representative patient. 187 9 Russell et al. 188 Work analysis 189 In the experimental study wasted work ratio calculated using strain by STE and 190 estimated LV pressure was compared to WWR calculated by strain by sonomicrometry and 191 invasively measured LVP. 192 In the patients with invasive LV pressure, work was analyzed by two different methods: 193 1. STE strain and measured LVP 194 2. STE strain and estimated LVP. 195 196 Statistical analysis 197 Values are expressed as mean±SD. Results from different methods of measurement 198 were compared using least-squares linear regression, Pearson correlation coefficients and 199 Bland-Altman plots with calculations of limits of agreement. For multiple comparisons we 200 used repeated measurements ANOVA with LSD post test (SPSS 15.0, SPSS Inc, Chicago, 201 IL). All post hoc tests are compared to baseline. P<0.05 was considered significant. 202 Results 203 204 Experimental study 205 Validation of WWR calculated from estimated LVP and echocardiography versus 206 measured LVP and sonomicrometry 207 The analysis which included measurements before and after induction of LBBB, 208 showed strong correlation (r = 0.94) and good agreement (SD = 0.07, mean difference = - 209 0.03) between global WWR calculated from estimated LVP and strain by STE versus WWR 210 by LV micromanometer and segment length by sonomicrometry. 10 Russell et al. 211 212 213 Changes in WWR from baseline to left bundle branch block Introduction of LBBB increased global WWR measured by LVP and echocardiography 214 from 0.13±0.05 to 0.37±0.11 (p<0.001). Peak strain for septum and lateral wall were 215 moderately reduced after induction of LBBB, from -15±4 to -10±4% (p=0.014) and -14±4 to 216 -11±7 % (p=ns), respectively. However, the work done by the septum decreased 217 substantially, from 951±320 to 349±346 mmHg•% (p=0.002). In contrast net work done by 218 the lateral wall increased from 756±266 to 1059±516 mmHg•% (p=0.026) despite the 219 tendency of decrease in peak strain. Therefore, changes in peak strain after induction of 220 LBBB did not reflect changes in regional work. 221 222 Clinical study 223 Validation of WWR using estimated versus measured LVP 224 There was a strong correlation (r=0.96) and good agreement (SD=0.03, mean 225 difference= -0.01) between global WWR calculated by STE and invasive vs. non-invasive 226 LV pressure (Figures 3 and 4). 227 228 229 Wasted work ratio in healthy normals Figure 5 shows a bull’s eye plot with segmental WWRs from a representative healthy 230 individual. The WWR was less than 0.14 in every segment, which implies that LV work was 231 dominated by positive work (i.e. shortening work) and there was very little negative work 232 (i.e. work wasted during systolic lengthening). The global WWR for the healthy normals was 233 0.09±0.03. 234 11 Russell et al. 235 236 Wasted work ratio in patients with cardiomyopathy In the patients with LBBB peak strain values for the septum were on average half of the 237 value of the lateral wall. For the septum the segmental WWR was 1.57±0.97. Since WWR > 238 1 implies more negative than positive work, this implies that on average net septal work was 239 negative. In some LBBB patients net septal work was positive, although it was markedly 240 reduced. The lateral wall, however, showed increased positive work compared to the control 241 group and the segmental WWR was increased, but to a moderate degree compared to the 242 septum (0.18±0.11) (Figure 5 A). 243 In patients with cardiomyopathy and narrow QRS (96±18ms), without LBBB 244 segmental WWR was moderately increased to 0.17±0.08 for septum, 0.27±0.26 for the LV 245 lateral wall and global WWR was 0.21±0.09. 246 247 Changes in wasted work ratio with CRT 248 When CRT was introduced in patients with LBBB, the septum showed a dramatic 249 increase in positive work and a reduction in negative work, and the septal WWR decreased to 250 0.18 ± 0.09 (Figure 5 B). The lateral wall showed only minor changes with CRT (Figure 2 251 and 4, Table 2). These changes in segmental work with CRT were reflected in a reduction in 252 global WWR from 0.36±0.16 to 0.17±0.07 253 254 255 . Discussion In the present study we introduce a novel, non-invasive method which quantifies how 256 much work is wasted in ventricles with dyssynchronous contraction patterns. The method 257 gives segmental information about positive work (systolic shortening) and negative work 258 (systolic lengthening), allowing for assessment of local and global energetic efficacy as the 12 Russell et al. 259 ratio between negative and positive work. The validity of this method was confirmed in the 260 experimental part of the study. Furthermore, in the clinical study we showed that WWR 261 based on a non-invasive LV pressure estimate corresponded well with calculations using 262 invasive LV pressure. We showed that significant work was wasted in patients with LBBB 263 and was subsequently recruited when CRT was introduced, suggesting that the work analysis 264 may represent a means to explore the hemodynamic impact of electrical dyssynchrony. 265 266 267 Work analysis As shown by Hisano (4), the area of the myocardial force-dimension loop represents 268 the work performed during a cardiac cycle. However, due to the complexities of measuring 269 force, LVP has been used as a surrogate to force. The use of pressure as a substitute for force 270 may be viewed as a limitation. However, previous studies from our group have shown that 271 pressure-lengths loops reflect regional changes in myocardial work when compared to force- 272 segment length loops (10). Furthermore, we have shown that stress-strain loop area, 273 calculated using curvature and area strain and showed quantitatively similar information 274 when compared to stress-segment length loop area when comparing regional differences 275 within the same heart. Another argument which supports that pressure strain loops reflect 276 regional work is our previous demonstration that pressure strain loop area reflects regional 277 glucose metabolism assessed my 18 flourodeoxyglucose positron emission tomography (9) 278 Since invasive LV pressure is often not available, we have introduced a non-invasive 279 estimate of the LV pressure curve, which is constructed by adjusting an empiric average 280 waveform according to duration of the isovolumic and ejection phases as defined by 281 echocardiography, and peak pressure is set equal to arterial cuff pressure. The validity of 282 calculating regional myocardial work from non-invasive LV pressure and strain by STE has 283 been confirmed both in an animal model and in patients (9). 13 Russell et al. 284 Using segment length for the assessment of regional work may be viewed as a 285 limitation as it depends on the relation of the crystal implantation site to myofiber orientation 286 which varies through the ventricular wall. Previous studies have assessed regional work using 287 wall thickness measurement as it does not dependent on fiber direction (3). Ideally regional 288 work should be calculated using area strain, however, in a clinical setting strain analysis are 289 commonly performed for longitudinal and circumferential segments and we therefore used 290 these measurements for work analysis in the present paper. Furthermore, we have previously 291 shown that work analysis by using segmental strain reflects work using area strain (9). 292 293 294 Wasted work In a normal heart, all segments contract almost simultaneously and they therefore 295 contract against a similar LV pressure. However, in a ventricle with regional differences in 296 timing of contraction, segmental contractions occur against different pressures. Therefore, 297 information about both degree of shortening and LV pressure during shortening is needed to 298 compare work between the segments. 299 The same is true for calculation of wasted energy during elongation of segments, since 300 the energy loss depends on both elongation distance and LV pressure during elongation. In 301 ventricles with non-uniformity in timing of relaxation, some segments will start relaxing and 302 elongate in late systole, at high LV pressure while other segments are still contracting. This 303 means that a substantial amount work done by the contracting segments is wasted on 304 stretching other segments. Typically, during LBBB much of septal contraction occurs during 305 the pre-ejection phase at a time when the LVP is low, and therefore the septum performs little 306 work (8). As seen in the present study peak septal strain during LBBB in the animal model is 307 only marginally reduced compared to the lateral wall, but net work done by the septum is 14 Russell et al. 308 approximately one third relative to the lateral wall (Table 1). In the patients with LBBB peak 309 strain for the septum was on average half of that for the lateral wall, which is in keeping with 310 previous studies (5). The average segmental WWR, however, was above 1.5, indicating that 311 negative (wasted) work exceeded positive work. Therefore, instead of the septum 312 contributing to the hemodynamic performance of the LV, external work was done on the 313 septum which thereby “absorbed” work done by other segments. 314 Measuring wasted work is therefore a method for quantifying work that is being done 315 by the ventricle but does not contribute to LV ejection, and provided the myocardium is 316 viable, should represent a measure of contractile reserve. This was supported by our findings 317 in patients with LBBB who showed a decrease in WWR and an increase in ejection fraction 318 when CRT was introduced (Table 2). 319 In a previous study wasted work was estimated as the difference between strain at end 320 systole and peak strain during or after systole (1). The main limitation of this method is that it 321 does not take into account pressure, which is higher during lengthening in late systole than 322 during post-systolic shortening. Therefore stretching of a segment before AVC represents a 323 greater degree of wasted work compared to shortening after AVC when pressure is rapidly 324 declining. Although this is an interesting index of mechanical dyssynchrony, it does not 325 provide a measure of work since it does not incorporate load. Our method incorporates a 326 measure of regional load (LVP), thereby taking into account the energetic effects of 327 deformation at different pressures. The importance of taking into account pressure was 328 illustrated by an additional data analysis in which we considered strain only as a marker of 329 wasted work. In this analysis, which is detailed in the appendix, we calculated work by 330 assuming a constant LV pressure, set to an arbitrary value of 1 mmHg. The result from this 331 analysis was that the wasted work and WWR differed substantially from results when cyclic 332 LV pressure was used, as illustrated in Figure 5. The septum which had a wasted work ratio 15 Russell et al. 333 larger than one in most segments during LBBB, and therefore performed more negative than 334 positive work, appeared to do predominantly positive work when looking at strain only. 335 Similarly, the effect of CRT as reflected in the difference in WWR between the septum and 336 lateral became far less pronounced when ignoring pressure (Figure 5 B and C). We therefore 337 propose that our method which incorporates a LV pressure estimate, gives important 338 additional information about regional myocardial function. 339 Since the myocytes are unable to recycle chemical energy when the segments are 340 stretched, this energy will instead be converted to heat in the tissue. Measurements of WWR 341 will for this reason indicate the overall efficacy of the LV myocardium in converting 342 metabolic substrates into cardiac work. Quantification of regional work in ventricles with 343 uncoordinated contractions may provide important insights into mechanisms of remodelling 344 and progressive LV dysfunction (1; 6; 7; 14). 345 346 347 348 Limitations When estimating the LV pressure curve by the non-invasive method, we use an empiric 349 standardized reference curve based on several invasively recorded pressure traces. One may 350 argue that a mathematically derived curve profile determined by regression analysis may be 351 used instead of a tabulated reference curve. A principal limitation of both concepts is that the 352 waveform might be inaccurate for some pathologies. The waveform found by regression 353 analysis will in addition contain errors caused by limitations in the number of degrees of 354 freedom used in the regression function. Using an empiric standardized reference curve based 355 on averaging of invasive measurements is for this reason expected to give a more accurate 356 profile, supporting its use over pressure traces defined as mathematical functions. 357 Furthermore, the method has been thoroughly validated and it performs well under a wide 16 Russell et al. 358 range of different hemodynamic conditions (9). However, for minor changes in regional work 359 the lack of a true LV pressure represents a limitation. The accuracy of the estimated LV 360 pressure curve may be improved by including data from arterial tonometry, and by using 361 specific reference curves for different patient populations. 362 The LV pressure-strain analysis does not provide a direct measure of work since 363 radius of curvature and wall thickness are not incorporated in the calculations. Therefore, 364 comparison of absolute positive or negative work estimates between different ventricles may 365 not be valid. Comparison of WWR between different hearts, however, should be valid 366 measure since it is a relative measure which compensates for limited information about local 367 geometry. The reproducibility for WWR was not assessed in the present paper, however, 368 interobserver variability for both strain and non-invasive pressure estimate (9) has previously 369 been evaluated. 370 The experimental dataset and the dataset from patients with simultaneous LVP 371 measurements and strain analysis has also been used in a previous publication from our group 372 (9). 373 The assessment of regional work proposed in the current study relies on strain rate 374 based on STE and relatively low time resolution may therefore represent a limitation. In the 375 current study we had a frame rate 64±12 s-1 in the experimental part and found this to be 376 sufficient when compared to results using sonomicrometry. 377 378 Conclusions 379 The present study introduces a non-invasive clinical method to quantify the negative impact 380 of dyssynchrony on myocardial work and energy utilization. Studies should be done to 381 determine if this new method will be useful in risk stratification and in the selection of 382 therapy for patients with dyssynchrony. 17 Russell et al. 383 384 Appendix 385 - Calculation of segmental work 386 Work of individual segments was calculated from the strain recordings and the left 387 ventricular pressure. Instead of calculating only one value of work in a completed cardiac 388 cycle for each segment, equal to the area of the strain – pressure loop, work was calculated as 389 a function of time throughout the cardiac cycle. This was done by obtaining the rate of 390 segmental shortening (strain rate) by differentiation of the strain curve (Figure 2A), and 391 multiplying this with instantaneous left ventricular pressure (Figure 2B). This resulted in a 392 measure of instantaneous power, which was integrated over time by the trapezoidal method to 393 give work as a function of time (Figure 2C). Performing this calculation for a complete cycle 394 is mathematically the same as calculation of the strain – pressure loop area according to 395 Green’s theorem. 396 In detail: 397 Let PLV(t) be the recorded or estimated pressure in the left ventricle as a function of 398 time, and ε(t) be the strain of a myocardial segment as a function of time. 399 The segment shortening rate (strain velocity) is: 400 401 402 1) v(t ) = − dε (t ) dt - and the power developed by the segment is: 2) P(t ) = v(t ) PLV (t ) = − dε (t )PLV (t ) dt 18 Russell et al. 403 The work performed by the segment as a function of time is the integral of power from t’ = 0 404 to t’ = t: 405 3) t t 0 0 W (t ) = P(t ′)dt ′ = − dε (t′) PLV (t′) dt′ dt 406 - where t’ is an integration variable. 407 - Calculation of WWF using constant pressure. 408 To highlight the importance of changes in regional load when assissing work we performed 409 calculations by using the non-weighted sum of segment shortening as a surrogate for positive 410 work, and the sum of elongation as negative work. This is equivalent to using our calculation 411 method as described in the paper, but assuming a constant pressure of 1 instead of a time- 412 varying pressure. The calculation were performed for ejection and isovolumic contraction and 413 relaxation phases using raw data from the same patients before and after CRT. The bull eye 414 plots in figure 5 show that when WWR is calculated using a constant pressue (C) the 415 difference in wasted work ratio between the septum and lateral wall was significantly 416 reduced, and the effect of CRT became far less pronounced. 417 Sources of funding 418 419 Dr Russell was recipient of a clinical research fellowship from the University of Oslo. Acknowledgements 420 421 We would like to thank Professor John V. Tyberg for his insightful comments. Disclosures 422 423 None. 19 Russell et al. 424 Reference List 425 426 1. Delhaas T, Arts T, Prinzen FW and Reneman RS. Regional fibre stress-fibre 427 strain area as an estimate of regional blood flow and oxygen demand in the 428 canine heart. J Physiol 477 ( Pt 3): 481-496, 1994. 429 2. Gjesdal O, Remme EW, Opdahl A, Skulstad H, Russell K, Kongsgaard E, 430 Edvardsen T and Smiseth OA. Mechanisms of abnormal systolic motion of 431 the interventricular septum during left bundle-branch block. Circ Cardiovasc 432 Imaging 4: 264-273, 2011. 433 3. Heusch G, Rose J, Skyschally A, Post H and Schulz R. Calcium 434 responsiveness in regional myocardial short-term hibernation and stunning in 435 the in situ porcine heart. Inotropic responses to postextrasystolic potentiation 436 and intracoronary calcium. Circulation 93: 1556-1566, 1996. 437 4. Hisano R and Cooper G. Correlation of force-length area with oxygen 438 consumption in ferret papillary muscle. Circ Res 61: 318-328, 1987. 439 5. Klimusina J, De Boeck BW, Leenders GE, Faletra FF, Prinzen F, Averaimo 440 M, Pasotti E, Klersy C, Moccetti T and Auricchio A. Redistribution of left 441 ventricular strain by cardiac resynchronization therapy in heart failure patients. 442 Eur J Heart Fail 13: 186-194, 2011. 20 Russell et al. 443 6. Prinzen FW, Augustijn CH, Arts T, Allessie MA and Reneman RS. 444 Redistribution of myocardial fiber strain and blood flow by asynchronous 445 activation. Am J Physiol 259: H300-H308, 1990. 446 7. Prinzen FW, Cheriex EC, Delhaas T, van Oosterhout MFM, Arts T, Wellens 447 HJJ and Reneman RS. Asymmetric thickness of the left ventricular wall 448 resulting from asynchronous electric activation: A study in dogs with ventricular 449 pacing and in patients with left bundle branch block. American Heart Journal 450 130: 1045-1053, 1995. 451 8. Prinzen FW, Hunter WC, Wyman BT and McVeigh ER. Mapping of regional 452 myocardial strain and work during ventricular pacing: experimental study using 453 magnetic resonance imaging tagging. J Am Coll Cardiol 33: 1735-1742, 1999. 454 9. Russell K, Eriksen M, Aaberge L, Wilhelmsen N, Skulstad H, Remme EW, 455 Haugaa KH, Opdahl A, Fjeld JG, Gjesdal O, Edvardsen T and Smiseth OA. 456 A novel clinical method for quantification of regional left ventricular pressure- 457 strain loop area: a non-invasive index of myocardial work. Eur Heart J 33: 724- 458 733, 2012. 459 10. Skulstad H, Edvardsen T, Urheim S, Rabben SI, Stugaard M, Lyseggen E, 460 Ihlen H and Smiseth OA. Postsystolic shortening in ischemic myocardium: 461 active contraction or passive recoil? Circulation 106: 718-724, 2002. 21 Russell et al. 462 463 464 11. Suga H. Total mechanical energy of a ventricle model and cardiac oxygen consumption. Am J Physiol 236: H498-H505, 1979. 12. Takaoka H, Takeuchi M, Odake M and Yokoyama M. Assessment of 465 myocardial oxygen consumption (Vo2) and systolic pressure-volume area 466 (PVA) in human hearts. Eur Heart J 13 Suppl E: 85-90, 1992. 467 13. Urheim S, Rabben SI, Skulstad H, Lyseggen E, Ihlen H and Smiseth OA. 468 Regional myocardial work by strain Doppler echocardiography and LV 469 pressure: a new method for quantifying myocardial function. Am J Physiol 470 Heart Circ Physiol 288: H2375-H2380, 2005. 471 14. van Oosterhout MF, Prinzen FW, Arts T, Schreuder JJ, Vanagt WY, 472 Cleutjens JP and Reneman RS. Asynchronous electrical activation induces 473 asymmetrical hypertrophy of the left ventricular wall. Circulation 98: 588-595, 474 1998. 475 476 477 478 22 Russell et al. 479 480 481 482 Table 1. Hemodynamic variables and work calculations for experimental study Baseline (n=6) LBBB (n=6) Heart rate, bpm 121±17 122±13 QRS width, ms 68±5 116±7* 1284±198 1098±189* LV EDP, mmHg 10±3 10±4 Peak LVP, mmHg 96±12 94±9 Wasted work ratio 0.13±0.05 0.37±0.11* Global measures Hemodynamic variables and WWR LV dP/dtmax, mmHg/s Regional measures Strain and work Septum Lateral Wall Septum Lateral wall -15±4 -14±4 -10±4* -11±7 Positive work, mmHg•% 1106±368 917±256 669±275 1295±615† Negative work, mmHg•% 155±134 164±102 320±288 236±170 Net Work, mmHg•% 951±320 756±266 349±346* 1059±516*† Segmental wasted work ratio 0.14±0.11 0.19±0.15 0.52±0.49* 0.18±0.09† Peak strain % Work analysis are calculated from longitudinal strain by speckle tracking echocardiography and invasively measured LVP; Septum, mid septal and anterioseptal segments; Lateral wall, mid lateral and posteriolateral segments; Values are mean±SD. LBBB, left bundle branch block; EDP, end diastolic pressure; *P<0.05 vs. baseline. † P<0.05 septum vs. lateral wall 483 23 Russell et al. 484 485 486 487 488 489 Table 2. Hemodynamic variables and non-invasive work calculation for CRT and control group of the clinical study Normals (n=20) LBBB (n=10) CRT (n=9) Heart rate, bpm 63±9 67±18 59±5 Age, years 63±8 65±7 65±6 Ejection fraction, % 60±4 29±6 42±14* QRS width, ms 90±8 171±16 145±13 0.09±0.03 0.36±0.16 0.17±0.07* Global measurements Hemodynamic variables and WWR Global Wasted work ratio Regional measurements Strain and work Septum Lateral wall Septum Lateral wall Septum Lateral wall -20±4 -19±3 -6±3 -12±5 -12±5* -12±5 Positive work, mmHg•% 2168+465 2084+327 434+202 1572+451† 1328+489* 1225+498 Negative work, mmHg•% 191+104 170+101 591+350 263+162† 212+120* 242+136 Net Work, mmHg•% 1978+483 1913+307 -158+384 1308+460† 1116+489* 983+505 Segmental wasted work ratio 0.09±0.06 0.08±0.05 1.57±0.97 0.18±0.11 0.18±0.09* 0.23±.014 Peak strain % Work analyses are calculated from longitudinal strain by speckle tracking echocardiography and estimated LV pressure curve. Septum, mid septal and anteroseptal segments; Lateral wall, mid lateral and posterolateral segments; Values are mean±SD. LBBB, left bundle branch block; EDP, end diastolic pressure; *P<0.05 LBBB vs.BVP. † P<0.05 septum vs. lateral wall 24 Russell et al. 490 491 492 Figure legends 493 494 Figure 1. Work of individual segments was calculated from the strain recordings and the left 495 ventricular pressure. Work was calculated as a function of time throughout the cardiac cycle. 496 This was done by obtaining the rate of segmental shortening (strain rate) by differentiation of 497 the strain curve (Figure 2A), and multiplying this with instantaneous left ventricular pressure 498 (Figure 2B). This resulted in a measure of instantaneous power, which was integrated over 499 time to give work as a function of time (Figure 2C). 500 501 Figure 2. Estimated LV pressure (upper panels), strain (middle panels) and calculation of 502 wasted work for septum and lateral wall (lower panels) in a representative patient with left 503 bundle branch block (LBBB) (left panel) and after treatment with cardiac resynchronization 504 therapy (CRT) (right panel). Vertical lines indicate valvular events measured by 505 echocardiography. Negative and positive work during systole is marked as red and black, 506 respectively. Wasted Work Ratios were calculated using cumulated work from mvc to mvo. 507 508 Figure 3. Representative traces from a patient with LBBB showing pressure-strain loops by 509 LVP and speckle tracking echocardiography (STE) (black line) vs. estimated LVP and STE 510 (red dotted line) for a later wall segment (A) and a septal segment (B). C. Correlation between 511 WWR by estimated LVP and STE vs. measured LVP and STE. 512 25 Russell et al. 513 Figure 4. Work analysis by LVP and speckle tracking echocardiography (STE) (solid line) vs. 514 the non-invasive method by estimated LVP and STE (dashed line), for a septal and lateral wall 515 segment in patient with the CRT device turned on and off. 516 517 Figure 5. Bulls eye plots showing segmental wasted work ratios. A: Plots from a normal 518 control and a patient with LBBB. B: Regional mean values for all patients before and after 519 CRT. WWR values > 1 implies more negative than positive work. C: Regional mean values 520 for all patients before and after CRT when assuming constant pressure and considering 521 changes in strain only. 522 523 524 525 526 527 528 529 530 531 532 533 534 535 536 537 26 Russell et al. 538 539 27 -100 0 100 -10 0 0 100 0 ”Work” 1000 (mmHg·%) 2000 0 ”Power” 5000 (mmHg·%/s) Segment shortening rate (%/s) Segment strain (%) LVP (mmHg) MVC 0.1 AVO Time (s) 0.4 AVC MVO 0.8 C.Integrate by LVP B.Multiply change sign A.Differentiate, Calculation steps LVP (mmHg) Before CRT 150 100 50 Septum Strain (%) 0 -5 Septum -10 Lateral wall -15 Work (mmHg·%) After CRT Lateral wall Ratio 0.11 Lateral Wall 1500 Lateral Wall Ratio 0.09 Ratio 0.08 1000 500 Septum Septum 0 0 0.2 mvc avo Ratio 1.51 0.4 Time (s) avc mvo 0.6 0 0.2 mvc avo Time (s) 0.4 avc mvo 0.6 Regional Wasted Work Ratio A. 0 0.05 0.13 0.04 0.10 0.05 0.25 0.04 0.78 0.06 1.32 0.06 3.72 0.00 4 0 Normal control 1.27 4 LBBB Estimated LV pressure B. 0 0.13 0.11 0.15 0.13 0.34 0.11 0.38 0.18 0.34 0.12 0.28 0.18 0.27 1.9 0 Before CRT 0.12 1.9 After CRT Constant pressure C. 0 0.29 0.36 0.29 0.36 0.50 0.39 0.48 0.40 0.43 0.30 0.39 0.34 0.43 Before CRT 1.9 0 0.30 After CRT 1.9