afterload hypersensitivity in patients with left bundle...

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Afterload Hypersensitivity in PatientsWith Left Bundle Branch Block
John Aalen, MD,a,b,c Petter Storsten, MD,a,b,c Espen W. Remme, Dr.ing., PHD,a,b Per A. Sirnes, MD, PHD,d
Ola Gjesdal, MD, PHD,c Camilla K. Larsen, MD,a,b,c Erik Kongsgaard, MD, PHD,b,c Espen Boe, MD,a,b

Helge Skulstad, MD, PHD,a,b,c,e Jonny Hisdal, PHD,e Otto A. Smiseth, MD, PHDa,b,c,e

ABSTRACT

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OBJECTIVES This study sought to investigate the hypothesis that patients with left bundle branch block (LBBB) are

hypersensitive to elevated afterload.

BACKGROUND Epidemiological data suggest that LBBB can provoke heart failure in patients with hypertension.

METHODS In 11 asymptomatic patients with isolated LBBB and 11 age-matched control subjects, left ventricular ejection

fraction (LVEF) and global longitudinal strain (GLS) were measured by echocardiography. Systolic arterial pressure

was increased by combining pneumatic extremity constrictors and handgrip exercise. To obtain more insight into

mechanisms of afterload response, 8 anesthetized dogs with left ventricular (LV) micromanometer and dimension

crystals were studied during acutely induced LBBB and aortic constriction. Regional myocardial work was assessed by LV

pressure-dimension analysis.

RESULTS Consistent with normal afterload dependency, elevation of systolic arterial pressure by 38 � 12 mm Hg

moderately reduced LVEF from 60 � 4% to 54 � 6% (p < 0.01) in control subjects. In LBBB patients, however, a similar

blood pressure increase caused substantially larger reduction in LVEF (p < 0.01), from 56 � 6% to 42 � 7% (p < 0.01).

There were similar findings for GLS. In the dog model, aortic constriction abolished septal shortening (p < 0.02), and

septal work decreased to negative values (p < 0.01). Therefore, during elevated systolic pressure, the septum made no

contribution to global LV work, as indicated by net negative work, and instead absorbed energy from work done by the

LV lateral wall.

CONCLUSIONS Moderate elevation of arterial pressure caused marked reductions in LVEF and GLS in patients with

LBBB. This reflects a cardiodepressive effect of elevated afterload in the dyssynchronous ventricle and was attributed to

loss of septal function. (J Am Coll Cardiol Img 2018;-:-–-) © 2018 by the American College of Cardiology Foundation.

L eft bundle branch block (LBBB) is relativelycommon in patients with congestive heart fail-ure and is associated with reduced left ven-

tricular (LV) function and increased mortality (1).Asymptomatic individuals with structurally normalhearts can also have LBBB, and the prevalence in-creases with age (2). These subjects are at increasedrisk of developing cardiovascular disease, including

m the aInstitute for Surgical Research, Oslo University Hospital, Riksh

ovation, Oslo University Hospital, Rikshospitalet, Oslo, Norway; cDep

shospitalet, Oslo, Norway; dOstlandske Hjertesenter, Moss, Norway; an

lo, Oslo, Norway. Dr. Aalen was supported by a grant from the Norweg

rsen were recipients of clinical research fellowships from the South-Ea

iseth is co-inventor but no longer has ownership of the patent “Method

ed to calculate myocardial work in the clinical study. All other autho

evant to the contents of this paper to disclose.

nuscript received August 31, 2017; revised manuscript received Novembe

congestive heart failure, which might reflect progres-sion of underlying cardiac disease (3). An alternativemechanism of heart failure may be a negative effectof LBBB on cardiac function, potentially actingtogether with other cardiovascular disturbances(4–6). As observed in the LIFE (Losartan Interventionfor Endpoint Reduction in Hypertension) study,which followed more than 500 patients with LBBB

ospitalet, Oslo, Norway; bCenter for Cardiological

artment of Cardiology, Oslo University Hospital,

d the eInstitute of Clinical Medicine, University of

ian Health Association. Drs. Storsten and Kjellstad

stern Norway Regional Health Authority. Professor

for myocardial segment work analysis,” which was

rs have reported that they have no relationships

r 15, 2017, accepted November 16, 2017.

https://doi.org/10.1016/j.jcmg.2017.11.025

TABLE 1 Baseline Characteristics: Clinical Study

ControlSubjects(n ¼ 11)

LBBBPatients(n ¼ 11)

Age, yrs 60 � 10 62 � 8

Male 5 5

Height, cm 176 � 10 172 � 11

Weight, kg 78 � 15 79 � 11

Past history

Hypertension 2 3

Paroxysmal atrial fibrillation 0 1

Medication

ACE inhibitor/ARB 2 3

Beta-blocker 0 3

ABBR EV I A T I ON S

AND ACRONYMS

CRT = cardiac

resynchronization therapy

GLS = global longitudinal

strain

LA = left atrial

LBBB = left bundle branch

block

LV = left ventricular

LVEF = left ventricular ejection

fraction

LVP = left ventricular pres

Aalen et al. J A C C : C A R D I O V A S C U L A R I M A G I N G , V O L . - , N O . - , 2 0 1 8

Afterload Sensitivity in Left Bundle Branch Block - 2 0 1 8 :- –-

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for nearly 5 years, the combination of LBBBand hypertension was associated with a 2-fold higher risk of hospitalization for heartfailure compared with hypertensive controlpatients (7). This may suggest that ventricleswith LBBB have reduced tolerance to arterialhypertension, which is consistent with theobservation that LBBB leads to impaired LVfunction (8,9) and therefore is expected torender the ventricle more sensitive to after-load elevation (10,11).

The general objective of the present studywas to investigate LV mechanical response to

Calcium-channel blockers 1 1

Loop diuretic agents 0 0

Aldosterone antagonists 0 0

Smoking 1 1

Sinus rhythm 11 11

QRS duration, ms 98 � 20 147 � 9*

Echocardiographic dimensions at enddiastole, mm

Septum 9 � 1 10 � 1

LV internal diameter 50 � 6 53 � 4

LV posterior wall 8 � 1 8 � 1

Values are mean � SD or n. *p < 0.05 vs. control subjects.

ACE ¼ angiotensin-converting enzyme; ARB ¼ angiotensin II receptor blocker;LBBB ¼ left bundle branch block; LV ¼ left ventricular.

elevated afterload in patients with LBBB. The specificobjectives were to: 1) determine to what extent acuteelevation of arterial pressure in patients with LBBBcauses more reduction in global LV function than incontrol subjects with normal electrical conduction;and 2) investigate how the early-activated septumand the late-activated LV free wall contribute to theresponse. As measures of global LV function, we usedleft ventricular ejection fraction (LVEF) and globallongitudinal strain (GLS). Furthermore, segmentalfunction was studied by use of a noninvasive leftventricular pressure (LVP) estimate and segmentalwork by pressure-strain analysis. Patients with LBBBand preserved LV systolic function were comparedwith control subjects of similar age. Blood pressureelevation was induced by a combination ofextremity cuff inflation and handgrip exercise. In anexperimental LBBB model, we studied afterload re-sponses by LVP-segment length analysis, which isconsidered the gold standard for assessment of LVfunction.

METHODS

CLINICAL STUDY. Study population. Eleven patients(62 � 8 years of age) with LBBB were recruitedthrough an outpatient cardiology practice, and acontrol group of 11 individuals of similar age (60 � 10years) were recruited through voluntary enrollmentin the community (Table 1). LBBB was definedaccording to Strauss et al. (12). All patients were insinus rhythm. One subject in the control group hadcomplete right bundle branch block. Medical history,clinical examination, electrocardiogram, and echo-cardiography were obtained in all participants.Patients with coronary artery disease were excluded.

The study was approved by the regional ethicscommittee, and written informed consent was ob-tained from all study participants.Echocardiography and strain analysis. Two-dimensionalgray-scale echocardiographic recordings were

sure

conducted during baseline and increased afterloadusing apical 2-, 3-, and 4-chamber views (Vivid E9, GEVingmed Ultrasound, Horten, Norway). In addition,during baseline, 2-dimensional gray-scale imageswere obtained in the parasternal long-axis view tomeasure LV dimensions. Doppler echocardiographywas used to assess heart valve function. Ventricularvolumes and LVEF were calculated by the biplaneSimpson method.

Global and segmental strain analyses were per-formed off-line with speckle tracking echocardiogra-phy (Echopac, GE Vingmed Ultrasound). Averageframe rate was 59 � 6/s. Segmental strains from theseptum and LV lateral wall were calculated as theaverage end-systolic value from single wall analysisin the apical 4-chamber view.Estimation of regional work. An index of segmentalmyocardial work was calculated by LV pressure-strainanalysis using a semiautomated analysis tool (Echo-pac, version 202, GE Vingmed Ultrasound). Themethod, which includes a noninvasive estimate ofLVP, was validated previously and has been describedin detail (13). The work index (mm Hg$%) was calcu-lated by multiplying the rate of segmental shortening(strain rate) with instantaneous LVP. This resulted ina measure of instantaneous power, which was inte-grated over time to give work as a function of time in

FIGURE 1 Clinical Experiment

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J A C C : C A R D I O V A S C U L A R I M A G I N G , V O L . - , N O . - , 2 0 1 8 Aalen et al.- 2 0 1 8 :- –- Afterload Sensitivity in Left Bundle Branch Block

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systole, defined as the time interval from mitral valveclosure to mitral valve opening (14).

In the present study, the net work for amyocardial segment was calculated as the sum ofpositive and negative work. Normally, LV segmentsshorten in systole when LVP is rising, and bydefinition do positive work. A segment that be-comes elongated in systole when LVP is rising,by definition does negative work because itis stretched as a result of contraction in othersegments.Elevation of afterload. Afterload was elevated bycombining 30 s of isometric handgrip exercise (80% ofmaximum voluntary contraction) performed by theright hand with inflation of cuffs placed around the 2lower extremities and the right upper extremity.Simultaneous with handgrip exercise, the bloodpressure cuffs were inflated to suprasystolic pressureto cause compression of extremity arteries. In a pilotstudy, the combined intervention was shown to givehigher blood pressure than either of the methodsalone. Arterial blood pressure was continuouslyrecorded during the intervention by a photo-plethysmographic pressure recording device

(Finometer, FMS Finapres Medical System, Amster-dam, the Netherlands) placed at the left hand. Thepressure recording device was calibrated againstbrachial blood pressure. The intervention wasrepeated to obtain echocardiographic images fromone apical view at a time, which allowed us to useheart beats with similar timing and afterload whenmeasuring LVEF and GLS. Figure 1 shows recordingsfrom a representative individual.EXPERIMENTAL STUDY. Animal preparation. Eightmongrel dogs of either sex and with a body weight of34 � 2 kg were anesthetized by use of barbituratesand opioids (n ¼ 7; thiopentone 25 mg/kg andmorphine 100 mg IV, followed by infusion ofmorphine 50 to 100 mg/h and pentobarbital 50 mg IVevery hour) or, because of change of anesthetic pro-tocol in our laboratory, propofol and opioids (n ¼ 1;single dose of methadone 0.2 mg/kg, followed bypropofol 3 to 4 mg/kg and a bolus of fentanyl 2 to3 mg/kg, then a continuous infusion of propofol 0.2 to1 mg/kg/min and fentanyl 5 to 40 mg/kg/h). The ani-mals were ventilated and surgically prepared asdescribed previously (15). To increase afterload, aninflatable silicone occluder was placed around the

TABLE 2 Data During Normal and Elevated Afterload: Clinical Study

Control Subjects (n ¼ 11) LBBB Patients (n ¼ 11)

ANOVABaseline Elevated Afterload Baseline Elevated Afterload

Heart rate, beats/min 68 � 10 88 � 13* 69 � 11 92 � 16* NS

Systolic blood pressure, mm Hg 137 � 23 175 � 28* 135 � 16 169 � 23* NS

Diastolic blood pressure, mm Hg 79 � 7 103 � 10* 77 � 7 103 � 13* NS

LV end-diastolic volume, ml 101 � 19 99 � 24 111 � 25 111 � 21 NS

LV end-systolic volume, ml 40 � 10 46 � 15 49 � 12 63 � 14*† p < 0.01

LV stroke volume, ml 61 � 10 53 � 13* 62 � 17 47 � 12* NS

LV ejection fraction, % 60 � 4 54 � 6* 56 � 6 42 � 7*† p < 0.01

Global longitudinal shortening, % 20.8 � 2.5 18.4 � 2.4* 17.1 � 2.2† 12.4 � 1.8*† p < 0.01

Septal systolic shortening, % 18.3 � 2.6 14.7 � 3.1* 11.7 � 3.8† 6.3 � 4.6*† NS

LV lateral wall systolic shortening, % 18.4 � 3.9 16.7 � 3.6 16.7 � 3.7 13.6 � 5.6 NS

Septal work, mm Hg$% 4,521 � 1,179 4,819 � 1,467 2,236 � 6,93† 1,107 � 856*† p < 0.01

LV lateral wall work, mm Hg$% 4,048 � 898 5,206 � 1,849* 4,113 � 937 4,474 � 1,290 NS

Values are mean � SD. *p < 0.05 vs. normal afterload. †p < 0.05 vs. control subjects. ANOVA refers to the interaction effect from a mixed between-within subjects ANOVA.

ANOVA ¼ analysis of variance; NS ¼ nonsignificant; other abbreviations as in Table 1.



4

ascending aorta. The National Animal Experimenta-tion Board approved the study. The animals weresupplied by the Center for Comparative Medicine(Oslo University Hospital, Rikshospitalet, Oslo,Norway).Pressures, dimensions, and electromyograms. Aortic, LV,and left atrial (LA) pressures were measured by 5-Fmicromanometer-tipped catheters (model MPC 500,Millar Instruments Inc., Houston, Texas). The LV andLA micromanometers were zero referenced to LApressure measured via a fluid-filled line during dia-stasis, using postextrasystolic beats with longdiastoles.

LV dimensions were measured as circumferentialsegment lengths by sonomicrometry using 2-mm-wide crystals (Sonometrics Corporation, London,Ontario, Canada) implanted in the inner third of themyocardium in the interventricular septum and in theposterior, anterior, and lateral LV walls. The ultra-sonic crystals were combined with a bipolar electrodefor recording of intramyocardial electromyograms.Data were sampled at 200 Hz.Experimental protocol. Induction of LBBB (OnlineFigure 1) was performed by radiofrequency ablationas described previously (16). Response to elevatedafterload by aortic constriction was studied shortlybefore and soon after induction of LBBB. By recordingbeat-to-beat changes at onset of aortic constriction,we could study direct afterload responses with min-imal influence from reflexes induced by the proced-ure. Data were recorded with the ventilatortemporarily switched off.Data analysis. Segmental work was obtained by asimilar principle as in the clinical study, but with themicromanometer instead of an estimate of LVP and

absolute dimensions by sonomicrometry instead ofpercentage strain. Net systolic shortening wasmeasured as end-diastolic minus end-systolicdimension. End diastole was defined as onset of theseptal electromyogram.

STATISTICAL ANALYSIS. Values are presented asmean � SD. Comparisons between 2 groups wereperformed with independent-samples t tests,whereas comparisons within the same group wereperformed by paired-samples t tests. Bonferronicorrection was applied to adjust for testing in 2groups. In Tables 2 and 3, significance of the interac-tion effect from an analysis of variance was reportedto highlight differences in afterload effect betweenLBBB and control conditions. A value of p < 0.05 wasconsidered significant. SPSS version 24.0 (SPSS Inc.,Chicago, Illinois) was used for the analyses.

RESULTS

CLINICAL STUDY. Characteristics of the study par-ticipants are provided in Table 1. None of the subjectshad more than mild valvular regurgitation.

There were no significant differences between thegroups in LV dimensions, volumes, or LVEF; how-ever, dimensions and volumes tended to be largerand LVEF somewhat lower in the LBBB group(Tables 1 and 2). LV longitudinal shortening by GLSwas 17.1 � 2.2% in the LBBB group compared with20.8 � 2.5% in the control group (p < 0.01). In theLBBB group, septal systolic shortening was 11.7 �3.8% compared with 18.2 � 2.6% in the control group(p < 0.01). There were also markedly lower values forseptal work in LBBB patients than in control subjects(Table 2). In the LV lateral wall, however, the work

TABLE 3 Hemodynamic Variables for All Animals Before (Controls) and After Induction of LBBB

Controls (n ¼ 8) LBBB (n ¼ 8)

ANOVABaseline Aortic Constriction Baseline Aortic Constriction

Heart rate, beats/min 124 � 16 122 � 17 127 � 15 126 � 15 NS

QRS duration, ms 54 � 5 55 � 5 112 � 10† 113 � 6† NS

LV pressure maximum, mm Hg 100 � 12 125 � 18* 94 � 10 118 � 16* NS

LV end-diastolic pressure, mm Hg 10 � 3 11 � 4* 11 � 3 13 � 4* NS

Minimum LV pressure, mm Hg 6 � 3 8 � 3* 8 � 3† 11 � 4*† p < 0.05

Tau, ms 36 � 5 41 � 7* 45 � 8† 51 � 10† NS

LV dP/dtmax, mm Hg/s 1,303 � 230 1,318 � 195 1,037 � 160† 1,127 � 197*† NS

LV stroke volume, ml 17 � 4 14 � 2* 16 � 4 11 � 4* NS

LV stroke work, mm Hg$ml 1,259 � 412 1,126 � 442 1,052 � 411 846 � 575 NS

Septal systolic shortening, mm 2.4 � 0.7 1.8 � 0.6* 1.2 � 0.5† 0.0 � 0.8*† p < 0.05

LV lateral wall systolic shortening, mm 4.8 � 2.0 4.1 � 1.8* 4.9 � 1.7 4.4 � 1.3 NS

Septal work, mm Hg$mm 496 � 161 440 � 224 78 � 171† �161 � 160*† p < 0.05

LV lateral wall work, mm Hg$mm 576 � 200 478 � 183 655 � 167 610 � 301 NS

Values are mean � SD. *p < 0.05 vs. normal afterload. †p < 0.05 vs. controls. Dimension data are circumferential. ANOVA refers to the interaction effect from a 2-wayrepeated-measures ANOVA.

dP/dtmax ¼ maximum rate of rise of left ventricular pressure; tau ¼ time constant of left ventricular relaxation; other abbreviations as in Tables 1 and 2.


5

index showed similar values in LBBB patients andcontrol subjects.

Cuff inflation in combination with handgrip effortresulted in increases in systolic blood pressure of 34� 13 and 38 � 12 mm Hg in LBBB patients and con-trol subjects, respectively (p ¼ NS). There was nochange in QRS duration, but a moderate increase inheart rate in the 2 groups (22 � 10 compared with 20� 11 beats/min in LBBB patients and control subjects,respectively; p ¼ NS). As illustrated in Figure 2, theeffect of elevated afterload on LVEF and GLS wasdifferent in the 2 groups. In the control group,elevation of systolic pressure was associated withmoderate reductions in LVEF (from 60 � 4% to 54 �6%; p < 0.01) and in GLS (from 20.8 � 2.5% to 18.4 �2.4%; p < 0.01). In LBBB patients, however, therewere marked reductions in LVEF (from 56 � 6% to 42� 7%; p < 0.01) and in GLS (from 17.1 � 2.2% to 12.4� 1.8%; p < 0.01). In absolute terms, the reduction inLVEF was 14% in patients with LBBB compared with7% in control subjects (95% confidence interval: 11%to 17% and 3% to 10%, respectively; p < 0.01), andthe reductions in GLS were 4.7% and 2.3% (95%confidence interval: 3.7% to 5.7% and 1.0% to 3.6%,respectively; p < 0.01). There was a similar trend instroke volume reduction (15 � 10 ml compared with8 � 6 ml in LBBB patients and control subjects,respectively).

As illustrated in Figure 2, the reduction in GLS withelevated afterload in patients with LBBB was attrib-uted to reduced septal function. There was reductionin systolic shortening from 11.7 � 3.8% to 6.3 � 4.6%(p < 0.01) (Table 2), which was attributed to reduction

in shortening during the LV ejection phase (p < 0.01)and a trend toward increased early systolic length-ening. In LBBB patients, septal contraction duringelevated afterload was highly inefficient, because thepressure-strain loops showed clockwise rotationduring a large portion of systole, which implies sys-tolic lengthening and therefore a large component ofnegative work (Figure 3C). The result was a markeddecrease in net septal work during elevation ofafterload (Table 2). Myocardial work in the lateral wallwas maintained, although systolic shortening tendedto decrease (Table 2).EXPERIMENTAL STUDY. Induction of LBBB causeddepression of global LV function, as indicated by amoderate fall in maximum rate of rise of LVP (LV dP/dtmax) (p < 0.01), and there was a marked reductionin septal systolic shortening (Table 3). In contrast topatients, there was no accompanying tachycardiasuggesting reflex activation during increasedafterload.

Aortic constriction increased LV systolic pressureby 24 � 12 and 24 � 11 mm Hg before and afterinduction of LBBB, respectively. Before LBBB, aorticconstriction caused only moderate reductions inseptal and LV lateral wall systolic shortening(Table 3). During LBBB, however, aortic constrictioncaused a marked reduction in septal systolic short-ening (p < 0.02) because of reduced shorteningduring LV ejection (p < 0.01) (Figure 4). There wasalso a trend toward an increase in systolic length-ening, in particular early-systolic lengthening,which contributed to the reduction in systolicshortening during aortic constriction. An increase in

FIGURE 2 Response to Increased Afterload

Septum LV Lateral Wall

-24

–20

–16

–12

120 150

p < 0.01

p < 0.01

180Systolic Blood Pressure (mm Hg)

Healthy Controls

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(Top) LV systolic function by LV ejection fraction and global longitudinal strain at baseline and during elevated LV afterload (mean � SD). Note the marked

decline in LV ejection fraction and global longitudinal strain among LBBB patients, which differs significantly from the moderate decline seen in control

subjects. (Bottom) Representative strain traces showing response to increase in LV afterload. In control subjects, elevation of afterload caused moderate

reductions in systolic shortening in septum and LV lateral wall. In LBBB patients, however, elevation of afterload caused marked reduction in septal

shortening, and this was mainly due to reduction in shortening during LV ejection. Systolic shortening was measured at AVC. AVC ¼ aortic valve closure;

AVO ¼ aortic valve opening; BP ¼ blood pressure; LBBB ¼ left bundle branch block; LV ¼ left ventricular; MVC ¼ mitral valve closure; MVO ¼mitral valve

opening.



6

systolic lengthening implies increased negativeseptal work (p < 0.05), and a reduction in septalshortening implies less positive work (p < 0.02); theresult was a shift from net positive to net negativeseptal work (p < 0.01) (Figure 3D, Figure 5, and Ta-ble 3). LV lateral wall shortening and work, how-ever, were maintained during aortic constriction.Septal pre-ejection shortening was unaffected byelevated afterload.

As shown in Table 3, responses in the time constant(tau) of LV relaxation and LV end-diastolic pressurewere similar during control conditions and LBBB.Minimum LVP, however, increased modestly butsignificantly more during LBBB.

DISCUSSION

The present study demonstrates increased afterloadsensitivity in patients with LBBB and preservedLV systolic function, as indicated by markedreductions in LVEF and GLS in response to moderateelevation of systolic arterial pressure. When subjectswithout LBBB were exposed to a similar risein arterial pressure, they showed only moderatereductions in LVEF and GLS, consistentwith normal afterload dependency of myofibershortening (17,18). This observation may haveimpact on strategies for management of patientswith LBBB.


7

MECHANISM OF REDUCTION IN SYSTOLIC FUNCTION

DURING ELEVATED AFTERLOAD. Consistent withprevious studies, we found impaired LV systolicfunction (8,9) and abnormal septal motion in patientswith LBBB (19). The cardiodepressive effect ofelevated afterload was attributed to aggravation ofseptal dysfunction, which included reduction inseptal shortening during LV ejection and septal sys-tolic lengthening. The responses to elevated arterialpressure in patients were reproduced in the experi-mental model, which provided a measure ofmyocardial segment length and not just strain.

When evaluating myocardial function in terms ofregional work, we confirmed the results of previousstudies that have shown markedly reduced work inthe septum during LBBB and during pacing-inducedLV dyssynchrony (13,20,21). In the clinical study,elevation of afterload caused further reduction inseptal work, in part because of increased negativeseptal work, which reflects septal lengthening causedby contractions in the LV lateral wall. In the dogmodel, septal work was converted to net negativevalues during elevation of afterload, which impliesthat the septum made no contribution to global LVwork but instead absorbed energy from work done inthe LV free wall. Myocardial work in the LV lateralwall was maintained during aortic constriction.Therefore, in patients with LBBB, the LV lateral wallcarries a relatively larger mechanical burden than innormal hearts, and this imbalance was even strongerduring elevated afterload. The additional workloadon the LV lateral wall when LBBB is combined withhypertension may represent a stimulus to remodeling(22). A similar mechanism could explain upregulationof proteins involved in myocardial hypertrophy inlate activated myocardium in dyssynchronous ven-tricles (23).

It was suggested in previous studies that the as-sociation between LBBB and congestive heart failurein otherwise apparently healthy individuals reflectsprogression of coexisting subclinical myocardial dis-ease (3,24). As shown in the present study, responseto elevated afterload during LBBB in the acute dogmodel was in principle similar to the response in pa-tients, which excludes that the increased afterloadsensitivity was entirely caused by preexisting orsubclinical myocardial dysfunction. Instead thissupports the notion that LV afterload hypersensitiv-ity is a direct consequence of LBBB itself.

CLINICAL IMPLICATIONS. The observation that amoderate acute elevation of aortic pressure caused amarked reduction in LVEF in patients with LBBBraises the question whether such patients are more

vulnerable to arterial hypertension. Potentially, theincreased risk of congestive heart failure for hyper-tensive patients with LBBB (7) is attributable toafterload-induced LV dysfunction in a ventricle withincreased sensitivity to afterload. If there is a similarresponse to chronic elevation of arterial pressure, thegrossly abnormal septal function and altered LV freewall function could lead to remodeling and precipi-tation of heart failure. There is need for future studiesto examine whether antihypertensive treatment hasbeneficial effects on LV contractile function in pa-tients with LBBB and whether treatment goals shouldbe stricter than for hypertensive patients in general.

The reductions in LVEF and GLS in response toelevated afterload in individuals without LBBB isconsistent with normal myocardial physiology (17).Afterload dependency is a known limitation of allejection phase indices of LV systolic function,including GLS (15). The augmented afterload sensi-tivity during LBBB could make interpretation of LVsystolic function more challenging in this group ofpatients. If similar afterload dependency exists forheart failure patients with LBBB, it could be impor-tant to take blood pressure into account when usingLVEF as a criterion for selection of patients for cardiacresynchronization therapy (CRT). In 4 of 11 patientswith LBBB, there was a fall in LVEF to values less than40% with elevated arterial pressure, which ap-proaches the levels of LVEF when CRT may beindicated.

To improve responder rates, different septaldeformation patterns have been suggested as pre-dictors of CRT response (25–27). The finding thatseptal motion is highly affected by differences inafterload suggests that arterial blood pressure shouldbe taken into account when evaluating patients forCRT based on such patterns.

STUDY LIMITATIONS. In the clinical study, afterloadwas increased by a procedure that activated reflexes,thereby increasing sympaticoadrenal tone (28). Thiswas reflected in the accompanying tachycardia andunchanged end-diastolic volume, which means theFrank-Starling mechanism was not activated. There-fore, this was not a pure afterload intervention. In thedog model, however, we confirmed that responsesto elevated afterload were immediate, occurring asbeat-to-beat changes, and therefore could not beattributed to reflex responses but reflected directmechanical interactions between afterload and con-tracting myofibers.

Measurement of arterial blood pressure at thefinger could have overlooked effects from the presentintervention on arterial wave reflection and pressure

FIGURE 3 Pressure-Strain and Pressure-Dimension Loops During Afterload Elevation

Clinical StudyA B Experimental StudyBaseline Increased Afterload Baseline Increased Afterload

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Time (s)

120

LVP

(mm

Hg)

60

00.0 0.5

Time (s)

120

60

00.0 0.5

Time (s)

180

LVP

(mm

Hg)

90

0–20 –10 0

LV Lateral Wall Strain (%) LV Lateral Wall Strain (%)

180

90

0–20 –10 0

120LV

P (m

m H

g)

60

041 43 45

LV Lateral WallSegment Length (mm)


120

60

041 43 45

Positive WorkPositive Work

LVP

(mm

Hg)

180

90

0–20 –10 0

Septal Strain (%) Septal Strain (%)

180

90

0–20 –10 0

LVP

(mm

Hg)

120

60

031 32 33

Septal Segment Length (mm) Septal Segment Length (mm)

120

60

031 32 33


(A) Clinical study: representative pressure-strain loops from a control subject during baseline and increased afterload. The area of the loops reflects myocardial work.

All loops show counterclockwise rotation (arrow), which indicates positive work. (B) Experimental study: representative pressure-length loops from a dog during

control conditions. The response to increased afterload is similar to that in the clinical study. (C) Clinical study: representative pressure-strain loops from a patient with

LBBB during baseline and increased afterload. For the LV lateral wall, the loops (lower panels) show positive work similar to control subjects. The septal pressure-

strain loop, however, with a disturbed shape during baseline, demonstrates clockwise rotation during elevated afterload, which implies negative work during part of

systole. (D) Experimental study: representative pressure-length loops from a dog after induction of LBBB. Note that response to elevated afterload by pressure-length

loops constructed from invasive LVP and segment lengths resembles observations in the clinical study, in which loops were constructed from noninvasive LV pressure

and strain (C). LVP ¼ left ventricular pressure; other abbreviations as in Figure 2.

Continued on the next page



8

augmentation and thereby included an error in theassessment of central blood pressure. However,because the main objective was to apply a similarafterload increase in patients with LBBB and controlsubjects, the absolute numbers for systolic and dia-stolic blood pressure were not essential.

Myocardial work was calculated with LVP as asubstitute for force. Measurement of force wouldhave been optimal but is complicated, because radiusof curvature and wall thickness change continuouslyduring the heart cycle. In a previous experimentalstudy from our laboratory, we showed that pressure-length loops during myocardial ischemia reflectedmyocardial work measured from force-segmentlength loops (29). In a validation study in LBBB, wefound excellent correlations between the noninvasive

work estimate and work by pressure-length analysisin a dog model and against LVP by micromanometerand strain in a clinical study (13). However, becausestrain is a relative measure, caution should be exer-cised when comparing work by pressure-strain anal-ysis from hearts with different sizes. In the presentstudy, we confirmed a detrimental effect of elevatedafterload on septal work when using sonomicrometryto measure absolute dimension.

In the experimental study, we assessed animalsthat were heavily instrumented and during generalanesthesia, both of which can cause deterioration incardiac function. Furthermore, we cannot excludethat myocardial function might have deterioratedduring the time that elapsed between control andLBBB conditions. However, when control conditions

FIGURE 3 Continued

Clinical StudyC D Experimental StudyBaseline Increased AfterloadBaseline

100

50

LVP

(mm

Hg)

00.0

Time (s)0.5

100

50

00.0

Time (s)0.5

150

75

LVP

(mm

Hg)

00.0

Time (s)0.5

150

75

00.0

Time (s)0.5

Increased Afterload


LVP

(mm

Hg)


100

50

040 43 46


100

50

040 43 46

LVP

(mm

Hg)

150

75

0–25 –10

LV Lateral Wall Strain (%)5

LV Lateral Wall Strain (%)

150

75

0–25 –10 5

Positive Work Negative Work Positive Work Negative WorkLV

P (m

m H

g)

Septal Segment Length (mm)

100

50

031 32 33

Septal Segment Length (mm)

100

50

031 32 33

LVP

(mm

Hg)

140

70

0–18 –9

Septal Strain (%)0

Septal Strain (%)

140

70

0–18 –9 0

FIGURE 4 Segmental Strain Traces During Normal and Elevated Afterload

Experimental StudyControl

100

50

LVP

(mm

Hg)

00.0

Time (s)0.4

Baseline

100

50

00.0

Time (s)0.4

Increased Afterload

LBBB

100

50

00.0

Time (s)0.4

Baseline

100

50

00.0

Time (s)0.4

Increased Afterload

5 MVC MVOAVO AVC

–5

Stra

in (%

)

0.0

–15

Time (s)0.4

MVC AVO MVOAVC5

–5

0.0

–15

Time (s)0.4

MVC AVO MVOAVC5

–5

0.0

–15

Time (s)0.4

MVC AVO MVOAVC5

–5

0.0

–15

Time (s)0.4

LV Lateral Wall Septum

Strain and LV pressure traces from the same animal before and after induction of LBBB. Similar to the clinical study, elevation of afterload caused only moderate

reduction in septal systolic shortening during control conditions, whereas there was a marked reduction during LBBB. Abbreviations as in Figures 2 and 3.


9

FIGURE 5 Segmental Work Distribution During Normal and

Elevated Afterload

800

*

Control LBBB

400

Wor

k (m

m H

g·m

m)

0

–400Septum LV Lateral Wall Septum LV Lateral Wall

Baseline *p < 0.05 vs. BaselineIncreased Afterload

*

Experimental study: septal and LV lateral wall work displayed during

baseline (solid bar) and increased afterload (open bar) before and after

induction of LBBB. There is uneven segmental work distribution in LBBB, in

which septal work is markedly reduced. Increased afterload causes septal

work to become negative, which indicates that the septum absorbs work

performed by the LV lateral wall. Abbreviations as in Figure 2.

PERSPECTIVES

COMPETENCY IN MEDICAL KNOWLEDGE:

Patients with LBBB are less tolerant to acute

elevations of blood pressure.

COMPETENCY IN PATIENT CARE AND

PROCEDURAL SKILLS: When evaluating patients

for CRT, the clinician should be aware that moderate

fluctuations in blood pressure, which occur frequently

in daily clinical practice, may have a significant impact

on LVEF and thus on the decision whether CRT is

indicated.

TRANSLATIONAL OUTLOOK 1: There is a need for

prospective trials to evaluate whether treatment

goals for hypertension should be different in patients

with LBBB.

TRANSLATIONAL OUTLOOK 2: Future studies

should emphasize whether LVEF and GLS are less

reliable markers for changes in systolic function in

patients with LBBB.



10

and LBBB were compared, there were no significantreductions in global LV function given as stroke work,stroke volume, and LV end-diastolic pressure, whichindicates limited deterioration.

CONCLUSIONS

The present study demonstrated marked reductionsin LVEF and GLS in response to a moderate elevationof blood pressure in individuals with LBBB and pre-served LV systolic function, and this response farexceeded reductions in LVEF and GLS when afterloadwas elevated in a control population. The mechanismof this exaggerated afterload response during LBBB

was septal dysfunction. Future studies shouldexplore whether a similar interaction between after-load and LV contractile function occurs in heartfailure patients with LBBB.

ACKNOWLEDGMENTS The authors thank Dr. AndersOpdahl, Dr. Kristoffer Russell, and Surgical NurseAurora Pamplona for their contribution to the animalexperiments.

ADDRESS FOR CORRESPONDENCE: Dr. Otto A.Smiseth, Department of Cardiology, Oslo UniversityHospital, Rikshospitalet, N-0027 Oslo, Norway.E-mail: [email protected].

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KEY WORDS dyssynchrony, heart failure,hypertension, left bundle branch block,myocardial work, strain

APPENDIX For a supplemental figure, pleasesee the online version of this article.






























































































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