Selecting Patients for Cardiac Resynchronization Therapy: Electrical or Mechanical Dyssynchrony?

Nathaniel M. Hawkins

Mark C. Petrie

John J.V. McMurray

Cardiac resynchronization therapy (CRT) improves functional status and reduces hospitalizations and mortality in patients with heart failure (HF). In the pivotal large, randomized trials, patients were selected on the basis of three main criteria: impaired functional status (New York Heart Association class III or IV), reduced left ventricular ejection fraction (≤ 0.35), and prolonged QRS duration (≥ 120 milliseconds). The latter was considered a marker of underlying ventricular dyssynchrony (so-called “electrical dyssynchrony”) (Table 4.1). Consequently, international guidelines recommend CRT based on the electrocardiographic (ECG) inclusion criteria in those trials.¹

Some have stated that around one-third of patients appear not to improve clinically or exhibit favorable echocardiographic remodeling (so-called “nonresponders”). It has been proposed that echocardiography may better identify those likely to respond to treatment by measuring actual mechanical dyssynchrony.² If correct, this alternate approach to patient selection has two important clinical consequences. First, nonresponders with a broad QRS would be spared an ineffective and invasive procedure, with resultant cost savings to health care providers. Conversely, patients with mechanical dyssynchrony but a narrow QRS complex, who were excluded from the landmark clinical trials, may benefit from CRT.

We review the meaning and measurement of electrical and mechanical dyssynchrony, the strengths and weaknesses of echocardiographic indices of dyssynchrony, and the controversial issue of predicting response to treatment. How valid is the concept of responders versus nonresponders? Should patients eligible for treatment based on inclusion criteria for clinical trials be excluded from that treatment in clinical practice? Why is such an approach advocated for devices but not for drug therapy?

ELECTRICAL DYSSYNCHRONY

What Is Electrical Dyssynchrony?

The QRS complex represents the vectorial sum of electrical forces generated by myocardial masses over time. Normal electrical activation propagates as a uniform high-velocity wavefront through the myocardial Purkinje network. In damaged myocardium, altered conduction properties impair the velocity and direction of electrical propagation. Abnormal ventricular depolarization, manifesting as QRS prolongation, generates regions of both early and delayed ventricular contraction. The delayed segments accommodate contractile force and volume, reducing systolic function.

Why Is Electrical Dyssynchrony Important?

A direct relationship exists between QRS duration and ejection fraction.³^,⁴^,⁵ Prevalence of bundle branch block (BBB) varies from around 20% in the general HF population³^,⁴ to 35% among patients with more severely impaired systolic function.⁵^,⁶ BBB is a powerful independent predictor of mortality,⁶ with no evidence of any threshold effect at 120 ms.⁷ QRS duration has been the principal entry point to all major CRT trials to date (Table 4.1). International guidelines recommend CRT in patients with medically refractory, symptomatic (NYHA III/IV) heart failure, with prolonged QRS duration ≥ 120 msec, and ejection fraction ≤ 35%.¹ Simultaneous biventricular (BiV) pacing resynchronizes both intraand interventricular contraction. The result is hemodynamic improvement,⁸^,⁹^,¹⁰^,¹¹ reduced mitral regurgitation,¹² and reversal of maladaptive remodeling.¹³^,¹⁴^,¹⁵^,¹⁶ CRT improves symptoms, quality of life and functional class,¹⁷ increases exercise tolerance,¹⁷^,¹⁸^,¹⁹^,²⁰ and reduces hospitalizations and mortality.²¹^, ²²

Baseline QRS duration consistently fails to predict response (Table 4.2). However, change in QRS duration (ΔQRS) following CRT differs significantly between responders and

nonresponders in a number of studies.²³^,²⁴^,²⁵^,²⁶ This correlation between QRS narrowing and clinical efficacy suggests that after LV lead implantation, positioning the RV lead to produce maximal QRS shortening may improve resynchronization.²⁶ In 139 consecutive patients, δQRS was an independent predictor of response after multivariate adjustment. The RV lead was positioned for maximum reduction in QRS duration at the apex, septum, anterior wall, or RV outflow tract, guided by intra-operative biventricular pace mapping.²³

TABLE 4.1 Inclusion Criteria and Outcomes of CRT Trials

Study Acronym (Ref. No.)

Design

Follow-up (Months)

QRSd (msec)

Mean QRSd (msec)

LVEDD (mm)

Echo

LVEF (%)

NYHA class

SR/AF

ICD

End-points

PATH-CHF²⁰

Crossover

≥120

175 ± 32

No cutoff

III, IV

6MWT +44m p<0.001

MLHFQ − 19.3 p<0.001

Peak Vo₂ + 1.8 p<0.001

PATH-CHF II⁹⁶

Crossover

≥120

155 ± 20

No cutoff

≤ 30

II – IV

Yes

6MWT +47m p=0.024

MLHFQ − 8.1 p=0.004

Peak Vo₂ +2.5 p<0.001

MUSTIC-SR¹⁸

Crossover

> 150

174 ± 20

> 60

< 35

III

6MWT +73m p<0.001

MLHFQ − 13.6 p<0.001

Peak Vo₂ +1.2 p=0.029

MUSTIC-AF⁹⁷

Crossover

> 200 paced

209 ± 18 paced

> 60

< 35

III

6MWT + 32m p=0.05

MLHFQ −4.3 p=0.11

Peak Vo₂ +1.7 p=0.04

MIRACLE¹⁷

453

Parallel

≥ 130

166 ± 20

≥55

≤ 35

III, IV

6MWT +29m p=0.005

MLHFQ − 9.0 p=0.001

NYHA p<0.001

MIRACLE -ICD⁹⁸

369

Parallel

≥ 130

164 ± 22

≥ 55

≤ 35

III, IV

Yes

6MWT +2m p=0.36

MLHFQ −6.5 p =0.02

NYHA p=0.007

MIRACLE – ICD II⁹⁹

186

Parallel

≥ 130

165 ± 23

≥55

≤35

Yes

6MWT +5m p=0.59

MLHFQ − 2.6 p=0.49

Peak Vo₂ +0.3 p=0.87

CONTAK-CD¹⁰⁰

490

Parallel

≥ 120

158 ± 26

No cutoff

≥ 35

II – IV

Yes

6MWT+20m p=0.043

MLHFQ −2 p=0.39

Peak Vo₂ + 0.8 p=0.03

COMPANION²¹

1520

Parallel

16.2 median

≥ 120

160 median

≥ 60

≤ 35

III, IV

Yes

Death, Admission HR 0.81 p=0.015

Death HR 0.76 p=0.06

HF Death, Admission HR 0.66 p=0.002

CARE-HF²²

813

Parallel

29.4 mean

≥ 150 ≥ 120 + echo

160 median

30 height indexed

Yes n=92

≤ 35

III, IV

Death or MACE HR 0.63 p<0.001

Death HR 0.64 p=0.002

HF Admission HR 0.48 p<0.001

6MWT, 6-minute walk test

AF, atrial fibrillation

HF, heart failure

HR, hazard ratio

ICD, implantable cardioverter defibrillator

LVEDD, left ventricular end diastolic diameter

LVEF, left ventricular ejection fraction

MACE, major adverse cardiovascular event

MLHFQ, Minnesota Living with Heart Failure Questionnaire

NYHA, New York Heart Association

SR, sinus rhythm

Vo₂, oxygen consumption (ml/min/kg)

MECHANICAL DYSSYNCHRONY

What Is Mechanical Dyssynchrony?

Mechanical dyssynchrony may be considered in terms of interventricular and intraventricular components. Interventricular dyssynchrony refers to delayed activation of the LV relative to the right ventricle. Intraventricular dyssynchrony refers to delayed activation of one left ventricular region relative to another. Correction of intraventricular delay frequently simultaneously improves interventricular delay through ventricular interdependence. CRT aims to correct both aspects of mechanical dyssynchrony.

Why Is Mechanical Dyssynchrony Important?

Baseline QRS duration consistently fails to predict response (Table 4.2). The ECG is unable to convey the presence and severity of electrical delay in all ventricular segments, and correlates particularly poorly with disturbance of distal conduction tissue. QRS morphology and duration are only influenced by significant myocardial masses. Regional changes represented by small vectors are inadequately displayed. In failing myocardium, heterogeneous interstitial fibrosis occurs with localized rearrangement of extracellular matrices and myocytes. Consequently, normal depolarization is replaced by a diffuse activation wave front travelling throughout the myocardial wall.²⁷ This disorganized depolarization generates abnormal regional loading conditions, inducing further localized fibrosis and hypertrophy with consequent mechanical dyssynchrony.

TABLE 4.2 Studies Defining Change in QRS Duration Following CRT

First Author		Inclusion QRS Duration	Follow-up	Response	Nonresponders	QRS Responders vs. Nonresponders (ms)
(Ref. No.)	n	(ms)	(Months)	Criteria	(%)	Baseline	ΔQRS
Lecoq.²³	139	> 150	6	Survival, and HF hospitalization, and NYHA ≥ 1 class, or peak Vo₂ ≥ 10% or 6 min walk ≥ 10%	28	192 vs. 180 p=0.018	37 vs. 11 p<0.001
Pitzalis.²⁴	60	> 130	14	Survival, and heart failure hospitalization	27	168 vs. 179 p=NS	45 vs. 31 p<0.05
Bax.²⁵	85	≥ 120	6	NYHA ≥ 1 class, and 6 min walk ≥ 25%	26	174 vs. 171 p=NS	32 vs. 6 p<0.01
Molhoek.¹⁰¹	61	> 120	6	NYHA ≥ 1 class	26	179 vs. 171 p=NS	29 vs. 11 p=0.07
Alonso.²⁶	26	> 120	6	Survival, and NYHA ≥ 1 class, and peak Vo₂ ≥ 10%	27	179 vs. 176 p=NS	23 vs. 4 p=0.04
Penicka.⁵⁶	49	≥ 130	6	≥ 25% LVEF	45	190 vs. 171 p<0.01	38 vs. 17 –
Sassone³⁶	48	≥ 120	6	≥ 15% LVESV	35	152 vs. 151 p=NS	10 vs. 3 p<0.001
Pitzalis.³⁷	20	≥ 140	1	≥ 15% LVESV	40	173 vs. 164 p=NS	21 vs. 22 p=NS
Yu.⁶⁸	30	> 140	3	≥ 15% LVESV	43	166 vs. 150 p=NS	24 vs. 19 p=NS
LVEF, left ventricular ejection fraction
LVESV, left ventricular end systolic volume
NYHA, New York Heart Association
Vo₂, oxygen consumption

Although coupling of electrical activation and mechanical contraction remains incompletely defined, there is convincing evidence of electromechanical dissociation. QRS duration has no correlation with intraventricular dyssynchrony, and only a limited relationship with interventricular dyssynchrony. Regional delays in time to peak systolic velocity (Ts) occur in addition to delays in isovolumic contraction, suggesting further mechanical limitation occurs after electrical activation.²⁸ In myocardial ischemia, impaired regional contractility and wall motion abnormalities frequently produce mechanical dyssynchrony without disturbing electrical conduction. Hemodynamic studies indicate both BiV and LV pacing similarly augment systolic function regardless of different electrical activation.⁸^,⁹ In fact, cardiac output improves during LV pacing despite a significant increase in QRS duration.²⁹^,³⁰ This suggests benefit from CRT relates to improved mechanical rather than electrical coordination.

How Do We Measure Mechanical Dyssynchrony Using Echocardiography?

Mechanical dyssynchrony may be assessed using conventional M-mode and Doppler echocardiography. Newer modalities include tissue Doppler imaging (TDI), tissue synchronization imaging (TSI), triplane tissue Doppler imaging, real-time three-dimensional echocardiography (RT3DE), strain rate imaging (SRI), and speckle tracking strain.

What Are the Limitations of Echocardiographic Parameters Using Conventional Measurements?

Left ventricular pre-ejection period (LVPEP), the time interval between QRS onset and beginning of the aortic Doppler flow velocity curve,³¹ represents a complex interaction between ventricular contraction, preload, and afterload. A delay ≥ 140 ms is considered indicative of intraventricular dyssynchrony.³¹^,³²^,³³

Interventricular mechanical delay (IVMD) is the difference in left and right ventricular pre-ejection periods (LVPEP – RVPEP), measured from QRS onset to the beginning of aortic and pulmonary Doppler flow velocity curves respectively.³¹ An IVMD ≥ 40 ms, 2SD above the mean of normal controls,³⁴ represents interventricular dyssynchrony.³¹^,³²^, ³⁵ Multiple factors influence ventricular ejection, including changes in preload and afterload. In particular, prolonged RVPEP in pulmonary hypertension or right ventricular dysfunction reduces IVMD and accuracy of assessment.³⁵

Left lateral wall diastolic contraction (LLWDC) describes delayed lateral wall contraction (using M-mode) after onset of diastolic filling (transmitral Doppler E wave onset).²²^, ³¹^, ³²^, ³⁶ Coexistence of postsystolic contraction and diastolic relaxation signifies severe intraventricular dyssynchrony. Specificity is thus high, but sensitivity low.

Septal-to-posterior wall motion delay (SPWMD) measures time between maximal incursion of the septum and posterior wall on M-mode, with delay ≥ 130 ms considered significant intraventricular dyssynchrony.²⁴^, ³⁶^,³⁷^,³⁸^,³⁹^,⁴⁰^,⁴¹ Many drawbacks exist. It is one dimensional, comparing only two basal segments and neglecting the more frequently delayed lateral wall. Septal motion reflects interventricular in addition to intraventricular dyssynchrony.³⁶ Feasibility is variably reported between 55% and 100%.²⁴^, ³⁶^,³⁷^,³⁸^,³⁹^,⁴⁰^,⁴¹ Maximal septal or posterior wall motion is often diminished or absent in ischemic populations, causing inaccurate assessment.³⁶^, ³⁸^,³⁹^,⁴⁰ Parasternal acoustic windows may be inadequate.⁴⁰ Perpendicular M-mode sections of the proximal left ventricle are often not possible.³⁹ A calculated anatomical M-mode lowers temporal resolution, while a skewed M-mode produces artefactual dyssynchrony by comparing segments at different longitudinal positions.

TISSUE DOPPLER IMAGING

Temporal vs. Spatial Dyssynchrony

Tissue Doppler imaging evaluates longitudinal myocardial contraction in varying numbers of basal and mid-segments from apical four-, three-, and two- chamber views. Either time to peak systolic velocity (Ts) or time to onset of systolic velocity (To) is measured relative to QRS onset. LV dyssynchrony is quantified either by the standard deviation of 12 segments (Ts-SD-12 or “dyssynchrony index”) or the maximal temporal difference between two (Ts-2, To-2) or more LV segments (e.g., Ts-6, Ts-12). Larger values indicate more severe dyssynchrony. The parameters neglect fundamental principles. Reduced cardiac ejection occurs through displacement of blood volume from early- to late-activated regions. More contractile force is accommodated when delayed segments are clustered together. The net impact is less when delays are dispersed throughout the ventricle.⁴² Variance in timing alone cannot differentiate between spatial patterns of dyssynchrony.

Alignment

The limitations of TDI are similar to those of conventional Doppler. Excessive gain causes spectral broadening and velocity overestimation. Alignment of the insonating beam and direction of myocardial movement is crucial. Error is unavoidable given the limited number of acoustic windows through the human thorax. Deviation underestimates velocities and creates erroneous peaks through inclusion of nonlongitudinal motion. Alignment is particularly challenging in dilated, thinned, and spherically distorted ventricles.

Longitudinal Motion

Transducer orientation and insonation angle restricts TDI assessment to the longitudinal plane. However, ventricular contraction involves complex torsional deformation originating in oppositely wound myocardial fiber helices.⁴²^,⁴³ In systole the base rotates clockwise, and the apex rotates counterclockwise.⁴³ This wringing motion combines longitudinal, circumferential, and radial vectors. Of these, longitudinal indexes have several disadvantages, including low amplitude, greater variance, and limited contribution to systolic function.⁴²

Pulsed Wave Analysis

Pulsed wave and color-coded TDI are compared in Table 4.3. Pulsed wave TDI is widely available and offers high temporal resolution. Sampling is restricted to a single position during each cardiac cycle, precluding post-hoc repositioning and analysis. Comparison of multiple segments requires separate acquisitions in different cycles, and is limited by differences in heart rate, loading conditions, and respiration. Atrial fibrillation is notably problematic.⁴⁴ By contrast, color-coded TDI stores time velocity data superimposed on 2-D cine loops, allowing offline analysis of multiple segments simultaneously during the same cardiac cycle.

Timing Velocities

Numerous issues confound timing of tissue Doppler velocities relative to the surface electrocardiogram. Errors may
result from imprecise identification of QRS onset, depending on morphology and electrical trace clarity. Measurement from a uniform point on the electrocardiogram is recommended if the QRS onset is unclear.⁴⁵ The period during which to measure peak velocity is controversial. Although analysis is typically confined to the ejection interval, extension into diastole has been advocated.⁴⁶^,⁴⁷^,⁴⁸ However, inclusion of postsystolic shortening yielded inferior results in comparative studies.⁴⁹^,⁵⁰

TABLE 4.3 Differences Between Color-Coded and Pulsed Wave Tissue Doppler Imaging

Color-coded TDI	Pulsed Wave TDI
Limited availability	Wider availability
Myocardial velocities 10%-20% lower compared to pulsed wave TDI	Myocardial velocities 10%-20% higher compared to color-coded TDI.
Lower temporal resolution	Higher temporal resolution
Higher spatial resolution	Lower spatial resolution
Rapid acquisition	Slower acquisition
Offline analysis	Online analysis
Post-hoc sample volume repositioning possible	Post-hoc sample volume repositioning impossible
Simultaneous comparison of multiple segments	Simultaneous comparison of segments impossible

Inconsistencies in choosing peak velocity greatly impair reproducibility. Suboptimal image quality, misalignment, translational vectors, and signal noise all create artefacts. Multiphasic or ambiguous velocity curves hinder uniform interpretation. A recent study invited nine expert faculty members of an international echocardiography congress to analyze velocity traces from 18 consecutive patients.⁵¹ Full agreement was achieved in just three cases, with an intraclass correlation coefficient of 0.42. For double peaks, selection of the highest was advised in the Cardiac Resynchronization Therapy in Patients with Heart Failure and Narrow QRS (RethinQ) trial.⁵²

Measuring the time to onset of systolic velocity avoids errors in identifying peak velocity, and is considered a surrogate for regional electromechanical coupling.³⁴^,³⁵^, ⁵³^,⁵⁴^,⁵⁵^,⁵⁶ The rationale for measuring time to onset as opposed to peak velocity depends on the perceived purpose of CRT. The former aims to synchronize ventricular depolarization, the latter synchronize mechanical contraction. Few studies have compared strategies, some favoring time to onset,⁵⁴ others time to peak.²⁸

Positioning Region of Interest (ROI)

Timing and velocities are neither homogeneous within segments, nor abruptly demarcated between segments. Delayed contraction occurs in all segments and all levels of the ventricle. Any given parameter will vary depending on the location interrogated. Moving the region of interest (ROI) within segments significantly alters timing. Mean septal-lateral delay (Ts-2) was 28 ms higher when comparing low-basal and midbasal ROIs in 41 consecutive patients (p<0.01).⁵¹ Bland-Altman limits of agreement were correspondingly wide (± 129 ms). Recent publications now advocate manually adjusting the ROI within the segment (up or down, left or right) to produce the most “representative” peak velocity.⁴⁵^,⁴⁶^,⁴⁷^,⁴⁸^,⁴⁹^,⁵⁰^,⁵¹^,⁵²^,⁵³^,⁵⁴^,⁵⁵^,⁵⁶^,⁵⁷ This contrasts starkly with the methods in earlier reports.

Feasibility

Remarkably few studies reported feasibility, given the aforementioned limitations (Table 4.4). Many enrolled nonconsecutive patients, or excluded patients with inadequate measurements from analysis.⁴¹^,⁴²^,⁴³^,⁴⁴^, ⁵⁴^,⁵⁵^,⁵⁶^,⁵⁷^,⁵⁸ Whether such perfect data acquisition translates to real-world practice is highly questionable. Exponents of echocardiographic dyssynchrony ignore the realities of clinical practice. Who will arbitrate image quality? What is suboptimal? Which patients are suitable for a dyssynchrony study? Contrast this with QRS duration, readily measured in every patient by anyone with basic technical training.

TISSUE SYNCHRONIZATION IMAGING

The TSI algorithm automatically detects peak systolic velocity. Color coding superimposed on real-time images displays regional delays, ranging from green (earliest) to red (latest). A quantitative tool automatically calculates the median Ts within a manually positioned sample volume, enabling rapid comparison of segments.⁴⁹^, ⁵⁹ As with traditional TDI, moving the region of interest within segments alters the measured delay. The TSI algorithm detects velocity peaks within a specified time interval. Systole must be manually defined according to aortic valve opening and closure. Incorrect timing introduces error through inclusion of peaks outside the ejection phase.

TRIPLANE TISSUE DOPPLER IMAGING

Color-coded TDI only compares opposing walls within one plane. Interrogation of all segments requires three separate acquisitions in orthogonal planes, neglecting heart rate variability. A single 3-D triplane dataset allows simultaneous comparison of all 12 segments during the same cardiac cycle. The technique reduces acquisition time, eliminates heart rate

variability, and more accurately defines LV volumes.⁶⁰^,⁶¹ However, many inherent TDI failings remain, including angle dependency, timing of peak velocities, ROI positioning, and assessment of only longitudinal motion.

TABLE 4.4 Design of Studies Investigating Parameters Predicting Response to CRT

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First Author	n	Follow-Up	Prospective	Consecutive	Blinded	Dyssynchrony	Cut-off	Cut-off	Feasibility	Variability
(Ref. No.)		(Months)		Patients	Analysis	Parameter	(ms)	Derivation	(%)	Intra-	Inter-
Conventional Parameters
Pitzalis³⁷	20	1	Yes	Yes	Yes	SPWMD	130	ROC curve	100	0.96	0.91
Pitzalis²⁴	51	14	Yes	Yes	Yes	SPWMD	130	previous study	93	–	–
Marcus³⁸	79	6	No	No	Yes	SPWMD	130	previous study	55	High	High
Diaz-Infante³⁹	67	6	Yes	Yes	Yes	SPWMD	130	previous study	79	0.97	0.98
Sassone³⁶	48	6	No	Yes	No	SPWMD	130	previous study	67	–	–
						LLWDC	present	present/absent	96	–	–
Da Costa⁷⁷	67	12	Yes	No	Yes	IVMD	50	previous study	100	–	–
Achilli⁵³	133	6	No	Yes	Yes	IVMD	44	ROC curve	100	–	–
Duncan⁷⁶	39	6	No	No	Yes	t-IVT	–	–	100	–	–
Tissue Doppler Imaging
Bleeker⁴⁰	98	6	No	Yes	Yes	Ts-2	65	previous study	96	4%	10%
						SPWMD	130	previous study	59	8%	14%
Bax⁷⁰	25	Acute	No	Yes	Yes	Ts-2	60	selected	100	–	–
Bleeker⁷¹	40	6	Yes	Yes	Yes	Ts-2	65	previous study	100	–	–
Soliman⁴⁴	60	12	No	Yes	Yes	Ts-2 Pulsed	60	previous study	93	Low	Low
Bax²⁵	80	6	No	Yes	Yes	Ts-4	65	ROC curve	100	–	–
Heist⁵⁸	39	Acute	No	Yes	No	dP/dt	600 mmHg/s	previous study	–	–	–
					Ts-4	100	previous study
Notabartolo⁴⁸	49	3	No	Yes	No	Ts-6	110	EP study	100	–	–
Yuan¹⁰²	18	3	Yes	Yes	Yes	Ts-6 Annular	105	ROC curve	100	–	–
Yu⁶⁸	30	3	No	No	No	Ts-SD-12	32.6	2 SD controls	100	<5%	<5%
Yu⁵⁰	54	3	No	No	No	Ts-SD-12	31.4	ROC curve	100	3%	5%
Yu⁶⁹	55	3	No	No	No	Ts-SD-12	31.4	ROC curve	100	–	–
						Ts-12	98.5	ROC curve
Yu.⁵⁷	256	6	No	No	Yes	Ts-SD-12	33	ROC curve

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