Open access peer-reviewed chapter - ONLINE FIRST

CRT Past, Present, and Future Directions: Toward Intelligent Responders Selection and Optimizing Pacing Modalities

Written By

Abdullah Alabdulgader

Submitted: October 6th, 2021 Reviewed: November 12th, 2021 Published: February 18th, 2022

DOI: 10.5772/intechopen.101608

Pacemakers and Defibrillators Edited by Mart Min

From the Edited Volume

Pacemakers and Defibrillators [Working Title]

Prof. Mart Min and Dr. Gabriel Cismaru

Chapter metrics overview

66 Chapter Downloads

View Full Metrics


Congestive heart failure (CHF) is a serious health problem affecting all nations of world. Its impact is increasing with increasing individual age. Ventricular dyssynchrony is well known to contribute to pathophysiological deterioration in more than one-third of CHF subjects. The therapeutic choices of CHF witnessed long decades of stagnant periods and a relative paucity of effective treatment. The discovery of the electrical therapy that is capable of reversing ventricular dyssynchrony, in the form of cardiac resynchronization therapy (CRT), is a true revolution in the timeline of CHF management. Despite the early enthusiasm associated with CRT implantations started in 2001, we know from the last two decades’ experience that non-responders constitute to nearly 40% of all CRT patients. This chapter is devoted to reviewing the past, present and future of CRT with special attention on better intelligent detection of the electrical substrate responsive to CRT as well as optimizing the choice of CRT subjects using the latest knowledge in electrocardiographic and state-of-art imagining technologies. Novel future directions are discussed with new scientific philosophies capable of optimizing CRT. Promising new implants techniques such as endocardial pacing of the left ventricle, His bundle pacing as well as His-optimized cardiac resynchronization therapy are discussed.


  • cardiac resynchronization therapy (CRT)
  • congestive heart failure (CHF)
  • electrical cardiac devices
  • left bundle branch block (LBBB)
  • right bundle branch block (RBBB)
  • future directions

1. Introduction

Congestive heart failure (CHF) is one of the most important epidemics in the current human species era affecting 1–2% of adults and around 10% of >70 years old in developed countries. The lifetime risk of developing heart failure is one in five after 40 years of age. In the United States, it costs around $39.2 billion in 2010. Sub group of CHF subjects with reduced ejection fraction and electrical dyssynchrony constitutes a true therapeutic challenge. Therapeutic strategies of this CHF sub group witnessed stagnant periods until electrical therapies were introduced to the world communities where cardiac resynchronization therapy (CRT) became available for clinical use first in 2001. Candidates for CRT are CHF subjects with reduced left ventricular systolic function, QRS duration of >120 ms with left bundle branch (LBB) morphology, and functional classification with NYHA class III-IV. Accumulative knowledge in the last two decades has shown that more than one-third of patients are not responding with lack of echocardiographic reverse remodeling or no improvement in quality of life (QOL). Intelligent CRT subjects selection with multidisciplinary expertise and improved procedural skills and strategies, as well as optimizing post-implant care are the main targets to achieve the improved outcomes for the non-responders. Nowadays, a new CRT imaging techniques and innovative pacing strategies are top priorities for us in CHF electrical therapies arena. This chapter is a journey in the CRT timeline reviewing the past, discussing the current situation, and elaborating in future directions for better psychophysiological well-being of CRT subjects.


2. Applying electrical therapy as medicine to treat human disease

Utilizing electric current to treat human disease is an idea that fascinated humans since antiquity. The electrical discharges produced by torpedo fish were utilized as an efficient natural source for electric shock generation by Hippocrates (460–370 BC), Scribonius Largus, and Galen (129–210 AC). It was prescribed for neurological diseases like headache, arthritis gout pain, and prolapsed anus. In 46 AD Scribonius Largus in his compendium of medical treatments known as Compositionesdescribed a novel treatment for headache, where, a living black torpedo is put on the place which is in pain, and results were very encouraging. The electric organ of the electric fish can produce amplitudes ranging from 10 to 860 V with a current of up to 1 A. In cardiac science, electrical stimulation was an attractive choice for incapacitating angina pain. An induction coil with sponge-tipped electrodes was used in 1853 to successfully treat abnormal heart rhythms and angina. Relief of angina pectoris by electrical stimulation of the carotid-sinus nerves was achieved repeatedly [1]. The introduction of coronary artery bypass shortly after this convert the electrical stimulation procedure to obsolete. The most fascinating and valuable incorporation of electric therapy in medicine was in the arena of treating rhythm disturbances, either in bradycardia or tachycardia management The first pacemaker was implanted in a person in 1958 and the first lithium battery was introduced in 1969. The deleterious hemodynamic effects of the left bundle branch block (LBBB) had been appreciated by many intelligent observers in the cardiac communities. About 30% of heart failure subjects with reduced ejection fraction with wide QRS interval in the electrocardiogram, tend to have worse clinical outcome [2, 3]. In addition, intraventricular conduction delay (IVCD) was observed as a pathological finding with multiple hemodynamic derangements, including reduced pulse pressure, impaired diastolic function, and mitral regurgitation of functional origin [4]. Early attempts to address this pathology which demonstrated favorable acute hemodynamics and medium-term functional improvements were observed using biventricular pacing [5, 6]. Multisite Stimulation in Cardiomyopathy (MUSTIC) Trial, published in 2001 was the first large trial demonstrating CRT benefits clinically, where three champers are paced, right atrium, right ventricle, and left ventricle. The first CRT device was implanted in the same year. In an attempt to improve the clinical outcome, 10 other prestigious trials were performed. Those 11 clinical trials constitute the determinants and guidelines dictator for CRT practice nowadays. Table 1 illustrate the details of the inclusion criteria, comparison, and the significant findings of the most influential CRT trials [14]. Nowadays, the cardiac electrical devices communities are investigating methodologies and techniques to improve CRT outcomes mainly in the non-responders group. The non-LBBB population is classically thought to be out of the selection criteria for CRT. In spite of that, we believe nowadays that 30–50% of these population will benefit from CRT. With this new knowledge, we should convert the necessity of LBBB criteria as lone evidence for ventricular dyssynchrony, an obsolete. In this chapter we are discussing with detail, an innovative diagnostic modalities to hunt the potential responders for CRT. Visionary insight for future speculations will conclude this CRT scientific journey.

NamePopulation (n)InclusionEndpointResults
MUSTIC SR58III, EF < 35%, QRS ≥ 1506MWT, QoL, pVO2, hospitalizationCRT-P improved : 6MWT, QOL, pVO2; reduced hospitalization
MIRACLE [7]228-CRT 25-controlIII-IV, EF <35%, QRS ≥130NYHA class, QoL, pVO2CRT-P improved: NYHA, pVO2, 6MWT
MIRACLE-ICD186II, EF < 35%, QRS ≥ 1306MWT,QoL, hospitalizationCRT-D improved all from baseline (not ICD)
COMPANION [8]ICM NICM 1,520III-IV, EF < 35%, QRS > 120All-cause mortality or hospitalizationCRT-P/CRT-D; reduced endpoints HR 0.80 (CRT vs medical)
CARE-HR [9]ICM NICM 813III-IV, EF < 35%, QRS > 120All-cause mortality or hospitalizationCRT-P/CRT-D; reduced endpoints HR 0.63
MUSTIC AF59III, EF < 35%, QRS ≥200 (paced QRS)6MWT, QoL, pVO2, hospitalizationCRT-P improved : 6MWT, QOL, pVO2, hospitalization
CONTAK-CDAll-cause death + HF hospitalization, pVO2, 6MWT, NYHA class, QoL, LVEDD, LVEFCRT-D improved: pVO2, 6MWT; reduced LVEDD and increased LVEF
RAFT [10]1798II, III, EF <30%, QRS ≥120Death from any cause or hospitalization for HFThe addition of CRT to an ICD reduced rates of death and hospitalization for HT
REVERSE [11]610I-II, EF <40%, QRS ≥ 120(i) % worsened by clinical composite endpoint, (ii) LVESVi, (iii) HF hospitalization, (iv) all-cause deathPrimary endpoint NS; CRT-P/CRT-D reduced (ii) and (iii) hospitalization but not (iv)
MADIT-CRT [12]ICM NICM 1820I-II, EF <30%, QRS ≥ 130(i) HF event or death, (ii) All-cause death, (iii) LVESVCRT-D reduced (i) and (iii) but not (ii)
MIRACLE-ICD II [13]186II, EF <35%, QRS ≥ 130VE/CO2, pVO2, NYHA, QOL, 6MWT, LV volumes, LVEFCRT-D improved: NYHA, VE/CO2; volumes, LVEF

Table 1.

Major clinical trials.


3. The dilemma of intelligent resynchronization therapy subjects selection

The philosophy of resynchronizing the electrical stimulation of both ventricles developed into more mature practice, nowadays. The current CRT guidelines are the product of knowledge of the aforementioned clinical trials (Table 1) in addition to the accumulation of personal and institutional expert opinions. The most important organizations contributing most importantly to today's guidelines are: American Heart Association, the American College of Cardiology, Heart Rhythm Society, the Heart Failure Society of America, and the European Society of Cardiology. American criteria to define LBBB as defined by AHA/ACC/HRS are as follows:

  • QRS >_120

  • Notch-, slurred R in I, aVL, V5, and V6

  • Occasional RS pattern in V5–V6

  • Absent q in I, V5–V6, and aVL

  • R peak time >60 ms in V5 and V6

  • Normal R-peak time in V1–V3

  • No negative concordance

  • Usually discordant ST-T segments

The vast majority of recommendations of those organizations are concordant to each other making class I indications clear for CRT specialists to implement. Class I indications are restricted to the symptomatic patients with LVEF ≤35%, NYHA II-IV, with a QRS duration ≥130 ms despite guideline-directed medical treatment (GDMT) [15]. The most recent guidelines are account for the observations that the greatest benefits are consistently seen in those with a QRS duration >150 ms and LBBB pattern [16, 17, 18]. On the other hand, echocardiographic evaluation looking for mechanical dyssynchrony results of the Predictors of Response to CRT (PROSPECT) Trial published in 2008 did not show superiority for CRT outcome for any of the predictors [19]. Accumulation of data in the last two decades demonstrated clearly that the CRT success in electrical resynchrony, mechanical remodeling, and quality of life improvement is not always directly linked to the current selection criteria. Response to CRT seems to be more complex than we thought earlier. Currently, 30–40% of our subjects are non-responders. We recommend extension criteria for CRT subjects selection considering the old criteria of QRS duration >130 ms, LV dysfunction (<35%), and NYHA class II-IV as a guideline with more extensive clinical, pathological, imaging and programming variables to be considered. Critical variables such as global scar burden, scar location, lead position, programmed AV and VV interval, mitral regurgitation, and irreversibly advanced heart failure cases are imperative considerations to improve the outcome [20] Despite the traditional dogma that normal QRS duration is a contraindication for CRT, recent challenging groups suggest that QRS complex <130 ms might benefit from CRT. This response as they describe it, is personalized but having QRS complex <130 ms should not be a reason to withhold the option of CRT in systolic heart failure if no other effective treatment is available [21]. Despite the claim that CRT is under-utilized worldwide, we suggest more wise selections with the advanced criteria for more intelligent selection. Our top priority should be the perfection of patients' choices to optimize benefits from CRT. Adjunction of defibrillator therapy with CRT as primary prevention of SCD is indicated in most CRT patients. For this reason, current guidelines advocate an implant of a CRT-D in eligible patients [9, 12]. Most of the systems we are implanting nowadays are CRT-D. This addition of defibrillator stress more for the need of more intelligent and comprehensive criteria for subjects selection. It is imperative to treat any primary disease before thinking of introducing the choice of CRT. Reversible heart diseases such as myocardial ischemia, arrhythmia (tachycardia-induced cardiomyopathy), or primary valvular heart disease must be treated. When AF is a risk factor, catheter ablation of AF is superior to AV node ablation combined with biventricular pacing. This superiority is increasing with the dramatic improvement in our skills and technology, especially with pulmonary veins cryoablation technique. In the subgroup of patients who received prior pacemaker or ICD with worsening heart functions, an upgrade plan for CRT-D seems appropriate. The majority of patients we are implanting, died without experiencing an appropriate ICD shock. A selection system that is capable of predicting survival in patients who received a CRT-D as primary prevention of SCD, identify a subgroup with a significantly poor prognosis despite a CRT-D, as well as being able to discriminate between patients with a low or high risk for mortality, is highly needed. The predictive HF meta-score is constructed of independent mortality predictors identified in a meta-analysis. Three continuous variables constitute this comprehensive evaluation score. In addition to age, LVEF and eGFR, New York Heart Association (NYHA) functional class; 11 dichotomous variables which give the score true discriminative strength including: male gender, African-American race, diabetes, chronic obstructive pulmonary disease, peripheral vascular disease, ischemic cardiomyopathy, HF admission within 1 year before implantation, past or present atrial fibrillation, wide QRS (≥120 ms), secondary prevention indication, and history of ICD shocks (appropriate and inappropriate) [22]. The authors of this meta-analysis found the HF meta-score, a good predictor for survival and useful to detect a subgroup with a significantly poor prognosis despite a CRT-D. In addition, accumulated medical literature in the last few years pin point other conduction system disorders in addition to the major well-known indication of the LBBB as potential indications for CRT. Those indications were based on evidence derived from sub-analyses from the landmark trials and will be discussed in the next section.


4. Understanding the pathophysiological mechanism for becoming a CRT responder

The presence of intrinsic LV electrical dyssynchrony is considered to be the traditional electrical substrate of CRT. Mechanical inefficiency is the result of inefficient electrical-mechanical coupling ending up with triggering two main important outcomes: first is a hemodynamic disturbance in the form of reduced stroke volume and second structural deformation in the form of a cardiac remodeling process. Biventricular pacing, delivered by a CRT device, by correcting the dyssynchrony can improve both hemodynamic and structural derangements [23]. Studying ventricular activation time (known also as intrinsicoid deflection) and variability in activation sequence and passive conduction properties of normal hearts must be perceived very well for accurate comparison and assessment of ventricular dyssynchrony or other activation disorders [24]. Building on this important consideration, we in pacing communities must remind ourselves always of the fact that biventricular pacing is never physiological. Biventricular pacing induces a stage of dyssynchronous electrical activation, remarkably observed at the level of the LV [25]. But with significant baseline electrical dyssynchrony, biventricular activation can be of benefit. Worsening of ventricular synchrony is expected in cases of little or no electrical dyssynchrony resulting in iatrogenic electrical dyssynchrony [25]. Being able to distinguish between patients that may or may not benefit from CRT, is based on a proper understanding of the true deviation from the normal activation pattern of ventricles and proper establishment of the presence of sufficient baseline electrical dyssynchrony.

Research projects supporting this important understanding in biventricular pacing science are multicenter randomized LESSER-EARTH (cardiac resynchronization therapy in patients with heart failure and a QRS complex <120 ms: the evaluation of resynchronization therapy for heart failure) in addition to ECHO-CRT (echocardiography in cardiac resynchronization therapy) trials. Premature termination of patients with narrow QRS duration was elected due to safety concerns [26, 27].

4.1 LBBB is deficient criteria to diagnose CRT responders

Incorporating LBBB as ECG criteria to anticipate responders to CRT is proved to be deficient criteria in at least one-third of patients [28]. In the current CRT literature, there are multiple 'criteria to define LBBB. Present examples are the American Heart Association/American College of Cardiology/Heart Rhythm Society (AHA/ACC/HRS), the European Society of Cardiology (ESC), and Strauss. Clinical outcomes in terms of remodeling reversal, hospitalization for heart failure, survival rates differ between those classifications, as well as clinical outcomes after CRT. In addition, interpretation of slurring and notching differs according to the format and filtering of the ECG. Positioning of the lateral leads is also an important contributing factor. In addition, interpersonal differences in reading ECG impact the LBBB diagnosis [29]. Significant interobserver, and to a lesser extent, intraobserver variability in the classification of LBBB by the use of the various definitions have been documented. Despite applying specific LBBB criteria, 1 in every 5 or 6 ECG will be classified differently by a different observer. If the same observer is tested, 1 in 10 ECG will be classified differently [30]. This conceivably means that a significant proportion of the scientific publications on CRT is niether mentioned nor nonspecific. It is astonishing to know that QRS morphology was not associated with response to CRT with regard to morbidity and mortality in five randomized key CRT trials constituting meta-analysis of data from 3782 patients (CAREHF [Cardiac Resynchronization in Heart Failure], RAFT [Resynchronization/Defibrillation for Ambulatory Heart Failure Trial], MIRACLE [Multicenter InSync Randomized Clinical Evaluation], MIRACLEICD [Multicenter InSync Randomized Clinical Evaluation—Implantable Cardioverter-Defibrillator], REVERSE [Resynchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction]) [31, 32]. It is clear at this point that what we are looking to treat with CRT is the dominance of leftward electrical delay, not LBBB.Subjects classified as having LBBB or non-LBBB may or may not have leftward electrical delay [25].

4.2 How to detect dominant left ward electrical delay (LED)

One of the best diagnostic modalities to diagnose electrical-mechanical coupling mismatch is endocardial electrical activation mapping where 3-dimensional electroanatomical reconstruction contact or noncontact mapping can be evaluated with extreme accuracy. Utilizing this unique diagnostic tool declare that in most patients with LBBB there is a dominant leftward electrical delay [33, 34, 35]. The ECG imaging or body surface mapping can display electrical activation sequences noninvasively. This predominant leftward electrical conduction delay is a critical component of the electrical substrate, which is amenable for CRT with expected electrical and mechanical derangements recovery.

4.3 The electrical substrate in Intraventricular conduction delay and CRT

A heterogenous and complex ventricular activation pattern, different from bundle branch pattern, is associated with IVCD. This is thought to be due to electrical disease in combination with the myocardial disease [35, 36]. Subjects with IVCD are known to have LV activation time shorter than LBBB subjects. In addition the latest activation time in IVCD is variable. In IVCD subjects electrical delay is not as advanced but there is evidence of underlying myocardial disease. This results in a less favorable response of CRT in IVCD subjects [33, 35, 37]. Ventricular activation studies displayed electrical conduction disturbance in IVCD similar to LBBB in 20–52% of IVCD subjects [33, 35, 37]. This group of patients has the potential of gaining the best advantage from CRT [3]. In patients with typical LBBB, change to atypical LBBB might be indicative of scar formation after myocardial infarction that may benefit from CRT. National Cardiovascular Data Registry Implantable Cardioverter-Defibrillator (NCDR ICD) registry studied 11,505 CRT patients with non-LBBB, demonstrated that CRT implantation appeared to be associated with better outcomes than did implantable cardioverter-defibrillator (ICD) therapy alone in IVCD patients with a QRS duration of > or =150 ms, but not in patients with QRS duration < 150 ms or RBBB [38].

4.4 The electrical substrate responsive to CRT in RBBB

In right bundle branch block (RBBB) subjects the RV is activated slowly after LV activation. This fact explains convincingly the failure of CRT in RBBB subjects. As a matter of fact conventional CRT induces, rather than resolves, electrical dyssynchrony in RBBB subjects. Preclinical research and computer simulations evaluating the hemodynamic consequences of RBBB failing heart document this state of dyssynchrony in this subset of patients [39, 40]. There was no significant difference in total and regional LV endocardial activation times between RBBB and LBBB patients [34]. This fact is not a contradiction to the fact of dyssynchrony induced by CRT in RBBB. The conclusive statement here is that: RBBB subjects who have concomitantly sufficiently significant coexisting LV conduction delay, CRT will result in hemodynamic improvement [39]. This is a new era of biventricular pacing where RBBB in the ECG may constitute an indication for CRT.In the 1960s Rosenbaum et al. intelligently mentioned a new RBBB pattern that he called “RBBB masking LBBB,” characterized by a broad slurred R wave in leads I and aVL, together with a left axis deviation [41]. In addition, Tzogias et al. in 2014 found that atypical RBBB(RBBB pattern in lead V1 and absent significant S-wave in the lateral leads I and aVL) might be explained as coexisting left bundle branch delay (bilateral bundle-branch delay) and might suggest possible CRT responders within a group of patients with RBBB [42]. Left hemiblock in the presence of RBBB is another indicator alarming for leftward conduction delay and supporting the decision for biventricular pacing with CRT in RBBB subjects, although heterogeneity of trials data are evident. The heterogeneity of positive outcomes in this group of patients can be explained by the fact that left hemiblock might be a primary conduction system disease with associated dyssynchrony, or by infarction of the proximal left anterior descending coronary artery, where dyssynchrony is absent [43].

4.5 Contribution of CRT to atrioventricular dyssynchrony

Ventricular resynchronization was thought to be the sole target of CRT. Atrioventricular conduction delay represented by prolonged PR interval in the ECG was found to be a potential target for CRT [44]. Consequences of inefficient atrioventricular coupling are elevated LV end-diastolic pressure, diastolic mitral regurgitation, and reduced stroke work. Atrioventricular conduction disturbances are frequent findings in the heart failure population with an increased rate of hospitalization, atrial fibrillation, and mortalities [45]. CRT was found to be associated with worsened outcomes in prolonged PR intervals compared to normal patients in several nonrandomized trials [46, 47]. In contrast, subanalyses in two of the MADIT-CRT trial, investigating CRT effects on patients with non-LBBB and long PR interval, document reduction in the risk of all-cause mortality as well as heart failure hospitalization [48, 49, 50]. In conclusion, our directions now considering differences in methodology, design, and outcome measures in different studies, obviate drawing solid conclusion to decide for atrioventricular dyssynchrony as electrical substrate responsive to CRT.


5. Response prediction of new echocardiographic mechanical dyssynchrony markers

5.1 Eye balling and time-based mechanical dyssynchrony markers

Accumulation of resynchronization trials knowledge demonstrated clearly that an important proportion of the CRT population is not responding. All-cause mortality combined including heart failure hospitalization, NYHA class, and patient global assessment were used in a heart failure clinical composite score (CCS) in Multicenter InSync Randomized Clinical Evaluation (MIRACLE) and was not able to show improvement in 34% of patients [7, 51]. A special new concern group in today's trials are the non-LBBB subjects. The use of echocardiographic markers before 2008 for this important group was not able to show additive benefit of the use of echocardiographic markers to predict CRT in important landmark trials like PROSPECT (Predictors of Response to Cardiac Resynchronization Therapy), ECHO-CRT, and others [26]. Iatrogenic electropathy has been reported as a possible deleterious effect of biventricular pacing [52]. New echocardiographic parameters to evaluate ventricular dyssynchrony were made available to provide proper measurement tool for resynchronization therapy[53, 54]. Two parameters are in clinical use nowadays: first is simple eyeballing to assess the degree of dyssynchrony. The second is more technical demanding based on strain study called strain-based speckle tracking echocardiography (STE). Mechanical dyssynchrony is present when an interventricular mechanical delay of > or = 40 ms and a septal-to-posterior radial peak strain delay of > or = 130 ms assessed with STE-strain curves.

Incorporation of echocardiographic mechanical parameters to evaluate ventricular dyssynchrony contribute significantly to the improvement of the prognostic value of guideline-based patient selection for CRT [54, 55]. Reduction of all-cause mortality was associated with incorporation of the apical rocking and/or septal flash at baseline evaluation for CRT [56, 57]. Incorporation of mechanical dyssynchrony parameters as a selection criterion for CRT was associated with a significant reduction in LV end-systolic pressure in comparison to the old criteria based on QRS duration and morphology alone [55]. Despite those early promising outcome studies, not all non-LBBB with mechanical dyssynchrony have improved outcomes. Here it is wise to remember that absence of response, especially in the time dyssynchrony-based studies, might be related to a non-electrical disease that is not responding to CRT like myocardial hypocontractility and scaring, which are very frequent pathologies in the heart failure population. Future randomized control trials must consider those important discriminative factors.

5.2 Septal rebound stretch analysis for the prediction of volumetric response to cardiac resynchronization therapy

Utilizing detection of specific wall motion patterns to serve as markers for CRT response is the most recent advance in the investigation toward optimal response prediction for CRT [54, 58, 59, 60]. It is promising as a superior ventricular dyssynchrony measure tool compared to timing-based measures. Early septal contraction and delayed lateral wall activation give rise to myocardial stretching of the opposing wall during systole [54, 59, 61, 62]. This stretching is paradoxical systolic LV motion that is not contributing to LV ejection and, will result in waste of energy. This myocardial stretch and the resulting waste of energy can be converted to myocardial shortening when we perform biventricular pacing [58, 63, 64]. Systolic rebound stretch of the septum (SRSsept) refers to the amount of systolic stretching of the septum after initial systolic shortening (Figure 1). It is considered as a good indicator to reflect the potential for recovery of LV function with CRT and might be one of the best response indicators for resynchronization therapy [53, 58, 66]. Salden et al. and after their pioneering publication in the strategies to improve the selection of patients without typical LBBB for cardiac resynchronization therapy [67] and in a recent publication, published the first results from the multicenter study that investigated the association of baseline echocardiographic SRSsept with the volumetric response after CRT. They found that SRSsept is independently associated with favorable changes in LVESV post CRT. In addition, they found that for the prediction of volumetric response, assessment of SRSsept implies additional predictive information compared to visual assessment of apical rock alone. For assessment of subjects without strict LBBB criteria, SRSsept is an excellent echocardiographic discriminator to predict response to CRT [65]. We and others recommend incorporation of echocardiographic SRSspet for future prospective validation studies for CRT subjects evaluation.

Figure 1.

Septal single wall image acquisition of systolic rebound stretch of the septum (SRSsept)-in red- defined as septal stretching after initial shortening. Speckle tracking echocardiography software was used to deduce strain curves of the focused LV septal wall image. MVC, mitral valve closing; AVC, aortic valve closing [65].


6. Cardiac resynchronization therapy guided by cardiovascular magnetic resonance

Cardiovascular magnetic resonance (CMR) is well known for its unprecedented image quality for cardiac structures as well as for functional assessment of cardiac functions. In addition, it has been introduced to CRT communities as a unique diagnostic tool in differentiating between the various causes of LV dysfunction. CMR is well known to be an excellent evaluating tool for critical factors in the potential response to CRT like a myocardial scar, the total amount of scar (scar burden), and scar location and its relationship to the pacing stimulus. The intricate arrangements of human heart myocardial fibers are a complex anisotropic fiber structure showing longitudinal, circumferential, and oblique layers that form a mechanical link between remote areas of the myocardium [68, 69, 70, 71]. Electrically heterogeneous conduction from endocardium to mid-myocardium and epicardium is also a feature of the human heart [72]. Conduction disturbances, superimposing in this inherent anatomical, functional, and electrical heterogeneity of the myocardium is expected to yield multiple areas of dyssynchrony [72, 73]. This finding raises the possibility that deploying an LV lead over a single site of late wall motion may not correct global cardiac dyssynchrony. By the same token, multiple LV leads may be preferable to one LV lead in some patients (Figure 2) [74].

Figure 2.

CMR radial wall mapping illustrating inward wall motion with colors ranging from blue to green and to red. Bull’s eye with a homogenous red color throughout denotes complete synchrony, where the bull eye with homogenous blue color denotes complete synchrony. Heterogenous color coding denotes dyssynchrony of radial motion where blue is representing early (global systolic phase) activation and red representing late (global diastolic phase) inward radial wall motion (from Foley et al. [74,75]).

With its unique discriminative and diagnostic accuracy, CMR has become the gold standard for the in vivo assessment of myocardial scarring. The cutoff point for scar burden, where more is associated with poor response to CRT, is different between different investigators but in general, we consider scar burden less than 15–33% is a potentially good indicator for better response to CRT [76, 77]. Another delicate feature of CMR contribution to CRT management is that CMR can be a fine assessment tool for diagnosing the substrate of heart failure. It is well known that myocardial infarctions can be silent in about one-third of patients and coronary angiography study can be normal after myocardial infarction. In addition, wall motion abnormalities are not equivalent to myocardial ischemia. Unparalleled anatomical imaging, combined with late gadolinium enhancement (LGE)-CMR findings, makes CMR an ideal radiation-free diagnostic tool for the actual heart failure substrate. Scarring in the subendocardial or transmural distribution along arterial territories is typical for infarcted myocardium. Lack of localized myocardial scarring is characteristic of non-ischemic cardiomyopathy or less often, by mid-wall LGE, characterized fibrosis. Myocarditis, sarcoidosis, and arrhythmogenic right ventricular cardiomyopathy are characterized by the patchy distribution of LGE. Amyloidosis and Anderson-Fabry diseases are characterized by diffuse LGE.


7. Cardiac resynchronization therapy guided by computed tomography

Although CMR is an excellent diagnostic tool for evaluating CRT response evaluation, the frequent presence of pacemakers in this group of patients renders its use limited especially in countries where MRI-compatible devices are not available. Non-response to CRT might be caused by factors other than dyssynchrony of electrical activation. Important hidden factors that must gain attention for non-responders are myocardial scar, myocardia hypocontractility, and suboptimal left ventricular (LV) lead location. All of these factors can be investigated with computed tomography (CT). Late iodine enhancement computed tomography (LIE-CT) was found to be an important elegant diagnostic modality in this regard. Théo Pezel et al. investigated CT dyssynchrony measurements for which the LV short-axis images from the multiphase reformatted reconstructions were used [78]. CT dyssynchrony indices used in their investigation were: global and segmental time to maximal wall thickness, global and segmental time to maximal inward wall motion, and time to minimum systolic volume. The dyssynchrony they measured were not the baseline dyssynchrony but the persistent dyssynchrony despite biventricular stimulation. LV lead malpositioning is a serious potentially avoidable reason for non-responders group. Pre-determination of LV lead positioning might be approached by invasive angiogram during implantation and CT coronary angiography. Short axis of the heart is used to determine LV lead final position as anterior, anterolateral, lateral, inferolateral, or inferior. In the long axis of the heart searched positions are basal, mid, or apical. Théo Pezel et al. evaluated concordance of the lead location to regional LV mechanical contraction, where they calculated the mean times to maximal wall thickness and maximal wall motion of each segment using an 8-segment model. Identification of the segment of the myocardium with the latest mean times to either maximal wall thickness or wall motion was determined. Greater global dyssynchrony, as measured by the time to maximal wall thickness, time to peak inward wall motion, and time-to-minimum systolic volume was found between non-responders. Greater segmental dyssynchrony between the anterior and inferior segments, between the inferoseptal and anterolateral segments, and between the anteroseptal and inferolateral segments was found between non-responders. In addition, in the non-responders, the LV lead location was less often concordant with the region of maximal wall thickness (9% vs. 72%, p = .001) [78].

In addition, CT was found to be an appropriate diagnostic tool to follow up the association of LV wall thickness and the ability to reverse LV remodeling and mitral regurgitation improvement after CRT [79].


8. Future directions to optimize cardiac resynchronization therapy

CRT is well known since its inception to be a promising electrical therapeutic device to treat CHF. After more than two decades in clinical use, we know that around 30–40% of CRT subjects do not exhibit any detectable clinical or echocardiographic benefit. As a matter of fact, some of them are deteriorating after resynchronization. For this reason, most of the discussion in this chapter and selected recent literature is devoted to non-responders toward optimizing resynchronization therapy [80, 81]. The special diagnostic tools mentioned earlier in this chapter are to refine our CRT subjects selection especially the subgroup without conspicuous LBBB criteria. Those special diagnostic tools can be still considered as future direction that has been started and in the way for mature applicable understandings in the field of CRT science. Promising new directions can be classified as new diagnostic tools and new basic knowledge with deeper investigation in the biomechanics of cardiac electromechanical coupling and spatial orientation of the ventricular muscles, as well as ,new advances in implant and resynchronization site.

8.1 Vectorcardiography guided cardiac resynchronization therapy

Vectorcardiography (VCG) was developed by E. Frank in the mid-1950s. The magnitude and direction of the electrical forces that are generated by the heart are recorded in 3-dimensional information format by means of a continuous series of vectors that form curving lines around a central point. The area under the 3-dimensional QRS complex (QRS area) is reflecting the electrical forces during depolarization and the area under the 3-dimensional T-wave (T area) is reflecting the electrical forces during repolarization. Volumetric response and survival after CRT were thought to be predicted strongly by the QRS area, but also T area and the sum of QRS and T areas (QRST area) [82, 83]. QRS area was also found repeatedly to be superior to QRS duration and morphology as a predictor of CRT response [28, 82, 84, 85]. One retrospective multicenter study displayed that this was true for a cohort of patients that received CRT and also for patients without a Class I indication for CRT according to American guideline recommendations [56] (QRS duration 120–149 ms or non-LBBB) [28]. Only the QRS area in these patients, was significantly associated with all-cause mortality. Reviewing volumetric CRT response, demonstrated that both QRS area and LBBB morphology were associated with an LV end-systolic volume reduction of = or >15 [28]. The advantage of the QRS area is that it is an objective measure and observer-independent parameter, whereas the definition for LBBB is subjective measure and operator-dependent. Variability in the QRS area is less than QRS duration as it is determined by QRS complex amplitude, not the beginning and end of the QRS complex [28]. VCG is not yet commercially available in clinical practice, but the QRS area is a promising non-invasive diagnostic evaluation tool for identifying possible CRT responders.

8.2 Improving our understanding of the biomechanics of cardiac electromechanical coupling and the contribution of spatial orientation of the ventricular muscle band to cardiac pumping functions

Perceiving heart pumping functions as a simple contraction of the bullet-shaped left ventricle is thought nowadays as a misunderstanding which contributes significantly to delaying the successful progress of electrical device treatment for heart failure. The process of contraction and myocardial stretch need more investigation at the cellular, as well as, at gross myocardial fibers orientation level. At the cellular level, electrical activation will trigger mechanical contraction via an intracellular calcium-dependent process known as excitation-contraction coupling. Disturbance of the process of cardiac myocyte intracellular calcium handling is a common feature of heart failure. At the organ scale, pump dysfunction is the end result of mechanical alterations secondary to electrical dyssynchrony in heart failure subjects. A reverse coupling between cardiac mechanics and electrophysiology is also well established. It is commonly referred to as cardiac mechanoelectric feedbackand is thought to be an important contributor to the increased risk of arrhythmia during pathological conditions that alter regional cardiac wall mechanics, including heart failure. The roles of stretch-activated ion channels and mechanisms that are independent of ionic currents need more investigation. We in the CRT community, are in high demand for new multicellular tissue-scale model systems and experiments to obtain a better understanding of how interactions between electrophysiological and mechanical processes at the cell scale affect ventricular electromechanical interactions at the organ scale in the normal and diseased heart [86]. At a gross level, many observations demand serious investigations considering proper understanding of the mechanics of heart pumping and the true contribution of the spatial orientation of the ventricular muscle band to cardiac pumping functions. Without this knowledge, our understanding and interpretation of ventricular activation and dyssynchrony will be deficient. The existence of right and left ventricles as a continuous muscle band has been proposed [87, 88, 89, 90]. The muscle band is organized in special spatial orientation as a helix formed by basal and apical loops. Both ventricular contraction and relaxation controlling the ejection and the filling of ventricles are thought to be affected by this unique arrangement [91, 92]. A deeper investigation of this spatial fibers orientation and the contribution of its activation sequence to cardiac pumping functions in health and disease will improve our therapeutic measures for proper resynchronization of dyssynchronized ventricles. Sengupta PP et al, elaborated in this direction and describe LV as a complex structure in which myofibers are arranged in the form of a left-handed helix in the subepicardium and of a right-handed helix in the subendocardium, while the mid-wall is consisting of circumferential fibers. This type of fibers arrangement allows for myocardial deformation in multiple planes and explains the complexity of the ventricular dyssynchrony process (Figure 3) [94]. During LV systole, there is apical counterclockwise rotation and basal clockwise rotation around the LV long axis. During LV diastole, there is Untwisting of the subendocardial layers that occurs during diastole and contribute to diastolic suctioning. Simultaneously, the LV shortens in systole and lengthens in diastole. At this level of understanding, we are confident that the extent of LV mechanical dysfunction is never a matter of one direction of motion or deformation. Future research for resynchronization therapy must consider this basic understanding.

Figure 3.

Twist mechanics of the left ventricle. A period of left ventricular isovolumic contraction (IVC) follows electrical and mechanical activation in the apical subendocardial region, during which (A), the subendocardial myofibers (right-handed helix) shorten with stretching of the subepicardial myofibres (left-handed helix) resulting in clockwise rotation of the apex and counterclockwise rotation of the base. Simultaneous shortening of the subendocardial and subepicardial layers is occurring during ejection (B). The larger arm of the moment of the subepicardial fibers dominates the direction of twist, causing counterclockwise and clockwise rotation of the apex and base, respectively. During isovolumic relaxation (IVR) (C). Subepicardial fibers lengthen from base to apex and subendocardial fibers lengthen from apex to base. In diastole, there is relaxation in both layers, with minimum untwisting (D). Illustration is from Sengupta PP [93].

8.3 Endocardial left ventricular pacing

Challenges of transvenous LV lead implantation including limitations of coronary sinus (CS) anatomy, high LV pacing threshold, and/or phrenic nerve capture, have led to serious efforts to look for better alternatives [94]. As compared to standard epicardial LV pacing, pacing the LV endocardium reflects a more rapid and physiological activation of the left ventricle. Shetty AK et al have identified greater acute hemodynamic improvements with endocardial versus conventional LV pacing [95]. Subjects who demonstrated CRT non-response or known to have LV lead technical difficulties were evaluated in the alternate site cardiac resynchronization study. Endocardial LV lead placement was found to be safe and reported clinical and echocardiographic improvement in two-third of subjects [96]. An important drawback of this new trend of an implant is the need for anticoagulation and the reported few cases of thromboembolic events despite anticoagulation. The endocardial wireless stimulation for CRT (EBR Systems, Sunnyvale, CA, USA) incorporates a pacing system using a small ultrasound-responsive leadless electrode placed onto the LV endocardial surface [97]. The safety and performance of electrodes implanted in the left ventricle study is coming up with encouraging results. A total of 35 patients who had failed conventional CRT implant, underwent successful implant in 97% of the sample [93]. At 6 months, approximately two-thirds of patients demonstrated LV reverse remodeling with improved LVEF ≥5%. LV endocardial pacing seems to be a revolution creator in CRT practice in the present and future.

8.4 His bundle pacing and His-optimized cardiac resynchronization therapy for electrical resynchronization in heart failure

In 1977, Narula et al. reported that the QRS complex may be normalized by pacing the distal His bundle in patients with LBBB [98]. Permanent pacing of the His bundle region to achieve ventricular resynchronizing has been described, with clear clinical advantages over traditional RV apical pacing [99, 100, 101, 102]. Medtronic has announced US Food and Drug Administration (FDA) clearance and commercial launch for the SelectSite C304-HIS deflectable catheter system for use in procedures involving His bundle pacing (HBP). The physiologic benefit of permanent His bundle pacing (HBP) is theresult of synchronous electrical and mechanical activation with stimulation of both ventricles through the intrinsic His-Purkinje system. The anatomic site of the conduction disorder seen with BBB is frequently located proximally within the bundle of His, with longitudinal dissociation of the conducting fibers [103, 104]. Overall, it has been reported that approximately three quarters of BBB patients were found to respond with QRS narrowing using HB pacing [103]. Using epicardial electrocardiography (ECG), imaging Arnold et al, demonstrated that HB pacing was superior to biventricular pacing for restoring LV synchrony in selected patients with LBBB [105]. In the presence of distal BBB or the co-existence of IVCD, QRS may not normalize. In patients without complete LBBB correction, Vijayaramanet P et al demonstrated that His-optimized CRT (HOT-CRT) with synchronized LV pacing resulted in significant QRS duration narrowing [106, 107]. In patients with atrioventricular (AV) block in whom fusion with intrinsic His-Purkinje conduction cannot be achieved, HOT-CRT may provide the new therapeutic option. However, it is wise to remember that QRS duration reflects total ventricular activation time which is not always equivalent to a perfect marker of LV synchrony. HOT-CRT was found to be a novel approach to further optimize electrical resynchronization by combining the concept of fused adaptive LV pacing with HBP.


9. Conclusion

CHF is one of the most important epidemics in the current human species era affecting 1–2% of adults and around 10% of >70 years old in developed countries. In addition to its psychophysiological and social burden, the economic impact of CHF on the world nations is Gargantum. Treatment options for CHF witnessed relative stagnation until 2001, where the first electrical device in the form of biventricular pacing to resynchronize the failing desynchronized ventricles, was implanted in 2001. In spite of the early excitement for this type of therapy most international landmark trials reported 30–40% of non-responders. Factors contributing to this large proportion of non-responders are related to scar burden and scar localization to the vicinity of the LV pacing stimulus, hypocontractility, and the degree of pre-implant mechanical dyssynchrony. It was surprising to medical communities to discover that a significant proportion of CHF without LBBB responds to CRT. This chapter is a scientific journey to understand the pathophysiological mechanism to optimize the selection of CRT responders. We confirm that LBBB is deficient criteria for selecting CHF patients for CRT. A spectrum of ventricular conduction disorders that might benefit from CRT, as derived from landmark trials were discussed including IVCD and RBBB. New techniques to detect dominant left ward electrical delay (LED) including endocardial 3-dimensional electroanatomical mapping and ECG imaging or body surface mapping to display electrical activation sequences as well as the elaboration of the best electrical substrate to optimize response to CRT in IVCD, RBBB, and atrioventricular delay are discussed. Determination of pre-implant degree of dyssynchrony is critical as pacing is known to induce more dyssynchrony for mild cases at the baseline with clinical and hemodynamic compromise. For this reason, special attention in this chapter was devoted to new echocardiographic mechanical dyssynchrony markers like eyeballing, septal flash, and time-based mechanical dyssynchrony markers. Systolic septal rebound stretch (SRSsept) was found to be an excellent echocardiographic discriminator to predict response to CRT. Cardiovascular Magnetic Resonance (CMR) was found to be an ideal radiation-free diagnostic tool for the diagnosis of the actual heart failure substrate and accordingly to optimize CRT responders selection. CRM is known to be the gold standard for scar diagnosis but is also considered to be an excellent diagnostic tool for fibrosis, myocarditis, sarcoidosis, arrhythmogenic right ventricular cardiomyopathy, amyloidosis, and Anderson-Fabry disease. Computed tomography is also an excellent tool to diagnose myocardial scar as well as for coronary venous system reconstruction images for optimal LV lead positioning. An innovative future direction for the best outcome of CRT is discussed. The non-invasive nature of vectorcardiography (VCG) with its strong prediction capabilities for volumetric as well as survival indicators after CRT, makes VCG an attractive adjunct diagnostic tool to optimize CRT responders selection. Improving our understanding of the biomechanics of cardiac electromechanical coupling and the contribution of the spatial orientation of the ventricular muscle band to cardiac pumping functions is creating a new visionary approach toward understanding the extent of LV mechanical dysfunction and perfective lead positioning in CRT subjects. New LV lead positions like pacing the LV endocardium reflect a more rapid and physiological activation of the left ventricle with excellent early results. Permanent pacing of the His bundle region to achieve ventricular resynchronizing has been described, with clear clinical advantages over biventricular pacing. Progressive narrowing in QRS duration was documented with HB pacing compared to conventional CRT with the best narrowing was gained with His-optimized cardiac resynchronization therapy (HOT-CRT). This multi-disciplinary approach to optimize CRT response is promising for a better future of resynchronization therapy aiming toward the best possible quality of life for this important group of CHF subjects in the next decades.


  1. 1. Braunwald E, Epstein SE, Glick G, Wechsler AS, Braunwald NS. Relief of angina pectoris by electrical stimulation of the carotid-sinus nerves. The New England Journal of Medicine. 1967;277(24):1278-1283. DOI: 10.1056/NEJM196712142772402
  2. 2. Aaronson KD, Schwartz JS, Chen TM, Wong KL, Goin JE, Mancini DM. Development and prospective validation of a clinical index to predict survival in ambulatory patients referred for cardiac transplant evaluation. Circulation. 1997;95:2660-2667
  3. 3. Baldasseroni S, Opasich C, Gorini M, et al. Left bundle-branch block is associated with increased 1-year sudden and total mortality rate in 5517 outpatients with congestive heart failure: A report from the Italian network on congestive heart failure. American Heart Journal. 2002;143:398-405
  4. 4. Stellbrink C, Nowak B. The importance of being synchronous: On the prognostic value of ventricular conduction delay in heart failure. Journal of the American College of Cardiology. 2002;40:2031-2033
  5. 5. Foster AH, Gold MR, McLaughlin JS. Acute hemodynamic effects of atrio-biventricular pacing in humans. The Annals of Thoracic Surgery. 1995;59:294-300
  6. 6. Leclercq C, Cazeau S, Le Breton H, et al. Acute hemodynamic effects of biventricular DDD pacing in patients with end-stage heart failure. Journal of the American College of Cardiology. 1998;32:1825-1831
  7. 7. Abraham WT, Fisher WG, Smith AL, Delurgio DB, Leon AR, Loh E, et al. Multicenter InSync Randomized Clinical Evaluation. Cardiac resynchronization in chronic heart failure. The New England Journal of Medicine. 2002;346:1845-1853
  8. 8. Bristow MR, Saxon LA, Boehmer J, Krueger S, Kass DA, De Marco T, et al. Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. The New England Journal of Medicine. 2004;350(21):2140-2150. DOI: 10.1056/NEJMoa032423. PMID: 15152059
  9. 9. Cleland JG, Daubert JC, Erdmann E, Freemantle N, Gras D, Kappenberger L, et al. The effect of cardiac resynchronization on morbidity and mortality in heart failure. New England Journal of Medicine. 2005;352:1539-1154
  10. 10. Tang ASL, Wells GA, Talajic M, et al. Cardiac-resynchronization therapy for mild-to-moderate heart failure. The New England Journal of Medicine. 2010;363:2385-2395. DOI: 10.1056/NEJMoa1009540
  11. 11. Linde C, Abraham WT, Gold MR, St John Sutton M, Ghio S, Daubert C, et al. Randomized trial of cardiac resynchronization in mildly symptomatic heart failure patients and in asymptomatic patients with left ventricular dysfunction and previous heart failure symptoms. Journal of the American College of Cardiology. 2008;52(23):1834-1843. DOI: 10.1016/j.jacc.2008.08.027. Epub 2008 Nov 7. PMID: 19038680
  12. 12. Moss AJ, Hall WJ, Cannom DS, Klein H, Brown MW, Daubert JP, et al. Cardiac resynchronization therapy for the prevention of heart failure events. New England Journal of Medicine. 2009;361:1329-1338
  13. 13. Abraham WT, Young JB, León AR, Adler S, Bank AJ, Hall SA, et al. Effects of cardiac resynchronization on disease progression in patients with left ventricular systolic dysfunction, an indication for an implantable cardioverter-defibrillator, and mildly symptomatic chronic heart failure. Circulation. 2004;110(18):2864-2868. DOI: 10.1161/01.CIR.0000146336.92331.D1 Epub 2004 Oct 25. PMID: 15505095
  14. 14. Gi-Byoung Nam recent clinical trials on cardiac resynchronization therapy. International Journal of Arrhythmia. 2012;13(3):17-21
  15. 15. Normand C, Linde C, Singh J, Dickstein K. Indications for cardiac resynchronization therapy: A comparison of the major international guidelines. JACC: Heart Failure. 2018;6:308-316
  16. 16. Stavrakis S, Lazzara R, Thadani U. The benefit of cardiac resynchronization therapy and QRS duration: A meta-analysis. Journal of Cardiovascular Electrophysiology. 2012;23:163-168
  17. 17. Kang SH, Oh IY, Kang DY, et al. Cardiac resynchronization therapy and QRS duration: Systematic review, meta-analysis, and meta-regression. Journal of Korean Medical Science. 2015;30:24-33
  18. 18. Boriani G, Nesti M, Ziacchi M, Padeletti L. Cardiac resynchronization therapy: An overview on guidelines. Heart Failure Clinics. 2017;13:117-137
  19. 19. Chung ES, Leon AR, Tavazzi L, et al. Results of the predictors of response to CRT (PROSPECT) trial. Circulation. 2008;117:2608-2616
  20. 20. Prinzen FW, Vernooy K, Auricchio A. Circulation. 2013;128(22):2407-2418. DOI: 10.1161/CIRCULATIONAHA.112.000112
  21. 21. Nakai T, Ikeya Y, Mano H, Kogawa R, Watanabe R, Arai M, et al. Efficacy of cardiac resynchronization therapy in patients with a narrow QRS complex. Journal of Interventional Cardiology. 2021: Article ID 8858836, 7 p. DOI: 10.1155/2021/8858836
  22. 22. Theuns DAMJ, Schaer BA, Caliskan K, Hoeks SE, Sticherling C, Yap SC, et al. Application of the heart failure meta-score to predict prognosis in patients with cardiac resynchronization defibrillators. International Journal of Cardiology. 2021;330:73-79. DOI: 10.1016/j.ijcard.2021.01.011
  23. 23. Vernooy K, Cornelussen RNM, Verbeek XAAM, et al. Cardiac resynchronization therapy cures dyssynchronopathy in canine left bundle-branch block hearts. European Heart Journal. 2007;28:2148-2155
  24. 24. Cardone-Noott L, Bueno-Orovio A, Minchole A, Zemzemi N, Rodriguez B. Human ventricular activation sequence and the simulation of the electrocardiographic QRS complex and its variability in healthy and intraventricular block conditions. Europace. 2016;18:iv4-iv15. DOI: 10.1093/europace/euw346
  25. 25. Ploux S, Eschalier R, Whinnett ZI, et al. Electrical dyssynchrony induced by biventricular pacing: Implications for patient selection and therapy improvement. Heart Rhythm. 2015;12:782-791
  26. 26. Ruschitzka F, Abraham WT, Singh JP, et al. Cardiac resynchronization therapy in heart failure with a narrow QRS complex. The New England Journal of Medicine. 2013;10:1395-1405
  27. 27. Thibault B, Harel F, Ducharme A, et al. Cardiac resynchronization therapy in patients with heart failure and a QRS complex <12 msec: The evaluation of resynchronization therapy for heart failure (LESSER-EARTH) trial. Circulation. 2013;127:873-881
  28. 28. Van Stipdonk AMW, Horst I, Kloosterman M, et al. QRS area is a strong determinant of outcome in cardiac resynchronization. Circulation. Arrhythmia and Electrophysiology. 2018;11:E006497
  29. 29. Van Stipdonk AMW, Vanbelle S, ter Horst IAH, et al. Large variability in clinical judgement and definitions of left bundle branch block to identify candidates for cardiac resynchronisation therapy. International Journal of Cardiology. 2019;286:61-65
  30. 30. Zareba W, Klein H, Cygankiewicz I, et al. Effectiveness of cardiac resynchronization therapy by QRS morphology in the Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy (MADIT-CRT). Circulation. 2011;123:1061-1072
  31. 31. Gold MR, Thébault C, Linde C, et al. Effect of QRS duration and morphology on cardiac resynchronization therapy outcomes in mild heart failure: Results from the Resynchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction (REVERSE) study. Circulation. 2012;126:822-829
  32. 32. Cleland JG, Abraham WT, Linde C, et al. An individual patient meta-analysis of five randomized trials assessing the effects of cardiac resynchronization therapy on morbidity and mortality in patients with symptomatic heart failure. European Heart Journal. 2013;34:3547-3556
  33. 33. Ploux S, Lumens J, Whinnett Z, et al. Noninvasive electrocardiographic mapping to improve patient selection for cardiac resynchronization therapy: Beyond QRS duration and left bundle branch block morphology. Journal of the American College of Cardiology. 2013;61:2435-2443
  34. 34. Fantoni C, Kawabata M, Massaro R, et al. Right and left ventricular activation sequence in patients with heart failure and right bundle branch block: A detailed analysis using three-dimensional nonfluoroscopic electroanatomic mapping system. Journal of Cardiovascular Electrophysiology. 2005;16:112-119; discussion 120-1
  35. 35. Derval N, Duchateau J, Mahida S, et al. Distinctive left ventricular activations associated with ECG pattern in heart failure patients. Circulation. Arrhythmia and Electrophysiology. 2017;10:E005073
  36. 36. Eschalier R, Ploux S, Ritter P, Haissaguerre M, Ellenbogen KA, Bordachar P. Nonspecific intraventricular conduction delay: Definitions, prognosis, and implications for cardiac resynchronization therapy. Heart Rhythm. 2015;12:1071-1079
  37. 37. Van Stipdonk A, Mafi Rad M, Luermans JGLM, Crijns HJ, Prinzen FW, Vernooy K. Identifying delayed left ventricular lateral wall activation in patients with non-specific intraventricular conduction delay using coronary venous electroanatomical mapping. Netherlands Heart Journal. 2016;24:58-65
  38. 38. Kawata H, Bao H, Curtis JP, et al. Cardiac resynchronization defibrillator therapy for nonspecific intraventricular conduction delay versus right bundle branch block. Journal of the American College of Cardiology. 2019;73:3082-3099
  39. 39. Auricchio A, Lumens J, Prinzen FW. Does cardiac resynchronization therapy benefit patients with right bundle branch block: Cardiac resynchronization therapy has a role in patients with right bundle branch block. Circulation. Arrhythmia and Electrophysiology. 2014;7:532-542
  40. 40. Byrne MJ, Helm RH, Daya S, et al. Diminished left ventricular dyssynchrony and impact of resynchronization in failing hearts with right versus left bundle branch block. Journal of the American College of Cardiology. 2007;50:1484-1490
  41. 41. Rosenbaum MB. Types of left bundle branch block and their clinical significance. Journal of Electrocardiology. 1969;2:197-206
  42. 42. Tzogias L, Steinberg LA, Williams AJ, et al. Electrocardiographic features and prevalence of bilateral bundle-branch delay. Circulation. Arrhythmia and Electrophysiology. 2014;7:640-644
  43. 43. Leeters IPM, Davis A, Zusterzeel R, et al. Left ventricular regional contraction abnormalities by echocardiographic speckle tracking in combined right bundle branch with left anterior fascicular block compared to left bundle branch block. Journal of Electrocardiology. 2016;49:353-361
  44. 44. Salden FCWM, Kutyifa V, Stockburger M, Prinzen FW, Vernooy K. Atrioventricular dromotropathy: Evidence for a distinctive entity in heart failure with prolonged PR interval? Europace. 2017;20:1067-1077
  45. 45. Kwok CS, Rashid M, Beynon R, et al. Prolonged PR interval, first-degree heart block and adverse cardiovascular outcomes: A systematic review and meta-analysis. Heart. 2016;102:672-680
  46. 46. Friedman DJ, Bao H, Spatz ES, Curtis JP, Daubert JP, Al-Khatib SM. Association between a prolonged PR interval and outcomes of cardiac resynchronization therapy: A report from the National Cardiovascular Data Registry. Circulation. 2016;134:1617-1628
  47. 47. Januszkiewicz Ł, Vegh E, Borgquist R, et al. Prognostic implication of baseline PR interval in cardiac resynchronization therapy recipients. Heart Rhythm. 2015;12:2256-2262
  48. 48. Kutyifa V, Stockburger M, Daubert JP, et al. PR interval identifies clinical response in patients with non-left bundle branch block: A Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy substudy. Circulation. Arrhythmia and Electrophysiology. 2014;7:645-651
  49. 49. Lin J, Buhr KA, Kipp R. Effect of PR interval on outcomes following cardiac resynchronization therapy: A secondary analysis of the COMPANION trial. Journal of Cardiovascular Electrophysiology. 2017;28:185-191
  50. 50. Olshansky B, Day JD, Sullivan RM, Young P, Galle E, Steinberg JS. Does cardiac resynchronization therapy provide unrecognized benefit in patients with prolonged PR intervals? The impact of restoring atrioventricular synchrony: An analysis from the COMPANION trial. Heart Rhythm. 2012;9:34-39
  51. 51. Packer M. Proposal for a new clinical end point to evaluate the efficacy of drugs and devices in the treatment of chronic heart failure. Journal of Cardiac Failure. 2001;7:176-182
  52. 52. Jackson T, Claridge S, Behar J, Sammut E, Webb J, Carr-White G, et al. Narrow QRS systolic heart failure: Is there a target for cardiac resynchronization? Expert Review of Cardiovascular Therapy. 2015;13(7):783-797. DOI: 10.1586/14779072.2015.1049945
  53. 53. Leenders GE, De Boeck BWL, Teske AJ, et al. Septal rebound stretch is a strong predictor of outcome after cardiac resynchronization therapy. Journal of Cardiac Failure. 2012;18:404-412
  54. 54. Gorcsan J III, Anderson CP, Tayal B, et al. Systolic stretch characterizes the electromechanical substrate responsive to cardiac resynchronization therapy. JACC. Cardiovascular Imaging. 2019;12:1741-1752
  55. 55. Beela AS, Serkan U, Ciarka A, et al. Assessment of mechanical dyssynchrony can improve the prognostic value of guideline based patient selection for cardiac resynchronization therapy. European Heart Journal Cardiovascular Imaging. 2019;20:66-74
  56. 56. Tracy CM, Epstein AE, Darbar D, et al. 2012 ACCF/AHA/HRS focused update incorporated into the ACCF/AHA/HRS 2008 guidelines for device based therapy of cardiac rhythm abnormalities: A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. Journal of the American College of Cardiology. 2013;61:e6-e75
  57. 57. Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure of the European Society of Cardiology (ESC): Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. European Heart Journal. 2016;37:2129-2200
  58. 58. De Boeck BWL, Teske AJ, Meine M, Leenders GE, Cramer MJ, Prinzen FW, et al. Septal rebound stretch reflects the functional substrate to cardiac resynchronization therapy and predicts volumetric and neurohormonal response. European Journal of Heart Failure. 2009;11:863-871
  59. 59. Lumens J, Tayal B, Walmsley J, Delgado-Montero A, Huntjens PR, Schwartzman D, et al. Differentiating electromechanical from non-electrical substrates of mechanical discoordination to identify responders to cardiac resynchronization therapy. Circulation. Cardiovascular Imaging. 2015;8:e003744
  60. 60. Risum N, Tayal B, Hansen TF, Bruun NE, Jensen MT, Lauridsen TK, et al. Identification of typical left bundle branch block contraction by strain echocardiography is additive to electrocardiography in prediction of long-term outcome after cardiac resynchronization therapy. Journal of the American College of Cardiology. 2015;66:631-641
  61. 61. Prinzen FW, Hunter WC, Wyman BT, Mcveigh ER. Mapping of regional myocardial strain and work during ventricular pacing: Experimental study using magnetic resonance imaging tagging. Journal of the American College of Cardiology. 1999;33:1735-1742
  62. 62. Leenders GE, Lumens J, Cramer MJ, De Boeck BWL, Doevendans PA, Delhaas T, et al. Septal deformation patterns delineate mechanical dyssynchrony and regional differences in contractility analysis of patient data using a computer model. Circulation. Heart Failure. 2012;5:87-96
  63. 63. Galli E, Leclercq C, Fournet M, Hubert A, Bernard A, Smiseth OA, et al. Value of myocardial work estimation in the prediction of response to cardiac resynchronization therapy. Journal of the American Society of Echocardiography. 2018;31:220-230
  64. 64. Smiseth OA, Russell K, Skulstad H. The role of echocardiography in quantification of left ventricular dyssynchrony: State of the art and future directions Otto. European Heart Journal Cardiovascular Imaging. 2012;13:61-68
  65. 65. Salden OAE, Zweerink A, Wouters P, Allaart CP, Geelhoed B, de Lange FJ, et al. The value of septal rebound stretch analysis for the prediction of volumetric response to cardiac resynchronization therapy. European Heart Journal—Cardiovascular Imaging. 2021;22(1):37-45. DOI: 10.1093/ehjci/jeaa190
  66. 66. Van Sant J, Horst IAH, Wijers SC, Mast TP, Leenders GE, Doevendans PA, et al. Measurements of electrical and mechanical dyssynchrony are both essential to improve prediction of CRT response. Journal of Electrocardiology. 2015;48:601-608
  67. 67. Salden OAE, Vernooy K, van Stipdonk AMW, Cramer MJ, Prinzen FW, Meine M. Strategies to improve selection of patients without typical left bundle branch block for cardiac resynchronization therapy. JACC: Clinical Electrophysiology. 2020;6(2):129-142. ISSN 2405-500X. DOI: 10.1016/j.jacep.2019.11.018
  68. 68. Torrent-Guasp F, Kocica MJ, Corno AF, Komeda M, Carreras-Costa F, Flotats A, et al. Towards new understanding of the heart structure and function. European Journal of Cardio-Thoracic Surgery. 2005;27:191-201
  69. 69. Greenbaum RA, Ho SY, Gibson DG, Becker AE, Anderson RH. Left ventricular fibre architecture in man. British Heart Journal. 1981;45(3):248-263
  70. 70. Yettram A, Vinson CA, Gibson DG. Effect of myocardial fibre architecture on the behaviour of the human left ventricle in diastole. Journal of Biomedical Engineering. 1983;5:321-328
  71. 71. Antzelevitch C, Fish J. Electrical heterogeneity within the ventricular wall. Basic Research in Cardiology. 2001;96:517-527
  72. 72. Cassidy D, Vassallo J, Miller J, Poll D, Buxton A, Marchinski F, et al. Endocardial catheter mapping in patients in sinus rhythm: Relationship to underlying heart disease and ventricular arrhythmias. Circulation. 1986;73:645-652
  73. 73. Tournoux F, Donal E, Leclercq C, De Place C, Crocq C, Solnon A, et al. Concordance between mechanical and electrical dyssynchrony in heart failure patients: A function of the underlying cardiomyopathy? Journal of Cardiovascular Electrophysiology. 2007;18:1022-1027
  74. 74. Leyva F. Cardiac resynchronization therapy guided by cardiovascular magnetic resonance. Journal of Cardiovascular Magnetic Resonance. 2010;12:64. DOI: 10.1186/1532-429X-12-64
  75. 75. Foley PW, Khadjooi K, Ward JA, Smith RE, Stegemann B, Frenneaux MP, et al. Radial dyssynchrony assessed by cardiovascular magnetic resonance in relation to left ventricular function, myocardial scarring and QRS duration in patients with heart failure. Journal of Cardiovascular Magnetic Resonance. 2009;11(1):50-56
  76. 76. White JA, Yee R, Yuan X, Krahn A, Skanes A, Parker M, et al. Delayed enhancement magnetic resonance imaging predicts response to cardiac resynchronization therapy in patients with intraventricular dyssynchrony. Journal of the American College of Cardiology. 2006;48(10):1953-1960
  77. 77. Chalil S, Foley P, Muyhaldeen S, Patel K, Yousef Z, Smith R, et al. Late gadolinium enhancement-cardiovascular magnetic resonance as a predictor of response to cardiac resynchronization therapy in patients with ischaemic cardiomyopathy. Europace. 2007;9:1031-1037
  78. 78. Pezel T, Mika D, Logeart D, et al. Characterization of non-response to cardiac resynchronization therapy by post-procedural computed tomography. Pacing and Clinical Electrophysiology. 2021;44:135-144. DOI: 10.1111/pace.14134
  79. 79. Galand V, Ghoshhajra B, Szymonifka J, Das S, Orencole M, Barré V, et al. Left ventricular wall thickness assessed by cardiac computed tomography and cardiac resynchronization therapy outcomes. EP Europace. 2020;22(3):401-411. DOI: 10.1093/europace/euz322
  80. 80. McAlister FA, Ezekowitz J, Hooton N, et al. Cardiac resynchronization therapy for patients with left ventricular systolic dysfunction: A systematic review. JAMA. 2007;297:2502-2514
  81. 81. Fornwalt BK, Sprague WW, BeDell P, et al. Agreement is poor among current criteria used to define response to cardiac resynchronization therapy. Circulation. 2010;121:1985-1991
  82. 82. Emerek K, Friedman DJ, Sørensen PL, et al. Vectorcardiographic QRS area is associated with long-term outcome after cardiac resynchronization therapy. Heart Rhythm. 2019;16:213-219
  83. 83. Engels EB, Végh EM, Van Deursen CJ, Vernooy K, Singh JP, Prinzen FW. T-wave area predicts response to cardiac resynchronization therapy in patients with left bundle branch block. Journal of Cardiovascular Electrophysiology. 2015;26:176-183
  84. 84. Van Deursen CJM, Vernooy K, Dudink E, et al. Vectorcardiographic QRS area as a novel predictor of response to cardiac resynchronization therapy. Journal of Electrocardiology. 2015;48:45-52
  85. 85. Maass AH, Vernooy K, Wijers SC, et al. Refining success of cardiac resynchronization therapy using a simple score predicting the amount of reverse ventricular remodelling: Results from the Markers and Response to CRT (MARC) study. Ep Europace. 2018;20:e1-e10
  86. 86. Pfeiffer ER, Tangney JR, Omens JH, McCulloch AD. Biomechanics of cardiac electromechanical coupling and mechanoelectric feedback. Journal of Biomechanical Engineering. 2014;136(2):021007. DOI: 10.1115/1.4026221
  87. 87. Torrent-Guasp F. Anatomía Funcional del Corazón. Madrid: PazMontalbo; 1957
  88. 88. Torrent-Guasp F. An Experimental Approach in Heart Dynamics Physiology and Pharmacology. Eugene Talmadge Hospital. Augusta (GA). Madrid: S. Aguirre Torre; 1959
  89. 89. Streeter DD, Torrent-Guasp F. Geodesic paths in the left ventricle of the mammalian heart. Circulation. 1973;48:471-477
  90. 90. Streeter DD, Powers WE, Ross MA, Torrent-Guasp F. Three-dimensional fiber orientation in the mammalian left ventricular wall. In: Barn J, Noordegraf A, Raines J, editors. Cardiovascular System Dynamics. Cambridge: MIT Press; 1978. p. 73
  91. 91. Torrent-Guasp F. Estructura y función del corazón. Revista Española de Cardiología. 1998;51:91-102
  92. 92. Ballester-Rodés M, Flotats A, Torrent-Guasp F, Carrió-Gasset I, Ballester-Alomar M, Carreras F, et al. The sequence of regional ventricular motion. European Journal of Cardio-Thoracic Surgery. 2006;29(Suppl_1):S139–S144. DOI: 10.1016/j.ejcts.2006.02.058
  93. 93. Sengupta PP, Khandheria BK, Narula J. Twist and untwist mechanics of the left ventricle. Heart Failure Clinics. 2008;4(3):315-324. DOI: 10.1016/j.hfc.2008.03.001
  94. 94. Reddy VY, Miller MA, Neuzil P, et al. Cardiac resynchronization therapy with wireless left ventricular endocardial pacing: The SELECT-LV study. Journal of the American College of Cardiology. 2017;69:2119-2129
  95. 95. Shetty AK, Sohal M, Chen Z, et al. A comparison of left ventricular endocardial, multisite, and multipolar epicardial cardiac resynchronization: An acute haemodynamic and electroanatomical study. Europace. 2014;16:873-879
  96. 96. Morgan JM, Biffi M, Gellér L, et al. ALternate Site Cardiac ResYNChronization (ALSYNC): A prospective and multicentre study of left ventricular endocardial pacing for cardiac resynchronization therapy. European Heart Journal. 2016;37:2118-2127
  97. 97. Auricchio A, Delnoy PP, Butter C, et al. Feasibility, safety, and short-term outcome of leadless ultrasoundbased endocardial left ventricular resynchronization in heart failure patients: Results of the wireless stimulation endocardially for CRT (WiSE-CRT) study. Europace. 2014;16:681-688
  98. 98. Narula OS. Longitudinal dissociation in the Hisbundle. Bundle branch block due to asynchronousconduction within the His bundle in man. Circulation. 1977;56:996-1006
  99. 99. Lustgarten DL, Calame S, Crespo EM, Calame J, Lobel R, Spector PS. Electrical resynchronization induced by direct His-bundle pacing. Heart Rhythm. 2010;7:15-21
  100. 100. Deshmukh P, Casavant DA, Romanyshyn M, Anderson K. Permanent, direct His-bundle pacing: A novel approach to cardiac pacing in patients with normal His-Purkinje activation. Circulation. 2000;101:869-877
  101. 101. Barba-Pichardo R, Manovel Sanchez A, Fernandez-Gomez JM, Morina-Vazquez P, Venegas-Gamero J, Herrera-Carranza M. Ventricular resynchronization therapy by direct His-bundle pacing using an internal cardioverter defibrillator. Europace. 2013;15:83-88
  102. 102. Sharma PS, Naperkowski A, Oren JW, Storm RH, Ellenbogen KA, Vijayaraman P. Permanent His-bundle pacing is feasible, safe, and superior to right ventricular pacing in routine clinical practice. Heart Rhythm. 2014;0:1-8
  103. 103. Lee MY, Yeshwant SC, Lustgarten DL. Honing in on optimal ventricular pacing sites: An argument for his bundle pacing. Current Treatment Options in Cardiovascular Medicine. 2015;17:372
  104. 104. Upadhyay GA, Cherian T, Shatz DY, et al. Intracardiac delineation of septal conduction in left bundle-branch block patterns. Circulation. 2019;139:1876-1888
  105. 105. Teng AE, Massoud L, Ajijola OA. Physiological mechanisms of QRS narrowing in bundle branch block patients undergoing permanent His bundle pacing. Journal of Electrocardiology. 2016;49:644-648
  106. 106. Arnold AD, Shun-Shin MJ, Keene D, et al. His resynchronization versus biventricular pacing inpatients with heart failure and left bundle branchblock. Journal of the American College of Cardiology. 2018;72:3112-3122
  107. 107. Vijayaraman P, Herweg B, Ellenbogen KA, Gajek J. His-optimized cardiac resynchronizationtherapy to maximize electrical resynchronization: a feasibility study. Circulation: Arrhythmia Electrophysiology. 2019;12:e006934

Written By

Abdullah Alabdulgader

Submitted: October 6th, 2021 Reviewed: November 12th, 2021 Published: February 18th, 2022