**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 [33–35]. The ECG imaging

*CRT Past, Present, and Future Directions: Toward Intelligent Responders Selection… DOI: http://dx.doi.org/10.5772/intechopen.101608*

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 [48–50]. *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.*
