Regression of left ventricular mass and wall thickness after cardiac resynchronization therapy: proof of pathophysiological concept.

Cardiac resynchronization therapy (CRT) has become an established therapy for patients with NYHA class 3 and 4 heart failure, with a left ventricular (LV) ejection fraction (EF) ,35%, and a wide QRS complex of .120 ms, especially in patients with a complete left bundle branch block (CLBBB). A number of studies have shown that patients with these characteristics may benefit from this therapy in terms of quality-of-life (QoL), exercise capacity, LV function, LV dimensions/volumes, morbidity, and even mortality. The key to understanding these effects lies in the term asynchrony as the most important determinant for success of CRT. Asynchrony, which means that parts of the heart and particularly the LV are out of phase during LV contraction and relaxation, can occur at three levels within the heart: atrioventricular (timing of atrial contraction to LV and RV contraction and relaxation, interventricular (between LV and RV), and intraventricular (between different segments of the LV). Asynchrony leads to several deleterious pathophysiological effects: abnormal interventricular septal wall motion, increased regional/global wall stress, reduced dP/dt, reduced pulse pressure, reduced EF and cardiac output, increased LV dimensions/volumes, LV regional hypertrophy, reduced diastolic filling time, increased mitral regurgitation, increased myocardial oxygen consumption, and decreased cardiac energetic efficiency. The final common pathway of all these effects is overt clinical heart failure with its inherent loss of QoL, hospital readmissions, and mortality. CRT may abolish and even reverse several, and sometimes all of these effects. If the effects of CRT are to be evaluated it is important to discriminate clinical responders from patients with so called reverse remodelling. In the former, the clinical improvement may be due to a placebo effect (estimated to occur in 40% of cases after CRT), whereas in the latter improvement is a reflection of favourable pathophysiological changes after CRT, which usually, but not invariably, are also accompanied by clinical improvement. In the next section, the focus will be on the pathophysiological changes after CRT. For the understanding of these changes there are three factors, which are of paramount importance in determining whether a patient will be a responder to CRT in terms of reverse remodelling. These are the magnitude and extent of mechanical asynchrony, the amount and localization of myocardial viability, and the position and timing of pre-excitation (and therefore pacemaker lead positioning, programming, and venous anatomy). It is obvious that QRS width, and morphology (which mainly reflect interventricular asynchrony) are poor indicators of mechanical asynchrony. Despite prolonged QRS duration, 20–30% of patients are non-responders to CRT. Therefore, assessment of asynchrony by ultrasound or other imaging techniques should be the goal. Although there is no doubt on the importance of optimizing the AV interval, there is still an ongoing debate and research about the predictive value of intervs. intraventricular mechanical asynchrony. To further complicate this matter, there are several ultrasound techniques for evaluating interventricular asynchrony (pulsed-wave Doppler vs. tissue Doppler), and intraventricular asynchrony [M-Mode echocardiography, 2Dand real-time 3D echocardiography, tissue Doppler imaging (TDI), and strain-, and strain rate imaging]. All of these techniques have their relative strengths and weaknesses, and a detailed description and discussion is beyond the scope of this editorial. After CRT, in patients with LV volumetric reverse remodelling, there is a reduction of LV dimensions/volumes, mitral regurgitation, and an improvement in LVEF. The time-course of these events may vary from acute to up to 18 months. LV reverse remodelling defined as a 10% reduction of LV endsystolic volume (LVESV) after 3–6 months of CRT was observed to be associated with a significantly lower allcause mortality and heart failure events. From experimental work and retrospective patient data it was already known that the early-activated region of the myocardium (i.e. the septum in CLBBB patients) is thinner than the