The Impact of Cardiac Resynchronization Therapy in the Treatment of Heart Failure The Impact of Cardiac Resynchronization Therapy in the Treatment of Heart Failure

The number of patients who suffer from heart failure is rapidly increasing. In about one‐ third of heart failure patients, conduction delays cause dyssynchronous left ventricular contractions, which leads to reduction in left ventricular function, adverse cardiac remod‐ elling and finally increased mortality. Cardiac resynchronization involves simultaneous pacing of both ventricles, and improves left ventricular contractile function. Although resynchronization does not restore myocardial function, multiple studies have shown that cardiac resynchronization therapy improves quality of life, exercise capacity, symp‐ toms of heart failure, left ventricular ejection fraction, morbidity and mortality. The use of cardiac resynchronization therapy has increased significantly, since its initial approval in 2001, in patients with advanced heart failure.


Introduction
The number of patients who suffer from chronic heart failure is rapidly growing. According to the 2016 update on heart disease and stroke statistics reported by the American Heart Association, an estimated 5.7 million Americans ≥20 years of age have a diagnosis of heart failure and projections show that the prevalence of heart failure will increase 46% from 2012 to 2030, resulting in >8 million people ≥18 years of age with heart failure [1]. In the year of 2013, heart failure was the underlying cause in >65,000 deaths and contributed to the death of >300,000 people [1]. In the same report, there is an estimate that a total cost of over $30 billion was used for the treatment of heart failure in 2012 [1]. Direct medical costs attributed to 68% of this total amount. The lifetime risk of developing heart failure is 20% for adults at the age of 40 years and goes up with age. Acute heart failure consists of one of the most common reasons for hospitalization, attributing to over 1 million discharges annually and high 30-day readmission rates (up to 25%) and 1 year (up to 60%) [1]. The prognosis for heart failure is poor, with an estimated mortality rate of 50% within 5 years of diagnosis.

Advent of CRT
An intraventricular conduction delay is found in approximately 20-30% of patients with symptomatic heart failure. Conduction delay causes dyssynchronous left ventricular contractions, which lead to left ventricular dysfunction, adverse cardiac remodelling and eventually high mortality [2][3][4]. Conduction delay may also lead to mitral valve regurgitation, thus increasing symptoms of heart failure. The prevalence of left ventricular dyssynchrony in heart failure has been shown to increase with reduced left ventricular ejection fraction and with increased QRS width [5][6][7].
Cardiac resynchronization therapy (CRT), which was first introduced for clinical use in 1996, attempts to restore ventricular synchrony in patients who suffer from dilated cardiomyopathy with a widened QRS complex to improve the mechanical efficiency of left ventricular contraction. Since U.S. Food and Drug Administration (FDA) approval, the use of CRT has steadily increased [8]. Sridhar and colleagues showed a trend in CRT device implantation in the United States [9] (Figure 1).

Mechanism of CRT
Janaswamy et al. listed the studies which demonstrated that the presence of a bundle branch block or other intraventricular conduction delay can worsen heart failure due to systolic dysfunction by causing ventricular dyssynchrony [10] ( Table 1). The rationale for CRT is based upon these findings. These acute mechanical benefits of CRT can be accompanied with more chronic adaptations that lead to long-term benefit in the patient who suffers from heart failure [11].
Nowadays, it has been reported that CRT improves quality of life, exercise capacity, symptoms of heart failure by [12][13][14][15][16] left ventricular ejection fraction [17,18], morbidity and mortality [18] in patients with moderate to severe left ventricular dysfunction with a wide QRS complex. The benefit of CRT in mild to moderate heart failure has also been demonstrated by several studies [19][20][21][22][23]. Long-term beneficial effects on left ventricular function were shown by positron emission tomography evaluations, and CRT enhances myocardial forward work efficiency at rest in patients with dilated cardiomyopathy and heart failure [24,25].
CRT improves left ventricular contractile function in patients with heart failure associated with left bundle branch block. Improved efficiency from resynchronization pacing is unlikely due to the alterations in intrinsic myocyte function. The improvement of ventricular function is the result of improved efficiency of the work performed by different regions of the wall. Nelson et al. demonstrated that pressure-volume loops display an increase in loop area and width (stroke work and volume, respectively) and a decline in end systolic volume with pacing [25]. In spite of improvements in systolic function, myocardial oxygen consumption decreases due to a slight fall in coronary flow as well as transcardiac oxygen gradient.

U.S. trends in CRT
CRT is now recommended for patients with heart failure due to systolic dysfunction combined with intraventricular delay. CRT is also recommended in addition to guideline-directed medical therapy, such as angiotensin-converting enzyme inhibitors, beta blockers, aldosterone antagonist therapy and implantable cardioverter defibrillators (ICDs) when indicated for primary or secondary prevention of sudden cardiac death.
Sridhar et al. used the Nationwide Inpatient Sample database to identify all patients who underwent CRT implantation during 2002-2010 [9]. The overall trends in CRT device implantation, patient characteristics and outcomes were studied in detail and comparisons among demographic subgroups were performed. They found that an average of 41,578 CRT device implantations was performed per year. There has been a significant increase in the percentage of CRTs implanted in patients with advanced age (≥85 years). There were significant differences in CRT utilization favouring male and whites compared with female and black patients, respectively, in spite of adjustments for rates of heart failure. The highest numbers of implants were found in the patient group with moderate comorbidity (48%), followed by mild comorbidity group (39/7%). The overall number of CRT implantations in the severe comorbidity group was the lowest (12.3%). However, in the recent years, there has been a significant increase in the number of CRT implantation in this category (Figure 2).

Outcomes of CRT implantation
The in-hospital mortality rates associated with CRT implantation is shown in Figure 3.
For an elective CRT procedure, the mean length of stay was 2.81 days and the median was 1.00 day. The overall in-hospital mortality following CRT implantation was 0.87%, which has decreased significantly from 2003 to 2010 (1.08 in 2003 to 0.70% in 2010; P = 0.03). Mortality following elective CRT implantation was 0.4% compared with 1.0% with non-elective CRT implantations. The mortality was higher in male (0.93%) compared with female (0.71%), and decrease in mortality was observed in both male and female. The mortality rate in advanced age group (≥85 years) was significantly higher compared with younger population (<85 years). However, the mortality rate in the ≥85-year group has significantly decreased in recent years. Patients with The Role of the Clinical Cardiac Electrophysiologist in the Management of Congestive Heart Failure severe comorbidities had significantly higher overall mortality (1.5%) compared with those with moderate (0.8%) or mild (0.7%) comorbidities (P < 0.001). However, mortality in all three comorbidity groups has decreased in recent years, most notably in the severe comorbidity group.
In terms of complications associated with CRT implantation, pericardial effusion was found in 0.2%, pneumothorax was found in 1.4% and hematoma was found in 3.0% of all CRT implantation procedures.

Implantation technique of CRT
Electrophysiologists are the main players for the CRT implantation. The CRT implantation requires the placement of a left ventricular pacing lead, which is fed onto the epicardial surface through a venous branch of the coronary sinus (Figure 4). Difficulty with coronary sinus cannulation, challenging anatomy of coronary sinus venous tributaries, unacceptable pacing and sensing thresholds, unavoidable phrenic nerve pacing and lead dislodgement have resulted in a 10-20% failure rate associated with left ventricular lead placement [16,26]. When a transvenous lead implantation at desired sites is not achievable, epicardial left ventricular leads can easily be placed surgically directly on the lateral or posterolateral wall. Garikipati et al. performed a randomized study and reported no difference in the echocardiographic and clinical outcomes comparing a conventional transvenous approach versus surgical epicardial left ventricular lead placement for CRT [27]. Therefore, surgical approaches are a viable alternative when a transvenous procedure has failed or is not feasible.
Zhang et al. reported that advanced age, male sex, ischemic cause, end-stage heart failure, inadequate electrical delay and absence of mechanical dyssynchrony are regarded as nonmodifiable risk factors for CRT non-responders [28]. However, efforts should be made to correct modifiable factors, such as suboptimal medical therapy, uncontrolled atrial fibrillation, left ventricular lead dislodgement or inappropriate location, loss of biventricular capture and lack of device optimization. Echocardiography and Cardiac Doppler of the Belgian Society of Cardiology. Prevalence of mechanical dyssynchrony in patients with heart failure and preserved left ventricular function (a report from the Belgian multicenter registry on dyssynchrony). Am J Cardiol. 2005;96(11):1543-8.