Number 39, 2008
Cardiac Efficiency in Health and Disease

Improvement of cardiac efficiency in heart failure by cardiac resynchronization therapy

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Matthew Ginks, C. Aldo Rinaldi
Department of Cardiology, St Thomas’ Hospital, London, UK
Correspondence: Dr C. A. Rinaldi, Department of Cardiology, St Thomas’ Hospital, London, SE1 7EH UK.
Tel: +44 0207 1889257; e-mail: aldo.rinaldi@gstt.nhs.uk

Introduction
Heart failure is frequently associated with intracardiac conduction delay, usually manifested on the surface electrocardiogram (ECG) as left bundle branch block [1]. Such conduction abnormalities may translate into mechanical “dyssynchrony”, with delayed stimulation and contraction of the lateral wall of the left ventricle. The uncoordinated contraction that arises causes the efficiency of the heart as a pump to be significantly reduced.
Cardiac resynchronization therapy (CRT) can be performed to normalize the timing of activation of the left ventricle and thereby restore coordinated contraction and mechanical efficiency. This is usually achieved by positioning a pacing lead on the epicardial surface of the left ventricle, via a tributary of the coronary sinus (Figure 1) [2]. Typically, empirical positioning of the lead in the posterolateral vein gives the best hemodynamic response [3].

Evidence for the benefit of CRT
Several large-scale randomized trials have shown CRT to be associated with improvements in New York Heart Association (NHYA) class, quality of life, 6-minute walk distance, and peak myocardial oxygen consumption (mV˙O2), in addition to a reduction in admissions to hospital because of heart failure [4–6]. More recently a mortality benefit has also been shown, in addition to the other positive effects of CRT [7]. CRT is able to improve cardiac output by correction of mechanical dyssynchrony, and this increase in cardiac output appears to take place without an increase in metabolic demand, thereby representing improved cardiac efficiency [8].
In the long term, CRT may also give rise to reverse remodeling, whereby pathological dilatation is reversed and mechanics of the left ventricle are improved [9]. A reduction in mitral regurgitation may also improve cardiac efficiency, either acutely if papillary muscle dyssynchrony is the cause, or in conjunction with reverse remodeling in the setting of functional mitral regurgitation as a result of mitral annular dilatation [10]. Optimization of both atrioventricular and interventricular delays by programming of the CRT device improves atrial transport and enhances diastolic function.
In addition to improvements in cardiac efficiency, and symptomatic and mortality benefits, CRT may also reduce neurohumoral activation [11] and promote upregulation of genes encoding myocardial contractile proteins [12].

Selection of candidates for CRT
Current guidelines suggest that patients will derive benefit from CRT if they fulfill the following criteria: they are significantly symptomatic (NYHA Class III or IV), with dilated (ischemic or non ischemic) cardiomyopathy, despite optimal medical therapy, and have poor left ventricular function (ejection fraction < 35%), with evidence of dyssynchrony on the ECG (QRS duration > 120 ms) (Table I) with or without additional assessment with echocardiography (if QRS duration < 150 ms) [16]. Most patients who meet these criteria are also candidates for implantable cardioverter-defibrillator (ICD) therapy, especially if their symptoms have an ischemic etiology [17].

Table I. Overview of cardiac resynchronization therapy (CRT) trials in patients with New York Heart Association (NYHA) Class III–IV heart failure, ejection fraction < 35% and QRS > 120 ms despite optimal medical therapy.

Response to treatment
There are numerous methods of assessing either acute or chronic response to treatment. Acute responses can be readily evaluated by hemodynamic parameters such as dp/dt or by echocardiography using the left ventricular velocity–time integral. Symptomatic assessment can be performed by assessing NYHA class, quality-of-life questionnaires, 6-minute walk test, mV˙O2 testing, and changes in echocardiographic parameters (such as left ventricular ejection fraction, end-diastolic dimension, and degree of mitral regurgitation). So-called “hard endpoints” include admission to hospital because of heart failure, adverse cardiac events, and death.

The challenge ahead: solving the problem of non response
Up to 30% of patients do not derive benefit from CRT, and this remains the driving factor behind much research in this field. Potential causes of non-response to treatment are outlined in Table II.

Table II. Potential reasons for non response to cardiac resynchronization therapy.

Positioning of the left ventricular lead
Perhaps the single most important factor affecting the outcome of CRT is the placement of the left ventricular lead. The main challenges of the implant procedure are coronary venous access, stability of the guide catheter, and variation in the anatomy of the coronary sinus. It is not always possible to achieve a favorable posterolateral position that is stable, with a good threshold, and avoids diaphragmatic pacing. In up to 10% of cases, transvenous placement of the left ventricular lead is not possible. The default option at present is surgical positioning of this lead, although, in the near future, multipolar left ventricular leads and percutaneous pericardial lead delivery systems may be able to overcome the need for this.

Device optimization
Device optimization is performed to attain the individual atrioventricular and ventriculoventricular delays that give rise to the optimal hemodynamic response to CRT. The gold standard is echo optimization, using the velocity–time integral and transmitral Doppler indices. Device manufacturers have developed algorithms that calculate optimal timings from intracardiac electrograms. An alternative approach is the use of hemodynamics (either invasive or non invasive) to achieve the optimal settings.

Should the current criteria be extended?
Controversy exists as to whether certain groups of patients with heart failure who fall outside current guidelines may benefit from CRT.
CRT in patients with a narrow QRS complex but echocardiographic evidence of dyssynchrony was evaluated in the Cardiac-Resynchronization Therapy in Heart Failure with Narrow QRS Complexes (RethinQ) study [22]. This included 172 patients with QRS duration < 130 ms but mechanical dyssynchrony on the echocardiogram, who received CRT-defibrillator devices and were randomly assigned to CRT or no CRT for a 6-month period. This study did not show a significant improvement in the primary endpoint of peak oxygen consumption in the group who underwent CRT.
Studies involving less symptomatic patients with heart failure (NYHA Class II) have provided some evidence that such patients may derive benefit from CRT [14,23]. It is hoped that this question will be answered with the results of the current Resynchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction (REVERSE) trial [24]. It is entirely plausible that, even if symptomatic improvement is limited in this group, the progression of heart failure may be slowed – or indeed improved – by reverse remodeling as a result of CRT.
Patients with atrial fibrillation may benefit from correction of dyssynchrony by CRT, despite the fact that the potential for atrioventricular synchrony is absent. Treatment with biventricular pacing appears to be superior to right ventricular pacing in terms of functional status [13]. For CRT to be effective in this group of patients, however, it seems that ablation of the atrioventricular node is required to ensure continuous biventricular stimulation [25].

Summary
CRT offers new hope for many patients with heart failure. Its ability to improve cardiac efficiency has transformed the outlook for this population, with demonstrated improvement in both symptoms and mortality. The aims of current work are to identify exactly which patients stand to benefit from the technique, and to optimize both positioning of leads and device programming in order to confer the maximum benefit possible.

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