Impact of Cardiac Resynchronization Therapy on the Management of Systolic Heart Failure

Heart failure is defined as a clinical syndrome that can result from any structural or functional cardiac disorder that impairs the ability of the ventricle to fill with or eject blood.  

Decompensated heart failure accounts for a majority of hospital admissions in the United States. Estimates arising from epidemiological studies such as the Framingham Heart Study indicate a rise in the incidence of heart failure, with an annual incidence of 500,000 new cases in the United States and two million cases worldwide.¹ As the population ages, the incidence and prevalence of heart failure rises. While the median age at time of diagnosis is in the mid 70s, there is a higher incidence in men compared to women. Due to this aging population, and coupled with improved survival from various cardiovascular conditions such as myocardial infarction, the prevalence of heart failure has increased to 2% of the adult population. Approximately five million Americans and six million Europeans are currently living with heart failure.² Mortality in this condition remains high, with a study in Minnesota indicating 20% mortality at three months and 34% mortality at one year.³

Pathophysiology of Heart Failure

Heart failure is a complex syndrome manifesting with signs of fluid retention and symptoms of shortness of breath and fatigue, on a background of structural or functional cardiac damage. The term congestive heart failure refers to the clinical manifestations of fluid retention such as elevated jugular venous pressure, pedal edema, and pulmonary and hepatic congestion. Numerous etiologic factors ranging from myocardial infarction, valvular abnormalities, and arrhythmias may initiate and propagate heart failure. On the molecular level, decreased function in contractile proteins as a result of numerous insults, results in myofibrillar impairment.⁸ Autonomic dysfunction with increased sympathetic tone and decreased vagal tone results in exaggerated systemic vascular resistance and deranged myocontractility. Activation of the renin-angiotensin-aldosterone (RAA) system leads to increased sodium and water retention — compensatory mechanisms aimed at maintaining adequate cardiac output. In order to counter peripheral vasoconstriction, a host of vasodilatory molecules including prostaglandins (PGE2 and PGI2) and nitric oxide are released. A combination of the above-mentioned mechanisms results in maladaptive changes in the myocardium known as left ventricular remodeling. Ultimately, the compensatory mechanisms sustaining cardiac output give way to a vicious cycle of deteriorating cardiac function.

Incidence of Intraventricular Conduction Delay and Left Bundle Branch Block in Heart Failure

Intraventricular conduction delay (IVCD) manifests as prolonged QRS duration with left bundle branch block (LBBB) pattern as the most common expression. Up to one-third of heart failure patients exhibit prolonged QRS duration. Widely viewed as an adverse prognostic factor in patients with heart failure, IVCD is responsible for an array of pathophysiological changes resulting in reduction of ventricular systolic function, altered cardiac metabolism and worsening ventricular remodeling, and progressive left ventricular dilatation — all leading to a vicious cycle perpetuating heart failure.^4,5 Increased mortality is observed with graded increase in the duration of IVCD, and is likely related to myocardial fibrosis, myocyte cell death, and a higher incidence of ventricular arrhythmias.⁶ 

Impact of LBBB in Heart Failure on Mortality

Baldasseroni et al led a large European registry of heart failure patients looking at QRS morphology that indicated presence of LBBB as an unfavorable prognostic factor, independent of other variables.⁷ Presence of LBBB was associated with increased clinical severity of heart failure compared to patients with non-LBBB pattern of QRS prolongation. All-cause mortality was significantly higher in the LBBB group (more than 36% at one year) compared to the non-LBBB group.⁷

Impact of Drug Therapy on Heart Failure

The cornerstone of heart failure management involves drugs interfering with the adrenergic and RAA systems. Angiotensin converting enzyme (ACE) inhibitors are indicated in heart failure with depressed ejection fraction (LVEF <40%), and beneficial effects include improvement of symptoms, cessation of left ventricular remodeling, reduced hospitalizations, and survival benefit. Results of the SAVE, SOLVED, and CONSENSUS studies indicated symptom improvement as well as mortality benefit.

Similarly, beta blockers modulate and in certain instances halt the process of left ventricular remodeling, decrease hospitalization rates, and confer survival benefit.¹⁰ Aldosterone antagonists such as spirinolactone or eplerenone are indicated in NYHA Class III/IV with reduced ejection fraction (LVEF <35%) in addition to guideline-based medical therapy, and also confer survival benefit.¹¹

Analysis of data from major clinical trials involving beta blockers and ACE inhibitors have shown a significant reduction of mortality in those on beta blockers and ACE inhibitors, leading to incorporation as a Class I indication in ACC/AHA guidelines for management of heart failure in patients with depressed left ventricular ejection fraction.²⁴ In the RALES trial in patients with more advanced heart failure (NYHA Class II-IV; LVEF <35%), the reduction in mortality associated with spironolactone was 30%. The EMPHASIS-HF study indicated the beneficial effects of eplerenone in a certain subgroup of heart failure patients (NYHA Class II, EF <35%), indicating lower risk of death and hospitalizations.²³ However, in spite of optimum medical therapy, cardiovascular mortality has remained high in patients with advanced heart failure. 

History of Pacing in Advanced Heart Failure

Initially introduced 20 years ago, early investigators performed pacing in advanced heart failure from the right ventricular apex, but subsequent studies did not express clinical benefit with right ventricular pacing alone and found it was in fact detrimental due to loss of AV synchrony and development of functional LBBB.¹⁴ Studies involving dual chamber pacing in the setting of dilated cardiomyopathy, first-degree AV block, and IVCD also did not show any clinical benefit. 

There is a high incidence of IVCD or LBBB in patients with heart failure, which leads to delayed activation of the LV lateral wall. A LBBB-type pattern leads to slower activation of the left ventricular free wall in comparison to the right ventricle, resulting in ventricular dyssynchrony. As a result, there are deteriorating hemodynamics secondary to paradoxical septal motion, mitral regurgitation, increased ventricular filling times, elevated wall stress, and depressed left ventricular stroke volume.¹⁵

Observation of delay in LV activation generated interest in performing biventricular pacing in patients with IVCD and advanced heart failure. The tributaries of the coronary sinus (posterior lateral branch and lateral branch) offer epicardial access for performing left ventricular pacing. The initial experience in placement of the left ventricular lead via the coronary sinus (CS) and its tributaries encountered difficulty in cannulating the CS, and in delivery of the left ventricular pacing lead. As operator experience has increased and with advancement of technology, delivery times now are shorter with minimal fluoroscopic exposure. Epicardial left ventricular placement via thoracotomy can be considered in rare cases.

In patients with IVCD or LBBB in the presence of severely depressed ejection fraction, simultaneous pacing of both ventricles enhances coordination between the septum and left ventricular free wall, improves intracardiac hemodynamics, and decreases mitral regurgitation.

Anatomy and Significance of the CS

The coronary sinus is a tubular structure measuring approximately 3 cm in length and 1 cm in width. It is situated in a groove between the left atrium and left ventricle posteriorly. The coronary venous circulation comprises the coronary sinus, cardiac veins, and Thebesian venous systems.¹² With regards to cardiac electrophysiology, coronary veins serve as important conduits for percutaneous mapping and pacing of ventricles. For the purpose of biventricular pacing, optimal lead position is via the posterolateral branch or the lateral branch of the CS.¹³ (Figures 1 and 2)

Studies with Biventricular Pacing

Meta-analyses of large clinical trials related to CRT indicate a 30% reduction in hospitalizations with a mortality benefit of 24% to 36%.^16,17 The Multisite Stimulation in Cardiomyopathy (MUSTIC) trial (study criteria: LVEF <45%, QRS >150 msec, NYHA Class III) in 2001 was the first prospective, randomized trial of CRT and showed significant improvement in quality of life indices and reduced hospitalizations in the pacing arm compared with standard medical therapy alone.¹⁸ 

Subsequently, the Multicenter InSync Randomized Clinical Evaluation (MIRACLE) trial (study criteria: LVEF <35%, QRS >130 msec, NYHA III/IV) compared biventricular pacing to a control group with continuation of standard medical therapy. There was a significant improvement in NYHA class, quality of life, and left ventricular ejection fraction in the pacing group.¹⁹ 

In the Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) trial (study criteria: LVEF <35%, QRS >120 msec, NYHA Class III/IV), standard medical therapy was compared with CRT with and without defibrillator. A reduction of 20% in primary composite endpoint was observed in the CRT arm compared with standard medical therapy alone.²⁰ Based on these landmark studies, the American College of Cardiology Foundation (ACCF) and American Heart Association (AHA) issued device-based therapy guidelines in 2008. 

The benefit of CRT is seen in patients with Class I and II heart failure as well. Studies now indicate significant benefit from placement of CRT in patients with QRS >150 msec.^21,22 In a recent meta-analysis involving over 6,500 patients with CRT, presence of QRS >150 msec was associated with a significantly reduced primary endpoint of death or hospitalization for heart failure (P < 0.00001), but not in patients with QRS <150 msec (P = 0.51).²¹ The mortality benefit seen in those patients with QRS >150 msec and CRT was observed regardless of NYHA severity. Sipahi et al evaluated specific QRS patterns in patients with CRT and correlated with clinical events in a meta-analysis involving 5,356 patients.²² CRT in the presence of LBBB significantly decreased adverse clinical events (P = 0.00001), whereas no benefit was observed in the non-LBBB group (including right bundle branch block and non-specific IVCD).²²

Latest Recommendations Regarding Biventricular Pacing

The ACCF/AHA have recommended significant changes in the 2012 focused update to the Device-Based Therapy Guidelines of 2008.¹⁶ The changes include:

• Class I indication for CRT limited to patients with QRS ≥150 msec in the presence of LBBB and encompassing NYHA Class II-IV.
• Class IIa recommendation for CRT in patients with QRS 120-149 msec with LBBB pattern and NYHA Class II-IV.
• Class IIa recommendation for CRT in patients with QRS ≥150 msec but non-LBBB pattern and NYHA Class II-IV.
• Class IIb recommendation for CRT in patients with QRS ≥150 msec with LBBB pattern and NYHA Class I.
• Class III – CRT not recommended for patients with QRS ≤150 msec and non-LBBB pattern with NYHA I/II.¹⁶

In spite of significant improvement in our understanding and treatment of heart failure, mortality rates tend to be high and patients are frequently readmitted to the hospital due to fluid overload. There are a number of reasons for this paradox and include noncompliance with medical and dietary restrictions, ongoing substance abuse, and lack of understanding about disease process.

Disclosure: Dr. Hussain has no conflicts of interest to report. Dr. Siddiqui reports that outside the submitted work he has received honoraria from St. Jude Medical. 

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