History
This patient had a history of lymph node tuberculosis during childhood, thyroid carcinoma (treated surgically and with radiotherapy), and depressive disorders.
A normal electrocardiogram (ECG) was recorded 20 years earlier at the time of the thyroidectomy. However, a progressive left bundle branch block (LBBB) pattern appeared with a QRS duration of 120 and 135 ms, 8 and 2 years earlier, respectively. Transthoracic echocardiography was performed 2 years earlier and showed normal left ventricular ejection fraction (LVEF) of 60%.
Comments
The patient’s history demonstrated a progressive widening of QRS complex and appearance of LBBB with a normal left ventricular function.
Current Medications
The patient is currently taking levothyroxine 75 mcg daily.
Current Symptoms
Over a 1-year period, the patient progressively experienced exercise intolerance, weight gain related to lower extremity edema, and shortness of breath (New York Heart Association [NYHA] class III). Treatment by ramipril, bisoprolol, and furosemide was initiated without significant efficacy. She was then hospitalized for a first episode of congestive heart failure.
Comments
The patient’s clinical history is suggestive of progressive congestive heart failure.
Physical Examination
Laboratory Data
Comments
The blood analysis showed only mild anemia, probably related to the congestive heart failure.
Electrocardiogram
Findings
The ECG showed sinus rhythm to be 80 bpm, normal atrioventricular conduction (PR interval, 160 ms), typical LBBB with a QRS duration of 135 ms, and a QRS axis of −35 degrees (Figure 4-1).
Comments
The LBBB is typical, with a QRS of 120 ms or greater; broad, notched, or slurred R wave in the lateral leads; absence of Q waves in leads I, V5, and V6; an upstroke of the R wave greater than 60 ms in leads V5 and V6; and ST and T waves opposite to the QRS polarity.
Echocardiogram
Findings
M-mode analysis of the left ventricle in parasternal long-axis view revealed a left ventricular end-diastolic diameter of 55 mm and a septal flash (Figure 4-2, A). LVEF was measured at 33% using the biplane Simpson method (see Figure 4-2, B). A mild mitral regurgitation also was observed (not shown). The atria were not dilated (diameter 3.2 cm and area 15 cm²).
Comments
Although left ventricular function is impaired, the left ventricle is not dilated (<33 mm/m²).
Findings
On the echocardiogram, the pulmonary preejection time was measured from the beginning of QRS complex to the beginning of the pulmonary flow velocity curve recorded by pulse-wave Doppler in the left parasternal view at 85 ms (Figure 4-3, A). The aortic preejection time measured from the beginning of QRS complex to the beginning of the aortic flow velocity curve recorded by pulse wave Doppler in the apical five-chamber view was 183 ms (Figure 4-3, B). The intraventricular mechanical delay was 98 ms, demonstrating interventricular dyssynchrony. Major atrioventricular dyssynchrony was demonstrated by left ventricular filling time over the RR cycle length ratio less than 40% (128/709 ms = 18%) (Figure 4-3, C). The apical four-chamber view showed (in red) the delayed motion of the anterolateral left ventricular wall (Figure 4-3, D). Delay between septal (red arrow) and anterolateral (yellow arrow) left ventricular walls of 301 ms demonstrated intraventricular dyssynchrony (Figure 4-3, E).
FIGURE 4-1
Catheterization
Coronary Angiography
Findings
Catheterization revealed normal coronary arteries with no stenosis.
Comments
Given the fact that the most common cause of left ventricular dilation is represented by coronary artery disease, a coronary angiography should always be performed to rule out coronary stenosis (an exercise test often is not helpful in patients with an LBBB pattern on the ECG). Usually, significant stenosis of the left anterior descending artery or of more than two other arteries is necessary to induce cardiomyopathy.
Focused Clinical Questions and Discussion Points
Question
What is the incidence of LBBB in the general population?
Discussion
In the general population, the prevalence of LBBB is estimated to be 0.3% to 1.2%, higher in men than women. In most cases, LBBB is associated with structural heart diseases (e.g., ischemic, dilated or valvular cardiomyopathies, and hypertension). The incidence increases with age. However, LBBB can be observed in 0.1% of healthy individuals. Epidemiologic studies demonstrated that this pattern is associated with a worse outcome and increased all-cause mortality.
Question
In the case of persistence of the symptoms and of impaired LVEF despite optimal medical therapy, would the patient be eligible for cardiac resynchronization therapy defibrillator (CRT-D) implantation?
Discussion
A class I, level A indication of CRT implantation is optimal medical therapy, symptomatic heart failure with NYHA III or IV functional class, typical LBBB pattern with QRS of 120 ms or greater, and sinus rhythm of LVEF of 35% or less; left ventricular dilation is not a required criterion anymore.6
For this indication, the CRT pacemaker (CRT-P) and CRT-D have similar levels of evidence. Patients with a secondary indication for an implantable cardioverter-defibrillator (ICD) should be implanted with a CRT-D device. A reasonable expectation of survival longer than 1 year with good functional status is required for CRT-D implantation.
A CRT-D device would be preferentially implanted (rather than a CRT-P device) in patients with mildly symptomatic heart failure and larger QRS complexes 150 ms or longer.
Question
What is the impact of QRS duration on clinical events reduction with CRT?
Discussion
Traditionally, guidelines recommend CRT implantation in patients with symptomatic heart failure (NYHA class III or IV) and QRS complex duration of 120 ms or longer. This recommendation was based on the inclusion criteria of the first two major clinical trials on CRT—the Cardiac Resynchronization Heart Failure (CARE-HF)2 study and the Comparison of Medical Therapy, Pacing and Defibrillation in Heart Failure (COMPANION)1 study. However, most patients included in recent CRT studies specifying an inclusion criteria of QRS duration of 120 ms or longer had a QRS wider than 150 ms.
Recently, the Resynchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction (REVERSE)5 and Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy (MADIT-CRT)7 studies extended the usual inclusion criteria of symptomatic heart failure to include patients with asymptomatic or mildly symptomatic heart failure (NYHA functional class II). Although no benefit was observed in asymptomatic patients, a significant reduction of the primary end point (i.e., heart failure clinical composite response and all-cause mortality and heart failure events, respectively) was observed in both studies.
In the REVERSE study, a prespecified subgroup analysis depending on baseline QRS duration showed that patients with a prolonged QRS complex (>150 ms) and those with pronounced interventricular dyssynchrony seemed to benefit most from resynchronization.3 Similarly, subgroup analysis of the MADIT-CRT trial suggested that patients with a QRS of 150 ms or greater were more likely to benefit from CRT-D than those with thinner QRS complexes.11 The recently published Resynchronization–Defibrillation for Ambulatory Heart Failure Trial (RAFT) confirmed these results because it showed a greater benefit of CRT-D over ICD alone in patients with large QRS of 150 ms or longer.9
These three recent studies led to a modification of the European Society of Cardiology (ESC) guidelines in 2010, considering the implantation of a CRT device in patients with mildly symptomatic heart failure and a QRS of 150 ms or longer as a class I indication.
However, these subgroup analyses and the cost, potential complications, and high rate of nonresponders to CRT raise the question of whether this therapy should be reserved for patients with a QRS longer than 150 ms, whether symptomatic or not. This question is a matter of debate, particularly because of the recent publication of a meta-analysis8 addressing this question and including the five previously cited studies (i.e., CARE-HF2, COMPANION1, REVERSE5, MADIT-CRT7, and RAFT9). A total of 5813 patients were included and analyzed, 62.3% and 37.7% of whom had severely and moderately prolonged QRS, respectively.8 A 40% reduction in composite clinical events was observed in patients with severely prolonged QRS (risk ratio, 0.6; 95% confidence interval (CI), 0.53-0.67). Conversely, no benefit was demonstrated for patients with moderately prolonged QRS (risk ratio, 0.95; 95% CI 0.82-1.1), regardless of NYHA functional class at implantation. A significant relationship (p <0.001) between baseline QRS duration and risk ratio was evidenced, the benefit of CRT appearing for QRS duration of 150 ms or longer. A trend for benefit in the moderately prolonged QRS subgroup (120 to 159 ms) from the CARE-HF study was observed.2 Of importance, in this study, patients with a QRS between 120 ms and 149 ms had to fulfill two of three echocardiogram criteria of dyssynchrony to be enrolled. Whether the benefit in the moderately prolonged QRS subgroup was driven by the patients with prolonged QRS between 150 and 159 ms or by patients with thinner QRS and overt dyssynchrony is unclear. Further studies are needed to address this issue.
Whether this meta-analysis, in addition to the subgroup analysis from each original trials, will lead to significant changes in guidelines and clinical practice is uncertain.
Along with QRS duration, QRS morphology was identified as another key predictor of CRT response and clinical outcome. Subgroup analyses from REVERSE3 and MADIT-CRT11 showed that LBBB pattern was associated with high probability of favorable outcome after CRT when patients with non-LBBB patterns, right BBB (RBBB), or nonspecific intraventricular conduction disturbances received no clinical benefit from CRT. These concordant data were used in the last version of the ESC guidelines on acute and chronic heart failure6: LBBB (with a QRS of ≥120 msec) is now the entry criteria for class I indication in patients with NYHA class II or III. Patients with a non-LBBB pattern can be considered for CRT (class IIa indication) if the QRS duration is 150 msec or greater.
Question
What are the predictors of super-response to CRT?
Discussion
Super-responders represent approximately 10% of CRT recipients. Criteria for super-response have not been clearly defined but could include an increase of LVEF of 15% to 20% compared with baseline or an LVEF of 50% or greater after therapy, associated with a decrease in NYHA class and no hospitalizations for heart failure during the follow-up.
Recently, Hsu and colleagues4 investigated the predictors of LVEF super-response to CRT and identified six clinical, electrocardiographic, or echocardiographic criteria predicting such a response: female sex (odds ratio [OR], 1.96; 95% CI, 1.32-2.9), body mass index (BMI) less than 30 kg/m² (OR, 1.51; 95% CI, 1.03-2.2), no previous myocardial infarction (OR, 1.8; 95% CI, 1.2-2.71), QRS duration of 150 ms or greater (OR, 1.79; 95% CI, 1.17-2.73), LBBB pattern (OR, 2.05; 95% CI, 1.24-3.4), and small baseline left atrial volume index (OR, 1.47; 95% CI, 1.21-1.79).
This patient therefore has all of the criteria of super-response except the wide QRS duration.
Final Diagnosis
This patient had congestive heart failure leading to the diagnosis of primary left ventricular dysfunction (LVEF, 33%), with mild left ventricular dilation, severe dyssynchrony, and an ECG demonstrating typical LBBB pattern and moderately prolonged QRS (135 ms).
The timeline of the development of LBBB is interesting to consider. The QRS, initially thin, progressively widens over time. In parallel, the LVEF, initially normal, becomes progressively impaired. This may support the diagnosis of dyssynchrony-induced cardiomyopathy.10
Plan of Action
Although the patient has a moderately prolonged QRS and may be part of a subgroup of patients who do not fully benefit from CRT, as previously explained, she has many of the criteria for super-response (i.e., sex, low BMI, no previous myocardial infarction, LBBB pattern, and small left atrium).
Furthermore, the timeline of QRS width and LVEF changes leading to cardiomyopathy secondary to severe dyssynchrony suggests a probable good response to CRT.
The important next step is to decide whether a CRT-P or CRT-D is to be implanted. The implantation of a CRT-P in this patient is a class IA indication of the ESC guidelines (NYHA class III/IV, QRS >120 ms, sinus rhythm, and LVEF ≤35%). The implantation of an ICD backup is a class IB indication of the ESC guidelines (i.e., NYHA II or III, LVEF ≤35%, nonischemic cause, and reasonable expectation of survival with good functional status for >1 year).
Intervention
An atriobiventricular device was implanted as follows:
• Atrial lead in the right atrial appendage
• Right ventricular lead in the medial interventricular septum
• Left ventricular lead in a lateral branch of the coronary sinus
No complications occurred during the implantation. The sensing and pacing thresholds were correct at implantation and the following day.
The postprocedure ECG demonstrated sinus rhythm with synchronized biventricular pacing with a paced QRS width of 120 ms and a QRS axis of 90 degrees.
After optimization by echocardiography, the interventricular mechanical delay was 22 ms (vs. 93 ms before implantation). The delay between septal and anterolateral left ventricular walls decreased dramatically to 23 ms, demonstrating that the resynchronization was efficient. The left ventricular filling time increased to 65% after appropriate programming.
An optimal medical therapy was prescribed (i.e., angiotensin-converting enzyme inhibitors, beta blockers, spironolactone, and diuretics).
Outcome
Six months after implantation, the patient reported no shortness of breath during exercise (NYHA functional class I). Clinical examination did not show signs of heart failure (i.e., disappearance of the edema and normal lung sounds were noted).
Findings
The interrogation of the device showed a 98% rate of biventricular pacing. Pacing and sensing thresholds were correct, as were lead impedances. No ventricular arrhythmia was detected during the follow-up.
Echocardiography demonstrated a dramatic improvement of the LVEF to 62%. Ventricular size was normalized with a left ventricular end-diastolic diameter of 48 mm.
Comments
Patients with a moderately prolonged QRS (<150 ms) seem to respond to a lesser extent to CRT, regardless of NYHA class. However, some of these patients may be super-responders to CRT. Although specific studies are needed to identify these particular subgroups of patients, some criteria can help to predict whether the patient will respond to the therapy. Two of them are presented in this case report—the mechanical dyssynchrony and a clinical history suggestive of LBBB-induced cardiomyopathy.
LBBB induces abnormal left ventricular activation and contraction; the septum is activated early, as opposed to the lateral wall, which is activated and contracts after a considerable delay, sometimes after mitral valve opening. Clinical and animal studies demonstrated that dyssynchrony causes global ventricular abnormalities such as shortening of left ventricular filling time, septal hypoperfusion, and reduction of circumferential shortening and myocardial blood flow. These abnormalities lead to adverse electrical and structural remodeling that eventually cause an impairment in left ventricular function. Resynchronization therapy, by correcting electrical and mechanical dyssynchrony, can reverse such remodeling and lead to LVEF improvement.10
Selected References
1. Bristow M.R., Saxon L.A., Boehmer J. et al. Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. N Eng J Med. 2004;350:2140–2150.
2. Cleland J.G., Daubert J.C., Erdmann E. et al. The effect of cardiac resynchronization on morbidity and mortality in heart failure. N Engl J Med. 2005;352:1539–1549.
3. Gold M.R., Thébault C., Linde C. et al. The effect of QRS duration and morphology on cardiac resynchronization therapy outcomes in mild heart failure: results from the REsynchronization reVErses Remodeling in Systolic left vEntricular dysfunction (REVERSE) Study. Circulation. 2012;126:822–829.
4. Hsu J.C., Solomon S.D., Bourgoun M. et al. Predictors of super-response to cardiac resynchronization therapy and associated improvement in clinical outcome: The MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial with the Cardiac Resynchronization Therapy) Study. J Am Coll Cardiol. 2012;59:2366–2373.
5. Linde C., Abraham W.T., Gold M.R. et al. Randomized trial of cardiac resynchronization therapy in mildly symptomatic heart failure patients and in asymptomatic patients with left ventricular dysfunction and previous heart failure symptoms. J Am Coll Cardiol. 2008;52:1823–1843.
6. McMurray J.J., Adamopoulos S., Anker S.D. et al. ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur Heart J. 2012;14:803–869.
7. Moss A.J., Hall W.J., Cannom D.S. et al. Cardiac resynchronization therapy for the prevention of heart failure events. N Eng J Med. 2009;361:1329–1338.
8. Sipahi I., Carrigan T.P., Rowland D.Y. et al. Impact of QRS duration on clinical event reduction with cardiac resynchronization therapy. Arch Intern Med. 2011;171:1454–1462.
9. Tang A.S., Wells G.A., Talajic M. et al. Cardiac resynchronization therapy for mild to moderate heart failure. N Engl J Med. 2010;363:2385–2395.
10. Vaillant C., Martins R.P., Donal E. et al. J Am Coll Cardiol. 2013;61:1089–1095.
11. Zareba W., Klein H., Cygankiewicz I. et al. Effectiveness of cardiac resynchronization therapy by QRS Morphology in the Multicenter Automatic Defibrillator Implantation Trial–Cardiac Resynchronization Therapy (MADIT-CRT). Circulation. 2011;123:1061–1072.
