History
A 63-year-old man presented to the emergency room with recent-onset episodic chest discomfort described as “muscle ache.” The chest discomfort was radiating to the upper neck and both arms, associated with a tingling sensation. It was not reproducible or worsened on deep inspiration. He recently noticed dyspnea with minimal effort without any associated chest discomfort. However, he denied orthopnea, paroxysmal nocturnal dyspnea, pedal edema, and loss of consciousness.
A year previously, he was diagnosed with coronary artery disease, requiring a bare metal stent insertion for revascularization of 95% obstructive stenosis in the proximal left anterior descending coronary artery. His left ventricular ejection fraction (LVEF) was 38% at the time, and his electrocardiogram (ECG) revealed left bundle branch block (LBBB) morphology. His medical history included 9 months of chemotherapy for non-Hodgkin’s lymphoma. Approximately 4 years before the current visit, he was diagnosed with right cavernous meningioma, which was successfully treated with stereotactic radiation therapy without mantle radiation. During the same year, he was treated for benign prostatic hypertrophy with transurethral resection of prostate. He was being treated for depression, anxiety disorder, and hypothyroidism. The patient was married for 35 years and had two grown children. He reported stress at work, was a nonsmoker, and consumed alcohol socially. During the period of chemotherapy, he used marijuana. He had two sisters, who had cardiomyopathy of unclear cause. Both of his sisters died young, at 16 and 42 years of age. The patient’s niece was diagnosed with cardiomyopathy at the age of 38 and eventually needed cardiac transplantation.
Current Medications
The patient was taking levothyroxine 175 mcg daily, metoprolol 25 mg twice daily, bupropion 150 mg twice daily for depression, valsartan 160 mg daily, hydrochlorthiazide 12.5 mg daily, atorvastatin 40 mg daily, lorazepam 0.5 mg three times daily as needed for anxiety, zolpidem 5 mg daily at bedtime as needed for insomnia, and aspirin 325 mg daily.
Current Symptoms
The patient’s current symptoms were chest discomfort of 2 weeks, exertional dyspnea, and reduced exercise tolerance. On examination, he was overweight and not in any apparent distress and had a temperature of 36.8° C (98.2° F) and oxygen saturation of 99% on room air. The neurologic examination was nonfocal.
Physical Examination
Laboratory Data
Electrocardiogram
The ECG showed sinus bradycardia at a rate of 55 bpm, first-degree atrioventricular block (PR interval of 210 ms), LBBB unchanged in contrast to ECG obtained 1 month earlier. The QRS duration was 164 ms. No ST-T changes suggestive of ischemia were noted (Figure 38-1).
FIGURE 38-1 Case 1. Baseline electrocardiogram showing sinus bradycardia, left bundle branch block, and first-degree atrioventricular block.
Chest Radiograph
The posteroanterior and lateral radiographic views demonstrated poor inspiration, mild cardiomegaly, and no evidence of infiltrate or effusion (Figure 38-2).
Comments
The patient’s chest discomfort and exertional dyspnea in the setting of prior coronary artery disease were concerning for acute coronary syndrome. It was reassuring that the initial myocardial markers were negative. Most important, the patient was not in acute heart failure.
Echocardiogram
The transthoracic echocardiogram showed normally functioning valves in mitral, aortic, tricuspid, and pulmonary positions. The left ventricle was diffusely hypokinetic with some regional variation, which was especially worse in the septum and apex. The LVEF diminished further to 32% in contrast to 38% 8 months previously.
Comments
The patient was admitted to the cardiac care unit. The serial cardiac enzyme examinations and ECGs showed no evidence of acute myocardial infarction.
Exercise Testing
The patient was able to complete a technetium-99m single-photon emission computed tomography (SPECT) myocardial perfusion scan. The exercise test was terminated because of the development of 2:1 atrioventricular block with hypotension. The SPECT perfusion imaging showed fixed perfusion defects in the anterior and septal segments. The left ventricle was dilated, demonstrating global systolic dysfunction.
FIGURE 38-2 Case 1. Posteroanterior and lateral views of chest radiograph showing no congestive changes, infiltrate, or effusion.
Cardiac Catheterization
Subsequently, coronary angiography was performed that showed no evidence of obstructive coronary artery disease. The proximal left anterior descending artery with a prior bare metal stent was patent. The right coronary artery, the left main coronary artery, and the left circumflex artery showed minor luminal irregularities. No obstructive lesions were present.
Cardiac Magnetic Resonance Imaging
Cardiac magnetic resonance (CMR) with and without gadopentetate dimeglumine showed no evidence of myocardial edema. Delayed enhancement was seen in the subendocardial region of mid-anterior, anterolateral, and lateral apical segment consistent with scar. Scar extent was about 2% of left ventricular mass (Figure 38-3).
Final Diagnosis
The patient’s final diagnosis was mixed ischemia and nonischemic cardiomyopathy.
Focused Clinical Questions and Discussion Points
Question
What is the best management strategy to minimize the risk for sudden cardiac death in this patient?
Discussion
The patient had cardiomyopathy with an LVEF of 32% associated with LBBB in the setting of coronary artery disease, as well as New York Heart Association (NYHA) class II heart failure. Further, an added burden of conduction system disease manifested as first-degree atrioventricular block and LBBB on baseline ECG and development of Mobitz type 2 atrioventricular block with exercise, were suggestive of atrioventricular nodal or infranodal disease. In addition, the patient had a family history of cardiomyopathy and sudden cardiac death. Overall, he was at high risk for sudden cardiac death. He met the class I indication for pacing and the primary prevention criteria for implantable cardioverter-defibrillator (ICD) implantation.7 Increasing the medical therapy, especially beta blocker dosage, was not a viable option because of the bradycardia and relative hypotension. Pacemaker implantation will allow increasing the dosage of beta blockers but not address the sudden cardiac death risk. Overall, the patient has cardiomyopathy with low LVEF and dyssynchrony, as indicated by LBBB and wide QRS that can be best managed with cardiac resynchronization therapy with backup defibrillator (CRT-D).
Question
What further investigation will help in the decision-making process?
Discussion
The patient’s cardiomyopathy was much more advanced than the degree of coronary artery disease would explain, raising the possibility of the coexistence of idiopathic dilated cardiomyopathy or sarcoidosis or chemotherapy-induced cardiomyopathy. CMR will not only assess cardiac substrate with better resolution but also determine the scar burden and the scar location. Delayed-enhancement CMR (DE-CMR) or Late Gadolinium Enhancement (LGE)-CMR has been demonstrated to identify and quantify the scar accurately. CMR myocardial tagging can perform radial strain analysis to identify areas of dyssynchrony. An equilibrium contrast CMR can assess diffuse myocardial scar. It is also able to assess coronary venous anatomy that would help identify a suitable branch in an optimal left ventricular segment for left ventricular lead implantation. In addition, CMR is the gold standard for determining left ventricular function and volumes.
Mixed ischemic and nonischemic cardiomyopathy with atrioventricular nodal and intraventricular conduction system disease.
FIGURE 38-3 Case 1. Cardiac magnetic resonance imaging with late gadolinium enhancement suggestive of scar in the anterior and anterolateral segments of left ventricle. Scar burden was estimated to be 2% of the total left ventricular mass.
FIGURE 38-4 Case 1. Left ventricular lead location in the basal lateral segment on a postimplant chest radiograph.
Question
What factors influenced the beneficial effect of CRT in this patient?
Discussion
The presence of LBBB, wide QRS duration (>150 ms), absence of atrial fibrillation, and optimal left ventricular lead location in a basal lateral segment are predictors of clinical response and left ventricular reverse remodeling.8 Patients with ischemic cardiomyopathy tend to benefit less from CRT than those with nonischemic cardiomyopathy.8 This has been attributed to the extent of myocardial viability and the myocardial scar.8 However, the patient’s myocardial scar burden was only 2% of total left ventricular mass, and based on CMR the scar appears to be located away from the region of left ventricular lead pacing site.
Plan of Action
The plan for this patient is CRT-D implantation. Further optimization of medical therapy was done after pacing had been established.
Intervention
A primary biventricular chamber ICD system was implanted transvenously with final left ventricular lead position in left ventricular basal lateral segments (Figure 38-4). The right ventricular lead location was apico-septal.
Outcome
The patient responded well to CRT, with an improvement in exercise capacity. He was able to walk for 1560 feet on the 6-minute walk test (6MWT), in contrast to 1060 feet before CRT. He scored 43 on the Minnesota Living with Heart Failure questionnaire in contrast to 48 at baseline. Subsequently, a 6-month transthoracic echocardiogram demonstrated an improvement in LVEF to 48% and good left ventricular reverse remodeling, demonstrated by a decrease in left ventricular internal dimensions in diastole at 6 months from 45 to 42 mm and in systole from 37 to 30 mm.
Case 2
| Age | Gender | Occupation | Working Diagnosis |
| 64 Years | Male | Teacher | Acute Coronary Syndrome |
History
A 64 year-old man arrived in the emergency room with a 2-day history of exertional shortness of breath and exertional chest pressure. He reported excessive sweating on exertion. However, he denied having nausea, vomiting, dizziness, and palpitations. He had a history of a five-vessel coronary artery bypass graft (CABG). Approximately 9 years later, he required a revision of CABG in addition to bioprosthetic mitral valve replacement. Four years previously, he experienced gastrointestinal bleeding that was thought to have originated from gastritis. In addition he had stage III chronic kidney disease.
Current Medications
The patient was taking hydrocholorothiazide 12.5 mg daily, lisinopril 2.5 mg daily, furosemide 20 mg daily orally, atorvastatin 20 mg daily, amiodarone 200 mg daily, atenolol 50 mg daily, gemfibrozil 600 mg daily, and aspirin 81 mg daily.
Physical Examination
Laboratory Data
Electrocardiogram
The ECG showed atrial fibrillation with a heart rate of 62 bpm and intraventricular conduction delay with a QRS duration of 129 ms (Figure 38-5). A few premature ventricular complexes were noted.
Chest Radiograph
A portable chest radiographic view demonstrated moderate cardiomegaly. Moderate-sized left-sided pleural effusion was evident.
FIGURE 38-5 Case 2. Baseline ECG demonstrating atrial fibrillation and nonspecific interventricular conduction delay.
Echocardiogram
A normally seated bioprosthetic valve was seen in the mitral position with normal leaflet motion. The left ventricle was dilated, with impaired systolic function and an LVEF of 31%. Focal wall thinning and increased reflectivity of the inferior wall were suggestive of scar. The estimated right ventricular systolic pressure was 28 mm Hg.
Comments
The patient was admitted to the intensive care unit to rule out acute coronary syndrome. Subsequent cardiac biomarkers were negative. He underwent myocardial perfusion imaging because of reluctance to perform cardiac catheterization because of compromised renal function.
Exercise Testing
99mTc sestamibi SPECT imaging at rest and stress revealed fixed perfusion defects at inferior basal, inferior middle, and inferior apical segments. Inferior wall akinesia and hypokinesia without evidence of reversible ischemia were present. The LVEF was 28%.
Cardiac Magnetic Resonance Imaging
CMR with and without gadopentetate dimeglumine demonstrated areas of delayed hyperenhancement in the inferior wall (Figure 38-6). Evidence of transmural infarction in the inferior wall was present, mostly in the apical segment; it was partially transmural in the basal to mid-ventricular segments of the inferior wall. Severe global left ventricular systolic dysfunction was present. The scar extent was estimated to be 12.3% of total left ventricular mass.
Question
FIGURE 38-6 Case 2. Cardiac magnetic resonance imaging demonstrating extensive inferior wall scar. Extent of myocardial scar is 12.3% of the total left ventricular mass.
Discussion
The patient in case 2 responded suboptimally to CRT. Although an improvement in activity level and a modest improvement in LVEF occurred, echocardiographic evidence of left ventricular reverse remodeling was found. Further, his clinical outcome was less than desired. He was hospitalized for congestive heart failure and ventricular arrhythmia. This suboptimal response could be attributed to the ischemic heart disease, higher scar burden, position of the left ventricular lead in the region of scar, relatively narrow QRS (129 ms), and nonspecific intraventricular conduction delay on baseline ECG. In addition, his scar burden level was 12.3% of total left ventricular mass. In a study of 137 patients referred for ICD, DE-CMR was performed to assess scar burden. The study reported fivefold increase in adverse events in patients with myocardial scar of more than 5% of the left ventricular mass.5 Figures 38-3 and 38-6 show the contrast in the scar burden in the patients in the two cases. In addition, the left ventricular lead in the patient in case 2 was located in the mid-posterolateral wall where partially transmural scar tissue was present, whereas in the patient in case 1 the left ventricular lead was located in a mid-lateral ventricular segment that was away from the scar segment. Left ventricular pacing on an area of scar may result in ineffectual pacing and inadequate resynchronization. A randomized controlled trial, the TARGET study, showed improved clinical outcome when the left ventricular lead was located away from the scar.10 All of these factors may have played a role in the suboptimal response to CRT seen in the patient in case 2.
Question
Which is more important—myocardial scar location or myocardial scar burden?
Discussion
Scar burden and scar location are increasingly recognized as important determinants of CRT response. Theoretically, higher scar burden implies lesser availability of viable and recruitable myocardium to improve ventricular contraction. Ypenburg and colleagues15 studied 34 patients and reported an inverse relationship between total scar burden, spatial extent, and transmurality of scar as measured by a 5-point hyperenhancement scale on CMR and change in left ventricular end-systolic volume at 6 months. In a study of 190 patients with ischemic cardiomyopathy,2 low scar burden (Summed Rest Score <27) as determined by thallium-201 myocardial perfusion imaging had a favorable rate and LVEF improvement in contrast to higher scar burden (SRS ≥27). The scar burden adversely affects CRT response in ischemic and nonischemic cardiomyopathy and hypertrophic cardiomyopathy. In a study of 213 patients with ischemic and nonischemic cardiomyopathy, the authors reported lower LVEF improvement with higher scar burden (>22% as assessed by CMR) in contrast to lower scar burden (<22%). In that study, left ventricular lead location on scar was not a significant predictor of CRT response.14 However, only 11% of left ventricular leads were located in the region of scar. Conversely, anatomic segmental location of scar tissue was found to have an adverse impact on CRT response in other studies. Bleeker and associates3 reported worse clinical outcome with transmural scar in a posterolateral segment of the left ventricle independent of scar burden, LVEF, left ventricular end-systolic volume, and QRS duration, although the sample size was much smaller, with only 40 patients. In a similar study, higher heart failure hospitalization rates and death were noted if the left ventricular lead was located in a segment of scar or in the presence of posterolateral scar.5
Current evidence, derived mostly from small cohort studies (Table 38-1), underscores the importance of scar burden, segmental scar location, and the relationship between scar tissue and left ventricular lead location. Scar burden and location have the potential to play a role in better patient selection and improvement of the rate of nonresponsiveness to CRT. Further studies are necessary to determine the most appropriate imaging modality to assess scar location, its burden before CRT-D implantation, and its impact on outcome. Furthermore, left ventricular pacing on a region of scar tissue would be ineffectual; therefore avoiding the region of scar tissue during device implantation is a reasonable approach.
TABLE 38-1
Selected Studies Investigating the Impact of Myocardial Scar on Cardiac Resynchronization Therapy Response
| Study | Patient Characteristics | Scar Assessment | Conclusions |
| Mele et al12 2009 |
71 patients with ICM | Echocardiography | Poor CRT response with a higher number of scar segments and closer location to pacing lead |
| Adelstein et al1 2007 |
50 patients with ICM | Myocardial perfusion Imaging | Higher nonresponse to CRT with higher SPS score, scar density, and greater scar density near the left ventricular lead |
| Ypenburg et al15 2007 | 34 patients with ICM | DE-CMR | Total scar burden was inversely related to CRT response |
| Delgado et al6 2011 |
397 patients with ICM | Speckle-tracking radial strain analysis and DE-CMR | Left ventricular lead location on scar was a predictor of worse outcome |
| Adelstein et al2 2011 | 190 patients with ICM | Thallium-201 SPECT MPI | Higher scar burden (SRS >27) was associated with poor survival |
| Chalil et al5 2007 | 62 patients with ICM | DE-CMR | Presence of posterolateral scar and pacing on scar were independent predictor of response |
| Jansen et al9 2008 |
57 patients with ICM + NICM | CMR | Left ventricular dyssynchrony is more important than scar |
| Ypenburg et al15 2007 |
51 patients with ICM | Technitium-99m SPECT | Both the extent of scar tissue and its location near the left ventricle lead prohibits CRT response |
| Birnie et al4 2009 | 49 patients with ICM and NICM | Rubidium and fluorine-18-fluorodeoxyglucose PET | Responders had less lateral wall scar than nonresponders but a similar extent of global and septal scar |
| Bleeker et al3 2006 |
40 patients with ICM | CMR | Posterolateral wall scar was associated with poor response to CRT |
| Riedlbauchova et al13 2009 | 66 patients with ICM | PET scan | Response to CRT was observed regardless of the presence of total scar and left ventricular lead location in the region of scar or ischemia or hibernation |
CMR, Cardiac magnetic resonance; CRT, cardiac resynchronization therapy; DE-CMR, delayed-enhancement CMR; ICM, ischemic cardiomyopathy; MPI, myocardial perfusion imaging; NICM, nonischemic cardiomyopathy; PET, positron emission tomography; SPECT, single-photon emission computed tomography; SRS, summed rest score; SPS, summed perfusion score.
Final Diagnosis
The final diagnosis in this patient was ischemic cardiomyopathy, NYHA class II to III heart failure, and left ventricular systolic dyssynchrony, as suggested by the wide QRS, together with chronic renal insufficiency.
Comments
The patient had worsening dyspnea resulting from progressive ischemic cardiomyopathy. Because of the absence of objective evidence of ischemia, his worsening symptoms might be attributed to progressive left ventricular remodeling and dyssynchrony. CRT may help in correcting dyssynchrony and reversing the left ventricular remodeling.
Intervention
CRT-D implantation was performed, and the postimplant chest radiograph showed final left ventricular lead in a mid-ventricular and posterolateral location.
Outcome
Six months after CRT device implantation, the patient demonstrated at best modest improvement. Although his LVEF improved from 21% to 28% and he was able to walk to 1080 feet in the 6MWT in contrast to 720 feet before CRT-D, he was only minimally better subjectively. He scored 24 on the Minnesota Living with Heart Failure quality of life score in contrast to 30 before CRT-D implantation. A follow-up echocardiogram at 6 months demonstrated left ventricular internal diameter–diastole of 74 mm and left ventricular internal diameter–systole of 63 mm, in contrast to 71 mm and 63 mm, respectively, on pre-CRT echocardiogram. He was hospitalized twice—for ventricular tachycardia and for worsening congestive heart failure—within a few months of CRT implantation
Selected References
1. Adelstein E.C., Saba S. Scar bruden by myocardial perfusion imaging predicts response to cardiac resynchronization therapy in ischemic cardiomyopathy. Am Heart J. 2007;153:105–112.
2. Adelstein E.C., Tanaka H., Soman P. et al. Impact of scar burden by single-photon emission computed tomography myocardial perfusion imaging on patient outcomes following cardiac resynchronization therapy. Eur Heart J. 2011;32:93–103.
3. Bleeker G.B., Kaandorp T.A., Lamb H.J. et al. Effect of posterolateral scar tissue on clinical and echocardiographic improvement after cardiac resynchronization therapy. Circulation. 2006;113:969–976.
4. Birnie D., DeKemp R.A., Ruddy T.D. et al. Effect of lateral wall scar on reverse remodeling with cardiac resynchronization therapy. Heart Rhythm. 2009;6:1721–1726.
5. Chalil S., Foley P.W., Muyhaldeen S.A. et al. Late gadolinium enhancement-cardiovascular magnetic resonance as a predictor of response to cardiac resynchronization therapy in patients with ischaemic cardiomyopathy. Europace. 2007;9:1031–1037.
6. Delgado V., van Bommel R.J., Bertini M. et al. Relative merits of left ventricular dyssynchrony, left ventricular lead position, and myocardial scar to protect long-term survival of ischemic heart failure patients undergoing cardiac resynchronization therapy. Circulation. 2011;123:70–78.
7. Epstein A.E., Dimarco J.P., Ellenbogen K.A. et al. ACC/AHA/HRS 2008 Guidelines for device-based therapy of cardiac rhythm abnormalities. Heart Rhythm. 2008;5:e1–62.
8. Goldenberg I., Moss A.J., Hall W.J. et al. Predictors of response to cardiac resynchronization therapy in the Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy (MADIT-CRT). Circulation. 2011;124:1527–1536.
9. Jansen A.H., Bracke F., van Dantzig J.M. et al. The influence of myocardial scar and dyssynchrony on reverse remodeling in cardiac resynchronization therapy. Eur J Echocardiogr. 2008;9:483–488.
10. Khan F.Z., Virdee M.S., Palmer C.R. et al. Targeted left ventricular lead placement to guide cardiac resynchronization therapy: the TARGET study: a randomized, controlled trial. J Am Coll Cardiol. 2012;59:1509–1518.
11. Klem I., Weinsaft J.W., Bahnson T.D. et al. Assessment of myocardial scarring improves risk stratification in patients evaluated for cardiac defibrillator implantation. J Am Coll Cardiol. 2012;60:408–420.
12. Mele D., Agricola E., Galderisi M. et al. Echocardiographic myocardial scar burden predicts response to cardiac resynchronization therapy in ischemic heart failure. J Am Soc Echocardiogr. 2009;22:702–708.
13. Riedlbauchova L., Brunken R., Jaber W.A. et al. The impact of myocardial viability on the clinical outcome of cardiac resynchronization therapy. J Cardiovasc Electrophysiol. 2009;20:50–57.
14. Xu Y.Z., Cha Y.M., Feng D. et al. Impact of myocardial scarring on outcomes of cardiac resynchronization therapy: extent or location? J Nucl Med. 2012;53:47–54.
15. Ypenburg C., Schalij M.J., Bleeker G.B. et al. Impact of viability and scar tissue on response to cardiac resynchronization therapy in ischaemic heart failure patients. Eur Heart J. 2007;28:33–41.
