History
The patient was diagnosed with myasthenia gravis at the age of 40 years. He reported no cardiologic symptoms until January 2009, when he started experiencing dyspnea on effort. In May 2009 he patient was hospitalized because of congestive heart failure; the echocardiographic examination revealed severe left ventricular dilation and dysfunction. Diuretics and angiotensin-converting enzyme inhibitor therapy were started during the hospitalization, and the patient’s condition improved.
The next month the patient was admitted to our hospital for a complete diagnostic workup and therapeutic optimization.
Comments
An association between myasthenia gravis and giant cell myocarditis has been described in the literature. Giant cell myocarditis is a severe autoimmune disease, and anticardiac antibodies have been demonstrated in the serum of affected patients; it is frequently associated with other autoimmune conditions, such as systemic lupus erythematosus, thyroiditis, polymyositis, and myasthenia gravis. Although the pathogenesis is poorly understood, the overall mechanisms for the generation of autoantibodies in giant cell myocarditis include self-sensitization to cardiac antigens in the thymus, production of self-reactive T cells, stimulation of B cells, production of cardiac autoantibodies, and myonecrosis. These antibodies include anti-titin, anti-ryanodine, anti–alpha actinin, anti-actin, and anti-myosin.
Current Medications
The patient was taking captopril 25 mg three times daily, furosemide 50 mg once daily, digoxin 0.125 mg once daily, potassium canrenoate 25 mg once daily, warfarin 2.5 mg once daily, pantoprazol 40 mg once daily, pyridostigmine bromide 60 mg once daily, prednisone 12.5 mg every other day.
Comments
Beta blocker therapy was contraindicated because of the myasthenia gravis.
Current Symptoms
The patient was experiencing dyspnea on minimal exertion (New York Heart Association [NYHA] class III).
Physical Examination
Comments
The patient had no clinical signs of pulmonary or systemic congestion.
Laboratory Data
Electrocardiogram
Findings
The electrocardiogram (ECG) showed sinus rhythm and complete left bundle branch block (Figure 39-1).
Comments
The ECG clearly suggested the possibility for performing cardiac resynchronization therapy (CRT).
Echocardiogram
Findings
The echocardiogram revealed a left ventricular end-diastolic diameter of 70 mm, end-systolic diameter of 68 mm, mitral annulus diameter of 36 mm, tenting length of 14 mm, and tethering area of 4 cm2 (Figure 39-2). 
Comments
The patient had severe left ventricular dilation and dysfunction, with tethering of the mitral papillary muscles and dilation of the mitral annulus (see Figure 39-2).
Findings
The echocardiogram showed a left ventricular end-diastolic volume index of 178 mL/m2, left ventricular end-systolic volume index of 149 mL/m2, left ventricular ejection fraction (LVEF) of 16%, and functional mitral regurgitation of ++/++++.
FIGURE 39-2 Parasternal long axis view. See expertconsult.com for video. 
Comments
Figure 39-3 shows severe left ventricular dilation and dysfunction. 
Comments
Findings
The time delay between anteroseptal and posterior segments at speckle-tracking radial strain analysis is 300 ms (Figure 39-5).3
Comments
No clear evidence of septal flash is present. The measurements of aortic and pulmonary preejection periods (not shown in figures) allowed calculation of an interventricular time delay of greater than 40 msec. Tissue Doppler analysis (not shown in figures) indicated a time delay between the basal lateral wall and basal septum of greater than 65 msec.
FIGURE 39-3 A, Apical four-chamber view. B, Mitral regurgitation. See expertconsult.com for video. 
FIGURE 39-4 Apical two-chamber view. See expertconsult.com for video. 
Magnetic Resonance Imaging
Findings
Magnetic resonance imaging (MRI) revealed a left ventricular end-diastolic volume of 435 mL, left ventricular end-diastolic volume index of 242 mL/m2, left ventricular end-systolic volume of 374 mL, left ventricular end-systolic volume index of 208 mL/m2, LVEF of 14%, left ventricular mass of 165 mL, right ventricular end-diastolic volume of 206 mL, right ventricular end-diastolic volume index of 114 mL/m2, right ventricular end-systolic volume of 157 mL, right ventricular end-systolic volume index of 87 mL/m2, right ventricular ejection fraction of 24%, and left ventricular mass-to-volume ratio of 0.37 (Figure 39-6).
FIGURE 39-5 A, Short-axis view at the level of papillary muscles. B, Speckle-tracking radial strain analysis. See expertconsult.com for video. 
Comments
The patient had severe biventricular dysfunction, with a low left ventricular mass-to-volume ratio (a marker of advanced cardiac remodeling) (see Figure 39-6).
Findings
The delayed enhancement quantification on MRI was 0 mL.
Comments
FIGURE 39-6 Cine steady-state free precession sequences. Short-axis stack from the left ventricular base to the apex. See expertconsult.com for video. 
Findings
The delayed enhancement quantification on MRI was 0 mL.
Comments
No fibrosis was present.4
Dobutamine Stress Echocardiography
Findings
Dobutamine stress echocardiography at 20 mcg/kg/min revealed a left ventricular end-diastolic volume of 295 mL, left ventricular end-diastolic volume index of 173 mL/m2, left ventricular end-systolic volume of 243 mL, left ventricular end-systolic volume index of 143 mL/m2, and LVEF of 18% (Figures 39-9 and 39-10). 
FIGURE 39-7 Late gadolinium (gadopentetate dimeglumine 0.15 mmol/kg) images in short-axis view from the left ventricle base to apex.
FIGURE 39-8 A, Late gadolinium image in two-chamber long-axis view. B, Late gadolinium image in four-chamber long-axis view.
FIGURE 39-9 Apical four-chamber view during dobutamine infusion at 20 mcg/kg/min. See expertconsult.com for video. 
Comments
In contrast to baseline, during inotropic stimulation a small reduction in left ventricular volumes was noted, but no significant improvement in contractility of the septum occurred and a modest improvement in contractility of the basal lateral wall was seen (Figure 39-9). 
Findings
No significant improvement in contractility of the inferior and anterior walls was seen in contrast to baseline.
Comments
During inotropic stimulation no significant improvement was seen in contractility of the inferior and anterior walls (Figure 39-10).1 
FIGURE 39-10 Apical two-chamber view during dobutamine infusion at 20 mcg/kg/min. See expertconsult.com for video. 
Findings
The calculated time delay between anterior septal and posterior segments at speckle-tracking radial strain analysis was 289 msec, compatible with significant left ventricular dyssynchrony. The appearance of septal flash also was noted. The patient’s blood pressure at 20 mcg/kg/min was 100/80 mm Hg.
Comments
During inotropic stimulation a significant worsening of left ventricular dyssynchrony occurred (Figure 39-11).2,3
Catheterization
At right heart catheterization, capillary wedge pressure was 7 mm Hg, pulmonary artery pressure (systolic/mean/diastolic) was 20/10/5 mm Hg, right atrial pressure was 4 mm Hg, and cardiac index (thermodilution) was 2.29 L/min/m2.
FIGURE 39-11 A, Short-axis view at the level of papillary muscles during dobutamine infusion at 20 mcg/kg/min. B, Speckle-tracking radial strain analysis during dobutamine infusion. See expertconsult.com for video. 
Findings
Coronary arteriography was the first examination performed during hospitalization and showed normal coronary arteries.
Comments
Myocardial biopsy was performed and revealed no signs of acute myocarditis, in particular giant cell myocarditis.
Focused Clinical Questions and Discussion Points
Question
Which response to CRT could be predicted in this patient on the basis of left ventricular dyssynchrony analysis?
Discussion
In this patient, significant interventricular and intraventricular dyssynchrony are seen, particularly interventricular (interventricular mechanical delay >40 msec) and intraventricular dyssynchrony (time delay >130 msec between anterior septal and posterior segments on speckle-tracking radial strain analysis and time delay >65 msec between septal and lateral segments on tissue Doppler analysis). Thus, according to extensive literature data, these findings would definitely predict a good response to CRT.
Question
Which response to CRT could be predicted in this patient on the basis of cardiac magnetic resonance (CMR) imaging data?
Discussion
In this case, delayed enhancement is absent, which would support the conclusion that the myocardium is viable; therefore this would predict a positive response to CRT. However, CMR can provide other information. This patient has a low left ventricular mass-to-volume ratio, which might be considered a marker of advanced left ventricular dysfunction (i.e., of a myocardium “too sick to respond to CRT”). CMR information thus is not consistent.
Question
Which response to CRT could be predicted in this patient on the basis of dobutamine stress echo data?
Discussion
Dobutamine infusion elicited only a small increase in left ventricular contractility, which would support the conclusion of the absence of myocardial viability and therefore of a negative response to CRT. However, a clear increase in ventricular dyssynchrony also could be noticed during stress. Therefore even dobutamine stress echo data are difficult to reconcile.
Final Diagnosis
The final diagnosis in this patient is primary dilated cardiomyopathy. It was decided to implant a cardiac resynchronization (and antitachycardia) device.
Outcome
At 6 months, the patient was in NYHA class II. On echocardiography no improvement in ejection fraction was found (ejection fraction ∼15%), but left ventricular end-diastolic and end-systolic volume indices were slightly reduced (respectively, from 178 to 166 mL/m2, 7%; and from 148 to 142 mL/m2, 4%). According to the reduction in end-systolic volume, the patient was classified as a nonresponder to CRT (the cutoff to define responsiveness is a reduction of at least 15% of end-systolic volume).
Intervention
However, at 6 months the shape of the ventricle clearly changed from a spherical to a more elongate appearance; mitral annulus diameter was reduced to 31 mm, tenting length to 11 mm, and tethering area to 3 cm2; and mitral regurgitation was trivial (in contrast to at least moderate at baseline).
Comments
The first important fact of this case is that no single technique or single parameter allows accurate prediction of response to CRT. The information derived by different techniques often is not consistent, and the best clinical approach is to combine information on dyssynchrony (obtained by several methods) with information on the mechanical substrate amenable to CRT in the failing left ventricle.
The second important point is that not only is predicting the response to CRT difficult but also that defining whether the patient is a positive responder or a negative responder is simplistic. According to the literature, the most commonly accepted definition of a positive response to CRT is a reduction in left ventricular end-systolic volume greater than 15%.
This case also challenges such a definition. The patient did not reach this level of improvement, although he improved subjectively (from NYHA class III to NYHA class II). This can be considered a placebo effect; however, it also could be speculated that the improvement in left ventricular shape and the reduction of mitral regurgitation after CRT may have contributed to the clinical improvement in this patient.
Selected References
1. Muto C., Gasparini M., Peraldo Neja C. et al. Presence of left ventricular contractile reserve predicts midterm response to cardiac resynchronization therapy: results from the LOw dose DObutamine Stress-Echo Test in Cardiac Resynchronization Therapy (LODO-CRT) trial. Heart Rhythm. 2010;7:1600–1605.
2. Rocchi G., Bertiniv M., Biffi M. et al. Exercise stress echocardiography is superior to rest echocardiography in predicting left ventricular reverse remodelling and functional improvement after cardiac resynchronization therapy. Eur Heart J. 2009;30:89–97.
3. Suffoletto M.S., Dohi K., Cannesson M. et al. Novel speckle-tracking radial strain from routine black-and-white echocardiographic images to quantify dyssynchrony and predict response to cardiac resynchronization therapy. Circulation. 2006;113:960–968.
4. White J.A., Yee R., Yuan X. et al. Delayed enhancement magnetic resonance imaging predicts response to cardiac resynchronization therapy in patients with intraventricular dyssynchrony. J Am Coll Cardiol. 2006;48:1953–1960.
