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Sudden Cardiac Death Ten Months After Delivery

Case Presentation:

A 45 year old woman was admitted to the hospital after resuscitation from ventricular fibrillation (VF). Cardiac risk factors were hypertriglyceridemia and positive family history of coronary artery disease (father and brother).  There was no history of sudden cardiac death (SCD) or known cardiomyopathy in the family. Her past medical history was significant only for bilateral carpal tunnel syndrome, for which she underwent right wrist operation several months prior to the present admission. She had always been an active person, working full time and enjoying a regular exercise schedule. She had  three uneventful pregnancies and deliveries, the latest delivery being 10 months prior to the present event.

Myocardial Disease


Case Context:

Two months before admission the patient started to experience exertional fatigue and mild shortness of breath while walking uphill. She attributed these complaints to the fact that she had resumed a full working schedule early after delivery and had to take care of her three children including a newborn.

One night, while getting-up to her crying baby and walking to the baby’s crib, she suddenly collapsed to the floor. Hearing the fall, her husband rushed to the other room and found his wife lying unconscious. He immediately called the emergency mobile services and initiated basic CPR, following instructions received over the phone from the dispatcher. On arrival of the ambulance team (within 6 minutes) the patient was found to be in ventricular fibrillation (VF). Two high-energy shocks were delivered, followed by asystole. Advanced CPR continued for 9 minutes, resulting in restoration of spontaneous circulation, stable sinus rhythm (80 bpm) and normal blood pressure (130/80 mmHg). In hospital, while ventilated and still comatose, a cooling therapy protocol was applied for 24 hours. Within 48 hours of admission the patient regained consciousness and underwent successful weaning from respiratory support, followed by full neurological recovery. While monitored in-hospital for arrhythmia, a single episode of non-sustained ventricular tachycardia (NSVT - 4 beats) was recorded. A procainamide challenge test failed to induce Brugada pattern on the electrocardiogram.

Admission blood tests included CBC (Hemoglobin 12.5 gr/dl, WBC 12,500 /µL, Platelets 413,000 /µL), Glucose 148 98 mg/dl, Na 137 mEq/L, K 4.0 mEq/L, Chloride 104 mEq/L, Magnesium 1.9 mEq/L, Creatinine 0.7 mg/dl, AST 118 54 IU/L, LDH 627 IU/L, CPK 981 474 29 IU/L, CRP < 0.5 mg/dl, Total Protein 6.4 gr/dl, Albumin 4.2 gr/dl; TSH 3.3 mIU/L, Calcium 10.8 mg/dl, Phosphor 3.8 mg/dl.
 
Figure 1: Initial electrocardiogram

Initial electrocardiogram

Chest X-ray showed a normal cardiac silhouette, mild pulmonary venous congestion and a small right-sided pleural effusion.
First echocardiogram was reported as “normal size ventricles with normal function and no significant valvular disease”.

Left heart catheterization showed normal left ventricular (LV) segmental contraction and systolic function, normal coronary arteries, the aortic pressure was 104/63 (mean 82) mmHg and LVEDP measured 18 and 20 mmHg (pre- and post-LV injection, respectively).
Based on these findings, the diagnosis of idiopathic VF was made. The patient underwent an uneventful ICD implantation and was discharged, being prescribed aspirin and a statin. However, within a month after discharge, her functional capacity deteriorated. She experienced general weakness, worsening shortness of breath with minimal effort, orthopnea and aggravating peripheral edema. Diuretic therapy was initiated.  A repeat echocardiogram was performed (figure 2) and the patient was referred to our service for further evaluation and treatment. 

Echocardiogram showing normal biventricular internal dimensions

Biventricular systolic function was normal and there were no segmental wall motion abnormalities.

 

LV inflow Doppler tracing, 2-D parasternal and four-chamber views are presented

Figure 2:
Echocardiogram showing normal biventricular internal dimensions, dilatation of both atria, concentric wall thickening (septal and posterior LV wall thickness 13-14 mm) and a small pericardial effusion. Biventricular systolic function was normal (estimated LVEF 60%) and there were no segmental wall motion abnormalities. LV inflow Doppler tracing, 2-D parasternal and four-chamber views are presented.

        

On examination she had a regular heart rate of 65 bpm and blood pressure of 110/65 mmHg, without postural hypotension. There was mild speech dyspnea, orthopnea, elevated jugular venous pressure and moderate (+2) peripheral edema. Heart sounds were somewhat distant, without diastolic gallop. A soft systolic murmur was heard at the left sternal border and apex. Chest auscultation was notable for bilateral basal rales and a small right pleural effusion. The liver was enlarged and palpable 3 cms below the right costal margin. There was no evidence of ascites.

What are the possible differential diagnoses in this case?
What are the recommended diagnostic procedures?
What treatment regimens should be considered?

Diagnosis, case resolution and treatment

 Sudden cardiac death (SCD) in a middle aged woman, 10 months after delivery, requires consideration of several possible diagnoses. The lack of a history of SCD in the family as well as the normal QT interval and absence of Brugada pattern on the presenting ECG (figure 1) make congenital long QT or Brugada syndrome very unlikely. This is further supported by the negative procainamide challenge test and by the fact that the patient was not receiving any medications to influence the conduction system or cause electrolyte imbalance.  An acute ischemic event or underlying “silent” coronary disease should be considered next.  Although a woman of young age, she had hyperlipidemia, a family history of coronary disease and symptoms which could reflect equivalent angina. Furthermore, the ECG (fig 1) was suggestive of an old anterior infarction (not supported by the normal left ventricular segmental wall motion and systolic function on echocardiography).

 

Two electrocardiograms recorded 5 years apart

 Figure 1: Two electrocardiograms recorded 5 years apart. There is a two- to three-fold increase in QRS amplitude, shorter PR interval and a lesser degree of left axis deviation. Poor R-wave progression in V1 V3 (“pseudo-infarction” pattern) is unchanged.

Thus, a coronary angiogram was performed and ruled out this diagnosis. Undiagnosed idiopathic dilated cardiomyopathy (DCM) or peripartum cardiomyopathy (PPCM) were not supported by the echocardiograms showing normal left ventricular (LV) size and systolic function. Myocarditis, in particular of giant cell type, may present as SCD due to malignant ventricular arrhythmias. However, the patient did not experience upper respiratory or gastrointestinal symptoms, nor did she have fever, to suggest a preceding acute viral infection. The lack of inflammatory markers (i.e. normal CRP) and the normal wall motion and systolic function further diminish the likelihood of this diagnosis. Modestly elevated CPK may reflect an acute myocardial injury, ischemic or inflammatory, but in her case could also be due to the delivery of electrical shocks during resuscitation (troponin measurement was not available at that time). A myocardial biopsy to rule out acute myocarditis or inflammatory cardiomyopathy could have been considered, but was not performed due to the low likelihood of these diagnoses.

Other forms of cardiomyopathy, hypertrophic and restrictive, may predispose to SCD in the middle age. The echocardiogram (figure 2) shows concentric biventricular wall thickening and biatrial enlargement. Doppler mitral flow-velocities are consistent with a restrictive filling pattern (E/A ratio = 3.7), suggestive of elevated LV diastolic pressure, in accordance with the measured LVEDP on heart catheterization.

 

LV inflow Doppler tracings taken 5 years apart

Figure 2: LV inflow Doppler tracings taken 5 years apart. The restrictive E/A pattern evident on the left has normalized on the right. However, mitral annular velocities are low (E’ = 5.5 cm/sec), suggesting significantly impaired myocardial relaxation (tracing not shown). Note: heart rate is similar on both tracings, 61-64 /min, despite different recording speeds


These findings may support either restrictive or hypertrophic cardiomyopathy (HCM). However, the ECG, showing an anterior pseudo-infarction pattern and no left ventricular hypertrophy, does not support the diagnosis of HCM. On the contrary, the combination of a relatively small QRS voltage in the limb leads with conduction disturbances (left axis deviation and prolonged PR interval), and the aforementioned pseudo-infarction pattern, pointed to restrictive amyloid cardiomyopathy as the likely diagnosis. Signs and symptoms of congestive heart failure, often with right-sided predominance, are common in cardiac amyloidosis (CA) and may progress rapidly (1-3). LVEDP, mean right atrial and mean pulmonary wedge pressures are elevated in up to 2/3 of patients with CA (1,4,5). In addition, carpal tunnel syndrome is present in 13-38% of patients with CA and may precede other organ involvement by a few years (1,4).

The preliminary diagnosis of CA in our patient was supported by abdominal fat-pad, rectal and bone marrow biopsies showing positive Congo red amyloid staining. Assessment of serum and urine free light chains revealed excess of free kappa chains with an abnormally elevated kappa-to-lambda ratio. Bone marrow plasma cell count was about 10% (elevated but not diagnostic of multiple myeloma), and immunoperoxidase staining was positive for kappa-producing plasma cells. Thus, the diagnosis of systemic AL amyloidosis with cardiac involvement was made.
The management of AL amyloid cardiomyopathy requires both control of cardiac-related symptoms and treatment of the underlying plasma cell dyscrasia. Heart failure symptoms are best managed by diuretics and modest salt restriction, while angiotensin converting enzyme inhibitors and angiotensin receptor blockers are poorly tolerated in these patients. The use of beta blockers is often limited due to hypotension and conduction abnormalities, and no data exist to suggest any survival benefit  from beta blockers in CA. Calcium channel blockers are contraindicated as they significantly worsen heart failure because of their negative inotropic effect. Cautious use of digoxin may be considered for heart rate control in patients with atrial fibrillation, although the risk of cardio-toxicity is increased due to avid binding of this drug to amyloid fibrils (1,3).

Treatment of AL amyloidosis requires anti-plasma cell therapy aimed at stopping, or significantly reducing, the production of amyloidogenic monoclonal light chains. Several chemotherapeutic regimens exist, including high-dose melphalan with autologous stem cell transplantation, standard dose melphalan with dexamethasone, and newer protocols incorporation thalidomide, lenalidomide and bortezomib, with or without steroids. Although controversial, heart transplantation followed by autologous stem cell transplantation may be considered in selected patients (3).

Our patient was initially treated with high dose melphalan and autologous bone marrow transplantation. Partial relapse of her disease was noted one year later. She was started on thalidomide but had only modest response. Due to inadequate control of disease and despite the increased risk, she underwent repeat stem cell transplantation. She currently receives lenalidomide as maintenance therapy. With time, her functional capacity markedly improved to NYHA class IIa. There was no recurrence of complex ventricular arrhythmias and no ICD discharge. At present, 6 years after diagnosis, she is active and working, with no signs of heart failure. She does not require diuretic therapy and does not receive antiarrhythmics. Reversal of ECG pathology and echo-Doppler findings has been noted on serial examinations (figures 3 and 4) and is consistent with her good clinical condition.

Conclusion:

Comments on special aspects of the case

1. Delay in diagnosis
CA is frequently overlooked at initial presentation. In a recent report of 30 patients with CA (83% AL type) the time to diagnosis after initial presentation with clinical and/or ECG signs was 6 months to 4 years (2). In another series, 45% of patients had a delay in diagnosis of over a year from the onset of symptoms (6). Patients were misdiagnosed as having hypertrophic cardiomyopathy, heart failure of uncertain etiology or constrictive pericarditis. The delay in diagnosis is due to unrecognized ECG and echocardiographic features of the disease, in particular the discrepancy between ECG voltage and echocardiographic ventricular wall thickness is overlooked. Thus, diagnosing CA requires a high index of suspicion, primarily in patients presenting with rapidly progressive dyspnea and peripheral edema of unknown origin, in conjunction with non-dilated ventricles and poor R-wave progression (2-4).

2. Sudden death as presenting symptom of CA and the role of ICD
About half of the patients with systemic AL amyloidosis have cardiac involvement (1,7). Nevertheless, ventricular tachyarrhythmias are an uncommon presenting feature (7-10). The reported incidence of SCD in those with CA is about 30% and most cases are due to electromechanical dissociation (EMD), atrioventricular block or asystole (11-12). Therefore, the protective role of ICD in CA is uncertain. Kristen et al. (9) implanted defibrillators in 19 patients with CA and syncope and/or high-grade ventricular premature beats or non-sustained VT. After a mean follow-up of 2.5 years, only 2 patients (10%) received shocks for sustained VT while 6 patients (32%) died of EMD (including one of the 2 patients who initially received a successful ICD intervention). Hess et al. (7) described 4 patients with CA who had out of hospital cardiac arrest, one of whom had VF as the presenting symptom of the disease, as documented in our patient. Up to nine consecutive shocks were needed to control recurrent VF and shocks often resulted in EMD or asystole, as was the case in our patient. The authors emphasized that CPR in CA is of limited effectiveness and carries a very poor prognosis (3 of the 4 patients died shortly after CPR, 2 of them in EMD). Finally, defibrillation thresholds may be elevated in patients with advanced CA, rendering ICD ineffective when repeat shocks for recurrent and persistent VF at high energy are needed (7, 9,10). Thus, ICD placement in AL amyloidosis should be limited to patients with documented malignant arrhythmias (3).

3. Prognosis
Cardiac involvement in AL amyloidosis is associated with poor prognosis. The median survival of untreated patients with CA is 9-12 months in the absence of heart failure and 4-6 month in those with symptomatic heart failure at diagnosis (3,13). Aggressive chemotherapy with stem cell transplantation induces complete hematologic remission in 40% of cases and improves overall prognosis in patients with CA, if it is initiated early in the course of the disease (3,9). Unfortunately, this regimen carries up to 30% risk of peritreatment mortality in patients with advanced cardiac involvement and is contraindicated in patients with a LVEF < 40% and NYHA class III heart failure (1). At diagnosis, our patient had ECG and echocardiographic evidence of significant amyloid infiltration of the heart. Nevertheless, her young age and preserved systolic function enabled her to undergo bone marrow transplantation (twice) and although not in complete remission, she is alive and almost free of symptoms 6 years after her dramatic presentation.

References


1. Falk RH. Diagnosis and management of the cardiac amyloidoses. Circulation 2005;112;2047-2060.
2. Piper C, Butz T, Farr M, et al. How to diagnose cardiac amyloidosis early: impact of ECG, tissue Doppler echocardiography, and myocardial biopsy. Amyloid 2010;17:1-9.
3. Falk RH, Dubrey SW. Amyloid heart disease. Prog CardiovascDis 2010;52:347-361.
4. Rapezzi C, Merlini G, Quarta CC, et al. Systemic cardiac amyloidoses: disease profiles and clinical courses of the 3 main types. Circulation 2009;120:1203-1212.
5. Shah KB, Inoue Y, Mehra MR. Amyloidosis and the heart: a comprehensive review. Arch Intern Med 2006;166:1805-1813.
6. Palladini G, Russo P, Lavatelli F, et al. Treatment of patients with advanced cardiac AL amyloidosis with oral melphalan, dexamethasone and thalidomide. Ann Hematol 2009;88:347-350.
7. Hess EP, White RD. Out-of-hospital cardiac arrest in patients with cardiac amyloidosis: presenting rhythms, management and outcomes in four patients. Resuscitation. 2004;60:105-111.
8. Falk RH, Rubinow A, Cohen AS. Cardiac arrhythmias in systemic amyloidosis: correlation with echocardiographic abnormalities. J Am Coll Cardiol 1984;3:107-113.
9. Kristen AV, Dengler TJ, Hegenbart U, et al. Prophylactic implantation of cardioverter-defibrillator in patients with severe cardiac amyloidosis and high risk for sudden cardiac death. Heart Rhythm 2008;5:235-240.
10. Dhoble A, Khasnis A, Olomu A, et al. Cardiac amyloidosis treated with an implantable cardioverter defibrillator and subcutaneous array lead system: report of a case and literature review. Clin Cardiol 2009;32:E63-E65.
11. Chamarthi B, Dubrey SW, Cha K, et al. Features and prognosis of exertional syncope in light-chain associated AL carciac amyloidosis. Am J Cardiol 1997;80:1242-1245.
12. Dubrey SW, Cha K, Anderson J, et al. The clinical features of immunoglobulin light-chain (AL) amyloidosis with heart involvement. QJM 1998;91:141-157.
13. Kyle RA, Gertz MA, Greipp PR, et al. A trial of three regimens for primary amyloidosis: colchicine alone, melphalan and prednisone, and melphalan, prednisone, and colchicine. New Engl J Med 1997;336:1202-1207.

Notes to editor


Presented by Arthur Pollak MD1, Dan Admon MD1, Dina Ben-Yehuda MD2, Andre Keren MD1 from the Division of Cardiology1 and the Department of Hematology2, Hadassah – Hebrew University Medical Center, Jerusalem, Israel
The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.

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