Features and Prognosis of Exertional Syncope in Light-Chain Associated AL Cardiac Amyloidosis

Primary (AL) amyloidosis is a multisystem disease caused by plasma cell dyscrasia and characterized by the extracellular deposition of immunoglobulin light chains within various organs. Cardiac dysfunction secondary to amyloid infiltration is a well-recognized feature occurring in up to 50% of patients with primary systemic amyloidosis. Clinically, cardiac amyloidosis frequently presents with a restrictive pathophysiology secondary to the deposition of the amyloid fibrillar protein within the myocardium,1Klein AL Hatle LK Burstow DJ Seward JB Kyle RA Bailey KR Luscher TF Gertz MA Tajik AJ Doppler characterization of left ventricular diastolic function in cardiac amyloidosis.J Am Coll Cardiol. 1989; 13: 1017-1026Abstract Full Text PDF PubMed Scopus (288) Google Scholarresulting in a “stiff heart syndrome.”2Chew C Ziady GM Raphael MK Oakley CM The functional defect in amyloid heart disease the “stiff heart” syndrome.Am J Cardiol. 1975; 36: 438-444Abstract Full Text PDF PubMed Scopus (127) Google ScholarConduction disturbances and coronary insufficiency due to amyloid deposition may also be part of the clinical picture of cardiac AL.3Roberts WC Waller BF Cardiac amyloidosis causing cardiac dysfunction analysis of 54 necropsy patients.Am J Cardiol. 1983; 52: 137-146Abstract Full Text PDF PubMed Scopus (243) Google ScholarCommon presenting symptoms of cardiac AL include fatigue, weakness, edema, dyspnea, light-headedness, and syncope.4Kyle RA Gertz MA Primary systemic amyloidosis, clinical and laboratory features in 474 cases.Semin Hematol. 1995; 32: 45-59PubMed Google ScholarThis study details an undescribed type of syncope in a group of patients with severe cardiac AL and contrasts the potential mechanism with other cases of syncope. A retrospective analysis of the medical records of 185 cases of AL with cardiac involvement was performed. All patients underwent a full clinical assessment, including a 12-lead electrocardiogram, chest x-ray, and echocardiogram with Doppler and 24-hour Holter recording. Study entry criteria required that patients have cardiac involvement and a history of syncope during the course of their illness. Syncope was defined as a temporary loss of consciousness due to impairment of cerebral blood flow. The records of all patients described as having experienced syncope were reviewed by 2 cardiologists with particular emphasis placed on establishing the events surrounding the syncopal episodes with a view to determining both the precipitating features and etiology of syncope for each patient. Patients with dizziness, light-headedness, or features of presyncope were not included. All patients studied had biopsy proven (light chain) systemic amyloidosis. Cardiac involvement was defined as unexplained low voltage on the electrocardiogram (mean voltage amplitude of 1 2 cm) in the absence of hypertension or significant valvular disease. Of 185 cases examined we identified 26 patients (14.1%), 20 men and 6 women, of mean age 55 ± 12 years, with AL cardiac amyloidosis and a history of ≥1 episodes of syncope during the course of their illness. Of these 26, syncope was solely related to postural changes in 7 patients who had a demonstrable postural fall in blood pressure (>20 mm Hg fall in systolic pressure) which was shown during clinical examination. Syncope was attributable to a cardiac arrhythmia in 3 patients (ventricular tachycardia in 2 and atrial fibrillation in 1), conduction disturbance in 2 patients (Table I), and a multifactorial etiology with a combination of postural and vasovagal mechanisms in 3 patients. A single patient had syncope related to micturition. Ten of the original 26 patients had a history of syncopal episodes that were not explained by any of the aforementioned mechanisms. Although no precipitating feature was found in 2 of these 10 patients, in 8 patients syncope was precipitated by physiologic stress, including physical exertion in 6 and by intense emotion in 2 patients. The intensity of exertion in these patients at the time of syncope ranged from running for a train in 2 cases to brisk walking in the remainder. In the emotion precipitated cases, syncope occurred while lying supine before cardiac catheterization and progressed to cardiac arrest with the need for cardiopulmonary resuscitation. In a second patient, syncope occurred after returning from a long overseas trip, climbing the stairs to his apartment, and greeting his wife. Similar episodes of syncope continued to recur in stressful or emotional situations. Patients experiencing stress-related syncope were clinically similar to the remaining patients, with syncope due to other causes, with the exception of being on average 12 years younger (Table I). All 8 patients with exertion- or emotion-related syncope had echocardiographic evidence of severe cardiac amyloidosis characterized by concentric ventricular wall thickening and a normal to small ventricular cavity size (Table II). In addition all 8 patients had associated class III to IV New York Heart Association symptoms of congestive heart failure. Exercise treadmill stress tests were performed in 6 of the 8 patients, the remaining 2 patients being too ill to exercise. Exertional hypotension occurred in all 6 subjects and exertional cyanosis was observed in 3. Five patients experienced symptoms during exercise testing similar to those preceding their episodes of syncope and 2 patients had syncopal episodes during maximum exercise (Fig. 1). Table ICharacteristics of the Eight Patients With Stress-Related Syncope Compared With the 18 Patients With Syncope Unrelated to StressFeatureStress Syncope Group (n = 8)Nonstress Syncope Group (n = 18)Men/women7/113/5Mean age (yrs)47 ± 0ap <0.05.59 ± 12ap <0.05.Median duration of symptoms (mo)810Congestive heart failure8 (100)11 (61)TreatmentsColchicine3 (38)11 (61)Oral melphalan+ prednisone4 (50)6 (33)Intravenous melphalan+ stem cell rescue1 (12)1 (6)Supine systolic BP (mm Hg)108 ± 18117 ± 17Supine diastolic BP (mm Hg)71 ± 1071 ± 9Standing systolic BP (mm Hg)108 ± 2797 ± 25Standing diastolic BP (mm Hg)70 ± 1361 ± 1724-hour Holter recordingSupraventricular tachycardia0 (0)3 (17)Ventricular tachycardia4 (50)4 (22)Sick sinus syndrome01 (6)Data are presented as absolute numbers (%) or as mean ± SD. Symptom duration represents median values.BP = blood pressure.a p <0.05. Open table in a new tab Table IIElectrocardiographic and Echocardiographic Measurements in the Eight Patients With Stress- (Exertion and Emotion) Related Syncope Compared With the Remaining 18 Patients With SyncopeFeatureStress Syncope Group (n = 8)Nonstress Syncope Group (n = 18)Electrocardiographic limb lead voltage (mV)0.48 ± 0.330.45 ± 0.18Pseudoinfarction pattern on electrocardiogram5 (62.5)10 (55.6)Left ventricular wall thickness (cm)1.53 ± 0.321.45 ± 0.34Left ventricular end-diastolic dimension (cm)4.38 ± 0.694.42 ± 0.97Left ventricular mass/body surface area (g/m)152 ± 40137 ± 45Left atrial dimension (cm)4.24 ± 0.694.08 ± 0.91Left ventricular ejection fraction (%)46 ± 1454 ± 12Data are presented mean ± SD or as absolute number (%). Pseudoinfarction pattern is defined as QS waves in anterior or inferior leads in the absence of prior myocardial infarction. Open table in a new tab Data are presented as absolute numbers (%) or as mean ± SD. Symptom duration represents median values. BP = blood pressure. Data are presented mean ± SD or as absolute number (%). Pseudoinfarction pattern is defined as QS waves in anterior or inferior leads in the absence of prior myocardial infarction. Twenty-three of the original 26 patients with syncope died during follow up; 1 patient who underwent cardiac transplantation was treated as a death equivalent from the date of the transplant procedure. The most common cause of death was sudden cardiac death (Fig. 2). Seven of the original 8 patients (87.5%) in the stress-associated syncope group died during follow up and all died from a sudden and presumed arrhythmic cardiac death. The median survival was significantly shorter for these 8 patients (2 months) than for the remaining 18 patients (13 months, p <0.005 (Fig. 3). In addition to surviving longer, the 18 patients in the nonstress related group experienced significantly less instances of sudden death (n = 4, 22.4%) than in the group where syncope was precipitated by stress (n = 7, 87.5%, p <0.005).Fig. 3Kaplan-Meier survival curves showing the significantly shorter survival in patients with stress related syncope compared with those in who syncope was unrelated to stress (p <0.0003 by log rank test).View Large Image Figure ViewerDownload (PPT) Syncope is common in AL amyloid heart disease. In several cases syncope was multifactorial, whereas in others a single mechanism, such as bradyarrhythmia or tachyarrhythmias, or postural hypotension due to autonomic neuropathy, could be identified. In almost 1/3 of patients, the episodes of syncope were precipitated by physiologic stress, either exertional or emotional. These patients were younger than the 18 patients with syncope unrelated to stressful situations. Although this suggests that those with exertion or emotion-related syncope might have had more extensive or more rapidly progressive myocardial infiltration, both groups were characterized by severe heart involvement and were statistically inseparable on electrocardiographic or echocardiographic measurements. However, there remained a trend for the younger stress syncope group to have both more detrimental values on echocardiography and a greater incidence of heart failure than the nonstress syncope group. We believe that the symptoms in these 8 patients represent a common pathophysiology, similar but not identical to that found in severe aortic stenosis where syncope may be provoked by exertion. In amyloid heart disease, cardiac output at rest is reduced, autonomic dysfunction may be present, and myocardial reserve is impaired. In addition, perivascular amyloid deposits may impair the ability of small vessels in the heart to vasodilate and there may be sinus node dysfunction. The combination of a blunted blood pressure response to exercise, chronotropic incompetence, and small vessel induced myocardial ischemia results in a failure to augment cardiac output despite an increased circulatory demand. In addition to ventricular diastolic and systolic dysfunction, the atria may also become stiff and dysfunctional as a result of amyloid infiltration. The resultant failure of the atria to adequately prime the ventricles further contributes to their decreased filling in late diastole At a critical level of exercise, tissue oxygen extraction may be so intense as to result in peripheral cyanosis as was observed in several of our patients on exercise testing. Exercise-induced shunting of blood to skeletal muscle results in further hypotension by underfilling of the stiff right ventricle or by producing further myocardial ischemia at the level of the small vessels. We postulate that it is this combination of events that leads to a reduction in cerebral blood and results in syncope. Syncope in patients with cardiovascular disease is associated with a high mortality within the first year5Kapoor WN Karpf M Wieand S Peterson JR Levey JS A prospective evaluation and follow-up of patients with syncope.N Engl J Med. 1983; 309: 197-204Crossref PubMed Scopus (702) Google Scholar; amyloid heart disease appears to be no exception, particularly when syncope is precipitated by stress. The majority of deaths in this group were sudden and although no satisfactory therapy exists for either this mechanism of syncope or indeed this mode of death, its recognition may prevent unnecessary pacemaker or implantable cardioverter-defibrillator implantation. At the present time, counseling on the restriction of physical activity is the suggested advice until disease regression can be achieved. We conclude that stress-precipitated syncope is a serious prognostic sign in AL amyloidosis and is often a precursor of sudden cardiac death, most likely due to electromechanical dissociation.