The 2013 ECG showed marked and diffuse voltage reduction (QS in V1-V3) and inferolateral T-wave inversion.
Echocardiogram of the patient in 2012 (parasternal view [A], apical 3-chamber view [B], and 4-chamber views [E and F]) showing asymmetric LV hypertrophy and systolic anterior movement of the mitral valve (arrowheads). Panels I, J, and M represent Doppler evidence of mild diastolic dysfunction: septal and lateral tissue Doppler imaging values (8 and 11 cm/s for panels I and J, respectively) and mitral inflow pattern (panel M: early filling velocity, 70 cm/s; atrial filling velocity, 78 cm/s; deceleration time, 230 milliseconds). Panel N represents continuous wave Doppler imaging showing LV outflow tract obstruction (systolic LV outflow tract gradient 69 mm Hg). Echocardiogram of the patient in 2013 (parasternal view [C], apical 3-chamber view [D], and 4-chamber views, [G and H]) showing abrupt changes with an increase of LV hypertrophy (from asymmetric to concentric), development of a granular sparkling appearance of the myocardium, thickening of the mitral valve leaflets (magenta arrowheads), less severe systolic anterior movement of the mitral valve, progression of marked biatrial enlargement, mild concentric pericardial effusion (asterisks), and binary sign of the interventricular septum (yellow arrowheads). Panels K, L, and O represent Doppler evidence of severe diastolic dysfunction: septal and lateral tissue Doppler imaging values (3 4 cm/s for panels K and L, respectively) and mitral inflow pattern (panel O: early filling velocity, 74 cm/s; atrial filling velocity, 22 cm/s; deceleration time, 244 milliseconds). Panel P represents continuous wave Doppler imaging showing loss of LV outflow tract obstruction (systolic LV outflow tract gradient, 12 mm Hg).
Ao, indicates aorta; IVS, interventricular septum; LA, left atrium; LV, left ventricle; RA, right atrium; RV, right ventricle.
Appearance of amyloid protein deposit on microscopic examination. Two different subcutaneous fat aspirates stained with Congo red and viewed under polarized light show the characteristic apple-green birefringence (original magnification x200).
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Tomberli B, Cappelli F, Perfetto F, Olivotto I. Abrupt Onset of Refractory Heart Failure Associated With Light-Chain Amyloidosis in Hypertrophic Cardiomyopathy. JAMA Cardiol. 2017;2(1):94–97. doi:10.1001/jamacardio.2016.3894
The natural history of hypertrophic cardiomyopathy (HCM) is complex and may include progressive heart failure and severe left ventricular dysfunction. When disease progression is abrupt, however, other coexisting diseases should be ruled out. This may be difficult in the case of amyloidosis, which classically mimics HCM.
We present an example of severe clinical deterioration in a patient with HCM due to superimposed amyloid light-chain amyloidosis. A man in his 70s with a longstanding history of genetically confirmed HCM presented with rapid development of congestive heart failure over 6 months, in sharp contrast to a previously stable, asymptomatic clinical course. He was diagnosed as having the illness in his late 40s after a resuscitated cardiac arrest and regularly followed up on a yearly basis. His most recent electrocardiogram was profoundly changed from previous tracings, with marked and diffuse voltage reduction (QS in V1-V3) and inferolateral T-wave inversion. The echocardiogram showed an abrupt increase in the severity of left ventricular (LV) hypertrophy, with a concentric rather than asymmetric appearance, granular sparkling of the myocardium, biatrial enlargement, thickening of the mitral valve leaflets, and interatrial septum and mild pericardial effusion. Severe LV dysfunction with a restrictive LV filling pattern was evident, which is associated with LV outflow tract obstruction loss and right ventricle systolic impairment. Following hospital admission, multiple myeloma was diagnosed and confirmed by bone marrow biopsy and aspiration. Furthermore, abdominal fat aspiration showed amyloid deposition and confirmed the diagnosis of amyloid light-chain amyloidosis. Electrocardiograms, echocardiographic images, and videos presented in this report describe the abrupt and marked evolution of a sarcomeric to infiltrative cardiomyopathy, leading to an ominous outcome in which the patient died despite specific treatment.
Conclusions and Relevance
While progression to the end-stage phase occurs over several years for patients with HCM and can be detected at relatively early stages, the abrupt onset of congestive heart failure is uncommon and should raise suspicion of other, superimposed cardiac diseases.
The natural history of hypertrophic cardiomyopathy (HCM) is complex and may include progressive heart failure and severe left ventricular (LV) dysfunction.1 When disease progression is abrupt, however, other coexisting diseases should be ruled out. This may be difficult in the case of amyloidosis, which classically mimics HCM.2 Here we report a rare case of cardiac amyloid phenotype developing in a patient with classic HCM and altering the disease’s clinical course.
A man in his 70s with HCM presented with recent-onset congestive heart failure. He was diagnosed as having HCM in his late 40s when he was resuscitated from an out-of-hospital cardiac arrest (well before the availability of an implantable defibrillator), discharged, and prescribed β-adrenergic blockers and amiodarone. He was followed up for a number of years with stable findings of LV hypertrophy on electrocardiograms (Figure 1) and moderate hypertrophy of the midbasal interventricular septum on echocardiogram (ECG), which is associated with mild systolic anterior motion of the anterior mitral leaflet, mild mitral regurgitation, and moderate dilatation of the left atrium (Figure 2A, B, E, and F and Video 1). Doppler studies showed mild LV diastolic dysfunction (Figure 2I, J, and M) and left ventricular outflow tract (LVOT) obstruction (Figure 2N). Stress echocardiography confirmed the presence of labile LVOT obstruction with good functional capacity (125 W; 87% predicted heart rate), absence of provocable arrhythmias, and normal blood response to exercise. The diagnosis was confirmed by genetic analysis, showing the p.Glu258Lys pathogenic variant in the gene coding for cardiac myosin binding protein C (MYBPC3).
Regular cardiovascular evaluations, including echocardiography and ambulatory 24-hour ECG, were stable over the last 6 years. The patient remained asymptomatic, leading a very active life—including hiking—without functional limitation, palpitations, lightheadedness, or angina. Despite a history of cardiac arrest, serial 24-hour ECG recordings were repeatedly negative for ventricular arrhythmias while the patient was taking amiodarone and β-blockade. Thus, he never received an implantable defibrillator.
Years later, he presented with rapid development of congestive heart failure, in sharp contrast to the previously stable, asymptomatic clinical course. Compared with earlier studies, his ECG now showed marked and diffuse voltage reduction, a QS pattern in V1 to V3, and inferolateral T-wave inversion (Figure 1). The echocardiogram showed an abrupt increase in the severity of LV hypertrophy (Figure 2), with a concentric rather than asymmetric appearance, granular sparkling of the myocardium, biatrial enlargement, thickening of atrioventricular valve leaflets and interatrial septum, and a mild pericardial effusion (Figure 2C, D, G, and H). Severe LV dysfunction with a restrictive LV filling pattern was evident, which is associated with loss of LVOT obstruction and systolic impairment of the right ventricle (Figure 2K, L, O, and P). Notably, the acoustic window and endocardial border definition had significantly improved, and there was a distinct binary appearance of the interventricular septum (Video 1 and Video 2).
Multiple myeloma was diagnosed following hospital admission. Protein electrophoresis showed hypogammaglobulinemia with increased κ-free light chains (824 mg/L; normal range, 3.3-19.4 mg/L), normal λ light chains, and very mild Bence Jones proteinuria. The bone marrow biopsy and aspiration confirmed the diagnosis of multiple myeloma, with a 40% proportion of κ-restricted monoclonal plasma cells infiltration. Abdominal fat aspiration showed amyloid deposition and confirmed the diagnosis of light-chain amyloidosis (Figure 3). Genetic testing results for transthyretin mutations were negative. Within 2 months, despite prompt initiation of chemotherapy and support treatment, the patient died of electromechanical dissociation.
Abrupt onset of congestive heart failure subtended by biventricular dysfunction is uncommon in patients with HCM, particularly in older patients. Once rare phenocopies (such as Danon or transthyrethin-related amyoloidosis) have been excluded from consideration, such a clinical course should raise suspicion of superimposed conditions such as coronary artery disease, myocarditis, and infiltrative or systemic conditions (including autoimmune and malignancy-related disease).1-4 Indeed, while the progression of HCM may lead to end-stage heart failure in approximately 5% to 7% of patients, such a progression generally occurs over several years and can be detected at relatively early stages. Physicians should always consider the presence of an associated disease process in patients with HCM with an atypical disease course to identify conditions amenable to specific treatment, as we attempted to do, unfortunately without success, for this patient.
Corresponding Author: Benedetta Tomberli, MD, PhD, Referral Center for Cardiomyopathies, Dipartimento Cuore e Vasi, Azienda Ospedaliera Universitaria Careggi, Largo Brambilla 3, 50124, Florence, Italy (firstname.lastname@example.org).
Accepted for Publication: August 9, 2016.
Published Online: November 2, 2016. doi:10.1001/jamacardio.2016.3894
Author Contributions: Dr Tomberli had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: Tomberli, Cappelli, Olivotto.
Acquisition, analysis, and interpretation of data: Tomberli, Perfetto, Olivotto.
Drafting of the manuscript: Tomberli, Cappelli, Olivotto.
Critical revision of the manuscript for important intellectual content: Tomberli, Perfetto, Olivotto.
Administrative, technical, or material support: Cappelli, Perfetto.
Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.