Author + information
- Wolfgang Poller, MDa,b,∗∗ (, )
- Carsten Skurk, MDa,b,∗,
- Felicitas Escher, MDb,c,d,
- Costantina Manes, MDa,
- Thomas Elgeti, MDe,
- Heinz-Peter Schultheiss, MDd,
- Matthias Taupitz, MDe and
- Ulf Landmesser, MDa,b,f
- aDepartment of Cardiology, Campus Benjamin Franklin, Charite–Universitätsmedizin Berlin, Berlin, Germany
- bGerman Center for Cardiovascular Research, Site Berlin, Berlin, Germany
- cDepartment of Cardiology, Campus Virchow-Klinikum, Charite–Universitätsmedizin Berlin, Berlin, Germany
- dInstitute for Cardiac Diagnostics and Therapy, Berlin, Germany
- eInstitute for Radiology, Charite–Universitätsmedizin Berlin, Berlin, Germany
- fBerlin Institute of Health, Berlin, Germany
- ↵∗Address for correspondence:
Prof. Wolfgang Poller, Department of Cardiology, Campus Benjamin Franklin, Charite Centrum 11, Charité-Universitätsmedizin Berlin, Hindenburgdamm 30, 12200 Berlin, Germany.
Cardiac amyloidosis is associated with very high morbidity and mortality. Only if treated early, cardiac amyloidosis responds well to therapy, and early recognition with a full differential diagnostic workup including multimodality imaging is therefore critical at first presentation. Closely meshed clinical monitoring and imaging are indispensable to ensure optimal individualized treatment. (Level of Difficulty: Beginner.)
- cardiac amyloidosis
- cardiovascular inflammation
- endomyocardial biopsy
- immunosuppressive therapy
- myocardial imaging
Amyloidosis encompasses a range of protein misfolding disorders causing organ dysfunction through fibril deposition (1). Cardiac involvement is associated with high mortality, and treatment options have been limited so far. The 2 main forms of cardiac amyloidosis (CA), light chain (CAAL) and transthyretin (CAATTR) amyloidosis, have distinct pathomechanisms differentially addressed by pharmacotherapies (2). Regarding CAAL, novel treatments beyond standard therapy with bortezomib are under investigation (3). Optimal monitoring of patients with CAAL to enable early adaptation of therapy is dependent on diagnostic methods sensitive to key components (amyloid deposition, myocardial fibrosis, inflammation) of pathogenesis.
• Only if treated early, CAAL responds well to targeted therapies. Early recognition with a full differential diagnostic workup is indispensable at first presentation.
• Optimal individualized treatment requires close-meshed monitoring to enable early recognition of treatment failure, a pre-requisite for therapeutic escalation before the “point-of-no-return” of right-sided heart failure.
• Multimodality imaging is essential for optimal pre-treatment risk stratification and assessment of differential treatment effects of novel therapeutics.
Noninvasive assessment of the response to therapy in CAAL encompasses free light chains in serum and urine, N-terminal pro–B-type natriuretic peptide (NT-pro-BNP), echocardiography (4), and cardiac magnetic resonance (CMR) imaging (1). The authors previously found myocardial inflammation to indicate a significantly worse prognosis (5), a finding implying that detection of treatment effects on inflammation is desirable. The characterization of myocardial inflammation requires both CMR (1) and endomyocardial biopsy (EMB) studies (6). The authors report on multimodality imaging revealing grossly divergent responses of the left and right sides of the heart to treatment in a patient with advanced CAAL.
History of Presentation
A previously healthy 50-year-old woman presented with New York Heart Association functional class III to IV dyspnea that had insidiously developed over several months and had rapidly progressed within the last weeks. On first admission she was orthopneic and tachypneic, and auscultation revealed signs of pulmonary congestion.
Past Medical History
The patient had no past medical history except common childhood infectious diseases.
The differential diagnosis in this patient with the classical syndrome of heart failure with preserved ejection fraction (HFpEF) encompasses multiple types of cardiomyopathies, including genetic forms and storage diseases. To differentiate among these entities, additional laboratory, imaging (CMR, osteo-computed tomography), and biopsy (myocardium, bone marrow) studies, as well as molecular genetic mutation screening and amyloid subtyping in the EMBs, were conducted.
Diagnostic studies included the following: electrocardiography, with nonspecific signs of disturbed repolarization and left ventricular (LV) hypertrophy (Supplemental Figure 1); chest radiography, with signs of chronic and acute pulmonary congestion (Supplemental Figure 1); body plethysmography, excluding pulmonary dysfunction; echocardiography, with concentric LV wall hypertrophy (15 mm), grade 3 diastolic dysfunction (E/A 3.0, E/Eʹ septal 29.2, lateral 24.5), “sparkling myocardium,” and preserved LV ejection fraction (64%); and CMR, which yielded further functional and morphological information (Figures 1A to 1D and 2A to 2F), as well as quantitative data on late gadolinium enhancement (LGE). The authors use phase-sensitive inversion recovery imaging because the image contrast of LGE versus normal myocardium is maximized over a wide range of inversion times. Phase-sensitive inversion recovery sequences are less prone to artifacts as a result of suboptimal myocardial nulling and are helpful if, as in this case, extensive LGE is present and the identification of normal myocardium is challenging.
Laboratory studies (Figure 1A), CMR (Figures 1D and 2B to 2F), EMB (Figures 1B, 1C, and 2A), and bone marrow biopsy identified cardiac involvement by CAAL. Bone marrow showed plasma cells <10% of total, with no amyloid deposition. Cytometry identified 10% of all leukocytes as CD45− CD38+ CD138+ CD56− cells with light chain restriction λ. Cytogenetics identified no clonal structural or numerical chromosomal aberrations. No osseous destructions or anomalies appeared on a Paris protocol osteo-computed tomography scan. Serum creatinine was 0.69 mg/dl, glomerular filtration rate was >90 ml/min, hemoglobin was 13.7 g/dl, leukocytes were 10.4/nl, and thrombocytes were 176/nl. Immunofixation electrophoresis detected monoclonal free λ light chain excretion in the urine.
Mutation scanning of 173 cardiomyopathy-causing genes, performed because of sudden cardiac death in the patient’s mother, detected a variant of unknown significance (Gly193Asp) in the TBX20 gene but no known pathogenic defect, in particular not regarding hereditary amyloid-forming protein mutants or gene defects associated with hypertrophic or restrictive cardiomyopathies. Further, immunohistochemical amyloid subtyping in EMBs was negative for amyloid AA, ATTR AHγ, Aβ2M, atrial fibrillation, and AApoAI.
In this patient, the diagnosis was established very late, with massive cardiac dysfunction at first presentation. The Mayo Clinic prognostic score, which is based on NT-pro-BNP, troponin, and free λ light chains, put her into stage III, with median survival ≈3 to 4 months. Detection of myocardial inflammation with massive perforin-positive cytotoxic T-cell infiltration (6) (Figure 1B) put her into a particularly high-risk group (5).
Reduction of the precursor protein that forms amyloid fibrils is prerequisite to improving prognosis in CAAL. Treatment with bortezomib is considered standard in the treatment of CAAL, for its tolerability and efficiency compared with chemotherapy. In addition, the patient was enrolled in a placebo-controlled phase 3 trial and was assigned to receive NEOD001 antibody-binding misfolded amyloid deposits (3). Sequential imaging including EMB enabled comparison of the systemic hematologic with local myocardial response, morphology, and function. Systemically, free λ light chains dropped from 344 mg/l (ratio κ/λ 0.04; Δ 330.4) to 90 mg/l (ratio κ/λ 0.12; Δ 79.8) and remained within this range for 12 months (Figure 1A). Locally in the myocardium, this was accompanied by highly significant regression of inflammation and disappearance of cytotoxic T cells (Figure 1B).
The clinical status of the patient rapidly improved from New York Heart Association functional class III to IV at initial presentation to class II 2 months after treatment initiation and remained stable for 12 months. In view of the expected survival of ≈3 of 4 months, this result implies therapeutic efficacy. However, stabilization was achieved for the left side of the heart only (Figure 1D). The concurrent development of insidiously progressive right-sided heart disease (Figure 2) was unexpected. After 15 months of therapy, free light chains rose rapidly to 224 mg/l (ratio κ/λ 0.1; Δ 201.5), and the patient died of refractory right-sided heart failure.
Patients presenting with advanced CAAL and heart failure are an enormous clinical challenge. In these patients, high-dose therapy with melphalan has high treatment-related mortality and is commonly unfeasible (1). Our patient instead received standard therapy with the relatively well-tolerated proteasome inhibitor bortezomib in addition to NEOD001 antibody. Regarding inflammation, the decisive and enduring reduction of pre-treatment myocardial inflammation suggests that the local antiamyloid immune reaction responded well to this treatment. Regarding amyloid deposition, sequential EMBs showed transient regression of deposits after 6 months of treatment, possibly mediated by monocytes and macrophages infiltrating the myocardium. Consistent with the reduced inflammation and amyloid deposition, the treatment clearly stabilized the patient’s left-sided heart disease. The observation of transient amyloid deposit regression is of interest in the context of pioneering experimental work attempting to induce immune cell-mediated degradation of amyloid deposits (7). Amyloid deposits appear to be at least partially reversible in humans, too, thus lending support to the respective approaches.
A critical clinical problem arises if light chains rise, myocardial inflammation is reignited, or cardiac function declines because no data from controlled clinical trials are available. Instead, an individualized response to each individual patient’s problems is required. Systematic imaging of the treatment response in the patient highlights a hitherto neglected aspect of particular clinical interest. The authors describe grossly dichotomous development of left- and right-sided heart function and morphology. One possible explanation for this dichotomy is suggested by our observation (Figure 2A) that, in addition to amyloid disposal between cardiomyocytes, histologic examination also revealed pronounced amorphic amyloid material around microvessels, accompanied by perivascular inflammatory cells. This finding led to significant stenosis secondary to massive amyloid deposition and suggests amyloid-induced microvascular dysfunction as a pathomechanism not blocked by the treatment. In addition to perivascular amyloid, which we documented directly in the myocardium (Figure 2A), a published study proved that amyloid itself exerts adverse effects on vascular function (8). Amyloid deposits need not be confined to a single organ, and perivascular amyloid may therefore affect any vascular bed.
Because right ventricular dysfunction (4) is prognostically critical and a harbinger of terminal heart failure, possible amyloid-induced development of pulmonary vascular disease in CAAL requires particular attention. Adequate treatment of pulmonary vascular disease needs detection in advance of an actual rise in pulmonary artery pressure, which occurs only late (9). The present case emphasizes that it is critical to pay close attention to the possible insidious development of right-sided heart failure even if, as in this patient, it is not apparent from a patient's good clinical status and standard laboratory and LV echocardiographic parameters. The authors therefore suggest invasive hemodynamic monitoring of patients with CAAL as soon as right-sided heart function is impaired, to enable switching to more aggressive anti–plasma cell therapies before the “point of no return” of irreversible right-sided heart failure. Otherwise, progressive generalized whole body deposition of amyloid renders heart transplantation, which is a viable option for some patients, nonfeasible. Assist device implantation in CAAL is problematic because of massive LV hypertrophy, in particular biventricular devices in the case of additional right-sided heart failure (10).
Regarding the development of novel therapeutics for patients with CAAL, it is important to note that inclusion in the NEOD001 trial did not generally require histological documentation of myocardial amyloid deposits or characterization of the local immune response known to influence prognosis critically (5). The NEOD001 program was terminated because it was unable to detect clinical benefit of the antibody (VITAL Amyloidosis Study, a global phase 3, efficacy and safety study of NEOD001 in patients with AL amyloidosis [VITAL]; NCT02312206), thus leaving the challenge to proceed beyond stabilization to regression of organ involvement unsolved. From the current perspective, trial inclusion criteria (11) without multimodality imaging including EMB do not enable state-of-the-art prognostic risk stratification and, accordingly, subgroup analysis. More stringent inclusion criteria will be indispensable for future trials of novel therapeutics because they are prerequisites to elucidate the differential impact on the distinct pathomechanisms clinically relevant in CAAL.
Optimal individualized treatment of patients with advanced CAAL remains a major clinical challenge. One key point is the heterogeneity of these patients regarding their molecular pathomechanisms (e.g., amyloid deposition, inflammation). The importance of this is exemplified by the critical impact of myocardial inflammation on survival. Although it is impossible to deduce a general treatment strategy from published data, 2 conclusions are evident from the present case. First, each case requires optimal pre-treatment risk stratification. Second, invasive hemodynamic monitoring is indicated at the first signs of right ventricular dysfunction and/or pulmonary vascular disease. This will enable switching to more aggressive anti–plasma cell therapies before the “point of no return” of right ventricular failure and save the patient’s option for heart transplantation.
↵∗ Drs. Poller and Skurk contributed equally to this work.
The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- amyloid light chain
- cardiac amyloidosis
- cardiac magnetic resonance
- endomyocardial biopsy
- late gadolinium enhancement
- left ventricular
- N-terminal pro–B-type natriuretic peptide
- Received May 13, 2019.
- Revision received July 29, 2019.
- Accepted July 31, 2019.
- 2019 The Authors
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