Author + information
- Melanie C. Bois, MD,
- Surendra Dasari, PhD,
- John R. Mills, PhD,
- Jason Theis, BS,
- William E. Highsmith, PhD,
- Julie A. Vrana, PhD,
- Martha Grogan, MD,
- Angela Dispenzieri, MD,
- Paul J. Kurtin, MD and
- Joseph J. Maleszewski, MD∗ ()
- ↵∗Department of Laboratory Medicine and Pathology, Mayo Clinic, 200 First Street SouthWest, Rochester, Minnesota 55905
Cardiac amyloidosis may be inherited or acquired, both forms resulting from deposition of insoluble, misfolded proteins in extracellular locations. To date, 11 amyloidogenic proteins have been documented in the heart (1). Among the rarely encountered causes of cardiac amyloidosis is apolipoprotein-derived disease. Apolipoprotein A-IV (apo A-IV) is a glycoprotein that is instrumental in the metabolism and transport of dietary lipids. The protein is commonly encountered as a constitutive, but noncausative, component of amyloid tissue plaques (2). Apo A-IV is a prominent component of amyloid’s proteomic fingerprint, and its ubiquitous presence in amyloid deposits introduces a confounding factor to interpretation of apo A-IV amyloidosis (AApoAIV) (3).
Nonetheless, cases of renal amyloidosis directly attributable to apo A-IV have been recently described as a result of mounting biochemical and clinical evidence of its amyloidogenic properties (3). Cardiac AApoAIV was described previously as a single case in a large series and in the context of co-deposition with transthyretin-type amyloid (ATTR). Here we present the clinical and histopathological characteristics of 13 patients with AApoAIV cardiac amyloidosis.
Laboratory archives at Mayo Clinic in Rochester, Minnesota were queried for cases of cardiac amyloidosis typed as AApoAIV by liquid chromatography tandem mass spectrometry (2006 to 2015) (2). The pattern of amyloid deposition was assessed as previously described (4). Salient clinical information was abstracted from the patients’ medical records. Genetic analysis was performed on available material.
Thirteen patients (11 men) with cardiac AApoAIV were identified (mean age 75 years; range 64–89 years) out of a total of 2,096 cases queried (0.6%). Nine cases (4 autopsy, 5 surgical) were available for clinicopathological review; 4 consultation cases had demographic information only.
All patients had symptomatic cardiac dysfunction. Patients had clinical diagnoses of hypertrophic obstructive cardiomyopathy (n = 2, both surgical), left ventricular outflow tract (LVOT) obstruction with aortic stenosis (n = 1, surgical), LVOT obstruction and coronary artery disease (CAD) (n = 1, surgical), (presumed) “senile” amyloidosis (n = 1, surgical), or CAD (n = 4, all autopsy) (Table 1). Although all autopsy-derived samples carried an antemortem diagnosis of CAD, only one-half showed at least severe 1-vessel atherosclerotic disease (grade 4 [of 4]) stenosis in a single epicardial coronary artery at the time of autopsy. Six of 8 patients with electrocardiographic data had conduction system abnormalities. Seven of 8 patients had serum creatinine values that were elevated at the time of biopsy or death (median 1.95 mg/dl; range 1.3 to 4.2 mg/dl; normal 0.9 to 1.4 mg/dl).
Amyloid extent was marked in 2 cases, moderate in 5, and mild in 2 cases, with the most common interstitial pattern of deposition being nodular (n = 7; 5 surgical and 2 autopsy). Involvement of the microvasculature was a striking feature of cardiac AApoAIV cases, and all had obstructive microvascular amyloidosis. In keeping with the vascular tropism noted in cardiac sections, all autopsy cases demonstrated small vessel involvement in other visceral organs and prominent medullary renal deposits.
No other known amyloidogenic proteins were identified by mass spectrometry in cardiac AApoAIV cases. Apo A-IV had a significantly higher spectral count in the study cohort (median 73; interquartile range: 45) when compared with non-AApoAIV cases of amyloidosis (median 35; interquartile range: 28; p < 0.0001). Genetic analysis did not identify definitive pathological mutations.
This cohort exhibited 2 basic clinical presentations: 1) LVOT obstructive; and 2) ischemic. All the patients who were alive when the diagnosis was made were still alive at last follow-up (median: 79.2 months since diagnosis; range 0.1 to 141.1 months), a finding suggesting that AApoAIV may have a more favorable prognosis than other types of cardiac amyloidosis.
Clinicians should keep in mind that amyloidosis of any type, but AApoAIV type in particular, may masquerade as other diseases such as CAD or hypertrophic obstructive cardiomyopathy. Given predilection of AApoAIV for the renal parenchyma, concurrent renal failure may bolster clinical suspicion for this unique amyloid type. In addition, the degree of microvascular involvement suggests that these patients may present with symptoms of mesenteric ischemia or other peculiar ischemic symptoms. The unusual pathological findings should alert the pathologist to evaluate for this less common form of systemic amyloidosis, particularly when there is extensive involvement of the microvasculature without underlying plasma dyscrasia. Our limited autopsy series documents involvement of multiple organ systems, thus implicating the need for meticulous attention to the microvasculature in both medical and surgical specimens.
Taken together, the data contained here support the notion that AApoAIV is a rare type of systemic amyloidosis that may involve the heart with distinctive, although not entirely specific, clinical and histological presentations. This series expands both the registry of organs known to be involved by AApoAIV and the differential diagnosis of cardiac amyloidosis. With the emergence of type-specific therapies for amyloidosis, accurate typing is paramount.
Please note: The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- 2017 American College of Cardiology Foundation
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